Substituted pyrazolo[4,3-D]pyrimidines as gut-targeted phosphodiesterase inhibitors
View Patent ↗Provided herein are compounds that inhibit phosphodiesterase 5 (PDE5) and methods of use thereof. In some forms, the compounds can have a structure according to Formula I: Also provided are pharmaceutical compositions and medicaments that include the compounds described herein as well as methods of treating gastrointestinal diseases and disorders such as intestinal cancers, chronic constipation, and inflammatory bowel disease.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof,
wherein:
R 1 is C 1-10 alkyl, wherein the C 1-10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , B(OH) 2 , C(O)H, C(O)CH 3 , C(O)NH 2 , C(O)OH, NH 2 , OH, OC 1-10 alkyl, S(O) 2 NH 2 , S(O) 2 OH, S(O) 2 ONa, C 3-10 cycloalkyl, aryl, and heteroaryl;
R 2 is C 1-10 alkyl, wherein the C 1-10 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , B(OH) 2 , C(O)H, C(O)CH 3 , C(O)NH 2 , C(O)OH, NH 2 , OH, OC 1-10 alkyl, S(O) 2 NH 2 , S(O) 2 OH, S(O) 2 ONa, C 3-10 cycloalkyl, aryl, and heteroaryl;
X is —O—;
R 3 is C 1-10 alkyl, OC 1-10 alkyl, C 3-10 cycloalkyl, aryl, or heteroaryl, wherein the C 1-10 alkyl is substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , B(OH) 2 , C(O)H, C(O)CH 3 , C(O)NH 2 , C(O)OH, NH 2 , OH, OC 1-10 alkyl, S(O) 2 NH 2 , S(O) 2 OH, S(O) 2 ONa, C 3-10 cycloalkyl, aryl, and heteroaryl;
R 4 is C(O)R 8 , C(O)CH 2 C(O)OH, C(O)(CH 2 ) n NR 6 R 7 , C(O)CH(R 9 )NH 2 , C(O)CH(R 9 )OH, or C(O)C(O)R 10 ;
R 6 is H or C 1-10 alkyl;
R 7 is H or C 1-10 alkyl;
R 8 is C 1-10 alkyl;
R 9 is C 1-10 alkyl;
R 10 is C 1-10 alkyl; and
n is 1, 2, 3, 4, 5, or 6.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R 4 is C(O)CH 2 CH 2 CH 3 , C(O)CH 2 NH 2 , C(O)CH 2 N(CH 3 ) 2 , C(O)CH 2 CH 2 N(CH 3 ) 2 , C(O)CH(CH 3 )NH 2 , C(O)CH(CH 3 )OH, or C(O)C(O)CH 3 .
3 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R 4 is C(O)CH 2 C(O)OH.
4 . A compound of Formula I:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof,
wherein:
R 1 is C 1-10 alkyl;
R 2 is C 1-10 alkyl;
X is —O—;
R 3 is C 1-10 alkyl;
R 4 is C(O)R 8 , C(O)CH 2 C(O)OH, C(O)(CH 2 ) n NR 6 R 7 , C(O)CH(R 9 )NH 2 , C(O)CH(R 9 )OH, or C(O)C(O)R 10 ;
R 6 is H or C 1-10 alkyl;
R 7 is H or C 1-10 alkyl;
R 8 is C 1-10 alkyl;
R 9 is C 1-10 alkyl;
R 10 is C 1-10 alkyl; and
n is 1, 2, 3, 4, 5, or 6.
5 . The compound of claim 4 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R 4 is C(O)CH 2 CH 2 CH 3 , C(O)CH 2 NH 2 , C(O)CH 2 N(CH 3 ) 2 , C(O)CH 2 CH 2 N(CH 3 ) 2 , C(O)CH(CH 3 )NH 2 , C(O)CH(CH 3 )OH, or C(O)C(O)CH 3 .
6 . The compound of claim 4 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R 4 is C(O)CH 2 C(O)OH.
7 . The compound of claim 4 , wherein the compound is:
8 . The compound of claim 4 , or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, or tautomer thereof.