WO2006110918A1

WO2006110918A1 - Pyrrole compounds and uses thereof

Info

Publication number: WO2006110918A1
Application number: PCT/US2006/014353
Authority: WO
Inventors: Andiliy G. Lai; Shamal Anil Mehta; Hitesh K. Patel; Shripad Bhagwat
Original assignee: Ambit Biosciences Corporation
Priority date: 2005-04-13
Filing date: 2006-04-13
Publication date: 2006-10-19

Abstract

Pyrrole compounds, compositions and methods are provided for the treatment, prevention, or amelioration of neurodegenerative diseases, cardiovascular diseases, proliferative diseases and visual disorders. In particular, pyrrole compounds, compositions and methods for the treatment of stroke are disclosed herein.

Description

P ROL COMPOUNDS AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of priority under 35 U.S.C. 119(e) to U.S. Provisional Patent Application Nos. 60/671,409 and 60/671 ,306, both filed on April 13, 2005, and the contents of both applications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION Pyrrole compounds, compositions and methods are provided for the treatment, prevention, or amelioration of neurodegenerative diseases, cardiovascular diseases, proliferative diseases and visual disorders. In particular, pyrrole compounds, compositions and methods for the treatment of stroke are provided herein.

BACKGROUND OF THE INVENTION

[0002] HMG-CoA reductase inhibitors such as statins are competitive inhibitors of the rate- limiting step in cholesterol biosynthesis. Several large landmark clinical studies have shown that statin treatment results in a marked reduction of cardiovascular mortality and morbidity. Because of the strong association between serum cholesterol levels and coronary artery disease, investigators initially assumed that the predominant beneficial effects of statins were the result of their lipid-lowering properties. However, more recent observations have suggested that some of the clinical benefits of statins may be due in part to other pleiotropic mechanisms of action of these compounds. [0003] The list of these pleiotropic effects of statins is still growing and includes, among others, the modulatory effects of statins on cancer, diabetes, cardiovascular disease, neurodegeneration, neuroprotection, osteoporosis, chronic kidney disease, dementia and stroke (Epstein et al., Am. J. Kidney Dis. (2005) 45(1):2-14; Miida et al., (2004) 11 (5):253-64; Yildirir et al., Curr. Vase. Pharmacol. (2004) 2 (4):309-18). The pleiotropic effects of statins might possibly be the result, at least in part, of the prevention of isoprenoid formation, lsoprenoids are products of the cholesterol biosynthetic pathway; they are involved in a certain type post- translational modification of protein called prenylation, in prenyl groups from the isoprenoid intermediates attach to certain proteins after translation. Prenylation is necessary for the membrane association and protein function of a variety of important signal transduction proteins including, for example, the low molecular weight GTP-binding proteins. Furthermore it has been established that certain atorvastatin derivatives can bind to the prenyl transport protein PDE65 , a protein that was first identified as the delta subunit of photoreceptor cGMP phosphodiesterase (See commonly owned US Application Nos. 10/848,584 Publication No. 20040259880 and 10/989,995 Publication No. 20050182125). In contrast to the catalytic photoreceptor cGMP phosphodiesterase (PDE6), which is expressed exclusively in photoreceptors, PDE65 is widely expressed in other tissues. In addition a PDE65 orthologue is present in eyeless invertebrates such as Caenorhabditis elegans suggesting that PDE65 may have more broad cellular based functions.

[0004] PDE68 is believed to bind to prenylated proteins, thereby releasing them from the plasma membrane. Release from the membrane results in uncoupling of the protein from signal transduction pathways and may play an important role in the process of controlling regulatory feedback in a wide variety of cellular processes. PDE65 may therefore play a role in mediating some or all of the known pleiotropic effects of atorvastatin.

[0005] Two-hybrid analysis using PDE65 as a bait has established that PDEβδ binds to many members of the Ras super family of low molecular weight GTP-binding proteins including for example, H-ras, Rap, Rho6, Rheb, Rab, Rac, Arfϊ , Arf6, and Arl2/3, as well as the photo- transduction related proteins PDE6, retinitis pigmentosa GTPase regulator (RPGR) and famesylated rhodopsin kinase (GRK1) (Hanzal-Bayer et al., EMBO J. (2002) 21 (9):2095-2106. Because RPGR and the ARF proteins are not post-translationally modified via prenylation it is now recognized that PDE65 can also interact with the N terminal regions of certain proteins. Based on structural analysis it has been proposed that AH2/3 serves as a GTP dependent switch that may mediate the release and or uptake of prenylated proteins by PDE68 (Hanzal- Bayer et al., EMBO J. (2002) 21 (9): 2095-2106).

[0006] The Ras superfamily is a class of low molecular weight (LMW) GTP-binding proteins that consist of 21-30 kDa polypeptides. These proteins regulate cell growth, cell cycle control, protein secretion, and intracellular vesicle interaction. In particular, the LMW GTP-binding proteins activate cellular proteins by transducing mitogenic signals involved in various cell functions in response to extracellular signals from receptors (Tavitian, A. (1995) C. R. Seances Soc. Biol. FiI. 189:7-12)). During this process, the hydrolysis of GTP acts as an energy source as well as an on-off switch for the GTPase activity of the LMW GTP-binding proteins. [0007] The Ras superfamily is comprised of five subfamilies: Ras, Rho, Ran, Rab, and ADP-ribosylation factor (ARF). Specifically, Ras genes are essential in the control of cell proliferation. Mutations in Ras genes have been associated with cancer. Rho proteins control signal transduction in the process of linking receptors of growth factors to actin polymerization which is necessary for cell division. Rab proteins control the translocation of vesicles to and from membranes for protein localization, protein processing, and secretion. Ran proteins are localized to the cell nucleus and play a key role in nuclear protein import, control of DNA synthesis, and cell-cycle progression. ARF and ARF-like proteins participate in a wide variety of cellular functions including vesicle trafficking, exocrine secretion, regulation of phospholipase activity, and endocytosis.

[0008] Given the importance of prenylation in controlling the sub-cellular localization, and thereby function of Ras super family members, it is not surprising that compounds that interfere with this process would be likely to exert significant and important effects on a wide range of cellular processes.

[0009] The crystal structure of PDE65 demonstrates that it features a deep hydrophobic binding pocket formed between the two β-sheets that can accommodate a large hydrophobic group. The structure thus supplies a structural explanation for the ability of PDE to extract the catalytic subunits of prenylated proteins from the membrane and to constitute a cytosolic pool of the enzyme. Interestingly PDE65 also bears structural similarity to RhoGDI a guanine nucleotide dissociation inhibitor (GDIs), which can solubilize the Rab and Rho guanyl nucleotide binding proteins (Hanzal-Bayer et al., EMBO J. (2002) 21 (9):2095-2106). [0010] The binding of PDE65 to the retinal phosphodiesterase has been shown to be blocked by short prenylated and carboxymethylated peptides derived from the C terminus of the phosphodiesterase alpha and beta subunits, and this effect required that the peptides be prenylated and methylated, indicating that PDE65 interacts directly with the prenylated C- terminal cysteine methyl ester residue. Additionally biochemical analysis has demonstrated that PDE65 can interact with both farnesyl (C15) and geranylgeranyl (C20) side chains in the absence of polypeptides, demonstrating that small molecules can be used to effectively block PDE6δ binding.

[0011] In addition to the potential interactions of statins, a number of drugs including bisphosphonates such as zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ and Basel, Switzerland) been identified that interact with enzymes directly or indirectly involved with protein prenylation (Green et al., Oncologist. (2004) 9 Suppl 4:3-13). However, in many cases these effects were unexpected or unpredicted consequences of blocking upstream lipid metabolism or utilization. Accordingly it is not surprising that such drugs themselves may not be particularly effective for these new indications, or may exhibit inappropriate tissue distributions or bioavailabilities to be fully effective in vivo.

[0012] Thus there is a need for the development of selective, high affinity PDE65 modulators, which can potently modulate the subcellular localization and activity of PDE65 interacting proteins, and which are soluble, exhibit good bioavailability and appropriate tissue exposure. Such modulators have specific utility in a wide range of applications including the regulation of normal and pathogenic processes, and for the treatment, and prevention of human and veterinary diseases. In one embodiment such diseases include those mediated via the pleiotropic effects of statins, and in one aspect, atorvastatin.

[0013] SUMMARY OF THE INVENTION

[0014] Compounds for use in pharmaceutical compositions and methods for modulating the activity, binding or sub-cellular distribution of proteins are provided. Such proteins provide for improved methods of modulating the pleiotropic therapeutic actions of atorvastatin. In one embodiment, the compounds for use in the compositions and methods provided herein have formula (I):

Formula (I) wherein

X is O or S; and

Y is -NR⁴- or -O-;

R¹ is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

R² is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkenylalkyl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, -R^B-OR⁹, -R⁸-SR⁹, -R⁸-S(O),R¹⁰ (where t is 1 or 2), -R⁸-N(R⁹)₂, -R⁸-CN, -R⁸-C(O)R⁹, -R⁸-C(S)R⁹, -R⁸-C(NR⁹)R⁹, -R⁸-C(O)OR⁹, -R⁸-C(S)OR⁹, -R⁸-C(NR⁹)OR⁹, -R⁸-C(O)N(R⁹)₂, -R⁸-C(S)N(R⁹)₂, -R⁸-C(NR⁹)N(R⁹)₂, -R⁸-C(O)SR⁹, -R⁸-C(S)SR⁹, -R⁸-C(NR⁹)SR⁹, -R⁸-S(O)_tOR⁹ (where t is 1 or 2), -R⁸-S(O)_tN(R⁹)₂ (where t is 1 or 2), -R⁸-S(O)_tN(R⁹)N(R⁹)₂ (where t is 1 or 2), -R⁸-S(O)_tN(R⁹)N=C(R⁹)₂, -R⁸-S(O)_tN(R⁹)C(O)R¹⁰ (where t is 1 or 2), -R⁸-S(O)_tN(R⁹)C(O)N(R⁹)₂ (where t is 1 or 2), -R⁸-S(O)_tN(R⁹)C(NR⁹)N(R⁹)₂ (where t is 1 or 2), -R⁸-N(R⁹)C(O)R¹⁰, -R⁸-N(R⁹)C(O)OR¹⁰, -R⁸-N(R⁹)C(O)SR¹⁰, -R⁸-N(R⁹)C(NR⁹)SR¹⁰, -R⁸-N(R⁹)C(S)SR¹⁰, -R⁸-N(R⁹)C(O)N(R⁹)₂, -R⁸-N(R⁹)C(NR⁹)N(R⁹)₂, -R⁸-N(R⁹)C(S)N(R⁹)_2l -R⁸-N(R⁹)S(O)_tR¹⁰ (where t is 1 or 2), -R⁸-OC(O)R¹⁰, -R⁸-OC(NR⁹)R¹⁰, -R⁸-OC(S)R¹⁰, -R⁸-OC(O)OR¹⁰, -R⁸-OC(NR⁹)OR¹⁰, -R⁸-OC(S)OR¹⁰, -R⁸-0C(0)SR⁹, -R⁸-OC(O)N(R⁹)₂₎ -R⁸-OC(NR⁹)N(R⁹)₂, -R⁸-OC(S)N(R⁹)₂ -R⁸-C(O)-R¹¹-C(O)R⁹, -R⁸-C(O)-R¹¹-C(S)R⁹, -R⁸-C(O)-R¹¹-C(NR⁹)R⁹, -R⁸-C(O)-R¹¹-C(O)OR⁹, -R⁸-C(O)-R¹¹-C(S)OR⁹, -R⁸-C(O)-R¹¹-C(NR⁹)OR⁹ _> -R⁸-C(O)-R¹¹-C(O)N(R⁹)₂₎ -R⁸-C(O)-R¹¹-C(S)N(R⁹)₂, -R⁸-C(O)-R¹¹-C(NR⁹)N(R⁹)₂, -R⁸-C(O)-R¹¹-C(O)SR⁹, -R⁸-C(O)-R¹¹-C(S)SR⁹ and -R⁸-C(O)-R¹¹-C(NR⁹)SR⁹;

R³ is optionally substituted alkyl, or optionally substituted alkenyl, or optionally substituted methoxy or optionally substituted ethoxy;

R⁴ is hydrogen or optionally substituted alkyl; R^andTR'^are selected from the group consisting of optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl and optionally substituted aryl;

R⁸ is independently a direct bond, an optionally substituted straight or branched alkylene chain, or an optionally substituted straight or branched alkenylene chain;

R⁹ is independently selected from (i) or (ii) below

(i) R⁹ is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or

(ii) two (R⁹)s together with the atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl;

R¹⁰ is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyciylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl; each R¹¹ is independently an optionally substituted straight or branched alkylene chain or an optionally substituted straight or branched alkenylene chain; with the proviso that if R²⁰, R⁶ and R⁴ are optionally substituted phenyl, X is O and Y is - NH- and R³ is isopropyl, then R² is hydrogen, amino-substituted alkyl, hydroxy-substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl wherein the heterocyclyl of said heterocyclylalkyl contains at least one nitrogen heteroatom, or -R⁸-N(R⁹)₂ wherein R⁸ and R⁹ are defined as above, as a single isomer, a mixture of isomers, or as a racemic mixture of isomers; or as a solvate or polymorph; or as a prodrug; or as a metabolite; or as a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is a compound of Formula (I) wherein R⁶ is optionally substituted heteroaryl; and X, Y, R¹, R² , R³and R⁵ are as described above for Formula (I).

In another embodiment, the present invention is a compound of Formula (II) wherein:

wherein n and p are each an integer from 0 to 3; R²⁰ and R³⁰ are each independently selected from the group consisting of halo, cyano, nitro, amino, hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl^" optionally substituted alkynyl; and X, R¹, R² and R³ , are as described above for Formula (I).

In another embodiment, the present invention is a compound of Formula (II) wherein R² is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, -R⁸-OR⁹, -R⁸-SR⁹ and -R⁸-N(R⁹)₂; where R⁸ and R⁹ are as described above in Formula (I).

In another embodiment, the present invention is a compound of Formula (III)

Formula (III) wherein: m, n and p are each an integer from 0 to 3; R⁴⁰ is selected from the group consisting of halo, cyano, nitro, amino, hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl; and X, R² , R³', R²⁰ and R³⁰ are as described above for Formula (II). In another embodiment, the present invention is a compound of Formula (III) wherein m is 1 , n is 0, p is 0, R² is hydrogen and R⁴⁰ is a substituent in the para-position selected from the group consisting of halo, cyano, nitro, amino, hydroxy, optionally substituted alkoxy and optionally substituted alkyl.

In another embodiment, the present invention is a compound of Formula (III) wherein m is 1 , n is 1 or 2, p is 0, R² is hydrogen, R⁴⁰ is a substituent in the para-position selected from the group consisting of halo, cyano, nitro, amino, hydroxy, optionally substituted alkoxy and optionally substituted alkyl, and when n is 1 , R³⁰ is a para-substituted halo, and when n is 2, one R³⁰ is a para-substituted halo and another R³⁰ is an ortho-substituted halo.

In another embodiment, the present invention is a compound of Formula (IV)

Formula (IV) wherein R³ is isopropyl and n, p, X, R² , R³', R²⁰ and R³⁰ are as described in Formula (ill).

In another embodiment, the present invention is a compound of Formula (IV) wherein n is 0; p is 1 ; R² is hydrogen; and R²⁰ and R³⁰ are para-substituted halo.

In another embodiment, the present invention is: 4,5-bis(4-fluorophenyl)-2-isopropyl-N- phenyl-1 H-pyrrole-3-carboxamide;

5-(4-bromophenyl)-4-(4-fluorophenyl)-2-isopropyl-N-phenyl-1H-pyrrole-3-carboxamide; and 4-(4-bromophenyl)-5-(4-fluorophenyl)-2-isopropyl-N-phenyl-1H-pyrrole-3-carboxamide.

In another embodiment, the present invention is a compound having the Formula (IV) wherein n is 1 or 2; p is 0; R² is -R⁸-N(R⁹)₂; R⁸ is an optionally substituted straight or branched alkylene chain; two (R⁹)s together with the atom to which they are attached form an optionally substituted heterocyclyl; and when n is 1 , R³⁰ is para-substituted halo and when n is 2, one R³⁰ is para-substituted halo and another R³⁰ is ortho-substituted halo.

In another embodiment, the present invention is a compound having the Formula (I) wherein R¹ is an optionally substituted heteroaryl; R² , R³', R⁵ and R⁶ are as described in Formula (I). In another embodiment, the present invention is a compound having the Formula (II) wherein R¹ is an optionally substituted heteroaryl; n,p, X, R², R³\ R²⁰ and R³⁰ are as described in Formula (II).

In another embodiment, the present invention is a compound having the Formula (II) wherein p is 0; R¹ is an optionally substituted heteroaryl; R³ is isopropyl; n, X, R², R²⁰ and R³⁰ are as described in Formula (II).

In another embodiment, the present invention is a compound having the Formula (II) wherein n is 0 or 1 ; p is 0; R¹ is an optionally substituted heteroaryl; R³ is isopropyl; R³⁰ is para- substituted halo; n, X, R² and R²⁰ are as described in Formula (II). In another embodiment, the present invention is a compound having the Formula (II) wherein n is 0 or 1 ; p is 0; R¹ is an optionally substituted heteroaryl; R³ is isopropyl; R² is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, -R⁸-OR⁹, -R⁸-SR⁹, -R⁸-N(R⁹)₂, -R⁸-C(NR⁹)R⁹, -R⁸-C(O)OR⁹,

-R⁸-C(S)OR⁹, -R⁸-C(NR⁹)OR⁹, -R⁸-C(O)N(R⁹)₂, -R⁸-C(S)N(R⁹)₂, -R⁸-C(NR⁹)N(R⁹)₂, -R⁸-C(O)SR⁹, -R⁸-C(S)SR⁹, -R⁸-C(NR⁹)SR⁹; R³⁰ is para-substituted halo and X, R⁸, R⁹ and R²⁰ are as described in Formula (II).

In another embodiment, the present invention is a compound having the Formula (II) wherein n is 0 or 1 ; p is 0; R¹ is an optionally substituted heteroaryl; R³ is isopropyl; R² is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, -R⁸-OR⁹, -R⁸-SR⁹, -R⁸-N(R⁹)₂, -R⁸-C(O)OR⁹, -R⁸-C(O)N(R⁹)₂, -R⁸-C(S)N(R⁹)₂; R³⁰ is para-substituted halo and X, R⁸, R⁹ and R²⁰ are as described in Formula (II).

In another embodiment, the present invention is a compound having the Formula (II) wherein n is 0 or 1 ; p is 0; R¹ is an optionally substituted heteroaryl; R³ is isopropyl; R² is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, -R⁸-OR⁹, -R⁸-SR⁹, and -R⁸-N(R⁹)₂; R³⁰ is para-substituted halo and X, R⁸, R⁹ and R²⁰ are as described in Formula (II).

In another embodiment, the present invention is a compound having the Formula (II) wherein n is 0 or 1; p is 0; R¹ is an optionally substituted heteroaryl; R³ is isopropyl; R² is hydrogen, amino-substituted alkyl, hydroxyl-substituted alkyl, -R⁸-OR⁹, -R⁸-SR⁹, and -R^δ-N(R⁹)₂; R⁸ is independently a direct bond, an optionally substituted straight or branched alkylene chain, or an optionally substituted straight or branched alkenylene chain; R^e , wnen at^'tacneα singly to an atom, is hydrogen, optionally substituted heterocyclyl wherein said heterocyclyi contains at least a nitrogen heteroatom; or two (R⁹)s together with the atom to which they are attached form an optionally substituted heterocyclyl; and R³⁰ is para- substituted halo. In another embodiment, the present invention is a compound having the Formula (II) wherein n is 1 or 2; p is 0; R¹ is optionally substituted heteroaryl; R² is -R⁸-N(R⁹)₂; R⁸ is an optionally substituted straight or branched alkylene chain; two (R⁹)s together with the atom to which they are attached form an optionally substituted heterocyclyl; and when n is 1 , R³⁰ is para- substituted halo and when n is 2, one R³⁰ is para-substituted halo and another R³⁰ is ortho- substituted halo.

In another embodiment, the present invention is a compound having the Formula (II) wherein n is 1; p is 0; R¹ is an optionally substituted heteroaryl; R³ is isopropyl; R² is -R⁸-N(R⁹)₂; R⁸ is an optionally substituted straight or branched alkylene chain; two (R⁹)s together with the atom to which they are attached form an optionally substituted heterocyclyl; and R³⁰ is para-substituted halo.

In another embodiment, the present invention is a compound having the Formula (II) wherein n is 1 ; p is 0; R¹ is an optionally substituted aryl or optionally substituted heteroaryl; R² is optionally substituted C₃-C₅ alkyl, -R⁸-OR⁹, -R⁸-SR⁹, and -R⁸-N(R⁹)₂; R³ is isopropyl; R⁸ is optionally substituted C₃-C₅ alkylene; R⁹ is independently selected from (i) or (ii) below: (i) R⁹ is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or (ii) two (R⁹)s together with the atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl; and R³⁰ is para-substituted halo.

[0016] Such compounds can bind to one or more proteins with high affinity and modulate their activity. Typically such compounds exhibit an EC₅₀ or IC ₅₀ of less than 1 μM, and in certain embodiments, less than about 0.5 μM, 250 nM, 100 nM or 50 nM. In one aspect, the compounds provided herein are selective for a specific chaperone protein, i.e. are at least 10, or in another aspect, at least 100 times more potent, as measured by any of the in vitro assays described herein, in binding to the desired protein compared to any other protein. In one aspect the compounds provided herein are selective for PDEδ.

[0017] Also of interest are any pharmaceutically acceptable derivatives of the compounds disclosed herein, including without limitation salts, esters, enol ethers, enol esters, solvates, hydrates, polymorphs and prodrugs of the compounds described. [0018j In another embodiment are methods of using the disclosed compounds and compositions, or pharmaceutically acceptable derivatives thereof, for the local or systemic treatment or prophylaxis of human and veterinary diseases, disorders and conditions modulated or otherwise affected mediated via the pleiotropic effects of a statin. In one aspect such diseases or disorders are modulated or mediated by PDEδ activity, or binding.

[0019] Also provided are pharmaceutical compositions formulated for administration by an appropriate route and means containing effective concentrations of one or more of the compounds provided herein, or pharmaceutically acceptable derivatives thereof, and comprising at least one pharmaceutical carrier, vehicle, binder, diluent, disintegrating agent, lubricant, glidant, sweetening agent or flavoring agent.

[0020] Such pharmaceutical compositions deliver amounts effective for the treatment, prevention, or amelioration of one or more symptoms of diseases or disorders that are modulated or otherwise affected via the pieiotropic effects of one or more statins. Such diseases or disorders include without limitation: [0021] 1) Diseases or disorders related to cellular proliferation and cancer, including the inhibition of tumor invasion (Green et al. Oncologist. (2004) 9 Suppl. 4:3-13; Woodward et al., Anticancer Drugs. (2.005) Jan;16(1):11-9), enhancement of radiation mediated therapies (Martin et al., Clin. Cancer Res. (2004) Aug 15; 10(16):5447-54), inhibition of cancer growth; cancers associated with mutant ras including without limitation, pancreatic, colon, bladder, thyroid tumors prostrate cancer, benign prostatic hyperplasia, ovarian cancer, endometrial cancer, breast cancer, leukemia and lymphoma (J. L. Bos, Cancer Res., (1989) 49:4682; US Patent No. 6,861 ,445; Segawa et al., Leuk. Res. (2005) Apr; 29(4):451-457).

[0022] 2) Diseases or disorders relating to diabetes, including hyperglycemia, insulin resistance, metabolic syndrome and vascular complications of diabetes (US Patent No. 6,057,108);

[0023] 3) Diseases or disorders relating to cardiovascular disease, atherosclerosis hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, and dyslipidemia, (US Patent No. 6,128,410, US Patent No. 6,057,108); [0024] 4) Inflammatory diseases or disorders related to immune dysfunction, including, immunodeficiency, immunomodulation, autoimmune diseases, tissue rejection, wound healing, kidney disease, allergies, inflammatory bowel disease, Lupus Erythematosis, arthritis, osteoarthritis, rheumatoid arthritis, asthma and rhinitis (Shah et al., Adv. Chronic. Kidney Dis. (2005) 12 (2):187-95; US Patent No. 6,128,410). [0025] 5) Diseases or disorders related to neurodegeneration and /or neuroprotection, including preventing, or reducing the effects of oxidative stress, improving neuronal survival, axon growth, dementia, regeneration and /or neuroprotection, including glaucoma, Parkinson's disease, multiple sclerosis, Alzheimer's disease (Cordle et al., J Neurosci. (2005) Jan 12;25(2):299-3077), human immunodeficiency virus (HIV) dementia, and prion diseases, (Am. J.

Geriatr. Cardiol. (2004) 13 (3 Supp 1):25-28; US Patent No. 6,855,688).

[0026] 6) Disease or disorders related to heart disease, including ischemic heart disease, heart failure, systolic impairment, diastolic impairment, myocardial necrosis, pulmonary venous congestion, atrial fibrillation, myocardial infarction, acute coronary syndrome (e.g., unstable angina, non-ST-elevation myocardial infarction (NSTEMI) or ST-elevation myocardial infarction

(STEMI)); myocardial fibrosis, chronic heart failure and for decreasing risk of a second myocardial infarction, (Takemoto et al., J. Clin. Invest. (2001) 108 (10): 1429-37);

[0027] 7) Diseases or disorders related to bone growth, the inhibition of bone resorption and osteoporosis, (Hatzigeargiou and Jackson Osteoporosis Int. (2005) 13:234-246; US Patent

Publication No. 20040106675);

[0028] 8) Diseases or disorders related to photo transduction, visual impairment, macular degeneration diseases, and retinitis pigmentosa;

[0029] 9) Disease or disorders related to stroke including for example, ischemic stroke (e.g., carotid and cardiogenic strokes) transient ischemic attack (TIA), hemorrhagic stroke, and ischemic reperfusion injury resulting from reintroduction of blood flow following cerebral ischemia or ischemic stroke (US Patent Publication No. 20040259880, and commonly owned

US patent application No. 10/989,995).

[0030] Also provided are methods of modulating the activity, or subcellular distribution, of prenylated proteins (or PDEδ interacting proteins) in a cell, tissue or whole organism, using the compounds and compositions provided herein, or pharmaceutically acceptable derivatives thereof.

[0031] Such methods also include methods of modulating endothelial function, cellular growth, apoptosis, immune function, blood coagulation, oxidative stress, neuronal survival, as well as, virus infection, replication and survival.

[0032] Also contemplated herein are combination therapies using one or more compounds or compositions provided herein, or pharmaceutically acceptable derivatives thereof, in combination with other pharmaceutically active agents for the treatment of the diseases and disorders described herein. [0033] In one embodiment, such additional pharmaceutical agents include one or more of the following; anti-cancer agents, anti-coagulants, anti-inflammatory agents, lipid-modulating agents, and glucose lowering agents.

[0034] The compound or composition provided herein, or pharmaceutically acceptable derivative thereof, may be administered simultaneously with, prior to, or after administration of one or more of the above agents. Pharmaceutical compositions containing a compound provided herein and one or more of the above agents are also provided.

[0035] In practicing the methods, effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds, which are formulated for systemic delivery, including parenteral, oral, or intravenous delivery, or for local or topical application are administered to an individual exhibiting the symptoms of the disease or disorder to be treated. The amounts are effective to ameliorate or eliminate one or more symptoms of the diseases or disorders. [0036] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use of sale for human administration. The pack or kit can be labeled with information regarding mode of administration, sequence of drug administration (e.g., separately, sequentially or concurrently), or the like.

[0037] DETAILED DESCRIPTION OF THE INVENTION

[0038] A. DEFINITIONS

[0039] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0040] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (or isopropyl), n-butyl, n-pentyl, 1 ,1-dimethylethyl (f-butyl), and the like.

[0041] "Alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1 ,4-dienyl, and the like. [0042] "Alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a triple bond, e.g., ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-3-ynyl and the like. [0043] "Alkylene" and "alkylene chain" refer to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having from one to eight carbon atoms, e.g., methylene, ethylene, propylene, n-butylene and the like. The alkylene chain may be attached to the rest of the molecule through any two carbons within the chain. "^■"

chain" refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to eight carbon atoms, wherein the unsaturation is present only as double bonds and wherein the double bond can exist between any two carbon atoms in the chain, e.g., ethenylene, prop-1-enylene, but-2-enylene and the like. The alkenylene chain may be attached to the rest of the molecule through any two carbons within the chain.

[0045] "Alkoxy" refers to the radical having the formula -OR wherein R is alkyl or haloalkyl. An "optionally substituted alkoxy" refers to the radical having the formula -OR wherein R is an optionally substituted alkyl as defined herein. Some examples of alkoxy groups are methoxy (where R is methyl) and ethoxy (where R is ethyl).

[0046] "Alkynylene" or "alkynylene chain" refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to eight carbon atoms, wherein the unsaturation is present only as triple bonds and wherein the triple bond can exist between any two carbon atoms in the chain, e.g., ethynylene, prop-1-ynylene, but-2-ynylene, pent-1-ynylene, pent-3-ynylene and the like. The alkynylene chain may be attached to the rest of the molecule through any two carbons within the chain. [0047] "Amino" refers to a radical having the formula -NR'R" wherein R' and R" are each independently hydrogen, alkyl or haloalkyl. An "optionally substituted amino" refers to a radical having the formula -NR'R" wherein one or both of R' and R" are optionally substituted alkyl as defined herein.

[0048] "Angiotensin converting enzyme inhibitors" or "ACE inhibitors" refers to factors that act to decrease the conversion of angiotensin I to angiotensin II. A representative group of ACE inhibitors includes the following compounds: AB-103, ancovenin, benazeprilat, BRL-36378, BW- A575C, CGS-13928C, CL-242817, CV-5975, Equaten, EU-4865, EU-4867, EU-5476, foroxymithine, FPL 66564, FR-900456, Hoe-065, I5B2, indolapril, ketomethylureas, KRI-1177, KRI-1230, L-681176, libenzapril, MCD, MDL-27088, MDL-27467A, moveltipril, MS-41 , nicotianamine, pentopril, phenacein, pivopril, rentiapril, RG-5975, RG-6134, RG-6207, RGH- 0399, ROO-911, RS-10085-197, RS-2039, RS 5139, RS 86127, RU-44403, S-8308, SA-291 , spiraprilat, SQ-26900, SQ-28084, SQ-28370, SQ-28940, SQ-31440, Synecor, utibapril, WF- 10129, Wy-44221 , Wy-44655, Y-23785, Yissum P-0154, zabicipril, Asahi Brewery AB-47, alatriopril, BMS 182657, Asahi Chemical C-111 , Asahi Chemical C-112, Dainippon DU-1777, mixanpril, Prentyl, zofenoprilat, 1-(-(1-carboxy-6-(4-piperidinyl)hexyl)amino)-1-oxopropyl octahydro-1H-indole-2-carboxylic acid, Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL- 66564, idrapril, Marion Merrell Dow MDL-100240, perindoprilat and Servier S-5590, alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat and spirapril. A group of ACE inhibitors of high interest includes the following compounds: alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, tosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat and spirapril.

[0049] "Angiotensin Il blockers" or "AT1 antagonists" refers to factors that act to reduce the binding of angiotensin Il to the Angiotensin Il receptor. A group of AT1 antagonists of high interest includes the following compounds: Atacand (candesartan cilexetil), Avapro (irbesartan), Cozaar (losartan), Diovan (valsartan), Micardis (telmisartan), and Teveten (eprosartan mesylate). [0050]

"Anti-cancer agents" refers to anti-metabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel, docetaxel), alkylating agents (e.g., cyclophosphamide, melphalan, carmustine, nitrosoureas such as bischloroethylnitrosurea and hydroxyurea), platinum agents

(e.g. cisplatin, carboplatin, oxaliplatin, JM-216, CI-973), anthracyclines (e.g., doxrubicin, daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase inhibitors (e.g., etoposide, camptothecins) or any other cytotoxic agents, (estramustine phosphate, prednimustine), hormones or hormone agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors, and radiation treatment. [0051] "Anticoagulants" refers to factors that act to reduce the clotting ability of blood. Examples available in the US include without limitation the brand names: Coumadin (warfarin), and Miradon (anisinidione).

[0052] "Anti-inflammatory agents" refers to matrix metalloproteinase inhibitors, inhibitors of pro-inflammatory cytokines (e.g., anti-TNF molecules, TNF soluble receptors, and IL1) nonsteroidal anti-inflammatory drugs (NSAIDs) such as prostaglandin synthase inhibitors (e.g., choline magnesium salicylate, salicylsalicyclic acid), COX-1 or COX-2 inhibitors), or glucocorticoid receptor agonists such as corticosteroids, methylprednisone, prednisone, or cortisone.

[0053] "Aryl" refers to a radical of carbocylic ring system wherein at least one of the rings is aromatic. The aryl may be fully aromatic, examples of which are phenyl, naphthyl, anthracenyl, acenaphthylenyl, azulenyl, fluorenyl, indenyl and pyrenyl. The aryl may also contain an aromatic ring in combination with a non-aromatic ring, examples of which are acenaphene, indene, and fluorene.

[0054] "Aralkyl" refers to a radical of the formula -R_aR_b where R_a is an alkyl radical as defined above, substituted by R_b, an aryl radical, as defined above, e.g., benzyl. Both the alkyl and aryl radicals may be optionally substituted as defined herein. [0055] "Aralkoxy" refers to a radical of the formula -OR_aR_b where -R_aR_b is an aralkyl radical as defined above. Both the alkyl and aryl radicals may be optionally substituted as defined herein. [0056] "Cardiovascular diseases" can be recognized and understood by physicians practicing in the relevant fields of medicine, and include without limitation, restenosis, coronary heart disease (also known as coronary artery heart disease or ischemic heart disease), cerebrovascular disease including ischemic stroke, multi-infarct dementia, and peripheral vessel disease, including intermittent claudication, and erectile dysfunction. Atherosclerosis refers to process whereby atherosclerotic plaques form within the inner lining of the artery wall leading to atherosclerotic cardiovascular diseases.

[0057] "Cycloalkyl" refers to a stable monovalent monocyclic or bicyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms, and which is saturated and attached to the rest of the molecule by a single bond, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norbornane, norbornene, adamantyl, bicyclo[2.2.2]octane and the like.

[0058] "Cycloalkylalkyl" refers to a radical of the formula -R_aR_d where R_a is an alkyl radical as defined above and R_d is a cycloalkyl radical as defined above. The alkyl radical and the cylcoalkyl radical may be optionally substituted as defined herein.

[0059] "Diuretics" refers to factors that act to reduce blood pressure by reducing the amount of sodium and water in the body. Diuretics include, thiazide diuretics, potassium-sparing diuretics and loop-acting diuretics. Examples of thiazide diuretics of high interest include the following compounds: Aquatensen (methyclothiazide), Diucardin (hydroflumethiazide), Diulo (metolazone), Diuril (chlorothiazide), Enduron (methyclothiazide), Esidrix (hydrochlorothiazide), Hydro-chlor (hydrochlorothiazide), Hydro-D (hydrochlorothiazide), HydroDIURIL (hydrochlorothiazide), Hydromox (quinethazone), Hygroton (chlorthalidone), Metahydrin (trichlormethiazide), Microzide (hydrochlorothiazide), Mykrox (metolazone), Naqua (trichlormethiazide), Naturetin (bendroflumethiazide), Oretic (hydrochlorothiazide), Renese (polythiazide), Saluron (hydroflumethiazide), Thalitone (chlorthalidone), Trichlorex (trichlormethiazide), and Zaroxolyn (metolazone). Examples of potassium-sparing diuretics of high interest includes the following compounds: Aldactone (spironolactone), Eplerenone, Dyrenium (triamterene), and Midamor (amiloride). Examples of loop-acting diuretics of high interest includes the following compounds: Bumex (bumetanide), Demadex (torsemide), Edecrin (ethacrynic acid), Lasix (furosemide), and Myrosemide (furosemide).

[0060] "Dyslipidemia" refers to abnormal levels of lipoproteins in blood plasma including both depressed and/or elevated levels of lipoproteins (e.g., elevated levels of Low Density Lipoprotein, (LDL), Very Low Density Lipoprotein (VLDL) and depressed levels of High Density Lipoprotein (HDL). [0061] "EC₅₀" refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound. [0062] "Endothelin blockers" refers to factors that act to reduce the action of endothelin at the endothelin ET_A or ET_B endothelin receptors. Examples include without limitation, Bosentan Acetelion (Roche), Ro-61-0612 (Roche), SB217242, SB247083, Enrasentan, (SmithKline Beecham Pharmaceuticals),TBC-11251 (Texas Biotechnology Corp., Houston, Tx), BMS187308 (Bristol-Myers Squibb Company, Princeton, NJ), PD-145065 (Parke-Davis & Co.), TAK-044 (Takeda), Tarasentan (Abbott), ZD-1611 (Zeneca Group pic) and J-104132 (Banyu Pharmaceutical Co. Ltd).

[0063] "Glucose lowering agents" refers to factors that act to reduce, or help control plasma glucose levels in, for example, diabetes, insulin insensitivity or hyperglycemia. Examples include, sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone); dehydroepiandrosterone (also referred to as DHEA or its conjugated sulphate ester, DHEA- SO₄); antiglucocorticoids; TNFα-inhibitors; α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose), pramlintide (a synthetic analog of the human hormone amylin), other insulin secretogogues (such as repaglinide, gliquidone, and nateglinide) and insulin. [0064] "Halo", "halogen" or "halide" refers to F, Cl, Br or I.

[0065] "Haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but^" are not limited to, chloromethyl, trifluoromethyl and 1-chloro-2-fluoroethyl.

[0066] "Haloalkenyl" refers to an alkenyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, 1-chloro-2-fluoroethenyl. [0067] "Heart disease" or "cardiac disease" refers to all forms of ischaemic heart disease, heart failure, systolic impairment, diastolic impairment, myocardial necrosis, pulmonary venous congestion, atrial fibrillation, myocardial infarction, myocardial fibrosis and chronic heart failure. [0068] "Heterocyclyl" refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heterocyclic ring system radical may be a monocyclic, bicyclic or tricyclic ring or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen or sulfur atoms in the heterocyclic ring system radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated or aromatic. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic radicals include, but are not limited to: acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzisoxazinyl, benzo[4,6]imidazo[1 ,2-a]pyridinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzofuranyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, Denzotniopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromanyl, chromonyl, cinnolinyl, coumariny!, decahydroisoquinolinyl, dibenzofuranyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydropyranyl, dioxolanyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1 ,4-dithianyl, furanonyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazopyridinyl, imidazothiazolyl, indazolyl, indolinyl, indolizinyl, indolyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, isochromanyl, isocoumarinyl, isolndolinyl, isoindolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroindolyl, octahydroisoindolyl, oxadiazolyl, oxazolidinonyl, oxazolidinyl, oxazolopyridinyl, oxazolyl, oxiranyl, perimidinyl, phenanthridinyl, phenathrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuryl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, tetrazolyl, thiadiazolopyrimidinyl, thiadiazolyl, thiamorpholinyl, thiazolidinyl, thiazolyl, thiophenyl, triazinyl, triazolyl and 1 ,3,5-trithianyl. [0069] "Heteroaralkyl" refers to a radical of the formula -R_aR_f where R₃ is an alkyl radical as defined above and R_f is a heteroaryl radical as defined herein. The alkyl radical and the heteroaryl radical may be optionally substituted as defined herein. [0070] "Heteroaralkoxy" refers to a radical of the formula -OR₃R_f where -R₃R_f is a heteroaralkyl radical as defined above. The alkyl radical and the heteroaryl radical may be optionally substituted as defined herein.

[0071] "Heteroaryl" refers to a heterocyclyl radical as defined above which is aromatic. The heteroaryl radical may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heteroaryl radicals include, but are not limited to: acridinyl, benzimidazolyl, benzindolyl, benzisoxazinyl, benzo[4,6]imidazo[1 ,2-a]pyridinyl, benzofuranyl, benzonaphthofuranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, β-carbolinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, imidazolyl, imidazopyridinyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isobenzothienyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, naphthyridinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxazolopyridinyl, oxazolyl, oxiranyl, perimidinyl, phenanthridinyl, phenathrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, triazinyl and triazolyl. [0072] "Heterocyclylalkyl" refers to a radical of the formula -R_aR_e wherein R₃ is an alkyl radical as defined above and R_e is a heterocyclyl radical as defined herein. The alkyl radical and the heterocydyl radical may be optionally substituted as defined herein. [0073] "Heterocyclylalkoxy" refers to a radical of the formula -OR_aR_e wherein -R_aR_e is a heterocyclylalkyl radical as defined above. The alkyl radical and the heterocyclyl radical may be optionally substituted as defined herein.

[0074] "Hyperlipidemia" refers to the presence of an abnormally elevated level of lipids in the blood. Hyperlipidemia can appear in at least three forms: (1) hypercholesterolemia, i.e., an elevated LDL cholesterol level above normal (2) hypertriglyceridemia, i.e., an elevated triglyceride level above normal and (3) combined hyperlipidemia, i.e., a combination of hypercholesterolemia and hypertriglyceridemia.

[0075] "Lipid-modulating agents" refer to factors that act to reduce cholesterol (LDL cholesterol, total cholesterol, or HDL cholesterol) and / or trigylceride levels in the plasma. Examples include without limitation: HMG-CoA reductase inhibitors (including statins such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and rivastatin), bile acid sequestrants (resins), nicotinic acid (niacin) and fibric acid derivatives (fibrates). [0076] "Meta" as used in the claims refers to the position on the benzene ring that is meta with respect to the attachment point of the benzene moiety to the rest of the molecule. [0077] "Natriuretic peptides" refers to naturally occurring forms or analogs of natriuretic peptides that are activated in CHF as a result of ventricular and atrial wall stretch.

[0078] "Optionally substituted alkyl", "optionally substituted alkenyi" and "optionally substituted alkynyl" refer to alkyl radicals, alkenyi radicals and alkynyl radicals, respectively, that may be optionally substituted by one or more substituents independently selected from the group consisting of nitro, halo, azido, cyano, cycloalkyl, heteroaryl, heterocyclyl, -OR^X, -N(R^y)(R^z), -SR^X, -C(J)R^X, -C(J)OR", -C(J)N(R^y)(R²), -C(J)SR*, -S(O)_tR^w (where t is 1 or 2), -OC(J)R^X, -OC(J)OR^X, -OC(J)N(R^y)(R^z), -OC(J)SR^X, -N(R^X)C(J)R^X, -N(R^X)C(J)OR^X, -N(R^x)C(J)N(R^y)(R²), -N(R^X)C(J)SR^X, -Si(R^w)₃, -N(R^X)S(O)₂R^W, -N(R^x)S(O)₂N(R^y)(R^z), -S(O)₂N(R^y)(R^z), -P(O)(R^V)₂, -OP(O)(R^V)₂, -C(J)N(R^X)S(O)₂R^W, -C(J)N(R^X)N(R^X)S(O)₂R^W, -C(R^X)=N(OR^X), and -C(R^x)=NN(R^y)(R^z), wherein: [0079] R^x is hydrogen, alkyl, alkenyi, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

[0080] R^y and R^z are each independently hydrogen, alkyl, alkenyi, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or [0081] R^y and R^z, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl;

[0082] R^w is alkyl, alkenyi, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; [0083] R^v is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy,-OR^xor-N(R^y)(R^z); and J is O₁ NR^X or S. [0084] Unless stated otherwise specifically in the specification, it is understood that the substitution can occur on any carbon of the alkyl, alkenyl or alkynyl group. [0085] Optionally substituted aryl", "optionally substituted cycloalkyl", "optionally substituted heteroaryl" and "optionally substituted heterocyclyl" refers to aryl, cycloalkyl, heterocyclyl and heteroaryl radicals, respectively, that are optionally substituted by one or more substituents selected from the group consisting of nitro, halo, haloalkyl, haloalkenyl, azido, cyano, oxo, thioxo, imino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -R^U-OR^X, -R^u -N(R^y)(R^z), -R^u -SR^X, -R^u -C(J)R^X, -R^u -C(J)OR^X, -R^u -C(J)N(R^y)(R^z), -R^ϋ -C(J)SR^X, -R^u -S(O)_tR^w (where t is 1 or 2), -R^u -OC(J)R^X, -R^u -OC(J)OR^X, -R^u -OC(J)N(R^y)(R^z), -R^U-OC(J)SR^X, -R^u -N(R^X)C(J)R^X, -R^u -N(R^X)C(J)OR^X, -R^u -N(R^x)C(J)N(R^y)(R^z), - R^u -N(R^X)C(J)SR^X, -R^u -Si(R^w)₃, -R^u -N(R^X)S(O)₂R^W, -R^u -N(R^x)S(O)₂N(R^y)(R^z), -R^u -S(O)₂N(R^y)(R^z), -R^u -P(O)(R^V)₂₎ -R^u -OP(O)(R^V)₂, -R^U-C(J)N(R^X)S(O)₂R^W, -R^u -C(J)N(R^X)N(R^X)S(O)₂R^W, -R^u -C(R^X)=N(OR^X) and -R^u -C(R^x)=NN(R^y)(R^z), wherein: [0086] each R^uis independently alkylene or a direct bond;

[0087] each R^v is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy,-OR^xor-N(R^y)(R^z); [0088] R^w is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

[0089] each R^x is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

[0090] R^y and R^z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; [0091] R^y and R^z, together with the nitrogen atom to which they are attached, form a heterocycle or heteroaryl; and [0092] J is O, NR^X or S.

[0093] Unless stated otherwise specifically in the specification, it is understood that the substitution can occur on any atom of the cycloalkyl, heterocyclyl, aryl or heteroaryl group. [0094] "Oxo" refers to =0.

[0095] "Ortho" as used in the claims refers to the position on the benzene ring that is ortho to the attachment point of the benzene moiety to the rest of the molecule. [0096] "Para" as used in the claims refers to the position on the benzene ring that is para with resepect to the attachment point of the benzene moiety to the rest of the molecule. [0097] "Phosphodiesterase 6 delta", "PED65" or "PEDδ" refers to all mammalian isoforms, splice variants and polymorphisms of PEDδ. Representative forms include, without limitation human, (Gene Bank Accession Number, NP_002592; 043924), mouse (Gene Bank Accession Number 055057), rat and bovine. [0098] "Pharmaceutically acceptable derivatives" of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization. The compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to Λ/,Λ/'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, /V-methylglucamine, procaine, /V-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal

- salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates,. valerates and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of formula C=C(OR) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of formula C=C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules. [0099] "Polymorph" refers to the different crystal forms of a compound, resulting from the possibility of at least two different arrangements of the molecules of the compound in the solid state. Polymorphs of a given compound will be different in crystal structure but identical in liquid or vapor states. Different polymorphic forms of a given substance may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, crystal shape, compaction behavior, flow properties, and/or solid state stability. [00100] "Prenyl transport proteins" refers to a protein that is capable of binding to a prenylated protein and mediating the translocation of that protein from the plasma membrane to the cytosol. Preferred prenyl transport proteins include PEDδ. [00101] "Prenyl transport protein interacting protein" refers to a protein that binds to a prenyl transport protein. Typically, but not exclusively, such binding is mediated via the interaction of isoprenoid groups on the interacting protein with a hydrophobic pocket on the transport protein. Preferred prenyl transport proteins include members of the ras low molecular weight GTP binding protein super family.

[00102] "Prodrug" is a compound that, upon in vivo administration, is metabolized by one or more steps or processes or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes. The prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).

[00103] As used herein, "substantially pure" means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound.

[00104] "Renal disease" or "Kidney disease", or refers to diabetic nephropathy, chronic glomerulonephritis, polycystic kidney disease, non diabetic nephropathy and all forms of chronic kidney disease. "Chronic Kidney Disease" or "CKD" or "renal failure" or "kidney failure" is typically characterized based on glomerular filtration rate or GFR: Typically Chronic Kidney Disease is suggested when the GFR is 90 or less.

[00105] "Stroke" refers to the development of neurological deficits associated with impaired blood flow to the brain regardless of cause. [00106] "Sulfide" refers to the radical having the formula -SR wherein R is an alkyl or haloalkyl group. An "optionally substituted sulfide" refers to the radical having the formula -SR wherein R is an optionally substituted alkyl as defined herein.

[00107] "Vasodilators" refers to compounds that act to cause vasodilation of blood vessels thereby increasing blood flow. Vasodilators of high interest include the following compounds: IMDUR (isosorbide mononitrate), ISMO (isosorbide mononitrate), lsordil (isosorbide dinitrate), Monoket (isosorbide mononitrate), Nitro-Dur (nitroglycerin), Nitrolingual (nitroglycerin), Nitrostat (nitroglycerin), and Sorbitrate (isosorbide dinitrate).

[00108] Unless specifically stated otherwise, where a compound may assume alternative tautomeric, regioisomeric and/or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the present invention. For example, where a compound is described as having one of two tautomeric forms, it is intended that the both tautomers be encompassed within the scope of the present invention. [00109] Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. In the case of amino acid residues, such residues may be of either the L- or D-form. The configuration for naturally occurring amino acid residues is generally L. When not specified the residue is the L form. As used herein, the term "amino acid" refers to α-amino acids which are racemic, or of either the D- or L-configuration. The designation "d" preceding an amino acid designation (e.g., dAla, dSer, dVal, etc.) refers to the D-isomer of the amino acid. The designation "dl" preceding an amino acid designation (e.g., dlPip) refers to a mixture of the L- and D-isomers of the amino acid. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.

[00110] It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof.

[00111] Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC.

[00112] Where the number of any given substituent is not specified (e.g., haloalkyl), there may be one or more substituents present. For example, "haloalkyl" may include one or more of the same or different halogens. [00113] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, Biochem. 1972, -/7:942-944).

[00114] B. FORMULATION OF PHARMACEUTICAL COMPOSITIONS

[00115] The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of the compounds or compositions, or pharmaceutically acceptable "defiVaWeS^''th'efebf,"prdv]^'cleci Fϊerein that are useful in the prevention, treatment, or amelioration of human and veterinary diseases, disorders and conditions affected by the pleiotropic actions of statins, and in one aspect atorvastatin. The compounds, compositions, or pharmaceutically acceptable derivatives thereof are preferably formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers. Typically the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 126; Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975). [00116] In the pharmaceutical compositions, effective concentrations of one or more compounds or pharmaceutically acceptable derivatives thereof is (are) mixed with at least one suitable pharmaceutical carrier, vehicle, diluent, or solvent. Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. The contemplated compositions may contain 0.001 %-100% active ingredient, preferably 0.1-85%, typically 75-95%. In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. [00117] The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The therapeutically effective concentration may be determined empirically by testing the compounds using in vitro and in vivo systems described herein and in International Patent Application Publication Nos. 99/27365 and 00/25134 and then extrapolated therefrom for dosages for humans.

[00118] The concentration of active compound in the pharmaceutical composition will depend on absorption, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of diseases or disorders associated with nuclear receptor activity or in which nuclear receptor activity is implicated, as described herein.

[00119] Typically a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/ml to about 50-100 μg/ml. The pharmaceutical compositions typically should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg and preferably from about 10 to about 500' mg'OπiiS essential active ingredient or a combination of essential ingredients per dosage unit form.

[00120] The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time by a suitable route, including orally, parenterally, rectally, topically and locally. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions. [00121] In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using co-solvents, such as dimethylsulfoxide (DMSO)₁ using surfactants, such as TWEEN®, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions. [00122] Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined. [00123] The pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof. The pharmaceutically therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms as used herein refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampoules and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit-doses that are not segregated in packaging.

[00124] Compositions for oral administration [00125] Oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric-coated, sugar-coated or film-coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.

[00126] In certain embodiments, the formulations are solid dosage forms, preferably capsules or tablets. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agenf; and a flavoring agent. [00127] Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, celluloses, polyvinyl . pyrrolidone, povidone, crospovidones, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol, carboxymethylcellulose and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited^'to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. [00128] In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. If oral administration is desired, the compound could be provided in a composition that protects it from the acidic environment of the stomach. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate. Emetic-coatings also include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. The composition may also be formulated in combination with an antacid or other such ingredient. [00129] When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

[00130] The active ingredient can also be mixed with other materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound or pharmaceutically acceptable derivative thereof as described herein.

[00131] Sugar-coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are applied. Film-coated tablets are compressed

- tablets which have been coated with a polymer or other suitable coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned.

[00132] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

[00133] Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms. [00134] Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water-soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation. [00135] For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration. [00136] Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include those set forth in U.S. Patent Nos. Re 28,819 and 4,358,603. Briefly, such formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly- alkylene glycol, including, but not limited to, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[00137] Other formulations include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal. Alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.

[00138] Injectables, solutions and emulsions

[00139] Parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.

[00140] In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. [00141] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof. [00142] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.

— [00143] Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment. [00144] The concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art. [00145] The unit-dose parenteral preparations are packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art. [00146] The compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective „ concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined.

[00147] Lyophilized powders [00148] Of interest herein are also lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels.

[00149] The sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent. The solvent may contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Generally, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dosage (10-1000 mg, preferably 100-500 mg) or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4 ⁰C to room temperature.

[00150] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, about 1-50 mg, preferably 5- 35 mg, more preferably about 9-30 mg of lyophilized powder, is added per mL of sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such amount can be empirically determined.

[00151] Topical administration

[00152] Topical mixtures are prepared as described for the local and systemic administration.

The resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.

[00153] The compounds or pharmaceutically acceptable derivatives thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. in such a case, the particles of the formulation will typically have diameters of less than 50 microns, preferably less than 10 microns.

[00154] The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered. [00155] These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% - 10% isotonic solutions, pH about 5-7, with appropriate salts.

[00156] Sustained Release Formulations

[00157] Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained (see, e.g., U.S. Patent No^~ 3,710,795) is also contemplated herein. Briefly, a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.

[00158] Compositions for other routes of administration

[00159] Other routes of administration, such as transdermal patches, ophthalmic solutions, and rectal administration are also contemplated herein.

[00160] Transdermal patches, including iotophoretic and electrophoretic devices, are well known to those of skill in the art. For example, such patches are disclosed in U.S. Patent Nos. 6,267,983, 6,261 ,595, 6,256,533, 6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433, and 5,860,957.

[00161] Pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2 to 3 gm. [00162] Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.

[00163] Ophthalmic formulations comprising eye drops, eye ointments,, powders, and solutions are also contemplated as being within the scope of the present invention.

[00164] Targeted Formulations

[00165] The compounds provided herein, or pharmaceutically acceptable derivatives thereof, may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non-limiting examples of targeting methods, see, e.g., U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874. [00166] In one embodiment, liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Patent No. 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLVs) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS. [00167] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use of sale for human administration. The pack or kit can be labeled with information regarding mode of administration, sequence of drug administration (e.g., separately, sequentially or concurrently), or the like. The pack or kit may also include means for reminding the patient to take the therapy. The pack or kit can be a single unit dosage of the combination therapy or it can be a plurality of unit dosages. In particular, the agents can be separated, mixed together in any combination, present in a single vial or tablet. Agents assembled in a blister pack or other dispensing means is preferred. For the purpose of this invention, unit dosage is intended to mean a dosage that is dependent on the individual pharmacodynamics of each agent and administered in FDA approved dosages in standard time courses.

[00168] C. EVALUATION OF THE ACTIVITY OF THE COMPOUNDS

[00169] Standard physiological, pharmacological and biochemical procedures are available for testing the compounds to identify those that possess biological activities that selectively modulate the activity of enzymes, and specifically PDEδ.

[00170] Such assays include, for example, biochemical assays such as binding assays, fluorescence polarization assays, fluorescence resonance energy transfer (FRET) based assays (see generally Glickman et al., J. Biomolecular Screening, 7 No. 1 3-10 (2002)), as well as a variety of cell based assays. [00171] High throughput screening systems are commercially available (see, e.g., Zymark Corp., Hopkinton, MA; Air Technical Industries, Mentor, OH; Beckman Instruments Inc., Fullerton, CA; Precision Systems, Inc., Natick, MA) that enable these assays to be run in a high throughput mode. These systems typically automate entire procedures, including all sample and reagent pipetting, liquid dispensing, timed incubations, and final readings of the microplate in detector(s) appropriate for the assay. These configurable systems provide high throughput and rapid start up as well as a high degree of flexibility and customization. The manufacturers of such systems provide detailed protocols for various high throughput systems. Thus, for example, Zymark Corp. provides technical bulletins describing screening systems for detecting the modulation of gene transcription, ligand binding, and the like. [00172] Assays that do not require washing or liquid separation steps are preferred for such high throughput screening systems and include biochemical assays such as fluorescence polarization assays (see for example, Owicki, J., Biomol Screen 2000 Oct;5(5):297) scintillation proximity assays (SPA) (see for example, Carpenter et a/., Methods MoI Biol 2002; 190:31-49) and FRET or time resolved FRET assays (Mukherjee et a/., J Steroid Biochem MoI Biol 2002 Jul;81(3):217-25; (Zhou et a/., MoI Endocrinol. 1998 Oct;12(10):1594-604). Generally such assays can be performed using either the full length PDEδ protein, or fragment thereof. [00173] If a fluorescently labeled ligand is available, fluorescence polarization assays provide a way of detecting binding of compounds to the protein of interest by measuring changes in fluorescence polarization that occur as a result of the displacement of a trace amount of the label ligand by the compound. Additionally this approach can also be used to monitor the ligand dependent association of a fluorescently labeled protein that is bound to PDEδ. [00174] The ability of a compound to bind to a protein of interest, can also be measured in a homogeneous assay format by assessing the degree to which the compound can compete off a radiolabeled ligand with known affinity for the protein using a scintillation proximity assay (SPA). In this approach, the radioactivity emitted by a radiolabeled compound (for example ³H- Atorvastatin) generates an optical signal when it is brought into close proximity to a scintillant such as a Ysi-copper containing bead, to which the protein of interest (PDEδ or the like) is bound. If the radiolabeled compound is displaced from the protein the amount of light emitted from the protein bound scintillant decreases, and this can be readily detected using standard microplate liquid scintillation plate readers such as, for example, a Wallac MicroBeta reader. [00175] The ability of a compound to effect a ligand dependent interaction of a PDEδ binding protein can also be assessed by fluorescence resonance energy transfer (FRET), or time resolved FRET, in order to characterize the effect of the compounds disclosed herein on the PDEδ protein interaction. Both approaches rely upon the fact that energy transfer from a donor molecule to an acceptor molecule only occurs when donor and acceptor are in close proximity. Typically the assay in this case involves the use a recombinant Glutathione-S-transferase (GST)- fusion protein and a synthetic biotinylated peptide sequenced derived from the receptor interacting domain of a PDEδ binding protein, for example derived from a low molecular weight GTP binding protein. Typically the GST-PDEδ is labeled with a europium chelate (donor) via a europium-tagged anti-GST antibody, and the interacting peptide is labeled with allophycocyanin via a streptavidin-biotin linkage. [00176] In the absence of an inhibitory compound the peptide is recruited to the GST-PDEδ bringing europium and allophycocyanin into close proximity to enable energy transfer from the europium chelate to the allophycocyanin. Upon excitation of the complex with light at 340 nm excitation energy absorbed by the europium chelate is transmitted to the allophycocyanin moiety resulting in emission at 665 nm. If the europium chelate is not brought in to close proximity to the allophycocyanin moiety there is little or no energy transfer and excitation of the europium chelate results in emission at 615 nm. Thus the intensity of light emitted at 665 nm gives an indication of the strength of the protein-protein interaction. The activity of a compound of interest to disrupt this interaction can thus be measured by determining the ability of a compound to competitively inhibit (i.e., IC₅₀) the binding activity of PDEδ. [00177] In addition a variety of cell based assay methodologies may be successfully used in screening assays to identify and profile the specificity of compounds of the present invention. [00178] Compound binding may also be determined using phage display of fusion proteins exposed on the outer surface of the phage head, for example using an affinity based phage display screening system as described in Fabian et al., (Nat Biotechnol. 2005 23(3):329-36). [00179] This approach employs an atorvastatin based competition binding assay to determine the relative affinity of a compound of interest to a protein expressed as a fusion protein on the surface of the T7 bacteriophage. In the case of PDEδ, the assay uses phage tagged PDEδ and immobilized atorvastatin which are combined with the compound to be tested. If the test compound binds to PDEδ and directly or indirectly occludes the atorvastatin binding site, it competes with the immobilized atorvastatin binding site and prevents the binding of the tagged PDEδ to the solid support. If the compound does not bind PDEδ, the tagged protein can bind to the solid support throuαh the interaction between the PDEδ and the immobilized atorvastatin based ligand. The results can be read out by quantifying the amount of fusion protein bound to the solid support, which can be accomplished by quantitative PCR (QPCR) using the phage genome as a template.

[00180] D. METHODS OF USE OF THE COMPOUNDS AND COMPOSITIONS

[00181] Also provided herein are methods of using the disclosed compounds and compositions, or pharmaceutically acceptable derivatives thereof, for the treatment, prevention, or amelioration of one or more symptoms of diseases or disorders that are modulated or otherwise affected via the pleiotropic effects of one or more statins. Such diseases or disorders include without limitation: [00182] 1) Diseases or disorders related to cellular proliferation and cancer, including the inhibition of tumor invasion (Green et al. Oncologist. (2004); 9 Suppl. 4:3-13; Woodward et al., Anticancer Drugs. (2005) 16 (1):11-9), enhancement of radiation mediated therapies (Martin et al., Clin. Cancer Res. (2004) IJ) (16):5447-54), inhibition of cancer growth. Cancers associated with mutant ras including without limitation, pancreatic, colon, bladder, thyroid tumors prostrate cancer, benign prostatic hyperplasia, ovarian cancer, endometrial cancer, breast cancer, leukemia and lymphoma (J. L. Bos, Cancer Res., (1989), 49:4682; US Patent No. 6,861,445; Segawa et al., Leuk. Res. (2005) 29(4):451-457);

[00183] 2) Diseases or disorders relating to diabetes, including hyperglycemia, insulin resistance, metabolic syndrome and vascular complications of diabetes (US Patent No. 6,057,108); [00184] 3) Diseases or disorders relating to cardiovascular disease, atherosclerosis hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, and dyslipidemia, (US Patent No. 6,128,410, US Patent No. 6,057,108); [00185] 4) inflammatory diseases or disorders related to immune dysfunction, including, immunodeficiency, immunomodulation, autoimmune diseases, tissue rejection, wound healing, kidney disease, allergies, inflammatory bowel disease, Lupus Erythematosis, arthritis, osteoarthritis, rheumatoid arthritis, asthma and rhinitis (Shah et al., (2005) Adv. Chronic. Kidney Dis. 12 (2) 187-95; US Patent No. 6,128,410).

[00186] 5) Diseases or disorders related to neurodegeneration and /or neuroprotection, including preventing, or reducing the effects of oxidative stress, improving neuronal survival, axon growth, dementia, regeneration and /or neuroprotection, including glaucoma, Parkinson's disease, multiple sclerosis, Alzheimer's disease (Cordle et al., J Neurosci. (2005) 25 (2):299- 3077), human immunodeficiency virus (HIV) dementia, and prion diseases, (Am. J. Geriatr. Cardiol. (2004) 13 (3 Supp 1) 25-28; US Patent No. 6,855,688);

[00187] 6) Disease or disorders related to heart disease, including ischemic heart disease, heart failure, systolic impairment, diastolic impairment, myocardial necrosis, pulmonary venous congestion, atriar fibrillation, myocardial infarction, acute coronary syndrome (e.g., unstable angina, non-ST-elevation myocardial infarction (NSTEMI) or ST-elevation myocardial infarction (STEMI)); myocardial fibrosis, chronic heart failure and for decreasing risk of a second myocardial infarction, (Takemoto et al., (2001); J. Clin. Invest. 108 (10) 1429-37); [00188] 7) Diseases or disorders related to bone growth, the inhibition of bone resorption and osteoporosis, (Hatzigeargiou and Jackson Osteoporosis Int. (2005) 13 234-246; US Patent Publication No. 20040106675);

[00189] 8) Diseases or disorders related to photo transduction, visual impairment, macular degeneration diseases, and retinitis pigmentosa;

[00190] 9) Disease or disorders related to stroke including for example, ischemic stroke (e.g., carotid and cardiogenic strokes) transient ischemic attack (TIA), hemorrhagic stroke, and ischemic reperfusion injury resulting from reintroduction of blood flow following cerebral ischemia or ischemic stroke (US Patent Publication No. 20040259880, and commonly owned US patent application No. 10/989,995).

[00191] Also provided are methods of modulating the activity, or subcellular distribution, of prenylated proteins (or PDEδ interacting proteins) in a cell, tissue or whole organism, using the compounds and compositions provided herein, or pharmaceutically acceptable derivatives thereof.

[00192] The present invention also includes methods of modulating endothelial function, nitric oxide formation, cellular growth, apoptosis, immune function, blood coagulation, oxidative stress, neuronal survival, as well as, virus infection, replication and survival. [00193] In one embodiment, the invention also relates to methods of treatment for the prevention of stroke or to reduce the susceptibility to stroke (for example, for individuals in an at- risk population such as those described herein); and for patients requiring treatment (e.g., .angioplasty, stents, coronary artery bypass graft) to restore blood flow in arteries (e.g., coronary arteries) and peripheral arterial occlusive disease.

[00194] An individual at risk for stroke is an individual who has at least one risk factor, such as previous stroke or TIA, an at-risk haplotype in one or more stroke risk genes; diabetes; hypertension; hypercholesterolemia; elevated 1p(a); obesity; a past or current smoker; an elevated inflammatory marker (e.g., a marker such as C-reactive protein (CRP), serum amyloid A, fibrinogen, tissue necrosis factor-alpha, a soluble vascular cell adhesion molecule (sVCAM), a soluble intervascular adhesion molecule (slCAM), E-selectin, matrix metalloprotease type-1, matrix metalloprotease type-2, matrix metalloprotease type-3, and matrix metalloprotease type- 9); increased LDL cholesterol and/or decreased HDL cholesterol; and/or at least one previous myocardial infarction, concurrent Ml, acute coronary syndrome, stable angina, atherosclerosis, carotid stenosis, peripheral vascular occlusive disease, requires treatment for restoration of coronary artery blood flow (e.g., angioplasty, stent, coronary artery bypass graft). [00195] The compounds and pharmaceutically acceptable derivatives thereof of the present invention can be administered prior to ischemia to prevent, inhibit, or protect against ischemia reperfusion injury to the brain. In an alternative embodiment, a composition of the invention can be administered during or following ischemia (including during or following reperfusion) to alleviate or heal ischemia reperfusion injury of the brain.

[00196] E. COMBINATION THERAPY

[00197] Furthermore, it will be understood by those skilled in the art that the compounds, isomers, prodrugs and pharmaceutically acceptable derivatives thereof of the present invention, including pharmaceutical compositions and formulations containing these compounds, can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, also contemplated herein is the use of compounds, isomers, prodrugs and pharmaceutically acceptable derivatives of the present invention in combination with other active pharmaceutical agents for the treatment of the disease/conditions described herein. [00198] In one embodiment, such additional pharmaceutical agents include one or more of the following; ACE inhibitors, Angiotensin Il blockers, anti-cancer agents, anti-coagulants, anti- oxidants, anti-inflammatory agents, lipid-modulating agents, diuretics, glucose lowering agents, cytokine antagonists, endothelin blockers, and vasodilators.

[00199] The compound or composition provided herein, or pharmaceutically acceptable derivative thereof, may be administered simultaneously with, prior to, or after administration of one or more of the above agents. [00200] Pharmaceutical compositions containing a compound provided herein or pharmaceutically acceptable derivative thereof, and one or more of the above agents are also provided. [00201] Also provided is a combination therapy that treats or prevents the onset of the symptoms, or associated complications of cancer and related diseases and disorders comprising the administration to a subject in need thereof, of one of the compounds or compositions disclosed herein, or pharmaceutically acceptable derivatives thereof, with one or more anti-cancer agents.

[00202] Also provided is a combination therapy that treats or prevents the onset of the symptoms, or associated complications of diabetes and related diseases and disorders, comprising the administration to a subject in need thereof, of one of the compounds or compositions disclosed herein, or pharmaceutically acceptable derivatives thereof, with one or more of the following active agents, a glucose lower agent, an anti-oxidant, lipid-modulating agent, an anti-inflammatory agent and a diuretic.

[00203] Also provided is a combination therapy that treats or prevents the onset of the symptoms, or associated complications of cardiovascular disease and related diseases and disorders, comprising the administration to a subject in need thereof, of one of the compounds or compositions disclosed herein, or pharmaceutically acceptable derivatives thereof, with one or more of the following active agents, diuretics, glucose lower agents, lipid-modulating agents, anti-inflammatory agents and a vasodilators.

[00204] Also provided is a combination therapy that treats or prevents the onset of the symptoms, or associated complications of immune dysfunction and related diseases and disorders, comprising the administration to a subject in need thereof, of one of the compounds or compositions disclosed herein, or pharmaceutically acceptable derivatives thereof, with one or more of the following active agents, selected from the group consisting of anti-inflammatory agents, ACE inhibitors, Angiotensin Il blockers, endothelin blockers, and cytokine antagonists. [00205] Also provided is a combination therapy that treats or prevents the onset of the symptoms, or associated complications of neurodegeneration and related diseases and disorders, comprising the administration to a subject in need thereof, of one of the compounds or compositions disclosed herein, or pharmaceutically acceptable derivatives thereof, with one or more of the following active agents, selected from the group consisting of anti-inflammatory agents, anti-oxidants, nitric oxide synthase inhibitors, neuronal growth factors, and stem cells. [00206] Also provided is a combination therapy that treats or prevents the onset of the symptoms, or associated complications of heart disease and related diseases and disorders, comprising the administration to a subject in need thereof, of one of the compounds or compositions disclosed herein, or pharmaceutically acceptable derivatives thereof, with one or more of the following active agents, selected from the group consisting of diuretics, glucose lower agents, lipid-modulating agents, anti-inflammatory agents, vasodilators, ACE inhibitors, Angiotensin Il blockers, anti-coagulants, anti-oxidants, cytokine antagonists, endothelin blockers, and vasodilators [00207] Also provided is a combination therapy that treats or prevents the onset of the symptoms, or associated complications of kidney disease, comprising the administration to a subject in need thereof, of one of the compounds or compositions disclosed herein, or pharmaceutically acceptable derivatives thereof, with one or more of the following active agents selected from the group consisting of ACE inhibitors, anti-inflammatory agents, Angiotensin Il blockers, lipid-modulating agents, cytokine antagonists, calcium channel antagonists, diuretics, endothelin blockers, and a vasodilators.

[00208] Also provided is a combination therapy that treats or prevents the onset of the symptoms, or associated complications of stroke and related diseases and disorders, comprising the administration to a subject in need thereof, of one of the compounds or compositions disclosed herein, or pharmaceutically acceptable derivatives thereof, with one or more of the following active agents selected from the group consisting of, ACE inhibitors, Angiotensin Il blockers, anti-inflammatory agents, anti-coagulants, anti-arrhythmics, beta blockers, lipid-modulating agents, cytokine antagonists, diuretics, endothelin blockers, and vasodilators.

[00209] F. PREPARATION OF THE COMPOUNDS OF THE INVENTION

[00210] Starting materials in the synthesis examples provided herein are either available from commercial sources or via literature procedures (e.g., March Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (1992) 4th Ed.; Wiley Interscience, New York). All commercially available compounds were used without further purification unless otherwise indicated. CDCI₃ (99.8% D, Cambridge Isotope Laboratories) was used in all experiments as indicated. Proton (¹H) nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 400 MHz NMR spectrometer. Significant peaks are tabulated and typically include: number of protons, and multiplicity (s, singlet; d, double; t, triplet; q, quartet; m, multiplet; br s, broad singlet). Chemical shifts are reported as parts per million (δ) relative to tetramethylsilane. Low resolution mass spectra (MS) were obtained as electrospray ionization (ESI) mass spectra, which were recorded on a Shimadzu HPLC/MS instrument using reverse-phase conditions (acetonitrile/water, 0.05% acetic acid). HPLC was performed using Varian HPLC systems and columns. Flash chromatography was performed using Merck Silica Gel 60 (230-400 mesh) following standard protocol (Still et al. (1978) J. Org. Chem. 43:2923). [00211] It is understood that in the following description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds under standard conditions.

[00212] It will also be appreciated by those skilled in the art that in the process described below the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. SuitaDie protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., if- butyldimethylsilyl, f-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like.

Suitable protecting groups for mercapto include -C(O)-R (where R is alkyl, aryl or aralkyl), p- methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or aralkyl esters.

[00213] Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P. G. M. Wutz, Protective Groups in

Organic Synthesis (1991), 2nd Ed., Wiley-lnterscience. [00214] One of ordinary skill in the art could easily ascertain which choices for each substituent are possible for the reaction conditions of each Scheme. Moreover, the substituents are selected from components as indicated in the specification heretofore, and may be attached to starting materials, intermediates, and/or final products according to schemes known to those of ordinary skill in the art. [00215] General procedures for the creation of pyrroles are also described in the following references; Woo et al., J. Labelled. Cpd. Radiopharm. (1999) 42 135-145; US patent No.

5,385,929 entitled [(hydroxyphenylamino) carbonyl] pyrroles"; Pandey et al., Bioorg. Med.

Chem. Lett. (2004) 14 129-131 ; Roth et al., J. Med. Chem. (1991) 34 357-366; Sliskovic et al., J. Med. Chem. (1991) 34 367-373; Takaya et al. Org. Lett. (2001) 3(3) 421-424; Dieter & Wu Org. Lett. (2000) 2(15) 2283-2286; Braun et al., Org. Lett. (2001) 3 (21) 3297-3300, the contents of which are all specifically incorporated by reference.

[00216] Also it will be apparent that many of the products could exist as one or more isomers, that is E/Z isomers, enantiomers and/or diastereomers.

[00217] Compounds of formula (I) may be prepared as depicted in Scheme 1. In the following schemes, unless otherwise noted, the various substituents R¹- R⁶ are as defined in the

Summary of the Invention.

[00218] Scheme 1. General synthesis of compounds of formula (I).

(I)

[00219] In general, condensation of a suitably substituted diketone with a primary amine, H₂N-R², can be preformed under acidic conditions, in toluene or other solvents to yield a pyrrole of formula (I). [00220] Additionally further N-substituted pyrroles may be prepared by reaction of an appropriate diketone with an amine of general formula H₂N-(CH₂)_n L (where L is a leaving group such as methanesulfonate, trifluoromethane-sulfonate, p-toluenesulfonate, and the like, or a halogen atom such as chlorine, bromine or iodine, and n is 1 to 6). The resulting pyrrole can be further reacted with a variety of reagents to create further diversity at R² as shown, for example, in reaction scheme 4.

[00221] A variety of diketone intermediates are available commercially. Further diversity can be created via the synthesis of appropriately substituted diketones as described in Scheme 2 (See generally Woo et al., J. Label. Cpds. Radiopharm 42 135-145 (1999)).

[00222] Scheme 2. General synthesis of diketones.

1. Toluene J

R⁶ CHO

l. Hexanes

[00223] A primary amine NH₂R⁴, (where R⁴ is an optionally substituted alkyl, aryl or heteroaryl) can be reacted with a ketoester (where R³ is aryl, heteroaryl or alkyl) under basic conditions in toluene, to yield the corresponding amino diketone intermediate. This intermediate can be further reacted with a primary aldehyde (R⁶CHO, where R⁶ is an optionally substituted aryl or heteroaryl) in the presence of an appropriate amino acid to afford the respective unsaturated intermediate. This intermediate can then be converted into its corresponding diketone, by further reaction with a phenolic aldehyde under typical conditions such as, for example, by first reaction with Et₃N in ethanol, followed by treatment with an appropriate thiazolium halide.

[00224] Other pyrrole derivatives, (wherein R² = H, and R⁴ and R⁶ are, for example, optionally substituted alkyl, aryl, cycloalkyl or heteroaryl), may be synthesized as shown in Scheme 3 (Pandey et al., Bioorg. Med. Chem. Lett. (2000) 14 129-131). £00225] Scheme 3. Preparation of other pyrrole derivatives

DCC in toluene

Reflux

[00226] Thus, for example, a primary amine (R⁴NH₂) and an alkene carboxylic acid derivative can be reacted to yield the corresponding amino derivative (Ilia), which can be used in a Michael addition to create a pyrrole. The appropriate cyclic carbanion can be created as shown in scheme 3 by reacting commercially available amino acids, and their derivatives with appropriate acid chlorides, followed by treatment with base and intramolecular condensation to form the appropriate carbanion. This intermediate can then be reacted with the amino intermediate (Ilia) to create a benzyl pyrrole derivate, which can be subsequently reacted with sodium in liquid ammonia and t-butanol to cleave the N-benzyl N-cap creating intermediate

(Mb).

[00227] Further modifications at R² can subsequently be introduced by reaction of the free nitrogen of the pyrrole ring as outlined in scheme 4.

[00228] Scheme 4

[00229] Here L is as defined previously, L₂ is typically a halogen atom such as chlorine, bromine or iodine, or a leaving group such as OTs, OTf or the like, and W is O or S. The reactions may be carried out in a solvent such as THF, DMF, DMSO, DME, DMA and the like. The reaction can be carried out using an inert atmosphere, and typically in the presence of a base. Alkali metal hydrides such as NaH, KH, K₂CO₃ can be used whenever the solvent employed does not contain a protic group. The reaction may be carried out at a temperature in the range 0 C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours. (See generally US Application No. US2003-0199498 A1 , published Oct 23, 2003). [00230] Further pyrrole derivatives can also be formed using alternative scheme 5. Scheme 5

Rh₄(CO)₁₂ 8O C, 14 h Toluene

5 [00231] Products of formula (I) in which R³ is an ester or ester derivative may be prepared as depicted in Scheme 5. This reaction sequence has been described in previous literature (See Takaya et al., Organic Lett (2001) 3 (3) 421-424). Further diversity at R³, may then be accomplished using standard chemical modification of the resulting ester derivative. Additional — - modification of R², may also be achieved using the methodology described in scheme 4. 10

Additional pyrrole derivates may also be obtained using the reaction scheme 6.

[00234] First an appropriate sulfonylamide is reacted with an appropriate phenolic aldehyde

15 in toluene to create the intermediate (Via) which can subsequently be reacted with an appropriate ester derivative (VIb) to introduce ester derivatives of R⁵ into the pyrrole intermediate. Intermediate (VIb) is readily available from commercially available precursors, for example through the reaction of brominated amino acid derivatives with appropriate aldehydes using the Wittig reaction. As discussed previously, the resulting pyrroles may be used as

20 described in scheme 4, as well as other reactions, to create additional diversity around the pyrrole ring.

[00235] Alternatively, additional diversity may also introduced into the ester derivative via the use of alternative reaction scheme 7. (Roth et al., J. Med. Chem. (1991) 34 357-366) Scheme 7

[00236] Intermediates are readily available commercially or can be readily prepared form commercially available reagents using standard synthetic procedures. Additional diversity may also be introduced at the R² and R⁵ positions via further chemical modifications of the pyrrole as described previously.

[00237] Additional pyrroles may also be prepared via reaction scheme 8 (Roth et al., J. Med. Chem. (1991) 34 357-366)

Scheme 8

[00238] Further reaction of the free aldehyde at R² may be accomplished via a variety of reaction methodologies, for the example, reduction, , reaction via a Schiffs base, or the Wittig reaction, to introduce further diversity at R².

[00239] Additional pyrroles may also be generated using reaction schemes 9 and 10 that can be used to introduce further diversity selectively either position of the pyrrole nitrogen (Dieter et al., Organic Lett. (2000) 2(15) 2283-2286). scheme 9

_R5_C0 — _P6 p-TSA,

² acetone-water

Scheme 10

[00240] Again, further reaction of the free aldehyde at R² may be accomplished via a variety of reaction methodologies,. for the example, reduction, reaction via a Schiff's base, or the Wittig reaction, to introduce further diversity at R². Additional pyrroles may also be formed using reaction scheme 11 (Progress in Med. Chem, 402002). Scheme 11

R⁶-CHO

BT = 2-(2-hydroxyethyl)- 3 -methyl-4-benzylthiazolium chloride

H. EXAMPLES

[00241] The following compounds were prepared following the general procedures of reaction schemes 1 and 2. 2-isopropyl-N,4,5-triphenyl-1 H-pyrrole-3-carboxamide; m/z 381 [M+H]⁺ Compound No. 10002

5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide; m/z 399 [M+H]⁺

(Compound No. 10003)

2-isopropyl-5-(4-methoxyphenyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide; m/z 411 [M+H]⁺

(Compound No. 10004) 5-(4-tert-butylphenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide; m/z 437 [M+H]⁺

(Compound No. 10005)

2-isopropyl-N,5-diphenyl-4-(pyridin-4-yl)-1H-pyrrole-3-carboxamide; m/z 382 [M+H]⁺

(Compound No. 10006)

2-isopropyl-1-methyl-N,5-diphenyl-4-(pyridin-4-yl)-1 H-pyrrole-3-carboxamide; m/z 396 [M+H]⁺ (Compound No. 10007)

4,5-bis(4-fluorophenyl)-2-isopropyl-N-phenyl-1 H-pyrrole-3-carboxamide; m/z 416 [M+H]⁺

(Compound No. 10010)

4-(4-bromophenyI)-5-(4-fluorophenyl)-2-isopropyl-N-phenyl-1 H-pyrrole-3-carboxamide; m/z 478

[M+H]⁺ (Compound No. 10011) 5-(4-bromophenyl)-4-(4-fluorophenyl)-2-isopropyl-N-phenyl-1 H-pyrrole-3-carboxamide; m/z 476

[M+H]⁺ (Compound No. 10012)

2-ethyl-5-(4-fluorophenyl)-N,4-diphenyl-1 H-pyrroIe-3-carboxamide; m/z 371 [M+H]⁺ (Compound

No. 10018) 5-(4-fluorophenyl)-2-methyl-N,4-diphenyl~1 H-pyrrole-3-carboxamide; m/z 385 [M+H]⁺

(Compound No. 10019)

2~isopropyl-N,4-diphenyl-5-(pyridin~4-yl)-1 H-pyrrole-3-carboxamide; m/z 382 [M+Hf

(Compound No. 10022)

5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(2-(piperidin-1-yl)ethyl)-1H-pyrrole-3- carboxamide; m/z 510 [M+H]⁺ (Compound No. 10023)

1-(2-(dimethyIamino)ethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3- carboxamide; m/z 470 [M+H]⁺ (Compound No. 10024)

5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(3-(pyrrolidin-1-yl)propy))-1H-pyrrole-3- carboxamide; m/z 510 [M+H]⁺ (Compound No. 10025) 5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(pyridin-2-ylmethyl)-1 H-pyrrole-3-carboxamide; m/z 490 [M+H]⁺ (Compound No. 10026)

1-(4-aminobutyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; m/z

470 [M+H]⁺ (Compound No. 10027)

1 -(3-aminopropyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; m/z 456 [M+H]⁺ (Compound No. 10028)

5-(4-fluorophenyI)-2-isopropyl-N,4-diphenyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3- carboxamide; m/z 496 [M+H]⁺ (Compound No. 10029)

5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1 -(3-(piperidin-1 -yl)propyl)-1 H-pyrrole-3- carboxamide; m/z 524 [M+H]⁺ (Compound No. 10030) 5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(4-(pyrrolidin-1-yl)butyl)-1H-pyrrole-3- carboxamide; m/z 524 [M+H]⁺ (Compound No. 10031)

N,5-bis(4-fluorophenyl)-2-isopropyl-4-phenyl-1 H-pyrrole-3-carboxamide; m/z 417 [M+H]⁺

(Compound No. 10035)

1 -(2-aminoethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; m/z 442 [M+H]⁺ (Compound No. 10036)

5-(4-fluorophenyl)-2-isopropyl-1-phenethyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; m/z 503

[M+H]⁺ (Compound No. 10039)

N,5-bis(4-fluorophenyl)-2-isopropyl-4-phenyl-1 -(3-(pyrrolidin-1 -yl)propyl)-1 H-pyrrole-3- carboxamidep; m/z 528 [M+H]⁺ (Compound No. 10040) N,5-bis(4-fluorophenyl)-2-isopropyl-4-phenyl-1-(4-(pyrrolidin-1-yl)butyl)-1H-pyrrole-3- carboxamide; m/z 542 [M+H]⁺ (Compound No. 10041)

N,5-bis(4-fluorophenyl)-2-isopropyl-1-((2S,3R,4R,5S)-2_I3,4,5,6-pentahydroxyhexyl)-4-phenyl-

1 H-pyrrole-3-carboxamide; m/z 581 [M+H]⁺ (Compound No. 10042) N,5-bis(4-fluorophenyl)-2-isopropyl-1-(3-morpholinopropyl)-4-phenyl-1H-pyrrole-3-carboxannide; m/z 544 [M+H]⁺ (Compound No. 10043)

N-(4-fluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-4-yl)-1 H-pyrrole-3-carboxamide; m/z 400

[MH-H]⁺ (Compound No. 10044) 5-(1 H-imidazol-5-yl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; m/z 371 [M+H]⁺

(Compound No. 10045)

5-(4-fluorophenyl)-2-isopropyl-1-(3-(2-methyl-1 H-imidazol-1-yl)propyl)-N,4-diphenyl-1 H-pyrrole-

3-carboxamide; m/z 521 [M+H]⁺ (Compound No. 10046)

5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(piperidin-4-ylmethyl)-1 H-pyrrole-3-carboxamide; m/z 496 [M+H]⁺ (Compound No. 10047)

(R)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(pyrrolidin-2-ylmethyl)-1H-pyrrole-3- carboxamide; m/z 482 [M+H]⁺ (Compound No. 10048)

5-(4-fluorophenyl)-2-isopropyl-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-N,4-diphenyl-1 H-pyrrole-3- carboxamide; m/z 510 [M+H]⁺ (Compound No. 10049) N-(4-fluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-4-yl)-1 H-pyrrole-3-carboxamide; m/z 400

[M+H]⁺ (Compound No. 10050)

5-(4-fluorophenyl)-1-(2-(2-hydroxypropylamino)ethyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3- carboxamide; m/z 500 [M+H]⁺ (Compound No. 10051)

5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(2-(pyridin-4-yl)ethyl)-1 H-pyrrole-3-carboxamide; m/z 504 [M+H]⁺ (Compound No. 10052)

2-isopropyl-1-(3-(2-methyl-1H-imidazol-1-yl)propyl)-N,4-diphenyl-5-(pyridin-4-yl)-1H-pyrrole-3- carboxamide; m/z 504 [M+H]⁺ (Compound No. 10054)

2-isopropyl-N,4-diphenyl-5-(pyridin-4-yl)-1-(3-(pyrrolidin-1-yl)propyl)-1 H-pyrrole-3-carboxamide; m/z 493 [M+H]⁺ (Compound No. 10055) 2-isopropyl-N,4-diphenyl-5-(pyridin-2-yl)-1 H-pyrrole-3-carboxamide; m/z 382 [M+H]

(Compound No. 10056)

2-isopropyl-N,4-diphenyl-5-(pyridin-3-yl)-1 H-pyrrole-3-carboxamide; m/z 382 [M+H]⁺

(Compound No. 10057)

5-(4-fluorophenyl)-2-isopropyl-1-(2-(isopropylamino)ethyl)-N,4-diphenyl-1H-pyrrole-3- carboxamide; m/z 484 [M+H]⁺ (Compound No. 10058)

1-((1-ethylpiperidin-4-yl)methyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3- carboxamide; m/z 524 [M+H]⁺ (Compound No. 10059)

N-(2,4-difluorophenyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1 H-pyrrole-3-carboxamide; m/z

435 [M+H]⁺ (Compound No. 10060) N-(2,4-difluorophenyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1-(3-(pyrrolidin-1-yl)propyl)-1 H- pyrrole-3-carboxamide; m/z 546 [M+H]⁺ (Compound No. 10061)

N-(2,4-difluorophenyl)-5-(4-fluorophenyl)-2-isopropyl-1-(3-(2-methyl-1H-imidazol-1-yl)propyl)-4- phenyl-1 H-pyrrole-3-carboxamide; m/z 557 [M+H]⁺ (Compound No. 10062) iN-(4-τιuorophenyl)-2-ιsopropyl-4-phenyl-5-(pyridin-4-yl)-1-(3-(pyrrolidin-1-yl)propyl)-1 H-pyrrole-

3-carboxamide; m/z 511 [M+H]⁺ (Compound No. 10063)

N-(4-fluorophenyl)-2-isopropyl-1-(3-(2-methyl-1H-imidazol-1-yl)propyl)-4-phenyl-5-(pyridin-4-yl)-

1H-pyrrole-3-carboxamide; m/z 522 [M+H]⁺ (Compound No. 10064) 5-(2-hydroxypyridin-4-yl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide; m/z 398 [M+H]⁺

(Compound No. 10065)

5-(4-cyanopheny!)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide; m/z 406 [M+H]⁺

(Compound No. 10066)

2-isopropyl-N,4-diphenyl-5-(pyrimidin-5-yl)-1H-pyrrole-3-carboxamide; m/z 383 [M+H]⁺ (Compound No. 10067)

5-(2-chloropyridin-4-yl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; m/z 416 [M+H]⁺

(Compound No. 10068)

5-(4-aminophenyl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; m/z 396 [M+H]⁺

(Compound No. 10069) N-(4-fluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-2-yl)-1H-pyrrole-3-carboxamide; m/z 400 [M+KT (Compound No. 10070)

N-(4-fluoropheηyI)-2-isopropyl-1-((2S,3R,4R,5S)-2,3,4,5,6-pentahyd.roxyhexyl)-4-phenyl-5-

(pyridin-4-yl)-1 H-pyrrole-3-carboxamide; m/z 564 [M+H]⁺

(Compound No. 10071) 5-(2-aminopyrimidin-5-yl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; m/z 398 [M+H]⁺

(Compound No. 10072)

5-(2-(dimethylamino)pyrimidin-5-yl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; m/z

426 [M+H]⁺ (Compound No. 10073)

N-(2,4-difluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-2-yl)-1 H-pyrrole-3-carboxamide; m/z 418 [M+H]⁺ (Compound No. 10074)

N-(2,4-difluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-3-yl)-1 H-pyrrole-3-carboxamide; m/z 418

[M+H]⁺ (Compound No. 10075)

N-(2,4-difluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-4-yl)-1 H-pyrrole-3-carboxamide; m/z 418

[M+H]⁺ (Compound No. 10076) N-(4-fluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-3-yl)-1 H-pyrrole-3-carboxamide; m/z ^' 400

[M+H]⁺ and (Compound No. 10077)

N-cyclopentyl-2-isopropyl-4,5-diphenyl-1 H-pyrrole-3-carboxamide. m/z 373 [M+H]⁺ (Compound No. 2003)

EXAMPLE 1 PREPARATION OF 5-(4-FLUORO-PHENYL)-2-METHYL-4-PHENYL-1 H-PYRROLE-3-

CARBOXYLIC ACID PHENYLAMIDE

A. Preparation Of 3-Oxo-N-phenyl-butyramide: A mixture of 3-Oxo-butyric acid methyl ester (15g, 129.2 mmol), and aniline (12.03g, 129.2 mmol) in toluene (50 ml_) was refluxed for 24hr using a dean Stark apparatus. The solvents were removed and the crude material purified by flash chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 15:85) to afford 3-Oxo-N- phenyl-butyramide as a yellow solid (11.3g, 50.3%); ¹HNMR (CDCI₃): δ 9.3-9.0(bs, 1H), 7.6- 7.5(m, 2H), 7.4-7.3(m, 2H), 7.2-7.0(m, 1H), 3.6(s, 2H), 2.3(s, 3H); MS (ESI) m/z 177 [M+H]⁺. B. Preparation Of 2-Benzylidene-3-oxo-N-phenyl-butyramide: The reaction was run in a 250 mL three necked round bottomed flask equipped with an electric motor-driven mechanical stirrer and an oil bath. The flask was fitted with a Dean-Stark trap and a condenser, and the entire apparatus was maintained under nitrogen. The flask was charged with 3-Oxo-N-phenyl- butyramide from Step A (5 g, 28.3 mmol), benzaldehyde (2.94 g, 27.7 mmol), β-alanine (0.54 g, 6.04 mmol), hexanes (90 mL), and glacial acetic acid (0.54 g, 8.95 mmol), and the contents were heated under reflux for 28h, resulting in a slurry. The solvents were removed and the crude material purified by flash chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 50:50) to afford 2-Benzylidene~3-oxo-pentanoic acid phenylamide as an off white solid (1.9g, 25%); ¹HNMR (CDCI₃): δ 7.8-7.1 (m, 11H)₁ 2.5(s,^~3H); MS (ESI) m/z 265 [M+H]⁺.

C. The intermediate of Step B (1eq) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (0.2eq) was placed in a 15 mL three-necked flask under argon. Absolute EtOH (1 mL), Et₃N (1eq), and 4-fluorobenzaldehyde (1.1eq) were added. The mixture was heated at 80 °C for 12h. To the resulting mass of solid was added isopropanol (5 mL) and the mixture was stirred at 70⁰C under argon for 5 mins and then at rt for 2h. The mixture was filtered and washed with isopropyl alcohol and then dried in vacuo to give the crude material. It was purified by flash chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 50:50) to afford 2-Acetyl-4-(4- fluoro-phenyl)-4-oxo-3,N-diphenyl-butyramide; MS (ESI) m/z 390 [M+H]⁺.

D. The intermediate of Step C was reacted with ammonium acetate (10 eq) and copper acetate (10 eq) in the presence of acetic acid to afford the title compound; m/z 371 [M+H]⁺.

EXAMPLE 2 PREPARATION OF 2-ETHYL-5-(4-FLUORO-PHENYL)-4-PHENYL-1 H-PYRROLE-3- CARBOXYLIC ACID PHENYLAMIDE

A. Preparation Of 3-oxo-pentanoic acid phenylamide: A mixture of 3-Oxo-pentanoic acid methyl ester (15g, 115.3 mmol), and aniline (10.73g, 115.2 mmol) in toluene (50 mL) was refluxed for 24hr using a dean Stark apparatus. The solvents were removed and the crude material purified by flash chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 15:85) to afford 3-Oxo- pentanoic acid phenylamide as an yellow solid (13.7g, 62%); ¹HNMR (CDCI₃): δ 9.3-9.0(bs, 1 H), 7.6-7.5(m, 2H), 7.4-7.3(m, 2H), 7.2-7.0(m, 1H), 3.6(s, 2H), 2.8(q, 2H), 1.1(t, 3H); MS (ESI); m/z 191 [M+H]⁺.

B. Preparation Of 2-benzylidene-3-oxo-pentanoic acid phenylamide: The reaction was run in a 250 mL three necked round bottomed flask equipped with an electric motor-driven mechanical stirrer and an oil bath. The flask was fitted with a Dean-Stark trap and a condenser, and the entire apparatus was maintained under nitrogen. The flask was charged with 3-Oxo-pentanoic acid phenylamide from Step A (5 g, 26.2 mmol), benzaldehyde (2.72 g, 25.6 mmol), β-alanine (0.54g, 6.04 mmol), hexanes (90 mL), and glacial acetic acid (0.54 g, 8.95 mmol), and the contents were heated under reflux for 28h, resulting in a slurry. The solvents were removed and the crude material purified by flash chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 50:50) to afford 2-benzylidene-3-oxo-pentanoic acid phenylamide as an off white solid (2.5g, 34.3%).

C. The intermediate of Step B (1eq) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (0.2eq) was placed in a 15 mL three-necked flask under argon. Absolute EtOH (1 mL), Et₃N (1eq), and 4-fluorobenzaldehyde (1.1eq) were added. The mixture was heated at 80 ⁰C for 12h. To the resulting mass of solid was added isopropanol (5 mL) and the mixture was stirred at 7O⁰C under argon for 5 mins and then at rt for 2h. The mixture was filtered and washed with isopropyl alcohol and then dried in vacuo to give the crude material. It was purified by flash chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 50:50) to afford 2-[2-(4-Fluoro- phenyl)-2-oxo-1-phenyl-ethyl]-3-oxo-pentanoic acid phenylamide; MS (ESI) m/z 404 [M+H]⁺. D. The intermediate of Step C was reacted with ammonium acetate (10 eq) and copper acetate (10 eq) in the presence of acetic acid to afford the title compound; m/z 385 [M+H]⁺.

EXAMPLE 3 PREPARATION OF METHYL 5-(4-FLUOROPHENYL)-2-ISOPROPYL-4-PHENYL-1 H-PYRROLE- 3-CARBOXYLATE

A. Preparation Of methyl 4-methyl-3-oxopentanoate: Sodium hydride (70.32 g, 2.1 eq, 50% dispersion in oil) was washed with toluene and decanted off. Dry toluene (500 mL) and dimethyl carbonate (329.3 g, 2 eq) were added and the stirred mixture was heated to 80⁰C under nitrogen whilst the methyl isopropyl ketone (120 g, 1 eq) in 240 ml toluene was added over a period of 5 hrs. Further the cooled mixture was poured into water (120 mL) containing glacial acetic acid (300 ml). The organic layer was separated and aqueous layer was further extracted with ethyl acetate (300 ml). The organic extracts were combined and evaporated and the residue was distilled to yield the methyl 4-methyl-3-oxopentanoate as a syrup (138 gm, 62.72%).

B. Preparation of methyl 2-benzylidene-4-methyl-3-oxopentanoate: A suspension of compound step A (15.09 g, 0.034 mol, 1 eq) in toluene (112 ml) was treated with piperidine (0.6 ml), benzaldehyde (12 g, 0.375 mol, 1.10 eq) and acetic acid (0.9 ml). The resulting suspension was heated to reflux with removal of water for 12 h. The solution was cooled and poured into ethyl acetate, washed with 1 M HCI, saturated aqueous sodium bi-carbonate and brine. The solvent was removed under reduced' pfessure and the product was recrystallized from n-hexane to give methyl 2-benzylidene-4-methyl-3-oxopentanoate (16.8 gm 70%); m/z 233 [M+H]⁺. HPLC: 90% pure.

C A solution of 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide (0.216 gm, 0.2 eq) in 10 ml of anhydrous ethanol was concentrated by distillation under nitrogen to 1 ml of ethanol. Intermediate from Step B (1gm, 1 eq), triethylamine (0.43 gm, 1 eq) and 4-fluorobenzaldehyde (0.58 gm, 1.1 eq) were added. The resulting solution was stirred and heated to 80⁰C for 24 h. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by recrystallization using di-isopropyl ether to give 0.92 gm of methyl 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxopentanoate (60%) as a mixture of isomers; m/z 356 [M+H]⁺; 1 H NMR (200 MHz, CDCI3) δ 0.45 (d, 3H), 1.0 (d, 3H), 1.05 (d, 3H), 1.21 (d, 3H), 2.2-2.4 (m, 1H), 2.80-2.95 (m, 1H), 3.50 (s, 3H), 3.70 (s, 3H), 4.70-4.80 (dd, 2H), 5.30-5.40 (dd, 2H), 6.90-7.10 (m, 5H), 7.15-7.40 (m, 8 H), 7.95-8.05 (m, 5H).

D. A solution of compound in Step C (4.5 gm, 1eq, 0.0168 mol), Cu(OAc)₂-H₂O (12.6 gm, 5 eq, 0.0842 mol) and NH₄OAc (7.725gm, 8 eq, 0.134 mol) in acetic acid (125 ml) was heated to reflux overnight. The reaction was monitored by TLC which showed reaction completion. The reaction mixture was evaporated to a small volume and the residual acetic acid was neutralized with aqueous ammonia. The obtained was filtered and dissolved in ethyl acetate. The insoluble solid was filtered off, filtrate was dried over anhydrous sodium sulfate, concentrated in vacuo to give crude product which was purified by column chromatography to give 1.5 gm of compound 2. (Yield: 35%) ¹H NMR, 200 MHz: δ 1.40 (d, 6H), 3.60 (s, 3H), 3.79-3.95 (m, 1 H), 6.80-7.0 (m, 2H), 7.0-7.20 (m, 2H), 7.20-7.40 (m, 5H), 8.25 (Br s, 1 H). M⁺ 338. HPLC: 95.5%

EXAMPLE 4 PREPARATION OF 2-(4-FLUORO-PHENYL)-5-ISOPROPYL-3-PHENYL-1 H-PYRROLE

A. To a mixture of 2-Benzylidene-4-methyl-3-oxo-pentanoic acid methyl ester from Example 3B (10.8g, 46.5 mmol), 4-Fluorobenzaldehyde (5.8g, 46.5 mmol) in Triethylamine (4mL) was added to 2-(2-hydroxyethyl)-3-methyl-4-benzylthiazolium chloride (1.8g, 6.97 mmol) and heated at 70°C for 24hrs. It was cooled to RT and acid/base extraction was done. The crude oil was dissolved in Tetrahydrofuran (6OmL) to which sodium hydroxide (5.46g) in water (31.5mL) was added. The mixture stirred overnight. Then it was acidified to pH 5 with 6N HCI and extracted with ether. The organic layer was washed several times with 3N NaOH, water, brine, and dried with magnesium sulfate. The crude material purified by column chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 30:70) to afford 1-(4-Fluoro-phenyl)-5-methyl-2-phenyl-hexane- 1 ,4-dione as a reddish brown liquid (9.4G, 68%) B. A mixture of 1-(4-Fluoro-phenyl)-5-methyl-2-phenyl-hexane-1 ,4-dione (5.Og₁ 16.8 mmol), Copper Acetate (15.2g, 83.8 mmol), Ammonium Acetate (6.5g, 83.8 mmol) in Acetic Acid (2OmL) was heated at 110⁰C for overnight. The solvents were removed and then neutralized with aqueous ammonium hydroxide and extracted with ethyl acetate. The crude was purified by flash chromatography EtOAc:Hexane (0:100 to 30:70) to afford 2-(4~Fluoro-phenyl)-5-isopropyl- 3-phenyl-1 H-pyrrole (475mg, 10%).

[00242] EXAMPLE 5 PREPARATION OF 5-(4-FLUORO-PHENYL)-2-ISOPROPYL-4-PHENYL-1 H- PYRROLE-3-CARBOXYUC ACID (4-FLUORO-PHENYL)-AMIDE

[00243] A. Preparation Of 4-Methyl-3-oxo-pentanoic acid (4-fluoro-phenyl)-amide: A mixture of 4-Methyl-3-oxo-pentanoic acid methyl ester (15g, 104-mmol), and 4-fluoroaniline (11.56, 104^' mmol) in toluene (50 mL) was refluxed for 24hr using a dean Stark apparatus. The solvents were removed and the crude material purified by flash chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 15:85) to afford 4-Methyl-3-oxo-pentanoic acid (4-fluoro-phenyl)- amide as an off white solid (2Og, 87%); ¹HNMR (CDCI₃): δ 9.4-9.2(bs, 1 H), 7.6-7.4(m, 2H), 7.1- 6.9(m, 2H), 4.7-4.5(s, 2H)₁ 3.8-3.6(septet, 1 H), 1.3-1.1(d, 6H); MS (ESI); m/z 223 [M+H]⁺.

B. Preparation of 2-benzylidene-4-methyl-3-oxo-pentanoic acid (4-fluoro-phenyl)-amide: The reaction was run in a 250 mL three necked round bottomed flask equipped with an electric motor-driven mechanical stirrer and an oil bath. The flask was fitted with a Dean-Stark trap and a condenser, and the entire apparatus was maintained under nitrogen. The flask was charged with 4-Methyl-3-oxo-pentanoic acid (4-fluoro-phenyl)-amide (5 g, 22.4 mmol), benzaldehyde (2.33 g, 22 mmol), β-alanine (502 mg, 5.92 mmol), hexanes (90 mL), and glacial acetic acid (503 mg, 8.8 mmol), and the contents were heated under reflux for 28h, resulting in a slurry. The solvents were removed and the crude material purified by flash chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 50:50) to afford 2-Benzylidene-4-methyl-3-oxo-pentanoic acid (4-fluoro-phenyl)-amide as an off white solid (6 g, 87.5%); ¹HNMR (CDCI₃): δ 7.7-7.2(m, 9H), 7.1-6.9(m, 2H), 3.4-3.2(m, 1H); 1.3-1.2(d,6H); MS (ESI); m/z 311 [M+H]⁺. [00244]

C. A mixture of pure 2-Benzylidene-4-methyl-3-oxo-pentanoic acid (4-fluoro-phenyl)-amide (3 g, 9.65 mmol) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (634 mg, 2.42 mmol) was placed in a 15 mL three-necked flask under argon. Absolute EtOH (1 mL), Et₃N (1.093 g, 10.81 mmol), and 4-fluorobenzaldehyde (1.2 g, 9.65 mmol) were added. The mixture was heated at 80 ⁰C for 12h. To the resulting mass of solid was added isopropanol (5 mL) and the mixture was stirred at 70⁰C under argon for 5 mins and then at room temperature for 2h. The mixture was filtered and washed with isopropyl alcohol and then dried in vacuo to give the crude material. It was purified by flash chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 50:50) to give 2-[2-(4-Fluoro-phenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid (4- fluoro-phenyl)-amide (1.6 g, 38%) as a white solid. The mixture was recrystallized from isopropyl alcohol and used for the next step; ¹HNMR (CDCI₃): δ 8.1-7.9(m, 2H), 6.8-7.3(m, 11 H), 5.4-5.3(d, 1H), 4.6-4.5(m, 1H), 3.1-2.9(m, 1H), 1.3-1.1(dd, 6H); MS (ESI); m/z 435 [M+H]⁺.

D. A solution of 2-[2-(4-Fluoro-phenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid (4- fluoro-phenyl)-amide in Step C (500 mg, 1.15 mmol), Cu(OAc)2.H2θ (2.09 g, 11.5 mol) and NH4OAC (885 mg, 11.5 mmol) in acetic acid (3 mL) was heated to reflux for overnight. The reaction mixture was evaporated to a small volume and the residual acetic acid was neutralized with aqueous ammonia. Precipitate was filtered and dissolved in ethyl acetate.

The insoluble solid was filtered off, filtrate was dried over anhydrous sodium sulfate, concentrated in vacuo to give crude product which was purified preparative reverse phase HPLC to give 5-(4-Bromo-phenyl)-4-(4-fluoro-phenyl)-2-isopropyl-1 H-pyrrole-3-carboxylic acid phenylamide (2 mg, 2%); ¹HNMR (CDCI₃): δ 7.4-6.8(m, 13H), 4.1-4.0(m, 1H), 1.4(d, 6H);

MS (ESI); m/z417 [M+H]⁺.

[00245]

[00246] EXAMPLE 6 PREPARATION OF 4,5-BIS-(4-FLUORO-PHENYL)-2-ISOPROPYL-I H-PYRROLE- 3-CARBOXYLIC ACID PHENYLAMIDE

A. Preparation of 2-(4-fluoro-benzylidene)-4-methyl-3-oxo-pentanoic acid (4-fluoro-phenyl)- amide: The reaction was run in a 250 mL three necked round bottomed flask equipped with an electric motor-driven mechanical stirrer and an oil bath. The flask was fitted with a Dean-Stark trap and a condenser, and the entire apparatus was maintained under nitrogen. The flask was charged with 4-Methyl-3-oxo-pentanoic acid (4-fluoro-phenyl)-amide from Example 5A (10 g, 44.8 mmol), benzaldehyde (5.45 g, 43.9 mmol), β-alanine (1.05 g, 6.04 mmol), hexanes (90 mL), and glacial acetic acid (1.05g, 17.57 mmol), and the contents were heated under reflux for 28h, resulting in a slurry. The solvents were removed and the crude material purified by flash chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 50:50) to afford 2-(4-Fluoro- benzylidene)-4-methyl-3-oxo-pentanoic acid (4-fluoro-phenyl)-amide as an off white solid (11.9 g, 80%); MS (ESI); m/z 329 [M+H]⁺.

[00247] B. A mixture of pure 2-(4-fluoro-benzylidene)-4-methyl-3-oxo-pentanoic acid 4-fluoro phenylamide (2.95 g, 9.65 mmol) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (0.63 g, 2.42 mmol) was placed in a 15 mL three-necked flask under argon. Absolute EtOH (1 mL), Et₃N (1.093 g, 10.81 mmol), and benzaldehyde (1.2 g, 9.65 mmol) were added. The mixture was heated at 80 ⁰C for 12h. To the resulting mass of solid was added isopropanol (5 ml_) and the mixture was stirred at 7O⁰C under argon for 5 mins and then at room temperature for 2h. The mixture was filtered and washed with isopropyl alcohol and then dried in vacuo to give the crude material. It was purified by flash chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 50:50) 2-[1 ,2-Bis-(4-f luoro-phenyl)-2-oxo-ethyl]-4-methyl-3-oxo- pentanoic acid phenylamide (2.5 g, 60%) as a white solid; MS (ESI); m/z 435 [M+H]⁺.

[00248] C. A solution of 2-[1 ,2-bis-(4-fluoro-phenyl)-2-oxo-ethyl]-4-methyl-3-oxo-pentanoic acid phenylamide (110 mg, 0.252 mmol), Cu(OAc)2.H2θ (460 mg, 2.52 mol) from Step B and NH₄OAc (195 g, 2.52 mol) in acetic acid (3 ml_) was heated to reflux for overnight. The reaction mixture was evaporated to a small volume and the residual acetic acid was neutralized with aqueous ammonia. Precipitate was filtered and dissolved in ethyl acetate. The insoluble solid was filtered off, filtrate was dried over anhydrous sodium sulfate, concentrated in vacuo to give crude product which was purified preparative HPLC to give 4,5-Bis-(4-fluoro-phenyl)-2-isopropyl-1 H-pyrrole-3-carboxylic acid phenylamide (4.16 mg, 4%); ¹HNMR (CDCI₃): δ 8.3(bs, 1H), 7.4-6.8(m, 13H), 7.1-6.9(m, 2H)₁ 4.1-3.9(m, 1 H), 1.4-1.3(d, 6H); MS (ESI) m/z 416 [M+H]⁺.

[00249] EXAMPLE 7 PREPARATION OF 4-(4-BROMO-PHENYL)-5-(4-FLUORO-PHENYL)-2- ISOPROPYL-1 H-PYRROLE-S-CARBOXYLIC ACID PHENYLAMIDE AND PREPARATION OF 5-(4-BROMO- PHENYL)-4-(4-FLUORO-PHENYL)-2-ISOPROPYL-1 H-PYRROLE-3-CARBOXYLIC ACID PHENYLAMIDE

[00250] A. A mixture of pure 2-(4-Bromo-benzylidene)-4-methyl-3-oxo-pentanoic acid phenylamide (0.295 g, 0.965 mmol) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazoIium bromide (63 mg, 0.24 mmol) was placed in a 15 ml_ three-necked flask under argon. Absolute EtOH (0.5 mL), Et₃N (0.1 g, 1.08 mmol), and 4-bromobenzaldehyde (0.12 g, 0.96 mmol) were added. The mixture was heated at 80 ⁰C for 12h. To the resulting mass of solid was added isopropanol (2 mL) and the mixture was stirred at 70⁰C under argon for 5 mins and then at room temperature for 2h. The mixture was filtered and washed with isopropyl alcohol and then dried in vacuo to give the crude material. It was then purified by flash chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 50:50) to give 2-[1-(4-Bromo-phenyl)-2-(4-fluoro-phenyl)-2-oxo-ethyl]- 4-methyl-3-oxo-pentanoic acid phenylamide and 5-(4-Bromo-phenyl)-4-(4-fluoro-phenyl)-2- isopropyl-1 H-pyrrole-3-carboxyiic acid phenylamide in a 1:1 ratio (0.25 g, 55%) as a white solid; MS (ESI); m/z 476 [M+H]⁺.

[00251]

B. A solution of 2-(1-(4-bromophenyl)-2-(4-fluorophenyl)-2-oxoethyl)-4-methyl-3-oxo-N- phenylpentanamide (110 mg, 0.252 mmol), Cu(OAc)2.H2O (460 mg, 2.52 mol) and NH4OAc (195 g, 2.52 mol) in acetic acid (3 ml_) was heated to reflux for overnight. The reaction mixture was evaporated to a small volume and the residual acetic acid was neutralized with aqueous ammonia. Precipitate was filtered and dissolved in ethyl acetate. The insoluble solid was filtered off, filtrate was dried over anhydrous sodium sulfate, concentrated in vacuo to give crude product which was purified preparative reverse phase HPLC to give 4-(4-bromo-phenyl)-5-(4- fluoro-phenyl)-2-isopropyl-1 H-pyrrole-3-carboxylic acid phenylamide (2 mg, 2%); ¹HNMR (CDCI₃): δ 8.3(bs, 1H), 7.4-6.8(m, 13H), 7.1-6.9(m, 2H), 4.1-3.9(m, 1 H), 1.4-1.3(d, 6H); MS (ESI); m/z 416 [M+H]⁺.

C. A solution of 2-[2-(4-Bromo-phenyl)-1-(4-fluoro-phenyl)-2-oxo-ethyl]-4-methyl-3-oxo- pentanoic acid phenylamide (110 mg, 0.252 mmol), Cu(OAc)2.H2O (460 mg, 2.52 mol) and NH4OAc (195 mg, 2.52 mol) in acetic acid (3 mL) was heated to reflux for overnight. The reaction mixture was evaporated to a small volume and the residual acetic acid was neutralized with aqueous ammonia. Precipitate was filtered and dissolved in ethyl acetate. The insoluble solid was filtered off, filtrate was dried over anhydrous sodium sulfate, concentrated in vacuo to give crude product which was purified preparative HPLC to give 5-(4-Bromo-phenyl)-4-(4-fluoro- phenyl)-2-isopropyl-1 H-pyrrole-3-carboxylic acid phenylamide (2 mg, 2%); MS (ESI) m/z 478 [MH-H]⁺.

EXAMPLE 8 PREPARATION OF 2-ISOPROPYL-4,5-DIPHENYL-1 H-PYRROLE-3-CARBOXYLIC ACID

A. Preparation of 4-Methyl-3-oxo-pentanoic acid benzyl ester: A mixture of Methyl lsobutyrylacetate (5Og, 346.8 mmol), Benzyl Alcohol (41.3g, 381.4 mmol), p-toluenesulfonic acid (100mg) in toluene (200 mL) was refluxed for 24hr using a Dean Stark apparatus. The solvents were removed and the crude material purified by column chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 30:70) to afford 4-Methyl-3-oxo-pentanoic acid benzyl ester as a yellow liquid (39.8G, 52.1%)

B. Preparation of 2-Benzylidene-4-methyl-3-oxo-pentanoic acid benzyl esteπTo a mixture of 4- Methyl-3-oxo-pentanoic acid benzyl ester (2Og, 90.7 mmol), Benzaldehyde (9.4g, 88.9 mmol) in toluene (50 mL), Acetic Acid (2.1g, 24mmol) was added and the reaction refluxed at 11O⁰C for 24hr using a Dean Stark apparatus. The solvents were removed and the crude material purified by column chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 30:70) to afford 2- Benzylidene-4-methyl-3-oxo-pentanoic acid benzyl ester as a yellow liquid (22.4G, 80.4%)

C. Preparation of 2-lsopropyl-4,5-diphenyl-1 H-pyrrole-3-carboxylic acid benzyl ester A mixture of 2-Benzylidene-4-methyl-3-oxo-pentanoic acid benzyl ester (9.5g, 30.8 mmol), Benzaldehyde (3.3g, 30.8 mmol), Triethylamine (3.5g, 34.5 mmol) in dimethylglycol (10 mL) was added to 3- ethyl-5-(2-hydroxyetthyl)-4-methylthiazolium bromide (1.94g, 7.7 mmol) and heated at 75°C overnight. The solvents were removed and the crude material purified by column chromatography (SiO₂), eluting with EtOAc/Hexanes (0:100 to 30:70) to afford 4-Methyl-3-oxo- 2-(2-oxo-1,2-diphenyl-ethyl)-pentanoic acid benzyl ester as a reddish brown liquid.

D. To 4-Methyl-3-oxo-2-(2-oxo-1 ,2-diphenyl-ethyl)-pentanoic acid benzyl ester from Step C

(5.Og, 12.1 mmol) in THF:Toluene (1 :1) (2OmL) liquid ammonium was bubbled in for 10min. and heated at 110⁰C overnight. The solvents were removed to afford 2-Isopropyl-4,5-diphenyl-1 H- pyrrole-3-carboxylic acid benzyl ester as a reddish brown solid (4.5g crude)

E. A mixture of 2-lsopropyl-4,5-diphenyl-1H-pyrrole-3-carboxylic acid benzyl ester (5.Og, 12.1 mmol), 10% Palladium Hydroxide/carbon in methanol (2OmL) was placed under the Parr at 45psi overnight. The solvents were removed and an acid/base extraction was done to afford 2- lsopropyl-4_L5-diphenyl-1 H-pyrrple-3-carboxylicacid as a yellow solid; m/z 382 [M+H]⁺.

F. Preparation of 2-lsopropyl-4,5-diphenyl-1H-pyrrole-3-carboxylic acid cyclopentylamide: A mixture of 2-lsopropyl-4,5-diphenyl-1H-pyrrole-3-carboxylic acid (40 mg, 0.13 mmol), EDCI (38mg, 0.2mmol), HOBt (27mg, 0.2mmol) was dissolved in 2mL DMF. To this mixture cyclopentylamine (14mg, 0.16 mmol) and DIEA (25mg, 0.2mmol) was added. The reaction stirred overnight at room temperature. Purified by HPLCto afford 3-2-lsopropyl-4,5-diphenyl-1 H- pyrrole-3-carboxylic acid cyclopentylamide (12mg, 24%); m/z 373 [M+H]⁺.

[00252] EXAMPLE 9 PREPARATION OF 5-(4-FLUORO-PHENYL)-2-ISOPROPYL-4-PHENYL-I H-

PYRROLE-3-CARBOXYLIC ACID (4-HYDROXY-PHENYL)-AMIDE

[00253] A. Preparation Of 4-Methyl-3-oxo-pentanoic acid (4-benzyloxy-phenyl)-amide: A mixture of 4-Methyl-3-oxo-pentanoic acid methyl ester from Example 3A (25g, 173 mmol), and 4-benzyloxyaniline (40.9g, 173 mmol), triethyl amine (17.54g, 173 mmol) in toluene (400 mL) was refluxed for 24hr using a Dean Stark apparatus. The solvents were removed and the crude material was dissolved in ethyl acetate and water. NaCI was added and extracted (3 x 100 mL). The organic layers was washed with 1M HCI (3 x 10OmL), water (3 x 100 mL), brine (3 x 100 mL) and dried over magnesium sulfate. It was purified by a silica pad (SiO₂), eluting with EtOAc/Hexanes (0:100 to 20:80) to afford 4-Methyl-3-oxo-pentanoic acid (4-benzyloxy-phenyl)- amide as a yellow solid (27g, 50%);

[00254] B. Preparation Of 2-Benzylidene-4-methyl-3-oxo-pentanoic acid (4-benzyloxy- phenyl)-amide: The reaction was run in a 1 L three necked round bottomed flask equipped with an electric motor-driven mechanical stirrer and an oil bath. The flask was fitted with a Dean- Stark trap and a condenser, and the entire apparatus was maintained under nitrogen. The flask . . was charged with 4-Methyl-3-oxo-pentanoic acid (4-benzyloxy-phenyl)-amide (27 g, 86.7 mmol), benzaldehyde (9.02 g, 85 mmol), β-alanine (2.04 g, 23 mmol), hexanes (400 ml_), and glacial acetic acid (2.04 g, 33.9 mmol), and the contents were heated under reflux for 28h, resulting in slurry. The crude mixture was filtered and then the filtrate was dissolved in dichloromethane and washed with water (3 x 100 mL). The organic layer was dried over magnesium sulfate. The solvents were removed and the product was purified by flash chromatography (SiOa), eluting with EtOAc/Hexanes (0:100 to 50:50) to afford 2-Benzylidene-4-methyl-3-oxo-pentanoic acid (4-benzyloxy-phenyl)-amide as a yellowish brown solid (16 g, 46.2%); ¹HNMR (CDCI₃): δ 7.8-7.2(m, 12H), 7.1-6.9(m, 2H), 6.7-6.6(m, 1 H), 5.1 (s, 2H), 3.5-3.3(m, 1H), 1.2(d, 6H); MS (ESI) m/z 400 [M+H]⁺. [00255]

[00256] C. 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (0.49 g, 1.94 mmol) was dissolved in ethanol (10 mL) and the solution was concentrated to dryness by evaporation thrice. The oil was dissolved in ethanol (50 mL), to which were added Benzylidene-4-methyl-3- oxo-pentanoic acid (4-benzyloxy-phenyl)-amide (3 g, 7.51 mmol), 4-fluorobenzaldehyde (1.32g, 10.63 mmol), and triethyl amine (0.78g, 7.71 mmol). The mixture was heated to 11O⁰C and then of triethyl amine (1 mL) was added. The solution stirred at 90⁰C for 12 h. The mixture was cooled to room temperature and diluted with ethyl acetate and washed with water (3 x 10 mL), 1M HCI (3 x 10 mL), brine (3 x 10 mL), and dried over magnesium sulfate. It was purified by reverse phase HPLC to afford 2-[2-(4-Fluoro-phenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo- pentanoic acid (4-benzyloxy-phenyl)-amide as a pale yellowish solid. (0.1g, 2.5%); MS (ESI); m/z 524 [M+H]⁺.

[00257] D. Preparation Of 5-(4-Fluoro-phenyl)-2-isopropyl-4-phenyl-1 H-pyrrole-3-carboxylic acid (4-benzyloxy-phenyl)-amide: A mixture of 2-[2-(4-Fluoro-phenyl)-2-oxo-1-phenyl-ethyl]-4- methyl-3-oxo-pentanoic acid (4-benzyloxy-phenyl)-amide (100 mg, 0.19 mmol), copper acetate (347 mg, 1.91 mmol), and ammonium acetate (147 mg, 1.91 mmol) was dissolved in acetic acid (2 mL). The mixture was heated to 100⁰C for 12h. The solvents were removed and neutralized with saturated ammonium hydroxide (5 mL). It was extracted ethyl acetate (2 x 30 mL). The organic layer was washed with brine (3 x 10 mL) and dried over magnesium sulfate. It was purified by reverse phase HPLC to afford 5-(4-Fluoro-phenyl)-2-isopropyl-4-phenyl-1 H-pyrrole- 3-carboxylic acid (4-benzyloxy-phenyl)-amide as an off white solid. (10 mg, 10.4%); MS (ESI); m/z 505 [M+H]⁺.

[00258] E. A mixture of 5-(4-Fluoro-phenyl)-2-isopropyl-4-phenyl-1 H-pyrrole-3-carboxylic acid (4-benzyloxy-phenyl)-amide (10 mg, 0.02 mmol) and a catalytic amount of Pd/C (5 mg) was dissolved in methanol (10 mL). A balloon of hydrogen gas was placed over the reaction mixture and the reaction stirred for 3h at room temperature. The Pd/C was filtered off and the solvent evaporated. It was purified by reverse phase HPLC to afford 5-(4-Fluoro-phenyl)-2-isopropyl-4- _„ ,. phenyl- 1 H-pyrrole-3-carbόxylic ibid (4-hydroxy-phenyl)-amide as a white solid (3 mg, 36.5%); MS (ESI); m/z 414 [M+H]⁺.

[00259] EXAMPLE 10 PREPARATION OF N-(4-FLUOROPHENYL)-2-ISOPROPYL-4-PHENYL-5-(PYRIDIN-4-YL)-I H-

PYRROLE-3-CARBOXAMIDE AND RELATED PYRiDINYL COMPOUNDS (Compound No. 10044)

A. A solution of 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide (0.64 gm, 0.2 eq) in 8 ml of anhydrous ethanol was concentrated by distillation of 5 ml of ethanol under nitrogen. 2-benzylidne-N-(4-fluorophenyl)-4-methyl-3-oxopentamide (4 gm, 1 eq), triethylamine 1.29 ml, 1 eq) and 4-pyridine-carboxaldehyde (1.5 gm, 1.1 eq) were added. The resulting solution was stirred and heated to 80⁰C for 24 h. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by - recrystallization using di-isopropyhether to give 2.6 gm of N-(4-fluorophenyl)-4-methyl-3-oxo-2- (2-oxo-1-phenyl-2-(pyridin-4-yl)ethyl) (49%); M⁺ 418.

B. The intermediate of Step A was reacted with ammonium acetate (10 eq) and copper acetate (10 eq) in the presence of acetic acid to afford N-(4-fluorophenyl)-2-isopropyl-4-phenyl- 5-(pyridin-4-yl)-1 H-pyrrole-3-carboxamid; m/z 400 [M+H]⁺.

EXAMPLE 11 PREPARATION OF N-(4-FLUOROPHENYL)-2-ISOPROPYL-4-PHENYL-5-(PYRIDIN-2-YL)-1 H- PYRROLE-3-CARBOXAMIDE

A. A solution of 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazoliumbromide (0.97 gm, 0.2 eq) in 6 ml of anhydrous ethanol was concentrated by distillation of 5 ml of ethanol under nitrogen. 2- benzylidne-N-(4-fluorophenyl)-4-methyl-3-oxopentamide (6 gm, 1 eq), triethylamine 1.9 gm, 1 eq) and 2-pyridine-carboxalaldehyde (2.27 gm, 1.1 eq) were added. The resulting solution was stirred and heated to 80⁰C for 24 h. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by recrystallization using di-isopropyl ether to give 4 gm of N-(4-fluorophenyl)-4-methyl-3-oxo-2-(2-oxo-1-phenyl-2- (pyridin-2-yl)ethyl)pentanamide (50%). M⁺418. 1H NMR (200 MHz, CDCI3) δ 8.3 (d, 1H), 7.8 (t, 1H), 7.7 (t, 1H), 7.2 (m, 5H), 4.7 (d, 1H), 4.3 (d, 1H), 3.1 (m, 1H), 1.6 (s, 6H).

B. The intermediate of Step A was reacted with ammonium acetate (10 eq) and copper acetate (10 eq) in the presence of acetic acid to afford N-(4-fluorophenyl)-2-isopropyl-4-phenyl-5- (pyridin-2-yl)-1H-pyrrole-3-carboxamide; m/z 400 [M+H]⁺. EXAMPLE 12 PREPARATION OF N-(4-FLUOROPHENYL)-2-ISOPROPYL-4-PHENYL-5-(PYRIDIN~3-YL)-1 H-

PYRROLE-3-CARBOXAMIDE

A. A solution of 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazoliumbromide (1.29 gm, 0.2 eq) in 10 ml of anhydrous ethanol was concentrated by distillation of 8 ml of ethanol under nitrogen. 2- benzylidne-N-(4-fluorophenyl)-4-methyl-3-oxopentamide (8 gm, 1 eq), triethylamine 2.5 gm, 1 eq) and 3-pyridine-carboxalaldehyde (3.03 gm, 1.1 eq) were added. The resulting solution was stirred and heated to 80⁰C for 24 h. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by recrystallization using di-isopropyl ether to give 5.2 gm of N-(4-fluorophenyl)-4~methyl-3-oxo-2-(2-oxo-1-phenyl- 2-(pyridin-3-yl)ethyl)pentanamide (48.5%). M⁺ 418. 1 H NMR (200 MHz, CDCI3) δ 9.1 (s, 1H), 8.8 (d, 1 H), 8.6 (t, 1 H), 8.2 (d, 1H), 7.3 (m, 5H), 4.8 (d, 1 H), 4.6 (d, 1H), 3.1 (m, 1 H), 1.6 (s, 6H). B. The intermediate of Step A was reacted with ammonium acetate (10 eq) and copper acetate (10 eq) in the presence of acetic acid to afford N-(4-fluorophenyl)-2-isopropyl-4-phenyl-5- (pyridin-3-yl)-1H-pyrrole-3-carboxamide; m/z 400 [M+H]⁺.

EXAMPLE 13 PREPARATION OF N-(2,4-DIFLUOROPHENYL)-2-ISOPROPYL-4-PHENYL-5-(PYRIDIN-2-YL)- 1 H-PYRROLE-3-CARBOXAMIDE

A. A solution of 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazoiiumbromide (0.765 gm, 0.2 eq, 0.003 mol) in 10 ml of anhydrous ethanol was concentrated by distillation to 8 ml of ethanol under nitrogen. 2-benzylidne-N-(2,4-difluorophenyl)-4-methyl-3-oxopentamide (5 gm, 1 eq, 0.015 mol), triethylamine 2.1 ml, 1 eq) and 2-pyridine-carboxalaldehyde (1.58 ml, 1.1 eq. 0.016 mol) were added. The resulting solution was stirred and heated to 80⁰C for 24 h. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by recrystallization using di-isopropyl ether to give 4.2 gm of N-(2,4-difluorophenyl)- 4-methyl-3-oxo-2-(2-oxo-1-phenyl-2-(pyridin-2-yl)ethyl)pentanamide (64%). M⁺436. 1H NMR (200 MHz, CDCI3)δ 8.3 (dd, 1H), 7.8-7.9 (m, 2H), 7.3 (m, 1H), 7.2 (m, 4H), 7.0 (m, 2H), 6.6-6.8 (m, 2H), 6.4 (br s, 1H), 4.7 (d, 1H), 4.5 (d, 1H), 3.1-3.3 (m, 1H), 1.1 (dd, 6H).

B. The intermediate of Step A was reacted with ammonium acetate (10 eq) and copper acetate (10 eq) in the presence of acetic acid to afford N-(2,4-difluorophenyl)-2-isopropyl-4-phenyl-5- (pyridin-2-yl)-1 H-pyrrole-3-carboxamide; m/z 418 [M+H]⁺. Example 14 Preparation Of N-(2,4-DIFLUOROPHENYL)-2-ISOPROPYL-4-PHENYL-5-(PYRIDIN-3-YL)-

1 H-PYRROLE-3-CARBOXAMIDE

A. A solution of 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazoliumbromide (0.765 gm, 0.2 eq, 0.003 mol) in 10 ml of anhydrous ethanol was concentrated by distillation to 8 ml of ethanol under nitrogen. 2-benzylidne-N-(2,4-difluorophenyl)-4-methyl-3-oxopentamide (5 gm, 1 eq, 0.015 mol), triethylamine 2.1 ml, 1 eq) and 3-pyridine-carboxalaldehyde (1.59 ml, 1.1 eq. 0.016 mol) were added. The resulting solution was stirred and heated to 80⁰C for 24 h. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by recrystallization using di-isopropyl ether to give 3.1 gm of N-(2,4-difluorophenyl)- 4-methyl-3-oxo-2-(2-oxo-1-phenyl-2-(pyridin-3-yl)ethyl)pentanamide (47%) as mixture of isomers (28:68). M⁺ 436. 1 H NMR (200 MHz, CDCI3) δ 9.2 (br s, 1 H), 8.7 (m, 1H), 8.5 (m, 1 H), 8.2 (m, 1 H), 7.8 (m, 1H), 7.3 (m, 4H), 7.1 (m, 2H), 6.8 (m, 2H), 5.3 (d, 1H), 4.6 (d, 1 H), 3.0 (m, 1H), 1.1 (dd, 6H).

B. The intermediate of Step A was reacted with ammonium acetate (10 eq) and copper acetate (10 eq) in the presence of acetic acid to afford N-(2,4-difluorophenyl)-2-isopropyl-4-phenyl-5-

(pyridin-3-yl)-1 H-pyrrole-3-carboxamide; m/z 418 [M+H]⁺

EXAMPLE 15 PREPARATION OF N-(2,4-DIFLUOROPHENYL)-2-ISOPROPYL-4-PHENYL-5-(PYRIDIN-4-YL)-

1 H-PYRROLE-3-CARBOXAMIDE

A. A solution of 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazoliumbromide (0.153 gm, 0.2 eq) in 10 ml of anhydrous ethanol was concentrated by distillation to 8 ml of ethanol under nitrogen. 2- benzylidne-N-(2,4-difluorophenyl)-4-methyl-3-oxopentamide (1 gm, 1 eq, 0.003 mol), triethylamine 0.42 ml, 1 eq) and 4-pyridine-carboxalaldehyde (0.318 ml, 1.1 eq. 0.003 mol) were added. The resulting solution was stirred and heated to 80⁰C for 24 h. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by recrystallization using di-isopropyl ether to give 0.596 gm of N-(2,4-difluorophenyl)-4- methyl-3-oxo-2-(2-oxo-1-phenyl-2-(pyridin-4-yl)ethyl)pentanamide (45%) as mixture of isomers (49:40). M⁺ 436. 1H NMR (200 MHz, CDCI3)α 8.7 (m, 1H), 8.6 (m, 2H), 7.7 (m, 1H), 7.3 (m, 4H), 7.0 (m, 2H), 6.8 (m, 2H), 4.6 (d, 1 H), 4.5 (d, 1H), 3.3 (m, 1 H), 1.1 (dd, 6H).

B. The intermediate of Step A was reacted with ammonium acetate (10 eq) and copper acetate (10 eq) in the presence of acetic acid to afford N-(2,4-difluorophenyl)-2~isopropyl-4-phenyl-5- (pyridin-4-yl)-1 H-pyrrole-3-carboxamide; m/z 418 [M+H]⁺ . [00260] EXAMPLE 16 PREPARATION OF 1 -BENZYL-5-(4-FLUORO-PHENYL)-2-lSOPROPYL-4- PHENYL-1 H-PYRROLE-S-CARBOXYLIC ACID (4-FLUORO-PHENYL)-AMIDE

[00261] A. Preparation Of 3-Phenyl-propynoic acid (4-fluoro-phenyI)-amide: 3- phenylpropiolic acid (2.0 g, 13.7 mmo!) was dissolved in neat thionyi chloride (3 mL) and heated at 70⁰C for 3 h. The excess thionyi chloride was removed and the mixture was dissolved in benzene (5 mL). The reaction flask was cooled to 0⁰C and 4-fluoroaniline (1.52 g, 13.7 mmol) was added slowly. The reaction stirred overnight at room temperature. The mixture was poured into cold water and extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with 5% HCI (3 x 100 mL), water (3 x 100 mL), 5% Na₂CO₃ (3 x 100 mL), water (3 x 100 mL), brine (3 x 100 mL), and dried over magnesium sulfate. It was recrystallized in ethanol and water to afford 3-Phenyl-propynoic acid (4-fluoro-phenyl)-amide as a yellow solid (1.68 g, 51.2%); MS (ESI) m/z 239 [M+H]⁺. - [00262]

B. In a reaction flask flushed with argon benzyl-L-valine methyl ester hydrochloric acid (3 g,

11.6 mmol) was dissolved in dichloromethane (50 mL). The reaction flask was cooled to O⁰C and triethy! amine (3.54 g, 34.9 mmol) and 4-fluorobenzyl chloride (2.02 g, 13.9 mmol) were added. The reaction was allowed to warm to room temperature over 12h and then the solvents were evaporated under reduced pressure. To the mixture a 2N solution of sodium hydroxide

(10 mL) was added and it was allowed to reflux for 3 h. The solvents were removed and it was then dissolved in ethyl acetate (10 mL). It was washed with water (3 x 10 mL) and 1N HCl solution was used to bring the pH down to 5. The organic layer was washed with brine (3 x 10 mL) and dried with magnesium sulfate. The solvent removed and afforded 2-[Benzyl-(4-fluoro- benzoyl)-amino]-3-methyl-butyric acid as a white solid. (3.83 g, 100%); MS (ESI) m/z 330

[M+H]⁺.

[00263] C. A mixture 2-[benzyl-(4-fluoro-benzoyl)-amino]-3-methyl-butyric acid from Step A (0. 75 g, 2.28 mmol) and N.N'-dicyclohexylcarbodiimide (0.564 g, 2.73 mmol) was dissolved in dry toluene (20 mL). The mixture was refluxed for 30 min and 3-phenyl-propynoic acid (4- fluoro-pheny!)-amide (0.6 g, 2.50 mmol) was added and refluxed for 7 h. The solid was filtered off and the filtrate was poured into a saturated solution of aqueous NaHCO₃ (5 mL) with chloroform (10 mL). The organic layer was extracted (3 x 10 mL) and dried over magnesium sulfate. It was purified by reverse phase HPLC to afford 1-Benzyl-5-(4-fluoro-phenyl)-2- isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (4-fluoro-phenyl)-amide as a yellow solid (0. 8 g, 69.2%); MS (ESl) m/z 507 [_M+H]⁺. [00264] EXAMPLE 17 EVALUATION OF THE ACTIVITY OF TEST COMPOUNDS [00265] A competitive binding assay was used to determine binding affinities for interactions between small molecules and PDE6<J (See commonly owned US Patent Application No. 10/406,797 Publication No 20040009470 entitled "Phage display affinity and specificity filters and forward screen", filed April 2, 2003 and commonly owned US Patent Application No. 10/115,442 Publication No 20030186221 entitled "Phage display affinity filter and forward screen", filed on April 2, 2002). In this competitive binding assay, PDE6£ is expressed as fusions to T7 bacteriophage particles and small molecules free in solution were individually tested for their ability to compete with the interaction between PDE66 and its immobilized ligand. The immobilized ligand, in this case, was an atorvastatin molecule in which the mevalonate head group of the atorvastatin was replaced with a modified PEG linker coupled to biotin which bound to streptavidin-coated magnetic beads (commonly owned PCT application No. PCT/US2005/000456, entitled "Conjugated small molecules", filed January 5, 2005). The - PDE65 fusion protein was prepared by cloning T7 phage stocks of PDEδ into a modified version of the commercially available T7 select 10-3 strain (Novagen) using cloning techniques described in commonly owned US Application No. 10/214,654, entitled "Uncoupling of DNA insert propagation and expression of protein for phage display", filed August 7, 2002. Alternatively, the fusion protein was cloned from a cDNA library screened via the use of phage display (See commonly owned US Application No. 09/653,668, entitled "Method to Identify Gene Function Using a Small Molecule probe", filed September 1 , 2000.) The fusion protein comprises of the N-terminus of the PDE65 fused to the C-terminus of the capsid protein 10B. The head portion of each phage particle includes 415 copies of the major capsid protein, and in this system approximately one to ten capsid proteins are expressed as fusion proteins. [00266] For the assay, phage-displayed PDE65 and immobilized atorvastatin are combined with the compound to be tested. If the test compound binds PDE65, it competes with the immobilized ligand and prevents binding to the solid support. If the test compound does not bind the PDE65, phage-dipslayed proteins are free to bind to the solid support through the interaction between the kinase and the immobilized ligand. The results are read out by quantitating the amount of fusion protein bound to the solid support, which is accomplished by either traditional phage plaque assays or by quantitative PCR (qPCR) using the phage genome as a template. To determine the affinity of the interactions between a test molecule and PDE65, the amount of phage-displayed fusion protein bound to the solid support is quantitated as a function of test compound concentration. The concentration of test molecule that reduces the number of phage bound to the solid support by 50% is equal to the Ka for the interaction between the kinase and the test molecule. Typically, data are collected for twelve concentrations of test compound and the resultant binding curve is fit to a non-cooperative binding isotherm to calculate K_d. [00267] QPCR Analysis

A Reagents and Equipment List

[00268] 1. 96 well polypropylene V-bottom plate (Greiner / 651201 )

[00269] 2. 384 well clear optical reaction plate with barcode (Applied Biosystems / 4343814)

[00270] 3. TaqMan Universal PCR Master Mix, No Amperase UNG (Applied Biosystems / 4326614)

[00271] 4. GeneAmp 10X PCR buffer & MgCI2 (Applied Biosystems / N8080190) [00272] 5. 2X QPCR buffer (1:5 dilution of component 4 into nuclease free H₂O) Ambit

[00273] 6. Nuclease Free H₂O (Ambion / 9932)

[00274] 7. T7_3prime-T7C Primer/Probe (Applied Biosystems / 4332079)

[00275] 8. Optical Adhesive Cover (Applied Biosystems / 4311971 )

B. Protocol

[00276] 1. A liquid handling robot (Perkin-Elmer, Evolution P3) is used to transfer 2.5 μl_ of each experimental eluate to be tested to a 384 well optical reaction plate, to which has already been added the following reagents.

2.3 μL TaqMan Universal PCR Master Mix 2.3 μL 2X QPCR buffer

2.75 μL Nuclease Free H₂O

0.15 μL T7_3prime-T7C Primer Mix

[00277] 2. The 384 well plate is then sealed with adhesive cover and centrifuged @ 750 x g for 5 minutes

[00278] 3. The plate was then processed on a Sequence Detection System (Model 7900HT, Applied Biosystems) using a PCR protocol of 15 minutes @ 95 ⁰C followed by 40 cycles of : 95 ⁰C for 15 seconds, 60 ⁰C for 1 minute.

[00279] 4. Results are analyzed using the SDS Enterprise Database software which accompanies the 7900HT

[00280] 5. Fluorescent dye, released from the probe component during the PCR and detected by the 7900HT, indicates a relative measure of phage DNA in the experimental eluates.

[00281] 6. PCR efficiency values (EV) are calculated from standard curves (known dilution series of phage) and used to express the experimental results in phage equivalent units (PEU) 1/ [00282] PEU = /EV ^CT

[00283] CT = fractional PCR cycle value at which dye fluorescence signal reaches an experimentally-determined level

[00284] To measure accurate K_d's for test compounds the concentration of immobilized ligand was below the K_d(p_robe), and the phage concentration was below the Kφrobe) and the K_d(t_est)- If both these concentrations were met the measured K_d for a test compound was independent of protein and immobilized ligand concentration (See commonly owned US application no. 10/406,797 entitled "Phage display affinity and specificity filters and forward screen", filed 04/02/03). [00285] T7 phage typically grow to a titre of 10⁸ to 10¹⁰ pfu/mL Each phage particle displays on average one to ten fusion molecules, so the concentration of phage-tagged protein in the binding reaction is therefore in the low picomolar range. During the binding reaction the fusion protein can bind to either the -test _ compound or the immobilized ligand. At low phage concentration the binding equilibrium equations yield the following expression for the binding constant of the interaction between the test compound and the fusion protein (K_d(test₎): K_d(t_est) = (K_d(p_ro_be)/(K_d(p_robe) + [Probe]))x[test]_1/2. K_d(probβ) is the binding constant for the interaction between the kinase and the immobilized ligand, [Probe] is the concentration of the immobilized ligand and [test]_1/2 is the concentration of the test compound at the midpoint of the transition. The concentration of the immobilized ligand is kept in the low nanomolar range, below its binding constant for the kinase. Under these conditions the expression simplifies to K_d(test₎ = [test]_1/2, and K_d(test) is independent of the affinity of the immobilized ligand for the fusion protein (Kφ_rob_e))- [00286] Representative results of the screening of compounds of the invention against the PDEδ fusion protein are shown in the Table 1 below. All data are the average of at least two independent experiments. Activities are represented using the following scheme; a = binding affinity for PDEδ greater than 10 μM or not determined; b = binding affinity for PDEδ greater than or equal to 2.5 μM, but less than 10 μM; c = binding affinity for PDEδ greater than or equal to 0.4 μM but less than 2.5 μM; d = binding affinity for PDEδ less than 0.4 μM.

Table t

Compound No. PDEdelta Binding Assay (Kd)

10002 d 10003 d

10004 d

10005 a

10006 a

10007 a 10010 a

10011 a

10012 b

10018 a

10019 c 10022 d

10023 c

10024 c

10025 d

10026 d 10027 d

10028 d

10029 c

10030 d

10031 c 10035 d

10036 c

10039 c

10041 d

10042 d 10043 d

10044 d

10045 c

10046 c

10047 c 10048 c

10049 d

10050 d

10051 d 10052 c

10053 c

10054 c

10055 d 10056 d

10057 d

10058 c

10059 d

10060 d 10061 d

10062 d

10063 d

10064 d

10065 c 10066 c

10067 d

10068 d

10069 d

10070 d 10071 c

10072 c

10073 b

10074 d

10075 d 10076 d

10077 d

20003 d

Claims

We claim:

1. A compound having the formula (I);

(I)

wherein

X is O or S; and Y is -NR⁴- or-O-;

R² is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, Optionally substituted alkynyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkenylalkyl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, -R⁸-OR⁹, -R⁸-SR⁹, -R⁸-S(O)_tR¹⁰ (where t is 1 or 2), -R⁸-N(R⁹)₂, -R⁸-CN, -R⁸-C(O)R⁹, -R⁸-C(S)R⁹, -R⁸-C(NR⁹)R⁹, -R⁸-C(O)OR⁹, -R⁸-C(S)OR⁹, -R⁸-C(NR⁹)OR⁹, -R⁸-C(O)N(R⁹)₂, -R⁸-C(S)N(R⁹)₂, -R⁸-C(NR⁹)N(R⁹)₂, -R⁸-C(O)SR⁹, -R⁸-C(S)SR⁹, -R⁸-C(NR⁹)SR⁹, -R⁸-S(O)_tOR⁹ (where t is 1 or 2), -R⁸-S(O)_tN(R⁹)₂ (where t is 1 or 2), -R⁸-S(O)_tN(R⁹)N(R⁹)₂ (where t is 1 or 2), -R⁸-S(O)_tN(R⁹)N=C(R⁹)₂, -R⁸-S(O)_tN(R⁹)C(O)R¹⁰ (where t is 1 or 2), -R⁸-S(O),N(R⁹)C(O)N(R⁹)₂ (where t is 1 or 2), -R⁸-S(O)_tN(R⁹)C(NR⁹)N(R⁹)₂ (where t is 1 or 2), -R⁸-N(R⁹)C(O)R¹⁰, -R⁸-N(R⁹)C(O)OR¹⁰, -R⁸-N(R⁹)C(O)SR¹⁰, -R⁸-N(R⁹)C(NR⁹)SR¹⁰, -R⁸-N(R⁹)C(S)SR¹⁰, -R⁸-N(R⁹)C(O)N(R⁹)₂, -R⁸-N(R⁹)C(NR⁹)N(R⁹)₂, -R⁸-N(R⁹)C(S)N(R⁹)₂, -R⁸-N(R⁹)S(O)_tR¹⁰ (where t is 1 or 2), -R⁸-OC(O)R¹⁰, -R⁸-OC(NR⁹)R¹⁰, -R⁸-OC(S)R¹⁰, -R⁸-OC(O)OR¹⁰, -R⁸-OC(NR⁹)OR¹⁰, -R⁸-OC(S)OR¹⁰, -R⁸-OC(O)SR⁹, -R⁸-OC(O)N(R⁹)₂, -R⁸-OC(NR⁹)N(R⁹)₂, -R⁸OC(S)N (R⁹)₂

-R⁸-C(O)-R¹¹-C(O)R⁹, -R⁸-C(O)-R¹¹-C(S)R⁹, -R⁸-C(O)-R¹¹-C(NR⁹)R⁹, -R⁸-C(O)-R¹¹-C(O)OR⁹, -R⁸-C(O)-R¹¹-C(S)OR⁹, -R⁸-C(O)-R¹¹-C(NR⁹)OR⁹, -R⁸-C(O)-R¹¹-C(O)N(R⁹)₂, -R⁸-C(O)-R¹¹-C(S)N(R⁹)₂, -R⁸-C(O)-R¹¹-C(NR⁹)N(R⁹)₂, -R⁸-C(O)-R¹¹-C(O)SR⁹, -R⁸-C(O)-R¹¹-C(S)SR⁹ and -R⁸-C(O)-R¹¹-C(NR⁹)SR⁹; R³ is optionally substituted alkyl, or optionally substituted alkenyl, or optionally substituted methoxy or optionally substituted ethoxy; R⁴ is hydrogen or optionally substituted alkyl; R⁵ is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl and optionally substituted aryl;

R⁶ is optionally substituted aryl or optionally substituted heteroaryl; R⁸ is independently a direct bond, an optionally substituted straight or branched alkylene chain, or an optionally substituted straight or branched alkenylene chain;

R⁹ is independently selected from (i) or (ii) below

(ii) two (R⁹)s together with the atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl; R¹⁰ is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl; each R¹¹ is independently an optionally substituted straight or branched alkylene chain or an optionally substituted straight or branched alkenylene chain; with the proviso that if R²⁰, R⁶ and R⁵ are optionally substituted phenyl, X is O and Y is - NH- and R³ is isopropyl, then R² is hydrogen, amino-substituted alkyl, hydroxy-substituted alkyl with the exception of -CH₂(CH(OH))₄CH₂OH, -CH₂CH₂CH(OH)CH₂ CH(OH)CH₂CH₂OH and - CH₂CH(OH)CH₂CH(OH)CH₂CH₂(OH), optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl wherein the heterocyclyl of said heterocyclylalkyl contains at least one nitrogen heteroatom, or -R⁸-N(R⁹)₂ wherein R⁸ and R⁹ are defined as above; and with the proviso that when X is O, Y is -NH-, R⁵ is optionally substituted heterocyclyl and R⁶ is optionally substituted phenyl, then R¹ is optionally substituted aryl or optionally substituted heteroaryl, or R³ is isopropyl; as a single isomer, a mixture of isomers, or as a racemic mixture of isomers; or as a solvate or polymorph; or as a prodrug; or as a metabolite; or as a pharmaceutically acceptable salt thereof.

2. The compound of Claim 1 having the formula (II):

(H) wherein:

X is O or S; p is an integer from 0 to 3; n is an integer from 0 to 3;

R¹ is optionally substituted aryl or optionally substituted heteroaryl;

R² is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkenylalkyl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, -R⁸-OR⁹, -R⁸-SR⁹, -R⁸-S(O)_tR¹⁰ (where t is 1 or 2), -R⁸-N(R⁹)₂, -R⁸-CN, -R⁸-C(O)R⁹, -R⁸-C(S)R⁹, -R⁸-C(NR⁹)R⁹, -R⁸-C(O)OR⁹, -R⁸-C(S)OR⁹, -R⁸-C(NR⁹)OR⁹, -R⁸-C(O)N(R⁹)₂, -R⁸-C(S)N(R⁹)_2> -R⁸-C(NR⁹)N(R⁹)₂, -R⁸-C(O)SR⁹, -R⁸-C(S)SR⁹, -R⁸-C(NR⁹)SR⁹, -R⁸-S(O)_tOR⁹ (where t is 1 or 2), -R⁸-S(O)_tN(R⁹)₂ (where t is 1 or 2), -R⁸-S(O)_tN(R⁹)N(R⁹)₂ (where t is 1 or 2), -R⁸-S(O)_tN(R⁹)N=C(R⁹)₂, -R⁸-S(O)_tN(R⁹)C(O)R¹⁰ (where t is 1 or 2), -R⁸-S(O),N(R⁹)C(O)N(R⁹)₂ (where t is 1 or 2), -R⁸-S(O)_tN(R⁹)C(NR⁹)N(R⁹)₂ (where t is 1 or 2), -R⁸-N(R⁹)C(O)R¹⁰, -R⁸-N(R⁹)C(O)OR¹⁰, -R⁸-N(R⁹)C(O)SR¹⁰, -R⁸-N(R⁹)C(NR⁹)SR¹⁰, -R⁸-N(R⁹)C(S)SR¹⁰, -R⁸-N(R⁹)C(O)N(R⁹)₂, -R⁸-N(R⁹)C(NR⁹)N(R⁹)_2l -R⁸-N(R⁹)C(S)N(R⁹)₂, -R⁸-N(R⁹)S(O)_tR¹⁰ (where t is 1 or 2), -R⁸OC(O)R¹⁰, -R⁸-OC(NR⁹)R¹⁰, -R⁸-OC(S)R¹⁰, -R⁸-OC(O)OR¹⁰, -R⁸-OC(NR⁹)OR¹⁰, -R⁸-OC(S)OR¹⁰, -R⁸-OC(O)SR⁹, -R⁸-OC(O)N(R⁹)₂, -R⁸-OC(NR⁹)N(R⁹)₂, -R⁸-OC(S)N(R⁹)₂ -R⁸-C(O)-R¹¹-C(O)R⁹, -R⁸-C(O)-R¹¹-C(S)R⁹, -R⁸-C(O)-R¹¹-C(NR⁹)R⁹, -R⁸-C(0)-R¹¹-C(O)0R⁹, -R⁸-C(O)-R¹¹-C(S)OR⁹, -R⁸-C(O)-R¹¹-C(NR⁹)OR⁹, -R⁸-C(O)-R¹¹-C(O)N(R⁹)₂, -R⁸-C(O)-R¹¹-C(S)N(R⁹)₂, -R⁸-C(O)-R¹¹-C(NR⁹)N(R⁹)₂, -R⁸-C(O)-R¹¹-C(O)SR⁹, -R⁸-C(O)-R¹¹-C(S)SR⁹ and -R⁸-C(O)-R¹¹-C(NR⁹)SR⁹;

R³ is optionally substituted C₁-C₄ alkyl, or optionally substituted C₁-C₄ alkenyl, or optionally substituted methoxy or optionally substituted ethoxy; and R^≤o and R^'80 are each independently selected from the group consisting of halo, cyano, nitro, amino, hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl.

3. The compound of Claim 2 wherein R² is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyciylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, -R⁸-OR⁹, -R⁸-SR⁹ and -R⁸-N(R⁹)₂;

R⁸ is independently a direct bond, an optionally substituted straight or branched alkylene chain, or an optionally substituted straight or branched alkenylene chain; and

R⁹ is independently selected from (i) or (ii) below

(ii) two (R⁹)s together with the atom to which they are attached form an optionally substituted heterocyclyl, or optionally substituted heteroaryl.

4. The compound of Claim 3 having the formula (III):

(III) wherein:

X is O or S; m is an integer from 0 to 3; n is an integer from 0 to 3; p is an integer from 0 to 3; β^≤ is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, -R⁸-OR⁹, -R⁸-SR⁹, and -R⁸-N(R⁹)₂;

R³ is optionally substituted C₁-C₄ alkyl, optionally substituted C₁-C₄ alkenyl, optionally substituted methoxy or optionally substituted ethoxy;

R⁹ is independently selected from (i) or (ii) below

(ii) two (R⁹)s together with the atom to which they are attached form an optionally substituted heterocyclyl, or optionally substituted heteroaryl; and R²⁰, R³⁰ and R⁴⁰ are each selected from the group consisting of halo, cyano, nitro, amino, hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl.

5. The compound of Claim 4 wherein m is 1, n is 0, p is 0, R² is hydrogen and R⁴⁰ is a substituent in the para-position selected from the group consisting of cyano, nitro, amino, hydroxy, optionally substituted alkoxy and optionally substituted alkyl.

6. The compound of Claim 5 selected from the group consisting of: 2-isopropyl-5-(4-methoxyphenyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide; 5-(4-tert-butylphenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide; 5-(4-cyanophenyl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; and 5-(4-aminophenyl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide.

7. The compound of Claim 4 having the formula (IV)

wherein:

X is O or S; n is an integer from 0 to 3; p is an integer from 0 to 3;

R² is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, -R⁸-OR⁹, -R⁸-SR⁹ and -R⁸-N(R⁹)₂;

R³ is isopropyl and

R⁸ is an optionally substituted straight or branched alkylene chain, or an optionally substituted straight or branched alkenylene chain;

R⁹ is independently selected from (i) or (ii) below

(i) R⁹ is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl or

(ii) two (R⁹)s together with the atom to which they are attached form an optionally substituted heterocyclyl, or optionally substituted heteroaryl; and

R²⁰ and R³⁰ is selected from the group consisting of halo, cyano, nitro, amino, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl.

8. The compound of Claim 7 wherein R² is hydrogen or -R⁸-N(R⁹)₂;

R⁸ is an optionally substituted straight or branched alkylene chain; and

R⁹ is independently selected from (i) or (ii) below

9. The compound of Claim 8 wherein n is 1 ; p is 0;

R² is hydrogen; and R³⁰ is para-substituent selected from hydroxy, optionally substituted alkyl and optionally substituted alkoxy.

10. The compound of Claim 9 selected from N-(4-(benzyloxy)phenyl)-5-(4-fluorophenyl)-2-iso^"propyl-4-phenyl-1H-pyrrole-3-carboxamide and 5-(4-fluorophenyl)-N-(4-hydroxyphenyl)-2-isopropyl-4-phenyl-1 H-pyrrole-3-carboxamide.

11. The compound of Claim 8 wherein n is 1 ; p is 0; R² is hydrogen; and

R³⁰ is a halo para-substituent.

12. The compound of Claim 11 wherein said compound is N,5-bis(4-fluorophenyl)-2-isopropyl-4-phenyl-1 H-pyrrole-3-carboxamide.

13. The compound of Claim 8 wherein n is 2; p is O;

R² is hydrogen; and and one R³⁰ is a halo in the ortho position and another R³⁰ is a halo in the para position.

14. The compound of Claim 13 wherein said compound is N-(2,4-difluorophenyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1 H-pyrrole-3-carboxamide.

15. The compound of Claim 8 wherein: n is 2; p is O; R² is -R⁸-N(R⁹)₂; and R^B is an optionally substituted straight or branched alkylene chain; two (R⁹)s together with the atom to which they are attached form an optionally substituted heterocyclyl, or optionally substituted heteroaryl; and one R³⁰ is halo in the ortho position and another R³⁰ is a halo in the para position.

16. The compound of Claim 15 wherein said compound is N-(2,4-difluorophenyl)-5-(4- fluorophenyl)-2-isopropyl-4-phenyl-1 -(3-(pyrrolidin-1 -yl)propyl)-1 H-pyrrole-3-carboxamide; or N-(2,4-difluorophenyl)-5-(4-fluorophenyl)-2-isopropyl-1-(3-(2-methyl-1H-imidazol-1-yl)propyl)-4- phenyl-1 H-pyrrole-3-carboxamide.

17. The compound of Claim 8 wherein: n is 0; p is 0;

R² is -R⁸-N(R⁹)₂; R⁸ is an optionally substituted straight or branched alkylene chain; and

R⁹ is independently selected from (i) or (ii) below

18. The compound of Claim 17 wherein said compound is 1-(2-(dimethylamino)ethyl)-5-(4- fluorophenyl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide;

(S)-5-(4-fluorophenyl)-1-(2-(2-hydroxypropylamino)ethyl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3- carboxamide;

5-(4-fluorophenyl)-1-(2-(2-hydroxypropylamino)ethyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3- carboxamide;

5-(4-fluorophenyl)-2-isopropyl-1-(2-(methylamino)ethyl)-N,4-diphenyl-1 H-pyrrole-3-carboxamide;

5-(4-fluorophenyl)-2-isopropyl-1-(2-(isopropylamino)ethyl)-N,4-diphenyl-1 H-pyrrole-3- carboxamide;

1-(2-aminoethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; 5-(4-fluorophenyl)-2-isopropyl-1-(2-(isopropylamino)ethyl)-N,4-diphenyl-1 H-pyrrole-3- carboxamide;

1-(4-aminobutyl)-5-(4-fiuorophenyl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide;

1-(3-aminopropyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; 5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(2-(piperidin-1-yl)ethyl)-1H-pyrrole-3- carboxamide;

5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(3-(pyrrolidin-1-yl)propyl)-1 H-pyrrole-3- carboxamide; 5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(2-(pyrrolidin-1-yl)ethyl)-1 H-pyrrole-3- carboxamide;

5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1 -(3-(piperidin-1 -yl)propyl)-1 H-pyrrole-3- carboxamide;

5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(4-(pyrrolidin-1-yl)butyl)-1H-pyrrole-3- carboxamide;

5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(piperidin-4-ylmethyl)-1 H-pyrrole-3-carboxamide;

5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(pyrrolidin-2-ylmethyl)-1H-pyrrole-3-carboxamide;

(R)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(pyrrolidin-2-ylmethyl)-1 H-pyrrole-3- carboxamide; 5-(4-fluorophenyl)-2-isopropyl-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-N,4-diphenyl-1H-pyrrole-3- carboxamide;

5-(4-fluorophenyl)-2-isopropyl-1-(3-(2-methyl-1H-imida2ol-1-yl)propyl)-N,4-diphenyl-1 H-pyrrole-

3-carboxamide; or

1-((1-ethylpiperidin-4-yl)methyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3- carboxamide.

19. The compound of Claim 8 wherein: n is 1 ; p is O; R² is -R⁸-N(R⁹)₂;

R⁸ is optionally substituted alkylene; and two (R⁹)s together with the atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl; and

R³⁰ is a halo substituent in the para-position.

20. The compound of Claim 19 wherein said compound is:

N,5-bis(4-fluorophenyl)-2-isopropyl-1-(3-morpholinopropyl)-4-phenyl-1 H-pyrrole-3-carboxamide; N,5-bis(4-fluorophenyl)-2-isopropyl-4-phenyl-1-(3-(pyrrolidin-1-yl)propyl)-1 H-pyrrole-3- carboxamide; N,5-bis(4-fluorophenyl)-2-isopropyl-4-phenyl-1-(4-(pyrrolidin-1-yl)butyl)-1 H-pyrrole-3- carboxamide;

N,5-bis(4-fluorophenyl)-2-isopropyl-1-((2S,3R,4R,5S)-2,3,4,5,6-pentahydroxyhexyl)-4-phenyl- 1 H-pyrrole-3-carboxamide; or N,5-bis(4-fluorophenyl)-2-isopropyl-1-(2,3,4,5,6-pentahydroxyhexyl)-4-phenyl-1H-pyrrole-3- carboxamide.

21. The compound of Claim 7 wherein: n is 0; p is 0; and

R² is optionally substituted aralkyl or optionally substituted heteroaralkyl.

22. The compound of Claim 21 wherein said compound is 5-(4-fluorophenyl)-2- 5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(pyridin-2-ylmethyl)-1H-pyrrole-3-carboxamide; 5-(4-fluorophenyl)-2-isopropyl-1-phenethyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; or 5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-(2-(pyridin-4-yl)ethyl)-1 H-pyrrole-3-carboxamide.

23. The compound bf Claim 2 wherein R¹ is optionally substituted heteroaryl and R³ is isopropyl.

24. The compound of Claim 23 wherein said. optionally substituted heteroaryl is selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, and isothiazolyl.

25. The compound of Claim 23 wherein said optionally substituted heteroaryl is pyridinyl.

26. The compound of Claim 25 wherein R² is hydrogen or -R⁸-N(R⁹)₂;

R⁸ is an optionally substituted straight or branched alkylene chain; and R⁹ is independently selected from (i) or (ii) below

27. The compound of Claim 26 wherein n is 0; p is 0; and R² is hydrogen.

28. The compound of Claim 27 wherein said compound is 2-isopropyl-N,4-diphenyl-5-(pyridin-4-yl)-1 H-pyrrole-3-carboxamide; 5-(2-hydroxypyridin-4-yl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide; 5-(2-chloropyridin-4-yl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; 2-isopropyl-N,4-diphenyl-5-(pyridin-2-yl)-1 H-pyrrole-3-carboxamide; or 2-isopropyl-N,4-diphenyl-5-(pyridin-3-yl)-1H-pyrrole-3-carboxamide.

29. The compound of Claim 26 wherein n is 1 ; p is O;

R² is hydrogen; and

R³⁰ is halo in the para position.

30. The compound of Claim 29 wherein said compound is N-(4-fluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-2-yl)-1 H-pyrrole-3-carboxamide; N-(4-fluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-4-yl)-1 H-pyrrole-3-carboxamide; or N-(4-fluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-3-yl)-1 H-pyrrole-3-carboxamide.

31. The compound of Claim 26 wherein: n is 2; p is O;

R² is hydrogen; and one R³⁰ is an a halo in the ortho position and another R³⁰ is a halo in the para position.

32. The compound of Claim 31 wherein said compound is:

N-(2,4-difluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-2-yl)-1 H-pyrrole-3-carboxamide; N-(2,4-difluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-3-yl)-1 H-pyrrole-3-carboxamide; or N- (2,4-difluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-4-yl)-1 H-pyrrole-3-carboxamide.

33. The compound of Claim 26 wherein:

R² is -R⁸-N(R⁹)₂;

R⁸ is optionally substituted alkylene; and two (R⁹)s together with the atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl.

34. The compound of Claim 33 wherein n is 0 and p is 0.

35. The compound of Claim 34 wherein said compound is:

2-isopropyl-1-(3-(2-methyl-1H-imida2ol-1-yl)propyl)-N,4-diphenyl-5-(pyridin-4-yl)-1H-pyrrole-3- carboxamide; or 2-isopropyl-N,4-diphenyl-5-(pyridin-4-yl)-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrrole-3-carboxamide.

36. The compound of Claim 26 wherein n is 1 , p is 0 and R³⁰ is a halo in the para position.

37. The compound of Claim 36 wherein said compound is: N-(4-fluorophenyl)-2-isopropyl-4-phenyl-5-(pyridin-4-yl)-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrrole- 3-carboxamide;

N-(4-fluorophenyl)-2-isopropyl-1-(3-(2-methyl-1 H-imidazol-1-yl)propyl)-4-phenyl-5-(pyridin-4-yl)-

1 H-pyrrole-3-carboxamide; or

N-(4-fluorophenyl)-2-isopropyl-1-((2S,3R_I4R,5S)-2,3,4,5,6-pentahydroxyhexyl)-4-phenyl-5-

(pyridin-4-yl)-1 H-pyrrole-3-carboxamide.

38. The compound of Claim 25 wherein R² is optionally substituted alkyl.

39. The compound of Claim 38 wherein said compound is N-(4-fluorophenyl)-2-isopropyl-1- (2,3,4,5,6-pentahydroxyhexyl)-4-phenyl-5-(pyridin-4-yi)-1 H-pyrrole-3-carboxamide.

40. The compound of Claim 23 wherein said heteroaryl is pyrimidinyl or imidazolyl.

41. The compound of Claim 40 selected from the group consisting of: 2-isopropyl-N,4-dipheny!-5-(pyrimidin-5-yl)-1 H-pyrrole-3-carboxamide; 5-(2-aminopyrimidin-5-yl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide;

5-(2-(dimethylamino)pyrimidin-5-yl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide; and 5-(1H-imidazol-5-yl)-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3-carboxamide.

42. A method for the treatment of a disease, or disorder associated with an excess or a deficiency PDEδ activity or endogenous regulators of said PDEδ activity, comprising: administering to a patient in need thereof, a pharmacologically active composition comprising a compound of Claim 1 or pharmaceutically acceptable derivative thereof.

43. The method of claim 42, wherein said disease or disorder associated with an excess or a deficiency PDEδ activity or endogenous regulators of said PDEδ activity is selected from the group consisting of cancer, diabetes, cardiovascular disease, immune dysfunction, neurodegeneration, heart disease, stroke, muscle wasting, osteoporosis, and retinal degenerative disease.

44. A pharmaceutical composition comprising a compound of Claim 1 and a pharmaceutically acceptable excipient.

45. The pharmaceutical composition of Claim 1 , further comprising one or more additional active ingredients.

46. The pharmaceutical composition of Claim 1 wherein said one or more additional active ingredients are selected from the group consisting of ACE inhibitors, Angiotensin Il blockers, anti-coagulants, anti-cancer agents, antiarrhythmics, anti-inflammatory agents, beta blockers, calcium channel antagonists, lipid-modulating agents, cytokine antagonists, digitalis medicines, diuretics, endothelin blockers, vasodilators, immune-suppressants, and glucose lowering agents.

47. A method of modulating the activity of PDEδ in a cell, tissue or whole organism, comprising administering a compound of Claim 1 to said cell, tissue or whole organism.