| Title of Invention | A HISTONE DEACETYLASE INHIBITOR |
|---|---|
| Abstract | The invention relates to the inhibition of histone deacetylase, particularly to inhibitors to inhibit histone deacetylase enzymatic activity. The invention provides compounds of Formula (3) for inhibiting histone deacetylase enzymatic activity: or pharmaceutically acceptable salts thereof, wherein Cy3, X2 and Ar3 are as defined in the specification, and methods for inhibiting histone deacetylase activity with such compounds. The invention also provides compositions and methods of inhibiting histone deacetylase in a cell in vitro." |
| Full Text | A HISTONE DEACETYLASE INHIBITOR BACKGROUND OF THE INVENTION Field of the Invention [0001] This invention relates to the inhibition of histone deacetylase. More particularly, the invention relates to compounds and methods for inhibiting histone deacetylase enzymatic activity. Summary of the Related Art [0002] In eukaryotic cells, nuclear DNA associates with histones to form a compact complex called chromatin. The histones constitute a family of basic proteins which are generally highly conserved across eukaryotic species. The core histones, termed H2A, H2B, H3, and H4, associate to form a protein core. DNA winds around this protein core, with the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA. Approximately 146 base pairs of DNA wrap around a histone core to make up a nucleosome particle, the repeating structural motif of chromatin. [0003] Csordas, Biochem. J., 286: 23-38 (1990) teaches that histones are subject to posttranslational acetylation of the ?,?-amino groups of /V-terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HAT1). Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure. Indeed, Taunton et a/., Science, 272: 408-411 (1996), teaches that access of transcription factors to chromatin templates is enhanced by histone hyperacetylation. Taunton et al., further teaches that an enrichment in underacetylated histone H4 has been found in transcriptionally silent regions of the genome. [0004] Histone acetylation is a reversible modification, with deacetylation being catalyzed by a family of enzymes termed histone deacetylases (HDACs). Grozinger et a/., Proc. Natl. Acad. Sci. USA, 96: 4868-4873 (1999), teaches that HDACs is divided into two classes, the first represented by yeast Rpd3-like proteins, and the second represented by yeast Hdal-like proteins. Grozinger et al. also teaches that the human HDAC1, HDAC2, and HDAC3 proteins are members of the first class of HDACs, and discloses new proteins, named HDAC4, HDAC5, and HDAC6, which-are members of the second class of HDACs. Kao et a/., Genes & Dev., 14: 55-66 (2000), discloses HDAC7, a new member of the second class of HDACs. Van den Wyngaert, FEBS, 478: 77-83 (2000) discloses HDAC8, a new member of the first class of HDACs. [0005] Richon et al., Proc. Natl. Acad. Sci. USA, 95: 3003-3007 (1998), discloses that HDAC activity is inhibited by trichostatin A (TSA), a natural product isolated from Streptomyces hygroscopicus, and by a synthetic compound, suberoylanilide hydroxamic acid (SAHA). Yoshida and Beppu, Exper. Cell Res., 177: 122-131 (1988), teaches that TSA causes arrest of rat fibroblasts at the G1 and G2 phases of the cell cycle, implicating HDAC in cell cycle regulation. Indeed, Finnin et al., Nature, 401: 188-193 (1999), teaches that TSA and SAHA inhibit cell growth, induce terminal differentiation, and prevent the formation of tumors in mice. Suzuki et al., U.S. Pat. No. 6,174,905, EP 0847992, JP 258863/96, and Japanese Application No. 10138957, disclose benzamide derivatives that induce cell differentiation and inhibit HDAC. Delorme et al., WO 01/38322 and PCT IB01/00683, disclose additional compounds that serve as HDAC inhibitors. [0006] The molecular cloning of gene sequences encoding proteins with HDAC activity has established the existence of a set of discrete HDAC enzyme isoforms. Grozinger et al., Proc. Natl. Acad. Sci. USA, 96:4868-4873 (1999), teaches that HDACs may be divided into two classes, the first represented by yeast Rpd3-like proteins, and the second represented by yeast Hdal-like proteins. Grozinger et al. also teaches that the human HDAC-1, HDAC-2, and HDAC-3 proteins are members of the first class of HDACs, and discloses new proteins, named HDAC-4, HDAC-5, and HDAC-6, which are members of the second class of HDACs. Kao et al., Gene & Development 14:55- 66 (2000), discloses an additional member of this second class, called HDAC-7. More recently, Hu, E. et al. J. Bio. Chem. 275:15254-13264 (2000) discloses the newest member of the first class of histone deacetylases, HDAC-8. It has been unclear what roles these individual HDAC enzymes play. [0007] These findings suggest that inhibition of HDAC activity represents a novel approach for intervening in cell cycle regulation and that HDAC inhibitors have great therapeutic potential in the treatment of cell proliferative diseases or conditions. To date, few inhibitors of histone deacetylase are known in the art. There is thus a need to identify additional HDAC inhibitors and to identify the structural features required for potent HDAC inhibitory activity. BRIEF SUMMARY OF THE INVENTION [0008] The invention provides compounds and methods for treating cell proliferative diseases. The invention provides new inhibitors of histone deacetylase enzymatic activity. [0009] In a first aspect, the invention provides compounds that are useful as inhibitors of histone deacetylase. [0010] In a second aspect, the invention provides a composition comprising an inhibitor of histone deacetylase according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. [0011] In a third aspect, the invention provides a method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase of the invention. [0012] The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below. BRIEF DESCRIPTION OF THE DRAWINGS [0013] Figure 1 is a graph showing the antitumor activity of compound 106 in an HCT 116 human colorectal tumor model. [0014] Figures 2-11 show additional data for other compounds used in the in vivo experiment described in Assay Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0015] The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions. The patent and scientific literature referred to herein establishes knowledge that is available to those with skill in the art. The issued patents, applications, and references that are cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference. In the case of inconsistencies, the present disclosure will prevail. [0016] For purposes of the present invention, the following definitions will be used (unless expressly stated otherwise): [0017] As used herein, the terms "histone deacetylase" and "HDAC" are intended to refer to any one of a family of enzymes that remove acetyl groups from the ,-amino groups of lysine residues at the N-terminus of a histone. Unless otherwise indicated by context, the term "histone" is meant to refer to any histone protein, including H1, H2A, H2B, H3, H4, and H5, from any species. Preferred histone deacetylases include class I and class II enzymes. Preferably the histone deacetylase is a human HDAC, including, but not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, and HDAC-8. In some other preferred embodiments, the histone deacetylase is derived from a protozoal or fungal source. [0018] The terms "histone deacetylase inhibitor" and "inhibitor of histone deacetylase" are used to identify a compound having a structure as defined herein, which is capable of interacting with a histone deacetylase and inhibiting its enzymatic activity. "Inhibiting histone deacetylase enzymatic activity" means reducing the ability of a histone deacetylase to remove an acetyl group from a histone. In some preferred embodiments, such reduction of histone deacetylase activity is at least about 50%, more preferably at least about 75%, and still more preferably at least about 90%. In other preferred embodiments, histone deacetylase activity is reduced by at least 95% and more preferably by at least 99%. [0019] Preferably, such inhibition is specific, i.e., the histone deacetylase inhibitor reduces the ability of a histone deacetylase to remove an acetyl group from a histone at a concentration that is lower than the concentration of the inhibitor that is required to produce another, unrelated biological effect. Preferably, the concentration of the inhibitor required for histone deacetylase inhibitory activity is at least 2-fold lower, more preferably at least 5-fold lower, even more preferably at least 10-fold lower, and most preferably at least 20-fold lower than the concentration required to produce an unrelated biological effect. [0020] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an "alkyl" moiety generally refers to a monovalent radical (e.g. CH3-CH2-), in certain circumstances 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 a divalent moiety is required and is stated as being "aryl," those skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S). On occasion a moiety may be defined, for example, as (A)a-B-, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B- and when a is 1 the moiety is A-B-. Also, a number of moieties disclosed herein exist in multiple tautomeric forms, all of which are intended to be encompassed by any given tautomeric structure. [0021] The term "hydrocarbyl" refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, each as defined herein. A "C0" hydrocarbyl is used to refer to a covalent bond. Thus, "Co-C3- hydrocarbyl" includes a covalent bond, methyl, ethyl, propyl, and cyclopropyl. [0022] The term "alkyl" as employed herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. A "Co" alkyl (as in "C0-C3-alkyl") is a covalent bond (like "Co" hydrocarbyl). [0023] The term "alkenyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl. [0024] The term "alkynyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl. [0025] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Preferred alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Preferred alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Preferred alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene. [0026] The term "cycloalkyl" as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. [0027] The term "heteroalkyl" refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are replaced by a heteratom selected from the group consisting of O, S, and N. [0098] An "aryl" group is a C6-C14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted. Preferably, the aryl group is a C6-C10 aryl group. Preferred aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An "aralkyl" or "arylalkyl" group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted. Preferably, the aralkyl group is (C1-C6)alk(C6-C10)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. [0029] A "heterocyclyl" or "heterocyclic" group is a ring structure having from about 3 to about 8 atoms, wherein one or more atoms are selected from the group consisting of N, 0, and S. The heterocyclic group is optionally substituted on carbon at one or more positions. The heterocyclic group is also independently optionally substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl. Preferred heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino. In certain preferred embodiments, the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group. Examples of such fused heterocyles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the scope of this term are compounds having adjacent annular 0 and/or S atoms. [0030] As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 n electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, 0, and S. A "heteroaralkyl" or "heteroarylalkyt" group comprises a heteroaryl group covalently linked to an alkyl group, either of which is independently optionally substituted or unsubstituted. Preferred heteroalkyl groups comprise a C1-C6 alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms. Specifically excluded from the scope of this term are compounds having adjacent annular 0 and/or S atoms. Examples of preferred heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, and thiazolylethyl. Specifically excluded from the scope of this term are compounds having adjacent annular 0 and/or S atoms. [0031] An "arylene," "heteroarylene," or "heterocyclylene" group is an aryl, heteroaryl, or heterocyclyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. [0032] Preferred heterocyclyls and heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH- carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyrtpnyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. [0033] As employed herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl, heteroaryl, heterocyclic, urea, etc.) is described as "optionally substituted" it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular - CH- substituted with oxo is -C(O)-) nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, , alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups. Preferred substituents, which are themselves not further substituted (unless expressly stated otherwise) are: (a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, (b) C1-C5 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkoxy, C1-C8 alkoxycarbonyl, aryloxycarbonyl, C2-C8 acyl, C2-C8 acylamino, C1-C8 alkylthio, arylalkylthio, arylthio, C1-C8 alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C1-C8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, Co-C6 /V-alkyl carbamoyl, C2-C15 N,N- dialkylcarbamoyl, C3-C7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C3-C7 heterocycle, or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; and (c) -(CH2)s-NR30R31, wherein s is from 0 (in which case the nitrogen is directly bonded to the moiety that is substituted) to 6, and R30 and R31 are each independently hydrogen, cyano, oxo, carboxamido, amidino, C1-C8 hydroxyalkyl, C1-C3 alkylaryl, aryl-C1-C3 alkyl, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkoxy, C1-C8 alkoxycarbonyl, aryloxycarbonyl, aryl-C1- C3 alkoxycarbonyl, C2-C8 acyl, C1-C8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, aroyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; or R30 and R31 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents from (a), above. [0034] In addition, substituents on cyclic moieties (i.e., cycloalkyl, heterocyclyl, aryl, heteroaryl) include 5-6 membered mono- and 10-12 membered bi-cyclic moieties fused to the parent cyclic moiety to form a bi- or tri-cyclic fused ring system. For example, an optionally substituted phenyl includes the following: [0035] A "halohydrocarbyl" is a hydrocarbyl moiety in which from one to all hydrogens have been replaced with one or more halo. [0036] The term "halogen" or "halo" as employed herein refers to chlorine, bromine, fluorine, or iodine. As herein employed, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent. The term "acylamino" refers to an amide group attached at the nitrogen atom (i.e., R-CO-NH-). The term "carbamoyl" refers to an amide group attached at the carbonyl carbon atom (i.e., NH2-CO-). The nitrogen atom of an acylamino or carbamoyl substituent is additionally substituted. The term "sulfonamido" refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom. The term "amino" is meant to include NH2, alkylamino, arylamino, and cyclic amino groups. The term "ureido" as employed herein refers to a substituted or unsubstituted urea moiety. [0037] The term "radical" as used herein means a chemical moiety comprising one or more unpaired electrons. [0038] A moiety that is substituted is one in which one or more hydrogens have been independently replaced with another chemical substituent. As a non-limiting example, substituted phenyls include 2-flurophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluor-3-propylphenyl. As another non-limiting example, substituted n-octyls include 2,4 dimethyl-5-ethyl-octyl and 3-cyclopentyi- octyl. Included within this definition are methylenes (-CH2-) substituted with oxygen to form carbonyl - CO-). [0039] An "unsubstituted" moiety as defined above (e.g., unsubstituted cycloalkyl, unsubstituted heteroaryl, etc.) means that moiety as defined above that does not have any of the optional substituents for which the definition of the moiety (above) otherwise provides. Thus, for example, while an "aryl" includes phenyl and phenyl substituted with a halo, "unsubstituted aryl" does not include phenyl substituted with a halo. [0040] Preferred embodiments of a particular genus of compounds of the invention include combinations of preferred embodiments. For example, paragraph [0042] identifies a preferred Ay1 and paragraph [0046] identifies preferred Ar1 (both for compound (1) of paragraph [0041]). Thus, another preferred embodiment includes those compounds of formula (1) in paragraph [0041] in which Ay1 is as defined in paragraph [0042] and Ar1 is as defined in paragraph [0046]. Compounds [0041] In a first aspect, the invention provides novel inhibitors of histone deacetylase. In a first embodiment, the novel inhibitors of histone deacetylase are represented by formula (1): and pharmaceutically acceptable salts thereof, wherein R3 and R4 are independently selected from the group consisting of hydrogen, L1, Cy1 and -L1- Cy1, wherein L1 is C1-C6 alkyl, C2-C6 heteroalkyl, or C3-C6 alkenyl; and Cy1 is cycloalkyl. aryl, heteroaryl, or heterocyclyl, each of which optionally is substituted, and each of which optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings optionally is substituted; or R3 and R4 are taken together with the adjacent nitrogen atom to form a 5-, 6-, or 7-membered ring, wherein the ring atoms are independently selected from the group consisting of C, 0, S, and N, and wherein the ring optionally is substituted, and optionally forms part of a bicyclic ring system, or optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings and ring systems optionally is substituted; Y1 is selected from the group consisting of -N(R1)(R2), -CH2C(O)-N(R1)(R2), halogen, and hydrogen, wherein R1 and R2 are independently selected from the group consisting of hydrogen, L1, Cy1, and -L1-Cy1. wherein L1 is C1-C6 alkyl, C2-C6 heteroalkyl, or C3-C6 alkenyl; and Cy1 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which optionally is substituted, and each of which optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings optionally is substituted; or R1 and R2 are taken together with the adjacent nitrogen atom to form a 5-, 6-, or 7- membered ring, wherein the ring atoms are independently selected from the group consisting of C, 0, S, and N, and wherein the ring optionally is substituted, and optionally may form part of a bicyclic ring system, or optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings and ring systems optionally is substituted; Y2 is a chemical bond or N(R°), where R° is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, and acyl; Ak1 is C1-C6 alkylene, C1-C6-heteroalkylene (preferably, in which one -CH2- is replaced with -NH-, and more preferably -NH-CH2-), C2-C6 alkenylene or C2-C6 alkynylene; Ar1 is arylene or heteroarylene, either of which optionally is substituted; and Z1 is selected from the group consisting of wherein Ay1 is aryl or heteroaryl, which optionally is substituted. [0042] Preferably in the compounds according to paragraph [0041], Ay1 is phenyl or thienyl, each substituted with -OH or -NH2. [0043] More preferably in the compounds according to paragraph [0041], Ay1 is optionally amino- or hydroxy-substituted phenyl or thienyl, wherein the amino or hydroxy substituent is preferably ortho to the nitrogen to which Ay2 is attached. [0044] More preferably in the compounds according to paragraph [0041], Ay1 is ortho aniline, ortho phenol, 3-amino-2-thienyl, or 3-hydroxy-2-thienyl, and tautomers thereof. [0045] In some preferred embodiments of the compounds according to paragraph [0041], Z1 is [0046] In some preferred embodiments of the compounds according to paragraph [0041], Ar1 is phenylene. In some embodiments, Ak1 is alkylene, preferably methylene. In some preferred embodiments, Y2 is -NH-. In some preferred embodiments, Yl is -N(R1)(R2) or -CH2C(O)-N(R1)(R2). [0047] In some embodiments of the compounds according to paragraph [0041], R1 and R2 are each independently selected from the group consisting of hydrogen, L1, Cy1, and -L'-Cy1. In some embodiments, R1 and/or R2 is hydrogen. In other embodiments, R1 and/or R2 is alkyl or alkenyl, preferably allyl. In still other embodiments, R1 and/or R2 is aryl, heteroaryl, aralkyl, or heteroaralkyl, the rings of each of which optionally is substituted and optionally is fused to one or more aryl rings. Some preferred aryl, heteroaryl, aralkyl, and heteroaralkyl groups comprise a phenyl, pyridyl, or pyrrolyl ring. In still other embodiments, R1 and/or R2 is cycloalkyl, e.g., cyclopropyl, cyclopentyl, or cyclohexyl, which optionally is substituted and optionally is fused to one or more aryl rings. [0048] In some embodiments of the compounds according to paragraph [0041], R3 and R4 are each independently selected from the group consisting of hydrogen, L1, Cy1, and -L1-Cy1. In some embodiments, R3 and/or R4 is hydrogen. In other embodiments, R3 and/or R4 is alkyl or alkenyl, preferably allyl. In still other embodiments, R3 and/or R4 is aryl, heteroaryl, aralkyl, or heteroaralkyl, the rings of each of which optionally is substituted and optionally is fused to one or more aryl rings. Some preferred aryl, heteroaryl, aralkyl, and heteroaralkyl groups comprise a phenyl, pyridyl, or pyrrolyl ring. In still other embodiments, R3 and/or R4 is cycloalkyl, e.g., cyclopropyl, cyclopentyl, or cyclohexyl, which optionally is substituted and optionally is fused to one or more aryl rings. [0049] As set forth above, L1 is C1-C6 alky!, C2-C6 heteroalkyl, or CrC6 alkenyl. However, one skilled in the art will understand that when L1 is not a terminal group, then L1 is C1-C6 alkylene, C2-C6 heteroalkylene, or C3-C6 alkenylene. In some embodiments, L1 is alkylene, preferably methylene or ethylene. In other embodiments, L1 is alkenyl, preferably allyl. In some embodiments, Cy1 is the radical of a heterocyclic group including, without limitation, piperidine, pyrrolidine, piperazine, and morpholine, each of which optionally is substituted and optionally is fused to one or more aryl rings. In other embodiments Cy1 is cycloalkyl, e.g., cyclopropyl, cyclopentyl, or cyclohexyl. In still other embodiments, Cy1 is aryl or heteroaryl, e.g., phenyl, pyridyl, or pyrrolyl, each of which optionally is substituted and optionally is fused to one or more aryl rings. In some embodiments, Cy1 is fused to one or two benzene rings. In some embodiments, Cy1 has between one and about five substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, and halo. Examples of preferred substituents include methyl, methoxy, and fluoro. [0050] In some embodiments of the compounds according to paragraph [0041], R1 and R2 and/or R3 and R4 are taken together with the adjacent nitrogen atom to form a 5- or 6-membered ring, wherein the ring atoms are independently selected from the group consisting of C, 0, and N, and wherein the ring optionally is substituted, and optionally is fused to one or more aryl rings. In some preferred embodiments, R1 and R2 and/or R3 and R4 are taken together with the adjacent nitrogen atom to form a ring such as, for example, pyrrolidine, piperidine, piperazine, and morpholine, wherein the ring optionally is substituted, and optionally is fused to an aryl ring. In some embodiments, the ring comprising R1 and R2 or R3 and R4 is fused to a benzene ring. In some embodiments, the ring comprising R1 and Rz or R3 and R4 has a substituent comprising an aryl or cycloalkyl ring, either of which optionally is substituted and optionally is fused to a cycloalkyl, aryl, heteroaryl, or heterocyclic ring. Preferred substituents include, without limitation, phenyl, phenylmethyl, and phenylethyl, the phenyl ring of which optionally is fused to a cycloalkyl, aryl, or heterocyclic ring. [0051] In a preferred embodiment, the HDAC inhibitors of the invention comprise compounds of formula l(a): and pharmaceutically acceptable salts thereof, wherein J is C1-C3-hydrocarbyl, -N(R20) -N(R20)-CH2-, -O-, or -O-CH2-; R20 is -H or -Me; X and Y are independently selected from -NH2l cycloalkyl, heterocyclyl, aryl, heteroaryl, and A-(C1-C6-alkyl)n-B-; A is H, C1-C6-alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is -NH-, -0-, or a direct bond; and n is 0 (in which case A is directly bonded to B) or 1. [0052] Preferably in the compounds according to paragraph [0051], A is phenyl optionally substituted with one or more moieties selected from halo (preferably chloro) and methoxy, and B is - NH-. In another preferred embodiment, A is selected from cyclopropyl, pyridinyl, and indanyl. [0053] Preferably in the compounds according to paragraph [0051], J is -NH-CH2-, -O-CH2-, - N(CH3)-CHr, -CH=CH-, or -CH2-CH2- [0054] Preferably in the compounds according to paragraph [0051], R20 is -H. [0055] In the compounds according to paragraph [0051] X is preferably selected from and Y is preferably selected from [0056] In a more preferred embodiment of the compounds according to paragraph [0051], the HDAC inhibitors of the invention comprise the following compounds of formula la: [0057] In a second aspect, the novel histone deacetylase inhibitors of the invention are represented by formula (2): and pharmaceutically acceptable salts thereof, wherein Cy2 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted and each of which is optionally fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings is optionally substituted; X1 is selected from the group consisting of a covalent bond, M1-L2-M1, and L2-M2-L2 wherein L2, at each occurrence, is independently selected from the group consisting of a chemical bond, C1-C4 alkylene, C2-C4 alkenylene, and C1-C4 alkynylene, provided that L2 is not a chemical bond when X1 is M1-L2-M1; M1, at each occurrence, is independently selected from the group consisting of-O-, -N(R7)-, -S-, -S(O)-, S(O)2, -S(O)2N(R7)-, -N(R7)-S(O)2-, -C(O)-, -C(O)-NH-, -NH-C(O)-, -NH-C(O)-O-and -O-C(O)-NH-, wherein R7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl; and M2 is selected from the group consisting of M1, heteroarylene, and heterocyclylene, either of which rings optionally is substituted; Ar2 is arylene or heteroarylene, each of which is optionally substituted; R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl; q is 0 or 1; and Ay2 is a 5-6 membered cycloalkyl, heterocyclyl, or heteroaryl substituted with an amino or hydroxy moiety (preferably these groups are ortho to the amide nitrogen to which Ay2 is attached) and further optionally substituted; provided that when Cy2 is naphthyl, X1 is -CH2-, Ar2 is phenyl, R5 and R6 are H, and q is 0 or 1, Ay2 is not phenyl or o-hydroxyphenyl. [0058] In a preferred embodiment of the compounds according to paragraph [0057], when Ay2 is o-phenol optionally substituted by halo, nitro, or methyl, Ar2 is optionally substituted phenyl, X1 is - O-, -CH2-, -S-, -S-CHr, -S(O) -S(O)2, -C(O) or -OCH2, then Cy2 is not optionally substituted phenyl or naphthyl. [0059] In another preferred embodiment of the compounds according to paragraph [0057], when Ay2 is o-anilinyl optionally substituted by halo, C1-C6-alkyl, C1-C6-alkoxy or -NO2, q is 0, Ar2 is phenyl, and X1 is -CH2-, then Cy2 is not substituted pyridone (which substituents of the pyridone are not limited to substituents described herein). [0060] In another preferred embodiment of the compounds according to paragraph [0057], when X1 is -CH2-, Ar2 is optionally substituted phenyl, q is 1, and R6 is H, then Cy2 is not optionally substituted imidazole. [0061] In another preferred embodiment of the compounds according to paragraph [0057], when Ar2 is amino or hydroxy substituted phenyl, X1 is Co-C8-alkyl-X1a- C0-C8-alkyl, wherein Xla is -CH2-, -O-, -S-, -NH-, -C(O)-, then Cy2 is not optionally substituted naphthyl or di- or -tetrahydronaphthalene. [0062] In another preferred embodiment of the compounds according to paragraph [0057], when Ay2 is o-phenol, Ar2 is substituted phenyl, X1 is -O-, -S-, -CH2-, -O-CH2-, -S-CH2-, or -C(O) and R5 and R6 are H, then Cy2 is not optionally substituted naphthyl. [0063] In another preferred embodiment of the compounds according to paragraph [0057], when Ay2 is o-anilinyl, q is 0, Ar2 is unsubstituted phenyl, X1 is -CH2-, then Cy2 is not substituted 6- hydroimidazolo[5,4-d]pyridazin-7-one-l-yl or substituted 6-hydroimidazolo[5,4-d]pyridazine-7-thione-l- yl. [0064] Preferably in the compounds according to paragraph [0057], Ay2 is phenyl or thienyl, each substituted with -OH or -NH2. [0065] More preferably in the compounds according to paragraph [0057], Ay2 is optionally amino- or hydroxy-substituted phenyl or thienyl, wherein the amino or hydroxy substituent is preferably ortho to the nitrogen to which Ay2 is attached. [0066] More preferably in the compounds according to paragraph [0057], Ay2 is ortho aniline, ortho phenol, 3-amino-2-thienyl, or 3-hydroxy-2-thienyl, and tautomers thereof. [0067] In a another embodiment, the novel histone deacetylase inhibitors of the invention are those according to paragraph [0057] wherein q is 1; M1 at each occurrence, is selected from the group consisting of -N(R7)-, -S-, -C(O)-NH-, and -O-C(O)-NH-, where R7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, and acyl; and Ay2 is anilinyl, which optionally is substituted. [0068] In some preferred embodiments of the compounds according to paragraph [0067], the -NH2 group of Ay2 is in an ortho position with respect to the nitrogen atom to which Ay2 is attached. In some embodiments, R5 and R6 are independently selected from the group consisting of hydrogen and C1-C4 alkyl. In some preferred embodiments, R5 and R6 are hydrogen. [0069] In some embodiments of the compounds according to paragraph [0067], Ar2 has the formula wherein G, at each occurrence, is independently N or C, and C optionally is substituted. In some preferred embodiments, Ar2 has the formula [0070] In some preferred embodiments of the compounds according to paragraph [0069], Ar2 is selected from the group consisting of phenylene, pyridylene, pyrimidylene, and quinolylene. [0071] In some embodiments of the compounds according to paragraph [0067], X1 is a chemical bond. In some embodiments, X1 is L2-M2-L2, and M2 is selected from the group consisting of -NH-, -N(CH3)-, -S-, -C(O)-N(H)-, and -O-C(O)-N(H)-. In some embodiments, X1 is L2-M2-L2, where at least one occurrence of L2 is a chemical bond. In other embodiments, X1 is L2-M2-L2, where at least one occurrence of L2 is alkylene, preferably methylene. In still other embodiments, X1 is L2-M2-L2, where at least one occurrence of L2 is alkenylene. In some embodiments, X1 is M1-L1-M1 and M1 is selected from the group consisting of -NH-, -N(CH3)-, -S-, and -C(O)-N(H)-. [0072] In some embodiments of the compounds according to paragraph [0067], Cy2 is aryl or heteroaryl, e.g., phenyl, pyridyl, imidazolyl, or quinolyl, each of which optionally is substituted. In some embodiments, Cy2 is heterocyclyl, e.g., each of which optionally is substituted and optionally is fused to one or more aryl rings. In some embodiments, Cy2 has from one and three substituents independently selected from the group consisting of alkyl, alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy. Examples of preferred substituents include methyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, nitro, amino, aminomethyl, and hydroxymethyl. [0073] In a preferred embodiment of the compounds of paragraph [0057], the invention comprises compounds of structural formula (2a): and pharmaceutically acceptable salts thereof, wherein Ara is phenyl or thienyl; R6 is H, or C1-C6-alkyl (preferably -CH3); Y and Z are independently -CH= or -N=; W is halo, (V1-L4)t-V-L3-; L3 is a direct bond, -C1-C6-hydrocarbyl, -(C1-C3-hydrocarbyl)m1-X'-(C1-C3- hydrocarbyl)m2, -NH- (Co-C3-hydrocarbyl), (C1-C3- hydrocarbyl)-NH-, or -NH+(C1-C3- hydrocarbyl)-NH-; m1 and m2 are independently 0 or 1; X1 is -N(R21) -C(O)N(R21)-, N(R21)C(O) -O-, or -S-; R21 is -H, V-(C1-C6-hydrocarbyl)c; L4 is (C1-C6-hydrocarbyl)a-M-(C1-C6-hydrocarbyl)b; a and b are independently 0 or 1; M is -NH-, -NHC(O)-, -C(O)NH-, -C(O)-, -SO2-, -NHSO2-. or -SO2NH- V, V', and V" are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; t is 0 or 1; or W, the annular C to which it is bound, and Y together form a monocyclic cycloalkyl, heterocyclyl, aryl, or heteroaryl; and wherein the A and Ara rings are optionally further substituted with from 1 to 3 substituents independently selected from methyl, hydroxy, methoxy, halo, and amino. [0074] In a preferred embodiment of the compound according to paragraph [0073]: Y and Z are -CH= and R6 is H; W is V-L3; L3 is -NH-CH- or -CH-NH-; V is phenyl optionally substituted with from 1 to 3 moieties independently selected from halo, hydroxy, C1-C6-hydrocarbyl, C1-C6-hydrocarbyl-oxy or -thio (particularly methoxy or methylthio), wherein each of the hydrocarbyl moieties are optionally substituted with one or more moieties independently selected from halo, nitroso, amino, sulfonamido, and cyano; and Ara is phenyl and the amino moieties to which it is bound are ortho to each other. [0075] In some preferred embodiments of the compound according to paragraph [0073], V is an optionally substituted ring moiety selected from: [0076] In another preferred embodiment of the compounds according to paragraph [0073], W is selected from:, [0077] In another preferred embodiment of the compounds according to paragraph [0073], the A and Ara rings are not further substituted. [0078] In a particularly preferred embodiment of the compounds according to paragraph [0073], the compounds of the invention are selected from the following, in which, unless expressly displayed otherwise, Ara is phenyl (and, preferably, the amide nitrogen and the amino nitrogen bound to Ara are ortho to each other): [0079] In a preferred embodiment of the compounds according to paragraph [0057], the invention comprises compounds of the formula (2b): and pharmaceutically acceptable salts thereof, wherein Ay2 is phenyl or thienyl, each substituted at the ortho position with -NH2 or -OH and each further optionally substituted with one to three substituents independently selected from -NH2, -OH, and halo; q is 0 or 1; X1 is selected from -CHr, -NH-CH2-, and -S-CH2-; Cy2 is monocyclic or fused bicyclic aryl or heteroaryl optionally substituted with one to three substituents selected from CHr, CH3O-, phenyl optionally substituted with one to three CH3O-, morphylinyl, morphylinyl-C1-C3-alkoxy, cyano, and CH3C(O)NH-; provided that when Cy2 is naphthyl, X1 is -CH2-. and q is 0 or 1, Ay2 is not o-hydroxyphenyl. [0080] Preferably in the compounds according to paragraph [0079], Ay2 is selected from: [0081] Preferably in the compounds according to paragraph [0079], Cy2 is phenyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, thienyl, tetrahydroquinozolinyl, or 1,3-dihydroquinazoline- 2,4-dione, each optionally substituted with one to three CH30-. More preferably, Cy2 is phenyl substituted with one to three CH3O-. [0082] In a third embodiment, the novel inhibitors of histone deacetylase are represented by formula (3): and pharmaceutical salts thereof, wherein Ar3 is arylene or heteroarylene, either of which optionally is substituted; Cy3 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which optionally is substituted, and each of which optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings optionally is substituted; provided that when Cy3 is a cyclic moiety having -C(O)-, -C(Sh -S(O) or -S(O)2- in the ring, then Cy3 is not additionally substituted with a group comprising an aryl or heteroaryl ring; and X2 is selected from the group consisting of a chemical bond, L3, Wl,L3, L3-W1 W1-L3-W1, and L3-W1-L3, wherein Wl, at each occurrence, is S, O, or N(R9), where R9 is selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl; and L3 is C1-C4 alkylene, C2-C4 alkenylene, or C2-C4 alkynylene; provided that X2 does not comprise a -C(O) -C(S)-, -S(O)-, or -S(O)2r group; and further provided that when Cy3 is pyridine, then X2 is L3, W1-L3, or L3-W1. [0083] Preferably, Ar3 has the structure: wherein Q, at each occurrence, is independently N or C, and C optionally is substituted. [0084] Preferably in the compounds according to paragraph [0082], X2 is selected from the group consisting of L3, W1-L3, L3-W1, W1-L1-W1, and L3-W1-L3. [0085] Preferably in the compounds according to paragraph [0082], when X2 is a chemical bond, then Ar3 is not and Cy3 is not the radical of a substituted or unsubstituted diazepine or benzofuran. [0086] In some embodiments of the compounds according to paragraph [0082], Q at each occurrence is C(R8), where R8 is selected from the group consisting of hydrogen, alky!, aryl, aralkyl, alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy. In some other embodiments, from one to about three variables Q are nitrogen. In some preferred embodiments, Ar3 is selected from the group consisting of phenylene, pyridylene, thiazolylene, and quinolylene. [0087] In some embodiments of the compounds according to paragraph [00821, X2 is a chemical bond. In other embodiments, X2 is a non-cyclic hydrocarbyl. In some such embodiments, X2 is alkylene, preferably methylene or ethylene. In other such embodiments, X2 is alkenylene or alkynylene. In still other such embodiments, one carbon in the hydrocaryl chain is replaced with -NH- or -S-. In some preferred embodiments, X2 is W1-L3-W1 and W1 is -NH- or -N(CH3)-, [0088] In some embodiments of the compounds according to paragraph [0082], Cy3 is cycloalkyl, preferably cyclohexyl. In other embodiments, Cy3 is aryl or heteroaryl, e.g., phenyl, pyridyl, pyrimidyl, imidazolyl, thiazolyl, oxadiazolyl, quinolyl, or fluorenyl, each of which optionally is substituted and optionally is fused to one or more aryl rings. In some embodiments, the cyclic moiety of Cy3 is fused to a benzene ring. In some embodiments, Cy3 has from one to three substituents independently selected from the group consisting of alkyl, alkoxy, aryl, aralkyl, amino, halo, haloalkyl, and hydroxyalkyl. Examples of preferred substituents include methyl, methoxy, fluoro, trifluoromethyl, amino, nitro, aminomethyl, hydroxymethyt, and phenyl. Some other preferred substituents have the formula -Kl-N(H)(R10), wherein K1 is a chemical bond or C1-C4 alkylene; R10 is selected from the group consisting of Z' and -Ak2-Z' wherein Ak2 is C1-C4 alkylene; and Z' is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which optionally is substituted, and each of which optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings. [0089] Examples of such preferred substituents according to paragraph [0088] include [0090] In some embodiments of the compounds according to paragraph [0082], Cy3 is heterocyclyl, e.g., each of which optionally is substituted and optionally is fused to one or more aryl rings. In some embodiments, the heterocycle of Cy3 is fused to a benzene ring. [0091] Preferably in the compounds of paragraph [0082], when Ar4 is quinoxalinylene, then X3 is not -CH(OH)-. [0092] In another preferred embodiment, Ar3 is wherein X is -CH2, -NH-, O, or S. Preferably Ar3 is and X is S or O. [0093] In a preferred embodiment, the novel histone deacetylase inhibitors of the invention are those according to paragraph [0057] wherein Ay2 is ortho-anilinyl; q is 0; and X1 is M1-L2-M1 or L2-M2-L2. [0094] In a preferred embodiment of the compounds according to paragraph [0093], Ar2 is aryl or heteroaryl; and Cy2-X1- is collectively selected from the group consisting of a) A1-L1-B1-, wherein A1 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L1 is -(CH2)0-1NH(CH2)o-r, -NHC(O)-, or -NHCH2-; and wherein B1 is phenyl or a covalent bond; b) A2-L2-B2-, wherein A2 is CH3(C=CH2)-, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted aryl; wherein L2 is -C=C-; and wherein B2 is a covalent bond; c) A3-L3-B3-, wherein A3 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L3 is a covalent bond; and wherein B3 is - CH2NH-; d) A4-L4-B4-, wherein A4 is an optionally substituted aryl; wherein L4 is -NHCH2-; and wherein B4 is a thienyl group; e) A5-L5-B5-, wherein A5 is an optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L5 is a covalent bond; and wherein B5 is -SCH2-; f) morpholinyl-CH2- g) optionally substituted aryl; h) A6-L6-B6-, wherein A6 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L6 is a covalent bond; and wherein B6 is - NHCH2-; i) A7-L7-B7-, wherein A7 is an optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L7 is a covalent bond; and wherein B7 is -CH2-; j) aptionally substituted heteroaryl or optionally substituted heterocyclyl; k) A8L8-B8, wherein A8 is optionally substituted phenyl; wherein L8 is a covalent bond; and wherein B8 is -O-; I) A9-L9-B9-, wherein A9 is an optionally substituted aryl; wherein L9 is a covalent bond; and wherein B9 is a furan group; m) A10-L10-B10-, wherein A10 is an optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L10 is -CH(CH2CH3)-; and wherein B10 is -NHCH2-; n) A11-L11-B11, wherein A11 is an optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L11 is a covalent bond; and wherein B11 is -OCH2-; 0) A12-L12-B12-. wherein A12 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L12 is-NHC(O)-; and wherein B12 is - N(optionally substituted aryl)CH2-; p) A13-L13-B13-, wherein A12 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L13 is a covalent bond; and wherein B13 is - NHC(O)-; q) A14-L14-B14-, wherein A14 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L14 is-NHC(O)(optionally substituted heteroaryl); and wherein B14 is -S-S-; r) F3CC(O)NH-; s) A15-L15-B15-, wherein A15 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L15 is-(CH2)0-1NH(optionally substituted heteroaryl)-; and wherein B15 is -NHCH2-; t) A16-L16-B16-, wherein A16 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L16 is a covalent bond; and wherein B16 is - N(optionally substituted alkyl)CH2-; and u) A16-L16-B16-, wherein A16 is an optionally substituted aryl, option ubstituted heteroaryl or optionally substituted heterocyclyl; wherein L16 is a covalent;. and wherein B16 is - (optionally substituted aryl-CH2)2-N-. [0095] In another preferred embodiment of the compounds according to paragraph [0093], Cy2- X1- is collectively selected from the group consisting of a) D1-E1-F1-, wherein D1 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E1 is -CH2- or a covalent bond; and wherein B1 is a covalent bond; b) D2-E2-F2-, wherein D2 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E2 is -NH(CH2)0-2-; and wherein F2 is a covalent bond; c) D3-E3-F3-, wherein D3 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E3 is -(CH2)o-2NH-; and wherein F3 is a covalent bond; d) D4-E4-F4-, wherein D4 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E4 is -S(CH2)0-1; and wherein F4 is a covalent bond; e) D5-E5-F5-, wherein D5 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E5 is -(CH2)0-2S-; and wherein F5 is a covalent bond; and f) D6-E6-F6-, wherein D6 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E6 is -NH(CH2)0-2NH-; and wherein F6 is a covalent bond. [0096] In a preferred embodiment, the HDAC inhibitors of the invention comprise compounds of paragraph [0057] having formula (3b): and pharmaceutically acceptable salts thereof, wherein Y and Z are independently N or CH and W is selected from the group consisting of: [0097] In a preferred embodiment of the compounds according to paragraph [0096], the compounds comprise those wherein Y, Z and W are as defined below: [0098] In another preferred embodiment of the compounds according to paragraph [0096], the compounds comprise those wherein Y, Z and W are as defined below: [0099] In yet another a preferred embodiment, the novel histone deacetyiase inhibitors of the invention are selected from the group consisting of the following and their pharmaceutically acceptable salts: [0100] In another preferred embodiment, the compounds are selected from those listed in Tables 2a-b, 3a-d, 4a-c, and 5a-5f. Synthesis [0101] Compounds of formula (1), wherein Y1 is -N(R1)(R2), preferably may be prepared according to the synthetic route depicted in Scheme 1. Thus, trichlorotriazine I reacts with amine II in the presence of diisopropylethylamine to produce dichloroaminotriazine III. The amine R1R2NH is added to dichloroaminotriazine III to produce diaminochlorotriazine V. Treatment of V with ammonia or R3R4NH in tetrahydrofuran (THF) or 1,4 dioxane affords triaminotriazine VI. [0102] Alternatively, dichloroaminotriazine III may be reacted with ammonia gas in 1,4 dioxane to produce diaminochlorotriazine IV. Treatment of IV with R1R2NH in THF or 1,4 dioxane in a sealed flask then affords triaminotriazine VI. [0103] Hydrolysis of the ester moiety in VI is effected by treatment with a hydroxide base, such as lithium hydroxide, to afford the corresponding acid VII. Treatment of the acid VII with 1,2- phenylenediamine in the presence of BOP reagent, triethylamine, and dimethylformamide (DMF) yields the anilinyl amide VIII. [0104] Compounds of formula (1), wherein Y1 is -CH2-C(O)-N(R1)(R2), preferably may be prepared as outlined in Scheme 2. Thus, piperazine IX is treated with acetyl chloride and triethylamine to produce amide X. Reaction of X with dichloromorpholyltriazine and lithium hexamethyldisiloxane affords compound XI. The chloride of XI is converted to the anilinyl amide of XII as described above with respect to Scheme 1: treatment with the amine and diisopropylethylamine; followed by lithium hydroxide; followed by BOP reagent, phenylenediamine, triethylamine, and DMF. Scheme 2 [0105] Compounds of formula (2), wherein Ar2 is pyridylene and X1 comprises -N(R7)-, compounds of formula (3), wherein Ar3 is pyridylene and X2 comprises -N(R9)-, and compounds of formula (4), wherein Ar4 is pyridylene and X3 comprises -N(R11)-, preferably may be prepared according to the procedures illustrated in Scheme 3. Dibromopyridine XIII or XIV is treated with amine RNH2 to produce aminobromopyridine XV or XVI, respectively. Treatment of XV or XVI with diacetoxypalladium, diphenylphosphinoferrocene, DMF, diisopropylethylamine, and phenylenediamine under carbon monoxide yields anilinyl amide XVII or XVIII, respectively. [0106] Treatment of XV or XVI with tert-butylacrylate, diisopropylethylamine, dibenzylacetone palladium, and tri-o-tolylphosphine (POT) in DMF under nitrogen affords compounds XIX and XX, respectively. The ester moiety of XIX or XX is hydrolyzed to produce the corresponding acid moiety in XXI or XXII, respectively, by reaction with trifluoroacetic acid in dichloromethane. Treatment of the acid XXI or XXII with phenylenediamine, BOP, and triethylamine affords the anilinyl amide XXIII or XXIV, respectively. [0107] Compounds of formula (2), wherein X1 comprises -O-C(O)-NH-, preferably may be prepared according to the synthetic route depicted in Scheme 4. Thus, carbinol XXV is added to bromobenzylamine XXVI with carbonyldiimidazole (CDI), triethylamine, and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF to produce compound XXVII. The remaining synthetic steps in the production of anilinyl amide XXVIII are as described above for Scheme 3. [0108] Compounds of formula (2), wherein X1 comprises -N(R7)-, preferably may be prepared as outlined in Scheme 5. Amine XXIX is reacted with p-bromobenzylbromide in the presence of potassium carbonate in DMF to produce bromobenzylamine XXX. Treatment of XXX with nitroacrylanilide, dibenzylacetone palladium, POT, anddiisopropylethylamine in DMF affords nitroanilide XXXI. Nitroanilide XXXI is converted to the corresponding anilinyl amide XXXII by treatment with stannous chloride in methanol and water. [0109] Treatment of amine XXXI in formic acid with paraformaldehyde provides methylamine XXXIII. The nitroanilide moiety in XXXIII is then converted to the corresponding anilinyl amide moiety in XXXIV by treatment with stannous chloride in methanol and water. [0110] Alternatively, compounds of formula (2), wherein X1 comprises -N(R7)-, may be prepared according to the synthetic route depicted in Scheme 6. Carboxylic acid XXXV in methanol is treated with hydrochloric acid to produce ester XXXVI. Conversion of the primary amine moiety in XXXVI to the secondary amine moiety in XXXVI is effected by treatment with a catalyst such as triethylamine, methoxybenzylchloride, sodium iodide, and potassium carbonate in DMF at 60°C. Ester XXXVI is converted to anilinyl amide XXXVII by treatment with sodium hydroxide, THF, and methanol, followed by BOP, triethylamine, and phenylenediamine in DMF, as described above for Scheme 3. [0111] Compounds of formula (2), wherein X1 comprises may be prepared according to the procedures illustrated in Scheme 7. Addition of amine 68 to haloaryl compound XXXVIII or XXXIX and potassium carbonate in DMF provides arylamine XL or XLl, respectively. Anilinyl amide XLII or XLIII is then prepared using procedures analogous to those set forth in Schemes 3-6 above. [0112] Compounds such as XLVII and XLIX preferably may be prepared as outlined in Scheme 8. Dibromopyridine is combined with diaminoethane to produce amine XLIV. Treatment of amine XLIV with isatoic anhydride LV in methanol and water, followed by refluxing in formic acid affords compound XLVI. Treatment of amine XLIV with the reaction products of benzylaminodiacetic acid and acetic anhydride provides compound XLVIII. Bromopyridylamines XLVI and XLVIII are then converted to the corresponding diene anilinylamides XLVII and XLIX, respectively, by procedures analogous to those set forth in Schemes 3-7 above. [0113] Compounds such as LIV preferably may be prepared according to the synthetic route depicted in Scheme 9. Trichlorotriazine is treated with aminoindan and diisopropylethylamine to produce dichloroaminotriazine L. Treatment with bromobenzylamine and diisopropylethylamine affords diaminochlorotriazine LI. Addition of ammonia gas and dioxane provides triaminotriazine Lll. Treatment with protected acrylanilide, triethylamine, POT, and dibenzylacetone palladium then yields diene anilinylamide LIII, which is deprotected with trifluoroacetic acid to provide the final product LIV. [0114] Compounds of formula (2), wherein Ar2 is quinolylene and X1 comprises -N(R7)-, compounds of formula (3), wherein Ar3 is quinolylene and X2 comprises -N(R9)-, and compounds of formula (4), wherein Ar4 is quinolylene and X3 comprises -N(R11)-, preferably may be prepared according to the procedures illustrated in Scheme 10. Dihydroxyquinoline LV with dimethylaminopyridine (DMAP) in pyridine is treated with trifluoromethanesulfonic anhydride to provide bis(trifluoromethanesulfonyloxy)-quinoline LVI. Treatment of LVI with p-methoxybenzylamine affords aminoquinoline LVII. Anilinyl amides LVIII and LIX are then prepared using procedures analogous to those described for Schemes 1-9 above. [0115] Compounds of formula (3), wherein X2 comprises a sulfur atom, and compounds of formula (4), wherein X3 comprises a sulfur atom, preferably may be prepared as outlined in Scheme 11. Bromide LX is converted to diaryl ester LXI using procedures analogous to those described for Scheme 6 above. Synthetic methods similar to those set forth in Scheme 1 above are then used to convert ester LXI to the corresponding acid LXIV. Alternatively, ester LXI may be treated with chloroethylmorphonline, sodium iodide, potassium carbonate, triethylamine, and tetrabutylammonium iodide (TBAI) in DMF to produce ester LXIII, which is then converted to acid LXIV as in Scheme 1. Conversion of the acid LXIV to the anilinyl amide LXV is effected by procedures analogous to those set forth in Scheme 1 above. [0116] Alternatively, compounds of formula (3), wherein X2 comprises a sulfur atom, and compounds of formula (4), wherein X3 comprises a sulfur atom, may be prepared according to the procedures illustrated in Scheme 12. Sulfanyl anilmylamide LXVIII is prepared using procedures analogous to those set forth in Schemes 3 and 5 above. [0117] Compounds of formula (3), wherein X2 comprises -N(R9)-, and compounds of formula (4), wherein X3 comprises -N(R11)-, preferably may be prepared according to the synthetic route depicted in Scheme 13. Amino anilinyl amide LXXI is prepared according to synthetic steps similar to those described for Schemes 1 and 6 above. [0118] Compounds of formula (3), wherein X2 comprises a sulfur atom, and compounds of formula (4), wherein X3 comprises a sulfur atom, preferably may be prepared as outlined in Scheme 14. Phenylenediamine is reacted with di-tert-butyldicarbonate, followed by iodobenzoic acid, dimethylaminopropylethylcarbodiimide, hydroxybenzotriazole, and triethylamine to provide protected anilinyl amide LXXII. The iodide moiety of LXXII is converted to the methyl ester moiety of LXXIII using procedures analogous to those set forth for Scheme 3 above. The methyl ester moiety of LXXIII is converted to the hydroxyl moiety of LXXIV by treatment with a reducing agent such as diisobutylaluminum hydride (DIBAL-H). Addition of the heterocyclylsulfhydryl compound Het-SH with triphenylphosphine and diethylazodicarboxylate converts the hydroxyl moiety of LXXIV to the sulfanyl moiety of LXXV. LXXV is deprotected with trifluoroacetic acid to afford the sulfanyl anilinyl amide LXXVI. [0119] Compounds of formula (3), wherein X2 is a chemical bond, preferably may be prepared according to the synthetic route depicted in Scheme 15. Thus, chtoroarylanilinylamide LXXVII is treated with aryl boronic acid, benzene, ethanol, aqueous sodium carbonate, and triphenylphosphine palladium to afford the diarylanilinylamide LXXVIII. [0120] Compounds such as LXXXI preferably may be prepared according to the procedues illustrated in Scheme 16. Thus, benzene-l,2-carbaldehyde LXXIX in acetic acid is treated with p- aminomethylbenzoic acid to produce the benzoic acid LXXX. The acid LXXX is converted to the corresponding anilinylamide LXXXI by treatment with hydroxybenzotriazole, ethylenedichloride, and phenylenediamine. [0121] Compounds such as LXXXVI and LXXXIX preferably may be prepared according to the procedures illustrated in Scheme 18. Phthalic anhydride LXXXV and p-aminomethylbenzoic acid are combined in acetic acid to produce an intermediate carboxylic acid, which is converted to the anilinylamide LXXXVI using procedures analogous to those set forth in Schemes 15 and 16 above. [0122] The addition of 4-(2-amin, yl)phenol to phthalic anhydride LXXXV in acetic acid affords the hydroxyl compound LXXXVII. That droxyl group of LXXXVII is converted to the triflate group of LXXXVIII by treatment with sodium hydride, THF, DMF, and phenylaminoditriflate. Treatment of LXXXVIII according to procedures analogous to those described for Scheme 3 above affords the anilinylamide LXXXIX. [0123] Compounds such as XCI-XCVI preferably may be prepared according to the synthetic route depicted in Scheme 19. Treatment of isatoic anhydride XC with p-aminomethylbenzoic acid in water and triethylamine, followed by formic acid affords an intermediate carboxylic acid, which is converted to anilinylamide XCI using procedures analogous to those described for Scheme 16 above. [0124] Alternatively, treatment of isatoic acid XC with p-aminomethylbenzoic acid in water and triethylamine, follwed by hydrochloric acid and sodium nitrite affords an intermediate carboxylic acid, which is converted to anilinylamide XCII using procedures analogous to those described for Scheme 16 above. [0125] Alternatively, treatment of isatoic acid XC with p-aminomethylbenzoic acid in water and triethylamine affords benzoic acid XCIII. Treatment of XCIII with sodium hydroxide, dioxane, methylchloroformate, and methanol affords an intermediate quinazolinedione carboxylic acid, the acid moiety of which is then converted to the anilinylamide moiety of XCIV using procedures analogous to those described for Scheme 16 above. Alternatively, the intermediate quanzolinedione carboxylic acid in DMF is treated with potassium carbonate and methyl iodide to produce an intermediate benzoic acid methyl ester, which is converted to an intermediate benzoic acid by treatment with sodium hydroxide, methanol, and water. The benzoic acid is then converted to the corresponding anilinylamide XCV using procedures analogous to those described for Scheme 16 above. [0126] Alternatively, treatment of XCIII with acetic anhydride followed by acetic acid produces an intermediate carboxylic acid, which is converted to anilinylamide XCVI using procedures analogous to those described for Scheme 16 above. [0127] Compounds such as C preferably may be prepared as outlined in Scheme 20. Alkylamine XCVII is treated with thiocarbonyl diimidazole in dichloromethane, follwed by ammonium hydroxide to afford thiourea XCVIII. Treatment of thiourea XCVIII with methylmethoxyacrylate in dioxane and N-bromosuccinimide produces thiazole ester IC. The ester IC is converted to the corresponding anilinylamine C using procedures analogous to those set forth in Scheme 1 above. [0128] Compounds of formula (3), wherein X2 is a chemical bond and Cy3 has an amino substituent preferably may be prepared according to the synthetic route depicted in Scheme 21. Thus, protected iodoarylanilinylamide Cl is treated according to procedures analogous to those described for Scheme 15 above afford the diarylanilinylamide CII. The aldehyde moiety in Cll is converted to the corresponding secondary amine moiety by treatment with the primary amine and sodium triacetoxyborohydride followed by glacial acetic acid. The resultant compound is deprotected to yield CHI using procedures analogous to those set forth in Scheme 3 above. [0129] Compounds of formula (3), wherein X2 comprises an alkynylene moiety, and compounds of formula (4), wherein X3 comprises an alkynylene moiety, preferably may be prepared as outlined in Scheme 22. Treatment of protected iodoarylanilinylamide Cl with triphenylphosphine palladium chloride, cuprous iodide, and 1-ethynylcyclohexylamine affords the alkynylarylanilinylamide CIV. The primary amine moiety in CIV is converted to the corresponding secondary amine and the aniline moiety is deprotected to afford CV using procedures analogous to those described for Scheme 21 above. [0130] Compounds such as CVIII preferably may be prepared according to the synthetic route depicted in Scheme 24. Dichloroaminotriazine CVI is treated with methyl-4-aminobenzoate in the presence of diisopropylethytamine to produce diaminotriazine CVII. Addition of ammonia gas and dioxane, followed by a saponification and a peptide coupling using the same procedures analogous to those described for Scheme 1 above. [0131] Compounds such as CX preferably may be prepared according to the synthetic route depicted in Scheme 30. The Grignard reaction of trichloroaminotriazine with various alkyl magnesium bromide, followed by a treatment with methyl-4-aminobenzoate in the presence of diisopropylethylamine yields alkylaminotriazine CIX. Synthetic methods similar to those set forth in Scheme 1 above are then used to convert ester CIX to the corresponding anilinyl amide CX. [0132] Amination of dichlorotriazine proceeded using the usual condition described in Scheme 1 to afford CXI. Stille coupling using vinyl stannane provides CXII. Treatment with protected iodoanilide, triethylamine, POT and dibenzylacetone palladium then yields anilinylamide, which is deprotected with trifluoroacetic acid to provide the alkene CXIII. Hydrogenation of the alkene affords the final compound CXIV. [0133] Compounds such as CXV1II preferably may be prepared according to the synthetic route depicted in Scheme 33. Treatment of methoxyaminobenzothiazole with tribromide boron affords the corresponding acid CXV. Mitsunobu reaction using hydroxyethyl morpholine in the presence of diethylazodicarboxylate and triphenylphosphine yields the amine CXVI. Reductive amination with methyl-4-formylbenzoate using phenylsilane and tin catalyst yields to the ester CXVII. Saponification followed by the usual peptide coupling analogous to those describe for Scheme 1 above provides the desired anilide CXVIII. [0134] Treatment 4-methylcyanobenzoic acid with hydrogen sulfide affords CXIX, which is subjected to cyclization in the presence of 1,3-dichloroacetone to yield CXX. Treatment with morpholine followed by a peptide coupling using the standard condition produces CXXI. [0135] Compounds such as CXXIII and CXXVII preferably may be prepared according to the synthetic scheme 49. Consecutive treatment of acetyl acetone with methyl bromomethylbenzoate in the presence of NaOMe and phenyl hydrazine followed by saponification, afforded the intermediate acid CXXII. This material was coupled with 1,2-diaminobenzene in a standard fashion to afford CXXIII. [0136] Consecutive treatment of acetyl acetone with methyl bromomethylbenzoate in the presence of NaOMe and a 1:1 mixture AcOH-HCI (conc.) afforded the intermediate acid CXXIV. This ketoacid reacting with sulfur and malonodinitrile in the presence of a base, produced the thiophene CXXV, which was converted into the desired CXXVII using standard procedures. [0137] Compounds such as CXXX preferably may be prepared according to the synthetic scheme 50. Treatment of 4-cyanomethylbenzoic acid with hydroxylamine produced the amidoxime CXXVIII, which upon treatment with acetic anhydride was converted into the oxadiazole CXXIX. The latter was coupled with 1,2-diaminobenzene in a standard fashion to afford CXXX. [0138] Compounds such as CXXXIII preferably may be prepared according to the synthetic route depicted in Scheme 57. Treatment of 4-formylbenzoic acid with thionyl chloride afford the acyl chloride which is coupled with protected anilide to produce CXXXI. Reductive amination with dimethoxyaniline using phenylsilane and tin catalyst yields to the protected anilide CXXXII. Treatment with isocyanate followed by deprotection with trifluoroacetic acid provides the ureidoanilide CXXXIII. Pharmaceutical Compositions [0139] In a second aspect, the invention provides pharmaceutical compositions comprising an inhibitor of histone deacetylase according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain preferred embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other preferred embodiments, administration may preferably be by the oral route. [0140] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredien(s). Thus, compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990. [0141] As used herein, the term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR + Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate). [0142] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. A preferred dose of the active compound for all of the above- mentioned conditions is in the range from about 0.01 to 300 mg/kg, preferably 0.1 to 100 mgAg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art. Inhibition of Histone Deacetylase [0143] In a third aspect, the invention provides a method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase according to the invention. Because compounds of the invention inhibit histone deacetylase, they are useful research tools for in vitro study of the role of histone deacetylase in biological processes. In addition, the compounds of the invention selectively inhibit certain isoforms of HDAC. [0144] Measurement of the enzymatic activity of a histone deacetylase can be achieved using known methodologies. For example, Yoshida et al., J. Biol. Chem., 265: 17174-17179 (1990), describes the assessment of histone deacetylase enzymatic activity by the detection of acetylated histones in trichostatin A treated cells. Taunton et al., Science, 272: 408-411 (1996), similarly describes methods to measure histone deacetylase enzymatic activity using endogenous and recombinant HDAC-1. [0145] In some preferred embodiments, the histone deacetylase inhibitor interacts with and reduces the activity of all histone deacetylases in the cell. In some other preferred embodiments according to this aspect of the invention, the histone deacetylase inhibitor interacts with and reduces the activity of fewer than all histone deacetylases in the cell. In certain preferred embodiments, the inhibitor interacts with and reduces the activity of one histone deacetylase (e.g., HDAC-1), but does not interact with or reduce the activities of other histone deacetylases (e.g., HDAC-2, HDAC-3, HDAC- 4, HDAC-5, HDAC-6, HDAC-7, and HDAC-8). As discussed below, certain particularly preferred histone deacetylase inhibitors are those that interact with, and reduce the enzymatic activity of, a histone deacetylase that is involved in tumorigenesis. Certain other preferred histone deacetylase inhibitors interact with and reduce the enzymatic activity of a fungal histone deacetylase. [0146] Preferably, the method according to the third aspect of the invention causes an inhibition of cell proliferation of the contacted cells. The phrase "inhibiting cell proliferation" is used to denote an ability of an inhibitor of histone deacetylase to retard the growth of cells contacted with the inhibitor as compared to cells not contacted. An assessment of cell proliferation can be made by counting contacted and non-contacted cells using a Coulter Cell Counter (Coulter, Miami, FL) or a hemacytometer. Where the cells are in a solid growth (e.g., a solid tumor or organ), such an assessment of cell proliferation can be made by measuring the growth with calipers and comparing the size of the growth of contacted cells with non-contacted cells. [0147] Preferably, growth of cells contacted with the inhibitor is retarded by at least 50% as compared to growth of non-contacted cells. More preferably, cell proliferation is inhibited by 100% (i.e., the contacted cells do not increase in number). Most preferably, the phrase "inhibiting cell proliferation" includes a reduction in the number or size of contacted cells, as compared to non- contacted cells. Thus, an inhibitor of histone deacetylase according to the invention that inhibits cell proliferation in a contacted cell may induce the contacted cell to undergo growth retardation, to undergo growth arrest, to undergo programmed cell death (i.e., to apoptose), or to undergo necrotic cell death. [0148] The cell proliferation inhibiting ability of the histone deacetylase inhibitors according to the invention allows the synchronization of a population of asynchronously growing cells. For example, the histone deacetylase inhibitors of the invention may be used to arrest a population of non-neoplastic cells grown in vitro in the Gl or G2 phase of the cell cycle. Such synchronization allows, for example, the identification of gene and/or gene products expressed during the Gl or G2 phase of the cell cycle. Such synchronization of cultured cells may also be useful for testing the efficacy of a new transfection protocol, where transfection efficiency varies and is dependent upon the particular cell cycle phase of the cell to be transfected. Use of the histone deacetylase inhibitors of the invention allows the synchronization of a population of cells, thereby aiding detection of enhanced transfection efficiency. [0149] In some preferred embodiments, the contacted cell is a neoplastic cell. The term "neoplastic cell" is used to denote a cell that shows aberrant cell growth. Preferably, the aberrant cell growth of a neoplastic cell is increased cell growth. A neoplastic cell may be a hyperplastic cell, a cell that shows a lack of contact inhibition of growth in vitro, a benign tumor cell that is incapable of metastasis in vivo, or a cancer cell that is capable of metastasis in vivo and that may recur after attempted removal. The term "tumorigenesis" is used to denote the induction of cell proliferation that leads to the development of a neoplastic growth. In some embodiments, the histone deacetylase inhibitor induces cell differentiation in the contacted cell. Thus, a neoplastic cell, when contacted with an inhibitor of histone deacetylase may be induced to differentiate, resulting in the production of a non-neoplastic daughter cell that is phylogenetically more advanced than the contacted cell. [0150] In some preferred embodiments, the contacted cell is in an animal. Thus, the invention provides a method for treating a cell proliferative disease or condition in an animal, comprising administering to an animal in need of such treatment a therapeutically effective amount of a histone deacetylase inhibitor of the invention. Preferably, the animal is a mammal, more preferably a domesticated mammal. Most preferably, the animal is a human. [0151] The term "cell proliferative disease or condition" is meant to refer to any condition characterized by aberrant cell growth, preferably abnormally increased cellular proliferation. Examples of such cell proliferative diseases or conditions include, but are not limited to, cancer, restenosis, and psoriasis. In particularly preferred embodiments, the invention provides a method for inhibiting neoplastic cell proliferation in an animal comprising administering to an animal having at least one neoplastic cell present in its body a therapeutically effective amount of a histone deacetylase inhibitor of the invention. [0152] It is contemplated that some compounds of the invention have inhibitory activity against a histone deacetylase from a protozoal source. Thus, the invention also provides a method for treating or preventing a protozoal disease or infection, comprising administering to an animal in need of such treatment a therapeutically effective amount of a histone deacetylase inhibitor of the invention. Preferably the animal is a mammal, more preferably a human. Preferably, the histone deacetylase inhibitor used according to this embodiment of the invention inhibits a protozoal histone deacetylase to a greater extent than it inhibits mammalian histone deacetylases, particularly human histone deacetylases. [0153] The present invention further provides a method for treating a fungal disease or infection comprising administering to an animal in need of such treatment a therapeutically effective amount of a histone deacetylase inhibitor of the invention. Preferably the animal is a mammal, more preferably a human. Preferably, the histone deacetylase inhibitor used according to this embodiment of the invention inhibits a fungal histone deacetylase to a greater extent than it inhibits mammalian histone deacetylases, particularly human histone deacetylases. [0154] The term "therapeutically effective amount" is meant to denote a dosage sufficient to cause inhibition of histone deacetylase activity in the cells of the subject, or a dosage sufficient to inhibit cell proliferation or to induce cell differentiation in the subject. Administration may be by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain particularly preferred embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other preferred embodiments, administration may preferably be by the oral route. [0155] When administered systemically, the histone deacetylase inhibitor is preferably administered at a sufficient dosage to attain a blood level of the inhibitor from about 0.01 ?M to about 100 ?M, more preferably from about 0.05 ?M to about 50 ?M, still more preferably from about 0.1 ?M to about 25 ?M, and still yet more preferably from about 0.5 ?M to about 25 ?M. For localized administration, much lower concentrations than this may be effective, and much higher concentrations may be tolerated. One of skill in the art will appreciate that the dosage of histone deacetylase inhibitor necessary to produce a therapeutic effect may vary considerably depending on the tissue, organ, or the particular animal or patient to be treated. [0156] In certain preferred embodiments of the third aspect of the invention, the method further comprises contacting the cell with an antisense oligonucleotide that inhibits the expression of a histone deacetylase. The combined use of a nucleic acid level inhibitor (e.g., antisense oligonucleotide) and a protein level inhibitor (i.e., inhibitor of histone deacetylase enzyme activity) results in an improved inhibitory effect, thereby reducing the amounts of the inhibitors required to obtain a given inhibitory effect as compared to the amounts necessary when either is used individually. The antisense oligonucleotides according to this aspect of the invention are complementary to regions of RNA or double-stranded DNA that encode HDAC-1, HDAC-2, HDAC-3, HDAC4, HDAC-5, HDAC-6, HDAC7, and/or HDAC-8 (see e.g., GenBank Accession Number U50079 for HDAC-1, GenBank Accession Number U31814 for HDAC-2, and GenBank Accession Number U75697 for HDAC-3). [0157] For purposes of the invention, the term "oligonucleotide" includes polymers of two or more deoxyribonucleosides, ribonucleosides, or 2'-substituted ribonucleoside residues, or any combination thereof. Preferably, such oligonucleotides have from about 6 to about 100 nucleoside residues, more preferably from about 8 to about 50 nucleoside residues, and most preferably from about 12 to about 30 nucleoside residues. The nucleoside residues may be coupled to each other by any of the numerous known internucleoside linkages. Such internucleoside linkages include without limitation phosphorothioate, phosphorodithioate, alkylphosphonate, alkylphosphonothioate, phosphotriester, phosphoramidate, siloxane, carbonate, carboxymethylester, acetamidate, carbamate, thioether, bridged phosphoramidate, bridged methylene phosphonate, bridged phosphorothioate and sulfone internucleoside linkages. In certain preferred embodiments, these internucleoside linkages may be phosphodiester, phosphotriester, phosphorothioate, or phosphoramidate linkages, or combinations thereof. The term oligonucleotide also encompasses such polymers having chemically modified bases or sugars and/ or having additional substituents, including without limitation lipophilic groups, intercalating agents, diamines and adamantane. [0158] For purposes of the invention the term "2'-substituted ribonucleoside" includes ribonucleosides in which the hydroxyl group at the 2' position of the pentose moiety is substituted to produce a 2'-O-substituted ribonucleoside. Preferably, such substitution is with a lower alkyl group containing 1-6 saturated or unsaturated carbon atoms, or with an aryl or allyl group having 2-6 carbon atoms, wherein such alkyl, aryl or allyl group may be unsubstituted or may be substituted, e.g., with halo, hydroxy, trifluoromethyl, cyano, nitro, acyl, acyloxy, alkoxy, carboxyl, carbalkoxyl, or amino groups. The term "2'-substituted ribonucleoside" also includes ribonucleosides in which the 2'- hydroxyl group is replaced with an amino group or with a halo group, preferably fluoro. [0159] Particularly preferred antisense oligonucleotides utilized in this aspect of the invention include chimeric oligonucleotides and hybrid oligonucleotides. [0160] For purposes of the invention, a "chimeric oligonucleotide" refers to an oligonucleotide having more than one type of internucleoside linkage. One preferred example of such a chimeric oligonucleotide is a chimeric oligonucleotide comprising a phosphorothioate, phosphodiester or phosphorodithioate region, preferably comprising from about 2 to about 12 nucleotides, and an alkylphosphonate or alkylphosphonothioate region (see e.g., Pederson et al. U.S. Patent Nos. 5,635,377 and 5,366,878). Preferably, such chimeric oligonucleotides contain at least three consecutive internucleoside linkages selected from phosphodiester and phosphorothioate linkages, or combinations thereof. [0161] For purposes of the invention, a "hybrid oligonucleotide" refers to an oligonucleotide having more than one type of nucleoside. One preferred example of such a hybrid oligonucleotide comprises a ribonucleotide or 2'-substituted ribonucleotide region, preferably comprising from about 2 to about 12 2'-substituted nucleotides, and a deoxyribonucleotide region. Preferably, such a hybrid oligonucleotide contains at least three consecutive deoxyribonucleosides and also contains ribonucleosides, 2'-substituted ribonucleosides, preferably 2'-O-substituted ribonucleosides, or combinations thereof (see e.g., Metelev and Agrawal, U.S. Patent No. 5,652,355). [0162] The exact nucleotide sequence and chemical structure of an antisense oligonucleotide utilized in the invention can be varied, so long as the oligonucleotide retains its ability to inhibit expression of the gene of interest. This is readily determined by testing whether the particular antisense oligonucleotide is active. Useful assays for this purpose include quantitating the mRNA encoding a product of the gene, a Western blotting analysis assay for the product of the gene, an activity assay for an enzymatically active gene product, or a soft agar growth assay, or a reporter gene construct assay, or an in vivo tumor growth assay, all of which are described in detail in this specification or in Ramchandani et al. (1997) Proc. Natl. Acad. Sci. USA 94: 684-689. [0163] Antisense oligonucleotides utilized in the invention may conveniently be synthesized on a suitable solid support using well known chemical approaches, including H-phosphonate chemistry, phosphoramidite chemistry, or a combination of H-phosphonate chemistry and phosphoramidite chemistry (i.e., H-phosphonate chemistry for some cycles and phosphoramidite chemistry for other cycles). Suitable solid supports include any of the standard solid supports used for solid phase oligonucleotide synthesis, such as controlled-pore glass (CPG) (see, e.g., Pon, R.T. (1993) Methods in Molec. Biol. 20: 465-496). [0164] Particularly preferred oligonucleotides have nucleotide sequences of from about 13 to about 35 nucleotides which include the nucleotide sequences shown in Table 1. Yet additional particularly preferred oligonucleotides have nucleotide sequences of from about 15 to about 26 nucleotides of the nucleotide sequences shown in Table 1. [0165] The following examples are intended to further illustrate certain preferred embodiments of the invention, and are not intended to limit the scope of the invention. Example 1 4-{[4-Amino-6-(2-indanyl-aminoHl,3,5]-triazin-2-yl-amino]-methyI}-N-(2-amino-phenyl)- benzamide (compound 8) Step 1: Methyt4-[(4,6-dichloro-[1,3,5]triazin-2-yl-amino)-methyl]-benzoate (compound 3) [0166] To a stirred solution at -78°C of cyanuric chloride 1 (8.23 g, 44.63 mmol) in anhydrous THF (100 mL) under nitrogen was added a suspension of methyl 4-(aminomethyl)benzoate.HCI 2 (10.00 g, 49.59 mmol), in anhydrous THF (50 mL), followed by i-Pr2NEt (19.00 mL, 109.10 mmol). After 30 min, the reaction mixture was poured into a saturated aqueous solution of NH4CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4CI, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH2Cl2: 5/95) to afford the title compound 3 (12.12 g, 38.70 mmol, 87% yield) as a pale yellow solid. 1H NMR (300 MHz, CDCI3) S (ppm): AB system (?A = 8.04, ?8 = 7.38, J = 8.5 Hz, 4H), 6.54 (bt, 1H), 4.76 (d, J = 6.3 Hz, 2H), 3.93 (s, 3H). Pathway A Step 2: Methyl-4-[(4-amino-6-chloro-[l,3,5]triazin-2-yl-amino)-methyl]-benzoate (compound 4) [0167] In a 150 mL sealed flask, a solution of 3 (6.00 g, 19.16 mmol) in anhydrous 1,4-dioxane (60 mL) was stirred at room temperature, saturated with NH3 gas for 5 min, and warmed to 70°C for 6 h. The reaction mixture was allowed to cool to room temperature, the saturation step with NH3 gas was repeated at room temperature for 5 min, and the reaction mixture was warmed to 70°C again for 18 h. Then, the reaction mixture was allowed to cool to room temperature, poured into a saturated aqueous solution of NH4CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4CI, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH2CI2: 30/70) to afford the title compound 4 (5.16 g, 17.57 mmol, 91% yield) as a white solid. lH NMR (300 MHz, CDCI3) ? (ppm): AB system (?A = 8.01, ?8 = 7.35, J = 8.1 Hz, 4H), 5.79 (bs, 1H), 5.40-5.20 (m, 2H), 4.72-4.63 (m, 2H), 3.91 (s, 3H). Pathway B Step 2: Methyl 4-[(4-chloro-6-(2-indanyl-amino)-[l,3,51triazin-2-yl-amino)-methyl]-benzoate (compound 5) [0168] To a stirred solution at room temperature of 3 (3.00 g, 9.58 mmol) in anhydrous THF (50 mL) under nitrogen were added i-Pr2NEt (8.34 mL, 47.90 mmol) and 2-aminoindan.HCI (1.95 g, 11.50 mmol) or R1R2NH (1.2 equiv), respectively. After 18 h, the reaction mixture was poured into a saturated aqueous solution of NH4CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4CI, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated to afford the title compound 5 (4.06 g, 9.91 mmol, quantitative yield) as a white powder. 1H NMR (300 MHz, CDCI3) 5 (ppm): mixture of rotamers, 8.06-7.94 (m, 2H), 7.43-7.28 (m, 2H), 7.24-7.12 (m, 4H), 6.41 and 6.05 (2 bt, 1H), 5.68-5.44 (m, 1H), 4.924.54 (m, 3H), 3.92 (bs, 3H), 3.41-3.12 (m, 2H), 2.90-2.70 (m, 2H). Step 3: Methyl-4-[(4-amino-6-(2-indanyl-amino)-[l,3,51triazin-2-yl-amino)-methyl1-benzoate (compound 6) General procedure for the amination with NH3 gas: [0169] In a 150 mL sealed flask, a solution of 5 (3.90 g, 9.51 mmol) in anhydrous 1,4-dioxane (80 mL) was stirred at room temperature, saturated with NH3 gas for 5 min, and warmed to 140°C for 6 h. The reaction mixture was allowed to cool to room temperature, the saturation step with NH3 gas was repeated for 5 min, and the reaction mixture was warmed to 140°C again for 18 h. Then, the reaction mixture was allowed to cool to room temperature, poured into a saturated aqueous solution of NH4CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4CI, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2CI2: 3/97) to afford the title compound 6 (3.50 g, 8.96 mmol, 94% yield) as a pale yellow sticky solid. 1H NMR (300 MHz, CDCI3) ? (ppm): 7.99 (bd, J = 8.2 Hz, 2H), 7.41-7.33 (m, 2H), 7.24-7.13 (m, 4H), 5.50-5.00 (m, 2H), 4.90-4.55 (m, 5H), 3.92 (s, 3H), 3.40-3.10 (m, 2H), 2.90-2.70 (m, 2H). 13C NMR: (75 MHz, CDCI3) 8 (ppm): 166.88, 167.35, 166.07, 144.77, 141.07. 129.82, 128.93, 127.01, 126.61, 124.70, 52.06, 51.80, 44.25, 40.16. HRMS (calc): 390.1804, (found): 390.1800. Pathways A and B. step 3. general procedure with primary and/or secondary amines: [0170] In a 50-75 mL sealed flask, a stirred solution of 4 (500 mg, 1.70 mmol, 1 equiv), i-Pr2NEt (1.48 mL, 8.51 mmol, 5 equiv) and R1R2NH or R3R4NH (1.5-3 equiv) in anhydrous THF or 1,4-dioxane (20-30 mL) was warmed to 120-140°C for 15-24 h. Then, the reaction mixture was allowed to cool to room temperature, poured into a saturated aqueous solution of NH4CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4CI, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel to afford the title compound. Step 4: 4-[(4-Amino-6-(2-indanyl-amino)-[l,3,5]triazin-2-yl-amino)-methyll-benzoic acid (compound 7) [0171] To a stirred solution at room temperature of 6 (2.07 g, 5.30mmol) in THF (50 mL) was added a solution of LiOH.H2O (334 mg, 7.96 mmol) in water (25 mL). After 18 h, the reaction mixture was diluted in water and acidified with 1 N HCI until pH 5-6 in order to get a white precipitate. After 1 h, the suspension was filtered off and the cake was abundantly washed with water, and dried to afford the title compound 7 (1.73 g, 4.60 mmol, 87% yield) as a white solid. 1H NMR (300 MHz, acetone-d6) ? (ppm): 8.05 (bd, J = 8.1 Hz, 2H), 7.56-7.42 (m, 2H), 7.30-7.10 (m. 4H), 5.90-5.65 (m, 2H), 4.854.60 (m, 4H), 3.40-2.80 (m, 4H). HRMS (calc): 376.1648, (found): 376.1651. Step 5: 4-[(4-Amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-yl-aminol-methyl)-N-(2-amino-Dhenyl)-benzamide (compound 8) [0172] To a stirred solution at room temperature of 7 (200 mg, 0.53 mmol) in anhydrous DMF (5 mL) under nitrogen were added Et3N (74 ?l, 0.53 mmol) and BOP reagent (282 mg, 0.64 mmol), respectively. After 40 min, a solution of 1,2-phenylenediamine (64 mg, 0.58 mmol), Et3N (222 ?l, 1.59 mmol) in anhydrous DMF (2 mL) was added dropwise. After 1.5 h, the reaction mixture was poured into a saturated aqueous solution of NH4CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat NH4CI, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2CI2: 2/98?5/95) to afford the title compound 8 (155 mg, 0.33 mmol. 63% yield) as a pale yellow foam. 1H NMR (300 MHz, acetone-d6) ? (ppm): 9.04 (bs, 1H), 7.96 (bd, J = 8.0 Hz, 2H), 7.50-7.40 (m, 2H), 7.30 (dd, J = 8.0 Hz, 1.4 Hz, 1H). 7.22-7.08 (m. 4H), 6.99 (ddd, J = 8.0 Hz, 7.5 Hz, 1.5 Hz, 1H), 6.86 (dd, J = 8.0 Hz, 1.4 Hz, 1H), 6.67 (dt, J = 7.5 Hz, 1.4 Hz, 1H), 6.60-5.49 (m, 4H), 4.804.50 (m, 4H), 3.30-3.08 (m, 2H), 2.96-2.74 (m, 2H). EXAMPLES 2-28 [0173] Examples 2 to 28 describe the preparation of compounds 9 to 35 using the same procedure as described for compound 8 of Example 1. Characterization data are presented in Tables 2a and 2b. Table 2a Characterization of Compounds Prepared in Examples 2-28 /V-(2-Amino-phenyl)-4-({4-[2-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-l-yl)-2-oxo-ethyl]-6- morpholin-4-yl-[1,3,5]triazin-2-ylamino}-methyl)-benzamide (compound 39) Step 1: N-Acetyl-1-piperonylpiperazine (compound 37) [0171] To a stirred solution at 0°C of 1-piperonylpiperazine 36 (5.00 g, 22.7 mmol) in anhydrous CH2CI2 (60 mL) was added Et3N (6.33 mL, 45.4 mmol) followed by acetyl chloride (1.94 mL, 27.2 mmol). The reaction mixture was stirred 30 min. at 0°C and then 2 h at room temperature. The reaction mixture was poured into a saturated aqueous solution of NH4CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat NH4CI, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2CI2: 4/96) to afford the title compound 37 (5.52 g, 21.11 mmol, 93% yield) as a yellow solid. 1H NMR: (300 MHz, CDCI3) 5 (pprn): 6.83 (s, 1H), 6.72 (m, 2H), 5.92 (s, 2H), 3.59 (t, J = 5.1 Hz, 2H), 3.44-3.40 (m, 4H). 2.42 (dt, J = 5.1 Hz. 5.1 Hz, 4H), 2.06 (s, 3H). Step 2: 2-Chloro-4-morpholin-4-yl-6-[2-(4-benzo[1,3]dioxol-5-ylmethvl-piperazin-1-yl)-oxo-ethyl]- [l,3,5]triazine (compound 38) [0172] To a stirred solution of 37 (3.00 g, 11.4 mmol) in anhydrous THF (25 mL) at -78°C was slowly added a solution of LiHMDS (11.4 mL, 11.4 mmol, 1 M in THF). The reaction mixture was stirred 1 h at -78°C and a solution of 2,4-dichloro-6-morpholin-4-yl-[l,3,5]triazine (2.69 g, 11.4 mmol) in anhydrous THF (25 mL) was added. The reaction mixture was slowly warmed up at room temperature and the reaction was quenched after 16 h with a saturated aqueous solution of NH4CI. The THF was evaporated and the residue was diluted with AcOEt. The organic layer was successively washed with sat. NH4CI and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2CI2: 1/99?3/97) to afford the title compound 38 (4.84 g, 10.49 mmol, 92% yield) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) ? (ppm): 6.84 (s, 1H), 6.77-6.69 (m, 2H), 5.95 (s, 2H), 3.75-3.43 (m, 16H), 2.42 (m, 4H). Step 3: N-(2-Amino-phenyl)-4-((4-[2-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-oxo-ethyl]-6- morpholin-4-yl-[1.3.5]triazin-2-vlamino)-methyl)-benzamide (compound 39) [0173] The title compound 39 was obtained following the same procedure as Example 1, step 5. 1H NMR (CDCI3) 5 (ppm): 7.96 (bs, 1H), 7.87 (d. J = 8.2 Hz. 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.5 Hz, 1H), 7.10 (dt, J = 7.6 Hz, 1.2 Hz, 1H), 6.87-6.81 (m, 3H), 6.75-6.68 (m, 2H), 5.93 (s, 2H), 5.67 (bs, 1H), 4.64 (s, 2H), 3.90 (bs, 2H), 3.75-3.35 (m, 16H), 2.45-2.30 (m, 4H). Example 40 N-(2-aminophenyl)-6-(2-phenylamino-ethylamino)-nicotinamide (compound 44) Step 1: N-5-Bromo-pyridin-2-yl)-/V-phenyl-ethane-1,2-diamine (compound 42) [0174] A mixture of 2,5-dibromopyridine 40 (2.08 g, 8.6 mmol) and phenyl-l,2-ethyldiamine (1.98 g, 14.6 mmol, 1.7 equiv.) was stirred under nitrogen at 120°C for 6h. After cooling down to room temperature, the solid mixture was ground in a mortar, dissolved in ethyl acetate (200 mL), washed with saturated NaHCO3 (2 x 50 mL), dried (MgSO4), filtered and concentrated. After a quick purification through a short chromatographic column (silica gel, elution 50% ether in hexanes), a pale yellow solid 42 (1.75 g, 6.01 mmol, 70% yield) was obtained. l3C NMR (300 MHz, acetone-d6) 5 (ppm): 158.6, 149.6, 148.8, 139.9, 129.8, 117.1, 113.1, 110.8, 106.6, 43.9, 41.5. LMRS = 294.0 (M+l). Step 2: N-(2-aminophenyl)-6-(2-phenylamino-ethylamino)-nicotinamide (compound 44) [0175] A mixture of 5-bromo-2-N-alkanyl-2-aminopyridine 42 (352 mg, 1.2 mmol), 1,2- phenylenediamine (3.95 mmol, 3.3 equiv.), Pd(OAc)2 (0.31 mrnol, 26% mol) and 1,1'-bis (diphenylphosphino) ferrocene (124 mg, 0.22 mmol) was suspended in degassed DMF (3mL), treated with diisopropylethyl amine (0.9 mL, 5.2 mmol) and the system flushed with CO. The reaction mixture was warmed up to 60°C and stirred under CO (balloon) for 18 h at this temperature. After evaporation of the DMF under vacuo, the residue was purified through a chromatographic column (silica gel, elution 3% to 6% methanol in dichloromethane) to give 258 mg (0.74 mmol, 62 % yield) of the aminoanilide 44. 1H-NMR (CD3OD-d4), ? (ppm): 8.67 (d, J = 2.2 Hz, 1H), 7.97 (dd, J= 8.9 Hz, 2.5 Hz, 1H), 7.58 (m, 1H), 7.51 (m, 1H), 7.15 (dd, J = 7.7 Hz, 1.1 Hz, 1H), 7.08 (m, 2H), 6.89 (dd, J = 8.0 Hz, 1.4 Hz, 1H), 6.76 (dt, J= 7.7 Hz, 4.4 Hz, 1H), 6.67 (t, J = 7.7 Hz, 2H), 6.60 (m, 2H), 4.87 (bs, 4H), 3.60 (t, J = 6.3 Hz, 2H), 3.35 (t, J = 6.3 Hz, 2H). Example 41 N-(2-amino-phenyl)-6-(4-methoxy-benzylamino)-nicotinamide (compound 45) Step 1: N-5-Bromo-pyridin-2-yl)-4-methoxybenzvlamine (compound 43) [0176] A mixture of 2,6-dibromopyridine 41 (6.03 mmol, 2 equiv.) and para-methoxybenzyl amine (413 mg, 3.01 mmol) was stirred under nitrogen at 120°C for 6h. After identical work-up procedure described before and purification through a pad of silica gel {elution 50% ether in hexanes), a pale yellow solid 43 (773 mg, 2.60 mmol, 87% yield) was obtained. 13C NMR (300 MHz, CDCI3) 5 (ppm): 159.1, 139.7, 132.1, 130.5, 128.9, 127.2, 116.2, 114.3, 104.8, 55.4, 46.0. LMRS = 295.0 (M+l). Step 2: N-2-amino-phenyl)-6-(4-methoxy-benzylamino)-nicotinamide (compound 45) [0177] Following the procedure described in Example 40, step 2, but substituting 43 for 42, the title compound 45 was obtained in 61% yield. Example 42 N-(2-aminophenyl)-3-[6-(2-phenylamino-ethylamino)-pyridin-3-yl]-acrylamide (compound 50) Step 2: 3-[6-(2-Phenylamino-ethylamino)- pyridin-3-yl)-acrylic acid tert-butyl ester (compound 46) [0178] In a 50 mL flask, a mixture of 42 (308 mg, 1.05 mmol), tert-butylacrylate (0.8 mL, 5.5 mmol), diisopropylethylamine (0.8 mL, 4.6 mmol), tri-o-tolylphosphine (POT, 192 mg, 0.63 mmol), Pd2(dba)3 (73 mg, 0.08 mmol) in anhydrous DMF (4 mL) was stirred at 120°C (preheated oil bath) for 2h under nitrogen. After DMF removal, the crude residue was submitted to a chromatographic purification (column silica gel, 50% ether in hexanes) to afford 316 mg of 46 (88% yield). 13C NMR (300 MHz, CDCI3) 5 (ppm): 166.6, 159.3, 149.6, 147.8, 140.7, 134.9, 129.1, 119.8, 117.3, 115.9, 112.6, 107.8, 80.0, 43.5, 40.9. 28.1. LRMS = 340.3 (M+1). Step 3: 3-[6-(2-Phenylamino-ethylamino)- pyridin-3-yl)-acrylic acid (compound 48) [0179] Ester 46 (0.93 mmol) was dissolved 40 % TFA in dichloromethane (10 mL) and the solution stirred at room temperature overnight. The solvent was removed under vacuo distilling with acetonitrile (3x10 mL) and stored under high vacuum for 6h. The solid residue 48 was employed for the next reaction without further purification. LRMS = 284.1 (M+1). Step 4: N-2-aminophenyl)-3-[6-(2-phenylamino-ethylamino)-pyridin-3-yl]-acrylamide (compound 50) [0180] A mixture of acid 48 (0.93 mmol), BOP (495 mg, 1.12 mmol) and 1,2-phenylenediamine (124 mg, 1.15 mmol) were dissolved in dry acetonitrile (4 mL) and treated with triethylamine (0.8 mL, 5.7 mmol). The solution was stirred under nitrogen at room temperature for 16h. After concentration under vacuo, the crude was purified through chromatographic column (5% methanol in dichloromethane), then was crystallized from chloroform to give 50 (247 mg, 71% yield). 1H-NMR (DMSO-d6), 5 (ppm): 9.25 (bs, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 15.7 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.24 (t, J = 1.0 Hz. 1H), 7.08 (t, J = 7.4 Hz, 2H), 6.91 (t, J = 8.0 Hz, 1H), 6.75 (dt, J= 8.0 Hz, 0.4 Hz, 1H), 6.57 (m, 6H). 5.20 (bs. 1H), 3.48 (t, J = 6.3 Hz, 2H), 3.33 (bs, 2H), 3.21 (t, J = 6.3 Hz, 2H). Example 43 N-(2-aminophenyl)-3-[6-(4-methoxy-benzylamino)-pyridin-2-yl]-acrylamide (compound 51) Step 2: N-2-aminophenyl)-3-[6-(4-methoxy-benzylamino)-pyridin-2-yl]-acrylamide (compound 51) [0181] Following the procedure described in Example 42, steps 2, 3, 4, but substituting 43 for 42, the title compound 51 was obtained in 50% yield (on 2 steps). 1H-NMR (CDCI3), 6 (ppm): 7.60 (bs, 1H), 7.55 (bs, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 15.1 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 6.88 (d, J = 8.3 Hz, 2H), 6.80 (m, 2H), 6.70 (m, 3H), 6.41 (d, J = 8.5 Hz, 1H), 4.50 (d, J = 5.5 Hz, 2H), 3.80 (s, 3H), 3.45 (bs, 2H). Example 44 4-[2-(2-amino-phenylcarbamoyl)-vinyl]-benzyl}-carbamic acid pyridin-3-yl methyl ester (compound 55) Step 1: (4-bromo-benzyl)-carbamic acid pyridin-3-yl-methyl ester (compound 54) [0182] 4-bromobenzylamine HCI (3.0g, 13.4 mmol) was dissolved in DMF (60 mL) at rt and then Et3N (4.13 mL, 29.7 mmol) was added dropwise over 10 min to give cloudy solution. To this, DBU (2.42 mL, 16.2 mmol) and l.l'-carbonyl diimidazole (2.41g, 14.8 mmol) were added. After being stirred for 1 h at rt, 3-pyridylcarbinol (1.44 mL, 14.8 mmol) was added dropwise over 10 min. The resulting reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue obtained was diluted with ether/EtOAc (9:1) and then washed with H2O. The organic layer was dried over Na2SO4, filtered and then concentrated to give the crude product which was recrystallized from EtOAc to give 2.55g of product 54 (59% yield, LRMS = 323 (M+1). Step 2: 4-[2-(2-amino-phenylcarbamoyl)-vinyn-benzyl)-carbamic acid pyridin-3-yl methyl ester (compound 55) [0183] Following the procedure described in Example 42, steps 2, 3, but substituting 54 for 42, and acrylic acid for tert-butyl acrylate the title compound 55 was obtained in an overall yield of 20%. 1H NMR: (DMSO-d6) ? (ppm): 10.03 (s, 1H), 9.32 (s, 1H), 8.65 (s, 1H), 8.55 (d, J = 3.3 Hz, 1H), 7.85 (d, J = 7.69 Hz, 1H), 7.40-7.60 (m, 6H), 7.31 (d, J = 7.69 Hz, 1H), 6.89 (dd, J = 7.14 Hz, J = 7 Hz, 1H), 6.71-6.79 (m, 2H), 6.55 (dd, J = 7.1 Hz, J = 7 Hz, 1H), 5.20 (s, 2H), 4.93 (bs, 2H). Example 45 N-(2-aminophenyl)-3-{4-[(3,4,5-trimethoxy-benzylamino)-methyl]-phenyl}-acrylamide (compound 59) Step 1: (4-Bromo-benzyl)-(3,4,5-trimethoxy-benzyl)-amine (compound 57) [0184] To a stirred suspension of K2CO3 (522 mg, 3.77 mmol) in dry DMF was added 3,4,5- trimethoxybenzylamine (1.10 mL, 6.44 mmol, 2.2 equiv.) followed by a solution of p-bromo benzylbromide (0.73 g, 2.91 mmol) in dry DMF (8 mL). The mixture was stirred at room temperature under nitrogen for two days in the dark, diluted with dichloromethane (200 mL), washed with brine, dried (MgS04), filtered and concentrated. The crude residue was purified by chromatographic column on silica gel (elution 5% methanol in dichloromethane) to give 2.59 mmol (89% yield) of dibenzylamine 57. 13C NMR (300 MHz, CDCI3) 8 (ppm): 152.5, 138.8, 136.1, 135.4, 130.6, 129.2, 119.8, 104.2, 59.9, 55.3, 52.6, 51.7. LRMS = 368.4 (M+1). Step 2: N-(2-Nitro-phenyl)-3-(4-r(3,4,5-trimethoxy-benzylamino)-methyl]-phenyl}-acrylamide (compound 58] Preparation of the nitroacrylanilide [0185] To a mixture of 2-nitroaniline (1.73 g, 12.5 mmol), DMAP (321 mg, 2.6 mmol) and 2,6-di- tert-butyl-4-methylphenol (308 mg) in dry dichloromethane (50 mL) at 0°C was added triethylamine (10.6 mL, 76 mmol) followed by acryloylchloride (3.2 mL, 38 mmol, 3.0 equiv.), and the mixture was stirred at room temperature for 16h. The solution was diluted with dichloromethane (250 mL), cooled to 0°C and the excess of reagent quenched with saturated NaHCO3 (stirring for 1 h). The organic layer was then washed (5% KHSO4, then brine), dried (MgSO4), filtered and concentrated under reduced pressure. After purification through chromatographic column on silica gel (elution 50% ether in hexanes), 642 mg (3.34 mmol, 27% yield) of the amide was obtained. l3C NMR (300 MHz, CDCI3) 8 (ppm): 163.6, 136.0, 135.6, 134.5, 131.3, 128.6, 125.4, 123.1, 121.8. LRMS = 193.2 (M+l). Step 3: N-(2-aminophenyl)-3-{4-[(3,4,5-trimethoxy-benzylamino)-methyl]-phenyl]-acrylamide (59) [0186] A mixture of nitro-compound 58 (127 mg, 0.27 mmol), SnCI2 (429 mg, 2.26 mmol, 8.4 equiv.) and NH4OAC (445 mg) was suspended in methanol (9.5 mL) and water (1.5 mL), and the mixture was heated at 70°C for 45 min. The mixture was diluted with ethylacetate (100 mL) and washed with brine and then saturated NaHCO3, dried (MgSO4), filtered, and concentrated. Purification by chromatographic column on silica gel (elution 5 to 10% methanol in dichloromethane) gave 52 mg (43% yield) of 59. 1H-NMR (CDCI3), ? (ppm): 8.25 (bs, 1H), 7.59 (d, J = 15.6 Hz, 1H), 7.38 (d, J = 7.5 Hz, 2H), 7.29 (d, J = 7.5 Hz, 2H), 7.25 (m 1H), 7.02 (t, J = 6.8 Hz, 1H), 6.75 (m, 2H), 6.62 (d, J = 15.6 Hz, 1H), 6.58 (s, 2H), 3.97 (bs, 3H), 3.80 (s, 9H), 3.78 (s, 2H). 3.72 (s, 2H). Example 46 N-(2-aminophenyl)-3-(4-{[(3,4,5-trimethoxy-benzyl)-amino]-methyl}- phenyl)-acrylamide (compound 61) Step 1: 3-[4-{[Methyl-(3,4,5-trimethoxy-benzyl)-amino]-methyl]-phenyl)-N-(2-nitro-phenyl)-acrylamide (compound 60) [0187] Amine 58 (180.2 mg, 0.38 mmol) was dissolved in 88% of HCO2H (6 mL), treated with excess of paraformaldehyde (7.67 mmol) and the mixture stirred at 70°C for 2.5h. A saturated NaHCO3 solution, was added slowly, extracted with dichloromethane (2 x 75 mL), dried (MgSO4, filtered and concentrated. After chromatographic column on silica gel (elution 3 to 5% methanol in dichloromethane), pure N-methyl amine 60 (118 mg, 63% yield) was obtained. 13C NMR (300 MHz, CDCI3) ? (ppm): 164.5, 153.1, 143.5, 142.3, 136.8. 136.1, 136.0, 135.3, 134.9, 132.9, 129.3, 128.2, 125.8, 123.1, 122.2, 120.3, 105.4, 62.2, 61.2, 60.8. 56.0, 42.5. LRMS = 492.5 (M+1). Step 2: N-2-aminophenyl)-3-(4-([(3,4,5-trimethoxy-benzyl)-aminol-methyl]- phenyl)-acrylamide (compound 61) [0188] Following the procedure described in Example 45, step 3, but substituting the nitro- compound 60 for 58, the title compound 61 was obtained in 72% yield. 1H-NMR (DMSO-d6), 5 (ppm): 9.15 (bs, 1H), 8.13 (bs, 1H), 7.58 (d, J = 1.9 Hz. 1H), 7.30 (m 4H), 7.12 (d, J = 7.7 Hz, 1H), 6.91 (m 3H), 6.75 (d, J = 7.8 Hz, 1H), 6.57 (m 2H), 4.83 (bs, 2H), 4.43 (d, J = 5.5 Hz, 2H), 3.72 (s, 3H), 3.33 (s, 3H). Example 47 N-(2-aminophenyl)-3-{4-(4-methoxy-benzylamino)-phenyl}-acrylamide (compound 65) Step 1: Methyl-3-(4-amino-phenyl)-acrylate hydrochloride (compound 63) [0189] 4-amino-cinnamic acid (10.41 g, 0.052 mol) was dissolved in methanol (100 mL) at rt. A solution of HCI in dioxane (15.6 mL, 4 N) was then added. The reaction mixture was heated at reflux overnight. The clear solution was evaporated to a half volume and then settled down at rt. The white suspension obtained was collected by vacuum filtration. The mother liquid was evaporated again to a quart volume and cooled down to rt. The suspension was filtered again. The combined the solid collected from two filtration was dried in vacuo to give 7.16 g of 63 (64.3% yield). LRMS: 178 (M+1). Step 2: Methyl-3-{4-(4-methoxy-benzylamino)-phenyl)- acrylate hydrochloride (compound 64) [0190] To a suspension of compound 63 (3.57 g, 16.7 mmol) in DMF (30 mL) was added Et3N. after 10 min 4-methoxybenzyl chloride (2.0 g, 12.8 mmol), Nal (0.38 g, 2.6 mmol) and K2CO3 (3.53 g, 25.5 mmol) were added successively. The mixture was heated at 60°C overnight and evaporated to dryness. The residue was partitioned between NaHCO3 sat. solution (50 mL) and EtOAc (50mLx3). The combined organic layers were washed with brine and then evaporated to dryness. The residue was purified by flash chromatography and then recrystallized from isopropylalcohol to give 1.16 g 64 (yield 30.6%, LRMS = 298) and 1.46g of 63 (49% recovered yield). Step 3: N-(2-aminophenyl)-3-{4-(4-methoxy-benzylamino)-phenyl}-acrylamide (compound 65) [0191] Following the procedure described in Example 42, step 4, but substituting 64 for 48, the title compound 65 was obtained in 32% yield. 1H NMR: (DMSO-d6) ? (ppm): 9.1.5 (s, 1H), 7.24 -7.38 (m, 6H), 6.84-6.90 (m, 3H), 6.72 (m, 2H), 6.49-6.60 (m, 4H), 4.84 (s, 2H ), 4.22 (d, J = 5.77 Hz, 2H). Example 48 N-(2-Amino-phenyl)-3-(4-styrylamino-phenyl)-acrylamide (compound 71) Step 1: N-(4-lodo-phenyl)-(3-phenyl-allyl)-amine (compound 69) [0192] Following the procedure described in Example 47, step 2, but substituting 68 for 63, the title compound 69 was obtained in 70% yield. LRMS = 288 (M+l) Step 2: N-(2-Amino-phenyl)-3-(4-styrylamino-phenyl)-acrylamide (71) [0193] Following the procedure described in Example 42, steps 2, 4, but substituting 69 for 42, and acrylic acid for tert-butyl acrylate the title compound 71 was obtained in an overall yield of 60%. 1H NMR: (DMSO-d6) ? (ppm): 9.22 (bs, 1H), 7.45 (d, J = 6.9 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H), 7.34 (d, J = 7.4 Hz, 2H), 7.26 (dt, J = 7.4 Hz, 6.8 Hz, 2H), 6.93 (dt, J = 7.9 Hz, 7.1 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H), 6.69 (d, J = 8.5 Hz, 2H), 6.63-6.55 (m, 4H), 6.44-6.37 (m, 1H), 4.95 (bs, 2H), 3.95 (bs, 2H). Example 49 N-{2-Amino-phenyl)-3-[4-(4-methoxy-benzamide)]-acrylamide (compound 72) Step 1: N-(4-lodo-phenyl)-4-methoxy-benzamide (compound 70) [0194] Following the procedure described in Example 47, step 2, but substituting 68 for 63, the title compound 70 was obtained in 90% yield. LRMS = 354.0 (M+1) Step 2: N-(2-Amino-phenyl)-3-[4-(4-methoxy-benzamide)]-acrylamide (compound 72) [0195] Following the procedure described in Example 42, steps 2, 4, but substituting 70 for 42, and acrylic acid for tert-butyl acrylate the title compound 72 was obtained in an overall yield of 90%. 1H NMR: (DMSO-d6) ? (ppm): 9.4 (bs, 1H), 7.60(d, J = 8.5 Hz, 1H), 7.54-7.45 (m, 3H), 7.87 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.95-6.77 (m, 3H), 6.62 (d, J = 7.7 Hz, 2H), 6.08-6.04 (m, 2H), 4.98 (bs, 2H), 3.72 (s, 3H). N-(2-aminophenyl)-3-{6-[2-(4-oxo-4H-quinazolin-3-yl)-ethylamino]-pyridin-3-yl}-acrylamide (compound 76) Step 1: N-(5-Bromo-pyridin-2-yl)-ethane-1.2-diamine (compound 73) [0196] Following the procedure described in Example 40, step 1, but using 1,2-diaminoethane as alkyl amine, the title compound 73 was obtained in 84% yield. 13C NMR (300 MHz, CD3OD): 159.1, 148.7, 140.7, 111.7, 107.2, 44.3, 41.7. LRMS = 218.1 (M+1) Step 2: 3-[2-(5-Bromo-pyridin-2-ylamino)-ethyl]-3H-quinazolin-4-one (compound 75) [0197] A suspension of primary amine 73 (1.17 g, 5.40 mmol) and isatoic anhydride 74 (880 mg, 5.40 mmol) in methanol (25 mL) was stirred for 3 h at 50°C and then concentrated. The resulting oily residue was dissolved in 88% formic acid (20 mL) and refluxed overnight. After removal of formic acid, the solid residue was purified through column chromatography on silica gel (5% methanol in dichloromethane) to give 1.24 g (3.6 mmol, 67% yield) of 75.13C NMR (300 MHz, CDCI3): 161.6, 156.8, 147.7, 147.6, 147.2, 139.8, 134.5, 127.4, 126.8, 126.3, 121.6, 110.1, 107.0, 46.3, 40.1. LRMS = 347.1 (M+l). Step 3: N-(2-aminophenyl)-3-{6-[2-(4-oxo-4H-quinazolin-3-yl)-ethylamino]-pyridin-3-yl)-acrylamide (compound 76) [0198] Following the procedure described in Example 42, steps 2 to 4, but substituting 75 for 42, the title compound 76 was obtained in an overall yield of 68 %. 1H-NMR (DMSO-d6), ? (ppm): 9.24 (bs, 1H), 8.17 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 8.11 (bs, 1H), 8.08 (d, J = 1.9 Hz, 1H), 7.82 (dt, J = 8.5 Hz, 1.4 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.25 (t, J = 5.8 Hz, 1H), 6.90 (dt, J = 15.7 Hz, 1H), 6.74 (dd, J = 8.0 Hz, 1.4 Hz, 1H), 6.58 (m, 3H), 4.95 (bs, 2H), 4.17 (t, J = 5.2 Hz, 2H), 3.68 (m, J = 5.2 Hz, 2H). Example 51 N-(2-aminophenyl)-3-{6-[2-(4-benzyl-2,6-dioxo-piperazin-1-yl)-ethylamino]-pyridin-3-yl}- acrylamide (compound 78) Step 2: 4-Benzyl-l-[2-(5-bromo-pyridin-2-ylamino)-ethyl]-piperazine-2,6-dione (ccmpound 77) [0199] A suspension of benzyliminodiacetic acid (702 mg, 3.15 mmol) and acetic anhydride (15 mL) was stirred at 120°C for 45 min. The reaction mixture was diluted with dry toluene and concentrated in vacuo to remove the volatiles. The residue was dissolved in dry toluene (15 mL) and transferred via cannula to a reaction flask containing the amine 73 (475 mg, 3.2 mmol). The mixture was heated at 90°C for 16 h, concentrated and chromatographed by column on silica gel (elution 5% methanol in dichloromethane) to give 684mg (1.70 mmol, 54% yield) of 77. Step 3: N-(2-aminophenyl)-3-{6-f2-(4-benzyl-2,6-dioxo-piperazin-l-yl)-ethylamino]-pyridin-3-yl]-acrylamide (compound 78) [0200] Following the procedure described in Example 42, steps 2 to 4, but substituting 77 for 42, the title compound 78 was obtained in an overall yield of 60%. 1H-NMR (CD3OD-d4), ? (ppm): 8.09 (dr J = 1.8 Hz, 1H), 7.68 (dd, J = 8.7 Hz, 2.1 Hz, 1H), 7.53 (d. J = 15.6 Hz, 1H), 7.29 (m, 6H), 7.20 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 7.02 (dt, J = 9.0 Hz, 1.2 Hz, 1H), 6.86 (dd, J = 8.1 Hz, 1.2 Hz, 1H), 6.73 (dt, J = 7.5 Hz, 1.5 Hz, 1H), 6.61 (d, J = 15.6 Hz, 1H), 6.50 (d, J = 8.7 Hz, 1H), 4.85 (bs, 3H), 3.97 (t, J = 7.5 Hz, 2H), 3.60 (s, 2H). 3.57 (t, J = 7.5 Hz, 2H), 3.38 (s, 4H). Example 52 (E)-4-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-/V-{2-amino-phenyl)- cinnamide (compound 83) Step 1: 4.6-Dichloro-2-(2-indanyl-amino)-[1,3,5]triazine (compound 79) [0201] To a stirred solution at -78°C of cyanuric chloride (13.15 g, 71.33 mmol) in anhydrous THF (100 mL) under nitrogen was slowly canulated a solution of 2-aminoindan (10.00 g, 75.08 mmol), i-Pr2NEt (14.39 mL, 82.59 mmol) in anhydrous THF (60 mL). After 50 min, the reaction mixture was poured into a saturated aqueous solution of NH4CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4CI, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH2CI2: 2/98?5/95) and by co-precipitation (AcOEt/hexanes) to afford the title compound 79 (18.51 g, 65.78 mmol, 92% yield) as a beige powder. 1H NMR (300 MHz, CDCl3) ? (ppm): 7.29-7.18 (m, 4H), 6.02 (bd, J = 6.3 Hz, 1H), 4.94-4.84 (m, 1H), 3.41 (dd, J = 16.2, 6.9 Hz, 2H), 2.89 (dd, J = 16.1, 4.5 Hz, 2H). Step 2: 2-(4-Bromo-benzyl-amino)-4-chloro-6-(2-indanyl-amino)-[l,3,5]triazine (compound 80) [0202] To a stirred solution at room temperature of 79 (2.68 g, 9.52 mmol) in anhydrous THF (50 mL) under nitrogen were added i-Pr2NEt (4.79 mL, 27.53 mmol) and 4-bromobenzylamine.HCI (2.45 g, 11.01 mmol), respectively. After 17 h, the reaction mixture was poured into a saturated aqueous solution of NH4CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4CI, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chrornatography on silica gel (AcOEt/CH2CI2: 3/97?5/95) to afford the title compound 80 (4.00 g, 9.29 mmol, 97% yield) as a white powder. 1H NMR (300 MHz, CDCI3) 5 (ppm): mixture of rotamers, 7.52-7.42 (m, 2H), 7.26-7.11 (m, 6H), 6.51 and 6.12 (2 m, 1H), 5.72-5.46 (m, 1H), 4.94-4.64 (m, 1H), 4.62-4.46 (m, 2H), 3.43- 3.16 (m,2H), 2.92-2.74 (m, 2H). Step 3: 4-Amino-2-(4-bromo-benzyl-amino)-6-(2-indanyl-amino)-[1,3,5]triazine (compound 81) [0203] In a 75 mL sealed flask, a solution of 80 (2.05 g, 4.76 mmol) in anhydrous 1,4-dioxane (60 mL) was stirred at room temperature, saturated with NH3 gas for 5 min, and warmed to 140°C for 18 h. The reaction mixture was allowed to cool to room temperature, the saturation step with NH3 gas was repeated for 5 min, and the reaction mixture was warmed to 140°C again for 24 h. Then, the reaction mixture was allowed to cool to room temperature, poured into 1N HCI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat NH4CI, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2CI2: 5/95) to afford the title compound 81 (1.96 g, 4.76 mmol, quantitative yield) as a colorless foam. 1H NMR (300 MHz, CDCI3) 6 (ppm): 7.43 (d, J = 8.2 Hz, 2H), 7.25-7.12 (m, 6H), 5.70-5.10 (m, 2H), 5.00-4.65 (m, 3H), 4.52 (bs. 2H), 3.40-3.10 (m, 2H), 2.90-2.65 (m, 2H). Step 4: (E)-([4-Amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl]-N-[2-(N-t-butoxycarbonyl)- amino-ohenyl]-cinamide (compound 82) Preparation of N-[2-(/V-t-Butoxycarbonyl)-arnino-phenyl]-acrylamide [0204] Following the procedure described in Example 45, step 2, but substituting the nitro- compound 2-(N-t-butoxycarbonyl)-amino-aniline for 2-nitroaniline, the title compound was obtained in 77% yield. 1H NMR (300 MHz, CDCI3) S (ppm): 8.51 (bs, 1H), 7.60-7.45 (m, 1H), 7.38-7.28 (m, 1H), 7.20-7.05 (m, 2H), 6.98 (bs, 1H), 6.41 (dd, J = 17.0 Hz, 1.1 Hz, 1H), 6.25 (dd, J = 16.9 Hz, 10.0 Hz, 1H), 5.76 (dd, J = 10.2 Hz, 1.4 Hz, 1H), 1.52 (s, 9H). [0205] In a 50 mL sealed flask, a solution of 81 (300 mg, 0.73 mmol), the acrylamide (230 mg, 0.88 mmol), Et3N (407 nl, 2.92 mmol), tri-o-tolylphosphine (POT, 13 mg, 0.04 mmol), Pd2(dba)3 (20 mg, 0.02 mmol) in anhydrous DMF (10 mL) was stirred at room temperature, saturated with N2 gas for 15 min, and warmed to 100°C for 15 h. Then, the reaction mixture was allowed to cool to room temperature, poured into a saturated aqueous solution of NH4CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4CI, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2CI2: 2/98?5/95) to afford the title compound 82 (240 mg, 0.41 mmol, 56% yield) as a beige solid. 1H NMR (300 MHz, CDCI3) 8 (ppm): 8.46 (bs, 1H), 7.71 (bd, J = 15.7 Hz, 1H), 7.62-7.05 (m, 13H), 6.54 (bd, J = 15.9 Hz, 1H), 5.954.90 (m, 4H), 4.854.48 (m, 3H), 3.40-3.14 (m, 2H), 2.90-2.70 (m, 2H), 1.52 (s, 9H). Step 5: (E)-4-l[4-Amino-6-(2-indanvl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)- cinnamide (compound 83) [0206] To a stirred solution at room temperature of 82 (230 mg, 0.39 mmol) in CH2CI2 (5 mL) was added TFA (1 mL, 95% in water). After 18 h, the reaction mixture was poured into a saturated aqueous solution of NaHCO3, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NaHCO3, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2CI2: 5/95) to afford the title compound 83 (170 mg, 0.35 mmol, 89% yield) as a yellow solid. 1H NMR (300 MHz, acetone-d6) ? (ppm): 8.87 (bs, 1H), 7.69 (d, J = 15.7 Hz, 1H), 7.59 (bd, J = 7.7 Hz, 2H), 7.49-7.34 (m, 3H), 7.28-7.11 (m, 4H), 7.05-6.91 (m, 2H), 6.88 (dd, J = 8.0, 1.4 Hz, 1H), 6.69 (td, J = 7.6, 1.4 Hz, 1H), 6.65-5.50 (m, 4H), 4.83-4.53 (m, 5H), 3.34-3.11 (m, 2H), 2.98- 2.80 (m, 2H). Example 53 N-(2-aminophenyl)-2-(4-methoxy-benzylamino)-quinolin-6-yl-amide (compound 87) Step 1: 2.6-ditrifluoromethanesulfonyloxy-quinoline (compound 85): [0207] A solution of 2,6-dihydroxyquinoline 84 (1.254 g, 7.78 mmol) and DMAP (a few crystals) in dry pyridine (15 mL) was treated with neat trifluoromethanesulfonic anhydride (5.2 g, 18,4 mmol, 1.2 equiv.) and stirred at 0°C for 5 h. This solution was then poured on a mixture brine/sat NaHCO3 and extracted with dichloromethane (2 x 150 mL), dried (MgSO4), filtered and concentrated. Purification by column chromatography on silica gel (30% to 50% ether in hexanes) gave 2.58 g (6.1 mmol, 78% yield) of 85. 13C NMR (300 MHz, CDCI3): 154.5, 147.8, 144.6, 142.0, 131.6, 127.8, 124.9, 119.3, 118.7, 114.9. LRMS = 426.0 (M+l). Step 2: N-(2-aminophenyl)-2-(4-methoxy-benzylamino)-quinolin-6-yl-amide (compound 87) [0208] Following the procedure described in Example 40, steps 1, 2, but substituting 85 for 40, the title compound 87 was obtained in 92% yield. 1H-NMR (DMSO-d6)( ? (ppm): 9.66 (bs, 1H), 8.32 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.96 (dd, J = 9.1 Hz, 2.2 Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 8.5 Hz, 2.2 Hz, 1H), 7.34 (dd, J = 8.5 Hz, 2.2 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.97 (t, J = 7.7 Hz, 1H), 6.90 (m 2H), 6.80 (d, J = 7.9 Hz, 1H), 6.61 (t, J = 6.3 Hz, 1H), 4.90 (bs 2H), 4.58 (d, J = 3.3 Hz, 2H), 3.73 (s, 3H), 3.33 (bs, 1H). Example 54 N-(2-aminophenyl)-3-[2-{4-methoxy-benzylamino)-quinolin-6-yl]-acrylamide (compound 88) Step 3: N-(2-aminophenyl)-3-[2-(4-methoxy-benzylamino)-auinolin-6-yl]-acrylamide (compound 88) [0209] Following the procedure described in Example 42, steps 1 to 4, but substituting 85 for 40, the title compound 88 was obtained in an overall yield of 71%. 1H-NMR (DMSO-d6), ? (ppm): 9.70 (bs, 1H), 9.40 (bs, 1H), 8.20 (d, J = 8.9 Hz, 1H), 8.03 (bs, 2H), 7.94 (d, J = 7.2 Hz, 1H), 7.64 (dd, J = 15.7 Hz, 2.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.39 (m, 1H), 7.14 (d, J = 8.9 Hz, 1H), 7.05 (d, J = 15.7 Hz, 1H), 6.97 (m, 1H), 6.95 (d, J = 8.5 Hz, 2H), 6.81 (d. J = 8.0 Hz, 1H), 6.65 (t, J = 7.2 Hz, 1H), 4.76 (s, 2H), 3.75 (s, 3H). Examples 55-84 [0210] Examples 55 to 84 describe the preparation of compounds 89 to 118 using the same procedures as described for compounds 44 to 88 in Examples 40 to 54. Characterization data are presented in Tables 3a-d. Example 85 N-(2-Amino-phenyl)-4-(1H-benzimidazol-2-ylsulfanylmethyl)-benzamide (compound 126) Step 1: 4-(lH-Benzimidazol-2-ylsulfanylmethyl)-benzoic acid methyl ester (compound 122) [0211] Following the procedure described in Example 47, step 2, but using 119 and substituting 121 for 63, the title compound 122 was obtained in 95% yield. LRMS = 299.1 (M+1). Step 2: N-(2-Amino-Phenyl)-4-(1H-benzimidazol-2-ylsulfanylmethyl)-benzamide (126) [0212] Following the procedure described in Example 1, steps 4 and 5, but substituting 122 for 6, the title compound 126 was obtained in 62% yield. 1H NMR: (DMSO-d6) ? (ppm): 9.57 (s, 1H), 7.89 (d, J= 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H). 7.53 (bs. 2H), 7.36 (bs, 2H), 7.14-7.08 (m, 3H), 6.94 (t, J = 8.2 Hz, 1H), 6.74 (d, J = 6.9 Hz, 1H), 6.56 (t, J = 8.0 Hz, 1H), 4.87 (bs, 2H), 4.62 (s, 2H). Example 87 N-(2-Amino-phenyl)-4-[6-(2-morpholin-4-yl-ethylamino)-benzothiazol-2-ylsulfanylmethyl]- benzamide (compound 128) Step 1: 4-(6-Amino-benzothiazol-2-ylsulfanylmethyl)-benzoic acid methyl ester (122) [0213] Following the procedure described in Example 47, step 2, but using 120 and substituting 121 for 63, the title compound 122 was obtained in 45% yield. LRMS = 331.0 (M+l). Step 2: 4-[6-(2-Morpholin-4-yl-ethylamino)-benzothiazol-2-ylsulfanylmethyn-benzoic acid methyl ester (compound 124) [0214] To a solution of 4-(6-Amino-benzothiazol-2-ylsulfanylmethyl)-benzoic acid methyl ester 122 (800 mg, 2.42 mmol), in DMF (24 mL), were added successively solid 4-(2-chloroethyl)morpholine hydrochloride (296 mg, 2.66 mmol), K2CO3(611 mg, 5.08 mmol), Nal (363 mg, 2.42 mmol), Et3N (370 ?L, 2.66 mmol) and tetrabutylammonium iodide (894 mg, 2.42 mmol), The mixture was stirred at 120°C for 24h and more 4-(2-chloroethyl)morpholine hydrochloride (296 mg, 2.66 mmol) was added. The mixture was stirred for 8h at 120°C and the solvent was removed in vacuo. The resulting black syrup was partitioned between H2O and EtOAc. The organic layer was successively washed with HCI 1N and saturated aqueous NaHCO3. The precipitate was extracted twice with EtOAc, dried over MgSO4 and concentrated. Purification by flash chromatography (MeOH/CHCI3: 5:95 to 10:90) afforded 48 mg (4% yield) of 124 as a light yellow oil. LRMS = 444.1 (M+1). Step 3: N-(2-Amino-Phenyl)-4-[6-(2-morpholin-4-yl-ethylamino)-benzothiazol-2-ylsulfanylmethyl]- benzamide (compound 128) [0215] Following the procedure described in Example 1, steps 4 and 5, but substituting 124 for 6, the title compound 128 was obtained in 76% yield. 1H NMR: (Acetone-d6) ? (ppm): 9.06 (bs, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 7.02-6.97 (m, 1H), 6.87-6.82 (m, 2H), 6.66 (dt, J = 7.4 Hz, 1.4 Hz, 1H), 4.63 (s, 2H), 3.64-3.60 (m, 4H), 3.25 (t, J = 6.3 Hz, 2H), 2.63 (t, J = 6.3 Hz, 2H), 2.54-2.42 (m, 4H). Example 88 N-(2-Amino-phenyl)-4-(quinolin-2-ylsulfanylmethyl)-benzamide (compound 131) Step 1: 2-(4-Bromo-benzylsulfanyl)-quinoline (compound 130) [0216] Following the procedure described in Example 47, step 2, but substituting 129 for 63, the title compound 130 was obtained in 89% yield. LRMS = 332.0 (M+1). Step 2: N-(2-Amino-phenyl)-4-(quinolin-2-ylsulfanylmethyl)-benzarnide (131) [0217] Following the procedure described in Example 40, step 2, but substituting 129 for 42, the title compound 131 was obtained in 70% yield. 1H NMR: (DMSO-d6) ? (ppm): 9.62 (bs, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.00-7.89 (m, 4H), 7.79 (dd, J = 6.8 Hz, 1.3 Hz, 1H), 7.68 (d, J = 6.3 Hz, 2H), 7.56 (t, J = 6.8 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 8.2 Hz. 1H), 6.99 (dt, J = 7.9 Hz, 7.4 Hz, 1H), 6.79 (d, J = 6.9 Hz, 1H), 6.61 (dt, J = 7.7 Hz, 7.4 Hz, 1H), 4.69 (s, 2H). Example 89 N-(2-Amino-phenyl)-4-(pyrimidin-2-ylaminomethyl)-benzamide (compound 134) Step 1: 4-(Pyrimidin-2-ylaminomethyl)-benzoic acid methyl ester (compound 133) [0218] Following the procedure described in Example 47, step 2, but substituting 132 for 63, the title compound 133 was obtained in 76% yield. LRMS = 244.2 (M+1). Step 2: N-(2-Amino-phenyl)-4-(pyrimidin-2-ylaminomethyl)-benzamide (134) [0219] Following the procedure described in Example 1, steps 4 and 5, but substituting 129 for 6, the title compound 134 was obtained in 91% yield. 1H NMR: (DMSO-d6) ? (ppm): 9.6 (bs, 1H). 8.32 (d, J = 4.9 Hz, 2H), 7.97 (dt, J = 9.9 Hz, 7.9 Hz, 2H), 7.85-7.83 (m, 1H), 7.47, (d, J = 8.2 Hz, 2H), 7.20 (d, J = 7.9 Hz, 1H), 7.01 (dt, J = 7.7 Hz, 7.4 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 6.66-6.62 (m, 1H), 4.98 (bs, 2H), 4.61 (d, 2H). Example 90 N-(2-Amino-phenyl)-4-(l-methyl-1H-imidazol-2-ylsulfanylmethyl]-benzamide (compound 139) Step 1: [2-(4-lodo-benzoylamino)-phenyl1-carbamic acid tert-butyl ester (compound 135) [0220] To a solution of di-tert-butyldicarbonate (39 g, 181 mmol) in THF (139 mL) placed in a water bath, was added 1,2-phenylenediamine (15 g, 139 mmol) and DMAP (1.7 g, 14 mmol). The mixture was stirred at r.t. for 16 h and the solvent was removed in vacuo. The crude material was partitioned between EtOAc and water. The organic layer was washed with HCI 1 N and then with aqueous saturated NaHCO3. The combined organic layers were washed with brine, dried over MgSO4 and concentrated affording the compound (18.9 g, 65% yield) as a light beige powder. LRMS = 209.1 (M+1). [0221] To a solution of 4-iodobenzoic acid (8.0 g, 32.3 mmol) in DMF (65 mL) at r.t., were successively added l-[3-(dimethylamino)propyl]-3-ethylcabodiimide hydrochloride (8.0 g, 41.9 mmol) and 1-hydroxybenzotriazole (5.2 g, 38.7 mmol). The mixture was stirred for 1 h and a solution of (2- amino-phenyl)-carbamic acid tert-butyl ester (6.3 g, 30.2 mmol) in DMF (20 mL) was added to the mixture via cannula, followed by triethylamine (5.9 mL, 4.9 mmol). The mixture was stirred for 16 h and the solvent was removed in vacuo. The crude material was partitioned between chloroform and water. The organic layer was washed with aqueous saturated NaHCO3, dried over MgSO4 and concentrated to a light brown syrup which was crystallized in hot EtOAc or Et2O, yielding 135 (9.3 g, 70% yield) as a white solid. LRMS = 461.0 (M+Na+). Step 2: N-[2-tert-butoxycarbonylamino-phenyl)-terephtalamic acid methyl ester (compound 136) [0222] Following the procedure described in Example 40, step 2, but substituting 135 for 42, the title compound 136 was obtained in 95% yield. LRMS = 393.1 (M+Na+). Step 3: [2(4-Hydroxymethyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester (137) [0223] To a solution of 136 (7.5g, 20.6 mmol) in THF (40 mL), cooled down to -20°C under N2, was added a 1M solution of DIBAL-H (122 mL, 122 mmol) in toluene. After stirring for 18 h. at r.t, the mixture was cooled down to 0°C and carefully quenched by a dropwise addition of H2O (10 mL) and of 2N NaOH (5 mL). The aluminum salts were allowed to decant and the supernatant was removed. The organic layer was washed with H2O, 1 N HCI (6 times), satd. aqueous NaHCO3, brine, dried over MgSO4 and concentrated (2.04 g, 43%). Purification of the crude material by flash chromatography (EtOAc/hexanes 50:50 to 70:30) afforded 137 (1.14 g, 16% yield) as a solid foam. LRMS = 365.2 (M+Na+). Step 4: l2-[4-(1-Methyl-imidazol-2-ylsulfanylmethyl)-benzoylamino1-phenyl)-carbamic acid tert-butyl ester (compound 138) [0224] To a solution of N-methyl-2-mercaptoimidazole (28 mg, 0.25 mmol) in THF (1 mL), at r.t. under N2 atmosphere were successively added 137 (70 mg, 0.20 mmol), triphenylphosphine (70 mg; 0.27 mmol) followed by dropwise addition of diethyl azodicarboxylate (48 ?L, 0.31 mmol). The mixture was stirred for 2 h and the solvent was removed in vacuo. Purification by flash chromatography using MeOH/CHCl3 (5:95) as the eluent afforded the title compound 138 (81 mg), in 91% yield, which was found to contain some diethyl hydrazodicarboxylate residus. The compound was used as is without further purification. Step 5: N-2-Amino-phenyl)-4-(l-methyl-lH-imidazol-2-ylsulfanylmethyn-benzamide (compound 139) [0225] Following the procedure described in Example 42, step 3, but substituting 138 for 46, the title compound 139 was obtained in 62% yield. 1H NMR: (Acetone-d6) ? (ppm): 9.07 (bs, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 1.1 Hz, 1H), 7.03-6.96 (m, 2H), 6.86 (dd, J = 8.0 Hz, 1.4 Hz, 1H), 6.67 (dt, J = 7.4 Hz, 1.1 Hz, 1H), 4.63 (bs, 2H), 4.29 (s, 2H), 3.42 (s, 3H). Example 91 N-(2-Amino-phenyl)-6-(3-methoxyphenyl)-nicotinarnide (compound 141} [0226] To a mixture of 3-methoxyphenyl boronic acid (152 mg, 1.0 mmol) and 140 (248 g, 1.0 mmol) were added benzene (8 mL) and ethanol (4 mL) followed by 2 M Na2CO3 aqueous solution (3.2 mL, 6.4 mmol). The reaction mixture was stirred under nitrogen for 30 min and then Pd(PPh3)4(58 mg, 0.05 mmol) was quickly added. After 24 h of reflux, the mixture was cooled to room temperature, filtered through a pad of celite and rinsed with ethyl acetate (30 mL). The organic solution was washed with brine (5 mL), dried (MgSO4), and concentrated. Purification by flash silica gel chromatography (Hexane/Ethyl acetate: 1/1) afforded 141 (302 mg, 95% yield). 1H NMR (CDCI3) 6 (ppm): 9.11 (d, J = 1.8 Hz, 1H), 8.30 (dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.52- 7.47 (m, 1H), 7.36 (m, 1H), 7.22 (m, 1H), 7.09-6.78 (m, 4H), 3.84 (s, 3H), 3.39 (br s, 2H). Example 92 N-(2-Amino-phenyl)-4-(l-oxo-1,3-dihydro-isoindol-2-ylmethyl)-benzamide (compound 144) Step 1: 4-(1-Oxo-l,3-dihydro-isoindol-2-ylmethyl)-benzoic acid (compound 143) [0227] To a solution of benzene-1,2-carbaldehyde 142 (1.0 g, 7.46 mmol) in 10 mL of acetic acid was added 4-aminomethylbenzoic acid (1.13 g, 7.46 mmol). The reaction mixture was refluxed 5 min and cooled to the room temperature. A crystalline precipitate was formed and triturated with CH2CI2 to produce the title compound 143 (1.29 g, 49%). Step 2: N-(2-Amino-phenyl)-4-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-benzamide (compound 144) [0228] To a solution of the carboxylic acid (0.32 g, 0.89 mmol) in DMF (8 mL) at rt, was added HOBt (0.16 g, 1.15 mmol) and EDC (0.25 g, 1.33 mmol) and the solution was stirred for 1.5 h. Lastly, phenylenediamine (0.12 g, 1.07 mmol) was added and the mixture was allowed to stir for 18- 20 h. DMF was removed in vacuo and the crude was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography (CH2CI2-MeOH (19:1)) afforded 144 in 46% yield. 1H NMR: (DMSO-d6) D 9.71 (s, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.55-7.70 (m, 3H), 7.46 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 7.7 Hz, 1H), 7.02 (t, J = 7.7 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.65 (t, J = 7.4 Hz, 1H), 4.93 (bs, 2 H), 4.87 (s, 2 H), 4.47 (s, 2H). Example 94 N-(2-Amino-phenyl)- 4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzamide (compound 149) [0229] Phthalic anhydride 148 (1.3 g, 8.9 mmol) and 4-aminomethylbenzoic acid in 20 mL acetic acid were refluxing for 3 h, cooled to the room temperature and evaporated to yield a solid residue which was triturated with water, filtered off and dried to produce the intermediate carboxylic acid (1.7 g, 68%). LMRS = 282.0 (M+l). [0230] Following a procedure analogous to that described in Example 92, step 2, but substituting the acid for 143, the title compound 149 was obtained in 17% yield. 1H NMR: (DMSO d6) D 9.59 (s, 1H), 7.82-7.91 (m, 6H), 7.40 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 1H), 6.93 (t, J = 7.7 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.55 (t, J = 7.4 Hz, 1H), 4,83 (bs, 4H). Example 95 N-(2-Amino-phenyl)-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-benzamide (compound 152) Step 1: 2-[2-(4-Hydroxy-phenyl)-ethyn-isoindole-1,3-dione (compound 150) [0231] Following a procedure analogous to that described in Example 94, step 1, but substituting 4-aminomethylbenzoic acid for tyramine the title compound 150 was obtained in 48% yield. LMRS = 268.0 (M+1). Step 2: 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)ethyl)-phenyl trifluoromethane-sulfonate (151) [0232] To a solution of sodium hydride (90 mg, 25 mmol) in dry THF (20 mL) at 0°C, 150 (500 mg, 8.9 mmol) was added followed by the addition of dry DMF (2 mL). The reaction mixture was stirred for 20 min at 0°C, treated portionwise with PhN(Tf)2, stirred for additional 2 h and evaporated to produce a solid material which was purified by chromatography on a silica gel column, (CH2CI2 - MeOH (19:1)) to provide 151 (639 mg, 86% yield). LMRS = 400.0 (M+1). Step 3: N-(2-Amino-phenyl)-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-benzamide (compound 152) [0233] Following a procedure analogous to that described in Example 40, step 2, but substituting 151 for 42, the title compound 152 was obtained in 15% yield. 1H NMR: (DMSO d6) D 9.57 (s, 1H), 7.78-7.87 (m, 6H), 7.31 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.7 Hz, 1H), 6.93 (t, J = 6.9 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.56 (t, J = 7.4 Hz, 1H), 4.83 (bs, 2 H), 3.85 (t, J = 7.1 Hz, 2 H), 3.00 (t, J = 7.1 Hz, 2 H). Example 96 N-(2-Amino-phenyl)-4-(4-oxo-4H-quinazolin-3-ylmethyl)-benzamide (compound 154) [0234] A suspension of 4-aminomethyl benzoic acid (1.00 g, 6.60 mmol) in water (20 mL) was treated with Et3N (0.86 mL, 6.60 mmol) followed by the addition of isatoic anhydride 153 (980 mg, 6.00 mmol). The reaction mixture was heated 3 h at 40°C and evaporated to form an oily residue, which was refluxing in formic acid (20 mL) for 7 h. Formic acid was removed in vacuum to produce a solid, which was triturated with water and filtered off to provide the carboxylic acid (1.61 g, 96%). LMRS = 281.0 (M+1). [0235] Following a procedure analogous to that described in Example 92, step 2, but substituting the carboxylic acid for 143, the title compound 154 was obtained was obtained in 43% yield. 1H NMR: (DMSO d6) D 9.71 (s, 1H), 8.68 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.92 (t, J = 8.0, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.4, 1H), 7.55 (d, J = 7.7 Hz, 2H). 7.22 (d, J = 7.4 Hz, 1H), 7.04 (t, J = 7.1 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.67 (t, J = 7.4 Hz, 1H), 5.35 (s, 2 H). Example 97 N-(2-Amino-phenyl)-4-(4-oxo-4H-benzo[d][1,2,3]triazin-3-ylmethyl)-benzamide (compound 155) [0236] A suspension of 4-aminomethyl benzoic acid (1.00 g, 6.60 mmol) in water (20 mL) was treated with Et3N (0.86 mL, 6.60 mmol) followed by the addition of isatoic anhydride (980 mg, 6.00 mmol). The reaction mixture was heated 3 h at 40°C and cooled to 0°C. The cold reaction mixture was acidified with cone. HCI (5 mL) and treated drop wise with NaNO2 solution (520 mg, 7.5 mmol in 5 mL water) over 5 min period of time, then left overnight at room temperature. A precipitate formed which was collected, washed with water and dried to provide the carboxylic acid (1.62 g, 96%). LMRS = 282.0 (M+1). [0237] Following a procedure analogous to that described in Example 92, step 2, but substituting the carboxylic acid for 143, the title compound 155 was obtained in 27% yield. 1H NMR: (DMSO d6) D 9.62 (s, 1H), 8.25 (t, J = 6.7 Hz, 2H), 8.11 (ddd, J = 7.1 Hz, 1.4 Hz, 1H), 7.93-7.98 (m, 3H), 7.49 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 7.7 Hz, 1H), 6.94 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.57 (t, J = 7.7 Hz, 1H), 5.66 (s, 2 H), 4.87 (bs, 2 H). Example 98 N-(2-Amino-phenyl)-4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide (compound 157) Step 1: 4-[(2-Amino-benzoylamino)-methyl]-benzoic acid (compound 156) [0238] To a suspension of 4-aminomethylbenzoic acid (5.09 g, 33.7 mmol) in H2O (50 mL), was added Et3N (4.7 mL, 33.7 mmol) followed by isatoic anhydride 153 (5.0 g, 30.6 mmol). The brown mixture was heated at 40°C for 2 h until the mixture became homogeneous and then Et3N was removed in vacuo. The resulting aqueous solution was acidified (10% HCI/H2O) and the mixture was partitioned between H2O and ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and evaporated to give,156 as a white solid (6.0 g, 72 %). LMRS = 271.0 (M+1). Step 2: N-(2-Amino-phenyl)-4-(2,4-doxo-1,4-dihydro-2H-quinazorin-3-ylmethyl)-benzamide (compound 157) [0239] The carboxylic acid 156 (1.72 g, 6.36 mmol) was suspended in a solution of NaOH (2.55 g, 63.6 mmol) in H2O (12 mL). To this solution was added dioxane (10 mL) until mixture became homogeneous. The solution was cooled to 0°C in an ice-bath and methyl chloroformate (1.25 mL, 16.1 mmol) was added portionwise over 2 h. After completion of the reaction, the excess methyl chloroformate and dioxane were removed in vacuo and the mixture was diluted with methanol (80 mL) and H2O (20 mL). The solution was heated to 50°C for 1 h. until the cyclization was complete. Methanol was removed in vacuo and then the aqueous layer was extracted with ethyl acetate. Subsequently, the aqueous phase was acidified (10% HCI/H2O) and extracted with ethyl acetate (2 X 300 mL). These organic extracts were combined, dried over Na2SO4, filtered and evaporated to dryness. The resulting crude was triturated with warm methanol to afford the carboxylic acid as a white solid (1.7 g, 90%). LMRS = 319.0 (M+Na). [0240] Following a procedure analogous to that described in Example 92, step 2, but substituting the quinazolinedione carboxylic acid for 143, the title compound 157 was obtained. 1H NMR: (DMSO-d6) 0 11.56 (brs, 1H), 9.59 (brs, 1H), 7.96-7.88 (m, 3H), 7.67 (dt, J = 8.4, 1.4 Hz, 1H), 7.30 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 7.5 Hz, 2H), 7.13 (d, J = 6.9 Hz, 1H), 6.92 (dt, J = 6.9, 1.2 Hz, 1H), 6.75 (d, J = 6.9 Hz, 1H), 6.57 (t, J = 6.9 Hz, 1H), 5.15 (brs, 2H), 4.86 (brs, 2H). Example 99 N-(2-Amino-phenyl)-4-(1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)- benzamide (compound 158) Step 2: 4-(1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylnnethyl)-benzoic acid methyl ester [0241] To a solution of the quinazolinedione carboxylic acid (1.0 g, 3.38 mmol) in DMF (7 mL), was added K2CO3 (1.4 g, 10.1 mmol) and the mixture was then cooled to 0°C. Subsequently, Mel (1.05 mL, 16.9 mmol) was added and the mixture was allowed to warm to rt in the ice bath overnight. Excess methyl iodide and DMF were removed in vacua and the crude was partitioned between ethyl acetate and H2O. The aqueous phase was washed again with ethyl acetate, the combined organic extracts were dried over Na2SO4 and then concentrated in vacuo to yield the desired product as an off-white solid (0.93 g, 85%). LMRS = 325.0 (M+l). Step 3: 4-(l-Methyl-2,4-dioxo-1,4-dihydro-2H-auinazolin-3-ylmethyl)-benzoic acid [0242] To a suspension of the methyl ester (1.25 g, 3.85 mmol) in methanol (35 mL), was added IN NaOH (30 mL, 38.5 mmol) and the mixture was heated to 45-50°C for 3 h. until it became homogeneous. Methanol was removed in vacuo and the crude was partitioned between ethyl acetate and H2O. The aqueous phase was acidified (10% HCI/H2O) and extracted with ethyl acetate (2 X 300 mL). These organic extracts were dried over Na2SO4 and concentrated in vacuo to afford product 5 as a white solid (1.15 g, 96%). LMRS = 311.0 (M+1). Step 4: N-(2-Arnino-phenyl)-4-(1-methyl-2,4-dioxo-l,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide (compound 158) [0243] Following a procedure analogous to that described in Example 92, step 2, but substituting the carboxylic acid for 143, the title compound 158 was obtained in 10% yield. 1H NMR: (DMSO-d6) ? 9.59 (brs, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.8 Hz, 2H) 7.80 (dt, J = 6.9, 1.5 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.32 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.57 |
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257-kolnp-2004-granted-abstract.pdf
257-kolnp-2004-granted-assignment.pdf
257-kolnp-2004-granted-claims.pdf
257-kolnp-2004-granted-correspondence.pdf
257-kolnp-2004-granted-description (complete).pdf
257-kolnp-2004-granted-drawings.pdf
257-kolnp-2004-granted-examination report.pdf
257-kolnp-2004-granted-form 1.pdf
257-kolnp-2004-granted-form 13.pdf
257-kolnp-2004-granted-form 18.pdf
257-kolnp-2004-granted-form 3.pdf
257-kolnp-2004-granted-form 5.pdf
257-kolnp-2004-granted-reply to examination report.pdf
257-kolnp-2004-granted-specification.pdf
| Patent Number | 223053 | |||||||||||||||||||||||||||
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| Indian Patent Application Number | 257/KOLNP/2004 | |||||||||||||||||||||||||||
| PG Journal Number | 36/2008 | |||||||||||||||||||||||||||
| Publication Date | 05-Sep-2008 | |||||||||||||||||||||||||||
| Grant Date | 03-Sep-2008 | |||||||||||||||||||||||||||
| Date of Filing | 25-Feb-2004 | |||||||||||||||||||||||||||
| Name of Patentee | METHYLGENE INC | |||||||||||||||||||||||||||
| Applicant Address | 7220, FREDERICK-BANTING, ST. LAURENT, QUEBEC H4S 2A1 | |||||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | A61K 31/44 | |||||||||||||||||||||||||||
| PCT International Application Number | PCT/US02/29017 | |||||||||||||||||||||||||||
| PCT International Filing date | 2002-09-12 | |||||||||||||||||||||||||||
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