Derivatives of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl]phosphonic acid and methods of making them

A compound of formula (II) or pharmaceutically acceptable salt thereof:

• wherein:
• R1 and R2 are, independently, is hydrogen or
• with the proviso that at least one of R1 and R2 is not hydrogen;
• R3 is hydrogen, —OR4, alkyl, aryl, or heteroaryl;
• R4 is hydrogen, alkyl, aryl, or heteroaryl;
• R5 and R6 are, independently, hydrogen, alkyl, hydroxyl, alkoxy, or C5 to C7 aryl;
• wherein any R1 to R6 group having an aryl or heteroaryl moiety can optionally be substituted on the aryl or heteroaryl moiety with 1 to about 5 substituents, independently, selected from the group consisting of halogen, cyano, nitro group, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

A compound of formula (III) or a pharmaceutically acceptable salt thereof:

• wherein:
• R1 and R2 are, independently, hydrogen or
• with the proviso that at least one of R1 and R2 is not hydrogen;
• and
• R3 is hydrogen, alkyl, aryl, or heteroaryl;
• wherein any aryl or heteroaryl moiety can optionally be substituted on the aryl or heteroaryl moiety with 1 to about 5 substituents, independently, selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

A compound of formula (III) or pharmaceutically acceptable salt thereof:

• wherein:
• R1 and R2 are, independently, hydrogen or
• with the proviso that at least one of R1 and R2 is not hydrogen;
• R3 is —OR4;
• and
• R4 is hydrogen, alkyl, aryl, or heteroaryl;
• wherein any aryl or heteroaryl moiety can optionally be substituted on the aryl or heteroaryl moiety with 1 to about 5 substituents, independently, selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

A method for making a compound of formula (I) or a pharmaceutically acceptable salt thereof:

• wherein:
• A is alkylenyl of 1 to 4 carbon atoms, or alkenylenyl of 2 to 4 carbon atoms;
• R1 and R2 are, independently, hydrogen or a C5 to C7 aryl optionally substituted with 1 to 2 substituents, independently, selected from the group consisting of —C(O)R3, halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy,
• with the proviso that at least one of R1 and R2 is not hydrogen;
• R3 is, independently, hydrogen, —OR4, alkyl, aryl, or heteroaryl;
• R4 is hydrogen, alkyl, aryl, or heteroaryl;
• R5 and R6 are, independently, hydrogen, alkyl, hydroxyl, alkoxy, or C5 to C7 aryl;
• wherein any R3 to R6 group having an aryl or heteroaryl moiety can optionally be substituted on the aryl or heteroaryl moiety with 1 to about 5 substituents, independently, selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy;
• said method comprising the step of reacting a compound of formula (2):
• or a pharmaceutically acceptable salt thereof, with a compound of formula (3):
• where A1 is alkenyl having 2 to 4 carbon atoms or alkynyl having 2 to 4 carbon atoms, under conditions effective to form a compound of formula (I) or a pharmaceutically acceptable salt thereof.

A method for making a compound of formula (I) or a pharmaceutically acceptable salt thereof:

• wherein:
• A is alkylenyl of 1 to 4 carbon atoms, or alkenylenyl of 2 to 4 carbon atoms;
• R1 and R2 are, independently, hydrogen or a C5 to C7 aryl optionally substituted with 1 to 2 substituents, independently, selected from the group consisting of —C(O)R3, halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy,
• with the proviso that at least one of R1 and R2 is not hydrogen;
• R3 is, independently, hydrogen, —OR4, alkyl, aryl, or heteroaryl;
• R4 is hydrogen, alkyl, aryl, or heteroaryl;
• R5 and R6 are, independently, hydrogen, alkyl, hydroxyl, alkoxy, or C5 to C7 aryl;
• wherein any R3 to R6 group having an aryl or heteroaryl moiety can optionally be substituted on the aryl or heteroaryl moiety with 1 to about 5 substituents, independently, selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy;
• said method comprising the steps of:
• reacting a disubstituted diaminoalkane derivative of formula (6):
• wherein Pg is a protecting group, with a dialkoxysquarate of formula
• wherein R is alkoxy, in a suitable solvent to yield a tri-substituted diaminoalkane derivative of formula (7):
• deprotecting and cyclizing the tri-substituted diaminoalkane derivative of formula (7) to produce said compound of formula (I).