Sulfonamidomethyl phosphonate inhibitors of β-lactamase

A compound of Formula (I):

• or a pro-drug or pharmaceutically acceptable salt thereof, wherein
• R1 is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
• n is 0, 1, or 2;
• R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl, wherein the aryl portion of any such group may be optionally substituted;
• R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, and (heteroaryl)alkyl, wherein the aryl or heteroaryl portion of any such group may be optionally substituted;
• R4 is OR8, where R8 is selected from the group consisting of phenyl substituted with at least one chloro, nitro, or fluoro substituent;
• heteroaryl;
• and substituted heteroaryl;
• and
• R5 is OR8, where R6 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteroaryl portion of any such group is unsubstituted.

A compound of Formula (II):

• or a pro-drug or pharmaceutically acceptable salt thereof, wherein
• R1 is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
• n is 0, 1, or 2;
• Y is O, NR7, or S;
• R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
• R4 is selected from the group consisting of OH, F, SR7, —O-aralkyl, —O-(heteroaryl)alkyl and —O-(heteroaryl, wherein the aryl or heteroaryl portion of any such —O-aralkyl, —O-(heteroaryl)alkyl and —O-(heteroaryl group may be optionally substituted;
• R5 is selected from the group consisting of F, OR6, SR7 and N(R7)2;
• where R6 is selected from the group consisting of aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteroaryl portion of any such group may be optionally substituted, and where R7 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl,
• provided that R4 and R5 are not both F.

A pharmaceutical composition comprising a compound of Formula (I):

• or a pro-drug or pharmaceutically acceptable salt thereof, wherein
• R1 is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
• n is 0, 1, or 2;
• R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl, wherein the aryl portion of any such group may be optionally substituted;
• R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, and (heteroaryl)alkyl, any of which groups may be optionally substituted;
• R4 is selected from the group consisting of OH, F, SR7, and N(R7)2;
• and
• R5 is selected from the group consisting of F, OR6, SR7, and N(R7)2,
• where R6 is selected from the group consisting of, cycloalkyl, aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteroaryl portion of any such group may be optionally substituted, and where R7 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
• and
• a pharmaceutically acceptable carrier or diluent,
• provided that R4 and R5 are not both F;
• and further provided that R1 is not 5-dimethylamino-1-naphthyl when R2 and R3 are both H, R4 is OH, and R5 is 4-nitrophenoxy.

A pharmaceutical composition comprising a compound of Formula (I):

• or a pro-drug or pharmaceutically acceptable salt thereof, wherein
• R1 is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
• n is 0, 1, or 2;
• R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl, wherein the aryl portion of any such group may be optionally substituted;
• R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, and (heteroaryl)alkyl, any of which groups may be optionally substituted;
• R4 is OR8, where R8 is selected from the group consisting of phenyl substituted with at least one chloro, nitro, or fluoro substituent;
• heteroaryl;
• and substituted heteroaryl;
• and
• R5 is OR6, where R6 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteroaryl portion of any such group may be optionally substituted;
• and a pharmaceutically acceptable carrier or diluent.

A pharmaceutical composition comprising a compound of Formula (II):

• or a pro-drug or pharmaceutically acceptable salt thereof, wherein
• R1 is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
• n is 0, 1, or 2;
• Y is O, NR7, or S;
• R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
• R4 is selected from the group consisting of OH, F, SR7, —O-aralkyl, —O-(heteroaryl)alkyl and —O-(heteroaryl, wherein the aryl or heteroaryl portion of any such —O-aralkyl, —O-(heteroaryl)alkyl and —O-(heteroaryl group may be optionally substituted;
• R5 is selected from the group consisting of F, SR7, N(R7)2 and OR6;
• where R6 is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteroaryl portion of any such group may be optionally substituted, and where R7 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
• provided that R4 and R5 are not both F;
• and a pharmaceutically acceptable carrier or diluent.

A method for inhibiting bacterial growth in a patient, such method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I):

• or a pro-drug or pharmaceutically acceptable salt thereof, wherein
• R1 is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
• n is 0, 1, or 2;
• R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl, wherein the aryl portion of any such group may be optionally substituted;
• R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, and (heteroaryl)alkyl, any of which groups may be optionally substituted;
• R4 is selected from the group consisting of OH;
• F, SR7, and N(R7)2;
• and
• R5 is selected from the group consisting of F, OR6, SR7, and N(R7)2,
• where R6 is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteroaryl portion of any such group may be optionally substituted, and where R7 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
• provided that R4 and R5 are not both F;
• and further provided that R1 not 5-dimethylamino-1-naphthyl when R2 and R3 are both H, R4 is OH, and R5 is 4-nitrophenoxy.

A method for inhibiting bacterial growth in a patient, such method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I):

• or a pro-drug or pharmaceutically acceptable salt thereof, wherein
• R1 is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
• n is 0, 1, or 2;
• R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl, wherein the aryl portion of any such group may be optionally substituted;
• R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, and (heteroaryl)alkyl, any of which groups may be optionally substituted;
• R4 is OR8, where R8 is selected from the group consisting of phenyl substituted with at least one chloro, nitro, or fluoro substituent;
• heteroaryl;
• and substituted heteroaryl;
• and
• R5 is OR6, where R6 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteroaryl portion of any such group may be optionally substituted.

A method for inhibiting bacterial growth in a patient, such method comprising administering to a patient in need thereof an effective amount of a compound of Formula (II):

• or a pro-drug or pharmaceutically acceptable salt thereof, wherein
• R1 is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
• n is 0, 1, or 2;
• Y is O, NR7, or S;
• R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
• R4 is selected from the group consisting of OH, F, SR7, —O-aralkyl, —O-(heteroaryl)alkyl and —O-(heteroaryl, wherein the aryl or heteroaryl portion of any such —O-aralkyl, —O-(heteroaryl)alkyl and —O-(heteroaryl group may be optionally substituted;
• R5 is selected from the group consisting of F, SR7, N(R7)2 and OR6;
• where R6 is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteroaryl portion of any such group may be optionally substituted, and where R7 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
• provided that R4 and R5 are not both F.