WO2009086012A1

WO2009086012A1 - Aurora inhibitors containing a zinc binding moiety

Info

Publication number: WO2009086012A1
Application number: PCT/US2008/087532
Authority: WO
Inventors: Xiong Cai; Changgeng Qian; Haixiao Zhai
Original assignee: Curis, Inc.
Priority date: 2007-12-20
Filing date: 2008-12-18
Publication date: 2009-07-09

Abstract

The present invention relates to Aurora inhibitors and their use in the treatment of cell proliferative diseases such as cancer. The said derivatives may further act as HDAC inhibitors.

Description

AURORA INHIBITORS CONTAINING A ZINC BINDING MOIETY

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No's. 61/015,275, filed on December 20, 2007 and 61/035,199, filed on March 10, 2008. The entire teachings of the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

One class of proteins found to play a part in cell cycling and, therefore, cell proliferation is the Aurora kinase family of proteins. Aurora kinases are enzymes of the serine/threonine kinase family of proteins, which play an important role in protein phosphorylation during the mitotic phase of the cell cycle. There are three known members of the Aurora kinase family, Aurora A, Aurora B and Aurora C, also commonly referred to as Aurora 2, Aurora 1, and Aurora 3, respectively.

During normal cell proliferation, these proteins are involved in chromosome segregation, mitotic spindle function, and cytokinesis. Aurora kinase expression is low in resting cells and peaks during the G2 and mitosis phases of the cell cycle. Several proposed mammalian substrates for Aurora kinases that are important for cell division include histone H3, TPX2, myosin II regulatory light chain, CENP-A, and protein phosphatase 1. Since the elucidation of their key role in mitotic progression and cell division, Aurora kinases have been closely linked to tumorigenesis. For example, Aurora kinase gene amplification and overexpression has been reported in many cancers. A coding single nucleotide polymorphism (SNP) has been identified that is significantly more frequent in advanced gastric cancer relative to early stage gastric cancer, and this SNP correlates with elevated kinase activity (Cancer Lett. 2006; 242 (2), 273-279). Overexpression of Aurora A induces centrosome amplification, aneuploidy and transformation in rodent fibroblasts

(Bischoff, J. R. et al. EMBO J. 1998, 17, 3052-3065; Nat. Genet. 1998, (2):189-93). This oncogenic activity is likely due to the generation of chromosome instability. Indeed, there is a strong correlation between Aurora A overexpression and chromosome aneuploidy in breast and gastric cancer. (Int., J. Cancer, 2001, 92, 370- 373; British Journal of Cancer 2001, 84, 824-831). Aurora B expression is elevated in cell lines derived from tumors of the colon, breast, lung, melanoma, kidney, ovary, pancreas, CNS, gastric tract and leukemias (Oncol Res. 2005; 15(l):49-57; Tatsuka et al, Cancer Res., 1998, 58, 4811-4816; British Journal of Cancer, 84, 824-831 (2001); EMBOJ., 17, 1998, 3052-3065). Aurora-A and Aurora-B have been found highly expressed in primary a human and mouse prostate cancer cell lines (Cancer Res, 2006, 66, 4996). In prostate cancer, increased nuclear expression of Aurora B was observed in high Gleason grade anaplastic prostate cancer tissues relative to low and intermediate grades, and Aurora B expression was accompanied by the phosphorylation of the histone H3 substrate (Prostat , 2003, 66(3): 326-33). Aurora C is overexpressed in primary colorectal cancer (Journal of Biological Chemistry, 1999, 274, 7334-7340; Jpn. J Cancer Res., 2000, 91, 1007-1014).

Aurora kinases appear to be viable targets for the treatment of cancer. Aurora kinases are overexpressed in various types of cancers, including colon, breast, lung, pancreas, prostate, bladder, head, neck, cervix, and ovarian cancers. The Aurora-A gene is part of an amplicon found in a subset of breast, colon, ovarian, liver, gastric and pancreatic tumors. Aurora-B has also been found to be overexpressed in most major tumor types. Overexpression of Aurora-B in rodent fibroblasts induces transformation, suggesting that Aurora-B is oncogenic. More recently, Aurora-B mRNA expression has been linked to chromosomal instability in human breast cancer. (Y. Miyoshi et al., Int. J Cancer, 2001, 92:370-373).

Further, inhibition of one or more of the Aurora kinases by several parties has been shown to inhibit cell proliferation and trigger apoptosis in several tumor cell lines. Particularly, inhibition of Aurora has been found to arrest cell cycling and promote programmed cell death via apoptosis. Accordingly, there has been a strong interest in finding inhibitors of Aurora kinase proteins.

The inhibition of Aurora kinases has been regarded as a promising approach for the development of novel anti-cancer agents. For example, WO 04/039774 describes aza-quinazolinones for treating cancer via inhibition of Aurora kinase, WO 04/037814 describes indazolinones for treating cancer via inhibition of Aurora-2 kinase, WO 04/016612 describes 2, 6, 9-substituted purine derivatives for treating cancer via inhibition of Aurora kinase, WO 04/000833 describes tri- and tetra- substituted pyrimidine compounds useful for treating Aurora-mediated diseases, WO 04/092607 describes crystals useful for screening, designing and evaluating compounds as agonists or antagonists of Aurora kinase and U.S. Pat. No. 6,919,338 and WO 03/055491 each describe substituted quinazoline derivatives as inhibitors of Aurora-2 kinase. Compound VX-680 has seen shown to inhibit all three Aurora kinases. Significant reduction in the number of tumor cells positive for histone H3 phosphorylation at serine 10 was observed when HCTl 16-derived tumors in nude rats when exposed to VX680 (Harrington, E.A. et. al, Nature Med. 2004, 10, 262- 267).

HN N

H hi N s N

H N Z.

H,: ^{N *}

V *•-€&} Elucidation of the complex and multifactorial nature of various diseases that involve multiple pathogenic pathways and numerous molecular components suggests that multi-targeted therapies may be advantageous over mono-therapies. Recent combination therapies with two or more agents for many such diseases in the areas of oncology, infectious disease, cardiovascular disease and other complex pathologies demonstrate that this combinatorial approach may provide advantages with respect to overcoming drug resistance, reduced toxicity and, in some circumstances, a synergistic therapeutic effect compared to the individual components.

Certain cancers have been effectively treated with such a combinatorial approach; however, treatment regimes using a cocktail of cytotoxic drugs often are limited by dose limiting toxicities and drug-drug interactions. More recent advances with molecularly targeted drugs have provided new approaches to combination treatment for cancer, allowing multiple targeted agents to be used simultaneously, or combining these new therapies with standard chemotherapeutics or radiation to improve outcome without reaching dose limiting toxicities. However, the ability to use such combinations currently is limited to drugs that show compatible pharmacologic and pharmacodynamic properties. In addition, the regulatory requirements to demonstrate safety and efficacy of combination therapies can be more costly and lengthy than corresponding single agent trials. Once approved, combination strategies may also be associated with increased costs to patients, as well as decreased patient compliance owing to the more intricate dosing paradigms required.

In the field of protein and polypeptide-based therapeutics it has become commonplace to prepare conjugates or fusion proteins that contain most or all of the amino acid sequences of two different proteins/polypeptides and that retain the individual binding activities of the separate proteins/polypeptides. This approach is made possible by independent folding of the component protein domains and the large size of the conjugates that permits the components to bind their cellular targets in an essentially independent manner. Such an approach is not, however, generally feasible in the case of small molecule therapeutics, where even minor structural modifications can lead to major changes in target binding and/or the pharmacokinetic/pharmacodynamic properties of the resulting molecule.

Histone acetylation is a reversible modification, with deacetylation being catalyzed by a family of enzymes termed HDACs. HDACs are represented by X genes in humans and are divided into four distinct classes {J MoI Biol, 2004, 338:1, 17-31). In mammalians class I HDACs (HDAC 1-3, and HDAC8) are related to yeast RPD3 HDAC, class 2 (HDAC4-7, HDAC9 and HDAClO) related to yeast HDAl, class 4 (HDACl 1), and class 3 (a distinct class encompassing the sirtuins which are related to yeast Sir2). Csordas, Biochem. J, 1990, 286: 23-38 teaches that histones are subject to post-translational acetylation of the, ε-amino groups of N-terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HATl). Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure. Indeed, access of transcription factors to chromatin templates is enhanced by histone hyperacetylation, and enrichment in underacetylated histone H4 has been found in transcriptionally silent regions of the genome (Taunton et al., Science, 1996, 272:408-411). In the case of tumor suppressor genes, transcriptional silencing due to histone modification can lead to oncogenic transformation and cancer. Several classes of HDAC inhibitors currently are being evaluated by clinical investigators. The first FDA approved HDAC inhibitor is Suberoylanilide hydroxamic acid (SAHA, Zolinza®) for the treatment of cutaneous T-cell lymphoma (CTCL). Other HDAC inhibitors include hydroxamic acid derivatives, PXDlOl, LBH589 and LAQ824, are currently in the clinical development. In the benzamide class of HDAC inhibitors, MS-275, MGCDO 103 and CI-994 have reached clinical trials. Mourne et al. (Abstract #4725, AACR 2005), demonstrate that thiophenyl modification of benzamides significantly enhance HDAC inhibitory activity against HDACl . Current therapeutic regimens of the types described above attempt to address the problem of drug resistance by the administration of multiple agents. However, the combined toxicity of multiple agents due to off-target side effects as well as drug-drug interactions often limits the effectiveness of this approach. Moreover, it often is difficult to combine compounds having differing pharmacokinetics into a single dosage form, and the consequent requirement of taking multiple medications at different time intervals leads to problems with patient compliance that can undermine the efficacy of the drug combinations. In addition, the health care costs of combination therapies may be greater than for single molecule therapies. Furthermore, it may be more difficult to obtain regulatory approval of a combination therapy since the burden for demonstrating activity/safety of a combination of two agents may be greater than for a single agent (Dancey J & Chen H, Nat. Rev. Drug Dis., 2006, 5:649). The development of novel agents that target multiple therapeutic targets selected not by virtue of cross reactivity, but through rational design will help improve patient outcome while avoiding these limitations. Thus, enormous efforts are still directed to the development of selective anti-cancer drugs as well as to new and more efficacious combinations of known anti-cancer drugs.

SUMMARY OF THE INVENTION

The present invention relates to Aurora inhibitors containing zinc-binding moiety based derivatives that have enhanced and unexpected properties as inhibitors of Aurora and their use in the treatment of Aurora related diseases and disorders such as cancer.

The compounds of the present invention may further act as HDAC or matrix metalloproteinase (MMP) inhibitors by virtue of their ability to bind zinc ions. Surprisingly these compounds are active at multiple therapeutic targets and are effective for treating disease. Moreover, in some cases it has even more surprisingly been found that the compounds have enhanced activity when compared to the activities of combinations of separate molecules individually having the Aurora and HDAC activities. In other words, the combination of pharmacophores into a single molecule may provide a synergistic effect as compared to the individual pharmacophores. More specifically, it has been found that it is possible to prepare compounds that simultaneously contain a first portion of the molecule that binds zinc ions and thus permits inhibition of HDAC and/or matrix metalloproteinase (MMP) activity and at least a second portion of the molecule that permits binding to a separate and distinct target that inhibits Aurora and thus provides therapeutic benefit. Preferably, the compounds of the present invention inhibit both Aurora and HDAC activity.

Accordingly, the present invention provides a compound having a general formula I:

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein

Cy and Cy₁ are independently selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; X and Y are independently NR₈, O, S, SO, SO₂, CO, alkylene, substituted alkylene, alkenylene or substituted alkenylene; where R₈ is hydrogen, acyl, aliphatic or substituted aliphatic;

Z is CRioo or N, where Rioo is independently selected from the group consisting of hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic;

B is linker; C is selected from:

; where Wi is O or S; Yi is absent, N, or CH; Zi is N or CH; R₇ and Rg are independently hydrogen, OR', aliphatic or substituted aliphatic, wherein R' is hydrogen, aliphatic, substituted aliphatic or acyl; provided that if R₇ and R9 are both present, one of R₇ or R₉ must be OR' and if Yl is absent, R₉ must be OR'; and Rg is hydrogen, acyl, aliphatic or substituted aliphatic;

where Wi is O or S; J is O, NH or NCH₃; and Ri₀ is hydrogen or lower alkyl;

C or

defined; Rn and Ri₂ are independently selected from hydrogen or aliphatic; R₁, R₂ and R3 are independently selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, CN, NO₂, N₃, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment of the compounds of the present invention are compounds represented by formula (I) as illustrated above, or geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof. In one embodiment of the compounds of the present invention are compounds represented by formula (II) as illustrated below, or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

wherein Bi is absent, O, S, NRg, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heterocyclic, aryl, heteroaryl; B₂ is absent, Ci-C₆ alkyl, , C₂-C₆ alkenyl, C₂-C₆ alkynyl, O, NH, alkylamine, S, SO, SO₂, heterocyclic, heteroaryl, aryl or C=O; B₃ is absent, O, NH, alkylamino, S, SO, SO₂, Ci-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, heterocyclic, heteroaryl, aryl or C=O; B₄ is absent, O, NH, alkylamino, CO, S, SO, SO₂, heterocyclic, heteroaryl or aryl; B₅ is absent, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heterocyclic, heteroaryl or aryl; Y₁₀-Y₁₃ are independently selected from CRioo, N, NR₈, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CR₁₀₀, where R₁₀₀ is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; R', Y₁, R₈, R₇, X and Y are as previously defined in the first embodiment. In one example, Bi is absent, O, S, NR₈, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heterocyclic, aryl, heteroaryl; B₂ is absent, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, O, NH, alkylamine, S, SO, SO₂, heterocyclic, heteroaryl, aryl or C=O; B₃ is absent, O, NH, alkylamino, S, SO, SO₂, Ci-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, heterocyclic, heteroaryl, aryl or C=O; B₄ is absent, O, NH, alkylamino, CO, S, SO, SO₂, heterocyclic, heteroaryl or aryl; B₅ is absent, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heterocyclic, heteroaryl or aryl; Yi_O-Yi₃ are independently selected from CR100, N, NR₈, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CR100, where R100 is independently selected from the group consisting of hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; R', Y₁, R₈, R₇, X and Y are as previously defined.

In one embodiment of the compounds of the present invention are compounds represented by formula (III) as illustrated below, or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

wherein Bi is absent, O, S, NRg, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heterocyclic, aryl, heteroaryl; B₂ is absent, Ci-C₆ alkyl, , C₂-C₆ alkenyl, C₂-C₆ alkynyl, O, NH, alkylamine, S, SO, SO₂, heterocyclic, heteroaryl, aryl or C=O; B₃ is absent, O, NH, alkylamino, S, SO, SO₂, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, heterocyclic, heteroaryl, aryl or C=O; B₄ is absent, O, NH, alkylamino, CO, S, SO, SO₂, heterocyclic, heteroaryl or aryl; B₅ is absent, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heterocyclic, heteroaryl or aryl; YiO-Yi₃ are independently selected from CRioo, N, NR₈, S, and O; X10-X14 are independently selected from the group consisting of N or CR100, where R100 is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; R', R₈, X and Y are as previously defined in the first embodiment. In one example, Bi is absent, O, S, NR₈, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heterocyclic, aryl, heteroaryl; B₂ is absent, Ci-C₆ alkyl, , C₂- C₆ alkenyl, C₂-C₆ alkynyl, O, NH, alkylamine, S, SO, SO₂, heterocyclic, heteroaryl, aryl or C=O; B₃ is absent, O, NH, alkylamino, S, SO, SO₂, Ci-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, heterocyclic, heteroaryl, aryl or C=O; B₄ is absent, O, NH, alkylamino, CO, S, SO, SO₂, heterocyclic, heteroaryl or aryl; B₅ is absent, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heterocyclic, heteroaryl or aryl; Y₁₀-Y₁₃ are independently selected from CRioo, N, NH, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CRioo, where Rioo is independently selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; R', R₈, X and Y are as previously defined.

In one embodiment of the compounds of the present invention are compounds represented by formula (IV) as illustrated below, or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

wherein YiO-Yi₃ are independently selected from CRioo, N, NR₈, S, and O; Xi₀-Xi₄ are independently selected from the group consisting of N or CRioo, where Rioo is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; X and Y are as previously defined in the first embodiment. In one example, Y₁₀-Y₁₃ are independently selected from CRioo, N, NH, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CRioo, where Rioo is independently selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF3, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; X and Y are as previously defined. In one embodiment of the compounds of the present invention are compounds represented by formula (V) as illustrated below, or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

wherein Y₁₀-Y₁₃ are independently selected from CRi₀₀, N, NRg, S, and O; Xi₀-Xi₄ are independently selected from the group consisting of N or CRi₀₀, where Ri₀₀ is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF3, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; X and Y are as previously defined in the first embodiment. In one example, Y₁₀-Y₁₃ are independently selected from CRi₀₀, N, NH, S, and O; Xi₀-Xi₄ are independently selected from the group consisting of N or CRi₀₀, where Ri₀₀ is independently selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; X and Y are as previously defined.

In one embodiment of the compounds of the present invention are compounds represented by formula (VI) as illustrated below, or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

wherein Y₁₀-Y₁₃ are independently selected from CRioo, N, NRs, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CRioo, where Rioo is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; X and Y are as previously defined in the first embodiment. In one example, YiO-Yi₃ are independently selected from CRioo, N, NH, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CRioo, where Rioo is independently selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; X and Y are as previously defined. In one embodiment of the compounds of the present invention are compounds represented by formula (VII) as illustrated below, or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

wherein Y₁₀-Y₁₃ are independently selected from CRioo, N, NRg, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CRioo, where Rioo is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF3, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; X and Y are as previously defined in the first embodiment. In one example, Y₁₀-Y₁₃ are independently selected from CRi₀₀, N, NH, S, and O; Xi₀-Xi₄ are independently selected from the group consisting of N or CRi₀₀, where Ri₀₀ is independently selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF3, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; X and Y are as previously defined.

In one embodiment of the compounds of the present invention are compounds represented by formula (VIII) as illustrated below, or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

wherein Y10-Y13 are independently selected from CR100, N, NRg, S, and O; X10-X14 are independently selected from the group consisting of N or CR100, where R100 is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF3, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; X and Y are as previously defined in the first embodiment. In one example, Y₁₀-Y₁₃ are independently selected from CR100, N, NH, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CR100, where R100 is independently selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF3, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; X and Y are as previously defined. In one embodiment of the compounds of the present invention are compounds represented by formula (IX) as illustrated below, or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

wherein Y₁₀-Y₁₃ are independently selected from CRioo, N, NRs, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CRioo, where Rioo is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF3, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; X5 is CH or N; m is 0 or 1; p is 0 to 3; X and Y are as previously defined in the first embodiment. In one example, Y₁₀-Y₁₃ are independently selected from CRi₀₀, N, NH, S, and O; Xi₀- X₁₄ are independently selected from the group consisting of N or CRi₀₀, where Ri₀₀ is independently selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; X and Y are as previously defined. In one embodiment of the compounds of the present invention are compounds represented by formula (X) as illustrated below, or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

wherein Y10-Y13 are independently selected from CR100, N, NR₈, S, and O; X10-X14 are independently selected from the group consisting of N or CR100, where R100 is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; q is 0 to 4; X and Y are as previously defined in the first embodiment. In one example, Y10-Y13 are independently selected from CR₁₀₀, N, NH, S, and O; Xi₀-Xi₄ are independently selected from the group consisting of N or CRi₀₀, where Ri₀₀ is independently selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; X and Y are as previously defined. One subset of preferred compounds of the invention includes compounds of

Formula I where Cy is phenyl substituted with an acylamino group, preferably a cycloalkylcarbonylamino group and most preferably, a cyclopropylcarbonylamino group. Such compounds include compounds of Formulas (II) to (X) where at least one of Xi₀ to Xi₄ is CRi₀₀, wherein Ri₀₀ is an amino group substituted by an acyl group, such as a (Ci-Ce)alkanoyl , (C₃-C6)cycloalkylcarbonyl , heterocyclic carbonyl, aroyl or heteroaroyl. Preferably, the acyl group is a (C₃- C₆)cycloalkylcarbonyl group, more preferably a cyclopropylcarbonyl group. In certain preferred embodiments, one of X₁₀ to Xi₄, preferably X12, is CRioo, where Rioo is acyl-substituted amino and each of X₁₀ to Xi₄ is CH. In particularly preferred embodiments, Xi₂ is CRioo, where Rioo is cyclopropylcarbonyl-amino and Xi₀, Xn, X₁₃ and X₁₄ are each CH.

Another subset of preferred compounds of the invention includes compounds of Formula I wherein Y is NRs, preferably NH, and Cy₁ is pyrazolyl substituted with a Ci-Cβ-alkyl group, preferably a methyl group. Such compounds include compounds of Formulas H-X wherein Y₁O and Yn, Yi₂ and Y₁₃ or Yn and Yi₂ are both N and at least one of the remaining positions is CRioo, where Rioo is C₁-C₆- alkyl, preferably methyl. In particularly preferred embodiments, Yi₂ and Y₁₃ are both N, and Yn is CRioo, where Rioo is Ci-C₆-alkyl, preferably methyl.

Representative compounds according to the invention are those selected from the Table A below or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

TABLE A

Compound # Structure

In one embodiment, compounds of the invention inhibit protein kinases, particularly Aurora kinases and glycogen synthase kinases.

In one embodiment, compounds of the invention are inhibitors of glycogen synthase kinase-3 (GSK-3). GSK-3 is a serine/threonine protein kinase comprised of α and β iso forms that are each encoded by distinct genes [Coghlan et al., Chemistry & Biology, 2000, 7, 793-803; and Kim and Kimmel, Curr. Opinion Genetics Dev., 2000, 10, 508-514]. GSK-3 has been implicated in various diseases including diabetes, Alzheimer's disease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy [see, e.g., WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol. 2000, 151, 117]. These diseases may be caused by, or may result in, the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role.

GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These include glycogen synthase, which is the rate- limiting enzyme required for glycogen synthesis, the microtubule-associated protein Tau, the gene transcription factor β-catenin, the translation initiation factor elF-2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-myc, c-myb, CREB, and CEPB. alpha. These diverse targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.

In a GSK-3 mediated pathway that is relevant for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. GSK-3 is a negative regulator of the insulin-induced signal in this pathway. Normally, the presence of insulin causes inhibition of GSK-3 -mediated phosphorylation and deactivation of glycogen synthase. The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93, 8455-9 (1996); Cross et al., Biochem. J, 303, 21-26 (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); and Massillon et al., Biochem J. 299, 123-128 (1994)]. However, where the insulin response is impaired in a diabetic patient, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood levels of glucose with acute and chronic effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also been reported that in patients with type II diabetes, GSK-3 is overexpressed [WO 00/38675]. Therapeutic inhibitors of GSK-3 are therefore potentially useful for treating diabetic patients suffering from an impaired response to insulin.

In a GSK-3 mediated pathway that is relevant for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. GSK-3 is a negative regulator of the insulin-induced signal in this pathway. Normally, the presence of insulin causes inhibition of GSK-3 -mediated phosphorylation and deactivation of glycogen synthase. The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS, 1996, 93, 8455-9; Cross et al., Biochem. J, 1994, 303, 21-26; Cohen, Biochem. Soc. Trans., 1993, 21, 555-567; and Massillon et al., Biochem J. 1994, 299, 123-128]. However, where the insulin response is impaired in a diabetic patient, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood levels of glucose with acute and chronic effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal insulin-induced inhibition of

GSK-3 fails to occur. It has also been reported that in patients with type II diabetes, GSK-3 is overexpressed [WO 00/38675]. Therapeutic inhibitors of GSK-3 are therefore potentially useful for treating diabetic patients suffering from an impaired response to insulin. GSK-3 activity has also been associated with Alzheimer's disease. This disease is characterized by the presence of the well-known β-amyloid peptide and the formation of intracellular neurofibrillary tangles. The neurofibrillary tangles contain hyperphosphorylated Tau protein, in which Tau is phosphorylated on abnormal sites. GSK-3 has been shown to phosphorylate these abnormal sites in cell and animal models. Furthermore, inhibition of GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells [Lovestone et al., Current Biology 4, 1994, 1077-86; and Brownlees et al., Neuroreport 8, 1997, 3251-55]. Therefore, it is believed that GSK-3 activity may promote generation of neurofibrillary tangles and progression of Alzheimer's disease.

Another substrate of GSK-3 is β-catenin, which is degraded after phosphorylation by GSK-3. Reduced levels of β-catenin have been reported in schizophrenic patients and have also been associated with other diseases related to increase in neuronal cell death [Zhong et al, Nature, 1998, 395, 698-702; Takashima et al., PNAS, 1993, 90, 7789-93; Pei et al., J. Neuropathol. Exp, 1997, 56, 70-78; and Smith et al., Bio-org. Med. Chem. 2001, 11, 635-639].

The invention further provides methods for the prevention or treatment of diseases or conditions involving aberrant proliferation, differentiation or survival of cells. In one embodiment, the invention further provides for the use of one or more compounds of the invention in the manufacture of a medicament for halting or decreasing diseases involving aberrant proliferation, differentiation, or survival of cells. In preferred embodiments, the disease is cancer. In one embodiment, the invention relates to a method of treating cancer in a subject in need of treatment comprising administering to said subject a therapeutically effective amount of a compound of the invention.

The term "cancer" refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. For example, cancers include, but are not limited to, mesothelioma, leukemias and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotrophic virus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodisplastic syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft- tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular), lung cancer (e.g., small-cell and non small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin's syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Additional exemplary forms of cancer which may be treated by the subject compounds include, but are not limited to, cancer of skeletal or smooth muscle, stomach cancer, cancer of the small intestine, rectum carcinoma, cancer of the salivary gland, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer. Additional cancers that the compounds described herein may be useful in preventing, treating and studying are, for example, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gall bladder carcinoma, bronchial carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma. In one aspect of the invention, the present invention provides for the use of one or more compounds of the invention in the manufacture of a medicament for the treatment of cancer.

In one embodiment, the present invention includes the use of one or more compounds of the invention in the manufacture of a medicament that prevents further aberrant proliferation, differentiation, or survival of cells. For example, compounds of the invention may be useful in preventing tumors from increasing in size or from reaching a metastatic state. The subject compounds may be administered to halt the progression or advancement of cancer or to induce tumor apoptosis or to inhibit tumor angiogenesis. In addition, the instant invention includes use of the subject compounds to prevent a recurrence of cancer. This invention further embraces the treatment or prevention of cell proliferative disorders such as hyperplasias, dysplasias and pre-cancerous lesions. Dysplasia is the earliest form of pre-cancerous lesion recognizable in a biopsy by a pathologist. The subject compounds may be administered for the purpose of preventing said hyperplasias, dysplasias or pre-cancerous lesions from continuing to expand or from becoming cancerous. Examples of pre-cancerous lesions may occur in skin, esophageal tissue, breast and cervical intra-epithelial tissue.

"Combination therapy" includes the administration of the subject compounds in further combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent) and non-drug therapies (such as, but not limited to, surgery or radiation treatment). For instance, the compounds of the invention can be used in combination with other pharmaceutically active compounds, preferably compounds that are able to enhance the effect of the compounds of the invention. The compounds of the invention can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.

In one aspect of the invention, the subject compounds may be administered in combination with one or more separate agents that modulate protein kinases involved in various disease states. Examples of such kinases may include, but are not limited to: serine/threonine specific kinases, receptor tyrosine specific kinases and non-receptor tyrosine specific kinases. Serine/threonine kinases include mitogen activated protein kinases (MAPK), meiosis specific kinase (Aurora), RAF and Aurora kinase. Examples of receptor kinase families include epidermal growth factor receptor (EGFR) (e.g. HER2/neu, HER3, HER4, ErbB, ErbB2, ErbB3, ErbB4, Xmrk, DER, Let23); fibroblast growth factor (FGF) receptor (e.g. FGF- R1,GFF-R2/BEK/CEK3, FGF-R3/CEK2, FGF-R4/TKF, KGF-R); hepatocyte growth/scatter factor receptor (HGFR) (e.g, MET, RON, SEA, SEX); insulin receptor (e.g. IGFI-R); Eph (e.g. CEK5, CEK8, EBK, ECK, EEK, EHK-I, EHK-2, ELK, EPH, ERK, HEK, MDK2, MDK5, SEK); AxI (e.g. Mer/Nyk, Rse); RET; and platelet-derived growth factor receptor (PDGFR) (e.g. PDGFα-R, PDGβ-R, CSFl- R/FMS, SCF-R/C-KIT, VEGF-R/FLT, NEK/FLK1, FLT3/FLK2/STK-1). Nonreceptor tyrosine kinase families include, but are not limited to, BCR-ABL (e.g. p43^abl, ARG); BTK (e.g. ITK/EMT, TEC); CSK, FAK, FPS, JAK, SRC, BMX, FER, CDK and SYK.

In another aspect of the invention, the subject compounds may be administered in combination with one or more separate agents that modulate non- kinase biological targets or processes. Such targets include histone deacetylases (HDAC), DNA methyltransferase (DNMT), heat shock proteins (e.g. Bcl-2), and proteosomes.

In a preferred embodiment, subject compounds may be combined with antineoplastic agents (e.g. small molecules, monoclonal antibodies, antisense RNA, and fusion proteins) that inhibit one or more biological targets such as Zolinza, Tarceva, Iressa, Tykerb, Gleevec, Sutent, Sprycel, Nexavar, Sorafmib, CNF2024, RG108, BMS387032, Affϊnitak, Avastin, Herceptin, Erbitux, AG24322, PD325901, ZD6474, PD 184322, Obatodax, ABT737 and AEE788. Such combinations may enhance therapeutic efficacy over efficacy achieved by any of the agents alone and may prevent or delay the appearance of resistant mutational variants.

In certain preferred embodiments, the compounds of the invention are administered in combination with a chemotherapeutic agent. Chemotherapeutic agents encompass a wide range of therapeutic treatments in the field of oncology. These agents are administered at various stages of the disease for the purposes of shrinking tumors, destroying remaining cancer cells left over after surgery, inducing remission, maintaining remission and/or alleviating symptoms relating to the cancer or its treatment. Examples of such agents include, but are not limited to, alkylating agents such as mustard gas derivatives (Mechlorethamine, cylophosphamide, chlorambucil, melphalan, ifosfamide), ethylenimines (thiotepa, hexamethylmelanine), Alkylsulfonates (Busulfan), Hydrazines and Triazines (Altretamine, Procarbazine, Dacarbazine and Temozolomide), Nitrosoureas (Carmustine, Lomustine and Streptozocin), Ifosfamide and metal salts (Carboplatin, Cisplatin, and Oxaliplatin); plant alkaloids such as Podophyllotoxins (Etoposide and Tenisopide), Taxanes (Paclitaxel and Docetaxel), Vinca alkaloids (Vincristine, Vinblastine, Vindesine and Vinorelbine), and Camptothecan analogs (Irinotecan and Topotecan); anti-tumor antibiotics such as Chromomycins (Dactinomycin and Plicamycin), Anthracyclines (Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, Valrubicin and Idarubicin), and miscellaneous antibiotics such as Mitomycin, Actinomycin and Bleomycin; anti-metabolites such as folic acid antagonists (Methotrexate, Pemetrexed, Raltitrexed, Aminopterin), pyrimidine antagonists (5- Fluorouracil, Floxuridine, Cytarabine, Capecitabine, and Gemcitabine), purine antagonists (6-Mercaptopurine and 6-Thioguanine) and adenosine deaminase inhibitors (Cladribine, Fludarabine, Mercaptopurine, Clofarabine, Thioguanine, Nelarabine and Pentostatin); topoisomerase inhibitors such as topoisomerase I inhibitors (Ironotecan, topotecan) and topoisomerase II inhibitors (Amsacrine, etoposide, etoposide phosphate, teniposide); monoclonal antibodies (Alemtuzumab, Gemtuzumab ozogamicin, Rituximab, Trastuzumab, Ibritumomab Tioxetan, Cetuximab, Panitumumab, Tositumomab, Bevacizumab); and miscellaneous anti- neoplastics such as ribonucleotide reductase inhibitors (Hydroxyurea); adrenocortical steroid inhibitor (Mitotane); enzymes (Asparaginase and Pegaspargase); anti-microtubule agents (Estramustine); and retinoids (Bexarotene, Isotretinoin, Tretinoin (ATRA).

In certain preferred embodiments, the compounds of the invention are administered in combination with a chemoprotective agent. Chemoprotective agents act to protect the body or minimize the side effects of chemotherapy. Examples of such agents include, but are not limited to, amfostine, mesna, and dexrazoxane.

In one aspect of the invention, the subject compounds are administered in combination with radiation therapy. Radiation is commonly delivered internally (implantation of radioactive material near cancer site) or externally from a machine that employs photon (x-ray or gamma-ray) or particle radiation. Where the combination therapy further comprises radiation treatment, the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co- action of the combination of the therapeutic agents and radiation treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the radiation treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

It will be appreciated that compounds of the invention can be used in combination with an immunotherapeutic agent. One form of immunotherapy is the generation of an active systemic tumor- specific immune response of host origin by administering a vaccine composition at a site distant from the tumor. Various types of vaccines have been proposed, including isolated tumor-antigen vaccines and antiidiotype vaccines. Another approach is to use tumor cells from the subject to be treated, or a derivative of such cells (reviewed by Schirrmacher et al. (1995) J. Cancer Res. Clin. Oncol. 121 :487). In U.S. Pat. No. 5,484,596, Hanna Jr. et al. claims a method for treating a resectable carcinoma to prevent recurrence or metastases, comprising surgically removing the tumor, dispersing the cells with collagenase, irradiating the cells, and vaccinating the patient with at least three consecutive doses of about 10⁷ cells.

It will be appreciated that the compounds of the invention may advantageously be used in conjunction with one or more adjunctive therapeutic agents. Examples of suitable agents for adjunctive therapy include a 5HTi agonist, such as a triptan (e.g. sumatriptan or naratriptan); an adenosine Al agonist; an EP ligand; an NMDA modulator, such as a glycine antagonist; a sodium channel blocker (e.g. lamotrigine); a substance P antagonist (e.g. an NKi antagonist); a cannabinoid; acetaminophen or phenacetin; a 5-lipoxygenase inhibitor; a leukotriene receptor antagonist; a DMARD (e.g. methotrexate); gabapentin and related compounds; a tricyclic antidepressant (e.g. amitryptilline); a neurone stabilizing antiepileptic drug; a mono-aminergic uptake inhibitor (e.g. venlafaxine); a matrix metalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor, such as an iNOS or an nNOS inhibitor; an inhibitor of the release, or action, of tumour necrosis factor .alpha.; an antibody therapy, such as a monoclonal antibody therapy; an antiviral agent, such as a nucleoside inhibitor (e.g. lamivudine) or an immune system modulator (e.g. interferon); an opioid analgesic; a local anaesthetic; a stimulant, including caffeine; an H₂-antagonist (e.g. ranitidine); a proton pump inhibitor (e.g. omeprazole); an antacid (e.g. aluminum or magnesium hydroxide; an antiflatulent (e.g. simethicone); a decongestant (e.g. phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine); an antitussive (e.g. codeine, hydrocodone, carmiphen, carbetapentane, or dextramethorphan); a diuretic; or a sedating or non-sedating antihistamine.

In one embodiment, compounds of the invention can be used to induce or inhibit apoptosis, a physiological cell death process critical for normal development and homeostasis. Alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases. Compounds of the invention, as modulators of apoptosis, will be useful in the treatment of a variety of human diseases with aberrations in apoptosis including cancer (particularly, but not limited to, follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostate and ovary, and precancerous lesions such as familial adenomatous polyposis), viral infections (including, but not limited to, herpes virus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune diseases (including, but not limited to, systemic lupus, erythematosus, immune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), AIDS, myelodysplastic syndromes, aplastic anemia, ischemic injury associated myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol induced liver diseases, hematological diseases (including, but not limited to, chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including, but not limited to, osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases, and cancer pain.

In one aspect, the invention provides the use of compounds of the invention for the treatment and/or prevention of immune response or immune -mediated responses and diseases, such as the prevention or treatment of rejection following transplantation of synthetic or organic grafting materials, cells, organs or tissue to replace all or part of the function of tissues, such as heart, kidney, liver, bone marrow, skin, cornea, vessels, lung, pancreas, intestine, limb, muscle, nerve tissue, duodenum, small-bowel, pancreatic-islet-cell, including xeno-transplants, etc.; to treat or prevent graft-versus-host disease, autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, thyroiditis, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes uveitis, juvenile-onset or recent-onset diabetes mellitus, uveitis, Graves disease, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, vasculitis, auto-antibody mediated diseases, aplastic anemia, Evan's syndrome, autoimmune hemolytic anemia, and the like; and further to treat infectious diseases causing aberrant immune response and/or activation, such as traumatic or pathogen induced immune disregulation, including for example, that which are caused by hepatitis B and C infections, HIV, staphylococcus aureus infection, viral encephalitis, sepsis, parasitic diseases wherein damage is induced by an inflammatory response (e.g., leprosy); and to prevent or treat circulatory diseases, such as arteriosclerosis, atherosclerosis, vasculitis, polyarteritis nodosa and myocarditis. In addition, the present invention may be used to prevent/suppress an immune response associated with a gene therapy treatment, such as the introduction of foreign genes into autologous cells and expression of the encoded product. Thus in one embodiment, the invention relates to a method of treating an immune response disease or disorder or an immune-mediated response or disorder in a subject in need of treatment comprising administering to said subject a therapeutically effective amount of a compound of the invention.

In one aspect, the invention provides the use of compounds of the invention in the treatment of a variety of neurodegenerative diseases, a non-exhaustive list of which includes: Disorders characterized by progressive dementia in the absence of other prominent neurologic signs, such as Alzheimer's disease; Senile dementia of the Alzheimer type; and Pick's disease (lobar atrophy); Syndromes combining progressive dementia with other prominent neurologic abnormalities such as A) syndromes appearing mainly in adults (e.g., Huntington's disease, Multiple system atrophy combining dementia with ataxia and/or manifestations of Parkinson's disease, Progressive supranuclear palsy (Steel-Richardson-Olszewski), diffuse Lewy body disease, and corticodentatonigral degeneration); and B) syndromes appearing mainly in children or young adults (e.g., Hallervorden-Spatz disease and progressive familial myoclonic epilepsy); Syndromes of gradually developing abnormalities of posture and movement such as paralysis agitans (Parkinson's disease), striatonigral degeneration, progressive supranuclear palsy, torsion dystonia (torsion spasm; dystonia musculorum deformans), spasmodic torticollis and other dyskinesis, familial tremor, and Gilles de Ia Tourette syndrome; Syndromes of progressive ataxia such as cerebellar degenerations (e.g., cerebellar cortical degeneration and olivopontocerebellar atrophy (OPCA)); and spinocerebellar degeneration

(Friedreich's ataxia and related disorders); Syndrome of central autonomic nervous system failure (Shy-Drager syndrome); Syndromes of muscular weakness and wasting without sensory changes (motorneuron disease such as amyotrophic lateral sclerosis, spinal muscular atrophy (e.g., infantile spinal muscular atrophy (Werdnig- Hoffman)), juvenile spinal muscular atrophy (Wohlfart-Kugelberg-Welander) and other forms of familial spinal muscular atrophy), primary lateral sclerosis, and hereditary spastic paraplegia; Syndromes combining muscular weakness and wasting with sensory changes (progressive neural muscular atrophy; chronic familial polyneuropathies) such as peroneal muscular atrophy (Charcot-Marie-Tooth), hypertrophic interstitial polyneuropathy (Dejerine-Sottas), and miscellaneous forms of chronic progressive neuropathy; Syndromes of progressive visual loss such as pigmentary degeneration of the retina (retinitis pigmentosa), and hereditary optic atrophy (Leber's disease). Furthermore, compounds of the invention can be implicated in chromatin remodeling.

The invention encompasses pharmaceutical compositions comprising pharmaceutically acceptable salts of the compounds of the invention as described above. The invention also encompasses pharmaceutical compositions comprising hydrates of the compounds of the invention. The term "hydrate" includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like. The invention further encompasses pharmaceutical compositions comprising any solid or liquid physical form of the compound of the invention. For example, the compounds can be in a crystalline form, in amorphous form, and have any particle size. The particles may be micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical form.

The compounds of the invention, and derivatives, fragments, analogs, homo logs, pharmaceutically acceptable salts or hydrate thereof can be incorporated into pharmaceutical compositions suitable for administration, together with a pharmaceutically acceptable carrier or excipient. Such compositions typically comprise a therapeutically effective amount of any of the compounds above, and a pharmaceutically acceptable carrier. Preferably, the effective amount when treating cancer is an amount effective to selectively induce terminal differentiation of suitable neoplastic cells and less than an amount which causes toxicity in a patient. Compounds of the invention may be administered by any suitable means, including, without limitation, parenteral, intravenous, intramuscular, subcutaneous, implantation, oral, sublingual, buccal, nasal, pulmonary, transdermal, topical, vaginal, rectal, and transmucosal administrations or the like. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. Pharmaceutical preparations include a solid, semisolid or liquid preparation (tablet, pellet, troche, capsule, suppository, cream, ointment, aerosol, powder, liquid, emulsion, suspension, syrup, injection etc.) containing a compound of the invention as an active ingredient, which is suitable for selected mode of administration. In one embodiment, the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, i.e., as a solid or a liquid preparation. Suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets and effervescent, powders, and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In one embodiment of the present invention, the composition is formulated in a capsule. In accordance with this embodiment, the compositions of the present invention comprise in addition to the active compound and the inert carrier or diluent, a hard gelatin capsule. Any inert excipient that is commonly used as a carrier or diluent may be used in the formulations of the present invention, such as for example, a gum, a starch, a sugar, a cellulosic material, an acrylate, or mixtures thereof. A preferred diluent is microcrystalline cellulose. The compositions may further comprise a disintegrating agent (e.g., croscarmellose sodium) and a lubricant (e.g., magnesium stearate), and may additionally comprise one or more additives selected from a binder, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof. Furthermore, the compositions of the present invention may be in the form of controlled release or immediate release formulations. For liquid formulations, pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, emulsions or oils. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Examples of oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish- liver oil. Solutions or suspensions can also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. In addition, the compositions may further comprise binders (e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g., cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers (e.g., tris-HCL, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol, cyclodextrins), a glidant (e.g., colloidal silicon dioxide), anti-oxidants (e.g., ascorbic acid, sodium metabisulfϊte, butylated hydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose, hydroxypropylmethyl cellulose), viscosity increasing agents (e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citric acid), flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g., colloidal silicon dioxide), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifϊers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g., ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.

In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat No. 4,522,811. It is especially advantageous to formulate oral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

Daily administration may be repeated continuously for a period of several days to several years. Oral treatment may continue for between one week and the life of the patient. Preferably the administration may take place for five consecutive days after which time the patient can be evaluated to determine if further administration is required. The administration can be continuous or intermittent, e.g., treatment for a number of consecutive days followed by a rest period. The compounds of the present invention may be administered intravenously on the first day of treatment, with oral administration on the second day and all consecutive days thereafter.

The preparation of pharmaceutical compositions that contain an active component is well understood in the art, for example, by mixing, granulating, or tablet- forming processes. The active therapeutic ingredient is often mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient. For oral administration, the active agents are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions and the like as detailed above.

The amount of the compound administered to the patient is less than an amount that would cause toxicity in the patient. In certain embodiments, the amount of the compound that is administered to the patient is less than the amount that causes a concentration of the compound in the patient's plasma to equal or exceed the toxic level of the compound. Preferably, the concentration of the compound in the patient's plasma is maintained at about 10 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 25 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 50 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 100 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 500 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 1000 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 2500 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 5000 nM. The optimal amount of the compound that should be administered to the patient in the practice of the present invention will depend on the particular compound used and the type of cancer being treated.

DEFINITIONS

Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

An "aliphatic group" or "aliphatic" is non-aromatic moiety that may be saturated (e.g. single bond) or contain one or more units of unsaturation, e.g., double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic, contain carbon, hydrogen or, optionally, one or more heteroatoms and may be substituted or unsubstituted. An aliphatic group, when used as a linker, preferably contains between about 1 and about 24 atoms, more preferably between about 4 to about 24 atoms, more preferably between about 4-12 atoms, more typically between about 4 and about 8 atoms. An aliphatic group, when used as a substituent, preferably contains between about 1 and about 24 atoms, more preferably between about 1 to about 10 atoms, more preferably between about 1-8 atoms, more typically between about 1 and about 6 atoms. In addition to aliphatic hydrocarbon groups, aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted. It is understood that aliphatic groups may be used in place of the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl groups described herein.

The term "substituted carbonyl" includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom, and tautomeric forms thereof. Examples of moieties that contain a substituted carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc. The term "carbonyl moiety" refers to groups such as "alkylcarbonyl" groups wherein an alkyl group is covalently bound to a carbonyl group, "alkenylcarbonyl" groups wherein an alkenyl group is covalently bound to a carbonyl group, "alkynylcarbonyl" groups wherein an alkynyl group is covalently bound to a carbonyl group, "arylcarbonyl" groups wherein an aryl group is covalently attached to the carbonyl group. Furthermore, the term also refers to groups wherein one or more heteroatoms are covalently bonded to the carbonyl moiety. For example, the term includes moieties such as, for example, aminocarbonyl moieties, (wherein a nitrogen atom is bound to the carbon of the carbonyl group, e.g., an amide).

The term "acyl" refers to hydrogen, alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocycle, aryl, and heteroaryl substituted carbonyl groups. For example, acyl includes groups such as (Ci-Ce)alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl, t- butylacetyl, etc.), (C₃-Ce)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl, pyrrolid-2-one-5 -carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl (e.g., thiophenyl-2-carbonyl, thiophenyl-3 -carbonyl, furanyl-2-carbonyl, furanyl-3 -carbonyl, lH-pyrroyl-2-carbonyl, lH-pyrroyl-3 -carbonyl, benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be any one of the groups described in the respective definitions. When indicated as being "optionally substituted", the acyl group may be unsubstituted or optionally substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted" or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be substituted as described above in the preferred and more preferred list of substituents, respectively. The term "alkyl" embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about eight carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.

The term "alkenyl" embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about ten carbon atoms and more preferably about two to about eight carbon atoms. Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl", and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. The term "alkynyl" embraces linear or branched radicals having at least one carbon-carbon triple bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having two to about ten carbon atoms and more preferably about two to about eight carbon atoms. Examples of alkynyl radicals include propargyl, 1- propynyl, 2-propynyl, 1-butyne, 2-butynyl and 1-pentynyl.

The term "cycloalkyl" embraces saturated carbocyclic radicals having three to about twelve carbon atoms. The term "cycloalkyl" embraces saturated carbocyclic radicals having three to about twelve carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "cycloalkenyl" embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called "cycloalkyldienyl". More preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term "alkoxy" embraces linear or branched oxy-containing radicals each having alkyl portions of one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to about ten carbon atoms and more preferably having one to about eight carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term "alkoxyalkyl" embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.

The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.

The terms "heterocyclyl", "heterocycle" "heterocyclic" or "heterocyclo" embrace saturated, partially unsaturated and unsaturated heteroatom-containing ring- shaped radicals, which can also be called "heterocyclyl", "heterocycloalkenyl" and "heteroaryl" correspondingly, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6- membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicals may include a pentavalent nitrogen, such as in tetrazolium and pyridinium radicals. The term "heterocycle" also embraces radicals where heterocyclyl radicals are fused with aryl or cycloalkyl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.

The term "heteroaryl" embraces unsaturated heterocyclyl radicals. Examples of heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H- 1,2,4- triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.) tetrazolyl (e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[l,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term "heterocycloalkyl" embraces heterocyclo-substituted alkyl radicals.

More preferred heterocycloalkyl radicals are "lower heterocycloalkyl" radicals having one to six carbon atoms in the heterocyclo radicals.

The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. Preferred alkylthio radicals have alkyl radicals of one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkylthio radicals have alkyl radicals are "lower alkylthio" radicals having one to about ten carbon atoms. Most preferred are alkylthio radicals having lower alkyl radicals of one to about eight carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.

The terms "aralkyl" or "arylalkyl" embrace aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl.

The term "aryloxy" embraces aryl radicals attached through an oxygen atom to other radicals. The terms "aralkoxy" or "arylalkoxy" embrace aralkyl radicals attached through an oxygen atom to other radicals.

The term "aminoalkyl" embraces alkyl radicals substituted with amino radicals. Preferred aminoalkyl radicals have alkyl radicals having about one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred aminoalkyl radicals are "lower aminoalkyl" that have alkyl radicals having one to about ten carbon atoms. Most preferred are aminoalkyl radicals having lower alkyl radicals having one to eight carbon atoms. Examples of such radicals include aminomethyl, aminoethyl, and the like. The term "alkylamino" denotes amino groups which are substituted with one or two alkyl radicals. Preferred alkylamino radicals have alkyl radicals having about one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkylamino radicals are "lower alkylamino" that have alkyl radicals having one to about ten carbon atoms. Most preferred are alkylamino radicals having lower alkyl radicals having one to about eight carbon atoms. Suitable lower alkylamino may be monosubstituted N-alkylamino or disubstituted N,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.

The term "linker" means an organic moiety that connects two parts of a compound. Linkers typically comprise a direct bond or an atom such as oxygen or sulfur, a unit such as NR₈, C(O), C(O)NH, SO, SO₂, SO₂NH or a chain of atoms, such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylhereroaryl, which one or more methylenes can be interrupted or terminated by O, S, S(O), SO₂, N(R₈), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; where R₈ is hydrogen, acyl, aliphatic or substituted aliphatic. In one embodiment, the linker B is between 1-24 atoms, preferably 4-24 atoms, preferably 4-18 atoms, more preferably 4-12 atoms, and most preferably about 4-10 atoms.

The term "substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, aminocarbonylcycloalkyl, aminocarbonylheterocyclyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic. It is understood that the substituent may be further substituted. For simplicity, chemical moieties are defined and referred to throughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.) or multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, an "alkyl" moiety can be referred to a monovalent radical (e.g. CH3-CH2-), or in other instances, a bivalent linking moiety can be "alkyl," in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH₂-CH₂-), which is equivalent to the term "alkylene." Similarly, in circumstances in which divalent moieties are required and are stated as being "alkoxy", "alkylamino", "aryloxy", "alkylthio", "aryl", "heteroaryl", "heterocyclic", "alkyl", "alkenyl", "alkynyl", "aliphatic", or "cycloalkyl", those skilled in the art will understand that the terms alkoxy", "alkylamino", "aryloxy", "alkylthio", "aryl", "heteroaryl",

"heterocyclic", "alkyl", "alkenyl", "alkynyl", "aliphatic", or "cycloalkyl" refer to the corresponding divalent moiety.

The terms "halogen" or "halo" as used herein, refers to an atom selected from fluorine, chlorine, bromine and iodine. As used herein, the term "aberrant proliferation" refers to abnormal cell growth.

The phrase "adjunctive therapy" encompasses treatment of a subject with agents that reduce or avoid side effects associated with the combination therapy of the present invention, including, but not limited to, those agents, for example, that reduce the toxic effect of anticancer drugs, e.g., bone resorption inhibitors, cardioprotective agents; prevent or reduce the incidence of nausea and vomiting associated with chemotherapy, radiotherapy or operation; or reduce the incidence of infection associated with the administration of myelosuppressive anticancer drugs. The term "angiogenesis," as used herein, refers to the formation of blood vessels. Specifically, angiogenesis is a multi-step process in which endothelial cells focally degrade and invade through their own basement membrane, migrate through interstitial stroma toward an angiogenic stimulus, proliferate proximal to the migrating tip, organize into blood vessels, and reattach to newly synthesized basement membrane (see Folkman et al., Adv. Cancer Res., Vol. 43, pp. 175-203

(1985)). Anti-angiogenic agents interfere with this process. Examples of agents that interfere with several of these steps include thrombospondin-1, angiostatin, endostatin, interferon alpha, and compounds such as matrix metalloproteinase (MMP) inhibitors that block the actions of enzymes that clear and create paths for newly forming blood vessels to follow; compounds, such as . alpha. v.beta.3 inhibitors, that interfere with molecules that blood vessel cells use to bridge between a parent blood vessel and a tumor; agents, such as specific COX-2 inhibitors, that prevent the growth of cells that form new blood vessels; and protein-based compounds that simultaneously interfere with several of these targets. The term "apoptosis" as used herein refers to programmed cell death as signaled by the nuclei in normally functioning human and animal cells when age or state of cell health and condition dictates. An "apoptosis inducing agent" triggers the process of programmed cell death.

The term "cancer" as used herein denotes a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue through invasion or by implantation into distant sites by metastasis.

The term "compound" is defined herein to include pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereoisomers, racemates and the like of the compounds having a formula as set forth herein.

The term "devices" refers to any appliance, usually mechanical or electrical, designed to perform a particular function. As used herein, the term "dysplasia" refers to abnormal cell growth, and typically refers to the earliest form of pre-cancerous lesion recognizable in a biopsy by a pathologist.

As used herein, the term "effective amount of the subject compounds," with respect to the subject method of treatment, refers to an amount of the subject compound which, when delivered as part of desired dose regimen, brings about, e.g. a change in the rate of cell proliferation and/or state of differentiation and/or rate of survival of a cell to clinically acceptable standards. This amount may further relieve to some extent one or more of the symptoms of a neoplasia disorder, including, but is not limited to: 1) reduction in the number of cancer cells; 2) reduction in tumor size; 3) inhibition (i.e., slowing to some extent, preferably stopping) of cancer cell infiltration into peripheral organs; 4) inhibition (i.e., slowing to some extent, preferably stopping) of tumor metastasis; 5) inhibition, to some extent, of tumor growth; 6) relieving or reducing to some extent one or more of the symptoms associated with the disorder; and/or 7) relieving or reducing the side effects associated with the administration of anticancer agents.

The term "hyperplasia," as used herein, refers to excessive cell division or growth.

The phrase an "immunotherapeutic agent" refers to agents used to transfer the immunity of an immune donor, e.g., another person or an animal, to a host by inoculation. The term embraces the use of serum or gamma globulin containing performed antibodies produced by another individual or an animal; nonspecific systemic stimulation; adjuvants; active specific immunotherapy; and adoptive immunotherapy. Adoptive immunotherapy refers to the treatment of a disease by therapy or agents that include host inoculation of sensitized lymphocytes, transfer factor, immune RNA, or antibodies in serum or gamma globulin.

The term "inhibition," in the context of neoplasia, tumor growth or tumor cell growth, may be assessed by delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, among others. In the extreme, complete inhibition, is referred to herein as prevention or chemoprevention. The term "metastasis," as used herein, refers to the migration of cancer cells from the original tumor site through the blood and lymph vessels to produce cancers in other tissues. Metastasis also is the term used for a secondary cancer growing at a distant site. The term "neoplasm," as used herein, refers to an abnormal mass of tissue that results from excessive cell division. Neoplasms may be benign (not cancerous), or malignant (cancerous) and may also be called a tumor. The term "neoplasia" is the pathological process that results in tumor formation.

As used herein, the term "pre-cancerous" refers to a condition that is not malignant, but is likely to become malignant if left untreated.

The term "proliferation" refers to cells undergoing mitosis.

The phrase a "radio therapeutic agent" refers to the use of electromagnetic or particulate radiation in the treatment of neoplasia.

The term "recurrence" as used herein refers to the return of cancer after a period of remission. This may be due to incomplete removal of cells from the initial cancer and may occur locally (the same site of initial cancer), regionally (in vicinity of initial cancer, possibly in the lymph nodes or tissue), and/or distally as a result of metastasis.

The term "treatment" refers to any process, action, application, therapy, or the like, wherein a mammal, including a human being, is subject to medical aid with the object of improving the mammal's condition, directly or indirectly.

The term "vaccine" includes agents that induce the patient's immune system to mount an immune response against the tumor by attacking cells that express tumor associated antigens (Teas). As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid or inorganic acid. Examples of pharmaceutically acceptable nontoxic acid addition salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid lactobionic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention. "Prodrug", as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of the invention. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development", Chapter 5, 113-191 (1991); Bundgaard, et al, Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer,

"Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002).

As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration, such as sterile pyrogen-free water. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin.

Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

The term "subject" as used herein refers to an animal. Preferably the animal is a mammal. More preferably the mammal is a human. A subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- , or as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al, Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefmic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers and/or cis- and trans- isomers. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon- heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.

Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.

As used herein, the term "pharmaceutically acceptable carrier or excipient" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; cyclodextrins such as alpha- (α), beta- (B) and gamma- (γ) cyclodextrins; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

For pulmonary delivery, a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system. Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example U.S. Pat. No. 5,767,068 to VanDevanter et al, U.S. Pat. No. 5,508,269 to Smith et al., and WO 98/43,650 by Montgomery, all of which are incorporated herein by reference). A discussion of pulmonary delivery of antibiotics is also found in U.S. Pat. No. 6,014,969, incorporated herein by reference.

By a "therapeutically effective amount" of a compound of the invention is meant an amount of the compound which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). An effective amount of the compound described above may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.

The total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.

The compounds of the formulae described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.1 to about 500 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with pharmaceutically excipients or carriers to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations may contain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.

Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

Synthetic Methods The compounds of formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Suitable processes for making certain intermediates include, for example, those illustrated in PCT publication No. WO 04/000833, which herein incorporated by reference. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of a chemist.

The compounds and processes of the present invention will be better understood in connection with the following representative synthetic schemes that illustrate the methods by which the compounds of the invention may be prepared, which are intended as an illustration only and not limiting of the scope of the invention.

Scheme 1

0101 0102

0106 0107

Scheme 2

0106 0201

Scheme 3

Scheme 4

HCOOMe (fP

-'v^^V^O^ _{NaH DME}

0 0. T T

O O^

0401 0402

EXAMPLES

The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims. EXAMPLE 1: Preparation of Cyclopropanecarboxylic acid N-(4-((4-(3-methyl- lH-pyrazol-5-ylamino)-6-(5-(hydroxycarbamoyl)pentylamino) pyrimidin-l-yljsulfanyljphenyljcyclopropanecarboxamide (Compound 3) Step Ia. Cyclopropanecarboxylic acid (4-mercapto-phenyl)-amide(Compound 0102)

To a mixture of 4-aminothiophenol 0101 (27.0 g, 0.22 mol) and pyridine (23.3 rnL, 0.29 mol) at O ⁰C was added cyclopropanecarbonyl chloride (13.2 mL, 0.14 mol) dropwise. The reaction was stirred at 0⁰C and then at room temperature overnight. The reaction was diluted with EtOAc and washed with 1 N HCl (150 mL x 3). The organic layer was collected, dried over Na₂SO₄, filtered and concentrated to yield the title compound 0102 (16.Og, 58%): LCMS: 194 [M+l]⁺. Step Ib. 4,6-Dichloro-2-methanesulfonyl-pyrimidine(Compound 0104)

To a stirred solution of 4, 6-Dichloro-2-methylsulfanyl-pyrimidine 0103 (5.0 g, 25.6 mmol) in CH₂Cl₂ (15 mL) at 0 ⁰C was added meta-chloroperoxybenzoic acid (11.06 g, 64.1 mmol) over a period of 20 minutes. The reaction was allowed to warm to room temperature and stirred for 2.5 hours. The mixture was filtrated and the filtrate was concentrated. The resulting residue was washed with saturated Na₂CO₃ solution and ether to form a white solid which was dried to obtain the title compound 0104 (2.6g, 44%): LCMS: 227 [M+l]⁺; ¹H NMR (CDCl₃) δ 3.4 (s, 3H), 7.75 (s, IH).

Step Ic. Cyclopropanecarboxylic acid [4-(4,6-dichloro-pyrimidin-2-ylsulfanyl)- phenyl]-amide(Compound 0105)

A suspension of compound 0104 (13 g, 57.3 mmol), compound 0102 (11.1 g, 57.3 mmol) and K₂CO₃ (4.0 g, 29.1 mmol) in t-butanol (250 mL) was degassed by vacuum and then flushed with nitrogen gas. The reaction mixture was then stirred at 20 ⁰C for 40 minutes. The resulting solid was collected by filtration, washed with water and t-butanol (50 mL) and dried to yield the title compound 0105 a white solid (8.0 g, 41.3%): LCMS: 340 [M+l] ⁺; ¹H NMR (DMSO-J₆) δ 0.84 (m, 4H), 1.84 (m, IH), 7.55 (m, 2H), 7.71 (m, 3H), 10.53 (s,lH).

Step Id. Cyclopropanecarboxylic acid {4-[4-chloro-6-(5-methyl-2H-pyrazol-3- ylamino)-pyrimidin-2-ylsulfanyl]-phenyl} -amide (Compound 0106)

A mixtrue of compound 0105 (3.0 g, 8.85 mmol) and 5-Methyl-2H-pyrazol-3- ylamine (0.94 g, 9.7 mmol)in DMF (16 mL) was treated with diisopropylethylamine (1.25 g, 9.7 mmol ) and potassium iodide (1.76 g, 10.6 mmol). The mixture was stirred at 50 ⁰C for 6 hours. The solvent was evaporated under reduce pressure and the residue was recrystallized in ethyl acetate. The title compound 0106 was obtained as a white solid (2.0 g, 91%): LCMS: 401 [M+l] ⁺; ¹U NMR (DMSO- d₆) δ 0.82 (d, J= 6.6 Hz , 4H), 1.85 (m, IH), 1.99 (s, IH), 5.24 (bs, IH), 6.47 (bs, IH), 7.55 (m, 2H), 7.71 (m, 2H), 10.22 (s,lH ), 11.95 (s,lH).

Step Ie. 6-[2-[4-(Cyclopropanecarbonyl-amino)-phenylsulfanyl]-6-(5-methyl-2H- pyrazol-3-ylamino)-pyrimidin-4-ylamino]-hexanoic acid methyl ester (Compound 0107-3) A solution of compound 0106 (200 mg, 0.5 mmol) in DMA (4 mL) was treated with 6-Amino-hexanoic acid methyl ester (1.1 g, 7.3 mmol). The mixture was stirred at 140 ⁰C for 3 hours. The solvent was evaporated under reduce pressure and the residue was purified by silica gel chromatography (CH2Cl2/methanol=60:l) to provide the title compound 0107-3 as a white solid (123 mg, 48%): LCMS: 509[M+l] ⁺.

Step If. Cyclopropanecarboxylic acid {4-[4-(5-hydroxycarbamoyl-pentylamino)-6- (5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl} -amide (Compound 3)

To a stirred solution of hydroxyamine hydrochloride (4.67 g, 67mmol) in methanol (24ml) at O⁰C was added a solution of potassium hydroxide (5.6 Ig, lOOmmol) in methanol (14ml). After addition, the mixture was stirred for 30 minutes at O⁰C, and was allowed to stand at low temperature. The resulting precipitate was isolated, and the solution was prepared to give free hydroxyamine. The above freshly prepared hydroxylamine solution (8 mL) was placed in 25 mL flask. Compound 0107-3 (123 mg, 0.24 mmol) was added to this solution and stirred for 10 minutes. The reaction process was monitored by TLC. The mixture was neutralized with acetic acid and concentrated under reduce pressure to form a residue which was purified by HPLC to give the title compound 3 as a white solid (27 mg, 22%): LCMS:510[M+l]⁺; ¹H NMR (DMSCM₆) ^ 0.80 (d, J= 4.5 Hz 4H), 1.21 (m, 2H),1.44 (m, 4H), 1.82 (m, IH), 1.93 (t, J= 6.9 Hz, 2H) 2.02 (s, IH), 3.0 (m, 2H), 5.44 (s, IH), 5.82 (bs, IH), 6.87(bs, IH), 7.46 (d, J= 8.7 Hz, 2H), 7.69 (d, J= 9.0 Hz, 2H), 9.03 (s,lH ),10.50 (bs,lH ), 11.68 (bs,lH). EXAMPLE 2: Preparation of 7V-(4-(4-(3-methyl-lH-pyrazol-5-ylamino)-6-(7- (hydroxyamino)-7-oxoheptylamino)pyrimidin-2-ylthio)phenyl) cyclopropanecarboxamide (Compound 4)

Step 2a. Methyl 7-(2-(4-(cyclopropanecarboxamido)phenylthio)-6-(3 -methyl- IH- pyrazol-5 -ylamino)pyrimidin-4-ylamino)heptanoate (Compound 0107-4)

The title compound 0107-4 was prepared as a white solid (107 mg, 55 %) from compound 0106 and ethyl 7-aminoheptanoate (1.26 g, 7.25 mmol) using a procedure similar to that described for compound 0107-3 (Example 1): LCMS: 537 [M+l]⁺. Step 2b. Λ/-(4-(4-(lH-Pyrazol-5-ylamino)-6-(7-(hydroxyamino)-7-oxoheptylamino) pyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide(Compound 4)

The title compound 4 was prepared as a white solid (20 mg, 55 %) from compound 0107-4 (107 mg, 0.199 mmol) using a procedure similar to that described for compound 3 (Example 1): LCMS: 524 [M+l]⁺; ¹H NMR (DMSO-J₆) δ 0.82 (d, J =6.0 Hz, 4H), 1.21-1.50 (m, 8H) 1.80 (m, IH), 1.95 (t, J= 7.2 Hz, 2H) , 2.03 (s, IH), 3.0 (m, 2H), 5.44 (s, IH), 5.82 (bs, IH), 6.87 (bs, IH), 7.46 (d, J= 8.7 Hz, 2H), 7.69 (d, J= 8.7 Hz, 2H), 8.68 (s,lH ),9.02 (s,lH ),10.36 (d, J= 11.1 Hz, 2H ), 11.64 (bs, IH).

EXAMPLE 3: Preparation of 7V-(4-(4-(2-(7-(hydroxyamino)-7-oxoheptylamino) ethylamino)-6-(3-methyl- lH-pyrazol-5-ylamino)pyrimidin-2- ylthio)phenyl) cyclopropanecarboxamide (Compound 18) Step 3a. Λ/-(4-(4-(2-Aminoethylamino)-6-(3-methyl-lH-pyrazol-5- ylamino)pyrimidin-2-ylthio)phenyl)cy clopropanecarboxamide (Compound 0201 )

A mixture of compound 0106 (1.18 g, 3.0 mmoL) in ethane- 1,2-diamine (22.0 mL) was stirred at 120 ⁰C for 2 hours. The mixture was cool to ambient temperature and poured into water. The resulting precipitate was isolated, filtrated and dried to yield the title compound 0201(1.17 g, 93%): LCMS: 425 [M+l]⁺. Step 3b. Ethyl 2-(2-(2-(4-(cyclopropanecarboxamido)phenylthio)-6-(3-methyl-lH- pyrazol-5-ylamino)pyrimidin-4-ylamino)ethylamino)acetate (Compound 0202-18)

A mixture of compound ethyl 7-bromoheptanoate (0.336 g, 1.4 mmoL) and compound 0201 (0.6 g, 1.4 mmoL) in DMF (4.0 mL) was stirred at 75⁰C for 10 hours. The mixture was poured into water and the precipitate was isolated, filtrated and dried to yield the title compound 0202-18 (69 mg, 8%): LCMS: 581 [M+l]⁺; ¹H NMR (DMSO- dβ) δ 0.79 (d, J= 6.3 Hz , 4H), 1.15 (t, j=6.9 Hz , 3H), 1.22 (m, 4H), 1.26 (t, j=3.9 Hz , 2H), 1.50 (m, 4H), 1.81 (m, IH), 2.00 (s, IH), 2.26 (t, j=7.2 Hz , 2H ), 2.69 (t, j=7.8 Hz , 2H), 2.78 (t, j=6.3 Hz , 2H), 4.02 (Q, j=7.2 Hz , 2H), 5.404 (s, IH), 5.85 (bs, IH), 6.95 (bs, IH), 7.45 (d, J=8.4 Hz , 2H), 7.68 (d, J=8.7 Hz , 2H), 9.1 (bs, IH), 10.4 (s, IH), 11.66 (bs, IH).

Step 3c. N-(4-(4-(2-(7-(Hydroxyamino)-7-oxoheptylamino)ethylamino)-6-(3- methyl-lH-pyrazol-5-ylamino)pyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide (Compound 18)

The title compound 18 was prepared as a white solid (27 mg, 42 %) from compound 0202-18 (65 mg, 0.12 mmol) using a procedure similar to that described for compound 3 (Example 1): LCMS: 568 [M+l]⁺; ¹H NMR (DMSO-J₆) δ 0.808 (d, J= 6 Hz , 4H), 1.25 (m, 4H), 1.36 (m, 2H), 1.48 (m, 2H), 1.82 (m, IH), 1.93 (t, j=6.9 Hz , 2H), 2.01 (s, 3H), 2.44 (t, j=6.3 Hz , 2H ), 2.55 (d, J=6.6 Hz , 2H), 3.1 (t, j=9.6 Hz , 2H), 5.4 (s, IH), 5.8 (bs, IH), 6.8 (bs, IH), 7.47 (d, J=8.7 Hz , 2H), 7.68 (d, J=9.0 Hz , 2H), 9.1 (bs , IH), 10.38 (s , IH), 10.42 (s, IH), 11.65 (bs, IH).

Example 4: Preparation of Cyclopropanecarboxylic acid {4-[4-[4-(3- hydroxycarbamoyl-propyl)-piperazin-l-yl]-6-(5-methyl-2H- pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl}-amide (Compound 19)

Step 4a. Cyclopropanecarboxylic acid {4-[4-(5-methyl-2H-pyrazol-3-ylamino)-6- piperazin- 1 -yl-pyrimidin-2-ylsulfanyl] -phenyl} -amide (Compound 0301) A mixture of compound 0106 (0.83 g, 2 mmol) and piperazine (1.82 g, 20 mmol) in DMA (5 mL) was stirred at 120⁰C for 2 hours. The solvent was evaporated under reduced pressure and the residue was washed with water and filtrated to yield the title compound 0301 as a white solid (0.9 Ig, 97%): LCMS: 451 [M+ 1] ⁺.

Step 4b. 4- {4-[2-[4-(Cyclopropanecarbonyl-amino)-phenylsulfanyl]-6-(5-methyl- 2H-pyrazol-3 -ylamino)-pyrimidin-4-yl]-piperazin- 1 -yl} -butyric acid ethyl ester (Compound 0302-19)

To a mixture of compound 0302-19 (225 mg, 0.50 mmol), 4-bromo-butyric acid ethyl ester (103 mg, 0.53 mmol) and DIPEA (65 mg, 0.50 mmol) was added DMA (1.5 mL). The mixture was stirred at 70⁰C for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified by prepared HPLC to yield the title compound 0302-19 as a white solid (95 mg, 34%): LCMS: 565 [M+l] ⁺; ¹H NMR (DMSO-J₆) δ 0.81 (d, J= 6.3Hz ,4H), 1.18 (t, J= 7.2 Hz, 3H), 1.71 (m, 2H), 1.79 (m, IH), 2.01 (s, 3H), 2.32 (m, 6H), 4.05 (q, J= 7.2 Hz, 2H), 5.43(bs, IH), 6.00 (bs, IH), 7.47 (d, J= 7.8 Hz, 2H), 7.69 (d, J= 7.8 Hz, 2H), 9.22 (bs,lH ), 10.38 (s,lH ), 11.69 (bs,lH).

Step 4c. Cyclopropanecarboxylic acid (4-[4-[4-(3-hydroxycarbamoyl-propyl)- piperazin- 1 -yl] -6-(5 -methyl-2H-pyrazol-3 -ylamino)-pyrimidin-2-ylsulfanyl] - phenyl} -amide (Compound 19)

The title compound 19 was prepared as a pale orange solid (35 mg, 72%) from compound 0302-19 (65 mg, 0.12 mmol) using a procedure similar to that described for compound 3 (Example 1): LCMS:551 [M+l]⁺¹; H NMR (DMSO-J₆) δ 0.81 (d, J= 5.7 Hz ,4H), 1.66 (m, 2H), 1.79 (m, IH), 1.98 (t, J= 7.5 Hz, 2H), 2.01 (s, 3H), 2.26 (t, J= 7.5 Hz, 2H), 2.35 (m, 4H), 5.43(bs, IH), 6.02 (bs, IH), 7.47 (d, J = 9.0 Hz, 2H), 7.69 (d, J= 6.9 Hz, 2H), 8.67 (bs,lH ), 9.22 (bs,lH ), 10.34 (s,lH ),10.39 (s,lH ), 11.68 (bs,lH).

Example 5: Preparation of Cyclopropanecarboxylic acid {4-[4-[4-(4- hydroxycarbamoyl-butyl)-piperazin-l-yl]-6-(5-methyl-2H-pyrazol- 3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl}-amide (Compound 20) Step 5a. 5-{4-[2-[4-(Cyclopropanecarbonyl-amino)-phenylsulfanyl]-6-(5-methyl- 2H-pyrazol-3 -ylamino)-pyrimidin-4-yl]-piperazin- 1 -yl} -pentanoic acid methyl ester (Compound 0302-20)

The title compound 0302-20 was prepared as a white solid ( 97 mg, 34 %) from compound 0301 and 5-bromo-pentanoic acid methyl ester ( 107 mg, 0.5 mmol) using a procedure similar to that described for compound 0302-19 (Example 4):

LCMS: 565 [M+l]⁺; ¹H NMR (DMSO-J₆) δ 0.81 (d, J= 5.7 Hz ,4Η), 1.39-1.59 (m, 4H), 1.79 (m, IH), 2.01 (s, 3H), 2.32 (m, 6H), 3.59 (s, 3H), 5.44 (bs, IH), 6.02 (bs, IH), 7.47 (d, J= 8.4 Hz, 2H), 7.69 (d, J= 8.4 Hz, 2H), 9.20 (bs,lH ), 10.38 (s,lH ), 11.69 (bs, IH). Step 5b. Cyclopropanecarboxylic acid (4-[4-[4-(4-hydroxycarbamoyl-butyl)- piperazin- 1 -yl]-6-(5 -methyl-2H-pyrazol-3 -ylamino)-pyrimidin-2-ylsulfanyl] - phenyl} -amide (Compound 20)

The title compound 20 was prepared as a pale orange solid ( 35 mg, 72 %) from compound 0302-20 (50 mg, 0.09 mmol) using a procedure similar to that described for compound 3 (Example 1): LCMS: 565 [M+l]⁺; ¹H NMR (DMSO-J₆) δ 0.81 (d, J = 5.7 Hz ,4H), 1.41-1.55 (m, 4H), 1.79 (m, IH), 1.96 (t, J= 6.9 Hz, 2H), 2.01 (s, 3H), 2.27 (t, J= 6.9 Hz, 2H), 2.35 (m, 4H), 5.43(bs, IH), 6.03 (bs, IH), 7.47 (d, J = 8.4 Hz, 2H), 7.69 (d, J= 8.4 Hz, 2H), 8.69 (bs,lH ), 9.22 (bs,lH ), 10.35 (s,lH ),10.4 (s,lH ), 11.70 (bs,lH).

Example 6: Preparation of Cyclopropanecarboxylic acid {4-[4-[4-(5- hydroxycarbamoyl-pentyl)-piperazin-l-yl]-6-(5-methyl-2H-pyrazol- 3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl}-amide (Compound 21) Step 6a. 6-{4-[2-[4-(Cyclopropanecarbonyl-amino)-phenylsulfanyl]-6-(5-methyl- 2H-pyrazol-3 -ylamino)-pyrimidin-4-yl]-piperazin- 1 -yl} -hexanoic acid ethyl ester (Compound 0302-21)

The title compound 0302-21 was prepared as a white solid (80 mg, 35 %) from compound 0301 and 6-bromo-hexanoic acid ethyl ester (200 mg, 0.57 mmol) using a procedure similar to that described for compound 0302-19 (Example 4):

LCMS: 607 [M+l]⁺; ¹H NMR (DMSO-J₆) δ 0.81 (d, J= 6.0 Hz ,4H), 1.18 (t, J= 7.2 Hz, 3H), 1.28 (m, 2H), 1.54 (m, 2H), 1.81 (m, IH), 2.01 (s, 3H), 2.29 (t, J= 7.5 Hz, 2H), 2.35 (m, 4H), 4.05 (q, J= 6.9 Hz, 2H), 5.43(bs, IH), 6.03 (bs, IH), 7.47 (d, J = 8.7 Hz, 2H), 7.69 (d, J= 8.1 Hz, 2H), 9.22 (bs,lH ), 10.39 (s,lH ), 11.70 (bs,lH). Step 6b. Cyclopropanecarboxylic acid (4-[4-[4-(5-hydroxycarbamoyl-pentyl)- piperazin- 1 -yl]-6-(5 -methyl-2H-pyrazol-3 -ylamino)-pyrimidin-2-ylsulfanyl] - phenyl} -amide (Compound 21)

The title compound 21 was prepared as a pale orange solid (14 mg, 41 %) from compound 0302-21 (35 mg, 0.06 mmol) using a procedure similar to that described for compound 3 (Example 1): LCMS: 580 [M+l]⁺; ¹H NMR (DMSO-J₆) δ 0.81 (d, J= 6.3 Hz ,4H), 1.25 (m, 2H), 1.45 (m, 4H), 1.81 (m, IH), 1.96 (t, J= 7.2 Hz, 2H), 2.01 (s, 3H), 2.25 (t, J= 7.8 Hz, 2H), 2.35 (bs, 4H), 5.43(bs, IH), 6.04 (bs, IH), 7.47 (d, J= 8.4 Hz, 2H), 7.69 (d, J= 7.8 Hz, 2H), 8.66 (bs,lH ), 9.20 (bs,lH ), 10.33 (S, 1H ),10.38 (S, 1H ), 11.69 (bs,lH).

Example 7: Preparation of Cyclopropanecarboxylic acid {4-[4-[4-(6- hydroxycarbamoyl-hexyl)-piperazin-l-yl]-6-(5-methyl-2H-pyrazol- 3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl}-amide (Compound 22) Step 7a. 7- {4-[2-[4-(Cyclopropanecarbonyl-amino)-phenylsulfanyl]-6-(5-methyl- 2H-pyrazol-3-ylamino)-pyrimidin-4-yl]-piperazin- 1 -yl} -heptanoic acid ethyl ester (Compound 0302-22)

The title compound 0302-22 was prepared as a white solid (80 mg, 26 %) from compound 0301 and 7-Bromo-heptanoic acid ethyl ester (136 mg, 0.57 mmol) using a procedure similar to that described for compound 0302-19 (Example 4): LCMS: 607 [M+l]⁺; ¹H NMR (DMSO-J₆) δ 0.81 (d, J= 6.0 Hz ,4H), 1.20 (t, J= 7.2 Hz, 3H), 1.42 (m, 4H), 1.50 (m, 2H), 1.54 (m, 2H), 1.79 (m, IH), 2.01 (s, 3H), 2.27 (t, J = 7.5 Hz, 2H), 2.35 (m, 4H), 4.05 (q, J= 7.2 Hz, 2H), 5.43(bs, IH), 6.03 (bs, IH), 7.47 (d, J= 8.4 Hz, 2H), 7.69 (d, J= 7.8 Hz, 2H), 9.20 (bs,lH ), 10.38 (s,lH ), 11.69 (bs,lH).

Step 7b. Cyclopropanecarboxylic acid (4-[4-[4-(6-hydroxycarbamoyl-hexyl)- piperazin- 1 -yl]-6-(5 -methyl-2H-pyrazol-3 -ylamino)-pyrimidin-2-ylsulfanyl] - phenyl} -amide (Compound 22)

The title compound 22 was prepared as a pale orange solid (40 mg, 82 %) from compound 0302-22 ( 50 mg, 0.08 mmol) using a procedure similar to that described for compound 3 (Example 1): LCMS: 594 [M+l]⁺; ¹H NMR (DMSO-J₆) δ 0.81 (d, J= 6.6 Hz ,4H), 1.25 (m, 4H), 1.47 (m, 4H), 1.81 (m, IH), 1.96 (t, J= 7.5 Hz, 2H), 2.01 (s, 3H), 2.39 (m, 6H), 5.43(bs, IH), 6.01 (bs, IH), 7.47 (d, J= 8.4 Hz, 2H), 7.69 (d, J= 8.7 Hz, 2H), 8.66 (bs,lH ), 9.22 (bs,lH ), 10.33 (s,lH ),10.40 (s,lH ), 11.69 (bs, IH).

EXAMPLE 8: Preparation of 2-(4-(2-(4

(cyclopropanecarboxamido)phenylthio)-6-(3-methyl-lH-pyrazol-5- ylamino)pyrimidin-4-yl)piperazin-l-yl)-N-hydroxypyrimidine-5-carboxamide (Compound 23)

Step 8a: Sodium 3,3-dimethoxy-2-methoxycarbonylprop-l-en-l-oxide (Compound

0402)

A 500 mL, three neck, round bottom flask equipped with magnetic stirrer and a reflux condenser is purged with nitrogen. The flask is then charged sequentially with methyl 3,3-dimethoxypropionate (0401) (26.1 g, 176 mmol), anhydrous 1,2- dimethoxyethane (125 mL), anhydrous methyl formate (25 mL, 400 mmol), 60% NaH (8.5 g, 212.5 mmol), and the mixture was heated to 40~50°C until evolution of hydrogen gas is observed. The reaction mixture was cooled in an ice bath and slowly warmed to room temperature and stirred for 20 h. The reaction mixture was filtered, washed with anhydrous ether, dried to provide desired product 0402 (25.4 g, 73%) as a white power.

Step 8b: Methyl 2-(4-benzylpiperazin-l-yl)pyrimidine-5-carboxylate (Compound

0405) A mixture of compound 1-benzylpiperazine, 0403 (3.0 g, 17 mmol), S- methylisothiouronium sulfate (4.74 g, 17 mmol), K2CO3 (3.4 g, 25 mmol) and H₂O (20 mL) was stirred for 6 h at 8O⁰C. The solvent was removed under reduced pressure and the residue was dilute with anhydrous ethanol. The resulting mixture was refluxing for 0.5 h and filtered. The organic layer was concentrated to get a crude colorless viscous oil.

To a solution of above oil in anhydrous DMF (40 mL) is added sodium 3,3- dimethoxy-2-methoxycarbonylprop-l -en- 1 -oxide (0402) (5.1 g, 25.6 mmol) and the reaction mixture was heated to 100⁰C under nitrogen. The mixture was then cooled to room temperature and diluted with water (120 mL). The precipitated was filtered, washed with water, dried to give product 0405 (2.47 g, in total yield of two steps: 46%) as a pale yellow solid: LCMS: 313 [M+l]⁺, ¹H NMR (DMSO-/) : δ 2.44 (t, J = 5.7 Hz, 4H), 3.52 (s, 2H), 3.80 (s, 3H), 3.86 (t, J= 5.7 Hz, 3H), 7.24-7.36 (m, 5H), 8.78 (s, 2H). Step 8c: Methyl 2-(piperazin-l-yl)pyrimidine-5-carboxylate (Compound 0406) A mixture of 0405 (1.5 g, 4.8 mmol), 10% Pd/C (150 mg) in dioxane (40 mL) and methanol (80 mL) was stirred for 24 h at room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (CH₂Cl₂ZMeOH= 40/1) to provide the target product 0406 (0.8 g, 77%) as a pale white solid: LCMS: 223 [M+l]⁺, ¹H NMR (DMSO-/; : δ 2.74 (t, J= 5.7 Hz, 4H), 3.78 (t, J= 5.7 Hz, 3H), 3.80 (s, 3H), 8.77 (s, 2H).

Step 8d: Methyl 2-(4-(2-(4-(cyclopropanecarboxamido)phenylthio)-6-(3-methyl- 1 H-pyrazol-5 -y lamino)pyrimidin-4-yl)piperazin- 1 -yl)pyrimidine-5 - carboxylate (Compound 0407) A mixture of Λ/-(4-(4-chloro-6-(3-methyl-l/-f-pyrazol-5-ylamino) pyrimidin-

2-ylthio)phenyl)cyclopropanecarboxamide (0106) (0.2 g, 0.5 mmoL) and methyl 2- (piperazin-l-yl)pyrimidine-5 -carboxylate (0406) (0.444 g, 2 mmol) in DMA(8 mL) was stirred at the temperature of 120⁰C for 3 hours. The reaction mixture was then cooled to room temperature and water was added. The resulting solid was collected by filtration, and dried to yield the title compound 0407 (0.2 g, 68%): LC-MS: 587 [M+l]⁺, ¹H NMR (DMSO-d6): δ 0.79 (d, J = 6.3 Hz , 4H), 1.15 (t, J=6.9 Hz , 3H), 1.22 (m, 4H), 1.26 (t, J=3.9 Hz , 2H), 1.50 (m, 4H), 1.81 (m, IH), 2.00 (s, IH), 2.26 (t, J=7.2 Hz , 2H ), 2.69 (t, J=7.8 Hz , 2H), 2.78 (t, J=6.3 Hz , 2H), 4.02 (Q, J=7.2 Hz , 2H), 5.404 (s, IH), 5.85 (bs, IH), 6.95 (bs, IH), 7.45 (d, J=8.4 Hz , 2H), 7.68 (d, J=8.7 Hz , 2H), 9.10 (bs, IH), 10.4 (s, IH), 11.66 (bs, IH). Step 8e: 2-(4-(2-(4-(Cyclopropanecarboxamido)phenylthio)-6-(3 -methyl- IH- pyrazol-5 -ylamino)pyrimidin-4-yl)piperazin- 1 -yl)-N-hydroxypyrimidine-5 - carboxamide (Compound 23) The title compound 23 was prepared as a white solid (89 mg, 44%) from compound 0407 (0.2 g, 0.34 mmoL) and freshly prepared hydroxylamine (3 mL) using a procedure similar to that described for compound 3 (Example 1): LCMS: 588 [M+l]⁺, ¹H NMR (DMSO-/) δ 0.80 (d, J= 6.3 Hz , 4H), 1.78 (m, IH), 1.99 (s, 2H), 3.48 (s, 4H), 3.84 (s, 4H), 5.42 (bs, IH), 6.05 (bs, IH), 7.47 (d, J=8.4 Hz , 2H ), 7.69 (d, J=8.4 Hz , 2H), 8.69 (s, 2H), 9.03 (bs, IH), 9.26 (s, IH), 10.40 (s, IH), 11.06 (bs,lH), 11.71 (bs, IH).

Biological Assays:

As stated hereinbefore the derivatives defined in the present invention possess anti- proliferation activity. These properties may be assessed, for example, using one or more of the procedures set out below:

(a) An in vitro assay which-determines the ability of a test compound to inhibit Aurora A serine/threonine kinase.

The ability of compounds to inhibit Aurora A kinase activity was assayed using standard radioisotope assay for kinase. Briefly, TV-terminal 6 His-tagged, recombinant full-length human Aurora A (GenBank accession No. NM 003600) was expressed using baculovirus expression system in Sf21 cells and purified using M2+/NTA agarose affinity column. Purified enzyme (63% purity) was induced to auto-activation by incubating with Mg and ATP. Excess ATP was then removed away form Aurora A kinase through dialysis. P33 ATP tracers were incubated with purified recombinant Aurora A kinase to monitor the enzyme activity. In this assay, reactions were carried out in the presence of 0.1 mg/ml Aurora A kinase and 200μM synthetic heptapeptide LRRASLG (Kemptide). Final assay condition was with 5OmM Tris-HCl, pH 7.5, 15OmM NaCl, O.lmM EGTA, 0.03% Brij 35, 27OmM sucrose, ImM benzamidine, 0.2mM PMSF, 0.1% 2-mercaptoethanol and lOOμM ATP and was carried out at 30⁰C for 120 minutes. An equal volume of 25% TCA was added to stop the reaction and precipitate the labeled peptides. Precipitated peptides were trapped onto glass fiber B fϊlterplates and excess unlabeled p33 ATP was washed off. Plates were allowed to air-dry prior to addition of 30 uL/well of Packard Microscint 20. The amount of incorporated isotope was measured using a Perkin Elmer TopCount plate reader. Different concentrations of compounds were added to reaction to assess the activity of compounds to inhibit Aurora A kinase. IC50 was calculated using Prism software with sigmoidal dose-response curve fitting. (b) An in vitro assay which determines the ability of a test compound to inhibit HDAC enzymatic activity.

HDAC inhibitors were screened using an HDAC fluorimetric assay kit (AK- 500, Biomol, Plymouth Meeting, PA). Test compounds were dissolved in dimethylsulphoxide (DMSO) to give a 20 mM working stock concentration. Fluorescence was measured on a WALLAC Victor 2 plate reader and reported as relative fluorescence units (RFU). Data were plotted using GraphPad Prism (v4.0a) and IC50's calculated using a sigmoidal dose response curve fitting algorithm. Each assay was setup as follows: Defrosted all kit components and kept on ice until use. Diluted HeLa nuclear extract 1 :29 in Assay Buffer (50 mM Tris/Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgC12). Prepared dilutions of Trichostatin A (TSA, positive control) and tested compounds in assay buffer (5x of final concentration). Diluted Fluor de LysTM Substrate in assay buffer to 100 uM (50 fold = 2x final). Diluted Fluor de LysTM developer concentrate 20-fold (e.g. 50 μl plus 950 μl Assay Buffer) in cold assay buffer. Second, diluted the 0.2 mM Trichostatin A 100-fold in the Ix Developer (e.g. 10 μl in 1 ml; final Trichostatin A concentration in the Ix Developer = 2 μM; final concentration after addition to HDAC/Substrate reaction = 1 μM). Added Assay buffer, diluted trichostatin A or test inhibitor to appropriate wells of the microtiter plate. Added diluted HeLa extract or other ©C sample to all wells except for negative controls. Allowed diluted Fluor de LysTM Substrate and the samples in the microtiter plate to equilibrate to assay temperature (e.g. 25 or 37°C). Initiated HDAC reactions by adding diluted substrate (25 μl) to each well and mixing thoroughly. Allowed ©C reactions to proceed for 1 hour and then stopped them by addition of Fluor de LysTM Developer (50 μl). Incubated plate at room temperature (25°C) for 10-15 min. Read samples in a microtiter-plate reading fluorimeter capable of excitation at a wavelength in the range 350- 380 nm and detection of emitted light in the range 440- 460 nm.

The following TABLE B lists compounds representative of the invention and their activity in HDAC and Aurora assays. In these assays, the following grading was used: I > 10 μM, 10 μM > II > 1 μM, 1 μM > III > 0.1 μM, and IV < 0.1 μM for IC₅₀.

TABLE B

The patent and scientific literature referred to herein establishes the knowledge that is available to those with skill in the art. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by reference.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A compound represented by formula I:

Cy and Cy i are independently selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;

X and Y are independently NR₈, O, S, SO, SO₂, CO, alkylene, substituted alkylene, alkenylene or substituted alkenylene; where Rg is hydrogen, acyl, aliphatic or substituted aliphatic; Z is CRioo or N, where Rioo is independently selected from the group consisting of hydrogen, hydro xyl, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, CF3, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; B is linker;

C is selected from:

where Wi is O or S; Yi is absent, N, or CH; Zi is N or

CH; R₇ and R9 are independently hydrogen, OR', aliphatic or substituted aliphatic, wherein R' is hydrogen, aliphatic, substituted aliphatic or acyl; provided that if R₇ and R9 are both present, one of R₇ or R₉ must be OR' and if Y is absent, R₉ must be OR'; and Rg is hydrogen, acyl, aliphatic or substituted aliphatic; (b)

; where Wi is O or S; J is O, NH or NCH₃; and Ri₀ is hydrogen or lower alkyl;

W₁

HO.

7^V^

(c) ^*»^ ; where Wi is O or S; Yi and Zi are independently N, C or CH; and

(d)

; where Zi, Yi, and Wi are as previously defined; Rn and Ri₂ are independently selected from hydrogen or aliphatic; R₁, R₂ and R₃ are independently selected from hydrogen, hydroxyl, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF₃, CN, NO₂, N₃, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.

2. A compound according to Claim 1 represented by formula (II):

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein Bi is absent, O, S, NRg, C₁- C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heterocyclic, aryl, heteroaryl; B₂ is absent, Ci-C₆ alkyl, , C₂-C₆ alkenyl, C₂-C₆ alkynyl, O, NH, alkylamine, S, SO, SO₂, heterocyclic, heteroaryl, aryl or C=O; B₃ is absent, O, NH, alkylamino, S, SO, SO₂, C₁-C₈ alkyl, C₂-Cs alkenyl, C₂-Cs alkynyl, heterocyclic, heteroaryl, aryl or C=O; B₄ is absent, O, NH, alkylamino, CO, S, SO, SO₂, heterocyclic, heteroaryl or aryl; B₅ is absent, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heterocyclic, heteroaryl or aryl; Y₁₀-Y₁₃ are independently selected from CRioo, N, NRg, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CRioo, where Rioo is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxyl, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, CF3, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; R', Yi, Rs, R7, X and Y are as previously defined in Claim 1.

3. A compound according to Claim 1 represented by formula (III):

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein Bi is absent, O, S, NRs, C₁- C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heterocyclic, aryl, heteroaryl; B₂ is absent, Ci-C₆ alkyl, , C₂-C₆ alkenyl, C₂-C₆ alkynyl, O, NH, alkylamine, S, SO, SO₂, heterocyclic, heteroaryl, aryl or C=O; B₃ is absent, O, NH, alkylamino, S, SO, SO₂, Ci-Cg alkyl, C₂-Cg alkenyl, C₂-Cg alkynyl, heterocyclic, heteroaryl, aryl or C=O; B₄ is absent, O, NH, alkylamino, CO, S, SO, SO₂, heterocyclic, heteroaryl or aryl; B₅ is absent, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heterocyclic, heteroaryl or aryl; Y₁₀-Y₁₃ are independently selected from CRi₀₀, N, NR₈, S, and O; Xi₀-Xi₄ are independently selected from the group consisting of N or CRi₀₀, where Ri₀₀ is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; R', Rg, X and Y are as previously defined in Claim 1.

4. The compound of claim 3 wherein at least one of X₁₀ to Xi₄ is CRioo, wherein Rioo is an acyl-substituted amino group.

5. The compound of claim 4 wherein the acyl group is a (C₃-Ce)cycloalkylcarbonyl group.

6. The compound of claim 5 wherein Xi₂ is CRioo, where Rioo is cyclopropylcarbonyl-amino and X₁₀, Xn, X₁₃ and Xi₄ are each CH.

7. A compound according to Claim 1 represented by formula (IV):

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein Y₁₀-Y₁₃ are independently selected from CRioo, N, NRs, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CRioo, where Rioo is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; and Rs, X and Y are as previously defined in Claim 1.

8. A compound according to Claim 1 represented by formula (V):

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein Y₁₀-Y₁₃ are independently selected from CR100, N, NRs, S, and O; X10-X14 are independently selected from the group consisting of N or CR100, where R100 is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; and Rg, X and Y are as previously defined in Claim 1.

9. A compound according to Claim 1 represented by formula (VI):

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein Y₁₀-Y₁₃ are independently selected from CR100, N, NRs, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CR100, where R100 is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; and Rg, X and Y are as previously defined in Claim 1.

10. A compound according to Claim 1 represented by formula (VII):

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein Y₁₀-Y₁₃ are independently selected from CRioo, N, NRs, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CRioo, where Rioo is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; and Rg, X and Y are as previously defined in Claim 1.

11. A compound according to claim 1 represented by Formula (VIII):

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein Y₁₀-Y₁₃ are each independently selected from CRioo, N, NRg, S, and O; X₁₀-X₁₄ are independently selected from the group consisting of N or CRioo, where Rioo is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; n is 1-9; Rg, X and Y are as defined in claim 1.

12. A compound according to claim 1 represented by Formula (IX):

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein Y₁₀-Y₁₃ are each independently selected from CRi₀₀, N, NRg, S, and O; Xi₀-Xi₄ are independently selected from the group consisting of N or CRi₀₀, where Ri₀₀ is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF₃, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; X5 is CH or N; m is 0 or 1 ; p is 0 to 3; Rg, X and Y are as defined in claim 1.

13. A compound according to claim 1 represented by Formula (X):

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein Y₁₀-Y₁₃ are independently selected from CRioo, N, NRg, S, and O; X₁O-X₁₄ are independently selected from the group consisting of N or CRioo; Rioo is independently selected from the group consisting of hydrogen, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted thio, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF3, CN, NO₂, N₃, substituted or unsubstituted alkylsulfonyl, substituted carbonyl, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, heteroaryl, and heterocyclic; q is 0 to 4; and R₁, R₂, R₃, Rs, X and Y are as defined in claim 1.

14. A compound according to Claim 1 selected from the compounds delineated in Table A or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof:

TABLE A

15. A pharmaceutical composition comprising as an active ingredient a compound of Claim 1 and a pharmaceutical acceptable carrier.

16. A method of treating cell proliferative disorder that requires or is facilitated by expression of an Aurora protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of Claim 15.

17. The method of Claim 16, wherein said cell proliferative disorder is selected from the group consisting of papilloma, blastoglioma, Kaposi's sarcoma, melanoma, non-small cell lung cancer, ovarian cancer, prostate cancer, colon cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast cancer, lung cancer, colorectal cancer, thyroid cancer, pancreatic cancer, renal cell carcinoma, gastric cancer, hepatocellular carcinoma, neuroblastoma, leukemia, lymphoma, vulvar cancer, Hodgkin's disease and Burkitt's disease.

18. A method of treating an HDAC-mediated disease comprising administering to a subject in need thereof a pharmaceutical composition of Claim 15.

19. A method of treating cell proliferative disorder that relates to Aurora and HDAC comprising administering to a subject in need thereof a pharmaceutical composition of Claim 15.

20. A method for the treatment or prophylaxis of cancer in a subject in need thereof, comprising administering to the subject a compound of Claim 15.