Bicyclic 6-alkylidene-penems as β-lactamase inhibitors

A compound of formula I:

• wherein:
• one of A and B is hydrogen and the other is an optionally substituted fused bicyclic heteroaryl group;
• X is O;
• R5 is H, C1-C6 alkyl, C5-C6 cycloalkyl, or CHR3OCOC1-C6alkyl;
• and
• R3 is hydrogen, C1-C6 alkyl, C5-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
• or a pharmaceutically acceptable salt thereof,
• wherein the bicyclic heteroaryl group has the formula 1-C,
• wherein
• Z1, Z2, Z3 and Z4 are independently CR2 or N, except one of Z1-Z4 is carbon and is bonded to the remainder of the molecule;
• W1, W2 and W3 are each independently CR4R4, S, SO, SO2,O, or N—R1 with the proviso that no S—S or O—O or S—O bond formation can occur to form the saturated ring system;
• R1 is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocyclyl, optionally substituted C5-C7 cycloalkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl with the proviso that neither the double bond nor the triple bond should be present at the carbon atom which is directly linked to N;
• optionally substituted C1-C6 perfluoroalkyl, —S(O)p optionally substituted alkyl or aryl where p is 0-2, optionally substituted —C(═O)heteroaryl, optionally substituted —C(═O)aryl, optionally substituted —C(═O)C1-C6alkyl, optionally substituted —C(═O)(C5-C6)cycloalkyl, optionally substituted —C(═O) mono or bicyclic saturated heterocyclyl, optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6 alkyl heteroaryl, optionally substituted aryl-C1-C6 alkyl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocyclyl, optionally substituted arylalkenyl of 8 to 16 carbon atoms, —CONR6R7, —SO2NR6R7, optionally substituted arylalkyloxyalkyl, optionally substituted -alky-O-alkyl-aryl, optionally substituted -alky-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl;
• R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano, NR6R7, optionally substituted C1-C6 alkoxy, hydroxy;
• optionally substituted aryl, optionally substituted heteroaryl, COOR6, optionally substituted alkyl aryloxy alkylamines, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylene dioxy, optionally substituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)q-optionally substituted C1-C6 akyl, S(O)q-optionally substituted aryl where q is 0, 1 or 2, CONR6R7, guanidino, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocyclyl, optionally substituted arylalkenyl of 8 to 16 carbon atoms, SO2NR6R7, optionally substituted arylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionally substituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl;
• R4 is H, optionally substituted C1-C6 alkyl, one of R4 is OH, C1-C6 alkoxy, —S—C1-C6 alkyl, COOR6, —NR6R7, —CONR6R7;
• or R4R4 may together be (═O) or R4R4 together with the carbon to which they are attached may form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S(═O)n (where n is 0 to 2), and N—R1;
• and
• R6 and R7 are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C6 alkylheteroaryl, or R6 and R7 together with the N to which they are attached, may form a 3-7 membered saturated ring system said ring system in addition to the N to which R6 and R7 are attached optionally having one or two heteroatoms selected from N, O or S;
• t is 1-4;
• and
• Y1 and Y2 are C.

A method for the treatment of bacterial infection or disease in a patient in need thereof which comprises providing to said patient an effective amount of a compound of formula I:

• wherein:
• one of A and B is hydrogen and the other is an optionally substituted fused bicyclic heteroaryl group;
• with the proviso that if the aromatic ring of the bicyclic heteroaryl group is imidazolo, the non-aromatic ring portion may not contain S adjacent to the bridgehead carbon;
• X is O;
• R5 is H, C1-C6 alkyl, C5-C6 cycloalkyl, or CHR3OCOC1-C6 alkyl;
• and
• R3 is hydrogen, C1-C6 alkyl, C5-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
• or a pharmaceutically acceptable salt thereof;
• wherein the bicyclic heteroaryl group has the formula 1-A,
• wherein
• Z1, Z2 and Z3 are independently CR2, N, O, S or N—R1, except one of Z1-Z3 is carbon and is bonded to the remainder of the molecule;
• W1, W2 and W3 are independently CR4R4, S, SO, SO2, O or N—R1;
• with the proviso that no S—S or O—O or S—O bond formation can occur to form the saturated ring system;
• t is an integer from 1 to 4;
• R1 is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocyclyl, optionally substituted C5-C7 cycloalkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl with the proviso that neither the double bond nor the triple bond should be present at the carbon atom which is directly linked to N;
• optionally substituted C1-C6 perfluoroalkyl, —S(O)p optionally substituted alkyl or aryl where p is 0-2, optionally substituted —C(═O)heteroaryl, optionally substituted —C(═O)aryl, optionally substituted —C(═O)C1-C6 alkyl, optionally substituted —C(═O)C5-C6cycloalkyl, optionally substituted —C(═O) mono or bicyclic saturated heterocyclyl, optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6 alkyl heteroaryl, optionally substituted arylC1-C6 alkyl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocyclyl, optionally substituted arylalkenyl of 8 to 16 carbon atoms, —CONR6R7, —SO2NR6R7, optionally substituted arylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl, optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted C1-C6alkylaryloxyaryl, optionally substituted C 1-C6 alkylaryloxyheteroaryl, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl;
• R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano, NR6R7, optionally substituted C1-C6 alkoxy, hydroxy;
• optionally substituted aryl, optionally substituted heteroaryl, COOR6, optionally substituted alkyl aryloxy alkylamines, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylene dioxy, optionally substituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)q-optionally substituted C1-C6 akyl, S(O)q-optionally substituted aryl where q is 0, 1 or 2, CONR6R7, guanidino, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionally substituted heteroarylC1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocyclyl, optionally substituted arylalkenyl of 8 to 16 carbon atoms, SO2NR6R7, optionally substituted arylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionally substituted C1-C6 alkyl aryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, or optionally substituted heteroaryloxyalkyl;
• R4 is H, optionally substituted C1-C6 alkyl, one of R4 is OH, C1-C6 alkoxy, —S—C1-C6 alkyl, COOR6, —NR6R7, —CONR6R7;
• or R4R4 may together be (═O) or R4R4 together with the carbon to which they are attached may form a spiro system of five to eight members with or without the presence of heteroatoms is selected from N, O, S(═O)n (where n is 0 to 2) and N—R1;
• and
• R6 and R7 are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C6 alkylheteroaryl, or R6 and R7 together with the N to which they are attached, may form a 3-7 membered saturated ring system said ring system in addition to the N to which R6 and R7 are attached optionally having one or two heteroatoms selected from N, O or S.

A method for the treatment of bacterial infection or disease in a patient in need thereof which comprises providing to said patient an effective amount of a compound of formula I:

• wherein:
• one of A and B is hydrogen and the other is an optionally substituted fused bicyclic heteroaryl group;
• X is O;
• R5 is H, C1-C6 alkyl, C5-C6 cycloalkyl or CHR3OCOC1-C6 alkyl;
• and
• R3 is hydrogen, C1-C6 alkyl, C5-C6 cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
• or a pharmaceutically acceptable salt thereof;
• wherein the bicyclic heteroaryl group has the formula 1-C,
• wherein
• Z1, Z2, Z3 and Z4 are independently CR2 or N, except one of Z1-Z4 is carbon and is bonded to the remainder of the molecule;
• W1, W2 and W3 are each independently CR4R4, S, SO, SO2, O, or N—R1 with the proviso that no S—S or O—O or S—O bond formation can occur to form the saturated ring system:
• t is 1-4;
• Y1 and Y2 are C;
• and
• R1 is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocyclyl, optionally substituted C5-C7 cycloalkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl with the proviso that neither the double bond nor the triple bond should be present at the carbon atom which is directly linked to N;
• optionally substituted C1-C6 perfluoroalkyl, —S(O)p optionally substituted alkyl or aryl where p is 0-2, optionally substituted —C(═O)heteroaryl, optionally substituted —C(═O)aryl, optionally substituted —C(═O)C1-C6alkyl, optionally substituted —C(═O)(C5-C6)cycloalkyl, optionally substituted —(C═O) mono or bicyclic saturated heterocyclyl, optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6 alkyl heteroaryl, optionally substituted aryl-C1-C6 alkyl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocyclyl, optionally substituted arylalkenyl of 8 to 16 carbon atoms, —CONR6,R7, —SO2NR6R7, optionally substituted arylalkyloxyalkyl, optionally substituted -alky-O-alkyl-aryl, optionally substituted -alky-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted heteroaryloxy carbonyl;
• R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano, NR6R7, optionally substituted C1-C6 alkoxy, hydroxy;
• optionally substituted aryl, optionally substituted heteroaryl, COOR6, optionally substituted aryloxy, optionally, substituted heteroaryloxy, optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylene dioxy, optionally substituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)q-optionally substituted C1-C6 akyl, S(O)q-optionally substituted aryl where q is 0, 1 or 2, CONR6R7, guanidino, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocyclyl, optionally substituted arylalkenyl of 8 to 16 carbon atoms, SO2NR6R7, optionally substituted arylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionally substituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, or optionally substituted heteroaryloxyalkyl;
• R4 is H, optionally substituted C1-C6 alkyl, one of R4 is OH, C1-C6 alkoxy, —S—C1-C6 alkyl, COOR6, —NR6R7, —CONR6R7;
• or R4R4 may together be (═O) or R4R4 together with the carbon to which they are attached may form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S(═O)n (where n is 0 to 2), and N—R1;
• and
• R6 and R7 are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C6 alkylheteroaryl, or R6 and R7 together with the N to which they are attached, may form a 3-7 membered saturated ring system said ring system in addition to the N to which R6 and R7 are attached optionally having one or two heteroatoms selected from N, O or S.