AU2006252047A9 - Inhibitors of histone deacetylase - Google Patents

Inhibitors of histone deacetylase Download PDF

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AU2006252047A9
AU2006252047A9 AU2006252047A AU2006252047A AU2006252047A9 AU 2006252047 A9 AU2006252047 A9 AU 2006252047A9 AU 2006252047 A AU2006252047 A AU 2006252047A AU 2006252047 A AU2006252047 A AU 2006252047A AU 2006252047 A9 AU2006252047 A9 AU 2006252047A9
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optionally substituted
compound according
aryl
phenyl
heteroaryl
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AU2006252047B2 (en
Inventor
Giliane Bouchain
Daniel Delorme
Sylvie Frechette
Silvana Leit
Oscar Moradel
Stephane Raeppel
Arkadii Vaisburg
Soon Hyung Woo
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Methylgene Inc
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Methylgene Inc
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Description

S&F Ref: 668457D1
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Methylgene, Inc., of 7220 Frederick-Banting, St. Laurent, Quebec, H4S 2A1, Canada Giliane Bouchain Daniel Delorme Sylvie Frechette Silvana Leit Oscar Moradel Stephane Raeppel Arkadii Vaisburg Soon Hyung Woo Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Inhibitors of histone deacetylase The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c(609550_1) INHIBITORS OF HISTONE DEACETYLASE cN BACKGROUND OF THE INVENTION S Field of the Invention [0001] This invention relates to the inhibition of histone deacetylase. More particularly, the invention relates to compounds and methods for inhibiting histone deacetylase enzymatic activity.
Summary of the Related Art 0 [0002] In eukaryotic cells, nuclear DNA associates with histones to form a compact complex S 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 S to form a protein core. DNA winds around this protein core, with the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA. Approximately 146 base pairs of DNA wrap around a histone core to make up a nucleosome particle, the repeating structural motif of chromatin.
[0003] Csordas, Biochem. 286: 23-38 (1990) teaches that histones are subject to posttranslational acetylation of the a,e-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.
[0004] 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: 48684873 (1999), teaches that HDACs is divided into two classes, the first represented by yeast Rpd3-like proteins, and the second represented by yeast Hdal-like proteins. Grozinger et al. also teaches that the human HDAC1, HDAC2, and HDAC3 proteins are members of the first class of HDACs, and discloses new proteins, named HDAC4, HDAC5, and HDAC6, which are members of the second class of HDACs. Kao et 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.
I0 [0005] Richon et al., Proc. Natl. Acad. Sci. USA, 95: 3003-3007 (1998), discloses that HDAC O activity is inhibited by trichostatin A (TSA), a natural product isolated from Streptomyces o hygroscopicus, and by a synthetic compound, suberoylanilide hydroxamic acid (SAHA). Yoshida and Q Beppu, Exper. Cell Res., 177:122-131 (1988), teaches that TSA causes arrest of rat fibroblasts at the Gi and G 2 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, 0 EP 0847992, JP 258863/96, and Japanese Application No. 10138957, disclose benzamide S derivatives that induce cell differentiation and inhibit HDAC. Delorme et al., WO 01/38322 and PCT N 1B01/00683, disclose additional compounds that serve as HDAC inhibitors.
[0006] The molecular cloning of gene sequences encoding proteins with HDAC activity has established the existence of a set of discrete HDAC enzyme isoforms. Grozinger et al., Proc. Natl.
Acad. Sci. USA, 96:4868-4873 (1999), teaches that HDACs may be divided into two classes, the first represented by yeast Rpd3-like proteins, and the second represented by yeast Hdal-like proteins. Grozinger et al. also teaches that the human HDAC-1, HDAC-2, and HDAC-3 proteins are members of the first class of HDACs, and discloses new proteins, named HDAC-4, HDAC-5, and HDAC-6, which are members of the second class of HDACs. Kao et al., Gene Development 14:55- 66 (2000), discloses an additional member of this second class, called HDAC-7. More recently, Hu, E. et al. J. Bio. Chem. 275:15254-13264 (2000) discloses the newest member of the first class of histone deacetylases, HDAC-8. It has been unclear what roles these individual HDAC enzymes play.
[0007] These findings suggest that inhibition of HDAC activity represents a novel approach for intervening in cell cycle regulation and that HDAC inhibitors have great therapeutic potential in the treatment of cell proliferative diseases or conditions. To date, few inhibitors of histone deacetylase are known in the art. There is thus a need to identify additional HDAC inhibitors and to identify the structural features required for potent HDAC inhibitory activity.
BRIEF SUMMARY OF THE INVENTION [0008] The invention provides compounds and methods for treating cell proliferative diseases.
The invention provides new inhibitors of histone deacetylase enzymatic activity.
[0009] In a first aspect, the invention provides compdonds that are useful as inhibitors of histone deacetylase.
NO
[0010] In a second aspect, the-invention provides a composition comprising an inhibitor of histone deacetylase according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
[0011] In a third aspect, the invention provides a method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase of the invention.
[0012] The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below.
BRIEF DESCRIPTION OF THE DRAWINGS [0013] Figure 1 is a graph showing the antitumor activity of compound 106 in an HCT 116 human colorectal tumor model.
[0014] Figures 2-11 show additional data for other compounds used in the in vive experiment described in Assay Example 2.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0015] The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions. The patent and scientific literature referred to herein establishes knowledge that is available to those with skill in the art. The issued patents, applications, and references that are cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference. In the case of inconsistencies, the present disclosure will prevail.
[0016] For purposes of the present invention, the following definitions will be used (unless expressly stated otherwise): [0017] As used herein, the terms "histone deacetylase" and "HDAC' are intended to refer to any one of a family of enzymes that remove acetyl groups from the ,-amino groups of lysine residues at the N-terminus of a histone. Unless otherwise indicated by context, the term "histone" is meant to refer to any histone protein, including H1, H2A, H2B, H3, H4, and H5, from any species. Preferred histone deacetylases include class I and class II enzymes. Preferably the histone deacetylase is a human HDAC, including, but not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6,
\O
0 c HDAC-7, and HDAC-8. In some other preferred embodiments, the histone deacetylase is derived 0 from a protozoal or fungal source.
[0018] The terms "histone deacetylase inhibitor" and "inhibitor of histone deacetylase' are used to identify a compound having a structure as defined herein, which is capable of interacting with a histone deacetylase and inhibiting its enzymatic activity. "Inhibiting histone deacetylase enzymatic Sactivity" means reducing the ability of a histone deacetylase to remove an acetyl group from a N histone. In some preferred embodiments, such reduction of histone deacetylase activity is at least N about 50%, more preferably at least about 75%, and still more preferably at least about 90%. In Sother preferred embodiments, histone deacetylase activity is reduced by at least 95% and more N preferably by at least 99%.
[0019] Preferably, such inhibition is specific, 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 lower, and most preferably at least 20-fold lower than the concentration required to produce an unrelated biological effect.
[0020] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties 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-CH-), 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 -CH 2
-CH
2 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 4 for carbon, 3 for N, 2 for 0, and 2, 4, or 6 for S, depending on the oxidation state of the On occasion a moiety may be defined, for example, as 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 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.
1 [0021] The term "hydrocarbyl" refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, S each as defined herein. A "Co" hydrocarbyl is used to refer to a covalent bond. Thus, "Co-Chydrocarbyl" includes a covalent bond, methyl, ethyl, propyl, and cyclopropyl.
S [0022] The term "alkyl" as employed herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. A "Co" alkyl (as in "Co-C 3 -alkyl") is a covalent bond (like "Co" hydrocarbyl).
[0023] The term "alkenyl" as used herein means an unsaturated straight or branched chain N aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
[0024] The term "alkynyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
[0025] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
Preferred alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
Preferred alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene.
Preferred alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.
[0026] The term "cycloalkyl" as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
[0027] The term "heteroalkyl" refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are replaced by a heteratom selected from the group consisting of 0, S, and N.
IN [0028] An 'aryl' group is a C 6
-C
14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted. Preferably, the aryl group is a C 6 -Co 1 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 (Ci-C 6 )alk(C 6 -Clo)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
S [0029] A "heterocyclyl" or "heterocyclic' group is a ring structure having from about 3 to about 8 atoms, wherein one or more atoms are selected from the group consisting of N, 0, and S. The heterocyclic group is optionally substituted on carbon at one or more positions. The heterocyclic group is also independently optionally substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl. Preferred heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino. In certain preferred embodiments, the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group. Examples of such fused heterocyles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the scope of this term are compounds having adjacent annular 0 and/or S atoms.
[0030] As used herein, the term 'heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 n electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, 0, and S. A 'heteroaralkyl" or "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 CiC 6 alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms. Specifically excluded from the scope of this term are compounds having adjacent annular 0 and/or S atoms. Examples of preferred heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, and thiazolylethyl. Specifically excluded from the scope of this term are compounds having adjacent annular 0 and/or S atoms.
[0031] An "arylene," "heteroarylene," or "heterocyclylene" group is an aryl, heteroaryl, or heterocyclyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
IND [0032] Preferred heterocyclyls and heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aHcarbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H-,6H-11,5,2-dithiazinyl, dihydrofuro[2, 3-bitetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 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, CK1 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, tetra hydrofu ra nyl, tetrahydroisoquinolinyl, tetra hydroqu inolinyl, tetrazolyl, 6H-1 ,2,5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2 ,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1,3 ,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1, 2,3-triazolyl, 1,2 ,4-triazolyl, 1,2, 5-triazolyl, 1 .3,4-triazolyl, and xanthenyl.
(0033] As employed herein, when a moiety 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 an annular CH- substituted with oxo is 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: halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino,
CI-C
5 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, CI-C 8 alkyl, CIrC8 alkenyl, C 1
-C
8 alkoxy, CI-C8 alkoxycarbonyl, aryloxycarbonyl, G 2
-C
8 acyl, C 2
-C
8 acylamino, CI-C 8 alkylthio, arylalkylthio, arylthio, CI-C 8 alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, CI-C 8 D alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, CoCs N-alkyl carbamoyl, C-Cs 1
N,N-
Sdialkylcarbamoyl, C-C7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C 3
-C
7 heterocycle, or any of these rings Sfused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in above; and
(CH
2 )s-NR 30
R
31 wherein s is from 0 (in which case the nitrogen is directly bonded to the moiety that is substituted) to 6, and R 30 and R 31 are each independently hydrogen, cyano, oxo, carboxamido, amidino, Ci-C8 hydroxyalkyl, Ci-C 3 alkylaryl, aryl-C 1
-C
3 alkyl, CrI-C alkyl, Ci-C 8 alkenyl, Ci-Cs alkoxy, Ci-Cs alkoxycarbonyl, aryloxycarbonyl, aryl-C 1 SC3 alkoxycarbonyl, Cz-Cs acyl, Cl-Cs alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, aroyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in above; or
R
30 and R 3 1 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 above.
[0034] In addition, substituents on cyclic moieties cycloalkyl, heterocyclyl, aryl, heteroaryl) include 5-6 membered mono- and 10-12 membered bi-cyclic moieties fused to the parent cyclic moiety to form a bi- or tri-cyclic fused ring system. For example, an optionally substituted phenyl includes the following: [0035] A "halohydrocarbyl" is a hydrocarbyl moiety in which from one to all hydrogens have been replaced with one or more halo.
[0036] The term 'halogen' or "halo' as employed herein refers to chlorine, bromine, fluorine, or iodine. As herein employed, the term "acyl' refers to an alkylcarbonyl or arylcarbonyl substituent.
The term "acylamino" refers to an amide group attached at the nitrogen atom R-CO-NH-). The term "carbamoyl" refers to an amide group attached at the carbonyl carbon atom NH 2 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 NH 2 alkylamino, arylamino, and cyclic amino groups. The term 'ureido' as employed herein refers to a substituted or unsubstituted urea moiety.
CK1 [0037] The term "radical" as used herein means a chemical moiety comprising one or more unpaired electrons.
[0038] A moiety that is substituted is one in which one or more hydrogens have been independently replaced with another chemical substituent. As a non-limiting example, substituted phenyls include 2-flurophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluor-3-propylphenyl. As another non-limiting example, substituted n-octyls include 2,4 dimethyl-5-ethyl-octyl and 3-cyclopenty- S octyl. Included within this definition are methylenes (-CH 2 substituted with oxygen to form carbonyl S CO-).
[0039] An "unsubstituted" moiety as defined above unsubstituted cycloalkyl, unsubstituted heteroaryl, etc.) means that moiety as defined above that does not have any of the optional substituents for which the definition of the moiety (above) otherwise provides. Thus, for example, while an "aryl" includes phenyl and phenyl substituted with a halo, "unsubstituted aryl" does not include phenyl substituted with a halo.
[0040] Preferred embodiments of a particular genus of compounds of the invention include combinations of preferred embodiments. For example, paragraph [0042] identifies a preferred Ay' and paragraph [0046] identifies preferred Ar' (both for compound of paragraph [0041]). Thus, another preferred embodiment includes those compounds of formula in paragraph [0041] in which Ay 1 is as defined in paragraph [00421 and Ar 1 is as defined in paragraph [0046].
Compounds [0041] In a first aspect, the invention provides novel inhibitors of histone deacetylase. In a first embodiment, the novel inhibitors of histone deacetylase are represented by formula
R
3
R
4
N
N N Y' N Y 2 (1) and pharmaceutically acceptable salts thereof, wherein
R
3 and R 4 are independently selected from the group consisting of hydrogen, Cy', and -L 1 Cy 1 wherein
L
1 is Ci-C 6 alkyl, C 2
-C
6 heteroalkyl, or C 3
-C
6 alkenyl; and 9
IO
0 1 Cy' 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
R
3 and R 4 are taken together with the adjacent nitrogen atom to form a or 7-membered ring, wherein the ring atoms are independently selected from the group consisting of C, 0, S, and N, 0 1 and wherein the ring optionally is substituted, and optionally forms part of a bicyclic ring system, or C1 optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially Sunsaturated cycloalkyl or heterocyclic rings, each of which rings and ring systems optionally is NC substituted; Y' is selected from the group consisting of 2
-CH
2 2 halogen, and hydrogen, wherein R' and R 2 are independently selected from the group consisting of hydrogen, Cy', and -L'Cy 1 wherein L' is Ci-C 6 alkyl, C 2
-C
6 heteroalkyl, or C 3
C
6 alkenyl; and Cy' 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 R' and R 2 are taken together with the adjacent nitrogen atom to form a or 7membered ring, wherein the ring atoms are independently selected from the group consisting of C, 0, S, and N, and wherein the ring optionally is substituted, and optionally may form part of a bicyclic ring system, or optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings and ring systems optionally is substituted;
Y
2 is a chemical bond or N(RO), where RO is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, and acyl; Ak' is CI-C 6 alkylene, Ci-C6-heteroalkylene (preferably, in which one -CH 2 is replaced with and more preferably -NH-CH 2
C
2
-C
6 alkenylene or C 2 -C alkynylene; Ar' is arylene or heteroarylene, either of which optionally is substituted; and Z' is selected from the group consisting of H H 'Ay1 /l N-Ay 0 and 0 0 wherein Ay 1 is aryl or heteroaryl, which optionally is substituted.
[0042] Preferably in the compounds according to paragraph [0041], Ay' is phenyl or thienyl, each substituted with -OH or -NH 2 [0043] More preferably in the compounds according to paragraph [0041], Ay' is optionally amino- or hydroxy-substituted phenyl or thienyl, wherein the amino or hydroxy substituent is S preferably ortho to the nitrogen to which Ay 2 is attached.
[0044] More preferably in the compounds according to paragraph [0041], Ay' is ortho aniline, I ortho phenol, 3-amino-2-thienyl, or 3-hydroxy-2-thienyl, and tautomers thereof.
[0045] In some preferred embodiments of the compounds according to paragraph [0041], Z' is H NH 2 0 [0046] In some preferred embodiments of the compounds according to paragraph [0041], Ar' is phenylene. In some embodiments, Ak' is alkylene, preferably methylene. In some preferred embodiments, Y 2 is In some preferred embodiments, Y' is 2 or -CH 2 2 [0047] In some embodiments of the compounds according to paragraph [0041], R' and R 2 are each independently selected from the group consisting of hydrogen, Cy', and In some embodiments, R' and/or R 2 is hydrogen. In other embodiments, R 1 and/or R 2 is alkyl or alkenyl, preferably allyl. In still other embodiments, R' and/or R 2 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, R 1 and/or R 2 is cycloalkyl, cyclopropyl, cyclopentyl, or cyclohexyl, which optionally is substituted and optionally is fused to one or more aryl rings.
[0048] In some embodiments of the compounds according to paragraph [0041], R 3 and R 4 are each independently selected from the group consisting of hydrogen, L 1 Cy', and In some embodiments, R 3 and/or R 4 is hydrogen. In other embodiments, R 3 and/or R 4 is alkyl or alkenyl, preferably allyl. In still other embodiments, R 3 and/or R 4 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.
I Some preferred aryl, heteroaryl, aralkyl, and heteroaralkyl groups comprise a phenyl, pyridyl, or 0 pyrrolyl ring. In still other embodiments, R 3 and/or R 4 is cycloalkyl, cyclopropyl, cyclopentyl, or cyclohexyl, which optionally is substituted and optionally is fused to one or more aryl rings.
[0049] As set forth above, L' is Ci-C 6 alkyl, C 2
-C
6 heteroalkyl, or C 3 -C alkenyl. However, one skilled in the art will understand that when L' is not a terminal group, then L 1 is CI-C 6 alkylene, C 2 -Cs heteroalkylene, or CrC 6 alkenylene. In some embodiments, L' is alkylene, preferably methylene or ethylene. In other embodiments, L' 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.
N In other embodiments Cy' is cycloalkyl, cyclopropyl, cyclopentyl, or cyclohexyl. In still other c embodiments, Cyl is aryl or heteroaryl, phenyl, pyridyl, or pyrrolyl, each of which optionally is substituted and optionally is fused to one or more aryl rings. In some embodiments, Cy' is fused to one or two benzene rings. In some embodiments, Cy' has between one and about five substituents selected from the group consisting of CI-C 4 alkyl, CI-C 4 alkoxy, and halo. Examples of preferred substituents include methyl, methoxy, and fluoro.
[0050] In some embodiments of the compounds according to paragraph [0041], R' and R 2 and/or R 3 and R 4 are taken together with the adjacent nitrogen atom to form a 5- or 6-membered ring, wherein the ring atoms are independently selected from the group consisting of C, 0, and N, and wherein the ring optionally is substituted, and optionally is fused to one or more aryl rings. In some preferred embodiments, R' and R 2 and/or R 3 and R 4 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 R' and R 2 or R 3 and R 4 is fused to a benzene ring. In some embodiments, the ring comprising R' and R 2 or R 3 and R 4 has a substituent comprising an aryl or cycloalkyl ring, either of which optionally is substituted and optionally is fused to a cycloalkyl, aryl, heteroaryl, or heterocyclic ring. Preferred substituents include, without limitation, phenyl, phenylmethyl, and phenylethyl, the phenyl ring of which optionally is fused to a cycloalkyl, aryl, or heterocyclic ring.
[0051] In a preferred embodiment, the HDAC inhibitors of the invention comprise compounds of formula l(a):
Y
\O
N
N
SX"N J H NH 2 U~ N-6 0 (la) and pharmaceutically acceptable salts thereof, wherein J is C-C 3 -hydrocarbyl, -N(R 20
-N(R
2 0
)-CH
2 or -0-CH 2
R
2 0 is -H or -Me; X and Y are independently selected from -NH 2 cycloalkyl, heterocyclyl, aryl, heteroaryl, and tn A-(Ci-C6-alkyl),-B-; 0 A is H, C 1
-C
6 -alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 0 SB is or a direct bond; and n is 0 (in which case A is directly bonded to B) or 1.
[0052] Preferably in the compounds according to paragraph [0051], A is phenyl optionally substituted with one or more moieties selected from halo (preferably chloro) and methoxy, and B is NH-. In another preferred embodiment, A is selected from cyclopropyl, pyridinyl, and indanyl.
[0053] Preferably in the compounds according to paragraph [0051], J is -NH-CH 2
N(CH
3
)-CH
2 -CH=CH-, or -CH 2
-CH-.
[0054] Preferably in the compounds according to paragraph [0051], R 20 is -H.
[0055] In the compounds according to paragraph [0051] X is preferably selected from N
NH
H vo. -OMe, o- H
S
2 N NN
HH
-MOMe OMe
-NH
2 1 H H6 N and N' and Y is preferably selected from and Y is preferably selected from -H,>-NH4 Hn-BuNH,
I
MeOCH 2
CH
2 NH, -N HNf HN HNHN OMe OMe
HNN
-H Me -OMe CH 3
(CH
2 3
NH-
and CH 3
O(CH
2 2 [0056] In a more preferred embodiment of the compounds according to paragraph [0051], the HDAC inhibitors ol tb 2aipfien comprise the following compounds of formula la: _p J x /y 204 -NH- CI)- _NH -NH 2 207 -OCH 2 I()O-NH -NH 2 210 -NHCH 2
H
212 -NHCH 2 -OMe -OMe 214 -NHCH 2 fj)1:-NH. -OMe 216 1H ~1~NH -Me 218 -NHCH 2 NH -Me 220 -CH=CH- -NH 2
-NH
2 223 -CH=CH- -NH 2 224 -CH 2 CHr' -NH 2
-NH
2
-N
470 -NHCHr- H NH 2 471 -NHCH 2
N
472 -NHCH 2 QI-NH _p J x y 474 -NHCH 2 O "N MeO(CH2) 2
NH
HN
476 *NHCH 2 C>-NH
H
HN
477 -NHCH 2 >-NH HNfI Me 478 -NHCH- C>-NH
IN
OMe 479
-NHCH
2 NHNJ6 Cpd J X Y 480 -NHCH 2
[-NH
HN 481 -NHCH 2 C >-N 482 -NHCH2 Cpd J X Y 483 -NHCH 2 .N Me
H
484 -NHCH 2 0/ NH 2 and 485 -NHCH 2
NH
o 9 [0057] In a second aspect, the novel histone deacetylase inhibitors of-the iivention-arerepresented by formula
R
5 0 Cy 2 -X'-Ar 2
N
R
6 q (2) and pharmaceutically acceptable salts thereof, wherein Cy 2 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; X' is selected from the group consisting of a covalent bond, M'-L 2
-M
1 and L 2
-M
2
-L
2 wherein
L
2 at each occurrence, is independently selected from the group consisting of a chemical bond, C1-C4 alkylene, Cz-C 4 alkenylene, and CrC4 alkynylene, provided that L 2 is not a chemical bond when X' is M'-L 2 at each occurrence, is independently selected from the group consisting of
-N(R
7 S(0) 2 -S(0) 2
N(R
7
-N(R
7 2 -NH-C(O)O-and wherein R 7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl; and
M
2 is selected from the group consisting of M 1 heteroarylene, and heterocyclylene, either of which rings optionally is substituted; Ar 2 is arylene or heteroarylene, each of which is optionally substituted;
R
5 and R 6 are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl; q is 0 or 1; and N Ay 2 is a 5-6 membered cycloalkyl, heterocyclyl, or heteroaryl substituted with an amino or 0 hydroxy moiety (preferably these groups are ortho to the amide nitrogen to which Ay 2 is attached) and further optionally substituted; provided that when Cy 2 is naphthyl, X' is -CH 2 Ar 2 is phenyl, R 5 and R 6 are H, and q is 0 or 1, S Ay 2 is not phenyl or o-hydroxyphenyl.
[0058] In a preferred embodiment of the compounds according to paragraph [0057], when Ay 2 S is o-phenol optionally substituted by halo, nitro, or methyl, Ar 2 is optionally substituted phenyl, X 1 is O -CH 2 -S-CHr, or -OCH 2 then Cy 2 is not optionally substituted phenyl or Vn naphthyl.
I0 [0059] In another preferred embodiment of the compounds according to paragraph [0057], when Ay 2 is o-anilinyl optionally substituted by halo, C 1
-C
6 -alkyl, Ci-C 6 -alkoxy or -NO 2 q is 0, Ar 2 is phenyl, and X 1 is -CH 2 then Cy 2 is not substituted pyridone (which substituents of the pyridone are not limited to substituents described herein).
[0060] In another preferred embodiment of the compounds according to paragraph [00571, when X' is -CH Ar 2 is optionally substituted phenyl, q is 1, and R 6 is H, then Cy 2 is not optionally substituted imidazole.
[0061] In another preferred embodiment of the compounds according to paragraph [0057], when Ar 2 is amino or hydroxy substituted phenyl, X' is Co-Cg-alkyl-Xl a Co-C-alkyl, wherein X 1 is -CH 2 then Cy 2 is not optionally substituted naphthyl or di- or -tetrahydronaphthalene.
[0062] In another preferred embodiment of the compounds according to paragraph [0057], when Ay 2 is o-phenol, Ar 2 is substituted phenyl, X' is -CH 2 or and R and R 6 are H, then Cy 2 is not optionally substituted naphthyl.
[0063] In another preferred embodiment of the compounds according to paragraph [0057], when Ay 2 is o-anilinyl, q is 0, Ar 2 is unsubstituted phenyl, X 1 is -CH 2 then Cy 2 is not substituted 6hydroimidazolo[5,4-d]pyridazin-7-one-1-yl or substituted 6-hydroimidazolo[5,4-d]pyridazine-7-thione-lyl.
[0064] Preferably in the compounds according to paragraph [0057], Ay 2 is phenyl or thienyl, each substituted with -OH or -NH 2 [0065] More preferably in the compounds according to paragraph [0057), Ay 2 is optionally amino- or hydroxy-substituted phenyl or thienyl, wherein the amino or hydroxy substituent is preferably ortho to the nitrogen to which Ay 2 is attached.
[0066] More preferably in the compounds according to paragraph [0057], Ay 2 is ortho aniline, ortho phenol, 3-amino-2-thienyl, or 3-hydroxy-2-thienyl, and tautomers thereof.
[0067] In a another embodiment, the novel histone deacetylase inhibitors sheinwentio are those according to paragraph [0057] wherein q is 1; at each occurrence, is selected from the group consisting of -N(R 7 and where R 7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, and acyl; and Ay 2 is anilinyl, which optionally is substituted.
[0068] In some preferred embodiments of the compounds according to paragraph [0067], the
-NH
2 group of Ay 2 is in an ortho position with respect to the nitrogen atom to which Ay 2 is attached.
In some embodiments, R 5 and R 6 are independently selected from the group consisting of hydrogen and Ci-C 4 alkyl. In some preferred embodiments, R 5 and R 6 are hydrogen.
[0069] In some embodiments of the compounds according to paragraph [0067], Ar 2 has the formula G> G GG G G GG
G
G G, G'GG ,or G G-,G wherein G, at each occurrence, is independently N or C, and C optionally is substituted. In some preferred embodiments, Ar 2 has the formula G' G--GY G/G or G GG [0070] In some preferred embodiments of the compounds according to paragraph [0069], Ar 2 is selected from the group consisting of phenylene, pyridylene, pyrimidylene, and quinolylene.
[0071] In some embodiments of the compounds according to paragraph [0067], X' is a chemical bond. In some embodiments, X' is L 2
-M
2
-L
2 and M 2 is selected from the group consisting of -N(CH 3 and In some embodiments, X' is L 2
-M
2
-L
2 where at least one occurrence of L 2 is a chemical bond. In other embodiments, X 1 is L 2
-M
2
-L
2 where at least one occurrence of L 2 is alkylene, preferably methylene. In still other embodiments, X 1 is L 2
-M'-L
2 where at least one occurrence of L 2 is alkenylene. In some embodiments, X' is M'-L 2 and M' is selected from the group consisting of -N(CH 3 and [0072] In some embodiments of the compounds according to paragraph [0067], Cy' is aryl or heteroaryl, phenyl, pyridyl, imidazolyl, or quinolyl, each of which optionally is substituted. In some embodiments, Cy 2 is heterocyclyl, e.g., 0 0O S 0, ,and 0 0 each of which optionally is substituted and optionally is fused to one or more aryl rings. In some embodiments, Cy 2 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, Ci aminomethyl, and hydroxymethyl.
[0073] In a preferred embodiment of the compounds of paragraph [0057], the invention comprises compounds of structural formula (2a): 0 Y N NH R A ra W z NH 2 (2a) and pharmaceutically acceptable salts thereof, wherein Ara is phenyl or thienyl;
R
6 is H, or C 1
-C
6 -alkyl (preferably -CH 3 Y and Z are independently -CH= or W is halo, 3
L
3 is a direct bond, -Cl-C 6 -hydrocarbyl, (C-C 3 -hydrocarbyl)m 1 -X'4C-C 3 hydrocarbyl)m 2
-NH-
(Co-C 3 -hydrocarbyl), (C-Cr 3 hydrocarbyl)-NH-, or -NH-(Ci-Cr hydrocarbyl-NH-; ml and m2 are independently 0 or 1; X' is -N(R 2 1 -C(0)N(R 2 1
N(R
21 or
R
21 is 1
-C
6 -hydrocarbyl)c;
L
4 is (C -C 6 -hydrocarbyl)-M-C -C 6 hydrocarbyl)b; a and b are independently 0 or 1; M is
-SO
2 -NHS0 2 or -SO 2
NH-
V, V, and V" are independently selected from cycloalkyl, heterocyclyl, aryl, and 0 heteroaryl; St is 0 or 1; o 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 Ar' rings are optionally further substituted with from 1 to 3 substituents independently selected from methyl, hydroxy, methoxy, halo, and amino.
[0074] In a preferred embodiment of the compound according to paragraph [0073]: In Y and Z are -CH= and R 6 is H; I0 W is V-L3; 0 L 3 is -NH-CH- or -CH-NH-; V is phenyl optionally substituted with from 1 to 3 moieties independently selected from halo, hydroxy, C 1
-C
6 -hydrocarbyl, C 1
-C
6 -hydrocarbyl-oxy or -thio (particularly methoxy or methylthio), wherein each of the hydrocarbyl moieties are optionally substituted with one or more moieties independently selected from halo, nitroso, amino, sulfonamido, and cyano; and Ara is phenyl and the amino moieties to which it is bound are ortho to each other.
[0075] In some preferred embodiments of the compound according to paragraph [0073], V is an optionally substituted ring moiety selected from: N III and [0076] In another preferred embodiment of the compounds according to paragraph [0073], W is selected from:, 0
CH
3
H
ON0
NN.
I. H
F
9H3C H3 H'0 0 N
NN
N~ 0-H 3 0CH 3
H
HCH
H
3 C
H
3 C. 10 0 0' N
H
H
3 C i S N/
H
H
F 3 C 00 N
H
N~
H
H
OCF
3
H
H
H
3 C
H
MeO eOe Br-, OMe MoOl 'H
N/
ome oMe MeO
CH
3 MeO)(
N),
H
fw NH2
H
H
H
N
N
Me l~e
*N
I H
OH
H
01N )CF 3
H
H
NN~
CF
3
H
[0077] In another preferred embodiment of the compounds according to paragraph [0073], the A and Ar rings are not further substituted.
[0078] In a particularly preferred embodiment of the compounds according to paragraph [0073], the compounds of the invention are selected from the following, in which, unless expressly displayed otherwise, Ara is phenyl (and, preferably, the amide nitrogen and the amino nitrogen bound to Ara are ortho to each other): Cpd W Y Z R 6 Cpd W Y Z R 6
H
3
C,
0 I N/ C NY N 481 H 3 C-O CH CH H 493 N CH CH H
H
3
C'
0 0
~CH
3 0
H
484 H, I NH 494 Kc CH CH H H3C O O2N 5 N v -H 495 CH CH H
H
3 CO N N\ NO AI f" Ir. rw wJ-J I NO,
IN
ID Cdw Y_ p w Y ZR N MeO 524 H N CH H 536 CH CH H MeOX N MeO OMe 525 H NCH H 57 MO CH CH H
OC
3 526 \M CH CH H C3538 CH CH H -C-CHHMeN N -H SO 2
NH
2 F H CH CH H 528 V H- CHC CHCH H _I M e o', rKN y N 540 e CH CHH Cpd W Y Z R 6
H
548 y CH CH H
H
549 CH CH H
H
550 2Na NT" CH CH H
H
551 CH CH H NOg
H
552 CH CH H
CI
553 CH CH H
H
554 N CH CH H SMe MeS
H
557 CH CH H N 558 CH CH H
H
558 CH CH H 559 FN-' CH CH H Cpd W Y Z R 6 569 H 3 Co CH N H
H
3
CA
O
570 1-1C H3C-O [0079] In a preferred embodiment of the compounds according to paragraph [0057], the ,invention comprises compounds of the formula (2b): 0 N Ay 2 C2, q H cy- 1 (2b) and pharmaceutically acceptable salts thereof, wherein Ay 2 is phenyl or thienyl, each substituted at the ortho position with -NH 2 or -OH and each further optionally substituted with one to three substituents independently selected from -NH 2
-OH,
and halo; q is 0 or 1; X' is selected from -CH 2
-NH-CH
2 and -S-CH 2 Cy 2 is monocyclic or fused bicyclic aryl or heteroaryl optionally substituted with one to three substituents selected from CH 3
CH
3 phenyl optionally substituted with one to three CH 3 0-, morphylinyl, morphylinyl-C-r 3 -alkoxy, cyano, and CH 3
C(O)NH-;
provided that when Cy 2 is naphthyl, X 1 is and q is 0 or 1, Ay 2 is not o-hydroxyphenyl.
[0080] Preferably in the compounds according to paragraph [00791, Ay 2 is selected from:
NH
2 OH NH 2 NHz I_ 2 and
F
[0081] Preferably in the compounds according to paragraph [0079], Cy 2 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, Cy 2 is phenyl substituted with one to three
IND
0 C N [0082] In a third embodiment, the novel inhibitors of histone deacetylase are represented by 0 formula 0 Cy -X 2 -Ar 3
NH
NH
2 SU(3)
N
c and pharmaceutical salts thereof, wherein
C
Ar 3 is arylene or heteroarylene, either of which optionally is substituted; oCy 3 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which optionally is substituted, and C 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 Cy 3 is a cyclic moiety having or in the ring, then Cy 3 is not additionally substituted with a group comprising an aryl or heteroaryl ring; and
X
2 is selected from the group consisting of a chemical bond, L 3
W
1
-L
3
L
3
W'-L
3
-W
1 and
L
3
-W'-L
3 wherein at each occurrence, is S, 0, or N(R 9 where R 9 is selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl; and
L
3 is Ci-C 4 alkylene, C 2
-C
4 alkenylene, or C 2
-C
4 alkynylene; provided that X 2 does not comprise a or -S(0) 2 group; and further provided that when Cy 3 is pyridine, then X 2 is L 3
W'-L
3 or [0083] Preferably, Ar 3 has the structure: Q ,Q ,or Q Q wherein Q, at each occurrence, is independently N or C, and C optionally is substituted.
[0084] Preferably in the compounds according to paragraph [00821, X 2 is selected from the group consisting of L 3
W'-L
3
W'-L
3 and L 3
-W'-L
3 [0085] Preferably in the compounds according to paragraph [00821, when X 2 is a chemical bond, then Ar 3 is not or "'QT Q-aQ SQ /A Q and Cy 3 is not the radical of a substituted or unsubstituted diazepine or benzofuran.
S [0086] In some embodiments of the compounds according to paragraph [0082], Q at each occurrence is C(R 8 where R 8 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, S alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy. In some other embodiments, from one to about three variables Q are nitrogen. In some preferred embodiments, Ar 3 is selected from the group consisting of phenylene, pyridylene, thiazolylene, and quinolylene.
[0087] In some embodiments of the compounds according to paragraph [00821, X 2 is a chemical bond. In other embodiments, X 2 is a non-cyclic hydrocarbyl. In some such embodiments,
X
2 is alkylene, preferably methylene or ethylene. In other such embodiments, X 2 is alkenylene or N alkynylene. In still other such embodiments, one carbon in the hydrocaryl chain is replaced with -NHor In some preferred embodiments, X 2 is and W 1 is -NH- or -N(CH 3 [0088] In some embodiments of the compounds according to paragraph [0082], Cy 3 is cycloalkyl, preferably cyclohexyl. In other embodiments, Cy 3 is aryl or heteroaryl, 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 Cy 3 is fused to a benzene ring. In some embodiments, Cy 3 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 wherein K' is a chemical bond or CL-C 4 alkylene;
R'
i is selected from the group consisting of Z' and -Ak 2 wherein Ak 2 is Ci-C 4 alkylene; and Z' is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which optionally is substituted, and each of which optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings.
[0089] Examples of such preferred substituents according to paragraph [0088] include H and H 3 C N I0 [0090] In some embodiments of the compounds according to paragraph [00821, Cy 3 is S heterocyclyl, e.g., 0 0 0 0 0 0 0 S, 0 H and 0 0 each of which optionally is substituted and optionally is fused to one or more aryl rings. In some embodiments, the heterocycle of Cy 3 is fused to a benzene ring.
N [0091] Preferably in the compounds of paragraph [0082], when Ar 4 is quinoxalinylene, then X 3 is N not -CH(OH)-.
0 [0092] In another preferred embodiment, Ar 3 is wherein X is -CH 2 0, or S. Preferably Ar 3 is and X is S or 0.
[0093] In a preferred embodiment, the novel histone deacetylase inhibitors of the invention are those according to paragraph [0057] wherein Ay 2 is ortho-anilinyl; q is 0; and X' is M'-L 2
-M
1 or L 2
-M
2
-L
2 [0094] In a preferred embodiment of the compounds according to paragraph [0093], Ar 2 is aryl or heteroaryl; and Cy 2 is collectively selected from the group consisting of a) A 1 wherein A, is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein Li is -{CH 2 )oiNH(CH 2 or
-NHCH
2 and wherein BI is phenyl or a covalent bond; b) A 2
-L
2
-B
2 wherein A 2 is CH 3
(C=CH
2 optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted aryl; wherein L 2 is and wherein B 2 is a covalent bond; N c) A 3
-L
3 wherein A 3 is an optionally substituted aryl, optionally substituted heteroaryl or Soptionally substituted heterocyclyl; wherein L 3 is a covalent bond; and wherein B 3 is
CH
2
NH-;
Sd) A 4
-L
4
-B
4 wherein A 4 is an optionally substituted aryl; wherein L 4 is -NHCH 2 and wherein
B
4 is a thienyl group; e) A 5
-L
5
-B
5 wherein As is an optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L 5 is a covalent bond; and wherein B 5 is -SCH-; f) morpholinyl-CHr g) optionally substituted aryl; S h) A 6
-L
6
-B
6 wherein A 6 is an optionally substituted aryl, optionally substituted heteroaryl or Soptionally substituted heterocyclyl; wherein L e is a covalent bond; and wherein B 6 is
NHCH
2 i) ArLrBr, wherein A 7 is an optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L 7 is a covalent bond; and wherein B 7 is -CHr; j) aptionally substituted heteroaryl or optionally substituted heterocyclyl; k) A 8 -LBr, wherein As is optionally substituted phenyl; wherein Ls is a covalent bond; and wherein B 8 is I) A 9
-L
9 wherein Ag is an optionally substituted aryl; wherein Lg is a covalent bond; and wherein B 9 is a furan group; m) Ai-Lio-Bo-, wherein Aio is an optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein Llo is -CH(CH 2
CH
3 and wherein Bio is -NHCH 2 n) Al-L 1 1
-B
11 wherein An is an optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L- 1 is a covalent bond; and wherein B is -OCHr; o) Ai-Liz-Br-, wherein A 1 2 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L12 is-NHC(O)-; and wherein Bi 2 is N(optionally substituted aryl)CHr; p) A 1 3 wherein A 12 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein Li 3 is a covalent bond; and wherein B 1 3 is
NHC(O)-;
1 IN q) At 4 -Li 4 -8 14 wherein Ai 4 is an optionally substituted aryl, optionally substituted heteroaryl 0 or optionally substituted heterocyclyl; wherein L 14 is-NHC(O)(optionally substituted Sheteroaryl); and wherein B 1 4 is r) F 3
CC(O)NH-;
s) A 15
-L
1 5
-B
15 wherein A 1 s is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein Lls is-(CH 2 0 .,NH(optionally substituted heteroaryl)-; and wherein Bis is -NHCH 2 t) A 16
-L
16
-B
16 wherein A 16 is an optionally substituted aryl, optionally substituted heteroaryl uI or optionally substituted heterocyclyl; wherein LI 6 is a covalent bond; and wherein B 1 6 is s0 N(optionally substituted alkyl)CH 2 and Su) A 1 6
-L
16
-B
16 wherein A 1 e is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L 16 is a covalent bond; and wherein B 16 is (optionally substituted aryl-CH 2 [0095] In another preferred embodiment of the compounds according to paragraph [0093], Cy 2 is collectively selected from the group consisting of a) Di-Et-F-, wherein D 1 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein El is -CH 2 or a covalent bond; and wherein
B
1 is a covalent bond; b) D 2
-E
2
-F
2 wherein D 2 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E 2 is -NH(CH 2 )o 2 and wherein F 2 is a covalent bond; c) D 3
-E
3
-F
3 wherein D 3 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E 3 is -(CH 2 )z 2 NH-; and wherein F 3 is a covalent bond; d) D 4
-E
4
-F
4 wherein D 4 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E 4 is -S(CH 2 )o 2 and wherein F 4 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 -(CH 2 2 and wherein Fs is a covalent bond; and f) D 6
-E
6
-F
6 wherein De is an optionally substituted aryl, optionally substituted heteroaryl or 0 optionally substituted heterocyclyl; wherein E 6 is -NH(CH 2 2 NH-; and wherein Fe is a covalent bond.
[0096] In a preferred embodiment, the HDAC inhibitors of the invention comprise compounds of paragraph [0057] having formula (3b): W H NH 2 S° (3b) cl and pharmaceutically acceptable salts thereof, wherein Y and Z are independently N or CH and W is cN selected from the group consisting of: ID0 m 0 F 0 0 0 \2/ c~ N N 0Me N IO I' NO C)N~DBr NN Nk,0NM In N'C30I c H 0 0 0 Br Br Ci CK N 2 C N'/ N 0I I Et N F F 0 NI N-fCO H H
MNN
N ON 0 N- N\ NC NC Me 'N s H H CN N' N N N Me 0 N S
I
A~ 0 \N OH 32 MeO 9\oMe N MeO
N
m 0rCH 3 0 eO N- HN BrCNH Ne )-No~j N MeO_NH y .OMe Ci-_DaNH \OMe N3~eome H H 3
C
N N-N F N, Sk H CH 3 NHN N -3h 0 H 3 C NN- H H 0H CM 3 3 l 'l ,z
H
3 C N YH 3 C, N N< H
H
o >0NHI
H
3
C
c>NH
H
3 0 N N H
H
H3CC Y
H
0 l CH 3 0
CH
3 0
CH
3
H
H3A
H
3 C-g
CH
3 0 lCH 3 r*zN. S, s cN:IajN
HNI
NH
2 33 Ho H NC H 0 N
N
H
3 C NCNN H3C H
H
Ni H
H
3
C'
NA I. H 3 C O OH
H
3 C. H 3
H
3 H C3 N~ CI I H 3
C
CH3 H H M0 N N N,.XNV MeI
H
H
3 C C c OMe H
H
N-N~r Ie' H Fo H
H
HC
N
FF Me H H H CI N N~-N N N.<
NN
CI ci MeO'N H
H
OCOcryF 3 0MB-
H
N- N' H N~V
CF
3
F
3 COO H MeDf HH
H
H H N N NA, H H 0 i MeO ~N N ,Y
F
3 N MOO N H MeG cl MDOMe 34
H
IND Or H N IH 'N HN OMe Nl~N H MeO N \r MeO 0_NY N,\ MeSfay He 1 H H Hew N N NX MeO y O
O
OMeOe
HAC*,H
3 OH
H
3 C Si
H
3 C CH 3 0 H
N
MO~qNMeO OO~e
H
NMeO NH NH
F
3 CO -C OC 3 MeO 0 NH H N NH H
N
Me0 N 'e N qNH 2 o H 2 N0 l HHMO\NNH,\ 1' NH,
H
2 N N MeO~o -N H 3
C
SNH,--,
N
N
OH
H
3 C
NHNN
HN MeO H m e 0 0 0
Q)
[0097] In a preferred embodiment of the compounds according to paragraph [0096], the compounds comprise those wherein Y, Z and W are as defined below: Cpd W Y Z Cpd W Y Z Cpd W Y Z MeO~, 0 N fV I 164 Me° J CH CH 170 s CH CH 179 CH CH OMe 0__ 165 HO N CH 171 mo rs N CH 180 Me CH CH 166 MeO/ CH CH 172 sN CHCH Me N 18 1 CH CH 167 CH N 174 CH N 167MeO _H3 168 N CH N 175 CH N 182 a CH CH MeO
CH
3 176 H CH N and MeON N N MeO 169 CH CH 18 OMey N 183 F I s CHCH OMe 177 S CH CH NN [0098] In another preferred embodiment of the compounds according to paragraph 10096], the compounds comprise those wherein Y, Z and W are as defined below: Cpd W Y Z Cpd W Y 2 187 CH CH 325 sC- HHs 188 6 CH CH 326 sr
H
Me325 N CHC #L rH NH H
N
189 CH CH N 4 327 s CH C H x__C 189 WO NO CH CH 32If\>SC OMe N
H
190 CH CH 328 CH C MeO-c 0,) MeO 193 H 2 C CH CH 329 MeO CH C
CH
3 OMe
NH
2 194 CH CH H c N N 330 H3C N CH CI
(DH
195 CH CH NH2
__H
3 C OH -331 HN N' CH C, 196 CH CH 332HN ci 321 c NH CH CH 333 CH C N H 322 s CH OH 3NH 334 H N N CH C e 33OMe5 323 CH CH S C1HIC Cpd W Y Z o 347 NBr CHCH ~N N.
0 348 c IN" CH CH
N
349 F.'N CH CH
H
350 F N CH CH
H
0 351 I I CH CH 352 C HCH Ph O, N 353 CH CH Me- KON 4 O CH
CH
355 QN CH
CH
356 CH CH HaC
ON
357 CH CH
N-N
358 CH CH
NC
359 HN CH CH S
U
Cpd W Y Z NC Me 360 HN-/ 4 CH OH 0 H H CN 361 0 S M CH CH 362 0 Nj 1 j OH CH 0 363 O H CH 364 O H CH 0 365 CH CH
OH
366 CH OH 367 M 0CH CH 368 Meo O" H CH- MeO N'- 369 t4CH OH c I N' C H,
N
370 OH O IND Cpd W Y Z Cpd W Y Z
CH
3 H 3 C 383 CH CH 395 1 CHCH H3C H CH3
H
3
CN
384 CHCH 396 CH CH
H
3 C' N' 0N/-
H
3
C
0 Y, N 0 HO Oq N, 385 CHCH 397 t CH CH N N/ IlCH
H
HC0' 386 CH CH 398 H NS-1- CH N 387,, CH OH 387 H,N< CH H 399 HN
H
H
388 NCNV H OCH 400 OH~B H H 3
C
0
H
389 jj)NH CH CH 401 0 3 NCH OH NH H3C H H 0 N NH,~~O CH CH 390 H3C 0 N N OH CH 402 -a
OH
HH
391 C H CH 430 /6 NH CO H
N
H
3
C
0
H
392 NYN CHOCH 404
CHOCH
0 l CH 3
H
3 C, 0'& 393 O3' H CH 405 1~ O~Q O, H OH 0
CH
3
H
39 H 3 OH OH 406 H 3 I4OH CHOCH ONC~S 0 Cpd W Y Z H3C,.qN~ 407 1 CH CH
CH
3 408 N 0 NH CH CH
CH
3
H
409 H3 CH CH CH3
H
410 Jc(N\ CH CH
H
3 C CH 3
H
~N CHC 4111NCH H 412 Iel; H CH CH 413 NA~ HOH CH 414 Me- H\ CH OH
H
415 aNVY CH CH 416 H' CH OH 417 O H OH
H
418 ~CI' N YNCHH Me Cpd W V Z 0 431 F 3 C N\ CH CH
H
H H N NIN 432 N CH CH MeO- C, MeO 433 OH CH MeO MOMe CIIC
N-
434 MeO H CH CH OMe 435 \NNYN_ CH ICH
N
H
N
436 CH CH 437 MeSAIXN CH CH 438 CH CH SMe
MO
NH
439 MeO CH CH
HCI
MeO 440 MO~ OH OH
N
H
3 C 0
H
441 Me O H OH OMe Cpd W Y Z 442 Meq CH CH OMe
H
3 C{H jV HO cH3
CHC
443 H3C CH3 e HC OMe
OH
444 N V CH CH MeOq OMe
H
445 M NI OH N MeO q OMe O H 446 C( N CH N 447 F 3 O C CHCH
H
3 N]C NH,\ 448 OH6 s CH CH
H
N NH
H
450 N 4II I CH CH
N
451 NJs( CH CH
H
452 D~ H HC 0 meo, F 3
C
IN kPa Wv I''v H- NH46NCHH Ne OHCH 454 1e~r \.N 2 42 cIN MeQ~c F
CH
3
F
H H463 N CH 0=NI CH CH eN~NH -IA- CH OH 464 C- s- N CH IND 0 H 2
N
NM6 CH CH 458 Meo CHCH 466
HC
MeO~r- -12
HN
0 458__ -N CH C 4676I>N CH CH OH OH
H
aN 468 CH CH N- HHNN 460 O H N 0 461 H OH 611 3 [0099] 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: H\ H NH
H
2 N Ia
U
HND H H0 H NHN
NP
N H H N~ r N
H
3 N 'Y
NH
2 0HNH) NO N H 0 H H
NH
HN N
NH
2 r 0 N H 0 0
HH
HNN
NH
0, NH
N~
0OH 3 S- N NN2 NCHN HNH 2 N HNH H-N
H
3 OH
CH
O dN N N H- H3o 0 N4 NH 2 O- H 0 0H 00 H 3 N I C H N H 2 I
N
H
3 C o 0IC 0 N 2 IH P Ia H O a- N N 0e Uo 0
NH
0 3 0 ID0MeOC~N
H
H
3 C-O N
HO
N- 0 1
NH
2
H
H
3 C N
H
2 N SMe
H
_0
N
HI IN H
N
NN
>MoO MeO N mo~ NHMeO NH 0 IND ~N N S NH 2 M O H
H
2
N
N--IyH
OH'
MeOl N e H0, N ,Cl H OH MOe MeO-q 0 \2 NN
HNH
S H 0 M e O M e 0 H N
NH
H
3 C ,HN N HN -,0 46
IND
[0100] In another preferred embodiment, the compounds are selected from those listed in Tables 2a-b, 3a-d, 4a-c, and Synthesis (0101] Compounds of formula wherein Y' is 2 preferably may be prepared according to the synthetic route depicted in Scheme 1. Thus, trichiorotriazine I reacts with amine 11 0 in the presence of diisopropylethylamine to produce dichioroaminotriazine Ill. The amine R 1 R NH is added to dichloroaminotriazine Ill to produce diaminochlorotriazine V. Treatment of V with ammonia IND ~or R 3 R 4 NH in tetrahydrofuran (THF) or 1,4 dioxane affords triaminotriazine VI.
(0102] Alternatively, dichloroaminotriazine Ill may be reacted with ammonia gas in 1,4 dioxane to produce diaminochlorotriazine IV. Treatment of IV with R'R'NH in THF or 1,4 dioxane in a sealed flask then affords triaminotriazine VI1.
(0103] Hydrolysis of the ester moiety in VI is effected by treatment with a hydroxide base, such as lithium hydroxide, to afford the corresponding acid ViIl. Treatment of the acid VII with 1,2phenylenediamine in the presence of BOP reagent, triethylamine, and dimethylformamide (DMF) yields the anilinyl amide ViII.
Scheme 1 c1 CI N 1N HC.H 2 N l> i-Pr2NEt N )I-N CI N C1 C0 2 Me CI N N I H C0 2 1ve
NH
3 a Pathway A N2 1,4 1on R R 2 NH ciPathway B N AN Cl A N 1
R
2 N N N j I IV C0 2 Me HKRN NN*' IV C0 2 Me
R
1
R
2
NH
THF or 1 ,4-dioxane NH 3 or R 3
R
4
NH
sealed flask THF or 1,4-dioxane
NR
3
R
4 N AlN 1- 2 N NR3N RR2N AIN
H
2 NcNAlN H 2 N AN I'lNH I1 C 0 R S O P r e a g e n t H N Vi: R =Me U1.-20 Et 3 N, DMF Vill ViI: R H .JTHFIH 2 0
\O
[0104] Compounds of formula wherein Y' is -CH 2 2 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 X!I 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 0 N N AcCI CI N CI NH Et 3 N Cl NC E$11Cr j LiHMOS Ix
X
SHCI.H
2 N O N i-Pr 2 NEI O NIN 0N N 0 NN N $N-~")NjlC CO 2 Me (NN -A N N H NH 2 O 2. LiOH. 2 0 N H XI
THF/H
2 0 XoI 0 3. SOP, Ph(NH 2 2
I
0 EtN DMF 0 0-I o---J [0105] Compounds of formula wherein Ar 2 is pyridylene and X' comprises -N(R 7 2H compounds of formula wherein Ar 3 is pyridylene and X2 comprises -N(R 9 and compounds of formula wherein Ar 4 is pyridylene and X' comprises -N(R 1 1 preferably may be prepared according to the procedures illustrated in Scheme 3. Dibromopyridine XIII or XIV is treated with amine RNH 2 to produce aminobromopyridine XV or XVI, respectively. Treatment of XV or XVI with diacetoxypalladium, diphenylphosphinoferrocene, DMF, diisopropylethylamine, and phenylenediamine under carbon monoxide yields anilinyl amide XVII or XVIII, respectively.
[0106] Treatment of XV or XVI with tert-butylacrylate, diisopropylethylamine, dibenzylacetone palladium, and tri-o-tolylphosphine (POT) in DMF under nitrogen affords compounds XIX and XX, respectively. The ester moiety of XIX or XX is hydrolyzed to produce the corresponding acid moiety in XXI or XXII, respectively, by reaction with trifluoroacetic acid in dichloromethane. Treatment of the acid XXI or XXII with phenylenediamine, BOP, and triethylamine affords the anilinyl amide XXIII or XXIV, respectively.
Scheme 3 RNH 2 Br N Y XIII: X Br, Y H XIV: X H, Y Br COtBu RHN N Y Pd 2 (dba) 3
POT
DMF I DIPEA XV X Br, Y H XVI: X H, Y Br CO (1 atn) Pd(OA) 2 dppf I OMF
DIPEA
Ph(NH 2 2 RHN N V XVII: X NH2 Y=H
X
RHN N Y XIX:X C 02BU Y=H XX :X H. Y -CO 2 tBu ITFA CH2CO x RHN N Y XXI:X C(C2H Y=H XXII: X HY C2H IPh(NH,), I SOP OMF I TEA x RHN N V XXIII X NH Y=H XXIV:X=H Y NH2
C.
NH
NH2 XVIII: X=W= [0107] Compounds of formula wherein X' comprises -OC(OVNH-, 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 1,8diazabicyclo[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 xxv XXVI CDI E1 3
NI
DBU /DMF0N
I
"N XXVI Or 1) POT Pd 2 (dba) 3 DIPEA /OMF j2) GOP /EI3NI/DMF
CH
2 =CHCOOH I Ph(NH 2 2 0 N NH 2 N N N XXVIII 0I [0108] Compounds of formula wherein X1 comprises -N(R 7 preferably may be prepared as outlined in Scheme 5. Amine XXIX is reacted with p-bromobenzylbromide in the presence of potassium carbonate in DMVF to produce bromobenzyla mine XXX. Treatment of XXX with nitroacrylanilide, dibenzylacetone palladium, POT, anddiisopropylethylamine in DMVF affords nitroanilidle XXXI. Nitroanilide XXXI is converted to the corresponding anilinyl amide XXXII by treatment with stannous chloride in methanol and water.
[0109] Treatment of amine XXXI in formic acid with paraformaldlehyde provides methylamine XXIII. The nitroanilidle moiety in XXXIII is then converted to the corresponding anilinyl amide moiety in XXXIV by treatment with stannous chloride in methanol and water.
Scheme MeO~ OMe
XXX
Or
I
Br
K
2
CO
3 J MF MeO Br4 X nUM H Pd 2 (dba) 3 POT I.NO, JOMF I DIPEA Me 9(NO N0 C0/ HCO,1 Me V
N
W~e 0 ISnCI4/ MeOHI
H
2
NH
Me W~e XXXII0 MeLI 0 N 2 Me
XXXIII
OMe 0 SnC I/MeOH/ MeO J4A Nil 2 me 11 NH OMe XXXIV 0 [0110] Alternatively, compounds of formula wherein X' comprises -N(R 7 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 OC. 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 0 HCI /MeOH
OH
xxxv Cat, Nat
K
2
CO
3 S OCH OMF 60 0
C
XNXXVI MeOPhCI4CI
XXXVI
0 H CH3 MeOO "N
XV
1) NaOH ITHF/ MeOH 2) BOPIEI 3 N I DMF Ph(NH 2 b N,
I
NH
2
XXXVII
[0111] Compounds of formula wherein X' comprises H or 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 XUI or XLIII is then prepared using procedures analogous to those set forth in Schemes 3-6 above.
Scheme 7 X 2C03
OMF
Ar-Z H 2 N Y 68 XXXVIII:Z-'; Br X=BroI XXXIX: Z =COCI Y= N or CH Ar-Z'NH
X
1-Pd 2 (dba) 3 IEt 3
NIDMI
CH2=CHC00HI1OO 0
C
2.BOPDMFIEt 3
N
Ph(NH 2 Ar 'ZNH NHl
NH
2
H
XLI: z XLIII: Z CO XL: Z XLI: Z=CO [0112] Compounds such as XLVII and XLIX preferably may be prepared as outlined in Scheme 8. Dibromopyridine is combined with diaminoethane to produce amine XLIV. Treatment of amine XLIV with isatoic anhydride LV in methanol and water, followed by ref luxing 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 13yr Br N H H N Ni' XLV 0 /MeOH/H0 /Ph,,e A.u Ume8 0 HC0 2 H reflux 0 XLVI H 0 H TC0 2 C 2.T.AICH cI 2 t I 2.TFA/CH 2
C
2 1.I C~ r.T I r.T Pd 2 (dba) 3 POT 3. Ph(NH 2 2 BOP Pd 2 (dba) 3 POT 3.PtfNH 2 2
SOP
DMF DIPEA 12O 0 C DMF TEA rT DMFIDIPEA /120 0 C IDMF TEA rT 00
NH
2
IHNH
2 N H 1 H XLVII 0XLIX [0113] Compounds such as LIV preferably may be prepared according to the synthetic route depicted in Scheme 9. Trichlorotriazine is treated with aminoindan and diisopropylethylamine to produce dichloroaminotriazine L. Treatment with bromobenzylamine and diisopropylethylamine affords diaminochlorotriazine LI. Addition of ammonia gas and dioxane provides triaminotriazine LII.
Treatment with protected acrylanilide, triethylamine, POT, and dibenzylacetone palladium then yields diene anilinylamide Lill, which is deprotected with trifluoroacetic acid to provide the final product LIV.
IN
Scheme 9 c1
AN
'N (3I3-NH2 i-Pr 2
NEI
CI
N N Cl L
H
HC.H
2
N>
i-Pr 2 NEt Ic ~N N
NAN-Y
U H U'a~
LI
NH
2 N N- N H~ H
NHR
HN<r 0
INH
Pd 2 (dba)3 HBoc Et 3 N. DMF
NH
3 gas 1.4-dioxane
NH
2 N H H III: R =Boc TFA Br LIV:R=H J 95% in water [0114] Compounds of formula wherein A is quinolylene and X 1 comprises -N(R 7 compounds of formula wherein Ar 3 is quinolylene and X 2 comprises -N(R 9 and compounds of formula wherein Ar 4 is quinolylene and X 3 comprises 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 rN OHa T LV LVI MeO
LVII
C d.e.f 0 NN NH 2 e iH N Meol( LVIII /1 0 N NH Ie l l H N a. T20/ Py IDMAP I 0 C b. p-melhawybenzytamine 1120 C c. I.2-phenyenediarnine I CO (40 psi) Pd(OAc) 2 I dppf DMF I DIPEA 70 C d. t Butylacrytale I Pd 2 (dba) 3 I POT! DMF I DIPEA I 120 C e. TFA DCM I ri f. 1.2-phenyienediamine I BOP I OMF I TEA I rT
O
O [0115] Compounds of formula wherein X 2 comprises a sulfur atom, and compounds of formula wherein X 3 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 tIr iodide (TBAI) in DMF to produce ester LXIII, which is then converted to acid LXIV as in Scheme 1.
0 Conversion of the acid LXIV to the anilinyl amide LXV is effected by procedures analogous to those 0 set forth in Scheme 1 above.
Scheme 11 SAr Br KCO 3 /DMF SAi SAr BOPI SAi ArSH iO xH 2 Ii"«"2<H2 Y 1 e-Pnylnediminc i o COOM NaHDMF/110C COOMc H20McOH COOH
M
N NH LX LXI DMF LXIV
INH,
rN,- Cl LXV UORxH,0/ H,O/MeOH TBAI, Nal. COMe DMF
K
2 CO, 3
COOM
EiN, DMF ArS
LXIII
[0116] Alternatively, compounds of formula wherein X 2 comprises a sulfur atom, and compounds of formula wherein X 3 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 CO/Pd(AcO)2/dppf S s r B D M F /K 2 C OD10 0NC FMF o C
S
c NI21SH C, c-nc-- N^ Ph(NH 2 2 BrVI U 'VB yr HN H2N
LXVIII
[0117] Compounds of formula wherein X 2 comprises -N(R 9 and compounds of formula wherein X 3 comprises -N(R 1 preferably may be prepared according to the synthetic route depicted
UN
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 f,'-N0 DM/(N 0 1.LiOHIH2O:MeOH 0 M F/I 3 N N OMe OMF NI NP NN HI H 2
N
C1HN 2+ BOP/Ph(NH 2 2 UN HNH LJCIX LXX CH 3 CN, Et 3 N
LXXI
[0118] Compounds of formula wherein X' comprises a sulfur atom, and compounds of formula wherein X 3 comprises a sulfur atom, preferably may be prepared as outlined in Scheme 14. Phenylenedia mine is reacted with di-tert-butyldicarbonate, followed by iodobenzoic acid, dimethylaminopropylethylcarbodlimide, 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 diisobutylaluminumn hydride (DIBAL-H). Addition of the heterocyclylsulfhydryl compound Het-SH with triphenylphosphine and diethylazodicarboxylate converts the hydroxyl moiety of LXXIIV to the sult anyl moiety of LXXV. LXXV is deprotected with trifluoroacetic acid to afford the sulfanyl anilinyl amide Scheme 14
H
2 NC~ 1 BOC 2 0O HN2. 4-Iadobenzoic acid I H
NH
2 EDCI, HO~t, Et 3 N I XI NHBoc PdCI 2 (dppf). C-o.
MeOH, i-Pr 2 EtN 'N DIBAL-H 'N ciJ IOOo MeO2C< H oc HI VV- NHBoMe 2 LXXIII H IDEAD, Ph 3
P
Het-SH HeIS'e -9 Noc
LXXV
TFA 'N 1eI
NH
2 .Me LXXVI Het= C
N
O
O
CK1 [0119] Compounds of formula wherein X 2 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 o B(OH) 2 ON O Hr Pd(PPh 3 )4 aq. Na 2 co 3 N NH IY NH 2 SCI N H
NH
2 OMe benzene-ethanol CI LXVIII SOMe [0120] 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 paminomethylbenzoic 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 Nm YH NH2 LXXIX LXXX LXXXI a. p-aminomethylbenzoic acid/AcOH/5 min/reflux b. HOBT/EDC/1,2-diamino benzene [0121] Compounds such as LXXXVI and LXXXIX preferably may be prepared according to the procedures illustrated in Scheme 18. Phthalic anhydride LXXXV and p-aminomethylbenzoic acid are combined in acetic acid to produce an intermediate carboxylic acid, which is converted to the anilinylamide LXXXVI using procedures analogous to those set forth in Schemes 15 and 16 above.
[0122] The addition of 4-2-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.
IO
SScheme 18 C ab OI C Y I H2 o OH LXXXVII LXXXV LXXXVI 0 I N,:NH
NH
2 8 LXXXVIII LXXXIX 0 a. p-aminomethylbenzoic acid/AcOH/reflux/3 hrs b. HOBT/EDC/1,2-diamino benzene c. 4-(2-aminoethyI)phenol/AcOH/5 hrs/reflux d. PhNTf 2 /NaH/THF-DMF/30 min/0°C e. 1. CO/Pd(OAc) 2 /dppf/Et 3 N/MeOH-DMF/4 days/75 0
C
2. AcOH/HCI/3 hrs/reflux [0123] Compounds such as XCI-XCVI preferably may be prepared according to the synthetic route depicted in Scheme 19. Treatment of isatoic anhydride XC with p-aminomethylbenzoic acid in water and triethylamine, followed by formic acid affords an intermediate carboxylic acid, which is converted to anilinylamide XCI using procedures analogous to those described for Scheme 16 above.
[0124] Alternatively, treatment of isatoic acid XC with p-aminomethylbenzoic acid in water and triethylamine, follwed by hydrochloric acid and sodium nitrite affords an intermediate carboxylic acid, which is converted to anilinylamide XCII using procedures analogous to those described for Scheme 16 above.
[0125] Alternatively, treatment of isatoic acid XC with p-aminomethylbenzoic acid in water and triethylamine affords benzoic acid XCIII. Treatment of XCIII with sodium hydroxide, dioxane, methylchloroformate, and methanol affords an intermediate quinazolinedione carboxylic acid, the acid moiety of which is then converted to the anilinylamide moiety of XCIV using procedures analogous to those described for Scheme 16 above. Alternatively, the intermediate quanzolinedione carboxylic acid in DMF is treated with potassium carbonate and methyl iodide to produce an intermediate benzoic acid methyl ester, which is converted to an intermediate benzoic acid by treatment with
I
sodium hydroxide, methanol, and water. The benzoic acid is then converted to the corresponding anilinylamide XCV using procedures analogous to those described for Scheme 16 above.
[0126] Alternatively, treatment of XCIIII with acetic anhydride followed by acetic acid produces an intermediate carboxylic acid, which is converted to anilinylamide XCVII using procedures analogous to those described for Scheme 16 above.
0 Scheme 19 c-I'N oa, b, d(X= C) N "H 2 Ib I I N NAO a, c, d (X N Xdi XCI (X C)0 c-IXCII (X N) 0 0 N *N e d H )1
HH
NH 2 e, gd (Y CH 3 N H) XCIV (V H) XCV (Y =CH 3 h, d 0 a. p-aminomethylbenzoic acdI/H 2 0IEt 3 NI3 hrs/40 0
C
I I Hb. HCOOH/reflux/6 hrs N Me c. NaNO 2 /HCI/OOC/2 hrs. then rtVl2 hrs 0 d. HOBTIEDC/1.2-diamino benzene XCVI e. CICOOMeIKOHI2 hrs, OoC f. RI/K 2
CO
3 IDMF/rt g. NaOHIKeOHIH 2
O
h. AC 2 0/1 hour/reflux thien AcOH/48 hrs/reflux (0127] Compounds such as C preferably may be prepared as outlined in Scheme Alkylamine XCVII is treated with thiocarbonyl diimidazole in dichloromethane, foliwed by ammonium hydroxide to afford thiourea XCVII Treatment of thiourea XCVIIII with methylmethoxya cryl ate in dioxane and N-bromosuccinimidle 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.
IO
0 Cl Scheme Ss
SNH
2 (Im) 2 CS DCM IrT N ,NHCOe COMe theO hen NH MeO NBS 1,4-dioxane M VMeOe xcvlU H 2 0 -10 0 C to 80C MeO IC
SXCVII
1. LOH THF /H20 2. 1.2-penylenediamine MeOH /600C then HC ether BOP DMF TEA rT N H N12 1n 0 CK1 c
\O
[0128] Compounds of formula wherein X 2 is a chemical bond and Cy 3 has an amino C1 substituent preferably may be prepared according to the synthetic route depicted in Scheme 21.
Thus, protected iodoarylanilinylamide Cl is treated according to procedures analogous to those described for Scheme 15 above afford the diarylanilinylamide CII. The aldehyde moiety in 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 o 1. NaBH(OAcH) NH &.NH Pd(PPh 3 4 tBo CH OOH aq.oc Na 2
CO
3 CH COOH benzene 2. TFA ethanol CHO RHN CI CIl CIII [0129] Compounds of formula wherein X 2 comprises an alkynylene moiety, and compounds of formula wherein X 3 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 0 I ~N~o 0 Pd(PPhS) 2
C
2 NII NNH Cul to
NH
2
-NH
CIV
1. NaSH(0Ach
CH
3
COOH
OH y OMe 2. TFA Scheme 24
ICI
Q )N A N ",CI
H
CVI
H
2
N
-OCO
2 Me i-Pr 2 NEt
THF
reflux N cII
C
2 Me Q )N IINN H H
CVII
1. NH 3. 1.2-phenylenediamine, BOP
NH
2 0 Nk N. NH H H
CVIII
[0130] Compounds such as CVIII preferably may be prepared according to the synthetic route depicted in Scheme 24. Dichloroaminotriazine CVI is treated with methyl-4-aminobenzoate in the presence of diisopropylethylamine to produce diaminotriazine CVII. Addition of ammonia gas and dioxane, followed by a saponification and a peptidle coupling using the same procedures analogous to those described for Scheme 1 above.
IND
Scheme cI N 11,N C I I N -1,CI 1) R 1 MgBr, THF/toluene -30 0 C, 1 hi, then rt over 3 h 2) HCI.H 2 N N
CO
2 Me i-Pr 2 NEt, THF, rt N "IIN CI AlN IllN
H
CIX C0 2 Me S1. R 2 R'NH, i-Pr 2 Nt THF, sealed flask 80-90*C 2. LiOH.H 2 0 3. 1,2-phenylened jamine, BOP [0131] Compounds such as CX preferably may be prepared according to the synthetic route depicted in Scheme 30. The Grignard reaction of trichioroaminotriazine with various alkyl magnesium bromide, followed by a treatment with methyl4-aminobenzoate in the presence of diisopropylethylamine yields alkylaminotriazine CIX. Synthetic methods similar to those set forth in Scheme I above are then used to convert ester CIX to the corresponding anilinyl amide CX.
Scheme 32
CA
N NH- 3 gas K"N~"~"Cl14-dioxane sealed tube
NH
2 N ""N O N N) cl cxl n -BU 3 Sn Pd(PPh 3 4 toluene lootC
NH"N
CXII
1"H NHtloc VPd 2 (dba) 3
POT
Et 3 N, DMF 2. TFA. cH 2 cI 2
NH
2 NJ N Ci N-N H NH- 2 C X 71 1 N CXII0
NH
2 N JN
H
2 (40 psi) O NX"NlK NH2 10% Pd/c CXI 1, NI~ MeOH
(NO
[0132] Arnination of dlichlorotriazine proceeded using the usual condition described in Scheme 1 to afford CXI. Stille coupling using vinyl stannane provides CXII. Treatment with protected iodoanilidle, triethylamine, POT and dlibenzylacetone palladium then yields anilinylamide, which is deprotected with trifluoroacetic acid to provide the alkene CXIII11. Hydrogenation of the alkene affords the final compound CXIV.
Scheme 33 (1MeO -s BBr 3 HO~ 0- 0" ~N y-s N DDPPh 3 o. 0CXV
CXVI
OHca 0M IN 4H'N THFH IN 0 1. OH 0 BU 2 SncI 2 PhSiH 3 0M H 20 C N> CXVIII H 2 N 2OP 12hetnyleedimin [0133] Compounds such as CXV111I preferably may be prepared according to the synthetic route depicted in Scheme 33. Treatment of methoxyaminobenzothiazole with tribromidle boron affords the corresponding acid CXV. Mitsunobu reaction using hydroxyethyl morpholine in the presence of diethylazodicarboxylate and triphenyiphosphine 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 CXVIII1.
Scheme 42 O 1-1 2 S, Et 3 N. Pyridine 1-2NO 0 CxIXo 1 .3-dichloroacetone NH 1 ro rp th o lin e T H IF
H
S0 I 2. 8P, Ph(NH 2 2 CS N. OH CODI Et 3 N, DMF, rt/ \I cXXI cxx 0 [0134] Treatment 4-rnethylcyanobenzoic 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 CXXI1.
Scheme 49 0 Me
OH
0 I Ai or vi, Iii NC 0 Me
H
2 N
IO
S
1,1,01
CXXII
CXXIII
IJCXXV
NC 0 Me Vill, Ix HN
OH
Me ON 0 xv NC 0 MeN MHN s H H N NH
CXXVII
iBrCH- 2
C
6
H-
4 000Me/MeONa/THF; ii: PhNHNH 2 iii: NaOH, then HCi iv: HOBI/EDCxHCI then 1 ,2-diaminobenzene; v: BrCH 2
C
6
H
4 COOMeIMeONaJMeOH, then HCIIAcOH; vi: CH 2
(CN)
2
/S
8 /Et 2
NH;
vii: AcCI; viii: 2-N-Bocamino aniline; ix: TFA; [0135] Compounds such as CXXIII and CXXVII preferably may be prepared according to the synthetic scheme 49. Consecutive treatment of acetyl acetone with methyl bromomethylbenzoate in the presence of NaOMe and phenyl hydrazine followed by saponification, afforded the intermediate acid CXXII. This material was coupled with 1,2-diaminobenzene in a standard fashion to afford =XXI1I.
[0136] Consecutive treatment of acetyl acetone with methyl bromomethylbenzoate in the presence of NaOMe and a 1:1 mixture AcOH-HCI (conc.) afforded the intermediate acid CXXIV. This keto-acid reacting with sulfur and malonodinitrile in the presence of a base, produced the thiophene CXXV, which was converted into the desired CXXV1I using standard procedures.
Scheme c-I0 0 tr~COOH HO, c-K N.I N ~OH OH NC
H
3
CO<\
H
2
NN
c-ICXXVIII
CXXIX
i: NH 2 0HIEtOH; fi: C20/yridne; NN9 i ii: A0VE CxCth1 2 -ydiaizne;
N
N
NH,
CXXX
[0137] Compounds such as CX)(X 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 Q COOH 1. SOd 2 DMF, DCM0
P
2H 2
CXXXI
NHLBoc DIPEA BU 2 snCI 2 PhSiH 3 THF, 12h 1. CHCI 3 ITHF 3,4-dimethoxyanifine SMe oC 0~iI MeS(:HH NHtBoc HNe 0 Me0o"'f CXXXII
HNH
2 2. TFA, DCM OMe Meop
CXXXIII
OMe [0138] Compounds such as CX)(XIlI preferably may be prepared according to the synthetic route depicted in Scheme 57. Treatment of 4-formylbenzoic acid with thionyl chloride afford the acyl
OD
0 chloride which is coupled with protected anilide to produce CXXXI. Reductive amination with S dimethoxyaniline using phenylsilane and tin catalyst yields to the protected anilide CXXXII. Treatment with isocyanate followed by deprotection with trifluoroacetic acid provides the ureidoanilide CXXXIII.
Pharmaceutical Compositions [0139] In a second aspect, the invention provides pharmaceutical compositions comprising an inhibitor of histone deacetylase according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain preferred embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other preferred embodiments, administration may preferably be by the oral route.
[0140] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active 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, Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990.
[0141] As used herein, the term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -0-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate,
IO
0 0 or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
[0142] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. A preferred dose of the active compound for all of the abovementioned 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 0 0 range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
Inhibition of Histone Deacetylase [0143] In a third aspect, the invention provides a method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase according to the invention. Because compounds of the invention inhibit histone deacetylase, they are useful research tools for in vitro study of the role of histone deacetylase in biological processes. In addition, the compounds of the invention selectively inhibit certain isoforms of HDAC.
[0144] Measurement of the enzymatic activity of a histone deacetylase can be achieved using known methodologies. For example, Yoshida et al., J. Biol. Chem., 265: 17174-17179 (1990), describes the assessment of histone deacetylase enzymatic activity by the detection of acetylated histones in trichostatin A treated cells. Taunton et al., Science, 272: 408-411 (1996), similarly describes methods to measure histone deacetylase enzymatic activity using endogenous and recombinant HDAC-1.
[0145] In some preferred embodiments, the histone deacetylase inhibitor interacts with and reduces the activity of all histone deacetylases in the cell. In some other preferred embodiments according to this aspect of the invention, the histone deacetylase inhibitor interacts with and reduces the activity of fewer than all histone deacetylases in the cell. In certain preferred embodiments, the inhibitor interacts with and reduces the activity of one histone deacetylase HDAC-1), but does not interact with or reduce the activities of other histone deacetylases HDAC-2, HDAC-3, HDAC-
\O
0 S 4, HDAC-5, HDAC-6, HDAC-7, and HDAC-8). As discussed below, certain particularly preferred histone deacetylase inhibitors are those that interact with, and reduce the enzymatic activity of, a histone deacetylase that is involved in tumorigenesis. Certain other preferred histone deacetylase inhibitors interact with and reduce the enzymatic activity of a fungal histone deacetylase.
[0146] Preferably, the method according to the third aspect of the invention causes an inhibition of cell proliferation of the contacted cells. The phrase "inhibiting cell proliferation" is used to denote S an ability of an inhibitor of histone deacetylase to retard the growth of cells contacted with the I inhibitor as compared to cells not contacted. An assessment of cell proliferation can be made by 0 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 a solid tumor or organ), such an assessment of cell proliferation can be made by measuring the growth with calipers and comparing the size of the growth of contacted cells with non-contacted cells.
[0147] Preferably, growth of cells contacted with the inhibitor is retarded by at least 50% as compared to growth of non-contacted cells. More preferably, cell proliferation is inhibited by 100% 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 noncontacted 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 to apoptose), or to undergo necrotic cell death.
(0148] The cell proliferation inhibiting ability of the histone deacetylase inhibitors according to the invention allows the synchronization of a population of asynchronously growing cells. For example, the histone deacetylase inhibitors of the invention may be used to arrest a population of non-neoplastic cells grown in vitro in the 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.
IO
0 [0149] In some preferred embodiments, the contacted cell is a neoplastic cell. The term "neoplastic cell" is used to denote a cell that shows aberrant cell growth. Preferably, the aberrant cell growth of a neoplastic cell is increased cell growth. A neoplastic cell may be a hyperplastic cell, a cell that shows a lack of contact inhibition of growth in vitro, a benign tumor cell that is incapable of metastasis in vivo, or a cancer cell that is capable of metastasis in vivo and that may recur after S attempted removal. The term 'tumorigenesis' is used to denote the induction of cell proliferation that leads to the development of a neoplastic growth. In some embodiments, the histone deacetylase inhibitor induces cell differentiation in the contacted cell. Thus, a neoplastic cell, when contacted with an inhibitor of histone deacetylase may be induced to differentiate, resulting in the production of a non-neoplastic daughter cell that is phylogenetically more advanced than the contacted cell.
[0150] In some preferred embodiments, the contacted cell is in an animal. Thus, the invention provides a method for treating a cell proliferative disease or condition in an animal, comprising administering to an animal in need of such treatment a therapeutically effective amount of a histone deacetylase inhibitor of the invention. Preferably, the animal is a mammal, more preferably a domesticated mammal. Most preferably, the animal is a human.
[0151] The term "cell proliferative disease or condition" is meant to refer to any condition characterized by aberrant cell growth, preferably abnormally increased cellular proliferation.
Examples of such cell proliferative diseases or conditions include, but are not limited to, cancer, restenosis, and psoriasis. In particularly preferred embodiments, the invention provides a method for inhibiting neoplastic cell proliferation in an animal comprising administering to an animal having at least one neoplastic cell present in its body a therapeutically effective amount of a histone deacetylase inhibitor of the invention.
[0152] It is contemplated that some compounds of the invention have inhibitory activity against a histone deacetylase from a protozoal source. Thus, the invention also provides a method for treating or preventing a protozoal disease or infection, comprising administering to an animal in need of such treatment a therapeutically effective amount of a histone deacetylase inhibitor of the invention.
Preferably the animal is a mammal, more preferably a human. Preferably, the histone deacetylase inhibitor used according to this embodimentofthe-inventioninhibits a protozoal histone deacetylase to a greater extent than it inhibits mammalian histone deacetylases, particularly human histone deacetylases.
IO
0 [0153] The present invention further provides a method for treating a fungal disease or infection comprising administering to an animal in need of such treatment a therapeutically effective amount of a histone deacetylase inhibitor-of-theinvention- 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.
C [0154] The term "therapeutically effective amount" is meant to denote a dosage sufficient to "1 cause inhibition of histone deacetylase activity in the cells of the subject, or a dosage sufficient to O inhibit cell proliferation or to induce cell differentiation in the subject. Administration may be by any C route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain particularly preferred embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other preferred embodiments, administration may preferably be by the oral route.
[0155] When administered systemically, the histone deacetylase inhibitor is preferably administered at a sufficient dosage to attain a blood level of the inhibitor from about 0.01 pM to about 100 pIM, more preferably from about 0.05 pM to about 50 pM, still more preferably from about 0.1 pM to about 25 pIM, and still yet more preferably from about 0.5 pM to about 25 pM. For localized administration, much lower concentrations than this may be effective, and much higher concentrations may be tolerated. One of skill in the art will appreciate that the dosage of histone deacetylase inhibitor necessary to produce a therapeutic effect may vary considerably depending on the tissue, organ, or the particular animal or patient to be treated.
[0156] In certain preferred embodiments of the third aspect of the invention, the method further comprises contacting the cell with an antisense oligonucleotide that inhibits the expression of a histone deacetylase. The combined use of a nucleic acid level inhibitor antisense oligonucleotide) and a protein level inhibitor 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 aeeording4to4his.aspeet-o.the.iveen ri 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 GenBank Accession Number U50079
\O
0 S for HDAC-1, GenBank Accession Number U31814 for HDAC-2, and GenBank Accession Number 0 U75697 for HDAC-3).
[0157] For purposes of the invention, the term "oligonucleotide" includes polymers of two or more deoxyribonucleosides, ribonucleosides, or 2'-substituted ribonucleoside residues, or any combination thereof. Preferably, such oligonucleotides have from about 6 to about 100 nucleoside S residues, more preferably from about 8 to about 50 nucleoside residues, and most preferably from r, about 12 to about 30 nucleoside residues. The nucleoside residues may be coupled to each other CN1 by any of the numerous known internucleoside linkages. Such internucleoside linkages include 0 without limitation phosphorothioate, phosphorodithioate, alkylphosphonate, alkylphosphonothioate, 1 phosphotriester, phosphoramidate, siloxane, carbonate, carboxymethylester, acetamidate, carbamate, thioether, bridged phosphoramidate, bridged methylene phosphonate, bridged phosphorothioate and sulfone internucleoside linkages. In certain preferred embodiments, these internucleoside linkages may be phosphodiester, phosphotriester, phosphorothioate, or phosphoramidate linkages, or combinations thereof. The term oligonucleotide also encompasses such polymers having chemically modified bases or sugars and/ or having additional substituents, including without limitation lipophilic groups, intercalating agents, diamines and adamantane.
[0158] For purposes of the invention the term 2'-substituted ribonucleoside" includes ribonucleosides in which the hydroxyl group at the 2' position of the pentose moiety is substituted to produce a 2'-O-substituted ribonucleoside. Preferably, such substitution is with a lower alkyl group containing 1-6 saturated or unsaturated carbon atoms, or with an aryl or allyl group having 2-6 carbon atoms, wherein such alkyl, aryl or allyl group may be unsubstituted or may be substituted, with halo, hydroxy, trifluoromethyl, cyano, nitro, acyl, acyloxy, alkoxy, carboxyl, carbalkoxyl, or amino groups. The term "2'-substituted ribonucleoside' also includes ribonucleosides in which the 2'hydroxyl group is replaced with an amino group or with a halo group, preferably fluoro.
[0159] Particularly preferred antisense oligonucleotides utilized in this aspect of the invention include chimeric oligonucleotides and hybrid oligonucleotides.
[0160] For purposes of the invention, a "chimeric oligonucleotide" refers to an oligonucleotide having more than one type of internucleoside linkage. One preferred example of such a chimeric oligonucleotide is a chimeric oligonucleotide comprising a phosphorothioate, phosphodiester or phosphorodithioate region, preferably comprising from about 2 to about 12 nucleotides, and an alkylphosphonate or alkylphosphonothioate region (see Pederson et al. U.S. Patent Nos.
IO
0 5,635,377 and 5,366,878). Preferably, such chimeric oligonucleotides contain at least three consecutive internucleoside linkages selected from phosphodiester and phosphorothioate linkages, or combinations thereof.
[0161] For purposes of the invention, a "hybrid oligonucleotide" refers to an oligonucleotide S having more than one type of nucleoside. One preferred example of such a hybrid oligonucleotide comprises a ribonucleotide or 2'-substituted ribonucleotide region, preferably comprising from about 2 to about 12 2'-substituted nucleotides, and a deoxyribonucleotide region. Preferably, such a hybrid oligonucleotide contains at least three consecutive deoxyribonucleosides and also contains ribonucleosides, 2'-substituted ribonucleosides, preferably 2'-O-substituted ribonucleosides, or combinations thereof (see Metelev and Agrawal, U.S. Patent No. 5,652,355).
[0162] The exact nucleotide sequence and chemical structure of an antisense oligonucleotide utilized in the invention can be varied, so long as the oligonucleotide retains its ability to inhibit expression of the gene of interest. This is readily determined by testing whether the particular antisense oligonucleotide is active. Useful assays for this purpose include quantitating the mRNA encoding a product of the gene, a Western blotting analysis assay for the product of the gene, an activity assay for an enzymatically active gene product, or a soft agar growth assay, or a reporter gene construct assay, or an in vivo tumor growth assay, all of which are described in detail in this specification or in Ramchandani et al. (1997) Proc. Natl. Acad. Sci. USA 94: 684-689.
[0163] Antisense oligonucleotides utilized in the invention may conveniently be synthesized on a suitable solid support using well known chemical approaches, including H-phosphonate chemistry, phosphoramidite chemistry, or a combination of H-phosphonate chemistry and phosphoramidite chemistry 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, Pon, R.T. (1993) Methods in Molec. Biol. 20: 465-496).
[0164] Particularly preferred oligonucleotides have nucleotide sequences of from about 13 to about 35 nucleotides which include the nucleotide sequences shown in Table 1. Yet additional particularly preferred oligonucleotides have nucleotide sequences of from about 15 to about 26 nucleotides of the nucleotide sequences shown in Table 1.
2006252047 14 Dec 2006 Table 1 Oligo Target Accession Nucleotide Position Sequence position wihin Number Gene HDAC1 ASL1 Human HDAC1 U50079 1585-1604 5'-GMAACGTGAGGGACTCAGCA-3' 3'-UTR HDAC1I AS2 Human HDAC1I U50079 1565-1584 5'-GGMAGCCAGAGCIGGAGAGG-3' 3'-ITR HDAC1 MM Human HDAC1 U50079 1585-1604 5'-GTTAGGTGAGGCACTGAGGA-3' 3'-UIR HDAC2 AS Human H-DAC2 U31814 1643-1622 5'-GCTGAGCTGTTCTGATTGG-3' 3'-ITR HDAC2 MM Human H-DAC2 U31814 1643-1622 5~-CGTGAGCACTTCTCATICC-3' 3'-JT HDAC3 AS Human HDAC3 AF039703 1276-1295 5'-CGCIITCCUGCATTGACA-3' 3'-UTR HDAC3 MM Human HDAC3 AF039703 1276-1295 5'-GCCTTCCTACTCATTGTGT-3' 3'-UTR HDAC4 AS I Human HDAC4 AB006626 5 14-33 5-GCTGCCTGCCGTGCCCACCC-3' HDAC4 MM1 Human HDAC4 AB006626 514-33 5'-CGTGCCTGCGCTGCCCACGG-3' HDAC4 AS2 Human HDAC4 AB006626 7710-29 5'-TACAGTCCATGCMACCTCCA-3' 3'-UTR HDAC4 MM4 Human HDAC4 AB006626 7710-29 5'-AICAGICCACCMACCICGT-3' 3'4JTR AS Human HDAC5 AF039691 2663-2682 5'-CT-TCGGTCTCACCTGCTTGG-3' 3'-IJ HDAC6 AS Human HDAC6 AJO1 1972 379 1-3810 5'-CAGGCTGGAATGAGCTACAG-3' 3'-UIR HDAC6 MM Human HDAC6 AJO1 1972 379 1-3810 5'-GACGCTGCAAICAGGTAGAC-3' 3'-IJTR HDAC7 AS Human HDAC7 AF239243 2896-2915 5'-CTTCAGCCAGGATGCCCACA-3' 3-IJTR HDAC8 ASi1 Human HDAC8 AF230097 5 1-70 5'-CTCCGGCTCCTCCATC1TCC-3' HDAC8 AS2 Human HDAC8 AF230097 1328-1347 5'-AGCCAGCTGCCACTTGATGC-3' 3-IJTR
IN
[0165] The following examples are intended to further illustrate certain preferred embodiments of the invention, and are not intended to limit the scope of the invention.
EXAMPLES
cI N -,IN cl 1 1N CI
HCI.H
2 N
I
AC0 2 Me
I
i-P r 2 N EI HF. -78*C ci N AI N11 N C02 R NH THF, fl Paltway A NH 3 gas 1 4-dioxane seallied flas Pathway 8 Ci A N N NN
HI
4 C0 2
M
CI
e
NN
R'RN N I'rN 5 H'a C0 2 Me
R
1
R
2
NH
THIF or 1.4-dioxan\ sealed flask 120- 140*C
N
3 or R 3 R 4NH TFor 1 .4-dioxafle sealed flask 120.1 N )IIN R IR2N N'l I
HI
C02 6: LIM OHH 2 0 7:RH THF/H 2 0
H
2
N
111 2
N)
SOP reagent
EI
3 N. DMVF
NR
3
R
4
R
1 R 2 N N N NNH 2 HI 2 R 3
R
4 =H 8O A Example I
IO
0 0Example 1 4-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-yl-amino]-methyl)-N-(2-amino-phenyl)benzamide (compound 8) Step 1: Methyl-4-[(4.6-dichloro-[1.3,51triazin-2-vl-amino)-methvll-benzoate (compound 3) [0166] To a stirred solution at -780C of cyanuric chloride 1 (8.23 g, 44.63 mmol) in anhydrous N THF (100 mL) under nitrogen was added a suspension of methyl 4-(aminomethyl)benzoate.HCI 2 N (10.00 g, 49.59 mmol), in anhydrous THF (50 mL), followed by iPr 2 NEt (19.00 mL, 109.10 mmol).
0 After 30 min, the reaction mixture was poured into a saturated aqueous solution of NH 4 CI, and rC diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgS0 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH 2
CI
2 5/95) to afford the title compound 3 (12.12 g, 38.70 mmol, 87% yield) as a pale yellow solid. 1 H NMR (300 MHz, CDCI 3 8 (ppm): AB system (6A 8.04, 6 B 7.38, J 8.5 Hz, 4H), 6.54 (bt, 1H), 4.76 J 6.3 Hz, 2H), 3.93 3H).
Pathway A Step 2: Methyv4-[(4-amino-6-chloro-,l.3,51triazin-2-vl-amino)-methyll-benzoate (compound 4) [0167] In a 150 mL sealed flask, a solution of 3 (6.00 g, 19.16 mmol) in anhydrous 1,4-dioxane mL) was stirred at room temperature, saturated with NH 3 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 NH 3 gas was repeated at room temperature for 5 min, and the reaction mixture was warmed to again for 18 h. Then, the reaction mixture was allowed to cool to room temperature, poured into a saturated aqueous solution of NH 4 CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgS0 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH 2 Cl2: 30/70) to afford the title compound 4 (5.16 g, 17.57 mmol, 91% yield) as a white solid. 'H NMR (300 MHz, CDC13) 8 (ppm): AB system (SA 8.01, SB 7.35, J 8.1 Hz, 4H), 5.79 (bs, 1H), 5.40-5.20 2H), 4.724.63 2H), 3.91 3H).
Pathway
B
S Step 2: Methyl 4-[(4-chloro-6-(2-indanvl-amino)-l[,3.51triazin-2-yl-amino)-methyll-benzoate (compound [0168] To a stirred solution at room temperature of 3 (3.00 g, 9.58 mmol) in anhydrous THF mL) under nitrogen were added -Pr 2 NEt (8.34 mL, 47.90 mmol) and 2-aminoindan.HCI (1.95 g, 11.50 mmol) or R'R 2 NH (1.2 equiv), respectively. After 18 h, the reaction mixture was poured into a saturated aqueous solution of NH 4 CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgS0 4 filtered and I concentrated to afford the title compound 5 (4.06 g, 9.91 mmol, quantitative yield) as a white powder. 'H NMR (300 MHz, CDCI 3 8 (ppm): mixture of rotamers, 8.06-7.94 2H), 7.43-7.28 (m, 2H), 7.24-7.12 4H), 6.41 and 6.05 (2 bt, 1H), 5.68-5.44 1H), 4.92-4.54 3H), 3.92 (bs, 3H), 3.41-3.12 2H), 2.90-2.70 2H).
Step 3: Methvl4-[(4-amino-6-2-indanvl-amino)-[l.3.51triazin-2-vl-amino)-methvll-benzoate (compound 6) General procedure for the amination with NH. gas: [0169] In a 150 mL sealed flask, a solution of 5 (3.90 g, 9.51 mmol) in anhydrous 1,4-dioxane mL) was stirred at room temperature, saturated with NH 3 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 NH 3 gas was repeated for 5 min, and the reaction mixture was warmed to 1400C again for 18 h. Then, the reaction mixture was allowed to cool to room temperature, poured into a saturated aqueous solution of NH 4 CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgS04, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH 2
CI
2 3/97) to afford the title compound 6 (3.50 g, 8.96 mmol, 94% yield) as a pale yellow sticky solid. 'H NMR (300 MHz, CDCI 3 8 (ppm): 7.99 (bd, J 8.2 Hz, 2H), 7.41-7.33 2H), 7.24-7.13 4H), 5.50-5.00 2H), 4.90-4.55 5H), 3.92 3H), 3.40-3.10 2H), 2.90-2.70 2H). 13C NMR: (75 MHz,
CDCI
3 8 (ppm): 166.88, 167.35, 166.07, 144.77, 141.07, 129.82, 128.93, 127.01, 126.61, 124.70, 52.06, 51.80, 44.25, 40.16. HRMS (calc.): 390.1804, (found): 390.1800.
Pathways A and B, step 3, general procedure with primary and/or secondary amines: [0170] In a 50-75 mL sealed flask, a stirred solution of 4 (500 mg, 1.70 mmol, 1 equiv), i-PrzNEt (1.48 mL, 8.51 mmol, 5 equiv) and R'R 2 NH or R 3
R
4 NH (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
IO
0 0 to room temperature, poured into a saturated aqueous solution of NH 4 CI, and diluted with AcOEt.
After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 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-642indanvl-amino)-11.3,5]triazin-2-vl-amino)-methvll-benzoic acid (compound 7) [0171] To a stirred solution at room temperature of 6 (2.07 g, 5.30mmol) in THF (50 mL) was added a solution of LiOH.H 2 0 (334 mg, 7.96 mmol) in water (25 mL). After 18 h, the reaction Smixture was diluted in water and acidified with 1 N HCI until pH 5-6 in order to get a white precipitate.
After 1 h, the suspension was filtered off and the cake was abundantly washed with water, and dried to afford the title compound 7 (1.73 g, 4.60 mmol, 87% yield) as a white solid. 'H NMR (300 MHz, acetone-d 6 8 (ppm): 8.05 (bd, J 8.1 Hz, 2H), 7.56-7.42 2H), 7.30-7.10 4H), 5.90-5.65 2H), 4.854.60 4H), 3.40-2.80 4H). HRMS (calc.): 376.1648, (found): 376.1651.
Step 5: 4-{[4-Amino-6-(2indanvl-amino)1 1351-triazin-2-yl-aminol-methyl)-N-2-amino-phenvl)-benzamide (compound 8) [0172] To a stirred solution at room temperature of 7 (200 mg, 0.53 mmol) in anhydrous DMF mL) under nitrogen were added Et 3 N (74 01, 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), Et 3 N (222 1 d, 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 NH 4 CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgS0 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH 2
CI
2 2/98-+5/95) to afford the title compound 8 (155 mg, 0.33 mmol, 63% yield) as a pale yellow foam. 'H NMR (300 MHz, acetone-d 6 8 (ppm): 9.04 (bs, 1H), 7.96 (bd, J 8.0 Hz, 2H), 7.50-7.40 2H), 7.30 (dd, J 8.0 Hz, 1.4 Hz, 1H), 7.22-7.08 4H), 6.99 (ddd, J 8.0 Hz, Hz, 1.5 Hz, 1H), 6.86 (dd, J 8.0 Hz, 1.4 Hz, 1H), 6.67 (dt, J 7.5 Hz, 1.4 Hz, 1H), 6.60-5.49 (m, 4H), 4.804.50 4H), 3.30-3.08 2H), 2.96-2.74 2H).
EXAMPLES 2-28 [0173] Examples 2 to 28 describe the preparation of compounds 9 to 35 using the same procedure as described for compound 8 of Example 1. Characterization data are presented in Tables 2a and 2b.
2006252047 14 Dec 2006 Table 2a Characterization of Compounds Prepared in Examples 2-28 x V N N NH 2 Ex. Cpd V X Name Characterization Schm 4-[(4-amino-6-rnorphoin- 'H NMR (CDCI 3 8 (PPM): 8.02 Ks 1H), 7.79 J 24y~ 9 H 1, 3,5-triazin-2- Hz, 2H), 7.34 J =8.0 Hz, 2H), 7.31 1H), 7.08 (dt 2 9NH2 ylamino)-methyl]-N42- J =7.6 Hz, 1.5 Hz, IH), 6.82 J 6.7 Hz, 2H), 5.62 IA amino-phenyl)- J 5.9 Hz, 1H), 4.90 (bs, 2H), 4.61 J 6.0 Hz, 2H), ________benzamide 3.75-3.62 (in, 10H). 'H NMR (acetone.d 6 8 (ppm): 9.07 (bs, 8.05-7.95 4-f [4-amino-6.{1-indanyl- (in, 2H), 7.55-7.45 (in, 2H), 7.37-7.10 (mn, 5H), 7.04 (clt, J amino)-[ 1,3,5]-triazin-2- 7.6 Hz, 1.6 Hz, 1H), 6.90 (dd, J 8.0 Hz, 1.4 Hz, 1H), 3 10 NH 2 ylaminol-rnethyl)-N.2- 6.71 (dt, J 7.6 Hz, 1.4 Hz, IH), 6.65-5.55 (in, 5H), IA HN-_ amino-phenyl)- 4.75-4.60 (mn, 3H), 3.05-2.75 (in, 2H), 2.60-2.45 (in, 1H) benzamide 2.00-1.84 (in, 1H). HRMS (calc.): 466.2229, (found): ___466.2225 'H NMR (acetone-d 6 8 (PPM): mixture of rotamers, 9.05-9.00 (in, 1H), 7.98 J 8.8 Hz, 2H), 7.93 N.(2-Amino-pheny)-4-14- 7.84 J 8.0 Hz), 7.72 J 8.2 Hz), 7.58-7.40 (mn, amino-6A4-phenyl- 3H), 7.31-7.19 (in, 3H), 7.12-7.05 6.98 J 8.1 4 11 N&NH 2 piperazin-1-yl)- Hz, 2H), 6.86 J 8.2 Hz, I 6.80 J 7. 1 Hz, IA [1,3,Sltriazin-2-ylamino- 1H), 6.67 J 7.7 Hz, 1H), 6.57-6.50 (in, 1H), 5.78inethyl)-benzamide 5.60 (mn, 2H), 4.67-4.64 (in, 2H), 3.88-3.84 (in, 4H), 3.14 (s 4H. ,HRMS (calc.): 477.2389 NHA) (found): ____1477.2383 2006252047 14 Dec 2006 Ex. Cp Y X Name Characterization Schm- 4-1[4-amino-6-(2- 1 H NMR (acetone-d 6 5 (PPM): 9.08 (bs, IN), 8.51 (bs, pyridinyl-methyl-amino- IH), 8.05-7.90 (in, 2H), 7.80-7.60 (in, 1 7.55-7.15 (in, 12 INH 1,3,5]-triazin-2- 5H), 7.04 (dt, J 7.6 Hz, 1. 6 Hz, I 6.90 (dd, J 8.0 l ylaminoj-methyl)-N42- Hz, 1.4 Hz, 1H), 6.71 (dt, J 7.6 Hz, 1.4 Hz, LH), 6.85amino-phenyl)- 6.55 (in, 1H), 5.84 (bs, 2H), 4.75-4.60 (in, 4H). HRMS ________benzamide (calc.): 441.2025, (found): 441.2029 'H NMR (acetone-d 6 8 (PPM): 9.08 (bs, 1H), 8.05-7.95 4-(14,6-bisQ(2ndanyl- (in, 2H), 7.56-7.44 (mn, 2H), 7.34 (bd, J 7.7 Hz, 1H), (~~~NNHaiino){1,3,5]-tdazin-2- 7.27-7.10 (in, 8H), 7.04 (td, J 7.6 Hz, 1.4 Hz, 1H), 6 13 Ii:J)-NH NH~- ylamninol-rnethyl)-N42- 6.90 (dd, J 8.0 Hz, 1.4 Hz, 1H), 6.71 Wdt. J 7.6 Hz, LB amino-phenyl)- 1.4 Hz, 1H), 6.65-5.90 (in, 3H), 4.90.4.58 (in, 6H), 3.40benzamide 2.80 (in, 4H). HRMS (calc.: 582.2855, (found): 582.2838 4-1[4-Amino-6-(9H 'H NMR (acetone-d 6 8 (ppm): 9.05-9.00 (in, 1H), 8.03fluoren-9-ylamino)- 7.87 (in, 2H), 7.80-7.70 (mn, 2H), 7.63-7.20 (in, 9H), 7.00 7 14 -NH. NH 2 [1,3,5]triazin-2-ylaminol- 1H), 6.86 1H), 6.66 1H), 6.50-5.50 (in, 6H), lB methyll-N42-amino- 4.75-4.55 (mn, 3H). HRMS (calc.: 514.2229, (found): phenyl)-benzainide 514.2232 NQ-aninopheyl H NMR (CDC1 3 8 (ppm): 7.96 (bs, 1H), 7.81 J Naminoierdin-- Hz, 2H), 7.38 J 8.0 Hz, 2H), 7.32 J 8.0 Hz, 8 15 H2 amino5--pierin--y 1H), 7.08 (dt, Ji 7.7 Hz, 1.4 Hz, 1H), 6.83 J =6.6 I 8 15 N) NH I1,351-tn zin- Hz, 2H), 5.47 (bs, 1H), 4.80 (bs, 2H), 4.60 J 6.0 LA belamiodety] Hz, 2H), 3.88 (bs, 2H), 3.67 Ji 5.2 Hz, 4H), 1.66benzamide 1.58 (in, 1.56-1.48 (in, 4H). 4-[(4-amino-6- 1H NMR (CDCI 3 8 (ppm): 7.97 (bs, 1H), 7.82 J 16 Q>NHcyclopentyl amino- Hz, 2H), 7.39-7.34 (mn, 3H), 7. 10 (dt, J 7.6 Hz, 1.4 Hz, 9 1NHNH 2 [1,3,5-triazin-2-yl- LH), 6.85 J =7.0 Hz, 2H), 5.56 (bs, LH), 4.90 (bs, 1A amino) -metll-N42- 3H), 4.62 2H), 4.25-4.19 (mn, 1H) 3.88 (bs, 2H), 1.95 ainino-phenyl)- (in, 2H), 1.71-1.59 (in, 4H), 1.43-1.37 (in, 2H).
_______benzainide 2006252047 14 Dec 2006 Ex. Cpd V X Name Characterization Schm 'H NMR (acetone-d 6 8 (PPM): 9.08 (bs, I1H), AB system CHl(R)-4-((4-amino-642- (8A 8.00, 8B 7.51, J 8.0 Hz, 4H), 7.33 (bd, J 7.7
C
3 exo-fenchy-amino- Hz, 7.03 (ddd, J 8.0 Hz, 7.3 Hz, 1.4 Hz, 1H), 6.90 17 .~"HNH NH 2 [1,3,5]-triazin-2- (dd, J 8.0 Hz, 1.4 Hz, 1H), 6.71 (dt, J 7.6 Hz, 1.4 Hz, 1A
H
3 C 'C 3 ylaminol-methll-V42- 1H), 6.60-6.28 Cm, 1H), 5.80-5.20 3H), 4.67 (bs, 4H), amino-phenyl)- 3.87 (bd, J 9.1 Hz, 1H), 1.80-1.60 (in, 4H), 1.56-1.42 benzamide Cm, 1.34-1.00 (m including 2 s, 8H), 0.84 3H-).
(calc.): 486.2855, (found): 486.2844 1H NMR (acetone-d 6 8 (PPM): 9.07 Cbs, 1H), 8.00 (bd, 4-1f4-allyI-amino-642- J 7.4 Hz, 2H), 7.58-7.42 Cm, 2H), 7.34 Cbd, J 8.0 Hz, 11 8 indanyl-amino-[ 1,3,51- 1 7.2 7-7. 10 Cm, 4H), 7.04 (td, J 7.6 Hz, 1. 5 Hz, ILH), 11 18 NjQ-N triazin-2-ylamino]- 6.90 (dd, J 8.0, 1.4 Hz, 1H), 6.71 Cdt, J =7.6 Hz, 1.4 1B methyl-NC2-amino- Hz, 6.60-5.70 Cm, 3H), 5.26-5.00 Cm, 2H), 4.86-4.54 phenyl)-benzamide (in, 4H), 4.10-3.90 Cm, 2H), 3.38-3. 10 (in, 211), 3.00-2.80 2H). HIRMS Ccalc.: 506.2542, (found): 506.2533 4-((-cylopopy-amn-' H NMR (acetone-d 6 8 (ppm): 9.07 (bs, 1H), 8.00 (bd, 4-ind4y-cy~pamino- J 7.7 Hz, 2H), 7.60-7.40 Cm, 2H), 7.33 Cdd, J 7.8 Hz, NH6- H 15- iday-in 1.3 Hz, LH), 7.28-7. 10 4H), 7.04 dt, J 7.6 Hz, 12 19 >-NH (1,3-5]tflazifl2- Hz, 1H), 6.90 Cdd, J 7.8 Hz, 1.4 Hz, 1H), 6.71 Cdt, J) 1 K~-KI yamino-mettyl--2 7.6 Hz, 1.3 Hz, 1H), 6.67-5.80 Cm, 2H), 4.90-4.50 Cm, bamipey) 4H), 3.40-3.10 Cm, 2H), 3.05-2.70 Cm, 3H), 0.75-0.43 Cm, benzam~de 4H). HRMS (calc.): 506.2542, found): 506.2548 44(4Amin-6- H NMR (acetone-cd) 8 (PPM): 9.03 Cs, 1H), 7.97 Cd, J 4-L(4-hyamino- 7.7 Hz, 2H), 7.55-7.40 Cm, 2H), 7.35-7. 10 Cm, 6H), 6.99 20 N INH 2 phene5tylin-amino (td? J 8.0 Hz, 1.3 Hz, IH), 6.86 (dd, J 8.0 Hz, 1.3 Hz, 1A [N3Stizn--lmn) IH), 6.6 7 Cdt, J 8. 0 Hz, 1. 4 Hz, 1 6.62-5.40 Cm, 5H), Hmethyll-UA2-amino- 4.75-4.45 Cm, 3H), 3.59-3.45 Cm, 2H), 2.95-2.70 Cm, 2H).
phenyl)-benzamide HIRMS (calc.): 454.2229, (found): 454.2235 2006252047 14 Dec 2006 Ex._ C.p. Y X Name Characterization Schm NA 2-Amino-phenyl)-4-( [4- H amino-643,4,5- 'H NMR (CDCI 3 /MeOD) 8 (ppm): 7.72 J 8.2 Hz, 1 21 MeO in N, H trimethoxy- 2H), 7.21 J 8.2 Hz, 2H), 7.04 J 7.7 Hz, 1H), LB
NH
2 phenylamino)- 6.91 (td, J 7.7 Hz, 1.2 Hz, 1H), 6.70-6.61 4H), OMe [l,3,5triazin-2-ylamino]- 4.61 (bs, 2H), 3.58-3.52 (in, 9H).
____________methyl)-benzamide 4-114-Amino-6-(2,3- 'H NMR (CDCI 3 /MeOD) 8 (ppm): 8.06 (bs, 1H), 7.82 (d, dihydroindol-1-y)- J 8.0 Hz, 2H), 7.37 J 8.2 Hz, 2H), 7.13 J 22 LL.2NH 2 (1,3,5triazin-2-ylamino]- 7.4 Hz, 1H), 7.06 J 7.4 Hz, IH), 7.02-6.96 (in, 2H), 1B methyl)4NA2-amino- 6.84-6.71 (in, 3H), 4.61 (bs, 2H), 4.03 J 8.5 Hz, _____phenyl)-benzamide 2H), 3.02 J 8.5 Hz, 2H).
4-{(4-Amino-6-[2-(2- 'H NMR (acetone-d 6 5 (PPM): mixture of rotamers, methoxy-phenyl)- 9.06 1H), 7.96 J =8.0 Hz, 2H), 7.55-7.40 2H), 16 23ethylaminoj- 7.28 J 7.4 Hz, 1H), 7.21-6.70 (in, 6H), 6.67 J H6 2 NH 2 [1,3,51triazin-2- 7.1z H,66-.0(n H,47-.5(n H,38 A O~e yamino-ety)-N2 3H), 3.55-3.45 (in, 2H), 2.90-2.78 (in, 2H). HRMS bamipey) (calc.): 484.2335, (found): 484.2331 4414-Amino-6-{2-2- 'H NMR (acetone-dr) 8 (ppm): mixture of rotamers, fluoro-phenyl)- 9.03 IHN, 7.97 J 8.0 Hz, 2H), 7.55-7.40 (nn, 2H), ettiylamino]- 7.38-7.17 (in, 2H), 7.17-6.95 (mn, 4H), 6.86 (dd, J 17 24 -NH 2 [1,3,51triazin-2- Hz, 1.4 Hz, 1H), 6.67 J 7.0 Hz, 1H), 6.50-5.60 (in, 1A F ylamino)-methyl-NA2- 5H), 4.75-4.55 (mn, 3H), 3.60-3.52 (nn, 2H), 2.95-2.85 (in, amnino-phenyl)- 2H). HRMS (calc.): 472.2135, (found): 472.2146 4-(4-bnzAamio-62-'H NMR (acetone-d 6 5 (PPM): 9.06 (bs, 1H),*8.04-7.'93 4-[bnday amino 2H), 7.57-7.12 12H), 7.04 (td, J 7.6 Hz, idan~-aino~1,35]- Hz, 1H), 6.91 (dd, J 8.0 Hz, 1. 1 Hz, LH), 6.72 (bt, J 18 25 UCE.J-NH H!J~ triazin-2-ylainino]- 7.6 Hz, 1H), 6.68-5.90 3H), 4.84-4.50 7H), 3.35- lB methyll-N42-amino- 3.13 (in, 2H), 3.00-2.80 (in, 2H). HRMS (calc.): phenyl)-enzainide 556.2699, (found): 556.2706 2006252047 14 Dec 2006 Ex. Cpd Y X Name Characterization Schm 'H NMR: (CDC1 3 8 (ppm): 7.83 J 8.2 Hz, 3H), 7.44 19N2 ,-Ai-pheriny J 8.2 Hz, 2H), 7.32 J 7.4, LH), 7.12-7.06 (m, 19 26 C N [14,,ipperidin-yl 1H), 6.87-6.82 2H), 5.11 J 6.2 Hz, 1H), 4.64 1B m1,3,ltrinzi-amin- J 6.3 Hz, 2H), 3.87 (bs, 2H), 3.69 Ct, J 5.4 Hz, 8H), methyl]-benzamide 1.153 ,12) 1.63-1.53 12H).
4-[6A2indanyl-amino)- 'H NMR (acetone-d 6 6 (ppm): 9.07 Cbs, 1H), 8.05-7.90 H 4-phenethyl-amino- Cm, 2H), 7.60-7.40 2H), 7.35-7.05 Cm, 10H), 7.04 (td, 27j: N (1,3,5-triazin-2- J 7.6 Hz, 1.5 Hz, 1H), 6.90(d, J 7.7 Hz, 1H), 6.71 Ct, lB K 27 (N ylamino]-inethyl)-N-{2- J 7.3 Hz, 1H), 6.60-5.70 3H), 4.95-4.50 Cm, amino-phenyl 3.70-2.80 Cm, 8H). HRMS (calc.): 552.2750 NH 4
I,
benzamide (found): 552.2746 4-114-benzylamino-642- 'H NMR (CDCI 3 5 (ppm): 7.83 Cd, J 8.2 Hz, 3H), 7.44 indanyl-amino)-[1,3,51- Cd, J 8.2 Hz, 2H), 7.32 Cd, J 7.4, 1H), 7.12-7.06 Cm, 21 28 1 Jj- NH 2 triazin-2-ylamino]- 1H), 6.87-6.82 Cm, 2H), 5.11 Ct, J 6.2 Hz, IH), 4.64 1A methyl)-N42-amino- J 6.3 Hz, 2H), 3.87 bs, 2H), 3.69 Ct, J 5.4 Hz), 1.63phenyDbenzamide 1.53 Cm, 12H).
'H NMR (acetone-d 6 6 (ppm): 9.04 1H), 7.95 Cd, J 4-44-Amino-6- 7.3 Hz, 2H), 7.45 Cd, J 7.1 Hz, 2H), 7.38-7.15 Cm, benzylamino- 6H), 7.00 td, J 8.0 Hz, 1.5 Hz, 1H), 6.86 Cdd, J 22 29 Hjri NH 2 1l,3,ltriazin-2-ylamino)- Hz, 1.4 Hz, 1H), 6.67 Cdt, J 8.0 Hz, 1.4 Hz, 1H), 6.67- IA methyll-N42-amino- 6.25 Cm, 3H), 5.85-5.55 Cm, 3H), 4.61 Cd, J 6.3 Hz, phenyl)benzamide 2H), 4.54 Cd, J 5.2 Hz, 2H). HRMS (calc.): 440.2073, (found): 440.2078 4-1[6-(2-indanyl-aminoY 'H NMR (acetone-d 6 6 (ppm): mixture of rotamers, 9.20-9.00 Cm, 1H), 8.70-8.35 Cm, 2H), 8.05-7.90 Cm, 2H), 4'.3-pyridinylmethAl- 7.85-7.55 LH), 7.55-7.10 Cm, 8H), 7.04 Cdt, J 7.6 23 30 rljN'H N amino13,triaziN2 Hz, 1.5 Hz, IH), 6.91 Cbd, J 7.4 Hz, 1H), 6.71 (bt, J lB N ylaminolnethyU-M2- 7.3 Hz, 1H), 6.80-6.00 3H), 4.84-4.50 Cm, 7H), 3.34ainino-phenyl)- 3.12 Cm, 2H), 3.00-2.80 Cm, 2H). HRMS (caic.): benzamide 539.2546
NH
4 I (found): 539.2533 2006252047 14 Dec 2006 Ex. Cd Y X Name Characterization Schm N(2-Anino-phenyl)-4-[(4- 'H NMR (CDCI 3 5 (ppm): 7.89 (bs, 7.82 J piperidin-1-y-6- 8.2 Hz, 2H), 7.42 J 8.0 Hz, 2H), 7.32 J 24 31 rNY-NH pyrrolidin-1-yi- Hz, 1H), 7.09 (dt, J 7.7 Hz, 1.6 Hz, 1H), 6.87-6.82 LB 2H), 4.83 (bs, 1H), 4.62 J 6.0 Hz, 2H), 4.24 (m, [1,3,ltrnzi-amin- 1H), 3.88 (bs, 1H), 2.04-1.96 2H), 1.70-1.52 (m, 1OH), 1.46-1.38 2H).
N42-Arino-phenyl)4-1[2- 'H NMR (CDCI 3 8 (ppm): 8.27 (bs, 1H), 7.74 J 7.4 H piperidin-1.y-642- Hz, 2H), 7.29 3H), 7.05 (dt, J 7.6 Hz, 1.4 Hz, 1H), 32 ('J3CN- pyrrolidin-1-0- 6.81-6.76 2H), 5.62 (bs, 2H), 4.57 (bs, 2H), 3.91 (bs, 1B etholamino)-pyrimidin-4eylamino)hyrimii- 2H), 3.69 4H), 3.45 2H), 2.57 J 6.2 Hz, 21), benzamide 2.47 4H), 1.71 4H), 1.59-1.50 6H).
'H NMR (acetone-d 6 6 (ppm): 9.07 (bs, 1H), 8.08-7.95 4-mor6A2inanyl-amino)- 2H), 7.60-7.43 2H), 7.33 J 8.0 Hz, 1H), 26 33 NH' 4morphoin4-y [1,3,5I- 7.28-7.12 4H), 7.04 (dt, J 7.6 Hz, 1.4 Hz, IH), [o"N metrn-2-amno- 6.91 J 7.4 Hz, 11), 6.72 J 7.4 Hz, 11), 6.55mhetyl)-benAamino- 6.05 21), 4.86-4.60 51), 3.80-3.56 8H), 3.38-3.12 21), 3.04-2.82 21).
N. 2-Amino-phenyl)-4-f[2- 'H NMR (acetone-d) 8 (ppm): 9.08 (bs, 1H), 8.01 (bd, H piperidin-1-yl-6-2- J 7.4 Hz, 2H), 7.56-7.43 2H), 7.33 (bd, J 8.0 Hz, 27 34 N pyrrolidin-1-y- 11), 7.28-7.12 4H), 7.04 (dt, J 7.6 Hz, 1.4 Hz, 1H), 1B ethylaiino)-pyriidin4 6.90 (dd, J 8.0 Hz, 1.4 Hz, LH), 6.71 Cdt, J 7.6 Hz, ylaiino-rethyl)- 1.4 Hz, 1H), 6.65-5.75 2H), 4.904.58 5H), 3.66benzamide 2.34 16).
4414-Aiino-6f2(1HR 'H NMR (acetone-d 6 8 (ppm): 10.00 11), 9.13 (s, indol-3-yl)-ethylamino]. 1H), 7.93 J 8.0 Hz, 21), 7.70-7.50 1H), 7.50- H [1,3,5triazin-2- 7.22 41), 7.18-6.91 4H), 6.85 Cd, J 7.1 Hz, 28 3 ylamino)3N ethylNH- IH), 6.67 J 7.4 Hz, 1H), 6.40-5.90(m, 3H), 4.71A amino-phenyol 4.50 (in, 21), 4.37 21), 3.62 Cd, J 6.3 Hz, 2H), 2.99 benzamide 2H).
2006252047 14 Dec 2006 Table 2b
Y
XN N NH '1,'HI H N Ex. Cpd X V Name Characterization Schm 4-1[4-amino-6.(3-phenyl- 'H N~MR (300 MHz, acetone-d 6 8 (ppm): 9.03 Cs, prop I-am1K),I 7.96 J=8.2 Hz, 2H), 7.46 J=737 Hz, 2H), 329 470 N" rpl1-mn 7.35-7.10 Cm, 6H), 7.00 J=737 Hz, 1H), 6.86 A 329N7 H NH 2 rl,3,5triazin-2-I-amino]- J=8. 0 Hz, 1I), 6.67 J=737 Hz, LH) 6.60-5.40 Cm, methyl)-N42-amino- 6H), 4.62 Cs, 2H), 3.35 Cdd, J=12.1, 6.9 Hz, 2H), phenyl)-benzamide 2.75-2.60 Cm, 2H), 1.95-1.80 (in, 2H).
N-(-amino-phenyl-4-[(4- H NMR (300 MHz, acetone-d 6 8 (ppm): 9.04 (s, cyclopropyi-amino#- 1H), 7.96 J=8.0 Hz, 2H), 7.55-7.40 (in, 2H), 7.35- 30471 >-NH phenethyl-amino- 7. 10 Cm, 6K), 6.98 J=7.4 Hz, 1H)R 6.85 J=6.9 1B 330'"'N Hz 1H), 6.66 J=7.3 Hz, 1H), 6.20-5.50 3H), H (1,3,5triazin-2-y-amino- 4.80-4.5 4H), 3.65-3.45 Cm, 2H), 3.00-2.60 (m, methyl]-benzamide 2K), 0.80-0.40 Cm, 4H).
N.(2-amino-phenyl--114- H NMR (300 MHz, acetone-d 6 5 (ppm): 9.06 Cbs, cyclproyl-1H), 8.00 Cbd, J 7.1, 2H), 7.50 Cbs, 7.33 (d, c eyclprol J 6.6 Hz, 1H), 7.28-7.07 Cm, 4H), 7.03 Ctd, J 7.6, H3 472hya(1n-6NH 1. 5 Hz, I1H), 6.90 Cdd, J 8.0, 1.4 Hz, 1LH), 6.71 td, 1B Co indanyl-amino)-[ J 1.4 Hz, 1K), 6.55-5.70 Cm, 3H), 4.90-4.50 triazin-2-y~amino1- Cm, 5K), 3.40-2.80 Cm, 6H), 1. 07 Cbs, IH)K 0.44 (bs, inethyl)-benzamide 2K), 0.23 Cbs, 2H).
N42-minopheyl)4W IH NMR (300 MHz, CDCI 3 5 (ppm): 8.08 1K), N.{2-amino-hnl6 C- 7.83 Cd, J 6.6 Hz, 2H), 7.45-7.05 Cm, 8H), 7.08 (td, 33 43 mnBuNK phn-buWIamino- J 7.8, 1.5 Hz, 1H) 6.84 Ct, J 8.1 Hz, 6.70- lB 33 phneh73mio 5.00 Cm, 3K), 4.70-4.50 Cm, 2H), 3.65-3.50 Cm, 2H), H [13,Sltriazin-2-yi-amino)- 3.45-3.25 Cm, 2K), 2.40-2.25 2H), 1.60-1.45 Cm, methyll-benzainide 12H), 1.45-1.00 Cm, 2H), 1.00-0.8 Cm, 2006252047 14 Dec 2006 Ex. Cpd X V Name Characterization Schmn Nq2-minophenl)-4 1 'H NMR (300 MHz, acetone-d 6 8 (PPM): 9.02 N2-mihox-hyl-4-- 8.58 8.40 (dd, J 7.2, 2 Hz, 1H), 7.97 J 333 74 -~MeOH 2
C
2 NHamino)-6-phenethyl- 7.5 Hz, 1H), 7.51-7.40 (in, 2H), 7.70-6.90 (in, 7H), 333 74 MeCH2H2N amno-[1, ,51riain--y 6.86 (dd, J 8.1, 1.2 Hz), 6.76 (dd, Ji 7.5, 1.8 Hz), lB H aio-ehl 6.67 (td, J =7.8,1.5 Hz,66055Cm, 3H), 4.75baidey) 4.55 (in, 4H), 3.65-3.35 (in, 6H), 3.35-3.20 3H), benzamide 2.95-2.75 Cm, 2H). 'H NMR (300 MHz, acetone-dr) 8 (ppm): 9.02 (s, N42-amino-phenyl)-4-1[4-1H,80-91(i,2)75874Cm2),.8(s Cl(4-chloro-phenethyl- 1H,807.1(,2)7.8.4(m2),.8(s amino)-6-cyclopropyl- 4H), 7.20-7.05 (in, 1H), 6.99 (td, J 7.5, 1.8 Hz, 334 475 [NHamino-[ 1, 3,5triazin-2-y- 1H), 6.86 Cd, J 7.8 Hz, 1H), 6.67 J 6.9 Hz, lB HN 1H), 6.60-5.60 3H), 4.75-4.50 Cm, 4H), 3.65-3.40 I amino-meLIhyl)- (bs, 2H), 2.95-2.65 2H), 0.75-0.55 2H), 0.55benzamide 0.40 (in, 2H).
N-(2-amino-phenyl)-4-I 6- Ome cyclopropyl-amino-4{4- 'H NMR (300 MHz, CDCI 3 8 (ppm): 8.55-7.72 (in, 335 methoxy-phenethy 4H), 7.55-6.75 Cm, 9H), 6.75-5.30 Cm, 3H), 4.69 (in, 35476 Namino)-I1,3,5triazin-2-y 2H), 3.85 3H), 3.63 Cbs, 2H), 2.86 Cm, 3H), 0.85 1 Iaminol-mnethyl)- Cbs, 2H), 0.61 Cbs, 2H).
Cl N(2-amino-phenyl)-4-1[4- 'H NMR (300 MHz, acetone-dr) 8 (ppm): 9.03 Cs, (3-chioro-phenethyl- LH), 7.96 Cd, J 7.5 Hz, 2H), 7.60-7.37 Cm, 2H), 336 77 I amino)-6-cyclopropyl- 7.37-7.12 Cm, 5H), 6.99 Ct, J =6.9 Hz, 1H), 6.86 Cd, J l 336 477 >-NH f6 amino-[ 1, 3,5triazin-2-y- 6.9 Hz, 1H), 6.67 J 7.2 Hz, 1H), 6.60-5.60 Cm, 1 HN amino]-rnethyl)- 3H), 4.75-4.50 Cm, 4H), 3.67-3.45 2H), 3.00-2.67 C(m, 3H), 0.75-0.40 4H). 2006252047 14 Dec 2006 Ex. Cpd X Y Name Characterization Schm OM ~2-amino-phenyI)-4-([6- I H NMR (300 MHz, acetone-d 6 5 (PPM): 9.02 (s, Ome m, cycoprpylamioA- 1H), 7.96 J 8.1 Hz, 2H), 7.60-7.40 (in, 2H), O 3,e-cycl oprymn- 7.29 J 8.1 Hz, 1H), 6.99 (td, J 8.1, 1.5 Hz, 337 478 I ph(34-iethaxyn- 1H), 6.95-6.72 (in, 4H), 6.67 (td, J 7.8, 1.5 Hz, lB HN f&hene,5tylainy-n noV 1H), 6.20-5.60 (in, 3H), 4.78-4.52 (in, 4H), 3.75 is, [1 ,3,5jtriaz 2-ami no) 6H): 3.65-3.42 2H), 2.95-2.65 3H), 0.72-0.40 O~e 2-ainopheyl)44[- IH NMR (300 MHz, acetone-d 6 J 8 (PPM): 9.02 (s, cyclopropy-amino-443- 1H) 7.96 J 7.8 Hz, 2H), 7.60-7.35 (in, 2H), 338 479>-N methoxy-phenethyl- 7.29 J 7.5 Hz, 1H), 7.18 J 7.8 Hz, 1H), 33 49 >-HaminoR-t,3,51triazin-2-y 6.99 (td, J 7.5, 1.5 Hz, 1 6.90-6.70 (mn, 4H), lB HN aio-ehl 6.67 J =7.8 Hz, 1H), 6.60-5.60 (in, 3H), 4.77bami-ehy) 4.50 4H), 3.76 3H), 3.65-3.45 2H), 2.92benzamide 2.65 (in, 3H), 0.72-0.42 (mn, 4H). 'H NMR (300 MHz, acetone-d 6 8 (ppm): 9.03 (s, N-2-amino,-pheny)-4-f[6- 1 8.50 J 2 Hz, 1 7.96 J 8. 1 Hz, cyclopropyl-aino-442- 2H), 7.66 J =7.5 Hz, 1H), 7.60-7.40 (mn, 2H), 33 40 pyridin-2-yI-ethyl- 1- 7.35-7.08 (in, 3H), 6.99 (td, J 8.1, 1.5 Hz, 1H), 339 80 _N HNamnino)-[1, 3,5triazin-2-y[ 6.86 (dd, J 8.1, 1.5 Hz, 1H), 6.67 (td, J 7.8, 1.5 lB HNainino-methyl- Hz, 1H), 6.6&-5.60 (mn, 3H), 4.75-4.50 (mn, 4H), 3.80benzamide 3.60 (in, 2H), 3.15-2.90 (mn, 2H), 2.90-2.65 (in, 1H), 0. 73-0.40 (mn, 4H).
N42-amnino-phenyl-4-1[6- 1 H NMR (300 MHz, acetone-d 6 8 (PPM): 9.20-9.00 cyclopropyl-amino-4-(3- (mn, 1H), 8.70,8.50 (mn, 2H), 8.00 and 7.88 (2d, J= J340 481 arn- N pYRridzin-2-yI-ty- 7' 9 Hz, 2H), 7.75-7.43 (in, 3H), 7.38-6.67 (in, 5H), LB HN aiio-13Stizn2y-6.22-5.78 (in, 3H), 4.80-4.55 (in, 4H), 3.61 (bs, 2H), Iamino]-rnethyll- 3.20-2.65 (in, 3H), 0.80-0.45 (mn, WH.
L lbenzainide 2006252047 14 Dec 2006 Ex.- .cp X V Name -I -Characterization Schm N42-amino-phenl)4[4- 1 H NMR (300 MHz, acetone-d 6 8 (PPM): 9.04 (s, cycoprpylamio-& 1H). 7.98 (d J 8.1 Hz, 2H), 7.60-7.40 (in, 2H), [ycop--NHin-6 7.35-7.15 Cm, 6H), 7.00 (td, J 7.5, 1.5 Hz, 1H), 341 482 phenethyl-oxy-686(J=8.Hz H,66(tJ=75H,1), ,2 [1,3,5triazin-2-y-amino -6.6(,J=81HH)6.7CJ=.5zH) 1,2 meth~enzmide 7.18-6.35 Cm, 2H), 4.75-4.30 (in, 6H), 3.10-2.92 Cm, methyj-benamide 2H), 0.75-0.63 (in, 2H), 0.57-0.48 (in, 2H). 1 H NMR (300 MHz, acetone-d 6 0 DMSO-d 6 M.2-amino-phenyl)-41C6- (ppm): mixture of rotamers, 9.62 (bs, 1H), 8.03 J methy-- 8.0 Hz, 2H), 7.80-7.44 Cm, 3H), 7.40-7.10 8H), 34N8 Me phenethylamino- 7.01 J 7.6 Hz, 1H), 6.87 (d J 7.9 Hz, 1H), H (1,3,S1triazin-2-yI-amino- 6.67 J 7.4 Hz, 1H), 4.85 (bs, 2H), 4. 724.54 (m, methyfl-benzamide 2H), 3.63-3.42 Cm, 2H), 2.96-2.74 2H), 2.21 and 2.13 (2s, 3H). 'H NMR (300 MHz, acetone-ds) 8 (ppm): mixture of NM2-amino-phenyl-4-C[4- rotamers, 9.08 Cbs, 1H), 8.48-8.36 2H), 8.02 J amino-6-phenyl-[1,3,5]- 8.2 Hz, 2H), 7.63-7.42 Cm, 5H), 7.33 (d J 7.7 343 484 Q)NH 2 Hz, 1H), 7.19 Cbs, 1H), 7.03 Ct, J 7.4 Hz, 1H), 6.88 triazin-2-y~amino- J 7.9 Hz, 1H) 6.70 J 7.6 Hz, 1H), 6.35 and methyll-benzamide 6.25 (2bs, 2H), 4.87 and 4.75 (2d, J 5.9 Hz, 2H), Cbs, 2H). N42amio-peny)-4([6 'H NMR (300 MHz, acetone-d 6 8 (ppm): mixture of N42amio-penl)--f 6-rotamers, 9.14-8.96 Cm, 1H), 8.54-8.30 Cm, 2H), _NHan~mio4 8.09-7.95 Cm, 2H), 7.68-7.40 Cm, 5H), 7.38-7.08 Cm, 344 485 ~~.~.Hphenyl-f1, 3,5]-triazin-2- 6H), 7.03 Ct, J~ 7. Hz, 1H), 6.94-6.76 Cm, 2H), 6.71 -amno~ethyl- Ct, J 7.3 Hz, 1H), 5.13-4.54 Cm, 5H), 3.49-3. 18 (mn, benzamide 12H), 3.12-2.90 (in, 2H).I 36 AcCI Et 3
N
CHZCI
2 O'C to r 0 37 0 N N cI N CI LiHMDS
THF
-76*C to rt
HCI.HN
C Pr 2
N
THF 60
CO
2 Me 2. LOH.H 2 0
THF/H
2 0, rt 3. BOP. Ph(NH 2 2
EI
3 N. OMF, rt
E
1*1 0 C O N- N N N N NH2 39 0 SExample 29 o Example 29 N-(2-Amino-phenyl)-4-({4-[2-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-oxo-ethyl]-6morpholin-4-yl-[1,3,5]triazin-2-ylamino}-methyl)-benzamide (compound 39) Step 1: NAcetvl-1-piperonvlpiperazine (compound 37) [0171] To a stirred solution at O°C of 1-piperonylpiperazine 36 (5.00 g, 22.7 mmol) in anhydrous CH 2
CI
2 (60 mL) was added Et 3 N (6.33 mL, 45.4 mmol) followed by acetyl chloride (1.94 mL, 27.2 mmol). The reaction mixture was stirred 30 min. at O°C and then 2 h at room temperature.
The reaction mixture was poured into a saturated aqueous solution of NH 4 CI, and diluted with AcOEt.
After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgS0 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH 2
CI
2 4/96) to afford the title compound 37 (5.52 g, 21.11 mmol, 93% yield) as a yellow solid. 'H NMR: (300 MHz, CDCI 3 8 (ppm): 6.83 1H), 6.72 2H), 5.92 2H), 3.59 J 5.1 Hz, 2H), 3.44-3.40 4H), 2.42 (dt, J 5.1 Hz, 5.1 Hz, 4H), 2.06 (s, 3H).
U Step 2: 2-Chloro-4-moroholin-4-vl-6-f2-{4-benzoi 1. 3ldioxol-5-vlmethvl-iierazin-1 -vl)2-oxo-ethvO- [1.3,51triazine (comoound 38) [0172] To a stirred solution of 37 (3.00 g, 11.4 mmol) in anhydrous THE (25 mL) at -780C was slowly added a solution of LiHMDS (11.4 mL, 11.4 mmol, 1 M in THE). The reaction mixture was stirred 1 h at -~780C and a solution of 2,4-dichloro-6-rnorpholin-4-yI-[1,3,5]triazine (2.69 g, 11.4 mmol) in anhydrous THEF (25 mL) was added. The reaction mixture was slowly warmed up at room V) temperature and the reaction was quenched after 16 h with a saturated aqueous solution of NH 4
CI.
ID The THE was evaporated and the residue was diluted with AcOEt. The organic layer was successively washed with sat. NH 4 CI and brine, dried over anhydrous MgS0 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH 2
CI
2 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, CDCI 3 8 (ppm): 6.84 1H), 6.77-6.69 (in, 2H), 5.95 2H), 3.75-3.43 (in, 16H), 2.42 (mn, 4H).
Step 3: Nq2-Amino-henvl)-4(4-[2-(4-benzo 1. 3ldioxo-5-vliethl-Diierazin-1 -vl)-2-oxo-ethvlV-6 morrholifl4-vIJ1 5ltriazin-2-ylamino)-methvl)-benzamide (comp~ound 39) [0173] The title compound 39 was obtained following the same procedure as Example 1, step 1H NMR (GDCI 3 8 (ppm): 7.96 (bs, 1H), 7.87 J 8.2 Hz, 2H), 7.39 J 8.2 Hz, 2H), 7.33 J 8.5 Hz, 1H), 7.10 (dt, J 7.6 Hz, 1.2 Hz, 1H), 6.87-6.81 (in, 3H), 6.75-6.68 (in, 2H), 5.93 2H), 5.67 (bs, 1H), 4.64 2H), 3.90 (bs, 2H), 3.75-3.35 (in, 16H), 2.45-2.30 (mn, 41-).
Ny x Br N V X Br, Y H 41: X= H, Y=Br RNHI xCOA 120 0 C RHN N Y P4(dba) 3 1 PI 42:XBrY=H, DMF/ DIPEA R PhNH(CH 2 2 43 X Y Br R= MeOPhCH 2 Co (1 atm) Pd(OAC)2
I
dppf IOMF DIPEA I 60 0
C
Ph(NH 2 2
X
RHN N Y 0 44:X= TNH2 Y=H R PhNH(CH 2 2 0 Example41 45:X=H Y= R MeOPhCH 2 lu
XI/I
3T RHN N Y I 120 0
C
46:X=
C
2 Bu Y=H R PhNH(CH 2 2 47 X =H Y C(tU R= MeOPhCH 2 ITFA I CHZC 2 RHN N Y 48X Cz Y=H R PhNH(0H 2 2 49 X H. Y NCOH R MeOPhCH 2 Pth(NH 2 2 I SOP DMF I TEAIrT RHN N Y Example42 50:X= b:r Y=- R PhNH(CH 2 2 0 Example43 51 :XH Y NH2 R MeOPhCH 2 Example N-(2-aminophenyl)-6-(2-phenylamino-ethylamno)-nicotifamidO (compound 44) Steo 1: M5-Bromo-Dvridin-2.vl)-henl-ethane-1.2-diamine (comoound 42) [0174] 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 0 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 NaHCO 3 (2 x 50 mL), dried (MgS0 4 filtered and concentrated. After a quick o 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. 13 C NMR (300 MHz, acetone-d 6 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 Step 2: N.(2-aminophenvl)-6.(2-ohenvlamino-ethvlamino)-ficotinamide (compound 44) [0175] A mixture of 5-bromo-2*Nq-alkanyl-2-aminopyridine 42 (352 mg, 1.2 mmol), 1,2phenylenediamine (3.95 mmol, 3.3 equiv.), Pd(OAc) 2 (0.31 mmol, 26% mol) and 1,1'-bis 0 (diphenylphosphino) ferrocene (124 mg, 0.22 mmol) was suspended in degassed DMF (3mL), treated ci with diisopropylethyl amine (0.9 mL, 5.2 mmol) and the system flushed with CO. The reaction mixture was warmed up to 60TC 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. 'H-NMR (CD 3 OD-d4), 5 (ppm): 8.67 J 2.2 Hz, 7.97 (dd, J= 8.9 Hz, Hz, IHN, 7.58 (in, IHN, 7.51 (in, 1H), 7.15 (dd, J 7.7 Hz, 1.1 Hz, 1H), 7.08 (in, 2H), 6.89 (dd, J Hz, 1.4 Hz, 1H), 6.76 (dt, J= 7.7 Hz, 4.4 Hz, 1H), 6.67 J 7.7 Hz, 2H), 6.60 (in, 2H), 4.87 (bs, 4H), 3.60 J 6.3 Hz, 2H), 3.35 J 6.3 Hz, 2H).
Example 41 N-(2-amino-phenyl)-6-(4-methoxy-benzylamino)-nicotinamide (compound Step 1: N45-Bromo-vridin-2-vl)-methoxybenzvlamine (comp~ound 43) [0176] A mixture of 2,6-dibromopyridine 41 (6.03 minol, 2 equiv.) and para-methoxybenzyl amine (413 mg, 3.01 mmol) was stirred under nitrogen at 120TC 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 minol, 87% yield) was obtained. 3 C NMR (300 MHz,
CDCI
3 8 (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 SteD) 2: N42amino-ohenvl)-6A4-methoxy-benzvlamino)nicotinamide (comp~ound [0177] Following the procedure described in Example 40, step 2, but substituting 43 for 42, the title compound 45 was obtained in 61% yield.
Example 42 N-(2-aminophenyl)-3-[6-(2-phenylamino-ethylamino)-pyridil-3-yl]-acrylamlide (compound Step 2: 3-1642-Phenlamino-ethylamino)- ovridin-3-vI)acrvlic acid tert-butvl ester (compound 46) [0178] In a 50 mL flask, a mixture of 42 (308 mg, 1.05 mmol), terttbutylacrylate (0.8 mL, C mmol), diisopropylethylamine (0.8 mL, 4.6 mmol), tri-o-tolylphosphine (POT, 192 mg, 0.63 mmol),
(N
Pd 2 (dba) 3 (73 mg, 0.08 mmol) in anhydrous DMF (4 ml-) was stirred at 120 0 C (preheated oil bath) for ID 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). 13 C NMR (300 MHz, CDC1 3 8 (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. LRMVS 340.3 1).
Step 3: 3-r6-(2-Phenvlamino-ethylamino)- Dvridin-3-vl)acrvlic acid (compound 48) [0179] Ester 46 (0.93 mmol) was dissolved 40 TFA in dichloromethane (10 mL) and the solution stirred at room temperature overnight. The solvent was removed under vacuo distilling with acetonitrile (3x10 ml) and stored under high vacuum for 6h. The solid residue 48 was employed for the next reaction without further purification. LRMS 284. 1 1).
Step 4: N.2-aminophenvl)3-[6{2-Dhenylamino-ethylamino)ridin-3-ylI-acrylamide (compound [0180] A mixture of acid 48 (0.93 mmol), BOP (495 mg, 1. 12 mmol) and 1,2-phenylenediamine (124 mg, 1. 15 mmol) were dissolved in dry acetonitrile (4 mL) and treated with triethylamine (0.8 mL, 5.7 mmol). The solution was stirred under nitrogen at room temperature for 16h. After concentration under vacua, the crude was purified through chromatographic column methanol in dichloromethane), then was crystallized from chloroform to give 50 (247 mg, 71% yield). 'H-NMR (DMSO-d6), 8 (ppm): 9.25 Cbs, 11H), 8.21 Cd, J 1.6 Hz, 1H), 7.67 J 8.5 Hz, 1H), 7.43 Cd, J= 15.7 Hz, 1H), 7.32 Cd, J 7.4 Hz, 1H), 7.24 J 1.0 Hz, 1H), 7.08 Ct, J 7.4 Hz, 2H), 6.91 J 8.0 Hz, 1H), 6.75 Cdt, J= 8.0 Hz, 0.4 Hz, 1H), 6.57 Cm, 6H), 5.20 Cbs, 1H), 3.48 J 6.3 Hz, 2H), 3.33 Cbs, 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) SteiD 2: N42-aminoihenvl)-3-i6A4-methoxv-benzvlamino)-nvridin-2-vll-acrylamide (comiound 51) [0181] Following the procedure described in Example 42, steps 2, 3, 4, but substituting 43 for 42, the title compound 51 was obtained in 50% yield (on 2 steps). 'H-NMR (CDCI 3 8 (ppm): 7.60 (bs, 1H), 7.55 (bs, 1H), 7.43 J =7.7 Hz, 1H), 7.29 J 8.3 Hz, 2H), 7.17 J 15.1 Hz, 1H), 7.06 J 7.7 Hz, 1 6.88 Kd J 8.3 Hz, 2H), 6.80 (in, 2H), 6.70 (in, 3H), 6.41 J =8.5 Hz, 1H), 4.50 J 5.5 Hz, 2H), 3.80 3H), 3.45 (bs, 21-).
CDI I E 3
NA
OH H 2 N DBU DMF fj r N 1 N ~Br N 4Br 52 53 1) POT Pd 2 (dba) 3 DIPEA /DMF I2) BOPIEtNI/ DMF
CH
2 =CHCOOH Ph(NH 2 2 1200C 0 H H
N
Example 44 4-[2-(2-amino-phenylcarbamoyl)-vinyl].benzyl)-carbamic acid pyridin-3-yl methyl ester (compound Step 1: (4-bromo-benzvl)-carbamic acid pvridin-3-vl-methyl ester (compound 54) [0182] 4-bromobenzyla mine HCI (3.0g, 13.4 mmol) was dissolved in DMF (60 mL) at rt and then Et 3 N (4.13 mL, 29.7 mnmol) was added dropwise over 10 min to give cloudy solution. To this, DBU (2.42 mL, 16.2 inmol) and 1,1'-carbonyl diimidazole (2.4 1g, 14.8 inmol) were added. After being stirred for 1 h at rt, 3-pyridylcarbinol (1.44 inL, 14.8 inmol) 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 1) and then washed with H 2 0. The organic layer was dried over Na 2
SO
4 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 1).
Step 2: 4-1242-amino-henylcarba-mol)-vinvll-benzl)-carbahic acid Dvridin-3-yl methyl ester (compound [0183] Following the procedure described in Example 42, steps 2, 3, but substituting 54 for 42, and acrylic acid for tert-butyl acrylate the title compound 55 was obtained in an overall yield of 'H NMVR: (DMSO-d6) 8 (ppm): 10.03 1H), 9.32 IH), 8.65 1H), 8.55 J 3.3 Hz, 1H), 7.85 Kd J 7.69 Hz, IN, 7.40-7.60 (in, 6H), 7.31 J 7.69 Hz, 1H), 6.89 (dd, J 7.14 Hz, J= 7 Hz, 1H), 6.71-6.79 (in, 2H), 6.55 (dd, J 7.1 Hz, J 7 Hz, IN, 5.20 2H), 4.93 (bs, 2H-).
MeO MeNl NH 2 Ome SBr
K
2 C0 3
OMF
ri to 80 C Me NV N N-
B
MeOB 7 OMe 0 Pd 2 (dba) 3 I POT N0 DMF I DIPEA Me N NN0N 2 CIH0IHCOt H I NH MeO 5 OMe 0 ISrCI 2 MeOH I
H
2 0 175 C P NH2 Mo OMe 59 0 Example 45 Me
N
Me OMe 0 Me~~ H 2 01 11 p Me NH Me Ome *~0 Example 46 Example N-(2-aminophenyl)-3-{4-[(3,4, 5-trimethoxy-benzylamino)-methylj-phenyl )-acrytamide (compound 59) Step 1: (4-3romo-benzyl)43.4. 5-trimethoxy-env)aieconud57 [0184] To a stirred suspension of K 2 C0 3 (522 mng, 3.77 inmol) in dry DMVF was added 3,4,5trimethoxybenzylamine 10 mL, 6.44 mmol, 2.2 equiv.) followed by a solution of p-bromo benzylbromide (0.73 g, 2.91 minol) in dry DMVF (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. IIC NMR (300 MHz, CDCI 3 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 1).
Ster, 2: N(2-Nitro-nhenl)-3-( 44(3.4. 5-trimethoxy-benzvlamino)-methvll-Dhenl-acrylamide (compound 58) Preparation of the nitroacrylanilide [0185] To a mixture of 2-nitroaniline (1.73 g, 12.5 mmol), DMAP (321 mg, 2.6 mmcl) and 2,6-dicitert-butyl4-methylphenol (308 mg) in dry dichloromethane (50 mL) at 0 0 C was added triethylamnine (10.6 mL, 76 mmol) followed by acryloylchioride (3.2 mL, 38 mmol, 3.0 equiv.), and the mixture was c-1 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 NaHCO 3 (stirring for 1 The organic layer was then washed KHSO 4 then brine), dried (MgSO 4 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. 1 3 C NMR (300 MHz, CDCI 3 8 (ppm): 163.6, 136.0, 135.6, 134.5, 131.3, 128.6, 125.4, 123.1, 121.8. LRMS 193.2 Stein 3: N-2-a min oohenyl)-3-444(3 5-tri methoxv-benzlamino-methll-Dhenl)-a crylamnide (59) [0186] A mixture of nitro-compound 58 (127 mg, 0.27 mmol), SflCl2 (429 mg, 2.26 mmcl, 8.4 equiv.) and NH 4 OAc (445 mg) was suspended in methanol (9.5 mL) and water (1.5 mnL), and the mixture was heated at 7000 for 45 min. The mixture was diluted with ethylacetate (100 mL) and washed with brine and then saturated NaHCO 3 dried (MgSOA) filtered, and concentrated. Purification by chromatographic column on silica gel (elution 5 to 10% methanol in dichloromethane) gave 52 mg (43% yield) of 59. 1 H-NMR (CDC1 3 8 (ppm): 8.25 (bs, 1H), 7.59 J 15.6 Hz, 1H), 7.38 Kd J Hz, 2H), 7.29 Kd J 7.5 Hz, 2H), 7.25 (m 1H), 7.02 J 6.8 Hz, 1H), 6.75 (in, 2H), 6.62 J 15.6 Hz, 1H), 6.58 2H), 3.97 (bs, 3H), 3.80 9H). 3.78 2H), 3.72 2H).
o Example 46 1 1 N-(2-aminophenyl)-3-(4-{[(3 5-trimethoxy-benzyl)-amino]-methyl)- phenyl)-acrylamide (compound 61) Step 1: 3-14-f MethlA 3.4. 5-trimethoxy-benzl-aminol-rnethvl l-ohenyl)-NA2-nitro-Dhenyl)-acrvlamide (compound Ni [0187] Amnine 58 (180.2 mg, 0.38 mmol) was dissolved in 88% of HC0 2 H (6 mL), treated with N" excess of paraformaldehyde (7.67 mmol) and the mixture stirred at 70 0 C for 2.5h. A saturated NaHCO 3 solution, was added slowly, extracted with dichloromethane (2 x 75 mL), dried (MgSO 4 filtered and concentrated. After chromatographic column on silica gel (elution 3 to 5% methanol in dichloromethane), pure N-methyl amnine 60 (118 mg, 63% yield) was obtained. 1 3 C NMR (300 MHz,
CDCI
3 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. LRMVS 492.5 Step 2: N-2-aminorhenyl)-344-If(3.4 .5-trimethox-benzl)-amino-methvll- Dhenvl)acrvlamide (compound 61) [0188] Following the procedure described in Example 45, step 3, but substituting the nitrocompound 60- for 58, the title compound 61 was obtained in 72% yield. 'H-NMVR (DMSO-d6), 8 (ppm): 9.15 (bs, 1H), 8.13 (bs, IH), 7.58 J 1.9 Hz, 1H), 7.30 (m 4H), 7.12 J 7.7 Hz, 1H), 6.91 (m 3H), 6.75 J 7.8 Hz, 1H), 6.57 (m 2H), 4.83 (bs, 2H), 4.43 J 5.5 Hz, 2H), 3.72 3H), 3.33 3H).
NC Mefk H 0N N C Cat, Nai K 2 C0 3 N. CH OH rek0 3 MF /60 0
C
H
2 N HzN Me0PhCl- Cl H' N 62 63 H' 1 NaOH /THF MeOH 2) BOP E1 3 N DMVF Ph( NH 2 2 HN
NH
2 Mea 6 Example 4?
IND
Example 47 NV-(2-aminophenyl)-3-{4-(4-methoxy-benzylamino)-phenyl)-acrylamide (compound Step 1: Methy[34-amino-Dhenl)-acrvlate hydrochloride (compound 63) [0189] 4-amiflo-cinnamic acid (10.41 g, 0.052 mol) was dissolved in methanol (100 mL) at rt. A solution of HCI in dioxane (15.6 mL, 4 N) was then added. The reaction mixture was heated at reflux N overnight. The clear solution was evaporated to a half volume and then settled down at rt. The white N isuspension obtained was collected by vacuum filtration. The mother liquid was evaporated again to 0 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-31f444-methoxy-benzylamino)-ohenvll- acrylate hydrochloride (compound 64) [0190] To a suspension of compound 63 (3.57 g, 16.7 mmol) in DMF (30 ml-) was added Et 3
N.
after 10 min 4-methoxybenzyl chloride (2.0 g, 12.8 mmol), Nal (0.38 g, 2.6 mmol) and K 2 C0 3 (3.53 g, 25.5 mrnol) were added successively. The mixture was heated at 60*C overnight and evaporated to dryness. The residue was partitioned between NaHCO 3 sat. solution (50 rnL) and EtOAc (5OmLx3). 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: N42-aminoohenvl)-3-444-methoxy-benzvlamino)-ohenyll-acrvlamide (compound [0191] Following the procedure described in Example 42, step 4, but substituting 64 for 48, the title compound 65 was obtained in 32% yield. 'H NMR: (DMSO-d6) 8 (ppm): 9.1 '5 IN), 7.24 -7.38 (in, 6H), 6.84-6.90 (mn, 3H), 6.72 (in, 2H), 6.49-6.60 (mn, 4H), 4.84 2H 4.22 J =5.77 Hz, 2H).
1 -Pd 2 (dbaW3Et 3 N/DMF/ -r ZN K2C03 Ar ZNH CH~CHCOOH/IOOPC A N I MP F 2-BOP/DMF/Et 3
N
Ar- OWC. Ph(NH 2 2
N
66Ar~P~ Br 6869 :ArZPhN N 2 67: ArZ =MeOPhCOCI 70: ArZ =MeOPhCO N1 Example 48 71:ArZ=P Example 49 72: ArZ =MeOPhCO Example 48 N-(2-Amino-phenyl)-3-(4-styrylamino-phenyl)-acrylamide (compound 71) Step 1: Nq44odo-phenl)N3iohenl-alll)-amine (compound 69) [0192] Following the procedure described in Example 47, step 2, but substituting 68 for 63, the title compound 69 was obtained in 70% yield. LRMS 288 (M+1) Step, 2: 1W2-Amino-phenyl)-3A4-stvrvlamino-nhenvl)-acrylamide (71) (0193] Following the procedure described in Example 42, steps 2, 4, but substituting 69 for 42, and acrylic acid for tert-butyl acrylate the title compound 71 was obtained in an overall yield of 'H NMR: (DMSO- 6 8 (PPM): 9.22 (bs, 1H), 7.45,(d, J 6.9 Hz, 2H), 7.39 J 9.0 Hz, 2H), 7.34 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 J 7.9 Hz, 1H), 6.69 J 8.5 Hz, 2H), 6.63-6.55 (in, 4H), 6.44-6.37 (in, LH), 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-44-odo-ohenv)4-methoxv-benzamide (compound [0194] Following the procedure described in Example 47, step 2, but substituting 68 for 63, the title compound 70 was obtained in 90% yield. LRMS 354.0 (M+1) Step 2: N-(2-Amino-ohenvl)-3-4-4-methoxy-benzamide)1-acrvlamide (comp~ound 72) [0195] Following the procedure described in Example 42, steps 2, 4, but substituting 70 for 42, and acrylic acid for tert-butyl acrylate the title compound 72 was obtained in an overall yield of 'H NMR: (DMSO-d 6 8 (PPM): 9.4 (bs, 1H), 7.60(d, J 8.5 Hz, 1H), 7.54-7.45 (mn, 3H), 7.87 J 7,7 Hz, 1H), 7.10 J 8.8 Hz, 1H), 6.95-6.77 (in, 6.62 (d J 7.7 Hz, 2H), 6.08-6.04 (in, 2H), 4.98 (bs, 2H), 3.72 3H).
~Br Br IN
H
2 N-_NH2 120C 42N, 0 H 74 0 IMeOH /IH O then 88 HCO 2 H I refiux nif Br C- N N IN O 75 H 1. "C0tBu 2 TFA CH 2
C
rT Pd 2 (dba)3 I POT 3.Ph(NH) 2
BOP
OMF DIPEA 1 120 0 C DMF TEA rT S HNH O 76 Example 50 N N 73 PhMe ru.x NN Br 0 7 H 1. CO 2 tBu 2.TFA /CH 2
CI
2 r.T Pd(dba) 3 POT 3. Ph(NH 2 2
BOP
DMF DIPEA 120 0 C DMF TEA rT I~ NIN
NH
2 0 78 H Example 51 Example N-(2-aminophenyl)-3-(6-[2-(4-oxo-4H-quinazolin-3-ylI)-ethylamino]-pyridin-3-yl}-acrylamide (compound 76) Step 1: N45-Bromo-vridin-2l)-ethane-1.2-diamine (compound 73) [0196] Following the procedure described in Example 40, step 1, but using 1,2-diaminoethane as alkyl amine, the title compound 73 was obtained in 84% yield. 3"C NMR (300 MHz, 159.1, 148.7, 140.7, 111.7, 107.2, 44.3, 41.7. LRMS 218.1 (M+1) Step 2: 3-12-(5-Bromo-pyvridin-2-ylamino)-ethyll-3H-quinaoinon-4-one (comDound [0197] A suspension of primary amine 73 (1.17 g, 5.40 mmol) and isatoic anhydride 74 (880 mg, 5.40 mmol) in methanol (25 mL) was stirred for 3 h at 5000 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 methanol in dichloromethane) to give 1.24 g (3.6 mmol, 67% yield) of 75. 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 Sten) 3: N42-aminophenvl)-3-f 6-[2A4-oxo4H--ouinazolin-3-yl)-ethvlaminol-ovridin-3vl Vacrlamide (comoound 76) [0198] Following the procedure described in Example 42, steps 2 to 4, but substituting 75 for 42, the title compound 76 was obtained in an overall yield of 68 'H-NMR (DMSO-d6), 8 (ppm): 9.24 (bs, 1H), 8.17 (dd, J 8.0 Hz, 1.6 Hz, 1H), 8.11 (bs, 1H), 8.08 J 1.9 Hz, 1H), 7.82 Cdt, J Hz, 1.4 Hz, 1H), 7.64 J 8.2 Hz, 2H), 7.25 Ct, J 5.8 Hz, 1H), 6.90 (dt, J 15.7 Hz, 1H), t~~6.74 (dd, J =8.0 Hz, 1.4 Hz, 6.58 Cm, 3H), 4.95 Cbs, 2H), 4.17 J 5.2 Hz, 2H), 3.68 Cm, J =5.2 Hz, 2H).
Example 51 N-(2-aminophenyl)-3-{6-[2-(4-benzyl-2,6-dioxo-piperazin-1 -yl)-ethylamino]-pyridin-3-yI)acrylamide (compound 78) Steg 2: 4-Benzvl-1 -[2A5-bromo-oridin-2-lamino)-ethylkiperazine-2 .6-dione (ccmround 77) [0199] A suspension of benzyliminodiacetic acid (702 mg, 3.15 mmol) and acetic anhydride mL) was stirred at 120'C for 45 min. The reaction mixture was diluted with dry toluene and concentrated in vacua, 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 methanol in dichloromethane) to give 684mg (1.70 mmol, 54% yield) of 77.
Step 3: N.2-aminothenvl)-3-l 6-I244-benzyl-2 .6-dioxo-Diperazin-1 -vl)-ethylaminol-pyridin-3-vlI-acrvlamide (comiound 78) [0200] Following the procedure described in Example 42, steps 2 to 4, but substituting 77 for 42, the title compound 78 was obtained in an overall yield of 60%. 'H-NMR (CD 3 OD-d4), 5 (ppm): 8.09 J 1.8 Hz, 1H), 7.68 (dd, J 8.7 Hz, 2.1 Hz, 1H), 7.53 J 15.6 Hz, 1H), 7.29 (in, 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 J 15.6 Hz, 6.50 J 8.7 Hz, 4.85 Cbs, 3H), 3.97 J 7.5 Hz, 2H), 3.60 Cs, 2H), 3.57 Ct, J 7.5 Hz, 2H), 3.38 Cs, 4H).
N N Al~H C11,~j r CI N P4lN C P 2 N il TNF 79 THF so o *7rC
NH
3 gas 1.4-60000
NH
2 0id(k 11 INH 120-140*C N' N "I NHBoc H NPOTN2
NHN
HNKI EW, MF .1 TFA 11CH 82: 1 9%1 3r8 CK1 Example 52 Example 52 (E)-4-{[4-Amino-6-(2-indanyl-amino)-[1 ,3,S~triazin-2-yl-amino]-methyl)-N-(2-amino-phenyl)cinnamide (compound 83) Step 1: 4.6-Dichloro-2-(2-indany~amino-f1 .3.5ltriazine (compound 79) [0201] To a stirred solution at -780C of cyanuric chloride (13.15 g, 71.33 mmol) in anhydrous THE (100 mL) under nitrogen was slowly canulated a solution of 2-aminoindan (10.00 g, 75.08 mmol), iWr 2 NEt (14.39 mL, 82.59 mmol) in anhydrous THE (60 mL) After 50 min, the reaction mixture was poured into a saturated aqueous solution of NH 4 CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI H 2 0 and brine, dried over anhydrous MgS0 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH 2
CI
2 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. 1 H NMR (300 MHz, CDCI 3 8 (ppm): 7.29-7.18 (in, 4H), 6.02 (bd, J 6.3 Hz, 1H), 4.94-4.84 (in, 1H), 3.41 (dd, J= 16.2, 6.9 Hz, 2H), 2.89 (dd, J 16.1, 4.5 Hz, 2H).
Steo) 2: 244-Broino-benzv~amino)4chloro-6Aindanl-amino)4 1.3. Sltriazine (compound [0202] To a stirred solution at room temperature of 79 (2.68 g, 9.52 mmol) in anhydrous THE mL) under nitrogen were added WPr 2 Nt (4.79 mL, 27.53 mmol) and 4-bromobenzyla mine. HCI (2.45 g, 11.01 mmol), respectively. After 17 h, the reaction mixture was poured into a saturated aqueous solution of NH 4 Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI H 2 0 and brine, dried over anhydrous MgSO 4 filtered and
IO
0 1 concentrated. The crude residue was then purified by flash chromatography on silica gel 0 (AcOEtCH 2
CI
2 3/97-+5/95) to afford the title compound 80 (4.00 g, 9.29 mmol, 97% yield) as a white powder. 'H NMR (300 MHz, CDCI 3 6 (ppm): mixture of rotamers, 7.52-7.42 2H), 7.26-7.11 6H), 6.51 and 6.12 (2 m, 1H), 5.72-5.46 1H), 4.944.64 1H), 4.624.46 2H), 3.43- 3.16 2H), 2.92-2.74 2H).
Step 3: 4-Amino-2.4-bromobenzvl-amino)-642-indanvl-amino)-[1.3,5]triazine (compound 81) [0203] In a 75 mL sealed flask, a solution of 80 (2.05 g, 4.76 mmol) in anhydrous 1,4-dioxane mL) was stirred at room temperature, saturated with NH 3 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
NH
3 gas was repeated for 5 min, and the reaction mixture was warmed to 140°C again for 24 h.
Then, the reaction mixture was allowed to cool to room temperature, poured into 1N HCI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgS0 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CHzCI 2 5/95) to afford the title compound 81 (1.96 g, 4.76 mmol, quantitative yield) as a colorless foam. 'H NMR (300 MHz, CDCI 3 5 (ppm): 7.43 J 8.2 Hz, 2H), 7.25-7.12 6H), 5.70-5.10 2H), 5.004.65 3H), 4.52 (bs, 2H), 3.40-3.10 (m, 2H), 2.90-2.65 2H).
Step 4: (E)-4-114-Amino-642-indanvl-amino)-[l,3,51triazin-2-vl-aminol-methvll-N-[2-(-t-butoxvcarbonvl)amino-phenvl-cinamide (compound 82) Preparation of N-2-(N-t-Butoxvcarbonvl)-amino-henvll-acrvlamide [0204] Following the procedure described in Example 45, step 2, but substituting the nitrocompound 24N-t-butoxycarbonyl)-amino-aniline for 2-nitroaniline, the title compound was obtained in 77% yield. 'H NMR (300 MHz, CDCl3) 8 (ppm): 8.51 (bs, 1H), 7.60-7.45 1H), 7.38-7.28 1H), 7.20-7.05 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 9H).
[0205] In a 50 mL sealed flask, a solution of 81 (300 mg, 0.73 mmol), the acrylamide (230 mg, 0.88 mmol), Et 3 N (407 pl, 2.92 mmol), tri-o-tolylphosphine (POT, 13 mg, 0.04 mmol), Pd2(dba) 3 mg, 0.02 mmol) in anhydrous DMF (10 mL) was stirred at room temperature, saturated with N 2 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 NH 4 CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over S anhydrous MgSO 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH 2
CI
2 2/98-65/95) to afford the title compound 82 (240 mg, 0.41 mmol, 56% yield) as a beige solid. 'H NMR (300 MHz, CDCI 3 8 (ppm): 8.46 LH), 7.71 (bd, Ji 15.7 Hz, 1H), 7.62-7.05 (in, 13H), 6.54 (bd, J 15.9 Hz, 1H), 5.95-4.90 (in, 4H), 4.85-4.48 (in, S 3H), 3.40-3.14 (in, 2H), 2.90-2.70 (in, 2H), 1.52 9H).
'l Step 5: t4-Amino-6A2 ndanvl-amino)-[1 .3.5Slriazin-2-vI-aininol-methyl l-N-(2-ainino-vhenvl)- IN cinnamide (comround 83) S [0206] To a stirred solution at room temperature of 82 (230 mg, 0.39 minol) in CH 2
CI
2 (5 mL) was added IFA (1 iL, 95% in water). After 18 h, the reaction mixture was poured into a saturated aqueous solution of NaHCO 3 and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NaHCO 3
H
2 0 and brine, dried over anhydrous MgSO 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH 2
CI
2 5/95) to afford the title compound 83 (170 mg, 0.35 inmol, 89% yield) as a yellow solid. 'H NMR (300 MHz, acetone-d 6 8 (ppm): 8.87 (bs, 1H), 7.69 J 15.7 Hz, 1H), 7.59 (bd, J 7.7 Hz, 2H), 7.49-7.34 (in, 3H), 7.28-7.11 (mn, 4H), 7.05-6.91 (in, 2H), 6.88 (dd, J 8.0, 1.4 Hz, 1H), 6.69 (td, J 1.4 Hz, 1H), 6.65-5.50 (in, 4H), 4.83-4.53 (in, 5H), 3.34-3.11 (mn, 2H), 2.98- 2.80 (mn, 2H).
O~OW
bN' N f HO N 94 TfO N as wHl
NN
NH, H N N V. 1 j0fNH2
NH
H87 Example 64 Example 53 9. Tf 2 0 I Py OMAP 10 C b. P4mehoxyberuylemlne 120 C c. 1.2-phenyl4wedlamine I CO (40 Pei) I Pd(OAc) 2 I dppf I DMF I OIPEA 1 70 C d. I Wtaffyta /P62(dbah POT I MF lPEA 1 120 C e. TFA/DCMIrT 1. 1,2-phenyie~diamine SOP/ OMPF TE.A/ rT Example 53 N.(2.aminophenyl).2-(4-methoxybenzylamino)-qunolin-6-yl-amlide (compound 87) Step 1: 2 .6-ditrifluoromethanesulfonloxvouinoline (compound [0207] A solution of 2,6-dihydroxyquinoline 84 (1.254 g, 7.78 mmol) and DMAP (a few crystals) r- in dry pyridine (15 mL) was treated with neat trifluoromethanesulfonic anhydride (5.2 g, 18,4 mmol, 0 1.2 equiv.) and stirred at 0 0 C for 5 h. This solution was then poured on a mixture brine/sat NaHCO 3 'n and extracted with dichloromethane (2 x 150 mL), dried (MgSO 4 filtered and concentrated.
ID Purification by column chromatography on silica gel (30% to 50% ether in hexanes) gave 2.58 g (6.1 mmol, 78% yield) of 85. 1 C NMR (300 MHz, CDCI 3 154.5, 147.8, 144.6, 142.0, 131.6, 127.8, 124.9, 119.3, 118.7, 114.9. LRMS 426.0 1).
Stein 2: N.2-aminoohenvl)-2A4-methoxv-benzvlamino)-auinolin-6-vl-amide (compound 87) [0208] Following the procedure described in Example 40, steps 1, 2, but substituting 85 for the title compound 87 was obtained in 92% yield. 'H-NMR (DMSO-d6), 8 (ppm): 9.66 (bs, I1H), 8.32 1H) 8.05 Kd J 8.8 Hz, 1H), 7.96 (dd, J 9.1 Hz, 2.2 Hz, 1H), 7.72 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 Kd J 7.7 Hz, IN), 6.97 J 7.7 Hz, 1H), 6.90 (m 2H), 6.80 (d J 7.9 Hz, 1H), 6.61 J 6.3 Hz, 1H), 4.90 (bs 2H), 4.58 (d J 3.3 Hz, 2H), 3.73 3H), 3.33 (bs, I1H).
Example 54 N-(2-aminophenyl)-3-(2-(4-methoxy-benzylamino)-quinolin-6-yl]-acrylamide (compound 88) Step 3: N42-aminoo~henyl).3-1244-methoxy-benzlamino)-auinolin-6-vDl-acrvlamide (compound 88) [0209] Following the procedure described in Example 42, steps 1 to 4, but substituting 85 for the title compound 88 was obtained in an overall yield of 71%. 'H-NMR (DMSO-d6), 8 (ppm): 9.70 (bs, 1 9.40 (bs, 1 8.20 (d J 8.9 Hz, 1 8.03 (bs, 2H), 7.94 J =7.2 Hz, 1 7.64 (dd, J 15.7 Hz, 2.5 Hz, 1H), 7.41 (d J 8.5 Hz, 7.39 (in, 1H), 7.14 (d J 8.9 Hz, 1H), 7.05 (d.
J 15.7 Hz, 1H), 6.97 (in, 1H), 6.95 J 8.5 Hz, 2H), 6.81 J 8.0 Hz, 1H), 6.65 J 7.2 Hz, 1H), 4.76 2H), 3.75 3H).
Examples 55-84 [0210] Examples 55 to 84 describe the preparation of compounds 89 to 118S using the same procedures as described for compounds 44 to 88 in Examples 40 to 54. Characterization data are presented in Tables 3a..d.
103 2006252047 14 Dec 2006 Table 3a Characterization of Compounds Prepared in Examples 42-84 0 y NH w z Ex. C pd. W Y Z R Name Characterization Schm- 'H-NMR (DMVSO-d6), 8 (ppm): 9.25 (bs, 1H), 8.21 N42-aminopheny)-3- J 1.6 Hz, 7.67 J 8.5 Hz, 11H), 7.43 H6(-hnyaio J 15.7 Hz, 1H), 7.32 J 7.4 Hz, 11H), 42 50 H N CH H ethylamino)-pyridin- 7.24 J 1.0 Hz, 1H), 7.08 J 7.4 Hz, 2H), 3 3-yljacrylmide 6.91 J 8.0 Hz, 1H), 6.75 (dt, J= 8.0 Hz, 0.4 3-yllacrylmide Hz, 1H), 6.57 (in, 6H), 5.20 (bs, 1H), 3.48 J Hz, 2H), 3.33 (bs, 2H), 3.21 J =6.3 Hz, 2H) 144242-amino- 'H NMVR: (DIMSO-d6) 8 (ppm): 10.03 1H), 9.32 0phenylcarbamoAYf 1H), 8.65 IH), 8.55 J 3.3 Hz, 1H), 44 55b N: 01 N~ CH CH H vinyll-phenyll- 7.85 J =7.69 Hz, 1H), 7.40-7.60 (mn, 6H), 7.31 4 Cr H carbamic acid J 7.69 Hz, 1H), 6.89 (dd, J 7.14 Hz, J 7 4 N pyridin-3-yl methyl Hz, 1H), 6.71-6.79 (in, 211), 6.55 (dd, J 7.1 Hz, J ____ester 7 Hz, 1H), 5.20 2H), 4.93 (bs, 2H). N-(2-aminopheny)-3- 'H-NMR (CDC1 3 5 (ppm): 8.25 (bs, 7.59 (d, MeO N N J 15.6 Hz, 11H), 7.38 J 7.5 Hz, 2H), 7.29 5Ie C H trimethoxy- J 7.5 Hz, 2H), 7.25 (m 11H), 7.02 Ct, J 6.85 MXpH H benzylamino)- Hz, 1H), 6.75 Cm, 2H1), 6.62 J 15.6 Hz, 1H-), W~e methyl-phenyll- 6.58 2H), 3.97 (bs, 3H), 3.80 9H), 3.78 (s, ____acrylamide 2H), 3.72 2H).
N-(2-aminopheny)-3- 'H-NMR (DMVSO-d6), 8 (ppm): 9.15 (bs, 8.13 NoC N~ [6-4methoxy- (bs, 1H), 7.58 J 1.9 Hz, 1H), 7.30 (mn 4H), 46 61b I H N CH Me benzylamino)- 7.12 J 7.7 Hz, 1H), 6.91 (in 3H), 6.75 J 3 MO pyridin 3-ylI-2- 1.8 Hz, 1H), 6.57 (in 2H), 4.83 (bs, 2H), 4.43 J iethyl-acrylainide 5.5 Hz, 2H), 3.72 3H), 3.33 Cs, 3H). 2006252047 14 Dec 2006 Ex. CPd. W Y Z R Name Characterization Schm N42-amino-phenyl)- 'H NMR: (DMSO-d6) 8 (ppm): 9.15 1H), 7.24 47 65 I N CH CH H 3-[4{4-methoxy- -7.38 6H), 6.84-6.90 3H), 6.72 2H), 6H Cbenzyamino 6.49-6.60 4H), 4.84 2H 4.22 J phenyn-acrylamide 5.77 Hz, 2H).
'H NMR: (DMSO-d 6 8 (ppm): 9.22 (bs, 1H), 7.45 J 6.9 Hz, 2H), 7.39 J 9.0 Hz, 2H), 7.34 N(2-Amino-phenyl) J 7.4 Hz, 2H), 7.26 (dt, J 7.4 Hz, 6.8 Hz, 48 71 H CH CH H 3-4-styrylamino- 2H), 6.93 (dt, J 7.9 Hz, 7.1 Hz, 1H), 6.78 J 7 phenyl)acrylamide 7.9 Hz, 1H), 6.69 J 8.5 Hz, 2H), 6.63-6.55 4H), 6.44-6.37 1H), 4.95 (bs, 2H), 3.95 _bs, 2H).
0U(442-Amino- 'H NMR: (DMSO-d 6 8 (ppm): 9.4 (bs, 1H), phnyca2-amnoy)- 7 60(d, J 8.5 Hz, 1H), 7.54-7.45 3H), 7.87 Svinyl-phenyl)4- J 7.7 Hz, 1H), 7.10 J 8.8 Hz, 1H), 6.95- 7 49oe 7 tinphe 6.77 3H), 6.62 J 7.7 Hz, 2H), 6.08-6.04 etoxy-enzamie 2H), 4.98 (bs, 2H), 3.72 3H).
'H-NMR (DMSO-d6), 5 (ppm): 9.24 (bs, IH), 8.17 N2-aminopheny)3- (dd, J 8.0 Hz, 1.6 Hz, 1H), 8.11 (bs, 1H), 8.08 N 16-[244-oxo-4H J 1.9 Hz, 1H), 7.82 (dt, J 8.5 Hz, 1.4 Hz, 76 N CH H quinazolin-3-yI) 1H), 7.64 J 8.2 Hz, 2H), 7.25 J 5.8 Hz, 8 0 H ethylaminol-pyridin- 1H), 6.90 (dt, J 15.7 Hz, 1H), 6.74 (dd, J 3-yl)-acrylamide Hz, 1.4 Hz, 1H), 6.58 3H), 4.95 (bs, 2H), 4.17 J 5.2 Hz, 2H), 3.68 J 5.2 Hz, 2H).
'H-NMR (CD 3 OD-d4), 8 (ppm): 8.09 J 1.8 Hz, 1H), 7.68 (dd, J 8.7 Hz, 2.1 Hz, 1H), 7.53 N2-aiinophenyl)3- J 15.6 Hz, 1H), 7.29 6H), 7.20 (dd, J 0 16-(2(4-benzyl-2,6- 7.8 Hz, 1.2 Hz, 1H), 7.02 (dt, J 9.0 Hz, 1.2 Hz, 51 78 1~1 N- N CH H dioxopiperazin-1-y) 1H), 6.86 (dd, J 8.1 Hz, 1.2 Hz, LH), 6.73 (dt, J 8 H ethylaminopyridin- 7.5 Hz, 1.5 Hz, 1H), 6.61 J 15.6 Hz, 1H), 3-yI)-acrylamide 6.50 J 8.7 Hz, LH), 4.85 (bs, 3H), 3.97 J 7.5 Hz, 2H), 3.60 2H), 3.57 J 7.5 Hz, 2H), 3.38 Cs, 4H).
2006252047 14 Dec 2006 Ex. Cpd. W Y Z R Name Characterization Schm 1 H NMR (300 MHz, acetone-d 6 8 (ppm): 8.87 (E)4-{[4-Amino-6-(2n-4 arino-- (bs, 1H), 7.69 J 15.7 Hz, 1H), 7.59 (bd, J
NH
2 indanyl-amino)- 7.7 Hz, 2H), 7.49-7.34 3H), 7.28-7.11 4H), )I ,2(1,3,51triazin-2- 52 83 N/ CH CH H 1n7.05-6.91 2H), 6.88 (dd, J 8.0, 1.4 Hz, 1H), 9 ylamino-iethyl)-N NH NH ylaminO-methylL 6.69 (td, J 7.6, 1.4 Hz, 1H), 6.65-5.50 4H), (2-amino-phenyt)aminen 4.834.53 5H), 3.34-3.11 2H), 2.98-2.80 cinamide 2H).
'H-NMR (DMSO-d6), 8 (ppm): 9.24 (bs, 1H), 8.19 NM2-aminophenyl)-3- J 1.6 Hz, 1H), 7.64 J 8.5 Hz, 1H), 7.52 S[6(4-methoxy- J 5.5 Hz, 1H), 7.42 J 15.7 Hz, 1H), 7.32 89 o H N CH H benzylamino)- J 7.4 Hz, 1H), 7.26 J 8.5 Hz, 2H), 6.90 3 Meo pyridin-3-yll- 1H), 6.88 (dd, J 8.5 Hz, 2H), 6.74 J 6.9 acrylamide Hz, 1H), 6.58 3H), 4.92 (bs, 2H), 4.45 J Hz, 2H), 3.72 3H).
'2-aminophenyl H-NMR (CD 3 OD-d4), 8 (ppm): 8.47 (bs, 1H), -a(pyridin3-3- 8.33 (bs, 1H), 8.02 1H), 7.73 1H), 7.61 (d, 9N O (6(pyridin3- J 8.5 Hz, 1H), 7.46 J 15.4 Hz, 1H), 7.29 56 90 N N CH H ylmethyl-amino- 1H), 7.14 J 7.7 Hz, 1H), 6.94 J 7.4 pyridin-3-yIi- Hz, 1H), 6.80 J 7.9 Hz, 1H), 6.66 J 7.9 acrylamide Hz, 1H), 6.53 2H), 4.54 2H), 3.59 (bs, 2H).
1 H-NMR (DMSO-d6), 8 (ppm): 9.27 (bs, 1H), 8.48 2-aminophenyl)-3- (dd, J 1.6 Hz, 4.4, 1H), 8.16 J 1.6 Hz, 1H), N 6-pyridin4- 7.70 (m 2H), 7.42 J 15.6 Hz, 1H), 7.31 (m 57 91 HN CH H meth~ylaminol- H ylmethyl)-aminol- 3H), 6.90 J 6.9 Hz, 1H), 6.73 J 6.9 Hz, Npyridin-3-y- 1H), 6.58 (m 4H), 4.98 (bs, 2H), 4.57 J acrylamide, 2H).
Hz, 2H).
106 2006252047 14 Dec 2006 Ex. Cpd W Y Z IR Name Characterization Schm 'H-NMR (DMSO-d6), 8 (ppm): 9.24 (bs, 1H), 8.18 N42-aminophenyl-3 J 1.6 Hz, 1H), 7.65 (dd, J 8.8 Hz, 0.8 Hz, CH H 6-4-fluoro- I 7.60 J 5.8 Hz, 1 7.42 J 15.7 Hz, 58 9 HN CH H benzylamino)- 1H), 7.36 (in, 3H), 7.13 J 8.8 Hz, 2H), 6.90 3 58 9 pyridin-3-yll- J 7.4 Hz, 1H), 6.73 (dd, J =6.9 Hz, 1.0 Hz, IH), acrylamide 6.58 (in, 3H), 4.91 (bs, 2H), 4.50 J 6.0 Hz, 2H).
'H-NMR (DMSO-d6), 8 (ppm): 9.24 (bs, 1H), 8.17 N42-aminophenyl)-3 J 1.9 Hz, 1H), 7.65 (dd, J 8.8 Hz, 1.6 Hz, N. (6-benzylamino- 1IH), 7.60 J 0 Hz, I1H), 7.41 J 15.7 Hz, 59 93 H N CH H p 1H), 7.31 (mn, 5H), 7.23 (in, 1H), 6.89 (dt, J 8.0 3 pidin-3-y)- Hz, 1.6 Hz, 1H), 6.73 (dd, J 8.0 Hz, 1.5 Hz, 1H), acry'Iamide 6.58 (m 3H), 4.92 (bs, 2H), 4.53 J 6.0 Hz, 2H) N42-minoheny~l 1H-NMR (DMSO-d6), 8 (ppm): 9.22 (bs, 1H), 8.18 N64--mphenyl)3 (ds, 1H), 7.63 J 8.8 Hz, 1H), 7.42 J 94 I N CH H roylmiN) 15.4 Hz, 1H), 7.22 (m 7H), 6.90 J 7.7 Hz, 60 9 H N CH proylamnoY1H), 6.75 J 8.0 Hz, LH), 6.57 (m 3H), 4.923 pcyid3ye (bs, 2H), 3.29 (dt, J 7.7 Hz, 6.0 Hz, 2H), 2.66 (t, acrylamide J 7.7 Hz, 2H), 1.84 (in, J 7.7 Hz, 2H). 'H-NMR (DMSO-d6), 8 (ppm): 9.22 (bs, 1H), 8.19 N(2-aminophenyl-- (bs, 1H), 7.62 J 8.5 Hz, 1H), 7.42 J N 164[244-mnethoxy- 15.7 Hz, 1H), 7.32 J 7.8 Hz, 1H), 7.16 J 61 95 N CH H phenyl)-ethylamino- 7.8 Hz, 2H), 7.13 Cm, 1H), 6.91 (in, 1LH), 6.85 3 MeO pyridin-3-yI). J 7.9 Hz, 1H), 6.74 J 7.8 Hz, 1H), 6.57 (in acrylamide 3H), 4.92 (bs, 2H), 3.71 3H), 3.47 (dd, J 7.3 1 Hz, 6.0 Hz, 2H), 2.78 J 7.3 Hz, 2006252047 14 Dec 2006 Ex. ad. W Y Z R Name Characterization Schm Nq2-aminophenyIY3- 'H-NMR (DMSO-d6), 8 (ppm): 9.23 (bs, 1H), 8.18 [644-dimethylamino- (bs, 1H), 7.63 J= 8.2 Hz, 1H), 7.41 (m 2H), 6 7.31 J 7.4 Hz, 1H), 7.15 J 8.5 Hz, 2H), Me 2 N H N H b yinoY 6.90 J 7.4 Hz, 1H), 6.74 J 7.0 Hz, 1H), pyridin-3-yI- 6.68 J 8.5 Hz, 2H), 6.58 3H), 4.91 (bs, acrylamide 2H), 4.39 J 5.5 Hz, 2H), Cbs, 2H).
'H-NMR (CD 3 OD-d4), 8 (ppm): 8.09 (bs, 1H), 8 05 J 1.9 Hz, 1H), 7.67 2H), 7.49 J N642-minazophenyD- 15.7 Hz, LH), 7.28 2H), 7.17 2H), 6.98 63 97 ONN C H (6A3-imiolY (dt, J 13.7 Hz, 7.7 Hz, 1H), 6.83 Cdd, J 8.0 Hz, 6 9 pyrpaino- 1.1 Hz, 1H), 6.69 (dt, J 9.1 Hz, 1.4 Hz, 1H), acrylamidn e 6.58 J 15.7 Hz, 1H), 6.51 Cd, J 8.8 Hz, 1H), 4.15 J 7.1 Hz, 2H), 3.29 2H), 2.08 J 6.9 Hz, 2H).
N(2-aminophenyD-3- 'H-NMR (acetone-d6), 5 (ppm): 8.75 (bs, IH), [643- 8.23 J 1.9 Hz, 1H), 7.69 J 8.2 Hz, 1H), 64 98 HN OH H trifluoromethoxy- 7.55 J 15.4 Hz, 1H), 7.43 2H), 7.34 (bs, ICF benzylaminoY 2H), 7.19 J 6.6 Hz, 1H), 6.93 2H), 6.83 pyridin-3-yl]. (dd, J 8.0 Hz, 1.4 Hz, 1H), 6.67 3H), 4.71 (d, acrylamide J 6.3 Hz, 2H), 4.65 (bs, 2H).
N(2-aminophenyl-3 'H-NMR (acetone-d6), 8 (ppm): 8.81 (bs, 1H), [644- 8.21 J 1.9 Hz, 1H), 7.66 Cd, J 7.4 Hz, 1H), 99 N OH H trifluoromethoxy- 7.56 J 15.7 Hz, 2H), 7.49 2H), J 8.2
F
3 CO H benzylamino Hz, 1H), 7.34 J 8.1 Hz, 1H), 7.25 J pyridin3-yg- Hz, 1H), 6.93 2H), 6.73 3H), 4.67 J= acryamide 6.0 Hz, 2H), 4.66 (bs, 2H).
2006252047 14 Dec 2006 Ex. Cpd. W Y Z R Name Characterization Schm 'H-NMR (DMSO-d6), 8 (ppm): 9.25 (bs, 1H), 8.18 N42-aminophenyI)-3- J 2.2 Hz, 1H), 7.67 2H), 7.42 J S [6-(3,5-difluoro- 15.7 Hz, 1H), 7.31 J 7.7 Hz, 1H), 7.08 (dt, J 66 100 H N CH H benzylamino)- 9.3 Hz, 2.2 Hz, 1H), 7.03 (dd, J 8.8 Hz, 1.9 3 F pyridin-3-yll- Hz, 2H), 6.90 (dt, J 7.3 Hz, 1.4 Hz, 1H), 6.73 acrylamide (dd, J 8.0 Hz, 1.4 Hz, 1H), 6.60 (m 3H), 4.92 (bs, 2H), 4.56 J 6.0 Hz, 2H).
N(2-aminophenyl)-3- 'H-NMR (DMSO-d6), 8 (ppm): 9.25 (bs, 1H), 8.14 Nr N [643-trifluoromethyl- (bs, 1H), 7.86 6H), 7.42 J 15.6 Hz, 1H), 67 101 K H N CH H benzylamino)- 7.31 J 7.4 Hz, 1H), 6.90 (dt, J 8.8 Hz, 1.1 3
CF
3 pyridin-3-yll- Hz, 1H), 6.74 (dd, J 8.0 Hz, 1.4 Hz, 1H), 6.60(m acrylamide 3H), 4.96 (bs, 2H), 4.63 J 5.8 Hz, 2H).
3-[6-3-aminomethyl- 'H-NMR (DMSO-d6), 8 (ppm): 9.28 (bs, 1H), 8.17 N benzylamino)- (bs, 1H), 7.66 J 5.8 Hz, 2H), 7.37 6H), 68 102 N CH H pyridin-3-yl]-N42- 6.88 (dd, J 8.0 Hz, 0.9 Hz, 1H), 6.73 (dd, J 3
NH
2 aminophenyl)- 8.0 Hz, 0.9 Hz, 1H), 6.59 (m 3H), 4.55 J 5.8 acrylamide Hz, 2H), 3.96 2H), 3.37 (bs, 4H).
(4-4242-amino- 'H NMR: (DMSO-d6) 8 (ppm): 9.36 1H), 8.57 o phenylcarbamoyl)- 1H), 8.51 J 4.6 Hz, 1H), 7.91 1H), LN H H H vinyl]-benzyl)- 7.77 J 7.68 Hz, 1H), 7.28-7.57 7H), 7 H carbamic acid 6.88 (dd, J 15.66 Hz, 4.4 0 Hz, 2H), 6.73 (m, N pyridin-3-yl methyl 1H), 6.56 1H), 5.01 2H), 4.93 (bs, 2H), ester 4.10 J 6.04 Hz, 2H).
C2-(4-2-(2-amnino- 2-amino- 'H NMR: (DMSO-d6) 8 (ppm): 9.34 8.52 o phenylcarbamoyl)- 71 105 o N CH CH H viylpeylehl-8H), 6.87 2H), 6.73 1H), 6.56 1H), 4 carbamic acid N pyridin-3-y methyl 5.03 2H), 4.92 2H), 3.30 2H), 2.75 (m, Spyridin-yl meester 2H).
ester 2006252047 14 Dec 2006 Ex. Cp. W Y Z R Name Characterization Schm N(2-aminophenyt3- 'H-NMR (acetone-d6), 8 (ppm): 8.49 (bs, 1H), H 8.41 J 7 Hz, 1H), 7.63 J 15.6 Hz, 1H), 7Ntrimethoxy- 7.56 J 8 Hz, 2H), 7.45 J 8 Hz, 2H), MeO 1HC phenylamino)- 7.07 2H), 6.90 J 15.6 Hz, 1H), 6.76 (m, OMe mettyliphenyl)- 1H), 6.74 LH), 5.99 2H), 4.36 2H), 3.69 acrylamide 6H), 3.68 (bs, 2H), 3.67 3H).
'H-NMR (CDCI 3 8 (ppm): 7.70 (bs, 1H), 7.43 Id, N(2-aminopheny)-3- J 7.4 Hz, 1H), 7.33 J 4.9 Hz, 2H), 7.26 (d, MeO J 4.9 Hz, 2H), 7.25 1H), 7.03 J 7.4 Hz, 73 107 MeO C- Me CH CH H trimethoxy-benzyl)- 1H), 6.78 J 7.4 Hz, I 6.75 1H), 6.61 OMe aminolnethyl)- 2H), 6.57 1H), 4.08 (bs, 2H), 3.86 6H), pheyl)acrylamide 3.83 Is, 3H), 3.50 2H), 3.47 2H), 2.21 (s, 3H).
me N2-aminophenyl)-3- 'H-NMR (CDCI 3 8 (ppm): 7.74 J 15.4 Hz, Ne 14-f(3,4,5- 1H), 7.50 J 7.4 Hz, 2H), 7.25 (m 3H), 7.06 It, 74 108 CII OH CH H trimethoxyphenyl)- J 1.9 Hz, 1H), 6.82 J 7.4 Hz, 2H), 6.58 Id, MeO) amino]-iethyll- J 15.4 Hz, 1H), 5.96 2H), 4.50 Is, 2H), 3.79 OMe phenyll-acrylamide Is, 6H), 3.78 (bs, 2H), 3.77 3H), 3.00 Is, 3H).
N(2-Amino-phenyl)- 'H NMR: (DMSO-d 6 8 (ppm): 9.4 (bs, 1H), 3-(4-[(6-methoxy- 7.60(d, J 8.5 Hz, 1H), 7.54-7.45 3H), 7.87 109 1 CH OH H pyridin-3-ylamino)- J 7.7 Hz, 1H), 7.10 Id, J 8.8 Hz, 1H), 6.95- MeO N methy-phenyl)- 6.77 3H), 6.62 Id, J 7.7 Hz, 2H), 6.086.04 Sacrylamide 2H), 4.98 (bs, 2H), 3.72 Is, 3H).
'H NMR: (DMSO-d 6 8 (ppm): 9.41 (bs, 1H), 8.21 N{2-Aino-phenyl) J 8.5, 1H), 7.97 Idt, J 7.7, 8.8 Hz, 2H), 76 10- HC 344-(quinolin-2- 7.78 (dt, J 7.1 Hz, 8.2 Hz, IH), 7.61-7.53 ylsulfanytmethyl 5H), 7.40 Idd, J 8.5 Hz, 7.6 Hz, 2H), 6.97-6.77 phenylg-acrytamide 4H), 6.6 (dt, J 7.7 Hz, 7.5 Hz, 1H), 4.98 (bs, 2H), 4.65 Ibs, 2H).
2006252047 14 Dec 2006 Ex. CPd. W Y Z R Name Characterization Schm N(2-amino-phenyl)- 'H NMR: (DMSO-d6) a (ppm): 9.15 Cs, LH), 7.24 7 13-(4-(pyridin-3- -7.38 6H), 6.84-6.90 3H), 6.72 2H), 77 1 11 H CH CH H N ylmethyl)-aminol- 6.49-6.60 4H), 4.84 2H 4.22 J= _phenyl)acrylamide 5.77 Hz, 2H).
'H NMR: (DMSO-d 6 8 (ppm): 7.96 Cd, J=9.1 Hz, 42-Amino-phenyl- 2H), 7.55 J 14.2 Hz, 1H), 7.48 J 7.4 78 112 IH N CH H pyridin-3-yl)- Hz, 2H), 7.39-7.29 4H), 7.07-6.91 3H), 7 pcryramidn-yI 6.81-6.64 Cm, 3H), 6.47-6.38 1H), 4.21 (bs, acrylamide 2) I I 2H).
N2-amino-phenyl) 'H NMR: (DMSO-d6) 8 (ppm): 9.30 1H), 8.58 79N 3[24-nro- (bs, 2H), 8.36 1H), 8.20 2H), 7.58 2H), 9 113 I H N N H benzylamino)- 7.28-7.42 2H), 6.52 -6.92 4H), 4.90 (s, 2H 4.64 J 6 Hz, 2H).
________acrylainide 'H NMR: (DMSO-d 6 5 (ppm): 10.87 (bs, 1H), N45-1242-Aino- 9.45 bs, 1H), 8.66 bs, 1H), 8.33 Cd, J 7.4 Hz, 8 phenylcarbamoyl- 1H), 8.14-8.08 Cm, 3H), 7.63 J 15.6 Hz, LH), 114 N N CH H 7.40 Cd, J 7.7 Hz, 1H), 7.08 J 6.8 Hz, 2H), 7 MeOj H vinylyridin-2-yI)-4- 6.97 Cd, J 12.3 Hz, 2H), 6.80 J 7.9 Hz, methoxy-benzainide 1H), 6.63 (dt, J 7.7 Hz, 7.4Hz, 1H), 5.06 Cbs, 2H), 3.88 3H) 3-f244-ainino- 'H NMR: (DMSO-d6) 8 (ppm): 9.27 1H), 8.83 benzylamino)- 2H), 7.97 J 6 Hz, 7.37 d, J 15.9 81 1Hzf 1H), 7.29 (d,J 7.11 Hz, 1H), 6.96(d, J 5 H 2 N H8.24 Hz, 2 6.88 1H), 6.70 2 6.55 amino-phenyl 1H), 6.47 J 8.2 Hz, 2H), 4.90 Cs, 4H), acrylainide 4.34 Cd, J 6.0 Hz, 2H).
2006252047 14 Dec 2006 Ex. d. W V Z R Name Characterization Schm 'H-NMR (CDCI 3 5 (ppm): 8.38 (bs, 1H), 7.49 Cm, N42-aminophenyl)3- 1H), 7.42 (dd, J 8.5 Hz, 2.2 Hz, 1H), 7.41 Cm, MeO [6-(3,4,5-rimethoxy- 1H), 7.30 J 7.9 Hz, 1H), 7.10 Cbs, 1H), 7.02 82 116 H N CH H benzylamino)- J 7.4 Hz, 1H), 6.75 J 15.0 Hz, 1H), 6.73 7, 3 OMe pyridin-3-yll- (m 1H), 6.65 Cm, 2H), 6.36 J 8.8 Hz, 1H), acrylamide 6.23 J 15.0 Hz, 1H), 4.34 2H and bs, 2H), 3.84 3H), 3.81 6H).
'H NMR: (DMSO-d 6 8 (ppm): 8.28 bs, 1H), 7.98 N42-Amino-phenyl)- J 9.6 Hz, 1H), 7.57 Cd, J 15.6 Hz, 1H), 3-644-rettyl- 7.38 Cd, J 7.7 Hz, 1H), 7.29 J 7.9 Hz, 2H), 83 117 H N CH H benzylamino)- 7.22 J 7.6 Hz, 2H), 7.08 Cdt, J 8.2 Hz, 7.7 7 pyridin-3-y- Hz, 1H), 6.98 Cd, J 9.1 Hz, 2H), 6.87 J 8.2 acrylamide Hz, 1H), 6.75 J 15.1 Hz, IH), 4.57 2H), 2.53 3H).
N(2-amino-phenyl) 1 H NMR: (DMSO-d6) 8 (ppm): 9.27 1H), 8.54 84 118 N3-124-methoxy Cs, 2H), 8.12 Cm, 1H), 7.30 Cm, 4H), 6.53-6.91 m, Hnylmino- 6H), 4.90 Cs, 2H), 4.46 Cd, J 4.9 Hz, 2H), 3.7 (s, pyrimidin-y] 3H).
1 H NMR (20% CD 3 OD in CDCI 3 008.75 Cs, 1H), 3-A643,4imi-henyl- 7.95 Cm, 1H), 7.74-7.59 Cm, 3H), 7.50 Cm, 1H), 84b 1 18b MeO N CH H 346-(3,4die3oy- 7.24 J 7.8 Hz, 1H), 7.07 Cm, 1H), 6.95 Cd, J 9,15 OMe pheylaidn3 8.4 Hz, 1H), 6.89-6.83 Cm, 3H), 3.96 3H), a1 a 3.91 Cs, 3H).
2006252047 14 Dec 2006 Table 3b 0 X N nNH
NH
2 N N N MeDj Ex. Cp.n Name Characterization Scheme 53 87 0 244-methoxy- 'H-NMR (DMSO-d6), 5 (ppmn): 9.66 (bs, IH), 8.32 1H), 8.05 Cd, J 8.8 Hz, ben zyla mino)-uinoline- 1H), 7.96 (dd, J 9.1 Hz, 2.2 Hz, 1H), 7.72 J 2.2 Hz, IHN, 7.55 (dd, J 6-carboxylic acid Hz, 2.2 Hz, 1H), 7.34 (dd, J 8.5 Hz, 2.2 Hz, IN), 7.20 J 7.7 Hz, 1H), 6.97 aminophenyl)-amide J 7.7 Hz, IH), 6.90 (mn 2H), 6.80 J 7.9 Hz, 1H), 6.61 J 6.3 Hz, 1H), (bs 2H), 4.58 J 3.3 Hz, 2H), 3.73 3H), 3.33 (bs, 1H).
54 88 1 NM2-aminophenyI)-3-2- 'H-NMR (DMSO-d6), 8 (ppmn): 9.70 (bs, 1 9.40 Cbs, 1 8.20 J 8.9 Hz, (4-methoxy- LH), 8.03 (bs, 2H), 7.94 Cd, J 7.2 Hz, 1H), 7.64 (dd, J =15.7 Hz, 2.5 Hz, 1H), benzyiamino)-quinolin-6- 7.41 J 8.5 Hz, 2H), 7.39 1H), 7.14 Cd, J 8.9 Hz, 1H), 7.05 J 15.7 yII-acrylamide Hz, 1H), 6.97 (in, IN), 6.95 J 8.5 Hz, 2H), 6.81 J 8.0 Hz, 1H), 6.65 Ct, J =7.2 Hz, 1H), 4.76 Cs, 2H), 3.75 Cs, 3H).
Table 3c
NH
2 Me0l(" NH 0
H
Ex. Cpd. Name _______Characterization Scheme 43 51 N42-.inophenyI)-3-[6-(4-methoxy- 'H-NMR (CDC1 3 8 (ppmn): 7.60 (bs, 1H), 7.55 Cbs, 1H), 7.43 Ct, J 7.7 3 benzylamino)-pyridin-2-yII-acrylamide Hz, 1H), 7.29 J 8.3 Hz, 2H), 7.17 J 15.1 Hz, 1H), 7.06 Ct, J= 7.7 Hz, 1H), 6.88 J 8.3 Hz, 2H), 6.80 (in, 2H), 6.70 Cm, 3H), 6.41 J 8.5 Hz, 1H), 4.50 Cd, J 5.5 Hz, 2H), 3.80 Cs, 3H), 3.45 (bs, 2H). 2006252047 14 Dec 2006 Table 3d 0 V' I N. NH W Z
R.
Ex. Cpd W Y Z R Name Characterization Schm H N42-Amino-phenyl)3- 'H-NMR (DMSO-d6), 5 (ppm): 9.36 (bs, 1H), 7.55 J I4-(4,6-dimethoxy- 7.4 Hz, 2H), 7.48 1H), 7.38 J 7.9 Hz, 2H), 7.33 (d 347 492 NCH H H pyrimidin-2-ylamino- J=7.9 Hz, 1H), 6.91 2H), 6.73 J=8.2 Hz, 1H), 6.56 3,7 methyilphenyl)- (dd, J 7.4, 7.7 Hz, 1H), 5.35 1H), 4.93 (bs, 2H), 4.46 0CH3I acrylamide (dd, J=6.04 2H), 3.32 6H)
H
CI,, NN- N2-Amino-phenyI)-3- 'H-NMR (DMSO-d6), 8 (ppm): 9.37 (bs, IH), 7.58-7.50 (4-I(4chloro-6- 34849 Hhlox r- 3H), 7.37-7.32 3 6.94-6.83 2H), 6.75 (d 348493CHC H methy J=8.O Hz, 1H), 6.57 J=7.5, 1H), 6.13 (bs. 1H), 4.94 0 yli-acrymI (bs, 2H), 4.48 J=6.0, 2H), 3.84 3H) CH3 phenyl)-acrylamic e
H
H
3 C Oq Nz. N(2-Amino-phenA).3- 'H-NMR (DMSO-d6), 8 (ppm): 9.38 (bs, 1H), 7.55-7.40 349 494 CH OH 14-3,5-dimethoxy- (m 6H), 6.88-6.57 3 6.35-6.32 1H), 5.73 3, 7 benzylaininophen 3H), 4.94 2 4.26 (s 2H), 3.63 6H).
0 C acrylamide CH3
H
0 2 N N N2.Amino-pheny-3- 'H-NMR (DMSO-d6), 8 (ppm): 9.38 (bs, 1H), 7.74 (bs, 495 OH OH H [443,5dinitro- 3H), 7.61 J=8.2 Hz, 2 7.56-7.44 3l0), 7.32 (d 3 benzylaminopheny- J=8.0 Hz, 1H), 6.91-6.85 2H), 6.73 (d J=7.9 Hz, 1H), acrylamide 6.66-6.56 1H), 4.93 (bs, 2H), 4.52 (bs, 2H).
2006252047 14 Dec 2006 Ex. Cpd W Y Z R Name Characterization Schm N(2-Amino-phenyI)-3- 'H-NMR (DMSO-d6), 5 (ppm): 9.22 Cbs, 1H), 7.52 (d,
IH
[443-trifluoromethoxy- J=7.9 Hz, 2H), 7.44 Cbs, 1H), 7.38 (bs, 3H), 7.28 (d benzylaminophenyO- J=6.9 Hz, 2H), 6.95-6.92 Cm, 2H), 6.79 (d J=8.2 Hz, 1H), 58 acrylamide 6.69-6.59 Cm, 3H), 4.95 Cbs, 2H), 4.45 bs, 2H).
9H 3 1 H-NMR (DMSO-d6), 6 (ppm): 9.45 Cbs, 1H), 8.01 (bs, 0 440.4 N -CAmi o xeyD- 2H), 7.78-7.5 Cm, 4H), 7.49-7.40 Cm, 1H), 6.98 (dd, 352 497 H 3 c CH CH H [4345tmethy 8.2 Hz, 1H), 6.82 J=7.0 Hz, 1H), 6.64 (dd J=7.0, 7.6 3, 7 o hHz, LH), 6.41 (bs, 2H), 5.17 2H), 3.81 Cs, 6H), 3.64 (s, phenyll-acrylamide H3C' 0 3H).
CH
3 N2-Amino-pheny)3. 'H-NMR (DMSO-d6), 5 (ppm): 9.22 (bs, 1H), 7.17 (d, ?(446,7-dimethoxy-3,4- J=8.2 Hz, 2H), 6.97 J=8.2 Hz, 2H), 6.93 Cd, J=7.6 Hz, 353 498 0 N CH CH H dihydro-IH-isoquinolin- 1H), 6.85 bs, 1H), 6.77 (bs, 1H), 6.60-6.53 Cm, 3H), 6.43- 37
H
3 C 2-yO-phenyg- 6.40 Cm, 2H), 4.97 (bs, 2H), 4.43 Cbs, 2H), 3.78 3H), o0 acrylamide 3.77 Cs, 3H), 2.87-2.85 Cm, 2H), 2.65-2.62 Cm, 2H).
NH MN.2Amino-phenyU)-3- 'H-NMR CDMSO-d6), 5 (ppm): 10.77 Cbs, 1H), 9.39 Cbs, C4-((IHindoQ2- 1H), 7.62 J=7.9 Hz, 1H), 7.49 Cd, J=5.7 Hz, 2H), 7.37 5Hylmethyl3,4,5- d, J=7.9 Hz, 2H), 7.26 d, J=7.9, 2H), 7.10 t, J=7.5 Hz, 354 trimethoxy-phenyl 2H), 7.00-6.83 Cm, 4H), 6.78 Cd, J=7.9 Hz, 1H), 6.61 Ct, 58
H
3 C' ii=7.5 Hz, 1H), 5.98 Cs, 1H), 5.32 Cbs, 1H), 4.98 Cbs, 2H),
H
3 aminyj-metyll- 4.32 J=5.2 Hz, 2H), 3.98 Cbs, 2H), 3.73 Cs, 3H), 3.67 phenyflacrylamide CS, 3H), 3.64 Cs, 3H).
0,CH3
H
3 C. (2-Amino-phenyip3 IH-NMR CDMSO-d6), 8 (ppm): 9.69 bs, 1H), 8.04 Cd, 1434 tr i J=8.3 Hz, 2H), 7.78 Cd, J=8.3 Hz, 2H), 7.58-7.55 Cm, 2H), 355 500 H 3 CI O CH OH H 14-(3,4,5-trimethy- 7 *06 J=6.2 Hz, LH), 6.96 Cd, J=7.3 Hz, 1H), 6.90 (d 3, 7 phenylslanrylamie J=7.0 Hz, 1H), 6.60 Cbs, 1H), 5.81 Cs, 2H), 4.34 Cbs, 2H), o phenyl-acrylamide 3.78 Cs, 6H), 3.67 Cs, 3H).
2006252047 14 Dec 2006 Ex. CPd W V Z R Name Characterization Schm 0 3-141(6Acetyl- 1 H-NMR (DMSO-d6, I (ppm): 9.81 (bs, 1H), 7.95 Cd, C benzof1,3dioxo 5- J=7.9 Hz, 2H), 7.58 Cd, J=7.9 Hz, 2H), 7.39 Cbs, 1H), 7.21 5651CH3 CH CH H yamino)methyll- i=7.4Hz, 1H), 7.02-7.00 Cm, 2H), 6.85 Cd, J= 7.5 Hz, 58 35601 N phenyl-N42-amino- 1H), 6.64 Ct, J=7.4 Hz, 1H), 6.60 Cbs, 1H), 6.36 Cbs, 1H), H phenyt)acrylamide 6.00 Cd, J=2.2 Hz, 2H), 4.60 Cbs, 2H), 2.50 Cbs, 3H).
NH N42-Amino-phenyI3- 1 H-NMR (DMSO-d6), 8 (ppm): 9.43 Cbs, 1H), 8.37 (bs, N (4-(5-methoxy- 1H), 7.66-7.57 3H), 7.49 Cd, J=7.5 Hz, 2H), 7.37-7.33 357 502 S OH OH H benzothiazo[2- Cm, 3H), 6.96-6.90 Cm, 1H), 6.87 Cd, J= 8.8 Hz, 1H), 6.80 58 ylamino)methy- Cd, J=7.9 Hz, 1H), 6.63 Ct, J=7.5 Hz, 1H), 4.99 Cbs, 2H), phenyl)-acrylamide 4.64 bs, 2H), 3.37 3H).
0
CH
3 NH N(2-Amino-pheny)3 'H-NMR (DMSO-d6), a (ppm): 9.42 Cbs, LH), 7.63-7.56 3 53/O H444-orphoin-4-y Cm, 3H), 7.47 Cd, J=7.9 Hz, 2H), 7.39 Cd, J=7.5 Hz, 1H), 585Hphenylaminoethy- 6.95 Cd, J=8.3 Hz, 1H), 6.82 Cbs, 1H), 6.77 Cd, J=8.4 Hz, 58 2H), 6.66-6.56 Cm, 3H), 5.91 Cbs, 1H), 5.01 Cbs, 2H), 4.30 N mbs, 2H), 3.74 Cbs, 4H), 2.93 Cbs, 4H).
HH-NMR (DMSO-dg), 6 (ppm): 9.42 Cs, 1H), 7.64 J= 7.9 Hz, 2H), 7.59 Cd, J 15.9 Hz, 1H), 7.48 Cd, J Hz, 2H), 7.39 Cd J=7.4 Hz, 1H), 7.10 Cd, J 8.2 Hz, 2H), 39504 COH OH H trifluoromethoxy- 6 99 Cd, J=7.1 Hz, IH), 6.92 Cd, J 15.4 Hz, 1H), 6.81 phenylamino)-methyll-
F
3 COja phenyl-yamio)met- (dd, J 1.3, 8.0 Hz, 1H), 6.61-6.68 Cm, 4H), 4.99 2H), 4.36 J=6.0 Hz, 2HI.
2006252047 14 Dec 2006 Ex.]Cpd W V Name Characterization 7.3C,= Schm H4-mn-pey~ 7 '7 Hz, 2H), 7.59 Cd. J 15.4 Hz, 1H), 7.47 Cd, J N Nj- N{2Anophy)3dx- Hz, 2H', 7.40 Ji 7.7 Hz, 1H), 6.99 J =7.1 Hz, IH), 36 55CHCHHylaminomethyl)- 6.92 J=16.2 Hz, 1H), 6.91 Cdd, J 1.4, 8.0 Hz, 1H), 3, 331 0 phenyh)-acrylamide 6.68 Cd, Ji 8.2 Hz, IH), 6.62 (dd, J 1.4, 7.7 Hz, 1H), 6.34 J 2.2 Hz, 1H), 6.05 (mn, 2H), 5.87 Cs, 2H), 4.99 H 2H), 4.29 J=6.0 Hz, 2H).
N N42-Amino-phenyl3 'H-NMR (DMSO-d 6 8 (ppm): 9.43 Cs, 1H), 7.57-7.66 Cm, 3H), 7.48 Cd, J 7.6 Hz, 2H), 7.40 J 7.6 Hz, LH), 361 506 C. H OH H trifluoromethoxy- 7.20 (dd, J 8.2, 8.2 Hz, 1LH), 6.99 Cd, J 7.6 Hz, 1 3, 33 phenylamino-methiyl- 6.93 J= 15.2 Hz, 1 6.81 Cm, 2H), 6.64 (in, 2H), 6.49-
OCF
3 Iphenyll-acrylamide 6.55 Cm, 2H), 5.00 2H), 4.38 J= 5.3 Hz, 2H).
H H-NMR (DMSO-dG), 8 (ppm): 9.42 1H), 7.63 Cd, J N '.7{N-(2-Amino-phenyl)-3 7.6 Hz, 2H), 7.59 J1= 15.8 Hz, 1H), 7.47 Cd, J 7.6 phenylamino)rnethyl)- Cd, J=7.6 Hz, 1H), 6.64 Cdd, J 7.0, 7.0 Hz, 1H), 6.36 Cm, phenyll-acrylarnide 1H), 6.24 Cd, J 8.2 Hz. 1H), 6.18 Cm, 2H), 5.00 Cs, 2H), OMe Cd, J= 5.3 Hz, 2H), 3.69 Cs, 3H).
-NMR (DMSO-dc 6 8 (ppm): 9.42 Cs, 1H), 7.62 Cd, J= H N4-mn-hnl 7. 0Hz, 2H), 7.58 Cd, J 15.2 Hz, 1H), 7.46 Cd, J 7.6 OH H H 4(2.rnethoxy- Hz, 2H), 7.40 Cd, J 7.0 Hz, 1H), 6.94-7.00 Cm, 1H), 6.87 363 58 CHCH Hphenylamino).rethy. Cd J=7 *6 Hz, 2H), 6.81 Cd, J 7.6 Hz, 1H), 6.73 Cdd, J 3, 33 363 508 OMe phnl-cyaie 1H), 5.68 Ct, J 5.9 Hz, LH), 4.99 Cs, 2H), 4.41 Cd, J 6.4 2H), 3.87 Cs, 3H). H 'H-NMR (DMSO-d 6 8 (ppm): 9.Al Cs, 1H), 7.63 Cd, J NQ-Ainophenl~l 7.9 Hz, 2H), 7.59 Cd. J 15.8 Hz, iH), 7.48 Cd, J=7.9 Hz, N6 0 HC NA-eyaminoehyl)- 2H), 7.39 Cd, J 7.5 Hz, IN), 7.10 C2d, J 7.5, 7.5 Hz, 33 36 59 H OH H phenylacamio ehl 2H) 6.99 Cd, .J 7 .5 Hz, 1H), 6.92 .J 16.2 Hz 1H)i, phenl)-arylaide 6.81 Cd, J 7.5 Hz, I 6.55-6.64 Cm, 4H), 6.32 Ct, J 1H), 4.99 Cs, 2H), 4.35 Cd, J 5.7 Hz, 2H). 2006252047 14 Dec 2006 Ex.- Cpd W 7 Z R Name Characterization Schm H 'H-NMR (DMSO-d 6 8 (ppm): 9.42 Cs, 1H), 7.62 J N-42-Amino-phenyI)-3 7.0 Hz, 2H), 7.59 Cd, J 15.8 Hz, LH), 7.47 Cd, J 8.2 36 1 3 .CH OH H 144(4-isopropyl- Hz, 2H), 7.40 J 7.6 Hz, 1H), 6.89-6.99 (in, 4H), 6.81 33 365 50 H3CphenylaminO)methyll. Cd, J=7.6 Hz, 1 6.64 (dd, J 7.0, 7.6 Hz, 1 6.56 (d, yphenyll-acrylamide J 8.2Hz, 2H), 6.14 J 5.9 Hz, 1H), 4.99 2H), 4.32
CH
3 d, J= 5.9 Hz, 2H), 2.76 (in, 1H), 1.17 J 7.0 Hz, 6H).
H 'H-NMR (DMSO-d.), 6 (ppm): 9.43 Cs, 1H), 7.57-7.66 (m, N42-Amino-phenOYIl3 5H), 7.40.7.52 (in, 7H), 7.27 (dd, J 7.0, 7.6 Hz, 1H), 366 511 HO 4Abipheny-4 6.98 J 7.6 Hz, 1Hi), 6.93 J=15.2 Hz, 1H), 6.81 Cd, ylaminoinethyl)- J 8.2 Hz, LH), 6.73 Cd, J 8.2Hz, 2H), 6.64 Cdd, Ti 7.6'3 3 phenyI1-acrylamide Hz, 1H), 6.56 J =5.9 Hz, 1H), 4.99 2H), 4.12 J= 5.9 Hz, 2H).
MeG H 'H-NMR (DMSO-d 6 (ppm): 9.50 Cs, 1H), 8.81 1H), N~j..~-N42-Amino-phenyl)-3 8.05 J 8.2 Hz, 1H), 7.64 J 15.7 Hz, 1H), 7.52 367 12 OHN H(64(3,4,5-trimethoxy- Cd, J=8.2 Hz, 1H), 7.39 Cd, J 7.4 Hz, 1H), 6.96-7.05 (in, 367 512CH N Hphenylamino)-rethyl- 2H), 6.81 Cd, J 8.0Hz, 1H), 6.64 Cdd, J 7.4, 7.4 Hz, 33 MeG pyridin.-3-yi)- 6.26 Cm, 1H), 5.96 2H), 5.01 2H), 4.43 Cd, J MeO acrlamide 5.5 Hz, 2H), 3.72 Cs, 6H), 3.56 Cs, 3H).
'H-NMR (DMSO-d6), 6 Cppm): 9.50(s, 1H), 8.28 Cd, J 0NM2-Ainino-phenyl)-3- 788 Hd, 1H) 7.15.2 Hz, 7. Cd, J 8.1 Hz, (44[143-b8 4 z, 1H) 7.88(,J=1.77 s, 7.6 Cd, J 8.1 Hz, (4.C1.(3benzV7- 7.26 Cm, 4H), 7.24-7.15 Cm, 2H), 7.00-6.86 (in, 2H), 6.84 369 514 N OH OH H chloro-4oxo-3,4- J 8.1 Hz, 1H), 6.68 Ct, J 7.5 Hz, 1H), 5.45 J N~ C 3 y).hyramqinaointh2) 16.8 Hz, 1H), 533 J 16.8 Hz, 1H), 4.62 Cbs, 1H), Cl N y C3 yi-etylamnolmethl)-4.25 J 12.9 Hz, 1H), 4.92 J= 12.9 Hz, 1H), 1.91 HN phenyl)-acrylamide 2H), 1. 28 Cm, 1 0.90 (in, I1H), 0. 72 Ct, J 7.5 Hz, 3H).
N.2-Amino-phenyl)-3 1 H NMR: (Acetone-d 6 6 (PPM): 9.47 (bs, 1H), 7.72-7.56 371 516 Br- OH OH OH (4-broino-phenyl). (in, 5H), 7.39 Cd, J=7.4 Hz, IH), 7.00-6.95 (in, 2H), 6.81 14 acrylamide Cd, J=6.9 Hz, LH), 6.64 t, J=7.1 Hz, 1H), 5.00 Cbs, 2H). 118 2006252047 14 Dec 2006 Ex. Cpd W Y Z R Name Characterization Schm OMe TH NMR: (CD30D) 5 (ppm): 7.61 J=15.4 Hz, 1H), Me M2-Amino-phenyl)-4- 7.44 J=8.4 Hz, 2H), 7.25 J=7.5 Hz, 1H), 7.10 (t, 372 517 0H H CH CHCH (2,4,5-trimethoxy- J=7.5 Hz, 1H), 7.00 1H), 6.94 J=8.4 Hz, 1H), 6.81 1,7,10 N~ benzylamino- J=7.0 Hz, 1H), 6.76 1H) 6.70 J=8.4 Hz, 2H), 6.92 benzamide J= 15.4 Hz, 1H), 4.35 2H), 3.94 3H), 3.92 3H), OMe 3.77 3H).
OMe N{2-Amino-phenyf)-3- MeO (4-[13,4,5Amino-pheny3- 1H NMR (DMSO-d6) 8 (ppm): 9.24 1H), 8.00 l(d, MeCH 3 CH H CH i44143,4,5- J=12Hz, 1H); 7.80 J=12Hz, 1H), 7.40-7.70 7H), e373 518 C tmet nbtoxy- 6.80-7.00 2H), 6.70 J 12Hz,1H), 6.20 2H), 58 MeO phenylamino)-ethyl 4.50 1H), 3.70 6H), 3.50 3H), 1.50 3H).
H phenyll-acrylamide 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.41 1H), N2-Aminophenyl)-3 8.00 J 7.9 Hz, 2H), 7.88 1H), 7.77-7.56 3H), 374 519 C CH H (9H-fluoren-2-yl)- 7.52-7.32 3H), 7.00 J 15.8 Hz, 1H), 6.96 J 59 W acrylamide 7.5 Hz, 1H), 6.80 J 7.9 Hz, 1H), 6.63 J 7.5 Hz, 1H), 5.00 2H), 4.03 2H).
NH2 H N{2-Amino-phenyi4- 'H NMR (300 MHz, DMSO-d 6 5 (ppm): 9.71 11H), N [242-amino 9.43 1H), AB system (SA 8.05, B 7.75, J 7.9 Hz, 375 520 CH CH H phenylcarbamoyl 4H), 7.62 J 15.8 Hz, 1H), 7.36 J 7.9 Hz, 1H), 59 0i phnylabamy) 7.18 J 7.5 Hz, 1H), 7.05-6.88 3H), 6.78 J O vinyl]-benzamide 7.9 Hz, 2H), 6.65-6.55 2H), 4.96 and 4.92 (2s, 4H).
H N42-Amino-pheny)-3- 'H NMR (300 MHz, DMSO-d 6 6 (ppm): 9.29 1H), N N 1 pyrimidi2- 8.32 J 4.9 Hz, 2H), 8.24 J 1.9 Hz, 1H), 7.71 (d, 376 521 N CH H ylaminothylamino- J 6.9 Hz, 1H), 7.48 J 15.7 Hz, 1H), 7.38 J 7.7 3 yrniHtylm Hz, 1H), 7.26 (bs, 2H), 6.96 J 6.9 Hz, 1H), 6.80 (dd, J N pyridi-3-y)- 1.1, 7.7 Hz, 1H), 6.69-6.61 4H), 5.00 2H), 3.52 acrylamide bs, 4), (bs, 4H), H M2-Amino-phenyl3- 'H NMR (300 MHz, CD 3 OD) 6 (ppm): 8.12 1H), 8.08 N (6-24thiazo- 1H), 7.78 J 8.8 Hz, 1H), 7.54 J 15.4 Hz, 1H), 377 522 s N CH H ylamino)thylaminol- 7.19 J 8.0 Hz, 1H), 7.04 J 7.4 Hz, 1H), 6.87 3 H pyridin-3-yli- J 8.0 Hz, 1H), 6.75 J 7.4 Hz, 1H), 6.64 J 15.4 N ayidi I Hz, 1H), 6.65 1H), 4.90 5H), 3.50-3.45 4H), 3.30 acrylamide1.3 Hz, 1).
J 1.3 Hz, 1H).
2006252047 14 Dec 2006 Ex. Cp W Y Z R Name Characterization Schm A (44(2-miophenr yl3 'H-NMR (CD 3 OD), 6 (ppm): 7.83 Cd, J 15.6 Hz, 1H), C4(C2mophln--y-7.67 J 7.8 Hz, 2H), 7.62-7.58 Cm, 2H), 7.53-7.*51 Cm' 3 3 37 53 yC H OCH H tnethy-phenl)- 2H), 7.49 Cd, J 7.8 Hz, 2H), 7.01 Cd, J 15.6 Hz, 37M5 3O W tramn ]eth yp eyl 4.99 (b 9H), 4.84 (bs, 2H), 4.22 Ct, J 6.5 Hz, 2H), 4.05 W phenyD-macrylm i 4H), 3.85 6H), 3.76 3H), 3.57-3.50 Cm, 4H).
N42-Amino-phenyl-3- H-NMR (DMSO-d 6 8 (ppm): 9.32 Cs, IH), 9.26 1H), 37952 N HH 16.{3-hydroxy- 8.19 1H), 7.66 Cd, J 8.5 Hz, IH), 7.57 Ct, J 6.0 Hz, 379524N C Hbenzylamino-pyridin-3- 1H), 7.41 J 15.7 Hz, lH), 7.32 Cd J=7.7 Hz), 7.10 Ct, 3 I'acyde J 7.6 Hz, IH), 6.91 Ct, J=7.6 Hz, 1H), 6.75 Cm, 3H), 6.59 OH (rc'a~ m, 4H), 4.98 Cbs, 2H), 4.46 Cd, J=5.8 Hz, 2H).
NNQ2Amino-phenyl3 1 NMR CDMSO-d 6 6 Cppm): 9.25 Cs, 1H), 8.18 Cs, 1H), H 16-3-2,2,2-tr~foro- 7.67 Cd, J 8.8 Hz, 1H), 7.59 Ct, J 6.0 Hz, I1H), 7.42 Cd, 380 525 CH H ethoxy).benzylaminol- J 15.7 Hz, 1H), 7.30 Cm, 2H), 7.00 (in, 2H), 6.92 Cm, 3 pyridin-3-yII- 2H), 6.74 Cd, J 8.0 Hz, 1H), 6.60 Cm, 3H), 4.92 Cs, 2H), acrylamide 4.73 Cq, J 8.8 Hz, 2H), 4.52 Cd, J 5.8 Hz, 2H). M2Amino-phenyl)-3 H-MR (CD 3 OD), 8 (ppm): 7.64 Cd, J 15.6 Hz, I1H), Me-N N NH C4-13-hydroxy-444- 7.56 Cd, J 8.0 Hz, 2H), 7.49 Cm, 1H), 7.40 Cd, J 8.0 33 381 526 C j H OH H metiypiperazin--yD- Hz, 2H), 7.21 Cm, 2H), 7.03 Ct, J 7.6 Hz, 1H), 6.88-6.71 8 CF3 phenylaminol-methyll- Cm, 4H), 4.88 Cbs, 4H), 4.34 Cs, 2H), 2.86 Ct, J 4.1 Hz,
CF
3 phenyl~acrylamide 4H), 2.67 Cbs, 4H), 2.41 Cs, H NQ-2Amino-phenyl)-3 'H-NMR (DMSO-d., 8 (ppm): 9.43 Cs, 1H), 7.61 Cd, J= Iuoro-444- 8.0 Hz, 2H), 7.45 Cd, J 8.0 Hz, 2H), 7.38 Cd, J 7.6 Hz, 3 382 527 N H OH H methyl~iperazin-1-y)- 1H), 7.00-6.88 Cm, 2H), 6.85-6.79 Cm, 2H), 6.63 Ct, J 7 6 r N- phenylaminoJ-methyl)- Hz, 1H), 6.44-6.30 Cm, 3H), 4.99 Cbs, 2H), 4.30 Cd, J 5.58 m A" F phenoYlacrylamide Hz, 2H), 2.87 Cbs, 4H), 2.55 Cm, 4H), 2.27 Cs, 3H).
H 'H-NMR (CDCI 3 5 Cppm): 7.49 Cd, J 14.0 Hz, 1H); 7.32 IVQ1-AmC3. hydy Cd, J 7.2 Hz, 2H), 7.15 Cd, J 7.2 Hz, 2H), 7.05 Cm, 1H), 383 528 H OH H 14(-yrx- 6 96 Cm, 1H), 6.90 Cm, 3H), 6.76 1H), 6.55 Cd, J 3, 33 phenocylami.rel 14. Hz, 1H), 6.03 Cm, 1H), 5.99 Cm, 1H), 4.30 Cbs, OH phnl-cyaie 4. 10 2H). 120 2006252047 14 Dec 2006 Ex._ Cpd W Y Z R Name Characterization Schm H TiFH-NMR (CDOD), 8 (ppm): 7.73 J 16.0 Hz, 1 H); H 42-Amino-phenyl)-3 7.63 J 8.5 Hz, 1 7.58 J 8.0 Hz, 2H), 7.46 (d, 144(4-trffluoromethy- J 8.0 Hz, 2H), 7.38 J 8.5 Hz, 1H), 7.20 Cd, J 384 529 H OH H pyrimidin-2-ylamino Hz, 1H), 7.03 Cdt, J 7.7, 1.4 Hz, 1H), 6.89(Cd, J 1.1 Hz, 3, 33 methyfl-henyl)- 1H), 6.85 Cm, 1H), 6.73 (dt, J 7.7, 1.1 Hz, 1H), 6.56 (d,
CF
3 acrylamide J 16.0 Hz, 1H), 5.27 Cs, 2H), 4.87 (bs, 2H), 4.62 (s, H.2Aiopey)3 I H-NMR (DMSO-ds), 8 (ppm): 9.90 IN), 7.58 Cm, 3H), 385530..-OH HN M24Am3ydo-yetyI 7.43 Cd, Ji 8.0 Hz, 2H); 7.37 d, J 8.0 Hz, 7.11 385530CHCH 14(pheymio)methyl Cm, 1H), 7.00 Cm, 3H), 6.85 Cd, J 15.4 Hz, 1H), 6.63 Cs, 3, 33 phenyl-cylami~eh 1H), 6.51 Cd, J 7.4, Hz, 1H), 6.46 Cd, J 7.7 Hz, 1H), HO 4.35 Cs, 2H), 4.32 Cs, 2H).
H Tf--M (DS6, 8 (PPM): C.6 s, 1 8.46 Cu, J NQ~-Amino-phenyD-3- 4.7 Hz, 2H); 7.55 Cd, J 8.0 Hz, 2H), 7.50 Cd, J 15.7 I C4-f(4-pyridin-4- Hz, IHN, 7.39 Cd, J 8.0 Hz, 2H), 7.28 Cd, J 4.7 Hz, 2H), 386 531 OH OH H ylmethyl~phenylamino- 7.00 Cd, J 15.7 Hz, 1H), 6.92 Cd, J 6.9 Hz, 2H), 6.90 3, 33 methyll-phenyl)- Cm, 1H), 6.75 J 8 Hz, 1H), 6.58 Cm, 2H), 6.52 Cd, J N Iacrylamide 6.9, Hz, 2H), 6. 10 Cbs, ILH), 4.26 Cbs, 2H), 3.80 Cs, 2H), N 2.08 Cd, J 1.9 Hz, 2H).
H4-nh)3 I H-NMR (DMSO-d 6 8 (ppm): 9.38 Cs, 1H), 7.58 Cd, J 387 532 OH OHH (44(3-cyano 7.7 Hz, 2H); 7.54 Cd, J 15.9 Hz, 1H), 7.41 J 7.7 Hz, 38p3 C H Hen-[-ylano).nty- 2H), 7.33 Cd, J 8.0 Hz, 1H), 7.24 Ct, J 7.7 Hz, 1H), 3, 33 phenamin~metyl 6.92-6.83 Cm, 5H), 6.75 Cd, J 8.0 Hz, 1H), 6.58 Ct, J CN phenyll-acrylamide 7.4 Hz, 1H), 4.95 Cbs, 2H), 4.34 Cd, J 5.8 Hz, 2H). 1 H-NMR (DMSO-d 6 8 Cppm): 9.37 Cbs, 1H), 8.21 Ct, J= H 5.8 Hz, 1H), 7.56 Cd, J 7.7 Hz, 2H), 7.53 Cd, J 15. 7Hz, N S-3(4.-[34Acetytamino- 1H), 7.41 Cd, J 8.0 Hz, 2H), 7.33 Cd, J 7.1 Hz, 1H), methyl)-phenylamino)- 6.97 Cm, 1H), 6.85 Cd, J =15.7 Hz, 1H), 6.74 Cdd, J 1.4.
388 33 C CH metyll-henyW2-8.0 Hz, 1H), 6.58 Cdt, J 8.0 Hz, 1H), 6.50 Cbs, 1H), 33 amino-henyl)- 6.41 Cd, J 8.0 Hz, 2H), 6.30 Ct, J 6.0 Hz, 1H), 4.94 Cbs, NHAc acrylamide 2H), 4.28 Cd, J 6.0 Hz, 2H), 4.09 Cd, J 6.0 Hz, 2H), 1.83 Cs, 3H). 2006252047 14 Dec 2006 Ex. Cp W Y Z R Name Characterization Schm H H-NMR (DMSO-d6), 8 (ppm): 9.37 Cbs, 1H), 7.56 Cd, J SN-42-Amino-pheny4)-- 8.0 Hz, 2H), 7.53 J 15.7H-z, 7.41 Ji 8.0 Hz, 389 534 CH OH H trforoethy 2H), 7.33 J 7.7 Hz, 1H), 6.92 J 7.7 Hz, 2H), 38034CNC pheylaorm)ethyl]- 6.85 J 15.7 Hz, 1H), 6.74 J 8.0 Hz, 1H), 6.67- 33 phenll-arylaide 6.55 Cm, 4H), 5.84 J 5.8 Hz, 1H), 4.94 Cbs, 2H), 4.22
CF
3 phnl-cyaie J 5.8 Hz, 2H).
CI N 4-mn-peO3 H-NMR (DMSO-d 6 5 (ppm): 9.39 Cbs, 1H), 7.60 J K phen4.amino~rehenl- 8.0 Hz, 2H), 7.54 J 15.7 Hz, 1H), 7.40 Cd, J 8.0 Hz, 390 53 CH CH Henylam-ichth- 2H), 7.33 Ji 7.1 Hz, 1H), 6.97-6.89 (in, 2H), 6.87 Cd, 3, 33 phenll-arylaide J 15.7 Hz, 11H), 6.75 (dd, J 1.4, 8.0 Hz, 1H), 6.60-6.55 phnl-crlmd Cm, 4H), 4.95 Cbs, 2H), 4.33 J 6.0 Hz, 2H).
MeO .2Amnino-pheny)-- 1 H-NMR (CDCI 3 a (ppm): 8.12 Cbs, 1H), 7.64 Cd, J (4-1243,4,5-142HI,74 b,4)7.3(s2H,69(dJ 391 536 OH OH H trimetioxy-phenyl- 142H,3) .2Cs H, .3Cs H,69 d MeO vinylJ-phenyll- 14.2 Hz, 11H), 6.94-6.82 Cm, 4H), 6.70 2H), 4.11 Cbs, Meacrylamide 2H), 3.87 6H), 3.84 Cs, 3H).
MeO OMe N42-Amino-phenyl)-3- 'H-NMR (DMVSO-de), 8 (ppm): 8.49 Cs, 1H), 7.58 J= (44243,4,5- 15.7 Hz, 11H), 7.33 Cd, J 8.5 Hz, 1H), 7.23 Cm, 4H), 7.00 392 537 MeQ- /C H OH H trimethoxy-phenyl)- Cd, J 8.5 Hz, 1H), 6.73 Cd, J 5.0 Hz, 2H), 6.69 Cd, J 3 vinyl]-phenyl)- 5.0 Hz, 2H), 6.58 Cd. J 15.4 Hz, 11H), 6.53 Cbs, 2H), 6.47 ___acrylamide Cs, 2H), 3.85 Cs, 3H), 3.63 Cs, 6H).
H
NQAnn-hnl3 I'H-NMR (CD 3
OD/CDCI
3 6 (ppm): 7.61 Cd, J =15.7 Hz, N42(-slamioeyl- 1H), 7.45 Cd, J 8.1 Hz, 2H), 7.29 Cd, J 8.1 Hz, 2H), 1, 3 393 538 H OH H (4-1C-sulariomeyl 7 *18 Cdd, J 8.0 Hz, 2H), 7.12 Cd, J 15.7 Hz, 1H), 7.10 ;3 phenll-arylaide Cm, 1H), 7.03 Ct, J 7.4 Hz, 6.83-6.66 Cm, 4H), 3.93
SO
2
N
2 penyl-acylamde bs, all NH signals).
2006252047 14 Dec 2006 Ex. Cpd W Y Z R Name Characterization Schm H TH-NMR (CDCI3, 8 (ppm): 8.34 (bs, 1H), 7.64 J WN{2-Amino-phenyl)-3- 15.4 Hz, 1H), 7.37 J 8.0 Hz, 2H), 7.34 1H), 7.26 (4-([3.(3-morpholin4- 3 5CO H 3lfaoyl). J 8.0 Hz, 2H), 7.23 J 15.4 Hz, 1H), 7.14 J 3, 33, 394539CH CH IH ly)propylsulfamoyl)- 0 2 HC H yphylsamnoJ yl 7.8 Hz, 1H), 7.04 2H), 6.74 4H), 4.85 (bs, 1H), 42 02S-N-I Nphenylaminol-methyll H (O phenyl)acrylamide 4.30 J 4.4 Hz, 2H), 3.69 J 4.4 Hz, 4H), 2.99 J 5.8 Hz, 2H), 2.40 (bs, 6H), 1.59 J 4.4 Hz, 2H).
MeO 1N{2-Aminophenyl)3- 1 H-NMR (CDC 3 8 (ppm): 8.53 1H), 7.72 J 15.6 (4-[243,45- Hz, 1H), 7.38 J 7.7 Hz, 2H), 7.33 1H), 7.16 J 395 540 CH CH H trimethoxy-phenyl)- 7.7 Hz, 2H), 7.07 1H), 6.79 2H), 6.69 J 3, 32 MeO ethyl-phenyll- 15.6 Hz, 1H), 6.41 2H), 4.04 (bs, 2H), 3.91 3H), OMe acrylamide 3.85 6H), 2.94 4H).
H-NMR (DMSO-d 6 6 (ppm): 9.35 1H), 7.56 J= 7.5 Hz, 2H), 7.52 J 15.4 Hz, 1H), 7.40 J 7.5 Hz, H I N2-Aminwphenyl)3- H N42-Ameoey- 2H), 7.33 J 7.7 Hz, 1H), 6.92 J 7.7 Hz, 1H), 396 541 (S N. CH CH H phe(4-(Cami4-nmethoxy- 6.85 J 15.4 Hz, 1H), 6.75 J 8.0 Hz, 1H), 6.67 3, 33 phenylaminomethyl-
H
3
C
0 phenyylaminet Cd, J 8.6 Hz, 2H), 6.58 1H), 6.52 J 8.6 Hz, 2H), 5.84 J 5.5 Hz, 1H), 4.23 J 5.5 Hz, 2H), 3.61 (s, 3H).
'H-NMR (CDCI 3 8 (ppm): 8.48 1H), 7.60 J 15.4 cm N-(H2-Aminophenyl)3-
H
3 H3 Hz, 1H), 7.27 5H), 6.97 J 7.5 Hz, 1H), 6.70 (m, 397 542 O CH CH H (4-(3,4-dimethoxy- 3H), 6.59 J 15.4 Hz, 1H), 6.25 1H), 6.12 J 3, 33 phenylaminotnethylF Hc penyaminoey 7.1 Hz, 1H), 4.23 2H), 3.93 (bs, 3H), 3.75 3H), 3.73 phenyl)-acrylamide Cs, 3H).
3H).
N42-Aminophenyl)-3- 'H-NMR (CD 3 OD), 8 (ppm): 7.75 J 15.2 Hz, 1H), 398 543 NHN CNOH OH H (4-([341H-tetrazo[5-yl)- 7.60 J 7.6 Hz, 2H), 7.48 J 7.6 Hz, 2H), 7.33 (m, 398NF 54 HCHC 3, 33 phenylaminol-methyll- 3H), 7.27 3H), 7.20 1H), 6.84 2H), 5.48 (bs, Y- phenyl)acrylamide 5H), 4.46 2H).
H N.2-Amino-phenyi)-3- H-NMR (CD 3 OD), 8 (ppm): 7.75 J 15.2 Hz, 1H), N-NN 4-(f441H-tetrazo-5- 7.58 J 8.2 Hz, 2H), 7.42 J 8.2 Hz, 2H), 7.29 (m, 399 544 NCH CH H ylmethyl- 2H), 7.20 2H), 7.04 J 8.2 Hz, 2H), 6.83 J 3, 33 N phenylaminol-methyll- 15.2 Hz, 1H), 6.67 J 8.2 Hz, 2H), 5.48 (bs, 5H), 4.39 H phenyl-acrylamide 2H). 4.16 2H).
123 2006252047 14 Dec 2006 Ex. Cpd W Y Z R Name Characterization Schm 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.42 1H), H NM2-Aminophenyl)-3- 7.62 J 8.5 Hz, 2H), 7.59 J 15.6 Hz, 1H), 7.45 CH H H 144(4-bromo- J 8.0 Hz, 2H), 7.40 J 7.5 Hz, 1H), 7.23 J 400 545 CH ICH H 3, 33 phenylaminomethyl- 8.5 Hz, 2H), 6.98 J 7.5 Hz, 1H), 6.92 J 15.6 Hz, Br phenyll-acrylamide 1H), 6.80 J 8.0 Hz, 1H), 6.66-6.57 4H), 4.99 (bs, 2H), 4.34 J 5.8 Hz, 2H).
HpH NMR (300 MHz, DMSO-d6) 6 (ppm): 9.36 1H), N(2-Amin phenyl)-3- N j 7.57 (d J 7.6 Hz, 2H), 7.54 J 15.8 Hz, 1H), 7.40 401 56 Ct- OH H(4-1(3-bromo- 401 546 hyCH CH H l)romo J 8.2 Hz, 2H), 7.33 J 7.6 Hz, 1H), 7.00-6.91 3, 33 phenylaminohnethyll- 2H), 6.86 J 15.8 Hz, 1H), 6.74 J 8.2 Hz, 2H), phenyl-acrylamide 6.66-6.54 4H), 4.93 (bs, 2H), 4.30 J 5.3 Hz, 2H).
'H NMR (300 MHz, DMSO-ds) 5 (ppm): 9.36 1H), H N2-Amino-pheny3- 7.56 J 8.0 Hz, 2H), 7.53 J 15.8 Hz, 1H), 7.39 H MN2Aminophenyl)-3 J 8.0 Hz, 2H), 7.35 1H), 7.31 J 8.2 Hz, 2H), 402 47 OH H H(44(4-iodo- 402547 CH CH H phenylaminomethyl- 6.92 J 7.1 Hz, 1H), 6.85 J 15.8 Hz, 1H), 6.75 3, 33 phenylaminol-methyl]- J 7.7 Hz, 1H), 6.57 J 8.0 Hz, 1H), 6.52 J phenyl-acrylaide 6.0 Hz, 1H), 6.42 J 8.5 Hz, 2H), 4.94 (bs, 2H), 4.28 J 6.0 Hz, 2H).
H p 'H NMR (300 MHz, DMSO-d) 8 (ppm): 9.40 1H), 43NO O ino-phenyl)-3- 7.57 J 7.6 Hz, 2H), 7.53 J 15.6 Hz, 1H), 7.40 403 548 CH CH H (4Niodo- J 8.2 Hz, 2H), 7.33 J 7.6 Hz, 1H), 6.92 3H), 3, 33 phenaminomethy 6.84 2H), 6.74 J 7.6 Hz, 1H), 6.60-6.50 3H), phenyll-acrylamide phenyll-acrylamide 4.93 (bs, 2H), 4.28 J 5.9 Hz, 2H).
H 'H NMR (300 MHz, DMSO-d 6 5 (ppm): 9.42 1H), N (2-Amin o-phenyl)-3- 7.63 J 8.2 Hz, 2H), 7.60 J 15.3 Hz, 1H), 7.46 -(4-11342-hydroxy- J 8.2 Hz, 2H), 7.40 d, J 7.6 Hz, 1H), 7.03-6.98 (m, 404 549 CH CH H ethoxy)-phenylamino]- 2H), 6.91 J 15.3 Hz, 1H), 6.81 J 7.6 Hz, 1H), 3, 33 methyl)-phenyl)- 6.64 J 7.6 Hz, 1H), 6.36 J 5.9 Hz, 1H), 6.28- O OH acrylamide 6.22 3H), 4.99 (bs, 3H), 4.61 2H), 4.34 J Hz, 2H) 4.28 J 5.0 Hz, 2H).
2006252047 14 Dec 2006 Ex. Cpd W Y Z R Name -Characterization Schm 1H NMR (300 MHz, DMSO-d 6 i) 8 (ppm): 9.38(s, 1H), 7.99 H N4{2Amino-phenyI)3- J 9.1 Hz, 2H), 7.85 Ct, J 5.9 Hz, 1H), 7.60 J N (4(4-nro-7.6 Hz, 2H), 7.54 J 15.8 Hz, IHN, 7.40 J 7.6 Hz, 405550CH H Hphenylamino)-methyl]- 2H), 7.34 J 7.6 Hz, 1H), 6.94-6.92 (in, 1H), 6.88 J 3, 33 02N~a henyl-acryamide 15.'8 Hz, I 6.75 J 7.6 Hz, I1H), 6.68 J 9.1 0 2 N henyl-arylaide Hz, 2H), 6.58 Ct, J 7.6 Hz, IH), 4.94 (bs, 2H), 4.46 J 5.9 Hz, 2H) H 'H NMR (300 MHz, DMSO-ds) 8 (ppm): 9.37 1H), N '~..>{NQ{-Amino-pheny)-3 7.59 J 7.6 Hz, 2H), 7.54 Cd, J 15.2 Hz, 1H), 7.43 4651CH CH H 14-1(3-nitro- Cd, J 7.6 Hz, 2H), 7.36-7.28 Cm, 4H), 7.05-6.98 2H), 33 406551phenylamino-methyU- 6.92 J 7.6 Hz, 1H), 6.88 J 15.2 Hz, 1H), 6.75 phenyll-acrylamide Cd, J 7.6 Hz, 1H), 6.58 Ct, J 7.6 Hz, 1H), 4.96 (bs, 2H),
NO
2 (d J 5.3 Hz, 2H).
'H NMR (300 MHz, DMS0-d 6 l 8 (ppm): 9.43 LH), H N 2Ah3 7.62 J 7.6 Hz, 2H), 7.59 J 15.8 Hz, 1H), 7.46 W-milo-pelY) Cd, J 7.6 Hz, 2H), 7.40 Cd, J 7.6 Hz, 1H),,7.12 Cd, J 407 552 OH CH H 1444chloro- 8 8 Hz, 2H), 6.98 Cd, J 7.6 Hz, 1H), 6.93 J 15.8 Hz, 3, 33 phenylamino)-fmethyl)- 1) .1CJ=76H,1) .2Ci=88H,2) phenl).arylaide 6.55 (bs, 2H), 4.99 Cbs, 2H), 4.46 Cd, J 5.9 Hz, 2H), 4.35 J 5.9 Hz, 2H) H 'H NMR (300 MHz, DMSO-dr 6 8 (ppm): 9.50 Cs, 1H), N P-Amino-phenyl)-3 7.65 Cd, J 8.2 Hz, 2H), 7.61 Cd, J 15.4 Hz, IH), 7.47 53 H H 14phelio).mthlJ Cd, J 7.6 Hz, 2H), 7.43 Cm, 1H), 6.93 Cd, J 7.0 Hz, 1H), 3, 33 phenamio)4ethll-6.79 Cd, J 15.4 Hz, IH)R 6.68 Cm, 3H), 6.59 Cm, 3H), phnl-crlmd 5.24 Cbs, 2H), 4.31 Cs, 2H).
H '-mn-hey~ H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.37(s, 1H), 7.63 NNJ.(4(-Amio-pei- J 8.2 Hz, 2H), 7.60 Cd, J 15.4 Hz, 1H), 7.47 Cd, J 409 554 N CH OH H ph4-.tC4 o-f neuoro 7 6 Hz, 2H), 7.41 Cm 1H), 7.016.90 Cm 4H), 6.75 Cd, J 3, 33 Fphenylcylami eyl 76 Hz, LH) 6.67-6.59 Cm 3H), 6.27 bs, 4.95 bs, F pheyl(-crylmide 2H), 4.27 Cs, 2H).
2006252047 14 Dec 2006 Ex. Cpd W Y Z R Name Characterization Schm H T 1 NMR (300 MHz, CD 3 OD) 6 (ppm): 7.64 J 15.9 N N{2.Amino-phenyl3 Hz, 1H), 7.47 J 7.5 Hz, 2H), 7.32 J 7.5 Hz, 2H), 410 555 C H OH H 144(3-methylsuffany- 7.19 J 7.5 Hz, 1H), 7.03 Ct, J 7.8 Hz, 1H), 6.82 33 phenylamino)-rethyll- J 7.5 Hz, 1H), 6.77 J 7.8 Hz, 1H), 6.70 J 15.9 phenyli-acrylamide Hz, 1H), 6.56 J 7.8 Hz, 1H), 6.49 1H), 6.37 J SMe 7.8 Hz, 1H), 4.29 2H), 4.05 Cbs, 4H), 2.37 3H).
'H NMR (300 MHz, DMSO-d 6 6 (PPM): 9.36 1H), H N.(2-Amino-phenyIl3 7.57 Cd. J 7.5 Hz, 2H), 7.53 Cd. J 15.8 Hz. 1H). 7.40 {4.f4-methylsulfany J 7.9 Hz, 2H), 7.34 J 7.9 Hz, 1H), 7.07 J 411 556 C H OH H peyaiomtq-8 3Hz, 2H), 6.92 Cd, J 7.5 Hz, 1H), 6.87 Ji 15.8 Hz, 3, 33 phenylamino)-mmieth 1H), 6.75 J 7.9 Hz, 1H), 6.60-6.54 Cm, 3H), 6.39 J MeS phnl-cyaie 5.7 Hz, 1H), 4.93 (bs, 2H), 4.29 J 6.1 Hz, 2H), Cs, 3H). H 'H NMR (300 MHz, DMSO-dr) a (ppm): 9.36 1H), N N....~.,-N{2Amino-phenyl)-3 8.02 J 1.7 Hz, 1H) 7.57-7.50 (in, 4H), 7.38-7.32 (in, 412 557 OH OH H (44(5-bromo-pyridin-2- 4H), 6.92 Cd, J 7.5 Hz, 1H), 6.86 Cd, J 16.3 Hz, 1H), 3, 33 ylamino).fnethyfl- 6.75 Cd, J 7.9 Hz, 1H), 6.59 Kd J 7.5 Hz, 1H), 6.53 Cd, Br I DII phenyll-acrylamide J 9.2 Hz, 1H), 4.94 Cbs, 2H), 4.48 Cd J 5.7 Hz, 2H). H 'H NMR (300 MHz, DMSO-d 6 6 (PPM): 9.37 1H), N 4 2-min-henI3- 8.25 Cm, IH), 7.76 Cm, 1H), 7.57 Cm, 2H), 7.47 (mn, 4H), OH H H[44naphthalen-1- 7.33 Cd, J 7.0 Hz, 1H), 7.17 Cm, 1H), 7.07 J 8.2 Hz, 413 558 C CHHylaininomethyl- 1H), 6.99 Ct, J 5.3 Hz, 1H), 6.92 Cd, J 7.0 Hz, 1H), 3, 33 phenfl-arylaide 6.85 Cd, J 16.4 Hz, LH), 6.74 Cd, Ji 7.6 Hz, 1H), 6.57 Ct, pheny-acryamide J 7.6 Hz, 1H) 6.36 Ct, J 7.6 Hz, 1H) 4.90 Cs, 2H), Cd, J 5.3 Hz, 2H).
H 'H NMR (300 MHz, DMSO-de) 6 (ppm): 9.39 Cs, 1H), F N W2-Ainino-phenyl)-3 7.57 Cd, J 7.0 Hz, 2H), 7.53 Cd, J 15.4 Hz, 1H), 7.40 414 559 OH OH H (44C34Iluoro- CK J 7.6 Hz, 2H), 7.36 Cd J 7.6 Hz, 1H), 7.02 J 33 phenylainino).methyll- 7.6 Hz, 1H), 6.90 Cm, 2H), 6.76 Cd, J 8.2 Hz, 1H). 6.58 phenyl)-acrylamide Cm, IH)K 6.40 Cd, J 8.2 Hz, I1H), 6.29 2H), 4.90 Cs, 1H), 4.29 bs, 2H), 4.02 Cs, 2H). 2006252047 14 Dec 2006 Ex. Cpd W I Z R Name Characterization Schm MeO 0 M(2-Amino-phenyl)-3-13,5- 'H-NMR (CDCI 3 8 (ppm): 7.73 (bs, 1H), H NH dimethoxy4-[(3,4,5- 7.63 J 14.9 Hz, 1H), 6.81 3H), 6.70 415 5M N trimethoxyphenylamino)- 2H), 6.6&6.56 2H), 6.07 2H), 4.35 M qOMeimethoxy-phnmio) 2H), 3.86 6H), 3.81 6H), 3.75 (s, me e methylj-phenyl)-acrylamide 3H).
Ex. Cpd W YIZI R Name Characterization Schm 'H NMR (300 MHz, CDCI 3 8 (ppM): 9.22 (s, 0N-2-Amino-3-hydroxy- 1H), 9.11 1H), 7.57 J 7.9 Hz, 2H), NH phenyl)3-(4-U3,4,5- 7.64 J 15.8 Hz, 1H), 7.44 J 7.9 Hz, 416H561 MeO N )-nNH 2 2H), 6.96 J 15.8 Hz, 1H), 6.78 J 7.9 trimethoxy-phenylamino)- Hz, 1H), 6.23 Ct, J 7.9 Hz, 1H), 6.16 J MeO XOH methyll-phenyl)- 7.9 Hz, lH), 6.09 J 6.2 Hz, 1H), 5.89 (s, OMe acrIamide 2H), 4.77 (bs, 2H), 4.27 J 5.7 Hz, 2H), 1 5.89 6H), 5.76 3H).
Ex. Cpd W Y Z R Name Characterization Schm 'H NMR (300 MHz, CDCI 3 8 (ppm): 8.25 (s, OMe 1H), 7.74 J 15.5 Hz, 1H), 7.44 J H -N(2Amino-phenyl-3-(4- 7.9 Hz, 2H), 7.37 J 7.9 Hz, 2H), 7.34- 417562 N [(2,3,4-trimethox- 7.29 2H), 7.08 7.5 Hz, 1H), 6.82 (t, phenylamino)-methyl. J 7.5 Hz, 1H), 6.79 1H), 6.66 J MeO~ phenyl)-acrylamide 15.5 Hz, 1H), 6.60 J 8.8 Hz, 1H), 6.31 J 8.8 Hz, 1H), 4.36 Cs, 2H), 4.18 (bs, 2H), 3.98 Cs, 3H), 3.96 3H), 3.84 3H).
OMe 'H NMR (300 MHz, CDCI 3 8 (ppm): 8.58 (s, '6 OMe N(2-Amino-pheny-3-[4{(4. 1H), 7.66 J 15.4 Hz, 1H), 7.33-7.28 (m, 418 5methoxy-3-I(3,4,5 3H), 7.23 Cd, J 7.0 Hz, 2H), 7.04 J 418 563 HNWe CH( CH H triiethoxy-phenylamino)- Hz, 1H), 6.77-6.70 4H), 6.64 J 15.4 3, 33 NH methyll-phenylaminol- Hz, 1H), 6.53 J 7.5 Hz, LH), 5.90 2H), I "methyl)-phenyll-acrylamide 4.27 2H), 4.25 2H), 4.08 (bs, 4H), 3.82 MeO s, 6H), 3.77 Cs, 6H).
2006252047 14 Dec 2006 Ex. Cpd W Y Z R Name Characterization Schm o 1 H NMR (300 MHz, CDCI 3 )5 (ppm): 7.64 (d, H NH N42,3-Diamino-phenyl)-3- J 15.4 Hz, 7.48 J 7.5 Hz, 2H), 4954 e NNH 2 14-[(3,4,5-trimethoxy- 7.35 J 7.5 Hz, 2H), 7.31-7.24 Cm, 2H), 419 5phenylaminomethyRl- 6.86 1H), 6.73 J 15.4 Hz, 1H), 5.84 Me NH 2 phenyll-acrylamide 2H), 4.27 2H), 4.00 bs, 6H), 3.71 (s, OMe 6H), 3.68 Cs, 3H).
Ex. Cpd W Y Z R Name Characterization Schm 'H-NMR (DMSO- 6 8 (ppm): 9.38 (bs, 1H), 7.58 J 7.5 Hz, 2H), 7.54 J 15.4Hz, H N2-Amino-phenyl)-3-(4-[(3- I1H), 7.40 J 7.9 Hz, 2H), 7.33 J 7.9 40565F N OH OH H fluoro4-methylsulfanyl- Hz, 1H), 7.14 Ct, J 8.3 Hz, 1H), 6.94-6.89 3
H
3 C, rXI:: phenylamino)-methyl 2H), 6.81 J 15.7 Hz, LH), 6.74 J S phenyll-acrylamide 8.3 Hz, 1H), 6.58 J 7.5 Hz, 1H), 6.43- 6.38 2H), 4.94 (bs, 2H), 4.30 Cd, J 5.7 Hz, 2H). 2.28 3H).
'H-NMR (DMSO-d 6 5 (ppm): 9.39 (bs, 1H), F Nq2-Amino-phenyl)-3-j4-[(4- 7.59 J 7.9 Hz, 2H), 7.54 Cd, J 15.8Hz, F H N H methylsulfanyl-3- IH), 7.41 J 7.9 Hz, 2H), 7.36 J 7.9 421 566 F J CH CH H trifluoromethyl- Hz, 1H), 7.33 J 6.2 Hz, 1H), 6.96-6.90 3, 33 phenylaminorethyl- Cm, 4H), 6.82 Cd, J 15.8Hz, 1H), 6.79-6.74 S phenyll-acrylamide Cm, 1H), 6.58 J 7.5 Hz, 1H), 4.95 (bs, 2H), 1 _4.35 J 6.2 Hz, 2H). 2.35 Cs, 3H).
Ex. Cpd W V Z R Name Characterization Schm 'H-NMR (DMSO-d 6 8 (ppm): 9.50 Cs, 1H), 0 8.09 Cs, 1H), 7.80 J 15.4 Hz, 1H), 7.81 NN NH N2-Amino-phenyl)-3-(3- Cs, 2H), 7.34 J 7.9 Hz, 1H), 6.94 J MaO N N NH, nitro-4-[3,4,5-trimethoxy- 7.5 Hz, 1H), 6.88 J 15.4 Hz, LH), 6.76 4 phenylamino)-methyll- Cd, J 7.9 Hz, 1H), 6.58 J 7.5 Hz, 1H), 0 NH2 phenyl)-acrylamide 6.26 Ct, J 6.2 Hz, 1H), 5.90 Cs, 2H), 4.96 Cbs, OMe 2H), 4.39 Cd, J 5.7 Hz, 2H), 3.66 Cs, 6H), 13.51 s, 3H).
128 2006252047 14 Dec 2006 Ex. Cp W Y IZ R Name Characterization Schm 0 'H-NMR (DMSO-d 6 8 (ppmn): 9.29 1H), H 2 NH N2amino-pheny)-33 7.72 J 15.4 Hz, 1H), 7.33 (in, 2H), 6.90 423568 MeO N j>NH 2 ario4(,45 1) 6.71 (2H) 6.62 (3H) 5.97 (1 H) 5.87 3, 33 42356 trimnethoxy-phenylamino- (2H) 54 2),49 (H .0(1i MeO 2 mnethylj-phenyll-acrylamnide (H .9(H .6(H .0(H O~e (6H) 3.51 (3H).
0 N H N 4 m noN .n y Y 424 569 N- 6N iNH2 N34-Ameo-phey)-6 LRS ac 7.,found: 376.4 3,
H
3 pyridin-3-yl-acrylamide 3 H-0
H
2 N 'H-NMR (DMSO-d6), 8 (ppm): 9.64 (bs, LH), 7.65 J=7.9 Hz, 2H), 7.60 J=14.0 HZ, CH N~ N-4-Amino-thiophen-3-y)- I1H), 7.50 J=7.9 Hz, 2H), 6.90 J= 15.'8 3 425 570 HC 0 s 3-(44(4.rnorpholin-4-yl- Hz, 1H), 6.15 J=4.0 Hz, 1H), 5.95 2H), 3 0 phenylamino)-rnethyl]- 5.82 1H), N 0 -1H phenyll-acrylamide 4.89 (bs, 2H), 4.33 J=5.7 Hz, 2H), 3.71 6
H
3 C-0 6H), 3.57 129 Br KCO 3 IDMF SAiW SArW BOPI SAiW WArSH o LiOHxH 2 OI ,2-Phefle4kdinine 12 COOMeNSlOMF/1OQC COOMC H 2 0/MtOH DMF/t3N N 121 122 DMF COOH NN C1I 0)i UOHxH, 2 0i TBM. Nal. H,O/MeOH
K
2
C
3 ~COOMC DMF Et 3 N. DMF WArSfi 124 1 Example xa7 18 WArS 18N >_S I19O:WArS= H S Example N-(2-Amino-phenyl)-4-( 1 H-benzimidazol-2-ylsulfanylmethyl)-benzamide (compound 126) Step 1: 41HBenzimidazo[2-vlsufanvlmethvl)-benzoic acid methyl ester (compound 122) [0211] Following the procedure described in Example 47, step 2, but using 119 and substituting 121 for 63, the title compound 122 was obtained in 95% yield. LRMS 299.1 Step 2: N(2-Amino-Dhenvl)4-1 Hbenzimidazol-2-vlsulfanvlmethvl)-benzamide (126) (0212] Following the procedure described in Example 1, steps 4 and 5, but substituting 122 for 6, the title compound 126 was obtained in 62% yield. 'H NMR: (DMSO-d 6 5 (ppm): 9.57 1H), 7.89 J= 8.2 Hz, 2H), 7.55 J 8.2 Hz, 2H), 7.53 (bs, 2H), 7.36 (bs, 2H), 7.14-7.08 3H), 6.94 J 8.2 Hz, 1H), 6.74 J 6.9 Hz, 1H), 6.56 J 8.0 Hz, 1H), 4.87 (bs, 2H), 4.62 (s, 2H).
Example 87 N-(2-Amino-phenyl)-4-[6-(2-morphol in-4yl-ethylamino)-benzothiazol-2-yisulfanyimethyl]benzamide (compound 128) Step 1: 446-Amino-benzothiazol-2-vlsulfanlmethvl)-benzoic acid methyl ester (122) (0213] Following the procedure described in Example 47, step 2, but using 120 and substituting 121 for 63, the title compound 122 was obtained in 45% yield. LRMS 331.0 130 C1 Step 2: 446A2-Moriholin-4-vl-ethylamino)-benzothiazo 2vlsulfanvlmethl1-benzoic acid methyl ester (compound 124) [0214] To a solution of 446-Amino-benzothiazol-2-ylsulfanylmethyl)-benzoic acid methyl ester 122 (800 mg, 2.42 mmol), in DMF (24 mL), were added successively solid 442-chloroethyl)morpholine hydrochloride (296 mg, 2.66 mmol), K 2 C0 3 (611 mg, 5.08 mmol), Nal (363 mg, 2.42 mmol), Et 3
N
(370 1 LL, 2.66 mmol) and tetrabutylammonium iodide (894 mg, 2.42 mmol), The mixture was stirred Ni at 120*C for 24h and more 442-chloroethyl~morpholine hydrochloride (296 mg, 2.66 mmol) was Ni added. The mixture was stirred for 8h at 120'C and the solvent was removed in vacuo. The 0 resulting black syrup was partitioned between H 2 0 and EtOAc. The organic layer was successively C] washed with H~l IN and saturated aqueous NaHCO 3 The precipitate was extracted twice with EtOAc, dried over MgSO 4 and concentrated. Purification by flash chromatography (MeOH/CHC 3 5:95 to 10:90) afforded 48 mg yield) of 124 as a light yellow oil. LRMS 444.1 1).
Step 3: N.(2-Amino-ohenvl)4-[642-moriholin-4-vl-ethlamino)-benzothiazol-2vlsulfanli nethyllbenzamide (compound 128) [0215] Following the procedure described in Example 1, steps 4 and 5, but substituting 124 for 6, the title compound 128 was obtained in 76% yield. 'H NMR: (Acetone-d 6 8 (PPM): 9.06 (bs, 1H), 7.98 J 8.2 Hz, 2H), 7.63 J 8.5 Hz, 2H), 7.62 J 8.8 Hz, 2H), 7.29 J 8.0 Hz, 1H), 7.06 J 2.2 Hz, 1H), 7.02-6.97 (in, 1H), 6.87-6.82 2H), 6.66 (dt, J 7.4 Hz, 1.4 Hz, 1H), 4.63 2H), 3.64-3.60 4H), 3.25 J 6.3 Hz, 2H), 2.63 J =6.3 Hz, 2H), 2.54-2.42 4H).
129 BrCO/Pd(AcO) 2 /dppf +DMFfl2C 01100C M /D CN
S
IN Ph(NH 2 2 19Br 130 HIiNL Example 88 131 Example 88 N-(2-Amino-phenyl)-4-(quinolin-2-ylsulfanylmethyl)-benzamide (compound 131) Step 1: 244-Bromo-benzvlsulfanvl)-auinoline (coingound 130) (0216] Following the procedure described in Example 47, step 2, but substituting 129 for 63, the title compound 130 was obtained in 89% yield. LRMS 332.0 1).
Stev 2: NA2Amino-ohenyl)-44auinolin-2-ylsulfanylmethyl~beflzamide (131) [0217] Following the procedure described in Example 40, step 2, but substituting 129 for 42, the title compound 131 was obtained in 70% yield. 11H NMR: (DMSO-d 6 8 (PPM): 9.62 (bs, 1H), 8.21 J 8.8 Hz, 1H), 8.00-7.89 (in, 4H), 7.79 (dd, J 6.8 Hz, 1.3 Hz, 11H), 7.68 J 6.3 Hz, 2H), 7.56 J 6.8 Hz, 1H), 7.44 J 8.7 Hz, 1H), 7.17 J 8.2 Hz, 1H), 6.99 (dt, J 7.9 Hz, 7.4 Hz, 1H), 6.79 J 6.9 Hz, 1H), 6.61 (dt, J 7.7 Hz, 7.4 Hz, 1H), 4.69 2H).
cI0 0 1 LiOHIH2O:MeOH 0 N DMFIE' 3 N N N OeDMFNN
NPHN
132H 2. BOPIPh(NH 2 2 HN H NH 2 13313 CH 3 CN.EtUP 0 EwtpWe 89 Example 89 N-(2-Amino-phenyl)-4-(pyrimidin-2-ylaminomethyl)-beflzamide (compound 134) Step 1: 4-Pvrimidin-2-laminomethyl)-benzoic acid methyl ester (comp~ound 133) [0218] Following the procedure described in Example 47, step 2, but substituting 132 for 63, the title compound 133 was obtained in 76% yield. LRMS 244.2 1).
Step 2: N.2-Amino-henvl)4Dv)rimidin-2-laminoinethyl)-benzamide (134) [0219] Following the procedure described in Example 1, steps 4 and 5, but substituting 129 for 6, the title compound 134 was obtained in 91% yield. 'H NMR: (DMSO-d 6 8 (PPM): 9.6 (bs, 1H), 8.32 J 4.9 Hz, 2H), 7.97 (dt, J 9.9 Hz, 7.9 Hz, 2H), 7.85-7.83 1H), 7.47, J 8.2 Hz, 2H), 7.20 J 7.9 Hz, 1H), 7.01 (dt, J 7.7 Hz, 7.4 Hz, 1H), 6.82 J 7.9 Hz, 1H), 6.66-6.62 (mn, LH), 4.98 (bs, 2H), 4.61 2H).
01.
BGC
2 0
NQ
H
2 N- 2. 4-Iodobenzoic acid H Ho N11 2 EDCI, HO~t, Et 3 N ie 13 PdCI 2 (dppo), CO, i-Pr 2 EtN c-i DIBAL-H N~j HOn NR 13 NHBoc DEAD, Ph 3
P
Het-SH 0< TFA N N II HetS N 2 Hets H- NHBoc 138Example 90 :139 Het=
N
Example N-(2-Amino-phenyl)-4-( 1-methyl-i H-imidazol-2-ylsulfanylmethyl]-benzamide (compound 139) Step 1: [24odo-benzovlamino)-ohenyll-carbamic acid tert-butvl ester (compound 135) (0220] To a solution of di-tert-butyldic arbon ate (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 vacua. The crude material was partitioned between EtOAc and water. The organic layer was washed with HCI 1 N and then with aqueous saturated NaHCO 3 The combined organic layers were washed with brine, dried over MgSO 4 and concentrated affording the compound (18.9 g, 65% yield) as a light beige powder. LRMS 209.1 [0221] To a solution of 4-iodobenzoic acid (8.0 g, 32.3 mmol) in DMF (65 mL) at 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 (2amino-phenyl)-arbamic acid tert-butyl ester (6.3 g, 30.2 mmol) in DMVF (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
IO
0 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 MgS0 4 and concentrated to a light brown syrup which was crystallized in hot EtOAc or Et20, yielding 135 (9.3 g, yield) as a white solid. LRMS 461.0 (M+Na).
Step 2: N[2-tert-butoxvcarbonvlamino-phenvl)-terephtalamic acid methyl ester (compound 136) [0222] Following the procedure described in Example 40, step 2, but substituting 135 for 42, the title compound 136 was obtained in 95% yield. LRMS 393.1 C Step 3: [2(4-Hvdroxvmethvl-benzovlamino)-phenvll-carbamic acid tert-butvl ester (137) [0223] To a solution of 136 (7.5g, 20.6 mmol) in THF (40 mL), cooled down to -20°C under N 2 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 0 C and carefully quenched by a dropwise addition of H 2 0 (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 HCI (6 times), satd. aqueous NaHCO 3 brine, dried over MgS0 4 and concentrated (2.04 g, 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 Step 4: 12-4-(1-Methl-imidazol-2-ylsulfanvlmethvl)-benzovlaminol-phenyl-carbamic acid tert-butvl ester (compound 138) [0224] To a solution of Nmethyl-2-mercaptoimidazole (28 mg, 0.25 mmol) in THF (1 mL), at r.t.
under N 2 atmosphere were successively added 137 (70 mg, 0.20 mmol), triphenylphosphine 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/CHCl3 (5:95) as the eluent afforded the title compound 138 (81 mg), in 91% yield, which was found to contain some diethyl hydrazodicarboxylate residus. The compound was used as is without further purification.
Step 5: M2-Amino-phenyl)-441-methl-1H-imidazol-2-vlsulfanylmethyll-benzamide (compound 139) [0225] Following the procedure described in Example 42, step 3, but substituting 138 for 46, the title compound 139 was obtained in 62% yield. 'H NMR: (Acetone-d 6 8 (ppm): 9.07 (bs, 1H), 7.93 J 8.2 Hz, 2H), 7.37 J 8.2 Hz, 2H), 7.29 J 8.0 Hz, 1H), 7.10 J 1.1 Hz, 1H), 7.03-6.96 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 2H), 3.42 3H).
cIN S Pd(PPh3)S aclNa2CO3 H Cl' N N114 OMe Example 91 Example 91 *j N(2-Amino-phenyl)-6-(3-methoxyphenyl)-nicotinamide (compound 141) ci [0226] To a mixture of 3-methoxyphenyl boronic acid (152 mg, 1.0 mmol) and 140 (248 g, cImmol) were added benzene (8 mL) and ethanol (4 ml-) followed by 2 M Na 2
CO
3 aqueous solution (3.2 S mL, 6.4 mmol). The reaction mixture was stirred under nitrogen for 30 min and then Pd(PPh 3 4 (58 c- 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 (MgSO 4 and concentrated. Purification by flash silica gel chromatography (Hexane/Ethyl acetate: 1/1) afforded 141 (302 mg, 95% yield). 'H NMVR (CDCI 3 (ppm): 9.11 J 1.8 Hz, 8.30 (dd, J 8.4 Hz, 1.8 Hz, 11H), 7.57 J 8.4 Hz, 7.52- 7.47 (in, 11H), 7.36 (in, 7.22 (in, 11H), 7.09-6.78 (in, 3.84 3.39 (br s, 2H-).
0 a
HN~
a CHO- OHN 142 4 o14 o Example 92 a. p-amrinomethylbenzoic acid/AcOHI5 min/reflux b. HOBTIEDC/1,2-diamino benzene Example 92 N-(2-Amino-phenyl)-4-( 1-oxo- 1,3-dihydro-isoindol-2-ylmethyl)-benzamide (compound 144) Step 1: 441Oxo-1.3dihydro-isoindol-2vlmethl-benzoic acid (coigound 143) [0227] To a solution of benzene- 1, 2-carbaldehyde 142 (1.0 g, 7.46 minol) in 10 mL of acetic acid was added 4-aminomethylbenzoic acid 13 g, 7.46 inmol). The reaction mixture was refluxed min and cooled to the room temperature. A crystalline precipitate was formed and triturated with
CH-
2
CI
2 to produce the title compound 143 (1.29 g, 49%).
SteiD 2: N-(2-Amino-ohenyl)-441-oxo-1 .3-dihydro-isoindo 2-vlmethvl)-enzamide (comp~ound 144) [0228] To a solution of the carboxylic acid (0.32 g, 0.89 inmol) in DMF (8 mL) at rt, was added HO~t 16 g, 1. 15 inmol) and EDC (0.25 g, 1.33 minol) and the solution was stirred for 1.5 h.
ON
Lastly, phenylenediamine (0.12 g, 1.07 mmol) was added and the mixture was allowed to stir for 18h. DMF was removed in vacuo and the crude was partitioned between ethyl acetate and H 2 0. The organic layer was dried over Na 2 S04 and concentrated. Purification by column chromatography
(CH
2 CIMeOH afforded 144 in 46% yield. 'H NMR: (DMSO-d 6 D 9.71 1H), 7.46 J Hz, 2H), 7.80 J 8.0 Hz, 2H), 7.55-7.70 3H), 7.46 J 8.2 Hz, 2H), 7.20 J 7.7 Hz, 1H), 7.02 J 7.7 Hz, 1H), 6.83 J 8.0 Hz, 1H), 6.65 J 7.4 Hz, 1H), 4.93 (bs, 2 4.87 2 4.47 2H).
0 a C a, b L(A N
H
0150 O0H 1400 0~ 149z Example 94 d e, bON e~b NH- 2 0151 OWt 152~ 152 Example a. p-aminomethylbenzoic acid/AcOH/reflux/3 hrs b. HOBTIEOC/1,2-diamno benzene c. 4-(2-aminoethyl)phenol/AcOH/5 hrsrefiux d. PhNTf 2 /NaHITHF-DMF/30 minOo 0
C
e. 1. COIPd(OAc) 2 /dppfEt 3 N/MeOH-DMF/4 daysf75 0
C
2. AcOHHCI/3 hrstrefiux Example 94 N-(2-Amino-phenyl)- 4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzamide (compound 149) [0229] Phthalic anhydride 148 (1.3 g, 8.9 mmol) and 4-aminomethylbenzoic acid in 20 mL acetic acid were refluxing for 3 h, cooled to the room temperature and evaporated to yield a solid residue which was triturated with water, filtered off and dried to produce the intermediate carboxylic acid (1.7 g, LMRS 282.0 [0230] Following a procedure analogous to that described in Example 92, step 2, but substituting the acid for 143, the title compound 149 was obtained in 17% yield. 'H NMR: (DMSO ds) O 9.59 1H), 7.82-7.91 6H), 7.40 J 8.0 Hz, 2H), 7.11 J 7.7 Hz, 1H), 6.93 J 7.7 Hz, 1H), 6.73 J 8.0 Hz, 1H), 6.55 J 7.4 Hz, 1H), 4.83 (bs, 4H).
136 Example N4-(2-Amino-phenyl)-4-[2-( 1,3-dioxo- 1,3-dihydro-isoindol-2-yI)-ethyl]-benzamide (compound 152) Step 1: 2-[244-Hvdroxv-o~henvl)-ethvllisoindole-1.3-dione (compound 150) [0231] Following a procedure analogous to that described in Example 94, step 1, but substituting 4-aminomethylbenzoic acid for tyramine the title compound 150 was obtained in 48% yield. LMVRS 268.0 1).
Step 2: 442-( 1. 3-dioxo-1 .3-dihvdroisoindol-2-vl)ethl)-iDhenyI trifluoromethane-sulfonate (151) [0232] To a solution of sodium hydride (90 mg, 25 mmol) in dry THF (20 mL) at 0 0 C, 150 (500 ci 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 0 C, treated portionwise with PhNCTf) 2 stirred for additional 2 h and evaporated to produce a solid material which was purified by chromatography on a silica gel column, (CH 2
CI
2 MeOH (19: to provide 151 (639 mg, 86% yield). LMVRS 400.0 Step 3: 1V2-Amino-ohenvl)-4-[241 .3-dioxo-1 .3-dihydro-isoindol-2-vl)-ethvll-benzamide (compound 152) [0233] Following a procedure analogous to that described in Example 40, step 2, but substituting 151 for 42, the title compound 152 was obtained in 15% yield. 1 H NMR: (DMSO dQ D 9.57 1H), 7.78-7.87 Cm, 6H), 7.31 Kd J =8.0 Hz, 2H), 7.12 Cd J 7.7 Hz, 1H), 6.93 J 6.9 Hz, 1H), 6.74 (d J 8.0 Hz, 1H), 6.56 J =7.4 Hz, 1H), 4.83 Cbs, 2 3.85 Ct, J =7.1 Hz, 2 H), 3.00 J 7.1 Hz, 2 H).
0 0 ab. d(X C) a ll- NH.
'153 H Example 96 154 (X .C) 0 Eicample9T: 155(XcN) 0 0 N e,d <N 'N.y N H
H
NH
2 O e. f,g. d (C CH 3 K'N--O H 2 Example 98: 157 (Y aH) Example 99 :158 (YVa CH 3 h. d 0 a. p-aminometho4benzaic acddIH 2 OIEt 3 NI3 hrs/40 0
C
b. HcooHrefluxJ6i his
NH
2 c NaNO 2
/HCIO
0 C/2 hrs, then rt/Il2 his Me I d.HBIDI diamino benzene N e CIOOMeIKOH/2 hrs, QoC
RI/K
2
CO
3 IOMF/fl 0 g. NaOHIMeOHJH 2 0 Example 100 159 h. AC 2 0/1 hour/reflux then AcOH/48 hrslreflux 137
IO
c Example 96 U N-(2-Amino-phenyl)-4-(4-oxo-4H-quinazolin-3-ylmethyl)-benzamide (compound 154) [0234] A suspension of 4-aminomethyl benzoic acid (1.00 g, 6.60 mmol) in water (20 mL) was treated with Et 3 N (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 0 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 N solid, which was triturated with water and filtered off to provide the carboxylic acid (1.61 g, 96%).
N LMRS 281.0 0 [0235] Following a procedure analogous to that described in Example 92, step 2, but N substituting the carboxylic acid for 143, the title compound 154 was obtained was obtained in 43% yield. 'H NMR: (DMSO d) 0 9.71 1H), 8.68 1H), 8.23 J=8.0 Hz, 1H), 8.01 J 8.0 Hz, 1H), 7.92 J 8.0, 2H), 7.78 J 8.0 Hz, 1H), 7.63 J 7.4, 1H), 7.55 J 7.7 Hz, 2H), 7.22 J 7.4 Hz, 1H), 7.04 J 7.1 Hz, 1H), 6.85 J 8.0 Hz, 1H), 6.67 J 7.4 Hz, 1H), 5.35 2 H).
Example 97 N-(2-Amino-phenyl)-4-(4-oxo-4H-benzo[d][1,2,3]triazin-3-ylmethyl)-benzamide (compound 155) [0236] A suspension of 4-aminomethyl benzoic acid (1.00 g, 6.60 mmol) in water (20 mL) was treated with Et 3 N (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 0 C and cooled to 0 0 C. The cold reaction mixture was acidified with conc. HCI (5 mL) and treated drop wise with NaN02 solution (520 mg, 7.5 mmol in 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 1).
[0237] Following a procedure analogous to that described in Example 92, step 2, but substituting the carboxylic acid for 143, the title compound 155 was obtained in 27% yield. 'H NMR: (DMSO ds) D 9.62 1H), 8.25 J 6.7 Hz, 2H), 8.11 (ddd, J 7.1 Hz, 1.4 Hz, 1H), 7.93-7.98 3H), 7.49 J 8.2 Hz, 2H), 7.13 J 7.7 Hz, 1H), 6.94 J 8.0 Hz, 1H), 6.75 J Hz, 1H), 6.57 J 7.7 Hz, 1H), 5.66 2 4.87 (bs, 2 H).
138 Example 98 o N-(2-Amino-phenyl)-4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide (compound 157) Step 1: 4-[(2-Amino-benzovlamino)-methyl-benzoic acid (compound 156) [0238] To a suspension of 4-aminomethylbenzoic acid (5.09 g, 33.7 mmol) in H 2 0 (50 mL), was S added Et 3 N (4.7 mL, 33.7 mmol) followed by isatoic anhydride 153 (5.0 g, 30.6 mmol). The brown 0 cN mixture was heated at 40°C for 2 h until the mixture became homogeneous and then Et 3 N was CN removed in vacuo. The resulting aqueous solution was acidified (10% HCI/H 2 0) and the mixture was 0 partitioned between H 2 0 and ethyl acetate. The combined organic extracts were dried over Na 2 S0 4 N filtered and evaporated to give 156 as a white solid (6.0 g, 72 LMRS 271.0 Step 2: N(2-Amino-phenvl)4-(2.4-dioxo-l,4-dihvdro-2H-quinazolin-3-vlmethvl)-benzamide (compound 157) [0239] The carboxylic acid 156 (1.72 g, 6.36 mmol) was suspended in a solution of NaOH (2.55 g, 63.6 mmol) in H 2 0 (12 mL). To this solution was added dioxane (10 mL) until mixture became homogeneous. The solution was cooled to 0 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 mL) and H 2 0 (20 mL). The solution was heated to 50 0 C for 1 h. until the cyclization was complete.
Methanol was removed in vacuo and then the aqueous layer was extracted with ethyl acetate.
Subsequently, the aqueous phase was acidified (10% HCI/H 2 0) and extracted with ethyl acetate (2 X 300 mL). These organic extracts were combined, dried over Na 2
SO
4 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, LMRS 319.0 (M+Na).
[0240] Following a procedure analogous to that described in Example 92, step 2, but substituting the quinazolinedione carboxylic acid for 143, the title compound 157 was obtained. 'H NMR: (DMSO-d 6 0 11.56 (brs, 1H), 9.59 (brs, 1H), 7.96-7.88 3H), 7.67 (dt, J 8.4, 1.4 Hz, 1H), 7.30 J 7.8 Hz, 2H), 7.21 J 7.5 Hz, 2H), 7.13 J 6.9 Hz, 1H), 6.92 (dt, J 6.9, 1.2 Hz, 1H), 6.75 J 6.9 Hz, 1H), 6.57 J 6.9 Hz, 1H), 5.15 (brs, 2H), 4.86 (brs, 2H).
139 Example 99 N-(2-Amino-phenyl)-4-(l1-methyl-2,4-dioxo-1 ,4-dihydro-2H-quinazolin-3-ylmethyl)benzamide (compound 158) Step, 2: 4A1.Methyl-2.4-dioxo-1.4-dihydro-2IH-uinazolin-3-ylmethyl~benzoic acid methyl ester [0241] To a solution of the quinazolinedione carboxylic acid (1.0 g, 3.38 mmol) in DMF (7 mL), was added K 2 C0 3 (1.4 g, 10. 1 mmol) and the mixture was then cooled to 0 0 C. Subsequently, Mel (1.05 mL, 16.9 mmol) was added and the mixture was allowed to warm to rt in the ice bath C1 overnight. Excess methyl iodide and DMVF were removed in vacuo and the crude was partitioned between ethyl acetate and H 2 0. The aqueous phase was washed again with ethyl acetate, the C1 combined organic extracts were dried over Na 2 S0 4 and then concentrated in vacuo to yield the desired product as an off-white solid (0.93 g, LMRS 325.0 SteD) 3: 4-41-Methyl-2 .4-dioxo-1 .4-dihydro-2-I-uinazolin-3-vlmethvl-benzoic acid [0242] 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 H 2 0. The aqueous phase was acidified (10% HCI/H20) and extracted with ethyl acetate (2 X 300 mL). These organic extracts were dried over Na 2
SO
4 and concentrated in vacua to afford product as a white solid 15 g, LMRS 311.0 (Mid1).
Step 4: NM2-Amino-phenvl)-4A 1 -methyl-? .4-dioxo-1 .4-dihydro-2-o-uinazolin-3-vlmethyl)-benzamide (comtoound 158) [0243] Following a procedure analogous to that described in Example 92, step 2, but substituting the carboxylic acid for 143, the title compound 158 was obtained in 10% yield. 'H NMR: (DMSO-d 6 8 9.59 (brs, 1H), 8.03 J 7.8 Hz, 7.89 J =7.8 Hz, 2H) 7.80 (dt, J 6.9, Hz, 1H), 7.49 Kd J =8.7 Hz, 1H), 7.42 J =8.1 Hz, 2H), 7.32 J =7.7 Hz, 1H), 7.13 Kd J 7.8 Hz, IH), 6.95 J =7.6 Hz, 1H), 6.75 Kd J =7.8 Hz, 1H), 6.57 J 7.5 Hz, 1H), 5.21 (brs, 2H), 4.86 (brs, 2H), 3.54 3H).
Example 100 N-(2-Amino-phenyI)-4-(2-methyl-4oxo-4H-ciuinazolin-3-ylmethyl)-beflzamide (compound 159) [0244] A suspension of 156 (903 mg, 3.34 mmol) in acetic anhydride (15 ml-) was heated at for 1 h. Acetic anhydride was evaporated under vacuum and the solid material formed was 140 dissolved in acetic acid (30 WL. This solution was refluxed 48h and evaporated to form another solid material, which was recrystallized from a mixture AcOEt/CHC 3 to produce the intermediate carboxylic acid (420 mg, 43% yield). LMRS 385.0 1).
(0245] 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. 'H NMR: (DMSO) 8 (ppm): 9.64 (bs, 1H), 8.17 (dd, J 8.0, 1.6 Hz, 1H), 7.95 J 8.2 Hz, 2H), 7.95 Ni (dd, J 8.8, 2.5 Hz, 1H), 7.84 (ddd, J 7.6, 7.0, 1.5 Hz, 11H), 7.64 Kd J 7.7 Hz, 1H), 7.53 (ddd, Ni J 7.6, 7.6, 1.1 Hz, 1H), 7.33 Kd J =8.2 Hz, 2H), 7.14 (dd, J 7.7, 1.1 Hz, 1H), 6.96 (ddd, J= 0 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, Ni 2H), 4.89 (bs, 2H) 2.5 3H, overlaps with the DMSO signals).
S
JjfNH2 (lM) 2 cS /DCM rT __Nmeo' C_2MeN HN S CO 2 Me MeOlo then NH 3 MeO 11 NBS 1.4-dioxae I0 H 161 H 2 0 -i 0 c to 8012M 1. LIOH THF H 2 0I 12phnlneim then HI-t ether BOP DMF TEA rT N AN5H 2 MeO'C 163 Example 101 Example 101 N-(2-aminophenyl)-2-(4-Methoxy-benzylamino)-thiazol-5-yl-amide (compound 163) Step 1: 4-Methoxybenzvkhiourea (compound 161) [0246] 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 0
C,
and the solution stirred from 0 0 C to 15 0 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 OTC and stirred at room temperature for 7 h. The solution was diluted with ethyl acetate (250 mW, washed with brine (2 x WL, dried (MgSO 4 filtered and concentrated. After purification by column chromatography (silica gel, elution 5% methanol in dichlorom ethane), 161 was obtained as yellow solid (700.2 mg, 3.6 mmol, 86% yield). 'H NMR: (Acetone-d 6 8 (ppm): 7.53 (bs, 1H), 7.28 J 8.8 Hz, 2H), 6.87 J 8.8 Hz, 2H), 6.67 (bs, 2H), 4.67 2H), 3.77 3H). LMRS 197.1 1).
IO
0 Step 2: 2-(4-Methoxvbenzvlamino)thiazole-5-carboxvlic acid methyl ester (compound 162) 0 [0247] A solution of trans methyl-2-methoxyacrylate (461 mg, 3.97 mmol, 1 equiv.) in 50% 1,4dioxane in water (4 mL) stirred at -10C, was treated with N-bromosuccinimide (792 mg, 4.46 mmol, 1.12 equiv.), stirred at the same temperature for lh, transferred to a flask containing the thiourea 161 (700.2 mg, 3.6 mmol) and the mixture was stirred at 80 0 C for 2h. After cooling down to room temperature, concentrated NH 4 0H (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 C1 mg additional (91 pure by HPLC) as residue from evaporation of the filtrated (ca. 77% overall yield). 1 H NMR: (Acetone-d 6 8 (ppm): 7.97 (bs, 1H), 7.72 (bs, 1H), 7.33 J 8.1 Hz, 2H), 6.90 (d, J 8.1 Hz, 2H), 4.52 2H), 3.78 3H), 3.75 3H). LMRS 279.1 Step 3: N2-aminoDhenvl)-244-Methoxv-benzvlamino)-thiazol5-vl-amide (compound 163) [0248] 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. 'H-NMR (methanol-d4), 8 (ppm): 7.86 1H), 7.29 J 8.8 Hz, 2H), 7.11 (dd, J 8.0 Hz, 1.4 Hz, 1H), 7.04 (dt, J 8.0 Hz, 1.4 Hz, 1H), 6.90 J 8.8 Hz, 2H), 6.86 1H), 6.74 (dt, J 7.4 Hz, 1.4 Hz, 1H), 4.85 (bs, 4H), 4.45 2H), 3.78 3H).
Examples 102-121 [0249] 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.
2006252047 14 Dec 2006 Table 4a Characterization of Compounds Prepared In Examples 102-121 WTN HNH2 Ex. Cpd W V Z Name Characterization Schm 102 164 me H CH CH N42-Amino-phenyt)-4- 'H NMVR: (Acetone-d 6 5 (ppm): 9.09 (bs, 1H), 7.99 J 11 [(3,4,5-trimethoxy- 8.2 Hz, 2H), 7.54 J 8.0 Hz, 2H), 7.29 J 7.7 Hz, MeO) f phenylamino)-mnethyl- 1 7. 00 Ct, J 6.6 Hz, 1 6.86 (dd, J 8.0 Hz, 1. 1 Hz, OMe benzamide 1H), 6.67 J= 8.0 Hz, 1H), 5.99 2H1), 5.46 (bs, 1H), 4.64 C(bs, 2H), 4.43 2H1), 3.69 6H), 3.60 103 165 CH NA-Amino-phenyl)-643- 'H NMR (20% CD 3 0D in CDCI 3 8 (PPM): 9.14 J 1.8 I hydoxymethyiphenyD- Hz, 1H), 8.33(dd, J 8.4 Hz, 1.8 Hz, 1H), 7.93 Cs, 1H), 7.82 YCHnicotinamide (in, 2H1), 7.50-7.40 Cm, 2H1), 7.22-6.45 Cm, 4H), 4.69 Cs, 2H).
104 166 rN CH CH N42-Amino-phenyl)-43- 1 H NMVR (CD 3 OD) 8 (ppm): 7.98 J 8.4 Hz, 2H), 7.65 J 1methoxy-phenyl- 8.4 Hz, 2H), 7.31-7.04 Cm, 5H), 6.92-6.80 Cm, 3H), 3.84 (s, OMe benzamide 3H).
105 167 NH CH N NA2-amino-phenyl)-6(4- 'H NMVR (DMSO-d 6 8 (PPM): 9.33 1H), 8.61 J 2.5 6 MeO101methoxy-benzylamino). Hz, 111), 7.89 (dd, J =8.8 Hz, 2.2 Hz, 1H), 7.57 J 5.8 HIz, nicotinamide 1H), 7.24 J 8.52 Hz, 2 7.11 Cd, J 7.69 Hz, 1H), 6.90 Cm, 3H), 6.73 J 8.0 Hz, 1H), 6.50-6.58 Cm, 211), Cs, 211), 4.45 J 5.8 Hz, 2H), 3.70 Cs, 106 168 NH CH N N42-amino-pheny)-6-[244- 'H NMVR (DMVSO-d 6 8 CPPM): 9.42 Cs, 111), 8.72 Cd, J 2.5 6 MeO methoxy-phenyl)- Hz, 1H), 7.97 (dd, J 8.8 Hz, 2.5 Hz, 1H), 7.23 Cm, 4H1), 6.81ethylaminoJ-riicotinamide 7.03 Cm, 4H), 6.64 Cm, 1H), 6.56 J 9.1 Hz, 111), 4.92 Cs, 3.78 Cs, 3H), 3.55 Cm, 2H), 2.85 Ct, J 7.3 Hz, 2H).
143 2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm 107 169 CH CH N2-Amino-phenyl)-4-[(4,6- 'H NMR: (DMSO-d 6 8 (ppm): 9.63 (bs, 1H), 7.95 J 7.9 11 MeO N N dimethoxy-pyrimidin-2- Hz, 2H), 7.85-7.82 1H), 7.48 J 7.9 Hz, 2H), 7.20 (d, N ylamino)-methyl]- J 7.1 Hz, 1H), 7.03 (dt, J 7.6 Hz, 7.4 Hz, 1H), 6.81 J OMe benzamide 7.9 Hz, 1H), 6.63 (dt, J 7.9 Hz, 7.7 Hz, 1H), 4.94 (bs, 2H), 4.54 J 6.0 Hz, 2H), 3.79 (bs, 6H).
108 170 CH CH N(2-Amino-phenyl)4- 'H NMR: (DMSO-d 6 8 (ppm): 9.62 (bs, 1H), 8.21 J 8.8 11 Ns (quinolin-2- Hz, 1H), 8.00-7.89 4H), 7.79 (dd, J 6.8 Hz, 1.3 Hz, 1H), M ylsulfanylmethyl)- 7.68 J 6.3 Hz, 2H), 7.56 J 6.8 Hz, 1H), 7.44 J benzamide 8.7 Hz, 1H), 7.17 J 8.2 Hz, 1H), 6.99 (dt, J 7.9 Hz, 7.4 Hz, 1H), 6.79 J 6.9 Hz, 1H), 6.61 (dt, J 7.7 Hz, 7.4 Hz, 1H), 4.69 2H).
109 171 N s N CH N(2-Amino-phenyl)-6-(4- 'H NMR: (DMSO-d 6 8 (ppm): 9.06 (bs, 1H), 8.17 (dt, J 12 o methoxy-benzylsulfanyl)- 10.9 Hz, 9.0 Hz, 1H), 7.46 J 8.5 Hz, 1H), 7.39 J nicotinamide 8.2 Hz, 2H), 7.21-7.13 2H), 7.01 (dt, J 7.6 Hz, 7.4 Hz, 1H), 6.91 J 8.5 Hz, 2H), 6.80 J 7.9 Hz, 1H), 6.62 J 7.4 Hz, 1H), 5.01 (bs, 2H), 4.47 2H), 3.76 3H).
110 172 s CH CH N2-Amino-phenyl-4- 'H NMR: (DMSO-d 6 8 (ppm): 8.01 J 8.0 Hz, 1H), 7.93 11 N (benzothiazo-2- J 8.2 Hz, 2H), 7.90 (dd, J 4.4 Hz, 0.6 Hz, 1H), 7.63 (d, ylsulfanylmethyl]- J 8.2 Hz, 2H), 7.48 (dt, J 8.0 Hz, 0.8 Hz, 1H), 7.37 (td, J benzamide 7.1 Hz, 1.1 Hz, 1H), 7.14 J 7.1 Hz, 1H), 6.96 J 6.3 Hz, 1H), 6.76 J 7.7 Hz, 1H), 6.58 J 6.6 Hz, 1H), 4.88 2H), 4.73 2H).
112 174 H CH N N2-amino-phenyl)-6-2-4- 'H NMR (DMSO-d 6 8 (ppm): 9.34 1H), 8.64 J 2.5 6 N fluorophenyl)-ethylamino]- Hz, 1H), 7.89 (dd, J 9 Hz, 2 Hz, 1H), 7.16-7.22 (m 3H), F nicotinamide 7.06-7.20 3H), 6.906.96 1H), 6.72-6.78 1H), 6.46-6.60 2H), 4.92 2H 3.50 2H), 2.92 2H).
113 175 I- N CH N N(2-amino-phenyl)-6-(4- 'H NMR (DMSO-d 6 8 (ppm): 9.34 1H), 8.61 J 2.2 6 F H fluoro-benzylamino)- Hz, 1H), 7.91 (dd, J 8.8 Hz, 2.2 Hz, 1H), 7.66 J 6 Hz, nicotinamide 1H), 7.32-7.37 2H), 7.08 -7.38 3H), 6.93 1H), 6.74 1H), 6.52-6.58 2H), 4.84 2H), 4.51 J _6.0 Hz) 2006252047 14 Dec 2006 Ex. Cpd W V Z Name Characterization Schm 0 r114 176 Meo NCH N M2-amino-phenyl)-6- 'H NMR (DMSO-ds) 8 (ppm): 9.34 1H), 8.63 J 2.2 6 Me H (3,4,5-trimethoxy- Hz, 1H), 7.92 (dd, J 8.8 Hz, 2.2 Hz, 1H), 7.57 J 6 Hz, OMe benzylamino)-nkicotinamide 1H), 7.10 1H), 6.93 1H), 6.74 1H), 6.66 2H), 6.56 2H), 4.84 2H), 4.45 J 6 Hz, 2H), 3.73 (s, 6H), 3.31 3H)..
115 177 N-N CH CH N42-Amino-phenyl45- 'H NMR: (Acetone-d 6 8 (ppm): 9.08 (bs, 1H), 8.02 (dd, J 14 Ph 0 phenyl[1,3,4oxadiazoQ2- 7.1 Hz, 1.9 Hz, 4H), 7.69 J 8.5 Hz, 2H), 7.62-7.57 (m, ylsulfanylmethyll- 3H), 7.28 J 7.7 Hz, 1H), 7.03-6.97 1H), 6.86 J benzamide 6.6 Hz, 1H), 6.67 J 7.7 Hz, 1H), 4.70 2H), 4.63 (bs, 2H).
116 178 N N CH N42-aminophenyl)-62- 'H-NMR (CD30D-d4), 8 (ppm): 8.67 J 2.2 Hz, 1H), 7.97 11 phenylamino-ethylamino- (dd, J= 8.9 Hz, 2.5 Hz, 1H), 7.58 1H), 7.51 1H), 7.15 nicotinamide (dd, J 7.7 Hz, 1.1 Hz, 1H), 7.08 2H), 6.89 (dd, J Hz, 1.4 Hz, 1H), 6.76 (dt, J= 7.7 Hz, 4.4 Hz, 1H), 6.67 J 7.7 Hz, 2H), 6.60 2H), 4.87 (bs, 4H), 3.60 J 6.3 Hz, 2H), 3.35 (t,J 6.3 Hz, 2H).
117 179 0 CH CH N(2-Amino-phenyl)-442,4- 'H NMR: (DMSO-d 6 8 (ppm): 9.62 1H), 8.00 (dd, J 8.2 11 N dioxo-4H- Hz, 1.9 Hz, 1H), 7.80-7.92 3H), 7.42-7.50 4H), 7.13 o o benzo[ell,3]oxazin-3- J 7.1 Hz, 1H), 6.95 (ddd, J 8.0 Hz, 1.6 Hz, 1H), 6.75 ylmethyl)-benzamide (dd, J 8.0 Hz, 1.4 Hz, 1H), 6.57 J 7.7 Hz, 1H), 5.13 (s, 2H), 4.87 (bs, 2H).
118 180 0 CH CH N(2-Aminophenyl)-44- 'H NMR: (DMSO-d 6 8 (ppm): 9.59 1H), 7.88 J 8.2 11 M. ethyi-4-methyl-2,6dioxo- Hz, 2H), 7.31 J 8.2 Hz, 2H), 7.13 J 7.4 Hz, 1H), piperidin-1-ylmethyl)- 6.95 J 8.0 Hz, 1H), 6.75 J 8.0 Hz, 1H), 6.57 J Me benzamide 7.4 Hz, 1H), 4.87 2H), 4.86 (bs, 2H), 2.61 2H), 2.55 (s, 2H), 1.31 J 7.7 Hz, 2H), 0.91 3H), 0.80 J 7.4 Hz, 3H).
119 181 CH CH IM2-Amino-phenyI4-(1- 'H NMR: (CDCI 3 8 (ppm): 8.23 (dd, J 7.8 Hz, 1.5 Hz, 1H), 19 WNN. ethyk2,4-dioxo-1,4- 8.01 (bs, IH), 7.80 J 8.0 Hz, 2H), 7.71-7.65 1H), N -dihydro-2H-quinazolin-3- 7.55 J 8.2 Hz, 2H), 7.27-7.20 3H), 7.05 (dt, J 7.7, Et ylmethyl)-benzamide 1.5 Hz, 1H), 6.81-6.77 2H), 5.29 (bs, 2H), 4.18 J 7.3 1_ Hz, 2H), 3.86 (bs, 2H), 1.33 J 7.1 Hz, 3H).
145 2006252047 14 Dec 2006 Ex. Cp W Y Z Name Characterization Schm 120 182 CH CH NW-2Amino-phenyI)-4-4,6- 'H NMR: (DMSO-d 6 8 (PPM): 9.66 (bs, 1H), 7.96 J =7.9 11 dimethyl-pyrimidin-2- Hz, 2H), 7.61 J 7.9 Hz, 2H), 7.21 J 7.9 Hz, 1H), ylsuffanylmethyl)- 7.04-6.99 (ri, 2H), 6.82 J =7.9 Hz, 111), 6.64 J =7.4 ____benzamide Hz, 1H), 4.49 2H1), 2.42 121 183 F eF OH CH N.{2-Amino-phenyl)-4-(4- VH NMR: (DMSO-dr 6 8 (ppm): 9.66 (bs, 1H), 9.07 J 5.2 11 C ety-prmii-2- Hz, 111), 7.97 J 7.4 Hz, 2H), 7.78 J 4.7 Hz, H), Nylsulfanylmethyl)benzamid 7.63 J 7.4 HzI 2H) J 7.7 Hz, 1, 7.1(t J e 7.7 Hz, 7.4 Hz, 1H), 6.81 J 8.2 Hz, 1H), 6.64 (dt, J __17.4 Hz, 7.1 Hz, 4.94 (bs, 2H), 4.57 2H).
Table 4b Ex. Cpd W Y Z Name Characterization Schm N-Q -Aminophenyl)- (,JN'N N 4-[3Apyridin- 'H NMVR (20% CD 3 0D in CDCI 3 5 (ppm): 8.46 (i, 123 187 NH C H OH 2ylmethyl- 1H), 7.95 J 8.4 Hz, 2H), 7.64-6.70 (in, 14 21 aminomethyl)phen 3.80 (br s, 4H).
____yI1-benzamide
NH
2 Biphenyl.4,4'- 'H NMR (CD 3 OD) 8 (ppm): 9.80 (bs, 2H), 8.16 (d, H dicarboxylic acid J=7.9 Hz, 4H), 7.96 J= 7.9 Hz, 4H), 7.23 J=7.4~ 124 18 NCHCHbis-[(2-amino- Hz, 2H), 7.03 (dd, J=6.9, 7.4 Hz, 2H), 6.84 J=8.2 1 phenyl)-amidel Hz, 2H), 6.66 (dd, J=6.9, 7.7 Hz, 2H), 5.06 (bs, 4H).
NA2-Amino-piienyl)- 1 H NMVR (DMSO-d 6 8 (ppm): 10. 15 (LH, brs), 8.17 H (2H, d, 7.90 (2H, d, 7.87 (111, brs), 2 115 19 MeO N H nHenrimeo 7.72 (1H, d, 7.54 (2H, in), 7.40 (IH, d, 2 125 189yamno OH OH in), 7.16 (1H, d, 7.07 (LH, in), 6.08 IOMa methyllpheny] (2H1, 4.42 (2H, 3.73 (6H, 3.58 (3H, d, J=0.8) 146 2006252047 14 Dec 2006 Ex. Cp4.. W Y IZ Name Characterization Schm 4V2-Amino-pheny- 'H NMR (DMSO-d 6 8 (ppm): 10.03 (1H, brs), 8.17 (2H, d, 7.88 (3H, 7.76 (1H, d, 7.52 126 190 a8 HC hnlmnt2 126 190 N> CH CHphenylarino- (2H, 7.35 (LH, d, 7. 17 (1H, 7.08-6.93 MeO__ benam-de (6H, 4.50 (3H, 3.75 (2H, s) benzamide N42-Amino-phenylY 128 193H 2 C O CH44,3ethylbut-3 2 128 193 HCH CH LRMS calc: 276.03, found: 277.2 22 en--ynyl)-
CH
3 benzamide N(2-Amino-phenyl)- 44 14ydroxy- 129 194 OH OH LRMS calc: 334.4, found: 335 22 oH cyclohexylethynyl)- OH_ benzamide N.42-Amino-phenyl)-
H
3 C OH methydroxy-3- LRMS calc: 294.35, found: 295.1 22 130 95 -e C CHmethyftbt-1-ynylY OH__ benzamide N(2-Amino-phenyl)- 131 196 C- OH OH 4-phenylethynyl- LRMS calc: 312.37, found: 313.2 (MH) 4 22 benzamide __I 'H NMR: (Acetone-d) 8 (ppm): 9.67 1H), 8.85 (s, N42-Amino-phenyl)- 1H), 8.01 J 8.2 Hz, 2H), 7.55 J 8.2 Hz, 2H), S -4-4(5-chloro- 7.45 J 8.8 Hz, IH), 7.36 J 2.3 Hz, 1H), 180 320/>NH CH CH benzooxazo2- 7.22 J 7.6 Hz, 1H), 7.07 (dd, J 8.8, 2.3 Hz, 01I N ylamino)-methyl]- 1H), 7.02 J 7.0 Hz, 1H), 6.84 J 7.6 Hz, 1H), benzaride 6.65 7.0 Hz, 1H), 4.94 2H), 4.67 J 5.3 Hz, 2H).
2006252047 14 Dec 2006 Ex._ Cp W Y Z Name Characterization Schm NQ-rnio-peny 'H NMR: (DMSO-d 6 8 (ppm): 9.67 (bs, 1H), 8.36 J s -Ami-chenl)- 5.8 Hz, LH), 8.00 J 8.2 Hz, 2H), 7.89 J .N s -114(4choro- 8.2 Hz, 2H), 7.57 J 8.2 Hz, 2H), 7.48 J 8.2 181 321 Il O>N H CH phenAYfthiazol-2- Hz, 2H). 7.20 1H), 7.02 J 8.5 Hz, 1H), 6.83'(d, 3 ylamino1-methy)- J 7.7 Hz, 1H), 6.65 J 7.1 Hz, 1H), 4.92 (bs, 2H), I benzamide 4.65 J 5.8 Hz, 2H).
N42-min-pheyY' H NMR: (DMSO-d 6 8 (ppm): 6.97 LH), 8.78 Cbs, s 2-A ino-phenyt)- 1H), 8.01 J 8.8 Hz, 2H), 8.00 1H), 7.55 J 182 322 -N OHH -5bomao- 8.2 Hz, 2H), 7.43-7.35 (in, 2H), 7.22 J 7.6 Hz, 33, Br., Nylamino)-rnethylj- 1H), 7.03 J 7.0 Hz, 1H), 6.83 J 7.6 Hz, 1H), 34 Brzaid 6.65 Ct, J 7.6 Hz, 1H), 4.94 2H), 7.74 J=5.9 Iezmd Hz, NM2-Amino-pheny)- Meo OMe trimethoxy- 183 323 MeO s C H OH phenylamino)- LRMS calc: 489.58, found: 490 21 HN methyll-hiophen-2ylmethyl)- ___benzamide N42-Ainino-pheny)- 'H NMR: (Acetone-dr 6 8 (ppm): 8.65 J 1.4 Hz, 18N2 4-16-[Cpyridin-3- LH), 8.44 (dd, J 4.7, 3.0 Hz, 1H), 7.97 J 8.2 18H2 a HC benzothiazoQ2- 2H), 7.09 J=2.5 Hz, 1H), 7.02.6.97 1H), 1 N ylsulfanylmethyfl. 6.91 (dd, J 8.8, 2.5 Hz, 1H), 6.86 (dd, J 8.0, 1.4 Hz, 1H), 6.69-6.64 LH), 4.64 Cs, 2H), 4.47 .1 2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm 'H NMR: (DMSO-d 6 8 (ppm): 9.59 1H), 8.52-8.51 N-(2-Amino-phenyl)- 1H), 7.89 J= 8.24 Hz, 2H), 7.71 (td, J 7.7,1.9 a N 4-16-[(pyridin-2- Hz, 1H), 7.59-7.53 3H), 7.34 J 8.0 Hz, 1H), 185 326 N s CH CH ylmethyl)-aminol- 7.25-7.21 1H), 7.12 J 6.9, Hz, 1H), 6.98-6.96 11, H benzothiazo[2- 1H), 6.93 J 7.4 Hz, 1H), 6.81 (dd, J 9.1, 34 ylsulfanylmethyl)- 2.5 Hz, 1H), 6.76-6.73 1H), 6.67 J 5.8 Hz, benzamide 1H), 6.56 J 7.4 Hz, 1H), 4.87 1H), 4.58 2H), 4.38 J 6.3 Hz, 2H).
'H NMR: (DMSO-d) 6 (ppm): 12.23 (bs, 1H), 9.59 (s, N 4 mizno-phenyl)- 1H), 7.86 J 8.2 Hz, 2H), 7.34 J 8.5 Hz, 2H), 186 327 C s CH CH 7.14-7.12 2H), 6.94-6.92 2H), 6.76 J 6.6 14 N ylsulfanylmethyl)- Nysulfanmethyl)- Hz, 1H), 6.57 J 7.4 Hz, 1H), 4.87 2H), 4.29 (s, H benzamide 2H).
2H).
'H NMR: (CD 3 OD) 8 (ppm): 8.03 J 8.4 Hz, 2H), N(2-Amino-phenyl)- N 4-morpholin4 l- 7.58 J 7.9 Hz, 2H), 7.26 J 7.0 Hz, 1H), 7.16 187 328 CH CH 4m hl J 6.6 Hz, 1H), 6.98 J 7.0 Hz, 1H), 6.85 J 37 O ylmethyl- 7.5 Hz, 1H), 3.78 J 4.4 Hz, 4H), 3.68 2H), benzamide benzamide 2.57-2.54 4H).
MeO 3',4',5'-Trimethoxy- 'H NMR: (CD 3 0D) 8 (ppm): 8.14 J 7.9 Hz, 2H), biphenyV-4- H boyi 7.85 J 8.4 Hz, 2H), 7.29 J 7.9 Hz, 2H), 7.17 188 329CH CH carboxylic acid 37 Meoc J 7.0 Hz, 1H), 7.04 2H), 7.00 J 8.4 Hz, q amino-phenyl)- OMe amino-phenyl 1H), 6.87 J 7.5Hz, 1H), 4.95 6H), 4.01 3H).
amide 'H NMR: (DMSO-d 6 8 (ppm): 9.65 1H), 7.96 J
NH
2 4-(2-Amino-9-butyl- 7.7 Hz, 2H), 7.95 (bs, 2H) 7.78 1H), 7.52 J 9+purin-6- 7.9 Hz, 2H), 7.22 J 7.7 Hz, 1H), 7.02 (dd, J 189 330 H 3 C' /N N CH CH ylamino)-nethyllN- 7.3, 8.0 Hz, 1H), 6.8 J 8.0 Hz, 1H), 6.65 (dd, J 39 (2-amino-phenyl)- 7.3, 7.7 Hz, 1H), 5.91 2H), 4.94 (bs, 2H), 4.77 (bs, benzamide 2H), 4.01 J 7.1 Hz, 1H), 1.78 2H), 1.3 2H), 1 1 0.95 J Hz, 1H) 2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm NH2 N42-Amino-pheny- Y'H NMR (DMSO-d 6 8 (ppm): 10.16 IH), 9.60 (br, 4-[(2-amino-9H 1H), 8.24 1H), 8.08 J 8.0 Hz, 2H), 7.62 (i, purin-6-ylamino)- 1H), 7.60 J 8.0 Hz, 2H), 7.40 1H), 7.20 (i, HN-/N methyll-benzamide 2H), 7.08 1H), 4.90 2H), 4.6 (br, 4H) N l I2m'H NMR (DMSO-d 6 8 (ppm): 9.67 1H), 8.80 (m, 4-[A2-Aminro-ph 1H), 8.24 1H), 7.99 J 7.8 Hz, 2H), 7.52 J 191 332 HN 'N CHCH 7.8 Hz, 2H), 7.21 J 7.8 Hz, 1H), 7,02 (dd, J 39 purin6-ylamino 6.3, 7.8 Hz, 1H), 6.82 J 8.1 Hz, 1H), 6.70 (d6, J N ethyll-benzamide 6.3, 8.1 Hz, 1H), 4.94 (br, 2H), 4.77 (br, 2H) 'H NMR (DMSO-d 6 5 (ppm): 9.60 1H), 8.72 (br, N42-Amino-phenyl)- 1H), 8.21 1H), 7.92 J 8.0 Hz, 2H), 7.45 J 4-[(9butyV2-chloro- 8.0 Hz, 2H), 1.15 J 8.0 Hz, 1H), 6.96 (dd, J 192 333 H 3 CN-"N\ NN CH CH 9Hpurin-6- 6.7, 8.0 Hz, 1H), 6.77 J 8.0 Hz, 1H), 6.58 (dd, J 39 t" N ylamino)-methyll- 6.7, 8.0 Hz, 2H), 4.88 LH), 4.71 2H), 4.11 HN-/ benzaiide 2H), 1.76 2H), 1.25 2H), 0.89 J=7.1 Hz, 3H) N42-Amino-phenyt)- 'H NMR: (DMSO-d 6 5 (ppm): 12.39 (bs, 1H), 9.32 (s, H 44(lH- 1H), 7.81 J=8.2 Hz, 2H), 7.56 (bs, 1H), 7.21-7.17 193 334 N NH CH CH benzoimidazol-2- 3H), 6.99-6.97 2H), 6.81 J=8.2 Hz, 1H), 11 yliethyl)amino]- 6.77 J=8.8 Hz, 2H), 6.63 J=7.0 Hz, 1H), 4.85 (s, benzaiide 2H), 4.62 J=5.3 Hz, 2H).
'H NMR: (CDC1 3 8 (ppm): 8.23 (dd, J 7.8, 1.5 Hz, 02-Amino-pheny- 1H), 8.01 (bs, 1H), 7.80 J 8.0 Hz, 2H), 7.71-7.65 4ioxo-1t,4-hyd- 1H), 7.55 J 8.2 Hz, 2H), 7.27-7.20 3H), 194 335 CH CH dioxo4ihyr- 7.05 (td, J 7.7, 1.5 Hz, 1H), 6.81-6.77 2H), 5.29 19 N~ 21-uinazolin-3- (bs, 2H), 4.18 J 7.3 Hz, 2H), 3.86 (bs, 2H), 1.33 Et ylmethyl)- J 7.1 Hz, 3H). MS: (calc.) 414.2; (obt.) 415.3 benzamide (MH)_ 150 2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm 'H NMR: (DMSO) 8 (ppm): 9.69 (bs, 1H, NH), 8.71 (s, N42-Amino-phenyl)- 0N42-Amo-p 1- 8.16 J 2.5 Hz, 1H), 8.01 J 8.2 Hz, 2H), 7.95 (dd, J 8.8, 2.5 Hz, 1H), 7.81 J 8.8 Hz, c5 33 C methyl-4oxo-4H- 195 336 CH CH 1H), 7.74 J 8.2 Hz, 2H), 7.20 J 7.1 Hz, 1H), 19 N M yl m e h yl)qu in a z o lin 3 C' M y zli3 ~7.02 (td, J 7.6, 1.5 Hz, 1H), 6.82 (dd, J 8.0, 1.4 N ym det Hz, 1H), 6.64 (td, J 7.6, 1.4 Hz, 1H), 5.34 2H), benzamide 4.94 (bs, 2H). MS: (calc.) 404.1; (obt.) 405.0(MH)' 'H NMR: (DMSO) 5 (ppm): 9.64 (bs, 1H), 8.17 (dd, J 1.6 Hz, 1H), 7.95 J 8.2 Hz, 2H), 7.95 (dd, J N42-Amino-phenyl)- 8.8, 2.5 Hz, 1H), 7.84 (ddd, J 7.6, 7.0, 1.5 Hz, 442-methyl-4-oxo- 1H), 7.64 J 7.7 Hz, 1H), 7.53 (ddd, J 7.6, 7.6, 196 337 N/ CH CH 4H-quinazolin-3- 1.1 Hz, 1H), 7.33 J 8.2 Hz, 2H), 7.14 (dd, J 19 N Me ylmethyl)- 7.7, 1.1 Hz, 1H), 6.96 (ddd, J 7.6, 7.6, 1.5 Hz, 1H), benzamide 6.77 (dd, J 8.0, 1.4 Hz, 1H), 6.58 (ddd, J 7.6, 7.6, 1.3 Hz, 1H), 5.46 2H), 4.89 (bs, 2H) 2.5 3H).
MS: (calc.) 384.2; (obt.) 385.0 (MH)' 'H NMR: (DMSO) 8 (ppm): 9.62 (bs, 1H), 8.50 1H), N42-Amino-phenyl)- 8.41 J 8.2 Hz, 2H), 7.47 1H), 7.46 J 7.7 S446,7-dimethoxy4- Hz, 2H), 7.17 1H), 7.15 J 8.5 Hz, 1H), 6.96 197 338 MeO N CH CH oxo-4H-quinazolin- (ddd, J 7.7, 7.7, 1.1 Hz, 1H), 6.76 J 6.9 Hz, 19 Me N-3 3-ylmethyl)- 1H), 6.58 (dd, J 6.9, 6.9 Hz, 1H), 5.26 2H), 4.88 benzamide (bs, 2H), 3.91 3H), 3.87 3H). MS: (calc.) 430.2; (obt.) 431.1 (MH)* 'H NMR: (DMSO) 8 (ppm): 9.66 (bs, 1H), 8.69 1H), O N42-Amino-phenyl)- 8.07 (dd, J 8.8, 10.4 Hz, 1H), 7.96 J 8.2 Hz, F 446,7-difluoro-4- 2H), 7.82 (dd, J 14.3, 11.3 Hz, 1H), 7.48 J 8.2 198 339 CH CH oxo-4H-quinazolin- Hz, 2H), 7.15 J 6.9 Hz, 1H), 6.96 (ddd, J 7.6, 19 FN- 3-ylmethyl 7.6, 1.5 Hz, 1H), 6.76 (dd, J 8.1, 1.2 Hz, 6.58 benzamide (ddd, J 7.5, 7.5, 1.2 Hz, 1H), 5.28 2H), 4.89 (bs, 2H). MS: (calc.) 406.1; (obt.) 407.0 (MH)' 2006252047 14 Dec 2006 Ex._ Cpd W Y IZ Name Characterization Schm N42Amio-penyY 'H NMR: (DMSO) 5 (ppm): 9.61 (bs, 1H), 8.09 (dd, J 0N-[42-nopey) 7.8, 1.5 Hz, I1H), 7.91 J 8.2 Hz, 2H), 7.81 (ddd, 4-1142-a ino J 7.8, 7.8, 1.6 Hz, 1LH), 7.52 J =8.2 Hz, ILH), diethylam4-ino- 7.42 J 8.2 Hz, 2H), 7.32 (dd, J 7.6 Hz, 19 30CH OH 1H), 7.14 J 6.9 Hz, 1H), 6.96 Cddd, J 7.6, 7.6, 19 NJ-- CH 1,-dihdro2H- 1.5 Hz, 1H), 6.77 Cdd, J 7.8, 1.2 Hz, 1H), 6.59 (ddd, L'-N'H quinazolin-3 J 7.5, 7.5, 1.2 Hz, 1H), 5.22 2H), 4.88 (bs, 2H), 6H 3 ylmethyl]- 4.24 Ct, J 7.1 Hz, 2H), 2.5 Cm, 2H) 2.22 6H). MS: benzamide (calc.) 457.2; (obt.) 458.1 (MH) 'H NMR: (DMSO) 8 (ppm): 9.61 (bs, 1H), 8.09 (dd, J oN42-Amino-phenyl)- 8.0, 1.6 Hz, 1H), 7.92 J 8.2 Hz, 2H), 7.81 Cddd, 0 4-[142-morphoi-= 7 7.8, 1.6 Hz, 1 7.54 J =8.5 Hz, 1LH), yI-ethyl)-2,4-dioxo- 7.43 J 8.2 Hz, 2H), 7.32 (dd, J 7.4, 7.4 Hz, 200 341 C- H OH 1,4-dihydro-2H- LH), 7.14 Ji 7.4 Hz, 1H), 6.96 (ddd, J 7.6, 7.6,1 NO qiaoi- 1. 5 Hz, 1 6.7 7 (dd, Ji 8.0, 1.4 Hz, I1H), 6.59 Cddd,1 quinazo~mthlin3 J 7.6, 7.6, 1.4 Hz, 1 5.22 Cs, 2H), 4.87 (bs, 2H), a, belmel 4.28 Ct, J 6.7 Hz, 2H), 3.50 Ct, J 4.5 Hz, 4H), 2.58 J 6.7 Hz, 2H), 2.47-2.44 Cm, 4H). MS: (caic.) 499.2; (obt.) 500.3 N42Amio-penyY 'H NMR: (DMSO) 8 (ppm): 9.65 Cbs, 1H), 8.25 Cd, J 0 ~~~42-Armno-2eyD 2.5 Hz 1 7.99 Cddd, J 8.5, 2.5 0. z H,79 Br methyk~~~~4-(6oo4- J= 8.8 Hz, 2H), 7.60(dJ=8.Hz1),73(,J 201 342 BC~ H OH methyzl--x4 8.2 Hz, 2H), 7.14 Cd, J 7.4 Hz, 1H), 6.96 (dd, J 19 NrI qunylin-3-l 7.4, 7.4 Hz, 1H), 6.76 Cd, J 8.0 Hz, 1H), 6.59 Cdd, J N Menylme 7.4, 7.4 Hz, LH), 5.45 Cs, 2H), 4.88 Cbs, 2H). MS: benzamide(calc.) 462.1; (obt.) 463.1 2006252047 14 Dec 2006 Ex. Cp W Y Z Name Characterization Schm N42,-mino-heyl- 1 H NMR: (DMSO) a (ppm): 9.61 (bs, 1H), 8.10 (dd, J 0 4,-ioo14 5.2, 0.5 Hz, 1H), 7.91 J 8.2 Hz, 2H), 7.40 J 33 ~CHdihydro-2H- 8.2 Hz, 2H), 7.15 J 7.1 Hz, 1H), 6.98-6.94 (in, 4 4 L HCH thieno[3,2- 2H), 6.77 (dd, J 1.1 Hz, 1H), 6.58 (dd, J 7.1, HNr dlpyrimidin-3- 7.1 Hz, 1H), 5.12 2H), 4.88 (bs, 2H). MS: (caic.) H ~~~~~ylmethylY 9.;(b.-330(H* ___benzamide39.;(b)330(M N42Amio-penyY 'H NMR: (DMSO) 8 (ppm): 9.61 (bs, 1H), 8.15 J NA2Arnno-henl)-2 5 Hz, 1H), 7.95 (dd, J 9.1, 4.9 Hz, IN), 7.91 J 0 446-bromo- 1-ethyl- Hz, 2H), 7.53 J =9.3 Hz, 1H), 7.42 J 20o4 r ICH2,4-dioxo-1 8.2 Hz, 2H), 7.15 J 6.9 Hz, 1H), 6.96 (ddd, 19 20N34CHC qinaroli-- 7.6, 7.6, 1.5 Hz, 1H), 6.77 (dd, J 8.1, 1.5 Hz, 1H), Et qiaoln3 6.59 (ddd, J 7.6, 7.6, 1.4 Hz, 1H), 5.20 2H1), 4.88 EtylmethyD- (bs, 2H) 4.14 J 7.0, 2H), 1.21 J 7.0, 3H).
benzamide MS: (catc.) 492. 1; (obt.) 493.0 1 H NMR: (DMSO) 8 (ppm): 9.62 (bs, 1H), 8.10 (dd, J= 0 N42-Arnino-pheny)- 7.7, 1.6 Hz, 1H), 7.93 J =8.2 Hz, 2H), 7.71 (ddd, J 4414methoxy- 7.9, 7.9, 1.5 Hz, IHN, 7.46 J 8.2 Hz, 2H), 7.38 benzyl)-2,4-dioxo- J 8.2 Hz, 2H), 7.31 J 7.4 Hz, LH), 7.26 J 204 345 (NO CH CH 1,4-dihydro-2H- 8.8 Hz, 2H), 7.15 J =6.6 IN), 6.96 (ddd, J 19 quinazolin-3- 7.6, 7.6, 1.2 Hz, 1H), 6.89 J 8.8 Hz, 2H), 6.77 O~eylmethyll- (dd, J 8.0, 1.4 Hz, 1H), 6.59 (ddd, J 7.5, 7.5, 1.2 Oebenzamide Hz, 1H), 5.33 2H), 5.28 2H), 4.89 (bs, 2H), 3.71 3H). MS: (calc.) 506.2; (obt.) 507.1 'H NMR: (DMSO) 5 (ppm): 9.61 (bs, 1H), 8.66 1H), 0N-(2-Amrino-phenyl)- 8.24 J 2.5 Hz, IH), 8.00 (dd, J 8.7, 2.3 Hz, Br44(6-bromo-4-oxo- IH), 7.95 J 8.2 Hz, 2H), 7.68 J 8.8 Hz, 1H), 205 346 r N/ CH CII 4"-uinazolin-3- 7.48 J 8.2 Hz, 2H), 7.15 J 8.0 Hz, 1H), 7.96 19 NYylmethyl)- (ddd, J 7.6, 7.6, 1.5 Hz, 1H), 6.77 (dd, J 8.0, 1.1 benzamide Hz, 1H), 6.59 (dd, J 7.4, 7.4 Hz, 111), 5.28 2H), 14.87 (bs, 2H). MS: (calc.) 448.0; (obt.) 449.0 153 2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm 'H NMR: (DMSO) 8 (ppm): 9.63 (bs, 1H), 8.38 J N-(2-Amin-phenyl)- 0 -Aomio-ph 1.9 Hz, 1H), 8.28 (dd, J 8.8, 2.2 Hz, 1H), 8.19 J 4H- 8.8 Hz, 1H), 7.95 J 8.0 Hz, 2H), 7.50 J 206 347 NCH CH 4H bo r- 8.2 Hz, 2H), 7.15 J 6.9 Hz, 1H), 7.96 (ddd, J 19 1 benzold][1,2,3]tria N 7.6, 7.6, 1.5 Hz, 1H), 6.77 (dd, J 8.0,1.4 Hz, 1H), Nnzmin e 6.59 (ddd, J 7.6, 7.6, 1.4 Hz, 1H), 5.67 2H), 4.87 benzamide (bs, 2H). MS: (calc.) 449.0; (obt.) 450.0 (2-Amino-phenyl H NMR: (DMSO) 8 (ppm): 9.63 (bs, 1H), 8.30-8.24 N(2-Amino-phenyl)- S446-chloro4oxo- 2H), 8.15 (ddd, J 8.6, 2.5, 0.8 Hz, 1H), 7.95 J o 4-(6-chloro4oxo- 34 N C OH 8.0 Hz, 2H), 7.50 J 8.2 Hz, 2HH), 7.15 J 207 348 CH CH 4 8.0 Hz, 1H), 7.96 (dd, J 7.4, 7.4 Hz, 1H), 6.77 J 19 I I benzoid][1,2,3]tria N ziylmethyl 8.0 Hz, 1H), 6.59 (dd, J 7.4, 7.4 Hz, 1H), 5.67 (s, benzamide 2H), 4.88 (bs, 2H). MS: (calc.) 405.1; (obt.) 406.0 benzamide(M).___ 'H NMR (acetone-d 6 8 (ppm): 9.07 (bs, 1H), 8.02 (d, -Amino-phenyl J 8.2 Hz, 2H), 7.64-7.44 3H), 7.33 (dd, J 7.8, 1.5 Hz, 1H), 7.03 (td, J 1.5 Hz, 1H), 6.90 (dd, J 4-N(3-fluoro-2- 208 349 pyrid amino)CH CH 8.0, 1.4 Hz, 1H), 6.78 (bs, 1H), 6.71 (td, J 7.6, 11 H methy-benzamide 1.4 Hz, 1H), 6.48 (dd, J 8.1, 2.6 Hz, 1H), 6.16 (dd, J methyll>enzamide 7.7, 2.5 Hz, 1H), 4.76-4.55 4H). HRMS (calc.): 336.1386, (found): 336.1389.
'H NMR (acetone-ds) 8 (ppm): 9.06 (bs, 1H), AB F r F N{2-Amino-phenyl)- FrX F N4,2-Amino-phenyl) system (SA 8.02, 8 7.56, J 8.3 Hz, 4H), 7.74- 4-[(3,4,5-trifluoro- 209 350 CH -pyridinyl-amino 7.65 1H), 7.33 J 8.0, 1H), 7.03 (td, J 11 methyl-benzamide 1.5 Hz, 1H), 6.96-6.83 2H), 6.71 (td, J 7.6, 1.4 SHz, 4.74 J 6.3 Hz, 2H), 4.65 (bs, 2H).methyl-benzamide Hz, 1H), 4.74 J 6.3 Hz, 2H), 4.65 (bs, 2H).
2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm N2-Amino-phenyl)- 'H NMR: (DMSO) 5 (ppm): 9.61 (bs, 1H), 8.10 Cdd, J 5.2, 0.5 Hz, 1H), 7.91 J 8.2 Hz, 2H), 7.40 J 210 dihydro-2H- 8.2 Hz, 2H), 7.15 J 7.1 Hz, 1H), 6.98-6.94 (m, HCH thieno3,2- 2H), 6.77 (dd, J 8.0, 1.1 Hz, 1H), 6.58 Cdd, J 7.1, H ylmethyl 7.1 Hz, LH), 5.12 2H), 4.88 (bs, 2H). MS: (caic.) Sbenzamide 392.1; (obt.) 393.0 1 H NMR: (DMSO) a (ppm): 9.85 (bs, 1H), 8.24-8.19 6H), 7.79-7.66 3H), 7.20 J 7.5 Hz, 1H), 24-{pheny 211 352 CH CH ,4oxadiazol-3 7.00 (dd, J 7.3, 7.3 Hz, 1H), 6.80 Cd, J 7.9 Hz, yl)-benzamide 1H), 6.61 (dd, J 7.3, 7.3 Hz, 1H), 4.96 (bs, 2H). MS: (calc.) 356.1; (obt.) 357.0 'H NMR: (DMSO) 8 (ppm): 9.81 bs, 1H), 8.17-8.11 NA2Amiheyl)- 4H), 7.18 J 7.9 Hz, 1H), 6.99 (dd, J 7.7, 212 353 CH CH 7 -7 Hz, 1H), 6.79 J 7.9 Hz, 1H), 6.61 (dd, J N E1,2,4]oxadiazol-3- Me o 7.5, 7.5 Hz, 1H), 4.94 (bs, 2H), 2.70 Cs, 3H). MS: yl-benzamide (calc.) 294.1; (obt.) 295.0 1H NMR: (acetone) 8 (ppm): 9.29 (bs, 1H), 8.21 Cm, in-phnl- 4H), 7.31(d, J 8.0Hz, 1H), 7.03(dd, J 7.0, 7.0 Hz, 45-pe 1H), 6.88 J 7.3Hz, 1H), 6.69 (dd, J 7.3, 7.3 21 34K~ N~CH CH ylmethyl- ~5Q 213,244NNxCHCHzol-- 1H), 4.68 (bs, 2H), 3.94 2H), 2.58 Ct, J= 5.1 Hz), 1.63-1.55 4H), 1.47-1.43 2H). MS (Caic) y)-benzamide 377.2; CObt.) 378.3MH)+ IH NMR: (acetone) 5 (ppm): 9.28 (bs, 1H), 8.21 (m, N42-miophnl- 4H), 7.31(d, J 8.1 Hz, 1HI, 7.03 (dd, J 7.0, 7.0 Hz, 21 355 CHC 5H orphoin-4 1H), 6.88 Cd, J 7.3 Hz, LH), 6.69 Cdd, J 7.3, 7.3 2 3 CH CH ylmethyl- zol-Hz, LH), 4.67 Cbs, 2H), 4.01 2H), 3.66 J= 4.8Hz), 0i 2.65 Ct, J= 4.4 Hz). MS: CCalc.) 379.2; 380.2 yenzamide MH)+ 155 2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm N'2-Amino-phenyl)- H NMR: (DMSO) 8 (ppm): 9.62 1H), 7.93 J N42-Aminsphenyl)- S445-propyl- 7.9 Hz, 2H), 7.42 J 7.9 Hz, 1H), 7.16 J 215 356 N CH CH (1,2,4oxadiazol-3- Hz, 1H), 6.97 J 7.0 Hz, 1H), 6.77 J 7.9 Hz, HNCO: y' methy- 1H), 6.59 J 7.5 Hz, 1H), 4.88 2H), 4.16 2H), C or 2.87 7.0, 2H), 1.72 J 7.5 Hz, 2H), 0.92 J benzamide Hz, 3H). 337.2.
1 H NMR: (DMSO) 8 (ppm): 9.64 1H), 9.24 d, J= N42-Amino-phenyl)- 1.8 Hz, 1H); 8.86 (dd, J 1.3 Hz, J 4.8 Hz, 1H), 445-pyridin-3-yl 8.45 (dd, J 1.8 Hz, J 6.2 Hz, 1H), 7.96 J 7.9 216 357 N CH CH [1,2,4]oxadiazol-3- Hz, 2H), 7.66 (dd, J 4.8 Hz, J 7.9 Hz, 1H), 7.50 I ylmethyl)- J 8.4 Hz, 2H), 7.16 J 7.5 Hz, 1H), 6.96 J N benzamide 7.0 Hz, 1H), 6.77 J 7.5 Hz, 1H), 6.59 J Hz, 1H), 4.89 2H), 4.31 2H). (MH)*.372.3.
N42-Amino-phenyl) 'H NMR: (DMSO) 5 (ppm): 9.63 1H), 8.87 J N 4-5-pyridin-4-y 6.2 Hz, 2H); 7.95-8.02 3H), 7.50 J 7.9 Hz, 217 358 N CH CH [1,2,4]oxadiazol-3- 2H), 7.16 J 7.5 Hz, 2H), 6.97 J 7.0 Hz, 1H), 0' ylmethyl)- 6.77 J 7.0 Hz, 1H), 6.59 J 7.9 Hz, 1H), 4.89 N benzamide 2H), 4.33 2H). 372.3.
1H NMR (DMSO) 5 (ppm): 11.62 1H), 9.60 (bs, NC 4-(5-Acetylamind4- N4a5o-Ath no-- 1H), 7.93 J 8.1 Hz, 2H), 7.39 J 8.1 Hz, 2H), cyano-thiophen-2- 218 359 HN /S CH CH cy th -2 6.97 J 7.3 Hz, 1H), 7.15 J 7.3 Hz, 1H), 218 359 HN CH CH lylmethyl)-N2- 49 Me aminphenyl) 6.98-6.94 2H), 6.77 J 7.3 Hz, 1H), 6.591 (dd, benzamide J 7.7, 7.7 Hz, 1H), 4.89 (bs, 2H), 4.13 2H), 2.17 3H). LRMS: 390.1 (calc) 391.2 (found).
445-Benzoylamino- 1H NMR (DMSO) 8 (ppm): 11.77 1H), 9.61 1H); NC Me 4-cyano-3-methyl- 7.93 J 7.0 Hz, 4H), 7.52-7.63 3H), 7.38 J 219 360 HN CH CH thiophen-2- 7.6 Hz, 2H), 7.16 J 7.6 Hz, 1H), 6.96 J 219 360 HN CH CH 49 Ph S ylmethyl)N42- 7.6 Hz, 1H), 6.77 J 7.6 Hz, 1H), 6.59 J 7.6 o amino-phenyl)- Hz, 1H), 4.89 2H), 4.15 2H), 2.24 3H). I I benzamide 467.0 156 2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm NC Me N42-Aminophenyl)- N2-Amino-pheny 1H NMR (DMSO) 8 (ppm): 10.12 1H), 9.61 1H), y 444-cyano-3- HN 44cyano-3- 9.21 1H); 7.93 J 7.6 Hz, 2H), 7.27-7.43 (m, 220 31 HNS methyl-5-(3-phenyl- 220 361 HN- 4 sCH CH methy53-phen- 6H), 7.16 J 7.6 Hz, 1H), 6.93-7.05 2H), 6.77 49 ureido)-thiophen-2- (d J 8.2 Hz, 1H), 6.59 J 7.6 Hz, 1H), 4.88 (s, ylmethyl]dethyl2H), 4.08 2H), 2.19 3H). 482.4 benzamide o N4 2-Aminophenyl)- 0 N42-Amino-pheny- H NMR: (DMSO) 8 (ppm): 9.60 1H), 7.92 J 43-oxo2,3- 8.2 Hz, 2H), 7.40 J 8.0 Hz, 2H), 7.13 J 6.9 221 362 r NCH CH dihydro- Hz, 1H), 6.92-7.04 5H), 6.75 (dd, J 8.1 Hz, 1.1 11 o benzoll,4]oxazin- 0 Hz, 1H), 6.57 (td, J 7.4 Hz, 1.4 Hz, 1H), 5.24 2H), 4-ymethyi) 4ymiethl 4.88 (bs, 2H); 4.82 2H). 374.1 benzamide o NA2-Amino-phenyl)- 'H NMR: (DMSO) 5 (ppm): 9.58 1H), 7.90 J 4-(3-oxo-2,3- 8.2 Hz, 2H), 7.42 (dd, J 8.0 Hz, J 1.4 Hz, 1H), 222 363 NCH CH dihydro- 7.32 J 8.2 Hz, 2H), 7.19-7.11 3H), 7.04-6.92 s benzo[1,4]thiazin- 2H), 6.75 (dd, J 8.0 Hz, 1.4 Hz, 1H), 6.57 (td, J 4-ylmethy)- 8.0 Hz, 1.6 Hz, 1H), 5.31 2H); 4.88 (bs, 2H); 3.70 benzamide 2H). 390.1 o N-(2-Amino-phenyl)- 'H NMR: (DMSO) 6 (ppm): 9.57 (bs, 1H), 7.98 J 443-oxo-2,3- 4.7 Hz, 1H), 7.89 J 8.2 Hz, 2H), 7.45-7.40 (m, 223 364 CH CH dihydro-pyrido[3,2- 3H), 7.15 J 8.2 Hz, 1H), 7.09-7.05 1H), 6.96 0 N bl][1,4]oxazin4- (dd, J 7.6, 7.6 Hz, 1H), 6.76 J 8.2 Hz, 1H), ylmethylY 6.58 (dd, J 7.6, 7.6 Hz, 1H), 5.31 2H), 4.90 (bs, benzamide 2H), 4.87 2H). 375.1 1 H NMR: (DMSO) 6 (ppm): 9.67 1H); 7.98 J o N42-Amino-phenyl)- 8.2 Hz, 2H), 7.73-7.84 3H), 7.53-7.62 3H), 224 365 CH CH 4-(1-hydroxy-3-oxo- 7.24 J 7.6 Hz, 1H), 7.04 J 7.6 Hz, 1H), 6.85 46 oH indan-2-ylmethyl- J 8.2 Hz, 1H), 6.67 J 7.6 Hz, 1H), 5.68 J benzamide 7.0 Hz, 1H), 5.27 J 6.4 Hz, 1H), 4.95 2H), 3.21-3.30 1H), 3.11-3.13 2H). 373.1 2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm 'H NMR: (DMSO) 8 (ppm): 9.61 1H); 8.01 J 225 366/CHCH 4-Ano-y- 8.8 Hz, 2H), 7.45 J 7.6 Hz, 2H), 7.06-7.24 (m, 225 366 2-mn-hnl-ezid CH OH4enoxy-e 6H), 6.97 J 7.6 Hz, 1H), 6.78 J 7.4 Hz, 1H), 6.59 J 7.6 Hz, 1H), 4.88 2H). 305.0 N42-Amino-phenyl) 1 H NMR (CDC 3 8 (ppm): 8.77 7.93 J 226 367o C OH4-[4-(ethoxy- 8.1 Hz, 2H), 7.42 J 8.4 Hz, 2H), 7.38-6.98 (m, 226 37 1 IH CH phenyO)-2,5- 226h36dCH CHuran-2- 6H), 6.91 J 8.4Hz, 2H), 6.09-5.98 4H), 3.81 dihydro-furan-2-yl]- s benzamide Me 0M2-Amino-pheny- 'H NMR (DMSO-d 6 8 10.08 (brs, 1H), 7.99 J Meo 0-N 4-[1,3-bis43,4- 7.9 Hz, 2H), 7.70 1H), 7.49 J 8.35 Hz, 4H), 230 371 meo_6 _NH Ne CH CH dimethoxy-phenyl)- 7.39-7.33 1H), 7.30-6.90 7H), 6.87 (dd, J 57 ureidomethyl]- 2.2, 8.35 Hz, 1H), 6.78 (dd, J 2.2, 8.35 Hz, LH), OMe benzamide 5.01 2H), 3.80 3H), 3.77 3H), 3.75 6H).
42-Amino-phenyl)- 'H NMR (CDCI 3 8 8.02 (brs, 1H), 7.90 J 7.9 0 4-13-4-chloro- Hz, 2H), 7.46 J 7.5 Hz, 2H), 7.42-7.24 6H), 231 372 N CH CH diety-phenyfl 7.16 i 7.5 Hz, LH), 6.91 (brd, J 5.71 Hz, 3H), 57 NH NOMe dimethoxyphenylY Ce -l 6.75 (brd, J 8.3 Hz, 1H), 6.70 J 1.8 Hz, 1H), e eidomel 4.99 1H), 3.97 3H), 3.86 3H).
___benzamide N4(2-Amino-phenyl)- 1 H NMR (DMSO-d 6 8 10.10 (brs, 1H), 7.99 J 0 )44143,4- 7 9 Hz, 2H), 7.88 IH), 7.80-7.72 LH), 7.50 (dd, 232 373 4NH CH CH diiethoxyheny J 7.0, 5.7 Hz, 4H), 7.37 J 7.9 Hz, 1H), 7.30- 57 6.94 7H), 6.78 J 6.6 Hz, 1H), 5.03 2H), OMe ureidomethyll- 3.80 3H), 3.78 3H).
benzamide 158 2006252047 14 Dec 2006 Ex._ Cp W Y Z Name Characterization Schm N-{2-Amino-phenyl)- 'H NMR (CDCI 3 8 8.02 Cbrs, LH), 7.92 J 7.9 44143,4- Hz, 2H), 7.49 J =8.35 Hz, 2H), 7.43-7.32 Cm, o dimethoxy-pheny)- 7.10-7.30 (2m, 5H), 7.19-7. 10 (in, 2H), 7.01 (dd, J 23 /7 O-FO -e CH CH 344-phenoxy- 8.35, 2.2 Hz, 3H), 6.94 J 7.5 Hz, 1H), 6.92 J 57 Oephenyl)- 8.8 Hz, 1H), 6.77 (dd, J 8.8, 2.2 Hz, 1H), 6.72 (d, OMe ureidometiyll- J 2.2 Hz, 1H), 6.34 2H), 5.02 2H), 3.98 (s, ___benzamide 3H), 3.87 3H).
0Biphenyl4,4'- 1 H NMR (CD 3 OD) 8 (ppm): 9.80 (bs, 2H), 8.16 (d, 234 375 N CH CH dicarboxylic acid J=7.9 Hz, 4H), 7.96 J= 7.9 Hz, 4H), 7.23 J=7.4 P H bis-[K2-amino- Hz, 2H), 7.03 Cdd, J=6.9, 7.4 Hz, 2H), 6.84 J=8.2
NH
2 phen Ylamidel Hz, 2H1), 6.66 (dd, J=6.9. 7.7 Hz, 2H), 5.06 (bs, 4H).
H N4~AI2-Ainhl 'H-NMR (DMSO-d6), 8 (ppm): 9.6 (bs, 1H), 8.32 (d, H ,j 44iid~i-2-l~ J=4.9 Hz, 2H), 7.97 (dt, J= 7.9, 9.9 Hz, 2H), 7.85-7.83 236 377 CH CH Cm, 1H), 7.47, J=8.2 Hz, 2H), 7.20 J=7.9 Hz, 13 Nylaminomethyl)- 1H), 7.01 (dt, J=7.4, 7.7 Hz, 1H), 6.82 J=7.9 Hz, I benzamide 1H), 6.66-6.62 Cm, 1H), 4.98 (bs, 2H), 4.61 2H).
H
3 C N ,NN42-Amino-phenyl)- 1 H-NMR (DMSO-d6), 8 (ppm): 9.66 (bs, 1H), 7.96 (d, NY,~ 4-(4,6-dimethyl- J=7.9 Hz, 2H), 7.61 J= 7.9 Hz, 2H), 7.21 J=7 .9 237 378 vyN CH CH pyrimidin-2- Hz 1H), 7.04-6.99 Cm, 2H), 6.82 J=7.9 Hz, 1H1),
CH
3 beslfnzameth 6.64 It, J=7.4 Hz, 1H), 4.49 Cs, 2H), 2.42 6H).
N-2-Amino-phenyl)- 'H-NMR (DMSO-d6), 6 (ppm): 9.66 Cbs, 1H), 9.07 (d, F444- J=5.2 Hz, LH), 7.97 Id, J=7.4 Hz, 2H), 7.78 J=4.7 238 37 F' Nj CH CH trifluoromethy[ Hz, 1H), 7.63 Id, J=7.4 Hz, 2H), 7.19 Id, J=7.7 Hz, 1 pyrimidin-2- 1H), 7.01 Cdt, J= 7.4, 7.7 Hz, 1H), 6.81 Id, J=8 .2 Hz, yisulfanylmethyl)- 1H), 6.64 Cdt, J=7.1, 7.4 Hz, 111), 4.94 Cbs, 2H), 4.57 __benzamide Cs, 2H).
NH
2 Pyridine-2,5- 'H-NMR CDMSOd6), 8 (ppm): 10.23 Cbs, LH), 10.04 dHaboyi acd bs, 1H), 9.30 Is, 1H1), 8.62 Cdd, J=1.8, 8.0 Hz, 1H), 239~~~ 380roxi acid 83 (,J81Hz H,75 IJ74Hz ,72 239 380 N CH 83 d z H,75 d z H,72 0 phenyD-amide] Cd, Hz, LH), 7.04 (dd, J=7.0, 14.0 Hz, 2H), Cm, 2H), 6.74-6.63 Cm, 2H), 5. 11 Cbs, 4H).
159 2006252047 14 Dec 2006 Ex. CdW Y Z Name Characterization Schm 'TH-NMR (DMSO-d6), 8 (ppm): 9.66 (bs, 1H), 8.52 (bs, N-(2-Amino-phenyl)- 1H), 7.96 J=7.4 Hz, 2H), 7.69 J=5.8 Hz, 1H), 240 381r'j C CH44pyridin-2- 7.59 J=7.4 Hz, 2H), 7.38 J=7.7 Hz, 1H), 7.19 240 81 N" C CHylsulfanylmethyiY (bs, 2H), 7.00 J=6.9 Hz, 1H), 6.83 J=6.9 Hz, 1 benzamide IH), 6.64 (dd, J=6.7, 7.2 Hz, 1H), 4.94 (bs, 2H), 4.55
CH
3 NA2-Amino-phenyl)- 'H-NMR (DMSO-d6), 8 (ppm): 9.65 (bs, 1H), 7.96 (d, 241 82 ~N C CH44(4,6-dimethy[ J=7.9 Hz, 2H),7.57 Cd, J=6.3 Hz, 1H), 7.47 J= 7.7 241 38 J -11,CHCHpyrimidin-2- Hz, 2H), 7.21 J=7.4 Hz, 1H), 7.00 J= 5.8 Hz, 33
H
3 C N N f ylamino)-methyll- 1H), 6.59 J=6.6 Hz, 1H), 6.64 (dd, J=6.0, 7.4 Hz, ___benzamide 1H), 5.01 Cs, 2H), 4.61 Cd, J=6.0 Hz, 2H), 2.24 Cs, 6H).
CH
3 N.2-Amino-phenyl)- H-NMR (DMSO-d6), 8 (ppm): 9.66 Cbs, 1H), 7.98 (d, 44(4,-dimthy J=7.9 Hz, 2H),7.50 Cd, J=8.2 Hz, 2H), 7.96 J= 7.9 242 383 CH CH 44C4,di-lmhY~ Hz, LH), 7.01 (dd, J=7.7, 7.4 Hz, 1H), 6.82 Cd, J= 7.9 33
H
3 C N N'2 peyridin-2 ami) Hz, LH), 6.64 J=7.4 Hz, 1H), 6.33 1H), 6.25 (s, H mhylbnade1H), 4.58 Cd, J=4.4 Hz, 2H), 2.28 Cs, 3H), 2.17 Cs, 3H).
CH
3 N42-Amino-phenyl)- 'H-NMR (DMSO-d6), 8 (ppm): 9.58 Cbs, LH), 7.88 Cd, 444,6-dimethy J=5.8 Hz, 2H),7.46 Cd, J=8.2 Hz, 2H), 6.90-6.81 Cm, 243 384 i N CH CH pyrimidin-?- 1H), 6.68 J=7.9 Hz, 1H), 6.50 Ct, J= 7.4 Hz, 1H), 11 H3C N oxymethyl)- 6.40-6.38 Cm, 1H), 6.29-6.26 Cm, 1H), 5.33 Cs, 2H),
H
3 Cbenzamide 2.25 Cs, 6H).
H3CN42-minophenl 'H-NMR CDMSO-d6), 5 (ppm): 9.64 Cbs, 1H), 8.21 Cbs,
HC
0 N-42-minhoxey- 1H), 7.95 Cd, J=7.96 Hz, 2H),7.83 Cd, J=5.8 Hz, 1H), 244 385CH CH prmethox- 7.44 Cd, J=7.9Hz, 2H), 7.19 J=7.7 Hz, LH), 7.00 3 244 el 38 HC yrmdn4dd, J= 7.4, 7.7 Hz, 1H), 6.80 Cd, J=7.9 Hz, 1H), 6.64 N ylenami)-etyl Cd, J=7.1 Hz, IH), 4.96 Cbs, 2H), 4.58 Cbs, 2H), 3.81 Cs, b1zmie3H).
160
I-
2006252047 14 Dec 2006 Ex._ Cp W Y Z Name Characterization Schm 04-((6Acetyl- 'H-NMR (DMSO-dG), 8 (ppm): 9.79 Cbs, IHN, 7.99 (d, benzo[1 ,3Idioxo65- J=8. 5 Hz, 2H), 7.48 Cd, J=7.96 Hz, 2H), 7.39 (bs, 1H), 245 386 <0 C H 3 CH CH ylamino)-methyl-N- 7.21 J=7.4Hz, 1H), 7.02 (dd, J=7.1, 7.7 Hz, 1H) 33 0 (2amin-pheyl)- 6.83 J= 7.7 Hz, LH), 6.64 J=7.4 Hz, 1H), 6.36 H benamidopeny) (bs, 1H), 6.00 J=2.2 Hz, 2H), 4.59 Cbs, 2H), 2.52 (bs, Ci N42-Amino-phenyl)- 'H-NMR (DMSO-d6), 5 (ppm): 9.66 (bs, 1H), 7.96 (d, N 4~44chtoro-6- J=7.9 Hz, 2H), 7.47 Cbs, 2H), 7.39 Cbs, 1H), 7.19 (d, 246 387 HO I CH CH methoxy-pyrimidin- J=7.4Hz, 1H), 7.00 (dd, J=6.9, 7.4 Hz, 1H), 6.81 33 0 -l N2-ylamino)-methyl]. J= 7.1 Hz, 1H), 6.63 (dd, J=7.7, 6.8 Hz, 1H), 6.10 Cbs, H __benzamide 1H), 4.56 Cd, J=6.0 Hz, 2H), 3.83 Cs, 3H).
1 H-NMR CDMSO-d6), 5 (ppm): 9.63 Cbs, 1H), 7.94 (d,
H
3 C- N-{2-Amino-phenyl)- J=6.9 Hz, 2H), 7.47 J=6.59 Hz, 2H), 7.15 Cd, J= 247 388 N N CH OH 4-[(2,6-dimethoxy- 7.9 Hz, 1H), 6.99 (dd, J=5.7, 7.4Hz, 1H), 6.80 Cd, J= 3 0 H pyridin-3-ylamino)- 7.8 Hz, 1H), 6.71 Cd, J= 6.6 Hz, 1H), 6.62 Cdd, J=.7,
H
3
C
0 methyll-benzamide 7.1 Hz, 1H), 6.15 Cd, J=8.2 Hz, 1H), 4.96 Cbs, 2H), Cbs, 2H), 3.94 3H), 3.75 Cs, N42-Amino-phenyfl- 1 H.NMR CDMSO-d6), 8 Cppm): 10.9 Cbs, 1H), 9.64 Cbs, 248~~ 38 CH( CH beziiazl2 7.99 Cbs, 2H), 7.55 Cbs, 2H), 7.2 1-7.17 Cm, 3H), N H ylmn)iehl-7.14-6.81 Cm, 4H), 6.64 Cd, J= 6.0 Hz, LH), 4.92 Cbs, ylnamiodethl 2H), 4.65 Cbs, 2H).
'H-NMR CDMSO-d6), 8 Cppm): 9.60 Cbs, 1H), 7.96 Cd, N.-(2-Amino-phenyl)- J=7.9 Hz, 1H), 7.52-7.50 Cm, 2H), 7.37-7.30 Cm, 1H), 4(C-methoxy- 7.25-7.21 Cm, 2H), 7.19-6.99 Cm, 1H), 6.84-6.81 Cm, 249 90 3C,0 N N C CHpyridin-2.ylamino)- 1H), 6.67-6.64 (in, 1H), 6.11-6.07 Cm, LH), 5.93-5.89 3 H methyl]-benzamide Cm, IH), 4.93 Cbs, 2H), 4.56 Cd, J=5.8 Hz, 2H), 3.80 Cs, 3H). 2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm M(2-ArninophenylY H-NMR (DMSO-d6), 8 (ppm): 9.68 (bs, 1H), 8.95 (bs, N4 2-Amiquinolin- h- 2H), 8.43-8.38 7.90 (bs, 2H), 7.80-7.55 (m, 250 391 CH OH ylsulfanylmethyl 6H), 7.22 J= 7.7 Hz, 1H), 7.03 J= 7.7 Hz, LH), 11 lsulbenzamide 6.63 J=7.4 Hz, 1H), 5.05 (bs, 2H), 4.48 J=7.7, 2H).
H N2-Amino-pheny) 'H-NMR (DMSO-d6), 8 (ppm): 9.66 (bs, 1H), 7.97 (d, 0, Tr J=27.9 Hz, 2H), 7.84 J=5.9 Hz, 1H), 7.46 J=7.46
H
3 C OH pyridiethy- Hz, 2H), 7.20 J=7.9 Hz, 1H), 7.04 J=6.6 Hz 251 392 N N CH C midi1H), 6.83 J= 7.9 Hz, LH), 6.64 (dd, J=7.7, 7.4 lz, 1 0aCHm benzamide 1H), 5.51 (bs, 1H), 4.57 2H), 3.82 3H), 3.84 3H).
1 H-NMR (DMSO-d6), 8 (ppm): 9.63 (bs, 1H), 7.79 (d,
H
3 C" N(2-Amino-phenyl)- J=8.5 Hz, 2H), 7.19 J=6.6 Hz, 1H), 7.00 (dd, 252 393 CH CH 4A3,5-dimethoxy- J=7.9, 7.1 Hz, 1H), 6.62 J=6.0 Hz, 1H), 6.82 (dd, 37 benzylaminoY J=1.4, 1.9 Hz, 1H), 6.67 J= 8.8 Hz, 2H), 6.58 (bs, CH3 benzamide 2H), 6.42 (bs, 1H), 4.87 (bs, 2H), 4.34 J=6.0 Hz, 2H), 3.77 6H).
N(2 (-Amino-phenyl)- 'H-NMR (DMSO-d6), 8 (ppm): 9.66 (bs, 1H), 7.96 (d, N.(2-Ainiox-ey) J=7.9 Hz, 2H), 7.55 J=8.2 Hz, 2H), 7.29-7.20 (in, 253 39 OH OH4-( 3-iettioxy- CH C phenylsulfanylmeth 2H), 7.02-6.95 2H), 6.84-6.79 LH), 6.67-6.62 11 0 1H), 6.57-6.54 1H), 6.44-6.41 1H), 4.93 3z (bs, 2H), 4.41 (bs, 2H), 3.79 3H).
0--VN42-Aino-phenyl- TH-NMR (DMSO-d6), 5 (ppm): 9.72 (bs, 1H), 8.05 (d,
H
3 C 4J=8.2 Hz, 2H), 7.61 J=7.9 Hz, 2H), 7.24 J=7.4 254 395 OH OH 44,5-imethoxy. Hz, 1H), 7.04 (dd, J=6.9, 7.1 Hz, 1H), 6.85 J=6.9 11 0, phenoxynethA Hz, 1H), 6.66 (dd, J= 7.4, 7.7 Hz, 1H), 6.27 2H), 0
CH
3 benzamide 6.26 1H), 5.23 2H), 5.21 (bs, 2H), 3.77 6H).
2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm 'H-NMR (DMSO-d6), 5 (ppm): 9.70 (bs, 1H), 8.35 (d, N.2-Amino-pheny)- J=9.1 Hz, 2H), 8.05 J=7.9 Hz, 2H), 7.96 J=7.9 4Aquinolin-2- Hz, 1H), 7.85 J=8.2 Hz, 1H), 7.76-7.69 2H), 36 NCH CH 11 yloxymethyl)- 7.51 (dd, J=6.9, 7.1 Hz, 1H), 7.24-7.16 2H), 7.02 benzamide (dd, J=6.9, 7.4 Hz, 1H), 6.83 J=8.2 Hz, 1H), 6.66 Cd, J=7.4 Hz, 1H), 5.66 2H), 4.94 (bs, 2H).
H 'H-NMR (DMSO-d6), 8 (ppm): 9.62 (bs, 1H), 7.96 (d, H3C OV N- N2-Arino-phenyl)- J=7.9 Hz, 2H), 7.49 J=7.9 Hz, 2H), 7.19 J=7.9 256 397 CH CH 443,5-dimethoxy- Hz, 1H), 7.00 (dd, J=7.5, 7.9 Hz, 1H), 6.81 J=7.9 phenylamino)- Hz, 1H), 6.63 (dd, J= 7.0, 8.0 Hz, 1H), 5.78 Cs, 2H), 0
,CH
3 methyl-benzamide 5.76 Cs, 1H), 4.92 2H), 4.35 Cd, J=5.7, 2H), 3.65 Cs, 6H).
O S, s bis(M2-Amino- 'H-NMR (DMSO-d6), 5 (ppm): 9.82 bs, 2H), 9.08 bs, 0 ~N pheny2 2H), 8.34 d, J=8.3 Hz, 2H), 7.83 d, J=8.3 Hz, 2H), 257 398 NH CH N nic 7.18 Cd, J=7.5 Hz, 2H), 7.01 Cdd, J=6.3, 7.0 Hz, 2H), I disulfide) 6.80(d, J=7.9 Hz, 2H), 6.61 Ct, J=7.03 Hz, 2H), 5.05
__NH
2 sbs, 4H).
'H-NMR (DMSO-d6), 8 (ppm): 9.90 Cbs, 1H), 8.16 Cbs, N f'J- inol-pnl- 2H), 7.65 Cd, J=4.8 Hz, 2H), 7.54 Cbs, 2H), 7.25 (d, 258 399 CH CH 4aoinol)n J=7.0 Hz, 2H), 7.11 Cbs, 2H), 7.07-7.02 2H), 6.84 33 y(damime h) J=7.9 Hz, 1H), 6.67 bs, 1H), 5.01 bs, 2H), 4.88 HN> ~benzamideCs,2) (bs, 2H).
N2-Amino-phenyl) 'H-NMR (DMSO-d6), S (ppm): 9.66 Cbs, LH), 7.97 Cd, HO N 4-[C2,3-dihydro- J=7.0 Hz, 2H), 7.51 Cd, J=7.0 Hz, 2H), 7.22 Cd, 259 400 CH CH benzo[1,4]dioxin-6- Hz, 1H), 7.02-6.97 Cm, IH), 6.84 Cbs, 1H), 6.82-6.71 33 0, ylamino)-methyll- 2H), 6.16 Cd, J=6.6 Hz, 1H), 6.08 Cs, 1H), 4.32 Cbs, benzamide 2H), 4.16-4.13 Cm, 4H).
2006252047 14 Dec 2006 Ex. Cd W Y Z Name Characterization Schm 'H-NMR (DMSO-d6), 8 (ppm): 9.66 (bs, 1H), 9.56 Cbs, H 44(4-Acetylamino- 1H), 7.97 J=7.9 Hz, 2H), 7.53 J=7.9 Hz, 2H), 260 401 i CH CH phenylamino)- 7.28 J=8.8 Hz, 2H), 7.22 J=7.9 Hz, IH), 7.02 (t,
H
3 C 'N4 methygl-N2-amino- J=7.5 Hz, LH), 6.83 J=7.9 Hz, 1H), 6.65 H phenyl)benzamide Hz, 1H), 6.55 J=8.3 Hz, 2H), 4.98 (bs, 2H), 4.38 Cbs, 2H), 2.00 3H).
HH-NMR (DMSO-d6), 8 (ppm): 9.65 (bs, LH), 7.98 (d, HN42-Amin-pheny- J=7.9 Hz, 2H), 7.52 Cd, J=7.9 Hz, 2H), 7.21 44(4-norpholin4- Hz, 1H), 7.02 (dd, J=7.0, 7.9 Hz, 1H), 6.83 Cd, J=7.9 yI-phenylaminoY Hz, LH), 6.78 Cd, J=8.8 Hz, 2H), 6.64 Ct, J=7.5 Hz, 1H), o methyll-benzamide 6.55 J=8.8 Hz, 2H), 4.94 Cbs, 2H), 4.35 J=5.7 Hz, 2H), 3.74 J=4.4 Hz, 4H), 2.92 Ct, J=4.4 Hz, 4H).
I(2-Amino-phenyl)- 'H-NMR (DMSO-d6), I (ppm): 9.64 (bs, 1H), 7.96 (d, H4-4methoxy-2- J=7.6 Hz, 2H), 7.52 J=7.6 Hz, 2H), 7.21 J=8.2 262 403 H N.2 CH CH methy Hz, 1H), 7.02 Ct, J=8.2, 7.0 Hz, 1H), 6.83 J=8.2 Hz, 33 M3- 0 phenylamino 1H), 6.71-6.53 Cm, 3H), 6.32-6.30 Cm, LH), 4.94 Cbs, metholJbenzamide 2H), 4.45 Cd, J=5.9 Hz, 2H), 3.65 Cs, 3H), 2.23 Cs, 3H).
N N42-Amino-phenyl)- 'H-NMR (DMSO-d6), 8 (ppm): 9.65 Cbs, 1H), 7.98 (d, H 4-[C2cyano4- J=7.4 Hz, 2H), 7.56 Cd, J=7.5 Hz, 2H), 7.19 Cd, J=7.9 263 404 N- kN..2 CH CH methoxy- Hz, 1H), 6.99 Cd, J= 7.5 Hz, 1H), 6.82 Cd, J=7.9 Hz, 33 phenylamino 1H), 6.63 Ct, J=6.6 Hz, 2H), 6.27 Cs, 1H), 4.93 Cbs, 2H), I methyl-benzamide 4.55 Cd, J=5.3 Hz, 2H), 3.69 Cs, 6H).
IH-NMR (DMSO-d6), 8 (ppm): 9.62 Cs, 1H), 8.72 Cs, 42[-Aminoxpey)- 1H), 8.49 Cd, J =10.1 Hz, 1H), 7.93 Cd, J =7.9 Hz, 2H), H 7.68 Cd, J 6.6 Hz, 1H), 7.37 Cd, J 7.5 Hz, 2H), 7.16 264 405 CH CH C)Ietdhn3 Cd, Hz, 1H), 6.97 Ct, J 7.5 Hz, 1H), 6.78 J 33
H
3 ylmethoxy- =7.9 Hz, 1H), 6.69 Cd, J 8.8 Hz, 1H), 6.62 Cd, ptheyl)-zamin- Hz, 1H), 6.23 Cd, J =2.6 Hz, 1H), 6.09 (J=8.8 Hz, 1H), 5.76 Cs, 1H), 4.64 Cbs, 4H), 3.62 Cs, 3H).
2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm H 2-[4-(2-Amino- 1 H-NMR (DMSO-d6), 8 (ppm): 9.67 (bs, 1H), 8.00 (d, phenylcarbamoyl J=7.9 Hz, 2H), 7.54 J=7.9 Hz, 2H), 7.34 IH), 265 406 H 3
C
0 N H CH CH benzylaminol4,5- 7.20 J= 7.9 Hz, 2H), 7.0 Ct, J=7.9 Hz, LH), 6.82 33 H3C ,oa OHdimethoxy-benzoic =7.9 Hz, 1H), 6.62 t, =7.9 Hz, 1H), 6.31 1H), 0 1 acid 4.95 (bs, 2H), 4.62 Cbs, 2H), 3.75 3H), 3.70 3H).
H Ai' pA nyI 'H-NMR (DMSO-d6), 8 (ppm): 9.60 1H), 7.93 (d, J=7.9 Hz, 2H), 7.45 J=7.9 Hz, 2 7.16 266 47 t H CH4-1(3,5-dimethyl- CH C phenylamino)- Hz, 1H), 6.97 J= 7.5 Hz, 1H), 6.78 J=7.9 Hz, 33 methyl]-benzamide 1H), 6.58 J= 7.0 Hz, 1H), 6.19-6.17 3H), 4.88 2H), 4.32 J=5.7 Hz, 2H), 2.10 6H).
H MH-NMR (DMSO-d6), 5 (ppm): 9.65 1H), 8.72 (s, H N-{~2-Aminophenyt)- N 1H), 8.54 1H), 8.49 J=10.9 Hz, LH), 7.97 (d, 4-(1pyridin-3- J=7.9 Hz, 2H), 7.71 J=7.9 Hz, 1H), 7.44 J=8.3 267 408CH CH ylmethoxyY 33 267 408C Heylame o- Hz, 2H), 7.41-7.36 1H), 7.20 J=7.9 Hz, 1H), 7.00 J= 7.4 Hz, 1H), 6.83 J=7.0 Hz, LH), 6.70methyly-benzamiue 6.60 4H), 4.62 4H).
'H-NMR (DMSO-d6), 8 (ppm): 9.58 1H), 7.90 (d,
CH
3 H N(2-Amino-phenyl) J=7.9 Hz, 2H), 7.45 J=7.5 Hz, 2H), 7.15 Cd, 268 409 N CH CH 4-1(2,4-dimethyl- Hz, 1H), 6.96 Ct, J=7.5 Hz, 1H), 6.79 Cs, 1H), 6.76 (d, I3C phenylamino J=9.6 Hz, JH), 6.68 J=7.9 Hz, 1H), 6.59 methyl]-benzamide Hz, 1H), 6.22 Cd, J=7.9 Hz, 1H), 4.89 Cbs, 2H), 4.39 Cd, J=5.7 Hz, 2H), 2.15 Cs, 3H), 2.10 Cs, 3H).
CH
3 H N-2-Amino-phenyl) 'H-NMR (CD 3 OD), 5 (ppm): 7.91 Cd, J=7.9 Hz, 2H), 269 410 N CH CH 4-[(2,4,6-trimethyl- 7.43 Cd, J=8.5 Hz, 2H), 7.18 Cd, J=7.5 Hz, 1H), 7.08 (t, phenylamino J=7.5 Hz, 1H), 6.92 Cd, J=7.9 Hz, 1H), 6.77 Cs, 3H),
H
3 C CH3_ methyg-benzamide 4.15 bs, 2H), 2.19 9H).
N(2-Amino-phenyl) 'H NMR (300 MHz, DMSO-D 6 5 (nny 9.66 Cs, H 4-[(4-chloro-6- LH), 7.97 J 8.0 Hz, 2H), 7.82 Cm, 1H), 7.47 Cd, J 270 411 ~N NIN CH CH morpholin4-yI- 7.7 Hz, 2H), 7.21 Cd, J 8.2 Hz, 1H), 7.03 Cdd, J 24, pyrimidin-2- 7.1, 7.1 Hz, 1H), 6.84 Cd, J 7.7 Hz, LH), 6.65 Cdd, J 33 a ylamino)-metyll- 7.4, 7.4 Hz, 1H 6.17(bs, 1H), 4.94 Cs, 2H, NH 2 I_ lbenzamide 14.53 Cd, J 5.8* Hz, 2H), 3.58 Cm, 4H), 3.62 Cm, 4H).
2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm N42Amio-henlY'H NMR (300 MHz, DMSO-d 6 6 (PPM): 9.33 1H), MeON 4434-Aiopey) 7.81 J 8.8 Hz, 2H), 7.19 J 7.7 Hz, it]) 6.99 271 1412 H CH H 3rimth5y (in, 6.87 (dd, J 6.0, 5.8Hz, 1H), 6.82 (in, 3 He CHC tietoy 6.77 2H), 6.71 (d J =8.8 Hz, 2H), 6.64 (in, 1H), OMe benz~'amino)- 4.87 2H, NH 2 4.32 J =5.5 Hz, 2H), 3.81 (s, benzamide 6H), 3.79 3H).
'H NMR (300 MHz, DMSO-d 6 8 6 (PPM): 9.31 i1H), N42-Amino-phenyl)- 7.79 J 8.7 Hz, 2H), 7.45 (dd, J 5.8, 8.5 Hz, 27 1 H CH CH] 444-fluoro- 2H), 7.21 (in, 3H), 6.91 (in, 2H), 6.81 (dd, J 1.1, 3 27 413 benzytamino)- 8.0Hz, 1H), 6.67 Kd J 8.8 Hz, 2H), 6.62 (dd, J 1.0, benzamide 7.2 Hz, i1H), 4.86 2H, NH 2 4.39 J 6.0 Hz, N42Amio-penyY IH NMR (300 MHz, DMSO-dr,) 8 (ppm): 9.31 it]), N- NA-minhoxy- 7.79 (dd, J 1. 1, 8.5 Hz, 2H), 7.33 Ji 7. 1 Hz, 273 414 Me IC H CH CH 4b4-nethmoy 2H), 7.19 J =7.7 Hz, 6.97 (in, 3H), 6.84 (in, 33 MeO benzyamino) 2H), 6.65 (in, 3H), 4.86 2H, NH 2 4.33 J benzmideHz, 2H), 3.58 J 1.6 Hz,3H).
'H -NMR (300 MHz, DMSO-d 6 8 (PPM): 9.66 1H), H N-(2-Amino-phenyl)- 7.99 J 7.9 Hz, 2H), 7.53 J =8.0 Hz, 2H), 7.21 274 415 <.iN\CH CH 4-1(4-fluoro- J 8.0 Hz, 7.02 (ddd J 7.1, 8.2 Hz,' 1H),'3 F->phenylamino)- 6.93 (dd, J 9 Hz, 2H), 6.83 (dd, J 1. 1, 8.0 Hz, methyfi-benzamide 6.63 (in, 3H), 6.35 J= 6.2 Hz, i1H), 4.94 2H, 4.38 J 6.3 Hz, 2H).
'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.32 it]), N42-Amino-phenyl)- 7.79, J 8.8 Hz, 2H), 7.44 (in, 7.26 (in, 1 H), N A- 7.18 (dd, J 1.4, 8.0 Hz, 2H), 7.12 (ddd, J 275 416 IH CH Ct] 443-fluoro- 8.2 Hz, 6.99 (in, 6.81 (dd, J 8.0 Hz, 33 F benzyamino) 6.67 (dd, J 1.6, 8.8 Hz, 2H), 6.62 (dd, J= 1.4, benzamide7.4 Hz, 4.87 2H, NH 2 4.45 J 6.0 Hz, 2H). 2006252047 14 Dec 2006 Ex. _Cpd W Y Z Name Characterization Schm 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.66 1H), H N42-Amino-phenyl)- 7.99 J 8.2 Hz, 2H), 7.52 J 8.0 Hz, 2H), 7.21 276 417 I CH CH 4-[(3-fluoro- J 7.7 Hz, 1H), 6.99-7.14 6.83 J 8.0 33 phenylamino)- Hz, 1H), 6.76 1H), 6.64 (dd, J 7.4 Hz, 1H), F methyll-benzamide 6.46 J 8.2 Hz, 1H), 6.34 2H), 4.94 2H,
NH
2 4.41 J 6.0 Hz, 2H).
H N-(2-Amino-phenyl)- 1 H NMR (300 MHz, DMSO-D) 5 (ppm): 9.66 1H), 277 418 N 4(4-chloro-6- 8.23 1H), 7.98 J 8.2 Hz, 2H), 7.47 J 277 418 CH CH methyl-pyrimidin-2- Hz, 2H), 7.21 J 7.7 Hz, 1H), 7.03 (ddd, J 1.5, 33 ylamino)-mnethyl]- 7.1, 8.0 Hz, 1H 6.83 (dd, J 1.5, 8.1 Hz, 1H), 6.65 benzamide 2H), 4.94 2H, NH 2 4.61 2H), 2.3 2(s, 3H).
N2-Amino-phenyl 1 H NMR (300 MHz, DMSO-D 6 8 (ppm): 9.69 1H), H 8.82 1H), 7.99 J 8.2 Hz, 2H), 7.48 J ci N N 4 -[(4,6-dichloro- 28 N YCH CH 4-ri(4,6dichloro- Hz, 2H), 7.27 J 7.7 Hz, 1H), 7.04 J 7.7 Hz, 278 419 pyrimidin-2- 1H), 7.0 J 1.6 Hz, 1H), 6.84 J 8.2Hz, 1H), cylamino)-methyll- 6.67 1H 5.0 (bs, 2H, NH 2 4.60 J 6.3 Hz, benzamide 2) 2H).
N42-Amino-phenyl- H H 44(4-chloro-6- 'H NMR (300 MHz, DMSO-D 6 8 (ppm): 9.87 1H), N N N [(pyridin-3- 8.49 (bs, 2H), 7.26-8.02 (bm, 8H), 7.22 J 8.0 Hz, 24 279 420 yN CH CH ylmethyl)-amino]- 1H), 7.03 (dd, J 7.4, 7.4 Hz, 1H), 6.84 J 8.2 24, N 6. CI pyrimidin-2- Hz, 1H 6.66 (dd, J 7.1, 8.0 Hz, 1H), 5.86 (bs, 1H), ylamino)-methyl)- 4.95 2H, NH 2 4.51 2H).
benzamide 'H NMR (300 MHz, DMSO-D 6 8 (ppm): 9.66 1H), H N42-Amino-phenyl)- 7.99 J 8.4 Hz, 2H), 7.54 J 7.9 Hz, 2H), 7.50 S4(6(methoxy- d, J 2.6 Hz, 1H), 7.21 J 7.5 Hz, 7.9 Hz, 1H), 280 421 CH CH 4-3(6-methoxy- 7.12 (dd, J 3.08 Hz, 8.79 Hz, 1H 7.02 (dd, J 7.0 33 pyridin-3-ylamino) Meo N ethylbenzaiide Hz, 7.5 Hz, 1H 6.83 J 7.0 Hz, 1H), 6.65 (m, 2H), 6.15 J 6.16 Hz, 1H), 4.94 2H, NH 2 4.39 J 6.15 Hz, 2H), 3.75 3H).
2006252047 14 Dec 2006 Ex. Cpd W V Z Name Characterization Schm N42-Aminophenyl)- 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.66 1H), H 7.99 J 8.0 Hz, 2H), 7.53 J 8.2 Hz, 2H), 7.21 281 422 CH CH trifluoromethoxy- J 7.7 Hz, 1H), 7.09 J 9.1 Hz, 2H), 7.03 (dd, 33 tif nlumthoxy J 7.1, 8.2 Hz, 1H), 6.83 J 8.0 Hz, 1H), 6.71 (t, Faco phenylamino)- Sheyl zamino) J 6.0 Hz, 1H), 6.63-6.67 3H), 4.94 2H, NH 2 methyll-benzamide 4.42 J 6.0 Hz, 2H).
H N-(2-Amino-phenyl)- 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.67 1H), N NV 8.00 J 8.2 Hz, 2H), 7.53 J 8.2 Hz, 2H), 7.19 282 423 K CH CH trifluoromethoxy- 2H), 7.03 (ddd, J 1.5, 8.0, 8.8 Hz, 1H), 6.85 33 y phenylamino)- 2H), 6.63 2H), 6.55 1H), 6.50 1H), 4.94 (s,
CF
3 methyl]-benzamide 2H, NH 2 4.44 J 6.0 Hz, 2H).
'H NMR (300 MHz, DMSO-d 6 5 (ppm): 9.65 1H), H N-(2-Amino-phenyl)- 7.98 J 7.9 Hz, 2H), 7.54 J 7.9 Hz, 2H), 7.22 N 444 e v- o-(3,4-dimethoxy- J 7.9 Hz, 1H), 7.02 (dd, J 7.9 Hz, 7.9 Hz. 1H), 283a 424b CH CH 4 -ieoy 6.83 J 7.9 Hz, 1H), 6.72 J 8.79 Hz, 1H), 33 henyleami 6.45 (dd, J 7.49 Hz, 7.49 Hz, LH), 6.39 J 2.2 OMe methylbenzamide Hz, 1H), 6.01-6.08 2H), 4.94 2H, NH 2 4.36 (d, J 6.16 Hz, 2H), 3.72 3H), 3.65 3H).
N42-Amino-phenyl)- 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.31 1H), Nk 443- 7.80 J 8.8 Hz, 2H), 7.45-7.56 2H), 7.39 (s, 284 425 N H CH CH trifluoromethoxy- 1H), 7.29 J 7.7 Hz, 1H), 7.18 J 6.6 Hz, 1H), 33 6.96-7.03 2H), 6.81 J 6.9 Hz, 1H), 6.68 i
OCF
3 benzylamino) 8.8 Hz, 2H), 6.64 i 7.7 Hz, 1H), 4.86 2H, benzamide
NH
2 4.48 J 5.8 Hz, 2H).
'H NMR (300 MHz, DMSO-d 6 5 (ppm): 9.31 1H), N42-Amin heny!) N42-Aminohen4- 7.79 J 8.8 Hz, 2H), 7.54 J 8.8 Hz, 2H), 7.39 285H2OH CH trifluoromethoxy- J 8.0 Hz, 2H), 7.18 (dd, J 1.4, 7.7 Hz, 1H), F8co 6.99 (ddd, J 1.4, 8.0, 8.5 Hz, 2H), 6.81 (dd, J 1.4, benzylamino)benzaminode 8.0, 1H), 6.68 J 8.8 Hz, 2H), 4.85 2H, NH 2 benzamide 4.45 J 6.0 Hz, 2H).
2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.64 1H), N2A h 7.97 J 8.2 Hz, 2H), 7.53 J 8.5 Hz, 2H), 7.21 N-(2-Amin phenyl)- H J 1.4, 8.0 Hz, 1H), 7.02 (ddd, J 1.4, 7.4, 286 427 CH CH 4(4-methoxy- Hz, 1H), 6.83 (dd, J 1.4, 8.0 Hz, 1H), 6.74 2H), 33 MeO phenylamino)- 6.65 (ddd, J 1.4, 7.7, 8.8 Hz, 1H), 6.58 2H), methyl]-benzamide 5.99 J 6.3 Hz, 1H), 4.93 2H, NH 2 4.36 J Hz, 2H), 3.68 3H).
'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.65 1H), N42-Amino-phenyl)- 7.98 J 7.9 Hz, 2H), 7.52 J 7.9 Hz, 2H), 7.21 N 4- J 7.5 Hz, 1H), 7.02 (dd, J 7.0, 7.0 Hz, 1H), 287 428 ,CH CH (benzol1,3]dioxol- 6.83 J 7.5 Hz, 1H), 6.63-6.69 2H), 6.33 J 33 0o 5-ylaminomethyl- 2.2 Hz, 1H), 6.15 J 6.16 Hz, 1H), 6.04 (dd, J benzamide 2.2, 8.4 Hz, 1H), 5.86 2H), 4.94 2H, NH 2 4.35 J 6.16 Hz, 2H).
'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.63 1H), H N42-Amino-phenyl)- 7.90 J 8.2 Hz, 2H), 7.52 J 8.2 Hz, 2H), 7.22 ,288 42 OH 4-(2-methoxy- J 7.7 Hz, 1H), 7.02 (ddd, J 1.4, 7.1, 8.0 Hz, phenylamino)- 1H), 6.86 2H), 6.56-6.75 3H), 6.43 (dd, J ome methyll]-benzamide 1.6, 7.7 Hz, 1H), 5.75 J 6.3 Hz, 1H), 4.93 2H,
NH
2 4.47 J 6.3 Hz, 2H), 3.88 3H).
'H NMR (300 MHz, DMSO-d 6 6 (ppm): 9.61 1H), H N-(2-Amino-phenyl)- 7.98 J 8.0 Hz, 2H), 7.53 J 8.2 Hz, 2H), 7.21 289 430 N CH CH 4-(3-methoxy- (dd, J 1.1, 7.7 Hz, 1H), 6.97-7.05 2H), 6.82 (dd, phenylamino)- J 1.2, 8.1 Hz, 1H), 6.46 (ddd, J 1.4, 7.7, 8.0 Hz, OMe methyllbenzamide 1H), 6.41 J 6.3 Hz, 1H), 6.16-6.25 3H), 4.93 2H, NH 2 4.39 J 6.0 Hz, 2H), 3.69 3H).
'H NMR (300 MHz, DMSO-ds) 8 (ppm): 11.53 1H), N42-Amino-phenyl)- 42-A io-p 9.71 1H), 8.08 J 8.2 Hz, 2H), 7.86 J 8.8 290 431 OH OH~ 4-42,2,2-trifluoro- 1 F 290 431 FC k NCH CH 4 2tro- Hz, 2H), 7.23 J 7.6 Hz, 1H), 7.03 (dd, J 7.0, 14 Fa acetylamino)- H .enami) 7.6 Hz, 1H), 6.84 J 8.2 Hz, 1H), 6.66 (dd, J benzamide.0, 7.6 Hz, 1H), 4.96 s, 2H, NH 2 7.6 Hz, 1H), 4.96 2H, NH2).
2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm N.C2-Amino-phenyl) 1H NMR (300 MHz, DMSO-d) 5 (ppm): 9.64 Cs, 1H), H H 4-([4chloro-6- N N IN 4-(-c7.95 Cd, J 7.5 Hz, 2H), 7.70 Cbs, 2H), 7.45 J ir (3,4,5-trimethoxy- 2 N CH( CH (3,4,-trimethoxY- 8.4 Hz, 2H), 7.22 J 7.9 Hz, 1H), 7.03 Cdd, J 24, 7.0, 7.5 Hz, 1H), 6.84 Cd, J 7.9, Hz, 1H), 6.60-6.72 33 MeO \l /pyrimidin-2- MeO OMe laminometyl)- Cm, 3H), 5.87 1H), 4.93 Cs, 2H, NH 2 4.54 J= Sbenzamide 6.2 Hz, 2H), 4.43 Cbs, 2H), 3.78 6H), 3.68 Cs, 3H).
N42-Amno-phenyl)- H H 4-114-chloro-6- 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.65 1H), MeO N N N (3,4,5-trimethoxy- 9.43 Cs, 1H), 7.97 3H), 7.46 (bs, 2H), 7.21 J 24 292 433 CH CH phenylamino)- 7.5 Hz, 1H), 7.02 3H), 6.83 Cd, J 7.0 Hz, LH), MeO N pyrimidin-2- 6.65 (dd, J 7.5, 7.5 Hz, 1H), 6.08 1H), 4.93 (s, OMe C ylamino-methyU- 2H, NH 2 4.69 (bs, 2H), 3.65 9H).
benzamide N(2-Amino-phenyl)- 1H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.31 Cs, 1H), 7.79 Cd, J 8.8 Hz, 2H), 7.19 J 7.9 Hz, 2H), 7.04 293 434 H CH CH 4.C3,4-dimethoxy- 1H), 6.92-7.01 Cm, 3H), 6.80-6.87 Cm, 2H), 6.69 33 OMe benzamin) J 8.8 Hz, 2H), 6.62 Cm, 1H), 4.87 Cs, 2H, NH 2 4.32 Cd, J 5.7 Hz, 2H), 3.80 3H), 3.78 Cs, 3H).
'H NMR (300 MHz, DMSO-d 6 S (ppm): 9.64 1H), N42-Amino-phenyl)- 7.95 Cd, J 8.4 Hz, 2H), 7.87 Cd, J 7.9 Hz, 1H), lH 4-(4-morphoin-4- 7.47 Cd, J 7.9 Hz, 2H), 7.31 Cbs, 1H), 7.21 Cd, J 294 435 N NCH CH yl-pyrimidin-2- 7.5, 1H), 7.02 Cdd, J 7.9 Hz, 1H), 6.83 Cd, J 7.9 y Y, 33 ylaminorethyll- Hz, 1H), 6.65 Cdd, J= 7.0, 7.0 Hz,lH), 6.09 Cd, J 6.2 benzamide Hz, 1H), 4.94 Cs, 2H, NH 2 4.54 Cd, J 5.7 Hz, 2H), 1_ 13.67 Cs,_4H),_3.53 2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 10.82 1H), SN42-Amino-phenyl 9.65 1H), 7.98 J 8.4 Hz, 2H), 7.56 J 7.9 H N42-Amino-phenyl)- 295 436 CHindol-3-y- Hz, 1H), 7.51 J 8.4 Hz, 2H), 7.38 J 7.9 Hz, HN Hindol-3-yl)- 295 436 CH CH ylamino- 2H), 7.18-7.23 2H), 7.11 (dd, J 7.0, 8.0 Hz, 1H), 57 methyl)-benzamide 7.01 2H), 6.83 J 7.9 Hz, 1H), 6.51 (dd, J methyll-benzamide 7.5, 6.6 Hz, 1H), 4.93 2H, NH2), 3.89 2H), 2.89 4H).
'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.67 1H), N(2-Amino-phenyl)- H 7.99 J 7.5 Hz, 2H), 7.52 J 7.5 Hz, 2H), 4-1(4- 296 437 Nv CH CH methylsulfanyl 7.21 J 7.5 Hz, 1H), 7.13 J 7.5 Hz, 2 H), 296 437 CH CH Imethylsulfanyl- 33 phenamino 7.03 (dd, J 7.5, 7.5 Hz, 1H), 6.83 J 7.9 Hz, Mesphnamo) 1methyll-benzamide 6.53 4H), 4.95 2H, NH 2 4.41 J 5.7 methyll-benzamide Hz, 2HI, 2.37 3H).
N2-Aino-pheny 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.66 1H), N42-Aminhenyl) H 7.99 J 7.5 Hz, 2H), 7.53 J 7.5 Hz, 2H), N 4(3- 7.21 J 7.5 Hz, 1H), 7.03 2H), 6.83 J 7.9 297 438 33VC 4[3 297 438 CH CH methylsulfanyl- 33 H Hmeylsfn- Hz, 1H), 6.65 (dd, J 7.5, 7.5 Hz, 1H), 6.39-6.51 (m, phenylamino)- SMe ethy-benzamide 4H), 4.94 2H, NH 2 4.41 J 5.7 Hz, 2H), 2.42 methyl~benzamide 3H).
Meo N42-Amino-phenyl)- 'H NMR (300 MHz, DMSO-d) 8 (ppm): 9.66 1H), H 4-(14-chloro-643,4- 8.37 1H), 7.99 J 7.5 Hz, 2H), 7.68-7.79 (m, 298 439 MeO I"NX CH CH dimethoxy-phenyl 2H), 7.55 (bs, 2H), 7.37 1H), 7.20 J 7.1 Hz, N pyrimidin-2- 1H), 7.11 (bs, 1H), 7.02 (dd, J 7.5, 7.5 Hz, 1H), 6.82 33 Sylaminol-methyl)- J 7.9 Hz, 1H), 6.64 (dd, J 7.5, 7.5 Hz, 1H), benzamide 4.93 2H, NH 2 4.86 2H), 3.88 6H).
N42-Amino-phenyl)- 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.64 1H), Meo 4-[443,4- 8.35 J 4.8 Hz, 1H), 7.97 J 7.9 Hz, 2H), 7.89 299 440 H N CH Hdimethoxy-phenyl)- 1H), 7.72 2H), 7.55 J 7.5 Hz, 2H), 7.2 15, 1, 299 440 Me 3 _NN CH CH C CHpyrimidin-2- J 5.3 Hz, 2H), 7.10 J 8.4 Hz, 1H), 7.01 1H), 33 N yfamino]-methyll- 6.82 J 7.0 Hz, 1H), 6.41 J 7.5 Hz, 1 4.92 Sbenzamide 2H, NH 2 4.68 J 6.2 Hz, 2H), 3.82 6H).
2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm- IH NMR (300 MHz, DMSO-d 6 8 (ppmn): 9.68 Cs, 1H),
H
3 C 0 4-t(2-Acetyl-4,5- 9.45 J 5.7 Hz, 1H), 8.01 Cd, J 7.9 Hz, 2H), 7.54 H dimnethoxy- J 8.4 Hz, 2H), 7.32 1H), 7.21 J 7.5 Hz, 300 441 H OH phenylamino)- 1H), 7.02,(dd, J 6.6, 7.5 Hz, 1H), 6.83 J 7.5 33 MeO methyg-N42-amino- Hz, 1H), 6.65 (dd, J 7.0, 7.5 Hz, 1H), 6.31 Cs, 1H), OMe pheno~benzamtide 4.95 2H, NH 2 4.63 J =5.7 Hz, 2H), 3.78 Cs, 3.76 3H).
N42-Amino-phenyl)- 'H NMR (300 MHz, CD 3
OD+CDCI
3 8 (ppm): 7.99 (d, H H 4I-(14-{3,4- J 7.9 Hz, 2H), 7.80 Ji 6.2 Hz, 1H), 7.76 1H), N N N dimethoxy- 7.52 J 8.4 Hz, 2H), 7.27 Cmn, 1H), 7.14 Cm, 1H), 301 442 I~ Nr 'I'OH OH phenylamino)- 7.05 (dd, J 2.2, 8.8 Hz, 1H), 6.95 J 7.9 Hz, 1, 33 OMe pyrimidin-2- 1H), 6.88 J 8.8 Hz, 1H), 6.83 J 7.9 Hz, 1H), ylamnino-nethyl)- 6.08 J 6.2 Hz, 1H), 4.75 Cs, 2H), 3.79 Cs, 3H), __benzamnide 3.42 Cs, 3H).
H N42Amin-pheyl)-'H NMR (300 MHz, DMSO-d 6 8 (ppmn): 9.66 Cs, 1H),
H
3 C PH 3 7.96Arino(dyD J 84Hz, 7.42 J 7.9Hz 7.20
H
3 C Sl' 7.96Cd, .4 ter bz, x-l2~etbW Cd, J 7.5 Hz, 1H), 7.02 J 6.6, 8.4 Hz, 1H), 302r 44C SOHC dimnethyl- 6.83 Cd, J 7.0 Hz, 1H), 6.77 Cd, J =8.8 Hz, 1H) 6.65 302 44 CH CHsilanyloxy)-ethytl- 3 N (3,4-dimethoxy- Cdd, J 7.0, 7.0 Hz, 1H), 6.44 J 2.6 Hz, I1H), MeO phenyl)-aminol- 6.19 Cdd, J 2.6, 8.8 Hz, 1H), 4.93 Cs, 2H), 4.67 Cs, 2H), 3.88 J 5.7 Hz, 2H), 3.71 Cs, 3H), 3.67 Cs, 3H), omemeLIhyl)-Ienzamide 3.60 Ct, J 5.5 Hz), 0.96 Cs, 9H), 0.06 Cs, 6H).
'H NMR (300 MHz, DMSO-d 6 8 (ppm)S (ppmn): 9.65 OH N42-Amino-phenyl)-s 1) 7.96 Cd, J 7.5 Hz H,7.42 KJ 7.5 Hz, K4]1C(3,4-dimnethoy%"- 2H), 7.21 Cd, J 7.5 Hz, 1H), 7.02 C(dd, J 7.0, Hz, 1H), 6.83 Cd, J 7.9 Hz, 1H), 6.78 J 8.8 Hz, 33, 303 444 -eq N OH OH phenyl)A2-hydroxy- 1H 6.65 Cdd, J 7.0, 7.5 Hz, 1H), 6.44 1H), 6.19 23 O~e ethyl)namide Cd, J 8.8 H z, 1 4.94 Cs, 2H), 4.79 Cm, 1 4.66 Cs, We mehyl)benzmide2H), 3.67 and 3.71 C2s and broading underneath, 8H), 13.55 Cm, 172 2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm I 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.82 1H), N42-Amino-phenyl)- H 6N4(4 9.13 1H), 8.33 J 8.0 Hz, 1H), 7.56 J Meo N tr6-1(3,4,- Hz, 1H), 7.21 J 7.7 Hz, 1H), 7.03 J 7.4, 304 445 CH N trimethoxy- 17.7 Hz, 1H), 6.82 J 8.0 Hz, 1H), 6.40 (dd, J 33 MeO phenylamino)- 7.4, 7,7 Hz, 1H), 6.31 J 5.8 Hz, 1H), 5.96 2H), one methyl]- OMe methyl- 5.01 2H), 4.48 J 5.8 Hz, 2H), 3.70 6H), nicotinamide nicoinamide 3.56 3H).
N42-Amino-phenyl)- 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 8.69 J o H 6-2444-oxo-4H- 2.2 Hz, 1H), 8.46 1H), 8.40 J 8.8 Hz, 1H), 305 446 /N;N CH N quinazolin-3-yl)- 8.32-8.36 1H), 7.91-7.96 1H), 7.77 1H), 3 ethylaminol- 7.67 1H) 7.5 4H), 7.2 1H), 4.46 J 5.9 nicotinamide Hz, 1H), 4.09 J 5.9 Hz, 2H).
N42-Amino-phenl)- 1'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.37 1H), 4-[bis-(3- 7.84 (d J 8.8 Hz, 2H), 7.54 (dd, J 7.9, 7.9 Hz, 2H), 306 447 F 3 co CH CH trifluoromethoxy- 7.18-7.37 6H), 7.17 J 7.0 Hz, 1H), 6.99 (dd, J 33
OCF
3 benzyl)aminol- 7.0, 7.9 Hz, 1H), 6.82 3H), 6.63 (dd, J benzamide 7.5 Hz, 1H), 4.94 4H), 4.86 2H).
'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.58 1H), N42-Aminophenyl)- 7.92 J 7.9 Hz, 2H), 7.49 J 7.9 Hz, 2H),
H
3 C N NH dmthyain 7.34 J 8.8 Hz, 1H), 7.15 J 7.5 Hz, 1H), 307 448 6N-K CH CH benzothiazo5- 6.96 J 7.9 Hz, 1H), 6.76 J 7.9 Hz, 1H), 6.59 33
H
3 C benzothiazo5- H ylaminmethyl- d, J 7.5 Hz, 1H), 6.55 1H), 6.44 J 8.4 Hz, ylamino)-methyll- 1benzamide 6.34 J 5.7 Hz, 1H), 4.88 (bs, 2H), 4.37 J benzamide 5.7 Hz, 2H), 3.06 6H).
'H NMR (300 MHz, DMSO-d) 8 (ppm): 10.2 1H), N(2-mino-phenyl)- (2-no-ph- 10.1 1H), 9.62 1H), 7.94 J 7.9 Hz, 2H), 4-((2-oxo-2, 3- H dihydro-H- 7.41 J 7.9 Hz, 2H), 7.15 J 7.5 Hz, 1H), 308 449 0o- N CH CH bimdao-5- 6.96 J 7.5 Hz, 1H), 6.77 J 7.9 Hz, 1H), 6.69 33 benzoimidazol-5ylamino)-methyll- d, J 8.4 Hz, 1H), 6.59 J 7.5 Hz, 1H), 6.34 J ylamino)methylli 8.4 Hz, 1H), 6.34 J 8.4 Hz, 1H), 6.30 1H), benzamide89 bs, 2H), 4.72 s, 2H).
4.89 (bs, 2H), 4.72 2H).
173 2006252047 14 Dec 2006 Ex. Cpd W Y IZ Name Characterization Schm 0 N4-mn-hnl-'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.60 1H), H I2-mNHo-4en(4 7.94 Cd, J 7.9 Hz, 2H), 7.46 J =7.9 Hz, 2H), 309 450 rN NH 2 OH OH trifluoromethyl sulfa 7.35 J 8.4 Hz, 2H), 7.15 J =7.9 Hz, 1H), 3 s ~nyl-phenylamino)- 7.11 Ji 6.2 Hz, 1H), 6.97 J 7.0 Hz, 1H1), 6.77 F4F methyi-benzamide Cd, J 7.5 Hz, 1H), 6.66 J 8.4 Hz, 2H), 6.60 J 7.9 Hz, 1H), 4.88 Cbs, 2H), 4.72 J 6.2 Hz, 2H).
'H NMR (300 MHz, CD 3 OD) 8 (ppm): 8.67 Cd, J =1.8 N-(2-Arnino-phenyl)- Hz, 1H), 8.47 (dd, J 4.4 Hz, 8.08 1H), N::a Nh44-1[2Apyridin-3- 8.03 Cd, J 7.9 Hz, 2H), 7.92 J 8.4 Hz, LH), 310 51 O OHylmethylsulfanyl) 7.87 Cd, J 7.9 Hz, 2H), 7.58 Cd, J 8.4 Hz, 11H), N 1H-benzoimidazol- 7.36-7.30 (in, 3H); 7.20-7.15 (in, 1H); 7.08 Cdt, J H 5-ylaminol-rnethyl)- 1.3, 8.4 Hz, IH), 6.94 (dd, J 1.3, 7.9 Hz, 1H), 6.77 benzamide Cd, J 2.2 Hz, 1H), 6.74 Cd, J 2.2 Hz, 1H), 6.65 Cd, J 1.8 Hz, 1H), 4.55 Cs, 2H); 4.20 (bs, 2H); 3.36 Cs, 2H).
N42Amio-peny-' H NMR (300 MHz, CD 3 OD) 8 (ppm): 8.60 1H), N.(24pAmiin-ten- 8.36 Cd, J 4.4 Hz, 1H), 7.89 Cd, Ji 7.9 Hz, 2H), Nf NH- OH 4.(r2Apyidin- 7.'87 Cm, 1H); 7.47 Cd, J =7.9 Hz, 2H), 7.30 Ct, J 6.6 311 452 CH C H bnoaz5- Hz, 1H), 7.20-7.15 Cm, 2H); 7.04 t, J 7.5 Hz, 1H), 33 ylamino]-methy)- 6.87 Cd, J 7.9 Hz, 1H1), 6.73 Ct, J 7.5 Hz, 1H), 6.66 benzaide Cs, 1H); 6.61 J 8.8 Hz, LH), 4.87 Cs, 2H); 4.45 Cs, benzamide 2H); 4.37 Cs, 2H); 3.35 Cs, 'H NMR (300 MHz, CDCI 3 8 (ppm): 8.21 1H); 7.90 0 trifluoromethy- Cd, J 8.4 Hz, 2H); 7.54 Cm, 1H); 7.50 Cd, J 8.4 Hz, 312 45 Me ~NH2 phenyI.4-[C3,4- 2H); 7.4 1-7.34 Cm, 2H); 6.87 Cd, J 8.4 Hz, 1H1); 7.77 JJ~fdimethoxy- J 8.4 Hz, 1H); 6.35 Cd, J 2.2 Hz, 1H); 6.20 Cdd, MeOa F 3 C phenylamino)- J 2.2, 8.8 Hz, 1H1); 4.43 Cs, 2H); 4.29 Cs, 2H); 3.84 __InethylU-benzamide Cs, 6H),.
2006252047 14 Dec 2006 Ex. Cpd W Y Z Name Characterization Schm 'H NMR (300 MHz, CDCI 3 8 (ppm): 8.21 1H); 7.84 o N42-Amino-4,5- H -I,-NH n4 d, J 7.9 Hz, 2H); 7.45 J 7.9 Hz, 2H); 7.20 (dd, SNHdifluoro-phenyl)-4 J 2.6, 8.4 Hz, 1H); 6.76 J 8.8 Hz, 1H); 6.57 313 4543,4-dimethoxy- 33 454Y F p(3,4-dimethoxy- (dd, J 3.9, 7.9 Hz, 1H); 6.32 J 2.6 Hz, 1H); phenylamino)- 6.16 (dd, J 2.6, 8.4 Hz, 1H); 4.40 2H); 3.82 (s, F methyll-benzamide 9H).
9H).
N42-Amino-phenyl)- 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.60 1H); H 4-((2-oxo-2,3- 7.93 J 7.9 Hz, 2H); 7.47 J 7.9 Hz, 2H); 314 455 NCH CHH dihydro- 7.16 J 7.5 Hz, 1H); 6.97 2H); 6.78 J 314 benzooxazo5- 7.5 Hz, 1H); 6.59 J 7.5 Hz, 1H); 6.35 J 5.7 ylamino)-methyl]- Hz, 1H); 6.27 2H); 4.88 (bs, 2H); 4.34 J 6.2 benzamide Hz, 2H).
'H NMR (300 MHz, DMSO-d 6 8 (ppm): 7.92 J N42-Amino-phenyl)- 7.9 Hz, 2H), 7.66 J 4.4 Hz, 1H), 7.49 J 7.9 N J NHA 4-[(2-methylamino- Hz, 2H), 7.26 J 8.4 Hz, 1H), 7.15 J 7.9 Hz, 315 456 MeHN CH CH benzothiazol5- 1H), 6.96 J 8.4 Hz, 1H), 6.59 J 7.9 Hz, 1H), 33 s ylamino)-methyll- 6.53(s, 6.40 (dd, J 1.3, 8.4 Hz, 1H); 6.28 (t, benzamide J 5.7 Hz, 1H), 4.88 (bs, 2H), 4.36 J 5.7 Hz, 2H), 2.85 J 4.4 Hz, 3H).
O H2N N42,6Diamino- 'H NMR (300 MHz, CDCI 3 8 (ppm): 8.09 1H); 7.88 phenyl)4-[(3,4- J 7.5 Hz, 2H); 7.48 J 7.5 Hz, 2H); 6.97 J 316 457 MeO H= dimethoxy- 7.9 Hz, 1H); 6.73 J 8.4 Hz, 2H); 6.64 J 33 2N phenylamino)- 7.9 Hz, 1H); 6.29 1H); 6.14 J 8.4 Hz, 1H); MeO methyll-benzamide 4.39 2H); 3.81 3H); 3.80 3H); 3.70 (bs, 5H) 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.61 1H); N-(2-Amino-phenyl)- 7.95 J 7.9 Hz, 2H); 7.73 J 5.7 Hz, 1H); 7.52 0 4-1[242-methoxy- J 8.4 Hz, 1H); 7.47 J 7.9 Hz, 2H); 7.15 (d, 317 458 CH CH ethyl)-1,3-dioxo- J 7.9 Hz, 1H); 6.97 J 7.5 Hz, 1H); 6.92 (bs, 31 58NCH CH 33 2,3dihydro-1H- 1H); 6.86 J 8.4 Hz, 1H); 6.77 J 7.9 Hz, 1H); 0 isoindol-5-ylamino]- 6.59 J 7.5 Hz, 1H); 4.89 (bs, 2H); 4.54 J methyll-benzamide 5.7 Hz, 2H); 3.65 J 5.3 Hz, 2H); 3.47 J 5.3 Hz, 2H); 3.20 3H); 175 2006252047 14 Dec 2006 Ex. Cpcd W Y Z Name Characterization Schm 2-Amin-phenyl 1 H NMR (300 MHz, DMSO-d 6 5 (ppm): 9.59 1H); i 1 4-1(3o- 0ioxolan7.92 J 8.3 Hz, 2H); 7.46 Cd, J 8.3 Hz, 2H); NH-_ spr7.15 J 7.5 Hz, 1H); 6.96 Ct, J 7.0 Hz, 1H); 6.78- 318 459NH4 I 33']ixoa2,cihdo- 180CH CH e--ethyl-2-oxo- 6.71 Cm, 3H); 6.62-6.54 2H); 6.26 J 7.5 Hz, N 2,dinydo5-ylam LH); 4.87 Cs, 2H); 4.364.32 4H); 4.23-4.19 Cm, HJ indol-5_ylaminoy 1 3C_ methyl)-benzamide 2H); 2.98 3H).
'H NMR (300 MHz, CD 3 OD) 8 (ppm): 8.67 J N42-Amino-phenyD)- 2.2 Hz, 1H), 7.97 (dd, J 2.5, 8.9 Hz, 1H), 7.58 Cm, NX- 6 6A2-phenylamino- 1H); 7.51 1H); 7.15 Cdd, J 1.1, 7.7 Hz, 1H), 7.08 319 460 CH N 2H); 6.89 (dd, J 1.4, 8.0 Hz, 1H), 6.76 Cdt, J 33 ectfiyaminin 4.4, 7.7 Hz, 1H), 6.67 Cd, J 7.7 Hz, 2H), 6.60 Cm, 2H); 4.87 Cbs, 2H); 3.60 Ct, J 6.3 Hz, 2H), 3.35 Ct, J 6.3 Hz, 2H).
N42-Amino-phenyI)- 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.59 Cs, 1H); O 44C1,3dimethyC 0N NH ,4-dixo- 4 7.92 Cd, J 7.9 Hz, 2H); 7.47 Cd, J 7.9 Hz, 2H); H3CIJ'HV)\ 2,4-dioxo-1,2,3,4- 3C C a 7.22 Cd, J 8.8 Hz, 1H); 7.16-7.09 Cm, 3H); 6.96 Ct, J 320 46 NH H tahro- 7.5 Hz, 1H); 6.76 Cd, J 7.9 Hz, 1H); 6.65-6.56 Cm, quinazin-& y 2H); 4.87 Cs, 2H); 4.42 Cd, J 5.3 Hz, 2H); 3.44 (s, 6H 3 ylamino)nethyll- 3H); 3.26 Cs, 3H).
benzamide 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.60 Cs, 1H); N42-Amino-phenyl *8.19 Cd, J 8.4 Hz, 1H); 8.05 Cd, J 8.4 Hz, 1H); 7.95 Cd, J 7.9 Hz, 2H); 7.76 Ct, J 7.0 Hz, 1H); 7.65 J 7.9 Hz, 1H); 7.57 J 7.9 Hz, 2H); 7.54 Cd, J 321 462 v CH indolo[2,3- 8.8 Hz, 1H); 7.41 Cd, J 1.3 Hz, LH): 7.22 Cdd, J 33 321 462 N N CH CH bl~~~~bquinoxalin-9- 88HI) z H;72 dJ=3 N CH blqinoxalin-9- 1.8, 8.8 Hz, 1H); 7.14 Cd, J 7.9 Hz, 1H); 6.95 Ct, J yleamiret 7.5 Hz, LH); 6.76 Ct, J 7.9 Hz, 1H); 6.57 Ct, J Hz, 1H); 6.51 bs, 1H); 4.86 Cbs, 2H); 4.54 Cd, J 4.8 Hz, 2H): 3.85 Cs, 3H).
2006252047 14 Dec 2006 Ex._ Cpd W Y Z Name Characterization Schm N-{-Amnino-pheny)- 322 463 N CH 6-(1-hydroxy- LRMS calc: 335.40, found: 336.1 (MH) 4 14, 3 OH cyclohexylethynylnicotinamide
H
3 C N42-Amino-phenyl)- 323 464 IN CH 6-p-tolylsulfanyl- LRMS calc: 335.42, found: 336.1 14, 3 nicotinamide N42-Amino-phenyl- 4-[b4indan-2- 324 465 CH CH ylaminomethyl)- RScl:436 fud 5. M) 21 thiopheri-2- LM ac 5.,fud 5. M HN ylmethyllbenzamide N-{2-Amino-phenylY 4-t54pyridin-2- 325 466 \S CH CH ylaminomethyl)- LRMS calc: 414.52, found: 415 21 thiophen-2- -N HN ylmethylj- ___benzamide H N42-Amino-phenyl)- 326 46 CH CH4-[((-bromo-thiazol- LRMS catc: 403.3, found: 404 2 2-ylamino)-rnethyll Brbenzamide H N.(2-Amino-phenyl)- N6 CH CH 4-((5-phenyl-1 H- LM ac 8.5 on:441(H*2 pyrazolylaminO-LMScc:434,fud48.(H) I_ H N methylJ-benzamide________ 177 2006252047 14 Dec 2006 Table 4c Characterization of Additional Compounds Ex. Cpd Compound Name Characterization Schm 'H NMR (DMSO-dr,): 5 9.57 (brs, LH), 7.98 Ji 8.3 NP N42-Hydroxy-phenyi).4- Hz, 2H), 7.75 (d J 7.5 Hz, 1H), 7.57 (d J 8.3 Hz, 426 H 57 eON,- H 13,4,5-trimethoxy- 2H), 7.07 Ct, J 8.3 Hz, 1H), 6.95 Cd J 7.0 Hz, 1H), 426 571 eo N OH phenylamino)-rnethyU- 6.85 J 7.9 Hz, 1H), 6.21 Ji 6.1 Hz, 1H), 5.95 335 benzamide 2H), 4.38 Cd, J 5.7 Hz, 2H), 3.70 Cs, 6H), 3.56 (s, MeO :13H).
W O H NMR (300 MHz, DMSO-De) 8 (ppm): 9.9 Cbs, 1H), N'Q U2-hyroxyphenl 4-9.'53 Cs, 1H), 7.97 J 7.9 Hz, 2H), 7.73 J N N.(24idrtoxyhn-- Hz, IN), 7.55 (d J 7.9 Hz, 2H), 7.08 Cdd, J 7.5, 427 572 NOH [(3,4-DinmethyU- Hz, 1H), 6.96 Cd, J 7.9, Hz, 1H), 6.88 Cdd, J 7.5, 33, penyaminoetyl 7.5 Hz, 1H), 6.72 J 8.8 Hz, 1H), 6.38 1H), 6.05 MeO (naid m, 2H), 4.36 Cd J 5.7 Hz, 2H), 3.72 (s 3H), 3.65 (s, e 3H).
0 /S 1 H NMR: (Acetone-ds) a (ppm): 9.09 Cbs, 1H), 8.03 (d, NJ H 2 N y W4-Amino-thiophen-3- J=7.9Hz, 2H), 7.96 J=7.5 Hz, 1H), 7.65 J=7.9 yI)4-([6.{2-morpholin-4- Hz, 2H), 7.61 Cd, J=3.5 Hz, 7.51 Cbs, 2H), 7.41 Cd, 428 573 N NH ythoxy).benzothiazo6 J=8.8 Hz, 1H), 7.36 1H), 6.95 Cd, J=6.2 Hz, 1H), 33, (0 N /2-ylaminoljrnethyl)- 6.35 Cd, J=3.5 Hz, 1H), 4.85 Cs, 2H), 4.20 Ct, J=537 Hz, S> H benzamide 2H), 3.69 J=4.4 Hz, 4H), 2.87-2.81(m, 2H), 2.62-2.57 0 Cm, 4H).
2006252047 14 Dec 2006 Characterization Schm 'H NMR (DMSO-d 6 8 9.66 Cbrs, ILH), 7.94 J Hz, 2H), 7.56 J 7.9 Hz, 2H), 6.22-6.16 (in, LH) 3,6 5.94 2H), 4.91 Cs, 2H), 4.38 J 5.7 Hz, 4H), 3.70 ~6 Cs, 6H), 3.55 3H).
(DMSO) 6 (ppm):12.43 (bs, 1H), 9.59 (bs, 1H), 7.84 (d, J 8.1 Hz, 2H), 7.56 Cd, J 8.1 Hz, 2H), 7.48 J 3.7 Hz, IH), 7.32 Cbs, 1H, SCt-), 6.96 (bs, 1H, SCH), 3,6 6.74 Cdd, J 8.8, 2.2 Hz, IH)K 6.1lId, J 3.7 Hz,l IH), 3,6 4.84 2H), 4.59 Cs, 2H), 3.76 3 H).RMS: 410. i(catc) 411 .2(found)(M+H)+ 'H-NMR (DMSO-d6), 6 (ppm): 9.22 Cbs, 1H), 8.19 Cbs, itI), 7.63 Cd, J=7.1 Hz, 1H), 7.53 Ct, J= 4.2 Hz, lH) 7.41 Cdd, J=9.2, 1.5 Hz, 1H), 7.25 Cd, J=8.3 Hz, 2H), 7.06 (d, J=7.1 Hz, 1H), 6.85 Cd J=8.3 Hz, 2H), 6.62-6.59 Cm, 3H). 4.51 Cd, J= 4.2 Hz, 2H), 3.78 Cs, 3H), 2.77 (d, J=3.1 Hz, 1H), 2.45 J=1.1 Hz, 1H), 1.22 Cm, 1H) 1.05 Cm, 1H).
'H NMR (DMSO-d 6 8 CPPM): 9.72 Cbrs, 1H), 8.23 Cd, J 7.5 Hz, 1H), 8.06 Cd, J 7.9 Hz, 2H), 7.67 Cd, J 7.9 Hz, 2H), 7.23 Cd, J 7.9 Hz, 1H), 7.15 Cd, J 7.9 Hz, I11 1H), 7.03 Ct, J 7.5 Hz, 1H), 6.84 Cd, J 7.9 Hz, 1H), 6.65 Ct, J 7.5 hz, IN), 5.62 Cbrs, 2H), 4.97 Cbrs, 2H) 'H NMR (300 MHz, DMSO-D.) 8 (ppm): 9.63 Cs, IH), 8.95 Cd, J 2.2 Hz, 1H), 8.40 Cd, J 5.3 Hz, 2H), 7.96 Cm, 3H), 7.54 Cd, J 7.5Hz, 2H), 7.22 Cdd, J 5.3, 7.8 15, 33 Hz, 2H), 7.01 Cm, 2H), 6.83 Cd. J =7.5 Hz, 1H), 6.64 Cdd, J 7.0, 7.9 Hz, 1H), 4.92 Cs, 2H), 4.70 J 6.2 Hz, 2H), 3.98 Cs, 179 2006252047 14 Dec 2006 ame Characterization Schm iino5-[42- 1 H NMR: (DMSO) 8 (ppm): 11.98 Cbs, 1H), 9.61 (bs, ~ino5-(42-1H), 7.93 Cd, J 8.1 Hz, 2H), 7.81 Cs, 1H), 7.45 Cs, 1H), )amoyl 7.38 Cd, J 8.1 Hz, 1H), 7.19 Cs, 1H), 7.16 Cd, J 7.3 4 ,amoyl)- Hz, 6.97 Cdd, J 7.0, 7.0 Hz, 1H), 6.77 Cd, J 7.3 ipene Hz, 1 6.59 Cdd, J 7.3, 7.3 Hz, 1 4.88 Cbs, 2H), ide 4.10 2H), 2.15 Cs, 3H).
;phenyl).4- 'H NMR (DMSO) 8 (ppm): 9.56 Cs, 1H), 7.90 J= 2- 7.9 Hz, 2H), 7.49 Cd, J 7.9 Hz, 2H), 7.15 Cd, J no-3H- Hz, 1 6.95 Ct, J 7.5 Hz, I1H), 6.78 (dd, Ji 13.2,' 6 azo 5- 8.3 5 Hz, 2 6.58 Ct, J 7.5 Hz, 1 6.39 Cs, 1 6.31 6 iethy1- Cm, 2H), 5.75 Ct, J 6.15 Hz, 1H), 4.87 2H), 4.32 Cd, J 5.7 Hz, 2H), 3.34 Cs, 3H), 2.82 Cd, J 8.5 Hz, 3H). )xy-1H- 1 H NMR (DMSO) 8 Cppm): 9.84 Cs, IH), 7.84 1H), azoQ-- 7.67 1H), 7.63 Cd, J 8.5 Hz, IH), 7.55 Cd, J lethyl). Hz, 1H), 7.17 J 8.0 Hz, 1H), 6.97 Ct, J 7.5 Hz, n-2- acd (21H), 6.78 J 8.0 Hz, 1H), 6.78-6.74 Cm, 3H), 6.59 64 acida (2 7.5 Hz, I1H), 5.71 2H), 4.94 Cs, IH), 4.65 Cs, 2H), nyl~am 3.76 Cs, 3H).
rimehox- IH NMR CDMSO) 8(ppm): 9.69 Cs, 1H), 7.47 I1H), rieo x' 7.41 Cd, J 8.8 Hz, 1H), 7.19 Cd, J 6.6 Hz, 1H), 6.97 n-2- (dd, J 7.5, 7.5 Hz, I 6.89 (dd, J 8.8, 2.2 Hz, I1H), 64 acid 6.79-6.78 2H), 6.74 Cs, 2H), 6.60 Cdd, J nyl)-amide Hz, 1H), 6.14 J 5.7 Hz, 1H), 4.92 Cs, 2H), 4.21 Cd, J Scheme 21 00 0 NH 1. NaBH(OAC) 3
N
NH Pd(PPh 3 4 NHfo RNH 2
H
(::NBCsq. Na 2 C0 3 N-e cYH9CC 3 00- H ethno CHO 2TARHN 184 185 Example 122 186: R~ IND Example 122 0 Step 1: 12-[(3'-Formyl-biohenvl-4-carbonvl)-aminol-D~henyll-carbamic acid tert-butvl ester (185) [0250] Following the procedure described in Example 15, step 1, but substituting 184 for 140, the title compound 185 was obtained in 74% yield. 11- NMR (CDCI 3 8 10. 10 I 9.4 1(s, 1 H), 8.13 (in, 11H), 8.07 J 8.4 Hz, 7.89 2H), 7.77 7.70 J 8.4 Hz, 7.64 (in, 7.27-7.09 (in, 7.03 1.52 91-).
Step 2: N.2-Aminophenvl)-4-[3indan-2-vaminomethvl)Dhenvl)l-benzamide (186) [0251] To a stirred solution of biphenyl aldehyde (104 mg, 0.25 mmol) and 2-aminoindane (33.3 mg, 0.25 mmol) in dichloroethane (lmL) was added sodium triacetoxyborohydride (80 mg, 0.375 mmol) followed by a glacial acetic acid (15u1, 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 (1 12mg, 84% yield) as a white solid. 'H- NMR (CDC1 3 009.21 1 8.03 J 8.7 Hz, 7.83 1 7.69 Cd, J 8.7 Hz, 7.65 1H), 7.54-7.38 (in, 7.28 (mn, 6.82 Cs, 3.95 Cs, 3.74 (mn, 3.22 (dd, J 15.6, 6.9 Hz, 2.89 (dd, J =15.6, 6.6 Hz, 1.53 91-).
[0252] 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. 11H NMR (20% CD 3 0D in CDC1 3 8 7.95 J 8.4 Hz, 7.65 J 8.4 Hz, 7.57 Cm, 1 7.54-6.79 Cm, 11 3.95 3.66 3.16 (dd, J =15.6, 6.9 Hz, 2.81 (dd, J 15.6, 6.6 Hz, 2H-).
o Examples 123-126 [0253] 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. NaSH(OAc) 3 c~K 0 d(Phi)Cl 2 CH'COOH 0 PdPh3212N
OHC'N
NNH
184 C< 191 192 Example 127 Example 127 Step 1: 12f441-Aminocycohexylethvnvl)-benzoylaminol-QhenylI-carbamic acid tert-butyl ester (191) [0254] A mixture of iodide 184 (438 mg, 1.0 mmol), Pd(PPh 3 2 Cl 2 (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 Cul (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). 'H NMR (CDCI 3 8 9.36 IHN, 7.94 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 (in, 3H), 2.10-1.30 (in. 10H), 1.51 9H).
SteiD 2: N2-Aminorhenvl)-4-fl .4-methoxy-benzlamino)-cclohexvlethynyl-belzamfide (192) [0255] Following the procedure described in Example 122, step 2, but substituting I,anisaldehyde for 2-aminoindane, the title compound 192 was obtained in 74 yield. 'H NMR (CDCI 3 8 8.44 1H), 7.82 (d J 8.1 Hz, 2H), 7.47 (d J 8.1 Hz, 2H), 7.31 Kd J 8.4 Hz, 2H), 7.23 (in, 1H), 7.05 6.84 J =8.7 Hz, 2H), 6.78 (in, 2H), 3.97 2H), 3.76 3H), 2.10-1.30 (in.
Scheme 23 TMS H NHBoC Pd(PPh 3 2
C
2 TMVSH Ho N ~CulH NHo 1 0 Et 3 N, THF10 0 184 *c to rt 197 0 I TBAF, T/HF
F
H 2*6 NH CHo
JCHO
morpholine Cul N NHo 2.TFA Example 132 198 R TMS TAH Example 133 109 R =H :1 (1:211
N
Example 133 Step 1: N24tButvloxcarbonvll-amino-ohenvII-44trimethlsiV~ethyflyl)beflzamide (197) (0256] To a stirred solution of 184 (5.00 g, 11.41 mmol) in anhydrous THIF (100 ml) under nitrogen at 0OC were added Pd(PPh 3 2 01 2 (240 mg, 0.34 mmol), Gui (130 mg, 0.69 mmol), and trimethylsilylacetylene (2.10 ml, 14.84 mmol), respectively. Then, anhydrous Et 3 N (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 NH 4 CI, and diluted with ethyl acetate. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgSO 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEtAexane: 20/80-+50/50) to afford the title compound 197 (4.42 g, 10.83 mmol, 94% yield) as a yellow powder. 1 H NMR (300 MHz, CDCI 3 8 (ppm): 9.26 (bs, 1H), AB system (8A 7.91, 8 B 7.55, J 8.3 Hz, 4H), 7.85 J 7.9 Hz, 1H), 7.32-7.13 (in, 3H), 6.70 (bs, 1H), 1.53 9H), 0.28 9H).
IO
0 0 Step 2: (2-Amino-ohenvl)-4-(trimethvlsilvlethvnyl)benzamide (198) [0257] 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. 'H NMR (300 MHz, acetone-d 6 8 (ppm): 9.20 (bs, 1H), AB system (SA 8.07, 8B 7.62, J 8.2 Hz, 4H), 7.32 J 7.6 Hz, 1H), 7.05 (td, 0 J 7.6, 1.2 Hz, 1H), 6.90 J 7.6 Hz, 1H), 6.72 J 7.3 Hz, 1H), 4.66 (bs, 2H), 0.30 9H).
in Step 3: W2-Amino-phenvl)-4-ethvnvlbenzamide (199) ^0 [0258] To a stirred solution at -20°C of a mixture of 198 and 199 in anhydrous THF (15 ml) O 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 NH 4 CI and diluted with ethyl acetate. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgS0 4 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. 'H NMR (300 MHz, acetone-d 6 (ppm): 9.19 (bs, 1H), AB system (SA 8.08, 5 7.66, J 8.5 Hz, 4H), 7.33 J 7.6 Hz, 1H), 7.05 J 7.3 Hz, 1H), 6.91 J 7.6 Hz, 1H), 6.72 J 7.6 Hz, 1H), 4.67 (bs, 2H), 3.88 (s, 1H).
Example 134 Step 1: N-[2-t-Butvloxvcarbonvl)-amino-Dhenvll4-ethvnylbenzamide (200) [0259] To a stirred solution at -20°C of a mixture of 199 (3.48 g, 8.53 mmol) in anhydrous THF 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 NH 4 CI, H 2 0 and brine, dried over anhydrous MgS0 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane: 25/75-430/70) to afford the title compound 200 (2.53 g, 7.53 mmol, 88% yield) as a pale yellow foam. 'H NMR (300 MHz, CDCI 3 5 (ppm): 9.31 (bs, 1H), AB system (SA 7.94, S8 7.59, J 8.5 Hz, 4H), 7.83 J 7.6 Hz, 1H), 7.30-7.10 3H), 6.75 (bs, 1H), 3.23 1H), 1.53 9H).
IO
0 Step 2: N42-amino-ohenvl)4- 4-c3(hlorophenvl)-3-morpholin-4-vl1-oropvn-1-vl-benzamide (201) S To a stirred solution at room temperature of 200 (200 mg, 0.60 mmol) in anhydrous 1,4-dioxane ml) under nitrogen were added 4-chlorobenzaldehyde (100 mg, 0.71 mmol), morpholine (60 p, 0.68 mmol), and Cul (6 mg, 0.03 mmol), respectively. The reaction mixture was bubbled with nitrogen for min and warmed up to 105°C. After 18 h, the reaction mixture was allowed to cool to room 0 temperature, diluted with ethyl acetate, and successively washed with a saturated aqueous solution n of NH 4 CI, H 2 0 and brine, dried over anhydrous MgS0 4 filtered and concentrated. The crude residue D was then purified by flash chromatography on silica gel (AcOEt/hexane: 40/60) to afford the desired 0 compound (193 mg, 0.35 mmol, 59% yield) as a pale yellow foam. 'H NMR (300 MHz, CDCI 3 8 (ppm): 9.40 (bs, 1H), AB system (A 7.96, 6B 7.36, J 8.5 Hz, 4H), 7.79 J 7.9 Hz, 1H), 7.59 J 8.4 Hz, 4H), 7.25-7.10 3H), 6.91 1H), 4.80 1H), 3.82-3.68 4H), 2.69- 2.58 4H), 1.53 9H).
[0260] 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. 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.80 (bs, 1H), AB system (SA 8.06, SB 7.71, J 8.1 Hz, 4H), AB system (SA 7.65, 68 7.52, J 8.3 Hz, 4H), 7.20 J 7.9 Hz, 1H), 7.02 J 7.3 Hz, 1H), 6.82 J 7.0 Hz, 1H), 6.64 J 7.5 Hz, 1H), 5.10 1H), 4.97 (bs, 2H), 3.72-3.58 4H), 2.67-2.46 4H).
Scheme 24
H
2
N
N CH N
CO
2 Me N A N CO 2Me N I N Cl i.Pr2NEl N' N I N H Pr 2 Nt H
H
THF
202 reflux 203 1. NH 2. 3. 1,2-phenylenediamine, BOP
NH
2 0 N N NH H H Example 135 204 185
IO
0 0 Example 135 Step 1: Methyl 444-chloro-6-(2indanyl-amino)-[1.3.5triazin-2-vl-amino)-benzoic ester (203) S [0261] To a stirred solution at room temperature of 202 (2.00 g, 7.11 mmol) in anhydrous THF ml) under nitrogen were added Pr 2 NEt (1.86 ml, 10.66 mmol) and methyl 4-aminobenzoate (1.29 g, 8.53 mmol) or ArNH 2 (1.2 equiv), respectively. The reaction mixture was then refluxed for 0 24 h. After cooling, the reaction mixture was poured into a saturated aqueous solution of NH 4 CI, and n diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 s0 and brine, dried over anhydrous MgS04, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH 2
CI
2 2/98-5/95) to afford the title compound 203 (1.70 g, 4.30 mmol, 60% yield) as a beige powder. 'H NMR (300 MHz, CDCI 3 8 (ppm): mixture of rotamers, 2 AB system (6A 8.03, 8 A. 8.00, 8 7.70, 6B' 7.61, JAB JAB' 8.8 Hz, 4H), 7.43 and 7.31 (2 bs, 1H), 7.29-7.19 4H), 5.84 and 5.78 (2 d, J 7.2 and 7.7 Hz, 1H), 4.984.77 (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-indanvl-amino) 1.3.51-triazin-2-vlaminol-M2-amino-ohenl)-benzamide (204) [0262] The title compound 204 was obtained from 203 in 3 steps following the same procedure as Example 1, Pathway B steps 3-5. 'H NMR (300 MHz, acetone-ds) 8 (ppm): mixture of rotamers, 8.98 8.49 and 8.28 (2m, 1H), 8.10-7.92 4H), 7.35-7.14 5H), 7.03 (td, J 7.6, 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 1H), 4.704.58 1H), 3.44-3.26 2H), 3.08-2.92 (m, 2H). HRMS (calc.): 452.2073, (found): 452.2062.
IND
Scheme C HO C N CO 2 Me N N I i-Pr 2 NlEt, NaH Q N N 0 H THF H 26 0' 0!l 205 1. NH 3 (1 LiOH.H- 2 0 3. 1 .2-phenylene- Ifdiamine, BOP
INNN
H H NH 207N Example 1367 Example 136 Step 1: Methyl 4-[(4-chloro-6-(24ndanl-amino)f 1.3. 5ltriazin-2-vloxv)-rrethyll-benzoic ester (206) [0263] To a stirred solution at 0OC of 205 (2.00 g, 7.11 mmol) in anhydrous THF (50 ml) under nitrogen were added WPr 2 Nt (1.86 ml, 10.66 mmol) and methyl 4Ahydroxymethyl~benzoate (1.30 g, 7.82 mmol). After few minutes, NaH 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 NH 4 CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgSO 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH 2
CI
2 2/98) to afford the title compound 206 (2.00 g, 4.88 mmol, 69% yield) as a colorless sticky foam. 'H NMR (300 MHz, CDCI 3 5 (PPM): mixture of rotamers, 2 AB system (8A 8.06, 8 A' 8.03, 8 B 7.52, 8B. 7.46, JAB JA'B 8.5 Hz, 411), 7.26-7.17 (in, 4H), 5.94 and 5.85 (2 bd, J 7.8 Hz, 1H), 5.48 and 5.39 (2 s, 2H), 4.924.76 (2 m, 3.94 and 3.92 (2 s, 3H), 3.39 and 3.33 (2 dd, J 16.0, 7.0 Hz, 2H1), 2.89 and 2.84 (2 dd, J 16.0, 4.9 Hz, 2H).
Step 2: 4] 4-amino-6-(2jndanl-anino)-f 1.3. 51-triazin-2-loxl-methl)-N42-amnovhenyl)-benzamide (207) [0264] The title compound 207 was obtained from 206 in 3 steps following the same procedure as Example 1, Pathway B steps 3-5. 'H NMR (300 MHz, acetone-d 6 0 DMSO-d 6 5 (PPM): 9.49 (mn,
IND
1H), 8.12-8.03 (in, 2H), 7.60 J 7.7 Hz, 2H), 7.35 J =7.1 Hz, 1H), 7.28-7.13 (in, 4H), 7.07- 6.94 (in, 2H), 6.90 (dd, J 7.3, 1.4 Hz, 1 6.70 (td, J 7.3, 1.1 Hz, 1 6.44 (bs, 1 6.25 (bs, 1H), 5.47 and 5.41 (2s, 2H), 4.87-4.68 (in, 3H), 3.35-3.20 (mn, 2H), 3.02-2.88 (in, 2H). HRMS (calc.: 467.2070, (found): 467.2063.
Scheme 26 C1
H
N H 2 (1atm) 11 Pd/C "N 0 1' N N N' N N- H H IMeOHN N N 208 CO 2 Me At H 29H 0m 1.LiOH.H 2 0 I2. 1 .2-phenylenedamine, BOP N NN H H NH~ 210 Example 137 0 Example 210 Methyl 4-H(4-chloro-6-ohenethl-amino-f 1. 3.5ltriazin-2-vl-ainino)-methvil-benzoic ester (208) [0265] The title compound 208 was obtained from 2 following the same procedure as in Example 1, pathway B steps 2 (R 1 R 2 NH phenethylamine).
SterD 1: Methyl 4-1(4-henethylamino-Il Sltriazin-2-vl-amino)-methvfl-benzoic ester (209) [0266] To a degazed solution of 208 (300 mg, 0.75 iniol) in MeOH (35 mL) was added Pd/C (24 mng, 0.023 minol). The reaction mixture was stirred under a 1 atm pressure of H 2 at room temperature for 20 h then it was purged with N 2 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/CH 2
CI
2 4/96) to afford the title compound 209 (135 ing, 0.37 inmol, 50% yield). 'H NMR (300 MHz, CDC1 3 8 (ppm): 8.08 J 8.1 Hz, 2H), 7.46 J 8.1 Hz, 2H), 7.50-7.15 (mn, 6H), 4.85-4.65 (mn, 2H), 3.98 3H), 3.82-3.62 (in, 2H), 3.05-2.85 (mn, 2H).
Step 2: NA2-Amino-ohenvl)-4-I(4-phenethylamino-[1 .3 .5lriazin-2-yl-amino)-rnethvll-benzamide (210) [0267] The title compound 210 was obtained from 209 in 2 steps following the same procedure as in Example 1, steps 4 and 5. 1 H NMR: (300 MHz, acetone-l 6 8 (PPM): 9.03 IHN, 8.17-7.87 (in, 3H), 7.49 (dd, J 19.2, 8.2 Hz, 2H), 7.32-7.03 (in, 6H), 6.99 J 7.6 Hz, 1H), 6.86 J= Hz, 1H), 6.67 J 7.4 Hz, 1H), 6.60-6.30 (in, 2H), 4.72 J 6.3 Hz, 1H), 4.65-4.56 (in, IN), 3.67-3.51 (in, 2H), 2.95-2.80 (in, 2H).
tim Scheme 27 0~ HCI.H 2 N OMe WeCO 2 Me N "N Me IPr 2 NE MeO N N Me- I, lTHF, sealed flask H CO 2 Me 800C 211 S2. 1,2-phenylenedia mine. BOP W~e N
NN
M e O A L N NH 2120 Example 138 Example 138 Stero 1: Methyl .6-dimethox-[1 Sltriazin-2-vI-amino)-methvll-benzoic ester (211) [0268] In a 75m1 sealed flask, a stirred suspension of 2-chloro.4,6-dimethoxy-1,3,5-triazine (540 mg, 3.08 mmol), methyl 4-(aminomethyl)benzoate.HCI 2 (689 mg, 3.42 mmol), iWr 2 NEt (1.49 ml, 8.54 mmol) in anhydrous THF (30 ml) was warmed at 800DC for 5 h. Then, the reaction mixture was allowed to cool to room temperature, poured into a saturated aqueous solution of NH 4 CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgSQ 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEVCH 2
CI
2 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, CDC1 3 8 (ppm): AB U system (8A 8.01, 8B 7.39, JAB 8.5 Hz, 4H), 6.08-6.00 (in, 1H), 4.73 J 6.3 Hz, 2H), 3.95 6H), 3.92 3H).
0269] The title compound 212 was obtained from 211 in 2 steps following the same procedure as Example 1, steps 4 and 5. 'H NMR (300 MHz, acetone-d6 Z DMSO-d 6 5 (PPM): 9.58 (bs, I1H), r- 8.27 J 6.3 Hz, III), AB system (bA= 8.04, 5B 7.53, JAB= 8.4 Hz, 4H), 7.31 Cd, J 6.9 Hz, C 1H), 7.02 td, J 1.6 Hz, 1H), 6.88 (dd, J 7.9, 1.4 Hz, 1H), 6.68 (td, J 7.6, 1.4 Hz, 11H), tn 4.86-4.78 (in, 2H), 4.69 J 6.3 Hz, 2H), 3.90 and 3.89 (2s, 6H). HRMS (calc.): 380.1597, ID (found): 380.1601.
Step, 2: N{2-Amino-henl)-4-(4.6-dimethox- 1.3 .5-triazin-2-vI-amino)-rnethyll-benzamide (212) Scheme 28 C1J. MeOH -m N N10% KOH
N"-N
NAN N ilN N N N H H THF/H 2 0 H H H 5 HC0 2 Me rt213 C0 2
H
S1 .2-p henylenediamine, BOP Et 3 N, DMVF, ft OMe H H I HNH 214IN Example 139 0 Example 139 Stei, 1: 4-U6A2-ndanyl-amino)-methoxy-f 5]triazin-2-yl-amino)-methyll-benzoic acid (213) [0270] To a stirred solution at room temperature of 5 (300 mg, 0.73 inmol) in a mixture of MeOH/THF (10 mI/5 ml) was added an aqueous solution of KOH 5 ml). After 3 days, the reaction mixture was concentrated on the rotavap, diluted in water and acidified with 1N HCI 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 mng, 0.72 mmol, 98% yield) as a white solid. MS: m/z 392.1 [MHI.
USterD 2: NA2-amino-ohenl-- r6A2-indanvl-amino)-4-methoxv-[ 1.3. 51-triazin-2-vI-aminol-methvlI) benzamide (214) (0271) The title compound 214 was obtained from 213 in one step following the same procedure as Example 1, step 5. 'H NMR (300 MHz, acetone-d 6 0i DMVSO-d 6 5 (ppm): mixture of rotamers, 9.69-9.53 (in, 1H), AB system 8 A 8.04, 5B 7.52, JAB 7.8 Hz, 4H), 7.80-7.60 (in, I1H), 7.45-7. 10 (in, 6H), 7.01 J 7.6 Hz, I1H), 6.88 J 8.2 Hz, I1H), 6.68 J 7.6 Hz, 1 H), 4.92-4.60 (in, 5H), 3.90-3.78 (in, 3H), 3.35-3.22 (in, 2H), 3.02-2.83 (in, 2H). HRMS (calc.): ID 481.2226, (found): 481.2231.
(1 Scheme 29 Cl Cl N" N ~MelN 'N CI l Nj t N i-rNt Cl AN -'IN H THIF
CO
2 Me ii Me CO 2 Me 215 J1. 2-Aminoindan 2. NH- 3 3. LiOH.H- 2 0 4. 1 .2-phenylenediamine, BOP
NH
2 N" N N Nt4 N H NH H Me Oy-N 2160 Example 140 Example 29 Step 1: Methyl 4-1(4 .6-dichloro 3.Sltriazin-2-yl-N-methvl-amino)-niethyll-benzoic ester (216) [0272] To a stirred suspension at room temperature of NaH 81 ing, 3.19 inmol) in anhydrous THF (10 ml) under nitrogen were successively added a solution of 3 (500 mg, 1.60 minol) in anhydrous THF (10 ml) and Mel (298 gl, 4.79 mmol). After 16 h, the reaction mixture was poured into a saturated aqueous solution of NH 4 CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgSO 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel
IND
0 (AcOEt/hexane: 10/90- 20/80) to afford the title compound 215 (200 mg, 0.61 mmol, 38% yield) as a white crystalline solid. 'H NMR (300 MHz, CDCI 3 8 (ppm): AB system 8 A 8.04, 8B 7.31, JAB 8.2 Hz, 4H), 4.93 2H), 3.93 3H), 3.18 3H).
Step 2: 4-1 r4-amino-6Aindany~amino~r 1.3. 51-triazin-2-v IN-methy~amino1-rnethl I-N-i2-amino-Dhenl)benzamide (216) 0 [0273] The title compound 216 from 215 in 4 steps was obtained following the same procedure as Example 1, Pathway B steps 2-5. 'H NMR (300 MHz, acetone-d 6 8 (PPM): 9.11 (bs, IN), 8.03 (d, INDJ 8.0 Hz, 2H), 7.43 (bs, 2H), 7.33 (d J 7.7 Hz, 1H), 7.28-7.09 (in, 4H), 7.04 (td, J Hz, 1H), 6.90 (dd, J 8.0, 1.4 Hz, 1H), 6.71 (td, J 7.5, 1.3 Hz, IN), 6.25-6.05 (in, 1H), 5.82 and 5.64 (2bs, 2H), 5.00-4.56 (in, 5H), 3.42-2.76 (in, 7H). HRMS (calc.): 480.2386, (found): 480.2377.
Scheme cl 1) R MgBr, THF/toluene
R
N -30*C.1 h, then rt over 3h N ClI N CI Cl N N 2) HCI.H 2 N NZ H COM C021Vle217 i-Pr 2 NEt, THF, rt 1R2 R3 NiP~ THF, sealed flask 80-90*C 2. LiOHH 2 0 3. 1 2-phenylenediamnine, BOP R'N )N N "][H6 H0 Example 141 218 Me. R 2
R
3 N =2-indanyl-amino Example 141: Step 1: Methyl 4-f(4-chloro-6-methvl-f Slriazin-2-vl-amino)-rethvll-benzoic ester (217) [0274] To a stirred solution at -300C of cyanuric chloride 1 (2.00 g, 10.85 minol) 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 44aminomethyl)benzoate.HCI 2 (2.08 g, 10.30 mmol) and WPr 2 Nt (3.78 ml, 21.69 mmol) were added, respectively. After 18 h, the reaction mixture was poured into a saturated aqueous solution of NH 4 CI, and diluted with AcOEt. After separation, the organic layer was successively washed with sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgSO 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/CH 2
CI
2 10/90.-+15/85) to afford the title compound 217 (780 mg, 2.67 mmol, 25% yield) as a yellow powder. 'HNMR (300 MHz, CDCI 3 5 (PPM): mixture of rotamers, 2 AB system (8A= 8.03, 8A' 8.02, 8 B =7.39? 8a- 7.38, J 8.5 Hz, 4H), 6.28-6.08 (2 m, 1H), 4.76 and 4.74 (2d, J IND 6.3 Hz, 2H), 3.92 3H), 2.46 and 2.42 (2s, 3H).
Step 2: NA2-amino-Dhenvl)--l[6-(2-indanyl-amino)-4-methl-f 1.3. 51.triazin-2-yl-aminol-mrethyl)-benzamide (218) [0275] The title compound 218 was obtained from 217 in 3 steps following the same procedure as Example 1, steps 3-5. 'H NMR (300 MHz, acetone-d 6 Z DMSO-d 6 8 (PPM): mixture of rotamers, 9.62-9.50 (in, 1H), 8.04 (d J 8.0 Hz, 2H), 7.68-7.37 (mn, 3H), 7.33 J 7.7 Hz, III), 7.28-7.07 (mn, 5H), 7.02 J 7.4 Hz, IN), 6.89 (d J 7.9 Hz, 1H), 6.69 J 7.4 Hz, IN), 4.92- 4.60 (mn, 5H), 3.35-3.10 (in, 2H), 3.02-2.82 (mn, 2H), 2.25-2.12 (mn, 3H).
Scheme 31 N H NHBoc jjH2 NH- N N 184 NJN N )IN 0 il 1" Ak -K
H
2 N N N H NHR
H
2 N NPd 2 (dba) 3
N
POT, Et 3
N
DMF, 100*C0 Exampi 219: R =Boc A Exml 142 220:R H 2TA Example 142 Step 1: (2-4-i2-i4.6-Diaminorl .3.5Slriazin-2-yl)-vinll-benzoylamino)-ohenylk-arbainic tert-butvl ester (219) [0276] To a dlegazed solution of 184 (40 mg, 0.091 minol) and 2-vinyl-4,6-diainino-1,3,5-triazine (11 ing, 0.083 iniol) in dry DMF (1 mL) was added tr~o-tolylphosphine (POT) (1.5 mg, 0.005 iniol) followed by Et 3 N (46 pL, 0.33 inmol) and tris(dibenzylideneacetone)dipalladiuin(0) (2 ing, 0.0025 minol). The solution was heated at 100'C for 16h. Then, DMF was removed under reduced 193 pressure. The reaction mixture was partitioned between AcOEt and a solution of sat. NH 4 CI After separation, the organic layer was washed with brine, dried over anhydrous Na 2
SO
4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH 2
CI
2 5/95) to afford the title compound 219 (25 mg, 0.056 mmol, 67% yield). 'H NMR (300 MHz, Acetone-d6) 5 (PPM): 8.27 1H), 8.06 J 8.1 Hz, 2H), 7.96 J 15.9 Hz, 1H), 7.79 J 8.1 Hz, 2H), 7.76-7.69 (in, 1H), 7.62-7.55 1H), 7.26-7.15 2H), 6.90 J= 15.9 Hz), 6.21 4H), 1.50 9H).
IDStep 2: N42.Amino-phenyl)-4-1244 .6-diamino-fi .3.51triazin-2vl~vinvll-benzamide (220) [0277] To a stirred solution at room temperature of 219 (25 mg, 0.056 mmol) in CH 2
CI
2 mL) was added TEA (0.3 mL, 4.3 mmol). After 30 min, a solution of sat. NaHCO 3 was slowly added until pH 8 is reached, CH 2
CI
2 was removed under reduced pressure, AcOEt was added, and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na 2
SO
4 filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/CH 2
CI
2 10/90) to afford the title compound 220 (19 mg, 0.054 minol, 98% yield). 'H NMR: (300 MHz, acetone-l 6 8 (ppm): 8.33, 8.13 (2d, J 7.5 Hz, 1H), 8.22 J 15.9 Hz, 1H), 8.01 (d, J 8.1 Hz, 2H), 7.84 J 8.1 Hz, 2H), 7.38-6.96 Cm, 2H), 7.03 J =15.9 Hz, IHN, 6.94-6.62 (in, 2H).
Scheme 32 ClN-2 n-BU 3 Sn NH- 2 N NH 3 gas N 1 N Pd(PPh 3 4 N N N 1,Cl 1,4-dioxane N N) CI toluene IN sealed tube Ioot 7*C 21 0 222 1. 1184 Pd 2 (dba) 3
POT
Et 3 N, DMVF if2. TFA,
CH
2
CI
2
NH
2 NI-12 N IL N N ",N I H 2 (40 psi)I N IN H NH 2 10 I/ H NH- 2 K> 224 NN MeOH 223 24 rt Example 143b Example 143a Example 143a Step 1: 2.Amino-4-chloro-6-oio~eridin-l-vl-[1.3.51triazin (221) [0278] Ammonia was bubbled for 5 min in a solution of 2,4-dichloro-6-piperidin-1-yl[l,3,5]triazine (500 mg, 2.15 mmol) in dry 1,4-dioxane (20 mL). The solution was heated at 70 0 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. NH 4 CI. After separation, the organic layer was washed with water and brine, dried over anhydrous Na 2
SO
4 filtered and concentrated to afford the title compound 221 (453 mg, 2.12 mmoi, 98% yield). LRMS: 214. 1.
Step~ 2: 2-Amino 4-piperidin-1-vl-6-vinyll .3.Sltriazin (222) C] [0279] To a solution of 221 (358 mg, 1.68 mmol) in dry toluene (7 mL) was added tributyl(vinyl)tin (514 pL, 1.76 mmol) followed by Pd(PPh 3 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/bexane: 10/90-+30/70) to afford the title compound 222 (containing tributyltin chloride).
Sters 3: N-(2-Amino-iDhenyl)-4-f2A4-amino-6-iieridin*-l-l 5ltriazin-2-vl)-vinll-benzamide (223) [0280] 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-d 6 5 (PPM): 9.69 1H), 8.01 (d J Hz, 2H), 7.87 J 16.0 Hz, 1H), 7.80 (d J 7.5 Hz, 2H), 7.18 Kd J 7.5 Hz, 1H), 7.04-6.92 (in, 1H), 6.91 Kd J 16 Hz, 1H), 6.85-6.68 (in, 3H), 6.60 J 7.2 Hz, 1H), 4.93 2H), 3.77 (s, 4H), 1.63 2H), 1.52 4H.
Example 143b Step 4: NA2-Amino-ohenvl)-44-amino-6-oiperidin-1-yf 1.3. Sltriazin-2-vl)-ethyll-benzamide (224) [0281] To a solution of 223 (18 mng, 0.043 minol) in MeOH (5 mL) was added 10% Pd/C mng, 0.021 mmol). The reaction mixture was shaked under a pressure of H 2 (40 psi) at room temperature for 16 h using an hydrogenation apparatus. Then, the reaction mixture was purged with
N
2 filtered through celite, and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH 2
CI
2 2/98-4/96) to afford the title compound 224 (10 mng, 0.024 mmol, 56% yield). 'H NMR (300 MHz, CDCI 3
-CD
3 OD) 5 (ppm): 7.82 J 8.1 Hz, 2H), 7.35 J 8.1 Hz, 2H), 7.08 J 7.0 Hz, 1H), 6.89-6.79 (in, 2H), 7.80-6.90 (in, 1H), 3.76 4H), 3.13 J 8.1 Hz, 2H), 2.88 Ct, J 8.1 Hz, 2H),1.90-1.40 (in,
O
Scheme 33 o N OH MeO0 s BBr 3 H-,s 0NO' 0 s MeO/ -N BBrN DEAD, PPh 3
NN
226 225 .,//COMe N 0 THF/20 N O2 1 OHC.'II1 S Bu 2 SnCI 2 PhSiH 3 -N 1,2-phenylenediamine 228 H 2 N BOP, E 3 N 227 Example 144 Example 144 Step 1: 2-Amino-benzothiazol-6-ol (225): [0282] A suspension of 2-amino-6-methoxybenzothiazole (5.00 g, 27.8 mmol) in dichloromethane mL) was cooled to 0 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 0OC to 10 0
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). 'H NMR: (CD30D) 8 (ppm): 7.27 J=8.8 Hz, 1H), 7.08 J=2.2 Hz, 1H), 6.80 (dd, J=8.4, 2.2 Hz, 1H).
Step 2: 6-(2-Morpholin-4-vl-ethoxv)-benzothiazol-2-ylamine (226) [0283] To a solution of benzothiazole 225 (3.62 g, 21.8 mmol) in THF at room temperature under nitrogen, were successively added 442-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 H 2 0. The combined organic layers were extracted with IN HCI. The combined acidic extracts were neutralized using a saturated aqueous solution of NaHCO 3 and the precipitate was dissolved with ethyl acetate. These combined organic layers were washed with brine, dried over MgS0 4 and concentrated. The filtrate was concentrated to afford the title compound 226 (5.83 g, 96% yield) as a light yellow oil. 'H NMR: (Acetone-d 6 8 196
IO
S (ppm): 7.37 J=8.8 Hz, 1H), 7.34 J=2.6 Hz, 1H), 6.94 (dd, J=8.8, 2.6 Hz, 1H), 6.60 (bs, 2H), 4.19 J=6.2 Hz, 2H), 3.70-3.67 4H), 2.90 2H), 2.81 J=6.2 Hz, 2H), 2.62-2.58 4H).
Step 3: 4-1[642-Morpholin-4-vl-ethoxv)-benzothiazol-2-ylamino]-methyll-benzoic acid methyl ester (227): [0284] 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, S1.04 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 Sfiltered. The filtrate was partitioned between ethyl acetate and water and the combined organic layers were washed with IN HCI. The combined acidic layers were neutralized using a saturated aqueous solution of NaHCO 3 and the precipitate was extracted with ethyl aceate. The combined organic layers were washed with brine, dried over MgS0 4 and concentrated. The resulting crude was purified by flash chromatography using MeOH/CHCI 3 (10:90) to afford 227 (3.69 g, 42% yield).
'H NMR: (Acetone-d 6 8 (ppm): 8.04 J=8.5 Hz, 2H), 7.65 J=8.8 Hz, 2H), 7.41 J= 8.8 Hz, 1H), 7.34 J=2.5 Hz, 1H), 6.94 (dd, J= 8.5, 2.7 Hz, 1H), 4.50 J=5.5 Hz, 2H), 3.86 3H).
Step 4: N-2-Amino-Dhenvl)4-([6-(2-morpholin4-.l-ethoxv)-benzothiazol-2-ylaminol-methl)-benzamide (228): [0285] 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. 'H NMR:
(CD
3 0D) 5 (ppm): 8.04 J=8.2 Hz, 2H), 7.62 J=8.5 Hz, 2H), 7.40 J=8.8 Hz, 1H), 7.31 (d, Hz, 1H), 7.25 J=7.4 Hz, 1H), 7.15 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 2H), 4.21 J=5.2 Hz, 2H), 3.81-3.77 4H), 2.87 J=5.5, 2H), 2.69- 3.66 4H).
IND
Scheme 34 r~C2Me )y>NH2 0HS- \C 2 M~e
BU
2 SnCI 2 PlhSiH 3 Br N229 Suzuki Coupling M T B (O H 2 OMe N O MeO 23 Me C NH 2 N 2. BOP Et 3 N M O 3 MeOl 231 1 ,2-phenylenediamine OMe ole Example 145 Example 145 Step 1: 4-r(5-Bromo-benzothiazo 2-vlamino-rethvI1-benzoic acid methyl ester (229): [0286] 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. 1 H NMR: (DMS0d 6 8 (ppm): 8.78 J= 5.9 Hz, 8.01 J= 8.2 Hz, 2H), 7.99 1H), 7.56 J= 8.2 Hz, 2H), 7.43-7.34 (in, 2H), 4.74 J= 5.9 Hz, 2H), 3.90 3H).
SteiD 2: 4-f l5-43.4. 5-Trimethoxv-phenyl)-benzothiazo 2-ylaminoi-methvll-benzoic acid methyl ester [0287] 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. 'H NMR: (DMSO-d 6 5 (PPM): 8.73 J=537 Hz, 1H), 8.11 J=1.8 Hz, 1H), 8.02 J=8.4 Hz, 2H), 7.63-7.57 (in, 3H), 7.48 (d, J=8.4 Hz, 1H), 6.97 2H), 4.77 J=537 Hz, 2H), 3.92 (in, 6H), 3.90 3H), 3.74 3H).
SteiD 3: N.2-Amino-Dhenvl)-4-f i5.3.4 ,5-trimethoxv-ohenvl)-benzothiazol-2vlaminol-rnethl I-benzamide (21) [0288] 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. 'H NMR: (Acetone-d 6 8 (PPM): 8.31 J=7.9 Hz, 2H), 8.20 J=7.5 Hz, 1H), 8.13 1H), 7.73-7.58 (in, 3H), 7.63 J=7.5 Hz, 2H), 7.48-7.43 (mn, 2H), 7.05 2H), 4.98 2H), 4.00 6H), 3.84 3H).
Scheme MeO~~
OHII
Y,>-NH2 H MO s OM NaHB(OAc) 3 N232 1. LiOH THF/1- 2
O
2. 1 .2-phenylenedia mine BOP, Et 3
N
MeO 233 1-1 2
N
CKI Example 146 Example 146 SteiD 1: 4-16-Methox-benzothiazol-2-lamino)-methyll-benzoic acid methyl ester (232): [0289] 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 NaHCO 3 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 MgSO 4 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, 5 1% yield). 'H NMR: (Acetone-d 6 8 (ppm): 8.04 J=8.5 Hz, 2H), 7.65 J=8.8 Hz, 2H), 7.41 J= 8.8 Hz, 1H), 7.34 J=2.5 Hz, 1H), 6.94 (dd, J= 8.5, 2.7 Hz, 1H), 4.50 J=5.5 Hz, 2H), 3.86 3H).
Steio 2: N.(2-Amino-henl)-4-(6-methoxy-benzothiazol-2-ylamino)-methll-benzamide(233): [0290] 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-d 6 5 (ppm): 9.68 IN, 8.44 J=5.8 Hz, 11H), 8.00 J=8.2 Hz, 2H), 7.55 J=8.2 Hz, 2H), 7.39 J=237 Hz, 1H), 7.34 J=8.8 Hz, 1H), 7.21 J=6.6 Hz, 1H, 7.05 J=6.3 Hz, 1H), 7.00 J=1.4 Hz, 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 2H), 4.70 J=5.8 Hz, 2H), 3.79 3H).
o Scheme 36 H CO 2 Me H DMF Br 234 1. BBr 3 PPh 3
DEAD
0f 1. LOH H
THF/H
2 O 2. 1.2-phenylenediamine 236 H 2 N BOP. Et 3 N 235 Example 147 Example 147 Step 1: 4-46-Methoxv-1 H-benzoimidazol-2-ylsulfanylmethyl)-benzoic acid methyl ester hydrobromide (234) [0291] To a solution of methyl 4-{bromomethyl)benzoate (2.5 1g, 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 K4.10g, 91 yield) as a colorless solid. 'H NMR: (DMSO-d 6 5 (ppm): 7.90 J= 8.2 Hz, 2H), 7.55 J= 8.2 Hz, 2H), 7.45 Cd, J= 8.2 Hz, 1H), 7.03 6.94 J= 8.2 Hz,LH), 4.65 3.82 3.79 3H).
Step 4-1642-Mornholin-4-vl-ethoxv-1 H-benzoimidazol-2-vlsulfanvlmethyll-benznic acid methyl ester (0292] 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. 1 H NMR: (CDC1 3 8 (ppm): 8.04-8.00 Cm, 2H), 7.77-7.72 (in, 1H), 7.69-7.59 (in, LH), 7.56- 7.49 Cm, 2H), 6.96-6.90 (in, 1H), 4.68 Cs, 2H), 4.31-4.16 (mn, 4H), 3.97 Cs, 3H), 3.98-3.91 Cm, 2H), 3.82-3.72 Cm, 2H), 2.75-2.47 Cm, 4H).
200 Step 3: N42-Amino-ohenvl4-r2-morholin-4-v-ethoxV)-1 H-benzoimidazol-2-vlsulfanvlmethvlbenzamnide (236): [0293] 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 NMVR: (CD 3 OD) 8 (ppm): 7.89 J= 8.2 Hz, 2H), 7.45 J= 8.2 Hz, 2H), 7.28 J= 8.5 Hz, 1H), 7.19-7.06 (in, 3H), 6.93- 6.79 Cm, 3H), 4.55 2H), 4.18 J= 6.3 Hz, 2H), 3.65-3.62 Cm, 4H), 2.51 Ct, J= 6.6 Hz, 2H), 2.46- 2.42 (in, 4H).
Scheme 37
CO
2 Me Pd(OAc)2 Cs2C3 coMe 2N2H 1. UOH N.
NH________THFIH
2 0 e EkBIAPN2. 1.2henlenediamtne H H Br BINAP
NH
BO, tN 238 237 Example 148 Example 148 Step 1: 4-Morpholin-4-vl-benzoic acid methyl ester (237): [0294] A flame-dried pressure vessel was charged with cesium carbonate (912 mg, 2.80 inmol) and toluene (8 mL) and the flasked was purged with nitrogen. Palladium acetate (9.0 mng, 0.004 mmol) and rac.2,2-Bis~diphenylphosphino)-1,1'tinaphthy (37 ing, 0.06 mmol). The mixture was dlegassed and heated at 100'C for 18 h. It was allowed to coot to room temperature and was fitered through celite, rinsed with ethyl acetate and partitioned between ethyl acetate and water. The organic layer was washed with a saturated solution of NaHCO 3 brine, dried over MgSO 4 and concentrated in vacuo to afford the title compound 237 (443 mg, 100% yield). 1 H NMR: (CDC1 3 8 (ppm):8.02 Cd, J=9.2 Hz, 2H), 6.95 J=8.8 Hz, 2H), 3.95 Cs, 4H), 3.92 3H), 3.38-3.35 (in, 4H).
Step 2: N42-Aiino-henv)-4-moroholin4-vl-benzamfide (238): [0295] 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 NMVR: CDMSO-d 6 8 (PPM): 7.20 Cd, J= 7.9 Hz, 1H), 7.07 Cd, J= 8.8 Hz, 2H), 7.01 J= 7.0 Hz, 1H), 6.83 Cd, J= 7.9 Hz, 1H), 6.65 J= 7.5 Hz, 1H), 4.90 2H), 3.81-3.79 Cm, 4H), 3.32-3.28 Cm, 4H).
IO
0 0 Scheme 38
NH
2 S S DMAP, Et 3 N 0 N NH H pyridine N I1 2 C N ^r V'-ylsl S C 0 2H ONH2 yN NaH, DMF N cN C2 HH 2. HOBt, EDC N N 240 n 239 DMF, ET 3 N 240 1,.2-phenylenediamine Example 149
O
Example 149 Step 1: 3-Methvlsulfanvy3-(pyridin4-ylamino)-acrvlonitrile (239) [0296] To a solution of pyridin-4-ylamine (1.0 g, 11.0 mmol) and 3,3-Bis-methylsulfanylacrylonitrile (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 OC, 60% NaH dispersion in oil (0.92 g, 23.0 mmol) was added portionwise over 1 hr. and it was stirred at 0 OC for an additional 2 hrs. The cold bath was removed and the mixture was stirred at room temperature for hrs. DMF was removed in vacuo and the crude was purified by column chromatography (gradient of EtOAc to 25% MeOH/EtOAc) to afford the desired product as an off-white solid (1.9 g, 89%).
Step 2: N.2-Amino-ohenvl)4-([2-cvano-1-(Dvridin4-vlamino)-vinvlaminol-methvll-benzamide (240) [0297] To a mixture of 3-methylsulfanyl-3-pyridin4-ylamino)-acrylonitrile (0.2 g, 1.0 mmol), 4aminomethyl-benzoic acid (0.173 g, 1.14 mmol), DMAP (1 mg) and Et 3 N (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 Et 3 N (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%).
[0298] 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. H NMR: 'H NMR: (300 MHz, DMSO-d 6 8 (ppm): 9.69 (br, 2H), 8.48 (br, 3H), 8.03 J 7.9 Hz, 2H), 7.51 J 8.4 Hz, 2H), 7.29 (br, 2H), 7.23 J 7.9 Hz, 1H), 7.03 J= 7.0 Hz, 1H), 6.84 J 7.9 Hz, 1H), 6.65 J 7.3 Hz, 1H), 4.96 (br, 2H), 4.62 J 5.7 Hz, 2H).
Scheme 39 HCl.H 2
N
CI
NH
N NN CO 2 Me 0 N CI N N H 2 0,NaHC0 3 OeCI' N N H reflux, 30 mm H 3-M ethoxy-propan-1-oI, C121P11 3 P. DEAD, DMVF. 00 to rt NH N NH 0~ N N N 1.LiOH, H0, THF0 Examp0 ExaExampl 150/ Step 1: 4-i(2-Chloro-9H-ourin-6-vlamino)-methvfl-enzoic acid methyl ester (241) [0299] A suspension of 2,6-dichloro-9--purine (1 g, 5.29 mmol), 4-aminomethyl-benzoic acid methyl ester hydrochloride (1.2 equiv., 1.28 g) and NaHCO 3 (2.1 equiv., 935 mg) in water was heated at 1000C. 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, LRMS calc:317.7, found: 318.3 (MH) 4 Step 2: 4-1 [2-Chloro-942-rnethoxvyethvlY9H-ourin-6-vlaminol-rnethvl l-benzoic acid methyl ester (242) [0300] Following the procedure described in Example 144, step 2 but substituting the previous compound for 2-amino-6nethoxybenzothiazole, the title compound 242 was obtained in 41% yield.
Step 3: NY42-Amino-iDhenl)-4-1 [2-chloro-94 2-rnethoxy-ethyl)-9Hiourin-6-ylaminol-methyl)-benzamide [0301] 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. 'H NMVR (CDCI 3 8 (PPM): 9.64 1H), 8.94 (bs, 1H), 8.18 1H), 7.96 J 7.8 Hz, 2H), 7.52 J 7.8 Hz, 2H), 7.21 J 7.7 Hz, 1H), 7,01 (dd, J 7.3, 8.0 Hz, 1H), 6.81 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 (in, 2H), 3.70 (in, 2H), 3.26 3H) o Scheme
-HCI.H
2 N F 0C0 2 Me c N i-Pr 2 NEt o H Oe 0l Me CH 2 N Me b eOC to n 244 0
FO.
2 0 2 N NaOHA M U0112 N in Me0H o N-O THF/H1 2 0 N I H OH DMF N.
NOrt 0 Me 245 0 c 246 1 .2-phenytenediamine Me 0 BOP reagent 0 N H *N1 Et 3 N DMF NN rii 247 Example 151 Example 151 Step 1: Methvl-4-( [3A 2-chloro-6-f luoro-phenvl)-5-methyksoxazole4-carbonll-amino-nethl l-benzoic acid ester (244) [0302] To a stirred suspension at 0"C of methyl 44aminomethyl)benzoate.HCI 2 (809 mg, 4.01 rnmol) in anhydrous CH 2
CI
2 (25 ml) under nitrogen were successively added W-r 2 NEt (1.91 ml, 10.95 mmol) and 3-(2-chloro-6-fluorophenyl)5-methylisoxazolek4carbony 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. NH 4
CI,
H
2 0, sat. NaHCO 3
H
2 0 and brine, dried over anhydrous MgSO 4 filtered and concentrated to afford the title compound 244 (1.50 g, quantitative yield) as a colorless sticky foam. 'H NMR (300 MHz, CDC1 3 5 (ppm): 7.93 J 7.9 Hz, 2H), 7.46-7.35 (in, 1H), 7.29 J 8.4 Hz, 7.15-7.05 (mn, 5.49 (bs, 1H), 4.46 J 5.7 Hz, 2H), 3.92 3H), 2.80 3H).
Step 2: 4-1 f3A2-Chloro-6-fluoro-phenvl)-5-methl-isoxazoleA-carbonllamino-methl)-benzoic acid (245) [0303] To a stirred solution at room temperature of 244 (1.45 g, 3.60 minol) in THF (20 ml) was added a solution of LiOH.H 2 0 (453 mng, 10.80 minol) in water (20 ml). After 20 h, the reaction
IO
0 0 mixture was concentrated, diluted with water and acidified with 1N HCI 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. 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 8.69 J 5.9 Hz, 1H), 7.91 J 7.9 Hz, 2H), 7.70- 7.58 1H), 7.51 J 7.9 Hz, 1H), 7.45-7.30 3H), 4.44 J 5.7 Hz, 2H), 2.72 3H).
Step 3: 49-Chloro-3-methvl-4-oxo-4HisoxazoloI4,3-clquinolin-5-ylmethyl)-benzoic acid (246) n [0304] To a stirred suspension at room temperature of 245 (795 mg, 2.05 mmol) in anhydrous 0 DMF (10 ml) was added a solution of NaOH (409 mg, 10.22 mmol) in anhydrous MeOH (5.1 ml).
0 Then, the reaction mixture was warmed up to 400C. After 3 days, the reaction mixture was concentrated, diluted with water and acidified with 1N HCI 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. 'H NMR (300 MHz, DMSO-d 6 8 (ppm): AB system (6A 7.92, 8B 7.40, J 8.4 Hz, 4H), 7.56 J 8.1 Hz, 1H), 7.47 J 7.5 Hz, 1H), 7.31 J 8.3 Hz, 1H), 5.59 (bs, 2H), 2.95 3H).
Step 4: N(2-Amino-phenvl-4-(9-chloro-3-methvl-4-oxo-4Hisoxazolor[4.3-c1uinolin-5-vlmethvl)benzamide (247) [0305] The title compound 247 was obtained from 246 in one step following the same procedure as Example 1, steps 5. 'H NMR (300 MHz, DMSO-d 6 6 (ppm): 9.65 1H), AB system (SA 7.95, 8 B 7.42, J 8.1 Hz, 4H), 7.58 J 8.1 Hz, 1H), 7.48 J 7.5 Hz, 1H), 7.35 J 8.3 Hz, 1H), 7.17 J 7.5 Hz, 1H), 7.00 J =7.3 Hz, 1H), 6.80 J 7.5 Hz, 1H), 6.62 J 7.3 Hz, 1H), 5.61 (bs, 2H), 4.91 2H), 2.97 3H).
Scheme 41 a. OHCCHO, OHC NH40H BOP. Ph(NH 2 2 OH HCI N Et 3 N, DMF, rt N N 28OH H H OH ON H NHI 248 249 Example 152 Example 152 Step 1: 4-(1H-midazol-2-vl)-benzoic acid (248) [0306] 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 205
\O
0 0 temperature. 1N HCI was added to the reaction mixture to acidify to pH 5. The solvent was Sevaporated 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-ohenvl)4-lHimidazol-2-yl)-benzamide (249) [0307] The title compound 249 was obtained following the same procedure as Example 1, step 'H NMR (CDCI 3 5 (ppm): 'H NMR: (DMSO) 8 (ppm): 9.72 (bs, 1H), 8.07 4H), 7.26 2H), 7.18 J 7.9 Hz, 1H), 6.98 (dd, J 7.5, 7.5 Hz, 1H), 6.79 J 7.9 Hz, 1H), 6.60 (dd, J 7.5, S Hz, 1H). MS: (calc.) 278.1; (obt.) 279.1 (MH).
0Scheme 42
H
2 S, Et 3 N, Pyridine H2N OH S 0H 0 25 0 0 S,3-dichloroacetone
THF
NH
NH
2 1. morpholine, THF SO 2. BOP, Ph(NH 2 2 Cl
OH
2 Et 3 N, DMF, rt
O
252 251 Example 153 Example 153 Step 1: 4-Thiocarbamolmethvl-benzoic acid (250) [0308] To a stirred suspension of 4-cyanomethyl-benzoic acid (1.65 g, 10.24 mmol) and Et 3 N ml) in pyridine, H 2 S 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 HCI. The solvent was evaporated and the residue was triturated 30 min. in water (20 ml) and filtered to obtain the title compound 250 (2.08 g, 83%) as a white solid. 'H NMR (DMSO) 8 (ppm): 12.85 (bs, 1H), 9.53 (bs, 1H), 9.43 (bs, 1H), 7.88 J 8.1 Hz, 2H), 7.44 J 8.1 Hz, 2H), 3.88 2H).
Step 2: 4-(4-Chloromethvl-thiazol-2-vlmethvl)-benzoic acid (251) [0309] 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 0 C during 48h. The solvent was evaporated then the residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous MgS0 4 filtered and 206 concentrated. The crude residue was purified by flash chromatography on silica gel (2-4% MeOH/CH 2
C
2 to afford the title compound (827 mg, 83% yield) as a white solid. 'H NMVR (DMS0) 8 (ppm): 12.93 (bs, 1H), 7.91 J 8.1 Hz, 2H), 7.63 1H), 7.46 J 8.1 Hz, 2H), 4.78 2H), 4.42 2H).
Steo 3: N42-Amino-henyl)4-(4.moriholin4-vlmethyl-thiazol-2-vlmethyl)-benzamide (252) [0310] K 2 C0 3 (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 IND evaporated. The crude residue was purified by flash chromatography on silica gel (3-50% MeOH/CH 2
CI
2 to afford the title compound 252 (238 mg, 38% yield) as a pale yellow solid. LRMS: 318.2 (calc) 319.2 (found).
[0311] The title compound 252 was obtained following the same procedure as Example 1, step 1 H NMVR (DMS0) 8 (ppm): 9.63 Cbs, 1 7.94 J 8.1 Hz, 2H), 7.45 Cd, J 8.1 Hz, 2H), 7.33 1 7.15 J 8. 1Hz, 1 6.97 (dd, J 7.7, 7.7 Hz, 1 6.77 Cd, J 7.3 Hz, 1 6.59 (dd, J 8.1, 8.1 Hz, 1H), 4.90 (bs, 2H), 4.40 2H), 3.59-3.56 Cm, 6H), 2.44-2.38 (in, 4H). LRMS: 408.2 (calc) 409.2 (found).
Scheme 43 0 0 1. Triphosgene, Et 3 N, We s O CM. -78 0 C to rt cI I O 0 I NH 2 2 m HC Et 3 N, DOM 0 253 a.NaHMeOH 0 S N H 1 EtI, K 2 00 3 DMF 1 s 102 OPh(NH 2 2
C
2 Et 3 N, DMF, rt H 255 254 Example 154 Example 154 Step 1: Methyl 3-13-(4-rethoxycarbonyl-benzyl)-ureido]-thiophene- -carboxylate (253) [0312] The procedure described by Nakao 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 U to afford the title compound 253 (1.01 g, 91%) as a yellow solid. 'H NMVR (CDCI 3 8 (PPM): 9.55 (bs, 8.00-7.97 (in, 3H), 7.42-7.37 (in, 5.45 J 5.8 Hz, 4.52 J =6.0 Hz, 3.91 3H), 3.82 3H).
SterD 2: 4-(2.4-Dioxo-1 .4-dihvdro-2H-thienol3.2dlr~vrimidifl-3&lmethvD-benzoic acid (254) r- [0313] To a suspension of 253 (422 mg, 1.21 mmol) in MeOH (15 ml) was added NaOH (145 0 mg, 3.63 mmol). The reaction mixture was heated at 60 0 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 ID was dissolved in water and acidified to pH 5 with HCI 1iM. The precipitate was filtered to afford the desired compound 254 (348 mg, 95%) as a white solid. LRMS: 302.0 (Calc.); 303.0 (found).
Steps 3: NM2-Amino-ohenvl)-44 1-ethvl-2 ,4-dioxo-1 .4-dihvdro-2 lIthieno[3. 2-d1Dvrimidin-3-vlmethvl) benzamide (255) (0314] The title compound 255 was obtained as a yellow solid following the same procedure as Example 99, step 2, 3, then followed by Example 1, step 5. 'H NMVR: (DMVSO) 8 (ppm): 9.61 (bs, 1H, NI-i, 8.22 J 5.5 Hz, IH, CH) 7.91 J 8.2 Hz, 2H, Cl-H, 7.43-7.40 (mn, 3H-, CM), 7.15 J 7.4 Hz, 11-, Cl-H, 6.96 (dd, J 7.6, 7.6 Hz, 1H, ClHf, 6.77 J 7.1 Hz, 1H, CH-.l 6.59 (dd, J 7.4, 7,4 Hz, 11-, Cl-f, 5.17 2H-, NCHA) 4.88 (bs, 2H-, NH 2 4.09 J 7.0, 21-,
CH
2 1.22 J 7.0, 3H, Cl- 3 LRMS: 420.1 (calc.); 421.0 (found).
Scheme 44 o 0 1. K 2 co 3 DMF o s HCHO, BrH -HaIH2
NH
2 N 2. LiOH, THF, H120 NN 256 3. BOP, Ph(NH 2 2 257 0 EtN, DMF, ft Example 155 Example 155 SteD) 1: 3H-Thienof3,2-dDyrimidin-4-one (256) (0315] Methy[3-amino-2-thiophene carboxylate (510 mg, 3.24 minol) 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 MeOH/CH 2 Cl 2 to afford the title compound 256 (157 mg, 32% yield). LRMS: 152.0 (Calc.); 152.9 (found).
208 U Step 2: NA2-Aminophenl)-44-oxo4H+tenof3.2-d1Drimidin-3-vlmethyl~benzamide (257) [0316] 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. 'H NMR: (DMSO) 5 (ppm): 9.61 (bs, 1H), 8.70 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, 1H1), 7.15 (d J 7.7 Hz, 1H), 6.96 (dd, J 6.9, 6.9 Hz, 1 6.77 J 1Hz, 1 6.58 (dd, J 7.0 Hz, 1 5.31 2H), tn 4.87 (bs, 2H). MS: 376.1 (calc.); 377.1 (found).
IND
Scheme (Ni 1. HCIIO reflux 2. K 2 C0 3
DMF
0 NC co 2 Me r 1 sulfur DE I-
N
2
M
morpholine
N
2 3.LiOH. THF,I-H 2 0 )S N 1] 258 4. BOP, Ph(NH 2 2 259 0 Et 3 N. DMF, rt Example 156 Example 156 Step 1: Methyl 2-amino-4. 5-dimethyl-thiophene-3-carboxvlate (258) [0317] The procedure described by Hozien A. Hozien, F. M. Atta, Kh. M. Hassan, A. A. Abde[- 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: N42-Amino-iDhenyl)4A 5. 6-dimethyl4-oxo-4H-thienol2 .3.dlivrimidin-3-vlmethyl)-benzamide (259) [0318] 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 'H NMR: (DMSO) 8 (ppm): 9.61 (bs, 1H), 8.57 1H), 7.94 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 Kd J 8.0 Hz, IHN, 6.59 (dd, J 7.4, 7.4 Hz, 1H), 5.25 (s, 2H), 4.87 (bs, 2H), 2.39 3H), 2.37 3H). LRMS: 404.1 (calc); 405.0 (found).
209
IND
U Scheme 46 0 Methyl-4-formylbenzoate 0 AcOH, H 2 S0 4 OMe 0 260 0 Pd/C, H 2 RCI.0 or 0tO
PSO
2
NHNH
2 (Ni DMF, 100 0
C
.j ~I OMe N Oe 261 0 263: X CH 2 0 1 .LOH, THF, H 2 0 264: X CO 2. BOP, Ph(NH- 2 2 Et 3 N, OMF. fl 1.UOH-, THF. H 2 0 2.BOP. Ph(NH2)2 2620 Eape157 Example 158 265: X =CH 2 Example 159 266: X CO Example 157 Step 1: Methyl 444-oxo-chroman-3-vlidenemethyl)-benzoate (260) [0319] Concentrated H 2 S0 4 (2 ml) was slowly added to a solution of 4-chromanone (2.00 g, 13.50 mmol) and methyW--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 cumpound 260 11 g, 82%) as a purple solid. 'H NMR: (DMS0) 8 (ppm): 8.05 J 8.2 Hz, 2H), 7.90 J 7.6 Hz, 1H), 7.79 1H), 7.64-7.59(m, 3H), 7.15 (dd, J 7.6, 7.6 Hz, 1H), 7.07 J 8-.2 Hz, 1H), 5.43 2H), 3.89 3H).
Step 2: Methvl4-i4-oxo-4H-chromen-3-vlmethvl)-benzoate (261) [0320) Water (0.2 ml) and RhCI 3
.H-
2 0 (7 mg, 0.034 mmol) was added to a suspension of compound 260 (200 mg, 0.680 mmol) in EtOH (2 ml) and CHCL 3 (2 ml). The reaction mixture was stirred 16 h at 70 0 C. The reaction mixture was cooled down and diluted in ethyl acetate, washed with 210
IND
0 0 brine, dried over anhydrous MgS04, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel MeOH/CH 2 Cl 2 )to afford the title compound 261 (118 mg, 59%) as a white solid. 'H NMR: (DMSO) 8 (ppm): 8.45 1H), 8.03 (dd, J 7.9, 1.8 Hz, 1H), 7.87 J 8.4 Hz, 2H), 7.83-7.77(m, 1H), 7.65 J 8.3 Hz, 1H), 7.50-7.43 (m3, 1H), 3.82 (s, 3H), 3.80 2H).
0 Step 3: (2-Amino-henl)4-(4-oxo4Hchromen-3-vlmethyl)-benzamide (262) 'n [0321] The title compound 262 was obtained following the same procedure as Example 1, step IN 4, 5. 'H NMR: (DMSO) 8 (ppm): 9.56 (bs, 1H), 8.45 1H), 8.04 J 7.9 Hz, 1H), 7.88 J S8.4 Hz, 2H), 7.80 (dd, J 7.5, 7.5 Hz, 1H), 7.65 J 8.4 Hz, 1H), 7.51-7.42 3H), 7.14 J 7.9 Hz, 1H), 6.96 (dd, J 7.3, 7.3 Hz, 1H), 6.76 J 7.9 Hz, 1H), 6.58 (dd, J 7.3, 7.3 Hz, 1H), 4.86 (bs, 2H), 3.80 2H). LRMS: 370.1 (calc.); 371.1 (found).
Example 158 Step 2: Methyl 4-chroman-3-ylmethvl-benzoate (263) [0322] 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 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-ohenvl)4-chroman-3-vlmethvl-benzamide (265) [0323] 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 J 7.9 Hz, 2H), 7.42 J 8.4 Hz, 2H), 7.31 J 7.9 Hz, 1H), 7.08-6.98 3H), 6.87 J 7.5 Hz, 1H),6.82-6.66 3H), 4.62 2H), 4.22-4.17 1H), 4.88-3.81 1H), 2.88-2.71 3H), 2.61-2.53 1H), 2.41-2.33 (m, 1H). LRMS: 358.2 (calc.); 359.1 (found).
Example 159 Step 2: Methyl 4-4-oxo-chroman-3-vlmethvl)-benzoate (264) [0324] A suspension of 260 (400 mg, 1.36 mmol) and benzenesulfonyl hydrazine (702 mg, 4.08 mmol) in DMF (7 ml) was stirred at 100°C during 48h. The solvent was evaporated and the residue was diluted in AcOlEt, washed with NH 4 CI sat., brine, dried over anhydrous MgSO 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel AcQEtA-IEx Ito afford the title compound 264 (170 mg, 42%) as a white solid. LRMS: 296.1 (Calc.); 297.0 (found).
SteD) 3: NM2.Amino-Dhenyl-44-oxochroman-3-vlmethyl)-benzamide (266) [0325] The title compound 266 was obtained following the same procedure as Example 1, steps 4 and 5. 'H NMR: (acetone) 8 (ppm): 9.62 (bs, 1H), 7.93 J 7.9 Hz, 2H), 7.79 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 (in, 3H), 6.97 (dd, J Hz, 1H), 6.78 J 7.9 Hz, 1H), 6.60 (dd, J 7.5, 7.5 Hz, 4.88 2H), 4.44-4.39 (in, 1H), 4.28-4.21 (mn, IN, 2.26-3.21 (in, 2H), 2.83-2.74 (in, 1H). LRMS: 372.1 (calc.); 372.1 (found).
Scheme 47 "N 0
H
Methyl-4-formyltbenzoate Et 3 N, AcOH, Reflux 0 HN LN~J 266 0 Pd/C, H 2 SMeOH, DMA 'NO 0 OMe H 267 KIL-. 0 OMe 268 0 I 1.LiOI, THF, H 2 0 2. BOP. Ph(NH 2 2 Et 3 N, DMF. rl N HNH 269 Example 160 Ell, K 2 C0 3 1 .LOH. TH-F, H 2 0 2. SOP, Ph(NH 2 2 Et 3 N, DMF, nl r 'r
NH_
270 Example 161 212
IND
o Example 160 Step 1: Methyl 4-13-oxo-3.4-dihydro-21-Ibenzo[1 .4loxazin-2-vlmethyl)-benzoate (266) [0326] Et 3 N (3.18 ml, 22.8 mmol) was added to a stirring solution of 2-H-i,4-benzoxazin-3- (4Mone (2.50 g, 16.8 mmol) and methyl 4-formylbenzoate (4.59 g, 27.5 mmcl) in AC 2 0 (20 ml). The reaction mixture was refluxed 16h. After this mixture was cooled for 3 days, the solid was filtered 0 and rinsed with ethyl acetate to afford the title compound 266 (657 mg, 13%) as a yellow solid.
V) LRMS: 295.1 (Calc.); 296.0 (found).
ID Step 2: Methyl 443-oxo-3.4-dihydro-benzo[1 .41oxazin-2-vlidenemethyl)-benzoate (267) [03273 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-henvl)4-4-ethyl-3-oxo-3.4-dihydro-2H-benzorl .41oxazin-2-ylmethyl)-benzamide (269) [0328] 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. 'H 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 J =7.9 Hz, 1H), 7.17 (d J =7.5 Hz, 1H), 7.11-6.91 (in, 4H), 6.77 J 7.0 Hz, 11H), 6.60 (dd, J 7.0, 7.0 Hz, 1H), 4.95-4.91 (in, 11H), 4.89 (bs, 2H), 3.95 J 7.0 Hz, 2H), 3.28-3.22 (in, 1H), 3.17-2.89 (in, 1H), 1.16 J 7.0 HZ, 3H). LRMS: 401.2 (calc.); 402.1 (obt.).
Example 161 SteD) 1: N-i2-Amino-nhenyl)-43-oxo-3 .4-dihvdro-2H-benzofl1.4]oxazin-2-vlmethyI benzamide (270) [0329] The title compound 270 was obtained from 267 following the same procedure as Example 1, step 4, 5. 'H NMR: (DMVSO) 8 (ppm): 10.74 (bs, 1H), 9.61 (bs, 11H), 7.91 J 8.4 Hz, 2H), 7.41 (d J 7.9 Hz, 2H), 7.17 (d J =7.5 Hz, 11H), 6.99-6.85 (mn, 5H), 6.78 J 7.5 Hz, 1H), 6.60 (dd, J 7.0, 7.0 Hz, 1H), 4.92-4.89 (mn, 3H), 3.29-3.23 (in, 1H), 3.15-3.07 (in, 11H). MS: (calc.) 373.1; (obt.) 374.1 213 O Scheme 48 0 4-carboxybenzaidehyde KOH, MeOH -OH 273 0 Methy4.4-bromomethylbenzoate BOP, Ph1(NH1 2 LDA 2M, THF Et 3 N, DMF, rt 0H O~ /H2N 271 274 0 1.1-01H, THF, H 2 0 aHM
H
2. BOP, Ph(NH 2 2 NaHMH 0 EI 3 N, DMF, rt O H NH 2 Nt 27mp2 0 275 0 Examle 12 0Example 163 Example 162 Step 1: Methyl 441-oxo-indan-2-lmethvl)-benzoate (271) [0330] A 2M LDA solution in THE (4.16 ml, 8.32 mmol) was added to a solution of indanone (1.00 g, 7.57 mmol) in THE (10 ml) at The solution was slowly warmed to 0 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 MgSO 4 filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (5-20% AcOEt/Ex hto afford the title compound 271 (245 mg, 17%) as a white solid. LRMS: 280.1 (Calc.); 281.1 (found).
Step 2: N2Amino-henl)-44-oxo-indan2.lmethvl)-benzamide (272) [03311 The title compound 272 was obtained following the same procedure as Example 1, step 4, 5. 1 H NMR: (DMSO) 8 (ppm): 9.59 (bs, IHN, 7.91 J 7.6 Hz, 2H), 7.69-7.64 (in, 2H), 7.54 (d, J =7.6 Hz, 1H), 7.45-7.40 (mn, 3H), 7.16 J 8.2 Hz, 6.96 (dd, J 7.3, 7.3 Hz, 1H), 6.77 Kd J 8.2 Hz, 6.59 (dd, J 7.3, 7.3 Hz, 1H), 4.87 (bs, 2H), 3.23-3.14 (in, 3H), 2.85-2.81 (in 2H). LRMS: 356.1 (calc.); 357.2 (found).
214
IO
0 0 Example 163 Q Step 1: 4-1-0xo-indan-2-vlidenemethvl)-benzoic acid (273) S [0332] 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 0 C. The reaction mixture was stirred 30 min at 0 0 C then at room temperature for 16 h. The solvent was evaporated and the 0 residue was dissolved in water, acidified to pH 5 with HCI 1 M. The precipitate was filtered and rinsed in with water to afford the title compound 273 (2.27 g, 57%) as a yellow solid. LRMS: 264.1 (Calc.); s 265.0 (found).
0 Step 2: N(2-Amino-phenvl)-4-(1-oxo-indan-2-vlidenemethyl)-benzamide (274) [0333] The title compound 274 was obtained following the same procedure as Example 1, step LRMS: 354.1 (Calc.); 355.0 (found).
Step 3: N(2-Amino-Dhenvl)4-(1-hvdroxvindan-2-vlmethyl)-benzamide (275) [0334] To a suspension of 274 (300 mg, 0.85 mmol) in MeOH (8 ml) and water (1 ml) was added NaBH 4 (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. 'H NMR: (acetone) 8 (ppm): 9.05 (bs, 1H), 8.00 (dd, J 8.2, 2.7 Hz, 2H), 7.47 J 8.5 Hz, 1H), 7.43 J =8.2 Hz, 1H), 7.38-7.30 2H), 7.22-7.12 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 J 5.8 Hz, 0.4H), 4.89 J 6.7 Hz, 0.6H), 4.63 (bs, 2H), 4.45 J 6.9 Hz, 0.6H), 4.06 J 6.0 Hz, 0.4H), 3.30-3.19 1H), 2.88-2.48 3H, CH 2 LRMS: 358.2 (calc.); 359.1 (found).
0 0 278 I Ai or vi,
III
NC 0 HN Me~
OR'
279 Scheme 49 0 ,Iiii N Me Ph-N' Me 276
N
H
NH
2 277 Example 164 I Vii NC 0 NC 0 iv or viii, ix HN Me N HN MeOH Me-~ s N NH 2 Me 0 280 281 IBrCH- 2
C
6
H-
4 COOMeI~eOWaTHF; Example 165 ii: PhNHNH 2 III: NaOH, then HCI iv: HOBtIEDC.HCI then 1 ,2-diaminobenzene; v: BrCH 2 CrH 4 COOMe/MeONa/MeOH, then HCVAcOH; vi: CH 2
(CN)
2
/S
8 /Et 2 NH(or Et 3
N);
vii: AcCI, PhOOCI or PhNCO: viii: 2-N-Bocamino aniline; ix: TFA; Example 164 Step 1: 443. 5-Dimethyl-l-ohenv[1 H-ovrazol4-vlmethyl)-benzoic acid (276) [0335] To a solution of NaH (60% in mineral oil, 250 mg, 6.3 mmol) at 0 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 ref luxed for 2 hours. Phenyl hydrazine (0.51 ml, 5.2 mmol) was added and the reaction mixture ref luxed 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) to produce an oily material (800mg) which was treated with a solution of 216
OD
0 NaOH (0.8 g, 20 mmol) in 20 ml water for 1 hour at room temperature. The following steps,- S acidification with HCI (pH 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 307.0 and 191.1.
This mixture was taken for the next step as is.
Step 2. N(2-Amino-ohenvl)4(3.5-dimethvl-l-phenyl-lH-ovrazol-4-vlmethvl)-benzamide (277) C [0336] Following a procedure analogous to that described in Example 92, step 2, but C substituting 276 for 143, the title compound 277 was obtained in 25% yield (purified by chromatography using as eluent EtOAc hexane, 'H NMR: (300 MHz, DMSO-d 6 8 (ppm): 9.64 1H); 7.97 J 7.6 Hz, 2H), 7.42-7.56 5H), 7.37 J 8.2 Hz, 2H), 7.22 J 7.6 Hz, 1H), 7.03 J 7.6 Hz, 1H), 6.84 J 8.2 Hz, 1H), 6.66 J 7.6 Hz, 1H), 4.93 2H), 3.92 2H), 2.34 3H), 2.18 3H).
Example 165 Step 1: 4-3-0xo-butvl)-benzoic acid (278) [0337] 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 HCI (pH Evaporation of the resultant solution yielded a residue, which was refluxed in a mixture of glacial AcOH (50 ml) and conc. HCI (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). 191.1.
Step 2. 4-(5-Amino4-cvano-3-methvl-thiophen-2-ylmethvl)-benzoic acid 279 [0338] 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 ml, 4.8 mmol) was added. The reaction mixture refluxed 1 hour, cooled to the room temperature, acidified with conc. HCI (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-d 6 6 ppm): 7.87 J 8.4 Hz, 2H), 7.29 J 7.9 Hz, 2H), 6.98 2H), 3.92 2H), 2.03 3H).
217 Step, 3. 4-(5-Acetvlamino4-cvano3-methl-thiohen2ymethl)-belzoic acid 280 (0339] To a solution of 45amino-4cyano-3-nethyhiophen-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-1i 313.1.
Step, 4: NA2-Amino-henl)-4-5-acetlamino-4-cyano-3-methvl-thiophen-2-vlmethylI) benzamide (281) IND [0340] 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 1H); 7.91 J 7.9 Hz, 2H), 7.34 J 8.4 Hz, 2H), 7.15 J 7.5 Hz, 11-), 6.96 J 6.6 Hz, 1H), 6.77 J 7.0 Hz, 1H), 6.59 J =7.9 Hz, 1H), 4.89 2H), 4.10 (s, 2H), 2.19 3H), 2.16 3H). [M+1i 405.0.
Scheme COOH 0o N H O O H 0 N -N O H
H
2 N N 282 283
NC
O- N ill or Iv, fi N H NH 2 i: NH 2 OH/EtOH; N ii: ROOCI or AC 2 O/pyridine or CICH 2 000I/tOluene: 284 iii: HQBtIEDCxHCI then 1 ,2-diaminobenzene: Example 166 iv: morpholine or pipenidine Example 166 Step 1. 44tVHdroxcarbamimidoylmethyl)-benzoic acid (282) [0341] A suspension of 4-cyanomethyl benzoic acid (2.07 g, 12.86 mmol), NH 2 OH.HCI (1.79 g, 25.71 mmol) and potassium hydroxide (2.16 g, 38.57 mmol) in 70 ml ethanol ref luxed for 36 hours, poured into 100 ml water and acidified with conc. HCI (pH 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 195. 1.
218 Ster) 2. 4A5-Methl.[.2.4loxadiazol-3-vlmethyl)-benzoic acid (283) [0342] A solution of 4-Nhydroxycarbamimidoylmethyl)-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 1) and finally EtOAc-MeCH to produce 283 (164 mg, 38% yield).[M-1]* 217.1 SteD) 3. NA 2-Amino-ohenvl)-4A5-methv[[I .2 .4Ioxadiazo 3-vlmethyl)-benzamide (284) IND [0343] 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 NMVR: 8 (ppm): 9.62 1H), 7.93 J 7.9 Hz, 2H), 7.42 J 8.4 Hz, 1H), 7.16 J Hz, 1H), 6.97 J 7.9 Hz, 1H), 6.78 J 7.5 Hz, 114), 6.60 J 7.9 Hz, 1H), 4.92 2H), 4.14 2H), 2.55 3H). 309.2 Scheme 51 0 i OH N 1 NH-N- N& 1 N-e H HNjeM-U Me 28 eU Me .286 285 Example 167 i: Acetyl acetone/EtOH; fi: HOBtIEDCxHCI then 1 ,2-diaminobenzene; Example 167 Step 1: 4-(3.5-Dimethvkpyrazol-l-vl)-benzoic acid (285) [0344] 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-1i* 215.1.
Step 2, N42Amino-ohenyl)443.5-dimethvl-Dvrazol-1-vl)-benzamide (286) [03451 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 CH 2
CI
2 -cethanol, 19:1). IH NMVR: (DMVSO) 8 (ppm): 9.73 Cs, 1H); 8.09 J 8.4 Hz, 2H), 7.64 J 8.4 Hz, 2H), 7.17 J 7.5 Hz, 1H), 6.98 J Hz, 1H), 6.78 J 7.9 Hz, 1H), 6.60 Ct, J 7.5 Hz, 1H), 6.13 Cs, 1H), 4.92 2H), 2.37 (s, 3H), 2.20 3H). 303.3 Scheme 52 0 Meo Meo a
KCIY
0 b MeO 7 N -I HP MeO 0
NH
2 Meo 289 Example 168 0 d MeO Q-I t MeO 0.100-* MeO 288 MeO N MeO H NH 2 MeO 290 Example 169 a. 2.5% Pd(OAc) 2 nBU 4 NCI (1 eq) KOAc (3 eq) 2.5% PPh 3 DMF 80 0
C
b. 3-4% Pd(OAc) 2 9% PPh 3 Ag 2 00 3 (2 eq) CH 3 CN 80 0
C
c. LiOH *H 2 0O/THF-H 2 0 1) d. 1 ,2-phenylenediamine BOP Et 3 N DMF e. Pt0 2
H
2 (1 atm) AcOEt Example 168 SteiD 1: 2(3 5-Trimethoxv-ohenv)-2. 3-dihydro-turan (287) [0346] To a solution of 5Aodo-1,2,3-trimethoxybenzene (900 mg, 3.06 mnmol) and 2,3dihydrofuran (1.16 mL, 15.3 mnmol) in dry DMF C8 mL) were added PPh 3 (20 mg, 0.077 mnmol), KOAc
\O
0 0 (901 mg, 9.18 mmol), n-Bu 4 NCI (850 mg, 3.06 mmol) and Pd(OAc)2 (17 mg, 0.077 mmol). The Q reaction mixture was stirred 18 h at 800C. The reaction mixture was diluted with AcOEt and water.
After separation, the organic layer was washed with brine, dried over anhydrous Na 2
SO
4 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: S (300 MHz, CDCI 3 8 (ppm): 6.59 2H), 6.45 1H), 5.45 (dd, J 10.5, 8.4 Hz, 1H), 4.97 (m,
(N
VD 1H), 3.87 6H), 3.84 3H), 3.06 1H), 2.62 1H).
(Nl 0 Step 2: 4-15-(3,4.5-Trimethoxv-phenvl)-2,5-dihvdro-furan-2-vl]-benzoic acid ethyl ester (288) S[0347] To a solution of 287 (200 mg, 0.846 mmol) and 4lodo-benzoic acid ethyl ester (468 mg, 1.69 mmol) in dry acetonitrile (4 mL) were added PPh 3 (20 mg, 0.076 mmol), Ag 2 C03 (467 mg, 1.69 mmol) and Pd(OAc) 2 (7 mg, 0.03 mmol). The reaction mixture was stirred 18 h at 800C. 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 Na 2 S0 4 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). 'H NMR (300 MHz, CDCI3) 8 (ppm): 8.05 J 7.5 Hz, 2H), 7.45 J 7.5 Hz, 2H), 6.61 2H), 6.18- 5.95 4H), 4.38 J 7.0 Hz, 2H), 3.88 6H), 3.84 3H), 1.39 J 7.0 Hz).
Step 3: N2-Amino-phenvl)4-[543.4.5-trimethoxv-phenvl)-2.5-dihvdro-furan-2-vl-benzamide (289) [0348] 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. 'H NMR (DMSO) 8 (ppm): 8.00 1H), 7.91 J 7.9 Hz, 2H), 7.48 J 7.9 Hz, 2H), 7.33 J 7.5 Hz, 1H), 7.09 J 7.5 Hz, 1H), 6.92-6.82 2H), 6.61 2H), 6.14-5.99 4H), 3.89 6H), 3.84 3H).
Example 169 Step 1: N2-Amino-ohenvl)4-[5(3.4,5-trimethoxv-Dhenvl)-tetrahvdro-furan-2-vn-benzamide. (290) [0349] To a degazed solution of 289 (43 mg, 0.096 mmol) in AcOEt (4 mL) was added Pt02 (3 mg, 0.01 mmol) and the reaction mixture was stirred at room temperature under a 1 atm pressure of H 2 for 16 h. The reaction flask was purged with N 2 then the reaction mixture was filtered through celite, rinsed with MeOH and concentrated. The crude residue was purified threc times by flash chromatography on silica gel (MeOH/DCM: 2/98, AcOEt/DCM: 30/70 and AcOEt/CHC3I: 30/70) to afford the title compound 290 (10 mg, 0.22 mmol, 23% yield). 'H NMR (CDCI3) 8 (ppm): 8.10 (s, 1H), 7.91 J 8.0 Hz, 2H), 7.50 J 8.0 Hz, 2H), 7.34 J 7.5 Hz, 1H), 7.10 J 7.5 Hz, 1H), 6.96-6.85 (in, 2H), 6.64 2H), 5.33 J 7.0 Hz, 1H), 5.21 J 7.0 Hz, 1H), 3.89 6H), 3.85 3H), 2.59-2.40 (in, 2H), 2.09-1.88 (in, 2H).
Scheme 53 N NH~oc 291 b 0 292 /C OMe MeO MeO IN'
H
293 R=BOC7 d 294 R=H Example 169 0 N
H
MeO\'~ 0 MeO 296 Example 170 MeOO N N I H 2 MeC
N
0 297 Example 171 a. Tributyl(vinyl)tin Pd(PPh 3 4 Toluene 100 0
C
b. m-CPBA CHC1 3 r.t.
c. 3,4,5-trimethoxyaniline COC1 2
ICH
3
CN
d. TFA /DCM e. 1, ,1-carbonyldiimidazole DCM Ir.t.
f. 1 ,1'-carbonyldiimidazolel Et 3 N I/Toluene I THF 90 0
C
222 0 Example 169 SStep 1: [2-4-Vinvl-benzovlamino)-phenyll-carbamic acid tert-butyl ester (291) S [0350] 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. 'H NMR: (300 MHz, CDC 3 8 (ppm): 9.18 1H), 7.94 J 8.5 Hz, 2H), 7.77 J 7.5 Hz, 1H), 0 7.49 J 8.5 Hz, 2H), 7.30-7.10 3H), 6.89 1H), 6.77 (dd, J 17.4, 11.0 Hz, 1H), 5.87 (d, kn J 17.4 Hz, 1H), 5.39 J 11.0 Hz, 1H), 1.52 9H).
0 Step 2: [2-(4-Oxiranvl-benzoylamino)-phenvll-carbamic acid tert-butyl ester (292) S[0351] To a solution of 291 (4.1 g, 12.1 mmol) in dry CHCI 3 (60 mL) was added m-CPBA (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 mCPBA (0.6 g, 2.4 mmol) was added and the reaction mixture was stirred for 16 h. Chloroform and a solution of NaHC03 were added and the phases were separated. The organic layer was washed with water and brine, dried over anhydrous Na 2
SO
4 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). 'H NMR (300 MHz, CDCI3) 8 (ppm): 9.20 1H), 7.95 J 8.1 Hz, 2H), 7.86-7.75 1H), 7.38 J 8.1 Hz, 2H), 7.26-7.10 3H), 6.84-6.70 1H), 3.93 J 3.0 Hz, 1H), 3.20 J 5.0 Hz, 1H), 2.80 (dd, J 5.0, 3.0 Hz, 1H), 1.52 9H).
Step 3: (2-14-41-Hvdroxv-2-(3.45-trimethoxv-phenvlamino)-ethl]-benzoylaminol-phenyl)-carbamic acid tert-butvl ester (295) and (2-14-12-Hvdroxv-1-(3.4.5-trimethoxy-phenylamino)-ethyll-benzoylamino}phenvl)carbamic acid tert-butvl ester (293) [0352] To a stirred solution of CoCI 2 (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 Na 2 S04, 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: 'H NMR (300 MHz,
CDCI
3 6 (ppm): Compound 292: 9.21 1H), 7.92 J 8.1 Hz, 2H), 7.73 J 6.6 Hz, 1H), 7.46 J 8.1 Hz, 2H), 7.28-7.10 3H), 6.90 1H), 5.83 2H), 4.54-4.44 1H), 3.93 (dd, 223
IO
0 0 J 8.1, 3.9 Hz, 1H), 3.84-3.72 1H), 3.71 3H), 3.66 6H), 1.47 9H). Compound 295: 9.22 1H), 7.91 J 8.1 Hz, 2H), 7.77 J 7.2 Hz, 1H), 7.46 J 8.1 Hz, 2H), 7.30-7.21 3H), 6.88 1H), 6.15 2H), 5.16-5.06 1H), 3.81 6H), 3.78 3H), 3.50-3.25 2H), 1.51 9H).
Step 4: M2-Amino-phenvl)-4-2-hvdroxv-143.4.5-trimethoxv-Dhenvlamino)-ethvll-benzamide (294) 0 [0353] Following a procedure analogous to that described in Example 42, step 3, but n substituting 293 for 46, the title compound 294 was obtained in 50% yield. 'H NMR (DMSO) 8 I0 (ppm): 8.36 1H), 7.74 J 6.9 Hz, 2H), 7.30 J 7.8 Hz, 2H), 7.18 J 6.9 Hz, 1H), S7.00 J 7.2 Hz, 1H), 6.72 2H), 5.69 2H), 4.34 1H), 4.02-3.52 2H), 3.66 3H), 3.57 6H).
Example 170 Step 1: N2-Amino-phenvl)4-f2-oxo-3-43.4.5-trimethoxv-ohenyl)-oxazolidin-4- ll-benzamide (296) [0354] To a solution of 293 (200 mg, 0.372 mmol) in toluene (5 mL) and THF (1 mL) was added 1,1'-carbonyldiimidazole (72 mg, 0.45 mmol) followed by Et 3 N (156 pL, 1.12 mmol) and the mixture was stirred at room temperature for 5 h then at 90'C for 48 h. The reaction mixture was diluted with AcOEt, a solution of sat. NH 4 CI was added and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na 2 S0 4 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). 'H NMR (DMSO) 8 (ppm): 9.37 1H), 7.98 J 8.1 Hz, 2H), 7.76 J 7.5 Hz, 1H), 7.41 J 8.1 Hz, 2H), 7.25-15 3H), 6.88 1H), 6.61 2H), 5.40 (dd, J 8.7, 6.0 Hz, 1H), 4.79 J 8.7 Hz, 1H), 4.19 (dd, J 8.7, 6.0 1H), 3.75 3H), 3.72 (s, 6H), 1.47 9H).
[0355] 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. 'H NMR (DMSO) 8 (ppm): 8.03 1H), 7.91 J 8.1 Hz, 2H), 7.41 J 8.1 Hz, 2H), 7.30 J Hz, 1H), 7.07 J 7.5 Hz, 1H), 6.82 J 7.5 Hz, 2H), 6.61 2H), 5.40 (dd, J 8.7, Hz, 1H), 4.78 J 8.7 Hz, 1H), 4.18 (dd, J 8.7, 6.0 Hz, 1H), 3.75 3H), 3.71 6H).
0Example 171 Step 1: 2-Amino-Dhenvl)4-f2-oxo-343.4.5-trimethoxy-Dhenvl)-oxazolidin-5-vl-benzamide (297) [0356] To a solution of 295 (130 mg, 0.242 mmol) in DCM (2 mL) was added 1,1'carbonyldiimidazole (47 mg, 0.29 mmol) and the mixture was stirred at room temperature for 16 h.
DCM was removed under reduced pressure, AcOEt and a solution of sat. NH 4 CI were added and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na 2 S0 4 n filtered and concentrated. The crude residue was purified by flash chromatography on silica gel \0 (Hexane/AcOEt: 30/70) to afford the desired compound (80 mg, 0.14 mmol, 58% yield). 'H NMR S(DMSO) 8 (ppm): 9.39 1H), 8.04 J 8.1 Hz, 2H), 7.84 J 7.5 Hz, 1H), 7.52 J 8.1 Hz, 2H), 7.26-7.12 3H), 6.86-6.74 3H), 5.70 J 8.4 Hz, 1H), 4.24 J 8.7 Hz, 1H), 3.97-3.87 1H), 3.87 6H), 3.82 3H), 1.52 9H).
[0357] 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. 'H NMR (DMSO) 8 (ppm): 8.38 1H), 7.97 J 7.5 Hz, 2H), 7.47 J 8.1 Hz, 2H), 7.35 J Hz, 1H), 7.08 J 7.0 Hz, 1H), 6.97-6.87 2H), 6.79 2H), 5.66 J 8.1 Hz, 1H), 4.41 J 9.0 Hz, 1H), 3.91 J 7.8 Hz, 1H), 3.86 6H), 3.82 3H).
225 Scheme 54 NHBoc a
OH
xH NHBoc 0N 298 X =N 3 b 299 X NH 2 MeO, MeO' NHBoc bN 302 x= N 3 b 303 X= NH 2
J
304 MeO OMe
-N
0
HNH
0N Id, e MeO OMe ~0
N
HNH
0 301 Example 172 305 Example 173 a. CeCI 3 heptahydrate NaN 3 I CH 3 CN H 2 0 (9 1)1/ reflux b. H 2 Pd/C MeOH c. 3,4-dimethoxybenzoyl chloride Et 3 N DCM -20 0 C to r.t.
d. Burgess reagent THF 70 0
C
e. TFAI/DCM 226 Scheme Me >-SH OMe DMF OMe EN
HW
a b c LiOH THF
H
2 0 MeO N BOP MeO N -esOTBDMS Et 3 N, DMF
S
-CC N l NH
H
H ~NH 2 f 0 OTBDMS d 0 e
TBAF
THFHO
M
eO N
IH
N} SN 0 MG 5833X Example 172 Step 1: 12-[441-Azido-2-hdroxyethl)-benzovlaminol-phenyl)-carbamic acid tert-butvl ester (298) and 2-14-(2-Azido-1 -hydroxy-ethvl)-benzovlaminol-henl l-carbamic acid tert-butvl ester (302) (0358] To a solution of 292 (210 mg, 0.59 mmol) in acetonitrile (9 mL) and water (1 mL) was added CeCI 3 heptahydrate (110 mg, 0.296 mmol) followed by NaN 3 (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 Na 2
SO
4 filtered and concentrated. Purification by flash chromatography on silica gel (AcOEtHexane: 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: Compound 298: 'H NMR: (300 MHz, CDCI/CD 3 00) 8 (ppm): 7.95 J 8.1 Hz, 2H), 7.70-7.63 1H), 7.43 J 8.1 Hz, 2H), 7.36-7.29 1H), 7.24-7.14 2H), 4.69 (dd, J 7.5, 4.8 Hz, 1H), 3.80-3.65 2H), 1.49 9H). Compound 302: 'H NMR: (300 MHz, CDC1 3 8 (ppm): 9.28 1H), 7.86 J 8.4 Hz, 2H), 7.71 J 7.5 Hz, 1H), 7.38 J 8.4 Hz, 2H), 7.25-7.08 3H), 7.01 1H), 4.87 (dd, J 6.9, 5.1 Hz, 1H), 3.47-3.38 2H), 3.32-3.21 (bs, 1H), 1.50 9H).
IO
0 0 Step 2: 12-[4-(l-Amino-2-hvdroxy-ethyl)-benzoylaminol-phenll-carbamic acid tert-butvl ester (299) [0359] To a solution of 298 (156 mg, 0.39 mmol) in MeOH (2 mL) was added Pd/C 10% 7mg, 0.02 mmol). The reaction mixture was stirred under a 1 atm pressure of H 2 at room temperature for 16 h then it was purged with N 2 The palladium was removed by filtration through celite and the MeOH was evaporated under reduced pressure to afford the title compound 299 (88 Smg, 0.24 mmol, 60% yield), which was used without purification. 'H NMR (300 MHz, CDCI 3 8 (ppm): 9.24 1H), 7.90 J 7.8 Hz, 2H), 7.71 J 6.6 Hz, 1H), 7.40 J 7.8 Hz, 2H), 7.31-7.10 3H), 7.06-6.94 1H), 4.12 (dd, J 7.5, 4.5 Hz, 1H), 3.74 (dd, J 7.8, 5.4 Hz, 1H), 3.64- S3.51 1H), 2.64 3H), 1.49 9H).
Step 3: (2-(4-1-(3.4-Dimethoxy-benzovlamino)-2-hydroxv-ethll-benzovlamino)-phenvl)-carbamic acid tert-butvl ester (300) [0360] To a stirred solution of 299 (88 mg, 0.24 mmol) in dry DCM (2 mL) at -20 0 C was added 3,4-dimethoxybenzoyl chloride (50 mg, 0.25 mmol) followed by Et 3 N (37 pL, 0.26 mmol). The reaction mixture was allowed to warm up to room temperature then was stirred for 48 h. A solution of sat. NH 4 CI was added, followed by DCM and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na 2 S0 4 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). 'H NMR (300 MHz, CDCI 3 8 (ppm): 9.29 1H), 7.81 J 8.1 Hz, 2H), 7.65-7.58 1H), 7.46 7H), 6.80 J 8.1 Hz, 1H), 5.20-5.10 1H), 3.95-3.78 (m, 2H), 3.88 3H) 3.84 3H), 1.47 9H).
Step 4: N2-Amino-ohenyl)4-[2-(3.4-dimethoxy-phenyl-4.5-dihydro-oxazol-4-v-benzamide (301) [0361] 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 0 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 Na 2 S0 4 filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/DCM: 3/97) to afford the Boc-protected intermediate mg, 0.14 mmol, 85% yield). 'H NMR (CDCI 3 6 (ppm): 9.31 1H), 7.94 J 8.4 Hz, 2H), 7.72 J 7.5 Hz, 1H), 7.66 J 8.1 Hz, 1H), 7.61 1H), 7.39 J 8.1 Hz, 2H), 7.27 J 6.0 Hz, 1H), 7.23-7.08 3H), 6.93 J 8.7 Hz, 1H), 5.43 J 9.0 Hz, 1H), 4.84 J 9.3 Hz, 1H), 4.26 J 8.4 Hz, 1H), 3.95 3H), 3.94 3H), 1.50 9H).
228 [0362] 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%. 1 H NMR (ODC1 3 8 (ppm): 8. 01 1 7.89 J =7.9 Hz, 2H), 7.65 (dd, J 8.4, 1.5 Hz, 1 7.60 J= Hz, 11H), 7.41 J 7.9 Hz, 2H), 7.32 J 7.9 Hz, 1H), 7.08 J 6.6 Hz, 6.92 J= 8.4 Hz, 1H), 6.84 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 J 8.1 Hz, 1H), 3.94 3H), 3.93 3H).
Example 173 IND Steo) 1: (2-14-(2-Amino-l-hvdroxv-thvl)-benzoylaminol-ohenvll-carbamic acid tert-butvl ester (303) [0363] 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.
Steo) 2: 2-14-f2-i3,4-Dimethoxy-benzolamino-1-hvdroxy-ethvll-benzovlamino)-D~henvl)-carbamic acid tert-butvl ester (304) [0364] 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. 1 H NMR (CDCI 3 S (ppm): 9.31 (s, 1H), 7.78 J 8.1 Hz, 2H), 7.68 J 6.9 Hz, 1H), 7.38 J 1.8 Hz, 1H), 7.33 J 8.1 Hz), 7.30-7.06 (in, 4H), 7.00-6.93 (in, 1H), 6.79 J 8.4 Hz, 1H), 4.89-4.82 (in, 1H), 3.88 (s, 3H), 3.86 3H), 3.85-3.73 (in, 1H), 3.44-3.32 (mn, 1H), 1.46 9H).
Step 3: N.2-Amino-johenvl)-4-[2A3,4-dimethoxy-ohenl-4. 5-dihydro-oxazol-5-yll-benzamide (305) [0365] 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%. 'H NMVR (CDCI 3 8 (PPM): 8.02 IHN, 7.93 J 8.1 Hz, 2H), 7.63 (dd, J 8.4, 1.8 Hz, 1H), 7.60 1H), 7.44 J =8.1 Hz, 2H), 7.33 J 7.5 Hz, 1H), 7.09 J 7.5 Hz, 11H), 6.91 J 8.1 Hz, 1H), 6.85 J =8.1 Hz, 2H), 5.74 (dd, J 10.0, 7.8 Hz, 1H), 4.51 (dd, J 14.5, 10.0 Hz, 4.00-3.90 (in, 7H).
Scheme 57 yCOOH SOCI 2 DMF. DCM 2.
I
H
2
NQ
NHtBoc
DIPEA
OHCf:: H NHtBoc 315
BU
2 SnCI 2 PhSiH 3 THF, 12h 3,4-dimethoxyaniline SMe HN0 N_ H NH 2 MeOq 317 OMe Example 178 1. CHCI 3
ITHF
~~NCO
MeSJC 2. TFA, DCM 76% 0 1~ H N N N H NHtBoc MeO qI 316 OMe Example 178 STEP 1: r244.FORMYL-BENZOYLAMINO PHENYLV-CARBAMIC ACID TERT-BUTYL ESTER (315) [0366] 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 O'C, was added a suspension of 4-formyl benzoyl chloride in dichloromethane (20 mL), followed by diisopropyl ethylamine (3.61 mL, 20 mmol, 1 ecO.
The mixture was stirred for 30 minutes at 0 0 C then at room t emperature for 30 minutes. The crude residue was diluted with dichloromethane (300 mL) and washed with water. The combined organic layers were dried (MgSO 4 filtered and concentrated under vacuo. The crude residue was purified by column chromatography on silica gel (elution 20% ethyl acetate in hexane) to give 6.1 g (45% yield) of anilide 315. 1H NMR (CDC1 3 8 10.18 1H), 9.64 (brs, 11H), 8.20 J 7.9 Hz, 2H), 8.06 J =7.9 Hz, 2H), 7.96 J 7.9 Hz, 1 7.2&-7.38 (in, 1 7.24 J 4.4 Hz, 1 6.84 I1H), 6.81 J 8.8 Hz, 1H), 1.58 9H).
230 Step 2: (2.I4-i(3.4-Dimethoxyohenvamino~ethll-Benzovlamino)-Phel)-Carbamic Acid Tert-Butvl Ester (316) [0367] 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. 'H NMVR (CDC1 3 5 9.21 (brs, 1H), 8.01 Cd, J 7.9 Hz, 2H), 7.86 J 7.0 Hz, 11H), 7.55 (d, J 8.3 Hz, 2H), 7.20-7.34 (in, 3H), 6.89 (brs, 1H), 6.81 J 8.8 Hz, 1H), 6.37 J 2.2 Hz, 1H), 6.23 (dd, J 2.6, 8.3 Hz, 1H), 4.45 2H), 3.89 3H), 3.88 3H), 1.58 9H).
INDStep 3: N42-Aminoihenvl)-4-f1 -3 .4-dimethoxyohenyl)-3A4-methylsulfanvlnhenyl)-ureidomethllbenzamide 317 [0368] To a solution of anilide 316 (500 mg, 1.047 mmol) in chloroform/THF' 10 ml-) was added isocyanate (169 iL, 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. 'H NMR (CDC1 3 8 9.25 1H), 7.96 J 8.3 Hz, 2H), 7.85 J 7.0 Hz, 1H), 7.44 J 8.3 Hz, 2H), 7.20-7.36 Cm, 6H), 6.93 J 3.5 Hz, 1H), 6.90 1H), 6.75 (dd, J 2.2, 8.3 Hz, 1H), 6.68 Cdd, J 2.6 Hz, 1H), 6.33 Cs, 1H), 5.0 2H), 3.97 Cs, 3H), 3.85 3H), 2.51 3H), 1.57 Cs, 9H).
[03691 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-d 6 8 10.14 (brs, 1 7.99 J 7.9 Hz, 2H), 7.93 1 7.49 J 8.35 Hz, 4H), 7.39 J 7.5 Hz, 1H), 7.10-7.30 (2m, 5H), 6.97 Cdd, J 2.2, 8.35 Hz, 1H), 6.77 Cdd, J 2.2, 8.35 Hz, 1H), 5.02 2H), 3.80 Cs, 3H), 3.77 3H), 2.48 Cs, 3H).
231 U Scheme 58 0 O BOPIPh(NH2)2IEI3Ni:MF 0 OH
N--
In N SH
K
2 C0 3 /DMF/1 00 0
C
0
N-'N
S& H NH- 2 N SN 319 Example 179 Example 179 Step 1: N42-Amino-ohenvl)-6-chloro-nicotinamide (318) (0370] 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: N42-Amino-Dhenvl)-6Aauinolin-2-vlsulfanyl)-ricotinamide (319) [0371] Following the procedure described in Example 45, step 1 but substituting 318 for 3,4,5trimethoxybenzylamine, the tite compound 319 was obtained in 20% yield. 'H NMR: (CD 3 OD-d6) 8 (ppm): 9.08 J= 1.9 Hz, 1H), 8.35-8.25 (in, 2H), 7.99-7.56 (in, 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, 1 H).
232 Scheme 59 0 0
NH
2
H
0 PhSiH 3 KNI HO I COH
NN
C02HN H H 2 NH2 402 a Exampe 2610 SteD 4-(4-Mrohoin-4vl-Denvlmlno-rnehvllbenzic aid (02a) Step 2: N-AMor~in4-ynl)-[(-mrhoin-vDhlamino)-methylll-benzamacide((402) [0373] TA sutnion of ac402amlb i acidg 8.3gm; 1. eq), 1 pee -ndoiam i e 93g; 8.36 mmol; 1 eq) and Bu2SP (50mg; 68 mol; 0 1 eq) in dry MF (20 ml) was ddaed with.6m1 Ph33.3 1. mmol 1 eq). Afeatrigoent mstmofrte Dfor1.Teato was reovdndrteendher anld phromutograp hed wix:th MO. 1:2/ yEtdcof The rcrytlo40 was obtaine 70%S (235).cH c31 2.9; found: 03..
233 0 Scheme
NH
2 0 PhSiH3 H SfAH ~Bu2SnC12 MeO H OH THF DMA eO H _OH OMe MeO" O 0 MeO 424a OMe 3,4-diaminolhiophene.2HCI
BOP
BOP Et 3
N
Et 3 N o-Ph(NH 2 2 0 s 1/r H N H N H NH 2 MeO N H NH 2 MeO 424b MeO" 424c OMe Example 283a Example 283b Example 283a Step 1. 4-(3.4-DimethoxvDhenvlamino)-methvll-benzoic acid (424a) [0374] 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 The combined aqueous layers were acidified with 6% of NaHS0 4 to pH 4. The resulting white suspension was filtrated and then the filter cake was washed with water (5 ml x The cake was dried over freeze dryer to afford acid (1.92 g, 67 white solid product. LRMS 288 (MH).
Step 2. N-2-AminoDhenvl)-4-(3.4-dimethoxyphenvlamino)-methyll-benzamide (424b) [0375] In a 150 ml flask, a mixture of acid (1.92 g, 6.69 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 3.26 g, 7.37 mmol), triethylamine 1.87 ml, 13.4 mmol), ophenylenediamine (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 NaHCO 3 saturated solution and brine 50 ml. The combined organic layers were dried over Na 2 S0 4 and the filtrate was concentrated to dryness. The crude material was submitted to a chromatographic purification (column silica, 55%-70 EtOAc in 1% Et 3 N of hexanes) and then the all interested fractions were concentrated to dryness. The residue was suspended in minimum U quantities of ethyl acetate and then filtered to afford final product (1.49 g, 59 NMR (300 MHz, DMSO-d 6 5 (PPM): 9.65 1H), 7.98 J 7.9 Hz, 2H), 7.54 J 7.9 Hz, 2H), 7.22 J 7.9 Hz, 1H), 7.02 (dd, J 7.9, 7.9 Hz, 1H), 6.83 J 7.9 Hz, 1H), 6.72 J 8.79 Hz, IHN, 6.45 (dd, J 7.5, 7.5 Hz, 1H), 6.39 J 2.2 Hz, 1H), 6.01-6.08 (in, 2H), 4.94 2H, NH 2 4.36 J =6.16 Hz, 2H), 3.72 3H), 3.65 3H).
CI Example 283b NK Step 1: NA4-Aminothioohen-3-l-4( 3.4-dimethoxyohenvlamino)-rnethyll-benzamide: 0 [0376] 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 J=7.9 Hz, 2H), 7.43 J 3.5 Hz, 1H), 7.38 J 7.9 Hz, 2H), 6.73 J 8.8 Hz, 1H), 6.33 J 3.5 Hz, 1H), 6.58 J 2.6 Hz, 1H), 6.13 (dd, J 2.6, 8.3 Hz, 1H), 4.33 2H), 3.80 3H), 3.78 3H). LRMS: calc: 383.4642; found: 384.2 406.2 (M+Na) and 192.6 (M+2H)/2.
Scheme 61
H
2 N N2Im 2 CS /DME me N 0 SnC6 INHOAc /THF Me N- H
K
2 COIrT /6h HN H~I Ill F, then 40% MeNH 2 HS:C H 2 0 MeOH 75C 2h H in H2O (8.6 eq) 650C I 2hi 456a 456b 4.formyQbenzoic acid IPhSiH 3 Bu 2 SnCI/ DME /rT/18h NH H CO 2
H
Me I 2 1,2-phenylenediamine MeNH ~jJ OP/MF/EA sii~iI1II45N H ~~456 (r46 Example 315 SteiD 1: MethvN45-nitrobenzothiazol-2-vl)-amine (456a) [0377] A mixture of 2-fluoro-5-nitroaniline (861 mg; 5.52 mmol; 1.02 eq); Im7 2 CS (960.3 mg; 5.39 mmol) and dry K 2 C0 3 (1.45g) was suspended in dry DME (10 mL) and stirred under nitrogen for min at room temperature. The yellow suspension was made fluid by diluting with DME (10 mL) followed by addition of 40% MeNH 2 in water (4.0 mL; 46.5 mmol; 8.6 eq). The system was heated up 235
\O
0 0 to 65C and stirred at this temperature for 3.5 h, cooled down, diluted with ethyl acetate and washed with saturated NaCI 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: NMethvl-benzothiazole-2.5-diamine (456b) [0378] A mixture of nitro compound 456a (593 mg; 2.83 mmol); SnCI 2 4.02 g; 20.8 mmol; n 7.35 eq) and NH 4 0Ac (4.5g) was suspended in THF:MeOH:H 2 0 1:1:1 (60 mL) and stirred at 0 for 2 h, cooled down, diluted with ethyl acetate and successively washed with saturated NaHC03 and brine; dried (MgS0 4 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-Methvlaminobenzothiazol-5-Ylamino)-Methy-Benzoic Acid (456c) [0379] A solution of aniline 456b (509 mg; 2.8 mmol); 4-formylbenzoic acid (426 mg; 2.8 mmol) and Bu 2 SnCl2 (198 mg; 0.65 mmol; 23% mol) in DME (14 mL) was stirred at room temperature for 3 min and treated with neat PhSiH 3 (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.
Step 4: N2-Aminophenyl)4-4(2-methylaminobenzothiazol-5-vlamino-nethyll-benzamide (456) [0380] 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. 'H-NMR (300 MHz; DMSO-d6) 8 (ppm): 9.57 1H), 7.92 J 7.9 Hz, 2H), 7.66 J 4.8 Hz, 1H), 7.48 J 8.3 Hz, 2H), 7.26 J 8.3 Hz, 1H), 7.15 J 7.9 Hz, 1H), 6.95 J Hz, 1H), 6.76 4.87 (bs, 2H), 6.58 J 7.5 Hz, 1H), 6.54 J 1.8 Hz, 1H), 6.13 (dd, J 1.8, 8.3 Hz, 1H), 6.27 J 5.7 Hz, 1H), 4.87 (bs, 2H), 4.36 J 5.7 Hz, 2H), 2.85 J 4.8 Hz, 3H). LRMS: calc: 403.5008, found: 404.2 (M+NH) and 202.6 (M+2H)/2.
236 o Scheme 62 MeD Br DF MeO <~N H-S OMe H H 376a
LIOH
THF /H 2 0 CI MeO N>N MeO -N H> NH BOP NEt 3 N, DMF K&~N H H H O 376 0 ,N2376b 0 Example 235 U NH 2 Example 235 Step 1: Methvl-4A5-methoxv-1 H-benzimidazol*2-vl-sulfanvlmethyl)-benzoate (376a) [0381] To a solution 5-rnethoxy-2-thiobenzimidazole (2.00 g, 11. 1 mmol of in anhydrous DMF ml) was added methy-4-{brornomethyl)-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 1H NMR: (DMSO) 8 (ppm): 7.90 J 8.8 Hz, 2H), 7.56-7.52 Cm, 3H), 7.09 J 2.2 Hz, 11H), 7.01 (dd, J 8.8, 2.2 Hz, 1H), 4.73 2H), 3.82 6H). MS: (calc.) 328.1, 329.2 Step 2: 4-5Methoxy- 1H-benzimidazo 2-vl-sulfanvlmethyl)-benzoic acid (376b) [0382] 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 HCI 1 M to pH 4. The desired product was triturated 20 min. at 0 0 C and then filtered and dried. Compound 376b was obtained as a white powder (100% yield, 3.05 11H NMR: (DMSO) 8 (ppm): 12.85 Cbs, 1H), 7.86 J 8.1 Hz, 2H), 7.53 J 8.1 Hz, 2H), 7.35 J 8.1 Hz, 1H), 6.97 Cd, J 2.2 Hz, 1H), 6.76 Cdd, J 8.8, 2.2 Hz, 1 4.60 Cs, 2H), 3.82 Cs, 3 MS: (calc. 314. 1, 315.1 USteiD 3: Ni2-Amino-phenyl)445-methoxy-1 H-benzimidazol-2-v~sulfanylmethyl)-benzamide (376) [0383] Following the procedure described in Example 1 step 5 but substituting 4A5-methoxy-1benzimidazol-2-yI-sulfanylmethyl)-benzoic acid 2 for 7 the title compound 376 was obtained as a white powder.: 36% yield (933 mg). 'H NMR: (DMSO) 8 (ppm): 12.42 (bs, 1H), 9.57 (bs, 1H), 7.89 (d, J 8.1 Hz, 2H), 7.55 J 8.1 Hz, 2H), 7.34 J 8.8 Hz, 7.14 J 7.3 Hz, 1H), 6.98- 6.93 (in, 2H), 6.77-6.55 (in, 2H), 6.58 (dd, J 7.3, 7.3 Hz, 1H), 4.87 2H), 4.59 2H), 3.77 (s, 3 MS: (calc.) 404. 1, 405.4
IND
Examples 180-328 Ni [0384] 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 [0385] 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 NH 2 1) OLi MeO~q O!Ve OMe Br ~THF/hexane *78*C, 30 min Br (Ac)-BNA H 2) OeOMe C2O N 'kN 486 0 toluene MeO CI01
THF
-78'C to rt, ON H
H
MeC 1) LiOH.H,0 MeOq N M H NH MeC OMe 2) 1,2-phenylene- MeO OMe 48 0 diamine, BOP OMe 0 488 Example 345
IND
0 0 0 Example 345 S Step 1; Methyl 344-bromo-phenvl)-acrvlic ester (486) [0386] To a solution of anhydrous iPr 2 NH (758 pl, 5.40 mmol) in anhydrous THF (25 ml) stirred at 0 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 l1, 5.40 mmol) was 0 added dropewise. After 30 min, a solution of 4-bromobenzaldehyde (500 mg, 2.70 mmol) in V anhydrous THF (10 ml) was slowly added. After 30 min, a solution of 2-chloro-4,6-dimethoxy-1,3,5- I triazine (569 mg, 3.24 mmol) in anhydrous THF (15 ml) was added. Then, the temperature was 0 allowed to warm up to room temperature overnight. A suspension appeared. The reaction mixture was poured into a saturated aqueous solution of NH 4 CI, and diluted with AcOEt. After separation, the organic layer was successively washed with H 2 0 and brine, dried over MgS0 4 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.
'H NMR (300 MHz, CDC1) 8 (ppm): 7.63 J 16.2 Hz, 1H), AB system (6A 7.53, s5 7.39, J 8.4 Hz, 4H), 6.43 J 15.8 Hz, 1H), 3.82 3H).
Step 2: Methyl 3-[4-3,4.5-trimethoxv-phenvlamino)-phenvll-acrylic ester (487) [0387] A mixture of Cs 2
CO
3 (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), 3,4,5trimethoxyaniline (182 mg, 0.99 mmol), and anhydrous toluene (5 ml) were added, respectively. The reaction mixture was heated to 100 0 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, H 2 0, sat. NH 4 CI, H 2 0 and brine, dried over anhydrous MgS0 4 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. 'H NMR (300 MHz,
CDCI
3 8 (ppm): 7.64 J 16.2 Hz, 1H), 7.43 (bd, J 7.9 Hz, 2H), 7.12-6.86 2H), 6.60-6.20 3H, included at 6.29, d, J 15.8 Hz), 3.84 9H), 3.80 3H).
Step 3: N2-Amino-phenvl)-3-[4-(3.4.5-trimethoxv-phenvlamino)-phenvll-acrvlamide (488) [0388] The title compound 488 was obtained from 487 in 2 steps following the same procedure as Example 1, steps 4 and 5. 'H NMR (300 MHz, DMSO-d 6 8 (ppm): 9.29 1H), 8.48 1H), 7.60-7.42 3H), 7.38 J 7.5 Hz, 1H), 7.12 J 8.4 Hz, 2H), 6.94 J 7.5 Hz, 1H), 6.78 239
IND
J 7.9 Hz, 1H), 6.71 J =15.8 Hz, 1H), 6.61 Ct, J =7.1 Hz, 1H), 6.47 Cs, 2H), 4.97 2H), 3.79 Cs, 6H), 3.66 3H).
Scheme 64 MeO &OH 1. (TfO) 2 01/ DIPEA MeO,: 3,4,5-tnmethoxyaNtline MeH NCO DMAP/DCM W- bpu MeO -N OHC) r 2/ OHC PhSiH 3
BU
2 SnCI 2 '1 49 cOtU489 DME MeO 490, In Pd 2 (dbab3 POT (NiDIPEA/DMF 120 0 C 1. O E 3
NDM
HMeO N MO-.N H NH 2 Ome Example 346 Step 1: 3A4-Formy 3-methoxy-nhenl-acrlic acid tert-butvl ester 489 [0389] Following the procedure described in Example 53, step 1, but substituting 4-hydroxy-2methoxy-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 Step 2: 3-I 3-Methoxyv-4-r( 3.4. 5-trimethoxy-phenylamino~nethll-phenvl-acrvlic acid tert-butyl ester 490 [0390] Following the procedure described in Example 144, step 3, but substituting 489 for 4formylbenzaldehyde, the title compound 490 was obtained in 69% yield. LRMS calc: 429, found: 430.5 Step 3: N-2-Amino-ohenl)-3-I 3-methoxy4[C3.4. 5-trimethoxv-ohenylamino)-methvfl-ohenl )-acrvlamide 491 [0391] 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 NMVR CCDCI 3 8 (ppm): 8.08 1H), 7.74 J 15.4 Hz, 1H), 7.30 (in, 1H), 7.06 Cm, 3H); 6.80 Cm, 3H), 6.70 J 15.A Hz, 5.98 Cs, 2H), 4.40 Cs, 2H); 4.12 (bs, 3H), 3.94 Cs, 3H), 3.84 3H), 3.77 6H).
Scheme X CHO 581: BrCH(COOMe) 2
X
K
2 C0 3 Toluene, reflux 582: HSCH 2 COOMe, 581: X=CH 3 Y=OH K 2 C0 3 DMVF, RT 58 582: X=N0 2 Y=Ci 58 583: NBS, VAZO, CC1 4 reflux BI N~ COOMe "0 585 N COOMe 3: X=CH 3 Y=0 4: X=N0 2
Y=S
54Fepowder
HCMOH
H
2 N N COOMe 588 3,4-dimethoxyanilineI
K
2 C0 3 DMF
I
N
0 H COOMe
IN
MeO OMe 586 1. LIOH, THF/H 2 0 2. 1 ,2-phenylenediamine, BOP, Et 3
N
j 3 ri~methoxybenzaldehyde
NS
MeO q W~e 589 1. LiOH, THF/H 2 0 2. 1 .2-phenylenediamine, BOP, Et 3
N
NS 0 MeO N NC :14 HN I H MeO qrH 2
N
W~e 590 Example 437 587 Example 436 Example 436 Step 1: Methyl-5-rethyl-benzofuran-2-carboxvlate (583) [0392] A stirring suspension of 5-methylsalicylaldehyde 0mg, 7.5 mnmol), K 2 C0 3 (1.55 g, 11 .0 mnmol), and BU 4 NBr (322 mg, 1 mmol) in toluene (30m1) was treated with dimethyibromomalo-nate (1.06 ml, 8.0 mnmol). The suspension was heated to reflux with a Dean-Stark trap for 20 h. The brown
IO
0 o suspension was cooled to 25 0 C and concentrated in vacuo. The residue was taken in DCM and S filtered. The filtrate was washed with H 2 0, 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).
0 Step 2: Methvl-5-bromomethvybenzofuran-2-carboxvlate (585) Vn [0393] A mixture of 583 (500 mg, 2.63 mmol), N-bromosuccinimide (561 mg, 3.15 mmol) and I0 1,1'-azobis(cyclohexanecarbonitrile) (Vazo) (63 mg, 0.26 mmol) in 15 ml of CCI 4 was heated O 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 MgS0 4 filtered and concentrated. The crude residue was purified by column chromatography (30% ethyl acetate/hexane) to afford the title compound 585 (680mg, 96% yield). 'H NMR: (CDCI 3 8 (ppm): 7.79 1H), 7.70- 7.52 3H), 4.69 2H), 4.06 3H), 3.72 2H). LRMS 268.2 (Calc.); 269.1 (found).
Step 3: Methvl-5-[(3.4-dimethoxy-phenylamino)-ethyll-benzofuran-2-carboxylate (586) [0394] 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-Dimethoxv-ohenvlamino-methyll-benzofuran-2-carboxvlic acid (2-amino-ohenvl)-amide (587) [0395] Following the procedure described in Example 1, steps 4,5, but substituting 585 for 6, the title compound 587 was obtained in 29% yield. 'H NMR: (DMSO) 8 (ppm): 9.83 1H), 7.75 (s, 1H), 7.64 1H), 7.62 J 8.0 Hz, 1H), 7.47 J 9.0 Hz, 1H), 7.18 J 8.0 Hz, 1H), 6.97 J 7.5 Hz, 1H), 6.78 J 8.0 Hz, 1H), 6.65 J 8.5 Hz, 1H), 6.59 J 7.5 Hz, 1H), 6.33 1H), 6.04 J 8.0 Hz, 1H), 5.92 J 5.5 Hz, 1H), 4.93 2H), 4.31 J 5.5 Hz, 1H), 2.82 3H), 2.76 3H). LRMS 417.46 (Calc.); 418.4 (found).
Example 437 Step 1: Methvl-5-nitro-benzo[blthioDhene-2-carboxylate (584) [0396] A stirring suspension of 5-nitro-2-chloro-benzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5 0 C was treated with K 2 C0 3 (3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25 0 C and stirred for 20h. The solution was then poured into 250ml of ice H 2 0 and the white precipitate that formed was collected by filtration. Crystallization 242 U from EtOAc afforded fine pale orange needles of 584 (3.54 g, LRMS 237.0 (Calc.); 238.1 (found), 'H NMR: (DMSO) 5 (ppm): 9.00 J 2.2 Hz, 1H), 8.45 IH), 8.39-8.30 (in, 2H), 3.93 (s, Step 2: Methvl-5-amino-benzofblth iophene-2-c arboxvl ate (588) r- [0397] A suspension of 584 (3.52 g, 14.8 minol) in methanol (100 ml) was treated with Fe 0 powder (6.63 g, 118.7 inmol). The resulting suspension was heated to reflux, and 12M HCI (8.5 ml) V) was slowly added over 15 min. The resulting green dark suspension was ref luxed for an additional 3 ID h, then cooled and concentrated. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO 3 then brine, dried over MgSO 4 filtered and concentrated to afford (2.57 g, 84%).
'H NMR: (DM50S) 5 (ppm): 7.92 1H), 7.65 J 8.8 Hz, 1H), 7.05 Kd J 1.5 Hz, 1H), 6.88 (dd, J 1.8, 8.4 Hz, IHN, 5.27 2H), 3.85 3H). LRMS 207.0 (Calc.); 208.1 (found).
Step 3: Methvl-5-(3.4. 5-trimethoxy-benzvlamino)-benzolblthion~hene-2-carboxylate (589) [0398] Following the procedure described in Example 144, step 3,'but substituting 588 for 226, the title compound 589 was obtained in 68% yield. (DMVSO) 5 (ppm): 7.94 IH), 7.69 J 8.8 Hz, 1H), 7.02-6.99 (in, 2H), 6.73 2H), 6.41 J 5.7 Hz, 1H), 4.21 (d J 5.9 Hz, 2H), 3.84 3H), 3.75 6H), 3.62 3H). LRMS 387.1 (Calc.); 388.3 (found).
Steio 4: 5A3.4.5-Trimethoxv-benzylamino)-benzolthiophene-2-carboxvlic acid (2-amino..Dhenvl)-amide (590) [0399] Following the procedure described in Example 1, steps 4,5, but substituting 589 for 6, the title compound 590 was obtained in yield'H NMR: (DMVSO) 8 (ppm): 7.79 1H), 7.60 J 8.8 Hz, 1H) 7.00-6.95 (in, 2H), 6.74 2H), 4.32 2H), 3.80 6H), 3.73 3H).
243
ICD
O
Examples 347-425 [0393] 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).
Assay Example 1 Inhibition of Histone Deacetylase Enzymatic Activity 0 cN 1. Human HDAC-1 NI [0394] 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, C 20,000 cpm of the 3 H]-metabolically labeled acetylated histone substrate Yoshida et al., J. Biol.
Chem. 265(28): 17174-17179 (1990)) was incubated with 30 pg of the cloned recombinant hHDAC- 1 for 10 minutes at 37 The reaction was stopped by adding acetic acid (0.04 M, final concentration) and HCI (250 mM. final concentration). The mixture was extracted with ethyl acetate and the released 3 H]-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 2. MTT Assay [0395] 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-dimethylthiazo-2-yl]-2,5 diphenyl tetrazolium bromide, Sigma) was added at a final concentration of 0.5 mg/ml and incubated with the cells for 4 hours before one volume of solubilization buffer (50% N,N-dimethylformamide, 20% SDS, pH 4.7) was added onto the cultured cells. After overnight incubation, solubilized dye was quantified by colorimetric reading at 570 nM using a reference at 630 nM using an MR700 plate reader (Dynatech Laboratories Inc.). OD values were converted to cell numbers according to a standard growth curve of the relevant cell line. The concentration which reduces cell numbers to 50% of that of solvent treated cells is determined as MTT ICso. ICso values for representative compounds are presented in the fourth column of Table
(O
0 3. Histone H4 acetvlation in whole cells by immunoblots [0396] 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. 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 H4 (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 0 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 H4 signal by 50% (ECso).
Table 5a: Inhibition of Histone Deacetylase I HumanHDAC-1 I MTTI 245 HumanHDAC-1 M7T(HCT1 16) II4Ac(T24) Cpd Structure 1C 50 (pim) IC 5 0 gM) EC 5 o 0
M
14 N 4 N NH20.315 ~Zt NH 2 N N kn 15 N N NH 2 0.5 0.2 3 I H I~
H
2
N
16 aN N N H' O NH, 1 0.41
NH
2 b CH3
NH
17 HI2N 0.9 1 2 HN 2 18 N IIN .NH2 0.8 0.6 3 H HI N
NII
0 N N 18b N N HNH2N 0.6 5
HA
19 NI A1N olN' HNH 2 0.911 H H N
NH
2 NANN':tHN20.5 0.31 246
IN
HumanHDAC- 1 MTT(HCT116) H4Ac(T24) Cpd StructureIC 5
NH
2 N N 29 A N N NH 2 2 2 1
HN
N N N N )N N 1 3 1 H H IN
NH
2 83~Z35 83 N N IkN N 355 H HiN~ (na not available; 99 >25 1 iM) Table
Y
N iN Xil N N
H
It" z NH~
IN
OMe N -,llN MeO ilN N'
H
U
250
IN
Ex Cd SrucureHuman HDAC-1 MTT(HCT1I6) H4Ac(T24) ExCp SrutueICsdp1m) lC 5 o(pim) ECso(iM)
NH
2 343 484 N N H 2 0.3 n xN 0 344 45Q 9 0.4 3 na N JN N NH 2 H H I H 0N_6 (na=nonavailable) Table
IN
253 254 MeO N -O N H Me I
I
OMe 0 OMe 255
IN
Table 256 HDAC-1 M7T(HCT116) H4Ac(T24) Ex. Cpd Structure 1C50(gM) IC50(gNM) EC50(j9A) H HI 347 492 H 3
C'
0 NN N NH 2 49 0
CH
3
N
348 493 CI'l NN ll) N NH 2 00 HN, H' 34 49 HC' N NH 2 34- 0 l CH 3 0 N~ H IH 350 495 0 2 N NN NH2 4 7 351 496 O F 8 13 )LXF HN-Q/
H
2 H3H
NH
352 497 H3,O~fqoH 2 15 6-
H
3 C 0 353 498 0H NNHY >2 257
IN
258
U
259 260 0 N NH
NH
262
IN
263 O E. Cd SrucureHDAC-1 MTT(HCT1 16) H4Ac(T24) 1 AM) IC50(A.M) ECSO(pM) H N
N
408 553 24 12 CI___6_ 0 H
N
409 554 NH15 12
NH
H
410 555 NN H?14 7 0 H
NH
411 556 NH,~ I 1 0.4 0 412 557 N NH46 412557N N N NH 2 46 Br N N N H 413 558 11 HI N 7 0
NN
0 Me0 N H I )~NH216 415 560 MeoO.<N Nm NH221 Me0>)
O
H3C: 416 56 1 H 3N0 NN2 2 2 H IH NH>2>5 -7N 6 0.
264 265 Ex. pd trucureHDAC-1 M1-T(HCT1 16) H4Ac(T24) Ex.Cp Srutue C50(IAM) IC5O(pM)
H
2
N
OH
3 HN-- 42 50~ \0 6 0.6 2 0 O NH-O Table 266 267 O Human HDAC-1 MTT(HCT116) H4 Ac (T24) Cpd Structure IC50 IPM) IC 50 (PM) EC 5 o (pM) NH2 169 MeO N NH0.3 0.7 1 OMe ci 171 NH, 8 3 S 172 N SH. NH 2 0.4 1 3 174 F 4 0.4
NH
175 j NN N24 0.5 3 176 M N H H 2 5 1 3 M O e H_ 17NNr S H NH 2 1 0.4 1 0 268 U Table 269
IN
270 E Human HDAC-1 MT (HCT116) H4 Ac (T24) Ex Cpd Structure IC 50 ICSO (PM) E
CI
134 201 rN 11 bQy N 0 0 144 228 3 0.3
H,N
CH
3 ''N 145 231 H,C.
0 34
H
3
C
0 H 2
N
HC'O\) H N 0 146 233 0.9 0.3
H,N
H NH 2 147 236 5 6 148 2 I 3 6 H NH 2 149 240 N H 1.8 N N
SNH
148 238 H-P 3 150 243 NH 2 0 H A N
NH
O N ''N 151 247 3 0.6 2 271 272 273 o Human HDAC-1 MTT (HCT116) H4 Ac (T24) Exso Cpd Struct(re
EC
H3C-O 172 301 NCI r NH 2 3
H
3
C-ON
173 305 4 2 c14 NH2
H
3 C MeO z~NH 174 311 C N N 1 6 0.9 0.7 1 H SMe
NH
2 178 317 HN 0 NIi 2 0.3 1 y K-r H MeOq OMe 0 179 319 nii,. NH 4 8 H ~0 N-P 180 320 N 2 1 or -11N' 181 321 0.5 0.3 \s 0 H H0.0.2 182 322 N "P 0.7 0.4 2 M OMe -9 183 323 H NH, 1 0.6 1
N
274 Ex Cp StrutureHuman HDAC-1 MiT (HCT1 16) H4 Ac (T24) Ex CdSrcue~ ~IC 50 IP) cs (PiM) EC 5 o p 0 N N 184 325 NyS N"2 0.3 1 2
NN
0H-9 N H 185 326 NNS N211 3 0 186 327 NHY 2 5 3 s"-N NH 2 187 328 17 N
NH
o N N 18 30 NH H2N N N 3 2
UNH
2 190 331 NH A HCIl 4 N
N
H
2 N H N H 2 H_ N NH 192 333 3NH CA', 2 0.11
NH
2 E pSrtrHuman HDAC-1 MiT IHCT116) H4 Ac (T24) Ex ICpd Structure M) IC0 (pM)
H
2
N
193 334 H 8 0.2 1 0 195 336 INH 2 1 0.4 <1 H NH2 196 33 I)I 2 N3C 3 0.6 1 00 MeN 197 338 I H 2 2 0.5 3 H_6 00 F NN 198 339 NI H 4 3 0 -W NI H 2 1 1 199 340 01-2 HCC N, CH 0 I H2 200 341 NIO 0 N 4 1 3 Br N N Hy NH230.
201 342 N 3 0 276
IN
IN
278
IN
U
280 E Human HDAC-1 MTT (HCT116) H4 Ac (T24) ICE Cpd SPrucreM)
IC
5 0 IPM) E j 240381NH 2 1 2 240 381 NH2
NH
241 382 HC N r NH, 3 1 3 r~l -N
CH,
H
3
C
H 0 242 383 H 3 0 2 0.5 2 O
NH
2 l13C N-It 3 2 243 384 NH 3 2 HN
N
244 385 HC, HN 3 1 2 H2N 245 386 0 .9ro 3 1 1 0 H N H
HN
\-N
247 388 N t- HN o 3 0.4
H
2 C HN 281 Human HDAC-1 MTT (HCT116) H14 Ac (T24) Ex Cpd Structure(M IC (M) 248 389 C CN 3 0.2 1 HC,. H,,0 N N"(:y 249 390 0 2 0.8 NM2 0 250 391 NH 1 0.9 3
O~NH,
0 H NH NH2 251 392 H 3 C r~ 4 1 1
H
3 C 0 252 393 N N H 0.6 1 H,C' 0 253 394 MC-o P 4 2
H
3 C-0 254 395 H C \0 N P2 1
H
H NH 2 07 255 396 NN6 2 o Human HDAC-1 MIT (HCT116) H4 Ac (T24) Ex Cpd Structure IC EC 5 0 (iJM) ,)CH3 0 256 397 NH 0 1 0.6 4
CH
3
NH
258 399 N 14 9 H 0 c-IN 0H 259 400 H2 NN H 0.3 2
H,C-
260 401 0 HNHQ 6 0.3 2 261 402 NH2 14 0.4 1 CH 0 262 403 NH HN\/ 1 0.2 1
HCH
H2N
N
H
3 C 263 440- ~NH 03 0.6
'CH
3
N
H
2 0 K H
N
264 405 I) r HP 515 283 284 285
IN
286
IN
IN
288 E pSrtrHuman HDAC-1 MTT (HCT116) H4 Ac (T24) Ex Cpd StructurePM) IC (PM) EC 5
(PM)
N N 304 445 Meo NM, 16 6 MeO
NH
H NH~ ~dj 3 0.2 2
I
H,C S4 (Ni H NH 308 449 N N NH 1 6 309 450 2 3 2
F+F
0 H
NH
H
311 452 9N NH 3 0.3 2 0 312 450 C N 3 2
F-I-F
0
-~NH
310 454 0 NH 4 2 3 S0F1NH 311 52 s.~~rN N~ 32.39 290 Human HDAC-1 MTT (HCT116) H4 Ac (T24) 0 Ex Cpd Structure s P I p 323 464 H 3 C 4 11
H
324 465 H NH, 2 9999 9999 N P 325 466 4 HNH, 3 2 1
H
326 467 N NJ H NH 2 4 0.4 2 H -NN 327 468 N H NH, 2 8 <1
N-N
H
H HP 426 571 Meo N OH 411 OMe 427 572 1.5 5 MeO 0 1,N 428 573 N Q Y 7 0.4 1 S 1H H 0 Nj-9 429 574 N1 13 0.7 3 Moo, 291
ID
Human HDAC-1 PATT (HCT116) H4 Ac (T24) Cu
IC
5 0 (pM IC 5 0 (pM) Eso PM) 4>HNC) 2 0.2 1 430 575 HC'0,, 00 0 0
NH
431 576 HC. IN~ No iiNH2 6
NH
432 577 NH 0.5 2 N
N
433 578 I HI I 0.6 0.1 1 Me NN 435~~~ K8 03< 432 7 H 3 CN 0.5 2 00
NH
435 578 H 4i 0.3 <1
NN
436 587 5e 0.8 MeN 437 590 HN 6N 2 2 3 H2NO
CON
OMe___ :a NH 0.3 <1 438 591 N e&NH 439 592 MeO 1N N -54 <1 MeO H 2
N
292
(O
0 Assay Example 2 Antineoplastic Effects of Histone Deacetylase Inhibitor son Human Tumor Xenografts In Vivo [0397] 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 C transplantations in the same strain of nude mice. Subsequently, tumor fragments of approximately 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 mm 3 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 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 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 106 126 62 b 9 5 1 b 87 30 b 157 66a 167 58" 26 b 168 26b 16 154 23" 98 52'
IO
0 a: 20 mg/kg i.p.
b: Table 7 Antineoplastic Effects Of Histone Deacetylase Inhibitors On Nude Mice Xenograft Models Inhibition Of Tumor Growth Scpd A 549 SW48 A 549 HCT 116 SW48 I, 106 40%(70 mg/kg) 16%(60mg/kg) S164 42% (70 mg/kg) 62% (60 mg/kg) 37% (20 m kg) 99% (25 mgg) \0 228 45% (70 mg/kg) 25% (60 mg/kg) 64% (20 mg/kg) 45% (20 mg/kg) 68% (20 mg/kg) O 424b 67%(50 mg/kg) 78%(30mg/kg) 60%(50mg/kg) 77%(75mg/kg) 68%(25mg/kg) (N Assay Example 3 Combined Antineoplastic Effect of Histone Deacetylase Inhibitors and Histone Deacetylase Antisense Oligonucleotides on Tumor Cells In Vivo [0398] 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.
[0399] As described in Example 126, mice bearing implanted HCT116 tumors (mean volume 100 mm 3 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 mg per kg body weight of HDAC inhibitor.
[0400] 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 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.
[0401] Tumor volume is measured with calipers. Treatment with the antisense oligonucleotide plus the histone deacetylase protein inhibitor according to the invention causes a significant reduction in tumor weight and volume relative to controls.

Claims (39)

1. A histone deacetylase inhibitor of formula R 3 R 4 N N N Y N Y 2 -Ak'-Ar 1 -Z 1 (1) or a pharmaceutically acceptable salt thereof, wherein NR 3 and R 4 are independently selected from the group consisting of hydrogen, Cy', 0 and wherein L' is Ci-C 6 alkyl, C 2 -C 6 heteroalkyl, or C 3 -C alkenyl; and Cy' is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted, and each of which is optionally fused to one or two aryl or heteroaryl rings, or to one or two saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings is optionally substituted; or R 3 and R 4 are taken together with the adjacent nitrogen atom to form a or 7- membered ring, wherein the ring atoms are independently selected from the group consisting of C, 0, S, and N, and wherein the ring is optionally substituted, and optionally forms part of a bicyclic ring system, or is optionally fused to one or two aryl or heteroaryl rings, or to one or two saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings and ring systems is optionally substituted; Y' is selected from the group consisting of 2 -CH 2 2 halogen, and hydrogen, wherein R' and R 2 are independently selected from the group consisting of hydrogen, Cy', and wherein L' is Ci-C 6 alkyl, C 2 -C 6 heteroalkyl, or C 3 -C alkenyl; and Cy 1 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted, and each of which is optionally fused to one or two aryl or heteroaryl rings, or to one or two saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings is optionally substituted; or R' and R 2 are taken together with the adjacent nitrogen atom to form a 6-, or 7-membered ring, wherein the ring atoms are independently selected from the 295 U group consisting of C, 0, S, and N, and wherein the ring is optionally substituted, and optionally forms part of a bicyclic ring system, or is optionally fused to one or two aryl or heteroaryl rings, or to one or two saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings and ring systems is optionally substituted; Y 2 is a chemical bond or N(RO), where RO is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, and acyl; Ak' is C 1 -C 6 alkylene, Cl-C 6 -heteroalkylene (preferably, in which one -CH 2 is replaced with and more preferably -NH-CH 2 C 2 -C 6 alkenylene or C 2 -C 6 alkynylene; Ar' is arylene or heteroarylene, either of which is optionally substituted; and Z' is selected from the group consisting of H O and H NAy i O wherein Ay' is aryl or heteroaryl, each of which is optionally substituted.
2. The compound according to claim OH or -NH 2
3. The compound according to claim nitrogen to which Ay 2 is attached.
4. The compound according to claim thienyl, or 3-hydroxy-2-thienyl. The compound according to claim 1 wherein Ay' is phenyl or thienyl, each substituted with 2 wherein the amino or hydroxy substituent is ortho to the 1 wherein Ay' is ortho aniline, ortho phenol, 3-amino-2- 1 wherein Z' is H NH 2 /yN 0
6. The compound according to claim 1 wherein Ar' is phenylene.
7. The compound according to claim 1 wherein Ak' is alkylene.
8. The compound according to claim 1 wherein Ak' is methylene. 296 IND 0 0 (N 0 9. The compound according to claim 1 wherein Y 2 is -NH-. The compound according to claim 1 wherein Y' is 2 or -CH 2 2
11. The compound according to claim 10 wherein R' and/or R 2 are hydrogen.
12. The compound according to claim 10 wherein R' and/or R 2 are C-C 6 alkyl or C 2 C 6 alkenyl.
13. The compound according to claim 10 wherein R' and/or R 2 are allyl. (N
14. The compound according to claim 10 wherein R 1 and/or R 2 are aryl, heteroaryl, aralkyl, or heteroaralkyl, the rings of each of which optionally are substituted and optionally fused to one or two aryl rings. The compound according to claim 14 wherein R' and/or R 2 are independently are phenyl, pyridyl, or pyrrolyl.
16. The compound according to claim 10 wherein R' and/or R 2 are independently cycloalkyl which is optionally substituted and optionally fused to one or two aryl rings
17. The compound according to claim 16 wherein R' and/or R 2 are independently cyclopropyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted and optionally fused to one or two aryl rings.
18. The compound according to claim 16 wherein R' and/or R 2 are independently cyclopropyl, cyclopentyl, or cyclohexyl.
19. The compound according to claim 1 wherein R 3 and/or R 4 are hydrogen. The compound according to claim 1 wherein R 3 and/or R 4 are independently Ci-C 6 alkyl or C 2 -C 6 alkenyl.
21. The compound according to claim 20 wherein R 3 and/or R 4 are allyl. 297 IND 0 0 o 22. The compound according to claim 1 wherein R 3 and/or R 4 are independently aryl, heteroaryl, Saralkyl, or heteroaralkyl, the rings of each of which is optionally substituted and optionally fused to one or two aryl rings.
23. The compound according to claim 22 wherein R 3 and/or R 4 are independently phenyl, pyridyl, -or pyrrolyl. S 24. The compound according to claim 1 wherein R 3 and/or R 4 are independently cycloalkyl. \CO The compound according to claim 24 wherein R 3 and/or R 4 are independently cyclopropyl, cyclopentyl, or cyclohexyl, which is optionally substituted and optionally fused to one or two aryl rings.
26. The compound according to claim 24 wherein R 3 and/or R 4 are independently cyclopropyl, cyclopentyl, or cyclohexyl.
27. The compound according to claim 1 wherein L' is Ci-C 6 alkyl, C 2 -C 6 heteroalkyl, or C 3 -C 6 alkenyl.
28. The compound according to claim 27 wherein L' is CI-C 6 alkylene
29. The compound according to claim 27 wherein L' is methylene or ethylene. The compound according to claim 27 wherein L' is allyl.
31. The compound according to claim 1 wherein Cy' is heterocyclyl that is optionally substituted and optionally fused to one or two aryl rings
32. The compound according to claim 31 wherein Cy' is piperidine, pyrrolidine, piperazine, or morpholine, each of which is optionally substituted and optionally fused to one or two aryl rings.
33. The compound according to claim 31 wherein Cy 1 is piperidine, pyrrolic;i.e, piperazine, or morpholine
34. The compound according to claim 1 wherein Cy' is cycloalkyl. 298 IO 0 (N 0 35. The compound according to claim 34 wherein Cy' is cyclopropyl, cyclopentyl, or cyclohexyl. a)
36. The compound according to claim 1 wherein Cy' is aryl or heteroaryl each of which is optionally substituted and is optionally fused to one or two aryl rings.
37. The compound according to claim 36 wherein Cy' is phenyl, pyridyl, or pyrrolyl, each of o which is optionally substituted and is optionally fused to one or two aryl rings. S 38. The compound according to claim 36 wherein Cy' is phenyl, pyridyl, or pyrrolyl. N 39. The compound according to claim 36 wherein Cy' is fused to one or two benzene rings. The compound according to claim 1 wherein Cy' has between one and about five substituents independently selected from the group consisting of Cl-C 4 alkyl, C 1 -C 4 alkoxy, and halo.
41. The compound according to claim 40 wherein the substituents independently selected from are methyl, methoxy, and fluoro.
42. The compound according to claim 1 wherein R' and R 2 together and/or R 3 and R 4 together, each with the adjacent nitrogen atom, form a 5- or 6-membered ring, wherein the ring atoms are independently selected from the group consisting of C, 0, and N, and wherein the ring is optionally substituted and is optionally fused to one or two aryl rings.
43. The compound according to claim 42 wherein the 5- or 6-membered ring is pyrrolidine, piperidine, piperazine, or morpholine, and wherein each ring is optionally substituted and optionally fused to an aryl ring.
44. The compound according to claim 43 wherein the aryl ring is benzene. The compound according to claim 43 wherein the substituent comprises an aryl or C3-C12 cycloalkyl ring, either of which is optionally substituted and optionally fused to a C 3 -C12 cycloalkyl, aryl, heteroaryl, or heterocyclic ring. 299 IO 0 0 46. The compound according to claim 44, wherein the substituent is phenyl, phenylmethyl, or Sphenylethyl, the phenyl ring of each of which is optionally fused to a Ci-C 12 cycloalkyl, aryl, or heterocyclic ring.
47. A histone deacetylase inhibitor of formula 1(a): Y SNNN X N J H NH 2 S(la) or a pharmaceutically acceptable salt thereof, wherein J is C-C 3 -hydrocarbyl, -N(R 20 -N(R 0 )-CH 2 or CH 2 R 20 is or -Me; X and Y are independently selected from -NH 2 cycloalkyl, heterocyclyl, aryl, heteroaryl, and A-(C-C 6 -alkyl),-B-; A is H, Ci-C 6 -alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is or a direct bond; and n is 0 (in which case A is directly bonded to B) or 1.
48. The compound according to claim 47 wherein A is phenyl optionally substituted with one or more moieties selected from halo and methoxy, and B is -NH-.
49. The compound according to claim 47 wherein A is selected from cyclopropyl, pyridinyl, and indanyl. The compound according to claim 47 wherein J is -NH-CH 2 -O-CH 2 -N(CH 3 )-CH 2 CH=CH-, or -CH 2 -CH 2
51. The compound according to claim 47 wherein R 20 is -H.
52. The compound according to claim 47 wherein X is selected from H N- o H -NH H and Y is selected from N N OMe CA MeOCH 2 CH 2 NH, NHF OMe OA OMe f 6'N- HHN HN M Me -OMe CH 3 (CH 2 3 NH- and CH 3 O(CH 2 2 -NH-.
53. The compound according to claim 47 wherein J, X, and Y are combinations: selected from the following Jp x V 220 -CH=CH- -NH 2 -NH 2 223 -CH=CH- ti)-NH 2 224 1-CH 2 CH 2 -NH 2 -NH 2 470 -NHCH 2 H NH- 2 471 -NHCH 2 [N-N HH 472 -NHCH 2 0:jX-NH 473 -NHCH 2 n-BuNH N Cpd J x Y 474 *NHCH 2 0 MeO(CH2) 2 NH HN W Oe 476 -NHCH 2 H H ci 477 -NHCH 2 7N OMe 478 -N'HCH 2 H H Jp x V W~e 479 -NHCH 2 7Nfl 480 -HCH2 >-NHf-"N NN N- 480 -NHCH 2 >-NH NN 481 -NHCH 2 [>-NH HN 482 -NHCH 2 II1 485 -NHCH 2 NHH
485-NHCH- 9 54. A histone deacetylase inhibitor of formula 0y 2 _X 1 N' Ay H or a pharmaceutically acceptable salt thereof, wherein Cy 2 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted and each of which is optionally fused to one or two aryl or heteroaryl rings, or to one or two saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings is optionally substituted; X1 is selected from the group consisting of a covalent bond, M'-L 2 _MI, and L 2 _M 2 4_ 2 wherein IO 0 L 2 at each occurrence, is independently selected from the group consisting of a chemical bond, C-C4 alkylene, C 2 -C 4 alkenylene, and C 2 -C 4 alkynylene, provided that L 2 is not a chemical bond when X' is M'-L 2 M'; at each occurrence, is independently selected from the group consisting of -N(R 7 S(O) 2 -S(O) 2 N(R 7 -N(R 7 S(0) 2 -NH-C(0)-0-and wherein R 7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl; and SM 2 is selected from the group consisting of heteroarylene, and 0heterocyclylene, either of which rings is optionally substituted; Ar 2 is arylene or heteroarylene, each of which is optionally substituted; R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl; q is 0 or 1; and Ay 2 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 Ay 2 is attached) and further optionally substituted; provided that when Cy 2 is naphthyl, X' is -CH 2 Ar 2 is phenyl, R 5 and R 6 are H, and q is 0 or 1, Ay 2 is not phenyl or o-hydroxyphenyl. The compound according to claim 54 wherein when Ay 2 is ophenol optio:.ally substituted by halo, nitro, or methyl, Ar 2 is optionally substituted phenyl, X' is -CH 2 -S-CH 2 S(0) 2 or -OCH 2 then Cy 2 is not optionally substituted phenyl or naphthyl. 56. The compound according to claim 54 wherein when Ay 2 is o-anilinyl optionally substituted by halo, Ci-C 6 -alkyl, Ci-C 6 -alkoxy or -NO 2 q is 0, Ar 2 is phenyl, and X' is -CH 2 then Cy 2 is not substituted pyridone (which substituents of the pyridone are not limited to substituents described herein). 57. The compound according to claim 54 wherein when X' is -CH 2 Ar 2 is optionally substituted phenyl, q is 1, and R 6 is H, then Cy 2 is not optionally substituted imidazole. IO 0 0 58. The compound according to claim 54 wherein when Ar 2 is amino or hydroxy substituted Sphenyl, X' is Co-Cs-alkyl-X L Co-Cs-alkyl, wherein XIa is -CH 2 then Cy 2 is not optionally substituted naphthyl or di- or -tetrahydronaphthalene. 59. The compound according to claim 54 wherein when Ay 2 is ophenol, Ar 2 is substituted phenyl, X' is -CH 2 -O-CH2-, -S-CH 2 or and R' and R 6 are H, then Cv 2 is not optionally C1 substituted naphthyl. 0 60. The compound according to claim 54 wherein when Ay 2 is o-anilinyl, q is 0, Ar 2 is 0 unsubstituted phenyl, X 1 is -CH 2 then Cy 2 is not substituted 6-hydroimidazolo[5,4-d]pyridazin- 7-one-l-yl or substituted 6-hydroimidazolo[5,4-d]pyridazine-7-thione-1-yl. 61. The compound according to claim 54 wherein Ay 2 is phenyl or thienyl, each substituted with -OH or -NH 2 62. The compound according to claim 54 wherein the amino or hydroxy substituent is ortho to the nitrogen to which Ay 2 is attached. 63. The compound according to claim 54 wherein Ay 2 is ortho aniline, ortho phenol, 3-amino-2- thienyl, or 3-hydroxy-2-thienyl. 64. The compound according to claim 54 wherein q is 1; M at each occurrence, is selected from the group consisting of -N(R 7 and where R 7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, and acyl; and Ay 2 is anilinyl, which is optionally substituted. The compound according to claim 64 wherein the -NH 2 group of Ay 2 is in an ortho position with respect to the nitrogen atom to which Ay 2 is attached. 66. The compound according to claim 65 wherein R 5 and R 6 are independently selected from the group consisting of hydrogen and Ci-C 4 alkyl. 67. The compound according to claim 65 wherein R 5 and R 6 are hydrogen. 304 IO (N 0 68. The compound according to claim 54 wherein Ar 2 has the formula GG ,G G G ,or G G and wherein G, at each occurrence, is independently N or C, and C is optionally substituted. 69. The compound according to claim 68 wherein Ar 2 has the formula L G-G G G G- -G*CG 0 Jr G GJ-,G S or G G The compound according to claim 54 wherein Ar 2 is selected from the group consisting of phenylene, pyridylene, pyrimidylene, and quinolylene. 71. The compound according to claim 54 wherein X' is a chemical bond. 72. The compound according to claim 54 wherein X' is L 2 -M 2 -L 2 and M 2 is selected from the group consisting of -N(CH 3 and 73. The compound according to claim 54 wherein X' is L 2 -M 2 -L 2 where at least one occurrence of L 2 is a chemical bond. 74. The compound according to claim 54 wherein X' is L 2 -M 2 -L 2 where at least one occurrence of L 2 is alkylene, preferably methylene. The compound according to claim 54 wherein X' is L 2 -M 2 -L 2 where at least one occurrence of L 2 is alkenylene. 76. The compound according to claim 54 wherein X' is M'-L 2 and M' is selected from the group consisting of -N(CH 3 and 77. The compound according to claim 54 wherein Cy 2 is aryl or heteroaryl, each optionally substituted. 78. The compound according to claim 54 wherein Cy 2 is phenyl, pyridyl, imidazolyl, or quinolyl, each of which is optionally substituted. IND 0 79. The compound according to claim 54 wherein Cy 2 is heterocyclyl. The compound according to claim 54 wherein Cy' is 0, 0,H N N ,or 0 0, (Ni each of which is optionally substituted and is optionally fused to one or two aryl rings. ID 81. The compound according to claim 54 wherein Cy 2 has from one and three substituents independently selected from the group consisting of alkyl, alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy. 82. The compound according to claim 54 wherein the substituents are seleuted from methyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, nitro, amino, aminomethyl, and hydroxymethyl 83. The compound of claim 54 of structural formula (2a): 0 Y NH W Z NH 2 (2a) wherein ~Ar is phenyl or thienyl; R 6 is H, or CI-C 6 -alkyl (preferably -OH 3 Y and Z are independently -CH= or W is halo, (V-L 4 3 L 3 is a direct bond, -C 1 -C 6 -hydrocarbyl, 4CI-C 3 -hydrocarbyl)mj.X'4Cr'C3 hydrocarbyl)m2, -N4H-C 3 -hydrocarbyl), (CI-C 3 hydrocarbyl)-NH-, or -NH4C,-Cr- hydrocarbyl)-NH-; ml and m2 are independently 0 or 1; X' is -N(R 21 -C(O)N(R 21 N(R 2 1 or R 2 1 is V"4C 1 -C 6 -hydrocarbyl)c; L" is (C 1 -C 6 -hydrocarbyl),-M-(C -C 6 -hydrocarbyl)b; 306 IO 0 0 a and b are independently 0 or 1; M is -S0 2 -NHSO 2 or -S0 2 NH- V, and V" are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; t is 0 or 1; Sor W, the annular C to which it is bound, and Y together form a monocyclic cycloalkyl, (N r) heterocyclyl, aryl, or heteroaryl; and Swherein the 4 and Ar" rings are optionally further substituted with from 1 to 3 Ssubstituents independently selected from methyl, hydroxy, methoxy, halo, and amino. 84. The compound according to claim 83 wherein: Y and Z are -CH= and R 6 is H; W is V-L 3 L 3 is -NH-CH- or -CH-NH-; V is phenyl optionally substituted with from 1 to 3 moieties independently selected from halo, hydroxy, C-C 6 -hydrocarbyl, C-C 6 -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 Ar" is phenyl and the amino moieties to which it is bound are ortho to each other. The compound according to claim 83 wherein V is an optionally substituted ring moiety selected from: N and 86. The compound according to claim 83 wherein W is selected from:, 307 H H 3 C' 0 O N, H 0 2 N 1q N0 2 F 9H 3 H 3 C 0 CH3 0 H N \~C 'H3 03C 0-M H 3 c 0 H C, 0- 0 H H 3 C S Nl N H 0\-N NH H F 3 CO H N 0 MO OMe N\ K-H OH 0O--CF 3 H N N N CF 3 H H F 3 ~)I1~f N and H3 40 H The compound according to claim 83 wherein the 4A and Ara rings are not further substituted. The compound according to claim 83 selected from the following, in which, unless expressly displayed otherwise, Are is phenyl: W Y Z R6 Cpd W Y Z R 6 H H H 3 C ~q ~N H 3 C' O'q H 3 0 OH CH H 494 OH CH H H 3 C 0 0 0 2 N N H NH 495 ICH CH H H 3 cc H* 496 FCH CH H HOC 01Y N YN 0 O~F k-N CH CH H Y3F ci'Y N H 497 H 3 C CH CH H O H CH H CdW Y ZR 6 H N, 511 a CH CH H H MeO N2~- fIk 512 CHO Njl H Oe)e 5161 Br- CHICH OH 3 OMe MeO 517 K H CH CH CH 3 N/ OMe 518 Me CH 3 CH CH CH 3 519 O H CH H NH 2 H 521 NNC CH H H N 522 N 'S N CH H N 522 CH NCH H MoO 524 H CHCH H 525 H N CH H 0O-1CF 3 H 526 (N CH CH H CF 3 310 IN Cpd W Y Z R 6 H 550 gfr N I CH CH H H 551 CH CH H NO 2 H 552 r CH CH H 553 CH CH H H 554 jhI CH CH H 555 CH CH H SMe H 556 CH CH H MeS H N N 557 iU CH CH H H 558 CH CH H H 559 CH CH H 0 MeOM NH 560 eo r, OMeo_ 0 H f^ "NH 561 OMe 89. The compound according to claim 88 wherein the amide nitrogen and the amino nitrogen bound to Ar 8 are ortho to each other) IO 0 The compound according to claim 54, the invention comprises compounds of the formula Q(2b): N Ay 2 Cy2" X I (2b) or a pharmaceutically acceptable salt thereof, wherein n Ay 2 is phenyl or thienyl, each substituted at the ortho position with -NH 2 or -OH and each I further optionally substituted with one to three substituents independently selected from -NH 2 -OH, and halo; q is 0 or 1; X' is selected from -CH 2 -NH-CH 2 and -S-CH 2 Cy 2 is monocyclic or fused bicyclic aryl or heteroaryl optionally substituted with one to three substituents selected from CH 3 CH30-, phenyl optionally substituted with one to three morphylinyl, morphylinyl-Cl-C 3 -alkoxy, cyano, and CH 3 C(O)NH-; provided that when Cy 2 is naphthyl, X' is -CH 2 and q is 0 or 1, Ay 2 is not o-hydroxyphenyl. 91. The compound according to claim 90 wherein Ay 2 is selected from: NH 2 NH 2 NH 2 and and F 92. The compound according to claim 90 wherein Cy 2 is phenyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, thienyl, tetrahydroquinozolinyl, or 1,3-dihydroquinazoline-2,4- dione, each optionally substituted with one to three 93. The compound according to claim 90 wherein Cy 2 is phenyl substituted with one to three IND O 0 94. A histone deacetylase inhibitor of formula 0 Cy 3 -X 2 -Ar 3 NH NH 2 (3) 0 or a pharmaceutically acceptable salt thereof, wherein iVn Ar 3 is arylene or heteroarylene, either of which is optionally substituted; 0Cy 3 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted, and 0 each of which is optionally fused to one or two aryl or heteroaryl rings, or to one or two saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings is optionally substituted; provided that when Cy 3 is a cyclic moiety having or -S(0) 2 in the ring, then Cy 3 is not additionally substituted with a group comprising an aryl or heteroaryl ring; and X 2 is selected from the group consisting of a chemical bond, L 3 W'-L 3 L 3 W'-L 3 and L 3 -W 1 -L 3 wherein at each occurrence, is S, 0, or where R 9 is selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl; and L 3 is CI-C 4 alkylene, C2-C4 alkenylene, or C 2 -C 4 alkynylene; provided that X 2 does not comprise a or -S(0) 2 group; and further provided that when Cy 3 is pyridine, then X 2 is L 3 W'-L 3 or L 3 The compound according to claim 94 wherein Ar 3 has the structure: IQ Q Q Q O 0 0QQ Q 0 ,or QQ"" wherein Q, at each occurrence, is independently N or C, and C is optionally substituted; 96. The compound according to claim 94 wherein X 2 is selected from the group consisting of L 3 W'-L 3 L 3 W'-L 3 -W 1 and L 3 W'-L 3 97. The compound according to claim 94 wherein when X 2 is a chemical bond, then Ar 3 is not -Q or -Q Q Q eO Q IN and Cy 3 is not the radical of a substituted or unsubstituted diazepine or benzofuran. 98. The compound according to claim 95 wherein Q at each occurrence is C(R 8 where R 8 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy. 99. The compound according to claim 95 wherein from one to about three Q are nitrogen. 100. The compound according to claim 94 wherein Ar 3 is selected from the group consisting of phenylene, pyridylene, thiazolylene, and quinolylene. 101. The compound according to claim 94 wherein X 2 is a chemical bond. 102. 103. 104. 105. 106. 107. 108. 109. The compound according to claim 94 wherein X 2 is a non-cyclic hydrocarbyl. The compound according to claim 94 wherein X 2 is alkylene. The compound according to claim 94 wherein X 2 methylene or ethylene. The compound according to claim 94 wherein X 2 alkenylene or alkynylene. The compound according to claim 102 wherein one carbon in the hydrocarbyl chain is replaced with -NH- or The compound according to claim 94 wherein X 2 is W-L 3 and W' is -NH- or -N(CH 3 The compound according to claim 94 wherein Cy 3 is cycloalkyl. The compound according to claim 94 wherein Cy 3 is cyclohexyl. 110. The compound according to claim 94 wherein Cy 3 is aryl or heteroaryl, each of which is optionally substituted and is optionally fused to one or two aryl rings. 111. The compound according to claim 94 wherein Cy 3 is phenyl, pyridyl, pyrimidyl, imidazolyl, thiazolyl, oxadiazolyl, quinolyl, or fluorenyl, each of which is optionally substituted and is optionally fused to one or two aryl rings. OD 0 0 112. The compound according to claim 94 wherein the cyclic moiety of Cy 3 is fused to a benzene ring. 113. The compound according to claim 94 wherein Cy 3 has from one to three substituents independently selected from the group consisting of alkyl, alkoxy, aryl, aralkyl, amino, halo, haloalkyl, and hydroxyalkyl. tn 114. The compound according to claim 113 wherein the substituents are selected from methyl, \O methoxy, fluoro, trifluoromethyl, amino, nitro, aminomethyl, hydroxymethyl, and phenyl. C 115. The compound according to claim 94 wherein Cy 3 has from one to three substituents of the formula wherein K' is a chemical bond or C1-C 4 alkylene; R' 0 is selected from the group consisting of Z' and -Ak 2 wherein Ak 2 is CI-C 4 alkylene; and Z' is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted, and each of which is optionally fused to one or two aryl or heteroaryl rings, or to one or two saturated or partially unsaturated cycloalkyl or heterocyclic rings. 116. The compound according to claim 115 wherein the substituent is selected from H ON N C 0 SH and H3C 117. The compound according to claim 94 wherein Cy 3 is heterocyclyl, each of which is optionally substituted and is optionally fused to one or two aryl rings. 118. The compound according to claim 94 wherein Cy 3 is selected from 0 0 0 0 0 0 0, 0, r 0, 1H V V 1 H and eoiVo 316 IO 0 0 119. The compound according to claim 117 wherein the heterocycle of Cy 3 is fused to a benzene Q) ring. 120. The compound of claim 94 wherein when Ar 4 is quinoxalinylene, then X 3 is not -CH(OH)-. 121. The compound of claim 94 wherein Ar 3 is \O Sand X is -CH 2 0, or S. 122. The compound of claim 94 wherein Ar 3 is and X is S or 0. 123. The compound according to claim 54 wherein Ay 2 is ortho-anilinyl; q is 0; and X' is M'-L2-M or L 2 2 -L 2 124. The compound according to claim 123 wherein Ar 2 is aryl or heteroaryl; and Cy 2 is collectively selected from the group consisting of a) AI-LI-B-, wherein A, is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L 1 is -(CH 2 )l.NH(CH 2 or -NHCH 2 and wherein B 1 is phenyl or a covalent bond; b) A 2 -L 2 -B 2 wherein A 2 is CH 3 (C=CH 2 optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted aryl; wherein L 2 is and wherein B 2 is a covalent bond; O o c) A 3 L 3 -6 3 wherein A 3 is an optionally substituted aryl, optionally substituted heteroaryl or Q optionally substituted heterocyclyl; wherein L 3 is a covalent bond; and wherein B3 is SCH 2 NH-; d) A 4 -L 4 wherein A 4 is an optionally substituted aryl; wherein L4 is -NHCH 2 and wherein B 4 is a thienyl group; O e) As-Ls-Bs-, wherein As is an optionally substituted heteroaryl or optionally substituted i'n heterocyclyl; wherein Ls is a covalent bond; and wherein Bs is -SCH 2 0 f) morpholinyl-CH 2 O g) optionally substituted aryl; h) A 6 -Le-B 6 wherein A 6 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L e is a covalent bond; and wherein B 6 is NHCH 2 i) A-L7-Br, wherein A 7 is an optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L 7 is a covalent bond; and wherein B 7 is -CH 2 j) aptionally substituted heteroaryl or optionally substituted heterocyclyl; k) A 8 sL-B 8 wherein As is optionally substituted phenyl; wherein La is a covalent bond; and wherein B 8 is I) A 9 -Lg-B 9 wherein Ag is an optionally substituted aryl; wherein L9 is a covalent bond; and wherein B9 is a furan group; m) Alo-Llo-BIo-, wherein Aio is an optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein Lio is -CH(CH 2 CH 3 and wherein Bio is -NHCH 2 n) A 1 1 -L 11 wherein All is an optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L 1 1 is a covalent bond; and wherein B 1 1 is -OCH 2 o) A 1 2 -Lt2-B3 2 wherein A 1 2 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L 12 is-NHC(O)-; and wherein B 1 2 is N(optionally substituted aryl)CH 2 p) A 1 3 -L 1 3 -Bi 3 wherein A 1 2 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L 1 3 is a covalent bond; and wherein Bi3 is- NHC(O)-; IO Sq) A 14 -L 14 -B 14 wherein A 14 is an optionally substituted aryl, optionally substituted heteroaryl Q or optionally substituted heterocyclyl; wherein L 1 4 is-NHC(O)(optionally substituted heteroaryl); and wherein B 1 4 is r) F 3 CC(O)NH-; s) A 15 -Li-Bs-, wherein As 1 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein Ls 5 is(CH 2 0 ~NH(optionally substituted Sheteroaryl)-; and wherein Bis is -NHCH 2 N t) A 16 -L 6 -Bi 6 wherein A 16 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L 16 is a covalent bond; and wherein Bi 6 is N(optionally substituted alkyl)CH 2 and u) A 16 -L 6 -B 6 wherein A 16 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein L 16 is a covalent bond; and wherein B 16 is (optionally substituted ary-CH 2 2 125. The compound according to claim 123 wherein Cy 2 is collectively selected from the group consisting of a) Di-E 1 wherein Di is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein El is -CH 2 or a covalent bond; and wherein B 1 is a covalent bond; b) D 2 -E 2 -F 2 wherein D 2 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E 2 is -NH(CH2)o- 2 and wherein F 2 is a covalent bond; c) D 3 -E 3 wherein D 3 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E 3 is -(CH 2 )0o 2 NH-; and wherein F 3 is a covalent bond; d) D 4 -E 4 -F 4 wherein D 4 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E 4 is -S(CH 2 )o. 2 and wherein F 4 is a covalent bond; e) Ds-Es-Fs-, wherein Ds is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E s is -(CH 2 0 2S-; and wherein Fs is a covalent bond; and IO O 0 f) D 6 -E 6 -F 6 wherein D e is an optionally substituted aryl, optionally substituted heteroaryl or Q optionally substituted heterocyclyl; wherein E6 is -NH(CH 2 2 NH-; and wherein F 6 is a covalent bond. 126. The compound of claim 54 having formula (3b): Y H NH2 o (3b) S wherein Y and Z are independently N or CH and W is selected from the group consisting of: 00 0 MeOc F N Me MeON O 00 N N Br A, N llO H IN O 'N N Me 0 N0 S 'NN~~OBr H a OMe I_ 0 0 0 BrBr yCI N 'NF F F N N' F N1N-/ N H H H N NO N N N No N\ H 3 -sN ~N 0N N NC NC Me N\ N HN t HN-7S I'N 0'Mei Ph-- N 0 0 H H ON NN;/Me 0 TN 0 N 0S 0 0 0 N N 321 MeO 0 1 HN Meo Meo N 322 IN "23 H H Ne N HN MeSS~ C C IH MeGe In H N N Ne MeG _NY Mei Ne Me H3C 3 C HH OH NYC MeGqI Ne MeG O~e H N N F 3 C O MeG A OCF 3 OMe H N H N H He HN FC,) MeO 0=NNH 00 H Ne H NH H H~ NI H 2 N::I 0e H 3 C MeN NH,, N2 N I Ke 0A H3 N NHH3 N BrfHS H MeG Nq O e MeG 324 IN 127. The compound according to claim 126 wherein Y, 7 and W are one of the following combinations: MO H 164 MeO CH CH MOe 165 HO /d N CH 166 MeO CH CH N 167 1 eI H CH N H 168 ie 'J ,CH N 19MeOIN rN CH H MeO N OMe Cd W y z 0 179 OJN N CH CH 0 180 me 0 CH CH Me 0 181 1 N CH CH Et H 3 C N 182 .N CH CH CH 3 and F F 183 F N CHC 325 128. The compound according to claim 126 wherein Y, Z and W are one of the following combinations: Cpd W Y Z Nz N N 187 C111'N CHCH NH2 H O 188 N CHCH 0" H 189 MeO N CH CH OMe 190 Ml NI CH CH MeO 193 H 2 C CH CH CH 3 194 CHCH OH 195 CH CH H 3 C OH 196 CH CH 320 c' E-NH OH CH 321 CH CH 322 Br H CH 322M >NHOMe CH CH 323 Me\r. HC Cpd W Y Z I- 325 s CH CH lHJH NNI <N A4 326 c CH CH 326 N H SOH H H 327 CH CH N H 328 CH CH 329OJ MeO OMe 330 H3CCN/ N OH CH N HN-/ NH 2 N~NH 331 MN7N CH CH N MNx C1 332 HN N CH CH 0 N 333 H3C.-"'N CH CH H OJ N NHOHH 334 1c CH CH 0 335 N-/V OH OH E t- N 326- Cpd W Y Z 0 Br N'J CH CH N 0 348 N/ CH CH I N 349 F N CH CH H F ~F 7Ni NJ CHICH 0 351 CHICH H 352N CH CH Ph-- o .N 353 N CH CH 353 Me~l<,N 0 354 ON CH CH 0' 3N CH CH 355 ON -ill 357 CH CH 358 CH CH N-J O- 358 /Il Irl CH CH ,N/\O-N NC 359 HN-7 CH CH 0 IN Cpd W Y Z MeO 0 371 NH HOMe CH CH OMe 372 Io i-N C CH CH OMe 373 CH CH NH O~e OMe 374 0§j-NH Ome CHCH OMe 0 375 Q- N CH CH NH 2 H H N, N 377 r;yN"~;CHOCH H 3 C NS, 378 -N CH CH CH 2 FF 379 F CH CH NH 2 H 380 N_ N N CH 0 381 N a SY' CHOCH CH 3 H 3 C N N N- H CHICH 328-. Cpd W Y Z 395 H 3 C' Nq HC 395l CH3HC 396 NCH CH H 397CH Oq N, CH CH 398 N H S1 CH N NH 2 399 LzNN CH CH HN> H 401 CH CH H 3 C H 402 0J~J~N CH CH H3C CHO 403 H 3 C0 N H CH CH N H 404 N3,J N\ CH CH 0 H 405 1 3C o)cJ NN CH CH H 0 N, H 3 C' HC 406 H 3 C,. 0 -OIH CHH 0 329 Cpd W Y Z H H 3 C N 407 O 1 CH CH OH, 408 CH CH CH 3 H 409 'N CHCH H 3 C OH 3 H 410 C C H3C ~7 CH, 410 N CH CH 412 MeO HCH CH H MeO OMe 413 J~ OHOCH 416 IH CH CH MeO H 415 CH CH H 417 IT CH CH Me Cpd W V Z H 419 NCHCH cI H H 420 NN )<NA CH CH H S N CHCH 421 Me N MeO'f H 422 F3COv'r N CH CH F 3 00 H 423 -y CH CH OCF 3 H 424b MeOq N CH CH OMe 425 Hj CH CH OCF 3 426 I3CO CHCH H 427 m No CH CH H 428 1 CHCH H 429 CH CH OMe H 430 CH H 330 IN Cpd W Y Z Cpd W Y 0HN- 455 o CH CH 463 NC 4 NHOH 456 Me N CH CH 464 H NC O H 2 N 457 eoH2N 465 CH C Me0~cr S O HN 458 MeO NNH\ CH CH 466 s CH C 0 N 1N H CH CH 467 s CH H0C H 4\ NQt' CHC 460 JCH 468 CH 0HN- H 3 C.N NH 461 0CNH CH CH CH 3 129. A compound selected from the group consisting of the following and their pharmaceutically acceptable salts: o H 2 NH O H 3 C S i H 3 C/0 6 J 0 p-NN H 3 C..N H N H 2 N 61 -N H C. N 0 0OH 3 ~c N C S N H 3 C 0 H 2 N H N 030 H3C'H 3 0 2 0 HN NH 2 0 0" Hr H H L,,N N> N0 NI I N HH H 2 N 0 NH H HN N N 0 0/O CH 0 aNH NH 2 N2 N N H HN C,0 NH N 0 HH 0H 0 I 3 N N N N H 3 C N NH i 0 ~0 333 334 \O 0 eo M H 3 0-O NJ H I1O** NDI N N 0 NH2 N Me MeO MeOH2N \oo OMe MeO" N F% H2 'N N, HeO NNA 0 H N q MeO N MeOOH OH OMe OMe Me N \ON N MeO N I HNH 2 OMe H 3 C O NN, H NH 2 0 N0H 3 HN N H 0 130. A histone deacetylase inhibitor selected from the compounds listed in Tables 2a-b, 3a-d, 4a- c, and 5a-5f, or a pharmaceutically acceptable salt thereof. 131. A composition comprising a compound according to any one of claim 1-130 and a pharmaceutically acceptable carrier. \O 132. A method of inhibiting histone deacetylase in a cell, the method comprising contacting a cell with a compound according to any one of claim 1-130. Dated 14 December, 2006 Methylgene, Inc. tl- Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON
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