Inhibitors of histone deacetylase

Abstract

The invention relates to the inhibition of histone deacetylase. 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.

Description

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to the inhibition of histone deacetylase. More particularly, the invention relates to compounds and methods for inhibiting histone deacetylase enzymatic activity.

[0004] 2. Summary of the Related Art

[0005] 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.

[0006] Csordas, Biochem. J., 286: 23-38 (1990) teaches that histones are subject to posttranslational acetylation of the α,ε-amino groups of N-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 al., 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.

[0007] Histone acetylation is a reversible modification, with deacetylation being catalyzed by a family of enzymes termed histone deacetylases (HDACs). Grozinger et al., 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 Hda1-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 al., 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.

[0008] 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.

[0009] 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 Hda1-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.

[0010] 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

[0011] The invention provides compounds and methods for treating cell proliferative diseases. The invention provides new inhibitors of histone deacetylase enzymatic activity.

[0012] In a first aspect, the invention provides compounds that are useful as inhibitors of histone deacetylase.

[0013] 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.

[0014] 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.

[0015] 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

[0016] FIG. 1 is a graph showing the antitumor activity of compound 106 in an HCT 116 human colorectal tumor model.

[0017] FIGS. 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

[0018] 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.

[0019] For purposes of the present invention, the following definitions will be used (unless expressly stated otherwise):

[0020] 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 α,ε-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.

[0021] 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%.

[0022] 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.

[0023] 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.

[0024] 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, “C0-C3-hydrocarbyl” includes a covalent bond, methyl, ethyl, propyl, and cyclopropyl.

[0025] 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 “C0” alkyl (as in “C0-C3-alkyl”) is a covalent bond (like “C0” hydrocarbyl).

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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, O, 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 O and/or S atoms.

[0033] 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 π 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, O, and S. A “heteroaralkyl” or “heteroarylalkyl” 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 O 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 O and/or S atoms.

[0034] 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.

[0035] 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-1,5,2-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, pyranyl, 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.

[0036] 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:

[0037] (a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino,

[0038] (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, C0-C6 N-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

[0039] (c) —(CH2), —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

[0040] 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.

[0041] 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: 1

[0042] A “halohydrocarbyl” is a hydrocarbyl moiety in which from one to all hydrogens have been replaced with one or more halo.

[0043] 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.

[0044] The term “radical” as used herein means a chemical moiety comprising one or more unpaired electrons.

[0045] 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-cyclopentyl-octyl. Included within this definition are methylenes (—CH2—) substituted with oxygen to form carbonyl —CO—).

[0046] 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.

[0047] Preferred embodiments of a particular genus of compounds of the invention include combinations of preferred embodiments. For example, paragraph [0043] identifies a preferred Ay1 and paragraph [0047] identifies preferred Ar1 (both for compound (1) of paragraph [0042]). Thus, another preferred embodiment includes those compounds of formula (1) in paragraph [0042] in which Ay1 is as defined in paragraph [0043] and Ar1 is as defined in paragraph [0047].

[0048] Compounds

[0049] 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): 2

[0050] and pharmaceutically acceptable salts thereof, wherein

[0051] R3 and R4 are independently selected from the group consisting of hydrogen, L1, Cy1, and -L1-Cy1, wherein

[0052] L1 is C1-C6 alkyl, C2-C6 heteroalkyl, or C3-C6 alkenyl; and

[0053] 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

[0054] 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, O, 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;

[0055] Y1 is selected from the group consisting of —N(R1)(R2), —CH2—C(O)—N(R1)(R2), halogen, and hydrogen, wherein

[0056] R1 and R2 are independently selected from the group consisting of hydrogen, L1, Cy1, and -L1-Cy1, wherein

[0057] L1 is C1-C6 alkyl, C2-C6 heteroalkyl, or C3-C6alkenyl; and

[0058] 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

[0059] 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, O, 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;

[0060] Y2 is a chemical bond or N(R0), where R0 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, and acyl;

[0061] 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;

[0062] Ar1 is arylene or heteroarylene, either of which optionally is substituted; and

[0063] Z1 is selected from the group consisting of 3

[0064]  wherein Ay1 is aryl or heteroaryl, which optionally is substituted.

[0065] Preferably in the compounds according to paragraph [0042], Ay1 is phenyl or thienyl, each substituted with —OH or —NH2.

[0066] More preferably in the compounds according to paragraph [0042], 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.

[0067] More preferably in the compounds according to paragraph [0042], Ay1 is ortho aniline, ortho phenol, 3-amino-2-thienyl, or 3-hydroxy-2-thienyl, and tautomers thereof.

[0068] In some preferred embodiments of the compounds according to paragraph [0042], Z1 is 4

[0069] In some preferred embodiments of the compounds according to paragraph [0042], Ar1 is phenylene. In some embodiments, Ak1 is alkylene, preferably methylene. In some preferred embodiments, Y2 is —NH—. In some preferred embodiments, Y1 is —N(R1)(R2) or —CH2—C(O)—N(R1)(R2).

[0070] In some embodiments of the compounds according to paragraph [0042], R1 and R2 are each independently selected from the group consisting of hydrogen, L1, Cy1, and -L1-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.

[0071] In some embodiments of the compounds according to paragraph [0042], 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.

[0072] As set forth above, L1 is C1-C6 alkyl, C2-C6 heteroalkyl, or C3-C6 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.

[0073] In some embodiments of the compounds according to paragraph [0042], 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, O, 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 R2 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.

[0074] In a preferred embodiment, the HDAC inhibitors of the invention comprise compounds of formula 1(a): 5

[0075] and pharmaceutically acceptable salts thereof, wherein

[0076] J is C1-C3-hydrocarbyl, —N(R20)—, —N(R20)—CH2—, —O—, or —O—CH2—;

[0077] R20 is —H or -Me;

[0078] X and Y are independently selected from —NH2, cycloalkyl, heterocyclyl, aryl, heteroaryl, and A-(C1-C6-alkyl)n-B-;

[0079] A is H, C1-C6-alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0080] B is —NH—, —O—, or a direct bond; and

[0081] n is 0 (in which case A is directly bonded to B) or 1.

[0082] Preferably in the compounds according to paragraph [0052], 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.

[0083] Preferably in the compounds according to paragraph [0052], J is —NH—CH2—, —O—CH2—, —N(CH3)—CH2—, —CH═CH—, or —CH2—CH2—.

[0084] Preferably in the compounds according to paragraph [0052], R20 is —H.

[0085] In the compounds according to paragraph [0052] X is preferably selected from

6            7
8            9
10           11
—OMe,        12
13           —NH2
14           15
16           17
18           19
and          20
and Y is preferably selected from
—NH2,        21
22           n-BuNH,
MeOCH2CH2NH, 23
24           25
26           27
28           29
—H           Me
—OMe         CH3(CH2)3NH—
and          CH3O(CH2)2—NH—.

[0086] In a more preferred embodiment of the compounds according to paragraph [0052], the HDAC inhibitors of the invention comprise the following compounds of formula 1a:

Cpd	J	X	Y
204	—NH—	30	—NH2
207	—OCH2—	31	—NH2
210	—NHCH2—	32	—H
212	—NHCH2—	—OMe	—OMe
214	—NHCH2—	33	—OMe
216	34	35	—Me
218	—NHCH2—	36	—Me
220	—CH═CH—	—NH2	—NH2—
223	—CH═CH—	37	—NH2
224	—CH2CH2—	—NH2	—NH2
470	—NHCH2—	38	NH2
471	—NHCH2—	39	40
472	—NHCH2—	41	42
473	—NHCH2—	43	n-BuNH
474	—NHCH2—	44	MeO(CH2)2NH
475	—NHCH2—	45	46
476	—NHCH2—	47	48
477	—NHCH2—	49	50
478	—NHCH2—	51	52
479	—NHCH2—	53	54
480	—NHCH2—	55	56
481	—NHCH2—	57	58
482	—NHCH2—	59	60
483	—NHCH2—	61	Me
484	—NHCH2—	62	NH2
and
485	—NHCH2—	63	64

[0087] In a second aspect, the novel histone deacetylase inhibitors of the invention are represented by formula (2): 65

[0088] and pharmaceutically acceptable salts thereof, wherein

[0089] 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;

[0090] X1 is selected from the group consisting of a covalent bond, M1-L2-M1, and L2-M2-L2 wherein

[0091] L2, at each occurrence, is independently selected from the group consisting of a chemical bond, C0-C4 hydrocarbyl, C0-C4-hydrocarbyl-(NH)—CO—C4-hydrocarbyl, C0-C4-hydrocarbyl-(S)—C0-C4-hydrocarbyl, and C0-C4-hydrocarbyl-(O)—C0-C4-hydrocarbyl, provided that L2 is not a chemical bond when X1 is M1-L2-M1;

[0092] 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

[0093] M2 is selected from the group consisting of M1, heteroarylene, and heterocyclylene, either of which rings optionally is substituted;

[0094] Ar2 is arylene or heteroarylene, each of which is optionally substituted;

[0095] R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl;

[0096] q is 0 or 1; and

[0097] 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;

[0098] 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.

[0099] In a preferred embodiment of the compounds according to paragraph [0058], when Ay2 is o-phenol optionally substituted by halo, nitro, or methyl, Ar2 is optionally substituted phenyl, X1 is —O—, —CH2—, —S—, —S—CH2—, —S(O)—, —S(O)2', —C(O)—, or —OCH2—, then Cy2 is not optionally substituted phenyl or naphthyl.

[0100] In another preferred embodiment of the compounds according to paragraph [0058], 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).

[0101] In another preferred embodiment of the compounds according to paragraph [0058], when X1 is —CH2—, Ar2 is optionally substituted phenyl, q is 1, and R6 is H, then Cy2 is not optionally substituted imidazole.

[0102] In another preferred embodiment of the compounds according to paragraph [0058], when Ar2 is amino or hydroxy substituted phenyl, X1 is C0-C8-alkyl-X1a-C0-C8-alkyl, wherein X1a is —CH2—, —O—, —S—, —NH—, —C(O)—, then Cy2 is not optionally substituted naphthyl or di- or -tetrahydronaphthalene.

[0103] In another preferred embodiment of the compounds according to paragraph [0058], when Ay2 is o-phenol, Ar2 is substituted phenyl, X1 is —O—, —S—, —CH2—, —O—CH2—, —S—CH2—, or —C(O)—, and R1 and R6 are H, then Cy2 is not optionally substituted naphthyl.

[0104] In another preferred embodiment of the compounds according to paragraph [0058], when Ay2 is o-anilinyl, q is O, Ar2 is unsubstituted phenyl, X1 is —CH2—, then Cy2 is not substituted 6-hydroimidazolo[5,4-d]pyridazin-7-one-1-yl or substituted 6-hydroimidazolo[5,4-d]pyridazine-7-thione-1-yl.

[0105] Preferably in the compounds according to paragraph [0058], Ay2 is phenyl or thienyl, each substituted with —OH or —NH2.

[0106] More preferably in the compounds according to paragraph [0058], 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.

[0107] More preferably in the compounds according to paragraph [0058], Ay2 is ortho aniline, ortho phenol, 3-amino-2-thienyl, or 3-hydroxy-2-thienyl, and tautomers thereof.

[0108] In a another embodiment, the novel histone deacetylase inhibitors of the invention are those according to paragraph [0058] wherein

[0109] q is 1;

[0110] 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

[0111] Ay2 is anilinyl, which optionally is substituted.

[0112] In some preferred embodiments of the compounds according to paragraph [0068], 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.

[0113] In some embodiments of the compounds according to paragraph [0068], Ar2 has the formula 66

[0114] wherein G, at each occurrence, is independently N or C, and C optionally is substituted. In some preferred embodiments, Ar2 has the formula 67

[0115] In some preferred embodiments of the compounds according to paragraph [0070], Ar2 is selected from the group consisting of phenylene, pyridylene, pyrimidylene, and quinolylene.

[0116] In some embodiments of the compounds according to paragraph [0068], 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-L2-M1 and M1 is selected from the group consisting of —NH—, —N(CH3)—, —S—, and —C(O)—N(H)—.

[0117] In some embodiments of the compounds according to paragraph [0068], 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., 68

[0118] 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.

[0119] In a preferred embodiment of the compounds of paragraph [0058], the invention comprises compounds of structural formula (2a): 69

[0120] and pharmaceutically acceptable salts thereof, wherein

[0121] Ara is phenyl or thienyl;

[0122] R6 is H, or C1-C6-alkyl (preferably —CH3);

[0123] Y and Z are independently —CH═ or —N═;

[0124] W is halo, (V′-L4)t-V-L3-;

[0125] L3 is a direct bond, —C1-C6-hydrocarbyl, —(C1-C3-hydrocarbyl)m1—X′—(C1-C3-hydrocarbyl)m2, —NH—(C0-C3-hydrocarbyl), (C1-C3-hydrocarbyl)-NH—, or —NH—(C1-C3-hydrocarbyl)-NH—;

[0126] m1 and m2 are independently 0 or 1;

[0127] X′ is —N(R21)—, —C(O)N(R21)—, N(R21)C(O{, —O—, or —S—;

[0128] R21 is —H, V″—(C1-C6-hydrocarbyl)c;

[0129] L4 is (C1-C6-hydrocarbyl)a-M-(C1-C6-hydrocarbyl)b;

[0130] a and b are independently 0 or 1;

[0131] M is —NH—, —NHC(O)—, —C(O)NH—, —C(O)—, —SO2—, —NHSO2—, or —SO2NH—

[0132] V, V′, and V″ are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0133] t is 0 or 1;

[0134] or W, the annular C to which it is bound, and Y together form a monocyclic cycloalkyl, heterocyclyl, aryl, or heteroaryl; and

[0135] wherein the and Ara rings are optionally further substituted with from 1 to 3 substituents independently selected from methyl, hydroxy, methoxy, halo, and amino.

[0136] In a preferred embodiment of the compound according to paragraph [0074]:

[0137] Y and Z are —CH═ and R6 is H;

[0138] W is V-L3;

[0139] L3 is —NH—CH— or —CH—NH—;

[0140] 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

[0141] Ara is phenyl and the amino moieties to which it is bound are ortho to each other.

[0142] In some preferred embodiments of the compound according to paragraph [0074], V is an optionally substituted ring moiety selected from:

70 71
72 73
74 75
76 77

[0143] In another preferred embodiment of the compounds according to paragraph [0074], W is selected from:

78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
Br—,
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147

[0144] In another preferred embodiment of the compounds according to paragraph [0074], the and Ara rings are not further substituted.

[0145] In a particularly preferred embodiment of the compounds according to paragraph [0074], 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):

Cpd	W	Y	Z	R6
481	148	CH	CH	H
484	149
492	150	CH	CH	H
493	151	CH	CH	H
494	152	CH	CH	H
495	153	CH	CH	H
496	154	CH	CH	H
497	155	CH	CH	H
498	156	CH	CH	H
499	157	CH	CH	H
500	158	CH	CH	H
501	159	CH	CH	H
502	160	CH	CH	H
503	161	CH	CH	H
504	162	CH	CH	H
505	163	CH	CH	H
506	164	CH	CH	H
507	165	CH	CH	H
508	166	CH	CH	H
509	167	CH	CH	H
510	168	CH	CH	H
511	169	CH	CH	H
512	170	CH	N	H
516	Br—	CH	CH	CH2
517	171	CH	CH	CH3
518	172	CH	CH	CH3
519	173	CH	CH	H
520	174	CH	CH	H
521	175	N	CH	H
522	176	N	CH	H
523	177	CH	CH	H
524	178	N	CH	H
525	179	N	CH	H
526	180	CH	CH	H
527	181	CH	CH	H
528	182	CH	CH	H
529	183	CH	CH	H
530	184	CH	CH	H
531	185	CH	CH	H
532	186	CH	CH	H
533	187	CH	CH	H
534	188	CH	CH	H
535	189	CH	CH	H
536	190	CH	CH	H
537	191	CH	CH	H
538	192	CH	CH	H
539	193	CH	CH	H
540	194	CH	CH	H
541	195	CH	CH	H
542	196	CH	CH	H
543	197	CH	CH	H
544	198	CH	CH	H
545	199	CH	CH	H
546	200	CH	CH	H
547	201	CH	CH	H
548	202	CH	CH	H
549	203	CH	CH	H
550	204	CH	CH	H
551	205	CH	CH	H
552	206	CH	CH	H
553	207	CH	CH	H
554	208	CH	CH	H
555	209	CH	CH	H
556	210	CH	CH	H
557	211	CH	CH	H
558	212	CH	CH	H
559	213	CH	CH	H
560	214
561	215
562	216	CH	CH	H
563	217	CH	CH	H
564	218
565	219	CH	CH	H
566	220	CH	CH	H
567	221
568	222
569	223	CH	N	H
570	224

[0146] In a preferred embodiment, the compounds of the invention comprise compounds of the formula (2b): 225

[0147] and pharmaceutically acceptable salts thereof, wherein

[0148] 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;

[0149] q is 0 or 1;

[0150] X1 is selected from —CH2—, —NH—CH2—, and —S—CH2—;

[0151] Cy2 is monocyclic or fused bicyclic aryl or heteroaryl optionally substituted with one to three substituents selected from CH3—, CH3O—, phenyl optionally substituted with one to three CH3O—, morphylinyl, morphylinyl-C1-C3-alkoxy, cyano, and CH3C(O)NH—;

[0152] provided that when Cy2 is naphthyl, X1 is —CH2—, and q is 0 or 1, Ay2 is not o-hydroxyphenyl.

[0153] Preferably in the compounds according to paragraph [0080], Ay2 is selected from: 226

[0154] Preferably in the compounds according to paragraph [0080], Cy2 is phenyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, thienyl, tetrahydroquinozolinyl, or 1,3-dihydroquinazoline-2,4-dione, each optionally substituted with one to three CH3O—. More preferably, Cy2 is phenyl substituted with one to three CH3O—.

[0155] In a third embodiment, the novel inhibitors of histone deacetylase are represented by formula (3): 227

[0156] and pharmaceutical salts thereof, wherein

[0157] Ar3 is arylene or heteroarylene, either of which optionally is substituted;

[0158] 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;

[0159] provided that when Cy3 is a cyclic moiety having —C(O)—, —C(S)—, —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

[0160] X2 is selected from the group consisting of a chemical bond, L3, W1-L3, L3-W1, W1-L3-W1, and L3-W1-L3, wherein

[0161] W1, at each occurrence, is S, O, or N(R9), where R9 is selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl; and

[0162] L3 is C1-C4 alkylene, C2-C4 alkenylene, or C2-C4 alkynylene;

[0163] provided that X2 does not comprise a —C(O)—, —C(S)—, —S(O)—, or —S(O)2— group; and further provided that when Cy3 is pyridine, then X2 is L3, W1-L3, or L3-W1.

[0164] Preferably, Ar3 has the structure: 228

[0165] wherein Q, at each occurrence, is independently N or C, and C optionally is substituted.

[0166] Preferably in the compounds according to paragraph [0083], X2 is selected from the group consisting of L3, W1-L3, L3-W1, W1-L3-W1, and L3-W1-L3

[0167] Preferably in the compounds according to paragraph [0083], when X2 is a chemical bond, then Ar3 is not 229

[0168] and Cy3 is not the radical of a substituted or unsubstituted diazepine or benzofuran.

[0169] In some embodiments of the compounds according to paragraph [0083], Q at each occurrence is C(R8), where R8 is selected from the group consisting of hydrogen, alkyl, 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.

[0170] In some embodiments of the compounds according to paragraph [0083], 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)—.

[0171] In some embodiments of the compounds according to paragraph [0083], 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, hydroxymethyl, and phenyl. Some other preferred substituents have the formula —K1—N(H)(R10), wherein

[0172] K1 is a chemical bond or C1-C4 alkylene;

[0173] R10 is selected from the group consisting of Z′ and -Ak2-Z′, wherein

[0174] Ak2 is C1-C4 alkylene; and

[0175] 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.

[0176] Examples of such preferred substituents according to paragraph [0089] include 230

[0177] In some embodiments of the compounds according to paragraph [0083], Cy3 is heterocyclyl, e.g., 231

[0178] 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.

[0179] Preferably in the compounds of paragraph [0083], when Ar4 is quinoxalinylene, then X3 is not —CH(OH)—.

[0180] In another preferred embodiment, Ar3 is 232

[0181] wherein X is —CH2—, —NH—, O, or S. Preferably Ar3 is 233

[0182] and X is S or O.

[0183] In a preferred embodiment, the novel histone deacetylase inhibitors of the invention are those according to paragraph [0058] wherein

[0184] Ay2 is ortho-anilinyl;

[0185] q is 0; and

[0186] X1 is M1-L2-M1 or L2-M2-L2.

[0187] In a preferred embodiment of the compounds according to paragraph [0094], Ar2 is aryl or heteroaryl; and Cy2-X1— is collectively selected from the group consisting of

[0188] 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)0-1—, —NHC(O)—, or —NHCH2—; and wherein B1 is phenyl or a covalent bond;

[0189] 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;

[0190] 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—;

[0191] d) A4-L4-B4—, wherein A4 is an optionally substituted aryl; wherein L4 is —NHCH2—; and wherein B4 is a thienyl group;

[0192] 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—;

[0193] f) morpholinyl-CH2—

[0194] g) optionally substituted aryl;

[0195] 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—;

[0196] 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—;

[0197] j) aptionally substituted heteroaryl or optionally substituted heterocyclyl;

[0198] k) A8L8-B8—, wherein A8 is optionally substituted phenyl; wherein L8 is a covalent bond; and wherein B8 is —O—;

[0199] l) A9-L9-B9—, wherein A9 is an optionally substituted aryl; wherein L9 is a covalent bond; and wherein B9 is a furan group;

[0200] 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—;

[0201] 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—;

[0202] o) 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—;

[0203] 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)—;

[0204] 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—;

[0205] r) F3CC(O)NH—;

[0206] 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—;

[0207] 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

[0208] u) 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 -(optionally substituted aryl-CH2)2—N—.

[0209] In another preferred embodiment of the compounds according to paragraph [0094], Cy2-X1— is collectively selected from the group consisting of

[0210] 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;

[0211] 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;

[0212] c) D3-E3—F3—, wherein D3 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E3 is —(CH2)0-2NH—; and wherein F3 is a covalent bond;

[0213] d) D4-E4—F4—, wherein D4 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E4 is —S(CH2)0-2—; and wherein F4 is a covalent bond;

[0214] 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

[0215] 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.

[0216] In a preferred embodiment, the HDAC inhibitors of the invention comprise compounds of paragraph [0058] having formula (3b): 234

[0217] and pharmaceutically acceptable salts thereof, wherein Y and Z are independently N or CH and W is selected from the group consisting of: 235236237238239240241242243244245246247248249250

[0218] In a preferred embodiment of the compounds according to paragraph [0097], the compounds comprise those wherein Y, Z and W are as defined below:

Cpd	W	Y	Z
164	251	CH	CH
165	252	N	CH
166	253	CH	CH
167	254	CH	N
168	255	CH	N
169	256	CH	CH
170	257	CH	CH
171	258	N	CH
172	259	CH	CH
174	260	CH	N
175	261	CH	N
176	262	CH	N
177	263	CH	CH
178	264	N	CH
179	265	CH	CH
180	266	CH	CH
181	267	CH	CH
182	268	CH	CH
and
183	269	CH	CH

[0219] In another preferred embodiment of the compounds according to paragraph [0097], the compounds comprise those wherein Y, Z and W are as defined below:

	Cpd	W	Y	Z
	187	270	CH	CH
	188	271	CH	CH
	189	272	CH	CH
	190	273	CH	CH
	193	274	CH	CH
	194	275	CH	CH
	195	276	CH	CH
	196	277	CH	CH
	320	278	CH	CH
	321	279	CH	CH
	322	280	CH	CH
	323	281	CH	CH
	325	282	CH	CH
	326	283	CH	CH
	327	284	CH	CH
	328	285	CH	CH
	329	286	CH	CH
	330	287	CH	CH
	331	288	CH	CH
	332	289	CH	CH
	333	290	CH	CH
	334	291	CH	CH
	335	292	CH	CH
	336	293	CH	CH
	337	294	CH	CH
	338	295	CH	CH
	339	296	CH	CH
	340	297	CH	CH
	341	298	CH	CH
	342	299	CH	CH
	343	300	CH	CH
	344	301	CH	CH
	345	302	CH	CH
	346	303	CH	CH
	347	304	CH	CH
	348	305	CH	CH
	349	306	CH	CH
	350	307	CH	CH
	351	308	CH	CH
	352	309	CH	CH
	353	310	CH	CH
	354	311	CH	CH
	355	312	CH	CH
	356	313	CH	CH
	357	314	CH	CH
	358	315	CH	CH
	359	316	CH	CH
	360	317	CH	CH
	361	318	CH	CH
	362	319	CH	CH
	363	320	CH	CH
	364	321	CH	CH
	365	322	CH	CH
	366	323	CH	CH
	367	324	CH	CH
	368	325	CH	CH
	369	326	CH	CH
	370	327	CH	CH
	371	328	CH	CH
	372	329	CH	CH
	373	330	CH	CH
	374	331	CH	CH
	375	332	CH	CH
	377	333	CH	CH
	378	334	CH	CH
	379	335	CH	CH
	380	336	N	CH
	381	337	CH	CH
	382	338	CH	CH
	383	339	CH	CH
	384	340	CH	CH
	385	341	CH	CH
	386	342	CH	CH
	387	343	CH	CH
	388	344	CH	CH
	389	345	CH	CH
	390	346	CH	CH
	391	347	CH	CH
	392	348	CH	CH
	393	349	CH	CH
	394	350	CH	CH
	395	351	CH	CH
	396	352	CH	CH
	397	353	CH	CH
	398	354	CH	N
	399	355	CH	CH
	400	356	CH	CH
	401	357	CH	CH
	402	358	CH	CH
	403	359	CH	CH
	404	360	CH	CH
	405	361	CH	CH
	406	362	CH	CH
	407	363	CH	CH
	408	364	CH	CH
	409	365	CH	CH
	410	366	CH	CH
	411	367	CH	CH
	412	368	CH	CH
	413	369	CH	CH
	414	370	CH	CH
	415	371	CH	CH
	416	372	CH	CH
	417	373	CH	CH
	418	374	CH	CH
	419	375	CH	CH
	420	376	CH	CH
	421	377	CH	CH
	422	378	CH	CH
	423	379	CH	CH
	424b	380	CH	CH
	425	381	CH	CH
	426	382	CH	CH
	427	383	CH	CH
	428	384	CH	CH
	429	385	CH	CH
	430	386	CH	CH
	431	387	CH	CH
	432	388	CH	CH
	433	389	CH	CH
	434	390	CH	CH
	435	391	CH	CH
	436	392	CH	CH
	437	393	CH	CH
	438	394	CH	CH
	439	395	CH	CH
	440	396	CH	CH
	441	397	CH	CH
	442	398	CH	CH
	443	399	CH	CH
	444	400	CH	CH
	445	401	CH	N
	446	402	CH	N
	447	403	CH	CH
	448	404	CH	CH
	449	405	CH	CH
	450	406	CH	CH
	451	407	CH	CH
	452	408	CH	CH
	453	409
	454	410
	455	411	CH	CH
	456	412	CH	CH
	457	413
	458	414	CH	CH
	459	415	CH	CH
	460	416	CH	N
	461	417	CH	CH
	462	418	CH	CH
	463	419	N	CH
	464	420	N	CH
	465	421	CH	CH
	466	422	CH	CH
	467	423	CH	CH
	468	424	CH	CH
	700	425	CH	CH

[0220] In yet another a preferred embodiment, the novel histone deacetylase inhibitors of the invention are selected from the group consisting of the following and their pharmaceutically acceptable salts: 426427428429430

[0221] In another preferred embodiment, the compounds are selected from those listed in Tables 2a-b, 3a-d, 4a-c, and 5a-5f.

Synthesis

[0222] 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 diusopropylethylamine 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.

[0223] Alternatively, dichloroaminbtriazine 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.

[0224] 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. 431

[0225] 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 diusopropylethylamine; followed by lithium hydroxide; followed by BOP reagent, phenylenediamine, triethylamine, and DMF. 432

[0226] 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, diusopropylethylamine, and phenylenediamine under carbon monoxide yields anilinyl amide XVII or XVIII, respectively.

[0227] 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. 433

[0228] 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 carbonyldulmidazole (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. 434

[0229] 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, and diisopropylethylamine in DMF affords nitroanilide XXXI. Nitroanilide XXXI is converted to the corresponding anilinyl amide XXXII by treatment with stannous chloride in methanol and water.

[0230] 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. 435

[0231] 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. 436

[0232] Compounds of formula (2), wherein X1 comprises 437

[0233] or —C(O)—NH—, preferably 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 XLI, respectively. Anilinyl amide XLII or XLIII is then prepared using procedures analogous to those set forth in Schemes 3-6 above. 438

[0234] 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. 439

[0235] 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 LII. 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. 440

[0236] 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. 441

[0237] 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. 442

[0238] 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 anilinylamide LXVIII is prepared using procedures analogous to those set forth in Schemes 3 and 5 above. 443

[0239] 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. 444

[0240] 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 diusobutylaluminum 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. 445

[0241] Compounds of formula (3), wherein X2 is a chemical bond, preferably may be prepared according to the synthetic route depicted in Scheme 15. Thus, chloroarylanilinylamide LXXVII is treated with aryl boronic acid, benzene, ethanol, aqueous sodium carbonate, and triphenylphosphine palladium to afford the diarylanilinylamide LXXVIII. 446

[0242] Compounds such as LXXXI preferably may be prepared according to the procedues illustrated in Scheme 16. Thus, benzene-1,2-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. 447

[0243] 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.

[0244] The addition of 4-(2-aminoethyl)phenol to phthalic anhydride LXXXV in acetic acid affords the hydroxyl compound LXXXVII. The hydroxyl 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. 448

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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. 449

[0249] 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. 450

[0250] 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 CI is treated according to procedures analogous to those described for Scheme 15 above afford the diarylanilinylamide CII. The aldehyde moiety in CII 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 CIII using procedures analogous to those set forth in Scheme 3 above. 451

[0251] 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 CI 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. 452

[0252] 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 diisopropylethylamine 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. 453

[0253] 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. 454

[0254] 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. 455

[0255] Compounds such as CXVIII 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. 456

[0256] 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. 457

[0257] 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.

[0258] Consecutive treatment of acetyl acetone with methyl bromomethylbenzoate in the presence of NaOMe and a 1:1 mixture AcOH—HCl (conc.) afforded the intermediate acid CXXIV. This keto-acid 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. 458

[0259] 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. 459

[0260] 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

[0261] 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.

[0262] 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 ingredient(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.

[0263] 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).

[0264] 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 mg/kg 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

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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, Fla.) 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.

[0269] 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.

[0270] 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 G1 or G2 phase of the cell cycle. Such synchronization allows, for example, the identification of gene and/or gene products expressed during the G1 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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 μM to about 100 μM, more preferably from about 0.05 μM to about 50 μM, still more preferably from about 0.1 μM to about 25 μM, and still yet more preferably from about 0.5 μM to about 25 μM. 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.

[0278] 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, HDAC-4, 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).

[0279] 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.

[0280] 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.

[0281] Particularly preferred antisense oligonucleotides utilized in this aspect of the invention include chimeric oligonucleotides and hybrid oligonucleotides.

[0282] 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. Pat. 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.

[0283] 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. Pat. No. 5,652,355).

[0284] 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.

[0285] 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).

[0286] 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.

	TABLE 1
	position
		Accession	Nucleotide		within
Oligo	Target	Number	Position	Sequence	Gene
HDAC1 AS1	Human HDAC1	U50079	1585-1604	5′-GAAACGTGAGGGACTCAGCA-3′	3′-UTR
HDAC1 AS2	Human HDAC1	U50079	1565-1584	5′-GGAAGCCAGAGCTGGAGAGG-3′	3′-UTR
HDAC1 MM	Human HDAC1	U50079	1585-1604	5′-GTTAGGTGAGGCACTGAGGA-3′	3′-UTR
HDAC2 AS	Human HDAC2	U31814	1643-1622	5′-GCTGAGCTGTTCTGATTTGG-3′	3′-UTR
HDAC2 MM	Human HDAC2	U31814	1643-1622	5′-CGTGAGCACTTCTCATTTCC-3′	3′-UTR
HDAC3 AS	Human HDAC3	AF039703	1276-1295	5′-CGCTTTCCTTGTCATTGACA-3′	3′-UTR
HDAC3 MM	Human HDAC3	AF039703	1276-1295	5′-GCCTTTCCTACTCATTGTGT-3′	3′-UTR
HDAC4 AS1	Human HDAC4	AB006626	514-33	5-GCTGCCTGCCGTGCCCACCC-3′	5′-UTR
HDAC4 MM1	Human HDAC4	AB006626	514-33	5′-CGTGCCTGCGCTGCCCACGG-3′	5′-UTR
HDAC4 AS2	Human HDAC4	AB006626	7710-29	5′-TACAGTCCATGCAACCTCCA-3′	3′-UTR
HDAC4 MM4	Human HDAC4	AB006626	7710-29	5′-ATCAGTCCAACCAACCTCGT-3′	3′-UTR
HDAC5 AS	Human HDAC5	AF039691	2663-2682	5′-CTTCGGTCTCACCTGCTTGG-3′	3′-UTR
HDAC6 AS	Human HDAC6	AJ011972	3791-3810	5′-CAGGCTGGAATGAGCTACAG-3′	3′-UTR
HDAC6 MM	Human HDAC6	AJ011972	3791-3810	5′-GACGCTGCAATCAGGTAGAC-3′	3′-UTR
HDAC7 AS	Human HDAC7	AF239243	2896-2915	5′-CTTCAGCCAGGATGCCCACA-3′	3′-UTR
HDAC8 AS1	Human HDAC8	AF230097	51-70	5′-CTCCGGCTCCTCCATCTTCC-3′	5′-UTR
HDAC8 A52	Human HDAC8	AF230097	1328-1347	5′-AGCCAGCTGCCACTTGATGC-3′	3′-UTR

[0287] 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.

EXAMPLES

[0288] 460

Example 1

[0289] 4-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)-benzamide (Compound 8)

[0290] Step 1: Methyl-4-[(4,6-dichloro-[1,3,5]triazin-2-yl-amino)-methyl]-benzoate (Compound 3)

[0291] 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.HCl 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 NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, 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, CDCl3) δ (ppm): AB system (δA=8.04, δB=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

[0292] Step 2: Methyl-4-[(4-amino-6-chloro-[1,3,5]triazin-2-yl-amino)-methyl]-benzoate (Compound 4)

[0293] 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 NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH2Cl2: 30/70) to afford the title compound 4 (5.16 g, 17.57 mmol, 91% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ (ppm): AB system (δA=8.01, δB=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

[0294] Step 2: Methyl 4-[(4-chloro-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino)-methyl]-benzoate (Compound 5)

[0295] 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.HCl (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 NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, 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, CDCl3) δ (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), 4.92-4.54 (m, 3H), 3.92 (bs, 3H), 3.41-3.12 (m, 2H), 2.90-2.70 (m, 2H).

[0296] Step 3: Methyl-4-[(4-amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino)-methyl]-benzoate (Compound 6) General Procedure for the Amination with NH3 Gas:

[0297] 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 NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2Cl2: 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, CDCl3) δ (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, CDCl3) δ (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.

[0298] Pathways A and B, Step 3, General Procedure with Primary and/or Secondary Amines:

[0299] 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 NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, 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.

[0300] Step 4: 4-[(4-Amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino)-methyl]-benzoic acid (Compound 7)

[0301] To a stirred solution at room temperature of 6 (2.07 g, 5.30 mmol) 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 HCl 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) δ (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), 4.85-4.60 (m, 4H), 3.40-2.80 (m, 4H). HRMS (calc.): 376.1648, (found): 376.1651.

[0302] Step 5: 4-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)-benzamide (Compound 8)

[0303] 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 μl, 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 μl, 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 NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2Cl2: 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) δ (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), 4.80-4.50 (m, 4H), 3.30-3.08 (m, 2H), 2.96-2.74 (m, 2H).

ExampleS 2-28

[0304] 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
461
Ex.	Cpd	Y	X	Name	Characterization	Schm
2	9	462	NH2	4-[(4-amino-6- morpholin-4-yl-[1,3,5]- triazin-2-ylamino)- methyl]-N-(2- amino-phenyl)- benzamide	1H NMR (CDCl3) δ (ppm): 8.02 (s, 1H), 7.79 (d, J=8.0Hz, 2H), 7.34 (d, J=8.0Hz, 2H), 7.31 (m, 1H), 7.08 (dt, J=7.6Hz, 1.5Hz, 1H), 6.82 (t, J=6.7Hz, 2H), 5.62 (t, J=5.9Hz, 1H), 4.90 (bs, 2H), 4.61 (d, J=6.0Hz, 2H), 3.75-3.62 (m, 10H).	1A
3	10	463	NH2	4-{[4-amino-6-(1- indanyl-amino)- [1,3,5]-triazin-2- ylamino]-methyl}-N-(2- amino-phenyl)- benzamide	1H NMR (acetone-d6) δ (ppm): 9.07 (bs, 1H), 8.05-7.95 (m, 2H), 7.55-7.45 (m, 2H), 7.37-7.10 (m, 5H), 7.04 (dt, J=7.6Hz, 1.6Hz, 1H), 6.90 (dd, J=8.0Hz, 1.4Hz, 1H), 6.71 (dt, J=7.6Hz, 1.4Hz, 1H), 6.65-5.55 (m, 5H), 4.75-4.60 (m, 3H),
# 3.05-2.75 (m, 2H), 2.60-2.45 (m, 1H)), 2.00-1.84 (m, 1H). HRMS (calc.): 466.2229, (found): 466.2225	1A
4	11	464	NH2	N-(2-Amino-phenyl)- 4-{[4-amino-6-(4-phenyl- piperazin-1-yl)- [1,3,5]triazin-2-ylamino]- methyl}-benzamide	1H NMR (acetone-d6) δ (ppm): mixture of rotamers, 9.05-9.00 (m, 1H), 7.98 (d, J=8.8Hz, 2H), 7.93 (s), 7.84 (d, J=8.0Hz), 7.72 (d, J=8.2Hz), 7.58-7.40 (m, 3H), 7.31-7.19 (m, 3H), 7.12-7.05 (m), 6.98 (d, J=8.1Hz, 2H), 6.86 (d, J=8.2Hz, 1H),
# 6.80 (t, J=7.1Hz, 1H), 6.67 (t, J=7.7Hz, 1H), 6.57-6.50 (m, 1H), 5.78-5.60 (m, 2H), 4.67-4.64 (m, 2H), 3.88-3.84 (m, 4H), 3.14 (s, 4H). HRMS (calc.): 477.2389 [M+—NH4], (found): 477.2383	1A
5	12	465	NH2	4-{[4-amino-6-(2- pyridinyl-methyl-amino)- [1,3,5]-triazin-2- ylamino]-methyl}-N-(2- amino-phenyl)- benzamide	1H NMR (acetone-d6) δ (ppm): 9.08 (bs, 1H), 8.51 (bs, 1H), 8.05-7.90 (m, 2H), 7.80-7.60 (m, 1H), 7.55-7.15 (m, 5H), 7.04 (dt, J=7.6Hz, 1.6Hz, 1H), 6.90Hz, (dd, J=8.0Hz, 1.4Hz, 1H), 6.71 (dt, J=7.6Hz, 1.4Hz, 1H), 6.85-6.55 (m, 1H),
# 5.84 (bs, 2H), 4.75-4.60 (m, 4H). HRMS (calc.): 441.2025, (found): 441.2029	1A
6	13	466	467	4-{[4,6-bis-(2-indanyl- amino)-[1,3,5]-triazin-2- ylamino]-methyl}-N-(2- amino-phenyl)- benzamide	1H NMR (acetone-d6) δ (ppm): 9.08 (bs, 1H), 8.05-7.95 (m, 2H), 7.56-7.44 (m, 2H), 7.34 (bd, J=7.7Hz, 7.27-7.10 (m, 8H), 7.04 (td, J=7.6Hz, 1.4Hz, 1H), 6.90 (dd, J=8.0Hz, 1.4Hz, 1H), 6.71 (dt, J=7.6Hz, 1.4Hz, 1H), 6.65-5.90 (m, 3H),
# 4.90-4.58 (m, 6H), 3.40-2.80 (m, 4H). HRMS (calc.): 582.2855, (found): 582.2838	1B
7	14	468	NH2	4-{[4-Amino-6-(9H- fluoren-9-ylamino)- [1,3,5]triazin-2-ylamino]- methyl}-N-(2-amino- phenyl)-benzamide	1H NMR (acetone-d6) δ (ppm): 9.05-9.00 (m, 1H), 8.03-7.87 (m, 2H), 7.80-7.70 (m, 2H), 7.63-7.20 (m, 9H), 7.00 (t, 1H), 6.86 (d, 1H), 6.66 (t, 1H), 6.50-5.50 (m, 6H), 4.75-4.55 (m, 3H). HRMS (calc.): 514.2229, (found): 514.2232	1B
8	15	469	NH2	N-(2-amino-phenyl)-4- [(4-amino-6-piperidin- 1-yl-[1,3,5]-triazin-2- ylamino)-methyl]- benzamide	1H NMR (CDCl3) δ (ppm): 7.96 (bs, 1H), 7.81 (d, J=8.0Hz, 2H), 7.38 (d, J=8.0Hz, 2H), 7.32 (d, J=8.0Hz, 1H), 7.08 (dt, J=7.7Hz, 1.4Hz, 1H), 6.83 (t, J=6.6Hz, 2H), 5.47 (bs, 1H), 4.80 (bs, 2H), 4.60
# (d, J=6.0Hz, 2H), 3.88 (bs, 2H), 3.67 (t, J=5.2Hz, 4H), 1.66-1.58 (m, 2H,), 1.56-1.48 (m, 4H).	1A
9	16	470	NH2	4-[(4-amino-6- cyclopentyl-amino- [1,3,5]-triazin-2-yl- amino)-methyl]-N-(2- amino-phenyl)- benzamide	1H NMR (CDCl3) δ (ppm): 7.97 (bs, 1H), 7.82 (d, J=8.0Hz, 2H), 7.39-7.34 (m, 3H), 7.10 (dt, J=7.6Hz, 1.4Hz, 1H), 6.85 (t, J=7.0Hz, 2H), 5.56 (bs, 1H), 4.90 (bs, 3H), 4.62 (s, 2H), 4.25-4.19 (m, 1H) 3.88 (bs, 2H), 1.95 (m, 2H), 1.71-1.59 (m, 4H), 1.43-1.37
# (m, 2H).	1A
10	17	471	NH2	(1R)-4-{[4-amino-6-(2- exo-fenchyl-amino)- [1,3,5]-triazin-2- ylamino]-methyl}-N-(2- amino-phenyl)- benzamide	1H NMR (acetone-d6) δ (ppm): 9.08 (bs, 1H), AB system (δA = 8.00, δB = 7.51, J=8.0Hz, 4H), 7.33 (bd, J=7.7Hz, 1H), 7.03 (ddd, J=8.0Hz, 7.3Hz, 1.4Hz, 1H), 6.90 (dd, J=8.0Hz, 1.4Hz, 1H), 6.71 (dt, J=7.6Hz, 1.4Hz, 1H),
# 6.60-6.28 (m, 1H), 5.80-5.20 (m, 3H), 4.67 (bs, 4H), 3.87 (bd, J=9.1Hz, 1H), 1.80-1.60 (m, 4H), 1.56-1.42 (m, 1H), 1.34-1.00 (m including 2s, 8H), 0.84 (s, 3H). HRMS (calc.): 486.2855, (found): 486.2844	1A
11	18	472	473	4-{[4-allyl-amino-6-(2- indanyl-amino)-[1,3,5]- triazin-2-ylamino]- methyl}-N-(2-amino- phenyl)-benzamide	1H NMR (acetone-d6) δ (ppm): 9.07 (bs, 1H), 8.00 (bd, J=7.4Hz, 2H), 7.58-7.42 (m, 2H), 7.34 (bd, J=8.0Hz, 1H), 7.27-7.10 (m, 4H), 7.04 (td, J=7.6Hz, 1.5Hz, 1H), 6.90 (dd, J=8.0, 1.4Hz, 1H), 6.71 (dt, J=7.6Hz, 1.4Hz, 1H),
# 6.60-5.70 (m, 3H), 5.26-5.00 (m, 2H), 4.86-4.54 (m, 4H), 4.10-3.90 (m, 2H), 3.38-3.10 (m, 2H), 3.00-2.80 (m, 2H). HRMS (calc.): 506.2542, (found): 506.2533	1B
12	19	474	475	4-{[4-allyl-amino-6-(2- 6-(2-indanyl-amino)- [1,3,5]-triazin-2- ylamino]-methyl}-N-(2- amino-phenyl)- benzamide	1H NMR (acetone-d6) δ (ppm): 9.07 (bs, 1H), 8.00 (bd, J=7.7Hz, 2H), 7.60-7.40 (m, 2H), 7.33 (dd, J=7.8Hz, 1.3Hz, 1H), 7.28-7.10 (m, 4H), 7.04 (dt, J=7.6Hz, 1.5Hz, 1H), 6.90 (dd, J=7.8Hz, 1.4Hz, 1H), 6.71 (dt, J=7.6Hz, 1.3Hz, 1H),
# 6.67-5.80 (m, 2H), 4.90-4.50 (m, 4H), 3.40-3.10 (m, 2H), 3.05-2.70 (m, 3H), 0.75-0.43 (m, 4H). HRMS (calc.): 506.2542, (found): 506.2548	1B
13	20	476	NH2	4-[(4-Amino-6- phenethylamino- [1,3,5]triazin-2-ylamino)- methyl]-N-(2-amino- phenyl)-benzamide	1H NMR (acetone-d6) δ (ppm): 9.03 (s, 1H), 7.97 (d, J=7.7Hz, 2H), 7.55-7.40 (m, 2H), 7.35-7.10 (m, 6H), 6.99 (td J=8.0Hz, 1.3Hz, 1H), 6.86 (dd, J=8.0Hz, 1.3Hz, 1H), 6.67 (dt, J=8.0Hz, 1.4Hz, 1H),
# 6.62-5.40 (m, 5H), 4.75-4.45 (m, 3H), 3.59-3.45 (m, 2H), 2.95-2.70 (m, 2H). HRMS (calc.): 454.2229, (found): 454.2235	1A
14	21	477	NH2	N-(2-Amino-phenyl)-4- {[4-amino-6-(3,4,5- trimethoxy- phenylamino)- [1,3,5]triazin-2-ylamino]- methyl}-benzamide	1H NMR (CDCl3/MeOD) δ (ppm): 7.72 (d, J=8.2Hz, 2H), 7.21 (d, J=8.2Hz, 2H), 7.04 (d, J=7.7Hz, 1H), 6.91 (td, J= 7.7Hz, 1.2Hz, 1H), 6.70-6.61 (m, 4H), 4.61 (bs, 2H), 3.58-3.52 (m, 9H).	1B
15	22	478	NH2	4-{[4-Amino-6-(2,3- dihydro-indol-1-yl)- [1,3,5]triazin-2-ylamino]- methyl}-N-(2-amino- phenyl)-benzamide	1H NMR (CDCl3/MeOD) δ (ppm): 8.06 (bs, 1H), 7.82 (d, J=8.0Hz, 2H), 7.37 (d, J=8.2Hz, 2H), 7.13 (d, J=7.4Hz, 1H), 7.06 (d, J=7.4Hz, 1H), 7.02-6.96 (m, 2H), 6.84-6.71 (m, 3H), 4.61 (bs, 2H), 4.03 (t, J=8.5Hz, 2H), 3.02 (t, J=8.5Hz, 2H).	1B
16	23	479	NH2	4-({4-Amino-6-[2-(2- methoxy-phenyl)- ethylamino]- [1,3,5]triazin-2- ylamino}-methyl)-N-(2- amino-phenyl)- benzamide	1H NMR (acetone-d6) δ (ppm): mixture of rotamers, 9.06 (s, 1H), 7.96 (d, J=8.0Hz, 2H), 7.55-7.40 (m, 2H), 7.28 (d, J=7.4Hz, 1H), 7.21-6.70 (m, 6H), 6.67 (t, J=7.4Hz, 1H), 6.60-5.70 (m, 5H), 4.75-4.55 (m, 3H),
# 3.81 (s, 3H), 3.55-3.45 (m, 2H), 2.90-2.78 (m, 2H). HRMS (calc.): 484.2335, (found): 484.2331	1A
17	24	480	NH2	4-({4-Amino-6-[2-(2- fluoro-phenyl)- ethylamino]- [1,3,5]triazin-2- ylamino}-methyl)-N-(2- amino-phenyl)- benzamide	1H NMR (acetone-d6) δ (ppm): mixture of rotainers, 9.03 (s, 1H), 7.97 (d, J=8.0Hz, 2H), 7.55-7.40 (m, 2H), 7.38-7.17 (m, 2H), 7.17-6.95 (m, 4H), 6.86 (dd, J=8.0Hz, 1.4Hz, 1H), 6.67 (t, J=7.0Hz, 1H), 6.50-5.60 (m, 5H),
# 4.75-4.55 (m, 3H), 3.60-3.52 (m, 2H), 2.95-2.85 (m, 2H). HRMS (calc.): 472.2135, (found): 472.2146	1A
18	25	481	482	4-{[4-benzyl-amino-6-(2- indanyl-amino)-[1,3,5]- triazin-2-ylamino]- methyl}-N-(2-amino- phenyl)-benzamide	1H NMR (acetone-d6) δ (ppm): 9.06 (bs, 1H), 8.04-7.93 (m, 2H), 7.57-7.12 (m, 12H), 7.04 (td, J=7.6Hz, 1.5Hz, 1H), 6.91 (dd, J=8.0Hz, 1.1Hz, 1H), 6.72 (bt, J=7.6Hz, 1H), 6.68-5.90 (m, 3H), 4.84-4.50 (m, 7H),
# 3.35-3.13 (m, 2H), 3.00-2.80 (m, 2H). HRMS (calc.): 556.2699, (found): 556.2706	1B
19	26	483	484	N-(2-Amino-phenyl)-4- [(4,6-di-piperidin-1-yl- [1,3,5ltriazin-2-ylamino)- methyl]-benzamide	1H NMR: (CDCl3) δ (ppm): 7.83 (d, J=8.2Hz, 3H), 7.44 (d, J=8.2Hz, 2H), 7.32 (d, J=7.4, 1H), 7.12-7.06 (m, 1H), 6.87-6.82 (m, 2H), 5.11 (t, J=6.2Hz, 1H), 4.64 (d, J=6.3Hz, 2H), 3.87 (bs, 2H), 3.69 (t, J=5.4Hz, 8H), 1.63-1.53 (m, 12H).	1B
20	27	485	486	4-{[6-(2-indanyl-amino)- 4-phenethyl-amino- [1,3,5]-triazin-2- ylamino]-methyl}-N-(2- amino-phenyl)- benzamide	1H NMR (acetone-d6) δ (ppm): 9.07 (bs, 1H), 8.05-7.90 (m, 2H), 7.60-7.40 (m, 2H), 7.35-7.05 (m, 10H), 7.04 (td, J=7.6Hz, 1.5Hz, 1H), 6.90 (d, J=7.7Hz, 1H), 6.71 (t, J=7.3Hz, 1H), 6.60-5.70 (m, 3H), 4.95-4.50 (m, 5H),
# 3.70-2.80 (m, 8H). HRMS (calc.): 552.2750 [M+—NH4], (found): 552.2746	1B
21	28	487	NH2	4-{[4-benzyl-amino-6-(2- indanyl-amino)-[1,3,5]- triazin-2-ylamino]- methyl}-N-(2-amino- phenyl)-benzamide	1H NMR (CDCl3) δ (ppm): 7.83 (d, J=8.2Hz, 3H), 7.44 (d, J=8.2Hz, 2H), 7.32 (d, J=7.4, 1H), 7.12-7.06 (m, 1H), 6.87-6.82 (m, 2H), 5.11 (t, J=6.2Hz, 1H), 4.64 (d, J=6.3Hz, 2H), 3.87 (bs, 2H), 3.69 (t, J=5.4Hz), 1.63-1.53 (m, 12H).	1A
22	29	488	NH2	4-[(4-Amino-6- benzylamino- [1,3,5]triazin-2-ylamino)- methyl]-N-(2-amino- phenyl)-benzamide	1H NMR (acetone-d6) δ (ppm): 9.04 (s, 1H), 7.95 (d, J=7.3Hz, 2H), 7.45 (d, J=7.1Hz, 2H), 7.38-7.15 (m, 6H), 7.00 (td, J=8.0Hz, 1.5Hz, 1H), 6.86 (dd, J=8.0Hz, 1.4Hz, 1H), 6.67 (dt, J=8.0Hz, 1.4Hz, 1H), 6.67-6.25 (m, 3H), 5.85-5.55 (m, 3H),
# 4.61 (d, J=6.3Hz, 2H), 4.54 (d, J=5.2Hz, 2H). HRMS (calc.): 440.2073, (found): 440.2078	1A
23	30	489	490	4-{[6-(2-indanyl-amino)- 4-(3-pyridinyl-methyl- amino)-[1,3,5]-triazin-2- ylamino]methyl}-N-(2- amino-phenyl)- benzamide	1H NMR (acetone-d6) δ (ppm): mixture of rotamers, 9.20-9.00 (m, 1H), 8.70-8.35 (m, 2H), 8.05-7.90 (m, 2H), 7.85-7.55 (m, 1H), 7.55-7.10 (m, 8H), 7.04 (dt, J=7.6Hz, 1.5Hz, 1H), 6.91 (bd, J=7.4Hz, 1H), 6.71
# (bt, J=7.3Hz, 1H), 6.80-6.00 (m, 3H), 4.84-4.50 (m, 7H), 3.34-3.12 (m, 2H), 3.00-2.80 (m, 2H). HRMS (calc.): 539.2546 [M+—NH4], (found): 539.2533	1B
24	31	491	492	N-(2-Amino-phenyl)-4- [(4-piperidin-1-yl-6- pyrrolidin-1-yl- [1,3,5]triazin-2-ylamino)- methyl]-benzamide	1H NMR (CDCl3) δ (ppm): 7.89 (bs, 1H,), 7.82 (d, J=8.2Hz, 2H), 7.42 (d, J=8.0Hz, 2H), 7.32 (d, J=8.0Hz, 1H), 7.09 (dt, J=7.7Hz, 1.6Hz, 1H), 6.87-6.82 (m, 2H), 4.83 (bs, 1H), 4.62 (d, J=6.0Hz, 2H),
# 4.24 (m, 1H), 388 (bs, 1H), 2.04-1.96 (m, 2H), 1.70-1.52 (m, 10H), 1.46-1.38 (m, 2H).	1B
25	32	493	494	N-(2-Amino-phenyl)-4- {[2-piperidin-1-yl-6-(2- pyrrolidin-1-yl- ethylamino)-pyrimidin-4- ylamino]-methyl}- benzamide	1H NMR (CDCl3) δ (ppm): 8.27 (bs, 1H), 7.74 (d, J=7.4Hz, 2H), 7.29 (m, 3H), 7.05 (dt, J=7.6Hz, 1.4Hz, 1H), 6.81-6.76 (m, 2H), 5.62 (bs, 2H), 4.57 (bs, 2H), 3.91 (bs, 2H), 3.69 (m, 4H), 3.45 (m, 2H), 2.57 (t, J=6.2Hz, 2H),
# 2.47 (m, 4H), 1.71 (m, 4H), 1.59-1.50 (m, 6H).	1B
26	33	495	496	4-{[6-(2-indanyl-amino)- 4-morpholin-4-yl-[1,3,5]- triazin-2-ylamino]- methyl}-N-(2-amino- phenyl)-benzamide	1H NMR (acetone-d6) δ (ppm): 9.07 (bs, 1H), 8.08-7.95 (m, 2H), 7.60-7.43 (m, 2H), 7.33 (d, J=8.0Hz, 1H), 7.28-7.12 (m, 4H), 7.04 (dt, J=7.6Hz, 1.4Hz, 1H), 6.91 (d, J=7.4Hz, 1H), 6.72 (t, J=7.4Hz,
# 1H), 6.55-6.05 (m, 2H), 4.86-4.60 (m, 5H), 3.80-3.56 (m, 8H), 3.38-3.12 (m, 2H), 3.04-2.82 (m, 2H).	1B
27	34	497	498	N-(2-Amino-phenyl)-4- {[2-piperidin-1-yl-6-(2- pyrrolidin-1-yl- ethylamino)-pyrimidin-4- ylamino]-methyl}- benzamide	1H NMR (acetone-d6) δ (ppm): 9.08 (bs, 1H), 8.01 (bd, J=7.4Hz, 2H), 7.56-7.43 (m, 2H), 7.33 (bd, J=8.0Hz, 1H), 7.28-7.12 (m, 4H), 7.04 (dt, J=7.6Hz, 1.4Hz, 1H), 6.90 (dd, J=8.0Hz,
# 1.4Hz, 1H), 6.71 (dt, J=7.6Hz, 1.4Hz, 1H), 6.65-5.75 (m, 2H), 4.90-4.58 (m, 5H), 3.66-2.34 (m, 16H).	1B
28	35	499	NH2	4-({4-Amino-6-[2-(1H- indol-3-yI)-ethylamino]- [1,3,5]triazin-2- ylamino}-methyl)-N-(2- amino-phenyl)- benzamide	1H NMR (acetone-d6) δ (ppm): 10.00 (s, 1H), 9.13 (s, 1H), 7.93 (d, J=8.0Hz, 2H), 7.70-7.50 (m, 1H), 7.50-7.22 (m, 4H), 7.18-6.91 (m, 4H), 6.85 (d, J=7.1Hz, 1H), 6.67 (t, J=7.4Hz, 1H),
# 6.40-5.90 (m, 3H), 4.75-4.50 (m, 2H), 4.37 (s, 2H), 3.62 (d, J=6.3Hz, 2H), 2.99 (s, 2H).	1A

[0305]

TABLE 2b
500
Ex.	Cpd	X	Y	Name	Characterization	Schm
329	470	501	NH2	4-{[4-amino-6- (3-phenyl-propyl-1- amino)- [1,3,5]triazin-2-yl- amino]-methyl}-N- (2-amino-phenyl)- benzamide	1 H NMR (300MHz, acetone-d6) δ (ppm): 9.03 (s, 1H), 7.96 (d, J=8.2Hz, 2H), 7.46 (d, J=7.7Hz, 2H), 7.35-7.10 (m, 6H), 7.00 (t, J=7.7Hz, 1H), 6.86(d, J=8.0Hz, 1H), 6.67 (t, J=7.7Hz, 1H), 6.60-5.40 (m, 6H), 4.62 (s, 2H),
# 3.35 (dd, J=12.1, 6.9 Hz, 2H), 2.75-2.60 (m, 2H), 1.95-1.80 (m, 2H).	1A
330	471	502	503	N-(2-amino- phenyl)-4-[(4- cyclopropyl-amino- 6-phenethyl-amino- [1,3,5]triazin-2-yl- amino)-methyl]- benzamide	1 H NMR (300MHz, acetone-d6) δ (ppm): 9.04 (s, 1H), 7.96 (d, J=8.0Hz, 2H), 7.55-7.40 (m, 2H), 7.35-7.10 (m, 6H), 6.98 (t, J=7.4Hz, 1H), 6.85 (d, J=6.9Hz, 1H), 6.66 (t, J=7.3Hz, 1H), 6.20-5.50 (m, 3H), 4.80-4.50 (m, 4H),
# 3.65-3.45 (m, 2H), 3.00-2.60 (m, 2H), 0.80-0.40 (m, 4H).	1B
331	472	504	505	N-(2-amino- phenyl)-4-{[4- cyclopropyl- methylamino-6-(2- indanyl-amino)- [1,3,5]-triazin-2-yl- amino]-methyl}- benzamide	1 H NMR (300MHz, acetone-d6) δ (ppm): 9.06 (bs, 1H), 8.00 (bd, J=7.1, 2H), 7.50 (bs, 1H),), 7.33 (d, J=6.6Hz, 1H), 7.28-7.07 (m, 4H), 7.03 (td, J=7.6, 1.5Hz, 1H), 6.90 (dd, J=8.0, 1.4Hz, 1H), 6.71 (td, J=7.6, 1.4Hz, 1H), 6.55-5.70 (m, 3H),
# 4.90-4.50 (m, 5H), 3.40-2.80 (m, 6H), 1.07 (bs, 1H), 0.44 (bs, 2H), 0.23 (bs, 2H).	1B
332	473	506	n-BuNH	N-(2-amino- phenyl)-4-[(4- n-butyl-amino-6- phenethyl-amino- [1,3,5]triazin-2- yl-amino)-methyl]- benzamide	1 H NMR (300MHz, CDCl3) δ (ppm): 8.08 (s, 1H), 7.83 (d, J=6.6Hz, 2H), 7.45-7.05 (m, 8H), 7.08 (td, J=7.8, 1.5Hz, 1H), 6.84 (t, J=8.1Hz, 2H), 6.70-5.00 (m, 3H), 4.70-4.50 (m, 2H), 3.65-3.50 (m, 2H), 3.45-3.25 (m, 2H), 2.40-2.25 (m, 2H),
# 1.60-1.45 (m, 2H), 1.45-1.00 (m, 2H), 1.00-0.8 (m, 3).	1B
333	474	507	MeOCH2CH2NH	N-(2-amino- phenyl)-4-{[4- (2-methoxy-ethyl-1- amino)-6-phenethyl- amino- [1,3,5]triazin-2-yl- amino]-methyl}- benzamide	1 H NMR (300MHz, acetone-d6) δ (ppm): 9.02 (s), 8.58 (s), 8.40 (dd, J=7.2, 2Hz, 1H), 1.97 (d, J=7.5Hz, 1H), 7.51-7.40 (m, 2H), 7.70-6.90 (in, 7H), 6.86 (dd, J=8.1, 1.2Hz), 6.76 (dd, J=7.5, 1.8Hz), 6.67 (td, J=7.8, 1.5Hz),
# 6.60-5.50 (m, 3H), 4.75-4.55 (m, 4H), 3.65-3.35 (m, 6H), 3.35-3.20 (s, 3H), 2.95-2.75 (m, 2H).	1B
334	475	508	509	N-(2-amino- phenyl)-4-{[4- (4-chloro-phenethyl- amino)-6- cyclopropyl-amino- [1,3,5]triazin-2- yl-amino]-methyl}- benzamide	1 H NMR (300MHz, acetone-d6) δ (ppm): 9.02 (s, 1H), 8.02-7.91 (m, 2H), 7.58-7.40 (m, 2H), 7.28 (s, 4H), 7.20-7.05 (m, 1H), 6.99 (td, J=7.5, 1.8Hz, 1H), 6.86 (d, J=7.8Hz, 1H), 6.67 (t, J=6.9Hz, 6.60-5.60 (m, 3H),
# 4.75-4.50 (m, 4H), 3.65-3.40 (bs, 2H), 2.95-2.65 (m, 2H), 0.75-0.55 (m, 2H), 0.55-0.40 (m, 2H).	1B
335	476	510	511	N-(2-amino- phenyl)-4-{[6- cyclopropyl-amino- 4-(4-methoxy- phenethyl-amino)- [1,3,5]triazin-2- yl-amino]-methyl}- benzamide	1 H NMR (300MHz, CDCl3) δ (ppm): 8.55-7.72 (m, 4H), 7.55-6.75 (m, 9H), 6.75-5.30 (m, 3H), 4.69 (m, 2H), 3.85 (s, 3H), 3.63 (bs, 2H), 2.86 (m, 3H), 0.85 (bs, 2H), 0.61 (bs, 2H).	1B
336	477	512	513	N-(2-amino- phenyl)-4-{[4- (3-chloro-phenethyl- amino)-6- cyclopropyl-amino- [1,3,5]triazin-2-yl- amino]-methyl- benzamide	1 H NMR (300MHz, acetone-d6) δ (ppm): 9.03 (s, 1H), 7.96 (d, J=7.5Hz, 2H), 7.60-7.37 (m, 2H), 7.37-7.12 (m, 5H), 6.99 (t, J=6.9Hz, 1H), 6.86 (d, J=6.9Hz, 1H), 6.67 (t, J=7.2Hz, 1H), 6.60-5.60 (m, 3H), 4.75-4.50 (m, 4H),
# 3.67-3.45 (m, 2H), 3.00-2.67 (m, 3H), 0.75-0.40 (m, 4H).	1B
337	478	514	515	N-(2-amino- phenyl)-4-{[6- cyclopropyl-amino- 4-(3,4-dimethoxy- phenethyl-amino)- [1,3,5]triazin-2- yl-amino]- methyl}-benzamide	1 H NMR (300MHz, acetone-d6) δ (ppm): 9.02 (s, 1H), 7.96 (d, J=8.1Hz, 2H), 7.60-7.40 (m, 2H), 7.29 (d, J=8.1Hz, 1H), 6.99 (td, J=8.1, 1.5Hz, 1H), 6.95-6.72 (m, 4H), 6.67 (td, J=7.8, 1.5Hz, 1H), 6.20-5.60 (m, 3H), 4.78-4.52
# (m, 4H), 3.75 (s, 6H), 3.65-3.42 (m, 2H), 2.95-2.65 (m, 3H), 0.72-0.40 (m, 4H).	1B
338	479	516	517	N-(2-amino- phenyl)-4-{[6- cyclopropyl-amino- 4-(3-methoxy- phenethyl-amino)- [1,3,5]triazin-2- yl-amino]-methyl}- benzamide	1 H NMR (300MHz, acetone-d6) δ (ppm): 9.02 (s, 1H), 7.96 (d, J=7.8Hz, 2H), 7.60-7.35 (m, 2H), 7.29 (d, J=7.5Hz, 1H), 7.18 (t, J=7.8Hz, 1H), 6.99 (td, J=7.5, 1.5Hz, 1H), 6.90-6.70 (m, 4H), 6.67 (t, J=7.8Hz, 1H), 6.60-5.60 (m, 3H), 4.77-4.50 (m, 4H),
# 3.76 (s, 3H), 3.65-3.45 (m, 2H), 2.92-2.65 (m, 3H), 0.72-0.42 (m, 4H).	1B
339	480	518	519	N-(2-amino- phenyl)-4-{[6- cyclopropyl-amino- 4-(2-pyridin-2-yl- ethyl-1-amino)- [1,3,5]triazin-2-yl- amino]-methyl}- benzamide	1 H NMR (300MHz, acetone-d6) δ (ppm): 9.03 (s, 1H), 8.50 (d, J=1.2Hz, 1H), 7.96 (d, J=8.1Hz, 2H), 7.66 (t, J=7.5Hz, 1H), 7.60-7.40 (m, 2H), 7.35-7.08 (m, 3H), 6.99 (td, J=8.1, 1.5Hz, 1H), 6.86 (dd, J=8.1, 1.5Hz, 1H), 6.67 (td, J=7.8, 1.5Hz, 1H),
# 6.60-5.60 (m, 3H), 4.75-4.50 (m, 4H), 3.80-3.60 (m, 2H), 3.15-2.90 (m, 2H), 2.90-2.65 (m, 1H), 0.73-0.40 (m, 4H).	1B
340	481	520	521	N-(2-amino- phenyl)-4-{[6- cyclopropyl-amino- 4-(3-pyridin-2-yl- ethyl-1-amino)- [1,3,5]triazin-2-yl- amino]-methyl}- benzamide	1 H NMR (300MHz, acetone-d6) δ (ppm): 9.20-9.00 (m, 1H), 8.70-8.50 (m, 2H), 8.00 and 7.88 (2d, J=7.9Hz, 2H), 7.75-7.43 (m, 3H), 7.38-6.67 (m, 5H), 6.22-5.78 (m, 3H), 4.80-4.55 (m, 4H), 3.61 (bs, 2H), 3.20-2.65 (m, 3H), 0.80-0.45 (m, 4H).	1B
341	482	522	523	N-(2-amino- phenyl)-4-[(4- cyclopropyl-amino- 6-phenethyl-oxy- [1,3,5]triazin-2-yl- amino)-methyl- benzamide	1 H NMR (300MHz, acetone-d6) δ (ppm): 9.04 (s, 1H), 7.98 (d, J=8.1Hz, 2H), 7.60-7.40 (m, 2H), 7.35-7.15 (m, 6H), 7.00 (td, J=7.5, 1.5Hz, 1H), 6.86 (d, J=8.1Hz, 1H), 6.67 (t, J=7.5Hz, 1H), 7.18-6.35 (m, 2H), 4.75-4.30 (m, 6H),
# 3.10-2.92 (m, 2H), 0.75-0.63 (m, 2H), 0.57-0.48 (m, 2H).	1, 25
342	483	524	Me	N-(2-amino- phenyl)-4-[(6- methyl-4- phenethylamino- [1,3,5]triazin-2- amino)-methyl]- benzamide	1 H NMR (300MHz, acetone-d6) +□ DMSO-d6) δ (ppm): mixture of rotamers, 9.62 (bs, 1H), 8.03 (d, J=8.0Hz, 2H), 7.80-7.44 (m, 3H), 7.40-7.10 (m, 8H), 7.01 (t, J=7.6Hz, 1H), 6.87 (d, J=7.9Hz, 1H), 6.67 (t, J=7.4Hz, 1H), 4.85 (bs, 2H), 4.72-4.54 (m, 2H),
# 3.63-3.42 (m, 2H), 2.96-2.74 (m, 2H), 2.21 and 2.13 (2s, 3H).	30
343	484	525	NH2	N-(2-amino- phenyl)-4-[{4- amino-6-phenyl- [1,3,5]triazin-2- yl-amino]-methyl}- benzamide	1 H NMR (300MHz, acetone-d6) δ (ppm): mixture of rotamers, 9.08 (bs, 1H), 8.48-8.36 (m, 2H), 8.02 (d, J=8.2Hz, 2H), 7.63-7.42 (m, 5H), 7.33 (d, J=7.7Hz, 1H), 7.19 (bs, 1H), 7.03 (t, J=7.4Hz, 1H), 6.88 (d, J=7.9Hz, 1H), 6.70 (t, J=7.6Hz, 1H),
# 6.35 and 6.25 (2bs, 2H), 4.87 and 4.75 (2d, J=5.9Hz, 2H), 4.65 (bs, 2H).	30
344	485	526	527	N-(2-amino- phenyl)-4-{[4- (2-indanyl-amino)- 4-phenyl-[1,3,5]- triazin-2-yl-amino]- methyl}-benzamide	1 H NMR (300MHz, acetone-d6) δ (ppm): mixture of rotamers, 9.14-8.96 (m, 1H), 8.54-8.30 (m, 2H), 8.09-7.95 (m, 2H), 7.68-7.40 (m, 5H), 7.38-7.08 (m, 6H), 7.03 (t, J=7.3Hz, 1H), 6.94-6.76 (m, 2H), 6.71 (t, J=7.3Hz, 1H), 5.13-4.54 (m, 5H), 3.49-3.18
# (m, 2H), 3.12-2.90 (m, 2H).	30

[0306] 528

Example 29

[0307] 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-ylamino)-methyl)-benzamide (Compound 39)

[0308] Step 1: N-Acetyl-1-piperonylpiperazine (Compound 37)

[0309] To a stirred solution at 0° C. of 1-piperonylpiperazine 36 (5.00 g, 22.7 mmol) in anhydrous CH2Cl2 (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 NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2Cl2: 4/96) to afford the title compound 37 (5.52 g, 21.11 mmol, 93% yield) as a yellow solid. 1H NMR: (300 MHz, CDCl3) δ (ppm): 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).

[0310] Step 2: 2-Chloro-4-morpholin-4-yl-6-[244-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-oxo-ethyl]-[1,3,5]triazine (Compound 38)

[0311] 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-[1,3,5]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 NH4Cl. The THF was evaporated and the residue was diluted with AcOEt. The organic layer was successively washed with sat. NH4Cl and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2Cl2: 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) δ (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).

[0312] 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-ylamino}-methyl)-benzamide (Compound 39)

[0313] The title compound 39 was obtained following the same procedure as Example 1, step 5. 1H NMR (CDCl3) δ (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). 529

Example 40

[0314] N-(2-aminophenyl)-6-(2-phenylamino-ethylamino)-nicotinamide (Compound 44)

[0315] Step 1: N-(5-Bromo-pyridin-2:yl)-N′-phenyl-ethane-1,2-diamine (Compound 42)

[0316] A mixture of 2,5-dibromopyridine 40 (2.08 g, 8.6 mmol) and phenyl-1,2-ethyldiamine (1.98 g, 14.6 mmol, 1.7 equiv.) was stirred under nitrogen at 120° C. for 6 h. After cooling down to room temperature, the solid mixture was ground in a mortar, dissolved in ethyl acetate (200 mL), washed with saturated NaHCO3 (2×50 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. 13C NMR (300 MHz, acetone-d6) δ (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+1).

[0317] Step 2: N-(2-aminophenyl)-6-(2-phenylamino-ethylamino)-nicotinamide (Compound 44)

[0318] 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 mmol, 26% mol) and 1,1′-bis (diphenylphosphino) ferrocene (124 mg, 0.22 mmol) was suspended in degassed DMF (3 mL), 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), δ (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

[0319] N-(2-amino-phenyl)-6-(4-methoxy-benzylamino)-nicotinamide (Compound 45)

[0320] Step 1: N-(5-Bromo-pyridin-2-yl)-4-methoxybenzylamine (Compound 43)

[0321] 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 6 h. 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, CDCl3) δ (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+1).

[0322] Step 2: N-(2-amino-phenyl)-6-(4-methoxy-benzylamino)-nicotinamide (Compound 45)

[0323] 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

[0324] N-(2-aminophenyl)-3-[6-(2-phenylamino-ethylamino)-pyridin-3-yl]-acrylamide (Compound 50)

[0325] Step 2: 3-[6-(2-Phenylamino-ethylamino)-pyridin-3-yl)-acrylic Acid Tert-butyl Ester (Compound 46)

[0326] 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 2 h 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, CDCl3) δ (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).

[0327] Step 3: 3-[6-(2-Phenylamino-ethylamino)-pyridin-3-yl)-acrylic Acid (Compound 48)

[0328] 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 (3×10 mL) and stored under high vacuum for 6 h. The solid residue 48 was employed for the next reaction without further purification. LRMS=284.1 (M+1).

[0329] Step 4: N-(2-aminophenyl)-3-[6-(2-phenylamino-ethylamino)-pyridin-3-yl]-acrylamide (Compound 50)

[0330] 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 16 h. 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), δ (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

[0331] N-(2-aminophenyl)-3-[6-(4-methoxy-benzylamino)-pyridin-2-yl]-acrylamide (Compound 51)

[0332] Step 2: N-(2-aminophenyl)-3-[6-(4-methoxy-benzylamino)-pyridin-2-yl]-acrylamide (Compound 51)

[0333] 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 (CDCl3), δ (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). 530

Example 44

[0334] 4-[2-(2-amino-phenylcarbamoyl)-vinyl]-benzyl}-carbamic Acid Pyridin-3-yl Methyl Ester (Compound 55)

[0335] Step 1: (4-bromo-benzyl)-carbamic Acid Pyridin-3-yl-Methyl Ester (Compound 54)

[0336] 4-bromobenzylamine HCl (3.0 g, 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 1,1′-carbonyl diimidazole (2.41 g, 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 2.55 g of product 54 (59% yield, LRMS=323 (M+1).

[0337] Step 2: 4[2-(2-amino-phenylcarbamoyl)-vinyl]-benzyl}-carbamic Acid Pyridin-3-yl Methyl Ester (Compound 55)

[0338] 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) δ (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). 531

[0339] N-(2-aminophenyl)-3-{4-[(3,4,5-trimethoxy-benzylamino)-methyl]-phenyl}-acrylamide (Compound 59)

[0340] Step 1: (4-Bromo-benzyl)-(3,4,5-trimethoxy-benzyl)-amine (Compound 57)

[0341] 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 (MgSO4), 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, CDCl3) δ (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).

[0342] Step 2: N-(2-Nitro-phenyl)-3-{4-[(3,4,5-trimethoxy-benzylamino)-methyl]-phenyl}-acrylamide (Compound 58)

[0343] Preparation of the Nitroacrylanilide

[0344] 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 16 h. 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. 13C NMR (300 MHz, CDCl3) δ (ppm): 163.6, 136.0, 135.6, 134.5, 131.3, 128.6, 125.4, 123.1, 121.8. LRMS=193.2 (M+1).

[0345] Step 3: N-(2-aminophenyl)-3-{4-[(3,4,5-trimethoxy-benzylamino)-methyl]-phenyl}-acrylamide (59)

[0346] A mixture of nitro-compound 58 (127 mg, 0.27 mmol), SnCl2 (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 (CDCl3), δ (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

[0347] N-(2-aminophenyl)-3-(4-{[(3,4,5-trimethoxy-benzyl)-amino]-methyl}-phenyl)-acrylamide (Compound 61)

[0348] Step 1: 3-{4-{[Methyl-(3,4,5-trimethoxy-benzyl)-amino]-methyl}-phenyl)-N-(2-nitro-phenyl)-acrylamide (Compound 60)

[0349] 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 2.5 h. A saturated NaHCO3 solution, was added slowly, extracted with dichloromethane (2×75 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, CDCl3) δ (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).

[0350] Step 2: N-(2-aminophenyl)-3-(4-{[(3,4,5-trimethoxy-benzyl)-amino]-methyl}-phenyl)-acrylamide (Compound 61)

[0351] 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), δ (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). 532

Example 47

[0352] N-(2-aminophenyl)-3-{4-(4-methoxy-benzylamino)-phenyl}-acrylamide (Compound 65)

[0353] Step 1: Methyl-344-amino-phenyl)-acrylate Hydrochloride (Compound 63)

[0354] 4-amino-cinnamic acid (10.41 g, 0.052 mol) was dissolved in methanol (100 mL) at rt. A solution of HCl 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).

[0355] Step 2: Methyl-3-{4-(4-methoxy-benzylamino)-phenyl}-acrylate Hydrochloride (Compound 64)

[0356] 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 (50 mL×3). 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 1.46 g of 63 (49% recovered yield).

[0357] Step 3: N-(2-aminophenyl)-3-{4-(4-methoxy-benzylamino)-phenyl}-acrylamide (Compound 65)

[0358] 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) δ (ppm): 9.15 (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). 533

Example 48

[0359] N-(2-Amino-phenyl)-3-(4-styrylamino-phenyl)-acrylamide (Compound 71)

[0360] Step 1: N-(4-Iodo-phenyl)-(3-phenyl-allyl)-amine (Compound 69)

[0361] 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+1)

[0362] Step 2: N-(2-Amino-phenyl)-3-(4-styrylamino-phenyl)-acrylamide (71)

[0363] 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) δ (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

[0364] N-(2-Amino-phenyl)-3-[4-(4-methoxy-benzamide)]-acrylamide (Compound 72)

[0365] Step 1: N-(4-Iodo-phenyl)-4-methoxy-benzamide (Compound 70)

[0366] 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)

[0367] Step 2: N-(2-Amino-phenyl)-3-[4-(4-methoxy-benzamide)]-acrylamide (Compound 72)

[0368] 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) δ (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). 534

Example 50

[0369] N-(2-amino phenyl)-3-{6-[2-(4-oxo-4H-quinazolin-3-yl)-ethylamino]-pyridin-3-yl}-acrylamide (Compound 76)

[0370] Step 1: N-(5-Bromo-pyridin-2-yl)-ethane-1,2-diamine (Compound 73)

[0371] 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)

[0372] Step 2: 3-[2-(5-Bromo-pyridin-2:ylamino)-ethyl]-3H-quinazolin-4-one (Compound 75)

[0373] 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, CDCl3): 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+1).

[0374] Step 3: N-(2-aminophenyl)-3-{6-[2-(4-oxo-4H-quinazolin-3-yl)-ethylamino]-pyridin-3-yl}-acrylamide (Compound 76)

[0375] 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), δ (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

[0376] N-(2-aminophenyl)-3-{6-[2-(4-benzyl-2,6-dioxo-piperazin-1-yl)ethylamino]-pyridin-3-yl}-acrylamide (Compound 78)

[0377] Step 2: 4-Benzyl-1-[2-(5-bromo-pyridin-2-ylamino)-ethyl]-piperazine-2,6-dione (Compound 77)

[0378] 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 684 mg (1.70 mmol, 54% yield) of 77.

[0379] Step 3: N-(2-aminophenyl)-3-{6-[2-(4-benzyl-2,6-dioxo-piperazin-1-yl)-ethylamino]-pyridin-3-yl}-acrylamide (Compound 78)

[0380] 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), δ (ppm): 8.09 (d, 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). 535

Example 52

[0381] (E)-4-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)-cinnamide (Compound 83)

[0382] Step 1: 4,6-Dichloro-2-(2-indanyl-amino)-[1,3,5]triazine (Compound 79)

[0383] 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 NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH2Cl2: 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) δ (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).

[0384] Step 2: 2-(4-Bromo-benzyl-amino)-4-chloro-6-(2-indanyl-amino)-[1,3,5]triazine (Compound 80)

[0385] 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.HCl (2.45 g, 11.01 mmol), respectively. After 17 h, the reaction mixture was poured into a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH2Cl2: 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, CDCl3) δ (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).

[0386] Step 3: 4-Amino-2-(4-bromo-benzyl-amino)-6-(2-indanyl-amino)-[1,3,5]triazine (Compound 81)

[0387] 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 HCl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2Cl2: 5/95) to afford the title compound 81 (1.96 g, 4.76 mmol, quantitative yield) as a colorless foam. 1H NMR (300 MHz, CDCl3) δ (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).

[0388] Step 4: (E)-4-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-N-[2-(N-t-butoxycarbonyl)-amino-phenyl]-cinamide (Compound 82)

[0389] Preparation of N-[2-(N-t-Butoxycarbonyl)-amino-phenyl]-acrylamide

[0390] 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, CDCl3) δ (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).

[0391] In a 50 mL sealed flask, a solution of 81 (300 mg, 0.73 mmol), the acrylamide (230 mg, 0.88 mmol), Et3N (407 μl, 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 NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2Cl2: 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, CDCl3) δ (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), 5.95-4.90 (m, 4H), 4.85-4.48 (m, 3H), 3.40-3.14 (m, 2H), 2.90-2.70 (m, 2H), 1.52 (s, 9H).

[0392] Step 5: (E)-4-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)-cinnamide (Compound 83)

[0393] To a stirred solution at room temperature of 82 (230 mg, 0.39 mmol) in CH2Cl2 (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/CH2Cl2: 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) δ (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). 536

Example 53

[0394] N-(2-aminophenyl)-2-(4-methoxy-benzylamino)-quinolin-6-yl-amide (Compound 87)

[0395] Step 1: 2,6-ditrifluoromethanesulfonyloxy-guinoline (Compound 85):

[0396] 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 (2×150 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. 3C NMR (300 MHz, CDCl3): 154.5, 147.8, 144.6, 142.0, 131.6, 127.8, 124.9, 119.3, 118.7, 114.9. LRMS=426.0 (M+1).

[0397] Step 2: N-(2-aminophenyl)-2-(4-methoxy-benzylamino)-quinolin-6-yl-amide (Compound 87)

[0398] 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), δ (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

[0399] N-(2-aminophenyl)-3-[2-(4-methoxy-benzylamino)-quinolin-6-yl]-acrylamide (Compound 88)

[0400] Step 3: N-(2-aminophenyl)-3-[2-(4-methoxy-benzylamino)-quinolin-6-yl]-acrylamide (Compound 88)

[0401] 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), δ (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

[0402] 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.

TABLE 3a
Characterization of Compounds Prepared in Examples 42-84
537
Ex.	Cpd.	W	Y	Z	R	Name	Characterization	Schm
42	50	538	N	CH	H	N-(2-aminophenyl)- 3-[6-(2- phenylamino- ethylamino)- pyrindin- 3-yl]-acrylamide	1H-NMR (DMSO-d6), δ (ppm): 9.25 (bs, 1H), 8.21 (d, J=1.6Hz, 1H), 7.67 (d, J=8.5Hz, 1H), 7.43 (d, J=15.7Hz, 1H), 7.32 (d, J=7.4Hz, 1H), 7.24 (t, J=1.0Hz, 1H), 7.08 (t, J=7.4Hz, 2H), 6.91 (t, J=8.0Hz, 1H), 6.75 (dt, J=8.0Hz, 0.4Hz, 1H), 6.57 (m, 6H), 5.20 (bs, 1H), 3.48 (t, J=6.3Hz, 2H),
# 3.33 (bs, 2H), 3.21 (t, J=6.3Hz, 2H)	3
44	55b	539	CH	CH	H	{4-[2-(2-amino- phenylcarbamoyl)- vinyl]-phenyl}- carbamic acid pyridin-3-yl methyl ester	1H NMR: (DMSO-d6) δ (ppm): 10.03 (s, 1H), 9.32 (s, 1H), 8.65 (s, 1H), 8.55 (d, J=3.3Hz, 1H), 7.85 (d, J=7.69Hz, 1H), 7.40-7.60 (m, 6H), 7.31 (d, J=7.69Hz, 1H), 6.89 (dd, J=7.14Hz, J=7Hz, 1H), 6.71-6.79 (m, 2H), 6.55 (dd, J=7.1Hz, J=7Hz, 1H), 5.20 (s, 2H), 4.93 (bs, 2H).	4
45	59	540	CH	CH	H	N-(2-aminophenyl)- 3-{4-[(3,4,5- trimethoxy- benzylamino)- methyl]-phenyl}- acrylamide	1H-NMR (CDCl3), δ (ppm): 8.25 (bs, 1H), 7.59 (d, J=15.6Hz, 1H), 7.38 (d, J=7.5Hz, 2H), 7.29 (d, J=7.5Hz, 2H), 7.25 (m 1H), 7.02 (t, J=6.8Hz, 1H), 6.75 (m, 2H), 6.62 (d, J=15.6Hz, 1H), 6.58 (s, 2H), 3.97 (bs, 3H), 3.80 (s, 9H), 3.78 (s, 2H), 3.72 (s, 2H).	5
46	61b	541	N	CH	Me	N-(2-aminophenyl)- 3-[6-(4-methoxy- benzylamino)- pyridin-3-yl]-2- methyl-acrylamide	1H-NMR (DMSO-d6), δ (ppm): 9.15 (bs, 1H), 8.13 (bs, 1H), 7.58 (d, J=1.9Hz, 1H), 7.30 (m 4H), 7.12 (d, J=7.7Hz, 1H), 6.91 (m 3H), 6.75 (d, J=7.8Hz, 1H), 6.57 (m, 2H), 4.83 (bs, 2H), 4.43 (d, J=5.5Hz, 2H), 3.72 (s, 3H), 3.33 (s, 3H).	3
47	65	542	CH	CH	H	N-(2-amino- phenyl)-3-[4- (4-methoxy- benzylamino)- phenyl]-acrylamide	1H NMR: (DMSO-d6) δ (ppm): 9.15 (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=5.77Hz, 2H).	6
48	71	543	CH	CH	H	N-(2-Amino- phenyl)- 3-(4-styrylamino- phenyl)-acrylamide	1H NMR: (DMSO-d6) δ (ppm): 9.22 (bs, 1H), 7.45 (d, J=6.9Hz, 2H), 7.39 (d, J=9.0Hz, 2H), 7.34 (d, J=7.4Hz, 2H), 1.26 (dt, J=7.4Hz, 6.8Hz, 6.93 (dt, J=7.9Hz, 7.1Hz, 1H), 6.78 (d, J=7.9Hz, 1H), 6.69 (d, J=8.5Hz, 2H), 6.63-6.55 (m, 4H), 6.44-6.37 (m, 1H), 4.95 (bs, 2H), 3.95 (bs, 2H).	7
49	72	544	CH	CH	H	N-{4-[2-(2-Amino- phenylcarbamoyl)- vinyl]-phenyl}-4- methoxy-benzamide	1H NMR: (DMSO-d6) δ (ppm): 9.4 (bs, 1H), 7.60 (d, J=8.5Hz, 1H), 7.54-7.45 (m, 3H), 7.87 (d, J=7.7Hz, 1H), 7.10 (d, J=8.8Hz, 1H), 6.95-6.77 (m, 3H), 6.62 (d, J=7.7Hz, 2H), 6.08-6.04 (m, 2H), 4.98 (bs, 2H), 3.72 (s, 3H).	7
50	76	545	N	CH	H	N-(2-aminophenyl)- 3-{6-[2-(4-oxo-4H- quinazolin-3-yl)- ethylamino]-pyridin- 3-yl}-acrylamide	1H-NMR (DMSO-d6), δ (ppm): 9.24 (bs, 1H), 8.17 (dd, J=8.0Hz, 1.6Hz, 1H), 8.11 (bs, 1H), 8.08 (d, J=1.9Hz, 1H), 7.82 (dt, J=8.5Hz, 1.4Hz, 1H), 7.64 (d, J=8.2Hz, 2H), 7.25 (t, J=5.8Hz, 1H), 6.90 (dt, J=15.7Hz, 1H), 6.74 (dd, J=8.0Hz, 1.4Hz, 1H), 6.58 (m, 3H), 4.95 (bs, 2H),
# 4.17 (t, J=5.2Hz, 2H), 3.68 (m, J=5.2Hz, 2H).	8
51	78	546	N	CH	H	N-(aminophenyl)- 3-{6-[2-(4-benzyl- 2,6-dioxo-piperazin- 1-yl)-ethylamino]- pyridin-3-yl}- acrylamide	1H-NMR (CD3OD-d4), δ (ppm): 8.09 (d, J=1.8Hz, 1H), 7.68 (dd, J=8.7Hz, 2.1Hz, 1H), 7.53 (d, J=15.6Hz, 1H), 7.29 (m, 6H), 7.20 (dd, J=7.8Hz, 1.2Hz, 1H), 7.02 (dt, J=9.0Hz, 1.2Hz, 1H), 6.86 (dd, J=8.1Hz, 1.2Hz, 1H), 6.73 (dt, J=7.5Hz, 1.5Hz, 1H), 6.61
# (d, J=15.6Hz, 6.50 (d, J=8.7Hz, 1H), 4.85 (bs, 3H), 3.97 (t, J=7.5Hz, 2H), 3.60 (s, 2H), 3.57 (t, J=7.5Hz, 2H), 3.38 (s, 4H).	8
52	83	547	CH	CH	H	(E)-4-{[4-Amino-6-( 2-indanyl-amino)- [1,3,5]triazin-2- ylamino]-methyl}- N-(2-amino- phenyl)-cinamide	1H NMR (300MHz, acetone-d6) δ(ppm): 8.87 (bs, 1H), 7.69 (d, J=15.7Hz, 1H), 7.59 (db, J=7.7Hz, 2H), 7.49-7.34 (m, 3H), 7.28-7.11 (m, 4H), 6.69 (td, J=7.6, 1.4Hz, 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).	9
55	89	548	N	CH	H	N-(2-aminophenyl)- 3-[6-(4-methoxy- benzylamino)- pyridin-3-yl]- acrylamide	1H-NMR (DMSO-d6), δ (ppm): 9.24 (bs, 1H), 8.19 (d, J=1.6Hz, 1H), 7.64 (d, J=8.5Hz, 1H), 7.52 (t, J=5.5Hz, 1H), 7.42 (d, J=15.7Hz, 1H), 7.32 (d, J=7.4Hz, 1H), 7.26 (d, J=8.5Hz, 2H), 6.90 (m, 1H), 6.88 (dd, J=8.5Hz, 2H), 6.74 (d, J=6.9 Hz, 1H), 6.58 (m, 3H), 4.92 (bs, 2H), 4.45 (d, J=5.5Hz, 2H), 3.72 (s, 3H).	3
56	90	549	N	CH	H	N-(2-aminophenyl)- 3-{6-[pyridin-3- ylmethyl)-amino]- pyridin-3-yl}- acrylamide	1H-NMR (CD3OD-d4), δ (ppm): 8.47 (bs, 1H), 8.33 (bs, 1H), 8.02 (m, 1H), 7.73 (m, 1H), 7.61 (d, J=8.5Hz, 1H), 7.46 (d, J=15.4Hz, 1H), 7.29 (m, 1H), 7.14 (d, J=7.7Hz, 1H), 6.94 (d, J=7.4Hz, 1H), 6.80 (d, J=7.9Hz, 1H), 6.66 (t, J=7.9Hz, 1H), 6.53 (m, 2H), 4.54 (m, 2H), 3.59 (bs, 2H).	3
57	91	550	N	CH	H	N-(2-aminophenyl)- 3-{6-[pyridin-3- ylmethyl)-amino]- pyridin-3-yl}- acrylamide	1H-NMR (DMSO-d6), δ (ppm): 9.27 (bs, 1H), 8.48 (dd, J=1.6Hz, 4.4, 1H), 8.16 (d, J=1.6Hz, 1H), 7.70 (m 2H), 7.42 (d, J=15.6Hz, 1H), 7.31 (m 3H), 6.90 (t, J=6.9Hz, 1H), 6.73 (d, J=6.9Hz, 1H), 6.58 (m 4H), 4.98 (bs, 2H), 4.57 (d, J=6.0Hz, 2H).	3
58	92	551	N	CH	H	N-(2-aminophenyl)- 3-6-(4-fluoro- benzylamino)-pyridin-3-yl]- acrylamide	1H-NMR (DMSO-d6), δ (ppm): 9.24 (bs, 1H), 8.18 (d, J=1.6Hz, 1H), 7.65 (dd, J=8.8Hz, 0.8Hz, 1H), 7.60 (t, J=5.8Hz, 1H), 7.42 (d, J=15.7Hz, 1H), 7.36 (m, 3H), 7.13 (t, J=8.8Hz, 2H), 6.90 (t, J=7.4Hz, 1H), 6.73 (dd, J=6.9Hz, 1.0Hz, 1H), 6.58 (m, 3H), 4.91 (bs, 2H), 4.50 (d, J=6.0Hz, 2H).	3
59	93	552	N	CH	H	N-(2-aminophenyl)- 3-(6-benzylamino- pyridin-3-yl)-acrylamide	1H-NMR (DMSO-d6), δ (ppm): 9.24 (bs, 1H), 8.17 (d, J=1.9Hz, 1H), 7.65 (dd, J=8.8Hz, 1.6Hz, 1H), 7.60 (t, J=6.0Hz, 1H), 7.41 (d, J=15.7Hz, 1H), 7.31 (m, 5H), 7.23 (m, 1H), 6.89 (dt, J=8.0Hz, 1.6Hz, 1H), 6.73 (dd, J=8.0Hz, 1.5Hz, 1H), 6.58 (m 3H), 4.92 (bs, 2H), 4.53 (d, J=6.0Hz, 2H)	3
60	94	553	N	CH	H	N-(2-aminophenyl)- 3-[6-(3-phenyl- propylamino)- pyridin-3-yl]- acrylamide	1H-NMR (DMSO-d6), δ (ppm): 9.22 (bs, 1H), 8.18 (ds, 1H), 7.63 (d, J=8.8Hz, 1H), 7.42 (d, J=15.4Hz, 1H), 7.22 (m 7H), 6.90 (t, J=7.7Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 6.57 (m 3H), 4.92 (bs, 2H), 3.29 (dt, J=7.7Hz, 6.0Hz, 2H), 2.66 (t, J=7.7Hz, 2H), 1.84 (m, J=7.7Hz, 2H).	3
61	95	554	N	CH	H	N-(2-aminophenyl)- 3-{6-[2-(4-methoxy- phenyl)- ethylamino]- pyridin-3-yl}- acrylamide	1H-NMR (DMSO-d6), δ (ppm): 9.22 (bs, 1H), 8.19 (bs, 1H), 7.62 (d, J=8.5Hz, 1H), 7.42 (d, J=15.7Hz, 1H), 7.32 (d, J=7.8Hz, 1H), 7.16 (d, J=7.8Hz, 2H), 7.13 (m, 1H), 6.91 (m, 1H), 6.85 (d, J=7.9Hz, 1H), 6.74 (d, J=7.8Hz, 1H), 6.57 (m 3H), 4.92 (bs, 2H),
# 3.71 (s, 3H), 3.47 (dd, J=7.3Hz, 6.0Hz, 2H), 2.78 (t, J=7.3Hz, 2H).	3
62	96	555	N	CH	H	N-(2-aminophenyl)- 3-[6-(4- dimethylamino- benzylamino)- pyridin-3-yl]- acrylamide	1H-NMR (DMSO-d6), δ (ppm): 9.23 (bs, 1H), 8.18 (bs, 1H), 7.63 (d, J=8.2Hz, 1H), 7.41 (m 2H), 7.31 (d, J=7.4Hz, 1H), 7.15 (d, J=8.5Hz, 2H), 6.90 (t, J=7.4Hz, 1H), 6.74 (d, J=7.0Hz, 1H), 6.68 (d, J=8.5Hz, 2H), 6.58 (m, 3H), 4.91 (bs, 2H), 4.39 (d, J=5.5Hz, 2H), (bs, 2H).	3
63	97	556	N	CH	H	N-(2-aminophenyl)- 3-[6-(3-imidazol-1- yl-propylamino)- pyridin-3-yl]- acrylamide	1H-NMR (CD3OD-d4), δ (ppm): 8.09 (bs, 1H), 8.05 (d, J=1.9Hz, 1H), 7.67 (m, 2H), 7.49 (d, J=15.7Hz, 1H), 7.28 (m, 2H), 7.17 (m, 2H), 6.98 (dt, J=13.7Hz, 7.7Hz, 1H), 6.83 (dd, J=8.0Hz, 1.1Hz, 1H), 6.69 (dt, J=9.1Hz, 1.4Hz, 1H), 6.58 (d, J=15.7Hz, 1H), 6.51 (d, J=8.8Hz, 1H), 4.15
# (t, J=7.1Hz, 2H), 3.29 (m, 2H), 2.08 (m, J=6.9Hz, 2H).	3
64	98	557	N	CH	H	N-(2-aminophenyl)- 3-[6-(3- trifluoromethoxy- benzylamino)- pyridin-3-yl]- acrylamide	1H-NMR (acetone-d6), δ (ppm): 8.75 (bs, 1H), 8.23 (d, J=1.9Hz, 1H), 7.69 (d, J=8.2Hz, 1H), 7.55 (d, J=15.4Hz, 1H), 7.43 (m, 2H), 7.34 (bs, 2H), 7.19 (d, J=6.6Hz, 1H), 6.93 (m, 2H), 6.83 (dd, J=8.0Hz, 1.4Hz, 1H), 6.67 (m, 3H), 4.71 (d, J=6.3Hz, 2H), 4.65 (bs, 2H).	3
65	99	558	N	CH	H	N-(2-aminophenyl)- 3-[6-(4- trifluoromethoxy- benzylamino)- pyridin-3-yl]- acrylamide	1H-NMR (acetone-d6), δ (ppm): 8.81 (bs, 1H), 8.21 (d, J=1.9Hz, 1H), 7.66 (d, J=7.4Hz, 1H), 7.56 (d, J=15.7Hz, 2H), 7.49 (d, 2H), J=8.2Hz, 1H), 7.34 (d, J=8.1Hz, 1H), 7.25 (t, J=8.0Hz, 1H), 6.93 (m, 2H), 6.73 (m, 3H), 4.67 (d, J=6.0Hz, 2H), 4.66 (bs, 2H).	3
66	100	559	N	CH	H	N-(2-aminophenyl)- 3-[6-(3,5-difluoro- benzylamino)- pyridin-3-yl]-acrylamide	1H-NMR (DMSO-d6), δ (ppm): 9.25 (bs, 1H), 8.18 (d, J=2.2Hz, 1H), 7.67 (m, 2H), 7.42 (d, J=15.7Hz, 1H), 7.31 (d, J=7.7Hz, 1H), 7.08 (dt, J=9.3Hz, 2.2Hz, 1H), 7.03 (dd, J=8.8Hz, 1.9Hz, 2H), 6.90 (dt, J=7.3Hz, 1.4Hz, 1H), (dd, J=8.0Hz, 1.4Hz, 1H), 6.60 (m 3H), 4.92 (bs, 2H), 4.56 (d, J=6.0Hz, 2H).	3
67	101	560	N	CH	H	N-(2-aminophenyl)- 3-[6-(3- trifluoromethyl- benzylamino)- pyridin-3-yl]- acrylamide	1H-NMR (DMSO-d6), δ (ppm): 9.25 (bs, 1H), 8.14 (bs, 1H), 7.86 (m, 6H), 7.42 (d, J=15.6Hz, 1H), 7.31 (d, J=7.4Hz, 1H), 6.90 (dt, J=8.8, 1.1Hz, 1H), 6.74 (dd, J=8.0Hz, 1.4Hz, 1H), 6.60 (m 3H), 4.96 (bs, 2H), 4.63 (d, J=5.8Hz, 2H).	3
68	102	561	N	CH	H	3-[6-(3- aminomethyl- benzylamino)- pyridin-3-yl]-N-(2- aminophenyl)- acrylamide	1H-NMR (DMSO-d6), δ (ppm): 9.28 (bs, 1H), 8.17 (bs, 1H), 7.66 (d, J=5.8Hz, 2H), 7.37 (m, 6H), 6.88 (dd, J=8.0Hz, 0.9Hz, 1H), 6.73 (dd, J=8.0Hz, 0.9Hz, 1H), 6.59 (m 3H), 4.55 (d, J=5.8Hz, 2H), 3.96 (s, 2H), 3.37 (bs, 4H).	3
70	103	562	CH	CH	H	{4-[2-(2-amino- phenylcarbmoyl)- vinyl]-benzyl}- carbamic acid pyridin-3-yl methyl ester	1H NMR: (DMSO-d6) δ (ppm): 9.36 (s, 1H), 8.57 (s, 1H), 8.51 (d, J=4.6Hz, 1H), 7.91 (m, 1H), 7.77 (d, J=7.68Hz, 1H), 7.28-7.57 (m, 7H), 6.88 (dd, J=15.66Hz, 4.40Hz, 2H), 6.73 (m, 1H), 6.56 (m, 1H), 5.01 (s, 2H), 4.93 (bs, 2H), 4.10 (d, J=6.04Hz, 2H).	4
71	105	563	CH	CH	H	(2-{4-[2-(2-amino- phenylcarbamoyl)- vinyl]-phenyl}-ethyl}- carbamic acid pyridin-3-yl methyl ester	1H NMR: (DMSO-d6) δ (ppm): 9.34 (s, 1H), 8.52 (m, 2H), 7.71 (d, J=7.69Hz, 1H), 7.20-7.60 (m, 8H), 6.87 (m, 2H), 6.73 (m, 1H), 6.56 (m, 1H), 5.03 (s, 2H), 4.92 (s, 2H), 3.30 (m, 2H), 2.75 (m, 2H).	4
72	106	564	CH	CH	H	N-(2-aminophenyl)- 3-{4-[(3,4,5- trimethoxy- phenylamino)- methyl]-phenyl}- arylamide	1H-NMR (acetone-d6), δ (ppm): 8.49 (bs, 1H), 8.41 (d, J=7Hz, 1H), 7.63 (d, J=15.6Hz, 1H), 7.56 (d, J=8Hz, 2H), 7.45 (d, J=8Hz, 2H), 7.07 (m, 2H), 6.90 (d, J=15.6Hz, 1H), 6.76 (m, 1H), 6.74 (m, 1H), 5.99 (s, 2H), 4.36 (s, 2H), 3.69 (s, 6H), 3.68 (bs, 2H), 3.67 (s, 3H).	5
73	107	565	CH	CH	H	N-(2-aminophenyl)- 3-(4-{[(3,4,5- trimethoxy-benzyl)- amino]-methyl}- pheyl)-arylamide	1H-NMR (CDCl3), δ (ppm): 7.70 (bs, 1H), 7.43 (d, J=7.4Hz, 1H), 7.33 (d, J=4.9Hz, 2H), 7.26 (d, J=4.9Hz, 2H), 7.25 (m, 1H), 7.03 (t, J=7.4Hz, 1H), 6.78 (d, J=7.4Hz, 1H), 6.75 (m, 1H), 6.61 (s, 2H), 6.57 (m, 1H), 4.08 (bs, 2H), 3.86 (s, 6H), 3.83 (s, 3H), 3.50 (s, 2H), 3.47 (s, 2H), 2.21 (s, 3H).	5
74	108	566	CH	CH	H	N-(2-aminophenyl)- 3-{4-[(3,4,5- trimethoxy-phenyl)- amino]-methyl}- phenyl}-arylamide	1H-NMR (CDCl3), δ (ppm): 7.74 (d, J=15.4Hz, 1H), 7.50 (d, J=7.4Hz, 2H), 7.25 (m 3H), 7.06 (t, J=1.9Hz, 1H), 6.82 (d, J=7.4Hz, 2H), 6.85 (d, J=15.4Hz, 1H), 5.96 (s, 2H), 4.50 (s, 2H), 3.79 (s, 6H), 3.78 (bs, 2H), 3.77 (s, 3H), 3.00 (s, 3H).	5
75	109	567	CH	CH	H	N-(2-Amino- phenyl)-3-{4- [(6-methoxy- pyridin-3-ylamino)- methyl]-phenyl}- acrylamide	1H NMR: (DMSO-d6) δ (ppm): 9.4 (bs, 1H), 7.60(d, J=8.5Hz, 1H), 7.54-7.45 (m, 3H), 7.87 (d, J=7.7Hz, 1H), 7.10 (d, J=8.8Hz, 1H), 6.95-6.77 (m, 3H), 6.62 (d, J=7.7Hz, 2H), 6.08-6.04 (m, 2H), 4.98 (bs, 2H), 3.72 (s, 3H).	5
76	110	568	CH	CH	H	N-(2-Amino- phenyl)- 3-[4-(quinolin-2- ylsulfanylmethyl)- phenyl]-acrylamide	1H NMR: (DMSO-d6) δ (ppm): 9.41 (bs, 1H), 8.21 (d, J=8.5, 1H), 7.97 (dt, J=7.7, 8.8Hz, 2H), 7.78 (dt, J=7.1Hz, 8.2Hz, 1H), 7.61-7.53 (m, 5H), 7.40 (dd, J=8.5Hz, 7.6Hz, 2H), 6.97-6.77 (m, 4H), 6.6 (dt, J=7.7Hz, 7.5Hz, 1H), 4.98 (bs, 2H), 4.65 (bs, 2H).	5
77	111	569	CH	CH	H	N-(2-amino- phenyl)-3-{4- [(pyridin-3- ylmethyl)-amino]- phenyl}-acrylamide	1H NMR: (DMSO-d6) δ (ppm): 9.15 (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=5.77Hz, 2H).	6
78	112	570	N	CH	H	N-(2-Amino- phenyl)- 3-(6-styrylamino- pyridin-3-yl)- acrylamide	1H NMR: (DMSO-d6) δ (ppm): 7.96 (d, J=9.1Hz, 2H), 7.55 (d, J=14.2Hz, 1H), 1.48 (d, J=7.4Hz, 2H), 7.39-7.29 (m, 4H), 7.07-6.91 (m, 3H), 6.81-6.64 (m, 3H), 6.47-6.38 (m, 1H), 4.21 (bs, 2H).	7
79	113	571	N	N	H	N-(2-amino- phenyl)- 3-[2-(4-nitro-benzylamino)- pyrimidin-5-yl]- acrylamide	1H NMR: (DMSO-d6) δ (ppm): 9.30 (s, 1H), 8.58 (bs, 2H), 8.36 (m, 1H), 8.20 (m, 2H), 7.58 (m, 2H), 7.28-7.42 (m, 2H), 6.52-6.92 (m, 4H), 4.90 (s, 2H), 4.64 (d, J=6Hz, 2H).	7
80	114	572	N	CH	H	N-(5-[2-(2-Amino- phenylcarbamoyl- vinyl)-pyridin-2-yl)-4- methoxy-benzamide	1H NMR: (DMSO-d6) δ (ppm): 10.87 (bs, 1H), 9.45 (bs, 1H), 8.66 (bs, 1H), 8.33 (d, J=7.4Hz, 1H), 8.14-8.08 (m, 3H), 7.63 (d, J=15.6Hz, 1H), 7.40 (d, J=7.7Hz, 1H), 7.08 (d, J=6.8Hz, 2H), 6.97 (d, J=12.3Hz, 2H), 6.80 (d, J=7.9Hz, 1H), 6.63 (dt, J=7.7Hz, 7.4Hz, 1H), 5.06 (bs, 2H), 3.88 (s, 3H)	7
81	115	573	N	N	H	3-[2-(4-amino- benzylamino)- pyrimidin-5-yl]- N-(2- amino-phenyl)- acrylamide	1H NMR: (DMSO-d6) δ (ppm): 9.27 (s, 1H), 8.83 (s, 2H), 7.97 (t, J=6Hz, 1H), 7.37 (d, J=15.9Hz, 1H), 7.29 (d, J=7.11Hz, 1H), 6.96 (d, J=8.24Hz, 2H), 6.88 (m, 1H), 6.70 (m, 2H), 6.55 (m, 1H), 6.47 (d, J=8.2Hz, 2H), 4.90 (s, 4H), 4.34 (d, J=6.0Hz, 2H).	7
82	116	574	N	CH	H	N-(2-aminophenyl)- 3-[6-(3,4,5- trimethoxy- benzylamino)- pyridin-3-yl]- acrylamide	1H-NMR (CDCl3), δ (ppm): 8.38 (bs, 1H), 7.49 (m, 1H), 7.42 (dd, J=8.5Hz, 2.2Hz, 1H), 7.41 (m, 1H), 7.30 (d, J=7.9Hz, 1H), 7.10 (bs, 1H), 7.02 (t, J=7.4Hz, 1H), 6.75 (d, J=15.0Hz, 1H), 6.73 (m 1H), 6.65 (m, 2H), 6.36 (d, J=8.8Hz, 1H), 6.23 (d, J=15.0Hz, 1H), 4.34 (s, 2H and bs, 2H),
# 3.84 (s, 3H), 3.81 (s, 6H).	7, 3
83	117	575	N	CH	H	N-(2-Amino- phenyl)- 3-[6-(4-methyl- benzylamino)- pyridin-3-yl]- acrylamide	1H NMR: (DMSO-d6) δ (ppm): 8.28 (bs, 1H), 7.98 (d, J=9.6Hz, 1H), 7.57 (d, J=15.6Hz, 1H), 7.38 (d, J=7.7Hz, 1H), 7.29 (d, J=7.9Hz, 2H), 7.22 (d, J=7.6Hz, 2H), 7.08 (dt, J=8.2Hz, 7.7Hz, H), 6.98 (d, J=9.1Hz, 2H), 6.87 (t, J=8.2Hz, 1H), 6.75 (d, J=15.1Hz, 1H), 4.57 (s, 2H), 2.53 (s, 3H).	7
84	118	576	N	N	H	N-(2-amino- phenyl)- 3-[2(4-methoxy- benzylamino)- pyrimidin-5-yl]- acrylamide	1H NMR: (DMSO-d6) δ (ppm): 9.27 (s, 1H), 8.54 (s, 2H), 8.12 (m, 1H), 7.30 (m, 4H), 6.53-6.91 (m, 6H), 4.90 (s, 2H), 4.46 (d, J=4.9Hz, 2H), 3.7 (s, 3H).	7
84b	118b	577	N	CH	H	N-(2-Amino- phenyl)- 3-[6-(3,4- dimethoxy- phenyl)-pyridin-3-yl]- acrylamide	1H NMR (20% CD3OD in CDCl3): □□8.75 (s, 1H), 7.95 (m, 1H), 7.74-7.59 (m, 3H), 7.50 (m, 1H), 7.24 (d, J=7.8Hz, 1H), 7.07 (m, 1H), 6.95 (d, J=8.4Hz, 1H), 6.89-6.83 (m, 3H), 3.96 (s, 3H), 3.91 (s, 3H).	9, 15

[0403]

TABLE 3b
578
Ex.	Cpd.	n	Name	Characterization	Scheme
53	87	0	2-(4-methoxy-	1 H-NMR (DMSO-d6), δ (ppm): 9.66	10
			benzylamino)-	(bs, 1H), 8.32 (s, 1H), 8.05 (d, J=8.8Hz, 1H),
			quinoline-	7.96 (dd, J=9.1Hz, 2.2Hz, 1H), 7.72 (d,
			6-carboxylic	J=2.2 Hz, 1H), 7.55 (dd, J=8.5Hz, 2.2Hz, 1H),
			acid (2-	7.34 (dd, J=8.5Hz, 2.2Hz, 1H), 7.20 (d, J=7.7Hz,
			aminophenyl)-	1H), 6.97 (t, J=7.7Hz, 1H), 6.90 (m 2H), 6.80
			amide	(d, J=7.9Hz, 1H), 6.61 (t, J=6.3Hz, 1H), 4.90
				(bs 2H), 4.58 (d, J=3.3Hz, 2H), 3.73 (s, 3H),
				3.33 (bs, 1H).
54	88	1	N-(2-aminophenyl)-3-[2-	1 H-NMR (DMSO-d6), δ (ppm): 9.70 (bs, 1H),	10
			(4-methoxy-	9.40 (bs, 1H), 8.20 (d, J=8.9Hz, 1H), 8.03
			benzylamino)-quinolin-6-	(bs, 2H), 7.94 (d, J=7.2Hz, 1H), 7.64 (dd,
			yl]-acrylamide	J=15.7Hz, 2.5Hz, 1H), 7.41 (d, J=8.5Hz, 2H),
				7.39 (m, 1H), 7.14 (d, J=8.9Hz, 1H), 7.05 (d,
				J=15.7 Hz, 1H), 6.97 (m, 1H), 6.95 (d, J=8.5Hz,
				2H), 6.81 (d, J=8.0Hz, 1H), 6.65 (t, J=7.2Hz,
				1H), 4.76 (s, 2H), 3.75 (s, 3H).

[0404]

TABLE 3c
579
Ex.	Cpd.	Name	Characterization	Scheme
43	51	N-(2-aminophenyl)-	1 H-NMR (CDCl3), δ (ppm):	3
		3-[6-(4-methoxy-	7.60 (bs, 1H), 7.55 (bs, 1H),
		benzylamino)-	7.43 (t, J=7.7Hz, 1H), 7.29
		pyridin-2-yl]-	(d, J=8.3Hz, 2H), 7.17 (d,
		acrylamide	J=15.1Hz, 1H), 7.06 (t, J=
			7.7Hz, 1H), 6.88 (d, J=8.3Hz,
			2H), 6.80 (m, 2H), 6.70
			(m, 3H), 6.41 (d, J=8.5Hz,
			1H), 4.50 (d, J=5.5Hz, 2H),
			3.80 (s, 3H), 3.45 (bs, 2H).

[0405]

TABLE 3d
Ex.	Cpd	W	Y	Z	R	Name	Characterization	Schm
347	492	580	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4,6-dimethoxy- pyrimidin-2-ylamino)- methyl]phenyl}- acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.36 (bs, 1H), 7.55 (d, J=7.4Hz, 2H), 7.48 (s, 1H), 7.38 (d, J=7.9Hz, 2H), 7.33 (d J=7.9Hz, 1H), 6.91 (m, 2H), 6.73 (d, J=8.2Hz, 1H), 6.56 (dd, J=7.4, 7.7Hz, 1H), 5.35 (s, 1H), 4.93 (bs, 2H), 4.46 (dd, J=6.04 2H), 3.32 (s, 6H)	3, 7
348	493	581	CH	CH	H	N-(2-Amino-phenyl)-3-{4-[(4-chloro-6- methoxy-pyrimidin-2- ylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.37 (bs, 1H), 7.58-7.50 (m, 3H), 7.37-7.32 (m, 3H), 6.94-6.83 (m, 2H), 6.75 (d J=8.0Hz, 1H), 6.57 (t, J=7.5, 1H), 6.13 (bs, 1H), 4.94 (bs, 2H), 4.48 (d, J=6.0, 2H), 3.84 (s, 3H)	3, 7
349	494	582	CH	CH	H	N-(2-Amino-phenyl)-3- [4-(3,5-dimethoxy- benzylamino)-phenyl]- acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.38 (bs, 1H), 7.55-7.40 (m 6H), 6.88-6.57 (m, 3H), 6.35-6.32 (m, 1H), 5.73 (m, 3H), 4.94 (s, 2H), 4.26 (s , 2H), 3.63 (s, 6H).	3, 7
350	495	583	CH	CH	H	N-(2-Amino-phenyl)-3- [4-(3,5-dinitro- benzylamino)-phenyl]- acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.38 (bs, 1H), 7.74 (bs, 3H), 7.61 (d, J=8.2Hz, 2H), 7.56-7.44 (m, 3H), 7.32 (d J=8.0Hz, 1H), 6.91-6.85 (m, 2H), 6.73 (d, J=7.9Hz, 1H), 6.66-6.56 (m, 1H), 4.93 (bs, 2H), 4.52 (bs, 2H).	3, 7
351	496	584	CH	CH	H	N-(2-Amino-phenyl)-3- [4-(3-trifluoromethoxy- benzylamino)-phenyl]- acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.22 (bs, 1H), 7.52 (d, J=7.9Hz, 2H), 7.44 (bs, 1H), 7.38 (bs, 3H), 7.28 (d J=6.9Hz, 2H), 6.95-6.92 (m, 2H), 6.79 (d, J=8.2Hz, 1H), 6.69-6.59 (m, 3H), 4.95 (bs, 2H), 4.45 (bs, 2H).	58
352	497	585	CH	CH	H	N-(2-Amino-phenyl)-3- [(4-(3,4,5-trimethoxy- phenoxymethyl)- phenyl]-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.45 (bs, 1H), 8.01 (bs, 2H), 7.78-7.5 (m, 4H), 7.49-7.40 (m, 1H), 6.98 (dd, J=7.0, 8.2Hz, 1H), 6.82 (d, J=7.0Hz, 1H), 6.64 (dd, J=7.0, 7.6Hz, 1H), 6.41 (bs, 2H), 5.17 (s, 2H), 3.81 (s, 6H), 3.64 (s, 3H).	3, 7
353	498	586	CH	CH	H	N-(2-Amino-phenyl)-3- [4-(6,7-dimethoxy-3,4- dihydro-1H-isoquinolin- 2-yl)-phenyl]-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.22 (bs, 1H), 7.17 (d, J=8.2Hz, 2H), 6.97 (d, J=8.2Hz, 2H), 6.93 (d, J=7.6Hz, 1H), 6.85 (bs, 1H), 6.77 (bs, 1H), 6.60-6.53 (m, 3H), 6.43-6.40 (m, 2H), 4.97 (bs, 2H), 4.43 (bs, 2H), 3.78 (s, 3H) 3.78 (s, 3H), 2.87-2.85 (m, 2H), 2.65-2.62 (m, 2H).	37
354	499	587	CH	CH	H	N-(2-Amino-phenyl)-3- (4-{[(1H-indol-2- ylmethyl)-(3,4,5- trimethyl-phenyl)- amino]-methyl}- phenyl)-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 10.77 (bs, 1H), 9.39 (bs, 1H), 7.62 (d, J=7.9Hz, 1H), 7.49 (d, J=5.7Hz, 2H), 7.37 (d, J=7.9Hz, 2H), 7.26 (d, J=7.9, 2H), 7.10 (t, J=7.5Hz, 2H), 7.00-6.83 (m, 4H), 6.78 (d, J=7.9Hz, 1H), 6.61 (t, J=7.5Hz, 1H), 5.98 (s, 1H), 5.32 (bs, 1H),
# 4.98 (bs, 2H), 4.32 (d, J=5.2Hz, 2H), 3.98 (bs, 2H), 3.73 (s, 3H), 3.67 (s, 3H), 3.64 (s, 3H).	58
355	500	588	CH	CH	H	N-(2-Amino-phenyl)-3- [4-(3,4,5-trimethoxy- phenylsulfanylmethyl)- phenyl]-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.69 (bs, 1H), 8.04 (d, J=8.3Hz, 2H), 7.78 (d, J=8.3Hz, 2H), 7.58-7.55 (m, 2H), 7.06 (d, J=6.2Hz, 1H), 6.96 (d, J=7.3Hz, 1H), 6.90 (d, J=7.0Hz, 1H), 6.60 (bs, 1H), 5.81 (s, 2H), 4.34 (bs, 2H), 3.78 (s, 6H), 3.67 (s, 3H).	3, 7
356	501	589	CH	CH	H	3-{4-[(6-Acetyl- benzo[1,3]dioxol-5- ylamino)-methyl]- phenyl}-N-(2-amino-phenyl)-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.81 (bs, 1H), 7.95 (d, J=7.9Hz, 2H), 7.58 (d, J=7.9Hz, 2H), 7.39 (bs, 1H), 7.21 (d, J=7.4Hz, 1H), 7.02-7.00 (m, 2H), 6.85 (d, J=7.5Hz, 1H), 6.64 (t, J=7.4Hz, 1H), 6.60 (bs, 1H), 6.36 (bs, 1H), 6.00 (d, J=2.2Hz, 2H), 4.60 (bs, 2H), 2.50 (bs, 3H).	58
357	502	590	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(methoxy- benzothiazol-2- ylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.43 (bs, 1H), 8.37 (bs, 1H), 7.66-7.57 (m, 3H), 7.49 (d, J=7.5Hz, 2H), 7.37-7.33 (m, 3H), 6.96-6.90 (m, 1H), 6.87 (d, J=8.8Hz, 1H), 6.80 (d, J=7.9Hz, 1H), 6.63 (t, J=7.5Hz, 1H), 4.99 (bs, 2H), 4.64 (bs, 2H), 3.37 (s, 3H).	58
358	503	591	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4-morpholin-4-yl- phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.42 (bs, 1H), 7.63-7.56 (m, 3H), 7.47 (d, J=7.9Hz, 2H), 7.39 (d, J=7.5Hz, 1H), 6.95 (d, J=8.3Hz, 1H), 6.82 (bs, 1H), 6.77 (d, J=8.4Hz, 2H), 6.66-6.56 (m, 3H), 5.91 (bs, 1H), 5.01 (bs, 2H), 4.30 (bs, 2H), 3.74 (bs, 4H), 2.93 (bs, 4H).	58
359	504	592	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4- trifluoromethyl-phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.42 (s, 1H), 7.64 (d, J=7.9Hz, 2H), 7.59 (d, J=15.9Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.39 (d J=7.4Hz, 1H), 7.10 (d, J=8.2Hz, 2H), 6.99 (d, J=7.1Hz, 1H), 6.92 (d, J=15.4Hz, 1H), 6.81 (dd, J=1.3, 8.0Hz, 1H), 6.61-6.68 (m, 4H), 4.99 (s, 2H), 4.36 (d, J=6.0Hz, 2H).	3, 33
360	505	593	CH	CH	H	N-(2-Amino-phenyl)-3- [4-(benzo[1,3]dioxol-5- ylaminomethyl)- phenyl-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.42 (s, 1H), 7.63 (d, J=7.7Hz, 2H), 7.59 (d, J=15.4Hz, 1H), 7.47 (d, J=8.0Hz, 2H), 7.40 (d, J=7.7Hz, 1H), 6.99 (d, J=7.1Hz, 1H), 6.92 (d, J=16.2Hz, 1H), 6.81 (dd, J=1.4, 8.0Hz, 1H), 6.68 (d, J=8.2Hz, 1H), 6.62 (dd, J=1.4, 7.7Hz, 1H), 6.34
# (d, J=2.2Hz, 1H), 6.05 (m, 2H), 5.87 (s, 2H), 4.99 (s, 2H), 4.29 (d, J=6.0Hz, 2H).	3, 33
361	506	594	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[3- trifluoromethoxy- phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.43 (s, 1H), 7.57-7.66 (m, 3H), 7.48 (d, J=7.6Hz, 2H), 7.40 (d, J=7.6Hz, 1H), 7.20 (dd, J=8.2, 8.2Hz, 1H), 6.99 (d, J=7.6Hz, 1H), 6.93 (d, J=15.2Hz, 1H), 6.81 (m, 2H), 6.64 (m, 2H), 6.49-6.55 (m, 2H), 5.00 (s, 2H), 4.38 (d, J=5.3Hz, 2H).	3, 33
362	507	595	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(2-methoxy- phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.42 (S, 1H), 7.63 (d, J=7.6Hz, 2H), 7.59 (d, J=15.8Hz, 1H), 7.47 (d, J=7.6Hz, 2H), 7.40 (d, J=7.6Hz, 1H), 6.90-7.02 (m, 3H), 6.81 (d, J=7.6Hz, 1H), 6.64 (dd, J=7.0, 7.0Hz, 1H), 6.36 (m, 1H), 6.24 (d, J=8.2Hz, 1H), 6.18 (m, 2H), 5.00 (s, 2H), 4.34 (d, J=5.3Hz, 2H), 3.69 (s, 3H).	3, 33
363	508	596	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(2-methoxy- phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.42 (s, 1H), 7.62 (d, J=7.0Hz, 2H), 7.58 (d, J=15.2Hz, 1H), 7.46 (d, J=7.6Hz, 2H), 7.40 (d, J=7.0Hz, 1H), 6.94-7.00 (m, 1H), 6.87 (d, J=7.6Hz, 2H), 6.81 (d, J=7.6Hz, 1H), 6.73 (dd, J=7.6, 7.6Hz, 1H), 6.56-6.66 (m, 2W), 6.45 (d, J=7.6Hz, 1H), 5.68 (t, J=5.9Hz, 1H),
# 4.99 (s, 2H), 4.41 (d, J=6.4Hz, 2H), 3.87 (s, 3H).	3, 33
364	509	597	CH	CH	H	N-(2-Amino-phenyl)-3- (4-phenylaminomethyl- phenyl)-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.42 (s, 1H), 7.63 (d, J=7.9Hz, 2H), 7.59 (d, J=15.8Hz, 1H), 7.48 (d, J=7.9Hz, 2H), 7.39 (d, J=7.5Hz, 1H), 7.10 (2d, J=7.5, 7.5Hz, 2H), 6.99 (d, J=7.5Hz, 1H), 6.92 (d, J=16.2Hz, 1H), 6.81 (d, J=7.5Hz, 1H), 6.55-6.64 (m, 4H), 6.32 (t, J=6.0, 1H), 4.99 (s, 2H), 4.35 (d, J=5.7Hz, 2H).	3, 33
365	510	598	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4-isopropyl- phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.42 (s, 1H), 7.62 (d, J=7.0Hz, 2H), 7.59 (d, J=15.8Hz, lH), 7.47 (d, J=8.2Hz, 2H), 7.40 (d, J=7.6Hz, 1H), 6.89-6.99 (m, 4H), 6.81 (d, J=7.6Hz, 1H), 6.64 (dd, J=7.0, 7.6Hz, 1H), 6.56 (d, J=8.2Hz, 2H), 6.14 (t, J=5.9Hz, 1H), 4.99 (s, 2H),
# 4.32 (d, J=5.9Hz, 2H), 2.76 (m, 1H), 1.17 (d, J=7.0Hz, 6H).	3, 33,
366	511	599	CH	CH	H	N-(2-Amino-phenyl)-3- [4-(biphenyl-4- ylaminomethyl)- phenyl]-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.43 (s, 1H), 7.57-7.66 (m, 5H), 7.40-7.52 (m, 7H), 7.27 (dd, J=7.0, 7.6Hz, 1H), 6.98 (d, J=7.6Hz, 1H), 6.93 (d, J=15.2Hz, 1H), 6.81 (d, J=8.2Hz, 1H), 6.73 (d, J=8.2Hz, 2H), 6.64 (dd, J=7.6 Hz, 1H), 6.56 (t, J=5.9Hz, 1H), 4.99 (s, 2H), 4.12 (d, J=5.9Hz, 2H).	3, 33
367	512	600	CH	N	H	N-(2-Amino-phenyl)-3- {6-[(3,4,5-trimethoxy- phenylamino)-methyl]- pyridin-3-yl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.50 (s, 1H), 8.81 (s, 1H), 8.05 (d, J=8.2Hz, 1H), 7.64 (d, J=15.7Hz, 1H), 7.52 (d, J=8.2Hz, 1H), 7.39 (d, J=7.4Hz, 1H), 6.96-7.05 (m, 2H), 6.81 (d, J=8.0Hz, 1H), 6.64 (dd, J=7.4, 7.4Hz, 1H), 6.26 (m, 1H), 5.96 (s, 2H), 5.01 (s, 2H),
# 4.43 (d, J=5.5Hz, 2H), 3.72 (s, 6H), 3.56 (s, 3H).	3, 33
369	514	601	CH	CH	H	N-(2-Amino-phenyl)-3- (4-{[1-(3-benzyl-7- chloro-4-oxo-3,4- dihydro-quinazolin-2- yl)-ethylamino]-methyl}- phenyl)-acrylamide	1 1H-NMR (DMSO-d6), δ (ppm): 9.50 (s, 1H), 8.28 (d, J=8.4Hz, 1H), 7.81-7.72 (s, 3H), 7.66 (d, J=8.1Hz, 2H), 7.88 (d, J=15.6Hz, 1H), 7.50 (d, J=8.1Hz, 2H), 7.45-7.26 (m, 4H), 7.24-7.15 (m, 2H), 7.00-6.86 (m, 2H), 6.84 (d, J=8.1Hz, 1H), 6.68 (t, J=7.5Hz, 1H), 5.45 (d, J=
# 16.8Hz, 1H), 533 (d, J=16.8Hz, 1H), 4.62 (bs, 1H), 4.25 (d, J=12.9Hz, 1H), 4.92 (d, J=12.9Hz, 1H), 1.91 (m, 2H), 1.28 (m, 1H), 0.90 (m, 1H), 0.72 (t, J=7.5Hz, 3H).	55
371	516	Br—	CH	CH	CH	N-(2-Amino-phenyl)-3-	1 H NMR: (Acetone-d6) δ (ppm): 9.47 (bs, 1H), 7.72-7.56	14
						(4-bromo-phenyl)-acrylamide	(m, 5H), 7.39 (d, J=7.4Hz, 1H), 7.00-6.95 (m, 2H), 6.81
							(d, J=6.9Hz, 1H), 6.64 (t, J=7.1Hz, 1H), 5.00 (bs, 2H).
372	517	602	CH	CH	CH	N-(2-Amino-phenyl)-4- (2,4,5-trimethoxy- benzylamino)-benzamide	1 H NMR: (CD3OD) δ (ppm): 7.61 (d, J=15.4Hz, 1H), 7.44 (d, J=8.4Hz, 2H), 7.25 (d, J=7.5Hz, 1H), 7.10 (t, J=7.5Hz, 1H), 7.00 (s, 1H), 6.94 (d, J=8.4Hz, 1H), 6.81 (t, J=7.0Hz, 1H), 6.76 (s, 1H) 6.70 (d, J=8.4Hz, 2H), 6.92 (d, J=15.4Hz, 1H), 4.35 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.77 (s, 3H).	1, 7, 10
373	518	603	CH	CH	CH	N-(2-Amino-phenyl)-3- {4-[1-(3,4,5- trimethoxy- phenylamino)-ethyl]- phenyl}-acrylamide	1 H NMR (DMSO-d6) δ (ppm): 9.24 (s, 1H), 8.00 1(d, J=12Hz, 1H); 7.80 (d, J=12Hz, 1H), 7.40-7.70 (m, 7H), 6.80-7.00 (m, 2H), 6.70 (d, J=12Hz,1H), 6.20 (s, 2H), 4.50 (m, 1H), 3.70 (s, 6H), 3.50 (s, 3H), 1.50 (d, 3H).	58
374	519	604	C	CH	H	N-(2-Amino-phenyl)-3- (9H-fluoren-2-yl)- acrylamide	1 H NMR (300MHz, DMSO-d6) 6 (ppm): 9.41 (s, 1H), 8.00 (t, J=7.9Hz, 2H), 7.88 (s, 1H), 7.77-7.56 (m, 3H), 7.52-7.32 (m, 3H), 7.00 (d, J=15.8Hz, 1H), 6.96 (t, J=6.80 (d,J=7.9Hz, 1H), 6.63 (t, J=7.5Hz, 1H), 5.00 (s, 2H), 4.03 (s, 2H).	59
375	520	605	CH	CH	H	N-(2-Amino-phenyl)-4- [2-(2-amino- phenylcarbamoyl)- vinyl]-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.71 (s, 1H), 9.43 (s, 1H), AB system (δA = 8.05, δB =7.75, J=7.9Hz, 4H), 7.62 (d, J=15.8Hz, 1H), 7.36 (d, J=7.9Hz, 1H), 7.18 (d, J=7.5Hz, 1H), 7.05-6.88 (m, 3H), 6.78 (t, J=7.9 Hz, 2H), 6.65-6.55 (m, 2H), 4.96 and 4.92 (2s, 4H).	59
376	521	606	N	CH	H	N-(2-Amino-phenyl)-3- {6-[2-(pyrimidin-2- ylamino)-ethylamino]- pyridin-3-yl}-acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.29 (s, 1H), 8.32 (d, J=4.9Hz, 2H), 8.24 (d, J=1.9Hz, 1H), 7.71 (d, J=6.9Hz, 1H), 7.48 (d, J=15.7Hz, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.26 (bs, 2H), 6.96 (t, J=6.9Hz, 1H), 6.80 (dd, J=1.1, 7.7Hz, 1H), 6.69-6.61 (m, 4H), 5.00 (s, 2H), 3.52 (bs, 4H),	3
377	522	607	N	CH	H	N-(2-Amino-phenyl)-3- {6-[2-(thiazol-2- ylamino)-ethylamino]- pyridin-3-yl}-acrylamide	1 H NMR (300MHz, CD3OD) δ (ppm): 8.12 (s, 1H), 8.08 (s, 1H), 7.78 (d, J=8.8Hz, 1H), 7.54 (d, J=15.4Hz, 1H), 7.19 (d, J=8.0Hz, 1H), 7.04 (t, J=7.4Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 6.75 (t, J=7.4Hz, 1H), 6.64 (d, J=15.4Hz, 1H), 6.65 (s, 1H), 4.90 (s, 5H), 3.50-3.45 (m, 4H), 3.30 (d, J=1.3Hz, 1H).	3
378	523	608	CH	CH	H	N-(2-Amino-phenyl)-3- (4-{[(2-morpholin-4-yl- ethyl)-(3,4,5- trimethoxy-phenyl)- amino]-methyl}- phenyl)-acrylamide	1 H-NMR (CD3OD), δ (ppm): 7.83 (d, J=15.6Hz, 1H), 7.67 (d, J=7.8Hz, 2H), 7.62-7.58 (m, 2H), 7.53-7.51 (m, 2H), 7.49 (d, J=7.8Hz, 2H), 7.01 (d, J=15.6Hz, 1H), ), 4.99 (bs, 9H), 4.84 (bs, 2H), 4.22 (t, J=6.5Hz, 2H),
# 4.05 (s, 4H), 3.85 (s, 6H), 3.76 (s, 3H), 3.57-3.50 (m, 4H).	3, 33, 57
379	524	609	N	CH	H	N-(2-Amino-phenyl)-3- ≢6-(3-hydroxy- benzylamino)-pyridin-3- yl]-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.32 (s, 1H), 9.26 (s, 1H), 8.19 (s, 1H), 7.66 (d, J=8.5Hz, 1H), 7.57 (t, J=6.0Hz, 1H), 7.41 (d, J=15.7Hz, 1H), 7.32 (d J=7.7Hz), 7.10 (t, J=7.6Hz, 1H), 6.91 (t, J=7.6Hz, 1H), 6.75 (m, 3H), 6.59 (m, 4H), 4.98 (bs, 2H), 4.46 (d, J=5.8Hz, 2H).	3
380	525	610	N	CH	H	N-(2-Amino-phenyl)-3- {(6-[3-(2,2,2-trifluoro- ethoxy)-benzylamino]- pyridin-3-yl}- acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.25 (s, 1H), 8.18 (s, 1H), 7.67 (d, J=8.8Hz, 1H), 7.59 (t, J=6.0Hz, 1H), 7.42 (d, J=15.7Hz, 1H), 7.30 (m, 2H), 7.00 (m, 2H), 6.92 (m, 2H), 6.74 (d, J=8.0Hz, 1H), 6.60 (m, 3H), 4.92 (s, 2H), 4.73 (q, J=8.8Hz, 2H), 4.52 (d, J=5.8Hz, 2H).	3
381	526	611	CH	CH	H	N-(2-Amino-phenyl)-3- (4-{[3-hydroxy-4-(4- methyl-piperazin-1-yl)- phenylamino]-methyl}- phenyl)-acrylamide	1 H-NMR (CD3OD), δ (ppm): 7.64 (d, J=15.6Hz, 1H), 7.56 (d, J=8.0Hz, 2H), 7.49 (m, 1H), 7.40 (d, J=8.0Hz, 2H), 7.21 (m, 2H), 7.03 (t, J=7.6Hz, 1H), 6.88-6.71 (m, 4H), 4.88 (bs, 4H), 4.34 (s, 2H), 2.86 (t, J=4.1Hz, 4H), 2.67 (bs, 4H), 2.41 (s, 3H).	3, 33, 58
382	527	612	CH	CH	H	N-(2-Amino-phenyl)-3- (4-{[3-fluoro-4-(4- methyl-piperazin-1-yl)- phenylamino]-methyl}- phenyl)-acrylamide	1 H-NMR (DMSO-d6, δ (ppm): 9.43 (s, 1H), 7.61 (d, J=8.0Hz, 2H), 7.45 (d, J=8.0Hz, 2H), 7.38 (d, J=7.6Hz, 1H), 7.00-6.88 (m, 2H), 6.85-6.79 (m, 2H), 6.63 (t, J=7.6Hz, 1H), 6.44-6.30 (m, 3H), 4.99 (bs, 2H), 4.30 (d, J=5.5Hz, 2H), 2.87 (bs, 4H), 2.55 (m, 4H), 2.27 (s, 3H).	3, 33, 58
383	528	613	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(3-hydroxy- phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (CDCl3), δ (ppm): 7.49 (d, J=14.0Hz, 1H); 7.32 (d, J=7.2Hz, 2H), 7.15 (d, J=7.2Hz, 2H), 7.05 (m, 1H), 6.96 (m, 1H), 6.90 (m, 3H), 6.76 (m, 1H), 6.55 (d, J=14.0Hz, 1H), 6.03 (m, 1H), 5.99 (m, 1H), 4.30 (bs, 5H), 4.10 (s, 2H).	3, 33
384	529	614	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4-trifluoromethyl- pyrimidin-2-ylamino)- methyl]-phenyl}- acrylamide	1 H-NMR (CD3OD), δ (ppm): 7.73 (d, J=16.0Hz, 1H); 7.63 (d, J=8.5Hz, 1H), 7.58 (d, J=8.0Hz, 2H), 7.46 (d, J=8.0Hz, 2H), 7.38 (d, J=8.5Hz, 1H), 7.20 (d, J=8.0Hz, 1H), 7.03 (dt, J=7.7, 1.4Hz, 1H), 6.89 (d, J=1.1Hz, 1H),
# 6.85 (m, 1H), 6.73 (dt, J=7.7, 1.1Hz, 1H), 6.56 (d, J=16.0Hz, 1H), 5.27 (s, 2H), 4.87 (bs, 2H), 4.62 (s, 2H).	3, 33
385	530	615	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(3-hydroxymethyl- phenylamino)-methyl]-phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.90 (s, 1H), 7.58 (m, 3H), 7.43 (d, J=8.0Hz, 2H); 7.37 (d, J=8.0Hz, 1H), 7.11 (m, 1H), 7.00 (m, 3H), 6.85 (d, J=15.4Hz, 1H), 6.63 (s, 1H), 6.51 (d, J=7.4,Hz, 1H), 6.46 (d, J=7.7Hz, 1H), 4.35 (s, 2H), 4.32 (s, 2H).	3, 33
386	531	616	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4-pyridin-4- ylmethyl-phenylamino)- methyl]-phenyl}- acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.66 (s, 1H), 8.46 (d, J=4.7Hz, 2H); 7.55 (d, J=8.0Hz, 2H), 7.50 (d, J=15.7Hz, 1H), 7.39 (d, J=8.0Hz, 2H), 7.28 (d, J=4.7Hz, 2H), 7.00 (d, J=15.7Hz, 1H), 6.92 (d, J=6.9Hz, 2H), 6.90 (m, 1H), 6.75 (d, J=8Hz, 1H), 6.58 (m, 2H), 6.52 (d, J=6.9, Hz,
# 2H), 6.10 (bs, 1H), 4.26 (bs, 2H), 3.80 (s, 2H), (d, J=1.9Hz, 2H).	3, 33
387	532	617	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(3-cyano- phenylamino)-methyl]-phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.38 (s, 1H), 7.58 (d, J=7.7Hz, 2H); 7.54 (d, J=15.9Hz, 1H), 7.41 (d, J=7.7Hz, 2H), 7.33 (d, J=8.0Hz, 1H), 7.24 (t, J=7.7Hz, 1H), 6.92-6.83 (m, 5H), 6.75 (d, J=8.0Hz, 1H), 6.58 (t, J=7.4Hz, 1H), 4.95 (bs, 2H), 4.34 (d, J=5.8Hz, 2H).	3, 33
388	533	618	CH	CH	H	3-(4-{[3-(Acetylamino- methyl)-phenylamino]- methyl}-phenyl)-N-(2- amino-phenyl)- acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.37 (bs, 1H), 8.21 (t, J=5.8Hz, 1H), 7.56 (d, J=7.7Hz, 2H), 7.53 (d, J=15.7Hz, 1H), 7.41 (d, J=8.0Hz, 2H), 7.33 (d, J=7.1Hz, 1H), 6.97 (m, 1H), 6.85 (d, J=15.7Hz, 1H), 6.74 (dd, J=1.4, 8.0Hz, 1H), 6.58 (dt, J=1.4, 8.0Hz, 1H), 6.50 (bs, 1H), 6.41
# (d, J=8.0Hz, 2H), 6.30 (t, J=6.0Hz, 1H), 4.94 9bs, 2H), 4.28 (d, J=6.0Hz, 2H), 4.09 (d, J=6.0Hz, 2H), 1.83(s, 3H).	3, 33
389	534	619	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4-nitro-3- trifluoromethyl- phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.37 (bs, 1H), 7.56 (d, J=8.0Hz, 2H), 7.53 (d, J=15.7Hz, 1H), 7.41 (d, J=8.0Hz, 2H), 7.33 (d, J=7.7Hz, 1H), 6.92 (d, J=7.7Hz, 2H), 6.85 (d, J=15.7Hz, 1H), 6.74 (d, J=8.0Hz, 1H), 6.67-6.55 (m, 4H), 5.84 (t, J=5.8Hz, 1H), 4.94 (bs, 2H), 4.22 (d, J=5.8Hz, 2H).	3, 33
390	535	620	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(3,5-dichloro- phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.39 (bs, 1H), 7.60 (d, J=8.0Hz, 2H), 7.54 (d, J=15.7Hz, 1H), 7.40 (d, J=8.0Hz, 2H), 7.33 (d, J=7.1Hz, 1H), 6.97-6.89 (m, 2H), 6.87 (d, J=15.7Hz, 1H), 6.75 (dd, J=1.4, 8.0Hz, 1H), 6.60-6.55 (m, 4H), 4.95 (bs, 2H), 4.33 (d, J=6.0Hz, 2H).	3, 33
391	536	621	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[2-(3,4,5- trimethoxy-phenyl)- vinyl]-phenyl}- arcylamide	1 H-NMR (CDCl3), δ (ppm): 8.12 (bs, 1H), 7.64 (d, J=14.2Hz, 1H), 7.42 (bs, 4H), 7.23 (bs, 2H), 6.97 (d, J=14.2Hz, 1H), 6.94-6.82 (m, 4H), 6.70 (s, 2H), 4.11 (bs, 2H), 3.87 (s, 6H), 3.84 (s, 3H).	3
392	537	622	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[2-(3,4,5- trimethoxy-phenyl)- vinyl]-phenyl}- arcylamide	1 H-NMR (DMSO-d6), δ (ppm): 8.49 (s, 1H), 7.58 (d, J=15.7Hz, 1H), 7.33 (d, J=8.5Hz, 1H), 7.23 (m, 4H), 7.00 (d, J=8.5Hz, 1H), 6.73 (d, J=5.0Hz, 2H), 6.69 (d, J=5.0Hz, 2H), 6.58 (d, J=15.4Hz, 1H), 6.53 (bs, 2H), 6.47 (s, 2H), 3.85 (s, 3H), 3.63 (s, 6H).	3
393	538	623	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(3-sulfmoyl- phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (CD3OD/CDCl3), δ (ppm): 7.61 (d, J=15.7Hz, 1H), 7.45 (d, J=8.1Hz, 2H), 7.29 (d, J=8.1Hz, 2H), 7.18 (dd, J=8.0Hz, 2H), 7.12 (d, J=15.7Hz, 1H), 7.10 (m, 1H), 7.03 (t, J=7.4Hz, 1H), 6.83-6.66 (m, 4H), 3.93 (bs, all NH signals).	1, 3, 33
394	539	624	CH	CH	H	N-(2-Amino-phenyl)-3- (4-{[3-(3-morpholin)- phenylamino]-methyl}- phenyl)-acrylamide	1 H-NMR (CDCl3), δ (ppm): 8.34 (bs, 1H), 7.64 (d, J=15.4Hz, 1H), 7.37 (d, J=8.0Hz, 2H), 7.34 (m, 1H), 7.26 (d J=8.0Hz, 2H), 7.23 (d, J=15.4Hz, 1H), 7.14 (d, J=7.8Hz, 1H), 7.04 (m, 2H), 6.74 (m, 4H), 4.85 (bs, 1H), 4.30 (d, J=4.4Hz, 2H), 3.69 (t, J=4.4Hz, 4H), 2.99 (t, J=5.8Hz, 2H),
# 2.40 (bs, 6H), 1.59 (t, J=4.4Hz, 2H).	3, 33, 42
395	540	625	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[2-(3,4,5- trimethoxy-phenyl)- ethyl]-phenyl}- acrylamide	1 H-NMR (CDCl3), δ (ppm): 8.53 (s, 1H), 7.72 (d, J=15.6Hz, 1H), 7.38 (d, J=7.7Hz, 2H), 7.33 (m, 1H), 7.16 (d, J=7.7Hz, 2H), 7.07 (m, 1H), 6.79 (m, 2H), 6.69 (d, J=15.6Hz, 1H), 6.41 (s, 2H), 4.04 (bs, 2H), 3.91 (s, 3H), 3.85 (s, 6H), 2.94 (m, 4H).	3, 33
396	541	626	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4-methoxy- phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.35 (s, 1H), 7.56 (d, J=7.5Hz, 2H), 7.52 (d, J=15.4Hz, 1H), 7.40 (d, J=7.5Hz, 2H), 7.33 (d, J=7.7Hz, 1H), 6.92 (d, J=7.7Hz, 1H), 6.85 (d, J=15.4Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 6.67 (d J=8.6Hz, 2H), 6.58 (m, 1H), 6.52 (d, J=8.6Hz, 2H),
# 5.84 (t, J=5.5Hz, 1H), 4.23 (d, J=5.5Hz, 2H), 3.61 (s, 3H).	3, 33
397	542	627	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(3,4-dimethoxy- phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (CDCl3), δ (ppm): 8.48 (s, 1H), 7.60 (d, J=15.4Hz, 1H), 7.27 (m, 5H), 6.97 (t, J=7.5Hz, 1H), 6.70 (m, 3H), 6.59 (d, J=15.4Hz, 1H), 6.25 (s, 1H), 6.12 (d, J=7.1Hz, 1H), 4.23 (s, 2H), 3.93 (bs, 3H), 3.75 (s, 3H), 3.73 (s, 3H).	3, 33
398	543	628	CH	CH	H	N-(2-Amino-phenyl)-3- (4-{[3-(1H-tetrazol-5-yl)- phenylamino]-methyl}- phenyl)-acrylamide	1 H-NMR (CD3OD), δ (ppm): 7.75 (d, J=15.2Hz, 1H), 7.60 (d, J=7.6Hz, 2H), 7.48 (d, J=7.6Hz, 2H), 7.33 (m, 3H), 7.27 (m, 3H), 7.20 (m, 1H), 6.84 (m, 2H), 5.48 (bs, 5H), 4.46 (s, 2H).	3, 33
399	544	629	CH	CH	H	N-(2-Amino-phenyl)-3- (4-{[4-(1H-tetrazol-5- ylmethyl)- phenylamino]-methyl}- phenyl)-acrylamide	1 H-NMR (CD3OD), δ (ppm): 7.75 (d, J=15.2Hz, 1H), 7.58 (d, J=8.2Hz, 2H), 7.42 (d, J=8.2Hz, 2H), 7.29 (m, 2H), 7.20 (m, 2H), 7.04 (d, J=8.2Hz, 2H), 6.83 (d, J=15.2Hz, 1H), 6.67 (d, J=8.2Hz, 2H), 5.48 (bs, 5H), 4.39 (s, 2H), 4.16 (s, 2H).	3, 33
400	545	630	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4-bromo- phenylamino)-methyl]- phenyl}-acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.42 (s, 1H), 7.62 (d, J=8.5Hz, 2H), 7.59 (d, J=15.6Hz, 1H), 7.45 (d, J=8.0Hz, 2H), 7.40 (d, J=7.5Hz, 1H), 7.23 (d, J=8.5Hz, 2H), 6.98 (d, J=7.5Hz, 1H), 6.92 (d, J=15.6Hz, 1H), 6.80 (d, J=8.0Hz, 1H), 6.66-6.57 (m, 4H), 4.99 (bs, 2H), 4.34 (d, J=5.8Hz, 2H).	3, 33
401	546	631	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(3-bromo- phenylamino)-methyl]- phenyl}acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.36 (s, 1H), 7.57 (d, J=7.6Hz, 2H), 7.54 (d, J=15.8Hz, 1H), 7.40 (d J=8.2Hz, 2H), 7.33 (d, J=7.6Hz, 1H), 7.00-6.91 (m, 2H), 6.86 (d, J=15.8Hz, 1H), 6.74 (d, J=8.2Hz, 2H), 6.66-6.54 (m, 4H), 4.93 (bs, 2H), 4.30 (d, J=5.3Hz, 2H).	3, 33
402	547	632	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4-iodo- phenylamino)-methyl]- phenyl}-acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.36 (s, 1H), 7.56 (d, J=8.0Hz, 2H), 7.53 (d, J=15.8Hz, 1H), 7.39 (d, J=8.0Hz, 2H), 7.35 (m, 1H), 7.31 (d, J=8.2Hz, 2H), 6.92 (d, J=7.1Hz, 1H), 6.85 (d, J=15.8Hz, 1H), 6.75 (d J=7.7Hz, 1H), 6.57 (t, J=8.0Hz, 1H), 6.52 (t, J=
# 6.0Hz, 1H), 6.42 (d, J=8.5Hz, 2H), 4.94 (bs, 2H), 4.28 (d, J=6.0Hz, 2H).	3, 33
403	548	633	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(3-iodo- phenylamino)-methyl]- phenylamino)-methyl]- phenyl}-acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.40 (s, 1H), 7.57 (d, 7.6Hz, 2H), 7.53 (d, 15.6Hz, 1H), 7.40 (d J=8.2Hz, 2H), 7.33 (d, J=7.6Hz, 1H), 6.92 (m, 3H), 6.84 (m, 2H), 6.74 (d, J=7.6Hz, 1H), 6.60-6.50 (m, 3H), 4.93 (bs, 2H), 4.28 (d, J=5.9Hz, 2H).	3, 33
404	549	634	CH	CH	H	N-(2-Amino-phenyl)-3- (4-{[3-(2-hydroxy-ethoxy)-phenylamino]- methyl}-phenyl)- acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.42 (s, 1H), 7.63 (d, J=8.2Hz, 2H), 7.60 (d, J=15.3Hz, 1H), 7.46 (d, J=8.2Hz, 2H), 7.40 (d, J=7.6Hz, 1H), 7.03-6.98 (m, 2H), 6.91 (d, J=15.3Hz, 1H), 6.81 (d, J=7.6Hz, 1H), 6.64 (t, J=7.6Hz, 1H), 6.36 (t, J=5.9Hz, 1H), 6.28-6.22 (m, 3H), 4.99 (bs, 3H), 4.61 (s, 2H),
# 4.34 (d, J=5.0Hz, 2H) 4.28 (d, J=5.0Hz, 2H).	3, 33
405	550	635	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4-nitro- phenylamino)-methyl]- phenyl}-acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.38(s, 1H), 7.99 (d J=9.1Hz, 2H), 7.85 (t, J=5.9Hz, 1H), 7.60 (d, J=7.6Hz, 2H), 7.54 (d, J=15.8Hz, 1H), 7.40 (d, J=7.6Hz, 2H), 7.34 (d, J=7.6Hz, 1H), 6.94-6.92 (m, 1H), 6.88 (d, J=15.8Hz, 1H), 6.75 (d, J=7.6Hz, 1H), 6.68 (d, J=9.1Hz, 2H), 6.58
# (t, J=7.6Hz, 1H), 4.94 (bs, 2H), 4.46 (d, J=5.9Hz, 2H)	3, 33
406	551	636	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4-nitro- phenylamino)-methyl]- phenyl}-acrylamide	hu 1H NMR (300MHz, DMSO-d6) δ (ppm): 9.37 (s, 1H), 7.59 (d, J=7.6Hz, 2H), 7.54 (d, J=15.2Hz, 1H), 7.43 (d, J=7.6Hz, 2H), 7.36-7.28 (m, 4H), 7.05-6.98 (m, 2H), 6.92 (d, J=7.6Hz, 1H), 6.88 (d, J=15.2Hz, 1H), 6.75 (d, J=7.6Hz, 1H), 6.58 (t, J=7.6Hz, 1H), 4.96 (bs, 2H), 4.39 (d, J=5.3Hz, 2H).	3, 33
407	552	637	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4-chloro- phenylamino)-methyl]- phenyl}-acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.43 (s, 1H), 7.62 (d, J=7.6Hz, 2H), 7.59 (d, J=15.8Hz, 1H), 7.46 (d, J=7.6Hz, 2H), 7.40 (d, J=7.6Hz, 1H), 7.12 (d, J=8.8Hz, 2H), 6.98 (d, J=7.6Hz, 1H), 6.93 (d, J=15.8Hz, 1H), 6.81 (d, J=7.6Hz, 1H), 6.62 (d, J=8.8Hz, 2H), 6.55 (bs, 2H), 4.99 (bs, 2H),
# 4.46 (d, J=5.9Hz, 2H), 4.35 (d, J=5.9Hz, 2H)	3, 33
408	553	638	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4-chloro- phenylamino)-methyl]- phenyl}-acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.50 (s, 1H), 7.65 (d, J=8.2Hz, 2H), 7.61 (d, J=15.4Hz, 1H), 7.47 (d, J=7.6Hz, 2H), 7.43 (m, 1H), 6.93 (d, J=7.0Hz, 1H), 6.79 (d, J=15.4Hz, 1H), 6.68 (m, 3H), 6.59 (m, 3H), 5.24 (bs, 2H), 4.31 (s, 2H).	3, 33
409	554	639	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(4-fluoro- phenylamino)-methyl]- phenyl}-acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.37 (s, 1H), 7.63 (d, J=8.2Hz, 2H), 7.60 (d, J=15.4Hz, 1H), 7.47 (d, J=7.6Hz, 2H), 7.41 (m, 1H), 7.01-6.90 (m, 4H), 6.75 (d, J=7.6Hz, 1H), 6.67-6.59 (m, 3H), 6.27 (bs, 1H), 4.95 (bs, 2H), 4.27 (s, 2H).	3, 33
410	555	640	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(3-methylsulfanyl- phenylamino)-methyl]- phenyl]-acrylamide	1 H NMR (300MHz, CD3OD) δ (ppm): 7.64 (d, J=15.9Hz, 1H), 7.47 (d, J=7.5Hz, 2H), 7.32 (d, J=7.5Hz, 2H), 7.19 (d, J=7.5Hz, 1H), 7.03 (t, J=7.8Hz, 1H), 6.82 (d, J=7.5Hz, 1H), 6.77 (d, J=7.8Hz, 1H), 6.70 (d, J=15.9Hz, 1H), 6.56 (d, J=7.8Hz, 1H), 6.49 (s, 1H), 6.37 (d, J=7.8Hz, 1H),
# 4.29 (s, 2H), 4.05 (bs, 4H), 2.37 (s, 3H).	3, 33
411	556	641	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(3-methylsulfanyl- phenylamino)-methyl]- phenyl]-acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.36 (S, 1H), 7.57 (d, J=7.5Hz, 2H), 7.53 (d, J=15.8Hz, 1H), 7.40 (d J=7.9Hz, 2H), 7.34 (d, J=7.9Hz, 1H), 7.07 (d, J=8.3Hz, 2H), 6.92 (d, J=7.5Hz, 1H), 6.87 (d, J=15.8Hz, 1H), 6.75 (d, J=7.9Hz, 1H), 6.60-6.54 (m, 3H), 6.39 (t, J=5.7Hz, 1H),
# 4.93 (bs, 2H), 4.29 (d, J=6.1Hz, 2H), 2.32 (s, 3H),.	3, 33
412	557	642	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(5-bromo-pyridin-2- ylamino)-methyl]- phenyl}-acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.36 (s, 1H), 8.02 (d, J=1.7Hz, 1H), 7.57-7.50 (m, 4H), 7.38-7.32 (m, 4H), 6.92 (d, J=7.5Hz, 1H), 6.86 (d, J=16.3Hz, 1H), 6.75 (d, J=7.9Hz, 1H), 6.59 (d, J=7.5Hz, 1H), 6.53 (d, J=9.2Hz, 1H), 4.94 (bs, 2H), 4.48 (d, J=5.7Hz, 2H).	3, 33
413	558	643	CH	CH	H	N-(2-Amino-phenyl)-3- [4-(naphthalen-1- ylaminomethyl)- phenyl]-acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.37 (s, 1H), 8.25 (m, 1), 7.76 (m, 1H), 7.57 (m, 2H), 7.47 (m, 4H), 7.33 (d, J=7.0Hz, 1H), 7.17 (m, 1H), 7.07 (d, J=8.2Hz, 1H), 6.99 (t, J=5.3Hz, 1H), 6.92 (d, J=7.0Hz, 1H), 6.85 (d, J=16.4Hz, 1H), 6.74 (d, J=7.6Hz, 1H), 6.57 (t, J=7.6Hz, 1H), 6.36 (t,
# J=7.6Hz, 1H), 4.90 (s, 2H), 4.54 (d, J=5.3Hz, 2H).	3, 33
414	559	644	CH	CH	H	N-(2-Amino-phenyl)-3- {4-[(3-fluoro- phenylamino)-methyl]-phenyl}-acrylamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.39 (s, 1H), 7.57 (d, J=7.0Hz, 2H), 7.53 (d, J=15.4Hz, 1H), 7.40 (d, J=7.6Hz, 2H), 7.36 (d, J=7.6Hz, 1H), 7.02 (q, J=7.6Hz, 1H), 6.90 (m, 2H), 6.76 (d, J=8.2Hz, 1H), 6.58 (m, 1H), 6.40 (d, J=8.2Hz, 1H), 6.29 (m, 2H), 4.90 (s, 1H), 4.29 (bs, 2H), 4.02 (s, 2H).	3, 33
415	560	645	N-(2-Amino-phenyl)-3-{3,5- dimethoxy-4-[(3,4,5- trimethoxy-phenylamino)- methyl]-phenyl}-acrylamide	1 H-NMR (CDCl3), δ (ppm): 7.73 (bs, 1H), 7.63 (d, J=14.9Hz, 1H), 6.81 (m, 3H), 6.70 (m 2H), 6.68-6.56 (m, 2H), 6.07 (s, 2H), 4.35 (s, 2H), 3.86 (s, 6H), 3.81 (s, 6H), 3.75 (s, 3H).	60
416	561	646	N-(2-Amino-3-hydroxy- phenyl)-3-{4-[(3,4,5- trimethoxy-phenylamino)- methyl]-phenyl}- acrylamide	1 H NMR (300MHz, CDCl3) δ (ppm): 9.22 (s, 1H), 9.11 (s, 1H), 7.57 (d, J=7.9Hz, 2H), 7.64 (d, J=15.8Hz, 1H), 7.44 (d, J=7.9Hz, 2H) 6.96 (d, J=15.8Hz, 1H) 6.78 (t J=7.9Hz, 1H), 6.23 (t, J=7.9Hz, 1H), 6.16 (d, J=7.9Hz, 1H), 6.09 (t, J=6.2Hz, 1H), 5.89 (s, 2H), 4.77 (bs, 2H),
# 4.27 (d, J=5.7Hz, 2H), 5.89 (s, 6H), 5.76 (s, 3H).	3, 33
417	562	647	CH	CH	H	N-(2-Amino-phenyl)-3-{4- [(2,3,4-trimethoxy- phenylamino)-methyl]- phenyl}-acrylamide	1 H NMR (300MHz, CDCl3) δ (ppm): 8.25 (s, 1H), 7.74 (d, J=15.5Hz, 1H), 7.44 (d, J=7.9Hz, 2H), 7.37 (d, J=7.9Hz, 2H), 7.34-7.29 (m, 2H), 7.08 (t, J=7.5Hz, 1H), 6.82 (t, J=7.5Hz, 1H), 6.79 (m, 1H), 6.66 (d, J=15.5Hz, 1H), 6.60 (d, J=8.8Hz, 1H), 6.31 (d, J=8.8Hz, 1H), 4.36 (s, 2H),
# 4.18 (bs, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 3.84 (s, 3H).	3, 33
418	563	648	CH	CH	H	N-(2-Amino-phenyl)-3-[4-({4- methoxy-3-[(3,4,5- trimethoxy-phenylamino)- methyl]-phenylamino}- methyl)-phenyl]-acrylamide	1 H NMR (300MHz, CDCl3) δ (ppm): 8.58 (s, 1H), 7.66 (d, J=15.4Hz, 1H), 7.33-7.28 (m, 3H), 7.23 (d, J=7.0Hz, 2H), 7.04 (t, J=7.0Hz, 1H), 6.77-6.70 (m, 4H), 6.64 (d, J=15.4Hz, 1H), 6.53 (d, J=7.5Hz, 1H), 5.90 (s, 2H), 4.27 (s, 2H), 4.25 (s, 2H),
# 4.08 (bs, 4H), 3.82 (s, 6H), 3.77 (s, 6H).	3, 33
419	564	649	N-(2,3-Diamino-phenyl)-3- {4-[(3,4,5-trimethoxy- phenylamino)-methyl]- phenyl}-acrylamino	1 H NMR (300MHz, CDCl3) δ (ppm): 7.64 (d, J = 15.4Hz, 1H), 7.48 (d, J = 7.5Hz, 2H), 7.35 (d, J = 7.5Hz, 2H), 7.31-7.24 (m, 2H), 6.86 (s, 1H), 6.73 (d, J=15.4Hz, 1H), 5.84 (s, 2H), 4.27 (s, 2H), 4.00 (bs, 6H), 3.71 (s, 6H), 3.68 (s, 3H).	3, 33
420	565	650	CH	CH	H	N-(2-Amino-phenyl)-3-{4-[(3- fluoro-4-methylsulfanyl- phenylamino)-methyl]-phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.38 (bs, 1H), 7.58 (d, J=7.5Hz, 2H), 7.54 (d, J=15.4Hz), 1H), 7.40 (d, J=7.9Hz, 2H), 7.33 (d, J=7.9Hz, 1H), 7.14 (t, J=8.3Hz, 1H), 6.94-6.89 (m, 2H), 6.81 (d, J=15.7Hz, 1H), 6.74 (d, J=8.3Hz, 1H), 6.58 (t, J=7.5Hz, 1H),
# 6.43-6.38 (m, 2H), 4.94 (bs, 2H), 4.30 (d, J=5.7Hz, 2H). 2.28 (s, 3H).	3, 33
421	566	651	CH	CH	H	N-(2-Amino-phenyl)-3-{4-[(4- methylsulfanyl-3- trifluoromethyl- phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.39 (bs, 1H), 7.59 (d, J=7.9Hz, 2H), 7.54 (d, J=15.8Hz, 1H), 7.41 (d, J=7.9Hz, 2H), 7.36 (d, J=7.9Hz, 1H), 7.33 (d, J=6.2Hz, 1H), 6.96-6.90 (m, 4H), 6.82 (d, J=15.8Hz, 1H), 6.79-6.74 (m, 1H), 6.58 (t, J=7.5Hz, 1H),
# 4.95 (bs, 2H), 4.35 (d, J=6.2Hz, 2H), 2.35 (s, 3H).	3, 33
422	567	652	N-(2-Amino-phenyl)-3-{3- nitro-4-[(3,4,5-trimethoxy-phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.50 (s, 1H), 8.09 (s, 1H), 7.80 (d, J=15.4Hz, 1H), 7.81 (s, 2H), 7.34 (d, J=7.9Hz, 1H), 6.94 (d, J=7.5Hz, 1H), 6.88 (d, J=15.4Hz, 1H), 6.76 (d, J=7.9Hz, 1H), 6.58 (t, J=7.5Hz, 1H), 6.26 (t, J=6.2Hz, 1H), 5.90 (s, 2H), 4.96 (bs, 2H), 4.39 (d, J=5.7Hz, 2H), 3.66 (s, 6H), 3.51 (s, 3H).	3, 33
423	568	653	N-(2-Amino-phenyl)-3-{3- amino-4-[(3,4,5- trimethoxy-phenylamino)- methyl]-phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.29 (s, 1H), 7.72 (d, J=15.4Hz, 1H), 7.33 (m, 2H), 6.90 (1H); 6.71 (2H), 6.62 (3H), 5.97 (1H), 5.87 (2H), 5.49 (2H), 4.96 C2H) , 4.10 (2H), 3.65 (6H), 3.51 (3H).	3, 33
424	569	654	N-(2-Amino-phenyl)-3-[6- (3,4-dimethyloxy-phenyl)- pyridin-3-yl]-acrylamide	LRMS: calc: 375.4, found: 376.4	3, 15, 33
425	570	655	N-(4-Amino-thiophen-3-yl)- 3-{4-[(4-morpholin-4-yl- phenylamino)-methyl]- phenyl}-acrylamide	1 H-NMR (DMSO-d6), δ (ppm): 9.64 (bs, 1H), 7.65 (d, J=7.9Hz, 2H), 7.60 (d, J=14.0Hz, 1H), 7.50 (d, J=7.9Hz, 2H), 6.90 (d, J=15.8Hz, 1H), 6.15 (d, J=4.0Hz, 1H), 5.95 (s, 2H), 5.82 (s, 1H), 4.89 (bs, 2H), 4.33 (d, J=5.7Hz, 2H), 3.71 (s, 6H), 3.57 (s, 3H).	3, 33, 60

[0406] 656

Example 85

[0407] N-(2-Amino-phenyl)-4-(1H-benzimidazol-2-ylsulfanylmethyl)-benzamide (Compound 126)

[0408] Step 1: 4-(1H-Benzimidazol-2-ylsulfanylmethyl)-benzoic Acid Methyl Ester (Compound 122)

[0409] 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).

[0410] Step 2: N-(2-Amino-phenyl)-4-(1H-benzimidazol-2-ylsulfanylmethyl)-benzamide (126)

[0411] 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) δ (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

[0412] N-(2-Amino-phenyl)-4-[6-(2-morpholin-4-yl-ethylamino)-benzothiazol-2-ylsulfanylmnethyl]-benzamide (Compound 128)

[0413] Step 1: 4-(6Amino-benzothiazol-2-ylsulfanylmethyl)-benzoic Acid Methyl Ester (122)

[0414] 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+1).

[0415] Step 2: 4-[6-(2-Morpholin-4-yl-ethylamino)-benzothiazol-2-ylsulfanylmethyl]-benzoic Acid Methyl Ester (Compound 124)

[0416] 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), NaI (363 mg, 2.42 mmol), Et3N (370 μL, 2.66 mmol) and tetrabutylammonium iodide (894 mg, 2.42 mmol), The mixture was stirred at 120° C. for 24 h and more 4-(2-chloroethyl)morpholine hydrochloride (296 mg, 2.66 mmol) was added. The mixture was stirred for 8 h 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 HCl 1N and saturated aqueous NaHCO3. The precipitate was extracted twice with EtOAc, dried over MgSO4 and concentrated. Purification by flash chromatography (MeOH/CHCl3: 5:95 to 10:90) afforded 48 mg (4% yield) of 124 as a light yellow oil. LRMS=444.1 (M+1).

[0417] Step 3: N-(2-Amino-phenyl)-4-[6-(2-morpholin-4-yl-ethylamino)-benzothiazol-2-ylsulfanylmethyl]-benzamide (Compound 128)

[0418] 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) 5 (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). 657

Example 88

[0419] N-(2-Amino-phenyl)-4-(quinolin-2-ylsulfanylmethyl)-benzamide (Compound 131)

[0420] Step 1: 2-(4-Bromo-benzylsulfanyl)-quinoline (Compound 130)

[0421] 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).

[0422] Step 2: N-(2-Amino-phenyl)-4-(quinolin-2-ylsulfanylmethyl)-benzamide (131)

[0423] 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) δ (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). 658

Example 89

[0424] N-(2-Amino-phenyl)-4-(pyrimidin-2-ylaminomethyl)-benzamide (Compound 134)

[0425] Step 1: 4-(Pyrimidin-2-ylaminomethyl)-benzoic Acid Methyl Ester (Compound 133)

[0426] 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).

[0427] Step 2: N-(2-Amino-phenyl)-4-(pyrimidin-2-ylaminomethyl)-benzamide (134)

[0428] 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) δ (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). 659

Example 90

[0429] N-(2-Amino-phenyl)-4-(1-methyl-1H-imidazol-2-ylsulfanylmethyl]-benzamide (Compound 139)

[0430] Step 1: [2-(4-Iodo-benzoylamino)-phenyl]-carbamic Acid Tert-butyl Ester (Compound 135)

[0431] 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 HCl 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).

[0432] To a solution of 4-iodobenzoic acid (8.0 g, 32.3 mmol) in DMF (65 mL) at r.t., were successively added 1-[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+).

[0433] Step 2: N-12-tert-butoxycarbonylamino-phenyl)-terephtalamic Acid Methyl Ester (Compound 136)

[0434] 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+).

[0435] Step 3: [2(4-Hydroxymethyl-benzoylamino)-phenyl]-carbamic Acid Tert-butyl Ester (137)

[0436] To a solution of 136 (7.5 g, 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 HCl (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+).

[0437] Step 4: {2-[4-(1-Methyl-imidazol-2-ylsulfanylmethyl)-benzoylamino]-phenyl}-carbamic Acid Tert-Butyl Ester (Compound 138)

[0438] 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 μL, 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.

[0439] Step 5: N-(2-Amino-phenyl)-4-(1-methyl-1H-imidazol-2-ylsulfanylmethyl]-benzamide (Compound 139)

[0440] 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) δ (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). 660

Example 91

[0441] N-(2-Amino-phenyl)-6-(3-methoxyphenyl)-nicotinamide (Compound 141)

[0442] 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 (CDCl3) δ (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). 661

Example 92

[0443] N-(2-Amino-phenyl)-4-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-benzamide (Compound 144)

[0444] Step 1: 4-(1-Oxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoic Acid (Compound 143)

[0445] 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 CH2Cl2 to produce the title compound 143 (1.29 g, 49%).

[0446] Step 2: N-(2-Amino-phenyl)-4-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-benzamide (Compound 144)

[0447] 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 (CH2Cl2-MeOH (19:1)) afforded 144 in 46% yield. 1H NMR: (DMSO-d6) 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, 2H), 4.87 (s, 2H), 4.47 (s, 2H). 662

Example 94

[0448] N-(2-Amino-phenyl)-4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzamide (Compound 149)

[0449] 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+1).

[0450] 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) 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

[0451] N-(2-Amino-phenyl)-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-benzamide (Compound 152)

[0452] Step 1: 2-[2-(4-Hydroxy-phenyl)-ethyl]-isoindole-1,3-dione (Compound 150)

[0453] 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).

[0454] Step 2: 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)ethyl)-phenyl trifluoromethane-sulfonate (151)

[0455] 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, (CH2Cl2—MeOH (19:1)) to provide 151 (639 mg, 86% yield). LMRS=400.0 (M+1).

[0456] Step 3: N-(2-Amino-phenyl)-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-benzamide (Compound 152)

[0457] 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) 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, 2H), 3.85 (t, J=7.1 Hz, 2H), 3.00 (t, J=7.1 Hz, 2H). 663

Example 96

[0458] N-(2-Amino-phenyl)-4-(4-oxo-4H-quinazolin-3-ylmethyl)-benzamide (Compound 154)

[0459] 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).

[0460] 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) 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, 2H).

Example 97

[0461] N-(2-Amino-phenyl)-4-(4-oxo-4H-benzo[d][1,2,3]triazin-3-ylmethyl)-benzamide (Compound 155)

[0462] 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 conc., HCl (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).

[0463] 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) [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, 2H), 4.87 (bs, 2H).

Example 98

[0464] N-(2-Amino-phenyl)-4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide (Compound 157)

[0465] Step 1: 4-[(2-Amino-benzoylamino)-methyl]-benzoic Acid (Compound 156)

[0466] 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% HCl/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).

[0467] Step 2: N-(2-Amino-phenyl)-4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide (Compound 157)

[0468] 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% HCl/H2O) and extracted with ethyl acetate (2×300 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).

[0469] 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) [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

[0470] N-(2-Amino-phenyl)-4-(1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide (Compound 158)

[0471] Step 2: 4-(1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzoic Acid Methyl Ester

[0472] 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, MeI (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 vacuo 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+1).

[0473] Step 3: 4-(1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzoic Acid

[0474] To a suspension of the methyl ester (1.25 g, 3.85 mmol) in methanol (35 mL), was added 1N 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% HCl/H2O) and extracted with ethyl acetate (2×300 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).

[0475] Step 4: N-(2-Amino-phenyl)-4-(1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide (Compound 158)

[0476] 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) δ 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 (t, J=7.5 Hz, 1H), 5.21 (brs, 2H), 4.86 (brs, 2H), 3.54 (s, 3H).

Example 100

[0477] N-(2-Amino-phenyl)-4-(2-methyl-4-oxo-4H-quinazolin-3-ylmethyl)-benzamide (Compound 159)

[0478] A suspension of 156 (903 mg, 3.34 mmol) in acetic anhydride (15 mL) was heated at 50° C. for 1 h. Acetic anhydride was evaporated under vacuum and the solid material formed was dissolved in acetic acid (30 mL). This solution was refluxed 48 h and evaporated to form another solid material, which was recrystallized from a mixture AcOEt/CHCl3 to produce the intermediate carboxylic acid (420 mg, 43% yield). LMRS=385.0 (M+1).

[0479] Following a procedure analogous to that described in Example 92, step 2, but substituting the carboxylic acid for 143, the title compound 159 was obtained in 49% yield. 1H NMR: (DMSO) δ (ppm): 9.64 (bs, 1H), 8.17 (dd, J=8.0, 1.6 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.95 (dd, J=8.8, 2.5 Hz, 1H), 7.84 (ddd, J=7.6, 7.0, 1.5 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.53 (ddd, J=7.6, 7.6, 1.1 Hz, 1H), 7.33 (d, J=8.2 Hz, 2H), 7.14 (dd, J=7.7, 1.1 Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.77 (dd, J=8.0, 1.4 Hz, 1H), 6.58 (ddd, J=7.6, 7.6, 1.3 Hz, 1H), 5.46 (s, 2H), 4.89 (bs, 2H) 2.5 (s, 3H, overlaps with the DMSO signals). 664

Example 101

[0480] N-(2-aminophenyl)-2-(4-Methoxy-benzylamino)-thiazol-5-yl-amide (Compound 163)

[0481] Step 1: 4-Methoxybenzyl-thiourea (Compound 161)

[0482] To a solution of thiocarbonyl diimidazole (1.23 g, 6.22 mmol, 1.5 equiv.) in dry dichloromethane (10 mL), neat alkylamine 160 (4.15 mmol, 1.0 equiv.) was added dropwise at 0° C., and the solution stirred from 0° C. to 15° C. during 16 h. A solution of concentrated ammonium hydroxide (3 mL, 45 mmol, 3.6 equiv.) in 1,4-dioxane (6 mL) was added at 0° C. and stirred at room temperature for 7 h. The solution was diluted with ethyl acetate (250 mL), washed with brine (2×50 mL), dried (MgSO4), filtered and concentrated. After purification by column chromatography (silica gel, elution 5% methanol in dichloromethane), 161 was obtained as yellow solid (700.2 mg, 3.6 mmol, 86% yield). 1H NMR: (Acetone-d6) δ (ppm): 7.53 (bs, 1H), 7.28 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 6.67 (bs, 2H), 4.67 (s, 2H), 3.77 (s, 3H). LMRS=197.1 (M+1).

[0483] Step 2: 2-(4-Methoxybenzylamino)thiazole-5-carboxylic Acid Methyl Ester (Compound 162)

[0484] A solution of trans methyl-2-methoxyacrylate (461 mg, 3.97 mmol, 1 equiv.) in 50% 1,4-dioxane in water (4 mL) stirred at −10° C., was treated with N-bromosuccinimide (792 mg, 4.46 mmol, 1.12 equiv.), stirred at the same temperature for 1 h, transferred to a flask containing the thiourea 161 (700.2 mg, 3.6 mmol) and the mixture was stirred at 80° C. for 2 h. After cooling down to room temperature, concentrated NH4OH (0.8 mL) was added, stirred for 10 min and the resulting precipitated filtered and washed with water, giving 363 mg (1.3 mmol, 36% yield) of 162, plus 454 mg additional (91% pure by HPLC) as residue from evaporation of the filtrated (ca. 77% overall yield). 1H NMR: (Acetone-d6) δ (ppm): 7.97 (bs, 1H), 7.72 (bs, 1H), 7.33 (d, J=8.1 Hz, 2H), 6.90 (d, J=8.1 Hz, 2H), 4.52 (s, 2H), 3.78 (s, 3H), 3.75 (s, 3H). LMRS=279.1 (M+1).

[0485] Step 3: N-(2-aminophenyl)-2-(4-Methoxy-benzylamino)-thiazol-5-yl-amide (Compound 163)

[0486] Following the procedure described in Example 1, steps 4 and 5, but substituting 162 for 6, the title compound 163 was obtained in 50% yield. 1H-NMR (methanol-d4), δ (ppm): 7.86 (s, 1H), 7.29 (d, J=8.8 Hz, 2H), 7.11 (dd, J=8.0 Hz, 1.4 Hz, 1H), 7.04 (dt, J=8.0 Hz, 1.4 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 6.86 (m, 1H), 6.74 (dt, J=7.4 Hz, 1.4 Hz, 1H), 4.85 (bs, 4H), 4.45 (s, 2H), 3.78 (s, 3H).

ExampleS 102-121

[0487] Examples 102 to 121 describe the preparation of compounds 164 to 183 using the same procedures as described for compounds 62 to 163 in Examples 47 to 101. Characterization data are presented in Tables 4a and 4b.

TABLE 4a
Characterization of Compounds Prepared in Examples 102-121
665
Ex.	Cpd	W	Y	Z	Name	Characterization	Schm
102	164	666	CH	CH	N-(2-Amino-phenyl)-4- [(3,4,5-trimethoxy- phenylamino)-methyl]- benzamide	1H NMR: (Acetone-d6) δ (ppm): 9.09 (bs, 1H), 7.99 (d, J=8.2Hz, 2H), 7.54 (d, J=8.0Hz, 2H), 7.29 (d, J=7.7Hz, 1H), 7.00 (t, J=6.6Hz, 1H), 6.86 (dd, J=8.0Hz, 1.1Hz, 1H), 6.67 (t, J=8.0Hz, 1H), 5.99 (s, 2H), 5.46 (bs, 1H), 4.64 (bs, 2H), 4.43 (s, 2H), 3.69 (s, 6H), 3.60 (s, 3H).	11
103	165	667	N	CH	N-(2-Amino-phenyl)-6-(3- hydoxymethyl-phenyl)- nicotinamide	1H NMR (20% CD3OD in CDCl3) δ (ppm): 9.14 (d, J=1.8Hz, 1H), 8.33 (dd, J=8.4Hz, 1.8Hz, 1H), 7.93 (s, 1H), 7.82 (m, 2H), 7.50-7.40 (m, 2H), 7.22-6.45 (m, 4H), 4.69 (s, 2H).	15
104	166	668	CH	CH	N-(2-Amino-phenyl)-4-(3- methoxy-pheny)- benzamide	1H NMR (CD3OD) δ (ppm): 7.98 (d, J=8.4Hz, 2H), 7.65 (d, J=8.4Hz, 2H), 7.31-7.04 (m, 5H), 6.92-6.80 (m, 3H), 3.84 (s, 3H)	15
105	167	669	CH	N	N-(2-amino-phenyl)-6-(4- methoxy-benzylamino)- nicotinamide	1H NMR (DMSO-d6) δ (ppm): 9.33 (s, 1H), 8.61 (d, J=2.5Hz, 1H), 7.89 (dd, J=8.8Hz, 2.2Hz, 1H), 7.57 (t, J=5.8Hz, 1H), 7.24 (d, J=8.52Hz, 2H), 7.11 (d, J=7.69Hz, 1H), 6.90 (m, 3H), 6.73 (d, J=8.0Hz, 1H), 6.50-6.58 (m, 2H), 4.83 (s, 2H), 4.45 (d, J=5.8Hz, 2H), 3.70 (s, 3H).	6
106	168	670	CH	N	N-(2-amino-phenyl)-6-[2- (4-methoxy-phenyl)- ethylamino]-nicotinamide	1H NMR (DMSO-d6) δ (ppm): 9.42 (s, 1H), 8.72 (d, J=2.5Hz, 1H), 7.97 (dd, J=8.8Hz, 2.5Hz, 1H), 7.23 (m, 4H), 6.81-7.03 (m, 4H), 6.64 (m, 1H), 6.56 (d, J=9.1Hz, 1H), 4.92 (s, 2H), 3.78 (s, 3H), 3.55 (m, 2H), 2.85 (t, J=7.3Hz, 2H).	6
107	169	671	CH	CH	N-(2-Amino-phenyl)-4- [(4,6-dimethoxy- pyrimidin-2- ylamino)-methyl]- benzamide	1H NMR: (DMSO-d6) δ (ppm): 9.63 (bs, 1H), 7.95 (d, J=7.9Hz, 2H), 7.85-7.82 (m, 1H), 7.48 (d, J=7.9Hz, 2H), 7.20 (d, J=7.1Hz, 1H), 7.03 (dt, J=7.6Hz, 7.4Hz, 1H), 6.81 (d, J=7.9Hz, 1H), 6.63 (dt, J=7.9Hz, 7.7Hz, 1H), 4.94 (bs, 2H), 4.54 (d, J=6.0Hz, 2H), 3.79 (bs, 6H).	11
108	170	672	CH	CH	N-(2-Amino-phenyl)-4- (quinolin-2- ylsulfanylmethyl)- benzamide	1H NMR: (DMSO-d6) δ (ppm): 9.62 (bs, 1H), 8.21 (d, J=8.8Hz, 1H), 8.00-7.89 (m, 4H), 7.79 (dd, J=6.8Hz, 1.3Hz, 1H), 7.68 (d, J=6.3Hz, 2H), 7.56 (t, J=6.8Hz, 1H), 7.44 (d, J=8.7Hz, 1H), 7.17 (d, J=8.2Hz, 1H), 6.99 (dt, J=7.9Hz, 7.4Hz, 1H), 6.79 (d, J=6.9Hz, 1H), 6.61 (dt, J=7.7Hz, 7.4Hz, 1H), 4.69 (s, 2H).	11
109	171	673	N	CH	N-(2-Amino-phenyl)-6-(4- methoxy-benzylsulfanyl)- nicotinamide	1H NMR: (DMSO-d6) δ (ppm): 9.06 (bs, 1H), 8.17 (dt, J=10.9Hz, 9.0Hz, 1H), 7.46 (d, J=8.5Hz, 1H), 7.39 (d, J=8.2Hz, 2H), 7.21-7.13 (m, 2H), 7.01 (dt, J=7.6Hz, 7.4Hz, 1H), 6.91 (d, J=8.5Hz, 2H), 6.80 (d, J=7.9Hz, 1H), 6.62 (t, J=7.4Hz, 1H), 5.01 (bs, 2H), 4.47 (s, 2H), 3.76 (s, 3H).	12
110	172	674	CH	CH	N-(2-Amino-phenyl)-4- (benzothiazol-2- ylsulfanylmethyl]- benzamide	1H NMR: (DMSO-d6) δ (ppm): 8.01 (d, J=8.0Hz, 1H), 7.93 (d, J=8.2Hz, 2H), 7.90 (dd, J=4.4Hz, 0.6Hz, 1H), 7.63 (d, J=8.2Hz, 2H), 7.48 (dt, J=8.0Hz, 0.8Hz, 1H), 7.37 (td, J=7.1Hz, 1.1Hz, 1H), 7.14 (d, J=7.1Hz, 1H), 6.96 (t, J=6.3Hz, 1H), 6.76 (d, J=7.7Hz, 1H), 6.58 (t, J=6.6Hz, 1H), 4.88 (s, 2H), 4.73 (s, 2H).	11
112	174	675	CH	N	N-(2-amino-phenyl)-6- [2-(4-fluoro-phenyl)- ethylamino]- nicotinamide	1H NMR (DMSO-d6) δ (ppm): 9.34 (s, 1H), 8.64 (d, J=2.5Hz, 1H), 7.89 (dd, J=9Hz, 2Hz, 1H), 7.16-7.22 (m, 3H), 7.06-7.20 (m, 3H), 6.90-6.96 (m, 1H), 6.72-6.78 (m, 1H), 6.46-6.60 (m, 2H), 4.92 (s, 2H), 3.50 (m, 2H), 2.92 (m, 2H).	6
113	175	676	CH	N	N-(2-amino-phenyl)-6-(4- fluoro-benzylamino)- nicotinamide	1H NMR (DMSO-d6) δ (ppm): 9.34 (s, 1H), 8.61 (d, J=2.2Hz, 1H), 7.91 (dd, J=8.8Hz, 2.2Hz, 1H), 7.66 (t, J=6Hz, 1H), 7.32-7.37 (m, 2H), 7.08-7.38 (m, 3H), 6.93 (m, 1H), 6.74 (m, 1H), 6.52-6.58 (m, 2H), 4.84 (s, 2H), 4.51 (d, J=6.0	6
114	176	677	CH	N	N-(2-amino-phenyl)-6- (3,4,5-trimethoxy- benzylamino)-nicotinamide	1H NMR (DMSO-d6) δ (ppm): 9.34 (s, 1H), 8.63 (d, J=2.2Hz, 1H), 7.92 (dd, J=8.8Hz, 2.2Hz, 1H), 7.57 (t, J=6Hz, 1H), 7.10 (m, 1H), 6.93 (m, 1H), 6.74 (m, 1H), 6.66 (s, 2H), 6.56 (m, 2H), 4.84 (s, 2H), 4.45 (d, J=6Hz, 2H), 3.73 (s, 6H), 3.31 (s, 3H).	6
115	177	678	CH	CH	N-(2-Amino-phenyl)-4-(5- phenyl-[1,3,4]oxadiazol-2- ylsulfanylmethyl]- benzamide	1H NMR: (Acetone-d6) δ (ppm): 9.08 (bs, 1H), 8.02 (dd, J=7.1Hz, 1.9Hz, 4H), 7.69 (d, J=8.5Hz, 2H), 7.62-7.57 (m, 3H), 7.28 (d, J=7.7Hz, 1H), 7.03-6.97 (m, 1H), 6.86 (d, J=6.6Hz, 1H), 6.67 (t, J=7.7Hz, 1H), 4.70 (s, 2H), 4.63 (bs, 2H).	14
116	178	679	N	CH	N-(2-aminophenyl)-6-(2- phenylamino-ethylamino)- nicotinamide	1H-NMR (CD3OD-d4), δ (ppm): 8.67 (d, J=2.2Hz, 1H), 7.97 (dd, J=8.9Hz, 2.5Hz, 1H), 7.58 (m, 1H), 7.51 (m, 1H), 7.15 (dd, J=7.7Hz, 1.1Hz, 1H), 7.08 (m, 2H), 6.89 (dd, J=8.0Hz, 1.4Hz, 1H), 6.76 (dt, J=7.7Hz, 4.4Hz, 1H), 6.67 (t, J=7.7Hz, 2H), 6.60 (m, 2H), 4.87 (bs, 4H), 3.60 (t, J=6.3Hz, 2H), 3.35 (t, J=6.3Hz, 2H).	11
117	179	680	CH	CH	N-(2-Amino-phenyl)-4- (2,4-dioxo-4H- benzo[e][1,3]oxazin-3- ylmethyl)-benzamide	1H NMR: (DMSO-d6) δ (ppm): 9.62 (s, 1H), 8.00 (dd, J=8.2Hz, 1.9Hz, 1H), 7.80-7.92 (m, 3H), 7.42-7.50 (m, 4H), 7.13 (d, J=7.1Hz, 1H), 6.95 (ddd, J=8.0Hz, 1.6Hz, 1H), 6.75 (dd, J=8.0Hz, 1.4Hz, 1H), 6.57 (t, J=7.7Hz, 1H), 5.13 (s, 2H), 4.87 (bs, 2H).	11
118	180	681	CH	CH	N-(2-Amino-phenyl)-4-(4- ethyl-4-methyl-2,6-dioxo- piperidin-1-ylmethyl)- benzamide	1H NMR: (DMSO-d6) δ (ppm): 9.59 (s, 1H), 7.88 (d, J=8.2Hz, 2H), 7.31 (d, J=8.2Hz, 2H), 7.13 (d, J=7.4Hz, 1H), 6.95 (t, J=8.0Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 6.57 (t, J=7.4Hz, 1H), 4.87 (s, 2H), 4.86 (bs, 2H), 2.61 (s, 2H), 2.55 (s, 2H), 1.31 (q, J=7.7Hz, 2H), 0.91 (s, 3H), 0.80 (t, J=7.4Hz, 3H).	11
119	181	682	CH	CH	N-(2-Amino-phenyl)-4-(1- ethyl-2,4-dioxo-1,4- dihydro-2H-quinazolin-3- ylmethyl)-benzamide	1H NMR: (CDCl3) δ (ppm): 8.23 (dd, J=7.8Hz, 1.5Hz, 1H), 8.01 (bs, 1H), 7.80 (d, J=8.0Hz, 2H), 7.71-7.65 (m, 1H), 7.55 (d, J=8.2Hz, 2H), 7.27-7.20 (m, 3H), 7.05 (dt, J=7.7, 1.5Hz, 1H), 6.81-6.77 (m, 2H), 5.29 (bs, 2H), 4.18 (q, J=7.3 Hz, 2H), 3.86 (bs, 2H), 1.33 (t, J=7.1Hz, 3H).	19
120	182	683	CH	CH	N-(2-Amino-phenyl)-4- (4,6-dimethyl- pyrimidin-2- ylsulfanylmethyl)- benzamide	1H NMR: (DMSO-d6) δ (ppm): 9.66 (bs, 1H), 7.96 (d, J=7.9Hz, 2H), 7.61 (d, J=7.9Hz, 2H), 7.21 (d, J=7.9Hz, 1H), 7.04-6.99 (m, 2H), 6.82 (d, J=7.9Hz, 1H), 6.64 (t, J=7.4Hz, 1H), 4.49 (s, 2H), 2.42 (s, 6H).	11
121	183	684	CH	CH	N-(2-Amino-phenyl)-4-(4- trifluoromethyl- pyrimidin-2- ylsulfanylmethy)benzamide	1H NMR: (DMSO-d6) δ (ppm): 9.66 (bs, 1H), 9.07 (d, J=5.2Hz, 1H), 7.97 (d, J=7.4Hz, 2H), 7.78 (d, J=4.7Hz, 1H), 7.63 (d, J=7.4Hz, 2H), 7.19 (d, J=7.7Hz, 1H), 7.01 (dt, J=7.7Hz, 7.4Hz, 1H), 6.81 (d, J=8.2Hz, 1H), 6.64 (dt, J=7.4Hz, 7.1Hz, 1H), 4.94 (bs, 2H), 4.57 (s, 2H).	11

[0488]

TABLE 4b
685
Ex.	Cpd	W	Y	Z	Name	Characterization	Schm
123	187	686	CH	CH	N-(2-Aminophenyl)- 4-[3-(pyridin- 2ylmethyl- aminomethyl)phenyl)]- benzamide	1 H NMR (20% CD3OD in CDCl3) δ (ppm): 8.46 (m, 1H), 7.95 (d, J=8.4Hz, 2H), 7.64-6.70 (m, 14 H), 3.80 (br s, 4H).	21
124	188	687	CH	CH	Biphenyl-4,4′- dicarboxylic acid bis-[(2-amino- phenyl)-amide]	1 H NMR (CD3OD) δ (ppm): 9.80 (bs, 2H), 8.16 (d, J=7.9Hz, 4H), 7.96 (d, J=7.9Hz, 4H), 7.23 (d, J=7.4Hz, 2H), 7.03 (dd, J=6.9, 7.4Hz, 2H), 6.84 (d, J=8.2Hz, 2H), 6.66 (dd, J=6.9, 7.7Hz, 2H), 5.06 (bs, 4H).	1
125	189	688	CH	CH	N-(2-Amino-phenyl)- 4-[4-{(3,4,5- trimethoxy- phenylamino)- methyl}phenyl]- benzamide	1 H NMR (DMSO-d6) δ (ppm): 10.15 (1H, brs), 8.17 (2H, d, J=8.0), 7.90 (2H, d, J=8.2), 7.87 (1H, brs), 7.72 (1H, d, J=6.6), 7.54 (2H, m), 7.40 (1H, d, J=8.5), 7.25 (1H, m), 7.16 (1H, d, J=7.4), 7.07 (1H, m), 6.08 (2H, s), 4.42 (2H, s), 3.73 (6H, s), 3.58 (3H, d, J=0.8)	21
126	190	689	CH	CH	N-(2-Amino-phenyl)- 4-[4-{(4-methoxy- phenylamino)- methyl}-phenyl]- benzamide	1 H NMR (DMSO-d6) δ (ppm): 10.03 (1H, brs), 8.17 (2H, d, J=7.7), 7.83(3H, m), 7.76(1H, d, J=7.1), 7.52 (2H, m), 7.35 (1H, d, J=8.0), 7.17 (1H, m), 7.08-6.93 (6H, m), 4.50 (3H, s), 3.75 (2H, s)	21
128	193	690	CH	CH	N-(2-Amino-phenyl)- 4-(3-methyl-but-3- en-1-ynyl)- benzamide	LRMS calc: 276.03, found: 277.2 (MH)+	22
129	194	691	CH	CH	N-(2-Amino-phenyl)- 4-(1-hydroxy- cyclohexylethynyl)- benzamide	LRMS calc: 334.4, found: 335 (MH)+	22
130	195	692	CH	CH	N-(2-Amino-phenyl)- 4-(3-hydroxy-3- methyl-but-1-ynyl)- benzamide	LRMS calc: 294.35, found: 295.1 (MH)+	22
131	196	693	CH	CH	N-(2-Amino-phenyl)- 4-phenylethynyl- benzamide	LRMS calc: 312.37, found: 313.2 (MH)+	22
180	320	694	CH	CH	N-(2-Amino-phenyl)- 4-[(5-chloro- benzooxazol-2- ylamino)-methyl]- benzamide	1 H NMR: (Acetone-d6) δ (ppm): 9.67 (s, 1H), 8.85 (s, 1H), 8.01 (d, J=8.2Hz, 2H), 7.55 (d, J=8.2Hz, 2H), 7.45 (d, J=8.8Hz, 1H), 7.36 (d, J=2.3Hz, 1H), 7.22 (d, J=7.6Hz, 1H), 7.07 (dd, J=8.8, 2.3Hz, 1H), 7.02 (d, J=7.0Hz, 1H), 6.84 (d, J=7.6Hz, 1H), 6.65 (t, 7.0Hz, 1H), 4.94 (s, 2H), 4.67 (d, J=5.3Hz, 2H).	35
181	321	695	CH	CH	N-(2-Amino-phenyl)- 4-{[4-(4-chloro- phenyl)-thiazol-2- ylamino]-methyl}- benzamide	1 H NMR: (DMSO-d6) δ (ppm): 9.67 (bs, 1H), 8.36 (t, J=5.8Hz, 1H), 8.00 (d, J=8.2Hz, 2H), 7.89 (d, J=8.2Hz, 2H), 7.57 (d, J=8.2Hz, 2H), 7.48 (d, J=8.2Hz, 2H), 7.20 (s, 1H), 7.02 (t, J=8.5Hz, 1H), 6.83 (d, J=7.7Hz, 1H), 6.65 (t, J=7.1Hz, 1H), 4.92 (bs, 2H), 4.65 (d, J=5.8Hz, 2H).	35
182	322	696	CH	CH	N-(2-Amino-phenyl)- 4-[(5-bromo- benzothiazol-2- ylamino)-methyl]- benzamide	1 H NMR: (DMSO-d6) δ (ppm): 6.97 (s, 1H), 8.78 (bs, 1H), 8.01 (d, J=8.8Hz, 2H), 8.00 (s, 1H), 7.55 (d, J=8.2Hz, 2H), 7.43-7.35 (m, 2H), 7.22 (d, J=7.6Hz, 1H), 7.03 (t, J=7.0Hz, 1H), 6.83 (d, J=7.6Hz, 1H), 6.65 (t, J=7.6Hz, 1H). 4.94 (s, 2H), 7.74 (d, J=5.9Hz, 2H).	33, 34
183	323	697	CH	CH	N-(2-Amino-phenyl)- 4-{5-[(3,4,5- trimethoxy- phenylamino)- methyl]-thiophen-2- ylmethyl}- benzamide	LRMS calc: 489.58, found: 490 (MH)+	21
184	325	698	CH	CH	N-(2-Amino-phenyl)- 4-{6-[(pyridin-3- ylmethyl)-amino]- benzothiazol-2- ylsulfanylmethyl}- benzamide	1 H NMR: (Acetone-d6) δ (ppm): 8.65 (d, J=1.4Hz, 1H), 8.44 (dd, J=4.7, 3.0Hz, 1H), 7.97 (d, J=8.2 Hz, 2H), 7.81-7.77 (m, 1H), 7.63 (m, 3H), 7.33-7.26 (m, 2H), 7.09 (d, J=2.5Hz, 1H), 7.02-6.97 (m, 1H), 6.91 (dd, J=8.8, 2.5Hz, 1H), 6.86 (dd, J=8.0, 1.4Hz, 1H),
# 6.69-6.64 (m, 1H), 4.64 (s, 2H), 4.47 (s, 2H).	11
185	326	699	CH	CH	N-(2-Amino-phenyl)- 4-{6-[(pyridin-2- ylmethyl)-amino]- benzothiazol-2- ylsulfanylmethyl}- benzamide	1 H NMR: (DMSO-d6) δ (ppm): 9.59 (s, 1H), 8.52-8.51 (m, 1H), 7.89 (d, J=8.24Hz, 2H), 7.71 (td, J=7.7, 1.9Hz, 1H), 7.59-7.53 (m, 3H), 7.34 (d, J=8.0Hz, 1H), 7.25-7.21 (m, 1H), 7.12 (d, J=6.9, Hz, 1H), (m, 1H), 6.93 (d, J=7.4Hz, 1H), 6.81 (dd, J=9.1, 2.5 Hz, 1H),
# 6.76-6.73 (m, 1H), 6.67 (t, J=5.8Hz, 1H), 6.56 (t, J=7.4Hz, 1H), 4.87 (s, 1H), 4.58 (s, 2H), 4.38 (d, J=6.3Hz, 2H).	11, 34
186	327	700	CH	CH	N-(2-Amino-phenyl)- 4-morpholin-4- ylmethyl- benzamide	1 H NMR: (DMSO-d6) δ (ppm): 12.23 (bs, 1H), 9.59 (s, 1H), 7.86 (d, J=8.2Hz, 2H), 7.34 (d, J=8.5Hz, 2H), 7.14-7.12 (m, 2H), 6.94-6.92 (m, 2H), 6.76 (d, J=6.6Hz, 1H), 6.57 (t, J=7.4Hz, 1H), 4.87 (s, 2H), 4.29 (s, 2H).	14
187	328	701	CH	CH	N-(2-Amino-phenyl)- 4-morpholin-4- ylmethyl- benzamide	1 H NMR: (CD3OD) δ (ppm): 8.03 (d, J=8.4Hz, 2H), 7.58 (d, J=7.9Hz, 2H), 7.26 (d, J=7.0Hz, 1H), 7.16 (t, J=6.6Hz, 1H), 6.98 (d, J=7.0Hz, 1H), 6.85 (t, J=7.5Hz, 1H), 3.78 (t, J=4.4Hz, 4H), 3.68 (s, 2H), 2.57-2.54 (m, 4H).	37
188	329	702	CH	CH	3′,4′,5′-Trimethoxy- biphenyl4- carboxylic acid (2- amino-phenyl)- amide	1 H NMR: (CD3OD) δ (ppm): 8.14 (d, J=7.9Hz, 2H), 7.85 (d, J=8.4Hz, 2H), 7.29 (d, J=7.9Hz, 2H), 7.17 (t J=7.0Hz, 1H), 7.04 (s, 2H), 7.00 (d, J=8.4Hz, 1H), 6.87 (t, J=7.5Hz, 1H), 4.95 (s, 6H), 4.01 (s, 3H).	37
189	330	703	CH	CH	4-[(2-Amino-9-butyl- 9H-purin-6- ylamino)-methyl]-N- (2-amino-phenyl)- benzamide	1 H NMR: (DMSO-d6) δ (ppm): 9.65 (s, 1H), 7.96 (d, J=7.7Hz, 2H), 7.95 (bs, 2H) 7.78 (s, 1H), 7.52 (d, J=7.9Hz, 2H), 7.22 (d, J=7.7Hz, 1H), 7.02 (dd, J=7.3, 8.0Hz, 1H), 6.8 (d, J=8.0Hz, 1H), 6.65 (dd, J=7.3, 7.7Hz, 1H), 5.91 (s, 2H), 4.94 (bs, 2H), 4.77 (bs, 2H),
# 4.01 (t, J=7.1Hz, 1H), 1.78 (m, 2H), 1.3 (m, 2H), 0.95 (t, J=7.4,Hz, 1H)	39
190	331	704	CH	CH	N-(2-Amino-phenyl)- 4-[(2-amino-9H- purin-6-ylamino)- methyl]-benzamide	1 H NMR (DMSO-d6) δ (ppm): 10.16 (s, 1H), 9.60 (br, 1H), 8.24 (s, 1H), 8.08 (d, J=8.0Hz, 2H), 7.62 (m, 1H), 7.60 (d, J=8.0Hz, 2H), 7.40 (m, 1H), 7.20 (m, 2H), 7.08 (m, 1H), 4.90 (m, 2H), 4.6 (br, 4H)	39
191	332	705	CH	CH	N-(2-Amino-phenyl)- 4-[(2-chloro-9H-purin-6-ylamino)- methyl]-benzamide	1 H NMR (DMSO-d6) δ (ppm): 9.67 (m, 1H), 8.80 (m, 1H), 8.24 (s, 1H), 7.99 (d, J=7.8Hz, 2H), 7.52 (d, J=7.8Hz, 2H), 7.21 (d, J=7.8Hz, 1H), 7,02 (dd, J=6.3, 7.8Hz, 1H), 6.82 (d, J=8.1Hz, 1H), 6.70 (d6, J=6.3, 8.1Hz, 1H), 4.94 (br, 2H), 4.77 (br, 2H)	39
192	333	706	CH	CH	N-(2-Amino-phenyl)- 4-[(9-butyl-2-chloro- 9H-purin-6- ylamino)-methyl]- benzamide	1 H NMR (DMSO-d6) δ (ppm): 9.60 (s, 1H), 8.72 (br, 1H), 8.21 (s, 1H), 7.92 (d, J = 8.0Hz, 2H), 7.45 (d, J=8.0Hz, 2H), 7.15 (d, J=8.0Hz, 1H), 6.96 (dd, J=6.7, 8.0Hz, 1H), 6.77 (d, J=8.0Hz, 1H), 6.85 (dd, J=6.7, 8.0Hz, 2H), 4.88 (s, 1H), 4.71 (m, 2H), 4.11 (m, 2H), 1.76 (m, 2H), 1.25 (m, 2H), 0.89 (t, J=7.1Hz, 3H)	39
193	334	707	CH	CH	N-(2-Amino-phenyl)- 4-[(1H- benzoimidazol-2- ylmethyl)-amino]- benzamide	1 H NMR: (DMSO-d6) δ (ppm): 12.39 (bs, 1H), 9.32 (s, 1H), 7.81 (d, J=8.2Hz, 2H), 7.56 (bs, 1H), 7.21-7.17 (m, 3H), 6.99-6.97 (m, 2H), 6.81 (d, J=8.2Hz, 1H), 6.77 (d, J=8.8Hz, 2H), 6.63 (t, J=7.0Hz, 1H), 4.85 (s, 2H), 4.62 (d, J=5.3Hz, 2H).	11
194	335	708	CH	CH	N-(2-Amino-phenyl)- 4-(1-ethyl-2,4- dioxo-1,4-dihydro- 2H-quinazolin-3- ylmethyl)- benzamide	1 H NMR: (CDCl3) δ (ppm): 8.23 (dd, J=7.8, 1.5Hz, 1H), 8.01 (bs, 1H), 7.80 (d, J=8.0Hz, 2H), 7.71-7.65 (m, 1H), 7.55 (d, J=8.2Hz, 2H), 7.27-7.20 (m, 3H), 7.05 (td, J=7.7, 1.5Hz, 1H), 6.81-6.77 (m, 2H), 5.29 (bs, 2H), 4.18 (q, J=7.3Hz, 2H), 3.86 (bs, 2H), 1.33 (t,
# J=7.1Hz, 3H). MS: (calc.) 414.2; (obt.) 415.3 (MH)+	19
195	336	709	CH	CH	N-(2-Amino-phenyl)- 4-(6-chloro-2- methyl-4-oxo-4H- quinazolin-3- ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.69 (bs, 1H, NH), 8.71 (s, 1H), 8.16 (d, J=2.5Hz, 1H), 8.01 (d, J=8.2Hz, 2H), 7.95 (dd, J=8.8, 2.5Hz, 1H), 7.81 (d, J=8.8Hz, 1H), 7.74 (d, J=8.2Hz, 2H), 7.20 (d, J=7.1Hz, 1H), 7.02 (td, J=7.6, 1.5Hz, 1H), 6.82 (dd, J=8.0, 1.4Hz, 1H), 6.64 (td, J=7.6, 1.4Hz, 1H), 5.34 (s, 2H), 4.94
# (bs, 2H). MS: (calc.) 404.1; (obt.) 405.0 (MH)+	19
196	337	710	CH	CH	N-(2-Amino-phenyl)- 4-(2-methyl4-oxo- 4H-quinazolin-3- ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.64 (bs, 1H), 8.17 (dd, J=8.0, 1.6Hz, 1H), 7.95 (d, J=8.2Hz, 2H), 7.95 (dd, J=8.8, 2.5Hz, 1H), 7.84 (ddd, J=7.6, 7.0, 1.5Hz, 1H), 7.64 (d, J=7.7Hz, 1H), 7.53 (ddd, J=7.6, 7.6, 1.1Hz, 1H), 7.33 (d, J=8.2Hz, 2H), 7.14 (dd, J=7.7, 1.1Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.5Hz, 1H), 6.77 (dd, J=8.0, 1.4Hz, 1H),
# 6.58 (ddd, J=7.6, 7.6, 1.3Hz, 1H), 5.46 (s, 2H), 4.89 (bs, 2H) 2.5 (s, 3H). MS: (calc.) 384.2; (obt.) 385.0 (MH)+	19
197	338	711	CH	CH	N-(2-Amino-phenyl)- 4-(6,7-dimethoxy-4- oxo-4H-quinazolin- 3-ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.62 (bs, 1H), 8.50 (s, 1H), 8.41 (d, J=8.2Hz, 2H), 7.47 (s, 1H), 7.46 (d, J=7.7Hz, 2H), 7.17 (s, 1H), 7.15 (d, J=8.5Hz, 1H), 6.96 (ddd, J=7.7, 7.7, 1.1Hz, 1H), 6.76 (d, J=6.9Hz, 1H), 6.58 (dd, J=6.9, 6.9Hz, 1H), 5.26 (s, 2H), 4.88 (bs, 2H),
# 3.91 (s, 3H), 3.87 (s, 3H). MS: (calc.) 430.2; (obt.) 431.1 (MH)+	19
198	339	712	CH	CH	N-(2-Amino-phenyl)- 4-(6,7-difluoro-4- oxo-4H-quinazolin- 3-ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.66 (bs, 1H), 8.69 (s, 1H), 8.07 (dd, J=8.8, 10.4Hz, 1H), 7.96 (d, J=8.2Hz, 2H), 7.82 (dd, J=14.3, 11.3Hz, 1H), 7.48 (d, J=8.2Hz, 2H), 7.15 (d, J=6.9Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.5Hz, 1H), 6.76 (dd, J=8.1, 1.2Hz, 1), 6.58 (ddd, J=7.5, 7.5, 1.2Hz, 1H),
# 5.28 (s, 2H), 4.89 (bs, 2H), MS: (calc.) 406.1; (obt.) 407.0 (MH)+	19
199	340	713	CH	CH	N-(2-Amino-phenyl)- 4-[1-(2-dimethylamino- ethyl)-2,4-dioxo- 1,4-dihydro-2H- quinazolin-3- ylmethyl]- benzamide	1 H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H), 8.09 (dd, J=7.8, 1.5Hz, 1H), 7.91 (d, J=8.2Hz, 2H), 7.81 (ddd, J=7.8, 7.8, 1.6Hz, 1H), 7.52 (d, J=8.2Hz, 1H), 7.42 (d, J=8.2Hz, 2H), 7.32 (dd, J=7.6, 7.6Hz, 1H), 7.14 (d, J=6.9Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.5Hz, 1H),
# 6.77 (dd, J=7.8, 1.2Hz, 1H), 6.59 (ddd, J=7.5, 7.5, 1.2Hz, 1H), 5.22 (s, 2H), 4.88 (bs, 2H), 4.24 (t, J=7.1Hz, 2H), 2.5 (m, 2H) 2.22 (s, 6H). MS: (calc.) 457.2; (obt.) 458.1 (MH)+	19
200	341	714	CH	CH	N-(2-Amino-phenyl)- 4-[1-(2-morpholin-4- yl-ethyl)-2,4-dioxo- 1,4-dihydro-2H- quinazolin-3- ylmethyl]- benzamide	1 H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H), 8.09 (dd, J=8.0, 1.6Hz, 1H), 7.92 (d, J=8.2Hz, 2H), 7.81 (ddd, J=7.8, 7.8, 1.6Hz, 1H), 7.54 (d, J=8.5Hz, 1H), 7.43 (d, J=8.2Hz, 2H), 7.32 (dd, J=7.4, 7.4Hz, 1H), 7.14 (d, J=7.4Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.5Hz, 1H),
# 6.77 (dd, J=8.0, 1.4Hz, 1H), 6.59 (ddd, J=7.6, 7.6, 1.4Hz, 1H), 5.22 (s, 2H), 4.87 (bs, 2H), 4.28 (t, J=6.7Hz, 2H), 3.50 (t, J=4.5Hz, 4H), 2.58 (t, J=6.7Hz, 2H), 2.47-2.44 (m, 4H). MS: (calc.) 499.2; (obt.) 500.3 (MH)+.	19
201	342	715	CH	CH	N-(2-Amino-phenyl)- 4-(6-bromo-2- methyl-4-oxo-4H- quinazolin-3- ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.65 (bs, 1H), 8.25 (d, J=2.5Hz, 1H), 7.99 (ddd, J=8.5, 2.5, 0.8Hz, 1H), 7.95 (d, J=8.8Hz, 2H), 7.60 (d, J=8.8Hz, 1H), 7.34 (d, J=8.2Hz, 2H), 7.14 (d, J=7.4Hz, 1H), 6.96 (dd, J=7.4, 7.4Hz, 1H), 6.76 (d, J=8.0Hz, 1H), 6.59 (dd, J=7.4, 7.4Hz, 1H), 5.45 (s, 2H),
# 4.88 (bs, 2H). MS: (calc.) 462.1; (obt.) 463.1 (MH)+.	19
202	343	716	CH	CH	N-(2-Amino-phenyl)- 4-(2,4-dioxo-1,4- dihydro-2H- thieno[3,2- d]pyrimidin-3- ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H), 8.10 (dd, J=5.2, 0.5Hz, 1H), 7.91 (d, J=8.2Hz, 2H), 7.40 (d, J=8.2Hz, 2H), 7.15 (d, J=7.1Hz, 1H), 6.98-6.94 (m, 2H), 6.77 (dd, J=8.0, 1.1Hz, 1H), 6.58 (dd, J=7.1, 7.1Hz, 1H), 5.12 (s, 2H), 4.88 (bs, 2H). MS: (calc.) 392.1; (obt.) 393.0 (MH)+.	43
203	344	717	CH	CH	N-(2-Amino-phenyl)- 4-(6-bromo-1-ethyl- 2,4-dioxo-1,4- dihydro-2H- quinazolin-3- ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H), 8.15 (d, J=2.5Hz, 1H), 7.95 (dd, J=9.1, 4.9Hz, 1H), 7.91 (d, J=8.2Hz, 2H), 7.53 (d, J=9.3Hz, 1H), 7.42 (d, J=8.2Hz, 2H), 7.15 (d, J=6.9Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.5Hz, 1H), 6.77 (dd, J=8.1, 1.5Hz, 1H), 6.59 (ddd, J=7.6, 7.6, 1.4Hz, 1H),
# 5.20 (s, 2H), 4.88 (bs, 2H) 4.14 (q, J=7.0, 2H), 1.21 (t, J=7.0, 3H). MS: (calc.) 492.1; (obt.) 493.0 (MH)+.	19
204	345	718	CH	CH	N-(2-Amino-phenyl)- 4-[1-(4-methoxy- benzyl)-2,4-dioxo- 1,4-dihydro-2H- quinazolin-3- ylmethyl]- benzamide	1 H NMR: (DMSO) δ (ppm): 9.62 (bs, 1H), 8.10 (dd, J=7.7, 1.6Hz, 1H), 7.93 (d, J=8.2Hz, 2H), 7.71 (ddd, J=7.9, 7.9, 1.5Hz, 1H), 7.46 (d, J=8.2Hz, 2H), 7.38 (d, J=8.2Hz, 2H), 7.31 (d, J=7.4Hz, 1H), 7.26 (d, J=8.8Hz, 2H), 7.15 (d, J=6.6Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.2Hz, 1H),
# 6.89 (d, J=8.8Hz, 2H), 6.77 (dd, J=8.0, 1.4Hz, 1H), 6.59 (ddd, J=7.5, 7.5, 1.2Hz, 1H), 5.33 (s, 2H), 5.28 (s, 2H), 4.89 (bs, 2H), 3.71 (s, 3H). MS: (calc.) 506.2; (obt.) 507.1 (MH)+.	19
205	346	719	CH	CH	N-(2-Amino-phenyl)- 4-(6-bromo-4-oxo- 4H-quinazolin-3- ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H), 8.66 (s, 1H), 8.24 (d, J=2.5Hz, 1H), 8.00 (dd, J=8.7, 2.3Hz, 1H), 7.95 (d, J=8.2Hz, 2H), 7.68 (d, J=8.8Hz, 1H), 7.48 (d, J=8.2Hz, 2H), 7.15 (d, J=8.0Hz, 1H), 7.96 (ddd, J=7.6, 7.6, 1.5Hz, 1H), 6.77 (dd, J=8.0, 1.1Hz, 1H),
# 6.59 (dd, J=7.4, 7.4Hz, 1H), 5.28 (s, 2H), 4.87 (bs, 2H). MS: (calc.) 448.0; (obt.) 449.0 (MH)+.	19
206	347	720	CH	CH	N-(2-Amino-phenyl)- 4-(6-bromo-4-oxo-4H- benzo[d][1,2,3]triazin-3-ylmethyl- benzamide	1 H NMR: (DMSO) δ (ppm): 9.63 (bs, 1H), 8.38 (d, J=1.9Hz, 1H), 8.28 (dd, J=8.8, 2.2Hz, 1H), 8.19 (d, J=8.8Hz, 1H), 7.95 (d, J=8.0Hz, 2H), 7.50 (d, J=8.2Hz, 2H), 7.15 (d, J=6.9Hz, 1H), 7.96 (ddd, J=7.6, 7.6, 1.5Hz, 1H), 6.77 (dd, J=8.0, 1.4Hz, 1H), 6.59 (ddd,
# J=7.6, 7.6, 1.4Hz, 1H), 5.67 (s, 2H), 4.87 (bs, 2H). MS: (calc.) 449.0; (obt.) 450.0 (MH)+.	19
207	348	721	CH	CH	N-(2-Amino-phenyl)- 4-(6-chloro-4-oxo- benzo[d][1,2,3]triazin-3-ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.63 (bs, 1H), 8.30-8.24 (m, 2H), 8.15 (ddd, J=8.6, 2.5, 0.8Hz, 1H), 7.95 (d, J=8.0Hz, 2H), 7.50 (d, J=8.2Hz, 2HH), 7.15 (d, J=8.0Hz, 1H), 7.96 (dd, J=7.4, 7.4Hz, 1H), 6.77 (d, J=8.0Hz, 1H),
# 6.59 (dd, J=7.4, 7.4Hz, 1H), 5.67 (s, 2H), 4.88 (bs, 2H). MS: (calc.) 405.1; (obt.) 406.0 (MH)+	19
208	349	722	CH	CH	N-(2-Amino-phenyl)- 4-[(3-fluoro-2- pyridinyl-amino)- methyl]-benzamide	1 H NMR (acetone-d6) δ (ppm): 9.07 (bs, 1H), 8.02 (d, J=8.2Hz, 2H), 7.64-7.44 (m, 3H), 7.33 (dd, J=7.8, 1.5Hz, 1H), 7.03 (td, J=7.6, 1.5Hz, 1H), 6.90 (dd, J=8.0, 1.4Hz, 1H), 6.78 (bs, 1H), 6.71 (td, J=7.6 1.4Hz, 1H), 6.48 (dd, J=8.1, 2.6Hz, 1H), 6.16 (dd, J=7.7, 2.5Hz, 1H),
# 4.76-4.55 (m, 4H). HRMS (calc.): 336.1386, (found): 336.1389.	11
209	350	723	CH	CH	N-(2-Amino-phenyl)- 4-4(3,4,5-trifluoro- 2-pyridinyl-amino)- methyl]-benzamide	1 H NMR (acetone-d6) δ (ppm): 9.06 (bs, 1H), AB system (δA = 8.02, δB = 7.56, J=8.3Hz, 4H), 7.74-7.65 (m, 1H), 7.33 (d, J=8.0, 1H), 7.03 (td, J=7.6, 15Hz, 1H), 6.96-6.83 (m, 2H), 6.71 (td, J=7.6, 1.4Hz, 1H), 4.74 (d, J=6.3Hz, 2H), 4.65 (bs, 2H).	11
210	351	724	CH	CH	N-(2-Amino-phenyl)- 4-(2,4-dioxo-1,4- dihydro-2H- thieno[3,2- d]pyrimidin-3- ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H), 8.10 (dd, J=5.2, 0.5Hz, 1H), 7.91 (d, J=8.2Hz, 2H), 7.40 (d, J=8.2Hz, 2H), 7.15 (d, J=7.1Hz, 1H), 6.98-6.94 (m, 2H), 6.77 (dd, J=8.0, 1.1Hz, 1H), 6.58 (dd, J=7.1, 7.1Hz, 1H), 5.12 (s, 2H), 4.88 (bs, 2H). MS: (calc.) 392.1; (obt.) 393.0 (MH)+.	43
211	352	725	CH	CH	N-(2-Amino-phenyl)- 4-(5-phenyl- [1,2,4]oxadiazol-3- yl)-benzamide	1 H NMR: (DMSO) δ (ppm): 9.85 (bs, 1H), 8.24-8.19 (m, 6H), 7.79-7.66 (m, 3H), 7.20 (d, J=7.5Hz, 1H), 7.00 (dd, J=7.3, 7.3Hz, 1H), 6.80 (d, J=7.9Hz, 1H), 6.61 (dd, J=7.3, 7.3Hz, 1H), 4.96 (bs, 2H). MS: (calc.) 356.1; (obt.) 357.0 (MH)+.	50
212	353	726	CH	CH	N-(2-Amino-phenyl)- 4-(5-methyl- [1,2,4]oxadiazol-3- yl)-benzamide	1 H NMR: (DMSO) δ (ppm): 9.81 (bs, 1H), 8.17-8.11 (m, 4H), 7.18 (d, J=7.9Hz, 1H), 6.99 (dd, J=7.7, 7.7Hz, 1H), 6.79 (d, J=7.9Hz, 1H), 6.61 (dd, J=7.5, 7.5Hz, 1H), 4.94 (bs, 2H), 2.70 (s, 3H). MS: (calc.) 294.1; (obt.) 295.0 (MH)+.	50
213	354	727	CH	CH	N-(2-Amino-phenyl)- 4-(5-piperidin-1- ylmethyl- [1,2,4]oxadiazol-3- yl)-benzamide	1 H NMR: (acetone) δ (ppm): 9.29 (bs, 1H), 8.21 (m, 4H), 7.31(d, J=8.0Hz, 1H), 7.03(dd, J=7.0, 7.0Hz, 1H), 6.88 (d, J=7.3Hz, 1H), 6.69 (dd, J=7.3, 7.3Hz, 1H), 4.68 (bs, 2H), 3.94 (s, 2H), 2.58 (t, J=5.1Hz), 1.63-1.55 (m, 4H), 1.47-1.43 (m, 2H). MS (Calc) 377.2; (Obt.) 378.3 (MH) +	50
214	355	728	CH	CH	N-(2-Amino-phenyl)- 4-(5-morpholin-4- ylmethyl- [1,2,4]oxadiazol-3- yl)-benzamide	1 H NMR: (acetone) δ (ppm): 9.28 (bs, 1H), 8.21 (m, 4H), 7.31 (d, J=8.1Hz, 1H), 7.03 (dd, J=7.0, 7.0Hz, 1H), 6.88 (d, J=7.3Hz, 1H), 6.69 (dd, J=7.3, 7.3Hz, 1H), 4.67 (bs, 2H), 4.01 (s, 2H), 3.66 (t, J=4.8Hz), 2.65 (t, J=4.4Hz). MS: (Calc.) 379.2; (Obt.): 380.2 (MH)+	50
215	356	729	CH	CH	N-(2-Amino-phenyl)- 4-(5-propyl- [1,2,4]oxadiazol-3- ymethyl)- benzamide	1 H NMR. (DMSO) δ (ppm): 9.62 (s, 1H), 7.93 (d, J=7.9Hz, 2H), 7.42 (d, J=7.9Hz, 1H), 7.16 (d, J=7.5Hz, 1H), 6.97 (t, J=7.0Hz, 1H), 6.77 (d, J=7.9Hz, 1H), 6.59 (t, J=7.5Hz, 1H), 4.88 (s, 2H), 4.16(s, 2H), 2.87 (t, 7.0, 2H), 1.72 (q, J=7.5Hz, 2H), 0.92 (t, J=7.0Hz, 3H). (MH)+: 337.2.	50
216	357	730	CH	CH	N-(2-Amino-phenyl)- 4-(5-propyl- [1,2,4]oxadiazol-3- ymethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.64 (s, 1H), 9.24 d, J=1.8Hz, 1H), 886 (dd, J=1.3Hz, J=4.8Hz, 1H), 8.45 (dd, J=1.8Hz, J=6.2Hz, 1H), 7.96.(d, J=7.9Hz, 2H), 7.66 (dd, J=4.8Hz, J=7.9Hz, 1H), 7.50 (d, J=8.4Hz, 2H), 7.16 (d, J=7.5Hz, 1H), 6.96 (t, J=7.0Hz, 1H),
# 6.77 (d, J=7.5Hz, 1H), 6.59 (t, J=7.5Hz, 1H), 4.89 (s, 2H), 4.31 (s, 2H). (MH)+. 372.3.	50
217	358	731	CH	CH	N-(2-Amino-phenyl)- 4-(5-propyl- [1,2,4]oxadiazol-3- ymethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.63 (s, 1H), 8.87 (d, J=6.2Hz, 2H); 7.95-8.02 (m, 3H), 7.50 (d, J=7.9Hz, 2H), 7.16 (d, J=7.5Hz, 2H), 6.97 (t, J=7.0Hz, 1H), 6.77 (d, J=7.0Hz, 1H), 6.59 (t, J=7.9Hz, 1H), 4.89 (s, 2H), 4.33 (s, 2H), (MH)+: 372.3.	50
218	359	732	CH	CH	4-(5-Acetylamino-4- cyano-thiophen-2- ylmethyl)-N-(2- amino-phenyl)- benzamide	1 H NMR (DMSO) δ (ppm): 11.62 (s, 1H), 9.60 (bs, 1H), 7.93 (d, J=8.1Hz, 2H), 7.39 (d, J=8.1Hz, 2H), 6.97 (d, J=7.3Hz, 1H), 7.15 (d, J=7.3Hz, 1H), 6.98-6.94 (m, 2H), 6.77 (d, J=7.3Hz, 1H), 6.591 (dd, J=7.7, 7.7Hz, 1H), 4.89 (bs, 2H), 4.13 (s, 2H), 2.17 (s, 3H). LRMS: 390.1 (calc) 391.2 (found).	49
219	360	733	CH	CH	4-(5-Benzoylamino- 4-cyano-3-methyl- thiophen-2- ylmethyl)-N-(2- amino-phenyl)- benzamide	1 H NMR (DMSO) δ (ppm): 11.77 (s, 1H) 9.61 (s, 1H); 7.93 (d, J=7.0Hz, 4H), 7.52-7.63 (m, 3H), 7.38 (d, J=7.6Hz, 2H), 7.16 (d, J=7.6Hz, 1H), 6.96 (t, J=7.6Hz, 1H), 6.77 (d, J=7.6Hz, 1H), 6.59 (t, J=7.6Hz, 1H), 4.89 (s, 2H), 4.15 (s, 2H), 2.24 (s, 3H). (MH)+: 467.0	49
220	361	734	CH	CH	N-(2-Amino-phenyl)- 4-[4-cyano-3- methyl-5-(3-phenyl)- ureido)-thiophen-2- ylmethyl]- benzamide	1 H NMR (DMSO) δ (ppm): 10.12 (s, 1H), 9.61 (s, 1H), 9.21 (s, 1H); 7.93 (d, J=7.6Hz, 2H), 7.27-7.43 (m, 6H), 7.16 (d, J=7.6Hz, 1H), 6.93-7.05 (m, 2H) 6.77 (d, J=8.2Hz, 1H), 6.59 (t, J=7.6Hz, 1H), 4.88 (s, 2H), 4.08 (s, 2H), 2.19 (s, 3H). (MH)+: 482.4	49
221	362	735	CH	CH	N-(2-Amino-phenyl)- 4-(3-oxo-2,3- dihydro- benzo[1,4]oxazin- 4-ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.60 (s, 1H), 7.92 (d, J=8.2Hz, 2H), 7.40 (d, J=8.0Hz, 2H), 7.13 (d, J=6.9Hz, 1H), 6.92-7.04 (m, 5H), 6.75 (dd, J=8.1Hz, 1.1Hz, 1H), 6.57 (td, J=7.4Hz, 1.4Hz, 1H), 5.24 (s, 2H), 4.88 (bs, 2H); 4.82 (s, 2H). (MH)+: 374.1	11
222	363	736	CH	CH	N-(2-Amino-phenyl)- 4-(3-oxo-2,3- dihydro- benzo[1,4]thiazin- 4-ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.58 (s, 1H), 7.90 (d, J=8.2Hz, 2H), 7.42 (dd, J=8.0Hz, J=1.4Hz, 1H), 7.32 (d, J=8.2Hz, 2H), 7.19-7.11 (m, 3H), 7.04-6.92 (m, 2H), 6.75 (dd, J=8.0Hz, 1.4Hz, 1H), 6.57 (td, J=8.0Hz, 1.6Hz, 1H), 5.31 (s, 2H); 4.88 (bs, 2H); 3.70 (s, 2H). (MH)+: 390.1	11
223	364	737	CH	CH	N-(2-Amino-phenyl)- 4-(3-oxo-2,3- dihydro-pyrido[3,2- b[1,4]oxazin-4- ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.57 (bs, 1H), 7.98 (d, J=4.7Hz, 1H), 7.89 (d, J=8.2Hz, 2H), 7.45-7.40 (m, 3H), 7.15 (d, J=8.2Hz, 1H), 7.09-7.05 (m, 1H), 6.96 (dd, J=7.6, 7.6Hz, 1H), 6.76 (d, J=8.2Hz, 1H), 6.58 (dd, J=7.6, 7.6Hz, 1H), 5.31 (s, 2H), 4.90 (bs, 2H), 4.87 (s, 2H). (MH)+: 375.1	11
224	365	738	CH	CH	N-(2-Amino-phenyl)- 4-(1-hydroxy-3-oxo- indan-2-ylmethyl)- benzamide	1 H NMR: (DMSO) δ (ppm): 9.67 (s, 1H); 7.98 (d, J=8.2Hz, 2H), 7.73-7.84 (m, 3H), 7.53-7.62 (m, 3H), 7.24 (d, J=7.6Hz, 1H), 7.04 (t, J=7.6Hz, 1H), 6.85 (d, J=8.2Hz, 1H), 6.67 (t, J=7.6Hz, 1H), 5.68 (d, J=7.0Hz, 1H), 5.27 (t, J=6.4Hz, 1H), 4.95 (s, 2H), 3.21-3.30 (m, 1H), 3.11-3.13 (m, 2H). (MH)+: 373.1	46
225	336	739	CH	CH	N-(2-Amino-phenyl)- 4-phenoxy- benzamide	1 H NMR: (DMSO) δ (ppm): 9.61 (s, 1H); 8.01 (d, J=8.8Hz, 2H), 7.45 (t, J=7.6Hz, 2H), 7.06-7.24 (m, 6H), 6.97 (t, J=7.6Hz, 1H), 6.78 (d, J=7.4Hz, 1H), 6.59 (t, J=7.6Hz, 1H), 4.88 (s, 2H). (MH)+: 305.0	1
226	367	740	CH	CH	N-(2-Amino-phenyl)- 4-[5-(4-methoxy- phenyl)-2,5- dihydro-furan-2-yl]- benzamide	1 H NMR (CDCl3) δ (ppm): 8.77 (s,1H), 7.93 (d, J=8.1Hz, 2H), 7.42 (d, J=8.4Hz, 2H), 7.38-6.98 (m, 6H), 6.91 (d, J=8.4Hz, 2H), 6.09-5.98 (m, 4H), 3.81 (s, 3H).	52
230	371	741	CH	CH	N-(2-Amino-phenyl)- 4-[1,3-bis-(3,4- dimethoxy-phenyl)-ureidomethyl]- benzamide	1 H NMR (DMSO-d6): δ 10.08 (brs, 1H), 7.99 (d, J=7.9Hz, 2H), 7.70 (s, 1H), 7.49 (d, J=8.35Hz, 4H), 7.39-7.33 (m, 1H), 7.30-6.90 (m, 7H), 6.87 (dd, J=2.2, 8.35Hz, 1H), 6.78 (dd, J=2.2, 8.35Hz, 1H), 5.01 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.75 (s, 6H).	57
231	372	742	CH	CH	N-(2-Amino-phenyl)- 4-[3-(4-chloro- phenyl)-1-(3,4- dimethoxy-phenyl)- ureidomethyl]- benzamide	1 H NMR (CDCl3): δ 8.02 (brs, 1H), 7.90 (d, J=7.9Hz, 2H), 7.46 (d, J=7.5Hz, 2H), 7.42-7.24 (m, 6H), 7.16 (t, J=7.5Hz, 1H), 6.91 (brd, J=5.71Hz, 3H), 6.75 (brd, J=8.3Hz, 1H), 6.70 (d, J=1.8Hz, 1H), 4.99 (s, 1H), 3.97 (s, 3H), 3.86 (s, 3H).	57
232	373	743	CH	CH	N-(2-Amino-phenyl)- 4-[1-(3,4- dimethoxy-phenyl)- 3-phenyl- ureidomethyl]- benzamide	1 H NMR (DMSO-d6): δ 10.10 (brs, 1H), 7.99 (d, J=7.9Hz, 2H), 7.88 (s, 1H), 7.80-7.72 (m, 1H), 7.50 (dd, J=7.0, 5.7Hz, 4H), 7.37 (d, J=7.9Hz, 1H), 7.30-6.94 (m, 7H), 6.78 (d, J=6.6Hz, 1H), 5.03 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H).	57
233	374	744	CH	CH	N-(2-Amino-phenyl)- 4-[1-(3,4- dimethoxy-phenyl)- 3-(4-phenoxy- phenyl)- ureidomethyl]- benzamide	1 H NMR (CDCl3): δ 8.02 (brs, 1H), 7.92 (d, J=7.9Hz, 2H), 7.49 (d, J=8.35Hz, 2H), 7.43-7.32 (m, 5H), 7.10-7.30 (2m, 5H), 7.19-7.10 (m, 2H), 7.01 (dd, J=8.35, 2.2Hz, 3H), 6.94 (d, J=7.5Hz, 1H), 6.92 (d, J=8.8Hz, 1H), 6.77 (dd, J=8.8, 2.2Hz, 1H),
# 6.72 (d, J=2.2Hz, 1H), 6.34 (s, 2H), 5.02 (s, 2H), 3.98 (s, 3H), 3.87 (s, 3H).	57
234	375	745	CH	CH	Biphenyl-4,4′- dicarboxylic acid bis-[(2-amino- phenyl)-amide]	1 H NMR (CD3OD) δ (ppm): 9.80 (bs, 2H), 8.16 (d, J=7.9Hz, 4H), 7.96 (d, J=7.9Hz, 4H), 7.23 (d, J=7.4Hz, 2H), 7.03 (dd, J=6.9, 7.4Hz, 2H), 6.84 (d, J=8.2Hz, 2H), 6.66 (dd, J=6.9, 7.7Hz, 2H), 5.06 (bs, 4H).	15
236	377	746	CH	CH	N-(2-Amino-phenyl)- 4-(pyrimidin-2- ylaminomethyl)- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.6 (bs, 1H), 8.32 (d, J=4.9Hz, 2H) 7.97 (dt, J=7.9, 9.9Hz, 2H), 7.85-7.83 (m, 1H), 7.47, (d, J=8.2Hz, 2H), 7.20 (d, J=7.9Hz, 1H), 7.01 (dt, J=7.4, 7.7Hz, 1H), 6.82 (d, J=7.9Hz, 1H), 6.66-6.62 (m, 1H), 4.98 (bs, 2H), 4.61 (d, 2H).	13
237	378	747	CH	CH	N-(2-Amino-phenyl)-4-(4,6-dimethyl- pyrimidin-2- ylsulfanylmethyl)- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 7.96 (d, J=7.9Hz, 2H), 7.61 (d, J=7.9Hz, 2H), 7.21 (d, J=7.9Hz, 1H), 7.04-6.99 (m, 2H), 6.82 (d, J=7.9Hz, 1H), 6.64 (t, J=7.4Hz, 1H), 4.49 (s, 2H), 2.42 (s, 6H).	11
238	379	748	CH	CH	N-(2-Amino-phenyl)- 4-(4-trifluoromethyl- pyrimidin-2- ylsulfanylmethyl)- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 9.07 (d, J=5.2Hz, 1H), 7.97 (d, J=7.4Hz, 2H), 7.78 (d, J=4.7Hz, 1H), 7.63 (d, J=7.4Hz, 2H), 7.19 (d, J=7.7Hz, 1H), 7.01 (dt, J=7.4, 7.7Hz, 1H), 6.81 (d, J=8.2Hz, 1H), 6.64 (dt, J=7.1, 7.4Hz, 1H), 4.94 (bs, 2H), 4.57 (s, 2H).	11
239	380	749	N	CH	Pyridine-2,5- dicarboxylic acid bis-[(2-amino- phenyl)-amide]	1 H-NMR (DMSO-d6), δ (ppm): 10.23 (bs, 1H), 10.04 (bs, 1H), 9.30 (s, 1H), 8.62 (dd, J=1.8, 8.0Hz, 1H), 8.30 (d, J=8.1Hz, 1H), 7.55 (d, J=7.4Hz, 1H), 7.24 (d J=7.4Hz, 1H), 7.04 (dd, J=7.0, 14.0Hz, 2H), 6.90-6.83 (m, 2H), 6.74-6.63 (m, 2H), 5.11 (bs, 4H).	1
240	381	750	CH	CH	N-(2-Amino-phenyl)- 4-(pyridin-2- ylsulfanylmethyl)- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 8.52 (bs, 1H), 7.96 (d, J=7.4Hz, 2H), 7.69 (d, J=5.8Hz, 1H), 7.59 (d, J=7.4Hz, 2H), 7.38 (d, J=7.7Hz, 1H), 7.19 (bs, 2H), 7.00 (d, J=6.9Hz, 1H), 6.83 (d, J=6.9Hz, 1H), 6.64 (dd, J=6.7, 7.2Hz, 1H), 4.94 (bs, 2H), 4.55 (b + s, 2H).	11
241	382	751	CH	CH	N-(2-Amino-phenyl)- 4-[(4,6-dimethyl- pyrimidin-2- ylamino)-methyl]- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.65 (bs, 1H), 7.96 (d, J=7.9Hz, 2H), 7.57 (d, J=6.3Hz, 1H), 7.47 (d, J=7.7Hz, 2H), 7.21 (d, J=7.4Hz, 1H), 7.00 (d, J=5.8Hz, 1H), 6.59 (d, J=6.6Hz, 1H), 6.64 (dd, J=6.0, 7.4Hz, 1H), 5.01 (s, 2H), 4.61 (d, J=6.0Hz, 2H), 2.24 (s, 6H).	33
242	383	752	CH	CH	N-(2-Amino-phenyl)- 4-[(4,6-dimethyl- pyridin-2-ylamino)- methyl]-benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 7.98 (d, J=7.9Hz, 2H),7.50 (d, J=8.2Hz, 2H), 7.96 (d, J=7.9Hz, 1H), 7.01 (dd, J=7.7, 7.4Hz, 1H), 6.82 (d, J=7.9Hz, 1H), 6.64 (t, J=7.4Hz, 1H), 6.33 (s, 1H), 6.25 (s, 1H), 4.58 (d, J=4.4Hz, 2H), 2.28 (s, 3H), 2.17 (s, 3H).	33
243	384	753	CH	CH	N-(2-Amino-phenyl)- 4-(4,6-dimethyl- pyrimidin-2- yloxymethyl)- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.58 (bs, 1H), 7.88 (d, J=5.8Hz, 2H), 7.46 (d, J=8.2Hz, 2H), 6.90-6.81 (m, 1H), 6.68 (d, J=7.9Hz, 1H), 6.50 (t, J=7.4Hz, 1H), 6.40-6.38 (m, 1H), 6.29-6.26 (m, 1H), 5.33 (s, 2H), 2.25 (s, 6H).	11
244	385	754	CH	CH	N-(2-Amino-phenyl)- 4-[(6-methoxy- pyrimidin-4- ylamino)-methyl]- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.64 (bs, 1H), 8.21 (bs, 1H), 7.95 (d, J=7.96Hz, 2H), 7.83 (d, J=5.8Hz, 1H), 7.44 (d, J=7.9Hz, 2H), 7.19 (d, J=7.7Hz, 1H), 7.00 (dd, J=7.4, 7.7Hz, 1H), 6.80 (d, J=7.9Hz, 1H), 6.64 (d, J=7.1Hz, 1H), 4.96 (bs, 2H), 4.58 (bs, 2H), 3.81 (s, 3H).	33
245	386	755	CH	CH	4-[(6-Acetyl- benzo[1,3]dioxol-5- ylamino)-methyl]-N- (2-amino-phenyl)- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.79 (bs, 1H), 7.99 (d, J=8.5Hz, 2H), 7.48 (d, J=7.96Hz, 2H), 7.39 (bs, 1H), 7.21 (d, J=7.4Hz, 1H), 7.02 (dd, J=7.1, 7.7Hz, 1H), 6.83 (d, J=7.7Hz, 1H), 6.64 (t, J=7.4Hz, 1H), 6.36 (bs, 1H), 6.00 (d, J=2.2Hz, 2H), 4.59 (bs, 2H), 2.52 (bs, 3H).	33
246	387	756	CH	CH	N-(2-Amino-phenyl)- 4-[(4-chloro-6- methoxy-pyrimidin- 2-ylamino)-methyl]- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 7.96 (d, J=7.9Hz, 2H), 7.47 (bs, 2H), 7.39 (bs, 1H), 7.19 (d, J=7.4Hz, 1H), 7.00 (dd, J=6.9, 7.4Hz, 1H), 6.81 (d, J=7.1Hz, 1H), 6.63 (dd, J=7.7, 6.8Hz, 1H), 6.10 (bs, 1H), 4.56 (d, J=6.0Hz,, 2H), 3.83 (s, 3H).	33
247	388	757	CH	CH	N-(2-Amino-phenyl)- 4-[(2,6-dimethoxy- pyridin-3-ylamino)- methyl]-benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.63 (bs, 1H), 7.94 (d, J=6.9Hz, 2H), 7.47 (d, J=6.59Hz, 2H), 7.15 (d, J=7.9Hz, 1H), 6.99 (dd, J=5.7, 7.4Hz, 1H), 6.80 (d, J=7.8Hz, 1H), 6.71 (d, J=6.6Hz, 1H), 6.62 (dd, J=7.7, 7.1Hz, 1H), 6.15 (d, J=8.2Hz, 1H), 4.96 (bs, 2H), 4.38 (bs, 2H), 3.94 (s, 3H), 3.75 (s, 3H).	33
248	389	758	CH	CH	N-(2-Amino-phenyl)- 4-[(1H- benzoimidazol-2- ylamino)-methyl]- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 10.9 (bs, 1H), 9.64 (bs, 7.99 (bs, 2H), 7.55 (bs, 2H), 7.21-7.17 (m, 3H), 7.14-6.81 (m, 4H), 6.64 (d, J=6.0Hz, 1H), 4.92 (bs, 2H), 4.65 (bs, 2H).	33
249	390	759	CH	CH	N-(2-Amino-phenyl)- 4-[(6-methoxy- pyridin-2-ylamino)- methyl]-benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.60 (bs, 1H), 7.96 (d, J=7.9Hz, 1H), 7.52-7.50 (m, 2H), 7.37-7.30 (m, 1H), 7.25-7.21 (m, 2H), 7.19-6.99 (m, 1H), 6.84-6.81 (m, 1H), 6.67-6.64 (m, 1H), 6.11-6.07 (m, 1H), 5.93-5.89 (m, 1H), 4.93 (bs, 2H), 4.56 (d, J=5.8Hz, 2H), 3.80 (s, 3H).	37
250	391	760	CH	CH	N-(2-Amino-phenyl)- 4-(quinolin-8- ylsulfanylmethyl)- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.68 (bs, 1H), 8.95 (bs, 2H), 8.43-8.38 (m, 1H), 7.90 (bs, 2H), 7.80-7.55 (m, 6H), 7.22 (d, J=7.7Hz, 1H), 7.03 (d, J=7.7Hz, 1H), 6.63 (d, J=7.4Hz, 1H), 5.05 (bs, 2H), 4.48 (d, J=7.7, 2H).	11
251	392	761	CH	CH	N-(2-Amino-phenyl)- 4-[(2,6-dimethoxy- pyrimidin-4- ylamino)-methyl]- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 7.97 (d, J=7.9Hz, 2H), 7.84 (t, J=5.9Hz, 1H), 7.46 (d, J=7.46Hz, 2H), 7.20 (d, J=7.9Hz, 1H), 7.04 (d, J=6.6Hz, 1H), 6.83 (d, J=7.9Hz, 1H), 6.64 (dd, J=7.7, 7.4Hz, 1H), 5.51 (bs, 1H), 4.57 (bs,, 2H), 3.82 (s, 3H), 3.84 (S, 3H).	37
252	393	762	CH	CH	N-(2-Amino-phenyl)- 4-(3,5-dimethoxy- benzylamino)- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.63 (bs, 1H), 7.79 (d, J=8.5Hz, 2H), 7.19 (d, J=6.6Hz, 1H), 7.00 (dd, J=7.9, 7.1Hz, 1H), 6.62 (t, J=6.0Hz, 1H), 6.82 (dd, J=1.4, 7.9Hz, 1H), 6.67 (d, J=8.8Hz, 2H), 6.58 (bs, 2H), 6.42 (bs, 1H), 4.87 (bs, 2H), 4.34 (d, J=6.0Hz, 2H), 3.77 (s, 6H).	37
253	394	763	CH	CH	N-(2-Amino-phenyl)- 4-(3-methoxy- phenylsulfanylmethyl)- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 7.96 (d, J=7.9Hz, 2H), 7.55 (d, J=8.2Hz, 2H), 7.29-7.20 (m, 2H), 7.02-6.95 (m, 2H), 6.84-6.79 (m, 1H), 6.67-6.62 (m, 1H), 6.57-6.54 (m, 1H), 6.44-6.41 (m, 1H), 4.93 (bs, 2H), 4.41 (bs, 2H), 3.79 (s, 3H).	11
254	395	764	CH	CH	N-(2-Amino-phenyl)- 4-(3,5-dimethoxy- phenoxymethyl)- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.72 (bs, 1H), 8.05 (d, J=8.2Hz, 2H), 7.61 (d, J=7.9Hz, 2H), 7.24 (d, J=7.4Hz, 1H), 7.04 (dd, J=6.9, 7.1Hz, 1H), 6.85 (d, J=6.9Hz, 1H), 6.66 (dd, J=7.4, 7.7Hz, 1H), 6.27 (s, 2H), 6.26 (s, 1H), 5.23 (s, 2H), 5.21 (bs, 2H), 3.77 (s, 6H).	11
255	396	765	CH	CH	N-(2-Amino-phenyl)- 4-(quinolin-2- yloxymethyl)- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.70 (bs, 1H), 8.35 (d, J=9.1Hz, 2H), 8.05 (d, J=7.9Hz, 2H), 7.96 (d, J=7.9Hz, 1H), 7.85 (d, J=8.2Hz, 1H), 7.76-7.69 (m, 2H), 7.51 (dd, J=6.9, 7.1Hz, 1H), 7.24-7.16 (m, 2H), 7.02 (dd, J=6.9, 7.4Hz, 1H), 6.83 (d, J=8.2Hz, 1H), 6.66 (d, J=7.4Hz, 1H), 5.66 (s, 2H), 4.94 (bs, 2H).	11
256	397	766	CH	CH	N-(2-Amino-phenyl)- 4-[(3,5-dimethoxy- phenylamino)- methyl]-benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.62 (bs, 1H), 7.96 (d, J=7.9Hz, 2H), 7.49 (d, J =7.9Hz, 2H), 7.19 (d, J=7.9Hz, 1H), 7.00 (dd, J=7.5, 7.9Hz, 1H), 6.81 (d, J=7.9Hz, 1H), 6.63 (dd, J=7.0, 8.0Hz, 1H), 5.78 (s, 2H), 5.76 (s, 1H), 4.92 (bs,, 2H), 4.35 (d, J=5.7, 2H), 3.65 (s, 6H).	33
257	398	767	CH	N	bis(N-(2-Amino- phenyl)- nicotinamide)-6- disulfide	1H-NMR (DMSO-d6), δ (ppm): 9.82 (bs, 2H), 9.08 (bs, 2H), 8.34 (d, J=8.3Hz, 2H), 7.83 (d, J=8.3Hz, 2H), 7.18 (d, J=7.5Hz, 2H), 7.01 (dd, J=6.3, 7.0Hz, 2H), 6.80 (d, J=7.9Hz, 2H), 6.61 (t, J=7.03Hz, 2H), 5.05 (bs, 4H).	1
258	339	768	CH	CH	N-(2-Amino-phenyl)- 4-(isoquinolin-1- ylaminomethyl)- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.90 (bs, 1H), 8.16 (bs, 2H), 7.65 (d, J=4.8Hz, 2H), 7.54 (bs, 2H), 7.25 (d, J=7.0Hz, 2H), 7.11 (bs, 2H), 7.07-7.02 (m, 2H), 6.84 (d, J=7.9Hz, 1H), 6.67 (bs, 1H), 5.01 (bs, 2H), 4.88 (bs, 2H).	33
259	400	769	CH	CH	N-(2-Amino-phenyl)- 4-[(2,3-dihydro- benzo[1,4]dioxin-6- ylamino)-methyl]- benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 7.97 (d, J=7.0Hz, 2H), 7.51 (d, J=7.0Hz, 2H), 7.22 (d, J=7.5Hz, 1H), 7.02-6.97 (m, 1H), 6.84 (bs, 1H), 6.82-6.71 (m, 2H), 6.16 (d, J=6.6Hz, 1H), 6.08 (s, 1H), 4.32 (bs, 2H), 4.16-4.13 (m, 2H).	33
260	401	770	CH	CH	4-[(4-Acetylamino- phenylamino)- methyl]-N-(2-amino- phenyl)-benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 9.56 (bs, 1H), 7.97 (d, J=7.9Hz, 2H), 7.53 (d, J=7.9Hz, 2H), 7.28 (d, J=8.8Hz, 2H), 7.22 (d, J=7.9Hz, 1H), 7.02 (t, J=7.5Hz, 1H), 6.83 (d, J=7.9Hz, 1H), 6.65 (t, J=7.5Hz, 1H), 6.55 (d, J=8.3Hz, 2H), 4.98 (bs, 2H), 4.38 (bs, 2H), 2.00 (s, 3H).	33
261	402	771	CH	CH	N-(2-Amino-phenyl)- 4-[(4-morpholin-4- yl-phenylamino)- methyl]-benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.65 (bs, 1H), 7.98 (d, J=7.9Hz, 2H), 7.52 (d, J=7.9Hz, 2H), 7.21 (d, J=7.5Hz, 1H), 7.02 (dd, J=7.0, 7.9Hz, 1H), 6.83 (d, J=7.9Hz, 1H), 6.78 (d, J=8.8Hz, 2H), 6.64 (t, J=7.5Hz, 1H), 6.55 (d, J=8.8Hz, 2H), 4.94 (bs, 2H), 4.35 (d, J=5.7Hz, 2H), 3.74 (t, J=4.4Hz, 4H), 2.92 (t, J=4.4Hz, 4H).	33
262	403	772	CH	CH	N-(2-Amino-phenyl)- 4-[(4-methoxy-2- methyl- phenylamino)- methyl]-benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.64 (bs, 1H), 7.96 (d, J=7.6Hz, 2H), 7.52 (d, J=7.6Hz, 2H), 7.21 (d, J=8.2Hz, 1H), 7.02 (t, J=8.2, 7.0Hz, 1H), 6.83 (d, J=8.2Hz, 1H), 6.71-6.53 (m, 3H), 6.32-6.30 (m, 1H), 4.94 (bs, 2H), 4.45 (d, J=5.9Hz, 2H), 3.65 (s, 3H), 2.23 (s, 3H).	33
263	404	773	CH	CH	N-(2-Amino-phenyl)- 4-[(2-cyano-4- methoxy- phenylamino)- methyl]-benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.65 (bs, 1H), 7.98 (d, J=7.4Hz, 2H), 7.56 (d, J=7.5Hz, 2H), 7.19 (d, J=7.9Hz, 1H), 6.99 (d, J=7.5Hz, 1H), 6.82 (d, J=7.9Hz, 1H), 6.63 (t, J=6.6Hz, 2H), 6.27 (s, 1H), 4.93 (bs, 2H), 4.55 (d, J=5.3Hz, 2H), 3.69 (s, 6H).	33
264	405	774	CH	CH	N-(2-Amino-phenyl)- 4-{[4-methoxy-3- (pyridin-3- ylmethoxy)- phenylamino]- methyl}-benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.62 (s, 1H), 8.72 (s, 1H), 8.49 (d, J=10.1Hz, 1H), 7.93 (d, J=7.9Hz, 2H), 7.68 (d, J=6.6Hz, 1H), 7.37 (d, J=7.5Hz, 2H), 7.16 (d J=7.5Hz, 1H), 6.97 (t, J=7.5Hz, 1H), 6.78 (d, J=7.9Hz, 1H), 6.69 (d, J=8.8Hz, 1H), 6.62 (d, J=7.5Hz, 1H), 6.23 (d, J=2.6Hz, 1H),
# 6.09 (J=8.8Hz, 1H), 5.76 (s, 1H), 4.64 (bs, 4H), 3.62 (s, 3H).	33
265	406	775	CH	CH	2-[4-(2-Amino- phenylcarbamoyl)- benzylamino]-4,5- dimethoxy-benzoic acid	1 H-NMR (DMSO-d6), δ (ppm): 9.67 (bs, 1H), 8.00 (d, J=7.9Hz, 2H), 7.54 (d, J=7.9Hz, 2H), 7.34 (s, 1H), 7.20 (d, J=7.9Hz, 2H), 7.0 (t, J=7.9Hz, 1H), 6.82 (d, J=7.9Hz, 1H), 6.62 (t, J=7.9Hz, 1H), 6.31 (s, 1H), 4.95 (bs, 2H), 4.62 (bs, 2H), 3.75 (s, 3H), 3.70 (s, 3H).	33
266	407	776	CH	CH	N-(2-Amino-phenyl)- 4-[(3,5-dimethyl- phenylamino)- methyl]-benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.60 (s, 1H), 7.93 (d, J=7.9Hz, 2H), 7.45 (d, J=7.9Hz, 2H), 7.16 (d, J=7.5Hz, 1H), 6.97 (t, J=7.5Hz, 1H), 6.78 (d, J=7.9Hz, 1H), 6.58 (t, J=7.0Hz, 1H), 6.19-6.17 (m, 3H), 4.88 (s, 2H), 4.32 (d, J=5.7Hz, 2H), 2.10 (s, 6H).	33
267	408	777	CH	CH	N-(2-Amino-phenyl)- 4-{[4-(pyridin-3- ylmethoxy)- phenylamino]- methyl}-benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.65 (s, 1H), 8.72 (s, 1H), 8.54 (s, 1H), 8.49 (d, J=10.9Hz, 1H), 7.97 (d, J=7.9Hz, 2H), 7.71 (d, J=7.9Hz, 1H), 7.44 (d, J=8.3Hz, 2H), 7.41-7.36 (m, 1H), 7.20 (d, J=7.9Hz, 1H), 7.00 (t, J=7.4Hz, 1H), 6.83 (d, J=7.0Hz, 1H), 6.70-6.60 (m, 4H), 4.62 (s, 4H).	33
268	409	778	CH	CH	N-(2-Amino-phenyl)- 4-[(2,4-dimethyl- phenylamino)- methyl]-benzamide	1 H-NMR (DMSO-d6), δ (ppm): 9.58 (s, 1H), 7.90 (d, J=7.9Hz, 2H), 7.45 (d, J=7.5Hz, 2H), 7.15 (d, J=7.5Hz, 1H), 6.96 (t, J=7.5Hz, 1H), 6.79 (s, 1H), 6.76 (d, J=9.6Hz, 1H), 6.68 (d, J=7.9Hz, 1H), 6.59 (t, J=7.0Hz, 1H), 6.22 (d, J=7.9Hz, 1H), 4.89 (bs, 2H), 4.39 (d, J=5.7Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H).	33
269	410	779	CH	CH	N-(2-Amino-phenyl)- 4-[(2,4,6-trimethyl- phenylamino)- methyl]-benzamide	1 H-NMR (CD3OD), δ (ppm): 7.91 (d, J=7.9Hz, 2H), 7.43 (d, J=8.5Hz, 2H), 7.18 (d, J=7.5Hz, 1H), 7.08 (t, J=7.5Hz, 1H), 6.92 (d, J=7.9Hz, 1H), 4.15 (bs, 2H), 2.19 (s, 9H).	33
270	411	780	CH	CH	N-(2-Amino-phenyl)- 4-[(4-chloro-6- morpholin-4-yl- pyrimidin-2- ylamino)-methyl]- benzamide	1 H NMR (300MHz, DMSO-D6) δ *** (ππμ): 9.66 (s, 1H), 7.97 (d, J=8.0Hz, 2H), 7.82 (m, 1H), 7.47 (d, J=7.7Hz, 2H), 7.21 (d, J=8.2Hz, 1H), 7.03 (dd, J=7.1, 7.1Hz, 1H), 6.84 (d, J=7.7Hz, 1H), 6.65 (dd, J=7.4, 7.4Hz, 1H), 6.17 (bs, 1H),
# 4.94 (s, 2H, NH2), 4.53 (d, J=5.8Hz, 2H), 3.58 (m, 4H), 3.62 (m, 4H).	24, 33
271	412	781	CH	CH	N-(2-Amino-phenyl)- 4-(3,4,5- trimethoxy- benzylamino)- benzamide	1 H NMR (300 MHz, DMSO-d6) δ (ppm): 9.33 (s, 1H), 7.81 (d, J=8.8Hz, 2H), 7.19 (d, J=7.7Hz, 1H), 6.99 (m, 1H), 6.87 (dd, J=6.0, 5.8Hz, 1H), 6.82 (m, 1H), 6.77 (s, 2H), 6.71 (d, J=8.8Hz, 2H), 6.64 (m, 1H), 4.87 (s, 2H, NH2). 4.32 (d, J=5.5Hz, 2H), 3.81 (s, 6H), 3.79 (s, 3H).	33
272	413	782	CH	CH	N-(2-Amino-phenyl)- 4-(4-fluoro- benzylamino)- benzamide	1 H NMR (300MHz, DMSO-d6) δ δ (ppm): 9.31 (s, 1H), 7.79 (d, J=8.7Hz, 2H), 7.45 (dd, J=5.8, 8.5Hz, 2H), 7.21 (m, 3H), 6.91 (m, 2H), 6.81 (dd, J=1.1, 8.0Hz, 1H), 6.67 (d, J=8.8Hz, 2H), 6.62 (dd, J=1.0, 7.2Hz, 1H), 4.86 (s, 2H, NH2), 4.39 (d, J=6.0Hz, 2H).	33
273	414	783	CH	CH	N-(2-Amino-phenyl)- 4-(4-methoxy- benzylamino)- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.31 (s, 1H), 7.79 (dd, J=1.1, 8.5Hz, 2H), 7.33 (d, J=7.1Hz, 2H), 7.19 (d, J=7.7Hz, 1H), 6.97 (m, 3H), 6.84 (m, 2H), 6.65 (m, 3H), 4.86 (s, 2H, NH2), 4.33 (d, J=5.5Hz, 2H), 3.58 (d, J=1.6Hz, 3H).	33
274	415	784	CH	CH	N-(2-Amino-phenyl)- 4-[(4-fluoro- phenylamino)- methyl]-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.66 (s, 1H), 7.99 (d, J=7.9Hz, 2H), 7.53 (d, J=8.0Hz, 2H), 7.21 (d, J=8.0Hz, 1H), 7.02 (ddd J=1.6, 7.1, 8.2Hz, 1H), 6.93 (dd, J=8.8, 9Hz, 2H), 6.83 (dd, J=1.1, 8.0Hz, 1H), 6.63 (m, 3H), 6.35 (t, J=6.2Hz, 1H), 4.94 (s, 2H, NH2), 4.38 (d, J=6.3Hz, 2H).	33
275	416	785	CH	CH	N-(2-Amino-phenyl)- 4-(3-fluoro- benzylamino)- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.32 (s, 1H), 7.79 (d, J=8.8Hz, 2H), 7.44 (m, 1H), 7.26 (m, 1H), 7.18 (dd, J=1.4, 8.0Hz, 2H), 7.12 (ddd, J=1.7, 8.0, 8.2Hz, 1H), 6.99 (m. 2H), 6.81 (dd, J=1.4, 8.0Hz, 1H), 6.67 (dd, J=1.6, 8.8Hz, 2H), 6.62 (dd, J=1.4, 7.4Hz, 1H), 4.87 (s, 2H, NH2), 4.45 (d, J=6.0Hz, 2H).	33
276	417	786	CH	CH	N-(2-Amino-phenyl)- 4[(3-fluoro- phenylamino)- methyl]-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.66 (s, 1H), 7.99 (d, J=8.2Hz, 2H), 7.52 (d, J=8.0Hz, 2H), 7.21 (d, J=7.7Hz, 1H), 6.99-7.14 (m, 2H), 6.83 (d, J=8.0Hz, 1H), 6.76 (m, 1H), 6.64 (dd, J=7.4, 7.4Hz, 1H), 6.46 (d, J=8.2Hz, 1H), 6.34 (m, 2H), 4.94 (s, 2H, NH2), 4.41 (d, J=6.0Hz, 2H).	33
277	418	787	CH	CH	N-(2-Amino-phenyl)- 4-[(4-chloro-6- methyl-pyrimidin-2- ylamino)-methyl]- benzamide	1 H NMR (300MHz, DMSO-D6) δ (ppm): 9.66 (s, 1H), 8.23 (m, 1H), 7.98 (d, J=8.2Hz, 2H), 7.47 (d, J=8.5Hz, 2H), 7.21 (d, J=7.7Hz, 1H), 7.03 (ddd, J=1.5, 7.1, 8.0Hz, 1H), 6.83 (dd, J=1.5, 8.1Hz, 1H), 6.65 (m, 2H), 4.94 (s, 2H, NH2), 4.61 (m, 2H), 2.32 (s, 3H).	33
278	419	788	CH	CH	N-(2-Amino-phenyl)- 4-[(4,6-dichloro- pyrimidin-2- yiamino)-methyl]- benzamide	1 H NMR (300MHz, DMSO-D6) δ (ppm): 9.69 (s, 1H), 8.82 (m, 1H), 7.99 (d, J=8.2Hz, 2H), 7.48 (d, J=8.0Hz, 2H), 7.27 (d, J=7.7Hz, 1H), 7.04 (d, J=7.7Hz, 1H), 7.0 (d, J=1.6Hz, 1H), 6.84 (d, J=8.2Hz, 1H), 6.67 (m, 1H), 5.0 (bs, 2H, NH2), 4.60 (d, J=6.3Hz, 2H).	33
279	420	789	CH	CH	N-(2-Amino-phenyl)- 4-({4-chloro-6- [(pyridin-3- ylmethyl)-amino]- pyrimidin-2- ylamino}-methyl)- benzamide	1 H NMR (300MHz, DMSO-D6) δ (ppm): 9.87 (s, 1H), 8.49 (bs, 2H), 7.26-8.02 (bm, 8H), 7.22 (d, J=8.0Hz, 1H), 7.03 (dd, J=7.4, 7.4Hz, 1H), 6.84 (d, J=8.2Hz, 1H), 6.66 (dd, J=7.1, 8.0Hz, 1H), 5.86 (bs, 1H), 4.95 (s, 2H, NH2), 4.51 (m, 2H).	24, 33
280	421	790	CH	CH	N-(2-Amino-phenyl)- 4-[(6-methoxy- pyridin-3-ylamino)- methyl]-benzamide	1 H NMR (300MHz, DMSO-D6) δ (ppm): 9.66 (s, 1H), 7.99 (d, J=8.4Hz, 2H), 7.54 (d, J=7.9Hz, 2H), 7.50 (d, J=2.6Hz, 1H), 7.21 (d, J=7.5Hz, 7.9Hz, 1H), 7.12 (dd, J=3.08Hz, 8.79Hz, 1H), 7.02 (dd, J=7.0Hz, 7.5Hz, 1H), 6.83 (d, J=7.0Hz, 1H), 6.65 (m, 2H), 6.15 (t, J=6.16Hz, 1H),
# 4.94 (s, 2H, NH2), 4.39 (d, J=6.15Hz, 2H), 3.75 (s, 3H).
281	422	791	CH	CH	N-(2-Amino-phenyl)- 4-[(4-trifluoromethoxy- phenylamino)- methyl]-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.66 (s, 1H), 7.99 (d, J=8.0Hz, 2H), 7.53 (d, J=8.2Hz, 2H), 7.21 J=7.7Hz, 1H), 7.09 (d, J=9.1Hz, 2H), 7.03 (dd, J=7.1, 8.2Hz, 1H), 6.83 (d, J=8.0Hz, 1H), 6.71 (t, J=6.0Hz, 1H), 6.63-6.67 (m, 3H), 4.94 (s, 2H, NH2), 4.42 (d, J=6.0Hz, 2H).	33
282	423	792	CH	CH	N-(2-Amino-phenyl)- 4-[(3-trifluoromethoxy- phenylamino)- methyl]-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.67 (s, 1H), 8.00 (d, J=8.2Hz, 2H), 7.53 (d, J=8.2Hz, 2H), 7.19 (m, 2H), 7.03 (ddd, J=1.5, 8.0, 8.8Hz, 1H), 6.85 (m, 2H), 6.63 (m, 2H), 6.55 (s, 1H), 6.50 (m, 1H), 4.94 (s, 2H, NH2), 4.44 (d, J=6.0Hz, 2H).	33
283a	424b	793	CH	CH	N-(2-Amino-pheny)- 4-[(3,4-dimethoxy-phenylamino)- methyl]-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.65 (s, 1H), 7.98 (d, J=7.9Hz, 2H), 7.54 (d, J=7.9Hz, 2H), 7.22 (d, J=7.9Hz, 1H), 7.02 (dd, J=7.9Hz, 7.9Hz, 1H), 6.83 (d, J=7.9Hz, 1H), 6.72 (d, J=8.79Hz, 1H), 6.45 (dd, J=7.49Hz, 7.49Hz, 1H), 6.39 (d, J=2.2Hz, 1H),
# 6.01-6.08 (m, 2H), 4.94 (s, 2H, NH2), 4.36 (d, J=6.16Hz, 2H), 3.72 (s, 3H), 3.65 (s, 3H).	33
284	425	794	CH	CH	N-(2-Amino-phenyl)- 4-(3-trifluoromethoxy- benzylamino)- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.31 (s, 1H), 7.80 (d, J=8.8Hz, 2H), 7.45-7.56 (m, 2H), 7.39 (s, 7.29 (d, J=7.7Hz, 1H), 7.18 (d, J=6.6Hz, 1H), 6.96-7.03 (m, 2H), 6.81 (d, J=6.9Hz, 1H), 6.68 (d, J=8.8Hz, 2H), 6.64 (d, J=7.7Hz, 1H), 4.86 (s, 2H, NH2), 4.48 (d, J=5.8Hz, 2H).	33
285	426	795	CH	CH	N-(2-Amino-phenyl)- 4-(4-trifluoromethoxy- benzylamino)- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.31 (s, 1H), 7.79 (d, J=8.8Hz, 2H), 7.54 (d, J=8.8Hz, 2H), 7.39 (d, J=8.0Hz, 2H), 7.18 (dd, J=1.4, 7.7Hz, 1H), 6.99 (ddd, J=1.4, 8.0, 8.5Hz, 2H), 6.81 (dd, J=1.4, 8.0, 1H), 6.68 (d, J=8.8Hz, 2H), 4.85 (s, 2H, NH2), 4.45 (d, J=6.0Hz, 2H).	33
286	427	796	CH	CH	N-(2-Amino-phenyl)- 4-[(4-methoxy phenylamino)- methyl]-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.64 (s, 1H), 7.97 (d, J=8.2Hz, 2H), 7.53 (d, J=8.5Hz, 2H), 7.21 (d, J=1.4, 8.0Hz, 1H), 7.02 (ddd, J=1.4, 7.4, 8.0Hz, 1H), 6.83 (dd, J=1.4, 8.0Hz, 1H), 6.74 (m, 2H), 6.65 (ddd, J=1.4, 7.7, 8.8Hz, 1H), 6.58 (m, 2H), 5.99 (t, J=6.3Hz, 1H), 4.93 (s, 2H, NH2), 4.36 (d, J=6.0Hz, 2H), 3.68 (s, 3H).	33
287	428	797	CH	CH	N-(2-Amino-phenyl)- 4-benzo[1,3]dioxol- 5-ylaminomethyl)- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.65 (s, 1H), 7.98 (d, J=7.9Hz, 2H), 7.52 (d, J=7.9Hz, 2H), 7.21 (d, J=7.5Hz, 1H), 7.02 (dd, J=7.0, 7.0Hz, 1H), 6.83 (d, J=7.5Hz, 1H), 6.63-6.69 (m, 2H), 6.33 (d, J=2.2Hz, 1H), 6.15 (t, J=6.16Hz, lH), 6.04 (dd, J=2.2, 8.4Hz, 1H), 5.86 (s, 2H),
# 4.94 (s, 2H, NH2), 4.35 (d, J=6.16Hz, 2H).	33
288	429	798	CH	CH	N-(2-Amino-phenyl)- 4-[(2-methoxy- phenylamino)- methyl]-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.63 (s, 1H), 7.90 (d, J=8.2Hz, 2H), 7.52 (d, J=8.2Hz, 2H), 7.22 (d, J=7.7Hz, 1H), 7.02 (ddd, J=1.4, 7.1, 8.0Hz, 1H), 6.86 (m, 2H), 6.56-6.75 (m, 3H), 6.43 (dd, J=1.6, 7.7Hz, 1H), 5.75 (t, J=6.3Hz, 1H), 4.93 (s, 2H, NH2), 4.47 (d, J=6.3Hz, 2H), 3.88 (s, 3H).	33
289	430	799	CH	CH	N-(2-Amino-phenyl)- 4-[(3-methoxy- phenylamino)- methyl]-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.61 (s, 1H), 7.98 (d, J=8.0Hz, 2H), 7.53 (d, J=8.2Hz, 2H), 7.21 (dd, J=1.1, 7.7Hz, 1H), 6.97-7.05 (m, 2H), 6.82 (dd, J=1.2, 8.1Hz, 1H), 6.46 (ddd, J=1.4, 7.7, 8.0Hz, 1H), 6.41 (t, J=6.3Hz, 1H), 6.16-6.25 (m, 3H), 4.93 (s, 2H, NH2), 4.39 (d, J=6.0Hz, 2H), 3.69 (s, 3H).	33
290	431	800	CH	CH	N-(2-Amino-phenyl)- 4-(2,2,2-trifluoro- acetylamino)- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 11.53 (s, 1H), 9.71 (s, 1H), 8.08 (d, J=8.2Hz, 2H), 7.86 (d, J=8.8Hz, 2H), 7.23 (d, J=7.6Hz, 1H), 7.03 (dd, J=7.0, 7.6Hz, 1H), 6.84 (d, J=8.2Hz, 1H), 6.66 (dd, J=7.0, 7.6Hz, 1H), 4.96 (s, 2H, NH2).	14
291	432	801	CH	CH	N-(2-Amino-phenyl)- 4-{[4-chloro-6- (3,4,5-trimethoxy- benzylamino)- pyrimidin-2- ylamino]-methyl}- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.64 (s, 1H), 7.95 (d, J=7.5Hz, 2H), 7.70 (bs, 2H), 7.45 (d, J=8.14Hz, 2H), 7.22 (d, J=7.9Hz, 1H), 7.03 (dd, J=7.0, 7.5Hz, 1H), 6.84 (d, J=7.9,Hz, 1H), 6.60-6.72 (m, 3H), 5.87 (s, 1H), 4.93 (s, 2H, NH2),
# 4.54 (d, J=6.2Hz, 2H), 4.43 (bs, 2H), 3.78 (s, 6H), 3.68 (s, 3H).	24, 33
292	433	802	CH	CH	N-(2-Amino-phenyl)- 4-{[4-chloro-6- (3,4,5-trimethoxy- phenylamino)- pyrimidin-2- ylamino]-methyl}- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.65 (s, 1H), 9.43 (s, 1H), 7.97 (m, 3H), 7.46 (bs, 2H), 7.5Hz, 1H), 7.02 (m, 3H), 6.83 (d, J=7.0Hz, 1H), 6.65 (dd, J=7.5, 7.5Hz, 1H), 6.08 (s, 1H), 4.93 (s, 2H, NH2), 4.69 (bs, 2H), 3.65 (s, 9H).	24, 33
293	434	803	CH	CH	N-(2-Amino-phenyl)- 4-(3,4-dimethoxy- benzylamino)- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.31 (s, 1H), 7.79 (d, J=8.8Hz, 2H), 7.19 (d, J=7.9Hz, 2H), 7.04 (s, 1H), 6.92-7.01 (m, 3H), 6.80-6.87 (m, 2H), 6.69 (d, J=8.8Hz, 2H), 6.62 (m, 1H), 4.87 (s, 2H, NH2), 4.32 (d, J=5.7Hz, 2H), 3.80 (s, 3H), 3.78 (s, 3H).	33
294	435	804	CH	CH	N-(2-Amino-phenyl)- 4-[(4-morpholin-4- yl-pyrimidin-2- ylamino)-methyl]- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.64 (s, 1H), 7.95 (d, J=8.4Hz, 2H), 7.87 (d, J=7.9Hz, 1H), 7.47 (d, J=7.9Hz, 2H), 7.31 (bs, 1H), 7.21 (d, J=7.5, 1H), 7.02 (dd, J=7.9Hz, 1H), 6.83 (d, J=7.9Hz, 1H), 6.65 (dd, J=7.0, 7.0Hz, 1H), 6.09 (d, J=6.2Hz, 1H),
# 4.94 (s, 2H, NH2), 4.54 (d, J=5.7Hz, 2H), 3.67 (s, 4H), 3.53 (s, 4H).	24, 1, 33
295	436	805	CH	CH	N-(2-Amino-phenyl)- 4-{[2-(1H-indol-3-yl)- ethylamino]- methyl}-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 10.82 (s, 1H), 9.65 (s, 1H), 7.98 (d, J=8.4Hz, 2H), 7.56 (d, J=7.9Hz, 1H), 7.51 (d, J=8.4Hz, 2H), 7.38 (d, J=7.9Hz, 2H), 7.18-723 (m, 2H), 7.11 (dd, J=7.0, 8.0Hz, 1H), 7.01 (m, 2H), 6.83 (d, J=7.9Hz, 1H),
# 6.51 (dd, J=7.5, 6.6Hz, 1H), 4.93 (s, 2H, NH2), 3.89 (s, 2H), 2.89 (m, 4H).	57
296	437	806	CH	CH	N-(2-Amino-phenyl)- 4-[(4-methylsulfanyl- phenylamino)- methyl]-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.67 (s, 1H), 7.99 (d, J=7.5Hz, 2H), 7.52 (d, J=7.5Hz, 2H), 7.21(d, J=7.5Hz, 1H), 7.13 (d, J=7.5Hz, 2H), 7.03 (dd, J=7.5, 7.5Hz, 1H), 6.83 (d, J=7.9Hz, 1H), 6.53 (m, 4H), 4.95 (s, 2H, NH2), 4.41 (d, J=5.7Hz, 2.37 (s, 3H).	33
297	438	807	CH	CH	N-(2-Amino-phenyl)- methylsulfanyl- phenylamino)- methyl]-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.66 (s, 1H), 7.99 (d, J=7.5Hz, 2H), 7.53 (d, J=7.5Hz, 2H), 7.21 (d, J=7.5Hz, 1H), 7.03 (m, 2H), 6.83 (d, J=7.9Hz, 1H), 6.65 (dd, J=7.5, 7.5Hz, 1H), 6.39-6.51 (m, 4H), 4.94 (s, 2H, NH2), 4.41 (d, J=5.7Hz, 2H), 2.42 (s, 3H).	33
298	349	808	CH	CH	N-(2-Amno-phenyl)- 4-{[4-chloro-6-(3,4- dimethoxy-phenyl)- pyrimidin-2- ylamino]-methyl}- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.66 (s, 1H), 8.37 (s, 1H), 7.99 (d, J=7.5Hz, 2H), 7.68-7.79 (m, 2H), 7.55 (bs, 2H), 7.37 (s, 1H), 7.20 (d, J=7.1Hz, 1H), 7.11 (bs, 1H), 7.02 (dd, J=7.5, 7.5Hz, 1H),
# 6.82 (d, J=7.9Hz, 1H), 6.64 (dd, J=7.5, 7.5Hz, 1H), 4.93 (s, 2H, NH2), 4.86 (s, 2H), 3.88 (s, 6H).	15, 33
299	440	809	CH	CH	N-(2-Amino-phenyl)- 4-{[4-(3,4- dimethoxy-phenyl)- pyrimidin-2- ylamino]-methyl}- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.64 (s, 1H), 8.35 (d, J=4.8Hz, 1H), 7.97 (d, J=7.9Hz, 2H), 7.89 (m, 1H), 7.72 (m, 2H), 7.55 (d, J=7.5Hz, 2H), 7.2 (d, J=5.3Hz, 2H), 7.10 (d, J=8.4Hz, 1H), 7.01 (m, 1H), 6.82 (d, J=7.0Hz, 1H), 6.41 (t, J=7.5Hz, 1 H), 4.92 (s, 2H, NH2), 4.68 (d, J=6.2Hz, 2H),
# 3.82 (s, 6H).	15, 1, 33
300	441	810	CH	CH	4-[(2-Acetyl-4,5- dimethoxy- phenylamino)- methyl]-N-(2-amino- phenyl)-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.68 (s, 1H), 9.45 (t, J=5.7Hz, 1H), 8.01 (d, J=7.9Hz, 2H), 7.54 (d, J=8.4Hz, 2H), 7.32 (s, 1H), 7.21 (d, J=7.5Hz, 1H), 7.02 (dd, J=6.6, 7.5Hz, 1H), 6.83 (d, J=7.5Hz, 1H), 6.65 (dd, J=7.0, 7.5Hz, 1H),
# 6.31 (s, 1H), 4.95 (s, 2H, NH2), 4.63 (d, J=5.7Hz, 2H), 3.78 (s, 3H), 3.76 (s, 3H).	33
301	442	811	CH	CH	N-(2-Amino-phenyl)- 4-{[4-(3,4- dimethoxy- phenylamino)- pyrimidin-2- ylamino]-methyl}- benzamide	1 H NMR (300MHz, CD3OD + CDCl3) δ (ppm): 7.99 (d, J=7.9Hz, 2H), 7.80 (d, J=6.2Hz, 1H), 7.76 (s, 1H), 7.52 (d, J=8.4Hz, 2H), 7.27 (m, 1H), 7.14 (m, 1H), 7.05 (dd, J=2.2, 8.8Hz, 1H), 6.95 (d, J=7.9Hz, 1H), 6.88 (d, J=8.8Hz, 1H),
# 6.83 (d, J=7.9Hz, 1H), 6.08 (d, J=6.2Hz, 1H), 4.75 (s, 2H), 3.79 (s, 3H), 3.42 (s, 3H).	1, 33
302	443	812	CH	CH	N-(2-Amino-phenyl)- 4-{[[2-(tert-butyl- dimethyl- silanyloxy)-ethyl]- (3,4-dimethoxy- phenyl)-amino]- methyl}-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.66 (s, 1H), 7.96 (d, J=8.4Hz, 2H), 7.42 (d, J=7.9Hz, 2H), 7.20 (d, J=7.5Hz, 1H), 7.02 ((dd, J=6.6, 8.4Hz, 1H), 6.83 (d, J=7.0Hz, 1H), 6.77 (d, J=8.8Hz, 1H), 6.65 (dd, J=7.0, 7.0Hz, 1H),
# 6.44 (d, J=2.6Hz, 1H), 6.19 (dd, J=2.6, 8.8Hz, 1H), 4.93 (s, 2H), 4.67 (s, 2H), 3.88 (t, J=5.7Hz, 2H), 3.71 (s, 3H), 3.67 (s, 3H), 3.60 (t, J=5.5Hz), 0.96 (s, 9H), 0.06 (s, 6H).	33
303	444	813	CH	CH	N-(2-Amino-phenyl)- 4-{[(3,4-dimethoxy- phenyl)-(2-hydroxy- ethyl)-amino]- methyl}-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm) δ (ppm): 9.65 (s, 1H), 7.96 (d, J=7.5Hz, 2H), 7.42 (d, J=7.5Hz, 2H), 7.21 (d, J=7.5Hz, 1H), 7.02 ((dd, J=7.0, 7.5Hz, 1H), 6.83 (d, J=7.9Hz, 1H), 6.78 (d, J=8.8Hz, 1H), 6.65 (dd, J=7.0, 7.5Hz, 1H), 6.44 (s, 1H), 6.19 (d, J=8.8Hz, 1H), 4.94 (s, 2H),
# 4.79 (m, 1H), 4.66 (s, 2H), 3.67 and 3.71 (2s and broading underneath, 8H), 3.55 (m, 2H).	33, 23
304	445	814	CH	N	N-(2-Amino-phenyl)- 6-[(3,4,5- trimethoxy- phenylamino)- methyl]- nicotinamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.82 (s, 1H), 9.13 (s, 1H), 8.33 (d, J=8.0Hz, 1H), 7.56 (d, J=8.5Hz, 1H), 7.21 (d, J=7.7Hz, 1H), 7.03 ((dd, J=7.4, 7.7Hz, 1H), 6.82 (d, J=8.0Hz, 1H), 6.40 (dd, J=7.4, 7.7Hz, 1H), 6.31 (t, J=5.8Hz, 1H), 5.96 (s, 2H), 5.01 (s, 2H), 4.48 (d, J=5.8Hz, 2H), 3.70 (s, 6H), 3.56 (s, 3H).	33
305	446	815	CH	N	N-(2-Amino-phenyl)- 6-[2-(4-oxo-4H- quinazolin-3-yl)- ethylamino]- nicotinamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 8.69 (d, J=2.2Hz, 1H), 8.46 (s, 1H), 8.40 (d, J=8.8Hz, 1H), 8.32-8.36 (m, 1H), 7.91-7.96 (m, 1H), 7.77 (m, 1H), 7.67 (m, 1H) 7.5 (m, 4H), 7.2 (s, 1H), 4.46 (t, J=5.9Hz, 1H), 4.09 (t, J=5.9Hz, 2H).	3
306	447	816	CH	CH	N-(2-Amino-phenyl)- 4-[bis-(3- trifluoromethoxy- benzyl)-amino]- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.37 (s, 1H), 7.84 (d J=8.8Hz, 2H), 7.54 (dd, J=7.9, 7.9Hz, 2H), 7.18-7.37 (m, 6H), 7.17 (d, J=7.0Hz, 1H), 6.99 (dd, J=7.0, 7.9Hz, 1H), 6.82 (m, 3H), 6.63 (dd, J=7.5, 7.5Hz, 1H), 4.94 (s, 4H), 4.86 (s, 2H).	33
307	448	817	CH	CH	N-(2-Amino-phenyl)- 4-[(2-dimethylamino- benzothiazol-5- ylamino)-methyl]- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.58 (s, 1H), 7.92 (d, J=7.9Hz, 2H), 7.49 (d, J=7.9Hz, 2H), 7.34 (d, J=8.8Hz, 1H), 7.15 (d, J=7.5Hz, 1H), 6.96 (t, J=7.9Hz, 1H), 6.76 (d, J=7.9Hz, 1H), 6.59 (d, J=7.5Hz, 1H), 6.55 (s, 1H), 6.44 (d, J=8.4Hz, 1H),
# 6.34 (t, J=5.7Hz, 1H), 4.88 (bs, 2H), 4.37 (d, J=5.7Hz, 2H), 3.06 (s, 6H).	33
308	449	818	CH	CH	N-(2-Amino-phenyl)- 4-[(2-oxo-2,3- dihydro-1H- benzoimidazol-5- ylamino)-methyl]- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 10.2 (s, 1H), 10.1 (s, 1H), 9.62 (s, 1H), 7.94 (d, J=7.9Hz, 2H), 7.41 (d, J=7.9Hz, 2H), 7.15 (d, J=7.5Hz, 1H), 6.96 (t, J=7.5Hz, 1H), 6.77 (d, J=7.9Hz, 1H), 6.69 (d, J=8.4Hz, 1H), 6.59 (t, J=7.5Hz, 1H), 6.34 (d, J=8.4Hz, 1H),
# 6.34 (t, J=8.4Hz, 1H), 6.30 (s, 1H), 4.89 (bs, 2H), 4.72 (s, 2H).	33
309	450	819	CH	CH	N-(2-Amino-phenyl)- 4-[(4- trifluoromethylsulfanyl- phenylamino)- methyl]-benzamide	1 H NMR (300 MHz, DMSO-d6) δ (ppm): 9.60 (s, 1H), 7.94 (d, J=7.9Hz, 2H), 7.46 (d, J=7.9Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 1.15 (d, J=7.9Hz, 1H), 7.11 (d, J=6.2Hz, 1H), 6.97 (t, J=7.0Hz, 1H), 6.77 (d, J=7.5Hz, 1H), 6.66 (d, J=8.4Hz, 2H), 6.60 (t, J=7.9Hz, 1H), 4.88 (bs, 2H), 4.72 (d, J=6.2Hz, 2H).	33
310	451	820	CH	CH	N-(2-Amino-phenyl)- 4-{[2-(pyridin-3- ylmethylsulfanyl)- 1H-benzoimidazol- 5-ylamino]-methyl}- benzamide	1 H NMR (300MHz, CD3OD) δ (ppm): 8.67 (d, J=1.8Hz, 1H), 8.47 (dd, J=1.3, 4.4Hz, 1H), 8.08 (s, 1H), 8.03 (d, J=7.9Hz, 2H), 7.92 (d, J=8.4Hz, 1H), 7.87 (d, J=7.9Hz, 2H), 7.58 (d, J=8.4Hz, 1H), 7.36-7.30 (m, 3H); 7.20-7.15 (m, 1H),
# 7.08 (dt, J=1.3, 8.4Hz, 1H), 6.94 (dd, J=1.3, 7.9Hz, 1H), 6.77 (d, J=2.2Hz, 1H), 6.74 (d, J=2.2Hz, 1H), 6.65 (d, J=1.8Hz, 1H), 4.55 (s, 2H); 4.20 (bs, 2H); 3.36 (s, 2H).	33
311	452	821	CH	CH	N-(2-Amino-phenyl)- 4-{[2-(pyridin-3- ylmethylsulfanyl)- benzooxazol-5- ylamino]-methyl}- benzamide	1 H NMR (300MHz, CD3OD) δ (ppm): 8.60 (s, 1H), 8.36 (d, J=4.4Hz, 1H), 7.89 (d, J=7.9Hz, 2H), 7.87 (m, 1H); 7.47 (d, J=7.9Hz, 2H), 7.30 (t, J=6.6Hz, 1H), 7.20-7.15 (m, 2H); 7.04 (t, J=7.5Hz, 1H), 6.87 (d, J=7.9Hz, 1H),
# 6.73 (t, J=7.5Hz, 1H), 6.66 (s, 1H); 6.61 (d, J=8.8Hz, 1H), 4.87 (s, 2H); 4.45 (s, 2H); 4.37 (s, 2H); 3.35 (s, 2H).	33
312	453	822			N-(2-Amino-5- trifluoromethyl- phenyl)-4-[(3,4- dimethoxy- phenylamino)- methyl]-benzamide	1 H NMR (300MHz, CDCl3) δ (ppm): 8.21 (s, 1H); 7.90 (d, J=8.4Hz, 2H); 7.54 (m, 1H); 7.50 (d, J=8.4Hz, 2H); 7.41-7.34 (m, 2H); 6.87 (d, J=8.4Hz, 1H); 7.77 (d, J=8.4Hz, 1H); 6.35 (d, J=2.2Hz, 1H); 6.20 (dd, J=2.2, 8.8Hz, 1H); 4.43 (s, 2H); 4.29 (s, 2H); 3.84 (s, 6H).	33
313	454	823			N-(2-Amino-4,5- difluoro-phenyl)-4- [(3,4-dimethoxy- phenylamino)- methyl]-benzamide	1 H NMR (300MHz, CDCl3) δ (ppm): 8.21 (s, 1H); 7.84 (d, J=7.9Hz, 2H); 7.45 (d, J=7.9Hz, 2H); 7.20 (dd, J=2.6, 8.4Hz, 1H); 6.76 (d, J=8.8Hz, 1H); 6.57 (dd, J=3.9, 7.9Hz, 1H); 6.32 (d, J=2.6Hz, 1H); 6.16 (dd, J=2.6, 8.4Hz, 1H); 4.40 (s, 2H); 3.82 (s, 9H).	33
314	455	824	CH	CH	N-(2-Amino-phenyl)- 4-[(2-oxo-2,3- dihydro- benzooxazol-5- ylamino)-methyl]- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.60 (s, 1H); 7.93 (d, J=7.9Hz, 2H); 7.47 (d, J=7.9Hz, 2H); 7.16 (d, J=7.5Hz, 1H); 6.97 (m, 2H); 6.78 (d, J=7.5Hz, 1H); 6.59 (t, J=7.5Hz, 1H); 6.35 (t, J=5.7Hz, 1H); 6.27 (m, 2H); 4.88 (bs, 2H); 4.34 (d, J=6.2Hz, 2H).	33
315	456	825	CH	CH	N-(2-Amino-phenyl)- 4-[(2-methylamino- benzothiazol-5- ylamino)-methyl]- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 7.92 (d, J=7.9Hz, 2H), 7.66 (d, J=4.4Hz, 1H), 7.49 (d, J=7.9Hz, 2H), 7.26 (d, J=8.4Hz, 1H), 7.15 (d, J=7.9Hz, 1H), 6.96 (d, J=8.4Hz, 1H), 6.59 (t, J=7.9Hz, 1H), 6.53 (s, 1H), ); 6.40 (dd, J=1.3, 8.4Hz, 1H); 6.28 (t, J=5.7Hz, 1H),
# 4.88 (bs, 2H), 4.36 (d, J=5.7Hz, 2H), 2.85 (d, J=4.4Hz, 3H).	33
216	457	826			N-(2,6-Diamino- phenyl)-4-[(3,4- dimethoxy- phenylamino)- methyl]-benzamide	1 H NMR (300MHz, CDCl3) δ (ppm): 8.09 (s, 1H); 7.88 (d, J=7.5Hz, 2H); 7.48 (d, J=7.5Hz, 2H); 6.97 (d, J=7.9Hz, 1H); 6.73 (d, J=8.4Hz, 2H); 6.64 (d, J=7.9Hz, 1H); 6.29 (s, 1H); 6.14 (d, J=8.4Hz, 1H); 4.39 (s, 2H); 3.81 (s, 3H); 3.80 (s, 3H); 3.70 (bs, 5H).	33
217	458	827	CH	CH	N-(2-Amino-phenyl)- 4-{[2-(2-methoxy- ethyl)-1,3-dioxo- 2,3-dihydro-1H- isoindol-5-ylamino]- methyl}-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.61 (s, 1H); 7.95 (d, J=7.9Hz, 2H); 7.73 (t, J=5.7Hz, 1H); 7.52 (d, J=8.4Hz, 1H); 7.47 (d, J=7.9Hz, 2H); 7.15 (d, J=7.9Hz, 1H); 6.97 (d, J=7.5Hz, 1H); 6.92 (bs, 1H); 6.86 (d, J=8.4Hz, 1H); 6.77 (d, J=7.9Hz, 1H); 6.59 (t, J=7.5Hz, 1H);
# 4.89 (bs, 2H); 4.54 (d, J=5.7Hz, 2H); 3.65 (t, J=5.3Hz, 2H); 3.47 (t, J=5.3Hz, 2H); 3.20 (s, 3H);	33
318	459	828	CH	CH	N-(2-Amino-phenyl)- 4-{[3-spiro[1′,2′]dioxolane- 1-methyl-2-oxo- 2,3-dihydro-1H- indol-5-ylamino)- methyl}-benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.59 (s, 1H); 7.92 (d, J=8.3Hz, 2H); 7.46 (d, J=8.3Hz, 2H); 7.15 (d, J=7.5Hz, 1H); 6.96 (t, J=7.0Hz, 1H); 6.78-6.71 (m, 3H); 6.62-6.54 (m, 2H);
# 6.26 (t, J=7.5Hz, 1H) 4.87 (s, 2H); 4.36-4.32 (m, 4H); 4.23-4.19 (m, 2H), 2.98 (s 3H).	33
319	460	829	CH	N	N-(2-Amino-phenyl)- 6-(2-phenylamino- ethylamino)- nicotinamide	1 H NMR (300MHz, CD3OD) δ (ppm): 8.67 (d, J=2.2Hz, 1H), 7.91 (dd, J=2.5, 8.9Hz, 1H), 7.58 (m, 1H); 7.51 (m, 1H); 7.15 (dd, J=1.1, 7.7Hz, 1H), 7.08 (m, 2H); 6.89 (dd, J=1.4, 8.0Hz, 1H), 6.76 (dt, J=4.4, 7.7Hz, 1H), 6.67 (d, J=7.7Hz, 2H), 6.60 (m, 2H); 4.87 (bs, 2H); 3.60 (t, J=6.3Hz, 2H), 3.35 (t, J=6.3Hz, 2H).	33
320	461	830	CH	CH	N-(2-Amino-phenyl)- 4-[(1,3-dimethyl- 2,4-dioxo-1,2,3,4- tetrahydro- quinazolin-6- ylamino)-methyl]- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.59 (s, 1H); 7.92 (d, J=7.9Hz, 2H); 7.47 (d, J=7.9Hz, 2H); 7.22 (d, J=8.8Hz, 1H); 7.16-7.09 (m, 3H); 6.96 (t, J=7.5Hz, 1H); 6.76 (d, J=7.9Hz, 1H); 6.65-6.56 )m, 2H); 4.87 (s, 2H); 4.42 (d, J=5.3Hz, 2H); 3.44 (s, 3H); 3.26 (s, 3H).	33
321	462	831	CH	CH	N-(2-Amino-phenyl)- 4-[(6-methyl-6H- indolo[2,3- b]quinoxalin-9- ylamino)-methyl]- benzamide	1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.60 (s, 1H); 8.19 (d, J=8.4Hz, 1H); 8.05 (d, J=8.4Hz, 1H); 7.95 (d, J=7.9Hz, 2H); 7.76 (t, J=7.0Hz, 1H); 7.65 (t, J=7.9Hz, 1H); 7.57 (d, J=7.9Hz, 2H); 7.54 (d, J=8.8Hz, 1H); 7.41 (d, J=1.3Hz, 1H); 7.22 (dd, J=1.8, 8.8Hz, 1H);
# 7.14 (d, J=7.9Hz, 1H); 6.95 (t, J=7.5Hz, 1H); 6.76 (t, J=7.9Hz, 1H); 6.57 (t, J=7.5Hz, 1H); 6.51 (bs, 1H); 4.86 (bs, 2H); 4.54 (d, J=4.8Hz, 2H); 3.85 (s, 3H).	33
322	463	832	N	CH	N-(2-Amino-phenyl)- 6-(1-hydroxy- cyclohexylethynyl)- nicotinamide	LRMS calc: 335.40, found: 336.1 (MH)+	14, 3
323	464	833	N	CH	N-2-Amino-phenyl)- 6-p-tolylsulfanyl- nicotinamide	LRMS calc: 335.42, found: 336.1 (MH)+	14, 3
324	465	834	CH	CH	N-(2-Amino-phenyl)- 4-[5-(indan-2- ylaminomethyl)- thiophen-2- ylmethyl]- benzamide	LRMS calc: 453.6, found: 454.2 (MH)+	21
325	466	835	CH	CH	N-(2-Amino-phenyl)- 4-[5-(pyridin-2- ylaminomethyl)- thiophen-2- ylmethyl]- benzamide	LRMS calc: 414.52, found: 415 (MH)+	21
326	467	836	CH	CH	N-(2-Amino-phenyl)- 4-[(5-bromo-thiazol- 2-ylamino)methyl]- benzamide	LRMS calc: 403.3, found: 404 (MH)+	21
327	468	837	CH	CH	N-(2-Amino-phenyl)- 4-[(5-phenyl-1H- pyrazol-3-ylamino)- methyl]-benzamide	LRMS calc: 483.45, found: 484.1 (MH)+	21

[0489]

TABLE 4c
Characterization of Additional Compounds
Ex.	Cpd	Compound	Name	Characterization	Schm
426	571	838	N-(2-Hydroxy-phenyl)-4- [(3,4,5-trimethoxy- phenylamino)-methyl]- benzamide	1 H NMR (DMSO-d6): δ 9.57(brs, 1H), 7.98(d, J=8.3Hz, 2H), 7.75(d, J=7.5Hz, 1H), 7.57(d, J=8.3Hz, 2H), 7.07(t, J=8.3Hz, 1H), 6.95(d, J=7.0Hz, 1H), 6.85(t, J=7.9Hz, 1H), 6.21(t, J=6.1Hz, 1H), 5.95(s, 2H), 4.38(d, J=5.7Hz, 2H), 3.70(s, 6H), 3.56(s, 3H).	33, 55
427	572	839	N-(2-hydroxy-phenyl)-4- [(3,4-Dimethoxy- phenylamino)-methyl]- benzamide	1 H NMR (300MHz, DMSO-D6) δ (ppm): 9.9(bs, 1H), 9.53(s, 1H), 7.97(d, J=7.9Hz, 2H), 7.73(d, J=7.5Hz, 1H), 7.55(d, J=7.9Hz, 2H), 7.08(dd, J=7.5, 7.5Hz, 1H), 6.96(d, J=7.9, Hz, 1H), 6.88(dd, J=7.5, 7.5Hz, 1H), 6.72(d, J=8.8Hz, 1H), 6.38(s, 1H), 6.05(m, 2H), 4.36(d, J=5.7Hz, 2H), 3.72(s, 3H), 3.65(s, 3H).	33, 55
428	573	840	N-(4-Amino-thiophen-3- yl)-4-{[6-(2-morpholin-4- yl-ethoxy)-benzothiazol- 2-ylamino]-methyl}- benzamide	1 H NMR: (Acetone-d6) δ (ppm): 9.09(bs, 1H), 8.03(d, J=7.9Hz, 2H), 7.96(d, J=7.5Hz, 1H), 7.65(d, J=7.9Hz, 2H), 7.61(d, J=3.5Hz, 1H), 7.51(bs, 2H), 7.41(d, J=8.8Hz, 1H), 7.36(s, 1H), 6.95(d, J=6.2Hz, 1H), 6.35(d, J=3.5Hz, 1H), 4.85(s, 2H), 4.20(t, J=5.7Hz, 2H), 3.69)t, J=4.4Hz, 4H),
# 2.87-2.81(m, 2H), 2.62-2.57(m, 4H).	33, 60
429	574	841	N-(4-Amino-thiophen-3- yl)-4-[(3,4,5-trimethoxy- phenylamino)-methyl]- benzamide	1 H NMR (DMSO-d6): δ 9.66(brs, 1H), 7.94(d, J=7.5Hz, 2H), 7.56(d, J=7.9Hz, 2H), 6.22-6.16(m, 1H), 5.94(s, 2H), 4.91(s, 2H), 4.38(d, J=5.7Hz, 4H), 3.70(s, 6H), 3.55(s, 3H).	33, 60
430	575	842	N-(4-Amino-thiophen-3- yl)-4-(5-methoxy-1H- benzoimidazol-2- ylsulfanylmethyl)- benzamide	(DMSO) δ (ppm): 12.43(bs, 1H), 9.59(bs, 1H), 7.84(d, J=8.1Hz, 2H), 7.56(d, J=8.1Hz, 2H), 7.48(d, J=3.7Hz, 1H), 7.32(bs, 1H, SCH), 6.96(bs, 1H, SCH), 6.74(dd, J=8.8, 2.2Hz, 1H), 6.11(d, J=3.7Hz, 1H), 4.84(s, 2H), 4.59(s, 2H), 3.76(s, 3H). LRMS: 410.1(calc) (M); 411.2(found)(M + H) +	36, 60
431	576	843	2-[4-(4-Methoxy- benzylamino)-phenyl]- cyclopropanecarboxylic acid (2-amino-phenyl)- amide	1 H-NMR (DMSO-d6), δ (ppm): 9.22(bs, 1H), 8.19(bs, 1H), 7.63(d, J=7.1Hz, 1H), 7.53(t, J=4.2Hz, 1H), 7.41(dd, J=9.2, 1.5Hz, 1H), 7.25(d, J=8.3Hz, 2H), 7.06(d, J=7.1Hz, 1H), 6.85(d, J=8.3Hz, 2H), 6.62-6.59(m, 3H), 4.51(d, J=4.2Hz, 2H), 3.78(s, 3H), 2.77(d, J=3.1Hz, 1H), 2.45(d, J=1.1Hz, 1H), 1.22(m, 1H), 1.05(m, 1H).
432	577	844	N-(2-Amino-phenyl)-4-(3- cyano-6-methyl-pyridin- 2-yloxymethyl)- benzamide	1 H NMR (DMSO-d6) δ (ppm): 9.72(brs, 1H), 8.23(d, J=7.5Hz, 1H), 8.06(d, J=7.9Hz, 2H), 7.67(d, J=7.9Hz, 2H), 7.23(d, J=7.9Hz, 1H), 7.15(d, J=7.9Hz, 1H), 7.03(t, J=7.5Hz, 1H), 6.84(d, J=7.9Hz, 1H), 6.65(t, J=7.5hz, 1H), 5.62(brs, 2H), 4.97(brs, 2H)	11
433	578	845	N-(2-Amino-phenyl)-4- {[4-(6-methoxy-pyridin- 3-yl)-pyrimidin-2- ylamino]-methyl}- benzamide	1 H NMR (300MHz, DMSO-D6) δ (ppm): 9.63(s, 1H), 8.95(d, J=2.2Hz, 1H), 8.40(d, J=5.3Hz, 2H), 7.96(m, 3H), 7.54(d, J=7.5Hz, 2H), 7.22(dd, J=5.3, 7.8Hz, 2H), 7.01(m, 2H), 6.83(d, J=7.5Hz, 1H), 6.64(dd, J=7.0, 7.9Hz, 1H), 4.92(s, 2H), 4.70(d, J=6.2Hz, 2H), 3.98(s, 3H).	15, 33
434	579	846	2-Acetylamino-5-[4-(2- amino- phenylcarbamoyl)- benzyl]-thiophene-3- carboxamide	1 H NMR: (DMSO) δ (ppm): 11.98(bs, 1H), 9.61(bs, 1H), 7.93(d, J=8.1Hz, 2H), 7.81(s, 1H), 7.45(s, 1H), 7.38(d, J=8.1Hz, 1H), 7.19(s, 1H), 7.16(d, J=7.3Hz, 1H), 6.97(dd, J=7.0, 7.0Hz, 1H), 6.77(d, J=7.3Hz, 1H), 6.59(dd. J=7.3, 7.3Hz, 1H), 4.88(bs, 2H), 4.10(s, 2H), 2.15(s, 3H).	49
435	580	847	N-(2-Amino-phenyl)-4- [(3-methyl-2- methylamino-3H- benzoimidazol-5- ylamino)-methyl]- benzamide	1 H NMR (DMSO) δ (ppm): 9.56(s, 1H), 7.90(d, J=7.9Hz, 2H), 7.49(d, J=7.9Hz, 2H), 7.15(d, J=7.5Hz, 1H), 6.95(t, J=7.5Hz, 1H), 6.78(dd, J=13.2, 8.35Hz, 2H), 6.58(t, J=7.5Hz, 1H), 6.39(s, 1H), 6.31(m, 2H), 5.75(t, J=6.15Hz, 1H), 4.87(s, 2H), 4.32(d, J=5.7Hz, 2H), 3.34(s, 3H), 2.82(d, J=8.5Hz, 3H).	61
438	591	848	5-(5-Methoxy-1H- benzoimidazol-2- ylsulfanylmethyl)- benzofuran-2- carboxylic acid (2- amino-phenyl)amide	1 H NMR (DMSO) δ (ppm): 9.84(s, 1H), 7.84(s, 1H), 7.67(s, 1H), 7.63(d, J=8.5Hz, 1H), 7.55(d, J=9.0Hz, 1H), 7.17(d, J=8.0Hz, 1H), 6.97(t, J=7.5Hz, 1H), 6.78(d, J=8.0Hz, 1H), 6.78-6.74(m, 3H), 6.59(t, J=7.5Hz, 1H), 5.71(s, 2H), 4.94(s, 1H), 4.65(s, 2H), 3.76(s, 3H).	64
439	592	849	5-(3,4,5-Trimethoxy- benzylamino)- benzofuran-2- carboxylic acid (2- amino-phenyl)-amide	1 H NMR (DMSO) δ(ppm): 9.69(s, 1H), 7.47(s, 1H), 7.41(d, J=8.8Hz, 1H), 7.19(d, J=6.6Hz, 1H), 6.97(dd, J=7.5, 7.5Hz, 1H), 6.89(dd, J=8.8, 2.2Hz, 1H), 6.79-6.78(m, 2H), 6.74(s, 2H), 6.60(dd, J=7.5, 7.5Hz, 1H), 6.14(t, J=5.7Hz, 1H), 4.92(s, 2H), 4.21(d, J=5.7Hz, 1H), 3.75(s, 6H), 3.31(s, 3H).	64

[0490] 850

[0491] Step 1: {2-[(3′-Formyl-biphenyl-4-carbonyl)-amino]-phenyl}-carbamic Acid Tert-Butyl Ester (185)

[0492] Following the procedure described in Example 15, step 1, but substituting 184 for 140, the title compound 185 was obtained in 74% yield. 1H NMR (CDCl3): δ 10.10 (s, 1H), 9.41(s, 1H), 8.13 (m, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.89 (m, 2H), 7.77 (m, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.64 (m, 1H), 7.27-7.09 (m, 3H), 7.03 (s, 1H), 1.52 (s, 9H).

[0493] Step 2: N-(2-Aminophenyl)-4-[3-(indan-2-ylaminomethyl)phenyl)]-benzamide (186)

[0494] To a stirred solution of biphenyl aldehyde (104 mg, 0.25 mmol) and 2-aminoindane (33.3 mg, 0.25 mmol) in dichloroethane (1 mL) was added sodium triacetoxyborohydride (80 mg, 0.375 mmol) followed by a glacial acetic acid (15 ul, 0.25 mmol), and then the mixture was stirred at room temperature for 3 h. After a removal of the volatiles, the residue was partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution. The combined organic layers were washed with water, dried and concentrated. Purification by flash chromatography (10% methanol in chloroform) gave the desired Boc-monoprotected product (112 mg, 84% yield) as a white solid. 1H NMR (CDCl3): 9.21 (s, 1H), 8.03 (d, J=8.7 Hz, 2H), 7.83 (m, 1H), 7.69 (d, J=8.7 Hz, 2H), 7.65 (s, 1H), 7.54-7.38 (m, 3H), 7.28 (m, 7H), 6.82 (s, 1H), 3.95 (s, 2H), 3.74 (m, 1H), 3.22 (dd, J=15.6, 6.9 Hz, 2H), 2.89 (dd, J=15.6, 6.6 Hz, 2H), 1.53 (s, 9H).

[0495] Following the procedure described in Example 42, step 3, but substituting the previous compound for 46, the title compound 186 was obtained in 98% yield. 1H NMR (20% CD3OD in CDCl3): δ 7.95 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.57 (m, 1H), 7.54-6.79 (m, 11H), 3.95 (s, 2H), 3.66 (m, 1H), 3.16 (dd, J=15.6, 6.9 Hz, 2H), 2.81 (dd, J=15.6, 6.6 Hz, 2H).

ExampleS 123-126

[0496] Examples 123 to 126 (compounds 187-190) were prepared using the same procedure as described for compound 186 in Example 122 (scheme 21). 851

Example 127

[0497] Step 1: {2-[4-(1-Amino-cyclohexylethynyl)-benzoylamino]-phenyl}-carbamic Acid Tert-Butyl Ester (191)

[0498] A mixture of iodide 184 (438 mg, 1.0 mmol), Pd(PPh3)2Cl2 (35 mg, 0.05 mmol), triphenylphosphine (7.6 mg, 0.025 mmol), and 1-ethynylcyclohexylamine (185 mg, 1.5 mmol) was stirred at room temperature in THF (4 mL) containing triethylamine (0.56 mL, 4.0 mmol) for 20 min. To this CuI (3.8 mg, 0.02 mmol) was added and stirring continued for 2 h. The reaction mixture was then diluted with ethyl acetate (30 mL), washed with water, and the organic layer was dried and concentrated. Purification by flash chromatography (10% methanol in chloroform) gave the desired product 191 (420 mg, 97% yield). 1H NMR (CDCl3): δ 9.36 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.77 (d, J=7.5 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.25-6.85 (m, 3H), 2.10-1.30 (m. 10H), 1.51 (s, 9H).

[0499] Step 2: N-(2-Aminophenyl)-4-[1-(4-methoxy-benzylamino)-cyclohexylethynyl]-benzamide (192)

[0500] Following the procedure described in Example 122, step 2, but substituting p anisaldehyde for 2-aminoindane, the title compound 192 was obtained in 74% yield. 1H NMR (CDCl3): δ 8.44 (s, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.23 (m, 1H), 7.05 (m, 1H), 6.84 (d, J=8.7 Hz, 2H), 6.78 (m, 2H), 3.97 (s, 2H), 3.76 (s, 3H), 2.10-1.30 (m. 10H). 852

Example 133

[0501] Step 1: N-[2-(t-Butyloxycarbonyl)-amino-phenyl]-4-(trimethylsilylethynyl)benzamide (197)

[0502] To a stirred solution of 184 (5.00 g, 11.41 mmol) in anhydrous THF (100 ml) under nitrogen at 0° C. were added Pd(PPh3)2Cl2 (240 mg, 0.34 mmol), CuI (130 mg, 0.69 mmol), and trimethylsilylacetylene (2.10 ml, 14.84 mmol), respectively. Then, anhydrous Et3N (6.36 ml, 45.66 mmol) was added dropwise. The temperature was slowly warmed up to room temperature over 4 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl, and diluted with ethyl acetate. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane: 20/80→50/50) to afford the title compound 197 (4.42 g, 10.83 mmol, 94% yield) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.26 (bs, 1H), AB system (δA=7.91, 6B=7.55, J=8.3 Hz, 4H), 7.85 (d, J=7.9 Hz, 1H), 7.32-7.13 (m, 3H), 6.70 (bs, 1H), 1.53 (s, 9H), 0.28 (s, 9H).

[0503] Step 2: N-(2-Amino-phenyl)-4-(trimethylsilylethynyl)benzamide (198)

[0504] Following the procedure described in Example 42, step 3, but substituting the previous compound for 46, the title compound 198 (70 mg, 0.23 mmol) was obtained as a white solid with a major fraction composed of a mixture of 198 and 199. 1H NMR (300 MHz, acetone-d6) δ (ppm): 9.20 (bs, 1H), AB system (δA=8.07, 6B=7.62, J=8.2 Hz, 4H), 7.32 (d, J=7.6 Hz, 1H), 7.05 (td, J=7.6, 1.2 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.72 (t, J=7.3 Hz, 1H), 4.66 (bs, 2H), 0.30 (s, 9H).

[0505] Step 3: N-(2-Amino-phenyl)-4-ethynylbenzamide (199)

[0506] To a stirred solution at −20° C. of a mixture of 198 and 199 in anhydrous THF (15 ml) under nitrogen was added a solution of TBAF (1 ml, 1.0 M in THF). The reaction mixture was allowed to warm up to room temperature over 2 h and stirred at room temperature for 18 h. Then, the reaction mixture was poured into a saturated aqueous solution of NH4Cl and diluted with ethyl acetate. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane: 30/70) to afford the title compound 199 (215 mg, 0.91 mmol, 46% yield over 2 steps) as a pale yellow powder. 1H NMR (300 MHz, acetone-d6) δ (ppm): 9.19 (bs, 1H), AB system (δA=8.08, 6B=7.66, J=8.5 Hz, 4H), 7.33 (d, J=7.6 Hz, 1H), 7.05 (t, J=7.3 Hz, 1H), 6.91 (d, J=7.6 Hz, 1H), 6.72 (t, J=7.6 Hz, 1H), 4.67 (bs, 2H), 3.88 (s, 1H).

Example 134

[0507] Step 1: N[2-(t-Butyloxycarbonyl)-amino-phenyl]-4-ethynylbenzamide (200)

[0508] To a stirred solution at −20° C. of a mixture of 199 (3.48 g, 8.53 mmol) in anhydrous THF (50 ml) under nitrogen was slowly added a solution of TBAF (9.4 ml, 9.38 mmol, 1.0 M in THF). The reaction mixture was allowed to warm up to room temperature over 2 h and stirred at room temperature for 4 h. Then, the reaction mixture was concentrated, diluted with ethyl acetate, and successively washed with a saturated aqueous solution of NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane: 25/75→30/70) to afford the title compound 200 (2.53 g, 7.53 mmol, 88% yield) as a pale yellow foam. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.31 (bs, 1H), AB system (δA=7.94, 6B=7.59, J=8.5 Hz, 4H), 7.83 (d, J=7.6 Hz, 1H), 7.30-7.10 (m, 3H), 6.75 (bs, 1H), 3.23 (s, 1H), 1.53 (s, 9H).

[0509] Step 2: N-(2-amino-phenyl)-4-[344-chlorophenyl)-3-morpholin-4-yl-1-propyn-1-yl]-benzamide (201)

[0510] To a stirred solution at room temperature of 200 (200 mg, 0.60 mmol) in anhydrous 1,4-dioxane (5 ml) under nitrogen were added 4-chlorobenzaldehyde (100 mg, 0.71 mmol), morpholine (60 μl, 0.68 mmol), and CuI (6 mg, 0.03 mmol), respectively. The reaction mixture was bubbled with nitrogen for min and warmed up to 105° C. After 18 h, the reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and successively washed with a saturated aqueous solution of NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane: 40/60) to afford the desired compound (193 mg, 0.35 mmol, 59% yield) as a pale yellow foam. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.40 (bs, 1H), AB system (δA=7.96, 6B=7.36, J=8.5 Hz, 4H), 7.79 (d, J=7.9 Hz, 1H), 7.59 (d, J=8.4 Hz, 4H), 7.25-7.10 (m, 3H), 6.91 (s, 1H), 4.80 (s, 1H), 3.82-3.68 (m, 4H), 2.69-2.58 (m, 4H), 1.53 (s, 9H).

[0511] Following the procedure described in Example 42, step 3, but substituting the previous compound for 46, the title compound 201 was obtained in 67% yield. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 9.80 (bs, 1H), AB system (δA=8.06, 6B=7.71, J=8.1 Hz, 4H), AB system (δA=7.65, 6B 7.52, J=8.3 Hz, 4H), 7.20 (d, J=7.9 Hz, 1H), 7.02 (t, J=7.3 Hz, 1H), 6.82 (d, J=7.0 Hz, 1H), 6.64 (t, J=7.5 Hz, 1H), 5.10 (s, 1H), 4.97 (bs, 2H), 3.72-3.58 (m, 4H), 2.67-2.46 (m, 4H). 853

Example 135

[0512] Step 1: Methyl 4(4-chloro-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino)-benzoic Ester (203)

[0513] To a stirred solution at room temperature of 202 (2.00 g, 7.11 mmol) in anhydrous THF (50 ml) under nitrogen were added i-Pr2NEt (1.86 ml, 10.66 mmol) and methyl 4-aminobenzoate (1.29 g, 8.53 mmol) or ArNH2 (1.2 equiv), respectively. The reaction mixture was then refluxed for 24 h. After cooling, the reaction mixture was poured into a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH2Cl2: 2/98→5/95) to afford the title compound 203 (1.70 g, 4.30 mmol, 60% yield) as a beige powder. 1H NMR (300 MHz, CDCl3) δ (ppm): mixture of rotamers, 2 AB system (δA=8.03, δA′=8.00, δB=7.70, δB′=7.61, JAB=JA′B′=8.8 Hz, 4H), 7.43 and 7.31 (2 bs, 1H), 7.29-7.19 (m, 4H), 5.84 and 5.78 (2 d, J=7.2 and 7.7 Hz, 1H), 4.98-4.77 (2 m, 1H), 3.91 and 3.90 (2 s, 3H), 3.41 (dd, J=16.1, 7.0 Hz, 2H), 2.94 and 2.89 (2 dd, J=15.9, 4.9 Hz, 2H).

[0514] Step 2: 4-[4-amino-6-(2-indanyl-amino)-[1,3,5-triazin-2-ylamino]-N-(2-amino-phenyl)-benzamide (204)

[0515] The title compound 204 was obtained from 203 in 3 steps following the same procedure as Example 1, Pathway B steps 3-5. 1H NMR (300 MHz, acetone-d6) δ (ppm): mixture of rotamers, 8.98 (m, 1H), 8.49 and 8.28 (2m, 1H), 8.10-7.92 (m, 4H), 7.35-7.14 (m, 5H), 7.03 (td, J=7.6, 1.5 Hz, 1H), 6.90 (dd, J=6.6, 1.3 Hz, 1H), 6.71 (td, J=7.6, 1.3 Hz, 1H), 6.57 and 6.42 (2m, 1H), 6.04 and 5.86 (2m, 2H), 4.92-4.76 (m, 1H), 4.70-4.58 (m, 1H), 3.44-3.26 (m, 2H), 3.08-2.92 (m, 2H). HRMS (calc.): 452.2073, (found): 452.2062. 854

Example 136

[0516] Step 1: Methyl 4-[(4-chloro-6-(2-indanyl-amino)-[1,3,5]triazin-2-yloxy)-methyl]-benzoic Ester (206)

[0517] To a stirred solution at 0° C. of 205 (2.00 g, 7.11 mmol) in anhydrous THF (50 ml) under nitrogen were added i-Pr2NEt (1.86 ml, 10.66 mmol) and methyl 4-(hydroxymethyl)benzoate (1.30 g, 7.82 mmol). After few minutes, NaH (95%, 186 mg, 7.11 mmol) was added portionwise. Then, the reaction mixture was allowed to warm to room temperature. After 24 h, the reaction mixture was poured into a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH2Cl2: 2/98) to afford the title compound 206 (2.00 g, 4.88 mmol, 69% yield) as a colorless sticky foam. 1H NMR (300 MHz, CDCl3) 3 (ppm): mixture of rotamers, 2 AB system (δA=8.06, δA′=8.03, δB=7.52, δB′=7.46, JAB=JA′B′=8.5 Hz, 4H), 7.26-7.17 (m, 4H), 5.94 and 5.85 (2 bd, J=7.8 Hz, 1H), 5.48 and 5.39 (2 s, 2H), 4.92-4.76 (2 m, 1H), 3.94 and 3.92 (2 s, 3H), 3.39 and 3.33 (2 dd, J=16.0, 7.0 Hz, 2H), 2.89 and 2.84 (2 dd, J=16.0, 4.9 Hz, 2H).

[0518] Step 2: 4-{[4-amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-yloxy]-methyl}-N-(2-amino-phenyl)-benzamide (207)

[0519] The title compound 207 was obtained from 206 in 3 steps following the same procedure as Example 1, Pathway B steps 3-5. 1H NMR (300 MHz, acetone-d6+ DMSO-d6) δ (ppm): 9.49 (m, 1H), 8.12-8.03 (m, 2H), 7.60 (t, J=7.7 Hz, 2H), 7.35 (d, J=7.1 Hz, 1H), 7.28-7.13 (m, 4H), 7.07-6.94 (m, 2H), 6.90 (dd, J=7.3, 1.4 Hz, 1H), 6.70 (td, J=7.3, 1.1 Hz, 1H), 6.44 (bs, 1H), 6.25 (bs, 1H), 5.47 and 5.41 (2s, 2H), 4.87-4.68 (m, 3H), 3.35-3.20 (m, 2H), 3.02-2.88 (m, 2H). HRMS (calc.): 467.2070, (found): 467.2063. 855

Example 210

[0520] Methyl 4-[(4-chloro-6-phenethyl-amino-[1,3,5]triazin-2-yl-amino)-methyl]-benzoic Ester (208)

[0521] The title compound 208 was obtained from 2 following the same procedure as in Example 1, pathway B steps 2 (R1R2NH=phenethylamine).

[0522] Step 1: Methyl 4-[(4-phenethylamino-[1,3,5]triazin-2-yl-amino)-methyl]-benzoic Ester (209)

[0523] To a degazed solution of 208 (300 mg, 0.75 mmol) in MeOH (35 mL) was added 10% Pd/C (24 mg, 0.023 mmol). The reaction mixture was stirred under a 1 atm pressure of H2 at room temperature for 20 h then it was purged with N2. The palladium was removed by filtration through celite and the reaction mixture was concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/CH2Cl2: 4/96) to afford the title compound 209 (135 mg, 0.37 mmol, 50% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 8.08 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 7.50-7.15 (m, 6H), 4.85-4.65 (m, 2H), 3.98 (s, 3H), 3.82-3.62 (m, 2H), 3.05-2.85 (m, 2H).

[0524] Step 2: N-(2-Amino-phenyl)-4-[(4-phenethylamino-[1,3,5]triazin-2-yl-amino)-methyl]-benzamide (210)

[0525] The title compound 210 was obtained from 209 in 2 steps following the same procedure as in Example 1, steps 4 and 5. 1H NMR: (300 MHz, acetone-d6) δ (ppm): 9.03 (s, 1H), 8.17-7.87 (m, 3H), 7.49 (dd, J=19.2, 8.2 Hz, 2H), 7.32-7.03 (m, 6H), 6.99 (t, J=7.6 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.67 (t, J=7.4 Hz, 1H), 6.60-6.30 (m, 2H), 4.72 (t, J=6.3 Hz, 1H), 4.65-4.56 (m, 1H), 3.67-3.51 (m, 2H), 2.95-2.80 (m, 2H). 856

Example 138

[0526] Step 1: Methyl 4-[(4,6-dimethoxy-[1,3,5]triazin-2-yl-amino)-methyl]-benzoic Ester (211)

[0527] In a 75 ml sealed flask, a stirred suspension of 2-chloro-4,6-dimethoxy-1,3,5-triazine (540 mg, 3.08 mmol), methyl 4-(aminomethyl)benzoate.HCl 2 (689 mg, 3.42 mmol), i-Pr2NEt (1.49 ml, 8.54 mmol) in anhydrous THF (30 ml) was warmed at 80° C. for 5 h. Then, the reaction mixture was allowed to cool to room temperature, poured into a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH2Cl2: 10/90→30/70) to afford the title compound 211 (870 mg, 2.86 mmol, 93% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ (ppm): AB system (δA=8.01, δB=7.39, JAB=8.5 Hz, 4H), 6.08-6.00 (m, 1H), 4.73 (d, J=6.3 Hz, 2H), 3.95 (s, 6H), 3.92 (s, 3H).

[0528] The title compound 212 was obtained from 211 in 2 steps following the same procedure as Example 1, steps 4 and 5. 1H NMR (300 MHz, acetone-d6+Σ DMSO-d6) δ (ppm): 9.58 (bs, 1H), 8.27 (t, J=6.3 Hz, 1H), AB system (δA=8.04, δB=7.53, JAB=8.4 Hz, 4H), 7.31 (d, J=6.9 Hz, 1H), ), 7.02 (td, J=7.6, 1.6 Hz, 1H), 6.88 (dd, J=7.9, 1.4 Hz, 1H), 6.68 (td, J=7.6, 1.4 Hz, 1H), 4.86-4.78 (m, 2H), 4.69 (d, J=6.3 Hz, 2H), ), 3.90 and 3.89 (2s, 6H). HRMS (calc.): 380.1597, (found): 380.1601.

[0529] Step 2: N-(2-Amino-phenyl)-4-[(4,6-dimethoxy-1,3,5]-triazin-2-yl-amino)-methyl]-benzamide (212) 857

Example 139

[0530] Step 1: 4-[(6-(2-Indanyl-amino)-4-methoxy-[1,3,5]triazin-2-yl-amino)-methyl]-benzoic Acid (213)

[0531] To a stirred solution at room temperature of 5 (300 mg, 0.73 mmol) in a mixture of MeOH/THF (10 ml/5 ml) was added an aqueous solution of KOH (10%, 5 ml). After 3 days, the reaction mixture was concentrated on the rotavap, diluted in water and acidified with 1N HCl until pH 5-6 in order to get a white precipitate. After 15 min, the suspension was filtered off and the cake was abundantly washed with water, and dried to afford the title compound 213 (282 mg, 0.72 mmol, 98% yield) as a white solid. MS: m/z=392.1 [MH].+.

[0532] Step 2: N-(2-amino-phenyl)-4-{[642-indanyl-amino)-4-methoxy-[1,3,5]-triazin-2-yl-amino]-methyl}-benzamide (214)

[0533] The title compound 214 was obtained from 213 in one step following the same procedure as Example 1, step 5. 1H NMR (300 MHz, acetone-d6+ DMSO-d6) δ (ppm): mixture of rotamers, 9.69-9.53 (m, 1H), AB system (δA=8.04, δB=7.52, JAB=7.8 Hz, 4H), 7.80-7.60 (m, 1H), 7.45-7.10 (m, 6H), 7.01 (t, J=7.6 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.68 (t, J=7.6 Hz, 1H), 4.92-4.60 (m, 5H), 3.90-3.78 (m, 3H), 3.35-3.22 (m, 2H), 3.02-2.83 (m, 2H). HRMS (calc.): 481.2226, (found): 481.2231. 858

Example 29

[0534] Step 1: Methyl 4-[(4,6-dichloro-[1,3,5]triazin-2-yl-N-methyl-amino)-methyl]-benzoic Ester (216)

[0535] To a stirred suspension at room temperature of NaH (95%, 81 mg, 3.19 mmol) in anhydrous THF (10 ml) under nitrogen were successively added a solution of 3 (500 mg, 1.60 mmol) in anhydrous THF (10 ml) and MeI (298 μl, 4.79 mmol). After 16 h, the reaction mixture was poured into a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane: 10/90→20/80) to afford the title compound 215 (200 mg, 0.61 mmol, 38% yield) as a white crystalline solid. 1H NMR (300 MHz, CDCl3) δ (ppm): AB system (δA=8.04, δB=7.31, JAB=8.2 Hz, 4H), 4.93 (s, 2H), 3.93 (s, 3H), 3.18 (s, 3H).

[0536] Step 2: 4-{[4-amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-yl-N-methyl-amino]-methyl}-N-(2-amino-phenyl)-benzamide (216)

[0537] The title compound 216 from 215 in 4 steps was obtained following the same procedure as Example 1, Pathway B steps 2-5. 1H NMR (300 MHz, acetone-d6) δ (ppm): 9.11 (bs, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.43 (bs, 2H), 7.33 (d, J=7.7 Hz, 1H), ), 7.28-7.09 (m, 4H), 7.04 (td, J=7.6, 1.5 Hz, 1H), 6.90 (dd, J=8.0, 1.4 Hz, 1H), 6.71 (td, J=7.5, 1.3 Hz, 1H), 6.25-6.05 (m, 1H), 5.82 and 5.64 (2bs, 2H), 5.00-4.56 (m, 5H), 3.42-2.76 (m, 7H). HRMS (calc.): 480.2386, (found): 480.2377. 859

Example 141

[0538] Step 1: Methyl 4-[(4-chloro-6-methyl-[1,3,5]triazin-2-yl-amino)-methyl]-benzoic Ester (217)

[0539] To a stirred solution at −30° C. of cyanuric chloride 1 (2.00 g, 10.85 mmol) in anhydrous THF (100 ml) under nitrogen was slowly added a solution of MeMgBr (17 ml, 23.86 mmol, 1.4 M in anhydrous THF/toluene). After 1 h, the reaction mixture was allowed to warm to room temperature over 3 h. Then, methyl 4-(aminomethyl)benzoate.HCl 2 (2.08 g, 10.30 mmol) and i-Pr2NEt (3.78 ml, 21.69 mmol) were added, respectively. After 18 h, the reaction mixture was poured into a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4Cl, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH2Cl2: 10/90→15/85) to afford the title compound 217 (780 mg, 2.67 mmol, 25% yield) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ (ppm): mixture of rotamers, 2 AB system (δA=8.03, δA′=8.02, δB=7.39, δB′=7.38, J=8.5 Hz, 4H), 6.28-6.08 (2 m, 1H), 4.76 and 4.74 (2d, J=6.3 Hz, 2H), 3.92 (s, 3H), 2.46 and 2.42 (2s, 3H).

[0540] Step 2: N-(2-amino-phenyl)-4-{[6-(2-indanyl-amino)-4-methyl-[1,3,5]-triazin-2-yl-amino]-methyl}-benzamide (218)

[0541] The title compound 218 was obtained from 217 in 3 steps following the same procedure as Example 1, steps 3-5. 1H NMR (300 MHz, acetone-d6+Σ DMSO-d6) δ (ppm): mixture of rotamers, 9.62-9.50 (m, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.68-7.37 (m, 3H), 7.33 (d, J=7.7 Hz, 1H), 7.28-7.07 (m, 5H), 7.02 (t, J=7.4 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 6.69 (t, J=7.4 Hz, 1H), 4.92-4.60 (m, 5H), 3.35-3.10 (m, 2H), 3.02-2.82 (m, 2H), 2.25-2.12 (m, 3H). 860

Example 142

[0542] Step 1: (2-{4-[2-(4,6-Diamino-[1,3,5]triazin-2-yl)-vinyl]-benzoylamino}-phenyl)-carbamic Tert-Butyl Ester (219)

[0543] To a degazed solution of 184 (40 mg, 0.091 mmol) and 2-vinyl-4,6-diamino-1,3,5-triazine (11 mg, 0.083 mmol) in dry DMF (1 mL) was added tri-o-tolylphosphine (POT) (1.5 mg, 0.005 mmol) followed by Et3N (46 μL, 0.33 mmol) and tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.0025 mmol). The solution was heated at 100° C. for 16 h. Then, DMF was removed under reduced pressure. The reaction mixture was partitioned between AcOEt and a solution of sat. NH4Cl. After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2Cl2: 5/95) to afford the title compound 219 (25 mg, 0.056 mmol, 67% yield). 1H NMR (300 MHz, Acetone-d6) δ (ppm): 8.27 (s, 1H), 8.06 (d, J=8.1 Hz, 2H), 7.96 (d, J=15.9 Hz, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.76-7.69 (m, 1H), 7.62-7.55 (m, 1H), 7.26-7.15 (m, 2H), 6.90 (d, J=15.9 Hz), 6.21 (s, 4H), 1.50 (s, 9H).

[0544] Step 2: N-(2-Amino-phenyl)-4-[2-(4,6-diamino-[1,3,5]triazin-2-yl)-vinyl]-benzamide (220)

[0545] To a stirred solution at room temperature of 219 (25 mg, 0.056 mmol) in CH2Cl2 (1.5 mL) was added TFA (0.3 mL, 4.3 mmol). After 30 min, a solution of sat. NaHCO3 was slowly added until pH 8 is reached, CH2Cl2 was removed under reduced pressure, AcOEt was added, and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/CH2Cl2: 10/90) to afford the title compound 220 (19 mg, 0.054 mmol, 98% yield). 1H NMR: (300 MHz, acetone-d6) δ (ppm): 8.33, 8.13 (2d, J=7.5 Hz, 1H), 8.22 (d, J=15.9 Hz, 1H), 8.01 (d, J=8.1 Hz, 2H), 7.84 (d, J=8.1 Hz, 2H), 7.38-6.96 (m, 2H), 7.03 (d, J=15.9 Hz, 1H), 6.94-6.62 (m, 2H). 861

Example 143a

[0546] Step 1: 2-Amino-4-chloro-6-piperidin-1-yl-[1,3,5]triazin (221)

[0547] Ammonia was bubbled for 5 min in a solution of 2,4-dichloro-6-piperidin-1-yl-[1,3,5]triazine (500 mg, 2.15 mmol) in dry 1,4-dioxane (20 mL). The solution was heated at 70° C. for 16 h in a sealed tube. The reaction mixture was allowed to cool to room temperature, and partitioned between AcOEt and a solution of sat. NH4Cl. After separation, the organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound 221 (453 mg, 2.12 mmol, 98% yield). LRMS: [MH].+=214.1.

[0548] Step 2: 2-Amino 4-piperidin-1-yl-6-vinyl-[1,3,5]triazin (222)

[0549] To a solution of 221 (358 mg, 1.68 mmol) in dry toluene (7 mL) was added tributyl(vinyl)tin (514 μL, 1.76 mmol) followed by Pd(PPh3)4 (97 mg, 0.084 mmol) and the reaction mixture was heated at 100° C. for 16 h in a sealed tube. Then, the reaction mixture was allowed to cool to room temperature, concentrated, and purified directly by flash chromatography on silica gel (AcOEt/hexane: 10/90→30/70) to afford the title compound 222 (containing tributyltin chloride).

[0550] Steps 3: N-(2-Amino-phenyl)-4-[2-(4-amino-6-piperidin-1-yl-[1,3,5]triazin-2-yl)-vinyl]-benzamide (223)

[0551] The title compound 223 was obtained from 222 in 2 steps following the same procedure as in scheme 31, steps 1 and 2. 1H NMR: (300 MHz, DMSO-d6) δ (ppm): 9.69 (s, 1H), 8.01 (d, J=7.5 Hz, 2H), 7.87 (d, J=16.0 Hz, 1H), 7.80 (d, J=7.5 Hz, 2H), 7.18 (d, J=7.5 Hz, 1H), 7.04-6.92 (m, 1H), 6.91 (d, J=16 Hz, 1H), 6.85-6.68 (m, 3H), 6.60 (t, J=7.2 Hz, 1H), 4.93 (s, 2H), 3.77 (s, 4H), 1.63 (s, 2H), 1.52 (s, 4H).

Example 143b

[0552] Step 4: N-(2-Amino-phenyl)-4-[2-(4-amino-6-piperidin-1-yl-[1,3,5]triazin-2-yl)-ethyl]-benzamide (224)

[0553] To a solution of 223 (18 mg, 0.043 mmol) in MeOH (5 mL) was added 10% Pd/C (10 mg, 0.021 mmol). The reaction mixture was shaked under a pressure of H2 (40 psi) at room temperature for 16 h using an hydrogenation apparatus. Then, the reaction mixture was purged with N2, filtered through celite, and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2Cl2: 2/98→4/96) to afford the title compound 224 (10 mg, 0.024 mmol, 56% yield). 1H NMR (300 MHz, CDCl3—CD3OD) δ (ppm): 7.82 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.08 (t, J=7.0 Hz, 1H), 6.89-6.79 (m, 2H), 7.80-6.90 (m, 1H), 3.76 (s, 4H), 3.13 (t, J=8.1 Hz, 2H), 2.88 (t, J=8.1 Hz, 2H),1.90-1.40 (m, 10H). 862

[0554] Step 1: 2-Amino-benzothiazol-6-ol (225):

[0555] A suspension of 2-amino-6-methoxybenzothiazole (5.00 g, 27.8 mmol) in dichloromethane (70 mL) was cooled to 0° C. under nitrogen and boron tribromide (3.93 mL, 41.6 mmol) was added dropwise. The light yellow mixture was stirred for 3 h, allowing to warm-up slowly from 0° C. to 10° C. The reaction was slowly quenched by dropwise addition of methanol and tafter stirring overnight at room temperature, the white solid was collected by filtration (6.04 g, 88% yield). This hydrobromic salt was dissolved in water, washed with ethyl acetate, and neutralized with a saturated aqueous solution of NaHCO3. The resulting crystals were collected by filtration and dried in the oven at 135° C. for 1 h to afford the title compound 225 as colorless crystals (3.63 g, 79% yield). 1H NMR: (CD3OD) δ (ppm): 7.27 (d, J=8.8 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.80 (dd, J=8.4, 2.2 Hz, 1H).

[0556] Step 2: 6-(2-Morpholin-4-yl-ethoxy)-benzothiazol-2-ylamine (226)

[0557] To a solution of benzothiazole 225 (3.62 g, 21.8 mmol) in THF at room temperature under nitrogen, were successively added 4-(2-hydroxyethyl)morpholine (3.17 mL, 26.1 mmol), triphenylphosphine (7.43 g, 28.3 mmol) followed by a dropwise addition of diethyl azodicarboxylate (4.46 mL, 28.3 mmol). The solution was stirred for 3.5 h and THF was partially removed in vacuo. The mixture was partitioned between ethyl acetate and H2O. The combined organic layers were extracted with 1N HCl. The combined acidic extracts were neutralized using a saturated aqueous solution of NaHCO3 and the precipitate was dissolved with ethyl acetate. These combined organic layers were washed with brine, dried over MgSO4, and concentrated. The filtrate was concentrated to afford the title compound 226 (5.83 g, 96% yield) as a light yellow oil. 1H NMR: (Acetone-d6) δ (ppm): 7.37 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 6.94 (dd, J=8.8, 2.6 Hz, 1H), 6.60 (bs, 2H), 4.19 (t, J=6.2 Hz, 2H), 3.70-3.67 (m, 4H), 2.90 (s, 2H), 2.81 (t, J=6.2 Hz, 2H), 2.62-2.58 (m, 4H).

[0558] Step 3: 4-{[6-(2-Morpholin-4-yl-ethoxy)-benzothiazol-2-ylamino]-methyl}-benzoic Acid Methyl Ester (227):

[0559] To a round-bottom flask containing benzothiazole 226 (5.80 g, 20.8 mmol) was added methyl 4-formylbenzoate (5.11 g, 31.1 mmol), followed by THF (8 mL), dibutyltin dichloride (315 mg, 1.04 mmol) and dropwise addition of phenylsilane (3.24 mL, 31.1 mmol). The resulting mixture was stirred overnight at room temperature under nitrogen. The mixture was diluted in ethyl acetate and filtered. The filtrate was partitioned between ethyl acetate and water and the combined organic layers were washed with 1N HCl. The combined acidic layers were neutralized using a saturated aqueous solution of NaHCO3 and the precipitate was extracted with ethyl aceate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The resulting crude was purified by flash chromatography using MeOH/CHCl3(10:90) to afford 227 (3.69 g, 42% yield). 1H NMR: (Acetone-d6) δ (ppm): 8.04 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.94 (dd, J=8.5, 2.7 Hz, 1H), 4.50 (t, J=5.5 Hz, 2H), 3.86 (s, 3H).

[0560] Step 4: N-(2-Amino-phenyl)-4-{[6-(2-morpholin-4-yl-ethoxy)-benzothiazol-2-ylamino]-methyl}benzamide (228):

[0561] Following the procedure described in Example 1, step 4, 5 but substituting the previous compound for 6, the title compound 228 was obtained (958 mg, 46%) as a colorless solid. 1H NMR: (CD3OD) δ (ppm): 8.04 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.8 Hz, 1H), 7.31 (d, J=2.5 Hz, 1H), 7.25 (d, J=7.4 Hz, 1H), 7.15 (t, J=7.4 Hz, 1H), 6.97 (dd, J=8.8, 2.5 Hz, 2H), 6.84 (t, J=7.4 Hz, 1H), 4.78 (s, 2H), 4.21 (t, J=5.2 Hz, 2H), 3.81-3.77 (m, 4H), 2.87 (t, J=5.5, 2H), 2.69-3.66 (m, 4H). 863

[0562] Step 1: 4-[(5-Bromo-benzothiazol-2-ylamino)-methyl]-benzoic Acid Methyl Ester (229):

[0563] Following the procedure described in Example 144, step 3, but substituting the 2-amino-6-bromobenzothiazole for 226, the title compound 229 was obtained in 56% yield. 1H NMR: (DMSO-d6) δ (ppm): 8.78 (t, J=5.9 Hz, 1H), 8.01 (d, J=8.2 Hz, 2H), 7.99 (s, 1H), 7.56 (d, J=8.2 Hz, 2H), 7.43-7.34 (m, 2H), 4.74 (d, J=5.9 Hz, 2H), 3.90 (s, 3H).

[0564] Step 2: 4-{[5-(3,4,5-Trimethoxy-phenyl)-benzothiazol-2-ylamino]-methyl}-benzoic Acid Methyl Ester (230):

[0565] Following the procedure described in Example 15, step 1, but substituting 229 for 140, the title compound 230 was obtained in 44%yield as colorless crystals. 1H NMR: (DMSO-d6) δ (ppm): 8.73 (t, J=5.7 Hz, 1H), 8.11 (d, J=1.8 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.63-7.57 (m, 3H), 7.48 (d, J=8.4 Hz, 1H), 6.97 (s, 2H), 4.77 (d, J=5.7 Hz, 2H), 3.92 (m, 6H), 3.90 (s, 3H), 3.74 (s, 3H).

[0566] Step 3: N-(2-Amino-phenyl)-4-{[5-(3,4,5-trimethoxy-phenyl)-benzothiazol-2-ylamino]-methyl}-benzamide (231):

[0567] Following the procedure described in Example 1, step 4, 5 but substituting the previous compound for 6, the title compound 231 was obtained in 69% yield. 1H NMR: (Acetone-d6) δ (ppm): 8.31 (d, J=7.9 Hz, 2H), 8.20 (d, J=7.5 Hz, 1H), 8.13 (s, 1H), 7.73-7.58 (m, 3H), 7.63 (d, J=7.5 Hz, 2H), 7.48-7.43 (m, 2H), 7.05 (s, 2H), 4.98 (s, 2H), 4.00 (s, 6H), 3.84 (s, 3H). 864

[0568] Step 1: 4-[(6-Methoxy-benzothiazol-2-ylamino)-methyl]-benzoic Acid Methyl Ester (232):

[0569] To a solution of 2-amino-6-methoxybenzothiazole (2.00 g, 11.1 mmol) in a mixture of dichloroethane (20 mL) and THF (20 mL), were successively added methyl 4-formylbenzoate (1.82 g, 11.1 mmol), sodium triacetoxyborohydride (3.53 g, 16.7 mmol) and acetic acid (1.27 mL, 22.2 mmol). The mixture was stirred over 2 days and was quenched by adding aqueous saturated solution of NaHCO3. The mixture was poured in a separating funnel containing water and was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography using EtOAc/hexane (20:80 to 30:70) to afford the title compound 232 (1.85 g, 51% yield). 1H NMR: (Acetone-d6) δ (ppm): 8.04 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.94 (dd, J=8.5, 2.7 Hz, 1H), 4.50 (t, J=5.5 Hz, 2H), 3.86 (s, 3H).

[0570] Step 2: N-(2-Amino-phenyl)-4-[(6-methoxy-benzothiazol-2-ylamino)-methyl]-benzamide (233):

[0571] Following the procedure described in Example 1, step 4, 5 but substituting the previous compound for 6, the title compound 233 was obtained in 19% yield as a light beige solid. 1H NMR: (DMSO-d6) δ (ppm): 9.68 (s, 1H), 8.44 (t, J=5.8 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.39 (d, J=2.7 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.21 (d, J=6.6 Hz, 1H), 7.05 (t, J=6.3 Hz, 1H), 7.00 (d, J=1.4 Hz, 1H), 6.88 (dd, J=8.8, 2.7 Hz, 1H), 6.86 (dd, J=8.0, 1.4 Hz, 1H), 6.65 (td, J=7.4, 1.4 Hz, 1H), 4.95 (s, 2H), 4.70 (d, J=5.8 Hz, 2H), 3.79 (s, 3H). 865

[0572] Step 1: 4-(6-Methoxy-1H-benzoimidazol-2-ylsulfanylmethyl)-benzoic Acid Methyl Ester Hydrobromide (234):

[0573] To a solution of methyl 4-(bromomethyl)benzoate (2.51 g, 11.0 mmol) in DMF (50 mL) was added 5-methoxy-2-benzimidazolethiol (1.98 g, 11.0 mmol). The mixture was stirred at room temperature for 24 h and the solvent was evaporated in vacuo. The residue was suspended in ethyl acetate and the hydrobromide salt was collected by filtration to afford the title compound 234 (4.10 g, 91% yield) as a colorless solid. 1H NMR: (DMSO-d6) δ (ppm): 7.90 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.2 Hz, 1H), 7.03 (s, 1H), 6.94 (d, J=8.2 Hz, 1H), 4.65 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H).

[0574] Step 2: 4-[6-(2-Morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-ylsulfanylmethyl]-benzoic Acid Methyl Ester (235):

[0575] Following the procedure described in Example 144, step 1, 2 but substituting the previous compound for 2-amino-6-methoxybenzothiazole, the title compound 235 was obtained in 37% yield. 1H NMR: (CDCl3) δ (ppm): 8.04-8.00 (m, 2H), 7.77-7.72 (m, 1H), 7.69-7.59 (m, 1H), 7.56-7.49 (m, 2H), 6.96-6.90 (m, 1H), 4.68 (s, 2H), 4.31-4.16 (m, 4H), 3.97 (s, 3H), 3.98-3.91 (m, 2H), 3.82-3.72 (m, 2H), 2.75-2.47 (m, 4H).

[0576] Step 3: N-(2-Amino-phenyl)-4-[6-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-ylsulfanylmethyl]-benzamide (236):

[0577] Following the procedure described in Example 1, step 4, 5 but substituting the previous compound for 6, the title compound 236 was obtained in 11% yield. 1H NMR: (CD3OD) δ (ppm): 7.89 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.5 Hz, 1H), 7.19-7.06 (m, 3H), 6.93-6.79 (m, 3H), 4.55 (s, 2H), 4.18 (t, J=6.3 Hz, 2H), 3.65-3.62 (m, 4H), 2.51 (t, J=6.6 Hz, 2H), 2.46-2.42 (m, 4H). 866

[0578] Step 1: 4-Morpholin-4-yl-benzoic Acid Methyl Ester (237):

[0579] A flame-dried pressure vessel was charged with cesium carbonate (912 mg, 2.80 mmol) and toluene (8 mL) and the flasked was purged with nitrogen. Palladium acetate (9.0 mg, 0.004 mmol) and rac-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (37 mg, 0.06 mmol). The mixture was degassed and heated at 100° C. for 18 h. It was allowed to cool to room temperature and was filtered through celite, rinsed with ethyl acetate and partitioned between ethyl acetate and water. The organic layer was washed with a saturated solution of NaHCO3, brine, dried over MgSO4 and concentrated in vacuo to afford the title compound 237 (443 mg, 100% yield). 1H NMR: (CDCl3) δ (ppm): 8.02 (d, J=9.2 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 3.95 (s, 4H), 3.92 (s, 3H), 3.38-3.35 (m, 4H).

[0580] Step 2: N-(2-Amino-phenyl)-4-morpholin-4-yl-benzamide (238):

[0581] Following the procedure described in Example 1, step 4, 5 but substituting the previous compound for 6, the title compound 238 was obtained in 33% yield. 1H NMR: (DMSO-d6) δ (ppm): 7.20 (d, J=7.9 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 7.01 (t, J=7.0 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 6.65 (t, J=7.5 Hz, 1H), 4.90 (s, 2H), 3.81-3.79 (m, 4H), 3.32-3.28 (m, 4H). 867

[0582] Step 1: 3-Methylsulfanyl-3-(pyridin-4-ylamino)-acrylonitrile (239)

[0583] To a solution of pyridin-4-ylamine (1.0 g, 11.0 mmol) and 3,3-Bis-methylsulfanyl-acrylonitrile (2.05 g, 12.6 mmol) in DMF at room temperature, was added powdered 4A molecular sieves. The mixture was stirred for 1 hr. Subsequently the mixture was cooled to 0° C., 60% NaH dispersion in oil (0.92 g, 23.0 mmol) was added portionwise over 1 hr. and it was stirred at 0° C. for an additional 2 hrs. The cold bath was removed and the mixture was stirred at room temperature for 20 hrs. DMF was removed in vacuo and the crude was purified by column chromatography (gradient of EtOAc to 25% MeOH/EtOAc) to afford the desired product as an off-white solid (1.9 g, 89%).

[0584] Step 2: N-(2-Amino-phenyl)-4-{[2-cyano-1-(pyridin-4-ylamino)-vinylamino]-methyl}-benzamide (240)

[0585] To a mixture of 3-methylsulfanyl-3-(pyridin-4-ylaminoacrylonitrile (0.2 g, 1.0 mmol), 4-aminomethyl-benzoic acid (0.173 g, 1.14 mmol), DMAP (1 mg) and Et3N (0.14 ml, 1.0 mmol) was added dry pyridine (0.5 ml). The resulting stirring mixture was heated to 55° C. for 4.5 hrs., additional Et3N (0.14 ml) was added and mixture was heated from 75° C. to 90° C. over a period of 30 hrs. When the reaction was complete, pyridine was partially removed in vacuo and the crude was purified by column chromatography (gradient of EtOAc to 20% MeOH/EtOAc) to afford the desired product as an off-white solid (130 mg, 44%).

[0586] Following the procedure described in Example 1, step 4, 5 but substituting the previous compound for 6, the title compound 240 was obtained in 33% yield. 1H NMR: 1H NMR: (300 MHz, DMSO-d6) δ (ppm): 9.69 (br, 2H), 8.48 (br, 3H), 8.03 (d, J=7.9 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.29 (br, 2H), 7.23 (d, J=7.9 Hz, 1H), 7.03 (t, J=7.0 Hz, 1H), 6.84 (d, J=7.9 Hz, 1H), 6.65 (t, J=7.3 Hz, 1H), 4.96 (br, 2H), 4.62 (d, J=5.7 Hz, 2H). 868

[0587] Step 1: 4-[(2-Chloro-9H-purin-6-ylamino)-methyl]-benzoic Acid Methyl Ester (241)

[0588] A suspension of 2,6-dichloro-9H-purine (1 g, 5.29 mmol), 4-aminomethyl-benzoic acid methyl ester hydrochloride (1.2 equiv., 1.28 g) and NaHCO3 (2.1 equiv., 935 mg) in water was heated at 100° C. The homogeneous solution thus formed was refluxed 30 min. The resulting white precipitate was filtered, washed with cold water and dried under vacuum giving the title compound 241 (1 g, 3.14 mmol, 60%). LRMS calc: 317.7, found: 318.3 (MH)+.

[0589] Step 2: 4-{[2-Chloro-9-(2-methoxy-ethyl)-9H-purin-6-ylamino]-methyl}-benzoic Acid Methyl Ester (242)

[0590] Following the procedure described in Example 144, step 2 but substituting the previous compound for 2-amino-6-methoxybenzothiazole, the title compound 242 was obtained in 41% yield.

[0591] Step 3: N-(2-Amino-phenyl)-4-{[2-chloro-9-(2-methoxy-ethyl)-9H-purin-6-ylamino]-methyl}-benzamide (243):

[0592] Following the procedure described in Example 1, step 4, 5 but substituting the previous compound for 6, the title compound 243 was obtained in 85% yield. 1H NMR (CDCl3) δ (ppm): 9.64(s, 1H), 8.94 (bs, 1H), 8.18 (s, 1H), 7.96 (d, J=7.8 Hz, 2H), 7.52 (d, J=7.8 Hz, 2H), 7.21 (d, J=7.7 Hz, 1H), 7,01 (dd, J=7.3, 8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.62 (dd, J=7.3, 7.7 Hz, 1H), 4.91 (bs, 2H), 4.78 (bs, 2H), 4.18 (m, 2H), 3.70 (m, 2H), 3.26 (s, 3H) 869

[0593] Step 1: Methyl-4-{[3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino-methyl}-benzoic Acid Ester (244)

[0594] To a stirred suspension at 0° C. of methyl 4-(aminomethyl)benzoate.HCl 2 (809 mg, 4.01 mmol) in anhydrous CH2Cl2 (25 ml) under nitrogen were successively added i-Pr2NEt (1.91 ml, 10.95 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (1.00 g, 3.65 mmol). After 45 min, the reaction mixture was allowed to warm up to room temperature for 3 h. Then, the reaction mixture was concentrated, diluted with AcOEt, and successively washed with sat. NH4C1, H2O, sat. NaHCO3, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated to afford the title compound 244 (1.50 g, quantitative yield) as a colorless sticky foam. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.93 (d, J=7.9 Hz, 2H), 7.46-7.35 (m, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.15-7.05 (m, 3H), 5.49 (bs, 1H), 4.46 (d, J=5.7 Hz, 2H), 3.92 (s, 3H), 2.80 (s, 3H).

[0595] Step 2: 4-{[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino-methyl}-benzoic Acid (245)

[0596] To a stirred solution at room temperature of 244 (1.45 g, 3.60 mmol) in THF (20 ml) was added a solution of LiOH.H2O (453 mg, 10.80 mmol) in water (20 ml). After 20 h, the reaction mixture was concentrated, diluted with water and acidified with 1N HCl until pH 6 in order to get a white precipitate. After 10 min, the suspension was filtered off and the cake was abundantly washed with water, and dried to afford the title compound 245 (1.23 g, 3.15 mmol, 88% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.69 (t, J=5.9 Hz, 1H), 7.91 (d, J=7.9 Hz, 2H), 7.70-7.58 (m, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.45-7.30 (m, 3H), 4.44 (d, J=5.7 Hz, 2H), 2.72 (s, 3H).

[0597] Step 3: 4-(9-Chloro-3-methyl-4-oxo-4H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-benzoic Acid (246)

[0598] To a stirred suspension at room temperature of 245 (795 mg, 2.05 mmol) in anhydrous DMF (10 ml) was added a solution of NaOH (409 mg, 10.22 mmol) in anhydrous MeOH (5.1 ml). Then, the reaction mixture was warmed up to 40° C. After 3 days, the reaction mixture was concentrated, diluted with water and acidified with 1N HCl until pH 5 in order to get a pale pinky precipitate. After 30 min, the suspension was filtered off and the cake was abundantly washed with water, and dried to afford the title compound 246 (679 mg, 1.84 mmol, 90% yield) as a pale pinky solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): AB system (δA=7.92, δB=7.40, J=8.4 Hz, 4H), 7.56 (t, J=8.1 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 5.59 (bs, 2H), 2.95 (s, 3H).

[0599] Step 4: N-(2-Amino-phenyl)-4-(9-chloro-3-methyl-4-oxo-4H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-benzamide (247)

[0600] The title compound 247 was obtained from 246 in one step following the same procedure as Example 1, steps 5. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 9.65 (s, 1H), AB system (δA=7.95, 6B=7.42, J=8.1 Hz, 4H), 7.58 (t, J=8.1 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 7.00 (t, J=7.3 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 6.62 (t, J=7.3 Hz, 1H), 5.61 (bs, 2H), 4.91 (s, 2H), 2.97 (s, 3H). 870

[0601] Step 1: 4-(1H-Imidazol-2-yl)-benzoic Acid (248)

[0602] To a stirred solution of 4-formylbenzoic acid (2.00 g, 12.3 mmol) in ammonium hydroxide (9 ml) was added glyoxal (2.86 ml, 20.0 mmol). The reaction mixture was stirred 16 h at room temperature. 1N HCl was added to the reaction mixture to acidify to pH 5. The solvent was evaporated and the residue was triturated 30 min. in water (20 ml) and filtered to obtain the title compound 248 (2.08 g, 83%) as a white solid. LRMS: 188.1 (Calc.); 189.1 (found).

[0603] Step 2: N-(2-Amino-phenyl)-4-(1H-imidazol-2-yl)-benzamide (249)

[0604] The title compound 249 was obtained following the same procedure as Example 1, step 5. 1H NMR (CDCl3) δ (ppm): 1H NMR: (DMSO) δ (ppm): 9.72 (bs, 1H), 8.07 (s, 4H), 7.26 (s, 2H), 7.18 (d, J=7.9 Hz, 1H), 6.98 (dd, J=7.5, 7.5 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.60 (dd, J=7.5, 7.5 Hz, 1H). MS: (calc.) 278.1; (obt.) 279.1 (MH)+. 871

Example 153

[0605] Step 1: 4-Thiocarbamoylmethyl-benzoic Acid (250)

[0606] To a stirred suspension of 4-cyanomethyl-benzoic acid (1.65 g, 10.24 mmol) and Et3N (5 ml) in pyridine, H2S was bubbled during 3 h. The reaction mixture was stirred 16 h at room temperature. Water was then added to the reaction mixture which was agitated for 1 h before acidifying to pH 6 with 1M HCl. The solvent was evaporated and the residue was triturated 30 min. in water (20 ml) and filtered to obtain the title compound 250 (2.08 g, 83%) as a white solid. 1H NMR (DMSO) δ (ppm): 12.85 (bs, 1H), 9.53 (bs, 1H), 9.43 (bs, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 3.88 (s, 2H).

[0607] Step 2: 4-(4-Chloromethyl-thiazol-2-ylmethyl)-benzoic Acid (251)

[0608] A solution of 250 (729 mg, 3.73 mmol) and 1,3-dichloroacetone (474 mg, 3.73 mmol) in THF (30 ml) was stirred at 40° C. during 48 h. The solvent was evaporated then the residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (2-4% MeOH/CH2Cl2) to afford the title compound (827 mg, 83% yield) as a white solid. 1H NMR (DMSO) δ (ppm): 12.93 (bs, 1H), 7.91 (d, J=8.1 Hz, 2H), 7.63 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 4.78 (s, 2H), 4.42 (s, 2H).

[0609] Step 3: N-(2-Amino-phenyl)-4-(4-morpholin-4-ylmethyl-thiazol-2-ylmethyl)-benzamide (252)

[0610] K2CO3 (599 mg, 4.33 mmol) was added to a solution of 251 (527 mg, 1.97 mmol) and morpholine (189 l, 2.17 mmol) in THF (15 ml) was refluxed during 48 h. The solvent was evaporated. The crude residue was purified by flash chromatography on silica gel (3-50% MeOH/CH2Cl2) to afford the title compound 252 (238 mg, 38% yield) as a pale yellow solid. LRMS: 318.2 (calc) 319.2 (found).

[0611] The title compound 252 was obtained following the same procedure as Example 1, step 5. 1H NMR (DMSO) δ (ppm): 9.63 (bs, 1H), 7.94 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.33 (s, 1H), 7.15 (d, J=8.1 Hz, 1H), 6.97 (dd, J=7.7, 7.7 Hz, 1H), 6.77 (d, J=7.3 Hz, 1H), 6.59 (dd, J=8.1, 8.1 Hz, 1H), 4.90 (bs, 2H), 4.40 (s, 2H), 3.59-3.56 (m, 6H), 2.44-2.38 (m, 4H). LRMS: 408.2 (calc) 409.2 (found). 872

Example 154

[0612] Step 1: Methyl 3-[3-(4-methoxycarbonyl-benzyl)-ureido]-thiophene-2-carboxylate (253)

[0613] The procedure described by Nakao (K. Nakao, R. Shimizu, H. Kubota, M. Yasuhara, Y. Hashimura, T. Suzuki, T. Fujita and H. Ohmizu; Bioorg. Med. Chem. 1998, 6, 849-868.) was followed to afford the title compound 253 (1.01 g, 91%) as a yellow solid. 1H NMR (CDCl3) δ (ppm): 9.55 (bs, 1H), 8.00-7.97 (m, 3H), 7.42-7.37 (m, 3H), 5.45 (t, J=5.8 Hz, 1H), 4.52 (d, J=6.0 Hz, 2H), 3.91 (s, 3H), 3.82 (s, 3H).

[0614] Step 2: 4-(2,4-Dioxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-ylmethyl)-benzoic Acid (254)

[0615] To a suspension of 253 (422 mg, 1.21 mmol) in MeOH (15 ml) was added NaOH (145 mg, 3.63 mmol). The reaction mixture was heated at 60° C. during 16 h. Water (1 ml) was then added and the reaction mixture was stirred for 1 more hour. The solvent was evaporated and the residue was dissolved in water and acidified to pH 5 with HCl 1M. The precipitate was filtered to afford the desired compound 254 (348 mg, 95%) as a white solid. LRMS: 302.0 (Calc.); 303.0 (found).

[0616] Steps 3: N-(2-Amino-phenyl)-4-(1-ethyl-2,4-dioxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-ylmethyl)-benzamide (255)

[0617] The title compound 255 was obtained as a yellow solid (73%) following the same procedure as Example 99, step 2, 3, then followed by Example 1, step 5. 1H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H, NH), 8.22 (d, J=5.5 Hz, 1H, CH), 7.91 (d, J=8.2 Hz, 2H, CH), 7.43-7.40 (m, 3H, CH), 7.15 (d, J=7.4 Hz, 1H, CH), 6.96 (dd, J=7.6, 7.6 Hz, 1H, CH), 6.77 (d, J=7.1 Hz, 1H, CH), 6.59 (dd, J=7.4, 7.4 Hz, 1H, CH), 5.17 (s, 2H, NCH2), 4.88 (bs, 2H, NH2) 4.09 (q, J=7.0, 2H, CH2), 1.22 (t, J=7.0, 3H, CH3). LRMS: 420.1 (calc.); 421.0 (found). 873

Example 155

[0618] Step 1: 3H-Thieno[3,2-d]pyrimidin-4-one (256)

[0619] Methyl-3-amino-2-thiophene carboxylate (510 mg, 3.24 mmol) was dissolved in formamide (20 ml) and heated at 170° C. 16 h. The solvent was evaporated. The crude residue was then purified by flash chromatography on silica gel (2-4% MeOH/CH2Cl2) to afford the title compound 256 (157 mg, 32% yield). LRMS: 152.0 (Calc.); 152.9 (found).

[0620] Step 2: N-(2-Aminophenyl)-4-(4-oxo-4H-thieno[3,2-d]pyrimidin-3-ylmethyl)-benzamide (257)

[0621] Following the procedure described in Example 85, step 1 but substituting the previous compound for 119, followed by Example 1, step 4, 5, the title compound 257 was obtained in 41% yield. 1H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H), 8.70 (s, 1H), 8.22 (dd, J=5.2, 0.5 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.44 (dd, J=5.2, 0.6 Hz, 1H), 7.15 (d, J=7.7 Hz, 1H), 6.96 (dd, J=6.9, 6.9 Hz, 1H), 6.77 (d, J=7.1 Hz, 1H), 6.58 (dd, J 7.0, 7.0 Hz, 1H), 5.31 (s, 2H), 4.87 (bs, 2H). MS: 376.1 (calc.); 377.1 (found). 874

Example 156

[0622] Step 1: Methyl 2-amino-4,5-dimethyl-thiophene-3-carboxylate (258)

[0623] The procedure described by Hozien (Z. A. Hozien, F. M. Atta, Kh. M. Hassan, A. A. Abdel-Wahab and S. A. Ahmed; Synht. Commun. 1996, 26(20), 3733-3755.) was followed to afford the title compound 258 (1.44 g, 17%) as a yellow solid. LRMS: 197.1 (Calc.); 200.1 (found).

[0624] Steps 2: N-(2-Amino-phenyl)-4-(5,6-dimethyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-ylmethyl)-benzamide (259)

[0625] Following the procedure described in Example 155, step 1, 2 but substituting 258 for 256, the title compound 259 was obtained as a white solid (55%). 1H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H), 8.57 (s, 1H), 7.94 (d, J=8.0 Hz, 2H), 7.45 (d, J=7.7 Hz, 2H), 7.16 (d, J=7.7 Hz, 1H), 6.96 (dd, J=7.6, 7.6 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.59 (dd, J=7.4, 7.4 Hz, 1H), 5.25 (s, 2H), 4.87 (bs, 2H), 2.39 (s, 3H), 2.37 (s, 3H). LRMS: 404.1 (calc); 405.0 (found). 875

Example 157

[0626] Step 1: Methyl 4-(4-oxo-chroman-3-ylidenemethyl)-benzoate (260)

[0627] Concentrated H2SO4 (2 ml) was slowly added to a solution of 4-chromanone (2.00 g, 13.50 mmol) and methylformylbenzoate (2.11 g, 12.86 mmol) in glacial acetic acid. The reaction mixture was stirred 16 h at room temperature. The solvent was concentrated to half volume the resulting precipitate was filtered and rinsed with ethyl acetate to afford the title compound 260 (3.11 g, 82%) as a purple solid. 1H NMR: (DMSO) δ (ppm): 8.05 (d, J=8.2 Hz, 2H), 7.90 (d, J=7.6 Hz, 1H), 7.79 (s, 1H), 7.64-7.59(m, 3H), 7.15 (dd, J=7.6, 7.6 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 5.43 (s, 2H), 3.89 (s, 3H).

[0628] Step 2: Methyl-4-(4-oxo-4H-chromen-3-ylmethyl)-benzoate (261)

[0629] Water (0.2 ml) and RhCl3.H2O (7 mg, 0.034 mmol) was added to a suspension of compound 260 (200 mg, 0.680 mmol) in EtOH (2 ml) and CHCL3 (2 ml). The reaction mixture was stirred 16 h at 70° C. The reaction mixture was cooled down and diluted in ethyl acetate, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (0.5-1% MeOH/CH2Cl2) to afford the title compound 261 (118 mg, 59%) as a white solid. 1H NMR: (DMSO) δ (ppm): 8.45 (s, 1H), 8.03 (dd, J=7.9, 1.8 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.83-7.77(m, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.50-7.43 (m3, 1H), 3.82 (s, 3H), 3.80 (s, 2H).

[0630] Step 3: N-(2-Amino-phenyl)-4-(4-oxo-4H-chromen-3-ylmethyl)-benzamide (262)

[0631] The title compound 262 was obtained following the same procedure as Example 1, step 4, 5. 1H NMR: (DMSO) δ (ppm): 9.56 (bs, 1H), 8.45 (s, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.80 (dd, J=7.5, 7.5 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.51-7.42 (m, 3H), 7.14 (d, J=7.9 Hz, 1H), 6.96 (dd, J=7.3, 7.3 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 6.58 (dd, J=7.3, 7.3 Hz, 1H), 4.86 (bs, 2H), 3.80 (s, 2H). LRMS: 370.1 (calc.); 371.1 (found).

Example 158

[0632] Step 2: Methyl 4-chroman-3-ylmethyl-benzoate (263)

[0633] Pd/C 10% was added to a suspension of 260 (200 mg, 0.68 mmol) in MeOH (40 ml) and DMA (10 ml) which was previously purged under vacuum. The reaction mixture was stirred during 4 h at room temperature. After evaporation of the MeOH, water was added to the oily residue and the precipitate obtained was filtered. The crude residue was then purified by flash chromatography on silica gel (5-8% AcOEt/Hex) to afford the title compound 263 (114 mg, 59%) as a white solid. LRMS: 282.1 (Calc.); 283.0 (found).

[0634] Step 3: N-(2-Amino-phenyl)-4-chroman-3-ylmethyl-benzamide (265)

[0635] The title compound 265 was obtained following the same procedure as Example 1, steps 4 and 5. 1H NMR: (acetone) δ (ppm): 9.06 (bs, 1H), 8.01 (d, J=7.9 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.31 (d, J=7.9 Hz, 1H), 7.08-6.98 (m, 3H), 6.87 (d, J=7.5 Hz, 1H),6.82-6.66 (m, 3H), 4.62 (s, 2H), 4.22-4.17 (m, 1H), 4.88-3.81 (m, 1H), 2.88-2.71 (m, 3H), 2.61-2.53 (m, 1H), 2.41-2.33 (m, 1H). LRMS: 358.2 (calc.); 359.1 (found).

Example 159

[0636] Step 2: Methyl 4-(4-oxo-chroman-3-ylmethyl)-benzoate (264)

[0637] A suspension of 260 (400 mg, 1.36 mmol) and benzenesulfonyl hydrazine (702 mg, 4.08 mmol) in DMF (7 ml) was stirred at 100° C. during 48 h. The solvent was evaporated and the residue was diluted in AcOEt, washed with NH4Cl sat., brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (5% AcOEt/HEx) to afford the title compound 264 (170 mg, 42%) as a white solid. LRMS: 296.1 (Calc.); 297.0 (found).

[0638] Step 3: N-(2-Amino-phenyl)-4-(4-oxo-chroman-3-ylmethyl)-benzamide (266)

[0639] The title compound 266 was obtained following the same procedure as Example 1, steps 4 and 5. 1H NMR: (acetone) 8 (ppm): 9.62 (bs, 1H), 7.93 (d, J=7.9 Hz, 2H), 7.79 (d, J=7.9 Hz, 1H), 7.58 (dd, J=7.0, 7.0 Hz, 1H), 7.39 (d, J=7.9 Hz, 2H), 7.17-7.04 (m, 3H), 6.97 (dd, J=7.0, 7.0 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.60 (dd, J=7.5, 7.5 Hz, 1H), 4.88 (s, 2H), 4.44-4.39 (m, 1H), 4.28-4.21 (m, 1H), 2.26-3.21 (m, 2H), 2.83-2.74 (m, 1H). LRMS: 372.1 (calc.); 372.1 (found). 876

Example 160

[0640] Step 1: Methyl 4-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-benzoate (266)

[0641] Et3N (3.18 ml, 22.8 mmol) was added to a stirring solution of 2-H-1,4-benzoxazin-3-(4H)one (2.50 g, 16.8 mmol) and methyl 4-formylbenzoate (4.59 g, 27.5 mmol) in Ac2O (20 ml). The reaction mixture was refluxed 16 h. After this mixture was cooled for 3 days, the solid was filtered and rinsed with ethyl acetate to afford the title compound 266 (657 mg, 13%) as a yellow solid. LRMS: 295.1 (Calc.); 296.0 (found).

[0642] Step 2: Methyl 4-(3-oxo-3,4-dihydro-benzo[1,4]oxazin-2-ylidenemethyl)-benzoate (267)

[0643] The title compound 267 was obtained following the same procedure as Example 158, step 2. LRMS: 297.1 (Calc.); 298.1 (found).

[0644] Step 3: N-(2-Amino-phenyl)-4-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-benzamide (269)

[0645] The title compound 269 was obtained from 267 following the same procedure as Example 99, step 2, 3, then followed by Example 1, step 4, 5. 1H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H), 7.91 (d, J=7.9 Hz, 2H), 7.39 (d, J=7.9 Hz, 2H), 7.22 (d, J=7.9 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 7.11-6.91 (m, 4H), 6.77 (d, J=7.0 Hz, 1H), 6.60 (dd, J=7.0, 7.0 Hz, 1H), 4.95-4.91 (m, 1H), 4.89 (bs, 2H), 3.95 (q, J=7.0 Hz, 2H), 3.28-3.22 (m, 1H), 3.17-2.89 (m, 1H), 1.16 (t, J=7.0 Hz, 3H). LRMS: 401.2 (calc.); 402.1 (obt.).

Example 161

[0646] Step 1: N-(2-Amino-phenyl)-4-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-benzamide (270)

[0647] The title compound 270 was obtained from 267 following the same procedure as Example 1, step 4, 5. 1H NMR: (DMSO) δ (ppm): 10.74 (bs, 1H), 9.61 (bs, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.41 (d, J=7.9 Hz, 2H), 7.17 (d, J=7.5 Hz, 1H), 6.99-6.85 (m, 5H), 6.78 (d, J=7.5 Hz, 1H), 6.60 (dd, J=7.0, 7.0 Hz, 1H), 4.92-4.89 (m, 3H), 3.29-3.23 (m, 1H), 3.15-3.07 (m, 1H). MS: (calc.) 373.1; (obt.) 374.1 (MH)+. 877

Example 162

[0648] Step 1: Methyl 4-(1-oxo-indan-2-ylmethyl)-benzoate (271)

[0649] A 2M LDA solution in THF (4.16 ml, 8.32 mmol) was added to a solution of indanone (1.00 g, 7.57 mmol) in THF (10 ml) at −60° C. The solution was slowly warmed to 0° C. during a period of 15 min. and was agitated for 15 more min. The reaction was then cooled to −78° C. and a solution of methyl-4-bromobenzoate (1.73 g, 7.57 mmol) was slowly added. The solution was slowly warmed to −20° C. and stirred during 4 hours. The reaction mixture was quenched with HCL 1M and the solvent was evaporated. The residue was diluted in ethyl acetate, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (5-20% AcOEt/HEx) to afford the title compound 271 (245 mg, 17%) as a white solid. LRMS: 280.1 (Calc.); 281.1 (found).

[0650] Step 2: N-(2-Amino-phenyl)-4-(1-oxo-indan-2-ylmethyl)-benzamide (272)

[0651] The title compound 272 was obtained following the same procedure as Example 1, step 4, 5. 1H NMR: (DMSO) δ (ppm): 9.59 (bs, 1H), 7.91 (d, J=7.6 Hz, 2H), 7.69-7.64 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.45-7.40 (m, 3H), 7.16 (d, J=8.2 Hz, 1H), 6.96 (dd, J=7.3, 7.3 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 6.59 (dd, J=7.3, 7.3 Hz, 1H), 4.87 (bs, 2H), 3.23-3.14 (m, 3H), 2.85-2.81 (m, 2H). LRMS: 356.1 (calc.); 357.2 (found).

Example 163

[0652] Step 1: 4-(1-Oxo-indan-2-ylidenemethyl)-benzoic Acid (273)

[0653] To a suspension of indanone (2.00 g, 15.1 mmol) and 4-carboxybenzaldehyde (1.89 g, 12.6 mmol) in EtOH (10 ml) was added KOH (1.77 g, 31.5 mmol) at 0° C. The reaction mixture was stirred 30 min at 0° C. then at room temperature for 16 h. The solvent was evaporated and the residue was dissolved in water, acidified to pH 5 with HCl 1 M. The precipitate was filtered and rinsed with water to afford the title compound 273 (2.27 g, 57%) as a yellow solid. LRMS: 264.1 (Calc.); 265.0 (found).

[0654] Step 2: N-(2-Amino-phenyl)-4-(1-oxo-indan-2-ylidenemethyl)-benzamide (274)

[0655] The title compound 274 was obtained following the same procedure as Example 1, step 5. LRMS: 354.1 (Calc.); 355.0 (found).

[0656] Step 3: N-(2-Amino-phenyl)-4-(1-hydroxy-indan-2-ylmethyl)-benzamide (275)

[0657] To a suspension of 274 (300 mg, 0.85 mmol) in MeOH (8 ml) and water (1 ml) was added NaBH4 (75 mg, 1.95 mmol). The reaction mixture was stirred at 50° C. 16 h and cooled down. Water was added to the solution and the precipitated was filtered and rinsed with cold water to afford the title compound 275 (224 mg, 74%) as a white solid. 1H NMR: (acetone) δ (ppm): 9.05 (bs, 1H), 8.00 (dd, J=8.2, 2.7 Hz, 2H), 7.47 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.38-7.30 (m, 2H), 7.22-7.12 (m, 3H), 7.01 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.87 (dd, J=8.0, 1.1 Hz, 1H), 6.68 (dd, J=7.6, 7.6 Hz, 1H), 4.98 (t, J=5.8 Hz, 0.4H), 4.89 (t, J=6.7 Hz, 0.6H), 4.63 (bs, 2H), 4.45 (d, J=6.9 Hz, 0.6H), 4.06 (d, J=6.0 Hz, 0.4H), 3.30-3.19 (m, 1H), 2.88-2.48 (m, 3H, CH2). LRMS: 358.2 (calc.); 359.1 (found). 878

Example 164

[0658] Step 1: 4-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-benzoic Acid (276)

[0659] To a solution of NaH (60% in mineral oil, 250 mg, 6.3 mmol) at 0° C. acetyl acetone (0.646 ml, 6.3 mmol) was added followed by 4-bromomethyl-benzoic acid methyl ester 2 (1.2 g, 5.2 mmol). The reaction mixture stirred 1 hour at room temperature and refluxed for 2 hours. Phenyl hydrazine (0.51 ml, 5.2 mmol) was added and the reaction mixture refluxed for an additional hour. THF was removed in vacuum and the oily residue was partitioned between water and ethyl acetate. Organic layer was separated, dried, evaporated and purify by chromatography on a silica gel column, eluent EtOAc—hexane (1:1) to produce an oily material (800 mg) which was treated with a solution of NaOH (0.8 g, 20 mmol) in 20 ml water for 1 hour at room temperature. The following steps,—acidification with HCl (pH 6), extraction of the resultant emulsion with ethyl acetate, drying the extract with sodium sulfate, evaporation and column chromatography (eluent EtOAc—hexane, 1:1) afforded 390 mg of a mixture of 276 (the title compound) and 278 (molar ratio 1:2). [M−1]+ 307.0 and 191.1. This mixture was taken for the next step as is.

[0660] Step 2. N-(2-Amino-phenyl)-4-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-benzamide (277)

[0661] Following a procedure analogous to that described in Example 92, step 2, but substituting 276 for 143, the title compound 277 was obtained in 25% yield (purified by chromatography using as eluent EtOAc—hexane, 1:1). 1H NMR: (300 MHz, DMSO-d6, δ (ppm): 9.64 (s, 1H); 7.97 (d, J=7.6 Hz, 2H), 7.42-7.56 (m, 5H), 7.37 (d, J=8.2 Hz, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.66 (t, J=7.6 Hz, 1H), 4.93 (s, 2H), 3.92 (s, 2H), 2.34 (s, 3H), 2.18 (s, 3H).

Example 165

[0662] Step 1: 4-(3-Oxo-butyl)-benzoic Acid (278)

[0663] To a solution of acetyl acetone (5.0 ml, 49 mmol) at room temperature NaOMe (25% wt, 10.8 ml, 47.3 mmol) was added followed by 4-bromomethyl-benzoic acid methyl ester 2 (9.0 g, 39.3 mmol). The reaction mixture refluxed 3 hours, cooled to the room temperature and acidified with HCl (pH 1-2). Evaporation of the resultant solution yielded a residue, which was refluxed in a mixture of glacial AcOH (50 ml) and conc. HCl (25 ml) for 4 hours. Acids were removed in vacuum and the residue was triturated with water to form a crystalline material, which was collected by filtration and dried to afford 278 (6.72 g, 80% yield). [M−1] 191.1.

[0664] Step 2. 4-(5-Amino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzoic Acid 279

[0665] To a refluxing suspension of 4-(3-oxo-butyl)-benzoic acid 278 (700 mg, 3.65 mmol), malonodinitrile (241 mg, 3.65 mmol) and sulfur (130 mg, 3.65 mmol) in 20 ml EtOH, diethylamine (0.5 ml, 4.8 mmol) was added. The reaction mixture refluxed 1 hour, cooled to the room temperature, acidified with conc. HCl (pH 4-5) and evaporated to yield a solid residue. This material was partitioned between water and ethyl acetate, organic layer was separated, dried, evaporated and chromatographed on a silica gel column, eluent EtOAc-hexane, 1:1, to afford the title compound 279 (300 mg, 30% yield). 1H NMR: (300 MHz, DMSO-d6, δ ppm): 7.87 (d, J=8.4 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 6.98 (s, 2H), 3.92 (s, 2H), 2.03 (s, 3H).

[0666] Step 3. 4-(5-Acetylamino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzoic Acid 280

[0667] To a solution of 4-(5-amino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzoic acid 279 (230 mg, 0.86 mmol) in a solvent mixture acetone (5 ml)—dichloromethane (5 ml) at room temperature acetyl chloride (0.305 ml, 4.3 mmol) was added. After 2 hours of stirring at the same conditions a precipitate of the title compound 280 formed which was collected and dried (200 mg, 75% yield). [M−1] 313.1.

[0668] Step 4: N-(2-Amino-phenyl)-4-(5-acetylamino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzamide (281)

[0669] Following a procedure analogous to that described in Example 92, step 2, but substituting 280 for 143, the title compound 281 was obtained in 25% yield. 1H NMR (DMSO) δ (ppm): 9.61 (s, 1H); 7.91 (d, J=7.9 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.15 (d, J=7.5 Hz, 1H), 6.96 (t, J=6.6 Hz, 1H), 6.77 (d, J=7.0 Hz, 1H), 6.59 (t, J=7.9 Hz, 1H), 4.89 (s, 2H), 4.10 (s, 2H), 2.19 (s, 3H), 2.16 (s, 3H). [M+1] 405.0. 879

Example 166

[0670] Step 1. 4-(N-Hydroxycarbamimidoylmethyl)-benzoic Acid (282)

[0671] A suspension of 4-cyanomethyl benzoic acid (2.07 g, 12.86 mmol), NH2OH.HCl (1.79 g, 25.71 mmol) and potassium hydroxide (2.16 g, 38.57 mmol) in 70 ml ethanol refluxed for 36 hours, poured into 100 ml water and acidified with conc. HCl (pH 5-6). EtOH was removed in vacuum and the remaining suspension was treated with another 100 ml water. A precipitate formed which was collected and dried to afford the title compound 282. [M+1]195.1.

[0672] Step 2. 4-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-benzoic Acid (283)

[0673] A solution of 44N-hydroxycarbamimidoylmethyl)-benzoic acid 282 (388 mg, 2.0 mmol) in pyridine (8 ml) was treated with acetic anhydride (0.283 ml, 3.0 mmol). The resultant solution refluxed 6 hours, evaporated in vacuum and the remaining solid was triturated with water, collected by filtration, dried and purified by chromatography on a silica gel column, eluent EtOAc, EtOAc-MeOH (10:1) and finally EtOAc-MeOH (1:1), to produce 283 (164 mg, 38% yield).[M−1]− 217.1

[0674] Step 3. N-(2-Amino-phenyl)-4-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-benzamide (284)

[0675] For the preparation of the title compound 284, a procedure analogous to that described in Example 92, step 2, but substituting 283 for 143, the title compound 284 was obtained. 1H NMR: (DMSO) δ (ppm): 9.62 (s, 1H), 7.93 (d, J=7.9 Hz, 2H), 7.42 (d, J=8.4 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 6.97 (t, J=7.9 Hz, 1H), 6.78 (d, J=7.5 Hz, 1H), 6.60 (t, J=7.9 Hz, 1H), 4.92 (s, 2H), 4.14 (s, 2H), 2.55 (s, 3H). [M+1]+ 309.2 880

Example 167

[0676] Step 1: 4-(3,5-Dimethyl-pyrazol-1-yl)-benzoic Acid (285)

[0677] A solution of 4-hydrazino-benzoic acid (0.60 g, 3.95 mmol) and acetyl acetone (0.405 ml, 3.95 mmol) in ethanol (20 ml) refluxed for 1 hour. Ethanol was removed in vacuum and the remaining solid was triturated with water and collected by filtration to produce 285 (0.71 mg, 83% yield). (M−1]− 215.1.

[0678] Step 2. N-(2-Amino-phenyl)-443,5-dimethyl-pyrazol-1-yl)-benzamide (286)

[0679] For the preparation of the title compound 286, a procedure analogous to that described in Example 92, step 2, but substituting 285 for 143, the title compound 286 was obtained in 34% yield (purified by chromatography using as eluent CH2Cl2-methanol, 19:1). 1H NMR: (DMSO) δ (ppm): 9.73 (s, 1H); 8.09 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.17 (d, J=7.5 Hz, 1H), 6.98 (t, J=7.0 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.60 (t, J=7.5 Hz, 1H), 6.13 (s, 1H), 4.92 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H). [M+1]+ 303.3 881

Example 168

[0680] Step 1: 2-(3,4,5-Trimethoxy-phenyl)-2,3-dihydro-furan (287)

[0681] To a solution of 5-iodo-1,2,3-trimethoxybenzene (900 mg, 3.06 mmol) and 2,3-dihydrofuran (1.16 mL, 15.3 mmol) in dry DMF (8 mL) were added PPh3 (20 mg, 0.077 mmol), KOAc (901 mg, 9.18 mmol), n-Bu4NCl (850 mg, 3.06 mmol) and Pd(OAc)2 (17 mg, 0.077 mmol). The reaction mixture was stirred 18 h at 80° C. The reaction mixture was diluted with AcOEt and water. After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/Hexane: 20/80) to afford the title compound 287 (311 mg, 1.32 mmol, 43% yield). 1H NMR: (300 MHz, CDCl3) δ (ppm): 6.59 (s, 2H), 6.45 (m, 1H), 5.45 (dd, J=10.5, 8.4 Hz, 1H), 4.97 (m, 1H), 3.87 (s, 6H), 3.84 (s, 3H), 3.06 (m, 1H), 2.62 (m, 1H).

[0682] Step 2: 4-[5-(3,4,5-Trimethoxy-phenyl)-2,5-dihydrofuran-2-yl]-benzoic Acid Ethyl Ester (288)

[0683] To a solution of 287 (200 mg, 0.846 mmol) and 4-Iodo-benzoic acid ethyl ester (468 mg, 1.69 mmol) in dry acetonitrile (4 mL) were added PPh3 (20 mg, 0.076 mmol), Ag2CO3 (467 mg, 1.69 mmol) and Pd(OAc)2 (7 mg, 0.03 mmol). The reaction mixture was stirred 18 h at 80° C. The reaction mixture was filtered through celite and washed with AcOEt. Water was added and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/Hexane: 30/70) to afford the title compound 288 (280 mg, 0.728 mmol, 86% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 8.05 (d, J=7.5 Hz, 2H), 7.45 (d, J=7.5 Hz, 2H), 6.61 (s, 2H), 6.18-5.95 (m, 4H), 4.38 (q, J=7.0 Hz, 2H), 3.88 (s, 6H), 3.84 (s, 3H), 1.39 (t, J=7.0 Hz).

[0684] Step 3: N-(2-Amino-phenyl)-4-[5-(3,4,5-trimethoxy-phenyl)-2,5-dihydro-furan-2-yl]-benzamide (289)

[0685] Following a procedure analogous to that described in Example 1, step 4, 5, but substituting 288 for 6, the title compound 289 was obtained in 48% yield. 1H NMR (DMSO) δ (ppm): 8.00 (s, 1H), 7.91 (d, J=7.9 Hz, 2H), 7.48 (d, J=7.9 Hz, 2H), 7.33 (d, J=7.5 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 6.92-6.82 (m, 2H), 6.61 (s, 2H), 6.14-5.99 (m, 4H), 3.89 (s, 6H), 3.84 (s, 3H).

Example 169

[0686] Step 1: N-(2-Amino-phenyl)-4-[5-(3,4,5-trimethoxy-phenyl)-tetrahydro-furan-2-yl]-benzamide. (290)

[0687] To a degazed solution of 289 (43 mg, 0.096 mmol) in AcOEt (4 mL) was added PtO2 (3 mg, 0.01 mmol) and the reaction mixture was stirred at room temperature under a 1 atm pressure of H2 for 16 h. The reaction flask was purged with N2 then the reaction mixture was filtered through celite, rinsed with MeOH and concentrated. The crude residue was purified three times by flash chromatography on silica gel (MeOH/DCM: 2/98, AcOEt/DCM: 30/70 and AcOEt/CHCl3: 30/70) to afford the title compound 290 (10 mg, 0.22 mmol, 23% yield). 1H NMR (CDCl3) δ (ppm): 8.10 (s, 1H), 7.91 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.34 (d, J=7.5 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 6.96-6.85 (m, 2H), 6.64 (s, 2H), 5.33 (t, J=7.0 Hz, 1H), 5.21 (t, 7.0 Hz, 1H), 3.89 (s, 6H), 3.85 (s, 3H), 2.59-2.40 (m, 2H), 2.09-1.88 (m, 2H). 882

Example 169

[0688] Step 1: [2-(4-Vinyl-benzoylamino)-phenyl]-carbamic Acid Tert-Butyl Ester (291)

[0689] Following a procedure analogous to that described in Example 143, step 2, but substituting 184 for 221, the title compound 291 was obtained in 90% yield as a dark yellow oil. 1H NMR: (300 MHz, CDCl3) δ (ppm): 9.18 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.77 (d, J=7.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 2H), 7.30-7.10 (m, 3H), 6.89 (s, 1H), 6.77 (dd, J=17.4, 11.0 Hz, 1H), 5.87 (d, J=17.4 Hz, 1H), 5.39 (d, J=11.0 Hz, 1H), 1.52 (s, 9H).

[0690] Step 2: [2-(4-Oxiranyl-benzovlamino)-phenyl]-carbamic Acid Tert-Butyl Ester (292)

[0691] To a solution of 291 (4.1 g, 12.1 mmol) in dry CHCl3 (60 ML) was added m-CPBA 70% (3.6 g, 14.5 mmol). The reaction mixture was stirred at room temperature for 5 h then additional m-CPBA (0.6 g, 2.4 mmol) was added and the stirring continued for 1 h. A further amount of m-CPBA (0.6 g, 2.4 mmol) was added and the reaction mixture was stirred for 16 h. Chloroform and a 10% solution of NaHCO3 were added and the phases were separated. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/Hexane: 1/3) to afford the title compound 292 (2.86 g, 8.07 mmol, 66% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.20 (s, 1H), 7.95 (d, J=8.1 Hz, 2H), 7.86-7.75 (m, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.26-7.10 (m, 3H), 6.84-6.70 (m, 1H), 3.93 (t, J=3.0 Hz, 1H), 3.20 (t, J=5.0 Hz, 1H), 2.80 (dd, J=5.0, 3.0 Hz, 1H), 1.52 (s, 9H).

[0692] Step 3: (2-{4-[1-Hydroxy-2-(3,4,5-trimethoxy-phenylamino)-ethyl]-benzoylamino}-phenyl)-carbamic Acid Tert-Butyl Ester (295) and (2-{4-[2-Hydroxy-1-(3,4,5-trimethoxy-phenylamino)-ethyl]-benzoylamino}-phenyl)-carbamic Acid Tert-Butyl Ester (293)

[0693] To a stirred solution of CoCl2 (8 mg, 0.06 mmol) in dry acetonitrile (10 mL) was added 292 (1 g, 2.8 mmol) followed by 3,4,5-trimethoxyaniline (516 mg, 2.8 mmol) and the reaction mixture was allowed to react for 16 h at room temperature then it was heated at 60° C. for 5 h. The reaction mixture was partitioned between AcOEt and water and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (AcOEt/Hexane: 1/1) to afford compounds 293 and 295 (combined: 1.07 g, 1.99 mmol, 71% yield, ratio 292/295=5/1) which can be separated by flash chromatography on silica gel (AcOEt/Hexane: 1/1). 1H NMR (300 MHz, CDCl3) δ (ppm): Compound 292: 9.21 (s, 1H), 7.92 (d, J=8.1 Hz, 2H), 7.73 (d, J=6.6 Hz, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.28-7.10 (m, 3H), 6.90 (s, 1H), 5.83 (s, 2H), 4.54-4.44 (m, 1H), 3.93 (dd, J=8.1, 3.9 Hz, 1H), 3.84-3.72 (m, 1H), 3.71 (s, 3H), 3.66 (s, 6H), 1.47 (s, 9H). Compound 295: 9.22 (s, 1H), 7.91 (d, J=8.1 Hz, 2H), 7.77 (d, J=7.2 Hz, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.30-7.21 (m, 3H), 6.88 (s, 1H), 6.15 (s, 2H), 5.16-5.06 (m, 1H), 3.81 (s, 6H), 3.78 (s, 3H), 3.50-3.25 (m, 2H), 1.51 (s, 9H).

[0694] Step 4: N-(2-Amino-phenyl)-4-[2-hydroxy-1-(3,4,5-trimethoxy-Phenylamino)-ethyl]-benzamide (294)

[0695] Following a procedure analogous to that described in Example 42, step 3, but substituting 293 for 46, the title compound 294 was obtained in 50% yield. 1H NMR (DMSO) δ (ppm): 8.36 (s, 1H), 7.74 (d, J=6.9 Hz, 2H), 7.30 (d, J=7.8 Hz, 2H), 7.18 (d, J=6.9 Hz, 1H), 7.00 (t, J=7.2 Hz, 1H), 6.72 (m, 2H), 5.69 (s, 2H), 4.34 (m, 1H), 4.02-3.52 (m, 2H), 3.66 (s, 3H), 3.57 (s, 6H).

Example 170

[0696] Step 1: N-(2-Amino-phenyl)-4-[2-oxo-3-(3,4,5-trimethoxy-Phenyl)-oxazolidin-4-yl]-benzamide (296)

[0697] To a solution of 293 (200 mg, 0.372 mmol) in toluene (5 mL) and THF (1 mL) was added 1,1′-carbonyldiimidazole (72 mg, 0.45 mmol) followed by Et3N (156 μL, 1.12 mmol) and the mixture was stirred at room temperature for 5 h then at 90° C. for 48 h. The reaction mixture was diluted with AcOEt, a solution of sat. NH4Cl was added and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (DCM/AcOEt: 80/20) to afford the desired compound (120 mg, 0.21 mmol, 57% yield). 1H NMR (DMSO) δ (ppm): 9.37 (s, 1H), 7.98 (d, J=8.1 Hz, 2H), 7.76 (d, J=7.5 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.25-15 (m, 3H), 6.88 (s, 1H), 6.61 (s, 2H), 5.40 (dd, J=8.7, 6.0 Hz, 1H), 4.79 (t, J=8.7 Hz, 1H), 4.19 (dd, J=8.7, 6.0 1H), 3.75 (s, 3H), 3.72 (s, 6H), 1.47 (s, 9H).

[0698] Following a procedure analogous to that described in Example 42, step 3, but substituting the previous compound for 46, the title compound 296 was obtained in 81% yield.). 1H NMR (DMSO) δ (ppm): 8.03 (s, 1H), 7.91 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.30 (d, J=7.5 Hz, 1H), 7.07 (t, J=7.5 Hz, 1H), 6.82 (d, J=7.5 Hz, 2H), 6.61 (s, 2H), 5.40 (dd, J=8.7, 6.0 Hz, 1H), 4.78 (t, J=8.7 Hz, 1H), 4.18 (dd, J=8.7, 6.0 Hz, 1H), 3.75 (s, 3H), 3.71 (s, 6H).

Example 171

[0699] Step 1: N-(2-Amino-phenyl)-4-[2-oxo-3-(3,4,5-trimethoxy-phenyl)-oxazolidin-5-yl]-benzamide (297)

[0700] To a solution of 295 (130 mg, 0.242 mmol) in DCM (2 mL) was added 1,1′-carbonyldiimidazole (47 mg, 0.29 mmol) and the mixture was stirred at room temperature for 16 h. DCM was removed under reduced pressure, AcOEt and a solution of sat. NH4Cl were added and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (Hexane/AcOEt: 30/70) to afford the desired compound (80 mg, 0.14 mmol, 58% yield). 1H NMR (DMSO) δ (ppm): 9.39 (s, 1H), 8.04 (d, J=8.1 Hz, 2H), 7.84 (d, J=7.5 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.26-7.12 (m, 3H), 6.86-6.74 (m, 3H), 5.70 (t, J=8.4 Hz, 1H), 4.24 (t, J=8.7 Hz, 1H), 3.97-3.87 (m, 1H), 3.87 (s, 6H), 3.82 (s, 3H), 1.52 (s, 9H).

[0701] Following a procedure analogous to that described in Example 42, step 3, but substituting the previous compound for 46, the title compound 297 was obtained in 94% yield.). 1H NMR (DMSO) δ (ppm): 8.38 (s, 1H), 7.97 (d, J=7.5 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.35 (d, J=7.0 Hz, 1H), 7.08 (t, J=7.0 Hz, 1H), 6.97-6.87 (m, 2H), 6.79 (s, 2H), 5.66 (t, J=8.1 Hz, 1H), 4.41 (t, J=9.0 Hz, 1H), 3.91 (t, J=7.8 Hz, 1H), 3.86 (s, 6H), 3.82 (s, 3H). 883884

Example 172

[0702] Step 1: {2-[4-(1-Azido-2-hydroxy-ethyl)-benzoylamino]-phenyl}-carbamic Acid Tert-Butyl Ester (298) and {2-[4-(2-Azido-1-hydroxy-ethyl)-benzoylamino]-phenyl}-carbamic Acid Tert-Butyl Ester (302)

[0703] To a solution of 292 (210 mg, 0.59 mmol) in acetonitrile (9 mL) and water (1 mL) was added CeCl3 heptahydrate (110 mg, 0.296 mmol) followed by NaN3 (42 mg, 0.65 mmol). The reaction mixture was refluxed for 3 h then acetonitrile was removed under reduced pressure. The residue was diluted with DCM, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash chromatography on silica gel (AcOEt/Hexane: 1/1) afforded a 1:1 mixture of title compounds 298 and 302 (combined: 187 mg, 0.47 mmol, 80% yield) which were separated by flash chromatography on silica gel (AcOEt/Hexane: 2/5). Compound 298: 1H NMR: (300 MHz, CDCl3/CD3OD) δ (ppm): 7.95 (d, J=8.1 Hz, 2H), 7.70-7.63 (m, 1H), 7.43 (d, J=8.1 Hz, 2H), 7.36-7.29 (m, 1H), 7.24-7.14 (m, 2H), 4.69 (dd, J=7.5, 4.8 Hz, 1H), 3.80-3.65 (m, 2H), 1.49 (s, 9H). Compound 302: 1H NMR: (300 MHz, CDCl3) δ (ppm): 9.28 (s, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.71 (d, J=7.5 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.25-7.08 (m, 3H), 7.01 (s, 1H), 4.87 (dd, J 6.9, 5.1 Hz, 1H), 3.47-3.38 (m, 2H), 3.32-3.21 (bs, 1H), 1.50 (s, 9H).

[0704] Step 2: {2-[4-(1-Amino-2-hydroxy-ethyl)-benzoylamino]-phenyl}-carbamic Acid Tert-Butyl Ester (299)

[0705] To a solution of 298 (156 mg, 0.39 mmol) in MeOH (2 mL) was added Pd/C 10% (20 mg, 0.02 mmol). The reaction mixture was stirred under a 1 atm pressure of H2 at room temperature for 16 h then it was purged with N2. The palladium was removed by filtration through celite and the MeOH was evaporated under reduced pressure to afford the title compound 299 (88 mg, 0.24 mmol, 60% yield), which was used without purification. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.24 (s, 1H), 7.90 (d, J=7.8 Hz, 2H), 7.71 (d, J=6.6 Hz, 1H), 7.40 (d, J=7.8 Hz, 2H), 7.31-7.10 (m, 3H), 7.06-6.94 (m, 1H), 4.12 (dd, J=7.5, 4.5 Hz, 1H), 3.74 (dd, J=7.8, 5.4 Hz, 1H), 3.64-3.51 (m, 1H), 2.64 (s, 3H), 1.49 (s, 9H).

[0706] Step 3: (2-{4-[1-(3,4-Dimethoxy-benzoylamino)-2-hydroxy-ethyl]-benzoylamino}-phenyl)-carbamic Acid Tert-Butyl Ester (300)

[0707] To a stirred solution of 299 (88 mg, 0.24 mmol) in dry DCM (2 mL) at −20° C. was added 3,4-dimethoxybenzoyl chloride (50 mg, 0.25 mmol) followed by Et3N (37 μL, 0.26 mmol). The reaction mixture was allowed to warm up to room temperature then was stirred for 48 h. A solution of sat. NH4Cl was added, followed by DCM and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/DCM: 4/96) to afford title compound 300 (91 mg, 0.17 mmol, 710% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.65-7.58 (m, 1H), 7.46 (m, 7H), 6.80 (d, J=8.1 Hz, 1H), 5.20-5.10 (m, 1H), 3.95-3.78 (m, 2H), 3.88 (s, 3H) 3.84 (s, 3H), 1.47 (s, 9H).

[0708] Step 4: N-(2-Amino-phenyl)-4-[2-(3,4-dimethoxy-phenyl)-4,5-dihydro-oxazol-4-yl]-benzamide (301)

[0709] To a solution of 300 (91 mg, 0.17 mmol) in dry THF (2 mL) was added the Burgess reagent (44 mg, 0.19 mmol) and the mixture was stirred at 70° C. for 2 h. The reaction mixture was partitioned between AcOEt and water and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/DCM: 3/97) to afford the Boc-protected intermediate (75 mg, 0.14 mmol, 85% yield). 1H NMR (CDCl3) δ (ppm): 9.31 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.72 (d, J=7.5 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.61 (s, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.27 (d, J=6.0 Hz, 1H), 7.23-7.08 (m, 3H), 6.93 (d, J=8.7 Hz, 1H), 5.43 (t, J=9.0 Hz, 1H), 4.84 (t, J=9.3 Hz, 1H), 4.26 (t, J=8.4 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 1.50 (s, 9H).

[0710] Following a procedure analogous to that described in Example 42, step 3, but substituting the previous compound for 46, the title compound 301 was obtained in 82%. 1H NMR (CDCl3) δ (ppm): 8.01 (s, 1H), 7.89 (d, J=7.9 Hz, 2H), 7.65 (dd, J=8.4, 1.5 Hz, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.41 (d, J=7.9 Hz, 2H), 7.32 (d, J=7.9 Hz, 1H), 7.08 (t, J=6.6 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.84 (d, J=7.9 Hz, 2H), 5.43 (dd, J=9.7, 8.4 Hz, 1H), 4.83 (dd, J=9.7, 8.4 Hz, 1H), 4.25 (t, J=8.1 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H).

Example 173

[0711] Step 1: {2-[4-(2-Amino-1-hydroxy-ethyl)-benzoylamino]-phenyl}-carbamic Acid Tert-Butyl Ester (303)

[0712] The title compound 303 was obtained in 94% yield from 302 following the same procedure as in Example 172, step 2. The compound 303 was used directly for next step without purification.

[0713] Step 2: 2-{4-[2-(3,4-Dimethoxy-benzoylamino)-1-hydroxy-ethyl]-benzoylamino}-phenyl)-carbamic Acid Tert-Butyl Ester (304)

[0714] The title compound 304 was obtained in 40% yield from 303 and 3,4-dimethoxybenzoyl chloride following the same procedure as in Example 172, step 3. 1H NMR (CDCl3) δ (ppm): 9.31 (s, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.68 (d, J=6.9 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.33 (d, J=8.1 Hz), 7.30-7.06 (m, 4H), 7.00-6.93 (m, 1H), 6.79 (d, J=8.4 Hz, 1H), 4.89-4.82 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.85-3.73 (m, 1H), 3.44-3.32 (m, 1H), 1.46 (s, 9H).

[0715] Step 3: N-(2-Amino-phenyl)-4-[2-(3,4-dimethoxy-phenyl)-4,5-dihydro-oxazol-5-yl]-benzamide (305)

[0716] Following a procedure analogous to that described in Example 172, step 4, 5, but substituting 304 for 300, the title compound 305 was obtained in 63%. 1H NMR (CDCl3) δ (ppm): 8.02 (s, 1H), 7.93 (d, J=8.1 Hz, 2H), 7.63 (dd, J=8.4, 1.8 Hz, 1H), 7.60 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.33 (d, J=7.5 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 6.85 (d, J=8.1 Hz, 2H), 5.74 (dd, J=10.0, 7.8 Hz, 1H), 4.51 (dd, J=14.5, 10.0 Hz, 1H), 4.00-3.90 (m, 7H). 885

Example 178

[0717] Step 1:[2-(4-formyl-benzoylamino)-phenyl]-carbamic Acid Tert-Butyl Ester (315)

[0718] To a suspension of 4-carboxybenzaldehyde (6 g, 40 mmol) in dichloromethane (10 mL) was added thionyl chloride (4.1 mL, 56 mmol, 1.4 eq), followed by DMF (1 mL) dropwise. The mixture was refluxed for 4 hours and excess of thionyl chloride and DMF were removed under reduced pressure. To a solution of (2-aminophenyl)-carbamic acid tert-butyl ester (8.32 g, 40 mmol, 1 eq) in dichloromethane (80 mL), stirred at 0° C., was added a suspension of 4-formyl benzoyl chloride in dichloromethane (20 mL), followed by diisopropyl ethylamine (3.61 mL, 20 mmol, 1 eq). The mixture was stirred for 30 minutes at 0° C. then at room temperature for 30 minutes. The crude residue was diluted with dichloromethane (300 mL) and washed with water. The combined organic layers were dried (MgSO4), filtered and concentrated under vacuo. The crude residue was purified by column chromatography on silica gel (elution 20% ethyl acetate in hexane) to give 6.1 g (45% yield) of anilide 315. 1H NMR (CDCl3): δ 10.18 (s, 1H), 9.64 (brs, 1H), 8.20 (d, J=7.9 Hz, 2H), 8.06 (d, J=7.9 Hz, 2H), 7.96 (d, J=7.9 Hz, 1H), 7.28-7.38 (m, 1H), 7.24 (d, J=4.4 Hz, 1H), 6.84 (s, 1H), 6.81 (d, J=8.8 Hz, 1H), 1.58 (s, 9H).

[0719] Step 2: (2-{4-[(3,4-Dimethoxyphenylamino)-Methyl-Benzoylamino]-Phenyl}-Carbamic Acid Tert-Butyl Ester (316)

[0720] Following a procedure analogous to that described in Example 144, step 3, but substituting the previous compound for 226, the title compound 316 was obtained in quantitative yield. 1H NMR (CDCl3): δ 9.21 (brs, 1H), 8.01 (d, J=7.9 Hz, 2H), 7.86 (d, J=7.0 Hz, 1H), 7.55 (d, J=8.3 Hz, 2H), 7.20-7.34 (m, 3H), 6.89 (brs, 1H), 6.81 (d, J=8.8 Hz, 1H), 6.37 (d, J=2.2 Hz, 1H), 6.23 (dd, J=2.6, 8.3 Hz, 1H), 4.45 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 1.58 (s, 9H).

[0721] Step 3: N-(2-Aminophenyl)-4-[1-(3,4-dimethoxyphenyl)-3-(4-methylsulfanylphenyl)-ureidomethyl]-benzamide 317

[0722] To a solution of anilide 316 (500 mg, 1.047 mmol) in chloroform/THF (1:1, 10 mL) was added isocyanate (169 μL, 1.205 mmol, 1.15 eq). The mixture was stirred overnight at room temperature under nitrogen and the crude residue was concentrated and purified by column chromatography on silica gel (elution 40% ethyl acetate in hexane) to give 606 mg (90% yield) of the desired compound. 1H NMR (CDCl3): δ 9.25 (s, 1H), 7.96 (d, J=8.3 Hz, 2H), 7.85 (d, J=7.0 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.20-7.36 (m, 6H), 6.93 (d, J=3.5 Hz, 1H), 6.90 (s, 1H), 6.75 (dd, J=2.2, 8.3 Hz, 1H), 6.68 (dd, J=2.6 Hz, 1H), 6.33 (s, 1H), 5.0 (s, 2H), 3.97 (s, 3H), 3.85 (s, 3H), 2.51 (s, 3H), 1.57 (s, 9H).

[0723] Following a procedure analogous to that described in Example 42, step 3, but substituting the previous compound for 46, the title compound 317 was obtained in 85% yield. 1H NMR (DMSO-d6): δ 10.14 (brs, 1H), 7.99 (d, J=7.9 Hz, 2H), 7.93 (s, 1H), 7.49 (d, J=8.35 Hz, 4H), 7.39 (d, J=7.5 Hz, 1H), 7.10-7.30 (2m, 5H), 6.97 (dd, J=2.2, 8.35 Hz, 1H), 6.77 (dd, J=2.2, 8.35 Hz, 1H), 5.02 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 2.48 (s, 3H). 886

Example 179

[0724] Step 1: N-(2-Amino-phenyl)-6-chloro-nicotinamide (318)

[0725] Following the procedure described in Example 42, step 2, the title compound 318 was obtained in 80% yield. LRMS=calc: 246.69, found: 247.7.

[0726] Step 2: N-(2-Amino-Phenyl)-6-(Quinolin-2-ylsulfanyl)-nicotinamide (319)

[0727] Following the procedure described in Example 45, step 1 but substituting 318 for 3,4,5-trimethoxybenzylamine, the tite compound 319 was obtained in 20% yield. 1H NMR: (CD3OD-d6) δ (ppm): 9.08 (d, J=1.9 Hz, 1H), 8.35-8.25 (m, 2H), 7.99-7.56 (m, 7H), 7.23 (dd, J=1.2, 7.9 Hz, 1H), 7.12 (dd J=1.4, 7.9, 14.0 Hz, 1H), 6.93 (dd, J=1.2, 8.0 Hz, 1H), 6.79 (ddd, J=1.4, 7.7, 13.7 Hz, 1H). 887

[0728] Step 1: 4-[(4-Morpholin-4-yl-phenylamino)-methyl]-benzoic Acid (402a).

[0729] A suspension of 4-formylbenzoic acid (2.53 g; 16.8 mmol; 1 eq), 4-morpholinoaniline (3 g; 16.8 mmol; 1 eq) and Bu2SnCl2 (510 mg; 1.68 mmol; 0.1 eq) in dry THF (20 ml) was treated with PhSiH3 (3.31 ml; 16.8 mmol; 1 eq) at room temperature for 12 h. The reaction was filtered and the solid product was washed with MeOH. The yield of the reaction was 5.25 g (99%). LRMS: calc 312.37; found: 313.2.

[0730] Step 2: N-(2-Amino-phenyl)4-[(4-morpholin-4-yl-phenylamino)-methyl]-benzamide (402)

[0731] To a solution of acid 402a (2.61 g; 8.36 mmol; 1 eq), 1,2-phenylenediamine (903 mg; 8.36 mmol; 1 eq) and BOP (3.70 g; 8.36 mmol; 1 eq) in dry DMF (20 ml) was added Et3N (4.64 ml; 33.4 mmol; 4 eq). After stirring overnight most of the DMF was removed under reduced pressure and chromatographed (Hex:EtAcO: 1:2/EtAcO). The crystal 402 was obtained in 70% (2.35 g). 1H-NMR (300.07 MHz; DMSO-d6) δ (ppm): 9.65 (s, 1H), 7.97 (d, J=7.9, 2H), 7.53 (d, J=7.9, 2H), 7.22 (d, J=7.5, 1H), 7.03 (dd, J=7.0, 7.5, 1H), 6.83 (d, J=7.9, 1H), 6.77 (d, J=8.8, 2H), 6.65 (dd, J=7.5, 7.0, 1H), 6.57 (d, J=8.8, 2H), 4.93 (bs, 2H), 4.36 (d, J=5.7, 2H), 3.75 (m, 4H), 2.93 (m, 4H). LRMS: calc 402.49; found: 403.4. 888

Example 283a

[0732] Step 1. 4-[(3,4-Dimethoxyphenylamino)-methyl]-benzoic Acid (424a)

[0733] In a 50 ml flask, a mixture of 4-aminoveratrole (1.53 g, 10 mmol), 4-formyl-benzoic acid (1.50 g, 10 mmol), dibutyltin dichloride (304 mg, 1 mmol), phenylsilane (2.47 ml, 20 mmol) in anhydrous THF (10 mL) and DMA (10 ml) was stirred overnight. at room temperature. After solvents removal, the crude residue was dissolved in ethyl acetate (100 ml) and then washed with saturated aqueous solution of NaHCO3 (50 ml x 3). The combined aqueous layers were acidified with 6% of NaHSO4 to pH=4. The resulting white suspension was filtrated and then the filter cake was washed with water (5 ml×3). The cake was dried over freeze dryer to afford acid (1.92 g, 67%) white solid product. LRMS=288 (MH)+.

[0734] Step 2. N-(2-Aminophenyl)-4-[(3,4-dimethoxyrhenylamino)-methyl]-benzamide (424b)

[0735] In a 150 ml flask, a mixture of acid (1.92 g, 6.69 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 3.26 g, 7.37 mmol), triethylamine (1.87 ml, 13.4 mmol), o-phenylenediamine (1.30 g, 12.02 mmol) in methylenechloride (67 ml) was stirred at rt for 2 h. After solvents removal, the crude residue was dissolved in EtOAc (100 ml) and then washed with NaHCO3 saturated solution and brine 50 ml. The combined organic layers were dried over Na2SO4 and the filtrate was concentrated to dryness. The crude material was submitted to a chromatographic purification (column silica, 55%-70% EtOAc in 1% Et3N of hexanes) and then the all interested fractions were concentrated to dryness. The residue was suspended in minimum quantities of ethyl acetate and then filtered to afford final product (1.49 g, 59%). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 9.65 (s, 1H), 7.98 (d, J=7.9 Hz, 2H), 7.54 (d, J=7.9 Hz, 2H), 7.22 (d, J=7.9 Hz, 1H), 7.02 (dd, J=7.9, 7.9 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 6.72 (d, J=8.79 Hz, 1H), 6.45 (dd, J=7.5, 7.5 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 6.01-6.08 (m, 2H), 4.94 (s, 2H, NH2), 4.36 (d, J=6.16 Hz, 2H), 3.72 (s, 3H), 3.65 (s, 3H).

Example 283b

[0736] Step 1: N-(4-Aminothiophen-3-yl)-4-[(3,4-dimethoxyphenylamino)-methyl]-benzamide:

[0737] Acid 424a (1040 mg; 3.62 mmol); 3,4-diaminothiophene dihydrochloride (1017 mg; 5.44 mmol; 1.50 eq.) and BOP (1770 mg; 4.0 mmol; 1.1 eq.) were suspended in MeCN, treated with triethylamine (4 mL; 29 mmol) and stirred for 18 h at room temperature; concentrated and purified by chromatographic column on silica gel (elution 50% EtOAc in DCM) to render 527 mg (1.37 mmol; 38% yield) of compound 424c which was 90% pure. 1H-NMR (300.07 MHz; DMSO-d6) δ (ppm): 8.56 (s, 1H), 7.78 (d, J=7.9 Hz, 2H), 7.43 (d, J=3.5 Hz, 1H), 7.38 (d, J=7.9 Hz, 2H), 6.73 (d, J=8.8 Hz, 1H), 6.33 (d, J=3.5 Hz, 1H), 6.58 (d, J=2.6 Hz, 1H), 6.13 (dd, J=2.6, 8.3 Hz, 1H), 4.33 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H). LRMS: calc: 383.4642; found: 384.2 (M+H); 406.2 (M+Na) and 192.6 (M+2H)/2. 889

[0738] Step 1: Methyl-(5-nitrobenzothiazol-2-yl)-amine (456a)

[0739] A mixture of 2-fluoro-5-nitroaniline (861 mg; 5.52 mmol; 1.02 eq); Im2CS (960.3 mg; 5.39 mmol) and dry K2CO3 (1.45 g) was suspended in dry DME (10 mL) and stirred under nitrogen for 90 min at room temperature. The yellow suspension was made fluid by diluting with DME (10 mL) followed by addition of 40% MeNH2 in water (4.0 mL; 46.5 mmol; 8.6 eq). The system was heated up to 65C and stirred at this temperature for 3.5 h, cooled down, diluted with ethyl acetate and washed with saturated NaCl (×2). After conventional work-up procedures, the dark crude mixture was purified through chromatographic column on silica gel (elution 50% EtOAc in hexane, then 5% MeOH in DCM), to afford 836.8 mg (4.0 mmol; 72% yield) of compound 456a.

[0740] Step 2: N-Methyl-benzothiazole-2,5-diamine (456b)

[0741] A mixture of nitro compound 456a (593 mg; 2.83 mmol); SnCl2 (4.02 g; 20.8 mmol; 7.35 eq) and NH4OAc (4.5 g) was suspended in THF:MeOH:H2O=1:1:1 (60 mL) and stirred at 70° C. for 2 h, cooled down, diluted with ethyl acetate and successively washed with saturated NaHCO3 and brine; dried (MgSO4) filtered and concentrated. The residue (443 mg; 2.43 mmol; 87%) showed consistent spectrum and suitable purity degree for synthetic purposes, therefore was submitted to the next step without further purification.

[0742] Step 3: 4-[2-Methylaminobenzothiazol-5-Ylamino)-Methyl]-Benzoic Acid (456c)

[0743] A solution of aniline 456b (509 mg; 2.8 mmol); 4-formylbenzoic acid (426 mg; 2.8 mmol) and Bu2SnCl2 (198 mg; 0.65 mmol; 23% mol) in DME (14 mL) was stirred at room temperature for 3 min and treated with neat PhSiH3 (0.6 mL; 4.7 mmol; 1.7 mmol) and allowed to react for 18 h. After quenching the excess of silane with MeOH, the mixture was concentrated and purified by chromatographic column on silica gel (elution 5% MeOH in DCM) to give 729 mg (2.54 mmol; 91% yield) of acid 456c.

[0744] Step 4: N-(2-Aminophenyl)-4-[(2-methylaminobenzothiazol-5-ylamino)-methyl]-benzamide (456)

[0745] A mixture of acid 456c (729 mg; 2.54 mmol), 1,2-phenylenediamine (376 mg; 3.47 mmol; 1.36 eq) and BOP (1.43 g; 3.23 mmol; 1.27 eq) was dissolved in acetonitrile (15 mL), treated with triethylamine (3 mL) and stirred overnight. The reaction mixture was quenched with methanol, concentrated and purified by chromatographic column on silica gel (40% EtOAc in DCM) and the obtained material crystallized from DCM to give 358 mg (0.88 mmol; 35% yield) of pure compound 456. 1H-NMR (300 MHz; DMSO-d6) δ (ppm): 9.57 (s, 1H), 7.92 (d, J=7.9 Hz, 2H), 7.66 (d, J=4.8 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 6.95 (t, J=7.5 Hz, 1H), 6.76 4.87 (bs, 2H), 6.58 (t, J=7.5 Hz, 1H), 6.54 (d, J=1.8 Hz, 1H), 6.13 (dd, J=1.8, 8.3 Hz, 1H), 6.27 (t, J=.5.7 Hz, 1H), 4.87 (bs, 2H), 4.36 (d, J=5.7 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H). LRMS: calc: 403.5008, found: 404.2 (M+NH) and 202.6 (M+2H)/2. 890

Example 235

[0746] Step 1: Methyl-4-(5-methoxy-1H-benzimidazol-2-yl-sulfanylmethyl)-benzoate (376a)

[0747] To a solution 5-methoxy-2-thiobenzimidazole (2.00 g, 11.1 mmol of in anhydrous DMF (40 ml) was added methy-4-(bromomethyl)-benzoate (2.54 g, 11.1 mmol). The reaction mixture was stirred 16 h at room temperature. The DMF was evaporated and the residue was triturated in ethyl acetate during 30 min and then filtered and dried. The desired compound was isolated as the HBr salt: 98% yield, (4.44 g). 1H NMR: (DMSO) δ (ppm): 7.90 (d, J=8.8 Hz, 2H), 7.56-7.52 (m, 3H), 7.09 (d, J=2.2 Hz, 1H), 7.01 (dd, J=8.8, 2.2 Hz, 1H), 4.73 (s, 2H), 3.82 (s, 6H). MS: (calc.) 328.1, (obt.), 329.2 (MH)+.

[0748] Step 2: 4-(5-Methoxy-1H-benzimidazol-2-yl-sulfanylmethyl)-benzoic Acid (376b)

[0749] A solution of LiOH.H2O (1.02 g, 24.4 mmol) in water (15 ml) was added to a suspension of 376a (3.99 g, 9.75 mmol of in THF (10 ml). The reaction mixture was stirred 16 h at room temperature. The reaction mixture was acidified with a solution of HCl 1 M to pH 4. The desired product was triturated 20 min. at 0° C. and then filtered and dried. Compound 376b was obtained as a white powder (100% yield, 3.05 g). 1H NMR: (DMSO) δ (ppm): 12.85 (bs, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.76 (dd, J 8.8, 2.2 Hz, 1H), 4.60 (s, 2H), 3.82 (s, 3H). MS: (calc.) 314.1, (obt.), 315.1 (MH)+.

[0750] Step 3: N-(2-Amino-phenyl)-4-(5-methoxy-1H-benzimidazol-2-yl-sulfanylmethyl)-benzamide (376)

[0751] Following the procedure described in Example 1 step 5 but substituting 445-methoxy-1H-benzimidazol-2-yl-sulfanylmethyl)-benzoic acid 2 for 7 the title compound 376 was obtained as a white powder: 36% yield (933 mg). 1H NMR: (DMSO) δ (ppm): 12.42 (bs, 1H), 9.57 (bs, 1H), 7.89 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.8 Hz, 1H), 7.14 (d, J=7.3 Hz, 1H), 6.98-6.93 (m, 2H), 6.77-6.55 (m, 2H), 6.58 (dd, J=7.3, 7.3 Hz, 1H), 4.87 (s, 2H), 4.59 (s, 2H), 3.77 (s, 3H). MS: (calc.) 404.1, (obt.), 405.4 (MH)+.

ExampleS 180-328

[0752] Examples 180 to 327 (compounds 320-468) were prepared using the same procedure as described for compound 126 to 319 in Example 85 to 179 (scheme 11 to 58).

ExampleS 329-344

[0753] Examples 329 to 344 (compounds 470-485) were prepared using the same procedure as described for compound 8 to 224 in Example 1 to 143 (scheme 1 to 32). 891

Example 345

[0754] Step 1: Methyl 3-(4-bromo-Phenyl)-acrylic Ester (486)

[0755] To a solution of anhydrous i-Pr2NH (758 μl, 5.40 mmol) in anhydrous THF (25 ml) stirred at 0° C. under nitrogen, was slowly added a solution of n-BuLi (2.22 ml, 5.54 mmol, 2.5 M in hexane). After 30 min, LDA was cooled to −78° C. and anhydrous methyl acetate (430 l, 5.40 mmol) was added dropewise. After 30 min, a solution of 4-bromobenzaldehyde (500 mg, 2.70 mmol) in anhydrous THF (10 ml) was slowly added. After 30 min, a solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine (569 mg, 3.24 mmol) in anhydrous THF (15 ml) was added. Then, the temperature was allowed to warm up to room temperature overnight. A suspension appeared. The reaction mixture was poured into a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (AcOEt/hexane: 10/90) to give the title product 486 (394 mg, 1.9 mmol, 61% yield) as a colorless crystalline solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.63 (d, J=16.2 Hz, 1H), AB system (δA=7.53, δB=7.39, J=8.4 Hz, 4H), 6.43 (d, J=15.8 Hz, 1H), 3.82 (s, 3H).

[0756] Step 2: Methyl 3-[4-(3,4,5-trimethoxy-Phenylamino)-phenyl]-acrylic Ester (487)

[0757] A mixture of Cs2CO3 (378 mg, 1.16 mmol), Pd(OAc)2 (6 mg, 0.025 mmol), (rac)-BINAP (23 mg, 0.037 mmol), was purged with nitrogen for 10 min. 486 (200 mg, 0.83 mmol), 3,4,5-trimethoxyaniline (182 mg, 0.99 mmol), and anhydrous toluene (5 ml) were added, respectively. The reaction mixture was heated to 100° C. under nitrogen for 24 h. Then, it was allowed to cool to room temperature, diluted with AcOEt, and successively washed with a saturated aqueous solution NaHCO3, H2O, sat. NH4C1, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane: 40/60) to afford the title compound 487 (280 mg, 0.82 mmol, 98% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.64 (d, J=16.2 Hz, 1H), 7.43 (bd, J=7.9 Hz, 2H), 7.12-6.86 (m, 2H), 6.60-6.20 (m, 3H, included at 6.29, d, J=15.8 Hz), 3.84 (s, 9H), 3.80 (s, 3H).

[0758] Step 3: N-(2-Amino-phenyl)-3-[4-(3,4,5-trimethoxy-phenylamino)-phenyl]-acrylamide (488)

[0759] The title compound 488 was obtained from 487 in 2 steps following the same procedure as Example 1, steps 4 and 5. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 9.29 (s, 1H), 8.48 (s, 1H), 7.60-7.42 (m, 3H), 7.38 (d, J=7.5 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.94 (t, J=7.5 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.71 (d, J=15.8 Hz, 1H), 6.61 (t, J=7.1 Hz, 1H), 6.47 (s, 2H), 4.97 (s, 2H), 3.79 (s, 6H), 3.66 (s, 3H). 892

Example 346

[0760] Step 1: 3-(4-Formyl-3-methoxy-phenyl)-acrylic Acid Tert-Butyl Ester 489

[0761] Following the procedure described in Example 53, step 1, but substituting 4-hydroxy-2-methoxy-benzaldehyde for 84, followed by Example 42, step 2, but substituting the previous compound for 42, the title compound 489 was obtained in 29% yield. LRMS=calc: 262, found: 263.2 (M+H+).

[0762] Step 2: 3-{3-Methoxy-4-[(3,4,5-trimethoxy-phenylamino)-methyl]-phenyl}-acrylic Acid Tert-Butyl Ester

[0763] Following the procedure described in Example 144, step 3, but substituting 489 for 4-formylbenzaldehyde, the title compound 490 was obtained in 69% yield. LRMS=calc: 429, found: 430.5 (M+H+).

[0764] Step 3: N-(2-Amino-phenyl)-3-{3-methoxy-4-[(3,4,5-trimethoxy-phenylamino)-methyl]-phenyl}-acrylamide 491

[0765] Following the procedure described in Example 42, step 3, 4, but substituting 490 for 46, the title compound 491 was obtained in 67% yield. 1H NMR (CDCl3), δ (ppm): 8.08 (s, 1H), 7.74 (d, J=15.4 Hz, 1H), 7.30 (m, 1H), 7.06 (m, 3H); 6.80 (m, 3H), 6.70 (d, J=15.4 Hz, 1H), 5.98 (s, 2H), 4.40 (s, 2H); 4.12 (bs, 3H), 3.94 (s, 3H), 3.84 (s, 3H), 3.77 (s, 6H). 893

Example 436

[0766] Step 1: Methyl-5-methyl-benzofuran-2-carboxylate (583)

[0767] A stirring suspension of 5-methylsalicylaldehyde (1.0 mg, 7.5 mmol), K2CO3(1.55 g, 11.0 mmol), and Bu4NBr (322 mg, 1 mmol) in toluene (30 ml) was treated with dimethylbromomalo-nate (1.06 ml, 8.0 mmol). The suspension was heated to reflux with a Dean-Stark trap for 20 h. The brown suspension was cooled to 25° C. and concentrated in vacuo. The residue was taken in DCM and filtered. The filtrate was washed with H2O, 1N NaOH and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (10% ethyl acetate/hexane) to afford the title compound 583 (600 mg, 42% yield). LRMS: 190.2 (Calc.); 191.1 (found).

[0768] Step 2: Methyl-5-bromomethyl-benzofuran-2-carboxylate (585)

[0769] A mixture of 583 (500 mg, 2.63 mmol), N-bromosuccinimide (561 mg, 3.15 mmol) and 1,1′-azobis(cyclohexanecarbonitrile) (Vazo) (63 mg, 0.26 mmol) in 15 ml of CCl4 was heated overnight under reflux. The mixture was cooled to room temperature, quenched by adding water and extracted with DCM. The organic layer was washed with brine and dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (30% ethyl acetate/hexane) to afford the title compound 585 (680 mg, 960% yield). 1H NMR: (CDCl3) δ (ppm): 7.79 (s, 1H), 7.70-7.52 (m, 3H), 4.69 (s, 2H), 4.06 (s, 3H), 3.72 (s, 2H). LRMS: 268.2 (Calc.); 269.1 (found).

[0770] Step 3: Methyl-5-[(3,4-dimethoxy-phenylamino)-methyl]-benzofuran-2-carboxylate (586)

[0771] Following the procedure described in Example 47, step 2, but substituting 585 for 63, the title compound 586 was obtained in 40% yield. LRMS: 341 (Calc.); 342.3 (found).

[0772] Step 4: 5-[(3,4-Dimethoxy-Phenylamino)-methyl]-benzofuran-2-carboxylic Acid (2-amino-phenyl)-amide (587)

[0773] Following the procedure described in Example 1, steps 4,5, but substituting 585 for 6, the title compound 587 was obtained in 29% yield. 1H NMR: (DMSO) δ (ppm): 9.83 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 6.97 (t, J=7.5 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H), 6.59 (t, J=7.5 Hz, 1H), 6.33 (s, 1H), 6.04 (d, J=8.0 Hz, 1H), 5.92 (d, J=5.5 Hz, 1H), 4.93 (s, 2H), 4.31 (d, J=5.5 Hz, 1H), 2.82 (s, 3H), 2.76 (s, 3H). LRMS: 417.46 (Calc.); 418.4 (found).

Example 437

[0774] Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584)

[0775] A stirring suspension of 5-nitro-2-chloro-benzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5° C. was treated with K2CO3(3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25° C. and stirred for 20 h. The solution was then poured into 250 ml of ice H2O and the white precipitate that formed was collected by filtration. Crystallization from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69%). LRMS: 237.0 (Calc.); 238.1 (found). 1H NMR: (DMSO) δ (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).

[0776] Step 2: Methyl-5-amino-benzo[b]thiophene-2-carboxylate (588)

[0777] A suspension of 584 (3.52 g, 14.8 mmol) in methanol (100 ml) was treated with Fe powder (6.63 g, 118.7 mmol). The resulting suspension was heated to reflux, and 12M HCl (8.5 ml) was slowly added over 15 min. The resulting green dark suspension was refluxed for an additional 3 h, then cooled and concentrated. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3, then brine, dried over MgSO4, filtered and concentrated to afford (2.57 g, 84%). 1H NMR: (DMSO) δ (ppm): 7.92 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H), 6.88 (dd, J=1.8, 8.4 Hz, 1H), 5.27 (s, 2H), 3.85 (s, 3H). LRMS: 207.0 (Calc.); 208.1 (found).

[0778] Step 3: Methyl-5-(3,4,5-trimethoxy-benzylamino)-benzo[b]thiophene-2-carboxylate (589)

[0779] Following the procedure described in Example 144, step 3, but substituting 588 for 226, the title compound 589 was obtained in 68% yield. (DMSO) δ (ppm): 7.94 (s, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.02-6.99 (m, 2H), 6.73 (s, 2H), 6.41 (t, J=5.7 Hz, 1H), 4.21 (d, J=5.9 Hz, 2H), 3.84 (s, 3H), 3.75 (s, 6H), 3.62 (s, 3H). LRMS: 387.1 (Calc.); 388.3 (found).

[0780] Step 4: 5-(3,4,5-Trimethoxy-benzylamino)-benzo[b]thiophene-2-carboxylic Acid (2-amino-Phenyl)-amide (590)

[0781] Following the procedure described in Example 1, steps 4,5, but substituting 589 for 6, the title compound 590 was obtained in % yield 1H NMR: (DMSO) δ (ppm): 7.79 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.00-6.95 (m, 2H), 6.74 (s, 2H), 4.32 (s, 2H), 3.80 (s, 6H), 3.73 (s, 3H).

ExampleS 347-425

[0782] Examples 347 to 425 (compounds 492-570) were prepared using the same procedure as described for compound 44 to 491 in Example 40 to 346 (scheme 3 to 64).

Example 426

Synthesis of N-(2-Amino-phenyl)-4-[(4-pyridin-3-yl-pyrimidin-2-ylamino)-methyl]-benzamide

[0783] 894

[0784] Step 1: Synthesis of 4-Guanidinomethyl-benzoic Acid Methyl Ester Intermediate 1

[0785] The mixture of 4-Aminomethyl-benzoic acid methyl ester HCl (15.7 g, 77.8 mmol) in DMF (85.6 mL) and DIPEA (29.5 mL, 171.2 mmol) was stirred at rt for 10 min. Pyrazole-1-carboxamidine HCl (12.55 g, 85.6 mmol) was added to the reaction mixture and then stirred at rt for 4 h to give clear solution. The reaction mixture was evaporated to dryness under vacuum. Saturated NaHCO3 solution (35 mL) was added to give nice suspension. The suspension was filtered and the filter cake was washed with cold water. The mother liquid was evaporated to dryness and then filtered. The two solids were combined and re-suspended over distilled H2O (50 ml). The filter cake was then washed with minimum quantities of cold H2O and ether to give 12.32 g white crystalline solid intermediate 1 (77% yield, M+1: 208 on MS).

[0786] Step 2: Synthesis of 3-Dimethylamino-1-pyridin-3-yl-propenone Intermediate 2

[0787] 3-Acetyl-pyridine (30.0 g, 247.6 mmol) and DMF dimethyl acetal (65.8 mL, 495.2 mmol) were mixed together and then heated to reflux for 4 h. The reaction mixture was evaporated to dryness and then 50 mL diethyl ether was added to give brown suspension. The suspension was filtered to give 36.97 g orange color crystalline product (85% yield, M+1: 177 on MS).

[0788] Step 3: Synthesis of 4-[(4-Pyridin-3-yl-pyrimidin-2-ylamino)-methyl]-benzoic Acid Methyl Ester Intermediate 3

[0789] Intermediate 1 (0.394 g, 1.9 mmol) and intermediate 2 (0.402 g, 2.3 mmol) and molecular sieves (0.2 g, 4A, powder, >5 micron) were mixed with isopropyl alcohol (3.8 mL). The reaction mixture was heated to reflux for 5 h. MeOH (50 mL) was added and then heated to reflux. The cloudy solution was filtrated over a pad of celite. The mother liquid was evaporated to dryness and the residue was triturated with 3 mL EtOAc. The suspension was filtrated to give 0.317 g white crystalline solid Intermediate 3 (52%, M+1: 321 on MS).

[0790] Step 4: Synthesis of N-(2-Amino-phenyl)-4-[(4-pyridin-3-yl-pyrimidin-2-ylamino)-methyl]-benzamide

[0791] Intermediate 3 (3.68 g, 11.5 mmol) was mixed with THF (23 mL),MeOH (23 mL) and H2O (11.5 mL) at rt. LiOH (1.06 g, 25.3 mmol) was added to reaction mixture. The resulting reaction mixture was warmed up to 40° C. overnight. HCl solution (12.8 mL, 2N) was added to adjust pH=3 when the mixture was cooled down to rt. The mixture was evaporated to dryness and then the solid was washed with minimum quantity of H2O upon filtration. The filter cake was dried over freeze dryer to give 3.44 g acid of the title compound (95%, M+1: 307 on MS).

[0792] Acid (3.39 g, 11.1 mmol) of the title compound, BOP (5.679 g, 12.84 mmol) and o-Ph(NH2)2 (2.314 g, 21.4 mmol) were dissolved in the mixture of DMF (107 mL) and Et3N (2.98 mL, 21.4 mmol). The reaction mixture was stirred at rt for 5 h and then evaporated to dryness. The residue was purified by flash column (pure EtOAc to 5% MeOH/EtOAc) and then interested fractions were concentrated. The final product was triturated with EtOAc to give 2.80 g of title product (66%, MS+1: 397 on MS). 1H NMR (400 MHz, DMSO-D6) δ (ppm): 9.57 (s, 1H), 9.22 (s, 1H), 8.66 (d, J=3.5 Hz, 1H), 8.39 (d, J=5.1 Hz, 2H), 8.00 (t, J=6.5 Hz, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.50 (m, 3H), 7.25 (d, J=5.1 Hz, 1H), 7.12 (d, J=7.4 Hz, 1H), 6.94 (dd, J=7.0, 7.8 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 6.57 (dd, J=7.0, 7.8 Hz, 1H), 4.86 (s, 2H), 4.64 (d, J=5.9 Hz, 2H).

ASSAY Example 1

Inhibition of Histone Deacetylase Enzymatic Activity

[0793] 1. Human HDAC-1

[0794] HDAC inhibitors were screened against a cloned recombinant human HDAC-1 enzyme expressed and purified from a Baculovirus insect cell expression system. For deacetylase assays, 20,000 cpm of the [3H]-metabolically labeled acetylated histone substrate (M. Yoshida et al., J. Biol. Chem. 265(28): 17174-17179 (1990)) was incubated with 30 gg of the cloned recombinant hHDAC-1 for 10 minutes at 37° C. The reaction was stopped by adding acetic acid (0.04 M, final concentration) and HCl (250 mM, final concentration). The mixture was extracted with ethyl acetate and the released [3H]-acetic acid was quantified by scintillation counting. For inhibition studies, the enzyme was preincubated with compounds at 4° C. for 30 minutes prior to initiation of the enzymatic assay. IC50 values for HDAC enzyme inhibitors were determined by performing dose response curves with individual compounds and determining the concentration of inhibitor producing fifty percent of the maximal inhibition. IC50 values for representative compounds are presented in the third column of Table 5.

[0795] 2. MTT Assay

[0796] HCT116 cells (2000/well) were plated into 96-well tissue culture plates one day before compound treatment. Compounds at various concentrations were added to the cells. The cells were incubated for 72 hours at 37° C. in 5% CO2 incubator. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide, Sigma) was added at a final concentration of 0.5 mg/ml and incubated with the cells for 4 hours before one volume of solubilization buffer (50% N,N-dimethylformamide, 20% SDS, pH 4.7) was added onto the cultured cells. After overnight incubation, solubilized dye was quantified by colorimetric reading at 570 nM using a reference at 630 nM using an MR700 plate reader (Dynatech Laboratories Inc.). OD values were converted to cell numbers according to a standard growth curve of the relevant cell line. The concentration which reduces cell numbers to 50% of that of solvent treated cells is determined as MTT IC50. IC50 values for representative compounds are presented in the fourth column of Table 5.

[0797] 3. Histone H4 Acetylation in Whole Cells by Immunoblots

[0798] T24 human bladder cancer cells growing in culture were incubated with HDAC inhibitors for 16 h. Histones were extracted from the cells after the culture period as described by M. Yoshida et al. (J. Biol. Chem. 265(28): 17174-17179 (1990)). 20 g of total histone protein was loaded onto SDS/PAGE and transferred to nitrocellulose membranes. Membranes were probed with polyclonal antibodies specific for acetylated histone H-4 (Upstate Biotech Inc.), followed by horse radish peroxidase conjugated secondary antibodies (Sigma). Enhanced Chemiluminescence (ECL) (Amersham) detection was performed using Kodak films (Eastman Kodak). Acetylated H-4 signal was quantified by densitometry. Representative data are presented in the fifth column of Table 5. Data are presented as the concentration effective for reducing the acetylated H-4 signal by 50% (EC50).

TABLE 5
Inhibition of Histone Deacetylase
		HumanHDAC-1	MTT(HCT116)	H4Ac(T24)
Cpd	Structure	IC50(μM)	IC50(μM)	EC50(μM)
8	895	0.4	0.5	1
9	896	2	0.7	5
10	897	2	0.6	1
11	898	2	0.6	2
12	899	2	2	5
14	900	0.3	1	5
15	901	0.5	0.2	3
16	902	1	0.4	1
17	903	0.9	1	2
18	904	0.8	0.6	3
18b	905	0.6	5	10
19	906	0.9	1	1
20	907	0.5	0.3	1
21	908	4	4	25
22	909	3	0.8	1
23	910	2	0.7	1
24	911	3	0.6	1
25	912	0.8	0.3	5
26	913	0.5	2	na
27	914	0.4	2	na
28	915	2	0.5	1
29	916	2	2	1
30	917	1	3	1
83	918	3	5	5
(na = not available; 99 = > 25 μM)
919
			Human HDAC-1	MTT(HCT116)	H4Ac(T24)
Ex	Cpd	Structure	IC50(μM)	IC50(μM)	EC50(μM)
135	204	920	4	na	5
136	207	921	0.4	0.6	2
137	210	922	3	0.9	1
138	212	923	3	1	1
139	214	924	3	0.9	1
140	216	925	0.5	0.4	2
141	218	926	0.1	0.5	na
142	220	927	7	6	na
143a	223	928	11	2	na
143b	224	929	5	3	na
329	470	930	2	0.7	3
330	471	931	0.4	1	3
331	472	932	3	1	1
332	473	933	4	3	na
333	474	934	3	1	1
334	475	935	0.6	2	na
335	476	936	2	1	2
336	477	937	1	0.7	na
337	478	938	3	0.7	na
338	479	939	0.4	0.6	na
339	480	940	0.8	0.5	na
340	481	941	6	0.7	na
341	482	942	0.1	0.7	na
342	483	943	4	na	na
343	484	944	2	0.3	na
344	485	945	0.4	3	na
(na = nonavailable)
		HumanHDAC-1	MTT(HCT116)	H4Ac(T24)
Cpd	Structure	IC50(μM)	IC50(μM)	EC50(μM)
51	946	22	4	na
55b	947	3	8	3
59	948	12	22	na
61b	949	7	12	na
65	950	4	37	na
71	951	10	44	na
72	952	16	21	na
88	953	na	>39	na
90	954	10	5	5
91	955	4	7	5
92	956	5	2	3
93	957	3	1	5
94	958	3	2	5
95	959	3	2	10
96	960	4	3	25
97	961	10	12	na
98	962	0.4	2	15
99	963	2	5	10
100	964	4	3	5
101	965	3	0.9	5
102	966	20	6	na
104	967	10	9	5
105	968	16	14	na
106	969	2	2	1
107	970	15	17	na
108	971	3	5	5
109	972	5	8	15
110	973	3	999	na
111	974	10	2	99
112	975	2	5	5
113	976		0.3	5
114	977	25	0.5	99
115	978	15	9	na
116	979	4	2	5
117	980	7	3	na
118	981	11	8	na
			HDAC-1	MTT(HCT116)	H4Ac(T24)
Ex.	Cpd	Structure	IC50(μM)	IC50(μM)	EC50(μM)
338	481	982	22	10	—
339	484	983	20	12	—
347	492	984	4	9	10
348	493	985	4	5	—
349	494	986	3	4	—
350	495	987	4	7	—
351	496	988	8	13	—
352	497	989	15	6	—
353	498	990	>25	—	—
354	499	991	>25	2	>25
355	500	992	23	37	—
356	501	993	4	10	—
357	502	994	3	>25	—
358	503	995	5	>25	—
359	504	996	5	>25	—
360	505	997	3	6	—
361	506	998	15	11	—
362	507	999	17	10	—
363	508	1000	22	11	—
364	509	1001	17	11	—
365	510	1002	6	5	—
366	511	1003	4	>25	—
367	512	1004	3	3	5
371	516	1005	15	15	—
372	517	1006	6	5	—
373	518	1007	4	2	5
374	519	1008	99	6	—
375	520	1009	5	3	—
376	521	1010	5	2	10
377	522	1011	17	30	—
378	523	1012	8	6	10
379	524	1013	3	2	3
380	525	1014	3	4	5
381	526	1015	2	0.8	1
382	527	1016	4	3	—
383	528	1017	20	32	—
384	529	1018	5	17	—
385	530	1019	8	9	—
386	531	1020	3	2	20
387	532	1021	3	5	—
388	533	1022	5	11	—
389	534	1023	3	5	—
390	535	1024	4	6	—
391	536	1025	18	9	—
392	537	1026	11	2	>25
393	538	1027	4	12	—
394	539	1028	2	10	—
395	540	1029	10	10	—
396	541	1030	4	12	—
397	542	1031	2	5	4
398	543	1032	15	>25	—
399	544	1033	17	45	—
400	545	1034	2	12	—
401	546	1035	3	10	—
402	547	1036	4	8	—
403	548	1037	3	9	—
404	549	1038	4	19	—
405	550	1039	4	15	—
406	551	1040	24	9	—
407	552	1041	4	22	—
408	553	1042	4	12	—
409	554	1043	15	12	—
410	555	1044	14	7	—
411	556	1045	1	0.4	15
412	557	1046	4	6	—
413	558	1047	7	10	—
414	559	1048	4	11	—
415	560	1049	21	6	—
416	561	1050	>25	>25	—
417	562	1051	5	5	—
418	563	1052	24	6	—
419	564	1053	>25	>25	—
420	565	1054	5	17	—
421	566	1055	3	16	—
422	567	1056	13	3	—
423	568	1057	>25	39	—
424	569	1058	18	6	—
425	570	1059	6	0.6	2
		Human HDAC-1	MTT(HCT116)	H4 Ac (T24)
Cpd	Structure	IC50 (μM)	IC50 (μM)	EC50 (μM)
87	1060	2	1	5
126	1061	0.3	0.2	1
128	1062	1	0.3	5
131	1063	0.3	0.9	2
139	1064	3	3	5
141	1065	7	10	na
149	1066	1	5	5
152	1067	0.3	11	na
154	1068	0.3	0.4	<1
155	1069	0.4	0.4	1
157	1070	2	0.6	1
158	1071	0.4	0.2	1
164	1072	3	2	3
165	1073	9	4	25
166	1074	2	5	5
167	1075	4	0.5	2
168	1076	3	0.8	2
169	1077	0.3	0.7	1
171	1078	8	3	25
172	1079	0.4	1	3
174	1080	4	0.4	5
175	1081	4	0.5	3
176	1082	5	1	3
177	1083	1	0.4	1
			Human HDAC-1	MTT (HCT116)	H4 Ac (T24)
Ex	Cpd	Structure	IC50 (μM)	IC50 (μM)	EC50 (μM)
117	179	1084	1	0.3	1
118	180	1085	3	2	5
119	181	1086	0.5	0.4	1
122	186	1087	2	2	2
123	187	1088	2	5	2
125	189	1089	3	2	5
126	190	1090	3	1	>5
127	192	1091	2	1	3
128	193	1092	4	16
129	194	1093	3	11
130	195	1094	7	9
131	196	1095	4	3
132	198	1096	24	14
133	199	1097	7	9
134	201	1098	11	5
144	228	1099	3	0.3	1
145	231	1100	4	1	3
146	233	1101	0.9	0.3	1
147	236	1102	5	6
148	238	1103	3	6
149	240	1104	1.8	10
150	243	1105	2	0.8	1
151	247	1106	3	0.6	2
152	249	1107	4	1	2
153	252	1108	8	1	2
154	255	1109	2	0.8	1
155	257	1110	0.4	0.4	1
156	259	1111	3	0.3	1
157	262	1112	0.5	0.3	1
158	265	1113	2	2	3
159	266	1114	0.4	0.9	2
160	269	1115	9	4
161	270	1116	4	1	5
162	272	1117	2	0.6	<1
163	275	1118	4	0.9	2
164	277	1119	4	0.3	1
165	281	1120	0.5	0.6	1
166	284	1121	3	5
167	286	1122	5	2
168	289	1123	17	5
169	290	1124	11	3
170	296	1125	20	7
171	297	1126	7	0.4	1
172	301	1127	3	3
173	305	1128	4	2
174	311	1129	0.9	0.7	1
178	317	1130	2	0.3	1
179	319	1131	4	8
180	320	1132	2		1
181	321	1133	0.5	0.3	5
182	322	1134	0.7	0.4	2
183	323	1135	1	0.6	1
184	325	1136	0.3	1	2
185	326	1137	1	1	3
186	327	1138	2	5	3
187	328	1139	17	10
189	330	1140	3	2	1
190	331	1141	4	10
191	332	1142	0.4	1	5
192	333	1143	2	0.1	1
193	334	1144	8	0.2	1
195	336	1145	1	0.4	<1
196	337	1146	3	0.6	1
197	338	1147	2	0.5	3
198	339	1148	4	3
199	340	1149	2	1	1
200	341	1150	4	1	3
201	342	1151	3	0.4	1
202	343	1152	0.5	0.3	1
203	344	1153	0.5	0.2	1
204	345	1154	0.4	0.8	1
205	346	1155	3	0.5	<1
206	347	1156	2	0.6	2
207	348	1157	2	0.3	1
208	349	1158	13	1	3
209	350	1159	2	1	5
211	352	1160	16	9
212	353	1161	3	10
213	354	1162	15	5
214	355	1163	25	10
215	356	1164	5	2
216	357	1165	4	0.4	2
217	358	1166	3	1	2
218	359	1167	2	0.3	1
219	360	1168	5	0.2	1
220	361	1169	2	0.5	1
221	362	1170	2	0.7	1
222	363	1171	1	0.3	3
223	364	1172	4	0.6
224	365	1173	3	0.6	3
225	366	1174	14	10
226	367	1175	6	2	5
230	371	1176	4	0.5	2
231	372	1177	2	0.2	1
232	373	1178	4	0.4	1
233	374	1179	2.5	0.3	1
234	375	1180	3	4	25
235	376	1181	3	0.1	1
236	377	1182	4	2	3
237	378	1183	2	0.7	2
238	379	1184	2	0.6	15
239	380	1185	6	8
240	381	1186	2	1	2
241	382	1187	3	1	3
242	383	1188	2	0.5	2
243	384	1189	3	2	5
244	385	1190	3	1	2
245	386	1191	3	1	1
246	387	1192	2	1	1
247	388	1193	3	0.4	5
248	389	1194	3	0.2	1
249	390	1195	2	0.8	5
250	391	1196	1	0.9	3
251	392	1197	4	1	1
252	393	1198	4	0.6	1
253	394	1199	4	2	25
254	395	1200	2	1	5
255	396	1201	2	0.7	5
256	397	1202	1	0.6	4
258	399	1203	14	9
259	400	1204	8	0.3	2
260	401	1205	6	0.3	2
261	402	1206	14	0.4	1
262	403	1207	1	0.2	1
263	404	1208	3	0.6	5
264	405	1209	5	1	5
265	406	1210	3	11
266	407	1211	3	2
267	408	1212	4	2
268	409	1213	3	1	9999
269	410	1214	0.9	0.1	>5
270	411	1215	2		1
271	412	1216	3	2	3
272	413	1217	2	2	3
273	414	1218	3	1	1
274	415	1219	3	1	3
275	416	1220	3	0.6	1
276	417	1221	3	1	1
277	418	1222	3	0.9	2
278	419	1223	2	1	5
279	420	1224	3	0.7	1
280	421	1225	4	0.6	1
281	422	1226	<0.05	0.9	5
282	423	1227	0.5	1	3
283a	424b	1228	2	0.4	1
283b	424c	1229	3	0.8	3
284	425	1230	2	0.6	5
285	426	1231	2	1	10
286	427	1232	0.6	2	1
287	428	1233	0.7	0.7	1
288	429	1234	4	0.9	1
289	430	1235	5	0.7	1
290	431	1236	5	5
291	432	1237	2	1	3
292	432	1238	2	0.6	1
293	434	1239	4	0.6	2
294	435	1240	3	0.6	1
295	436	1241	5	0.8	5
296	437	1242	3	0.4	1
297	438	1243	5	0.6	1
298	439	1244	3	0.4	1
299	440	1245	4	0.1	2
300	441	1246	2	0.8	2
301	442	1247	17	0.4	1
302	443	1248
303	444	1249
304	445	1250	16	6
305	446	1251	21	7
307	448	1252	3	0.2	2
308	449	1253	1	6
309	450	1254	3	2
310	451	1255	4	0.2	3
311	452	1256	3	0.3	2
312	453	1257	9999	37
313	454	1258	4	2	5
314	455	1259	4	0.7	1
315	456	1260	3	0.4	8888
316	457	1261	9999	9999
317	458	1262	3	0.3	2
318	459	1263	4	0.3	1
319	460	1264	3	1	1
320	461	1265	1.4	0.3	1
321	462	1266	4	0.3	1
322	463	1267	12	6
323	464	1268	4	11
324	465	1269	2	9999	9999
325	466	1270	3	2	1
326	467	1271	4	0.4	2
327	468	1272	2	8	<1
426	571	1273	4	11
427	572	1274	1.5	5	5
428	573	1275	7	0.4	1
429	574	1276	13	0.7	3
430	575	1277	2	0.2	1
431	576	1278	5	6
432	577	1279	2	0.5	2
433	578	1280	0.6	0.1	1
434	579	1281	2	0.5	1
435	580	1282	4	0.3	<1
436	587	1283	5	0.8	2
437	590	1284	2	2	3
438	591	1285	4	0.3	<1
439	592	1286	5	0.4	<1

ASSAY Example 2

Antineoplastic Effects of Histone Deacetylase Inhibitors on Human Tumor Xenografts In Vivo

[0799] Eight to ten week old female BALB/c nude mice (Taconic Labs, Great Barrington, N.Y.) were injected subcutaneously in the flank area with 2×106 preconditioned HCT116 human colorectal carcinoma cells. Preconditioning of these cells was done by a minimum of three consecutive tumor transplantations in the same strain of nude mice. Subsequently, tumor fragments of approximately 30 mgs were excised and implanted subcutaneously in mice, in the left flank area, under Forene anesthesia (Abbott Labs, Geneve, Switzerland). When the tumors reached a mean volume of 100 mm3, the mice were treated intravenously, subcutaneously, or intraperitoneally by daily injection, with a solution of the histone deacetylase inhibitor in an appropriate vehicle, such as PBS, DMSO/water, or Tween 80/water, at a starting dose of 10 mg/kg. The optimal dose of the HDAC inhibitor was established by dose response experiments according to standard protocols. Tumor volume was calculated every second day post infusion according to standard methods (e.g., Meyer et al., Int. J. Cancer 43: 851-856 (1989)). Treatment with the HDAC inhibitors according to the invention caused a significant reduction in tumor weight and volume relative to controls treated with vehicle only (i.e., no HDAC inhibitor). In addition, the level of histone acetylation when measured was significantly elevated relative to controls. Data for selected compounds are presented in Table 6. FIG. 1 shows the full experimental results for compound 106, which inhibits tumor growth by 80%. FIGS. 2-10 show the results of additional compounds tested.

TABLE 6
Antitumor Activity in HCT 116 Colorectal Tumor Model In Vivo
Compound % Inhibition of Tumor Growth
106      80a
126      62b
9        51b
87       30b
157      66a
167      58a
15       26b
168      26b
16       50b
154      23a
98       52a
a20 mg/kg i.p.
b40 mg/kg i.p.

[0800]

TABLE 7
Antineoplastic Effects Of Histone Deacetylase
Inhibitors On Nude Mice Xenograft Models
	% Inhibition Of Tumor Growth
cpd	A 549 (p.o.)	SW48 (p.o.)	A 549 (i.p.)	HCT 116 (i.p.)	SW 48 (i.p.)
106	40% (70 mg/kg)	16% (60 mg/kg)	—	—	—
164	42% (70 mg/kg)	62% (60 mg/kg)	—	37% (20 mg/kg)	99% (25 mg/kg)
228	45% (70 mg/kg)	25% (60 mg/kg)	64% (20 mg/kg)	45% (20 mg/kg)	68% (20 mg/kg)
424b	67% (50 mg/kg)	78% (30 mg/kg)	60% (50 mg/kg)	77% (75 mg/kg)	68% (25 mg/kg)

ASSAY Example 3

[0801] Combined Antineoplastic Effect of Histone Deacetylase Inhibitors and Histone Deacetylase Antisense Oligonucleotides on Tumor Cells In Vivo

[0802] The purpose of this example is to illustrate the ability of the combined use of a histone deacetylase inhibitor of the invention and a histone deacetylase antisense oligonucleotide to enhance inhibition of tumor growth in a mammal. Preferably, the antisense oligonucleotide and the HDAC inhibitor inhibit the expression and activity of the same histone deacetylase.

[0803] As described in Example 126, mice bearing implanted HCT116 tumors (mean volume 100 mm3) are treated daily with saline preparations containing from about 0.1 mg to about 30 mg per kg body weight of histone deacetylase antisense oligonucleotide. A second group of mice is treated daily with pharmaceutically acceptable preparations containing from about 0.01 mg to about 5 mg per kg body weight of HDAC inhibitor.

[0804] Some mice receive both the antisense oligonucleotide and the HDAC inhibitor. Of these mice, one group may receive the antisense oligonucleotide and the HDAC inhibitor simultaneously intravenously via the tail vein. Another group may receive the antisense oligonucleotide via the tail vein, and the HDAC inhibitor subcutaneously. Yet another group may receive both the antisense oligonucleotide and the HDAC inhibitor subcutaneously. Control groups of mice are similarly established which receive no treatment (e.g., saline only), a mismatch antisense oligonucleotide only, a control compound that does not inhibit histone deacetylase activity, and a mismatch antisense oligonucleotide with a control compound.

[0805] Tumor volume is measured with calipers. Treatment with the antisense oligonucleotide plus the histone deacetylase protein inhibitor according to the invention causes a significant reduction in tumor weight and volume relative to controls.

Claims

1. A histone deacetylase inhibitor of formula (1):

2. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

3. A method of inhibiting histone deacetylase in a cell, the method comprising contacting a cell with a compound according to claim 1.

4. A method of inhibiting histone deacetylase in a cell, the method comprising contacting a cell with a composition according to claim 2.