Anti-biofilm compounds

A method of preventing the formation of a biofilm of bacteria on a solid substrate comprising contacting the solid substrate with

• (a) compound of formula I:
• wherein:
• X is —(CH2)S(═O)nphenyl-;
• or
• X is phenyl and (a) at least one of R1 or R2 is an optionally substituted 5-6 membered heteroaryl;
• or (b) Y is heteroaryl, (C3-C7)carbocycle, or aryl wherein the heteroaryl, (C3-C7)carbocycle, or aryl is substituted with at least one —NRjRk wherein at least one of Rj or Rk is optionally substituted phenyl and wherein the heteroaryl, (C3-C7)carbocycle, or aryl is further optionally substituted with one or more Z1 groups;
• n is 1 or 2;
• Y is heteroaryl, (C3-C7)carbocycle, or aryl wherein any heteroaryl, (C3-C7)carbocycle, or aryl of Y is optionally substituted with one or more Z1 groups;
• R1 is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl, or 5-6 membered heteroaryl wherein the aryl or 5-6 membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, halo (C1-C3)alkyl, —CN, NO2, halogen, —ORa, —SRa, —S(O)2NRbRc, —NRbRc, —NRaCORd, —C(O)Ra, —C(O)ORa, and —C(O)NRbRc;
• R2 is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl, or 5-6 membered heteroaryl wherein the aryl or 5-6 membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, halo (C1-C3)alkyl, —CN, NO2, halogen, —ORe, —SRe, —S(O)2NRfRg, —NRfRg, —NReCORh, —C(O)Re, —C(O)ORe, and —C(O)NRfRg;
• each Ra is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, and aryl;
• Rb and Rc are each independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle and aryl, or Rb and Rc together with the nitrogen to which they are attached form a 5, 6 or 7-membered heterocycle;
• Rd is independently selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, and aryl;
• each Re is independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, and aryl;
• Rf and Rg are each independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle and aryl, or Rf and Rg together with the nitrogen to which they are attached form a 5, 6 or 7-membered heterocycle;
• Rh is selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle and aryl;
• each Z1 is independently selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C6)haloalkyl, —ORi, —NRjRk and —NRiCORm;
• Ri is H, (C1-C6)alkyl, (C1-C6)haloalkyl or phenyl wherein phenyl is optionally substituted with one or more halogen or (C1-C6)alkyl;
• Rj and Rk are each independently selected from H, (C1-C8)alkyl or phenyl wherein phenyl is optionally substituted with one or more halogen or (C1-C6)alkyl;
• Rm is (C1-C6)alkyl
• or a salt thereof, or
• (b) a composition comprising compound of formula I:
• wherein:
• X is —(CH2)S(═O)nphenyl-;
• or
• X is phenyl and (a) at least one of R1 or R2 is an optionally substituted 5-6 membered heteroaryl;
• or (b) Y is heteroaryl, (C3-C7)carbocycle, or aryl wherein the heteroaryl, (C3-C7)carbocycle, or aryl is substituted with at least one —NRjRk wherein at least one of Rj or Rk is optionally substituted phenyl and wherein the heteroaryl, (C3-C7) carbocycle, or aryl is further optionally substituted with one or more Z1 groups;
• n is 1 or 2;
• Y is heteroaryl,(C3-C7) carbocycle, or aryl wherein any heteroaryl, (C3-C7)carbocycle, or aryl of Y is optionally substituted with one or more Z1 groups;
• R1 is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl, or 5-6 membered heteroaryl wherein the aryl or 5-6 membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, halo(C1-C3)alkyl, —CN, NO2, halogen, —ORa, —SRa, —S(O)2NRbRc, —NRbRc, —NRaCORd, —C(O)Ra, —C(O)ORa, and —C(O)NRbRc;
• R2 is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl, or 5-6 membered heteroaryl wherein the aryl or 5-6 membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, halo(C1-C3)alkyl, —CN, NO2, halogen, —ORe, —SRe, —S(O)2NRfRg, —NRfRg, —NReCORh, —C(O)Re, —C(O)ORe, and —C(O)NRfRg;
• each Ra is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, and aryl;
• Rb and Rc are each independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle and aryl, or Rb and Rc together with the nitrogen to which they are attached form a 5, 6 or 7-membered heterocycle;
• Rd is independently selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, and aryl;
• each Re is independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, and aryl;
• Rf and Rg are each independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle and aryl, or Rf and Rg together with the nitrogen to which they are attached form a 5, 6 or 7-membered heterocycle;
• Rh is selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle and aryl;
• each Z1 is independently selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C6)haloalkyl, —ORi, —NRjRk and —NRiCORm;
• Ri is H, (C1-C6)alkyl, (C1-C6)haloalkyl or phenyl wherein phenyl is optionally substituted with one or more halogen or (C1-C6)alkyl;
• Rj and Rx are each independently selected from H, (C1-C8)alkyl or phenyl wherein phenyl is optionally substituted with one or more halogen or (C1-C6)alkyl;
• Rm is (C1-C6) alkyl
• or a salt thereof, and a physiologically acceptable carrier.

A method of preventing the formation of a biofilm of bacteria in vivo comprising contacting a tissue surface with

• (a) compound of formula I:
• wherein:
• X is —(CH2)S(═O)nphenyl-;
• or
• X is phenyl and (a) at least one of R1 or R2 is an optionally substituted 5-6 membered heteroaryl;
• or (b) Y is heteroaryl, (C3-C7)carbocycle, or aryl wherein the heteroaryl, (C3-C7)carbocycle, or aryl is substituted with at least one —NRjRk wherein at least one of Rj or Rk is optionally substituted phenyl and wherein the heteroaryl, (C3-C7)carbocycle, or aryl is further optionally substituted with one or more Z1 groups;
• n is 1 or 2;
• Y is heteroaryl, (C3-C7)carbocycle, or aryl wherein any heteroaryl, (C3-C7)carbocycle, or aryl of Y is optionally substituted with one or more Z1 groups;
• R1 is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl, or 5-6 membered heteroaryl wherein the aryl or 5-6 membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, halo (C1-C3)alkyl, —CN, NO2, halogen, —ORa, —SRa, —S(O)2NRbRc, —NRbRc, —NRaCORd, —C(O)Ra, —C(O)ORa, and —C(O)NRbRc;
• R2 is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl, or 5-6 membered heteroaryl wherein the aryl or 5-6 membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, halo (C1-C3)alkyl, —CN, NO2, halogen, —ORe, —SRe, —S(O)2NRfRg, —NRfRg, —NReCORh, —C(O)Re, —C(O)ORe, and —C(O)NRfRg;
• each Ra is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, and aryl;
• Rb and Rc are each independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle and aryl, or Rb and Rc together with the nitrogen to which they are attached form a 5, 6 or 7-membered heterocycle;
• Rd is independently selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, and aryl;
• each Re is independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, and aryl;
• Rf and Rg are each independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle and aryl, or Rf and Rg together with the nitrogen to which they are attached form a 5, 6 or 7-membered heterocycle;
• Rh is selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle and aryl;
• each Z1 is independently selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C6)haloalkyl, —ORi, —NRjRk and —NRiCORm;
• Ri is H, (C1-C6)alkyl, (C1-C6)haloalkyl or phenyl wherein phenyl is optionally substituted with one or more halogen or (C1-C6)alkyl;
• Rj and Rk are each independently selected from H, (C1-C8)alkyl or phenyl wherein phenyl is optionally substituted with one or more halogen or (C1-C6)alkyl;
• Rm is (C1-C6)alkyl
• or a salt thereof, or
• (b) a composition comprising compound of formula I:
• wherein:
• X is —(CH2)S(═O)nphenyl-;
• or
• X is phenyl and (a) at least one of R1 or R2 is an optionally substituted 5-6 membered heteroaryl;
• or (b) Y is heteroaryl, (C3-C7)carbocycle, or aryl wherein the heteroaryl, (C3-C7)carbocycle, or aryl is substituted with at least one —NRjRk wherein at least one of Rj or Rk is optionally substituted phenyl and wherein the heteroaryl, (C3-C7)carbocycle, or aryl is further optionally substituted with one or more Z1 groups;
• n is 1 or 2;
• Y is heteroaryl, (C3-C7)carbocycle, or aryl wherein any heteroaryl, (C3-C7)carbocycle, or aryl of Y is optionally substituted with one or more Z1 groups;
• R1 is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl, or 5-6 membered heteroaryl wherein the aryl or 5-6 membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, halo(C1-C3)alkyl, —CN, NO2, halogen, —ORa, —SRa, —S(O)2NRbRc, —NRbRc, —NRaCORd, —C(O)Ra, —C(O)ORa, and —C(O)NRbRc;
• R2 is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl, or 5-6 membered heteroaryl wherein the aryl or 5-6 membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, halo(C1-C3)alkyl, —CN, NO2, halogen, —ORe, —SRe, —S(O)2NRfRg, —NRfRg, —NReCORh, —C(O)Re, —C(O)ORe, and —C(O)NRfRg;
• each Ra is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, and aryl;
• Rb and Rc are each independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle and aryl, or Rb and Rc together with the nitrogen to which they are attached form a 5, 6 or 7-membered heterocycle;
• Rd is independently selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, and aryl;
• each Re is independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, and aryl;
• Rf and Rg are each independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle and aryl, or Rf and Rg together with the nitrogen to which they are attached form a 5, 6 or 7-membered heterocycle;
• Rh is selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle and aryl;
• each Z1 is independently selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C6)haloalkyl, —ORi, —NRjRk and —NRiCORm;
• Ri is H, (C1-C6)alkyl, (C1-C6)haloalkyl or phenyl wherein phenyl is optionally substituted with one or more halogen or (C1-C6)alkyl;
• Rj and Rk are each independently selected from H, (C1-C8)alkyl or phenyl wherein phenyl is optionally substituted with one or more halogen or (C1-C6)alkyl;
• Rm is (C1-C6)alkyl
• or a salt thereof, and a physiologically acceptable carrier.