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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  • C07D333/04—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
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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
  • C07D333/26—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
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  • 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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  • C07D333/52—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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  • C07D417/02—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 N-terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HAT1). Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure.
• HAT1 histone acetyl transferase
• Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure.
• Taunton e al., 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
• Grozinger et al. Proc. Natl. Acad. Sci. USA, 96: 4868-4873 (1999), teaches that HDACs are divided into two classes, the first represented by yeast Rpd3-like proteins, and the second represented by yeast Hdal-like proteins. Grozinger et al. also teaches that the human HDAC1, HDAC2, and HDAC3 proteins are members of the first class of HDACs, and discloses new proteins, named HDAC4, HDAC5, and HDAC6, which are members of the second class of HDACs.
• 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.
• TSA trichostatin A
• SAHA suberoylanilide hydroxamic acid
• 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 -0CH 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 comp ⁇ sing 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.
• the figures displays antineoplastic effects of a histone deacetylase inhibitor according to the invention on human tumor xenografts in vivo, as described in Assay Example 2, infra.
• Fig. 1 displays antineoplastic effects of a histone deacetylase inhibitor in hctll ⁇ human colorectal carcinoma cells using compound 6.
• 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 hctll ⁇ 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 /V-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, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-10, and HDAC-11.
• the histone deacetylase is de ⁇ ved 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 n -C m " heterocyclyl or "C n -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 3 -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.
• An "aryl” group is a C 5 -C 14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted.
• the aryl group is a C 6 -C 10 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 (C ⁇ -C 6 )alk(CrC ⁇ o)aryl I 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-l,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(0)-) nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkyicarbonyl, acyloxy, cyano, and ureido groups.
• Preferred substituents, which are themselves not further substituted are:
• R 30 and R 31 are each independently hydrogen, cyano, oxo, carboxamido, amidino, C r C 8 hydroxyalkyl, CrC 3 alkylaryl, aryl-C r C 3 alkyl, C r C 8 alkyl, CrC 8 alkenyl, C ⁇ -C 8 alkoxy, C ⁇ -C 8 alkoxycarbonyl, aryloxycarbonyl, aryl-C r C 3 alkoxycarbonyl, C 2 -C 8 acyl, C r C 8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, aroyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein each of the foregoing is further optionally
• R 30 and R 31 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents from (a), above.
• 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 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-).
• carbamoyl refers to an amide group attached at the carbonyl carbon atom (i.e., NH 2 -CO-). 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 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-chloro-4-fluoro-phenyl, 2-fluoro-3-propylphenyl.
• substituted /V-octyls include 2,4 d im et y l-5-ethy l-o ctyl and 3-cyclopentyl- octyl. Included within this definition are methylenes (-CH 2 -) substituted with oxygen to form carbonyl -
• 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.
• Cy 2 is as described in paragraph [0055] and Ay 2 and R 1 to R 4 are as described in paragraph [0071].
• Some compounds of the invention may have chiral centers and/or geometric isomeric centers (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers.
• the invention also comprises all tautomeric forms of the compounds disclosed herein.
• the compounds of the invention may be administered in the form of an in vivo hydrolyzable ester or in vivo hydrolyzable amide.
• An in vivo hydrolyzable ester of a compound of the invention containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid or alcohol.
• esters for carboxy include d-e-alkoxymethyl esters (e.g., methoxymethyl), Cr 6 -alkanoyloxymethyl esters (e.g., for example pivaloyloxymethyl), phthalidyl esters, C 3 - 8 -cycloalkoxycarbonyloxyC ⁇ - 6 -alkyl esters (e.g., 1-cyclohexylcarbonyloxyethyl); 1,3-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.
• esters e.g., methoxymethyl
• Cr 6 -alkanoyloxymethyl esters e.g., for example pival
• 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 N-(N,N-dialkylaminoethyl)-N-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 N-C r6 -alkyl or , -di-C ⁇ - 6 -a I kyl amide such as N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N,N-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 r C 7 -alkyl, hydroxy, CrC 7 -alkoxy, 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 r C 7 -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, C 3 -C 8 -cycloalkyl, heteroaryl, C ⁇ -C 7 -akyl, haloalkyl, C].-C
• R 1 is a mono-, bi-, or tri-cyclic aryl or heteroaryl, each of which is optionally substituted; ⁇ is -NH 2 or -OH and
• Y is any pharmaceutically acceptable chemical moiety consisting of 1 to 50 atoms; provided that when R 1 is N-imidazolyl, R 2 -R 4 are H, q is 0, and Ar 2 is pyridine, Y is not CI; and when R 1 is p-aminophenyl, R 2 -R 4 are H, q is 0, and Ar 2 is phenyl, Y is not H.
• 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.
• Y moieties of the compounds of the present invention also can be found in the following publications (either per se or as part of a disclosed molecule): WO 03/024448, 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 [0034].
• 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.
• 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, M 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, C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(NH)-C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(S)- C 0 -C 4 -hydrocarbyl, and C 0 -C -hydrocarbyl
• the optional substituents of Cy 2 are selected from C ⁇ -C 7 -alkyl, CrC 7 -alkoxy, halo, di-C ⁇ -C 7 -aikylamino-C ⁇ -C -alkoxy 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 )-, -S-, -C(0)-N(H)-, and -0-C(0)-N(H)-.
• 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 M M 1 and M 1 is selected from the group consisting of -NH-, -N(CH 3 )-, -S-, and -C(0)-N(HK 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.,
• Cy 2 has from one and three substituents independently selected from the group consisting of alkyl, alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy.
• 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
• 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, -CrC 6 -hydrocarbyl, -(C r C 3 -hydrocarbyl) ml -X'-(C ⁇ -C 3 - hydrocarbyl) m2 , -NH-(C 0 - C 3 -hydrocarbyl), (C r C 3 - hydrocarbyl)-NH-, or -NH-(C r C 3 - hydrocarbyl)-NH-; ml and m2 are independently 0 or 1;
• X' is -N(R 21 )-, -C(0)N(R 21 )-, N(R 21 )C(0)-, -0-, or -S-;
• R 21 is -H, V"-(C ⁇ -C 6 -hydrocarbyl) a ;
• L 4 is (C ⁇ -C 6 -hydrocarbyl) a -M-(C ⁇ -C 6 -hydrocarbyl)b; a and b are independently 0 or 1;
• M is -NH-, -NHC(O)-, -C(0)NH-, -C(O)-, -S0 2 -, -NHS0 2 -, or -S0 2 NH- V, V, and V" are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; t is 0 or 1.
• 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, C r C 6 -hydrocarbyl-oxy or -thio (particularly methoxy or methylthio), wherein each of the hydrocarbyl moieties are optionally substituted with one or more moieties independently selected from halo, 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 -;
• 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 0-, morphylinyl, morphylinyl-C r 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 0-, phenyl optionally substituted with one to three CH 3 0-, morphylinyl, morphylinyl-C r C 3 -alkoxy, cyano, and CH 3 C(0)NH-.
• Cy 2 is phenyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, thienyl, tetrahydroquinozolinyi, or l,3-dihydroquinazoline-2,4-dione, each optionally substituted with one to three CH 3 0-. More preferably, Cy 2 is phenyl substituted with one to three CH 3 0-. [0063] In yet other embodiments of the compound according to paragraph [0046],
• 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(O)-, -C(S)-, -S(O)-, 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 , WM. 3 , LAW 1 , W ⁇ W 1 , and
• LAW 1 ! 3 wherein W ⁇ at each occurrence, is S, 0, or N(R 9 ), where R 9 is selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl; and L 3 is C ⁇ C 4 alkylene, C 2 -C 4 alkenylene, or C 2 -C 4 alkynylene.
• X 2 is selected from the group consisting of L 3 , W 1 ! 3 , L 3 -W ⁇ W ⁇ lA-W 1 , and LAW 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 ⁇ lA-W 1 and W 1 is -NH- or -N(CH 3 )-.
• 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.
• the cyclic moiety of 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.
• substituents include methyl, methoxy, fluoro, trifluoromethyl, amino, nitro, aminomethyl, hydroxymethyl, and phenyl.
• Some other preferred substituents have the formula -K 1 -N(H)(R 10 ), wherein
• K 1 is a chemical bond or C 1 -C 4 alkylene
• R 10 is selected from the group consisting of Z' and -Ak 2 -Z', wherein Ak 2 is C r C 4 alkylene;
• Cy 2 is heterocyclyl, e.g.,
• 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 2 -E 2 -F 2 -, wherein D 2 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E 2 is -NH(CH 2 )o- 2 -; and wherein F 2 is a covalent bond; c) D 3 -E 3 -F 3 -, wherein D 3 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein E 3 is -(CH 2 )o- 2 NH-;
• R 2 to R 4 are independently hydrogen, -NH 2 , nitro, furanyl, chloro, fluoro, butyl, trifluoromethyl, bromo, thienyl, phenyl, -CHCHC(0)-NH 2 , -C ⁇ CCH 2 -R 9 wherein R 9 is hydrogen, C r 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-CH 2 - and -CH 2 -.
• 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 C r C 7 -alkyl. In some more preferred embodiments, G is -CH-.
• the compounds according to paragraph [0074] are those wherein 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 C r C 7 -alkyl, C r C 7 -alkoxy, halo, di-C r C 7 - alkylamino-C r C 7 -alkoxy and heteroaryl. More preferably, the substituents of Cy 2 are selected from methyl, methoxy, fluoro, chloro, pyridinyl and dimethylamino-ethoxy.
• the moiety formed by Cy ⁇ X 1 is selected from the following:
• the compounds according to paragraph [0079] 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, Cre-alkyl, C 2 - 6 - alkenyl, C 2 - 6 -alkynyl, d-e-alkoxy, Cre-alkanoyl, d-e-alkanoyloxy, N-(C ⁇ - 6 -alkyl)amino, N,N- (C ⁇ - 6 -alkyl) 2 amino, C ⁇ - 6 -alkanoylamino, N-(C ⁇ - 6 -alkyl)carbamoyl, /V,/V-(Ci-6-alkyl) 2 carbamoyl, Cr 6 -alkylS(0) a wherein a is 0 to 2, C r6 -alkoxycarbonyl, N-(C ⁇
• W is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ - 5 -alkyl, C 2 - 6 -alkenyl, C 2 - 6 -alkynyl, C r6 -alkoxy, d- 6-alkanoyl, C ⁇ - 6 -alkanoyloxy, /V-(C ⁇ - 6 -alkyl)amino, ,/ ⁇ Z-(C ⁇ - 6 -alkyl) 2 amino, C ⁇ - 6 - alkanoylamino, /V-(Cr 6 -alkyl)carbamoyl, N,/ ⁇ l-(C ⁇ -e-alkyl) 2 carbamoyl, d- 6 -alkylS(0) a wherein a is 0 to 2, Cre-alkoxycarbonyl, -(C ⁇
• Y and Z are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ - 6 -alkyl, C 2 - 6 - alkenyl, C 2 - 6 -alkynyl , C r6 -alkoxy, C ⁇ - 6 -alkanoyl, d-e-alkanoyloxy, /V-(C ⁇ - 6 -alkyl)amino, A/,/V-(Ci- 6 -alkyl) 2 amino, C ⁇ - 6 -alkanoylamino, /V-(C r6 -alkyl)carbamoyl, AI,/V-(C ⁇ - 6 - alkyl) 2 carbamoyl, C ⁇ - 6 -alkylS(0) a wherein a is 0 to 2, C r5
• G, J and K are independently selected from C ⁇ - 8 -alkyl, C r8 -alkenyl, Crs-alkanoyl, Crs- alkylsulphonyl, C ⁇ - 8 -alkoxycarbonyl, carbamoyl, /V-(C r8 -alkyl)carbamoyl, N,N-(C ⁇ -8- alkyDcarbamoyl, benzyloxycarbonyl, benzoyl, phenylsulphonyl, aryl, aryld-e-alkyl or (heterocyclic group)C ⁇ - 6 -alkyl; wherein G, J, and K are optionally substituted on carbon by one or more Q; and wherein if said heterocyclic group contains an -NH- moiety that nitrogen is optionally substituted by hydrogen or C 16 alkyl;
• Q is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C r5 -alkyl, C 2 - 6 -alkenyl, C 2 - 6 -alkynyl, d-e-alkoxy, C r 6 -alkanoyl, d-e-alkanoyloxy, /V-(d- 6 -alkyl)amino, ,/V-(C ⁇ - 6 -alkcyl) 2 amino, d- 6 - alkanoylamino, ! ⁇ l-(C ⁇ - 6 -alkyl)carbamoyl, /V,/V-(d- 6 -alkyl) 2 carbamoyl, d- 6 -alkylS(0) a wherein a is 0 to 2, Cre-alkoxycarbonyl, d
• a substituent on carbon is selected from halo, amino, C ⁇ - 6 -alkyl, Cre-alkoxy, /V-(Ci- 6 -alkyl)amino, aryl, aryloxy, aryld-e-alkyl, heterocyclic group, (heterocyclic group)C ⁇ - 6 -alkyl, or a group (B-E-); wherein R 5 , including group (B-E-), is optionally substituted on carbon by one or more W; and wherein if said heterocyclic group contains an -NH- moiety that nitrogen is optionally substituted by J; W is hydroxy, mercapto, d-e-alkyl, d-e-alkoxy, tyAKCre-alkyl amino or a group (B'-E'-); wherein W, including group (B'-E'-), is optionally substituted on carbon by one or more Y; Y and Z are independently selected from halo, nitro
• E, E' and E" are independently selected from -N(R a )-, -0-, -C(0)0-, -OC(O)-, -C(O)-, - N(R a )C(0)-, -N(R a )C(0)N(R b )-, -N(R a )C(0)0-, -OC(0)N(R a )-, -C(0)N(R a )-, -S(0) r -, - S0 2 N(R a )-, -N(R a )S0 2 -, wherein R a and R b are independently selected from hydrogen or Ci-e-alkyl optionally substituted by one or more F and r is 0-2;
• D and F are independently selected from halo, d- 6 -alkoxy or A/,A/-(C r6 - alkyl) 2 amino.
• a substituent on carbon is selected from fluoro, chloro, amino, methyl, ethyl, propyl, methoxy, /V-methylamino, A/-ethylamino, ⁇ l-propylamino, ⁇ f-butylamino, phenyl, naphthylethyl, piperizin-4-yl, piperidin-1-yl, piperdin-4-yl, 2-(thiomethyl)- pyrimidin-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydropyran-2-ylmethyl, 1,2,5- thiadiazol-3-ylethyl, piperidin-1-ylmethyl, pyridin-2-ylmethyl, or a group (B-B-); wherein R 5 , including group (
• W is hydroxy, methyl, ethyl, ethoxy, /V,/V-(diethyl)amino, /V, ⁇ /-(dibutyl)amino, or a group (B'-E'-); wherein W, including group (B'-E'-), is optionally substituted on carbon by one or more Y;
• Y and Z are independently selected from fluoro, chloro, bromo, nitro, cyano hydroxy, methoxy, ⁇ I,/V-(dimethyl)amino or methylcarbonylamino;
• G, J and K are independently selected from methyl, ethyl, propyl, pentyl, 2- methylbutyl, butyl, acetyl, benzyl, 3-(pyrrol-l-yl)propyl or pyrrolidin-2-one-(5S)- methyl; wherein G, J and K are optionally substituted on carbon by one or more Q; and wherein if said heterocyclic group contains an -NH- moiety that nitrogen is optionally substituted by hydrogen or methyl;
• Q is cyano, hydroxy, methoxy, ethoxy, methylcarbonyloxy, methoxycarbonyl, t- butoxycarbonlyamino, phenyl or a group (B"-E"-); wherein Q, including group (B"-E"-), is optionally substituted on carbon by one or more Z;
• R a is hydrogen or methyl optionally substituted by one or more F; D and F are independently selected from fluoro, methoxy or ethoxy; (c) fluoro, chloro, amino, methyl, methoxy, 3-morpholin-4-ylpropylamino, (3-morpholin- 4-yl)ethylamino, acetyl, benzyl, methoxycarbonylmethyl, 2-pyrrolidin-l-ylethoxy, 3- morpholinopropoxy, /V-(2-fluorophenyl)propanamide, 4- (diethylamino)phenylcarbonylmethyl, 3-(4-methylpiperazin-l-yl)propylamino, 2- piperidin-1-ylethylamino, 2-[/V,N-(diethyl)amino-ethylamino, pyridin-3-ylmethylamino, 3-piperidin-l-ylpropyla
• Ring A is a heterocyclyl
• R 5 is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-e-alkyl, C 2 - 6 -alkenyl, C 2 - 6 -alkynyl, C r6 -alkoxy, C ⁇ - 6 - alkanoyl, Cre-alkanoyloxy, /V-(C ⁇ - 6 -alkyl)amino, /V,/V-(Cr 6 -alkyl) 2 amino, d- 6 -alkanoylamino, N- (C ⁇ -6-alkyl)carbamoyl, N,/V-(C ⁇ - 6 -alkyl) 2 carbamoyl, C ⁇ - 6 -alkylS(0) a wherein a is 0 to 2, C r6 - alkoxycarbonyl, /V-(C 6
• E is -N(R a )-, -0-, -C(0)0-, -OC(O)-, -C(O)-, -N(R a )C(0)-, -C(0)N(R a )-, -S(0) r -, -S0 2 N(R a )-, -N(R a )S0 2 - wherein R a is hydrogen or C r6 -alkyl optionally substituted by one or more D and r is
• D is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C r6 -alkyl, C 2 - 6 - alkenyl, C 2 -e-alkynyl, d- 6 -alkoxy, Ci-e-alkanoyl, C r6 -alkanoyloxy, /V-(C ⁇ - 6 -alkyl)amino,
• Ring A is a pyridyl, quinolyl, indolyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl, pyradazinyl, pyrazinyl, thiazolyl, thienyl, thienopyrimidinyl, thienopyridinyl, purinyl, triazinyl, oxazolyl, pyrazolyl, or furanyl; wherein if Ring A 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, amino, C ⁇ - 6 -alkyl, C ⁇ - 6 -alkoxy, N-(C ⁇ - 6 - alkyDamino, aryl, aryloxy, arylCre-alkyl, heterocyclic group, (heterocyclic group)Cr 6 -alkyl, or a group (
• Y; Y and Z are independently selected from halo, nitro, cyano, hydroxy, C r6 -alkoxy, /V,/V-(d- 6-alkyl) 2 amino or Cr 6 -alkanoylamino;
• G, J and K are independently selected from C r8 -alkyl, d-s-alkenyl, d-s-alkanoyl, aryl, arylCre-alkyl or (heterocyclic group)d-6-alkyl; wherein G, J and K are optionally substituted on carbon by one or more Q; and wherein if said heterocyclic group contains an -NH- moiety that nitrogen is optionally substituted by hydrogen or d-e- alkyl;
• Q is cyano, hydroxy, Cre-alkoxy, d- 6 -alkanoyloxy, Cre-alkoxycarbonyl, d-e- alkoxycarbonylamino, aryl, aryloxy or a group (B"-E"-); wherein Q, including group (B"- E"-), is optionally substituted on carbon by one or more Z;
• B, B' and B" are independently selected from Ci-e-alkyl, C 2 - 6 -alkenyl, C 2 - 5 -alkynyl, C 3 - 8 - cycloalkyl, C 3 - 8 -cycloalkylC ⁇ - 6 -alkyl, aryl, aryld-e-alkyl, heterocyclic group, (heterocyclic group)C ⁇ - 6 -alkyl, phenyl or phenyld-e-alkyl; wherein B, B' and B" are optionally substituted on carbon by one or more D; and wherein if said heterocyclic group contains an -NH- moiety that nitrogen is optionally substituted by a group selected from G;
• E, E' and E" are independently selected from -N(R a )-, -0-, -C(0)0-, -OC(O)-, -C(O)-,
• R a and R b are independently selected from hydrogen or C ⁇ - 6 -alkyl optionally substituted by one or more F and r is 0-2;
• D and F are independently selected from halo, C ⁇ -6-alkoxy or /V,/V-(Ci- 6 -alkyl) 2 amino; m is 0, 1, 2, 3 or 4; wherein the values of R 5 are the same or different;
• R 6 is fluoro or chloro; and n is 0, 1 or 2, wherein the values of R 6 are the same or different;
• Ring A is pyridin-4-yl, pyridin-3-yl, pyriclin-2-yl, quinolin-8-yl, pyrimidin-6-yl, pyrimidin-5-yl, pyrimidin-4-yl, morpholin-4-yl, piperidin-4-yl, piperidin-3-yl, piperdin-2-yl, piperazin-4-yl, pyridazin-5-yl, pyrazin-6-yl, thiazol-2-yl, thien-2-yl, thieno[3,2d]pyrimidinyl, thieno[3,2b]pyrimidinyl, thieno[3,2b]pyridinyl, purin-6-yl or triazin-6-yl; wherein if Ring A 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 fluoro, chloro, amino,
• R 1 , R 2 , R 3 , and R 4 are as defined in paragraphs [0048] and [0049].
• the compounds according to paragraph [0083] are the compounds of Tables 1-8 and
• Alkyl includes both straight and branched chain alkyl groups.
• C ⁇ - 8 -alkyl and “Ci-e-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, benzimid
• 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-dioxoimidazolidinyl, 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-dioxolanyl, homopiperazinyl, thiophen
• d-e-alkanoyloxy is acetoxy.
• C ⁇ - 8 -alkoxycarbonyl examples include methoxycarbonyl, ethoxycarbonyl, N- and t- butoxycarbonyl.
• C 2 - 6 -alkynyl examples are ethynyl and 2-propynyl.
• Examples of "Cre-alkoxy” include methoxy, ethoxy and propoxy.
• Examples of "Cre-alkanoylamino” and C r3 -alkanoylamino examples include formamido, acetamido and propionylamino.
• Cre-alkylS(0) a wherein a is 0 to 2 include Cre-alkylsulphonyl, C ⁇ - 3 -alkylS(0) a , methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsuiphonyl.
• C ⁇ - 8 -alkanoyl “Ci-e-alkanoyl” and d- 4 -alkanoyl include C ⁇ - 3 -alkanoyl, propionyl and acetyl.
• Examples of " ⁇ f-C ⁇ - 6 -alkylamino" and /V-(C ⁇ - 3 -alkyl)amino include methylamino and ethylamino.
• Examples of "/V,l ⁇ l-(C ⁇ - 6 -alkyl) 2 amino" and ⁇ /,/V-(C ⁇ - 2 -alkyl) 2 amino include di-N-methylamino, di-(/V-ethyl)amino, di-(/V-butyl)amino and N-ethyl-N-methylamino.
• C 2 - 8 -alkenyl are C ⁇ - 5 - alkenyl and C 2 - 3 -alkenyl, and include vinyl, allyl, and 1-propenyl.
• Examples of " -(C ⁇ - 3 -aikyl)sulphamoyi” and “/V-(Ci 5 alkyl)sulphamoyl” are -(C 3 -alkyl)sulphamoyl, /V-(methyl)sulphamoyl and N- (ethyl)sulphamoyl.
• Examples of "/V-(C ⁇ - 6 -alkyl) 2 sulphamoyl" are IV,/V-(C ⁇ - 3 -alkyl) 2 sulphamoyl, N,N- (dimethyl)sulphamoyl and /V-(methyl)-N-(ethyl)sulphamoyl.
• N-(C ⁇ - 8 -alkyl)carbamoyl and “N- (Cre-alkyl)carbamoyl” are /V-(Cr 4 -alkyl)carbamoyl, /V-(C ⁇ - 3 -alkyl)carbamoyl, methylaminocarbonyl, and ethylaminocarbonyl.
• N,/V-(C ⁇ - 8 -alkyl) 2 carbamoyl and "AI,N-(C ⁇ - 5 -alkyl) 2 carbamoyl” are N,lV-(C ⁇ - 4 -alkyl) 2 carbamoyl, /V,/V-(Cr 2 -alkyl) 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 “arylCre-alkyl” include benzyl, 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl.
• aryloxy examples include phenoxy and naphthyloxy.
• d-s-cycloalkyl examples include cyclopropyl and cyclohexyl.
• C 3 - 8 " cycloalkylCre-alkyl” examples include cyclopropylmethyl and 2-cyclohexylpropyl.
• 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.
• aryld-e-alkyl comprises d- 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 [0046], R 2 , R 3 , and R 4 are as defined in paragraph [0046]; R 12 is hydrogen, halo, hydroxy, amino, nitro, d-e-alkyl, C ⁇ - 6 -alkyloxy, trifluoromethyl, di(d- 6 - alkyDamino, hydroxyamino and naphthalenylsulfonylpyrazinyl; -L- is a direct bond or a bivalent radical selected from d-e-alkanediyl, amino, carbonyl
• R 5 and R 6 are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloC ⁇ - 6 - alkyl; trihaloCre-alkyloxy; Ci-e-alkyl; Ci-e-alkyl substituted with aryl and C 3 - 10 -cycloalkyl; C r e-alkyloxy; Cre-alkyloxyC ⁇ - 6 -alkyloxy; C ⁇ - 5 -alkylcarbonyl; C ⁇ - 6 -alkyloxycarbonyl; C r6 - alkylsulfonyl; cyanoCre-alkyl; hydroxyC ⁇ - 6 -alkyl; hydroxyd-e-alkyloxy; hydroxyCre- alkylamino; aminoCre-alkyloxy; di(C ⁇ - 5 -alkyl)aminocarbonyl; di(hydroxyC ⁇ - 6 -alkyl)amino; (aryl)(Cre-alkyl)
• t is O
• R 12 is hydrogen, halo, hydroxy, amino, nitro, Ci-e-alkyl, Cre-alkyloxy, trifluoromethyl or di(Cre-alkyl)amino
• R 14 is hydrogen, hydroxy, amino, hydroxyCre-alkyl, C r6 -alkyl, d-e-alkyloxy, aryld-e-alkyl, aminocarbonyl, aminoCi- 6 -alkyl, Cre-alkylaminoCre-alkyl or dKCre-alkyDaminoCre-alkyl
• the A ring is a radical selected from (a-1), (a-3), (a-4), (a-5), (
• each s is independently 0, 1, 2, 3 or 4;
• R 5 is hydrogen; halo; hydroxy; amino; nitro; trihaloCre-alkyl; trihalod-e-alkyloxy; Ci-e-alkyl;
• R 12 is hydrogen, halo, hydroxy, amino, nitro, Ci-e-alkyl, Cre-alkyloxy, trifluoromethyl, hydroxyamino or naphthalenylsulf onylpyrazinyl ;
• R 14 is hydrogen, hydroxy, amino, hydroxyd-e-alkyl, Cre-alkyloxy, arylC r e-alkyl, aminocarbonyl, hydroxycarbonyl, aminoCre-alkyl, aminocrbonyld-e-alkyl, hydroxycarbonylCre-alkyl, hydroxyaminocarbonyl, Ci-e-alkyloxycarbonyl, C ⁇ - 6 - alkylaminoCre-alkyl or dKCre-alkyDaminoCre-alkyl;
• the A ring is a radical selected from (a-1), (
• each R 5 and R 6 are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloCre-alkyl; trihaloC r6 -alkyloxy; Cre-alkyl; Cre-alkyloxy; Cre-alkyloxyCre-alkyloxy; Cre-alkylcarbonyl; d-e-alkylsulf
• R 14 is hydrogen, hydroxy, amino, hyroxyC r6 -alkyl, Cre-alkyloxy, aryld- 6 -alkyl, aminocarbonyl, hydroxycarbonyl, aminoCre-alkyl, aminocarbonyld-e-alkyl, hydroxycarbonylCre-alkyl, hydroxyaminocarbonyl, Ci-e-alkyloxycarbonyl, Cre-alkylaminoCre-alkyl or dKCre- alkyDaminoCre-alkyl;
• the A ring is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8),
• R 12 is hydrogen, halo, hydroxy, amino, nitro, Cre-alkyl, Cre-alkoxy, trifluoromethyl or di(Cr 6 - alkyDamino;
• -L- is a direct bond or a bivalent radical selected from C ⁇ - 6 -alkanediyl, amino and carbonyl;
• R 14 is hydrogen, hydroxy, amino, hydroxyCre-alkyl, d-e-alkyl, d-e-alkoxy, aryld-e-alkyl, aminocarbonyl, aminoC ⁇ - 6 -alkyl, C ⁇ - 6 -alkylaminoC ⁇ - 6 -alkyl or di(CI-6alkyl)aminoC ⁇ - 6 -alkyl;
• the A ring is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), tel l), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34
• R 5 is hydrogen; halo; hydroxy; amino; nitro; trihaloCre-alkyl; trihaloC r6 -alkyloxy; Cre-alkyl; C r e-alkyloxy; C ⁇ - 6 -alkylcarbonyl; Ci-e-alkyloxycarbonyl; Ci-e-alkylsulfonyl; hydroxyC r6 -alkyl; aryloxy; di(Cr 6 -alkyl)amino; cyano; thiophenyl; furanyl; furanyl substituted with hydroxyd- e-alkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and Cre-alkyl; Cre- alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinyl; C ⁇ - 6 -alkylmorpholinyl; piperazin
• R 12 is hydrogen, nitro, Cre-alkyloxy, trifluoromethyl, di(C ⁇ - 6 -alkyl)amino, hydroxyamino or naphtalenylsulfonylpyrazinyl;
• -L- is a direct bond or a bivalent radical selected from Cre-alkanediyl, carbonyl and aminocarbonyl; each R 13 represents a hydrogen atom;
• R 14 is hydrogen, hydroxyCre-alkyl, aminocarbonyl, hydroxyaminocarbonyl or dKCre- alkyDaminoCre-alkyl;
• the A ring is a radical selected from (a-1), (a-7), (a-9), (a-10), (a-12), (a-14), (a-19), (a-20), (a- 21), (a-22), (a-23), (a-30), (a-34), (a-49) and (a-50); each s is independently 0, 1, 2 or 5; each R 5 and R 5 is independently selected from hydrogen; halo; nitro; trihaloC ⁇ - 6 -alkyl; trihaloCre-alkyloxy; Cre-alkyl; d-e-alkyloxy; C ⁇ - 6 -alkylsulfonyl; (aryD(Cre-alkyl)amino; arylsulfonyl; aryloxy; arylC 2 - 6 -alkenediy
• R 12 is hydrogen
• each R 13 is hydrogen
• R 14 is hydrogen; the A ring is a radical selected from (a-1), (a-9), (a-19), (a-20), (a-21), (a-22), (a-23), (a-49) and (a-50); each s is independently 0, 1, 2 or 5; each R 5 and R 6 is independently selected from hydrogen; halo; trihaloCre-alkyl; trihaloCre- alkyloxy; Cre-alkyl; Cre-alkyloxy; arylC 2 - 6 -alkenediyl; di(C ⁇ - 6 -alky)amino; thiophenyl; thiophenyl substituted with dKCre-alkyDaminoCre-alkyKCre-alkyDaminoCre-alkyl di(Cr 6 - alkyDaminoCre-alkyl, Cre-alkylpiperazinylCre-alkyl, hydroxyd-e-alkylpiperazinyld-e-alkyl,
• Z is nitrogen; R 12 is hydrogen; -L-is a direct bond; each R 13 is hydrogen; R 14 is hydrogen; the A ring is radical selected from (a-1) and (a-20); each s is independently 0 or 1; each R 5 and R 6 is independently selected from hydrogen; thiophenyl; thiophenyl substituted with di.d-e-alkyDaminoCre-alkyl, or Cre-alkylpiperazinylCre-alkyl; furanyl; phenyl; and phenyl substituted with one substituents independently selected from di(C ⁇ - 4 - alkyl)aminoC ⁇ - 4 -alkyloxy, di(C x - 4 -alkyl)amino, di(Cr 4 -alkyl)aminoC ⁇ - 4 -alkyl, di(C ⁇ - 4 - alkyl)aminoC ⁇ - 4 -alkyl(C ⁇ - 4 -alkyl)aminoCr
• R ⁇ R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraphs [0098] - [0109], R ⁇ R 2 , R 3 , and R 4 are all H.
• Halo is generic to fluoro, chloro, bromo and iodo;
• d- 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;
• d-e-alky includes C ⁇ - 4 -alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like;
• Cre-alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methylene, 1,2- ethanediyl, 1,3-propanediyl 1,4-butanediyl, 1,5-pentanediyl, 1,6
• the term "another Zn-chelating group” refers to a group which is capable of interacting with a Zn 2+ -ion, which can be present at an enzymatic binding site.
• the N-oxide forms of the compounds of paragraph [0098] comprise those compounds wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those 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):
• R 1 is H or as defined in paragraph [0046];
• R 2 , R 3 , and R 4 are as defined in paragraph [0046];
• ii is 0, 1, 2 or 3 m ⁇ when n is 0 then a direct bond is intended;
• X is nitrogen or
• Y is nitrogen or 'C ⁇ ⁇ .
• R is selected from the group consisting of hydrogen, halogen, -NH 2 , nitro, hydroxy, aryl, heterocyclyl, C 3 -C 8 -cycloalkyl, heteroaryl, C ⁇ -C 7 -akyl, haloalkyl, d-d-alkenyl, C ⁇ -C 7 -alkynyl, C r C 7 -acyl, C ⁇ -C 7 - alkyl-aryloxy, C ⁇ -C 7 -alkyl-arylsulfanyl, C ⁇ -C 7 -alkyl-arylsulfinyl, C ⁇ -C 7 -alkyl-arylsulfonyl, C ⁇ -C 7 -alkyl- arylaminosulfonyl, C ⁇ -C 7 -alkyl-arylamine, Ci-C 7 -alkynyl-C(0)-amine, CrC 7 -alkenyl-C(0)-amine, C r C 7
• R 13 is hydrogen, Ch lk ], aryIC 2 .6alkenedJyi» furanyicarbonyl, naphtalenylcarbonyl, -C(0)phenylR 9 , Cj-salkylam ⁇ iocarbonyl, aminosulfonyl, arylammosulfonyl, aminosulfonylamino, di(Ci alkyl)aminosulfo ⁇ y ⁇ amino s arylamin ⁇ sulfonylaj ⁇ rii ⁇ o, aminosuIfonylaminoC ⁇ .6atkyl, di(C ⁇ .6alkyl)aminosulfonylaminoCi.6alkyl, arylarni ⁇ osulfonylarninoC caJkyl, di(C ⁇ .
• each R is independently selected from phenyl; phenyl substituted with one, two or three substituents independently selected from halo, amino, Chalky!, C ⁇ .galkylo y, di(C ⁇ . 6 alkyl)aminoC ⁇ .6alkyl J d ⁇ (C ⁇ .
• R 14 is hydrogen, hydroxy, amino, hydroxyCi-ealkyl, Ci ⁇ afkyl, Cj .galkyloxy, arylCi-ealkyl, aminocarbonyl, hydroxycarbonyl, aminoCi ⁇ alkyl, aminocarbonylCi. ⁇ alkyl, hydroxycarbonylC .galkyl, hydroxyaminocarbonyl, Ci-ealkyioxycarbonyl, or di(C ⁇ jaJky!
• aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, C ⁇ . 6 alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl
• n is O orl
• R 12 is hydrogen or nitro
• R 13 is Cf -6 alkyl, arylC ⁇ alkenediyl, furanyicarbonyl, naphtalenylcarbonyl,
• MhaIoC ⁇ alkylsuIfonyl, thiophenylC 1 . 6 alky]carbonyl, pyridinylcarbonyl
• R 14 is hydrogen; when R 13 & R 14 are present on the same carbon atom R 13 & R 14 together may form a bivalent radical of formula (a-1) wherein R 10 is aryl; when R 13 & R 14 are present on adjacent carbon atoms R 13 & R 14 together may form a bivalent radical of formula (b-1),
• R 12 is hydrogen
• R 13 is naphtalenylcarbonyl, Ci.iialkylstilfonyl or di(aryl)C ⁇ . 6 alkylcarbonyl;
• R 14 is hydrogen
• R 12 is H.
• R 12 is hydrogen, halo, hydroxy, amino, nitro, trifluoromethyl or di(C ⁇ , 6 alkyl)a ino;
• R 13 is hydrogen, arylC alkenediyl, furanyicarbonyl, naphtalenyloarbonyl, -C(0)phenylR 9 , C ⁇ alkylarninocarbonyl, aminosulfonyl, aiylam iosulfonyl, annnosulfonylarruno 1 i(C ⁇ .6alkyl)a ⁇ mnosulfonylamino, dl(C ⁇ alkyl)aminoCi ⁇ alkyl, Cj.jaalkylsulfonyl, di(C ⁇ alkyl ⁇ amin ⁇ suIfonyI or pyridinyJcarbonyl wherein each R ? is independently selected from phenyl; phenyl substituted with one, two or three substituents independently selected from halo, Ci ⁇ alkyl, C ⁇ .6alkyi ⁇ xy; or thiophenyl;
• R 14 is hydrogen, hydroxy, amino, hydroxyC f -galkyl C h lky!, Ci-galkyl ⁇ xy, acylCi. ⁇ alkyl, ami ocarbonyl, aminoCi ⁇ alkyl, C
• R 12 is hydrogen, halo, hydroxy, amino, nitro, C h alk !, di (C i .6alkyl)amin o;
• >13 is hydrogen, C h al y!, furanyicarbonyl naphtalenylcarbonyl, -C(0)phenylE 9 , aminosulfonyl, aryl aminosulfonyl, arninosulfonylarnino, di ⁇ C ⁇ .
• >14 is hydrogen, hydroxy, amino, hydroxyCi ⁇ alkyl, C h alk !, C ⁇ galkyloxy, arylCi ⁇ alkyl, aminocarbonyl, arninoCi-ealkyl, Ci ⁇ alkylaminoCi ⁇ alkyl or di (C i . 6 alkyl)aminoCt ⁇ alkyl .
• R 12 is hvdrosen or nitro:
• R 13 is C ⁇ alkyl, furanyicarbonyl, naphtalenylcarbonyl, aminosulfonyl, di(C ⁇ alkyl)aminosuIfonylaminoC ⁇ . 6 alkyl, di(C ⁇ . 6 alkyl)aminoC ⁇ alkyl, C ⁇ .i2dIky]8i ⁇ lfonyI t dJCe ⁇ a ⁇ ky armnosulfonyl, trihaloCi-ealkylsuIfonyl, thiophenyiCi.
• R 14 j s hydrogen; when R 13 and R 14 are present on the same carbon atom R « & R H together may form a bivalent radical of formula (a-1) wherein R 10 is aryl; or when R 13 & R 14 are present on adjacent carbor atoms R 13 & R 14 together may form a bivalent radical of formula (b-1).
• R 1 , R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0048] and [0049], while in other embodiments of the compounds of paragraphs [0115] -[0123], R 1 , R 2 , R 3 , and R 4 are all H.
• the invention comprises compounds of the following structural formula (6): 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]; a is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended
• m is 0 or I and when 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 ⁇ ⁇ , ⁇ , or CH ⁇ ;
• X is nitrogen or
• R 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, C r C 7 -akyl, haloalkyl, C r C 7 -alkenyl, C r C 7 -alkynyl, C r C 7 - acyl, C -C 7 -alkyl-aryloxy, C r C 7 -alkyl-arylsulfanyl, C r C 7 -alkyl-arylsulfinyl, C r C 7 -alkyl-arylsulfonyl, C r Cy-alkyl-arylaminosulfonyl, C ⁇ -C 7 -alkyl-arylamine, C r C 7 -alkynyl-C(0)-amine, CrC 7 -alkenyl-C(0)-
• R 12 is hydrogen, halo, hydroxy, amino, nitro, C h alky], Cj. e alkyIoxy, trifluoromethyl, di(C ⁇ alkyl)arnrno ⁇ hydroxyamino or naphtalenylsulfonylpyrazinyl;
• -L- is a direct bond or a bivalent radical selected from Ci ⁇ aJ anediy ⁇ , Ci-galkanecfiyloxy, 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, ar lCMalkyl, aminocarbonyl, hydroxycarbonyl, aminocarbonylCi ⁇ alkyL hydt xycafbonylCi-eallcyl, hydtoxyaminocarbonyl,
• R 15 is hydrogen, C w a ⁇ ky ⁇ oxy € ⁇ . 6 alky!, or aryl;
• each s is independently 0, 1, 2 » 3, 4 or 5; each R 6 an ! 7 are independently selected from hydrogen; halo; hydroxy; amino; nitro; substituted with aryl and
• each R 6 and R 7 can be placed on the nitrogen in replacement of fhe hydrogen; aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, Ci-ga ⁇ kyl, trifluoromethyl, cyan
• .Q is """0 ⁇ , - ⁇ , or — CH C ;
• R 12 is hydrogen or C M alfeyl
• nis 1 is O or l
• t is 0,1 or 2;
• each s is independently 0, 1, 2 or 3; each R 6 is independently selected from hydrogen * halo. C h lk ! or Ci ⁇ alkyloxy.
• R i5 - is hydrogen, C 6 alkyl, C M ⁇ cyctoalkyl, hydr ⁇ xyCi ⁇ alkyl, Ci. 6 alkyloxyC ⁇ alkyl is , a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-li), (a 2), (a-13), (a-14), (a-15), (a- 6), (a-17)» (a-18), (a-19), (a-20), (a-21), (a-22), (a»23), (a-24), (a-25), (a-26), (a-27), (a-28), (a-29), (a-30), (a-31), (a-32), (a ⁇ 33), (a-34), (a-35), (a 36), (a-37)» (a-38), (a ⁇ 39), (a-40), (a-41), (a-42) (a-43) or(a-
• each K $ and R 7 are independently selected from hydrogen; halo; hydroxy; amino; nitro; C ⁇ . 6 alkyloxyC ⁇ 6 alkyloxy; Ci_ 6 alkylcarbonyl cyanoC ⁇ . 6 aIkyl; hydroxyCi. e alI yl; hydroxyC ⁇ _ 6 a ⁇ kyloxy; hydroxy C ⁇ alkylamino; di(C i . 6 alkyl)aminocarbonyl; di(hyd ⁇ oxyC ⁇ personally alkyl)amino; arylC 1 . lky!amino; dr C ⁇ .
• pyrrolidinylCi-ealkyloxy pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents pyridinyl; pyridinyl substituted with or aryl; pyrimidinyl; quinolinyl; indole; phenyl; phenyl substituted with one, two or three substituents independently selected from halo, amino, Chal y!, Cj.galkyloxy, hydroxyC ⁇ .
• aIkyl trifluoromethyl, fluoromethyloxy, h roxy ⁇ alkyloxy, Ci ⁇ iJ ⁇ lo Ci ⁇ kylo , aminoCi ⁇ alkyloxy, di(C w alkyl)ammoC ⁇ , 4 alkyloxy, di(C w alkyl)a ino, di(C ⁇ .
• R l is hydrogen, hydroxy, amino, hydroxyCi-galkyl, Ci ⁇ lk i, Gi-galkyloxy arylCi. 6 alkyI, aminocarbonyl, or R 15 is hydrogen; (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a 3), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a «34), (a 35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41) t (a-42), (a-44), (a-
• R 6 is hydrogen; halo; hydroxy; amino; nitro; trihafoCi.galkyl; trihaloCt ⁇ alkyloxy; C h alky]; C ] , ⁇ ja ⁇ kylsul bnyli hydroxyCi-galkyl; aryloxy; c ⁇ (C ⁇ diligent 6 alkyl)an ⁇ ino; cyano; thiophenyl; furanyl; furanyl substituted with hydroxyCi.gaJkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and Ci ⁇ alkyl; C ⁇ .
• IS is hydrogen, C h alky!, C 3 - ⁇ ocycloalkyl, hydroxyCi ⁇ alkyl, C ⁇ . 6 alkyloxyC ⁇ alkyl or di(C ⁇ . 6 alkyl)aminoC ⁇ .galkyl;
• - ⁇ is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15),
• each R 6 and R 7 are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloCi» 6 alkyl; trihaloCi.galkyloxy; Ch l !
• R 12 is hydrogen * halo, hydroxy, amino, nitro, Chalky!, C ⁇ . 6 alkyloxy, trifluoromethyl or di(C ⁇ .6alkyl)amino;
• - - is a direct bond or a bivalent radical selected from Ci ⁇ alkanediyl, Cx ⁇ alkanediyloxy, amino or carbonyl;
• RH is hydrogen, hydroxy, amino, hydroxyCi-ealkyl, C h ly!, C ⁇ alkyloxy, arlC ⁇ -galkyI, aminocarbonyl, aminoCi.ealkyl, C ⁇ .. 6 al laminoC ⁇ _ 6 lyl or mC ⁇ kl)aminoC ⁇ . 6 lkyl;
• R 15 is H
• ⁇ - ⁇ is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20),
• each s is independently 0, 1, 2, 3 or 4;
• R 6 is hydrogen; halo; hydroxy; amino; nitro; trihaloC 1 .galkyl trihalo .galkyioxy;
• R 12 is hydrogen or Ch lky!; -Lr is a direct bond;
• R 14 and R 15 are H
• ⁇ - ⁇ is a radical selected from (a-1), (a-20), (a-25), (a-27), (a-28), (a-29), (a-41) or (a-42); each s is independently 0, 1 or 2; and each R 6 is independently selected from hydrogen, halo, C h lk ! or Ci-galkyloxy.
• R 12 is hydrogen; -L- is a direct bond;
• R 14 and R 15 are H
• j is a radical selected from (a-1), (a-20), (a-27), (a-28), (a-29),
• each s is independently 0, 1 or 2; and each R 6 is independently selected from hydrogen, halo, C h alky! or Ci-galkyloxy,
• R 1 is H or as defined in paragraph [0046];
• R 2 , R 3 , and R 4 are as defined in paragraph [0046];
• X is nitrogen or f
• 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, d-C 7 -akyl, haloalkyl, CrC 7 -alkenyl, C ⁇ -C 7 - alkynyl, C r C 7 -acyl, C r C 7 -alkyl-aryloxy, C r C 7 -alkyl-arylsulfanyl, C ⁇ -C 7 -alkyl-arylsulfinyl,
• R 9 is hydrogen , hydroxy, amino, CrC 7 -alkyl or C r C 7 -alkoxy;
• R 12 h l l lf ⁇ l i l ⁇ » is a direct bond or a bivalent radical selected from Ci ⁇ alkanediyl, d-galkyloxy, 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, hydroxyCi ⁇ alkyl, C ⁇ . 6 al yl, Ci-galkyloxy, arylC ⁇ . 6 alkyl, aminocarbonyl, hydroxycarbonyl, aminoCi-galkyl, aminocarbonylC ⁇ . 6 alkyl, hydroxycarbonylCi.gal yl, hyc oxyaminocarbonyl, Ci-galkyloxycarbonyl, Ci ⁇ alkylaminoCi-galkyl or di C ⁇ . 6 lkyl armnoC ⁇ - 6 allQfl;
• -®- is a radical selected from
• each s is independently 0, 1, , 3, 4 or 5; each R 5 and R 6 are independently selected ftom hydrogen; halo; hydroxy; amino; nitro; trihaloCi-galkyl t ⁇ ihaloC ⁇ .ealkyloxy; Chalky!; Cj.galkyl substituted with aiyl and Cs-i fl cycloalkyl; Ci.galkylcarbonyl; Ci-ealkyt ⁇ xycarbonyl; Ci.galkylsnltnyl; cyanoCi ⁇ alkyl; hydaroxyCi ⁇ alkyl; hydroxyCi-galkyloxy hydroxyCi ⁇ al ylamino; aminoCi ⁇ alkyloxy; di(hydroxyC ⁇ .
• each R 5 and R 6 can be placed on the nitrogen in replacement of the hydrogen;
• aryl in die above is phenyl, or phenyl substituted with one or more substituents each
• - - is a direct bond or a bivalent radical selected from
• R 4 is hydrogen
• ⁇ - ⁇ is a radical selected from (a-l) J (a-2) I (a-3), (a-5), (a-6), (a-11), (a-18), (a-20), (a-21), (&-32) ⁇ (a ⁇ 33), (a 47) or (a-51); . , ' each s is independently 0, 1, 2, or 4; each R 5 and R 6 are independently selected from hydrogen; halo; rih loC ⁇ _6alkyl; C galkyl; C h alk !
• i s n trogen Y is nitrogen;
• i R 2 is hydrogen; ' : ' ⁇ • ' . ' - i -L-is a direct bond; _ .- , ' ' .. eacli R 3 independently represents a hydrogen atom; * • . ' "' ⁇ ' . ' ' .
• L is a direct bond.
• Other embodiments of the compound according to paragraph [0136] are those in which one or more of the following apply (wherein each of R 2 , R 3 , and R 4 in this paragraph corresponds to R 12 , R 13 , and R 14 , respectively, in paragraph [0136]): t is 1, 2, 3, or 4;
• R 2 is hydrogen, halo, hydroxy, amino, nitro, Cwalkyl, trifluoromethyl or di(C ⁇ . 6 alkyI)an ⁇ o;
• -L- is a direct bond or a bivalent radical selected from Ci ⁇ alkanediyl,
• R 4 is hydrogen, hydroxy, amino, hydroxyCi-galkyl, C ⁇ galkyl, G ⁇ alkyloxy, ar lC , 6 alk l » aminocaibonyl, or di(C ⁇ _ 6 alkyl)aminoC ⁇ .
• 6 allyl is a radical selected from (a-1), (a-3), (a-4), (a-3), (a-6), (a-7), (a-8), (a-9), (a-10), (a-li (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24); (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47),, (a ⁇ 48) and (a-51); each s is independently 0, 1, 3 or 4;
• R 5 is hydrogen; halo; hydroxy; amino; nitro; trihaloC ⁇ . lkyl; ttihaloCi ⁇ aUcyloxy; C h l !; Cj-galkyloxy; Cj.ealkylcarbonyl; C ⁇ gatkylsulfonyl; hy roxyCi ⁇ alkyl; aryloxy; dr(C ⁇ _ 6 alkyl)amino; cyano; . thiophenyl; furanyl; furanyl substituted with bydroxy €
• Ci ⁇ alkyltriazolyl Ci ⁇ alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholmyl; Ci-galfcylmorpholinyl; piperazinyl; hydroxyC ⁇ , 6 alkyl ⁇ iperazinyl v .
• pyrazoly pyrazoly; pyrazolyl substituted with one or two substituents selected from Ci-galkyl or trihaloC ⁇ _ 6 alkyl; pyridinyl; pyridinyl substituted with Ci ⁇ alkyloxy, aryloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C h alky!, Cj-galkyloxy or trifluoromethyl;
• R 6 is hydrogen; halo; hydroxy; amino; nitro; trihaloC ⁇ .eaIkyl; Ci ⁇ al yl; C ⁇ alky ⁇ oxy; C ⁇ galkylcarbonyl; C ⁇ alkyloxycarbonyl;
• R 5 fs hydr ⁇ geni ' halo; hydroxy l amino; nitro; trihaloGi ⁇ allcyl; trihaloC ⁇ . 6 alkyloxy; ,-
• R 6 is hydrogen; halo; hydroxy; amino; nitro; trihaloC ⁇ . 6 aIkyl; aryloxy; cyano; pyridinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, Gi ⁇ alk l, C ⁇ alkyloxy or trifluoromethyl,
• R 2 is H or nitro:
• - - is a ditect bond or a bivalent radical selected from Ci ⁇ alkanediyl;
• R 4 is , hydrogen;
• _ / is a radical selected from (a-l),(a-2), (a-3), (a-5), (a-6) ⁇ (a-11), , 1,
• t is 0 or 1 ;
• X is "rntrogen; ) Y is nitrogen;
• R 2 is hydrogen; - - is a direct bond; each R 3 , independently
• R 1 , R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0048] and [0049]. 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 (8):
• R 1 is H or as defined in paragraph [0046];
• R 2 , R 3 , and R 4 are as defined in paragraph [0046];
• ri is 0, l t 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 ⁇ ? CR ⁇ or CH ⁇ ;
• R is selected from the group consisting of hydrogen, halogen, -NH 2 , nitro, hydroxy, aryl, heterocyclyl, C 3 -C 8 -cycloalkyl, heteroaryl, CrC 7 -akyl, haloalkyl, C r C 7 -alkenyl, CrC -alkynyl, C r C 7 -acyl, C ⁇ -C 7 - alkyl-aryloxy, C r C 7 -alkyl-arylsulfanyl, C ⁇ -C 7 -alkyl-arylsulfinyl, CrC 7 -alkyl-arylsulfonyl, C r C 7 -alkyl- arylaminosulfonyl, C r C 7 -alkyl-arylamine, C r C -alkynyl-C(0)-amine, CrC 7 -alkenyl-C(0)-amine, C r C 7 - alkyny
• R 12 is hydrogen, halo, hydroxy. amino, nitro, Ct ⁇ alkyl, C ⁇ . 6 alkyIoxy, trifluoromethyl, di(C ⁇ ,6alkyi)amino, hydroxyamino ornaphtalenylsulfonylpyrazinyl; each R 13 independently represents a hydrogen atom and one hydrogen atom can he replaced by a substituent selected from aryl;
• R 14 is hydrogen, hydroxy, amino, hydroxyCi- ⁇ alkyi, Ci-galkyl, Ci ⁇ alkyloxy, am ocarbonylCi ⁇ alkyl, hydroxycarbonyJCi-ealkyl, hydroxyaminocarbonyl,
• R 15 is hydrogen, C h alky!, C 3 . ⁇ ocycloalkyl, hydroxyC ⁇ alkyl, C ⁇ . 6 alkyloxyC ⁇ . 6 aIkyl t di(C
• 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 ⁇ . 6 aIkyl; C h alky!; C h alky! substituted with aryl and
• Ci ⁇ alkylpiperazmylCi.ealkylaminoCj.galky Ci.ealkylpiperazinylsulfonyi; aminosulfonylpiperazinyICt, 6 alkyloxy; aminosulfonylpiperazinyl; aminosulfonyIpiperazinylCi ⁇ alkyl; di(C ⁇ alkyl)aminosulfonylpiperazinyl; di(Ci. 6 alkyl)aminosulfonyJ ⁇ iperazinylCj ⁇ alkyl; hydroxyC
• hydroxyCi ⁇ alkyl trifluoromethyl, tiifluoromethyloxy, hydroxyCi ⁇ alkyloxy, Ci.4aIlkylsulfonyI, aminoC ⁇ .4aIkyloxy f di(C ⁇ . 4 lkyl) ⁇ mnoCi lk lo y, di(C ⁇ personally4alkyl)amino, di(C ⁇ .4alkyl)a ⁇ mnocarbonyi, diCCi lkyl) minoCi.4 lkyl t di(C ⁇ 4aIkyl)aminoC ⁇ alkyIaminoCi.
• R 2 is hydrogen, or napmaienyisuironylpyrazinyl; each R 3 independently represents a hydrogen atom;
• R 4 is hydrogen, hydroxy, hydroxyCj-galkyl or Ci.galkyloxy
• R 5 is hydrogen, C h alky!, hydroxyC ⁇ . 6 alkyi orC ⁇ alkyloxyCi-ealkyl;
• R 2 each R 3 independently represents a hydrogen atom
• R 4 is hydrogen
• R 5 is hydrogen or Ci ⁇ alkyloxyCi ⁇ alkyl; (a-20); each s is independently 0 or 1; each R* is independently selected from hydrogen; thiophenyl; furanyl; benzofuranyl; phenyl; or phenyl substituted with one substituents independently selected from or di(C ⁇ - 4 alkyI)amino.
• R 5 is hydrogen or Ci ⁇ alkyloxyCi ⁇ alkyl; (a-20); each s is independently 0 or 1; each R* is independently selected from hydrogen; thiophenyl; furanyl; benzofuranyl; phenyl; or phenyl substituted with one substituents independently selected from or di(C ⁇ - 4 alkyI)amino.
• R 12 is H.
• R 2 is hydrogen, halo, hydroxy, amino, nitro, C h alky!, Cj. ⁇ > a ⁇ kyloxy, trifluoromethyl or di(Ci- ⁇ alkyl)amino;
• i R 4 is hydrogen, hydroxy, amino, hydroxyCi ⁇ alkyl, C h alky!, € ⁇ . 6 alkyloxy, or di(C ⁇ ,ealkyl)aminoC ⁇ . 6 alkyl;
• R 5 is hydrogen
• s is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a ⁇ 13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51); each s is independently 0, , 2, 3 or 4;
• R 6 is hydrogen; halo; hydroxy; amino; nitro; trihaloCi-galkyl; trihaloCi.galkyloxy; Cj-galkyl; C L galkyloxy; Ci ⁇ alkylcarbonyl; C
• R 5 is hydrogen, C ⁇ ,ga ⁇ kyl, Ca-jocyeloalkyl, hydroxyC w a]kyl, Ct_g lkyl yC ⁇ . 6 a ⁇ or i(C ⁇ , 6 al yI minoCi- 6 l yl - Is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8) (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19) » (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-27), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-3 ), (a-35), (a-36), (a-37), (a-38), (
• each R 6 and R 7 are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloCi-galkyl; trihaloC ⁇ . 6 alkyloxy; C ⁇ alkyJ; Ct-galkyloxy; Ci-galkylsulfonyl; cyanoCi-galkyl; hydroxyC ⁇ alkyl; hydroxyC
• R 5 is hydrogen, C h alky!, C 3 . ⁇ ocycloalkyl, or i(C ⁇ . 6 alkyl a i ⁇ oC ⁇ . 6 alkyl
• ⁇ - is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-27), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42) (a-43) or (a-44); each R 6 and R 7 are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaioCi-galkyl; C h alky!; C
• Ci 4 alkylpiperaziny ⁇ Ci 4 alkylpiperazinylCi 4 alkyloxy
• R is hydrogen, halo, hydroxy, amino, nitro, Ci ⁇ alkyl, C ⁇ .6alkyloxy, trifluoromethyl or di(Cj- 6 alkyl)amino;
• R 4 is hydrogen, hydroxy, amino, C h alky!, arylC ⁇ . 6 alkyl, aminocarbonyl, aminoC ⁇ . 6 alkyl,
• - ⁇ is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a ⁇ lO), (a-11), (a-12), (a-13), (a ⁇ 4), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48)or (a-51); each s is independently 0, 1, 2, 3 or 4;
• R 6 is hydrogen; halo; hydroxy; amino; nitro; trihaloCi.galkyloxy; C f .galkylcarbonyl; Ci-galkyloxycarbonyl; Ci-ealkylsulfonyl; aryloxy; di(C ⁇ . lkyI)amitto; cyano; thiophenyl; furanyl; furanyl substituted with hydroxyCi .galkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and C h lk !
• Ci-ealkyltriazolyl tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinyl; Ci-galkylmorpholinyl; piperazinyl; hydroxyCi- ⁇ alkylpiperazi ⁇ yl; Ci- ⁇ alkyloxypiperidinyl; pyrazoly; pyrazolyl substituted with one or two substituents selected from Ch lky!
• R 7 is hydrogen; halo; hydroxy; amino; nitro; trihaloCi.ealkyl; Ci ⁇ alkyl; Ci-ealkyloxy; Ci.galkylcarbonyl; Ci.ealkyloxycarbonyl; Ct-galkylsulfonyl; hydroxyCi. galkyl; aryloxy; di(C ⁇ . 6 alkyi)a ⁇ mino; cyano; pyridinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, Ci ⁇ alkyl, C ⁇ . $ alkyloxy or trifluoromethyl.
• R 2 is hydrogen, Q ⁇ alkyl or naphtalenylsulfonylpyrazinyl; each R 3 independently represents a hydrogen atom; * is hydrogen, hydroxy, hydroxyC j.galkyl or Ci-galkyloxy; R 5 is hydrogen, or Ci-ealkyloxyCi-galkyl;
• ⁇ — ' is a radical selected from (a-1), (a-7) or (a-20); each s is independently 0 or 1; each 6 is independently selected from hydrogen; thiophenyl; furanyl; benzofuranyl; phenyl; or phenyl substituted with one substituents independently selected from Ci ⁇ alkyl, Ci-galkyloxy, hydroxyCi 4 alkyl, Ci 4 alkylsulfonyl or di(Ci 4 alkyI)amino and each R 7 is independently selected from hydrogen.
• R 2 is hydrogen or Ci-galkyl; each R 3 independently represents a nyorogen atom; R 4 is
• R 5 is hydrogen or Ci ⁇ alkyloxyC ⁇ galkyl
• ⁇ - ⁇ is a radical selected from (a-1) or (a-20); each s is independently 0 or 1; and each R 6 is independently selected from hydrogen; thiophenyl; furanyl; benzofuranyl; phenyl; or phenyl substituted with one substituents independently selected from C h al y!, Ci-galkyloxy, hydroxyCi 4 alkyl or di(Cj 4 alkyl)amino.
• Particular embodiments of the compound according to paragraph [0136] include the following in which the terminal hydroxamic acid moiety (-C(O)-NH-OH) is replaced with
• R ⁇ R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0048] and [0049]. 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 (9):
• 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;
• X is nitrogen or ⁇ ;
• Y is nitrogen or ⁇ c ⁇
• 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, CrC 7 -akyl, haloalkyl, CrC 7 -alkenyl, C r C 7 -alkynyl, C ⁇ -C 7 -acyl, C 1 -C 7 - alkyl-aryloxy, CrC 7 -alkyl-arylsulfanyl, C r C 7 -alkyl-arylsulfinyl, CrC -alkyl-arylsulfonyl, C ⁇ -C 7 -alkyl- arylaminosulfonyl, C r C 7 -alkyl-arylamine, C r C 7 -alkynyl-C(0)-amine, C r C 7 -alkenyl-C(0)-amine, C r C 7 - alky
• R 13 is hydrogen, hydroxy, amino, hydroxyCi ⁇ alkyl, Cj-galkyl, Ci ⁇ alkyloxy, arylCi-galkyl, aminocarbonyl, hydroxycarbonyl, aminocarbonylC
• R 14 is hydrogen, Ci ⁇ alk l, C 3 _ ⁇ 0 cycloa ⁇ yl, hydroxyCi ⁇ alkyl, Ci. 6 alIcyioxyCi_ 6 alkyl, or aryl;
• 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; nitxo; trihaloC ⁇ , 6 alkyl; trihaloCi-ealkyloxy; Ci-galkyl; Ci ⁇ alkyl substituted with aryl and
• aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, Ci-galkyl, trifluoromethyl, cyano or hydroxycarbonyL
• R 3 is hydrogen; when Z is equal to ⁇ , then -L- is the bivalent radical -C ⁇ galkanediylNE-;
• R 4 is hydrogen, or aryl
• each R 5 is independently selected from hydrogen; halo; trih loCi-ealkyl; trihaloCi-ealkyloxy Ci ⁇ alkyl; C ⁇ lkyloxy; C ⁇ .ealkylcarbonyl; aryloxy; cyano or phenyl,
• ⁇ s is the radical (a-1); i each s is independently 0 or 1; each R 5 is independently selected from hydrogen or phenyl,
• R is hydrogen, halo, hydroxy, amino, nitro, or di(C ⁇ .6alkyl)amino;
• ⁇ R 3 is hydrogen, hydroxy, amino, hydroxyC ⁇ alkyl, C h alk ], Ci.galkyloxy, arylC gal yl, aminocarbonyl, aminoCi-ealkyl, or i(C ⁇ .6al yl)ammcC ⁇ _6aIc l;
• ⁇ is hydrogen;
• ⁇ - ⁇ is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (SL-9 (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20),
• hydroxyCi-ealkylpiperazinyl pyrazolyl substituted with one or two substituents selected from C ⁇ .galkyl or trihaloC ⁇ Ucyl; pyridinyl; pyridinyl substituted with aryloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C h lky!, Ci ⁇ alkyloxy or trifluoromethyl; R 6 is hydrogen; halo; hydroxy; amino; nitro; ttJhaloC ⁇ . 6 aI yl; C h lk !
• R z is hydrogen, halo, hydroxy, amino, rritro. C ⁇ . 6 alkyl, trifluoromethyl or di(C ⁇ - 6 alkyl)arnino;
• R 3 is hydrogen, hydroxy, amino, hydroxyCi-ealky], Ci-e lkyl Ci-galkyloxy, arylCi ⁇ alkyl, aminocarbonyl, aminoC ⁇ .galkyl, Ci ⁇ alkylaminoCi-galkyl or di(C ⁇ . 6 alkyl)aminoCi- 6 alkyl;
• R 4 is hydrogen;
• ⁇ - ⁇ is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-S), (a-9),
• each s is independently 0, 1 * 2, 3 or 4;
• R 5 is hydrogen; halo; hydroxy; amino; nitro; trihaloCi- ⁇ alkyi;
• Ci-eal yl C ⁇ galkyloxy; C ⁇ alkylcarbonyl; C ⁇ ealkyloxycarbonyl;
• Ci- ⁇ alkyl orpholtnyl piperazinyl
• Ci ⁇ alkylpiperazinyl Ci ⁇ alkylpiperazinyl
• hy ⁇ r ⁇ xyC ⁇ alkylpiperazittyi C ⁇ . 6 alkyloxy ⁇ iperidinyl; pyrazolyl; pyrazolyl substituted with one or two substituents selected from Ci-g l l or trihaloC ⁇ .galkyl; pyridiny!; pyridinyl substituted with C ⁇ alkyloxy, aryloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; or phenyl substituted with one or two substituents independently selected from halo, or trifluoromethyl; and 6 is hydrogen; halo; hydroxy; amino; nitro; trihaloC ⁇ , 6 aIkyl; teihaloCi- ⁇ alkyloxy; Ci ⁇ alkyl; Ci-galkyloxy; C ⁇ alkylcarbonyl; C ⁇ alkyloxycarbonyl; C t .
• R 4 is hydrogen, a radical selected from (a-1) or (a-21); each s is independently 0, 1 or 2; and each R 5 is independently selected from hydrogen; halo; C h alky!; C ⁇ galkyloxy; C ⁇ alkylcarbonyl; aryloxy; cyano or phenyl.
• R is hydrogen; R is hydrogen; when Z is equal to ⁇ , then - - is the bivalent radical R 4 is hydrogen, C ⁇ profession 6 a3kyl or aryl;
• ⁇ — is the radical (a-1); each s is independently 0 or 1; and each R 5 is independently selected from hydrogen or phenyl,
• R 1 , R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0048] and [0049]. 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 (10):
• 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 it is 0 then a direct bond is intended;
• t is 0 or I and when t is 0 then a direct bond is intended;
• X is nitrogen or
• Y is nitrogen or ⁇ ;
• Z is-CHa- or-O-;
• R is selected from the group consisting of hydrogen, halogen, -NH 2 , nitro, hydroxy, aryl, heterocyclyl, C 3 -C 8 -cycloalkyl, heteroaryl, CrC r akyl, haloalkyl, C r C 7 -alkenyl, C r C 7 -alkynyl, C r C -acyl, C r C 7 - alkyl-aryloxy, CrC 7 -alkyl-arylsulfanyl, CrC 7 -alkyl-arylsulfinyl, C r C 7 -alkyl-arylsulfonyl, CrC ⁇ alkyl- arylaminosulfonyl, C r C 7 -alkyl-arylamine, C r C 7 -alkynyl-C(0)-amine, C r C 7 -alkenyl-C(0)-amine, CrC 7 - alkynyl-R
• R 12 is hydrogen, hydroxy amino, hydroxyCi- ⁇ alkyl, Ci ⁇ alkyl, C ⁇ alkyloxy, arylCi ⁇ alkyl, aminocarbonyl, hydroxycarbonyl, aminoCi ⁇ alkyl, an ⁇ nocarbonylCi ⁇ alkyJ. hydroxycarbonylCi.galkyl, hydroxyaminocarbonyl, Ci-ealkyloxycarbonyl,
• -L- is a bivalent radical selected from Ct. & alkanediyl, carbonyl, sulfonyl, or C ⁇ .ealkanediyl substituted with phenyl;
• each s is independently 0, 1, 2, 3 T 4 or 5; each R 3 and R 6 are independently selected from hydrogen; halo; hydroxy; amino; nitro; tjihaloCi-galkyl; trihaloCi-galkyloxy; Chalky!; Ct. $ alkyl substituted with aryl and C3-jocycloalkyl; C ⁇ alkyloxy; Ci-ealkyloxyC ⁇ galkyloxy; Ci-ealkylcarbonyl; hydroxyC j-galkyl; hydroxyC ⁇ .
• C ⁇ - 6 alkylpiperazinyIC ⁇ C ⁇ - 6 alkylpiperazinyIC ⁇ . f ialkyloxy piperazinylC ⁇ , 6 alkyl; naphtalenylsulfonylpiperazinyl; naphtalenylsulfonylpiperidinyl; naphtalenylsulfony] ; Ci-ealkylpiperazinylCi-galkyl; Ci-ga kylpiperazinylCi ⁇ alkylamino; Cj ⁇ aIkylpiperazinylC ⁇ alkylarninoC ⁇ .eaIkyi; C ⁇ - 6 alkyl ⁇ iperazinylsulfonyl; aminosulfonyipiperazinyJCi ⁇ alkyloxy; aminosulfonylpiperazinyl; aminosulfonyl ⁇ iperazinylC ⁇ .
• Ci ⁇ alkylsulfonyl Ci ⁇ a ⁇ kyloxyC ⁇ alkyloxy
• Ci ⁇ alkyloxycarbonyl di(Ci- 4 aikyl)aminocarbony di(C ⁇ alkyl)aminoC ⁇ alkyl- di(Ci. 4 alkyl)aminoCi alkylaminoCi. 4 alkyl, di(C ⁇ - 4 alkyl)amino(C ⁇ . 4 alkyl)amino, di(C ⁇ .
• aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, -ualkyl, trifluoromethyl, cyano or hydroxycarbonyl.
• R 2 is hydrogen
• -L- is a bivalent radical selected from carbonyl, sulfonyl, or Ci.galkanediyl substituted with phenyl;
• ⁇ A is a radical selected from (a-1), (a-20) or (a-43); each s is independently 0 or 1; each R 5 is independently selected from hydrogen or phenyi
• X is nitrogen
• R 2 is hydrogen
• • - ⁇ is a bivalent radical selected from carbonyl or sulfonyl; — (A) — / is a radical selected from (a-1) or (a-20); i each s is independently 0 or 1; . each R 5 is independently selected from hydrogen or aryL
• -L- is a bivalent radical selected from carbonyl or sulfonyl
• ⁇ - ⁇ is a radical selected from (a-1), (a-3) ⁇ (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-!5), (a-16), (a-17) t (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), ⁇ a-26), (a-28), (a-29), ⁇ a 30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (*38), (a-39) (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51); each s is independently 0, 1, 2, or 4;
• R 5 is hydrogen; halo; hydroxy; amino; nitro; C ⁇ . ⁇ $ alky ⁇ ; Ci.galkyloxy; C f . $ a1kyIoxycarbonyJ; aryloxy; di(C ⁇ . 6 alkyl)amino; cyano; thiophenyl; furanyl; furanyl substituted with hydroxyCi-ealkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and ⁇ g lk l; C t -ealkyltriazoiyi; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinyl;
• R is hydrogen, hydroxy, amino, hydroxyC ⁇ . 6 alkyl, C galkyl, Ci ⁇ alky ⁇ oxy, arylCi-e lkyl, aminocarbonyl, aminoC ⁇ galkyi, Ci ⁇ alkylaminoCi ⁇ alkyl or di(C ⁇ alkyl)aminoC ⁇ alkyl;
• -L- is a bivalent radical selected from Cj-galkanediyi, carbonyl or sulfonyl;
• R s is hydrogen; halo; hydroxy; amino; nitro; trihal ⁇ C
• Ci.galkylmorpholinyl piperazinyl; Ci.galkyipiperazinyl; hydr ⁇ xyC ⁇ profession ⁇ alkylpi ⁇ erazinyl Ci ⁇ alkyloxypiperidinyl; pyrazoly; pyrazolyl substituted with one or two substituents selected from C ⁇ profession 6 !kyl or trihaloCi.galkyl;
• pyridinyl pyridinyl substituted with Cj-galkyloxy, aryloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; or phenyl substimted with one or two substituents independently selected from halo, C j.galkyL or trifluoromethyl; and R 6 is hydrogen; halo; hydroxy; amino; nitro; trihaloCi.galkyl; C galkyl; aryloxy; di(C ⁇ 6 alkyl)amino; cyano; pyridinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C h lky!, Ci-galkyloxy or trifluoromethyL
• ⁇ — ' is a radical selected from (a-1), (a-20) or (a-43); s is 0 or 1; and each R 5 is independently selected from hydrogen or phenyl
• - - is a bivalent radical selected from carbonyl or
• R 1 , R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0048] and [0049]. 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 t 3 or 4 and when t is 0 then a direct bond is intended;
• 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, C r C 7 -akyl, haloalkyl, CrC 7 -alkenyl, C r C 7 -alkynyl, C r C 7 -acyl, C r Cr alkyl-aryloxy, C r C 7 -alkyl-arylsulfanyl, C r C 7 -alkyl-arylsulfinyl, C ⁇ -C 7 -alkyl-arylsulfonyl, C r C 7 -alkyl- arylaminosulfonyl, C ⁇ -C -alkyl-arylamine, Ci-C 7 -alkynyl-C(0)-amine, C r C 7 -alkenyl-C(0)-amine, C r
• arylCi-galkyl aminocarhonyl, hydroxycarbonyl, aminoCi ⁇ alkyl, aminocarhonylCi ⁇ alkyl, hydroxycarbony ⁇ C ⁇ alkyl, hydroxyaminoeaAonyl, or di(C ⁇ . 6 alkyl)aminoC ⁇ ,6alkyl;
• -L- is a bivalent radical selected from -NR 9 C(0)- ⁇ -NR & S0 2 - or NR 9 CH 2 - wherein 9 is hydrogen, C t ⁇ alkyl, C 3 . ⁇ ocycloalkyl» hydroxyC ⁇ . 6 alkyl, i(Ci-6al l)ammoC ⁇ . 6 ⁇ l
• each s is independently 0, 1, 2, 3, 4 or 5; each R 5 and 6 are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloCi-galkyl; trihaloCi.galkyloxy; Ci-el yl; Ci ⁇ alkyl substituted with aryl and
• C ⁇ . ⁇ alkylox iperiQnylC ⁇ .ealkyl; ⁇ ipe ⁇ idinyla ⁇ ninoC ⁇ .6allcyla ⁇ nino; i e ⁇ i inyla ⁇ ninoC ⁇ .6a ⁇ r ⁇ lm oC ⁇ - 6 alkyl;
• X is nitrogen;
• R 12 is hydrogen, hydroxy, C h l y!, or arylCi ⁇ alkyl;
• -L- is a bivalent radical selected from -NHC(0)- or -NHSG 2 - is a radical selected from (a-1) or (a-20); each s is independently 0 or 1; each R 5 is independently selected from hydrogen or phenyl [0178]
• Other embodiments of the compound according to paragraph [0176] are those in which one or more of the following apply (wherein each of R 2 , R 3 , and R 4 in this paragraph corresponds to R 12 , R 13 , and R 14 , respectively, in paragraph [0176]): t is l; careful drawing/ /
• X is nitrogen; Y Is nitrogen;
• R 12 is H
• -L- is a bivalent radical selected from -NHC(0>- or -NHSOa-; -> A is a radical selected from (a-1) or (a-20);
• each s is independently 0 or 1;
• each R s is independently selected from hydrogen or phenyl
• Rl2 is hydrogen, hydroxy, amino * Ci-galk l, arylC ⁇ profession 6 aikyl » aminocarbonyl, aminoCi ⁇ alc l, Ci-gal yla ⁇ noCi ⁇ alkyl or di(Ci. 6 alkyl)aminoCi ⁇ alkyl;
• -L- is a bivalent radical selected from TMNHC(0> or -NHS0 2 ⁇
• - ⁇ is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-35), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (ihSl); each s is independently 0, 1, 2, 3 or 4; R 5 is hydrogen; halo; hydroxy; amino; nitro; Ci ⁇ alk l; Ci
• pyridinyl pyridinyl substituted with C ⁇ alkyloxy, aryloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C ⁇ galkyl, Ci ⁇ alkyl ⁇ xy or trifluoromethyl;
• R 6 is hydrogen; halo; hydroxy; amino; nitro; trihaloCj_ 6 alkyl; trihaloCi-gaikyloxy; Ci ⁇ alkyl; C ⁇ galkyloxy; Ci-ealkylcarbonyl; C ⁇ alkyloxycarbonyl; C
• each R 3 and R 6 are independently selected from hydrogen; halo; hydroxy; amino; nitro; Ci-galkyl; C ⁇ .
• R 3 and R 4 are each independently selected from hydrogen, hydroxy, hydroxyCi ⁇ alkyl, aminoCi-ealkyl or aminoaryl;
• js radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a 8), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-27), (a-28), (a-29), (a-30) compassion (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42) (a-43) or (a-44);
• each R 5 and R e are independently selected ftom hydrogen; halo; hydroxy; amino; nitro; Ci.ealkyloxy;
• Ci-galkyltriazolyl Ci-galkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinyl;
• Ci-galkylmorpholinyl piperazinyl
• Other embodiments of the compound according to paragraph [0176] include the following (wherein each of R 2 , R 3 , and R 4 in this paragraph corresponds to R 12 , R 13 , and R 14 , respectively, in paragraph [0176]):
• R i2 is hydrogen, hydroxy, C ⁇ galkyl or arylC ⁇ alkyl; -L- is a bivalent radical selected
• ⁇ - ⁇ is a radical selected from (a-1) or (a-20); each s is independently 0 or 1; and each R 5 is independently selected from hydrogen or phenyl.
• t is 1;
• Q is — ° ⁇ ' — CR ⁇ , or — CH ⁇ ⁇ ' •
• X is nitrogen;
• Y is nitrogen;
• Z is -
• R 2 is hydrogen; -L- is a bivalent radical selected
• ⁇ ⁇ - is a radical selected from (a-1) or (a-20); each s is independently 0 or 1; and each R 5 is independently selected from hydrogen or phenyl.
• R 1 , R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0048] and [0049]. 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 (12):
• R 1 is H or as defined in paragraph [0046];
• R 2 , R 3 , and R 4 are as defined in paragraph [0046];
• Ring A is a heterocyclyl, wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from O;
• R 11 is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ -*alkyl, N-(C ⁇ . 6 alkyl)amino, N,N-(C M alkyl) 2 a ⁇ mno, N,N-(C ⁇ . 6 alkyl) 2 earbamoyI, C ⁇ al ylSCO ⁇ wherein a is 0 to 2, C
• W and Z axe independently selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci- ⁇ alkyl, C ⁇ -ealkenyl, Ca ⁇ alkynyl, Ci-galkoxy, C alkanoyl, Ct- ⁇ alkanoyloxy, iV-(C ⁇ -6allyl)ammo, C ⁇ . 6 alkanoylamino, W-(Ct. ⁇ ;aIkyl)carbamoyl, Cj.
• alkylS(0) a wherein a is 0 to 2, Cj-galkoxycarbonyl, V-(C «alkyl)sulphamoyl or JV, ⁇ -(C ⁇ . ⁇ jalkyl) 2 Sulpharnoyl;
• G, ,T and K are independently selected from Cj-galkyl, Cj-salkenyl, CVsalkynyl, C ⁇ al anoyl, C ⁇ .salkylsulphonyl, C ⁇ . 8 allcoxycarbonyl, carbamoyl, iV-(Ci.salkyl)carbamoyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl, aryl, arylCi- ⁇ alky] or (heterocyclic group)Ci.gaIkyl; wherem Q, J and K may be optionally substituted on carbon by one or more Q; and wherein if said heterocyclic group contains an - ⁇ H- moiety that nitrogen may be optionally substituted by a group selected ftom hydrogen or Ci-salkyl;
• Q is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C2. ⁇ alkenyl, Ca- ⁇ lkyn l, Ci-ealkanoylamino, iV-(C ⁇ .
• D* and D" are independently selected from Cj- ⁇ alkenyl, C ⁇ - ⁇ aEcynyl, i C 3 .scycloalI yl, Cs-scycloalkylCt-salkyl, aryl, arylCi-galkyl, heterocyclic group, (Iieterocyclic grou ⁇ )C ⁇ .
• E, E' and E" are independently selected from - ⁇ ( a )-, -0-, -C(0)0-, -OC(0)-, 3 -C(0)-, -N( a )C(0)-, -N(R a )C(0)N(R b )-, -N(R a )C(0)0-, -OC(0)N(R a h -C(O)N0R a )-, -S(0) r> -S ⁇ 2 (R a )-, -N(R a )S02-; wherein R a andR are independently selected from hydrogen or Ci-callcyl 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 ⁇ profession 6 ar yl, Ca
• Ring B is a ling selected from
• X 1 and X 2 are selected from CH or ⁇ , and
• Y 1 , Y 2 , Y 3 and Y 4 are selected from CH or ⁇ provided that at least one of Y 1 , Y 2 , Y 3 a d ⁇ is ⁇ ;
• R 12 is halo; n is 0, 1, or 2, wherein the values of R 12 are the same or different. 88] In some embodiments of the compound according to paragraph [0187],
• Ring A is a pyridyl, quinolyl, indolyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl, pyridazinyl, pyrazinyl, thiazolyl, thienyl, thienopyrimidinyl, thienopyridinyl, purinyl, triazinyl, ⁇ xazolyl, pyrazolyl, or furanyl; wherein if Ring A contains an -MH- moiety that nitrogen may be optionally substituted by a group selected from G.
• Ring A is ⁇ yridin-4-yl, pyridin-3-yl, pyridin-2-yl, quinolin-8-yl, pyrimidin-6-yi, ⁇ yrimidin-5-yl, pyrirmdin-4-yl, morpholin-4-yl, piperidin-4-yl, ⁇ iperidin-3-yl, piperdin-2-yl, piperazin-4-yl, pyridazin-5-yl, pyrazin- ⁇ -yl, thiazol-2-yl, thien-2-yl, thieno[3,2d]pyrimidinyl, thieno[3,2b3 ⁇ yrimidinyI, thieno[3,2b]pyridinyl, purin-6-yl, l ⁇ 2 3 ⁇ 6 , -tetrahydropyrid ⁇ n-4'-yl • Ring A is pyridin-4-yl, pyridin-3-yl, pyr
• Ring A is ⁇ yri ⁇ m-4-yl, pyridin-3-yi, pyridin-2-yI, morpholin-4-yl, ⁇ iperidm-4-yl, piperidin-3-yl, piperdin-2-yl, piperazin-4-yl, thiazol-2-yl, tMen-2-yl, furan-3-yl, pyrroEdin-1- yl, piperidm-1-yl, triazol-1-yl or 102' 3 306'-tetrahydropyridin-4-yl wherein if Ring A contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from G.
• Ring A is a pyridyl, pyrtmidyl, morpholinyl, piperidinyl, piperazinyl, pyridazinyl, thienyl, pyrazinyl, thiazolyl, 1,2,4-triazolyl or furanyl.
• Ring A is py ⁇ idin-4-yl, pyridm-3-yl, pyridin-2-yl or 1 ,2,4-triazolyi RingB is thienyl, tliiadiazolyl, thiazolyl, pyrimidyl, pyrazinyl, p) ⁇ idazinyl or pyridyl.
• Rin B is thienyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyL
• RingB is thienyl or pyridyl
• Ring B is thienyl or pyridyl wherein both the thienyl and the pyridyl are attached to Ring A in the 2-pos on of the thienyl or pyridyl ring and to the amide group of formula OD in the 5-position of the thienyl or pyridyl ring.
• RH is halo, amino, C ⁇ profession 6 alkyl, Cj.galkoxy, C ⁇ . 3 al anoyloxy, N-(C w all ⁇ l)amino, N,N-(C ⁇ 3 al yl)2ami o, C ⁇ - 3 alkanoylamino, N-(C ⁇ . 3 alky])carbamoyl, N,N-(Ci- 3 allcyl) 2 carbamoyl.
• R 11 is halo, amino
• R 11 is halo, amrao, methyl or methoxy.
• R 11 is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-ealkanoyl, Ci-salkanoyloxy, -ealkanoylamino, wherein a is 0 to 2, C I . 6 alkoxycarbonyl, N-(C ⁇ . 6 alkj'l)sulphamoyl, N,N-(C M alkyI)2Sulphamoyl, aryl, aryloxy, arylCi.
• heterocyclic group (heterocyclic group)Cv t ;alkyl or a group (D-E-); wherein R l , including group (D-E-), may be optionally substituted on carbon by one or more V; and wherein, if said heterocyclic group contains an - ⁇ H- moiety that nitrogen may be optionally substituted by a group selected from J;
• V is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C h alky!, Ca-eal enyl, Ca-gal ynyl, Cwalkoxy, Cu ⁇ alkanoyl, C ⁇ - ⁇ allcanoyloxy,
• Z are independently selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, a ino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-galkyl, N- ⁇ C ⁇ -6arkyl)amino, Ci-eaUcanoy ⁇ ammo, N,N-(Ci.(5allcyl)2carbamoyl, C ⁇ - ⁇ salkylS ⁇ O) a wherein a is 0 to 2, Ci- ⁇ alkoxycarbonyl, N-(C ⁇ - 6 alkyl ⁇ sulphamoyl or N»N-(C ⁇ - ⁇ $alkyl) 2 Sul ⁇ han ⁇ yl;
• G, J and K are independently selected from Ci-gaikyl, C 2 .salkenyl, Ca.gall ynyl, Ci-galkanoyl, Ci-salkylsulphonyl, C
• D, D' and D" are independently selected from Ci-ealkyl, C 2 . ⁇ ;alkenyl, C 2 .( > alkyr ⁇ yl 1 C 3 . 8 cycloalkyl, aryl, heterocyclic group, (heterocyclic group)C ⁇ . 6 alkyl; wherein D, D' and D" may be optionally substimted on carbon by one or more F ; and wherein if said heterocyclic group contains an - ⁇ H- moiety that nitrogen may be optionally substituted by a group selected from K;
• E, B' and E" are independently selected from - ⁇ (R a )-, -O-, -C(O)O-, -OC(O)-, -C(O)-, -N(R ft )C(OK -N(R ft )C(O)NCR b )-, -N(R a )C(O)O-, -OC(O)N(R a )-, -C(O)NCR")-, -S(O) ,
• R a and R b aro independently selected from hydrogen or Ci- ⁇ 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, Ci- ⁇ alkyl, C ⁇ - ⁇ alkenyl, C 2 - ⁇ aIkynyl, Cwalkoxy, C ⁇ . fi alkanoyl, C l . 6 alkanoyloxy,N-(C ⁇ -6alkyl)amino, N,N-(C ⁇ alkyl) 2 amino, Ci-galkanoylamino, ⁇ r -(C ⁇ .
• R n is a substituent on carbon and is selected from cyano, hydroxy, Ci- ⁇ alkyl or a group ⁇ -E ⁇ ); wherein R u including group (D-E-), may be optionally substituted on carbon by one or more V;
• V is cyano, hydroxy or a group (D'-E'-); wherein V, including group (D'-B'-), may be optionally substituted on carbon by one or more ;
• W and Z are independently selected from cyano, Chalky! or Ci-galkoxy;
• G and K. are independently selected from Q-galkyl, C 2- 8alkenyl, C 2 -salkynyl, arylC ⁇ . 6 alkyl or (heterocyclic grou ⁇ )C w alkyl; wherein G and K may be optionally substimted on carbon by one or more Q;
• Q is cyano, hydroxy, oxo, C.-ealkyl, C ⁇ - ⁇ alkanoyloxy, N-(C M alky!)carbamoyl, N,N C ⁇ .6alkyl) 2 carbamoyl, Ci-oalkoxycarb ⁇ nyL C ⁇ . 6 alkoxycarbonylamino, aryl, aiyloxy or a group (D"-E"->; wherein Q, including group (D"-E"-). may be optionally substimted on carbon by one or more Z;
• D, D' and D" are independently selected from aryl, or heterocyclic group; wherein D, D' and D" may be optionally substituted on carbon by one or more F; i wherein if said heCerocyctic group contains an -NH- moiety that nitrogen may be optional!; substituted by a group selected from K;
• E, E" and E" are independently selected from -O-, -C(O)O-, -OC(OX -C(O)-, -N(R a )C(O>, -C(O)N(R a K -S(O) r ; wherein R* is selected from hydrogen or Cwalkyl optionally substituted by one or more F and r is 0-2; and
• P and F are independently selected from nitro, hydroxy, Ci. ⁇ jaikyl, Ci-e Uco y, C
• m 0, 1, 2, 3 or 4; wherein the values of R 11 are the same or different m is 0 5 1, or 2; wherein the values of R 11 are the same or different , m is 0. m is 1.
• R 12 is halo
• R 12 is fluoro
• R 12 is chloro. n is 0, 1, or 2; wherein the values of R 12 are the same or different; n is 0; n is 1.
• Ring A is a pyridyl, indolyl, pyrimidyl, morpholinyl, piperidinyl, piperazinyl, pyridazinyl, thienyl, pyrazinyl, thiazolyl, oxazolyl, 1,2,4-tria ⁇ lyl, isoxazolyl, isothiazolyl, pyrazolyl, or furanyl;
• RingB is thienyl, thiadiazolyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl;
• R 11 is halo, ammo, C ⁇ -6 alkyl, Ci-galkoxy, C ⁇ alkanoyloxy, N"(C . 3 alkyl)amino s
• Ring A is pyridhH-y ⁇ , ⁇ yridi ⁇ -3-yi, ⁇ yri.din-2 ⁇ yi or 1,2,4-triazo ⁇ yl;
• Mimg B is thienyl or pyridyl;
• R 11 is halo, amino, methyl or ⁇ iethoxy m is 0, 1, 2, wherein the values of R 11 are the same or different.
• n is O or 1;
• R 12 is F.
• Other embodiments of the compound according to paragraph [0187] include the following (wherein each of R 2 in this paragraph corresponds to R 12 in paragraph [0187]):
• Ring A is a pyridyl, quinolyl, indolyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl, pyridazinyl, pyrazinyl, thiazolyl, thienyl, thienopyrimidinyl, thienopyridinyl, purinyl, I'.a' ⁇ '-tetxahydropyridinyl, triazinyl, oxazolyl, pyrazolyl, or furanyl; wherein if Ring A contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from G;
• Ring B is thienyl, thiadiazolyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl;
• R 11 is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C ⁇ alkenyl, C ⁇ all ynyl, C ⁇ alkoxy, C ⁇ . 6 alkanoyl, C ⁇ .
• heterocyclic group contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from J;
• V is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C h alky!, C ⁇ alkcnyl, C 2-6 allcynyl, C ⁇ -6 alk ⁇ xy, Ci-ealkanoyl, Ci- ⁇ alkanoyloxy, iY-(C M alk ⁇ 4)amino, N,N-(C ⁇ .
• W and Z are independently selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ . 6 alkyl, N-(C w alkyl)amino, N,N-(C 1 . 6 alkyl) 2 amino, C w alkanoylamino, N-(C ⁇ - 6 allcyl)carbamoyl, C ⁇ .
• G, J and K are independently selected from C 2- 8allcenyI, C 2 - 8 alkynyl, Ci-galkanoyl, C ⁇ - 8 alkylsulphonyl, Ci.gaUcoxycarbonyl, carbamoyl, N-(C ⁇ -saEcyl)carbamoyl, N,N-(C ⁇ , 8 alkyl)carbamoyl, benzyloxycarbonyl, benzoyl and pheaylsulphonyl, aryl, arylCi-galkyl or (heterocyclic giOup)C ⁇ - 6 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 - ⁇ H- moiety that nitrogen may be optionally substituted by a group selected from hydrogen or C ⁇ . ⁇ alkyl;
• Q is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, ammo, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ alkyl, Ca-ealkenyl, C ⁇ alkynyl, Ci- ⁇ alcoxy, N-(Ci- 6 aUcyl)amino, N,N-(C ⁇ .. 6 al l) 2 ino ⁇ C ⁇ .
• D, D' andD are independently selected from C ⁇ punishment 6 alkyl s C 2 - f ialkenyl, Cs- f salkynyl, Cs-scycloallcyl, C3.scycloalkylC]. 6 alkyl, aryl, arylCi-galkyl, heterocyclic group, (heterocyclic group)C ⁇ .ealkyl; wherein D, D' and D 5 ' may be optionally substituted on carbon by one or
• heterocyclic group contains an - ⁇ H- moiety that nitrogen may be optionally substituted by a group selected from K;
• E,E* an E" are independently selected from -N(R*h -0". ⁇ C(O)O ⁇ , -OC(O)- s -C(OK -N(R a )C(O ⁇ -, ⁇ N(R a )C(0)N(R b K -N(R s )C(O)O-, -OC(O)N ⁇ R -C(0)N(R a , -S(O) r , ⁇ SO 2 N( a )- » -N(R a )SO 2 -; wherein R R and R b are independently selected from hydrogen or Ci-salkyl optionally substimted by one or more F and r is 0-2;
• F are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-garkyl, C 2 -salkenyl, C 2 - 6 alkynyl.
• Ring A is ⁇ yridin-4-yl, pyridin-3-yl, ⁇ yridm-2-yl, morpholin- -yl, piperidin-4-yl, piperidin-3-yl, ⁇ iperdin-2-yl, piperazin-4-yl, thiazol ⁇ 2-yl, thien-2-yl, furan-3-yl, pyrrolidin ⁇ l- yl, piperidm-l-yl t triazol-t-yl or wherein if Ring A contains an - ⁇ H- moiety that nitrogen may be optionally substituted by a group selected from G; Ring B is thienyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl; R 11 is a substituent on carbon and is selected from cyano, hydroxy, Ch l ! or a group (D-E-); wherein R 11 , including group (D-E-
• G andIC are independently selected from C ⁇ . 8 alkyl, Ca-galkenyl, j-salkynyl, arylC ⁇ .6 alkyl or (heterocyclic group)C M alkyl; wherein G and K ma be optionaUy substimted on carbon by one or more Q; Q is cyano, hydroxy, oxo, C ⁇ alkyl, C ⁇ alkenyl, C ⁇ . 6 a ⁇ koxy, C ⁇ . 6 allcanoyL C ⁇ .
• D, D' and D" are independently selected from aryl, arylCi-ea ⁇ kyl or heterocyclic group; wherein D. D 1 andD" may be optionaUy substituted on carbon by one or more P; and wherein if said heterocycle group contains an - ⁇ H- moiety that nitrogen may be optionally substituted by a group selected from K;
• E, E* and E" are independently selected from -O-, ⁇ C(G)O-, -OC(O>, -C(O>, - ⁇ (R a )C(O)-, -C(O)N(R a h -S(O) ; wherein R a is selected from hydrogen or Q.galkyl optionally substituted by one or more F and r is 0-2;
• F and F are independently selected from nitro, hydroxy, Ch lk ! C ⁇ - ⁇ alkoxy, Cwsalkan ⁇ yl, N-(Cwalkyl)amino s N,N C ⁇ - ⁇ l yl)2 mino, or Ci-galkoxycarbonyl; ' m is 0, 1, or 2, wherein the values of R 11 are the same or different;
• R 12 is F; n is O or 1.
• R 11 is selected from:
• R ⁇ R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraph [0187] - [0193], R ⁇ R 2 , R 3 , and R 4 are all H.
• the invention comprises the compounds of WO 03/024448 in which the terminal moieties -C(0)-NH-Ay ⁇ -C(0)-NH-Ay 2 , -C(0)-NH-Ar a -NH 2l and:
• the invention comprises compounds of the following structural formula (13):
• ⁇ 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];
• Ar, A, D, E, and G are as defined in JP 2003137866.
• R ⁇ R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0048] and [0049].
• R 1 , R 2 , R 3 , and R 4 are all H.
• Particular embodiments of the compounds of paragraph [0196] are those obtained by substituting the terminal moiety:
• the invention comprises compounds of the following structural formula (14): or a pharmaceutically acceptable salt thereof, wherein
• ⁇ is -NH 2 or -0H
• R 1 is H or as defined in paragraph [0046];
• R 2 , R 3 , and R 4 are as defined in paragraph [0046];
• X, Y, and A are as defined in JP 11-269146 (1999);
• R 11 is the same as R 1 of JP 11-269146 (1999). [0199] In the compounds of paragraph [0198], R 1 , R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraph [0198], R 1 , R 2 , R 3 , and R 4 are all H. Particular embodiments of the compounds of paragraph [0198] are those obtained by substituting the terminal moiety:
• the invention comprises compounds of the following structural formula (15):
• ⁇ 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, X, Q, and A are as defined in JP 11-302173 (1999); and
• R 11 is the same as R 1 of JP 11-302173 (1999). [0201]
• R ⁇ R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0048] and [0049].
• R 1 , R 2 , R 3 , and R 4 are all H.
• Particular embodiments of the compounds of paragraph [0200] are those obtained by substituting the terminal moiety:
• ⁇ , R ⁇ R 2 , R 3 , and R 4 are as defined in accordance with paragraph [0046], and preferably [0048] and [0049].
• the invention comprises compounds of the following structural formula (16):
• R 1 is H or as defined in paragraph [0046];
• R 2 , R 3 , and R 4 are as defined in paragraph [0046];
• n, Q, X, and A are as defined in JP 2001131130; and
• R u is the same as R 1 of JP 2001131130. [0203] In the compounds of paragraph [0202], R 1 , R 2 , R 3 , and R 4 are preferably as defined in paragraphs [0048] and [0049]. In other embodiments of the compounds of paragraph [0202], R 1 , R 2 , R 3 , and R 4 are all H. Particular embodiments of the compounds of paragraph [0202] are those obtained by substituting the terminal moieties:
• the invention comprises compounds of the following structural formula (17):

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• 2004
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