INHIBITORS OF HISTONE DEACETYLASE CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims priority to U. S. Application 10/358, 556.

BACKGROUND OF THE INVENTION Field of the Invention [0002] This invention relates to the inhibition of histone deacetylase. More particularly, the invention relates to compounds and methods for inhibiting histone deacetylase enzymatic activity.

Summary of the Related Art [0003] 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.

[0004] Csordas, Biochem. J., 286 : 23-38 (1990) teaches that histones are subject to posttranslational acetylation of the aes-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.

[0005] 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 Joy yeast Hdal-like proteins. Grozinger et al. also teaches that the human HDAC1, HDAC2, and HDAC3 proteins are members of the first class of HDACs, and discloses new proteins, named HDAC4, HDAC5, and HDAC6, which are members of the second class of HDACs. Kao et 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.

[0006] 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.

[0007] The molecular cloning of gene sequences encoding proteins with HDAC activity has established the existence of a set of discrete HDAC enzyme isoforms. Grozinger et al., Proc. Natl. Acad. Sci. USA, 96 : 4868-4873 (1999), teaches that HDACs may be divided into two classes, the first represented by yeast Rpd3-like proteins, and the second represented by yeast Hdal-like proteins. Grozinger et al. also teaches that the human HDAC-1, HDAC-2, and HDAC-3 proteins are members of the first class of HDACs, and discloses new proteins, named HDAC-4, HDAC-5, and HDAC-6, which are members of the second class of HDACs.

Kao et al., Gene & Development 14 : 55-66 (2000), discloses an additional member of this second class, called HDAC-7. More recently, 'Hu, E. et al. J. Bio. Chem. 275 : 15254-13264 (2000) discloses the newest member of the first class of histone deacetylases, HDAC-8. It has been unclear what roles these individual HDAC enzymes play.

[0008] 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 [0009] The invention provides compounds and methods for treating cell proliferative diseases. The invention provides new inhibitors of histone deacetylase enzymatic activity.

[0010] In a first aspect, the invention provides compounds that are useful as inhibitors of histone deacetylase.

[0011] 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.

[0012] 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.

[0013] 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 [0014] Figure 1 is a graph showing the antitumor activity of compound 106 in an HCT 116 human colorectal tumor model.

[0015] Figures 2-11 show additional data for other compounds used in the in vivo experiment described in Assay Example 2.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0016] 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.

[0017] For purposes of the present invention, the following definitions will be used (unless expressly stated otherwise) : [0018] 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 aes-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.

[0019] 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%.

[0020] 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.

[0021] 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.

[0022] The term"hydrocarbyl"refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, each as defined herein. A"Co" hydrocarbyl is used to refer to a covalent bond. Thus,"Co-C3- hydrocarbyl"includes a covalent bond, methyl, ethyl, propyl, and cyclopropyl.

[0023] The term"alkyl"as employed herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms, which is optionally substituted with one, two or three substituents.

Preferred alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. A"Co"alkyl (as in"Co-C3-alkyl") is a covalent bond (like "Co"hydrocarbyl).

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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-Clo 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 (Cl-C6) alk (C6-Clo) aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.

[0030] 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.

[0031] As used herein, the term"heteroaryl"refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms ; having 6, 10, or 14 n electrons shared in a cyclic array ; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, 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 0 and/or S atoms.

[0032] 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.

[0033] 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.

[0034] As employed herein, when a moiety (e. g., cycloalkyl, hydrocarbyl, aryl, heteroaryl, heterocyclic, urea, etc.) is described as"optionally substituted"it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, oxo (e. g., an annular-CH- substituted with oxo is-C (O)-) nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl,, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.

Preferred substituents, which are themselves not further substituted (unless expressly stated otherwise) are : (a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, (b) Ci-Cg alkyi or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, Cl-C8 alkyl, Cl-C8 alkenyl, Cl-C8 alkoxy, Cl-C8 alkoxycarbonyl, aryloxycarbonyl, C2-C8 acyl, C2-C8 acylamino, Ci-Cg alkylthio, arylalkylthio, arylthio, Cl-Ce alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C1-C8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, Co-Gg N- alkyl carbamoyl, C2-C1s N, N-dialkylcarbamoyl, CDC cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C3-C7 heterocycle, or any of these rings fused or spiro- fused to a cycloalkyl, heterocyclyl, or aryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above ; and (c)-(CH2) s-NR3°R31, 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, Cl-Ca hydroxyalkyl, Cl-C3 alkylaryl, aryl-Cl-C3 alkyl, Cl-C8 alkyl, Ci-Cg alkenyl, Cl-C8 alkoxy, Ci-Cg alkoxycarbonyl, aryloxycarbonyl, aryl-Ci-C3 alkoxycarbonyl, C2-C8 acyl, Ci-Cg alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, aroyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above ; or R30 and R31 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents from (a), above.

[0035] 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 : [0036] A"halohydrocarbyl"is a hydrocarbyl moiety in which from one to all hydrogens have been replaced with one or more halo.

[0037] 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.

[0038] The term"radical"as used herein means a chemical moiety comprising one or more unpaired electrons.

[0039] 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-).

[0040] 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.

[0041] Preferred embodiments of a particular genus of compounds of the invention include combinations of preferred embodiments. For example, paragraph [0043] identifies a preferred Ayl and paragraph [0047] identifies preferred Arl (both for compound (1) of paragraph [0042]). Thus, another preferred embodiment includes those compounds of formula (1) in paragraph [0042] in which Ayl is as defined in paragraph [0043] and Ar1 is as defined in paragraph [0047].

10 Compounds [0042] In a first aspect, the invention provides novel inhibitors of histone deacetylase. In a first embodiment, the novel inhibitors of histone deacetylase are represented by formula (1) : and pharmaceutically acceptable salts thereof, wherein R3 and R4 are independently selected from the group consisting of hydrogen, L', Cyl, and-L1-Cyl, wherein Ll is Ci-Cg alkyl, C2-C6 heteroalkyl, or C3-C6 alkenyl ; and Cyl is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which optionally is substituted, and each of which optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings optionally is substituted ; or R3 and R4 are taken together with the adjacent nitrogen atom to form a 5-, 6-, or 7-membered ring, wherein the ring atoms are independently selected from the group consisting of C, 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 ; Yl is selected from the group consisting of-N (Rl) (R2),-CH2-C (O)- N (R1) (R2), halogen, and hydrogen, wherein R'and R'are independently selected from the group consisting of hydrogen, Lu, Cyl, and-L1-Cyl, wherein L1 is Cl-C6 alkyl, C2-C6 heteroalkyl, or C3-C6 alkenyl ; and Cyl is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which optionally is substituted, and each of which optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings optionally is substituted ; or R1 and R2 are taken together with the adjacent nitrogen atom to form a 5-, 6-, or 7-membered ring, wherein the ring atoms are independently selected from the group consisting of C, 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 ; y2 is a chemical bond or N (R°), where R° is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, and acyl ; Ak1 is C1-C6 alkylene, C1-C6-heteroalkylene (preferably, in which one-CH2-is replaced with-NH-, and more preferably-NH-CH2-), C2-C6 alkenylene or C2-C6 alkynylene ; Arl is arylene or heteroarylene, either of which optionally is substituted ; and Z1 is selected from the group consisting of wherein Ayl is aryl or heteroaryl, which optionally is substituted.

[0043] Preferably in the compounds according to paragraph [0042], Ay is phenyl or thienyl, each substituted with-OH or-NH2.

[0044] More preferably in the compounds according to paragraph [0042], Au1 ils 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.

[0045] More preferably in the compounds according to paragraph [0042], Ayl is ortho aniline, ortho phenol, 3-amino-2-thienyl, or 3- hydroxy-2-thienyl, and tautomers thereof.

[0046] In some preferred embodiments of the compounds according to paragraph [0042], Z1 is [0047] In some preferred embodiments of the compounds according to paragraph [0042], Arl is phenylene. In some embodiments, Au1 ils alkylene, preferably methylene. In some prererrea embodiments, Y2 is -NH-. In some preferred embodiments, Y''is-N (Rl) (RZ) or-CH2-C (0)- N (R') (R).

[0048] In some embodiments of the compounds according to paragraph [0042], R1 and R2 are each independently selected from the group consisting of hydrogen, L1, Cyl, and-L1-Cyl. 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.

[0049] In some embodiments of the compounds according to paragraph [0042], R3 and R4 are each independently selected from the group consisting of hydrogen, L1, Cyl, and-L1-Cyl. 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.

[0050] As set forth above, Ll 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 Ll is Cl-C6 alkylene, Cz-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, Cyl 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 Cyl is cycloalkyl, e. g., cyclopropyl, cyclopentyl, or cyclohexyl. In still other embodiments, Cyl 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, Cyl is fused to one or two benzene rings. In some embodiments, Cyl has between one and about five substituents selected from the group consisting of Cl-C4 alkyl, C1-C4 alkoxy, and halo.

Examples of preferred substituents include methyl, methoxy, and fluoro.

[0051] 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.

[0052] In a preferred embodiment, the HDAC inhibitors of the invention comprise compounds of formula l (a) : and pharmaceutically acceptable salts thereof, wherein J is Cl-C3-hydrocarbyl,-N (R20)-,-N (R2°)-CH2-,-O-, or-O-CH2-; R20 is-H or-Me ; X and Y are independently selected from-NHZ, cycloalkyl, heterocyclyl, aryl, heteroaryl, and A-(C1-C6-alkyl) n-B-; A is H, C1-C6-alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl ; B is-NH-,-0-, or a direct bond ; and n is 0 (in which case A is directly bonded to B) or 1.

[0053] 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.

[0054] Preferably in the compounds according to paragraph [0052], J is-NH-CH2-,-0-CH2-,-N (CH3)-CH2-,-CH=CH-, or-CH2-CH2-.

[0055] Preferably in the compounds according to paragraph [0052], R20 is-H.

[0056] In the compounds according to paragraph [0052] X is preferably selected from and Y is preferably selected from OMe OMe OMe I iN I \ // !/ CH3 (CHz) 3N -H Me-OMe CH3 (CH2) 3N H- and CH30 (CH2) 2- and NH-.

[0057] In a more preferred embodiment of the compounds according to paragraph [0052], the HDAC inhibitors of the invention comprise the following compounds of formula la : Cpd X q Y Cpd \/ OMe 204-NH-NH-NH2 t OMe 476-NHCHZ-D--N' 207-OCH2-v NH-NH2 H IN ci 210-NHCHz- i N-H 477-NHCHz-D--NH H 212-NHCH2--OMe-OMe r\/OMe 214-NHCHz-/H-OMe e OMe 216-ICH3 N-cHz-\/478-NHCH2-D--NH 216 1 NH-Me A HAN 218-NHCHZ-, NH-Me OMe 220-CH=CH--NH2-NH2-479-NHCH2-D--NH 223-CH=CH--NH2 HO 224-CH2CH2--NH2-NH2 ß 470-NHCH2- I H/NHZ 480-NHCH2-D--NH HN N PhNH zu 471-NHCHZ-/Ni I/-NH/ H 481-NHCH2-D--NH >/H I 472-NHCHZ- \ H H HN han 472-NHCH,, -N/H -0 473-NHCH2-X Nz n-BuNH H 483-NHCH2-Me H 474-NHCH2-X N MeO (CH2) 2NH H 484-NHCH2-NH2 ci I and j) j and 475-NHCHz->-NH HN 485-NHC 12-NH [0058] In a second aspect, the novel histone deacetylase inhibitors of the invention are represented by formula (2) : and pharmaceutically acceptable salts thereof, wherein Cy2 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted and each of which is optionally fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings is optionally substituted ; Xl is selected from the group consisting of a covalent bond, M1- L2-Ml, and L2 wherein L2, at each occurrence, is independently selected from the group consisting of a chemical bond, Co-C4 hydrocarbyl, C0-C4- hydrocarbyl- (NH)-Co-C4-hydrocarbyl, Co-C4-hydrocarbyl- (S)-Co-C4- hydrocarbyl, and Co-C4-hydrocarbyl- (O)-Co-C4-hydrocarbyl, provided that L is not a chemical bond when Xl is Ml-L2-Ml ; Ml, at each occurrence, is independently selected from the group consisting of-O-,-N (R')-,-S-,-S (O)-, S (O) 2-,- S (O) 2N (R')-,-N (R')-S (0) 2-,-C (O)-,-C (O)-NH-,-NH-C (O)-, -NH-C(O)-O--and -O-C(O)-NH-, wherein R7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl ; and M2 is selected from the group consisting of Ml, heteroarylene, and heterocyclylene, either of which rings optionally is substituted ; Ar2 is arylene or heteroarylene, each of which is optionally substituted ; R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl ; q is 0 or 1 ; and Ay2 is a 5-6 membered cycloalkyl, heterocyclyl, or heteroaryl substituted with an amino or hydroxy moiety (preferably these groups are ortho to the amide nitrogen to which Ay2 is attached) and further optionally substituted ; provided that when Cy2 is naphthyl, Xl is-CH2-, Ar2 is phenyl, R5 and R6 are H, and q is 0 or 1, Ay2 is not phenyl or o-hydroxyphenyl.

[0059] 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 (0) 2-,-C (O)-, or-OCH2-, then Cy2 is not optionally substituted phenyl or naphthyl.

[0060] In another preferred embodiment of the compounds according to paragraph [0058], when Ay2 is o-anilinyl optionally substituted by halo, Cl-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).

[0061] In another preferred embodiment of the compounds according to paragraph [0058], when Xl is-CH2-, Ar2 is optionally substituted phenyl, q is 1, and R6 is H, then Cy2 is not optionally substituted imidazole.

[0062] In another preferred embodiment of the compounds according to paragraph [0058], when Ar is amino or hydroxy substituted phenyl, Xl is Co-C8-alkyl-Xla-Co-Cs-alkyl, wherein Xla is-CH2-,-O-,-S-,-NH-,- C (O)-, then Cy2 is not optionally substituted naphthyl or di-or- tetrahydronaphthalene.

[0063] 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 R5 and R6 are H, then Cy2 is not optionally substituted naphthyl.

[0064] In another preferred embodiment of the compounds according to paragraph [0058], when Ay2 is o-anilinyl, q is 0, Ar2 is unsubstituted phenyl, X1 is-CH2-, then Cy2 is not substituted 6-hydroimidazolo [5, 4- d]pyridazin-7-one-1-yl or substituted 6-hydroimidazolo [5, 4- d] pyridazine-7-thione-1-yl.

[0065] Preferably in the compounds according to paragraph [0058], Ay2 is phenyl or thienyl, each substituted with-OH or-NH2.

[0066] 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.

[0067] 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.

[0068] In a another embodiment, the novel histone deacetylase inhibitors of the invention are those according to paragraph [0058] wherein q is 1 ; M1, at each occurrence, is selected from the group consisting of -N (R7)-,-S-,-C (O)-NH-, and-O-C (O)-NH-, where R7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, and acyl ; and Ay2 is anilinyl, which optionally is substituted.

[0069] In some preferred embodiments of the compounds according to paragraph [0068], the-NH 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.

[0070] In some embodiments of the compounds according to paragraph [0068], Ar2 has the formula wherein G, at each occurrence, is independently N or C, and C optionally is substituted. In some preferred embodiments, Ar2 has the formula [0071] In some preferred embodiments of the compounds according to paragraph [0070], Ar2 is selected from the group consisting of phenylene, pyridylene, pyrimidylene, and quinolylene.

[0072] 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-0-C (O)-N (H)-. In some embodiments, X1 is L2-M2-L2, where at least one occurrence of L 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, Xl is Ml-L2-Ml and Ml is selected from the group consisting of-NH-,-N (CH3)-,-S-, and-C (O)-N (H)-.

[0073] 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., 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.

[0074] In a preferred embodiment of the compounds of paragraph [0058], the invention comprises compounds of structural formula (2a) : and pharmaceutically acceptable salts thereof, wherein Ara is phenyl or thienyl ; R6 is H, or Cl-C6-alkyl (preferably--CH3) ; Y and Z are independently-CH= or-N= ; W is halo, (V'-L4)t-V-L3-; L3 is a direct bond,-C1-C6-hydrocarbyl,-(C1-C3-hydrocarbyl) ml- X'- (C1-C3-hydrocarbyl) m2,-NH- (Co-C3-hydrocarbyl), (C1-C3- hydrocarbyl)-NH-, or-NH-(C1-C3-hydrocarbyl)-NH-; mi and m2 are independently 0 or 1 ; X'is-N (R21)-,-C (O) N (R21)-, N(R21) C (0)-,-0-, or-S- ; R21 is-H, V"- (Cl-C6-hydrocarbyl) c ; L4 is (Cl-C6-hydrocarbyl) a-M- (C,,-C6-hydrocarbyl) b ; a and b are independently 0 or 1 ; M is-NH-,-NHC (O)-,-C (O) NH-,-C (O)-,-SO2-,-NHSO2-, or- SOzNH- V, V', and V"are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl ; t is 0 or 1 ; or W, the annular C to which it is bound, and Y together form a monocyclic cycloalkyl, heterocyclyl, aryl, or heteroaryl ; and wherein the A and Ara rings are optionally further substituted with from 1 to 3 substituents independently selected from methyl, hydroxy, methoxy, halo, and amino.

[0075] In a preferred embodiment of the compound according to paragraph [0074] : Y and Z are-CH= and R6 is H ; W is V-L3 ; L3 is -NH-CH- or -CH-NH-; V is phenyl optionally substituted with from 1 to 3 moieties independently selected from halo, hydroxy, C1-C6-hydrocarbyl, C1-C6-hydrocarbyl-oxy or-thio (particularly methoxy or methylthio), wherein each of the hydrocarbyl moieties are optionally substituted with one or more moieties independently selected from halo, nitroso, amino, sulfonamido, and cyano ; and Ara is phenyl and the amino moieties to which it is bound are ortho to each other.

[0076] In some preferred embodiments of the compound according to paragraph [0074], V is an optionally substituted ring moiety selected from : [0077] In another preferred embodiment of the compounds according to paragraph [0074], W is selected from :, [0078] In another preferred embodiment of the compounds according to paragraph [0074], the A and Ara rings are not further substituted.

[0079] 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 R Cpd W Y Z R H H HsC. O y N HaC, o'y Nw. i 4 81 H3C0 I/CH CH H 4 94 CH CH H H3Cz CH3 _ _ _ H __. P ONN H NH 495 CH CH H 484 H3 ceo : qn NH2 NOz 3 N C. O i HaC. O w N,,,' H3C'O X H H, c LJ H H3C'0 H 496 F H CH CH H HsCY" °f' 492 X N CH CH H CH3 ol CH3 O"L, H Cl X N Y N \ 497 H3Cso 9 CH CH H 493 9 N CH CH H ol CH3 H3C 3 Cpd w Y Z R6 Cpd w Y Z R CH3 Me0 H p W N w. l ; 498 3 O < CH CH H 512 OMe CH N H H3c, Meo OMe ) 516 Br-CH CH CH3 HN N OMe 499 0 cIH3 CH CH H MeO OMe 517 H OH CH CH3 I RCH3 O-CH3 H3C, 0 OMe 0 OMe 500 H3c0H t CH CH H 518 OMe CH CH CH3 H3Cso S/> MeO H/ 0 H 0\ fYY 501 CH CH H 519 Y CH CH H 0/. W H NHZ N 520 N CH CH H 502 PhNH CH CH Ho CHUS H 521 NH N CH H 503 o PhNH CH CH H C N H 0\-2 H H N 504 CH CH H 522 s N\ N CH H H H H N N 505 j ! J CH CH H 523 orin CH CH H O oye zozo H Me0 OMe w N- w N5 506 y CH CH H 524 H N CH H OCF3 OH w nez 507 CH CH H 525 H N CH H OMe OCFs H T-\ 508 a OMe CH CH H 526 MNJN N_ CH CH H /OMe H /\ 509 H CH CH H 527 MeN<_JN >NH CH CH H IF H N : N''3. 510 CH3 CH CH H 528 H CH CH H CHUS OH H 511/\/\ N CH CH H NN' 529 N CH CH H CF3 Cpd W Y Z R Cpd W Y Z R N N , 530 CH CH H I 530 lu CH CH H Ho, N NH /==\ NH 531 2 CH CH CH N--N H HO 543 N ß CH CH H H N. 532 CH CH H H H H 545 N, _\ CH CH H Br LJ CH CH H H N 534 J ! J CH CH CH H N i Br 534 , CH CH H 534 CF3 547 f\ CH CH H CL3 I H CI N1, 1 535 C, q N CH CH H 548 CH CH H MeO H Me0 \ ce CH H 536 536 MeO CH CH H 549 y CH CH H MeO' MeO-OH 537 Meo CH CH H N 550 CH CH H HZN . N H zu SOzNHz Y N 539 T CH CH H 552 f ! CH GH H 538 551 CH CH H 2nu2 NOS N' H N ' CH CH H 539 y CH CH H 552 CH CH H 02S, *, H co H MeO 553 y CH CH H 540 MeO CH CH H H H ORME H 5 5 4 '''CH CH H 5 41 3 \0 CH CH H N o HgC0'v \ N. H 555 CH CH H 542 O ( N CH CH H Hz u Cpd W Y Z R Cpd W Y Z R O 556 I CH CH H H i. l \ NH MeS < _ 564 MeO < N @ < NH2 564 Me0 N \ Nhz Oh H mye 557 I I. CH CH H OMe Br/F N H 565 CH CH H H3C- S/ 558 CH CH H H3C, s F 566 F + N \ CH CH H F N HS/ 559 F N-CH CH H Hs'S / O H°2N seNH Me0/\ 567 Me0 N \ /NHZ H I NH I I Me0 N \ NH2 MeO NH 5 6 0 \/OMe 'v) eu) H OMe OMe H2 0 NH N Nu H 561 NH 568 MeO N Me I I OH OMe Orme OMe H I 562 MeOtN < CH CH H 569 H3CX < CH N H MeO H3C H3C OMe f,. zN OMe CHs HN- ( S oye 563 N CH CH H 570 O > N < S W f MeO 4 H3C-O HIC [0080] In a preferred embodiment, the compounds of the invention comprise compounds of the formula (2b) : and pharmaceutically acceptable salts thereof, wherein Ay2 is phenyl or thienyl, each substituted at the ortho position with-NH2 or-OH and each further optionally substituted with one to three substituents independently selected from-NH2,-OH, and halo ; q is 0 or 1 ; Xl is selected from-CH2-,-NH-CH2-, and-S-CH2- ; Cy2 is monocyclic or fused bicyclic aryl or heteroaryl optionally substituted with one to three substituents selected from CH3-, CH30-, phenyl optionally substituted with one to three CH30-, morphylinyl, morphylinyl-C1-C3-alkoxy, cyano, and CH3C (O) NH-; provided that when Cy2 is naphthyl, X1 is-CH2-, and q is 0 or 1, Ay2 is not o-hydroxyphenyl.

[0081] Preferably in the compounds according to paragraph [0080], Ay2 is selected from : [0082] 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 CH30-. More preferably, Cy2 is phenyl substituted with one to three CH30-.

[0083] In a third embodiment, the novel inhibitors of histone deacetylase are represented by formula (3) : and pharmaceutical salts thereof, wherein Ar3 is arylene or heteroarylene, either of which optionally is substituted ; Cy3 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which optionally is substituted, and each of which optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings optionally is substituted ; provided that when Cy3 is a cyclic moiety having-C (0)-,-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 X2 is selected from the group consisting of a chemical bond, L3, W1-L3 L3_Wl, W'-L 3_Wl, and L3-W1-L3, wherein 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 L3 is Cl-C4 alkylene, C2-C4 alkenylene, or C2-C4 alkynylene ; provided that 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, Wl-L3, or L3-W1.

[0084] Preferably, Ar3 has the structure : wherein Q, at each occurrence, is independently N or C, and C optionally is substituted.

[0085] Preferably in the compounds according to paragraph [0083], X2 is selected from the group consisting of L3,, Wl-L3, L3-Wl, Wl-L3-Wl, and L3 W1 L3 [0086] Preferably in the compounds according to paragraph [0083], when X2 is a chemical bond, then Ar3 is not and Cy3 is not the radical of a substituted or unsubstituted diazepine or benzofuran.

[0087] 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.

[0088] 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-Wl and W1 is-NH-or-N (CH3)-.

[0089] 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-K'-N (H) (Rl0), wherein K1 is a chemical bond or C1-C4 alkylene ; R1° is selected from the group consisting of Z'and-Ak2-Z', wherein Ak2 is Cl-C4 alkylene ; and Z'is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which optionally is substituted, and each of which optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings.

[0090] Examples of such preferred substituents according to paragraph [0089] include [0091] In some embodiments of the compounds according to paragraph [0083], Cy3 is heterocyclyl, e. g., each of which optionally is substituted and optionally is fused to one or more aryl rings. In some embodiments, the heterocycle of Cy3 is fused to a benzene ring.

[0092] Preferably in the compounds of paragraph [0083], when Ar4 is quinoxalinylene, then is not-CH (OH)-.

[0093] In another preferred embodiment, Ar3 is wherein X is-CH2-,-NH-, 0, or S. Preferably Ar3 is and X is S or 0.

[0094] In a preferred embodiment, the novel histone deacetylase inhibitors of the invention are those according to paragraph [0058] wherein Ay2 is ortho-anilinyl ; q is 0 ; and Xl is Ml-L2-Ml or L2-M2-L2.

[0095] 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 a) A1-Ll-Bl-, wherein A1 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein Li is- (CH2) o-1NH (CH2) 0-1-,-NHC (O)-, or - NHCHz- ; and wherein B, is phenyl or a covalent bond ; b) A2-L2-B2-, wherein A2 is CH3 (C=CH2)-, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted aryl ; wherein L2 is-C-C-; and wherein B2 is a covalent bond ; c) A3-L3-B3-, wherein A3 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein L3 is a covalent bond ; and wherein B3 is -CH2NH-; d) A4-L4-B4-, wherein A4 is an optionally substituted aryl ; wherein L4 is-NHCH2- ; and wherein B4 is a thienyl group ; e) As-L5-Bs-, wherein As is an optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein L5 is a covalent bond ; and wherein Bs is -SCH2-; f) morpholinyl-CH2- g) optionally substituted aryl ; h) A6-L6-B6-, wherein AG is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein L6 is a covalent bond ; and wherein B6 is - NHCHz- ; i) A7-L7-B7-, wherein A7 is an optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein L7 is a covalent bond ; and wherein B7 is -CH2-; j) aptionally substituted heteroaryl or optionally substituted heterocyclyl ; k) AgLg-Ba-, wherein As is optionally substituted phenyl ; wherein L8 is a covalent bond ; and wherein B8 is -O-; 1) Ag-L9-B9-, wherein Ag is an optionally substituted aryl ; wherein Lg is a covalent bond ; and wherein Bg is a furan group ; m) Alo-Llo-Blo-, wherein Alo is an optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein LIO is- CH (CH2CH3)- ; and wherein B10 is-NHCHz- ; n) A11-L11-B11-, wherein All is an optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein LI, is a covalent bond ; and wherein B11 is -OCH2-; 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-; p) A13-L13-B13-, wherein A12 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein L13 is a covalent bond ; and wherein B13 is-NHC (O)- ; q) A14-L14-B14-, wherein A14 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein L14 is-NHC (o) (optionally substituted heteroaryl) ; and wherein, B14 is-S-S- ; r) F3CC (O) NH- ; s) Als-Lis-Bls-, wherein Als is an optionally substituted aryl, optionally substituted. heteroaryl or optionally substituted heterocyclyl ; wherein L1s is -(CH2)0-1NH (optionally substituted heteroaryl)- ; and wherein Bls is-NHCH2-; t) A16-L16-B16-, wherein A16 is an optionally substituted aryl,. optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein L16 is a covalent bond ; and wherein B16 is-N (optionally substituted alkyl) CH2-; and u) A16-Ll6-Bl6-, wherein Als is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein L16 is a covalent bond ; and wherein Big is- (optionally substituted aryl-CH2)2-N-.

[0096] In another preferred embodiment of the compounds according to paragraph [0094], Cy2-Xl-is collectively selected from the group consisting of a) D1-El-Fl-, wherein D1 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein Ei is-CH2-or a covalent bond ; and wherein B1 is a covalent bond ; b) D2-E2-F2-, wherein Dz is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein E2 is-NH (CH2) 0-2-; and wherein F2 is a covalent bond ; c) D3-E3-F3-, wherein D3 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein E3 is- (CH2) 0-2NH- ; and wherein F3 is a covalent bond ; d) D4-E4-F4-, wherein D 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 ; e) Ds-Es-Fs-, wherein Ds is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein Es is -(CH2)0-2S-; and wherein Fs is a covalent bond ; and f) D6-E6-F6-, wherein D6 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl ; wherein E6 is-NH (CH2)0-2NH- ; and wherein F6 is a covalent bond.

[0097] In a preferred embodiment, the HDAC inhibitors of the invention comprise compounds of paragraph [0058] having formula (3b) : and pharmaceutically acceptable salts thereof, wherein Y and Z are independently N or CH and W is selected from the group consisting of : [0098] 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 Cpd w Y Z Cpd w z MeO H 0 16 17 s N CH 18 Meo S O oMe 17 17 s jo 16 Hp N O /\ N CH-_ 5 L6 17 N CH N 18 CH CH 1 4 N-'--0 17 I H CH N 16 H/CH N 5 F/12 I CH CH 7/Me0 Ni CH MeO N N 6 met 16 F Me0 I 17 N, N 13 F. _ NS CH CH 7 S CH CH N 16 Me0-N Ph O -S\_ CH CH N 7 pu 0 Orme /\ O ° "0-0 0 \ i oo [0099] 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 Cpd W Y Z rN ur 187 Lf H j CH CH 195 3< CH CH H3C OH NU2 H H 196 CH CH 188 N CH CH 0 c : o i--NH CH CH Cri N 189 eu : q CH CH cl MeO X 321 X/W NH CH CH Oye con 190 N CH CH ! ber N Me0'v Me OMe 190 cl 193 3 HzC CH CH CL3 HAN 194 CH CH OH Cpd VA Y Z Cpd nI y Z N O __.. tNJ H F N I, H F \ I NJ N _ n 326 < N g S CH CH 340 \ CH CH i N H j/N. CH3 N F$~ CH3 N -CHs 327 C S CH CH CH N, N^,, f° 341 \ I CH CH 328 ! j CH CH CH 0 Met 0 329 MeO X CH CH 342 Br < N-< CH CH OMe N l Me N Hz o 3 3 0 H3CN N N CH CH 343 X N-g CH CH ', N HN-- H HN H NH p 331 HN-N CH CH 344 CH CH , \ Ni O rß _ CI g cri 3 3 2 HN1. N CH CH N N HN-345 N CH CH Han N NaOMe 3 3 3 H3CN N N CH CH O 346 N CH CH HN HN---/ H N 334 \ N NH CH CH O 347 Br I N'. r CH CH O '-N. N 0 334 Y"CH CH, ? Et I NN N '"0 348''YY CH CH w I H N Me F \ F "NMe f O 350 F I N N. ' CH CH H 337 CH CH H vNlMe S/t 0 N 351 CH CH 338 MeO CH CH ILI H MeO+NJ N 352 Ph o CH CH Pu CpdWJLJL CpdW y Z H 353 Me O CH CH 368 MeO CH CH Me--, 0'N I N MeO N) 354 C CH CH ON N O'HN) 0 HN N han 356 _ N CH CL H C'\ N Br'v'NH ". 3 7 0 O, CH CH N ni 357 cl CH CH OMe NC, N Me0 O N zon N NC OMe 359 HN- CH CH CH s 0 Me-- S O 372 \ OMe NC Me CI Orme /Y OMe 360 H N-\/S CH CH Ph S 'OO, N H CN 373/ NIH/CH CH \ OMe N N 3 61 , o S/Me CH CH OMe 0 0-1 vin 3 O-r\-NH CH CH O N 362 O X N X CH CH OMe /i O 3 7 5 I N CH CH NHz 363 CH CH H 377 CH CH ZON 364 O a N N CH CH 378 N CH CH 4 7 8 N CH CH oGHz o chu 365 CH CH jF OH 379 F CH CH \J\ O s, i N 366 C CH NHZ H'. N CH N 380 N N 367 CH CH \ 3 81 \ CH CH N S, CpdW Y Z CpdW y Z Cl3 I I 382 jan CH 396 CH CH H3C N H/ CH3 H3C'O \ N '383 r CH CH 397" CH CH ''o H3C N CH3 CH3 O 384 X HN CH CH 398 >N< s-g-CH N H3C N O^ NH z H3C. 0// 385 N N 385 Nl ß CH CH 399 CH CH H N Hz O H 386 CH CH 400 CO < N, CH CH H O < Ci H cl H O N \8 387 N CH CH ol H3C, H3C N" ( : H 402 NH CH CH 3 8 8 N/N CH CH 6"/CHs N 0 NH N/'-_ 389 < \eNH CH CH \ N N H 404 I \ N CH CH 'N N H i ) <) 404. JN, CH CH 390 HA, CH CH HAj H O \ \ 11 N 391 (N"CH CH 405 CH CH s\ HgJJ H H H3C. ONui H3C. 0 \ Nuc 392 NYN CH CH 406 H, C, 0 OH CH CH O. CH3 H 393 CH CH CH 407 CH CH CH3 CH3 CH3 -- F no \/\/ r'Tj r'Tj 408 NH CH CH 394 0-as CH3 H 395 H3C'CH CH 409 H3C ( : N CH CH 395 Y CH CH H3C 0 ? H CH3 410 N,,, \- CH CH H3C CH3 Cpd W Y Z Cpd W y Z _.. " N s 1C1 H Me0, N 427 I N CH CH 412 MeOX CH CH MeO. OMe, ~Ns \_ met 427 CH CH 413 H CH CH O Me H H 414 X H CH CH 429 H CH CH Mu0 OMe 415 CNs, \ CH CH Fla 430 y CH CH N ;''OMe 416 C N3\ CH CH OMe F 431 F3CANX CH CH H H N 417 9 CH CH gN, NrN \, F 432 l CH CH H MeO ci Cl N N,, MeO Me 418 l 1l CH CH H H Me 433 MeO v N 4r N >-CH CH H Me H Meo )-N 419 Cl CH CH r N H H OMe CL HHOMe N YN N- 420 N CH CH 435 XNtrN \ CH CH Cri H H nip Cl N 436 CH CH Me0 N/ Hz 422 CH CH N 437 CH CH 3 H mes r-r" 423 ly CH CH 438 CH CH y OCF3 SMe H some MeO 424b L CH CH w N N 424b MeO CH CH 439 Me0 v Y CH CH OMe % N N 425 9 CH CH OCF3 Cpd w Y Z Cpd W y Z Mezzo I H 440 MeOV CH CH H if N 454 H3C O Me0 F H 441 CH CH H NH 4 41 CH CH F Me0 NH OMe 455 p I j CH CH Z N NYN R N NH>, \, 442 MeO 4 4 N CH CH 456 MEHN N Me0 OMe O H2N MeOi : N CH CH HZN 4 4 3 HaC 3Ha I CH CH Mye0 OMe o Me0 NH t, i OH 458"__NaNH, CH CH 444 N CH CH 0 0 )) Q. P NH Meo pMe 4 5 9 O I \ V CH CH H N/ MeO H3c 445 LU CH N NH CH N 460 H OMe/ H O . N. H3C NHv 446 \ I J. CH N 461 CH CH N ? CH3 N ; , ; CHa 447 F3CO < CH CH s=<ND hic H3C N NHV 'i hic HC S--CHs NHV 449 H3Cs (J J CH CH 463 OH N CH N H N N H H3 449 HN g NH CH CH 464 ! j) N CH N \ /\ rJ NHv 451 CH CH 465 CH CH N : HN-S" N NU ho 452 CH CH N 0 : : : o 466 CH CH 0 NH N HN 453 H NH N Me0 F3C Br CpdWY cJpaW Y Z H i N 468/-, CH CH 700-CH CH HN-'N NJ [0100] 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 : [0101] In another preferred embodiment, the compounds are selected from those listed in Tables 2a-b, 3a-d, 4a-c, and 5a-5f.

Synthesis [0102] Compounds of formula (1), wherein Yl is-N (Rl) (R2), preferably may be prepared according to the synthetic route depicted in Scheme 1.

Thus, trichlorotriazine I reacts with amine II in the presence of diisopropylethylamine to produce dichloroaminotriazine III. The amine RlR2NH 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.

[0103] Alternatively, dichloroaminotriazine III may be reacted with ammonia gas in 1, 4 dioxane to produce diaminochlorotriazine IV.

Treatment of IV with RNH in THF or 1, 4 dioxane in a sealed flask then affords triaminotriazine VI.

[0104] 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. Scheme 1 CI CI NN + HCLHZN i-Pr2NEt NN CIlNlCl wCO2Me c NzlN gß )"'LA III CO2Me NH3 gas/ Pathway A 1, 4-dioxanX \R1R2NH Pathway B Cri NN X \ N4N CI NN Cl N N z JI N H I C02Me R R N N H. IV COzMe R'R2NH THF or 1, 4-dioxane/NH ;} or R3R4NH sealed flask THF or 1, 4-dioxane NR 3R 4 N-N"Y N)"N H2N NR 3R4 N N R1R2NJ (N1NX H2Nb 14, 1 vCO2R'R1R2N N HNm H NH2 BOP reagent N VI : R = Me Et3N, DMF Vil LiOH. H20 VII : R = H THF/H20 [0105] Compounds of formula (1), wherein Y1 is -CH2-C(O)-N(R1)(R2), preferably may be prepared as outlined in Scheme 2. Thus, piperazine IX is treated with acetyl chloride and triethylamine to produce amide X. Reaction of X with dichloromorpholyltriazine and lithium hexamethyldisiloxane affords compound XI. The chloride of XI is converted to the anilinyl amide of XII as described above with respect to Scheme 1 : treatment with the amine and diisopropylethylamine ; followed by lithium hydroxide ; followed by BOP reagent, phenylenediamine, triethylamine, and DMF.

Scheme 2 [0106] Compounds of formula (. 2), wherein Ar is pyridylene and X1 comprises-N (R')-, 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 (R1l)-, preferably may be prepared according to the procedures illustrated in Scheme 3. Dibromopyridine XIII or XIV is treated with amine RNH2 to produce aminobromopyridine XV or XVI, respectively. Treatment of XV or XVI with diacetoxypalladium, diphenylphosphinoferrocene, DMF, diisopropylethylamine, and phenylenediamine under carbon monoxide yields anilinyl amide XVII or XVIII, respectively.

[0107] 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,'a'nd triethylamine affords the anilinyl amide XXIII or XXIV, respectively.

Scheme 3 [0108] Compounds of formula (2), wherein X1 comprises-O-C (O)-NH-, preferably may be prepared according to the synthetic route depicted in Scheme 4. Thus, carbinol XXV is added to bromobenzylamine XXVI with carbonyldiimidazole (CDI), triethylamine, and 1, 8- diazabicyclo [5. 4., 0] undec-7-ene (DBU) in DMF to produce compound XXVII.

The remaining synthetic steps in the production of anilinyl amide XXVIII are as described above for Scheme 3.

Scheme 4 [0109] Compounds of formula (2), wherein X1 comprises-N (R7)-, preferably may be prepared as outlined in Scheme 5. Amine XXIX is reacted with p-bromobenzylbromide in the presence of potassium carbonate in DMF to produce bromobenzylamine XXX. Treatment of XXX with nitroacrylanilide, dibenzylacetone palladium, POT, anddiisopropylethylamine in DMF affords nitroanilide XXXI. Nitroanilide XXXI is converted to the corresponding anilinyl amide XXXII by treatment with stannous chloride in methanol and water.

[0110] 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.

Scheme 5 [0111] Alternatively, compounds of formula (2), wherein X1 comprises - N (R')-, 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.

Scheme 6 [0112] Compounds of formula (2), wherein X1 comprises -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.

Scheme 7 [0113] 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.

Scheme 8 Br Br N |H2N~NH2 Br H2N NO H O XLIV O ISO XLV o/MeOH/H2O/\ n /\/PhMe/reflux then 88 % HCO2H/reflux/\ r \ Nw \ Br \ N O Br N N N ICN O XLVI 0 XLVIII 1. eCO2tBu 2. TFA/CH2C12 1. CO2tBu 2. TFA/CH2C12 Pda (dba) 3/POT r'T r. T Pd2 (dba) 3/POT 3 Ph (NHa) 2/BOP Pda (dba) 3/POT 3 Ph (NH2) 2/BOP DMF/DIPEA/120°C DMF/TEA/rT DMF/DIPEA/120°C DMF/TEA/rT ri N N'kan N1 I \ H \ I \ N I \ \ \ 0 H XLVII 0 XLIX O XLVII XLIX XLIX [0114] 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.

Scheme 9 NH2 ci HCI. H2N Cl N N I Br \/N J \/"-NNN CI N CI i-Pr2NEt NNCI i-Pr2NEt H H I L Li NH3 gas 1, 4-dioxane nu2 0 \/N NH I Pd NHBoc "CUO NHR E \/N N HN N N N "'N N N H H I/ Llil : R = Boc TFA Lp Br LIV : R = H 2 95% in water [0115] Compounds of formula (2), wherein Ar2 is quinolylene and X1 comprises-N (R')-, 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 (Rll)-, 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.

Scheme 10 \ \ OH \ \ OTf \ \ OTf 0 H'OTf HO I N/Tf0 I N//H LVII LV LVI Me0 H 2 NU, N N O \ NH Meo- ( :)", LVIII \ N I N//NHZ H Me0'v I/\ I LIX Me0 LVIII a. Tf2O Py DMAP 0 C b. p-methoxybenzylamine/120 C c. 1, 2-phenylenediamine/CO (40 psj)/Pd (OAc) 2/dppf/ DMF/DIPEA/70 C d. t Butylacrylate/Pd2 (dba) 3/POT/DMF/DIPEA/120 C e. TFA/DCM/rT f. 1, 2-phenylenediamine/BOP/DMF/TEA/rT A [0116] Compounds of formula (3), wherein X'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.

Scheme 11 SAr Br K2CO3/DMF SAr SAr BOP/SAr 100°C SAr BOPI ArSH + I I LiOHxI-IZO/1, 2-Phenylenediamine O ou COOMeNaI-I/DMF/110°C/COOMe HZO/MeOH I/DMF/Et3N COOH LX LXI DMF LXIV NH zu LAV °J LioHxH2o/ MeOH TBAI, Nal, DMF KZC03 ArS/ Et3N, DME Acm [0117] Alternatively, compounds of formula (3), wherein X'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.

Scheme 12 [0118] 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.

Scheme 13 [0119] Compounds of formula (3), wherein X'comprises a sulfur atom, and compounds of formula (4), wherein X3 comprises a sulfur atom, preferably may be prepared as outlined in Scheme 14. Phenylenediamine is reacted with di-tert-butyldicarbonate, followed by iodobenzoic acid, dimethylaminopropylethylcarbodiimide, hydroxybenzotriazole, and triethylamine to provide protected anilinyl amide LXXII. The iodide moiety of LXXII is converted to the methyl ester moiety of LXXIII using procedures analogous to those set forth for Scheme 3 above. The methyl ester moiety of LXXIII is converted to the hydroxyl moiety of LXXIV by treatment with a reducing agent such as diisobutylaluminum hydride (DIBAL-H). Addition of the heterocyclylsulfhydryl compound Het-SH with triphenylphosphine and diethylazodicarboxylate converts the hydroxyl moiety of LXXIV to the sulfanyl moiety of LXXV. LXXV is deprotected with trifluoroacetic acid to afford the sulfanyl anilinyl amide LXXVI.

Scheme 14 1. boy20 1. bozo H2N \ N 2. 4-H NH lodobenzoic acid /NHBoc EDCI, HOBt, Et3N I LXXII PdCI2 (dppfl, CO, MeOH, i-Pr2EtN o > DIBAL-H I H'-I/H NHBoc HO NHBoc MeO2C LXXIV LXXIII DEAD, Ph3P Het-SH O s TFA N \ HetS H NH2 HetS H NHBoc , mye LXXIV N LXXVI Het=C N [0120] 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.

Scheme 15 0 0 B (OH) 2 Pd (PPh3) 4/aq. Na2CO3 gf HJ ; 3 + I,- ; H-P I H NH N H NHZ OMe benzene-ethanol CI N LXXVIII LXXXVII OMe [0121] 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.

Scheme 16 0 0 /CHO a \ I N'\ I N \ NH . 3cyx y LXXLY LXXX O LXXXI o a. p-aminomethylbenzoic acid/AcOH/5 min/reflux b. HOBT/EDC/1, 2-diamino benzene [0122] 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.

[0123] 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.

Scheme 18 0 \ c \ a, b \ "T /N \ O I OH O O LXXXVII LXXXV nid 0 o nid N \ =, I/N I\ H NHz O/O O/N \ LXXXVIII LXXXIX O a. p-aminomethylbenzoic acid/AcOH/reflux/3 hrs b. HOBT/EDC/1, 2-diamino benzene c. 4- (2-aminoethyl) phenol/AcOH/5 hrs/reflux d. PhNTf2/NaH/THF-DMF/30 min/0°C e. 1. CO/Pd (OAc) 2/dppf ! Et3N/MeOH-DMF/4 days/75°C 2. AcOH/HCI/3 hrs/reflux [0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

Scheme 19 0 Xo a, b, d (X = C) I \ N, \ H NHZ (N \ NXO a, c, d (X = N)/NX/ Xf XCI (X = C) O/ XCII (X = N) a O O I \ N I \ e, d (Y = H) I \ N I \ NHz H N uNH2 WOH e f g d (Y = CH3)/N O/ XCIII O XCIV (Y H) XCV (Y = CH3) h, d O a. p-aminomethylbenzoic acid/H20/Et3N/3 hrsl40°C b. HCOOH/reflux/6 hrs /N--Me/N \ c. NaNO2/HCI/0°C/2 hrs, then rt/12 hrs O d. HOBT/EDC/1, 2-diamino benzene XCVI e. CICOOMe/KOH/2 hrs, OoC f. RI/K2CO3/DMF/rt g. NaOH/MeOH/H20 h. Ac2O/1 hour/reflux then AcOH/48 hrs/reflux [0128] 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.

Scheme 20 s MeO N N NH -/ H \ N g COZMe MeO "thenNHs MeO-" NBS/1, 4dioxane/ J H XCVII XCVIII H20/-10°C to 80°C MeO IC 1. LiOH I THo/H20 2. 1, 2-phenylenediamine MeOzJ3~ O t then HCI/ether I N NHz N N, H O Met c [0129] 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.

Scheme 21 0 0 0 1. NaBH (OAc) 3 NH NH Pd (PPh3) 4 NH RNH2 NH2 NtBoc aqy I //I NtBoc CH3COOH / benzene 2. TFA ,, e,, ethanol CHO RHN CI Cil bill [0130] 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.

Scheme 22 Scheme 24 HAN CO Me N"N C02Me NC, N 2 THF N H THE THF CVI reflux CVli 1. nu 2. LiOH. H2O 3. 1, 2-phenylene- diamine, BOP NHz O N"N N-9 \ H NHz H H H H CVIII [0131] 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.

Scheme 30 1 CI 1) R'MgBr, THF/toluene Ri N"N-30'C, 1 h, then rt over 3 h NN CI'-N-'CI CI''NN CO2Me CIX "COzMe OX 'CO Me CIX z i-Pr2NEt, THF, rt 1. R2R3NH, i-Pr2NEt THF, sealed flask 80-90°C 2. LiOH. H20 3. 1, 2-phenylene- diamine, BOP R' NON NNNY NHz RHN R H 0 N_6 cx [0132] 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.

Scheme 32 CI NH n-BU3Sn NH2 NN NH3 gas N4N Pd (PPh3) 4 N4N Cl 1, 4-dioxane N-11, ci toluene I/NN- sealed tube 100°C 0°C G CXI CXII H NHtBoc 1. ub, N Nb Pd2 (dba) 3, POT Et3N, DMF 2. TFA, CH2C ! 2 NHz NHz NXN N N ),, N H2 (40 psi) GNN I HNH210% GNN/I HNHz N MEOH N, 6 6 "o [0133] 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.

Scheme 33 N MeO s BBr3 HO s 0 OH 0 s />-NH2 N 'cr_N N DEAD, PPh3//-NH2 CXV CXVI Cyme OHC Bu2SnCI2, PhSiH3 O _ 1. LiOH NO % S--NH HN E THF/Hz0 O NO N NH C°2Me 2. 1, 2-phenylenediamine H CXVIII H2N BOP, Et3N CXVII [0134] 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.

Scheme 42 HZN NC<, H2S, Et3N, Pyridine A OH /OH S I/OH OH) m O CXIXO 1, 3-dichloroacetone THF N 1. morpholine, THF THF S N 0 2. BOP, Ph (NH2) 2, cl OH C I Et3N, DMF, rt O XX CXX CXX [0135] 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.

Scheme 49 0 0 /OH V p Ir h III N Me/ Me < f 0/e CXXH O Me CXXII CXXIV vi or vi, iii I I iv NC 0 0 Me OH/N Me N-P H2N Ph-N H NH2 H N S I I \ I H NHz Me CXXIII Me Nu oui NC O Me/N \ Nu 0 mye Me/OH NH HN MEOH Me HN NH2 Me-o S-o o CXXV) CXXVI I i : BrCH2C6H4COOMe/MeONa/THF ; ii : PhNHNH2 ; iii : NaOH, then HCI iv : HOBt/EDCxHCI then 1, 2-diaminobenzene ; v : BrCH2C6H4COOMe/MeONa/MeOH, then HCI/AcOH ; vi : CH2 (CN) 2/S8/Et2NH ; vii : AcCI ; viii : 2-N-Bocamino aniline ; ix : TFA ; [0136] 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.

[0137] 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.

Scheme 50 0 0 < COOH, < A A O_ C OH aN NC \ N \ CXXVIII CXXIX iii i : NH20H/EtOH ; ° n O ii : AczO/pyridine ; iii : HOBt/EDCxHCI then 1, 2-diaminobenzene ; Me oN N \ \ I H NHZ CXXX cxxx [0138] 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.

Scheme 57 o COOH 1. SOC12, DMF, DCM I _ N w H2Nt CXXXI CXXXI HN NHtBoc DIPEA THF, PhSiH3, THF, 12h 1. CHCI3/THF 3, 4-dimethoxyaniline SMe NCO i H HzN i O MeS NH NHtBoc H N 9 H NH2 2. TFA, DCM OMe CXXXIII OMe OMe [0139] 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 [0140] 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.

[0141] 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.

[0142] 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).

[0143] 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 [0144] 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.

[0145] 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.

[0146] 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.

[0147] Preferably, the method according to the third aspect of the invention causes an inhibition of cell proliferation of the contacted cells. The phrase"inhibiting cell proliferation"is used to denote an ability of an inhibitor of histone deacetylase to retard the growth of cells contacted with the inhibitor as compared to cells not contacted.

An assessment of cell proliferation can be made by counting contacted and non-contacted cells using a Coulter Cell Counter (Coulter, Miami, FL) or a hemacytometer. Where the cells are in a solid growth (e. g., a solid tumor or organ), such an assessment of cell proliferation can be made by measuring the growth with calipers and comparing the size of the growth of contacted cells with non-contacted cells.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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 pM to about 100 jn. M, more preferably from about 0. 05 gM to about 50 J. M, still more preferably from about 0. 1 pM to about 25 pM, and still yet more preferably from about 0. 5 gM to about 25 RM. 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.

[0157] 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).

[0158] 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.

[0159] 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'-0- 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.

[0160] Particularly preferred antisense oligonucleotides utilized in this aspect of the invention include chimeric oligonucleotides and hybrid oligonucleotides.

[0161] For purposes of the invention, a"chimeric oligonucleotide" refers to an oligonucleotide having more than one type of internucleoside linkage. One preferred example of such a chimeric oligonucleotide is a chimeric oligonucleotide comprising a phosphorothioate, phosphodiester or phosphorodithioate region, preferably comprising from about 2 to about 12 nucleotides, and an alkylphosphonate or alkylphosphonothioate region (see e., g., Pederson et al. U. S. Patent Nos. 5, 635, 377 and 5, 366, 878). Preferably, such chimeric oligonucleotides contain at least three consecutive internucleoside linkages selected from phosphodiester and phosphorothioate linkages, or combinations thereof.

[0162] 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'- 0-substituted ribonucleosides, or combinations thereof (see e. g., Metelev and Agrawal, U. S. Patent No. 5, 652, 355).

[0163] 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.

[0164] 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).

[0165] 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., Oligo Target Number Position Sequence within Number Position-. Gene 5'-GAAACGTGAGGGACTCAGCA- HDAC1 AS1 Human HDAC1 U50079 1585-1604 3 3'-UTR HDAC1 AS2 Human HDAC1 U50079 1565-1584 3-GGAAGCCAGAGCTGGAGAGG-3.-R HDAC1 MM Human HDAC1 U50079 1585-1604 5'-GTTAGGTGAGGCACTGAGGA-3'-UTR 3' 5'-GCTGAGCTGTTCTGATTTGG- HDAC2 AS Human HDAC2 U31814 1643-1622 3'3'-UTR HDAC2 MM Human HDAC2 U31814 1643-1622 5'-CGTGAGCACTTCTCATTTCC-3'-UTR 3' 5'-CGCTTTCCTTGTCATTGACA- HDAC3 AS Human HDAC3 AF039703 1276-1295 3'3'-UTR HDAC3 MM Human HDAC3 AF039703 1276-1295 5'-GCCTTTCCTACTCATTGTGT-3'-UTR 3' 5-GCTGCCTGCCGTGCCCACCC- 3' HDAC4 AS1 Human HDAC4 AB006626 514-33 5'-CGTGCCTGCGCTGCCCACGG-5'-UTR HDAC4 MM1 Human HDAC4 AB006626 514-33 3'5'-UTR HDAC4 AS2 Human HDAC4 AB006626 7710-29 5'-TACAGTCCATGCAACCTCCA-3'-UTR HDAC4 MM4 Human HDAC4 AB006626 7710-29 3'3'-UTR 5'-ATCAGTCCAACCAACCTCGT- 3' . HDAC5 AS Human HDAC5 AF039691 2663-2682 5-CTTCGGTCTCACCTGCTTGG-3'-UTR 5'-CAGGCTGGAATGAGCTACAG- HDAC6 AS Human HDAC6 AJ011972 3791-3810 3'3'-UTR HDAC6 MM Human HDAC6 AJ011972 3791-3810 5'-GACGCTGCAATCAGGTAGAC-3'-UTR 3' HDAC7 AS Human HDAC7 AF239243 2896-2915 5'-CTTCAGCCAGGATGCCCACA-3'-UTR Accession Nucleotide position Oligo Target Number Position Sequence within Gene 3' 5'-CTCCGGCTCCTCCATCTTCC- HDAC8 AS1 Human HDAC8 AF230097 51-70 3'5'-UTR HDAC8 AS2 Human HDAC8 AF230097 1328-1347 5'-AGCCAGCTGCCACTTGATGC-3'-UTR 3' [0166] 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 Cl N---N HCT. H2N / Cl N. Cl CO2Me 1 2 i-Pr2NEt THF,-78°C ci I Jtj J. CL MYE Pathway A NH3 9as S 2 Pathway B 1, 4-dioxane/\ R1R NH sealed flask THF, rt NH, 70°CX ci N)"N N'N ! t J H J ci N-li, N R'R 2N-"-N--'-N 4 CO2Me 5 CO2Me 1 2 THF or 1, 4 dioxane NH3 or R3R4NH sealed flask NRsRa THF or 1, 4-dioxane 120-140°C sealed flask 120-140HC I. H H20 H 6 : R=M LiO. CO2R 7 : R = H THF/H2O HZN H2N BOP reagent /EtgN, DMF HzN NR3R4 NON RR2 = NH RRZN N N \ NHZ N R3R4 = H 8 N, 6 Example 1 Example 1 4- { [4-Amino-6- (2-indanyl-amin. p)- [l, 3, 5]-triazin-2-yl-amino]-methyl}-N-(2- amino-phenyl)-benzamide (compound 8) Step 1 : Methyl-4- [ (4, 6-dichloro- [1, 3, 5] triazin-2-yl-amino)-methyl]- benzoate (compound 3) [0167] 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. NH4Cl, H2O and brine, dried over anhydrous MgS04, 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) 8 (ppm) : AB system (6A = 8. 04, #H = 7. 38, J = 8. 5 Hz, 4H), 6. 54 (bt, 1H), 4. 76 (d, J = 6. 3 Hz, 2H), 3. 93 (s, 3H).

Pathway A Step 2 : Methyl-4- [ (4-amino-6-chloro- [1, 3, 5] triazin-2-yl-amino)-methyl]- benzoate (compound 4) [0168] 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 NH4C1, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4Cl, H20 and brine, dried over anhydrous MgS04, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH2Clz : 30/70) to afford the title compound 4 (5. 16 g, 17. 57 mmol, 91% yield) as a white solid. 1H NMR (300 MHz, CDC13) 6 (ppm) : AB system (8A = 8. 01, bB = 7. 35, J = 8. 1 Hz, 4H), 5. 79 (bs, 1H), 5. 40-5. 20 (m, 2H), 4. 72-4. 63 (m, 2H), 3. 91 (s, 3H).

Pathway B Step 2 : Methyl 4- [ (4-chloro-6- (2-indanyl-amino)- [1, 3, 5] triazin-2-yl- amino)-methyl]-benzoate (compound 5) [0169] 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 RNH (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. NH4Cl, 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, CDC13) 8 (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).

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 : [0170] 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 NH 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. NH4Cl, H2O and brine, dried over anhydrous MgS04, 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, CDC13) 8 (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, CDC13) 5 (ppm) : 166. 88, 167. 35, 166. 07, 144. 77, 141. 07, 129. 82, 128. 93, 127. 01, 126. 61, 124. 70, 52. 06, 51. 80, 44. 25, 40. 16. HRMS (calc.) : 390. 1804, (found) : 390. 1800.

Pathways A and B, step 3, general procedure with primary and/or secondary amines : [0171] 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, H20 and brine, dried over anhydrous MgS04, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel to afford the title compound.

Step 4 : 4- [ (4-Amino-6- (2-indanyl-amino)- [1, 3, 5] triazin-2-yl-amino)- methyl]-benzoic acid (compound 7) [0172] To a stirred solution at room temperature of 6 (2. 07 g, 5. 30mmol) in THF (50 mL) was added a solution of LiOH. HzO (334 mg, 7. 96 mmol) in water (25 mL). After 18 h, the reaction mixture was diluted in water and acidified with 1 N HC1 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) 8 (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.

Step 5 : 4- { [4-Amino-6- (2-indanyl-amino)- [1, 3, 5]-triazin-2-yl-amino]- methyl}-N- (2-amino-phenyl)-benzamide (compound 8) [0173] 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 jul, 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. NH4Cl, H20 and brine, dried over anhydrous MgS04, 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) 8 (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 [0174] 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 Ex. Cpd X Name Characterization Schm. 4-[(4-amino-6-1H NMR (CDC13) 0 (ppm) : 8. 02 (s, 1H), morpholin-4-yl-7. 79 (d, J = 8. 0 Hz, 2H), 7. 34 (d, J = / [1, 3, 5]-triazin- 8. 0 Hz, 2H), 7. 31 (m, 1H), 7. 08 (dt, J = 2 9 J NHZ 2-ylamino)-7. 6 Hz, 1. 5 Hz, 1H), 6. 82 (t, J = 6. 7 1A methyl]-N- (2- Hz, 2H), 5. 62 (t, J = 5. 9 Hz, 1H), 4. 90 amino-phenyl)- (bs, 2H), 4. 61 (d, J = 6. 0 Hz, 2H), benzamide 3. 75-3. 62 (m, 10H). 4- { [4-amino-6-1H NMR (acetone-d6) 8 (ppm) : 9. 07 (bs, (1-indanyl-1H), 8. 05-7. 95 (m, 2H), 7. 55-7. 45 (m, 2H), 7. 37-7. 10 (m, 5H), 7. 04 (dt, J = amino)- (l, 3, 5]- 7. 6 Hz, 1. 6 Hz, 1H), 6. 90 (dd, J = 8. 0 3 10 NH2 triazin-2-Hz, 1. 4 Hz, IH), G. 71 (dt, J-= 7. 6 Hz, 1A ylamino]- HN-ylaminol-1. 4 Hz, 1H), 6. 65-5. 55 (m, 5H), 4. 75- methyl}-N-(2-4. 60 (m, 3H), 3. 05-2. 75 (m, 2H), 2. 60- benzamide 2. 45 (m, 1H)), 2. 00-1. 84 (m, 1H). HRMS (calc.) : 466. 2229, (found) : 466. 2225 Ex. Cpd Y X Name Characterization Schm lH NMR (acetone-d6) 0 (ppm) : mixture of N- (2-Amino- rotamers, 9. 05-9. 00 (m, 1H), 7. 98 (d, J phenyl)-4-{[4-= 8. 8 Hz, 2H), 7. 93 (s), 7. 84 (d, J = amino-6-(4-8. 0 Hz), 7. 72 (d, J = 8. 2 Hz), 7. 58-7. 40 rN phenyl- (m, 3H), 7. 31-7. 19 (m, 3H), 7. 12-7. 05 4 11 NH(m) 6. 98 (d, J = 8. 1 Hz, 2H), 6. 86 (d NHZ piperazin-1-yl)-J-g-2 Hz, 1H), 6. 80 (t, J =7. 1 Hz, lA 2-yiaminol-1H), G. 67 (t, J = 7. 7 Hz, 1H), 6. 57-6. 50 2-y amlno- (m, 1H), 5. 78-5. 60 (m, 2H), 4. 67-4. 64 methyl}- benzamide (m, 2H), 3. 88-3. 84 (m, 4H), 3. 14 (s, 4H). HRMS (calc.) : 477. 2389 [M+-- NH4], (found) : 477. 2383 4- ( [4-amino-6- 3*H NMR (acetone-d6)'8 (ppm) : 9. 08 (bs, (2-pyridinyl-1H), 8. 51 (bs, 1H), 8. 05-7. 90 (m, 2H), methyl-amino)-7. 80-7. 60 (m, 1H), 7. 55-7. 15 (m, 5H), wsA 7. 04 (dt, J = 7. 6 Hz, 1. 6 Hz,, 1H) 6. 90 5 12 2 H H [1, 3, 5-triazin- (dd, J = 8. 0 Hz, 1. 4 Hz, 1H), 6. 71 (dt, 1A ethyl 2-ylamlno]-J = 7. 6 Hz, 1. 4 Hz, 1H), 6. 85-6. 55 (m, methylN- (2- g 4. 75-4. 60 (m, 4H). amino-phenyl)-HRMS (calc.) : 441. 2025, (found) : benzamide 441. 2029 'H NMR (acetone-d6) 8 (ppm) : 9. 08 (bs, 4-f [4, 6-bis- (2- 1H), 8. 05-7. 95 (m ; 2H), 7. 56-7. 44 (m, indanyl-amino)-2H), 7. 34 (bd, J = 7. 7 Hz, 1H), 7. 27- 1, 3, 5-triazin- 7. 6 dz, 1. 4 6 13 v NH W 2-ylamino]-Hz, 1H), 6. 90 (dd, J = 7. 0 Hz, 1. 4 Hz, 1B 1H), 6. 90 (dd, J = 8. 0 Hz, 1. 4 Hz, 1B methyl}-N-(2-1H), 6. 71 (dt, J = 7. 6 Hz, 1. 4 Hz, 1H), amino-phenyl)-6. 65-5. 90 (m, 3H), 4. 90-4. 58 (m, 6H), benzamide 3. 40-2. 80 (m, 4H). HRMS (calc.) : 582. 2855, (found) : 582. 2838 Ex. Cpd Name Characterization Schm 4-{[4-Amino-6- (9H-fluoren-9-1H NMR (acetone-d6) 5 (ppm) : 9. 05-9. 00 ylamino)- (m, 1H), 8. 03-7. 87 (m, 2H), 7. 80-7. 70 7 14 ANH NH [1, 3, 5] triazin- (m, 2H), 7. 63-7. 20 (m, 9H), 7. 00 (t, 1B 2-ylamino]-1H), 6.86 (d, 1H), 6. 66 (t, 1H), 6. 50- W methyl}-N-(2-5. 50 (m, 6H), 4. 75-4. 55 (m, 3H). HRMS amino-phenyl)- (calc.) : 514. 2229, (found) : 514. 2232 benzamide N- (2-amino-'H NMR (CDC13) 8 (ppm) : 7. 96 (bs, 1H), phenyl)-4- [ (4-7. 81 (d, J = 8. 0 Hz, 2H), 7. 38 (d, J amino-6-8 0 Hz, 2H), 7. 32 (d, J = 8. 0 Hz, 1H), N 7. 08 (dt, J = 7. 7 Hz, 1. 4 Hz, 1H), 6. 83 8 15 G NHZ piperidin-1-yl-1A 1, 3, 5]-triazin- (t, J = 6. 6 Hz, 2H), 5 47 (bs, 1H), ,,-l 4. 80 (bs, 2H), 4. 60 (d, J = 6. 0 Hz, 2H), L, J, urj. ii g g Q 2-ylamino)-3. 88 (bs, 2H), 3. 67 (t, J = 5 : 2 Hz, 4H), l. GG-1. 58 (m, 2H,), 1. 56-1. 48 (m, 4H). 4-[(4-amino-6-lH NMR (CDCl3) 6 (ppm) : 7. 97 (bs, 1H), cyclopentyl-7. 82 (d, J = 8. 0 Hz, 2H), 7. 39-7. 34 (m, amino- [1, 3, 5]- 3H), 7. 10 (dt, J = 7. 6 Hz, 1. 4 Hz, 1H), 9 16. NH NH2 triazin-2-yl-6. 85 (t, J = 7. 0 Hz, 2H), 5. 56 (bs, 1A amino)-methyl]-1H), 4. 90 (bs, 3H), 4. 62 (s, 2H), 4. 25- N- (2-amino- 4. 19 (m, 1H) 3. 88 (bs, 2H), 1. 95 (m, phenyl)-2H), 1. 71-1. 59 (m, 4H), 1. 43-1. 37 (m, benzamide 2H). 'H NMR (acetone-d6) 8 (ppm) : 9. 08 (bs, 1H), A63 system (6A = 8. 00, aB = 7. 51, J = (1)-4- { [4- g, 0 Hz, 4H), 7. 33 (bd, J = 7. 7 Hz, 1H), CH3 amino-6-(2-exo-7. 03 (ddd, J = 8. 0 Hz, 7. 3 Hz, 1. 4 Hz, CH3 fench 1-amino)- .""'Y 1H), 6. 90 (dd, J = 8. 0 Hz, 1. 4 Hz, 1H), 10 17 NH NH2 [1, 3, 5]-triazin-6. 71 (dt, J = 7. 6 Hz,, 6. 60- H3C'CH3\ 2-ylamino]-6. 28 (m, 1H), 5. 80-5. 20 (m, 3H), 4. 67 methyl}-N-(2- (bs, 4H), 3. 87 (bd, J = 9. 1 Hz, 1H), amino-phenyl)-1. 80-1. 60 (m, 4H), 1. 56-1. 42 (m, 1H), benzamide 1. 34-1. 00 (m including 2 s, 8H), 0. 84 (s, 3H). HRMS (calc.) : 486. 2855, (found) : 486. 2844 Ex. Cpd Y X Name Characterization Schm 1H NMR (acetone-d6) 6 (ppm) : 9. 07 (bs, 4-f [4-allyl- 1H), 8. 00 (bd, J = 7. 4 Hz, 2H), 7. 58- amino-6-(2-7. 42 (m, 2H), 7. 34 (bd, J = 8. 0 Hz, 1H), indanyl-amino)-7. 27-7. 10 (m, 4H), 7. 04 (td, J = 7. 6 Hz, 11 18 \ H N (1, 3, 5]-triazin- 1. 5 Hz, 1H), 6. 90 (dd, J = 8. 0, 1. 4 Hz, 1H), 6. 71 (dt, J = 7. 6 Hz, 1. 4 Hz, 1H), IB methyll N (2 6. 60-5. 70 (m, 3H), 5. 26-5. 00 (m, 2H), amino-phenyl)-4-86-4. 54 (m, 4H), 4. 10-3. 90 (m, 2H), amino-phenyl)-3. 38-3. 10 (m, 2H), 3. 00-2. 80 (m, 2H). benzamide HRMS (calc.) : 506. 2542,. (found) : 506. 2533 4-{[4-1H NMR (acetone-d6) 6 (ppm) : 9. 07 (bs, cyclopropyl-1H), 8. 00 (bd, J = 7. 7 Hz, 2H), 7. 60- amino-6-(2-7. 40 (m, 2H), 7. 33 (dd, J = 7. 8 Hz, 1. 3 indanyl-amino)-Hz, 1H), 7. 28-7. 10 (m, 4H), 7. 04 (dt, J 12 1, 9 NI'H [>-NH [1, 3, 5]-triazin- 1B 2-ylamino]-Hz, 1. 4 Hz, 1H), G. 71 (dt, J = 7. G Hz, methyl-N- (2- 1. 3 Hz, 1H), 6. 67-5. 80 (m, 2H), 4. 90- amino-phenyl)-4. 50 (m, 4H), 3. 40-3. 10 (m, 2H), 3. 05- benzamide 2. 70 (m, 3H), 0. 75-0. 43 (m, 4H). HRMS (calc.) : 506. 2542, (found) : 506. 2548 1H NMR (acetone-d6) 8 (ppm) : 9. 03 (s, 4- [ (4-Amino-6- 1H), 7. 97 (d, J = 7. 7 Hz, 2H), 7. 55-7. 40 phenethylamino- (m, 2H), 7. 35-7. 10 (m, 6H), 6. 99 (td, J 13 20 [1, 3, 5] triazin- = 8. 0 Hz, 1. 3 Hz, 1H), 6. 86 (dd, J = 8. 0 NH2 2-ylamino)-Hz, 1. 3 Hz, 1H), 6. 67 (dt, J = 8. 0 Hz, 1A H methyl]-N- (2- 1. 4 Hz, 1H), 6. 62-5. 40 (m, 5H), 4. 75- amino-phenyl)-4. 45 (m, 3H), 3. 59-3. 45 (m, 2H), 2. 95- benzamide 2. 70 (m, 2H). HRMS (calc.) : 454. 2229, (found) : 454. 2235 Ex. Cpd Y X Name Characterization Schm N- (2-Amino- phenyl)-4-{[4- H amino-6-(3, 4, 5-1H NMR (CDCl3/MeOD) 6 (ppm) : 7. 72 (d, J = MeO NX trimethoxy-8. 2 Hz, 2H), 7. 21 (d, J = 8. 2 Hz, 2H), 14 21 ß d NH2 phenylamino)-7. 04 (d, J = 7. 7. Hz, 1H), 6. 91 (td, J = 1B MeO T [1, 3, 5] triazin- 7. 7 Hz, 1. 2 Hz, 1H), 6. 70-6. 61 (m, 4H), OMe 2-ylamino]-4. 61 (bs, 2H), 3. 58-3. 52 (m, 9H). methyl}- benzamide 4- { [4-Amino-6- (2, 3-dihydrõ-1H NNR (CDCl3/MeOD) 6 (ppm) : 8. 06 (bs, indol-1-yl)-1H), 7. 82 (d, J = 8. 0 Hz, 2H), 7. 37 (d, tfT n 3 5ltriazin- = S. 2 Hz, 2H), 7. 13 (d, J = 7. 4 Hz, 15 22 i N 2 2-ylamino]-1H), 7. 06 (d, J = 7. 4 Hz, 1H), 7. 02-6. 96 1B \ methyl}-N-(2- (m, 2H), 6. 84-6. 71 (m, 3H), 4. 61 (bs, amino-phenyl)-J-8 5 Hz, 2H), 3. 02 (t, benzamide _,. benzamid 4-({4-Amino-6-1H NMR (acetone-d6) 6 (ppm) : mixture of phenyl)-rotamers, 9. 06 (s, 1H), 7. 96 (d, J = 8. 0 Hz, 2H), 7. 55-7. 40 (m, 2H), 7. 28 (d, J = ethylamino]- 16 23 I i N NHz [1, 3, 5] triazin- 7-4 Hz, 1H), 7. 21-6. 70 (m, 6H), 6. 67 (t, lA J = 7. 4 Hz, 1H), 6. 60-5. 70 (m, 5H), OMe H 2-ylamino-4. 75-4. 55 (m, 3H), 3. 81 (s, 3H), 3. 55- .-', \. 3. 45 (m, 2H), 2. 90-2. 78 (m, 2H). HRMS amino-phenyl)- benzamide (calc.) : 484. 2335, (found) : 484. 2331 benzamlde 4-({4-Amino-6-1H NMR (acetone-d6) 6 (ppm) : mixture of [2- (2-fluoro- rotamers, 9. 03 (s, 1H), 7. 97 (d, J = 8. 0 phenyl)-Hz, 2H), 7. 55-7. 40 (m, 2H), 7. 38-7. 17 ethylamino]- (m, 2H), 7. 17-6. 95 (m, 4H), 6. 86 (dd, J 17 24 N NH2 [1, 3, 5] triazin-= 8. 0 Hz, 1. 4 Hz, 1H), 6. 67 (t, J = 7. 0 1A 2-ylamino}-Hz, 1H), 6. 50-5. 60 (m, 5H), 4. 75-4. 55 methyl)-N- (2- (m, 3H), 3. 60-3. 52 (m, 2H), 2. 95-2. 85 amino-phenyl)- (m, 2H). HRMS (calc.) : 472. 2135, benzamide (found) : 472. 2146 Ex. Cpd Y X Name Characterization Schm 4-f [4-benzyl-'H NMR (acetone-d6) 5 (ppm) : 9. 06 (bs, amino-6- (2- 1H), 8. 04-7. 93 (m, 2H), 7. 57-7. 12 (m, indanyl-amino)-12H), 7. 04 (td, J = 7. 6 Hz, 1. 5 Hz, 1H), N [1, 3, SI-triazin-6-91 (dd, J = 8. 0 Hz, 1. 1 Hz, 1H), 6. 72 1B 25 < 9 2-ylamino]- (bt, J = 7. 6 Hz, 1H), 6. 68-5. 90 (m, 3H), methyl}-N- (2-4. 84-4. 50 (m, 7H), 3. 35-3. 13 (m, 2H), amino-phenyl)-3. 00-2. 80 (m, 2H). HRMS (calc.) : benzamide 556. 2699, (found) : 556. 2706 N- (2-Amino-1H NMR : (CDC13) 8 (ppm) : 7. 83 (d, J = 8. 2 phenyl)-4- [ (4, 6- di-piperidin 6-Hz, 3H), 7. 44 (d, J = 8. 2 Hz, 2H), 7. 32 di-piperldln-l- (d, J = 7. 4, 1H), 7. 12-7. 06 (m, 1H), [1, 3, 5] triazin- 6-87-6. 82 (m, 2H), 5. 11 (t, J = 6. 2 Hz, 1B 2-ylamino)-1H), 4. 64 (d, J = 6. 3 Hz, 2H), 3. 87 (bs, methyl- 3. 69 (t, J = 5. 4 Hz, 8H), 1. 63-1. 53 methyl]- (m 12H) benzamlde, 4-f [6- (2-1H NMR (acetone-d6) b (ppm) : 9. 07 (bs, indanyl-amino)- 4-phenethyl-1H), 8. 05-7. 90 (m, 2H), 7. 60-7. 40 (m, _ 2H), 7. 35-7. 05 (m, 10H), 7. 04 (td, J = rx/r' ammo-Ll, 3, 5J-.,, N", amino-fl, 3, S]-7. 6 Hz, 1. 5 Hz, 1H), 6. 90 (d, J = 7. 7 ylaminol-Hz, 1H), 6. 71 (t, j = 7. 3 Hz, 1H), 6. 60- methyl I-N- (2-5-70 (m, 3H), 4. 95-4. 50 (m, 5H), 3. 70- amino-phenyl)-2- 80 (m, 8H). HRMS (calc.) : 552. 2750 amino-phenyl)- (found) : 552. 2746 benzamide am no-6-(2-1H NMR (CDCl3) 6 (ppm) : 7. 83 (d, J = 8. 2 a. m-LIlO 0-- indanyl-amino)-Hz, 3H), 7. 44 (d, J= 8. 2 Hz, 2H), 7. 32 1, 3, 5-triazin- (d J = 7. 4, 1H), 7. 12-7. 06 (m, 1H), 21 28 N-'2 2-ylamino]-6-87-6. 82 (m, 2H), 5. 11 (t, J = 6. 2 Hz, lA methyl}-N-(2-2H), 3. 69 (t, J = 6. 3 Hz, 2H), 3. 87 (bs, amino-phenyl)-2H), 3. 69 (t, J = 5. 4 Hz), 1. 63-1,. 53 (m, amino-phenyl)-' benzamide Ex. Cpd X Name Characterization Schm 1H NMR (acetone-d6) 8 (ppm) : 9. 04 (s, 4- [ (4-Amino-6- 1H), 7. 95 (d, J = 7. 3 Hz, 2H), 7. 45 (d, benzylamino-J = 7. 1 Hz, 2H), 7. 38-7. 15 (m, 6H), 7. 00 [1, 3, 5] triazin- (td, J = 8. 0 Hz, 1. 5 Hz, 1H), 6. 86 (dd, 22 29 H NH2 2-ylamino)-J = 8. 0 Hz, 1. 4 Hz, 1H), 6. 67 (dt, J = 1A methyl]-N-(2-8. 0 Hz, 1. 4 Hz, 1H), 6. 67-6. 25 (m, 3H), amino-phenyl)-5. 85-5. 55 (m, 3H), 4. 61 (d, J = 6. 3 Hz, benzamide 2H), 4. 54 (d, J = 5. 2 Hz, 2H). HRMS (calc.) : 440. 2073, (found) : 440. 2078 4 {[6-(2 1H NMR (acetone-d6) 6 (ppm) : mixture of indanyl-amino)-rotamers, 9. 20-9. 00 (m, 1H), 8. 70-8. 35 4-(3-pyridinyl- (m, 2H), 8. 05-7. 90 (m, 2H), 7. 85-7. 55 methyl-amino)- (m, 1H), 7. 55-7. 10 (m, 8H), 7. 04 (dt, J 23 30 II NH H (1, 3, 5]-triazin- = 7-6 Hz, 1. 5 Hz, 1H), 6. 91 (bd, J = 7. 4 23 30 H [1, 3, S]-triazin-1B 2-ylamlno]-6. 80-6. 00 (m, 3H), 4. 84-4. 50 (m, 7H), amino-phenyl)-3-34-3. 12 (m, 2H), 3. 00-2. 80 (m, 2H). amino-phenyl)-HRMS (calc.) : 539. 2546 [M+--NH4], (found) : 539. 2533 N- (2-Amino-'H NMR (CDC13) 5 (ppm) : 7. 89 (bs, 1H,), phenyl)-4- [ (4-. 7-82 (d, J = 8. 2 Hz, 2H), 7. 42 (d, J = piperidin-1-yl-8. 0 Hz, 2H), 7. 32 (d, J = 8. 0 Hz, 1H), "\ 6 pyrrolidin-1- 24 31 N (NH 1_ 7-09 (dt, J = 7. 7 Hz, 1. 6 Hz, 1H), 6. 87- 1B 24 6. 82 (m, 2H), 4. 83 (bs, 1H), 4. 62 (d, J [1, 3, 5] triazin- 2-ylamino)-= 6. 0 Hz, 2H), 4. 24 (m, 1H), 3. 88 (bs, methyl]-1H), 2. 04-1. 96 (m, 2H), 1. 70-1. 52 (m, benzamide 10H), 1. 46-1. 38 (m, 2H). benzamide Ex. Cpd Y X Name Characterization Schm N- (2-Amino- phenyl)-4-{[2-1H NMR (CDCl3). 6 (ppm) : 8. 27 (bs, 1H), piperidin-1-yl-7. 74 (d, J = 7. 4 Hz, 2H), 7. 29 (m, 3H), H 6- (2-pyrrolidin- 7. 05 (dt, J = 7. 6 Hz, 1. 4 Hz, 1H), 6. 81- 25 32 CN-CNN 1-yl-6. 76 (m, 2H), 5. 62 (bs, 2H), 4. 57 (bs, 1B ethylamino)-2H), 3. 91 (bs, 2H), 3. 69 (m, 4H), 3. 45 pyrimidin-4- (m, 2H), 2. 57 (t, J = 6. 2 Hz, 2H), 2. 47 ylamino]- (m, 4H), 1. 71 (m, 4H), 1. 59-1. 50 (m, methyl}-6H). benzamide 4- { [G- (2-'H NMR (acetone-d6) 5 (ppm) : 9. 07 (bs, indanyl-amino)- 4-morpholin-4-1H), 8. 08-7. 95 (m, 2H), 7. 60-7. 43 (m, yl r 3] 2H), 7. 33 (d, J = 8. 0 Hz, 1H), 7. 28-7. 12 26 33 NH C No triazin-2- (m, 4H), 7. 04 (dt, J= 7. 6 Hz, 1. 4 Hz, 26 33 NI/M triazin-2-113 ylaminoj (2- 7. 4 Hz, 1H), 6. 55-6. 05 (m, 2H), amino-phenyl)-4 86-4. 60 (m, 5H), 3. 80-3. 56 (m, 8H), benzamide 3. 38-3. 12 (m, 2H), 3. 04-2. 82 (m, 2H). benzamlde N- (2-Amino- phenyl)-4-{[2-1H NMR (acetone-d6) 6 (ppm) : 9. 08 (bs, piperidin-1-yl-1H), 8. 01 (bd, J = 7. 4 Hz, 2H), 7. 56- N 6- (2-pyrrolidin- 7. 43 (m, 2H), 7. 33 (bd, J = 8. 0 Hz, 1H), N 1-yl-7. 28-7. 12 (m, 4H), 7. 04 (dt, J = 7. 6 Hz, 1B ethylamino)-1. 4 Hz, 1H), 6. 90 (dd, J = 8. 0 Hz, 1. 4 pyrimidin-4-Hz, 1H), 6. 71 (dt, J = 7. 6 Hz, 1. 4 Hz, ylamino]-1H), 6. 65-5. 75 (m, 2H), 4. 90-4. 58 (m, methyl}-5H), 3. 66-2. 34 (m, 16H). benzamide 4-({4-Amino-6-1H NMR (acetone-d6) 6 (ppm) : 10. 00 (s, [2-(lH-indol-3-1H), 9. 13 (s, 1H), 7. 93 (d, J = 8. 0 Hz, N-yl)-ethylamino]-2H), 7. 70-7. 50 (m, 1H), 7. 50-7. 22 (m, 28 35 H NH [1, 3, 5] triazin- 4H), 7. 18-6. 91 (m, 4H), 6. 85 (d, J = 7. 1 1A 2-ylamino}-Hz, 1H), 6. 67 (t, J = 7. 4 Hz, 1H), 6. 40- methyl)-N- (2- 5. 90 (m, 3H), 4. 75-4. 50 (m, 2H), 4. 37 amino-phenyl)- (s, 2H), 3. 62 (d, J = 6. 3 Hz, 2H), 2. 99 benzamide (s, 2H).

Table 2b Ex. Cpd X Name Characterization Schm 4-{[4-amino-6-(3-1H NMR (300 MHz, acetone-d6) 8 (ppm) : phenyl-propyl-1-9. 03 (s, 1H), 7. 96 (d, J=8. 2 Hz, 2H), amino)-7. 46 (d, J=7. 7 Hz, 2H), 7. 35-7. 10 (m, N [1, 3, 5] triazin-2-6H), 7. 00 (t, J=7. 7 Hz, 1H), 6. 86 (d, lA 329 470 U NH2 yl-amino]-J=8. 0 Hz, 1H), 6. 67 (t, J=7. 7 Hz, 1H), methyl}-N-(2-6. 60-5. 40 (m, 6H), 4. 62 (s, 2H), 3. 35 amino-phenyl)- (dd, J=12. 1, 6. 9 Hz, 2H), 2. 75-2. 60 benzamide (m, 2H), 1. 95-1. 80 (m, 2H). N- (2-amino-1H NMR (300 MHz, acetone-d6) 8 (ppm) : phenyl)-4- [ (4- 9. 04 (s, 1H), 7. 96 (d, J=8. 0 Hz, 2H), cyclopropyl-7. 55-7. 40 (m, 2H), 7. 35-7. 10 (m, 6H), I>-NH amino-6-6. 98 (t, J=7. 4 Hz, 1H), 6. 85 (d, J=6. 9 1B phenethyl-amino-Hz, 1H), 6. 66 (t, J=7. 3 Hz, 1H), 6. 20- H [1, 3, 5] triazin-2-5. 50 (m, 3H), 4. 80-4. 50 (m, 4H), 3. 65- yl-amino)-3. 45 (m, 2H), 3. 00-2. 60 (m, 2H), 0. 80- methyl]-benzamide 0. 40 (m, 4H). N- (2-amino-1H NMR (300 MHz, acetone-d6) 8 (ppm) : phenyl)-4-{[4-9. 06 (bs, 1H), 8. 00 (bd, J = 7. 1, 2H), cyclopropyl-7. 50 (bs, 1H),), 7. 33 (d, J = 6. 6 Hz, g/H methylamino-6-(2-1H), 7. 28-7. 07 (m, 4H), 7. 03 (td, J = 331 472 JNH/ indanyl-amino)-- --5'1H), 6. 90 (dd, J = 8. 0, 1B indanyl-amino)- 2-yl-amino]-Hz, 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). Ex. Cpd X Y Name Characterization Schm 1V- (2-amino-'H NMR (300 MHz, CDC3) b (ppm) : 8. 08 phenyl)-4- [ (4-n- (s, 1H), 7. 83 (d, J = 6. 6 Hz, 2H), 7. 45-7. 05 (m, 8H), 7. 08 (td, J = 7. 8, w butyl-amino-6-1_5 Hz, 1H), 6. 84 (t, J = 8. 1 Hz, 2H), 1B 332 473 N n-BuNH phenethyl-amino-6_70-5. 00 (m, 3H), 4. 70-4. 50 (m, 2H), 1B H [1, 3, 5] triazin-2- 3. 65-3. 50 (m, 2H), 3. 45-3. 25 (m, 2H), yl-amino)-2. 40-2. 25 (m, 2H), 1. 60-1. 45 (m, 2H), methyl]-benzamide 1. 45-1. 00 (m, 2H), 1. 00-0. 8 (m, 3). 'H NMR (300 MHz, acetone-d6) 8 (ppm) : phenv°n4- (2-- S. 58 (s), 8. 40 (dd, J= 7. 2, methoxy-ethyl-1-2 Hz, 1H), 7. 97 (d, J = 7. 5 Hz, 1H), w 7. 51-7. 40 (m, 2H), 7. 70-6. 90 (m, 7H), amino)-6-1. 2 Hz), 6. 76 (dd, in phenethyl-amino- . phenethyl-amino- . = 7. 5, 1. 8 Hz), 6. 67 (td, J = yl-aminol-7. 8, 1-5 Hz), G. GO-5. 50 (m, 3H), 4. 75- "n 3 5ltriazin-2- = - - '- ' = methyl}-benzamide 4. 55 (m, 4H), 3. 65-3. 35 (m, 6H), 3. 35- methyl-benzamide 3. 20 (s, 3H), 2. 95-2. 75 (m, 2H). N- (2-amino-1H NMR (300 MHz, acetone-d6) 5 (ppm) : phenyl)-4- { [4- (4-9. 02 (s, 1H), 8. 02-7. 91 (m, 2H), 7. 58- CI chloro-phenethyl-7. 40 (m, 2H), 7. 28 (s, 4H), 7. 20-7. 05 amino)-6- (m, 1H), 6. 99 (td, J = 7. 5, 1. 8 Hz, 334 475 >-NH cyclopropyl-1H), 6. 86 (d, J = 7. 8 Hz, 1H), 6. 67 1B HN amino- (t, J = 6. 9 Hz, 1H), 6. 60-5. 60 (m, [1, 3, 5] triazin-2- 3H), 4. 75-4. 50 (m, 4H), 3. 65-3. 40 (bs, yl-amino]-2H), 2. 95-2. 65 (m, 2H), 0. 75-0. 55 (m, methyl}-benzamide 2H), 0. 55-0. 40 (m, 2H). N- (2-amino- phenyl)-4-{[6- OMe cyclopropyl-1H NMR (300 MHz, CDC13) 8 (ppm) : 8. 55- amino-4- (4- 7. 72 (m, 4H), 7. 55-6. 75 (m, 9H), 6. 75- 335 476 X NH f methoxy-5. 30 (m, 3H), 4. 69 (m, 2H), 3. 85 (s, 1B HN phenethyl-amino)-3H), 3. 63 (bs, 2H), 2. 86 (m, 3H), 0. 85 [1, 3, 5] triazin-2- (bs, 2H), 0. 61 (-bs, 2H). yl-amino]- methyl}-benzamide Ex. Cpd X Name Characterization Schm N-(2-amino-1 Cl (2-amino-1H NMR (300 MHz, acetone-d6) 8 (ppm) : CI phloro) phe {ethyl- 9-03 (s, 1H), 7. 96 (d, J = 7. 5 Hz, amino)-6-2H), 7. 60-7. 37 (m, 2H), 7. 37-7. 12 (m, 336 477 cyclopropyl-5H), 6. 99 (t, J = 6. 9 Hz, 1H), 6. 86 1B amino- (d, J = 6. 9 Hz, 1H), 6. 67 (t, J = 7. 2 HN °... Hz, 1H), 6. 60-5. 60 (m, 3H), 4. 75-4. 50 yl-amino]- (m, 4H), 3. 67-3. 45 (m, 2H), 3. 00-2. 67 methyl}-benzamide (m, 3H), 0. 75-0. 40 (m, 4H). N- (2-amino-1H NMR (300 MHz, acetone-d6) 8 (ppm) : phenyl)-4-{[6-9. 02 (s, 1H), 7. 96 (d, J = 8. 1 Hz, OMe cyclopropyl-2H), 7. 60-7. 40 (m, 2H), 7. 29 (d, J = amino-4- (3, 4- 8. 1 Hz, 1H), 6. 99 (td, J = 8. 1, 1. 5 337 478 F NH v dimethoxy-Hz, 1H), 6. 95-6. 72 (m, 4H), 6. 67 (td, 1B HN) phenethyl-amino)-J = 7. 8, 1. 5 Hz, 1H), 6. 20-5. 60 (m, [1, 3, 5] triazin-2- 3H), 4. 78-4. 52 (m, 4H), 3. 75 (s, 6H), yl-amino]-3. 65-3. 42 (m, 2H), 2. 95-2. 65 (m, 3H), methyl}-benzamide 0. 72-0. 40 (m, 4H). N-(2-amino-1H NMR (300 MHz, acetone-d6) 8 (ppm) : OM phenyl)-4-{[6-9. 02 (s, 1H), 7. 96 (d, J = 7. 8 Hz, l e cyclopropyl-2H), 7. 60-7. 35 (m, 2H), 7. 29 (d, J = amino-4- (3- 7. 5 Hz, 1H), 7. 18 (t, J = 7. 8 Hz, 1H), 338 479 >-NH methoxy-6. 99 (td, J = 7. 5, 1. 5 Hz, 1H), 6. 90- 1B J phenethyl-amino)-6. 70 (m, 4H), 6. 67 (t, J = 7. 8 Hz, HIN [1, 3, 5] triazin-2- 1H), 6. 60-5. 60 (m, 3H), 4. 77-4. 50 (m, yl-amino]-4H), 3. 76 (s, 3H), 3. 65-3. 45 (m, 2H), methyl}-benzamide 2. 92-2. 65 (m, 3H), 0. 72-0. 42 (m, 4H). Ex. Cpd X Y Name Characterization Schm 1H NMR (300 MHz, acetone-d6) 8 (ppm) : N- (2-amino- 9. 03 (s, 1H), 8. 50 (d, J = 1. 2 Hz, phenyl)-4-{[6-1H), 7. 96 (d, J = 8. 1 Hz, 2H), 7. 66 cyclopropyl- (t, J = 7. 5 Hz, 1H), 7. 60-7. 40 (m, amino-4- (2- 2H), 7. 35-7. 08 (m, 3H), 6. 99 (td, J = 339 480 F NH f N'pyridin-2-yl-8. 1, 1. 5 Hz, 1H), 6. 86 (dd, J = 8. 1, 1B HN ethyl-l-amino)-1. 5 Hz, 1H), 6. 67 (td, J = 7. 8, 1. 5 [1, 3, 5] triazin-2-Hz, 1H), 6. 60-5. 60 (m, 3H), 4. 75-4. 50 yl-amino]- (m, 4H), 3. 80-3. 60 (m, 2H), 3. 15-2. 90 methyl}-benzamide (m, 2H), 2. 90-2. 65 (m, 1H), 0. 73-0. 40 (m, 4H). N- (2-amino- phenyl)-4-{[6-1H NMR (300 MHz, acetone-d6) 8 (ppm) : cyclopropyl-9. 20-9. 00 (m, 1H), 8. 70-8. 50 (m, 2H), amino-4- (3- 8. 00 and 7. 88 (2d, J = 7. 9 Hz, 2H), 340 481 >-NH pyridin-2-yl-7. 75-7. 43 (m, 3H), 7. 38-6. 67 (m, 5H), 1B HN ethyl-l-amino)-6. 22-5. 78 (m, 3H), 4. 80-4. 55 (m, 4H), [1, 3, 5] triazin-2-3. 61 (bs, 2H), 3. 20-2. 65 (m, 3H), yl-amino]-0. 80-0. 45 (m, 4H). methyl}-benzamide N- (2-amino-1H NMR (300 MHz, acetone-d6) 8 (ppm) : phenyl)-4- [ (4- 9. 04 (s, 1H), 7. 98 (d, J = 8. 1 Hz, cyclopropyl-2H), 7. 60-7. 40 (m, 2H), 7. 35-7. 15 (m, 341 482 6 F NH amino-6-6H), 7. 00 (td, J = 7. 5, 1. 5 Hz, 1H), 1 25 0 phenethyl-oxy-6. 86 (d, J = 8. 1 Hz, 1H), 6. 67 (t, J = [1, 3, 5] triazin-2- 7. 5 Hz, 1H), 7. 18-6. 35 (m, 2H), 4. 75- yl-amino)-4. 30 (m, 6H), 3. 10-2. 92 (m, 2H), 0. 75- methyl]-benzamide 0. 63 (m, 2H), 0. 57-0. 48 (m, 2H). H NMR (300 MHz, acetone-d6 + DMSO- N- (2-amino- de) 8 (ppm) : mixture of rotamers, 9. 62 phenyl)-4-[(6- (bs, 1H), 8. 03 (d, J = 8. 0 Hz, 2H), methyl-4-7. 80-7. 44 (m, 3H), 7. 40-7. 10 (m, 8H), 342 483 N Me phenethylamino-7. 01 (t, J = 7. 6 Hz, 1H), 6. 87 (d, J = 30 H [1, 3, 5] triazin-2-7. 9 Hz, 1H), 6. 67 (t, J = 7. 4 Hz, 1H), yl-amino)-4. 85 (bs, 2H), 4. 72-4. 54 (m, 2H), methyl]-benzamide 3. 63-3. 42 (m, 2H), 2. 96-2. 74 (m, 2H), 2. 21 and 2. 13 (2s, 3H). Ex. Cpd X Name Characterization Schm 1H NMR (300 MHz, acetone-d6) 6 (ppm) : N- (2-amino- mixture of rotamers, 9. 08 (bs, 1H), phenyl)-4-{[4-8. 48-8. 36 (m, 2H), 8. 02 (d, J = 8. 2 t9ke'amino-6-phenyl-Hz, 2H), 7. 63-7. 42 (m, 5H), 7. 33 (d, J 343 484 h j NHz... = 7. 7 Hz, 1H), 7. 19 (bs, 1H), 7. 03 (t, 30 L1. 3, 5J-triazin- j gg j 2-yl-amino]-J = 7. 4 Hz, 1H), 6. 88 (d, J = 7. 9 Hz, methyll-benzamide 1H), 6. 70 (t, J = 7. 6 Hz, 1H), 6. 35 and 6. 25 (2bs, 2H), 4. 87 and 4. 75 (2d, J = 5. 9 Hz, 2H), 4. 65 (bs, 2H). N- (2-amino- 1H NMR (300 MHz, acetone-d6) 5 (ppm) : ure of rotamers, 9. 14-8. 96 (m, indanyl-amino)-4-1H), 8. 54-8. 30 (m, 2H), 8. 09-7. 95 (m, 344 485 ti 2H), 7. 68-7. 40 (m,-5H), 7. 38-7. 08 (m, triazin-2-yl-6H),, 7. 03 (t, J = 7. 3 Hz, 1H), 6. 94- triazin-2-yl-6. 76 (m, 2H), 6. 71 (t, J = 7. 3 Hz, amino]-methyl}-1H), 5. 13-4. 54 (m, 5H), 3. 49-3. 18 (m, benzamide 2H), 3. 12-2. 90 (m, 2H). N NON ACCU f'N) , NH O/ \ (NJ CHZCh O \ I N LIHMDS 36 0'Cto rt 37 THF - to rt 0 HCI. H2N O N fb l-Pr2NEt N O NN \ THF60°C p NJ'N 'I I t) NS jl C02Me N4N H<l H NH2 NJ 2. LiOH. H20 38 THF/H20, rt 39 0 3. BOP, Ph (NH2) 2 t Example 29 O J Et3N, DMF, rt O J O-J Example 29 N-(2-Amino-phenyl)-4-({4-[2-(4-benzof1, 3] dioxol-5-ylmethyl-piperazin- 1-yl)-2-oxo-ethyl]-6-morpholin-4-yl- [1, 3, 5] triazin-2-ylamino}-methyl)- benzamide (compound 39) Step 1 : N-Acetyl-1-piperonylpiperazine (compound 37) [0175] To a stirred solution at 0°C of 1-piperonylpiperazine 36 (5. 00 g, 22. 7 mmol) in anhydrous CH2C12 (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 NH4C1, 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, CDC13) 8 (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).

Step 2 : 2-Chloro-4-morpholin-4-yl-6- [2- (4-benzo [1, 3] dioxol-5-ylmethyl- piperazin-1-yl)-2-oxo-ethyl]- [1, 3, 5] triazine (compound 38) [0176] 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 NH4C1. 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/CH2C12 : 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, CDC13) 8 (ppm) : 6. 84 (s, 1H), 6. 77-6. 69 (m, 2H), 5. 95 (s, 2H), 3. 75-3. 43 (m, 16H), 2. 42 (m, 4H).

Step 3 : N- (2-Amino-phenyl)-4- (f4- [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) [0177] The title compound 39 was obtained following the same procedure as Example 1, step 5. lu NMR (CDCl3) 8 (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). X X , Ja RNH2, Ja eGO2tBu, ¢AX Br N y 1200C RHN Y Pd2 (dba) 3/POT RHN N Y 40 : X=Br, Y=H 42 : X=Br, Y=H DMF/DIPEA/120°C 41 : X = H, Y = Br R = PhNH (CH2) 2 46 : X = AC02tBu y = H 43 : X = H, Y = Br R = PhNH (CH2) 2 R = MeOPhCH2 cOztBu 47 : X=H, Y= CO (1 atm) R = MeOPhCH2 Pd (OAc) 2/ dppf/DMF TFA/CH2C12 DIPEA/60°C r. T Ph (NH2) 2 x nix RHN N Y RHN N Y 48 : X=/» C02H Y=H go R = PhNH (CH2) 2 'NH Example 40 44 : X = XNH2 y H 49 : X = H, Y =CH R = MeOPhCH2 R = PhNH (CH2) 2 Ph (NH2) 2/BOP DMF/TEA/rT , NH X Example 41 45 : X = H Y = NHZ RHN'N Y R = MeOPhCH2 0 ',', ' 'NH Example 42 50 X NH2 Y=H R = PhNH (CH2) 2 0 NH Example 43 51 : X=H Y= tzNH2 R = MeOPhCH2 Example 40 N-(2-aminophenyl)-6-(2-phenylamino-ethylamino)-nicotinamide (compound 44) Step 1 : N-(5-Bromo-pyridin-2-yl)-N'-phenyl-ethane-1, 2-diamine (compound 42) [0178] 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 6h. After cooling down to room temperature, the solid mixture was ground in a mortar, dissolved in ethyl acetate (200 mL), washed with saturated NaHCO3 (2 x 50 mL), dried (MgS04), 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) 8 (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 <BR> <BR> <BR> (M+1).<BR> <BR> <BR> <BR> <BR> <P>Step 2 : N (2-aminophenyl)-6-(2-phenylamino-ethylamino)-nicotinamide (compound 44) [0179] 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 (3mL), treated with diisopropylethyl amine (0. 9 mL, 5. 2 mmol) and the system flushed with CO. The reaction mixture was warmed up to 60°C and stirred under CO (balloon) for 18 h at this temperature. After evaporation of the DMF under vacuo, the residue was purified through a chromatographic column (silica gel, elution 3% to 6% methanol in dichloromethane) to give 258 mg (0. 74 mmol, 62 % yield) of the aminoanilide 44. lH-NMR (CD30D-d4), 6 (ppm) : 8. 67 (d, J = 2. 2 Hz, 1H), 7. 97 (dd, J= 8. 9 Hz, 2. 5 Hz, 1H), 7. 58 (m, 1H), 7. 51 (m, 1H), 7. 15 (dd, J = 7. 7 Hz, 1. 1 Hz, 1H), 7. 08 (m, 2H), 6. 89 (dd, J = 8. 0 Hz, 1. 4 Hz, 1H), 6. 76 (dt, J= 7. 7 Hz, 4. 4 Hz, 1H), 6. 67 (t, J = 7. 7 Hz, 2H), 6. 60 (m, 2H), 4. 87 (bs, 4H), 3. 60 (t, J = 6. 3 Hz, 2H), 3. 35 (t, J = 6. 3 Hz, 2H).

Example 41 N- (2-amino-phenyl)-6- (4-methoxy-benzylamino)-nicotinamide (compound 45) Step 1 : N- (5-Bromo-pyridin-2-yl)-4-methoxybenzylamine (compound 43) [0180] A mixture of 2, 6-dibromopyridine 41 (6. 03 mmol, 2 equiv.) and para-methoxybenzyl amine (413 mg, 3. 01 mmol) was stirred under nitrogen at 120°C for 6h. After identical work-up procedure described before and purification through a pad of silica gel (elution 50% ether in hexanes), a pale yellow solid 43 (773 mg, 2. 60 mmol, 87% yield) was obtained. 13C NMR (300 MHz, CDC13) S (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). Step 2 :. N-(2-amino-phenyl)-6- (4-methoxy-benzylamino)-nicotinamide (compound 45) [0181] Following the procedure described in Example 40, step 2, but substituting 43 for 42, the title compound 45 was obtained in 61% yield.

Example 42 N- (2-aminophenyl)-3- [6- (2-phenylamino-ethylamino)-pyridin-3-yl]- acrylamide (compound 50) Step 2 : 3- [6- (2-Phenylamino-ethylamino)- pyridin-3-yl)-acrylic acid tert-butyl ester (compound 46) [0182] 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), Pdz (dba) 3 (73 mg, 0. 08 mmol) in anhydrous DMF (4 mL) was stirred at 120°C (preheated oil bath) for 2h under nitrogen. After DMF removal, the crude residue was submitted to a chromatographic purification (column silica gel, 50% ether in hexanes) to afford 316 mg of 46 (88% yield). 13C NMR (300 MHz, CDC13) b (ppm) : 166. 6, 159. 3, 149. 6, 147. 8, 140. 7, 134. 9, 129. 1, 119. 8, 117. 3, 115. 9, 112. 6, 107. 8, 80. 0, 43. 5, 40. 9, 28. 1. LRMS = 340. 3 (M+1).

Step 3 : 3- [6- (2-Phenylamino-ethylamino)- pyridin-3-yl)-acrylic acid (compound 48) [0183] Ester 46 (0. 93 mmol) was dissolved 40 % TFA in dichloromethane (10 mL) and the solution stirred at room temperature overnight. The solvent was removed under vacuo distilling with acetonitrile (3x10 mL) and stored under high vacuum for 6h. The solid residue 48 was employed for the next reaction without further purification. LRMS = 284. 1 (M+1).

Step 4 : N- (2-aminophenyl)-3- [6- (2-phenylamino-ethylamino)-pyridin-3- yl]-acrylamide (compound 50) [0184] A mixture of acid 48 (0. 93 mmol), BOP (495 mg, 1. 12 mmol) and 1, 2-phenylenediamine (124 mg, 1. 15 mmol) were dissolved in dry acetonitrile (4 mL) and treated with triethylamine (0. 8 mL, 5. 7 mmol).

The solution was stirred under nitrogen at room temperature for 16h.

After concentration under vacuo, the crude was purified through chromatographic column (5% methanol in dichloromethane), then was crystallized from chloroform to give 50 (247 mg, 71% yield). 1H-NMR (DMSO-d6), 8 (ppm) : 9. 25 (bs, 1H), 8. 21 (d, J = 1. 6 Hz, 1H), 7. 67 (d, J = 8. 5 Hz, 1H), 7. 43 (d, J = 15. 7 Hz, 1H), 7. 32 (d, J = 7. 4 Hz, 1H), 7. 24 (t, J = 1. 0 Hz, 1H), 7. 08 (t, J = 7. 4 Hz, 2H), 6. 91 (t, J = 8. 0 Hz, 1H), 6. 75 (dt, J= 8. 0 Hz, 0. 4 Hz, 1H), 6. 57 (m, 6H), 5. 20 (bs, 1H), 3. 48 (t, J = 6. 3 Hz, 2H), 3. 33 (bs, 2H), 3. 21 (t, J = 6. 3 Hz, 2H).

Example 43 N- (2-aminophenyl)-3- [6- (4-methoxy-benzylamino)-pyridin-2-yl]- acrylamide (compound 51) Step 2 : N- (2-aminophenyl)-3- [6- (4-methoxy-benzylamino)-pyridin-2-yl]- acrylamide (compound 51) [0185] 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 (CDC13), 8 (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). 0 \ CDI/Et3N OH H2N DBU DMF 0 N + Br N 54 Br 52 53 1) POT/Pd2 (dba) 3 DIPEA/DMF 2) BOP/Et3N/DMF CH2=CHCOOH Ph (NH2) 2 120°C oit N NH2 H H 55 O Example 44 Example 44 4-[2-(2-amino-phenylcarbamoyl)-vinyl]-benzyl}-carbamic acid pyridin-3- yl methyl ester (compound 55) Step 1 : (4-bromo-benzyl)-carbamic acid pyridin-3-yl-methyl ester (compound 54) [0186] 4-bromobenzylamine HC1 (3. 0g, 13. 4 mmol) was dissolved in DMF (60 mL) at rt and then Et3N (4. 13 mL, 29. 7 mmol) was added dropwise over 10 min to give cloudy solution. To this, DBU (2. 42 mL, 16. 2 mmol) and 1, 1'-carbonyl diimidazole (2. 41g, 14. 8 mmol) were added. After being stirred for 1 h at rt, 3-Pyridylcarbinol (1. 44 mL, 14. 8 mmol) was added dropwise over 10 min. The resulting reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue obtained was diluted with ether/EtOAc (9 : 1) and then washed with H2O. The organic layer was dried over Na2SO4, filtered and then concentrated to give the crude product which was recrystallized from EtOAc to give 2. 55g of product 54 (59% yield, LRMS = 323 (M+1).

Step 2 : 4- [2- (2-amino-phenylcarbamoyl)-vinyl]-benzyl}-carbamic acid pyridin-3-yl methyl ester (compound 55) [0187] 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) 8 (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). Me0 \ NHa Br I Me0 I H I \ Br Me /mye0/ Mye0 Me OMe rT to 80 C 57 OMe O 56 vNH NH Pd2 (dba) 3/POT DMF ! DIPEA/ 120 C \ I Me0 N \ NO Me0 \ N \ \ NOZ CHaO/HCOH I \ H rcefl., Me NH Me0 5$ Me0 60 OMe. 0 OMe O SnCI2/MeOH/ I H20 75 C Ha0/75 C/ MeO4f <) OMe 61 ° sNH2 H 2/MeOH Me0 I I NH Me0 OMe 59 O OMe, g O Example 45 Example 45 Example 45 N- (2-aminophenyl)-3- {4- [ (3, 4, 5-trimethoxy-benzylamino)-methyl]- phenyl}-acrylamide (compound 59) Step 1 : (4-Bromo-benzyl)- (3, 4, 5-trimethoxy-benzyl)-amine (compound 57) [0188] To a stirred suspension of K2CO3 (522 mg, 3. 77 mmol) in dry DMF was added 3, 4, 5-trimethoxybenzylamine (1. 10 mL, 6. 44 mmol, 2. 2 equiv.) followed by a solution of p-bromo benzylbromide (0. 73 g, 2. 91 mmol) in dry DMF (8 mL). The mixture was stirred at room temperature under nitrogen for two days in the dark, diluted with dichloromethane (200 mL), washed with brine, dried (MgS04), filtered and concentrated.

The crude residue was purified by chromatographic column on silica gel (elution 5% methanol in dichloromethane) to give 2. 59 mmol (89% yield) of dibenzylamine 57. 13C NMR (300 MHz, CDC13) 8 (ppm) : 152. 5, 138. 8, 136. 1, 135. 4, 130. 6, 129. 2, 119. 8, 104. 2, 59. 9, 55. 3, 52. 6, 51. 7. LRMS = 368. 4 (M+1).

Step 2 : N-(2-Nitro-phenyl)-3-{4-[(3, 4, 5-trimethoxy-benzylamino)- methyl]-phenyl}-acrylamide (compound 58) Preparation of the nitroacrylanilide [0189] To a mixture of 2-nitroaniline (1. 73 g, 12. 5 mmol), DMAP (321 mg, 2. 6 mmol) and 2, 6-di-tert-butyl-4-methylphenol (308 mg) in dry dichloromethane (50 mL) at 0°C was added triethylamine (10. 6 mL, 76 mmol) followed by acryloylchloride (3. 2 mL, 38 mmol, 3. 0 equiv.), and the mixture was stirred at room temperature for 16h. The solution was diluted with dichloromethane (250 mL), cooled to 0°C and the excess of reagent quenched with saturated NaHC03 (stirring for 1 h). The organic layer was then washed (5% KHS04, then brine), dried (MgS04), 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) 8 (ppm) : 163. 6, 136. 0, 135. 6, 134. 5, 131. 3, 128. 6, 125. 4, 123. 1, 121. 8. LRMS = 193. 2 (M+1).

Step 3 : N- (2-aminophenyl)-3- {4- [ (3, 4, 5-trimethoxy-benzylamino)- methyl]-phenyl}-acrylamide (59) [0190] A mixture of nitro-compound 58 (127 mg, 0. 27 mmol), SnCl2 (429 mg, 2. 26 mmol, 8. 4 equiv.) and NH40Ac (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 (MgS04), filtered, and concentrated. Purification by chromatographic column on silica gel (elution 5 to 10% methanol in dichloromethane) gave 52 mg (43% yield) of 59.'H-NMR (CDC13), 5 (ppm) : 8. 25 (bs, 1H), 7. 59 (d, J = 15. 6 Hz, 1H), 7. 38 (d, J = 7. 5 Hz, 2H), 7. 29 (d, J = 7. 5 Hz, 2H), 7. 25 (m 1H), 7. 02 (t, J = 6. 8 Hz, 1H), 6. 75 (m, 2H), 6. 62 (d, J = 15. 6 Hz, 1H), 6. 58 (s, 2H), 3. 97 (bs, 3H), 3. 80 (s, 9H), 3. 78 (s, 2H), 3. 72 (s, 2H).

Example 46 N-(2-aminophenyl)-3-(4-{[(3, 4, 5-trimethoxy-benzyl)-amino]-methyl}- phenyl)-acrylamide (compound 61) Step 1 : 3-{4-{[Methyl-(3, 4, 5-trimethoxy-benzyl)-amino]-methyl}- phenyl)-N- (2-nitro-phenyl)-acrylamide (compound 60) [0191] Amine 58 (180. 2 mg, 0. 38 mmol) was dissolved in 88% of HGOH (6 mL), treated with excess of paraformaldehyde (7. 67 mmol) and the mixture stirred at 70°C for 2. 5h. A saturated NaHC03 solution, was added slowly, extracted with dichloromethane (2 x 75 mL), dried (MgSO4), filtered and concentrated. After chromatographic column on silica gel (elution 3 to 5% methanol in dichloromethane), pure N- methyl amine 60 (118 mg, 63% yield) was obtained. 13C NMR (300 MHz, CDC13) 8 (ppm) : 164. 5, 153. 1, 143. 5, 142. 3, 136. 8, 136. 1, 136. 0, 135. 3, 134. 9, 132. 9, 129. 3, 128. 2, 125. 8, 123. 1, 122. 2, 120. 3, 105. 4, 62. 2, 61. 2, 60. 8, 56. 0, 42. 5. LRMS = 492. 5 (M+1).

Step 2 : N- (2-aminophenyl)-3- (4- { [ (3, 4, 5-trimethoxy-benzyl)-amino]- methyl}-phenyl)-acrylamide (compound 61) [0192] 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), 8 (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). 0 P HCI/MeOH 0 CH Cat, Nal/K2CO3 Ao, CH3 rOH reflux ¢ o 3 DMF/60°C NzW N H2Nw 62 H2N 63 MeOPhCH2CI OJO/\H 64 62 63 Me 1) NaOH/THF/MeOH 2) BOP/Et3N/DMF Ph (NH H \ \ H \ MeO" Me0 I H 65 Example 47 Example 47 N-(2-aminophenyl)-3-{4-(4-methoxy-benzylamino)-phenyl}-acryl amide (compound 65) Step 1 : Methyl-3- (4-amino-phenyl)-acrylate hydrochloride (compound 63) [0193] 4-amino-cinnamic acid (10. 41 g, 0. 052 mol) was dissolved in methanol (100 mL) at rt. A solution of HC1 in dioxane (15. 6 mL, 4 N) was then added. The reaction mixture was heated at reflux overnight.

The clear solution was evaporated to a half volume and then settled down at rt. The white suspension obtained was collected by vacuum filtration. The mother liquid was evaporated again to a quart volume and cooled down to rt. The suspension was filtered again. The combined the solid collected from two filtration was dried in vacuo to give 7. 16 g of 63 (64. 3% yield). LRMS : 178 (M+1).

Step 2 : Methyl-3- {4- (4-methoxy-benzylamino)-phenyl}- acrylate hydrochloride (compound 64) [0194] 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), NaI (0. 38 g, 2. 6 mmol) and K2C03 (3. 53 g, 25. 5 mmol) were added successively. The mixture was heated at 60°C overnight and evaporated to dryness. The residue was partitioned between NaHCO3 sat. solution (50 mL) and EtOAc (50mLx3). The combined organic layers were washed with brine and then evaporated to dryness. The residue was purified by flash chromatography and then recrystallized from isopropylalcohol to give 1. 16 g 64 (yield 30. 6%, LRMS = 298) and 1. 46g of 63 (49% recovered yield).

Step 3 : N-(2-aminophenyl)-3-{4-(4-methoxy-benzylamino)-phenylT- acrylamide (compound 65) [0195] 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) 8 (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). 1-Pd2 (dba) 3/Et3N/DMF/ Ar z, NH K2CO3 Ar NH CH2=CHCOOH/100°C DMF 2-BOP/DMF/Et3N I 000C Ph (NH2) 2 // 68 I 66 : ArZ =PhBr 69 : ArZ =Ph N O NHzH 67 : ArZ = MeOPhCOCI 70 : ArZ = MeOPhCO Example 48 71 : ArZ = Ph/\ Example 49 72 : ArZ = MeOPhCO Example 48 N- (2-Amino-phenyl)-3- (4-styrylamino-phenyl)-acrylamide (compound 71) Step 1 : N- (4-Iodo-phenyl)- (3-phenyl-allyl)-amine (compound 69) [0196] 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) Step 2 : N- (2-Amino-phenyl)-3- (4-styrylamino-phenyl)-acrylamide (71) [0197] 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) 8 (ppm) : 9. 22 (bs, 1H), 7. 45 (d, J = 6. 9 Hz, 2H), 7. 39 (d, J = 9. 0 Hz, 2H), 7. 34 (d, J = 7. 4 Hz, 2H), 7. 26 (dt, J = 7. 4 Hz, 6. 8 Hz, 2H), 6. 93 (dt, J = 7. 9 Hz, 7. 1 Hz, 1H), 6. 78 (d, J = 7. 9 Hz, 1H), 6. 69 (d, J = 8. 5 Hz, 2H), 6. 63-6. 55 (m, 4H), 6. 44-6. 37 (m, 1H), 4. 95 (bs, 2H), 3. 95 (bs, 2H).

Example 49 N- (2-Amino-phenyl)-3- [4- (4-methoxy-benzamide)]-acrylamide (compound 72) Step 1 : N- (4-Iodo-phenyl)-4-methoxy-benzamide (compound 70) [0198] 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+l) Step 2 : N- (2-Amino-phenyl)-3- [4- (4-methoxy-benzamide)]-acrylamide (compound 72) [0199] 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) 8 (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). BrAN Br''I NJ' N H, N _NH2 120 C bu H HzNN I N H'N N 73 \ N O iso 74 0/MEOH H20 0 /\/PhMe/reflux then 88 % HC02H/reflux N Br N O Br /N1 I N I/NN I N 6 75 0 H 77 1. C02tBu 2. TFA/CH2Ciz 1, C02tBu 2. TFA/CH2CIz Pd2 (dba) 3/POT 3. Ph (NH2) 2/BOP Pd2 (dba) 3/POT 3. Ph (NH2) 2/BOP DMF/DIPEA/120°C DMF/TEA/rT DMF/DIPEA/120°C DMF/TEA/rT ozon ¢4 H NJ H NH2 >N N N) J H NH2 N-P N'p ICI H IN H O 7g O 78 Example S0 Example 51 Example 50 N- (2-aminophenyl)-3- {6- [2- (4-oxo-4H-quinazolin-3-yl)-ethylamino]- pyridin-3-yl}-acrylamide (compound 76) Step 1 : N- (5-Bromo-pyridin-2-yl)-ethane-1, 2-diamine (compound 73) [0200] 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, CD30D) : 159. 1, 148. 7, 140. 7, 111. 7, 107. 2, 44. 3, 41. 7. LRMS = 218. 1 (M+1) Step 2 : 3- [2- (5-Bromo-pyridin-2-ylamino)-ethyl]-3H-quinazolin-4-one (compound 75) [0201] 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, CDC13) : 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).

Step 3 : N- (2-aminophenyl)-3- {6- [2- (4-oxo-4H-quinazolin-3-yl)- ethylamino]-pyridin-3-yl}-acrylamide (compound 76) [0202] 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), 6 (ppm) : 9. 24 (bs, 1H), 8. 17 (dd, J = 8. 0 Hz, 1. 6 Hz, 1H), 8. 11 (bs, 1H), 8. 08 (d, J = 1. 9 Hz, 1H), 7. 82 (dt, J = 8. 5 Hz, 1. 4 Hz, 1H), 7. 64 (d, J = 8. 2 Hz, 2H), 7. 25 (t, J = 5. 8 Hz, 1H), 6. 90 (dt, J = 15. 7 Hz, 1H), 6. 74 (dd, J = 8. 0 Hz, 1. 4 Hz, 1H), 6. 58 (m, 3H), 4. 95 (bs, 2H), 4. 17 (t, J = 5. 2 Hz, 2H), 3. 68 (m, J = 5. 2 Hz, 2H).

Example 51 N- (2-aminophenyl)-3- {6- [2- (4-benzyl-2, 6-dioxo-piperazin-1-yl)- ethylamino]-pyridin-3-yl}-acrylamide (compound 78) Step 2 : 4-Benzyl-l- [2- (5-bromo-pyridin-2-ylamino)-ethyll-piperazine- 2, 6-dione (compound 77) [0203] A suspension of benzyliminodiacetic acid (702 mg, 3. 15 mmol) and acetic anhydride (15 mL) was stirred at 120°C for 45 min. The reaction mixture was diluted with dry toluene and concentrated in vacuo to remove the volatiles. The residue was dissolved in dry toluene (15 mL) and transferred via cannula to a reaction flask containing the amine 73 (475 mg, 3. 2 mmol). The mixture was'heated at 90°C for 16 h, concentrated and chromatographed by column on silica gel (elution 5% methanol in dichloromethane) to give 684mg (1. 70 mmol, 54% yield) of 77.

Step 3 : N- (2-aminophenyl)-3- {6- [2- (4-benzyl-2, 6-dioxo-piperazin-1-yl)- ethylamino]-pyridin-3-yl}-acrylamide (compound 78) [0204] 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 (CD30D-d4), 6 (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). N /NHZ. \/N HCLHzN j Br C "'N N \ THF N)-ci I-Pr2NEt Br 79 THF 80 78 C gp/Br rut Nu3 pas 1, 4-dioxane NH, 0 sealed flask m N ; N vNH 120-140QC Pd2 (dba) 3 NH2 POT \// NHR Et3N, DMF N N HN sealed flask (Da)' 82 : R = Boc TFA /100°C H I/Br 95% inwater g 83 : R= H ^2 rt rt Example 52 Example 52 (E)-4- { [4-Amino-6- (2-indanyl-amino)- [1, 3, 5] triazin-2-yl-amino]- methyl)-N- (2-amino-phenyl)-cinnamide (compound 83) Step 1 : 4, 6-Dichloro-2- (2-indanyl-amino)- [1, 3, 5] triazine (compound 79) [0205] 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. NH4Cl, HZO 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) 8 (ppm) : 7. 29-7. 18 (m, 4H), 6. 02 (bd, J = 6. 3 Hz, 1H), 4. 94-4. 84 (m, 1H), 3. 41 (dd, J = 16. 2, 6. 9 Hz, 2H), 2. 89 (dd, J = 16. 1, 4. 5 Hz, 2H).

Step 2 : 2- (4-Bromo-benzyl-amino)-4-chloro-6- (2-indanyl-amino)- [1, 3, 5] triazine (compound 80) [0206] 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. NH4Cl, H2O and brine, dried over anhydrous MgS04, 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, CDC13) 8 (ppm) : mixture of rotamers, 7. 52-7. 42 (m, 2H), 7. 26-7. 11 (m, 6H), 6. 51 and 6. 12 (2 m, 1H), 5. 72-5. 46 (m, 1H), 4. 94-4. 64 (m, 1H), 4. 62-4. 46 (m, 2H), 3. 43-3. 16 (m, 2H), 2. 92-2. 74 (m, 2H).

Step 3 : 4-Amino-2- (4-bromo-benzyl-amino)-6- (2-indanyl-amino)- [1, 3, 5] triazine (compound 81) [0207] 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 HC1, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4Cl, H2O and brine, dried over anhydrous MgS04, 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. lH NMR (300 MHz, CDCl3) 8 (ppm) : 7. 43 (d, J = 8. 2 Hz, 2H), 7. 25-7. 12 (m, 6H), 5. 70-5. 10 (m, 2H), 5. 00-4. 65 (m, 3H), 4. 52 (bs, 2H), 3. 40-3. 10 (m, 2H), 2. 90-2. 65 (m, 2H).

Step 4 : (E)-4- { [4-Amino-6- (2-indanyl-amino)- [1, 3, 5] triazin-2-yl- amino]-methyl}-N- [2- (N-t-butoxycarbonyl)-amino-phenyl]-cinamide (compound 82) Preparation of N- [2- (N-t-Butoxycarbonyl)-amino-phenyl]-acrylamide [0208] 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. lH NMR (300 MHz, CDC13) 8 (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).

[0209] In a 50 mL sealed flask, a solution of 81 (300 mg, 0. 73 mmol), the acrylamide (230 mg, 0. 88 mmol), Et3N (407 gel, 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. NH4Cl, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated.

The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2Cl2 : 2/9895/95) to afford the title compound 82 (240 mg, 0. 41 mmol, 56% yield) as a beige solid. 1H NMR (300 MHz, CDC13) 8 (ppm) : 8. 46 (bs, 1H), 7. 71 (bd, J = 15. 7 Hz, 1H), 7. 62-7. 05 (m, 13H), 6. 54 (bd, J = 15. 9 Hz, 1H), 5. 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).

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) [0210] 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. NaHC03, Hz0 and brine, dried over anhydrous MgS04, 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. lH NMR (300 MHz, acetone-d6) 5 (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). OH OTf OTf HO J Tf 0 N N 84 85 Me c/\d, e, f NH Nu 2 Nu N N'"'6r H Me 88 Me0' 87 Example 54 Example 53 a. Tf2O/Py/DMAP/0 C b. p-methoxybenzylamine/120 C c. 1, 2-phenylenediamine I CO (40 ps !)/PdfOAc) /dppf/ DMF/DPEA/70C d. t Butylacrylate I Pd2 (dba) 3/POT/DMF/DIPEA/120 C e. TFA/DCM/rT f. 1, 2-phenylenediamine/BOP/DMF/TEA/rT Example 53 N- (2-aminophenyl)-2- (4-methoxy-benzylamino)-quinolin-6-yl-amide (compound 87) Step 1 : 2, 6-ditrifluoromethanesulfonyloxy-quinoline (compound 85) : [0211] 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 NaHC03 and extracted with dichloromethane (2 x 150 mL), dried (MgS04), filtered and concentrated. Purification by column chromatography on silica gel (30% to 50% ether in hexanes) gave 2. 58 g (6. 1 mmol, 78% yield) of 85. 13C NMR (300 MHz, CDC13) : 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).

Step 2 : N- (2-aminophenyl)-2- (4-methoxy-benzylamino)-quinolin-6-yl- amide (compound 87) [0212] Following the procedure described in Example 40, steps 1, 2, but substituting 85 for 40, the title compound 87 was obtained in 92% yield. lH-NMR (DMSO-d6), 6 (ppm) : 9. 66 (bs, 1H), 8. 32 (s, 1H), 8. 05 (d, J = 8. 8 Hz, 1H), 7. 96 (dd, J = 9. 1 Hz, 2. 2 Hz, 1H), 7. 72 (d, J = 2. 2 Hz, 1H), 7. 55 (dd, J = 8. 5 Hz, 2. 2 Hz, 1H), 7. 34 (dd, J = 8. 5 Hz, 2. 2 Hz, 1H), 7. 20 (d, J = 7. 7 Hz, 1H), 6. 97 (t, J = 7. 7 Hz, 1H), 6. 90 (m 2H), 6. 80 (d, J = 7. 9 Hz, 1H), 6. 61 (t, J = 6. 3 Hz, 1H), 4. 90 (bs 2H), 4. 58 (d, J = 3. 3 Hz, 2H), 3. 73 (s, 3H), 3. 33 (bs, 1H).

Example 54 N- (2-aminophenyl)-3- [2- (4-methoxy-benzylamino)-quinolin-6-yl]- acrylamide (compound 88) Step 3 : N- (2-aminophenyl)-3- [2- (4-methoxy-. benzylamino)-quinolin-6-y1]- acrylamide (compound 88) [0213] 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), 8 (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 [0214] 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 Ex Cpd w Y Z R Name Characterization Schm _ 1H-NMR (DMSO-d6), 6 (ppm) : 9. 25 (bs, N-(2-1H), 8. 21 (d, J = 1. 6 Hz, 1H), 7. 67 aminophenyl)- (d, J = 8. 5 Hz, 1H), 7. 43 (d, J = 15. 7 Hz, 1H), 7. 32 (d, J= 7. 4 Hz, 3- [6- (2- 1H), 7. 24 (t, J = 1. 0 Hz, 1H), 7. 08 3 42 50 /H N CH H phenylamino- (t J = 7. 4 Hz, 2H), 6. 91 (t, J = ethylamino)-8. 0 Hz, 1H), 6. 75 (dt, J= 8. 0 Hz, pyridin-3-yll-0. 4 Hz, 1H), 6. 57 (m, 6H) 5. 20 (bs, acrylamido (bs, 2H), 3. 21 (t, J = 6. 3 Hz, 2H) (bs, 2H), 3. 21 (t, J = 6. 3 Hz, 2H) (bs, 2H), 3. 21 (t, J == 6. 3 Hz, 2H) 1H NNR : (DMSO-d6) 8 (ppm) : 10. 03 (s, 1H), 9. 32 (s, 1H), 8. 65 (s, 1H), amino- 8. 55 (d, J = 3. 3 Hz, 1H), 7. 85 (d, J 'it, Jt phenylcarbamoy = 7. 69 Hz, 1H), 7. 40-7. 60 (m, 6H), 44 55b ff » n Nz CH CH H 7. 31 (d, J = 7. 69 Hz, 1H), 6. 89 (dd ;. 4 H phenyl)- pyridin-3-yl 6-9 (m, 2H), J =55 (dd, J = 7. 1 Hz, Pyy'-- - (dd, J-7. 1Hz, (bs, 2H). " (bs, 2H). Ex Cpd _ Z R Name Characterization Schm N- (2-1H-NMR (CDC13), 6 (ppm) : 8. 25 (bs, aminophenyl)-1H), 7. 59 (d, J = 15. 6 Hz, 1H), 7. 38 MeO N 3- {4- [ (3, 4, 5- (d, J = 7. 5 H-z, 2H), 7. 29 (d, J = 45 59 H CH CH H trimethoxy-7. 5 Hz, 2H), 7. 25 (m 1H), 7. 02 (t, J 5 MeO T benzylamino)-= 6. 8 Hz, 1H), 6. 75 (m, 2H), 6. 62 OMe methyl- (d, J = 15. 6 Hz, 1H), 6. 58 (s, 2H), phenyl}-3. 97 (bs, 3H), 3. 80 (s, 9H), 3. 78 acrylamide (s, 2H), 3. 72 (s, 2H). aminopheny-)-1H-NMR (DMSO-d6), 8 (ppm) : 9. 15 (bs, aminophenyl)- g , N methox-Hz, 1H), 7. 30 (m 4H), 7. 12 (d, J = 46 Glb H N CH Me m 7 7 Hz, 1H), 6. 91 (m 3H), 6. 75 (d, J 3 benzylamino)- 2-methyl- (bs, 2H), 4. 43 (d, J = 5. 5 Hz, 2H), 2-metiiyl acrylamide 3. 72 (s, 3H), 3. 33 (s, 3H). N-(2-amino-1H NMR : (DMSO-d5) 6 (ppm) : 9. 15 (s, phenyl)-3- [4- N (4-methoxy- N (4-methoxy- 47 65 J J H CH H benzylamino)- (m, 3H), 6. 72 (m, 2H), 6. 49-6 60 (m, 6 Me0 phenyl]-4H), 4. 84 (s, 2H), 4. 22 (d, J = acrylamide 5. 77 Hz, 2H). acryLmide S. 77Hz, 2H). H NMR : (DMSO-d6) 8 (ppm) : 9. 22 (bs, 1H), 7. 45 (d, J = 6. 9 Hz, 2H), 7. 39 N- (2-Amino- (d, J = 9. 0 Hz, 2H), 7. 34 (d, J = phenyl)-3- (4- 7. 4 Hz, 2H), 7. 26 (dt, J = 7. 4 Hz, 48 71 CH CH CH H styrylamino-6. 8 Hz, 2H), 6. 93 (dt, J = 7. 9 Hz, 7 phenyl)-7. 1 Hz, 1H), 6. 78 (d, J = 7. 9 Hz, acrylamide 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). Ex Cpd Ex Cpd W y Z R Name Characterization Schm N- {4- [2- (2-1H NMR : (DMSO-d6) 8 (ppm) : 9. 4 (bs, Amino-1H), 7. 60 (d, J = 8. 5 Hz, 1H), 7. 54- phenylcarbamoy 7. 45 (m, 3H), 7. 87 (d, J = 7. 7 Hz, 49 72 m H CH CH H l)-vinyl]-1H), 7. 10 (d, J = 8. 8 Hz, 1H), 6. 95- 7 Met 6. 77 (m, 3H), 6. 62 (d, J = 7. 7 Hz, methoxy-2H), 6. 08-6. 04 (m, 2H), 4. 98 (bs, benzamide 2H), 3-72 (s, 3H). N- (2-1H-NMR (DMSO-d6), 8 (ppm) : 9. 24 (bs, aminophenyl)-1H), 8. 17 (dd, J = 8. 0 Hz, 1. 6 Hz, _ 1H), 8. 11 (bs, 1H), 8. 08 (d, J = 1. 9 -Y N oxo-4H-Hz, 1H), 7. 82 (dt, J = 8. 5 Hz, 1. 4 50 76 < N Nz N CH H quinazolin-3-Hz, 1H), 7. 64 (d, J = 8. 2 Hz, 2H), 8 yl)-7. 25 (t, J = 5. 8 Hz, 1H), 6. 90 (dt, O ethylamino]-J = 15. 7 Hz, 1H), 6. 74 (dd, J = 8. 0 pyridin-3-yl}-Hz, 1. 4 Hz, 1H), 6. 58 (m, 3H), 4. 95 acrylamide (bs, 2H), 4. 17 (t, J = 5. 2 Hz, 2H), 3. 68 (m, J = 5. 2 Hz, 2H). 1H-NMR (CD30D-d4), 8 (ppm) : 8. 09 (d, N- (2- J = 1. 8 Hz, 1H), 7. 68 (dd, J = 8. 7 aminophenyl)-Hz, 2. 1 Hz, 1H), 7. 53 (d, J = 15. 6 3-16- [2- (4- Hz, 1H), 7. 29 (m, 6H), 7. 20 (dd, J = 0 benzyl-2, 6- 7. 8 Hz, 1. 2 Hz, 1H), 7. 02 (dt, J = dioxo-9. 0 Hz, 1. 2 Hz, 1H), 6. 86 (dd, J = t N piperazin-l-8. 1 Hz, 1. 2 Hz, 1H), 6. 73 (dt, J = 0 H yl)-7. 5 Hz, 1. 5 Hz, 1H), 6. 61 (d, J = ethylamino]-15. 6 Hz, 1H), 6. 50 (d, J = 8. 7 Hz, pyridin-3-yl}-1H), 4. 85 (bs, 3H), 3. 97 (t, J = 7. 5 acrylamide Hz, 2H), 3. 60 (s, 2H), 3. 57 (t, J = 7. 5 Hz, 2H), 3. 38 (s, 4H). Ex Cpd w Y Z R Name Characterization Schm (E)-4-{[4-1H NMR (300 MHz, acetone-d6) 8 (ppm) : Amino-6- (2- 8. 87 (bs, 1H), 7. 69 (d, J = 15. 7 Hz, indanyl-1H), 7. 59 (bd, J = 7. 7 Hz, 2H), NH2 amino)-7. 49-7. 34 (m, 3H), 7. 28-7. 11 (m, 52 83 m Nlr CH CH H [1, 3, 5] triazin 4H), 7. 05-6. 91 (m, 2H), 6. 88 (dd, J 9 NH'INNH'-2-ylamino]-= 8. 0, 1. 4 Hz, 1H), 6. 69 (td, J = methyl}-N-(2-7. 6, 1. 4 Hz, 1H), 6. 65-5. 50 (m, 4H), amino-phenyl)-4. 83-4. 53 (m, 5H), 3. 34-3. 11 (m, cinamide 2H), 2. 98-2. 80 (m, 2H). 1H-NMR (DMSO-d6), 8 (ppm) : 9. 24 (bs, N- (2- 1H), 8. 19 (d, J = 1. 6 Hz, 1H), 7. 64 aminophenyl)- (d, J = 8. 5 Hz, 1H), 7. 52 (t, J = 5. 5 Hz, 1H), 7. 42 (d, J = 15. 7 Hz, N 1H), 7. 32 (d, J = 7.. 4 Hz, 1H), 7. 26 3 Meo benzylamino)- (d J = 8. 5 Hz, 2H), 6. 90 (m, 1H), pyridin-3-yl]-6-88 (dd, J = 8. 5 Hz, 2H), 6. 74 (d, acrylamide J = 6. 9 Hz, 1H, 6. 58 (m, 3H), 4. 92 (bs, 2H), 4. 45 (d, J = S. 5 Hz, 2H), 3. 72 (s, 3H). N- (2-1H-NMR (CD30D-d4), 8 (ppm) : 8. 47 (bs, aminophenyl)-1H), 8. 33 (bs, 1H), 8. 02 (m, 1H), 3-6-7-73 (m, 1H), 7. 61 (d, J = 8. 5 Hz, i 1H), 7. 46 (d, J = 15. 4 Hz, 1H), 7. 29 56 90 (je N CH H . . (m, 1H), 7. 14 (d, J = 7. 7 Hz, 1H), 3 ylmethyl)- N 6. 94 (d, J = 7. 4 Hz, 1H), 6. 80 (d, J amino]-_ 7. 9 Hz, 1H), 6. 66 (t, J = 7. 9 Hz, pyridin-3-yl-1H), 6. 53 (m, 2H), 4. 54 (m, 2H), acrylamide 3-59 (bs, 2H). Ex Cpd Ex Cpd W y Z R Name Characterization Schm N- (2-1H-NMR (DMSO-d6), 6 (ppm) : 9. 27 (bs, aminophenyl)-1H), 8. 48 (dd, J = 1. 6 Hz, 4. 4, 1H), 3-{6-8. 16 (d, J = 1. 6 Hz, 1H), 7. 70 (m N [ (pyridin-4- 2H), 7. 42 (d, J = 15. 6 Hz, 1H), 7. 31 3 57 91 H N CH H ylmethyl)- (m 3H), 6. 90 (t, J = 6. 9 Hz, 1H), amino]-6. 73 (d, J = 6. 9 Hz, 1H), 6. 58 (m pyridin-3-yl}-4H), 4. 98 (bs, 2H), 4. 57 (d, J = 6. 0 acrylamide Hz, 2H). 1H-NMR (DMSO-d6), 8 (ppm) : 9. 24 (bs, N- (2- 1H), 8. 18 (d, J = 1. 6 Hz, 1H), 7. 65 aminophenyl)- (dd, J = 8. 8 Hz, 0. 8 Hz, 1H), 7. 60 --rNH' 3- [6- (4- (t, J = 5. 8 Hz, 1H), 7. 42 (d, J = 58 92 N CH H fluoro-15. 7 Hz, 1H), 7. 36 (m, 3H), 7. 13 (t, 3 benzylamino)-J = 8. 8 Hz, 2H), 6. 90 (t, J = 7. 4 pyridin-3-yl]-Hz, 1H), 6. 73 (dd, J = 6. 9 Hz, 1. 0 acrylamide Hz, 1H), 6. 58 (m, 3H), 4. 91 (bs, 2H), 4. 50 (d, J = 6. 0 Hz, 2H). H-NMR (DMSO-d6), 6 (ppm) : 9. 24 (bs, N- (2-1H), 8. 17 (d, J = 1. 9 Hz, 1H), 7. 65 aminophenyl)- (dd, J = 8. 8 Hz, 1. 6 Hz, 1H), 7. 60 1H), 7. 41 (d, J = 59 93 - (6- 15. 7 Hz, 1H), 7. 31 (m, 5H), 7. 23 (m, 3 59 93 H N CH H 15. 7 Hz, 1H), 7. 31 (m, 5H), 7. 23 (m, 3 , benzylamino-1H), 6. 89 (dt, J = 8. 0 Hz, 1. 6 Hz, pyridin-3-yl)-1H), 6. 73 (dd, J = 8. 0 Hz, 1. 5 Hz, acrylamide 1H), 6. 58 (m 3H), 4_92 (bs, 2H), 4. 53 (d, J = 6. 0 Hz, 2H) Ex Cpd Ex Cpd Z R Name Characterization Schm 1H-NMR (DMSO-d6), 8 (ppm) : 9. 22 (bs, N- (2- 1H), 8. 18 (ds, 1H), 7. 63 (d, J = 8. 8 aminophenyl)-Hz, 1H), 7. 42 (d, J = 15. 4 Hz, 1H), 3- [6- (3-7. 22 (m 7H), 6. 90 (t, J = 7. 7 Hz, 60 94 ll l H N CH H phenyl-1H), 6. 75 (d, J = 8. 0 Hz, 1H), 6. 57 3 propylamino)- (m 3H), 4. 92 (bs, 2H), 3. 29 (dt, J = pyridin-3-yl]-7. 7 Hz, 6. 0 Ez, 2H), 2. 66 (t, J = acrylamide 7. 7 Hz, 2H), 1. 84 (m, J = 7. 7 Hz, 2H). 1H-NMR (DMSO-d6), 8 (ppm) : 9. 22 (bs, N- (2- 1H), 8. 19 (bs, 1H), 7. 62 (d, J = 8. 5 aminophenyl)-Hz, 1H), 7. 42 (d, J = 15. 7 Hz, 1H), H 3-f6- [2- (4- 7. 32 (d, J = 7. 8 Hz, 1H), 7. 16 (d, J Gi 95 NI-I N CH H methoxy-= 7. 8 Hz, 2H), 7. 13 (m, 1H), 6. 91 3 phenyl)- (m, 1H), 6. 85 (d, J = 7. 9 Hz, 1H), MeO 'ethylamino]-6. 74 (d, J = 7. 8 Hz, 1H), 6. 57 (m pyridin-3-yl}-3H), 4. 92 (bs, 2H), 3. 71 (s, 3H), acrylamide 3. 47 (dd, J = 7. 3 Hz, 6. 0 Hz, 2H), 2. 78 (t, J = 7. 3 Hz, 2H). 1H-NMR (DMSO-d6), 8 (ppm) : 9. 23 (bs, N- (2- 1H), 8. 18 (bs, 1H), 7. 63 (d, J= 8. 2 aminophenyl)-Hz, 1H), 7. 41 (m 2H), 7. 31 (d, J = NI'll 3- [G- (4- 7. 4 Hz, 1H), 7. 15 (d, J = 8. 5 Hz, 62 96 4 N CH H dimethylamino-2H), 6. 90 (t, J = 7. 4 Hz, 1H), 6. 74 3 Me2N benzylamino.)- (d, J = 7. 0 Hz, 1H), 6. 68 (d, J = pyridin-3-yl]-8. 5 Hz, 2H), 6. 58 (m, 3H), 4. 91 (bs, acrylamide 2H), 4. 39 (d, J = 5. 5 Hz, 2H), (bs, 2H). Ex Cpd Y Z R Name Characterization Schm H-NMR (CD30D-d4), 8 (ppm) : 8. 09 (bs, 1H), 8. 05 (d, J = 1. 9 Hz, 1H), 7. 67 N- (2- (m, 2H), 7. 49 (d, J = 15. 7 Hz, 1H), aminophenyl)-7. 28 (m, 2H), 7. 17 (m, 2H), 6. 98 3- [6- (3- (dt, J = 13. 7 Hz, 7. 7 Hz, 1H), 6. 83 63 97 N N N CH H imidazol-1-yl- (dd, J = 8. 0 Hz, 1. 1 Hz, 1H), 6. 69 3 propylamino)- (dt, J = 9. 1 Hz, 1. 4 Hz, 1H), 6. 58 pyridin-3-yl]- (d, J = 15. 7 Hz, 1H), 6. 51 (d, J = acrylamide 8. 8 Hz, 1H), 4. 15 (t, J = 7. 1 Hz, 2H), 3. 29 (m, 2H), 2. 08 (m, J = 6. 9 Hz, 2H). N- (2-1H-NMR (acetone-d6), 8 (ppm) : 8. 75 aminophenyl)- (bs, 1H), 8. 23 (d, J = 1. 9 Hz, 1H), N 3- [6- (3- 7. 69 (d, J = 8. 2 Hz, 1H), 7. 55 (d, J 64 98 C H N CH H trifluorometho = 15. 4 Hz, 1H), 7. 43 (m, 2H), 7. 34 3 Oxy- (bs, 2H), 7. 19 (d, J = 6. 6 Hz, 1H), OCF3 benzylamino)-6. 93 (m, 2H), 6. 83 (dd, J = 8. 0 Hz, pyridin-3-yl]-1. 4 Hz, 1H), 6. 67 (m, 3H), 4. 71 (d, acrylamide J = 6. 3 Hz, 2H), 4. 65 (bs, 2H). N- (2-'H-NMR (acetone-d6), 6 (ppm) : 8. 81 aminophenyl)- (bs, 1H), 8. 21 (d, J = 1. 9 Hz, 1H), 3- [6- (4- 7. 66 (d, J = 7. 4 Hz, 1H), 7. 56 (d, J 65 99 N N CH H trifluorometho = 15. 7 Hz, 2H), 7. 49 (d, 2H), J = 3 Fy-8. 2 Hz, 1H), 7. 34 (d, J = 8. 1 Hz, F3C0 benzylamino)-1H), 7. 25 (t, J = 8. 0 Hz, 1H), 6. 93 pyridin-3-yl]- (m, 2H), 6. 73 (m, 3H), 4. 67 (d, J = acrylamide 6. 0 Hz, 2H), 4. 66 (bs, 2H). Ex Cud Ex Cpd _ z R Name Characterization Schm 1H-NMR (DMSO-d6), 8 (ppm) : 9. 25 (bs, - (2 1H), 8. 18 (d, J = 2. 2 Hz, 1H), 7. 67 aminophenyl)- (m 2H), 7_42 (d, J = 15. 7 Hz, 1II), F 7. 31 (d, J = 7. 7 Hz, 1H), 7. 08 (dt, 0 = 9. 3 Hz, 2. 2 Hz, 1H), 7. 03 (dd, J = 8. 8 Hz, 1. 9 Hz, 2H), 6. 90 (dt, i IF benzylamino)-7. 3 Hz, 1. 4 Hz, 1H), 6. 73 (dd, J = pyridin-3-yll-8. 0 Hz, 1. 4 Hz, 1H), 6. 60 (m 3H), acrylamide 4. 92 (bs, 2H), 4. 56 (d, J = 6. 0 Hz, 2H). N- (2-'H-NMR (DMSO-d6), 8 (ppm) : 9. 25 (bs, 1H), 8. 14 (bs, 1H), 7. 86 (m, 6H), N 3- [G- (3- 7. 42 (d, J = 15. 6 Hz, 1H), 7. 31 (d, 67 101 W H N CH H trifluoromethy J = 7. 4 Hz,, 1H) 6. 90 (dt, J = 8. 8 3 CF3 benzylamino)-Hz, 1. 1 Hz, 1H), 6. 74 (dd, J = 8. 0 i Hz, 1. 4 Hz, IH), G. GO (m 3H), 4. 96 acrylamide (bs, 2H), 4. 63 (d, J = 5. 8 Hz, 2H). 3- [6- (3-1H-NMR (DMSO-d6), 8 (ppm) : 9. 28 (bs, aminomethyl-1H), 8. 17 (bs, 1H), 7. 66 (d, J = 5. 8 benzylamino)-Hz, 2H), 7. 37 (m, 6H), 6. 88 (dd, J = 68 102 T N CH H pyridin-3-yl]-8. 0 Hz, 0. 9 Hz, 1H), 6. 73 (dd, J = 3 NH2 N- (2- 8. 0 Hz, 0. 9 Hz, 1H), 6. 59 (m 3H), aminophenyl)--4. 55 (d, J = 5. 8 Hz, 2H), 3. 96 (s, acrylamide 2H), 3. 37 (bs, 4H). Ex Cpd _ Z R Name Characterization Schm {4-[2-(2-1H NMR : (DMSO-d6) 8 (ppm) : 9. 36 (s, amino-1H), 8. 57 (s, 1H), 8. 51 (d, J = 4. 6 O phenylcarbamoy Hz, 1H), 7. 91 (m, 1H), 7. 77 (d, J = 70 104 M OAN CH CH H l)-vinyl]-7. 68 Hz, 1H), 7. 28-7. 57 (m, 7H), 4 t J H benzyl}-6. 88 (dd, J = 15. 66 Hz, 4. 4 0 Hz, N carbamic acid 2H), 6. 73 (m, 1H), 6. 56 (m, 1H), pyridin-3-yl 5. 01 (s, 2H), 4. 93 (bs, 2H), 4. 10 methyl ester (d, J = 6. 04 Hz, 2H). (2- {4- [2- (2- amino-1H NMR : (DMSO-d6) 6 (ppm) : 9. 34 (s, phenylcarbamoy phenylcarbamoy 1H), 8. 52 (m, 2H), 7. 71 (d, J = 7 : 69 1)-vinyl]-Hz, 1H), 7. 20-7. 60 (m, 8H), 6. 87 (m, 4 H 2H), 6. 73 (m, 1H), 6. 56 (m, 1H), ethyl)- carbamic acid 2H), 2. 75 (m, 2H). pyridin-3-yl methyl ester N- (2-1H-NMR (acetone-d6), 8 (ppm) : 8. 49 aminophenyl)- (bs, 1H), 8. 41 (d, J = 7 Hz, 1H), MeO N 3-{4-[(3, 4, 5- 7. 63 (d, J = 15. 6 Hz, 1H), 7. 56 (d, trimethoxy-J = 8 Hz, 2H), 7. 45 (d, J = 8 Hz, MeO) , phenylamino)-2H), 7. 07 (m, 2H), 6. 90 (d, J = 15. 6 OMe methyl]-Hz, 1H), 6. 76 (m, 1H), 6. 74 (m, 1H), phenyl}-5. 99 (s, 2H), 4. 36 (s, 2H), 3. 69 (s, acrylamide 6H), 3. 68 (bs, 2H), 3. 67 (s, 3H). Ex Cpd Y Z R Name Characterization Schm N- (2-1H-NMR (CDC13), 8 (ppm) : 7. 70 (bs, aminophenyl)-1H), 7. 43 (d, J = 7. 4 Hz, 1H), 7. 33 3-(4-{[(3, 4, 5- (d, J = 4. 9 Hz, 2H), 7. 26 (d, J = trimethoxy-. 4. 9 Hz, 2H), 7. 25 (m, 1H), 7. 03 (t, 73 107 MeOe Me CH CH H benzyl)-J = 7. 4 Hz, 1H), 6. 78 (d, J = 7. 4 5 OMe amino]-Hz, 1H), 6. 75 (m, 1H), 6. 61 (s, 2H), methyl}-6. 57 (m, 1H), 4. 08 (bs, 2H), 3. 86 pheyl)- (s, 6H), 3. 83 (s, 3H), 3. 50 (s, 2H), acrylamide 3. 47 (s, 2H), 2. 21 (s, 3H). N- (2-1H-NMR (CDC13), 8 (ppm) : 7. 74 (d, J = aminophenyl)-15. 4 Hz, 1H), 7. 50 (d, J 7. 4 Hz, I 2H), 7. 25 (m 3H), 7. 06 (t, J = 1. 9 MeO trimethoxy-Hz, 1H), 6. 82 (d, J = 7. 4 Hz, 2H), 74 108 CH CH H phenyl)-5 " m : }- -0 <-'- < ' OMe methyl-2H), 4. 50 (s, 2I), 3. 77 (s, 6H), phenyl}-3-78 (bs, 2H), 3. 77 (s, 3H), 3_00 acrylamide N- (2-Amino-1H NMR : (DMSO-ds) 8 (ppm) : 9. 4 (bs, phenyl)-3- {4- [ (6-methoxy- 1H), 7. 60 (d, J = 8. 5 Hz, 1H), 7. 54- H 7. 45 (m, 3H), 7. 87 (d, J = 7. 7 Hz, 75 109 CH CH H pyridin-3-1H), 7. 10 (d, J 8. 8 Hz, 1H), 6. 95- 5 MeO N 6. 77 (m, 3H), 6. 62 (d, J = 7. 7 Hz, phenyl-2H), 6_08-6. 04 (m, 2H), 4. 98 (bs, phenyl}- acrylamide 2H), 3. 72 (s, 3H). Ex Cpd Ex Y Z R Name Characterization Schm 1H NMR : (DMSO-d6) 8 (ppm) : 9. 41 (bs, N- (2-Amino- 1H), 8. 21 (d, J = 8. 5, 1H), 7. 97 phenyl)-3- [4- (dt, J = 7. 7, 8. 8 Hz, 2H), 7. 78 (dt, (quinolin-2-J = 7. 1 Hz, 8. 2 Hz, 1H), 7. 61-7. 53 5 76 110 N g CH CH H 5 ylsulfanylmeth (m, 5H), 7. 40 (dd, J = 8. 5 Hz, 7. 6 yl)-phenyl]-Hz, 2H), 6. 97-6. 77 (m, 4H), 6. 6 (dt, acrylamide J = 7. 7 Hz, 7. 5 Hz, 1H), 4. 98 (bs, 2H), 4. 65 (bs, 2H). N- (2-amino- phenyl)-3- {4- 1H NMR : (DMSO-d6) 8 (ppm) : 9. 15 (s, [ (pyridin-3- 1H), 7. 24-7 38 (m, 6H), 6. 84-6. 90 77 111 t J H CH CH H ylmethyl)- (m, 3H), 6. 72 (m, 2H), 6. 49-6. 60 (m, 6 N amino]-4H), 4. 84 (s, 2H), 4. 22 (d, J = phenyl}-5. 77 Hz, 2H) acrylamide N- (2-Amino-1H NMR : (DMSO-d6) 8 (ppm) : 7. 96 (d, phenyl)-3- (6-J=9. 1 Hz, 2H), 7. 55 (d, J = 14. 2 Hz, 1H), 7. 48 (d, J = 7. 4 Hz, 2H), 7. 39- 78 112 H N CH H styrylamino-. 29 (m, 4H), 7. 07-6. 91 (m, 3H), 7 pyridin-3-yl)-7. 29 (m, 3H), 6. 47-6. 38 (m, 1H), 4. 21 (bs, 2H). N- (2-amino- 1H NMR : (DMSO-d6) 8 (ppm) : 9. 30 (s, phenyl)-3- [2-1H), 8. 58 (bs, 2H), 8. 36 (m, 1H), (4-nitro-8. 20 (m, 2H), 7. 58 (m, 2H), 7. 28- 7 own benzylamino)-7. 42 (m, 2H), 6. 52-6. 92 (m, 4H), pyrimidin-5-4. 90 (s, 2H), 4. 64 (d, J = 6 Hz, yl]-acrylamide 2H). Ex Cpd W y Z R Name Characterization Schm 1H NMR : (DMSO-d6) 8 (ppm) : 10. 87 (bs, N- (5- [2- (2- 1H), 9. 45 (bs, 1H), 8. 66 (bs, 1H), Amino-8. 33 (d, J = 7. 4 Hz, 1H), 8. 14-8. 08 phenylcarbamoy (m, 3H), 7. 63 (d, J = 15. 6 Hz, 1H), 80 114 m H N CH H l-vinyl)-7. 40 (d, J = 7. 7 Hz, 1H), 7. 08 (d, J 7 MeOS pyridin-2-yl)-= 6. 8 Hz, 2H), 6. 97 (d, J = 12. 3 Hz, 4-methoxy-2H), 6. 80 (d, J = 7. 9 Hz, 1H), 6. 63 benzamide (dt, J = 7. 7 Hz, 7. 4Hz, 1H), 5. 06 (bs, 2H), 3. 88 (s, 3H) 1H NMR : (DMSO-d6) 6 (ppm) : 9. 27 (s, 3- [2- (4-amino- 1H), 8. 83 (s, 2H), 7. 97 (t, J = 6 benzylamino)-Hz, 1H), 7. 37 (d, J = 15. 9 Hz, 1H), N-5-7. 29 (d, i = 7. 11 Hz, 1H), 6. 96 ( pyrimidin-5-7. 29 (d, J = 7. 11 Hz, 1H), 6. 96 (7 81 115 H2N H N N H yl]-N- (2- d, J = 8. 24 Hz, 2 H), 6. 88 (m, 1H), amino-phenyl)-6. 70 (m, 2 H), 6. 55 (m, 1H), 6. 47 acrylamide (d, J = 8. 2 Hz, 2H), 4. 90 (s, 4H), 4. 34 (d, J = 6. 0 Hz, 2H). 1H-NMR (CDC13), 5 (ppm) : 8. 38 (bs, - 1H), 7. 49 (m, 1H), 7. 42 (dd, J = 8. 5 aminophenyl)-Hz, 2. 2 Hz, 1H), 7. 41 (m, 1H), 7. 30 Meo r (d, J = 7. 9 Hz, 1H), 7. 10 (bs, 1H), \ N 3- [6- (3, 4, 5- lde -''-'° '''*''°' 82 116/N CH H trimethoxy-7. 3 Meo benzylamino)-= 15. 0 Hz, 1H), 6. 73 (m 1H), 6. 65 oMe pyridin-3-yl]- (m 2H), G. 3 6 (d, J = 8. 8. Hz, 1H), acrylamide 6. 23 (d, J = 15. 0 Hz, 1H), 4. 34 (s, 2H and bs, 2H), 3. 84 (s, 3H), 3. 81 (s, 6H). Fx Cpd W y Z R Name Characterization Schm 'H NMR : (DMSO-d6) 8 (ppm) : 8. 28 (bs, N- (2-Amino- 1H), 7. 98 (d, J = 9. 6 Hz, 1H), 7. 57 phenyl)-3- [6- (d, J = 15. 6 Hz, 1H), 7. 3 8 (d, J (4-methyl-7. 7 Hz, 1H), 7. 29 (d, J = 7. 9 Hz, i benzylamino)-J = 7. 6 Hz, 2H),7. 08 7 Me (dt, J = 8. 2 Hz, 7. 7 Hz, 1H), 6. 98 pyridin-3-yl]- acrylamide (d, J-9 1 Hz, 2H), 6 87 (t, J = 8. 2 Hz, 1H), 6. 75 (d, J = 15. 1 Hz, 1H), 4. 57 (s, 2H), 2. 53 (s, 3H). 0 N- (2-amino-1H NMR : (DMSO-d6) 8 (ppm) : 9. 27 (s, [2 (4-methoxy- 84 118 \ H/N N H 7H30 (m544H), 6H53-6. 91 (m, 6H), 7 Meo benz,lam,no)- -- S"--'-<.- yl]-acrylamide 2H), 3. 7 (s, 3H). phenyl) (2-Amino-1H NMR (20% CD30D in CDC13) : 008. 75 _ (s, 1H), 7_95 (m, 1H), 7. 74-7. 59 (m, 84 118 (3, 4- 3H), 7. 50 (m, 1H), 7. 24 (d, J = 7. 8 9, b b MeO N CH H dimethoxy-Hz, 1H), 7. 07 (m, 1H), 6. 95 (d, J = 15 q phenyl)- pyrn-3-yl]- acrylamide Table 3b Ex Cpd n Name Characterization Scheme 53 87 0 2- (4-methoxy-'H-NMR (DMSO-d6), 5 (ppm) : 9. 66 (bs, 1H), 8. 32 (s, 1H), 10 benzylamino)-8. 05 (d, J = 8. 8 Hz, 1H), 7. 96 (dd, J = 9. 1 Hz, 2. 2 Hz, quinoline-6-1H), 7. 72 (d, J = 2. 2 Hz, 1H), 7. 55 (dd, J = 8. 5 Hz, 2. 2 carboxylic acid Hz, 1H), 7. 34 (dd, J = 8. 5 Hz, 2. 2 Hz, 1H), 7. 20 (d, J = (2-aminophenyl)-7. 7 Hz, 1H), 6. 97 (t, J = 7. 7 Hz, 1H), 6. 90 (m 2H), 6. 80 amide (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). 54 88 1 N- (2-1H-NMR (DMSO-d6), 6 (ppm) : 9. 70 (bs, 1H), 9. 40 (bs, 1H), 10 aminophenyl)-3-8. 20 (d, J = 8. 9 Hz, 1H), 8. 03 (bs, 2H), 7-. 94 (d, J = 7. 2 [2- (4-methoxy- Hz, 1H), 7. 64 (dd, J = 15. 7 Hz, 2. 5 Hz, 1H), 7. 41. (d, J = benzylamino)-8. 5 Hz, 2H), 7. 39 (m, 1H), 7. 14 (d, J = 8. 9 Hz, 1H), 7. 05 quinolin-6-yl]- (d, J = 15. 7 Hz, 1H), 6. 97 (m, 1H), 6. 95 (d, J = 8. 5 Hz, acrylamide 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).

Table 3c Ex. Cpd. Name Characterization Scheme 43 51 N-(2-aminophenyl)-3-[6- 1H-NMR (CDCl3), # (ppm) : 7.60 (bs, 1H), 7.55 (bs, 3 (4-methoxy-benzylamino)- 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 8.3 Hz, pyridin-2-yl]-acrylamide 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).

Table 3d Ex. Cpd W Y Z R Name Characterization Schm N- (2-Amino- H phenyl)-3-{4-1H-NMR (DMSO-d6), 8 (ppm) : 9. 36 (bs, 1H), ZOZO N N- [(4, 6-7. 55 (d, J = 7. 4 Hz, 2H), 7. 48 (s, 1H), 3 dimethoxy-7. 38 (d, J = 7. 9 Hz, 2H), 7. 33 (d J=7. 9 347 492 CH CH H pyrimidin-2-Hz, 1H), 6. 91 (m, 2H), 6. 73 (d, J=8. 2 Hz, 3, 7 ylamino)-1H), 6. 56 (dd, J = 7. 4, 7. 7 Hz, 1H), 5. 35 methyl]- (s, 1H), 4. 93 (bs, 2H), 4. 46 (dd, J=6. 04 CH3 phenyl}-2H), 3. 32 (s, 6H) acrylamide Ex. Cpd W Y'Z R Name Characterization Schm N- (2-Amino- H phenyl)-3-14-'H-NMR (DMSO-d6), 8 (ppm) : 9. 37 (bs, 1H), [ (4-chloro-6- CI NYN 7. 58-7. 50 (m, 3H), 7. 37-7. 32 (m, 3 H), methoxy- T ylamino)-6. 57 (t, J=7. 5, 1H), 6. 13 (bs, 1H), 4. 94 ylamino)- (bs, 2H), 4. 48 (d, J=G. 0, 2H), 3. 84 (s, methyl]- (bs, 2H), 4. 48 (d, J=6. 0, 2H), 3. 84 (s, CH3 phenyl}- acrylamide H N- (2-Amino- H3C"OQN-, A phenyl)-3- [4-'H-NMR- (DMSO-d6), 5 (ppm) : 9. 38 (bs, 1H), 349 494 t/J CH CH H (3, 5-dimethoxy-7. 55-7. 40 (m, 6H), 6. 88-6. 57 (m, 3 H), 3, 7 benzylamino)-6. 35-6. 32 (m, 1H), 5. 73 (m, 3H), 4. 94 (s, phenyl]-2 H), 4. 26 (s, 2H), 3. 63 (s, 6H). CH3 acrylamide H N- (2-Amino-1H-NMR (DMSO-d6), 6 (ppm) : 9. 38 (bs, 1H), 02N N,, A- phenyl)-3- [4-7. 74 (bs, 3H), 7. 61 (d, J=8. 2 Hz, 2 H}, 350 495 ll | CH CH H (3, 5-dinitro-7. 56-7. 44 (m, 3H), 7. 32 (d J=8. 0 Hz, 3, 7 v benzylamino)-1H), 6. 91-6. 85 (m, 2H), 6. 73 (d, J=7. 9 phenyl]-Hz, 1H), 6. 66-6. 56 (m, 1H), 4. 93 (bs, acrylamide 2H), 4. 52 (bs, 2H). 1V- (2-Amino-'-H-NMR (DMSO-d6), 8 (ppm) : 9. 22 (bs, 1H), Phenyl)-3- [4- H (3-7. 52 (d, J=7. 9 Hz, 2H), 7. 44 (bs, 1H), 351 496 CH CH H trifluoromethox 7-38 (bs, 3H), 7. 28 (d J=6. 9 Hz, 2H), 58 6. 95-6. 92 (m, 2H), 6. 79 (d, J=8. 2 Hz, y-benzylamino)-1H), 6. 69-6. 59 (m, 3H), 4. 95 (bs, 2H), F phenyll-4. 45 (bs, 2H). acrylamid P"3, '"'r. H-NMR (DMSO-d), 5 (ppm) : 9. 45 (bs, 1H), (3, 4, 5- 8-01 (bs, 2H), 7. 78-7. 5 (m, 4H), 7. 49- 7. 40 (m, 1H), 6. 98 (dd, J=7. 0, 8. 2 Hz, 352 497 H3C, 0 CH CH H trimethoxy-IH), 6. 82 (d, J=7. 0 Hz, IH) f 6. 64 (dd 31 7 O phenoxymethyl)-J=7. 0, 7. 6 Hz, 1H), 6. 41 (bs, 2H), 5. 17 phenyl]- H3C acrylamide (s. 2H), 3. 81 (s, 6H), 3. 64 (s, 3H). 3C acrylamide Ex. Cpd w Y Z R Name'Characterization Schm X N- (2-Amino-1H-NMR (DMSO-d6), 8 (ppm) : 9. 22 (bs, 1H), CH3 phenyl)-3- [4-7. 17 (d, J=8. 2 Hz, 2H), 6. 97 (d, J=8. 2 Hz, 0 (6, 7-dimethoxy- 2H), 6. 93 (d, J=7. 6 Hz, 1H), 6. 85 (bs, 353 498 N CH CH H 3, 4-dihydro-lH-1H), 6. 77 (bs, 1H), 6. 60-6. 53 (m, 3H), 37 isoquinolin-2-6. 43-6. 40 (m, 2H), 4. 97 (bs, 2H), 4. 43 HCT O yl)-phenyl]- (bs, 2H), 3. 78 (s, 3H), 3. 77 (s, 3H), acrylamide 2. 87-2. 85 (m, 2H), 2. 65-2. 62 (m, 2H). N- (2-Amino- IH-NMR (DMSO-d6), 6 (ppm) : 10. 77 (bs, 1H), NH phenyl)-3- (4- 9. 39 (bs, 1H), 7. 62 (d, J=7. 9 Hz, 1H), 1 I {[(lH-indol-2-7. 49 (d, J=5. 7 Hz, 2H), 7. 37 (d, J=7. 9 ylmethyl)-Hz, 2H), 7. 26 (d, J=7. 9, 2H), 7. 10 (t, 354 499 CH CH H 58 354 499 l CH CH H (3, 4, 5-J=7. 5 Hz, 2H), 7. 00-6. 83 (m, 4H), 6. 78 (d, 58 0 NA trimethoxy-T=7. 9 Hz, 1H), 6. 61 (t, J=7. 5 Hz, 1H), phenyl)-amino]-5. 98 (s, 1H), 5. 32 (bs, 1H), 4. 98 (bs, H3CsO e methyl}-2H), 4. 32 (d, J=5. 2 Hz, 2H), 3. 98 (bs, phenyl)-2H), 3. 73 (s, 3H), 3. 67 (s, 3H), 3. 64 (s, acrylamide 3H). N- (2-Amino-1H-NMR (DMSO-d6) 8 (ppm) : 9. 69 (bs, 1H), H3CXO phenyl)-3- [4- 8. 04 (d, J=8. 3 Hz, 2H), 7. 78 (d, J=8. 3 (3, 4, 5- Hz, 2H), 7. 58-7. 55 (m, 2H), 7. 06 (d, 355 500 H3C"0 CH CH H trimethoxy-J=6. 2 Hz, 1H), 6. 96 (d, J=7. 3 Hz, 1H), 3, 7 H phenylsulfanylm 6. 90 (d, J=7. 0 Hz, 1H), 6. 60 (bs, 1H), C, ethyl)-phenyll-5. 81 (s, 2H), 4. 34 (bs, 2H), 3. 78 (s, acrylamide 6H), 3. 67 (s, 3H). 3- {4- [ (6- iH- (DMSO-d6), 8 (ppm) : 9. 81 (bs, 1H), 0 Acetyl-7. 9S (d, J=7. 9 Dz, 2H), 7. 58 (d, J=7. 9 Hz, benzo [1, 3] dioxo CH 1-5-ylamino)-2H), 7. 39 (bs, 1H), 7. 21 (d, J=7. 4Hz, 356 501/I \ 3 CH CH H methyl]-1H), 7. 02-7. 00 (m, 2H), 6. 85 (d, J= 7. 5 58 methyl- H amino-phenyl)-1H), 6. 36 (bs, 1H), 6. 00 (d, J=2. 2 Hz, acrylamide 2H), 4. 60 (bs, 2H), 2. 50 (bs, 3H). Ex. Cpd _ Z R Name Characterization Schm N- (2-Amino- NH phenyl)-3- {4-'-H-MM (DMSO-d6), 5 (ppm) : 9. 43 (bs, 1H), N [ (5-methoxy- 8-37 (bs, 1H), 7. 66-7. 57 (m, 3H), 7. 49 (d, benzothiazol-2-T7. 5 Hz, 2H), 7. 37-7. 33 (m, 3H), 6. 96- 357 502 s CH CH H ylamino)-6. 90 (m, IH), 6-8 7 (d, J= 8. 8 Hz, 1H), 58 methyll-G. 80' (d,-J=7. 9 Hz, 1H), 6. 63 (t, J=7. 5 Hz, phenyl}-1H), 4. 99 (bs, 2H), 4. 64 (bs, 2H), 3. 37 0 acrylamide' CH3 \/ NH N-(2-Amino-1H-NMR (DMSO-d6), 6 (ppm) : 9. 42 (bs, 1H), NH phenyl)-3-4- NH (4-morpholin- 7. 63-7. 56 (m, 3H), 7. 47 (d, J=7. 9 Hz, 2H), 4-yl-7. 39 (d, J=7. 5 Hz, 1H), G. 95 (d, J=8. 3 Hz, 358 503 CH CH H phenylamino)-1H) 6-82 (bs, 1H), 6. 77 (d, J=8. 4 Hz, 58 0 methyll-2H)'f 6. 66-6. 56 (m, 3H), 5. 91 (bs, 1H), N phenyl}-5. 01 (bs, 2H), 4. 30 (bs, 2H), 3. 74 (bs, acrylamide 4H), 2. 93 (bs, 4H). N- (2-Amino- 1H-NMR (DMSO-d6), 8 (ppm) : 9. 42 (s, 1H), H phenyl)-3- {4-7. 64 (d, J = 7. 9 Hz, 2H), 7. 59 (d, J = [ (4- 15. 9 Hz, 1H), 7. 48 (d, J = 8. 0 Hz, 2H), 359 504 CH CH H trifluoromethox 7. 39 (d J=7. 4 Hz, 1H), 7. 10 (d, J-= 8. 2 l y-phenylamino)-Hz, 2H), 6. 99 (d, J=7. 1 Hz, 1H), 6. 92 (d, methyl]-J = 15. 4 Hz, 1H), 6. 81 (dd, J = 1. 3, 8. 0 3 phenyl}-Hz, 1H), 6. 61-6. 68 (m, 4H), 4. 99 (s, 2H), acrylamide 4. 36 (d, J=6. 0 Hz, 2H). Ex. Cpd w Y Z R Name Characterization Schm 1H-NMR (DMSO-d6) y 8 (ppm) : 9. 42 (s, 1H), N- (2-Amino-7-63 (d, J = 7. 7 Hz, 2H), 7. 59 (d, J = phenyl)-3- [4-15. 4 Hz, 1H), 7. 47 (d, J = 8. 0 Hz, 2H), fuzz 7. 40 (d, J = 7_7 Hz, 1H), 6. 99 (d, J = (benzo [1, 3] diax 7. 1 Hz, 1H) 6. 92 (d, J=16. 2 Hz, 1H) 6. 81 360 505 I/CH CH H ol-5- (dd, J = 1. 4, 8-0 Hz, 1H), 6. 68 (d, J =, 33 ylaminomethyl)- 8. 2 Hz, 1H), 6. 62 (dd, J = 1. 4, 7. 7 Hz, phenyl]- acrylamide 1H), 6. 34 (d, J = 2. 2 Hz, 1H), 6. 05 (m, 2H), 5. 87 (s, 2H), 4. 99 (s, 2H), 4. 29 (d, J=6. 0 Hz, 2H). N- (2-Amino- H N- (2-Amino-'H-NMR (DMSO-d6) (ppm) : 9. 43 (s, 1H), \ N ph3nyl)-3- {4- 7_57_7_66 (m, 3H), 7. 48 (d, J = 7. 6 Hz, [ (3- 2H), 7. 40 (d, J = 7-6 Hz, 1H), 7. 20 (da, 361'506 cl CH CH H J = B. 2 f 8. 2 Hz, 1H), 6-99 (df T = 7. 6 Hz, 3, 33 y-phenylamino)-1H), 6. 93 (d, J=15. 2 Hz, 1H), 6. 81 (m, methyll-2H), 6. 64 (m, 2H), 6. 49-6. 55 (m, 2H), 5. 00 phenyl- (s 2H), 4. 38 (d, J= 5. 3 Hz, 2H). acrylamide N- (2-Amino-1H-NMR (DMSO-d6), 8 (ppm) : 9. 42 (s, 1H), phenyl)-3- {4- 7. 63 (d, J = 7. 6 Hz, 2H), 7. 59 (d, J = \ N phenyl)-3-4-15. 8 Hz, 1H), 7. 47 (d, J = 7. 6 Hz, 2H), 362 50i l CH CH H phenylamino)-7. 40 (d, J = 7 6 Hz, 1H), 6. 90-7. 02 (m, 3 33 362 507 I/CH CH H phenylamino)-3, 33 methyl]-3H), 6. 81 (d, J=7.. 6 Hz, 1H), 6. 64 (dd, J = phenyl}-7-0. 7-0 Hz, 1H), 6. 36 (m, 1H), 6. 24 (d, J O Me acrylamide = 8. 2 Hz, 1H), 6. 18 (m, 2H), 5. 00 (s, 2H), 4. 34 (d, J= 5. 3 Hz, 2H), 3. 69 (s, 3H). 1H-NMR (DMSO-d6), 6 (ppm) : 9. 42 (s, 1H), N- (2-Amino- 7-62 (d, J = 7. 0 Hz, 2H), 7. 58 (d, J = 15. 2 Hz, 1H), 7. 46 (d, J = 7. 6 Hz, 2H) phenyl)-3- {4- 1H), 6. 87 (d, J=7. 6 Hz, 2H), 6. 81 (d, J = 363 508 CH CH CH CH H phenylamino)-3, 33 methyl]-7-6 Hz, 1H), 6. 73 (dd, J = 7. 6, 7. 6 Hz, OMe phenyl}-1H), 6. 56-6. 66 (m, 2H), 6. 45 (d, J = 7. 6 acrylamide Hz, 1H), 5. 68 (t, J = 5. 9 Hz, IH), 4. 99 (s, 2H), 4. 41 (d, J = 6. 4 Hz, 2H), 3. 87 (s, 3H). Ex. Cpd SV Y Z R Name Characterization Schm H-NMR (DMSO-d6), 8 (ppm) : 9. 42 (s, 1H), 7. 63 (d, J = 7. 9 Hz, 2H), 7. 59 (d, J = H N- (2-Amino- 15. 8 Hz, 1H), 7. 48 (d, J=7. 9 Hz, 2H), 7. 39 phenyl)-3- (4- (d, J = 7. 5 Hz, 1H), 7. 10 (2d, J = 7. 5, 364 509 CH CH H phenylaminometh 7. 5 Hz, 2H), 6. 99 (d, J = 7. 5 Hz, 1H), 3, 33 yl-phenyl)-6. 92 (d, J = 16. 2 Hz, 1H), 6. 81 (d, J = acrylamide 7. 5 Hz, 1H), 6. 55-6. 64 (m, 4H), 6. 32 (t, J = 6. 0, 1H), 4. 99 (s, 2H), 4. 35 (d, J = 5. 7 Hz, 2H). 1H-NMR (DMSO-d6), 8 (ppm) : 9. 42 (s, 1H), H N- (2-Amino- 7. 62 (d, J = 7. 0 Hz, 2H), 7. 59 (d, J = N phenyl)-3- {4- 15. 8 Hz, 1H), 7. 47 (d, J = 8. 2 Hz, 2H), [ (4-isopropyl- 7. 40 (d, J = 7. 6 Hz, 1H), 6. 89-6. 99 (m, 365 510 H3C CH CH H phenylamino)-4H), 6. 81 (d, J=7. 6 Hz, 1H), 6. 64 (dd, J = 3, 33 methyl-7. 0, 7. 6 Hz, 1H), 6. 56 (d, J = 8. 2Hz, 2H), l phenyl}-6. 14 (t, J = 5-9 Hz, 1H), 4. 99 (s, 2H), CH3 acrylamide 4. 32 (d, J= 5. 9 Hz, 2H), 2. 76 (m, 1H), 1. 17 (d, J = 7. 0 Hz, 6H). H 1H-NMR (DMSO-d6), 6 (ppm) : 9. 43 (s, 1H), N- (2-Amino-7. 57-7. 66 (m, 5H), 7. 40-7. 52 (m, 7H), 7. 27 phenyl)-3- [4- (dd, J = 7. 0, 7. 6 Hz, 1H), 6. 98 (d, J = 366 511 l CH CH H (biphenyl-4-7. 6 Hz, 1H), 6. 93 (d, J=15. 2 Hz, 1H), 6. 81 3 33 ylaminomethyl)- (d, J = 8. 2 Hz, 1H), 6. 73 (d, J = 8. 2Hz, phenyl]-2H), 6. 64 (dd, J = 7. 6 Hz, 6. 56 (t, acrylamide J = 5. 9 Hz, 1H), 4. 99 (s, 2H), 4. 12 (d, J= 5. 9 Hz, 2H).- N-(2-Amino-1H-NMR (DMSO-d6), 6 (ppm) : 9. 50 (s, 1H), M eO H phenyl)-3-{6-8. 81 (s, 1H), 8. 05 (d, J = 8. 2 Hz, 1H), [ (3, 4, 5- 7. 64 (d, J = 15. 7 Hz, 1H), 7. 52 (d, J=8. 2 trimethoxy-Hz, 1H), 7. 39 (d, J = 7. 4 Hz, 1H), 6. 96- 367 512 CH N H 7. 05 (m, 2H), 6. 81 (d, J = 8. OHz, 1H), 3, 33 phenylamino)-6. 64 (dd, J = 7. 4, 7. 4 Hz, 1H), 6. 26 (m, Me0 methyl]- pyridin-3-yl}-1H), 5. 96 (s, 2H), 5. 01 (s, 2H), 4. 43 (d, MeO acrylamide J = 5. 5 Hz, 2H), 3. 72 (s, 6H), 3. 56 (s, 3H). > < z R Xe < Sck. . Z R) Name Characterization H-NMR (DMSO-. : 26', 5 (ppm).-9. 5Ci (s,'Ll. ... '-n-l-'"- '-''= S Hz, 2H), 7. 8. 72 (s, _. p' I. e6 (d ; _.-8_3 Hz, Hf,, _8B. (tiy V. i ; :' (-. _l- 3H) ? 2 .. C1'Z.'' (3-belii. ;,,'- i Hl, 7. 5 (d, J = 8. 1. Hz, 2H)., I7-ehlo-o-4-oiro- 4-1--),-. 24-7-15 (ni,'2H), N 7. 00--6. 86 (rn,. 2H), 6. 84 td, J = 8. 1 Hz, 55 H CH H cyz_ _azolim-2-5 - JH) 6. 68 (c ; 7 = 7. Hz, lfij ; 5. 45 td. J '16. 8 Hz, lHl,. 533 (d, J = 16. 8 Hz, 1H),.. i I.','t " ethylaniimo] f. methyl ?- 4. 52 (bs, 1H), 4. 25 (d, a-= 12. 9 EIz 1H), . i-jlj 4. °2 (d, J= 12. 9HS, 1H), 1. 91 (m, 2H),. \ Phenyl)- aeryla. niide 1. 28 (, m, 1H} ; 0. °0 (in,'-_H), 2 7. 5 Hz, 3H). AT- ("'"ino-HNMR. (Acetoue-d,) 5 (ppm) : 3. 47 (bs, I rnino- ... ! pl-enylf-3- (4-iH), 7. 72-7. 56 (m, 5H.), 7 39 (d, J=7 4 liz,.. 371 51e, Eim-CH CH CFI 1H), ?. CO-G. r (rr, 2H), 6'81 td,. J=6. 9 HZ, l4 brbtno-phenyl)-1H) 6. 64 (t, J=7. 3 Hz, 1H),. 5. 00 (bs., 2H). . 2H). .. H NNR : (CD30D) S (ppm) : 7. 61 (d, J=15. 4 . . OMe., N'- (2-Amino- Hz, 1H), 7-44 (d, J=8 4 Hz, 2H), 725. (d', Me0 plienyl)-4-J=7. 5 Hz, 1H), 7. 10 (t, J=7.. 5 Hz, 1H), 7.. 00 (s, IH), 694 J=8. 4 Hz, lq) (34 al It 7. j, 3 7 : ? 517 v CFl. CH CHv r.. .. trimethoxy- (t, J=7. 0 Hz, 1H), 6. 76 (s, 1H) 6. 70 (d, 10 benZY18LMino)-T=8-4 Hz, 2H3, 5. 92 (d, J=15.. 4. LIz, IH), OMe benzamide 4. 35 (s, 2H), 3,, 94 (s, 3E1), 3. 92. (s, H),., 3. 3. 77 (s,. 3H).. OMe phenyl)-3-'4-IH NMR (DMSO-d6) i (ppm) :. 9. 24 (s, 1H), r.,. g 8. 00 ltd, J=12Hz, 1H) ; 7. 80 (d, J=12Hz,.. . fvle0 , f. I fl- (3,. , 5- MeO 3i3 518 < 7 C CH CH CH trlmethóxy-1H3, 7. 40-7. 70 {m 7H3, 6 80-7. Q0 (m, 2H), 58 : Gril- % : phenyl_ami. no)-4. 50 m 1H ;. 3. 70'3 . ethyl]-pheilyl ;- (.. .. s, 6H), 3. _50 (s ; H), acryI, amide 1-50 (d, 3H) _,. acr-ylamide Ex. Cpd W Y Z R Name Characterization Schm 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 41 N- (2-Amino- (s. 1H), 8. 00 (t, J = 7. 9 Hz, 2H), 7. 88 y phenyl)-3- (9H- (s, 1H), 7. 77-7. 56 (m, 3H), 7. 52-7. 32 (m, 374 519 C CH H fluoren-2-yl)-3H), 7. 00 (d, J = 15. 8 Hz, 1H), 6. 96 (t, J 59 acrylamide = 7. 5 Hz, 1H), 6. 80 (d, J = 7. 9 Hz, 1H),. 6. 63 (t, J = 7_5 Hz, 1H), 5. 00 (s, 2H), 4. 03 (s, 2H). 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 71 NH2 N- (2-Amino- (s 1H), 9. 43 (s, 1H), AB system (8A = H pheny,)-4- [2 (d, 375 520 \ N'8. 05, 8B = 7. 75, J = 7. 9 Hz, 4H), 7. 62 (d, II (2-amino- CH CH H phenylcarbamoyl J = 15. 8 Hz, 1H), 7. 36 (d, J = 7. 9 Hz, 59 )-vinyl]-1H), 7. 18 (d, J = 7. 5 Hz, 1H), 7. 05-6. 88 benzamide (m, 3H), 6. 78 (t, J = 7. 9 Hz, 2H), 6. 65- 6. 55 (m, 2H), 4. 96 and 4. 92 (2s, 4H). N- (2-Amino-1H NMR (300 MHz, DMSO-d6) 5 (ppm) : 9. 29 H phenyl)-3-{6- (s, 1H), 8. 32 (d, J 4. 9 Hz, 2H), 8. 24 N N (d, J = 1. 9 Hz, 1H), 7. 71 (d, J = 6. 9 Hz, \^ [2- (pyrimidin- N 1H), 7. 48 (d, J = 15. 7 Hz, 1H), 7. 38 (d, J l I ethylamino]-= 7. 7 Hz, 1H), 7. 26 (bs, 2H), 6. 96 (t, J ethylamino]- \H pyridin-3-yl}-6. 9 Hz, 1H), 6 80 (dd, J = 1. 1, 7. 7 Hz, acrylamide 1H), 6. 69-6. 61 (m, 4H), 5. 00 (s, 2H), 3. 52 (bs, 4H), N- (2-Amino-1H NMR (300 MHz, CD30D) 8 (ppm) : 8. 12 (s, phenyl)-3- {6- 1H), 8. 08 (s, 1H), 7. 78 (d, J = 8. 8 Hz, N [2- (thiazol-2-IH), 7. 54 (d, J = 15. 4 Hz, 1H), 7. 19 (d, i 377 522 sS/\/\N XL N CH H ylamino)-= 8-0 Hz, 1H), 7. 04 (t, J = 7. 4 Hz, iH), 3 H ethylaminol-6. 87 (d, J = 8. 0 Hz, 1H), 6. 75 (t, J = 7. 4 H ethylamino]-Hz, 1H), 6. 64 (d, J = 15. 4 Hz, 1H), 6. 65 N pyridin-3-yl}- acrylamide (s, 1H), 4. 90 (s, 5H), 3. 50-3. 45 (m, 4H), _ 3. 30 (d, J = 1. 3 Hz, 1H). . yT. _ ( ?-mino.. _-I 3- .. irphin-" (CD, OD) 8 (pp). 7. 83 (d,. J = I5. o'. 1. 1) 7,,--) 7 dz J =-7. S Hz, 2H), 7. 62- . f.'"-'7. 58 (m, 2H), 7. 53-7. 51 (m, 2H), 7. 49 (d,-3,... , 378. 523'c ; CH CH H'.. J = 7. 8 Hz., 2H), 7. 01 (d, J = 15. 6 Hz, 33, 1H7 s i f Q 99 (hs 9H) f 4. 84 (bs. GH} 4. 22 l. 57 phenyl) 7aMin0l-. M. o. c. metjbvH-'J=6.. SHz, 2H),. 4. 05,. ! s. 4H), 3.. 85 3. 76 H-), 3. 5--3'SO'- (m, : 4H).. acrylamido H-IFiR (Dc-B'3-da). ii (rpi't) : 9 _ 32 (s. IH), -. tu- (2-Amino- plaenyl)-3- (6-9-26 (s, 1H), 8 1. 9 (9, lli.)-6 6 (d, I r v I H 8. H, 1H), 7_57, t, J = 6. 0 Hz ; 1H} , 379 524 N CH'H 7. 41 (d, J=15-7HlH),.. 732 (dJ=7. 7 3 _- ben2ylamino)-H, ) y 1D ft, J = 7. 6 Hz, 1H), 6_91 (t, pridin-3-=3} = OH j=7. G. Hz, 7. H), 6. 75 (m, 3H), 6_59 (mf 4H), .. 4. 98 (Is, 2H) f 4 : 48. (d,. J=5. : 8 Hz, 2H)-' N- (2-Amino-xH_ (DilSO-r36) $ (Rpm). . 2 .. (S f 1H).. _. _ . . i°. I, phenyl)-3-f 6- N 8. 18 1H), 7. G7., (d, LT 8'Hz, 1H), 7-59 (t,. T = 6. 0 Hz,-1H)', 7. a42 trifluor- 38052-5-''Y'N CH H-15. 7 Hz, 1H), 7. 30 (m,. 2H),'.. 7. 00 (m, 2H). r.'3 6 9 2 (-, 11, 2H), 6674 (d, J'='8-0 Hz,. 1H) a' pyridin-3-y'L 6. 60 (m, 3H), 4. 9 (s, 2H).. 4. 73. r, J = yrldm-3 3}-q acrylamide 8. 8 Hz, 2H), 4_52 (d,. J. °.. 5_8 Hz, 2H) : N- (2-Amino- phenyl-)-3- (4--N-M . . {L hydroxy-4 _ pp _ Hz., IH), 7-5G J''-8. 0. llz, 214), 7-49 'V N. (m,-IR) 7-40 (d, J 8. 9 112, 2H), 7. 21 3p 381. 526'\/--/\. CH CH H (m,'2H), 7. 03 (t, J= 7. 6.. Hz, 1H), 6. 88- 33, ;. 6 71 (m,, 4H), 4. 88 (bs, 41T-) 4. 34 (j,, 58. . F. phenylamino]- 2. 86 (t, J = 4-1 ! T-z, 4H), 2. 67 (bs,. 4H)., : . 2_4I (s,. 3H). Phenyl)- , acrylamide Ex. Cpd Y Z R Name Characterization Schm N- (2-Amino- phenyl)-3-14- phenyl)-3- (4-iH-N (DMSO-ds, 8 (ppm) : 9. 43 (s, 1H), H { [3-fluoro-4- 7. 61 (d, J = B. 0 Hz, 2H), 7. 45 (d, J 8. 0 -iL (4-methyl-Hz, _ 2H), 7. 38 (d, J = 7. 6 Hz, 1H), 7. 00- 3, 382 527 CH CH H yperazin-1-6. 8g (m, 2H), 6. 85-6. 79 (m, 2H), 6. 63 (t, 33, J ? J = 7. 6 Hz, IH), 6. 44-6. 30 (m, 3H), 4. 99 58 Mé v methyl}- (bs, 2H), 4. 30 (d, J = 5. 5 Hz, 2H), 2. 87 phenyl)- (bs, 4H), 2. 55 (m, 4H), 2. 27 (s, 3H). acrylamide acrylamide H N- (2-Amino-iH- (CDCl3), 8 (ppm) : 7. 49 (d, J = 14. 0 phenyl)-3-f4-Hz, 1H) ; 7. 32 (d, J = 7. 2 Hz, 2H), 7. 15 [ (3-hydroxy- 2H) 7. 15 383 528 ll, J CH CH H phenylamino)- (d, J = 7. 2 Hz, 2H), 7. 05 (m, 1H), 6. 96 3 33 \jZ (m, 1H), 6. 90 (m, 3H), 6. 76 (m, 1H), 6. 55 methyl- I phenyl}- (d, J = 14. 0 Hz, 1H), 6. 03 (m, 1H), 5. 99 OH acrylamide (m, 1H), 4. 30 (bs, 5H), 4. 10 (s, 2H). N- (2-Amino- 1H-NMR (CD30D), 8 (ppm) : 7. 73 (d, J-= 16. 0 phenyl)-3- 4-Hz, 1H) ; 7. 63 (d, J = 8. 5 Hz, 1H), 7. 58 N N [ (4- (d, J = 8. 0 Hz, 2H), 7. 46 (d, J = 8. 0 Hz, , of trifluoromethyl 2H), 7. 38 (d, J = 8. 5 Hz, 1H), 7. 20 (d, J 384 529 N CH CH H-pyrimidin-2-= 8. 0 Hz, 1H), 7. 03 (dt, J = 7. 7, 1. 4 Hz, 3, 33 ylamino)-1H), 6. 89 (d, LT 1. 1 Hz, 1H), 6. 85 (m, CF3 methyl]-1H), 6. 73 (dt, J = 7. 7, 1. 1 Hz, 1H), 6. 56 phenyl}- (d, J = 16. 0 Hz, 1H), 5. 27 (s, 2H), 4. 87 acrylamide (bs, 2H), 4. 62 (s, 2H). N- (2-Amino- N- (2-Amino- iH-NMR (DMSO-d6), 8 (ppm) : 9. 90 (s, 1H), ph3nyl)-3-4-7. 58 (m, 3H)., 7. 43 (d, J = 8. 0 Hz, 2H} ; hydroxymethyl-7 . 37 (d, J = 8. 0 Hz, 1H), 7. 11 (m, 1H), 385 530 CH CH H 7. 00 (m, 3H), 6. 85 (d, J = 15. 4 Hz, 1H), 3, 33 phenylamino)-6. 63 (s, 1H), 6. 51 (d, J = 7. 4, Hz, 1H), methyl-6. 46 (d, J = 7. 7 Hz, 1H), 4. 35 (s, 2H), Ho phenyl}-4. 32 (s, 2H). acrylamide Ex. Cpd W _ z R Name Characterization Schm 1X-NMR (DMSO-d6), 6 (ppm) : 9. 66 (s, 1H), H N- (2-Amino- 8. 46 (d, J = 4_7 Hz, 2H) ; 7. 55 (d, J = 8. 0 phenyl)-3- {4- Hz, 2H), 7. 50 (d, J = 15. 7 Hz, 1H), 7. 39 [ (4-pyridin-4- (d, J = 8. 0 Hz, 2H), 7. 28 (d, J = 4. 7 Hz, 386 531 CH CH H ylmethyl-2H), 7. 00 (d, J = 15. 7 Hz, 1H), 6. 92 (d, 386 531 CH CH H 3. 33 phenylamino)-J = 6. 9 Hz, 2H), 6. 90 (m, 1H), 6. 75 (d, J methyl-= 8 Hz, 1H), 6. 58 (m, 2H), 6. 52 (d, J = phenyl}-6. 9, Hz, 2H), 6. 10 (bs, 1H), 4. 26 (bs, N acrylamide 2H), 3. 80 (s, 2H), 2. 08 (d, J = 1. 9 Hz, 2H). N- (2-Amino- 1H-NMR (DMSO-d6), 8 (ppm) : 9. 38 (s, 1H), phenyl)-3- {4- 7. 58 (d, J = 7 7 Hz, 2H} ; 7. 54 (d, J = <\ìl/c, [ (3-cyano-15. 9 Hz, 1H), 7. 41 (d, J = 7. 7'Hz, 2H), 387 532 wu CH CH H phenylamino)-7. 33 (d, J = 8. 0 Hz, 1H), 7. 24 (t, J = 7. 7 3, 33 methyl]-Hz, 1H), 6. 92-6. 83 (m, 5H), 6. 75 (d, J = CN phenyl}-8. 0 Hz, 1H), 6-58 (t, J = 7. 4 Hz, 1H), acrylamide 4. 95 (bs, 2H), 4. 34 (d, J = 5. 8 Hz, 2H). 1H-NMR (DMSO-d6), 8 (ppm) : 9. 37 (bs, 1H), 3-(4-{ [3-8. 21 (t, J = 5. 8 Hz, 1H), 7. 56 (d, J = 7. 7 , H (Acetylamino-Hz, 2H), 7. 53 (d, J = 15. 7Hz, 1H), 7. 41 methyl)- (d, J = 8. 0 Hz, 2H), 7. 33 (d, J = 7. 1 Hz, phenylamino]-1H), 6. 97 (m, 1H), 6. 85 (d, J = 15. 7 Hz, 388 533 CH CH H methyll-IH), 6. 74 (dd, J = 1. 4, 8. 0 Hz, IH), 6. 58 3, 33 phenyl)-N- (2- (dt, J = 1. 4, 8. 0 Hz, 1H), 6. 50 (bs, 1H), amino-phenyl)-6. 41 (d, J = 8 0 Hz, 2H), 6. 30 (t, J = 6. 0 NHAC Hz, 1H), 4. 94 (bs, 2H), 4. 28 (d, J = 6. 0 acrylamide Hz, 2H), 4. 09 (d, J = 6. 0 Hz, 2H), 1. 83 (s, 3H). N- (2-Amino- 1H-NMR (DMSO-d6), 8 (ppm) : 9. 37 (bs, 1H), N phenyl)-3- {4-7. 56 (d, J = 8. 0 Hz, 2H), 7. 53 (d, J = (4-nitro-3-15. 7Hz, 1H), 7. 41 (d, J = 8. 0 Hz, 2H), trifluoromethyl 7. 33 (d, J = 7. 7 Hz, 1H), 6. 92 (d, J = 7. 7 3 33 02N \r-phenylamino)-Hz, 2H), 6. 85 (d, J = 15. 7 Hz, 1H), 6. 74 l methyl3- (d, J = 8. 0 Hz, 1H), 6. 67-6. 55 (m, 4H), phenyl-5. 84 (t, J = 5_8 Hz, 1H), 4. 94 (bs, 2H), acrylamide 4. 22 (d, J = 5-8 Hz, 2H). Z 3 >'/'<'u--í rertf a r. SG ta, tT o. C. HS. 2F. 1, ti. 5t (d, 8. 0'i. 54 (dz'y £ _ I = 1.. ^'i"17 : ai- i'1' (3c. r' Cl . i.. --n v : i, 11J3.-r_), i 33< : r53P CjljaH K phayla. c. inc)'-'7. 33. (d, J ='7 H. ;, 1B),. &. 9T-6. 65L 3, 33 1 I i--j' t-a - ! ; ; ; F 1., ; a. S-, 9it, d-J- i : _7 H, 2), i. 4G ; c, -t. 0 Fi, ? ; t, I x'af i5 i . lf C3f iC°_fi :' H'pu> ?. y°i, ; __i_ : : _F. _ 7., 3 ( : i,, = 7. ; . : ; 1),. i ;. 9 t-6. E . ; W, 3. 33 j _ j, f :. nmyij__ J 1. 4. &. 0 liz, ii ; , 6-. 50-5 : 55 (m, Iif. (C1 ! r-x : l., ti : i 1, 4, 8-D IIZ, iii-F, 6-130-6. 55 (m, 4E) f' :'' iff--Amino-..'''.'' . s0 . . j phenyl)-3- (- - ? 8. (CDCl 5 (ppm ; 8, IX {bs, H ;/.' -4 95 (bZ, 4. 33 (d-, Ll'=. 6. 0 112, 2 TI) C 7 64. (d, ki 1, 4-'2 Iiz,'3. F) 2 (b---4R'l - j r. [< pjl. en. yl}- 2H), 3-&7 , 6H). 3. S4 (n, 3H). ÍÍýýýý1 Fph. enyl- 23) 3 _7 ÍÍýýýý1 :, 61), 3. 24 { : . 3). _ i -duc-. MeO i i acrtilasni de -3-' 7-5B (d, r 15. 7 Hr, I. H) 7-33 (, 1, T- [-e/3 |l3herv1}-3-t4-7 5B (d, d = 1S. ? Hz, 3E1, 7 3s tA, a C _ I H taca. metlo : ci. - e_5 3-i. r 1$), 6. T3 (d,.. T. = 4. 0 H2.,. 2Rkr 3 ' F h n 1 ri-r : -_ y FF Y ' _ G (d,, 1 = 5. 0 i2-. ? F13. ; _=8 c, ; '- phsnylj-. IS. Rs. IH), &-53 {bs, 2). 6. 47 (R. 2a). _ acyl. d 3_BS (s, 3H), 3. 63- {s_. _61i)- H B-t | 5-Aina 1g_ 1X30DiOCl3.} ppm) :. S1 1d, J-l 'J, -- phejiyl)-3- {4- 1E-7HS, im,'7. 45- (d.'J=a-lz, 2HL'' J ft E'"-''fO-sulfame-yl-7. 29 [d, J = 8-T-Hz. 3H}, 7. 1B tdd ; 1 3 5R_.. r I -. 1 _'. 1 r " ! methylj-7. 10 (i, 1K) 7. 03 (t,. 1 =. 7. 4 Hs, IH),)' ) t : CSVI. j-'6 _ B3-6. 5fi til3, 4ri), 3 (t7Si 8. .'h'H I }-s'. SOsNH ! i acr-atnia signals).' ! Ex. Cpd W Y Z R Name Characterization Schm N- (2-Amìno-1H-NMR (CDC13), 6 (ppm) : 8. 34 (bs, 1H), H phenyl)-3- (4- 7. 64 (d, J = 15. 4 Hz, 1H), 7. 37 (d, J = /%,, N K {t3 (3 8. 0 Hz, 2H), 7. 34 (m, 1H), 7. 26 (d, J = morpholin-4-yl-8. 0 Hz, 2H), 7. 23 (d, J = 15. 4 Hz, 1H), 3, 394 539 y CH CH H propylsulfamoyl 7. 14 (d, J = 7. 8 Hz, 1H), 7. 04 (m, 2H), 33, 02S N\Nt)-phenylamino]-6. 74 (m, 4H), 4. 85 (bs, 1H), 4. 30 (d, J = 42 H l o methyl}-4. 4 Hz, 2H), 3. 69 (t, J = 4. 4 Hz, 4H), phenyl)-2. 99 (t, J = 5. 8 Hz, 2H), 2. 40 (bs, 6H), acrylamide 1. 59 (t, J = 4. 4 Hz, 2H). MeO N- (2-Amino- 1H-NMR (CDC13), 5 (ppm) : 8. 53 (s, 1H), phenyl)-3- {4- 7.-72 (d, J 15. 6 Hz, 1H), 7. 38 (d, J = [2- (3, 4, 5- 7. 7 Hz, 2H) 7. 33 (m, 1H), 7. 16 (d, J = 395 540 CH CH H trimethoxy-7. 7 Hz, 2H), 7. 07 (m, 1H), 6. 79 (m, 2H), 3, 32 MeO T phenyl)-ethyl]-6. 69 (d, J = 15. 6 Hz, 1H), 6. 41 (s, 2H), phenyl}-4. 04 (bs, 2H), 3. 91 (s, 3H), 3. 85 (s, 6H), OMe acrylamide 2. 94 (m, 4H). 1H-NMR (DMSO-d6), 5 (ppm) : 9. 35 (s, 1H), N- (2-Amino- 7. 56 (d, J = 7. 5 Hz, 2H), 7. 52 (d, J = phenyl)-3- {4- 15. 4 Hz, 1H), 7. 40 (d, J = 7. 5 Hz, 2H), N [ (4-methoxy- 7. 3 3 (d, J = 7. 7 Hz, 1H), 6. 92 (d, J = 7. 7 N 396 541 A CH CH H phenylamino)-Hz, 1H), 6. 85 (d, J = 15. 4 Hz, 1H), 6. 75 3, 33 H3Cs Jv methyl]- (d, J = 8. 0 Hz, 1H), 6. 67 (d, J = 8. 6 Hz, . O phenyl}-2H), 6. 58 (m, 1H), 6. 52 (d, J = 8. 6 Hz, acrylamide 2H), 5. 84 (t, J = 5. 5 Hz, 1H), 4. 23 (d, J = 5. 5. Hz, 2H), 3. 61 (s, 3H). N- (2-Amino- phenyl)-3- 4-1H-NMR (CDCl3), 8 (ppm) : 8. 48 (s, 1H), CH3 H [ (3, 4- 7. 60 (d, J = 15. 4 Hz, 1H), 7. 27 (m, 5H), 397 542 N CH CH H dimethoxy-6. 97 (t, J = 7. 5 Hz, 1H), 6. 70 (m, 3H), 3, 33 j ! j'phenylamino)-6. 59 (d, J = 15. 4 Hz, 1H), 6. 25 (s, 1H), 7. 1 Hz, 1H), 4. 23 (s, 2H), phenyl}-3. 93 (bs, 3H), 3. 75 (s, 3H), 3. 73 (s, 3H). acrylamide Ex. Cpd W Y Z R Name Characterization Schm N- (2-Amino- phenyl)-3- (4-iH-NMR (CD30D), 8 (ppm) : 7. 75 (d, J = 15. 2 [3- (1H- Hz, 1H), 7. 60 (d, J = 7. 6 Hz, 2H), 7. 48 N \ tetrazol-5-yl)- 398 543 NvS elH CH CH H (d, J = 7. 6 Hz, 2H), 7. 33 (m, 3H), 7. 27 3, 33 phenylamino]- methyl- (m. 3H), 7. 20 (m, 1H), 6. 84 (m, 2H), 5. 48 phenyl)- (bs, 5H), 4. 46 (s, 2H). acrylamide N- (2-Amino- phenyl)-3- (4-1H-NMR (CD30D), 8 (ppm) : 7. 75 (d, J = 15. 2 H { [4- (1H- Hz, 1H), 7. 58 (d, J = 8. 2 Hz, 2H), 7. 42 N-N ("_ tetrazol-5- (d, J = 8. 2 Hz, 2H), 7. 29 (m, 2H), 7. 20 399 544 Ns CH CH H ylmethyl)- (m, 2H), 7. 04 (d, J = 8. 2 Hz, 2H), 6. 83 3, 33 phenylamino]- (d, J = 15. 2 Hz, 1H), 6. 67 (d, J = 8. 2 Hz, H methyl}-2H), 5. 48 (bs, 5H), 4. 39 (s, 2H). 4. 16 (s, phenyl)-2H). acrylamide N- (2-Amino-1H NMR (300 MHZ, DMSO-d6) 6 (ppm) : 9. 42 H phenyl)-3-{4- (s, 1H), 7. 62 (d, J = 8. 5 Hz, 2H), 7. 59 (d, J = 15. 6 Hz, 1H), 7. 45 (d, J = 8. 0 Hz, 400 545 CH CH H phenylamino)-2H), 7. 40 (d, J = 7. 5 Hz, 1H), 7. 23 (d, J 3 33 methyl]-= 8-5 Hz, 2H), 6. 98 (d, J = 7. 5 Hz, 1H), Br phenyl}-6. 92 (d, J = 15. 6 Hz, 1H), 6. 80 (d, J = phenyl}- acrylamide 8. 0 Hz, 1H), 6. 66-6. 57 (m, 4H), 4. 99 (bs, 2H), 4. 34 (d, J = 5. 8 Hz, 2H). N- (2-Amino- NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 36 H phenyl)-3- {4- (s, 1H), 7. 57 (d, J = 7. 6 Hz, 2H), 7. 54 s<N X [(3-bromo- (d, J = 15. 8 Hz, 1H), 7. 40 (d, J = 8. 2 Hz, 401 546 CH CH H phenylamino)-2H), 7. 33 (d, J = 7. 6 Hz, 1H), 7. 00-6. 91 3, 33 methyl- (m, 2H), 6. 86 (d, J = 15. 8 Hz, 1H), 6. 74 Br phenyl}- (d, J = 8. 2 Hz, 2H), 6. 66-6. 54 (m, 4H), acrylamide 4. 93 (bs, 2H), 4. 30 (d, J=5. 3Hz, 2H). Ex. Cpd W Y Z R Name Characterization Schm 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 36 N- (2-Amino- (s, 1H), 7. 56 (d, J = 8. 0 Hz, 2H), 7. 53 phenyl)-3- {4- (d, J = 15. 8 Hz, 1H), 7. 39 (d, J = 8. 0 Hz, [. (4-iodo- 2H), 7. 35 (m, 1H), 7. 31 (d, J = 8. 2 Hz, 402 547 CH CH H phenylamino)-2H), 6. 92 (d, J = 7. 1 Hz, 1H), 6. 85 (d, J 3, 33 methyl-= 15. 8 Hz, 1H), 6. 75 (d, J = 7. 7 Hz, 1H), phenyl}-6. 57 (t, J = 8. 0 Hz, 1H), 6. 52 (t, J = 6. 0 acrylamide Hz, 1H), 6. 42 (d, J = 8. 5 Hz, 2H), 4. 94 (bs, 2H), 4. 28 (d, J = 6. 0 Hz, 2H). N- (2-Amino- 1H NMR (300 MHz, DMSO-d6) 5 (ppm) : 9. 40 H phenyl)-3- {4- (s, 1H), 7. 57 (d, J = 7. 6 Hz, 2H), 7. 53 N [ (3-iodo- (d, J = 15. 6 Hz, 1H), 7. 40 (d, J = 8. 2 Hz, 403 548 I CH CH H phenylamino)-2H), 7. 33 (d, J = 7. 6 Hz, 1H), 6. 92 (m, 3, 33 T methyl]-3H), 6. 84 (m, 2H), 6. 74 (d, J = 7. 6 Hz, phenyl}-1H), 6. 60-6. 50 (m, 3H), 4. 93 (bs, 2H), acrylamide 4. 28 (d, J = 5. 9 Hz, 2H). 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 42 N- (2-Amino- (s, 1H), 7. 63 (d, J = 8. 2 Hz, 2H), 7. 60 H H phenyl)-3- (4- (d, J = 15. 3 Hz, 1H), 7. 46 (d, J = 8. 2 Hz, { [3- (2-hydroxy- 2H), 7. 40 (d, J = 7. 6 Hz, 1H), 7. 03-6. 98 404549 t. J CH CH H ethoxy)- (m, 2H), 6. 91 (d, J = 15. 3 Hz, 1H), 6. 81 g gg phenylamino]- (d, J = 7. 6 Hz, 1H), 6. 64 (t, J = 7. 6 Hz, methyl}-1H), 6. 36 (t, J = 5. 9 Hz, 1H), 6. 28-6. 22 \/\OH phenyl)- (m, 3H), 4. 99 (bs, 3H), 4. 61 (s, 2H), 4. 34 acrylamide (d, J = 5. 0 Hz, 2H) 4. 28 (d, J = 5. 0 Hz, 2H). 1H NMR (300 MHZ, DMSO-d6) 6 (ppm) : 9. 38 (s, N- (2-Amino- 1H), 7. 99 (d, J = 9. 1 Hz, 2H), 7. 85 (t, J H phenyl)-3- {4- = 5. 9 Hz, 1H), 7. 60 (d, J = 7. 6 Hz, 2H), <N X, [(4-nitro-7. 54 (d, J = 15. 8 Hz, 1H), 7. 40 (d, J = 405 550 CH CH H phenylamino)-7. 6 Hz, 2H), 7. 34 (d, J = 7. 6 Hz, 1H), 3, 33 /methyl]-6. 94-6. 92 (m, 1H), 6. 88 (d, J = 15. 8 Hz, 02N phenyl}-1H), 6. 75 (d, J = 7. 6 Hz, 1H), 6. 68 (d, J acrylamide = 9. 1 Hz, 2H), 6. 58 (t, J = 7. 6 Hz, 1H), 4. 94 (bs, 2H), 4. 46 (d, J = 5. 9 Hz, 2H) Ex. Cpd W Y Z R Name Characterization Schm H N- (2-Amino-1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 37 v<N (s, 1H), 7. 59 (d, J = 7. 6 Hz,. 2H), 7. 54 phenyl)-3- {4- 406 551 CH CH H phenylamino)- (d'J = 15. 2 Hz, 1H), 7. 43 (d, J = 3, 33 2H), 7. 36-7. 28 (m, 4H), 7. 05-6. 98 (m, 2H), methyll-6. 92 (d, T = 7. 6 Hz, 1H), 6. 88 (d, J = T phenyl}-15. 2 Hz, 1H), 6. 75 (d, J 7. 6 Hz, 1H), N02 acrylamide 6 58 (t, J-7 6 Hz, 1H), 4. 96 (bs, 2H), 4. 39 (d, J = 5. 3 Hz, 2H). 1H NMR (300 MHz, DMSO-d6) (ppm) : 9. 43 N- (2-Amino- (s, 1H), 7. 62 (d, J = 7. 6 Hz, 2H), 7. 59 phenyl)-3- {4- (d, J = 15. 8 Hz, 1H), 7. 46 (d, J = 7. 6 Hz, N [ (4-chloro- 2H), 7. 40 (d, J = 7. 6 Hz, 1H), 7. 12 (d, J J = 7. 6 Hz, 3, 33 407 552 CH CH H phenylamino)-= 8. 8 Hz, 2H), 6. 98 (d, J = 7. 6 Hz, 1H), 3, 33 methyl-6. 93 (d, J = 15. 8 Hz, 1H), 6. 81 (d, J = Cl phenyl}-7. 6 Hz, 1H), 6. 62 (d, J = 8. 8 Hz, 2H), acrylamide 6. 55 (bs, 2H), 4. 99 (bs, 2H), 4. 46 (d, J = 5. 9 Hz, 2H), 4. 35 (d,'J = 5. 9 Hz, 2H) N- (2-Amino-1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 50 phenyl)-3- {4- (s, 1H), 7. 65 (d, J = 8. 2 Hz, 2H), 7. 61 [ (3-chloro- (d, J = 15. 4 Hz, 1H), 7. 47 (d, J = 7. 6 Hz, 408 553 CH CH H phenylamino)-2H), 7. 43 (m, 1H), 6. 93 (d, J = 7. 0 Hz, 3, 33 methyl]-1H), 6. 79 (d, J = 15. 4 Hz, 1H), 6. 68 (m, ci phenyl}-3H), 6. 59 (m, 3H), 5. 24 (bs, 2H), 4. 31 (s, acrylamide 2H). N- (2-Amino-1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 37 (s, H phenyl)-3- {4- N [ (4-fluoro- 1H), 7. 63 (d, J = 8. 2 Hz, 2H), 7. 60 (d, J 409 554 ff- CH CH H phenylamino)-= . 4 Hz 1H) 7. 47 (d, J-7. 6 Hz 2H),, h , n 7. 41 (m, 1H), 7_01-6. 90 (m, 4H), 6. 75 (d, phenyl-J = 7. 6 Hz, 1H), 6. 67-6. 59 (m, 3H), 6. 27 acrylamide (bs, 1H), 4. 95 (bs, 2H), 4. 27 (s, 2H). Ex. Cpd z R Name Characterization Schm N- (2-Amino-1H NMR (300 MHz, CD30D) 8 (ppm) : 7. 64 (d, H phenyl5. 9 Hz, 1H), 7. 47 (d, J = 7. 5 Hz, ph3nyl)-3- {4- 2H), 7. 32 (d, J = 7. 5 Hz, 2H), 7. 19 (d, J methylsulfanyl-75 Hz. 1H), 7. 03 (t, J = 7. 8 Hz, 1H), 410 555 CH CH H phenylamino)-6. 82 (d, J = 7. 5 Hz, (tl) 6. 77 (d, J = 7. 8 3, 33 T methyl]-Hz, 1H), 6. 70 (d, J = 15. 9 Hz, 1H), 6. 56 SMe phenyl- (d J = 7. 8 Hz, 1H), 6. 49 (s, 1H), 6. 37 acrylamide (d J = 7. 8 Hz, 1H), 4. 29 (s, 2H), 4. 05 (bs, 4H), 2. 37 (s, 3H). N- (2-Amino- 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 36 H phenyl)-3-{4- (s, 1X), 7. 57 (d, J = 7. 5 Ez, 2H), 7. 53 [ (4- (d, J = 15. 8 Hz, 1H), 7. 40 (d, J = 7. 9 Hz, methylsulfanyl-2H), 7. 34 (d, J = 7. 9 Hz, 1H), 7. 07 (d, J 411 556 CH CH H phenylamino)-. = 8-3 Hz, 2H), 6. 92 (d, J = 7. 5 Hz, 1H), 3, 33 methyl]-6-87 (d, J = 15_8 Hz, 1H), 6. 75 (d, J = MeS phenyll-7. 9 Hz, 1H), 6. 60-6 54- (m, 3H), 6. 39 (t, J acrylamide = 5. 7 Hz, 1H), 4. 93 (bs, 2H), 4. 29 (d, J = 6. 1 Hz, 2H), 2. 32 (s, 3H),. _ _ N-(2-Amino- N- (2-Amino-'H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 36 phenyl)-3- {4- N N, [(5-bromo- (s, 1H), 8. 02 (d, J = 1. 7 Hz, 1H), 7. 57- pyridin-2-7. 50 (m, 4H), 7. 38 7. 32 (m, 4H), 6. 92 (d, 3 33 412 557 \ CH CH H J = 7. 5 Hz, 1H), 6. 86 (d, J = 1. 6. 3 Hz,. ylamino)-1H), 6. 75 (d, J = 7. 9 Hz, 1H), 6. 59 (d, J methyll-= 7. 5 Hz, 1H), 6. 53 (d, J = 9. 2 Hz, 1H), BI'phenyl}-- acrylamide 4-94 (bs, 2H), 4. 48 (d, J = 5. 7 Hz, 2H). 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 37 f" (s, 1H), 8. 25 (rn, 1H), 7. 76 (m, 1H), 7. 57 N- (2-Amino- N phenyl)-3- [4- (m, 2H), 7. 47 (m, 4H), 7. 33 (d, J = 7. 0 413 558 I CH CH H (naphthalen-1-HZ ; 1H), 7. 17 (rn, 1H), 7. 07 (d, J = B. 2 /ylaminomethyl)-1H). 6. 99 (t, J = 5. 3 Hz, 1H), 6. 92 3, 33 (d, J = 7. 0 Hz, 1H), 6. 85 (d, J = 16. 4 Hz, acrylamide IH), 6. 74 (d, J = 7. 6 Hz, 1H), 6. 57 (t, J acrylamide 7. 6 Hz, 1H), 6. 36 (t, J = 7. 6 Hz, 1H), 4. 90 (s, 2H), 4. 54 (d, J = 5. 3 Hz, 2H). Ex. Cpd W Y Z R Name Characterization Schm H (2-Amino-1H NMR (300 MHz, DMSO-ds) 8 (ppm) : 9. 39 (s, 1H), 7. 57 (d, J = 7. 0 Hz, 2H), 7. 53 p enyl)-3- {4- (d J = 15. 4 Hz, 1H), 414 559 CH CH H phenylamino)-7. 7 36 (d, J-7. 6 Hz, 1H) 7 02 (q, J 3, 33 2H), 7. 36 (d, J = 7. 6 Hz, 1H), 7. 02 (q, J phenyl)-8. 2 Hz, 1H), 6-5 8 (m, 1H), 6. 4 0 (d, J = phenyl}-8. 2 Hz, 1H), 6_58 (m, 1H), 6. 40 (d, J = acrylamide 8. 2 Hz, 1H), 6_29 (m, 2H), 4. 90 (s, 1H), 4. 29 (bs, 2H), 4. 02 (s, 2H). Ex Cpd W Y Z R Name Characterization Schm 0 N- (2-Amino-phenyl)-1H-NMR (CDC13), 6 (ppm) : 7. 73 MeO NH 3- {3, 5-dimethoxy-4- (bs, 1H), 7. 63 (d, J = 14. 9 Hz, 41 560 MeO NX XNH2 [ (3, 4, 5-trimethoxy-1H), 6. 81 (m, 3H), 6. 70 (m, 2H), 60 oye phenylamino)-6. 68-6. 56 (m, 2H), 6. 07 (s, 2H), MeO IT methyll-phenyll-4. 35 (s, 2H), 3. 86 (s, 6H), 3. 81 OMe acrylamide (s, 6H), 3. 75 (s, 3H). Ex. Cpd W Y Z R Name Characterization Schm H NMR (300 MHz, CDC13) 8 (ppm) : 9. 22 (s, 1H), 9. 11 (s, 1H), 7. 57 O N- (2-Amino-3- (d, J = 7. 9 Hz, 2H), 7. 64 (d, J = hydroxy-phenyl)-15. 8 Hz, 1H), 7. 44 (d, J = 7. 9 H 3- {4- [ (3, 4, 5- Hz, 2H), 6. 96 (d, J = 15. 8 Hz, 3 416 561 Me0 N /NH2 trimethoxy-1H), 6. 78 (t, J = 7. 9 Hz, 1H), 33 phenylamino)-6. 23 (t, J = 7. 9 Hz, 1H), 6. 16 MeO T OH methyl]-phenyl}- (d, J = 7. 9 Hz, 1H), 6. 09 (t, J = OMe acrylamide 6. 2 Hz, 1H), 5. 89 (s, 2H), 4. 77 (bs, 2H), 4. 27 (d, J = 5. 7 Hz, 2H), 5. 89 (s, 6H), 5. 76 (s, 3H). Ex Ex Cpd W Y Z R Name Characterization Schm 'H NMR (300 MHz, CDC13) 8 (ppm) : 8. 25 (s, 1H), 7. 74 (d, J = 15. 5 N- (2-Amino- Hz, 1H), 7. 44 (d, J = 7. 9 Hz, OMe phenyl)-3- {4-2H), 7 37 (d, J _ 7 9 Hz, 2H), H 7. 34-7. 29 (m, 2H), 7. 08 (t, J = 471 562 MeO>, R CH CH H trimethõxy-7 5 Hz, H), 6 82 (t, J-7. 5 Hz, 33 7 1H), 6. 79 (m, 1H), 6. gag (d, J = phenylamino)-15. 5 Hz, 1H), 6. 60 (d, J = 8. 8 0 acrylamide Hz, 1H), 6. 31 (d, J = 8. 8 Hz, 1H), 4. 36 (s, 2H), 4. 18 (bs, 2H), 3. 98 (s, 3H), 3. 96 (s, 3H), 3. 84 (s, 3H). N- (2-Amino-1H NMR (300 MHz, CDC13) 8 (ppm) : OMe phenyl)-3- [4- ( {4- 8. 58 (s, 1H), 7. 66 (d, J = 15. 4 OMe methoxy-3- [ (3, 4, 5- Hz, 1H), 7. 33-7. 28 (m, 3H), 7. 23 (d, J = 7. 0 Hz, 2H), 7. 04 (t, J = 41 563 HN'jl : tOMe CH CH H phenylamino)-7. 0 Hz, 1H) 6. 7 7-G. 7 0 (m, 4H), 3', 8 NH methyll-6. 64 (d, J 1-5. 4 Hz, 1H), G. S3 33 T ? TC phenylamino}-2H) 4. 27 (s, 2H), 4. 25 (s, 2H), Me0 methyl)-phenyl]-4 _ 08 (bs, 4H), 3. 82 (s, 6H), 3. 77 acrylamido Cpd W Y Z R Name Characterization Schm N- (2, 3-Diamino- 1H NMR (300 MHz, CDC13) 8 (ppm) : O _ 7. 64 (d, J = 15. 4 Hz, 1H), 7. 48 NH phenyl)-3- {4 (d, J = 7. 5 Hz, 2H), 7. 35 (d, J 4 564 MeO NHoX 4, NH2 trimethoxy-7 5 HZ, 2H) 7 3713 (d J-15 4 33 SG4 Meo N NH2 trimethoxy- Me0 NH2 methyl]-phenyl}- OMe acrylamide 2H), 4. 00 (bs, 6H), 3. 71 (s, 6H), 3. 68 (s, 3H). Cpd W Y Z R Name Characterization Schm E x Cpd W Y Z R Name Characterization Schm H-NMR (DMSO-d6), 6 (ppm) : 9. 38 (bs, 1H), 7. 58 (d, J = 7. 5 Hz, N- (2-Amino- 2H), 7. 54 (d, J = 15. 4Hz, 1H), phenyl)-3- {4- [ (3- 7. 40 (d, J = 7. 9 Hz, 2H), 7. 33 42 F N X, fluoro-4- (d, J = 7. 9 Hz, 1H), 7. 14 (t, J = 3 Q 565 I CH CH H methylsulfanyl-8. 3 Hz, 1H), 6. 94-6. 89 (m, 2H), 33 H3CsSw phenylamino)-6. 81 (d, J = 15. 7 Hz, 1H), 6. 74 meth 1]-phen 1- methyl]-phenyl}- (d, J = 8. 3 Hz, 1H), 6. 58 (t, J = acrylamide 7. 5 Hz, 1H), 6. 43-6. 38 (m, 2H), 4. 94 (bs, 2H), 4. 30 (d, J = 5. 7 Hz, 2H). 2. 28 (s, 3H). 1H-NMR (DMSO-d6), 5 (ppm) : 9. 39 N- (2-Amino- (bs, 1H), 7 59 (d, J = 7. 9 Hz, F phenyl)-3- {4- [ (4- 2H), 7. 54 (d, J = 15. 8Hz, 1H), F H 7. 41 (d, J = 7. 9 Hz, 2H), 7. 36 42 566 F IV2, methylsulfanyl-3- (d J = 7. 9 Hz, 2H), 7. 33 (d, J = 3, CH CH H trifluoromethyl-6_2 Hz, 1H), 6. 96-6. 90 (m, 4H), 33 H3C\/phenylamino)-6_g2 (d, J = 15. 8Hz, 1H), 6. 79- acrylamide 6. 74 (m, 1H), 6. 58 (t, J = 7. 5 Hz, 1H), 4. 95 (bs, 2H), 4. 35 (d, J = 6. 2 Hz,-2H). 2. 35 (s, 3H). Ex Cpd _ z R Name Characterization Schm Ex Ex Cpd W Y Z R Name Characterization Schm H-NMR (DMSO-d6), 6 (ppm) : 9. 50 (s, 1H), 8. 09 (s, 1H), 7. 80 (d, J o N- (2-Amino-= 15. 4 Hz, 1H), 7. 81 (s, 2H), 02N kJIs phenyl)-3- {3- 7. 34 (d, J = 7. 9 Hz, 1H), 6. 94 42 H NH nitro-4- [ (3, 4, 5- (d, J = 7. 5 Hz, 1H), 6. 88 (d, J = 3 2 567 MeOqN NH2 trimethoxy-15. 4 Hz, 1H), 6. 76 (d, J = 7. 9 33 2 33 phenylamino)-Hz, 1H), 6. 58 (t, J = 7. 5 Hz, MeO/\ o/NH2 methyl]-phenyl}-1H), 6. 26 (t, J = 6. 2 Hz, 1H), OMe acrylamide 5. 90 (s, 2H), 4. 96 (bs, 2H), 4. 39 (d, J = 5. 7 Hz, 2H), 3. 66 (s, 6H), 3. 51 (s, 3H). O N- (2-Amino-1H-NNR (DMSO-d6), 6 (ppm) : 9. 29 H2N NH phenyl)-3- {3- (s, 1H), 7. 72 (d, J = 15. 4 Hz, 42 H nu amino-4- [ (3, 4, 5- 1H), 7. 33 (m, 2H), 6. 90 (1H) ; 3 3 568 N NH2 trimethoxy-6. 71 (2H), 6. 62 (3H), 5. 97 33 J l !, J u phenylamino)- (1H), 5. 87 (2H), 5. 49 (2H) Me0 NH2 methyl]-phenyl}-4. 96 (2H), 4.. 10 (2H), 3. 65 OMe acrylamide (6H), 3. 51 (3H). 0 NH N- (2-Amino- 42 NIH2 phenyl)-3-- [6- (3, 4- 3, 569 N dimethoxy-phenyl)-LRMS : calc : 375. 4, found : 376. 4 15, H3C, pyridin-3-yll-33 'acrylamide HgC Ex Cpd W Y Z R Name Characterization Schm 1H-NMR (DMSO-d6), 8 (ppm) : 9. 64 H2N 1V- (4-Amino- (bs, 1H), 7 65 (d, J=7. 9 Hz, thiophen-3-yl)-3 2H), 7. 60 (d, J=14. 0 Hz, 1H), 4 CH3 HN--6-7. 5 0 (d, J=7. 9 Hz, 2H), G. 9 0 (d'3, J=15. 8 Hz, 1H), 6. 15 (d, J=4. 0 2 570/\/4-yl-33, 2H), H3C0/\ NH C phenylamino)-iHj'1H), 5. 95 (s, 5. 82 (s, 60 e/methyl]-phenyl}-4. 89 (bs, 2H), 4. 33 (d, J=5. 7 H3C-O acrylamide Hz, 2H), 3. 71 (s, 6H), 3. 57 (s, 3H). SArW Br K2C03/DMF SARW BOP/ WARSH + loopc LiOHxH, O/ SARW 1, 2-Phenylenediamine 0 or 121 coome oa-122 Coome H2OfMeOH COOH DMF/Ft3N NH DMF 125 rN-,., N~CI. NH2 CI. LiOHxH2O/ TBAI, Nal, H20/MeOH K2C03 COOMe DMF Et3N, DMF WARS H HzN Example 85 126 : WArS= C/>S N N 119 : WArS= -s N H H NN S Example 87 128 : WArS= !) -S HAN 120 : WArS= I/S N Example 85 N- (2-Amino-phenyl)-4- (1H-benzimidazol-2-ylsulfanylmethyl)-benzamide (compound 126) Step 1 : 4-(lH-Benzimidazol'2-ylsulfanylmethyl)-benzo'ic acid methyl ester (compound 122) [0215] Following the procedure described in Example 47, step 2, but using 119 and substituting 121 for 63, the title compound 122 was obtained in 95% yield. LRMS = 299. 1 (M+1).

Step 2 : N- (2-Amino-phenyl)-4- (lH-benzimidazol-2-ylsulfanylmethyl)- benzamide (126) [0216] 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) 8 (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 H, z, 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 <BR> <BR> <BR> <BR> N- (2-Amino-phenyl)-4- [6- (2-morpholin-4-yl-ethylamino)-benzothiazol-2- ylsulfanylmethyl]-benzamide (compound 128) Step 1 : 4- (6-Amino-benzothiazol-2-ylsulfanylmethyl)-benzoic acid methyl ester (122) [0217] 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).

Step 2 : 4- [6- (2-Morpholin-4-yl-ethylamino)-benzothiazol-2- ylsulfanylmethyll-benzoic acid methyl ester (compound 124) [0218] 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 pL, 2. 66 mmol) and tetrabutylammonium iodide (894 mg, 2. 42 mmol), The mixture was stirred at 120°C for 24h and more 4- (2-chloroethyl) morpholine hydrochloride (296 mg, 2. 66 mmol) was added. The mixture was stirred for 8h at 120°C and the solvent was removed in vacuo. The resulting black syrup was partitioned between Ha0 and EtOAc. The organic layer was successively washed with HC1 1N and saturated aqueous NaHC03. The precipitate was extracted twice with EtOAc, dried over MgS04 and concentrated. Purification by flash chromatography (MeOH/CHC13, 5 : 95 to 10 : 90) afforded 48 mg (4% yield) of 124 as a light yellow oil. LRMS = 444. 1 (M+1).

Step 3 : N- (2-Amino-phenyl)-4- [6- (2-morpholin-4-yl-ethylamino)- benzothiazol-2-ylsulfanylmethyl]-benzamide (compound 128) [0219] 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) 8 (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). form CO/Pd (Ac0) 2/dppf \ I N S Br DMF/K2C03/100°C/\ DMF/100°C N 13H + N S 0 129 ber Br 130 I HN \ t Br HN g Example 88 H2N 131 Example 88 N- (2-Amino-phenyl)-4- (quinolin-2-ylsulfanylmethyl)-benzamide (compound 131) Step 1 : 2- (4-Bromo-benzylsulfanyl)-quinoline (compound 130) [0220] Following the procedure described in Example 47, step 2, but substituting 129 for 63, the title compound 130 was obtained in 89% yield. LRMS = 332. 0 (M+1).

Step 2 : N- (2-Amino-phenyl)-4- (quinolin-2-ylsulfanylmethyl)-benzamide<BR> <BR> (131) [0221] 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) 8 (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). 0 el ° 1. LiOH/H20. MeOH (> O > + + 3 N N I DMF _rN N/ N 01 HzN/HN/2. BOP/Ph (NHZ H'1N I/H NHz 132 133 CH3CN, Et3N 134 Example 89 Example 89 N- (2-Amino-phenyl)-4- (pyrimidin-2-ylaminomethyl)-benzamide (compound 134) Step 1 : 4-(Pyrimidin-2-ylaminomethyl)-benzoic acid methyl ester (compound 133) [0222] Following the procedure described in Example 47, step 2, but substituting 132 for 63, the title compound 133 was obtained in 76% yield. LRMS = 244. 2 (M+1).

Step 2 : N- (2-Amino-phenyl)-4- (pyrimidin-2-ylaminomethyl)-benzamide (134) [0223] 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) 8 (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). O/ H2N N HzN/_ N H2N 2. 4-lodobenzoic acid H'NHBoc EDCI, HOBt, Et3N I 135 PdC12 (dppf), CO, MeOH, i-Pr2EtN DIBAL-H N N eH 136 136 137 DEAD, Ph3P Het-SH 0 o t TFA vNS vNX HetS X H NH2 Zon HetS H NHBoc, Me Me 138 N Example 90 : 139 Het= lL N Example 90 N- (2-Amino-phenyl)-4- (1-methyl-lH-imidazol-2-ylsulfanylmethyl]- benzamide (compound 139) Step 1 : [2- (4-Iodo-benzoylamino)-phenyl]-carbamic acid tert-butyl ester (compound 135) [0224] 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 HC1 1 N and then with aqueous saturated NaHC03. The combined organic layers were washed with brine, dried over MgS04 and concentrated affording the compound (18. 9 g, 65% yield) as a light beige powder. LRMS = 209. 1 (M+1).

[0225] 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 NaHC03, dried over MgS04 and concentrated to a light brown syrup which was crystallized in hot EtOAc or Et2O, yielding 135 (9. 3 g, 70% yield) as a white solid.

LRMS = 461. 0 (M+Na+).

Step 2 : N- [2-tert-butoxycarbonylamino-phenyl)-terephtalamic acid methyl ester (compound 136) [0226] Following the procedure described in Example 40, step 2, but substituting 135 for 42, the title compound 136 was obtained in 95% yield. LRMS = 393. 1 (M+Na+).

Step 3 : [2 (4-Hydroxymethyl-benzoylamino)-phenyl]-carbamic acid tert- butyl ester (137) [0227] To a solution of 136 (7. 5g, 20. 6 mmol) in THF (40 mL), cooled down to-20°C under N2, was added a 1M solution of DIBAL-H (122 mL, 122 mmol) in toluene. After stirring for 18 h. at r. t., the mixture was cooled down to 0°C and carefully quenched by a dropwise addition of H20 (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 H20, 1 N HC1 (6 times), satd. aqueous NaHC03, brine, dried over MgS04 and concentrated (2. 04 g, 43%). Purification of the crude material by flash chromatography (EtOAc/hexanes 50 : 50 to 70 : 30) afforded 137 (1. 14 g, 16% yield) as a solid foam. LRMS = 365. 2 (M+Na+).

Step 4 : {2- [4- (l-Methyl-imidazol-2-ylsulfanylmethyl)-benzoylamino] ; phenyl}-carbamic acid tert-butyl ester (compound 138) [0228] 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 pL, 0. 31 mmol). The mixture was stirred for 2 h and the solvent was removed in vacuo. Purification by flash chromatography using MeOH/CHC13 (5 : 95) as the eluent afforded the title compound 138 (81 mg), in 91% yield, which was found to contain some diethyl hydrazodicarboxylate residus.

The compound was used as is without further purification.

Step 5 : N- (2-Amino-phenyl)-4- (l-methyl-lH-imidazol-2- ylsulfanylmethyl]-benzamide (compound 139) [0229] Following the procedure described in Example 42, step 3, but substituting 138 for 46, the title compound 139 was obtained in 62% yield. lH NMR : (Acetone-d6) 8 (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). 0 9 f, YB (OH), pppq Y ° Pd (PPh3) 4/aq. Na2CO3 < N X H I + I / H NH2 N NH OMe benzene-ethanol C N i 141 140 ! 140 OMe Example 91 Example 91 N- (2-Amino-phenyl)-6- (3-methoxyphenyl)-nicotinamide (compound 141) [0230] 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 (MgS04), and concentrated.

Purification by flash silica gel chromatography (Hexane/Ethyl acetate : 1/1) afforded 141 (302 mg, 95% yield). 1H NMR (CDC13) 8 (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). 0 0 CHO a a Ccn CHO/OH N I\ 142 143 O 144 O / Example 92 a. p-aminomethylbenzoic acid/AcOH/5 min/reflux b. HOBT/EDC/1, 2-diamino benzene Example 92 <BR> <BR> N- (2-Amino-phenyl)-4- (l-oxo-1, 3-dihydro-isoindol-2-ylmethyl)-benzamide (compound 144) <BR> <BR> Step 1 : 4- (1-Oxo-1, 3-dihydro-isoindol-2-ylmethyl)-benzoic acid<BR> <BR> <BR> <BR> <BR> <BR> (compound 143) [0231] 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%). <BR> <BR> <BR> <BR> <P> Step 2 : N- (2-Amino-phenyl)-4- (l-oxo-1, 3-dihydro-isoindol-2-ylmethyl)- benzamide (compound 144) [0232] 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 H20. 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) D 9. 71 (s, 1H), 7. 46 (d, J = 8. 0 Hz, 2H), 7. 80 (d, J = 8. 0 Hz, 2H), 7. 55-7. 70 (m, 3H), 7. 46 (d, J = 8. 2 Hz, 2H), 7. 20 (d, J = 7. 7 Hz, 1H), 7. 02 (t, J = 7. 7 Hz, 1H), 6. 83 (d, J = 8. 0 Hz, 1H), 6. 65 (t, J = 7. 4 Hz, 1H), 4. 93. (bs, 2 H), 4. 87 (s, 2 H), 4. 47 (s, 2H). 0 0 0 \ c \ a, b \ C ( : O N O/ Example 94 d D 0 OTf Nd \ u 0 'vS JO/N 151 152 0 Example 95 a. p-aminomethylbenzoic acid/AcOH/refluxt3 hrs b. HOBT/EDC/1, 2-diamino benzene c. 4-(2-aminoethyl) phenol/AcOH/5 hrs/reflux d. PhNTf2/NaH/THF-DMF/30 min/0°C -e. 1. CO/Pd (OAc) 2/dppf/Et3N/MeOH-DMF/4 days/75°C 2. AcOH/HCI/3 hrs/reflux Example 94 N- (2-Amino-phenyl)- 4- (1, 3-dioxo-1, 3-dihydro-isoindol-2-ylmethyl)- benzamide (compound 149) [0233] 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).

[0234] Following a procedure analogous to that described in Example 92, step 2, but substituting the acid for 143, the title compound 149 was obtained in 17% yield. 1H NMR : (DMSO d6) D 9. 59 (s, 1H), 7. 82-7. 91 (m, 6H), 7. 40 (d, J = 8. 0 Hz, 2H), 7. 11 (d, J = 7. 7 Hz, 1H), 6. 93 (t, J = 7. 7 Hz, 1H), 6. 73 (d, J = 8. 0 Hz, 1H), 6. 55 (t, J = 7. 4 Hz, 1H), 4. 83 (bs, 4H).

Example 95 N- (2-Amino-phenyl)-4- [2- (1, 3-dioxo-1, 3-dihydro-isoindol-2-yl)-ethyl]- benzamide (compound 152) Step 1 : 2- [2- (4-Hydroxy-phenyl)-ethyl]-isoindole-1, 3-dione (compound 150) [0235] Following a procedure analogous to that described in Example 94, step 1, but substituting 4-aminomethylbenzoic acid for tyramine the title compound 150 was obtained in 48% yield. LMRS = 268. 0 (M+1).

Step 2 : 4- [2- (1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) ethyl)-phenyl trifluoromethane-sulfonate (151) [0236] 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). <BR> <BR> <BR> <P>Step 3 : N- (2-Amino-phenyl)-4- [2- (1, 3-dioxo-1, 3-dihydro-isoindol-2-yl)- ethyl]-benzamide (compound 152) [0237] Following a procedure analogous to that described in Example 40, step 2, but substituting 151 for 42, the title compound 152 was obtained in 15% yield. 1H NMR : (DMSO d6) D 9. 57 (s, 1H), 7. 78-7. 87 (m, 6H), 7. 31 (d, J = 8. 0 Hz, 2H), 7. 12 (d, J = 7. 7 Hz, 1H), 6. 93 (t, J = 6. 9 Hz, 1H), 6. 74 (d, J = 8. 0 Hz, 1H), 6. 56 (t, J = 7. 4 Hz, 1H), 4. 83 (bs, 2 H), 3. 85 (t, J = 7. 1 Hz, 2 H), 3. 00 (t, J = 7. 1 Hz, 2 H). 0 0 a, b, d (X=C) I I I I N 2 /NO a, c, d (X= N)/N-. X/\ 1 153 H Example 96 : 154 (X = C) 0 Example 97 : 155 (X = N) a 0 0 e, d (Y=H) HZN /NHZ/OH e, f, g, d (Y = CHs)/N'O/\ 156 0 y O v Example 98 : 157 (Y= H) Example 99 : 158 (Y = CH3) h, d O a. p-aminomethylbenzoic acid/H2O/Et3N/3 hrs/40°C b. HCOOH/reflux/6 hrs ~ Nm NH2 c. NaNO2/HCU0°C/2 hrs, then rt/12 hrs d. HOBT/EDC/1, 2-diamino benzene N e. CICOOMe/KOH/2 hrs, OoC f. RI/K2C03/DMF/rt O v g. NaOH/MeOH/H20 Example 100 : 159 h. Ac20/1 hour/reflux then AcOH/48 hrs/reflux Example 96 N- (2-Amino-phenyl)-4- (4-oxo-4H-quinazolin-3-ylmethyl)-benzamide (compound 154) [0238] 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).

[0239] Following a procedure analogous to that described in Example 92, step 2, but substituting the carboxylic acid for 143, the title compound 154 was obtained was obtained in 43% yield. 1H NMR : (DMSO d6) D 9. 71 (s, 1H), 8. 68 (s, 1H), 8. 23 (d, J=8. 0 Hz, 1H), 8. 01 (d, J = 8. 0 Hz, 1H), 7. 92 (t, J = 8. 0, 2H), 7. 78 (d, J = 8. 0 Hz, 1H), 7. 63 (t, J = 7. 4, 1H), 7. 55 (d, J = 7. 7 Hz, 2H), 7. 22 (d, J = 7. 4 Hz, 1H), 7. 04 (t, J = 7. 1 Hz, 1H), 6. 85 (d, J = 8. 0 Hz, 1H), 6. 67 (t, J = 7. 4 Hz, lE), 5. 35 (s, 2 H).

Example 97 N- (2-Amino-phenyl)-4- (4-oxo-4H-benzo [d] [1, 2, 3] triazin-3-ylmethyl)- benzamide (compound 155) [0240] 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. HC1 (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).

[0241] 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) 0 9. 62 (s, 1H), 8. 25 (t, J = 6. 7 Hz, 2H), 8. 11 (ddd, J = 7. 1 Hz, 1. 4 Hz, 1H), 7. 93-7. 98 (m, 3H), 7. 49 (d, J = 8. 2 Hz, 2H), 7. 13 (d, J = 7. 7 Hz, 1H), 6. 94 (t, J = 8. 0 Hz, 1H), 6. 75 (d, J = 8. 0 Hz, 1H), 6. 57 (t, J = 7. 7 Hz, 1H), 5. 66 (s, 2 H), 4. 87 (bs, 2 H).

Example 98 N- (2-Amino-phenyl)-4- (2, 4-dioxo-1, 4-dihydro-2H-quinazolin-3-ylmethyl)- benzamide (compound 157) Step 1 4-[(2-Amino-benzoylamino)-methyl]-benzoic acid (compound 156) [0242] To a suspension of 4-aminomethylbenzoic acid (5. 09 g, 33. 7 mmol) in H20 (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% HC1/H20) and the mixture was partitioned between H20 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 <BR> <BR> <BR> <BR> (M+1).<BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>Step 2 N-(2-Amino-phenyl)-4-(2, 4-dioxo-1, 4-dihydro-2H-quinazolin-3- ylmethyl)-benzamide (compound 157) [0243] The carboxylic acid 156 (1. 72 g, 6. 36 mmol) was suspended in a solution of NaOH (2. 55 g, 63. 6 mmol) in H20 (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 (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% HC1/H20) and extracted with ethyl acetate (2 X 300 mL). These organic extracts were combined, dried over Na2SO4, filtered and evaporated to dryness. The resulting crude was triturated with warm methanol to afford the carboxylic. acid as a white solid (1. 7 g, 90%). LMRS = 319. 0 (M+Na).

[0244] Following a procedure analogous to that described in Example 92, step 2, but substituting the quinazolinedione carboxylic acid for 143, the title compound 157 was obtained. 1H NMR : (DMSO-d6) 0 11. 56 (brs, 1H), 9. 59 (brs, 1H), 7. 96-7. 88 (m, 3H), 7. 67 (dt, J = 8. 4, 1. 4 Hz, 1H), 7. 30 (d, J = 7. 8 Hz, 2H), 7. 21 (t, J = 7. 5 Hz, 2H), 7. 13 (d, J = 6. 9 Hz, 1H), 6. 92 (dt, J = 6. 9, 1. 2 Hz, 1H), 6. 75 (d, J = 6. 9 Hz, 1H), 6. 57 (t, J = 6. 9 Hz, 1H), 5. 15 (brs, 2H), 4. 86 (brs, 2H).

Example 99 N- (2-Amino-phenyl)-4- (1-methyl-2, 4-dioxo-1, 4-dihydro-2H-quinazolin-3- ylmethyl)-benzamide (compound 158) Step 2 :'4- (l-Methyl-2, 4-dioxo-l, 4-dihydro-2H-quinazolin-3-ylmethyl)- benzoic acid methyl ester [0245] 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 H20. 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).

Step 3 : 4- (1-Methyl-2, 4-dioxo-1, 4-dihydro-2H-quinazolin-3-ylmethyl)- benzoic acid [0246] 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 H20. The aqueous phase was acidified (10% HC1/H20) and extracted with ethyl acetate (2 X 300 mL). These organic extracts were dried over Na2SO4 and concentrated in vacuo to afford product 5 as a white solid (1. 15 g, 96%). LMRS = 311. 0 (M+1).

Step 4 : N- (2-Amino-phenyl)-4- (l-methyl-2, 4-dioxo-1, 4-dihydro-2H- quinazolin-3-ylmethyl)-benzamide (compound 158) [0247] 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) 8 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 N- (2-Amino-phenyl)-4- (2-methyl-4-oxo-4H-quinazolin-3-ylmethyl)- benzamide (compound 159) [0248] 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 48h and evaporated to form another solid material, which was recrystallized from a mixture AcOEt/CHC13 to produce the intermediate carboxylic acid (420 mg, 43% yield). LMRS = 385. 0 (M+1).

[0249] 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) 8 (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). s II MeO NI NH2 (Im) zCS ! DCM/rT NNH C°zMe N \CO Me Me0 H S 2 then NH3 Me0 NBS/1, 4-dioxan/ 160 161 Hz0/-10°C to 80°C Me0 162 1. LiOH/THo/H20 2, 1, 2-phenylenediamine MEOH/600C then HCI/ether 01 BOP/DMF TEA/rT then HCI/ether N NH2 163 mye0 163 Example 101 Example 101<BR> <BR> <BR> <BR> <BR> N- (2-aminophenyl)-2- (4-Methoxy-benzylamino)-thiazol-5-yl-amide (compound 163) Step 1 : 4-Methoxybenzyl-thiourea (compound 161) [0250] To a solution of thiocarbonyl diimidazole (1. 23g, 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 x 50 mL), dried (MgS04), 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) 8 (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).

Step 2 : 2- (4-Methoxybenzylamino) thiazole-5-carboxylic acid methyl ester (compound 162) [0251] 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 1h, transferred to a flask containing the thiourea 161 (700. 2 mg, 3. 6 mmol) and the mixture was stirred at 80°C for 2h. After cooling down to room temperature, concentrated NH40H (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) 8 (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). <BR> <BR> <BR> <BR> <P>Step 3 : N- (2-aminophenyl)-2- (4-Methoxy-benzylamino)-thiazol-5-yl-amide (compound 163) [0252] 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), 6 (ppm) : 7. 86 (s, 1H), 7. 29 (d, J = 8. 8 Hz, 2H), 7. 11 (dd, J = 8. 0 Hz, 1. 4 Hz, IH), 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 [0253] 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<BR> Characterization of Compounds Prepared in Exampels 102-121 Ex. Cpd W Y Z Name Characterization Schm 102 164 MeO NH CH, $H N-(2-Amino-phenyl)-4-1H NMR : (Acetone-d6) 6 (ppm) : 9. 09 (bs, 1H), 7. 99 (d, J = 11 [ (3, 4, 5-trimethoxy-8. 2 Hz, 2H), 7. 54 (d, J = 8. 0 Hz, 2H), 7. 29 (d, J = 7. 7 Hz, MeOX phenylamino)-methyl]-1H), 7. 00 (t, J = 6. 6 Hz, 1H), 6. 86 (dd, J = 8. 0 Hz, 1. 1 Hz, OMe benzamide 1H), 6. 67 (t, J= 8. 0 Hz, 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). 103 165 X N CH N-(2-Amino-phenyl)-6-1H NMR (20% CD30D in CDC13) 8 (ppm) : 9. 14 (d, 15 (3-hydoxymethyl-J = 1. 8 Hz, 1H), 8. 33 (dd, J = 8. 4 Hz, 1. 8 phenyl)-nicotinamide Hz, 1H), 7. 93 (s, 1H), 7. 82 (m, 2H), 7. 50- OH. 7 40 (m, 2H), 7. 22-6-45, (m, 4H), 4. 69 (s, 2H). 104 166/CH CH N-(2-Amino-phenyl)-4-1H NNR (CD30D) 6 (ppm) : 7. 98 (d, J = 8. 4 Hz, 15 (3-methoxy-phenyl)-2H), 7. 65 (d, J = 8. 4 Hz, 2H), 7. 31-7. 04 (m, OMe benzamide 5H), 6. 92-6. 80 (m, 3H), 3. 84 (s, 3H). 105 167 NH CH N N-(2-amino-phenyl)-6-1H NMR (DMSO-d6) 8 (ppm) : 9. 33 (s, 1H), 8. 61 (d, J = 6 Meo (4-methoxy-2. 5 Hz, 1H), 7. 89 (dd, J = 8. 8 Hz, 2. 2 Hz, 1H), 7. 57 (t, J = benzylamino)-5. 8 Hz, 1H), 7. 24 (d, J = 8. 52 Hz, 2 H), 7. 11 (d, J = 7. 69 Hz, nicotinamide 1H), 6. 90 (m, 3H), 6. 73 (d, J = 8. 0 Hz, 1H), 6. 50-6. 58 (m, 2H), 4. 83 (s, 2H), 4. 45 (d, J o 58 Hz, 2H), 3. 70 (s, 3H). 106 168 NH CH N N (2-amino-phenyl)-6-1H NMR (DMSO-d6) 8 (ppm) : 9. 42 (s, 1H), 8. 72 (d, J = 6 [2- (4-methoxy-phenyl)- 2. 5 Hz, 1H), 7. 97 (dd, J = 8. 8 Hz, 2. 5 Hz, 1H), 7. 23 (m, 4H), Me0 ethylamino]-6. 81-7. 03 (m, 4H), 6. 64 (m, 1H), 6. 56 (d, J = 9. 1 Hz, 1H), nicotinamide 4. 92 (s, 2H), 3. 78 (s, 3H), 3. 55 (m, 2H), 2. 85 (t, J = 7. 3 Hz, 2H). Ex. Cgd W Y Z Name Characterization Schm 107 169 CH CH N (2-Amino-phenyl)-4-1H NMR : (DMSO-d6) 8 (ppm) : 9. 63 (bs, 1H), 7. 95 (d, J = 11 MeOyNq, N [(4, 6-dimethoxy-7. 9 Hz, 2H), 7. 85-7. 82 (m, 1H), 7. 48 (d, J = 7. 9 Hz, 2H), W pyrimidin-2-ylamino)-7. 20 (d, J = 7. 1 Hz, 1H), 7. 03 (dt, J = 7. 6 Hz, 7. 4 Hz, 1H), OMe methyl]-benzamide 6. 81 (d, J = 7. 9 Hz, 1H), 6. 63 (dt, J = 7. 9 Hz, 7. 7 Hz, 1H), 4. 94 (bs, 2H), 4. 54 (d, J = 6. 0 Hz, 2H), 3. 79 (bs, 6H). 108 170 CH CH N-(2-Amino-phenyl)-4-1H NMR : (DMSO-d6) fi (ppm) : 9. 62 (bs, IH), 8. 21 (d, J= 11 (quinolin-2-8. 8 Hz, 1H), 8. 00-7. 89 (m, 4H), 7. 79 (dd, J = 6. 8 Hz, 1. 3 Hz, ylsulfanylmethyl)-1H), 7. 68 (d, J = 6. 3 Hz, 2H), 7. 56 (t, J = 6. 8 Hz, 1H), 7. 44 benzamide (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). 109 171 SI- N CH N-(2-Amino-phenyl)-6-1H NMR : (DMSO-d6) 8 (ppm) : 9. 06 (bs, 1H), 8. 17 (dt, J = 12 Me0 (4-methoxy-10. 9 Hz, 9. 0 Hz, 1H), 7. 46 (d, J = 8. 5 Hz, 1H), 7. 39 (d, J = benzylsulfanyl)-8. 2 Hz, 2H), 7. 21-7. 13 (m, 2H), 7. 01 (dt, J = 7. 6 Hz, 7. 4 Hz, nicotinamide. 1H), 6. 91 (d, J = 8. 5 Hz, 2H), 6. 80 (d, J = 7. 9 Hz, 1H), 6. 62 . (t, J = 7. 4 Hz, 1H), 5. 01 (bs, 2H), 4. 47 (s, 2H), 3. 76 (s, 3H). 110 172 w S CH CH N-(2-Amino-phenyl)-4-1H NMR : (DMSO-d6) 8 (ppm) : 8. 01 (d, J = 8. 0 Hz, 1H), I I (benzothiazol-2-7. 93 (d, J = 8. 2 Hz, 2H), 7. 90 (dd, J = 4. 4 Hz, 0. 6 Hz, 1H), ylsulfanyhnethyl]-7. 63 (d, J = 8. 2 Hz, 2H), 7. 48 (dt, J = 8. 0 Hz, 0. 8 Hz, 1H), benzamide 7. 37 (td, J = 7. 1 Hz, 1. 1 Hz, 1H), 7. 14 (d, J = 7. 1 Hz, 1H), 6. 96 (t, J = 6. 3 Hz, 1H), 6. 76 (d, J = 7. 7 Hz, 1H), 6. 58 (t, J = 6. 6 Hz, 1H), 4. 88 (s, 2H), 4. 73 (s, 2H). 112 174 N CH N N (2-amino-phenyl)-6-1H NMR (DMSO-d6) 8 (ppm) : 9. 34 (s, 1H), 8. 64 (d, J = 6 [2- (4-fluoro-phenyl)- 2. 5 Hz, IH), 7. 89 (dd, J = 9 Hz, 2 Hz, 1H), 7. 16-7. 22 (m, ethylamino]-3H), 7. 06-7. 20 (m, 3H), 6. 90-6. 96 (m, 1H), 6. 72-6. 78 (m, nicotinamide 1H), 6. 46-6. 60 (m, 2H), 4. 92 (s, 2H), 3. 50 (m, 2H), 2. 92 (m, 2H). Ex. Cpd W Y Z Name Characterization Schm 113 175 CH N N (2-amino-phenyl)-6-1H NMR (DMSO-d6) 8 (ppm) : 9. 34 (s, 1H), 8. 61 (d, J = 6 (4-fluoro-benzylamino)-2. 2 Hz, 1H), 7. 91 (dd, J = 8. 8 Hz, 2. 2 Hz, 1H), 7. 66 (t, J = 6 nicotinamide Hz, 1H), 7. 32-7. 37 (m, 2H), 7 087. 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. 0Hz) 114 176 MeO N CH N N-(2-amino-phenyl)-6-1H NMR (DMSO-d6) 8 (ppm) : 9. 34 (s, 1H), 8. 63 (d, J = 6 nneo I H (3, 4, 5-trimethoxy- 2. 2 Hz, 1H), 7. 92 (dd, J = 8. 8 Hz, 2. 2 Hz, 1H), 7. 57 (t, J = 6 OMe benzylamino)-Hz, 1H), 7. 10 (m, 1H), 6. 93 (m, 1H), 6. 74 (m, 1H), 6. 66 (s, nicotinamide 2H), 6. 56 (m, 2H), 4. 84 (s, 2H), 4. 45 (d, J = 6 Hz, 2H), 3. 73 (s, 6H), 3. 31 (s, 3H). 115 177 N-N CH CH N- (2-Amino-phenyl)-4-1H NMR : (Acetone-d6) 8 (ppm) : 9. 08 (bs, 1H), 8. 02 (dd, J 14 (5-phenyl-= 7. 1 Hz, 1. 9 Hz, 4H), 7. 69 (d, J = 8. 5 Hz, 2H), 7. 62-7. 57 [1, 3, 4] oxadiazol-2- (m, 3H), 7. 28 (d, J = 7. 7 Hz, 1H), 7. 03-6. 97 (m, 1H), 6. 86 ylsulfanylmethyl]- (d, J = 6. 6 Hz, 1H), 6. 67 (t, J = 7. 7 Hz, 1H), 4. 70 (s, 2H), benzamide 4. 63 (bs, 2H). 116 178 N'-'-"NH N CH N- (2-aminophenyl)-6- (2-'H-NMR (CD30D-d4), 5 (ppm) : 8. 67 (d, J = 2. 2 Hz, 1H), 11 NH phenylamino-7. 97 (dd, J= 8. 9 Hz, 2. 5 Hz, 1H), 7. 58 (m, 1H), 7. 51 (m, ethylamino)-1H), 7. 15 (dd, J = 7. 7 Hz, 1. 1 Hz, 1H), 7. 08 (m, 2H), 6. 89 nicotinamide (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). 117 179 9 CH CH N-(2-Amino-phenyl)-4-1H NMR : (DMSO-d6) 8 (ppm) : 9. 62 (s, 1H), 8. 00 (dd, J= 11. lí N (2, 4-dioxo-4H-8. 2 Hz, 1. 9 Hz, 1H), 7. 80-7. 92 (m, 3H), 7. 42-7. 50 (m, 4H), benzo [e] [1, 3] oxazin-3- 7. 13 (d, J = 7. 1 Hz, 1H), 6. 95 (ddd, J = 8. 0 Hz, 1. 6 Hz, 1H), ylmethyl)-benzamide 6. 75 (dd, J = 8. 0 Hz, 1. 4 Hz, 1H), 6. 57 (t, J = 7. 7 Hz, 1H), 5. 13 (s, 2H), 4. 87 (bs, 2H). Ex. Cpd W Y Z Name Characterization Schm 118 180 CH CH N-(2-Amino-phenyl)-4-'1H NMR : (DMSO-d6) 6 (ppln) : 9. 59 (s, 1H), 7. 88 (d, J = 11 Me eN (4-ethyl-4-methyl-2, 6-8. 2 Hz, 2H), 7. 31 (d, J = 8. 2 Hz, 2H), 7. 13 (d, J = 7. 4 Hz, Mye v dioxo-piperidin-1-1H), 6. 95 (t, J = 8. 0 Hz, 1H), 6. 75 (d, J = 8. 0 Hz, 1H), 6. 57 Me ylmethyl)-benzamide (t, J = 7. 4 Hz, 1H), 4. 87 (s, 2H), 4. 86 (bs, 2H), 2. 61 (s, 2H), 2. 55 (s, 2H), 1. 31 (q, J = 7. 7 Hz, 2H), 0. 91 (s, 3H), 0. 80 (t, J =7. 4Hz, 3H). 119 181 CH CH CH N (2-Amino-phenyl)-4-1H NMR : (CDCI3) 8 (ppm) : 8. 23 (dd, J = 7. 8 Hz, 1. 5 Hz, 19 eN (l-ethyl-2, 4-dioxo-1, 4-1H), 8. 01 (bs, 1H), 7. 80 (d, J = 8. 0 Hz, 2H), 7. 71-7. 65 (m, vNAO dihydro-2H-quinazolin-1H), 7. 55 (d, J = 8. 2 Hz, 2H), 7. 27-7. 20 (m, 3H), 7. 05 (dt, J Et 3-ylmethyl)-benzamide = 7. 7, 1. 5 Hz, 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. 1 Hz, 3H). 120 182 \NqzSuo CH CH N-(2-Amino-phenyl)-4-1H NMR : (DMSO-d6) 8 (ppm) : 9. 66 (bs, 1H), 7. 96 (d, J = 11 (4, 6-dimethyl-pyrimidin- 7. 9 Hz, 2H), 7. 61 (d, J = 7. 9 Hz,. 2H), 7. 21 (d, J = 7. 9 Hz, 2-ylsulfanyhnethyl)-1H), 7. 04-6. 99 (m, 2H), 6. 82 (d, J = 7. 9 Hz, 1H), 6. 64 (t, J = benzamide 7. 4 Hz, 1H), 4. 49 (s, 2H), 2. 42 (s, 6H). 121 183 fi CH CH N-(2-Amino-phenyl)-4-1H NMR : (DMSO-d6) 8 (ppm) : 9. 66 (bs, 1W, 9. 07 (d, J = 11 FXNtS (4-trifluoromethyl-5. 2 Hz, 1H), 7. 97 (d, J = 7. 4 Hz, 2H), 7. 78 (d, J = 4. 7 Hz, pyrimidin-2-1H), 7. 63 (d, J = 7. 4 Hz, 2H), 7. 19 (dj J = 7. 7 Hz, 1H), 7. 01 ylsulfanylmethyl) benza (dt, J = 7. 7 Hz, 7. 4 Hz, 1H), 6. 81 (d, J = 8. 2 Hz, 1H), 6. 64 mide (dt, J = 7. 4 Hz, 7. 1 Hz, 1H), 4. 94 (bs, 2H), 4. 57 (s, 2H).

Table 4b Ex. Cpd Z Name Characterization Schm N-(2- Aminophenyl)-4-1 0 N H NMR (20% CD30D in CDC13) 8 (ppm) : 8. 46 (m, 123 187 H CH CH" 1H), 7. 95 (d, J = 8. 4 Hz, 2H), 7. 64-6. 70 (m, 14 H), 3. 80 21 N 2ylmetllyl- (br s, 4H). aminomethyl) phen yl)]-benzamide 1H NMR (CD30D) 8 (ppm) : 9. 80 (bs, 2H), 8. 16 Biphenyl-4, 4'- (d, J=7. 9 Hz, 4H), 7. 96 (d, J= 7. 9 Hz, NH2 H dicarboxylic acid 4H), 7. 23 (d, J=7. 4 Hz, 2H), 7. 03 (dd, C o bis-[(2-amino-J=6. 9, 7. 4 Hz, 2H), 6. 84 (d, J=8 2 Hz, 0 phenyl)-amide] 2H), 6. 66 (dd, J=6. 9, 7. 7 Hz, 2H), 5. 06 (bs, 4H). X (2-Amin-'H NMR (DMSO-d6) 8 (ppm) : 10. 15 (1H, brs), 8. 17 (2H, H phenyl)-4- [4- nneo rv \ f (3, 4 ; 5-trimethoxy- d° J=8. 0), 7. 90 (2H, d, J=8. 2), 7. 87 (1H, brs), 7. 72 (1H, d, 125 189 CH CH J=6. 6), 7. 54 (2H, m), 7. 40 (1H, d, J=8. 5), 7. 25 (1H, m), 21 Me phenylamino)-7. 16 (lH, d, J=7. 4), 7. 07 (IH, m), 6. 08 (2H, s), 4. 42 (2H, oMe methyl}-phenyl]-s) 3. 73 (6H, s), 3. 58 (3H, d, J=0. 8) benzamid N (2-Amino- phenyl)-4- [4-1 (4-'H NMR (DMSO-d6) 8 (ppm) : 10. 03 (1H, brs), 8. 17 126 methoxy- (2H d J=7. 7), 7. 88 (3H, m), 7. 76 (1H, d, J=7. 1), 7. 52 21 126 190 w CH CH'''21 JC phenylamino)- (2H, m), 7. 35 (1H, d, J=8. 0), 7. 17 (1H, m), 7. 08-6. 93 MeO methyl}-phenyl]- (6H, m), 4. 50 (3H, s), 3. 75 (2H, s) benzamide Ex. Cpd W Y Z Name Characterization Schm N- (2-Amino- 128 193 H2 CH CH phenyl)-4- (3- LRMS calc : 276. 03, found : 277. 2 (MH) + 22 methyl-but-3-en-l- ynyl)-benzamide N (2-Amino- phenyl)-4- (l- 129 194 CkX CH CH hydroxy-LRMS calc : 334. 4, found : 335 (MH) + 22 OH cyclohexylethynyl) - benzamide N (2-Amino- HC phenyl)-4- (3- 130 195 CH CH hydroxy-3-methyl-LRMS calc : 294. 35, found : 295. 1 (MH) 22 H3C OH but-1-ynyl)- benzamide N- (2-Amino- 131 196 CH CH phenyl)-4-LRMS calc-312. 37, found : 313. 2 (MH) + 22 phenylethynyl- benzamide N-(2-Amino-1H NMR : (Acetone-d6) 8 (ppm) : 9. 67 (s, 1H), 8. 85 (s, phenyl)-4- [ (5- 1H), 8. 01 (d, J = 8. 2 Hz, 2H), 7. 55 (d, J = 8. 2 Hz, 2H), Ar0 rE-chloro-7. 45 (d, J = 8. 8 Hz, 1H), 7. 36 (d, J = 2. 3 Hz, 1H), 7. 22 (d, 35 NH CH CH benzooxazol-2-J = 7. 6 Hz, 1H), 7. 07 (dd, J = 8. 8, 2. 3 Hz, 1H), 7. 02 (d, J Cl. ylamino)-methyl]-= 7. 0 Hz, 1H), 6. 84 (d, J = 7. 6 Hz, 1H), 6. 65 (t, 7. 0 Hz, benzamide 1H), 4. 94 (s, 2H), 4. 67 (d, J = 5. 3 Hz, 2H). N (2-Amino-1H NMR : (DMSO-d6) 8 (ppm) : 9. 67 (bs, 1H), 8. 36 (t, J = phenyl)-4- { [4- (4- 58 Hz, lI, 8. 00 (d, J = 8. 2 Hz, 2H), 7. 89 (d, J = 8. 2 Hz, 181 321 2H), 7. 57 (d, J = 8. 2 Hz, 2H), 7. 48 (d, J = 8 2 Hz, 2H), 35 NH CH CH chloro-phenyl)- (1 7. p2 (t J = 8. 5 Hz 1H) 6. 83 (d J = 7. 7 Hz 35 CI N thiazol-2-ylamino]-720 s,,,,,, methyl}-benzamide 5. 8 Hz, ZH). Ex. Cpd W Y Z Name Characterization Schm N (2-Amino-1H NMR : (DMSO-d6) 8 (ppm) : 6. 97 (s, 1H), 8. 78 (bs, phenyl)-4- [ (5- iH), g. 01 (d, J = 8. 8 Hz, 2H), 8. 00 (s, 1H), 7. 55 (d, J = 8. 2 S 182 322 J tNH CH CH..'... Hz, 2H), 7. 43-7. 35 (m, 2H), 7. 22 (d, J = 7 : 6 Hz, 1H), 7. 03 33, 34 benzothiazol-2-t J = 7. 0 Hz 1 6. 83 d J = 7. 6 Hz 1 6. 65 t J = ylamino)-methyl]-7.'6 Hz, *lH), 4. 94 (s, 2H), 7. 74 (d, J=5. 9 Hz, 2H). ylammo)-methyl]-7. 6 Hz, 1H), 4. 94 (s, 2H), 7. 74 (d, J=5. 9 Hz, 2H). benzamide N (2-Amino- phenyl)-4-{5- ""eo \ [ (3, 4, 5-trimethoxy- 183 323 MeO 10 CH CH phenylamino)-LRMS calc : 489. 58, found : 490 (MH) + 21 HN methyl]-thiophen- 2-ylmethyl}- benzamide N (2-Amino-1H NMR : (Acetone-d6) 8 (ppm) : 8. 65 (d, J = 1. 4 Hz, N phenyl)-4- {6- _ __ i S [yrih-amino-2 7 : 81 7a77 (m4lH),. 7. 63 (m 7, 97 (d'J 8. 2 Hz 11 3H) 7. 33-7. 26 (m, 2H),, 184 325 NS CH CH ylm y)] benzothiazol-77 09 (d, J=2. 5 Hz, 1H), 7. 02-6. 97 (m, 1H), 6. 91 (dd, J N'J H benzothiazol-2-8. 8, 2. 5 Hz, 1H), 6. 86 (dd, J = 8. 0, 1. 4 Hz, 1H), 6. 69-6. 64 benzamide (m, 1H), 4. 64 (s, 2H), 4. 47 (s, 2H). benzamide N (2-Amino-1H NMR : (DMSO-d6) 8 (ppm) : 9. 59 (s, 1H), 8. 52-8. 51 pheny1) 4-{6- 1H), 7. 89 (d, J= 8. 24 Hz, 2H), 7. 71 (td, J = 7. 7, 1. 9 Hz, phenyl)-4-f 6-1H), 7. 59-7. 53 (m, 3H), 7. 34 (d, J = 8. 0 Hz, 1H), 7. 25- v w S - [ (pyridin-2- 7, 21 (m 1H) 7. 12 (d J = 6. 9 Hz 1H), 6. 98-6. 96 (m,), 185 326 NS CH CH ylmethyl)-amino]-''-'''1H 11, 34 H benzothiazol-2-6. 93 (d, J = 7. 4 Hz, 1H), 6. 81 (dd, J = 9. 1, 2. 5 Hz, 1H), ylsulfanyhnethyl}-6'76-6'73 (m, 1H), 6. 67 (t, J = 5. 8 Hz, 1H), 6. 56 (t, J = 7. 4 ylsulfanylmethyl}-.-r., o4 i'rT\ o TT\ oo T \TT benzamide Hz, 1H), 4. 87 (s, 1H), 4. 58 (s, 2H), 4. 38 (d, J = 6. 3 Hz, 2H). Ex. Cpd W Y Z Name Characterization Schm N-(2-Amino-1H NMR : (DMSO-d6) 8 (ppm) : 12. 23 (bs, 1H), 9. 59 (s, N phenyl)-4- (lH- lH), 7. 86 (d, J = 8. 2 Hz, 2H), 7. 34 (d, J = 8. 5 Hz, 2H), 186 327 C S CH CH imidazol-2-7. 14-7. 12 (m, 2H), 6. 94-6. 92 (m, 2H), 6. 76 (d, J = 6. 6 14 N ylsulfanylmethyl)-Hz, 1H), 6. 57 (t, J = 7. 4 Hz, 1H), 4. 87 (s, 2H), 4. 29 (s, Y Y Y)-> > > > > > > _ benzamide 2H)- N-(2-Amino-1H NMR : (CD30D) 6 (ppm) : 8. 03 (d, J = 8. 4 Hz, 2H), phenyl)-4-7. 58 (d, J = 7. 9 Hz, 2H), 7. 26 (d, J = 7. 0 Hz, 1H), 7. 16 (t, 187 328 CH CH morpholin-4-J = 6. 6 Hz, 1H), 6. 98 (d, J = 7. 0 Hz, 1H), 6. 85 (t, J = 7. 5 37 ylmethyl-Hz, 1H), 3. 78 (t, J = 4. 4 Hz, 4H), 3. 68 (s, 2H), 2. 57-2. 54 benzamide (m, 4H). Met 3', 4', 5'Trimethoxy-1H NMR : (CD30D) 6 (ppm) : 8. 14 (d, J = 7. 9 Hz, 2H), biphenyl-4- () p) ('' 188 329 Meo I CH CH carboxylic acid (2-7'85 (d, J = 8. 4 Hz, 2H), 7. 29 (d, J = 7. 9 Hz, 1H), 37 a ino- CH nyl)-J = 7. 0 Hz, 1H), 7. 04 (s, 2H), 7. 00 (d, J = 8. 4 Hz, 1H), OMe amide 6. 87 (t, J = 7. 5Hz, 1H), 4. 95 (s, 6H), 4. 01 (s, 3H). amide 1H NMR : (DMSO-d6) 8 (ppm) : 9. 65 (s, 1H), 7. 96 (d, J = NH2 4-[(2-Amino-9-7. 7 Hz, 2H), 7. 95 (bs, 2H) 7. 78 (s, 1H), 7. 52 (d, J = 7. 9 N-- butyl-9H-purin-6-Hz, 2H), 7. 22 (d, J = 7. 7 Hz, 1H), 7. 02 (dd, J = 7. 3, 8. 0 189 330 H3C/\N/\N CH CH ylamino)-methyl]-Hz, 1H), 6. 8 (d, J = 8. 0 Hz, 1H), 6. 65 (dd, J = 7. 3, 7. 7 Hz, 39 N e X N-(2-amino-1H), 5. 91 (s, 2H), 4. 94 (bs, 2H), 4. 77 (bs, 2H), 4. 01 (t, J = phenyl)-benzamide 7. 1 Hz, 1H), 1. 78 (m, 2H), 1. 3 (m, 2H), 0. 95 (t, J =7. 4, Hz, 1H) NH2 N-(2-Amino-1H NMR (DMSO-d6) 8 (ppm) : 10. 16 (s, 1H), 9. 60 (br, 190 331 HN \\r CH CH paminol9H [purin-6- 1'8. 24 (s, 1H), 8. 08 (d, J = 8. 0 Hz, 2H), 7. 62 (m, 1H), 39 L ylamino)-methyl]-760 (d, J = 8. 0 Hz, 2H), 7. 40 (m, 1H), 7. 20 (m, 2H), 7. 08 ''benzamide (m lI, 4. 90 (m, 2H), 4. 6 (br, 4H) benzamide"''"' Ex. Cpd Z Name Characterization Schm | cl N-(2-Amino-1H NMR (DMSO-d6) 8 (ppm) : 9. 67 (m, 1H), 8. 80 (m, phenyl)-4- [ (2- 1H), 8. 24 (s, 1H), 7. 99 (d, J = 7. 8 Hz, 2H), 7. 52 (d, J = 7. 8 191 332 HNt/\N CH CH chloro-9H-purm-6-Hz, 2H), 7. 21 (d, J = 7. 8-Hz, 1H), 7, 02 (dd, J = 6. 3, 7. 8 39 ylamino)-methyl]-Hz, 1H), 6. 82 (d, J = 8. 1 Hz, 1H), 6. 70 (d6, J = 6. 3, 8. 1 HN benzamide Hz, 1H), 4. 94 (br, 2H),. 4. 77 (br, 2H) N (2-Amino-1H NMR (DMSO-d6) 5 (ppm) : 9. 60 (s, 1H), 8. 72 (br, cl-(mmo-1H), 8. 21 (s, 1H), 7. 92 (d, J = 8. 0 Hz, 2H), 7. 45 (d, J = 8. 0 192 333"3cN N CH CH butyl-2-chloro-9H Hz, 2H), 7. 15 (d, J8 0 Hz, 1H), 6 96 (dd, J = 6. 7, 8. 0 39 purin-6-ylamino)-Hz, 1H), 6. 77 (d, J = 8. 0 Hz, lli), 6. 58 (dd, J = 6. 7, 8. 0 methyl]-benzamide W 2H), 4. 88 (s, lI, 4 : 71 (m, 2H), 4. 11 (m, 2H), 1. 76 2H), 1. 25 (m, 2H), 0. 89 (t, J=7. 1 Hz, 3H) N (2-Amino-1H NMR : (DMSO-d6) 8 (ppm) : 12. 39 (bs, 1H), 9. 32 (s, H phenyl)-4-[(lH-1H), 7. 81 (d, J=8. 2 Hz, 2H), 7. 56 (bs, 1H), 7. 21-7. 17 (m, 193 334 N NH CH CH benzoimidazol-2-3H), 6. 99-6. 97 (m, 2H), 6. 81 (d, J=8. 2 Hz, 1H), 6. 77 (d, 11 -N ylmethyl)-amino]-J=8. 8 Hz, 2H), 6. 63 (t, J=7. 0 Hz, 1H), 4. 85 (s, 2H), 4. 62 benzamide (d, J=5. 3 Hz, 2H). benzamide (d, J=5. 3 HZ, 2H). o phenyl)-4- (1-ethyl- 1 g. 01 (bs, 1H), 7. 80 (d, J = 8. 0 Hz, 2H), 7. 71-7. 65 (m, 2 4-dioxo-1, 4-_ 194 335 T CH CH dm2 1H), 7. 55 (d, J= 8. 2 Hz, 2H), 7. 27-7. 20 (m, 3H), 7. 05 (td, qui a olin-3-J = 7. 7, 1. 5 Hz, 1H), 6. 81-6. 77 (m, 2H), 5. 29 (bs, 2H), Et yeyl)-4. 18 (q, J = 7. 3 Hz, 2H), 3. 86 (bs, 2H), 1. 33 (t, J = 7. 1 Hz, benzamide 3H). MS : (calc.) 414. 2 ; (obt.) 415. 3 (mu) benzamide. N-(2-Amino 1H NMR : (DMSO) 8 (ppm) : 9. 69 (bs, 1H, Nase, 8. 71 (s, N- (2-Amino- o phenyl)-4- (6- 1H), 8. 16 (d, J = 2 5 Hz, 1H), 8. 01 (d, J = 8. 2 Hz, 2H), Cil chloro-2-methyl-4-795 (dd, J = 8. 8, 2. 5 Hz, 1H), 7. 81 (d, J = 8. 8 Hz, 1H), UL. oxo-4Hqumazolm-j bede (td, J=7. 6, 1. 4Hz, lH), 5. 34 (s, 2H), 4. 94 (bs, 2H). MS : oxo-4H-quinazolin-J = 7. 6, 1. 5 Hz, 1H), 6. 82 (dd, J = 8. 0, 1. 4 Hz, IH), 6. 64. nne 3-ylxnethyl)- (td, J = 7. 6, 1. 4 Hz, 1H), 5. 34 (s, 2H), 4. 94 (bs, 2H). MS : benzamide (calc.) 404. 1 ; (obt.) 405. 0 (MH) + Ex. Cpd W Y Z Name Characterization Schm 1H NMR : (DMSO) 8 (ppm) : 9. 64 (bs, 1H), 8. 17 (dd, J = N-(2-Amino-8. 0, 1. 6 Hz, 1H), 7. 95 (d, J = 8. 2 Hz, 2H), 7. 95 (dd, J = o phenyl)-4-(2-8. 8, 2. 5 Hz, 1H), 7. 84 (ddd, J = 7. 6, 7. 0, 1. 5 Hz, 1H), 7. 64 methyl-4-oxo-4H- (d'J = 7. 7 Hz, 1H), 7. 53 (ddd, J = 7. 6, 7. 6, 1. 1 Hz, IH), 196 337 CH CH quinazolin-3-7. 33 (d, J = 8. 2 Hz, 2H), 7. 14 (dd, J = 7. 7, 1. 1 Hz, 1H), 19 q 6. 96 (ddd, J = 7. 6, 7. 6, 1. 5 Hz, 1H), 6. 77 (dd, J = 8. 0, 1. 4 NMe ylmethyl) _ benzamide 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). MS : (calc.) 384. 2 ; (obt.) 385. 0 . (MH) + N-(2-Amino-1H NMR : (DMSO) 6 (ppm) : 9. 62 (bs, 1H), 8. 50 (s, 1H), o phenyl)-4- (6, 7- 8. 41 (d, J = 8. 2 Hz, 2H), 7. 47 (s, 1H), 7. 46 (d, J = 7. 7 Hz, 197 338 MeO CH CH di-inethoxy-4-oxo-2H), 7 ; 17 (s, 1H), 7. 15 (d, J= 8. 5 Hz, 1H), 6. 96 (ddd, J = 19 4H-quinazolin-3-7. 7, 7. 7, 1. 1 Hz, 1H), 6_76 (d, J = 6. 9 Hz, 1H), 6. 58 (dd, J MeO/N'ylmethyl)-= 6. 9, 6. 9 Hz, 1H), 5. 26 (s, 2H), 4. 88 (bs, 2H), 3. 91 (s, benzamide 3H), 3. 87 (s, 3H). MS : (calc.) 430. 2 ; (obt.) 431. 1 (MH) + N-(2-Amino-1H NMR : (DMSO) 6 (ppm) : 9. 66 (bs, 1H), 8. 69 (s, 1H), O phenyl)-4-(6, 7-8. 07 (dd, J = 8. 8, 10. 4 Hz, 1H), 7. 96 (d, J = 8. 2 Hz, 2H), F H 1n A 7. 82 (dd, J = 14. 3, 11. 3 Hz, 1H), 7. 48 (d, J = 8. 2 Hz, 2H), CH CH quinazolin-3-7. 15 (d, J = 6. 9 Hz, 1H), 6. 96 (ddd, J = 7. 6, 7. 6, 1. 5 Hz, 19 F NJ yhnethyl)-1H), 6. 76 (dd, J = 8. 1, 1. 2 Hz, 1), 6. 58 (ddd, J = 7. 5, 7. 5, benzamide 1. 2 Hz, 1H), 5. 28 (s, 2H), 4. 89 (bs, 2H). MS : (calc.) 406. 1 ; (obt.) 407. 0 (MH) + N-(2-Amino-1H NMR : (DMSO) 8 (ppm) : 9. 61 (bs, 1H), 8. 09 (dd, J = 0 4 ' - - = 2H), 7. 81 (ddd, J = 0 phenyl)-4- [l- (2- 7. 8, 1. 5 Hz, IH), 7. 91 (d, J =. 8. 2 Hz, 2H), 7. 81 (ddd, J = /N^ dimethylamino-78, 7. 8, 1. 6 Hz, 1H), 7. 52 (d, J = 8. 2 Hz, 1H), 7. 42 (d, J = ethyl)-2, 4-dioxo- 8. 2 Hz, 2H), 7. 32 (dd, J = 7. 6, 7. 6 Hz, 1H), 7. 14 (d, J = 199 340 CH CH 6. 9 Hz, 1H), 6. 96 (ddd, J = 7. 6, 7. 6, 1. 5 Hz, 1H), 6. 77 (dd, 19 N o 1, 4-dihydro-2H- N. CH3 quinazolin-3-J = 7. 8, 1-2 Hz, 1H), 6. 59 (ddd, J = 7. 5, 7. 5, 1. 2 Hz ; 1H), CH3 ylmethyl]-5. 22 (s, 2H), 4. 88 (bs, 2H), 4. 24 (t, J = 7. 1 Hz, 2H), 2. 5 benzamide (m, 2H) 2. 22 (s, 6H). MS : (calc.) 457. 2 ; (obt.) 458. 1 (MH) + Ex. Cpd W Y Z Name Characterization Schm N- (2-Amino-'H NMR : (DMSO) 6 (ppm) : 9. 61 (bs, 1H), 8. 09 (dd, J = 0 phenyl)-4- [I-8-0, 1. 6 Hz, 1H), 7. 92 (d, J = 8. 2 Hz, 2H), 7. 81 (ddd, J = t A (2-morpholin-7. 8, 7. 8, 1. 6 Hz, 1H), 7. 54 (d, J = 8. 5 Hz, 1H), 7. 43 (d, J = 4-yl-ethyl)-8. 2 Hz, 2H), 7. 32 (dd, J = 7. 4, 7. 4 Hz, 1H), 7. 14 (d, J= (J = 7. 6 7. 6, 1. 5 Hz ; 1H), 6. 77 (dd, 19 200 341 N"o CH CH 2, 4-dioxo-i, 4-7. 4 Hz, 1H), 6. 96 (ddd, J = 7. 6, 7. 6, 1. 5 Hz, 1H), 6. 77 (dd, 19 dihydro-2H-J = 8. 0, 1. 4 Hz, 1H), 6. 59 (ddd, J = 7. 6, 7. 6, 1. 4 Hz, 1H), zu quinazolin-3-5. 22 (s, 2H), 4. 87 (bs, 2H), 4. 28 (t, J = 6. 7 Hz, 2H), 3. 50 ylmethyl- (t, J = 4. 5 Hz, 4H), 2. 58 (t, J = 6. 7 Hz, 2H), 2. 47-2. 44 (m, benzamide 4H). MS : (cale.) 499. 2 ; (obt.) 500. 3 (NW. N- (2-Amino- 1H NMR : (DMSO) 5 (ppm) : 9. 65 (bs, 1H), 8. 25 (d, J = 0 phenyl)-4- (6- 2. 5 Hz, IH), 7. 99 (ddd, J = 8. 5, 2. 5, 0. 8 Hz, 1H), 7. 95 (d, Br ., s' bromo-2-methyl-4-J-8'8 Hz, 2H), 7. 60 (d, J = 8. 8 Hz, 1H), 7. 34 (d, J = 8. 2 201 342 N CH CH Hz, 2H), 7. 14 (d, J 7. 4 Hz, 1H), 6. 96 (dd, J = 7. 4, 7. 4 19 oxo-4H-quinazolin- 1H), 6. 76 (d, J = 8. 0 Hz, 1H), 6. 59 (dd, J = 7. 4, 7. 4 N Me 3-yimethyl)-gz, 1H), 5. 45 (s, 2H), 4. 88 (bs, 2H). MS : (calc.) 462. 1 ; (obt.) 463. 1 (MW. N-(2-Amino-1H NMR : (DMSO) 8 (ppm) : 9. 61 (bs, 1H), 8. 10 (dd, J = 202 343 r'i CHCH2He P O phenyl)-4-(2, 4-5. 2, 0. 5 Hz, 1H), 7. 91 (d, J = 8. 2 Hz, 2H), 7. 40 (d, J= 8. 2 dioxo-1, 4-dihydro- benzamide ' s dioxo-1, 4-dihydro- Hz, 2H), 7. 15 (d, J == 7. 1 Hz, 1M, 6. 98-6. 94 (m, 2H), 6 77 202 343 CH CH 2H-thieno [3, 2- (dd, J = 8. 0, 1. 1 Hz, 1H), 6. 58 (dd, J = 7. 1, 7. 1 Hz, lI, N O dJpyrimidm-3-5. 12 (s, 2H), 4. 88 (bs, 2H). MS : (calc.) 392. 1 ; (obt.) 393. 0 H ylmethyl)- (MH). benzamide 1H NMR : (DMSO) 6 Wpm) : 9. 61 (bs, 1H), 8. 15 (d, J = 0 phenyl)-4- (6- 2. 5 Hz, 1H), 7. 95 (dd, J = 9. 1, 4. 9 Hz, 1H), 7. 91 (d, J = 8. 2 Hz, 2H), 7. 53 (d, J = 9. 3 Hz, I M, 7. 42 (d, J = 8. 2 Hz, 203 344 ! ! ! ? CH CH dioxo-14-dihvdro-2H), 7. 15 (d, J = 6. 9 Hz, 1H), 6. 96 (ddd, J = 7. 6, 7. 6, 1. 5 203 2-3 Hz, 1H), 6. 77 (dd, J = 8. 1, 1. 5 Hz, 1H), 6. 59 (ddd, J= 7. 6,- N O 2H-quinazolin-3-7. 6, 1. 4 Hz, 1H), 5. 20 (s, 2H), 4. 88 (bs, 2H) 4. 14 (q, J = Et ylmethyl)-7. 0, 2H), 1. 21 (t, J = 7. 0, 3H). MS : (calc.) 492. 1 ; (obt.) 493. 0). Ex. Cpd W Y Z Name Characterization Schm .. *H NMR : (DMSO) 8 (ppm) : 9. 62 (bs, 1H), 8. 10 (dd, J = 0 phenyl)-4- [I- (4- 7. 7, 1. 6 Hz, 1H), 7. 93 (d, J = 8. 2 Hz, 2H), 7. 71 (ddd, J = methoxy benzyl)-7'9, 7-9, 1. 5 Hz, 1H), 7. 46 (d, J = 8. 2 Hz, 2H), 7. 38 (d, J = w I 2, 4-dioxo-1, 4- 82 Hz, 2H) ; 7. 31 (d, J = 7. 4 Hz, 1H), 7 26 (d, J = 8. 8 Hz, 204 345 N CH CH d'ihydro-2H-'2H), 7. 15 (d, J = 6. 6 Hz, 1H), 6. 96 (ddd, J = 7. 6, 7. 6, 1. 2 19 quinazolin-3-Hz, 1H), 6. 89 (d, J = 8. 8 Hz, 2H), 6. 77 (dd, J = 8. 0, 1. 4 quinazolin-3-Hz, 1H), 6. 59 (ddd, J = 7. 5, 7. 5, 1. 2 Hz, 1H), 5. 33 (s, 2H), OMe 5. 28 (s, 2H), 4. 89 (bs, 2H), 3. 71 (s, 3H). MS : (calc.) benzamide 506. 2 ; (obt.) 507. 1 (MH) +. N- (2-Amino- 1H NMR : (DMSO) 8 (ppm) : 9. 61 (bs, 1H), 8. 66 (s, 1H), 8. 24 (d, J = 2. 5 Hz, 1H), 8. 00 (dd, J = 8. 7, 2. 3 Hz, 1H), bromo-4-oxo-4H-7. 95 (d, J = 8. 2 Hz, 2H), 7. 68 (d, J = 8. 8 Hz, 1H), 7. 48 (d, 205 346 N-s' CH CH _ _ J = 8. 2 Hz, 2H), 7. 15 (d, J = 8. 0 Hz, 1H), 7. 96 (ddd, J = 19 ylmethyl)-3 7. 6, 7. 6, 1. 5 Hz, 1H), 6. 77 (dd, J = 8. 0, l. l Hz, 1H), 6. 59 (du, J = 7. 4 ; 7. 4 Hz, 1H), 5. 28 (s, 2H), 4. 87 (bs, 2H). MS : (calc.) 448. 0 ; (obt.) 449. 0 (MH) +. nzamide g Q - N- (2-Amino- 1H NMR : (DMSO) 8 (ppm) : 9. 63 (bs, 1H), 8. 38 (d, J= phenyl)-4- (6- 1. 9 Hz, 1H), 8. 28 (dd, J = 8. 8, 2. 2 Hz, 1H), 8. 19 (d, J = Br ^ bromo-4-oxo-4H-8'8 Hz, 1H), 7. 95 (d, J = 8. 0 Hz, 2H), 7. 50 (d, J = 8. 2 Hz, 206 347 Br>nuNo> CH CH benzo [d] [l, 2, 3] tria 2H), 7. 15 (d, J = 6. 9 Hz, 1H), 7. 96 (ddd, J = 7. 6, 7. 6,' 1. 5-19 N zin-3-yhnethyl)-Hz, 1H), 6. 77 (dd, J = 8. 0, 1. 4 Hz, 1H), 6. 59 (ddd, J = 7. 6, 7. 6, 1. 4 Hz, 1H), 5. 67 (s, 2H), 4. 87 (bs, 2H). MS : (calc.) 449. 0 ; (obt.) 450. 0 (MH) +. N-(2-Amino-1H NMR : (DMSO) 8 (ppm) : 9. 63 (bs, 1H), 8. 30-8. 24 (m, o phenyl)-4- (6- 2H), 8. 15 (ddd, J = 8. 6, 2. 5, 0. 8 Hz, 1H), 7. 95 (d, J = 8. 0 207 348 CH CH chloro-4-oxo-4H-Hz, 2H), 7. 50 (d, J = 8. 2 Hz, 2H$, 7. 15 (d, J = 8. 0 Hz, 19 207 348 I N- CH CH 19 benzo [d] [1, 2, 3] tria 1H), 7. 96 (dd, J = 7. 4, 7. 4 Hz, 1H), 6. 77 (d, J = 8. 0 Hz, zin-3-ylmethyl)-1H), 6. 59 (dd, J = 7 4, 7. 4 Hz, 1H), 5. 67 (s, 2H), 4. 88 (bs, benzamide 2H). MS : (calc.) 405. 1 ; (obt.) 406. 0 (MH) +. Ex. Cpd W Y Z Name Characterization Schm 1H NMR (acetone-d6) 8 (ppm) : 9. 07 (bs, 1H), 8. 02 (d, J = N (2-Amino-8. 2 Hz, 2H), 7. 64-7. 44 (m, 3H), 7. 33 (dd, J = 7. 8, 1. 5 Hz, phenyl)-4- [ (3- 1H), 7. 03 (td, J =7. 6, 1. 5 Hz, 1H), 6. 90 (dd, J = 8. 0, 1. 4 208 349 _ CH CH fluoro-2-pyridinyl-Hz, 1H), 6. 78 (bs, 1H), 6. 71 (td, J = 7. 6, 1. 4 Hz, 1H), 6. 48 11 F N N amino)-methyl]- (dd, J = 8. 1, 2. 6 Hz, 1H), 6. 16 (dd, J = 7. 7, 2. 5 Hz, 1H), benzamide 4. 76-4. 55 (m, 4H). HRMS (calc.) : 336. 1386, (found) : 336. 1389. N (2-Amino-1H NMR (acetone-d6) 8 (ppm) : 9. 06 (bs, 1H), AB system 11 C phenyl)-4- [ (3, 4, 5- (8A = 8. 02, 83 = 7. 56, J = 8. 3 Hz, 4H), 7. 74-7. 65 (m, 1H), 209 350 A-1N/CH CH trifluoro-2-7. 33 (d, J= 8. 0, 1H), 7. 03 (td, J =7. 6, 1. 5 Hz, 1H), 6. 96- 11 H pyridinyl-amino)-6. 83 (m, 2H), 6. 71 (td, J = 7. 6, 1. 4 Hz, 1H), 4. 74 (d, J = methyl]-benzamide 6. 3 Hz, 2H), 4. 65 (bs, 2H). N- (2-Arflino-'H NMR : (DMSO) 8 (ppm) : 9. 61 (bs, 1H), 8. 10 (dd, J = ? 5. 2, 0. 5 Hz, lH), 7. 91 (d, J=8. 2Hz, 2H), 7. 40 (d, J = 8. 2 s dioxo-1, 4-dihydro- 210 351 fY' rHrHPH-nnn ? Hz, 2H), 7. 15 (d, J = 7. 1 Hz, 1H), 6. 98-6. 94 (m, 2H), 6. 77 '- St (dd, J = 8. 0, 1. 1 Hz, 1H), 6. 58 (dd, J = 7. 1, 7. 1Hz, lH), yhnethyl)-5. 12 (s, 2H) +4. 88 (bs, 2H). MS : (calc.) 392. 1 ; (obt.) benzamide N-(2-Amino-1H NMR : (DMSO) 8 (ppm) : 9. 85 (bs, 1H), 8. 24-8. 19 (m, N phenyl)-4- (5- 6H), 7. 79-7. 66 (m, 3H), 7. 20 (d, J = 7. 5 Hz, 1H), 7. 00 (dd, 211 352 t \\N CH CH phenyl-J = 7. 3, 7. 3 Hz, 1H), 6. 80 (d, J=7. 9Hz, lH), 6. 61 (dd, J 50 Ph-o [l, 2, 4] oxadiazol-3- = 7. 3, 7. 3 Hz, 1H), 4. 96 (bs, 2H). MS : (calc.) 356. 1 ; yl)-benzamide (obt.) 357. 0 (MH) +. N-(2-Amino-1H NMR : (DMSO) 8 (ppm) : 9. 81 (bs, 1H), 8. 17-8. 11 (m, phenyl)-4- (5- 4H), 7. 18 (d, J = 7. 9 Hz, 1H), 6. 99 (dd, J = 7. 7, 7. 7 Hz, 212 353 CH CH methyl-1H), 6. 79 (d, J = 7. 9 Hz, 1H), 6. 61 (dd, J = 7. 5, 7. 5 Hz, 50 Me O [1, 2, 4] oxadiazol-3- 1H), 4. 94 (bs, 2H), 2. 70 (s, 3H). MS : (calc.) 294. 1 ; (obt.) yl)-benzamide 295. 0 (MH) +. Ex. Cpd W Y Z Name Characterization Schm N-(2-Amino-1H NMR : (acetone) 8 (ppm) : 9. 29 (bs, 1H), 8. 21 (m, phenyl)-4- (5- 4H), 7. 31 (d, J = 8. 0Hz, 1H), 7. 03 (dd, J = 7. 0, 7. 0 Hz, 1H), N piperidin-1-6. 88 (d, J = 7. 3Hz, 1H), 6. 69 (dd, J = 7. 3, 7. 3 Hz, 1H), 213 354 N CH CH hneth 1-4 s 2 2 50 toN ylmethyl-4. 68 (bs, 2H), 3. 94 (s, 2H), 2. 58 (t, J= 5. 1 Hz), 1. 63-1. 55 [1, 2, 4] oxadiazol-3- (m, 4H), 1. 47-1. 43 (m, 2H). MS (Calc) 377. 2 ; (Obt.) yl)-benzamide 378. 3 (MH) + N- (2-Amino- o, phenyl)-4-(5-1H NMR : (acetone) 8 (ppm) : 9. 28 (bs, 1H), 8. 21 (m, phenyl)-4- (5- 214 355 y CH CH lH), 6. 88 (d, J=7. 3Hz, lH), 6. 69 (dd, J = 7. 3, 7. 3 Hz, 50 y 1H), 4. 67 (bs,, [1, 2, 4] oxadiazol-3- 2 4. 01 (s, 2H), 3. 66 (t, J= 4. 8Hz), 2. 65 yl)-benzamide (t, J= 4. 4 Hz). MS : (Calc.) 379. 2 ; (Obt.) : 380. 2 (MH) + N- (2-Amino-'H NMR : (DMSO) 8 (ppm) : 9. 62 (s, 1H), 7. 93 (d, J = 7. 9 phenyl)-4- (5- Hz, 2H), 7. 42 (d, J = 7. 9 Hz, 1H), 7. 16 (d, J = 7. 5 Hz, 215 356 NX CH CH propyl-1H), 6. 97 (t, J = 7. 0 Hz, 1H), 6. 77 (d, J = 7. 9 Hz, 1H), 50 H N [1, 2, 4] oxadiazol-3-6. 59 (t, J = 7. 5 Hz, 1H), 4. 88 (s, 2H), 4. 16 (s, 2H), 2. 87 (t, ylmethyl)-7. 0, 2H), 1. 72 (q, J = 7. 5 Hz, 2H), 0. 92 (t, J = 7. 0 Hz, 3H). benzamide (MH) + : 337. 2. N-(2-Amino-1H NMR : (DMSO) 8 (ppm) : 9. 64 (s, 1H), 9. 24 d, J = 1. 8 phenyl)-4- (5- 1H) ; 8. 86 (dd, J =1. 3 Hz, J = 4. 8 Hz, 1H), 8. 45 (dd, J N =1. 8 Hz, J = 6. 2 Hz, 1H), 7. 96 (d, J = 7. 9 Hz, 2H), 7. 66 N CH CH pdin-3-yl- (dd J = 4. 8 Hz, J = 7. 9 Hz, 1H), 7. 50 (d, J = 8. 4 Hz, 2H), 50 216 357 o, [1 2 4] oxadiazol-3-''''''' ylmethyl)-7. 16 (d, J = 7. 5 Hz, 1H), 6. 96 (t, J =. 7. 0 Hz, 1H), 6. 77 (d, N J = 7. 5 Hz, 1H), 6. 59 (t, J = 7. 5 Hz, IH), 4. 89 (s, 2H), benzamide 4. 31 (s, 2H). (MH) +. 372. 3. S-phenyl)-4-(5-tH NMR : (DMSO) 8 (ppm) : 9. 63 (s, 1H), 8. 87 (d, J = 6. 2 phenyl)-4- (5- 217 358 N"din-4-1_ Hz, 2H) ; 7. 95-8. 02 (m, 3H), 7. 50 (d, J = 7. 9 Hz, 2H), 7. 16 N CH CH p y (d J = 7. 5 Hz 2H) 6. 97 (t, J = 7 0 Hz, 1H), 6 77 (d, J = 50 - p' [1 2 4] oxadiazol-3-''''''' ylmethyl)- ylmethyl)-2H). (+ : 372. 3. benzamid Ex. Cpd W Y Z Name Characterization Schm NC 4- (5-Acetylamino- 1H IVMR (DMSO) 8 (ppm) : 11. 62 (s, 1H), 9. 60 (bs, 1H), hen-7. 93 (d, J = 8. 1 Hz, 2H), 7. 39 (d, J = 8. 1 Hz, 2H), 6. 97 (d, 4-eyano-thiop J = 7. 3 Hz, 1H), 7. 15 (d, J = 7. 3 Hz, 1H), 6. 98-6. 94 (m, Me-5"S S ), 6. 77 (d, J = 7. 3 Hz, 1H), 6. 591 (dd, J = 7. 7, 7. 7 Hz, '0 ?' ''-"'-''- 390. 1 (calc) 391. 2 (found). 4- (5- NC Benzoylamino-4-1H NMR (DMSO) 8 (ppm) : 11. 77 (s, 1H), 9. 61 (s, 1H) ; cyano-3-methyl-7. 93 (d, J = 7. 0 Hz, 4H), 7. 52-7. 63 (m, 3H), 7. 38 (d, J = 219 360 CH CH thiophen-2-7. 6 Hz, 2H), 7. 16 (d, J = 7. 6 Hz, 1H), 6. 96 (t, J = 7. 6 Hz, 49 Ph-O S ''ylmethyl)-N- (2- 1H), 6. 77 (t, J = 7. 6 Hz, lH), J = 7. 6 Hz 1H) 6. 59 (t, J = 7. 6 Hz, 1H), amino-phenyl)-4. 89 (s, 2H), 4. 15 (s, 2H), 2. 24 (s, 3H). (mu+ : 467. 0 benzamide NC Me N- (2-Amino- phenyl)-4- [4- 1H NMR (DMSO) 8 (ppm) : 10. 12 (s, 1H), 9. 61 (s, 1H), HNAsCL'cyano-3-methyl-5-9. 21 (s, 1H) ; 7. 93 (d, J = 7. 6 Hz, 2H), 7. 27-7. 43 (m, 6H), 220 361 HN-1o CH CH (3-phenyl-ureido)-7. 16 (d, J = 7. 6 Hz, 1H), 6. 93-7. 05 (m, 2H), 6. 77 (d, J = 49 thiophen-2-8. 2 Hz, 1H), 6. 59 (t, J = 7. 6 Hz, 1H), 4. 88 (s, 2H), 4. 08 (s, yhnethyl]-2H), 2. 19 (s, 3H). (MFi) + : 482. 4 benzamide 0 N-(2-Amino-1H NMR : (DMSO) 8 (ppm) : 9. 60 (s, 1H), 7 92 phenyl)-4- (3-oxo- (d, J = 8. 2 Hz, 2H), 7. 40 (d, J = 8. 0 Hz, 2, 23-dihvdro- 7. 13 (d, J= 6. 9 Hz, 1H), 6. 92-7. 04 221 362 CH CH (m, 5H), 6. 75 (dd, J = 8. 1 Hz, 1. 1 Hz, 11 O, benzo [1, 4] oxazin- 4-ylrilethyl)-1H), 6. 57 (td, J = 7. 4 Hz, 1. 4 Hz, 1H), b) 4-ylmethyl)-5. 24 (s, 2H), 4. 88 (bs, 2H) ; 4. 82 (s, 2H). benzamide (MH) + : 374. 1 Ex. Cpd W Y Z Name Characterization Schm o N-(2-Amino-1H SMR : (DMSO) (ppm) : 9. 58 (s, 1H), 7. 90 phenyl)-4- (3-oxo-- (d, J = 8. 2 Hz, 2H), 7. 42 (dd, J = 8. 0 Hz, 2, 3-dihydro- T = 1. 4 Hz, 1H) 7. 32 (d, J = 8. 2 Hz, 2H), /C C benzo [1, 4] thiazm- 7'19-7-11 (m, 3H), 7. 04-6. 92 (m, 2H), 6. 75 11 (dd, J = 8. 0 Hz, 1. 4 Hz, 1H), 6. 57 (td, J 4-yhnethyl)-= 8. 0 Hz, 1. 6 Hz, 1H), 5.-3 1 (s, 2H) ; 4. 8 8 benzamide (bs, 2H) ; 3. 70 (s, 2H). (MH) : 390. 1 N-(2-Amino-1H NMR : (DMSO) 6 (ppm) : 9. 57 (bs, 1H), 7. 98 o phenyl)-4- (3-oxo- (d, J = 4. 7 Hz, 1H), 7. 89 (d, J = 8. 2 Hz, 2, 3-dihydro- 2H), 7. 45-7. 40 (m, 3H), 7. 15 (d, J = 8. 2 223 364 r, CH CH pyrido [3, 2- Hz, 1H), 7. 09-7. 05 (m, 1H), 6. 96 (dd, J = 11 t b] [l, 4] oxazin-4-7 6, 7 6 Hz, 1H), 6. 76 (d, J = 8. 2 Hz, 1H), 6. 58 (dd, J = 7. 6, 7. 6 Hz, 1H), 5. 31 ylmethyl)- (s, 2H), 4. 90 (bs, 2H), 4. 87 (s, 2H). benzamide (MH) + : 375. 1 1H NMR : (DMSO) 5 (ppm) : 9. 67 (s, 1H) ; 7. 98 0 N-(2-Amino- (d, J = 8. 2 Hz, 2H), 7. 73-7. 84 (m, 3H), phenyl)-4- (1- 7-53-7. 62 (m, 3H), 7. 24 (d, J = 7. 6 Hz, 224 365 CH CH hydroxy-3-oxo-1H), 7. 0 4 (t, J = 7. 6 Hz, 1H), 6. 8 5, (d, 1 46 OH indan-2-yhnethyl)-= 8. 2 Hz,-1H), G. 6 7 (t, J = 7. 6 Hz, 1H), OH benzamlde Hz, 1H), 4. 95 (s, 2H), 3. 21-3. 30 (m, 1H), 3. 11-3. 13 (m, 2H). (MH) + : 373. 1 N-(2-Amino-1H NMR : (DMSO) 8 (ppm) : 9. 61 (s, 1H) ; 8. 01 (d, J = 8. 8 225 366 CH CH phenyl)-4-Hz, 2H), 7. 45 (t, J = 7. 6 Hz, 2H), 7. 06-7. 24 (m, 6H), 6. 97 1 I 225 366 CH CH'''1 phenoxy- (t, J = 7. 6 Hz, 1H), 6. 78 (d, J = 7. 4 Hz, 1H), 6. 59 (t, J = benzamide 7. 6 Hz, 1H), 4. 88 (s, 2H). (MH) + : 305. 0 N (2-Amino- MeO phenyl)-4- [5- (4-'H NMR (CDCI3) 8 (ppm) : 8. 77 (s, lH), 7. 93 (d, J = 8. 1 226 367 CH CH methoxy-phenyl)-Hz, 2H), 7. 42 (d, J = 8. 4 Hz, 2H), 7. 38-6. 98 (m, 6H), 6. 91 52 2, 5-dihydro-furan- (d, J = 8. 4Hz, 2H), 6. 09-5. 98 (m, 4H), 3. 81 (s, 3H). 2-yl]-benzamide Ex. CpdWYZNameCharacterizationSchm N (2-Amino-1H NMR (DMSO-d6) : 8 10. 08 (brs, 1H), 7. 99 (d, J = 7. 9 MeO o phenyl)-4- [1, 3-bis- nneo o N phenyl)-4- [1, 3-bis- Hz 2H), 7. 70 (s, 1H), 7. 49 (d, J = 8. 35 Hz, 4H), 7. 39-7. 33 OMe benzamide 3H), 3 77 (s, 3H), 3 75 (s, 6H). N-(2-Arnino- V- (2-Ammo- benzamide 3H), 3. 77 (s, 3H), 3. 75 (s, 6H). N (2-Amino- phenyl)-4- [3- (4-'H NMR (CDC13) : 8 8. 02 (brs, 1H), 7. 90 (d, J = 7. 9 Hz, chloro-phenyl)-l-2H), 7. 46 (d, J = 7. 5 Hz, 2H), 7. 42-7. 24 (m, 6H), 7. 16 (t, 231 372 CI 4 NH mOMe CH CH (3, 4-dimethoxy-J = 7. 5 Hz, 1H), 6. 91 (brd, J = 5. 71 Hz, 3H), 6. 75 (brd, J = 57 phenyl)-8. 3 Hz, 1H), 6. 70 (d, J = 1. 8 Hz, 1H), 4. 99 (s, 1H), 3. 97 orme ureidomethyl]- (s, 3H), 3. 86 (s, 3H). benzamide N- (2-Amino-'H NMR (DMSO-d6) : 8 10. 10 (brs, 1H), 7. 99 (d, J = 7. 9 o phenyl)-4- [l- (3, 4-Hz, 2H), 7. 88 (s, 1H), 7. 80-7. 72 (m, 1H), 7. 50 (dd, J = 232 373 N OMe CH CH dimethoxy-7. 0, 5. 7 Hz, 4H), 7. 37 (d, J = 7. 9 Hz, 1H), 7. 30-6. 94 (m, 57 \ NH \ OMe phenyl)-3-phenyl-''''''' 71-1), 6. 78 (d, J = 6. 6 Hz, 1H), 5. 03 (s, 2H), 3. 80 (s, 3H), OMe ureidomethyl]- benzamide.,. N (2-Amino-iH NMR (CDC13) : 8 8. 02 (brs, 1H), 7. 92 (d, J = 7. 9 Hz, 0 phenyl)-4- [l- (3, 4- ditnethoxy-2H), 7. 49 (d, J = 8. 35 Hz, 2H), 7. 43-7. 32 (m, 5H), 7. 10- dimethoxy- 233 374 __nu CH CH phenyl)-3- (4- 730 (2m, SH), 7. 19-7. 10 (m, 2H), 7. 01 (dd, J = 8. 35, 2. 2 57 phenoxy-phenyl)-'3 6. 94 (d, J = 7. 5 Hz, 1H), 6. 92 (d, J = 8. 8 Hz, OMe ureidomethyl]-1H), 6. 77 (dd, J = 8. 8, 2. 2 Hz, 1H), 6. 72 (d, J = 2. 2 Hz, benzamide 1H), 6. 34 (s, 2H), 5. 02 (s, 2H), 3. 98 (s, 3H), 3. 87 (s, 3H). n ° Biphenyl-4, 4'-1H NMR (CD30D) 8 (ppm) : 9. 80 (bs, 2H), 8. 16 (d, 234 375 N CH CH dicarboxylic acid J=7. 9 Hz, 4H), 7. 96 (d, J= 7. 9 Hz, 4H), 7. 23 (d, J=7. 4 Hz, 15 NHZ H bis- [ (2-amino- 2H), 7. 03 (dd,. J=6. 9, 7. 4 Hz, 2H), 6. 84 (d, J=8. 2 Hz, 2H), phenyl)-amide] 6. 66 (dd, J=6. 9, 7. 7 Hz, 2H), 5. 06 (bs, 4H). Ex. Cpd W Z Name Characterization Schm N (2-Amino-1H-NMR (DMSO-d6), 8 (ppm) : 9. 6 (bs, 1H), 8. 32 (d, phenyl)-4-J=4. 9 Hz, 2H), 7. 97 (dt, J= 7. 9, 9. 9 Hz, 2H), 7. 85-7. 83 (m, 236 377 CH CH (pyrimidin-2-1H), 7. 47, (d, J=8. 2 Hz, 2H), 7. 20 (d, J=7. 9 Hz, 1H), 7. 01 13 ylaminomethyl)- (dt, J=7. 4, 7. 7 Hz, 1H), 6. 82 (d, J=7. 9 Hz, 1H), 6. 66-6. 62 benzamide (m, 1H), 4. 98 (bs, 2H), 4. 61 (d, 2H). N (2-Amino- H3C S,, X phenyl)-4- (4, 6-'H-NMR (DMSO-d6), 8 (ppm) : 9. 66 (bs, 1H), 7. 96 (d, dimethyl-J=7. 9 Hz, 2H), 7. 61 (d, J= 7. 9 Hz, 2H), 7. 21 (d, J=7. 9 Hz, 11 237 378 N CH CH 11 pyrimidin-2-1H), 7. 04-6. 99 (m, 2H), 6. 82 (d, J=7. 9 Hz, 1H), 6. 64 (t, 3 ylsulfanylmethyl)-J=7. 4 Hz, 1H), 4. 49 (s, 2H), 2. 42 (s, 6H). benzamide F (2-Amino-'H-NMR (DMSO-d6), 8 (ppm) : 9. 66 (bs, 1H), 9. 07 (d, F F phenyl)-4- (4- J=5. 2 Hz, 1H), 7. 97 (d, J=7. 4 Hz, 2H), 7. 78 (d, J=4. 7 Hz, trifluoromethyl- 238 379 F NS CH CH 1H), 7. 63 (d, J=7. 4 Hz, 2H), 7. 19 (d, J=7. 7 Hz, 1H), 7. 01 11 pyrimidin-2- N ylsulfanyhnethyl)- (dt, J= 7. 4, 7. 7 Hz, 1H), 6. 81 (d, J=8. 2 Hz, 1H), 6. 64 (dt, benzamide J=7. 1, 7. 4 Hz, 1H), 4. 94 (bs, 2H), 4. 57 (s, 2H). benzamide. NH2 P dine-2 5-1H-NMR (DMSO-de pm) : 10. 23 (bs, 1H), 10. 04 N dicarboxylic acid (bs, IH), 9. 30 (s, IH), 8. 62 (dd, J=1. 8, 8. 0 Hz, 1H), 8. 30 239 380 < f N CH (d, J=8. 1 Hz, 1H), 7. 55 (d, J=7. 4 Hz, 1H), 7. 24 (d, J=7. 4 1 phenyl)-amide] Hz, 1H), 7. 04 (dd, J=7. 0, 14. 0 Hz, 2H), 6. 90-6. 83 (m, 2H), 6. 74-6. 63 (m, 2H), 5. 11 (bs, 4H). N-(2-Amino-1H-NMR (DMSO-de pm) : 9. 66 (bs, 1H), 8. 52 (bs, phenyl)-4- (pyridin- 1H), 7. 96 (d, J=7. 4 Hz, 2H), 7. 69 (d, J=5. 8 Hz, 1H), 7. 59 240 381 t CH CH 2- (d, J=7. 4 Hz, 2H), 7. 38 (d, J=7. 7 Hz, 1H), 7. 19 (bs, 2H), 11 - ylsulfanylmethyl)-7. 00 (d, J=6. 9 Hz, 1H), 6. 83 (d, J=6. 9 Hz, 1H), 6. 64 (dd, benzamide J=6. 7, 7. 2 Hz, 1H), 4. 94 (bs, 2H), 4. 55 (b+s, 2H). Ex. Cpd W Y Z Name Characterization Schm CH3 h 1 4 4 6 tH-NMR MSO-d6, 6 (ppm) : 9. 65 (bs, 1H), 7. 96 (d, XN p eny)--[(,-J=7. 9 Hz, 2H), 7. 57 (d, J=6. 3 Hz, 1H), 7. 47 (d, J= 7. 7 Hz, 241 382 N CH CH CH"" 2H), 7. 21 (d, J=7. 4 Hz, 1H), 7. 00 (d, J= 5. 8 Hz, 1H), 6. 59 33 HgCNN methvn - '- - '- H C NN^ p (d, J=6. 6 Hz, 1H), 6. 64 (dd, J=6. 0, 7. 4 Hz, 1H), 5. 01 (s, ylamino)-methyl]- H 2H), 4. 61 (d, J=6. 0 Hz, 2H), 2. 24 (s, 6H). benzamide CH3 _ N-(2-Amino--1H-NMR (DMSO-de, 6 (ppm) : 9. 66 (bs, 1H), 7. 98 (d, phenyl)-4- [ (4, 6- J=7. 9 Hz, 2H), 7. 50 (d, J=8. 2 Hz, 2H), 7. 96 (d, J= 7. 9 Hz, 242 383 CH CH dimethyl-pyridin-2-1H), 7. 01 (dd, J=7. 7, 7. 4 Hz, 1H), 6. 82 (d, J= 7. 9 Hz, 33 H3C NJNN' ylamino)-methyl]-1H), 6. 64 (t, J=7. 4 Hz, 1H), 6. 33 (s, 1H), 6. 25 (s, 1H), H benzamide 4. 58 (d, J=4. 4 Hz, 2H), 2. 28 (s, 3H), 2. 17 (s, 3H). N (2-Amino- CH3 phenyl)-4-(4, 6-1H-NMR (DMSO-d6, 6 (ppm) : 9. 58 (bs, 1H), 7. 88 (d, dimethyl-J=5. 8 Hz 2H), 7. 46 (d, J=8. 2 Hz, 2H), 6. 90-6. 81 (m, 1H), 11 pyrimidin-2-6. 68 (d, J=7. 9 Hz, 1H), 6. 50 (t, J= 7. 4 Hz, 1H), 6. 40-6. 38 H3C N O W yloxymethyl)- (m, 1H), 6. 29-6. 26 (m, 1H), 5. 33 (s, 2H), 2. 25 (s, 6H). benzamide N- (2-Axnino- 1H-NMR (DMSO-d, 8 (ppm) : 9. 64 (bs, 1H), 8. 21. (bs, o phenyl)-4- [ (6- 1H), 7. 95 (d, J=7. 96 Hz, 2H), 7. 83 (d, J=5. 8 Hz, 1H), 7. 44 244 385 CH CH methoxy- (d, J=7. 9Hz, 2H), 7. 19 (d, J=7. 7 Hz, 1H), 7. 00 (dd, J= 7. 4, 33 i. -11 pyrimidin-4-7. 7 Hz, 1H), 6. 80 (d, J=7. 9 Hz, 1H), 6. 64 (d, J=7. 1 Hz, ber' '-" '-" - H ylamino)-methyl]-1H), 4. 96 (bs, 2H), 4. 58 (bs, 2H), 3. 81 (s, 3H). benzamlde. O 4-[(6-Acetyl-tH-NMR MSO-de, 6 (ppm) : 9. 79 (bs, 1H), 7. 99 (d, t enzo [, l oxo-J=8. 5 Hz, 2H), 7. 48 (d, J=7. 96 Hz, 2H), 7. 39 (bs, 1H), 245 386 CH3 CH CH 5-ylamino)-7. 21 (d, J=7. 4Hz, 1H), 7. 02 (dd, J=7. 1, 7. 7 Hz, 1H), 6. 83 33 (d, J= 7. 7 Hz, 1H), 6. 64 (t, J=7. 4 Hz, 111), 6. 36 (bs, 1H), amino-phenyl)-6. 00. (d, J=2. 2 Hz, 2H), 4. 59 (bs, 2H), 2. 52 (bs, 3H). benzamide Ex. Cpd W Y Z Name Characterization Schm N- (2-Amino- iH- (DMSO-d, 8 (ppm) : 9. 66 (bs, 1H), 7. 96 (d, phenyl)-4- [ (4- 2H), 7. 47 (bs, 2H) 7. 39 (bs 1H), 7. 19 (d, chloro-6-methoxy-J-7. 9 Hz,,,,,,, 246 387 H3C CH CH CH J=7. 4Hz, 1H), 7. 00 (dd, J=6. 9, 7. 4 Hz, 1H), 6. 81 (d, J= 33 1 pyrimidin-2- N H ylamino)-methyl]-7 1 Hz,,,.,, benzamide 4. 56 (d, J=6. 0 Hz"2H), 3. 83 (s, 3H). "H-NMR (DMSO-d6), 6 (ppm) : 9. 63 (bs, 1H), 7. 94 (d, HsC 4 ? 2 6- 2H), 7. 47 (d, J=6. 59 Hz, 2H), 7. 15 (d, J= 7. 9 247 388 eH CH CH dimethoxy-pyridin-lHj, 6. 99 (dd, J=5. 7, 7. 4Hz, 1H), 6. 80 (d, J= 7. 8 Hz, 33 o H 3-lamino-1 6. 71 (d, J= 6. 6 Hz, 1H), 6. 62 (dd, J=7. 7, 7. 1 Hz, 1H), m thyl]-benzamide 6 15 (d, J=8. 2 Hz, 1H), 4. 96 (bs, 2H), 4. 38 (bs, 2H), 3. 94 ,,.,. NH (2-o-.'H-NMR (DMSO-d6), 8 (ppm) : 10. 9 (bs, 1H), 9. 64 (bs, NH phenyl)-4- [ (lH- 1 7. 99 s,,,,,, 248 389 N= CH CH benzoimidazol-2-'33 NH 7. 14-6. 81 (m, 411), 6. 64 (d, J= 6. 0 Hz, 1H), 4. 92 (bs, 2H), benzamide 4. 65 (bs, 2H). N-(2-Amino-1H-NMR (DMSO-de pm) : 9. 60 (bs, 1H), 7. 96 (d, phenyl)-4- [ (6- J=7. 9 Hz, 1H), 7. 52-7. 50 (m, 2H), 7. 37-7. 30 (m, 1H), 249 390 H3C ^ CH CH methoxy-pyridin-2-7. 25-7. 21 (m, 2H), 7. 19-6. 99 (m, 1H), 6. 84-6. 81 (m, 1H), 37 H ylamino)-methyl]-6. 67-6. 64 (m, lH), 6. 11-6. 07 (m, 1H), 5. 93-5. 89 (m, 1H), benzamide 4. 93 (bs, 2H), 4. 56 (d, J=5. 8 Hz, 2H), 3. 80 (s, 3H). N N-(2-Amino-1H-NMR (DMSO-de pm) : 9. 68 (bs, 1H), 8. 95 (bs, phenyl)-4= 250 391 N CH CH (quinolin-8-2H), 8. 43-8. 38 (m, 1H), 7. 90 (bs, 2H), 7. 80-7. 55 (m, 6H), g ylsulfanylmethyl)-722 (d, J= 7. 7 Hz, 1H), 7. 03 (d, J= 7. 7 Hz, 1H), 6. 63 (d, 'benzamide J=7. 4 Hz, 1H), 5. 05 (bs, 2H), 4. 48 (d, J=7. 7, 2H). Ex. Cpd W Y Z Name Characterization Schm j ? 26-'H-NMR (DMSO-, 8 (ppm) : 9. 66 (bs, lu), 7. 97 (d, HiCethoxy J=7. 9 Hz, 2H), 7. 84 (t, J=5. 9 Hz, 1H), 7. 46 (d, J=7. 46 Hz, 251 392 N N CH CH 2H), 7. 20 (d, J=7. 9 Hz, 1H), 7. 04 (d, J=6. 6 Hz, 1H), 6. 83 37 pyrimidin-4- (d J= 7. 9 Hz, 1H), 6. 64 (dd, J=7. 7, 7. 4 Hz, 1H), 5. 51 (bs, ylamino)-methyl]- CCH3 benzamide 1 4. 57 (bs"2H), 3. 82 (s, 3H), 3. 84 (s, 3H). benzamide N- (2-Amino-'H-NMR (DMSO-d6), 8 (ppm) : 9. 63 (bs, 1H), 7. 79 (d, H3C N phenyl)-4- (3,-5- J=8. 5 Hz, 2H), 7. 19 (d, J=6. 6 Hz, 1H), 7. 00 (dd, J=7. 9, 252 393 H CH CH dimethoxy-7. 1 Hz, 1H), 6. 62 (t, J=6. 0 Hz, 1H), 6. 82 (dd, J=1. 4, 7. 9 37 benzylamino)-Hz, 1H), 6. 67 (d, J= 8. 8 Hz, 2H), 6. 58 (bs, 2H), 6. 42 (bs, CH3 benzamide 1H), 4. 87 (bs, 2H), 4. 34 (d, J=6. 0 Hz, 2H), 3. 77 (s, 6H). (bs, 1H), 7. 96 (d, N- (2-Amino-'H-NIMR (DMSO-d6), 8 (ppm) : 9. 66 (bs, 1H), 7. 96 (d, 11 l phenyl)-4-(3-J=7. 9 Hz, 2H), 7. 55 (d, J=8. 2 Hz, 2H), 7. 29-7. 20 (m, 2H), 253 394 Y CH CH methoxy-7. 02-6. 95 (m, 2H), 6. 84-6. 79 (m, 1II), 6. 67-6. 62 (m, 1H), 11 Os phenylsulfanylmeth 6. 57-6. 54 (m, 1H), 6. 44-6. 41 (m,. 1H), 4. 93 (bs, 2H), 4. 41 CH3 yl)-benzamide (bs, 2H), 3. 79 (s, 3H). H3C o 0,, , N- (2-Amino-'H-NMR (DMSO-d6), 8 (ppm) : 9. 72 (bs, 1H), 8. 05 (d, phenyl)-4- (3, 5- J=8. 2 Hz, 2H), 7. 61 (d, J=7. 9 Hz, 2H), 7. 24 (d, J=7. 4 Hz, 254 395 \jP CH CH dimethoxy-1H), 7. 04 (dd, J=6. 9, 7. 1 Hz, 1H), 6. 85 (d, J=6. 9 Hz, 11 Ou phenoxymethyl)-1H), 6. 66 (dd, J= 7. 4, 7. 7 Hz, 1H), 6. 27 (s, 2H), 6. 26 (s, CH3 benzamide 1H), 5. 23 (s, 2H), 5. 21 (bs, 2H), 3. 77 (s, 6H). 1H-NMR (DMSO-d, 8 (ppm) : 9. 70 (bs, 1H), 8. 35 (d, N (2-Amino-. J=9. 1 Hz, 2H), 8. 05 (d, J=7. 9 Hz, 2H), 7. 96 (d, J=7. 9 Hz, phenyl)-4-1H), 7. 85 (d, J=8. 2 Hz, IH), 7. 76-7. 69 (m, 2H), 7. 51 (dd 255 396 gN CH CH (quinolin-2-11 benzamide 7. 4 Hz, 1H), 6. 83 (d, J=8. 2 Hz, 1H), 6. 66 (d, J=7. 4 Hz, 1H), 5. 66 (s, 2H), 4. 94 (bs, 2H). Ex. Cpd W Y Z Name Characterization Schm . H N-(2-Amino-1H-NMR (DMSO-d6, 6 (ppm) : 9. 62 (bs, 1H), 7. 96 (d, H3C o phenyl)-4- [ (3, 5- J=7. 9 Hz, 2H), 7. 49 (d, J=7. 9 Hz, 2H), 7. 19 (d, J=7. 9 Hz, 256 397 CH CH dimethoxy-1H), 7. 00 (dd, J=7. 5, 7. 9 Hz, 1H), 6. 81 (d, J=7. 9 Hz, 33 phenylamino)-1H), 6. 63 (dd, J= 7. 0, 8. 0 Hz, 1H), 5. 78 (s, 2H), 5. 76 (s, CH3 methyl]-benzamide 1H), 4. 92 (bs"2H), 4. 35 (d, J=5. 7, 2H), 3. 65 (s, 6H). s, v N s bis (N- (2-Amino-'H-NMR (DMSO-d6), 8 (ppm) : 9. 82 (bs, 2H), 9. 08 (bs, phenyl)-2H), 8. 34 (d, J=8. 3 Hz, 2H), 7. 83 (d, J=8. 3 Hz, 2H), 7. 18 1 nicotinamide)-6- (d, J=7. 5 Hz, 2H), 7. 01 (dd, J=6. 3, 7. 0 Hz, 2H), 6. 80 (d, disulfide J=7. 9 Hz, 2H), 6. 61 (t, J=7. 03 Hz, 2H), 5. 05 (bs, 4H). ""NHz N- (2-Amino-'H-NMR (DMSO-d6), 8 (ppm) : 9. 90 (bs, 1H), 8. 16 (bs, phenyl)-4-2H), 7. 65 (d, J=4. 8 Hz, 2H), 7. 54 (bs, 2H), 7. 25 (d, J=7. 0 258 399 CH CH (isoquinolin-1-''''''33 258 399 CH CH (isoquinolin-l-Hz, 2H), 7. 11 (bs, 2H), 7. 07-7. 02. (m, 2H), 6. 84 (d,'J=7. 9 33 benzamide 1H), 6. 67 (bs, 1H), 5. 01 (bs, 2H), 4. 88 (bs, 2H). N-(2-Amino-IH-NMR (DMSO-d6, 6 (ppm) : 9. 66 (bs, 1H), 7. 97 (d, H phenyl)-4-[(2, 3-J=7. 0 Hz, 2H), 7. 51 (d, J=7. 0 Hz, 2H), 7. 22 (d, J=7. 5 Hz, 259 400 tO3cN a CH CH dihydro-1H), 7. 02-6. 97 (m, 1H), 6. 84 (bs, 1H), 6. 82-6. 71 (m ; 2H), 33 , benzo [1, 4] dioxin- 6. 16 (d, J=6. 6 Hz, 1H), 6. 08 (s, 1H), 4. 32 (bs, 2H), 4. 16- O 6-ylammno)- methyl]-benzamide '- . 1H-NMR (DMSO-d6, 6 (ppm) : 9. 66 (bs, 1H), 9. 56 (bs, H 1H), 7. 97 (d, J=7. 9 Hz, 2H), 7. 53 (d J=7. 9 Hz, 2H), 7. 28 o XN » \-phenylamino)- (d, J=8 8 Hz, 2H), 7. 22 (d, J=7. 9 Hz, 1H), 7. 02 (t, J=7. 5 260 'a Hz, IH), 6. 83 (d, J=7. 9 Hz, 1H), 6. 65 (t, J=7. 5 Hz, 1H), H3C N amino-phenyl)- H benzamide 6. 55 (d, J=8. 3 Hz, 2H), 4. 98 (bs, 2H), 4. 38 (bs, 2H), 2. 00 (s, 3H). Ex. Cpd W Y Z Name Characterization Schm 1H-NMR (DMSO-d6), 6 (ppm) : 9. 65 (bs, 1H), 7. 98 (d, H N (2-Amino- w N,'phenyl)-4- [ (4- J=7. 9 Hz, 2H), 7. 52 (d, J=7. 9 Hz, 2H), 7. 21 (d, J=7. 5 Hz, 1H) 7. 02 (dd J=7. 0 7. 9 Hz, 1H), 6. 83 (d, J=7. 9 Hz, 1H), -6. 78 (d, J=8. 8-Hz, 211), 6. 64 (t, J=7. 5 Hz, 1H 6. 55 d 33 phenylamino)- 0 phenylamino)-J=8. 8 Hz, 2H), 4. 94 (bs, 2H), 4. 35 (d, J=5. 7 Hz, 2H), 3. 74 methyl]-benzamide (t, J=4. 4 Hz, 4H), 2. 92 (t, J=4. 4 Hz, 4H). CH3 N-(2-Amino-1H-NMR (DMSO-d6, 6 (ppm) : 9. 64 (bs, 1H), 7. 96 (d, phenyl)-4- [ (4- J=7. 6 Hz, 2H), 7. 52 (d, J=7. 6 Hz, 2H), 7. 21 (d, J=8. 2 Hz,. 262 403 CH CH methoxy-2-methyl-1H), 7. 02 (t, J=8. 2, 7. 0 Hz, 1H), 6. 83 (d, J=8. 2 Hz, 1H), 33 H3Cuow phenylamino)-6. 71-6. 53 (m, 3H), 6. 32-6. 30 (m, 1H), 4. 94 (bs, 2H), 4. 45 methyl]-benzamide (d, J=5. 9 Hz, 2H), 3. 65 (s, 3H), 2. 23 (s, 3H). N N-(2-Amino-1H-NMR (DMSO-de, 6 (ppm) : 9. 65 (bs, 1H), 7. 98 (d, 11 H phenyl)-4-[(2-J=7. 4 Hz, 2H), 7. 56 (d, J=7. 5 Hz, 2H), 7. 19 (d, J=7. 9 Hz, 263 40. 4 CH CH cyano-4-methoxy-1H), 6. 99 (d, J= 7. 5 Hz, 1H), 6. 82 (d, J=7. 9 Hz, 1H), 6. 63 33 H C Jl, J phenylamino)- (t, J=6. 6 Hz, 2H), 6 27 (s, 1H), 4. 93 (bs, 2H), 4. 55 (d, o methyl]-benzamide J=5. 3 Hz, 2H), 3. 69 (s, 6H). N-(2-Amino-1H-NMR (DMSO-d6, 6 (ppm) : 9. 62 (s, 1H), 8. 72 (s, phenyl)-4-{[4-1H), 8. 49 (d, J =10. 1 Hz, 1H), 7. 93 (d, J =7. 9 Hz, 2H), H methoxy-3-7. 68 (d, J = 6. 6 Hz, 1H), 7. 37 (d, J = 7. 5 Hz, 2H), 7. 16 (d, 264 405 No N ; CH CH'din-3-J=7. 5 Hz l t. 5 (pyn, H), 6. 97 (t, J = 7. 5 Hz, 1H), 6. 78 (d, J =7. 9 Hz, 33 HsC ylmethoxy)-1H), 6. 69 (d, J = 8. 8 Hz, 1H), 6. 62 (d, J=7. 5 Hz, 1H), 6. 23 phenylamino]- (d, J =2. 6 Hz, 1H), 6. 09 (J=8. 8 Hz, 1H), 5. 76 (s, 1H), 4. 64 methyl}-benzamide (bs, 4H), 3. 62 (s, 3H). H 2- [4- (2-Amino-'H-NMR (DMSO-d6), 5 (ppm) : 9. 67 (bs, 1H), 8. 00 (d, 0 phenylcarbamoyl)-J=7. 9 Hz, 2H), 7. 54 (d, J=7. 9 Hz, 2H), 7. 34 (s, 1H), 7. 20 265 406 H3Cs a1 OH CH CH benzylamino]-4, 5- (d, J= 7. 9 Hz, 2H), 7. 0 (t, J=7. 9 Hz, 1H), 6. 82 (d, J=7. 9 33 o dimethoxy-benzoic Hz, 1H), 6. 62. (t, J=7. 9 Hz, 1H), 6. 31 (s, 1H), 4. 95 (bs, o acid 2H), 4. 62 (bs, 2H), 3. 75 (s, 3H), 3. 70 (s, 3H). Ex. Cpd Z Name Characterization Schm H N-(2-Amino-1H-NMR (DMSO-d6 6 (ppm) : 9. 60 (s, 1H), 7. 93 (d, H3C pheny)-4- [ (3, 5- J=7. 9 Hz, 2H), 7. 45 (d, J=7. 9 Hz, 2 H), 7. 16 (d, J=7. 5 Hz, 266 407 CH CH dimethyl-1H), 6. 97 (t, J= 7. 5 Hz, 1H), 6. 78 (d, J=7. 9 Hz, 1H), 6. 58 33 phenylamino)- (t, J= 7. 0 Hz, 1H), 6. 19-6. 17 (m, 3H), 4. 88 (s, 2H), 4. 32 __ methyl]-benzamide (d, J=5. 7 Hz, 2H), 2. 10 (s, 6H). H N-(2-Amino-1H-NMR (DMSO-d6, 6 (ppm) : 9. 65 (s, 1H), 8. 72 (s, phenyl)-4-f [4-1H), 8. 54 (s, 1H), 8. 49 (d, J=10. 9 Hz, 1H), 7. 97 (d, J=7. 9 267 408 CH (pyridin-3-Hz, 2H), 7. 71 (d, J=7. 9 Hz, 1H), 7. 44 (d, J=8. 3 Hz, 2H), 33 p ylmethoxy)-7. 41-7. 36 (m, 1H), 7. 20 (d, J=7. 9 Hz, 1H), 7. 00 (t, J= 7. 4 phenylamino]-Hz, 1H), 6. 83 (d, J=7. 0 Hz, 1H), 6. 70-6. 60 (m, 4H), 4. 62 methyl}-benzamide (s, 4H). N 1H-NMR (DMSO-d6, 6 (ppm) : 9. 58 (s, 1H), 7. 90 (d, cH3 H phenyl)-4- [ (2, 4- J=7. 9 Hz, 2H), 7. 45 (d, J=7. 5 Hz, 2H), 7. 15 (d, J=7. 5 Hz, 268 409 Ar CHCHdSyI-"" 33 268 409 N" CH CH dimethyl-1 6. 96 (t, J=7. 5 Hz, 1H), 6. 79 (s, 1H), 6. 76 (d, J=9. 6 33 i phenylamino)-Hz, 1H), 6. 68 (d, J=7. 9 Hz, 1H), 6. 59 (t, J=7. 0 Hz, 1H), methyl]-benzamide 3H) ; 2. 10 (s, 3H). 2H), 2. 15 (s, 3H), 2. 10 (s, 3H). N (2-Amino-y CH3 H H-NMR (CD30D), 5 (ppm) : 7. 91 (d, J=7. 9 Hz, 2H), phenyl)-4- [ (2 ; 4, 6- 269 410 N"'CH CH trimethyl-7. 43 (d, J=8. 5 Hz, 2H), 7. 18 (d, J=7. 5 Hz, 1H), 7. 08 (t, _ J=7. 5 Hz, 1H), 6. 92 (d, J=7. 9 Hz, 1H), 6. 77 (s, 3H), 4. 15 33 H3C CH3 (bs, 2H), 2. 19 (s, 9H). methyl]-benzanude N (2-Amino-iH (300 MHz, DMSO-D6) 8 *** (p.) : 9. 66 (s, phenyl)-4- [ (4- o H [ (4- 1H), 7. 97 (d, J = 8. 0 Hz, 2H), 7. 82 (m, 1H), 7. 47 (d, J = chloro-6- .,,, \/< cmoro-o 7. 7Hz, 2H), 7. 21 (d, J=8. 2Hz, lH), 7. 03 (dd, J 7. 1, 7. 1 Hz, 1H), 6. 84 (d, J = 7. 7 Hz, lH), 6. 65 (dd, J = 7. 4, I-zyN pyrimidin-2-7. 1 Hz, 1H), 6. 84 (d, J 7. 7 Hz, 1H), 6. 65 (dd, J 7'4, ylamino)-methyl]-S. g Hz, 2H), 3. 58 (m, 4H), 3. 62 (m, 4H). benzaxnide Ex. Cpd W Y Z Name Characterization Schm N-(2-Amino-1E NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 33 (s, 1H), Meo phenyl)-4- (3, 4, 5- 7. 81 (d, J = 8 : 8 Hz, 2H), 7. 19 (d, J = 7. 7 Hz, 1H), 6. 99 (m, 271 412 Meo CH CH trimethoxy-1H), 6. 87 (dd, J = 6. 0, 5. 8Hz, 1H), 6. 82 (m, 1H), 6. 77 (s, 33 OMe benzylamino)-2H), 6. 71 (d, J = 8. 8 Hz, 2H), 6. 64 (m, 1H), 4. 87 (s, 2H, benzamide NH2), 4. 32 (d, J = 5. 5 Hz, 2H), 3. 81 (s, 6H), 3. 79 (s, 3H). N-(2-Amino-1H NMR (300 MHz, DMSO-d6) 8 8 (ppm) : 9. 31 (s, 1H), phenyl)-4- (4- 7. 79 (dj J = 8. 7 Hz, 2H), 7. 45 (dd, J = 5. 8, 8. 5 Hz, 2H), 272 413 FX H CH CH fluoro-7. 21 (m, 3H), 6. 91 (m, 2H), 6. 81 (dd, J = 1. 1, 8. 0Hz, 1H), 33 benzylamino)-6. 67 (d, J = 8. 8 Hz, 2H), 6. 62 (dd, J = 1. 0, 7. 2 Hz, 1H), benzamide'4. 86 (s, 2H, NHZ), 4. 39 (d, J = 6. 0 Hz, 2H). N-(2-Amino--1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 31 (s, 1H), N phenyl)-4- (4- 7. 79 (dd, J = 1. 1, 8. 5 Hz, 2H), 7. 33 (d, J = 7. 1 Hz, 2H), 273 414 josh CH CH methoxy-7. 19 (d, J =7. 7 Hz, 1H), 6. 97 (m, 3H), 6. 84 (m, 2H), 6. 65 33 MeO benzylamino)- (m, 3H), 4. 86 (s, 2H, NH2), 4. 33 (d, J = 5. 5 Hz, 2H), 3. 58 benzamide (d, J =1. 6 Hz, 3H). N-(2-Amino 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 66 (s, 1H), H phenyl)-4- [ (4'- 7. 99 (d, J = 7. 9 Hz, 2H), 7. 53 (d, J = 8. 0 Hz, 2H), 7. 21 (d, i. ; J = 8. 0 Hz, 1H), 7. 02 (ddd J =1. 6, 7. 1, 8. 2 Hz, 1H), 6. 93 'FH phenylamino) (dd, J =8. 8, 9 Hz, 2H), 6. 83 (dd, J =1. 1, 8. 0 Hz, 1H), 6. 63 33 p y) (m, 3H), 6. 35 (t, J= 6. 2 Hz, 1H), 4. 94 (s, ZH, NHZ), 4. 38 methyl]-benzamide (d, J = 6. 3 Hz, 2H). N- (2-Amino- 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 32 (s, 1H), _ 7. 79 (d, J = 8. 8 Hz, 2H), 7. 44 (m, 1H), 7. 26 (m, 1H),, 7. 18 275 416 H CH CH fluoro- (dd, J = 1. 4, 8. 0 H :, 2H), 7. 12 (ddd, J =1. 7, 8. 0, 8. 2 Hz, H CH CH "- 33 benzylamino)-1 6. 99 (m, 2H), 6. 81 (dd, J =1. 4, 8. 0 Hz, 1H), 6. 67 (dd, b'd J = 1. 6, 8. 8 Hz, 2H), 6. 62-(dd, J= 1. 4, 7. 4 Hz, 1H), 4. 87 (s, . enzaml e 2H, NH2), 4. 45 (d, J = 6. 0 Hz, 2H). Ex. Cpd Z Name Characterization Schm N- (2-Amino-'H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 66 (s, 1H), H 7. 99 (d, J = 8. 2 Hz, 2H), 7. 52 (d, J = 8. 0 Hz, 2H), 7. 21 (d, 276 417 I CH CH fluoro-J = 7. 7 Hz, 1H), 6. 99-7. 14 (m, 2H), 6. 83 (d, J = 8. 0 Hz, 33 '" . 1H), 6. 76 (m, 1H), 6. 64 (dd, J =7. 4, 7. 4 Hz, 1H), 6. 46 (d, y phenylamino)- methylj-benzamide j=6. QHz, 2H). J=6. OHz, 2 N- (2-Amino- H phenyl)-4-[(4-1H NMR (300 MHz, DMSO-D6) 8 (ppm) : 9. 66 (s, 1H), CI N N 8. 23 (m, 1H), 7. 98 (d, J = 8. 2 Hz, 2H), 7. 47 (d, J = 8. 5 Hz, chloro-6-methyl- 277 418 -N CH CH. 2H), 7. 21 (d, J = 7. 7 Hz, 1H), 7. 03 (ddd, J =1. 5, 7. 1, 8. 0 33 'pyrimidin-2- 1H), 6. 83 (dd, J =1. 5, 8. 1 Hz, 1H), 6. 65 (m, 2H), Me 4. 94 (s, 2H,m, 4. 61 (m, 2H), 2. 3 2 (s,]. benzamide 4. 94 (s, 2H, NH2), 4. 61 (m, 2H), 2. 3 2 (s, 3H). N-(2-Amino-1H NMR (300 MHz, DMSO-D6) 8 (ppm) : 9. 69 (s, 1H), CI N N phenyl)-4- [ (4, 6- 8. 82 (m, 1H), 7. 99 (d, J = 8. 2 Hz, 2H), 7. 48 (d, J = 8. 0 Hz, 278 419 iìr CH CH dichloro-pyrimidin-2H), 7. 27 (d, J = 7. 7 Hz, 1H), 7. 04 (d, J = 7. 7 Hz, 1H), 33 2-ylamino)-7. 0 (d, J = 1. 6 Hz, 1 H), 6. 84 (d, J = 8. 2Hz, 1H), 6. 67 (m, ci methyl]-benzamide 1H), 5. 0 (bs, 2H, NH2), 4. 60 (d, J = 6. 3 Hz, 2H). N- (2-Amino- H H'phenyl)-4-({4-1H NMR (300 MH : z, DMSO-D6) 8 (ppm) : 9. 87 (s, 1H), N N N", chloro-6- [ (pyridin- 8. 49 (bs, 2H), 7. 26-8. 02 (bm, 8H), 7. 22 (d, J = 8. 0 Hz, 279 420 1 TON CH CH 3-ylmethyl)-1H), 7. 03 (dd, J = 7. 4, 7. 4 Hz, 1H), 6. 84 (d, J = 8. 2 Hz, 24, 33 N ß ci amino]-pyrimidin-1H), 6. 66 (dd, J = 7. 1, 8. 0 Hz, 1H), 5. 86 (bs, 1H), 4. 95 (s, 2-ylamino}-2H, NH2), 4. 51 (m, 2H). methyl)-benzamide 1H NMR (300 MHz, DMSO-D6) 8 (ppm) : 9. 66 (s, 1H), N- (2-Amino- 7. 99 (d, J = 8. 4 Hz, 2H), 7. 54 (d, J = 7. 9 Hz, 2H), 7. 50 (d, N phenyl)-4-[(6-J = 2. 6 Hz, 1H), 7. 21 (d, J = 7. 5 Hz, 7. 9 Hz, 1H), 7. 12 421 CH CH methoxy-pyridin-3- (dd, J=3. 08Hz, 8. 79 Hz, 1H), 7. 02 (dd, J = 7. 0 Hz, 7. 5 33 MeO N ylamino)-methyl]-Hz, 1H), 6. 83 (d, J= 7. 0 Hz, 1H), 6. 65 (m, 2H), 6. 15 (t, J benzamide = 6. 16 Hz, 1H), 4. 94 (s, 2H, NH2), 4. 39 (d, J = 6. 15 Hz, 2H), 3. 75 (s, 3H). Ex. Cpd W _ z Name Characterization Schm N- (2-Amino- 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 66 (s, 1H), H phenyl)-4- [ (4- 7. 99 (d-, J = 8. 0 Hz, 2H), 7. 53 (d, J = 8. 2 Hz, 2H), 7. 21 (d, J = 7. 7 Hz 1H) 7. 09 (d J = 9. 1 Hz 2H) 7. 03 (dd, J = 281 422 E N"CH CH trifluoromethoxy-'''''33 F3co 7. 1, 8. 2 Hz, 1H), 6_83 (d, J = 8. 0 Hz, 1H), 6. 71 (t, J = 6. 0 phenylamino)- 1 6. 63-6. 67 (m, 3H), 4. 94 (s, 2H, NH2), 4. 42 (d, J methyl]-benzamide = 6. 0 Hz, 2H). - O. UJrLZ, ZjnL). H'N-(2-Amino-H NMR (300 MHz, DMSO-d6) 6 (ppm) : 9. 67 (s, 1H), phenyl)-4- [ (3- 8. 00 (d, J = 8. 2 Hz, 2H), 7. 53 (d, J = 8. 2 Hz, 2H), 7. 19 (m, 282 423 wu CH CH trifluoromethoxy-2H), 7. 03 (ddd, J = 1. 5, 8. 0, 8. 8 Hz, 1H), 6. 85 (m, 2H), 33 OCF phenylamino)-6. 63 (m, 2H), 6. 55 (s, 1H), 6. 50 (m, 1H), 4. 94 (s, 2H, methyl]-benzamide NH2), 4. 44 (d, J = 6. 0 Hz, 2H). 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 65 (s, 1H), N- (2-Amino- 7. 98 (d, J = 7. 9 Hz, 2H), 7. 54 (d, J = 7. 9 Hz, 2H), 7. 22 (d, N phenyl)-4- [ (3, 4- J = 7. 9 Hz, 1H), 7. 02 (dd, J = 7. 9 Hz, 7. 9 Hz, 1H), 6. 83 283a 424b MeO CH CH methoxy- (d, J = 7. 9 Hz, 1H), 6. 72 (d, J = 8. 79 Hz, 1H), 6. 45 (dd, J 33 phenylamino)-= 7. 49 Hz, 7. 49 Hz, 1H), 6. 39 (d, J = 2. 2 Hz, 1H), 6. 01- OMe methyl]-benzamide 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). N- (2-Amino-'H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 31 (s, 1H), 7. 80 (d, J = 8. 8 Hz, 2H), 7. 45-7. 56 (m, 2H), 7. 39 (s, 1H), phenyl)-4- (3- 7. 29 (d J = 7. 7 Hz, 1H), 7. 18 (d, J = 6. 6 Hz, 1H), 6. 96- 284 425 CH CH trifluoromethoxy-'33 ocF3 benzylamino)-7-03 (m, 2H), 6. 81 (d, J = 6. 9 Hz, 1H), 6. 68 (d, J = 8. 8 Hz, benzamide 2H), 6. 64 (d, J = 7. 7 Hz, 1H), 4. 86 (s, 2H, NHZ), 4. 48 (d, J = 5. 8 Hz, 2H). N- (2-Amino-'H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 31 (s, 1H), phenyl)-4- (4- 7. 79 (d J = 8. 8 Hz, 2H), 7. 54 (d, J = 8. 8 Hz, 2H), 7. 39 (d, J = 8. 0 Hz, 2H), 7. 18 (dd, J = 1. 4, 7. 7 Hz, 1H), 6. 99 (dud, 285 426 F co H CH CH trifluoromethoxy-J =1. 4, 8. 0, 8. 5 Hz, 2H), 6. 81 (dd, J =1. 4, 8. 0, 1H), 6. 68 33 benzamide (d, J = 8. 8 Hz, 2H), 4. 85 (s, 2H, NH2), 4. 45 (d, J = 6. 0 Hz, benzamlde. 2H). Ex. Cpd W Y Z Name Characterization Schm 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 64 (s, 1H), N- (2-Amino- 7. 97 (d, J = 8. 2 Hz, 2H), 7. 53 (d, J = 8. 5 Hz, 2H), 7. 21 (d, H phenyl)-4- [ (4- J=1. 4, 8. 0 Hz, 1H), 7. 02 (ddd, J = 1. 4, 7. 4, 8. 0 Hz, 1H), 286 427 S wa CH CH methoxy-6. 83 (dd, J = 1. 4, 8. 0 Hz, 1H), 6. 74 (m, 2H), 6. 65 (ddd, J 33 Meo" phenylamino)-= 1. 4, 7. 7, 8. 8 Hz, 1H), 6. 58 (m, 2H), 5. 99 (t, J = 6. 3 Hz, methyl]-benzamide 1H), 4. 93 (s, 2H, NH2), 4. 36 (d, J = 6. 0 Hz, 2H), 3. 68 (s, 3H). 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 65 (s, 1H), N- (2-Amino- 7. 98 (d, J = 7. 9 Hz, 2H), 7. 52 (d, J = 7. 9 Hz, 2H), 7. 21 (d, , wNs S_ phenyl)-4-J = 7. 5 Hz, 1H), 7. 02 (dd, J = 7. 0, 7. 0 Hz, 1H), 6. 83 (d, J 287 428 CH CH (benzo [1, 3] dioxol- = 7. 5 Hz, 1H), 6. 63-6. 69 (m, 2H), 6. 33 (d, J = 2. 2 Hz, 33 5-ylaminomethyl)-1H), 6. 15 (t, J = 6. 16 Hz, 1H), 6. 04 (dd, J = 2. 2j 8. 4 Hz, benzamide 1H), 5. 86 (s, 2H), 4. 94 (s, 2H, NHZ), 4. 35 (d, J = 6. 16 Hz, 2H). N- (2-Amino- 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 63 (s, 1H), H phenyl)-4- [ (2- 7. 90 (d, J = 8. 2 Hz, 2H), 7. 52 (d, J = 8. 2 Hz, 2H), 7. 22 (d, J = 7. 7 Hz 1H) 7. 02 (ddd J =1. 4 _71, 8. 0 Hz 1H) 6. 86 288 429 --CH CH mxy"' = J ''T'' ? 7 33 onze phenylamino)- () (3H) 6. 43 (du J =1 6 7. 7 Hz 1H) methyl]-benzamide 5. 75 (t, J = 6. 3 Hz, I H), 4. 93 (s, 2H, NH2), 4. 47 (d, J = 6. 3 Hz, 2H), 3. 88 (s, 3H). thyl]-benzam. de .. H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 61 (s, 1H), . 1H NMR (300 MHzj DMSO-d6) 6 (ppm) : 9. 61 (s, 1H), N'-phenyl)-4- [ (3- H 7. 98 (d, J =1. 1, 7. 7 Hz, 1H), 7. 97-7. 05 (m, 2H), 6. 82 (dd, J= phenylamino)-1. 2, 8. 1 Hz, 1H), 6. 46 (ddd, J 1. 4, 7. 7, 8. 0 Hz, 1H), 6. 41 33 OMe phenylammo)- (t, J = 6. 3 Hz, 1H), 6. 16-6. 25 (m, 3H), 4. 93 (s, 2H, NH2), 4. 39 (d, J = 6. 0 Hz, 2H), 3. 69 (s, 3H). N-(2-Amino-1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 11. 53 (s, 1H), o phenyl)-4- (2, 2, 2- 9. 71 (s, 1H), 8. 08 (d, J = 8. 2 Hz, 2H), 7. 86 (d, J = 8. 8 Hz, 290 431 F3C) 4NX CH CH tnRuoro-2H), 7. 23 (d, J = 7. 6 Hz, 1H), 7. 03 (dd, J = 7. 0, 7. 6 Hz, 14 acetylamino)-1H), 6. 84 (d, J = 8. 2 Hz, 1H), 6. 66 (dd, J = 7. 0, 7. 6 Hz, benzamide 1H), 4. 96 (s, 2H, NHz). Ex. Cpd W Y Z Name Characterization Schm N- (2-Amino- H H phenyl)-4-{[4-1H NMR (300 MH : z, DMSO-d6) 8 (ppm) : 9. 64 (s, 1H), N N \, chloro-6-(3, 4, 5- 7. 95 (d, J = 7. 5 Hz, 2H), 7. 70 (bs, 2H), 7. 45 (d, J = 8. 4 291 432-. N CH CH methoxy Hz, 2H), 7. 22 (d, J = 7. 9 Hz, 1H), 7. 03 (dd, J = 7. 0, 7. 5 24, 33 MeO ci benzylamino)-Hz, 1H), 6. 84 (d, J = 7. 9, Hz, 1H), 6. 60-6. 72 (m, 3H), MeO OMe pyrimidin-2-5. 87 (s, 1H), 4. 93 (s, 2H, NH2), 4. 54 (d, J = 6. 2 Hz, 2H), ylamino]-methyl}-4. 43 (bs, 2H), 3. 78 (s, 6H), 3. 68 (s, 3H). benzamide N- (2-Amino- chlorol 6 (3 445-1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 65 (s, 1H), MeO N tri etho 9. 43 (s, 1H), 7. 97 (m, 3H), 7. 46 (bs, 2H), 7. 21 (d, J = 7. 5 trimethoxy- 292 433 I CH. CH Hz 1H) 7. 02 (m 3H) 6. 83 (d J = 7. 0 Hz, 1H), 6. 65 (du 24, 33 Me0 \ N phenylamino)-'''''' oMe ci pyrmrndin-2-J = 7. 5, 7. 5 Hz, 1H), 6. 08 (s, 1H), 4. 93 (s, 2H, NH2), 4. 69 i. (bs, 2H), 3. 65 (s, 9H). ylammo]-methyl}-"'- benzamide N-(2-Amino-1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 31 (s, 1H), N-V phenyl)-4- (3, 4- 7. 79 (d, J = 8. 8 Hz, 2H), 7. 19 (d, J = 7. 9 Hz, 2H), 7. 04 (s, 293 434 MeO H CH CH dimethoxy-1H), 6. 92-7. 01 (m, 3H), 6. 80-6. 87 (m, 2H), 6. 69 (d, J= 33 OMe benzylamino)-8. 8 Hz, 2H), 6. 62 (m, 1H), 4. 87 (s, 2H, NHZ), 4. 32 (d, J = benzamide 5. 7 Hz, 2H), 3. 80 (s, 3H), 3. 78 (s, 3H). N-(2-Amino-1H NMR (300 MHz, DMSO-d6) 6 (ppm) : 9. 64 (s, 1H), H phenyl)-4- [ (4- 7. 95 (d, J = 8. 4 Hz, 2H), 7. 87 (d, J = 7. 9 Hz, 1H), 7. 47 (d, o N N N morpholin-4-yl-J = 7. 9 Hz, 2H), 7. 31 (bs, 1H), 7. 21 (d, J = 7. 5, 1H), 7. 02 24, 1, ! {j""pyrimidm-2- (dd, J = 7. 9 Hz, 1H), 6. 83 (d, J = 7. 9 Hz, 1H), 6. 65 (dd, J= 33 ylamino)-methyl]-7. 0, 7. 0 Hz, lH), 6 09 (d, J = 6. 2 Hz, 1H), 4. 94 (s, 2H, benzamide NH2), 4. 54 (d, J = 5. 7 Hz, 2H), 3. 67 (s, 4H), 3. 53 (s, 4H). Ex. Cpd W Y Z Name Characterization Schm N- (2-Amino-'H NMR (300 MHz, DMSO-d6) 8 (ppm) : 10. 82 (s, 1H), H 9 65 (s, IH), 7. 98 (d, J = 8. 4 Hz, 2H), 7. 56 (d, J = 7. 9 Hz, 295 1436 HN CH CH indol-3-yl)-1 7-51 (d, J = 8_4 Hz, 2H), 7. 38 (d, J = 7. 9 Hz, 2H), ""- Hmdoijyi 7. 18-7. 23 (m, 2H), 7. 11 (dd, J=7. 0, 8. 0Hz, lH), 7. 01 (m," ethylamino]-2 6. 83 (d, J = 7. 9 Hz, 1H = 6. 51 (dd, J = 7. 5, 6. 6 Hz, methyl}-benzamide 1H), 4. 93 (s, 2H, Nui32), 3. 89 (s, 2H), 2. 89 (m, 4 N-(2-Amino-1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 67 (s, 1H), H phenyl)-4- [ (4- 7. 99 (d, J = 7. 5 Hz, 2H), 7. 52 (d, J = 7. 5 Hz, 2H), 7. 21 (d, 296 437 N CH CH methylsulfanyl-J = 7. 5 Hz, 1H), 7. 13 (d, J = 7. 5 Hz, 2 H), 7. 03 (dd, J = 33 Mes"phenylamino)-7. 5, 7. 5 Hz, 1H), 6. 83 (d, J = 7. 9 Hz, 1H), 6. 53 (m, 4H), methyl]-benzamide 4. 95 (s, 2H, NH2), 4. 41 (d. J = 5. 7 Hz, 2H), 2. 37 (s, 3H). N- (2-Amino- 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 66 (s, 1H), phenyl)-4- [ (3- 7. 99 (d, J = 7. 5 Hz, 2H), 7. 53 (d, J = 7. 5 Hz, 2H), 7. 21 (d, 297 438 WJ CH CH methylsulfanyl-J = 7. 5 Hz, 1H), 7. 03 (m, 2H), 6. 83 (d, J = 7. 9 Hz, 1H), 33 T phenylamino)-6. 65 (dd, J = 7. 5, 7 5 Hz, 1H), 6. 39-6. 51 (m, 4H), 4. 94 (s, methyl]-benzamide 2H, NH2), 4. 41 (d. J = 5. 7 Hz, 2H), 2. 42 (s, 3H). N-(2-Amino-1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 66 (s, 1H), Me0/phenyl)-4- { [4- _ 8. 37 (s, 1H), 7. 99 (d, J = 7. 5 Hz, 2H), 7. 68-7. 79 (m, 2H), 298 439 eo CHCHdox 7. 55 (bs, 2H), 7. 37 (s, IH), 7. 20 (d, J = 7. 1 Hz, 1H), 7. 11 298 439 ly CH CH dimethoxy-15, 33 phenyl)-pynmidin-Hz, 1, 6. 64 dd, J = 7. 5, 7. 5 Hz, 1H, 4. 93 s, 2H, NHZ, -., 4. 86 (s, 2H), 3. 88 (s, 6H). methyl)-benzamide N-(2-Amino-1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 64 (s, 1H), MeO phenyl)-4- {[4-(3, 4-8. 35 (d, J = 4. 8 Hz, 1H), 7. 97 (d, J = 7. 9 Hz, 2H), 7. 89 (m, 299 440 > H dimethoxy-1H), 7. 72 (m, 2H), 7. 55 (d, J = 7. 5 Hz, 2H), 7. 2 (d, J = 5. 3 15, 1, MeO r-r a CH CH phenyl)-pyrimidin-Hz, 2H), 7. 10 (d, J = 8. 4 Hz, 1H), 7. 01 (m, 1H), 6. 82 (d, J 33 2-ylamino]-= 7. 0 Hz, 1H), 6. 41 (t, J = 7. 5 Hz, 1 H), 4. 92 (s, 2H, NH2), methyl}-benzamide 4. 68 (d, J = 6. 2 Hz, 2H), 3. 82 (s, 6H). Ex. Cpd W Y Z Name Characterization Schm 4-[(2-Acetyl-4, 5-tH NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 68 (s, 1H), Y H dimethoxy-9. 45 (t, J = 5. 7 Hz, 1H), 8. 01 (d, J = 7. 9 Hz, 2H), 7. 54 (d, 300 441 Ns \ CH CH phenylamino)-J = 8. 4 Hz, 2H), 7. 32 (s, 1H), 7. 21 (d, J = 7. 5 Hz, 1H), 33 MeOAJ methyl]-N-(2-7. 02 (dd, J = 6. 6, 7. 5 Hz, 1H), 6. 83 (d, J = 7. 5 Hz, 1H), OMe amino-phenyl)-6. 65 (dd, J = 7. 0, 7. 5 Hz, 1H), 6. 31 (s, 1H), 4. 95 (s, 2H, benzamide NH2), 4. 63 (d, J = 5. 7 Hz, 2H), 3. 78 (s, 3H), 3. 76 (s, 3H). hen (2-Ainino-'H NMR (300 MHz, CD30D+CDC13) 8 (ppm) : 7. 99 (d, H H phenyl)-4- { [4- (3, 4- J = 7. 9 Hz, 2H), 7. 80 (d, J = 6. 2 Hz, 1H), 7. 76 (s, 1H), tw-,, dimethoxy 7. 52 (d, J = 8. 4 Hz, 2H), 7. 27 (m, 1H), 7. 14 (m, 1H), 7. 05 301 442 I N CH CH phenylamino)-1, 33 pyrimidin-2- (dd, J = 2. 2, 8. 8 Hz, 1H), 6. 95 (d, J = 7. 9 Hz, 1H), 6. 88 (d, Me0 OMe ylamino]-methyl}-J8. 8 Hz, 1H), 6 83 (d, J = 7. 9 Hz, 1H), 6. 08 (d, J = 6. 2 benzarnide Hz, IH), 4. 75 (s, 2H), 3. 79 (s, 3H), 3. 42 (s, 3H). N-(2-Amino-1H NMR (300 MHz, DMSO-d6) 6 (ppm) : 9. 66 (s, 1H), H3C phenyl)-4- { [ [2- 7. 96 (d, J = 8. 4 Hz, 2H), 7. 42 (d, J = 7. 9 Hz, 2H), 7. 20 (d, H3C CH3 (tert-butyl-J = 7. 5 Hz, 1H), 7. 02 ( (dd, J = 6. 6, 8. 4 Hz, 1H), 6. 83 (d, J 302 443 CH CH dimethyl-= 7. 0 Hz, 1H), 6. 77 (d, J = 8. 8 Hz, 1H), 6. 65 (dd, J = 7. 0, 33 silanyloxy)-ethyl]-7. 0 Hz, 1H), 6. 44 (d, J = 2. 6 Hz, 1H), 6. 19 (dd, J=2. 6, (3, 4-dimethoxy- 8. 8 Hz, 1H), 4. 93 (s, 2H), 4. 67 (s, 2H), 3. 88 (t, J = 5. 7 Hz, Me0 \ MeO phenyl)-amino]-2H), 3. 71 (s, 3H), 3. 67 (s, 3H), 3. 60 (t, J = 5. 5 Hz), 0. 96 methyl}-benzamide (s, 9H), 0. 06 (s, 6H). N-(2-Amino-1H NMR (300 MHz, DMSO-d6) 6 (ppm) 8 (ppm) : 9. 65 tOH phenyl)-4-{[(3, 4- (s, 1H), 7. 96 (d, J = 7. 5 Hz, 2H), 7. 42 (d, J = 7. 5 Hz, 2H), dimethoxy-7. 21 (d, J = 7. 5 Hz, 1H), 7. 02 ( (dd, J = 7. 0, 7. 5 Hz, 1H), 303 444 N CH CH phenyl)- (2- 6. 83 (d, J = 7. 9 Hz, 1H), 6. 78 (d, J= 8. 8 Hz, 1H), 6. 65 33, 23 J hydroxy-ethyl)- (dd, J = 7. 0, 7. 5 Hz, 1H), 6. 44 (s, 1H), 6. 19 (d, J = 8. 8 Hz, OMe amino]-methyl}-1H), 4. 94 (s, 2H), 4. 79 (m, 1H), 4. 66 (s, 2H), 3. 67 and benzamide 3. 71 (2s and broading underneath, 8H), 3. 55 (m, 2H). Ex. Cpd W Y Z Name Characterization Schm N-(2-Amino-1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 82 (s, 1H), H phenyl)-6- [ (3, 4, 5- 9. 13 (s, 1H), 8. 33 (d, J = 8. 0 Hz, 1H), 7. 56 (d, J = 8. 5 Hz, Me0 N ttmethoxy-IH), 7. 21 (d, J = 7. 7 Hz, 1H), 7. 03 ( (dd, J = 7. 4, 7. 7 Hz, 304-445 I CH N-33 MeO~ß/phenylamino)-1H), 6. 82 (d, J = 8. e Hz, 1H), 6. 40 (dd, J = 7. 4, 7. 7 Hz, OMe methyl]-1H), 6. 31 (t, J = 5. 8 Hz, 1H), 5. 96 (s, 2H), 5. 01 (s, 2H), nicotinamide 4. 48 (d, J = 5. 8 Hz, 2H), 3. 70 (s, 6H), 3. 56 (s, 3H). N-(2-Amino-1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 8. 69 (d, J = 2. 2 11 H phenyl)-6- [2- (4- Hz, 1H), 8. 46 (s, 1H), 8. 40 (d, J = 8. 8 Hz, 1H), 8. 32-8. 36 305 446 XN~N>s CH N oxo-4H-quinazolin- (m, 1H), 7. 91-7. 96 (m, 1H), 7. 77 (m, 1H), 7. 67 (m, 1H) 3 3-yl)-ethylamino]-7. 5 (m, 4H), 7. 2 (s, 1H), 4. 46 (t, J = 5. 9 Hz, 1H), 4. 09 (t, J nicotinamide = 5. 9 Hz, 2H). N-(2-Amino-1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 37 (s, 1H), N phenyl)-4- [bis- (3- 7. 84 (d J = 8. 8 Hz, 2H), 7. 54 (dd, J = 7. 9, 7. 9 Hz, 2H), 306 447 F3COv Vq CH CH trifluoromethoxy-7. 18-7. 37 (m, 6H), 7. 17 (d, J = 7. 0 Hz, 1H), 6. 99 (dd, J = 33 wOCF3 benzyl)-arnino]-7. 0, 7. 9 Hz, 1H), 6. 82 (m, 3H), 6. 63 (dd, J = 7. 5, 7. 5 Hz, benzamide 1H), 4. 94 (s, 4H), 4. 86 (s, 2H). N- (2-Amino-'H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 58 (s, 1H), phenyl)-4- [ (2- 7. 92 (d, J = 7. 9 Hz, 2H), 7. 49 (d, J = 7. 9 Hz, 2H), 7. 34 (d, HgC N NHv' J = 8. 8 Hz, 1H), 7. 15 (d, J = 7. 5 Hz, 1H), 6. 96 (t, J = 7. 9 N 307 448 CH CH 11-1), 6. 76 (d, J = 7. 9 Hz, 11-1), 6. 59. (d, J = 7. 5 Hz, 33 Hz benzamide, ' ' '" ylamino)-methyl]-iiz, benzamide-1H), 4. 88 (bs, 2H), 4. 37 (d, J = 5. 7 Hz, 2H), 3. 06 (s, 6H). N- (2-Amino-'H NMR (300 MHz, DMSO-d6) 8 (ppm) : 10. 2 (s, 1H), H phenyl)-4- [ (2-oxo- 10. 1 (s, 1H), 9. 62 (s, 1H), 7. 94 (d, J = 7. 9 Hz, 2H), 7. 41 NHv, 1 (d, J = 7. 9 Hz, 2H), 7. 15 (d, J = 7. 5 Hz, 1H), 6. 96 (t, J = 308 449 H CH CH CH ,-7. 5Hz, lH), 6. 77 (d, J = 7. 9 Hz, 1H), 6. 69 (d, J = 8. 4 Hz, 33 benzoimidazol-5-J = 8. 4 Hz 33 ylamino ?-methyl]-6. 34 (t, J = 7. 5 Hz, 1H), 6. 34 (d, J = 8. 4 Hz, 1H), benzamide 6. 34 (t, J = 8. 4 Hz, 1H), 6. 30 (s, 1H), 4. 89 (bs, 2H), 4. 72 (s, 2H). Ex. Cpd W Y Z Name Characterization Schm o 1H NMR (300 MHz, DMSO-d6) 6 (ppm) : 9. 60 (s, 1H), N- (2-Amino- NH phen 1-4 4 7. 94 (d, J = 7. 9 Hz, 2H), 7. 46 (d, J = 7. 9 Hz, 2H), 7. 35. (d, N /NHZ y)- [ (-J = 8. 4 Hz 2H) 7. 15 (d, J = 7. 9 Hz 1H) 7. 11 (d, J = 6. 2 309 450 CH CH trifluoromethylsulf''''33 vt ( = 7. 0 Hz, 1H), 6. 77 (d, J = 7. 5 Hz, 1H), Tmethyl]-bcnzamide j _ F 2H), 4. 72 (d, J = 6. 2 Hz, 2H). N- (2-Amino- 1H NMR (300 MHz, CD30D) 8 (ppm) : 8. 67 (d, J = 1. 8 phenyl)-4- { [2- Hz, 1H), 8. 47 (dd, J = 1. 3, 4. 4 Hz, 1H), 8. 08 (s, IH), 8. 03 . (d, J = 7. 9 Hz, 2H), 7. 92 (d, J = 8. 4 Hz, 1H), 7. 87 (d, J = /\ N \ NHv (pyridin-3- 7. 9 Hz, 2H), 7. 58 (d, J = 8. 4 Hz, 1H), 7. 36-7. 30 (m, 3H) ; 310 451 N s-- CH CH ylmethylsulfanyl)-33 7. 20-7. 15 (m, 1H) ; 7. 08 (dt, J =1. 3, 8. 4 Hz, 1H), 6. 94 H 1H-benzoimidazol- (dd, J = 1. 3, 7. 9 Hz, 1H), 6. 77 (d, J = 2. 2 Hz, 1H), 6. 74 (d, 5-ylamino]- methyl)-benzamide J = 2. 2 Hz, 1H), 6. 65 (d, J =1. 8 Hz, 1H), 4. 55 (s, 2H) ; 4. 20 (bs, 2H) ; 3. 36 (s, 2H). N-(2-Amino-1H NMR (300 MHz, CD30D) 8 (ppm) : 8. 60 (s, 1H), 8. 36 phenyl)-4-{[2- (d, J = 4. 4 Hz, 1H), 7. 89 (d, J = 7. 9 Hz, 2H), 7. 87 (m, (pyridin-3-1H) ; 7. 47 (d, J = 7. 9 Hz, 2H), 7. 30 (t, J = 6. 6 Hz, 1H), 311 452 N=/\S/, v CH CH ylmethylsulfanyl)-7. 20-7. 15 (m, 2H) ; 7. 04 (t, J = 7. 5 Hz, 1H), 6. 87 (d, J= 33 benzooxazol-5-7. 9 Hz, 1H), 6. 73 (t, J = 7. 5 Hz, 1H), 6. 66 (s, 1H) ; 6. 61 (d, ylamino]-methyl}-J = 8. 8 Hz, 1H), 4. 87 (s, 2H) ; 4. 45 (s, 2H) ; 4. 37 (s, 2H) ; benzamide3. 35 (s, 2H). N- (2-Amino-5- ,. NH 3 = ''- '- - = - | H CNH l of4 (d, J 8. 4Hz 2 9, 7. 54 (n, IH) ; 7. 51 (d r-8. 4 Hz, 312 453 Me0 N w NHZ 2H) ; 7. 41-7. 34 (m, 2H) ; 6. 87 (d, J = 8. 4 Hz, 1H) ; 7. 77 (d, 33 A. J = 8. 4 Hz, 1H) ; 6. 35 (d, J = 2. 2 Hz, 1H) ; 6. 20 (dd, J = Me0 F3C phenylamino)- methyl]-benzamide 22, 8. 8 Hz, 1H) ; 4. 43 (s, 2H) ; 4. 29 (s, 2H) ; 3. 84 (s, 6H). methyl]-benzamide Ex. Cpd W Y Z Name Characterization Schm N-(2-Amino-4, 5-1H NMR (300 MHz, CDC13) 8 (ppm) : 8. 21 (s, 1H) ; 7. 84 n NH difluoro-phenyl)-4- (d, J = 7. 9 Hz, 2H) ; 7 45 (d, J = 7. 9 Hz, 2H) ; 7. 20 (dd, J = 313 454 MeO N qNH [ (3, 4-dimethoxy- 2. 6, 8. 4 Hz, 1H) ; 6. 76 (d, J = 8. 8 Hz,. 1H) ; 6. 57 (dd, J = 33 Meo FK phenylamino)-3. 9, 7. 9 Hz, 1H) ; 6. 32 (d, J = 2. 6 Hz, 1H) ; 6. 16 (dd, J = F methyl]-benzamide 2. 6, 8. 4 Hz, 1H) ; 4. 40 (s, 2H) ; 3. 82 (s, 9H). N-(2-Amino--1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 60 (s, 1H) ; H NH phenyl)-4-[(2-oxo-7. 93 (d, J = 7. 9 Hz, 2H) ; 7. 47 (d, J = 7. 9 Hz, 2H) ; 7. 16 (d, 314 455 CH CH 2, 3-dihydro- J 7. 5 Hz, 1H) ; 6. 97 (m, 2H) ; 6. 78 (d, J = 7. 5 Hz, 1H) ; 33 benzooxazol-5-6. 59 t, J = 7. 5 Hz ; lI ; 6. 35 (t, J = 5. 7 Hz, 1H) ; 6. 27 (m, benzamide 2H) ; 4. 88 (bs, 2H) ; 4. 34 (d, J 6. 2 Hz, 2H). benzamlde N-(2-Am 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 7. 92 (d, J = phenyl)-4- [ (2- 7. 9 Hz, 2H), 7. 66 (d, J = 4. 4 Hz, 1H), 7. 49 (d, J = 7. 9 Hz, NH 2H), 7. 26 (d, J = 8. 4 Hz, 1H), 7. 15 (d, J = 7. 9 Hz, 1H), 315 456 MEHN CH CH benzothiazol-5-6. 96 (d, J=8. 4Hz, IH), 6. 59 (t, J=7. 9Hz, lH), 6. 53 (s, 33 1H),) ; 6. 40 (dd, J =1. 3, 8. 4 Hz, 1H) ; 6. 28 (t, J = 5. 7 Hz, ylamino)-methyl]- benzamide 1H), 4. 88 (bs, 2H), 4. 36 (d, J = 5. 7 Hz, 2H), 2. 85 (d, J = 4. 4 Hz, 3H). o H2N N-(2, 6-Diamino-1H NMR (300 MHz, CDC13) 8 (ppm) : 8. 09 (s, 1H) ; 7. 88 phenyl)-4- [ (3, 4- (d, J = 7. 5 Hz, 2H) ; 7. 48 (d, J = 7. 5 Hz, 2H) ; 6. 97 (d, J = 316 457 MeO NHsX Hv dimethoxy-7. 9 Hz, 1H) ; 6. 73 (d, J = 8. 4 Hz, 2H) ; 6. 64 (d, J = 7. 9 Hz, 33 316 457 Meo N w Y W () ( S H2N phenylamino)-1H) ; 6. 29 (s, 1H) ; 6. 14 (d, J = 8. 4 Hz, 1H) ; 4. 39 (s, 2H) ; methyl]-benzamide 3. 81 (s, 3H) ; 3. 80 (s, 3H) ; 3. 70 (bs, 5H). N- (2-Amino- 1H NMR (300 MHz, DMSO-d6) 8 (ppm) : 9. 61 (s, 1H) ; mxvethvl) - = - H H - - = - H H - phenyl)-4- { [2- (2- 7, 95 (d, J = 7. 9 Hz, 2H) ; 7. 73 (t, J = 5. 7 Hz, 1H) ; 7. 52 (d, o methoxy-ethyl)- Me0 e N"', 1 J = 8.. 4 Hz, 1H) ; 7. 47 (d, J = 7. 9 Hz, 2H) ; 7. 15 (d, J = 7. 9 1, 3-dioxo-2, 3- 317 458"N j ! J CH CH '. iTr Hz, 1H) ; 6. 97 (d, J = 7. 5 Hz, 1H) ; 6. 92 (bs, 1H) ; 6. 86 (d, J 33 v i y o--= 8. 4 Hz, 1H) ; 6. 77 (d, J = 7. 9 Hz, 1H) ; 6. 59 (t, J = 7. 5 O isoin O--Hz, 1H) ; 4. 89 (bs, 2H) ; 4. 54 (d, J = 5. 7 Hz, 2H) ; 3. 65 (t, J ylamino]-methyl}-= 5. 3 Hz, 2H) ; 3. 47 (t, J = 5. 3 Hz, 2H) ; 3. 20 (s, 3H) ; benzamide . _-_. _.... . ___--.. _. _ S cliin Cpd Cpd WYZ'tName"CharacterizationjSctim.' - , pi'R NMR (,--100 MHz, F,, IqSO-d (,) 6 (pprri) : 9. 5. 9 (s,'I T-1) ;' o nu 318 459 n=/ f."'' ! CH CH e-l-methyi-2-oxo-J ==7. 5 Hz, m) ; 6. 96 (t, =7. 0Hzr ; 6. 7S-6. 71'tmv'33 .. \- 2. 3-dihydro-m- 3H) ; 6. 62-6. 54 (m, 2H) ; 6. 26 (t, J= 7. 5 Hz, IH) ; 4. 8 ;' (s, r _.. _ Hc.'. mdo]-5-yiammo)-2H) ; 4, 36-4. 32 (m, 4H) ; 4. 23-4. 1, 9 (t. t ; 9. 98. (s, 3Xi). .. |. X methyl}-benzal-nBc.,.. ' methy !}-benzami'de '''. ,-HNMR (300MHCD30D) 5 (ppm) : 8. 67 (d, J=2. 2 Hz. I B-), 7. 97 (dd, J == 2. 5, 8. 9 Hz, 1 H). 7. 58. (m, 1H) ; -'19'4, NHx N pt el 7 5), 7 ; 15 (dd ; 7 7 > 1r-l). 7 os, 33 II, 7. 18 I s 3 I 9 450 j H CH h Ixhcnylamino-'''°'33 -li, ylarni 0)-211) ; 6. 89 (dd, 1. 4, 8-0 Hz, 1H), 6. 76 (dt, J = 4. 4, 7. 7 ___ I, __ IllCG lllal e 1N4X ; 3. tiO (t J = 6. 3 <1,) __ Hz, IH), 6-67 (d, J = 7.'I'Hz, 2H), 6. 60 (m-,'-) H) ; 4, 87 'bs, i. mcouMmqe 2H) ; 3. 60 (t, J-6. 3 Hz, 2H), 3. 35 (t, J = 6. 3 Hz, 2H). !..',... - (2-Amino-.". 0 ? ''HNM : R (300MHz, DMSO-d6) S (ppm) : 9 : 59 (s, lH) ; diilloth) 1-274-' . u crt' c. . f : _ 7. L (d, T. = 7. 9 Hz ) 7. . 7. (d, T =. I : zH) ; 7 : (a, )/-0 461 CH--CH J = 8. 8 Hz', IH) ; 7. 16-7. 09 (m, 3H) ; 6. 96 (t, J = 7. 5 Hz, 33 _ ,'I . C'H. CH, te_rh dro-T-8. 8 I-iz,), () > R (, quina7, oliii-6- :)-6. 56 (i, 2H) ; 4. 87 quixiazolizx-6-' C3 : 2H)-4. 42 (d, T = 5. 3 Hz, 2H) ;. 3. 44 (s, 3H) ;. 3. ? 6 (s, 3II). 3. 26 (s. . l bcnzatoide .. ... NA''HNMR (300MHz, DMSO-d6) 8 (ppm) : 9. 60 (s,,. IM ;. 8. 19 (d J 8. 4 Hz, 1 F.-) ; 8. 05 (d--8. 4 Hz,'lI4-)' : 7. 95 ! ^ i ioezzSI}-G.- [ ( - (d, J 7. 9 Hz, 2H) ; 7. 76 (1, J=7. 0 Hz, lH) 7. 65' (i/J= I a. _, _ rH w n ethyl-H- . j ! " ;-. 1H) ; 7 (d. J=1. 3HlH) ; 7. 22 (dd, J=1. 8, 8. 8Hz,- - (. iiidolo [2,, 3- . _ -LIIj ; 7. 14 (d, T = 7. 9 I, I H} ; 6. 95 (t, J = 7. 5 Hz, I H ; ylanxino)-zxe : diylJ- ienzami. ee _ 6. 76 (t, T = 7. 9 Hz, II) ; 6. 57 (t, T = 7. 5 Hz, IH) ; &. I (bs, '.. IH} ; 4. 86 (bs, 2H) ; 4. 54 (dJ=4. 8H2H) ; 3. 85 (s, 3H). JEx. JCpd.'W Y Z'Name Characterization.. Scrim .. I _ _. _. I _ _ _,.. __ _ __ _ --122 li, 161, llq, Cf-i ;. ; pI ? enyl-L-1- <t ?, » i CT-I |hydrox ! L. B4S calc : 335. 4J.). found : j.'t (M1 : 4) ' !-' ! J'"" '. J, J. ;.. l l HoCs z Aw HC. . ! jMimo-'.. 323'464 j) N CH Py'P"'LlScak. : 335. 42. found : 336. 1 (MH)" 14, 3 tolylstnanyl- ...., _. _. _ __ _, _ _ | N-(nrD . plie ? _ 131iv . i ph. cn,'L) _. __..,, l (indai)-2- 324 ) <''CH. CH ylaminomethy !)- LRScalc : 453. 6, found : 454. 2 (MH)'. 21 its í'1 ij,., HN''Iylmcthyl0,-,' , 1 3 i, __Ibenza nide_. :-_ _..'_ _ I I. W2-Ami11o-.... (pvr in,-)- _ I. t2-. mino- -'L'5'- 66-21 325-466. . -S CHCRylammomethyt)-. LRM. S. calc :. 414. 52, &und : 415 (MH)'. 21.' N han =N HN-"..'.,./..-,...' b-iiz-aiiiide L. RTYIS cale : : 1 ... be, nz, mide..,.. 1467 C. H Cl iaz. 0, ,...'. --, l : . . V2'zz', jr ; et ? 'F-- (. s26 :. C7.. y -CH.-, CI'Qrorro-tniaol-2- ! LRI calc : -03. 3, ound : 404 (IvI-' _, y 1 ylaii-iino)-methyl]- bei-izuiiide Ex. Cpd W Y Z Name Characterization Schm N (2-Amino- n\ N C, phenyl)-4-[(5- 327 468 CH CH phenyl-lH-pyrazol-LSS calc : 483. 45, found : 484. 1 (MH) + 21 HN_N 3-ylamino)- methyl]-benzamide Table 4c<BR> Characterization of Additional Compounds Ex. Cpd Compound Name Characterization Schm O n N- (2-Hydroxy-l H NMR (DMSO-d6) : 8 9. 57 (brs, 1H), 7. 98 (d, J = 8. 3 Hz, 2H) 7. 75 (d, J = 7. 5 N JL (3, 4, 5- Hz, IH), 7. 5 7 (d, J 8. 3 Hz, 2H), 7. 07 426 571 SMeO \ N I/OH trimethoxy- (t J = 8. 3 Hz, 1H), 6. 95 (d, J = 7. 0 33, phenylamino)-Hz, 1H), 6. 85 (t, J = 7. 9 Hz, 1H), 6. 21 55 (t, J = 6. 1 Hz, 1H), 5. 95 (s, 2H), 4. 38 Me0/benzamide (d, J = 5. 7 Hz, 2H), 3. 70 (s, 6H), 3. 56 OMe (s, 3H). OMe 1H NMR (300 MHz, DMSO-D6) 5 (ppm) : 9. 9 N- (2-hydroxy- (bs, 1H), 9. 53 (s, 1H), 7. 97 (d, J = 7. 9 ~ N dz, 2H), 7. 73 (d, J = 7. 5 Hz, 1H), 7. 55 - N phenyl)-4- [ (3, 4- Dimethoxy- (d J = 7. 9 Hz, 2H), 7. 08 (dd, J =, 7. 5. 33, 427 572 \ NaH 7. 5 Hz, 1H), 6. 96 (d, J = 7. 9, Hz, 1H), phenylamino)-6_88 (dd, J = 7. 5, 7. 5 Hz, 1H), 6. 72 (d, 55 methyl]- Me0/benzamide J = 8.8 Hz, 1H), 6. 38 (s, 1H), 6. 05 (m, 2H), 4. 36 (d, J = 5. 7 Hz, 2H), 3. 72 (s, OMe 3H), 3. 65 (s, 3H). g\0 S N- (4-Amino-1H NMR : (Acetone-d6) 8 (ppm) : 9. 09 (bs, thiophen-3-yl)-1H), 8. 03 (d, J=7. 9Hz, 2H), 7. 96 (d, NJ H2N/4- [6- (2- J=7. 5 Hz, 1H), 7. 65 (d, J=7. 9 Hz, 2H), morpholin-4-yl-7. 61 (d, J=3. 5 Hz, 1H), 7. 51 (bs, 2H), 428 573 NH ethoxy)-7. 41 (d, J=8. 8 Hz, 1H), 7. 36 (s, 1H),. 60 benzothiazol-2-6. 95 (d, J=6. 2 Hz, 1H), 6. 35 (d, J=3. 5 ylamino]-Hz, 1H), 4. 85 (s, 2H), 4. 20 (t, J=5. 7 0 methyl}-Hz, 2H), 3. 69) t, J=4. 4 Hz, 4H), 2. 87- benzamide 2. 81 (m, 2H), 2. 62-2. 57 (m, 4H). Ex. Cpd Compound Name Characterization Schm O S N- (4-Amino- l thiophen-3-yl)-1H NMR (DMSO-d6) : 8 9. 66 (brs, 1H), 7. 94 H I \ H 4- [ (3, 4, 5- (d, J = 7. 5 Hz, 2H), 7. 56 (d, J = 7. 9 429 574 Me0 N/. NH2 trimethoxy-Hz, 2H), 6. 22-6. 16 (m, 1H), 5. 94 (s, 60 phenylamino)-2H), 4. 91 (s, 2H), 4. 38 (d, J = 5. 7 Hz, MeO methyl]-4H), 3. 70 (s, 6H), 3. 55 (s, 3H). OMe benzamide (DMSO) 5 (ppm) : 12. 43 (bs, 1H), 9. 59 (bs, N- (4-Amino- 1H), 7. 84 (d, J = 8. 1 Hz, 2H), 7. 56 (d, /q thiophen-3-yl)-J = 8. 1 Hz, 2H), 7. 48 (d, J = 3. 7 Hz, 430 HNn S 4- (5-methoxy-lH-1H), 7. 32 (bs, 1H, SCH), 6. 96 (bs, 1H, 36, N benzoimidazol-2-SCH), 6. 74 (dd, J = 8. 8, 2. 2 Hz, 1H), 60 ll | FS O ylsulfanylmethyl 6. 11 (d, J = 3. 7 Hz, 1H), 4. 84 (s, 2H), )-benzamide 4. 59 (s, 2H), 3. 76 (s, 3 H). LRMS : 410. l (calc) (M) ; 411. 2 (found) (M+H) + 1H-NMR (DMSO-d6), 8 (ppm) : 9. 22 (bs, 1H), 0 2- [4- (4-Methoxy-8. 19 (bs, 1H), 7. 63 (d, J=7. 1 Hz, 1H), benzylamino)-7. 53 (t, J= 4. 2 Hz, 1H), 7. 41 (dd, w\V NH phenyl]-J=9. 2, 1. 5 Hz, 1H), 7. 25 (d, J=8. 3 Hz, 431 576 NH2 cyclopropanecarb 2H), 7. 06 (d, J=7. 1 Hz, 1H), 6. 85 (d, mN N fY 2 oxylic acid (2-J=8. 3 Hz, 2H), 6. 62-6. 59 (m, 3H), 4. 51 H3Csopv H ç amino-phenyl)- (d, J= 4. 2 Hz, 2H), 3. 78 (s, 3H), 2. 77 amide (d, J=3. 1 Hz, 1H), 2. 45 (d, J=l. l Hz, 1H), 1. 22 (m, 1H), 1. 05 (m, 1H). N N- (2-Amino NMR (DMSO-d6) 8 (ppm) : 9. 72 (brs, 1H), phenyl)-4- (3-8. 23 (d, J = 7. 5 Hz, 1H), 8. 06 (d, J = 7. 9 Hz, 2H), 7. 67 (d, T 7. 9 Hz, 2H), 432 577 HgC N O I \ H NH 7. 23 (d, J = 7. 9 Hz, 1H), 7. 15 (d, J = 2 pyridin-2-11 H 7. 9 Hz, 1H), 7. 03 (t, J benzamide 684 (d, J = 7. 9 Hz, 1H), 6. 65 (t, J = 0 7. 5 hz, 1H), 5. 62 (brs, 2H), 4. 97 (brs, 2H) Ex. Cpd Compound Name Characterization Schm N- (2-Amiho- 1H NMR (300 MHz, DMSO-D6) 8 (ppm) : 9. 63 N phenyl)-4-{ [4- (s, 1H), 8. 95 (d, J = 2. 2 Hz, 1H), 8. 40 (6-methoxy- (d, J = 5. 3 Hz, 2H), 7. 96 (m, 3H), 7. 54 N N pyridin-3-yl)- (d, J = 7. 5Hz, 2H), 7. 22 (dd, J = 5. 3, 15, N pyrimidin-2-7. 8 Hz,-2H), 7. 01 (m, 2H), 6. 83 (d, J = 33 ylamino7-7. 5 Hz, 1H), 6. 64 (dd, J = 7. 0, 7. 9 Hz, O v methyl}-1H), 4. 92 (s, 2H), 4. 70 (d, J = 6. 2 Hz, benzamide 2H), 3. 98 (s, 3H). 1H NMR : (DMSO) 8 (ppm) : 11. 98 (bs, 1H), 0 2-Acetylamino-5-9. 61 (bs, 1H), 7. 93 (d, J = 8. 1 Hz, 2H), HsC- S (4- (2-amino- * 7. 8 1 (s, 1H), 7. 45 (s, 1H), 7. 38 (d, J = 434 579 NH2 phenylcarbamoyl) 8. 1 Hz, 1H), 7. 19 (s, 1H), 7. 16 (d, J 49 N-benzyll-7. 3 Hz, 1H), 6. 97 (dd, J = 7. 0, 7. 0 Hz, H2NA ° W thiophene-3-1H), 6. 77 (d, J = 7. 3 Hz, 1H), 6. 59 (dd, O carboxamide J = 7. 3, 7. 3 Hz, 1H), 4. 88 (bs, 2H), 4. 10 (s, 2H), 2. 15 (s, 3H). AT (2-Amino-1H NM (DMSO) 8 (ppm) : 9. 56 (s, 1H), N f 7. 90 (d, J = 7. 9 Hz, 2H) 7. 49 (d, J 7. 9 Hz, 2H), 7. 15 (d, J = 7. 5 Hz, 1H), MeN- methyl-2- MeN--- methyl-2-6. 95 (t, J = 7. 5 Hz, 1H), G. 78 (dd, J 435 580 c H H 13. 2, 8. 35 Hz, 2H), 6. 58 (t, J = 7. 5 Hz, 61 1S y benzoimidazol-5-1H), 6. 39 (s, 1H), 6. 31 (m,-2H), 5. 75 ylamino)- 0 I methyl7- (t, J = 6. 15 Hz, 1H), 4. 87 (s, 2H), 4. 32 benzamide (d J = 5. 7 Hz, 2H), 3. 34 (s, 3H), 2. 82 (d, J = 8. 5 Hz, 3H). 5- (5-Methoxy-lH-1H NMR (DMSO) 8 (ppm) : 9. 84 (s, 1H), 0 0 benzoimidazol-2-7. 84 (s, 1H), 7. 67 (s, 1H), 7. 63 (d, J = ylsulf ylsulfanylmethyl 8. 5 Hz, 1H), 7. 55 (d, J = 9. 0 Hz, 1H), N)-benzofuran-2 (d, 6. 97 (t, J = 64 carboxylic acid7. 5 Hz, 1H), 6. 78 (d, J = 8. 0 Hz, 1H}, MeO/-NH H2N (2-amino-6. 78-6. 74 (m, 3H), 6. 59 (t, J = 7. 5 Hz, phenyl) am 1H), 5. 71 (s, 2H), 4. 94 (s, 1H), 4. 65 ide (s, 2H), 3. 76 (s, 3H). Ex. Cpd Compound Name Characterization Schm 1H NMR (DMSO) 8 (ppm) : 9. 69 (s, 1H), 5- (3, 4, 5- 7. 47 (s, 1H), 7. 41 (d, J = 8. 8 Hz, 1H),- Trimethoxy-7. 19 (d, J = 6 Hz,,, J = Me benz, benzylamino)-7. 5, 7. 5 Hz, 1H), 6. 89H (dd6J7= (8a8, 2. 2 439 592 H benzofuran-2-Hz, 1H), 6. 79-6. 78 (m, 2H), 6. 74 (s, 64 H2N carboxylic acid 2H), 6. 60 (dd, J = 7. 5, 7. 5 Hz, 1H), (2-amino-6. 14 (t, J = 5 7 Hz, 1H), 4. 92 (s, 2H), OMe phenyl)-amide 4. 21 (d, J = 5 7 Hz, 1H), 3. 75 (s, 6H), 3. 31 (s, 3H).

Scheme 21 0 0 9 A 0 NH 1. NBH (OAc), NH NH Pd (PPh3) 4 < C RNH2 t f NH2 u I//NHiBoc aG I //I NHtBoc CH3 /w benzene 2. TFA ethanol CHO RHN 184 185 Example 122 186 : = ess .Example122<BR> <BR> <BR> <BR> <BR> <BR> Step 1 : {2- [ (3'-Formyl-biphenyl-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (185) [0254] 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 (CDC13) : 6 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).

Step 2 : N- (2-Aminophenyl)-4- [3- (indan-2-ylaminomethyl) phenyl)]- benzamide (186) [0255] To a stirred solution of biphenyl aldehyde (. 104 mg, 0. 25 mmol) and 2-aminoindane (33. 3 mg, 0. 25 mmol) in dichloroethane (ImL) was added sodium triacetoxyborohydride (80 mg, 0. 375 mmol) followed by a glacial acetic acid (15ul, 0. 25 mmol), and then the mixture was stirred at room temperature for 3h. 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 (112mg, 84% yield) as a white solid. 1H NMR (CDC13) : 009. 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).

[0256] 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% CD30D in CDC13) : 57. 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 [0257] Examples 123 to 126 (compounds 187-190) were prepared using the same procedure as described for compound 186 in Example 122 (scheme 21).

Scheme 22 1. NaBH (OAc CH3COOH 0 0 0 OHC NH NH Pd (PPh3) 2cl2 NH OHC NH /NHfBoc C/I//NHtBoc OMe///I NHx /NHa 2. TFA HN NH2 2. TFA 184 191 192 Example 127 Example 127 Step 1 : {2- [4- (1-Amino-cyclohexylethynyl)-benzoylamino]-phenyl}- carbamic acid tert-butyl ester (191) [0258] 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 (CDC13) : 6 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).

Step 2 : Step 2 : N-(2-Aminophenyl)-4-[1-(4-methoxy-benzylamino)- cyclohexylethynyl]-benzamide (192) [0259] 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 (CDC13) : # 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, lH), 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).

Scheme 23 TMS = NHBoc Pd (PPh3) 2CI2 TMS N Cul \ H NHBoc /Et3N, THF I/N 184 0°C to rt 197 0 v TBAF, THF TFA - 20°C to rt CHCI2 ru R \ Rsw H NH2 H NHBoc /NHz 200 0 Example 132 198 R = TMS'TBAF, THF TBAF, THF Example 133 199 R = N,'J 20°C to rt CHO 2. TFA cl morpholine Cul 1, 4-dioxane 0 105°C t N f ci H NHR N, 6 I 201 0 Example 134 Example 133 Step 1 : N- [2- (t-Butyloxycarbonyl)-amino-phenyl]-4- (trimethylsilylethynyl) benzamide (197) [0260] 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 NH4C1, and diluted with ethyl acetate. After separation, the organic layer was successively washed with sat. NH4C1, H20 and brine, dried over anhydrous MgS04, 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, CDC13) 8 (ppm) : 9. 26 (bs, 1H), AB system (6A = 7. 91, aB = 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). <BR> <BR> <BR> <P>Step 2 : N- (2-Amino-phenyl)-4- (trimethylsilylethynyl) benzamide (198) [0261] 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) 8 (ppm) : 9. 20 (bs, 1H), AB system (6A = 8. 07, bB = 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).

Step 3 : N-(2-Amino-phenyl)-4-ethynylbenzamide (199) [0262] 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. NH4Cl, H2O and brine, dried over anhydrous MgS04, 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) 8 (ppm) : 9. 19 (bs, 1H), AB system (8A = 8. 08, Sa = 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 <BR> <BR> <BR> <BR> Step 1 : N- [2- (t-Butyloxycarbonyl)-amino-phenyl]-4-ethynylbenzamide<BR& gt; <BR> <BR> <BR> <BR> (200) [0263] 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 NH4Cl, Hz0 and brine, dried over anhydrous MgS04, filtered and concentrated. The crude residue was then purified by rlasn cnromatograpny 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) 8 (ppm) : 9. 31 (bs, 1H), AB system (8A= 7. 94, 8B = 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).

Step 2 : N-(2-amino-phenyl)-4-[3-(4-chlorophenyl)-3-morpholin-4-yl-1- propyn-1-yl]-benzamide (201) 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 Rl, 0. 68 mmol), and CuI (6 mg,. 0. 03 mmol), respectively. The reaction mixture was bubbled with nitrogen for 5 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) 8 (ppm) : 9. 40 (bs, 1H), AB system (#A = 7. 96, bB = 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).

[0264] 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) 8 (ppm) : 9. 80 (bs, 1H), AB system (8A = 8. 06, bB = 7. 71, J = 8. 1 Hz, 4H), AB system (6A = 7. 65, bB = 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).

Scheme 24 H2N Cl. C, J CO Me N'N C02Me NN C02Me 1/1 I. THF THE 202 reflux 203 1. NH 2. LiOH. H20 3. 1, 2-phenylene- diamine, BOP NUS O 9 / \L-J (t))) H) H H Example 135 204 Example 135 Step 1 : Methyl 4- (4-chloro-6- (2-indanyl-amino)- [1, 3, 5] triazin-2-yl- amino)-benzoic ester (203) [0265] 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 NH4C1, and diluted with AcOEt. After separation, the organic layer was successively washed with sat'. NH4C1, H20 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, CDC13) 8 (ppm) : mixture of rotamers, 2 AB system (8A = 8. 03, #A' = 8.00, #B = 7. 70, 83. = 7. 61, J = 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).

Step 2 : 4- [4-amino-6- (2-indanyl-amino)- [l, 3, 5]-triazin-2-ylamino]-N- (2-amino-phenyl)-benzamide (204) [0266] 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) 8 (ppm) : mixture of rotamers, 8. 98 (m, lH), 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.

Scheme 25 ci HO I ci oN14N CO2Me X 14N III HNCI i-Pr2NEt, NaH HNO I The 'TLJC -oL 205 THF 206 CO2Me 1. NH3 2. LiOH. H20 3. 1, 2-phenylene- diamine, BOP NH Non H N /N 207 207 j) ! ! Example 136 0 Example 136 Step 1 : Methyl 4- [ (4-chloro-6- (2-indanyl-amino)- [1, 3, 5] triazin-2- yloxy)-methyl]-benzoic ester (206) [0267] 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 NH4C1, and diluted with AcOEt. After separation, the organic layer was successively washed with sat.

NH4C1, H20 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, CDC13) 8 (ppm) : mixture of rotamers, 2 AB system (8A = 8. 06, #A' = 8. 03, Sa = 7. 52, bB'= 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). <BR> <BR> <BR> <BR> <P>Step 2 : 4-{[4-amino-6-(2-indanyl-amino)-[1, 3, 5]-triazin-2-yloxy]-<BR> <BR> <BR> <BR> <BR> <BR> methyl}-N- (2-amino-phenyl)-benzamide (207) [0268] 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 + e DMSO-d6) 8 (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.

Scheme 26 cri H N4N H2 (1 atm) X 10% Pd/C N''N N N MEOH N-"-N---N H H I/CO Me d H H I, 208 z C02Me 208"209' 1. LiOH. HzO 1. LiOH. H20 2. 1, 2-phenylene- diamine, BOP HzN HzN u NHz H H I N 210 Example 137 Example 210 Methyl 4- [ (4-chloro-6-phenethyl-amino- [1, 3, 5] triazin-2-yl-amino)- methyl]-benzoic ester (208) [0269] The title compound 208 was obtained from 2 following the same procedure as in Example 1, pathway B steps 2 (R1R2NH = phenethylamine).

Step 1 : Methyl 4- [ (4-phenethylamino- [1, 3, 5] triazin-2-yl-amino)- methyl]-benzoic ester (209) [0270] 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, CDC13) 8 (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). <BR> <BR> <BR> <BR> <P>Step 2 : N- (2-Amino-phenyl)-4- [ (4-phenethylamino- [1, 3, 5] triazin-2-yl-<BR> <BR> <BR> <BR> <BR> <BR> amino)-methyl]-benzamide (210) [0271] 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) 8 (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).

Scheme 27 ome HCI. H2N I OMe OMe/ COzMe z N N I MeolN'lCl i-Pr2NEt MeO N1N < THF, sealed flask v \CO2Me 80C 211 80°C 211 1. LiOH. H20 2. 1, 2-phenylene- diamine, BOP OMe N N H J.. H N N 212 0 o L' Example 138 Example 138 <BR> <BR> <BR> <BR> Step 1 : Methyl 4- [ (4, 6-dimethoxy- [1, 3, 5] triazin-2-yl-amino)-methyl]- benzoic ester (211) [0272] In a 75ml 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 NH4C1, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, Hz0 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, CDC13) 8 (ppm) : AB system (8A = 8. 01, #B = 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).

[0273] 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 + E DMSO-d6) 6 (ppm) : 9. 58 (bs, 1H), 8. 27 (t, J = 6. 3 Hz, 1H), AB system (#A = 8. 04, #B = 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. <BR> <BR> <P>Step 2 : N- (2-Amino-phenyl)-4- [ (4, 6-dimethoxy- [l,'3, 5]-triazin-2-yl-<BR> amino)-methyl]-benzamide (212) Scheme 28 , OMe MeOH \/NN 10% KOH \/ THF/H20 H H 5 CO2Me 213 CO2H COzMe 5 2 213 g COzMe 213 1, 2-phenylene- diamine, BOP Et3N, DMF, rt OMe I (e, 14 N HO N 214 Example 139 0 Example 139 Step 1 : _ 4- [ (6- (2-Indanyl-amino)-4-methoxy- [1, 3, 5] triazin-2-yl- amino)-methyl]-benzoic acid (213) [0274] 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 HC1 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]-+.

Step 2 : N- (2-amino-phenyl)-4- { [6- (2-indanyl-amino)-4-methoxy- [l, 3, 5]- triazin-2-yl-amino]-methyl}-benzamide (214) [0275] 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 + e DMSO-d6) 8 (ppm) : mixture of rotamers, 9. 69-9. 53 (m, 1H), AB system (8A = 8. 04, 8a = 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.

Scheme 29 CI ci i Me ! ! i-Pr2NEt N N i-Pr2NEt H tuf Cl I/THF CI N Me / H tj 1 ! nr) N COZMe 215 C02Me 1. 2-Aminoindan 2. NH3 3. LiOH. H20 4. 1, 2-phenylene- diamine, BOP _ NH NON XN) 0N1 sN H NH2 Meon 216 MNt Example 140 Example 29 Step 1 : Methyl 4-[(4,6-dichloro-[1, 3, 5] triazin-2-yl-N-methyl-amino)- methyl]-benzoic ester (216) [0276] 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 jn. l, 4. 79 mmol). After 16 h, the reaction mixture was poured into a saturated aqueous solution of NH4C1, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H0 and brine, dried over anhydrous MgS04, 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, CDC13) 8 (ppm) : AB system (6A = 8.04, #B = 7. 31, JAB = 8. 2 Hz, 4H), 4. 93 (s, 2H), 3. 93 (s, 3H), 3. 18 (s, 3H).

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) [0277] 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) 8 (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.

Scheme 30 pi Cl 1) R1MgBr, THF/toluene, 4 N"N-30'C, 1 h, then rt over 3 h N N CI N CI''NCI 2) HCLHzN COzMe CO2Me'217 i-Pr2NEt, THF, rt 1. R2R3NH, i-Pr2NEt THF, sealed flask 80-90°C 2. LiOH. H20 3. 1, 2-phenylene- diamine, BOP Ri N"N R2, N-"i N HZ '3 N R H Example 141 218 : R1 = Me, R2R3N = 2-indanyl-amino Example 141 : Step 1 : Methyl 4- [ (4-chloro-6-methyl- [1, 3, 5] triazin-2-yl-amino)- methyl]-benzoic ester (217) [0278] 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. HC1 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 NH4C1, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH4C1, H2O and brine, dried over anhydrous MgS04, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel. (AcOEt/CHzCl2 : 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, CDC13) 8 (ppm) : mixture of rotamers, 2 AB system (6A =, 8. 03, #A' = 8. 02, 8B = 7.39, #B' = 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).

Step 2 : N- (2-amino-phenyl)-4- { [6- (2-indanyl-amino)-4-methyl- [l, 3, 5]- triazin-2-yl-amino]-methyl}-benzamide (218) [0279] 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 + # DMSO-d6) # (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).

Scheme 31 H nu H NHBoc NH2 184 N"I"N NN O I/ I 1N'H2N) % Nm H NHR H2N Pd2 (dba) 3 No8 POT, Et3N DMF, 100°C 0 219 : R = Boc Example 142 220 : R = H Example 142 Step 1 : (2- {4- [2- (4, 6-Diamino- [1, 3, 5] triazin-2-yl)-vinyl]- benzoylamino}-phenyl)-carbamic tert-butyl ester (219) [0280] 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 ßL, 0. 33 mmol) and tris (dibenzylideneacetone) dipalladium (0) (2 mg, 0. 0025 mmol). The solution was heated at 100°C for 16h. 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, O. 056 mmol, 67% yield). 1H NMR (300 MHz, Acetone-d6) 5 (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). <BR> <BR> <BR> <BR> <P>Step 2 : N- (2-Amino-phenyl)-4- [2- (4, 6-diamino- [1, 3, 5] triazin-2-yl)- vinyl]-benzamide (220) [0281] 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. NaHC03 was slowly added until pH 8 is reached, CH2C12 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, O. 054 mmol, 98% yield). 1H NMR : (300 MHz, acetone-d6) 8 (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).

Scheme 32 X NH2 n-Bu3Snr NH2 N N NH3 gas li"Pd (PPh3) 4 Cl 1, 4-dioxane eN) 0NlCI toluene N) 0N sealed tube G 100°C 70°C 221, G 222 1. 184 Pd2 (dba) 3, POT Et3N, DMF 2. TFA, CH2CI2 NHZ NH2 NON NON H2 (40 psi) I HZ _10% Pd/C 2214 N MEOH 223 N rt 223 ! ! i Example 143b O Example 143a O Example 143a Step 1 : 2-Amino-4-chloro-6-piperidin-1-yl- [1, 3, 5] triazin (221) [0282] 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 16h in a sealed tube. The reaction mixture was allowed to cool to room temperature, and partitioned between AcOEt and a solution of sat. NH4C1. 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.

Step 2 : 2-Amino 4-piperidin-1-yl-6-vinyl- [1, 3, 5] triazin (222) [0283] To a solution of 221 (358 mg, 1. 68 mmol) in dry toluene (7 mL) was added tributyl (vinyl) tin (514 gL, 1. 76 mmol) followed by Pd (PPh3) 4 (97 mg, 0. 084 mmol) and the reaction mixture was heated at 100°C for 16h 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). <BR> <BR> <BR> <BR> <P>Steps 3 : N- (2-Amino-phenyl)-4- [2- (4-amino-6-piperidin-1-yl-<BR> <BR> <BR> <BR> <BR> <BR> <BR> [1, 3, 5] triazin-2-yl)-vinyl]-benzamide (223) [0284] 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) 8 (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 <BR> <BR> <BR> <BR> Step 4 : N- (2-Amino-phenyl)-4- [2- (4-amino-6-piperidin-1-yl-<BR> <BR> <BR> <BR> <BR> <BR> <BR> [1, 3, 5] triazin-2-yl)-ethyl]-benzamide (224) [0285] 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, CDC13-CD30D) 8 (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).

Scheme 33 N MeO S BBr3 HO omN OH O s yNH2 NHz I JN [I i-NHZ N N DEAD, PPh3 O N 225 226 gaCO2Me OHC COzMe OHC' t f Bu2SnCI2, PhSiH3 O 1. LiOH N THF/H20 H N NN \/ OJ , N NH H 2, 1, 2-phenylenedlamine 228 BOP, Et3N Example 144 Example 144 Step 1 : 2-Amino-benzothiazol-6-ol (225) : [0286] 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 NaHC03. The resulting crystals were collected by' filtration and dried in the oven at 135°C for lh to afford the title compound 225 as colorless crystals (3. 63 g, 79% yield). 1H NMR : (CD30D) 8 (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).

Step 2 : 6- (2-Morpholin-4-yl-ethoxy)-benzothiazol-2-ylamine (226) [0287] 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 H20. The combined organic layers were extracted with 1N HC1. The combined acidic extracts were neutralized using a saturated aqueous solution of NaHC03 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) 8 (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).

Step 3 : 4-{[6-(2-Morpholin-4-yl-ethoxy)-benzothiazol, 2-ylamino]- methyl}-benzoic acid methyl ester (227) : [0288] 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 HC1. The combined acidic layers were neutralized using a saturated aqueous solution. of NaHC03 and the precipitate was extracted with ethyl aceate. The combined organic layers were washed with brine, dried over MgS04, 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) 8 (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).

Step 4 : N- (2-Amino-phenyl)-4- { [6- (2-morpholin-4-yl-ethoxy)- benzothiazol-2-ylamino]-methyl}-benzamide (228) : [0289] 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 : (CD30D) 6 (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).

Scheme 34 CO2Me S _ N nah BrN I N grN Bu2SnC12, PhSiH3 Suzuki 229 Coupling \ MeO~B (OH) 2 \ MeOF OMe 1. LIOH Meo N S 1. LiOH Me0 , N NH MeO N HH HN--Q THFIH20 N Me0 230 MeO H2N 2. BOP, Et3N OMe Me0/231 1, 2-phenylenediamine OMe Example 145 Example 145 <BR> <BR> <BR> Step 1 : 4- [ (5-Bromo-benzothiazol-2-ylamino)-methyl]-benzoic acid<BR> <BR> <BR> <BR> <BR> methyl ester (229) : [0290] 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) 5 (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). <BR> <BR> <BR> <P>Step 2: 4-{[5-(3, 4, 5-Trimethoxy-phenyl)-benzothiazol-2-ylamino]-<BR> <BR> <BR> <BR> methyl}-benzoic acid methyl ester (230) : [0291] 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) 8 (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).

Step 3 : N- (2-Amino-phenyl)-4- { [5- (3, 4, 5-trimethoxy-phenyl)- benzothiazol-2-ylamino]-methyl}-benzamide (231) : [0292] 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) 8 (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).

Scheme 35 A CO2Me Me0 fY/=. //-N MeO s N iN zon NaHB (OAc) 3 N 2 232 1. LiOH THF/H20 2. 1, 2-phenylenediamine BOP, Et3N 0 Met -N/-' ZON 233 HN Example 146 Example 146 Step 1 : 4- [ (6-Methoxy-benzothiazol-2-ylamino)-methyl]-benzoic acid methyl ester (232) : [0293] 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 MgS04 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. 85g, 51% yields NMR : (Acetone-d6) 8 (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).

Step 2 : N-(2-Amino-phenyl)-4-[(6-methoxy-benzothiazol-2-ylamino)- methyl]-benzamide (233) : [0294] 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) (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).

Scheme 3 6 H H MeO N Br", C02Me MeO N C02Me DMF H Br NUI- DMF bu 234 1. BBr3 2. N-'"OH PPh3, DEAD 0S 1. LiOH H N I C/l, C02Me 0 THF/H20 N 2. 1, 2-phenylenediamine 236 H2N BOP, Et3N 235 Example 147 Example 147 <BR> <BR> <BR> <BR> Step 1 : 4- (6-Methoxy-lH-benzoimidazol-2-ylsulfanylmethyl)-benzoic acid methyl ester hydrobromide (234) : [0295] To a solution of methyl 4- (bromomethyl) benzoate (2. 51g, 11. 0 mmol) in DMF (50 mL) was added 5-methoxy-2-benzimidazolethiol (1. 98g, 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. 10g, 91% yield) as a colorless solid. 1H NMR: (DMSO-d6) # (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, lH), 6. 94 (d, J= 8. 2 Hz, 1H), 4. 65 (s, 2H), 3. 82 (s, 3H), 3. 79 (s, 3H).

Step 2 : : 4- [6- (2-Morpholin-4-yl-ethoxy)-lH-benzoimidazol-2- ylsulfanylmethyl]-benzoic acid methyl ester (235) : [0296] 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 : (CDC13) 8 (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).

Step 3 : N- (2-Amino-phenyl)-4- [6- (2-morpholin-4-yl-ethoxy)-1H- benzoimidazol-2-ylsulfanylmethyl]-benzamide (236) : [0297] 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 :, (CD30D) 5 (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).

Scheme 37 0 H + C02Me Pd (OAc) 2, Cs2C03 . COe. r J _. N Br BINAP N i NH2 2. 1, 2-phenylenediamine N BOP, Et3N oJ 238 237 Example 148 Example 148 step 1 : 4-Morpholin-4-yl-benzoic acid methyl ester (237) : [0298] 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)-l/ll-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 NaHC03, brine, dried over MgS04 and concentrated in vacuo to afford the title compound 237 (443 mg, 100% yield). 1H NMR : (CDC13) 8 (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).

Step 2 : N- (2-Amino-phenyl)-4-morpholin-4-yl-benzamide (238) : [0299] 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) 8 (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. 50 (s, 2H), 3. 81-3. 79 (m, 4H), 3. 32-3. 28 (m, 4H).

Scheme 38 NH2 S S 1. nj DMAP, Et3N o H pyridinyl NHZ CN, N S C02H H H'N N. I N I , N N I H NH2 NaH, DMF CN 2. HOBt, EDC N I 239 DMF, ET3N 239 1, 2-phenylenediamine Example 149 Example 149 Step 1 : 3-Methylsulfanyl-3- (pyridin-4-ylamino)-acrylonitrile (239) [0300] 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 O °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 <BR> <BR> <BR> <BR> g, 89%).<BR> <BR> <BR> <BR> <BR> <P>Step 2 : N-(2-Amino-phenyl)-4-{[2-cyano-1-(pyridin=4-ylamino)-<BR& gt; <BR> <BR> <BR> <BR> <BR> vinylamino]-methyl}-benzamide (240) [0301] To a mixture of 3-methylsulfanyl-3- (pyridin-4-ylamino)- acrylonitrile (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%).

[0302] 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) 5 (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).

Scheme 39 HCI. H2N ci nu N > C02Me 01 z CllN NH H20, NaHCO3 CIAN HN reflux, 30 min H 241 3-methoxy-propan-1-ol, Ph3P, DEAD, DMF, 0° to rt NH NH ) : N 1. LIOH, H20, THF N zon 2. BOP, Et3N Cl N N 'NH 1, 2-phenylenediamine a / Example 150 Example 150 Step 1 : 4- [ (2-Chloro-9H-purin-6-ylamino)-inethyl]-benzoic acid methyl ester (241) [0303] 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 NaHC03 (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) +.

Step 2 : 4-{[2-Chloro-9-(2-methoxy-ethyl)-9H-purin-6-ylamino]- methyl}-benzoic acid methyl ester (242) [0304] 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.

Step 3 : N-(2-Amino-phenyl)-4-{[2-chloro-9-(2-methoxy-ethyl)-9H- purin-6-ylamino]-methyl}-benzamide (243) : [0305] 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 (CDC13) 8 (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) Scheme 40 \/F HCLHaN I \/F O LiOH. COMe CI ci 0 C02Me ci N NO Me CH ChOMe 0°C to rt 244 O Mye 0 LiOH. H20 F0 2 N NAOH Me 0N <\y-F Me 0 CI \--- N/ THF/H20 N H OH DMF I rt O Me Y 40°C Cl ° 245 0 246 1, 2-phenylene- diamine Me BOP reagent 01 N H_6 N Et3N, DMF rut 0 247 Example 151 Example 151 <BR> <BR> <BR> <BR> Step 1 : Methyl-4-{[3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-& lt;BR> <BR> <BR> <BR> <BR> 4-carbonyl]-amino-methyl}-benzoic acid ester (244) [0306] To a stirred suspension at 0°C of methyl 4- (aminomethyl) benzoate. HC1 2 (809 mg, 4. 01 mmol) in anhydrous CH2C12 (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, H20, sat. NaHCO3, H20 and brine, dried over anhydrous MgS04, filtered and concentrated to afford the title compound 244 (1. 50 g, quantitative yield) as a colorless sticky foam. 1H NMR (300 MHz, CDC13) 8 (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).

Step 2 4-{[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4- carbonyl]-amino-methyl}-benzoic acid (245) [0307] 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. H20 (453 mg, 10. 80 mmol) in water (20 ml). After 20 h, the reaction mixture was concentrated, diluted with water and acidified with 1N HC1 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) 8 (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).

Step 3 : 4- (9-Chloro-3-methyl-4-oxo-4H-isoxazolo [4, 3-c] quinolin-5- ylmethyl)-benzoic acid (246) [0308] 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 HC1 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) (ppm) : AB system (8A = 7. 92, aS = 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).

Step. 4 : N- (2-Amino-phenyl)-4- (9-chloro-3-methyl-4-oxo-4H- isoxazblo [4, 3-c] quinolin-5-ylmethyl)-benzamide (247) [0309] 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) 8 (ppm) : 9. 65 (s, 1H), AB system (6A = 7. 95, 8B = 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).

Scheme 41 a. OHCCHO, OHC I NH40H N BOP, Ph (NHZ) 2 OH b. HCI N Et3N, DMF, rt N H NHZ 30 H I OH 0. H I N 0 248 o 249 0 Example 152 Example 152 Step 1 : 4-(lH,-Imidazol-2-yl)-benzoic acid (248) [0310] 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 HC1 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).

Step 2 : N- (2-Amino-phenyl)-4- (lH-imidazol-2-yl)-benzamide (249) [0311] The title compound 249 was obtained following the same procedure as Example 1, step 5. 1H NMR (CDC13) 8 (ppm) : 1H NMR : (DMSO) 8 (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) +.

Scheme 42 HZN NC< H2S, Et3N, Pyridine f AOH /OH S 0OH 250 0 1, 3-dichloroacetone THF H 1. morpholine, THF vs O O /2. BOP, Ph (NH2) 2, OH Et3N, DMF, rt ci Example 153 Example 153 Step 1 : 4-Thiocarbamoylmethyl-benzoic acid (250) [0312] 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 HC1. 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, 83po) as a white solid. 1H NMR (DMSO) 8 (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).

Step 2 : 4- (4-Chloromethyl-thiazol-2-ylmethyl)-benzoic acid (251) [0313] 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 48h. 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) 5 (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).

Step 3 : N- (2-Amino-phenyl)-4- (4-morpholin-4-ylmethyl-thiazol-2- ylmethyl)-benzamide (252) [0314] K2C03 (599 mg, 4. 33 mmol) was added to a solution of 251 (527 mg, 1. 97 mmol) and morpholine (189 01, 2. 17 mmol) in THF (15 ml) was refluxed during 48h. 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).

[0315] The title compound 252 was obtained following the same procedure as Example 1, step 5. 1H NMR (DMSO) 8 (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. 1Hz, 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).

Scheme 43 0 0 1. Triphosgene, Et3N, S OMe S t DCM-78°C to rt f W OMe 'o 2. * 0 u r s/OMe I o m O NHz HZNOMe NH OMe Et3N, DCM ° 253 a. NaOH, MeOH b. H20 0 S z I N HZ 1. Eti, K2CO3, DMFs N i N Np \ 2. sOP, Ph (NHz) z I I NI \-0 I CO H Et3N, DMF, rt IL H J S ! LJ 2. BOP, Ph (NH'--kO, H 'EtsN. DMF. rt)-j 255 254 Example 154 Example 154 Step 1 : Methyl 3- [3- (4-methoxycarbonyl-benzyl)-ureido]-thiophene-2- carboxylate (253) [0316] 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 (CDC13) 8 (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).

Step 2 : 4-(2, 4-Dioxo-1, 4-dihydro-2H-thieno [3, 2-d] pyrimidin-3- ylmethyl)-benzoic acid (254) [0317] 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 HC1 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). <BR> <BR> <BR> <BR> <P>Steps 3 : N- (2-Amino-phenyl)-4- (l-ethyl-2, 4-dioxo-1, 4-dihydro-2H-<BR> <BR> <BR> <BR> <BR> thieno [3, 2-d] pyrimidin-3-ylmethyl)-benzamide (255) [0318] 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) (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, NHZ) 4. 09 (q, J = 7. 0, 2H, CH2), 1. 22 (t, J = 7. 0, 3H, CH3). LRMS : 420. 1 (calc.) ; 421. 0 (found).

Scheme 44 O 0 1. K2COg, DMF o HCHO, g Br S'0 il H 2 _ i y N NHZ N 2. LiOH, THF, H20 N 256 3. BOP, Ph (NH2) 2 257 ° 4J Et3N, DMF, rt Example 155 Example 155 Step 1 : 3H-Thieno [3, 2-d] pyrimidin-4-one (256) [0319] Methyl-3-amino-2-thiophene carboxylate (510 mg, 3. 24 mmol) was dissolved in formamide (20 ml) and heated at 170°C 16h. 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).

Step 2 : N- (2-Aminophenyl)-4- (4-oxo-4H-thieno [3, 2-d] pyrimidin-3- ylmethyl)-benzamide (257) [0320] 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) 8 (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. 1Hz, 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).

Scheme 45 1. HCHO reflux 2. K2C03, DMF O O 0 NC^CO2Me Br \ H NH2 OEt' CO2Me I I N su fur J i N morpholine S NH2 3. LiOH, THF, H20 S N morpholine 258 4. BOP, Ph (NHZ) 2 259 0 S EtN, DMF, rt Example 156 Example 156 Step 1 : Methyl 2-amino-4, 5-dimethyl-thiophene-3-carboxylate (258) [0321] 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).

Steps 2 : N- (2-Amino-phenyl)-4- (5, 6-dimethyl-4-oxo-4H-thieno [2, 3- d] pyrimidin-3-ylmethyl)-benzamide (259) [0322] 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) 8 (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).

Scheme 46 0 Methyl-4-formylbenzoate 0 O AcOH, HzS04 /OMe po O 260 O Pd/C, H2 RhCI3. H20 or EtOH PhSO2NHNH2 O DMF, 100C OMe zu 261 \ I i OMe '- ! f I. LiOH, THF, H20 263 : X = CHZO 264 : X = CO 2. BOP, Ph (NH2) 2 Et3N, DMF, rt 1. LiOH, THF, H20 2. BOP, Ph (NH2) 2 O Et3N, DMF, rt H NH \ O i N X \ H NHZ I cr H NH2 z Example 157 Example 158 265 : X = CH2 Example 159 266 : X = CO Example 157 Step. 1 : Methyl 4- (4-oxo-chroman-3-ylidenemethyl)-benzoate (260) [0323] Concentrated H2SO4. (2 ml) was slowly added to a solution of 4-chromanone (2. 00 g, 13. 50 mmol) and methyl-4-formylbenzoate (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) 8 (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, <BR> <BR> <BR> <BR> 3H).<BR> <BR> <BR> <BR> <BR> <BR> <P>Step 2 : Methyl-4- (4-oxo-4H-chromen-3-ylmethyl)-benzoate (261) [0324] Water (0. 2 ml) and RhCl3. H0 (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 MgS04, 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) 8 (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). <BR> <BR> <BR> <BR> <P>Step 3 : N- (2-Amino-phenyl)-4- (4-oxo-4H-chromen-3-ylmethyl)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> (262) [0325] The title compound 262 was obtained following the same procedure as Example 1, step 4, 5. 1H NMR : (DMSO) 8 (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 Step 2 : Methyl 4-chroman-3-ylmethyl-benzoate (263) [03261 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).

Step 3 : N- (2-Amino-phenyl)-4-chroman-3-ylmethyl-benzamide (265) [0327] The title compound 265 was obtained following the same procedure as Example 1, steps 4 and 5. 1H NMR : (acetone) 8 (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 Step 2 : Methyl 4- (4-oxo-chroman-3-ylmethyl)-benzoate (264) [0328] A suspension of 260 (4. 00 mg, 1. 36 mmol) and benzenesulfonyl hydrazine (702 mg, 4. 08 mmol) in DMF (7 ml) was stirred at 100°C during 48h. The solvent was evaporated and the residue was diluted in AcOEt, washed with NH4C1 sat., brine, dried over anhydrous MgS04, 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).

Step 3 : N- (2-Amino-phenyl)-4- (4-oxo-chroman-3-ylmethyl)-benzamide (266) [0329] The title compound 266 was obtained following the same procedure as Example 1, steps 4 and 5. 1H NMR : (acetone) b (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).

Scheme 47 Methyl4-formylbenzoate ° : Lo Et3Ni ACOH, Reflux H N 0 OMe ou - IH /266 O Pd/C. H2 MeOH, DMA oye Etl, K2C03, O 268 0 H 267 0 J 268 ° 267 ° 1. LiOH. THF, H20 I. LiOH, THF, HO 2. BOP, Ph (NH2) 2 2. BOP, Ph (NH2) 2 Et3N, DMF, rt Et3N, DMF, rt ojxo N N /N N O i N Ho J 269 270 0 H J 269 270, Example 160 Example 161 Example 160 Step 1 : Methyl 4- (3-oxo-3, 4-dihydro-2H-benzo [1, 4] oxazin-2-ylmethyl)- benzoate (266) [0330] 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 AczO (20 ml). The reaction mixture was refluxed 16h. 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).

Step 2 : Methyl 4- (3-oxo-3, 4-dihydro-benzo [1, 4] oxazin-2- ylidenemethyl)-benzoate (267) [0331] The title compound 267 was obtained following the same procedure as Example 158, step 2. LRMS : 297. 1 (Calc.) ; 298. 1 (found).

Step 3 : N- (2-Amino-phenyl)-4- (4-ethyl-3-oxo-3, 4-dihydro-2H- benzo [1, 4] oxazin-2-ylmethyl)-benzamide (269) [0332] 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) 8 (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 Step 1 : N- (2-Amino-phenyl)-4- (3-oxo-3, 4-dihydro-2H-benzo [l, 4] oxazin- 2-ylmethyl)-benzamide (270) [0333] The title compound 270 was obtained from 267 following the same procedure as Example 1, step 4, 5. 1H NMR : (DMSO) 8 (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) +.

Scheme 48 0 4-carboxybenzaldehyde KOH, MeOH-yOH 273 o i 273 O Methyl-4-bromomethylbenzoate BOP, Ph (NH2) 2 LDA 2M, THF Et3N, DMF, rt 0 i i H H2N i i-w N \/O w 271 \ OMe 274 0 1. LiOH, THF, H20 2. BOP, Ph (NH2) 2 NaBH4, MeOH Et3N, DMF, rt O OH 2 I II H NH2 r I I H NH mHe2 mN t2 72 Example 163 Example 162 Step 1 : Methyl 4- (1-oxo-indan-2-ylmethyl)-benzoate (271) [0334] 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 MgS04, 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).

Step 2 : N-(2-Amino-phenyl)-4-(1-oxo-indan-2-ylmethyl)-benzamide (272) [0335] The title compound 272 was obtained following the same procedure as Example 1, step 4, 5. 1H NMR ! (DMSO) 5 (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 Step 1 : 4- (1-Oxo-indan-2-ylidenemethyl)-benzoic acid (273) [0336] To a suspension of indanone (2. 00 g, 15. 1 mmol) and 4- carboxybenzaldehyde (1. 89g,. 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 HC1 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). <BR> <BR> <BR> <P>Step 2 : N- (2-Amino-phenyl)-4- (l-oxo-indan-2-ylidenemethyl)-benzamide (274) [0337] The title compound 274 was obtained following the same procedure as Example 1, step 5. LRMS : 354. 1 (Calc.) ; 355. 0 (found).

Step 3 : N- (2-Amino-phenyl)-4- (1-hydroxy-indan-2-ylmethyl)-benzamide (275) [0338] 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 16h 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) 8 (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).

Scheme 49 0 0 ome v 0 Ph-NIN Me OH ", 78 ° '" zozo Me 276 O iv I in O vi Or VI, III N Me/N \ COzMe \ NHz NU O Me OR'Me 277 HaN \ Example 164 s 279 vii NC O 1 NC O Me/N I\ /, M ee 0 H iv or viii, ix I I H HN I Me- S NH Me S \ 280 281 i : BrCH2C6H4COOMe/MeONa/THF ; Example 165 ii : PhNHNH2 ; iii : NaOH, then HCI iv : HOBt/EDC. HCI then 1, 2-diaminobenzene ; v : BrCH2C6H4COOMe/MeONa/MeOH, then HCI/AcOH ; vi : CH2 (CN) 2/S8/Et2NH (or. Et3N) ; vii : AcCI, PhCOCI or PhNCO ; viii : 2-N-Bocamino aniline ; ix : TFA ; Example 164 <BR> <BR> <BR> Step 1 : 4- (3, 5-Dimethyl-l-phenyl-lH-pyrazol-4-ylmethyl)-benzoic acid (276) [0339] 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 (800mg) 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 HC1 (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] + 3, 07. O and 191. 1. This mixture was taken for the next step as is.

Step 2. N- (2-Amino-phenyl)-4- (3, 5-dimethyl-l-phenyl-lH-pyrazol-4- ylmethyl)-benzamide (277) [0340] 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, 5 (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 Step 1 : 4- (3-Oxo-butyl)-benzoic acid (278) [0341] 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 HC1 (pH 1-2). Evaporation of the resultant solution yielded a residue, which was refluxed in a mixture of glacial ACOH (50 ml) and conc. HC1 (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.

Step 2. 4- (5-Amino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzoic acid 279 [0342] 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 (O. 5 ml, 4. 8 mmol) was added. The reaction mixture refluxed 1 hour, cooled to the room temperature, acidified with conc. HC1 (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, 5 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).

Step 3. 4- (5-Acetylamino-4-cyano-3-methyl-thiophen-2-ylmethyl)- benzoic acid 280 [0343] 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.

Step 4 : N- (2-Amino-phenyl)-4- (5-acetylamino-4-cyano-3-methyl- thiophen-2-ylmethyl)-benzamide (281) [03441 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) 8 (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.

Scheme 50 COOH 0 0 HO N OH O-N /HZN ' nec 282 283 NC , k, b iii or iv, iii N ") NH2 i : NH20H/EtOH ; ii : RCOCI or Ac20/pyridine or CICH2COCI/toluene ; 284 iii : HOBt/EDCxHCI then 1, 2-diaminobenzene ; Example 166 iv : morpholine or piperidine Example 166 Example 166 Step 1. 4- (N-Hydroxycarbamimidoylmethyl)-benzoic acid (282) [0345] A suspension of 4-cyanomethyl benzoic acid (2. 07 g, 12. 86 mmol), NH20H. HC1 (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. HC1 (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.

Step 2. 4- (5-Methyl- [1, 2, 4] oxadiazol-3-ylmethyl)-benzoic acid (283) [0346] A solution of 4- (N-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 Step 3. N- (2-Amino-phenyl)-4- (5-methyl- [1, 2, 4] oxadiazol-3-ylmethyl)- benzamide (284) [0347] 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) 8 (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 Scheme 51 0 0 O N-P HzN - N-N 2 286 285 ' i i Me Me 2g6 285 Example 167 i : Acetyl acetone/EtOH ; ii : HOBt/EDCxHCI then 1, 2-diaminobenzene ; Example 167 Step 1 : 4- (3, 5-Dimethyl-pyrazol-1-yl)-benzoic acid (285) [0348] 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. <BR> <BR> <BR> <BR> <P>Step 2. N- (2-Amino-phenyl)-4- (3, 5-dimethyl-pyrazol-1-yl)-benzamide (286) [0349] 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).

'H NMR : (DMSO) 8 (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+l]"303. 3 Scheme 52 MeO MeO) MeO Me0 MeO03 I MeO A W OEt meo. OEt Met MeO 0 287 287 O/ MeO ° N MeO XOEt Me0, Met H NH2 MeO mye0 Mu0 Me non 288 0 r. 0 17 Example 168 0, < MeO 0 H NH2 00 290 Met Me0 29 Example 169 a. 2. 5% Pd (OAc) 2/nBu4NCI (1 eq)/KOAc (3 eq)/2. 5% PPh3/DMF/80°C b. 3-4% Pd (OAc) 2/9% PPh3/Ag2CO3 (2 eq)/CH3CN/80°C c. LiOH'H20/THF-H2O (2 : 1) d. 1, 2-phenylenediamine/BOP/Et3N/DMF e. Pt02/H2 (1 atm)/AcOEt Example 168 Step 1 : 2- (3, 4, 5-Trimethoxy-phenyl)-2, 3-dihydro-furan (287) [0350] 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).'H NMR : (300 MHz, CDC13) 5 (ppm) : 6. 59 (s, 2H), 6. 45 (m, 1H), 5. 45 (dd, J = 10. 5, 8. 4 Hz, 1H), 4. 97 (m, 1H), 3. U'7 (s, 6H), 3. 84 (s, 3H), 3. 06 (m ; 1H), 2. 62 (m, 1H).

Step 2 : 4- [5- (3, 4, 5-Trimethoxy-phenyl)-2, 5-dihydro-furan-2-yl]- benzoic acid ethyl ester (288) [0351] 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), Ag2C03 (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, CDC13) 8 (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). <BR> <BR> <BR> <BR> <P>Step 3 : N- (2-Amino-phenyl)-4- [5- (3, 4, 5-trimethoxy-phenyl)-2, 5-<BR> <BR> <BR> <BR> <BR> <BR> dihydro-furan-2-yl]-benzamide (289) [0352] 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) 8 (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 Step 1 : N- (2-Amino-phenyl)-4- [5- (3, 4, 5-trimethoxy-phenyl)- tetrahydro-furan-2-yl]-benzamide. (290) [0353] To a degazed solution of 289 (43 mg, 0. 096 mmol) in AcOEt (4 mL) was added PtO2 (3 mg, O. 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/CHC13 : 30/70) to afford the title compound 290 (10 mg, 0. 22 mmol, 23% yield). 1H NMR (CDC13) 8 (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, J = 7. 0 Hz, 1H), 3. 89 (s, 6H), 3. 85 (s, 3H), 2. 59-2. 40 (m, 2H), 2. 09-1. 88 (m, 2H).

Scheme 53 0. NHBoc H NHBoc H NHBoc <Af Nt a wNt < wNt 0 \ I 0 \ I O OMe 292 OMe MeO OH f, d Me0 \ H/I H NHR 2g4 R=Boc d \, N O Example 169 o + 0 ou H OH N/H NHZ Me0 \ N/NHBoc i \ I N/ \ I N met 0 Me0 'O, \ I Me0 OMe 295 O MeO Me0 296 Example 170 e, d Memo N Met Me0/NHZ H MeO N 297 MeO a <+ H NH2 MeO <NsA 297 0 Example 171 o a. Tributyl (vinyl) tin/Pd (PPh3) 4/Toluene/1 00°C b. m-CPBA/CHCI3/r. t. c. 3, 4, 5-trimethoxyaniline/CoCi2/CH3CN d. TFA/DCM e. 1, 1'-carbonyldiimidazole/DCM/r. t. f. 1, 1'-carbonyldiimidazole/Et3N/Toluene/THF/90°C Example 169 Step 1 : [2- (4-Vinyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester (291) [0354] 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, CDC13) 5 (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).

Step 2 : [2- (4-Oxiranyl-benzoylamino)-phenyl]-carbamic acid tert- butyl ester (292) [0355] To a solution of 291 (4. 1 g, 12. 1 mmol) in dry CHC13 (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 NaHCOz 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, CDC13) b (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).

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) [0356] 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, CDC13) 5 (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). <BR> <BR> <BR> <BR> <P>Step 4 : N- (2-Amino-phenyl)-4- [2-hydroxy-1- (3, 4, 5-trimethoxy-<BR> <BR> <BR> <BR> <BR> <BR> phenylamino)-ethyl]-benzamide (294) [0357] 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) 6 (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 Step 1 : N- (2-Amino-phenyl)-4- [2-oxo-3- (3, 4, 5-trimethoxy-phenyl)- oxazolidin-4-yl]-benzamide (296) [0358] To a solution of 293 (200 mg, 0. 372 mmol) in toluene (5 mL) and THF (1 mL) was added 1, l'-carbonyldiimidazole (72 mg, 0. 45 mmol) followed by Et3N (156 L, 1. 12 mmol) and the mixture was stirred at room temperature for 5 h then at 90oC for 48 h. The reaction mixture was diluted with AcOEt, a solution of sat. NH4C1 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) 8 (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).

[0359] 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) 8 (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 <BR> <BR> <BR> Step 1 : N- (2-Amino-phenyl)-4- [2-oxo-3- (3, 4, 5-trimethoxy-phenyl)-<BR> <BR> <BR> <BR> <BR> oxazolidin-5-yl]-benzamide (297) [0360] To a solution of 295 (130 mg, 0. 242 mmol) in DCM (2 mL) was added l, l'-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. NH4C1 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) 8 (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).

[0361] 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) S (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 H. z, 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).

Scheme 54 0 X OH H NHBoc HO NHBoc x H NHBoc \ N/ \ _N/+ \ N 0 0 + 0nt 292 298X=N3 < b 302X=N3 z b 299 X = NH2 303 X = NH2 OMe OMe C MeO C Met Me0/ O NH 0 NH MeO 0 OH HO H NHBoc HN NHBoc N_b I H 300 o 304 0 N_b 304 I d, e I d, e MeOOMe MeO OMe zozo N N /H NHZ I \ H NHZ \ I N//N \ 0 0 301 305 Example 172 Example 173 a. CeCI3 heptahydrate/NaN3/CH3CN-H20 (9 : 1)/reflux b. H2/Pd/C (10%)/MeOH c. 3, 4-dimethoxybenzoyl chloride/Et3N/DCM/-20°C to r. t. d. Burgess reagent/THF/70°C e. TFA/DCM Scheme 55 Example 172 Step 1 : {2- [4- (1-Azido-2-hydroxy-ethyl)-benzoylamino]-phenyl}- <BR> <BR> <BR> carbamic acid tert-butyl ester (298) and {2- [4- (2-Azido-l-hydroxy- ethyl)-benzoylamino]-phenyl}-carbamic acid tert-butyl ester (302) [0362] 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, CDC13/CD30D) (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, CDC13) 8 (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).

Step 2 : {2- [4- (l-Amino-2-hydroxy-ethyl)-benzoylamino]-phenyl}- carbamic acid tert-butyl ester (299) [0363] 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, CDC13) 8 (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).

Step 3 : (2- {4- [1- (3, 4-Dimethoxy-benzoylamino)-2-hydroxy-ethyl]- benzoylamino}-phenyl)-carbamic acid tert-butyl ester (300) [0364] 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 ßL, 0. 26 mmol). The reaction mixture was allowed to warm up to room temperature then was stirred for 48 h. A solution of sat. NH4C1 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, 71% yield). 1H NMR (300 MHz, CDC13) 8 (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).

Step 4 : N- (2-Amino-phenyl)-4- [2- (3, 4-dimethoxy-phenyl)-4, 5-dihydro- oxazol-4-yl]-benzamide (301) [0365] 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 (CDC13) 8 (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).

[0366] 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 (CDC13) 8 (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 Step 1 : {2- [4- (2-Amino-l-hydroxy-ethyl)-benzoylamino]-phenyl}- carbamic acid tert-butyl ester (303) [0367] 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. <BR> <BR> <BR> <P>Step 2 : 2- {4- [2- (3, 4-Dimethoxy-benzoylamino)-i-hydroxy-ethyll-<BR> <BR> <BR> <BR> benzoylamino}-phenyl)-carbamic acid tert-butyl ester (304) [0368] 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 (CDC13) 8 (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). <BR> <BR> <BR> <P>Step 3 : N- (2-Amino-phenyl)-4- [2- (3, 4-dimethoxy-phenyl)-4, 5-dihydro-<BR> <BR> <BR> <BR> oxazol-5-yl]-benzamide (305) [0'369] 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 (CDC13) 8 (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).

Scheme 57 COOH 1. SOC12, DMF, DCM N OHC H2NQ OHC H NHtBoc HZN 315 NHtBoc DIPEA Bu2SnCl2, PhSiH3, THF, 12h 3, 4-dimethoxyaniline 1. CHC13/THF SMe NCO 0 MeS, cr MeS'v N w H NHtBoc t vN MeOv 316 HN, O N w I Me I 316 N H NH2 2. TFA, DCM OMe MeO 76% OMe Example 178 Example 178 STEP 1 : [2.- (4-FORMYL-BENZOYLAMINO)-PHENYL]-CARBAMIC ACID TERT-BUTYL ESTER (315) [0370] 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. 'H NMR (CDC13) : 8 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).

Step 2 : (2- {4- [ (3, 4-Dimethoxyphenylamino)-Methyl]-Benzoylamino}- Phenyl)-Carbamic Acid Tert-Butyl Ester (316) [0371] 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) : 8 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).

Step 3 : N- (2-Aminophenyl)-4- [l- (3, 4-dimethoxyphenyl)-3- (4-<BR> methylsulfanylphenyl)-ureidomethyl]-benzamide 317 [0372] To a solution of anilide 316 (5'00 mg, 1. 047 mmol) in chloroform/THF (1 : 1, 10 mL) was added isocyanate (169 pL, 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 (CD13) 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).

[0373] 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) : 810. 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).

Scheme 58 BOP/Ph (NH2) 2/Et3N/DMF OH N CI \N CI N I H NHZ 318 318 N SH K2COiDMF/1 00°C, N \ \/N \ I/ I H NH2 N S N 319 Example 179 Example 179 Step 1 : N-(2-Amino-phenyl)-6-chloro-nicotinamide. (318) [0374] 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.

Step 2 : N- (2-Amino-phenyl)-6- (quinolin-2-ylsulfanyl)-nicotinamide (319) [0375] 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 : (CD30D-d6) 8 (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. 0Hz, 1H), 6. 79 (ddd, J=1. 4, 7. 7, 13. 7 Hz, 1H).

Scheme 59 0 O O PhSiH3 N + H BU2SnCI2 I 0,-a N C02H H I/OH NH2 402a 0 BOP/Ph (NH2) 2 09 Et3N/DMF ON if I N \ H NH2 H I/N \ 402 Example 261 0 Step 1 : 4- [ (4-Morpholin-4-yl-phenylamino)-methyl]-benzoic acid (402a).

[0376] A suspension of 4-formylbenzoic acid (2. 53g ; 16. 8 mmol ; 1 eq), 4-morpholinoaniline (3g ; 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. 31ml ; 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. 25g (99%). LRMS : calc 312. 37 ; found : 313. 2.

Step 2 : N- (2-Amino-phenyl)-4- [ (4-morpholin-4-yl-phenylamino)- methyl]-benzamide (402) [0377] To a solution of acid 402a (2. 61g ; 8, 36 mmol ; 1 eq), 1, 2- phenylenediamine (903 mg ; 8. 36 mmol ; 1 eq) and BOP (3. 70g ; 8. 36 mmol ; 1 eq) in dry DMF (20 ml) was added Et3N (4. 64ml ; 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. 35g). 1H-NMR (300. 07 MHz ; DMSO-d6) 8 (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.

Scheme 60 0 NH2 0 PhSiH3 OH Be2SnCl2 H I'OH Me0''H \ THF/DMA/I N OMe OMe O MeO 424a OMe 3, 4-diaminothiophene. 2HCl BOP BOP Et3N Et3N o-Ph (NHz) 2 0 s 0 /N \ H/I N I/\ N \ I H NH2 Me0 \ N \ H NH I/ mye0 424b MeO 424c OMe Example 283a Example 283b Example 283a step 1. 4- [ (3, 4-Dimethoxyphenylamino)-methyl]-benzoic acid (424a) [0378] 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 NaHC03 (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 x 3). The cake was dried over freeze dryer to afford acid (1. 92 g, 67 %) white solid product. LRMS = 288 (MH) +.

Step 2. N- (2-Aminophenyl)-4- [ (3, 4-dimethoxyphenylamino)-methyl]- benzamide (424b) [0379] 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. 30g, 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 NaHC03 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) 8 (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 Step 1 : N- (4-Aminothiophen-3-yl)-4- [ (3, 4-dimethoxyphenylamino)- methyl]-benzamide : [0380] 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 18h 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) 8 (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.

Scheme 61 H2NvNO2 Im2CSlDME MeX qN3aNO2 SnCI2/NH40Ac/THF MeX qNvNH2 I N/I l IN-</S : 11 : :)" F then 40°/0 MeNH H S H20/MeOH/75C/2h H S then 40% MeNHZ in H20 (8. 6 eq)/650C/2h 456a 456b 4-formylbenzoic acid/PhSiH3 BU2SnC'2/DME/rT/18h o /COACH I N Me N N I/NHZ 1, 2-phenylenediamine Me N N// zu BOP/DMF/TEA H S I/456c 456 s Example 315 Step 1 : Methyl- (5-nitrobenzothiazol-2-yl)-amine (456a) [0381] 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. 45g) 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 (X2). 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.

Step 2 : N-Methyl-benzothiazole-2, 5-diamine (456b) [0382] A mixture of nitro compound 456a (593 mg ; 2. 83 mmol) ; SnCl2 (4. 02 g ; 20. 8 mmol ; 7. 35 eq) and NH40Ac (4. 5g) was suspended in THF : MeOH : H : : 0. = 1 : 1 : 1 (60 mL) and stirred at 70°C for 2 h, cooled down, diluted with ethyl acetate and successively washed with saturated NaHC03 and brine ; dried (MgS04) 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.

Step 3 : 4- [ (2-Methylaminobenzothiazol-5-Ylamino)-Methyl]-Benzoic Acid (456c) [0383] 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 18h. 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. <BR> <BR> <BR> <BR> <P>Step 4 : N- (2-Aminophenyl)-4- [ (2-methylaminobenzothiazol-5-ylamino)- methyl]-benzamide (456) [0384] 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 (3mL) 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) 8 (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.

Scheme 62 MeO N Me0 I NSH gr \ DMF I H H OMe H H I/OMe 0 376a 0 LiOH THF/H2O MeO N MeO N \>--NH BOP ION H 6 Et3N, DMF-IN U W H /OH NH2 H OH Example 235 -NH z Example 235 Step 1 : Methyl-4- (5-methoxy-lH-benzimidazol-2-yl-sulfanylmethyl)- benzoate (376a) [0385] 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) (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) +.

Step 2 : 4- (5-Methoxy-lH-benzimidazol-2-yl-sulfanylmethyl)-benzoic acid (376b) [0386] A solution of LiOH. H20 (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 HC1, 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, 3w05 g) @ 1H NMR : (DMSO) 8 (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, 3 H). MS : (calc.) 314. 1, (obt.), 315. 1 (MH) +.

Step 3 : N- (2-Amino-phenyl)-4- (5-methoxy-lH-benzimidazol-2-yl- sulfanylmethyl)-benzamide (376) [0387] Following the procedure described in Example 1 step 5 but substituting 4- (5-methoxy-lH-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) 8 (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, 3 H). MS : (calc.) 404. 1, (obt.), 405. 4 (MH) +.' Examples 180-328 [0388] 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 [0389] 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).

Scheme 63 MeO NH2 OLi MeO Mu0 AOMe OMe THF/hexane Pd (OAc) 2 lí q-78°C, 30 min Brr> (rac)-BINAP 2) OMe O I a s N-k-N 486 0 toluene 100°C Me0 N CI THF THF -78°C to rt, ON H H MeO N 1) LiOH. H20 MeO N H_6 2 MeOJg WOMe 2) 1, 2-phenylene- Me0 OMe 487 diamine, BOP OMe 0 488 Example 345 Example 345 Step 1 : Methyl 3- (4-bromo-phenyl)-acrylic ester (486) [0390] To a solution of anhydrous i-Pr2NH (758 p. l, 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 Dl, 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 NH4C1, and diluted with AcOEt. After separation, the organic layer was successively washed with H20 and brine, dried over MgS04, 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, CDC13) 8 (ppm) : 7. 63 (d, J = 16. 2 Hz, 1H), AB system (8A = 7. 53, 8n = 7. 39, J = 8. 4 Hz, 4H), 6. 43 (d, J = 15. 8 Hz, 1H), 3. 82 (s, 3H).

Step 2 : Methyl 3- [4- (3, 4, 5-trimethoxy-phenylamino)-phenyl]-acrylic ester (487) [0391] 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 NaHC03, H20, sat. NH4C1, H20 and brine, dried over anhydrous MgS04, 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, CDC13) 8 (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)..

Step 3 : N- (2-Amino-phenyl)-3- [4- (3, 4, 5-trimethoxy-phenylamino)- phenyl]-acrylamide (488) [0392] 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) 8 (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).

Scheme 64 Me0 OH 1. (Tf0) O/DIPEA He0 \ COOtB \ MeOCOOtBu 3, 4, 5-trimethoxyaniline \ u DMAP/DCM I _ Me0 N ,/i 2. DCOOtBu OHC v PhSiH3, Bu2SnC12 Jl I '/489 DME MeO Y 490 Pd2 (dba) 3/POT OMe DIPEA/DMF/120°C 1. TFA 2. BOP/Et3N/DMF Ph (NH2) 2 0 0 ri MET H \ \ N w Me0 N I i H NHZ Me0 I 491 Example 346 OMe Example 346 Step 1 : 3- (4-Formyl-3-methoxy-phenyl)-acrylic acid tert-butyl ester 489 [0393] 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+).

Step 2 : 3- {3-Methoxy-4- [ (3, 4, 5-trimethoxy-phenylamino)-methyl]- phenyl}-acrylic acid tert-butyl ester 490 [0394] 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+). <BR> <BR> <BR> <BR> <P>Step 3 : N- (2-Amino-phenyl)-3-f3-methoxy-4- [ (3, 4, 5-trimethoxy-<BR> <BR> <BR> <BR> <BR> <BR> phenylamino)-methyl]-phenyl}-acrylamide 491 [0395] Following the procedure described in Example 42, step 3, 4, but substituting 490 for 46, the title compound 491 was obtained in 67% yield.'H NMR (CDCl3), # (ppm) : 8. 08 (s, 1H), 7. 74 (d, Je = 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).

Scheme 65 CHO 581 : BrCH (COOMe) 2, X X I CHO K2C03, Toluene, reflux \ COOMe Y\ Y 582 HSCH2COOMe 581 : X=CH3, Y=OH K2CO3, DMF, RT 583 : X=CH3, Y=O 582 : X=N02, Y=CI 584 : X=N02, Y=S '4. F, CC4, reflux HCI, MeOH HAN Br COOME COOME S 585 588 3, 4-dimethoxyaniline 3, 4, 5-trimethoxybenzaldehyde K2CO3, DMF Bu2SnCI2, PhSiH3 O S H 0 COOME Me COOME N. 0N Me0 Me0 OMe 586 OMe 589 1. LiOH, THF/H20 1. LiOH, THFlH20 1. LIOH, THF/H20 2. 1, 2-phenylenediamine, 2. 1, 2-phenylenediamine, BOP, Et3N BOP, Et3N M S H O 0 Me0 N [i/HN H MeO N HN /Me0 HN MeO H2N OMe OMe 587 590 Example 436 Example 437 Example 436 Step 1 : Methyl-5-methyl-benzofuran-2-carboxylate (583) [0396] A stirring suspension of 5-methylsalicylaldehyde (1. 0 mg, 7. 5 mmol), Kas03 (1. 55 g, 11. 0 mmol), and Bu4NBr (322 mg, 1 mmol) in toluene (30ml) 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 H20, 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 (600mg, 42% yield). LRMS : 190. 2 (Calc.) ; 191. 1 (found).

Step 2 : Methyl-5-bromomethyl-benzofuran-2-carboxylate (585) [0397] 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 CC14 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 MgS04, filtered and concentrated. The crude residue was purified by column chromatography (30% ethyl acetate/hexane) to afford the title compound 585 (680mg, 96% yield).

1H NMR : (CDC13) 8 (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 <BR> <BR> <BR> <BR> (found).<BR> <BR> <BR> <BR> <BR> <BR> <P>Step 3 : Methyl-5- [ (3, 4-dimethoxy-phenylamino)-methyl]-benzofuran-2- carboxylate (586) [0398] 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).

Step 4 : 5- [ (3, 4-Dimethoxy-phenylamino)-methyl]-benzofuran-2- carboxylic acid (2-amino-phenyl)-amide (587) [0399] 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) 8 (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 Step 1 : Methyl-5-nitro-benzo [b] thiophene-2-carboxylate (584) [0400] 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 K2C03 (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 20h. The solution was then poured into 250ml of ice Ha0 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) 8 (ppm) : 9. 00 (d, J = 2. 2 Hz, 1H), 8. 45 (s, 1H), 8. 39-8. 30 (m, 2H), 3. 93 (s, 3H).

Step 2 : Methyl-5-amino-benzo [b] thiophene-2-carboxylate (588) [0401] 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 HC1 (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 NaHC03, then brine, dried over MgS04, filtered and concentrated to afford (2. 57 ut 84%). 1H NMR : (DMSO) 8 (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). <BR> <BR> <BR> <BR> <P>Step 3 : Methyl-5- (3, 4, 5-trimethoxy-benzylamino)-benzo [b] thiophene-2- carboxylate (589) [0402] Following the procedure described in Example 144, step 3, but substituting 588 for 226, the title compound 589 was obtained in 68% yield. (DMSO) 8 (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).

Step 4 : 5- (3, 4, 5-Trimethoxy-benzylamino)-benzo [b] thiophene-2- carboxylic acid (2-amino-phenyl)-amide (590) [0403] Following the procedure described in Example 1, steps 4, 5, but substituting 589 for 6, the title compound 590 was obtained in % yields NMR : (DMSO) 8 (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 [0404] 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 4 Synthesis of N- (2-Amino-phenyl)-4- [ (4-pyridin-3-yl-pyrimidin-2- ylamino)-methyl]-benzamide Scheme 66 H2N OMe HCI DMF/DIPEA + gNoN 77% H I \ intermediate 1 N ICI 0 HN NH Iso-Propyl 0 reflux 0 alcohol/MS reflux reflux $5% N O 52% N N 52% N'N intermediate 2 N I nit H OMe 0 intermediate 3 1) LiOH/THF 2) BOP MeOH/H20 oPh (NH2) 2 40°C NEt3/DMF 63% ovr two steps ZON H w I wNH I/N NH2 0, : r 0 Step 1 : Synthesis of 4-Guanidinomethyl-benzoic acid methyl ester Intermediate 1 [0405] The mixture of 4-Aminomethyl-benzoic acid methyl ester HC1 (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 HC1 (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 NaHC03 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 H20 (50 ml). The filter cake was then washed with minimum quantities of cold H20 and ether to give 12. 32 g white crystalline solid intermediate 1 (77% yield, M+1 : 208 on MS).

Step 2 : Synthesis of 3-Dimethylamino-l-pyridin-3-yl-propenone Intermediate 2 [0406] 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 4h. 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). <BR> <BR> <BR> <BR> <BR> <P>Step 3 : Synthesis of 4- [ (4-Pyridin-3-yl-pyrimidin-2-ylamino)-methyl]- benzoic acid methyl ester Intermediate 3 [0407] 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 5h. 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. 317g white crystalline solid Intermediate 3 (52%, M+1 : 321 on MS). <BR> <BR> <BR> <BR> <BR> <BR> <P>Step 4 : Synthesis of N- (2-Amino-phenyl)-4- [ (4-pyridin-3-yl-pyrimidin-<BR> <BR> <BR> <BR> <BR> 2-ylamino)-methyl]-benzamide [0408] Intermediate 3 (3. 68 g, 11. 5 mmol) was mixed with THF (23 mL) , MeOH (23 mL) and H20 (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. HC1 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 H20 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).

[0409] Acid (3. 39g, 11. 1 mmol) of the title compound, BOP (5. 679g, 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 5h 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) 6 (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. 2Hz, 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 1. Human HDAC-1 [0410] 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 Lg 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 HC1 (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. ICso 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. ICso values for representative compounds are presented in the third column of Table 5.

2. MTT Assay [0411] 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% C02 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 63 0 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 ICso. ICso values for representative compounds are presented in the fourth column of Table 5.

3. Histone H4 acetylation in whole cells by immunoblots [0412] 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 5a : Inhibition of Histone Deacetylase HumanHDAC-1 MTT (HCT116) H4Ac (T24) AN N>N ICso (X) ICso () ECso () HN ZON 8 N I \ H HaN 0. 4 0. 5 1 "-LYS NH Z.- NXN NNN H NH 2 0. 7 5 r3 H N p I i HumanHDAC-1 MTT (HCT116) H4Ac (T24) Cpd Structure ICso NAN ICSO () ECso (E. IM) NHz Non 10 N'illNlo, 2 0. 6 1 ho H N'0 N 0 NHz Non I 11 f N N N, <, H. NH2 2 0. 6 2 \ NJ HN 0 NHz N ill N 12 I \ H''N''H I \ H NHZ 2 2 5 inn NH NON NN 14 aN+N'AN NH O. 3 1 5 H HN Oui NHz NN N ; N He2 0. 5 0. 2 3 H I, N \ O I i H2N NON HN Cl f 16 aN lil-NN H NH2. 1 0. 4 1 ZON 0 NHz .. CHs 1 O I i NHZ c3 H3 ho HsC CH H H /N 0 / HAN N4N Non NNN NHZ 0. 8 0. 6 3 Non 2 ho H NHz NHZ _ O NN 18b rDN) , 'N'N H H2N 0. 6 5 10 0 k,, N H N_b 0'il Cpd Structure HumanHDAC-1 MTT (HCT116) H4Ac (T24) Cpd Structure ICso (Pld) ICso (PI4) ECso (pM) HN, non 19 NNN 0. 9 1 1 s N 4 N N) ION U NHz NN I 20 N, AN NC H NH2 0-5 0. 3 1 H H/N . O / OMe NHz Me0/NN w I 21 Me0 H N H I/N NHa 4 4 25 H H N NHZ 0 NHz NN 22 NKN NH2 3 0. 8 1 H I, N f NN NH2 N N 23 I NNN H NH2 2 0. 7 1 OMe H H Ni 0 NHz NON 24 \ I NNN H NH 3 0. 6 1 F H H I/N w F H H N HAN /\ HzN 25 NN H NH2 0-8 0. 3 5 H N H /N NH2 0 N 26 NN 0. 5 2 na GN N N I H NH2 i N\ où HN 27 N"N 27 HNH I NH 0. 4 2 na H H N-6 ZON 0' w w F s Cpd Structure. HumanHDAC-1 MTT (HCT116) H4Ac (T24) Cod Structure aH2 ICso (pM) ICso (pM) ECso (p) NHz NON 28 CNJ+NkH<He2 2 0. 5 1 N NU2 NHz N"N i 29 f. N'NN. H NH2 2 2 1 H H-fl N 0 HN'j As N ! : 30 H N H I H NHz 1 3 1 N 0' NHz tN1N'1 83 N N N H NH 3 5 5 H H I//N C I/ (na = not available ; 99 = >25 µM) Table 5b Ex Cpd Structure Human HDAC-1 MTT (HCT116) H4Ac (T24) Ex Cpd Structure,-..... . c- . ICSO M ICSO M ECSO (M Nu2 0 135 204 N"N N-9 4 na 5 NNN NH2 HO _ NHZ. H2 fi 136 207 N- N-)-O NH 0. 4 0. 6 2 _ O tu f f NN 137 210 N N-- N NH 3 0. 9 1 L JL M JL _ O e Human HDAC-1 MTT (HCT116) H4Ac (T24) ICSO M ICSO M ECSO M OMe NON NN 138 212 MeO'Ji, N N 3 1 1 /N H NAN orme Oye 139 214 N)'N-)-N NH 3 0. 9 1 0 N I'I- _ nu2 \/J ! J 140 218 N1N N<HNt2 H 2 Meon Me N non (/J ! J 141 218 N) N'-N NH2 0. 1 0. 5 na H H H NHZ non NON 142 220 HZNN/I H NH 7 6 na /N NU2 NH 'ill 143a 223 N 11 2 na HzN _ NtXN' 2 N 43b 224 N N 1 N42 na e N Onze NIEZ Tit N N 329 470 CHN) 0NlHN<AcH42 2 3 //N N Ex Cpd Structure Human HDAC-1 MTT (HCT116) H4Ac (T24) ICSO M ICSO M ECSO M) HO /HzN 330 471' O', N)' N. ; ll H H I/N zu O I/ HN 331 472 N)'N-)-N NH23 1 1 Z NN O I/ HNCH3 NN 332 473 H HA H4Z 4 3 na HH N \ _ HN~ CH3 N) ion 333 H /N NHz \ N H HN A. 334 475 t3N1N N H NH2 3 1 1 H H I/N \ HNiA O NAN HN HA 335 476 UHN) (N HA He2 2 1 2 H H I/N ho H N ci NA X H H<H42 s 07 na 337 8 tN9H<H42 na Ho ri NIB 0 MEON met H H /. Z o J I N Ex Cpd Structure """ T ICSO (M ICSO M ECSO M OMe HN' Zon ""k/N. H H H hua 0 I/ HN Zon N N N N H H (/N z 0 I/ HNA /HzN 340 481 HN H t (N4Z 0. 7 na H H /N z Zu HN HNA tt 341 482 NN' NH2 0. 1 0. 7 na Hz 0 Me T ! 342 483 H N H ( H NHz 4 na na H H H Nus N Hz _ It 343 484 N N 2 0. 3 na H N N N / '" zon /N (na=nonavailable) Table 5c HumanHDAC-1 MTT(CHT116) H4Ac(T24) Cpd Structure IC50(xM) IC50(xM) EC50(xM) Cpd Structure HumanHDAC-1 MTT (HCT116) H4Ac (T24) IC50 (, ) ICso M ECSO M 51 PNH2 22 4 na 51 , NH NH2 22 4 na N N _ Me O H o O 0 0 YNH H "NHz Me0 r 59 Meo N 1 : NH2 12 22 na mye0 OMe 0 nu 61 b NH 7 12 na XN Mezzo O 0 '65 H NH 4 37 na H Me0 0 fuzz N 71 H 10 44 na N NH2 0 0 rNH mye0 O nit 2 H 88 NH na >39 na Me0 H Nu fVNH I H N i I N H Nu "r r" NAH Cpd Structure HumanHDAC-1 MTT (HCT116) H4Ac (T24) ICSO M ICSO M ECSO M o NH NH, 5 2 3 N N H nu 93 NH 3 1 5 nu2 N N : r-l Ho zu" 0 H 0 H N w I - NH2 N N ho 0 Me. \ H \ Me 0 NH 97 HJ 0 VN H N 0 NH OCFs 0 OUF 3 OUF 3 nu NH2 2 5 10 N N 0 O nu nu / F H nu 100 N. N NH NH2 3 0. 9 5 F . rrNH 101 frYN"N"rr' CF3 Cpd Structure HumanHDAC-1 MTT (HCT116) H4Ac (T24) ICso M ICSO M ECso M o nu 102 N N NH NH2 20 6 na 20 6 na I NH2 "NHz nib 9 5 N Po 0' O O i N 105 H 16 14 na 1-11 NH2 OMe N OMe MeO 106 Me OtN vNH 2 2 1 H NH 0 Me 107 MeO N vNH2 17 na Me M » 8 yNH OMe 0 OMe MYE0 108 w 3 108 N NH2 Me NH 0 0 Nu is-NH 109 D C 5 8 15 MeO N 0 N 110 s NH2 3. 999 na e O N NH2 10 2 99 NC N HumanHDAC-1 MTT (HCT116) H4Ac (T24) Cpd Structure ICSO M ICSO M ECso M 112 tC 2 5 5 N 112 Z 2 5 5 \ H N/I NH ---- Ni \ N 113 H 0. 3 5 NU2 OZON 0 /\ 114 \ o N N I i H NHz 25 0. 5' 99 N N Me 0 P/ N N '-J" Hz 0 NU2 /\ NH 116 Me0 I NHZ H N/ 4 2 5 _ OMe OMe 0 i \ NH met Me'v \ 0 118 N Njp 8 na r"""' N N Mye0/ Table 5d HDAC-1 MTT (HCT116) H4Ac (T24) -StructureIC50 (M) IC50 (M) EC50 (HM) H Me0 N H NH2 338 481 Me0 I I /N 22 10- OMe, O I/ 0 H NU H Me OYE Me0 OMe HDAC-1 MTT (HCT116) H4Ac (T24) Ex. Cpd structure IC50 (pM) IC50 (ym EC50 (pM) 0 \ H/I v H 347 492 H3C'01N N H NH2 4 9 10 ZAIN CH, 0 fez \ \ H N 348493 CtN NJ H NH2 4 5- ion N 0 raj 0 H 1_ I H 349 494 H3C'C I \ Nw/\J NHz 3 4 °"CH3 Zu \ \ /N 350 495 OZN \ N \, H NHz 4 7 _ Nos Nos 351 496 0 F _Q 8 13 351 496 O F HN O 8 13 X V H2N H2N 0 tu HsC vlH 352 497 O O . NHz] 5 6- H3C. 0 I/ Ho HsC H3 N'p CH3/\ N 353498 'JLJ H >25 ow NH2 N - nu 0 i/\ N \ I 354 499 H3C0 N \ H NHz >25 2 >25 Hz H3c. o ol CH3 HDAC-1 MTT (HCT116) H4Ac (T24) StructureIC50 (M) IC50 (M) EC50 (M) H3C-O- \/\ O 355 500 H3C \/S HN 23 37- HsC-O)- HZN 0 CH3 356 501 0 N 4 10 O \/ H2N zoo 357 502 NH 3 >25 HIC 3 HZN 3c H2N 358 503 O N NH HN \/5 >25- HzN H2N \ N rYNr 359 504 H'H 5 >25 N NH2 CO LO \/\-O 3 6 360 505 3 6 Han-P Han O/ N 361506, NJ"NHz 15 t1- OCF3 O/ 0 /v ZON 362 507 N NH2 17 10 OMe O/ /\ N 363 508 H ! j H ! 22 11 zone HDAC-1 MTT (HCT116) H4Ac (T24) EX. Cpd structure IC50 (RM) IC50 (EC50 (M) 0 fuzz N 364 509 3, N vH NH2 17 11 nu2 i | 0 H vu H 365 510 N NH2 6 5 H t3 H, CH3 0 fun H H 366 511 HN NH2 4 vGC X N MeO o/ MeO-Y MeO 0 Me0 371 516 N 15 15- BAJ"NH, 372 S17-. HzN Mu0 - HN O 3 7 2 517, N+O 6 5 ome HZN Me0 HsC 0 3 73 518 MW3Ca 4 2 5 Mu0 H2N o o 374 519 Cbo-'N) 99 6- o 4 0 ' 0 /o N NH2 NH 376 521 H 5 2 10 N N I (Ii N H \ o-- 3 NH 377 522 S N NHZ 17 30- H N I \ _ HDAC-1} 1TT (HCT116) H4AC (T24) IC50 (gM) IC50 (PM EC50 (RM) 0 N \ 378 523 NH 8 6 10 Me0 I N/I \ NHa MeOH Met MET /'nu 37g 524 I \ N N l/I NHZ 3 2 3 Sij o H N /. NH 380 525 I \ N N I/ 3 4 5 tU" CL3 0 O \ \ NH 381 526 2 0. 8 1 M6 nez _ H HNH _ 0 \ \ nu 382 527 NH2 4 3 H wNH Me' MYE 0 \ NH 383 528 XNX f NH2 20 3@ HO Ho O \ NH H rN H NH NH2 5 17 N wNH CL3 /I \ NH. 385 530 NH2 8 9 HOU Ha HDAC-1 MTT (HCT116) H4Ac (T24) _ o IC50 (pM) IC50 (pM) ECSO (pM) o Nu NU2 386 531 ß 3 2 20 N \N O N H NH, 3 5 387 532, I N W I/I NH 3 5- NU nec N HNH 388 533 NH f NH2 5 11 _ NHZ 0 H NH NH2 NH 389 534 N 3 5 on/ caf3 O NH H 390 S35 N i cl 0 / NH 391 536 18 9 MeO 0 Melt O NH NH MeO OMe 392 S37 11 2 >25 Mu0 Met \PhNH 393 93 53 8 HN NH2 4 12 / SOzNHz HDAC-1 MTT (HCT116) H4Ac (T24) IC50 (gm) IC50 (gm) EC50 (gM) 0 \ \ NH N I//I, NHz _ 394 539 2 10 ozs\H H 00 0 /I NH met Met Met 0 Nu 39G 541 NH HsC. C / H3C, 0 9H3 H NH o 397 542 p I N /I \ NHz. 2 5 4 Hz H \ 'N H H nu 398 543 15 >25 NAH Non H NU Nu 399 544 N-N H Nez N H O \ NH 400 545 N NH2 Br 0 H nu 401 546 N NH2 3. 10 fizz 0 O NH 402 547 H NH 4 8 N NH2 HDAC-1 MTT (HCT116) H4Ac (T24) Ex. Cpd 8tructure IC50 (pM) IC50 (pM) EC50 (pM) 0 NU 403 548 2 3 9 y r 0 H NU PHNH 404 549 4 19 0---'OH o NU 405 550 H NH On 0 Nu 406 551 y N NH2 24 9 NOs 0 nu 4'0 7 552 H NH 4 22 f L oN<$NHz 4 12- ci 0 H NU NJ :) - zu CI ci Nu 409 554 H NH F N Nu 410 55S N NH2 14 7 U SMe 0 NU 411556 yHjU H, 1 0. 4 15 MEUS 0 NH 412 557 H NH 4 6 w/ Br I/ HDAC-1 MTT (HCT116) H4Ac (T24) Ex. Cpd structure IC50 (pM) IC50 (pM) EC50 (pM) 413 558 H 7 10 H N 0 0 \ 414 559 H NH 4 11 / zizi 0 Me0/\ NH H 415 560 Me0 N \ I/NHz 21 6 MeOMe OMe OMe H3C°Ht HsC. o s 416 561 3 sO H | Hß >25 >25 OMe H wNH nec ZOU 0 417 562 MeOtzN9tJ f NH2 5 Me OMe oye OMe \ 418 563 HN H\ NH 24 6- I\ N I//I NHz Mu0 Hso H3Coo H3C. 0 i 419 564 3C, 0 N NH2 >25 >25 H H Nu2 0 ruz O 420 565 F N \ H NH 5 17 H3CxSD -- F N'p F F H/\ N 421 566 NsH9H 3 16 F ON 02No+N H H ozN y/W 42 2 567 H Co4N~ H NH2 13 3 H3C, o s ° HDAC-1 MTT (HCT116) H4Ac (T24) IC50 (M) IC50 (IVn EC50 (, M) __ N N 423 568 H3c0N H NH2 >25 39 H3C. I i ol CH3 NU C) l3 NH, 424 569 H I NJ \ I NHZ 18 6- 3 han Cl3 HzN Con3 HN H3C 0 0--NH NU H, C H3C-O Table 5e Human HDAC-1 MTT (HCT116) H4 AC (T24) ICso (M) ICso (M) ECso (CM) 0 8 NH 2 1 5 , ¢ f H f rNN- Sr' lf"I Me0 126 xCHN4i/O. 3 0. 2 1 SNH Ny nu 0'N'al s 128 H 0. 3 5 HAN -S 0 131 N \/HN 0. 3 0. 9 2 H2N 0 vu 13 9 Me 3 3 5 -N Me N-N 141 7 10 na N-N M O N H, N HZN HzN ". Human HDAC-1 MTT (HCT116) H4 Ac (T24) Cpd Structure ICso ( (M) ECgo (M) 0 149 aN H H 0 w 0 O 0 N 15 2 U t O. 3 11 na 0\ II N w 0 0 TN) ] H NHz nu2 0. 3 0. 4 <1 N C O fiTN'Y H NHz 155 (ly--Hl Z 0. 4 0. 4 1 o 0 0 w NON y H O H NH2 0 158 O RNt 0. 4 0. 2 1 Endo Mye O 0 N MeO H NH2 3 Me0 MeO \/\ CHs _ H3CP H, C H, C HsC 166 met N--Q 2 5 5 Han HzN o ruz 167 H NH 4 0. 5 2 H N Me0 H 0 MeO"Z4 NP 16 8 Me0 3 0. 8 2 . _. H N N H Human HDAC-1 MTT (HCT116) H4 Ac (T24) ICso (M) ICso (/M) ECso 0 vNH NH NH2 169 MeO N NH 0. 7 1 I OMe OMe O 171 NH 171, Cf s N f 2 8 3 25 I S N I MeO 0 \ nez 172 N NH2 s 0 174 F N-Q 4 0. 4 5 ., A NH, H 0 O \ \ 175 j) J H L 4 0. 5 3 H N N N XI N 176 Me0 N H NH2 5 1 3 Met H OMe OMe N \ , N S I/H NH2 ( 177 N Y 1 0. 4 1 0 0 Table 5f H4 Ac Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structure (T24) ICso (/. tM) ICso (FM) ECso (lM) 0 N i NHZ 0 0 o I w o/ - rYi H NH, N H, c o I/ Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structure (T24) EC50 (ILM) ECso (IM) /N NHZ 119 l81 , No I/N 0. 5 0. 4 1 J o J _ o 4 hazy °' N 122 186 HNH, 2 2 2 ! 1 Nay I 123 187 H NH, 2 5 2 nu o ruz N . _ O/ Melon MeON-A' 12 5 18 9 Me0 N / mye0 Me0 N 126 190 H NH2 3 1 >5 N t X MeO o N /H NH2 JL H NHz 127 192 2 1 3 NH BZW OMe O H 128 193 NH2 4 16 H2C CH3 Cl s NHz 129 194 0 H, C-0 HZN Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structure ICSO (M) ICSO (M) (T24) ECSO (AM) 0 NH 130 195 H3Ct J f NH2 7 9 H CHU CH3 0 I 131 196 nb'NH2 4 3 CL2 PH3 CH3 H CSi NH Hic HsC . , 132 198 mNt2 24 14 /N Nu H NH2 133 199 Nt 7 9 _ b t l 134 201 S 5 O I H NHz "toys zozo Osa /N\/O \ I SN \ O 144 228 H 3 0. 3 1 HZN HN e--NW O C S 145 231 H3C, 03 ? HN--) 4 1 3 H C'0 HZN N _H 0 H, C, 0a S 146 233 ° S H 0. 9 0. 3 1 HAN HN cyH 147 236 H N\b 5 6 N />-S O Human HDAC-1 MTT (HCT116) R4 Ac Ex Cpd Structure (T24) ECBD (ftm) \ N N NH2 0 0 xi 149 240 NH No<H NH2 1. 8 10 \ N N=N NU 0 I/N \ N 150 243 2 0. 8 1 CI N. p_CH3 NHz O/N p N w N CI/1111Wp/ 1, 5J- 247 0\ N 0 3 0. 6 2 NU c. L cil 51 247 > Nt 4 _ H v NH2 Mn) 152 249 /N N o/ N IH NH2 H 153 252 s N_d 8 1 2 0 0 S N NHZ 154 255 N p I i N 2 0. 8 1 N H3C) 0 0 Il 257 H_6 0. 4 0. 4 1 155 N O 0 156 259 H3C N H NH2 3 0. 3 1 H3C S N o zu NHz Son-) 157 262 H 0. 5 0. 3 1 N o/ ß v- NHZ 158 265 mNf 2 2 3 0 0-6 Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structure (T24) ICso <M) ICs. (M) 0 H ECSO NHZ 15 9 2 6 6 H 2 N o 0 0 \ nu 160 269 H3C /N 9 4 o po oh 161 270 HN H NH2 4 1 5 i o (i o- 0 0 162 272 H NH2 2 0. 6 <1 o OH /\ 163 275 H NH2 4 0. 9 2 zu O CH3 N. NH2 164 277 vH, oS 4 0. 3 1 o i chus CH3 NC NH2 165 281 s N 0. 5 0. 6 1 C3 O - 166 284 O-N vN 3 5 H3C'\N I \ I H NHZ p H NH2 H I 3C-0-H NH, N - "3 CHs fi) , » N 9 i N 168 8 2 8 9 H C° AmS 17 5 hic O CH3 CH3 p-CH3 i HZN 169 290 3 Hic \/ \/Q Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structure ICso (CM) ICso (M) (T24) ECso ( ! M) 0 Q N 20 7 170 296' N 20 7 oxo Ho H3 N3 H3C Mezzo \ N 171 297 Meo H NH2 7 0. 4 met Mu0 0 O 172 301 H3C-0 n 3 3 NU p 2 P / 173 305 30-0 N 4 2 O met N N Me (-N YS- H ? H 17 3 3 0 5 H3gNX 4 2 174 311 N r N 0. 9 0. 7 1 H SUE NH2 NHZ f ! NHZ T ? Y1 178 317 HN 0 ICH Meon OMe 0 0 179 9 319 XSJNH2 4 8 Nu2 zu O 0 H 180 320 N N I H NHZ 2 1 0 CI 0 181 321 N n"P 0. 5 0. 3 5 Nu, zu Nip 182 322 H H 0. 7 0. 4 2 N yN NH, Br--C : s tT-Rr* Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structure (T24) ICSO (NM) ICso (/. tM) ECso (FM) O Me0 OMe 183 323 H NHz 1 0. 6 1 Me0 r N H \ nez S I H NHz 184 325 N,, S NH2 0. 3 1 2 N zon H H as 326 NZ s 1 3 H H ! N H 186 327 I \ NH 2 5 3 N NH2 NH. / 187 328 \ N \ ( 17 10 N I/H NH NH 0 N N fY"T 189 330 NN i 3 2 1 HZN N CH, NH HzN O I/N \ N 190 331 NH \>HCI 4 10 NU N NH2 NH O I/N \ N 191 332 NH \ 0. 4 1 5 ci Ob N NHz NH 1 nu z NH 192 333 I \, cIN 2 0. 1 1 ( : NH2 HIC Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structure =Cso (M) ICSO (, M) (T24) ECgo ( (M) HZN 193 334 H HN 8 0. 2 1 Cr N HN zizi N CI/N \ NHz 195 336 O I/ 0 /N \ NH 196 337 N H15 N CH3 \ CL3 0 0 met zu 0 /N NH2 198 339 4 3 F N-) N 0 N N. I \ NHZ H 199 340/Np/I \ 2 1 1 0 H3CNCH3 0 N I NHZ N pin 200 341 p /4 1 3 N p bu 201 342 j N NHZ 201 342 H N CH3 O I/ O H 202 343 H NHZ 0. 5 0. 3 1 /N I Human HDAC-1 MTT (HCT116) H4 Ac ex Cpd Structure (T24) ICso (tM) ICso (tM) ECso (/. tM) B io Br/N \ NH 203 344 H3I cN0 0 1-6 0. 5 0. 2 1 0 H3J 6 NH, N I NHZ 204 345 N 0. 4 0. 8 1 o Met 0 346 Br N 205 N) N 3 0. 5 <1 zu O I/ - Br N H2N 'N N 2 0. 6 2 e o- N 2 0. 3 1 CL 207 348 N N N 0/ I\ F'N'N \ NHa 208 3 4'9 F N N 13 1 3 0 0 F F JT'rJ,. 209 350 F N H /N H2N 2 1 5 H N zu zon N 211 352 N °-N o H3C-\v I 212 353 H3C N H NH2 3 10 N te N XH9N 213 354 N H NH2 15 5 N O-N Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structure ICso (M) ICso (M) (T24) ECso (IM) N f'N O 214 355 N HN--p 25 10 HzN 0 215 356 FA0s Nt 5 2 _ /v I/H NHz H, N 216 357 \N'0 N 4 0. 4 2 N I/H NHz N NH2 217 3S8 P-N N 3 1 2 H NH2 - S I/N 218 359 HN 2 0. 3 mon /cl3 CHs NC y NH2 N 5 0. 2 1 NH O I/ CH3 NC H NHz 220 361 O S i N 2 0. 5 1 fY-N 0 U 361 N, 16 F\-N'H 0 Fi CH3 r _N \ H NHx 221 362 il 1"6 2 0. 7 1 0 0 tN H NH2 222 363 oo 2 0. 3 3 - o 223 364 0'H 4 0. 6 \ N/NHz Zon 0 O 224 365 OH HN-Q 3 0. 6 3 H2N Human HDAC-1 MTT (HCT116) R4 A Ex Cpd Structure (T24) ECgo (jUM) 01 ( : yNI \ H NH2- 225 366 ¢y ANß 14 10 o 0 226 367 MeO 0 1 ; 2 5 HN OMe OMe Han 230 371 HN N 4 0. 5 2 ich N/ MET OMe Cl 0 1 /p zN/ 231 372 HNs¢O NX 2 O. 2 1 H. \ N/ Me0 I/ OMe H2N O/ Han 0 232 373 /H 4 0. 4 1 Me0/ OMe OYE °0 o- 233 374 NH 2. 5 0. 3 1 , o/\ N/\ o HsC HN H2NP han NU NH2 \ NHZ 234 3 4 3 7 5 HN 3 4 25 HNy HAN h Human HDAC-1 MTT (HCT116) H4 Ac Cpd Structure (T24) ECso ßHNe Ho H / 235 376 3 0. 1 1 H /-S Mye0 N CN/kNv />--N O N 236 377 aNH 4 2 3 /NHZ . 0 N 237 378 H, C IN5 NH2 2 0. 7 2 iN \ 0 0 'NH 238 379 N g \ (NH 2 0. 6 15 e owo ion 239 380 H N-NH 6 8 NHZ NH \ s o N 240 381 NH 2 1 2 NHZ 0 PHNH 241 382 H, C N NH 3 1 3 Cl, CH, H3C QN O 242 383 H3C gH 2 0. 5 2 cl HsC \/> 0 n0-O 243 384 H3C N \/NH 3 2 5 NHZ H4 Ac Human HDAC-1 MTT (HCT116) H4 Ac ---ß o ICSO (wM) ICSO (fM) HO HN N/0 244 385 H3Cuo NJ HNn 3 1 2 Ho, HZN Ho Ouzo 245 38G 3 1 1 o I\ HZN Cl -.- ,, o 246 387 H3c-o N H 2 1 1 3 NNz HN \ H3f, _0/^y il\/O 247 388 N\ J HN \ 3 0. 4 5 H, C'° H, N H3c 10 H2N H 0 \ N 248 389 N H f NH2 3 0. 2 1 2 H3C. 0''N''N \ H 249 390 2 0. 8 5 NU NH N 0 250 391 Vs G 1 0. 9 3 /NHZ 0 NU H\y/I 251 392 H3C-o'N w/I NH2 4 1 1 H 3 C , \ H, C' 0 ANS 252 393 H3 N \ I Z 4 0. 6 1 H HC zut, Humaa HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structure (T24) "\/=\ ECso (M) s o 2 5 3 3 9 4 H3co NH 4 2 2 5 NH H, C-0 O 254 395 o 2 5 H3c-o HN han \ 255 nNß 2 o 7 N 0 , PH3 0 256 397 O-NH. 0 1 0. 6 4 _ H2N R WHo 14 9 CH3 HAN NHz nu iN nu o 259 400 H 8 0. 3 2 \ HN NH 0 HN NH O 260 401 6 0. 3 2 HN 0 fuzz . r nu2, 14 0. 4 1 261 402 N ( ou Hic HgN H3C HzN Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structure (T24) kc5o (gm) N N\ \ HsCO/ 263 404 NH O 3 0. 6 5 -/1,,/ + H2N HZN 264 405 HsC. O H3C, 0 HO O/ HO 265 406 H3Cso4N 2 3 11 0, cl3 N . oui 266 407 H3C,, qN NH2 3 2 CHs Hz H j H 267 408' 4 2 N (Nr /N 268 409 H H 3 1 9999 HsC CL3 N CH3 N 269 410 H H 0. 9 0. 1 >5 H3C CH3 X X 270 N cor Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structure (T24) Ecso (AM) o fuzz r 2 71 412 W 3 2 3 H Mu0 OMe \ 272 413 H NH 2 2 3 \ I H 0 N 273 414 H NH2 3 1 1 : ru 0 Me0 \ O 274 415 3 1 3 N NH2 O/ /N \ 275 416 WHN 2 3 0. 6 1 n n H \ F O 276 417 aN N 2) l 1 y 0 0 I 277 418 CI N/N \ I NHZ 3 0. 9 2 \, TN Me Me 278 419 CI4yN NH2 2 1 5 sly N ci 0 H/I H 279 420 CI N, YN \ NH 3 0. 7 1 /N/ HAN N Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structura (T24) ICSO (LM) ICSO (tM) ECSO (M) - 280 421 H 4 0. 6 1 N, _Io NH2 H NX 281 422/'N \ H NHz <0. 05 0. 9 5 Fui H) t ! H) N NH2 F N \ I NHz 282 423 FO O. 5 1 3 \ F 0 F-Y F \ H 283a 424b H H2 2 0. 4 1 MeO OMe "FIZZ H H H 283b 424c j9, N9 NH2 3 0. 8 3 Me0 I MeO 0 OMe 284 425 N 2 0. 6 5 Zu OF OCF3 285 426 H-P 2 1 10 Ich NIO NH, /\ 286 427 H H 0. 6 2 1 Meon Meon H sJIsNX 287 428 N H NH2 0, 1 (au \ (liCT116) H4 Ac Human HDAC-1 MTT (HCT116) H4 AC Ex Cpd Structure....'. T24 ICs, (M) ICso (/<M) N ANX 1 fez \ 288 429 H H 4 0. 9 1 atome N zoé 011N 289 430 \ N \ I NHz 5 0. 7 1 ORME oye \ \ 290 431 5 5 F O N /H NHZ Fah F H cri ci 2 91 4 3 2 MeO NiN1N NH2 2 1 3 H H H //\ Mu0 OMe | A OMe CI me0 292 432 Me0 \ I N NN \ NH2 2 0. 6 1 H i"1 H H'N 0 O I/ H H OMEN MET Me0/ OMe z NON 294 435 ! ! H H ! 3 0. 6 1 . s 2iNX 295 436 H 0Njp _ Hv NU /N \ 296 437 N H NH 3 0. 4 1 2 H3C.. S TTAn Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd structure ICso (#M) ICso (yM) (T24) E, Cpd O \ 297 438, N \ I H NHz 5 0. 6 1 \I SMe cri jN 'N- 298 439 \ I N'H I j N NHZ 3 0. 4 1 mye0 I MeO OMe Zu NN u NHz 299 440 H3C, 0 H N, 6 4 0. 1 2 -Y H3C 0 0 0 cl3 O CH3/N N \ H NHa 300 441 I . 2 0. 8 2 H3C 10 Met N Mye0 N 301 442 H H H 17 0. 4 1 ZON 3C,' _ C H HsCgj HO o a X N 302 443 H t NH2 HsC" H3 . 0 Oh 0 N 303 444, N \ I H NH Oye ORME 0 N-9 OYE 304 445 met N I N H NHz 16 6 mye0 OMe O H N N\ H 305 446 H NH, 21 7 ° trAn Ex Cpd Structure Human. HDAC-1 MTT (HCT116) H4 Ae Ex Cpd Structure' (T24 O 0 NH 307 448 NH 3 0. 2 2 N H3C S. % 0 HZN 308 449 N N w I NHZ 1 6 NX zu H H 0 0 H f<NH 309 450 3 2 s FiF F 0 N 310 451 H NH N nu N 2 4 H O N 311 452 gNgN<NH2 3 O. 3 2 s-- (o I/ 0 CH NH 312 453 oA NX WNH2 9999 37 HsC. O /F 0 F .. Zu CH3 H eNH c H rr' 313 454 0 N NH2 4 2 5 H3Cso) FS ol . C /NH H N NH, 4 0. 7 1 ou 0 oRoU U S X M <NHz 3 0. 4 8888 _ HNMe< X -S /NHz F4 NH 316 457 Meo N I/ 9999 9999 HzN Mu0 Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structure =C5o (FM) ICso (M) (T24) 0 O H eNH 0 nu 317 458 H3C \NX X f NH2 3 O. 3 2 'yU U 0 0 0 o ro H rr 318 NH NH2 4 0. 3 1 o N I \ I _ H CNH HsC hic I H N I H NU ZON HJXNH H U Hz O N CH3 0 nu H I 321 462 N ON H j [ 321 N &NH2 4 0. 3 1 N H3c \ N \ 322 463 N H NH2 No- OH O 323 464 H3° \ i N I 4 11 I I H NHZ NH2 nez 324 465 NH2 2 9999 9999 s XNX I \ N 325 466 < H NH2 3 2 1 /\ \ s N J horn H nez w fV 326 467 N H 4 0. 4 2 VS Br H4 Ac Human HDAC-1 MTT (HCT116) H4 Ac Ex Cpd Structure ICso (M) ICSO (M) (T24) 327 468 Hil 2 8 [ H N 327 468 N I/H NH 2 $ <1 . NN H zon . ruz 426 571 MeON H OH 4 11 Me0 OMe 0 fuzz rV _ H X 427 572 OH 1. 5 5'5 S ! . OMe H2N OYE 0-\ HN N 428 573 N-7 0. 4 1 --H O ____ O zu me0 H 429 574 I \ N/NHz 13 0. 7 3 Me0 OMe HN han \ H, C' / H 0 NU O NH 431 576 NH2 5 6 v,, p, N 432 ß H3CAN10<H42 2 05 2 zon N H NH2 run 0 N ZON w 433 578 0. 6 0. 1 Me0 N N I \ Met N o _ __ H3C- s 434 579 HN H NH2 HzN O I/ 0 0 '"H4Ac* Human HDAC-1 MTT (HCT116),.., n Ex Cpd Structure.., -',. (T24) ECso (FM) N' N 435 580 H3C H<He2 4 0. 3 <1 o o 0 Me0'"HN Oye MeO-q H2N OMe \ d O 437 590 H2N 2 2 3 Met OMe f 438 591 N HN--p 4 0. 3 <1 Me0 \ NH HzN ci0 439 592 OMe 5 0. 4 <1 Me0'HzN OMe Assay Example 2 Antineoplastic Effects of Histone Deacetylase Inhibitors on Human Tumor Xenografts In Vivo [0413] Eight to ten week old female BALB/c nude mice (Taconic Labs, Great Barrington, NY) were injected subcutaneously in the flank area with 2 x 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 62 9 51b 87 3 ob 157 66a 167. 58a 15 26b 168 26b 16 50b 154 23a 98 52a a : 20, mg/kg i. p. b : 40 mg/kg i. p.

Table 7 Antineoplastic Effects Of Histone Deacetylase Inhibitors On Nude Mice Xenograft Models % Inhibition Of Tumor Growth cpd A 549 SW48 (p. o.) A 549 HCT 116 SW 48 (p.o.) (i.p.) (i.p.) (i.p.) 106 40% (70 16% (60 - - - mg/kg) mg/kg) 164 42% (70 62% (60 37% (20 99% (25 mg/kg) mg/kg) mg/kg) mg/kg) 228 45% (70 25% (60 64% (20 45% (20 68% (20 mg/kg) mg/kg) mg/kg) mg/kg) mg/kg) 424. 67% (50 78% (30 60% (50 77% (75 68% (25 b mg/kg) mg/kg) mg/kg) mg/kg) mg/kg) Assay Example 3 Combined Antineoplastic Effect of Histone Deacetylase Inhibitors and Histone Deacetylase Antisense Oligonucleotides on Tumor Cells In Vivo [0414] 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.

[0415] 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.

10416] 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.

[0417] 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.