Methods and compositions of novel triazine compounds
View Patent ↗The present invention relates to methods and compositions comprising compounds that treat pathophysiological conditions arising from inflammatory responses. In particular, the present invention is directed to compounds that inhibit or block glycated protein produced induction of the signaling-associated inflammatory response in endothelial cells. The present invention relates to compounds that inhibit smooth muscle proliferation. In particular, the present invention is directed to compounds that inhibit smooth muscle cell proliferation by modulating HSPGs such as Perlecan. The present invention further relates to the use of compounds to treat vascular occlusive conditions characterized by smooth muscle proliferation such as restenosis and atherosclerosis.
1. A compound having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
a) R 1 , in each occurrence, is selected independently from H; a linear or a branched alkyl with up to 10 carbon atoms; a cycloalkyl with up to 10 carbon atoms; a cycloalkenyl with up to 10 carbon atoms; benzyl; CH 2 NH 2 ; CH 2 OH; aryl; or O 2 CR, C(O), or C(O)OR, wherein R is H, or linear or branched alkyl with up to 10 carbon atoms;
b) G is NR 1 or O;
c) J is CH or N;
d) n is an integer from 0 to 2;
e) X 1 is selected from o-R 1 , m-R 1 , m-OR 1 , m-OCF 3 , o-F, o-Cl, m-F, m-Cl, m-Br, m-I, m-CF 3 , m-CN, m-NO 2 , m-C(O)OR 1 , C(O)OLi, C(O)ONa, m-SO 2 R 1 , m-NC(O)R 1 , or m-SO 2 OR 1 ; or X 1 and X 2 together is a fused benzene, pyridine, dioxane, or tetrahydropyran ring;
f) X 2 is selected from o-R 1 ; p-R 1 ; p-OR 1 ; p-OCF 3 ; o-F; o-Cl; o-Br; o-I; o-CF 3 ; m-F; m-Cl; m-Br; m-I; m-CN; m-CF 3 ; m-OCF 3 ; p-SR 1 ; p-N(R 1 )(R 1A ); p-F; p-Cl; p-Br; p-CF 3 ; p-OCF 3 ; p-C(O)OR 1 ; p-OC(O)R 1 ; p-CN; p-NO 2 ; p-NC(O)R 1 ; o-C≡CC(CH 3 ) 2 OR 1 ; p-C≡CC(CH 3 ) 2 OR 1 ; p-OM, p-SM, m-C(O)OM, or p-C(O)OM wherein M is selected from Li, Na, K, 0.5 Mg, or 0.5 Ca; p-O(CH 2 ) m ZR 1 wherein m is an integer from 0 to 3 and Z is selected from O, S, —S(O)—, —SO 2 —, —OP(O)(OH)O—, —P(O)(OH)O—, or —C(O)—; p-OC(O)(CH 2 CH 2 O) r R 1 or p-O(CH 2 CH 2 O) r R 1 wherein r is an integer from 0 to 6;
g) R 1A , in each occurrence, is selected independently from: a linear or a branched alkyl with up to 10 carbon atoms; a cycloalkyl with up to 10 carbon atoms; a cycloalkenyl with up to 10 carbon atoms; benzyl; CH 2 NH 2 ; CH 2 OH; aryl; or O 2 CR, C(O)R, or C(O)OR, wherein R is H, or linear or branched alkyl with up to 10 carbon atoms;
h) X 3 is selected from o-R 1 , m-R 1 , p-R 1 , o-OR 1 , m-OR 1 , or p-OR 1 ; or X 2 and X 3 together is a fused benzene, pyridine, dioxane, or tetrahydropyran ring;
i) either: 1) AY 1 in combination is
wherein x is 5;
wherein G is selected from NH, CH 2 or SH; or
2) A is O or NR 1 , and Y 1 is selected from:
a. (CHR 1 ) q CF 3 ;
wherein n is 1 or 2 and Q is selected from CH or N; or
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , C═O, or C═NR 1 ;
wherein W − is selected from Cl − , Br − , I − , [O 2 CCH 2 CH 2 CO 2 R 1 ] − , [O 2 CCHCHCO 2 R 1 ] − , or [O 2 CCF 3 ] − ;
wherein q is an integer from 0 to 3, L is selected from CH or N, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein q is an integer from 0 to 3, and X 6 is selected from H, 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein T is selected from CO 2 H, CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
j. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
k. C(O)Z 1 , wherein Z 1 is selected from NR 1 2 ,
wherein x is an integer from 3 to 5,
wherein t is an integer from 0 to 6;
l. (CHR 1 ) z Z 2 , wherein z is an integer from 0 to 6, and Z 2 is selected from NR 1 2 ,
wherein t is an integer from 0 to 6; or
m. (CHR 1 ) z Z 3 , wherein z is an integer from 1 to 6, and Z 3 is
wherein x is an integer from 3 to 5; and
j) either: 1) DY 2 in combination is
wherein x is an integer from 3 to 5;
wherein G is selected from NH, CH 2 or SH; or
2) D is O or NR 1 , and Y 2 is selected from:
a. R 1 , (CHR 1 ) q R 1 ; (CHR 1 ) q CF 3 ;
wherein n is 1 or 2 and Q is selected from CH or N; or
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein W − is selected from Cl − , Br − , I − , [O 2 CCH 2 CH 2 CO 2 R 1 ] − , [O 2 CCHCHCO 2 R 1 ] − , or [O 2 CCF 3 ] − ;
wherein q is an integer from 0 to 3, L is selected from CH or N, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3 and X 1 , X 2 , and X 3 are selected as defined above;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein q is an integer from 0 to 3, and X 6 is selected from H, 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein T is selected from CO 2 H, CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
i. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6; or
j. C(O)Z 1 or (CHR 1 ) z Z 1 , wherein z is an integer from 0 to 6, and Z 1 is selected from NR 1 2 ,
wherein x is an integer from 3 to 5,
wherein t is an integer from 0 to 6.
2. A compound according to claim 1 having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
1) DY 2 in combination is
wherein x is an integer from 3 to 5;
wherein G is selected from NH, CH 2 or SH; or
2) D is O or NR 1 , and Y 2 is selected from:
a. R 1 ; (CHR 1 ) q R 1 ;
wherein n is 1 or 2 and Q is selected from CH or N; or
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein W − is selected from Cl − , Br − , [O 2 CCH 2 CH 2 CO 2 R 1 ] − , [O 2 CCHCHCO 2 R 1 ] − , or [O 2 CCF 3 ] − ;
wherein q is an integer from 0 to 3, L is selected from CH or N, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3 and X 1 , X 2 , and X 3 are selected as defined above;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
g. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6; or
h. C(O)Z 1 or (CHR 1 ) z Z 1 , wherein z is an integer from 0 to 6, and Z 1 is selected from NR 1 2 ,
wherein x is an integer from 3 to 5,
wherein t is 0 or 1.
3. A compound according to claim 1 having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
1) DY 2 in combination is
wherein x is an integer from 3 to 5;
wherein G is selected from NH, CH 2 or SH; or
2) D is O or NR 1 , and Y 2 is selected from:
a. R 1 ; (CHR 1 ) q R 1 ;
wherein n is 1 or 2 and Q is selected from CH or N; or
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein W − is selected from Cl − , Br − , [O 2 CCH 2 CH 2 CO 2 R 1 ] − , [O 2 CCHCHCO 2 R 1 ] − , or [O 2 CCF 3 ] − ;
wherein q is an integer from 0 to 3, L is selected from CH or N, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3 and X 1 , X 2 , and X 3 are selected as defined above;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
f. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6; or
g. C(O)Z 1 or (CHR 1 ) z Z 1 , wherein z is an integer from 0 to 6, and Z 1 is selected from NR 1 2 ,
wherein x is an integer from 3 to 5,
wherein t is 0.
4. A compound according to claim 1 having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
1) AY 1 in combination is
wherein x is 5; or
wherein G is selected from NH, CH 2 or SH; or
2) A is O or NR 1 , and Y 1 is selected from:
a. (CHR 1 ) q CF 3 ;
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3, L is selected from CH or N, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4NH 2 ;
wherein q is an integer from 0 to 3, and X 6 is selected from H, 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein T is selected from CO 2 H, CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
i. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
j. C(O)Z 1 , wherein Z 1 is selected from NR 1 2 ,
wherein x is an integer from 3 to 5,
wherein t is 0 or 1;
k. (CHR 1 ) z Z 2 , wherein z is an integer from 0 to 6, and Z 2 is selected from NR 1 2 ,
wherein t is 0 or 1; or
l. (CHR 1 ) z Z 3 , wherein z is an integer from 1 to 6, and Z 3 is
wherein x is an integer from 3 to 5.
5. A compound according to claim 1 having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
1) AY 1 in combination is
wherein x is 5; or
wherein G is selected from NH, CH 2 or SH; or
2) A is O or NR 1 , and Y 1 is selected from:
a. (CHR 1 ) q CF 3 ;
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3, L is selected from CH or N, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4NH 2 ;
wherein q is an integer from 0 to 3, and X 6 is selected from H, 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein T is selected from CO 2 H, CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
i. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
j. C(O)Z 1 , wherein Z 1 is selected from NR 1 2 ,
wherein x is an integer from 3 to 5,
wherein t is 0;
k. (CHR 1 ) z Z 2 , wherein z is an integer from 1 to 6, and Z 2 is selected from NR 1 2 ,
wherein t is 0; or
l. (CHR 1 ) z Z 3 , wherein z is an integer from 1 to 6, and Z 3 is
wherein x is an integer from 3 to 5.
6. A compound according to claim 1 having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
a) X 1 is selected from o-R 1 , m-R 1 , m-OR 1 , m-OCF 3 , o-F, o-Cl, m-F, m-Cl, m-Br, m-I, m-CF 3 , m-CN, m-NO 2 , m-C(O)OR 1 , C(O)OLi, C(O)ONa, m-SO 2 R 1 , m-NC(O)R 1 , or m-SO 2 OR 1 ; or X 1 and X 2 together is a fused benzene, pyridine, dioxane, or tetrahydropyran ring;
b) X 2 is selected from o-R 1 ; p-R 1 ; p-OR 1 ; p-OCF 3 ; o-F; o-Cl; o-Br; o-I; o-CF 3 ; m-F; m-Cl; m-Br; m-I; m-CN; m-CF 3 ; m-OCF 3 ; p-SR 1 ; p-N(R 1 )(R 1A ); p-F; p-Cl; p-Br; p-CF 3 ; p-OCF 3 ; p-C(O)OR 1 ; p-OC(O)R 1 ; p-CN; p-NO 2 ; p-NC(O)R 1 ; p-OM, p-SM, m-C(O)OM, or p-C(O)OM wherein M is selected from Li, Na, K, 0.5 Mg, or 0.5 Ca; p-O(CH 2 ) m ZR 1 wherein m is an integer from 0 to 3 and Z is selected from O, S, —S(O)—, —SO 2 —, —OP(O)(OH)O—, —P(O)(OH)O—, or —C(O)—; p-OC(O)(CH 2 CH 2 O) r R 1 or p-O(CH 2 CH 2 O) r R 1 wherein r is 0 or 1; and
c) X 3 is selected from o-R 1 , m-R 1 , p-R 1 , o-OR 1 , m-OR 1 , or p-OR 1 ; or X 2 and X 3 together is a fused benzene, dioxane, or tetrahydropyran ring.
7. A compound according to claim 1 having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
a) X 1 is selected from o-R 1 , m-R 1 , m-OR 1 , m-OCF 3 , o-F, o-Cl, m-F, m-Cl, m-Br, m-I, m-CF 3 , m-CN, m-NO 2 , m-C(O)OR 1 , C(O)OLi, C(O)ONa, or m-SO 2 OR 1 ; or X 1 and X 2 together is a fused benzene, pyridine, dioxane, or tetrahydropyran ring;
b) X 2 is selected from o-R 1 ; p-R 1 ; p-OR 1 ; p-OCF 3 ; o-F; o-Cl; o-Br; o-I; o-CF 3 ; m-F; m-Cl; m-Br; m-I; m-CN; m-CF 3 ; m-OCF 3 ; p-SR 1 ; p-N(R 1 )(R 1A ); p-F; p-Cl; p-Br; p-CF 3 ; p-OCF 3 ; p-C(O)OR 1 ; p-OC(O)R 1 ; p-OM, p-SM, m-C(O)OM, or p-C(O)OM wherein M is selected from Li, Na, K, 0.5 Mg, or 0.5 Ca; or p-O(CH 2 ) m ZR 1 wherein m is an integer from 0 to 3 and Z is selected from O, S, —S(O)—, —SO 2 —, —OP(O)(OH)O—, —P(O)(OH)O—, or —C(O)—; and
c) X 3 is selected from o-R 1 , m-R 1 , p-R 1 , o-OR 1 , m-OR 1 , or p-OR 1 .
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
a) R 1 , in each occurrence, is selected independently from H; a linear or a branched alkyl with up to 10 carbon atoms; a cycloalkyl with up to 10 carbon atoms; a cycloalkenyl with up to 10 carbon atoms; benzyl; CH 2 NH 2 ; CH 2 OH; aryl; or O 2 CR, C(O)R, or C(O)OR, wherein R is H, or linear or branched alkyl with up to 10 carbon atoms;
b) G is NR 1 or O;
c) J is CH or N;
d) n is an integer from 0 to 2;
e) X 1 is selected from o-R 1 , m-R 1 , m-OR 1 , m-OCF 3 , o-F, o-Cl, m-F, m-Cl, m-Br, m-I, m-CF 3 , m-CN, m-NO 2 , m-C(O)OR 1 , C(O)OLi, C(O)ONa, m-SO 2 R 1 , m-NC(O)R 1 , or m-SO 2 OR 1 ; or X 1 and X 2 together is a fused benzene, pyridine, dioxane, or tetrahydropyran ring;
f) X 2 is selected from o-R 1 ; p-R 1 ; p-OR 1 ; p-OCF 3 ; o-F; o-Cl; o-Br; o-I; o-CF 3 ; m-F; m-Cl; m-Br; m-I; m-CN; m-CF 3 ; m-OCF 3 ; p-SR 1 ; p-N(R)(R 1A ); p-F; p-Cl; p-Br; p-CF 3 ; p-OCF 3 ; p-C(O)OR 1 ; p-OC(O)R 1 ; p-CN; p-NO 2 ; p-NC(O)R 1 ; o-C≡CC(CH 3 ) 2 OR 1 ; p-C≡CC(CH 3 ) 2 OR 1 ; p-OM, p-SM, m-C(O)OM, or p-C(O)OM wherein M is selected from Li, Na, K, 0.5 Mg, or 0.5 Ca; p-O(CH 2 ) m ZR 1 wherein m is an integer from 0 to 3 and Z is selected from O, S, —S(O)—, —SO 2 —, —OP(O)(OH)O—, —P(O)(OH)O—, or —C(O)—; p-OC(O)(CH 2 CH 2 O) r R 1 or p-O(CH 2 CH 2 O) r R 1 wherein r is an integer from 0 to 6;
g) R 1A , in each occurrence, is selected independently from: a linear or a branched alkyl with up to 10 carbon atoms; a cycloalkyl with up to 10 carbon atoms; a cycloalkenyl with up to 10 carbon atoms; benzyl; CH 2 NH 2 ; CH 2 OH; aryl; or O 2 CR, C(O)R, or C(O)OR, wherein R is H, or linear or branched alkyl with up to 10 carbon-atoms;
h) X 3 is selected from o-R 1 , m-R 1 , p-R 1 , o-OR 1 , m-OR 1 , or p-OR 1 ; or X 2 and X 3 together is a fused benzene, pyridine, dioxane, or tetrahydropyran ring;
i) either: 1) AY 1 in combination is
wherein x is 5;
wherein G is selected from NH, CH 2 or SH; or
2) A is O or NR 1 , and Y 1 is selected from:
a. (CHR 1 ) q CF 3 ;
wherein n is 1 or 2 and Q is selected from CH or N; or
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , C═O, or C═NR 1 ;
wherein W − is selected from Cl − , Br − , I − , [O 2 CCH 2 CH 2 CO 2 R 1 ] − , [O 2 CCHCHCO 2 R 1 ] − , or [O 2 CCF 3 ] − ;
wherein q is an integer from 0 to 3, L is selected from CH or N, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein q is an integer from 0 to 3, and X 6 is selected from H, 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein T is selected from CO 2 H, CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
j. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
k. C(O)Z 1 , wherein Z 1 is selected from NR 1 2 ,
wherein x is an integer from 3 to 5,
wherein t is an integer from 0 to 6;
l. (CHR 1 ) z Z 2 , wherein z is an integer from 0 to 6, and Z 2 is selected from NR 1 2 ,
wherein t is an integer from 0 to 6; or
m. (CHR 1 ) z Z 3 , wherein z is an integer from 1 to 6, and Z 3 is
wherein x is an integer from 3 to 5; and
j) either: 1) DY 2 in combination is;
wherein x is an integer from 3 to 5;
wherein G is selected from NH, CH 2 or SH; or
2) D is O or NR 1 , and Y 2 is selected from:
a. R 1 ; (CHR 1 ) q R 1 ; (CHR 1 ) q CF 3 ;
wherein n is 1 or 2 and Q is selected from CH or N;
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein W − is selected from Cl − , Br − , I − , [O 2 CCH 2 CH 2 CO 2 R 1 ] − , [O 2 CCHCHCO 2 R 1 ] − , or [O 2 CCF 3 ] − ;
wherein q is an integer from 0 to 3, L is selected from CH or N, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3 and X 1 , X 2 , and X 3 are selected as defined above;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein q is an integer from 0 to 3, and X 6 is selected from H, 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein T is selected from CO 2 H, CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
i. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6; or
j. C(O)Z 1 or (CHR 1 ) z Z 1 , wherein z is an integer from 0 to 6, and Z 1 is selected from NR 1 2 ,
wherein x is an integer from 3 to 5,
wherein t is an integer from 0 to 6.
9. A pharmaceutical composition according to claim 8 , further comprising at least one of the following:
a pharmaceutically acceptable auxiliary;
a pharmaceutically acceptable preservative;
a pharmaceutically acceptable excipient; or
any combination thereof.
10. A pharmaceutical composition according to claim 9 , wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.
11. A compound having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
a) R 1 , in each occurrence, is selected independently from H; a linear or a branched alkyl with up to 10 carbon atoms; a cycloalkyl with up to 10 carbon atoms; a cycloalkenyl with up to 10 carbon atoms; benzyl; CH 2 NH 2 ; CH 2 OH; aryl; or O 2 CR, C(O)R, or C(O)OR, wherein R is H, or linear or branched alkyl with up to 10 carbon atoms;
b) G is NR 1 or O;
c) J is CH or N;
d) n is an integer from 0 to 2;
e) X 1 is selected from o-R 1 , m-R 1 , m-OR 1 , m-OCF 3 , o-F, o-Cl, m-F, m-Cl, m-Br, m-I, m-CF 3 , m-CN, m-NO 2 , m-C(O)OR 1 , C(O)OLi, C(O)ONa, m-SO 2 R 1 , m-NC(O)R 1 , or m-SO 2 OR 1 ; or X 1 and X 2 together is a fused benzene, pyridine, dioxane, or tetrahydropyran ring;
f) X 2 is selected from o-R 1 ; p-R 1 ; p-OR 1 ; p-OCF 3 ; o-F; o-Cl; o-Br; o-I; o-CF 3 ; m-F; m-Cl; m-Br; m-I; m-CN; m-CF 3 ; m-OCF 3 ; p-SR 1 ; p-NR 1 2 ; p-F; p-Cl; p-Br; p-CF 3 ; p-OCF 3 ; p-C(O)OR 1 ; p-OC(O)R 1 ; p-CN; p-NO 2 ; p-NC(O)R 1 ; o-C≡CC(CH 3 ) 2 OR 1 ; p-C≡CC(CH 3 ) 2 OR 1 ; p-OM, p-SM, m-C(O)OM, or p-C(O)OM wherein M is selected from Li, Na, K, 0.5 Mg, or 0.5 Ca; p-O(CH 2 ) m ZR 1 wherein m is an integer from 0 to 3 and Z is selected from O, S, —S(O)—, —SO 2 —, —OP(O)(OH)O—, —P(O)(OH)O—, or —C(O)—; p-OC(O)(CH 2 CH 2 O) r R 1 or p-O(CH 2 CH 2 O) r R 1 wherein r is an integer from 0 to 6;
g) X 3 is selected from o-R 1 , m-R 1 , p-R 1 , o-OR 1 , m-OR 1 , or p-OR 1 ; or X 2 and X 3 together is a fused benzene, pyridine, dioxane, or tetrahydropyran ring;
h) either: 1) AY 1 in combination is
wherein x is 5;
wherein G is selected from NH, CH 2 or SH; or
2) A is O or NR 1 , and Y 1 is selected from:
a. (CHR 1 ) q CF 3 ;
wherein n is 1 or 2 and Q is selected from CH or N; or
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , C═O, or C═NR 1 ;
wherein W − is selected from Cl − , Br − , I − , [O 2 CCH 2 CH 2 CO 2 R 1 ] − , [O 2 CCHCHCO 2 R 1 ] − , or [O 2 CCF 3 ] − ;
wherein q is an integer from 0 to 3, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3, and U is selected from CHR 1 or CHOH;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein q is an integer from 0 to 3, and X 6 is selected from H, 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein T is selected from CO 2 H, CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
k. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NHR 1 wherein x is an integer from 1 to 6;
l. C(O)Z 1 , wherein Z 1 is selected from NR 1 2 ,
wherein x is an integer from 3 to 5,
wherein t is an integer from 0 to 6;
m. (CHR 1 ) z Z 2 , wherein z is an integer from 0 to 6, and Z 2 is selected from NHR 1 ,
wherein t is an integer from 0 to 6; or
n. (CHR 1 ) z Z 3 , wherein z is an integer from 1 to 6, and Z 3 is
wherein x is an integer from 3 to 5; and
i) either: 1) DY 2 in combination is
wherein x is an integer from 3 to 5;
wherein G is selected from NH, CH 2 or SH; or
2) D is O or NR 1 , and Y 2 is selected from:
a. R 1 ; (CHR 1 ) q R 1 ; (CHR 1 ) q CF 3 ;
wherein n is 1 or 2 and Q is selected from CH or N; or
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein W − is selected from Cl − , Br − , I − , [O 2 CCH 2 CH 2 CO 2 R 1 ] − , [O 2 CCHCHCO 2 R 1 ] − , or [O 2 CCF 3 ] − ;
wherein q is an integer from 0 to 3, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3, and U is selected from CHR 1 or CHOH;
wherein q is an integer from 0 to 3 and X 1 , X 2 , and X 3 are selected as defined above;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein q is an integer from 0 to 3, and X 6 is selected from H, 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein T is selected from CO 2 H, CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
j. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NHR 1 wherein x is an integer from 1 to 6; or
k. C(O)Z 1 or (CHR 1 ) z Z 1 , wherein z is an integer from 0 to 6, and Z 1 is selected from NHR 1 ,
wherein x is an integer from 3 to 5,
wherein t is an integer from 0 to 6;
wherein R 1A , in each occurrence, is selected independently from: a linear or a branched alkyl with up to 10 carbon atoms; a cycloalkyl with up to 10 carbon atoms; a cycloalkenyl with up to 10 carbon atoms; benzyl; CH 2 NH 2 ; CH 2 OH; aryl; or O 2 CR, C(O)R, or C(O)OR, wherein R is H, or linear or branched alkyl with up to 10 carbon atoms.
12. A compound according to claim 1 having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
1) DY 2 in combination is
wherein x is an integer from 3 to 5;
wherein G is selected from NH, CH 2 or SH; or
2) D is O or NR 1 , and Y 2 is selected from:
a. R 1 ; (CHR 1 ) q R 1 ;
wherein n is 1 or 2 and Q is selected from CH or N;
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein W − is selected from Cl − , Br − , [O 2 CCH 2 CH 2 CO 2 R 1 ] − , [O 2 CCHCHCO 2 R 1 ] − , or [O 2 CCF 3 ] − ;
wherein q is an integer from 0 to 3, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3, and U is selected from CHR 1 or CHOH;
wherein q is an integer from 0 to 3 and X 1 , X 2 , and X 3 are selected as defined above;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
h. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NHR 1 wherein x is an integer from 1 to 6; or
i. C(O)Z 1 or (CHR 1 ) z Z 1 , wherein z is an integer from 0 to 6, and Z 1 is selected from NHR 1 ,
wherein x is an integer from 3 to 5,
wherein t is 0 or 1.
13. A compound according to claim 1 having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
1) DY 2 in combination is
wherein x is an integer from 3 to 5;
wherein G is selected from NH, CH 2 or SH; or
2) D is O or NR 1 , and Y 2 is selected from:
a. R 1 ; (CHR 1 ) q R 1 ;
wherein n is 1 or 2 and Q is selected from CH or N;
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein W − is selected from Cl − , Br − , [O 2 CCH 2 CH 2 CO 2 R 1 ] − , [O 2 CCHCHCO 2 R 1 ] − , or [O 2 CCF 3 ] − ;
wherein q is an integer from 0 to 3, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3, and U is selected from CHR 1 or CHOH;
wherein q is an integer from 0 to 3 and X 1 , X 2 , and X 3 are selected as defined above;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
g. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NHR 1 wherein x is an integer from 1 to 6; or
h. C(O)Z 1 or (CHR 1 ) z Z 1 , wherein z is an integer from 0 to 6, and Z 1 is selected from NHR 1 ,
wherein x is an integer from 3 to 5,
wherein t is 0.
14. A compound according to claim 1 having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
1) AY 1 in combination is
wherein x is 5;
wherein G is selected from NH, CH 2 or SH; or
2) A is O or NR 1 , and Y 1 is selected from:
a. (CHR 1 ) q CF 3 ;
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3, and U is selected from CHR 1 or CHOH;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein q is an integer from 0 to 3, and X 6 is selected from H, 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein T is selected from CO 2 H, CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
j. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NHR 1 wherein x is an integer from 1 to 6;
k. C(O)Z 1 , wherein Z 1 is selected from NR 1 2 ,
wherein x is an integer from 3 to 5,
wherein t is 0 or 1;
l. (CHR 1 ) z Z 2 , wherein z is an integer from 0 to 6, and Z 2 is selected from NHR 1 ,
wherein t is 0 or 1; or
m. (CHR 1 ) z Z 3 , wherein z is an integer from 1 to 6, and Z 3 is
wherein x is an integer from 3 to 5.
15. A compound according to claim 1 having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
1) AY 1 in combination is
wherein x is 5;
wherein G is selected from NH, CH 2 or SH; or
2) A is O or NR 1 , and Y 1 is selected from:
a. (CHR 1 ) q CF 3 ;
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3, and U is selected from CHR 1 or CHOH;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein q is an integer from 0 to 3, and X 6 is selected from H, 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein T is selected from CO 2 H, CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
j. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NHR 1 wherein x is an integer from 1 to 6;
k. C(O)Z 1 , wherein Z 1 is selected from NR 1 2 ,
wherein x is an integer from 3 to 5,
wherein t is 0;
l. (CHR 1 ) z Z 2 , wherein z is an integer from 1 to 6, and Z 2 is selected from NHR 1 ,
wherein t is 0; or
m. (CHR 1 ) z Z 3 , wherein z is an integer from 1 to 6, and Z 3 is
wherein x is an integer from 3 to 5.
16. A compound according to claim 1 having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
a) X 1 is selected from o-R 1 , m-R 1 , m-OR 1 , m-OCF 3 , o-F, o-Cl, m-F, m-Cl, m-Br, m-I, m-CF 3 , m-CN, m-NO 2 , m-C(O)OR 1 , C(O)OLi, C(O)ONa, m-SO 2 R 1 , m-NC(O)R 1 , or m-SO 2 OR 1 ; or X 1 and X 2 together is a fused benzene, pyridine, dioxane, or tetrahydropyran ring;
b) X 2 is selected from o-R 1 ; p-R 1 ; p-OR 1 ; p-OCF 3 ; o-F; o-Cl; o-Br; o-I; o-CF 3 ; m-F; m-Cl; m-Br; m-I; m-CN; m-CF 3 ; m-OCF 3 ; p-SR 1 ; p-N(R)(R 1A ); p-F; p-Cl; p-Br; p-CF 3 ; p-OCF 3 ; p-C(O)OR 1 ; p-OC(O)R 1 ; p-CN; p-NO 2 ; p-NC(O)R 1 ; p-OM, p-SM, m-C(O)OM, or p-C(O)OM wherein M is selected from Li, Na, K, 0.5 Mg, or 0.5 Ca; p-O(CH 2 ) m ZR 1 wherein m is an integer from 0 to 3 and Z is selected from O, S, —S(O)—, —SO 2 —, —OP(O)(OH)O—, —P(O)(OH)O—, or —C(O)—; p-OC(O)(CH 2 CH 2 O) r R 1 or p-O(CH 2 CH 2 O) r R 1 wherein r is 0 or 1; and
c) X 3 is selected from o-R 1 , m-R 1 , p-R 1 , o-OR 1 , m-OR 1 , or p-OR 1 ; or X 2 and X 3 together is a fused benzene, dioxane, or tetrahydropyran ring.
17. A compound according to claim 1 having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
a) X 1 is selected from o-R 1 , m-R 1 , m-OR 1 , m-OCF 3 , o-F, o-Cl, m-F, m-Cl, m-Br, m-I, m-CF 3 , m-CN, m-NO 2 , m-C(O)OR 1 , C(O)OLi, C(O)ONa, or m-SO 2 OR 1 ; or X 1 and X 2 together is a fused benzene, pyridine, dioxane, or tetrahydropyran ring;
b) X 2 is selected from o-R 1 ; p-R 1 ; p-OR 1 ; p-OCF 3 ; o-F; o-Cl; o-Br; o-I; o-CF 3 ; m-F; m-Cl; m-Br; m-I; m-CN; m-CF 3 ; m-OCF 3 ; p-SR 1 ; p-N(R 1 )(R 1A ); p-F; p-Cl; p-Br; p-CF 3 ; p-OCF 3 ; p-C(O)OR 1 ; p-OC(O)R 1 ; p-OM, p-SM, m-C(O)OM, or p-C(O)OM wherein M is selected from Li, Na, K, 0.5 Mg, or 0.5 Ca; or p-O(CH 2 ) m ZR 1 wherein m is an integer from 0 to 3 and Z is selected from O, S, —S(O)—, —SO 2 —, —OP(O)(OH)O—, —P(O)(OH)O—, or —C(O)—; and
c) X 3 is selected from o-R 1 , m-R 1 , p-R 1 , o-OR 1 , m-OR 1 , or p-OR 1 .
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the formula:
or a stereoisomer, an enantiomer, a diastereomer, a racemic mixture, a salt, or any combination thereof, wherein:
a) R 1 , in each occurrence, is selected independently from H; a linear or a branched alkyl with up to 10 carbon atoms; a cycloalkyl with up to 10 carbon atoms; a cycloalkenyl with up to 10 carbon atoms; benzyl; CH 2 NH 2 ; CH 2 OH; aryl; or O 2 CR, C(O)R, or C(O)OR, wherein R is H, or linear or branched alkyl with up to 10 carbon atoms;
b) G is NR 1 or O;
c) J is CH or N;
d) n is an integer from 0 to 2;
e) X 1 is selected from o-R 1 , m-R 1 , m-OR 1 , m-OCF 3 , o-F, o-Cl, m-F, m-Cl, m-Br, m-I, m-CF 3 , m-CN, m-NO 2 , m-C(O)OR 1 , C(O)OLi, C(O)ONa, m-SO 2 R 1 , m-NC(O)R 1 , or m-SO 2 OR 1 ; or X 1 and X 2 together is a fused benzene, pyridine, dioxane, or tetrahydropyran ring;
f) X 2 is selected from o-R 1 ; p-R 1 ; p-OR 1 ; p-OCF 3 ; o-F; o-Cl; o-Br; o-I; o-CF 3 ; m-F; m-Cl; m-Br; m-I; m-CN; m-CF 3 ; m-OCF 3 ; p-SR 1 ; p-NR 1 2 ; p-F; p-Cl; p-Br; p-CF 3 ; p-OCF 3 ; p-C(O)OR 1 ; p-OC(O)R 1 ; p-CN; p-NO 2 ; p-NC(O)R 1 ; o-C≡CC(CH 3 ) 2 OR 1 ; p-C≡CC(CH 3 ) 2 OR 1 ; p-OM, p-SM, m-C(O)OM, or p-C(O)OM wherein M is selected from Li, Na, K, 0.5 Mg, or 0.5 Ca; p-O(CH 2 ) m ZR 1 wherein m is an integer from 0 to 3 and Z is selected from O, S, —S(O)—, —SO 2 —, —OP(O)(OH)O—, —P(O)(OH)O—, or —C(O)—; p-OC(O)(CH 2 CH 2 O) r R 1 or p-O(CH 2 CH 2 O) r R 1 wherein r is an integer from 0 to 6;
g) X 3 is selected from o-R 1 , m-R 1 , p-R 1 , o-OR 1 , m-OR 1 , or p-OR 1 ; or X 2 and X 3 together is a fused benzene, pyridine, dioxane, or tetrahydropyran ring;
h) either: 1) AY 1 in combination is
wherein x is 5;
wherein G is selected from NH, CH 2 or SH; or
2) A is O or NR 1 , and Y 1 is selected from:
a. (CHR 1 ) q CF 3 ;
wherein n is 1 or 2 and Q is selected from CH or N; or
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , O, S, C═O, or C═NR 1 ;
wherein q is an integer from 0 to 3; E is selected from NR 1A , C═O, or C═NR 1 ;
wherein W − is selected from Cl − , Br − , I − , [O 2 CCH 2 CH 2 CO 2 R 1 ] − , [O 2 CCHCHCO 2 R 1 ] − , or [O 2 CCF 3 ] − ;
wherein q is an integer from 0 to 3, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3, and U is selected from CHR 1 or CHOH;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein q is an integer from 0 to 3, and X 6 is selected from H, 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein T is selected from CO 2 H, CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
k. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NHR 1 wherein x is an integer from 1 to 6;
l. C(O)Z 1 , wherein Z 1 is selected from NR 1 2 ,
wherein x is an integer from 3 to 5,
wherein t is an integer from 0 to 6;
m. (CHR 1 ) z Z 2 , wherein z is an integer from 0 to 6, and Z 2 is selected from NHR 1 ,
wherein t is an integer from 0 to 6; or
n. (CHR 1 ) z Z 3 , wherein z is an integer from 1 to 6, and Z 3 is
wherein x is an integer from 3 to 5; and
i) either: 1) DY 2 in combination is
wherein x is an integer from 3 to
wherein G is selected from NH, CH 2 or SH; or
2) D is O or NR 1 , and Y 2 is selected from:
a. R 1 ; (CHR 1 ) q R 1 ; (CHR 1 ) q CF 3 ;
wherein n is 1 or 2 and Q is selected from CH or N; or
wherein q, in each occurrence, is an integer from 0 to 3 and E, in each occurrence, is selected independently from NR 1 , O, S, C═O, or C═NR 1 ;
wherein W − is selected from Cl − , Br − , I − , [O 2 CCH 2 CH 2 CO 2 R 1 ] − , [O 2 CCHCHCO 2 R 1 ] − , or [O 2 CCF 3 ] − ;
wherein q is an integer from 0 to 3, and U is selected from O, NR 1 , S, SO 2 , CHR 1 , or CHOH;
wherein q is an integer from 0 to 3, and U is selected from CHR 1 or CHOH;
wherein q is an integer from 0 to 3 and X 1 , X 2 , and X 3 are selected as defined above;
wherein q is an integer from 0 to 3, and X 4 is selected from H, 2-R 1 , 3-R 1 , 2-OH, 3-OH, 2-NH 2 , or 3-NH 2 ;
wherein q is an integer from 0 to 3, and X 5 is selected from 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein q is an integer from 0 to 3, and X 6 is selected from H, 2-R 1 , 3-R 1 , 4-R 1 , 2-OH, 3-OH, 4-OH, 2-NH 2 , 3-NH 2 , or 4-NH 2 ;
wherein T is selected from CO 2 H, CH 2 OH, or (CHR 1 ) x NR 1 2 wherein x is an integer from 1 to 6;
j. CH 2 R 1 , CH 2 CF 3 , C(O)CHR 1 NH 2 , CHR 1 CH 2 OH, or (CHR 1 ) x NHR 1 wherein x is an integer from 1 to 6; or
k. C(O)Z 1 or (CHR 1 ) z Z 1 , wherein z is an integer from 0 to 6, and Z 1 is selected from NHR 1 ,
wherein x is an integer from 3 to 5,
wherein t is an integer from 0 to 6;
wherein R 1A , in each occurrence, is selected independently from: a linear or a branched alkyl with up to 10 carbon atoms; a cycloalkyl with up to 10 carbon atoms; a cycloalkenyl with up to 10 carbon atoms; benzyl; CH 2 NH 2 ; CH 2 OH; aryl; or O 2 CR, C(O)R, or C(O)OR, wherein R is H, or linear or branched alkyl with up to 10 carbon atoms.
19. A pharmaceutical composition according to claim 18 , further comprising at least one of the following:
a pharmaceutically acceptable auxiliary;
a pharmaceutically acceptable preservative;
a pharmaceutically acceptable excipient; or
any combination thereof.
20. A pharmaceutical composition according to claim 19 , wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.