WO2005007123A2 - Pin1-modulating compounds and methods of use thereof - Google Patents

Pin1-modulating compounds and methods of use thereof Download PDF

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Publication number
WO2005007123A2
WO2005007123A2 PCT/US2004/023399 US2004023399W WO2005007123A2 WO 2005007123 A2 WO2005007123 A2 WO 2005007123A2 US 2004023399 W US2004023399 W US 2004023399W WO 2005007123 A2 WO2005007123 A2 WO 2005007123A2
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group
moφholino
combination
amides
esters
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PCT/US2004/023399
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French (fr)
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WO2005007123A3 (en
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Robert K. Suto
Timothy D. Mckee
Thomas Tibbitts
Janusz M. Sowadski
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Pintex Pharmaceuticals, Inc.
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Publication of WO2005007123A2 publication Critical patent/WO2005007123A2/en
Publication of WO2005007123A3 publication Critical patent/WO2005007123A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate

Definitions

  • PTZ-075-5 entitled "Pinl -Modulating Compounds and Methods of Use Thereof, filed June 10, 2004.
  • This application is related to U.S. Provisional Application No. 60/451,838, attorney docket no. PTZ-046-2, entitled “Pinl -Modulating Compounds and Methods of Use Thereof, filed March 3, 2003;
  • U.S. Provisional Application No. 60/361,206 attorney docket no. PTZ-035-1, filed March 1, 2002, entitled “Pinl -Modulating Compounds and Methods of Use Thereof;
  • PTZ-037-1 entitled “Methods of Treating Pinl Associated Disorders”
  • U.S. Provisional Application No. 60/451,807 attorney docket no. PTZ-034- 2, entitled “Pinl -Modulating Compounds and Methods of Use Thereof, filed March 3, 2003
  • U.S. Provisional Application 60/469,546, attorney docket no. BIZ-046-2 entitled “Pinl Ablated Animal Model for Neurodegenerative Diseases", filed May 8, 2003
  • PPIases peptidyl-prolyl cis-frans isomerases
  • rotamases a family of ubiquitous enzymes that catalyze the cis/trans isomerization ofthe peptide bond on the N-terminal side of proline residues in proteins (Hunter, Cell 92:141-142, 1998).
  • PPIases are divided into three classes, cyclophilins (Cyps), FK-506 binding proteins (FKBPs) and the Pinl/parvulin class.
  • Cyclophilins and FKBPs are distinguished by their ability to bind the clinically immunosuppressive drugs cyclosporin and FK506, respectively (Schreiber, Science 251:283-7, 1991; Hunter, supra). Upon binding of these drugs, there are two common outcomes: inhibition ofthe PPIase activity and inhibition ofthe common target calcineurin.
  • the inhibition of calcineurin phosphatase activity prevents lymphocytes from responding to antigen-induced mitogenic signals, thus resulting in i munusuppression.
  • the inhibition ofthe PPIase activity is apparently unrelated to the immunosuppressive property ofthe drug PPIase complexes.
  • Pinl is a highly conserved protein that catalyzes the isomerization of only phosphorylated Ser/Thr-Pro bonds (Rananathan, R. et al. (1997) Cell 89:875-86; Yaffe, et al. 1997, Science 278:1957-1960; Shen, et al. 1998,Genes Dev.
  • Pinl contains an N-terminal WW domain, which functions as a phosphorylated Ser/Thre-Pro binding module (Sudol, M. (1996) Prog. Biophys. Mol. Biol. 65:113-32).
  • This phosphorylation-dependent interaction targets Pinl to a subset of phosphorylated substrates, including Cdc25, Wee 1, Mytl, Tau-Rad4, and the C-terminal domain of RNA polymerase II large domain (Crenshaw, D.G., et al. (1998) Embo. J. 17:1315-27; Shen, M. (1998) Genes Dev. 12:706-20; Wells, NJ. (1999) J. Cell. Sci. 112: 3861-71).
  • Pinl activity is essential for cell growth; depletion or mutations of Pinl cause growth arrest, affect cell cycle checkpoints and induce premature mitotic entry, mitotic arrest and apoptosis in human tumor cells, yeast or Xenopus extracts (Lu, et al. 1996, Nature 380:544-547; Winkler, et al. 200, Science 287:1644-1647; Hani, et al. 1999. J. Biol. Chem. 274:108-116).
  • Pinl is dramatically misexpressed in human cancer samples and the total level or concentration of Pinl are correlated with the aggressiveness of tumors.
  • Pinl antisense polynucleotides or genetic depletion kills human and yeast dividing cells by inducing premature mitotic entry and apoptosis.
  • Pinl -catalyzed prolyl isomerization regulates the conformation and function of these phosphoprotein substrates and facilitates dephosphorylation because of the conformational specificity of some phosphatases.
  • Pinl-dependent peptide bond isomerization is a critical post-phosphorylation regulatory mechanism, allowing cells to turn phosphoprotein function on or off with high efficiency and specificity during temporally regulated events, including the cell cycle (Lu et al., supra).
  • the invention is directed to modulators of Pinl and Pinl- related proteins and the use of such modulators for treatment of Pinl associated states, e.g., for the treatment of cancer or neurodegenerative diseases.
  • the invention pertains, at least in part, to a method for treating a Pinl -associated state in a subject. The method includes administering to the subject an effective amount of a Pinl -modulating compound of formula (I g ):
  • AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O) 2 O-, -S-, or -OCH 2 -, wherein the aromatic groups, heterocyclic groups, linking groups, and carbocyclic groups may be substituted with one or more substituents; such substituents can include, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl
  • Rt is selected from the group consisting of - H; -C ⁇ -6 (e.g., -CH 3 , -CH 2 CH 2 CH 2 CH 2 -), -CH 2 CHCH 2) -NH 2 , -(X) p Ra, -(X) p C(O)R a , wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH 2 - or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of -H, -C ⁇ - 6 (e.g., -CH 3 , -CH 2 CH 2 CH 2 CH 2 -), mo ⁇ holino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, friazole, piperidine, -O-, -S-, -N-, -
  • the invention pertains, at least in part, to a method for modulating, e.g., treating, cyclin DI expression, e.g., overexpression, in a subject.
  • This method includes administering to the subject an effective amount of a Pinl -modulating compound of formula (I g ):
  • Ri is selected from the group consisting of - H; -C 1-6 (e.g., -CH 3 , -CH 2 CH 2 CH 2 CH 2 -), -CH 2 CHCH 2 , -NH 2 , -(X) p R a , -(X) p C(O)R a , wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH 2 - or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -C 1-6 (e.g., -CH 3; -CH2CH 2 CH 2 CH 2 -), mo ⁇ holino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -S-, -N-,
  • AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O) 2 O-, -S-, or -OCH 2 -, wherein the aromatic groups, heterocyclic groups, linking groups, and carbocyclic groups may be substituted with one or more substituents; such substituents can include, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl
  • Ri is selected from the group consisting of - H; -C ⁇ .6 (e.g., -CH 3 , -CH 2 CH 2 CH 2 CH2-), -CH 2 CHCH 2 , -NH 2 , -(X)pR ⁇ , -(X) P C(O)R a , wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH 2 - or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -C 1-6 (e.g., -CH 3 , -CH 2 CH 2 CH 2 CH 2 -X mo ⁇ holino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -S-, -N-, -OH,
  • p is selected
  • R a is selected from the group consisting of OH, -C 1-6 (e.g., -CH 3; -CH 2 CH 2 CH 2 CH2-X mo ⁇ holino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -
  • R 3 is selected from the group consisting of-H, -OH, -O-, -C 1-6
  • each R 5 is independently selected from the group consisting of -
  • the invention pertains, at least in part, to a method for treating a Pinl -associated state in a subject.
  • the method includes administering to a subject an effective amount of a combination of a Pinl -modulating compound of formula (I g ) :
  • Ri is selected from the group consisting of - H; -Ci- ⁇ (e.g., -CH 3 , -CH 2 CH 2 CH 2 CH 2 -), -CH 2 CHCH 2; -NH 2 , -(X) P R a , -(X) P C(O)R a , wherein p is selected from the group consisting of 1 tlirough 6, wherein each X is independently selected from -CH 2 - or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -C ⁇ - 6 (e.g., -CH 3 , -CH 2 CH 2 CH 2 CH 2 -) , mo ⁇ holino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -S
  • the invention pertains, at least in part, to a method for freating cancer in a subject.
  • the method includes administering to the subj ect an effective amount of a combination of a Pinl -modulating compound of formula (I g ):
  • AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O) 2 ⁇ -, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, linking groups, and carbocyclic groups may be substituted with one or more substituents; such substituents can include, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl,
  • Ri is H or is selected from one or a combination of alkyl groups, aromatic groups, heterocyclic groups, and carbocyclic groups, which may be mdirectly linked to the nitrogen ofthe core ring of
  • -H is selected from the group consisting of-H; -C 1-6 (e.g., -CH 3> -CH2CH2CH2CH2-), -CH 2 CHCH 2 , -NH 2 , -(X) P R a , - (X) p C(O)R a , wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH 2 - or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -C 1-6 (e.g., -CH 3j -CH 2 CH 2 CH 2 CH 2 -), mo ⁇ holino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -S-, -N-, -OH, -
  • the invention is a method for modulating, e.g., freating cyclin DI overexpression in a subject.
  • the method includes administering to the subject an effective amount of a combination of a Pinl -modulating compound of formula (I g ):
  • AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O) O-, -S-, or -OCH 2 -, wherein the aromatic groups, heterocyclic groups, linking groups, and carbocyclic groups may be substituted with one or more substituents; such substituents can include, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl,
  • Ri is selected from the group consisting of - H; -C 1-6 (e.g., -CH 3; -CH2CH 2 CH 2 CH 2 -), -CH 2 CHCH 2> -NH 2 , -(X) p R a , -(X) p C(O)R a , wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH 2 - or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -C ⁇ -6 (e.g., -CH 3> -CH2CH 2 CH 2 CH 2 -), mo ⁇ holino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -S-, -N-, -OH
  • Another embod ment ofthe invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a Pinl -modulating compound as prepared according to the methodology of this invention, and a pharmaceutically acceptable carrier.
  • the invention is directed to modulators, of Pinl and Pinl-related proteins and the use of such modulators for freatment of Pinl associated states, e.g. , for the freatment of cancer.
  • the invention pertains, at least in part, to a method for freating a Pinl -associated state in a subject.
  • the method includes administering to the subject an effective amount of a Pinl -modulating compound ofthe invention having formula (I):
  • Ri is selected from the group consisting of-H; -C 1-6 (e.g., -CH 3> - CH 2 CH 2 CH 2 CH 2 -X -CH 2 CHCH 2 , -NH 2 , -(X) P R a , -(X) p C(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH 2 - or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, C 1- (e.g.
  • R a is selected from the group consisting of OH and mo ⁇ holino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -CH 2 -, -C(O)NH 2 , -C(O)R 3 , -N(R 5 ) 2 , and any combination thereof; wherein R 3 is selected from the group consisting of-H, -OH, -O-, C 1-4 (e.g.
  • each R 5 is independently selected from the group consisting of-H, -F, -OH, -O-, C 1- (e.g.
  • R a is selected from the group consisting of OH, H, mo ⁇ holino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -C 1-6 (e.g., -CH 3, -CH 2 CH 2 CH 2 CH 2 -X -C(O)NH 2 , -C(O)R , - N(R 5 ) 2 , and any combination thereof; wherein R b is selected from the group consisting of-H,
  • R 4 is H or lower alkyl, e.g., Cl-C6, e.g., CH 3 ;
  • Xi, X 2 , X 3 , X-i, and X 5 are independently selected from the group consisting of C, CH, NH, O, S, and N;
  • X 2 , X 3 , X 4 , and X 5 are independently selected from the group consisting of C, CH, NH, O, S, and N;
  • R 4 is H or lower alkyl, e.g., C1-C6, e.g., CH 3 ;
  • Xi is selected from the group consisting of C, CH, ⁇ H, O, S, and ⁇ ;
  • each R 5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -C 1-6 (e.g., -CH 3> -CH 2 CH 2 CH 2 CH2-), mo ⁇ holino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - (CH 2 ) 3 C(O)NH 2 , -CH 2 CH(OH)CH 3 , -C(O)N(CH 3 )-, -COOH and esters and amides thereof, -CH 2 COOH and esters and amides thereof, and any combination thereof; wherein each R 5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -C 1-6 (e.g., -CH 3
  • the Pinl -modulating compound is a compound having formula (INa):
  • n is O or l
  • R 4 is H or lower alkyl, e.g., C1-C6, e.g., CH 3
  • Xi, X 2 , X 3 , ⁇ and X 5 are independently selected from the group consisting of C, CH, NH, O, S, and N
  • n is selected from the group consisting of 0 through 5.
  • the aromatic groups, heterocyclic groups, and carbocyclic groups are selected from the group consisting of a pyridine, a phenyl, a IH-imidazole, a thiazolidine, a pyrrolidone, a hexahydro-pyrimidine, a 3-hydroxy-pyrrolidin-2-one, a pyrrolidine-2,3- dione, a pyrrolidine-2,5-dione, a pyrrolidin-2-one, a cyclopentyl, a [l,4]dioxepane, a tefrahydrofuran, an isoxazole, a mo ⁇ holino, a [l,3]dioxolane, apyrimidine,
  • Ri is -(X) p C(O)R a
  • R a is the formula Rj:
  • R 8 is selected from H, F or OH.
  • Ri is -(X) p C(O)R a
  • R a is
  • the invention is directed to a compound of formula (IT), having the formula (VI):
  • R 2 and R 3 are independently selected from the group consisting of H, -O-, -C 1-5 (e.g., -CH 3 ,-CH 2 CH 2 CH 2 CH 2 -),F, CH 2 OH, NH 2 , OH, CF 3> CI, Br, I, -
  • the invention is directed to a compound of formula (V), having the formula (VH):
  • R 2 and R 3 are independently selected from the group consisting of H, -O-, -C 1-6 (e.g., -CH 3, -CH 2 CH 2 CH 2 CH 2 -),F, CH 2 OH, NH 2 , OH, CF 3 , CI, Br, I, - NC(O)CH 3 , -C(O)-OC(CH 3 ) 3 , -N-C(O)-OC(CH 3 ) 3 , -C(O)-NH 2 , -C(O)-NHCH 3 , - CH 2 NH 2 ,
  • the invention is directed to a compound of formula (II): 2-Fluoro-4-(3- ⁇ 5-[4-(4-fluoro-3-trifluoromethyl- ⁇ henyl)-thiophen-2- yhnethylene]-4-oxo-2-thioxo-thiazolidin-3-yl ⁇ -propionylamino)-benzoic acid (J a ):
  • the invention is directed to a compound of formula (V): 4-(3- ⁇ 5-[4-(2-M ⁇ holin-4-yl-ethoxy)-3',5 , -Bis-trifluoromethyl-biphenyl-3- ylmethylene]-2,4-dioxo-thiazolidin-3-yl ⁇ -propionylamino)-benzoic acid (Jb) :
  • the invention is directed to a compound of formula (V): 4-(3- ⁇ 5-[6-(2-Mo ⁇ holin-4-yl-ethoxy)- S'jS'-Bis-trifluorometliyl-biplienyl- 3-yhnethylene]-4-oxo-2-thioxo-thiazolidin-3-yl ⁇ -propoxy)-benzoic acid (J 0 ):
  • the invention is directed to a compound of formula (V): 4-(2- ⁇ 5-[6-(2-Mo ⁇ holin-4-yl-ethoxy)-3',6'-dichloro-biphenyl-3- ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl ⁇ -ethyl)-benzoic acid (J ):
  • the invention is directed to a compound of formula (V): 4-(3- ⁇ 5-[4-(2-Mo ⁇ holin-4-yl-ethoxy)- 3',6'-dichloro-biphenyl-3- ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl ⁇ -propoxy)-benzoic acid (J e ):
  • the invention is directed to a compound of formula (V): 4-(3- ⁇ 5-[4-(2-Mo ⁇ holin-4-yl-ethoxy)-3',4'-dichloro biphenyl-3- ylmemylene]-4-oxo-2-lMoxo-tMazohdin-3-yl ⁇ -propionylamino)-benzoic acid (J f ):
  • the invention is directed to a compound of formula (V), having the formula (VIII):
  • R 2 , R 3 and Re are independently selected from the group consisting of H, -O-, -C 1-6 (e.g., -CH 3 , -CH 2 CH 2 CH 2 CH2-), F, CH 2 OH, NH 2> OH, CF 3 , CI, Br, I, -NC(O)CH 3 ,-C(O)-OC(CH 3 ) 3 , -N-C(O)-OC(CH 3 ) 3 , -C(O)-NH 2 , -C(O)-NHCH 3 , -
  • the invention is directed to a compound of formula (V), having the formula (IX):
  • R 2 , R 3 and Re are independently selected from the group consisting of H, -O-, -C 1-6 (e.g., -CH 3 , -CH2CH2CH2CH 2 -), F, CH 2 OH, NH 2 , OH, CF 3 , CI, Br, I, -NC(O)CH 3; -C(O)-OC(CH 3 ) 3 , -N-C(O)-OC(CH 3 ) 3 , -C(O)-NH 2 , -C(O)-NHCH 3 , - -OCH 2 C(O)NH-NH 2 , -CH 2 C(O)CH 3 , mo ⁇ holino, -C(O)mo ⁇ holino, -CH 2 C(O)C(CH 3 ) 3 , -C(O)-OCH 2 CH 3 , one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which maybe directly linked, joined
  • the invention is directed to a compound of formula (V), having the formula (X): wherein the dashed line indicates a single or a double bond; n is 0 or 1 ; Xi, X 2 , X 3 , X , X 5 and X 6 are independently selected from the group consisting of C, CH, NH, N, S and O; R ⁇ , R 12 , and R 13 are independently selected from the group consisting of H, -O-, -C 1-6 (e.g., -CH 3; -CH 2 CH 2 CH 2 CH 2 -) ) F, -N(H)-, CH 2 OH, CH2CH 2 OH, NH 2 , OH, CF 3 , CI, Br, I, -(CH 2 )o- 2 NC(O)CH 3 , -C(O)-OC(CH 3 ) 3 , -N-C(O)- OC(CH 3 ) 3 , -C(O)
  • the invention is directed to a compound of formula (V): 4-(2- ⁇ 5-[4-(2-Mo ⁇ holin-4-yl-ethoxy)-3-naphthalen-2-yl-benzylidene]-4- oxo-2-thioxo-thiazolidin-3 -yl ⁇ -ethyl)-benzoic acid ( J g ) :
  • the invention is directed to a compound of formula (V): 4-(2- ⁇ 5-[4-(2-Mo ⁇ holin-4-yl-ethoxy)-3-quinolin-3-yl-benzylidene]-4-oxo- 2-thioxo-thiazolidin-3-yl ⁇ -ethyl)-benzoic acid (J ):
  • the invention is directed to a compound of formula (V): 4-(2- ⁇ 5-[3-(2-Amino-pyrido[3,2-d]pyrimidin-7-yl)-4-(2-mo ⁇ holin-4-yl- ethoxy)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl ⁇ -ethyl)-benzoic acid (Ji):
  • the invention is directed to a compound of formula (V), having the formula XI:
  • R 2 , R 3 and R are independently selected from the group consisting of H, -O-, -C 1-6 (e.g., -CH 3 , -CH 2 CH 2 CH 2 CH 2 -), F, CH 2 OH, NH 2) OH, CF 3 , CI, Br, I, -NC(O)CH 3, -C(O)-OC(CH 3 ) 3 , -N-C(O)-OC(CH 3 ) 3 , -C(O)-NH 2 , -C(O)-NHCH 3 , -
  • e e (e.g., -CH 3j -CH 2 CH 2 CH 2 CH 2 -), mo ⁇ holino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -CH 2 (CH 2 ) 2 C(O)NH 2 ,
  • E is selected from the goup consisting of-H, -F, -Br, -CI, -I, - OH, -O-, -C ⁇ -6 (e.g., -CH 3; -CH 2 CH 2 CH CH 2 -X mo ⁇ holino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -
  • a is 3 ⁇ 5-[4-(2-M ⁇ holin-4-yl-ethoxy)-3-naphthalen-2-yl-benzylidene]-3-[3- (2H-tefrazol-5-yl)-propyl]-2-thioxo-thiazolidin-4-one ⁇ , 4 ⁇ 5-[4-(2-Mo ⁇ holin-4-yl- ethoxy)-3-naphthalen-2-yl-benzylidene]-3-[4-(2H-tefrazol-5-yl)-butyl]-2-thioxo- thiazolidin-4-one ⁇ or 5 ⁇ 5-[4-(2-Mo ⁇ holin-4-yl-ethoxy)-3-naphthalen-2-yl- benzylidene]-3-[5-(2H-tefrazol-5-yl)-pentyl]-2-tMoxo-thiazolidin-4-one ⁇ ;
  • a is 3 ⁇ 5-[2',4'-Dichloro-6-(2-mo ⁇ holin-4-yl-ethoxy)-biphenyl-3-ylmethylene]- 3-[3-(2H-tefrazol-5-yl)-propyl]-2-thioxo-thiazolidin-4-one ⁇ , 4 ⁇ 5-[2',4'-Dichloro-6-(2- mo ⁇ holin-4-yl-ethoxy)-biphenyl-3 -yhnethylene]-3 - [4-(2H-tetrazol-5 -yl)-butyl] -2- thioxo-thiazolidin-4-one ⁇ or 5 ⁇ 5-[2',4'-Dichloro-6-(2-mo ⁇ holin-4-yl-ethoxy)- biphenyl-3-yhnethylene]-3-[5-(2H-tetrazol-5-yl)-pentyl]-2-
  • Xi and X 2 are independently selected from the group consisting of C and ⁇ ; Rio * Rn » arid R 12 are independently selected from the group consisting of H, F, CH 2 OH, -O-, -C ⁇ -6 (e.g., -CH 3 ,-CH 2 CH 2 CH 2 CH2-X ⁇ H2, OH, CF 3 , CI, Br, I, NC(O)CH 3 , -C(O)-OC(CH 3 ) 3 , -N-C(O)-OC(CH 3 ) 3 , -C(O)-NH 2 , -C(O)-NHCH 3 , -CH 2 NH 2 , -OCH 2 C(O)NH-NH 2 , -CH 2 C(O)CH 3 , -mo ⁇ holino, -C(O)mo ⁇ holino, - CH 2 C(O)C(CH 3 ) 3 , -C(O)-OCH 2 CH 3 and any
  • each R 5 is independently selected from the group consisting of-H, -F, -OH, -O-, -Ci- ⁇ (e.g., -CH 3 ⁇ -CH 2 CH 2 CH2CH 2 -), mo ⁇ holino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH 2 (CH 2 ) 2 C(O)NH 2j -CH 2 CH2OH, -CH 2 CH(OH)CH 3; -C(O)N(CH 3 )-, -COOH and esters and amides thereof, -CH 2 COOH and esters and amides thereof, and any combination thereof; wherein
  • the invention is directed to a compound of formula (V): 3-Methoxy-4-(3- ⁇ 5-[4-(2-mo ⁇ holin-4-yl-ethoxy)-3 5 l -bis-tri ⁇ luoromethyl- biphenyl-3-ylmethylene]-4-oxo-2-tMoxo-tln ⁇ olidin-3-yl ⁇ -piOpoxy)-benzoic acid (J ⁇ c ):
  • the invention is directed to a compound of formula (V): 3-Methoxy-4-(3- ⁇ 5-[6-(2-mo ⁇ holin-4-yl-ethoxy)-3',5 , -bis-trifluoromethyl- biphenyl-3-ylmethylene]-4-oxo-2-tWoxo-tniazolidin-3-yl ⁇ -propoxy)-benzoic acid (Ji):
  • the invention is directed to a compound of formula (III): 3-[3-(2H-Tefrazol-5-yl)-propyl]-2-thioxo-5-[6-(3,5-bis-trifluoromethyl- phenyl)-pyridin-2-ylmethylene]-thiazolidin-4-one (J m ):
  • the invention is directed to a compound of formula (V): 5-(4,5-Dimethoxy-3 ⁇ 5 l -bistrifluoromethyl-biphenyl-3-ylmethylene)-2- tln ⁇ xo-thiazohdin-4-one (J n ):
  • the invention is directed to a compound of formula (V): 5-(6-Methoxy-3',5'-bistrifluoromethyl-biphenyl-3-ylmethylene)-2-thioxo- thiazolidin-4-one (J 0 ):
  • the invention is directed to a compound of formula (V): 5-(5,6-Dimethoxy-3',5'-bistrifluoromethyl-biphenyl-3-ylmethylene)-2- thioxo-thiazolidin-4-one (J p ):
  • the invention is directed to a compound of formula (V): 4-(3- ⁇ 5-[4-(2-Mo ⁇ holin-4-yl-ethoxy)-3',5 l -bistrifluoromethyl-biphenyl-3- ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl ⁇ -propionylamino)-benzoic acid 2,3- including salts thereof, e.g., pharmaceutically acceptable salts.
  • the invention is directed to a compound of formula (V): 4-(3- ⁇ 5-[3',4'-Difluoro-4-(2-mo ⁇ holin-4-yl-ethoxy)-biphenyl-3- ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl ⁇ -propoxy)-benzoic acid (J r ):
  • the invention is directed to a compound of formula (V): 4-(3- ⁇ 5-[4-(2-Mo ⁇ holin-4-yl-ethoxy)-3',5'-bistrifluoromethyl-biphenyl-3- ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl ⁇ -propoxy)-benzoic acid (J s ):
  • the invention is directed to a compound of formula (V): 4-(3- ⁇ 5-[3 l -Chloro-4-(2-mo ⁇ holin-4-yl-ethoxy)-biphenyl-3-ylmethylene]- 4-oxo-2-thioxo-thiazolidin-3-yl ⁇ -propoxy)-benzoic acid (J t ):
  • the invention is directed to a compound of formula (V): 4-(3- ⁇ 5-[4-(2-Mo ⁇ holin-4-yl-ethoxy)- -chloro-4 , -trifluoromethyl- biphenyl-3-yhnethylene]-4-oxo-2-thioxo-thiazolidm-3-yl ⁇ -propoxy)-benzoic acid (J u ):
  • the invention is directed to a compound of formula (V): 4-(2- ⁇ 5-[3-(lH-Indol-5-yl)-4-(2-mo ⁇ holin-4-yl-ethoxy)-benzylidenel-4- oxo-2-thioxo-thiazoUdin-3-yl ⁇ -ethyl)-benzoic acid (J v ):
  • the invention is directed to a compound of fo ⁇ mula (V): 4-(2- ⁇ 5-[2 , -Cmoro-4-(2-mo ⁇ holm-4-yl-ethoxy)-5 , -t ⁇ ifluoromethyl- biphenyl-3-ylmethylene]-4-oxo-2-tMoxo-tMazohdin-3-yl ⁇ -ethyl)-benzoic acid (J w ):
  • the invention is directed to a compound of formula (V): 4-(2- ⁇ 5-[3',4'-Dichloro-6-(2-mo ⁇ holin-4-yl-ethoxy)-biphenyl-3- ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl ⁇ -ethyl)-benzoic acid (J x ):
  • the invention is directed to a compound of formula (V): 4-(2- ⁇ 5-[3',5'-Dichloro-6-(2-mo ⁇ holin-4-yl-ethoxy)-biphenyl-3- ylmethylene]-4-oxo-2-tMoxo-thiazohdin-3-yl ⁇ -ethyl)-benzoic acid (Jy):
  • a compound of formula VI, VII, VUI, IX, X XI, XLT, XIII, and XJN, a compound of formula (V) having the formula J a , Jb, J , J ⁇ ⁇ , Je, Jf, Jg, Jh, Ji, Jk, Ji, Jn, Jo, J P , Jq, Jr, Js, Jt, Ju, Jv Jw, Jx, Jy, and a compound of formula (IE) having the formula J m can be administered using all ofthe methods described herein, such as combining the compound with a carrier material suitable for oral, nasal, topical, fransdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • formulations ofthe invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets and lozenges.
  • Pinl -associated state or "Pinl associated disorder” includes disorders and states (e.g., a disease state) that are associated with the misexpression or misregulation of Pinl. This misexpression or misregulation can be as a result ofthe altered production, degradation, or regulation of Pinl, e.g., the phosphorylation/ dephosphorylation of Pinl.
  • Pinl associated disorders that are related to higher than necessary levels of Pinl can be caused by (1) an increase in the level of transcription or translation, or a decrease in the level of degradation of Pinl, such that an abnormally high amount of Pinl polypeptide is present in a cell, or (2) the amount Pinl that is present in the unphosphorylated, i.e., active form, is abnormally high due to either an increase in the dephosphorylation of Pinl or a decrease in the phosphorylation of Pinl.
  • Pinl disorders are often associated with abnormal cell growth, abnormal cell proliferation, or misexpression of Pinl (e.g., Pinl protein or nucleic acid).
  • Pinl -associated states include states resulting from an elevation in the expression of cyclin DI and/or Pinl.
  • Pinl -associated states also include states resulting from an elevation in the phosphorylation level of c- Jun, particularly phosphorylation of c- Jun on Ser 63 73 -Pro, and/or from an elevation in the level of c- Jun amino terminal kinases (JNKs) present in a cell.
  • Pinl -associated states include neoplasia, cancer, undesirable cell growth, and/or tumor growth.
  • Pinl -associated states include states caused by DNA damage, an oncogenic protein (i.e. Ha-Ras), loss of or reduced expression of a tumor suppressor (i.e. Brcal), and/or growth factors.
  • Pinl- associated state is also intended to include diseases or disorders caused by, or associated with, deregulation of genes and/or gene products involved in a biological pathway that includes Pinl and/or cyclin DI (e.g. beta-catenin, APC or WNT).
  • beta-catenin, APC and WNT have been linked to cancer development as demonstrated in Biochim Biophys Acta. (2003) 1653: 1-24 and Eur J Surg Oncol. (2003) 29: 107-117.
  • Pinl associated states further include disorders and states associated with regulation or activity of Pinl in the brain, e.g., neurodegenerative disorders such as Alzheimer's disease, wherein the phosphorylation state of tau is influenced by the activity of Pinl.
  • expression and regulation are used interchangeably herein. These terms are intended to include non- wild type pattern of gene expression or regulation. Expression and regulation, as used herein, include transcriptional, post transcriptional, e.g., mRNA stability, translational, and post translational stages.
  • Misexpression includes: expression at non-wild type levels, i.e., over or under expression; a pattern of expression that differs from wild type in terms ofthe time or stage at which the gene is expressed, e.g., increased or decreased expression (as compared with wild type) at a predetermined developmental period or stage; a pattern of expression that differs from wild type in terms of decreased expression (as compared with wild type) in a predetermined cell type or tissue type; a pattern of expression that differs from wild type in terms ofthe splicing size, amino acid sequence, post- transitional modification, or biological activity ofthe expressed polypeptide; a pattern of expression that differs from wild type in terms ofthe effect of an environmental stimulus or extracellular stimulus on expression of the gene, e.g.
  • Misexpression includes any expression from a transgenic nucleic acid. Misexpression includes the lack or non-expression of a gene or transgene, e.g. , that can be induced by a deletion of all or part of the gene or its confrol sequences. Misregulation can include aberrant levels of phosphorylation ofthe enzyme.
  • Pinl is an important regulator of cyclin DI expression. Because of Pinl's role in regulating the expression of cyclin DI, many ofthe tumor causing effects of cyclin DI can be regulated tlirough Pinl.
  • modulators of Pinl can be used to modulate or regulate cyclin DI (i.e., or the expression thereof), and the resulting effects of cyclin DI over- or under-expression.
  • inhibitors of Pinl can be used to freat, inhibit, and/or prevent undesirable cell growth, neoplasia, and/or cancer in any subject but particularly in humans.
  • Other examples of Pinl associated states include, but are not limited to, for example, those tumor types disclosed in Table 10.
  • the term "treated,” “treating” or “treatment” includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being freated.
  • the freatment comprises the induction of a Pinl inhibited state, followed by the activation ofthe Pinl modulating compound, which would in turn diminish or alleviate at least one symptom associated or caused by the Pinl associated state, disorder or disease being freated.
  • treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.
  • subject is intended to include organisms, e.g., prokaryotes and eukaryotes, which are capable of suffering from or afflicted with a Pinl associated disorder. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from a Pinl associated disorder.
  • the language "Pinl modulating compound” refers to compounds that modulate, e.g., inhibit, promote, or otherwise alter, the activity of Pinl. Pinl modulating compounds include both Pinl agonists and antagonists, hi certain embodiments, the Pinl modulating compound induces a Pinl inhibited-state.
  • Pinl modulating compounds include compounds of formula (I), formula (la), formula (II), formula (Ila), formula (III), formula (Ilia), formula (IV), formula (INa), formula (N), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XT), formula (XLT), formula (XILT) and formula (XIN). Additional examples of Pinl modulating compounds include compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8 or derivatives thereof. In certain embodiments, the Pinl modulating compounds include compounds that interact with the PPI and/or the WW domain of Pinl. In certain embodiments, the Pinl modulating compound is substantially specific to Pinl.
  • substantially specific for Pinl is intended to include inhibitors ofthe invention that have a Kj or K that is at least 2, 3, 4, 5, 10, 15, or 20 times less than the Kj or K d for other peptidyl prolyl isomerases, e.g., hCyP-A, hCyP- B, hCyP-C, ⁇ KCA, hFKBP-12, hFKBP-13, and hFKBP-25.
  • the Pinl polypeptide can be phosphorylated or unphosphorylated. Pinl activity is known to be controlled by a phosphorylation mechanism (Lu et al. (1999) Science 283:1325-8).
  • the modulators ofthe invention can be designed to specifically interact with either form of Pinl.
  • a Pinl modulator may be capable of interacting with either the phosphorylated or unphosphorylated form ofthe polypeptide.
  • the Pinl modulating compound of the invention is capable of chemically interacting with Cysll3 of Pinl.
  • the language "chemical interaction" is intended to include, but is not limited to reversible interactions such as hydrophobic/hydrophilic, ionic (e.g., coulombic attraction/repulsion, ion-dipole, charge-transfer), covalent bonding, Van der Waals, and hydrogen bonding.
  • the chemical interaction is a reversible Michael addition.
  • the Michael addition involves, at least in part, the formation of a covalent bond.
  • the method includes adn ⁇ nistering to a subject an effective amount of a Pinl modulating compound of the invention, e.g. , Pinl -modulating compounds of formula (I), formula (la), formula (IT), formula (Ila), formula (HT), formula (Ilia), formula (IN), formula (INa), formula (N), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII) and formula (XIN) that have been modified in order to decrease the ability ofthe compound to cross the blood-brain barrier.
  • a Pinl modulating compound of the invention e.g. , Pinl -modulating compounds of formula (I), formula (la), formula (IT), formula (Ila), formula (HT), formula (Ilia), formula (IN), formula (INa), formula (N), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII),
  • Pinl inhibiting compounds include compounds of formula (I), formula (la), formula (II), formula (Ha), formula (LU), formula (ffla), formula (IN), formula (INa), formula (N), formula (VI), formula (Nil), formula (NIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII) and formula (XIN). Additional examples of Pinl inhibiting compounds include compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8 or derivatives thereof. In certain embodiments, the Pinl inhibiting compounds include compounds that interact with the PPI and/or the WW domain of Pinl . In certain embodiments the inhibitors have a Kj for Pinl of less than
  • Pinl inhibited-state is intended to include states in which one activity of Pinl is inhibited in cells, e.g., cells in a subject, that have been treated with a Pinl modulating compound.
  • Pinl inbited-state is also intended to include states wherein the Pinl modulating compound is administered to a subject, allowed to remain in a preactivated state, and subsequently activated by a stimulus.
  • the stimulus may be selected from a natural event, artificial event, or the combination thereof.
  • the natural event may be the action of an enzyme and/or the artificial event may be the addition of a hype ⁇ lastic inhibitory agent or the addition of energy to the subjects system in any manner that achieves activation, e.g., by radiation, e.g., by light with a wavelength greater than about 400 nm, e.g., greater than about 600 nm, e.g., greater than about 620 nm, e.g., greater than about 630 nm, e.g., greater than about 640 nm, e.g., greater than about 650 nm.
  • radiation e.g., by light with a wavelength greater than about 400 nm, e.g., greater than about 600 nm, e.g., greater than about 620 nm, e.g., greater than about 630 nm, e.g., greater than about 640 nm, e.g., greater than about 650 nm.
  • the cells enter a Pinl inhibited-state for a designated period of time prior to activation ofthe modulating compound sufficient to allow the modulation the activity of Pinl by the activated modulating compound.
  • the designated period of time prior to activation is greater than about 1 hour, e.g., greater than about 2 hours, e.g., greater than about 3 hours, e.g., greater than about 6 hours, e.g., greater than about 12 hours, e.g., greater than about 24 hours, e.g., greater than about 36 hours, e.g., greater than about 48 hours, e.g., greater than about 72 hours, hi a specific embodiment, the designated period of time prior to activation is 3 days.
  • the Pinl modulating compound is preactivated prior to administration to a subject followed by the introduction of at least one stimulus sufficient to allow the modulation the activity of Pinl by the modulating compound, hi certain embodiment ofthe invention, the activity ofthe modulating compound is enhanced by the entrance ofthe cells, e.g., cells of a subject, into a Pinl inhibited state.
  • the Pinl modulating compounds of the invention have a characteristic inhibition profile (CIP) and have an effective cytotoxicity, e.g., effective to freat a Pinl associated state.
  • CIP characteristic inhibition profile
  • the Pinl -modulating compounds described herein may be substituted with any substituent that allows the Pinl -modulating compound to perform its intended function.
  • the Pinl -modulating compounds described herein may be substituted with any substituent which allows the Pinl -modulating compound to perform its intended function, possess a CIP, and/or be effectively cytotoxic, as defined herein.
  • the cytotoxicity ofthe compounds can be determined by using the CPCA given in Example 1.
  • the measurement ofthe activity ofthe Pinl -modulating compounds in the determination the inhibition constant at 50% inhibition of enzyme activity (IC 50 ), which is used to characterize the CIP, may be performed by using the analysis described in Example 2.
  • An ordinarily skilled artisan would be able to use data generated by the assays to modify substituents on the Pinl modulating compounds to obtain effectively cytotoxic Pinl modulating compounds with characteristic inhibition profiles.
  • Characteristic inhibition profile is a characterization of the modulating compound ofthe invention such that the Pinl -associated state is inhibited. Characterization ofthe modulating compounds includes measurement ofthe inhibition constant at 50% inhibition of enzyme activity (IC 50 ).
  • Compounds that demonstrate a CIP include modulating compounds with and IC 50 of less than about 40 ⁇ M. In certain embodiments ofthe invention, the IC 50 is between about 10-40 ⁇ M. In additional embodiments, the IC 50 is between about 1-10 ⁇ M. In certain embodiments, the IC 50 is less than about 1 ⁇ M.
  • cytotoxicity or "effectively cytotoxic” includes cytotoxicities of Pinl -modulating compounds which allow the Pinl -modulating compound to perform its intended function, e.g., treat Pinl associated states. Cytotoxicities can be measured, for example, by using the Cell Based Cytotoxicity Assay (CBCA) method described in Example 1.
  • CBCA Cell Based Cytotoxicity Assay
  • the Pinl- modulating compound has a cytotoxicity (as measured by the CBCA in Example 1) of 50 ⁇ M or less, 45 ⁇ M or less, 40 ⁇ M or less, 35 ⁇ M or less, 30 ⁇ M or less, 25 ⁇ M or less, 20 ⁇ M or less, 15 ⁇ M or less, 10 ⁇ M or less, 9 ⁇ M or less, 8 ⁇ M or less, 7 ⁇ M or less, 6 ⁇ M or less, 5 ⁇ M or less, 4 ⁇ M or less, 3 ⁇ M or less, 2 ⁇ M or less, 1 ⁇ M or less, 0.9 ⁇ M or less, 0.8 ⁇ M or less, 0.7 ⁇ M or less, 0.6 ⁇ M or less, 0.5 ⁇ M or less, 0.4 ⁇ M or less, or, preferably, 0.3 ⁇ M or less, or 0.05 ⁇ M or less.
  • the Pinl modulating compounds ofthe invention are substantially soluble, e.g., water soluble, and have an effective cytotoxicity, e.g., effective to freat a Pinl associated state.
  • Methods for altering the solubility of organic compounds are known in the art. For example, one of ordinary skill in the art will be able to modify the Pinl modulating compounds ofthe invention such that they have a desirable logP. Ordinarily skilled artisans will be able to modify the compounds by adding and removing hydrophilic and hydrophobic moieties, such that a Pinl- modulating compound with a desired solubility is obtained.
  • the Pinl -modulating compounds described herein may be substituted with any substituent which allows the Pinl -modulating compound to perform its intended function, be substantially soluble, and/or be effectively cytotoxic, as defined herein.
  • any substituent which allows the Pinl -modulating compound to perform its intended function be substantially soluble, and/or be effectively cytotoxic, as defined herein.
  • an ordinarily skilled artisan would understand that the addition of heteroatoms (hydroxy, amino, nitro, carboxylic acid groups, etc.) or other polar moieties would generally increase the solubility ofthe Pinl modulating compound in water, while addition of non-polar moieties such as aryl or alkyl groups would generally decrease the solubility ofthe compound in water.
  • the Pinl modulating compound can then be tested for substantial solubility by determining the logP value, e.g., by using a log octanol- water partition coefficient program such as "KOWWTN" (Meylan, W.M. and P.H. Howard. 1995. Atom/fragment contribution method for estimating octanol-water partition coefficients. J. Pharm. Sci. 84: 83-92, inco ⁇ orated herein by reference in its entirety).
  • KWWTN log octanol- water partition coefficient program
  • An ordinarily skilled artisan would be able to use data generated by these programs and assays to modify substituents on the Pinl modulating compounds to obtain substantially soluble and effectively cytotoxic Pinl modulating compounds.
  • substantially soluble includes solubilities (e.g., aqueous solubilities) of Pinl -modulating compounds that allow the Pinl -modulating compounds to perform their intended function, e.g. , treat Pinl associated states.
  • solubility of a particular Pinl -modulating compound can be measured by any method known in the art, e.g., experimentally, computationally, etc.
  • one method for determining the solubility of a compound computationally is by calculating logP values using a log octanol- water partition coefficient program (KOWNvTN).
  • the Pinl- modulating compounds of the invention have logP values less than Pinl -modulating, e.g., less than 6.6.
  • the Pinl -modulating compounds ofthe invention may have a logP value between about 1 to about 6, between about 1 to about 5, between about 1.5 to about 5, between about 2 to about 5, between about 2.5 to about 4.5, between about 2.75 to about 4.25, between about 3.0 to about 4.0, between about 3.25 to about 4.0, between about 3.5 to about 4.0, and between about 3.5 to about 3.75. Values and ranges included and/or intermediate ofthe values set forth herein are also intended to be within the scope ofthe present invention.
  • the aqueous solubility ofthe compound is about 0.01 mg/L or greater, about 0.1 mg/L or greater, about 1 mg/L or greater, or about 2 mg/L or greater.
  • derivative is intended to include isomers, modification, e.g., addition or removal, of substituents on the Pinl -modulating compound, fragements and pharmaceutically acceptable salts thereof, as well as formulations, such that the Pinl- modulating compound treats the Pinl -associated state.
  • Pinl modulating compounds ofthe invention include fragments of Pinl modulating compounds of formula (I), formula (la), formula (IT), formula (Ila), formula (ILT), formula (Ilia), formula (TV), formula (TVa), formula (V), formula (VI), formula (NH), formula (NIII), formula (IX), formula (X), formula (XT), formula (XII), formula (XIII) and formula (XIN), including the compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8 or derivatives thereof.
  • the language "fragments of Pinl modulating compounds” as used herein, is intended to include portions of Pinl modulating compounds described herein that modulate the activity of Pinl.
  • alkyl includes saturated aliphatic groups, including straight- chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • straight- chain alkyl groups e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
  • alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone.
  • a sfraight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone (e.g., C1-C1 0 for sfraight chain, C 3 -C 10 for branched chain), and more preferably 6 or fewer.
  • preferred cycloalkyls have from 4-7 carbon atoms in their ring stracture, and more preferably have 5 or 6 carbons in the ring structure.
  • substituted is intended to describe moieties having substituents replacing a hydrogen on one or more atoms, e.g. C or N, of a molecule.
  • substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ure
  • alkyl includes both "unsubstituted alkyls" and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons ofthe hydrocarbon backbone.
  • substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
  • Cycloalkyls can be further substituted, e.g., with the substituents described above.
  • An "alkylaryl” or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenyhnethyl (benzyl)).
  • the term “alkyl” also includes the side chains of natural and unnatural amino acids. Examples of halogenated alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, perfluoromethyl, perchloromethyl, perfluoroethyl, perchloroethyl, etc.
  • aryl includes groups, including 5- and 6-membered single- ring aromatic groups that may include from zero to four heteroatoms, for example, phenyl, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • aryl includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
  • aryl groups having heteroatoms in the ring stracture may also be referred to as "aryl heterocycles", “heterocycles,” “heteroaryls” or “heteroaromati.es”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
  • Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tefralin).
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, bulenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, bulenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl
  • alkenyl further includes alkenyl groups that include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone.
  • a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for sfraight chain, C 3 -C 6 for branched chain).
  • cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C 2 -C 6 includes alkenyl groups containing 2 to 6 carbon atoms.
  • alkenyl includes both "unsubstituted alkenyls" and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight-chain alkynyl groups (e.g. , ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
  • alkynyl further includes alkynyl groups that include oxygen, nifrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • C 2 -C 6 includes alkynyl groups containing 2 to 6 carbon atoms.
  • alkynyl includes both "unsubstituted alkynyls" and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, arninocarbonyl, alkylaminocarbonyl, dial laminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone stracture.
  • Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
  • acyl includes compounds and moieties which contain the acyl radical (CH 3 CO-) or a carbonyl group.
  • substituted acyl includes acyl groups where one or more ofthe hydrogen atoms are replaced by for example, alkyl group's, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulf
  • acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
  • the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of ar yl groups include phenylcarboxy, naphthyl carboxy, etc.
  • alkoxyalkyl examples include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons ofthe hydrocarbon backbone, e.g., oxygen, nifrogen or sulfur atoms.
  • alkoxy includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups and may include cychc groups such as cyclopentoxy.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, al
  • halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc.
  • amine or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
  • alkyl amino includes groups and compounds wherein the nifrogen is bound to at least one additional alkyl group.
  • dialkyl amino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups.
  • arylamino and diarylamino include groups wherein the nifrogen is bound to at least one or two aryl groups, respectively.
  • alkylarylamino refers to an amino group that is bound to at least one alkyl group and at least one aryl group.
  • alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nifrogen atom that is also bound to an alkyl group.
  • amide or "aminocarboxy” includes compounds or moieties that contain a nifrogen atom that is bound to the carbon of a carbonyl or a thiocarbonyl group.
  • alkaminocarboxy groups that include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups that include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.
  • alkylaminocarboxy alkenylaminocarboxy
  • alkynylaminocarboxy arylaminocarboxy
  • carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom, and tautomeric forms thereof. Examples of moieties that contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • carboxy moiety or “carbonyl moiety” refers to groups such as “alkylcarbonyl” groups wherein an alkyl group is covalently bound to a carbonyl group, "alkenylcarbonyl” groups wherein an alkenyl group is covalently bound to a carbonyl group, "alkynylcarbonyl” groups wherein an alkynyl group is covalently bound to a carbonyl group,
  • arylcarbonyl groups wherein an aryl group is covalently attached to the carbonyl group.
  • the term also refers to groups wherein one or more heteroatoms are covalently bonded to the carbonyl moiety.
  • the term includes moieties such as, for example, aminocarbonyl moieties, (wherein a nitrogen atom is bound to the carbon ofthe carbonyl group, e.g., an amide), aminocarbonyloxy moieties, wherein an oxygen and a nifrogen atom are both bond to the carbon ofthe carbonyl group (e.g., also referred to as a "carbamate").
  • aminocarbonylamino groups are also include as well as other combinations of carbonyl groups bound to heteroatoms (e.g.,. nifrogen, oxygen, sulfur, etc. as well as carbon atoms).
  • heteroatom e.g.,. nifrogen, oxygen, sulfur, etc. as well as carbon atoms.
  • the heteroatom can be further substituted with one or more alkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, etc. moieties.
  • thiocarbonyl or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • thiocarbonyl moiety includes moieties that are analogous to carbonyl moieties.
  • thiocarbonyl moieties include aminothiocarbonyl, wherein an amino group is bound to the carbon atom ofthe thiocarbonyl group, furthermore other thiocarbonyl moieties include, oxythiocarbonyls (oxygen bound to the carbon atom), aminothiocarbonylamino groups, etc.
  • ether includes compounds or moieties that contain an oxygen bonded to two different carbon atoms or heteroatoms.
  • alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom that is covalently bonded to another alkyl group.
  • esters includes compounds and moieties that contain a carbon or a heteroatom bound to an oxygen atom that is bonded to the carbon of a carbonyl group.
  • ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
  • alkyl, alkenyl, or alkynyl groups are as defined above.
  • thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms.
  • thioethers include, but are not limited to alkftnoalkyls, alkthioalkenyls, and alkthioalkynyls.
  • alkthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom that is bonded to an alkyl group.
  • alkthioalkenyls and alkthioalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
  • hydroxy or “hydroxyl” includes groups with an -OH or -O " .
  • halogen includes fluorine, bromine, chlorine, iodine, etc.
  • perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
  • polycyclyl or “polycyclic radical” include moieties with two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings".
  • Rings that are joined through non-adjacent atoms are termed "bridged” rings.
  • Each ofthe rings ofthe polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbo ⁇ yl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino
  • heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
  • heterocycle or “heterocyclic” includes saturated, unsaturated, aromatic (“heteroaryls” or “heteroaromatic”) and polycyclic rings which contain one or more heteroatoms.
  • heterocycles include, for example, benzodioxazole, benzofuran, benzoimidazole, benzothiazole, b ⁇ nzothiophene, benzoxazole, deazapurine, furan, indole, indolizine, imidazole, isoxazole, isoquinoline, isothiaozole, methylenedioxyphenyl, napthridine, oxazole, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, tefrazole, thiazole, thiophene, and triazole.
  • heterocycles include mo ⁇ holino, piprazine, piperidine, thiomo ⁇ holino, and thioazohdine.
  • the heterocycles may be substituted or unsubstituted.
  • substituents include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and al
  • the structures of some ofthe compounds of this invention include asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the stractures and other compounds and moieties discussed in this application also include all tautomers thereof. Compounds described herein may be obtained though art recognized synthesis strategies. It will also be noted that the substituents of some ofthe compounds of this invention include isomeric cyclic structures.
  • tefrazole includes tefrazole, 2H-tefrazole, 3H-tefrazole, 4H-tefrazole and 5H-tefrazole.
  • any combination thereof implies that any number ofthe listed functional groups and molecules may be combined to create a larger molecular architecture.
  • the Pinl modulating compound of formula (I) is any one ofthe compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8 or derivatives thereof.
  • the invention pertains to the Pinl -modulating compounds of formula (I), formula (la), formula (II), formula (Ila), formula (III), formula (Ilia), formula (IV), formula (TVa), formula (V), formula (VI), formula (VII), formula (VIET), formula (IX), formula (X), formula (XI), formula (XII), formula (XITI) and formula (XIN) described herein.
  • Particular embodiments ofthe invention pertain to the modulating compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8 or derivatives thereof.
  • the invention pertains to pharmaceutical compositions comprising the Pinl -modulating compounds described herein and a pharmaceutical acceptable carrier.
  • the invention includes any novel compound or pharmaceutical compositions containing compounds ofthe invention described herein.
  • compounds and pharmaceutical compositions containing compounds set forth herein are part of this invention, including salts thereof, e.g., a pharmaceutically acceptable salt.
  • the compounds in Tables 1, 2, 3, 4, 5, 6, 7 and 8 can be administered using all ofthe methods described herein, such as combining the compound with a carrier material suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • a carrier material suitable for oral such as combining the compound with a carrier material suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • formulations ofthe invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets and lozenges.
  • the compounds ofthe invention include analogs ofthe compounds described above containing art-recognized substituents that do not significantly effect the analog's ability to perform its intended function
  • the invention pertains, at least in part, to a method for treating cyclin DI overexpression in a subject.
  • This method includes administering to the subject an effective amount of a Pinl -modulating compound of formula (I), formula (la), formula (II), formula (Ila), formula (III), formula (Ilia), formula (IN), formula (IVa), formula (N), formula (NI), formula (Nil), formula (NIH), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII) and formula
  • cyclin DI overexpression
  • the overexpression of cyclin DI is associated with the presence of breast cancer in the subject.
  • Pinl may cause changes in the expression, e.g., underexpression or overexpression of endogenous cyclin DI.
  • Pinl is believed to regulate, e.g., activate, the expression of cyclin DI by acting cooperatively with c-Jun to activate the cyclin DI promoter, hi order to activate cyclin DI expression, c-Jun must be phosphorylated.
  • Pinl binds to c-Jun mainly via phosphorylated S 63 73 -P motifs.
  • Pinl activates phosphorylated c-Jun to induce cyclin DI expression by regulating the conformation of the phosphorylated S-P motifs in c-Jun.
  • the activity of c-Jun is also enhanced by phosphorylation induced by growth factors, oncogenic proteins, DMA damage or other stress conditions. Although different pathways may be involved, they eventually lead to activation of Pro-directed ⁇ /7*2 kinases, J ⁇ Ks, which phosphorylate c-Jun on S -P and enhance its transcriptional activity. Binetruy, et al. 1991. Nature 351:122-127. Smeal, et al. 1991. Nature 354:494-
  • cyclin DI underexpression includes both small and large decreases in the levels of cyclin DI compared with normal levels.
  • cyclin DI overexpression is considered in the context ofthe phase ofthe cell cycle. In actively proliferating normal cells, cyclin DI reaches a peak in mid Gi phase, decreases during S-phase, and remains low throughout the rest ofthe cycle. By contrast, in transformed cells the level of cyclin DI is more variable. Therefore, cyclin DI underexpression includes the expression of cyclin DI at levels that are abnormally low for the particular cell cycle phase ofthe cell. Cyclin DI underexpression can manifest itself as a Pinl -associated state.
  • cyclin DI overexpression includes cells having higher than normal levels of cyclin DI.
  • Significant cyclin DI overexpression includes both small and large increases in the levels of cyclin DI compared with normal levels.
  • cyclin DI overexpression is considered in the context ofthe phase ofthe cell cycle. In actively proliferating normal cells, cyclin DI reaches a peak in mid G t phase, decreases during S-phase, and remains low throughout the rest ofthe cycle. By contrast, in transformed cells the level of cyclin DI is more variable. Therefore, cyclin DI overexpression includes the expression of cyclin DI at levels that are abnormally high for the particular cell cycle phase ofthe cell.
  • Cyclin DI overexpression can manifest itself as tumor growth or cancer.
  • One skilled in the art would recognize that studies have been done measuring the level cyclin DI expression in normal cells and cells having a cancerous state. Increased cyclin DI expression has been found in a vast range of primary human tumors. Increased cyclin DI expression has been detected in the form of gene amplification, increased cyclin DI RNA expression, and increased cyclin DI protein expression. Most clinical studies comparing cyclin DI gene amplification with expression of cyclin DI have found that more cases show over-expression of both RNA and protein than show amplification ofthe gene. The presence of increased cyclin DI RNA and/or protein expression without gene amplification suggests that other cellular genes such as pRb may affect the expression cyclin DI.
  • Human tumors found to have increased cyclin DI expression include: parathyroid adenomas, mantle cell lymphomas, breast cancers, head and neck squamous cell carcinomas (i.e. squamous carcinomas in the oral cavity, nasopharynx, pharynx, hypopharynx, and larynx), esophageal cancers, hepatocellular carcinomas, colorectal cancers, genitourinary cancers, lung cancers (i.e. squamous cell carcinomas ofthe lung), skins cancers (i.e.
  • squamous cell carcinomas melanomas, and malignant fibrous histiocytomas
  • sarcomas and central nervous system malignancies (i.e. astrocytomas and glioblastomas), gastric adenocarcinomas, pancreatic adenocarcinomas, squamous carcinomas ofthe gall bladder.
  • Donnellan et al. 1998. J. Clin. Pathol: Mol. Pathol. 51:1-7.
  • the cyclin DI gene is amplified in approximately 20% of mammary carcinomas and the protein is overexpressed in approximately 50% of mammary carcinomas. Barnes, et al. 1998. Breast Cancer Research and Treatment. 52:1-15.
  • Cyclin DI overexpression in mantle cell lymphoma is discussed in Espinet, et al. 1999. Cancer Genet Cytogenet. lll(l):92-8 and Stamatopoulous, et al. 1999. Br. J. Haematol. 105(l):190-7. Cyclin DI overexpression in breast cancer is discussed in Fredersdorf, et al. 1997. PNAS 94(12):6380-5. Cyclin DI overexpression in head and neck cancers is discussed in Matthias, et al. 1999. Cancer Epidemiol. Biomarkers Prev. 8(9):815-23; Matthias, et al. 1998. Clin. Cancer Res. 4(10):2411-8; and Kyomoto, et al. 1997.
  • Cyclin DI overexpression in laryngeal carcinoma is discussed in Bellacosa, et al. 1996. Clin. Cancer Res. 2(1):175- 80. Cyclin DI overexpression in multiple myeloma is discussed in Hoechtlen-Nollmar, et al. 2000. Br. J. Haematol. 109(l):30-8; Pruneri, et al. 2000. Am. J. Pathol. 156(5):1505-13; and Janssen, et al. 2000. Blood 95(8):2691-8. It is believed that in many tumors, cyclin DI acts in co-operation with other oncogenes or tumor suppressor genes.
  • Cyclin DI expression is regulated by many factors. Growth factors (i.e. CSF1, platelet-derived growth factor, insulin-like growth factor, steroid hormones, prolactin, and serum stimulation) promote the synthesis of cyclin DI and removal of growth factors will lead to a drop in cyclin DI levels and arrest the cell in G t phase. Hosokawa, et al. 1996. J. Lab. Clin. Med. 127:246-52. In addition, hypophosphorylated pRb stimulates cyclin DI transcription, while cyclin DI activity is inhibited by transforming growth factor ⁇ -l, p53, and cyclin dependent kinase inhibitors (CKIs).
  • CSF1 growth factor 1
  • CKIs cyclin dependent kinase inhibitors
  • CKIs bind to cdks and reduce the ability of cyclins to activate the cdks.
  • the Kip/Cip family members are capable of binding to and inhibiting most cyclin-cdk complexes, whereas the JNK4 family members seem to be specific inhibitors of cyclin Dl-cdk complexes.
  • Donnellan et al. 1998. J. Clin. Pathol: Mol. Pathol. 51:1-7.
  • pRb and E2F are activators of CKI pl6, and the levels of p27 may be increased by TGF-/3, cAMP, contact inhibition, and serum deprivation.
  • Cyclin DI is believed to act through the phosphorylation of pRB.
  • pRB is hypophosphorylated throughout the Gi phase, phosphorylated just before the S phase, and remains phosphorylated until late mitosis.
  • Hypophosphorylated pRB arrests cells in Gi by forming a complex with the E2F family of DNA binding proteins, which are transcription factors that transcribe genes associated with DNA replication (the S phase ofthe cell cycle).
  • Cyclin DI can form a complex with either cdk4 or cdk6 to form activated cdk4 or cdk6.
  • Activated cdk4 or cdk6 induces the phosphorylation of pRb changing pRb from its hypophosphorylated form in which it binds to and inactivates E2F - transcription factors to phosphorylated pRb which no longer binds to and inactivates , E2F transcription factors, h some mouse lymphoma cells overexpressing D cyclins, pRb is hyperphosphorylated compared with pRb in cells not overexpressing D cyclins.
  • Neoplasma or “neoplastic transformation” is the pathologic process that results in the formation and growth of a neoplasm, tissue mass, or tumor. Such process includes uncontrolled cell growth, including either benign or malignant tumors. Neoplasms include abnormal masses of tissue, the growth of which exceeds and is uncoordinated with that ofthe normal tissues and persists in the same excessive manner after cessation ofthe stimuli that evoked the change. Neoplasms may show a partial or complete lack of structural organization and functional coordination with the normal tissue, and usually form a distinct mass of tissue.
  • Neoplasms tend to grow and function somewhat independently ofthe homeostatic mechanisms that control normal tissue growth and function. However, some neoplasms remain under the control ofthe homeostatic mechanisms that control normal tissue growth and function. For example, some neoplasms are estrogen sensitive and can be arrested by anti-estrogen therapy. Neoplasms can range in size from less than 1 cm to over 6 inches in diameter. A neoplasm even 1 cm in diameter can cause biliary obstructions and jaundice, if it arises in and obstructs the ampulla of Vater. Neoplasms tend to morphologically and functionally resemble the tissue from which they originated.
  • neoplasms arising within the islet tissue of the pancreas resemble the islet tissue, contain secretory granules, and secrete insulin.
  • Clinical features of a neoplasm may result from the function of the tissue from which it originated. For example, excessive amounts of insulin can be produced by islet cell neoplasms resulting in hypoglycemia which, in turn, results in headaches and dizziness.
  • islet cell neoplasms resulting in hypoglycemia which, in turn, results in headaches and dizziness.
  • some neoplasms show little morphological or functional resemblance to the tissue from which they originated. Some neoplasms result in such non-specific systemic effects as cachexia, increased susceptibility to infection, and fever.
  • neoplasm By assessing the histology and other features of a neoplasm, it can be determined whether the neoplasm is benign or malignant. Invasion and metastasis (the spread ofthe neoplasm to distant sites) are definitive attributes of malignancy. Despite the fact that benign neoplasms may attain enormous size, they remain discrete and distinct from the adjacent non-neoplastic tissue. Benign tumors are generally well circumscribed and round, have a capsule, and have a grey or white color, and a uniform texture. In contrast, malignant tumors generally have fingerlike projections, irregular margins, are not circumscribed, and have a variable color and texture. Benign tumors grow by pushing on adjacent tissue as they grow.
  • the benign tumor enlarges it compresses adjacent tissue, sometimes causing atrophy.
  • the junction between a benign rumor and surrounding tissue may be converted to a fibrous connective tissue capsule allowing for easy surgical removal ofthe benign tumor.
  • malignant tumors are locally invasive and grow into the adjacent tissues usually giving rise to irregular margins that are not encapsulated making it necessary to remove a wide margin of normal tissue for the surgical removal of malignant tumors.
  • Benign neoplasms tend to grow more slowly and tend to be less autonomous than malignant tumors. Benign neoplasms tend to closely histologically resemble the tissue from which they originated.
  • cancers More highly differentiated cancers, i.e., cancers that resemble the tissue from which they originated, tend to have a better prognosis than poorly differentiated cancers, while malignant tumors are more likely than benign tumors to have an aberrant function, e.g., the secretion of abnormal or excessive quantities of hormones.
  • the histological features of cancer are summarized by the term "anaplasia.” Malignant neoplasms often contain numerous mitotic cells. These cells are typically abnormal. Such mitotic aberrations account for some ofthe karyotypic abnormalities found in most cancers. Bizarre multinucleated cells are also seen in some cancers, especially those that are highly anaplastic.
  • the term "anaplasia" includes histological features of cancer.
  • the cytologic features of anaplasia include an increased nuclear-cytoplasmic ratio (nuclear-cytoplasmic ratio can be over 50% for malignant cells), nuclear pleomorphism, clumping ofthe nuclear chromatin along the nuclear membrane, increased staining ofthe nuclear chromatin, simplified endoplasmic reticulum, increased free ribosomes, pleomo ⁇ hism of mitochondria, decreased size and number of organelles, enlarged and increased numbers of nucleoli, and sometimes the presence of intermediate filaments.
  • dysplasia includes pre-malignant states in which a tissue demonstrates histologic and cytologic features intermediate between normal and anaplastic. Dysplasia is often reversible.
  • cancer includes malignancies characterized by deregulated or uncontrolled cell growth, for instance carcinomas, sarcomas, leukemias, and lymphomas.
  • cancer includes primary malignant tumors, e.g., those whose cells have not migrated to sites in the subject's body other than the site ofthe original tumor, and secondary malignant tumors, e.g., those arising from metastasis, the migration of tumor cells to secondary sites that are different from the site ofthe original tumor.
  • carcinoma includes malignancies of epithelial or endocrine tissues, including respiratory system carcinomas, gastrointestinal system carcinomas, gemtourinary system carcinomas, testicular carcinomas, breast carcinomas, prostate carcinomas, endocrine system carcinomas, melanomas, choriocarcinoma, and carcinomas ofthe cervix, lung, head and neck, colon, and ovary.
  • carcinoma also includes carcinosarcomas, which include malignant tumors composed of carcinomatous and sarcomatous tissues.
  • sarcoma includes malignant tumors of mesodermal connective tissue, e.g., tumors of bone, fat, and cartilage.
  • leukemia and “lymphoma” include malignancies ofthe hematopoietic cells ofthe bone marrow. Leukemias tend to proliferate as single cells, whereas lymphomas tend to proliferate as solid tumor masses.
  • leukemias include acute myeloid leukemia (AML), acute promyelocytic leukemia, chronic myelogenous leukemia, mixed-lineage leukemia, acute monoblastic leukemia, acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, blastic mantle cell leukemia, myelodyplastic syndrome, T cell leukemia, B cell leukemia, and chronic lymphocytic leukemia.
  • AML acute myeloid leukemia
  • AML acute promyelocytic leukemia
  • chronic myelogenous leukemia mixed-lineage leukemia
  • acute monoblastic leukemia acute lymphoblastic leukemia
  • acute non-lymphoblastic leukemia acute non-lymphoblastic leukemia
  • blastic mantle cell leukemia myelodyplastic syndrome
  • T cell leukemia B cell leukemia
  • chronic lymphocytic leukemia chronic lymphocytic leukemia
  • lymphomas examples include Hodgkni's disease, non- Hodgkin's lymphoma, B cell lymphoma, epitheliotropic lymphoma, composite lymphoma, anaplastic large cell lymphoma, gastric and non-gastric mucosa-associated lymphoid tissue lymphoma, lymphoproliferative disease, T cell lymphoma, Burkitt's lymphoma, mantle cell lymphoma, diffuse large cell lymphoma, lymphoplasmacytoid lymphoma, and multiple myeloma.
  • the therapeutic methods ofthe present invention can be applied to cancerous cells of mesenchymal origin, such as those producing sarcomas (e.g., fibrosarcoma, myxosarcoma, liosarcoma, chondrosarcoma, osteogenic sarcoma or chordosarcoma, angiosarcoma, endotheliosardcoma, lympangiosarcoma, synoviosarcoma or mesothelisosarcoma); leukemias and lymphomas such as granulocytic leukemia, monocytic leukemia, lymphocytic leukemia, malignant lymphoma, plasmocytoma, reticulum cell sarcoma, or Hodgkin's disease; sarcomas such as leiomysarcoma or rhabdomysarcoma, tumors of epithelial origin such as squamous cell carcinoma, basal cell carcinoma,
  • Additional cell types amenable to treatment according to the methods described herein include those giving rise to mammary carcinomas, gastrointestinal carcinoma, such as colonic carcinomas, bladder carcinoma, prostate carcinoma, and squamous cell carcinoma ofthe neck and head region.
  • Examples of cancers amenable to treatment according to the methods described herein include vaginal, cervical, and breast cancers.
  • the language "inhibiting undesirable cell growth” is intended to include the inhibition of undesirable or inappropriate cell growth.
  • the inhibition is intended to include inhibition of proliferation including rapid proliferation.
  • the cell growth can result in benign masses or the inhibition of cell growth resulting in malignant tumors.
  • Examples of benign conditions which result from inappropriate cell growth or angiogenesis are diabetic retinopathy, retrolental fibrioplasia, neovascular glaucoma, psoriasis, angiofibromas, rheumatoid arthritis, hemangiomas, Karposi's sarcoma, and other conditions or dysfunctions characterized by dysregulated endothelial cell division.
  • the language "inhibiting tumor growth” or “inhibiting neoplasia” includes the prevention ofthe growth of a tumor in a subject or a reduction in the growth of a pre-existing tumor in a subject. The inhibition also can be the inhibition ofthe metastasis of a tumor from one site to another.
  • tumor is intended to encompass both in vitro and in vivo tumors that form in any organ or body part ofthe subject.
  • the tumors preferably are tumors sensitive to the Pinl -modulating compounds ofthe present invention.
  • Examples ofthe types of tumors intended to be encompassed by the present invention include those tumors associated with breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer ofthe larynx, gallbladder, esophagus, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys.
  • the tumors whose growth rate is inhibited by the present invention include basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hype ⁇ lasia, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglloneuromas, hype ⁇ lastic corneal nerve tumor, marfanoid habitus tumor, Wihn's tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin
  • AD Alzheimer's disease
  • a neuropathological hallmark in Alzheimer's disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, and parkinsonism linked to chromosome 17 (FTDP-17) is the neurofibrillary tangles, whose main component is the microtubule-associated protein tau (Selkoe, DJ.
  • Pinl is required for efficient dephosphorylation of tau in vitro, because Pro-directed phosphatases such as tau phosphatase PP2A are conformation-specific, dephosphorylating only trans (but not cis) pSer/Thr-Pro motifs.
  • the term "neurodegenerative” as used herein, is used to designate a group of disorders in which there is gradual, generally relentlessly progressive wasting away of structural elements ofthe nervous system.
  • neurodegenerative phenotype includes any parameter related to neurodegeneration, e.g., a reduction in mobility, a reduction in vocalization, abnormal limb-clasping reflex, inability to succeed in a hang test as a result of retinal atrophy, an increased level of MPM-2, an increased level of neurofibril tangles, increased tau phosphorylation, tau filament formation, abnormal neuronal mo ⁇ hology, lysosomal abnormalities, neuronal degeneration, and gliosis.
  • neurodegenerative disease or disorder includes any disease disorder or condition that affects neuronal homeostasis, e.g., results in the degeneration or loss of neuronal cells.
  • Neurodegenerative diseases include conditions that the development ofthe neurons, i.e., motor or brain neurons, is abnormal, as well as conditions in which result in loss of normal neuron function.
  • Examples of such neurodegenerative disorders include Alzheimer's disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, frontaltemporal dementia and parkinsonism linked to chromosome 17.
  • the Pinl modulating compounds ofthe present invention may be used to treat, inhibit, and/or prevent undesirable cell growth, neoplasia, and/or cancer in any subject.
  • the Pinl modulating compounds ofthe present invention may be used to inhibit Pinl activity in a subject.
  • the Pinl modulating compounds ofthe present invention may be used to inhibit cyclin DI expression in a subject.
  • the invention pertains, at least in part, to a method for treating a Pinl -associated state in a subject.
  • the method includes administering to a subject an effective amount of a combination of a Pinl modulating compound ofthe invention, e.g., Pinl-modulating compounds of formula (I), formula (la), formula (II), formula (Ila), formula (IH), formula (Ilia), formula (IV), formula (IVa), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII) formula (XIH) and formula (XIV), as described above, and a hype ⁇ lastic inhibitory agent to treat the Pinl associated states.
  • the invention pertains, at least in part, to a method for treating cyclin DI overexpression in a subject.
  • the method includes administering to a subject an effective amount of a combination of a Pinl modulating compound ofthe invention, e.g., Pinl-modulating compounds of formula (I), formula (la), formula (II), formula (Ha), formula (III), formula (Ilia), formula (IN), formula (JNa), formula (V), formula (VI), formula (Nil), formula (V ⁇ T), formula (IX), formula (X), formula (XI), formula (XII) formula (XIII) and formula (XIN), as described above, and a hype ⁇ lastic inhibitory agent to treat the cyclin DI overexpression.
  • the invention pertains, at least in part, to a method for treating cancer in a subject.
  • the method includes administering to a subject an effective amount of a combination of a Pinl modulating compound ofthe invention, e.g., Pinl-modulating compounds of formula formula (I), formula (la), formula (II), formula (Ila), formula (Til), formula (Ilia), formula (IN), formula (INa), formula (N), formula (VI), formula (NH), formula (NIII), formula (IX), formula (X), formula (XI), formula (XII), formula (X ⁇ i) and formula (XIN), as described above, and a hype ⁇ lastic inhibitory agent to treat the cancer.
  • a hype ⁇ lastic inhibitory agent includes agents that inhibit the growth of proliferating cells or tissue wherein the growth of such cells or tissues is undesirable.
  • the inhibition can be ofthe growth of malignant cells, such as in neoplasms or benign cells, e.g., in tissues where the growth is inappropriate.
  • agents that can be used include chemotherapeutic agents, radiation therapy treatments, including therapeutically effective ranges of light (e.g., laser light and/or immunofluorescent compounds), and associated radioactive compounds and methods, immunotoxins, and combinations thereof.
  • chemotherapeutic agent includes chemical reagents that inhibit the growth of proliferating cells or tissues wherein the growth of such cells or tissues is undesirable.
  • Chemotherapeutic agents are well known in the art (see e.g., Gihnan A.G., et al., The Pharmacological Basis of Therapeutics, 8th Ed., Sec 12:1202- 1263 (1990)), and are typically used to treat neoplastic diseases.
  • the chemotherapeutic agents generally employed in chemotherapy treatments are listed below in Table 9.
  • chemotherapeutic agents include: bleomycin, docetaxel (Taxotere), doxorubicin, edatrexate, etoposide, finasteride (Proscar), flutamide (Eulexin), gemcitabine (Gemzar), goserelin acetate (Zoladex), granisetron (Kytril), irinotecan (Campto/Camptosar), ondansetron (Zofran), paclitaxel (Taxol), pegaspargase (Oncaspar), piloca ⁇ ine hydrochloride (Salagen), porfimer sodium (Photofrin), interleukin-2 (Proleukin), rituximab (Rituxan), topotecan (Hycamtin), trastuzumab (Herceptin), tretinoin (Retin-A), Triapine, vincristine, and vinorelbine tartrate ( ⁇ avelbine
  • the chemotherapeutic agent can be, for example, a cancer associated polypeptide inhibitor, e.g., herceptin, or a compound that alters the expression of a cancer associated polyeptide.
  • a cancer associated polypeptide inhibitor e.g., herceptin
  • a compound that alters the expression of a cancer associated polyeptide e.g., herceptin
  • the use of Pinl binding compounds in addition to a second anticancer treatment is described in "Use of Pinl Inliibitors for Treatment of Cancer," USSN: 60/504117, filed September 17, 2003, the content of which is hereby expressly inco ⁇ orated by reference in its entirety.
  • the term "cancer associated polypeptide” refers to a polypeptide whose misexpression has been shown to cause, or be associated with aberrant cell growth, e.g. , cancer. Further, cancer associated polypeptides are those that are differentially expressed in cancer cells.
  • the cancer associated polypeptide is a encoded by an oncogene.
  • the cancer associated polypeptide is a polypeptide whose expression has been linked to cancer, e.g., as a marker.
  • the presence of a cancer associated polypeptide can be determined by the presence of the polypeptide or nucleic acid molecules, e.g., mRNA or genomic DNA, that encodes the cancer associated polypeptide.
  • Exemplary cancer associated polypeptides include the protein encoded by Her2/neu, (c-erb-2) (Liu et al. (1992) Oncogene7: 1027-32); ras (Nakano, et al. (1984) Proc. Natl. Acad. Sci.
  • radiation therapy includes the application of a genetically and somatically safe level of electrons, protons, or photons, both localized and non- localized, to a subject to inhibit, reduce, or prevent symptoms or conditions associated with undesirable cell growth.
  • X-rays is also intended to include machine- generated radiation, clinically acceptable radioactive elements, and isotopes thereof, as well as the radioactive emissions therefrom. Examples ofthe types of emissions include alpha rays, beta rays including hard betas, high-energy electrons, and gamma rays.
  • Radiation therapy is well known in the art (see e.g., Fishbach, F., Laboratory Diagnostic Tests, 3rd Ed., Ch.
  • immunotoxins includes immunotherapeutic agents that employ cytotoxic T cells and/or antibodies, e.g., monoclonal, polyclonal, phage antibodies, or fragments thereof, which are utilized in the selective destruction of undesirable rapidly proliferating cells.
  • immunotoxins can include antibody-toxin conjugates (e.g., Ab-ricin and Ab-diptheria toxin), antibody-radiolabels (e.g., Ab-1135) and antibody activation ofthe complement at the tumor cell.
  • the invention pertains to a method for photochemotherapeutically treating a Pinl -associated state in a subject comprising administering to said subject an effective amount of a Pinl-modulating compound of formulas (I), (la), (II), (na), (ILT), (HIa), (TV), (INa), (V), (NT), (Nil), (NIH), (BO, (X), (XI), (XH), (X ⁇ H) and (XIN) and activation ofthe Pinl-modulating compound with a sufficent amount of light, such that said Pinl -associated state is photochemotherapeutically treated.
  • a Pinl-modulating compound of formulas (I), (la), (II), (na), (ILT), (HIa), (TV), (INa), (V), (NT), (Nil), (NIH), (BO, (X), (XI), (XH), (X ⁇ H) and (XIN) and activation ofthe Pinl-modulating compound with a sufficent amount of light, such
  • photochemotherapy or “photochemotherapeutically treating” is intended to include the art-recognized practice for the treatment of various abnormalities or disorders ofthe skin, or other epithelial organs, especially cancers or pre-cancerous lesions, e.g., melanoma, as well as certain nonmalignant lesions, for example, skin complaints such as psoriasis.
  • Photochemotherapy involves the application of photosensitizing (photochemotherapeutic) agents to the affected area ofthe body or systemic application, followed by exposure to photoactivating light in order to activate the photosensitizing agents and convert them into cytotoxic form, whereby the affected cells are killed or their proliferative potential is diminished.
  • the language "sufficient amount of light” is intended to include the amount of light sufficient to activate the Pinl modulating compound, e.g., prior to or subsequent to administration ofthe Pinl modulating compound to a subject.
  • the light may be produced and transmitted from a point external to the subject, e.g., from conventional sources (e.g., a xenon arc lamp) or from a laser, through the exterior surface ofthe subject, or via optical fibers inserted into the subject.
  • the light also may be produced from within the subject by a coadministered photoluminescent compound or the Pinl modulating compound itself (which may additionally comprise a photoluminescent molecule).
  • the light used for the photochemotherapy ofthe present invention may comprise radiation, i.e., light, of a wavelength substantially equal to the maximum abso ⁇ tion wavelength of the Pinl modulating compound, or of a wavelength band that embraces the maximum abso ⁇ tion wavelength ofthe compound.
  • the light comprises a wavelength in the region of 600 to 1,300 nm.
  • the exposure dose of light varies depending on the type and condition ofthe therapeutic target, the condition, age, sex, body weight and constitution ofthe patient, the type of he compound used, etc.
  • the wavelength of light used for irradiation may be selected to achieve a more efficacious photochemotherapeutic effect.
  • the wavelength of light used for the treatment is not less than 600 nm.
  • the invention includes a packaged Pinl-associated state treatment.
  • the packaged treatment includes a Pinl modulating compound ofthe invention, e.g., Pinl-modulating compounds of formula (I), formula (la), formula (H), formula (Ha), formula (III), formula (Hla), formula (IN), formula (INa), formula (V), formula (VI), formula (VH), formula (NET), formula (IX), fo ⁇ nula (X), formula (XT), fo ⁇ nula (XII), fo ⁇ nula (XIII) and fo ⁇ nula (XIV), as described above, packaged with instructions for using an effective amount ofthe Pinl modulating compound.
  • the invention includes a packaged cyclin DI expression treatment.
  • This packaged treatment include a Pinl modulating compound of the invention, e.g., Pinl-modulating compounds of formula (I), formula (la), formula (II), formula (Ha), fo ⁇ nula (IH), formula (IHa), formula (IV), formula (INa), fo ⁇ nula (V), formula (VI), formula (VII), fo ⁇ nula (VIII), fo ⁇ nula (IX), fo ⁇ nula (X), fo ⁇ nula (XI), formula (XII), formula (XIII) and formula (XIV), as described above, packaged with instructions for using an effective amount ofthe Pinl modulating compound to modulate, e.g., treat, cyclin DI overexpression.
  • a Pinl modulating compound of the invention e.g., Pinl-modulating compounds of formula (I), formula (la), formula (II), formula (Ha), fo ⁇ nula (IH), formula (IHa), formula (IV), formula (INa), fo ⁇ nula (V), formula (
  • the invention also pertains, at least in part to a packaged cancer treatment, which includes a Pinl-modulating compound ofthe invention, e.g., Pinl-modulating compounds of formula (I), formula (la), formula (II), fo ⁇ nula (Ila), formula (HI), fo ⁇ nula (IHa), fo ⁇ nula (IN), fo ⁇ nula (IVa), formula (V), formula (NI), formula (NH), formula (VIII), formula (IX), fo ⁇ nula (X), formula (XI), formula (XII), formula (XIII) and formula (XIN), as described above, packaged with instructions for using an effective amount ofthe Pinl-modulating compound to treat cancer.
  • a Pinl-modulating compound ofthe invention e.g., Pinl-modulating compounds of formula (I), formula (la), formula (II), fo ⁇ nula (Ila), formula (HI), fo ⁇ nula (IHa), fo ⁇ nula (IN), fo ⁇ nula (IVa), formula (
  • the invention also pertains, at least in part, to pharmaceutical compositions of Pinl-modulating compounds ofthe invention, e.g., Pinl-modulating compounds of formulas (I), (la), (H), (Ha), (IH), (Hla), (IN), (INa), (N), (VI), (VH), (NIII), (IX), (X), (XI), (XII), (Xm) and (XIN), as described above, and, optionally, a pharmaceutically acceptable carrier.
  • the language "effective amount" ofthe compound is that amount necessary or sufficient to treat or prevent a Pinl associated state, e.g. prevent the various mo ⁇ hological and somatic symptoms of a Pinl associated state.
  • an effective amount ofthe Pinl-modulating compound is the amount sufficient lo inhibit undesirable cell growth in a subject.
  • an effective amount ofthe Pinl-modulating compound is the amount sufficient to reduce the size of a pre-existing benign cell mass or malignant tumor in a subject.
  • the effective amount can vary depending on such factors as the size and weight ofthe subject, the type of illness, or the particular Pinl binding compound. For example, the choice ofthe Pinl binding compound can affect what constitutes an "effective amount".
  • One of ordinary skill in the art would be able to study the factors contained herein and make the determination regarding the effective amount ofthe Pinl binding compound without undue experimentation.
  • an effective amount of a Pinl-modulating compound can be determined by assaying for the expression of cyclin DI and determining the amount ofthe Pinl-modulating compound sufficient to modulate, e.g., reduce, the levels of cyclin DI to that associated with a non-cancerous state.
  • the regimen of administration can affect what constitutes an effective amount.
  • the Pinl binding compound can be administered to the subject either prior to or after the onset of a Pinl associated state. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection.
  • the dosages ofthe Pinl binding compound(s) can be proportionally increased or decreased as indicated by the exigencies ofthe therapeutic or prophylactic situation.
  • pharmaceutical composition includes preparations suitable for administration to mammals, e.g., humans. When the compounds ofthe present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds ofthe present invention to mammals.
  • the carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion ofthe body, to another organ, or portion ofthe body.
  • Each carrier must be "acceptable” in the sense of being compatible with the other ingredients ofthe formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ring
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, ⁇ -tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin
  • Formulations ofthe present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount ofthe compound that produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound ofthe present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound ofthe present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations ofthe invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • a compound ofthe present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl py ⁇ olidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; abso ⁇ tion accelerators, such as quaternary am
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropyhnethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture ofthe powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms ofthe pharmaceutical compositions of the present invention such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release ofthe active ingredient therein using, for example, hydroxypropyhnethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by inco ⁇ orating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more ofthe above-described excipients.
  • Liquid dosage forms for oral administration ofthe compounds ofthe invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations ofthe pha ⁇ naceutical compositions ofthe invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds ofthe invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations ofthe present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray fo ⁇ nulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound ofthe present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Abso ⁇ tion enhancers can also be used to increase the flux ofthe compound across the skin.
  • the rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
  • Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds ofthe invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous ⁇ solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance ofthe required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • microorganisms Prevention ofthe action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • prolonged abso ⁇ tion ofthe injectable pharmaceutical form may be brought about by the inclusion of agents that delay abso ⁇ tion such as aluminum monostearate and gelatin.
  • the rate of abso ⁇ tion ofthe drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
  • delayed abso ⁇ tion of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature ofthe particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • the preparations ofthe present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each adminisfration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred.
  • parenteral adminisfration and “administered parenterally” as used herein means modes of administration other than enteral and topical adminisfration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, infrathecal, infracapsular, intraorbital, infracardiac, intradermal, intraperitoneal, franstracheal, subcutaneous, subcuticular, infraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of admimstration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions ofthe present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels ofthe active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount ofthe active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity ofthe particular compound ofthe present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion ofthe particular compound being employed, the duration ofthe treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history ofthe patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount ofthe pharmaceutical composition required. For example, the physician or veterinarian could start doses ofthe compounds ofthe invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound ofthe invention will be that amount ofthe compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • intravenous and subcutaneous doses ofthe compounds of this invention for a patient when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 1.0 to about 100 mg per kg per day.
  • An effective amount is that amount treats an Pinl associated state.
  • the effective daily dose ofthe active compound maybe administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. While it is possible for a compound ofthe present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition.
  • EXEMPLIFICATION OF THE INVENTION The invention is further illustrated by the following examples, which should not be construed as further limiting. The animal models used throughout the Examples are accepted animal models and the demonstration of efficacy in these animal models is predictive of efficacy in humans.
  • Pinl-modulating compounds are potent antitumor agents.
  • the anti-tumor activity of Pinl-modulating compounds against glioblastoma cells is comparable to 1,3- bis(2-chloroethyl)- 1 -nitrosourea (BCNU), one of the most potent clinical useful antitumor agents. Misra, et al. 1982. J. Am. Chem. Soc. 104: 4478-4479
  • In vitro anti-tumor activity of Pinl-modulating compounds can be assayed by measuring the ability of Pinl-modulating compounds to kill tumor cells.
  • Examples of appropriate cells lines include: human lung (A549); resistant human lung with low topo H activity (A549-VP); murine melanoma (B16); human colon tumor (HCT116); human colon tumor with elevated pi 70 levels (HCTVM); human colon tumor with low topo H activity (HCTVP); P388 murine lymph leukemia cells; and human colon carcinoma cell line (Moser) under standard conditions.
  • a plate i.e. a 96- well flat bottom plate
  • the cells are incubated for 72 hours with serially diluted concentrations of Pinl- modulating compounds. From this data, the concentration ofthe compound at which 50% ofthe cells are killed (IC 50 ) is determined.
  • In vivo anti-tumor activity of Pinl-modulating compounds can be assayed for by a reduction of tumor cells in mammals (i.e. mice) and a resulting increase in survival time compared to untreated tumor bearing mammals.
  • mammals i.e. mice
  • CDFi mice are injected inte ⁇ eritoneally with a suspension of P388 murine lymph leukemia cells, Ehrlich carcinoma cells, B16 melanoma cells, or Meth-A fibrosarcoma cells or other appropriate tumor cell line. Some ofthe mice are treated intraperitoneally with a Pinl-modulating compounds.
  • mice are treated with saline.
  • the in vivo activity of the compound is determined in terms ofthe % T/C which is the ratio ofthe mean survival time ofthe treated group to the mean survival time ofthe saline treated group times 100.
  • % T/C is the ratio ofthe mean survival time ofthe treated group to the mean survival time ofthe saline treated group times 100.
  • a knockout-Pinl -animal that overexpresses a cancer associated polypeptide is tested for the development of cancer.
  • USSN: 60/504117 demonstrates that an animal that is deficient in Pinl expression does not develop cancer when overexpressing a known oncogene.
  • the in vivo anti-tumor activity of Pinl-modulating compounds can also be assayed as inhibitors against an ovarian tumor growing in a human tumor cloning system. Tebbe, et al. 1971 J. Am. Chem. Soc. 93:3793-3795.
  • the invention is further illustrated by the following examples, which should not be construed as further limiting.
  • Mammalian cells were seeded in 96 well flat bottom microtiter plates at a density of 5,000 6000 cells per well on day 0 in 0.1 mL of an appropriate growth media. On Day 1 , the wells were aspirated and 0.1 mL of fresh media was added. The cells were then treated with 0.01 mL of lOx drug dilutions in 10% DMSO in media and incubated at 37° C in a humidified, 5% CO 2 atmosphere. The assay contained eight drug concentrations in triplicate as well as a triplicate control where cells were treated with 0.01 mL of 10% DMSO in media.
  • a colorimetric cell-viability assay solution prepared from 20 parts (3-(4,5- dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (Promega) at 2.0 mg/mL in PBS and 1 part phenazine methosulfate (Sigma) at 0.92 mg/mL in PBS for 2-3 hours at 37 °C.
  • Background wells were prepared by incubating 0.02 mL ofthe colorimetric cell- viability assay solution with 0.1 mL of media in parallel with the cell containing wells.
  • proline isomerase activity assay is based on the method described by Fisher et al. (Biomed. Biochim. Acta, 1984, 43: 1101-1111). Specifically, the enzyme (3 ng) was preincubated with 236 uM substrate at 4 °C for 30 minutes in an 80 ⁇ L reaction volume containing 0.1 mg/ ⁇ L BSA, 0.2 mM DTT, and 35 mM HEPES (pH 7.8).
  • Proteolysis ofthe substrate was initiated by the addition of 80 ⁇ L of trypsin at 0.4 mg/mL in 35 mM HEPES (pH 7.8) and the release of p-nitroaniline was monitored every 10 seconds at 390 nm using a microplate reader (MRD/8V/DIAS, Dynex Technologies). Inhibition studies were preformed by adding 5 ⁇ L of inhibitors added in the pre-incubation mix. Inhibitors were at 0.4 mg/mL in 10% DMSO. Multiple activity-based assays at multiple dilutions, performed as described above, were used to generate the curve from which the IC50 was determined. Several IC50 results were obtained for the compounds ofthe invention using this experimental protocol.
  • the specificity ofthe Pinl inhibitor compounds ofthe invention can be determined by the protease-coupled PPIase assay developed by Fischer et al. (Bio ed. Biochim. Acta, 1984, 43: 1101-1111).
  • the enzyme activity of Pinl can be compared to members ofthe other known classes of PPIases, cyclophilins (e.g., hCyplS, hCyP-A, hCyP-B, hCyP-C, and NKCA) and FKBPs (e.g., hFKBP12, hFKBP-12, hFKBP-13, and hFKBP-25) in the presence and absence ofthe compound.
  • cyclophilins e.g., hCyplS, hCyP-A, hCyP-B, hCyP-C, and NKCA
  • FKBPs e.g., hFKBP12, hFK
  • hPinl activity measurements are determined using bovine trypsin (final concentration 0.21 mg/mL, Sigma) as an isomer specific protease and Ac-Ala-Ala-Ser(P)-Pro-Arg-pNA (Jerini, Germany) as a substrate.
  • PPIase activity of hFKBP12 (Sigma) and hCypl ⁇ (Sigma) is determined with the peptide substrate Suc-Ala-Phe-Pro-Phe-pNA (Bachem) and the protease ⁇ -chymotrypsin (final concentration 0.41 mg/mL, Sigma).
  • the test can be performed by observing the released 4-nitroanilide at 390 nm with a Hewlett-Packard 8453 UN-vis spectrophotometer at 10°C.
  • the total reaction volume is adjusted to 1.23 mL by mixing appropriate volumes of 35 mM HEPES (pH 7.8) with enzyme and effector solutions.
  • the Pinl inhibitor compound is freshly diluted from a 1 mg/mL stock solution in DMSO, and pre-incubated at varying concentrations with the enzyme for 5 min (10°C). Prior to the start of reaction by addition ofthe respective protease, 2 ⁇ L ofthe peptide substrate stock solution (10 mg/mL in DMSO) is added. The amount of organic solvent is kept constant within each experiment ( ⁇ 0.1%).
  • the pseudo-first-order rate constant k o s for cis/trans isomerization in the presence of PPIase and the first-order rate constant k 0 ofthe uncatalyzed cis/trans isomerization can be calculated using the Kinetics Software of Hewlett-Packard as well as SigmaPlot2000 for Windows 6.0 (SPSS).
  • the Kj value for inhibition of Pinl PPIase activity by a Pinl inhibitor compound ofthe invention at constant concentrations of substrate ([S 0 ] «K M ) can then be calculated by fitting the data according to the equation for a competitive "tight-binding" inhibitor using SigmaPlot2000
  • WD 8 or PC3 cells were trypsonized and diluted to a concentration of approximately 2000 cells per 100 ul of solution.
  • 100 ul of cell solution was added to each well of a micortitre plate. After the cells had grown for approximately 1 day, 10 ⁇ L of a test compound stock solution was added to each well. After approximately 2 days of growth, the media was removed from each well and ty ⁇ sin was added. After a short incubation, the trypsin was inactivated and the cells were counted using a Guava Cell Analysis System (Hayward, CA).
  • a duplicate sample, without cells added was analyzed by HPLC and the amount of test compound was determined by comparison with a standard curve. ED 5 fj values were adjusted based on the amount of soluble test compound in each well. The results of this experiment are presented below.
  • the automated cellular imaging system was used to dete ⁇ nine tissues with elevated Pinl Levels.
  • the methodology that was used to collect the data that is presented in Table 10 is described in U.S. Patent Application Publication No. US 2003-0068626 Al, the entire contents of which are inco ⁇ orated herein by reference.
  • Micro-histoarray sections were scanned and images were captured using the automated cellular imaging system (ChromaNision Medical Systems, Inc., San Juan Capistrano, CA), which combines automated microscopy and computerized image processing to analyze multiple tissues on a single shde.
  • ACIS was used to analyze microarray tissue sections on glass slides stained using a diaminodenzidine chromagen (DAB) and hematoxylin counterstain. Positive staining (brown color) as viewed by light microscope indicates the presence ofthe protein, and color intensity co ⁇ elates directly with protein quantity (expression).
  • the ACIS was able to recognize 255 levels of immunohistochemical staining intensity (0-255) and converted these to fractional scores for the selected individual areas.
  • the base limit on the threshold for the Generic DAB is pre-set at 50 by the manufacturer because the system is very sensitive. Therefore, any intensity below 50 was treated as 0 in this study. Entire immunostained tissue sections were scanned using the 4 X objective and images were captured using the 10X objective.
  • the immunohistochemical staining was quantitated without knowledge of a pathologist' s score. All tissue samples were immunostained twice at one location, and confirmed at a second location, followed by an evaluation ofthe two data sets.
  • score intensity + (X percent positive staining).
  • the % of total cases showing elevated levels (over-expression) of Pin 1 [numbers of tumor samples with score larger than the score ofthe highest normal case] total number of tumor samples multiplied by 100.
  • Liquid chromatography data was obtained using an Hewlett-Packard (HP) 1100 Series Liquid Chromatograph coupled to a Diode Array Detector [ Zorbax Eclipse XDB-C8 column; particle size 5 ⁇ m, 150 mm column length, 4.6m column diameter; flow rate of ImL/min; Solvent program, from 95% H 2 O (w/ 0.1% TFA)/ 5% Acetonitrile ( w/0.1% TFA ) to 100% Acetonitrile in 18 minutes, then held constant for 2 minutes; detection wavelength 254 nm].
  • HP Hewlett-Packard
  • Mass spectrometric data was obtained using a HP 6980 Gas Chromatograph coupled to a 5973 Mass Selective Detector: Agilent HP1 column, 15 m column length, 0.25 mm column diameter, 0.1 ⁇ m column film, 280°C injector temperature, initial oven temperature of 200°C for 3 minutes, changed to 325°C over 5 minutes, and held constant for 6 minutes. Thin-layer chromatography was performed on EM Science MK6F silica gel glass TLC plates and UN light was used for detecting compounds on the TLC plates.
  • Reagents used in reactions were purchased from Aldrich Chemical Company (Milwaukee, MO), Sigma Chemical Company (Milwaukee, MO), Fluka Chemical Company (Milwaukee, MO), Fisher Scientific (Pittsburg, PA), TCI America (Portland, OR), Ryan Scientific (Isle of Palms, SC), Lancaster Synthesis (Windham, ⁇ H ), Asinex (Moscow, Russia), Chembridge Co ⁇ oration (San Diego, CA), Matrix Scientific (Columbia, SC) or Oakwood Products Inc. (West Columbia, SC). Four synthetic routes have been used to prepare rhodanine analogs described in this invention.
  • Method A condenses an aldehyde with the active methylene of an appropriately substituted rhodanine carboxylic acid under Aldol conditions.
  • Method B condenses the aldehydes with the co ⁇ esponding ester-protected carboxylic acid, followed by hydrolytic cleavage ofthe ester to provide the carboxylic acid.
  • Method C demonstrates that the Aldol condensation can be carried out using polymer-bound rhodanine. The final product can subsequently be released from the polymer support under mild conditions to provide the analogs ofthe invention. Suzuki cross coupling reactions (method scheme not shown) can also be employed to make the compounds of the invention.
  • the crude product was dissolved in ⁇ 500 mL of acetone and warmed on a hot plate, filtered warm and washed with warm acetone. The clear yellow/orange solution was placed back on a hot plate and brought to a gentle reflux. After ⁇ 50 mL of acetone had evaporated, ⁇ 50 mL of water was added and the solution allowed to continue gentle refluxing until an additional ⁇ 50 mL of acetone had evaporated. An additional 50 mL of water was added and the solution was allowed to continue refluxing until it became cloudy, at which point is was removed from the hot plate. The cloudy solution was washed down the sides with acetone, allowed to cool to room temperature, and then placed overnight in a refrigerator.
  • Reaction Reflux for 5 hours.
  • the product subsequently precipitated from the reaction mixture; it was filtered off and washed with ethanol, resulting in 157mg of product.
  • the product of condensation reaction may be hydrolyzed by stirring in 10 mL of HCl gas diluted in dioxane for 4-10 hours. The solvent is evaporated in vacuo and the crystalline product is triturated with diethylether, then filtered off.

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Abstract

The invention is directed to modulators, e.g., inhibitors, of Pin1 and Pin1-related proteins and the use of such modulators for treatment of Pin1 associated states, e.g., for the treatment of cancer.

Description

PIN1-MODULATING COMPOUNDS AND METHODS OF USE THEREOF
Related Applications
This application claims priority to U.S. Provisional Application No. 60/488,262, attorney docket no. PTZ-075-1, entitled "Pinl -Modulating Compounds and Methods of Use Thereof, filed July 18, 2003; U.S. Provisional Application No.
60/537,171, attorney docket no. PTZ-075-2, entitled "Pinl -Modulating Compounds and Methods of Use Thereof, filed January 16, 2004; U.S. Provisional Application 60/558,916, attorney docket no. PTZ-075-3, entitled "Pinl -Modulating Compounds and Methods of Use Thereof, filed April 1, 2004; U.S. Provisional Application 60/561,131, attorney docket no. PTZ-075-4, entitled "Pinl -Modulating Compounds and Methods of Use Thereof, filed April 8, 2004; U.S. Provisional Application 60/579,262, attorney docket no. PTZ-075-5 entitled "Pinl -Modulating Compounds and Methods of Use Thereof, filed June 10, 2004. This application is related to U.S. Provisional Application No. 60/451,838, attorney docket no. PTZ-046-2, entitled "Pinl -Modulating Compounds and Methods of Use Thereof, filed March 3, 2003; U.S. Provisional Application No. 60/361,206, attorney docket no. PTZ-035-1, filed March 1, 2002, entitled "Pinl -Modulating Compounds and Methods of Use Thereof; U.S. Provisional Application Serial No. 60/361,246, attorney docket no. PTZ-034-1, filed March 1, 2002, entitled "Pinl -Modulating Compounds and Methods of Use Thereof; U.S. Provisional Application Serial No: 60/361,231, attorney docket no. PTZ-036-1, filed March 1, 2002, entitled "Pinl -Modulating Compounds and Methods of Use Thereof; U.S. Provisional Application Serial No. 60/361,227, attorney docket no. PTZ-009-1, filed on March 1, 2002; entitled "Methods for Designing Specific Inhibitors for Pinl Proline Isomerase and Pinl-Related Molecules"; U.S. Provisional Application No. 60/360,799 filed March 1, 2002, attorney docket no. PTZ-037-1, entitled "Methods of Treating Pinl Associated Disorders"; U.S. Provisional Application No. 60/451,807, attorney docket no. PTZ-034- 2, entitled "Pinl -Modulating Compounds and Methods of Use Thereof, filed March 3, 2003; U.S. Provisional Application No. 60/463,271, attorney docket no. PTZ-060-1, entitled "Photochemotherapeutic Compounds for Use in Treatment of Pinl -Associated States", filed April 16, 2003; U.S. Provisional Application 60/469,546, attorney docket no. BIZ-046-2, entitled "Pinl Ablated Animal Model for Neurodegenerative Diseases", filed May 8, 2003; and U.S. Patent Application 60/469,542, attorney docket no. BIZ- 048, entitled "Novel Regulatory Mechanisms of NF-kappaB", filed May 7, 2004. The entire contents of each ofthe aforementioned applications are hereby expressly incoφorated herein by reference in their entireties.
Background of the Invention The peptidyl-prolyl cis-frans isomerases (PPIases), or rotamases, are a family of ubiquitous enzymes that catalyze the cis/trans isomerization ofthe peptide bond on the N-terminal side of proline residues in proteins (Hunter, Cell 92:141-142, 1998). PPIases are divided into three classes, cyclophilins (Cyps), FK-506 binding proteins (FKBPs) and the Pinl/parvulin class. Cyclophilins and FKBPs are distinguished by their ability to bind the clinically immunosuppressive drugs cyclosporin and FK506, respectively (Schreiber, Science 251:283-7, 1991; Hunter, supra). Upon binding of these drugs, there are two common outcomes: inhibition ofthe PPIase activity and inhibition ofthe common target calcineurin. The inhibition of calcineurin phosphatase activity prevents lymphocytes from responding to antigen-induced mitogenic signals, thus resulting in i munusuppression. However, the inhibition ofthe PPIase activity is apparently unrelated to the immunosuppressive property ofthe drug PPIase complexes. Even more surprisingly, deletion of all 8 known cyclophilins and 4 FKBPs in the same cells does not result in any significant phenotype (Dolinski et al., Proc. Natl. Acad. Sci. USA 94:13093-131098, 1997). In contrast, members ofthe Pinl/parvulin class of PPIases bind neither of these immunosuppressive drugs, and are structurally unrelated to the other two classes of PPIases. Known members ofthe Pinl/parvulin class include Pinsl-3 (Lu et al., Nature 380;544-547, 1996), Pin-L (Campbell et al., Genomics 44: 157- 162, 1997), parvulin
(Rahfeld, et al., Proc. Natl. Acad. Sci. USA 93:447-451, 1996) and Essl/Pftl (Hanes et al., Yeast 5:55-72, 1989; and Hani, et al. FEBS Letts 365:198-202, 1995). Pinl is a highly conserved protein that catalyzes the isomerization of only phosphorylated Ser/Thr-Pro bonds (Rananathan, R. et al. (1997) Cell 89:875-86; Yaffe, et al. 1997, Science 278:1957-1960; Shen, et al. 1998,Genes Dev. 12:706-720; Lu, et al. 1999, Science 283:1325-1328; Crenshaw, et al. 1998, Embo J. 17:1315-1327; Lu, et al. 1999, Nature 399:784-788; Zhou, et al. 1999, Cell Mol. Life Sci. 56:788-806). In addition, Pinl contains an N-terminal WW domain, which functions as a phosphorylated Ser/Thre-Pro binding module (Sudol, M. (1996) Prog. Biophys. Mol. Biol. 65:113-32). This phosphorylation-dependent interaction targets Pinl to a subset of phosphorylated substrates, including Cdc25, Wee 1, Mytl, Tau-Rad4, and the C-terminal domain of RNA polymerase II large domain (Crenshaw, D.G., et al. (1998) Embo. J. 17:1315-27; Shen, M. (1998) Genes Dev. 12:706-20; Wells, NJ. (1999) J. Cell. Sci. 112: 3861-71). The specificity of Pinl activity is essential for cell growth; depletion or mutations of Pinl cause growth arrest, affect cell cycle checkpoints and induce premature mitotic entry, mitotic arrest and apoptosis in human tumor cells, yeast or Xenopus extracts (Lu, et al. 1996, Nature 380:544-547; Winkler, et al. 200, Science 287:1644-1647; Hani, et al. 1999. J. Biol. Chem. 274:108-116). In addition, Pinl is dramatically misexpressed in human cancer samples and the total level or concentration of Pinl are correlated with the aggressiveness of tumors. Moreover, inhibition of Pinl by various approaches, including Pinl antisense polynucleotides or genetic depletion, kills human and yeast dividing cells by inducing premature mitotic entry and apoptosis. Thus, Pinl -catalyzed prolyl isomerization regulates the conformation and function of these phosphoprotein substrates and facilitates dephosphorylation because of the conformational specificity of some phosphatases. Thus, Pinl-dependent peptide bond isomerization is a critical post-phosphorylation regulatory mechanism, allowing cells to turn phosphoprotein function on or off with high efficiency and specificity during temporally regulated events, including the cell cycle (Lu et al., supra).
Summary of the Invention A need exists for new diagnostic and therapeutic compounds for diseases characterized by uncontrolled cell proliferation and primarily malignancies associated with the Pin-1 subfamily of enzymes. Accordingly, the invention is directed to modulators of Pinl and Pinl- related proteins and the use of such modulators for treatment of Pinl associated states, e.g., for the treatment of cancer or neurodegenerative diseases. In one embodiment, the invention pertains, at least in part, to a method for treating a Pinl -associated state in a subject. The method includes administering to the subject an effective amount of a Pinl -modulating compound of formula (Ig):
Figure imgf000005_0001
wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of
O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2O-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, linking groups, and carbocyclic groups may be substituted with one or more substituents; such substituents can include, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl arnino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tetrazole, friazole, piperidine, or an aromatic or heteroaromatic moiety; and any combination thereof; Ri is H or is selected from one or a combination of alkyl groups, aromatic groups, heterocyclic groups, and carbocyclic groups, which may be indirectly linked to the nitrogen ofthe core ring of formula I via alkyl, substituted alkyl, alkenyl, -O-, - N(H)-, -C(O)~, -S-, or -S(O)2O-, and any combination thereof; which may be further substituted with one or more substituents; such substituents can include alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tetrazole, friazole, piperidine, or an aromatic or heteroaromatic moiety, and any combination thereof; such that the Pinl -associated state is freated. In a particular embodiment, Rt is selected from the group consisting of - H; -Cι-6 (e.g., -CH3, -CH2CH2CH2CH2-), -CH2CHCH2) -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of -H, -Cι-6 (e.g., -CH3, -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, friazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, -C1-6 (e.g., -CH3, -CH2CH2CH CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, friazole, piperidine, -O-, - C(O)NH2, -C(O)R , -N(R5)2, and any combination thereof; wherein R3 is selected from the group consisting of — H, -OH, -O-, -C1-6 (e.g., -CH3) -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, friazole, piperidine, -C(O)NH2, -CH CH(OH)CH3, - C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of - H, -CI, -Br, -I, -F, OH, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-); moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, friazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof. In a second embodiment, the invention pertains, at least in part, to a method for modulating, e.g., treating, cyclin DI expression, e.g., overexpression, in a subject. This method includes administering to the subject an effective amount of a Pinl -modulating compound of formula (Ig):
Figure imgf000007_0001
(Ig) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2O-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, linking groups, and carbocyclic groups may be substituted with one or more substituents; such substituents can include, alkenyl, alkynyl, halogen, hydroxyl, alkylearbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylai lamino), acylarriino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, or an aromatic or heteroaromatic moiety; and any combination thereof; Ri is H or is selected from one or a combination of alkyl groups, aromatic groups, heterocyclic groups, and carbocyclic groups, which may be indirectly linked to the nitrogen ofthe core ring of formula I via alkyl, substituted alkyl, alkenyl, -O-, - N(H)-, -C(O)-, -S-, or -S(O)2O-, and any combination thereof; which may be further substituted with one or more substituents; such substituents can include alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,' imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, or an aromatic or heteroaromatic moiety, and any combination thereof; packaged with instructions for using an effective amount ofthe Pinl- modulating compound to freat a Pinl associated state. In a particular embodiment, Ri is selected from the group consisting of - H; -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-), -CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -C1-6 (e.g., -CH3; -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, -C1-6 (e.g., -CH3( -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, - C(O)NH2, -C(O)R3, -N(R5)2, and any combination thereof; wherein R3 is selected from the group consisting of-H, -OH, -O-, -C1-6 (e.g., -CH3)-CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -CH2(CH2)2C(O)NH2, - CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of - H, -CI, -Br, -I, -F, OH, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2- moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, CH2(CH2)2C(O)NH2> -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof. The invention also includes a packaged cyclin DI expression, e.g., overexpression, treatment. This packaged treatment include a Pinl -modulating compound of formula (Ig) :
Figure imgf000009_0001
(Ig) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of
O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2O-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, linking groups, and carbocyclic groups may be substituted with one or more substituents; such substituents can include, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, or an aromatic or heteroaromatic moiety; and any combination thereof; Ri is H or is selected from one or a combination of alkyl groups, aromatic groups, heterocyclic groups, and carbocyclic groups, which may be indirectly linked to the nitrogen ofthe core ring of formula I via alkyl, substituted alkyl, alkenyl, -O-, - N(H)-, -C(O)-, -S-, or -S(O)2θ-, and any combination thereof; which may be further substituted with one or more substituents; such substituents can include alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, or an aromatic or heteroaromatic moiety, and any combination thereof; packaged with instractions for using an effective amount ofthe Pinl- modulating compound to treat cancer. In a particular embodiment, Ri is selected from the group consisting of - H; -Cι.6 (e.g., -CH3, -CH2CH2CH2CH2-), -CH2CHCH2, -NH2, -(X)pRα, -(X)PC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-X moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -S-, -N-, -OH,
CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, -C1-6 (e.g., -CH3; -CH2CH2CH2CH2-X moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -
C(O)NH2, -C(O)R3, -N(R5)2, and any combination thereof; wherem R3 is selected from the group consisting of-H, -OH, -O-, -C1-6
(e.g., -CH3; -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -CH2(CH2)2C(O)NH2, -
CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of -
H, -CI, -Br, -I, -F, OH, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-X moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine,
CH2(CH2)2C(O)NH2( -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof. In another embodiment, the invention pertains, at least in part, to a method for treating a Pinl -associated state in a subject. The method includes administering to a subject an effective amount of a combination of a Pinl -modulating compound of formula (Ig) :
Figure imgf000011_0001
(Ig) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2O-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, linking groups, and carbocyclic groups may be substituted with one or more substituents; such substituents can include, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, - alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, or an aromatic or heteroaromatic moiety; and any combination thereof; Ri is H or is selected from one or a combination of alkyl groups, aromatic groups, heterocyclic groups, and carbocyclic groups, which may be indirectly linked to the nitrogen ofthe core ring of formula I via alkyl, substituted alkyl, alkenyl, -O-, - N(H)-, -C(O)-, -S-, or -S(O)2O-, and any combination thereof; which may be further substituted with one or more substituents; such substituents can include alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, or an aromatic or heteroaromatic moiety, and any combination thereof; and a hypeφlastic inhibitory agent such that the Pinl associated state is treated. In a particular embodiment, Ri is selected from the group consisting of - H; -Ci-β (e.g., -CH3, -CH2CH2CH2CH2-), -CH2CHCH2; -NH2, -(X)PRa, -(X)PC(O)Ra, wherein p is selected from the group consisting of 1 tlirough 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -Cι-6 (e.g., -CH3, -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, -C1-6 (e.g., -CH3; -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, - C(O)NH2, -C(O)R3, -N(R5)2, and any combination thereof; wherein R is selected from the group consisting of — H, -OH, -O-, -C1-6 (e.g., -CH , -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -CH2(CH2)2C(O)NH2, - CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of - H, -CI, -Br, -I, -F, OH, -O-, -C1-6 (e.g., -CH3> -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof. hi another embodiment, the invention pertains, at least in part, to a method for freating cancer in a subject. The method includes administering to the subj ect an effective amount of a combination of a Pinl -modulating compound of formula (Ig):
Figure imgf000014_0001
(Ig) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of
O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2θ-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, linking groups, and carbocyclic groups may be substituted with one or more substituents; such substituents can include, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino
(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, or an aromatic or heteroaromatic moiety; and any combination thereof; Ri is H or is selected from one or a combination of alkyl groups, aromatic groups, heterocyclic groups, and carbocyclic groups, which may be mdirectly linked to the nitrogen ofthe core ring of formula I via alkyl, substituted alkyl, alkenyl, -O-, - N(H)-, -C(O)-, -S-, or -S(O)2θ-, and any combination thereof; which may be further substituted with one or more substituents; such substituents can include alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, or an aromatic or heteroaromatic moiety, and any combination thereof; and a hypeφlastic inhibitory agent such that the cancer is treated. In a particular embodiment,
Figure imgf000015_0001
is selected from the group consisting of-H; -C1-6 (e.g., -CH3> -CH2CH2CH2CH2-), -CH2CHCH2, -NH2, -(X)PRa, - (X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -C1-6 (e.g., -CH3j -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, -C1-6 (e.g., -CH ; -CH2CH2CH2CH2-X moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, - C(O)NH2, -C(O)R3, -N(R5)2, and any combination thereof; wherein R3 is selected from the group consisting of-H, -OH, -O-, -Cι-6 (e.g., -CH3j-CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -CH2(CH2)2C(O)NH2, - CH2CH(OH)CH3, -C(O)N(CH3>, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of - H, -CI, -Br, -I, -F, OH, -O-, -C1-6 (e.g., -CH3) -CH2CH2CH2CH2-X moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2j -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof. In an additional embodiment, the invention is a method for modulating, e.g., freating cyclin DI overexpression in a subject. The method includes administering to the subject an effective amount of a combination of a Pinl -modulating compound of formula (Ig):
Figure imgf000016_0001
wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of
O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O) O-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, linking groups, and carbocyclic groups may be substituted with one or more substituents; such substituents can include, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diaiylamino, and alkylarylaniino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, or an aromatic or heteroaromatic moiety; and any combination thereof; Ri is H or is selected from one or a combination of alkyl groups, aromatic groups, heterocyclic groups, and carbocyclic groups, which may be indirectly linked to the nitrogen ofthe core ring of formula I via alkyl, substituted alkyl, alkenyl, -O-, - N(H)-, -C(O)-, -S-, or -S(O)2θ-, and any combination thereof; which may be further substituted with one or more substituents; such substituents can include alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, or an aromatic or heteroaromatic moiety, and any combination thereof. In a particular embodiment, Ri is selected from the group consisting of - H; -C1-6 (e.g., -CH3; -CH2CH2CH2CH2-), -CH2CHCH2> -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -Cι-6 (e.g., -CH3> -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, -C1-6 (e.g., -CH3> -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, - C(O)NH2, -C(O)R3, -N(R5)2, and any combination thereof; wherein R3 is selected from the group consisting of-H, -OH, -O-, -C1-6 (e.g., -CH3> -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -CH2(CH2)2C(O)NH2, - CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of -
H, -CI, -Br, -I, -F, OH, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-X moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -
CH2(CH2)2C(O)NH2j -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof. Another embod ment ofthe invention is a pharmaceutical composition comprising a Pinl -modulating compound as prepared according to the methodology of this invention, and a pharmaceutically acceptable carrier.
Detailed Description ofthe Invention The invention is directed to modulators, of Pinl and Pinl-related proteins and the use of such modulators for freatment of Pinl associated states, e.g. , for the freatment of cancer. In one embodiment, the invention pertains, at least in part, to a method for freating a Pinl -associated state in a subject. For example, the method includes administering to the subject an effective amount of a Pinl -modulating compound ofthe invention having formula (I):
Figure imgf000018_0001
(I) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, wliich may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2O-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups may be substituted with one or more substituents selected from the group consisting of H, CH3, F, CH2OH, NH2, OH, CF3, CI, Br, I, -O-, -C1-6 (e.g., -CH3( -CH2CH2CH2CH2-X -CH=CHCH2-, =O, =NH, =N-NH2, -NC(O)CH3, -C(O)-OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NΗ2, -C(0)-
NHCH3, -CH2NH2, -OCH2C(O)NH-NH2, -CH2C(O)CH3, moφholino, C(O)moφholino, -CH2C(O)C(CH3)3, -C(O)-OCH2CH3, and any combination thereof; Ri is selected from the group consisting of-H; -C1-6 (e.g., -CH3>- CH2CH2CH2CH2-X -CH2CHCH2, -NH2, -(X)PRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, C1- (e.g. -CH2CH3), - CH2CH2-, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -CH2-, -C(O)NH2, -C(O)R3, -N(R5)2, and any combination thereof; wherein R3 is selected from the group consisting of-H, -OH, -O-, C1-4 (e.g. -CH2CH3), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -C(O)NH2> -CH2CH2OH, - CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherem each R5 is independently selected from the group consisting of-H, -F, -OH, -O-, C1- (e.g. -CH2CH3), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; such that the Pinl -associated state is treated. In one embodiment, m is not 0, when n is 1. In another embodiment, m is not 1 , when n is 1. In another embodiment, the Pinl -modulating compound is a compound having formula (la):
Figure imgf000020_0001
(la) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by alkylene, -S(O)2θ-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups', and carbocyclic groups may be substituted with one or more substituents selected from the group consisting of H, CH3, F, CH2OH, NH2, OH, CF3, CI, Br, OCH3, =O, =NH, =N-NH2, ~(CH2)0- 2NC(O)CH3, -C(O)-OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, - CH2NH2, -OCH2C(O)NH-NH25 -CH2C(O)CH3, -(CH2)o-2moφholino, -(CH2)0- iC(O)moφholine, -CH2C(O)C(CH3)3, -C(O)-OCH2CH3, and any combination thereof; Ri is selected from the group consisting of H; -(X)pC(O)R2, wherein p is selected from the group consisting of 1 through 6, wherein X is CH2 or NH, wherein R2 is selected from the group consisting of OH and tefrazole; -CH2-; - C(O)NH2-, C(O)R3, wherein R3 is selected from the group consisting of OH and tefrazole; -CH(CH3); -CH2CH2-; phenol; benzene; piperazine; -CH2(CH2)2C(O)NH2; - CH2CH2OH; -CH2CH(OH)CH3; -C(O)N(CH3 ; and any combination thereof; such that the Pinl -associated state is freated. In one embodiment, m is not 0, when n is 1. In another embodiment, m is not 1, when n is 1. In yet another embodiment, the Pinl -modulating compound is a compound having formula (II):
(H) wherein the dashed line indicates a single or a double bond; n is O or l; is H or lower alkyl, e.g. , C 1 -C6, e.g. , CH3 ; X1, X2 and X3 are independently selected from the group consisting of C, CH, NH, O, S', and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-) F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -NC(O)CH3j-C(O)OC(CH3)3i -NC(O)-OC(CH3)3, -C(O)NH2, - C(O)NHCH3, -CH2NH2, -OCH2C(O)NH-NH2, -CH2C(O)CH3, -moφholino, - C(O)moφholino, -CH2C(O)C(CH3) , -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xl3 X2, and X , and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Cι-6 (e.g., -
CH3; -CH2CH2CH2CH2-), -CH2CHCH2) -NH2, -(X)pRa, -{X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, C1-6 (e.g. CH , -CH2CH2CH2CH2-); moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-X -C(O)NH2, -C(O)R , - N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -C1-6 (e.g., -CH3>-CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - (CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -C1-6 (e.g., -CH3> -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -CH2(CH2)2C(O) H2, -CH2CH2OH, -CH2CH(OH)CH3, - C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, - CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R ' are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-), -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof; such that the Pinl -associated state is treated. In yet another embodiment, the Pinl-modulating compound is a compound having formula (Ha):
Figure imgf000023_0001
(Ila) wherein the dashed line indicates a single or a double bond; n is O or l; R is H or lower alkyl, e.g., C1-C6, e.g., CH3; Xi, X2 and X3 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R , and Rδ are independently selected from the group consisting of H; CH3; F; CH2OH; NH2; OH; CF3; CI; Br; OCH3; =O; =NH; =N-NH2; - (CH2)0-2NC(O)CH3; -C(O)-OC(CH3)3; -N-C(O)-OC(CH3)3; -C(O)-NH2; -C(O)-NHCH3; -CH2NH2; -OCH2C(O)NH-NH2; -CH2C(O)CH3; -(CH2)0- moφhohno; -(CH2)0- ιC(O)moφholine; -CH2C(O)C(CH3)3; -C(O)-OCH2CH3; one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by alkylene, -S(O)2O- , -S-, or -OCH2-; and wherein R2 and R3, R2 and R6, and/or R3 and R6 can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X ; and any combination thereof; i is selected from the group consisting of H; -(X)pC(O)R2, wherein p is selected from the group consisting of 1 through 6, wherein X is CH2 or NH, wherein R2 is selected from the group consisting of OH and tetrazole; -CH2-; - C(O)NH2-, C(O)R3, wherem R3 is selected from the group consisting of OH and tetrazole; -CH(CH3); -CH2CH2-; phenol; benzene; piperazine; -CH2(CH2)2C(O)NH2; - CH2CH2OH; - CH2CH(OH)CH3; -C(O)N(CH3)-; and any combination thereof; such that the Pinl -associated state is treated. In yet another embodiment, the Pinl -modulating compound is a compound having formula (III):
Figure imgf000024_0001
(in) wherein the dashed line indicates a single or a double bond; n is 0 or 1 ; R4 is H or lower alkyl, e.g., Cl-C6, e.g., CH3 ; Xi, X2, X3, X-i, and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and R are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3) -CH2CH2CH2CH2-X F, NH2; CF3, CI, Br, I, =O, =NH, =N-NH2> -(CH2)0-2NC(O)CH3, -C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, - C(O)NHCH3, -CH2NH2, -OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, - (CH2)0-ιC(O)moφholino, -CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xls X2, and X3, and any combination thereof; Ri is selected from the group consisting of — H, -O-, -Cι.e (e.g., - CH3>-CH2CH2CH2CH2-X-CH2CHCH2) -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 tlirough 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -C1-6 (e.g., - CH3; -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -C1-6 (e.g., -CH3) -CH2CH2CH2CH2-X -C(O)NH2, -C(O)Rb, - N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - (CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of -H, -F, -CI, -Br, -I, -OH, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3> - C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, - CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R ' are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3( -CH2CH2CH2CH2-X -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tefrazole, triazole, piperidine, and any combination thereof; such that the Pinl -associated state is freated. In another embodiment, Pinl -modulating compound is a compound having formula (Ilia):
Figure imgf000026_0001
(Ilia) wherein the dashed line indicates a single or a double bond; n is O or l; R4 is H or lower alkyl, e.g., C1-C6, e.g., CH3; X1? X2, X3, X4, and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Rζ are independently selected from the group consisting of H; CH3; F; CH2OH; NH2; OH; CF3; CI; Br; OCH3; =O; =NH; =N-NH2; - (CH2)o-2NC(O)CH3; -C(O)-OC(CH3)3; -N-C(O)-OC(CH3)3; -C(O)-NH2; -C(O)-NHCH3; -CH2NH2; -OCH2C(O)NH-NH2; -CH2C(O)CH3; -(CH2)0-2moφholino; -(CH2)0- iC(O)moφholine; -CH2C(O)C(CH3)3; -C(O)-OCH2CH3; one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by alkylene, -S(O)2O- , -S-, or -OCH2-; and wherein R2 and R3, R2 and R6, and/or R3 and R6 can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3; and any combination thereof; Ri is selected from the group consisting of H; -(X)pC(O)R2, wherein p is selected from the group consisting of 1 through 6, wherein X is CH2 or NH, wherein R2 is selected from the group consisting of OH and tefrazole; -CH2-; - C(O)NH2-, C(O)R3, wherein R3 is selected from the group consisting of OH and tefrazole; -CH(CH3); -CH2CH2-; phenol; benzene; piperazine; -CH2(CH2)2C(O)NH2; - CH2CH2OH; -CH2CH(OH)CH3; -C(O)N(CH3)-; and any combination thereof; such that the Pinl -associated state is freated. In yet another embodiment, the Pinl -modulating compound is a compound having formula (IN):
Figure imgf000027_0001
(IN) wherein the dashed line indicates a single or a double bond; is O or 1; R4 is H or lower alkyl, e.g., C1-C6, e.g., CH3; Xi is selected from the group consisting of C, CH, ΝH, O, S, and Ν; R2, R3, and Re are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-X F, ΝH2) CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)o-2NC(O)CH3;-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, - C(O)NHCH3, -CH2NH2, -OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)o-2moφholino, - (CH2)0-ιC(O)moφholino, -CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xl5 X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -C1-6 (e.g., - CH3; -CH2CH2CH2CH2-X -CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of — H, -O-, -C1-6 (e.g., - CH3)-CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -C1-6 (e.g., -CH3) -CH2CH2CH2CH2-X -C(O)NH2, -C(O)R , - N(R5)2, and any combination thereof; wherein R is selected from the group consisting of-H, -OH, -O-, -Cι.6 (e.g., -CH3, -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - (CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -C1-6 (e.g., -CH3> -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -CH2(CH2)2C(O)NH2> -CH2CH2OH, -CH2CH(OH)CH3> -
C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, - CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R7' are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-X -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tefrazole, triazole, piperidine, and any combination thereof; such that the Pinl -associated state is freated.
In another embodiment, the Pinl -modulating compound is a compound having formula (INa):
Figure imgf000029_0001
(INa) wherein the dashed line indicates a single or a double bond; n is O or 1; l^t is H or lower alkyl, e.g. , C 1 -C6, e.g. , CH3 ; Xi is selected from the group consisting of C, CH, ΝH, O, S, and Ν; R2, R3, and Re are independently selected from the group consisting of H; CH3; F; CH2OH; ΝH2; OH; CF3; CI; Br; OCH3; =O; =NH; =N-NH2; - (CH2)0-2NC(O)CH3; -C(O)-OC(CH3)3; -N-C(O)-OC(CH3)3; -C(O)-NH2; -C(O)-NHCH3; -CH2NH2; -OCH2C(O)NH-NH2; -CH2C(O)CH3; -(CH2)0-2moφholino; -(CH2)o- ιC(O)moφholine; -CH2C(O)C(CH3)3; -C(O)-OCH2CH3; one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, jomed to form a multi-cyclic structure, or indirectly linked by alkylene, -S(O)2O- , -S-, or -OCH2-; and wherein R2 and R3, R2 and R6, and/or R3 and R6 can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi; and any combination thereof; Ri is selected from the group consisting of H; -(X)pC(O)R2, wherein p is selected from the group consisting of 1 through 6, wherein X is CH2 or NH, wherein R2 is selected from the group consisting of OH and tetrazole; -CH2-; - C(O)NH2-, C(O)R3, wherein R3 is selected from the group consisting of OH and tetrazole; -CH(CH3); -CH2CH2-; phenol; benzene; piperazine; -CH2(CH2)2C(O)NH2; - CH2CH2OH; -CH2CH(OH)CH3; -C(O)N(CH3)-; and any combination thereof; such that the Pinl-associated state is freated. In another embodiment, the Pinl -modulating compound is a compound having formula
Figure imgf000030_0001
wherein the dashed line indicates a single or a double bond; n is O or l; R4 is H or lower alkyl, e.g., C1-C6, e.g., CH3; Xi, X2, X3, Λ and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-X F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)o-2NC(O)CH3) -C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, - C(O)NHCH3, -CH2NH2, -OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, - (CH2)o-ιC(O)moφholino, -CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Cι-6 (e.g., - CH3,-CH2CH2CH2CH2-X-CH2CHCH2; -NH2, -<X)PRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Cι-6 (e.g., - CH3, -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -C1-6 (e.g., -CH3> -CH2CH2CH2CH2-X -C(O)NH2, -C(O)Rb, - N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-X moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - (CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Cι-6 (e.g., -CH3, -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, - C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, - CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R7' are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-), -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof; such that the Pinl -associated state is freated. In certain embodiments ofthe invention, Z is S. In certain embodiments, Zi is O. In addition, in certain embodiments ofthe invention, n is selected from the group consisting of 0 through 5. Additionally, in particular embodiments ofthe invention, the aromatic groups, heterocyclic groups, and carbocyclic groups are selected from the group consisting of a pyridine, a phenyl, a IH-imidazole, a thiazolidine, a pyrrolidone, a hexahydro-pyrimidine, a 3-hydroxy-pyrrolidin-2-one, a pyrrolidine-2,3- dione, a pyrrolidine-2,5-dione, a pyrrolidin-2-one, a cyclopentyl, a [l,4]dioxepane, a tefrahydrofuran, an isoxazole, a moφholino, a [l,3]dioxolane, apyrimidine, a furan, a thiophene, a pyrrole, a naphthalene, a pyrazole, a 3 -(methylene)- 1 -methyl- 1,3 -dihydro- indol-2-one, a benzo[l,3]dioxole, a piperazine, and a furazan 2-oxide. In another embodiment ofthe invention, Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000032_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH. In another embodiment ofthe invention, Ri is -(X)pC(O)Ra, and Ra is the formula Rj:
Figure imgf000032_0002
wherein R8 is selected from H, F or OH. In another embodiment ofthe invention, Ri is -(X)pC(O)Ra, Ra is
N(R5)2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O- (CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino. In another embodiment ofthe invention, R is selected from the group consisting of -N-(CH2)2-moφholino,-O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino. In still another embodiment, the invention is directed to a compound of formula (IT), having the formula (VI):
Figure imgf000032_0003
wherein R2 and R3 are independently selected from the group consisting of H, -O-, -C1-5 (e.g., -CH3,-CH2CH2CH2CH2-),F, CH2OH, NH2, OH, CF3> CI, Br, I, -
NC(O)CH3, -C(O)-OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-KHCH3, -
CH2NH2,
-OCH2C(O)NH-NH2, -CH2C(O)CH3, -, -(CH2)0-1C(O)moφholino, -CH2C(O)C(CH3)3, - C(O)-OCH2CH3, one or a combination of aromatic groups, heterocychc groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -S-, or -OCH2-;
1 wherein R and R ' are independently selected from the group consisting of H; -O-, -Cι-6 (e.g., -CH3, -CH2CH2CH2CH2-), -S-, -N-, -CH=CHCH3> moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tefrazole, triazole, piperidine, and any combination thereof; wherein R and R9' are independently selected from the group consisting of H, -O-, -Cι-6 (e.g., -CH3> -CH2CH2CH2CH2-),F, CH2OH, NH2> OH, CF3, CI, Br, I, - COOH, -S-, -N-, -CH=CHCH3; moφholino, phenol, phenyl, piperazine, cyclopentane, -
COOH, cyclohexane, pyridine, tefrazole, triazole, piperidine, and any combination thereof. In still another embodiment, the invention is directed to a compound of formula (V), having the formula (VH):
Figure imgf000033_0001
wherein R2 and R3 are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3,-CH2CH2CH2CH2-),F, CH2OH, NH2, OH, CF3, CI, Br, I, - NC(O)CH3, -C(O)-OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, - CH2NH2,
-OCH2C(O)NH-NH2, -CH2C(O)CH3, -, -(CH2)0-ιC(O)moφholino, -CH2C(O)C(CH3)3, - C(O)-OCH2CH3, one or a combmation of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -S-, or -OCH2-; wherein R and R ' are independently selected from the group consisting of H; -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-), -S-, -N-, -CH=CHCH3j moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof; wherein R9 and R ' are independently selected from the group consisting of H, -O-, -Cι-6 (e.g., -CH3)-CH2CH2CH2CH2-),F, CH2OH, NH2, OH, CF3, CI, Br, I, - COOH, -S-, -N-, -CH=CHCH3; moφholino, phenol, phenyl, piperazine, cyclopentane, - COOH, cyclohexane, pyridine, tefrazole, triazole, piperidine, and any combination thereof. In yet another embodiment, the invention is directed to a compound of formula (II): 2-Fluoro-4-(3- {5-[4-(4-fluoro-3-trifluoromethyl-ρhenyl)-thiophen-2- yhnethylene]-4-oxo-2-thioxo-thiazolidin-3-yl} -propionylamino)-benzoic acid (Ja):
Figure imgf000034_0001
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(3-{5-[4-(2-Mθφholin-4-yl-ethoxy)-3',5,-Bis-trifluoromethyl-biphenyl-3- ylmethylene]-2,4-dioxo-thiazolidin-3-yl} -propionylamino)-benzoic acid (Jb) :
Figure imgf000034_0002
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(3-{5-[6-(2-Moφholin-4-yl-ethoxy)- S'jS'-Bis-trifluorometliyl-biplienyl- 3-yhnethylene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propoxy)-benzoic acid (J0):
Figure imgf000035_0001
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(2-{5-[6-(2-Moφholin-4-yl-ethoxy)-3',6'-dichloro-biphenyl-3- ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl} -ethyl)-benzoic acid (J ):
Figure imgf000035_0002
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(3-{5-[4-(2-Moφholin-4-yl-ethoxy)- 3',6'-dichloro-biphenyl-3- ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl} -propoxy)-benzoic acid (Je):
Figure imgf000035_0003
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(3-{5-[4-(2-Moφholin-4-yl-ethoxy)-3',4'-dichloro biphenyl-3- ylmemylene]-4-oxo-2-lMoxo-tMazohdin-3-yl}-propionylamino)-benzoic acid (Jf):
Figure imgf000036_0001
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V), having the formula (VIII):
Figure imgf000036_0002
wherein R2, R3 and Re are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-), F, CH2OH, NH2> OH, CF3, CI, Br, I, -NC(O)CH3,-C(O)-OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, -
-OCH2C(O)lS[H-NH2, -CH2C(O)CH3, moφholino, -C(O)moφholino, -CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure containing carbons a and b, b and c, c and d or d and e; and any combination thereof; Ri is selected from the group consisting of-H, -O-, -C1-6 (e.g., -CH3(- CH2CH2CH2CH2-), -CH2CHCH2, - ϊ2, -(X)pRa, -(X)PC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -C1-6 (e.g., -CH ι - CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -CH2-, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -C1-6 (e.g., -CH3, -
CH2CH2CH2CH2-X moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -CH2(CH2)2C(O) H2, -CH2CH2OH, - CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of -
H, -F, -CI, -Br, -I, -OH, -O-, -C1-6 (e.g., -CH3) -CH2CH2CH2CH2-X moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2) -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; In still another embodiment, the invention is directed to a compound of formula (V), having the formula (IX):
Figure imgf000037_0001
wherein R2, R3 and Re are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-), F, CH2OH, NH2, OH, CF3, CI, Br, I, -NC(O)CH3; -C(O)-OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, - -OCH2C(O)NH-NH2, -CH2C(O)CH3, moφholino, -C(O)moφholino, -CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which maybe directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure containing carbons a and b, b and c, c and d or d and e; and any combination thereof; Ri is selected from the group consisting of-H, -O-, -C1-6 (e.g., -CH3, - CH2CH CH2CH2-X -CH2CHCH2, -NH2, -(X)PRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-,
Figure imgf000038_0001
(e.g., -CH3; - CH2CH2CH2CH2-X moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-), -C(O)NH2, -C(O)Rb, - N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Cι-6 (e.g., -CH3> -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, - CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of - H, -F, -OH, -O-, -Ci-e (e.g., -CH3, -CH2CH2CH2CH2-X moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2) -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof. In another embodiment, the invention is directed to a compound of formula (V), having the formula (X):
Figure imgf000039_0001
wherein the dashed line indicates a single or a double bond; n is 0 or 1 ; Xi, X2, X3, X , X5 and X6 are independently selected from the group consisting of C, CH, NH, N, S and O; Rπ, R12, and R13 are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3;-CH2CH2CH2CH2-))F, -N(H)-, CH2OH, CH2CH2OH, NH2, OH, CF3, CI, Br, I, -(CH2)o-2NC(O)CH3, -C(O)-OC(CH3)3, -N-C(O)- OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, -CH2NH2, -OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)o-2moφholino, -(CH2)0-1C(O)moφholino, -CH2C(O)C(CH3)3, -C(O)-OCH2CH3 and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Cι_6 (e.g., - CH3, -CH2CH2CH2CH2-); -CH2CHCH2, -NH2, -(X)PRa, -(X O)!^, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Ci-e (e.g., - CH3j-CH2CH2CH2CH2-); moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -CH2-, -C(O) ϊ2, -C(O)Rb, -N(Rs)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -C1-6 (e.g., -CH3) - CH2CH2CH CH2-)j moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, friazole, piperidine, -CH2(CH2)2C(O)NH2, -CH2CH2OH, - CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -OH, -O-, -C1-6 (e.g., -CH3; -CH2CH2CH2CH2-X moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2; -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R7' are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-), -S-, -N-, -CH=CHCH3j moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof. In still another embodiment, the invention is directed to a compound of formula (V): 4-(2- {5-[4-(2-Moφholin-4-yl-ethoxy)-3-naphthalen-2-yl-benzylidene]-4- oxo-2-thioxo-thiazolidin-3 -yl} -ethyl)-benzoic acid ( Jg) :
Figure imgf000040_0001
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(2-{5-[4-(2-Moφholin-4-yl-ethoxy)-3-quinolin-3-yl-benzylidene]-4-oxo- 2-thioxo-thiazolidin-3-yl}-ethyl)-benzoic acid (J ):
Figure imgf000040_0002
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(2- {5-[3-(2-Amino-pyrido[3,2-d]pyrimidin-7-yl)-4-(2-moφholin-4-yl- ethoxy)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-ethyl)-benzoic acid (Ji):
Figure imgf000041_0001
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V), having the formula XI:
Figure imgf000041_0002
wherein the dashed line indicates a single or a double bond; wherein R2, R3 and R are independently selected from the group consisting of H, -O-, -C1-6 (e.g., -CH3, -CH2CH2CH2CH2-), F, CH2OH, NH2) OH, CF3, CI, Br, I, -NC(O)CH3, -C(O)-OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, -
CH2NH2,
-OCH2C(O)NH-NH2, -CH2C(O)CH3, moφholino, -C(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure containing carbons a and b, b and c, c and d or d and e; and any combination thereof; wherein G is selected from the group consisting of (CH2)1-6, -C(O)-, -O-, -N(R5)-, and any combination thereof; wherein R5 is selected from the group consisting of-H, -F, -OH, -O-, -Ci. e (e.g., -CH3j-CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -CH2(CH2)2C(O)NH2,
-CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein E is selected from the goup consisting of-H, -F, -Br, -CI, -I, - OH, -O-, -Cι-6 (e.g., -CH3; -CH2CH2CH CH2-X moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -
CH2(CH2)2C(O)NH2> -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R ' are independently selected from the group consisting of H; CH3; CH2CH3; -O-, -S-, -N-, -CH=CHCH3, -C1-6 (e.g., -CH3) -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof; wherein f is 0 or 1. hi another embodiment, the invention is directed to a compound of formula (V), having the formula (XII):
Figure imgf000042_0001
wherein a is 3 {5-[4-(2-Mθφholin-4-yl-ethoxy)-3-naphthalen-2-yl-benzylidene]-3-[3- (2H-tefrazol-5-yl)-propyl]-2-thioxo-thiazolidin-4-one}, 4 {5-[4-(2-Moφholin-4-yl- ethoxy)-3-naphthalen-2-yl-benzylidene]-3-[4-(2H-tefrazol-5-yl)-butyl]-2-thioxo- thiazolidin-4-one} or 5 {5-[4-(2-Moφholin-4-yl-ethoxy)-3-naphthalen-2-yl- benzylidene]-3-[5-(2H-tefrazol-5-yl)-pentyl]-2-tMoxo-thiazolidin-4-one} ; including salts thereof, e.g., pharmaceutically acceptable salts. In another embodiment, the invention is directed to a compound of formula (V) having fonnula (XIII):
Figure imgf000043_0001
wherein a is 3 {5-[2',4'-Dichloro-6-(2-moφholin-4-yl-ethoxy)-biphenyl-3-ylmethylene]- 3-[3-(2H-tefrazol-5-yl)-propyl]-2-thioxo-thiazolidin-4-one} , 4 {5-[2',4'-Dichloro-6-(2- moφholin-4-yl-ethoxy)-biphenyl-3 -yhnethylene]-3 - [4-(2H-tetrazol-5 -yl)-butyl] -2- thioxo-thiazolidin-4-one} or 5 { 5-[2',4'-Dichloro-6-(2-moφholin-4-yl-ethoxy)- biphenyl-3-yhnethylene]-3-[5-(2H-tetrazol-5-yl)-pentyl]-2-thioxo-thiazolidin-4-one; including salts thereof, e.g., pharmaceutically acceptable salts. In another embodiment, the invention is directed to a compound of formula (V), having the formula (XIN):
Figure imgf000043_0002
wherein Xi and X2 are independently selected from the group consisting of C andΝ; Rio* Rn» arid R12 are independently selected from the group consisting of H, F, CH2OH, -O-, -Cι-6 (e.g., -CH3,-CH2CH2CH2CH2-XΝH2, OH, CF3, CI, Br, I, NC(O)CH3, -C(O)-OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, -CH2NH2, -OCH2C(O)NH-NH2, -CH2C(O)CH3, -moφholino, -C(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3 and any combination thereof; Ri is selected from the group consisting of — H, -O-, -C1-6 (e.g., - CH3, -CH2CH2CH2CH2-X -CH2CHCH2; -NH2, -PQ R -(X)PC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -C1-6 (e.g., - CH3; -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazme, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -CH2-, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -C1-6 (e.g., -CH3j - CH2CH2CH CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -CH2(CH2)2C(O)NH2, - CH2CH2OH, -
CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -OH, -O-, -Ci-β (e.g., -CH3ι -CH2CH2CH2CH2-), moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2j -CH2CH2OH, -CH2CH(OH)CH3; -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R7' are independently selected from the group consisting of H; CH3; CH2CH3; -O-, -S-, -N-, -CH=CHCH3, -C1-6 (e.g., -CH3, -
CH2CH2GH2CH -), moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
In still another embodiment, the invention is directed to a compound of formula (V): 3-Methoxy-4-(3-{5-[4-(2-moφholin-4-yl-ethoxy)-3 5l-bis-triιluoromethyl- biphenyl-3-ylmethylene]-4-oxo-2-tMoxo-tln^olidin-3-yl}-piOpoxy)-benzoic acid (Jιc):
Figure imgf000045_0001
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 3-Methoxy-4-(3- {5-[6-(2-moφholin-4-yl-ethoxy)-3',5,-bis-trifluoromethyl- biphenyl-3-ylmethylene]-4-oxo-2-tWoxo-tniazolidin-3-yl}-propoxy)-benzoic acid (Ji):
Figure imgf000045_0002
(Ji) including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (III): 3-[3-(2H-Tefrazol-5-yl)-propyl]-2-thioxo-5-[6-(3,5-bis-trifluoromethyl- phenyl)-pyridin-2-ylmethylene]-thiazolidin-4-one (Jm):
Figure imgf000045_0003
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 5-(4,5-Dimethoxy-3^5l-bistrifluoromethyl-biphenyl-3-ylmethylene)-2- tln^xo-thiazohdin-4-one (Jn):
Figure imgf000046_0001
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 5-(6-Methoxy-3',5'-bistrifluoromethyl-biphenyl-3-ylmethylene)-2-thioxo- thiazolidin-4-one (J0):
Figure imgf000046_0002
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 5-(5,6-Dimethoxy-3',5'-bistrifluoromethyl-biphenyl-3-ylmethylene)-2- thioxo-thiazolidin-4-one (Jp):
Figure imgf000046_0003
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(3- {5-[4-(2-Moφholin-4-yl-ethoxy)-3',5l-bistrifluoromethyl-biphenyl-3- ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl} -propionylamino)-benzoic acid 2,3-
Figure imgf000047_0001
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(3- {5-[3',4'-Difluoro-4-(2-moφholin-4-yl-ethoxy)-biphenyl-3- ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propoxy)-benzoic acid (Jr):
Figure imgf000047_0002
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(3- {5-[4-(2-Moφholin-4-yl-ethoxy)-3',5'-bistrifluoromethyl-biphenyl-3- ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl} -propoxy)-benzoic acid (Js):
Figure imgf000047_0003
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(3- {5-[3l-Chloro-4-(2-moφholin-4-yl-ethoxy)-biphenyl-3-ylmethylene]- 4-oxo-2-thioxo-thiazolidin-3-yl}-propoxy)-benzoic acid (Jt):
Figure imgf000048_0001
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(3-{5-[4-(2-Moφholin-4-yl-ethoxy)- -chloro-4,-trifluoromethyl- biphenyl-3-yhnethylene]-4-oxo-2-thioxo-thiazolidm-3-yl} -propoxy)-benzoic acid (Ju):
Figure imgf000048_0002
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(2- {5-[3-(lH-Indol-5-yl)-4-(2-moφholin-4-yl-ethoxy)-benzylidenel-4- oxo-2-thioxo-thiazoUdin-3-yl}-ethyl)-benzoic acid (Jv):
Figure imgf000048_0003
including salts thereof, e.g. , pharmaceutically acceptable salts. hi still another embodiment, the invention is directed to a compound of foιmula (V): 4-(2-{5-[2,-Cmoro-4-(2-moφholm-4-yl-ethoxy)-5,-tτifluoromethyl- biphenyl-3-ylmethylene]-4-oxo-2-tMoxo-tMazohdin-3-yl}-ethyl)-benzoic acid (Jw):
Figure imgf000049_0001
including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(2-{5-[3',4'-Dichloro-6-(2-moφholin-4-yl-ethoxy)-biphenyl-3- ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl}-ethyl)-benzoic acid (Jx):
Figure imgf000049_0002
(Jx) including salts thereof, e.g., pharmaceutically acceptable salts. In still another embodiment, the invention is directed to a compound of formula (V): 4-(2-{5-[3',5'-Dichloro-6-(2-moφholin-4-yl-ethoxy)-biphenyl-3- ylmethylene]-4-oxo-2-tMoxo-thiazohdin-3-yl}-ethyl)-benzoic acid (Jy):
Figure imgf000049_0003
(Jy) including salts thereof, e.g., pharmaceutically acceptable salts. A compound of formula VI, VII, VUI, IX, X XI, XLT, XIII, and XJN, a compound of formula (V) having the formula Ja, Jb, J , J<ι, Je, Jf, Jg, Jh, Ji, Jk, Ji, Jn, Jo, JP, Jq, Jr, Js, Jt, Ju, Jv Jw, Jx, Jy, and a compound of formula (IE) having the formula Jm can be administered using all ofthe methods described herein, such as combining the compound with a carrier material suitable for oral, nasal, topical, fransdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration. For example, formulations ofthe invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets and lozenges. The term "Pinl -associated state" or "Pinl associated disorder" includes disorders and states (e.g., a disease state) that are associated with the misexpression or misregulation of Pinl. This misexpression or misregulation can be as a result ofthe altered production, degradation, or regulation of Pinl, e.g., the phosphorylation/ dephosphorylation of Pinl. Without wishing to be bound by theory, Pinl associated disorders that are related to higher than necessary levels of Pinl can be caused by (1) an increase in the level of transcription or translation, or a decrease in the level of degradation of Pinl, such that an abnormally high amount of Pinl polypeptide is present in a cell, or (2) the amount Pinl that is present in the unphosphorylated, i.e., active form, is abnormally high due to either an increase in the dephosphorylation of Pinl or a decrease in the phosphorylation of Pinl. Pinl disorders are often associated with abnormal cell growth, abnormal cell proliferation, or misexpression of Pinl (e.g., Pinl protein or nucleic acid). Pinl -associated states include states resulting from an elevation in the expression of cyclin DI and/or Pinl. Pinl -associated states also include states resulting from an elevation in the phosphorylation level of c- Jun, particularly phosphorylation of c- Jun on Ser63 73-Pro, and/or from an elevation in the level of c- Jun amino terminal kinases (JNKs) present in a cell. Pinl -associated states include neoplasia, cancer, undesirable cell growth, and/or tumor growth. Pinl -associated states include states caused by DNA damage, an oncogenic protein (i.e. Ha-Ras), loss of or reduced expression of a tumor suppressor (i.e. Brcal), and/or growth factors. Pinl- associated state is also intended to include diseases or disorders caused by, or associated with, deregulation of genes and/or gene products involved in a biological pathway that includes Pinl and/or cyclin DI (e.g. beta-catenin, APC or WNT). hi fact, beta-catenin, APC and WNT have been linked to cancer development as demonstrated in Biochim Biophys Acta. (2003) 1653: 1-24 and Eur J Surg Oncol. (2003) 29: 107-117. Pinl associated states further include disorders and states associated with regulation or activity of Pinl in the brain, e.g., neurodegenerative disorders such as Alzheimer's disease, wherein the phosphorylation state of tau is influenced by the activity of Pinl. The terms "misexpression" and "misregulation" are used interchangeably herein. These terms are intended to include non- wild type pattern of gene expression or regulation. Expression and regulation, as used herein, include transcriptional, post transcriptional, e.g., mRNA stability, translational, and post translational stages. Misexpression includes: expression at non-wild type levels, i.e., over or under expression; a pattern of expression that differs from wild type in terms ofthe time or stage at which the gene is expressed, e.g., increased or decreased expression (as compared with wild type) at a predetermined developmental period or stage; a pattern of expression that differs from wild type in terms of decreased expression (as compared with wild type) in a predetermined cell type or tissue type; a pattern of expression that differs from wild type in terms ofthe splicing size, amino acid sequence, post- transitional modification, or biological activity ofthe expressed polypeptide; a pattern of expression that differs from wild type in terms ofthe effect of an environmental stimulus or extracellular stimulus on expression of the gene, e.g. , a pattern of increased or decreased expression (as compared with wild type) in the presence of an increase or decrease in the strength ofthe stimulus. Misexpression includes any expression from a transgenic nucleic acid. Misexpression includes the lack or non-expression of a gene or transgene, e.g. , that can be induced by a deletion of all or part of the gene or its confrol sequences. Misregulation can include aberrant levels of phosphorylation ofthe enzyme. Pinl is an important regulator of cyclin DI expression. Because of Pinl's role in regulating the expression of cyclin DI, many ofthe tumor causing effects of cyclin DI can be regulated tlirough Pinl. In particular, modulators of Pinl can be used to modulate or regulate cyclin DI (i.e., or the expression thereof), and the resulting effects of cyclin DI over- or under-expression. Moreover, inhibitors of Pinl can be used to freat, inhibit, and/or prevent undesirable cell growth, neoplasia, and/or cancer in any subject but particularly in humans. Other examples of Pinl associated states include, but are not limited to, for example, those tumor types disclosed in Table 10. The term "treated," "treating" or "treatment" includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being freated. In certain embodiments, the freatment comprises the induction of a Pinl inhibited state, followed by the activation ofthe Pinl modulating compound, which would in turn diminish or alleviate at least one symptom associated or caused by the Pinl associated state, disorder or disease being freated. For example, treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder. The term "subject" is intended to include organisms, e.g., prokaryotes and eukaryotes, which are capable of suffering from or afflicted with a Pinl associated disorder. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from a Pinl associated disorder. The language "Pinl modulating compound" refers to compounds that modulate, e.g., inhibit, promote, or otherwise alter, the activity of Pinl. Pinl modulating compounds include both Pinl agonists and antagonists, hi certain embodiments, the Pinl modulating compound induces a Pinl inhibited-state. Examples of Pinl modulating compounds include compounds of formula (I), formula (la), formula (II), formula (Ila), formula (III), formula (Ilia), formula (IV), formula (INa), formula (N), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XT), formula (XLT), formula (XILT) and formula (XIN). Additional examples of Pinl modulating compounds include compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8 or derivatives thereof. In certain embodiments, the Pinl modulating compounds include compounds that interact with the PPI and/or the WW domain of Pinl. In certain embodiments, the Pinl modulating compound is substantially specific to Pinl. The phrase "substantially specific for Pinl" is intended to include inhibitors ofthe invention that have a Kj or K that is at least 2, 3, 4, 5, 10, 15, or 20 times less than the Kj or Kd for other peptidyl prolyl isomerases, e.g., hCyP-A, hCyP- B, hCyP-C, ΝKCA, hFKBP-12, hFKBP-13, and hFKBP-25. The Pinl polypeptide can be phosphorylated or unphosphorylated. Pinl activity is known to be controlled by a phosphorylation mechanism (Lu et al. (1999) Science 283:1325-8). The modulators ofthe invention can be designed to specifically interact with either form of Pinl. Conversely, a Pinl modulator may be capable of interacting with either the phosphorylated or unphosphorylated form ofthe polypeptide. In one embodiment ofthe invention, the Pinl modulating compound of the invention is capable of chemically interacting with Cysll3 of Pinl. The language "chemical interaction" is intended to include, but is not limited to reversible interactions such as hydrophobic/hydrophilic, ionic (e.g., coulombic attraction/repulsion, ion-dipole, charge-transfer), covalent bonding, Van der Waals, and hydrogen bonding. In certain embodiments, the chemical interaction is a reversible Michael addition. In a specific embodiment, the Michael addition involves, at least in part, the formation of a covalent bond. Additionally, the method includes adnήnistering to a subject an effective amount of a Pinl modulating compound of the invention, e.g. , Pinl -modulating compounds of formula (I), formula (la), formula (IT), formula (Ila), formula (HT), formula (Ilia), formula (IN), formula (INa), formula (N), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII) and formula (XIN) that have been modified in order to decrease the ability ofthe compound to cross the blood-brain barrier. The language "Pinl inhibiting compound" includes compounds that reduce or inhibit the activity of Pinl. Examples of Pinl inhibiting compounds include compounds of formula (I), formula (la), formula (II), formula (Ha), formula (LU), formula (ffla), formula (IN), formula (INa), formula (N), formula (VI), formula (Nil), formula (NIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII) and formula (XIN). Additional examples of Pinl inhibiting compounds include compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8 or derivatives thereof. In certain embodiments, the Pinl inhibiting compounds include compounds that interact with the PPI and/or the WW domain of Pinl . In certain embodiments the inhibitors have a Kj for Pinl of less than
0.2mM, less than O.lmM, less than 750 μM, less than 500 μM, less than 250 μM, less than 100 μM, less than 50 μM, less than 500 nM, less than 250nM, less than 50 nM, less than 10 nM, less than 5 nM, or or less than 2 nM. The language "Pinl inhibited-state" is intended to include states in which one activity of Pinl is inhibited in cells, e.g., cells in a subject, that have been treated with a Pinl modulating compound. "Pinl inbited-state" is also intended to include states wherein the Pinl modulating compound is administered to a subject, allowed to remain in a preactivated state, and subsequently activated by a stimulus. The stimulus may be selected from a natural event, artificial event, or the combination thereof. For example, the natural event may be the action of an enzyme and/or the artificial event may be the addition of a hypeφlastic inhibitory agent or the addition of energy to the subjects system in any manner that achieves activation, e.g., by radiation, e.g., by light with a wavelength greater than about 400 nm, e.g., greater than about 600 nm, e.g., greater than about 620 nm, e.g., greater than about 630 nm, e.g., greater than about 640 nm, e.g., greater than about 650 nm. In one embodiment, the cells enter a Pinl inhibited-state for a designated period of time prior to activation ofthe modulating compound sufficient to allow the modulation the activity of Pinl by the activated modulating compound. In certain embodiments ofthe invention, the designated period of time prior to activation is greater than about 1 hour, e.g., greater than about 2 hours, e.g., greater than about 3 hours, e.g., greater than about 6 hours, e.g., greater than about 12 hours, e.g., greater than about 24 hours, e.g., greater than about 36 hours, e.g., greater than about 48 hours, e.g., greater than about 72 hours, hi a specific embodiment, the designated period of time prior to activation is 3 days. In one embodiment, the Pinl modulating compound is preactivated prior to administration to a subject followed by the introduction of at least one stimulus sufficient to allow the modulation the activity of Pinl by the modulating compound, hi certain embodiment ofthe invention, the activity ofthe modulating compound is enhanced by the entrance ofthe cells, e.g., cells of a subject, into a Pinl inhibited state. In one embodiment ofthe invention, the Pinl modulating compounds of the invention have a characteristic inhibition profile (CIP) and have an effective cytotoxicity, e.g., effective to freat a Pinl associated state. The Pinl -modulating compounds described herein may be substituted with any substituent that allows the Pinl -modulating compound to perform its intended function. In certain embodiments the Pinl -modulating compounds described herein may be substituted with any substituent which allows the Pinl -modulating compound to perform its intended function, possess a CIP, and/or be effectively cytotoxic, as defined herein. The cytotoxicity ofthe compounds can be determined by using the CPCA given in Example 1. The measurement ofthe activity ofthe Pinl -modulating compounds in the determination the inhibition constant at 50% inhibition of enzyme activity (IC50), which is used to characterize the CIP, may be performed by using the analysis described in Example 2. An ordinarily skilled artisan would be able to use data generated by the assays to modify substituents on the Pinl modulating compounds to obtain effectively cytotoxic Pinl modulating compounds with characteristic inhibition profiles. The term "characteristic inhibition profile (CTP)" is a characterization of the modulating compound ofthe invention such that the Pinl -associated state is inhibited. Characterization ofthe modulating compounds includes measurement ofthe inhibition constant at 50% inhibition of enzyme activity (IC50). Compounds that demonstrate a CIP include modulating compounds with and IC50 of less than about 40 μM. In certain embodiments ofthe invention, the IC50 is between about 10-40 μM. In additional embodiments, the IC50 is between about 1-10 μM. In certain embodiments, the IC50 is less than about 1 μM. The term "effective cytotoxicity" or "effectively cytotoxic" includes cytotoxicities of Pinl -modulating compounds which allow the Pinl -modulating compound to perform its intended function, e.g., treat Pinl associated states. Cytotoxicities can be measured, for example, by using the Cell Based Cytotoxicity Assay (CBCA) method described in Example 1. In one embodiment, the Pinl- modulating compound has a cytotoxicity (as measured by the CBCA in Example 1) of 50 μM or less, 45 μM or less, 40 μM or less, 35 μM or less, 30 μM or less, 25 μM or less, 20 μM or less, 15 μM or less, 10 μM or less, 9 μM or less, 8 μM or less, 7 μM or less, 6 μM or less, 5 μM or less, 4 μM or less, 3 μM or less, 2 μM or less, 1 μM or less, 0.9 μM or less, 0.8 μM or less, 0.7 μM or less, 0.6 μM or less, 0.5 μM or less, 0.4 μM or less, or, preferably, 0.3 μM or less, or 0.05 μM or less. Values and ranges included and/or intermediate ofthe values set forth herein are also intended to be within the scope ofthe present invention. In one embodiment, the Pinl modulating compounds ofthe invention are substantially soluble, e.g., water soluble, and have an effective cytotoxicity, e.g., effective to freat a Pinl associated state. Methods for altering the solubility of organic compounds are known in the art. For example, one of ordinary skill in the art will be able to modify the Pinl modulating compounds ofthe invention such that they have a desirable logP. Ordinarily skilled artisans will be able to modify the compounds by adding and removing hydrophilic and hydrophobic moieties, such that a Pinl- modulating compound with a desired solubility is obtained. The Pinl -modulating compounds described herein may be substituted with any substituent which allows the Pinl -modulating compound to perform its intended function, be substantially soluble, and/or be effectively cytotoxic, as defined herein. For example, an ordinarily skilled artisan would understand that the addition of heteroatoms (hydroxy, amino, nitro, carboxylic acid groups, etc.) or other polar moieties would generally increase the solubility ofthe Pinl modulating compound in water, while addition of non-polar moieties such as aryl or alkyl groups would generally decrease the solubility ofthe compound in water. The Pinl modulating compound can then be tested for substantial solubility by determining the logP value, e.g., by using a log octanol- water partition coefficient program such as "KOWWTN" (Meylan, W.M. and P.H. Howard. 1995. Atom/fragment contribution method for estimating octanol-water partition coefficients. J. Pharm. Sci. 84: 83-92, incoφorated herein by reference in its entirety). An ordinarily skilled artisan would be able to use data generated by these programs and assays to modify substituents on the Pinl modulating compounds to obtain substantially soluble and effectively cytotoxic Pinl modulating compounds. The term "substantially soluble" includes solubilities (e.g., aqueous solubilities) of Pinl -modulating compounds that allow the Pinl -modulating compounds to perform their intended function, e.g. , treat Pinl associated states. The solubility of a particular Pinl -modulating compound can be measured by any method known in the art, e.g., experimentally, computationally, etc. For example, one method for determining the solubility of a compound computationally is by calculating logP values using a log octanol- water partition coefficient program (KOWNvTN). In one embodiment, the Pinl- modulating compounds of the invention have logP values less than Pinl -modulating, e.g., less than 6.6. In a further embodiment, the Pinl -modulating compounds ofthe invention may have a logP value between about 1 to about 6, between about 1 to about 5, between about 1.5 to about 5, between about 2 to about 5, between about 2.5 to about 4.5, between about 2.75 to about 4.25, between about 3.0 to about 4.0, between about 3.25 to about 4.0, between about 3.5 to about 4.0, and between about 3.5 to about 3.75. Values and ranges included and/or intermediate ofthe values set forth herein are also intended to be within the scope ofthe present invention. In another embodiment, the aqueous solubility ofthe compound is about 0.01 mg/L or greater, about 0.1 mg/L or greater, about 1 mg/L or greater, or about 2 mg/L or greater. • The term "derivative" is intended to include isomers, modification, e.g., addition or removal, of substituents on the Pinl -modulating compound, fragements and pharmaceutically acceptable salts thereof, as well as formulations, such that the Pinl- modulating compound treats the Pinl -associated state. hi particular embodiments, Pinl modulating compounds ofthe invention include fragments of Pinl modulating compounds of formula (I), formula (la), formula (IT), formula (Ila), formula (ILT), formula (Ilia), formula (TV), formula (TVa), formula (V), formula (VI), formula (NH), formula (NIII), formula (IX), formula (X), formula (XT), formula (XII), formula (XIII) and formula (XIN), including the compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8 or derivatives thereof. The language "fragments of Pinl modulating compounds" as used herein, is intended to include portions of Pinl modulating compounds described herein that modulate the activity of Pinl. The term "alkyl" includes saturated aliphatic groups, including straight- chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. The term alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone. In an embodiment, a sfraight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone (e.g., C1-C10 for sfraight chain, C3-C10 for branched chain), and more preferably 6 or fewer. Likewise, preferred cycloalkyls have from 4-7 carbon atoms in their ring stracture, and more preferably have 5 or 6 carbons in the ring structure. The term "substituted" is intended to describe moieties having substituents replacing a hydrogen on one or more atoms, e.g. C or N, of a molecule. Such substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, or an aromatic or heteroaromatic moiety. Moreover, the term alkyl includes both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons ofthe hydrocarbon backbone. Such substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can be further substituted, e.g., with the substituents described above. An "alkylaryl" or an "aralkyl" moiety is an alkyl substituted with an aryl (e.g., phenyhnethyl (benzyl)). The term "alkyl" also includes the side chains of natural and unnatural amino acids. Examples of halogenated alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, perfluoromethyl, perchloromethyl, perfluoroethyl, perchloroethyl, etc. The term "aryl" includes groups, including 5- and 6-membered single- ring aromatic groups that may include from zero to four heteroatoms, for example, phenyl, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term "aryl" includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having heteroatoms in the ring stracture may also be referred to as "aryl heterocycles", "heterocycles," "heteroaryls" or "heteroaromati.es". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tefralin). The term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, bulenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. The term alkenyl further includes alkenyl groups that include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for sfraight chain, C3-C6 for branched chain). Likewise, cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The term C2-C6 includes alkenyl groups containing 2 to 6 carbon atoms. Moreover, the term alkenyl includes both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. The term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, the term "alkynyl" includes straight-chain alkynyl groups (e.g. , ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups. The term alkynyl further includes alkynyl groups that include oxygen, nifrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term C2-C6 includes alkynyl groups containing 2 to 6 carbon atoms. Moreover, the term alkynyl includes both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, arninocarbonyl, alkylaminocarbonyl, dial laminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone stracture. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for example, 2-5 carbon atoms. The term "acyl" includes compounds and moieties which contain the acyl radical (CH3CO-) or a carbonyl group. The term "substituted acyl" includes acyl groups where one or more ofthe hydrogen atoms are replaced by for example, alkyl group's, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. The term "acylamino" includes moieties wherein an acyl moiety is bonded to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups. The term "aroyl" includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of ar yl groups include phenylcarboxy, naphthyl carboxy, etc. The terms "alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons ofthe hydrocarbon backbone, e.g., oxygen, nifrogen or sulfur atoms. The term "alkoxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups and may include cychc groups such as cyclopentoxy. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc. The term "amine" or "amino" includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom. The term "alkyl amino" includes groups and compounds wherein the nifrogen is bound to at least one additional alkyl group. The term "dialkyl amino" includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups. The term "arylamino" and "diarylamino" include groups wherein the nifrogen is bound to at least one or two aryl groups, respectively. The term "alkylarylamino," "afkylaminoaryl" or "arylaminoalkyl" refers to an amino group that is bound to at least one alkyl group and at least one aryl group. The term "alkaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group bound to a nifrogen atom that is also bound to an alkyl group. The term "amide" or "aminocarboxy" includes compounds or moieties that contain a nifrogen atom that is bound to the carbon of a carbonyl or a thiocarbonyl group. The term includes "alkaminocarboxy" groups that include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups that include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. The terms "alkylaminocarboxy," "alkenylaminocarboxy," "alkynylaminocarboxy," and "arylaminocarboxy" include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group. The term "carbonyl" or "carboxy" includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom, and tautomeric forms thereof. Examples of moieties that contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc. The term "carboxy moiety" or "carbonyl moiety" refers to groups such as "alkylcarbonyl" groups wherein an alkyl group is covalently bound to a carbonyl group, "alkenylcarbonyl" groups wherein an alkenyl group is covalently bound to a carbonyl group, "alkynylcarbonyl" groups wherein an alkynyl group is covalently bound to a carbonyl group,
"arylcarbonyl" groups wherein an aryl group is covalently attached to the carbonyl group. Furthermore, the term also refers to groups wherein one or more heteroatoms are covalently bonded to the carbonyl moiety. For example, the term includes moieties such as, for example, aminocarbonyl moieties, (wherein a nitrogen atom is bound to the carbon ofthe carbonyl group, e.g., an amide), aminocarbonyloxy moieties, wherein an oxygen and a nifrogen atom are both bond to the carbon ofthe carbonyl group (e.g., also referred to as a "carbamate"). Furthermore, aminocarbonylamino groups (e.g., ureas) are also include as well as other combinations of carbonyl groups bound to heteroatoms (e.g.,. nifrogen, oxygen, sulfur, etc. as well as carbon atoms). Furthermore, the heteroatom can be further substituted with one or more alkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, etc. moieties. The term "thiocarbonyl" or "thiocarboxy" includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom. The term "thiocarbonyl moiety" includes moieties that are analogous to carbonyl moieties. For example, "thiocarbonyl" moieties include aminothiocarbonyl, wherein an amino group is bound to the carbon atom ofthe thiocarbonyl group, furthermore other thiocarbonyl moieties include, oxythiocarbonyls (oxygen bound to the carbon atom), aminothiocarbonylamino groups, etc. The term "ether" includes compounds or moieties that contain an oxygen bonded to two different carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl" which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom that is covalently bonded to another alkyl group. The term "ester" includes compounds and moieties that contain a carbon or a heteroatom bound to an oxygen atom that is bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are as defined above. The term "thioether" includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms. Examples of thioethers include, but are not limited to alkftnoalkyls, alkthioalkenyls, and alkthioalkynyls. The term "alkthioalkyls" include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom that is bonded to an alkyl group. Similarly, the term "alkthioalkenyls" and alkthioalkynyls" refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group. The term "hydroxy" or "hydroxyl" includes groups with an -OH or -O". The term "halogen" includes fluorine, bromine, chlorine, iodine, etc. The term "perhalogenated" generally refers to a moiety wherein all hydrogens are replaced by halogen atoms. ' The terms "polycyclyl" or "polycyclic radical" include moieties with two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each ofthe rings ofthe polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarboηyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety. The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus. The term "heterocycle" or "heterocyclic" includes saturated, unsaturated, aromatic ("heteroaryls" or "heteroaromatic") and polycyclic rings which contain one or more heteroatoms. Examples of heterocycles include, for example, benzodioxazole, benzofuran, benzoimidazole, benzothiazole, bβnzothiophene, benzoxazole, deazapurine, furan, indole, indolizine, imidazole, isoxazole, isoquinoline, isothiaozole, methylenedioxyphenyl, napthridine, oxazole, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, tefrazole, thiazole, thiophene, and triazole. Other heterocycles include moφholino, piprazine, piperidine, thiomoφholino, and thioazohdine. The heterocycles may be substituted or unsubstituted. Examples of substituents include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety. It will be noted that the structures of some ofthe compounds of this invention include asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the stractures and other compounds and moieties discussed in this application also include all tautomers thereof. Compounds described herein may be obtained though art recognized synthesis strategies. It will also be noted that the substituents of some ofthe compounds of this invention include isomeric cyclic structures. It is to be understood accordingly that constitutional isomers of particular substituents are included within the scope of this invention, unless indicated otherwise. For example, the term "tefrazole" includes tefrazole, 2H-tefrazole, 3H-tefrazole, 4H-tefrazole and 5H-tefrazole. Additionally, the phrase "any combination thereof implies that any number ofthe listed functional groups and molecules may be combined to create a larger molecular architecture. For example, the terms "phenyl," "carbonyl" (or "=O"), "-O-," "-OΗ," and C1-6 (i.e., -CH3 and -CH2CH2CH2-) can be combined to form a 3-methoxy- 4-propoxy-benzoic acid substituent. It is to be understood that when combining functional groups and molecules to create a larger molecular architecture, hydrogens can be removed or added, as required to satisfy the valence of each atom. In a particular embodiment ofthe invention, the Pinl modulating compound of formula (I) is any one ofthe compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8 or derivatives thereof. In another embodiment, the invention pertains to the Pinl -modulating compounds of formula (I), formula (la), formula (II), formula (Ila), formula (III), formula (Ilia), formula (IV), formula (TVa), formula (V), formula (VI), formula (VII), formula (VIET), formula (IX), formula (X), formula (XI), formula (XII), formula (XITI) and formula (XIN) described herein. Particular embodiments ofthe invention pertain to the modulating compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8 or derivatives thereof. In yet another embodiment, the invention pertains to pharmaceutical compositions comprising the Pinl -modulating compounds described herein and a pharmaceutical acceptable carrier. In another embodiment, the invention includes any novel compound or pharmaceutical compositions containing compounds ofthe invention described herein. For example, compounds and pharmaceutical compositions containing compounds set forth herein (e.g., Tables 1, 2, 3, 4, 5, 6, 7 and 8) are part of this invention, including salts thereof, e.g., a pharmaceutically acceptable salt.
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Figure imgf000192_0001
In particular embodiments, the compounds in Tables 1, 2, 3, 4, 5, 6, 7 and 8 can be administered using all ofthe methods described herein, such as combining the compound with a carrier material suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration. For example, formulations ofthe invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets and lozenges. Additionally, the compounds ofthe invention include analogs ofthe compounds described above containing art-recognized substituents that do not significantly effect the analog's ability to perform its intended function In an additional embodiment, the invention pertains, at least in part, to a method for treating cyclin DI overexpression in a subject. This method includes administering to the subject an effective amount of a Pinl -modulating compound of formula (I), formula (la), formula (II), formula (Ila), formula (III), formula (Ilia), formula (IN), formula (IVa), formula (N), formula (NI), formula (Nil), formula (NIH), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII) and formula
(XIN), as described above, such that the cyclin DI overexpression is treated. In certain embodiments, the overexpression of cyclin DI is associated with the presence of breast cancer in the subject. Additionally, Pinl may cause changes in the expression, e.g., underexpression or overexpression of endogenous cyclin DI. hi fact, Pinl is believed to regulate, e.g., activate, the expression of cyclin DI by acting cooperatively with c-Jun to activate the cyclin DI promoter, hi order to activate cyclin DI expression, c-Jun must be phosphorylated. Pinl binds to c-Jun mainly via phosphorylated S63 73-P motifs. Pinl activates phosphorylated c-Jun to induce cyclin DI expression by regulating the conformation of the phosphorylated S-P motifs in c-Jun. The activity of c-Jun is also enhanced by phosphorylation induced by growth factors, oncogenic proteins, DMA damage or other stress conditions. Although different pathways may be involved, they eventually lead to activation of Pro-directed β /7*2 kinases, JΝKs, which phosphorylate c-Jun on S -P and enhance its transcriptional activity. Binetruy, et al. 1991. Nature 351:122-127. Smeal, et al. 1991. Nature 354:494-
496. Derijard, et al. 1994. Cell. 76:1025-1037. Thus, phosphorylation of c-Jun on g63 73_ ^s a y regulatory mechanism that converts inputs from various signaling pathways into changes in cyclin DI gene expression. Oncogenic and tumor suppressor pathways may also affect the activity of Pinl . Pathways activated by oncogenic Ras may contribute to up-regulation of Pinl , while wildrype Brca (a tumor suppressor) suppresses the expression of Pinl. "Decreased cyclin DI expression" or "cyclin DI underexpression" includes cells having lower than normal levels of cyclin DI. Significant cyclin DI underexpression includes both small and large decreases in the levels of cyclin DI compared with normal levels. Preferably, cyclin DI overexpression is considered in the context ofthe phase ofthe cell cycle. In actively proliferating normal cells, cyclin DI reaches a peak in mid Gi phase, decreases during S-phase, and remains low throughout the rest ofthe cycle. By contrast, in transformed cells the level of cyclin DI is more variable. Therefore, cyclin DI underexpression includes the expression of cyclin DI at levels that are abnormally low for the particular cell cycle phase ofthe cell. Cyclin DI underexpression can manifest itself as a Pinl -associated state. "Increased cyclin DI expression" or "cyclin DI overexpression" or "elevation in the expression of cyclin D 1 " includes cells having higher than normal levels of cyclin DI. Significant cyclin DI overexpression includes both small and large increases in the levels of cyclin DI compared with normal levels. Preferably, cyclin DI overexpression is considered in the context ofthe phase ofthe cell cycle. In actively proliferating normal cells, cyclin DI reaches a peak in mid Gt phase, decreases during S-phase, and remains low throughout the rest ofthe cycle. By contrast, in transformed cells the level of cyclin DI is more variable. Therefore, cyclin DI overexpression includes the expression of cyclin DI at levels that are abnormally high for the particular cell cycle phase ofthe cell. Cyclin DI overexpression can manifest itself as tumor growth or cancer. One skilled in the art would recognize that studies have been done measuring the level cyclin DI expression in normal cells and cells having a cancerous state. Increased cyclin DI expression has been found in a vast range of primary human tumors. Increased cyclin DI expression has been detected in the form of gene amplification, increased cyclin DI RNA expression, and increased cyclin DI protein expression. Most clinical studies comparing cyclin DI gene amplification with expression of cyclin DI have found that more cases show over-expression of both RNA and protein than show amplification ofthe gene. The presence of increased cyclin DI RNA and/or protein expression without gene amplification suggests that other cellular genes such as pRb may affect the expression cyclin DI. Human tumors found to have increased cyclin DI expression include: parathyroid adenomas, mantle cell lymphomas, breast cancers, head and neck squamous cell carcinomas (i.e. squamous carcinomas in the oral cavity, nasopharynx, pharynx, hypopharynx, and larynx), esophageal cancers, hepatocellular carcinomas, colorectal cancers, genitourinary cancers, lung cancers (i.e. squamous cell carcinomas ofthe lung), skins cancers (i.e. squamous cell carcinomas, melanomas, and malignant fibrous histiocytomas), sarcomas, and central nervous system malignancies (i.e. astrocytomas and glioblastomas), gastric adenocarcinomas, pancreatic adenocarcinomas, squamous carcinomas ofthe gall bladder. Donnellan, et al. 1998. J. Clin. Pathol: Mol. Pathol. 51:1-7. The cyclin DI gene is amplified in approximately 20% of mammary carcinomas and the protein is overexpressed in approximately 50% of mammary carcinomas. Barnes, et al. 1998. Breast Cancer Research and Treatment. 52:1-15. Cyclin DI overexpression in mantle cell lymphoma is discussed in Espinet, et al. 1999. Cancer Genet Cytogenet. lll(l):92-8 and Stamatopoulous, et al. 1999. Br. J. Haematol. 105(l):190-7. Cyclin DI overexpression in breast cancer is discussed in Fredersdorf, et al. 1997. PNAS 94(12):6380-5. Cyclin DI overexpression in head and neck cancers is discussed in Matthias, et al. 1999. Cancer Epidemiol. Biomarkers Prev. 8(9):815-23; Matthias, et al. 1998. Clin. Cancer Res. 4(10):2411-8; and Kyomoto, et al. 1997. Int. J. Cancer. 74(6):576-81. Cyclin DI overexpression in laryngeal carcinoma is discussed in Bellacosa, et al. 1996. Clin. Cancer Res. 2(1):175- 80. Cyclin DI overexpression in multiple myeloma is discussed in Hoechtlen-Nollmar, et al. 2000. Br. J. Haematol. 109(l):30-8; Pruneri, et al. 2000. Am. J. Pathol. 156(5):1505-13; and Janssen, et al. 2000. Blood 95(8):2691-8. It is believed that in many tumors, cyclin DI acts in co-operation with other oncogenes or tumor suppressor genes. Cyclin DI expression is regulated by many factors. Growth factors (i.e. CSF1, platelet-derived growth factor, insulin-like growth factor, steroid hormones, prolactin, and serum stimulation) promote the synthesis of cyclin DI and removal of growth factors will lead to a drop in cyclin DI levels and arrest the cell in Gt phase. Hosokawa, et al. 1996. J. Lab. Clin. Med. 127:246-52. In addition, hypophosphorylated pRb stimulates cyclin DI transcription, while cyclin DI activity is inhibited by transforming growth factor β-l, p53, and cyclin dependent kinase inhibitors (CKIs). High levels of CKIs bind to cdks and reduce the ability of cyclins to activate the cdks. There are 2 classes of CKIs: (1) the Kip/Cip family including p21, p27, and p57 and (2) the IΝK4 family including pl5, pl6, 18, and pl9. The Kip/Cip family members are capable of binding to and inhibiting most cyclin-cdk complexes, whereas the JNK4 family members seem to be specific inhibitors of cyclin Dl-cdk complexes. Donnellan, et al. 1998. J. Clin. Pathol: Mol. Pathol. 51:1-7. For example, pRb and E2F are activators of CKI pl6, and the levels of p27 may be increased by TGF-/3, cAMP, contact inhibition, and serum deprivation. Barnes, et al. 1998. Breast Cancer Research and Treatment. 52:1-15. Cyclin DI is believed to act through the phosphorylation of pRB. pRB is hypophosphorylated throughout the Gi phase, phosphorylated just before the S phase, and remains phosphorylated until late mitosis. Hypophosphorylated pRB arrests cells in Gi by forming a complex with the E2F family of DNA binding proteins, which are transcription factors that transcribe genes associated with DNA replication (the S phase ofthe cell cycle). Cyclin DI can form a complex with either cdk4 or cdk6 to form activated cdk4 or cdk6. Activated cdk4 or cdk6 induces the phosphorylation of pRb changing pRb from its hypophosphorylated form in which it binds to and inactivates E2F - transcription factors to phosphorylated pRb which no longer binds to and inactivates , E2F transcription factors, h some mouse lymphoma cells overexpressing D cyclins, pRb is hyperphosphorylated compared with pRb in cells not overexpressing D cyclins. It appears that cyclin Dlis required to initiate the phosphorylation of pRb, which in turn, drives the cell through the restriction point at which stage the cell is committed to divide. "Neoplasia" or "neoplastic transformation" is the pathologic process that results in the formation and growth of a neoplasm, tissue mass, or tumor. Such process includes uncontrolled cell growth, including either benign or malignant tumors. Neoplasms include abnormal masses of tissue, the growth of which exceeds and is uncoordinated with that ofthe normal tissues and persists in the same excessive manner after cessation ofthe stimuli that evoked the change. Neoplasms may show a partial or complete lack of structural organization and functional coordination with the normal tissue, and usually form a distinct mass of tissue. One cause of neoplasia is dysregulation ofthe cell cycle machinery. Neoplasms tend to grow and function somewhat independently ofthe homeostatic mechanisms that control normal tissue growth and function. However, some neoplasms remain under the control ofthe homeostatic mechanisms that control normal tissue growth and function. For example, some neoplasms are estrogen sensitive and can be arrested by anti-estrogen therapy. Neoplasms can range in size from less than 1 cm to over 6 inches in diameter. A neoplasm even 1 cm in diameter can cause biliary obstructions and jaundice, if it arises in and obstructs the ampulla of Vater. Neoplasms tend to morphologically and functionally resemble the tissue from which they originated. For example, neoplasms arising within the islet tissue of the pancreas resemble the islet tissue, contain secretory granules, and secrete insulin. Clinical features of a neoplasm may result from the function of the tissue from which it originated. For example, excessive amounts of insulin can be produced by islet cell neoplasms resulting in hypoglycemia which, in turn, results in headaches and dizziness. However, some neoplasms show little morphological or functional resemblance to the tissue from which they originated. Some neoplasms result in such non-specific systemic effects as cachexia, increased susceptibility to infection, and fever. By assessing the histology and other features of a neoplasm, it can be determined whether the neoplasm is benign or malignant. Invasion and metastasis (the spread ofthe neoplasm to distant sites) are definitive attributes of malignancy. Despite the fact that benign neoplasms may attain enormous size, they remain discrete and distinct from the adjacent non-neoplastic tissue. Benign tumors are generally well circumscribed and round, have a capsule, and have a grey or white color, and a uniform texture. In contrast, malignant tumors generally have fingerlike projections, irregular margins, are not circumscribed, and have a variable color and texture. Benign tumors grow by pushing on adjacent tissue as they grow. As the benign tumor enlarges it compresses adjacent tissue, sometimes causing atrophy. The junction between a benign rumor and surrounding tissue may be converted to a fibrous connective tissue capsule allowing for easy surgical removal ofthe benign tumor. Conversely, malignant tumors are locally invasive and grow into the adjacent tissues usually giving rise to irregular margins that are not encapsulated making it necessary to remove a wide margin of normal tissue for the surgical removal of malignant tumors. Benign neoplasms tend to grow more slowly and tend to be less autonomous than malignant tumors. Benign neoplasms tend to closely histologically resemble the tissue from which they originated. More highly differentiated cancers, i.e., cancers that resemble the tissue from which they originated, tend to have a better prognosis than poorly differentiated cancers, while malignant tumors are more likely than benign tumors to have an aberrant function, e.g., the secretion of abnormal or excessive quantities of hormones. The histological features of cancer are summarized by the term "anaplasia." Malignant neoplasms often contain numerous mitotic cells. These cells are typically abnormal. Such mitotic aberrations account for some ofthe karyotypic abnormalities found in most cancers. Bizarre multinucleated cells are also seen in some cancers, especially those that are highly anaplastic. The term "anaplasia" includes histological features of cancer. These features include derangement ofthe normal tissue architecture, the crowding of cells, lack of cellular orientation termed dyspolarity, and cellular heterogeneity in size and shape termed "pleomorphism." The cytologic features of anaplasia include an increased nuclear-cytoplasmic ratio (nuclear-cytoplasmic ratio can be over 50% for malignant cells), nuclear pleomorphism, clumping ofthe nuclear chromatin along the nuclear membrane, increased staining ofthe nuclear chromatin, simplified endoplasmic reticulum, increased free ribosomes, pleomoφhism of mitochondria, decreased size and number of organelles, enlarged and increased numbers of nucleoli, and sometimes the presence of intermediate filaments. The term "dysplasia" includes pre-malignant states in which a tissue demonstrates histologic and cytologic features intermediate between normal and anaplastic. Dysplasia is often reversible. The term "cancer" includes malignancies characterized by deregulated or uncontrolled cell growth, for instance carcinomas, sarcomas, leukemias, and lymphomas. The term "cancer" includes primary malignant tumors, e.g., those whose cells have not migrated to sites in the subject's body other than the site ofthe original tumor, and secondary malignant tumors, e.g., those arising from metastasis, the migration of tumor cells to secondary sites that are different from the site ofthe original tumor. The term "carcinoma" includes malignancies of epithelial or endocrine tissues, including respiratory system carcinomas, gastrointestinal system carcinomas, gemtourinary system carcinomas, testicular carcinomas, breast carcinomas, prostate carcinomas, endocrine system carcinomas, melanomas, choriocarcinoma, and carcinomas ofthe cervix, lung, head and neck, colon, and ovary. The term "carcinoma" also includes carcinosarcomas, which include malignant tumors composed of carcinomatous and sarcomatous tissues. The term "adenocarcinoma" includes carcinomas derived from glandular tissue or a tumor in which the tumor cells form recognizable glandular structures. The term "sarcoma" includes malignant tumors of mesodermal connective tissue, e.g., tumors of bone, fat, and cartilage. The terms "leukemia" and "lymphoma" include malignancies ofthe hematopoietic cells ofthe bone marrow. Leukemias tend to proliferate as single cells, whereas lymphomas tend to proliferate as solid tumor masses. Examples of leukemias include acute myeloid leukemia (AML), acute promyelocytic leukemia, chronic myelogenous leukemia, mixed-lineage leukemia, acute monoblastic leukemia, acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, blastic mantle cell leukemia, myelodyplastic syndrome, T cell leukemia, B cell leukemia, and chronic lymphocytic leukemia. Examples of lymphomas include Hodgkni's disease, non- Hodgkin's lymphoma, B cell lymphoma, epitheliotropic lymphoma, composite lymphoma, anaplastic large cell lymphoma, gastric and non-gastric mucosa-associated lymphoid tissue lymphoma, lymphoproliferative disease, T cell lymphoma, Burkitt's lymphoma, mantle cell lymphoma, diffuse large cell lymphoma, lymphoplasmacytoid lymphoma, and multiple myeloma. For example, the therapeutic methods ofthe present invention can be applied to cancerous cells of mesenchymal origin, such as those producing sarcomas (e.g., fibrosarcoma, myxosarcoma, liosarcoma, chondrosarcoma, osteogenic sarcoma or chordosarcoma, angiosarcoma, endotheliosardcoma, lympangiosarcoma, synoviosarcoma or mesothelisosarcoma); leukemias and lymphomas such as granulocytic leukemia, monocytic leukemia, lymphocytic leukemia, malignant lymphoma, plasmocytoma, reticulum cell sarcoma, or Hodgkin's disease; sarcomas such as leiomysarcoma or rhabdomysarcoma, tumors of epithelial origin such as squamous cell carcinoma, basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, undifferentiated carcinoma, bronchogenic carcinoma, melanoma, renal cell carcinoma, hepatoma-liver cell carcinoma, bile duct carcinoma, cholangiocarcinoma, papillary carcinoma, transitional cell carcinoma, chorioaencinoma, semonoma, or embryonal carcinoma; and tumors ofthe nervous system including gioma, menigoma, medulloblastoma, schwannoma or epidymoma. Additional cell types amenable to treatment according to the methods described herein include those giving rise to mammary carcinomas, gastrointestinal carcinoma, such as colonic carcinomas, bladder carcinoma, prostate carcinoma, and squamous cell carcinoma ofthe neck and head region. Examples of cancers amenable to treatment according to the methods described herein include vaginal, cervical, and breast cancers. The language "inhibiting undesirable cell growth" is intended to include the inhibition of undesirable or inappropriate cell growth. The inhibition is intended to include inhibition of proliferation including rapid proliferation. For example, the cell growth can result in benign masses or the inhibition of cell growth resulting in malignant tumors. Examples of benign conditions which result from inappropriate cell growth or angiogenesis are diabetic retinopathy, retrolental fibrioplasia, neovascular glaucoma, psoriasis, angiofibromas, rheumatoid arthritis, hemangiomas, Karposi's sarcoma, and other conditions or dysfunctions characterized by dysregulated endothelial cell division. The language "inhibiting tumor growth" or "inhibiting neoplasia" includes the prevention ofthe growth of a tumor in a subject or a reduction in the growth of a pre-existing tumor in a subject. The inhibition also can be the inhibition ofthe metastasis of a tumor from one site to another. In particular, the language "tumor" is intended to encompass both in vitro and in vivo tumors that form in any organ or body part ofthe subject. The tumors preferably are tumors sensitive to the Pinl -modulating compounds ofthe present invention. Examples ofthe types of tumors intended to be encompassed by the present invention include those tumors associated with breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer ofthe larynx, gallbladder, esophagus, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys. Specifically, the tumors whose growth rate is inhibited by the present invention include basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hypeφlasia, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglloneuromas, hypeφlastic corneal nerve tumor, marfanoid habitus tumor, Wihn's tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosis fungoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic and other sarcoma, malignant hypercalcemia, renal cell tumor, polycythermia vera, adenocarcinoma, glioblastoma multiforma, leukemias, lymphomas (i.e. maglinant lymphomas, mantle cell lymphoma), malignant melanomas, multiple myeloma, epidermoid carcinomas, and other carcinomas and sarcomas. Additionally, several in vitro results imply the involvement of Pinl with neurodegenerative disease, e.g., Alzheimer's disease (AD). A neuropathological hallmark in Alzheimer's disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, and parkinsonism linked to chromosome 17 (FTDP-17) is the neurofibrillary tangles, whose main component is the microtubule-associated protein tau (Selkoe, DJ. Trends Cell Biol 8, 447-453, 1998; Mandelkow, E.M. et al. Trends Cell Biol 8, 425-427, 1998; Lee, N.M. Annu Rev Neurosci 24, 1121-1159, 2001). In contrast to many cancer tissues, where Pinl is overexpressed, Pinl is depleted in AD brains due to its high affinity with phosphorylated tau in the tangles (Jicha, G.A., et al. JNeurochem 69, 2087-2095, 1997). Pinl can directly bind phosphorylated tau and restore its ability to bind microtubules and promote microtubule assembly in vitro. Furthermore, Pinl is required for efficient dephosphorylation of tau in vitro, because Pro-directed phosphatases such as tau phosphatase PP2A are conformation-specific, dephosphorylating only trans (but not cis) pSer/Thr-Pro motifs. The term "neurodegenerative" as used herein, is used to designate a group of disorders in which there is gradual, generally relentlessly progressive wasting away of structural elements ofthe nervous system. As used herein, the term "neurodegenerative phenotype" includes any parameter related to neurodegeneration, e.g., a reduction in mobility, a reduction in vocalization, abnormal limb-clasping reflex, inability to succeed in a hang test as a result of retinal atrophy, an increased level of MPM-2, an increased level of neurofibril tangles, increased tau phosphorylation, tau filament formation, abnormal neuronal moφhology, lysosomal abnormalities, neuronal degeneration, and gliosis. As used herein, the term "neurodegenerative disease or disorder" includes any disease disorder or condition that affects neuronal homeostasis, e.g., results in the degeneration or loss of neuronal cells. Neurodegenerative diseases include conditions that the development ofthe neurons, i.e., motor or brain neurons, is abnormal, as well as conditions in which result in loss of normal neuron function. Examples of such neurodegenerative disorders include Alzheimer's disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, frontaltemporal dementia and parkinsonism linked to chromosome 17.
The Pinl modulating compounds ofthe present invention may be used to treat, inhibit, and/or prevent undesirable cell growth, neoplasia, and/or cancer in any subject. The Pinl modulating compounds ofthe present invention may be used to inhibit Pinl activity in a subject. In one embodiment, the Pinl modulating compounds ofthe present invention may be used to inhibit cyclin DI expression in a subject. In one embodiment, the invention pertains, at least in part, to a method for treating a Pinl -associated state in a subject. The method includes administering to a subject an effective amount of a combination of a Pinl modulating compound ofthe invention, e.g., Pinl-modulating compounds of formula (I), formula (la), formula (II), formula (Ila), formula (IH), formula (Ilia), formula (IV), formula (IVa), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII) formula (XIH) and formula (XIV), as described above, and a hypeφlastic inhibitory agent to treat the Pinl associated states. In another embodiment, the invention pertains, at least in part, to a method for treating cyclin DI overexpression in a subject. The method includes administering to a subject an effective amount of a combination of a Pinl modulating compound ofthe invention, e.g., Pinl-modulating compounds of formula (I), formula (la), formula (II), formula (Ha), formula (III), formula (Ilia), formula (IN), formula (JNa), formula (V), formula (VI), formula (Nil), formula (VΪΪT), formula (IX), formula (X), formula (XI), formula (XII) formula (XIII) and formula (XIN), as described above, and a hypeφlastic inhibitory agent to treat the cyclin DI overexpression. In yet another embodiment, the invention pertains, at least in part, to a method for treating cancer in a subject. The method includes administering to a subject an effective amount of a combination of a Pinl modulating compound ofthe invention, e.g., Pinl-modulating compounds of formula formula (I), formula (la), formula (II), formula (Ila), formula (Til), formula (Ilia), formula (IN), formula (INa), formula (N), formula (VI), formula (NH), formula (NIII), formula (IX), formula (X), formula (XI), formula (XII), formula (Xπi) and formula (XIN), as described above, and a hypeφlastic inhibitory agent to treat the cancer. The language "hypeφlastic inhibitory agent" includes agents that inhibit the growth of proliferating cells or tissue wherein the growth of such cells or tissues is undesirable. For example, the inhibition can be ofthe growth of malignant cells, such as in neoplasms or benign cells, e.g., in tissues where the growth is inappropriate. Examples ofthe types of agents that can be used include chemotherapeutic agents, radiation therapy treatments, including therapeutically effective ranges of light (e.g., laser light and/or immunofluorescent compounds), and associated radioactive compounds and methods, immunotoxins, and combinations thereof. The language "chemotherapeutic agent" includes chemical reagents that inhibit the growth of proliferating cells or tissues wherein the growth of such cells or tissues is undesirable. Chemotherapeutic agents are well known in the art (see e.g., Gihnan A.G., et al., The Pharmacological Basis of Therapeutics, 8th Ed., Sec 12:1202- 1263 (1990)), and are typically used to treat neoplastic diseases. The chemotherapeutic agents generally employed in chemotherapy treatments are listed below in Table 9. Other similar examples of chemotherapeutic agents include: bleomycin, docetaxel (Taxotere), doxorubicin, edatrexate, etoposide, finasteride (Proscar), flutamide (Eulexin), gemcitabine (Gemzar), goserelin acetate (Zoladex), granisetron (Kytril), irinotecan (Campto/Camptosar), ondansetron (Zofran), paclitaxel (Taxol), pegaspargase (Oncaspar), pilocaφine hydrochloride (Salagen), porfimer sodium (Photofrin), interleukin-2 (Proleukin), rituximab (Rituxan), topotecan (Hycamtin), trastuzumab (Herceptin), tretinoin (Retin-A), Triapine, vincristine, and vinorelbine tartrate (Νavelbine). TABLE 9
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
In certain embodiments, the chemotherapeutic agent can be, for example, a cancer associated polypeptide inhibitor, e.g., herceptin, or a compound that alters the expression of a cancer associated polyeptide. The use of Pinl binding compounds in addition to a second anticancer treatment is described in "Use of Pinl Inliibitors for Treatment of Cancer," USSN: 60/504117, filed September 17, 2003, the content of which is hereby expressly incoφorated by reference in its entirety. The term "cancer associated polypeptide" refers to a polypeptide whose misexpression has been shown to cause, or be associated with aberrant cell growth, e.g. , cancer. Further, cancer associated polypeptides are those that are differentially expressed in cancer cells. In one embodiment, the cancer associated polypeptide is a encoded by an oncogene. In a related embodiment, the cancer associated polypeptide is a polypeptide whose expression has been linked to cancer, e.g., as a marker. The presence of a cancer associated polypeptide can be determined by the presence of the polypeptide or nucleic acid molecules, e.g., mRNA or genomic DNA, that encodes the cancer associated polypeptide. Exemplary cancer associated polypeptides include the protein encoded by Her2/neu, (c-erb-2) (Liu et al. (1992) Oncogene7: 1027-32); ras (Nakano, et al. (1984) Proc. Natl. Acad. Sci. U.S.A 81:71-5); Cyclin DI (Bartkova, et al. (1995) Oncogene 10:775-8, Shamma, et al. (1998) Int. J. Oncol. 13:455-60); E2F1 (Johnson et al. (1994) Proc. Natl. Acad. Sci. 91:12823-7); myc (Corcoran et al. (1984) Cell 37:113-22, Goddard et al. (1986) Nature 322:555-557); jun (Vogt et al. (1990) Adv. Cancer Res. 55:1-35); p53 (Levine et al. (1989) Princess Takamatsu Symp. 20:221-230). The language "radiation therapy" includes the application of a genetically and somatically safe level of electrons, protons, or photons, both localized and non- localized, to a subject to inhibit, reduce, or prevent symptoms or conditions associated with undesirable cell growth. The term X-rays is also intended to include machine- generated radiation, clinically acceptable radioactive elements, and isotopes thereof, as well as the radioactive emissions therefrom. Examples ofthe types of emissions include alpha rays, beta rays including hard betas, high-energy electrons, and gamma rays. Radiation therapy is well known in the art (see e.g., Fishbach, F., Laboratory Diagnostic Tests, 3rd Ed., Ch. 10: 581-644 (1988)), and is typically used to treat neoplastic diseases. The term "immunotoxins" includes immunotherapeutic agents that employ cytotoxic T cells and/or antibodies, e.g., monoclonal, polyclonal, phage antibodies, or fragments thereof, which are utilized in the selective destruction of undesirable rapidly proliferating cells. For example, immunotoxins can include antibody-toxin conjugates (e.g., Ab-ricin and Ab-diptheria toxin), antibody-radiolabels (e.g., Ab-1135) and antibody activation ofthe complement at the tumor cell. The use of immunotoxins to inhibit, reduce, or prevent symptoms or conditions associated with neoplastic diseases are well known in the art (see, e.g., Harlow, E. and Lane, D., Antibodies, (1988)). In another embodiment, the invention pertains to a method for photochemotherapeutically treating a Pinl -associated state in a subject comprising administering to said subject an effective amount of a Pinl-modulating compound of formulas (I), (la), (II), (na), (ILT), (HIa), (TV), (INa), (V), (NT), (Nil), (NIH), (BO, (X), (XI), (XH), (XΓH) and (XIN) and activation ofthe Pinl-modulating compound with a sufficent amount of light, such that said Pinl -associated state is photochemotherapeutically treated. While the aspect ofthe use ofthe compounds ofthe present invention in photochemotherapy is discussed herein, it should be understood that this discussion is not meant to be exclusive. In fact, further aspects of photochemotherapy are more fully discussed in U.S. Provisional Application No. 60/463271 (which is hereby expressly incoφorated herein by reference), including radiation sources, doses, and more specific methods of use, etc.; and the scope the present invention includes those aspects of photochemotherapy described therein. The language "photochemotherapy" or "photochemotherapeutically treating" is intended to include the art-recognized practice for the treatment of various abnormalities or disorders ofthe skin, or other epithelial organs, especially cancers or pre-cancerous lesions, e.g., melanoma, as well as certain nonmalignant lesions, for example, skin complaints such as psoriasis. Photochemotherapy involves the application of photosensitizing (photochemotherapeutic) agents to the affected area ofthe body or systemic application, followed by exposure to photoactivating light in order to activate the photosensitizing agents and convert them into cytotoxic form, whereby the affected cells are killed or their proliferative potential is diminished. The language "sufficient amount of light" is intended to include the amount of light sufficient to activate the Pinl modulating compound, e.g., prior to or subsequent to administration ofthe Pinl modulating compound to a subject. The light may be produced and transmitted from a point external to the subject, e.g., from conventional sources (e.g., a xenon arc lamp) or from a laser, through the exterior surface ofthe subject, or via optical fibers inserted into the subject. The light also may be produced from within the subject by a coadministered photoluminescent compound or the Pinl modulating compound itself (which may additionally comprise a photoluminescent molecule). Methods for irradiation of different areas ofthe body, e.g., by lamps or lasers, are well known in the art (see for example Nan den Bergh, Chemistry in Britain, May 1986 p. 430-439). The light used for the photochemotherapy ofthe present invention may comprise radiation, i.e., light, of a wavelength substantially equal to the maximum absoφtion wavelength of the Pinl modulating compound, or of a wavelength band that embraces the maximum absoφtion wavelength ofthe compound. In one embodiment, the light comprises a wavelength in the region of 600 to 1,300 nm. The exposure dose of light varies depending on the type and condition ofthe therapeutic target, the condition, age, sex, body weight and constitution ofthe patient, the type of he compound used, etc. It is within the scope ofthe invention to use either a single type of light of a single wavelength or a single band of wavelengths, or to use two or more types of light of different wavelengths or different bands of wavelength. The wavelength of light used for irradiation may be selected to achieve a more efficacious photochemotherapeutic effect. In certain embodiments, the wavelength of light used for the treatment is not less than 600 nm. In one embodiment, the invention includes a packaged Pinl-associated state treatment. The packaged treatment includes a Pinl modulating compound ofthe invention, e.g., Pinl-modulating compounds of formula (I), formula (la), formula (H), formula (Ha), formula (III), formula (Hla), formula (IN), formula (INa), formula (V), formula (VI), formula (VH), formula (NET), formula (IX), foπnula (X), formula (XT), foπnula (XII), foπnula (XIII) and foπnula (XIV), as described above, packaged with instructions for using an effective amount ofthe Pinl modulating compound. In another embodiment, the invention includes a packaged cyclin DI expression treatment. This packaged treatment include a Pinl modulating compound of the invention, e.g., Pinl-modulating compounds of formula (I), formula (la), formula (II), formula (Ha), foπnula (IH), formula (IHa), formula (IV), formula (INa), foπnula (V), formula (VI), formula (VII), foπnula (VIII), foπnula (IX), foπnula (X), foπnula (XI), formula (XII), formula (XIII) and formula (XIV), as described above, packaged with instructions for using an effective amount ofthe Pinl modulating compound to modulate, e.g., treat, cyclin DI overexpression. In yet another embodiment, the invention also pertains, at least in part to a packaged cancer treatment, which includes a Pinl-modulating compound ofthe invention, e.g., Pinl-modulating compounds of formula (I), formula (la), formula (II), foπnula (Ila), formula (HI), foπnula (IHa), foπnula (IN), foπnula (IVa), formula (V), formula (NI), formula (NH), formula (VIII), formula (IX), foπnula (X), formula (XI), formula (XII), formula (XIII) and formula (XIN), as described above, packaged with instructions for using an effective amount ofthe Pinl-modulating compound to treat cancer. The invention also pertains, at least in part, to pharmaceutical compositions of Pinl-modulating compounds ofthe invention, e.g., Pinl-modulating compounds of formulas (I), (la), (H), (Ha), (IH), (Hla), (IN), (INa), (N), (VI), (VH), (NIII), (IX), (X), (XI), (XII), (Xm) and (XIN), as described above, and, optionally, a pharmaceutically acceptable carrier. The language "effective amount" ofthe compound is that amount necessary or sufficient to treat or prevent a Pinl associated state, e.g. prevent the various moφhological and somatic symptoms of a Pinl associated state. In an example, an effective amount ofthe Pinl-modulating compound is the amount sufficient lo inhibit undesirable cell growth in a subject. In another example, an effective amount ofthe Pinl-modulating compound is the amount sufficient to reduce the size of a pre-existing benign cell mass or malignant tumor in a subject. The effective amount can vary depending on such factors as the size and weight ofthe subject, the type of illness, or the particular Pinl binding compound. For example, the choice ofthe Pinl binding compound can affect what constitutes an "effective amount". One of ordinary skill in the art would be able to study the factors contained herein and make the determination regarding the effective amount ofthe Pinl binding compound without undue experimentation. In one possible assay, an effective amount of a Pinl-modulating compound can be determined by assaying for the expression of cyclin DI and determining the amount ofthe Pinl-modulating compound sufficient to modulate, e.g., reduce, the levels of cyclin DI to that associated with a non-cancerous state. The regimen of administration can affect what constitutes an effective amount. The Pinl binding compound can be administered to the subject either prior to or after the onset of a Pinl associated state. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages ofthe Pinl binding compound(s) can be proportionally increased or decreased as indicated by the exigencies ofthe therapeutic or prophylactic situation. The language "pharmaceutical composition" includes preparations suitable for administration to mammals, e.g., humans. When the compounds ofthe present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier. The phrase "pharmaceutically acceptable carrier" is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds ofthe present invention to mammals. The carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion ofthe body, to another organ, or portion ofthe body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients ofthe formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Formulations ofthe present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount ofthe compound that produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent. Methods of preparing these formulations or compositions include the step of bringing into association a compound ofthe present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound ofthe present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Formulations ofthe invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound ofthe present invention may also be administered as a bolus, electuary or paste. In solid dosage forms ofthe invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyπolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absoφtion accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropyhnethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture ofthe powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms ofthe pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release ofthe active ingredient therein using, for example, hydroxypropyhnethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incoφorating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more ofthe above-described excipients. Liquid dosage forms for oral administration ofthe compounds ofthe invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert dilutents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations ofthe phaπnaceutical compositions ofthe invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds ofthe invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Formulations ofthe present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray foπnulations containing such carriers as are known in the art to be appropriate. Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Transdermal patches have the added advantage of providing controlled delivery of a compound ofthe present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absoφtion enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel. Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds ofthe invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous ι solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers that maybe employed in the pharmaceutical compositions ofthe invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance ofthe required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absoφtion ofthe injectable pharmaceutical form may be brought about by the inclusion of agents that delay absoφtion such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to slow the absoφtion ofthe drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amoφhous material having poor water solubility. The rate of absoφtion ofthe drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absoφtion of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature ofthe particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue. The preparations ofthe present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each adminisfration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred. The phrases "parenteral adminisfration" and "administered parenterally" as used herein means modes of administration other than enteral and topical adminisfration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, infrathecal, infracapsular, intraorbital, infracardiac, intradermal, intraperitoneal, franstracheal, subcutaneous, subcuticular, infraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. These compounds may be administered to humans and other animals for therapy by any suitable route of admimstration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually. Regardless of the route of adminisfration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions ofthe present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art. Actual dosage levels ofthe active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount ofthe active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity ofthe particular compound ofthe present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion ofthe particular compound being employed, the duration ofthe treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history ofthe patient being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount ofthe pharmaceutical composition required. For example, the physician or veterinarian could start doses ofthe compounds ofthe invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound ofthe invention will be that amount ofthe compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous and subcutaneous doses ofthe compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 1.0 to about 100 mg per kg per day. An effective amount is that amount treats an Pinl associated state. If desired, the effective daily dose ofthe active compound maybe administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. While it is possible for a compound ofthe present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition. EXEMPLIFICATION OF THE INVENTION: The invention is further illustrated by the following examples, which should not be construed as further limiting. The animal models used throughout the Examples are accepted animal models and the demonstration of efficacy in these animal models is predictive of efficacy in humans.
Tumor Inhibition Assays Pinl-modulating compounds are potent antitumor agents. The anti-tumor activity of Pinl-modulating compounds against glioblastoma cells is comparable to 1,3- bis(2-chloroethyl)- 1 -nitrosourea (BCNU), one of the most potent clinical useful antitumor agents. Misra, et al. 1982. J. Am. Chem. Soc. 104: 4478-4479 In vitro anti-tumor activity of Pinl-modulating compounds can be assayed by measuring the ability of Pinl-modulating compounds to kill tumor cells. Examples of appropriate cells lines include: human lung (A549); resistant human lung with low topo H activity (A549-VP); murine melanoma (B16); human colon tumor (HCT116); human colon tumor with elevated pi 70 levels (HCTVM); human colon tumor with low topo H activity (HCTVP); P388 murine lymph leukemia cells; and human colon carcinoma cell line (Moser) under standard conditions. After the cells are cultured for twenty-four hours and allowed to attach to a plate (i.e. a 96- well flat bottom plate), the cells are incubated for 72 hours with serially diluted concentrations of Pinl- modulating compounds. From this data, the concentration ofthe compound at which 50% ofthe cells are killed (IC50) is determined. Kelly, et al., U.S. Patent No. 5,166,208 and Pandey, et. al. 1981. J. Antibiot. 34(11):1389-401. In vivo anti-tumor activity of Pinl-modulating compounds can be assayed for by a reduction of tumor cells in mammals (i.e. mice) and a resulting increase in survival time compared to untreated tumor bearing mammals. For example, CDFi mice are injected inteφeritoneally with a suspension of P388 murine lymph leukemia cells, Ehrlich carcinoma cells, B16 melanoma cells, or Meth-A fibrosarcoma cells or other appropriate tumor cell line. Some ofthe mice are treated intraperitoneally with a Pinl-modulating compounds. Other mice are treated with saline. The in vivo activity of the compound is determined in terms ofthe % T/C which is the ratio ofthe mean survival time ofthe treated group to the mean survival time ofthe saline treated group times 100. Yokoi, et al, U.S. Patent No. 4,584,377; Kelly, et al., U.S. Patent No. 5,166,208; Warnick-Pickle, et al. 1981. J. Antibiot. 34(11): 1402-7; and Pandey, et. al. 1981. J. Antibiot. 34(11):1389-401 hi vivo anti-tumor activity of Pinl-modulating compounds can be assayed for using a transgenic animal, e.g. a mouse, that overexpresses a particular oncogene. For example, "Use of Pinl Inhibitors for Treatment of Cancer," USSN: 60/504117, filed September 17, 2003, the content of which is hereby expressly incoφorated by reference in its entirety, describes methods of evaluating a biological sample that is obtained from a subject for the presence of a cancer associated polypeptide; wherein the presence ofthe cancer associated polypeptide indicates that the subject will benefit from treatment with a Pinl inhibitor. In one embodiment of this application, a knockout-Pinl -animal that overexpresses a cancer associated polypeptide is tested for the development of cancer. USSN: 60/504117 demonstrates that an animal that is deficient in Pinl expression does not develop cancer when overexpressing a known oncogene. The in vivo anti-tumor activity of Pinl-modulating compounds can also be assayed as inhibitors against an ovarian tumor growing in a human tumor cloning system. Tebbe, et al. 1971 J. Am. Chem. Soc. 93:3793-3795. The invention is further illustrated by the following examples, which should not be construed as further limiting.
Example 1 Cell Based Cytotoxicity Assay (CBCA) of Pinl Modulating Compounds
Mammalian cells were seeded in 96 well flat bottom microtiter plates at a density of 5,000 6000 cells per well on day 0 in 0.1 mL of an appropriate growth media. On Day 1 , the wells were aspirated and 0.1 mL of fresh media was added. The cells were then treated with 0.01 mL of lOx drug dilutions in 10% DMSO in media and incubated at 37° C in a humidified, 5% CO2 atmosphere. The assay contained eight drug concentrations in triplicate as well as a triplicate control where cells were treated with 0.01 mL of 10% DMSO in media. On Day 4, the cells were incubated with 0.02 mL of a colorimetric cell-viability assay solution (MTS) prepared from 20 parts (3-(4,5- dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (Promega) at 2.0 mg/mL in PBS and 1 part phenazine methosulfate (Sigma) at 0.92 mg/mL in PBS for 2-3 hours at 37 °C. Background wells were prepared by incubating 0.02 mL ofthe colorimetric cell- viability assay solution with 0.1 mL of media in parallel with the cell containing wells. The absorbance at 490 nm was then measured with an ELISA plate reader and the absorbance recorded for the background wells was averaged and the mean value was subtracted from the cell containing wells. Percent cell viabilities at each drug concentration were calculated by dividing the mean absorbance at 490 nm ofthe treated wells by the mean absorbance at 490 nm ofthe untreated wells. ED50 values (the effective dose required to for 50% viability) were calculated by plotting drug concentrations versus percent cell viability. To count cells, suspended cells (0.02 mL) were diluted into 0.18 mL of 0.2% trypan blue solution in PBS. Approximately 0.015 mL of the suspension was added to a chamber of a Levy counting hemacytometer. The viable cells were counted in each ofthe four sets of 16 squares that are at the corners ofthe closely ruled lines. The total number of viable cells from the 64 squares were then multiplied by 0.025 to obtain the concentration of cells in the stock suspension. (Number of cells in the 64 wells) x (0.025) = lxlO6 cells/mL (original stock).
Example 2 Specificity Assay for Inhibition ofProline Isomerase by Pinl Modulating Compounds The proline isomerase activity assay is based on the method described by Fisher et al. (Biomed. Biochim. Acta, 1984, 43: 1101-1111). Specifically, the enzyme (3 ng) was preincubated with 236 uM substrate at 4 °C for 30 minutes in an 80 μL reaction volume containing 0.1 mg/μL BSA, 0.2 mM DTT, and 35 mM HEPES (pH 7.8). Proteolysis ofthe substrate was initiated by the addition of 80 μL of trypsin at 0.4 mg/mL in 35 mM HEPES (pH 7.8) and the release of p-nitroaniline was monitored every 10 seconds at 390 nm using a microplate reader (MRD/8V/DIAS, Dynex Technologies). Inhibition studies were preformed by adding 5 μL of inhibitors added in the pre-incubation mix. Inhibitors were at 0.4 mg/mL in 10% DMSO. Multiple activity-based assays at multiple dilutions, performed as described above, were used to generate the curve from which the IC50 was determined. Several IC50 results were obtained for the compounds ofthe invention using this experimental protocol.
Figure imgf000219_0001
Example 3 Specificity Assay for Inhibition of Pinl by Pinl Modulating Compounds
The specificity ofthe Pinl inhibitor compounds ofthe invention can be determined by the protease-coupled PPIase assay developed by Fischer et al. (Bio ed. Biochim. Acta, 1984, 43: 1101-1111). For example, the enzyme activity of Pinl can be compared to members ofthe other known classes of PPIases, cyclophilins (e.g., hCyplS, hCyP-A, hCyP-B, hCyP-C, and NKCA) and FKBPs (e.g., hFKBP12, hFKBP-12, hFKBP-13, and hFKBP-25) in the presence and absence ofthe compound. In one assay, hPinl activity measurements are determined using bovine trypsin (final concentration 0.21 mg/mL, Sigma) as an isomer specific protease and Ac-Ala-Ala-Ser(P)-Pro-Arg-pNA (Jerini, Germany) as a substrate. PPIase activity of hFKBP12 (Sigma) and hCyplδ (Sigma) is determined with the peptide substrate Suc-Ala-Phe-Pro-Phe-pNA (Bachem) and the protease α-chymotrypsin (final concentration 0.41 mg/mL, Sigma). The test can be performed by observing the released 4-nitroanilide at 390 nm with a Hewlett-Packard 8453 UN-vis spectrophotometer at 10°C. The total reaction volume is adjusted to 1.23 mL by mixing appropriate volumes of 35 mM HEPES (pH 7.8) with enzyme and effector solutions. The Pinl inhibitor compound is freshly diluted from a 1 mg/mL stock solution in DMSO, and pre-incubated at varying concentrations with the enzyme for 5 min (10°C). Prior to the start of reaction by addition ofthe respective protease, 2 μL ofthe peptide substrate stock solution (10 mg/mL in DMSO) is added. The amount of organic solvent is kept constant within each experiment (< 0.1%). The pseudo-first-order rate constant ko s for cis/trans isomerization in the presence of PPIase and the first-order rate constant k0 ofthe uncatalyzed cis/trans isomerization can be calculated using the Kinetics Software of Hewlett-Packard as well as SigmaPlot2000 for Windows 6.0 (SPSS). The Kj value for inhibition of Pinl PPIase activity by a Pinl inhibitor compound ofthe invention at constant concentrations of substrate ([S0]«KM) can then be calculated by fitting the data according to the equation for a competitive "tight-binding" inhibitor using SigmaPlot2000
Example 4 Cellular Screen Secondary Cell Based Activity Assay (Determination of ED so)
WD 8 or PC3 cells were trypsonized and diluted to a concentration of approximately 2000 cells per 100 ul of solution. 100 ul of cell solution was added to each well of a micortitre plate. After the cells had grown for approximately 1 day, 10 μL of a test compound stock solution was added to each well. After approximately 2 days of growth, the media was removed from each well and tyφsin was added. After a short incubation, the trypsin was inactivated and the cells were counted using a Guava Cell Analysis System (Hayward, CA). In order to determine the amount of soluble test compound in each assay, a duplicate sample, without cells added, was analyzed by HPLC and the amount of test compound was determined by comparison with a standard curve. ED5fj values were adjusted based on the amount of soluble test compound in each well. The results of this experiment are presented below.
Figure imgf000221_0001
Example 5 Method for Evaluating Pinl Levels
In one embodiment, the automated cellular imaging system (ACIS) was used to deteπnine tissues with elevated Pinl Levels. The methodology that was used to collect the data that is presented in Table 10 is described in U.S. Patent Application Publication No. US 2003-0068626 Al, the entire contents of which are incoφorated herein by reference. Micro-histoarray sections were scanned and images were captured using the automated cellular imaging system (ChromaNision Medical Systems, Inc., San Juan Capistrano, CA), which combines automated microscopy and computerized image processing to analyze multiple tissues on a single shde. ACIS was used to analyze microarray tissue sections on glass slides stained using a diaminodenzidine chromagen (DAB) and hematoxylin counterstain. Positive staining (brown color) as viewed by light microscope indicates the presence ofthe protein, and color intensity coπelates directly with protein quantity (expression). The ACIS was able to recognize 255 levels of immunohistochemical staining intensity (0-255) and converted these to fractional scores for the selected individual areas. However, the base limit on the threshold for the Generic DAB is pre-set at 50 by the manufacturer because the system is very sensitive. Therefore, any intensity below 50 was treated as 0 in this study. Entire immunostained tissue sections were scanned using the 4 X objective and images were captured using the 10X objective.
Calculation of Pin protein expression in human cancers: In this study, intensity scoring and the percent positive scoring (brown area was divided by total area) were used with the entire individual tissue dot selected.
The immunohistochemical staining was quantitated without knowledge of a pathologist' s score. All tissue samples were immunostained twice at one location, and confirmed at a second location, followed by an evaluation ofthe two data sets.
For example, the final score was obtained by using the average ofthe two data sets and was calculated by the formulation: score = intensity + (X percent positive staining).
The % of total cases showing elevated levels (over-expression) of Pin 1 = [numbers of tumor samples with score larger than the score ofthe highest normal case] total number of tumor samples multiplied by 100.
Results: Table 10 Pinl protein over-expression in human tissues mieroarray
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
2005/007123
Figure imgf000225_0001
Example 6 Synthetic Methods of Preparation of Compounds of the Invention
General Experimental Conditions Liquid chromatography data was obtained using an Hewlett-Packard (HP) 1100 Series Liquid Chromatograph coupled to a Diode Array Detector [ Zorbax Eclipse XDB-C8 column; particle size 5μm, 150 mm column length, 4.6m column diameter; flow rate of ImL/min; Solvent program, from 95% H2O (w/ 0.1% TFA)/ 5% Acetonitrile ( w/0.1% TFA ) to 100% Acetonitrile in 18 minutes, then held constant for 2 minutes; detection wavelength 254 nm]. Mass spectrometric data was obtained using a HP 6980 Gas Chromatograph coupled to a 5973 Mass Selective Detector: Agilent HP1 column, 15 m column length, 0.25 mm column diameter, 0.1 μm column film, 280°C injector temperature, initial oven temperature of 200°C for 3 minutes, changed to 325°C over 5 minutes, and held constant for 6 minutes. Thin-layer chromatography was performed on EM Science MK6F silica gel glass TLC plates and UN light was used for detecting compounds on the TLC plates. Reagents used in reactions were purchased from Aldrich Chemical Company (Milwaukee, MO), Sigma Chemical Company (Milwaukee, MO), Fluka Chemical Company (Milwaukee, MO), Fisher Scientific (Pittsburg, PA), TCI America (Portland, OR), Ryan Scientific (Isle of Palms, SC), Lancaster Synthesis (Windham, ΝH ), Asinex (Moscow, Russia), Chembridge Coφoration (San Diego, CA), Matrix Scientific (Columbia, SC) or Oakwood Products Inc. (West Columbia, SC). Four synthetic routes have been used to prepare rhodanine analogs described in this invention.
General description of synthetic schemes
Method A
Figure imgf000226_0001
Method B C °
Figure imgf000226_0002
Figure imgf000226_0003
Method C
Figure imgf000226_0004
HJ ssKK V)
Figure imgf000226_0005
Method A condenses an aldehyde with the active methylene of an appropriately substituted rhodanine carboxylic acid under Aldol conditions. Method B condenses the aldehydes with the coπesponding ester-protected carboxylic acid, followed by hydrolytic cleavage ofthe ester to provide the carboxylic acid. Method C demonstrates that the Aldol condensation can be carried out using polymer-bound rhodanine. The final product can subsequently be released from the polymer support under mild conditions to provide the analogs ofthe invention. Suzuki cross coupling reactions (method scheme not shown) can also be employed to make the compounds of the invention.
Preparation of Carboxylic Acid Derivatives (Intermediates for Method A :
Procedure 1
Figure imgf000227_0001
The synthesis of this material followed established literature procedures. See JOC, USSR, Engl. Transl. 2, 1315 (1966). A representative example follows:
To 10.0 g aminocaporic acid ( 76.2 mmol) in 34.1 mL 22% KOH (~ 1.75 eq.), CS2 (5.0 mL, ~ 1.1 eq.) was added dropwise, making sure the temperature ofthe reaction did not exceed 25 °C. The yellow mixture was allowed to mix at room temperature for approximately 3 hours, at wliich time 10.6 g (1.0 eq.) of bromoacetic acid was added as a solid in small portions over about 20 minutes. The reaction was subsequently allowed to mix at room temperature for an additional 3 hours, during which time a precipitate formed. The reaction mixture pH was adjusted to 3 - 4 using concentrated sulfuric acid, and allowed lo stand overnight at room temperature. The resulting yellow/orange material was filtered and washed with water. Recrystallization was accomplished using 1 : 1 EtOH:H2O. Isolated ~ 11.5 g of material (- 61%) Procedure 2
Figure imgf000228_0001
3-(4-Oxo-2-thioxo-thiazolidin-3-yl)-propionic acid To 3.4 g β-alanine (38.1 mmol) in 17 mL 22% KOH (1.75 eq.), CS2 2.5 mL. (1.1 eq.) was added dropwise making sure the temperature ofthe reaction does not exceed 25 °C . The mixture was allowed to mix at room temperature for approximately 3 hours at which time 5.3 g (38.1 mmol) of bromoacetic acid was added as a solid in small portions over about 20 minutes. The reaction was subsequently allowed to mix at room temperature for an additional 3 hours, during wliich time a precipitate formed. The reaction mixture pH was adjusted to 3-4 using cone, sulfuric acid and allowed to stand overnight at room temperature. The product was filtered off and washed with water.
Yield: 3.1 gm (39.6 %) TLC: Rf = 0.75 (CHC13 - MeOH = 10 - 1)
Procedure 3
Figure imgf000228_0002
2-Hydroxy-4-[3-(4-oxo-2-thioxo-thiazoIidin-3-yl)-propionylamino]-benzoic acid
2.05 g (10 mmol) 3-(4-Oxo-2-thioxo-thiazolidin-3-yl)-propionic acid (from Preparation of Carboxylic Acid Derivatives, Procedure 2) and 1.42 g (11 mmol) N,N- diisopropylethylamine were dissolved in 40 mL of dry 1,2-dichloroethane and 1.33 g (11 mmol) pivaloyl chloride was added dropwise. The mixture was stfrred at room temperature for 1 hour (using CaCl2 tube), then 1.45 g (9.5 mmol) 4-amino-salicylic acid was added. The mixture was stirred at room temperature for 18 hours. The precipitated solid was filtered off, and washed with 1,2-dichloroethane and ether.
Yield: 2.8 gm (82 %)
TLC: Rf = 0.45 (CHC13 - MeOH = 4 - 1)
Procedure 4
Figure imgf000229_0001
2.07 g (10.09 mmol) 3-(4-Oxo-2-thioxo-tIιiazolidin-3-yI)-propionic acid (from Preparation of Carboxylic Acid Derivatives, Procedure 2) and 1.93 mL (1.1 equiv., 11.1 mmol) N,N-diisopropylethylamine were dissolved in 40 mL of dry 1 ,2-dichloroethane and 1.37 mL (1.1 equiv., 11.1 mmol) pivaloyl chloride was added dropwise. The mixture was stkred at room temperature for 1 hour (using CaCl2 tube) then 1.0 g (1 equiv., 10.09 mmol) aminomethyltetrazole was added. The mixture was stirred at room temperature for 18 hours. The precipitated product was filtered off and washed with dichloroethane.
Yield: 1.96 g (68 %
TLC: Rf= 0.15 (1,2-dichloroethane - EtOH = 2 - 1)
Procedure 5
Figure imgf000230_0001
To 5-(2H-Tefrazol-5-yl)-pentylamine (1 eq.) in 22% KOH (1.75 eq.) was added dropwise CS2 (1.1. eq.) making sure the temperature ofthe reaction did not exceed 25°C. The mixture was allowed to mix at room temp, for 3 hours at wliich time bromoacetic acid was added (1 eq.) as a solid in small portions over about 20 minutes. The reaction was stirred at room temp, overnight. Then pH was adjusted to 3 and the mixture was stiπed for another 2 hours. Then the mixture was evaporated. The crude product was obtained as an oil. The crude product was purified by semi preparative RP HPLC.
Preparation of Final Products Using Method A:
Procedure 1
Figure imgf000230_0002
0.4 mmol ofthe appropriate rhodanine derivative and 0.4 mmol ofthe aldehyde derivative and 0.4 mmol of triethylamine was dissolved in 5 mL of ethanol.
The mixture was heated under reflux for hours (the reaction was monitored by TLC).
After disappearance ofthe starting compounds the reaction mixture was cooled down and the precipitated product was filtered off, washed with EtOH. Procedure 2
Figure imgf000231_0001
102 mg (0.3 mmol) 2-Hydroxy-4-[3-(4-oxo-2-thioxo-thiazolidin-3-yl)- propionylamino]-benzoic acid (from Preparation of Carboxylic Acid Derivatives, Procedure 3) and 67 mg (0.3 mmol) 4-(3,4-difluoro-phenyl)-thiophen-2-carbaldehyde were dissolved in 5 mL of ethanol. Triethylamine (5 drops) was added, the mixture was heated under reflux for 30 minutes, and then diluted with 15 mL 5% HCl. The resulting precipitated solid was filtered, and washed with ether. Yield: 75 mg (46.6 %)
Procedure 3
Figure imgf000231_0002
102 mg (0.3 mmol) 2-Hydroxy-4-[3-(4-oxo-2-thioxo-thiazolidin-3-yl)- propionylamϊno]-benzoic acid (from Preparation of Carboxylic Acid Derivatives, Procedure 3) and 97 mg (0.3 mmol) 4-(3,4-bis-trifluoromethyl-phenyl)-thiophen-2- carbaldehyde were dissolved in 5 mL of ethanol. Triethylamine (5 drops) was added, the mixture was heated under reflux for 30 minutes, and then diluted with 15 mL 5% HCL The resulting precipitated solid was filtered, and washed with ether. Yield: 101 mg (52 %) Procedure 4
Figure imgf000232_0001
In ~ 20 mL of toluene was added 1.0 g (~ 4 mmol) ofthe rhodanine-C-6 carboxylic acid and 970 mg (1 eq.) ofthe furaldehyde. A layer of molecular sieves and ~ 15mg of pyridinium tosylate were then added. The reaction was brought to gentle reflux for about 3 — 4 hours, was monitored by TLC, to determine when consumption of starting materials was complete. The reaction was then filtered hot and washed with hot toluene and hot ethanol. The mother liquor was evaporated to dryness to result in the crude product.
The crude product was dissolved in ~ 500 mL of acetone and warmed on a hot plate, filtered warm and washed with warm acetone. The clear yellow/orange solution was placed back on a hot plate and brought to a gentle reflux. After ~ 50 mL of acetone had evaporated, ~ 50 mL of water was added and the solution allowed to continue gentle refluxing until an additional ~ 50 mL of acetone had evaporated. An additional 50 mL of water was added and the solution was allowed to continue refluxing until it became cloudy, at which point is was removed from the hot plate. The cloudy solution was washed down the sides with acetone, allowed to cool to room temperature, and then placed overnight in a refrigerator.
The resulting crystals were filtered, washed with cold acetone (~ 100 mL) and water. A bright orange material was isolated, ~ 930 mg (— 49%). The LC suggested a trace contaminant and the material was re-recrystalized as above, yielding ~ 840 mg from the second recrystalization.
To make the Na salt, ~ 435 mg ofthe free acid was dissolved in ~ 500 mL of acetone, and 77 mg (~1 eq.) of NaHCO3 in ~ 1 mL of water was added. The mixture was allowed to mix for about 5 minutes and then concentrated on a rotary evaporator. The material was triturated with ether/acetone, filtered and washed with ether to yield — 350 mg of an orange product material. Procedure 5
Figure imgf000233_0001
140 mg (1 eq.; 0.4 mmol) aldehyde (I.)
112 mg (1 eq.; 0.4 mmol) rhodanine (II.)
100 mg Tetrakis(triphenylphosphine)palladium(0) (III.)
30 microliter (0.5 eq.; 0.2 mmol) triethylamine
2 ml ethanol
Reaction: Reflux for 5 hours. The product subsequently precipitated from the reaction mixture; it was filtered off and washed with ethanol, resulting in 157mg of product.
Preparation of Ester Derivatives (Intermediates for Method B)
Procedure 1
Figure imgf000233_0002
4.55 g (26.65 mmol) II. 2.73 mL (3.0g; 25 mmol) I. 875 microL (625 mg; 7.5 mmol) triethylamine 50 mL 1,2-dichloroethane (HPLC purity)
Reaction: I. and H. were dissolved in 1,2-dichloroethane and TEA was added. The reaction mixture was stirred for 1 hour at r.t. Work up: The solvent was removed in vacuo, isopropanol was added (25 mL) to the residue and the mixture was cooled to 0°C. The precipitated product was then filtered off and washed two times with 5 mL of cooled isopropanol.
TLC: silica/dichloroethane : ethanol = 10 : 1.
Product: 5.5 g (Yield=89%)
Procedure 2
Figure imgf000234_0001
1.06 g (5.17 mmol) 3-(4-Oxo-2-thioxo-thiazolidin-3-yl)-propionic acid (from Preparation of Carboxylic Acid Derivatives, Procedure 2) and 0.99 mL (1.1 equiv., 5.7 mmol) N,N-diisopropylethylamine were dissolved in 20 mL of dry 1,2-dichloroethane and 0.7 mL (1.1 equiv., 5.7 mmol) pivaloyl chloride was added dropwise. The mixture was stirred at room temperature for 1 hour (using CaCl tube), then 1.0 g (1 equiv., 5.17 mmol) 4-amino-benzoic acid t-butyl ester was added. Subsequently, the mixture was stiπed at room temperature for 18 hours, and extracted once with 20 mL of HCl solution (3%), once with Na2CO3 solution (5%), and once with water. The organic phase was dried over MgSO4 then evaporated in vacuo.
Yield: 1.55 g (78 %) (V)
TLC: Rf = 0.75 (1,2-dichloroethane - EtOH = 10 - 1)
Synthesis of Final Product Using Method B
Procedure 1
Figure imgf000235_0001
2 = 5-(4-nitropheπyl)furanyt-
Step l) Alkylation of rhodanine Rhodanine (MW=133.19) n=50 mmol, m=6.66 g ethyl-4-bromobutyrate (MW=195.06) 1.1 eq, 55 mmol, V=7.9 mL NaH 1.5 eq, 75 mmol, m=2.9 g (60% suspension in THF) To the cooled (-10 0 °C) THF, NaH was added dropwise under argon. After 10 minutes of stirring, rhodanine was added, and after another 15 minutes ethyl-4- bromobutyrate was added dropwise. The mixture was stirred under reflux for about 1.5- 2 h (monitored by TLC), and left to cool down. The NH4CI was added and THF was evaporated. The residue was dissolved in ethyl acetate and extracted with brine. After drying (MgSO4) the crude product was used in the next reaction without further purification.
Step 2) Condensation of rhodanine with an aldehyde - alkylated rhodanine (MW=247) n=5 mmol, m=1.24 g 5-(4-nifrophenyl)-furfural (MW=251.09) 1 eq, m=l .26g piperidine 0.03 eq, 0.15 mmol, V=0.015 mL AcOH 0.03 eq, 0.15 mmol, V=0.008 mL A mixture of all the compounds in toluene (100 mL) was heated under reflux with azeofropic removal of water for about 5 h. The mixture was cooled to 5 °C, and filtration gave crude product, which was used without further purification.
Step 3 a) Hydrolysis of ethyl ester The product ofthe previous reaction (MW=480, n=3 mmol) was dissolved in MeOH, and IN NaOH was added (1.1 eq). The mixture was stirred at room temperature for about 6 h. After that time the mixture was acidified with IN HCl to the pH 6 and MeOH was evaporated. The residue was acidified to the pH 2 and extracted with ethyl acetate (4 times). After drying (MgSO4) the crude product was crystallised (MeOH/ Et2O). Step 3b) Alternate Hydrolysis In certain embodiments, in which a t-butyl ester is used in replacement of the ethyl ester (e.g., the step 1 reactant is t-butyl-4-bromobutyrate) the t-butyl group of , the product of condensation reaction may be hydrolyzed by stirring in 10 mL of HCl gas diluted in dioxane for 4-10 hours. The solvent is evaporated in vacuo and the crystalline product is triturated with diethylether, then filtered off.
Synthesis of Compounds on Solid Support
Procedure 1
1) Coupling of Fmoc-γ-Abu-OH with Wang resin (symmetrical anhydride coupling).
2) Synthesis of rhodanine on solid support To 1 g Fmoc-γ- Abu- Wang resin was added 20% piperidine in DMF and the mixture was shaken for 30 minutes The resin was washed (DMF, MeOH and CH2C12) and dried. A mixture of resin, thiocarbonyldiimidazole (5 mol eq) and triethylamine (3 mol eq) in CH2C12 was shaken for 1 h. The filtrate was drained away and the resin was swollen in CH2C12 and methyl thioglycolate (5 mol eq) was added. The reaction mixture was further shaken for about 16 h. The resin was washed (DMF, MeOH and CH2C12) and dried.
3) Condensation of aldehydes with rhodanine (and subsequent cleavage ofthe product from the resin) The loaded resin and an aldehyde (5 mol eq) was heated in toluene for about 6 h. The resin was washed (DMF, MeOH and CH2C12), resuspended in 20% trifluoroacetic acid CH2Cl2 and shaken for 1 h. The filtrate was pooled and concentrated to yield an exact product (Yield = 80-90%).
Prep, of Starting Materials for Final Product via Suzuki Cross Coupling:
Procedure 1
Figure imgf000237_0001
0.805g (1.1 eq.; 6.6 mmol) Phenylboronic acid (I.) 1.05 g (1 eq.; 6 mmol) 5-Bromo-2-furaldehyde (H.) 0.2g TefraMs(friphenylphosphine)palladium(0) (IH.) 1.59 g (2.5 eq.; 15 mmol) Na2CO3 10 mL distilled water 25 mL Ethylene glycol dimethyl ether (Peroxide free)
Reaction: 5-bromo-2-furaldehyde (H.) was dissolved in ethylene glycol dimethyl ether (25 mL) under nitrogen (inert atmosphere) then Pd(PPh3)4 catalyst was added and the mixture was stirred for 10 minutes. Then phenylboronic acid (I.) and the solution of Na2CO3 in 10 mL distilled water was added and the reaction mixture refluxed for minutes 4 hours. The reaction was monitored by TLC (on silica, eluent: hexane : ethylacetate = 3 :2). Work up: 30 mL distilled water was added to the reaction mixture, then it was extracted with ethylacetate 3 times. The organic phase was dried over MgSO4 then evaporated.
Purification: The crude product was purified by liquid chromatography (on silica, eluent: chloroform). After evaporation the crystalline product was washed with diethylether. Yield: about 70 %. (Stored under inert atmosphere at 0-5 °C).
Procedure 2
Figure imgf000238_0001
0.742g (1.1 eq.; 2.878 mmol) 3,5 bis-trifluoromethyl phenylboronic acid (I.) 0.500 g (1 eq.; 2.617 mmol) 4-bromothiophene-2-carboxaldehyde (H.) 0.25g Tetrakis(triphenylphosphine)palladium(0) (HI.) 0.693 g (2.5 eq.; 6.54 mmol) Na2CO3 8 mL distilled water 25 mL ethylene glycol dimethyl ether (Peroxide free)
Reaction: 4-bromothiophene-2-carboxaldehyde (H.) was dissolved in ethylene glycol dimethyl ether (25 mL) under nitrogen (inert atmosphere) then Pd(PPh3) catalyst was added and the mixture was stiπed for 10 minutes. Then phenylboronic acid (I.) and the solution of Na2CO3 in 8 mL of distilled water was added and the reaction mixture refluxed for 8 hours. The reaction was monitored by TLC (on silica, eluent: hexane : ethylacetate = 3 :2) Work up: 30 mL of distilled water was added to the reaction mixture, which was subsequently exfracted with ethylacetate 3 times. The organic phase was dried over MgSO4) and evaporated in vacuo.
Purification: The crude product was purified by chromatography (on silica, eluent: hexane : ethylacetate = 3 :2 ).
Yield: ( 0.72 g) 84.8 %. (Stored under inert atmosphere at 0-5 °C)
Procedure 3
Figure imgf000239_0001
500 mg (1 eq.; 1.59 mmol) (I.)
333 mg (1.3 eq.; 2.07 mmol) 5-indolylboronic acid (II.)
100 mg TetraMs(1riphenylphosphine)palladium(0) (III.)
422 g (2.5 eq.; 3.97 mmol) Na2CO3
10 ml distilled water
20 ml Ethylene glycol dimethyl ether (Peroxide free)
Reaction: (I.) was dissolved in Ethylene glycol dimethyl ether (20 ml) under nitrogen (inert atmosphere). Pd(PPh3) catalyst (III.) was then added and the mixture was stirred for 10 minutes. 5-hιdolylboronic acid (II.) and a solution of Na2CO3 in 10 ml distilled water was added and the reaction mixture was refluxed for 6 hours. The reaction was monitored by TLC (on silica, eluent: hexane : acetone = 1 : 1). (Note: the Rf ofthe starting aldehyde and the coupled product are very similar.) Work up: 30 ml distilled water was added to the reaction mixture, followed by three extractions with ethyl acetate. The organic phase was dried over MgSO4 then evaporated.
Purification: The crude product was purified by chromatography (on silica, eluent: hexane : acetone = 10:4), resulting in 564mg of product.
Preparation of Pd(0) catalyst for Suzuki Cross Coupling Procedure 1
DMSO PdCI2 + P(Ph)3 + H2N-NH2 * H20 - Pd(PPh3)4 III.
1.77 g PdCl2 (I.) 13.1 g Triphenylphosphine (II.) 2 mL Hydrazine monohydrate (HI.) 120 mL Dimethyl sulfoxide
I. and H. were added to DMSO under nifrogen at room temperature. The mixture was heated using a hot oil bath at 140 °C and kept at this temperature until the mixture became a clear solution (around 15-30 minutes). Then IH. was added dropwise (over 1 minute) to the vigorously stiπed reaction mixture. After addition of UI. to the reaction mixture, the reaction was cooled immediately to room temperature with a water bath. The precipitate was filtered off and washed quickly 3 times with 5 mL of cool ethanol, followed by 4 times with 5 mL diethylether. (The reaction was kept under a blanket of nitrogen during the entire course ofthe above reaction.)
Reference: Coulson, Inorg. Synth. 1972 (13) 121
EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope ofthe following claims. INCORPORATION BY REFERENCE
The entire contents of all patents, published patent applications and other references cited herein are hereby expressly incoφorated herein in their entireties by reference.

Claims

1. A method for freating a Pinl-associated state in a subject comprising administering to said subject an effective amount of a Pinl-modulating compound of foπnula (Ig):
Figure imgf000242_0001
wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2O-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, linking groups, and carbocyclic groups may be substituted with one or more substituents; such substituents can include, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino
(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, or an aromatic or heteroaromatic moiety; and any combination thereof; Ri is H or is selected from one or a combination of alkyl groups, aromatic groups, heterocyclic groups, and carbocyclic groups, which may be indirectly linked to the nifrogen ofthe core ring of formula I via alkyl, substituted alkyl, alkenyl, - O-, -N(H)-, -C(O)-, -S-, or -S(O)2O-, and any combination thereof; which may be further substituted with one or more substituents; such substituents can include alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonyl, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, moφholino, phenol, phenyl, piperizine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, or an aromatic or heteroaromatic moiety, and any combination thereof; such that said Pinl -associated state is treated.
2. A method for freating a Pinl -associated state in a subject comprising administering to said subject an effective amount of a Pinl-modulating compound of formula (I):
Figure imgf000243_0001
(I) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2O-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups may be substituted with one or more substituents selected from the group consisting of H, CH3, F, CH2OH, NH , OH, CF3, CI, Br, I, -O-, -C1-6> -CH=CHCH2-, =O, =NH, =N-NH2, -NC(O)CH3, -C(O)- OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, -CH2NH2, -OCH2C(O)NH- NH2, -CH2C(O)CH3, moφholino, C(O)moφholino, -CH2C(O)C(CH3)3, -C(O)- OCH2CH3, and any combination thereof; Ri is selected from the group consisting of-H; -C1-6, -CH CHCH2) -NH2, -pQpRa, X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of — H, C1-4, -CH2CH -, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -CH2-, -C(O)NH , -C(O)R3, -N(R5)2, and any combination thereof; wherein R3 is selected from the group consisting of — H, -OH, -O-, C1- , moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, - C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -OH, -O-, C1-4, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -C(O)NH2, - CH2CH2OH, -CH2CH(OH)CH3! -C(O)N(CH3)-, -COOH and esters and amides thereof, - CH2COOH and esters and amides thereof, and any combination thereof; such that said Pinl -associated state is treated.
3. The method of claim 1, wherein Z is S.
4. The method of claim 1, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups are selected from the group consisting of a pyridine, a phenyl, a lH-imidazole, a thiazolidine, a pyπolidone, a hexahydro-pyrimidine, a 3-hydroxy- pyrrolidin-2-one, a pyπolidine-2,3-dione, a pyrrolidine-2,5-dione, a pyπolidin-2-one, a cyclopentyl, a [l,4]dioxepane, a tetrahydrofuran, an isoxazole, a moφholino, a [l,3]dioxolane, apyrimidine, a furan, athiophene, apyπole, a naphthalene, apyrazole, a 3-(methylene)-l-methyl-l,3-dihydro-indol-2-one, a benzo[l,3]dioxole, a piperazine, and a furazan 2-oxide.
5. The method of claim 1, wherein n is selected from the group consisting of 0 through 5.
6. The method of claim 1, wherein Zi is O.
7. The method of claim 1 , wherein the Pinl-modulating compound of formula (Ig) is a compound of formula (II): '
Figure imgf000245_0001
(H) wherein the dashed line indicates a single or a double bond; n is O or 1; Ri is H or lower alkyl Xi, X2 and X3 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and R are independently selected from the group consisting of H, -O-, -C1-6)F, NH2, CF3> CI, Br, I, =O, =NH, =N-NH2, -NC(O)CH3)- C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -moφholino, -C(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -C1-6) - CH2CHCH2j -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, C1-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -C1-6, -C(O)NH2, -C(O)Rb, -N(Rs)2, and any combination thereof; wherein R is selected from the group consisting of-H, -OH, -O-, -C1-6; moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each Rg is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and ' esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R ' are independently selected from the group consisting of H, -O-, -C1-6, -S-, -N-, -CH==CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
8. The method of claim 7, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000247_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
9. The method of claim 7, wherein R\ is -(X)pC(O)Ra, and Ra is the foπnula
Figure imgf000247_0002
wherem Rs is selected from H, F or OH.
10. The method of claim 7, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, ethyl-moφholino, or CH=CHCH2-moφholino.
11. The method of claim 7, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2- moφholino.
12. The method of claim 1 , wherein the Pinl -modulating compound of formula (Ig) is a compound of formula (πi):
Figure imgf000248_0001
(IH) wherein the dashed line indicates a single or a double bond; n is O or l; i is H or lower alkyl Xls X2, X-3, j, and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and RQ are independently selected from the group consisting of H, -O-, -C1-6,F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3, -C(O)QC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)o-1C(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH -; and wherein R2 and R3, R2 and R , and/or R3 and Re can together form a multicyclic aromatic, heterocychc, or carbocyclic stracture with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-6, - CH2CHCH2, -NH2, -(X)pRa, K9PC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of — H, -O-, -C1-6) moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -C1-6)-C(O)NH2, -C(O)Rb, -N(Rs)2, and any combination thereof; wherein R is selected from the group consisting of — H, -OH, -O-, -C1-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -C1-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R ' are independently selected from the group consisting of H, -O-, -C1-6, -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
13. The method of claim 12, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000249_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
14. The method of claim 12, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000250_0001
wherein R8 is selected from H, F or OH.
15. The method of claim 12, wherein Ri is -<X)pC(O)Ra, Ra is N(R5)2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, - ethyl-moφholino, or CH=CHCH2-moφholino.
16. The method of claim 12, wherein R is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2- moφholino.
17. The method of claim 12, wherein the Pinl-modulating compound of formula (Ig) is a compound of fomiula (IN):
Figure imgf000250_0002
(IV) wherein the dashed line indicates a single or a double bond; n is 0 or 1; i is H or lower alkyl Xi is selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and R are independently selected from the group consisting of H, -O-, -C1-6)F, NH2, CF3) CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3) -C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)o-2moφholino, -(CH2)o-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xls X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-6) - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Ci.6,-C(O)NH2, -C(O)Rb, -N(Rs)2, and any combination thereof; wherein R is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH CH(OH)CH3, -C(O)N(CH3)~, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -C1-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R7' are independently selected from the group consisting of H, -O-, -C1-6,-S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
18. The method of claim 17, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000252_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
19. The method of claim 17, wherein Ri is -{X)pC(O)Ra, and Ra is the formula Ri:
Figure imgf000252_0002
wherein R8 is selected from H, F or OH.
20. The method of claim 17, wherein Ri is -(X)pC(O)Ra, Ra is N(Rs)2, and R5 is selected from the group, consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, - ethyl-moφholino, or CH=CHCH2-moφholino.
21. The method of claim 17, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2- moφholino.
22. The method of claim 1 , wherein the Pinl -modulating compound of foπnula (Ig) is a
Figure imgf000253_0001
wherein the dashed line indicates a single or a double bond; n is O or 1; R is H or lower alkyl Xi, X2, X3, i and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and R6 are independently selected from the group consisting of H, -O-, -C1-6, F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3,-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)o-2moφholino, -(CH2)o-ιC(O)moφholmo9 - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xl5 X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -C1-6; - CH2CHCH2, -NH2, KOpRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -C1-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -0.6, -C(O)NH2, -C(O)Rb, -N(R.5)2, and any combination thereof; wherein Rb is selected from the group consisting of — H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, - COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci_6; moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof.
23. The method of claim 22, wherein Ra Ri is -(X)pC(O)Ra, and Ra is the formula R<.:
Figure imgf000254_0001
or esters and amides thereof; and wherein Rs is selected from H, F or OH.
24. The method of claim 22, wherein Ri is -(X)pC(O)Ra, and a is the formula R^:
Figure imgf000255_0001
wherein R8 is selected from H, F or OH.
25. The method of claim 22, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, - ethyl-moφholino, or CH=CHCH2-moφholino.
26. The method of claim 22, wherein R7 is selected from the group consisting of-N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2- moφholino.
27. The method of claim 1, wherein said Pinl-modulating compound is a Pinl -inhibiting compound.
28. The method of claim 1, wherein said compound is selected from the group consisting of compounds listed in Table 1, and derivatives thereof.
29. The method of claim 1 , wherein said compound is selected from the group consisting of compounds listed in Table 2, and derivatives thereof.
30. The method of claim 1, wherein said compound is selected from the group consisting of compounds listed in Table 3, and derivatives thereof.
31. The method of claim 1 , wherein said compound is selected from the group consisting of compounds listed in Table 4, and derivatives thereof.
32. The method of claim 1, wherein said compound is selected from the group consisting of compounds fisted in Table 5, and derivatives thereof.
33. The method of claim 1 , wherein said compound is selected from the group consisting of compounds listed in Table 6, and derivatives thereof.
34. The method of claim 1, wherein said compound is selected from the group consisting of compounds listed in Table 7, and derivatives thereof.
35. The method of claim 1 , wherein said compound is selected from the group consisting of compounds listed in Table 8, and derivatives thereof.
36. The method of claim 1, wherein said Pinl -associated state is a cyclin DI elevated state.
37. The method of claim 1 , wherein said Pinl -associated state is neoplastic fransformation.
38. The method of claim 1, wherein said Pinl -associated state is cancer.
39. The method of claim 1, wherein said Pinl -associated state is tumor growth.
40. The method of claim 1 , wherein said method of treating said Pinl - associated state comprises inhibiting tumor growth.
41. The method of claim 1 , wherein said method of treating said Pinl - associated state comprises preventing the occurrence of tumor growth in the subject.
42. The method of claim 1 , wherein said method of freating said Pinl - associated state comprises reducing the growth of a pre-existing tumor in the subject.
43. The method of claim 1, wherein said Pinl -associated state is colon cancer or breast cancer.
44. The method of claim 1, wherein said Pinl -associated state is sarcoma or a malignant lymphoma.
45. The method of claim 1 , wherein said Pinl -associated state is esophageal cancer, ohgodendroglioma, asfrocytoma, glioblastomamultiforme, cervical carcinoma, ovary endomefroid cancer, ovary Brenner tumor, ovary mucinous cancer, ovary serous cancer, uterus carcinosarcoma, breast lobular cancer, breast ductal cancer, breast medullary cancer, breast mucinous cancer, breast tubular cancer, thyroid adenocarcinoma, or thyroid follicular cancer.
46. The method of claim 1, wherein said Pinl -associated state is thyroid medullary cancer, thyroid papillary carcinoma, parathyroid adenocarcinoma, adrenal gland adenoma, adrenal gland cancer, pheochromocytoma, colon adenoma mild displasia, colon adenoma moderate displasia, colon adenoma severe displasia, or colon adenocarcinoma.
47. The method of claim 1, wherein said Pinl -associated state is esophagus adenocarcinoma, hepatocelluar carcinoma, mouth cancer, gall bladder adenocarcinoma, pancreatic adenocarcinoma, prostate, prostate cancer, testis non-seminomatous cancer, testis seminoma, urinary bladder transitional carcinoma, lung adenocarcinoma, lung large cell cancer, lung small cell cancer, lung squamous cell carcinoma, MALT lymphoma, NHL diffuse large B, non-Hodgkin's lymphoma (NHL), thymoma, skin malignant melanoma, skin basolioma, skin squamous cell cancer, skin merkel zell cancer, skin benign nevus, lipoma, endometriod carcinoma, endometrium serous carcenoma, small intestine adenocarcinoma, stomach diffuse adenocarcinoma, kidney chromophobic carcinoma, kidney clear cell carcinoma, kidney oncocytoma, kidney papillary carcinoma, Hodgkin lymphoma or liposarcoma.
48. The method of claim 1, wherein said Pinl -associated state is associated with the misexpression of Pinl and or DNA damage.
49. The method of claim 1 , wherein said Pinl -associated state is associated with an oncogenic protein.
50. The method of claim 1, wherein said Pinl -associated state is associated with Ha-Ras.
51. The method of claim 1 , wherein said Pinl -modulating compound has a characteristic inhibition profile (CJP) and has a cytotoxicity effective to treat said Pinl- associated state.
52. The method of claim 51, wherein said Pinl-modulating compound has an IC5Q value of less than about 40.
53. The method of claim 52, wherein said IC50 value of between about 10 and about 40.
54. The method of claim 52, wherein said IC50 value of between about 1 and about 10.
55. The method of claim 52, wherein said IC50 value of less than about 1.
56. The method of claim 51 , wherein said Pinl-modulating compound has a cytotoxicity of about 3 μM or less as measured by the CBCA.
57. The method of claim 56, wherein said Pinl-modulating compound has a cytotoxicity of about 1.5 μM or less as measured by the CBCA.
58. The method of claim 57, wherein said Pinl-modulating compound has a cytotoxicity of about 1 μM or less as measured by the CBCA.
59. A method for treating cyclin DI overexpression in a subject comprising administering to said subject an effective amount of a Pinl-modulating compound of formula (I):
Figure imgf000258_0001
) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2θ-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups, may be substituted with one or more substituents selected from the group consisting of H, CH3, F, CH2OH, NH2, OH, CF3, CI, Br, I, -O-, -C1-6, -CH=CHCH2-, =O5 =NH, =N-NH2, -NC(O)CH3, -C(O)- OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, -CH2NH2, -OCH2C(O)NH- NH2, -CH2C(O)CH3, moφholino, C(O)moφholino, -CH2C(O)C(CH3)3, -C(O)- OCH2CH3, and any combination thereof; Ri is selected from the group consisting of-H; -C1-6, -CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 througli 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, C1-4, -CH2CH2-, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -CH2-, -C(O)NH2, -C(O)R3, -N R5)2, and any combination thereof; wherein R3 is selected from the group consisting of-H, -OH, -O-, C1- , moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, - C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -OH, -O-, C1- , moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -C(O)NH2, - CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, - CH2COOH and esters and amides thereof, and any combination thereof; such that said cyclin DI overexpression is treated.
60. The method of claim 59, wherein Z is S.
61. The method of claim 59, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups are selected from the group consisting of a pyridine, a phenyl, a lH-imidazole, a thiazolidine, a pyπolidone, a hexahydro-pyrimidine, a 3- hydroxy-pyπolidin-2-one, a pyπolidine-2,3-dione, a pyπolidine-2,5-dione, apyπolidin- 2-one, a cyclopentyl, a [l,4]dioxepane, a tetrahydrofuran, an isoxazole, a moφholino, a [l,3]dioxolane, apyrimidine, a furan, a thiophene, apyπole, a naphthalene, apyrazole, a 3-(methylene)-l-methyl-l,3-dihydro-indol-2-one, abenzo[l,3]dioxole, a piperazine, and a furazan 2-oxide.
62. The method of claim 59, wherein n is selected from the group consisting of 0 tlirough 5.
63. The method of claim 59, wherein Zi is O.
64. The method of claim 59, wherein the Pinl-modulating compound of formula (I) is a compound of formula (II):
Figure imgf000260_0001
(H) wherein the dashed fine indicates a single or a double bond; nis O or 1; t is H or lower alkyl Xi, X2 and X3 are independently selected from the group consisting of C, CH, NH, O, S, andN; R2, R3, and 5 are independently selected from the group consisting of H, -O-, -Cι-6)F, NH2; CF3, CI, Br, I, =O, =NH, =N-NH2) -NC(O)CH3ι- C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -moφholino, -C(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which maybe directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and R4 can together foπn a multicyclic aromatic, heterocyclic, or carbocyclic stracture with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of — H, -O-, -C1-6, - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, C1-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -C1-6, -C(O)NH2, -C(O)Rb, -N(Rs)2, and any combination thereof; wherein R is selected from the group consisting of-H, -OH, -O-, -Ci_6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each 5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Cι.6;moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH25 -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3 , -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R ' are independently selected from the group consisting of H, -O-, -Ci.6,-S-, -N-, -CH=CHCH3s moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tefrazole, triazole, piperidine, and any combination thereof.
65. The method of claim 64, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000262_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
66. The method of claim 64, wherein Ri is -(X)pC(O)Ra, and Ra is the foπnula Rj:
Figure imgf000262_0002
wherein R8 is selected from H, F or OH.
67. The method of claim 64, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, - ethyl-moφholino, or CH=CHCH2-moφholino.
68. The method of claim 64, wherem ^ is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2- moφholino.
69. The method of claim 64, wherein the Pinl -modulating compound of formula (I) is a compound of formula (IH):
Figure imgf000263_0001
(IH) wherein the dashed line indicates a single or a double bond; n is O or l; P is H or lower alkyl Xi, X2, X , t, and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -C1-6 F, NH2j CF3> CI, Br, I, =O, =NH, =N-NH2) -(CH2)0- 2NC(O)CH3,-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-1C(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH , one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and R5, and/or R3 and e can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combmation thereof; Ri is selected from the group consisting of — H, -O-, -Ci-β, - CH2CHCH2, -NH2, KOpRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Ci-6, -C(O)NH2, -C(O)Rb, -N(Rs)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -0.6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R ' are independently selected from the group consisting of H, -O-, -Ci-6, -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
70. The method of claim 69, wherein Ri is -(X)pC(O)Ra, and Ra is the formula R^
Figure imgf000264_0001
or esters and amides thereof; and wherein Rs is selected from H, F or OH.
71. The method of claim 69, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Rj:
Figure imgf000265_0001
wherein R8 is selected from H, F or OH.
72. The method of claim 69, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH )2-moφholino, - ethyl-moφholino, or CH=CHCH -moφholino.
73. The method of claim 69, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino,-O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2- moφholino.
74. The method of claim 59, wherein the Pinl-modulating compound of formula (I) is a compound of formula (IN):
Figure imgf000265_0002
(IN) wherein the dashed line indicates a single or a double bond; n is O or 1; R4 is H or lower alkyl Xi is selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and R are independently selected from the group consisting of H, -O-, -CW,F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3,-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic stracture with ring containing Xl5 X2, and X , and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Cι-6, - CH2CHCH2, -NH2, -(X)pRa, -(X)PC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Ci.6, -C(O)NH2, -C(O)Rb, -N(R5) , and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -C1-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group - consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -C1-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R7' are independently selected from the group consisting of H, -O-, -C1-6, -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
75. The method of claim 74, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re-.
Figure imgf000267_0001
or esters and amides thereof; and wherein Rs is selected from H, F or OH.
76. The method of claim 74, wherein Ri is -(X)pC(O)Ra, and Ra is the formula a:
Figure imgf000267_0002
wherein R8 is selected from H, F or OH.
77. The method of claim 74, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, - ethyl-moφholino, or CH=CHCH2-moφholino.
78. The method of claim 74, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2- moφholino.
79. The method of claim 59, wherein the Pinl-modulating compound of foπnula (I) is a compound of foπnula (V):
Figure imgf000268_0001
wherein the dashed line indicates a single or a double bond; n is O or 1; t is H or lower alkyl Xi, X2, X3, 4 and X5 are independently selected from the group consisting of C, CH, ΝH, O, S, and Ν; R2, R3, and Rδ are independently selected from the group consisting of H, -O-, -Cι.6) F, ΝH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3,-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xl9 X2, and X3, and any combination thereof; Ri is selected from the group consisting of — H, -O-, -Ci-6, - CH2CHCH2, -NH2, KOpRa, -(X)pC(O)Ra, wherem p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -C1-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -0.6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -C1-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, - COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -C1-6> moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2> -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof.
80. The method of claim 79, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000269_0001
or esters and amides thereof; and wherein R§ is selected from H, F or OH.
81. The method of claim 79, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000270_0001
wherein Rs is selected from H, F or OH.
82. The method of claim 79, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, - ethyl-moφholino, or CH=CHCH2-moφholino.
83. The method of claim 79, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2- moφholino.
84. The method of claim 59, wherein the cyclin DI overexpression results in neoplastic transformation.
85. The method of claim 59, wherein the cyclin DI overexpression results in tumor growth.
86. The method of claim 59, wherein said method for freating cyclin D 1 overexpression comprises inhibiting tumor growth.
87. The method of claim 59, wherein said method for treating cyclin D 1 overexpression comprises preventing the occurrence of tumor growth in the subject.
88. The method of claim 59, wherein said method for freating cyclin DI overexpression comprises reducing the growth of a pre-existing tumor in the subject.
89. The method of claim 59, wherein the cyclin D 1 overexpression results in colon cancer or breast cancer.
90. The method of claim 59, wherein the cyclin D 1 overexpression results in a sarcoma or a malignant lymphoma.
91. The method of claim 59, wherein the cyclin D 1 overexpression results in esophageal cancer, ohgodendroglioma, asfrocytoma, glioblastomamultiforme, cervical carcinoma, ovary endomefroid cancer, ovary Brenner tumor, ovary mucinous cancer, ovary serous cancer, uterus carcinosarcoma, breast lobular cancer, breast ductal cancer, breast medullary cancer, breast mucinous cancer, breast tubular cancer, thyroid adenocarcinoma, or thyroid follicular cancer.
92. The method of claim 59, wherein the cyclin 1 overexpression results in thyroid medullary cancer, thyroid papillary carcinoma, parathyroid adenocarcinoma, adrenal gland adenoma, adrenal gland cancer, pheochromocytoma, colon adenoma mild displasia, colon adenoma moderate displasia, colon adenoma severe displasia, or colon adenocarcinoma.
93. The method of claim 59, wherein the cyclin DI overexpression results in esophagus adenocarcinoma, hepatocelluar carcinoma, mouth cancer, gall bladder adenocarcinoma, pancreatic adenocarcinoma, prostate, prostate cancer, testis non- seminomatous cancer, testis seminoma, urinary bladder transitional carcinoma, lung adenocarcinoma, lung large cell cancer, lung small cell cancer, lung squamous cell carcinoma, MALT lymphoma, NHL diffuse large B, non-Hodgkin's lymphoma (NHL), thymoma, skin malignant melanoma, skin basolioma, skin squamous cell cancer, skin merkel zell cancer, skin benign nevus, lipoma, endometriod carcinoma, endometrium serous carcenoma, small intestine adenocarcinoma, stomach diffuse adenocarcinoma, kidney chromophobic carcinoma, kidney clear cell carcinoma, kidney oncocytoma, kidney papillary carcinoma, Hodgkin lymphoma, or a liposarcoma.
94. The method of claim 59, wherein the cyclin DI overexpression is caused by misexpression of Pinl.
95. The method of claim 59, wherein the cyclin DI overexpression is caused by DNA damage.
96. The method of claim 59, wherein the cyclin DI overexpression is caused by an oncogenic protein.
97. The method of claim 59, wherein cyclin DI overexpression is caused by Ha-Ras.
98. The method of claim 59, wherein said Pinl modulating compound is a Pinl inhibiting compound.
99. The method of claim 59, wherein said compound is selected from the group consisting of compounds listed in Table 1, and derivatives thereof.
100. The method of claim 59, wherein said compound is selected from the group consisting of compounds listed in Table 2, and derivatives thereof.
101. The method of claim 59, wherein said compound is selected from the group consisting of compounds listed in Table 3, and derivatives thereof.
102. The method of claim 59, wherein said compound is selected from the group consisting of compounds listed in Table 4, and derivatives thereof.
103. The method of claim 59, wherein said compound is selected from the group consisting of compounds listed in Table 5, and derivatives thereof.
104. The method of claim 59, wherein said compound is selected from the group consisting of compounds listed in Table 6, and derivatives thereof.
105. The method of claim 59, wherein said compound is selected from the group consisting of compounds listed in Table 7, and derivatives thereof.
106. The method of claim 59, wherein said compound is selected from the group consisting of compounds listed in Table 8, and derivatives thereof.
107. The method of claim 59, wherein said Pinl-modulating compound has a characteristic inhibition profile (CTP) and has a cytotoxicity effective to treat said Pinl- associated state.
108. The method of claim 107, wherein said Pinl-modulating compound has an IC50 value of less than about 40.
109. The method of claim 108, wherein said IC50 value of between about 10 and about 40.
110. The method of claim 108, wherein said ICso value of between about 1 and about 10.
111. The method of claim 108, wherein said IC50 value of less than about 1.
112. The method of claim 107, wherein said Pinl-modulating compound has a cytotoxicity of about 3 μM or less as measured by the CBCA.
113. The method of claim 112, wherein said Pinl-modulating compound has a cytotoxicity of about 1.5 μM or less as measured by the CBCA. -
114. The method of claim 113, wherein said Pinl-modulating compound has a cytotoxicity of about 1 μM or less as measured by the CBCA.
115. A packaged Pinl -associated state treatment, comprising a Pinl - modulating compound of formula (I):
Figure imgf000273_0001
(I) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2θ-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups may be substituted with one or more substituents selected from the group consisting of H, CH3, F, CH2OH, NH2, OH, CF3, CI, Br, I, -O-, -C1-6) -CH=CHCH2-, =O, =NH, =N-NH2, -NC(O)CH3, -C(O)- OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, -CH2NH2, -OCH2C(O)NH- NH2, -CH2C(O)CH3, moφholino, C(O)moφholino, -CH2C(O)C(CH3)3, -C(O)- OCH2CH3, and any combination thereof; Ri is selected from the group consisting of-H; -Ci-6, -CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, C1-4, -CH2CH2-, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -CH2-, -C(O)NH2, -C(O)R3, -N(T 5)2, and any combination thereof; wherein R3 is selected from the group consisting of-H, -OH, -O-, C1-4, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, - C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -OH, -O-, C1-4, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -C(O)NH2, - CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, - CH2COOH and esters and amides thereof, and any combination thereof; packaged with instractions for using an effective amount ofthe Pinl-modulating compound to treat a Pinl -associated state.
116. The packaged Pinl -associated state treatment of claim 115, wherein Z is
117. The packaged Pinl -associated state freatment of claim 115, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups are selected from the group consisting of a pyridine, a phenyl, a IH-imidazole, a thiazolidine, a pyπolidone, a hexahydro-pyrimidine, a 3-hydroxy-pyrrolidin-2-one, apyπolidine-2,3-dione, a pyπolidine-2,5-dione, a pyπolidin-2-one, a cyclopentyl, a [l,4]dioxepane, a tetrahydrofuran, an isoxazole, a moφholino, a [l,3]dioxolane, apyrimidine, a furan, a thiophene, a yπole, a naphthalene, apyrazole, a 3-(methylene)-l-methyl-l,3-dihydro- indol-2-one, a benzo[l,3]dioxole, a piperazine, and a furazan 2-oxide.
118. The packaged Pinl -associated state freatment of claim 115, wherein n is selected from the group consisting of 0 through 5.
119. The packaged Pinl -associated state freatment of claim 115, wherein Zi is O.
120. The packaged Pinl -associated state treatment of claim 115, wherein the Pinl-modulating compound of formula (I) is a compound of foπnula (H):
Figure imgf000275_0001
(H) wherein the dashed line indicates a single or a double bond; n is O or 1; 4 is H or lower alkyl Xi, X2 and X3 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R , and Re are independently selected from the group consisting of H, -O-, -C1-6 F, NH2, CF3) CI, Br, I, =O, =NH, =N-NH2, -NC(O)CH3, - C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -moφholino, -C(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R , R2 and Re, and/or R3 and Rό can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xl5 X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -C1-6; - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, - -e, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of — H, -OH, -O-, -Ci-6, moφhohno, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-β, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2j -CH2CH2OH, -CH2CH(OH)CH3; -C(O)N(CH3>, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R ' are independently selected from the group consisting of H, -O-, -Cι-6,-S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
121. The packaged Pinl -associated state freatment of claim 120, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000277_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
122. The packaged Pinl -associated state freatment of claim 120, wherein Ri is -(X)pC(O)Ra, and Ra is the foπnula R :
Figure imgf000277_0002
wherein Rs is selected from H, F or OH.
123. The packaged Pinl -associated state treatment of claim 120, wherein Ri is -(X)pC(O)Ra5, Ra is N(Rs)2, and R5 is selected from the group consisting of -N-(CH2)2- moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
124. The packaged Pinl -associated state treatment of claim 120, wherein R is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, - ethyl-moφholino, or CH=CHCH2-moφholino.
125. The packaged Pinl -associated state freatment Pinl -associated state treatment of claim 115, wherein the Pinl-modulating compound of formula (I) is a compound of formula (HI):
Figure imgf000278_0001
(HI) wherein the dashed line indicates a single or a double bond; n is O or l; R4 is H or lower alkyl Xi, X2, X3, X , and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -C1-6,F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3,-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCtl2CH , one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci_6, - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Ci-e, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2~, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, > moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Cι.6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rt, is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH )3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2) -CH2CH2OH, -CH2CH(OH)CH3; -C(O)N(CH3 , -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R7' are independently selected from the group consisting of H, -O-, -Ci-6, -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
126. The packaged Pinl -associated state freatment of claim 125, wherein Ri is
-(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000279_0001
or esters and amides thereof; and wherein Rg is selected from H, F or OH.
127. The packaged Pinl -associated state freatment of claim 125, wherein Ri is
-(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000280_0001
wherein R8 is selected from H, F or OH.
128. The packaged Pinl -associated state treatment of claim 125, wherein Ri is -YX)pC(O)Ra, Ra is N(R5)2, and R5 is selected from the group consisting of -N-(CH2)2- moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
129. The packaged Pinl -associated state treatment of claim 125, wherein R is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, - ethyl-moφholino, or CH=CHCH2-moφholino.
130. The packaged Pinl -associated state treatment Pinl -associated state freatment of claim 115, wherein the Pinl-modulating compound of formula (I) is a compound of foπnula (IV):
Figure imgf000280_0002
(IV) wherein the dashed line indicates a single or a double bond; n is O or 1; i is H or lower alkyl Xi is selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -C1-6;F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0. 2NC(O)CH3;-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH -; and wherein R2 and R3, 2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic stracture with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-6, - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of — H, -O-, -0.6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Ci-6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-5 -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R7' are independently selected from the group consisting of H, -O-, -0.6, -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
131. The packaged Pinl -associated state freatment of claim 130, wherein Ri is
-(X)PC(O)RB, and Ra is the formula Re:
Figure imgf000282_0001
or esters and amides thereof; and wherein Rg is selected from H, F or OH.
132. The packaged Pinl -associated state freatment of claim 130, wherein Ri is
-(X)pC(O)Ra, and Ra is the foπnula Rd".
Figure imgf000282_0002
wherein R§ is selected from H, F or OH.
133. The packaged Pinl -associated state freatment of claim 130, wherein Ri is -(X)pC(O)Ra, Ra is N(Rs)2, and R5 is selected from the group consisting of -N-(CH2)2- moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
134. The packaged Pinl -associated state freatment of claim 130, wherein R is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, - ethyl-moφholino, or CH=CHCH2-moφholino.
135. The packaged Pinl -associated state freatment of claim 115, wherein the
Pinl-modulating compound of formula (I) is a compound of formula (V):
Figure imgf000283_0001
wherein the dashed line indicates a single or a double bond; n is O or 1; R is H or lower alkyl Xi, X2, X3, Xi and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and R are independently selected from the group consisting of H, -O-, -Cι-6> F, NH2, CF3; CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3, -C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)o-iC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, 2 and Re, and/or R and Kg can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xls X2, and X3, and any combination -thereof; R\ is selected from the group consisting of-H, -O-, -Ci-6, - CH2CHCH2, -NH2, KOpRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -0-6 -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein R is selected from the group consisting of-H, -OH, -O-, -Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, - COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -C1-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2; -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof.
136. The packaged Pinl -associated state freatment of claim 135, wherein Ri is
-(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000284_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
137. The packaged Pinl -associated state treatment of claim 135, wherein Ri is
-(X)pC(O)Ra, and Ra is the formula Rj:
Figure imgf000285_0001
wherein R8 is selected from H, F or OH.
138. The packaged Pinl -associated state treatment of claim 135, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5 is selected from the group consisting of - -(CH2)2- moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
139. The packaged Pinl -associated state treatment of claim 135, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, - ethyl-moφholino, or CH=CHCH2-moφholino.
\
140. The packaged Pinl -associated state freatment of claim 115, wherein said
Pinl modulating compound is a Pinl inhibiting compound.
141. The packaged Pinl -associated state freatment of claim 115, wherein said compound is selected from the group consisting of compounds listed in Table 1, and derivatives thereof.
142. The packaged Pinl-associated state treatment of claim 115, wherein said compound is selected from the group consisting of cpmpounds listed in Table 2, and derivatives thereof.
143. The packaged Pinl -associated state treatment of claim 115, wherein said compound is selected from the group consisting of compounds listed in Table 3, and derivatives thereof.
144. The packaged Pinl-associated state treatment of claim 115, wherein said compound is selected from the group consisting of compounds listed in Table 4, and derivatives thereof.
145. The packaged Pinl -associated state freatment of claim 115, wherein said compound is selected from the group consisting of compounds listed in Table 5, and derivatives thereof.
146. The packaged Pinl -associated state freatment of claim 115, wherein said compound is selected from the group consisting of compounds listed in Table 6, and derivatives thereof.
147. The packaged Pinl-associated state freatment of claim 115, wherein said compound is selected from the group consisting of compounds listed in Table 7, and derivatives thereof.
148. The packaged Pinl -associated state treatment of claim 115, wherein said compound is selected from the group consisting of compounds listed in Table 8, and derivatives thereof.
149. A packaged cyclin DI overexpression treatment, comprising a Pinl- modulating compound of formula (I):
Figure imgf000286_0001
(I) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2O-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups may be substituted with one or more substituents selected from the group consisting of H, CH3, F, CH2OH, NH2, OH, CF3, CI, Br, I, -O-, -C,.6,-CH=CHCH2-, =O, =NH, =N-NH2, -NC(O)CH3, -C(O)- OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, -CH2NH2, -OCH2C(O)NH- NH2, -CH2C(O)CH3, moφholino, C(O)moφholino, -CH2C(O)C(CH3)3, -C(O)- OCH2CH3, and any combination thereof; Ri is selected from the group consisting of-H; -Ci-6, -CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, C1-4, -CH2CH2-, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -CH2-, -C(O)NH2, -C(O)R3, -N(R5)2, and any combination thereof; wherein R3 is selected from the group consisting of-H, -OH, -O-, C1-4, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, - C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -OH, -O-, Cι-4, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -C(O)NH2, - CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, - CH2COOH and esters and amides thereof, and any combination thereof; packaged with instractions for using an effective amount ofthe Pinl-modulating compound to treat cyclin DI overexpression.
150. The packaged cyclin D 1 overexpression freatment Pinl -associated state treatment of claim 149, wherein Z is S.
151. The packaged cyclin D 1 overexpression freatment Pinl -associated state treatment of claim 149, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups are selected from the group consisting of a pyridine, a phenyl, a IH- imidazole, a thiazolidine, a pyπolidone, a hexahydro-pyrimidine, a 3-hydroxy- pyπolidin-2-one, a pyrrolidine-2,3-dione, a pynolidine-2,5-dione, a pynolidin-2-one, a cyclopentyl, a [l,4]dioxepane, a tefrahydrofuran, an isoxazole, a moφholino, a [l,3]dioxolane, apyrimidine, a furan, a thiophene, a pynole, a naphthalene, apyrazole, a 3-(methylene)-l -methyl- l,3-dihydro-indol-2-one, abenzo[l,3]dioxole, a piperazine, and a furazan 2-oxide.
152. The packaged cyclin D 1 overexpression treatment Pinl -associated state freatment of claim 149, wherein n is selected from the group consisting of 0 through 5.
153. The packaged cyclin D 1 overexpression freatment Pinl -associated state treatment of claim 149, wherein Zi is O.
154. The packaged cyclin D 1 overexpression treatment Pinl -associated state freatment of claim 149, wherein the Pinl-modulating compound of formula (I) is a compound of formula (H):
Figure imgf000288_0001
(H) wherein the dashed line indicates a single or a double bond; n is O or 1; R4 is H or lower alkyl Xi, X2 and X3 are independently selected from the group consisting of C, CH, NH, O, S, andN; R2, R3, and Re are independently selected from the group consisting of H, -O-, -Cι-6,F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -NC(O)CH3,- C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -moφholino, -C(O)moφholino, - CH2C(O)C(CH )3, -C(O)-OCH2CH , one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-6, - CH2CHCH2) -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, Ci-e, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Ci-6,-C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein R is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci _e, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R ' are independently selected from the group consisting of H, -O-, -Ci-6,-S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
155. The packaged cyclin DI overexpression freatment of claim 154, wherein
Ri is -(X)pC(O)Ra, and Ra is the formula R,:
Figure imgf000290_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
156. The packaged cyclin DI overexpression treatment of claim 154, wherein
Ri is -(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000290_0002
wherein Rg is selected from H, F or OH.
157. The packaged cyclin D 1 overexpression freatment of claim 154, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5 is selected from the group consisting of -N- (CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2- moφholino.
158. The packaged cyclin DI overexpression treatment of claim 154, wherein R is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2- moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
159. The packaged cyclin DI overexpression freatment Pinl-associated state freatment of claim 149, wherein the Pinl-modulating compound of foπnula (I) is a compound of formula (IH):
Figure imgf000291_0001
(πi) wherein the dashed line indicates a single or a double bond; n is O or 1; 4 is H or lower alkyl Xi, X2, X3, i, and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and are independently selected from the group consisting of H, -O-, -Ci-e.F, NH2, CF3j CI, Br, I, =O, =NH, =N-NH2, -(CH2)0. 2NC(O)CH3, -C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which maybe directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-β, - CH2CHCH2) -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Cι-6,-C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of — H, -OH, -O-, -Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-β, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R7' are independently selected from the group consisting of H, -O-, -Ci-6, -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
160. The packaged cyclin DI overexpression freatment of claim 159, wherein
Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000292_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
161. The packaged cyclin D 1 overexpression freatment of claim 159, wherein
Ri is -(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000293_0001
wherein R8 is selected from H, F or OH.
162. The packaged cyclin DI overexpression freatment of claim 94, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5is selected from the group consisting of -N- (CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH^CHCH moφholino.
163. The packaged cyclin DI overexpression treatment of claim 159, wherein R7is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2- moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
164. The packaged cyclin DI overexpression treatment Pinl-associated state freatment of claim 149, wherein the Pinl-modulating compound of formula (I) is a compound of
Figure imgf000293_0002
(IN) wherein the dashed line indicates a single or a double bond; n is O or 1; Ri is H or lower alkyl Xi is selected from the group consisting of C, CH, ΝH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -Cι-6,F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3, -C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0.ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Rό, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of — H, -O-, -Ci-6, - CH2CHCH2, -NH2, -(X)PRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -QH CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -C1-6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R ' are independently selected from the group consisting of H, -O-, -Cι-6,-S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
165. The packaged cyclin D 1 overexpression treatment of claim 164, wherein
Ri is -(X)pC(O)Ra, and Ra is the foπnula Re".
Figure imgf000295_0001
or esters and amides thereof; and wherein Rs is selected from H, F or OH.
166. The packaged cyclin DI overexpression treatment of claim 164, wherein
Ri is -(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000295_0002
wherein Rs is selected from H, F or OH.
167. The packaged cyclin D 1 overexpression treatment of claim 164, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5 is selected from the group consisting of -N- (CH2) -moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2- moφholino.
168. The packaged cyclin DI overexpression freatment of claim 164, wherein R is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2- moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
169. The packaged cyclin DI overexpression freatment Pinl-associated state freatment of claim 149, wherein the Pinl-modulating compound of formula (I) is a compound of
Figure imgf000296_0001
wherein the dashed line indicates a single or a double bond; n is O or 1; Rt is H or lower alkyl Xi, X2, X3, i and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -Cι-6, F, NH2, CF3> CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3, -C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)o.2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-6, - CH2CHCH2) -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Ci-β, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, - COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof.
170. The packaged cyclin D 1 overexpression freatment of claim 169, wherein
Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000297_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
171. The packaged cyclin D 1 overexpression treatment of claim 169, wherein
Ri is -(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000297_0002
wherein R8 is selected from H, F or OH.
172. The packaged cyclin D 1 overexpression freatment of claim 169, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5 is selected from the group consisting of -N- (CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2- moφholino.
173. The method of claim 169, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
174. The packaged cyclin D 1 overexpression treatment Pinl-associated state freatment of claim 149, wherein said Pinl modulating compound is a Pinl inhibiting compound.
175. The packaged cyclin D 1 overexpression treatment Pinl -associated state treatment of claim 149, wherein said compound is selected from the group consisting of compounds listed in Table 1, and derivatives thereof.
176. The packaged cyclin DI overexpression treatment Pinl-associated state freatment of claim 149, wherein said compound is selected from the group consisting of compounds listed in Table 2, and derivatives thereof.
177. The packaged cyclin DI overexpression freatment Pinl-associated state treatment of claim 149, wherein said compound is selected from the group consisting of compounds listed in Table 3, and derivatives thereof.
178. The packaged cyclin DI overexpression treatment Pinl-associated state freatment of claim 149, wherein said compound is selected from the group consisting of compounds listed in Table 4, and derivatives thereof.
179. The packaged cyclin DI overexpression treatment Pinl-associated state freatment of claim 149, wherein said compound is selected from the group consisting of compounds listed in Table 5, and derivatives thereof.
180. The packaged cyclin D 1 overexpression freatment Pinl -associated state treatment of claim 149, wherein said compound is selected from the group consisting of compounds listed in Table 6, and derivatives thereof.
181. The packaged cyclin D 1 overexpression freatment Pinl -associated state freatment of claim 149, wherein said compound is selected from the group consisting of compounds listed in Table 7, and derivatives thereof.
182. The packaged cyclin D 1 overexpression freatment Pinl -associated state treatment of claim 149, wherein said compound is selected from the group consisting of compounds listed in Table 8, and derivatives thereof.
1 3. A packaged cancer treatment, comprising a Pinl -modulating compound of formula (I):
Figure imgf000299_0001
(I) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2θ-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups may be substituted with one or more substituents selected from the group consisting of H, CH3, F, CH2OH, NH2, OH, CF3, CI, Br, I, -O-, -C1-6, -CH=CHCH2-, =O, =NH, =N-NH2, -NC(O)CH3, -C(O)- OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, -CH2NH2, -OCH2C(O)NH- NH2, -CH2C(O)CH3, moφholino, C(O)moφholino, -CH2C(O)C(CH3)3, -C(O)- OCH2CH3, and any combination thereof; Ri is selected from the group consisting of-H; -Cι_6, -CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, Cι-4, -CH2CH2-, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -CH2-, -C(O)NH2, -C(O)R3, -N(R5)2, and any combination thereof; wherein R3 is selected from the group consisting of-H, -OH, -O-, Cι-4, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, - C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -OH, -O-, Cw, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -C(O)NH2, - CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, - CH2COOH and esters and amides thereof, and any combination thereof; packaged with instructions for using an effective amount ofthe Pinl-modulating compound to freat cancer.
184. The packaged cancer freatment of claim 183, wherein Z is S.
185. The packaged cancer freatment of claim 183, wherein the the aromatic groups, heterocyclic groups, and carbocyclic groups are selected from the group consisting of a pyridine, a phenyl, a IH-imidazole, a thiazolidine, a pyrrolidone, a hexahydro-pyrimidine, a 3-hydroxy-pyπolidin-2-one, apyπolidine-2,3-dione, a pyrrolidine-2,5-dione, a pyπolidin-2-one, a cyclopentyl, a [l,4]dioxeρane, a tefrahydrofuran, an isoxazole, a moφholino, a [l,3]dioxolane, apyrimidine, a furan, a thiophene, apyπole, a naphthalene, a pyrazole, a 3 -(methylene)- 1 -methyl- 1,3-dihydro- indol-2-one, a benzo[l,3]dioxole, a piperazine, and a furazan 2-oxide.
186. The packaged cancer treatment of claim 183, wherein n is selected from the group consisting of 0 through 5.
187. The packaged cancer freatment of claim 183, wherein Zi is O.
188. The packaged cancer treatment of claim 183, wherein the Pinl- modulating
Figure imgf000301_0001
(H) wherein the dashed line indicates a single or a double bond; n is O or 1; Ri is H or lower alkyl Xi, X2 and X3 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -Cι-6, F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2> -NC(O)CH3) - C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -moφholino, -C(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic stracture with ring containing Xi, X2, and X , and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Cι_6, - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group, consisting of-H, -O-, Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -Ci-6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein R is selected from the group consisting of-H, -OH, -O-, -Cι_6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Cι_6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R ' are independently selected from the group consisting of H, -O-, -Ci-e.-S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
189. The packaged cancer treatment of claim 188, wherein Ri is -(X)pC(O)Ra, and Ra is the formula R^
Figure imgf000303_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
190. The packaged cancer treatment of claim 188, wherein Ri is -(X)pC(O)Ra and Ra is the formula Ra:
Figure imgf000303_0002
wherein Rs is selected from H, F or OH.
191. The packaged cancer treatment of claim 188, wherein Ri is -YX)pC(O)Ra
Ra is N(R5)2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O- (CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
192. The packaged cancer treatment of claim 188, wherein R is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl- moφholino, or CH=CHCH2-moφholino.
193. The packaged cancer treatment of claim 183, wherein the Pinl - modulating compound of foπnula (I) is a compound of formula (IH):
Figure imgf000304_0001
(III) wherein the dashed line indicates a single or a double bond; n is O or 1; i is H or lower alkyl Xi, X2, X3, , and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R , and Re are independently selected from the group consisting of H, -O-, -Cι-6,F, NH2, CF3) CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3;-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)o-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, wliich may be directly linked, joined to form a multi-cyclic structure, or indirectly hnked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R and Kg can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X , and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-e,- CH2CHCH2> -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Cι-6,,-C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Cι-6,moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2> -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R ' are independently selected from the group consisting of H, -O-, -Ci-6, -S-, -N-, -CH=CHCH , moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
194. The packaged cancer freatment of claim 193 , wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re-.
Figure imgf000305_0001
or esters and amides thereof; and wherein Rs is selected from H, F or OH.
195. The packaged cancer freatment of claim 193, wherein Ri is -(X)pC(O)Ra and Ra is the formula Ra:
Figure imgf000306_0001
wherein R8 is selected from H, F or OH.
196. The packaged cancer freatment of claim 193, wherein Ri is -(X)pC(O)Ra, Ra is N(R )2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O- (CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
197. The packaged cancer treatment of claim 193, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl- moφholino, or CH=CHCH2-moφholino.
198. The packaged cancer treatment of claim 183, wherein the Pinl- modulating
Figure imgf000306_0002
(TV) wherein the dashed line indicates a single or a double bond; n is O or 1; Ri is H or lower alkyl Xi is selected from the group consisting of C, CH, ΝH, O, S, and Ν; R2, R3, and R are independently selected from the group consisting of H, -O-, -0-6, F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3, -C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and or R3 and R can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of — H, -O-, -Ci-6, - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Cι_6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-e, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R7' are independently selected from the group consisting of H, -O-, -Ci_6,-S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tefrazole, triazole, piperidine, and any combination thereof.
199. The packaged cancer treatment of claim 198, wherein Ri is -(X)pC(O)Ra and Ra is the formula R^
Figure imgf000308_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
200. The packaged cancer treatment of claim 198, wherein Ri is -(X)pC(O)Ra and Ra is the formula R :
Figure imgf000308_0002
wherein R8 is selected from H, F or OH.
201. The packaged cancer freatment of claim 198, wherein Ri is -(X)pC(O)Ra, Ra is N(Rs)2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O- (CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
202. The packaged cancer freatment of claim 198, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH )2-moφholino, -ethyl- moφholino, or CH=CHCH2-moφhohno.
203. The packaged cancer freatment of claim 183, wherein the Pinl - modulating compound of formula (I) is a compound of formula (V):
Figure imgf000309_0001
wherein the dashed line indicates a single or a double bond; n is O or 1; R4 is H or lower alkyl Xls X2, X3, Xi and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -C1-6> F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3,-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)o-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing i, X2, and X3, and any combmation thereof; Ri is selected from the group consisting of-H, -O-, -Ci-β, - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -C1-6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, - COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2) C(O)NH2> -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof.
204. The packaged cancer freatment of claim 203 , wherein Ri is -(X)pC(O)Ra, and Ra is the formula R^
Figure imgf000310_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
205. The packaged cancer freatment of claim 203, wherein Ri is -(X)pC(O)Ra and Ra is the formula Ra:
Figure imgf000310_0002
wherein s is selected from H, F or OH.
206. The packaged cancer treatment of claim 203, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5is selected from the group consisting of -N-(CH2)2-moφholino, -O- (CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
207. The packaged cancer freatment of claim 203, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl- moφholino, or CH=CHCH2-moφholino.
208. The packaged cancer treatment of claim 183, wherein said Pinl modulating compound is a Pinl inhibiting compound.
209. The packaged cancer treatment of claim 183, wherein said compound is selected from the group consisting of compounds listed in Table 1, and derivatives thereof.
210. The packaged cancer treatment of claim 183, wherein said compound is selected from the group consisting of compounds listed in Table 2, and derivatives thereof.
211. The packaged cancer freatment of claim 183, wherein said compound is selected from the group consisting of compounds listed in Table 3, and derivatives thereof.
212. The packaged cancer freatment of claim 183, wherein said compound is selected from the group consisting of compounds listed in Table 4, and derivatives thereof.
213. The packaged cancer treatment of claim 183, wherein said compound is selected from the group consisting of compounds listed in Table 5, and derivatives thereof.
214. The packaged cancer freatment of claim 183, wherein said compound is selected from the group consisting of compounds listed in Table 6, and derivatives thereof.
215. The packaged cancer treatment of claim 183, wherein said compound is selected from the group consisting of compounds listed in Table 7, and derivatives thereof.
216. The packaged cancer treatment of claim 183, wherein said compound is selected from the group consisting of compounds listed in Table 8, and derivatives thereof.
217. A method for treating a Pinl-associated state in a subject comprising administering to a subject an effective amount of a combination of a Pinl-modulating compound of formula (I):
Figure imgf000312_0001
(I) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2O-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups may be substituted with one or more substituents selected from the group consisting of H, CH3, F, CH2OH, NH2, OH, CF3, CI, Br, I, -O-, -Ci-e, -CH=CHCH2-, =O, =NH, =N-NH2, -NC(O)CH3, -C(O OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH , -C(O)-NHCH3, -CH2NH2, -OCH2C(O)NH- NH2, -CH2C(O)CH3, moφholino, C(O)moφholino, -CH2C(O)C(CH3)3, -C(O)- OCH2CH3, and any combination thereof; Ri is selected from the group consisting of-H; -Cι-6, -CH2CHCH2, -NH2, -fX)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, CM , -CH2CH2-, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -CH2-, -C(O)NH2, -C(O)R3, -N(R5)2, and any combination thereof; wherein R3 is selected from the group consisting of-H, -OH, -O-, Cι-4 , moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, - C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; , wherein each R5 is independently selected from the group consisting of-H, -F, -OH, -O-, C1-4 , moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -C(O)NH2, - CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, - CH2COOH and esters and amides thereof, and any combination thereof; and a hypeφlastic inhibitory agent such that the Pinl-associated state is treated.
218. The method of claim 217, wherein Z is S.
219. The method of claim 217, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups are selected from the group consisting of a pyridine, a phenyl, a IH-imidazole, a thiazolidine, a pyπolidone, a hexahydro-.pyrimidine, a 3- hydroxy-pyπolidin-2-one, apyrrolidine-2,3-dione, a pyπolidine-2,5-dione, apyrrolidin- 2-one, a cyclopentyl, a [l,4]dioxepane, a tefrahydrofuran, an isoxazole, a moφholino, a [l,3]dioxolane, a pyrimidine, a furan, a thiophene, a pyrrole, a naphthalene, a pyrazole, a 3-(methylene)-l-methyl-l,3-dihydro-indol-2-one, abenzo[l,3]dioxole, a piperazine, and a furazan 2-oxide.
220. The method of claim 217, wherein n is selected from the group consisting ofO through 5.
221. The method of claim 217, wherein Zi is O.
222. The method of claim 217, wherein the Pinl-modulating compound of foπnula (I) is a compound of foπnula (II):
Figure imgf000314_0001
CD) wherein the dashed line indicates a single or a double bond; n is O or 1; R-i is H or lower alkyl Xi, X and X3 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consistmg of H, -O-, -Cι.6,F, NH2, CF3> CI, Br, I, =O, =NH, =N-NH2, -NC(O)CH3; - C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -moφholino, -C(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocychc groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein 2 and R3, R2 and Re, and or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Cι_6, - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Cι_6, -C(O)NH2, -C(O)Rb, -N(Rs)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-e, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2) -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R7' are independently selected from the group consisting of H, -O-, -Cι-6,-S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
223. The method of claim 222, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000316_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
224. The method of claim 222, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000316_0002
wherein Rs is selected from H, F or OH.
225. The method of claim 222, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2- moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
226. The method of claim 222, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
227. The method of claim 217, wherein the Pinl-modulating compound of foπnula (I) is a compound of formula (HI):
Figure imgf000317_0001
(HI) wherein the dashed line indicates a single or a double bond; n is O or l; R4 is H or lower alkyl Xi, X2, X3, i, and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -d-6,F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3>-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cychc stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic stracture with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-6, - CH2CHCH2, -NH2, — (X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is," independently, optionally substituted with one or more substiments selected from the group consisting of-H, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Cι.6,-C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Cι_6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of -H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R7' are independently selected from the group consisting of H, -O-, -Cι-6,-S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tefrazole, triazole, piperidine, and any combination thereof.
228. The method of claim 227, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000318_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
229. The method of claim 227, wherein Ri is -(X)pC(O)Ra, and Ra is the foπnula Ra:
Figure imgf000319_0001
wherein R8 is selected from H, F or OH.
230. The method of claim 227, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5is selected from the group consisting of-N-(CH2)2-moφholino, -O-(CH2)2- moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
231. The method of claim 227, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
232. The method of claim 217, wherein the Pinl-modulating compound of formula (I) is a compound of formula (IV):
Figure imgf000319_0002
(IV) wherein the dashed line indicates a single or a double bond; n is O or 1; Ri is H or lower alkyl Xi is selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -Ci.6,F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0. 2NC(O)CH3,-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Rδ can together form a multicyclic aromatic, heterocyclic, or carbocyclic stracture with ring containing Xi, X2, and X , and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Cι-6;- CH2CHCH2, -NH2, -(X)PRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCTΪ2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -Ci-6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-e, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2; -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R ' are independently selected from the group consisting of H, -O-, -Ci-e, -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
233. The method of claim 232, wherein Ri is -(X)pC(O)Ra, and Ra is the foπnula Re:
Figure imgf000321_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
234. The method of claim 232, wherein Ri is -CX)pC(O)Ra, and Ra is the formula Ra-.
Figure imgf000321_0002
wherein R8 is selected from H, F or OH.
235. The method of claim 232, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2- moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
236. The method of claim 232, wherein R is selected from the group consisting of -N-(CH2) -moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholinό.
237. The method of claim 227, wherein the Pinl-modulating compound of foπnula (I) is a compound of foπnula (V):
Figure imgf000322_0001
wherein the dashed line indicates a single or a double bond; n is O or 1; Ri is H or lower alkyl Xi, X2, X3, i and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Rβ are independently selected from the group consisting of H, -O-, -Cι-6, F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3, -C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)o-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, 2 and Re, and or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-6, - CH CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substituents selected from the group consisting of-H, -O-, -Ci-β, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -Cι-6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein R is selected from the group consisting of-H, -OH, -O-, -Ci-e, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH CH(OH)CH3, -C(O)N(CH3)-, - COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof.
238. The method of claim 237, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000323_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
239. The method of claim 237, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000323_0002
wherein Rg is selected from H, F or OH.
240. The method of claim 237, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2- moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
241. The method of claim 237, wherein R is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
242. The method of claim 217, wherein said Pinl modulating compound is a Pinl inhibiting compound.
243. The method of claim 217, wherein said compound is selected from the group consisting of compounds listed in Table 1, and derivatives thereof.
244. The method of claim 217, wherein said compound is selected from the group consisting of compounds listed in Table 2, and derivatives thereof.
245. The method of claim 217, wherein said compound is selected from the group consisting of compounds listed in Table 3, and derivatives thereof.
246. The method of claim 217, wherein said compound is selected from the group consisting of compounds listed in Table 4, and derivatives thereof.
247. The method of claim 217, wherein said compound is selected from the group consisting of compounds listed in Table 5, and derivatives thereof.
248. The method of claim 217, wherein said compound is selected from the group consisting of compounds listed in Table 6, and derivatives thereof.
249. The method of claim 217, wherein said compound is selected from the group consisting of compounds listed in Table 7, and derivatives thereof.
250. The method of claim 217, wherein said compound is selected from the group consisting of compounds listed in Table 8, and derivatives thereof.
251. The method of claim 217, wherein said Pinl -modulating compound has a characteristic inhibition profile (CIP) and has a cytotoxicity effective to freat said Pinl- associated state.
252. The method of claim 251 , wherein said Pinl-modulating compound has an IC50 value of less than about 40. 1
253. The method of claim 252, wherein said IC50 value of between about 10 and about 40.
254. The method of claim 252, wherein said IC50 value of between about 1 and about 10.
255. The method of claim 252, wherein said IC50 value of less than about 1.
256. The method of claim 251, wherein said Pinl-modulating compound has a cytotoxicity of 3 μM or less as measured by the CBCA.
257. The method of claim 256, wherein said Pinl-modulating compound has a cytotoxicity of 1.5 μM or less as measured by the CBCA.
258. The method of claim 257, wherein said Pinl-modulating compound has a cytotoxicity of 1 μM or less as measured by the CBCA.
259. The method of claim 217, wherein the hypeφlastic mnibitory agent is tamoxifen.
260. The method of claim 217, wherein the hypeφlastic inhibitory agent is paclitaxel.
261. The method of claim 217, wherein the hypeφlastic inlήbitory agent is docetaxel.
262. The method of claim 217, wherein the hypeφlastic inhibitory agent is interleukin-2.
263. The method of claim 217, wherein the hypeφlastic inhibitory agent is rituximab.
264. The method of claim 217, wherein the hypeφlastic inhibitory agent is tretinoin.
265. The method of claim 217, wherein the hypeφlastic inhibitory agent is methotrexate.
266. The method of claim 217, wherein the hypeφlastic inhibitory agent is a radiation therapy freatment.
267. A method for treating cancer in a subject comprising administering to a subject an effective amount of a combination of a Pinl-modulating compound of formula (I):
Figure imgf000326_0001
(I) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocychc groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2O-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups may be substituted with one or more substituents selected from the group consisting of H, CH3, F, CH2OH, NH2, OH, CF3, CI, Br, I, -O-, -d-6, -CH=CHCH2-, =O, =NH, =N-NH2, -NC(O)CH3, -C(O)- OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, -CH2NH2, -OCH2C(O)NH- NH2, -CH2C(O)CH3, moφholino, C(O)moφholino, -CH2C(O)C(CH3)3, -C(O OCH2CH3, and any combination thereof; Ri is selected from the group consisting of-H; -Cι-6, -CH2CHCH2, -NH2, ~(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substituted with one or more substiments selected from the group consisting of-H, Cι-4 , -CH2CH2-, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -CH2-, -C(O)NH2, -C(O)R3, -N(R5)2, and any combination thereof; wherein R3 is selected from the group consisting of-H, -OH, -O-, Ci^ , moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, - C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -OH, -O-, C1-4 , moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -C(O)NH2, - CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, - CH2COOH and esters and amides thereof, and any combmation thereof; and a hypeφlastic inhibitory agent such that the cancer is treated.
268. The method of claim 267, wherein Z is S.
269. The method of claim 267, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups are selected from the group consisting of a pyridine, a phenyl, a IH-imidazole, a thiazolidine, a pynolidone, a hexahydro-pyrimidine, a 3- hydroxy-pyπolidin-2-one, a pyπolidine-2,3-dione, a pyπohdine-2,5-dione, a pyrrolidin- 2-one, a cyclopentyl, a [l,4]dioxepane, a tefrahydrofuran, an isoxazole, a moφholino, a [l,3]dioxolane, apyrimidine, a furan, a thiophene, a ynole, a naphthalene, apyrazole, a 3-(methylene)-l-methyl-l,3-dihydro-indol-2-one, abenzo[l,3]dioxole, a piperazine, and a furazan 2-oxide.
270. The method of claim 267, wherein n is selected from the group consisting ofO through 5.
271. The method of claim 267, wherein Zi is O.
272. The method of claim 267, wherein the Pinl-modulating compound of formula (I) is a compound of foπnula (II):
Figure imgf000328_0001
(II) wherein the dashed line indicates a single or a double bond; n is O or 1; R4 is H or lower alkyl Xi, X2 and X3 are independently selected from the group consisting of C, CH, NH, O, S, andN; R2, R3, and Re are independently selected from the group consisting of H, -O-, -Cι-6,F, NH2, CF3j CI, Br, I, =O, =NH, =N-NH2, -NC(O)CH3, - C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -moφholino, -C(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocychc groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and R<5 can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-e, - CH2CHCH2, -NH2, -(X)PRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substiments selected from the group consisting of-H, -O-, Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Ci-6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein R is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R ' are independently selected from the group consisting of H, -O-, -Ci-β, -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
273. The method of claim 272, wherein i is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000330_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
274. The method of claim 272, wherein Ri is -(X)pC(O)Ra, and Ra is the formula R :
Figure imgf000330_0002
wherein R8 is selected from H, F or OH.
275. The method of claim 272, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2- moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
276. The method of claim 272, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
277. The method of claim 267, wherein the Pinl -modulating compound of formula (I) is a compound of formula (HI):
Figure imgf000331_0001
(IH) wherein the dashed line indicates a single or a double bond; n is 0 or 1 ; R4 is H or lower alkyl Xi, X2, X3, i, and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -Cι-6,F, NH2, CF3; CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3,-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-6, - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substimted with one or more substiments selected from the group consisting of-H, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consistmg of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -Cι-6,-C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -0.6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridme, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R7' are independently selected from the group consisting of H, -O-, -Cι-6,-S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
278. The method of claim 277, wherein Ri is -<X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000332_0001
or esters and amides thereof; and wherein Rg is selected from H, F or OH.
279. The method of claim 277, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000333_0001
wherein R8 is selected from H, F or OH.
280. The method of claim 277, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2- moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
281. The method of claim 277, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
282. The method of claim 267, wherein the Pinl -modulating compound of formula (I) is a compound of formula (TV):
Figure imgf000333_0002
(IV) wherein the dashed line indicates a single or a double bond; nis O or 1; R4 is H or lower alkyl Xi is selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and R are independently selected from the group consisting of H, -O-, -Cι-6;F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3, -C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R , R2 and Re, and/or R3 and e can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-6, - CH2CHCH2, -NH2, -(X)pRa, -(XY OjRa, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substimted with one or more substituents selected from the group consisting of-H, -O-, -Ci -e, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -Ci-6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3>, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R$ is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R7' are independently selected from the group consisting of H, -O-, -Cι-6,-S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
283. The method of claim 282, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re".
Figure imgf000335_0001
or esters and amides thereof;- and wherein R8 is selected from H, F or OH.
284. The method of claim 282, wherein Ri is -(X)pC(O)Ra, and Ra is the foπnula Ra-.
Figure imgf000335_0002
wherein R8 is selected from H, F or OH.
285. The method of claim 282, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2- moφholino, -ethyl-moφholino, or CH=CHCH -moφholino.
286. The method of claim 282, wherein R is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
287. The method of claim 267, wherein the Pinl-modulating compound of formula (I) is a compound of formula (V):
Figure imgf000336_0001
wherein the dashed line indicates a single or a double bond; n is 0 or 1; ^ is H or lower alkyl Xi, X2, X3, Xi and X5 are independently selected from the group consisting of C, CH, NH, O, S, andN; R2, R3, and 5 are independently selected from the group consisting of H, -O-, -Cι-6, F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)o- 2NC(O)CH3, -C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-ιC(O)moφholino5 - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which maybe directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing i, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-β, - CH2CHCH2; -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substimted with one or more substiments selected from the group consisting of-H, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Cι.6,-C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3>, - COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2; -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof.
288. The method of claim 287, wherein Ri is -(X^C^Ra, and Ra is the formula Re:
Figure imgf000337_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
289. The method of claim 287, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000337_0002
wherein Rs is selected from H, F or OH.
290. The method of claim 287, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2- moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
291. The method of claim 287, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
292. The method of claim 287, wherein said Pinl modulating compound is a Pinl inhibiting compound.
293. The method of claim 267, wherein said compound is selected from the group consisting of compounds listed in Table 1, and derivatives thereof.
294. The method of claim 267, wherein said compound is selected from the group consisting of compounds listed in Table 2, and derivatives thereof.
295. The method of claim 267, wherein said compound is selected from the group consisting of compounds listed in Table 3, and derivatives thereof.
296. The method of claim 267, wherein said compound is selected from the group consisting of compounds listed in Table 4, and derivatives thereof.
297. The method of claim 267, wherein said compound is selected from the group consisting of compounds listed in Table 5, and derivatives thereof.
298. The method of claim 267, wherein said compound is selected from the group consisting of compounds listed in Table 6, and derivatives thereof.
299. The method of claim 267, wherein said compound is selected from the group consisting of compounds listed in Table 7, and derivatives thereof.
300. The method of claim 267, wherein said compound is selected from the group consisting of compounds listed in Table 8, and derivatives thereof.
301. A method for treating cyclin D 1 overexpression in a subj ect comprising administering to a subject an effective amount of a combination of a Pinl-modulating compound of formula (I):
Figure imgf000339_0001
(I)
' wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or m saturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2θ-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups may be substimted with one or more substiments selected from the group consisting of H, CH3, F, CH2OH, NH2, OH, CF3, CI, Br, I, -O-, -Cι-6, -CH=CHCH2-, =O, =NH, =N-NH2, -NC(O)CH3, -C(O)- OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, -CH2NH2, -OCH2C(O)NH- NH2, -CH2C(O)CH3, moφholino, C(O)moφholino, -CH2C(O)C(CH3)3, -C(O> OCH2CH3, and any combination thereof; Ri is selected from the group consisting of-H; -Cι_e, -CH2CHCH2) -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substimted with one or more substiments selected from the group consisting of-H, C1-4 , -CH2CH2-, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -CH2-, -C(O)NH2, -C(O)R3, -N(R5)2, and any combination thereof; wherein R3 is selected from the group consisting of-H, -OH, -O-, C1. , moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, - C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is mdependently selected from the group consisting of-H, -F, -OH, -O-, CM, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -C(O)NH2> - CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, - CH2COOH and esters and amides thereof, and any combination thereof; and a hypeφlastic inhibitory agent such that the cyclin DI overexpression is freated.
302. The method of claim 301 , wherein Z is S.
303. The method of claim 301, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups are selected from the group consisting of a pyridine, a phenyl, a IH-imidazole, a thiazolidine, a pynolidone, a hexahydro-pyrimidine, a 3- hydroxy-pyπolidin-2-one, a pyπolidine-2,3-dione, a pynohdine-2,5-dione, a pyrrolidin- 2-one, a cyclopentyl, a [l,4]dioxepane, a tefrahydrofuran, an isoxazole, a moφholino, a [l,3]dioxolane, apyrimidine, a furan, a thiophene, apynole, a naphthalene3 apyrazole, a 3-(methylene)-l-methyl-l,3-dihydro-indol-2-one, abenzo[l,3]dioxole, a piperazine, and a furazan 2-oxide.
304. The method of claim 301 , wherein n is selected from the group consisting of 0 through 5.
305. The method of claim 301, wherein Zi is O.
306. The method of claim 301 , wherem the Pinl-modulating compound of formula (I) is a compound of formula (II):
Figure imgf000341_0001
(II) wherein the dashed line indicates a single or a double bond; n is O or 1; R4 is H or lower alkyl Xi, X2 and X3 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -Cι-6,F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -NC(O)CH3> - C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -moφholino, -C(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to foπn a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicycHc aromatic, heterocychc, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-6, - CH2CHCH2, -NH2, -(X)PRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substimted with one or more substiments selected from the group consisting of-H, -O-, Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -Cι-6; -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Cι_6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; , wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R ' are independently selected from the group consisting of H, -O-, -Ci-6, -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
307. The method of claim 306, wherein Ri is -(X)pC(O)Ra, and Ra is the formula R^:
Figure imgf000342_0001
or esters and amides thereof; and wherein Rs is selected from H, F or OH.
308. The method of claim 306, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Ra".
Figure imgf000343_0001
wherein R8 is selected from H, F or OH.
309. The method of claim 306, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2- moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino. <
310. The method of claim 306, wherein R is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino. i
311. The method of claim 301, wherein the Pinl-modulating compound of formula (I) is a compound of formula (IH):
Figure imgf000343_0002
(m) wherein the dashed line indicates a single or a double bond; n is 0 or 1 ; R4 is H or lower alkyl Xi, X2, X3, X , and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and R^ are independently selected from the group consisting of H, -O-, -Cι-6,F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3,-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-ιC(O)moφholino, - , CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, wliich may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic stracture with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-6, - CH2CHCH2, -NH2, -(X)PRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substimted with one or more substiments selected from the group consisting of-H, -O-, -Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCHr, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Ci-β, -C(O)NH2, -C(O)Rb, -N(Rs)2, and any combination thereof; wherein Rb is selected from the group consisting of — H, -OH, -O-, -Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-e, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3) -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R7' are independently selected from the group consisting of H, -O-, -Cι-6,-S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
312. The method of claim 311, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000345_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
313. The method of claim 311, wherein Ri is -YX)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000345_0002
wherein Rg is selected from H, F or OH.
314. The method of claim 311, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and Rsis selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2- moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
315. The method of claim 311, wherein R7 is selected from the group consisting of-N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
316. The method of claim 301, wherein the Pinl-modulating compound of formula (I) is a compound of foπnula (TV):
Figure imgf000346_0001
(IV) wherein the dashed line indicates a single or a double bond; n is O or l; R4 is H or lower alkyl Xi is selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -Cι.6,F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3)-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)o-2moφholino, -(CH2)o-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which maybe directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3s R2 and Re, and/or R3 and Re can together form a multicyclic aromatics heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of — H, -O-, -Ci-6, - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substimted with one or more substiments selected from the group consisting of-H, -O-, -Cι_6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -Cι-6,-C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein R is selected from the group consisting of-H, -OH, -O-, -Cι-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -0.6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R ' are independently selected from the group consisting of H, -O-, -Ci-6, -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tefrazole, triazole, piperidine, and any combination thereof.
317. The method of claim 316, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000347_0001
or esters and amides thereof; and wherein Rs is selected from H, F or OH.
318. The method of claim 316, wherem Ri is -(X)pC(O)Ra, and Ra is the foπnula Ra".
Figure imgf000348_0001
wherein R8 is selected fro Η, F or OH.
319. The method of claim 316, wherein Ri is -<X)pC(O>Ra, Ra is N(R5)2, and Rsis selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2) - moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
320. 166g. The method of claim 316, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
321. The method of claim 301, wherein the Pinl-modulating compound of foπnula (I) is a compound of foπnula (V):
Figure imgf000348_0002
wherein the dashed line indicates a single or a double bond; n is O or 1; Ri is H or lower alkyl Xi, X2, X3, Xi and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and R are independently selected from the group consisting of H, -O-, -d.6, F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3, -C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and R^ can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X , and any combination thereof; Ri is selected from the group consisting of-H, -O-, -0.6, - CH2CHCH2, -NH2, -(X)PRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2-. or -NH- , wherein each X is, independently, optionally substimted with one or more substiments selected from the group consisting of-H, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Cι-6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3 , - COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof.
322. The method of claim 321, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000350_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
323. The method of claim 321 , wherein Ri is -(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000350_0002
wherein Rs is selected from H, F or OH.
324. The method of claim 321 , wherein Ri is -(X)pC(O)Ra, Ra is N(R )2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2) - moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
325. The method of claim 321, wherein R7 is selected from the group consisting of -N-(CH2) -moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφhohno .
326. The method of claim 301, wherein said Pinl modulating compound is a Pinl inhibiting compound.
327. The method of claim 301, wherein said compound is selected from the group consisting of compounds hsted in Table 1, and derivatives thereof.
328. The method of claim 301, wherein said compound is selected from the group consisting of compounds listed in Table 2, and derivatives thereof.
329. The method of claim 301 , wherein said compound is selected from the group consisting of compounds listed in Table 3, and derivatives thereof.
330. The method of claim 301 , wherein said compound is selected from the group consisting of compounds listed in Table 4, and derivatives thereof.
331. The method of claim 301, wherein said compound is selected from the group consisting of compounds listed in Table 5, and derivatives thereof.
332. The method of claim 301 , wherein said compound is selected from the group consisting of compounds listed in Table 6, and derivatives thereof.
333. The method of claim 301 , wherein said compound is selected from the group consisting of compounds listed in Table 7, and derivatives thereof.
334. The method of claim 301 , wherein said compound is selected from the group consisting of compounds listed in Table 8, and derivatives thereof.
335. A Pinl -modulator comprising formula (I):
Figure imgf000351_0001
(I) wherein the dashed line indicates a single or a double bond; n is selected from the group consisting of 0 through 10; m is 0 or 6; Z and Zi are independently selected from the group consisting of O or S; AR is H or is selected from one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -N(H)-, -S(O)2O-, -S-, or -OCH2-, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups may be substimted with one or more substiments selected from the group consisting of H, CH3, F, CH2OH, NH2, OH, CF3, CI, Br, I, -O-, -Cι_6, -CH=CHCH2-, =O, =NH, =N-NH2, -NC(O)CH3, -C(O)- OC(CH3)3, -N-C(O)-OC(CH3)3, -C(O)-NH2, -C(O)-NHCH3, -CH2NH2, -OCH2C(O)NH- NH2, -CH2C(O)CH3, moφholino, C(O)moφholino, -CH2C(O)C(CH3)3, -C(O> OCH2CH3, and any combination thereof; Ri is selected from the group consisting of-H; -Ci-6, -CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of. 1 through 6, wherein each X is independently selected from -CH2- or -NH-, wherein each X is, independently, optionally substimted with one or more substiments selected from the group consisting of-H, CM, -CH2CH2-, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -S-, -N-, -OH, - CH=CHCH -, and any combination thereof; wherein Ra is selected from the group consisting of OH and moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -CH2-, -C(O)NH2, -C(O)R3, -N(R5)2, and any combination thereof; wherein R3 is selected from the group consisting of — H, -OH, -O-, C , moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, - C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -OH, -O-, CM, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -C(O)NH2, - CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, - CH2COOH and esters and amides thereof, and any combination thereof.
336. The Pinl -modulator of claim 335, wherein Z is S.
337. The Pinl -modulator of claim 335, wherein the aromatic groups, heterocyclic groups, and carbocyclic groups are selected from the group consisting of a pyridine, a phenyl, a IH-imidazole, a thiazolidine, a pyπolidone, a hexahydro- pyrimidine, a 3-hydroxy-pyπolidin-2-one, a pyπolidine-2,3-dione, a pyπolidine-2,5- dione, a pyπolidin-2-one, a cyclopentyl, a [l,4]dioxepane, a tefrahydrofuran, an isoxazole, a moφholino, a [l,3]dioxolane, apyrimidine, a furan, athiophene, apyπole, a naphthalene, apyrazole, a 3-(methylene)-l-methyl-l,3-dihydro-indol-2-one, a benzo[l,3]dioxole, a piperazine, and a furazan 2-oxide.
338. The Pinl -modulator of claim 335, wherein n is selected from the group consisting of 0 through 5.
339. The Pinl -modulator of claim 335, wherein Zi is O.
340. The Pinl -modulator of claim 335, wherein the Pinl-modulating compound of formula (I) is a compound of formula (H):
(D) wherein wherein the dashed line indicates a single or a double bond; n is O or 1; Ri is H or lower alkyl Xi, X2 and X3 are independently selected from the group consisting of C, CH, NH, O, S, andN; R2, R3, and Re are independently selected from the group consisting of H, -O-, -d-6,F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -NC(O)CH3, - C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -moφholino, -C(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R , R2 and Re, and/or R3 and R can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-6, - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 tlirough 6, wherein each X is independently selected from -CH2- or-NH- , wherein each X is, independently, optionally substimted with one or more substiments selected from the group consisting of-H, -O-, Cι_6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -Cι_6, -C(O)NH2, -C(O)Rb, -N(Rs)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-e, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2> -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R ' are independently selected from the group consisting of H, -O-, -Ci-6, -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
341. The Pinl -modulator of claim 340, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000355_0001
or esters and amides thereof; and wherein Rs is selected from H, F or OH.
342. The Pinl -modulator of claim 340, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000355_0002
wherein Rs is selected from H, F or OH.
343. The Pinl -modulator of claim 340, wherein Ri is -(X)pC(O)Ra, Ra is N(R.5)2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O- (CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
344. The Pinl -modulator of claim 340, wherein R is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
345. The Pinl -modulator of claim 335, wherein the Pinl-modulating compound of formula (I) is a compound of formula (IH):
Figure imgf000356_0001
(IH) wherein the dashed line indicates a single or a double bond; n is 0 or 1 ; R4 is H or lower alkyl Xi, X2, X3, Xi, and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and ^ are independently selected from the group consisting of H, -O-, -d-6,F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3,-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)o-2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic structure, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2O-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R3 and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; , Ri is selected from the group consisting of — H, -O-, -Ci-e, - CH2CHCH2, -NH2, K pRa, - X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substituted with one or more substiments selected from the group consisting of-H, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH -, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -Ci-6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Ci-β, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Cι-6) moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R7 and R7' are independently selected from the group consisting of H, -O-, -Ci-6, -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
346. The Pinl -modulator of claim 345, wherein Ri is -(X)pC(O)Ra, and Ra is the formula R^:
Figure imgf000357_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
347. The Pinl -modulator of claim 345, wherein Ri is -(X)pC(O)Ra, and Ra is the formula R :
Figure imgf000358_0001
wherein R8 is selected from H, F or OH.
348. The Pinl -modulator of claim 345 , wherein Ri is -(X)pC(O)Ra, Ra is N( s)2, and R5is selected from the group consisting of -N-(CH2)2-moφholino, -O- (CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
349. The Pinl -modulator of claim 345, wherein R7 is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-mcrpholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
350. The Pinl -modulator of claim 335, wherein the Pinl-modulating compound of formula (I) is a compound of formula (IN):
Figure imgf000358_0002
(TV) wherein the dashed line indicates a single or a double bond; n is O or 1; R4 is H or lower alkyl Xi is selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -Cι-6,F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)o- 2NC(O)CH3,-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0.2moφholino, -(CH2)0-ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly linked, joined to form a multi-cyclic stracture, or indirectly linked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Re, and/or R and Re can together form a multicyclic aromatic, heterocyclic, or carbocyclic structure with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-6, - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substimted with one or more substituents selected from the group consisting of-H, -O-, -Cι_6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -O-, -Ci-6, -C(O)NH2, -C(O)Rb, -N(R5)2, and any combination thereof; wherein R is selected from the group consisting of-H, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein R and R7' are independently selected from the group consisting of H, -O-, -Ci-e, -S-, -N-, -CH=CHCH3, moφholino, phenol, phenyl, piperazine, cyclopentane, -COOH, cyclohexane, pyridine, tetrazole, triazole, piperidine, and any combination thereof.
351. The Pinl -modulator of claim 350, wherein Ri is -(X)pC(O)Ra, and Ra is the foπnula Re'.
Figure imgf000360_0001
or esters and amides thereof; and wherein R8 is selected from H, F or OH.
352. The Pinl -modulator of claim 350, wherein Ri is -(X)pC(O)Ra, and Ra is the foπnula Ra:
Figure imgf000360_0002
wherein Rs is selected from H, F or OH.
353. The Pinl -modulator of claim 350, wherein Ri is -(X)pC(O)Ra, Ra is
N(Rs)2, and R5 is selected from the group consisting of -N-(CH2)2-moφholino, -O- (CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
354. The Pinl -modulator of claim 350, wherein R is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
355. The Pinl -modulator of claim 335, wherein the Pinl-modulating compound of fomiula (I) is a compound of formula (V):
Figure imgf000361_0001
wherein the dashed line indicates a single or a double bond; n is O or l; R4 is H or lower alkyl Xi, X2, X3, X4 and X5 are independently selected from the group consisting of C, CH, NH, O, S, and N; R2, R3, and Re are independently selected from the group consisting of H, -O-, -Cι-6, F, NH2, CF3, CI, Br, I, =O, =NH, =N-NH2, -(CH2)0- 2NC(O)CH3,-C(O)OC(CH3)3, -NC(O)-OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -CH2NH2, - OCH2C(O)NH-NH2, -CH2C(O)CH3, -(CH2)0-2moφholino, -(CH2)o.ιC(O)moφholino, - CH2C(O)C(CH3)3, -C(O)-OCH2CH3, one or a combination of aromatic groups, heterocyclic groups, and carbocyclic groups, which may be directly hnked, joined to form a multi-cyclic stracture, or indirectly hnked by saturated or unsaturated, branched or unbranched aliphatic group, -S(O)2θ-, -N(H)-, -S-, or -OCH2-; and wherein R2 and R3, R2 and Kg, and/or R3 and e can together form a multicyclic aromatic, heterocyclic, or carbocyclic stracture with ring containing Xi, X2, and X3, and any combination thereof; Ri is selected from the group consisting of-H, -O-, -Ci-e, - CH2CHCH2, -NH2, -(X)pRa, -(X)pC(O)Ra, wherein p is selected from the group consisting of 1 through 6, wherein each X is independently selected from -CH2- or -NH- , wherein each X is, independently, optionally substimted with one or more substituents selected from the group consisting of-H, -O-, -Ci-e, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, -S-, -N-, -OH, -CH=CHCH2-, and any combination thereof; wherein Ra is selected from the group consisting of OH, H, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -O-, -C e, -C(O)NH2, -C(O)R , -N(Rs)2, and any combination thereof; wherein Rb is selected from the group consisting of-H, -OH, -O-, -Ci-e, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tetrazole, triazole, piperidine, -(CH2)3C(O)NH2, -CH2CH(OH)CH3, -C(O)N(CH3)-, - COOH and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof; wherein each R5 is independently selected from the group consisting of-H, -F, -CI, -Br, -I, -OH, -O-, -Ci-6, moφholino, phenol, phenyl, piperazine, cyclopentane, cyclohexane, pyridine, tefrazole, triazole, piperidine, - CH2(CH2)2C(O)NH2, -CH2CH2OH, -CH2CH(OH)CH3, -C(O)N(CH3)-, -COOH and esters and amides thereof and esters and amides thereof, -CH2COOH and esters and amides thereof, and any combination thereof.
356. The Pinl-modulator of claim 355, wherein Ri is -{X)pC(O)Ra, and Ra is the formula Re:
Figure imgf000362_0001
or esters and amides thereof; and wherein Rs is selected from H, F or OH.
357. The Pinl-modulator of claim 355, wherein Ri is -(X)pC(O)Ra, and Ra is the formula Ra:
Figure imgf000362_0002
wherein Rs is selected from H, F or OH.
358. The Pinl-modulator of claim 355, wherein Ri is -(X)pC(O)Ra, Ra is N(R5)2, and R5is selected from the group consisting of -N-(CH2)2-moφholino, -O- (CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino.
359. The Pinl-modulator of claim 355, wherein R is selected from the group consisting of -N-(CH2)2-moφholino, -O-(CH2)2-moφholino, -ethyl-moφholino, or CH=CHCH2-moφholino. i
360. The Pinl-modulator of claim 355, wherein said Pinl modulating compound is a Pinl inhibiting compound.
361. The Pinl -modulator of claim 335, wherein said compound is selected from the group consisting of compounds listed in Table 1, and derivatives thereof.
362. The Pinl-modulator of claim 335, wherein said compound is selected from the group consisting of compounds listed in Table 2, and derivatives thereof.
363. The Pinl -modulator of claim 335, wherein said compound is selected from the group consisting of compounds listed in Table 3, and derivatives thereof.
364. The Pinl-modulator of claim 335, wherein said compound is selected from the group consisting of compounds listed in Table 4, and derivatives thereof.
365. The Pinl-modulator of claim 335, wherein said compound is selected from the group consisting of compounds listed in Table 5, and derivatives thereof.
366. The Pinl-modulator of claim 335, wherein said compound is selected from the group consisting of compounds hsted in Table 6, and derivatives thereof.
367. The Pinl-modulator of claim 335, wherein said compound is selected from the group consisting of compounds listed in Table 7, and derivatives thereof.
368. The Pinl-modulator of claim 335, wherein said compound is selected from the group consisting of compounds listed in Table 8, and derivatives thereof.
369. A pharmaceutical composition comprising a Pinl -modulating compound of claim 1, 2, 59, 115, 149, 183, 217, 267, 301, or 335 and a pharmaceutically acceptable carrier.
370. The pharmaceutical composition of claim 369, wherein said compound is selected from the group consisting of compounds listed in Table 1, and derivatives thereof.
371. The pharmaceutical composition of claim 369, wherein said compound is selected from the group consisting of compounds listed in Table 2, and derivatives thereof.
372. The pharmaceutical composition of claim 369, wherein said compound is selected from the group consisting of compounds listed in Table 3, and derivatives thereof.
373. The phannaceutical composition of claim 369, wherein said compound is selected from the group consisting of compounds listed in Table 4, and derivatives thereof.
374. The pharmaceutical composition of claim 369, wherein said compound is selected from the group consisting of compounds listed in Table 5, and derivatives thereof.
375. The pharmaceutical composition of claim 369, wherein said compound is selected from the group consisting of compounds hsted in Table 6, and derivatives thereof.
376. The pharmaceutical composition of claim 369, wherein said compound is selected from the group consisting of compounds listed in Table 7, and derivatives thereof.
377. The pharmaceutical composition of claim 369, wherein said compound is selected from the group consisting of compounds hsted in Table 8, and derivatives thereof.
378. A compound selected from the group consisting of compounds listed in Table 1, and derivatives thereof.
379. A compound selected from the group consisting of compounds listed in
Table 2, and derivatives thereof. i
380. A compound selected from the group consisting of compounds listed in Table 3, and derivatives thereof.
381. A compound selected from the group consisting of compounds listed in Table 4, and derivatives thereof.
382. A compound selected from the group consisting of compounds listed in Table 5, and derivatives thereof.
383. A compound selected from the group consisting of compounds listed in Table 6, and derivatives thereof.
384. A compound selected from the group, consisting of compounds listed in
Table 7, and derivatives thereof.
385. A compound selected from the group consisting of compounds listed in
Table 8, and derivatives thereof.
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