Gyrase inhibitors and uses thereof

A method of treating a bacterial infection in a mammal in need thereof, comprising the step of administering to said mammal a therapeutically effective amount of a compound of formula I:

• 258
• or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
• Z is O or N—R4;
• W is nitrogen or CRa;
• Ra is selected from hydrogen, halogen, —CF3, R7, —OR7, or —N(R7)2;
• R1 is an aryl or heteroaryl ring, wherein said ring is optionally substituted by up to four R9;
• wherein an R9 substituent in the ortho-position of R1 taken together with R2 may form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring having 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur;
• R2 and R3 are each independently selected from R6, halogen, CN, SR6, OR6, N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2, or NRSO2R6;
• or R2 and R3 are taken together to form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur;
• R4 is selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2, or (CH2)yR2;
• y is 1-6;
• R5 is selected from R7, Ar, COAr, CON(R7) Ar, (CH2)yCO2R, (CH2)yN(R7)2, C(═NR10)—N(R7)2, C(═NR10)—NRCOR, C(═S)—N(R7)2, CON(R7)2, COR, SO2R, or SO2N(R7)2;
• Ar is a five membered heteroaryl, heterocyclyl, or carbocyclyl ring, wherein said ring is optionally substituted by up to three substituents selected from oxo, halogen, CN, NO2, R8, OR8, NHR8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2NHR8 or SO2NHR8;
• each R6 is independently selected from R7 or an optionally substituted group selected from alkoxy, hydroxyalkyl, heterocyclyl, heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl;
• each R7 is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons, or two R7 on the same nitrogen taken together with the nitrogen optionally form a four to six member, saturated or unsaturated heterocyclic ring having one to three heteroatoms;
• R8 is a C1-C4 aliphatic group, wherein two R8 on adjacent positions of Ar, or an aryl or heteroaryl ring, may be taken together with their intervening atoms to form a three to six membered fused ring;
• each R9 is independently selected from oxo, halogen, CN, NO2, Tn(haloalkyl) , R6, SR6, OR6, OR8, N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2, N(R)TnCO2R6, N(R)TnCON(R6)2, N(R)TnN(R6)2, N(R)TnNRCO2R6, N(R)TnNRCON(R6)2, N(R)TnCOR6, N(R)TnNRCOR6, N(R)TnSO2N(R6)2, N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2, or TnNPO(OR7)2;
• each Q is an independently selected C1-C3 branched or straight alkyl;
• T is selected from —Q— or —Qm—CH(Qm—R2)—;
• each m and n are independently selected from zero or one;
• and R10 is selected from R7 or Ar.

A compound of formula IIa or IIb:

• 262
• or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
• or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
• W is nitrogen or CRa;
• Ra is selected from hydrogen, halogen, —CF3, R7, —OR7, or —N(R7)2;
• R1 is an aryl or heteroaryl ring, wherein said ring is optionally substituted by up to four R9;
• wherein an R9 substituent in the ortho-position of R1 taken together with R2 may form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring having 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur;
• R2 and R3 are each independently selected from R6, halogen, CN, SR6, OR6, N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2, or NRSO2R6;
• or R2 and R3 are taken together to form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur;
• R4 is selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2, or (CH2)yR2;
• y is 1-6;
• Ar is a five membered heteroaryl, heterocyclyl, or carbocyclyl ring, wherein said ring is optionally substituted by up to three substituents selected from oxo, halogen, CN, NO2, R8, OR8, NHR8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2NHR8 or SO2NHR8;
• each R6 is independently selected from R7 or an optionally substituted group selected from alkoxy, hydroxyalkyl, heterocyclyl, heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl;
• each R7 is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons, or two R7 on the same nitrogen taken together with the nitrogen optionally form a four to six member, saturated or unsaturated heterocyclic ring having one to three heteroatoms;
• R8 is a C1-C4 aliphatic group, wherein two R8 on adjacent positions of Ar, or an aryl or heteroaryl ring, may be taken together with their intervening atoms to form a three to six membered fused ring;
• each R9 is independently selected from oxo, halogen, CN, NO2, Tn(haloalkyl), R6, SR6, OR6, OR8, N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2, N(R)TnCO2R6, N(R)TnCON(R6)2, N(R)TnN(R6)2, N(R)TnNRCO2R6, N(R)TnNRCON(R6)2, N(R)TnCOR6, N(R)TnNRCOR6, N(R)TnSO2N(R6)2, N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2, or TnNPO(OR7)2;
• each Q is an independently selected C1-C3 branched or straight alkyl;
• T is selected from —Q— or —Qm—CH(Qm—R2)—;
• and
• each m and n are independently selected from zero or one.

A compound of formula IIIa or IIIb:

• 263
• or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
• W is nitrogen or CRa;
• Ra is selected from hydrogen, halogen, —CF3, R7, —OR7, or —N(R7)2;
• Ring A is optionally substituted with up to three R9;
• wherein when an R9 substituent is in the ortho-position of Ring A, said R9 substituent may be taken together with R2 to form an optionally substituted 5-7 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur;
• R2 and R3 are each independently selected from R6, halogen, CN, SR6, OR6, N(R6)2, NRCO2R6, NRCON(R6)2, CON(R6)2, NRCOR6, NRN(R6)2, COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2, or NRSO2R6;
• or R2 and R3 are taken together to form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur;
• R4 is selected from R6, CON(R6), COR6, CO2R6, COCOR6, SO2R6, SO2N(R6)2, or (CH2)yR2;
• y is 1-6;
• R5 is selected from R7, Ar, COAr, CON(R7)Ar, (CH2)yCO2R, (CH2)yN(R7)2, C(═NR10)—N(R7)2, C(═NR10)—NRCOR, C(═S)—N(R7)2, CON(R7)2, COR, SO2R, or SO2N(R7)2;
• Ar is a five membered heteroaryl, heterocyclyl, or carbocyclyl ring, wherein said ring is optionally substituted by up to three substituents selected from oxo, halogen, CN, NO2, R8, OR8, NHR8, NHCOR8, NHCONHR8, COR8, CONHR8, SO2R8, NHSO2NHR8 or SO2NHR8;
• each R6 is independently selected from R7 or an optionally substituted group selected from alkoxy, hydroxyalkyl, heterocyclyl, heterocyclcylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl;
• each R7 is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons, or two R7 on the same nitrogen taken together with the nitrogen optionally form a four to six member, saturated or unsaturated heterocyclic ring having one to three heteroatoms;
• R8 is a C1-C4 aliphatic group, wherein two R8 on adjacent positions of Ar, or an aryl or heteroaryl ring, may be taken together with their intervening atoms to form a three to six membered fused ring;
• each R9 is independently selected from oxo, halogen, CN, NO2, Tn(haloalkyl), R6, SR6, OR6, OR8, N(R6)2, CON(R6)2, CON(R)COR6, COR6, CO2R6, CO2N(R6)2, COCOR6, SO2R6, SO2N(R6)2, N(R)TnCO2R6, N(R)TnCON(R6)2, N(R)TnN(R6)2, N(R)TnNRCO2R6, N(R)TnNRCON(R6)2, N(R)TnCOR6, N(R)TnNRCOR6, N(R)TnSO2N(R6)2, N(R)TnSO2R6, TnPO(OR7)2, TnOPO(OR7)2, TnSP(OR7)2, TnPO(OR7)2, or TnNPO(OR7)2;
• each Q is an independently selected C1-C3 branched or straight alkyl;
• T is selected from —Q— or —Qm—CH(Qm—R2)—;
• each m and n are independently selected from zero or one;
• and R10 is selected from R7 or Ar.