Benzenesulfonyl Compounds and the Use Thereof

A compound having the Formula I:

• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halo(C1-C6)alkyl, C1-C6 alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, C1-C6 alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, cycloalkyl, cycloalkenyl, and heterocyclo(C1-C6)alkyl, all of which can be optionally substituted;
• R2 is selected from the group consisting of C1-C6 alkyl, cycloalkyl, cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and di(C1-C6)alkylamino;
• Z is selected from the group consisting of Z1, Z2, and Z3 wherein:
• Z1 is
• Z2 is
• and
• Z3 is
• m is 0, 1, or 2;
• n is 0, 1 or 2;
• p is 0 or 1;
• r is 0 or 1;
• provided that n and p are not both 0;
• R3 and R4 are each independently hydrogen, alkyl, or alkenyl;
• or
• R3 and R4 together form ═O;
• or
• R3 and R4 together with the carbon atom to which they are attached form a saturated C3-7 cycloalkyl ring optionally substituted with one substituent selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, amino, and ═O, wherein one or more carbon atoms of the C3-7 cycloalkyl ring are optionally replaced with NR16, O, S, or SO2, wherein R16 is hydrogen or C1-3 alkyl, to form a heterocyclic ring;
• R5 is selected from the group consisting of alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroaryl;
• R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroaryl;
• or
• R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic ring to give Z11 having the structure:
• where
• A is CH2, CHF, CF2 or CHOH;
• B is CH2, O, or N—R51, where R51 is CH3 or C(O)CH3;
• s is 0, 1, or 2;
• p is 0 or 1;
• R3 is as defined above and R4 is hydrogen;
• R7 is selected from the group consisting of alkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and —CH2—U—V, wherein U is CH2, CHF, CF2 or CHOH and V is hydrogen, alkyl, or alkenyl;
• R8 is selected from the group consisting of hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
• (i) R9 and R10 are each independently selected from the group consisting of
• hydrogen;
• alkyl;
• alkenyl;
• hydroxyalkyl;
• alkoxyalkyl;
• cycloalkyl;
• cycloalkenyl, and
• phenyl optionally substituted with one substituent selected from the group consisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro, hydroxyalkyl, haloalkyl, and alkoxy;
• or
• R9 is hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, or phenyl optionally substituted with one substituent selected from the group consisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro, hydroxyalkyl, haloalkyl, and alkoxy;
• and
• R10 is R17—C(O)—, where
• R17 is selected from the group consisting of alkyl, alkoxy, optionally substituted benzyl, and optionally substituted benzyloxy;
• or
• R9 and R10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring wherein one or more carbon atoms of the heterocyclic ring are optionally replaced with NR18, O, or S, wherein R18 is hydrogen or C1-3 alkyl;
• R11 and R12 are each independently selected from the group consisting of
• hydrogen;
• alkyl;
• alkenyl;
• hydroxyalkyl;
• aminoalkyl;
• cycloalkyl;
• cycloalkenyl;
• heterocyclo;
• heterocycloalkyl;
• phenyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro, hydroxyalkyl, haloalkyl, and alkoxy;
• benzyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro, hydroxyalkyl, haloalkyl, and alkoxy;
• benzyloxyalkyl;
• heteroaryl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro, hydroxyalkyl, haloalkyl, and alkoxy;
• and
• heteroarylalkyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, cycloalkyl, halogen, cyano, amino, alkylamino, dialkylamino, hydroxy, nitro, hydroxyalkyl, haloalkyl, and alkoxy;
• or
• R11 and R12 together form ═O;
• or
• R11 and R12 together with the carbon atom to which they are attached form a saturated or unsaturated C3-7 cycloalkyl ring optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, amino, carboxy, alkoxycarbonyl, alkylamino, dialkylamino, phenyl, and ═O, wherein one or more carbon atoms of the C3-7 cycloalkyl ring are optionally replaced with NR19, O, S, or SO2, wherein R19 is hydrogen or C1-3 alkyl, to form a heterocyclic ring;
• or wherein two adjacent carbon atoms of the C3-7 cycloalkyl ring can form a bridge —O— to form a bicyclic ring;
• or wherein two adjacent carbon atoms of the C3-7 cycloalkyl ring together form a fused phenyl group optionally substituted with alkyl, haloalkyl, amino, cyano, or hydroxy;
• or
• R12 is hydrogen, alkyl, or alkenyl;
• R9 is as defined above;
• and R10 and R11 together form a bridge —CH2—CH2—CH2— or —CH2—CHG1-CHG2-CH2—, wherein G1 and G2 are both hydrogen or together with the carbon atoms to which they are attached form a fused phenyl group;
• or
• (ii) R9 is selected from the group consisting of alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and —CH2—U—V, wherein U is CH2, CHF, CF2 or CHOH and V is hydrogen, alkyl, or alkenyl;
• and
• R10 is selected from the group consisting of hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
• or
• R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclic ring to give Z31 having the structure:
• where
• A is CH2, CHF, CF2 or CHOH;
• B is CH2, O, or N—R51, where R51 is CH3 or C(O)CH3;
• and
• s is 0, 1, or 2;
• r is 0 or 1;
• and
• R11 and R12 together form ═O;
• or
• R11 and R12 are each independently selected from the group consisting of hydrogen, alkyl, and alkenyl or together with the carbon atom to which they are attached form a saturated or unsaturated C3-7 cycloalkyl ring optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, amino, carboxy, alkoxycarbonyl, alkylamino, dialkylamino, phenyl, and ═O, wherein one or more carbon atoms of the C3-7 cycloalkyl ring are optionally replaced with NR19, O, S, or SO2, wherein R'9 is hydrogen or C1-3 alkyl, to form a heterocyclic ring;
• or
• (iii) R11 and R12 are both hydrogen or together form ═O, R9 is selected from the group consisting of alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and —CH2—U—V, wherein U is CH2, CHF, CF2 or CHOH and V is hydrogen, alkyl, or alkenyl;
• and R10 and R1 together form a bridge -D-E-G-, wherein
• D is CH2, C(O), CHCH3, C(CH3)2 or absent;
• E is CH2, C(O), C(S), CHF, CF2 or CHOH;
• and
• G is CH2, C(O), CHCH3, C(CH3)2 or absent;
• and
• Y is O or S;
• with the following provisos:
• 1) R7 is not optionally substituted 2-thiazolyl or optionally substituted benzothiazolyl;
• 2) when Z is Z2, R2 is not C1-6 alkyl, cycloalkyl or unsubstituted phenyl;
• 3) when Z is Z2, R8 is hydrogen or alkyl, and R7 is an optionally substituted phenyl or biphenyl, then R1 is other than hydrogen or unsubstituted C1-6 alkyl;
• 4) when Z is Z3 and m is 2, then R2 is not phenyl substituted with CN or R9 and R10 are not both hydrogen;
• 5) when Z is Z3 and R9 and R19 are both hydrogen, then R1 is other than hydrogen;
• or
• 6) when Z is Z3, r is 0, and R11 and R12 are both hydrogen, then R1 is other than unsubstituted C1-6 alkyl.