1. A compound having the structure of Formula I:
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R\u2032;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(Rt);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(Rt);
m is 0 or 1;
n is 0, 1, 2, or 3; and
p is 0, 1, 2, 3, or 4;
and its pharmaceutically acceptable esters and salts thereof;
with the proviso that the compound does not have the structure of Formula A
2. The compound of claim 1, having the stereochemistry of Formula IA:
3. A compound having the structure of Formula II:
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)q(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(Rt);
n is 0, 1, 2 or 3; and
p is 0, 1, 2, 3 or 4;
and its pharmaceutically acceptable esters and salts thereof.
4. The compound of claim 3 having the stereochemistry of Formula IIA:
5. A compound of Formula III:
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)jCONH2R\u2032, or (CH2)jCOOR\u2032 where j is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R7 is H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2014R\u2032, halogen, \u2014COOR\u2032, \u2014COOCH2R\u2032, \u2014C(R)2\u2014COOCH2C\u2550CR\u2032, \u2014COCH2R\u2032, \u2014C(R)2\u2014COCH2C\u2550CR\u2032, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylalkenyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkylalkenyl, optionally substituted heteroalkyl, optionally substituted heteroalkylalkenyl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, or optionally substituted cycloheteroalkyl;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2, or 3; and
p is 0, 1, 2, 3, or 4;
and its pharmaceutically acceptable esters and salts thereof.
6. The compound of claim 5 having the stereochemistry of Formula IIIA
7. The compound of Formula III, which is
8. A compound of Formula W
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014W, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb, when the ring carbon to which R4 is attached is unsaturated;
X1, X2, and X3, are independently C(R1)2, O, S, or N(R1);
Y is O or N(Rt);
n is 0, 1, 2, or 3;
and j is 1 or 2, with the proviso that when j is 2, and X1, X2, and X3 are all O, then n is not 0;
and its pharmaceutically acceptable esters and salts thereof.
9. The compound of claim 8, having the stereochemistry of Formula IVA:
10. The compound of claim 9, which is
11. A compound of Formula V or Formula VI
wherein
R1, R2, and R5 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R6 is independently H, \u2014OH or R;
R8 is H, OH, or R;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
j and k are independently 1 or 2;
p is chosen independently for each ring to be 0, 1, 2, or 3;
B, D, E, G, and K are independently CRaRb, C\u2550O, H, O, S, or NR\u2032, where Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R\u2032; Rc and Rd are independently H, alkyl, alkenyl or alkynyl, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
optionally A is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally B is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally D is linked with K or G to forma substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally E is linked with B, D, K, or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally E is linked with B and G or D and K to form a substituted or unsubstituted bicyclic ring of 7-14 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally K is linked with B and E to form a substituted or unsubstituted bicyclic ring of 7-14 members having 0, 1, 2, 3, or 4 heteroatoms; and wherein the linker linking any of A, B, D, E, K or G comprises two to seven C(R)2 groups, and each C(R)2 may be optionally be substituted by a hetero atom, or \u2014C(O)\u2014;
and its pharmaceutically acceptable salts and esters thereof.
12. The compound of claim 11 having the stereochemistry of Formula VA:
13. The compound of claim 11 having the stereochemistry of Formula VIA:
14. The compound of claim 11 which is:
and their pharmaceutically acceptable salts and esters thereof.
15. A pharmaceutical composition comprising a compound of Formula I, II, III, IV, V or VI and a pharmaceutically acceptable excipient, where Formula I, II, III, V and VI are the following:
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)q\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
m is 0 or 1;
p is 0, 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R\u2032;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2 or 3; and
p is 0, 1, 2, 3 or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R7 is H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2014R\u2032, halogen, \u2014COOR\u2032, \u2014COOCH2R\u2032, \u2014C(R)2\u2014COOCH2C\u2550CR\u2032, \u2014COCH2R\u2032, \u2014C(R)2\u2014COCH2C\u2550CR\u2032, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylalkenyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkylalkenyl, optionally substituted heteroalkyl, optionally substituted heteroalkylalkenyl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, or optionally substituted cycloheteroalkyl;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2, or 3; and
p is 0, 1, 2, 3, or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)q\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb, when the ring carbon to which R4 is attached is unsaturated;
X1, X2, and X3, are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2, or 3;
and j is 1 or 2, with the proviso that when j is 2, and X1, X2, and X3 are all O, then n is not 0;
or
wherein
R1, R2, and R5 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R6 is independently H, \u2014OH or R;
R8 is H, OH, or R;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(Rt);
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(Rt);
Y is O or N(R1);
j and k are independently 1 or 2;
p is chosen independently for each ring to be 0, 1, 2, or 3;
B, D, E, G, and K are independently CRaRb, C\u2550O, H, O, S, or NR\u2032, where Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R; Rc and Rd are independently H, alkyl, alkenyl or alkynyl, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
optionally A is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally B is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally D is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally E is linked with B, D, K, or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally E is linked with B and G or D and K to form a substituted or unsubstituted bicyclic ring of 7-14 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally K is linked with B and E to form a substituted or unsubstituted bicyclic ring of 7-14 members having 0, 1, 2, 3, or 4 heteroatoms; and wherein the linker linking any of A, B, D, E, K or G comprises two to seven C(R)2 groups, and each C(R)2 may be optionally substituted by a hetero atom, or \u2014C(O)\u2014 and its pharmaceutically acceptable salts and esters thereof.
16. The pharmaceutical composition further comprising a second therapeutic agent having immunosuppressive activity via a mechanism distinct from that of bryostatin.
17. A method of treatment for a disorder responsive to byrostatin therapy, comprising administering to a mammal in need thereof an effective amount of a compound or pharmaceutically acceptable ester or salt of Formula I, II, III, IV, V, or VI, where Formula I, II, III, V and VI are the following:
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONR\u2032Rd or R;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
m is 0 or 1;
n is 0, 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2 or 3; and
p is 0, 1, 2, 3 or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)q\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R7 is H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2014R\u2032, halogen, \u2014COOR\u2032, \u2014COOCH2R\u2032, \u2014C(R)2\u2014COOCH2C\u2550CR\u2032, \u2014COCH2R\u2032, \u2014C(R)2\u2014COCH2C\u2550CR\u2032, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylalkenyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkylalkenyl, optionally substituted heteroalkyl, optionally substituted heteroalkylalkenyl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, or optionally substituted cycloheteroalkyl;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2, or 3; and
p is 0, 1, 2, 3, or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOK’, \u2014CONRcRd or R\u2032;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb, when the ring carbon to which R4 is attached is unsaturated;
X1, X2, and X3, are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2, or 3;
and j is 1 or 2, with the proviso that when j is 2, and X1, X2, and X3 are all O, then n is not 0;
or
wherein
R1, R2, and R5 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted awl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R6 is independently H, \u2014OH or R\u2032;
R8 is H, OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
j and k are independently 1 or 2;
p is chosen independently for each ring to be 0, 1, 2, or 3;
B, D, E, G, and K are independently CRaRb, C\u2550O, H, O, S, or NR\u2032, where Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R\u2032; Rc and Rd are independently H, alkyl, alkenyl or alkynyl, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
optionally A is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally B is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally D is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally E is linked with B, D, K, or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally E is linked with B and G or D and K to form a substituted or unsubstituted bicyclic ring of 7-14 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally K is linked with B and E to form a substituted or unsubstituted bicyclic ring of 7-14 members having 0, 1, 2, 3, or 4 heteroatoms;
and its pharmaceutically acceptable salts and esters thereof.
18. The method of claim 17 wherein said compound is administered orally, parenterally, intramuscularly, intravenously, intradermally, subcutaneously, transdermally, bronchially, pharyngolaryngeally, intranasally, topically, rectally, intracisternally, intravaginally, intraperitoneally, bucally, or intrathecally.
19. The method of claim 17 wherein said compound is administered in a formulation further comprising an excipient.
20. The method of claim 17 wherein said compound is administered as a solid, a powder, a liquid, an aerosol, a gel, an ointment, a suppository, adermal patch, a suspension, microencapsulated matrix, liposomes, emulsions or incorporated into or onto a stent.
21. The method of claim 17 wherein said compound is administered at least once a day.
22. The method of treatment of claim 17 further comprising the step of co-administering a second agent having therapeutic activity via an immunosuppressive mechanism distinct from that of byrostatin.
23. A method of treatment comprising administering to a mammal suffering from a hyperproliferative cellular disorder or an immune related disorder a pharmaceutically effective amount of a compound or pharmaceutically acceptable ester or salt of Formula I, II, III, IV, V, or VI, where Formula I, II, III, V and VI are the following:
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRh when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
m is 0 or 1;
n is 0, 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted awl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2 or 3; and
p is 0, 1, 2, 3 or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2), 0(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted awl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R7 is H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2014R\u2032, halogen, \u2014COOR\u2032, \u2014COOCH2R\u2032, \u2014C(R)2\u2014COOCH2C\u2550CR\u2032, \u2014COCH2R\u2032, \u2014C(R)2\u2014COCH2C\u2550CR\u2032, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylalkenyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkylalkenyl, optionally substituted heteroalkyl, optionally substituted heteroalkylalkenyl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, or optionally substituted cycloheteroalkyl;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2, or 3; and
p is 0, 1, 2, 3, or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)q\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb, when the ring carbon to which R4 is attached is unsaturated;
X1, X2, and X3, are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2, or 3;
and j is 1 or 2, with the proviso that when j is 2, and X1, X2, and X3 are all O, then n is not 0;
or
wherein
R1, R2, and R5 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R6 is independently H, \u2014OH or R;
R8 is H, OH, or R;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
j and k are independently 1 or 2;
p is chosen independently for each ring to be 0, 1, 2, or 3;
B, D, E, G, and K are independently CRaRb, C\u2550O, H, O, S, or NR\u2032, where Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R; Rc and Rd are independently H, alkyl, alkenyl or alkynyl, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
optionally A is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally B is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally D is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally E is linked with B, D, K, or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally E is linked with B and G or D and K to form a substituted or unsubstituted bicyclic ring of 7-14 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally K is linked with B and E to form a substituted or unsubstituted bicyclic ring of 7-14 members having 0, 1, 2, 3, or 4 heteroatoms; and wherein the linker linking any of A, B, D, E, K or G comprises two to seven C(R)2 groups, and each C(R)2 may be optionally substituted by a hetero atom, or \u2014C(O)\u2014;
and its pharmaceutically acceptable salts and esters thereof.
24. The method of treatment of claim 23, further comprising the step of co-administering a second agent having therapeutic activity via an immunosuppressive mechanism distinct from that of byrostatin.
25. The method of treatment of claim 23 further comprising the step of co-administering a second agent having an immunosuppressive mechanism of action.
26. The method of claim 23 wherein said compound is administered orally, parenterally, intramuscularly, intravenously, intradermally, subcutaneously, transdermally, bronchially, pharyngolaryngeally, intranasally, topically, rectally, intracisternally, intravaginally, intraperitoneally, bucally, or intrathecally.
27. A method of treating a mammal suffering from a disorder mediated by protein kinase C activity comprising administering to said mammal a therapeutically effective amount of a compound or pharmaceutically acceptable ester or salt of Formula I, II, III, IV, V, or VI, where Formula I, II, III, V and VI are the following:
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHR\u2032Rd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(Rt);
n is 0 or 1;
n is 0, 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014W, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is H, \u2014OH, or O(CO)R\u2032;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R\u2032;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2 or 3; and
p is 0, 1, 2, 3 or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R7 is H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2014R\u2032, halogen, \u2014COOR\u2032, \u2014COOCH2R\u2032, \u2014C(R)2\u2014COOCH2C\u2550CR\u2032, \u2014COCH2R\u2032, \u2014C(R)2\u2014COCH2C\u2550CR\u2032, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylalkenyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkylalkenyl, optionally substituted heteroalkyl, optionally substituted heteroalkylalkenyl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, or optionally substituted cycloheteroalkyl;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2, or 3; and
p is 0, 1, 2, 3, or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb, when the ring carbon to which R4 is attached is unsaturated;
X1, X2, and X3, are independently C(R1)2, O, S, or N(R1);
Y is O or N(Rt);
n is 0, 1, 2, or 3;
and j is 1 or 2, with the proviso that when j is 2, and X1, X2, and X3 are all O, then n is not 0;
or
wherein
R1, R2, and R5 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014W, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted awl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R6 is independently H, \u2014OH or R;
R8 is H, OH, or R;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
j and k are independently 1 or 2;
p is chosen independently for each ring to be 0, 1, 2, or 3;
B, D, E, G, and K are independently CRaRb, C\u2550O, H, O, S, or NR\u2032, where Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R\u2032; Rc and Rd are independently H, alkyl, alkenyl or alkynyl, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
optionally A is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally B is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally D is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally E is linked with B, D, K, or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally E is linked with B and G or D and K to form a substituted or unsubstituted bicyclic ring of 7-14 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally K is linked with B and E to form a substituted or unsubstituted bicyclic ring of 7-14 members having 0, 1, 2, 3, or 4 heteroatoms; and, wherein the linker linking any of A, B, D, E, K or G comprises two to seven C(R)2 groups, and each C(R)2 may be optionally substituted by a hetero atom, or \u2014C(O)\u2014;
and its pharmaceutically acceptable salts and esters thereof.
28. A method of treating a mammal suffering from a hyperproliferative cellular disorder or an immune-related disorder comprising administering a therapeutically effective amount of a compound of Formula I, I, III, IV, V or VI, or its pharmaceutically acceptable salts, to said mammal, where Formula I, II, III, V and VI are the following:
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(Rt);
Y is O or N(R1);
m is 0 or 1;
n is 0, 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R\u2032;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRh when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2 or 3; and
p is 0, 1, 2, 3 or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2), 0(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted awl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R7 is H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2014R\u2032, halogen, \u2014COOR\u2032, \u2014COOCH2R\u2032, \u2014C(R)2\u2014COOCH2C\u2550CR\u2032, \u2014COCH2R\u2032, \u2014C(R)2\u2014COCH2C\u2550CR\u2032, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylalkenyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkylalkenyl, optionally substituted heteroalkyl, optionally substituted heteroalkylalkenyl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, or optionally substituted cycloheteroalkyl;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb when the ring carbon to which R4 is attached is unsaturated;
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2, or 3; and
p is 0, 1, 2, 3, or 4;
or
wherein:
R1 and R2 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R3 is independently H, \u2014OH, or O(CO)R;
R4 is \u2550CRaRb or CHRcRd;
Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R;
Rc and Rd are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, (CH2)tCONH2R\u2032, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
R6 is H, \u2014OH, or R\u2032;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
the ring containing A is optionally partially unsaturated, provided that R4 is not \u2550CRaRb, when the ring carbon to which R4 is attached is unsaturated;
X1, X2, and X3, are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
n is 0, 1, 2, or 3;
and j is 1 or 2, with the proviso that when j is 2, and X1, X2, and X3 are all O, then n is not 0;
or
wherein
R1, R2, and R5 are independently H, \u2014OH, \u2014OR\u2032, \u2014NH2, \u2014NR\u2032, \u2550CH2, \u2550CHR\u2032, \u2550O, \u2014R\u2032, halogen, \u2014C(R)2\u2014COOR\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014R\u2032, \u2014C(R)2\u2014COO\u2014C(R)2\u2014C\u2550CR\u2032, \u2014(CH2)qO(O)CR\u2032 or \u2014(CH2)qCO2-haloalkyl where q is 0, 1, 2, 3, 4 or 5, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkyl amino, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkylthio, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl, providing that valency is not violated;
R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl);
R6 is independently H, \u2014OH or R;
R8 is H, OH, or R;
R\u2032 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, optionally substituted alkyl(cycloheteroalkyl), (CO)R\u2033, or (COO)R\u2033;
R\u2033 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heteroalkyl, or optionally substituted alkyl(cycloheteroalkyl);
A is C(R1)2, O, S, or N(R1);
X1, X2, X3, and X4 are independently C(R1)2, O, S, or N(R1);
Y is O or N(R1);
j and k are independently 1 or 2;
p is chosen independently for each ring to be 0, 1, 2, or 3;
B, D, E, G, and K are independently CRaRb, C\u2550O, H, O, S, or NR\u2032, where Ra and Rb are independently H, \u2014COOR\u2032, \u2014CONRcRd or R; Rc and Rd are independently H, alkyl, alkenyl or alkynyl, or (CH2)tCOOR\u2032 where t is 1, 2 or 3;
optionally A is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally B is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally D is linked with K or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally E is linked with B, D, K, or G to form a substituted or unsubstituted monocyclic or bicyclic ring of 5-10 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally E is linked with B and G or D and K to form a substituted or unsubstituted bicyclic ring of 7-14 members having 0, 1, 2, 3, or 4 heteroatoms;
optionally K is linked with B and E to form a substituted or unsubstituted bicyclic ring of 7-14 members having 0, 1, 2, 3, or 4 heteroatoms; and wherein the linker linking any of A, B, D, E, K or G comprises two to seven C(R)2 groups, and each C(R)2 may be optionally substituted by a hetero atom, or \u2014C(O)\u2014;
and its pharmaceutically acceptable salts and esters thereof.
29. The method of claim 28 wherein the hyperproliferative cellular disorders or immune related disorders are tumors and cancers; unwanted angiogenesis, psoriasis, blood vessel proliferation disorders, fibrotic disorders, autoimmune disorders, disorders brought about by abnormal proliferation of mesangial cells, such as glomerulonephritis, diabetic nephropathy, neuropathic pain, malignant nephrosclerosis, thrombotic micro-angiopathy syndromes, transplant rejection, and glomerulopathies, rheumatoid arthritis, ischemic heart disease, post-dialysis syndrome, leukemia, vasculitis; lipid histiocytosis, septic shock, inflammation, acute and chronic nephropathies, arterial restenosis, autoimmune diseases, or ocular diseases with retinal vessel proliferation.
30. A method of manufacture of a compound of Formula VIII comprising the steps of:
(a) hydroxylating asymmetrically a compound of Formula VII to form a diol;
(b) acetalizing said diol; and
(c) deprotecting a primary alcohol and oxidizing said primary alcohol to form an acid of Formula VIII.
31. A method of manufacture of a compound of Formula IX, comprising the steps of:
(a) reacting a compound of Formula VIII with a compound of Formula X to form an ester; and
(b) deprotecting and macrotransacetalizing said ester with hydrogen fluoridepyridine to form a compound of Formula IX.
32. A method of manufacture of a compound of Formula XI, comprising the steps of:
(a) reacting a compound of Formula XIII with a compound of Formula X to form an ester; and
(b) deprotecting and macrotransacetalizing said ester with hydrogen fluoridepyridine to form a compound of Formula XII.
33. A method of manufacture of a compound of Formula XIV, comprising the steps of:
(a) reacting a compound of Formula XV with a compound of Formula X to form an ester; and
(b) deprotecting and macrotransacetalizing said ester with hydrogen fluoridepyridine to form a compound of Formula XIV.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method for enabling a capability of a terminal in a device management system including a server capable of at least one of enabling and disabling capabilities of the terminal, the method comprising the steps of:
determining if a condition has been met for requesting enablement of a disabled capability of the terminal;
transmitting a request message to the server including information related to the condition being met, based on a determination that the condition has been met; and
receiving a control command for the disabled capability from the server to process the control command.
2. The method as claimed in claim 1, wherein the request message includes a Device Management (DM) message.
3. The method as claimed in claim 1, wherein the request message includes a Generic Alert message.
4. The method as claimed in claim 3, wherein the request message includes a Uniform Resource Identifier (URI) indicating a location on a DM tree of a node including additional information used for requesting enablement of the disabled capability.
5. The method as claimed in claim 3, wherein the Generic Alert message includes data indicating additional information used for requesting enablement of the disabled capability.
6. The method as claimed in claim 1, wherein the condition for requesting enablement of the disabled capability is met if a request is made by a user.
7. The method as claimed in claim 1, wherein the condition for requesting enablement of the disabled capability is automatically met when one or more preset requirements are met.
8. The method as claimed in claim 7, wherein the one or more preset requirements include a terminal exiting a control area and an occurrence of an emergency communication.
9. The method as claimed in claim 1, further comprising a step of including an authorization code for requesting the enablement of the disabled capability in the request message.
10. A device management system for enabling a capability of a terminal, comprising:
a server for at least one of enabling and disabling capabilities of the terminal; and
the terminal for transmitting a request message including information related to an enablement request to the server when a condition has been met for requesting enablement of a disabled capability, for receiving a control command for the disabled capability from the server, and for processing the control command.
11. The device management system as claimed in claim 10, wherein the request message includes a Device Management (DM) message.
12. The device management system as claimed in claim 10, wherein the request message includes a Generic Alert message.
13. The device management system as claimed in claim 12, wherein the request message includes a Uniform Resource Identifier (URI) indicating a location on a DM tree of a node including additional information used for requesting enablement of the disabled capability.
14. The device management system as claimed in claim 12, wherein the Generic Alert message includes data indicating additional information used for requesting enablement of the disabled capability.
15. The device management system as claimed in claim 10, wherein the condition for requesting enablement of the disabled capability is met when a request is made by a user.
16. The device management system as claimed in claim 10, wherein the condition for requesting enablement of the disabled capability is automatically met when one or more preset requirements are met.
17. The device management system as claimed in claim 16, wherein the one or more preset requirements include a terminal exiting a control area and an occurrence of an emergency communication.
18. The device management system as claimed in claim 10, wherein the terminal puts an authorization code for authorizing the enablement of the disabled capability in the request message.
19. The method as claimed in claim 1, wherein the enablement request includes a message requesting the enablement of every capability of the terminal.
20. The device management system as claimed in claim 10, wherein the enablement request is a message requesting the enablement of every capability of the terminal.
21. A terminal for enabling a disabled capability in a device management system including a server for at least one of enabling and disabling capabilities of the terminal, the terminal comprising:
a device capability enablement determining unit for determining if a condition has been met for requesting enablement of the disabled capability of the terminal; and
a DM client for receiving a notification of the condition being met for requesting enablement of the disabled capability from the device capability enablement determining unit when the condition has been met, for generating a request message including information related to the condition being met, and for transmitting the generated request message to the server.
22. The terminal as claimed in claim 21, wherein the request message includes a Device Management (DM) message.
23. The terminal as claimed in claim 21, wherein the request message includes a Generic Alert message.
24. The terminal as claimed in claim 21, wherein the request message includes a Uniform Resource Identifier (URI) indicating a location on a DM tree of a node including additional information used for requesting enablement of the disabled capability.
25. A server for managing a capability of a terminal in a device management system, comprising:
an enablement request processing unit for receiving a request message requesting an enablement of a capability of the terminal from the terminal;
a device capability at least one of enablement and disablement determining unit for determining whether or not to enable the capability when receiving the request message; and
a device capability at least one of enablement and disablement commanding unit for generating a command for controlling the capability based on a determination result in the device capability at least one of enablement and disablement determining unit regarding whether or not to allow the enablement of the capability, to transmit the generated command to the terminal.