Glucose transport inhibitors and methods of use

A compound having the formula:

• wherein
• Y is selected from the group consisting of (CH2)n, (CH2)mCH═CH, CH═CH(CH2)m and CH2CH═CHCH2, wherein n is an integer from 1 to 3, m is an integer from 0 to 2, and each hydrogen independently may be optionally replaced with a substituent independently selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and C3-C6 cycloalkyloxy;
• R1 is selected from the group consisting of hydrogen, halo, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)C1-C3 alkyl, (C3-C10 cycloalkyloxy)C1-C3 alkyl, (C1-C4 alkyloxy)C1-C3 alkyl, (C1-C4 alkylamino)C1-C3 alkyl, di-(C1-C3 alkylamino)C1-C3 alkyl, C1-C6 alkyloxy, C3-C10 cycloalkyloxy, hydroxy, cyano and nitro;
• and
• R3 is selected from the group consisting of hydrogen, halo, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)C1-C3 alkyl, (C3-C10 cycloalkyloxy)C1-C3 alkyl, (C1-C4 alkyloxy)C1-C3 alkyl, (C1-C4 alkylamino)C1-C3 alkyl, di-(C1-C3 alkylamino)C1-C3 alkyl, C1-C6 alkyloxy, C3-C10 cycloalkyloxy, hydroxy, cyano and nitro,
• wherein in cycloalkyl groups or portions, one or two methylene groups are optionally replaced independently of one another by O, S, CO, SO or SO2.

A compound of the formula:

• wherein
• Q is selected from the group consisting of hydroxy, a protected hydroxy group, and C2-C5 alkenyl;
• X is selected from the group consisting of oxygen;
• sulfur;
• SO;
• SO2;
• methylene optionally substituted with one to two substituents independently selected from halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy;
• C3-C5 1,1-cycloalkylene optionally substituted with one to two substituents independently selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and C3-C6 cycloalkyloxy;
• and NH optionally substituted with a substituent independently selected from C1-C6 alkyl, C3-C6 cycloalkyl and (C1-C4 alkyl)carbonyl;
• Z is a member selected from the group consisting of oxygen;
• sulfur;
• SO;
• SO2;
• 1,1-cyclopropylene;
• carbonyl;
• and methylene optionally substituted with one to two substituents independently selected from halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and C3-C6 cycloalkyloxy;
• R1 is a member selected from the group consisting of hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, (C3-C10)cycloalkyl-(C1-C3)alkyl, (C2-C4 alkenyl)C1-C3 alkyloxy, (C2-C4 alkynyl)C1-C3 alkyloxy, (C3-C10 cycloalkyl)C2-C4 alkenyl, C3-C6 cycloalkylidenmethyl, (C3-C10 cycloalkyloxy)C1-C3 alkyl, C5-C10 cycloalkenyl, (C5-C10)cycloalkenyl-(C1-C3)alkyl, (C1-C4 alkyloxy)C1-C3 alkyl, (C1-C4 alkylamino)C1-C3 alkyl, di-(C1-C3 alkylamino)C1-C3 alkyl, aryl, heteroaryl, (C1-C4 alkyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxycarbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl, di-(C1-C3 alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C1-C4 alkyl)piperazin-1-ylcarbonyl, (C1-C4 alkyloxy)carbonyl, amino, C1-C4 alkylamino, di-(C1-C3 alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-(C1-C4 alkyl)piperazin-1-yl, (C1-C4 alkyl)carbonylamino, arylcarbonylamino, C1-C4 alkylsulfonylamino, arylsulfonylamino, heteroarylcarbonylamino, C1-C6 alkyloxy, C3-C10 cycloalkyloxy, C5-C7 cycloalkenyloxy, aryloxy, heteroaryloxy, (aryl)C1-C3 alkyloxy, (heteroaryl)C1-C3 alkyloxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C3-C10 cycloalkylsulfanyl, C3-C10 cycloalkylsulfinyl, C3-C10 cycloalkylsulfonyl, C5-C10 cycloalkenylsulfanyl, C5-C10 cycloalkenylsulfinyl, C5-C10 cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, hydroxy, cyano or nitro;
• wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups or portions are optionally partly or completely fluorinated and optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C1-C3 alkoxy and C1-C3 alkyl, and
• in cycloalkyl and cycloalkenyl groups one or two methylene groups are optionally replaced independently of one another by O, S, CO, SO or SO2, and
• in N-heterocycloalkyl groups a methylene group is optionally replaced by CO or SO2;
• R2 is a member selected from the group consisting of hydrogen, halo, hydroxy, C1-C4 alkyl, C3-C10 cycloalkyl, C1-C4 alkyloxy, C3-C10 cycloalkyloxy, cyano and nitro, wherein alkyl groups or portions are optionally mono- or polysubstituted by fluorine, or
• in the event that R1 and R2 are bound to two adjacent C atoms of the phenyl ring, R1 and R2 are optionally joined together such that R1 and R2 together form a C3-C5 alkylene, C3-C5 alkenylene or butadienylene bridge, which is optionally partly or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C1-C3 alkoxy and C1-C3 alkyl, and wherein one or two methylene groups are optionally replaced independently of one another by O, S, CO, SO, SO2 or NRa, and wherein one or two methyne groups are optionally replaced by an N atom;
• R3 is a member selected from the group consisting of hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, (C3-C10)cycloalkyl-(C1-C3)alkyl, C5-C10 cycloalkenyl, (C5-C10)cycloalkenyl-(C1-C3)alkyl, (C1-C4 alkyloxy)C1-C3 alkyl, (C3-C10 cycloalkyloxy)C1-C3 alkyl, (C1-C4 alkylamino)C1-C3 alkyl, di-(C1-C3 alkylamino)C1-C3 alkyl, (C3-C10 cycloalkyl)C2-C4 alkenyl, C3-C6 cycloalkylidenmethyl, aryl, heteroaryl, (C1-C4 alkyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl, di-(C1-C3 alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C1-C4 alkyl)piperazin-1-ylcarbonyl, hydroxycarbonyl, (C1-C4 alkyloxy)carbonyl, C1-C4 alkylamino, di-(C1-C3 alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-(C1-C4 alkyl)piperazin-1-yl, (C1-C4 alkyl)carbonylamino, arylcarbonylamino, heteroaryl-carbonylamino, C1-C4 alkylsulfonylamino, arylsulfonylamino, C1-C6 alkyloxy, C3-C10 cycloalkyloxy, C5-C7 cycloalkenyloxy, aryloxy, heteroaryloxy, (C2-C4 alkenyl)C1-C3 alkyloxy, (C2-C4 alkynyl)C1-C3 alkyloxy, (aryl)C1-C3 alkyloxy, (heteroaryl)C1-C3 alkyloxy, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C3-C10 cycloalkylsulfanyl, C3-C10 cycloalkylsulfinyl, C3-C10 cycloalkylsulfonyl, C5-C10 cycloalkenylsulfanyl, C5-C10 cycloalkenylsulfinyl, cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, amino, hydroxy, cyano or nitro,
• wherein alkyl, alkenyl, alkynyl, cycloalkyl- and cycloalkenyl groups or portions are optionally partly or completely fluorinated and optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C1-C3 alkoxy and C1-C3 alkyl, and
• in cycloalkyl and cycloalkenyl groups one or two methylene groups are optionally replaced independently of one another by O, S, CO, SO or SO2, and
• in N-heterocycloalkyl groups a methylene group is optionally replaced by CO or SO2;
• R4 is a member selected from the group consisting of hydrogen, halo, hydroxy, cyano, nitro, C1-C3 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkyloxy and C1-C3 alkyloxy, wherein alkyl groups or portions may be mono- or polysubstituted by fluorine, or
• if R3 and R4 are bound to two adjacent C atoms of the phenyl ring, R3 and R4 are optionally joined together such that R3 and R4 together form a C3-C5 alkylene, C3-C5 alkenylene or butadienylene bridge, which is optionally partly or completely fluorinated and optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C1-C3 alkoxy and C1-C3 alkyl, and wherein one or two methylene groups can be replaced independently of one another by O, S, CO, SO, SO2 or NRa, and wherein in the case of a butadienylene bridge one or two methyne groups are optionally replaced by an N atom;
• R5 is a member selected from the group consisting of hydrogen, halo, hydroxy, cyano, nitro, C1-C3 alkyl, C3-C10 cycloalkyl and C1-C3 alkyloxy, wherein alkyl groups or portions may be mono- or polysubstituted by fluorine;
• and
• R6, R7, R8 and R9 are each members independently selected from the group consisting of hydroxy, (C1-C18 alkyl)carbonyloxy, (C1-C18 alkyl)oxycarbonyloxy, arylcarbonyloxy, aryl-(C1-C3 alkyl)carbonyloxy, hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C10)cycloalkyl-(C1-C3)alkyl, (C5-C7)cycloalkenyl-(C1-C3)alkyl, aryl-(C1-C3)alkyl, heteroaryl-(C1-C3)alkyl, C1-C6 alkyloxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, (C3-C7)cycloalkyloxy, C5-C7 cycloalkenyloxy, aryloxy, heteroaryloxy, (C3-C7)cycloalkyl-(C1-C3)alkyloxy, (C5-C7)cycloalkenyl-(C1-C3)alkyloxy, aryl-(C1-C3)alkyloxy, heteroaryl-(C1-C3)alkyloxy, aminocarbonyl, hydroxycarbonyl, (C1-C4 alkyl)aminocarbonyl, di-(C1-C3 alkyl)aminocarbonyl, (C1-C4 alkyloxy)carbonyl, aminocarbonyl-(C1-C3)alkyl, (C1-C4 alkyl)aminocarbonyl-(C1-C3)alkyl, di-(C1-C3 alkyl)aminocarbonyl-(C1-C3)alkyl, hydroxycarbonyl-(C1-C3)alkyl, (C1-C4 alkyloxy)carbonyl-(C1-C3)alkyl, (C3-C7)cycloalkyloxy-(C1-C3)alkyl, (C5-C7)cycloalkenyloxy-(C1-C3)alkyl, aryloxy-(C1-C3)alkyl, heteroaryloxy-(C1-C3)alkyl, C1-C4 alkylsulfonyloxy, arylsulfonyloxy, aryl-(C1-C3)alkyl-sulfonyloxy, trimethylsilyloxy, t-butyldimethylsilyloxy, and cyano,
• wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups or portions are optionally partly or completely fluorinated and optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C1-C3 alkoxy and C1-C3 alkyl, and
• in cycloalkyl and cycloalkenyl groups one or two methylene groups are optionally replaced independently of one another by NRa, O, S, CO, SO or SO2;
• and
• Ra is a member selected from the group consisting of H, C1-C4 alkyl and C1-C4 alkylcarbonyl.