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US 7,112,582 B2Granted
Bicyclic 6-alkylidene-penems as β-lactamase inhibitors
AssigneeWyeth
InventorsAranapakam Mudumbai Venkatesan, Tarek Suhayl Mansour, Takao Abe, Itsuki Yamamura, Tsuyoshi Takasaki, Atul Agarwal, Osvaldo dos Santos, Fuk-Wah Sum, Yang-I Lin
Life of this patent
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Abstract
The present invention provides a compound of formula I, pharmaceutical compositions and the use thereof for the treatment of bacterial infection or disease in a patient in need thereof. wherein one of A and B denotes hydrogen and the other an optionally substituted fused bicyclic heteroaryl group; and X is S.
Claims57
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 portion of the bicyclic heteroaryl group is imidazole, the nonaromatic ring portion may not contain a S adjacent to the bridgehead carbon;
- X is S;
- R5 is H, C1–C6 alkyl, C5–C6 cycloalkyl, CHR3OCOC1–C6alkyl;
- and
- R3 is hydrogen, C1–C6 alkyl, C5–C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;
- or a pharmaceutically acceptable salt thereof;
- wherein the bicyclic heteroaryl group is
- 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=1 to 4;
- R1 is H, optionally substituted C1–C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, 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═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O(C1–C6) alkyl, optionally substituted —C═O(C5–C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, 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 heterocycles, 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 C1–C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, 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, N—R6R7, 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 or cyclic 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 heterocycles, 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, or optionally substituted alkylaryloxyalkylamine;
- 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=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 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.
19 more elements
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 portion of the bicyclic heteoaryl group is imidazole, the nonaromatic ring portion may not contain a S adjacent to the bridgehead carbon;
- X is S;
- 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
- 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=1 to 4;
- R1 is H, optionally substituted C1–C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, 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═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O(C1–C6) alkyl, optionally substituted —C═O(C5–C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, 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 heterocycles, 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 C1–C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, 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, N—R6R7, 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 or cyclic 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 heterocycles, 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, or optionally substituted alkylaryloxyalkylamine;
- 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=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.
18 more elements
A compound of formula I:
- wherein:
- one of A ad B is hydrogen and the other is an optionally substituted fused bicyclic heteroaryl group;
- with the proviso that if the aromatic ring portion of the bicyclic heteroaryl group is imidazole, the nonaromatic ring portion may not contain a S adjacent to the bridgehead carbon;
- X is S;
- R5 is H, C1–C6 alkyl, C1–C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
- or a pharmaceutically acceptable salt thereof;
- wherein the bicyclic heteroaryl group is
- 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;
- t=1 to 4;
- Y1 and Y2 are independently N or C;
- R1 is H, optionally substituted C1–C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, 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═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O(C1–C6) alkyl, optionally substituted —C═O(C5–C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, 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 heterocycles, 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 C1–C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, 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, N—R6R7, 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 or cyclic 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 heterocycles, 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, or optionally substituted alkylaryloxyalkylamine;
- 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=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.
17 more elements
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 S;
- R5 is hydrogen, 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 is
- 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 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=1 to 4;
- Y1 and Y2 are C;
- R1 is H, optionally substituted C1–C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, 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═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O(C1–C6) alkyl, optionally substituted —C═O(C5–C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, 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 heterocycles, 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 C1–C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, 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, N—R6R7, 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 or cyclic 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 heterocycles, 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, or optionally substituted alkylaryloxyalkylamine;
- 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=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.
19 more elements
A selected from the group consisting of
- a. (5R,6Z)-6-[(5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- b. (5R),(6Z)-6-(7-Methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- c. (5R),(6Z)-7-Oxo-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- d. (5R,6Z)-6-{[5-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- e. (5R),(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- f. (5R),(6Z)-6-(6,7-Dihydro-5H-pyrrolo[1,2-a]imidazol-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- g. (5R),(6Z)-6-(5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- h. (5R),(6Z)-6-(5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- i. (5R)(6Z)-7-Oxo-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- j. (5R),(6Z)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt;
- k. (5R)(6Z)-6-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- l. (5R)(6Z)-7-Oxo-6-(4H-5-thia-1,6a-diazapentalen-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- m. (5R)(6Z)-6-(7H-Imidazo[1,2-c]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- n. (5R,6Z)-7-oxo-6-[(4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methylene]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- o. 6-(6,7-Dihydro-4H-thieno[3,2-c]pyran-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- p. 6-(6,7-Dihydro-4H-thieno[3,2-c]thiopyran-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- q. 6-(5-Methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- r. 2-(2-Carboxy-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-en-6-ylidenemethyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid ethyl ester;
- s. 7-Oxo-6-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-2-ylmethylene)-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- t. (5R),(6Z)-6-(7-Benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- u. (5R,6Z)-7-oxo-6-{[5-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- v. (5R,6Z)-7-oxo-6-{[5-(pyridin-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- w. (5R,6Z)-7-oxo-6-{[5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- x. (5R),(6Z)-6-(5,5-Dioxo-4,5,6,7-tetrahydro-5λ6-pyrazolo[5,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- y. (5R),(6Z)-7-Oxo-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene)-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- z. (5R)(6Z)-6-(5,5-Dimethyl-4H-1,6a-diazapentalen-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt 5,5-Dimethyl-2-piperidone;
- aa. (5R),(6Z)-6-(5,6-Dihydro-4H-cyclopenta[b]furan-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- bb. (5R)(6Z)-6-(4,5-Dihydro-6-thia-1,7a-diazainden-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- cc. (5R),(6Z)-6-(6,6-Dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrizin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- dd. (5R),(6Z)-6-(5,6-Dihydro-8-H-imidazo[2,1-c][1,4]thiazin-3-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- ff. (5R)(6Z)-6-(2,3-Dihydropyrazolo[5,1-b]thiazol-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- gg. (5R)(6Z)-6-(2,3-Dihydropyrazolo[5,1-b]oxazol-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- hh. (5R,6Z)-6-[(5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methylene]-oxo-4-thia-1-azabicyclo[3.2.0.]hept-2-ene-2-carboxylic acid (E+Z Isomers mixture, Sodium salt);
- ii. (5R,6Z)-6-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- jj. (5R)(6Z)-6-(6,7-5H-Dihydropyrazolo[5,1-b]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
- kk. (5R),(6Z)-6-[5-(3-carboxypropionyl)-4, 5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid, disodium salt;
- ll. (5R),(6Z)-6-[5-(2-methoxyacetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid, sodium salt;
- mm. (5R),(6Z)-6-[5-(4,5-dihydrothiazol-2yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid, sodium salt;
- and
- nn. (5R,6Z)-6-{[6-(ethoxycarbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid.
37 more elements
A method for the treatment of bacterial infection of 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 portion of the bicyclic heteroaryl group is imidazole, the nonaromatic ring portion may not contain a S adjacent to the bridgehead carbon;
- X is S;
- R5 is H, C1–C6 alkyl, C5–C6 cycloalkyl, CHR3OC1–C6alkyl;
- and
- R3 is hydrogen, C1–C6 alkyl, C5–C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;
- or a pharmaceutically acceptable salt thereof;
- where the bicyclic heteroaryl group is
- 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;
- t=1 to 4;
- Y1 and Y2 are independently N or C;
- R1 is H, optionally substituted C1–C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, 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═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O (C1–C6) alkyl, optionally substituted —C═O(C5–C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, 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 heterocycles, 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 C1–C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, 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, N—R6R7, 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 or cyclic 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 heterocycles, 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, or optionally substituted alkylaryloxyalkylamine;
- 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=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.
19 more elements
A method for the treatment of bacterial infection of 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 S;
- R5 is H, C1–C6 alkyl, C5–C6 cycloalkyl, CHR3OC1–C6alkyl;
- and
- R3 is hydrogen, C1–C6 alkyl, C5–C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;
- or a pharmaceutically acceptable salt thereof;
- where the bicyclic heteroaryl group is
- 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 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=1 to 4;
- Y1 and Y2 are C;
- R1 is H, optionally substituted C1–C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, 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═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O (C1–C6) alkyl, optionally substituted —C═O(C5–C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, 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 heterocycles, 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 C1–C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, 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, N—R6R7, 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 or cyclic 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 heterocycles, 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, or optionally substituted alkylaryloxyalkylamine;
- 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=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.
19 more elements
A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and 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 portion of the bicyclic heteroaryl group is imidazole, the nonaromatic ring portion may not contain a S adjacent to the bridgehead carbon;
- X is S;
- R5 is H, C1–C6 alkyl, C5–C6 cycloalkyl, CHR3OC1–C6alkyl;
- and
- R3 is hydrogen, C1–C6 alkyl, C5–C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;
- or a pharmaceutically acceptable salt thereof;
- where the bicyclic heteroaryl group is
- wherein
- Z1, Z2 and Z3 are independently CR2N, 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=1 to 4;
- R1 is H, optionally substituted C1–C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, 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═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O (C1–C6) alkyl, optionally substituted —C═O(C5–C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, 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 heterocycles, 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 C1–C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, 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, N—R6R7, 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 or cyclic 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 heterocycles, 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, or optionally substituted alkylaryloxyalkylamine;
- 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=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.
19 more elements
A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and 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 portion of the bicyclic heteroaryl group is imidazole, the nonaromatic ring portion may not contain a S adjacent to the bridgehead carbon;
- X is S;
- R5 is H, C1–C6 alkyl, C5–C6 cycloalkyl, CHR3OC1–C6alkyl;
- and
- R3 is hydrogen, C1–C6 alkyl, C5–C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;
- or a pharmaceutically acceptable salt thereof;
- where the bicyclic heteroaryl group is
- 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;
- t=1 to 4;
- Y1 and Y2 are independently N or C;
- R1 is H, optionally substituted C1–C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, 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═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O (C1–C6) alkyl, optionally substituted —C═O(C5–C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, 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 heterocycles, 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 C1–C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, 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, N—R6R7, 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 or cyclic 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 heterocycles, 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, or optionally substituted alkylaryloxyalkylamine;
- 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=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.
19 more elements
A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and 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 S;
- R5 is H, C1–C6 alkyl, C5–C6 cycloalkyl, CHR3OC1–C6alkyl;
- and
- R3 is hydrogen, C1–C6 alkyl, C5–C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;
- or a pharmaceutically acceptable salt thereof;
- where the bicyclic heteroaryl group is
- 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 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=1 to 4;
- Y1 and Y2 are C;
- R1 is H, optionally substituted C1–C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, 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═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O (C1–C6) alkyl, optionally substituted —C═O(C5–C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, 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 heterocycles, 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 C1–C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, 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, N—R6R7, 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 or cyclic 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 heterocycles, 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, or optionally substituted alkylaryloxyalkylamine;
- 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=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.
19 more elements
Dependencies are inferred from the claim text.