Classifications

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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
  • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • C—CHEMISTRY; METALLURGY
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
  • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
  • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
  • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
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  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
  • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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  • C07C255/00—Carboxylic acid nitriles
  • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
  • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
  • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
  • C07C323/40—Y being a hydrogen or a carbon atom
  • C07C323/42—Y being a carbon atom of a six-membered aromatic ring
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  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
  • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
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  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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  • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
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  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
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  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D333/30—Hetero atoms other than halogen
  • C07D333/34—Sulfur atoms
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  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D333/30—Hetero atoms other than halogen
  • C07D333/36—Nitrogen atoms
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  • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
  • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
  • C07D333/58—Radicals substituted by nitrogen atoms
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  • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
  • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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  • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
  • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
  • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
  • C07F7/1804—Compounds having Si-O-C linkages

Definitions

• This invention relates to the inhibition of histone deacetylase. More particularly, the invention relates to compounds and methods for inhibiting histone deacetylase enzymatic activity.
• chromatin 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 ⁇ , ⁇ -amino groups of / ⁇ terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HAT1). Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure.
• HAT1 histone acetyl transferase
• Taunton et a/. Science, 272: 408-411 (1996), teaches that access of transcription factors to chromatin templates is enhanced by histone hyperacetylation.
• Taunton et a/ 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).
• HDACs histone deacetylases
• 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. [0006] Richon et al., Proc. Nati. Acad. Sci.
• TSA trichostatin A
• SAHA suberoylanilide hydroxamic acid
• HDAC inhibition 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.
• few inhibitors of histone deacetylase are known in the art.
• BRIEF SUMMARY OF THE INVENTION [0009] 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 -CH 3 , -F, or -OCH 3 can be tolerated to a certain extent.
• 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.
• the present invention provides new compounds and methods for treating cell proliferative diseases.
• the invention provides new inhibitors of histone deacetylase enzymatic activity.
• the invention provides compounds that are useful as inhibitors of histone deacetylase.
• 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.
• 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.
• Fig. 2 displays antineoplastic effects of a histone deacetylase inhibitor in A549 human lung cancer using compound 29.
• Fig. 3 displays antineoplastic effects of a histone deacetylase inhibitor in SW48 human colorectal cancer using compound 29.
• Fig. 4 displays antineoplastic effects of a histone deacetylase inhibitor in W48 human colorectal cancer usingcompound 67.
• Fig. 5 displays antineoplastic effects of a histone deacetylase inhibitor in A549 human lung cancer using compound 258aa.
• Fig. 6 displays antineoplastic effects of a histone deacetylase inhibitor in A549 human lung cancer using compound 43.
• Fig. 7 displays antineoplastic effects of a histone deacetylase inhibitor in A431 vulval carcinoma using compound 43.
• Fig. 8 displays antineoplastic effects of a histone deacetylase inhibitor in A431 vulval carcinoma using compound 258aa.
• Fig. 9 displays antineoplastic effects of a histone deacetylase inhibitor in hctl 16 human colorectal cancer using compound 258aa.
• Fig. 10 displays antineoplastic effects of a histone deacetylase inhibitor in colo205 human colorectal cancer using compound 29.
• 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.
• histone deacetylase and "HDAC” are intended to refer to any one of a family of enzymes that remove acetyl groups from the ⁇ -amino groups of lysine residues at the N-terminus of a histone. Unless otherwise indicated by context, the term “histone” is meant to refer to any histone protein, including HI, H2A, H2B, H3, H4, and H5, from any species. Preferred histone deacetylases include class I and class II enzymes.
• the histone deacetylase is a human HDAC, including, but not limited to, HDAC-1 , HDAC-2, HDAC-3, HDAC4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-10, and HDAC-11.
• the histone deacetylase is derived from a protozoal or fungal source.
• 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%.
• 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.
• 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.
• 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., -CH 2 -CH 2 -), which is equivalent to the term “alkylene.”
• alkyl a divalent radical
• aryl a divalent moiety that is required and is stated as being “aryl”
• All atoms are understood to have their normal number of valences for bond formation [i.e., 4 for carbon, 3 for N, 2 for 0, and 2, 4, or 6 for S, depending on the oxidation state of the S).
• a moiety may be defined, for example, as (A) a -B-, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B- and when a is 1 the moiety is A-B-.
• reference to a "C Intel-C m " heterocyclyl or “C Intel-C m “ heteroaryl means a heterocyclyl or heteroaryl having from “n” to "m” annular atoms, where "n” and "m” are integers.
• a C 5 -C 6 -heterocyclyl is a 5- or 6- membered ring having at least one heteroatom, and includes pyrrolidinyl (C 5 ) and piperidinyl (C 6 );
• C 6 -hetoaryl includes, for example, pyridyl and pyrimidyl.
• hydrocarbyl refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, each as defined herein.
• a “C 0 " hydrocarbyl is used to refer to a covalent bond.
• C 0 -C 3 - hydrocarbyl includes a covalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl, propynyl, and cyclopropyl.
• alkyl 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 "C 0 " alkyl (as in "C 0 -C r alkyl") is a covalent bond (like "C 0 " hydrocarbyl).
• 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.
• 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.
• alkylene is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
• Preferred alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
• Preferred alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene.
• Preferred alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.
• 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.
• 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 0, S, and N.
• An "aryl” group is a C 6 -C ⁇ aromatic moiety comprising one to three aromatic rings, which is optionally substituted.
• the aryl group is a C 6 -C ⁇ 0 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.
• the aralkyl group is including, without limitation, benzyl, phenethyl, and naphthylmethyl.
• a “heterocyclic” group 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, 0, 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.
• the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group.
• fused heterocycles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the scope of this term are compounds where an annular 0 or S atom is adjacent to another 0 or S atom.
• the heterocyclic group is a heteroaryl group.
• 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, 0, and S.
• 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 C ⁇ -C 6 alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms.
• Specifically excluded from the scope of this term are compounds having adjacent annular 0 and/or S atoms.
• heteroaralkyl groups examples 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-1 ,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H- indazolyl, indo
• a moiety e.g., cycloalkyl, hydrocarbyl, aryl, heteroaryl, heterocyclic, urea, etc.
• a moiety e.g., cycloalkyl, hydrocarbyl, aryl, heteroaryl, heterocyclic, urea, etc.
• the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents.
• Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(O)-) nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.
• Preferred substituents which are themselves not further substituted (unless expressly stated otherwise) are: (a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, (b) C 1 -C 5 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, C ⁇ -C 8 alkyl, C ⁇ -C 8 alkenyl, C ⁇ -C 8 alkoxy, C ⁇ -C 8 alkoxycarbonyl, aryloxycarbonyl, C 2 -C 8 acyl, C 2 -C 8 acylamino, C ⁇ -C 8 alkylthio, arylalkylthio, arylthio, C ⁇ -C 8 alkylsulfinyl, arylalkylsulfinyl,
• substituents on cyclic moieties 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.
• an optionally substituted phenyl includes, but not limited to, the following:
• halohydrocarbyl is a hydrocarbyl moiety in which from one to all hydrogens have been replaced with one or more halo.
• halogen or “halo” as employed herein refers to chlorine, bromine, fluorine, or iodine.
• acyl refers to an alkylcarbonyl or arylcarbonyl substituent.
• acylamino refers to an amide group attached at the nitrogen atom [i.e., R-CO-NH-).
• carbbamoyl refers to an amide group attached at the carbonyl carbon atom (i.e., NH 2 -C0-).
• the nitrogen atom of an acylamino or carbamoyl substituent is additionally substituted.
• sulfonamido refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom.
• amino is meant to include NH 2 , alkylamino, arylamino, and cyclic amino groups.
• ureido refers to a substituted or unsubstituted urea moiety.
• 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.
• substituted phenyls include 2-flurophenyl, 3,4-dichlorophenyl, 3-chloro4-fluoro-phenyl, 2-fluoro-3-propylphenyl.
• substituted ⁇ foctyls include 2,4 dimethyl-5-ethyl-octyl and 3-cyclopentyl- octyl. Included within this definition are methylenes (-CH 2 -) 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.
• an "aryl” includes phenyl and phenyl substituted with a halo
• "unsubstituted aryl” does not include phenyl substituted with a halo.
• 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.
• esters for carboxy include C ⁇ - 6 -alkoxymethyl esters (e.g., methoxymethyl), C ⁇ - 6 -alkanoyloxymethyl esters [e.g., for example pivaloyloxymethyl), phthalidyl esters, C 3 - ⁇ -cycloalkoxycarbonyloxyC ⁇ - 6 -alkyl esters (e.g., 1-cyclohexylcarbonyloxyethyl); l,3-dioxolen-2- onylmethyl esters (e.g., 5-methyl-l ,3-dioxolen-2-onylmethyl; and C ⁇ - 6 -alkoxycarbonyloxyethyl esters (e.g., 1-methoxycarbonyloxyethyl) and may be formed at any carboxy group in the compounds of this invention.
• C ⁇ - 6 -alkoxymethyl esters e.g., methoxymethyl
• An in vivo hydrolyzable ester of a compound of the invention containing a hydroxy group includes inorganic esters such as phosphate esters and a-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
• inorganic esters such as phosphate esters and a-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
• ⁇ -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 ⁇ H ⁇ /,/ ⁇ r-dialkylaminoethyl)- ⁇ r-alkylcarbamoyl (to give carbamates), N,N- dialkylaminoacetyl and carboxyacetyl.
• 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 /V-C ⁇ - 6 -alkyl or N,N-di-C ⁇ - 6 -alkyl amide such as N-methyl,V-ethyl, /V-propyl, N,/V-dimethyl, ethyl-N-methyl or ,/V-diethyl amide.
• the invention comprises the histone deacetylase inhibitors of formula
• Ar 2 is a saturated or mono- or poly- unsaturated C 5 -C ⁇ -mono- or fused poly- cyclic hydrocarbyl, optionally containing one, two, three, or four annular heteroatoms per ring optionally substituted with one or more groups selected from C ⁇ -C r alkyl, hydroxy, Ci-Cralkoxy, halo, and amino, provided that an annular 0 or S is not adjacent to another annular 0 or S; R 5 and R 6 are independently selected from the group consisting of hydrogen, C ⁇ -C r alkyl, aryl, and aralkyl; R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, -NH 2 , nitro, hydroxy, aryl, heterocyclyl, CrC ⁇ -cycloalkyl, heteroaryl, Ci-Crakyl, haloalkyl, CrCy- alkenyl, C ⁇ -C r al
• the atoms that comprise the Y moiety are preferably those found in pharmaceuticals, including, but not limited to, H, C, N, 0, S, F, CI, Br, I, and P. Numerous representative examples of Y are displayed in paragraphs [0061] - [0095], [0105] - [0106], and [0111] - [0148].
• 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 03/087057, WO 03/076422, WO 03/024448, US 6,174,905, JP 11-269146 (1999), JP 11-302173 (1999), JP 2001131130, EP 0847992, JP 10152462, JP 2002332267, JP 11302173, and JP 2003137866.
• R 1 is an aryl selected from phenyl, naphthyl, anthracenyl, and fluorenyl. In another preferred embodiment, R 1 is a heteroaryl selected from those recited in paragraph [0045].
• Other preferred R 1 moieties include azolyls (e.g., thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, etc.), pyridyl, and pyridinyl. More preferably, R 1 is furanyl or thienyl.
• R 2 , R 3 , and R 4 are all hydrogen. Also preferred are compounds in which ⁇ is -NH 2 or OH.
• Y is Cy ⁇ X 1 -, wherein Cy 2 is hydrogen, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted and each of which is optionally fused to one or two aryl or heteroaryl rings, or to one or two saturated or partially unsaturated cycloalkyl or heterocyclic rings, and wherein any of the aforementioned rings are optionally substituted; and X 1 is selected from the group consisting of a covalent bond, MM M 1 , and L 2 -M 2 -L 2 wherein L 2 , at each occurrence, is independently selected from the group consisting of a chemical bond, Co-C 4 -hydrocarbyl, C 0 -C -hydrocarbyHNH)-Co-C 4 -hydrocarbyl, C 0 -C -hydrocarbyKS)- Co-C 4
• the optional substituents of Cy 2 are selected from C ⁇ -C r alkyl, halo, di-Ci-Cralkylamino-Ci-Cralkoxy and heteroaryl.
• X 1 is a chemical bond.
• X 1 is L 2 -M 2 -L 2
• M 2 is selected from the group consisting of -NH-, -N(CH 3 h -S-, -C(0)-N(H and -0-C(0rN(Hk)
• X 1 is L 2 -M 2 -L 2 , where at least one occurrence of L 2 is a chemical bond.
• X 1 is L 2 -M 2 -L 2 , where at least one occurrence of L 2 is alkylene, preferably methylene.
• X 1 is L 2 -M 2 -L 2 , where at least one occurrence of L 2 is alkenylene.
• X 1 is M4 M 1 and M 1 is selected from the group consisting of -NH-, -N(CH 3 )-, -S-, and -C(0)-N(H Preferred X 1 are selected from methylene, aminomethyl, and thiomethyl.
• Cy 2 is aryl or heteroaryl, e.g., phenyl, pyridyl, imidazolyl, or quinolyl, each of which optionally is substituted.
• Cy 2 is heterocyclyl, e.g., each of which optionally is substituted and optionally is fused to one or more aryl rings.
• Cy 2 has from one and three substituents independently selected from the group consisting of alkyl, alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy. Examples of preferred substituents include methyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, nitro, amino, aminomethyl, and hydroxymethyl.
• Cy 2 is phenyl, pyrimidinyl, benzimidazolyl or benzothiazolyl, each optionally substituted with one to three CH 3 O-, dimethylamnio-ethoxy, chloro, fluoro and pyridinyl. In a more preferred embodiment, Cy 2 is phenyl substituted with one to three CH 3 0-.
• Y is (V'-L -V-L 3 -, wherein L 3 is a direct bond, -C ⁇ -C 6 -hydrocarbyl, -(C ⁇ -C r hydrocarbyl) ml -X'-(C ⁇ -C 3 - hydrocarbyl) m2 , -N HCo- C 3 -hydrocarbyl), (C 1 -C 3 - hydrocarbylMMH-, or -NH-tCi-Ca- hydrocarbylHNH-; ml and m2 are independently 0 or 1; X' is -N(R 21 K -C(0)N(R 21 )-, N(R 21 )C(0K -0-, or -S-; R 21 is -H, V"-(Ci-C 6 -hydrocarbyl) a ; L 4 is (C ⁇ -C 6 -hydrocarbyl) a
• Y is V-L 3 , wherein L 3 is -NH-CH- or -CH-NH-; V is phenyl optionally substituted with from 1 to 3 moieties independently selected from halo, hydroxy, C ⁇ -C 6 -hydrocarbyl, Ci-Ce-hydrocarbyl-oxy or -thio (particularly methoxy or methylthio), wherein each of the hydrocarbyl moieties are optionally substituted with one or more moieties independently selected from halo, nitro, nitroso, formyl, acetyl, amino, sulfonamido, and cyano.
• V is an optionally substituted ring moiety selected from:
• Y is selected from:
• X 1 is selected from -CH 2 -, -NH-CH 2 -, and -S-CH 2 -; and Cy 2 is monocyclic or fused bicyclic aryl or heteroaryl optionally substituted with one to three substituents selected from CH 3 -, CH 3 0-, phenyl optionally substituted with one to three CH 3 O-, morphylinyl, morphylinyl-C ⁇ -C 3 -alkoxy, cyano, and CH 3 C(0)NH-.
• X 1 is selected from -0CH 2 , -CH 2 0-, -CH 2 -NH 2 -, and -CH 2 S-; and Cy 2 is monocyclic or fused bicyclic aryl or heteroaryl optionally substituted with one to three substituents selected from CH 3 -, CH 3 O-, phenyl optionally substituted with one to three CH 3 O-, morphylinyl, morphylinyl-Ci-C r alkoxy, cyano, and CH 3 C(0)NH-.
• Cy 2 is phenyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, thienyl, tetrahydroquinozolinyl, or l,3-dihydroquinazoline-2,4-dione, each optionally substituted with one to three CH 3 O-. More preferably, Cy 2 is phenyl substituted with one to three CH 3 0-.
• Cy 2 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which optionally is substituted, and each of which optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings optionally is substituted, provided that when Cy 2 is a cyclic moiety having -C(0K -C(S)-, -S(0K or -S(0) 2 - in the ring, then Cy 2 is not additionally substituted with a group comprising an aryl or heteroaryl ring; and X 1 is selected from the group consisting of a chemical bond, L 3 , W 1 -!.
• X 2 is selected from the group consisting of L 3 , W ] -L 3 , LAW 1 , WM W 1 , and L ⁇ W 1 --. 3 .
• X 1 is a chemical bond.
• X 1 is a non-cyclic hydrocarbyl.
• X 1 is alkylene, preferably methylene or ethylene.
• X 1 is alkenylene.
• one carbon in the hydrocarbyl chain is replaced with -NH- or -S-, and in others with a -0-.
• X 1 is W'-U /V 1 and W 1 is -NH- or -N(CH 3 [0077]
• Cy 2 is cycloalkyl, preferably cyclohexyl.
• Cy 2 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.
• Cy 2 is fused to a benzene ring.
• Cy 2 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.
• K 1 is a chemical bond or C ⁇ -C alkylene
• R 10 is selected from the group consisting of Z' and -Ak 2 -Z', wherein Ak 2 is C ⁇ -C alkylene
• T is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which optionally is substituted, and each of which optionally is fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings.
• Cy 2 is heterocyclyl, e.g.,
• each o which optionally is substtuted and tionally is fused to one or more aryl rings.
• the heterocycle of Cy 2 is fused to a benzene ring.
• Cy 2 - X 1 - is collectively selected from the group consisting of a) D 1 -E 1 -F 1 -, wherein Di is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein Ei is -CH 2 - or a covalent bond; and wherein Fi is a covalent bond; b) D r E 2 -F 2 -, wherein D 2 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E 2 is -NH(CH 2 ) 0 - 2 -; and wherein F 2 is a covalent bond; c) D 3 -E 3 -F 3 -, wherein D 3 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E 3 is -(CH 2 )o- 2 NH-
• R 2 to R 4 are independently hydrogen, -NH 2 , nitro, furanyl, chloro, fluoro, butyl, trifluoromethyl, bromo, thienyl, phenyl, -CHCHC(0HNH 2 , -C ⁇ CCH 2 -R 9 wherein R 9 is hydrogen, C ⁇ -C 7 -alkyl, hydroxy, amino, or C r C 7 - alkoxy.
• q is 0 and X 1 is independently selected from the group consisting of -NH-CH 2 -, -S-CHr and -CH r .
• q is 0 and X 1 is independently selected from the group consisting of -0CH 2 , -CH 2 0-, -
• G at each occurrence, is independently N or C, and C is optionally substituted.
• G at each occurrence is C(R 8 ), wherein R 8 is selected from the group consisting of hydrogen and Cj-Cralkyl. In some more preferred embodiments, G is -CH-.
• the compounds according to paragraph [0085] are those wherein Ar 2 is selected from the group consisting of phenylene, benzofuranylene and indolinylene.
• Ar 2 is selected from the group consisting of phenylene, benzofuranylene and indolinylene.
• Cy 2 is aryl or heteroaryl, each of which is optionally substituted. More preferably, Cy 2 is phenyl, pyrimidinyl, benzimidazolyl or benzothiazolyl, each of which is optionally substituted.
• Preferred substituents of Cy 2 are from one to three substituents independently selected from the group consisting of Ci-Cralkyl, C ⁇ -C 7 -alkoxy, halo, di-Ci-Cr alkylamino-Ci-Cralkoxy and heteroaryl. More preferably, the substituents of Cy 2 are selected from methyl, methoxy, fluoro, chloro, pyridinyl and dimethylamino-ethoxy. [0089] In some preferred embodiments, the moiety formed by Cy 2 -X ! is selected from the following:
• the compounds according to paragraph [0090] are those in which Cy 2 is selected from:
• the A ring is not further substituted.
• R 2 and R 3 are both -H.
• the invention comprises compounds of the general formula (3):
• ⁇ is -NH 2 or -OH
• Ring A is a heterocyclyl, wherein if said heterocyclyl contains an -NH- moiety that nitrogen is optionally substituted by a group selected from K
• R 5 is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ - 6 -alkyl, C 2 - 6 - alkenyl, C 2 - 6 -alkynyl, d- ⁇ -alkoxy, C ⁇ - 6 -alkanoyl, C ⁇ - 6 -alkanoyloxy, ⁇ KC ⁇ - 6 -alkyl)amino, /V, ⁇ KC ⁇ - 6 -alkyl) 2 amino, C ⁇ - 6 -alkan
• R 1 , R 2 , R 3 , and R 4 are as defined in paragraphs [0059] and [0060].
• the compounds according to paragraph [0094] are the compounds of WO 03/087057, particularly those of Tables 1- 8 and 13, modified by replacing the terminal moiety:
• Alkyl includes both straight and branched chain alkyl groups.
• “Ci-s-alkyl” and “C ⁇ - 6 -alkyl” includes methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, and t-butyl.
• 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.
• halo refers to fluoro, chloro, bromo and iodo.
• 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).
• 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).
• heterocyclyl examples and suitable values of the term "heterocyclyl” are thiazolidinyl, pyrrolidinyl, 1,3-benzodioxolyl, 1 ,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl, morpholinyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, pyrrolyl, pyrazolyl, oxadiazolyl, tetrazolyl, oxazolyl, thienopyrimidinyl, thienopyridinyl, thieno ⁇ 3,2d]pyrimidinyl, 1,3,5-triazinyl, purinyl, 1 ,2,3,4-tetrahydroquinolinyl,
• 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 CH 2 group is optionally replaced by a C(O), and wherein a ring sulphur atom is optionally oxidized to form the S- oxide(s).
• 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 CH 2 group is optionally replaced by a C(0), and wherein a ring sulphur atom is optionally oxidized to form S-oxide(s).
• heterocyclic group examples and suitable values of the term "heterocyclic group" are pyrrolidinyl, 2-pyrrolidonyl 2,5-dioxopyrrolidinyl, 2,4- ioxoimidazolidinyl, 2-oxo-l,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-dioxola ⁇ yl, homopiperazinyl, thioph
• C ⁇ - 6 -alkanoyloxy is acetoxy.
• C ⁇ - 8 -alkoxycarbonyl examples include methoxycarbonyl, ethoxycarbonyl, N- and t- butoxycarbonyl.
• Examples of C 2 - 6 -alkynyl are ethynyl and 2-propynyl.
• Examples of "C ⁇ - 6 -alkoxy” include methoxy, ethoxy and propoxy.
• C ⁇ - 6 -alkanoylamino and C ⁇ - 3 -alkanoylamino include formamido, acetamido and propionylamino.
• Examples of u C ⁇ - 6 -alkylS(O) a wherein a is 0 to 2" include Ci-e-alkylsulphonyl, Ci- 3 -alkylS(0) a , methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsuiphonyl.
• C ⁇ - 8 -alkanoyl examples include C ⁇ - 3 -alkanoyl, propionyl and acetyl.
• Examples of "N-C ⁇ - 6 -alkylamino” and l ⁇ HC ⁇ - 3 -alkyl)amino include methylamino and ethylamino.
• N,/ ⁇ HC ⁇ - 6 -alkyl) 2 amino and N,N-(C ⁇ - 2 -alkyl) 2 amino include di-N-methylamino, dH -ethyDamino, dHN-butyl)amino and N-ethyl- -methylamino.
• Examples of “Crs-alkenyl” are C ⁇ - 6 - alkenyl and C 2 - 3 -alkenyl, and include vinyl, allyl, and 1-propenyl.
• Examples of and "WCi 5 alkyl)sulphamoyl” are WC.- 3 -alkyl)sulphamoyl, WmethyDsulphamoyl and - (ethyl)sulphamoyl.
• Examples of "WCre-alkyD ⁇ sulphamoyl” are N,WC ⁇ - 3 -alkyl) 2 sulphamoyl, N,N- (dimethyl)sulphamoyl and Wmethyl)-N-(ethyl)sulphamoyl.
• N-(C ⁇ - 8 -alkyl)carbamoyl and “N- (Ci- 6 -alkyl)carbamoyl” are WC ⁇ - -alkyl)carbamoyl, WCi-ralkyDcarbamoyl, methylaminocarbonyl, and ethylaminocarbonyl.
• N,WC ⁇ -s-alkyl) 2 carbamoyr and “N,l ⁇ KC ⁇ - 6 -alkyl) 2 carbamoyl” are N,WC ⁇ - -alkyl) 2 carbamoyl, N,WC ⁇ -ralkyl) 2 carbamoyl, dimethylaminocarbonyl and methylethylaminocarbonyl.
• Examples of "(heterocyclic group)C ⁇ - 6 -alkyl” include piperidin-1-ylmethyl, piperidin-1-ylethyl, piperdin-1-ylpropyl, pyridylmethyl, 3-morpholinopropyl, 2-morpholinoethyl and 2- pyrimid-2-ylethyl.
• Examples of "(heterocyclic group)C ⁇ - 6 -alkoxy” include (heterocyclic group)methoxy, (heterocyclic group)ethoxy and (heterocyclic group)propoxy.
• Examples of "arylC ⁇ - 6 -alkyl” include benzyl, 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl.
• Examples of "aryloxy” include phenoxy and naphthyloxy.
• Examples of "C 3 - 8 -cycloalkyr include cyclopropyl and cyclohexyl.
• C 3 -s cycloalkylC ⁇ - 6 -alkyl
• C ⁇ - 6 - alkoxycarbonylamino examples include methoxycarbonylamino and t-butoxycarbonylamino.
• Composite terms are used to describe groups comprising more than one functionality such as arylC ⁇ - 4 -alkyl. Such terms are to be interpreted as is understood by a person skilled in the art.
• arylC ⁇ - 6 -alkyl comprises C ⁇ - 6 -alkyl substituted by aryl and such a group includes benzyl, 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl.
• the invention comprises compounds of the following general formula (4):
• N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof wherein ⁇ is -NH 2 or -OH; n is 0,1 , 2 or 3, wherein when n is 0 then a direct bond is intended; t is 0, 1 , 2, 3 or 4, wherein when t is 0 then a direct bond is intended; Q, X, Y, and Z are independently N or CH; R 1 is H or as defined in paragraph [0057], R 2 , R 3 , and R 4 are as defined in paragraph [0057]; R 12 is hydrogen, halo, hydroxy, amino, nitro, C ⁇ - 6 -alkyl, C 6 -alkyloxy, trifluoromethyl, di(C ⁇ - 6 - alkyDamino, hydroxyamino and naphthalenylsulfonylpyrazinyl; -L- is a direct bond or a bivalent radical selected from C ⁇ - 6 -alkanediyl
• each s is independently 0, 1, 2, 3, 4 or 5;
• R 5 and R 6 are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloCre- alkyl; trihaloC r6 -alkyloxy; C ⁇ - 6 -alkyl; C ⁇ - 6 -alkyl substituted with aryl and C ⁇ o-cy oalkyl; Ci-e- alkyloxy; Cr 6 -alkyloxyC ⁇ - 6 -alkyloxy; C ⁇ - 6 -alkylcarbonyl; C ⁇ - 6 -alkyloxycarbonyl; C ⁇ - 6 - alkylsulfonyl; cyanod- 6 -alkyl; hydroxyC ⁇ - 6 -alkyl; hydroxyC ⁇ - 6 -alkyloxy; hydroxyC ⁇ - 5 - alkylamino; aminoC ⁇ - 6 -alkyloxy; di(d- 6 -alkyl
• R 1 , R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0059] and [0060]. In other embodiments of the compounds of paragraph [0105], R ⁇ R 2 , R 3 , and R 4 are all H.
• Other preferred embodiments of the compounds of paragraph [0105] include the compounds of pages 21 and 22 and Table F-1 of WO 03/076422 in which the terminal hydroxamic acid moiety (HO-NH-C(O)- ) is replaced with
• paragraph [0107] the definitions in paragraphs [0108] - [0110] supplement the definitions in paragraphs [0031] - [0053]. To the extent there are any inconsistencies between the definitions in paragraphs [0031] - [0053] and in paragraphs [0108] - [0110], the definitions in paragraphs [0108] - [0110] take precedence for the compounds of paragraph [0105] only.
• Halo is generic to fluoro, chloro, bromo and iodo
• C ⁇ - 4 -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
• C ⁇ - 6 -alky includes C ⁇ - -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
• d- 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-pentaned
• N-oxide forms of the compounds of paragraph [0105] comprise those compounds wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N- oxides wherein one or more of the piperidine-, piperazine or pyridazinyl-nitrogens are N-oxidized.
• the invention comprises compounds of the following structural formula (5):
• ⁇ is -NH 2 or -OH
• R 1 is H or as defined in paragraph [0046]
• R 2 , R 3 , and R 4 are as defined in paragraph [0046]
• n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended:
• Q is nitrogen or ⁇ , ⁇ , or ⁇
• X is nitrogen or ⁇
• R 12 is hydrogen, halo, hydroxy, amino, nitro, trifluoromethyl, di(Ci.6aJkyl)amino, hydroxyamino ornaphtalenylsulfonylpyrazinyl;
• )13 is hydrogen, Ci-galkyl, arylC2.6alkenediyl, furanylcarbonyl, naphtalenylcarbonyl, -C(O)phenylR 9 , aminosulfonyl, arylaminosulfonyl, aminosulfonyla ino, di(C ⁇ alkyl)aminosulfonylarnino, arylaminosulfonylarnino, di(C ⁇ . 6 alkyl)arninosulfonylaminoC alkyl, arylaminosulfonylaminoCi- ⁇ alkyl.
• each R 9 is independently selected from phenyl; phenyl substituted with one, two or three substituents independently selected from halo, amino, C ⁇ alkyl, C ⁇ _ 6 alkyloxy, hydroxyC alkyl, hydroxyC 1 .
• R 14 is hydrogen, hydroxy, amino, hydroxyCi-ealkyl, arylC ⁇ . 6 aJkyl, aminocarbonyl, hydroxycarbonyl, aminoCi ⁇ alkyl, aminocarbonylCi- ⁇ alkyl, hydroxycarbonylCi. ⁇ alkyl, hydroxyaminocarbonyl, C ⁇ . 6 alkyloxycarbonyl, Ci-ealkylaminoCi-ealkyl or di(C ⁇ .ealkyl)aminoC ⁇ .
• Particular embodiments of the compound according to paragraph [0111] include the following
• R 1 , R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0059] and [0060], while in other embodiments of the compounds of paragraphs [0111] -[0112], R ⁇ R 2 , R 3 , and R 4 are all H.
• the invention comprises compounds of the following structural formula (6):
• ⁇ is -NH 2 or -OH;
• R 1 is H or as defined in paragraph [0046];
• R 2 , R 3 , and R 4 are as defined in paragraph [0046];
• n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended;
• m is 0 or 1 and when m is 0 then a direct bond is intended;
• t is 0, 1, 2, 3 or 4 and when t is 0 then a direct bond is intended;
• X Q is nitrogen or -CR -CH.
• X is nitrogen or
• Y is nitrogen or ⁇ ;
• R is selected from the group consisting of hydrogen, halogen, -NH 2 , nitro, hydroxy, aryl, heterocyclyl, C 3 -Cs-cycloalkyl, heteroaryl, Ci-d-akyl, haloalkyl, d-d-alkenyl, C ⁇ -C -alkynyl, Ci-Cracyl, d-C 6 - alkyl-aryloxy, d-d-alkyl-arylsulfanyl, Ci-C ⁇ alkyl-arylsulfinyl, C ⁇ -C 7 -al kyl-aryl su If onyl , C ⁇ -C 7 -alkyl- arylaminosulfonyl, C ⁇ -C 7 -alkyl-arylamine, Ci-C 7 -alkynyl-C(0)-amine, Ci-C r alkenyl-C(0)-amine, C ⁇ -C 7 - alkynyl-R 9 ,
• -L- is a direct bond or a bivalent radical selected from Ci ⁇ alkanediyl, C ⁇ _6alkanediyloxy, amino, carbonyl or aminocarbonyl; each R 13 is independently represents a hydrogen atom and one hydrogen atom can be replaced by a substituent selected from aryl; R 14 is hydrogen, hydroxy, amino, hydroxyC ⁇ .
• R 15 is hydrogen, Ct- ⁇ alkyloxyCi-ealkyl, or aryl;
• each s is independently 0, 1, 2, 3, 4 or 5; each R 6 and R 7 are independently selected from hydrogen; halo; hydroxy, amino; nitro; trihaloC substituted with aryl and C 3 . 10 cycloa.kyl; C ⁇ - 6 alkyloxy; C ⁇ . 6 alkyloxycarbonyl; Ci ⁇ alkylsulfonyl; cyanoC ⁇ _$alkyl; hydroxyCi-ealkyl; hydroxyCi-ealkyloxy; aminoCi- ⁇ alkyloxy; di(C ⁇ - 6 alkyl)aminocarbonyl; di(hydroxyC ⁇ .
• each R 6 and R 7 can be placed on the nitrogen in replacement of the hydrogen;
• aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, trifluoromethyl, cyano or hydroxycarbonyl.
• the invention comprises compounds of the following structural formula (7):
• ⁇ is -NH 2 or -OH;
• R 1 is H or as defined in paragraph [0046];
• R 2 , R 3 , and R 4 are as defined in paragraph [0046];
• n 0, 1, 2 or 3 and when n is 0 then a direct bond is intended;
• t is 0, 1, 2, 3 or 4 and when t is 0 then a direct bond is intended; is nitrogen or ⁇ ⁇ ⁇ *
• X is nitrogen or ⁇ ;
• Y is nitrogen or ⁇ ;
• —CSX' Z is nitrogen or ;
• R is selected from the group consisting of hydrogen, halogen, -NH 2 , nitro, hydroxy, aryl, heterocyclyl, CrCs-cycloalkyl, heteroaryl, d-Crakyl, haloalkyl, Ci-Cralkenyl, d-Cr alkynyl, Ci-Cracyl, Ci-Cralkyl-aryloxy, C ⁇ -C ⁇ -alkyl-arylsulfanyl, Ci-Cr-alkyl-arylsulfinyl, C ⁇ -C ⁇ -alkyl-arylsulfonyl, C ⁇ -C ⁇ -alkyl-arylaminosulfonyl, d-C 7 -alkyl-arylamine, C ⁇ -C 7 - alkynyl-C(0)-amine, d-C 7 -alkenyl-C(0)-amine, d-C 7 -alkynyl-R 9 , Ci-Cralkenyl-R 9
• R 12 is hydrogen, halo, hydroxy, amino, nitro, C ⁇ -6alkyl, trifluoromethyl, difC ⁇ alk ⁇ l)amino, hydroxyamino ornaphtalenylsulfonylpyrazinyl;
• -L- is a direct bond or a bivalent radical selected from Ci-galkanediyl, Ci ⁇ alkyloxy, amino, carbonyl or aminocarbonyl;
• each R 13 independently represents a hydrogen atom and one hydrogen atom can be replaced by a substituent selected from aryl;
• R 14 is hydrogen, hydroxy, amino, hydroxyC ⁇ . 6 alkyl, Ci ⁇ alkyl, Ci ⁇ alkyloxy, arylC ⁇ . 6 alky], aminocarbonyl, hydroxycarbonyl, aminoCi-ealkyl, aminocarbonylC ⁇ . 6 all yl, hydroxycarbonylCi- ⁇ alkyl, hydroxyaminocarbonyl, Ci-ealkyloxycarbonyl,
• - ⁇ is a radical selected from
• each s is independently 0, 1, 2, 3, 4 or 5; each R 5 and R 6 are independently selected from hydrogen; halo; hydroxy; ami o; nitro; trihaloC ⁇ . 6 alkyl; trihaloC ⁇ alkyloxy; Ci ⁇ alkyl; C h lky!
• each R 5 and R 6 can be placed on the nitrogen in replacement of the hydrogen; aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, trifluoromethyl, cyano or hydroxycarbonyl.
• R 1 , R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0059] and [0060]. In other embodiments of the compounds of paragraphs
• R ⁇ R 2 , R 3 , and R 4 are all H.
• the invention comprises compounds of the following structural formula (8):
• ⁇ is -NH 2 or -OH
• R 1 is H or as defined in paragraph [0046]
• R 2 , R 3 , and R 4 are as defined in paragraph [0046]
• n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended
• t is 0, 1 , 2, 3 or 4 and when t is 0 then a direct bond is intended
• / Q is nitrogen or - ⁇ - C C R R "CH. ⁇ or
• X is nitrogen or - ⁇ .
• Y is nitrogen or ⁇ ;
• R is selected from the group consisting of hydrogen, halogen, -NH 2 , nitro, hydroxy, aryl, heterocyclyl, C 3 -C 8 -cycloalkyl, heteroaryl, Ci-Crakyl, haloalkyl, Ci-C r alkenyl, C ⁇ -C 7 -alkynyl, Ci-Cracyl, Ci-Cr alkyl-aryloxy, C ⁇ -C 7 -alkyl-arylsulfanyl, C 1 -C 7 — alkyl-arylsulfinyl, d-C 7 -alkyl-arylsulfonyl, C ⁇ -C -alkyl- arylaminosulfonyl, C ⁇ -C ⁇ -alkyl-arylamine, d-C 7 -alkynyl-C(0)-amine, d-Cralkenyl-Cr ⁇ r-amine, C 1 -C 7 - alkynyl-R
• R 12 is hydrogen, halo, hydroxy, amino, nitro, C h alky!, trifluoromethyl, di(C ⁇ alkyl)amino, hydroxyamino or naphtalenylsulfonylpyrazinyl; each R 13 independently represents a hydrogen atom and one hydrogen atom can be replaced by a substituent selected from aryl;
• R 14 is hydrogen, hydroxy, amino, hydroxyC ⁇ _ 6 alkyl, Ci-galkyl, Ci ⁇ alkyloxy, arylC ⁇ _ 6 alkyl, aminocarbonyl, hydroxycarbonyl, aminoC ⁇ . $ alkyl, arninocarbonylC ⁇ . 6 alkyl, hydroxycarbonylCi.galkyl, hydroxyaminocarbonyl,
• R 15 is hydrogen, di(C
• each R 6 and R 7 are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloC ⁇ _ 6 alkyl; substituted with aryl and C 3 - ⁇ ocycloalkyi; Cj-ealkyloxycarb nyl; Ci ⁇ alkylsulfonyl; cyanoCi ⁇ alkyl; hydroxyCi ⁇ alkyl; hydroxyCi-ealkyloxy; hydroxyCi. 6 alkylamino; aminoCi ⁇ alkyloxy; di(C ⁇ .
• Ci-ealkyloxypiperidinyl Ci ⁇ alkyloxypiperidinylCi-fialkyl, mo holinylC ⁇ .6alkyI, hydroxyC ⁇ . 6 alkyl(C 6alkyl)arr noC
• each R 6 and R 7 can be placed on the nitrogen in replacement of the hydrogen;
• aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, Chalky!, trifluoromethyl, cyano or hydroxycarbonyl.
• R ⁇ R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0059] and [0060]. In other embodiments of the compounds of paragraphs
• R 1 , R 2 , R 3 , and R 4 are all H.
• the invention comprises compounds of the following structural formula (9):
• ⁇ is -NH 2 or -OH
• R 1 is H or as defined in paragraph [0046]
• R 2 , R 3 , and R 4 are as defined in paragraph [0046]
• n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended; . .. — C CR CH t Q is nitrogen or ⁇ , ⁇ , or ⁇ i X is nitrogen or ⁇ * ;
• i Y is nitrogen or ⁇ * ;
• -CH: i Z is nitrogen or " -
• R is selected from the group consisting of hydrogen, halogen, -NH 2 , nitro, hydroxy, aryl, heterocyclyl, C 3 -C 8 -cycloalkyl, heteroaryl, Ci-Crakyl, haloalkyl, Ci-Cralkenyl, C ⁇ -C 7 -alkynyl, Ci-Cracyl, C ⁇ -C 7 - alkyl-aryloxy, Ci-Cralkyl-arylsulfinyl, C i-C ⁇ -al kyl-ary I sulfonyl , d-Cr-alkyl- arylaminosulfonyl, Ci-C alkyl-arylamine, Ci-C 7 -alkynyl-C(0)-amine, C ⁇ -C r alkenyl-C(0)-amine, Ci-Cr alkynyl-R 9 , C ⁇ -C r alkenyl-R 9 wherein R 9 is hydrogen , hydroxy,
• R 12 is hydrogen, halo, hydroxy, amino, nitro, trifluoromethyl, di(Ci salkyl)amino, hydroxyamino or naphtalenylsulfonylpyrazinyl;
• R 13 is hydrogen, hydroxy, amino, hydroxyCi ⁇ alkyl, C].ca1k l.
• R 14 is hydrogen, C ⁇ . 6 l yIoxyC ⁇ . 6 alkyl, ⁇ (C ⁇ . 6 al l)arninoC ⁇ . 6 alkyl or aryl; —(A) . v — IS a radical selected from
• each s is independently 0, 1, 2, 3, 4 or 5; each R 5 and R 6 are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloC ⁇ _ 6 alkyl; C ⁇ - 6 alkyl; C ⁇ . 6 alkyl substituted with aryl and C 3 . ⁇ ocycloalkyl; Ci ⁇ alkyloxy; C ⁇ . 6 alkyloxyC 1 . 6 alkyloxy; Ci- ⁇ alkylcarbonyl; Ci ⁇ alkyloxycarbonyl; Ci ⁇ alkylsulfonyl; cyanoC ⁇ alkyl; hydroxyC ⁇ .6alkyl; hydroxyC ⁇ .
• mo ⁇ holinylC ⁇ l ⁇ yl mo ⁇ holinylC ⁇ . 6 alkylarnJno; mo ⁇ holinylC ⁇ .6alkylaminoC ⁇ . 6 alkyl; piperazinyl; Ci- ⁇ alkylpiperazinyl; C ⁇ - 6 alkylr ⁇ perazinylC ⁇ .
• each R 5 and R 6 can be placed on the nitrogen in replacement of the hydrogen; aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, Ci-ealkyl, trifluoromethyl, cyano or hydroxycarbony
• ⁇ , R ⁇ R 2 , R 3 , and R 4 are as defined in accordance with paragraph [0057], and preferably [0059] and [0060].
• R 1 , R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0059] and [0060]. In other embodiments of the compounds of paragraphs [0123] - [0124], R 1 , R 2 , R 3 , and R 4 are all H.
• the invention comprises compounds of the following structural formula (10):
• ⁇ is -NH 2 or -OH;
• R 1 is H or as defined in paragraph [0046];
• R 2 , R 3 , and R 4 are as defined in paragraph [0046];
• ⁇ is 0, 1 , or 3 and when n is 0 then a direct bond is intended;
• m is 0, 1, 2 or 3 and when m is 0 then a direct bond is intended;
• t is 0 or 1 and when t is 0 then a direct bond is intended;
• Q is nitrogen or / • / CR CH ⁇ , or
• X is nitrogen or ⁇ ;
• Y is nitrogen or — c ⁇ C ;
• Z is -CH 2 - or-O-;
• R is selected from the group consisting of hydrogen, halogen, -NH 2 , nitro, hydroxy, aryl, heterocyclyl, d-Cs-cycloalkyl, heteroaryl, C ⁇ -C ⁇ -akyI, haloalkyl, d-C 7 -alkenyl, Ci-d-alkynyl, d-C 7 -acyl, Ci-d- alkyl-aryloxy, C ⁇ -C ⁇ -alkyl-arylsulfonyl, C ⁇ -C ⁇ -alkyl- arylaminosulfonyl, C ⁇ -C ⁇ -alkyl-arylamine, d-C 7 -alkynyl-C(0)-amine, d-C ⁇ -alkenyl-C(0)-ar ⁇ ine, C 1 -C 7 - alkynyl-R 9 , Ci-Cralkenyl-R 9 wherein R 9 is hydrogen , hydroxy, amino, d-C 7 -alkyl
• R 12 is hydrogen, hydroxy, amino, hydroxyCi ⁇ alkyl, Ci ⁇ alkyl, C ⁇ .$alkyloxy, arylCi- ⁇ alkyl, aminocarbonyl, hydroxycarbonyl, aminocarbonylCi_ 6 alkyl, hydroxycarbonylCi. 6 alkyl, hydroxyaminocarbonyl, C
• -L- is a bivalent radical selected from Ci ⁇ alkanediyl, carbonyl, sulfonyl, or Ci. ⁇ alkanediyl substituted with phenyl;
• - ⁇ is a radical selected from (a-1) (a-2) (a-3) (a )
• each s is independently 0, 1, 2, 3, 4 or 5; each R 5 and R 6 are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloCi-galkyl; trihaloCt- ⁇ alkyloxy; Ci ⁇ alkyl; Ci ⁇ alkyl substituted with aryl and C 3 -ioeycloalkyI; C ⁇ - 6 alkyloxy; Ci- G alkylo yCi-ealkyloxy; Ci- ⁇ alkylcarbonyl; hydroxyCj.ealkyl; hydroxyCi ⁇ alkyloxy; hydroxyC). ⁇ alkylamino; aminoC ⁇ _ 6 alkyloxy; di (C ⁇ .( 5 alkyl)ami nocarbonyl ; di(h ydroxyCi _ 6 aIkyl)amino; (aryl)(C i ⁇ alkyl)amino ; di (C i
• C ⁇ _ 6 alkyloxypipcridinyl C
• R 1 , R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0059] and [0060]. In other embodiments of the compounds of paragraphs
• R ⁇ R 2 , R 3 , and R 4 are all H.
• the invention comprises compounds of the following structural formula (11): or a pharmaceutically acceptable salt thereof, wherein ⁇ is -NH 2 or -OH; R 1 is H or as defined in paragraph [0046]; R 2 , R 3 , and R 4 are as defined in paragraph [0046]; t is 0, 1, 2, 3 or 4 and when t is 0 then a direct bond is intended; / ⁇ . . - ⁇ CR CH . Q is nitrogen or ⁇ * , ⁇ , or ⁇ ;
• R 12 is hydrogen, hydroxy, amino, hydroxyC ⁇ . 6 alkyl, C h lky!, Ci-ealkyloxy, arylCi- ⁇ alkyl, aminocarbonyl, hydroxycarbonyl, aminoC ⁇ _ 6 alkyl, aminocarbonylC ⁇ . 6 alkyi, hydroxycarbonylC._ 6 alkyl, hydroxyaminocarbonyl, C ⁇ _ 6 aIkylaminoC I . 6 alkyl or di(C ⁇ _ 6 alkyl)aminoC ⁇ _6alkyl;
• -L- is a bivalent radical selected from -NR 9 C(O , -NR 9 S0 2 - or -NR 9 CH 2 - wherein R 9 is hydrogen, Ci ⁇ gal yl, C 3 - ⁇ ocycloalkyl, hydroxyCi ⁇ alkyl, C ⁇ _ 6 alkyloxyC ⁇ _ 6 aIkyl or di(C ⁇ _ 6 alkyl)aminoC ⁇ alkyl; v» -- is a radical selected from
• each s is independently 0, 1, 2, 3, 4 or 5; each R 5 and R 6 are independently selected from hydrogen; halo; hydroxy; amino; nitro; tr aloCi-ealkyl; trihaloC ⁇ _6alkyloxy; Cj_6alkyl; Ci-ealkyl substituted with aryl and
• Ci- ⁇ alkyloxypiperidinyl Ci- ⁇ alkyloxypipericunylCj-ealkyl, mo ⁇ holinylC ⁇ _ 6 alkyl, hycIroxyC ⁇ - 6 alkyl(C ⁇ . 6 all£yl)aminoC ⁇ .6alkyl, or cu(hyclroxyC ⁇ alkyl)aminoC ⁇ .
• al yl or trihaloCi- ⁇ alkyl pyridinyl; pyridinyl substituted with Ci-galkyloxy, aryloxy or aryl; pyrimidinyl; tetrahydropyri ⁇ udBnylpiperazinyl; tet ⁇ quinolinyl; indole; phenyl; phenyl substituted with one, two or three substituents independently selected from halo, amino, nitro, Ci ⁇ alkyl, Ci-galkyloxy, hydroxyCi_ 4 alkyl, tdfluoromethyl, trifluoromethyloxy, hydroxyCi_4alkyloxy,
• Ci- ⁇ alkylsulfo ⁇ yl C -dkyloxyCi ⁇ alkyloxy, Ci ⁇ alkyloxycarbonyl, aminoCi_ 4 alkyloxy, di(C ⁇ . 4 altyl)arrjinoC ⁇ .
• ⁇ , R ⁇ R 2 , R 3 , and R 4 are as defined in accordance with paragraph [0057], and preferably [0059] and [0060].
• R ⁇ R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0059] and [0060]. In other embodiments of the compounds of paragraphs [0129] - [0130], R ⁇ R 2 , R 3 , and R 4 are all H. [0132] In another embodiment, the invention comprises compounds of the following structural formula (12):
• Ring A is a heterocyclyl, wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from G;
• R 11 is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C h alky., C ⁇ alkenyl, C 2 - 6 alkynyl, Ci-ealkoxy, C ⁇ .
• V including group (D'-E'-) ( may be optionally substituted on carbon by one or more W; W and Z are independendy selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-salkyl, C t ⁇ alkenyl, C_- f ialkynyl, C ⁇ - & alkoxy, C ⁇ alkanoyl, - f ialkanoyloxy, .V-(C ⁇ - 6 aucyl)amino, NN-(C ⁇ _ 5 alkyl) 2 amino, Ci- ⁇ alkanoylamino, N-(Cj- 5 alkyl)carbamoyl, ⁇ W-(C ⁇ .e.a]ky-) 2 carbarnoyl, C ⁇ -
• G, J and K are independently selected from C 2 -galkenyl, C 2 -_alkynyl, Ci- ⁇ alkanoyl, Ci- ⁇ alkylsulphonyl, carbamoyl, AK -s-dkyOcarbarnoyl, N,N-(C]_salkyl)carbamoyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl, aryl, or (heterocyclic grou ⁇ )Cj ..alkyl; wherein G, J and K may be optionally substituted on carbon by one or more Q; and wherein if said heterocyclic group contains an - NH- moiety that nitrogen may be optionally substituted by a group selected from hydrogen or Ct-ealkyl; Q is halo, nitro, cyano, hydroxy
• R a and R are independentiy selected from hydrogen or C ⁇ ._alkyl optionally substituted by one or more F and r is 0-2; F and F' are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 2 .
• Ring B is a ring selected from
• X 1 and X 2 are selected from CH or ⁇
• Y 1 , Y 2 , Y 3 and Y 4 are selected from CH or ⁇ v-2 3 Y
• v J and Y is ⁇
• R 12 is halo
• n is 0, 1, or 2 wherein the values of R 12 are the same or different.
• R 11 is selected from:
• R ⁇ R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0059] and [0060]. In other embodiments of the compounds of paragraph [0132] - [0133], R ⁇ R 2 , R 3 , and R 4 are all H. [0135] In another embodiment, the invention comprises the compounds of WO 03/024448 in which the terminal moieties -Cr ⁇ J-NH-Ay 1 , -C(0)-NH-Ay 2 , -C(OWrW- H 2l and:
• the invention comprises compounds of the following structural formula (13):
• the invention comprises compounds of the following structural formula (14):
• the invention comprises compounds of the following structural formula (15):
• the invention comprises compounds of the following structural formula (16):
• the invention comprises compounds of the following structural formula (17):
• the invention comprises compounds of the following structural formula (18):
• the invention comprises compounds of WOOl/70675 wherein the terminal moiety -C(0HNH0H, -C(0rCH 2 -SC(0)CH 3 , -C(0rCH r SH, -C(0rCH 2 -SCH 3 , -C(0)-CH 2 -SCH 2 -phenyl, -C(0rCH 2 -S-phenyl, -C(0rCH r SC(0)-phenyl and
• ⁇ , R ⁇ R 2 , R 3 , and R 4 are as defined in accordance with paragraph [0057], and preferably [0059] and [0060].
• the invention provides a composition comprising a compound according to any one of paragraphs [0057] - [0095], [0105] - [0106], and [0111] -[0148], 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 [0057] - [0095], [0105] - [0106], and [0111] - [0148] or as depicted in any of the tables herein, or with a composition according to paragraph [0149].
• 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 [0057] - [0095], [0105] - [0106], and [Oi l 1] - [0148] or as depicted in any of the tables herein, or a composition according to paragraph [0149].
• the organism is a mammal, more preferably a human.
• HDAC inhibitors of the invention 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/ FR901228 ASCO Abstract No. 88, 2002).
• SAHA ASCO Abstract No. 2321, 2003
• peripheral T-cell lymphoma depsipeptide/ FR901228 ASCO Abstract No. 88, 2002.
• HDAC-1 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, MA 02140, Namepro version 5.09, which is available from ACD labs, 90 Sydney Street West, Toronto, Ontario, M5H, 3V9, Canada, or were derived therefrom. Table 1
• the compound's HDAC inhibitory activity 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.
• R 1 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 R 1 is not further substituted. In other preferred embodiments, R 1 is substituted with a moiety of from 1-5 atoms, e.g., methyl, hydroxymethyl, halomethyl, halo, hydroxy, amino, etc. In other embodiments, R 1 is substituted with a larger moiety, e.g., from 6-25 atoms.
• HDAC inhibitory activity of such compounds is substantially independent of the identity of the chemical moiety bound to the carbonyl of the amide in paragraph [0057].
• Y is any chemical moiety (preferably physiologically non-reactive) consisting of 1 to 50 atoms.
• 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.
• Step 3 4-[(3,4-Dimethoxy-phenylamino)-methyl]-N-(2-nitro-5-thiophen-2-yl-phenyl)- benzamide (5).
• Step 1 Methyl 2,3-Dihydro-lH-indole-5-carboxylate (20).
• 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.
• Step 3 l-(3,4,5-Trimethoxy-benzyl)-2,3-dihydro-lH-indole-5-carboxylic acid (22).
• a solution of LiOH x H 2 0 (75 mg, 1.78 mmol) in H 2 0 (5ml) 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 IN HCl. A precipitate formed which was collected by filtration, washed with H 2 0 and dried to give the title compound 22 as a white solid, (320 mg, 78%).
• Step 1 Ethyl 5-Methyl-benzofuran-2-carboxylate (25).
• Step 4 Ethyl 5-Formyl-benzofuran-2-carboxylate (27).
• Step 5 5-[(3,4,5-Trimethoxy-phenylamJno)-methyl]-benzofuran-2-carboxylic acid ethyl ester (28).
• Steps 6-8 5-[(3,4,5-Trimethoxy-phenylamino)-methyl]-benzofuran-2-carboxylic acid (2- amino-5-thiophen-2-yl-phenyl)-amide (29)
• Step 2 4-[(3,4-Dimethoxy-phenylamino)-methyl]-N-(3-thiophen-2-yl-phenyl)-benzamide (32).
• Step 3 Methyl 4-[(4-pyridin-3-yl-pyrimidin-2-ylamino)-methyl]-benzoate (41) [0205] 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, 4 ⁇ , powder). The reaction mixture was refluxed for 5h. MeOH (50 ml) was added, and the reaction mixture was brought to reflux again.
• Step 4 4-[(4-Pyridin-3-yl-pyrimidin-2-ylamino)-methyl]-benzoic acid (42)
• Step 5 -(2-Amino-5-thiophen-2-yl-phenyl)-4-[(4-pyridin-3-yl-pyrimidin-2-ylamino)-methyl]- benzamide (43)
• Step 2 4-[(6-Hydroxy-benzothiazol-2-ylamino)-methyl]-benzoic acid methyl ester (46): [0210]
• the title compound 46 was obtained following the same procedure as for the reductive amination described in U.S. Patent Application No. 10/242,304, which is incorporated by reference in its entirety. The yield of the title compound was 92% yield.
• Step 3 4- ⁇ [6-(2-Dimethylamino-ethoxy)-benzothiazol-2-ylamino]-methyl ⁇ -benzoic acid methyl ester (47):
• Step 4 4- ⁇ [6-(2-Dimethylamino-ethoxy)-benzothiazol-2-ylamino]-methyl ⁇ -benzoic acid (48):
• Step 5 4-[6-(2-Dimethylamino-ethoxy)-lH-benzoimidazol-2-ylsulfanylmethyl]-N-(2-nitro-5- thiophen-2-yl-phenyl)-benzamide (49)
• Step 6 ⁇ f-[2-amino-5-(2-thienyl)phenyl]-4-[( ⁇ 6-[2-(dimethylamino)ethoxy]-lH-benzimidazol- 2-yl ⁇ thio)methyl]benzamide ⁇ I-(2-Amino-5-thiophen-2-yl-phenyl)-4- ⁇ [6-(2-dimethylamino- ethoxy)-benzothiazol-2-ylamino]-methyl ⁇ -benzamide (50)
• Step 1 4-(b-unioro-b-fluoro-lH-benzoimidazol-2-ylsulfanylmethyl)-benzoic acid methyl ester (52)
• Step 2 4- ⁇ 6-[(Pyridin-3-ylmethyl)-amino]-benzothiazol-2-ylsulfanylmethyl ⁇ -benzoic acid methyl ester (53):
• Step 3 N ⁇ (2-Amino-phenyl)-4- ⁇ 6-[(pyridin-3-ylmethyl)-amino]-benzothiazol-2-yl sulfanylmethylj-benzamide (54):
• Step 4 -(2-Amino-5-thiophen-2-yl-phenyl)-4-(6-chloro-5-fluoro-lH-benzoimidazol-2- ylsulfanylmethyl)-benzamide (55)
• Step 1 (4-tert-Butoxycarbonylamino-thiophen-3-yl)-carbamic acid tert-butyl ester (57) [0222] To a vigorously stirred THF (40 mL) solution of 3,4-diaminothiophene light petroleum ether (300 mL) was added (l.OOg, 8.77mmol). To this mixture a solution of di-t-butyldicarbonate (3.82g, 17.5mmol) in petroleum ether (lOOmL) was added over a period of 30 min. Stirring was continued for 16h and the solvents were distilled off.
• Neutral 3,4-d ⁇ am ⁇ noth ⁇ ophene is obtained by dissolving 3,4-d ⁇ am ⁇ noth ⁇ ophene dihydrochloride (Toronto Research) (2.0g, lOJmmol ) in a minimum volume of IN 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 MgS0 and concentrated (l.OOg, 82% recovery).
• Step 2 (2-Bromo-4-tert-butoxycarbonylamino-thiophen-3-yl)-carbamic acid tert-butyl ester (58)
• Step 5 N-(4-Amino-5-phenyl-thiophen-3-yl)-4-[(3,4-dimethoxy-phenylamino)-methyl]- benzamide (61)
• Steps 1-3 3- ⁇ 4-[(3,4,5-Trimethoxy-phenylamino)-methyl]-phenyl ⁇ -acrylic acid (66)
• Step 2 5-[3-(tert-Butyl-diphenyl-silanyloxy)-prop-l-ynyl]-2-nitro-phenylamine (73)
• Step 3 N-(5-[3-(tert-Butyl-diphenyl-silanyloxy)-prop-l-ynyl]-2-nitro-phenyl ⁇ -4-[(3,4- dimethoxy-phenylamino)-methyl]-benzamide (74)
• Step 4 4-[(3,4-Dimethoxy-phenylamino)-methyl]-N-[5-(3-hydroxy-prop-l-ynyl)-2-nitro- phenyl]-benzamide (75)
• 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 12h, diluted with ethyl acetate (200 mL) and washed with saturated NaHC0 3 (50 mL) and then with water (6x100 mL), dried (Na 2 S0 ), filtered and concentrated in vacuum. The crude material (647 mg) was pure enough for the next step without further purification.
• Step 5 /V-[2-Amino-5-(3-hydroxy-prop-l-ynyl)-phenyl]-4-[(3,4-dimethoxy-phenyl amino)- methyrj-benzamide (76)
• Step 2 4-[(3,4-Dimethoxy-phenylamino)-methyl]-N-[5-(3-dimethylamino-prop-l-ynyl)-2- nitro-phenyl]-benzamide (78)
• Step 1 3-(3-Amino-4-nitro-phenyl)-propionaldehyde (80).
• Step 2 3-(3-Amino-4-nitro-phenyl)-propan-l-ol (81).
• 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% KHS0 in water, then saturated NaHC0 3 and finally with water, dried (MgS0 4 ), and used for the next step without further purification.
• Step 4 N- ⁇ 5-[3-(tert-Butyl-diphenyl-silanyloxy)-propyl]-2-nitro-phenyl ⁇ -4-[(3,4-dimethoxy- phenylamino)-methyl]-benzamide (83)
• Step 5 4-[(3,4-Dimethoxy-phenylamino)-methyl]-N-[5-(3-hydroxy-propyl)-2-nitro-phenyl]- benzamide (84)
• Step 6 ⁇ [2-Amino-5-(3-hydroxy-propyl)-phenyl]-4-[(3,4-dimethoxy-phenylamino)-methyl]- benzamide (85)
• Step 1 /V-(5-Bromo-2-nitro-phenyl)-4-[(3,4-dimethoxy-phenylamino)-methyl]-benzamide
• Step 2 V-(2-Amino-5-bromo-phenyl)-4-[(3,4-dimethoxy-phenylamino)-methyl]-benzamide
• Step 3 ⁇ /-[2-Amino-5-(2-carbamoyl-vinyl)-phenyl]-4-[(3,4-dimethoxy-phenylamino)-methyl]- benzamide (88)
• Step 4 N-(2-amino-5-(4-((tert-butyldimethylsilyloxy)methyl)phenyl)phenyl)-4-((3,4- dimethoxyphenylamino)methyl)benzamide (99) and N-(2-amino-5-(4- (hydroxymethyl)phenyl)phenyl)-4-((3,4-dimethoxyphenylamino)methyl)benzamide (100) [0280] The compounds 99 and 100 were obtained following the same procedure as in Examples 19 and 20, step 4 (scheme 17).
• BoCzO, ET 3 N H 2 0-Dioxane 108 Example 25 Phenylamine, BOP Et 3 N, DMF Et 3 N, DMF
• Step 2 tert-Butyl 2-(4-methoxybenzamido)-4-(phenylcarbamoyl)phenylcarbamate (111) [0291] A solution of 110 (373 mg, 0.965 mmol), aniline (0.11 ml, 1.16 mmol), BOP (640 mg, 1.45 mmol) and Et 3 N (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 NH 4 CI, NaHC0 3 and NaCI, dried over MgS0 4 , filtered and concentrated.
• 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.
• 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%).
• N-[2-Amino-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]4- methoxy-benzamide (116) (170 mg, 0.462 mmol), l-(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 H 2 0 (2.15 mL per mmol of 116) were added. Air was then removed by vacuum and then the vessel was purged with nitrogen.
• a flame-dried pressure vessel was charged with 5-fluoro-2-n ⁇ trobenzo ⁇ c acid 118 (5.00g, 27.0 mmol) and dry t-butyl alcohol (50 mL). To this solution were successively added /V, /V-d ⁇ - ⁇ sopropyl-/V- ethylamme (5 mL) and diphenylphosphorylazide (6.42 mL, 29.7 mmol). The vessel was closed with teflon cap and the mixture was heated at 90°C for 2h. It 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 H 2 0.
• Step 2 tert-Butyl 2-nitro-5-(thiophen-2-ylthio) phenylcarbamate (120) [0297] A pressure vessel was charged with th ⁇ ophene-2-th ⁇ ol (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 90°C for 2h. It was allowed to cool to r.t.; and the reaction was quenched with H 2 0, followed by THF removal in vacuo. The residue was partitioned between EtOAc and H 2 0.
• step 3 (scheme 20) substituting compound 111 for compound 120 (550 mg, 1.56 mmol), the title compound 121 was obtained (271 mg, 69% yield).
• Steps 2 and 3 4-((3,4-Dimethoxyphenylamino)methyl)-N-(2-amino-5-(2- phenylethynyl)phenyl)benzamide (125) [0301] 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).
• 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).
• 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).
• Step 2 4-Acetylamino-N-[2-nitro-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]- benzamide (133) [0307] 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 (dimethylamino)pyridine (8 mg, 0.07mmol) and the mixture was stirred for 16 h. at r.t.
• Step 1 N-(2-amino-5-(thiophen-2-carbonyl)-phenyl)4-methoxybenzamide (136) [0309] 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).
• Step 3 (E)-N-(2-amino-5-(thiophen-2-yl)phenyl)-3-(4-(tosylamino)phenyl) acrylamide (146) [0317]
• a pressure vessel was charged with compound 144 (70mg, 0.287 mmol), DMF (800 ⁇ L), and compound 145 (WO 02/069947) (89 mg, 0.239 mmol).
• the solution was degassed under vacuum and put under N 2 atmosphere (3 cycles). Then, tr ⁇ s(d ⁇ benzyl ⁇ deneacetone)d ⁇ pallad ⁇ um (7 mg, 0.007 mmol) was added and the red solution was degassed again (3 cycles).
• Tr ⁇ -o-tolylphosph ⁇ ne (4 mg, 0.014 mmol) was added and the solution rapidly turned dark. Triethylamine (lOO ⁇ L, 0.717 mmol) was added and it was degassed twice again and allowed to stir under N 2 atmosphere at 90°C for 3h. Then it was passed through ce te 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.
• Step 4 tert-Butyl 4-(3-(4-methoxybenzamido)-4-nitrophenyl)thiazol-2-ylcarbamate (151) [0321] 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,N-d ⁇ methylam ⁇ no)py ⁇ d ⁇ ne (13 mg, 0.11 mmol). The mixture was stirred for 16h and partitioned between EtOAc and H 2 0. The organic layer was washed with brine and some compound was collected by filtration.
• 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)
• LRMS (m/z): 273.1/275.1 (M7M+2).
• Step 2 N-(2-Amino-5-(4-tert-butylcarbamoyl-3-pyridyl)phenyl)-4-methoxybenzamide (156) [0325] 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).
• N-(4,4'-Diamino-3'-f luoro-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.
• Example 45
• 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).
• Step 2 ⁇ f-(4-amino-4'-hydroxybiphen-3-yl)-4-methoxybenzamide (160) [0329] 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).
• Example 50 173 Example 49 172: Example 48
• Step 2 N-(2-Nitro-5-(thiophen-2-yl)phenyl)-4-(lH-tetrazol-5-yl)benzamide (171).
• nitro-cyano compound 170 (60.5 mg, 0.17 mmol) was heated to 95°C in the presence of tnbutyltin 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 (51.4mg, 76% yield).
• 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 Ce te®, 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).
• Step 1 N-(2-Amino-5-(thiophen-2-yl)phenyl)-4-(4,5-dihydro-lH-imidazol-2-yl)benzamide (174)
• N-(2-Am ⁇ no-5-(th ⁇ ophen-2-yl)phenyl)4-cyanobenzam ⁇ de 173 (30 mg, 0.1 mmol), ethylenediamine (0.126 mL, 1.9 mmol.) and carbon disulfide (catalyst) were stirred at 50°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%).
• Step 2 tert-Butyl 2-nitro-4-(thiophen-2-yl)phenylcarbamate (177)
• a solution of tert-butyl 4-bromo-2-n ⁇ trophenylcarbamate 175 (3.97g, 12.5 mmol), 2- thiophene boronic acid 176 (1.68g, 13.4 mmol), sodium carbonate (3.98g, 37.56 mmol) and Pd(PPh 3 ) 4 (0.94g, 0.814 mmol) were stirred at 110°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.
• Step 5 N-(2-Amino-5-(thiophen-2-yl)phenyl)-3-methoxybenzamide trifluoroacetate (181) [0345] tert-Butyl 2-(3-methoxybenzam ⁇ do)4-(th ⁇ ophen-2-yl)phenylcarbamate 180 (0.214g, 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 (0.22g, 100%).
• Step 1 Acetic acid 4-(2-tert-butoxycarbonylamino-5-thiophen-2-yl-phenylcarbamoyl)-phenyl ester (183)
• Step 2 Acetic acid 4-(2-amino-5-thiophen-2-yl-phenylcarbamoyl)-phenyl ester trifluoroacetate (184)
• Step 2 4-(2-(Piperidin-l-yl)ethylamino)benzoic acid trifluoroacetate (188) [0349] 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 (0.37g, 90.5%). !
• Step 3 4-(2-(Piperidin-l-yl)ethylamino)-N-(2-nitro-5-(thiophen-2-yl)phenyl)benzamide (189)
• 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).
• Step 4 4-(2-(Piperidin-l-yl)ethylamino)-N-(2-amino-5-(thiophen-2-yl)phenyl)benzamide
• Step 4 4-(2-Morpholinoethoxy)-N-(2-nitro-5-(thiophen-2-yl)phenyl)benzamide (196) [0355] 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).
• Step 5 4-(2-Morpholinoethoxy)-N-(2-amino-5-(thiophen-2-yl)phenyl)benzamide (197)

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