JP2006513205A - Benzamide inhibitor of P2X7 receptor - Google Patents

Abstract

The present invention, R ¹ to R ³ to provide a benzimide inhibitors of P2X ₇ receptor expression defined herein (I). The compounds of the present invention include inflammatory diseases such as osteoarthritis and rheumatoid arthritis; reperfusion or ischemia in allergies, asthma, COPD, cancer, stroke or heart failure, autoimmune diseases, and other disorders Useful for the treatment of IL-1 mediated disorders not limited to:
[Chemical 1]

Description

The present invention relates to novel benzamide inhibitors of the P2X ₇ receptor, methods for their preparation, intermediates useful for their preparation, pharmaceutical compositions containing them, and their use in therapy. These active compounds of the present invention are useful for inflammatory diseases such as osteoarthritis and rheumatoid arthritis; reperfusion or ischemia in allergies, asthma, COPD, cancer, stroke or heart failure, autoimmune diseases, and other disorders. Useful for treatment. These active compounds are also antagonists of the P2X ₇ receptor.

P2X ₇ receptor (formerly known as P2Z receptor), a ligand-gated ion channel, is known to be involved in a variety of cell types, primarily inflammatory / immune processes, especially Present on macrophages, mast cells, and lymphocytes (T and B). Activation of P2X ₇ receptors by extracellular nucleotides, specifically adenosine triphosphate, leads to the release of interleukin-1β (IL-1β) and the formation of giant cells (macrophages / microglia), degranulation (obesity) Cells) and proliferation (T cells), apoptosis, and L-selectin shedding (lymphocytes). P2X ₇ receptors are also on antigen-providing cells (APC), keratinocytes, salivary acinar cells (parotid gland cells), hepatocytes, and mesangial cells.

International Patent Publication Nos. WO01 / 46200, WO01 / 42194, WO / 01/44213, WO99 / 29660, WO00 / 61569, WO99 / 29661, WO99 / 29686, WO00 / 71529, and those described in WO01 / 44170, as well as U.S. Patent Application No. P2X ₇ antagonists are known in the art, such as those described in No. (Attorney Docket No. PC23106A, filing date November 12, 2002).

Benzamides, heteroaryl amides, and reverse amides used in addition to the inhibition of the P2X ₇ receptor are described in International Patent Publication No. WO97 / 22600, European Patent No. EP138,527, International Patent Publication No. WO00 / 71509, WO98. / 28269, WO99 / 17777, and WO01 / 58883.

  The present invention has the formula

Wherein R ¹ is (C ₁ -C ₆ ) alkyl, optionally (C ₃ -C ₁₀ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₀ ) heterocyclyl, or (C ₁ ~C ₁₀₎ is substituted by a heteroaryl, said (C ₁ ~C ₆₎ alkyl, (C ₃ ~C ₁₀₎ cycloalkyl, (C ₆ ~C ₁₀₎ aryl, (C ₁ ~C ₁₀₎ heterocyclyl Or (C ₁ -C ₁₀ ) heteroaryl is optionally selected from hydroxy, halogen, CN-, (C ₁ -C ₆ ) alkyl, HO (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl -NH (C = O) -, NH 2 (C = O) -, the one independently selected from (C ₁ -C ₆₎ alkoxy or (C ₃ ~C _10), the group consisting of cycloalkyl is substituted by three suitable moieties, said (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - one also be selected from It is replaced by a plurality of parts;
R ² is hydrogen, halogen, —CN, and (C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is optionally halo, hydroxy, amino, —CN, (C ₁ -C ₆₎ ) alkyl, (C ₁ ~C _{6) alkoxy, -CF 3, CF 3 O -} , (C 1 ~C 6) alkyl _{-NH -, [(C 1 ~C} 6) alkyl] ₂ -N -, (C ₁ -C ₆₎ alkyl _{-S -, (C 1 ~C 6} ) alkyl - (S = O) -, (C 1 ~C 6) alkyl _{- (SO) 2 -, (} C 1 ~C 6) alkyl - O- (C = O) -, formyl, (C ₁ ~C ₆₎ alkyl - (C = O) -, and (C ₃ -C ₆₎ from one independently selected from the group consisting of cycloalkyl 3 Substituted with appropriate moieties; and
R ³ is the formula

A suitably substituted nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl represented by ]
Or a pharmaceutically acceptable salt or solvate thereof, or a prodrug thereof.

  The present invention has the formula

Wherein R ¹ is (C ₁ -C ₆ ) alkyl, optionally (C ₃ -C ₁₀ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₀ ) heterocyclyl, or (C ₁ ~C ₁₀₎ is substituted by a heteroaryl, said (C ₁ ~C ₆₎ alkyl, (C ₃ ~C ₁₀₎ cycloalkyl, (C ₆ ~C ₁₀₎ aryl, (C ₁ ~C ₁₀₎ heterocyclyl , or (C ₁ ~C ₁₀₎ heteroaryl each optionally hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO- (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O) -, the one independently selected from (C ₁ -C ₆₎ alkoxy or (C ₃ ~C _10), the group consisting of cycloalkyl is substituted by three suitable moieties, said (C ₃ ~C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - one also be selected from It is replaced by a plurality of parts;
R ² is hydrogen, halogen, —CN, and (C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is optionally halo, hydroxy, amino, —CN, (C ₁ -C ₆₎ ) alkyl, (C ₁ ~C _{6) alkoxy, -CF 3, CF 3 O -} , (C 1 ~C 6) alkyl _{-NH -, [(C 1 ~C} 6) alkyl] ₂ -N -, (C ₁ -C ₆₎ alkyl _{-S -, (C 1 ~C 6} ) alkyl - (S = O) -, (C 1 ~C 6) alkyl _{- (SO) 2 -, (} C 1 ~C 6) alkyl - O- (C = O) -, formyl, (C ₁ ~C ₆₎ alkyl - (C = O) -, and (C ₃ -C ₆₎ from one independently selected from the group consisting of cycloalkyl 3 Replaced by the appropriate moiety;
R ³ is the formula

Wherein R ⁴ and R ⁵ are independently a group of suitable substituents such as hydrogen, halo, hydroxy, —CN, HO— (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl. (C ₁ -C ₆ ) alkyl, optionally selected from: (C ₁ -C ₆ ) alkoxy, optionally substituted with 1-3 fluorines, optionally 1-3 fluorines, HO ₂ C -, (C ₁ ~C ₆₎ alkyl -O- (C = O) -, R 6 R 8 N (O 2 S) -, (C 1 ~C 6) alkyl - (O ₂ S) -NH-, (C ₁ ~C ₆₎ alkyl _{-O 2 S - [(C 1} ~C 6) alkyl ^{-N] -, R 6 R 8} N (C = O) -, R 6 R 8 N (CH 2) m - , (C ₆ ~C ₁₀₎ the aryl, (C ₃ ~C ₈₎ cycloalkyl, (C ₁ ~C ₁₀₎ heteroaryl, (C ₁ ~C ₁₀₎ heterocyclyl, (C ₆ ~C ₁₀₎ the aryl -O- , (C ₃ ~C ₈₎ cycloalkyl -O -, substituted (C ₁ ~C ₁₀₎ heteroaryl -O-, and (C ₁ ~C ₁₀₎ heterocyclyl -O- And
R ⁷ is independently hydrogen, (C ₁ -C ₆ ) alkyl, hydroxy, —CN, (C ₁ -C ₆ ) alkoxy-, (C ₂ -C), optionally substituted with 1 to 3 halogens. ₆₎ alkenoxy, (C ₁ -C ₆₎ alkyl _{-SO 2 -, NH 2 -,} ((C 1 ~C 6) _{alkyl) n -N -, n -N- (} (C 2 ~C 6) alkenyl) , ((C ₂ ~C _{6) alkynyl) n -N-, NH 2 (C} = O) -, (C 1 ~C 6) alkyl - (C = O) n - , ((C 1 ~C 6) _{alkyl) n -N- (C = O)} -, (C 2 ~C 6) alkenyl - (C = O) n - , ((C 2 ~C 6) _{alkenyl) n -N- (C = O)} - , (C ₂ ~C ₆₎ alkynyl - (C = O) n - , ((C 2 ~C 6) _{alkynyl) n -N- (C = O)} -, (C 1 ~C 6) alkyl - (C _{= O) -, (C 2} ~C 6) alkenyl) - (C = O) - , (C 2 ~C 6) alkynyl - (C = O) -, (C 3 ~C 10) cycloalkyl - (C = O) -, ((C 1 ~C 10) heterocyclyl) - (C = O) - , C ₆ -C ₁₀₎ aryl - (C = O) -, (C 1 ~C 10) heteroaryl - (C = O) -, (C 1 ~C 6) alkyl - (C = O) O - , ( C ₂ -C ₆₎ alkenyl - (C = O) O - , (C 2 ~C 6) alkynyl - (C = O) O - , (C 1 ~C 6) alkyl -O (C = O) -, (C ₂ ~C ₆₎ alkenyl -O (C = O) -, (C 2 ~C 6) alkynyl -O (C = O) -, (C 3 ~C 10) cycloalkyl, (C ₆ ~C ₁₀ ) aryl is selected from (C ₁ -C ₁₀₎ heterocyclyl, and (C ₁ -C ₁₀₎ group of suitable substituents such as heteroaryl;
Where R ⁴ , R ⁵ , and R ⁷ are each optionally on any aliphatic or aromatic carbon atom, halo, hydroxy, amino, —CN, (C ₁ -C ₆ ) alkyl, (C ₁ -C _{6) alkoxy, -CF 3, CF 3 O -} , (C 1 ~C 6) alkyl _{-NH -, [(C 1 ~C} 6) _{alkyl] 2 -N -, (C 1} ~C 6) alkyl _{-S -, (C 1 ~C 6} ) alkyl - (S = O) -, (C 1 ~C 6) alkyl _{- (SO) 2 -, (} C 1 ~C 6) alkyl -O- (C = O) -, formyl, (C ₁ ~C ₆₎ alkyl - (C = O) -, and (C ₃ ~C _{6) 3} pieces of appropriate parts from one independently selected from the group consisting of cycloalkyl May be replaced by;
R ⁶ and R ⁸ are each independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, HO- (C ₂ -C ₆ ) alkyl, and (C ₃ -C ₈ ) cycloalkyl. Or, optionally, R ⁶ and R ⁸ together with the nitrogen atom to which they are attached may form a 3-8 membered heterocycle. )
In nitrogen bond (C ₁ ~C ₁₀₎ represented heterocyclyl;
n is an integer from 0 to 2; and
m is an integer from 0 to 2. ]
Or a pharmaceutically acceptable salt or solvate thereof or a prodrug thereof.

  The present invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula I. The acids used in the preparation of the pharmaceutically acceptable acid addition salts of the above basic compounds of the invention are non-toxic acid addition salts, i.e. chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphorus. Acid salt, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharide, Benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (ie, 1,1'-methylene-bis- (2-hydroxy-3-naphthoic acid) A salt containing a pharmacologically acceptable anion such as a salt)).

  The invention also relates to base addition salts of compounds of formula I. Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of these compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts are derived from such pharmacologically acceptable cations such as alkali metal cations (eg potassium and sodium) and alkaline earth metal cations (eg potassium and magnesium). And ammonium salts such as N-methylglucamine- (meglumine) or water-soluble amine addition salts, lower alkanol ammonium salts, and other pharmaceutically acceptable organic amine base salts, but are not limited thereto. .

  The invention also encompasses pharmaceutical compositions containing a prodrug of the compound of formula I. Compounds of formula I having a free amino, amido, hydroxy, or carboxyl group can be converted into prodrugs. Prodrugs include either amino acid residues or a polypeptide chain of two or more (eg 2, 3, or 4) amino acid residues that are covalently linked through a peptide. And a compound bonded to a free amino, amide, hydroxy, or carboxyl group of the above compound. These amino acid residues include 20 naturally occurring amino acids, usually represented by three letter codes, such as 4-hydroxyproline, hydroxylysine, demosin, isodesomosin, 3-methylhistidine, norvaline, β- Also included are alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides, and alkyl esters are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug side chain.

  The present invention also includes compounds of Formula I that contain a protecting group. One of ordinary skill in the art will also appreciate that certain protecting groups can be prepared with certain protecting groups that are useful for purification or storage and can be removed prior to administration to a patient. For protection and deprotection of functional groups, edited by JWF McOmie, “Protective Groups in Organic Chemistry”, Plenum Press (1973) and TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis”, 3rd edition, Wiley-Interscience (1999) It is described in.

  The compounds of the present invention include all stereoisomers (eg cis and trans isomers) and all optical isomers (eg R and S enantiomers) of compounds of formula I, as well as racemic, diastereo, and such Other mixtures of isomers are included.

The compounds, salts, and prodrugs of the present invention can exist in several tautomeric forms, including enol and imine forms, keto and enamine forms, geometric isomers, and mixtures thereof. All such tautomers are included within the scope of the present invention. Tautomers exist as a mixture of a set of tautomers in solution. In the solid form, usually one kind of tautomer is mainly used. Even if one kind of tautomer is described, the present invention includes all tautomers of these compounds. In one example of a tautomeric structure, R ³ is a formula

This is the case of

  One skilled in the art will recognize this group as its tautomer.

You should understand that you can also draw as.

  The present invention also includes the atropisomers of the present invention. Atropisomers refer to compounds of formula I that can be separated into rotationally hindered isomers.

  The compounds of the present invention can contain double bonds such as olefins. When such a bond is present, the compounds of the invention exist as cis and trans forms and as mixtures thereof.

“Suitable substituent” is intended to mean a chemically and pharmaceutically acceptable functional group, ie, a moiety that does not abolish the biological activity of the compounds of the invention. Such suitable substituents can be routinely selected by those skilled in the art. Examples of suitable substituents are halo, perfluoroalkyl, perfluoroalkoxy, alkyl, alkenyl, alkynyl, hydroxy, oxo, mercapto, alkylthio, alkoxy, aryl or heteroaryl groups Aryloxy or heteroaryloxy group, aralkyl or heteroaralkyl group, aralkoxy or heteroaralkoxy group, HO- (C = O)-group, amino group, alkylamino and dialkylamino group, carbamoyl group, alkylcarbonyl group, Examples thereof include, but are not limited to, an alkoxycarbonyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an arylcarbonyl group, an aryloxycarbonyl group, an alkylsulfonyl group, and an arylsulfonyl group. One skilled in the art should appreciate that many substituents can be substituted with additional substituents. Further examples of suitable substituents include those cited in the definition of compounds of formula I, including R ^{1 to} R ⁷ as defined herein before.

  The term “spiro” as used herein refers to a bond between two groups, between substituents, etc.

Can be represented by

As used herein, the term “alkyl” and the alkyl portion of other groups referred to herein (eg, alkoxy) may be linear or branched (methyl, ethyl, n-propyl, isopropyl, n- butyl, iso - butyl, secondary butyl, etc. tertiary butyl); fluorine, optionally, chlorine, trifluoromethyl, (C ₁ -C ₆₎ alkoxy, (C ₆ -C ₁₀₎ aryloxy, trifluoro Substituted by 1 to 3 suitable substituents as defined above, such as methoxy, difluoromethoxy, or (C ₁ -C ₆ ) alkyl. As used herein, the term “each of the above alkyls” means any of the foregoing alkyl moieties within a group such as alkoxy, alkenyl, or alkylamino. Preferred alkyl includes (C ₁ -C ₆ ) alkyl, more preferred is (C ₁ -C ₄ ) alkyl, and most preferred is methyl and ethyl.

As used herein, the term “cycloalkyl” refers to a monocyclic, bicyclic, or tricyclic carbocycle (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclo Hexenyl, bicyclo [2.2.1] heptanyl, bicyclo [3.2.1] octanyl, and bicyclo [5.2.0] nonanyl); these are optionally one or two double containing bonds or fluorine optionally chlorine, trifluoromethyl, (C ₁ ~C ₆₎ alkoxy, (C ₆ ~C ₁₀₎ aryloxy, trifluoromethoxy, difluoromethoxy or (C ₁ -C, ₆ ) Substituted by 1 to 3 suitable substituents as defined above, such as alkyl.

  The term “halogen” as used herein includes fluorine, chlorine, bromine, or iodine, or fluoride, chloride, bromide, iodide.

The term “alkenyl” as used herein refers to a straight or branched unsaturated radical of 2 to 6 carbon atoms, such as, but not limited to, ethenyl, 1-propenyl, 2-propenyl (allyl) ), Iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like; optionally fluorine, chlorine, trifluoromethyl, (C ₁ -C ₆ ) alkoxy, (C _6- Substituted by 1 to 3 suitable substituents as defined above, such as C ₁₀ ) aryloxy, trifluoromethoxy, difluoromethoxy, or (C ₁ -C ₆ ) alkyl.

The term “alkynyl” as used herein means a straight or branched hydrocarbon chain radical having one triple bond, such as, but not limited to, ethynyl, propynyl, butynyl, etc .; any fluorine selection, chlorine, trifluoromethyl, (C ₁ -C ₆₎ alkoxy, (C ₆ ~C ₁₀₎ aryloxy, trifluoromethoxy, from one such difluoromethoxy or (C ₁ -C ₆₎ alkyl, Substituted by three suitable substituents as defined above.

  As used herein, the terms “carbonyl” or “(C═O)” (used in phrases such as alkylcarbonyl, alkyl- (C═O) —, or alkoxycarbonyl) refer to the> C═O moiety. And the junction of a second part such as an alkyl or amino group (ie an amide group). Alkoxycarbonylamino (ie alkoxy (C═O) —NH—) means an alkyl group of carbamate. A carbonyl group is also defined herein with the same meaning as (C═O). Alkoxycarbonylamino means a group such as acetamide.

  As used herein, the term “oxo” is used herein to refer to a double bond oxygen (═O) radical whose bond partner is a carbon atom. Such radicals can also be considered carbonyl groups.

As used herein, the term “(C ₁ -C ₄ ) alkyl-O ₂ S — [(C ₁ -C ₄ ) alkyl-N]” refers herein to the formula

Used to refer to the radical of

The term “aryl” as used herein refers to an aromatic radical such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and optionally fluorine, chlorine, trifluoromethyl, (C ₁ -C ₆ ) alkoxy, ( Substituted by 1 to 3 suitable substituents as defined above, such as C ₆ -C ₁₀ ) aryloxy, trifluoromethoxy, difluoromethoxy, or (C ₁ -C ₆ ) alkyl.

The term “heteroaryl” as used herein refers to an aromatic heterocyclic group usually having one heteroatom selected from O, S, and N in the ring. In addition to the heteroatoms, the aromatic group can optionally have up to 4 N atoms in the ring. For example, heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (eg, 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (eg, 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (eg 1, 2, 3-triazolyl, 1, 2, 4-triazolyl), oxadiazolyl (eg 1, 2, 3-oxadiazolyl), thiadiazolyl (eg 1, 3 , 4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, include indolyl; fluorine, optionally, chlorine, trifluoromethyl, (C ₁ -C ₆₎ alkoxy, (C ₆ -C ₁₀₎ aryloxy, trifluoromethoxy, difluoromethoxy or, (C ₁ ~C ₆₎ alkyl Is substituted with one of the three suitable substituents as defined above. Particularly preferred heteroaryl include oxazolyl, imidazolyl, pyridyl, thienyl, furyl, thiazolyl, and pyrazolyl.

As used herein, the term “heterocyclic” contains 1 to 9 carbon atoms and 1 to 4 heteroatoms selected from N, O, S (O) _n , or NR. Refers to a cyclic group. Examples of such rings include azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, Examples include thiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzooxazinyl and the like. Examples of the monocyclic saturated or partially saturated ring system are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1. -Yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl 1,3-oxazolidine-3-yl, isothiazolidine, 1,3-thiazolidine-3-yl, 1,2-pyrazolidine-2-yl, 1,3-pyrazolidin-1-yl, thiomorpholin-yl, 1 , 2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl, 1,2-tetrahydrodiazin-2-yl, 1, Such as 3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl, 1,2,5-oxathiazin-4-yl; optionally containing one or two double bonds and fluorine and optionally, chlorine, trifluoromethyl, (C ₁ ~C ₆₎ alkoxy, (C ₆ ~C ₁₀₎ aryloxy, trifluoromethoxy, difluoromethoxy, or (C ₁ ~C _6), such as alkyl Substituted by 1 to 3 suitable substituents as defined above. Preferred heterocycles include tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.

  As used herein, a nitrogen heteroatom means N =,> N, and -NH, -N = means a nitrogen double bond, and> N is a nitrogen containing a bond of two bonds And -N means nitrogen containing one bond.

As used herein, an “embodiment” refers to a particular taxonomic group of compounds or is used for a jumping subclass. Such subclasses may be recognized by certain special substituents such as certain R ¹ or R ³ groups. Other subclasses include various substitutions, such as all compounds where R ² is chlorine and R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl. Recognized by a combination of groups. The phrase “in combination with each of the foregoing embodiments” means a combination of the identified embodiment with each embodiment identified earlier in the specification. Thus, embodiments of compounds wherein R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl “in combination with each of the foregoing embodiments” are described herein Means additional embodiments including combinations with each of the embodiments previously identified in.

Thus, the present invention also provides that (R ¹ ) is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, and the (C ₁ -C ₄ ) alkyl or (C _3- C ₁₀₎ hydroxyalkyl cycloalkyl optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) Substituted with 1 to 3 suitable moieties independently selected from the group consisting of —, NH ₂ (C═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl Wherein (C ₃ -C ₁₀ ) cycloalkyl provides a compound optionally substituted by one or more moieties selected from halogen or (C ₁ -C ₆ ) alkyl-.

The present invention further relates to (C ₁ -C ₄ ) alkyl, optionally substituted by (C ₆ -C ₁₀ ) aryl, wherein R ¹ is (C ₁ -C ₄ ) alkyl or (C ₆ -C _10). ) aryl hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ -C ₆₎ alkyl -NH (C = O) -, NH Substituted with 1 to 3 suitable moieties independently selected from the group consisting of ₂ (C═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, (C ₃ -C ₁₀ ) cycloalkyl provides a compound that is optionally substituted from halogen or by (C ₁ -C ₆ ) alkyl-selected one or more moieties.

The present invention further contemplates compounds wherein R ² is halogen and (C ₁ -C ₆ ) alkyl, preferably compounds wherein R ² is chlorine, methyl or ethyl.

In one embodiment of the invention, R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄ ) alkyl, preferably Is hydrogen or methyl and R ⁷ is independently selected from the group of appropriate substituents such as hydrogen and (C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is optionally halogen, _{hydroxy, CN -, (C 1 ~C} 6) alkoxy -, (C ₂ ~C ₆₎ alkenoxy, (C ₁ ~C ₆₎ alkyl _{-SO 2 -, NH 2 -,} ((C 1 ~C 6) alkyl _{) n -N -, ((C} 2 ~C 6) _{alkenyl) n -N -, ((C} 2 ~C 6) _{alkynyl) n -N-, NH 2 (C} = O) -, (C 1 ~C ₆₎ alkyl - (C = O) n - , ((C 1 ~C 6) _{alkyl) n -N- (C = O)} -, (C 2 ~C 6) alkenyl - (C = O) N-, ((C ₂ ~C _{6) alkenyl) n -N- (C = O)} -, (C 2 ~C 6) alkynyl - (C = O) N - , ((C 2 ~C 6) _{alkynyl) n -N- (C = O)} -, (C 1 ~C 6) alkyl - (C = O) -, (C 2 ~ C ₆₎ alkynyl - (C = O) -, (C 2 ~C 6) alkynyl - (C = O) -, (C 3 ~C 10) cycloalkyl - (C = O) -, (C 1 ~C ₁₀₎ heterocyclyl - (C = O) -, (C 6 ~C 10) aryl - (C = O), ( C 1 ~C 10) heteroaryl - (C = O), ( C 1 ~C 6) alkyl - (C = O) O - , (C 2 ~C 6) alkenyl - (C = O) O - , (C 2 ~C 6) alkynyl - (C = O) O - , (C 1 ~C 6) alkyl -O (C = O) -, (C 2 ~C 6) alkenyl -O- (C = O) -, (C 2 ~C 6) alkynyl -O- (C = O) -, (C 3 ~ Substituted with 1 to 3 substituents independently selected from C ₁₀ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₀ ) heterocyclyl, and (C ₁ -C ₁₀ ) heteroaryl It is; R ⁷ is optionally any cyclic aliphatic or aromatic carbon On atoms, halo, hydroxy, _{amino, -CN, (C 1 ~C 4} ) alkyl, (C ₁ ~C _{4) alkoxy, -CF 3, CF 3 O -} , (C 1 ~C 4) alkyl -NH _{-, [(C 1 ~C 4} ) _{alkyl] 2 -N -, (C 1} ~C 4) alkyl _{-S -, (C 1 ~C 4} ) alkyl - (S = O) -, (C 1 ~C ₄₎ alkyl _{- (SO 2) -, (} C 1 ~C 4) alkyl -O- (C = O) -, formyl, (C ₁ -C ₄₎ alkyl - (C = O) -, and (C ₃ -C ₆₎ may be replaced by three suitable portion from one independently selected from the group consisting of cycloalkyl.

Another embodiment of the present invention is a compound wherein R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄₎ alkyl, preferably hydrogen or methyl, also R ⁷ is hydrogen.

A further embodiment of the invention is a compound wherein R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄₎ alkyl, preferably hydrogen or methyl, also R ⁷ is (C ₁ -C ₄₎ alkyl, halogen, optionally, hydroxy, -CN, (C ₁ -C ₄₎ alkoxy -, (C ₂ -C ₄₎ alkenoxy, and (C ₁ -C ₄₎ alkyl -SO ₂ - it is substituted with one to three substituents selected independently from the substituents. Preferably R ⁷ is optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxy, —CN, or (C ₁ -C ₄ ) alkoxy-.

The present invention further provides compounds wherein R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄ ) alkyl. , Preferably hydrogen or methyl, and R ⁷ is (C ₁ -C ₄ ) alkyl, optionally NH _2- , ((C ₁ -C ₄ ) alkyl) _n -N-, ((C ₂ -C _{4) alkenyl) n -N -, ((C} 2 ~C 4) _{alkynyl) n -N-, NH 2 (C} = O) -, (C 1 ~C 4) alkyl - (C = O) n _{-, ((C 1 ~C 4} ) _{alkyl) n -N- (C = O)} -, (C 2 ~C 4) alkenyl - (C = O) n - , ((C 2 ~C 4) alkenyl) _{n -N- (C = O) -} , (C 2 ~C 4) alkynyl - from - (C = O) N-, and ((C ₂ ~C ₄₎ alkynyl) _n -N- (C = O) Substituted with 1 to 3 independently selected substituents. Preferably R ⁷ is optionally NH ₂ —, ((C ₁ -C ₄ ) alkyl) _n —N—, NH ₂ (C═O) —, (C ₁ -C ₄ ) alkyl- (C═O ) n-, and ((C ₁ ~C _{4) alkyl) n -N- (C = O)} - substituted with 1-3 substituents from one independently selected from (C ₁ -C ₄₎ Alkyl.

The present invention also provides compounds wherein R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄ ) alkyl. , Preferably hydrogen or methyl, and R ⁷ is (C ₁ -C ₄ ) alkyl, optionally (C ₁ -C ₄ ) alkyl- (C═O) —, (C ₂ -C ₄ ). alkenyl - (C = O) -, (C 2 ~C 4) alkynyl - (C = O) -, (C 3 ~C 10) cycloalkyl - (C = O) -, (C 1 ~C 10) heterocyclyl - (C = O) -, (C 6 ~C 10) aryl - from one selected from independently - (C = O) -, and (C ₁ -C ₁₀₎ heteroaryl - (C = O) Substituted with 3 substituents, preferably R ⁷ is optionally (C ₁ -C ₄ ) alkyl- (C═O) —, (C ₃ -C ₁₀ ) cycloalkyl- (C═O) —, (C ₁ ~C ₁₀₎ heterocyclyl - (C = O) -, (C 6 ~C 10) aryl - (C = O) -, and (C ₁ ~C ₁₀₎ Heteroaryl - (C = O) - substituted with 1-3 substituents from one independently selected from (C ₁ -C ₄₎ alkyl.

Another embodiment of the present invention is a compound wherein R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄₎ alkyl, preferably hydrogen or methyl, also R ⁷ is (C ₁ -C ₄₎ alkyl, optionally (C ₁ -C ₄₎ alkyl - (C = O) O - , (C 2 -C ₄₎ alkenyl - (C = O) O - , (C 2 ~C 4) alkynyl - (C = O) O - , (C 1 ~C 4) alkyl -O (C = O) -, (C Substituted with 1 to 3 substituents independently selected from ₂ -C ₄ ) alkenyl-O (C═O) — and (C ₂ -C ₄ ) alkynyl-O (C═O) — . Preferably R ⁷ is optionally (C ₁ -C ₄₎ alkyl - from one independently selected from - (C = O) O- and (C ₁ -C ₄₎ alkyl -O (C = O) (C ₁ -C ₄ ) alkyl substituted with 3 substituents.

The present invention further provides compounds wherein R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄ ) alkyl. , Preferably hydrogen or methyl, and R ⁷ is (C ₁ -C ₄ ) alkyl, optionally (C ₃ -C ₁₀ ) cycloalkyl-, (C ₆ -C ₁₀ ) aryl-, (C Substituted with 1 to 3 substituents independently selected from ₁ -C ₁₀ ) heterocyclyl-, and (C ₁ -C ₁₀ ) heteroaryl-.

In one embodiment of the invention, R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄ ) alkyl, preferably Is hydrogen or methyl, and R ⁷ is independently selected from the group of hydrogen and a suitable substituent such as (C ₁ -C ₆ ) alkyl, wherein the (C ₁ -C ₆ ) alkyl is optionally halogen, _{hydroxy, -CN, (C 1 ~C 6} ) alkoxy -, (C ₂ ~C ₆₎ alkenoxy, (C ₁ ~C ₆₎ alkyl _{-SO 2 -, NH 2 -,} ((C 1 ~C 6) alkyl _{) n -N -, ((C} 2 ~C 6) _{alkenyl) n -N -, ((C} 2 ~C 6) _{alkynyl) n -N-, NH 2 (C} = O) -, (C 1 ~C ₆₎ alkyl - (C = O) n - , ((C 1 ~C 6) _{alkyl) n -N- (C = O)} -, (C 2 ~C 6) alkenyl - (C = O) N-, ((C ₂ ~C _{6) alkenyl) n -N- (C = O)} -, (C 2 ~C 6) alkynyl (C = O) N -, ((C 2 ~C 6) _{alkynyl) n -N- (C = O)} -, (C 1 ~C 6) alkyl - (C = O) -, (C 2 ~C ₆₎ alkenyl - (C = O) -, (C 2 ~C 6) alkynyl - (C = O) -, (C 3 ~C 10) cycloalkyl - (C = O) -, (C 1 ~C 10 ) heterocyclyl - (C = O) -, (C 6 ~C 10) aryl - (C = O), ( C 1 ~C 10) heteroaryl - (C = O), ( C 1 ~C 6) alkyl - (C = O) O -, (C 2 ~C 6) alkenyl - (C = O) O - , (C 2 ~C 6) alkynyl - (C = O) O - , (C 1 ~C 6) alkyl -O (C = O) -, (C 2 ~C 6) alkenyl -O- (C = O) -, (C 2 ~C 6) alkynyl -O- (C = O) -, (C 3 ~C ₁₀₎ cycloalkyl, substituted with (C ₆ -C ₁₀₎ aryl, (C ₁ -C ₁₀₎ heterocyclyl, and (C ₁ -C ₁₀₎ from one independently selected from heteroaryl three substituents ; R ⁷ optionally may be any cyclic aliphatic or aromatic carbon On atoms, halo, hydroxy, _{amino, -CN, (C 1 ~C 4} ) alkyl, (C ₁ ~C _{4) alkoxy, -CF 3, CF 3 O -} , (C 1 ~C 4) alkyl -NH _{-, [(C 1 ~C 4} ) _{alkyl] 2 -N -, (C 1} ~C 4) alkyl _{-S -, (C 1 ~C 4} ) alkyl - (S = O) -, (C 1 ~C ₄₎ alkyl _{- (SO 2) -, (} C 1 ~C 4) alkyl -O- (C = O) -, formyl, (C ₁ -C ₄₎ alkyl - (C = O) -, and (C ₃ -C ₆₎ may be replaced by three suitable portion from one independently selected from the group consisting of cycloalkyl.

Another embodiment of the invention is a compound wherein R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄₎ alkyl, preferably hydrogen or methyl, also R ⁷ is hydrogen.

A further embodiment of the present invention is a compound wherein R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄₎ alkyl, preferably hydrogen or methyl, also R ⁷ is (C ₁ -C ₄₎ alkyl, halogen, optionally, hydroxy, -CN, (C ₁ -C ₄₎ alkoxy -, (C ₂ -C ₄₎ alkenoxy, and (C ₁ -C ₄₎ alkyl - (SO ₂₎ - it is substituted with 3 substituents from one independently selected from. Preferably R ⁷ is optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxy, —CN, or (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) Alkyl.

Furthermore, the present invention is a compound wherein R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄ ) alkyl, Preferably it is hydrogen or methyl, and R ⁷ is (C ₁ -C ₄ ) alkyl, optionally NH _2- , ((C ₁ -C ₄ ) alkyl) _n -N-, ((C _2- C _{4) alkenyl) n -N -, ((C} 2 ~C 4) _{alkynyl) n -N-, NH 2 (C} = O) -, (C 1 ~C 4) alkyl - (C = O) N- , ((C ₁ ~C _{4) alkyl) n -N- (C = O)} -, (C 2 ~C 4) alkenyl - (C = O) n - , ((C 2 ~C 4) alkenyl) _n -N- (C = O) -, (C 2 ~C 4) alkynyl - (C = O) N-, and ((C ₂ ~C _{4) alkynyl) n -N- (C = O)} - independent of the Is substituted with 1 to 3 substituents selected. Preferably R ⁷ is optionally NH ₂ —, ((C ₁ -C ₄ ) alkyl) _n —N—, NH ₂ (C═O) —, (C ₁ -C ₄ ) alkyl- (C═O ) n-, and ((C ₁ ~C _{4) alkyl) n -N- (C = O)} - substituted with 1-3 substituents from one independently selected from (C ₁ -C ₄₎ Alkyl.

The present invention also provides compounds wherein R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄ ) alkyl. , Preferably hydrogen or methyl, and R ⁷ is (C ₁ -C ₄ ) alkyl, optionally (C ₁ -C ₄ ) alkyl- (C═O) —, (C ₂ -C ₄ ). alkenyl - (C = O) -, (C 2 ~C 4) alkynyl - (C = O) -, (C 3 ~C 10) cycloalkyl - (C = O) -, (C 1 ~C 10) heterocyclyl - (C = O) -, (C 6 ~C 10) aryl - from one selected from independently - (C = O) -, and (C ₁ -C ₁₀₎ heteroaryl - (C = O) Substituted with 3 substituents, preferably R ⁷ is optionally (C ₁ -C ₄ ) alkyl- (C═O) —, (C ₃ -C ₁₀ ) cycloalkyl- (C═O) —, (C ₁ ~C ₁₀₎ heterocyclyl - (C = O) -, (C 6 ~C 10) aryl - (C = O) -, and (C ₁ ~C ₁₀₎ f (C ₁ -C ₄ ) alkyl substituted with 1 to 3 substituents independently selected from teroaryl- (C═O) —.

Another embodiment of the invention is a compound wherein R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄₎ alkyl, preferably hydrogen or methyl, also R ⁷ is (C ₁ -C ₄₎ alkyl, optionally (C ₁ -C ₄₎ alkyl - (C = O) O - , (C 2 -C ₄₎ alkenyl - (C = O) O - , (C 2 ~C 4) alkynyl - (C = O) O - , (C 1 ~C 4) alkyl -O (C = O) -, (C Substituted with 1 to 3 substituents independently selected from ₂ -C ₄ ) alkenyl-O (C═O) — and (C ₂ -C ₄ ) alkynyl-O (C═O) — . Preferably R ⁷ is optionally (C ₁ -C ₄₎ alkyl - from one independently selected from - (C = O) O- and (C ₁ -C ₄₎ alkyl -O (C = O) (C ₁ -C ₄ ) alkyl substituted with 3 substituents.

The present invention further provides compounds wherein R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V), wherein R ⁴ and R ⁵ are independently hydrogen or (C ₁ -C ₄ ) alkyl. , Preferably hydrogen or methyl, and R ⁷ is (C ₁ -C ₄ ) alkyl, optionally (C ₃ -C ₁₀ ) cycloalkyl-, (C ₆ -C ₁₀ ) aryl-, (C Substituted with 1 to 3 substituents independently selected from ₁ -C ₁₀ ) heterocyclyl-, and (C ₁ -C ₁₀ ) heteroaryl-.

The present invention also provides that R ³ has the formula (IV):

Wherein R ⁴ is hydrogen or methyl, and
R ⁷

Selected from the group consisting of ]
A compound of formula (I) which is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl represented by

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), R ⁴ is hydrogen or methyl, and R ⁷ is

A compound of formula (I) is provided.

The invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), R ⁴ is hydrogen or methyl, and R ⁷ is

Consider a compound of formula (I) selected from the group consisting of:

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), R ⁴ is hydrogen or methyl, and R ⁷ is

A compound of formula (I) is provided.

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), R ⁴ is hydrogen or methyl, and R ⁷ is

A compound of formula (I) selected from:

Finally, the present invention further provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), R ⁴ is hydrogen or methyl, and R ⁷ is

A compound of formula (I) selected from:

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from the group consisting of and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from the group consisting of and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

And
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

And
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from the group consisting of and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - to examine compounds of formula substituted (I) by one or more moieties selected from.

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from the group consisting of and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

And
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

And
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The present invention further provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

Finally, the invention further provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV)
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from the group consisting of
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from the group consisting of
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

And
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halide, or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).
R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

And
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from the group consisting of
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - to examine compounds of formula substituted (I) by one or more moieties selected from.

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from the group consisting of
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - to examine compound of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

And
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

And
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The present invention further provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV);
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

Finally, the invention further provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (IV)
R ⁴ is hydrogen or methyl,
R ⁷ is

Selected from
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The invention also provides that R ³ is represented by formula (V)

A nitrogen bond (C ₁ ~C ₁₀₎ heterocyclyl,
R ⁴ and R ⁵ are independently hydrogen or methyl, and
R ⁷ is

A compound of formula (I) selected from the group consisting of:

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V), R ⁴ and R ⁵ are independently hydrogen or methyl, and R ⁷ is

A compound of formula (I) is provided.

The invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V), R ⁴ and R ⁵ are independently hydrogen or methyl, and R ⁷ is

Consider a compound of formula (I) selected from the group consisting of:

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V), R ⁴ and R ⁵ are independently hydrogen or methyl, and R ⁷ is

A compound of formula (I) is provided.

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V), R ⁴ and R ⁵ are independently hydrogen or methyl, and R ⁷ is

A compound of formula (I) selected from:

Finally, the present invention further provides that R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V), R ⁴ and R ⁵ are independently hydrogen or methyl, and R ⁷ is

A compound of formula (I) selected from:

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from the group consisting of and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halide, or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from the group consisting of and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

And
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halide, or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

And
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from the group consisting of and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - to examine compounds of formula substituted (I) by one or more moieties selected from.

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from the group consisting of and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - to examine compound of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

And
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halide, or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

And
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halide, or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The invention further provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halide, or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

Finally, the invention further provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from the group consisting of
R ² is chlorine, methyl or ethyl, and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halide, or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from the group consisting of
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

And
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halide, or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

And
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from the group consisting of
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - to examine compounds of formula substituted (I) by one or more moieties selected from.

The present invention also provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from the group consisting of
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - to examine compound of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

And
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halide, or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

And
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halide, or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

The invention further provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₃ -C ₁₀ ) cycloalkyl, wherein (C ₁ -C ₄ ) alkyl or (C ₃ -C ₁₀ ) cycloalkyl is hydroxy optionally _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C ═O) —, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halide, or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

Finally, the invention further provides that R ³ is a nitrogen-bonded (C ₁ -C ₁₀ ) heterocyclyl of formula (V);
R ⁴ and R ⁵ are independently hydrogen or methyl,
R ⁷ is

Selected from
R ² is chlorine, methyl, or ethyl; and
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with (C ₆ -C ₁₀ ) aryl, wherein (C ₁ -C ₄ ) alkyl or (C ₆ -C ₁₀ ) aryl is optionally selected in hydroxy, _{halogen, CN -, (C 1 ~C} 6) alkyl, HO (C ₁ ~C ₆₎ alkyl, (C ₁ ~C ₆₎ alkyl -NH (C = O) -, NH 2 (C = O )-, (C ₁ -C ₆ ) alkoxy, or (C ₃ -C ₁₀ ) cycloalkyl, substituted with 1 to 3 suitable moieties independently selected from the group (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - provides compounds of formula substituted by one or more moieties selected from (I).

Examples of compounds of formula I are
2-chloro-5- (3-ethyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -N- (1-hydroxy-cycloheptylmethyl) -benzamide,
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (3-methoxymethyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -benzamide,
2-chloro-5- (3-cyclopropyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -N- (1-hydroxy-cycloheptylmethyl) -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3- (2-hydroxy-ethyl) -5-oxo-4,5-dihydro- [1,2,4] triazole-1- Il] -benzamide,
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (5-oxo-3-phenyl-4,5-dihydro- [1,2,4] triazol-1-yl) -benzamide;
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (5-oxo-3-pyridin-4-yl-4,5-dihydro- [1,2,4] triazol-1-yl) -Benzamide,
2-chloro-N- (1-hydroxy-cyclohexylmethyl) -5- (3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -benzamide,
2-Chloro-N- [2- (2-chloro-phenyl) -ethyl] -5- (3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -Benzamide,
2-chloro-5- (3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -N- (1-p-tolyl-cyclohexylmethyl) -benzamide,
2-chloro-5- (3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -N- (1-p-tolyl-cyclohexylmethyl) -benzamide,
2-Chloro-5- [4- (2,3-dihydroxy-propyl) -3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -N- ( 1-hydroxy-cycloheptylmethyl) -benzamide,
2-Chloro-5- {4-[(cyclopropylmethyl-carbamoyl) -methyl] -3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl} -N -(1-hydroxy-cycloheptylmethyl) -benzamide,
2-Chloro-5- (4-dimethylcarbamoylmethyl-3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -N- (1-hydroxy-cycloheptyl) Methyl) -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (3-methyl-4-methylcarbamoylmethyl-5-oxo-4,5-dihydro- [1,2,4] triazole-1- Yl) -benzamide,
2-Chloro-5- (4-ethylcarbamoylmethyl-3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -N- (1-hydroxy-cycloheptyl) Methyl) -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (3-methyl-4-{[(oxetane-3-ylmethyl) -carbamoyl] -methyl} -5-oxo-4,5-dihydro -[1, 2, 4] triazol-1-yl) -benzamide,
5- [4- (Azetidin-3-ylcarbamoylmethyl) -3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl] -2-chloro-N- ( 1-hydroxy-cycloheptylmethyl) -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3-methyl-5-oxo-4- (pyrrolidin-3-ylcarbamoylmethyl) -4,5-dihydro- [1, 2, 4] triazol-1-yl] -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3-methyl-5-oxo-4- (piperidin-4-ylcarbamoylmethyl) -4,5-dihydro- [1, 2, 4] triazol-1-yl] -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {3-methyl-5-oxo-4-[(tetrahydro-pyran-4-ylcarbamoyl) -methyl] -4,5-dihydro- [1, 2, 4] triazol-1-yl} -benzamide,
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {3-methyl-5-oxo-4-[(tetrahydro-furan-3-ylcarbamoyl) -methyl] -4,5-dihydro- [1, 2, 4] triazol-1-yl} -benzamide,
2-Chloro-5- [4- (3-dimethylamino-2-hydroxy-propyl) -3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl)- N- (1-hydroxy-cycloheptylmethyl) -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-hydroxy-3-pyrrolidin-1-yl-propyl) -3-methyl-5-oxo-4,5-dihydro -[1, 2, 4] triazol-1-yl] -benzamide,
5- [4- (3-Amino-2-hydroxy-propyl) -3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl] -2-chloro-N -(1-hydroxy-cycloheptylmethyl) -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {4- [2-hydroxy-3- (oxetane-3-yloxy) -propyl] -3-methyl-5-oxo-4, 5 -Dihydro- [1,2,4] triazol-1-yl} -benzamide,
5- {4- [3- (azetidin-3-yloxy) -2-hydroxy-propyl] -3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl} -2-chloro-N- (1-hydroxy-cycloheptylmethyl) -benzamide,
5- {4- [3- (azetidin-3-yloxy) -propyl] -3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl} -2-chloro -N- (1-hydroxy-cycloheptylmethyl) -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {4- [2-hydroxy-3- (pyrrolidin-3-yloxy) -propyl] -3-methyl-5-oxo-4, 5 -Dihydro- [1,2,4] triazol-1-yl} -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {3-methyl-5-oxo-4- [3- (pyrrolidin-3-yloxy) -propyl] -4,5-dihydro- [ 1, 2, 4] triazol-1-yl} -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {4- [2-hydroxy-3- (piperidin-4-yloxy) -propyl] -3-methyl-5-oxo-4, 5 -Dihydro- [1,2,4] triazol-1-yl} -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {3-methyl-5-oxo-4- [3- (piperidin-4-yloxy) -propyl] -4,5-dihydro- [ 1, 2, 4] triazol-1-yl} -benzamide,
2-Chloro-5- [4- (3,4-dihydroxy-butyl) -3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl] -N- ( 1-hydroxy-cycloheptylmethyl) -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3-methyl-5-oxo-4- (2-trifluoromethoxy-ethyl) -4,5-dihydro- [1, 2, 4] triazol-1-yl] -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-methoxy-ethyl) -5-oxo-4,5-dihydro- [1,2,4] triazole-1- Il] -benzamide,
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -benzamide;
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-hydroxy-ethyl) -5-oxo-4,5-dihydro- [1,2,4] triazole-1- Il] -benzamide,
2-chloro-5- (4-cyanomethyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -N- (1-hydroxy-cycloheptylmethyl) -benzamide;
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-methoxy-ethyl) -3-methyl-5-oxo-4,5-dihydro- [1, 2, 4] Triazol-1-yl] -benzamide,
2-Chloro-5- (4-cyanomethyl-3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -N- (1-hydroxy-cycloheptylmethyl) -Benzamide,
2-Chloro-N- (1-hydroxy-3,3-dimethyl-cyclohexylmethyl) -5- (3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl ) -Benzamide,
5- (4-Carbamoylmethyl-3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -2-chloro-N- (1-hydroxy-cycloheptylmethyl) ) -Benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-hydroxy-ethyl) -3-methyl-5-oxo-4,5-dihydro- [1, 2, 4] Triazol-1-yl] -benzamide
5- [4- (2-Amino-ethyl) -3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl] -2-chloro-N- (1- Hydroxy-cycloheptylmethyl) -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-hydroxy-3-methoxy-propyl) -3-methyl-5-oxo-4,5-dihydro- [1, 2,4] triazol-1-yl] -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-hydroxy-3-methoxy-propyl) -3-methyl-5-oxo-4,5-dihydro- [1, 2,4] triazol-1-yl] -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-hydroxy-2-methyl-propyl) -3-methyl-5-oxo-4,5-dihydro- [1, 2,4] triazol-1-yl] -benzamide,
2-chloro-N- (1-hydroxy-cyclohexylmethyl) -5- (4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl) -benzamide,
2-chloro-N- (1-hydroxy-cyclohexylmethyl) -5- (2-oxo-2,3-dihydro-imidazol-1-yl) -benzamide,
2-chloro-5- (4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl) -N- (1-p-tolyl-cyclohexylmethyl) -benzamide;
2-chloro-5- (2-oxo-2,3-dihydro-imidazol-1-yl) -N- (1-p-tolyl-cyclohexylmethyl) -benzamide;
2-chloro-N- (4,4-difluoro-1-p-tolyl-cyclohexylmethyl) -5- (4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl) -benzamide;
2-chloro-N- (4,4-difluoro-1-p-tolyl-cyclohexylmethyl) -5- (2-oxo-2,3-dihydro-imidazol-1-yl) -benzamide;
2-Chloro-5- [3- (2,3-dihydroxy-propyl) -4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl] -N- (1-hydroxy-cycloheptylmethyl ) -Benzamide,
2-chloro-5- [3- (2,3-dihydroxy-propyl) -2-oxo-2,3-dihydro-imidazol-1-yl] -N- (1-hydroxy-cycloheptylmethyl) -benzamide;
2-Chloro-5- {3-[(cyclopropylmethyl-carbamoyl) -methyl] -4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl} -N- (1-hydroxy-cyclo Heptylmethyl) -benzamide,
2-Chloro-5- {3-[(cyclopropylmethyl-carbamoyl) -methyl] -2-oxo-2,3-dihydro-imidazol-1-yl} -N- (1-hydroxy-cycloheptylmethyl)- Benzamide,
2-chloro-5- (3-dimethylcarbamoylmethyl-4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl) -N- (1-hydroxy-cycloheptylmethyl) -benzamide;
2-chloro-5- (3-dimethylcarbamoylmethyl-2-oxo-2,3-dihydro-imidazol-1-yl) -N- (1-hydroxy-cycloheptylmethyl) -benzamide;
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (4-methyl-3-methylcarbamoylmethyl-2-oxo-2,3-dihydro-imidazol-1-yl) -benzamide;
2-chloro-5- (3-dimethylcarbamoylmethyl-2-oxo-2,3-dihydro-imidazol-1-yl) -N- (1-hydroxy-cycloheptylmethyl) -benzamide;
2-chloro-5- (3-ethylcarbamoylmethyl-4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl) -N- (1-hydroxy-cycloheptylmethyl) -benzamide;
2-chloro-5- (3-ethylcarbamoylmethyl-2-oxo-2,3-dihydro-imidazol-1-yl) -N- (1-hydroxy-cycloheptylmethyl) -benzamide;
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (4-methyl-3-{[(oxetane-3-ylmethyl) -carbamoyl] -methyl} -2-oxo-2,3-dihydro -Imidazol-1-yl) -benzamide,
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (3-{[(oxetane-3-ylmethyl) -carbamoyl] -methyl} -2-oxo-2,3-dihydro-imidazole-1 -Yl) -benzamide,
5- [3- (Azetidin-3-ylcarbamoylmethyl) -4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl] -2-chloro-N- (1-hydroxy-cycloheptylmethyl) ) -Benzamide,
5- [3- (azetidin-3-ylcarbamoylmethyl) -2-oxo-2,3-dihydro-imidazol-1-yl] -2-chloro-N- (1-hydroxy-cycloheptylmethyl) -benzamide;
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4-methyl-2-oxo-3- (pyrrolidin-3-ylcarbamoylmethyl) -2,3-dihydro-imidazol-1-yl ] -Benzamide,
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [2-oxo-3- (pyrrolidin-3-ylcarbamoylmethyl) -2,3-dihydro-imidazol-1-yl] -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4-methyl-2-oxo-3- (piperidin-4-ylcarbamoylmethyl) -2,3-dihydro-imidazol-1-yl ] -Benzamide,
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [2-oxo-3- (piperidin-4-ylcarbamoylmethyl) -2,3-dihydro-imidazol-1-yl] -benzamide,
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {4-methyl-2-oxo-3-[(tetrahydro-pyran-4-ylcarbamoyl) -methyl] -2,3-dihydro- Imidazol-1-yl} -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {2-oxo-3-[(tetrahydro-pyran-4-ylcarbamoyl) -methyl] -2,3-dihydro-imidazole-1- Il} -benzamide,
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {4-methyl-2-oxo-3-[(tetrahydro-furan-3-ylcarbamoyl) -methyl] -2,3-dihydro- Imidazol-1-yl} -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {2-oxo-3-[(tetrahydro-furan-3-ylcarbamoyl) -methyl] -2,3-dihydro-imidazole-1- Il} -benzamide,
2-Chloro-5- [3- (3-dimethylamino-2-hydroxy-propyl) -4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl] -N- (1-hydroxy- Cycloheptylmethyl) -benzamide,
2-Chloro-5- [3- (3-dimethylamino-2-hydroxy-propyl) -2-oxo-2,3-dihydro-imidazol-1-yl] -N- (1-hydroxy-cycloheptylmethyl) -Benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3- (2-hydroxy-3-pyrrolidin-1-yl-propyl) -4-methyl-2-oxo-2,3-dihydro -Imidazol-1-yl] -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3- (2-hydroxy-3-pyrrolidin-1-yl-propyl) -2-oxo-2,3-dihydro-imidazole-1 -Yl] -benzamide,
5- [3- (3-Amino-2-hydroxy-propyl) -4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl] -2-chloro-N- (1-hydroxy-cyclo Heptylmethyl) -benzamide,
5- [3- (3-Amino-2-hydroxy-propyl) -2-oxo-2,3-dihydro-imidazol-1-yl] -2-chloro-N- (1-hydroxy-cycloheptylmethyl)- Benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {3- [2-hydroxy-3- (oxetane-3-yloxy) -propyl] -4-methyl-2-oxo-2, 3 -Dihydro-imidazol-1-yl] -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {3- [2-hydroxy-3- (oxetane-3-yloxy) -propyl] -2-oxo-2,3-dihydro-imidazole -1-yl} -benzamide,
5- {3- [3-azetidin-3-yloxy) -2-hydroxy-propyl] -4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl} -2-chloro-N- ( 1-hydroxy-cycloheptylmethyl) -benzamide,
5- {3- [3-azetidin-3-yloxy) -2-hydroxy-propyl] -2-oxo-2,3-dihydro-imidazol-1-yl} -2-chloro-N- (1-hydroxy- Cycloheptylmethyl) -benzamide,
5- {3- [3- (azetidin-3-yloxy) -propyl] -4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl} -2-chloro-N- (1-hydroxy -Cycloheptylmethyl) -benzamide,
5- {3- [3- (azetidin-3-yloxy) -propyl] -2-oxo-2,3-dihydro-imidazol-1-yl} -2-chloro-N- (1-hydroxy-cycloheptylmethyl) ) -Benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {3- [2-hydroxy-3- (pyrrolidin-3-yloxy) -propyl] -4-methyl-2-oxo-2,3 -Dihydro-imidazol-1-yl} -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {3- [2-hydroxy-3- (pyrrolidin-3-yloxy) -propyl] -2-oxo-2,3-dihydro-imidazole -1-yl} -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {4-methyl-2-oxo-3- [3- (pyrrolidin-3-yloxy) -propyl] -2,3-dihydro-imidazole -1-yl} -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {2-oxo-3- [3- (pyrrolidin-3-yloxy) -propyl] -2,3-dihydro-imidazol-1-yl } -Benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {3- [2-hydroxy-3- (piperidin-4-yloxy) -propyl] -4-methyl-2-oxo-2,3 -Dihydro-imidazol-1-yl} -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {3- [2-hydroxy-3- (piperidin-4-yloxy) -propyl] -2-oxo-2,3-dihydro-imidazole -1-yl} -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {4-methyl-2-oxo-3- [3- (piperidin-4-yloxy) -propyl] -2,3-dihydro-imidazole -1-yl} -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- {2-oxo-3- [3- (piperidin-4-yloxy) -propyl] -2,3-dihydro-imidazol-1-yl } -Benzamide,
2-Chloro-5- [3- (3,4-dihydroxy-butyl) -4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl] -N- (1-hydroxy-cycloheptylmethyl ) -Benzamide,
2-chloro-5- [3- (3,4-dihydroxy-butyl) -2-oxo-2,3-dihydro-imidazol-1-yl] -N- (1-hydroxy-cycloheptylmethyl) -benzamide;
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4-methyl-2-oxo-3- (2-trifluoromethoxy-ethyl) -2,3-dihydro-imidazole-1- Il] -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [2-oxo-3- (2-trifluoromethoxy-ethyl) -2,3-dihydro-imidazol-1-yl] -benzamide ,
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl) -benzamide;
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (2-oxo-2,3-dihydro-imidazol-1-yl) -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3- (2-hydroxy-ethyl) -4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl]- Benzamide,
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3- (2-hydroxy-ethyl) -2-oxo-2,3-dihydro-imidazol-1-yl] -benzamide,
2-chloro-5- (3-cyanomethyl-4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl) -N- (1-hydroxy-cycloheptylmethyl) -benzamide;
2-chloro-5- (3-cyanomethyl-2-oxo-2,3-dihydro-imidazol-1-yl) -N- (1-hydroxy-cycloheptylmethyl) -benzamide;
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3- (2-methoxy-ethyl) -4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl]- Benzamide,
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3- (2-methoxy-ethyl) -2-oxo-2,3-dihydro-imidazol-1-yl] -benzamide,
5- (3-carbamoylmethyl-4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl) -2-chloro-N- (1-hydroxy-cycloheptylmethyl) -benzamide;
5- (3-carbamoylmethyl-2-oxo-2,3-dihydro-imidazol-1-yl) -2-chloro-N- (1-hydroxy-cycloheptylmethyl) -benzamide;
5- [3- (2-Amino-ethyl) -4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl] -2-chloro-N- (1-hydroxy-cycloheptylmethyl)- Benzamide,
5- [3- (2-amino-ethyl) -2-oxo-2,3-dihydro-imidazol-1-yl] -2-chloro-N- (1-hydroxy-cycloheptylmethyl) -benzamide;
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3- (2-hydroxy-3-methoxy-propyl) -4-methyl-2-oxo-2,3-dihydro-imidazole-1 -Yl] -benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3- (2-hydroxy-3-methoxy-propyl) -2-oxo-2,3-dihydro-imidazol-1-yl]- Benzamide,
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3- (2-hydroxy-2-methyl-propyl) -4-methyl-2-oxo-2,3-dihydro-imidazole-1 -Yl] -benzamide, and
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [3- (2-hydroxy-2-methyl-propyl) -2-oxo-2,3-dihydro-imidazol-1-yl]- Benzamide.

  Some specific compounds of the invention are those compounds identified in Examples 1-14, which are incorporated herein by reference.

The invention also includes isotope-labeled compounds in which one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Except that, it is the same as listed in Formula I. Examples of isotopes that can be incorporated into the compounds of the present invention include ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ There are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, respectively, such as Cl. Compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of such compounds or prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. is there. Some isotope-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful for drug and / or substrate tissue distribution assays. Tritiated or ³ H isotopes and carbon-14 or ¹⁴ C isotopes are preferred because of their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium i.e., ² H, from greater metabolic stability, be given several therapeutic advantages example results from the reduction or increased dosage requirements half-life And therefore may be preferred under some conditions. Isotopically labeled compounds of Formula I of the present invention and their prodrugs are generally represented in the “Scheme” below by replacing the non-isotopically labeled reagent with a readily available isotope-labeled reagent. And / or by performing the procedures disclosed in the "Examples" and "Preparation Methods".

  Compounds of formula I or their pharmaceutically acceptable salts are exacerbated by the production of excessive or disordered cytotoxicity by human or other mammalian cells such as, but not limited to, mononuclear cells and / or macrophages It can be used in the manufacture of a medicament for the prevention or therapeutic treatment of any disease state in such mammals that is caused or caused.

  The present invention relates to a method of treating an IL-1-mediated disease in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of formula I.

  The invention also relates to a method for treating IL-1 mediated conditions. As defined herein, “IL-1 mediated condition” includes administering to a mammal, including a human, an amount of a compound of formula I effective to treat a condition such as: Arthritis in mammals, including arthritic psoriasis, Reiter syndrome, rheumatoid arthritis, gout, traumatic arthritis, arthritis rubella, rheumatoid arthritis, osteoarthritis, arthritic gout, and acute synovitis Bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, asthma, bronchial chronic obstructive pulmonary disease, chronic inflammatory lung disease, silicosis, pulmonary sarcoidosis, allergic reaction, allergic contact hypersensitivity reaction , Eczema, contact dermatitis, psoriasis, sunburn, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, osteoporosis, relaxation of prosthetic implant, atherosclerosis, aortic aneurysm, congestive Heart failure, myocardial infarction, stroke, cerebral ischemia, head traumatic disorder, neurotrauma, spinal cord injury, neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid vascular disorder, Psychotropic or cognitive elevation, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, corneal scar, capsulitis, pathological wound healing, burns, autoimmune disorders, Huntington's disease, diabetes, AIDS, cachexia, sepsis, septic shock, endotoxic shock, conjunctivitis shock, gram-negative sepsis, toxic shock syndrome, cerebral malaria, heart and kidney reperfusion injury, thrombosis, glomerulus Includes, but is not limited to, a disease or disorder selected from the group consisting of nephritis, graft-versus-host reaction, allograft rejection, organ transplant poisoning, ulcerative colitis, or muscle degeneration. Yes.

  The present invention relates to a pharmaceutical composition for the treatment of IL-1-mediated diseases in mammals comprising an effective amount of a compound according to formula I and a pharmaceutically acceptable carrier.

  The present invention relates to a pharmaceutical composition for the treatment of such conditions comprising a compound of formula I effective for the treatment of IL-1 mediated conditions in mammals, including humans, and a pharmaceutically acceptable carrier. .

  Preferably, the compound of the present invention comprises rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, bronchial chronic obstructive pulmonary disease (COPD), airway hypersensitivity reaction, septic shock, glomerulonephritis, hypersensitivity Bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, malignant cell growth and metastasis, myogenic leukemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burns, ischemic heart disease, stroke, and Effective for treating varicose veins.

  The present invention also provides a compound of formula (I) as defined hereinbefore or a pharmaceutically acceptable salt or solvate thereof for use in therapy.

  In another aspect, the invention provides the use of a compound of formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in therapy. .

  The present invention further comprises administering to a patient a therapeutically effective amount of a compound of formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt or solvate thereof. A method of treatment is provided.

  The present invention further comprises immunosuppression comprising administering to a patient a therapeutically effective amount of a compound of formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt or solvate thereof. For example, methods of causing rheumatoid arthritis, irritable bowel disease, atherosclerosis, or psoriasis are provided.

  The present invention also includes airway obstructive activity comprising administering to a patient a therapeutically effective amount of a compound of formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt or solvate thereof. Methods of treating a disease (eg, asthma or COPD) are provided.

  As used herein, the term “treat” refers to reversing, alleviating, inhibiting, or the progression of a disorder or symptom to which such term applies, or one or more symptoms of such disorder or symptom. Means to prevent. As used herein, the term “treatment” refers to a therapeutic action as defined in “immediately before” “treat”.

  The present invention also provides a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutically acceptable adjuvant, diluent or carrier. A pharmaceutical composition is provided.

  The invention further provides a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutically acceptable adjuvant, diluent or carrier. And a method for preparing the pharmaceutical composition of the present invention.

  When used for such treatment, the dose administered will, of course, vary depending on the compound employed, the manner of administration, the intended treatment, and the disorder for which therapy is desired. The daily dose of the compound of formula (I) / salt / solvate (active ingredient) is in the range 1 mg to 1 g, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg.

  The present invention also includes sustained release compositions.

  The invention also relates to processes for the preparation of compounds of formula (I) and intermediates used in such processes.

  One embodiment of the method of the invention relates to the preparation of compounds of formula (I) and can be performed by one or more of the synthetic methods outlined in Schemes I-VIII and detailed below. The present invention also provides methods and intermediates identified in Schemes I-VIII below that are useful for the synthesis of compounds of formula (I).

  One skilled in the art should appreciate that the compounds of the present invention are effective in the treatment of various diseases. One skilled in the art should also understand that when the compounds of the present invention are used to treat a particular disease, those compounds of the present invention can be combined with a variety of existing therapeutic agents used for that disease.

For the treatment of rheumatoid arthritis, the compounds of the present invention include TNF-, such as anti-TNF monoclonal antibodies (such as Remicade, CDP-870, and D ₂ E ₇ ) and TNF receptor immunoglobulin molecules (Enbrel®). alpha inhibitors, COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, paracoxib, and etoroxib), low-dose methotrexate, lefnomide, ciclesonide, hydroxychloroquine, d-penicillamine, auranofin, or parenteral or oral gold Can be combined with other chemicals.

  The present invention further includes zileuton; ABT-761; phenleuton; tepoxaline; Abbott-79175; Abbott-85761; N- (5-substituted) -thiophene-2-alkylsulfonamides; 2,6-di-tert-butylphenol Hydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; compound SB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline compounds such as L-746,530; MK-591 and MK-886 And a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor, or 5-lipoxygenase activating protein (FLAP) antagonist selected from the group consisting of indole and quinoline compounds such as BAY x 1005 and It relates to combinations with the compounds of the invention.

The present invention further includes phenothiazin-3-ones such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and zafirlukast, abrukast, Leukotrienes selected from the group consisting of compounds such as Montelukast, Pranlukast, Berlukast (MK-679), RG-12525, Ro-245913, Iralukast (CGP 45715A) and BAY x 7195 It relates to a combination of a receptor antagonist for LTB ₄ , LTC ₄ , LTD ₄ and LTE _{4 with} a compound of the invention.

  The invention further relates to the combination of a PDE4 inhibitor, including an inhibitor of isoform PDE4D, and a compound of the invention.

The present invention further relates to the combination of an antihistamine H ₁ receptor antagonist, including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine, with a compound of the present invention.

The present invention further relates to the combination of a gastroprotective H ₂ receptor antagonist and a compound of the present invention.

The present invention further includes α ₁ -and α, including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethyl norepinephrine hydrochloride. ₂ -Adrenergic receptor agonist vasoconstrictor sympathomimetic and a combination of the compounds of the present invention.

  The present invention further relates to combinations of compounds of the invention with anticholinergic drugs including ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine; and telenzepine.

The present invention further includes β _1- to β ₄ -adrenergic receptor agonists including metaproterenol, isoproterenol, isoprenaline, albuterol, salbuterol, formoterol, salmeterol, terbutaline, orciprenaline, vitorterol mesylate, and pyrbuterol. Or methylxanthanine, including theophylline and aminophylline, or sodium cromoglycate, or a muscarinic receptor (M1, M2, and M3) antagonist and a compound of the invention.

  The invention further relates to a combination of an insulin-like mimicking type I growth factor (IGF-1) and a compound of the invention.

  The present invention further includes inhaled glucocorticoids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate, and compounds of the present invention Related to the combination.

The present invention further comprises (a) a tryptase inhibitor; (b) a platelet activating factor (PAF) antagonist; (c) an interleukin converting enzyme (ICE) inhibitor; (d) an IMPDH inhibitor; Adhesion molecule inhibitors including 4 antagonists; (f) cathepsins; (g) MAP kinase inhibitors; (h) glucose-6-phosphate dehydrogenase inhibitors; (i) kinin-B ₁ -and B ₂ -receptors Antagonists; (j) anti-gout drugs such as cortisin; (k) xanthine oxidase inhibitors such as allopurinol; (l) uric acid excretion enhancers such as probenside, sulfinpyrazone, and benzbromarone; (m) growth hormone secretion (N) Transforming growth factor (TGFβ); (o) Platelet-derived growth factor (PDGF); (p) Fibroblast growth factor such as basic fibroblast growth factor (bFGF); (q) Granules Sphere Macrophage Lonny stimulating factor (GM-CSF); (r) capsaicin cream; (s) NKP-608C, SB-233412 (talnetant); and tachykinin NK ₁ and NK ₃ receptor antagonists selected from the group consisting of D-4418 And (t) a combination of an elastase inhibitor selected from the group consisting of UT-77 and ZD-0892 and a compound of the present invention.

  The present invention further provides matrix metalloproteases (MMP), ie inhibitors of stromelysin, collagenases, and gelatinases, and aggrecanases; in particular collagenase-1 (MMP-1), collagenase-2 (MMP-8) , Inhibitors of collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11), and the present invention In combination with a compound of

  The compounds of the present invention can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable drugs that can be used in combination include standard non-steroidal anti-inflammatory drugs such as piroxicam and diclofenac (hereinafter NSAIDs) and naproxen, flubiprofen, fenoprofen, ketoprofen, and ibuprofen. Propionic acids, phenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, and COX-2 inhibitors such as celecoxib, valdecoxib, rofecoxib, and etoroxib There are intra-articular treatments such as corticosteroids and hyaluronic acids such as hyalgan and symbsk.

  The compounds of the present invention also include anticancer agents such as endostatin and angiostatin, or cytotoxic agents such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere, and farnesyltransferase inhibitors, VegF inhibitors, COX -2 inhibitors and antimetabolites such as methotrexate antineoplastic agents, especially mitotic inhibitors including vinca alkaloids such as vinblastine and vincristine.

  The compounds of the present invention can also be used in combination with antiviral agents such as biraccept, AZT, acyclovir, and famciclovir, and antiseptic compounds such as Valant.

  The compounds of the present invention also include cardiovascular drugs such as calcium channel blockers, lipid lowering agents such as statins, fibrates, β-blockers, Ace inhibitors, angiotensin-2 receptor antagonists, and platelet aggregation reaction inhibitors Can also be used in combination.

  The compounds of the present invention also include CNS drugs such as antidepressants (such as sertalin), antiparkinson drugs (MAOB inhibitors such as deprenyl, L-dopa, Requip, mirapex, selegin and rasagiline, comP inhibitors such as Tasmar, A- 2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists, and inhibitors of neuronal nitric oxide synthase), and donepezil, tacrine, COX-2 inhibitor, propentophilin, or metricon It can also be used in combination with anti-Alzheimer drugs such as acid salts.

  The compounds of the present invention may also be used in combination with osteoporotic drugs such as lorooxyphene, drolooxyphene, lasofooxylene, or fosomax, and immunosuppressive agents such as FK-506, rapamycin, cyclosporine, azathioprine, and methotrexate You can also.

Compounds of formula I can be prepared according to the following reaction schemes and considerations. Unless otherwise indicated, the following reaction schemes and R ¹ to R ⁷ under consideration are as defined above.

Scheme 1 refers to the preparation of compounds of formula VI. Compounds of formula VI can be prepared from compounds of formula I by reacting with compounds L-R ⁷ of formula VII in the presence of a base, wherein L is chlorine, bromine, iodine, tosylate or Suitable leaving groups such as mesylate. Suitable bases include, but are not limited to, triethylamine, polymer supported BEMP, cesium carbonate, potassium carbonate, and sodium hydride, among which cesium carbonate is preferred. The above reaction is generally performed in the presence of dimethyl sulfoxide, dimethylformamide, the same amount of dimethyl sulfoxide and acetone, or a polar solvent including the same amount of dimethylformamide and acetone, generally for 2 hours to 72 hours, 0 It can be carried out at a temperature in the range of from 0 to 100 ° C., the preferred condition being dimethylformamide at ambient temperature for 18 hours.

  The compound of formula VI can also be obtained by reaction of a suitably substituted epoxide of formula VIII either in the presence of a polar solvent, including but not limited to, dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran. It can be prepared from a compound of formula I. The above reaction can be carried out at a temperature ranging from 0 ° C. to 100 ° C. for 2 hours to 72 hours, with dimethylformamide at 60 ° C. being preferred for 24 hours.

Scheme 2 refers to the preparation of compounds of formula I. The compound of formula I is 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDCI), dicyclohexylcarbodiimide (DDC) dissolved in an aprotic solvent such as methylene chloride, dimethylformamide, or dimethylsulfoxide, 1- [3- (dimethylamino) propyl dissolved in dimethylformamide, preferably in the presence of a coupling reagent such as 1,1'-carbonyldiimidazole (CDI) and a base such as dimethylaminopyridine (DMAP) or triethylamine It can be prepared from a compound of formula IX by reacting with a compound H ₂ N—R ¹ of formula XI in the presence of] -3-ethylcarbodiimide and dimethylaminopyridine. The above reaction can be carried out at a temperature of 22 ° C. to 60 ° C. for 1 hour to 20 hours, preferably at 22 ° C. for 18 hours.

  The compounds of formula I are also dissolved in, but not limited to, aprotic solvents such as methylene chloride, ethyl acetate, dichloroethane, dimethylformamide, or dimethyl sulfoxide, preferably aqueous sodium hydroxide and dichloroethane aprotic solvents. Can be prepared from compounds of formula X by reacting with compounds of formula XI in the presence of a base including dimethylaminopyridine (DMAP), triethylamine, aqueous sodium hydroxide, or aqueous potassium hydroxide. The above reaction can be carried out at a temperature of 22 ° C. to 60 ° C. for 1 hour to 24 hours, preferably at ambient temperature for 3 hours. Compound X produces an acid chloride such as thionyl chloride or oxalyl chloride in the presence of a polar aprotic solvent such as ethyl acetate, methylene chloride, or dichloroethane at a temperature of 22 ° C. to 60 ° C. for 1 hour to 24 hours. Can be prepared from compound IX by reacting with a reagent capable of reacting with oxalyl chloride dissolved in methylene chloride, preferably at ambient temperature for 16 hours.

  Scheme 3 refers to the preparation of compounds of formulas XIV and IX. Compounds of formula IX can be converted to compounds of formula I by the methods described in Scheme 2. The compound of formula IX is prepared at a temperature between 80 ° C. and 120 ° C. for 2 to 16 hours, preferably at 120 ° C. for 2 hours, with diphenylphosphoryl azide and a base such as triethylamine, pyridine or diisopropylethylamine, preferably It can be prepared from a compound of formula XIV by reacting.

The compound of formula XIV is reacted with the compound HO ₂ C (CO) R ^{4 of} formula XIII in the presence of 10% hydrochloric acid at a temperature between 20 ° C. and 80 ° C. for 1-24 hours, preferably 1.5 hours at ambient temperature. Can be prepared from the compound of formula XII.

  Scheme 4 refers to the preparation of compounds of formula XVI and XII. Compounds of formula XII can be converted to compounds of formula XIV by the methods described in Scheme 3. A compound of formula XII is prepared from a compound of formula XVI by reacting with an acid such as hydrochloric acid and / or glacial acetic acid followed by treatment with sodium nitrite dissolved in a solvent such as water at a temperature between 0 ° C. and 25 ° C. This reaction is generally carried out for 30 minutes to about 2 hours, preferably at 0 ° C. for 30 minutes. This intermediate is then treated with tin (II) chloride dihydrate in an acid, preferably a solvent such as hydrochloric acid, at a temperature between 0 ° C. and 25 ° C. for 2 to 8 hours, preferably at 0 ° C. for 30 minutes. .

  A compound of formula XVI may be prepared from a compound of formula XV by reacting with methanol in the presence of an acid such as sulfuric acid for 4 to 24 hours at a temperature between ambient and reflux, preferably 4 hours at reflux. it can.

  Scheme 5 refers to the preparation of compounds of formula XVII. A compound of formula XVII can be prepared from a compound of formula I by reacting with a compound of formula VII in the presence of a base, wherein L is chlorine, bromine, iodine, tosylate or mesylate, etc. Is a suitable leaving group. Suitable bases include, but are not limited to, triethylamine, polymer supported BEMP, cesium carbonate, potassium carbonate, and sodium hydride, among which cesium carbonate is preferred. The above reaction is generally performed in the presence of dimethyl sulfoxide, dimethylformamide, the same amount of dimethyl sulfoxide and acetone, or a polar solvent including the same amount of dimethylformamide and acetone, generally for 2 hours to 72 hours, 0 C. to 100.degree. C., and the preferred condition is dimethylformamide at ambient temperature for 18 hours.

  A compound of formula XVII can also be obtained by reaction of an appropriately substituted epoxide of formula VIII either in the presence of a polar solvent, including but not limited to, dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran. It can be prepared from a compound of formula I. The above reaction can be carried out at a temperature ranging from 0 ° C. to 100 ° C. for 2 hours to 72 hours, with dimethylformamide at 60 ° C. being preferred for 24 hours.

  Scheme 6 refers to the preparation of compounds of formula XIX. A compound of formula XIX is reacted with a base such as NaOH followed by 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide dissolved in an aprotic solvent such as methylene chloride, dimethylformamide, or dimethyl sulfoxide. (EDCI), dicyclohexylcarbodiimide (DDC), 1, 1'-carbonyldiimidazole (CDI) and other coupling reagents and dimethylaminopyridine (DMAP) or bases such as triethylamine, preferably dissolved in dimethylformamide It can be prepared from a compound of formula XVIII by reacting with a compound of formula XI in the presence of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide and dimethylaminopyridine. The above reaction can be carried out at a temperature of 22 ° C. to 60 ° C. for 1 hour to 20 hours, preferably at 22 ° C. for 18 hours.

Scheme 7 refers to the preparation of compounds of formula XXII and XVIII. A compound of formula XIX can be prepared from a compound of formula XXII by reacting with an acid such as dilute sulfuric acid or concentrated hydrochloric acid at ambient temperature to reflux temperature for 2-16 hours. The compound of formula XXII is compound H ₂ NCH of formula XXI in the presence of an organic base such as triethylamine, diisopropylethylamine, or pyridine in a solvent such as dimethyl sulfoxide at a temperature from ambient to 60 ° C. for 2 to 24 hours. It can be prepared from a compound of formula XX by reacting with a compound of (R ⁴ ) CR ⁵ (OCH ₃ ) ₂ .

  Scheme 8 refers to the preparation of compounds of formula XX. Compounds of formula XX can be converted to compounds of formula XXII and XVIII by the methods described in Scheme 7. The compound of formula XX is obtained by reacting an organic base such as pyridine dissolved in a solvent such as tetrahydrofuran with phenyl chloroformate at a temperature from 0 ° C. to ambient temperature for 2 to 24 hours, preferably at ambient temperature for 12 hours. It can be prepared from a compound of XVI.

The activity of the compounds of the invention against the various disorders described above can be determined by one or more of the following assays. All of the compounds of the invention tested showed an IC ₅₀ of less than 10 μM in the following in vitro assay.

Preferably, the compounds of the invention have an IC ₅₀ of less than 100 nM, more preferably less than 50 nM, and most preferably less than 10 nM in the following in vitro assays. Furthermore, the compounds of the invention preferably have an IC ₅₀ in the range of 0.01 nM to 100 nM, more preferably between 0.05 nM and ₅₀ nM, most preferably between 0.10 nM and 10 nM.

Pharmacological analysis Several compounds, such as adenosine triphosphate benzoylbenzoyl (bbATP), are known to be agonists of the P2X ₇ receptor that cause pore formation in the plasma membrane (Drug Development Research (1996) ), 37 (3), p126). Thus, when this receptor is activated with bbATP in the presence of ethidium bromide (a fluorescent DNA probe), an increase in the fluorescence emission of ethidium bromide bound to DNA in the cell is observed. Alternatively, the propidium dye YOPRO-1 can be used in place of ethidium bromide to detect dye uptake. The increase in fluorescence emission can be used as a measure of P2X ₇ receptor activity and can therefore be used to quantify the effect of a compound on the P2X ₇ receptor.

In this way, the antagonistic activity of the compounds of the invention can be tested at the P2X ₇ receptor. A 96-well flat-bottomed microtiter plate is used to express receptor expression as described above in a suspension of THP-1 cells containing 10 ^-4 M ethidium bromide (2.5 x 10 ⁶ cells / mL, more preferably 200 μL pre-stimulated with a combination of LPS and TNF to promote) and high potassium low sodium buffer containing 10 ⁻⁵ M bbATP (10 mM Hepes, 150 mM KCl, 5 mM D-glucose, and 1.0 % FBS, pH 7.5) 25 μL and 3 x 10 ^-5 M test compound (more preferably 5 x 10 ^-4 M, more preferably 1 x 10 ^-4 M, more preferably 1 x 10 ^-3 M) Fill with 250 μL of test solution containing 25 μL of high potassium buffer. Cover the plate with a plastic sheet and incubate at 37 ° C. for 1 hour. The plate is then read on a Perkin-Elmer fluorescent plate reader (excitation 520 nm, emission 595 nm, slit width Ex 15 nm, Em 20 nm). For comparison, bbATP (P2X ₇ receptor agonist) and 5-phosphate pyridoxal (P2X ₇ receptor antagonist) can be used separately as controls in this test. From the readings obtained, a pIC ₅₀ value can be calculated for each test compound, which is the negative logarithm of the concentration of test compound required to reduce bbATP agonist activity by 50%.

The compounds of the present invention in a similar way, can be tested for antagonist activity at the P2X ₇ receptor using the cytokine IL-l [beta] as a display value. Blood collected from healthy volunteers is fractionated using lymphocyte separation media obtained from Organon Technica (Westchester, PA) in the presence of heparin. Gradient regions containing the resulting zonal mononuclear cells are collected, diluted with 10 mL of maintenance solution (RPMI 1640, 5% FBS, 25 mM hepes, pH 7.2, 1% penicillin / streptomycin), and the cells are centrifuged. Collect. The obtained cell pellet was suspended in 10 mL of the maintenance solution, and the number of cells was counted. In one average experiment, 2 x 10 ⁵ mononuclear cells are seeded in each well of a 96-well plate with a total volume of 0.1 mL. Monocytes are allowed to adhere for 2 hours, after which the supernatant is discarded and the bound cells are washed twice with water and then incubated overnight at 37 ° C. in maintenance solution in a 5% CO ₂ environment.

The cultured monocytes can be activated at 10 ng per mL of LPS (E. coli serotype 055: B5, Sigma Chemicals, St. Louis, MO). After 2 hours of incubation, the activation medium is removed and the cells are washed twice with chase medium (RPMI 1640, 1% FBS, 20 mM Hepes, 5 mM NaHCO ₃ , pH 6.9) and then the test substance is removed. Add 0.1 mL of the containing chase medium and incubate the plate for 30 minutes. The concentration value for each test substance can be determined in three wells. APT is then introduced (from 100 mM stock solution, pH 7) to a final concentration of 2 mM and the plate is incubated at 37 ° C. for an additional 3 hours. The medium was collected and clarified by centrifugation, and their IL-1β content was determined by ELISA (R & D Systems, Minneapolis, Minn.).

  The composition of the present invention can be formulated by a usual method using one or more kinds of pharmaceutically acceptable carriers. Accordingly, the active compounds of the invention are suitable for oral, sublingual, intranasal, parenteral (eg, intravenous, intramuscular, or subcutaneous), topical, or rectal administration, or in a form suitable for administration by inhalation or insufflation. It can be formulated.

  For oral administration, the pharmaceutical composition comprises a binder (eg, ungelatinized corn starch, polyvinyl pyrrolidone, or hydroxypropyl methylcellulose); a filler (eg, lactose, microcrystalline cellulose, or calcium phosphate); Pharmaceutically acceptable excipients such as agents (eg, magnesium stearate, talc, or silica); disintegrants (eg, potato starch, or sodium starch glycolate); or wetting agents (eg, sodium lauryl sulfate); It can take the form of, for example, tablets or capsules prepared together by conventional means. These tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be dried so as to be combined with water or other suitable vehicle before use. It can also be provided as a product. Such liquid formulations include suspending agents (eg, sorbitol syrup, methylcellulose, or hydrogenated edible fat); emulsifiers (eg, lecithin or gum arabic); non-aqueous vehicles (eg, tonsil oil, oily esters, Or ethyl alcohol); and preservatives (eg, methyl or propyl p-hydroxybenzoate, or sorbic acid) and can be prepared by conventional means together with pharmaceutically acceptable additives.

  For sublingual administration, the composition can take the form of tablets or lozenges formulated in conventional manner.

  The compounds of formula I can also be formulated for sustained broadcast delivery by methods well known to those skilled in the art. Examples of such formulations can be found in U.S. Pat.Nos. 3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397. All of which are incorporated herein by reference.

  The active compounds of the present invention can be formulated for parenteral administration by injection, including the use of conventional catheterization techniques or infusions. Formulations for injection can be provided in unit dosage form with additional preservatives, such as ampoules or multiple dose containers. These compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain suspending agents, stabilizers, and / or dispersing agents. it can. Alternatively, the active ingredient may be present in the form of a powder that is reconstituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.

  The active compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

  For intranasal administration or administration by inhalation, the active compounds of the invention may conveniently be in the form of a solution, dry powder formulation, or suspension from a pump spray container that the patient squeezes or pumps, or Given by aerosol spray from a pressurized container or nebulizer by using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide, or other suitable gas Delivered as. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Pressurized containers or nebulizers can contain a solution or suspension of the active compound. Capsules and cartridges (eg, made of gelatin) for use in inhalers or insufflators containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch may be formulated.

  The proposed dose of the active compound of the present invention for oral, parenteral or buccal administration to an average adult human for the treatment of the above mentioned symptoms (inflammation) is 0.1% active ingredient per unit dose. ˜200 mg, for example, which can be administered 1 to 4 times per day.

  The compound of formula (I) and pharmaceutically acceptable salts and solvates thereof can be used alone, but usually the compound of formula (I) / salt / solvate (active ingredient) is pharmaceutical. Should be administered in the form of a pharmaceutical composition together with an acceptable adjuvant, diluent or carrier. Depending on the mode of administration, this pharmaceutical composition preferably contains 0.05 to 99% w (wt%), more preferably 0.10 to 70% w active ingredient, and a pharmaceutically acceptable adjuvant, diluent or carrier. It should contain 1-99.95% w, more preferably 30-99.90 w%. All these weight ratios are based on the total composition.

  Aerosol formulations for the treatment of the symptoms referred to above in the average adult human preferably have each metered dose of aerosol or “puff” contain 20 μg to 1000 μg of the compound of the invention. Adjusted. The overall daily dose with an aerosol should be in the range of 100 μg to 10 mg. Administration can be several times daily, for example 2, 3, 4, or 8 times, giving for example, 1, 2, or 3 doses each time.

  Aerosol combinations for the treatment of the above-mentioned symptoms in average adult humans (eg adult respiratory distress syndrome) preferably have each metered dose of aerosol, or “puff dose”, of a compound of the invention Is adjusted to contain about 1 μg to 1000 μg. The overall daily dose for an aerosol should be within the range of 100 μg to 10 mg. Administration can be several times daily, for example 2, 3, 4, or 8 times, giving for example, 1, 2, or 3 doses each time.

Aerosol formulations for the treatment of the symptoms referred to above (eg adult respiratory distress syndrome) in the average adult human preferably have each metered dose of aerosol, or “puff dose”, of the compound of the invention It is adjusted to contain about 20 μg to 1000 μg. The overall daily dose for an aerosol should be in the range of 100 μg to 10 mg of P2X ₇ receptor inhibitor. Administration can be several times daily, for example 2, 3, 4, or 8 times, giving for example, 1, 2, or 3 doses each time.

  The invention also encompasses pharmaceutical compositions containing a compound of formula I and methods of treatment or prevention comprising administering a prodrug of the compound of formula I. Compounds of formula I having a free amino, amido, hydroxy, or carboxyl group can be converted into prodrugs. Prodrugs include either amino acid residues or two or more (eg 2, 3, or 4) peptide chains covalently linked through a peptide, free of a compound of formula I Compounds that are bound to amino, hydroxy, or carboxylic acid groups are included. These amino acid residues include the 20 naturally occurring amino acids, usually represented by three letter codes, and also 4-hydroxyproline, hydroxylysine, demosin, isodesomosin, 3-methylhistidine, norvaline, β -Alanine, γ-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides, and alkyl esters are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug side chain.

  The following examples illustrate the preparation of compounds of the present invention. Melting points are uncorrected. NMR data is expressed in ppm (d) and is based on the deuterium lock signal from the sample solvent (deuterium chloroform unless otherwise indicated). Mass spectrometry data was obtained using a Micromass ZMD APCI mass spectrometer equipped with a Gilson gradient high performance liquid chromatograph. The following solvents and gradients were used for analysis. Solvent A is 98% water / 2% acetonitrile / 0.01% formic acid and solvent B is acetonitrile containing 0.005% formic acid. Typically, the gradient started over about 4 minutes starting with solvent A 95% and ending with solvent B 100%. Mass spectra of the major eluting components were then obtained in positive or negative ion mode scanning the molecular weight range from 165 AMU to 1100 AMU. Specific rotation was measured at room temperature using sodium D line (589 nm). Commercial reagents were used without further purification. THF means tetrahydrofuran. DMF means N, N-dimethylformamide, chromatography means column chromatography performed using 32-63 mm silica gel and performed under nitrogen pressure (flash chromatography) conditions. Room or ambient temperature means 20-25 ° C. All non-aqueous reactions were performed in a nitrogen atmosphere for maximum convenience and yield. Concentration under reduced pressure means using a rotary evaporator.

  One skilled in the art should understand that in some cases a protecting group may be required during preparation. Once the target molecule is obtained, this protecting group is well known to those skilled in the art, such as those described in Greene and Wuts, “Protective Groups in Organic Synthesis” (3rd edition, John Wiley & Sons, 1999). It can be removed by conventional methods.

Example 1
2-Chloro-N- (1-hydroxy-chloroheptylmethyl) -5- [4- (2-methoxy-ethyl) -5-oxo-4,5-dihydro- [1,2,4] triazole-1- Il] -benzamide

(A) 5-Amino-2-chlorobenzoic acid methyl ester Concentrated sulfuric acid (25 mL) was added to a slurry of 5-amino-2-chlorobenzoic acid (20.0 g, 0.12 mol) dissolved in methanol (150 mL). . The resulting reaction was heated at reflux for 4 hours, cooled and concentrated under reduced pressure. The residue was dissolved in water and neutralized with Na ₂ CO ₃ . This aqueous liquid was extracted with CH ₂ Cl ₂ (3 ×). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the compound shown above (14.0 g).

(B) 2-Chloro-5-hydrazinobenzoic acid methyl ester hydrochloride 5-amino-2-chlorobenzoic acid methyl ester (14.0 g, 75.0 mmol) dissolved in water (100 mL) and concentrated HCl (100 mL) Followed by glacial acetic acid (100 mL). The solution was stirred at ambient temperature for 15 minutes. The reaction was then cooled to 0 ° C. and a solution of sodium nitrite (5.69 g, 82.5 mmol) dissolved in water (15 mL) was added dropwise over 30 minutes keeping the temperature at 0 ° C. The resulting reaction was stirred at 0 ° C for 30 minutes, then a solution of SnCl ₂ · 2H ₂ O (50.8 g, 225 mmol) dissolved in concentrated HCl (100 mL) was added over 30 minutes while maintaining the temperature at 0 ° C. Added. The slurry was stirred at 0 ° C. for 30 minutes and the resulting precipitate was collected by filtration and washed with water followed by hexane. The solid was dried in a vacuum oven at 50 ° C. to give the title compound (16.3 g).

(C) 5- (N'-carboxymethylene-hydrazino) -2-chlorobenzoic acid methyl ester
2-Chloro-5-hydrazinobenzoic acid methyl ester hydrochloride (2.0 g, 8.5 mmol) and oxoacetic acid (1.0 g, 10 mmol) were dissolved in 10% HCl and stirred at ambient temperature for 1.5 hours. The resulting orange precipitate was collected by filtration. The filter cake was dissolved in EtOAc, washed with brine and dried over sodium sulfate. Concentration under reduced pressure gave the compound shown above (1.2 g).

(D) 2-Chloro-5- (5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) benzoic acid methyl ester 5- (N--) dissolved in toluene (15 mL) Carboxymethylene-hydrazino) -2-chlorobenzoic acid methyl ester (514.0 mg, 2.0 mmol), diphenylphosphoryl azide (605.0 mg, 2.2 mmol), and triethylamine (0.3 mL, 2.2 mmol) at 120 ° C. under N _2. For 1 hour. The reaction was cooled, then 1.0M NaOH (20 mL) was added and the resulting solution was stirred for 10 minutes. The layers were separated and the organic layer was acidified to pH 1 with 1.0N HCl. The resulting precipitate was collected by filtration, washed with hexane, and dried in a vacuum oven at 50 ° C. for 12 hours to give the title compound (0.24 g).

(E) 2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -benzamide
To 2-chloro-5- (5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) benzoic acid methyl ester (48.0 mg, 0.2 mmol) dissolved in DMF (3 mL) , 1-aminomethyl-cycloheptanol HCl (54.0 mg, 0.3 mmol), polymer supported CDI (660 mg, 0.6 mmol), polymer supported DMAP (280 mg, 0.20 mmol), and HOBt (40.0 mg, 0.3 mmol). added. The resulting reaction was shaken for 3 hours at ambient temperature. The reaction was filtered and washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC using (5-100% gradient of 0.1% formic acid in acetonitrile and 0.1% formic acid in water) to give the compound shown above (20 mg).

(F) 2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-methoxy-ethyl) -5-oxo-4,5-dihydro- [1,2,4] triazole -1-yl] -benzamide
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -benzamide (44.4 mg, 0.122 mmol ) And CS ₂ CO ₃ (66.0 mg, 0.202 mmol) were stirred in DMSO (0.813 mL) at ambient temperature for 20 minutes. 2-Bromoethyl methyl ether (17.0 mg, 0.122 mmol) was added and the reaction was stirred at ambient temperature for 48 hours. The reaction was diluted with water (15 times), and extract the aqueous solution with CH ₂ Cl ₂ (3x). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC using (25-65% gradient of 0.1% formic acid in acetonitrile and 0.1% formic acid in water) to give the title compound (18 mg). LCMS (m / z) 423.5 M + 1.

  The compounds of Examples 2-11 identified in Table 1 below could be prepared according to the method of Example 1.

Example 12
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-hydroxy-3-methoxy-propyl) -3-methyl-5-oxo-4,5-dihydro- [1, 2,4] Triazol-1-yl] -benzamide

(A) 2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-hydroxy-3-methoxy-propyl) -3-methyl-5-oxo-4,5-dihydro- [1, 2, 4] Triazol-1-yl] -benzamide
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) dissolved in DMF (0.1 mL) -Benzamide (38 mg, 0.1 mmol) and R-(-)-glycidyl methyl ether (0.3 mL) were heated at 80 ° C for 2 hours. The reaction was concentrated under reduced pressure and then purified by reverse phase HPLC using (25-50% gradient of 0.1% formic acid in acetonitrile and 0.1% formic acid in water) to give the title compound (20 mg). . LCMS (m / z) 467.6 M + 1.

  The compounds of Examples 13-14 identified in Table 2 below could be prepared according to the method of Example 12.

  The present invention should not be limited to the scope according to the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

  All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety.

Claims (12)

formula

Wherein R ¹ is (C ₁ -C ₆ ) alkyl, optionally (C ₃ -C ₁₀ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₀ ) heterocyclyl, or (C ₁ ~C ₁₀₎ is substituted by a heteroaryl, wherein the (C ₁ ~C ₆₎ alkyl, (C ₃ ~C ₁₀₎ cycloalkyl, (C ₆ ~C ₁₀₎ aryl, (C ₁ ~C ₁₀₎ heterocyclyl Or (C ₁ -C ₁₀ ) heteroaryl is optionally selected from hydroxy, halogen, CN-, (C ₁ -C ₆ ) alkyl, HO (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl -NH (C = O) -, NH 2 (C = O) -, the one independently selected from (C ₁ -C ₆₎ alkoxy or (C ₃ ~C _10), the group consisting of cycloalkyl is substituted by three suitable moieties, said (C ₃ -C ₁₀₎ cycloalkyl halogen or (C ₁ -C ₆₎ alkyl optionally - one also be selected from It is replaced by a plurality of parts;
R ² is hydrogen, halogen, —CN, and (C ₁ -C ₆ ) alkyl, wherein said (C ₁ -C ₆ ) alkyl is optionally halo, hydroxy, amino, —CN, (C ₁ -C ₆₎ ) alkyl, (C ₁ ~C _{6) alkoxy, -CF 3, CF 3 O -} , (C 1 ~C 6) alkyl _{-NH -, [(C 1 ~C} 6) alkyl] ₂ -N -, (C ₁ -C ₆₎ alkyl _{-S -, (C 1 ~C 6} ) alkyl - (S = O) -, (C 1 ~C 6) alkyl _{- (SO) 2 -, (} C 1 ~C 6) alkyl - O- (C = O) -, formyl, (C ₁ ~C ₆₎ alkyl - (C = O) -, and (C ₃ -C ₆₎ from one independently selected from the group consisting of cycloalkyl 3 Substituted with the appropriate moiety; and
R ³ is the formula

A suitably substituted nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl represented by ]
Or a pharmaceutically acceptable salt or solvate thereof, or a prodrug thereof. formula

Wherein R ¹ is (C ₁ -C ₆ ) alkyl, optionally (C ₃ -C ₁₀ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₀ ) heterocyclyl, or (C ₁ ~C ₁₀₎ is substituted by a heteroaryl, wherein the (C ₁ ~C ₆₎ alkyl, (C ₃ ~C ₁₀₎ cycloalkyl, (C ₆ ~C ₁₀₎ aryl, (C ₁ ~C ₁₀₎ heterocyclyl , Or (C ₁ -C ₁₀ ) heteroaryl is optionally selected from hydroxy, halogen, CN—, (C ₁ -C ₆ ) alkyl, HO— (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆₎ ) alkyl -NH (C = O) -, NH 2 (C = O) -, 1 substituents selected independently from (C ₁ -C ₆₎ alkoxy or (C ₃ ~C _10,) the group consisting of cycloalkyl It is substituted by three suitable portion from the (C ₃ -C ₁₀₎ cycloalkyl halogen or optionally (C ₁ -C ₆₎ alkyl - one selected from or It is replaced by a plurality of parts;
R ² is hydrogen, halogen, —CN, and (C ₁ -C ₆ ) alkyl, wherein said (C ₁ -C ₆ ) alkyl is optionally halo, hydroxy, amino, —CN, (C ₁ -C ₆₎ ) alkyl, (C ₁ ~C _{6) alkoxy, -CF 3, CF 3 O -} , (C 1 ~C 6) alkyl _{-NH -, [(C 1 ~C} 6) alkyl] ₂ -N -, (C ₁ -C ₆₎ alkyl _{-S -, (C 1 ~C 6} ) alkyl - (S = O) -, (C 1 ~C 6) alkyl _{- (SO) 2 -, (} C 1 ~C 6) alkyl - O- (C = O) -, formyl, (C ₁ ~C ₆₎ alkyl - (C = O) -, and (C ₃ -C ₆₎ from one independently selected from the group consisting of cycloalkyl 3 Replaced by the appropriate moiety;
R ³ is the formula

Wherein R ⁴ and R ⁵ are independently a group of suitable substituents such as hydrogen, halo, hydroxy, —CN, HO— (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl. is selected from the optionally (C ₁ ~C ₆₎ alkyl, 1-3 fluorines is substituted with 1-3 fluorines, optionally (C ₁ ~C ₆₎ alkoxy, HO ₂ C -, (C ₁ ~C ₆₎ alkyl -O- (C = O) -, R 6 R 8 N (O 2 S) -, (C 1 ~C 6) alkyl - (O ₂ S) -NH-, (C ₁ ~C ₆₎ alkyl _{-O 2 S - [(C 1} ~C 6) alkyl ^{-N] -, R 6 R 8} N (C = O) -, R 6 R 8 N (CH 2) m - , (C ₆ ~C ₁₀₎ aryl, (C ₃ ~C ₈₎ cycloalkyl, (C ₁ ~C ₁₀₎ heteroaryl, (C ₁ ~C ₁₀₎ heterocyclyl, (C ₆ ~C ₁₀₎ aryl -O- , (C ₃ ~C ₈₎ cycloalkyl -O -, substituted (C ₁ ~C ₁₀₎ heteroaryl -O-, and (C ₁ ~C ₁₀₎ heterocyclyl -O- And
R ⁷ is independently hydrogen, (C ₁ -C ₆ ) alkyl, hydroxy, —CN, (C ₁ -C ₆ ) alkoxy, optionally substituted with 1 to 3 halogens, (C ₂ -C ₆ ) alkenoxy, (C ₁ -C ₆₎ alkyl _{-SO 2 -, NH 2 -,} ((C 1 ~C 6) _{alkyl) n -N -, n -N- (} (C 2 ~C 6) alkenyl), ((C ₂ ~C _{6) alkynyl) n -N-, NH 2 (C} = O) -, (C 1 ~C 6) alkyl - (C = O) n - , ((C 1 ~C 6) alkyl _{) n -N- (C = O)} -, (C 2 ~C 6) alkenyl - (C = O) n - , ((C 2 ~C 6) _{alkenyl) n -N- (C = O)} -, (C ₂ ~C ₆₎ alkynyl - (C = O) n - , ((C 2 ~C 6) _{alkynyl) n -N- (C = O)} -, (C 1 ~C 6) alkyl - (C = _{O) -, (C 2 ~C} 6) alkenyl - (C = O) -, (C 2 ~C 6) alkynyl - (C = O) -, (C 3 ~C 10) cycloalkyl - (C = O _{) -, ((C 1 ~C} 10) heterocyclyl) - (C = O) - , (C 6 -C ₁₀₎ aryl - (C = O) -, (C 1 ~C 10) heteroaryl - (C = O) -, (C 1 ~C 6) alkyl - (C = O) O - , (C 2 -C ₆₎ alkenyl - (C = O) O - , (C 2 ~C 6) alkynyl - (C = O) O - , (C 1 ~C 6) alkyl -O (C = O) -, (C ₂ -C ₆₎ alkenyl -O (C = O) -, (C 2 ~C 6) alkynyl -O (C = O) -, (C 3 ~C 10) cycloalkyl, (C _{6 ~C 10)} aryl It is selected from the group of suitable substituents such as (C ₁ ~C ₁₀₎ heterocyclyl, and (C ₁ ~C ₁₀₎ heteroaryl;
Where R ⁴ , R ⁵ , and R ⁷ are each optionally on any aliphatic or aromatic carbon atom, halo, hydroxy, amino, —CN, (C ₁ -C ₆ ) alkyl, (C ₁ -C _{6) alkoxy, -CF 3, CF 3 O -} , (C 1 ~C 6) alkyl _{-NH -, [(C 1 ~C} 6) _{alkyl] 2 -N -, (C 1} ~C 6) alkyl _{-S -, (C 1 ~C 6} ) alkyl - (S = O) -, (C 1 ~C 6) alkyl _{- (SO) 2 -, (} C 1 ~C 6) alkyl -O- (C = O) -, formyl, (C ₁ ~C ₆₎ alkyl - (C = O) -, and (C ₃ ~C _{6) 3} pieces of appropriate parts from one independently selected from the group consisting of cycloalkyl May be replaced by;
R ⁶ and R ⁸ are each independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, HO- (C ₂ -C ₆ ) alkyl, and (C ₃ -C ₈ ) cycloalkyl. Or, optionally, R ⁶ and R ⁸ together with the nitrogen atom to which they are attached may form a 3-8 membered heterocycle. )
In nitrogen bond (C ₁ ~C ₁₀₎ represented heterocyclyl;
n is an integer from 0 to 2; and
m is an integer from 0 to 2. ]
Or a pharmaceutically acceptable salt or solvate thereof, or a prodrug thereof. The compound according to claim 1 or 2, wherein R ² is chlorine, methyl, or ethyl. R ³ is the formula (IV)

Wherein R ⁴ is hydrogen or methyl, and
R ⁷

Selected from the group consisting of ]
In a nitrogen linked (C ₁ -C ₁₀₎ heterocyclyl represented, any one compound according to claims 1-3. R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), R ⁴ is hydrogen or methyl, and R ⁷ is

The compound according to any one of claims 1 to 4, wherein R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), R ⁴ is hydrogen or methyl, and R ⁷ is

6. The compound according to any one of claims 1 to 5, which is selected from the group consisting of: R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), R ⁴ is hydrogen or methyl, and R ⁷ is

The compound according to any one of claims 1 to 6, wherein R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), R ⁴ is hydrogen or methyl, and R ⁷ is

8. The compound according to any one of claims 1 to 7, which is selected from: R ³ is a nitrogen bond (C ₁ -C ₁₀ ) heterocyclyl of formula (IV), R ⁴ is hydrogen or methyl, and R ⁷ is

9. A compound according to any one of claims 1 to 8, which is selected from: 2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-methoxy-ethyl) -5-oxo-4,5-dihydro- [1,2,4] triazole-1- Il] -benzamide;
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -benzamide;
2-chloro-N- (1-hydroxy-cycloheptylmethyl) -5- (3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -benzamide;
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-hydroxy-ethyl) -5-oxo-4,5-dihydro- [1,2,4] triazole-1- Il] -benzamide;
2-chloro-5- (4-cyanomethyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -N- (1-hydroxy-cycloheptylmethyl) -benzamide;
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-methoxy-ethyl) -3-methyl-5-oxo-4,5-dihydro- [1, 2, 4] Triazol-1-yl] -benzamide;
2-Chloro-5- (4-cyanomethyl-3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -N- (1-hydroxy-cycloheptylmethyl) -Benzamide;
2-Chloro-N- (1-hydroxy-3,3-dimethyl-cyclohexylmethyl) -5- (3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl ) -Benzamide;
5- (4-Carbamoylmethyl-3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl) -2-chloro-N- (1-hydroxy-cycloheptylmethyl) ) -Benzamide;
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-hydroxy-ethyl) -3-methyl-5-oxo-4,5-dihydro- [1, 2, 4] Triazol-1-yl] -benzamide;
5- [4- (2-Amino-ethyl) -3-methyl-5-oxo-4,5-dihydro- [1,2,4] triazol-1-yl] -2-chloro-N- (1- Hydroxy-cycloheptylmethyl) -benzamide;
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-hydroxy-3-methoxy-propyl) -3-methyl-5-oxo-4,5-dihydro- [1, 2, 4] triazol-1-yl] -benzamide;
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-hydroxy-3-methoxy-propyl) -3-methyl-5-oxo-4,5-dihydro- [1, 2, 4] triazol-1-yl] -benzamide;
2-Chloro-N- (1-hydroxy-cycloheptylmethyl) -5- [4- (2-hydroxy-2-methyl-propyl) -3-methyl-5-oxo-4,5-dihydro- [1, 2, 4] A compound selected from the group consisting of triazol-1-yl] -benzamide.   A therapeutic for a mammalian IL-1-mediated disease in need thereof comprising a therapeutically effective amount of the compound of claim 1 or a salt or prodrug thereof and a pharmaceutically acceptable carrier or diluent. Pharmaceutical composition for.   A method for treating an IL-1-mediated disease in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the compound according to claim 1 or a salt or prodrug thereof.