Patent Application
20080132459
1. Field of the Invention
This invention relates to the inhibition of histone deacetylase. More particularly, the invention relates to compounds and methods for inhibiting histone deacetylase enzymatic activity.
2. Summary of the Related Art
In eukaryotic cells, nuclear DNA associates with histones to form a compact complex called chromatin. The histones constitute a family of basic proteins which are generally highly conserved across eukaryotic species. The core histones, termed H2A, H2B, H3, and H4, associate to form a protein core. DNA winds around this protein core, with the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA. Approximately 146 base pairs of DNA wrap around a histone core to make up a nucleosome particle, the repeating structural motif of chromatin.
Csordas, Biochem. J., 286: 23-38 (1990) teaches that histones are subject to posttranslational acetylation of the α,ε-amino groups of (V-terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HATI). 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.
Histone acetylation is a reversible modification, with deacetylation being catalyzed by a family of enzymes termed histone deacetylases (HDACs). Grozinger et al., Proc. Natl. Acad. Sci. USA, 96: 4868-4873 (1999), teaches that HDACs are 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 HDACI, 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. More recently, Hu et al. J. Bio. Chem. 275:15254-13264 (2000) and Van den Wyngaert, FEBS, 478: 77-83 (2000) disclose HDAC8, a new member of the first class of HDACs.
Richon et al., Proc. Natl. Acad. Sd. USA, 95: 3003-3007 (1998), discloses that HDAC activity is inhibited by trichostatin A (TSA), a natural product isolated from Streptomyces hygroscopicus, and by a synthetic compound, suberoylanilide hydroxamic acid (SAHA). Yoshida and Beppu, Exper. Cell Res., 177: 122-131 (1988), teaches that TSA causes arrest of rat fibroblasts at the Gi and G2 phases of the cell cycle, implicating HDAC in cell cycle regulation. Indeed, Finnin et al., Nature, 401: 188-193 (1999), teaches that TSA and SAHA inhibit cell growth, induce terminal differentiation, and prevent the formation of tumors in mice. Suzuki et al., U.S. Pat. No. 6,174,905, EP 0847992, JP 258863/96, and Japanese Application No. 10138957, disclose benzamide derivatives that induce cell differentiation and inhibit HDAC. Delorme et al., WO 01/38322 and PCT/IBO1/00683, disclose additional compounds that serve as HDAC inhibitors.
The molecular cloning of gene sequences encoding proteins with HDAC activity has established the existence of a set of discrete HDAC enzyme isoforms. Some isoforms have been shown to possess specific functions, for example, it has been shown that HDAC-6 is involved in modulation of microtubule activity. However, the role of the other individual HDAC enzymes has remained unclear.
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.
Ortho-amino benzamides are known HDAC inhibitors. Substitutions at the ortho- and meta-positions relative to the amino group are detrimental to the potency of the inhibitors; however, some small substituents such as —CH3, —F, or —OCH3 can be tolerated to a certain extent. We have now found that o-amino benzamide HDAC inhibitors having a much bigger but flat aromatic and heteroaromatic substituents such as phenyl, furyl, thienyl and the like para to the amino moiety are not only well tolerated but cause significant increase in HDAC inhibition activity.
Accordingly, the present invention provides new compounds and methods for treating cell proliferative diseases. The invention provides new inhibitors of histone deacetylase enzymatic activity.
In a first aspect, the invention provides compounds that are useful as inhibitors of histone deacetylase.
In a second aspect, the invention provides a composition comprising an inhibitor of histone deacetylase according to the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or diluent.
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.
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. All publications (patent or other) are hereby incorporated by reference in their entirety; in the event of any conflict between these materials and the present specification, the present specification shall control.
The figures displays antineoplastic effects of a histone deacetylase inhibitor according to the invention on human tumor xenografts in vivo, as described in Assay Example 2, infra.
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.
For purposes of the present invention, the following definitions will be used (unless expressly stated otherwise):
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 ω-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 HI, 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-I, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-IO1 and HDAC-II. In some other preferred embodiments, the histone deacetylase is derived from a protozoal or fungal source.
The terms “histone deacetylase inhibitor” and “inhibitor of histone deacetylase” are used to identify a compound having a structure as defined herein, which is capable of interacting with a histone deacetylase and inhibiting its enzymatic activity. “Inhibiting histone deacetylase enzymatic activity” means reducing the ability of a histone deacetylase to remove an acetyl group from a histone. In some preferred embodiments, such reduction of histone deacetylase activity is at least about 50%, more preferably at least about 75%, and still more preferably at least about 90%. In other preferred embodiments, histone deacetylase activity is reduced by at least 95% and more preferably by at least 99%.
Preferably, such inhibition is specific, i.e., the histone deacetylase inhibitor reduces the ability of a histone deacetylase to remove an acetyl group from a histone at a concentration that is lower than the concentration of the inhibitor that is required to produce another, unrelated biological effect. Preferably, the concentration of the inhibitor required for histone deacetylase inhibitory activity is at least 2-fold lower, more preferably at least 5-fold lower, even more preferably at least 10-fold lower, and most preferably at least 20-fold lower than the concentration required to produce an unrelated biological effect.
For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety generally refers to a monovalent radical (e.g. CH3CH2—), in certain circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., —CH2—CH2—), which is equivalent to the term “alkylene.” (Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation [i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S). On occasion a moiety may be defined, for example, as (A)a-B—, wherein a is O or 1. In such instances, when a is O the moiety is B— and when a is 1 the moiety is A-B—.
For simplicity, reference to a “Cn—Cm” heterocyclyl or “Cn—Cm” heteroaryl means a heterocyclyl or heteroaryl having from “n” to “m” annular atoms, where “n” and “m” are integers. Thus, for example, a C5-C6-heterocyclyl is a 5- or 6-membered ring having at least one heteroatom, and includes pyrrolidinyl (C5) and piperidinyl (C6); C6-hetoaryl includes, for example, pyridyl and pyrimidyl.
The term “hydrocarbyl” refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, each as defined herein. A “C0” hydrocarbyl is used to refer to a covalent bond. Thus, “C0-C3-hydrocarbyl” includes a covalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl, propynyl, and cyclopropyl.
The term “alkyl” as employed herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. A “C0” alkyl (as in “C0-C3-alkyl”) is a covalent bond (like “C0” hydrocarbyl).
The term “alkenyl” as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
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.
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 butenylene.
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.
The term “heteroalkyl” refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from the group consisting of O, S, and N.
An “aryl” group is a C6-C14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted. Preferably, the aryl group is a C6-C10 aryl group. Preferred aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An “aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted. Preferably, the aralkyl group is (Ci-C6)alk(C9-Cio)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
A “heterocyclic” group (or “heterocyclyl) is an optionally substituted non-aromatic mono-, bi-, or tricyclic structure having from about 3 to about 14 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S. One ring of a bicyclic heterocycle or two rings of a tricyclic heterocycle may be aromatic, as in indan and 9,10-dihydro anthracene. The heterocyclic group is optionally substituted on carbon with oxo or with one of the substituents listed above. The heterocyclic group may also independently be 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 heterocycles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the scope of this term are compounds where an annular O or S atom is adjacent to another O or S atom.
In certain preferred embodiments, the heterocyclic group is a heteroaryl group. As used herein, the term “heteroaryl” refers to optionally substituted groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array; and having, in addition to carbon atoms, between one or more heteroatoms selected from the group consisting of N, O, and S. For example, a heteroaryl group may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl, benzofuranyl and indolinyl. Preferred heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, and isoxazolyl.
A “heteroaralkyl” or “heteroarylalkyl” group comprises a heteroaryl group covalently linked to an alkyl group, either of which is independently optionally substituted or unsubstituted. Preferred heteroalkyl groups comprise a C1-C6 alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms. Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms. Examples of preferred heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, and thiazolylethyl.
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.
Preferred heterocyclyls and heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-I,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-I,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.
As employed herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl, heteroaryl, heterocyclic, urea, etc.) is described as “optionally substituted” it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular —CH-substituted with oxo is —C(O)—) nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups. Preferred substituents, which are themselves not further substituted (unless expressly stated otherwise) are:
In addition, substituents on cyclic moieties (i.e., cycloalkyl, heterocyclyl, aryl, heteroaryl) include 5-6 membered mono- and 9-14 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, but not limited to, the following:
A “halohydrocarbyl” is a hydrocarbyl moiety in which from one to all hydrogens have been replaced with one or more halo.
The term “halogen” or “halo” as employed herein refers to chlorine, bromine, fluorine, or iodine. As herein employed, the term “acyl” refers to an alkylcarbonyl or arylcarbonyl substituent. The term “acylamino” refers to an amide group attached at the nitrogen atom (i.e., R—CO—NH—). The term “carbamoyl” refers to an amide group attached at the carbonyl carbon atom (i.e., NH2—CO—). The nitrogen atom of an acylamino or carbamoyl substituent is additionally substituted. The term “sulfonamido” refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom. The term “amino” is meant to include NH2, alkylamino, arylamino, and cyclic amino groups. The term “ureido” as employed herein refers to a substituted or unsubstituted urea moiety.
The term “radical” as used herein means a chemical moiety comprising one or more unpaired electrons.
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-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluoro-3-propylphenyl. As another non-limiting example, substituted N-octyls include 2,4 dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included within this definition are methylenes (—CH2—) substituted with oxygen to form carbonyl —CO—).
An “unsubstituted” moiety as defined above (e.g., unsubstituted cycloalkyl, unsubstituted heteroaryl, etc.) means that moiety as defined above that does not have any of the optional substituents for which the definition of the moiety (above) otherwise provides. Thus, for example, while an “aryl” includes phenyl and phenyl substituted with a halo, “unsubstituted aryl” does not include phenyl substituted with a halo.
Throughout the specification preferred embodiments of one or more chemical substituents are identified. Also preferred are combinations of preferred embodiments. For example, paragraph [0055] describes preferred embodiments of Cy2 in the compound of formula (1) and paragraph [0071] describes preferred embodiments of R2 to R4 of the compound of formula (1). Thus, also contemplated as within the scope of the invention are compounds of formula (1) in which Cy2 is as described in paragraph [0055] and Ay2 and R1 to R4 are as described in paragraph [0071].
Some compounds of the invention may have chiral centers and/or geometric isomeric centers (E- and Z-isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers. The invention also comprises all tautomeric forms of the compounds disclosed herein.
The compounds of the invention may be administered in the form of an in vivo hydrolyzable ester or in vivo hydrolyzable amide. An in vivo hydrolyzable ester of a compound of the invention containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include Cr6-alkoxymethyl esters (e.g., methoxymethyl), -Walkanoyloxymethyl esters (e.g., for example pivaloyloxymethyl), phthalidyl esters, C3-8-cycloalkoxycarbonyloxyCr6-alkyl esters (e.g., 1-cyclohexylcarbonyloxyethyl); 1,3-dioxolen-2-onylmethyl esters (e.g., 5-methyl-1,3-dioxolen-2-onylmethyl; and Cr6-alkoxycarbonyloxyethyl esters (e.g., 1-methoxycarbonyloxyethyl) and may be formed at any carboxy group in the compounds of this invention.
An in vivo hydrolyzable ester of a compound of the invention containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolyzable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and IV—(N,IV-dialkylaminoethyl)-N-alkylcarbamoyl(to give carbamates), N1N-dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring. A suitable value for an in vivo hydrolyzable amide of a compound of the invention containing a carboxy group is, for example, a N—Cre-alkyl or N,N-di-Ci-6-alkyl amide such as N-methyl, N-ethyl, IV-propyl, N,N-dimethyl, N-ethyl-N-methyl or IV,N-diethylamide.
In the first aspect, the invention comprises the histone deacetylase inhibitors of formula (1):
or a pharmaceutically acceptable salt thereof, wherein
The atoms that comprise the Y moiety are preferably those found in pharmaceuticals, including, but not limited to, H, C, N, O, S, F, Cl, Br, I, and P. Numerous representative examples of Y are displayed in paragraphs [0050]-[0088], [0098]-[0110], and [0115]-[0207]. Y moieties of the compounds of the present invention also can be found in the following publications (either per se or as part of a disclosed molecule): WO 03/024448, U.S. Pat. No. 6,174,905, JP 11-269146 (1999), JP 11-302173 (1999), JP 2001131130, EP 0847992, JP 10152462, JP 2002332267, JP 11302173, and JP 2003137866. For example, in these publications many different Y moieties are readily identified in molecules of structure Y—Ar(CH═CH)a—C(O)—NH-Z, wherein Ar2 is defined herein, a is 0 or 1, Z is —OH or aryl, and the Ar2, —CH═CH—, and aryl moieties may be optionally substituted as suggested in the publication.
In a preferred embodiment of the compounds according to paragraph [0046], R1 is an aryl selected from phenyl, naphthyl, anthracenyl, and fluorenyl. In another preferred embodiment, R1 is a heteroaryl selected from those recited in paragraph [0034]. Other preferred R1 moieties include azolyls (e.g., thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, etc.), pyridyl, and pyridinyl. More preferably, R1 is furanyl or thienyl.
In a preferred embodiment of all the compounds of the invention, R2, R3, and R1 are all hydrogen. Also preferred are compounds in which Φ is —NH2 or —OH.
In a preferred embodiment of the compounds of paragraphs [0046], [0048], and [0049], Y is Cy2—X1—, wherein
In some preferred embodiments according to paragraph [0050], the optional substituents of Cy2 are selected from CrC7-alkyl, Ci-C7alkoxy, halo, di-Ci-C7-alkylamino-Ci-C7-alkoxy and heteroaryl.
In some preferred embodiments according to paragraph [0050], X1 is selected from the group consisting of a —N(Z)-C0-C7-alkyl-, —O—C0-C7-alkyl-, —C(H)═CH—C0-C7-alkyl-, —S—C0-C7-alkyl-, or —C1-C7-alkyl-, wherein Z is —H or —Ci-C7-alkyl-optionally substituted with —OH, —NH2, or halo.
In some embodiments of the compounds according to paragraph [0050], X1 is a chemical bond. In some embodiments, X1 is L2-M2-L2, and M2 is selected from the group consisting of —NH—, —N(CH3)—, —S—, —C(O)—N(H)—, and -0-C(O)—N(H)—. In some embodiments, X1 is L2-M2-L2, where at least one occurrence of L2 is a chemical bond. In other embodiments, X1 is L2-M2-L2, where at least one occurrence of L2 is alkylene, preferably methylene. In still other embodiments, X1 is L2-M2-L2, where at least one occurrence of L2 is alkenylene. In some embodiments, X1 is M1-LΛM1 and M1 is selected from the group consisting of —NH—, —N(CH3)—, —S—, and —C(O)—N(H)—. Preferred X1 are selected from methylene, aminomethyl, and thiomethyl.
In some embodiments of the compounds according to paragraph [0050], Cy2 is aryl or heteroaryl, e.g., phenyl, pyridyl, imidazolyl, or quinolyl, each of which optionally is substituted. In some embodiments, Cy2 is heterocyclyl, e.g.,
each of which optionally is substituted and optionally is fused to one or more aryl rings. In some embodiments, Cy2 has from one and three substituents independently selected from the group consisting of alkyl, alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy. Examples of preferred substituents include methyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, nitro, amino, aminomethyl, and hydroxymethyl.
In some preferred embodiments of the compounds according to paragraph [0050], Cy2 is phenyl, pyrimidinyl, benzimidazolyl or benzothiazolyl, each optionally substituted with one to three CH3O—, dimethylamino-ethoxy, chloro, fluoro and pyridinyl. In a more preferred embodiment, Cy2 is phenyl substituted with one to three CH3O—.
In some embodiments according to paragraph [0046], Y is (V-L4VV-L3-, wherein
X′ is —N(R21)—, —C(O)N(R21)—, N(R21)JC(O)—, -0-, or —S—;
In some embodiments according to paragraph [0056], Y is V-L3, wherein L3 is —NH—CH— or —CH—NH—;
In some preferred embodiments of the compound according to paragraph [0056], V is an optionally substituted ring moiety selected from:
In another preferred embodiment of the compounds according to paragraph [0046], Y is selected from:
In other embodiments of the compounds according to paragraph [0046],
In other embodiments of the compounds according to paragraph [0046],
In one embodiment according to paragraph [0060], Cy2 is phenyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, thienyl, tetrahydroquinozolinyl, or I,3-dihydroquinazoline-2,4-dione, each optionally substituted with one to three CH3O—. More preferably, Cy2 is phenyl substituted with one to three CH3O—.
In yet other embodiments of the compound according to paragraph [0046],
Preferably in the compounds according to paragraph [0063], X2 is selected from the group consisting of L3, W1-L3, L3-W\W1-IAW1, and IAW1-L3.
In some embodiments of the compounds according to paragraph [0063], X1 is a chemical bond. In other embodiments, X1 is a non-cyclic hydrocarbyl. In some such embodiments, X1 is alkylene, preferably methylene or ethylene. In other such embodiments, X1 is alkenylene. In still other such embodiments, one carbon in the hydrocarbyl chain is replaced with —NH— or —S—, and in others with a -0-. In some preferred embodiments, X1 is W4AW1 and W1 is —NH— or —N(CH3)—.
In some embodiments of the compounds according to paragraph [0063], Cy2 is cycloalkyl, preferably cyclohexyl. In other embodiments, Cy2 is aryl or heteroaryl, e.g., phenyl, pyridyl, pyrimidyl, imidazolyl, thiazolyl, oxadiazolyl, quinolyl, or fluorenyl, each of which optionally is substituted and optionally is fused to one or more aryl rings. In some embodiments, the cyclic moiety of Cy2 is fused to a benzene ring. In some embodiments, Cy2 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 —KMN(H)(R10), wherein
Examples of such preferred substituents according to paragraph [0066] include
In some embodiments of the compounds according to paragraph [0063], Cy2 is heterocyclyl, e.g.,
each of which optionally is substituted and optionally is fused to one or more aryl rings. In some embodiments, the heterocycle of Cy2 is fused to a benzene ring.
In certain preferred embodiments of the compound according to paragraph [0046], Cy2—X1— is collectively selected from the group consisting of
In another preferred embodiment of the compounds according to paragraph [0046], Cy2—X1— is collectively selected from the group consisting of
In some embodiments according to paragraphs [0046] and [0048H0063], R2 to R4 are independently hydrogen, —NH2, nitro, furanyl, chloro, fluoro, butyl, trifluoromethyl, bromo, thienyl, phenyl, —CHCHC(O)—NH2, —C≡CCH2—R9 wherein R9 is hydrogen, CrC7-alkyl, hydroxy, amino, or Ci-C7-alkoxy.
In some preferred embodiments of the compound according to paragraphs [0046] and [0048H0071], q is O and X1 is independently selected from the group consisting of —NH—CH2, —S—CH2— and —CH2—.
In some preferred embodiments of the compound according to paragraphs [0046] and [0048H0071], q is O and X1 is independently selected from the group consisting of —OCH2, —CH2O—, —CH2—NH2—, and —CH2S—.
In some embodiments of the compound according to paragraphs [0046] and [0048]-[0072], the compound has Ar2 of formula
wherein G, at each occurrence, is independently N or C, and C is optionally substituted.
In some embodiments of the compounds according to paragraph [0074], G at each occurrence is C(R8), wherein R8 is selected from the group consisting of hydrogen and CrC7-alkyl. In some more preferred embodiments, G is —CH—.
In some preferred embodiments, the compounds according to paragraph [0074] are those wherein Ar2 is selected from the group consisting of phenylene, benzofuranylene and indolinylene.
In some preferred embodiments, Cy2 is aryl or heteroaryl, each of which is optionally substituted. More preferably, Cy2 is phenyl, pyrimidinyl, benzimidazolyl or benzothiazolyl, each of which is optionally substituted. Preferred substituents of Cy2 are from one to three substituents independently selected from the group consisting of Ci-Cr-alkyl, CrCralkoxy, halo, CJi-Ci-C7-alkylamino-Ci-Cralkoxy and heteroaryl. More preferably, the substituents of Cy2 are selected from methyl, methoxy, fluoro, chloro, pyridinyl and dimethylamino-ethoxy.
In some preferred embodiments, the moiety formed by Cy2o<1 is selected from the following:
In a preferred embodiment, the compounds of paragraph [0050] are represented by the general formula (2):
In some preferred embodiments, the compounds according to paragraph [0079] are those in which Cy2 is selected from:
In other preferred embodiments of the compounds according to paragraphs [0079] and [0080], the A ring is not further substituted.
In another preferred embodiment of the compounds according to paragraphs [0079]-[0081], R2 and R3 are both —H.
In another embodiment of this aspect, the invention comprises compounds of the general formula (3):
Particular values of Ring A, R5, R6, m, and n include the following:
Ring A:
R6:
m:
R5:
n:
Other embodiments of the compound according to paragraph [0083], include those in which:
In another embodiment of the compound according to paragraph [0083],
In another embodiment of the compound according to paragraph [0083],
in the embodiments of the compounds according to paragraphs [0083] and [0085]-[0087], R1, R2, R3, and R4 are as defined in paragraphs [0048] and [0049], in other preferred embodiments, the compounds according to paragraph [0083] are the compounds of Tables 1-8 and 13 of WO 03/087057 modified by replacing the terminal moiety:
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraphs [0046], and preferably [0048] and [0049].
The definitions in paragraphs [0090]-[0097] apply to R5 and R6 in paragraphs [0083]-[0088] and supplement the definitions in paragraphs [0020]-[0042]. To the extent there are any inconsistencies between the definitions in paragraphs [0020]-[0042] and in paragraphs [0090]-[0097], the definitions in paragraphs [0090]-[0097] shall take precedence for the compounds of paragraphs [0083]-[0088] only.
“Alkyl” includes both straight and branched chain alkyl groups. For example, “Crs-alkyl” and “Ci-6-alkyl” includes methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, and t-butyl. However, references to individual alkyl groups such as ‘propyl’ are specific for the straight-chained version only and references to individual branched chain alkyl groups such as ‘isopropyl’ are specific for the branched chain version only.
The term “halo” refers to fluoro, chloro, bromo and iodo.
Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
A “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a ring sulphur atom is optionally oxidized to form the S-oxide(s). Preferably a “heterocyclyl” is a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen or a 8-10 membered bicyclic ring which may, unless otherwise specified, be carbon or nitrogen linked, wherein a ring sulphur atom is optionally oxidized to form S-oxide(s). Examples and suitable values of the term “heterocyclyl” are thiazolidinyl, pyrrolidinyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.IIheptyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, pyrrolyl, pyrazolyl, oxadiazolyl, tetrazolyl, oxazolyl, thienopyrimidinyl, thienopyridinyl, thieno{3,2-d]pyrimidinyl, 1,3,5-triazinyl, purinyl, 1,2,3,4-tetrahydroquinolinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzothienyl, benzofuranyl, indazolyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, napthyridinyl, benzotriazolyl, pyrrolothienyl, imidazothienyl, isoxazolyl, imidazolyl, thiadiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, quinolyl, quinazolinyl, and 1-isoquinolinyl.
A “heterocyclic group” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a CH2 group is optionally replaced by a C(O), and wherein a ring sulphur atom is optionally oxidized to form the S-oxide(s). Preferably a “heterocyclic group” is a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen or a 9 or 10 membered bicyclic ring which may, unless otherwise specified, be carbon or nitrogen linked, wherein a CH2 group is optionally replaced by a C(O), and wherein a ring sulphur atom is optionally oxidized to form S-oxide(s). Examples and suitable values of the term “heterocyclic group” are pyrrolidinyl, 2-pyrrolidonyl 2,5-dioxopyrrolidinyl, 2,4-dioxoimidazolidinyl, 2-oxo-I,3,4-triazolinyl, oxazolidinyl, 2-oxazolidonyl, 5,6-dihydro-uracilyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl, morpholinyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, 1,3-dioxolanyl, homopiperazinyl, thiophenyl, thienopyridinyl, thienopyrimidinyl, thieno[3,2-d]pyrimidinyl, 1,3,5-triazinyl, purinyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, tetrahydroisoquinolinyl, imidazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl, indazolyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, napthyridinyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-trazolyl, pyranyl, indolyl, isoindolyl, pyrimidinyl, thiazolyl, pyrazolyl, 3-pyrrolinyl, pyrazinyl, pyridazinyl, pyridinyl, pyridonyl, pyrimidonyl and 1-isoquinolinyl.
An “aryl” group is, for example, phenyl, indenyl, indanyl, naphthyl, tetrahydronaphthyl or fluorenyl, preferably phenyl.
An example of “Ci-6-alkanoyloxy” is acetoxy. Examples of “d-a-alkoxycarbonyl”, “Cr6-alkoxycarbonyl” and Cr4-alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, N- and t-butoxycarbonyl. Examples of C2-6-alkynyl are ethynyl and 2-propynyl. Examples of “Cr6-alkoxy” include methoxy, ethoxy and propoxy. Examples of “Ci-5-alkanoylamino” and Ci-3-alkanoylamino include formamido, acetamido and propionylamino. Examples of “Ci-6-alkylS(O)a wherein a is O to 2” include Ci-6-alkyl sulphonyl, Ci-3-alkylS(O)a, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of “Crs-alkanoyl”, “Ci-6-alkanoyl” and Cr4-alkanoyl include Cr3-alkanoyl, propionyl and acetyl. Examples of “N—Ci-6-alkylamino” and N—(Cr3-alkyl)amino include methylamino and ethylamino. Examples of “N,IV—(C1-6-alkyl)2amino” and N,N—(Cr2-alkyl)2amino include di-N-methylamino, di-(N-ethyl)amino, di-(N-butyl)amino and N-ethyl-N-methylamino. Examples of “C2-8-alkenyl” are Cr6-alkenyl and C2-3-alkenyl, and include vinyl, alkyl, and 1-propenyl. Examples of “N—(Cr3-alkyl)sulphamoyl” and “N—(C1-5alkyl)sulphamoyl” are N—(Ci-3-alkyl)sulphamoyl, N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of “N—(Ci-6-alkyl)2sulphamoyl” are N,M-Cr3-alkyl)2sulphamoyl, N1N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of “N—ICrs-alkyDcarbamoyl” and “N—(Ci-6-alkyl)carbamoyl” are N—(Ci-4-alkyl)carbamoyl, N—(Cr3-alkyl)carbamoyl, methylaminocarbonyl, and ethylaminocarbonyl. Examples of “N,N—C1-8-alkyl)2carbamoyl” and “N,N—(Ci-6-alkyl)2carbamoyl” are N,N—(Ci-4-alkyl)2carbamoyl, N,N—(Cr2-alkyl)2carbamoyl, dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of “(heterocyclic group ICre-alkyl” include piperidin-1-ylmethyl, piperidin-1-ylethyl, piperidin-1-ylpropyl, pyridylmethyl, 3-morpholinopropyl, 2-morpholinoethyl and 2-pyrimid-2-ylethyl. Examples of “(heterocyclic group) Cr6-alkoxy” include (heterocyclic group) methoxy, (heterocyclic group methoxy and (heterocyclic group) propoxy. Examples of “arylCi-5-alkyl” include benzyl, 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl. Examples of “aryloxy” include phenoxy and naphthyloxy. Examples of “Ca-s-cycloalkyl” include cyclopropyl and cyclohexyl. Examples of “C3-8 cycloalkylCi-e-alkyl” include cyclopropylmethyl and 2-cyclohexylpropyl. Examples of “Cr6-alkoxycarbonylamino” include methoxycarbonylamino and t-butoxycarbonylamino.
Composite terms are used to describe groups comprising more than one functionality such as arylCi-4-alkyl. Such terms are to be interpreted as is understood by a person skilled in the art. For example arylCi-6-alkyl comprises Ci-6-alkyl substituted by aryl and such a group includes benzyl, 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl.
In another embodiment of this aspect, the invention comprises compounds of the following general formula (4):
In one embodiment of the compound according to paragraph [0098], one or more of the following apply:
In another embodiment of the compound according to paragraph [0098], one or more of the following apply:
In another embodiment of the compound according to paragraph [0098], one or more of the following apply:
In another embodiment of the compound according to paragraph [0098], L is a direct bond and/or R12 is H.
In another embodiment of the compound according to paragraph [0098], one or more of the following apply:
In another embodiment of the compound according to paragraph [0098], one or more of the following apply:
In another embodiment of the compound according to paragraph [0098],
In another embodiment of the compound according to paragraph [0098],
In another embodiment of the compound according to paragraph [0098],
In another embodiment of the compound according to paragraph [0098],
In another embodiment of the compound according to paragraph [0098],
In the compounds of paragraphs [0098]-[0109], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraphs [0098]-[0109], R1, R2, R3, and R4 are all H. Other preferred embodiments of the compounds of paragraph [0098]-[0109] include the compounds of pages 21 and 22 and Table F-I of WO 03/076422 in which the terminal hydroxamic acid moiety (HO—NH—C(O)—) is replaced with
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
In paragraphs [0098]-[0110] the definitions in paragraphs [0112]-[0114] supplement the definitions in paragraphs [0020]-[0042]. To the extent there are any inconsistencies between the definitions in paragraphs [0020]-[0042] and in paragraphs [0112]-[0114], the definitions in paragraphs [0112]-[0114] take precedence for the compounds of paragraphs [0098]-[0110] only.
Halo is generic to fluoro, chloro, bromo and iodo; Cr4-alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, e.g., methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; Ci-6-alky includes Ci-4-alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; Ci-6-alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof such as, 2-methylpentanediyl, 3-methylpentanediyl, 2,2-dimethylbutanediyl, 2,3-dimethylbutanediyl and the like; trihaloCre-alkyl defines Cr6-alkyl containing three identical or different halo substituents for example trifluoromethyl; C2-6-alkenediyl defines bivalent straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenediyl, 2-propenediyl, 3-butenediyl, 2-pentenediyl, 3-pentenediyl, 3-methyl-2-butenediyl, and the like; aryl defines phenyl, and phenyl substituted with one or more substituents each independently selected from halo, Cr6-alkyl, Ci-6-alkyloxy or trifluoromethyl, cyano, hydroxycarbonyl; aminoaryl defines aryl substituted with amino; C3-io-cycloalkyl includes cyclic hydrocarbon groups having from 3 to 10 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl and the like.
The term “another Zn-chelating group” refers to a group which is capable of interacting with a Zn2+-ion, which can be present at an enzymatic binding site.
The N-oxide forms of the compounds of paragraph [0098] comprise those compounds wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those IM-oxides wherein one or more of the piperidine-, piperazine or pyridazinyl-nitrogens are N-oxidized.
In another embodiment, the invention comprises compounds of the following structural formula (5):
—C(O)—NH—CH2—NR10 (a-1)
═CH—CH═CH═ (b-1);
In some embodiments of the compound according to paragraph [0115], one or more of the following restrictions apply:
In another embodiment of the compound according to paragraph [0115], one or more of the following restrictions apply:
In another embodiment of the compound according to paragraph [0115], R12 is H.
In another embodiment of the compound according to paragraph [0115]:
In some embodiments of the compound according to paragraph [0115],
In some embodiments of the compound according to paragraph [0115],
or —NHC(O)C1-6alkanediylSH; R12 is hydrogen or nitro; R13 is Cl1-6alkyl, arylC2-6alkenediyl, furanylcarbonyl, naphtalenylcarbonyl, C1-6alkylaminocarbonyl, aminosulfonyl, di(C1-6alkyl)aminosulfonylaminoC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl), C1-12alkylsulfonyl, di(C1-6alkyl)aminosulfonyl, trihaloC1-6alkylsulfonyl, di(aryl)C1-6alkylcarbonyl, thiophenylC1-6alkylcarbonyl, pyridinylcarbonyl or arylC1-6alkylcarbonyl; R14 is hydrogen; when R13 and R14 are present on the same carbon atom R13 & R14 together may form a bivalent radical of formula (a-1) wherein R10 is aryl; or when R13 & R14 are present on adjacent carbon atoms R13 & R14 together may form a bivalent radical of formula (b-1).
In some embodiments of the compound according to paragraph [0115],
Particular embodiments of the compound according to paragraph [0115] include the following
in which the terminal hydroxamic acid moiety (—C(O)NH—OH) is replaced with
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
In the compounds of paragraphs [0115]-[0123], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049], while in other embodiments of the compounds of paragraphs [0115]-[0123], R1, R2, R3, and R4 are all H.
In another embodiment, the invention comprises compounds of the following structural formula (6):
is a radical selected from
In some embodiments of the compound according to paragraph [0125], one or more of the following restrictions apply:
is a radical selected from (a-1), (a-20), (a-25), (a-27), (a-28), (a-29), (a-41) or (a-42);
In other embodiments of the compound according to paragraph [0125], one or more of the following restrictions apply:
is a radical selected from (a-1), (a-20), (a-25), (a-27), (a-28), (a-29), (a-41) or (a-42);
In other embodiments of the compound according to paragraph [0125], one or more of the following restrictions apply:
is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-27), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42) (a-43) or (a-44);
In some embodiments of the compound according to paragraph [0125], one or more of the following restrictions apply:
is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40) (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51);
In some embodiments of the compound according to paragraph [0125]:
is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-27), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36, (a-37), (a-38), (a-39), (a-40), (a-41), (a-42) (a-43) or (a-44); and
In some embodiments of the compound according to paragraph [0125], t is 0, m is 0 and:
is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-4), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51);
In some embodiments of the compound according to paragraph [0125],
is a radical selected from (a-1), (a-20), (a-25), (a-27), (a-28), (a-29), (a-41) or (a-42); each s is independently 0, 1 or 2; and each R6 is independently selected from hydrogen, halo, C1-6alkyl or C1-6alkyloxy.
In some embodiments of the compound according to paragraph [0125],
is a radical selected from (a-1), (a-20), (a-27), (a-28), (a-29), (a-41) or (a-42); each s is independently 0, 1 or 2; and each R6 is independently selected from hydrogen, halo, C1-6alkyl or C1-6alkyloxy.
Particular embodiments of the compound according to paragraph [0125] include the following
in which the terminal hydroxamic acid moiety (—C(O)NH—OH) is replaced with
In the compounds of paragraph [0125]-[0134], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraphs [0125]-[0134], R1, R2, R3, and R4 are all H.
In another embodiment, the invention comprises compounds of the following structural formula (7):
is a radical selected from
Other embodiments of the compound according to paragraph [0136] are those in which one or more of the following apply (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0136]):
is a radical selected from (a-1), (a-2), (a-3), (a-5), (a-6), (a-11), (a-18), (a-20), (a-21), (a-32), (a-33), (a-47) or (a-51);
Other embodiments of the compound according to paragraph [0136] are those in which one or more of the following apply (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0136]):
is a radical selected from (a-6), (a-11), (a-20), (a-47) or (a-51);
Other embodiments of the compound according to paragraph [0136] L is a direct bond.
Other embodiments of the compound according to paragraph [0136] are those in which one or more of the following apply (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0136]:
is a radical selected from (a-1), (a-3), (a-4) (a-5) (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-1), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (4-24); (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (ea-39); (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-8) and (a-51);
Other embodiments of the compound according to paragraph [0136] include those in which the following are true (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0136]):
is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8, (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47); (a-48) and (a-51);
Other embodiments of the compound according to paragraph [0136] are the following (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0136]):
is a radical selected from (a-1), (a-2), (a-3), (a-5), (a-6), (a-11), (a-18), (a-20), (a-21), (a-32), (a-33), (a-47) or (a-51); each s is independently 0, 1, 2, or 4; each R5 and R6 independently selected from hydrogen; halo; trihaloC1-6alkyl; C1-6alkyl; C1-6alkyl substituted with aryl and C3-10cycloalkyl; C1-6alkyloxy, C1-6alkylcarbonyl; benzofuranyl; naphtalenylsulfonyl; pyridinyl substituted with aryloxy phenyl; or phenyl substituted with one substituent independently selected from hydroxyC1-4alkyl or morpholinylC1-4alkyl.
Other embodiments of the compound according to paragraph [0136] are the following (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0136]):
is a radical selected from (a-6), (a-11), (a-20), (a-47) or (a-51); each s is independently 0, 1, or 4; and each R5 and R6 are independently selected from hydrogen; C1-6alkyl; C1-6alkyloxy; naphtalenylsulfonyl; or aryl substituted with hydroxyC1-4alkyl or morpholinylC1-4alkyl.
Particular embodiments of the compound according to paragraph [0136] include the following
in which the terminal hydroxamic acid moiety (—C(O)—NH—OH) is replaced with
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049]:
In the compounds of paragraphs [0136]-[0144], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraphs [0136]-[0144], R1, R2, R3, and R4 are all H.
In another embodiment, the invention comprises compounds of the following structural formula (8):
is a radical selected from
Other embodiments of the compound according to paragraph [0146] are those in which one or more of the following apply (wherein each of R2, R3, R4 and R5 in this paragraph corresponds to R12, R13, R14, and R15, respectively, in paragraph [0146]):
is a radical selected from (a-1), (a-7) or (a-20);
Other embodiments of the compound according to paragraph [0146] are those in which one or more of the following apply (wherein each of R2, R3, R4 and R5 in this paragraph corresponds to R12, R13, R14, and R15, respectively, in paragraph [0146]):
is a radical selected from (a-1) or (a-20);
Other embodiments of the compound according to paragraph [0146] are those in which R12 is H.
Other embodiments of the compound according to paragraph [0146] are those in which one or more of the following apply (wherein each of R2, R3, R4 and R5 in this paragraph corresponds to R12, R13, R14, and R15, respectively, in paragraph [0146]):
is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51);
Other embodiments of the compound according to paragraph [0146] are those in which one or more of the following apply (wherein each of R2, R3, R4 and R5 in this paragraph corresponds to R12, R13, R14, and R15, respectively, in paragraph [0146]):
is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-27), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42) (a-43) or (a-44);
Other embodiments of the compound according to paragraph [0146] include those in which the following are true (wherein each of R2, R3, R4 and R5 in this paragraph corresponds to R12, R13, R14, and R15, respectively, in paragraph [0146]):
is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-27), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42) (a-43) or (a-44);
Other embodiments of the compound according to paragraph [0146] include those in which the following are true (wherein each of R2, R3, R4 and R5 in this paragraph corresponds to R12, R13, R14, and R15, respectively, in paragraph 101461):
is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51);
Other embodiments of the compound according to paragraph [0146] include those in which the following are true (wherein each of R2, R3, R4 and R5 in this paragraph corresponds to R12, R13, R14, and R15, respectively, in paragraph [0146]):
is a radical selected from (a-1), (a-7) or (a-20); each s is independently 0 or 1; each R6 is independently selected from hydrogen; thiophenyl; furanyl; benzofuranyl; phenyl; or phenyl substituted with one substituents independently selected from C1-6alkyl, C1-6alkyloxy, hydroxyC1-4alkyl, C1-4alkylsulfonyl or di(C1-4alkyl)amino and each R7 is independently selected from hydrogen.
Other embodiments of the compound according to paragraph [0146] include those in which the following are true (wherein each of R2, R3, R4 and R5 in this paragraph corresponds to R12, R13, R14, and R15, respectively, in paragraph [0146]):
is a radical selected from (a-1) or (a-20); each s is independently 0 or 1; and each R6 is independently selected from hydrogen; thiophenyl; furanyl; benzofuranyl; phenyl; or phenyl substituted with one substituents independently selected from C1-6alkyl, C1-6alkyloxy, hydroxyC1-4alkyl or di(C1-4alkyl)amino.
Particular embodiments of the compound according to paragraph [0136] include the following
in which the terminal hydroxamic acid moiety (—C(O)NH—OH) is replaced with
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
In the compounds of paragraph [0146]-[0156], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraphs [0146]-[0156], R1, R2, R3, and R4 are all H.
In another embodiment, the invention comprises compounds of the following structural formula (9):
, then -L- is —NH— or the bivalent radical —C1-6alkanediylNH—;
is a radical selected from
Other embodiments of the compound according to paragraph [0158] are those in which one or more of the following apply (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0158]):
then -L- is the bivalent radical —C1-6alkanediylNH—;
is a radical selected from (a-1) or (a-21);
Other embodiments of the compound according to paragraph [0158] are those in which one or more of the following apply (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0158]):
then -L- is the bivalent radical —C1-6alkanediyl NH—;
is the radical (a-1);
Other embodiments of the compound according to paragraph [0158] are those in which one or more of the following apply (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0158]):
is a radical selected form (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51);
Other embodiments of the compound according to paragraph [0158] include the following (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0158]):
is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51);
Other embodiments of the compound according to paragraph [0158] include the following (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R3, and R14, respectively, in paragraph [0158]):
to then -L- is the bivalent radical —C1-6alkanediylNH—; R4 is hydrogen, C1-6alkyl or aryl;
is a radical selected from (a-1) or (a-21); each s is independently 0, 1 or 2; and each R5 is independently selected from hydrogen; halo; trihaloC1-6alkyl; trihaloC1-6alkyloxy; C1-6alkyl; C1-6alkyloxy; C1-6alkylcarbonyl; aryloxy; cyano or phenyl.
Other embodiments of the compound according to paragraph [0158] include the following (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0158]):
then
is the radical (a-1); each s is independently 0 or 1; and each R1 is independently selected from hydrogen or phenyl.
Particular embodiments of the compound according to paragraph [0158] include the following
in which the terminal hydroxamic acid moiety (C(O)—NH—OH) is replaced with
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
In the compounds of paragraphs [0158]-[0165], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraphs [0158]-[0165], R1, R2, R3, and R4 are all H.
In another embodiment, the invention comprises compounds of the following structural formula (10):
is a radical selected from
Other embodiments of the compound according to paragraph [0167] are those in which one or more of the following apply (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0167]):
is a radical selected from (a˜1), (a-20) or (a-43);
Other embodiments of the compound according to paragraph [0167] are those in which one or more of the following apply (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0167]):
Other embodiments of the compound according to paragraph [0167] are those in which one or more of the following apply (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0167]):
is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-4), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-1), (a-42), (a-44), (a-45), (a-46), (a 47), (a-48) or (a-51);
Other embodiments of the compound according to paragraph [0167] include the following (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0167]):
is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51);
Other embodiments of the compound according to paragraph [0167] include the following (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0167]):
is a radical selected from (a-1), (a-20) or (a-43); s is 0 or 1; and each R5 is independently selected from hydrogen or phenyl
Other embodiments of the compound according to paragraph [0167] include the following (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0167]):
is a radical selected from (a-1) or (a-20); each s is independently 0 or 1; and each R5 is independently selected from hydrogen or aryl,
Particular embodiments of the compound according to paragraph [0167] include the following
in which the terminal hydroxamic acid moiety (—C(O)—NH—OH) is replaced with
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
In the compounds of paragraphs [0167]-[0174], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraphs [0167]-[0174], R1, R2, R3, and R4 are all H.
In another embodiment, the invention comprises compounds of the following structural formula (11):
is a radical selected from
Other embodiments of the compound according to paragraph [0176] are those in which one or more of the following apply (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0176]):
is a radical selected from (a-1) or (a-20);
Other embodiments of the compound according to paragraph [0176] are those in which one or more of the following apply (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph 101761):
is a radical selected from (a-1) or (a-20);
Other embodiments of the compound according to paragraph [0176] are those in which one or more of the following apply (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0176]):
is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-480), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51);
Other embodiments of the compound according to paragraph [0176] are those in which one or more of the following apply (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0176]):
is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-27), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42) (a-43) or (a-44);
Other embodiments of the compound according to paragraph [0176] include the following (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R3, and R14, respectively, in paragraph [0176]):
is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a 6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-27), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-3), (a-39), (a-40), (a-41), (a-42) (a-43) or (a-44);
Other embodiments of the compound according to paragraph [0176] include the following (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0176]):
is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51);
Other embodiments of the compound according to paragraph [0176] include the following (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and Ru respectively, in paragraph [0176]):
is a radical selected from (a-1) or (a-20); each s is independently 0 or 1; and each R5 is independently selected from hydrogen or phenyl.
Other embodiments of the compound according to paragraph [0176] include the following (wherein each of R2, R3, and R4 in this paragraph corresponds to R12, R13, and R14, respectively, in paragraph [0176]):
is a radical selected from (a-1) or (a-20); each s is independently O or 1; and each R5 is independently selected from hydrogen or phenyl
Particular embodiments of the compound according to paragraph [0176] include the following
in which the terminal hydroxamic acid moiety (—C(O)NH—OH) is replaced with
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
in the compounds of paragraphs [0176]-[0185], R1, R2, R3, and R41 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraphs [0176]-[0185], R1, R2, R3, and R4 are all H.
In another embodiment, the invention comprises compounds of the following structural formula (12):
In some embodiments of the compound according to paragraph [0187],
Ring A is pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, quinolin-8-yl, pyrimidin-6-yl, pyrimidin-5-yl, pyrimidin-4-yl, morpholin-4-yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl, piperazin-4-yl, pyridazin-5-yl, pyrazin-6-yl, thiazol-2-yl, thien-2-yl, thieno[3,2d]pyrimidinyl, thieno[3,2b]pyrimidinyl, thieno[3,2b]pyridinyl, purin-6-yl, 1′,2′,3′,6′-tetrahydropyridin-4-yl
Other embodiments of the compound according to paragraph [0187] include the following (wherein each of R2 in this paragraph corresponds to R12 in paragraph [0187]):
Other embodiments of the compound according to paragraph [0187] include the following (wherein each of R2 in this paragraph corresponds to R12 in paragraph [0187]):
Other embodiments of the compound according to paragraph [0187] include the following (wherein each of R2 in this paragraph corresponds to R12 in paragraph [0187]):
Other embodiments of the compound according to paragraph [0187] include the following (wherein each of R2 in this paragraph corresponds to R12 in paragraph [0187]):
The following are particular embodiments of the compounds according to paragraph [0187]:
wherein R11 is selected from:
In the compounds of paragraph [0187]-[0193], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraph [0187]-[0193], R1, R2, R3, and R4 are all H.
In another embodiment, the invention comprises the compounds of WO 03/024448 in which the terminal moieties —C(O)—NH-Ay1, —C(O)NH-Ay2, —C(O)NH—Ara—NH2, and:
are replaced with the moiety:
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
In another embodiment, the invention comprises compounds of the following structural formula (13):
In the compounds of paragraph [0196], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraph [0196], R1, R2, R3, and R4 are all H. Particular embodiments of the compounds of paragraph [0196] are those obtained by substituting the terminal moiety:
of the compounds of JP 2003137866 with the moiety:
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
In another embodiment, the invention comprises compounds of the following structural formula (14):
In the compounds of paragraph [0198], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraph [0198], R1, R2, R3, and R4 are all H. Particular embodiments of the compounds of paragraph [0198] are those obtained by substituting the terminal moiety:
of compounds 1-50 of Tables 24 of JP 11-269146 (1999) with the moiety:
wherein φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
In another embodiment, the invention comprises compounds of the following structural formula (15):
In the compounds of paragraph [0200], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraph [0200], R1, R2, R3, and R4 are all H. Particular embodiments of the compounds of paragraph [0200] are those obtained by substituting the terminal moiety:
of the compounds 1-67 of JP 11-302173 (1999) with the moiety:
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
In another embodiment, the invention comprises compounds of the following structural formula (16):
In the compounds of paragraph [0202], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraph [0202], R1, R2, R3, and R4 are all H. Particular embodiments of the compounds of paragraph [0202] are those obtained by substituting the terminal moieties:
of the compounds of JP 2001 131 130 with the moiety:
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
In another embodiment, the invention comprises compounds of the following structural formula (17):
In the compounds of paragraph [0204], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraph [0204], R1, R2, R3, and R4 are all H. Particular embodiments of the compounds of paragraph [0204] are those obtained by substituting the terminal moiety:
of the compounds of JP 10152462, JP 2002332267, and JP 11-302173 with the moiety:
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
In another embodiment, the invention comprises compounds of the following structural formula (18):
In the compounds of paragraph [0206], R1, R2, R3, and R4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraph [0206], R1, R2, R3, and R4 are all H. Particular embodiments of the compounds of paragraph [0206] are those obtained by substituting the terminal moiety:
of the compounds of Table 1 of U.S. Pat. No. 6,174,905 and the terminal moiety:
of the compounds of Tables 2-4 of U.S. Pat. No. 6,174,905 with the moiety:
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
In another embodiment according to paragraph [0046], the invention comprises compounds of WO01/70675 wherein the terminal moiety —C(O)—NHOH, —C(O)—CH2—SC(O)CH3, —C(O)—CH2—SH, —C(O)—CH2—SCH3, —C(O)—CH2—SCH2-phenyl, —C(O)—CH2—S-phenyl, —C(O)CH2—SC(O)-phenyl and
of the compounds of Tables 2 and 3 are replaced by the moiety
wherein Φ, R1, R2, R3, and R4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
In the second aspect, the invention provides a composition comprising a compound according to any one of paragraphs [0046]-[0088], [0098]-[0110], and [0115]-[0207], or as depicted in any of the tables herein together with a pharmaceutically acceptable excipient.
The third aspect of the invention provides a method of inhibiting histone deacetylase, the method comprising contacting the histone deacetylase with a compound according to any one of paragraphs [0046]-[0088], [0098]-[0110], and [0115]-[0207] or as depicted in any of the tables herein, or with a composition according to paragraph [0209]. Inhibition of the histone deacetylase can be in a cell or a multicellular organism. If in a multicellular organism, the method according to this aspect of the invention comprises administering to the organism a compound according any one of paragraphs [0046]-[0088], [0098]-[0110], and [0115]-[0207] or as depicted in any of the tables herein, or a composition according to paragraph [0209]. Preferably the organism is a mammal, more preferably a human.
The data presented herein demonstrate the anti-tumor effects of the HDAC inhibitors of the invention. Recent publications reporting on HDAC inhibitor human clinical trials suggest that these inhibitors can effectively treat human solid tumors or cancer (lung, colon, prostrate, stomach, breast, leukemia), including complete remissions of transformed lymphoma (SAHA, ASCO Abstract No. 2321, 2003) and peripheral T-cell lymphoma (depsipeptide/FR901 228 ASCO Abstract No. 88, 2002). Together with the data presented herein demonstrating surprising efficacy at inhibiting HDAC-1 and tumor growth inhibition in vivo, these data lead on to reasonably expect that the HDAC-I inhibitors of the invention are useful not only for inhibition of HDAC, but as therapeutic agents for the treatment of cancer as well.
Preferred compounds according to the invention include those in the Table 1, which were prepared essentially using the methods described herein and illustrated below in the schemes. All of the compounds in this application were named using Chemdraw Ultra version 6.0.2, which is available through Cambridgesoft. co, 100 Cambridge Park Drive, Cambridge, Mass. 02140, Namepro version 5.09, which is available from ACD labs, 90 Adelaide Street West, Toronto, Ontario, M5H, 3V9, Canada, or were derived therefrom.
We have unexpectedly found that when HDAC inhibitors including within them the benzamide moiety:
are substituted on the aniline ring at the 5-position (para to the —NH2 group) with a substantially planar ring or ring system (aryl or heteroaryl), the compound's HDAC inhibitory activity (as measured by the human HDAC-I inhibition assay described below) increases by a factor of from 3 to 10 or more compared to similar compounds in which the aniline ring is unsubstituted or substituted with a smaller, non-planar moiety, or if the planar moiety is at other than the 5-position of the aninlinyl ring. Additionally, we have found that the planar moiety itself can be substituted. Accordingly, R1 in the compounds of the invention is a mono-, bi-, or tri-cyclic aryl or heteroaryl moiety, which moiety is optionally substituted. In some preferred embodiments R1 is not further substituted. In other preferred embodiments, R1 is substituted with a moiety of from 1-5 atoms, e.g., methyl, hydroxymethyl, halomethyl, halo, hydroxy, amino, etc. In other embodiments, R1 is substituted with a larger moiety, e.g., from 6-25 atoms.
This is surprising in view of T. Suzuki et. al., J. Med. Chem., 1999, 42, 3001-3003, which teaches that the substitution pattern on the aniline ring of the benzamide fragment of known HDACs (wherein the amino group is ortho to the amide nitrogen) is highly sensitive to substitutions. Substituents such as Me and OMe ortho- or meta-relative to the amino group are detrimental to HDAC inhibitory activity, causing complete loss of HDAC potency. The same type of substituents in the para-position relative to the amino group did not cause significant drop of potency which allowed assuming that only small substituents such as Me, MeO, F, Cl might be tolerated.
Furthermore, we have surprisingly found that the HDAC inhibitory activity of such compounds (i.e., compounds comprising the chemical moiety of paragraph [0046] and having a substantially planar ring or ring system at the 5-position of the aniline ring) is substantially independent of the identity of the chemical moiety bound to the carbonyl of the amide in paragraph [0046]. Accordingly, in compounds of formula 1 Y is any chemical moiety (preferably physiologically non-reactive) consisting of 1 to 50 atoms.
The following are representative examples of the compounds according to the embodiments described above.
1H NMR: (DMSO) δ (ppm): 9.52 (s, 1H);7.89 (d, J = 8.2, 2H); 7.46 (d, J = 8.2, 2H);7.25 (d, J = 1.9, 1H); 7.04 (dd, J = 1.9, 8.2,1H); 6.70 (d, J = 8.2, 1H); 6.64 (d, J = 8.6,1H); 6.31 (d, J = 2.5, 1H); 5.98 (m, 2H); 5.35(bs, 2H); 4.29 (d, J = 6.1, 2H); 4.26 (s, 2H);3.65 (s, 3H); 3.58 (s, 3H); 3.29 (s, 3H). MS:calc: 445.5; found: 446.4 (M + H)
1H NMR: (DMSO) δ (ppm): 9.54 (s, 1H),7.96 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 5.1Hz, 1H), 7.28 (d, J = 1.8 Hz, 1H), 7.09-7.02(m, 4H), 6.81 (d, J = 8.2 Hz, 1H), 5.05 (s,2H), 4.82 (s, 2H), 3.83 (s, 3H), 0.87 (s, 9H),0.06 (s, 6H). MS: (calc.) 468.2; (obt.) 491.2(M + Na)+.
1H NMR: (DMSO) δ (ppm): 9.76 (s, 1H),7.99 (d, J = 2.9 Hz, 1H), 7.82 (d, J = 4.9 Hz,1H), 7.40 (s, 1H), 7.34 (d, J = 5.1 hz, 1H),7.29 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 3.9 Hz,1H), 7.20 (t, J = 3.9 Hz, 1H), 7.03 (t, J = 3.5Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 5.17 (s,2H). MS: 300.04 (calc) 301.1 (obs)
1H NMR: (DMSO) δ (ppm): 9.59 (s, 1H),7.97 (d, J = 8.8, Hz, 2H), 7.59 (ddd, J =12.7, 7.8, 2.3, 1H), 7.49 (d, J = 2.3 Hz,1H), 745-7.36 (m, 2H), 6.32 (dd, J = 8.2,2.2 Hz, 1H), 7.04 (d, J = 8.8, Hz, 2H), 6.84(d, 8.2, Hz, 1H), 5.15 (s, 1H), 3.83 (s,3H). MS: (calc.) 354.1; (obt.) 355.2 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),7.97 (d, J = 9.0, Hz, 2H), 7.38-7.36 (m,3H), 7.21, (dd, J = 8.2, 2.2 Hz, 1H), 7.04 (d,J = 8.8 Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H),6.75 (d, J = 9.0 Hz, 2H), 4.89 (sb, 2H),3.83 (s, 3H), 2.90 (s, 6H). MS: (calc.) 361.1;(obt.) 362.3 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.59 (s, 1H),7.97 (d, J = 8.8, Hz, 2H), 7.47-7.22 (m,10H), 7.04 (d, J = 9.0 Hz, 2H), 6.82 (d, J =8.4 Hz, 1H), 5.18 (s, 2H), 5.06 (sb, 2H),3.83 (s, 3H). MS: (calc.) 442.2; (obt.) 443.4(MH)+.
1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),7.98 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 2.2Hz, 1H), 7.32-7.26 (m, 2H), 7.12-7.10 (m,1H), 7.05-7.02 (m, 3H), 6.84 (d, J = 8.2 Hz,1H), 6.80 (ddd, J = 8.2, 2.5, 0.8 Hz, 1H),5.07 (sb, 2H), 3.84 (s, 3H), 3.79 (s, 3H).MS: (calc.) 348.2; (obt.) 349.2 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.67 (s, 1H),7.94 (d, J = 1.6 Hz, 1H), 7.83 (dd, J = 8.6,1.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.35(d, J = 2.2 Hz, 1H), 7.26 (dd, J = 5.0, 1.2Hz, 1H), 7.22 (dd, J = 8.2, 2.3 Hz, 1H), 7.15(dd, J = 3.6, 1.2 Hz, 1H), 6.96 (dd, J = 5.0,3.5 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.14(s, 2H). MS: 374.05 (calc), 375.0 (obs).
1H NMR: (DMSO) δ (ppm): 10.03 (s, 1H),8.74 (s, 1H), 8.15 (d, J = 9.4 Hz, 1H), 8.02(d, J = 9.4 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H),7.33 (d, J = 5.1 Hz, 1H), 7.30 (dd, J = 8.4,2.0 Hz, 1H), 7.23 (d, J = 3.5 Hz, 1H), 7.03 (t,J = 4.9 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H),5.32 (s, 2H). MS: 336.07 (calc), 337.0(obs).
1H NMR: (DMSO) δ (ppm): 10.25 (s, 1H),9.52 (s, 1H), 8.27 to 8.21 (m, 2H), 8.20 to7.99 (m, 2H), 7.66 (d, J = 2.2 Hz, 1H), 7.35(dd, J = 5.1, 0.98 Hz, 1H), 7.31 (dd, J = 8.2,2.2 Hz, 1H), 7.25 (dd, J = 3.5, 0.98 Hz, 1H),7.04 (dd, J = 5.1, 3.5 Hz, 1H), 6.83 (d, J =8.4 Hz, 1H), 5.28 (s, 2H). MS: 346.09(calc), 347.1 (obs).
1H NMR: (DMSO) δ (ppm): 9.57 (s, 1H),7.96 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 5.1Hz, 1H), 7.23 (d, J = 1.8 Hz, 1H), 7.09-7.02(m, 4H), 6.81 (d, J = 8.0 Hz, 1H), 5.51 (t,J = 5.4 Hz, 1H), 5.01 (s, 2H), 4.64 (d, J = 5.3Hz, 2H), 3.83 (s, 3H). MS: (calc.) 354.1;(obt.) 354.1 (M + Na)+.
1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),7.98 (d, J = 8.8, Hz, 2H), 7.51-7.47 (m,3H), 7.32-7.28 (m, 3H), 7.04 (d, J = 8.8 Hz,2H), 6.84 (d, J = 8.2 Hz, 1H), 5.15 (t, J =5.8 Hz, 1H), 5.04 (sb, 2H), 4.49 (d, J = 5.7Hz, 2H), 3.84 (s, 3H). MS: (calc.) 348.1;(obt.) 349.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),7.98 (d, J = 9.0 Hz, 2H), 7.50-7.49 (m, 2H),7.40 (d, J = 8.0 Hz, 1H), 7.34-7.29 (m, 2H),7.17 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 9.0Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 5.19 (t,J = 5.8 Hz, 1H), 5.06 (sb, 2H), 5.52 (d, J =2.8 Hz, 2H), 3.84 (s, 3H). MS: (calc.)348.2; (obt.) 349.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.89 (s, 1H),9.14 (d, J = 1.6 Hz, 1H), 8.73 (dd, J = 4.9,1.8 Hz, 1H), 8.33 (dt, J = 8.0, 1.9 Hz, 1H),6.54 (dd, J = 7.4, 5.2 Hz, 1H), 7.51-7.49(m, 3H), 7.34-7.30 (m, 3H), 6.84 (d, J = 8.4Hz, 1H), 5.18 (sb, 3H), 4.49 (d, J = 5.5 Hz,2H). MS: (calc.) 319.1; (obt.) 320.2 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.60 (s, 1H),7.97 (d, J = 9.0, Hz, 2H), 7.40 (d, J = 2.2Hz, 1H), 7.23 (dd, J = 8.2, 2.2 Hz, 1H),7.06-7.02 (m, 3H), 6.85 (d, J = 3.5 Hz, 1H),6.78 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 5.10(sb, 2H), 4.57 (sb, 2H), 3.83 (s, 3H). MS:(calc.) 354.1; (obt.) 355.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.66 (s, 1H),7.93 (d, J = 8.0 Hz, 2H), 7.52-7.46 (m, 5H),7.31-7.29 (m, 3H), 6.84 (d, J = 7.6 Hz, 1H),6.64 (d, J = 8.6 Hz, 1H), 6.32 (s, 1H), 6.00-5.98 (m, 2H), 5.06 (s, 2H), 4.70 (s, 2H),4.30 (d, J = 5.9 Hz, 2H), 3.66 (s, 3H), 3.59(s, 3H), 0.91 (s, 9H), 0.10 (s, 6H). MS:(calc.) 597.2 (obt.) 598.5 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.67 (s, 1H),7.93 (d, J = 7.8 Hz, 2H), 7.50-7.46 (m, 5H),7.31-7.29 (m, 3H), 6.84 (d, J = 8.0 Hz, 1H),6.64 (d, J = 8.4 Hz, 1H), 6.32 (d, J = 2.0Hz, 1H), 6.00-5.98 (m, 2H), 5.15 (t, J = 5.5Hz, 1H), 5.06 (s, 2H), 4.49 (d, J = 5.7 Hz,2H), 4.31 (d, J = 5.9 Hz, 2H), 3.66 (s, 3H),3.59 (s, 3H). MS: (calc.) 483.2; (obt.) 484.4(MH)+.
1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),7.98 (d, J = 8.8, Hz, 2H), 7.95 (d, J = 8.4Hz, 2H), 7.71, (d, J = 8.4 Hz, 2H), 7.60 (d,J = 2.2 Hz, 1H), 7.43 (dd, J = 8.4, 2.2 Hz,1H), 7.04 (d, J = 8.8 Hz, 2H), 6.86 (d, J =8.4 Hz, 1H), 5.27 (sb, 2H), 3.85 (s, 3H),3.84 (s, 3H). MS: (calc.) 376.1; (obt.) 377.1(MH)+.
1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),7.98 (d, J = 8.6, Hz, 2H), 7.93 (d, J = 8.2Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.58 (d,J = 2.0 Hz, 1H), 7.40 (dd, J = 8.2, 2.0 Hz,1H), 7.04 (d, J = 8.8 Hz, 2H), 6.86 (d, J =8.4 Hz, 1H), 5.23 (sb, 2H), 3.84 (s, 3H).MS: (calc.) 362.1; (obt.) 363.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.51 (s, 1H),7.96 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 2.0Hz, 1H), 7.56 (dd, J = 8.4, 2.0 Hz, 1H), 7.03(d, J = 9.0 Hz, 2H), 6.75 (d, J = 8.4 Hz, 1H),5.80 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H). MS:(calc.) 300.1; (obt.) 301.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.55 (s, 1H),7.95 (d, J = 8.8 Hz, 2H), 7.63-7.47 (m, 7H),7.02 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.4Hz, 1H), 5.98 (s, 2H), 3.83 (s, 3H). MS:(calc.) 346.1; (obt.) 347.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.52 (s, 1H),7.96 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 2.0Hz, 1H), 7.54 (dd, J = 8.4, 2.0 Hz, 1H), 7.02(d, J = 9.0 Hz, 2H), 6.74 (d, J = 8.4 Hz, 1H),5.69 (s, 2H), 3.83 (s, 3H). MS: (calc.)361.1; (obt.) 362.3 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.57 (s, 1H),7.96 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 2.2Hz, 1H), 7.59 (sb, 1H), 7.52 (dd, J = 8.2,2.0 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.90(sb, 1H), 6.72 (d, J = 8.4 Hz, 1H), 5.41 (s,2H), 3.83 (s, 3H). MS: (calc.) 285.1; (obt.)286.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.83 (s, 1H),9.62 (s, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.82(d, J = 2.0 Hz, 1H), 7.73 (dd, J = 8.8, 1.2Hz, 2H), 7.67 (dd, J = 8.4, 2.2 Hz, 1H),7.31-7.27 (m, 2H), 7.05-7.01 (m, 3H), 6.80(d, J = 8.4 Hz, 1H), 3.84 (s, 3H). MS: (calc.)361.1; (obt.) 362.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.87 (s, 1H),9.62 (s, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.82(d, J = 2.2 Hz, 1H), 7.75 (dt, J = 9.0, 2.7Hz, 2H), 7.67 (dd, J = 8.4, 2.2 Hz, 1H),7.38-7.32 (m, 2H), 7.10-6.94 (m, 7H), 6.80(d, J = 8.4 Hz, 1H), 5.56 (sb, 2H), 3.84 (s,3H). MS: (calc.) 453.2; (obt.) 454.2 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.52 (s, 1H),7.93 (d, J = 9.0 Hz, 2H), 7.34 (d, J = 2.3 Hz,1H), 7.08 (dd, J = 8.6, 2.3 Hz, 1H), 7.02 (d,J = 9.0 Hz, 2H), 6.71 (d, J = 8.6 Hz, 1H), 5.10(s, 2H), 3.82 (s, 3H). MS: 321.17 (calc)321.0/323.0 (found).
1H NMR: (DMSO) δ (ppm): 9.59 (s, 1H),7.97 (d, J = 8.8 Hz, 2H), 7.71 (dd, J = 7.2,2.3 Hz, 1H), 7.56-7.52 (m, 1H), 7.51 (d, J =2.2 Hz, 1H), 7.40 (t, J = 9.0 1H), 7.33 (dd,J = 8.2, 2.3, 1H), 7.04 (d, J = 9.0 Hz, 2H),6.84 (d, J = 8.4 Hz, 1H), 5.16 (sb, 2H), 3.84(s, 3H). MS: (calc.) 370.1; (obt.) 371.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 400 MHz,(DMSO) d (ppm): 9.59 (s, 1H), 7.97 (d, J =8.4 Hz, 2H), 7.58-7.54 (m, 2H), 7.46 (bs,1H), 7.27 (d, J = 8.0 Hz, 1H), 7.19 (t, J =8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.84(d, J = 8.4 Hz, 1H), 5.07 (sb, 2H), 3.83 (s,3H). MS: (calc.) 336.1; (obt.) 337.2 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.60 (s, 1H),7.97 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.8Hz, 2H), 7.50 (s, 1H), 7.36-7.31 (m, 3H),7.04 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.4Hz, 1H), 5.15 (sb, 2H), 3.83 (s, 3H). MS:(calc.) 402.1; (obt.) 403.4 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),7.98 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.2Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.58 (s,1H), 7.40 (d, J = 8.6 Hz, 1H), 7.04 (d, J =8.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 5.25(sb, 2H), 3.84 (s, 3H). MS: (calc.) 386.1;(obt.) 387.4 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.47 (s, 1H),7.95 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 1.4 Hz,1H), 7.24 (dd, J = 7.8, 1.4 Hz, 1H), 7.01 (d,J = 8.8 Hz, 2H), 6.70 (d, J = 7.8 Hz, 1H), 5.31(s, 2H), 3.82 (s, 3H), 1.25 (s, 12H). MS:368.24 (calc) 369.1 (found)
1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),7.96 (dd, J = 12.8, 8.8 Hz, 4H), 7.70 (d,J = 8.8 Hz, 2H), 7.60 (d, J = 2.1 Hz, 1H), 7.42(dd, J = 8.4, 2.3 Hz, 1H), 7.04 (d, J = 8.8 Hz,2H), 6.86 (d, J = 8.2 Hz, 1H), 5.26 (s, 2H),3.84 (s, 3H), 2.58 (s, 3H). MS: 360.41 (calc)361.1 (MH+) (found)
1H NMR: (DMSO) δ (ppm): 9.64 (s, 1H),8.01 (d, J = 8.8 Hz, 2H), 7.57 (dd, J = 8.4, 1.2Hz, 2H), 7.51 (d, J = 2.0 Hz, 1H), 7.40 (t,J = 7.8 Hz, 2H), 7.34 (dd, J = 8.2, 2.0 Hz, 1H),7.25 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 8.8 Hz,2H), 6.88 (d, J = 8.2 Hz, 1H), 5.10 (s, 2H),3.87 (s, 3H). MS: 318.37 (calc) 319.1 (found)
1H NMR: (DMSO) δ (ppm): 9.59 (s, 1H),7.98 (d, J = 9.0 Hz, 2H), 7.81-7.73 (m, 4H),7.61 (d, J = 2.2 Hz, 1H), 7.43 (dd, J = 8.4, 2.3Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.86 (d,J = 8.4 Hz, 1H), 5.32 (s, 2H), 3.84 (s, 3H).MS: 343.38 (calc) 344.1 (MH+) (found)
1H NMR: (DMSO) δ (ppm): 9.59 (s, 1H),7.97 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 4.1 Hz,1H), 7.57 (d, J = 2.2 Hz, 1H), 7.39 (dd,J = 8.3, 2.3 Hz, 1H), 7.37 (d, J = 3.9 Hz, 1H),7.04 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.4 Hz,1H), 5.42 (s, 2H), 3.84 (s, 3H), 2.50 (s, 3H).MS: 366.43 (calc) 367.1 (MH+) (found)
1H NMR: (DMSO) δ (ppm): 9.60 (s, 1H),7.97 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.4 Hz,3H), 7.27 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.4Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 6.83 (d,J = 8.4 Hz, 1H), 5.01 (d, J = 10.4 Hz, 2H),4.64 (t, J = 5.3 Hz, 1H), 3.84 (s, 3H), 3.63-3.58 (m, 2H), 2.72 (t, J = 7.0 Hz, 2H). MS:362.43 (calc) 363.1 (MH+) (found)
1H NMR: (DMSO) δ (ppm): 9.62 (s, 1H),8.77 (s, 1H), 8.42 (d, J = 4.7 Hz, 1H), 7.98(d, J = 7.0 Hz, 2H), 7.93 (d, J = 7.9 Hz, 1H),7.53 (s, 1H), 7.40-7.36 (m, 2H), 7.04 (d,J = 8.8 Hz, 2H), 6.87 (d, J = 8.2 Hz, 2H), 5.16(d, J = 9.7 Hz, 2H), 3.84 (s, 3H). MS:319.36 (calc) 320.1 (MH+) (found)
1H NMR: (DMSO) δ (ppm): (DMSO-d6)d(ppm): 9.61 (s, 1H), 7.98 (d, J = 9.0 Hz, 2H),7.89 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 8.8 Hz,2H), 7.62-7.61 (m, 1H), 7.43 (dd, J = 8.4, 2.3Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.88 (d,J = 8.4 Hz, 1H), 5.30 (s, 2H), 3.84 (s, 3H),3.22 (s, 3H). MS: 396.46 (calc) 397.2(MH+) (found)
1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),7.98 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 6.5 Hz,3H), 7.29 (dd, J = 8.4, 2.2 Hz, 1H), 7.25 (d,J = 8.2 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.84(d, J = 8.4 Hz, 1H), 5.05 (s, 2H), 3.84 (s, 3H),3.56 (s, 3H). MS: 376.41 (calc) 377.2(MH+) (found)
1H NMR: (DMSO) δ (ppm): 9.92 (s, 1H),9.60 (s, 1H), 7.97 (d, J = 8.8 Hz, 2H), 7.57(d, J = 8.8 Hz, 2H), 7.48-7.44 (m, 3H), 7.27(d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H),6.83 (d, J = 8.2 Hz, 1H), 5.00 (d, J = 10.2 Hz,2H), 3.84 (s, 3H), 2.04 (s, 3H). MS:375.43 (calc) 376.3 (MH+) (found)
1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),8.49 (d, J = 5.9 Hz, 2H), 7.98 (d, J = 8.8 Hz,2H), 7.65 (d, J = 2.2 Hz, 1H), 7.57 (dd,J = 4.5, 1.6 Hz, 2H), 7.49 (dd, J = 8.4, 2.2 Hz,1H), 7.04 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 8.4Hz, 1H), 5.34 (d, J = 8.6 Hz, 2H), 3.84 (s,3H). MS: 319.36 (calc) 320.2 (MH+) (found)
1H NMR: (DMSO) δ (ppm): 9.59 (s, 1H),9.32 (s, 1H), 7.97 (d, J = 9.0 Hz, 2H), 7.37(d, J = 2.2 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H),7.19 (dd, J = 8.2, 2.2 Hz, 1H), 7.03 (d, J = 9.0Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 6.76 (d,J = 8.6 Hz, 2H), 4.92 (s, 2H), 3.83 (s, 3H).MS: 334.37 (calc) 335.1 (MH+) (found)
1H NMR: (DMSO) δ (ppm): 9.60 (s, 1H),7.97 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz,2H), 7.41 (d, J = 2.3 Hz, 1H), 7.23 (dd,J = 8.2, 2.1 Hz, 1H), 7.03 (d, J = 9.1 Hz, 2H),6.94 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.5 Hz,1H), 4.97 (s, 2H), 3.83 (s, 3H), 3.76 (s, 3H).MS: 348.40 (calc) 349.2 (MH+) (found)
1H NMR: (DMSO) δ (ppm): 9.63 (s, 1H),8.02-7.97 (m, 4H), 7.60-7.57 (m, 2H), 7.40(dd, J = 8.2, 2.1 Hz, 1H), 7.04 (d, J = 8.8 Hz,2H), 6.87 (d, J = 8.5 Hz, 1H), 5.11 (s, 2H),3.84 (s, 3H), 2.80 (s, 3H). MS: 389.47(calc) 390.2 (MH+) (found)
1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),7.98 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 2.0 Hz,1H), 7.38-7.34 (m, 2H), 7.30-7.25 (m, 2H),7.07 (d, J = 7.4 Hz, 2H), 7.04 (d, J = 9.0 Hz,1H), 6.84 (d, J = 8.2 Hz, 1H), 5.04 (s, 2H),4.64 (t, J = 5.3 Hz, 1H), 3.84 (s, 3H), 3.63(quad, J = 7.0 Hz, 2H), 2.76 (t, J = 7.0 Hz,2H). MS: 362.43 (calc) 363.3 (MH+) (found)
1H NMR (DMSO) δ (ppm): 9.64 (s, 1H),9.02 (s, 1H), 9.00 (s, 2H), 7.98 (d, J = 8.6Hz, 2H), 7.61 (d, J = 1.6 Hz, 1H), 7.46 (dd,J = 8.4, 1.8 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H),6.90 (d, J = 8.2 Hz, 1H), 5.30 (s, 2H), 3.84(s, 3H). MS: 320.35 (calc) 321.2 (MH+) (found)
1H NMR (DMSO) δ (ppm): 9.58 (s, 1H),7.97 (d, J = 8.4 Hz, 2H), 7.61 (s, 2H), 7.51(d, J = 1.2 Hz, 1H), 7.43 (dd, J = 3.9, 1.0 Hz,1H), 7.32 (dd, J = 8.4, 1.4 Hz, 1H), 7.23 (d,J = 3.9 Hz, 1H), 7.04 (d, J = 8.2 Hz, 2H), 6.81(d, J = 8.2 Hz, 1H), 5.35 (s, 2H), 3.84 (s,3H). MS: 403.47 (calc) 404.2 (MH+) (found)
1H NMR (DMSO) δ (ppm): 9.60 (s, 1H),8.24 (s, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.31(s, 1H), 7.13 (d, J = 9.4 Hz, 1H), 7.03 (d,J = 8.2 Hz, 2H), 6.81 (d, J = 7.9 Hz, 1H), 5.06(s, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.83 (s,3H). MS: 380.40 (calc) 381.4 (MH+) (found)
1H NMR (DMSO) δ (ppm): 9.64 (s, 1H),8.01 (d, J = 9.0 Hz, 2H), 7.82 (d, J = 8.6 Hz,2H), 7.76 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 2.2Hz, 1H), 7.43 (dd, J = 8.6, 6.3 Hz, 1H), 7.33(s, 2H), 7.07 (d, J = 9.0 Hz, 2H), 6.89 (d,J = 8.2 Hz, 1H), 5.27 (s, 2H), 3.86 (s,3H). MS: 397.45 (calc) 398.4 (found)
1H NMR (DMSO) δ (ppm): 9.58 (s, 1H),7.97 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.49(d, J = 2.3 Hz, 1H), 7.44 (d, J = 3.9 Hz, 1H),7.32 (dd, J = 8.2, 2.2 Hz, 1H), 7.22 (d, J = 3.9Hz, 1H), 7.03 (d, J = 9.0 Hz, 2H), 6.80 (d,J = 8.2 Hz, 1H), 5.36 (s, 2H), 3.83 (s, 3H),1.99 (s, 2H), 1.17 (s, 6H). MS: 459.59(calc) 460.4 (found)
1H NMR (DMSO) δ (ppm): 9.62 (s, 1H),7.99 (s, 1H), 7.98 (d, J = 8.8 Hz, 2H), 7.77(d, J = 8.6 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H),7.55 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 2.5 Hz,1H), 7.36 (dd, J = 8.2, 2.0 Hz, 1H), 7.35 (s,2H), 7.03 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.4Hz, 1H), 5.20 (s, 2H), 3.83 (s, 3H). MS:397.45 (calc) 398.3 (found)
1H NMR (Acetone-d6) d(ppm): 7.89 (d,J = 8.8 Hz, 2H), 7.77 (d, J = 4.1 Hz, 1H), 7.61(d, J = 2.2 Hz, 1H), 7.31 (dd, J = 8.4, 2.3 Hz,1H), 7.26 (d, J = 4.1 Hz, 1H), 6.91 (d, J = 9.0Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 3.75 (s,3H). MS: 391.45 (calc) 392.3 (found)
1H NMR (Acetone-d6) d(ppm): 9.08 (bs,1H), 8.40 (d, J = 2.2 Hz, 1H), 8.12 (ddd,J = 8.4, 7.8, 2.7 Hz, 1H), 8.04 (d, J = 8.6 Hz,2H), 7.64 (t, J = 2.3 Hz, 1H), 7.36 (ss, J = 8.2,2.2 Hz, 1H), 7.10 (ddd, J = 8.6, 2.5, 0.6 Hz,1H), 7.06 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 8.2Hz, 1H), 4.89 (bs, 2H), 3.90 (s, 3H). MS:337.35 (calc) 338.1 (found)
1H NMR (Acetone-d6) d(ppm): 8.04 (d,J = 9.0 Hz, 2H), 7.68 (t, J = 2.2 Hz, 1H), 7.63(d, J = 3.9 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H),6.92 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H). MS:367.43 (calc) 368.1 (found)
1H NMR: (DMSO) δ (ppm): 9.58 (s, 1H),7.97 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 2.2 Hz,1H), 7.22 (dd, J = 8.2, 2.2 Hz, 1H), 7.05-7.02(m, 3H), 6.81 (dd, J = 3.5, 0.8 Hz, 1H), 6.77(d, J = 8.2 Hz, 1H), 5.48 (d, J = 4.7 Hz, 1H),5.09 (s, 2H), 4.88 (quint, J = 5.3 Hz, 1H),3.83 (s, 3H), 1.42 (d, J = 6.3 Hz, 3H). MS:368.45 (calc) 369.1 (MH+) (found)
1H NMR (DMSO) δ (ppm): 9.56 (s, 1H),7.97 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 2.2 Hz,1H), 7.52 (d, J = 3.9 Hz, 1H), 7.38 (d, J = 3.9Hz, 1H), 7.37 (dd, J = 8.4, 2.2 Hz, 1H), 7.03(d, J = 9.0 Hz, 2H), 6.81 (d, J = 8.4 Hz, 1H),5.41 (s, 2H), 3.83 (s, 3H), 2.67 (s, 6H). MS:431.53 (calc) 432.2 (found)
1H NMR: (DMSO) δ (ppm): 9.57 (s, 1H),7.87 (d, J = 8.4 Hz, 2H), 7.57 (dd, J = 5.3, 1.2Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.27 (d,J = 2.0 Hz, 1H), 7.19 (dd, J = 3.5, 1.2 Hz, 1H),7.05 (dd, J = 8.2, 2.2 Hz, 1H), 7.01 (dd,J = 5.3, 3.5 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H),6.63 (d, J = 8.6 Hz, 1H), 6.30 (d, J = 2.5 Hz,1H), 5.97 (dd, J = 8.4, 2.5 Hz, 1H), 5.96 (d,J = 6.5 Hz, 1H), 5.20 (s, 2H), 4.28 (d, J = 6.3Hz, 2H), 3.65 (s, 3H), 3.58 (s, 3H). MS:491.63 (calc) 492.5 (found)
1H NMR (DMSO-d6) d(ppm): 9.57 (s, 1H),7.89 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.0 Hz,2H), 7.23 (d, J = 0.4 Hz, 1H), 7.01 (dd,J = 8.4, 2.2 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H),6.63 (d, J = 8.6 Hz, 1H), 6.31 (d, J = 2.3 Hz,1H), 5.98 (dd, J = 8.2, 2.5 Hz, 1H), 5.97 (d,J = 5.9 Hz, 1H), 5.04 (s, 2H), 4.29 (d, J = 5.9Hz, 2H), 3.65 (s, 3H), 3.58 (s, 3H), 2.71 (t,J = 7.0 Hz, 2H), 1.50 (sext, J = 7.0 Hz, 2H),0.93 (t, J = 7.2 Hz, 3H). LRMS: 451.59 (calc)452.5 (found)
1H NMR: (CD3OD) d(ppm): 7.93 (d, J = 8.4Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.44 (dd,J = 8.2, 1.8 Hz, 2H), 7.35-7.29 (m, 4H), 7.21(dd, J = 8.2, 2.0 Hz, 1H), 6.85 (d, J = 8.4 Hz,1H), 6.71 (d, J = 8.4 Hz, 1H), 6.36 (d, J = 2.7Hz, 1H), 6.13 (dd, J = 8.4, 2.5 Hz, 1H), 4.39(s, 2H), 3.75 (s, 3H), 3.71 (s, 3H). MS:477.56 (calc) 478.5 (found)
1H NMR: (DMSO) δ (ppm): 9.55 (s, 1H);8.65 (dd; J = 0.9, 2.2 Hz; 1H); 8.49 (dd; J =1.6, 4.8 Hz, 1H); 7.91 (d, J = 8.2, 2H); 7.87(m, 1H); 7.46 (d, J = 8.2, 2H); 7.40 (dd;J = 0.9, 4.8 Hz; 1H);7.39 (m, 1H); 7.17 (dd;J = 2.0, 8.3 Hz; 1H); 6.76 (d, J = 8.3, 1H);6.64 (d, J = 8.6, 1H); 6.31 (d, J = 2.7, 1H);5.98 (m, 2H); 5.51 (bs, 2H); 4.30 (d, J = 6.3,2H); 3.66 (s, 3H); 3.58 (s, 3H). MS: calc:478.5; found: 478.5 (M + H)
1H NMR: (Acetone-d6) d(ppm): 9.07 (s,1H), 8.01 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2Hz, 2H), 7.55-7.52 (m, 3H), 7.32 (t, J = 7.4Hz, 2H), 7.28 (dd, J = 8.2, 2.2 Hz, 1H), 7.19(t, J = 7.2 Hz, 1H), 7.13 (d, J = 16.4 Hz, 1H),7.0 (d, J = 16.2 Hz, 1H), 6.89 (d, J = 8.2 Hz,1H), 6.70 (d, J = 8.4 Hz, 1H), 6.41 (d, J = 2.7Hz, 1H), 6.12 (dd, J = 8.6, 2.7 Hz, 1H), 5.33(bs, 1H), 4.85 (bs, 2H), 4.43 (s, 2H), 3.72 (s,3H), 3.67 (s, 3H). MS: 479.58 (calc) 480.5(found)
1H NMR (Acetone-d6) d(ppm): 9.07 (s,1H), 7.99 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.6Hz, 2H), 7.27-7.22 (m, 5H), 7.19-7.14 (m,1H), 6.87 (dd, J = 8.0, 2.0 Hz, 1H), 6.79 (d,J = 8.0 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.40(d, J = 2.8 Hz, 1H), 6.11 (dd, J = 8.4, 2.5 Hz,1H), 5.33 (bs, 1H), 4.51 (bs, 2H), 4.42 (s,2H), 3.72 (s, 3H), 3.67 (s, 3H). MS:481.59 (calc) 482.2 (found)
1H NMR (Acetone-d6) d(ppm): 9.03 (bs,1H), 7.94 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.8Hz, 2H), 7.28-7.23 (m, 5H), 7.18-7.13 (m,1H), 6.87 (dd, J = 8.0, 2.0 Hz, 1H), 6.79 (d,J = 8.2 Hz, 1H), 4.48 (bs, 2H), 2.90-2.86 (m,2H), 2.83-2.78 (m, 2H), 2.42 (s, 3H). MS: LRMS: 330.43 (calc) 331.1 (found)
1H NMR (Acetone-d6) d(ppm): 9.16 (bs,1H), 7.97 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 2.9Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.32 (dd,J = 8.2, 2.2 Hz, 1H), 7.28 (bs, 0.5 H), 7.27(dd, J = 5.1, 1.0 Hz, 1H), 7.26 (bs, 0.5 H),7.22 (dd, J = 3.5, 1.0 Hz, 1H), 7.21 (bs, 1H),7.03 (dd, J = 5.1, 3.5 Hz, 1H), 6.89 (d, J = 8.2Hz, 1H), 4.87 (bs, 2H), 4.65 (s, 2H), 4.16 (t,J = 5.7 Hz, 2H), 2.73 (t, J = 5.9 Hz, 2H), 2.30(s, 6H). MS: 561.70 (calc) 562.3 (found)
1H NMR (Acetone-d6) d(ppm): 9.42 (bs,1H), 9.03 (bs, 1H), 8.03 (d, J = 8.8 Hz, 2H),7.77 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 1.6 Hz,1H), 7.39 (dd, J = 8.0, 1.6 Hz, 1H), 6.84 (d,J = 7.8 Hz, 1H), 5.01 (bs, 2H), 2.13 (s, 3H),1.31 (s, 12H). MS: (calc.) 395.3 (calc)396.1 (found)
1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),8.02 (d, J = 6.3 Hz, 1H), 8.01 (d, J = 8.6 Hz,2H), 7.83 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 3.2Hz, 1H), 7.63 (dd, J = 8.4, 2.0 Hz, 1H), 7.29(dd, J = 4.9, 3.2 Hz, 1H), 7.08 (d, J = 8.8 Hz,2H), 6.87 (d, J = 8.6 Hz, 1H), 6.01 (s, 2H),3.88 (s, 3H). MS: 352.41 (calc)353.1 (found)
1H NMR: (DMSO) δ (ppm): (CD3OD)d(ppm): 7.99 (d, J = 8.8 Hz, 2H), 7.77 (d,J = 8.8 Hz, 2H), 7.48 (d, J = 2.2 Hz, 1H), 7.35(dd, J = 8.2, 2.2 Hz, 1H), 7.22 (dd, J = 5.1,1.2 Hz, 1H), 7.20 (td, J = 3.5, 1.2 Hz, 1H),7.01 (dd, J = 5.1, 3.7 Hz, 1H), 6.90 (d, J = 8.6Hz, 1H), 3.24 (s, 2H), 2.43 (s, 6H). MS:394.5 (calc) 395.1 (found)
1H NMR (DMSO) δ (ppm): 9.69 (bs, 1H),8.58 (s, 1H), 8.53-8.51 (m, 1H), 7.98-7.96(m, 1H), 7.94 (d, J = 7.8 Hz, 2H), 7.78-7.76(m, 1H), 7.46 (s, 1H), 7.40-7.38 (m, 1H),7.37 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.8 Hz,1H), 7.24-7.23 (m, 1H), 7.05-7.03 (m, 1H),6.80 (d, J = 8.4 Hz, 1H), 5.15 (bs, 2H), 5.10(s, 2H), 4.29 (d, J = 6.1 Hz, 2H). MS: 458.54(calc) 459.2 (found)
1H NMR (DMSO) δ (ppm): 9.73 (s, 1H),8.06 (dd, J = 8.6, 5.5 Hz, 2H), 7.43 (d, J = 1.8Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.33 (dd,J = 6.3, 5.1 Hz, 2H), 7.22 (dd, J = 3.7, 1.2 Hz,1H), 7.03 (dd, J = 5.1, 3.5 Hz, 1H), 6.78 (d,J = 8.2 Hz, 1H), 5.17 (s, 2H). MS: 312.36(calc) 313.1 (found)
1H NMR (DMSO) δ (ppm): 8.09 (d, J = 8.6Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.58 (d,J = 2.2 Hz, 1H), 7.36 (dd, J = 8.2, 2.2 Hz, 1H),7.23 (dd, J = 5.1, 3.9 Hz, 1H), 7.21 (dd,J = 3.7, 1.2 Hz, 1H), 7.01 (dd, 5.1, 3.7 Hz,1H), 6.90 (d, J = 8.4 Hz, 1H). MS: 394.44(calc) 395.1 (found)
1H NMR (Acetone-d6) d(ppm): 8.22 (d,J = 7.2 Hz, 1H), 8.08 (bs, 2H), 7.61 (s, 1H),7.48 (t, J = 8.8 Hz, 1H), 7.35 (dd, J = 8.6, 2.0Hz, 1H), 7.29 (d, J = 5.1 Hz, 1H), 7.23 (d,J = 3.7 Hz, 2H), 7.04 (dd, J = 7.5, 4.3 Hz, 1H),6.91 (d, J = 8.2 Hz, 1H), 4.88 (bs, 1H). MS:346.86 (calc) 347.1 (found)
1H NMR: (DMSO) δ (ppm): 9.79 (s, 1H),8.10 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.4 Hz,2H), 7.43 (bs, 1H), 7.32 (d, J = 5.2 Hz, 1H),7.28 (dd, J = 8.4, 2.0 Hz 1H), 7.22 (bd,J = 3.6 Hz, 1H), 7.02 (dd, J = 3.6, 5.2 Hz, 1H),6.78 (d, J = 8.4 Hz, 1H). MS: (calc.) 378;(obt.) 379 (MH)+.
1H NMR (DMSO) δ (ppm): 9.82 (s, 1H),8.01 (d, J = 10.4 Hz, 1H), 7.85 (d, J = 7.2 Hz,1H), 7.75 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 2.2Hz, 1H), 7.33 (d, J = 5.1 Hz, 1H), 7.28 (dd,J = 8.4, 1.8 Hz, 1H), 7.22 (d, J = 3.5 Hz, 1H),7.02 (dd, J = 4.9, 3.5 Hz, 1H), 6.78 (d, J = 8.4Hz, 1H), 5.23 (s, 2H). MS: 346.86 (calc)347.1/349.1 (found)
1H NMR: (DMSO) δ (ppm): 9.87 (s, 1H),9.14 (d, J = 1.8, Hz, 1H), 8.73 (dd, J = 4.9,1.8 Hz, 1H), 8.32 (dt, J = 8.0, 2.0 Hz, 1H),7.54 (dd, J = 7.8, 5.3 Hz, 1H), 7.46 (d, J =2.2 Hz, 1H), 7.34 (dd, J = 5.1, , 1.2 Hz, 1H),7.29 (dd, J = 8.4, 2.3 Hz, 1H), 723 (dd, J =3.5, 1.0 Hz, 1H), 7.03 (dd, J = 5.1, 3.7 Hz,1H), 6.79 (d, J = 8.4 Hz, 1H), 5.24 (sb,2H). MS: (calc.) 295.1; (obt.) 296.3 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.95 (s, 1H),7.76 (d, J = 6.1, Hz, 2H), 7.90 (d, J = 6.1Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.34 (dd,J = 5.1, 1.2 Hz, 1H), 7.30 (dd, J = 8.4, 2.3Hz, 1H), 7.23 (dd, J = 3.7, 1.2 Hz, 1H), 7.03(dd, J = 5.1, 3.7 Hz, 1H), 6.79 (d, J = 8.4Hz, 1H), 5.24 (sb, 2H). MS: (calc.) 295.1;(obt.) 296.3 (MH)+.
1H NMR: (DMSO) δ (ppm): 10.18 (s, 1H),7.60 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 1.2, 5.2Hz, 1H), 7.30 (dd, J = 2.4, 8.0 Hz, 1H), 7.23(dd, J = 1.2, 3.2 Hz, 1H), 7.04 (dd, J = 3.6,5.2 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 5.15(bs, 2H), 2.32 (s, 3H) MS: (calc.) 380.36;(obt.) 381.2 (MH)+.
1H NMR (Acetone-d6) d(ppm): 9.20 (bs,1H), 8.84 (bs, 1H), 7.72 (d, J = 8.0 Hz, 3H),7.58 (d, J = 15.7 Hz, 1H), 7.54 (d, J = 8.4 Hz,2H), 7.34 (d, J = 8.6 Hz, 2H), 7.29-7.27 (m,4H), 7.22 (d, J = 3.5 Hz, 1H), 7.04 (t, J = 4.9Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.86 (d,J = 15.3 Hz, 1H), 4.84 (bs, 2H), 2.38 (s, 3H).MS: 489.62 (calc) 490.1 (found)
1H NMR: (DMSO) δ (ppm): 9.55 (s, 1H),7.96 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 2.2 Hz,1H), 7.39 (d, J = 8.2, 2.0 Hz, 1H), 7.02 (d,J = 9.0 Hz, 2H), 6.90 (s, 2H), 6.73 (d, J = 8.4Hz, 1H), 6.63 (s, 1H), 4.98 (s, 2H), 3.83 (s,3H). MS: 340.4 (calc) 341.2 (found)
1H NMR (Acetone-d6) d(ppm): 8.94 (bs,1H), 8.03 (d, J = 1.8 Hz, 1H), 7.88 (d, J = 8.8Hz, 1H), 7.47 (dd, J = 8.9, 2.5 Hz, 1H), 7.36(d, J = 2.3 Hz, 1H), 7.07 (dd, J = 8.2, 2.3 Hz,1H), 6.89 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.2Hz, 1H), 6.45 (dd, J = 8.4, 0.6 Hz, 1H), 5.29(bs, 2H), 3.74 (s, 3H). MS: 334.38 (calc)335.1 (found)
1H NMR (CD3OD) d(ppm): 7.97 (d, J = 8.6Hz, 2H), 7.37 (d, J = 1.6 Hz, 1H), 7.28 (dd,J = 8.4, 2.2 Hz, 1H), 7.20-7.13 (m, 2H), 7.03(d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H),6.85 (t, J = 9.0 Hz, 1H), 3.88 (s, 3H). MS:351.38 (calc) 352.3 (MS+) (found)
1H NMR (DMSO) δ (ppm): 9.58 (s, 1H),9.35 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.43(s, 1H), 7.23 (dd, J = 8.2, 1.4 Hz, 1H), 7.16(t, J = 7.6 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H),6.95 (d, J = 7.6 Hz, 1H), 6.91 (s, 1H), 6.82(d, J = 8.4 Hz, 1H), 6.62 (dt, J = 8.0, 1.0 Hz,1H), 5.05 (s, 2H), 3.84 (s, 3H). MS: 334.37(calc) 335.2 (MH+) (found) CHECK NMR
1H NMR: (DMSO) δ (ppm): 9.59 (s, 1H),9.31 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.36(d, J = 2.0 Hz, 1H), 7.18 (td, J = 8.4, 2.0 Hz,2H), 7.06-7.02 (m, 3H), 6.87 (dd, J = 7.8, 0.8Hz, 1H), 6.82-6.77 (m, 2H), 4.92 (s, 2H),3.83 (s, 3H). MS: 334.37 (calc) 335.1(MH+) (found) CHECK NMR
1H NMR: (DMSO) δ (ppm): 400 MHz,(DMSO) d (ppm): 9.57 (s, 1H), 8.80 (s, 1H),7.89 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.8Hz, 2H), 7.44 (d, J = 2.2 Hz, 1H), 7.34 (dd,J = 5.1, 1.0 Hz, 1H), 7.27 (dd, J = 8.2, 2.2Hz, 1H), 7.23 (dd, J = 3.5, 1.2 Hz, 1H),7.03 (dd, J = 5.1, 3.5 Hz, 1H), 6.79 (d, J =8.4 Hz, 1H), 5.12 (sb, 2H), 3.46 (t, J = 4.8Hz, 4H), 2.33 (t, J = 4.9 Hz, 4H). MS: (calc.)435.2; (obt.) 436.4 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.57 (1H, s),8.81 (1H, s), 7.90 (2H, d, 8.8 Hz), 7.60(2H, d, 9.0 Hz), 7.45 (1H, d, 2.2 Hz), 7.34(1H, dd, 3.9 and 1.2 Hz), 7.27 (1H, dd, 6.1 and2.2 Hz), 7.22 (1H, dd, 2.3 and 1.2 Hz), 7.03(1H, m), 6.78 (1H, d, 8.2 Hz), 5.12 (2H, s),3.62 (4H, t, 4.5 Hz), 3.45 (4H, t, 5.1 Hz) MS:422.14 (calc), 423.3 (obs).
1H NMR: (DMSO) δ (ppm): 9.54 (1H, s),9.10 (1H, s), [8.37 (2H, s) comes from formicsalt], 7.87 (2H, d, 8.6), 7.49 (2H, d, 8.8 Hz),7.44 (1H, d, 2.2 Hz), 7.34 (1H, dd, 3.9 and 1.2Hz), 7.27 (1H, dd, 6.1 and 2.2 Hz), 7.23(1H, dd, 2.5 and 1.0), 7.03 (1H, dd, 3.5 and1.6), 6.79 (1H, d, 8.2 Hz), 6.36 to 6.34(1H, m), 5.11 (2H, s), 3.2 to 3.1 (2H, m), 2.33(2H, s), 2.18 (6H, s) MS: 423.2 (calc),424.2 (obs).
1H NMR: (DMSO) δ (ppm): 9.99 (1H, s),9.59 (1H, s), [8.28 (1H, s) comes from formicacid salt], 7.92 (2H, d, 8.8), 7.57 (2H, d, 9.0Hz), 7.44 (1H, d, 2.0 Hz), 7.34 (1H, dd, 3.7and 1.2 Hz), 7.27 (1H, dd, 6.1 and 2.2 Hz),7.23 (1H, dd, 2.3 and 1.2), 7.03 (1H, dd, 3.3and 1.8), 6.79 (1H, d, 8.6 Hz), 4.18 (2H, t, 5.7Hz, 2.20 (6H, s) MS: 424.2 (calc), 425.2 (obs).
1H NMR: (DMSO) δ (ppm): 9.56 (s, 1H);8.56 (s, 1H); 7.88 (d, J = 8.8 Hz; 2H); 7.60(d; J = 8.8 Hz; 2H); 7.44 (d; J = 2.2 Hz; 1H);7.34 (dd; J = 1.2, 5.1 Hz; 1H); 7.27 (dd;J = 2.2, 8.4 Hz; 1H); 7.22 (dd; J = 1.2, 3.5 Hz;1H); 7.03 (dd; J = 3.5, 5.1 Hz; 1H); 6.79 (d,J = 8.4 Hz; 1H); 5.12 (bs, 2H); 2.95 (s, 6H).MS: calc: 380.4; found: 381.2 (M + H)
1H NMR: (DMSO) δ (ppm): 9.72 (s, 1H),8.19 (s, 1H), 7.67 (abq, J = 29.4, 7.6, Hz,2H), 7.52 (d, J = 7.6 Hz, 2H), 7.36 (s, 1H),7.31 (d, J = 6.5 Hz, 1H), 7.26 (s, 1H), 7.06(s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.52 (s,1H), 5.16 (s, 2H), 3.90 (s, 3H). MS: 347.1(calc), 348.1 (obs).
1H NMR: (DMSO) δ (ppm): 9.71 (s, 1H),8.07 (d, J = 8.2 Hz, 2H), 8.00 (d, J = 8.2 Hz,2H), 7.48 (s, 1H), 7.34 (d, J = 5.1 Hz, 1H),7.28 (dd, J = 8.2. 2.0 Hz, 1H), 7.24 (d, J =3.5 Hz, 1H), 7.03 (t, J = 3.7 Hz, 1H), 6.79 (d,J = 8.4 Hz, 1H), 5.17 (s, 2H). MS: 362.09(calc), 363.1 (obs).
1H NMR: (DMSO) δ (ppm): 9.92 (s, 1H),8.14 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz,2H), 7.44 (d, J = 2.0 Hz, 1H), 7.34 (dd, J =5.1, 0.98 Hz, 1H), 7.30 (dd, J = 8.2, 2.2 Hz,1H), 7.23 (d, J = 3.5 Hz, 1H), 7.03 (dd, J =5.1, 3.5 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H),5.24 (s, 2H). MS: 319.08 (calc), 320.1(obs).
1H NMR: (DMSO) δ (ppm): 9.78 (s, 1H),8.02 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz,2H), 7.45 (s, 1H), 7.33 (d, J = 5.1 Hz, 1H),7.28 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 3.3 Hz,1H), 7.03 (t, J = 3.9 Hz, 1H), 6.79 (d, J = 8.2Hz, 1H), 5.18 (s, 2H), 3.63 (s, 4H). MS: 362.12 (calc), 363.1 (obs).
1H NMR: (DMSO) δ (ppm): 9.96 (1H, s),7.59-7.52 (3H, m), 7.46-7.41 (3H, m), 7.39(1H, d, 2.2 Hz), 7.33 (1H, dd, 2.5 and 1.0 Hz),7.16 (1H, dd, 5.7 and 1.8 Hz), 6.98 (1H, d, 8.4Hz), 3.84 (3H, s) MS: 324.1 (calc), 325.1(obs).
1H NMR: (DMSO) δ (ppm): 10.05 (s, 1H),8.35 (d, J = 8.6 Hz, 2H), 8.22 (d, J = 8.6 Hz,2H), 7.46 (s, 1H), 7.36 (d, J = 4.1 Hz, 1H),7.33 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 2.5 Hz,1H), 7.04 (t, J = 3.5 Hz, 1H), 6.83 (d, J = 8.4Hz, 1H), (missing NH2). MS: 339.07 (calc),340.1 (obs).
1H NMR: (DMSO) δ (ppm): 10.14 (1H, s),8.82 (1H, s), 8.43 (2H, d, 6.3 Hz), 7.82(1H, t, 7.8 Hz), 7.46 (1H, d, 2.0 Hz), 7.37-7.33 (2H, m), 7.27 (1H, d, 3.3), 7.05(1H, dd, 3.5 and 1.4 Hz), 6.85 (1H, d, 8.4 Hz)MS: 339.1 (calc) 340.1 (obs).
1H NMR: (DMSO) δ (ppm): 9.97 (1H, s),8.45 (1H, s), 8.27 (1H, d, 8.0 Hz), 8.05(1H, d, 7.8 Hz), 7.74 (1H, t, 8.0 Hz), 7.48(1H, d, 1.8 Hz), 7.38-7.3 (1H, d, 8.4 Hz) 7.38-7.33 (2H, m), 7.27 (1H, d, 3.52 Hz), 7.05(1H, dd, 3.5 and 1.4 Hz), 6.86 (1H, d, 8.4).MS: 319.1 (calc) 320.1 (obs).
1H NMR: (DMSO) δ (ppm): 9.90 (1H, s),8.18 (1H, s), 7.98 (1H, d, 7.4 Hz), 7.50-7.45(2H, m), 7.37-7.32 (2H, m), 7.27 (1H, d, 3.3Hz), 7.05 (1H, dd, 3.5 and 1.6 Hz), 6.85(1H, d, 8.4 Hz) MS: 371.9 (calc) 373.0(obs).
1H NMR: (DMSO) δ (ppm): 10.00 (1H, s),8.34 (1H, s), 8.29 (1H, d, 8.0 Hz), 7.95(1H, d, 8.0 Hz), 7.76 (1H, t, 7.6 Hz), 7.44(1H, s), 7.36-7.31 (2H, m), 7.25 (1H, d, 3.3Hz), 7.04 (1H, t, 3.7 Hz), 6.82 (1H, d, 8.2Hz) MS: 362.1 (calc) 363.1 (obs)
1H NMR: (DMSO) δ (ppm): 9.73 (1H, s),8.03 (2H, d, 8.4), 7.45 (1H, s,), 7.34(1H, d, 9.0 Hz), 7.30-7.22 (4H, m), 7.04(1H, dd, 3.5 and 1.6 Hz), 6.79 (1H, d, 8.4 Hz),5.18 (2H, s), 2.31 (3H, s) MS: 352.1 (calc),353.1 (obs)
1H NMR: (DMSO) δ (ppm): 9.64 (1H, s),7.45 (1H, s), 7.34 (1H, dd, 3.9 and 1.2 Hz),7.29-7.26 (4H, m), 7.24-7.22 (1H, m), 7.03(1H, dd, 3.7 and 1.4 Hz), 6.90 (1H, d, 8.2 Hz),6.80 (1H, d, 8.2 Hz), 5.10 (2H, s), 2.96 (6H, s)MS: 337.1 (calc) 338.1 (obs).
1H NMR: (DMSO) δ (ppm): 10.11 (1H, s),9.83 (1H, s), 8.11 (1H, s), 7.79 (1H, d, 6.7 Hz),7.67 (1H, d, 7.6 Hz), 7.49 (1H, s), 7.43(1H, t, 7.8 Hz), 7.38 (1H, d, 4.9 Hz), 7.34(1H, d, 8.4 Hz), 7.28 (1H, d, 3.3 Hz), 7.05(1H, t, 3.7 Hz), 6.89 (1H, d , 8.4 Hz), 2.07(3H, s) MS: 351.1 (calc) 352.1 (obs)
1H NMR: (DMSO) δ (ppm): 9.34 (1H, s),[8.25 (2H, s) comes from formic salt], 7.77(2H, d, 8.8), 7.44 (1H, d, 2.2 Hz), 7.34(1H, dd, 4.0 and 1.2 Hz), 7.26-7.21 (2H, m),7.03 (1H, dd, 3.5 and 1.4), 6.78 (1H, d, 8.2),6.62 (1H, d, 8.8 Hz), 6.09 (1H, m), 3.25-3.15 (8H, m), 1.53 to 1.49 (4H, m), 1.39(2H, m) MS: 420.2 (calc), 421.3 (obs).
1H NMR: (DMSO) δ (ppm): 9.67 (1H, s),8.01 (2H, d, 8.8), 7.44 (1H, d, 2.0 Hz), 7.36(1H, dd, 4.1 and 1.0 Hz), 7.30 (1H, dd, 6.1 and2.2 Hz), 7.24 (1H, dd, 2.5 and 1.2), 7.12(2H, d, 8.8), 7.04 (1H, dd, 3.5 and 1.6 Hz),6.82 (1H, d, 8.4 Hz), 4.44 (2H, t, 4.1), 3.65 to3.15 (10H, m) MS: 423.2 (calc), 424.2(obs).
1H NMR: (DMSO) δ (ppm): 9.56 (bs, 1H),7.89 (d, J = 8.0 Hz, 2H), 7.52 (bs, 1H), 7.45(d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 1H),6.63 (d, J = 8.4 Hz, 1H), 6.30 (d, J = 2.4 Hz,1H), 5.99-5.95 (m, 2H), 5.74 (bs, 1H), 4.92(bs, 2H), 3.64 (s, 3H), 3.32 (s, 3H). MS:(calc.); 402.5 (obt.) 403.4 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.65 (s, 1H),7.96 (d, J = 8.0 Hz, 2H), 7.48-7.51 (m, 4H),7.31 (d, J = 4.0 Hz, 1H), 7.11 (d, J = 4.0 Hz,1H), 6.80 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 13.6Hz, 1H), 6.35 (d, J = 2.8 Hz, 1H), 6.03-6.01(m, 2H), 5.50 (bs, 2H), 4.34 (d, J = 6.0 Hz,2H), 3.70 (s, 3H), 3.62 (s, 3H). MS: (calc.)477.6; (obt.) 478.4 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.5 (s, 1H),7.86 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz,2H), 7.2 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H),6.90 (s, 1H), 6.6 (d, J = 8.8 Hz, 1H), 6.56 (d,J = 11.6 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H),5.95 (dd, J = 2.4, 8.8 Hz, 2H), 5.52 (bs, 2H),4.28 (bs, 2H), 3.64 (s, 6H), 3.57 (s, 3H). MS:(calc.) 507.6; (obt.) 508.4 (MH)+.
1H NMR: (DMSO) δ (ppm): 7.87 (d, J = 8.4Hz, 2H), 7.75 (bs, 1H), 7.60 (d, J = 8.0 Hz,2H), 7.44 (d, J = 8.4 Hz, 2H), 7.26 (bs, 1H),7.14 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz,2H), 6.723 (d, J = 13.2 Hz, 1H), 6.62 (d,J = 8.4 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H), 5.96(dd, J = 2.4, 8.8 Hz, 2H), 4.28 (bs, 2H), 3.64(s, 3H), 3.57 (s, 3H) MS: (calc.) 553.6; (obt.)554.5 (MH)+.
1H NMR: (DMSO) δ (ppm): 10.11 (s, 1H),9.48 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.56(d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.4 Hz, 1H),6.86 (dd, J = 2.0, 4.0 Hz, 2H), 6.62 (d,J = 12.8 Hz, 1H), 6.10 (2H, dd, J = 2.0, 4.0 Hz,2H), 5.28 (bs, 2H), 2.09 (s, 3H). MS: (calc.)352.36; (obt.) 353.2 (MH)+.
1H NMR: (DMSO) δ (ppm): 8.08 (bs, 1H),7.96 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz,2H), 7.41-7.50 (m, 2H), 7.40 (d, J = 8.0 Hz,1H), 7.35 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.0Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.72 (d,J = 8.8 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 6.15(dd, J = 2.4, 8.8 Hz, 1H), 4.41 (bs, 2H), 3.76(s, 3H), 3.73 (s, 3H). MS: (calc.) 535.5;(obt.) 536.3 (MH)+.
1H NMR: (CD3OD) δ (ppm): 7.95 (d, J = 8.8Hz, 2H), 7.60 (d, J = 3.2 Hz, 1H), 7.73-7.71(m, 2H), 7.56 (d, J = 3.2 Hz, 1H), 7.48 (bs,1H), 7.32 (bs, 2H), 2.17 (s, 3H) MS:(calc.) 352.4; (obt.) 353.2 (MH)+.
1H NMR: (CD3OD) δ (ppm): 7.97 (d, J = 8.4Hz, 2H), 7.77 (d, J = 2.0 Hz, 1H), 7.71-7.73(m, 3H), 7.56 (d, J = 3.20 Hz, 1H), 7.48 (bs,1H), 7.32 (bs, 2H), 6.92 (d, J = 8.8 Hz, 1H),2.17 (s, 3H) MS: (calc.) 352.41; (obt.)353.2 (MH)+.
1H NMR: (DMSO) δ (ppm): 10.18 (s, 1H),9.64 (s, 1H), 8.00-7.94 (m, 5H), 7.84 (d,J = 2.0 Hz, 1H), 7.68 (dd, J = 1.6, 7.2 Hz,2H), 7.61 (dd, J = 2.0, 8.4 Hz, 1H), 7.42 (dt,J = 1.6, 7.2 Hz, 2H), 7.32 (d, J = 1.6, 7.2 Hz,1H), 6.84 (d, J = 8.4 Hz, 1H), 5.52 (bs, 2H),2.09 (s, 3H). MS: (calc.) 428.5; (obt.)429.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 10.25 (s, 1H),9.63 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.68-7.67 (m, 3H), 7.41 (dd, J = 2.0, 8.4 Hz, 1H),6.77 (d, J = 8.4 Hz, 1H), 5.40 (bs, 2H), 2.32(s, 3H), 2.24 (s, 3H), 2.08 (s, 3H) MS:(calc.) 380.4; (obt.) 381.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 10.22 (s, 1H),9.62 (s, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.89(d, J = 8.4 Hz, 2H), 7.80 (1H, dd, J = 2.0, 8.4Hz, 1H), 7.68-7.73 (m, 4H), 7.33-7.35 (m,2H), 6.91 (d, J = 8.4 Hz, 1H), 5.86 (bs, 2H),2.12 (s, 3H) MS: (calc.) 386.41; (obt.) 387.1(MH)+.
1H NMR: (DMSO) δ (ppm): 9.42 (bs, 1H),7.66-7.32 (m, 7H), 7.22-7.14 (m, 2H), 7.10-7.00 (m, 2H), 6.87-6.74 (m, 1H), 6.62-6.50(m, 4H), 5.19 (bs, 1H), 4.29 (d, J = 5.6 Hz,2H), MS: (calc.) 459.2; (obt.) 460.3 (MH)+.
1H NMR: (DMSO) δ (ppm10.79 (br s, 1H),9.75 (br s, 1H), 8.90 (s, 1H), 8.31 (d, J = 9.4Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H),7.33 (m, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.22 (s,1H), 7.02 (m, 1H), 6.78 (d, J = 8.0 Hz, 1H),5.20 (br s, 2H), 2.13 (s, 3H). MS: (calc.)352.1; (obt.) 353.2 (MH)+.
1H NMR: (DMSO) δ (ppm): 10.09 (br s, 1H),9.04 (dd, J = 6.7, 1.8 Hz, 2H), 8.79 (d, J = 1.8Hz, 1H), 8.37 (dd, J = 8.9, 2.0 Hz, 1H), 8.20(d, J = 8.6 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H),7.34 (dd, J = 4.9, 1.0 Hz, 1H), 7.30 (dd,J = 2.1, 8.1 Hz, 1H), 7.24 (dd, J = 3.5, 1.2 Hz,1H), 7.04 (dd, J = 4.9, 3.5 Hz, 1H), 6.81 (d,J = 8.2 Hz, 1H), 5.28 (br s, 2H). MS: (calc.)346.1 (obt.) 347.1 (MH)+.
1H NMR: (CD3OD) δ (ppm): 8.56 (s, 1H),8.21 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 8.8 Hz,1H), 7.63 (s, 2H), 7.45 (d, J = 1.7 Hz, 1H),7.27 (d, J = 8.4 Hz, 1H), 7.13-7.12 (m, 2H),6.90 (t, J = 4.1 Hz, 1H), 6.83 (d, J = 8.4 Hz,1H), 6.69 (t, J = 3.9 Hz, 2H), 6.55-6.56 (m,2H). MS: (calc.) 478.1; (obt.) 479.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 10.09 (s, 1H),8.75 (d, J = 1.8 Hz, 1H), 8.32 (dd, J = 8.6, 2.0Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.84-7.82(m, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.35-7.24(m, 5H), 7.14-7.11 (m, 2H), 7.03 (dd, J = 5.0,3.5 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 5.29 (s,2H). MS: (calc.) 510.1; (obt.) 511.1 (MH)+.
1H NMR: (CDCl3) δ 8.61-8.59 (m,1H), 8.02 (br s, 1H), 7.86 (d, J = 8.0 Hz, 2H),7.53 (br s, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.33(dd, J = 8.2, 2.2 Hz, 1H), 7.30-7.26 (m, 1H),7.17 (dd, J = 5.1, 1.2 Hz, 1H), 7.15-7.14 (m,1H), 7.01 (dd, J = 5.1, 3.5 Hz, 1H), 6.82 (d,J = 8.2 Hz, 1H), 3.73 (t, J = 4.7 Hz, 4H), 3.57(s, 2H), 2.47 (t, J = 4.3 Hz, 4H). MS: (calc.)393.2; (obt.) 394.2 (MH)+.
1H NMR: (DMSO) δ (ppm): 10.01 (s, 1H),8.05 (d, J = 1.6 Hz, 1H), 7.69-7.67 (m, 2H),7.61 (dd, J = 8.8, 2.0 Hz, 1H), 7.44 (d, J = 2.2Hz, 1H), 7.34 (dd, J = 5.1, 1.2 Hz, 1H), 7.30(dd, J = 8.4, 2.2 Hz, 1H), 7.23 (dd, J = 3.6, 1.2Hz, 1H), 7.02 (dd, J = 4.9, 3.6 Hz, 1H), 6.79(d, J = 8.4 Hz, 1H), 5.24 (s, 2H). MS: (calc.)413.0 (d); (obt.) 414.0 (d) (MH)+.
1H NMR: (DMSO) δ (ppm9.77 (s, 1H), 7.64(s, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.37 (dd,J = 5.1, 1.2 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H),7.31-7.30 (m, 2H), 7.26 (dd, J = 3.7, 1.2 Hz,1H), 7.06 (dd, J = 5.1, 3.5 Hz, 6.83 (d,J = 8.5 Hz, 1H), 5.22 (s, 2H), 3.88 (s, 3H),3.85 (s, 3H). MS: (calc.) 394.1; (obt.) 395.1(MH)+.
1H NMR: (DMSO) δ (ppm): 9.98 (s, 1H),7.75-7.71 (m, 2H), 7.63 (dd, J = 9.0, 2.8 Hz,1H), 7.44 (d, J = 2.0 Hz, 1H), 7.36-7.29 (m,3H), 7.23 (dd, J = 3.5, 1.1 Hz, 1H), 7.03 (dd,J = 5.1, 3.7 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H),5.24 (s, 2H). MS: (calc.) 352.1; (obt.) 353.1(MH)+.
1H NMR: (DMSO) δ (ppm): 10.04 (s, 1H),7.95 (dd, J = 1.6, 1.0 Hz, 1H), 7.85 (s, 1H),7.63 (d, J = 1.6 Hz, 1H), 7.43 (d, J = 2.2 Hz,1H), 7.34 (dd, J = 5.1, 1.2 Hz, 1H), 7.30 (dd,J = 8.4, 2.3 Hz, 1H), 7.23 (dd, J = 3.5, 1.2 Hz,1H), 7.03 (dd, J = 5.1, 3.5 Hz, 1H), 6.78 (d,J = 8.3 Hz, 1H), 5.28 (s, 2H) MS: (calc.)403.0 (d); (obt.) 404.0 (d) (MH)+.
1H NMR: (DMSO) δ (ppm): 9.68 (s, 1H),7.64 (s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.32 (d,J = 1.0 Hz, 1H), 7.27 (dd, J = 8.2, 2.1 Hz, 1H),7.22 (dd, J = 3.5, 1.0 Hz, 1H), 7.02 (dd,J = 4.9, 3.5 Hz, 1H), 6.84 (s, 1H), 6.78 (d,J = 8.4 Hz, 1H), 6.47 (d, J = 1.7 Hz, 1H), 5.20(s, 2H), 3.90 (s, 3H), 3.83 (s, 3H). MS: (calc.)394.1; (obt.) 395.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.60 (s, 1H),7.51-7.49 (m, 3H), 7.33 (dd, J = 5.1, 1.2 Hz,1H), 7.27 (dd, J = 8.2, 2.1 Hz, 1H), 7.22 (dd,J = 3.5, 1.2 Hz, 1H), 7.02 (dd, J = 5.0, 3.5 Hz,1H), 6.80-6.76 (m, 3H), 5.17 (s, 2H), 3.40(q, J = 6.8 Hz, 4H), 1.13 (t, J = 7.0 Hz,6H). MS: (calc.) 405.1; (obt.) 406.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 10.90 (s, 1H),9.87 (s, 1H), 9.16 (s, 2H), 7.47 (d, J = 2.2 Hz,1H), 7.36 (dd, J = 5.1, 1.2 Hz, 1H), 7.32 (dd,J = 8.4, 2.2 Hz, 1H), 7.25 (dd, J = 3.5, 1.1 Hz,1H), 7.05 (dd, J = 5.1, 3.7 Hz, 1H), 6.81 (d,J = 8.4 Hz, 1H), 5.33 (br s, 2H), 2.26 (s, 3H).MS: (calc.) 353.1; (obt.) 354.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.81 (s, 1H),8.09 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.6 Hz,2H), 7.46 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 5.1,1.2 Hz, 1H), 7.28 (dd, J = 8.2, 2.2 Hz, 1H),7.23 (dd, J = 3.5, 1.0 Hz, 1H), 7.03 (dd,J = 5.1, 3.5 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H),6.12 (s, 1H), 5.19 (s, 2H), 2.38 (s, 3H), 2.20(s, 3H). MS: (calc.) 388.1; (obt.) 389.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.85 (s, 1H),8.14 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 2.0 Hz,1H), 7.44 (d, J = 8.4 Hz, 2H), 7.37 (dd, J = 5.1,1.2 Hz, 1H), 7.32 (dd, J = 8.5, 2.4 Hz, 1H),7.26 (dd, J = 3.6, 1.0 Hz, 1H), 7.07 (dd,J = 5.1, 3.5 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H),5.86 (s, 2H), 5.24 (s, 2H), 2.05 (s, 6H). MS:(calc.) 387.1; (obt.) 388.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.59 (s, 1H),7.60 (dd, J = 8.0, 1.6 Hz, 1H), 7.55 (d, J = 1.6Hz, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.35 (dd,J = 4.9, 0.6 Hz, 1H), 7.29 (dd, J = 8.2, 2.2 Hz,1H), 7.24 (dd, J = 3.7, 1.0 Hz, 1H), 7.06-7.04 (m, 2H), 6.79 (d, J = 8.2 Hz, 1H), 6.13 (s,2H), 5.15 (br s, 2H). MS: (calc.) 338.1;(obt.) 339.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.57 (s, 1H),7.54 (d, J = 2.1 Hz, 1H), 7.51 (dd, J = 8.4, 2.1Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.33 (dd,J = 5.1, 1.2 Hz, 1H), 7.26 (dd, J = 8.4, 2.3 Hz,1H), 7.22 (dd, J = 3.5, 1.2 Hz, 1H), 7.02 (dd,J = 5.1, 3.5 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H),6.79 (d, J = 8.4 Hz, 1H), 5.11 (s, 2H), 4.31-4.28 (m, 4H). MS: (calc.) 352.1; (obt.) 353.1(MH)+.
1H NMR: (DMSO) δ (ppm): 9.60 (s, 1H),7.41 (d, J = 2.2 Hz, 1H), 7.36 (d, J = 1.4 Hz,1H), 7.34 (dd, J = 5.2, 1.2 Hz, 1H), 7.30-7.26 (m, 2H), 7.23 (dd, J = 3.6, 1.2 Hz, 1H),7.04 (dd, J = 4.9, 3.5 Hz, 1H), 6.79 (d, J = 8.4Hz, 1H), 6.10 (s, 2H), 5.14 (br s, 2H), 3.91 (s,3H). MS: (calc.) 368.1; (obt.) 369.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.64 (s, 1H),7.63 (dd, J = 8.2, 2.0 Hz, 1H), 7.57 (d, J = 2.2Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.33 (dd,J = 5.1, 1.2 Hz, 1H), 7.28 (dd, J = 8.3, 2.3 Hz,1H), 7.23 (dd, J = 3.5, 1.2 Hz, 1H), 7.05 (d,J = 8.6 Hz, 1H), 7.02 (dd, J = 5.1, 3.6 Hz, 1H),6.79 (d, J = 8.3 Hz, 1H), 5.12 (br s, 2H), 3.83(s, 3H), 3.82 (s, 3H). MS: (calc.) 354.1; (obt.)355.1 (MH)+.
1H NMR: (DMSO) δ (ppm9.90 (s, 1H), 8.66(s, 1H), 8.05 (d, J = 9.8 Hz, 1H), 7.96 (d,J = 8.6 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.33(dd, J = 5.1, 1.2 Hz, 1H), 7.30 (dd, J = 8.2, 2.2Hz, 1H), 7.23 (dd, J = 3.5, 1.1 Hz, 1H), 7.03(dd, J = 5.0, 3.7 Hz, 1H) 6.81 (d, J = 8.4 Hz,1H), 5.23 (br s, 2H). MS: (calc.) 335.1; (obt.)336.0 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.94 (s, 1H),8.78 (m, 3H), 8.11 (dd, J = 4.3, 1.6 Hz, 2H),7.64 (d, J = 2.2 Hz, 1H), 7.38 (dd, J = 5.1, 1.0Hz, 1H), 7.33 (dd, J = 8.2, 2.1 Hz, 1H), 7.28(dd, J = 3.7, 1.2 Hz, 1H), 7.07 (dd, J = 5.1, 3.7Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.23 (s,2H). MS: (calc.) 378.0; (obt.) 379.0 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.72 (s, 1H),8.34 (s, 2H), 7.87-7.85 (m, 2H), 7.48 (d,J = 1.8 Hz, 1H), 7.34 (dd, J = 5.1, 1.0 Hz, 1H),7.28 (dd, J = 8.1, 5.2 Hz, 1H), 7.23 (dd,J = 3.5, 1.2 Hz, 1H), 7.03 (dd, J = 5.1, 3.6 Hz,1H), 6.80 (d, J = 8.4 Hz, 1H), 5.15 (s,2H). MS: (calc.) 334.1; (obt.) 335.0 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.90 (s, 1H),8.62 (s, 1H), 8.07-7.98 (m, 4H), 7.63-7.60(m, 2H), 7.51 (d, J = 2.1 Hz, 1H), 7.34 (dd,J = 5.1, 1.2 Hz, 1H), 7.30 (dd, J = 8.4, 2.2 Hz,1H), 7.24 (dd, J = 3.5, 1.2 Hz, 1H), 7.04 (dd,J = 5.1, 3.7 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H),5.21 (s, 2H). MS: (calc.) 344.1; (obt.)345.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.99 (s, 1H),8.32 (s, 1H), 8.03 (dd, J = 8.4, 2.0 Hz, 1H),7.97 (dd, J = 6.6, 2.7 Hz, 1H), 7.49-7.43 (m,3H), 7.33 (dd, J = 5.0, 1.1 Hz, 1H), 7.30 (dd,J = 8.2, 2.2 Hz, 1H), 7.24 (dd, J = 3.6, 1.0 Hz,1H), 7.03 (dd, J = 5.2, 3.7 Hz, 1H), 6.80 (d,J = 8.4 Hz, 1H), 5.24 (s, 2H). MS: (calc.)350.0; (obt.) 351.0 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),7.63 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 8.4, 2.2Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.33 (d,J = 5.1 Hz, 1H), 7.27 (dd, J = 8.2, 2.2 Hz, 1H),7.22 (dd, J = 3.5, 1.0 Hz, 1H), 7.06-7.01 (m,2H), 6.78 (d, J = 8.4 Hz, 1H), 5.12 (br s, 2H),4.22-4.17 (m, 4H), 2.16 (quintet, J = 5.5 Hz,2H) MS: (calc.) 366.1; (obt.) 367.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 10.19 (s, 1H),9.61 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.68(d, J = 8.6 Hz, 2H), 7.44 (d, J = 2.2 Hz, 1H),7.34 (dd, J = 5.1, 1.2 Hz, 1H), 7.27 (dd, J =8.2, 2.2 Hz, 1H), 7.23 (dd, J = 3.7, 1.2 Hz,1H), 7.03 (dd, J = 5.1, 4.1 Hz, 1H), 6.79 (d,J = 8.4 Hz, 1H), 5.13 (s, 2H), 2.09 (s, 3H). MS:(calc.) 351.1; (obt.) 352.3 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.46 (s, 1H),7.68 (s, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.57(d, J = 7.8 Hz, 1H), 7.48 (s, 2H), 7.34 (dd,J = 5.2, 1.0 Hz, 1H), 7.23 (dd, J = 8.4, 2.2 Hz,1H), 7.20 (dd, J = 3.6, 1.2 Hz, 1H), 7.03 (dd,J = 5.1, 3.7 Hz, 1H), 6.85 (d, J = 15.7 Hz,1H), 6.76 (d, J = 8.4 Hz, 1H), 5.20 (s, 2H).MS: 400.07 (calc), 401.1 (obs).
1H NMR: (DMSO) δ (ppm): 9.97 (s, 1H),8.99 (dd, J = 4.1, 1.6 Hz, 1H), 8.68 (d, J =1.8 Hz, 1H), 8.50 (d, J = 8.2 Hz, 1H), 8.29(dd, J = 8.8, 2.0, 1H), 8.10 (d, J = 8.8 Hz,1H), 7.62 (dd, J = 8.2, 4.3 Hz, 1H), 7.50 (d,J = 2.2 Hz, 1H), 7.34 (dd, J = 4.9, 0.98 Hz,1H), 7.30 (dd, J = 8.2, 2.2 Hz, 1H), 7.24 (dd,J = 3.5, 1.2 Hz, 1H), 7.04 (dd, J = 5.1, 3.5Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.24 (s, 2H)MS: 345.09 (calc), 346.0 (obs).
1H NMR: (DMSO) δ (ppm): 9.33 (s, 1H),7.68 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 15.5 Hz,1H), 7.33 (dd, J = 5.1, 0.98 Hz, 1H), 7.22 (d,J = 2.2 Hz, 1H), 7.20 (d, J = 0.98 Hz, 2H),7.19 (d, J = 1.2 Hz, 1H), 7.16 (d, J = 8.2 Hz,1H), 7.02 (dd, J = 5.1, 3.7 Hz, 1H), 7.00 (d,J = 8.4 Hz, 1H), 6.76 (t, J = 8.6 Hz, 1H), 5.19(s, 2H), 3.81 (s, 3H), 3.79 (s, 3H). MS:380.12 (calc), 381.1 (obs).
1H NMR: (DMSO) δ (ppm): 9.73 (s, 1H),8.07 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz,2H), 7.51 (d, J = 1.8 Hz, 2H), 7.44 (s, 1H),7.33 (d, J = 5.1 Hz, 1H), 7.28 (dd, J = 8.2, 1.6Hz, 1H), 7.23 (d, J = 3.5 Hz, 1H), 7.03 (t, J =4.1 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.30 (s,2H), 5.16 (s, 2H). MS: 359.11 (calc), 360.1(obs).
1H NMR: (DMSO) δ (ppm): 9.79 (s, 1H),8.40 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 7.88 (s,1H), 7.82 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 1.8Hz, 1H), 7.33 (dd, J = 4.9, 0.78 Hz, 1H), 7.29(d, J = 8.2, 2.2 Hz, 1H), 7.23 (d, J = 3.5 Hz,1H), 7.13 (s, 1H), 7.04 to 7.02 (m, 1H), 6.79(d, J = 8.4 Hz, 1H), 5.19 (s, 2H). MS: 360.1(calc), 361.1 (obs).
1H NMR: (DMSO) δ (ppm): 9.68 (s, 1H),7.40 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 5.1, 1.2Hz, 1H), 7.27 (dd, J = 8.2, 2.2 Hz, 1H), 7.21(dd, J = 3.5, 1.2 Hz, 1H), 7.13 (d, 2.2 Hz, 2H),7.01 (dd, J = 5.1, 3.5 Hz, 1H), 6.78 (d, J = 8.2Hz, 1H), 6.66 (t, J = 2.2 Hz, 1H), 5.11 (s, 2H),3.79 (s, 6H). MS: 354.1 (calc), 355.1 (obs).
1H NMR: (DMSO) δ (ppm): 9.72 (1H, s),7.97 (2H, d, 8.6 Hz), 7.50 to 7.46 (3H, m,),7.34 (1H, dd, 3.9 and 1.2 Hz), 7.28 (1H, dd, 6.1and 2.3 Hz), 7.23 (1H, dd, 2.3 and 1.2 Hz),7.04 (1H, dd, 3.5 and 1.4 Hz), 6.79 (1H, d, 8.4Hz, 6.59 (1H, s), 5.18 (2H, s), 3.52 (3H, s),2.25 (6H, s,) MS: 429.2 (calc), 430.2 (obs).
1H NMR: (DMSO) δ (ppm): 9.49 (1H, s),7.88 (2H, d, 8.6 Hz), 7.43 (1H, s), 7.35(1H, d, 8.0 Hz), 7.26 to 7.21 (2H, m), 7.04 to6.99 (3H, m), 6.78 (1H, d, 8.4), 5.1 (2H, s),3.74 to 3.73 (4H, m), 3.29 to 3.23 (4H, m)MS: 379.1 (calc), 380.1 (obs).
1H NMR: (DMSO) δ (ppm): 9.70 (1H, s),8.03 (2H, d, 8.8 Hz), 7.93 (1H, d, 8.8), 7.70-7.62 (1H, m), 7.46 (1H, d, 2.2 Hz), 7.34(1H, dd, 4.1 and 1.0 Hz), 7.28 (1H, dd, 6.1 and2.2 Hz), 7.24 (1H, dd, 2.5 and 1.0), 7.03(1H, dd, 3.5 and 1.6), 6.80 (1H, d, 8.4 Hz),5.14 (1H, s), 4.19 (2H, m), 2.12 (3H, s) MS:390.1 (calc, 391.2 (obs).
1H NMR: (DMSO) δ (ppm): 9.48 (s, 1H),7.87 (d, J = 9.0 Hz, 2H), 7.44 (d, J = 2.2 Hz,1H), 7.34 (d, J = 4.9 Hz, 1H), 7.26 (dd, J =8.4, 2.2 Hz, 1H), 7.23 (d, J = 3.5 Hz, 1H),7.03 (dd, J = 5.1, 3.7 Hz, 1H), 6.99 (d, J = 9.0Hz, 2H), 6.79 (d, J = 8.2 Hz, 1H), 5.09 (s,2H), 3.36 (t, J = 6.7 Hz, 4H), 2.45 (t, J = 4.9Hz, 4H), 2.23 (s, 3H). MS: 392.17 (calc),393.2 (obs).
1H NMR: (DMSO) δ (ppm): 9.87 (s, 1H),9.55 (s, 1H), 8.83 (s, 1H), 8.17 (q, J = 8.4 Hz,2H), 7.50 (s, 1H), 7.35 (d, J = 5.1 Hz, 1H),7.30 (dd, J = 8.2, 1.8 Hz, 1H), 7.24 (d, J = 3.3Hz, 1H), 7.04 (t, J = 4.5 Hz, 1H), 6.84 (d, J =8.4 Hz, 1H), 5.23 (s, 2H). MS: 351.05 (calc),352.0 (obs).
1H NMR: (DMSO) δ (ppm): 9.76 (1H, s),8.07 (2H, d, 8.6), 7.97 (2H, d, 8.4 Hz), 7.46(1H, s), 7.39-7.33 (3H, m), 7.29 (1H, dd, 6.1and 2.2), 7.24 (1H, d, 3.5), 7.04 (1H, dd, 3.5and 1.6 Hz), 6.91-6.89 (2H, m), 6.80(1H, d, 8.4), 5.19 (2H, s), 4.15 (1H, s). MS:430.1 (calc), 431.1 (obs).
1H NMR: (DMSO) δ (ppm): 9.58 (s, 1H),8.32 (s, 1H), 7.62 (d, J = 2.0 Hz, 2H), 7.42 (d,J = 2.0 Hz, 1H), 7.34 (d, J = 5.1 Hz, 1H), 7.28(dd, J = 8.2, 2.0 Hz, 1H), 7.23 (d, J = 2.9 Hz,1H), 7.03 (dd, J = 5.1, 3.7 Hz, 1H), 6.79 (d,J = 8.4 Hz, 1H), 5.15. (s, 2H). MS: 300.04(calc) 301.1 (obs)
1H NMR: (DMSO) δ (ppm): 9.58 (s, 1H),7.97 (dt, J = 41.5, 3.7 Hz, 2H), 7.54 (s, 1H),7.49 (t, J = 5.1 Hz, 1H), 7.29 (dd, J = 8.2, 2.0Hz, 1H), 7.24 (d, J = 2.9 Hz, 1H), 7.04 (t, J =4.9 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.17 (s,2H), 2.68 (s, 3H). MS: 364.07 (calc) 365.1(obs)
1H NMR: (DMSO) δ (ppm): 9.49 (1H, s),7.85 (2H, d, 8.6), 7.43 (1H, s), 7.34 (1H, d, 5.1Hz, 7.26 (1H, d, 6.1 Hz), 7.22 (1H, d, 3.5 Hz),7.03 (1H, dd, 5.1 and 0 Hz), 6.84-6.77(3H, m), 5.09 (2H, s) MS: 310.1 (calc), 311.1(obs).
1H NMR: (DMSO) δ (ppm): 9.59 (s, 1H);7.97 (d, J = 8.8 Hz; 2H);7.43 (d; J = 2.2 Hz;1H); 7.34 (dd; J = 1.2, 5.1 Hz; 1H); 7.27 (dd;J = 2.2, 8.2 Hz; 1H); 7.23 (dd; J = 1.2, 3.5 Hz;1H); 7.04 (d; J = 8.8 Hz; 2H); 7.03 (m, 1H);6.79 (d; J = 8.2 Hz; 1H); 5.12 (bs, 2H); 3.84(s, 3H). MS: calc: 324.4; found: 325.2 (M + H)
1H NMR: (DMSO) δ (ppm): 9.78 (s, 1H);7.93 (d, J = 8.5 Hz; 2H); 7.71 (d, J = 8.5 Hz;2H); 7.43 (d; J = 1.9 Hz; 1H); 7.33 (dd; J = 1.2,5.1 Hz; 1H); 7.28 (dd; J = 1.9, 8.3 Hz; 1H);7.23 (dd; J = 1.2, 3.5 Hz; 1H); 7.03 (dd; J =3.5, 5.1 Hz; 1H); 6.78 (d; J = 8.3 Hz; 1H);5.20 (bs, 2H). MS: calc: 371.9 and 373.9;found: 373.1 and 375.1 (M + H)
1H NMR: (DMSO) δ (ppm): 9.73 (s, 1H);7.99 (s, 1H); 7.97 (s, 1H); 7.56 (d, J = 7.2 Hz;1H); 7.50 (m, 2H); 7.45 (d; J = 2.1 Hz; 1H);7.33 (dd; J = 1.0, 5.1 Hz; 1H); 7.28 (dd;J = 2.1, 8.2 Hz; 1H); 7.23 (dd; J = 1.0, 3.5 Hz;1H); 7.03 (dd; J = 3.5, 5.1 Hz; 1H); 6.79 (d;J = 8.1 Hz; 1H); 5.12 (bs, 2H). MS: calc:334.4; found: 335.1 (M + H)
1H NMR: (CD3OD) δ (ppm): 8.52 (s, 1H);7.76 (d; J = 7.4 Hz; 1H); 7.65 (d; J = 8.4 Hz;1H); 7.63 (s, 1H); 7.56 (d; J = 2.0 Hz; 1H);7.49 (m, 1H); 7.37 (dd; J = 2.1, 8.3 Hz; 1H);7.34 (m, 1H); 7.23 (m, 2H); 7.02 (dd;
1H NMR: (DMSO) δ (ppm): 9.40 (s, 1H),7.50 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.34 (d,J = 5.3 Hz, 2H), 7.25 (d, J = 8.2 Hz, 1H), 7.22(d, J = 2.7 Hz, 1H), 7.03 (t, J = 4.9 Hz, 1H),6.78 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.6 Hz,1H), 5.06 (s, 2H), 4.23 (d, J = 4.1 Hz, 2H),3.30 (m, 2H), 2.93 (s, 3H) MS: 365.12 (calc)366.1 (obs)
1H NMR: (DMSO) δ (ppm): 9.90 (s, 1H);7.71 (s, 1H); 7.46 (d, J = 2.0 Hz; 1H); 7.35 (s,1H); 7.34 (m, 1H); 7.30 (dd; J = 2.0, 8.4 Hz;1H); 7.27 (d; J = 7.9 Hz; 1H); 7.24 (m, 1H);7.08 (d; J = 7.9 Hz; 1H); 7.04 (dd; J = 3.7, 5.1Hz; 1H); 6.80 (d; J = 8.2 Hz; 1H); 5.12 (bs,2H); 3.98 (s; 3H). MS: calc: 364.4; found:365.1 (M + H)
1H NMR: (DMSO) δ (ppm): 10.08 (s, 1H),8.27 (s, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.02 (d,J = 8.6 Hz, 1H), 7.60 (dd, J = 8.6, 2.0 Hz, 1H),7.43 (d, J = 2.3 Hz, 1H), 7.34 (dd, J = 5.0, 1.2Hz, 1H), 7.30 (dd, J = 8.2, 2.2 Hz, 1H), 7.24(dd, J = 3.5, 1.2 Hz, 1H), 7.03 (dd, J = 5.1, 3.5Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 5.25 (s,2H). MS: (calc.) 429.0 (d); (obt.) 430.0 (d)(MH)+.
1H NMR: (DMSO) δ (ppm): 9.87 (s, 1H),8.14 (s, 1H), 7.58 (s, 1H), 7.44 (d, J = 2.2 Hz,1H), 7.41 (s, 1H), 7.34 (dd, J = 5.1, 1.1 Hz,1H), 7.29 (dd, J = 8.4, 2.3 Hz, 1H), 7.03 (dd,J = 4.9, 3.5 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H),5.20 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H). MS:(calc.) 410.1; (obt.) 411.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 10.09 (s, 1H),8.99 (dd, J = 2.3, 0.8 Hz, 1H), 8.58 (dd,J = 4.7, 1.6 Hz, 1H), 8.38 (s, 1H), 8.33 (d,J = 1.4 Hz, 1H), 8.17 (ddd, J = 9.6, 3.9, 1.8 Hz,1H), 7.83 (dd, J = 8.5, 1.8 Hz, 1H), 7.53-7.50 (m, 2H), 7.46 (d, J = 2.2 Hz, 1H), 7.34(dd, J = 5.1, 1.2 Hz, 1H), 7.31 (dd, J = 8.2, 2.2Hz, 1H), 7.25 (dd, J = 3.5, 1.2 Hz, 1H), 7.03(dd, J = 5.1, 3.7 Hz, 1H), 6.81 (d, J = 8.4 Hz,1H), 5.74 (s, 2H). MS: (calc.) 427.1; (obt.)428.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.60 (s, 1H),7.82 (dd, J = 8.6, 2.2 Hz, 1H), 7.74 (d, J = 2.1Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.33 (dd,J = 5.1, 1.2 Hz, 1H), 7.26 (dd, J = 8.4, 2.3 Hz,1H), 7.21 (dd, J = 3.5, 1.2 Hz, 1H), 7.02 (dd,J = 5.1, 3.8 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H),6.77 (d, J = 8.4 Hz, 1H), 5.32 (s, 2H), 5.11 (s,2H), 4.94 (s, 2H). MS: (calc.) 352.1; (obt.)353.1 (MH)+.
1H NMR: (DMSO) δ (ppm): 7.21 (d, 1H),7.14 (d, 2H), 6.95 (d, 1H), 6.84-6.79 (m,3H), 6.62-6.57 (m, 2H), 6.49 (d, 1H), 3.80(m, 2H), 3.30 (m, 4H), 2.46 (m, 2H), 2.21 (m,4H). MS: (calc.) 463.2; (obt.) 464.2 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.62 (s, 1H);8.08 (bs, 2H); 7.97 (d, J = 8.5 Hz; 2H); 7.62(s, 1H); 7.45 (d, J = 8.2 Hz; 1H); 7.03 (d,J = 8.5 Hz; 2H); 6.82 (d, J = 8.2 Hz; 1H); 5.11(bs, 2H); 3.83 (s, 3H).MS: calc: 309.3; found: 310.1 (M + H)
1H NMR: (DMSO) δ (ppm): 9.63 (s, 1H);7.98 (d, J = 8.8 Hz; 2H); 7.81 (d, J = 2.0 Hz;1H); 7.61 (dd; J = 2.0, 8.4 Hz; 7.04 (d,J = 8.8 Hz; 2H); 6.85 (d, J = 8.4 Hz; 1H);3.85 (s, 3H).MS: calc: 310.3; found: 311.1 (M + H)
1H NMR: (DMSO) δ (ppm): 9.75 (s, 1H),8.38 (d, J = 1.0 Hz, 1H), 8.34 (s, 1H), 7.95(dd; J = 1.4, 8.4 Hz; 1H); 7.68 (d, J = 8.4 Hz,1H), 7.50 (d; J = 2.2 Hz; 1H); 7.34 (dd;J = 1.0, 5.0 Hz; 1H); 7.28 (dd; J = 2.2, 8.4 Hz;1H); 7.24 (dd; J = 1.4, 3.6 Hz; 1H); 7.04 (dd;J = 3.6, 5.0 Hz; 1H); 6.81 (d; J = 8.4 Hz; 1H);3.90 (s, 3H).MS: calc: 348.4; found: 349.1 (M + H)
1H NMR: (DMSO) δ (ppm): 9.88 (s, 1H);8.75 (s, 1H), 8.15 (dd; J = 1.0, 8.6 Hz; 1H);7.95 (dd, J = 1.0, 8.6 Hz, 1H), 7.49 (d, J =2.0 Hz, 1H), 7.34 (dd; J = 1.2, 5.1 Hz; 1H);7.30 (dd; J = 2.0, 8.3 Hz; 1H); 7.24 (dd;J = 1.2, 3.5 Hz; 1H); 7.04 (dd; J = 3.5, 5.1Hz; 1H); 6.81 (d; J = 8.3 Hz; 1H); 5.24 (bs,2H); 4.37 (s, 3H).MS: calc: 349.4; found: 350.1 (M + H)
1H NMR: (DMSO) δ (ppm): 9.80 (s, 1H);8.29 (d, J = 1.4 Hz, 1H), ), 8.00 (dd; J = 1.4,8.4 Hz; 1H); 7.76 (d, J 32 8.2 Hz, 1H), 7.46(d; J = 2.0 Hz; 1H); 7.34 (dd; J = 1.0, 5.0 Hz;1H); 7.30 (dd; J = 2.0, 8.4 Hz; 1H); 7.23 (dd;J = 1.0, 3.5 Hz; 1H); 7.04 (dd; J = 3.5, 5.0Hz; 1H); 6.80 (d; J = 8.2 Hz; 1H); 5.20 (bs,2H); 2.67 (s, 3H).MS: calc: 349.4; found: 350.0 (M + H)
1H NMR: (CD3OD) δ (ppm): 9.19 (s, 1H);7.99 (s, 1H); 7.86 (d; J = 8.5 Hz; 1H); 7.67(s, 1H), 7.64 (d; J = 8.5 Hz; 1H); 7.50 (s, 1H);7.37 (d; J = 8.5 Hz; 1H); 7.22 (d; J = 4.9 Hz;1H); 7.21 (m, 1H); 7.01 (t; J = 4.9 Hz; 1H);6.91 (d; J = 8.5 Hz; 1H).MS: calc: 334.4; found: 335.1 (M + H)
1H NMR: (DMSO) δ (ppm): 9.73 (s, 1H),8.62 (dt, J = 1.2; 6.8 Hz, 1H), 8.50 (d, J =0.7 Hz; 1H); 7.76 (d; J = 2.2 Hz; 1H); 7.66 (d,J = 0.7 Hz, 1H), 7.39 (dd; J = 1.6, 6.8 Hz;1H); 7.36 (dt; J = 1.6, 4.9 Hz; 1H); 7.26 (dd;J = 2.2, 8.2 Hz; 1H); 7.24 (dd; J = 1.2, 3.6Hz; 1H); 7.05 (m; 1H); 7.01 (dd; J = 1.2, 6.8Hz; 1H); 6.84 (d; J = 8.2 Hz; 1H); 5.13 (bs,2H).MS: calc: 334.4; found: 335.1 (M + H).
1H NMR: (DMSO) δ (ppm): 10.1 (s, 1H);9.52 (s, 1H); 8.00 (s, 1H); 7.92 (d, J = 7.0,2H); 7.49 (d, J = 7.0, 2H); 7.42 (m, 1H); 7.33(d, J = 8.0, 1H); 7.29 (s, 1H); 7.07 (s, 1H);6.93 (d, J = 8.0, 1H); 6.65 (d, J = 8.5, 1H);6.32 (s, 1H); 5.98 (m, 2H); 4.30 (s, 2H);3.65 (s, 3H); 3.58 (s, 3H).MS: calc: 460.5; found: 461.1 (M + H)
1H NMR: (DMSO) δ (ppm): 9.60 (s, 1H),7.96 (d, J = 8.0, Hz, 2H); 7.36 (d, J = 2.1Hz, 1H); 7.20 (dd, J = 2.1, 8.3 Hz, 1H); 7.03(d, J = 8.0, Hz, 2H); 7.00 (d, J = 3.5 Hz,1H); 6.78 (d, J = 8.3 Hz, 1H), 6.70 (dd, J =1.1, 3.5 Hz, 1H); 3.83 (s, 3H); 2.42 (d, J =1.1 Hz, 3H).MS: calc: 338.4; found: 338.4 (M + H).
1H NMR: (DMSO) δ (ppm): 9.70 (s, 1H),8.23 (s, 1H), 7.87 (dd; J = 1.0, 8.4 Hz; 1H);7.62 (d, J = 8.4 Hz, 1H), 7.48 (d; J = 2.0 Hz;1H); 7.34 (dd; J = 0.8, 4.8 Hz; 1H); 7.28 (dd;J = 2.0, 8.0 Hz; 1H); 7.23 (dd; J = 0.8, 3.6 Hz;1H); 7.03 (dd; J = 1.2, 4.8 Hz; 1H); 6.81 (d;J = 8.0 Hz; 1H); 5.15 (bs, 2H); 4.52 (t; J = 4.8Hz; 2H); 4.35 (t; J = 4.8 Hz; 2H); 2.60 (s, 3H);1.91 (s, 3H).MS: calc: 434.5; found: 435.2 (M + H)
1H NMR: (DMSO) δ (ppm): 9.70 (s, 1H),8.22 (s, 1H), 7.84 (dd; J = 1.4, 8.2 Hz; 1H);7.57 (d, J = 8.4 Hz, 1H), 7.49 (d; J = 2.2 Hz;1H); 7.34 (dd; J = 1.4, 5.1 Hz; 1H); 7.28 (dd;J = 2.2, 8.2 Hz; 1H); 7.23 (dd; J = 1.0, 3.5 Hz;1H); 7.04 (dd; J = 3.5, 5.1 Hz; 1H); 6.80 (d;J = 8.4 Hz; 1H); 5.14 (bs, 2H); 5.00 (bs, 1H);4.28 (t; J = 5.4 Hz; 2H); 3.72 (t; J = 5.4 Hz;2H); 2.59 (s, 3H);MS: calc: 392.5; found: 393.2 (M + H)
1H NMR: (DMSO) δ (ppm): 3.62 (s, 3H),3.69 (s, 3H), 4.34 (d, J = 5.7 Hz, 2H), 6.03(m, 2H), 6.35 (d, J = 2.2 Hz, 1H), 6.68 (d,J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H),7.32 (t, J = 7.2 Hz, 1H), 7.37 (dd, J = 10.4,1.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.52(d, J = 8.0 Hz, 2H), 7.59 (d, J = 7.6 Hz, 2H),7.95 (d, J = 8.0 Hz, 2H), 8.03 (br s, 1H),9.58 (br s, 1H), 10.00 (br s, 1H)MS: (calc.) 454.5; (obt.) 455.4 (MH)+
1H NMR: (DMSO) δ (ppm): 3.54 (s, 3H),3.68 (s, 3H), 4.30 (d, J = 5.9 Hz, 2H), 5.92(s, 2H), 6.13 (t, J = 6.3 Hz, 1H), 7.01 (d, J =8.2 Hz, 1H), 7.21 (d, J = 15.7 Hz, 1H), 7.29(dd, J = 8.4, 2.3 Hz, 1H), 7.33 (d, J = 7.2Hz, 1H), 7.42-7.50 (m, 4H), 7.54-7.64(m, 4H), 8.34 (s, 1H), 9.55 (br s, 1H), 10.21(br s, 1H)MS: (calc.) 510.6; (obt.) 511.2 (MH)+
1H NMR: (DMSO) δ (ppm): 4.30 (d, J = 5.9Hz, 2H), 6.98 (d, J = 8.3 Hz, 1H), 7.26-7.36(m, 2H), 7.42 (t, J = 7.3 Hz, 2H), 7.50-7.60(m, 2H), 7.97 (br s, 1H), 9.47 (br s, 1H), 9.93(br s, 1H)MS: (calc.) 347.4; (obt.) 348.1 (MH)+
1H NMR: (DMSO) δ (ppm): 1.34-1.46(m, 4H), 1.60-1.74 (m, 4H), 2.38 (t, J = 6.8Hz, 2H), 2.47 (t, J = 7.0 Hz, 2H), 6.98 (d,J = 8.2 Hz, 1H), 7.20-7.70 (m, 15H), 7.96(s, 1H), 8.10 (s, 1H), 9.34 (br s, 1H), 10.00(br s, 1H)MS: (calc.) 492.6: (obt.) 493.5 (MH)+
1H NMR: (400.2 MHz, DMSO) δ (ppm):9.52 (bs, 1H); 8.83 (s, 2H); 8.44 (s, 1H);8.20 (d, J = 7.6 Hz, 1H); 8.15 (d, J = 8.6 Hz,1H); 8.05 (d, J = 8.0 Hz, 1H); 7.75 (dd;J = 1.8, 8.6 Hz; 1H); 7.69 (m, 2H); 7.37 (d,J = 1.8 Hz, 1H); 7.31 (dd; J = 1.2, 5.1 Hz;1H); 7.25 (dd; J = 2.2, 8.4 Hz; 1H); 7.19 (dd;J = 1.2, 3.5 Hz; 1H); 7.01 (dd; J = 3.5, 5.1Hz; 1H); 6.74 (d, J = 8.2 Hz, 1H); 5.16 (bs,2H); 3.96 (t, J = 4.3 Hz, 4H); ); 3.07 (t, J =4.3 Hz, 4H); MS: calc: 570.7; found: 571.3(M + H)
1H NMR: (400.2 MHz, DMSO) δ (ppm):9.59 (bs, 1H); 8.92 (s, 2H); 8.75 (bs, 1H);7.63 (d, J = 1.2 Hz, 1H); 7.61 (m, 1H); 7.57(m, 4H); 7.41 (m, 3H); 7.33 (dd; J = 1.2, 5.1Hz; 1H); 7.29 (m, 2H); 7.23 (dd; J = 1.2, 2.5Hz; 1H); 7.03 (dd; J = 3.7, 5.1 Hz; 1H); 6.78(d, J = 8.2 Hz, 1H); 5.22 (bs, 2H); 3.93 (t, J =3.9 Hz, 4H); ); 3.60 (t, J = 3.9 Hz, 4H).MS: calc: 575.7; found: 576.3 (M + H)
1H NMR: (400 MHz, DMSO-d6) δ (ppm):9.80 (s, 1H), 8.98 (d, J = 2.2 Hz, 1H), 8.60(dd, J = 4.7, 1.6 Hz, 1H), 8.17 (d, J = 8.6 Hz,1H), 8.12 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.6Hz, 2H), 7.52 (dd, J = 7.2, 4.1 Hz, 1H), 7.48(s, 1H), 7.35 (d, J = 4.1 Hz, 1H), 7.29 (dd,J = 8.4, 2.3 Hz, 1H), 7.24 (d, J = 3.3 Hz, 1H),7.04 (dd, J = 5.1, 1.4, 1H), 6.80 (d, J = 8.2Hz, 1H), 5.19 (s, 2H).LRMS: (m/z): 372.3 (MH+).
1H NMR: (Acetone-d6) δ (ppm): 9.37 (bs,1H), 9.35 (bs, 1H), 8.47 (d, 1.2 Hz, 8.38(d, J = 3.9 Hz, 1H), 7.97 (s, 1H), 7.87 (d,J = 8.4 Hz, 2H), 7.64 (d, J = 7.4 Hz, 1H), 7.35(d, J = 8.2 Hz, 2H), 7.25 (dd, J = 8.4, 2.3 Hz,1H), 7.22 (dd, J = 5.1, 1.2 Hz, 1H), 7.16 (dd,J = 3.7, 1.2 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H),6.93 (d, J = 1.6 Hz, 1H), 6.86 (d, J = 8.4 Hz,1H), 5.01 (s, 2H), 4.31 (d, J = 6.3 Hz, 2H).LRMS: (m/z): 460.2 (MH+).
1H NMR: (400.2 MHz, CD3OD) δ (ppm):7.95 (br.s, 1H), 7.75 (m, 1H), 7.68 (m, 2H),7.53 (t, 1H, J = 7.6 Hz), 7.42 (s, 1H), 7.33 (d,1H, J = 8.2 Hz), 7.20 (m, 2H), 7.00 (m, 1H),6.87 (d, 1H, J = 8.3 Hz), 3.72 (s, 2H), 3.60(m, 4H), 2.68 (m, 4H).MS: calc: 500.1; found: 501.2 (M + H)
1H NMR: (400.2 MHz, CDCl3) δ (ppm):2.625 (t, J = 5 Hz, 4H), 3.35 (t, J = 5 Hz, 4H),3.59 (s, 2H), 4.00 (s, 2H), 6.84 (d, J = 8 Hz,1H), 6.90 (d, J = 9 Hz, 2H), 7.01 (m, 1H), 7.16(m, 2H), 7.25 (m, 6H), 7.50 (s, 1H), 7.75 (s,1H), 7.81 (d, J = 9 Hz, 2H).MS: calc: 468.0; found: 469.0 (M + H)
1H NMR: (400.2 MHz, CD3OD) δ (ppm):7.51 (br.s. 2H), 7.38 (s, 1H), 7.16-7.27 (m,5H), 6.9-7.1 (m, 2H), 6.84 (m, 1H), 2.42 (m,4H), 1.76 (m, 4H), 1.49 (m, 4H).MS: calc: 421.2; found: 422.2 (M + H)
1H NMR (DMSO-d6) D(ppm): 11.57 (s, 1H),9.81 (s, 1H), 7.95-7.92 (m, 3H), 7.68 (td,J = 7.2, 1.4 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H),7.42 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 5.1 Hz,1H), 7.34 (dd, J = 8.2, 2.0 Hz, 1H), 7.27 (d,J = 3.3 Hz, 1H), 7.24-7.20 (m, 2H), 7.05 (dd,J = 4.9, 3.5 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H),5.17 (s, 2H). (The NH2 group is missing,overlapped by H2O).MS (m/z): 468.53 (calc) 469.2 (MH+)(found).
1H NMR: (CD3OD) δ (ppm) 7.73 (d, J = 3.3Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.34 (dd,J = 8.2, 2.2 Hz, 1H), 7.23-7.19 (m, 2H),7.01 (dd, J = 4.7, 3.7 Hz, 1H), 6.96 (d, J = 3.9Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 4.17 (d,J = 13.1 Hz, 2H), 3.00-2.90 (m, 2H), 2.04(d, J = 12.1 Hz, 2H), 1.60-1.54 (m, 2H).
1H NMR: (DMSO) δ (ppm): 10.03 (s, 1H),8.45 (s, 1H), 8.38 (d, J = 7.6 Hz, 1H), 7.99(d, J = 7.6 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H),7.32 (dd, J = 11.9, 5.1 Hz, 1H), 7.28 (d, J =2.0 Hz, 1H), 7.03 (d, J = 4.9 Hz, 1H), 6.78(d, J = 8.2 Hz, 1H), 5.27 (s, 2H), 3.73 (t, J =6.3 Hz, 2H), 3.48 (m, 4H), 2.54 (t, J = 6.5Hz, 2H), 2.41 (m, 4H). MS: 476.15 (calc),477.2 (obs).
1H NMR: (DMSO) δ (ppm): 9.62 (s, 1H),7.96 (d, J = 9.0 Hz, 3H), 7.52 (m, 1H), 7.42(d, J = 2.5 Hz, 1H), 7.19 (dd, J = 8.6, 2.5 Hz,1H), 7.04 (d, J = 8.8 Hz, 2H), 7.03 (s, 1H),6.85 (d, J = 8.4 Hz, 1H), 5.11 (s, 2H), 3.83(s, 3H). MS: 308.13 (calc), 309.2 (obs).
The compounds of the invention can be prepared according to the reaction schemes for the examples illustrated below utilizing methods known to one of ordinary skill in the art. These schemes serve to exemplify some procedures that can be used to make the compounds of the invention. One skilled in the art will recognize that other general synthetic procedures may be used.
The compounds of the invention can be prepared from starting components that are commercially available. Any kind of substitutions can be made to the starting components to obtain the compounds of the invention according to procedures that are well known to those skilled in the art.
The compounds according to paragraphs [0083]-[0088] can be routinely synthesized using techniques described herein in conjunction with the teachings of WO 03/087057.
The compounds according to paragraphs [0098]-[0110] can be routinely synthesized using techniques described herein in conjunction with the teachings of WO 03/076422.
The compounds according to paragraphs [0115]-[0124] can be routinely synthesized using techniques described herein in conjunction with the teachings of WO 03/075929.
The compounds according to paragraphs [0125]-[0135] can be routinely synthesized using techniques described herein in conjunction with the teachings of WO 03/076395.
The compounds according to paragraphs [0136]-[0145] can be routinely synthesized using techniques described herein in conjunction with the teachings of WO 03/076400.
The compounds according to paragraphs [0146]-[0157] can be routinely synthesized using techniques described herein in conjunction with the teachings of WO 03/076401.
The compounds according to paragraphs [0158]-[0166] can be routinely synthesized using techniques described herein in conjunction with the teachings of WO 03/076421.
The compounds according to paragraphs [0167]-[0175] can be routinely synthesized using techniques described herein in conjunction with the teachings of WO 03/076430.
The compounds according to paragraphs [0176]-[0186] can be routinely synthesized using techniques described herein in conjunction with the teachings of WO 03/076438.
The compounds according to paragraphs [0187]-[0194] can be routinely synthesized using techniques described herein in conjunction with the teachings of WO 03/92686.
The compounds according to paragraph [0195] can be routinely synthesized using techniques described herein in conjunction with the teachings of WO 03/024448.
The compounds according to paragraphs [0196]-[0197] can be routinely synthesized using techniques described herein in conjunction with the teachings of JP 2003137866.
The compounds according to paragraph [0198]-[0199] can be routinely synthesized using techniques described herein in conjunction with the teachings of JP 11-269146 (1999).
The compounds according to paragraphs [0200]-[0201] can be routinely synthesized using techniques described herein in conjunction with the teachings of JP 11-302173 (1999).
The compounds according to paragraphs [0202]-[0203] can be routinely synthesized using techniques described herein in conjunction with the teachings of JP 2001131130.
The compounds according to paragraphs [0204]-[0205] can be routinely synthesized using techniques described herein in conjunction with the teachings of JP 10152462, JP 2002332267, and JP 11-302173.
The compounds according to paragraphs [0206]-[0207] can be routinely synthesized using techniques described herein in conjunction with the teachings of U.S. Pat. No. 6,174,905.
The compounds according to paragraphs [0206] can be routinely synthesized using techniques described herein in conjunction with the teachings of WO01/70675.
To a solution of potassium tert-butoxide (14.5 g; 129.2 mmol) and copper(I) chloride (301 mg; 3.04 mmol) in ethyleneglycol dimethylether (120 ml_), stirred at O° C. under nitrogen, a solution of I-bromo-4-nitro-benzene (I1 6.141 g; 30.4 mmol) and O-methyl-hydroxylamine hydrochloride (3.174 g; 38 mmol) in N,N-dimethylformamide (65 mU was added drop wise over 103 min, the cooling bath was removed and the mixture was allowed to react at room temperature for 3 h, diluted with ethyl acetate (600 mU and washed with saturated aqueous ammonium chloride. The organic layer was dried (MgSO4), filtered and concentrated. After purification by flash chromatography (eluent 25% ethyl acetate in hexane), 4.96 g (75% yield) of compound 2 were obtained.
1H NMR: (400.2 MHz, CDCl3) δ (ppm): 7.98 (d, J=9.24, IH); 7.02 (d, J=I.98, IH); 6.82 (dd, J=1.98 and 9.24, IH); 6.12 (bs, 2H).
A suspension of bromoarene 2 (5.85 g; 26.9 mmol) (or any other haloarene of choice); 2-thiopheneboronic acid (4.56 g, 35.6 mmol); (or the any other arylboronic acid of choice), tri-o-tolyl-phosphine (2.69 g; 8.8 mmol) and potassium carbonate (11.1 g; 80 mmol) in degassed ethyleneglycol dimethylether (70 mL) and water (35 mU, was treated with tetrakis(triphenylphosphine)palladium(0) (2.04 g, 1.77 mmol) and the mixture stirred on a preheated oil bath at 80° C. for 18 h, diluted with dichloromethane (300 mL), washed with water, dried (MgSO4) and concentrated. Purification by flash chromatography (eluent 50% ether in hexane) afforded compound 3 (5.63 g, 95% yield).
1H NMR: (400.2 MHz, DMSO) δ (ppm): 7.97 (d, J=9.0, IH); 7.69 (dd, J=1.2 and 5.1, IH); 7.60 (dd, J=1.2 and 3.6, 1H); 7.49 (bs, 2H); 7.27 (d, J=2.0, IH); 7.18 (dd, J=3.6 and 5.1, IH); 6.97 (dd, J=2.0 and 9.0, IH).
To a solution of nitrophenylamine (3, 460 mg, 2.1 mmol), (or any other nitrophenylamine of choice, 1 eq); 4-[(3,4-dimethoxy-phenylamino-4-methyl]-benzoic acid (4, see below), 761 mg, 2.65 mmol) (or any other acid of choice, 1.3 eq) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1095 mg, 2.47 mmol) in pyridine (15 mL), 60% sodium hydride in oil (563 mg, 14.1 mmol) was added portion wise under a stream of nitrogen, and the reaction was allowed to progress at room temperature for 2.5 h and diluted with toluene. Excess of NaH was quenched with acetic acid and the whole mixture was concentrated, re-dissolved in ethyl acetate and washed with a solution of NaHCO3 in brine, dried (MgSO4) and concentrated. After purification by flash chromatography (eluent 30% to 75% AcOEt in hexane), 883 mg (1.80 mmol, 86% yield) of amide 5 were obtained.
1H NMR: (400.2 MHz, DMSO) δ (ppm): 10.8 (s, IH); 8.10 (d, J=2.0, IH); 8.06 (d, J=8.6, 1H); 7.90 (d, J=8.2, 2H); 7.74 (dd, J=LO and 4.9, IH); 7.72 (dd, J=LO and 3.5, IH); 7.69 (dd, J=2.2 and 8.7, IH); 7.53 (d, J=8.2, 2H); 7.22 (dd, J=3.5 and 4.9, IH); 6.64 (d, J=8.6, IH); 6.31 (d, J=2.0, IH); 6.01 (t, J=6.1, IH); 5.98 (dd, J=2.2 and 8.4, IH); 4.32 (d, J=6.1, 2H); 3.66 (s, 3H); 3.59 (s, 3H).
To a solution of 3,4-dimethoxy-phenylamine (786 mg; 5.13 mmol) and dibutyltridichloride (219 mg; 0.72 mmol) in ethyleneglycol dimethylether (7 ml_), 4-formyl-benzoic acid (748 mg; 4.98 mmol) was added. The suspension was stirred at room temperature for 10 min, treated with phenylsilane (1.0 mL; 7.9 mmol) and the mixture stirred at the same temperature for 12 h. Methanol and a few drops of water were added, stirred for 5 h, concentrated under vacuum, suspended in dichloromethane and stirred for one day at room temperature. After filtration, pure acid 4 (1.13 g; 79% yield) was obtained as a beige solid.
1H NMR: (400.2 MHz, DMSO) δ (ppm): 7.86 (d, J=8.2, 2H); 7.44 (d, J=8.2, 2H); 6.63 (d, J=8.5, IH); 6.29 (d, J=2.3, IH); 5.96 (dd, J=2.3, 8.5, IH); 5.96 (bs, IH); 4.28 (s, 2H); 3.64 (s, 3H); 3.58 (s, 3H).
A suspension of compound 5 (250 mg, 0.511 mmol) (or any other nitroamide of choice, 1 eq) and tin(II) chloride dihydrate (2.30 g, 10.2 mmol) in a 1:1:1 mixture THF/MeOH/water (18 mU was stirred at 75° C. in a sealed tube for I h, diluted with ethyl acetate and washed with saturated aqueous solution of NaHCO3, dried over Na2SO4 and purified by flash chromatography, eluent 20% EtOAc in dichloromethane, to afford 138 mg (59% yield) of the title compound 6.
1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.66 (s, IH); 7.92 (d, J=8.4, 2H); 7.46 (d, J=8.4, 2H); 7.44 (d, J=2.0, IH); 7.34 (dd, J=I.1; 5.0, IH); 7.27 (dd, J=2.0; 8.2, IH); 7.22 (dd, J=LI and 3.6, IH); 7.03 (dd, J=3.6, 5.0, IH); 6.78 (d, J=8.5, IH); 6.64 (d, J=8.5, IH); 6.31 (d, J=2.5, IH); 6.01-5.97 (m, 2H); 5.14 (bs, 2H); 4.30 (d, J=6.1, 2H); 3.66 (s, 3H); 3.58 (s, 3H).
1H NMR: (DMSO) δ (ppm): 9.66 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H),7.55-7.53 (m, 2H), 7.49-7.43 (m, 3H), 7.39 (dd, J = 4.7, 1.6 Hz, 1H), 7.33(dd, J = 8.2, 2.2 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.6 Hz, 1H),6.31 (d, J = 2.7 Hz, 1H), 6.00-5.75 (m, 2H), 5.01 (s, 2H), 4.30 (d, J = 6.1Hz, 2H), 3.66 (s, 3H), 3.59 (s, 3H). MS: (calc.) 459.2; (obt.) 460.5 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.65 (s, 1H), 7.94-7.91 (m, 3H), 7.64 (s, 1H),7.46 (d, J = 7.4 Hz, 2H), 7.36 (s, 1H), 7.21 (d, J = 7.4 Hz, 1H), 6.79-6.76(m, 2H), 6.64 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 6.01-5.97 (m, 2H), 4.96 (s,2H), 4.30 (d, J = 4.3 Hz, 2H), 3.66 (s, 3H), 3.59 (s, 3H). MS: (calc.) 443.2;(obt.) 444.5 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.66 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H),7.54-7.46 (m, 5H), 7.37 (dd, J = 7.7, 7.7 Hz, 2H), 7.31 (dd, J = 8.4, 2.3 Hz,1H), 7.22 (dd, J = 7.2, 7.2 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.64 (d,J = 8.6 Hx, 1H), 6.31 (d, J = 2.5 Hz, 1H), 6.00-5.97 (m, 2H), 5.08 (s, 2H),4.30 (d, J = 6.1 Hz, 2H), 3.66 (s, 3H), 3.59 (s, 3H). MS: (calc.) 453.2; (obt.)454.5 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.67 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.87 (d,J = 8.0, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H), 7.55 (s,1H), 7.48 (d, J = 8.0 Hz, 2H), 7.41 (dd, J = 8.3, 2.3 Hz, 1H), 7.32 (ddd,J = 7.4, 7.4, 1.2 Hz, 1H), 7.25 (ddd, J = 7.5, 7.5, 1.2 Hz, 1H), 6.83 (d,J = 8.4 Hz, 1H), 6.64 (d, J = 8.6 Hz, 1H), 6.32 (d, J = 2.5 Hz, 1H),6.00-5.97 (m, 2H), 5.32 (s, 2H), 4.31 (d, J = 6.3 Hz, 2H), 3.66 (s, 3H),3.59 (s, 3H). MS: (calc.) 509.2; (obt.) 510.5 (MH)+.
1H NMR: (DMSO) δ (ppm): 9.60 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.46 (d,J = 8.2 Hz, 2H), 7.23 (dd, J = 3.3, 1.8 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H),6.91 (dd, J = 8.2, 2.2 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 6.64 (d, J = 8.6 Hz,1H), 6.31 (d, J = 2.5 Hz, 1H), 6.20 (t, J = 6.5 Hz, 1H), 6.08 (dd, J = 3.3, 1.8Hz, 1H), 5.99-5.96 (m, 2H), 5.00 (s, 2H), 4.29 (d, J = 6.1 Hz, 2H), 3.65 (s,3H), 3.58 (s, 3H), 1.35 (s, 9H). MS: (calc.) 542.3; (obt.) 543.5 (MH)+.
1H NMR (400 MHz, DMSO d6); 9.64 (s, 1H); 7.92 (d, 2H, J = 8.2 Hz);7.45 (d, 2H, J = 8.2 Hz); 7.43 (s, 1H); 7.35 (dd, 1H, J = 1.0, 5.1 Hz); 7.27(dd, 1H, J = 2.2, 8.4 Hz); 7.21 (dd, 1H, J = 1.2, 3.5 Hz); 7.02 (dd, 1H;J = 3.7, 5.1 Hz); 6.85 (t, 1H, J = 8.9 Hz); 6.78 (d, 1H, J = 8.2 Hz); 6.40(dd, 1H, J = 2.7, 14.0 Hz); 6.31-6.28 (m, 1H); 6.23 (bt, 1H, J = 6.2Hz); 5.13 (s, 2H); 4.30 (d, 2H, J = 6.0 Hz), 3.66 (s, 3H).
Following the same procedure as described in Example 11 Step 2, but substituting compound 1 for compound 13, the title compound 14 was obtained in 89% yield.
1H NMR: (400.2 MHz1 DMSO) δ (ppm): 8.11 (d, J=2.15, IH); 7.73 (dd, J=2.15, 8.8, IH); 7.59 (bs, 2H); 7.45 (dd, J=LI, 5.4, IH); 7.40 (dd, J=I.1, 3.8, IH); 7.09 (m, IH); 7.08 (dd, J=5.6, 8.8, IH).
Following the same procedure as described in Example 1, Step 3, but substituting compound 3 for compound 14, the title compound was obtained in 68% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 10.7 (s, IH); 8.19 (d, J=2.0, IH); 8.00 (dd, J=1.7, 8.6, IH); 7.89 (d, J=8.0, 2H); 7.80 (d, J=8.4, IH); 7.67 (d, J=3.8, IH); 7.64 (d, J=5.1, IH); 7.51 (d, J=8.0, 2H); 7.18 (t, J=3.8, IH); 6.64 (d, J=8.6, IH); 6.31 (d, J=2.4, IH); 6.31-5.96 (m, 2H); 4.31 (d, J=6.1, 2H); 3.66 (s, 3H); 3.59 (s13H).
Following the same procedure as described in Example 1, Step 4, but substituting compound 5 for compound 15, the title compound was obtained in 47% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.59 (s, IH); 7.90 (d, J=8.0, 2H); 7.46 (d, J=8.0, 2H); 7.45 (d, J=LI, IH); 7.34 (dd, J=I.1, 3.5, IH); 7.20 (d, J=8.1, IH); 7.09 (dd, J=3.5, 4.9, IH); 6.89 (dd, J=2.2, 8.1, IH); 6.64 (d, J=8.6, IH); 6.32 (d, J=2.5, IH); 6.00-5.97 (m, 2H); 5.07 (bs, 2H); 4.30 (d, J=6.1, 2H); 3.66 (s, 3H); 3.59 (s, 3H).
Following the same procedure as described in Example 2, Step 2, but substituting compound 14 for compound 13, the compound 17 was obtained in 92% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 10.72 (s, IH); 8.17 (d, J=2.0, IH); 7.96 (dd, J=2.0, 8.6, IH); 7.86 (d, J=7.9, 2H); 7.69 (d, J=8.6, IH); 7.51 (d, J=7.9, 2H); 6.63 (d, J=8.4, IH); 6.32 (d, J=2.0, IH); 6.01-5.96 (m, 2H); 4.31 (d, J=5.9, 2H); 3.65 (s, 3H); 3.58 (s, 3H).
Following the same procedures as described in Example 2, Steps 3, but substituting compound 15 for compound 17, the compound 18 was obtained in 46% yield.
1H NMR, (400.2 MHz, DMSO) δ (ppm): 9.55 (s, IH), 7.89 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, IH), 6.92 (d, J=2.3 Hz, IH), 6.69 (dd, J=8.4, 2.3 Hz, IH), 6.63 (d, J=8.4 Hz, IH), 6.30 (d, J=2.5 Hz, IH), 6.00-5.96 (m, 2H), 5.22 (s, 2H), 4.29 (d, J=6.3 Hz, 2H), 3.65 (s, 3H), 3.58 (s, 3H). MS: (calc.) 455.1; (obt.) 456.4, 458.4 (MH)+.
To a cold solution of methyl indole-5-carboxylate (2 g, 11.4 mmol) in glacial acetic acid at O° C. (15 ml) sodium cyanoborohydride (1.075 g, 17.1 mmol) was slowly added. The mixture was allowed to warm-up and stirred at room temperature for one more hour, cooled again to O° C. and quenched with H2O. The pH of the resultant solution was adjusted to the value of 12 by adding aqueous NaOH, extracted with DCM, washed with brine and dried over MgSO4. The dried extract was concentrated in vacuum and purified by flash chromatography (eluent 30% EtOAc in hexane) to give the title compound 20 (1.62 g, 80%) as a beige solid. 1H-NMR (DMSO) δ: 2.94 (t, J=8.6 Hz, 2H); 3.51 (dt, J=1.2, 8.6 Hz, 2H); 3.71 (s, 3H); 6.42 (d, J=8.0 Hz, 2H); 7.54 (m, 2H).
To a solution of 20 (300 mg, 1.69 mmol), 3,4,5-trimethoxybenzaldehyde (365 mg, 1.86 mmol) and dibutyltin dichloride (51 mg, 0.17 mmol) in THF (8 mL) was added phenylsilane (229 μl, 1.86 mmol). The mixture was stirred overnight at room temperature under nitrogen. Additional aldehyde and phenylsilane were added and the stirring continued until starting material was consumed. THF was evaporated in vacuum and the residue was purified by flash chromatography (eluent 20% EtOAc in hexane). The compound was further purified by re-crystallization in a mixture EtOAc/hexane and finally by a second flash chromatography (eluent 20% EtOAc in hexane) to give the title compound 21 (428 mg, 71%) as a white solid. 1H-NMR (DMSO) δ: 2.96 (t, J=8.4 Hz, 2H); 3.45 (t, J=8.7 Hz, 2H); 3.61 (s, 3H); 3.71 (s, 6H); 3.72 (s, 3H); 4.30 (s, 2H); 6.59 (s, 2H); 6.61 (d, J=8.4 Hz, IH), 7.54 (d, J=1.6 Hz, IH); 7.63 (dd, J=1.8, 8.4 Hz, IH).
A solution of LiOH×H2O (75 mg, 1.78 mmol) in H2O (5 ml) was added to a solution of ester 21 (426 mg, 1.19 mmol) in THF (5 ml). The mixture was stirred at room temperature overnight. THF was removed in vacuum and the remained aqueous solution was acidified to pH 1 using I N HCl. A precipitate formed which was collected by filtration, washed with H2O and dried to give the title compound 22 as a white solid, (320 mg, 78%). 1H-NMR (DMSO) δ: 2.96 (t, J=8.6 Hz, 2H); 3.43 (t, J=8.6 Hz, 2H); 3.62 (s, 3H); 3.72 (s, 6H); 4.29 (s, 2H); 6.58 (s, IH); 6.60 (s, 2H); 7.53 (s, IH); 7.61 (d, J=8.8 Hz, IH).
Following the procedures described in Example 1, steps 3 and 4, the title compound 23 was obtained as a yellow solid (294 mg, 41%). 1H NMR: (DMSO) δ (ppm): 9.37 (s, IH), 7.73 (d, J=8.4 Hz, IH), 7.70 (s, IH), 7.44 (d, J=2.0 Hz, IH), 7.33 (d, J=5.1 Hz, IH), 7.25 (dd, J=8.2, 2.0 Hz1 IH), 7.22 (d, J=3.3 Hz, IH), 7.03 (dd, J=4.2, 4.2 Hz, IH), 6.78 (d, J=8.4 Hz, IH), 6.66 (d, J=8.2 Hz, IH), 6.64 (s, 2H), 5.06 (s, 2H), 4.32 (s, 2H), 3.75 (s, 6H), 3.64 (s, 3H), 3.45 (t, J=8.3 Hz, 2H), 3.00 (t, J=8.5 Hz, 2H). MS: (calc.) 515.2; (obt.) 513.7 (MH)+.
To a stirred suspension of 2-hydroxy-5-methylbenzaldehyde (5 g, 36.7 mmol) and K2CO3 (12.7 g, 91.8 mmol) in DMF (30 ml_), ethyl bromoacetate (4.07 ml, 36.7 mmol) was added drop-wise. This mixture was allowed to stir for two hours under nitrogen at room temperature, and was then heated to 8O° C. and stirred overnight. The reaction was quenched with H2O to form a precipitate which was collected by filtration and purified by flash chromatography (eluent 5% EtOAc in hexane) to give the title compound 25 (2.30 g, 31%). 1H-NMR (CDCl3) δ: 1.45 (t, J=7.0 Hz, 3H); 2.47 (s, 3H); 4.45 (q, J=7.0 Hz, 2H); 7.26 (m, IH); 7.46 (m, 3H).
A mixture of the ester 25 (2.26 g, 11.1 mmol), JV-bromosuccinimide (2.37 g, 13.3 mmol) and VAZO (271 mg, 1.11 mmol) was refluxed overnight in CCl4 (50 mL) under nitrogen. The reaction mixture was cooled to the room temperature, diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuum. The residue was purified by flash chromatography (eluent 5% EtOAc in hexane) to give ethyl 5-bromomethyl-benzofuran-2-carboxylate. This compound was dissolved in dioxane (20 ml) and a solution of NaHCO3 (1.76 g, 20.9 mmol) in water (20 ml) was added. The reaction was stirred at 8O° C. during 16 h. The solvent was evaporated and the product was dissolved in EtOAc and washed with brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuum. The residue was purified by flash chromatography (eluent 20-40% EtOAc in hexane to give the title compound 26 (2.55 g, 61%) as a white solid. 1H-NMR (DMSO) δ: 7.74 (d, J=1.0 Hz, IH), 7.71-7.70 (m, IH), 7.65 (d, J=8.6 Hz, IH), 7.44 (dd, J=8.6, 1.8 Hz, IH), 5.31 (t, J=5.8 Hz, IH), 4.59 (d, J=5.7 Hz, 2H), 4.35 (q, J=7.1 Hz, 2H); 1.34 (t, J=7.0, 3H).
To a solution of the compound 26 (2.53 g, 11.49 mmol) in DCM (70 ml) was added MnO2 (9.99 g, 114.9 mmol). The reaction mixture was stirred at room temperature for 16 h and then filtered through a celite pad. The filtrate was concentrated in vacuum to give the title compound 27 (2.19 g, 87%) as a white solid. 1H-NMR (DMSO) δ: 10.07 (s, IH), 8.40-8.39 (m, IH), 8.03 (dd, J=8.6, 1.6 Hz, IH), 7.93-7.92 (m, 2H), 4.38 (q, J=7.1 Hz, 2H); 1.35 (t, J=7.0, 3H).
Following the same procedure as described in Example 4, Step 2, but substituting compound 20 and 3,4,5-trimethoxybenzaldehyde for 3,4,5-trimethoxyaniline and compound 27, the title compound was obtained in 99% yield. 1H NMR: (DMSO) δ (ppm): 7.75 (d, J=1.0 Hz, IH), 7.73 (d, J=1.0 Hz, IH), 7.66 (d, J=8.6 Hz, IH), 7.51 (dd, J=8.6, 1.8 Hz, IH), 6.11 (t, J=6.1 Hz, IH), 5.89 (s, 2H), 4.37-4.32 (m, 4H), 3.63 (s, 6H), 3.49 (s, 3H), 1.33 (t, J=7.0, 3H).
Following the same procedure as described in Example 4 step 3 and then the procedures described in Example 1, steps 3 and 4, the title compound 29 was obtained as an orange solid in 73% yield. 1H NMR: (DMSO) δ (ppm): 9.92 (s, IH), 7.77 (d, J=1.0 Hz, IH), 7.70 (s, IH), 7.65 (d, J=8.6 Hz, IH), 7.49 (dd, J=8.6, 1.8 Hz, IH), 7.46 (d, J=2.2 Hz, IH), 7.34 (dd, J=5.1, 1.0 Hz, IH), 7.30 (dd, J=8.2, 2.2 Hz, IH), 7.23 (dd, J=3.5, 1.2 Hz, IH), 7.04 (dd, J=5.1, 3.5 Hz, IH), 6.80 (d, J=8.4 Hz, IH), 6.12 (t, J=5.8 Hz, IH), 5.91 (s, 2H), 4.35 (d, J=5.9 Hz, 2H), 3.64 (s, 6H), 3.50 (s, 3H). MS: (calc.) 529.2; (obt.) 530.7 (MH)+.
Following the same procedure as described in Example 1 step 2, but substituting compound 2 for compound 30, the title compound 31 was obtained in 50% yield. 1H NMR: (DMSO) δ (ppm): 7.45 (dd, J=5.1, 1.2 Hz, IH), 7.32 (dd, J=3.7, 1.2 Hz, IH), 7.07 (dd, J=3.7, 1.2 Hz, IH), 7.02 (dd, J=7.7, 7.7 Hz, IH), 6.81 (dd, J=1.9, 1.9 Hz, IH), 6.78 (ddd, J=7.4, 1.6, 0.8 Hz, IH), 6.48 (ddd, J=8.0, 2.3, 1.0 Hz, IH), 5.20 (s, 2H). MS: (calc.) 176.4; (obt.) 175.1 (MH)+.
To a stirred solution of 31 (122 mg, 0.696 mmol), acid 4 (182 mg, 0.633 mmol) and BOP (308 mg, 0.696 mmol) in DMF (4 ml) was added B3N (265 μl, 1.90 mmol). The reaction was stirred 3 h at room temperature under nitrogen, quenched with H2O and evaporated. The residue was extracted with ethyl acetate, washed with saturated solutions of NH4Cl, NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuum to form a material which was purified by flash chromatography (eluent 40% EtOAc in hexane) to give the title compound 32 (70 mg, 25%) as a yellow solid. 1H NMR: (DMSO) δ (ppm): 10.25 (s, IH), 8.09-8.08 (m, IH), 7.73 (ddd, J=7.6, 3.7, 3.7 Hz, IH), 7.54 (dd, J=5.1, 1.0 Hz, IH), 7.49 (d, J=8.2 Hz, 2H), 7.45 (dd, J=3.7, 1.2 Hz, IH), 7.42-7.32 (m, 2H), 7.13 (dd, J=5.1, 3.7 Hz, IH), 6.64 (d, J=8.6 Hz, IH), 6.31 (d, J=2.5 Hz, IH), 6.00-5.97 (m, 2H), 4.31 (d, J=6.1 Hz, 2H), 3.65 (s, 3H), 3.59 (s, 3H). MS: (calc), 444.2; (obt.) 445.5 (MH)+.
1H NMR (400 MHz, DMSO d6): 10.07 (s, 1H); 7.98 (d, 2H, J = 8.3Hz); 7.64 (t, 1H, J = 7.5 Hz); 7.55 (d, 2H, J = 8.0 Hz); 7.35-7.27 (m,3H); 6.71 (d, 1H, J = 8.8 Hz); 6.38 (s, 1H); 6.05 (d, 1H, J = 8.8 Hz);5.80 (d, 1H, J = 3.5 Hz); 4.36 (s, 2H), 3.71 (s, 3H); 3.65 (s, 3H).
1H NMR (400 MHz, DMSO d6): 9.71 (s, 1H); 7.94 (d, 2H, J = 8.2 Hz);7.82 (s, 1H); 7.63 (d, 1H, J = 7.6 Hz); 7.52 (d, 1H; J = 7.82 Hz);7.48 (d, 2H, J = 8.4 Hz); 7.28-7.24 (m, 1H); 7.14-7.10 (m, 1H); 7.05 (s,1H); 6.64 (d, 1H, J = 8.6 Hz); 6.32 (d, 1H, J = 2.5 Hz); 6.03-5.97 (m,2H); 5.24 (s, 2H); 4.30 (d, 2H, J = 6.26 Hz), 3.65 (s, 3H); 3.58 (s, 3H).
1H NMR (400 MHz, DMSO d6): 9.53 (s, 1H); 7.88 (d, 2H, J = 8.2 Hz);7.45 (d, 2H, J = 8.4 Hz); 7.27 (d, 1H, J = 8.0 Hz); 6.67 (d, 1H, J = 11.5Hz); 6.30 (d, 1H, J = 2.5 Hz); 5.98-5.95 (m, 2H); 5.40 (s, 2H); 4.29 (d,2H, J = 6.4 Hz), 3.64 (s, 3H); 3.58 (s, 3H).
1H NMR (400 MHz, DMSO d6): 9.53 (s, 1H); 7.88 (d, 2H, J = 8.0Hz); 7.44 (d, 2H, J = 8.2 Hz); 7.27 (d, 1H, J = 8.0 Hz); 6.63 (d, 1H,J = 8.4 Hz); 6.30 (d, 1H, J = 2.0 Hz); 5.60-5.96 (m, 2H);5.40 (s, 2H); 4.27 (d, 2H, J = 6.0 Hz), 3.65 (s, 3H); 3.57 (s, 3H).
A stirred solution of 3-acetylpyridine (37, 30.0 g, 247.6 mmol) and N1N-dimethylformamide dimethylacetal (65.8 ml, 495.2 mmol) was refluxed under nitrogen for 4 h. The reaction mixture was concentrated to dryness and 50 ml of diethyl ether were added to give a brown suspension. The solid was separated by filtration, rinsed with Et2O and dried to afford the title compound 38 (36.97 g, 85% yield) as an orange crystalline solid. 1H NMR (400 MHz, CDCl3) δ(ppm): 9.08 (d, J=2.2 Hz, IH), 8.66 (dd, J=4.9, 1.4 Hz, IH), 8.26-8.23 (m, IH), 7.85 (d, J=12.1 Hz, IH), 7.40 (dd, J=7.8, 4.9 Hz, IH), 5.68 (d, J=12.1 Hz, IH), 3.20 (s, 3H), 2.97 (s, 3H).
To a stirred suspension of methyl 4-aminomethyl-benzoate hydrochloride (39, 15.7 g, 77.8 mmol) and diisopropylethylamine (29.5 ml, 171.2 mmol) in DMF (85.6 ml) at room temperature under nitrogen was added pyrazole-1-carboxamidine hydrochloride (12.55 g, 85.6 mmol). After 4 h the reaction mixture as a clear solution was concentrated to dryness under vacuum and saturated aqueous solution of NaHCO3 (35 ml) was added to give a suspension. The solid was separated by filtration and washed with cold water. The mother liquor was concentrated to produce additional amount of a solid material which was also collected by filtration. Both solids were combined, triturated with H2O (50 ml), filtered off, washed with cold H2O and diethyl ether, and dried to afford the title compound 40 (12.32 g, 77% yield) as a white crystalline solid. 1H NMR: (400 MHz, DMSO-d6) δ (ppm): 9.20-8.00 (m, 4H), AB system (δA=7.91, δB=7.39, JAB=8.2 Hz, 4H)1 4.39 (bs, 2H), 3.83 (s, 3H).
To a stirred suspension of compounds 38 (0.394 g, 1.9 mmol) and 40 (0.402 g, 2.3 mmol) in isopropyl alcohol (3.8 ml) at room temperature under nitrogen were added molecular sieves (0.2 g, 4A, powder). The reaction mixture was refluxed for 5 h. MeOH (50 ml) was added, and the reaction mixture was brought to reflux again. A cloudy solution formed which was filtered through a celite pad, filtrate was concentrated to dryness and the residue was triturated with ethyl acetate (3 ml), filtered off and dried to afford the title compound 41 (0.317 g, 52%) as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (bs, IH), 8.64 (m, IH), 8.38 (m, 2H), 7.98 (t, J=6.3 Hz, IH)17.88 (m, 2H), 7.48 (m, 3H)1 7.24 (d, J=5.1 Hz, IH)1 4.64 (d, J=6.1 Hz, 2H)1 3.81 (s, 3H).
To a stirred solution of 41 (3.68 g, 11.5 mmol) in a mixture of THF (23 ml) and MeOH (23 ml) was added a solution of LiOH—H2O (1.06 g, 25.3 mmol) in water (11.5 ml) at room temperature. The reaction mixture was stirred at 40° C. overnight, cooled to the room temperature, and an aqueous solution of HCl (12.8 ml, 2N) was added (pH˜4-5). The mixture was concentrated to dryness; the formed solid was triturated with water, filtered off, washed with minimum H2O and dried to afford the title compound 42 (3.44 g, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 12.83 (bs, IH), 9.23 (bs, IH)18.73-8.66 (m, IH) 8.46-8.36 [m, included at 8.42 (d, J=5.1 Hz)1 2H]1 8.02 (t, J=6.3 Hz, IH), 7.91 (d, J=8.2 Hz, 2H), 7.60-7.40 (m, 3H), 7.28 (d, J=5.1 Hz, IH), 4.67 (d, J=6.3 Hz, 2H).
Following the same procedure as described in Example 1, Steps 34, but substituting compound 4 for compound 42, the title compound was obtained in 62% yield.
1H NMR (400 MHz, DMSOd6), δ (ppm): 9.65 (s, IH), 9.22 (s, IH), 8.66 (d, J=3.7 Hz, IH), 8.39 (d, J=5.3 Hz, 2H), 8.01 (t, J=6.5 Hz, IH), 7.93 (d, J=8.4 Hz, 2H), 7.53-7.44 (m, 4H), 7.32 (dd, J=5.1, 1.2 Hz, IH), 7.28-7.24 (m, 2H), 7.21 (dd, J=3.7, 1.2 Hz, IH), 6.02 (dd, J=5.1, 3.5 Hz, IH), 6.78 (d, J=8.4 Hz, IH), 5.13 (s, 2H), 4.65 (d, J=5.7, 2H). MS: (calc.) 478.2; (obt.) 479.5 (MH)+.
The title compound 45 was obtained following the same procedure described in U.S. patent application Ser. No. 10/242,304, which is incorporated by reference in its entirety. The yield of the title compound was 49% yield. 1H NMR: (CD3OD) δ(ppm): 7.93 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz, 2H), 7.31 (bs, IH), 6.86 (bs, IH), 6.76 (dd, J=8.8, 2.47 Hz, IH), 4.49 (s, 2H), 3.94 (s, 3H).
The title compound 46 was obtained following the same procedure as for the reductive amination described in U.S. patent application Ser. No. 10/242,304, which is incorporated by reference in its entirety. The yield of the title compound was 92% yield. 1H NMR: (Acetone-d6) δ(ppm): 8.06 (t, J=7.9 Hz, 2H), 7.65 (d, J=8.4 Hz1 2H), 7.36 (d, J=8.8 Hz, IH), 7.21 (d, J=2.2 Hz, IH), 6.88 (dd, J=8.8, 2.6 Hz, IH), 4.87 (s, 2H), 3.95 (s, 3H). m/z: 315.2 (MH+).
The title compound 47 was obtained following the same procedure as for the Mitsunobu reaction described in U.S. patent application Ser. No. 10/242,304, which is incorporated by reference in its entirety. The yield of the title compound was 61% yield). 1H NMR: (CD3OD) δ(ppm): 7.98 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.8 Hz, IH), 7.22 (d, J=2.5 Hz, IH), 6.89 (dd, J=8.8, 2.7 Hz, IH), 4.68 (s, 2H), 4.09 (t, J=5.5 Hz, 2H), 3.88 (s, 3H), 2.77 (t, J=5.5 Hz, 2H), 2.35 (s, 6H). m/z: 386.4 (MH+).
The title compound 48 was obtained following the same procedure as for the ester hydrolysis described in U.S. patent application Ser. No. 10/242,304, which is incorporated by reference in its entirety. The yield of the title compound was 63% yield. 1H NMR: (CD3OD) δ(ppm): 8.43 (bs, IH), 7.92 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 7.38 (s, IH), 7.30 (d, J=8.4 Hz, IH), 6.87 (d, J=9.2 Hz, IH), 4.66 (d, J=5.1 Hz, 2H), 4.17 (t, J=4.7 Hz, 2H), 3.06 (bs, 2H), 2.54 (s, 6H). m/z: 372.4 (MH+).
The title compound 49 was obtained following the same procedure as Example 11 step 3, but substituting compound 4 for compound 48 in 83% yield. 1H NMR: (DMSOd6) δ(ppm): 10.92 (bs, IH), 8.26 (bs, IH), 8.16 (s, IH), 8.05 (d, J=9.0 Hz, IH), 7.82 (d, J=7.4 Hz, 2H), 7.74-7.67 (m, 2H), 7.31-7.21 (m, 5H), 6.79 (d, J=8.4 Hz, IH), 4.54 (d, J=4.7 Hz, 2H), 3.99 (bs, 2H), 2.59 (t, J=5.9 Hz, 2H), 2.20 (s, 6H).
The title compound 50 was obtained following the same procedures as Example 1, step 4, but substituting compound 5 for compound 49 in Tk yield. 1H NMR: (DMSCkl6) d (ppm): 9.68 (s, IH), 8.39 (bs, IH), 7.95 (d, J=7.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.44 (s, IH), 7.32 (s, IH), 7.27-7.21 (m, 3H), 7.02 (s, IH), 6.80 (t, J=9.8 Hz, 2H), 5.14 (s, 2H), 5.63 (d, J=4.5 Hz, 2H), 4.05 (bs, 2H), 2.76 (bs, 2H), 2.32 (s, 6H). m/z: 544.5 (MH+).
The title compound 52 was obtained following the same procedure as for the S-alkylation described in U.S. patent application Ser. No. 10/242,304, which is incorporated by reference in its entirety. The yield of the title compound was 55% yield.
1H NMR: (DMSOd6) δ(ppm): 7.85 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 3.80 (s, 2H), 3.34 (s, 3H). m/z: 351.2 (MH+).
The title compound 53 was obtained following the same procedure as for the ester hydrolysis described in U.S. patent application Ser. No. 10/242,304, which is incorporated by reference in its entirety. The yield of the title compound was 83% yield.
1H NMR: (DMSOd6) δ(ppm): 7.88 (d, J=8.2 Hz, 2H), 7.67 (d, J=6.8 Hz, IH), 7.55 (d, J=8.2 Hz, 2H), 7.53 (d, J=6.8 Hz, IH), 4.65 (s, 2H).
The title compound 54 was obtained following the same procedure as Example 1, step 3, but substituting compound 4 for compound 53 in 66% yield.
1H NMR: (DMSOd6) δ(ppm): 12.89 (bs, IH), 10.79 (s, IH), 8.12 (d, J=2.0 Hz, IH), 8.05 (d, J=8.8 Hz, 2H), 7.90-7.68 (m, 3H), 7.62 (d, J=8.4 Hz, 2H), 7.48 (bs, IH), 7.21 (dd, J=4.9, 3.7 Hz, IH), 4.65 (s, 2H). m/z: 539.5
The title compound 55 was obtained following the same procedure as Example 1, step 4, but substituting compound 5 for compound 54 in 14% yield. 1H NMR: (DMSOd6) d (ppm): 12.96 (s, 0.5H), 12.92 (s, 0.5H), 9.71 (s, IH), 7.96 (d, J=8.0 Hz, 2H), 8.35 (s, 0.5H), 7.79 (d, J=7.0 Hz, 0.5H), 7.64 (d, J=7.0 Hz, 0.5H), 7.62 (d, J=7.8 Hz, 2H), 7.50 (s, 0.5H), 7.48 (s, IH), 7.38 (d, J=4.9 Hz, IH), 7.32 (d, J=8.4 Hz, IH), 7.27 (d, J=3.1 Hz, IH), 7.08 (t, J=3.7 Hz, IH), 6.83 (d, J=8.4 Hz, IH), 5.19 (s, 2H), 4.69 (d, J=3.5 Hz, 2H). m/z: 509.5
To a vigorously stirred THF (40 mL) solution of 3,4-diaminothiophene light petroleum ether (300 mL) was added (1.00 g, 8.77 mmol). To this mixture a solution of di-t-butyldicarbonate (3.82 g, 17.5 mmol) in petroleum ether (10O mL) was added over a period of 30 min. Stirring was continued for 16 h and the solvents were distilled off. The residue was dissolved in DCM and washed twice with I N HCl1 dried over MgSO4 and concentrated in vacuum to a ˜20 mL volume. Hexane was slowly added with stirring and brown crystalline material precipitated out. The product was collected by filtration, washed with hexane and the mother liquor was allowed to crystallize again to yield a second crop of the product. The two crops were combined thus affording the title compound 57 (2.19 g, 80% yield). This procedure is essentially as described in Brugier et al., Tetrahedron (1997) 30: 10331-10344, which is incorporated by reference in its entirety. 1H NMR: (CDCl3) δ(ppm): 7.14 (s, 2H), 6.66 (bs, IH), 1.54 (s, 18H).
Neutral 3,4-diaminothiophene is obtained by dissolving 3,4-diaminothiophene dihydrochloride (Toronto Research) (2.O g, IO Jmmol) in a minimum volume of I N aqueous HCl and make the solution basic by addition of 2N aqueous NaOH. The precipitate is extracted twice with EtOAc and the combined organic layers dried with MgSO4 and concentrated (1.00 g, 82% recovery).
NBS (1.22 g, 6.87 mmol) was added to a solution of compound 57 (2.16 g, 6.87 mmol) in CCl4 (137 mL) at r.t. The mixture was stirred for 16 h. The solid material was filtered off and the filtrate was collected and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuum. The residue was purified by flash chromatography with DCM as an eluent affording the title compound 58 (1.92 g, 71% yield). 1H NMR: (CDCl3) δ(ppm): 7.30 (bs, IH), 6.00 (s, IH), 1.45 (s, 9H), 1.43 (s, 9H). m/z: 415.4/417.4 (M+Na/M+2+Na). This procedure is essentially as described in Brugier et al., Tetrahedron, 56: 2985-2993 (2000), which is incorporated by reference in its entirety.
In a flame-dried round-bottom flask, tetrakis(triphenylphosphine) palladium (59 mg, 0.051 mmol) was added to a degassed solution of compound 58 (400 mg, 1.02 mmol) in DME (5 mL). Phenylboronic acid (186 mg, 1.53 mmol), water (2.5 mL), and Na2CO3 (324 mg, 3.06 mmol) were successively added, degassing and purging with nitrogen between each addition. The mixture was refluxed under nitrogen atmosphere for 3 h and partitioned between Et2O and water. The organic layer was dried over MgSO4 and concentrated in vacuum. The title compound 59 (398 mg, 100% yield) was obtained as a brown oil. 1H NMR: (CDCl3) δ(ppm): 7.51-7.31 (m, 6H)1 1.54 (s, 18H). m/z: 413.5 (M+Na+). This procedure is essentially as described in Brugier et al., Tetrahedron, 56: 2985-2993 (2000), which is incorporated by reference in its entirety.
To a solution of compound 59 in glacial acetic acid (102 μL) was added a 30% solution of HBr in acetic acid (102 μL). The mixture was stirred for 16 h at r.t. and Et2O (10 mL) was added. The precipitate was collected by filtration and immediately dissolved in water, neutralized by addition of 2N aqueous NaOH and the precipitate was extracted with Et2O. The organic layer was dried over MgSO4 and concentrated in vacuum affording the title compound 60 (34 mg, 69% yield). This procedure is essentially as described in Brugier et al., Tetrahedron, 30: 10331-10344 (1997), which is incorporated by reference in its entirety. 1H NMR: (CDCl3) δ(ppm): 7.49 (dd, J=8.4, 1.4 Hz, 2H), 7.41 (t, J=7.6 Hz1 2H), 7.26 (dd, J=10.2, 7.2 Hz, IH), 6.22 (s, IH), 3.51 (bs, 4H). m/z: 191.3 (MH+).
The title compound 61 was obtained following the same procedure as described in Example 6, step 2, but substituting compound 31 for compound 60 in 73% yield).
1H NMR: (CD3OD) δ(ppm): 7.91 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.51 (dd, J=7.0, 1.2 Hz, 2H), 7.42 (t, J=7.4 Hz, 2H), 7.38 (s, IH), 7.28 (tt, J=7.4, 1.8 Hz, IH), 6.71 (d, J=8.6 Hz, IH), 6.37 (d, J=2.7 Hz, IH), 6.13 (dd, J=8.6, 2.5 Hz, IH), 4.38 (s, 2H), 3.74 (s, 3H), 3.71 (s, 3H). m/z: 460.5 (MH+).
The title compound 62 was obtained following the same procedures as Example 10, substituting phenylboronic acid in the step 3 for 2-thiopheneboronic acid in 29% yield. 1H NMR: (DMSOd6) δ(ppm): 7.90 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.37 (dd, J=5.1, 1.2 Hz, IH), 7.36 (s, IH), 7.14 (dd, J=3.7, 1.2 Hz, IH), 7.10 (dd, J=5.1, 3.5 Hz, IH), 6.71 (d, J=7.4 Hz, IH), 6.36 (d, J=2.5 Hz, IH), 4.38 (s, 2H), 3.74 (s, 3H), 3.71 (s, 3H), m/z: 466.5 (MH+).
The title compound 66 and the synthetic pathway depicted in scheme 10 were described in U.S. patent application Ser. No. 10/242,304, which is incorporated by reference in its entirety.
The title compound 67 was obtained following the same procedures described in Example 1, steps 3 and 4, but substituting compound 4 for compound 66 in 32% yield.
1H NMR (400 MHz, DMSO d6): 9.40 (s, IH); 7.67 (s, IH); 7.56 (d, 2H, J=7.6 Hz); 7.51 (s, IH); 7.42 (d, 2H, J=8.0 Hz); 7.33 (d, IH, J=5.1 Hz); 7.23-7.19 (m, 2H); 7.03 (dd, IH, J=3.7, 4.9 Hz); 6.85 (d, IH, J=15.7 Hz); 6.76 (d, IH, J=8.2 Hz); 6.08 (dd, IH; J=5.7, 6.0 Hz); 5.87 (s, 2H); 5.19 (s, 2H); 4.25 (d, 2H, J=5.9 Hz), 3.63 (s, 6H); 3.49 (s, 3H).
A stirred solution of nitrocompound 5 (207 mg; 0.42 mmol) and nickelflOchloride hexahydrate (595 mg; 2.5 mmol) in methanol (6 mL) at O° C. was treated with the solid sodium borohydride (430 mg; 11.4 mmol) and the mixture stirred at the same temperature for 2 h, quenched with acetone, poured into 5% NH4OH in brine and extracted with dichloromethane. The organic layer was dried (Na2S04), filtered and concentrated. After flash chromatography on a silica gel column (eluent 20% AcOEt in dichloromethane), compound 68 (62 mg; 0.143 mmol, 34%) and 69 (22 mg, 0.078 mmol, 19%) were obtained.
Compound 68: 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.58 (s, IH); 7.89 (d, J=8.2, 2H); 7.45 (d, J=8.2, 2H); 6.97 (s, IH); 6.78 (dd, J=2.0; 8.2, IH); 6.67 (d, J=8.0, IH); 6.64 (d, J=8.6, IH); 6.31 (d, J=2.5, IH); 5.99-5.96 (m, 2H); 4.68 (bs, 2H); 4.29 (d, J=6.3, 2H); 3.65 (s, 3H); 3.58 (s, 3H); 2.43 (t, J=7.4, 2H); 1.49 (m, J=7.4, 2H); 1.30 (m, J=7.4, 2H); 0.89 (t, S═IA, 3H).
Compound 69: 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.57 (s, IH); 7.86 (d, J=8.1, 2H); 7.30 (d, J=8.1, 2H); 6.78 (dd, J=2.0; 8.0, IH); 6.68 (d, J=8.0, IH); 4.67 (bs, 2H); 2.44 (t, J=7.4, 2H); 2.38 (s, 3H); 1.49 (m, J=7.4, 2H); 1.31 (m, J=7.4, 2H); 0.89 (t, J=7.4, 3H).
Following the same procedure as described in Example 13, but substituting the compound 5 for compound 15 in 53 and 9% yields, respectively.
Compound 70: 1H NMR: (400.2 MHz, DMSO) δ(ppm): 9.51 (s, IH); 7.88 (d, J=8.4, 2H); 7.44 (d, J=8.4, 2H); 7.00 (d, J=8.3, IH); 6.63 (d, J=8.3, IH); 6.58 (d, J=2.0, IH); 6.30 (d, J=2.5, IH); 5.99-5.96 (m, 2H); 4.79 (bs, 2H); 4.29 (d, J=6.1, 2H); 3.65 (s, 3H); 3.59 (s, 3H); 2.45 (t, J=7.4, 2H); 1.52 (m, J=7.4, 2H); 1.30 (m, J=7.4, 2H); 0.90 (t, J=7.4, 3H).
Compound 71: 1H NMR: (400.2 MHz, DMSO) δ(ppm): 9.51 (s, IH); 7.85 (d, J=8.0, 2H); 7.28 (d, J=8.0, 2H); 7.01 (d, J=8.5, IH); 6.58 (d, J=2.0, IH); 6.40 (d, J=2.0, 8.5, IH); 4.78 (bs, 2H); 2.45 (t, J=7.4, 2H); 2.38 (s, 3H); 1.53 (m, J=7.4, 2H); 1.31 (m, J=7.4, 2H); 0.90 (t, J=7.4, 3H).
A suspension of bromoarene 2 (447 mg g; 2.06 mmol); tetrakis(triphenylphosphine) palladium(O) (145 mg, 0.12 mmol) and copper(I)iodide (143 mg, 0.75 mmol) in degassed ethyleneglycol dimethylether (2.5 mL) and triethylamine (1.5 mU, was stirred at room temperature under nitrogen in the dark for 10 min and then treated with neat prop-2-yn-I-ol (0.7 mL, 12 mmol) (or any other alkyne of choice, 5 eq.), and the mixture stirred under the same conditions for 48 h, diluted with dichloromethane (50 mL), filtered through a celite pad and concentrated. Purification by flash chromatography (eluent 50 to 75% AcOEt in hexane) afforded compound 72 (328 mg, 83% yield).
1H NMR: (400.2 MHz, DMSO) δ(ppm): 7.92 (d, J=8.8, IH); 7.46 (bs, 2H); 7.04 (d, J=1.7, IH); 6.57 (dd, J=IJ1 8.8, IH); 5.41 (t, J=6.1, IH); 4.30 (d, J=6.1, 2H).
A solution of alcohol 72 (328 mg, 1.71 mmol) and imidazole (308 mg, 4.5 mmol) in IV7N-dimethylformamide (3 mL) was treated with neat tert-butyl-chloro-diphenyl-silane (0.5 mL, 1.9 mmol) and the solution stirred under nitrogen for 18 h, diluted with ethyl acetate (300 mL), washed with 5% aqueous KHSO4, then with saturated NaHCO3 and finally with water, dried (MgSO4), filtered and concentrated in vacuum. The crude mixture was purified by flash chromatography (eluent 50% ether in hexane, then 50% EtOAc in dichloromethane) to give compound 73 (691 mg, 94% yield).
1H NMR: (400.2 MHz, DMSO) δ (ppm): 7.91 (d, J=8.8, IH); 7.68-7.66 (m, 4H) 7.46-7.44 (m, 6H); 7.01 (d, J=1.7, IH); 6.46 (dd, J=1.7, 8.8, IH); 4.61 (d, 2H); 1.03 (d, 9H).
Following the same procedure as described in Example 1, step 3, but substituting compound 3 for compound 73 title compound was obtained in 77% yield.
1H NMR: (400.2 MHz, DMSO) δ (ppm): 10.7 (s, IH); 7.97 (d, J=8.6, IH); 7.88 (d, J=8.4, 2H); 7.76 (d, J=I.8, IH); 7.70-7.67 (m, 4H); 7.52 (d, J=8.4, 2H); 7.47-7.44 (m, 6H); 7.25 (d, J=7.4, IH); 6.64 (d, J=8.6, IH); 6.31 (d, J=2.8, IH); 6.01-5.96 (m, 2H); 4.65 (s, 2H); 4.31 (d, J=6.1, 2H); 3.65 (s, 3H); 3.55 (s, 3H); 1.03 (d, 9H).
A solution of compound 74 (871 mg, 1.24 mmol) in THF (3 mL) was treated with 1.0 M solution of tetrabutylammonium fluoride in THF (2.0 mL, 2.0 mmol) followed by 70% hydrogen fluoride in pyridine (0.1 mL), and the solution stirred under nitrogen for 12 h, diluted with ethyl acetate (200 mL) and washed with saturated NaHCO3 (50 mL) and then with water (6×100 mL), dried (Na2SO4), filtered and concentrated in vacuum. The crude material (647 mg) was pure enough for the next step without further purification.
Following the same procedure as described in Example I1 Step 4, but substituting compound 5 for compound 75 in 52% yield.
1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.51 (s, IH); 7.88 (d, J=8.2, 2H); 7.45 (d, J=8.2, 2H); 7.22 (d, J=1.8, IH); 6.99 (dd, J=1.8, 8.2, IH); 6.69 (d, J=8.4, IH); 6.63 (d, J=8.4, IH); 6.31 (d, J=2.3, IH); 5.99-5.96 (m, 2H); 5.30 (s, 2H); 5.19 (d, J=5.9, IH); 4.29 (d, J=5.9, 2H); 4.23 (d, J=5.3, 2H); 3.65 (s, 3H); 3.55 (s, 3H).
Following the same procedure described in Example 15, step 1 but substituting propargyl alcohol for N,N-dimethylpropargyl amine, the title compound was obtained in 80% yield.
1H NMR: (400.2 MHz, DMSO) δ (ppm): 8.02 (d, J=8.8, IH); 6.87 (d, J=1.6, IH); 6.69 (dd, J=1.6, 8.8, IH); 6.18 (bs, 2H); 3.48 (s, 2H); 2.38 (s, 6H).
Following the same procedure described in Example 15, step 3 but substituting compound 73 for compound 77, the title compound was obtained in 86% yield.
1H NMR: (400.2 MHz, DMSO) δ (ppm): 10.74 (s, IH); 8.0 (d, J=8.4, 2H); 7.88 (d, J=8.4, 2H); 7.83 (d, J=1.8, IH); 7.52 (d, J=8.4, 2H); 7.41 (dd, J=1.8, 8.4, IH); 6.64 (d, J=8.6, IH); 6.31 (d, J=2.6, IH); 6.30 (d, J=6.6, IH); 5.97 (dd, J=2.6, 8.6, IH); 4.30 (d, J=6.6, 2H); 3.65 (s, 3H); 3.64 (s, 3H); 3.58 (s, 2H); 2.25 (s, 6H).
Following the same procedure described in Example 15, step 5 but substituting compound 75 for compound 78, the title compound 79 was obtained in 63% yield.
1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.53 (s, IH); 7.89 (d, J=8.2, 2H); 7.45 (d, J=8.2, 2H); 7.22 (d, J=1.8, IH); 7.01 (dd, J=1.8, 8.2, IH); 6.69 (d, J=8.2, IH); 6.63 (d, J=8.2, IH); 6.30 (d, J=2.5, IH); 5.99-5.96 (m, 2H); 5.28 (s, 2H); 4.29 (d, J=6.1, 2H); 3.65 (s, 3H); 3.58 (s, 3H); 3.37 (s, 2H); 2.21 (s, 6H).
A solution of bromoarene 2 (1.544 g, 7.11 mmol) (or any haloarene of choice); tri-o-tolyl-phosphine (280 mg; 0.9 mmol) and trkdibenzylidene acetone)dipalladium(0) (280 mg; 0.3 mmol) in N,IV-dimethylformamide (6 mU and ethyl diisopropyl amine (3 mL) was treated with prop-2-en-I-ol (3 ml—, 40 mmol) (or any alken-1-ol of choice, 6 eq.) and the solution was stirred at 120° C. for 3 h under nitrogen. The reaction mixture was concentrated under high vacuum and the residue was purified by flash chromatography (eluent 5% MeOH in dichloromethane) to afford the aldehyde 80 (253 mg, 18% yield).
1H NMR: (400.2 MHz, CDCl3) δ (ppm): 9.68 (t, J=0.8, IH); 7.89 (d, J=8.7, IH); 6.51 (d, J=1.6, IH); 6.39 (dd, J=2.0, 8.7, IH); 6.02 (bs, 2H); 2.78 (t, J=6.7, 2H); 2.69 (m, J=0.8, 6.7, 2H).
A solution of aldehyde 80 (253 mg, 1.3 mmol) in tetrahydrofurane (1 mL) and propan-2-ol (2 mL) was treated with solid sodium borohydride (175 mg, 4.6 mmol) and stirred at −5° C. for 15 min. Acetone (5 mL) was added, stirred at the same temperature for 10 min and then diluted with ethyl acetate (100 mL), washed with 5% KHSO4 in water, then saturated NaHCO3 and finally with water, dried (MgSO4), and used for the next step without further purification.
1H NMR: (400.2 MHz, CDCl3) δ (ppm): 8.01 (d, J=8.8, IH); 6.64 (d, J=1.8, IH); 6.54 (dd, J=1.8, 8.8, IH); 6.18 (bs, 2H); 3.69 (t, S═I.2, 2H); 2.68 (t, J=7.2, 2H); 1.91 (m, J=7.2, 2H).
Following the same procedure described in Example 15, step 2 but substituting compound 72 for compound 81, the title compound was obtained in 78% yield.
1H NMR: (400.2 MHz, CDCl3) δ (ppm): 7.99 (d, J=8.8, IH); 7.73 (d, J=1.6, IH); 7.65-7.63 (m, 4H); 7.46-7.37 (m, 6H); 6.49 (dd, J=1.6, 8.8, IH); 4.02 (bs, 2H); 3.71 (t, J=7.4, 2H); 2.69 (t, J=7.2, 2H); 1.87 (m, J=7.2, 2H); 1.10 (s, 9H).
Following the same procedure described in Example 15, step 3 but substituting compound 73 for compound 82, the title compound was obtained in 71% yield.
1H NMR: (400.2 MHz, CDCl3) δ (ppm): 11.3 (s, IH); 8.75 (d, J=2.0, IH); 8.61 (d, J=8.6, IH); 7.86 (d, J=8.4, 2H); 7.57-7.54 (m, 4H); 7.44 (d, J=8.4, 2H); 7.34-7.27 (m, 6H); 6.88 (dd, J=2.0, 8.4, IH); 6.62 (d, J=8.6, IH); 6.21 (d, J=2.5, IH); 6.08 (dd, J=2.5, 8.6, IH); 4.32 (s, 2H); 3.72 (s, 3H); 3.71 (s, 3H); 3.62 (t, J=7.4, 2H); 2.76 (t, J=7.2, 2H); 1.84 (m, J=7.2, 2H); 0.99 (s, 9H).
Following the same procedure described in Example 15, step 4 but substituting compound 74 for compound 83, the title compound was obtained in 99% yield.
1H NMR: (400.2 MHz, CDCl3) δ (ppm): 11.4 (s, IH); 8.86 (d, J=2.0, IH); 8.21 (d, J=8.6, IH); 7.95 (d, J=8.4, 2H); 7.57 (d, J=8.4, 2H); 7.07 (dd, J=2.0, 8.6, IH); 6.74 (d, J=8.6, IH); 6.42 (d, J=2.3, IH); 6.31 (d, J=8.6, IH); 4.43 (s, 2H); 3.83 (s, 3H); 3.82 (s, 3H); 3.74 (t, J=7.4, 2H); 2.87 (t, J=7.2, 2H); 2.01 (m, J=7.2, 2H); 1.62 (bs, IH).
Following the same procedure described in Example 15, step 5 but substituting compound 75 for compound 84, the title compound was obtained in 62% yield.
1H NMR: (400.2 MHz, CDCl3) δ (ppm): 9.58 (s, IH); 7.89 (d, J=8.1, 2H); 7.45 (d, J=8.1, 2H); 6.98 (s, IH); 6.78 (dd, J=1.8, 8.0, IH); 6.67 (d, J=8.0, IH); 6.64 (d, J=8.6, IH); 6.31 (d, J=2.5, IH); 5.98 (m, IH); 4.68 (bs, 2H); 4.40 (t, J=5.1, IH); 4.29 (d, J=6.4, 2H); 3.65 (s, 3H); 3.58 (s, 3H); 3.37 (dt, J=5.1, 7.6, 2H); 2.46 (t, J=7.6, 2H); 1.65 (m, J=7.2, 2H).
Following the same procedure as described in Example 1 step 3 but substituting compound 3 for compound 2, the title compound was obtained, which was used without further purification.
1H NMR: (400.2 MHz, DMSO) δ (ppm): 10.4 (s, IH); 8.08 (d, J=2.2, IH); 7.96 (d, J=8.6, IH); 7.87 (d, J=8.4, 2H); 7.60 Wd1J=2.2, 8.6, IH); 7.52 (d, J=8.4, 2H); 6.64 (d, J=8.4, IH); 6.30 (d, J=2.5, IH); 5.97 (m, 2H); 4.31 (d, J=6.1, 2H); 3.65 (s, 3H); 3.58 (s, 3H).
Following the same procedure described in Example 1, step 4 but substituting compound 5 for compound 86, the title compound was obtained in 28% yield (over two steps).
1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.58 (s, IH), 7.89 (d, J=8.2 Hz, 2H)1 7.46 (d, J=8.4 Hz, 2H), 7.35 (d, J=2.3 Hz, IH), 7.08 (dd, J=8.4, 2.3 Hz, IH), 6.70 (d, J=8.6 Hz, IH), 6.64 (d, J=8.6 Hz, IH), 6.31 (d, J=2.5 Hz, IH), 5.99-5.96 (m, 2H), 5.12 (s, 2H), 4.29 (d, J=6.1 Hz, 2H), 3.65 (s, 3H), 3.58 (s, 3H).
Following the same procedure described in Example 17, step 1 but substituting compound 2 for compound 87, the title compound was obtained in 18% yield.
1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.57 (s, IH), 7.91 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.38 (d, J=2.0 Hz, IH), 7.32 (bs, IH); 7.23 (d, J=16 Hz, IH), 7.15 (dd, J=2.0, 8.4 Hz, IH); 6.82 (bs, IH); 6.74 (d, J=8.4 Hz, IH), 6.64 (d, J=8.6 Hz, IH), 6.32 (m, IH), 6.29 (d, J=16 Hz, IH), 5.98 (m, 2H), 5.39 (bs, 2H), 4.30 (d, J=6.1 Hz, 2H), 3.66 (s, 3H), 3.59 (s, 3H).
A suspension of the aldehyde 89 (500 mg, 3.21 mmol) and sodium borohydride (121 mg, 3.21 mmol) in isopropanol (5 ml) was stirred at O° C. during 3 h. The excess of hydride was quenched with acetone, and the solvent was evaporated. A suspension of the resulting boronic acid (or any other boronic acid), 5-bromo-2-nitroaniline (2) (697 mg, 3.21 mmol) (scheme 1, Example 1) POT (305 mg, 1.00 mmol), Pd(PPh3U (241 mg, 0.209 mmol) and K2CO3 (1.33 g, 9.63 mmol) in DME (12 ml) and water (4 ml) was stirred during 16 h at 8O° C. The solvent was evaporated; ethyl acetate was added and washed with saturated solution of NaCl. The organic layer was dried over MgSO4, filtered and concentrated. After purification by flash chromatography on silica gel (eluent 40% EtOAc in Hexanes), 605 mg (75%) of compound 90 was obtained as a orange oil. 1H NMR: (400 MHz, DMSO) δ (ppm): 7.98 (d, J=9.0 Hz, IH), 7.52 (d, J=5.3 Hz, IH), 7.44 (s, 2H), 7.15 (d, J=5.3 Hz, IH), 7.02 (d, J=1.8 Hz, IH), 6.73 (dd, J=9.0, 2.0 Hz, IH), 5.72 (t, J=5.4 Hz, IH), 4.70 (d, J=5.5 Hz, 2H).
A solution of 90 (600 mg, 2.39 mmol), imidazole (245 mg, 3.60 mmol) and TBDMSCI (543 mg, 3.60 mmol) in DMF (20 ml) was stirred at room temperature during 16 h. The solvent was evaporated, ethyl acetate was added and washed with saturated solution of NaCl. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (eluent 5-10% EtOAc in hexanes) to afford 674 mg (77%) of compound 91 as a yellow oil. 1H NMR: (400 MHz, DMSO) δ (ppm): 7.97 (d, J=8.8 Hz, IH), 7.53 (d, J=5.1 Hz, IH), 7.45 (s, 2H), 7.15 (d, J=5.3 Hz, IH), 6.98 (d, J=1.8 Hz, IH), 6.70 (dd, J=8.8, 2.0 Hz, IH), 4.91 (s, 2H), 0.89 (s, 9H), 0.07 (s, 6H).
A solution of 91 (636 mg, 1.74 mmol) and 4-methoxybenzoyl chloride (446 mg, 2.62 mmol) in pyridine (10 ml) was stirred at room temperature during 16 h. The solvent was evaporated, ethyl acetate was added and washed with a saturated solution of NH4Cl and then with a saturated solution NaCl. The organic layer was dried over MgSO4, filtered and concentrated. After purification by flash chromatography on silica gel (eluent 5-10% EtOAc in Hexanes), 804 mg (93%) of compound 92 was obtained as a yellow oil. 1H NMR: (400 MHz, DMSO) δ (ppm): 10.64 (s, IH), 8.05 (d, J=8.6 Hz, IH), 7.95-7.93 (m, 3H), 7.59 (d, J=5.3 Hz, IH), 7.46 (dd, J=8.6, 2.0 Hz, IH), 7.28 (d, J=5.3 Hz, IH), 7.10 (dt, J=9.0, 2.2 Hz, 2H), 4.95 (s, 2H), 3.85 (s, 3H), 0.88 (s, 9H), 0.09 (s, 6H).
A suspension of 92 (800 mg, 1.60 mmol), SnCl2.2H2O(2.17 g, 9.63 mmol) and NH4OAc (1.23 g, 16.0 mmol) in a 1:1:1 mixture of MeOH/THF/water was stirred at room temperature during 16 h. Tin salts were filtered out and rinsed with EtOAc. The solvent was evaporated, ethyl acetate was added and washed with a saturated solution of NaHCO3 and then with a saturated solution NaCl. The organic layer was dried OVER MgSO4, filtered and concentrated. After purification by flash chromatography on silica gel (eluent 0.5-5% MeOH in DCM), 200 mg (27%) of compound 93 was obtained as a beige powder and 92 mg (16%) of compound 94 was obtained as a beige powder.
Compound 93: 1H NMR: (DMSO) δ (ppm): 9.54 (s, IH), 7.96 (d, J=8.8 Hz, 2H), 7.43 (d, J=5.1 Hz, IH), 7.28 (d, J=1.8 Hz, IH), 7.09-7.02 (m, 4H), 6.81 (d, J=8.2 Hz, IH), 5.05 (s, 2H), 4.82 (s, 2H), 3.83 (s, 3H), 0.87 (s, 9H), 0.06 (s, 6H). MS: (calc.) 468.2; (obt.) 491.2 (M+Na)+.
Compound 94: 1H NMR: (DMSO) δ (ppm): 9.57 (s, IH), 7.96 (d, J=8.8 Hz, 2H), 7.40 (d, J=5.1 Hz, IH), 7.23 (d, J=1.8 Hz, IH), 7.09-7.02 (m, 4H), 6.81 (d, J=8.0 Hz, IH), 5.51 (t, J=5.4 Hz, IH), 5.01 (s, 2H), 4.64 (d, J=5.3 Hz, 2H), 3.83 (s, 3H). MS: (calc.) 354.1; (obt.) 354.1 (M+Na)+.
The compound 97 was obtained following the same procedure as for the Examples 19 and 20, steps 1 and 2 (scheme 17) in 78% yield. 1H NMR: (400 MHz, DMSO) δ (ppm): 8.01 (d, J=9.0 Hz, IH), 7.61 (d, J=8.2 Hz, 2H), 7.46 (s, 2H), 7.41 (d, J=8.0 Hz1 2H), 7.27 (d, J=2.0 Hz, IH), 6.91 (dd, J=9.0, 2.0 Hz1 IH), 0.92 (s, 9H), 0.11 (s, 6H).
The compound 98 was obtained following the same procedure as in the Example 1, step 3 (scheme 1) in 28% yield. 1H NMR: (DMSO) δ (ppm): 10.77 (s, IH)1 8.14 (d, J=2.0 Hz, IH)1 8.09 (d, J=8.6 Hz1 2H)1 7.91 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.2 Hz, 2H)1 7.68 (dd, J=8.6, 2.2 Hz1 IH), 7.53 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz1 2H)1 6.65 (d, J=8.6 Hz1 2H)1 5.99-5.97 (m, 2H), 4.78 (s, 2H), 4.32 (d, J=6.3 Hz1 2H)1 3.66 (s, 3H), 3.59 (s, 3H)1 0.93 (s, 9H), 0.11 (s, 6H).
The compounds 99 and 100 were obtained following the same procedure as in Examples 19 and 20, step 4 (scheme 17).
Compound 99: 1H NMR: (DMSO) δ (ppm): 9.66 (s, IH), 7.93 (d, J=8.0 Hz, 2H), 7.52-7.46 (m, 5H), 7.31-7.29 (m, 3H), 6.84 (d, J=7.6 Hz, IH), 6.64 (d, J=8.6 Hz, IH), 6.32 (s, IH), 6.00-5.98 (m, 2H), 5.06 (s, 2H), 4.70 (s, 2H), 4.30 (d, J=5.9 Hz, 2H), 3.66 (s, 3H), 3.59 (s, 3H), 0.91 (s, 9H), 0.10 (s, 6H). MS: (calc.) 597.2 (obt.) 598.5 (MH)+.
Compound 100: 1H NMR: (DMSO) δ (ppm): 9.67 (s, IH), 7.93 (d, J=7.8 Hz, 2H), 7.50-7.46 (m, 5H), 7.31-7.29 (m, 3H), 6.84 (d, J=8.0 Hz, IH), 6.64 (d, J=8.4 Hz1 IH), 6.32 (d, J=2.0 Hz, IH), 6.00-5.98 (m, 2H), 5.15 (t, J=5.5 Hz, IH), 5.06 (s, 2H), 4.49 (d, J=5.7 Hz, 2H), 4.31 (d, J=5.9 Hz, 2H), 3.66 (s, 3H), 3.59 (s, 3H). MS: (calc.) 483.2; (obt.) 484.4 (MH)+.
The compound 102 was obtained following the same procedure as in Example 19 and 20, step 1 (scheme 17) but substituting the boronic acid 89 for the boronic acid 101 in 70% yield. 1H NMR: (400 MHz, DMSO) δ (ppm): 8.07-8.04 (m, 3H), 7.78 (d, J=8.2 Hz, 2H), 7.50 (s, 2H), 7.34 (d, J=2.0 Hz, IH), 6.96 (dd, J=9.0, 2.2 Hz, IH), 3.88 (s, 3H).
A suspension of 102 (599 mg, 2.20 mmol), NaH 60% (141 mg, 3.52 mmol) and 4-methoxybenzoyl chloride (450 mg, 2.64 mmol) in pyridine (5 ml) and DMF (12 ml) was stirred at room temperature during 48 h. The solid was filtered out and rinsed with MeOH to give 584 mg (82%) of the title compound 103 as a yellow solid. 1H NMR: (400 MHz, DMSO) δ (ppm): 10.72 (s, IH), 8.13-8.08 (m, 3H), 7.96 (d, J=8.8 Hz, 2H), 7.90 (d, J=8.6 Hz, 2H), 7.74 (dd, J=8.6, 2.2 Hz, IH), 7.11 (d, J=8.8 Hz, IH), 3.89 (s, 3H), 3.86 (s, 3H).
The compound 104 was obtained following the same procedure as in Example 19 and 20, step 4 (scheme 17) in 10% yield. 1H NMR: (DMSO) δ (ppm): 9.61 (s, IH), 7.98 (d, J=8.8, Hz, 2H), 7.95 (d, J=8.4 Hz, 2H), 7.71, (d, J=8.4 Hz, 2H), 7.60 (d, J=2.2 Hz, IH), 7.43 (dd, J=8.4, 2.2 Hz, IH), 7.04 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.4 Hz, IH), 5.27 (sb, 2H), 3.85 (s, 3H), 3.84 (s, 3H). MS: (calc.) 376.1; (obt.) 377.1 (MH)+.
A solution of 104 (44 mg, 0.117) and NaOH I M (0.24 ml, 0.24 mmol) in THF (1 ml) and water (1 ml) was stirred 48 h at 40° C. HCl I M was added and the precipitate was filtered out. The solid was further purified by flash chromatography (eluent 3-5% MeOH in DCM), to give the compound 105 (34 mg, 80% yield). 1H NMR: (DMSO) δ (ppm): 9.61 (s, IH), 7.98 (d, J=8.6 Hz, 2H), 7.93 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.58 (d, J=2.0 Hz, IH), 7.40 (dd, J=8.2, 2.0 Hz, IH), 7.04 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.4 Hz, IH), 5.23 (s, 2H), 3.84 (s, 3H). MS: (calc.) 362.1; (obt.) 363.1 (MH)+.
A solution of 4-methoxybenzoyl chloride (1.03 g, 6.02 mmol) in CH3CN (6 ml) was added drop wise to a solution of methyl 3,4-diaminobenzoate (106) (1.00 g, 6.02 mmol) and pyridine (0.49 ml, 6.02 mmol) in CH3CN (25 ml) at O° C. The reaction mixture was stirred for 3 h at O° C. and the solvent was evaporated. Ethyl acetate was added and the organic layer was washed successively with saturated solutions of NH4Cl, NaHCO3 and NaCl, dried over MgSO4, filtered and concentrated. After purification by flash chromatography on silica gel (eluent 1-3% MeOH in DCM), 1.03 g (56%) of compound 107 was obtained as a off white solid. 1H NMR: (DMSO) δ(ppm): 9.51 (s, IH), 7.96 (d, J=8.8 Hz, 2H), 7.75 (d, J=2.0 Hz, IH), 7.56 (dd, J=8.4, 2.0 Hz, IH), 7.03 (d, J=9.0 Hz, 2H), 6.75 (d, J=8.4 Hz, IH), 5.80 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H). MS: (calc.) 300.1; (obt.) 301.1 (MH)+.
A suspension of 107 (400 mg, 1.33 mmol) and I M NaOH (2.7 ml, 2.66 mmol) in 1:1 THF:MeOH (6 ml) was heated at 50° C. for 16 h. HCl I M was added to reach pH=4 and the solid was filtered to give 370 mg (97%) of compound 108 as a white solid. 1H NMR: (DMSO) δ (ppm): 9.52 (s, IH), 7.96 (d, J=8.8 Hz, 2H), 7.71 (d, J=2.0 Hz, IH), 7.54 (dd, J=8.4, 2.0 Hz, IH), 7.02 (d, J=9.0 Hz, 2H), 6.74 (d, J=8.4 Hz, IH), 5.69 (s, 2H), 3.83 (s, 3H). MS: (calc.) 361.1; (obt.) 362.3 (MH)+.
A solution of 108 (200 mg, 0.70 mmol), NH4Cl (74 mg, 1.40 mmol), HOBT-hydrate (104 mg, 0.77 mmol), EDC (119 mg, 0.77 mmol) and Et3N (0.29 ml, 2.1 mmol) in DMF (3 ml) was stirred for 16 h at room temperature. The solvent was evaporated, ethyl acetate was added and the organic layer was washed successively with saturated solutions of NH4Cl, NaHCO3 and NaCl, dried over MgSO4, filtered and concentrated. The crude product was triturated in ethyl acetate and filtered to give the title compound 109 (60 mg, 30%). 1H NMR: (DMSO) δ (ppm): 9.57 (s, IH), 7.96 (d, J=8.8 Hz, 2H), 7.67 (d, J=2.2 Hz, IH), 7.59 (sb, IH), 7.52 (dd, J=8.2, 2.0 Hz, IH), 7.02 (d, J=8.8 Hz, 2H), 6.90 (sb, IH), 6.72 (d, J=8.4 Hz, IH), 5.41 (s, 2H), 3.83 (s, 3H). MS: (calc.) 285.1; (obt.) 286.1 (MH)+.
A solution of 108 (700 mg, 2.45 mmol), BoC2O (801 mg, 3.67 mmol) and Et3N (0.51 ml, 3.67 mmol) in 2:1 dioxane:water (15 ml) was stirred for 16 h at room temperature. The solvent was concentrated and HCl 1 M was added to reach a pH=5. The precipitate was filtered to give 736 mg (78%) of the title compound 110 as a beige solid. 1H NMR: (DMSO) δ (ppm): 9.81 (s, IH), 8.87 (s, IH), 8.02 (d, J=1.6 Hz, IH), 7.95 (dt, J=9.0, 2.2 Hz, 2H), 7.75-7.74 (m, 2H)1 7.07 (dt, J=9.0, 2.2 Hz, 2H), 3.84 (s, 3H), 1.46 (s, 9H).
A solution of 110 (373 mg, 0.965 mmol), aniline (0.11 ml, 1.16 mmol), BOP (640 mg, 1.45 mmol) and Et3N (0.40 ml, 1.45 mmol) in DMF (3 ml) was stirred during 16 h at room temperature. The solvent was evaporated, ethyl acetate was added and the organic layer was washed with saturated solutions of NH4Cl, NaHCO3 and NaCl, dried over MgSO4, filtered and concentrated. After purification by flash chromatography on silica gel (eluent 30-40% AcOEt in hexane), 352 mg (79%) of compound III was obtained as a white solid. 1H NMR: (DMSO) δ (ppm): 10.17 (s, IH), 9.86 (s, IH), 8.83 (s, IH), 7.97 (dt, J=9.0, 2.2 Hz, 2H), 7.84-7.73 (m, 4H), 7.35-7.31 (m, 2H), 7.10-7.05 (m, 3H), 3.85 (s, 3H), 1.47 (s, 9H).
A solution of 111 (343 mg, 0.743 mmol) and TFA (0.5 ml) in DCM (3 ml) was stirred for 16 h at room temperature. The solvent was evaporated and the solid was purified by flash chromatography (eluent 2-3% MeOH/DCM) to afford the title compound 112 as an off-white solid (230 mg, 86% yield). 1H NMR: (DMSO) δ (ppm): 9.83 (s, IH), 9.62 (s, IH), 7.99 (d, J=8.8 Hz, 2H), 7.82 (d, J=2.0 Hz1 IH), 7.73 (dd, J=8.8, 1.2 Hz, 2H), 7.67 (dd, J=8.4, 2.2 Hz, IH), 7.31-7.27 (m, 2H), 7.05-7.01 (m, 3H), 6.80 (d, J=8.4 Hz, IH), 3.84 (s, 3H). MS: (calc.) 361.1; (obt.) 362.1 (MH)+.
In aflame dried, round bottom flask, 5-bromo-2-nitro-aniline (2) (10.66 g, 49.09 mmol), (scheme 1, Example 1), and 4-methoxybenzoyl chloride (8.37 g, 49.09 mmol) were added. The mixture was heated to 90° C. The melted solids were stirred overnight to give a yellow-brown solid. THF (250 mL) was then added and the solution was treated with SnCl22H2O (55.38 g, 245.45 mmol, 5.0 eq) and stirred at room temperature for 2 hrs. Approx. half of the THF was evaporated then 200 mL of EtOAc and 100 mL sat. NaHCO3 were added. The precipitated tin salt was taken out by filtration and a work-up was done on the filtrate with EtOAc. The combined organic layers were washed with water and brine and dried over MgSO4. Most of the EtOAc was evaporated then hexane was added and the precipitate was collected by filtration to give the title compound 114 as a beige powder (13.40 g, 85% yield). 1H NMR (DMSO-d6) δ(ppm): 9.52 (s, IH), 7.93 (d, J=9.0 Hz, 2H), 7.34 (d, J=2.3 Hz, IH), 7.08 (dd. J=8.6, 2.3 Hz, IH), 7.02 (d, J=9.0 Hz, 2H), 6.71 (d, J=8.6 Hz, IH) 5.10 (s, 2H), 3.82 (s, 3H).
The compound 115 was obtained following the same Suzuki coupling procedure as in Examples 19 and 20 step 1 (scheme 17) in 84% yield. 1H NMR (DMSO) δ (ppm): 9.59 (s, IH), 7.97 (d, J=8.8 Hz, 2H), 7.71 (dd, J=7.2, 2.3 Hz, IH), 7.56-7.52 (m, IH), 7.51 (d, J=2.2 Hz, IH), 7.40 (t, J=9.0 IH), 7.33 (dd, J=8.2, 2.3, IH), 7.04 (d, J=9.0 Hz, 2H), 6.84 (d, J=8.4 Hz, IH), 5.16 (sb, 2H), 3.84 (s, 3H). MS: (calc.) 370.1; (obt.) 371.1 (MH)+.
In a 75 ml_pressure vessel, N-(2-amino-5-bromo-phenyl)4-methoxy-benzamide (114) (2.95 g, 9.19 mmol.), bis(pinacolato)diboron (2.80 g, 11.03 mmol) and THF (25 πt ) were added. Air was then removed by vacuum and then the vessel was purged with nitrogen. Pd(P(t-Bu)3)2 (0.070 g, 0.14 mmol), Pd2(dba)3 (0.063 g, 0.07 mmol) and KF (1.76 g, 30.34 mmol, 3.3 eq.) were then added and the air was removed after each addition. The pressure vessel was sealed and the mixture was stirred at 50° C. for a week. The two palladium catalysts were added again after 2 and 4 days. After completion of the reaction, the mixture was extracted with EtOAc. The combined organic layers were rinsed with water and brine and concentrated. The obtained oil was then purified by column chromatography on silica gel with EtOAc/hexane (50:50) to give the title compound 116 as a pale yellow solid (1.53 g, 45%). 1H NMR (DMSO-d6) δ(ppm): 9.47 (s, IH)1 7.95 (d, J=8.8 Hz1 2H), 7.41 (d, J=1.4 Hz1 IH), 7.24 (dd, J=7.8, 1.4 Hz, IH), 7.01 (d, J=8.8 Hz, 2H), 6.70 (d, J=7.8 Hz, IH), 5.31 (s, 2H), 3.82 (s, 3H), 1-25 (s, 12H).
In a pressure vessel, N-[2-Amino-5-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-4-methoxybenzamide (116) (170 mg, 0.462 mmol), 1-(4-bromophenyl)ethanone (184 mg, 0.923 mmol), (or any aryl bromide from the tables below), DME (4,6 ml_per mmol of 116) and H2O (2.15 ml_per mmol of 116) were added. Air was then removed by vacuum and then the vessel was purged with nitrogen. Pd(PPh3U (27 mg, 0.023 mmol, 0.05 eq.) and Na2CO3 (147 mg, 1.38 mmol, 3.0 eq.) were then added and oxygen was removed after each addition. The pressure vessel was sealed and the mixture was stirred at 75° C. overnight. The mixture was cooled at room temp., water was added and the mixture was extracted with EtOAc. The combined organic layers were rinsed with brine, dried over MgSO4 and concentrated to give 42 mg (25%) of the title compound 117. 1H NMR (DMSO-d6) δ(ppm): 9.61 (s, IH), 7.96 (dd, J=12.8, 8.8 Hz, 4H)1 7.70 (d, J=8.8 Hz, 2H), 7.60 (d, J=2.1 Hz, IH), 7.42 (dd, J=8.4, 2.3 Hz, IH), 7.04 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.2 Hz, IH), 5.26 (s, 2H)1 3.84 (s, 3H), 2.58 (s, 3H). MS (m/z): 360.41 (calc) 361.1 (MH+) (found).
1-(5-Bromothiophen-2-yl)ethanolA suspension of lithium aluminum hydride (364 mg, 9.76 (mmol) indiethyl ether (40 mL) was cooled down to −78° C. under N2 and asolution of 2-acetyl-5-bromothiophene (1.00 g, 4.88 mmol) was slowlytransferred via canula into the stirring suspension. The mixture wasstirred for 2 h at −78° C. and quenched with caution with a 5% HClsolution. The grey mixture was allowed to warm to rt and stirredfor additional 16 h. The supernatant was decanted and concentrated invacuo. The remaining white aluminum aqueous layer was extractedtwice with EtOAc. The extracts were combined with the residueproduced after evaporation of the supernatant and were washed withH2O, brine, dried over MgSO4, filtered and concentrated again in vacuoaffording the title 1-(5-bromothiophen-2-yl)ethanol (870 mg, 87% yield).1H NMR: (400 MHz, DMSO-d6) δ (ppm): 7.00 (d, J = 3.7 Hz, 1H),6.72 (dd, J = 3.7, 1.0 Hz, 1H), 5.66 (d, J = 4.9 Hz, 1H), 4.85 (quintd,J = 6.1, 1.2 Hz, 1H).LRMS (m/z): 188.9 (M-H2O).
5-Bromothiophene-2-(N,N-dimethyl)sulfonamideA round-bottom flask was charged with 5-bromothiophene-2-sulfonylchloride (1.00 g, 3.82 mmol) and a 2 M solution of N,N-dimethylamine (6 mL, 11.46 mmol) in THF was added. The mixture wasstirred for 1 h and the solvent was removed in vacuo. The residue waspartitioned between EtOAc and H2O. The organic layer was washed withH2O, brine, dried over MgSO4, filtered and concentrated. The resultingcolorless liquid was purified by flash chromatography on silica gel usingEtOAc/hexanes as an eluent with increasing polarity (10:90 to 20:80)affording the title 5-bromothiophene-2-(N,N-dimethyl)sulfonamide (340mg, 33% yield).1H NMR: (400 MHz, CDCl3) δ (ppm): 7.30 (d, J = 4.0 Hz, 1H), 7.13(d, J = 4.0 Hz, 1H), 2.78 (s, 6H).LRMS: (m/z): 270.0/272.0 (M/M + 2)+.
A flame-dried pressure vessel was charged with 5-fluoro-2-nitrobenzoic acid 118 (5.0O g, 27.0 mmol) and dry t-butyl alcohol (50 mL). To this solution were successively added iv7Akli-isopropyl-N-ethylamine (5 mL) and diphenylphosphorylazide (6.42 mL, 29.7 mmol). The vessel was closed with teflon cap and the mixture was heated at 9O° C. for 2 h. t was then allowed to cool to r.t. over 16 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and H2O. The aqueous layer was extracted with fresh EtOAc and the combined organic layers were washed with HCl IN, sat. NaHCO3, brine, dried over MgSO4, filtered and concentrated. The resulting yellow oil was purified by flash chromatography on silica gel using EtOAc/hexanes (10:90) as an eluent, affording the title compound 119 (6.03 g, 87% yield) as light yellow crystals. LRMS: (m/z): 279.3 (M+Na+).
A pressure vessel was charged with thiophene-2-thiol (236 mg, 2.03 mmol) and THF (4 mL). To this solution were successively added sodium hydride (60% suspension in mineral oil) (86 mg, 2.15 mmol) and compound 119 (500 mg, 1.95 mmol). The vessel was closed with teflon cap and the mixture heated to 9O° C. for 2 h. Ht was allowed to cool to r.t.; and the reaction was quenched with H2O, followed by THF removal in vacuo. The residue was partitioned between EtOAc and H2O. The aqueous layer was extracted with fresh EtOAc and the combined organic layers were washed with HCl IN, sat. NaHCO3, brine, dried over MgSO4, filtered and concentrated. The residue was allowed to crystallize from a mixture of EtOAc/hexane over 72 hours, affording the title compound 120 (610 mg, 88% yield). 1H NMR: (400 MHz, Acetone-d5) δ (ppm): 9.67 (s, IH), 8.32 (d, J=2.2 Hz, IH), 8.13 (d, J=8.8 Hz, IH), 7.90 (dd, J=5.3, 1.2 Hz, IH), 7.50 (dd, J=3.5, 1.2 Hz, IH), 7.28 (dd, J=5.3, 3.5 Hz, IH), 6.81 (dd, J=8.8, 2.0 Hz, IH), 1.53 (s, 9H). LRMS: (m/z): 275.2 (M+Na+).
Following the same procedure as in Example 27, step 3 (scheme 20) substituting compound III for compound 120 (550 mg, 1.56 mmol), the title compound 121 was obtained (271 mg, 69% yield). 1H NMR: (400 MHz, acetone-d6) δ (ppm): 7.97 (d, J=9.0 Hz, IH), 7.87 (dd, J=5.3, 1.2 Hz, IH), 7.44 (dd, J=3.5, 1.2 Hz, IH), 7.25 (dd, J=5.5, 3.7 Hz, IH), 7.11 (bs, 2H), 6.66 (d, J=2.0 Hz, IH), 6.42 (dd, J=9.0, 2.0 Hz, IH). LRMS: (m/z): 253.1 (MH+).
Following the same procedures as in Example 21, steps 3 and 4 (scheme 18) but substituting compound 97 for compound 121 the title compound 122 was obtained in 6% yield (over 2 steps). 1H NMR: (400 MHz, DMSO-d6) δ (ppm): 9.57 (s, IH), 7.87 (d, J=8.4 Hz, 2H), 7.57 (dd, J=5.3, 1.2 Hz, IH), 7.44 (d, J=8.4 Hz, 2H), 7.27 (d, J=2.0 Hz, IH), 7.19 (dd, J=3.5, 1.2 Hz, IH), 7.05 (dd, J=8.2, 2.2 Hz, IH), 7.01 (dd, J=5.3, 3.5 Hz, IH), 6.72 (d, J=8.2 Hz, IH), 6.63 (d, J=8.6 Hz, IH), 6.30 (d, J=2.5 Hz, IH), 5.97 (dd, J=8.4, 2.5 Hz, IH), 5.96 (d, J=6.5 Hz, IH), 5.20 (s, 2H), 4.28 (d, J=6.3 Hz, 2H), 3.65 (s, 3H), 3.58 (s, 3H). LRMS: (m/z): 492.5 (MH+).
Following the same procedures as in Example 21, steps 3 and 4 (scheme 18) but substituting compound 97 for the commercially available 2-nitro-5-(propylthio)aniline (121, R=n-propyl) (222 mg, 1.04 mmol), afforded the title compound (123) as a light yellow oil (102 mg, 22% yield for 2 steps). 1H NMR: (400 MHz1 DMSOd6) δ (ppm): 9.57 (s, IH), 7.89 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.23 (d, J=0.4 Hz, IH), 7.01 (dd, J=8.4, 2.2 Hz, IH), 6.71 (d, J=8.4 Hz, IH), 6.63 (d, J=8.6 Hz, IH), 6.31 (d, J=2.3 Hz, IH), 5.98 (dd, J=8.2, 2.5 Hz, IH), 5.97 (d, J=5.9 Hz, IH), 5.04 (s, 2H), 4.29 (d, J=5.9 Hz, 2H), 3.65 (s, 3H), 3.58 (s, 3H), 2.71 (t, J=7.0 Hz, 2H), 1.50 (sext, J=7.0 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H). LRMS: (m/z): 452.5 (MH+).
A flame-dried flask was charged with the 5-bromo-2-nitroaniline (2, 300 mg, 1.38 mmol) (scheme I1 Example 1), phenylacetylene (155 mg, 1.52 mmol) and ethyl acetate (13.8 mL). The solution was degassed under vacuum and put under N2 atmosphere. Then, dichlorobis(triphenylphosphine)palladium (48 mg, 0.069 mmol) and copper iodide (26 mg, 0.138 mmol) were added. The yellow solution was degassed again (3 cycles) N7zv-diisopropylamine (231 μl—, 1.68 mmol) was added and the solution rapidly turned dark. It was degassed twice again and allowed to stir under N2 atmosphere at r.t. over 16 h. Then it was passed through celite and the filtrate was successively washed with dilute aqueous ammonia (NH4OH), saturated NaHCO3, saturated NH4Cl, brine, dried over MgSO4, filtered and concentrated. The resulting dark solid was purified by flash chromatography on silica gel using EtOAc/hexanes as the eluent with increasing polarity (10:90 to 15:85) affording the title compound 124 (242 mg, 74% yield) as a deep yellow solid. 1H NMR: (400 MHz, CD3OD) δ(ppm): 8.04 (dd, J=8.8, 0.4 Hz, IH), 7.54-7.51 (m, 2H), 7.40-7.37 (m, 3H), 7.11 (dd, J=1.8, 0.4 Hz, IH), 6.73 (dd, J=8.8, 1.8 Hz, IH). LRMS: (m/z): 239.3 (MH+).
Following the same procedures as in Example 21, steps 3 and 4 (scheme 18) but substituting compound 97 for compound 124 (240 mg, 1.01 mmol), compound 125 was synthesized (136 mg, 31% yield for 2 steps). 1H NMR: (400 MHz, CD3OD) δ (ppm): 7.93 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.44 (dd, J=8.2, 1.8 Hz, 2H), 7.35-7.29 (m, 4H), 7.21 (dd, J=8.2, 2.0 Hz, IH), 6.85 (d, J=8.4 Hz, IH), 6.71 (d, J=8.4 Hz, IH), 6.36 (d, J=2.7 Hz, IH), 6.13 (dd, J=8.4, 2.5 Hz, IH), 4.39 (s, 2H), 3.75 (s, 3H), 3.71 (s, 3H). LRMS: (m/z): 478.5 (MH+).
Following the same procedure as in Example 1, step 2 (scheme 1) but substituting 2-thiopheneboronic acid for trans-2-phenylvinylboronic acid (245 mg, 1.66 mmol), the title compound 126 was prepared (230 mg, 69% yield). 1H NMR: (400 MHz, acetone-d6) δ (ppm): 7.89 (d, J=8.8 Hz, IH), 7.49 (d, J=7.0 Hz, 2H), 7.27-7.18 (m, 3H), 7.19 (d, J=16.2 Hz, IH), 7.05 (d, J=15.3 Hz, IH), 7.02 (s, IH), 6.93 (bs, 2H), 6.87 (dd, J=9.0, 1.6 Hz, IH). LRMS: (m/z): 241.3 (MH+).
Following the same procedures as in Example 21, steps 3 and 4 (scheme 18) but substituting compound 97 for compound 126 (230 mg, 0.957 mmol), the title compound 127 was prepared (159 mg, 35% yield for 2 steps). 1H NMR: (400 MHz, Acetone-d6) δ (ppm): 9.07 (s, IH), 8.01 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.55-7.52 (m, 3H), 7.32 (t, J=7.4 Hz, 2H), 7.28 (dd, J=8.2, 2.2 Hz, IH), 7.19 (t, J=7.2 Hz, IH)1 7.13 (d, J=16.4 Hz, IH), 7.0 (d, J=16.2 Hz, IH), 6.89 (d, J=8.2 Hz, IH), 6.70 (d, J=8.4 Hz, IH), 6.41 (d, J=2.7 Hz, IH), 6.12 (dd, J=8.6, 2.7 Hz, IH), 5.33 (bs, IH), 4.85 (bs, 2H), 4.43 (s, 2H), 3.72 (s, 3H), 3.67 (s, 3H). LRMS: (m/z): 480.5 (MH+).
To a degassed solution of compound 127 (100 mg, 0.209 mmol) in a mixture of methanol and ethyl acetate (1:1) was added was added a catalytic amount of 10% palladium on charcoal and the mixture was put under H2 atmosphere (latm) and stirred for 1 h and filtered through celite and the filtrate was concentrated in vacuo. The mixture was separated by flash chromatography on silica gel using EtOAc/Hexanes with increasing polarity (40:60 to 60:40) as the eluent. The least polar compound 129 was isolated as a white solid (31 mg, 31% yield) and the most polar compound was further purified by crystallization from a mixture of ethyl acetate and hexanes affording compound 128 as light beige crystals (18 mg, 18% yield).
Compound 128: 1H NMR: (400 MHz, acetone-d6) δ (ppm): 9.07 (s, IH), 7.99 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 7.27-7.22 (m, 5H), 7.19-7.14 (m, IH), 6.87 (dd, J=8.0, 2.0 Hz, IH), 6.79 (d, J=8.0 Hz, IH), 6.70 (d, J=8.4 Hz, IH), 6.40 (d, J=2.8 Hz, IH), 6.11 (dd, J=8.4, 2.5 Hz, IH), 5.33 (bs, IH), 4.51 (bs, 2H), 4.42 (s, 2H), 3.72 (s, 3H), 3.67 (s, 3H). LRMS: (m/z): 482.2 (MH+). Compound 129: 1H NMR: (400 MHz, acetone-d6) δ (ppm): 9.03 (bs, IH), 7.94 (d, J=8.0 Hz, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.28-7.23 (m, 5H), 7.18-7.13 (m, IH), 6.87 (dd, J=8.0, 2.0 Hz, IH), 6.79 (d, J=8.2 Hz, IH), 4.48 (bs, 2H), 2.90-2.86 (m, 2H), 2.83-2.78 (m, 2H), 2.42 (s, 3H). LRMS: (m/z): 331.1 (MH+).
Following the same procedures as in Example 1, steps 3 and 4 (scheme 1) but substituting compound 4 for compound 130 (300 mg, 0.559 mmol, described in the Patent Application WO 03/024448) the title compound 131 was prepared (7 mg, 3.7% yield over 2 steps). 1H NMR: (400 MHz, acetone-d6) δ (ppm): 9.16 (bs, IH), 7.97 (d, J=8.4 Hz, 2H), 7.62 (d, J=2.9 Hz, IH), 7.61 (d, J=8.4 Hz, 2H), 7.32 (dd, J=8.2, 2.2 Hz, IH), 7.28 (bs, 0.5H), 7.27 (dd, J=5.1, 1.0 Hz, IH), 7.26 (bs, 0.5H), 7.22 (dd, J=3.5, 1.0 Hz, IH), 7.21 (bs, IH), 7.03 (dd, J=5.1, 3.5 Hz, IH)1 6.89 (d, J=8.2 Hz1 IH), 4.87 (bs, 2H)14.65 (s, 2H)1 4.16 (t, J=5.7 Hz, 2H), 2.73 (t, J=5.9 Hz, 2H), 2.30 (s, 6H). LRMS: (m/z): 562.3 (MH+).
Title compound 132 was prepared according to the procedure described in J. Org. Chem. 1995, 60, 7508-7510. The synthesis was performed starting from 2-nitro-5-bromoaniline (2, 300 mg, 1.38 mmol) (scheme I1 Example 1) and using dioxane as a solvent. Amount of the prepared compound 132 was 191 mg (52% yield). 1H NMR: (400 MHz, acetone-d6) δ(ppm): 8.02 (d, J=8.6 Hz, IH), 7.46 (d, J=1.0 Hz, IH), 6.99 (s, 2H), 6.97 (dd, J=8.4, 1.2 Hz, IH), 1.37 (s, 12H).
To a solution of compound 132 (18 mg, 0.689 mmol) in pyridine (2.8 ml_) was added 4-acetamidobenzoyl chloride (150 mg, 0.758 mmol) and 4-(dimethylamino)pyridine (8 mg, 0.07 mmol) and the mixture was stirred for 16 h. at r.t. Then, it was partitioned between EtOAc and H2O, The aqueous layer was extracted with fresh EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude oil was purified by flash chromatography on silica gel using methanol/EtOAc (5:95) as the eluent affording the title compound 133 (47 mg, 16% yield) as a 1:1 mixture with 4-acetamidobenzoic acid (hydrolyzed starting material). 1H NMR: (Acetone-d6) δ(ppm): 10.76 (bs, IH), 9.52 (bs, IH), 9.00 (d, J=I.O Hz, IH), 8.20 (d, J=7.2 Hz, IH), 7.99 (d, J=8.6 Hz, 2H), 7.85 (d, J=8.6 Hz, 2H), 7.64 (dd, J=8.2, 1.2 Hz, IH), 2.15 (s, 3H), 1.40 (s, 12H).
Following the same procedures as in Example 19, step 4 (scheme 17) but substituting compound 92 for compound 133 (75 mg, 0.176 mmol), the title compound 134 was obtained (11 mg, 31% yield). 1H NMR: (acetone-d6) δ(ppm): 9.42 (bs, IH), 9.03 (bs, IH), 8.03 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.60 (d, J=1.6 Hz, IH), 7.39 (dd, J=8.0, 1.6 Hz, IH), 6.84 (d, J=7.8 Hz, IH), 5.01 (bs, 2H), 2.13 (s, 3H), 1.31 (s, 12H). LRMS: (m/z): 396.1 (MH+).
Following the same procedure as in Example 24, step 1 (scheme 20) but substituting compound 106 for 3,4-diaminobenzothiophenone dihydrochloride (135, 200 mg, 0.687 mmol) the title compound 136 was prepared as an orange foam (102 mg, 42% yield). I H NMR: (400 MHz, DMSO-dδ) δ(ppm): 9.61 (s, IH), 8.02 (d, J=6.3 Hz, IH), 8.01 (d, J=8.6 Hz, 2H), 7.83 (d, J=2.0 Hz, IH), 7.75 (d, J=3.2 Hz, IH), 7.63 (dd, J=8.4, 2.0 Hz, IH), 7.29 (dd, J=4.9, 3.2 Hz, IH), 7.08 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.6 Hz, IH), 6.01 (s, 2H), 3.88 (s, 3H). LRMS: (m/z): 353.1 (MH+).
To a solution of N,N-dimethylaminoacetyl chloride hydrochloride (137, 10.I g, 64.2 mmol) in acetonitrile (300 ml.) was added powdered sodium bicarbonate (11.9 g, 141 mmol) followed by 4-aminobenzoic acid (138, 9.68 g, 70.6 mmol). The mixture was vigorously stirred over 16 h at r.t. and acetonitrile was decanted. The remaining gum was triturated with methanol and filtration afforded the title compound 139 (10.9 g, 76% yield). 1H NMR: (400 MHz, DMSOd6) δ(ppm): 10.21 (s, IH), 7.84 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.6 Hz1 2H), 4.17 (bs, 2H), 2.27 (s, 6H). LRMS: (m/z): 223.3 (MH+).
Following the same procedures as in Example 1, steps 3 and 4 (scheme 1) but substituting compound 4 for compound 139 [798 mg (37% pure), 1.24 mmol], the title compound 140 was prepared (7.4 mg, 1.5% yield over 2 steps). I H NMR: (400 MHz, CD30D) δ (ppm): 7.99 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.48 (d, J=2.2 Hz, IH), 7.35 (dd, J=8.2, 2.2 Hz, IH), 7.22 (dd, J=5.1, 1.2 Hz, IH), 7.20 (td, J=3.5, 1.2 Hz, IH), 7.01 (dd, J=5.1, 3.7 Hz, IH), 6.90 (d, J=8.6 Hz, IH), 3.24 (s, 2H), 2.43 (s, 6H). LRMS: (m/z): 395.1 (MH+).
To a suspension of compound 141a (U.S. Pat. No. 6,174,905 BI) (533 mg, 1.75 mmol), in pyridine (5 ml_, was added compound 3 (424 mg, 1.93 mmol), Example 1 (scheme 1). The resultant solution was stirred at r.t. for 4 h and concentrated in vacuo. The crude compound 142a (855 mg, 1.75 mmol) was dissolved in a 1:1 mixture of THF and methanol (14 mU and tin chloride (II) dihydrate (1.97 g, 8.75 mmol) was added. The mixture was stirred for 3 h and solvents were removed in vacuo. The residue was suspended in methanol, adsorbed on silica gel and purified by flash chromatography on silica gel using methanol/dichlromethane (10:90) as an eluent. The resultant gum was dissolved in methanol and allowed to crystallize. Ethyl acetate was added and the remainder of the compound crashed out of solution by swirling in an ultra-sound bath. Filtration afforded the title compound 143a (63 mg, 8% yield over 2 steps) as a white solid. I H NMR: (400 MHz, DMSO-dβ) δ(ppm): 9.69 (bs, IH), 8.58 (s, IH), 8.53-8.51 (m, IH), 7.98-7.96 (m, IH), 7.94 (d, J=7.8 Hz, 2H), 7.78-7.76 (m, IH), 7.46 (s, IH), 7.40-7.38 (m, IH), 7.37 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.8 Hz, IH), 7.24-7.23 (m, IH), 7.05-7.03 (m, IH), 6.80 (d, J=8.4 Hz, IH), 5.15 (bs, 2H), 5.10 (s, 2H), 4.29 (d, J=6.1 Hz, 2H). LRMS: (m/z): 459.2 (MH+).
Compound 143b (Example 41b) was obtained similarly to the compound 143a (Example 41a) according to the scheme 29 starting from 4-fluorobenzoyl chloride (141b) via the nitro intermediate 142b. Yield 44% (over two steps).
Compound 143c (Example 41c) was obtained similarly to the compound 143a (Example 41a) according to the scheme 29 starting from 4-(trifluoromethylthio)benzoyl chloride (141c) via the nitro intermediate 142c. Yield 1.4% (over two steps).
Compound 143d (Example 41d) was obtained similarly to the compound 143a (Example 41a) according to the scheme 29 starting from 3-chloro-4-fluorobenzoyl chloride (141d) via the nitro intermediate 142d. Yield 30% (over two steps).
A flame-dried r.b flask was charged with compound 3 (IOO mg, 0.453 mmol) and put under N2 atmosphere. A trace amount of p-methoxyphenol (to prevent polymerization) was added followed by acryloyl chloride (74 μL, 0.906 mmol). The mixture was stirred for 1 h and put under high vacuum for I h. Then, THF (500 μL) was added followed by tin chloride (II) dihydrate (510 mg, 2.27 mmol). The solution was stirred for I h and purified by flash chromatography on silica gel using EtOAc/Hex with increasing polarity (50:50 to 90:10) as the eluent (traced of p-methoxyphenol was added before concentrating to avoid polymerization) affording the title compound 144 (70 mg, 63% yield for 2 steps). 1H NMR: (400 MHz, acetone-d5) δ(ppm): 8.37 (d, J=I.8 Hz, IH), 7.59 (dd, J=8.2, 1.9 Hz, IH), 7.51 (d, J=1.6 Hz1 IH), 7.50 (dd, J=2.5, 1.2 Hz, IH), 7.23 (d, J=8.2 Hz, IH), 7.15 (dd, J=4.9, 3.7 Hz, IH), 6.75 (d, J=0.8 Hz, IH), 6.52 (dd, J=16.8, 10.0 Hz, IH), 6.38 (d, J=16.8, 1.8 Hz, IH), 5.80 (dd, J=10.2, 2.0 Hz, IH). LRMS: (m/z): 245.1 (MH+).
A pressure vessel was charged with compound 144 (70 mg, 0.287 mmol), DMF (800 μl_), and compound 145 (WO 02/069947) (89 mg, 0.239 mmol). The solution was degassed under vacuum and put under N2 atmosphere (3 cycles). Then, tris(dibenzylideneacetone)dipalladium (7 mg, 0.007 mmol) was added and the red solution was degassed again (3 cycles). Tri-o-tolylphosphine (4 mg, 0.014 mmol) was added and the solution rapidly turned dark. Triethylamine (IOO μL, 0.717 mmol) was added and it was degassed twice again and allowed to stir under N2 atmosphere at 90° C. for 3 h. Then it was passed through celite and the filtrate was concentrated in vacuo. It was purified by flash chromatography on silica gel using EtOAc as the eluent and then purified again but using methanol/chloroform (5:95) as the eluent. The combined fractions were allowed to crystallize from this mixture of solvent (methanol/chloroform 5:95) affording the title compound 146 (3.8 mg, 3% yield). 1H NMR: (400 MHz, Acetone-d6) δ (ppm): 9.20 (bs, IH), 8.84 (bs, IH), 7.72 (d, J=8.0 Hz, 3H), 7.58 (d, J=15.7 Hz, IH), 7.54 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.6 Hz, 2H), 7.29-7.27 (m, 4H), 7.22 (d, J=3.5 Hz, IH), 7.04 (t, J=4.9 Hz, IH), 6.88 (d, J=8.4 Hz, IH), 6.86 (d, J=15.3 Hz, IH), 4.84 (bs, 2H), 2.38 (s, 3H). LRMS: (m/z): 490.1 (MH+).
Title compound 148 was prepared in 96% yield according to the procedure described in J. Heterocyclic Chem. 1970, 7, 1137-1141, starting from 2-bromo-4′-nitroacetophenone 147. 1H NMR: (400 MHz, DMSOd6) δ(ppm): 8.21 (d, J=8.8 Hz, 2H), 8.02 (d, J=8.8 Hz, 2H), 7.40 (s, IH)1 7.22 (s, 2H). LRMS (m/z): 222.1 (MH+).
To a solution of compound 148 (1.00 g, 4.52 mmol) in THF (20 mL), was added di-tert-butyl dicarbonate (I.I. βg, 9.94 mmol) and 4-(dimethylamino)pyridine (55 mg, 0.45 mmol) and the mixture was stirred at r.t. for 4 days. The remaining yellow solid was filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crystallization from EtOAc/Hex (twice) afforded the title compound 149 (1.23 g, 65% yield) as beige crystals. 1H NMR: (400 MHz, DMSO-d6) δ(ppm): 8.26 (d, J=9.0 Hz, IH), 8.21 (s, IH), 8.09 (d, J=9.0 Hz, IH), 1.53 (s, 18H). LRMS: (m/z): 422.2 (MH+).
Title compound 150 was prepared in 62% yield according to the procedure described in J. Chem. Soc. Perkin Trans. 1999, 1437-1444; starting from the compound 149. 1H NMR: (400 MHz, DMSOd6) δ(ppm): 11.68 (s, IH), 7.97 (d, J=9.0 Hz, IH), 7.71 (s, IH), 7.54 (s, 2H), 7.45 (d, J=2.0 Hz, IH), 7.07 (dd, J=9.0, 2.0 Hz, IH), 1.50 (s, 9H). LRMS: (m/z): 337.2 (MH+).
To a solution of compound 150 (390 mg, 1.28 mmol) in pyridine was added 4-methoxybenzoyl chloride (181 mg, 1.06 mmol) and 4-(N,IV-dimethylamino)pyridine (13 mg, 0.11 mmol). The mixture was stirred for 16 h and partitioned between EtOAc and H2O. The organic layer was washed with brine and some compound was collected by filtration. The filtrate was dried over MgSO4, filtered and concentrated in vacuo and then crystallized from a mixture of EtOAc/Hexanes. The two crops were combined affording the title compound 151 (358 mg, 72% yield). 1H NMR: (400 MHz, CD3OD) δ(ppm): 11.73 (s, IH), 10.71 (s, IH), 8.36 (d, J=2.0 Hz, IH), 8.08 (d, J=8.6 Hz, IH), 7.95 (d, J=9.0 Hz, 2H), 7.86 (d, J=0.8 Hz, IH), 7.83 (dd, J=8.6, 2.0 Hz, IH), 7.10 (d, J=9.0 Hz, 2H), 3.85 (s, 3H), 1.50 (s, 9H).
Following the same procedure as in Example 19, step 4 (scheme 17) but substituting compound 92 for compound 151 the title compound 152 was prepared in 62% yield. 1H NMR: (400 MHz, DMSO-d6) δ (ppm): 8.06 (d, J=8.6 Hz, 2H), 7.83 (d, J=2.2 Hz, IH), 7.55 (d, J=8.2, 2.0 Hz, IH), 7.12 (s, IH), 7.05 (d, J=9.0 Hz, 2H), 6.88 (d, J=8.2 Hz, IH), 3.90 (s, 3H), 1.55 (s, 9H). LRMS: (m/z): 441.4 (MH+).
Following the same procedure as in Example 27, step 3 (scheme 20) but substituting compound III for compound 152 (201 mg, 0.457 mmol), the title compound 153 was obtained (63 mg, 100% yield). 1H NMR: (400 MHz, DMSO-d6) δ (ppm): 9.55 (s, IH), 7.96 (d, J=9.0 Hz, 2H), 7.60 (d, J=2.2 Hz, IH), 7.39 (dd, J=8.2, 2.0 Hz, IH), 7.02 (d, J=9.0 Hz, 2H), 6.90 (s, 2H), 6.73 (d, J=8.4 Hz, IH), 6.63 (s, IH), 4.98 (s, 2H), 3.83 (s, 3H). LRMS: (m/z): 341.2 (MH+).
Following the same procedure as in Example 43, step 2 (scheme 31) but substituting compound 148 for 5-bromo-pyridine-2-yl-amine (154, 972 mg, 5.62 mmol) the title compound 155 was prepared (313 mg, 20% yield) 1H NMR: (400 MHz, CD3OD) δ (ppm): 8.55 (dd, J=2.5, 0.8 Hz, IH), 8.06 (dd, J=8.6, 2.5 Hz, IH), 7.45 (dd, J=8.4, 0.6 Hz, IH), 1.43 (s, 9H). LRMS: (m/z): 273.1/275.1 (M7M+2).
Following the same procedure as in Example 31, step 2 (scheme 21) but substituting compound 148 for compound 155 (135 mg, 0.494 mmol), the title compound 156 was obtained (36 mg, 25% yield). 1H NMR: (400 MHz, CD3OD) δ (ppm): 8.41 (d, J=2.2 Hz, IH), 7.98 (d, J=9.0 Hz, 2H), 7.92 (dd, J=8.8, 2.3 Hz1 IH), 7.85 (d, J=8.4 Hz, IH), 7.45 (s, IH), 7.34 (dd, J=8.4, 2.0 Hz, IH), 7.04 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.4 Hz, IH), 3.88 (s, 3H), 1.55 (s, 9H). LRMS: (m/z): 435.2 (MH+).
Following the same procedure as in Example 27, step 3 (scheme 20) but substituting compound 111 for compound 156 (36 mg, 0.083 mmol), the title compound 157 was obtained (7 mg, 25% yield). 1H NMR: (400 MHz, acetone-d6) δ (ppm): 8.94 (bs, IH), 8.03 (d, J=1.8 Hz1 IH), 7.88 (d, J=8.8 Hz, IH), 7.47 (dd, J=8.9, 2.5 Hz, IH)1 7.36 (d, J=2.3 Hz1 IH)1 7.07 (dd, J=8.2, 2.3 Hz, IH), 6.89 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.2 Hz, IH), 6.45 (dd, J=8.4, 0.6 Hz, IH), 5.29 (bs, 2H), 3.74 (s, 3H). LRMS: (m/z): 335.1 (MH+).
N-(4,4′-Diamino-3′-fluoro-biphenyl-3-yl)-4-methoxy-benzamide (157a) was prepared similarly to the compound 157 (Example 44) according to the scheme 32 using instead of 5-bromo-pyridine-2-yl-amine (154) 4-bromo-2-fluoroaniline as a starting material.
Following the same procedure as in Example 19, step 2 (scheme 17) substituting compound 90 for 3-bromophenol 158 (200 mg, 0.501 mmol), the title compound 159 was obtained (14 mg, 5% yield). 1H NMR: (400 MHz, DMSOd6) δ (ppm): 7.21 (t, J=8.0 Hz, IH), 7.14 (d, J=7.8 Hz, IH), 7.01 (s, IH), 6.86 (d, J=8.0 Hz, IH), 0.95 (d, J=LO Hz, 9H), 0.20 (d, J=1.2 Hz, 6H).
Following the same procedure as in Example 31, step 1 (scheme 21) but substituting 1-(4-bromophenyl)ethanone for compound 159 (312 mg, 1.09 mmol), the title compound 160 was obtained (79 mg, 44% yield). 1H NMR: (400 MHz, DMSOd6) δ (ppm): 9.58 (s, IH), 9.35 (s, IH), 7.97 (d, J=8.4 Hz, 2H), 7.43 (s, IH), 7.23 (dd, J=8.2, 1.4 Hz, IH), 7.16 (t, J=7.6 Hz, IH), 7.04 (d, J=8.4 Hz, 2H), 6.95 (d, J=7.6 Hz, IH), 6.91 (s, IH), 6.82 (d, J=8.4 Hz, IH), 6.62 (dt, J=8.0, 1.0 Hz, IH), 5.05 (s, 2H), 3.84 (s, 3H). LRMS: (m/z): 335.2 (MH+).
A solution of N-methylpiperazine (0.61 ml, 5.49 mmol) and 4-ethylisocyanatobenzoate 161 (1.00 g, 5.23 mmol) in THF (10 mU was stirred at room temperature for 16 h. The precipitate was filtered and rinsed with ether to give 1.40 g (92%) of the title compound 162 as a white powder. 1H NMR: (400 MHz, DMSO) δ (ppm): 8.87 (s, IH), 7.81 (d, J=8.4 Hz, 2H)1 7.59 (d, J=8.4 Hz, 2H), 7.25 (q, J=6.8 Hz, 2H), 3.45 (d, J=4.9 Hz, 4H), 2.31 (t, J=4.9 Hz, 4H), 2.19 (s, 3H), 1.30 (t, J=6.8 Hz, 3H).
A solution of 162 (1.39 g, 4.77 mmol) and LiOH.H2O (300 mg, 7.16 mmol) in 1:1 THF:water (8 ml) was stirred at room temperature for 24 h. 1 M HCl was added to reach pH=5 and the solvent was evaporated. The title compound was purified by preparative HPLC (Aquasil C18, reverse phase, eluent: MeOH/water) to give 979 mg (78%) of the title compound 163 as a white powder. 1H NMR: (400 MHz, DMSO) δ (ppm): 8.81 (s, IH), 7.78 (dt, J=8.6, 1.8 Hz, 2H), 7.53 (dt, J=8.8, 2.0 Hz, 2H), 3.44 (t, J=4.9 Hz, 4H), 2.31 (t, J=5.0 Hz, 4H), 2.19 (s, 3H).
Following the same procedures as in Example 1, steps 3 and 4 (scheme 1) but substituting compound 4 for compound 163 title compound 164 was obtained in 8.4% yield (over two steps). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.57 (s, IH), 8.80 (s, IH), 7.89 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 7.44 (d, J=2.2 Hz, IH), 7.34 (dd, J=5.1, 1.0 Hz, IH), 7.27 (dd, J=8.2, 2.2 Hz, IH), 7.23 (dd, J=3.5, 1.2 Hz, IH), 7.03 (dd, J=5.1, 3.5 Hz, IH), 6.79 (d, J=8.4 Hz, IH), 5.12 (sb, 2H), 3.46 (t, J=4.8 Hz, 4H), 2.33 (t, J=4.9 Hz, 4H). MS: (calc.) 435.2; (obt.) 436.4 (MH)+.
IH-Indole-6-carboxylic acid 37 (0.2O g, 1.24 mmol) was dissolved in dimethylformamide (10 mU and cooled to O° C. for the portion-wise addition of sodium hydride (0.2O g, 4.96 mmol). After complete addition, the reaction mixture was allowed to warm to rt and stirred for 1 hr then methyl iodide (0.15 mL, 2.48 mmol) was added to the reaction mixture. Quenching with water followed by rotary evaporation led to the crude residue, which was taken up with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated to provide crude 166 (it was used crude in the next step). MS: 189.08 (calc), 190.1 (obs).
Methyl I-methyl-IH-indole-6-carboxylate 166 (1.24 mmol) was stirred with sodium hydroxide (0.59 g, 14.88 mmol) in a 2:2:1 mixture of methanolΛ HF/water (7.5 mL) for 36 hrs at rt to form a precipitate which was collected by filtration and lyophilized overnight to give the title compound 167 (0.54 g, 99% yield). MS: 175.06 (calc), 176.1 (obs).
Following the same procedures as in Example I1 steps 3 and 4 (scheme 1) but substituting compound 4 for compound 167 title compound 168 was obtained in 0.5% yield (over two steps). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.72 (s, IH), 8.19 (s, IH), 7.67 (abq, J=29.4, 7.6 Hz, 2H), 7.52 (d, J=7.6 Hz, 2H), 7.36 (s, IH), 7.31 (d, J=6.5 Hz, IH), 7.26 (s, IH), 7.06 (s, IH), 6.83 (d, J=8.0 Hz, IH), 6.52 (s, IH), 5.16 (s, 2H), 3.90 (s, 3H). MS: 347.11 (calc), 348.1 (obs).
Following the same procedures as in Example 1, step 3 (scheme 1) but substituting compound 4 for compound 169 the title compound 170 was obtained in 51% yield. 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) δ (ppm): 8.15 (d, J=8.0 Hz, 2H), 8.10 (d, J=2.0 Hz, IH), 7.93 (d, J=8.0 Hz, 2H), 7.85 (d, J=8.6 Hz, IH), 7.67 (dd, J=4.9, 1.0 Hz, IH), 7.64 (dd, J=3.7, 1.7 Hz, IH), 7.45 (dd, J=8.4, 1.4 Hz, IH), 7.20 to 7.17 (m, IH). MS: 349.05 (calc), 348.0 (obs).
The nitro-cyano compound 170 (60.5 mg, 0.17 mmol) was heated to 95° C. in the presence of tributyltin azide (0.06 ml—, 0.21 mmol) in toluene (2 mL) for 24 hrs then solvent was evaporated and the residues was purified by flash chromatography (1:1 ethyl acetate:hexane) to provide tetrazole 171 (51.4 mg, 76% yield). 1H NMR: (DMSO) δ (ppm): 10.85 (s, IH), 8.17 (d, J=14.9 Hz, 2H), 8.13 (s, IH), 8.08 (d, J=8.4 Hz, IH)1 7.99 (d, J=7.4 Hz, 2H), 7.74 (m, 3H), 7.23 (d, J=3.7 Hz, IH). MS: 392.07 (calc), 393.1 (obs).
The nitro compound 171 (20 mg, 0.05 mmol) was hydrogenated (1 atm) in the presence of 10% palladium on charcoal (catalytic amount) in methanol (1 ml_) at room temperature for 2-3 hrs. The reaction mixture was filtered through a pad of Celite®, the filtrate was evaporated to give the crude product which was suspended in dichloromethane and stirred overnight at room temperature, then filtered to provide the title compound 172 (6.3 mg, 27% yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.71 (s, IH), 8.07 (d, J=8.2 Hz, 2H), 8.00 (d, J=8.2 Hz, 2H), 7.48 (s, IH), 7.34 (d, J=5.1 Hz, IH), 7.28 (dd, J=8.2, 2.0 Hz, IH), 7.24 (d, J=3.5 Hz, IH), 7.03 (t, J=3.7 Hz, IH), 6.79 (d, J=8.4 Hz, IH), 5.17 (s, 2H). MS: 362.09 (calc), 363.1 (obs).
Following the same procedures as in Example 1, step 4 (scheme 1) but substituting compound 4 for compound 170 the title compound 173 was obtained in 56% yield. 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.92 (s, IH), 8.14 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 2H), 7.44 (d, J=2.0 Hz, IH), 7.34 (dd, J=5.1, 0.98 Hz, IH), 7.30 (dd, J=8.2, 2.2 Hz, IH), 7.23 (d, J=3.5 Hz, IH), 7.03 (dd, J=5.1, 3.5 Hz, IH), 6.79 (d, J=8.4 Hz, IH), 5.24 (s, 2H). MS: 319.08 (calc), 320.1 (obs).
N-(2-Amino-5-(thiophen-2-yl)phenyl)-4-cyanobenzamide 173 (30 mg, 0.1 mmol), ethylenediamine (0.126 ml—, 1.9 mmol.) and carbon disulfide (catalyst) were stirred at 5O° C. in DMF overnight. The reaction mixture was then evaporated to dryness, taken up in methanol and filtered to give the title compound 174 as a yellow solid (16.3 mg, 48%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.78 (s, IH)1 8.02 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H), 7.45 (s, IH), 7.33 (d, J=5.1 Hz, IH), 7.28 (d, J=8.2 Hz, IH), 7.22 (d, J=3.3 Hz, IH), 7.03 (t, J=3.9 Hz, IH), 6.79 (d, J=8.2 Hz, IH), 5.18 (s, 2H), 3.63 (s, 4H). MS: 362.12 (calc), 363.1 (obs).
To a solution of 4-bromo-2-nitroaniline 13 (5.0O g, 23.07 mmol) in dimethylformamide (55 mL) at O° C. was added sodium hydride (1.02 g, 25.38 mmol, 1.1 equ.) portion-wise. After complete H2 evolution, a solution of Boc anhydride (5.04 g, 23.07 mmol, 1 equ.) in dimethylformamide (20 mU was cannulated slowly into the reaction mixture over 30 minutes. The reaction was allowed to warm to rt then stirred overnight. It was then quenched with water and the DMF was removed in vacuo. The residue was taken up in water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to provide 175 (3.72 g, 51%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.67 (s, IH), 8.10 (d, J=2.3 Hz, IH), 7.84 (dd, J=8.6, 2.3 Hz, IH), 7.56 (d, J=8.8 Hz, IH), 1.44 (s, 9H). MS: (calc.) 316.01; (obt.) 217.1 (M—BoC)+.
A solution of tert-butyl 4-bromo-2-nitrophenylcarbamate 175 (3.97 g, 12.5 mmol), 2-thiophene boronic acid 176 (1.68 g, 13.4 mmol), sodium carbonate (3.98 g, 37.56 mmol) and Pd(PPh3)4 (0.94 g, 0.814 mmol) were stirred at H O° C. in a mixture of DME and water (2:1, 70 mL overnight. The solution was evaporated to dryness, diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to provide the crude product which was purified by flash chromatography (10% ethyl acetate in hexane) to provide the title compound 177 (2.14 g, 53% yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.63 (s, IH), 8.12 (d, J=2.3 Hz, IH), 7.92 (dd, J=8.4, 2.2 Hz, IH), 7.66 (d, J=8.4 Hz, IH), 7.61 (q, J=2.2 Hz, 2H), 7.15 (dd, J=5.1, 3.7 Hz, IH), 1.46 (s, 9H). MS: (calc.) 320.08; (obt.) 343.1 (M+Na).
Following the same procedures as in Example 48, step 3 (scheme 36) but substituting compound 171 for compound 177 the title compound 178 was obtained (68% yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 8.34 (s, IH), 7.43 (dd, J=5.1, 1.2 Hz, IH), 7.27 (dd, J=3.5, 1.2 Hz, IH), 7.24 (d, J=8.0 Hz, IH), 7.06 (dd, J=5.1, 3.7 Hz, IH), 6.95 (d, J=2.2 Hz, IH), 6.82 (dd, J=8.2, 2.2 Hz, IH), 5.00 (s, 2H), 1.47 (s, 9H). MS: (calc.) 290.11; (obt.) 291.1 (MH)+.
3-Methoxybenzoyl chloride 179 (0.20 g, 1.17 mmol) and 178 (0.34 g, 1.17 mmol) were stirred in pyridine (15 mL) at rt for 4 hrs then the pyridine was removed by rotary evaporation and the crude material was purified by column chromatography (25% ethyl acetate in hexanes) to provide the title compound 180 (0.44 g, 89% yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.88 (s, IH), 8.72 (s, IH), 7.80 (s, IH), 7.60 (d, J=8.4 Hz, IH), 7.43 to 7.55 (m, 6H), 7.17 (dd, J=7.6, 1.8 Hz, IH), 7.11 (dd, J=4.9, 3.5 Hz, IH), 3.84 (s, 3H), 1.46 (s, 9H). MS: (calc.) 424.15; (obt.) 425.1 (MH)+.
tert-Butyl 2-(3-methoxybenzamido)-4-(thiophen-2-yl)phenylcarbamate 180 (0.214 g, 0.504 mmol) was stirred in trifluoroacetic acid: dichloromethane solution (1:3, 4 mL) at rt for 5 hrs then solvent was evaporated. The crude residue was washed with dichloromethane and evaporated several times to get rid of excess trifluoroacetic acid to provide the title compound 181 (0.22 g, 100%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.96 (IH, s), 7.59-7.52 (3H, m), 7.46-7.41 (3H, m), 7.39 (IH, d, 2.2 Hz)1 7.33 (IH, dd, 2.5 and 1.0 Hz)1 7.16 (IH, dd, 5.7 and 1.8 Hz)1 6.98 (IH, d, 8.4 Hz), 3.84 (3H, s). MS: 324.09 (calc), 325.1 (obs).
tert-Butyl 2-amino-4-(thiophen-2-yl)phenylcarbamate 178 (0.198 g, 0.68 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (0.302 g, 0.68 mmol) and 4-acetoxybenzoic acid (182) (0.123 g, 0.68 mmol) were stirred in pyridine at rt overnight then solvent evaporated and purified by flash chromatography (35% ethyl acetate in hexanes) to provide 183 (0.1I g, 36%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.91 (s, IH), 8.72 (s, IH), 8.01 (d, J=8.8 Hz, 2H), 7.78 (d, J=1.8 Hz, IH), 7.63 (d, J=8.4 Hz, IH), 7.51 (dd, J=4.9, 0.98 Hz, 2H), 7.44 (dd, J=3.7, 0.98 Hz, IH), 7.30 (d, J=8.6 Hz, IH), 7.11 (dd, J=5.1 Hz, IH), 2.32 (s, 3H), 1.46 (s, 9H). MS: (calc.) 452.14; (obt.) 475 (M+Na).
Following the same procedure as for the Example 51, step 5 (the same scheme 37) but substituting compound 180 for the compound 183, the title compound 184 was obtained (16% yield). 1H NMR: (DMSO) o (ppm): 400 MHz, (DMSO) d (ppm): 9.73 (IH, s), 8.03 (2H, d, 8.4), 7.45 (IH1S1), 7.34 UH, d, 9.0 Hz), 7.30-7.22 (4H, m), 7.04 (IH, dd, 3.5 and 1.6 Hz), 6.79 (IH, d, 8.4 Hz), 5.18 (2H, s), 2.31 (3H, s). MS: 352.1 (calc), 353.1 (obs).
tert-Butyl 4-fluorobenzoate 185 (0.502 g, 2.55 mmol) and 2-(piperidin-I-yl)ethanamine 186 (1.46 mL, 10.21 mmol) were stirred neat at 12O° C. overnight then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate (Ix), brine (Ix), dried over magnesium sulfate and evaporated to give 187 (0.501 g, 64%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 7.59 (d, J=8.8 Hz, 2H), 6.55 (d, J=8.8 Hz, 2H), 6.24 (t, J=5.1 Hz, IH), 4.11 (m, 2H), 3.21 to 3.13 (m, 6H), 2.44 (t, J=7.1 Hz, 2H), 2.37 (m, 2H), 1.49 (s, 9H), 1.47 to 1.38 (m, 2H). MS: 304.22 (calc), 249.1 (M-tBu).
Following the same procedure as for the Example 51, step 5 (scheme 37) but substituting compound 187 for the compound 183, the title compound 188 was obtained (0.37 g, 90.5%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 7.69 (d, J=8.6 Hz, 2H), 6.62 (d, J=8.8 Hz1 2H), 6.51 (t, J=6.8 Hz, IH), 3.46 (d, J=5.7 Hz, 2H), 3.33 (s, 2H), 3.14 (d, J=11.5 Hz, 4H), 1.72 (m, 6H). MS: 248.15 (calc), 249.2 (obs).
Following the same procedure as for the Example 1, step 3 (scheme 1), but substituting acid 4 for the acid 188, the title compound 189 was obtained (19% yield). MS: 450.17 (calc), 451.2 (obs).
Following the same procedure as for the Example 51, step 3 (scheme 37), but substituting nitro compound 177 for the nitro compound 189, the title compound 190 was obtained (8% Yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.34 (IH, s), [8.25 (2H, s) comes from formic salt], 7.77 (2H, d, 8.8), 7.44 (IH, d, 2.2 Hz), 7.34 (IH, dd, 4.0 and 1.2 Hz), 7.26-7.21 (2H, m), 7.03 (IH, dd, 3.5 and 1.4), 6.78 (IH, d, 8.2), 6.62 (IH, d, 8.8 Hz), 6.09 (IH, m), 3.25-3.15 (8H, m), 1.53 to 1.49 (4H, m), 1.39 (2H, m). MS: 420.2 (calc), 421.3 (obs).
To a stirring solution of methyl 4-hydroxybenzoate 191 (I.O δg, 7.10 mmol) and 4-(2-chloroethyDmorpholine hydrochloride 192 (1.45 g, 7.82 mmol) in acetonitrile was added potassium carbonate (2.95 g, 21.3 mmol). The reaction mixture was heated to 5O° C. overnight then cooled to rt and the resulting precipitate was filtered and washed with methanol to provide methyl 4-(2-morpholinoethoxy)benzoate 193 (2.67 g, 142%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 7.87 (s, J=9.0 Hz1 2h), 7.03 (d, J=9.0 Hz, 2H), 4.15 (t, J=5.7 Hz, 2H), 3.80 (s, 3H), 3.56 (t, J=4.5 Hz, 4H), 2.69 (t, J=5.7 Hz, 4H), 2.47 (m, 4H). MS: 265.13 (calc), 266.1 (obs).
Lithium hydroxide (hydrated) (0.59 g, 14.1 mmol) was added to a solution of methyl 4-(2-morpholinoethoxy)benzoate 193 (1.25 g, 4.7 mmol) in a 1:1 mixture of THF-water (20 ml_). The reaction mixture was stirred at rt overnight then acidified with I N HCl to pH 2, solvent was evaporated and the residue was lyophilized to provide crude 194 (1.66 g, >>100% Yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 7.88 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 4.53 (m, 2H), 3.89 (m, 4H), 3.53 (m, 2H), 3.26 to 3.14 (m, 4H). MS: 251.12 (calc), 252.1 (obs).
4-(2-Morpholinoethoxy)benzoic acid 194 (330 mg, 1.31 mmol) was dissolved in thionyl chloride (4 ml_) and a few drops of dimethylformamide were added. The reaction mixture was allowed to stir at 8O° C. in a sealed tube for 1.5 hrs then opened to leave evaporate overnight. The residue was placed on a vacuum pump overnight and used as is in the next reaction (0.3O g1 100%). MS: 269.08 (calc, COCl), 265.13 (calc, Me ester), 266.2 (obs, Me ester)
Following the same procedure as for the Example 51, step 4 (scheme 37) but substituting compound 178 for the compound 3, and compound 179 for compound 195, the title compound 196 was obtained (3% yield). MS: 453.14 (calc), 454.2 (obs).
Following the same procedure as for the Example I1 step 4 (scheme 1) but substituting the nitro compound 5 for the nitro compound 196, title compound 197 was obtained (3 mg, 19%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.67 (IH, s), 8.01 (2H, d, 8.8), 7.44 (IH, d, 2.0 Hz), 7.36 (IH, dd, 4.1 and 1.0 Hz), 7.30 (IH, dd, 6.1 and 2.2 Hz), 7.24 (IH, dd, 2.5 and 1.2), 7.12 (2H, d, 8.8), 7.04 (IH, dd, 3.5 and 1.6 Hz), 6.82 (IH, d, 8.4 Hz), 4.44 (2H, t, 4.1), 3.65 to 3.15 (10H, m). MS: 423.16 (calc), 424.2 (obs).
Following the same procedure as described in Example 27, step 2 (scheme 20), the title compound 199 was obtained in 16% yield. 1H NMR: (DMSO) δ (ppm): 9.56 (bs, IH)1 7.89 (d, J=8.0 Hz, 2H), 7.52 (bs, IH), 7.45 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.4 Hz, IH), 6.63 (d, J=8.4 Hz, IH), 6.30 (d, J=2.4 Hz, IH), 5.99-5.95 (m, 2H), 5.74 (bs, IH), 4.92 (bs, 2H), 3.64 (s, 3H), 3.32 (s, 3H). MS: (calc); 402.5 (obt.) 403.4 (MH)+.
Following the procedure described in Example 43, step 2 (scheme 31) using THF as a solvent but substituting compound 108 for compound 200, the title compound 201 was obtained in 55% yield. MS: (calc.) 390.8; (obt.) 413 (M+Na)+.
Following the same procedure described in Example 1, step 2 (scheme 1), but substituting bromoarene 2 for compound 201, the title compound 202 was obtained (36% yield). 1H NMR: (CDCl3) δ (ppm): 7.85 (d, J=10.4 Hz1 IH), 7.56-7.54 (m, IH), 7.49 (d, J=6.8 Hz, IH), 7.44 (dd, J=1.2, 5.2 Hz, IH), 7.10 (dd, J=0.8, 5.2 Hz, IH), 1.36 (bs, 18H). MS: (calc.) 438.4; (obt.) 239.1 (MH−2 tert-Boc)+.
Following the procedure described in Example 27, step 3 (scheme 20) but substituting compound 111 for compound 202, the title compound 203 was obtained (32% yield). 1H NMR: (CD3OD) δ (ppm): 7.86 (d, J=12.0 Hz, IH), 7.63-7.60 (m, 2H), 7.31 (d, J=6.8 Hz, IH), 7.17 (t, J=4.4 Hz, IH). MS: (calc.) 238.3; (obt.) 239.1 (MH)+.
Following the procedure described in Example 1, step 3 (scheme 1) but substituting compound 3 for compound 203, the title compound 204 was obtained (89% yield). 1H NMR: (DMSO) δ (ppm): 10.70 (bs, IH), 8.17 (d, J=7.2z, IH), 8.10 (d, J=10.8 Hz, IH), 7.90 (d, J=8.8 Hz, 2H), 7.85 (dd, J=5.2; 1.2 Hz, IH), 7.73 (d, J=4.0 Hz, IH), 7.52 (d, J=8.8 Hz1 2H), 7.62 (dt, J=5.2; 1.2 Hz, IH), 6.40 (d, J=8.8 Hz, IH), 6.31 (d, J=2.4 Hz, IH), 6.01-5.96 (m, 2H), 4.31 (d, J=6.6 Hz, 2H), 3.65 (s1 3H), 3.58 (s, 3H). MS: (calc.) 507.5; (obt.) 508.3 (MH)+.
Following the procedure described in Example 1, step 4 (scheme 1) but substituting compound 5 for compound 204 and running the reaction at room temperature, the title compound 205 was obtained (41% yield).̂ NMR: (DMSO) δ (ppm): 9.65 (s, IH), 7.96 (d, J=8.0 Hz, 2H), 7.48-7.51 (m, 4H), 7.31 (d, J=4.0 Hz, IH), 7.11 (d, J=4.0 Hz, IH), 6.80 (d, J=8.8 Hz, IH), 6.50 (d, J=13.6 Hz, IH), 6.35 (d, J=2.8 Hz, IH), 6.03-6.01 (m, 2H)1 5.50 (bs, 2H), 4.34 (d, J=6.0 Hz, 2H), 3.70 (s, 3H), 3.62 (s, 3H). MS: (calc.) 477.6; (obt.) 478.4 (MH)+.
To a stirred solution of 206 (500 mg, 2.8 mmol) in DMF (20 mL), was added 1-methyl-IH-imidazole-2-thiol (207a, 2.8 mmol, 328 mg) and potassium carbonate (1.58 g, 11.49 mmol). The reaction mixture was stirred at 60° for 5 hours. Ethyl acetate was added and K2CO3 was removed by filtration. The filtrate was concentrated, evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluents hexane-EtOAc (1:2), then EtOAc (100%) to afford 208a (751 mg, 98% yield). MS: (calc.) 268.3; (obt.) 269.1 (MH)+.
Following the procedures described in Example 1, steps 3 and 4 (scheme 1) but substituting compound 3 for compound 208a the title compound 209a was obtained in 28% yield. 1H NMR: (DMSO) δ (ppm): 9.5 (s, IH)1 7.86 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.2 (s, IH), 7.10 (d, J=8.4 Hz, IH), 6.90 (s, IH), 6.6 (d, J=8.8 Hz, IH), 6.56 (d, J=11.6 Hz, IH), 6.29 (d, J=2.4 Hz, IH), 5.95 (dd, J=2.4, 8.8 Hz, 2H), 5.52 (bs, 2H), 4.28 (bs, 2H), 3.64 (s, 6H)1 3.57 (s, 3H). MS: (calc.) 507.6; (obt.) 508.4 (MH)+.
Following the same procedure as described in Example 57a, step 1 (scheme 42) but substituting imidazole 207a for 4-(IH-imidazol-1-yl)phenol (207b), the compound 208b was obtained in 23% yield. MS: (calc.) 314.6; (obt.) 315.1 (MH)+.
Following the procedures described in Example 1, steps 3 and 4 (scheme 1) but substituting compound 3 for compound 208b the title compound 209b was obtained in 65% yield. 1H NMR: (DMSO) δ (ppm): 7.87 (d, J=8.4 Hz, 2H), 7.75 (bs, IH), 7.60 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.26 (bs, IH), 7.14 (d, J=8.0 Hz, IH), 7.03 (d, J=8.0 Hz, 2H), 6.723 (d, J=13.2 Hz, IH), 6.62 (d, J=8.4 Hz, IH), 6.29 (d, J=2.4 Hz, IH), 5.96 (dd, J=2.4, 8.8 Hz, 2H), 4.28 (bs, 2H) 3.64 (s, 3H), 3.57 (s, 3H). MS: (calc.) 553.6; (obt.) 554.5 (MH)+.
To a stirred solution of 206 (500 mg, 2.87 mmol) and pyrrole (210, 239 uL, 3.44 mmol) in DMF (10 mU, was added NaH (207 mg, 5.17 mmol). The reaction mixture was stirred for 18 hours at 50°, quenched with water (100 mL) and extracted with DCM (2×50 ml_). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluents hexanes-EtOAc 4:1, then hexanes-EtOAc 1:1, to afford the title compound 211 (145 mg, 25% yield). 1H NMR: (DMSO) δ: 7.94 (d, J=12.0 Hz, IH), 7.12 (q, J=2.4, 4.4 Hz, 2H), 7.02 (d, J=6.8 Hz, IH), 6.32 (t, J=2.4, 4.8 Hz, 2H). MS: (calc.) 221.8; (obt.) 222.1 (MH)+.
Following the procedures described in Example 1, steps 3 and 4 (scheme 1) but substituting amine 3 for compound 211, and the acid 4 for 4-acetamidobenzoic acid (212) the title compound 213 was obtained in 40% yield. 1H NMR: (DMSO) δ (ppm): 10.11 (s, IH), 9.48 (s, IH), 7.83 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.4 Hz, IH), 6.86 (dd, J=2.0, 4.0 Hz, 2H), 6.62 (d, J=12.8 Hz, IH), 6.10 (2H, dd, J=2.0, 4.0 Hz, 2H), 5.28 (bs, 2H), 2.09 (s, 3H). MS: (calc.) 352.36; (obt.) 353.2 (MH)+.
Following the procedure described in Example 43, step 2 (scheme 31) but substituting compound 148 for compound 206, the title compound 214 was obtained in 89% yield. 1H NMR: (CDCl3) δ (ppm): 7.99 (dd, J=7.6, 9.6 Hz, IH), 7.18 (ddFJ=7.2, 9.6 Hz, IH), 1.42 (bs, 18H). MS: (calc.) 374.3; (obt.) 397.2 (MNa)+.
Following the same procedure as described in Example 57a, step I1 but substituting DMF for DMSO and 1-methyl-IH-imidazole-2-thiol (207a) for IH-indole-5-carbonitrile (215) the title compound 216 was obtained in 28% yield. 1H NMR: (CDCl3) δ (ppm): 9.71 (bs, IH), 8.88 (d, J=3.2 Hz, IH), 8.21 (d, J=10.8 Hz, IH), 8.02 (s, IH), 7.55 (bs, IH), 7.43 (dd, J=2.4, 6.0 Hz, IH), 6.83 (d, J=3.6 Hz, IH), 1.55 (s, 18H). MS: (calc.) 496.5; (obt.) 436.3 (M+K)+.
Following the procedure described in Example 27, step 3 (scheme 20) but substituting 111 for compound 216, the title compound 217 was obtained in 99% yield. MS: (calc.) 296.3; (obt.) 297.2 (MH)+.
Following the procedures described in Example 1, steps 3 and 4 but substituting compound 3 for compound 217 the title 218 was obtained in 41% yield. 1H NMR: (DMSO) δ (ppm): 8.08 (bs, IH), 7.96 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.41-7.50 (m, 2H), 7.40 (d, J=8.0 Hz, IH), 7.35 (d, J=7.6 Hz, IH), 6.83 (d, J=8.0 Hz, IH), 6.80 (d, J=2.4 Hz, IH), 6.72 (d, J=8.8 Hz, IH), 6.38 (d, J=2.4 Hz, IH), 6.15 (dd, J=2.4, 8.8 Hz, IH), 4.41 (bs, 2H), 3.76 (s, 3H), 3.73 (s, 3H). MS: (calc.) 535.5; (obt.) 536.3 (MH)+.
To a stirred solution of 219 (1.96 g, 12.02 mmol) in pyridine (15 mL) and Et3N (6 ml) was bubbled hydrogen sulfide for 40 minutes. When the reaction was completed nitrogen was bubbled for another 40 min. The residue was diluted in DCM and washed with water, HCl 10% and brine. Organic phases were collected, dried with sodium sulfate and concentrated under reduced pressure to afford the title compound 220 (2.11 g, 89% yield). 1H NMR: (DMSO) δ (ppm): 9.04 (bs, IH), 8.31 (d, J=9.2 Hz, IH), 7.28 (d, J=8.8 Hz, IH). MS: (calc.) 197.2; (obt.) 198.1 (MH)+.
To a stirred suspension of 220 (500 mg, 2.53 mmol) in ethanol (15 mL) was added chloroacetaldehyde (50% solution in water, 0.796 ml, 5.0 mmol). The mixture was heated at 8O° C. for 18 hours, evaporated under reduced pressure and the residue was dissolved in DCM, washed with brine, dried with sodium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel, eluents hexane-EtOAc (4:1), then EtOAC (100%), to afford the title compound 221a (104 mg, 19% yield). 1H NMR: (CD3OD) δ (ppm): 8.62 (d, J=2.0 Hz, IH), 7.91 (dd, J=2.4, 8.8 Hz, IH), 7.78 (d, J=3.2 Hz, IH), 7.51 (d, J=3.2 Hz, IH), 7.07 (d, J=8.8 Hz, IH). MS: (calc.) 221.2; (obt.) 222.1 (MH)+.
Following the procedure described in Example 1, step 4 (scheme 1) but substituting 5 for compound 221a, the title compound 222a was obtained (53% yield). 1H NMR: (CD3OD) δ (ppm): 7.68 (d, J=3.2 Hz1 IH), 7.38 (d, J=3.6 Hz, IH), 7.26 (d, J=2.0 Hz, IH), 7.19 (dd, J=2.0, 8.0 Hz, IH), 6.70 (d, J=8.0 Hz, IH). MS: (calc.) 191.2; (obt.) 192.3 (MH)+.
To a stirred suspension of 222a (47 mg, 0.25 mmol) in acetonitrile (10 mL) and pyridine (20 uL) was added 4-acetamidobenzoyl chloride (49 mg, 0.25 mmol) in acetonitrile (1 mL) at O° C. for 15 min. The reaction mixture was warmed up to room temperature and stirred for 4 hours, concentrated under reduced pressure. The crude was diluted in DCM and washed with NaHCO3 and brine. The organic layer was dried with Na2SO4 and evaporated. The residue was purified by flash chromatography on silica gel, eluents hexane-EtOAc (1:3), then EtOAc (100%) to afford the title compounds 223 (3 mg, 4% yield) and 224a (5 mg, 5% yield).
223: 1H NMR: (CD3OD) δ (ppm): 7.95 (d, J=8.8 Hz, 2H), 7.60 (d, J=3.2 Hz, IH), 7.73-7.71 (m, 2H), 7.56 (d, J=3.2 Hz, IH), 7.48 (bs, IH), 7.32 (bs, 2H), 2.17 (s, 3H). MS: (calc.) 352.4; (obt.) 353.2 (MH)+.
224a: 1H NMR: (DMSO) δ (ppm): 10.18 (s, IH), 9.64 (s, IH), 8.00-7.94 (m, 5H), 7.84 (d, J=2.0 Hz, IH), 7.68 (dd, J=1.6, 7.2 Hz, 2H), 7.61 (dd, J=2.0, 8.4 Hz, IH), 7.42 (dt, J=1.6, 7.2 Hz, 2H), 7.32 (d, J=1.6, 7.2 Hz, IH), 6.84 (d, J=8.4 Hz, IH), 5.52 (bs, 2H), 2.09 (s, 3H). MS: (calc.) 428.5; (obt.) 429.1 (MH)+.
Following the same procedures as described in Example 61a, steps 1-4 (scheme 44) but substituting chloroacetaldehyde in the second step by 2-chloro-1-phenylethanone, the title 224b was obtained in 24% overall yield.
Following the same procedures as described in Example 61a, steps 14 (scheme 44) but substituting chloroacetaldehyde in the second step by 3-chlorobutan-2-one, the title 224c was obtained in 3% overall yield.
Hydrogen chloride was bubbled into a reaction flask containing absolute ethanol (10 mU during 5 min at O° C. The compound 219 (2.00 g, 12.26 mmol) was added to the solution. The mixture was stirred at room temperature for 18 h, concentrated under reduced pressure and the solid residue was triturated with ethyl acetate to afford the title compound 225 as a yellow solid (2.72 g, 79% yield). 1H NMR: (DMSO) δ (ppm): 8.40 (d, J=2.0 Hz, IH)1 8.05 (bs, 2H), 7.65 (dd, J=2.0, 8.8 Hz, IH), 7.06 (d, J=8.8 Hz, IH). MS: (calc.) 209.2; (obt.) 210.1 (MH)+.
The imidate 225 (500 mg, 1.77 mmol) in anhydrous ethanol (25 mL) was treated with o-aminophenol (232 mg, 2.1 mmol) and heated in a sealed flask at 95° C. for 5 h. The solvent was evaporated under reduced pressure and the residue was triturated with ethyl acetate to afford the title compound 226 (517 mg, quant, yield.). 1H NMR: (DMSO) δ (ppm): 8.45 (d, J=2.0 Hz, IH), 8.14 (dd, J=2.0, 8.8 Hz, IH), 8.06 (bs, 2h), 7.79-7.75 (M, 2H), 7.41-7.39 (m, 2h), 7.20 (d, J=1.6 Hz, IH). MS: (calc.) 255.2; (obt.) 256.0 (MH)+.
To a stirred solution of 226 (517 mg, 1.77 mmol) in methanol (20 mL) was added palladium on charcoal (10%, 188 mg). The reaction was stirred under hydrogen atmosphere for 18 hours, filtered through a celite pad; the filtrate was evaporated under reduced pressure to afford title compound 227 (350 mg, 87% yield). 1H NMR: (DMSO) δ 7.673-7.641 (m, 2H), 7.39 (d, J=2.0 Hz, IH), 7.32-7.30 (m, 3H), 6.64 (d, J=8.0 Hz, IH). MS: (calc.) 225.2; (obt.) 226.1 (MH)+.
To a stirred suspension of 227 (350 mg, 1.55 mmol) in acetonitrile (20 mL) and pyridine (2 ml) was added 4-acetamidobenzoyl chloride (307 mg, 1.55 mmol) in acetonitrile (5 ml) at O° C. The solution was warmed up to room temperature and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluents hexane-EtOAc (1:3), then EtOAc (100%), to afford 228 as a beige solid (5 mg, 1% yield). 1H NMR: (DMSO) δ (ppm): 10.22 (s, IH), 9.62 (s, IH), 8.05 (d, J=2.4 Hz, IH), 7.89 (d, J=8.4 Hz, 2H), 7.80 (IH, dd, J=2.0, 8.4 Hz, IH), 7.68-7.73 (m, 4H), 7.33-7.35 (m, 2H), 6.91 (d, J=8.4 Hz, IH), 5.86 (bs, 2H), 2.12 (s, 3H). MS: (calc.) 386.41; (obt.) 387.1 (MH)+.
To a solution of (E)-3-(4-formylphenyl)acrylic acid 229 (1 g, 5.67 mmol) and 3-chlorobenzenamine 230 (596 DL, 5.67 mmol) in THF (8 ml), dibutyltin dichloride (173 mg, 0.57 mmol) was added followed by dropwise addition of phenylsilane (697 uL, 5.67 mmol). The resulting mixture was stirred at room temperature in the nitrogen atmosphere overnight, diluted with MeOH and concentrated under reduced pressure. The solid residue was triturated with DCM to yield the title compound 231 (1.24 g, 76% yield). 1H NMR: (DMSO) δ (ppm): 7.61 (d, J=8.0 Hz, 2H), 7.53 (d, J=16.0 Hz1, IH), 7.34 (d, J=8.4 Hz, 2H), 7.00 (t, J=8.0 Hz, IH), 6.53 (t, J=2.0 Hz, IH), 6.49-6.48 (m, 2H), 6.46 (d, J=16.0 Hz, IH), 4.28 (bs, 2H). MS: (calc.) 287.7; (obt.) 288.1 (MH)+.
Following the procedure described in Example I1 steps 34 (scheme 1) but substituting acid 4 for the acid 231 title compound 232 was obtained in 60% yield. 1H NMR: (DMSO) δ (ppm): 9.42 (bs, IH), 7.66-7.32 (m, 7H)1 7.22-7.14 (m, 2H), 7.10-7.00 (m, 2H), 6.87-6.74 (m, IH), 6.62-6.50 (m, 4H), 5.19 (bs, IH), 4.29 (d, J=5.6 Hz, 2H). MS: (calc.) 459.2; (obt.) 460.3 (MH)+.
To a stirred solution of 233 (2 g, 14.48 mmol) in pyridine (60 mU was added acetic anhydride (1.62 ml—15.93 mmol). The reaction mixture was heated to 13O° C. in a sealed vessel, stirred for 16 hours, concentrated under reduced pressure to 30 mL and cooled to O° C. The resulting precipitate was filtered, washed with cold pyridine and water, and dried. This afforded 234 as a white solid (1.85 g, 71% yield). 1H-NMR (DMSO) δ: 10.82 (s, IH), 8.77 (dd, J=2.2, 0.8 Hz, IH), 8.20 (dd, J=8.7, 2.2 Hz, IH), 8.14 (d, J=8.7 Hz, IH), 2.12 (s, 3H).
Following the procedures described in Example I1 steps 3 and 4 (with DMF as a co-solvent), but substituting acid 4 for the acid 234, the title compound 235 was obtained as a yellow solid (20 mg, 9% yield). 1H NMR: (DMSO) δ 10.79 (br s, IH), 9.75 (br s, IH), 8.90 (s, IH), 8.31 (d, J=9.4 Hz, IH), 8.15 (d, J=8.5 Hz, IH), 7.42 (s, IH), 7.33 (m, IH), 7.28 (d, J=8.5 Hz, IH), 7.22 (s, IH), 7.02 (m, IH), 6.78 (d, J=8.0 Hz, IH), 5.20 (br s, 2H), 2.13 (s, 3H)
To a stirred solution of 3,4-diamino-benzoic acid methyl ester (236, 2 g, 12.03 mmol) in isopropanol (50 mL) was added oxaldehyde as a 40% solution in water (13.23 mmol, 1.52 mL). The reaction mixture was heated at 8O° C. for 2 hours, the solvent was removed under reduced pressure and the residue was dried under vacuum to yield 237a as a yellow solid (2.09 g, 93% yield). 1H NMR: (DMSO) δ 9.01 (s, 2H), 8.54 (d, J=1.6 Hz, IH), 8.23 (dd, J=8.6, 2.0 Hz, IH), 8.14 (dd, J=8.6, 0.6 Hz, IH), 3.35 (s, 3H).
Following the same procedure as described in Example 4 step 3 and then the procedures described in Example 1, steps 3 and 4, (with DMF as a co-solvent), the title compound 238a was obtained as an orange solid in 26% yield (over the 3 steps). 1H NMR: (DMSO) δ 10.09 (br s, IH), 9.04 (dd, J=6.7, 1.8 Hz, 2H), 8.79 (d, J=1.8 Hz, IH), 8.37 (dd, J=8.9, 2.0 Hz, IH), 8.20 (d, J=8.6 Hz, IH), 7.51 (d, J=2.2 Hz, IH), 7.34 (dd, J=4.9, 1.0 Hz, IH), 7.30 (dd, J=2.1, 8.1 Hz, IH), 7.24 (dd, J=3.5, 1.2 Hz, IH), 7.04 (dd, J=4.9, 3.5 Hz, IH), 6.81 (d, J=8.2 Hz, IH), 5.28 (br s, 2H).
Following the same procedures as described in Example 65a but substituting in the step 1 oxaldehyde with 1,2-di(furan-2-yl)ethane-1,2-dione, the title compound 238b was obtained as an yellow solid in 28% yield (over the four steps). 1H NMR: (CD3OD) δ 8.56 (s, IH), 8.21 (d, J=8.6 Hz, IH), 8.03 (d, J=8.8 Hz, IH), 7.63 (s, 2H), 7.45 (d, J=1.7 Hz, IH), 7.27 (d, J=8.4 Hz, IH), 7.13-7.12 (m, 2H), 6.90 (t, J=4.1 Hz, IH), 6.83 (d, J=8.4 Hz, IH), 6.69 (t, J=3.9 Hz, 2H), 6.55-6.56 (m, 2H).
Following the same procedure as described in Example 65a but substituting in the step 1 oxaldehyde with 1,2-di(thiophen-2-yl)ethane-1,2-dione, the title compound 65c was obtained as an yellow solid in 25% yield (over the four steps). 1H NMR: (DMSO) δ 10.09 (s, IH), 8.75 (d, J=1.8 Hz, IH), 8.32 (dd, J=8.6, 2.0 Hz, IH), 8.12 (d, J=8.6 Hz, IH), 7.84-7.82 (m, 2H), 7.52 (d, J=2.0 Hz, IH), 7.35-7.24 (m, 5H), 7.14-7.11 (m, 2H), 7.03 (dd, J=5.0, 3.5 Hz, IH), 6.81 (d, J=8.4 Hz, IH), 5.29 (s, 2H).
To a stirred solution of 4-bromomethyl-benzoic acid (239, 1.5 g, 6.78 mmol) in THF (15 mL) was added morpholine (0.61 ml—, 6.78 mmol). The reaction mixture was allowed to stir for 10 minutes before the resulting white precipitate was filtered off and discarded. The filtrate was evaporated under reduced pressure and the remaining solid was dried under vacuum to afford the title compound 240 as a white solid (1.15 g, 75% yield). 1H NMR: (DMSO) δ 7.89-7.86 (m, 2H), 7.52 (d. J=8.4 Hz, IH), 7.41 (d, J=8.0 Hz, IH), 4.12 (s, 2H), 3.75-3.72 (m, IH), 3.56-3.58 (m, 4H), 3.10-3.07 (m, IH), 2.45-2.35 (m, 2H).
To a stirred solution of 240 (221 mg, 1.0 mmol) in DCM (10 mL) was added oxalyl chloride (2M, 0.5 mL, 1.0 mmol) and DMF (1 drop). The resulting solution was stirred for 20 minutes. The DCM was removed under reduced pressure and pyridine was added (10 mL), followed by 2-nitro-5-(thiophen-2-yl-aniline (3, 220 mg, 1.0 mmol), and NaH (160 mg, 4.0 mmol). The reaction mixture was stirred for 1 hour before being quenched with acetic acid (2.0 mL). The pyridine was removed under reduced pressure and the residue was purified by flash chromatography on silica gel, eluent EtOAc-hexanes (4:1), to afford the title compound 241 as an orange solid (75 mg, 18% yield).
Following the same procedure as described in Example 1, step 4, and the title compound 242 was obtained as beige solid in 59% yield. 1H NMR: (CDCl3) δ 8.61-8.59 (m, IH), 8.02 (br s, IH), 7.86 (d, J=8.0 Hz, 2H), 7.53 (br s, IH), 7.44 (d, J=8.0 Hz, 2H), 7.33 (dd, J=8.2, 2.2 Hz, IH), 7.30-7.26 (m, IH), 7.17 (dd, J=5.1, 1.2 Hz, IH), 7.15-7.14 (m, IH), 7.01 (dd, J=5.1, 3.5 Hz, IH), 6.82 (d, J=8.2 Hz, IH), 3.73 (t, J=4.7 Hz, 4H), 3.57 (s, 2H), 2.47 (t, J=4.3 Hz, 4H).
To a stirred solution of 5-bromo-2-hydroxybenzaldehyde (14a, 1.5 g, 7.46 mmol) in DMF (20 mL), was added methyl bromoacetate (8.21 mmol, 0.78 mL) and potassium carbonate (4.12 g, 29.84 mmol). The reaction mixture was heated at 80° and stirred for 15 hours, quenched with water (100 mL) and extracted with ethyl acetate (2×50 ml_). The organic phase was dried with sodium sulfate, concentrated and the residue was purified by flash chromatography on silica gel, eluent hexanes-EtOAc (9:1). This afforded 244a as a white solid (650 mg, 35% yield). 1H NMR: (DMSO) δ 8.01-8.00 (m, IH), 7.73-7.70 (m, 2H), 7.66-7.63 (m, IH), 3.89 (s, 3H).
Following the same procedure as described in Example 4 step 3 and then the procedures described in Example 66 step 2, and Example 1 step 3 and 4 (with DMF as a co-solvent), the title compound 245a was obtained as an orange solid in 13% yield (over the three steps). 1H NMR: (DMSO) δ 10.01 (s, IH), 8.05 (d, J=I.6 Hz1 IH), 7.69-7.67 (m, 2H), 7.61 (dd, J=8.8, 2.0 Hz, IH), 7.44 (d, J=2.2 Hz, IH), 7.34 (dd, J=5.1, 1.2 Hz, IH), 7.30 (dd, J=8.4, 2.2 Hz, IH), 7.23 (dd, J=3.6, 1.2 Hz, IH), 7.02 (dd, J=4.9, 3.6 Hz, IH), 6.79 (d, J=8.4 Hz, IH), 5.24 (s, 2H).
To a stirred solution of 2-(benzyloxy)-4,5-dimethoxybenzaldehyde (246, 5.05 g, 18.6 mmol) in ethyl acetate (100 mL) was added 10% palladium on charcoal (250 mg). The flask was purged with hydrogen and then the reaction mixture was stirred under a hydrogen atmosphere (1 atm) for 15 hours, filtered through a celite pad, the filtrate was evaporated under reduced pressure, and the resulting solid dried under vacuum to afford 243b as a white solid (3.3 g, 98% yield). 1H NMR: (DMSO) δ 11.39 (s, IH), 9.68 (s, IH), 6.90 (d, J=2.5 Hz, IH), 6.47 (s, IH), 3.94 (s, 3H), 3.89 (s, 3H).
The title compound 245b was obtained as a light yellow solid in 9.1% yield (over four steps) following the same procedures as described in Example 67, but starting from 2-hydroxy-4,5-dimethoxybenzaldehyde (243b) instead of 243a, via the intermediate 244b. 1H NMR: (DMSO) δ 9.77 (s, IH), 7.64 (s, IH), 7.51 (d, J=2.1 Hz, IH), 7.37 (dd, J=5.1, 1.2 Hz, IH), 7.33 (d, J=2.2 Hz, IH), 7.31-7.30 (m, 2H), 7.26 (dd, J=3.7, 1.2 Hz, IH), 7.06 (dd, J=5.1, 3.5 Hz, IH), 6.83 (d, J=8.5 Hz, IH), 5.22 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H).
The title compound 245c was obtained as a light yellow solid in 5.6% yield (over four steps) following the same procedures as described in Example 67, but starting from 5-fluoro-2-hydroxybenzaldehyde (243c) instead of 243a, via the intermediate 244c. 1H NMR: (DMSO) δ 9.98 (s, IH), 7.75-7.71 (m, 2H), 7.63 (dd, J=9.0, 2.8 Hz, IH), 7.44 (d, J=2.0 Hz, IH), 7.36-7.29 (m, 3H), 7.23 (dd, J=3.5, 1.1 Hz, IH), 7.03 (dd, J=5.1, 3.7 Hz, IH)1 6.79 (d, J=8.4 Hz, IH)1 5.24 (s, 2H).
The title compound 245d was obtained as a light yellow solid in 5.9% yield (over four steps) following the same procedures as described in Example 67, but starting from 2,4-dichloro-6-hydroxybenzaldehyde (243d) instead of 243a, via the intermediate 244d. 1H NMR: (DMSO) δ 10.04 (s, IH), 7.95 (dd, J=1.6, 1.0 Hz1 IH), 7.85 (s, IH)1 7.63 (d, J=1.6 Hz, IH), 7.43 (d, J=2.2 Hz, IH), 7.34 (dd, J=5.1, 1.2 Hz1 IH), 7.30 (dd, J=8.4, 2.3 Hz, IH), 7.23 (dd, J=3.5, 1.2 Hz1 IH)1 7.03 (dd, J=5.1, 3.5 Hz, IH), 6.78 (d, J=8.3 Hz1 IH)1 5.28 (s, 2H).
The title compound 245e was obtained as a light yellow solid in 4.8% yield (over four steps) following the same procedures as described in Example 67, but starting from 2-hydroxy-4,6-dimethoxybenzaldehyde (243e) instead of 243a, via the intermediate 244e. 1H NMR: (DMSO) δ 9.68 (s, IH), 7.64 (s, IH), 7.46 (d, J=2.0 Hz, IH), 7.32 (d, J=1.0 Hz, IH), 7.27 (dd, J=8.2, 2.1 Hz, IH), 7.22 (dd, J=3.5, 1.0 Hz, IH), 7.02 (dd, J=4.9, 3.5 Hz, IH), 6.84 (s, IH), 6.78 (d, J=8.4 Hz, IH), 6.47 (d, J=1.7 Hz, IH), 5.20 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H).
The title compound 245f was obtained as a light yellow solid in 18.1% yield (over four steps) following the same procedures as described in Example 67, but starting from 4-(diethylamino)-2-hydroxybenzaldehyde (243f), instead of 243a via the intermediate 244f. 1H NMR: (DMSO) δ 9.60 (s, IH), 7.51-7.49 (m, 3H), 7.33 (dd, J=5.1, 1.2 Hz, IH), 7.27 (dd, J=8.2, 2.1 Hz, IH), 7.22 (dd, J=3.5, 1.2 Hz, IH), 7.02 (dd, J=5.0, 3.5 Hz, IH), 6.80-6.76 (m, 3H), 5.17 (s, 2H), 3.40 (q, J=6.8 Hz, 4H), 1.13 (t, J=7.0 Hz, 6H).
5-Iodo-pyrimidin-2-ylamine (17, 1.1 g, 4.98 mmol) and acetic anhydride (14.94 mmol, 1.41 mL) were dissolved in pyridine (20 mL) and stirred at H O° C. for 48 hours. The reaction mixture was cooled and quenched with water (50 mL). Ethyl acetate (100 mL) was added and the resulting white precipitate was collected by filtration to afford title compound 248 as a white solid (300 mg, 23% yield). 1H NMR: (DMSO) δ 10.67 (s, IH), 8.85 (s, 2H), 2.18 (s, 3H).
To a stirred solution of 248 (265 mg, 1.01 mmol) and Pd(PPh3)2Cl2 (35 mg, 0.05 mmol) in DMF (4 mL) was added 2-nitro-5-(thiophen-2-yl-aniline (3, 288 mg, 1.3 mmol) and triethylamine (1.5 mmol, 0.2 mL). The solution was purged with carbon monoxide and pressurized to 65 psi before being heated at 65° C. with stirring for 15 hours. The solution was cooled and diluted with ethyl acetate (20 mL). The resulting yellow precipitate was collected by filtration to afford 249 as a yellow solid (145 mg, 40% yield). 1H NMR: (DMSO) δ 11.02 (s, IH), 10.97 (s, IH), 9.15 (s, 2H), 8.10 (d, J=8.6 Hz, IH), 8.03 (d, J=2.0 Hz, IH), 7.80-7.76 (m, 3H), 7.26 (dd, J=4.9, 3.7 Hz, IH), 2.28 (s, 3H).
Following the same procedure as described in Example I1 step 4, (with DMF as a co-solvent), the title compound 250 was obtained as a yellow solid in 32% yield. 1H NMR: (DMSO) δ 10.90 (s, IH), 9.87 (s, IH)1 9.16 (s, 2H), 7.47 (d, J=2.2 Hz1 IH)1 7.36 (dd, J=5.1, 1.2 Hz, IH), 7.32 (dd, J=8.4, 2.2 Hz1 IH)1 7.25 (dd, J=3.5, 1.1 Hz, IH)1 7.05 (dd, J=5.1, 3.7 Hz, IH) 16.81 (d, J=8.4 Hz, IH), 5.33 (br s, 2H), 2.26 (s, 3H).
4-Hydrazinylbenzoic acid (251a, 2 g, 13.2 mmol) and pentane-2,4-dione (1.35 mL, 13.2 mmol) were dissolved in isopropanol (40 mL) and refluxed for 15 hours. The solvent was removed under reduced pressure to afford 252a as a white solid (2.85 g, 99% yield). 1H NMR: (DMSO) δ 8.04 (d, J=8.6 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 6.14 (s, IH), 2.39 (s, 3H), 2.22 (s, 3H).
Starting from the acid 252a and following the same procedures as described in Example 66 step 2, and Example 1 step 4, (with DMF as a co-solvent), the title compound 253a was obtained as a white solid in 14% yield (over two steps). 1H NMR: (DMSO) δ 9.81 (s, IH), 8.09 (d, J=8.4 Hz, 2H)1 7.64 (d, J=8.6 Hz1 2H), 7.46 (d, J=2.0 Hz, IH), 7.33 (dd, J=5.1, 1.2 Hz, IH)1 7.28 (dd, J=8.2, 2.2 Hz, IH), 7.23 (dd, J=3.5, 1.0 Hz, IH), 7.03 (dd, J=5.1, 3.5 Hz, IH), 6.80 (d, J=8.3 Hz, IH), 6.12 (s, IH), 5.19 (s, 2H), 2.38 (s, 3H), 2.20 (s, 3H).
4-Aminobenzoic acid (25Ib1 1.5 g, 10.9 mmol) and hexane-2,5-dione (1.28 mL, 10.9 mmol) were dissolved in isopropanol (40 mL) and refluxed for 15 hours. The solvent was removed under reduced pressure to afford 252b as a white solid (2.35 g, 99% yield). 1H NMR: (DMSO) δ 8.02 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.6 Hz, 2H), 5.81 (s, 2H), 1.98 (s, 6H).
Starting from the acid 252b and following the same procedures as described in Example 66 step 2, and Example 1 step 4, (with DMF as a co-solvent), the title compound 253b was obtained as beige solid in 28% yield over two steps. 1H NMR: (DMSO) δ 9.85 (s, IH), 8.14 (d, J=8.4 Hz, 2H), 7.49 (d, J=2.0 Hz, IH), 7.44 (d, J=8.4 Hz, 2H), 7.37 (dd, J=5.1, 1.2 Hz, IH), 7.32 (dd, J=8.5, 2.4 Hz, IH), 7.26 (dd, J=3.6, 1.0 Hz, IH), 7.07 (dd, J=5.1, 3.5 Hz, IH)1 6.83 (d, J=8.4 Hz, IH) 15.86 (s, 2H), 5.24 (s, 2H)1 2.05 (s, 6H).
To a stirred solution of benzo[d][1,3]dioxole-5-carbaldehyde (254a, 2 g, 13.3 mmol), Na2H2PO4 (6.38 g, 53.2 mmol), and 2-methyl-2-butene (9.85 ml—, 93.1 mmol) in t-BuOH (41 mL) and water (17 mL) was added sodium chlorite (7.19 g, 79.9 mmol). The resulting reaction mixture was stirred for 2 hours at room temperature. Water (100 mL) and I M HCl (25 mL) were added and the mixture was extracted with EtOAc (2×50 mL). The organic phase was separated, dried with sodium sulfate and evaporated under reduced pressure. The resulting solid was triturated with EtOAc (20 mL) to yield the title compound 255a as a white solid (1.9 g, 86% yield). 1H NMR: (DMSO) δ 12.72 (br s, IH), 7.53-7.50 (m, IH), 7.34-7.32 (m, IH), 6.99-6.95 (m, IH), 6.10 (s, 2H).
Following the same procedures as described in Example 1, steps 3 and 4, (with DMF as a co-solvent), the title compound 256a was obtained as a light orange solid in 22% yield (over two steps). 1H NMR: (DMSO) δ 9.59 (s, IH), 7.60 (dd, J=8.0, 1.6 Hz, IH), 7.55 (d, J=1.6 Hz, IH), 7.43 (d, J=2.2 Hz, IH), 7.35 (dd, J=4.9, 0.6 Hz, IH), 7.29 (dd, J=8.2, 2.2 Hz, IH), 7.24 (dd, J=3.7, 1.0 Hz, IH), 7.06-7.04 (m, 2H), 6.79 (d, J=8.2 Hz, IH), 6.13 (s, 2H), 5.15 (br s, 2H).
Following the same procedures as described in Example 70a step 1 and Example 1, steps 3 and 4, (with DMF as a co-solvent), the title compound 256b was obtained as an orange solid in 38% yield (over three steps). 1H NMR: (DMSO) δ 9.57 (s, IH), 7.54 (d, J=2.1 Hz, IH), 7.51 (dd, J=8.4, 2.1 Hz, IH), 7.42 (d, J=2.1 Hz, IH), 7.33 (dd, J=5.1, 1.2 Hz, IH), 7.26 (dd, J=8.4, 2.3 Hz, IH), 7.22 (dd, J=3.5, 1.2 Hz, IH), 7.02 (dd, J=5.1, 3.5 Hz, IH), 6.95 (d, J=8.2 Hz, IH), 6.79 (d, J=8.4 Hz, IH), 5.11 (s, 2H), 4.31-4.28 (m, 4H).
Following the same procedures as described in Example 70a step 1 and Example 1, steps 3 and 4, (with DMF as a co-solvent), the title compound 256c was obtained as an orange solid in 20% yield (over three steps). 1H NMR: (DMSO) δ 9.60 (s, IH), 7.41 (d, J=2.2 Hz, IH), 7.36 (d, J=1.4 Hz, IH), 7.34 (dd, J=5.2, 1.2 Hz, IH), 7.30-7.26 (m, 2H), 7.23 (dd, J=3.6, 1.2 Hz, IH), 7.04 (dd, J=4.9, 3.5 Hz, IH), 6.79 (d, J=8.4 Hz, IH), 6.10 (s, 2H), 5.14 (br s, 2H), 3.91 (s, 3H).
Following the same procedures as described in Example 1, steps 3 and 4, (with DMF as a co-solvent), but substituting compound 4 with compound 257a, the title compound 258a was obtained as a beige solid in 56% yield. 1H NMR: (DMSO) δ 9.64 (s, IH), 7.63 (dd, J=8.2, 2.0 Hz, IH), 7.57 (d, J=2.2 Hz, IH), 7.42 (d, J=2.2 Hz, IH), 7.33 (dd, J=5.1, 1.2 Hz, IH), 7.28 (dd, J=8.3, 2.3 Hz, IH), 7.23 (dd, J=3.5, 1.2 Hz, IH), 7.05 (d, J=8.6 Hz, IH), 7.02 (dd, J=5.1, 3.6 Hz, IH), 6.79 (d, J=8.3 Hz, IH), 5.12 (br s, 2H), 3.83 (s, 3H), 3.82 (s, 3H).
Following the same procedures as described in Example 1, steps 3 and 4, (with DMF as a co-solvent), but substituting compound 4 with compound 257b, the title compound 258b was obtained as an orange solid in 16% yield (over two steps). 1H NMR: (DMSO) δ 9.90 (s, IH), 8.66 (s, IH), 8.05 (d, J=9.8 Hz, IH), 7.96 (d, J=8.6 Hz, IH), 7.49 (d, J=2.0 Hz, IH), 7.33 (dd, J=5.1, 1.2 Hz, IH), 7.30 (dd, J=8.2, 2.2 Hz, IH), 7.23 (dd, J=3.5, 1.1 Hz, IH), 7.03 (dd, J=5.0, 3.7 Hz, IH) 6.81 (d, J=8.4 Hz, IH), 5.23 (br s, 2H).
Following the same procedures as described in Example 1, steps 3 and 4, (with DMF as a co-solvent), but substituting compound 4 with compound 257c, the title compound 258c was obtained as an off white solid in 28% yield (over two steps). 1H NMR: (DMSO) δ 9.94 (s, IH), 8.78 (m, 3H), 8.11 (dd, J=4.3, 1.6 Hz, 2H), 7.64 (d, J=2.2 Hz, IH), 7.38 (dd, J=5.1, 1.0 Hz, IH), 7.33 (dd, J=8.2, 2.1 Hz, IH), 7.28 (dd, J=3.7, 1.2 Hz, IH), 7.07 (dd, J=5.1, 3.7 Hz, IH), 6.86 (d, J=8.4 Hz, IH), 5.23 (s, 2H).
Following the same procedures as described in Example I1 steps 3 and 4, (with DMF as a co-solvent), but substituting compound 4 with compound 257d, the title compound 258d was obtained as a white solid in 29% yield (over two steps). 1H NMR: (DMSO) δ 9.72 (s, IH), 8.34 (s, 2H), 7.87-7.85 (m, 2H), 7.48 (d, J=1.8 Hz, IH)1 7.34 (dd, J=5.1, 1.0 Hz, IH), 7.28 (dd, J=8.1, 5.2 Hz, IH), 7.23 (dd, J=3.5, 1.2 Hz, IH), 7.03 (dd, J=5.1, 3.6 Hz, IH), 6.80 (d, J=8.4 Hz, IH), 5.15 (s, 2H).
Following the same procedures as described in Example 1, steps 3 and 4, (with DMF as a co-solvent), but substituting compound 4 with compound 257e, the title compound 258e was obtained as a yellow solid in 15% yield (over two steps). 1H NMR: (DMSO) δ 9.90 (s, IH), 8.62 (s, IH), 8.07-7.98 (m, 4H), 7.63-7.60 (m, 2H), 7.51 (d, J=2.1 Hz, IH), 7.34 (dd, J=5.1, 1.2 Hz, IH), 7.30 (dd, J=8.4, 2.2 Hz, IH), 7.24 (dd, J=3.5, 1.2 Hz, IH), 7.04 (dd, J=5.1, 3.7 Hz, IH), 6.81 (d, J=8.4 Hz, IH), 5.21 (s, 2H).
Following the same procedures as described in Example I1 steps 3 and 4, (with DMF as a co-solvent), but substituting compound 4 with compound 257f, the title compound 258f was obtained as a brown solid in 12% yield (over two steps). 1H NMR: (DMSO) δ 9.99 (s, IH), 8.32 (s, IH), 8.03 (dd, J=8.4, 2.0 Hz, IH), 7.97 (dd, J=6.6, 2.7 Hz, IH), 7.49-7.43 (m, 3H), 7.33 (dd, J=5.0, 1.1 Hz, IH), 7.30 (dd, J=8.2, 2.2 Hz, IH), 7.24 (dd, J=3.6, 1.0 Hz, IH), 7.03 (dd, J=5.2, 3.7 Hz, IH), 6.80 (d, J=8.4 Hz, IH), 5.24 (s, 2H).
Following the same procedures as described in Example 1, steps 3 and 4, (with DMF as a co-solvent), but substituting compound 4 with compound 257g, the title compound 258g was obtained as an orange solid in 15% yield (over two steps). 1H NMR: (DMSO) δ 9.61 (s, IH), 7.63 (d, J=2.2 Hz, IH), 7.59 (dd, J=8.4, 2.2 Hz, IH), 7.41 (d, J=2.0 Hz, IH), 7.33 (d, J=5.1 Hz, IH), 7.27 (dd, J=8.2, 2.2 Hz, IH), 7.22 (dd, J=3.5, 1.0 Hz, IH), 7.06-7.01 (m, 2H), 6.78 (d, J=8.4 Hz, IH), 5.12 (br s, 2H), 4.22-4.17 (m, 4H), 2.16 (quintet, J=5.5 Hz1 2H).
To a stirred solution of 259a (2 g, 9.90 mmol) in DMF (20 ml_) was added methyl thioglycolate (10.9 mmol, 0.97 mL) and potassium carbonate (5.47 g, 39.6 mmol). The resulting mixture was stirred at 6O° C. for 15 hours. The DMF was removed under reduced pressure, water (50 ml_) was added and the mixture was extracted with ethyl acetate (2×40 mL). The organic phase was separated and dried with sodium sulfate, the solvent was removed under reduced pressure and the resulting solid was dried under vacuum. This afforded 26Oa as a white solid (1.3 g, 49% yield). 1H NMR: (DMSO) δ 8.22 (d, J=2.0 Hz, IH), 8.11 (s, IH), 8.00 (d, J=8.0 Hz, IH), 7.62 (dd, J=8.6, 2.0 Hz, IH), 3.88 (s, 3H).
Following the same procedure as described in Example 4 step 3 and then the procedures described in Example 66 step 2, and Example 1 step 4, (with DMF as a co-solvent), the title compound 261a was obtained as a beige solid in 32% yield (over three steps). 1H NMR: (DMSO) δ 10.08 (s, IH), 8.27 (s, IH), 8.23 (d, J=1.8 Hz, IH), 8.02 (d, J=8.6 Hz, IH), 7.60 (dd, J=8.6, 2.0 Hz, IH), 7.43 (d, J=2.3 Hz, IH), 7.34 (dd, J=5.0, 1.2 Hz, IH), 7.30 (dd, J=8.2, 2.2 Hz, IH), 7.24 (dd, J=3.5, 1.2 Hz, IH), 7.03 (dd, J=5.1, 3.5 Hz, IH), 6.79 (d, J=8.2 Hz, IH), 5.25 (s, 2H).
Following the same procedure as described in Example 72a step 1, but substituting compound 259a with compound 259b, then following the procedures described in Example 4 step 3 and Example 1, steps 3 and 4, (with DMF as a co-solvent), the title compound 261b was obtained as a yellow solid in 20% yield (over four steps). 1H NMR: (DMSO) δ 9.87 (s, IH), 8.14 (s, IH), 7.58 (s, IH), 7.44 (d, J=2.2 Hz, IH), 7.41 (s, IH), 7.34 (dd, J=5.1, 1.1 Hz, IH), 7.29 (dd, J=8.4, 2.3 Hz, IH), 7.03 (dd, J=4.9, 3.5 Hz, IH), 6.80 (d, J=8.4 Hz, IH), 5.20 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H).
To a stirred solution of 261a (120 mg, 0.26 mmol) and pyridin-3-yl-3-boronic acid (123 mg, 0.34 mmol) in a 2:1 mixture of DME-water (9 mL), was added Pd(PPh3)4 (22 mg, 0.018 mmol), tri-o-toly phosphine (6 mg, 0.018 mmol) and potassium carbonate (109 mg, 0.79 mmol). The solution was degassed with N2 for 5 minutes and then heated at 80° C. for 15 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2×40 mL). The organic layer was separated, dried with sodium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluent ethyl acetate. A subsequent trituration was performed with DCM for 15 minutes to yield 262 as a white solid (80 mg, 67% yield). 1H NMR: (DMSO) δ 10.09 (s, IH), 8.99 (dd, J=2.3, 0.8 Hz, IH), 8.58 (dd, J=4.7, 1.6 Hz, IH), 8.38 (s, IH), 8.33 (d, J=1.4 Hz, IH), 8.17 (ddd, J=9.6, 3.9, 1.8 Hz, IH), 7.83 (dd, J=8.5, 1.8 Hz, IH), 7.53-7.50 (m, 2H), 7.46 (d, J=2.2 Hz, IH), 7.34 (dd, J=5.1, 1.2 Hz, IH), 7.31 (dd, J=8.2, 2.2 Hz, IH), 7.25 (dd, J=3.5, 1.2 Hz, IH), 7.03 (dd, J=5.1, 3.7 Hz, IH), 6.81 (d, J=8.4 Hz, IH), 5.74 (s, 2H).
Title compound 263 was prepared starting from methyl 4-hydroxybenzoate according to the procedure described in Monatsh. Chem., 102; 1971; 946-950.
Following the same procedure as described in Example 4 step 3, but substituting compound 21 with compound 263, then following the procedures described in Example 1, steps 3 and 4, (with DMF as a co-solvent), the title compound 264 was obtained as an off white solid in 37% yield (over three steps). 1H NMR: (DMSO) δ 9.60 (s, IH), 7.82 (dd, J=8.6, 2.2 Hz, IH), 7.74 (d, J=2.1 Hz, IH), 7.41 (d, J=2.1 Hz, IH), 7.33 (dd, J=5.1, 1.2 Hz, IH), 7.26 (dd, J=8.4, 2.3 Hz, IH), 7.21 (dd, J=3.5, 1.2 Hz, IH), 7.02 (dd, J=5.1, 3.8 Hz, IH), 6.94 (d, J=8.6 Hz, IH), 6.77 (d, J=8.4 Hz, IH), 5.32 (s, 2H), 5.11 (s, 2H), 4.94 (s, 2H).
Following the same procedure as described in Example 67a step 1, but substituting compound 243a with compound 265, the title compound 266 was obtained as a white solid in 49% yield. 1H NMR: (DMSO) δ 7.68-7.64 (m, 2H), 7.49-7.45 (m, 2H), 7.42-7.31 (m, 4H), 7.07-7.04 (m, IH), 5.18 (s, 2H), 3.85 (s1 2H).
To a stirred solution of 266 (1.2 g, 4.26 mmol) in methanol (20 mL) was added 10% palladium on charcoal (250 mg). The flask was purged with hydrogen gas for 1 minute and then the reaction was stirred under a hydrogen atmosphere for 15 hours. The palladium was filtered through a celite pad, the filtrate was evaporated under reduced pressure, and the resulting solid dried under vacuum to afford 267 as a white solid (700 mg, 86%). 1H NMR: (DMSO) δ 10.07 (s, IH), 7.63 (s, IH), 7.56 (d, J=8.0 Hz, IH), 6.98 (s, IH), 6.84 (d, J=9.0 Hz, IH), 3.84 (s, 3H).
To a stirred solution of 267 (650 mg, 3.39 mmol) in a 1:1 mixture of DMF-acetone (20 mL) was added 4-(2-chloroethyl)morpholine (630 mg, 3.39 mmol) and potassium carbonate (937 mg, 6.78 mmol). The reaction mixture was stirred at 6O° C. for 72 hours. The solvents were removed under reduced pressure and water (50 mL) was added to the residue. 2M Sodium carbonate solution (20 mL) was added and the resultant solution was extracted with ethyl acetate (2×40 mU. The organic phase was separated, dried with sodium sulfate and the solvents removed under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 1:1 ethyl acetate-hexanes, then ethyl acetate, then 9:1 ethyl acetate-methanol. This afforded 268 as a clear oil (760 mg, 73% yield). 1H NMR: (DMSO) δ 7.67-7.63 (m, 2H), 7.32 (s, IH), 6.98 (d, J=8.5 Hz, IH), 4.14-4.16 (m, 2H), 3.85 (s, 3H), 3.57-3.55 (m, 4H), 2.88-2.86 (m, 2H), 2.72-2.70 (m, 4H).
Following the same procedure as described in Example 4 step 3, but substituting compound 21 with compound 268, then following the procedures described in Example 1, steps 3 and 4, the title compound 269 was obtained as an off white solid in 1.3% yield (over three steps). 1H NMR: (DMSO) δ 7.21 (d, IH), 7.14 (d, 2H), 6.95 (d, IH), 6.84-6.79 (m, 3H), 6.62-6.57 (m, 2H), 6.49 (d, IH), 3.80 (m, 2H), 3.30 (m, 4H), 2.46 (m, 2H), 2.21 (m, 4H).
Following a procedure described in Example 15, step 1 (scheme 13) but running the reaction at 80° C. instead of the room temperature the title compound 270 was obtained in 68% yield. 1H NMR: (400.2 MHz, CDCl3) δ (ppm): 8.06 (d, J=8.8 Hz; IH); 6.92 (d, J=1.6 Hz; IH); 6.76 (dd, J=1.6, 8.8 Hz; IH); 5.70 (bs; 2H); 0.29 (s; 9H). MS: calc: 234.3; found: 235.1 (M+H).
The cleavage of the trimethylsilyl group was achieved employing the same procedure as described in Example 4, step 3 (scheme 3) but substituting compound 21 for the compound 270. The crude product was used in the next cycloaddition step following the procedure described in Example 48, step 2 (scheme 26) but using m-xylene instead of toluene as a solvent, to afford the title compound 271 (9% yield in two steps). MS: calc: 205.2; found: 206.1 (M+H)
Following the same procedure described in Example 43, step 4 (scheme 31) but substituting compound 150 for compound 271, the title compound 272 was obtained as an oil and used in the next step without further purification.
Following the same procedure as described in Example 48, step 3 (scheme 36) but substituting compound 171 for the compound 272 and using ethyl acetate as a solvent instead of methanol, the title compound 273 was obtained in 25% yield (over two steps). 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.62 (s, IH); 8.08 (bs, 2H); 7.97 (d, J=8.5 Hz; 2H); 7.62 (s, IH); 7.45 (d, J=8.2 Hz; IH); 7.03 (d, J=8.5 Hz; 2H); 6.82 (d, J=8.2 Hz; IH); 5.11 (bs, 2H); 3.83 (s, 3H). MS: calc: 309.3; found: 310.1 (M+H)
A suspension of bromoarene 2 (801 mg; 3.7 mmol) and zinc cyanide (570 mg; 4.85 mmol; 1.3 eq.) in degassed dimethylformamide (15 mU was stirred at room temperature under nitrogen in the dark for 45 min and then treated with tetrakis(triphenylphosphine) palladium(O) (310 mg, I.βmmol). The mixture was stirred at 90° C. for 18 h; filtered through a celite pad, concentrated under reduced pressure and purified by flash chromatography on silica gel, eluent EtOAc-hexane (1:1) to afford the title compound 274 (380 mg, 63% yield). 1H NMR: (400.2 MHz1 CDCl3) δ (ppm): 8.22 (d, J=8.6 Hz; IH); 7.19 (d, J=1.8 Hz; IH); 6.95 (dd, J=1.8, 8.6 Hz; IH); 6.27 (bs; 2H). MS: calc: 163.1; found: 164.1 (M+H)
Following the procedure as described in Example 48, step 2 (scheme 36), but using m-xylene instead of toluene as a solvent, the title compound 275 was obtained in 79% yield. 1H NMR: (400.2 MHz, CDCl3) δ (ppm): 8.21 (d, J=9.0 Hz; IH); 7.74 (d, J=1.6 Hz; IH); 7.50 (dd, J=1.6, 9.0 Hz; IH); 6.29 (bs; 2H). MS: calc: 206.2; found: 207.1 (M+H)
Following the same procedure as described in Example 43, step 4 (scheme 31) but substituting compound 150 for compound 275, the title compound 276 was obtained as an oil and was taken to the next step without further purification.
Following the same procedure as described in Example 48, step 3 (scheme 36) but substituting compound 171 for the compound 276 the title compound 277 was obtained in 14% yield (over two steps). 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.63 (s, IH); 7.98 (d, J=8.8 Hz; 2H); 7.81 (d, J=2.0 Hz; IH); 7.61 (dd; J=2.0, 8.4 Hz; IH); 7.04 (d, J=8.8 Hz; 2H); 6.85 (d, J=8.4 Hz; IH); 3.85 (s, 3H). MS: calc: 310.3; found: 311.1 (M+H)
A 40% solution of methylamine in water (11 mL; 128 mmol) (or any other primary amine) was slowly added to a stirring suspension of 4-fluoro-3-nitrobenzoic acid (278, 6.1 g; 32.9 mmol) in DMF (2O mL) at room temperature. After the addition was completed the mixture was stirred at the same temperature for 60 min; concentrated in vacuo, and suspended in 5% KHSO4 (final pH=2). The suspension was stirred overnight; the precipitate was collected by filtration, washed with water, then with ether and dried to afford the title compound 279 (6.5 g; 100% yield). 1H NMR: (400.2 MHz, DMSO) δ (ppm): 12.8 (bs; IH), 8.59 (d, J=2.0 Hz; IH); 8.55 (q, J=5.0 Hz; IH); 7.96 (dd, J=2.0, 9.1 Hz; IH); 7.04 (d, J=9.1 Hz; IH); 3.00 (d, J=5.0 Hz; 3H). MS: calc: 196.2; found: 197.1 (M+H)
Following the same procedure as described in Example 48, step 3 (scheme 36) but substituting compound 171 for compound 279, to give the title compound in 81% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 7.48 (d, J=8.6 Hz; IH); 7.42 (s; IH); 7.54 (d, J=8.6 Hz; IH); 3.57 (bs; >4H); 2.80 (s; 3H). MS: calc: 166.1; found: 167.1 (M+H)
A solution of the di-amino compound 280 (678 mg; 4.1 mmol) (or an o-aminophenol) in 50% HCO2H (or any other carboxylic acid or an ortho-ester) in water (or anhydrous solvent if an ortho-ester is used) was stirred at 85° C. for 13 h, concentrated, the residue was re-dissolved in water and lyophillized to afford the title compound 281 (712 mg, 99% yield). 1H NMR: (400.2 MHz, DMSO) δ (ppm): 12.9 (bs; IH); 8.80 (s; IH); 8.26 (d, J=1.6 Hz; IH); 7.96 (dd, J=1.6, 8.6 Hz; IH); 7.79 (d, J=8.6 Hz; IH); 3.95 (s, 3H). MS: calc: 176.2; found: 177.1 (M+H).
Following the same procedure as described in Example 11 step 3 (scheme 1) but substituting compound 4 for compound 281 the title compound 282 was obtained in 56% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 10.9 (bs, IH); 8.35 (bs, 2H), 8.24 (d, J=2.1 Hz, IH), 8.01 (d, J=8.6 Hz, IH), 7.91 (dd; J=1.6, 8.4 Hz; IH); 7.75 (m, 3H), 7.70 (dd; J=2.1, 8.6 Hz; IH); 7.23 (dd; J=3.7, 4.9 Hz; IH); 3.91 (s, 3H). MS: calc: 378.4; found: 379.1 (M+H)
Following the same procedure as described in Example 1, step 4 (scheme 1) but substituting compound 5 for compound 282, the title compound 283 was obtained in 99% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.75 (s, IH), 8.38 (d, J=1.0 Hz, IH), 8.34 (s, IH), 7.95 (dd; J=1.4, 8.4 Hz; IH); 7.68 (d, J=8.4 Hz, IH), 7.50 (d; J=2.2 Hz; IH); 7.34 (dd; J=LO1 5.0 Hz; IH); 7.28 (dd; J=2.2, 8.4 Hz; IH); 7.24 (dd; J=1.4, 3.6 Hz; IH); 7.04 (dd; J=3.6, 5.0 Hz; IH); 6.81 (d; J=8.4 Hz; IH); 3.90 (s, 3H). MS: calc: 348.4; found: 349.1 (M+H)
To a stirred suspension of the diamine 280 (1.08 g; 6.48 mmol) (or any other o-arylenediamine) in water (25 mL) at O° C., concentrated HCl (5.4 mL) was added drop wise followed by slow addition of a solution of NaNO2 (643 mg; 9.3 mmol) in water (10 mL). The reaction mixture was stirred at O° C. for 2 h and then was allowed to warm up to 1O° C. over 4 h; neutralized with a solution of KOH (5.6 g) in water (30 mL) (final pH=6); concentrated and purified by preparative HPLC in reverse phase mode (column aquasil C-18, elution 5% to 95% MeOH in water), to afford the title compound 284 (211 mg; 18% yield). 1H NMR: (400.2 MHz, DMSO) δ (ppm): 8.35 (s; IH); 8.08 (dd, J=1.4, 8.6 Hz; IH); 7.75 (d, J=1.4 Hz; IH); 4.03 (s, 3H). MS: calc: 177.1; found: 178.1 (M+H).
Following the same procedure as described in Example 1, step 3 (scheme 1) but substituting compound 4 for compound 284, the title compound 285 was obtained in 56% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 11.0 (bs, IH); 8.72 (bs, IH), 8.12 (m, 2H), 8.07 (d, J=8.7 Hz, IH), 8.01 (d, J=8.7 Hz, IH), 7.73 (m, 3H), 7.23 (t; J=4.7 Hz; IH); 4.38 (s, 3H). MS: calc: 379.4; found: 380.0 (M+H)
Following the same procedure described in Example 1, step 4 (scheme 1) but substituting compound 5 for compound 285, the title compound 286 was obtained in 99% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.88 (s, IH); 8.75 (s, IH), 8.15 (dd; J=LO1 8.6 Hz; IH); 7.95 (dd, J=1.0, 8.6 Hz, IH), 7.49 (d, J=2.0 Hz, IH), 7.34 (dd; J=1.2, 5.1 Hz; IH); 7.30 (dd; J=2.0, 8.3 Hz; IH); 7.24 (dd; J=1.2, 3.5 Hz; IH); 7.04 (dd; J=3.5, 5.1 Hz; IH); 6.81 (d; J=8.3 Hz; IH); 5.24 (bs, 2H); 4.37 (s, 3H). MS: calc: 349.4; found: 350.1 (M+H)
A solution of 2-(bromomethylyl-I,3-dioxolane (0.18 mL; 1.67 mmol) in THF (3 mL) and water (0.2 mL) was treated with concentrated HCl (3 drops) and stirred at 88° C. for 50 min. The solution was cooled down to O° C. and transferred into a vial containing 2-amino-5-methoxycarbonylpyridine (287, 204 mg; 1.34 mmol), Bu2SnCl2 (134 mg; 0.40 mmol) and NaHCO3 (410 mg) and stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate (60 mL) and washed with saturated aqueous sodium chloride. The organic layer was dried (MgSO4), filtered and concentrated. After chromatographic purification of the residue using preparative TLC on silica gel (eluent 50% ethyl acetate in dichloromethane), the title compound 288 was obtained (74 mg, 31% yield). 1H NMR: (500.7 MHz, CDCl3) δ (ppm): 9.00 (s, IH); 7.80 (m, 4H); 4.00 (s, 3H). MS: calc: 176.1; found: 177.1 (M+H)
Following the same procedure described for Example 46, step 2 (scheme 34) but substituting compound 162 for compound 288, the title compound 289 was obtained in 99% yield. MS: calc: 162.1; found: 163.1 (M+H)
Following the same procedure as described in Example I1 step 3 (scheme 1) but substituting compound 4 for compound 289, the title compound 290 was obtained in 22% yield. MS: calc: 364.2; found: 365.2 (M+H)
Following the same procedure described in Example I1 step 4 (scheme 1) but substituting compound 5 for compound 290, the title compound 291 was obtained in 45% yield. 1H NMR (400.2 MHz, DMSO) δ (ppm): 9.19 (s, IH); 7.99 (s, IH); 7.86 (d; J=8.5 Hz; IH); 7.67 (s, IH); 7.64 (d; J=8.5 Hz; IH); 7.50 (s, IH); 7.37 (d; J=8.5 Hz; IH); 7.22 (d; J=4.9 Hz; IH); 7.21 (m, IH); 7.01 (t; J=4.9 Hz; IH); 6.91 (d; J=8.5 Hz; IH). MS: calc: 334.4; found: 335.1 (M+H)
To a solution of 2-aminopyridine (292, 1.1022 g; 11.71 mmol) and Bu2SnCl2 (431 mg; 1.3 mmol) in DME (20 mL), ethyl 3-bromopyruvate (1.56 mL; II.I δmmol) was added to give an instant yellow precipitate. The suspension was stirred at room temperature for 2 h, then solid K2CO3 (2.6 g; 18.8 mmol) was added and the mixture stirred for additional 2O h at the same temperature. The reaction mixture was then diluted with ethyl acetate (20O mL) and washed with saturated aqueous sodium chloride. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (eluent 50% ethyl acetate in dichloromethane), to afford the title compound 293 (1.31 g, 59% yield) as a white crystalline material. 1H NMR (400.2 MHz, DMSO) δ (ppm): 8.54 (m, IH); 8.53 (d; J=0.9 Hz; IH); 7.59 (ddd; J=1.3, 2.0, 9.2 Hz; IH); 7.33 (ddd; J=1.3, 6.7, 9.2 Hz; IH); 6.98 (dt; J=0.9, 7.8 Hz; IH); 4.30 (q; J=7.0 Hz; 2H); 1.32 (t; J=7.0 Hz; 3H). MS: calc: 190.0; found: 191.1 (M+H).
Following the same procedure described in Example 46, step 2 (scheme 34) but substituting compound 162 for compound 293, the title compound 294 was obtained in 99% yield. 1H NMR (400.2 MHz, DMSO) δ (ppm): 8.63 (dt, J=1.2, 6.7 Hz; IH); 8.55 (d; J=0.8 Hz; IH); 7.63 (m; IH); 7.42 (ddd; J=1.2, 6.7, 7.8 Hz; IH); 7.06 (dt; J=1.2, 7.8 Hz; IH); MS: calc: 162.1; found: 163.1 (M+H)
Following the same procedure as described in Example 1, step 3 (scheme 1) but substituting compound 4 for compound 294 the title compound 295 was obtained in 95% yield. 1H NMR (400.2 MHz, DMSO) δ (ppm): 11.9 (s, IH); 9.07 (d, J=1.8 Hz; IH); 8.63 (m; 2H); 8.25 (d, J=8.8 Hz; IH); 7.77 (ddd; J=1.0, 5.0, 12.3 Hz; IH); 7.71 (dd; J=LO, 9.2 Hz; IH); 7.66 (dd; J=1.8, 8.8 Hz; IH); 7.41 (ddd; J=1.2, 6.7, 9.2 Hz; IH); 7.25 (dd; J=3.7, 5.0 Hz; IH); 7.05 (dt; J=1.2, 12.3 Hz; IH). MS: calc: 364.2; found: 365.1 (M+H).
Following the same procedure described in Example 1, step 4 (scheme 1) but substituting compound 5 for compound 223, the title compound 296 was obtained in 85% yield. 1H NMR (400.2 MHz, DMSO) o (ppm): 9.73 (s, IH), 8.62 (dt, J=1.2; 6.8 Hz, IH), 8.50 (d, J=0.7 Hz; IH); 7.76 (d; J=2.2 Hz; IH); 7.66 (d, J=0.7 Hz, IH), 7.39 (dd; J=1.6, 6.8 Hz; IH); 7.36 (dt; J=1.6, 4.9 Hz; IH); 7.26 (dd; J=2.2, 8.2 Hz; IH); 7.24 (dd; J=1.2, 3.6 Hz; IH); 7.05 (m; IH); 7.01 (dd; J=1.2, 6.8 Hz; IH); 6.84 (d; J=8.2 Hz; IH); 5.13 (bs, 2H). MS: calc: 334.4; found: 335.1 (M+H).
Following the same procedure as described in Example 1, step 2 (scheme 1) but substituting compound 2 for compound 297, the title compound 298 was obtained in 18% yield. 1H NMR: (499.7 MHz, DMSO) δ (ppm): 8.09 (s, IH); 7.82 (d, J=9.0 Hz; IH); 7.54 (d, J=3.5 Hz; IH); 7.50 (s, IH); 7.18 (d, J=9.0 Hz; IH); 7.13 (m, IH). MS: calc: 221.0; found: 219.9 (M−H).
Following the same procedure as described in Example 19, step 2 (scheme 17) but substituting compound 90 for the compound 298 and using dichloromethane as a solvent instead of DMF, the title compound 299 was obtained which was used in the next step without further purification.
Following the same procedure described for Example 48, step 3 (scheme 36) but substituting compound 171 for compound 299 and using ethyl acetate and triethylamine as a solvent instead methanol, the title compound 300 was obtained in 41% yield over two steps. MS: calc: 305.5; found: 306.1 (M+H).
Following the same procedure as described in Example I1 step 3 (Example 1) but substituting compound 3 for compound 300 and not using NaH as a base, the title compound 301 was obtained in 17% yield (with 10% recovery of the starting material 228). 1H NMR: (400.2 MHz, DMSO) δ (ppm): 10.1 (s, IH); 9.52 (s, IH); 8.00 (s, IH); 7.92 (d, J=7.0, 2H); 7.49 (d, J=7.0, 2H); 7.42 (m, IH); 7.33 (d, J=8.0, IH); 7.29 (s, IH); 7.07 (s, IH); 6.93 (d, J=8.0, IH); 6.65 (d, J=8.5, 1H); 6.32 (s, IH); 5.98 (m, 2H); 4.30 (s, 2H); 3.65 (s, 3H); 3.58 (s, 3H). MS: calc: 460.5; found: 461.1 (M+H)
Following the same procedure as described in Example 48, step 3 (scheme 36) but substituting compound 171 for compound 94dd and using ethyl acetate as a solvent instead of methanol, the title compound 302 was obtained in 26% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.60 (s, IH), 7.96 (d, J=8.0, Hz, 2H); 7.36 (d, J=2.1 Hz1 IH); 7.20 (dd, J=2.1, 8.3 Hz, IH); 7.03 (d, J=8.0, Hz, 2H); 7.00 (d, J=3.5 Hz, IH); 6.78 (d, J=8.3 Hz, IH), 6.70 (dd, J=1.1, 3.5 Hz, IH); 3.83 (s, 3H); 2.42 (d, J=1.1 Hz, 3H). MS: calc: 338.4; found: 338.4 (M+H).
Following the same procedure as described for Example 78, step 1 (scheme 61) but using ethanolamine instead of methylamine and isopropanol as a solvent instead of DMF, the title compound 303 was obtained in 99% yield. MS: calc: 226.2; found: 225.1 (M−H).
Following the same procedure described for Example 78, step 2 (scheme 61), the title compound 304 was obtained in 100% yield. MS: calc: 196.2; found: 197.1 (M+H).
A stirred suspension of diamine 304 (1.18 g; β.OI mmol) in triethylortoacetate (20 mL; 109 mmol; 18 eq.) was treated with trifluoroacetic acid (1.10 mL) at room temperature. In 5 min the mixture turned into an amber solution which was stirred at the same temperature for 4 h; concentrated and purified by preparative HPLC (C-18 aquasil column, elution with 5% to 95% MeOH in water) to afford hydroxyacid 305 (701 mg; 53% yield) and, as a side product, ketene acetal 306 (373 mg; 21% yield).
Compound 305: 1H NMR: (499.7 MHz, DMSO) δ (ppm): 13.1 (bs; IH), 8.21 (s; IH); 7.9 (d, J=8.0 Hz; IH); 7.84 (d, J=8.0 Hz; IH); 5.1 (bs; IH); 4.42 (s; 2H); 3.75 (s; 2H); 2.75 (s; 3H);. MS: calc: 220.2; found: 221.1 (M+H)
Compound 306: 1H NMR: (400.2 MHz, DMSO) δ (ppm): 8.17 (m; 2H); 8.08 (d, J=9.2 Hz; IH); 5.03 (d, J=3.9 Hz; IH); 4.84 (d, J=3.9 Hz; IH); 4.63 (t, J=4.5 Hz; 2H); 4.22 (q, J=7.0 Hz; 2H); 3.84 (t, J=4.5 Hz; 2H); 2.92 (s; 3H); 1.39 (t; J=7.0 Hz; 3H). MS: calc: 290.3; found: 291.1 (M+H)
Following the same procedure as described in Example 1, step 3 (scheme 1) but substituting compound 4 for compound 306 the title compound 307 was obtained in 6% yield. MS: calc: 464.49; found: 465.2 (M+H)
Following the same procedure as described in Example 48, step 3 (scheme 36) but substituting compound 171 for the compound 307 and using ethyl acetate as a solvent instead of methanol, the title compound 308 was obtained in 96% yield. 1H NMR: (DMSO) δ (ppm): 9.70 (s, IH), 8.23 (s, IH), 7.87 (dd; J=1.0, 8.4 Hz; IH); 7.62 (d, J=8.4 Hz; IH), 7.48 (d; J=2.0 Hz; IH); 7.34 (dd; J=0.8, 4.8 Hz; IH); 7.28 (dd; J=2.0, 8.0 Hz; IH); 7.23 (dd; J=0.8, 3.6 Hz; IH); 7.03 (dd; J=1.2, 4.8 Hz; IH); 6.81 (d; J=8.0 Hz; IH); 5.15 (bs, 2H); 4.52 (t; J=4.8 Hz; 2H); 4.35 (t; J=4.8 Hz; 2H); 2.60 (s, 3H); 1.91 (s, 3H). MS: calc: 434.5; found: 435.2 (M+H)
A solution of acetate 308 (18 mg; 41 μmol) and triethylamine (0.5 mL) in dry methanol (2.0 mL) was stirred at room temperature for 16 h and then concentrated in vacuo to give the title compound 309 in quantitative yield. 1H NMR: (400.2 MHz1 DMSO) δ (ppm): 9.70 (s, IH), 8.22 (s, IH), 7.84 (dd; J=1.4, 8.2 Hz; IH); 7.57 (d, J=8.4 Hz, IH), 7.49 (d; J=2.2 Hz; IH); 7.34 (dd; J=1.4, 5.1 Hz; IH); 7.28 (dd; J=2.2, 8.2 Hz; IH); 7.23 (dd; J=LO1 3.5 Hz; IH); 7.04 (dd; J=3.5, 5.1 Hz; IH); 6.80 (d; J=8.4 Hz; IH); 5.14 (bs, 2H); 5.00 (bs, IH); 4.28 (t; J=5.4 Hz; 2H); 3.72 (t; J=5.4 Hz; 2H); 2.59 (s, 3H). MS: calc: 392.5; found: 393.2 (M+H).
To a solution of the 2-amino-4-phenylphenol (310, 2.05 g, 11.06 mmol) and triethylamine (3.08 mL, 22.12 mmol) in THF (20 mL) was added TBDMSCI (2.00 g, 13.28 mmol). The resulting solution was stirred at room temperature for 4 days prior to being diluted with saturated NaCl solution (25 mL), and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated. After purification by flash chromatography (eluent 0-50% EtOAc in hexanes), of the title compound 311 was obtained as a reddish-brown solid (2.51 g, 77% yield). 1H NMR: (DMSO) δ (ppm): 0.05 (s, 6H), 1.05 (s, 9H), 6.49-6.57 (m, 2H), 6.72 (d, J=8.1 Hz, IH), 7.25 (m, IH), 7.29-7.38 (m, 2H), 7.50 (d, J=7.9 Hz, 2H). MS: (calc.) 299.5; (obt.) 300.2 (MH)+.
To a solution of acid 4 (scheme 1) (125 mg, 0.439 mmol) in DMF (3 mL) was added BOP (293 mg, 0.662 mmol). After stirring this solution for 10 minutes, aniline 311 (197 mg, 0.659 mmol) was added, along with triethylamine (0.31 mL, 2.22 mmol). The resulting solution was stirred at room temperature for 16 h prior to removal of the solvent, and dissolution of the residue in THF (5 mL). A solution of TBAF in THF (1.0 M, 0.66 mL, 0.659 mmol) was then added, and the reaction mixture was stirred at room temperature for 5 minutes, diluted with a saturated solution of NaCl (10 mL), and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated. After purification by flash chromatography (eluent 0-80% EtOAc in hexanes), the title compound 312 was obtained as a light yellow solid (82 mg, 41% yield). 1H NMR: (DMSO) δ (ppm): 3.62 (s, 3H), 3.69 (s, 3H), 4.34 (d, J=5.7 Hz, 2H), 6.03 (m, 2H), 6.35 (d, J=2.2 Hz, IH), 6.68 (d, J=8.4 Hz, IH), 7.03 (d, J=8.4 Hz, IH), 7.32 (t, J=7.2 Hz, IH), 7.37 (dd, J=10.4, 1.6 Hz, IH), 7.45 (t, J=7.6 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.59 (d, J=7.6 Hz, 2H), 7.95 (d, J=8.0 Hz, 2H), 8.03 (br s. IH), 9.58 (br S1IH)1 10.00 (br s, IH). MS: (calc.) 454.5; (obt.) 455.4 (MH)+.
Following the same procedure as described in Example 86 but substituting acid 4 for the acid 66 (scheme 10) the compound 313 was obtained as a light yellow solid in 22% yield. 1H NMR: (DMSO) δ (ppm): 3.54 (s, 3H), 3.68 (s, 3H), 4.30 (d, J=5.9 Hz, 2H), 5.92 (s, 2H), 6.13 (t, J=6.3 Hz, IH), 7.01 (d, J=8.2 Hz, IH), 7.21 (d, J=15.7 Hz, IH), 7.29 (dd, J=8.4, 2.3 Hz, IH), 7.33 (d, J=7.2 Hz, IH), 7.42-7.50 (m, 4H), 7.54-7.64 (m, 4H), 8.34 (s1IH)1 9.55 (br s1IH), 10.21 (br s, IH). MS: (calc.) 510.6; (obt.) 511.2 (MH)+.
Following the same procedure as described in Example 86 but substituting acid 4 for the acid 255a (scheme 53) the compound 314 was obtained as a light yellow solid in 22% yield. 1H NMR: (DMSO) δ (ppm): 4.30 (d, J=5.9 Hz, 2H), 6.98 (d, J=8.3 Hz, IH), 7.26-7.36 (m, 2H), 7.42 (t, J=7.3 Hz, 2H), 7.50-7.60 (m, 2H), 7.97 (br s. IH), 9.47 (br s, IH), 9.93 (br s, IH). MS: (calc.) 347.4; (obt.) 348.1 (MH)+.
To a solution of 3-amino-biphenyl (315, 536 mg, 3.17 mmol) in THF/pyridine (2:1, 6 mL) was added methyl 7-(chlorocarbonyl)heptanoate (0.49 mL, 3.48 mmol), and the resulting solution was stirred at room temperature for 16 h. After dilution with saturated NaCl solution (15 mL) and extraction with ethyl acetate, the organic layer was dried over Na2SO4, filtered and concentrated. The residue was then dissolved in THF/methanol/H2O (1:1:2, 8 mL), followed by the treatment of LiOH—H2O (665 mg, 15.85 mmol). The reaction mixture was stirred at room temperature for 1 h prior to acidification (pH=1), and extraction with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated. After purification by flash chromatography (eluent 0-100% EtOAc in hexanes), the title compound 316 was obtained as a white solid (889 mg, 86% yield). 1H NMR: (DMSO) δ (ppm): 1.30-1.40 (m, 4H), 1.50-1.59 (m, 2H), 1.60-1.68 (m, 2H), 2.24 (t, J=7.4 Hz, 2H), 2.37 (t, J=7.4 Hz, 2H), 7.32 (dt, J=7.8, 1.6 Hz, IH), 7.36-7.42 (m, 2H), 7.46-7.52 (m, 2H), 7.58-7.64 (m, 3H), 7.96 (s, IH), 10.07 (br s, IH). MS: (calc.) 325.4; (obt.) 326.1 (MH)+.
Following the same procedure as described in Example 86, step 2 (scheme 68) but substituting acid 4 for the acid 316 the compound 317 was obtained as a light brown solid in 31% yield. 1H NMR: (DMSO) δ (ppm): 1.34-1.46 (m, 4H), 1.60-1.74 (m, 4H), 2.38 (t, J=6.8 Hz, 2H), 2.47 (t, J=7.0 Hz, 2H), 6.98 (d, J=8.2 Hz, IH), 7.20-7.70 (m, 15H), 7.96 (s, IH), 8.10 (s, IH), 9.34 (br s, IH), 10.00 (br s, IH). MS: (calc.) 492.6; (obt.) 493.5 (MH)+.
Following the same procedure as described in Example 52, step 1 (scheme 37) but substituting compound 182 for 2-[4-(naphthalene-2-sulfonyl)-piperazin-1-yl]-pyrimidine-5-carboxylic acid (318, WO 03/076422) title compound 319 was obtained in 75% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.7 (bs, IH); 8.81 (s, 2H); 8.60 (bs, IH); 8.44 (s, IH); 8.20 (d, J=7.6 Hz, IH); 8.15 (d, J=8.6 Hz, IH); 8.05 (d, J=6.9 Hz, IH); 7.75 (dd; J=1.8, 8.6 Hz; IH); 7.71 (dd; J=1.3, 6.9 Hz; IH); 7.68 (m, 2H); 7.63 (d, J=8.6 Hz, IH); 7.47 (m, 2H); 7.40 (dd; J=1.3, 3.5 Hz; IH); 7.09 (dd; J=3.5, 5.1 Hz; IH); 3.97 (t, J=4.1 Hz, 4H); 3.07 (t, J=4.1 Hz, 4H); 1.41 (s, 9H). MS: calc: 670.8; found: 671.3 (M+H)
Following the same procedure described in Example 52, step 2 (scheme 37) but substituting compound 183 for compound 319 the title compound 320 was obtained in 99% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.52 (bs, IH); 8.83 (s, 2H); 8.44 (s, IH); 8.20 (d, J=7.6 Hz, IH); 8.15 (d, J=8.6 Hz, IH); 8.05 (d, J=8.0 Hz, IH); 7.75 (dd; J=1.8, 8.6 Hz; IH); 7.69 (m, 2H); 7.37 (d, J=1.8 Hz, IH); 7.31 (dd; J=1.2, 5.1 Hz; IH); 7.25 (dd; J=2.2, 8.4 Hz; IH); 7.19 (dd; J=1.2, 3.5 Hz; IH); 7.01 (dd; J=3.5, 5.1 Hz; IH); 6.74 (d, J=8.2 Hz, IH); 5.16 (bs, 2H); 3.96 (t, J=4.3 Hz, 4H); 3.07 (t, J=4.3 Hz, 4H); MS: calc: 570.7; found: 571.3 (M+H)
Following the same procedure as described in Example 52, step 1 (scheme 37) but substituting compound 182 for 2-[4-(biphenyl-4-ylcarbamoyl)piperazin-1-yl]-pyrimidine-5-carboxylic acid sodium salt (321, WO 03/076421) the title compound 322 was obtained in 29% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.78 (bs, IH); 8.93 (s, 2H); 8.75 (bs, IH); 8.67 (bs, IH); 7.76 (d, J=2.0 Hz, IH); 7.67 (d, J=8.4 Hz, IH); 7.63 (d, J=1.2 Hz, IH); 7.61 (m, IH); 7.57 (m, 4H); 7.50 (m, 2H); 7.42 (m, 3H); 7.29 (m, IH); 7.11 (dd; J=3.5, 5.1 Hz; IH); 3.94 (t, J=4.5 Hz, 4H); 3.60 (t, J=4.5 Hz1 4H); 1.47 (s, 9H). MS: calc: 675.8; found: 698.5 (M+Na)
Following the same procedure as described in Example 52, step 2 (scheme 37) but substituting compound 183 for compound 322 the title compound 323 was obtained in 99% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.59 (bs, IH); 8.93 (s, 2H); 8.75 (bs, IH); 7.63 (d, J=1.2 Hz, IH); 7.61 (m, IH); 7.57 (m, 4H); 7.41 (m, 3H); 7.33 (dd; J=1.2, 5.1 Hz; IH); 7.29 (m, 2H); 7.23 (dd; J=1.2, 2.5 Hz; IH); 7.03 (dd; J=3.7, 5.1 Hz; IH); 6.78 (d, J=8.2 Hz, IH); 5.22 (bs, 2H); 3.93 (t, J=3.9 Hz, 4H); 3.60 (t, J=3.9 Hz, 4H). MS: calc: 575.7; found: 576.3 (M+H
Following the same procedure as in Example 52, step 1 (scheme 37) but substituting compound 182 for compound 324 title compound 325 was obtained in 47% yield. 1H NMR: (400 MHz, DMSOd6) δ (ppm): 9.94 (s, IH), 8.72 (s, IH), 7.91 (d, J=8.6 Hz, 2H), 7.76 (d, J=8.2, 2H), 7.75 (d, J=2.2 Hz, IH), 7.62 (d, J=8.9 Hz, IH), 7.51 (dd, J=4.9, 1.2 Hz, IH), 7.50 (dd, J=8.6, 2.2 Hz, 7.44 (d, J=3.7, 1.2 Hz, IH), 7.11 (dd, J=5.1, 3.5 Hz, IH), 1.45 (s, 9H). LRMS: (m/z): 495.1/497.1 ((M/M+2)+23).
Following the same procedure as in Example 29, step 1 (scheme 21) but substituting bromide 114 for the bromide 325 and using 3-pyridine boronic acid as a coupling partner, (Suzuki coupling) the compound 326 was obtained and used without purification for the next step.
Following the same procedure as in Example 52, step 2 (scheme 37) but replacing compound 183 by compound 326 the title compound 327 was obtained (14% yield over the two steps). 1H NMR: (400 MHz, DMSOd6) δ (ppm): 9.80 (s, IH), 8.98 (d, J=2.2 Hz, IH), 8.60 (dd, J=4.7, 1.6 Hz, IH), 8.17 (d, J=8.6 Hz, IH), 8.12 (d, J=8.0 Hz, 2H), 7.90 (d, J=8.6 Hz, 2H), 7.52 (dd, J=7.2, 4.1 Hz, IH), 7.48 (s, IH), 7.35 (d, J=4.1 Hz, IH), 7.29 (dd, J=8.4, 2.3 Hz, IH), 7.24 (d, J=3.3 Hz, IH), 7.04 (dd, J=5.1, 1.4, IH), 6.80 (d, J=8.2 Hz, IH), 5.19 (s, 2H). LRMS: (m/z): 372.3 (MH+).
A solution of 4-bromo-2-nitrophenol (297, 1.0O g, 4.59 mmol) (scheme 65) in acetic anhydride (10 mU was heated in a pressure vessel at 130-140° C. for 16 h. Most of the solvent was evaporated in vacuo and the resulting oil was kept in the freezer for 3 days. Crystallization occurred while thawing. The white crystals were suspended in a mixture of EtOAc/hexanes (9:1) and collected by filtration affording the title compound 328 (1.03 g, 87% yield). 1H NMR: (400 MHz, DMSOd6) δ (ppm): 8.33 (d, J=2.3 Hz, IH), 8.02 (dd, J=8.6, 2.3 Hz, IH), 7.45 (d, J=8.6 Hz, IH), 2.33 (s, 3H). LRMS: (m/z): 282.0/284.0 ((M+/M+2)+23).
Following the same procedure as in Example 44, step 2 (scheme 32) but substituting bromide 155 for bromide 328 (1.00 g, 3.85 mmol) and boronate 116 for 2-thiophene boronic acid (517 mg, 4.04 mmol) and heating at 120° C., the title compound 298 was obtained (270 mg, 32% yield). 1H NMR: (DMSOd6) δ (ppm): 11.21 (bs, IH), 8.07 (d, J=2.3 Hz, IH), 7.80 (dd, J=8.6, 2.3 Hz, IH)1 7.49 (dd, J=3.5, 1.2 Hz, IH), 7.16 (d, J=8.6 Hz, IH), 7.11 (dd, J=5.1, 3.5 Hz, IH), 7.07 (d, J=8.8 Hz, IH).
Following the same procedure as in Example 51, step 3 (scheme 37) but substituting compound 177 for compound 298 (270 mg, 1.22 mmol), the title compound 329 was obtained (233 mg, 100% yield). 1H NMR: (DMSCkl6) δ (ppm): 9.21 (bs, IH), 7.33 (dd, J=5.1, 1.0 Hz, IH), 7.14 (dd, J=3.5, 1.2 Hz, IH), 7.01 (dd, J=5.1, 3.5 Hz, IH), 6.85 (d, J=2.2 Hz, IH), 6.63 (d, J=8.0 Hz, IH), 6.53 (d, J=8.2 Hz, IH), 4.65 (bs, 2H). LRMS: (m/z): 192.1 (MH+).
Following the same procedure as in Example 19, step 2 (scheme 17) but substituting compound 90 for compound 329 (233 mg, 1.22 mmol), the title compound 330 was obtained (211 mg, 57% yield). 1H NMR: (DMSOd6) δ (ppm): 7.75 (dd, J=5.1, 1.2 Hz, IH), 7.66 (dd, J=3.5, 1.2 Hz, IH), 7.50 (d, J=2.2 Hz, IH), 7.47 (dd, J=5.3, 3.7 Hz, IH), 7.28 (dd, J=8.2, 2.2 Hz, IH), 7.21 (d, J=8.2 Hz, IH), 4.88 (bs, 2H), 1.50 (s, 9H), 0.73 (s, 6H). LRMS: (m/z): 306.3 (MH+).
To a solution of acid 331 (383 mg, 0.691 mmol) (U.S. Pat. No. 6,174,905 BI) in DMF (6 mU was added Et3N (194 μL, 1.39 mmol) and BOP (954 mg, 2.08 mmol). The mixture was stirred for 15 min. and a solution of compound 330 (211 mg, 0.691 mmol) in DMF (4 mL) was added followed by Et3N (510 μL, 3.66 mmol). The mixture was stirred for 16 hours at rt and then concentrated in vacuo at 80° C. The residue was partitioned between EtOAc and H2O, the organic phase was extracted twice with HCl I N and the combined acidic extracts were neutralized with saturated NaHCO3. A precipitate formed which was extracted with EtOAc; the extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting material was purified by flash chromatography using as an eluent a mixture MeOH/DCM with increasing polarity (7:93 to 10:90) affording the intermediate compound 332 (99 mg, 20% yield). 1H NMR: (DMSO-d6) δ (ppm): 10.11 (s, IH), 8.56 (bs, 2H), 8.51 (bs, 2H), 8.02 (d, J=7.8 Hz, 2H), 7.92-7.90 (m, 2H), 7.79 (d, J=8.2 Hz, 2H), 7.76-7.74 (m, 2H), 7.61 (d, J=7.4 Hz, IH), 7.57 (d, J=5.1 Hz, IH), 7.53 (d, J=3.5 Hz, IH), 7.41 (d, J=8.2 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 7.29 (d, J=8.2 Hz, IH), 7.27 (d, J=5.9 Hz, IH), 7.16 (dd, J=5.1, 3.7 Hz, IH), 5.08 (s, 2H), 5.07 (s, 2H), 4.28 (d, J=7.2 Hz, 2H), 7.23 (d, J=5.5 Hz, 2H). LRMS: (m/z): 728.3 (MH+).
To a solution of compound 332 (10 mg, 0.0137 mmol) in THF (500 μL) was added excess NaOH (500 μL of a solution prepared by dissolving one pellet in 1 mL of H2O). The mixture was stirred at 60° C. for 1 h, partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc and the organic phase was extracted with HCl IN. The acidic extract was neutralized with saturated NaHCO3 to form a precipitate which was extracted with EtOAc; the extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting material was purified by preparative TLC using MeOH/DCM (7:93) affording the title compound 333 (2.9 mg, 46% yield). 1H NMR: (Acetone-d6) δ (ppm): 9.37 (bs, IH), 9.35 (bs, IH), 8.47 (d, J=1.2 Hz, 8.38 (d, J=3.9 Hz, IH), 7.97 (s, IH), 7.87 (d, J=8.4 Hz, 2H), 7.64 (d, J=7.4 Hz, IH), 7.35 (d, J=8.2 Hz, 2H), 7.25 (dd, J=8.4, 2.3 Hz, IH), 7.22 (dd, J=5.1, 1.2 Hz, IH), 7.16 (dd, J=3.7, 1.2 Hz, IH), 6.93 (d, J=8.1 Hz, IH), 6.93 (d, J=1.6 Hz, IH), 6.86 (d, J=8.4 Hz, IH), 5.01 (s, 2H), 4.31 (d, J=6.3 Hz, 2H). LRMS: (m/z): 460.2 (MH+).
A solution of tert-butyl piperazine-1-carboxylate (334, 1 g, 5.37 mmol), 3-(bromomethyl)benzonitrile (335, 1.26 g, 6.45 mmol) and K2CO3 (1.48 g, 10.74 mmol) in EtOH (20 mU was refluxed for four hours. The reaction mixture was then concentrated, diluted with EtOAc (20 ml.) and washed with water (20 mL). The organic phase was separated, dried with Na2SO4, filtered and concentrated. Crude product was purified by flash chromatography using the gradient 10%-25% EtOAc in hexanes as an eluent to afford the title compound 336 (1.374 g 85%). MS: calc: 301.3; found: 302.1 (M+H)
A solution of tert-butyl 4-(4-cyanobenzyl)piperazine-1-carboxylate (336, 1.374 g, 4.56 mmol) in DCM (5 mL) and TFA (5 mL) was stirred at room temperature for one hour. The reaction mixture was concentrated and the residue was added to a solution of thiocarbonyldiimidazole (1.21 g, 6.84 mmol, 1.5 equiv.) in dry DCM (20 mL) under N2 at O° C. Obtained solid was diluted with MeOH (20 mL) and transferred to a pressure vial. Ammonia gas was bubbled in for 10 min and the flask was capped and stirred at 8O° C. for two days. The reaction mixture was concentrated and purified by flash chromatography using 60% EtOAc in hexane as an eluent, to afford the title compound 337 (593 mg, 50% yield). MS: calc: 260.1; found: 261.2 (M+H)
A solution of (E)-methyl 3-methoxyacrylate (290 mg, 280 ml—, 2.51 mmol) in 1:1 mixture of dioxane/water (4 ml_) was treated with NBS (507 mg, 2.85 mmol) at 0° C. and stirred for 1 hour. The mixture was transferred to a flask containing the thioamide 337 (593 mg, 2.28 mmol) at room temperature and the resulting mixture was refluxed for 1.5 hours. It was cooled down, quenched by adding saturated NH4Cl solution (5 mL) and concentrated. Obtained material was partitioned between EtOAc and water. Organic phase was dried with Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using 60% EtOAc in hexanes as an eluent, to afford the title compound 338 (602 mg, 77% yield). MS: calc: 342.1; found: 343. KM+H)
1:1:1 solution of THF/water/MeOH (9 mL) of ester 338 (602 mg, 1.76 mmol) and KOH (600 mg, 10.71 mmol, 6 equiv.) was stirred at room temperature for 1 hour. The reaction mixture was then concentrated and partitioned between ether and water. Aqueous layer was collected and acidified with I M HCl solution to pH=3 and extracted with EtOAc (3×5 mL). Organic phase was dried with Na2SO4, filtered and concentrated. Crude product 339 (WO 03/092686) was used directly in the next step. MS: calc: 328.1; found: 329.1 (M+H)
A solution of acid 339 (113 mg, 0.34 mmol) amine 178 (100 mg, 0.34 mmol) and BOP (152 mg, 0.34 mmol) in pyridine (2 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by flash chromatography using gradient eluent 50%-75% EtOAc in hexanes to afford the title compound 340 (96 mg, 47% yield). MS: calc: 600.1; found: 601.3 (M+H)
A solution of compound 340 (96 mg, 0.16 mmol) in 1:1 DCM/TFA (6 mU was stirred at room temperature for 1 hour. The mixture was concentrated and purified by flash chromatography using EtOAc as an eluent, to afford the title compound 341 (47 mg, 59% yield). 1H NMR: (400.2 MHz, CD3OD) δ (ppm): 7.95 (br.s, IH), 7.75 (m, IH), 7.68 (m, 2H), 7.53 (t, IH, J=7.6 Hz), 7.42 (s, IH), 7.33 (d, IH, J=8.2 Hz), 7.20 (m, 2H), 7.00 (m, IH), 6.87 (d, IH, J=8.3 Hz), 3.72 (s, 2H), 3.60 (m, 4H), 2.68 (m, 4H). MS: calc: 500.1; found: 501.2 (M+H)
Following the procedure as described in Example 94, step 5 (scheme 74) but substituting 2-(4-(4-cyanobenzyl)piperazin-1-yl)thiazone-5-carboxylicacjd (339 WO 03/092686)) for 4-(4-benzylpiperazin-1-yl)benzoic acid (342, WO 03/087057) the title compound 343 was obtained in 18% yield. MS: calc: 568.2; found: 569.3 (M+H)
A solution of compound 343 (36 mg, 0.06 mmol) in 1:1 DCMAFA (6 mL) was stirred at room temperature for 1 hour. The mixture was concentrated and partitioned between water and EtOAc. Organic phase was washed with NaHCO3 solution, dried with Na2SO4, filtered and concentrated to afford the title compound 344 (5 mg, 17% yield). 1H NMR: (400.2 MHz, CDCl3) δ (ppm): 2.625 (t, J=5 Hz, 4H), 3.35 (t, J=5 Hz, 4H), 3.59 (s, 2H), 4.00 (s, 2H), 6.84 (d, J=8 Hz, IH), 6.90 (d, J=9 Hz, 2H), 7.01 (m, IH), 7.16 (m, 2H), 7.25 (m, 6H), 7.50 (s, IH), 7.75 (s, IH), 7.81 (d, J=9 Hz, 2H). MS: calc: 468.0; found: 469.0 (M+H)
A solution of methyl 7-(phenylcarbamoyl)heptanoate (345, U.S. Pat. No. 5,369,108) (124 mg, 0.46 mmol) and KOH (100 mg, 1.77 mmol) in THF/water/MeOH (1:1:1, 9 mL) was stirred at room temperature for 1 hour. The reaction mixture was then concentrated and partitioned between ether and water! Aqueous layer was collected, acidified with I M HCl solution to pH=3 and extracted with EtOAc (3×5 mL). Combined organic phase was dried with Na2SO4, filtered and concentrated. Crude acid was diluted in thionyl chloride (3 mL) and DMF (1 drop) and stirred at room temperature for 20 min. The reaction mixture was concentrated in vacuo, diluted with THF (3 mL) and cooled to O° C. a was treated with Et3N (62 mg, 86 □L, 0.61 mmol) and amine 178 (120 mg, 0.41 mmol) and stirred at 0° C. for 30 min. The reaction mixture was quenched by the addition of saturated NH4Cl solution and extracted with EtOAc (3×3 mL). Combined organic phase was dried with Na2SO4, filtered and concentrated. Crude product was purified by flash chromatography using 50% EtOAc in hexanes as an eluent, to afford the title compound 346 (111 mg, 52% yield). MS: calc: 521.2; found: 522.3 (M+H)
A solution of compound 346 (111 mg, 0.06 mmol) in 2:1 DCMAFA (3 mL) was stirred at room temperature for 1 hour. The mixture was quenched by addition of saturated NaHCO3 solution and extracted with DCM. Organic phase was dried with Na2SO4, filtered and concentrated. Crude product was purified by flash chromatography using EtOAc as an eluent to afford the title compound 347 (20 mg, 22% yield). 1H NMR: (400.2 MHz, CD3OD) δ (ppm): 7.51 (br.s, 2H), 7.38 (s, IH), 7.16-7.27 (m, 5H), 6.9-7.1 (m, 2H), 6.84 (m, IH), 2.42 (m, 4H), 1.76 (m, 4H), 1.49 (m, 4H). MS: calc: 421.2; found: 422.2 (M+H)
Following the same procedures as described in Example 52, steps 1 and 2 (scheme 37) but substituting acid 182 for 4-((I,2-dihydro-2,4-dioxoquinazolin-3(4H)-yl)methyl)benzoic acid 348 (WO 03/024448 or JP 2003137866A); the title compound 349 was obtained in 55% yield. 1H NMR (DMSO-de) D(ppm): 11.57 (s, IH), 9.81 (Sf IH), 7.95-7.92 (m, 3H), 7.68 (td, J=7.2, 1.4 Hz, IH), 7.48 (d, J=1.8 Hz, IH), 7.42 (d, J=8.2 Hz, 2H), 7.38 (d, J=5.1 Hz, IH)1 7.34 (dd, J=8.2, 2.0 Hz, IH), 7.27 (d, J=3.3 Hz, IH), 7.24-7.20 (m, 2H), 7.05 (dd, J=4.9, 3.5 Hz, IH), 6.89 (d, J=8.4 Hz, IH), 5.17 (s, 2H). (The NH2 group is missing, overlapped by H2O). MS (m/z): 468.53 (calc) 469.2 (MH+) (found).
Butyl lithium (14.96 mmol, 1.4M, 2.09 mU and diisopropyl amine (14.96 mmol, 10.68 ml) were added to dry THF at −78° C. to generate LDA in solution. Tert-butyl 4-oxopiperidine-1-carboxylate (350, 2.71 g, 13.6 mmol) in THF (10 mU was added to the LDA solution. The resulting reaction mixture was warmed to room temperature and allowed to stir for additional 30 minutes, cooled to −78° C. once again, and N-phenyltrifluoromethanesulfonimide (5.1 g, 14.3 mmol) solution in THF was added via syringe. The combined reaction mixture was warmed to room temperature and allowed to stir for 3 additional hours, quenched with water (50 mL) and extracted with ethyl acetate (2×50 mL). The extract was dried over sodium sulfate, evaporated and the residue was purified by flash chromatography on silica gel, eluent 7:1 mixture hexanes-ethyl acetate, to afford the title compound 351 as light yellow oil (2.55 g, 57% yield). 1H-NMR (DMSO) δ: 6.00 (s, IH), 3.97-3.96 (m, 2H), 3.53 (t, J=5.7 Hz, 2H), 2.41-2.40 (m, 2H), 1.41 (s, 9H).
To a stirred solution of 351 (1.1 g, 3.32 mmol) and 352 (571 mg, 3.32 mmol) in a 2:1 mixture of DME-water (30 mL), was added Pd(PPh3U (268 mg, 0.232 mmol), tri-o-tolyl phosphine (71 mg, 0.232 mmol) and potassium carbonate (1.38 g, 9.96 mmol). The reaction mixture was degassed with nitrogen for 5 minutes and stirred at 80° C. for 15 hours, cooled, treated with water (50 mL) and extracted with ethyl acetate (2×40 mL). The organic layer was separated, dried with sodium sulfate and evaporated under reduced pressure to form a residue which was purified by flash chromatography, eluting with a gradient solvent system from 2:1 hexanes-ethyl acetate to 1:1 hexanes-ethyl acetate. A subsequent trituration was performed with 10% ethyl acetate in hexanes for 15 minutes to afford 353 as a beige solid (330 mg, 33% yield). 1H NMR: (DMSO) δ 7.60 (d, J=2.2 Hz, IH), 7.14 (d, J=3.7 Hz, IH), 6.28-6.29 (m, IH), 4.00-3.99 (m, 2H), 3.52 (t, J=5.9 Hz, 2H), 2.45-2.46 (mf 2H), 1.42 (s, 9H).
Compound 353 (270 mg, 0.87 mmol), 2-nitro-5-(thiophen-2-yl)benzenamine (3, 193 mg, 0.87 mmol), and BOP (386 mg, 0.87 mmol) were dissolved in dry pyridine (10 ml_). Sodium hydride (140 mg, 3.50 mmol) was added and the resulting solution was stirred at room temperature for 2 hours, quenched with glacial acetic acid (1 mL), and the pyridine was removed under reduced pressure. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The extract was dried with sodium sulphate and evaporated to yield a residue which was triturated with ethyl acetate for 15 minutes, to afford the title compound 354 as a yellow solid (270 mg, 61% yield). 1H NMR: (DMSO) δ 10.79 (s, IH), 8.06-8.04 (m, 2H), 7.86 (d, J=3.9 Hz, IH), 7.75-7.68 (m, 3H), 7.25-7.20 (m, 2H), 6.32 (s, IH), 4.04-4.01 (m, 2H), 3.54 (t, J=5.3 Hz, 2H), 1.43 (s, 9H).
To a stirred solution of 354 (270 mg, 0.53 mmol) in methanol (25 mL) was added 10% palladium on charcoal (150 mg). The resulting mixture was purged with H2 gas and stirred under a hydrogen atmosphere for 3 days, filtered through a celite pad, evaporated and purified by flash chromatography, eluent 1:1 hexanes-ethyl acetate, to afford the title compound 355 as a white solid (24 mg, 10% yield). 1H NMR: (CD3OD) δ 7.73 (d, J=3.3 Hz, IH), 7.45 (d, J=2.1 Hz, IH), 7.34 (dd, J=8.2, 2.2 Hz, IH), 7.23-7.19 (m, 2H), 7.01 (dd, J=4.7, 3.7 Hz, IH), 6.96 (d, J=3.9 Hz, IH), 6.88 (d, J=8.1 Hz, IH), 4.17 (d, J=13.1 Hz, 2H), 3.00-2.90 (m, 2H), 2.04 (d, J=12.1 Hz, 2H), 1.60-1.54 (m, 2H).
1,2,4-Benzenetricarboxylic anhydride (356, 0.487 g, 2.53 mmol) and 4-(2-aminoethyDmorpholine (0.33 g, 2.53 mmol) were allowed to stir 2 hours at 130° C. in acetic acid (10 mL). The reaction mixture was then cooled to room temperature and the precipitated solid was collected by filtration, washed with H2O and dried under vacuum, to afford title compound 357 as a white powder (0.63 g, 82% yield). 1H NMR (DMSO) δ (ppm): 8.26 (dd, J=7.6, 1.4 Hz, IH), 8.15 (dd, J=1.4, 0.6 Hz1 IH), 7.92 (dd, J=7.6, 0.6 Hz, IH), 3.73 (t, J=6.5 Hz1 2H), 3.50 (t, J=4.5 Hz, 4H), 2.59 (t, J=6.5 Hz1 2H), 2.47 (overlapped with DMSO, 4H). MS: 304.3 (calc), 305.1 (obs).
Following the same procedures outlined in Example 71a, steps 2 and 3 (scheme 54) but substituting 3,4-dimethoxybenzoic acid (257a) for compound 357, the title compound 358 was obtained in 18% yield (over the two steps). 1H NMR: (DMSO) δ (ppm): 10.03 (s, IH), 8.45 (s, IH), 8.38 (d, J=7.6 Hz, IH), 7.99 (d, J=7.6 Hz, IH), 7.44 (d, J=2.0 Hz, IH), 7.32 (dd, J=11.9, 5.1 Hz, IH), 7.28 (d, J=2.0 Hz, IH), 7.03 (d, J=4.9 Hz, IH), 6.78 (d, J=8.2 Hz, IH), 5.27 (s, 2H), 3.73 (t, J=6.3 Hz, 2H), 3.48 (m, 4H), 2.54 (t, J=6.5 Hz, 2H), 2.41 (m, 4H). MS: 476.15 (calc), 477.2 (obs).
Following the same procedure as described in Example 1, step 1 (scheme 1) but substituting I-bromo-4-nitrobenzene (1) for I-(4-nitrophenyl)-IH-imidazole (359), title compound 360 was obtained in 32% yield. MS: 204.06 (calc), 205.1 (found).
Following the same procedure as described in Example 19, steps 3 and 4 (scheme 17) but substituting compound 91 for compound 360, the title compound 361 was obtained in 10.5% yield (over 2 steps). 1H NMR: (DMSO) δ (ppm): 9.62 (s, IH), 7.96 (d, J=9.0 Hz, 3H), 7.52 (m, IH), 7.42 (d, J=2.5 Hz, IH), 7.19 (dd, J=8.6, 2.5 Hz, IH), 7.04 (d, J=8.8 Hz, 2H), 7.03 (s, IH), 6.85 (d, J=8.4 Hz, IH), 5.11 (s, 2H), 3.83 (s, 3H). MS: 308.13 (calc), 309.2 (obs).
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.
The characteristics of the carrier will depend on the route of administration. As used herein, the term “pharmaceutically acceptable” means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
As used herein, the term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for Example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula —NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate). As used herein, the term “salt” is also meant to encompass complexes, such as with an alkaline metal or an alkaline earth metal.
The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. A preferred dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
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 histone deacetylases and their role in biological processes. In addition, the compounds of the invention selectively inhibit certain isoforms of HDAC.
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-I.
In some preferred embodiments, the histone deacetylase inhibitor interacts with and reduces the activity of all histone deacetylases in the cell. In some other preferred embodiments according to this aspect of the invention, the histone deacetylase inhibitor interacts with and reduces the activity of fewer than all histone deacetylases in the cell. In certain preferred embodiments, the inhibitor interacts with and reduces the activity of one histone deacetylase (e.g., HDAC-I), but does not interact with or reduce the activities of other histone deacetylases (e.g., HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, and HDAC-8). As discussed below, certain particularly preferred histone deacetylase inhibitors are those that interact with, and reduce the enzymatic activity of, a histone deacetylase that is involved in tumorigenesis. Certain other preferred histone deacetylase inhibitors interact with and reduce the enzymatic activity of a fungal histone deacetylase.
Preferably, the method according to the third aspect of the invention causes an inhibition of cell proliferation of the contacted cells. The phrase “inhibiting cell proliferation” is used to denote an ability of an inhibitor of histone deacetylase to retard the growth of cells contacted with the inhibitor as compared to cells not contacted. An assessment of cell proliferation can be made by counting contacted and non-contacted cells using a Coulter Cell Counter (Coulter, Miami, Fla.) or a hemacytometer. Where the cells are in a solid growth (e.g., a solid tumor or organ), such an assessment of cell proliferation can be made by measuring the growth with calipers and comparing the size of the growth of contacted cells with non-contacted cells.
Preferably, growth of cells contacted with the inhibitor is retarded by at least 50% as compared to growth of non-contacted cells. More preferably, cell proliferation is inhibited by 100% (i.e., the contacted cells do not increase in number). Most preferably, the phrase “inhibiting cell proliferation” includes a reduction in the number or size of contacted cells, as compared to non-contacted cells. Thus, an inhibitor of histone deacetylase according to the invention that inhibits cell proliferation in a contacted cell may induce the contacted cell to undergo growth retardation, to undergo growth arrest, to undergo programmed cell death (i.e., to apoptose), or to undergo necrotic cell death.
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 GI or G2 phase of the cell cycle. Such synchronization allows, for Example, the identification of gene and/or gene products expressed during the GI 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.
In some preferred embodiments, the contacted cell is a neoplastic cell. The term “neoplastic cell” is used to denote a cell that shows aberrant cell growth. Preferably, the aberrant cell growth of a neoplastic cell is increased cell growth. A neoplastic cell may be a hyperplastic cell, a cell that shows a lack of contact inhibition of growth in vitro, a benign tumor cell that is incapable of metastasis in vivo, or a cancer cell that is capable of metastasis in vivo and that may recur after attempted removal. The term “tumorigenesis” is used to denote the induction of cell proliferation that leads to the development of a neoplastic growth. In some embodiments, the histone deacetylase inhibitor induces cell differentiation in the contacted cell. Thus, a neoplastic cell, when contacted with an inhibitor of histone deacetylase may be induced to differentiate, resulting in the production of a non-neoplastic daughter cell that is phylogenetically more advanced than the contacted cell.
In some preferred embodiments, in neoplastic cells, antitumor activity of an HDAC inhibitor can be assessed by analyzing expression of certain tumor suppressor genes, such as P21WAFVCiPi. HDAC jn′ninhibitors induce p21WAF1/CiP1 expression in human cancer cells, which leads to retardation of cell proliferation.
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.
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.
It is contemplated that some compounds of the invention have inhibitory activity against a histone deacetylase from a protozoal source. Thus, the invention also provides a method for treating or preventing a protozoal disease or infection, comprising administering to an animal in need of such treatment a therapeutically effective amount of a histone deacetylase inhibitor of the invention. Preferably the animal is a mammal, more preferably a human. Preferably, the histone deacetylase inhibitor used according to this embodiment of the invention inhibits a protozoal histone deacetylase to a greater extent than it inhibits mammalian histone deacetylases, particularly human histone deacetylases.
The present invention further provides a method for treating a fungal disease or infection comprising administering to an animal in need of such treatment a therapeutically effective amount of a histone deacetylase inhibitor of the invention. Preferably the animal is a mammal, more preferably a human. Preferably, the histone deacetylase inhibitor used according to this embodiment of the invention inhibits a fungal histone deacetylase to a greater extent than it inhibits mammalian histone deacetylases, particularly human histone deacetylases.
The term “therapeutically effective amount” is meant to denote a dosage sufficient to cause inhibition of histone deacetylase activity in the cells of the subject, or a dosage sufficient to inhibit cell proliferation or to induce cell differentiation in the subject. Administration may be by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain particularly preferred embodiments, compounds of the” invention are administered intravenously in a hospital setting. In certain other preferred embodiments, administration may preferably be by the oral route.
When administered systemically, the histone deacetylase inhibitor is preferably administered at a sufficient dosage to attain a blood level of the inhibitor from about 0.01 μM to about 100 μM, more preferably from about 0.05 μM to about 50 μM, still more preferably from about 0.1 μM to about 25 μM, and still yet more preferably from about 0.5 μM to about 25 μM. For localized administration, much lower concentrations than this may be effective, and much higher concentrations may be tolerated. One of skill in the art will appreciate that the dosage of histone deacetylase inhibitor necessary to produce a therapeutic effect may vary considerably depending on the tissue, organ, or the particular animal or patient to be treated.
In certain preferred embodiments of the third aspect of the invention, the method further comprises contacting the cell with an antisense oligonucleotide that inhibits the expression of a histone deacetylase. The combined use of a nucleic acid level inhibitor (e.g., antisense oligonucleotide) and a protein level inhibitor (i.e., inhibitor of histone deacetylase enzyme activity) results in an improved inhibitory effect, thereby reducing the amounts of the inhibitors required to obtain a given inhibitory effect as compared to the amounts necessary when either is used individually. The antisense oligonucleotides according to this aspect of the invention are complementary to regions of RNA or double-stranded DNA that encode HDAC-I, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, and/or HDAC-8 (see e.g., GenBank Accession Number U50079 for HDAC-1, GenBank Accession Number U31814 for HDAC-2, and GenBank Accession Number U75697 for HDAC-3).
For purposes of the invention, the term “oligonucleotide” includes polymers of two or more deoxyribonucleosides, ribonucleosides, or 2-substituted ribonucleoside residues, or any combination thereof. Preferably, such oligonucleotides have from about 6 to about 100 nucleoside residues, more preferably from about 8 to about 50 nucleoside residues, and most preferably from about 12 to about 30 nucleoside residues. The nucleoside residues may be coupled to each other by any of the numerous known internucleoside linkages. Such internucleoside linkages include without limitation phosphorothioate, phosphorodithioate, alkylphosphonate, alkylphosphonothioate, phosphotriester, phosphoramidate, siloxane, carbonate, carboxymethylester, acetamidate, carbamate, thioether, bridged phosphoramidate, bridged methylene phosphonate, bridged phosphorothioate and sulfone internucleoside linkages. In certain preferred embodiments, these internucleoside linkages may be phosphodiester, phosphotriester, phosphorothioate, or phosphoramidate linkages, or combinations thereof. The term oligonucleotide also encompasses such polymers having chemically modified bases or sugars and/or having additional substituents, including without limitation lipophilic groups, intercalating agents, diamines and adamantane.
For purposes of the invention the term “2′-substituted ribonucleoside” includes ribonucleosides in which the hydroxyl group at the 2′ position of the pentose moiety is substituted to produce a 2′-0-substituted ribonucleoside. Preferably, such substitution is with a lower alkyl group containing 1-6 saturated or unsaturated carbon atoms, or with an aryl or alkyl group having 2-6 carbon atoms, wherein such alkyl, aryl or alkyl group may be unsubstituted or may be substituted, e.g., with halo, hydroxy, trifluoromethyl, cyano, nitro, acyl, acyloxy, alkoxy, carboxyl, carbalkoxyl, or amino groups. The term “2′-substituted ribonucleoside” also includes ribonucleosides in which the 2′-hydroxyl group is replaced with an amino group or with a halo group, preferably fluoro.
Particularly preferred antisense oligonucleotides utilized in this aspect of the invention include chimeric oligonucleotides and hybrid oligonucleotides.
For purposes of the invention, a “chimeric oligonucleotide” refers to an oligonucleotide having more than one type of internucleoside linkage. One preferred Example of such a chimeric oligonucleotide is a chimeric oligonucleotide comprising a phosphorothioate, phosphodiester or phosphorodithioate region, preferably comprising from about 2 to about 12 nucleotides, and an alkylphosphonate or alkylphosphonothioate region (see e.g., Pederson et al. U.S. Pat. Nos. 5,635,377 and 5,366,878). Preferably, such chimeric oligonucleotides contain at least three consecutive internucleoside linkages selected from phosphodiester and phosphorothioate linkages, or combinations thereof.
For purposes of the invention, a “hybrid oligonucleotide” refers to an oligonucleotide having more than one type of nucleoside. One preferred Example of such a hybrid oligonucleotide comprises a ribonucleotide or 2′-substituted ribonucleotide region, preferably comprising from about 2 to about 12 2′-substituted nucleotides, and a deoxyribonucleotide region. Preferably, such a hybrid oligonucleotide contains at least three consecutive deoxyribonucleosides and also contains ribonucleosides, 2′-substituted ribonucleosides, preferably 2′-0-substituted ribonucleosides, or combinations thereof (see e.g., Metelev and Agrawal, U.S. Pat. No. 5,652,355).
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.
Antisense oligonucleotides utilized in the invention may conveniently be synthesized on a suitable solid support using well known chemical approaches, including H-phosphonate chemistry, phosphoramidite chemistry, or a combination of H-phosphonate chemistry and phosphoramidite chemistry (i.e., H-phosphonate chemistry for some cycles and phosphoramidite chemistry for other cycles). Suitable solid supports include any of the standard solid supports used for solid phase oligonucleotide synthesis, such as controlled-pore glass (CPG) (see, e.g., Pon, R. T. (1993) Methods in Molec. Biol. 20: 465-496).
Particularly preferred oligonucleotides have nucleotide sequences of from about 13 to about 35 nucleotides which include the nucleotide sequences shown in Table 4. Yet additional particularly preferred oligonucleotides have nucleotide sequences of from about 15 to about 26 nucleotides of the nucleotide sequences shown in Table 1.
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.
The following protocol was used to assay the compounds of the invention. In the assay, the buffer used was 25 mM HEPES, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2 and the substrate was Boc-Lys(Ac)-AMC in a 5O mM stock solution in DMSO. The enzyme stock solution was 4.08 μg/mL in buffer.
The compounds were pre-incubated (2 μl in DMSO diluted to 13 μl in buffer for transfer to assay plate) with enzyme (20 μl of 4.08 μg/ml) for 10 minutes at room temperature (35 μl pre-incubation volume). The mixture was pre-incubated for 5 minutes at room temperature. The reaction was started by bringing the temperature to 37° C. and adding 16 μl substrate. Total reaction volume was 501. The reaction was stopped after 20 minutes by addition of 50 μl developer, prepared as directed by Biomol (Fluor-de-Lys developer, Cat. # KI-105). A plate was incubated in the dark for 10 minutes at room temperature before reading (λEx=360 nm, λEm=470 nm, Cutoff filter at 435 nm).
Unless specified otherwise, in all the tables in this specification:
a<1; 1≦b≦20; c≧20; d=9999
Tables 6A and 6b below display comparative data for the compounds of the invention demonstrating the increased HDAC-I inhibitory activity resulting from incorporating a planar substituent.
Eight to ten week old female BCDI mice (Taconic Labs, Great Barrington, N.Y.) were injected subcutaneously in the flank area with 2×106 preconditioned HCTI 16 human colorectal carcinoma cells, A549 human lung cancer, SW48 human colorectal cancer, A431 vulval caracinoma and colo205 human colorectal cancer. Preconditioning of these cells was done by a minimum of three consecutive tumor transplantations in the same strain of nude mice. Subsequently, tumor fragments of approximately 30 mgs were excised and implanted subcutaneously in mice, in the left flank area, under Forene anesthesia (Abbott Labs, Geneva, Switzerland). When the tumors reached a mean volume of 100 mm3, the mice were treated intravenously, subcutaneously, or intraperitoneal̂ by daily injection, with a solution of the histone deacetylase inhibitor in an appropriate vehicle, such as PBS, DMSO/water, or Tween 80/water, at a starting dose of 10 mg/kg— The optimal dose of the HDAC inhibitor was established by dose response experiments according to standard protocols. Tumor volume was calculated every second day post infusion according to standard methods (e.g., Meyer et al., Int. J. Cancer 43: 851-856 (1989)). Treatment with the HDAC inhibitors according to the invention caused a significant reduction in tumor weight and volume relative to controls treated with vehicle only (i.e., no HDAC inhibitor). The results for histone deacetylase inhibitors compounds 6, 29, 67, 258aa, and 43 are displayed in
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.
Mice bearing implanted HCTI 16 tumors (mean volume 100 mm3) are treated daily with saline preparations containing from about 0.1 mg to about 30 mg per kg body weight of histone deacetylase antisense oligonucleotide. A second group of mice is treated daily with pharmaceutically acceptable preparations containing from about 0.01 mg to about 5 mg per kg body weight of HDAC inhibitor.
Some mice receive both the antisense oligonucleotide and the HDAC inhibitor. Of these mice, one group may receive the antisense oligonucleotide and the HDAC inhibitor simultaneously intravenously via the tail vein. Another group may receive the antisense oligonucleotide via the tail vein, and the HDAC inhibitor subcutaneously. Yet another group may receive both the antisense oligonucleotide and the HDAC inhibitor subcutaneously. Control groups of mice are similarly established which receive no treatment (e.g., saline only), a mismatch antisense oligonucleotide only, a control compound that does not inhibit histone deacetylase activity, and a mismatch antisense oligonucleotide with a control compound.
Tumor volume is measured with calipers. Treatment with the antisense oligonucleotide plus the histone deacetylase protein inhibitors according to the invention causes a significant reduction in tumor weight and volume relative to controls.
Table 6C provides data on inhibition of HDACI enzyme, on antiproliferative activities (HCTI 16 human colon cancer cells) of the compounds using 3-[4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium]bromide (MTT) assay, as well as induction of p21WAF1/Cipl tumor suppressor gene.
wiπ Assay.
Compounds at various concentrations were added to human colon cancer HCTI 16 cells plated in 96-well plates. Cells were incubated for 72 hours at 37° C. in 5% CO2 incubator. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide, Sigma) was added at a final concentration of 0.5 mg/ml and incubated with the cells for 4 hours before an equal volume of solubilization buffer (50% N,N-dimethylformamide, 20% SDS, pH 4.7) was added onto cultured cells. After overnight incubation, solubilized dye was quantified by colorimetric reading at 570 nM using a reference at 630 nM. 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 those of DMSO-treated cells is determined as MTT IC50,
p21WAF1/Cipl Assay.
HCTI 16 cells were stably transfected with reporter plasmids encoding the p21 promoter-driven luciferase. Cells were treated with indicated concentration of HDAC inhibitors for 16 hours before cells were harvested and luciferase activity analyzed. The effective concentration (EC) of MS-275 was designated as 1 uM. The ability of HDAC inhibitor was compared with that of MS-275 (T. Suzuki, et. al J. Med. Chem., 1999, 3001-3003). Lower EC of a given compound indicates that this compound is more potent than MS-275 to induce p21 expression.
This application claims priority from U.S. Provisional Patent Application No. 60/505,884, filed on Sep. 24, 2003, U.S. Provisional Patent Application No. 60/532,973, filed on Dec. 29, 2003, and U.S. Provisional Patent Application No. 60/561,082, filed on Apr. 9, 2004
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US04/31591 | 9/24/2004 | WO | 00 | 1/30/2007 |
| Number | Date | Country | |
|---|---|---|---|
| 60505884 | Sep 2003 | US | |
| 60532973 | Dec 2003 | US | |
| 60561082 | Apr 2004 | US |
