CROSS-REFERENCE TO RELATED APPLICATION 0001 This application is a continuation-in-part application of PCT/JP98/04782 filed on Oct. 22, 1998.

TECHNICAL FIELD 0002 The present invention relates to amide derivatives useful as a medicament. The amide derivatives of the present invention are useful as a medicament for treating retinal neurodegenerative disorders and the like.

BACKGROUND ART 0003 N-t-Butyl-benzamide, N-t-butyl-4-bromobenzamide, N-t-butyl-4-nitrobenzamide, etc. are known to be useful as a medicament for treating neurodegenerative disorders such as Parkinson's disease, multiple sclerosis, Alzheimer's disease and the like (WO 95/28153, WO 96/31462). N-t-Butyl-3-chloro-2-pyridinecarboxamide, N-(2-hydroxy-1,1-dimethylethyl)-6-chloro-2-pyridinecarboxamide, etc. are known to be useful as a herbicide (JP 48-26918(A), JP 60-72803(A), JP 61-151174(A)). 0004 It has been known that N-t-butyl-4-fluorobenzamide, N-t-butyl-2-fluorobenzamide, N-(2-hydroxy-1,1-dimethylethyl)-2,4,5-trifluorobenzamide, N-(2-hydroxy-1,1-1-dimethylethyl)-2,5-difluorobenzamide, N-(2-hydroxy-1,1-dimethylethyl)-2-fluorobenzamide, N-(2-hydroxy-1,1-dimethylethyl)-5-chloro-2-fluorobenzamide, N-(2-hydroxy-1,1-dimethylethyl)-2-fluoro-6-iodobenzamide, N-(2-hydroxy-1,1-dimethylethyl)-2,6-difluorobenzamide, N-(2-hydroxy-1,1-dimethylethyl)-2-chloro-4-fluorobenzamide, etc. were produced as synthetic intermediates (EP 511073, WO 89/06649, J. Org. Chem., 52, 713(1987), J. Org. Chem., 53, 345(1988), EP 538231, U.S. Pat. No. 3,985,889, etc.). 0005 However, these documents do not disclose that the amide derivatives are effective for treating retinal neurodegenerative disorders.

DESCRIPTION OF THE INVENTION 0006 The present invention is intended to provide a medicament for treating retinal neurodegenerative disorders and the like. 0007 The inventors of the present invention have intensively carried out research, and found that amide derivatives are useful as a medicament for treating retinal degenerative disorders and the like. Thus, the present invention has been accomplished. 0008 The present inventions are as follows: 0009 1 a medicament for treating retinal neurodegenerative disorder comprising a compound of the formula: 2

0010 wherein Ar is optionally substituted phenyl or optionally substituted aromatic heterocyclic group; 0011 n is 0, 1 or 2; 0012 R1 is hydogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxycarbonyl, carbamoyl, alkanoyl or cyano; R2 and R3 are independently optionally substituted alkyl; or any two groups of R1, R2 and R3 may be taken together with the carbon atom adjacent thereto to form cycloalkane, or all of R1, R2 and R3 may be taken together with the carbon atom adjacent thereto to form bicycloalkane or tricycloalkane, wherein the cycloalkane, the bicycloalkane and the tricycloalkane may be substituted optionally; 0013 R4 and R5 are independently hydrogen atom or optionally substituted alkyl; 0014 R6 is hydrogen atom, hydroxy or alkyl; 0015 or a pharmaceutically acceptable salt thereof; 0016 2 a medicament comprising a compound of the formula: 3

0017 wherein Ar1 is phenyl substituted by fluorine atom at the 2 or 4 position which may be substituted by further 1 or 2 halogen atoms, or optionally substituted 6-membered heteroaryl; 0018 n, R1, R2, R3, R4, R5 and R6 are as defined above; 0019 or a pharmaceutically acceptable salt thereof; and 0020 3 a compound of the formula: 4

0021 wherein Ar2 is a group of the formula: 5

0022 or 6-membered heteroaryl substituted by 1 to 3 halogen atoms; 0023 n, R1, R2, R3 and R6 are as defined above; 0024 one of R7 and R8 is fluorine atom; the other is hydrogen atom or halogen atom; 0025 R9 is hydrogen atom or halogen atom; 0026 provided that the compound is not the following compound: 0027 N-t-butyl-4-fluorobenzamide, 0028 N-t-butyl-2-fluorobenzamide, 0029 N-(2-hydroxy-1,1-dimethylethyl)-2,4,5-trifluorobenzamide, 0030 N-(2-hydroxy-1,1-dimethylethyl)-2,5-difluorobenzamide, 0031 N-(2-hydroxy-1,1-dimethylethyl)-2-fluorobenzamide, 0032 N-(2-hydroxy-1,1-dimethylethyl)-5-chloro-2-fluorobenzamide, 0033 N-(2-hydroxy-1,1-dimethylethyl)-2-fluoro-6-iodobenzamide, 0034 N-(2-hydroxy-1,1-dimethylethyl)-2,6-difluorobenzamide, 0035 N-(2-hydroxy-1,1-dimethylethyl)-2-chloro-4-fluorobenzamide, 0036 N-t-Butyl-3-chloro-2-pyridinecarboxamide and 0037 N-(2-hydroxy-1,1-dimethylethyl)-6-chloro-2-pyridinecarboxamide, 0038 or a pharmaceutically acceptable salt thereof. 0039 Aromatic heterocyclic group includes, for example, 5- or 6-membered aromatic heterocyclic group containing 1 to 3 atoms selected independently from the group consisting of nitrogen atoms, sulfur atoms and oxygen atoms, and the like. Nitrogen atom or sulfur atom constituting heteroaryl may be oxidized. 5-Membered aromatic heterocyclic group includes, for example, the 5-membered aromatic heterocyclic group containing 1 or 2 atoms selected independently from the group consisting of nitrogen atoms, sulfur atoms and oxygen atoms, such as pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl and the like, and the like. 6-Membered aromatic heterocyclic group includes, for example, the 6-membered aromatic heterocyclic group containing 1 to 3 nitrogen atoms, and the like. Typical examples are pyridyl, 1-oxido-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like. 0040 Heterocyclic group includes aromatic heterocyclic group, aliphatic heterocyclic group and the like. Aliphatic heterocyclic group includes, for example, 5- or 6-membered aliphatic heterocyclic group containing 1 to 3 atoms selected independently from the group consisting of nitrogen atoms, sulfur atoms and oxygen atoms, and the like. 5-Membered aliphatic heterocyclic group includes, for example, the 5-membered aliphatic heterocyclic group containing 1 or 2 atoms selected independently from the group consisting of nitrogen atoms, sulfur atoms and oxygen atoms, such as pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dioxolanyl and the like, and the like. 6-Membered aliphatic heterocyclic group includes, for example, the 6-membered aliphatic heterocyclic group containing 1 or 2 atoms selected independently from the group consisting of nitrogen atoms, sulfur atoms and oxygen atoms, such aspiperidyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl and the like, and the like. 0041 The substituent of the substituted phenyl, the substituted aromatic heterocyclic group, the substituted 5-membered aromatic heterocyclic group and the substituted 6-membered aromatic heterocyclic group may be one or more and includes, for example, halogen atom, cyano, nitro, alkyl, alkyl substituted by halogen atom(s), alkoxy, alkoxy substituted by halogen atom(s), alkoxycarbonyl, alkanoylamino, amino, phenyl, alkylaminocarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, carbamoyl, carbamoyl substituted by alkyl(s) and the like. 0042 Preferable substituents of the substituted phenyl include, for example, halogen atom, cyano, nitro, alkyl substituted by halogen atom(s), alkoxy substituted by halogen atom(s), alkoxycarbonyl, alkanoylamino, amino, phenyl, alkylaminocarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, carbamoyl, carbamoyl substituted by alkyl(s) and the like. More preferable examples are the electron-withdrawing groups such as halogen atom, cyano, nitro, trifluoromethyl and the like. Furthermore, preferable is halogen atom, and the most preferable is fluorine atom. 0043 Preferable substituents of the substituted aromatic heterocyclic group, the substituted 5-membered aromatic heterocyclic group and the substituted 6-membered aromatic heterocyclic group include, for example, halogen atom, cyano, nitro, alkyl, alkyl substituted by halogen atom(s), alkoxycarbonyl, alkanoylamino, amino, phenyl, alkylaminocarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, carbamoyl, carbamoyl substituted by alkyl(s) and the like. Particularly preferable is halogen atom. 0044 The number of substituents of the substituted phenyl may be 1, 2 or 3. Preferable examples are 1 and 2, and more preferable is 2. Preferable position of the substitution is the 4 position, and the positions are the 2 and 4 positions if the phenyl is substituted by multiple substituents. The number of substituents of the substituted aromatic heterocyclic group, the substituted 5-membered aromatic heterocyclic group and the substituted 6-membered aromatic heterocyclic group may be 1, 2 or 3. Preferable examples are 1 and 2, and more preferable is 1. 0045 Alkyl includes straight or branched C1-C6 alkyl. Typical examples are methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1,2-dimethylpropyl, hexyl, 3-methylpentyl and the like. 0046 Alkoxy includes straight or branched C1-C6 alkoxy. Typical examples are methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, pentyloxy, 1,2-dimethylpropoxy, hexyloxy, 3-methylpentoxy and the like. 0047 Alkoxyalkoxy is the alkoxy substituted by alkoxy. Alkoxycarbonyl is the carbonyl substituted by alkoxy. 0048 Alkyl substituted by halogen atom(s) and alkoxy substituted by halogen atom(s) are the alkyl and alkoxy substituted by one halogen atom or more. Typical examples are trifluoromethyl, trifluoromethoxy and the like. 0049 Alkenyl includes straight or branched alkenyl having 6 carbon atoms or less. Typical examples are vinyl, allyl, 1-propenyl, 2-butenyl, 5-hexenyl and the like. 0050 Alkynyl includes straight or branched alkynyl having 6 carbon atoms or less. Typical examples are ethynyl, propargyl, 2-butynyl, 5-hexynyl and the like. 0051 Alkanoyl includes, for example, straight or branched alkanoyl having 6 carbon atoms or less. Typical examples are formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 2-methylbutyryl, hexanoyl and the like. 0052 Cycloalkyl, includes, for example, C3-C8 cycloalkyl. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. 0053 In the carbamoyl substituted by alkyl(s), the carbamoyl may be substituted independently by 1 or 2 alkyls. 0054 Halogen atom includes, for example, fluorine atom, chlorine atom, bromine atom, iodine atom and the like. Preferable examples are fluorine atom, chlorine atom and bromine atom, and particularly preferable is fluorine atom. 0055 Cycloalkane includes, for example, C3-C8 cycloalkane. Typical examples are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like. 0056 Bicycloalkane includes, for example, C7-C10 bicycloalkane. Typical examples are bicyclo2.2.1heptane, bicyclo2.2.2octane and the like. 0057 Tricycloalkane includes, for example, C7-C13 tricycloalkane. Typical examples are adamantane and the like. 0058 Substituents of the substituted alkyl, the substituted alkenyl, the substituted alkynyl, the substituted cycloalkane, the substituted bicycloalkane and the substituted tricycloalkane include, for example, cycloalkyl, alkoxy, hydroxy, halogen atom, alkoxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, heterocyclic group such as pyrrolidino, piperidino, piperazino, 4-alkylpiperazino, morpholino and the like, and the like. Alkyl, alkenyl, alkynyl, cycloalkane, bicycloalkane and tricycloalkane may be substituted independently by one or more substituents. 0059 Preferable examples of R1, R2 and R3 as indicated in formulae 1, 2 and 3 are optionally substituted alkyl. More preferable are alkyl optionally substituted byhydroxy, and particularly preferable are methyl, ethyl, hydroxymethyl and hydroxyethyl. 0060 Preferable example of R6 as indicated in formulae 1, 2 and 3 is hydrogen atom. 0061 Preferable examples of n as indicated in formulae 1 and 2 are 0 and 1, and particularly preferable is 0. 0062 The pharmaceutically acceptable salts include, for example, salts with inorganic acids and salts with organic acids. Examples of the inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and the like. Examples of the organic acids include acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid and the like. The compounds of formula 1, 2 or 3 and the pharmaceutically acceptable salts thereof include their solvates such as the hydrate and the like. The compounds of formula 1, 2 or 3 include their tautomers if the tautomers exist. The compounds of formula 1, 2 or 3 include the mixture of their geometrical isomers and the isolated isomer if the geometrical isomers exist. 0063 The compound of formula 1, 2 or 3 can be produced, for example, by the following methods. In the following description, the production process is illustrated with the compound of formula 1 as a representative. 6

0064 wherein R10 is hydrogen atom, protected hydroxy or alkyl; Ar, n, R1, R2, R3, R4, R5 and R6 are as defined above. 0065 Protective groups in the protected hydroxy of R10 include conventionally used protective groups (e.g. Protective Groups in Organic Synthesis T. W. Greene, P. M. Wuts John. Wiley and sons 1991, pp. 10-142). Typical examples are substituted silyl such as trimethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, diphenylmethylsilyl, t-butyldiphenylsilyl and the like; optionally substituted alkyl such as t-butyl, benzyl, trityl, methoxymethyl, methylthiomethyl, benzyloxymethyl, methoxyethoxymethyl, tetrahydropyranyl and the like, and the like. Preferable are t-butyl, benzyl, trityl, methoxymethyl, tetrahydropyranyl, benzyloxymethyl, methoxyethoxymethyl and the like. 0066 Condensation reaction of the compound of formula 4 and the compound of formula 5 can be carried out by conventional methods in peptide chemistry (Basis and Experiment in Peptide Synthesis by Nobuo Izumiya et.al., Maruzen, etc.). Typical methods are C-terminal activation methods (e.g. acid halide methods, acid azide methods, mixed acid anhydride methods, activated ester methods, symmetrical acid anhydride methods and the like), methods using coupling agents (e.g. methods using N,N-dicyclohexylcarbodiimide and the like), N-terminal activation methods (e.g. isocyanate methods, phosphazo methods, phosphorous ester methods and the like) and the like. 0067 Acid halide methods can be performed, for example, by converting the compound of formula 4 to an acid halide by a conventional method, followed by condensing with the compound of formula 5 in the presence of a base in an inert solvent such as methylene chloride and the like at 0 C. to room temperature. The bases include, for example, organic bases such as triethylamine and the like. 0068 Methods using coupling agents can be performed, for example, by condensing the compound of formula 4 with the compound of formula 5 in the presence of coupling agents such as N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (WSC HCl) and the like, if desired, in the presence of 1-hydroxybenzotriazole (HOBt), in an inert solvent such as methylene chloride, N,N-dimethylformamide (DMF) and the like at 0 C. to room temperature. When Ar is optionally substituted pyridyl, the corresponding N-oxide compound can be prepared by oxidation with suitable oxidizing agents after condensation of the compound of formula 4 and the compound of formula 5. The oxidation can be performed by using an oxidizing agent such as hydrogen peroxide and the like in a solvent such as acetic acid, trifluoroacetic acid and the like at room temperature to temperature of reflux. 0069 When R10 is protected hydroxy, the protecting group can be removed by a conventional method. When the protecting group is t-butyl, benzyl, trityl, methoxymethyl, tetrahydropyranyl, benzyloxymethyl, methoxyethoxymethyl and the like, it can be removed by hydrogenation or hydrolysis using an acid catalyst. 0070 The compound of formula 1, 2 or 3 can be purified by a conventional method such as column chromatography, recrystallization and the like. Recrystallization solvent includes, for example, alcohol such as methanol, ethanol, 2-propanol and the like; ether such as diethyl ether and the like; ester such as ethyl acetate and the like; aromatic solvent such as toluene and the like; ketone such as acetone and the like; hydrocarbon solvent such as hexane and the like; water and the like; and mixture thereof. Pharmaceutically acceptable salt of the compound of formula 1, 2 or 3 can be formed by conventional methods, and the salt may be purified by recrystallization or the like. 0071 The compound of formula 1, 2 or 3 or the pharmaceutically acceptable salt thereof may be administered orally or parenterally (e.g. intramuscular injection, intravenous injection, rectal administration by suppository, dermal application for liniments, eye drops or the like). Pharmaceutical forms for oral administration include, for example, tablets, capsules, syrups, suspensions and the like. Pharmaceutical forms for injection include, for example, solutions, emulsions, suspensions and the like. These compositions can be prepared by mixing the active compound with conventional carriers, excipients, binders, stabilizers and the like by conventional methods. Injection may contain buffers, solubilizers, agents for influencing osmotic pressure and the like. 0072 Though the dose and the times for administration varies depending on the grade of the symptoms, the patient's age, body weight, administration route and the like, the compound is usually administered to an adult in a dose of approximately 1-1000 mg, preferably 10-500 mg per day in one portion or several portions, by the oral route. By injection, the compound is usually administered to an adult in a dose of approximately 0.1-500 mg, preferably 3-100 mg per day in one portion or several portions. 0073 Eye drops can be formed into various formulations. The examples of the eye drops are described in Tenganzai written by Kenji MOTOSE (published by Nanzando, 1984) and Shin-Sogoyakuzaigaku II edited by Sadao IGUCHI, pp.77-91 (published by Ishiyaku-Shuppan, 1982). Typical examples of the eye drops include aqueous eye drops (aqueous eye drop solution, sticky eye drop solution, aqueous eye drop suspension, etc.) and non-aqueous eye drops (non-aqueous eye drop solution, non-aqueous eye drop suspension, ophthalmic ointment, etc.) and so on. 0074 Eye drops can be added to by conventional additives, if necessary. Examples of the additive include buffer agents, tonicity agents, thickening agents, preservatives, solubilizing agents, suspending agents, ointment bases, non-aqueous solvents, pH adjusting agents and so on. 0075 Examples of the buffer agents include boric acid, sodium dihydrogenphosphate, disodiumhydrogenphosphate, borax, sodium carbonate, sodium hydrogencarbonate, citric acid, sodium citrate, acetic acid, sodium acetate, sodium carbonate and so on. 0076 Examples of the tonicity agents include sodium chloride, boric acid, sodium nitrate, potassium nitrate, potassium chloride and so on. 0077 Examples of the thickening agents include methylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, hydroxyethylcellulose, chondroitin sulfuric acid, polyvinylpyrrolidone, gelatine, glycerin, macrogolum and so on. 0078 Examples of the preservatives include benzalkonium chloride, phenymercuric nitrate, phenymercuric acetate, thimerosal, chlorhexidine acetate, chlorobutanol, phenylethyl alcohol, paraoxybenzoate esters, sodium dehydroacetate, cetylpyridinium chloride, alkylpolyaminoethylglycine, sorbic acid and its salts and so on. 0079 Examples of the solubilizing agents include sodium carboxymethylcellulose, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyethylene glycol monolaurate, polyethylene glycol monooleate and so on. 0080 Examples of the suspending agents include polysorbate 80, aluminum monostearate and so on. 0081 Examples of the ointment bases include vaseline, purified lanolin, zeren, plastibase and so on. 0082 Examples of the non-aqueous solvents include vegetable oil, liquid paraffin, propylene glycol, mineral oil, -octyldodecanol and so on. 0083 Examples of the pH adjusting agents include sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, citric acid, phosphoric acid, acetic acid and so on. 0084 Though the usage and dose of the eye drops of the invention varies depending on the concentration of the medicament, the patient's symptoms and age and so on, the eye drops are usually administrated in 1 to 2 drops per one time and 1 to 6 times per day. A suitable amount of ophthalmic ointment is usually applied in saccus conjunctivae in 1 to 2 times per day.

EXAMPLES 0085 The present invention will be described in detail below, referring to examples, which are not limitative of the present invention. 0086 The following compounds are shown as examples of the present invention: 0087 N-t-butyl-2-fluoro-4-bromobenzamide, 0088 N-t-butyl-2-fluoro-4-trifluoromethylbenzamide, 0089 N-t-butyl-2-fluoro-4-cyanobenzamide, 0090 N-t-butyl-2-fluoro-4-nitrobenzamide, 0091 N-t-butyl-2-fluoro-4-methanesulfonylaminobenzamide, 0092 N-t-butyl-2-fluoro-4-phenylbenzamide, 0093 N-t-butyl-2-fluoro-4-trifluoromethoxybenzamide, 0094 N-t-butyl-3-fluoro-4-chlorobenzamide, 0095 N-t-butyl-3-fluoro-4-bromobenzamide, 0096 N-t-butyl-3-fluoro-4-trifluoromethylbenzamide, 0097 N-t-butyl-3-fluoro-4-cyanobenzamide, 0098 N-t-butyl-3-fluoro-4-nitrobenzamide, 0099 N-t-butyl-6-chloro-nicotinamide, 0100 N-t-butyl-5-chloro-2-thiophenecarboxamide, 0101 N-t-butyl-4-chloro-2-thiophenecarboxamide, 0102 N-t-butyl-3-fluoro-4-chlorobenzamide, 0103 N-t-butyl-2,4-difluorobenzamide, 0104 N-(2-hydroxy-1,1-dimethylethyl)-2,4-difluorobenzamide, 0105 N-(2-hydroxy-1,1-dimethylethyl)-2,4,5-trifluorobenzamide, 0106 N-(2-hydroxy-1,1-dimethylethyl)-6-chloro-3-pyridazinecarboxamide, 0107 N-t-butyl-5-chloro-2-pyridinecarboxamide, 0108 N-(2-hydroxy-1,1-dimethylethyl)-5-chloro-2-pyridinecarboxamide, 0109 N-t-butyl-1-oxido-5-chloro-2-pyridinecarboxamide, 0110 N-t-butyl-1-oxido-2-pyridinecarboxamide, 0111 N-(2-hydroxy-1,1-dimethylethyl)-1-oxido-5-chloro-2-pyridinecarboxamide, 0112 N-(2-hydroxy-1,1-dimethylethyl)-6-chloro-3-pyridazinecarboxamide, 0113 N-(2-hydroxy-1,1-dimethylethyl)-3-fluoro-2-pyridinecarboxamide, 0114 N-(2-hydroxy-1,1-dimethylethyl)-5-fluoro-2-pyridinecarboxamide, 0115 N-(2-hydroxy-1,1-dimethylethyl)-6-chloronicotinamide, 0116 N-t-butyl-pyrazinecarboxamide, 0117 N-(2-hydroxy-1,1-dimethylethyl)-pyrazinecarboxamide, 0118 N-t-butyl-4-pyridazinecarboxamide, 0119 N-(2-hydroxy-1,1-dimethylethyl)-4-pyridazinecarboxamide, 0120 N-(2-hydroxy-1,1-dimethylethyl)-2-pyrimidinecarboxamide, and 0121 N-(2-hydroxy-1,1-dimethylethyl)-4-bromo-2-pyrimidinecarboxamide.

Example 1 0122 N-t-Butyl-2,4-difluorobenzamide 0123 A solution of t-butylamine (0.2962 g, 4.05 mmol) and triethylamine (0.70 ml, 5.02 mmol) in dichloromethane (2 ml) was cooled to 0 C. in an ice-bath. To the above solution was added a solution of 2,4-difluorobenzoyl chloride (0.3652 g, 2.07 mmol) in dichloromethane (3 ml) dropwise and stirred for 2.5 hours. The mixture was added to saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous NaHCO3 and dried over MgSO4. The solvent was evaporated to give the title compound (0.4086 g; 93%). 0124 1H-NMR(270 MHz, CDCl3) 8.08 (td, 1H, J8.9, 6.6 Hz), 7.02-6.93 (m, 1H), 6.84 (ddd, 1H, J11.9, 8.6, 2.6 Hz), 6.5 (br, s, 1H), 1.47 (s, 9H)

Example 2 0125 N-t-Butylbenzamide 0126 The title compound (0.3028 g; 84%) was prepared by the same method as that described in Example 1, using benzoyl chloride (0.2851 g, 2.03 mmol). 0127 1H-NMR(270 MHz, CDCl3) 7.74-7.70 (m, 2H), 7.48-7.37 (m, 3H), 5.94 (br, 1H), 1.48 (s, 9H)

Example 3 0128 N-t-Butyl-3,4-difluorobenzamide 0129 The title compound (0.3867 g; 90%) was prepared by the same method as that described in Example 1, using 3,4-difluorobenzoyl chloride (0.3563 g, 2.02 mmol). 0130 1H-NMR(270 MHz, CDCl3) 7.58 (ddd, 1H, J10.9, 7.6, 2.3 Hz), 7.48-7.41 (m, 1H), 7.19 (ddd, 1H, J9.6, 8.5, 7.7 Hz), 5.84 (br, 1H), 1.47 (s, 9H)

Example 4 0131 N-t-Butyl-3,5-difluorobenzamide 0132 The title compound (0.3996 g; 93%) was prepared by the same method as that described in Example 1, using 3,5-difluorobenzoyl chloride (0.3555 g, 2.01 mmol). 0133 1H-NMR(270 MHz, CDCl3) 7.26-7.19 (m, 2H), 6.92 (tt, 1H, J8.6, 2.3 Hz), 5.82 (br, 1H), 1.47 (s, 9H)

Example 5 0134 N-t-Butyl-2,6-difluorobenzamide 0135 The title compound (0.4130 g; 97%) was prepared by the same method as that described in Example 1, using 2,6-difluorobenzoyl chloride (0.3547 g, 2.01 mmol). 0136 1H-NMR(270 MHz, CDCl3) 7.38-7.29 (m, 1H), 6. 92 (dd, 2H, J8.4, 7.6 Hz), 5.79 (br, 1H), 1.47 (s, 9H)

Example 6 0137 N-t-Butyl-4-fluorobenzamide 0138 The title compound (0.3767 g; 96%) was prepared by the same method as that described in Example 1, using 4-fluorobenzoyl chloride (0.3165 g, 2.00 mmol). 0139 1H-NMR(270 MHz, CDCl3) 7.72 (dd, 2H, J9.2, 5.3 Hz), 7.09 (t, 2H, J8.6 Hz), 5.86 (br, 1H), 1.47 (s, 9H)

Example 7 0140 N-t-Butyl-4-bromobenzamide 0141 The title compound (0.4794 g; 95%) was prepared by the same method as that described in Example 1, using 4-bromobenzoyl chloride (0.4301 g, 1.97 mmol). 0142 1H-NMR(270 MHz, CDCl3) 7.59 (d, 2H, J8.9 Hz), 7.54 (d, 2H, J8.9 Hz), 5.88 (br, 1H), 1.47 (s, 9H)

Example 8 0143 N-t-Butyl-4-methylbenzamide 0144 The title compound (0.3611 g; 93%) was prepared by the same method as that described in Example 1, using 4-methylbenzoyl chloride (0.3153 g, 2.04 mmol). 0145 1H-NMR(270 MHz, CDCl3) 7.61 (d, 2H, J8.2 Hz), 7.21 (d, 2H, J8.2 Hz), 5.91 (br, 1H), 2.38 (s, 3H), 1.47 (s, 9H)

Example 9 0146 N-t-Butyl-2,4-dichlorobenzamide 0147 The title compound (0.5017 g; >99%) was prepared by the same method as that described in Example 1, using 2,4-dichlorobenzoyl chloride (0.4169 g, 1.99 mmol). 0148 1H-NMR(270 MHz, CDCl3) 7.57 (d, 1H, J8.1 Hz), 7.40 (d, 1H, J2.0 Hz), 7.29 (dd, 1H, J8.1, 2.0 Hz), 5.92 (br, 1H), 1.47 (s, 9H)

Example 10 0149 N-t-Butyl-4-nitrobenzamide 0150 The title compound (1.0567 g; 94%) was prepared by the same method as that described in Example 1, using 4-nitrobenzoyl chloride (0.9356 g, 5.04 mmol). 0151 1H-NMR(270 MHz, CDCl3) 8.28 (d, 2H, J8.9 Hz), 7.88 (d, 2H, J8.9 Hz), 5.96 (br, 1H), 1.50 (s, 9H)

Example 11 0152 N-t-Butyl-4-aminobenzamide 0153 Ten percent Pd/C (0.1003 g) was added to a solution of N-t-butyl-4-nitrobenzamide (0.7349 g, 3.31 mmol) in ethyl acetate (10 ml), and stirred under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite bed and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane/ethyl acetate/triethylamine50/100/1) to give the title compound (0.6156 g; 97%). 0154 1H-NMR(270 MHz, CDCl3) 7.55 (d, 2H, J8.7 Hz), 6.65 (d, 2H, J8.7Hz), 5.81 (br, 1H), 3.92 (br, 2H), 1.45 (s, 9H)

Example 12 0155 N-t-Butyl-4-chlorobenzamide 0156 The title compound (0.4204 g; 99%) was prepared by the same method as that described in Example 1, using 4-chlorobenzoyl chloride (0.3507 g, 2.00 mmol). 0157 1H-NMR(270 MHz, CDCl3) 7.65 (d, 2H, J8.6 Hz), 7.38 (d, 2H, J8.6 Hz), 5.88 (br, 1H), 1.47 (s, 9H)

Example 13 0158 N-t-Butyl-4-methoxybenzamide 0159 The title compound (0.4104 g; 98%) was prepared by the same method as that described in Example 1, using 4-methoxybenzoyl chloride (0.3444 g, 2.02 mmol). 0160 1H-NMR(270 MHz, CDCl3) 7.68 (d, 2H, J8.9 Hz), 6.90 (d, 2H, J8.9 Hz), 5.87 (br, 1H), 3.84 (s, 3H), 1.47 (s, 9H)

Example 14 0161 N-t-Butyl-4-chloro-2-fluorobenzamide 0162 To a suspension of 4-chloro-2-fluorobenzoic acid (0.3494 g, 2.00 mmol) in methylene chloride (10 ml) were added t-butylamine (0.32 ml, 3.05 mmol) and HOBt (0.3248 g, 2.40 mmol), and then WSC HCl (0.4596 g, 2.40 mmol) was added and stirred for 3 hours. The reaction mixture was added into water and extracted three times with ethyl acetate. The combined extracts were dried over MgSO4. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane/ethyl acetate5/1) to give the title compound (0.4403 g; 96%). 0163 1H-NMR(270 MHz, CDCl3) 8.01 (t, 1H, J8.6 Hz), 7.24 (dd, 1H, J8.6, 2.0 Hz), 7.13 (dd, 1H, J11.6, 2.0 Hz), 6.50 (br, 1H), 1.47 (s, 9H)

Example 15 0164 N-Isopropyl-2,4-difluorobenzamide 0165 The title compound (0.3804 g; 95%) was prepared by the same method as that described in Example 1, using 2,4-difluorobenzoyl chloride (0.3532 g, 2.00 mmol) and isopropylamine (0.26 ml, 3.05 mmol). 0166 1H-NMR(270 MHz, CDCl3) 8.12 (td, 1H, J8.9, 6.6 Hz), 6.98 (tdd, 1H, J8.9, 2.3, 1.0 Hz), 6.85 (ddd, 1H, J12.0, 8.4, 2.3 Hz), 6.45 (br, 1H), 4.35-4.25 (m, 1H), 1.27 (d, 6H, J6.6 Hz)

Example 16 0167 N-t-Butyl-4-methoxycarbonylbenzamide 0168 The title compound (0.2134 g; 39%) was prepared by the same method as that described in Example 1, using 4-methoxycarbonylbenzoyl chloride (0.3933 g, 1.98 mmol). 0169 1H-NMR(270 MHz, CDCl3) 8.08 (d, 2H, J8.7 Hz), 7.77 (d, 2H, J8.7 Hz), 5.95 (br, 1H), 3.94 (s, 3H), 1.48 (s, 9H)

Example 17 0170 N-t-Butylisonicotinamide 0171 The title compound (0.3017 g; 84%) was prepared by the same method as that described in Example 1, using isonicotinoyl chloride hydrochloride (0.3606 g, 2.02 mmol). 0172 1H-NMR(270 MHz, CDCl3) 8.72 (dd, 2H, J4.3, 1.7 Hz), 7.56 (dd, 2H, J4.3, 1.7 Hz), 5.95 (br, 1H), 1.48 (s, 9H)

Example 18 0173 N-t-Butyl-2-chloro-4-fluorobenzamide 0174 The title compound (0.4278 g; 93%) was prepared by the same method as that described in Example 14, using 2-chloro-4-fluorobenzoic acid (0.3492 g, 2.00 mmol). 0175 1H-NMR(270 MHz, CDCl3) 7.64 (dd, 1H, J8.6, 6.3 Hz), 7.12 (dd, 1H, J8.6, 2.4 Hz), 7.03 (td, 1H, J8.6, 2.4 Hz), 5.91 (br, 1H), 1.47 (s, 9H)

Example 19 0176 N-t-Butyl-3-thiophenecarboxamide 0177 The title compound (0.1856 g; 51%) was prepared by the same method as that described in Example 14, using 3-thiophenecarboxylic acid (0.2567 g, 2.00 mmol). 0178 1H-NMR(270 MHz, CDCl3) 7.77 (dd, 1H, J2.6, 1.7 Hz), 7.33 (dd, 1H, J5.2, 2.6 Hz), 7.31 (dd, 1H, J5.2, 1.7 Hz), 5.76 (br, 1H), 1.46 (s, 9H)

Example 20 0179 N-t-Butylnicotinamide 0180 The title compound (0.2966 g; 83%) was prepared by the same method as that described in Example 1, using nicotinoyl chloride hydrochloride (0.3569 g, 2.00 mmol). 0181 1H-NMR(270 MHz, CDCl3) 8.91 (dd, 1H, J2.3, 0.8 Hz), 8.70 (dd, 1H, J4.9, 1.7 Hz), 8.07 (ddd, 1H, J7.9, 2.3, 1.7 Hz), 7.37 (ddd, 1H, J7.9, 4.9, 0.8 Hz), 5.95 (br, 1H), 1.49 (s, 9H)

Example 21 0182 N-t-Butylpicolinamide 0183 The title compound (0.3109 g; 86%) was prepared by the same method as that described in Example 1, using picolinoyl chloride hydrochloride (0.3624 g, 2.04 mmol). 0184 1H-NMR(270 MHz, CDCl3) 8.52 (ddd, 1H, J4.6, 1.7, 1.0 Hz), 8.18 (ddd, 1H, J7.9, 1.3, 1.0 Hz), 8.00 (br, 1H), 7.83 (ddd, 1H, J7.9, 7.6, 1.7 Hz), 7.40 (ddd, 1H, J7.6, 4.6, 1.3 Hz), 1.50 (s, 9H)

Example 22 0185 N-t-Butyl-2,3-difluorobenzamide 0186 The title compound (0.3873 g; 91%) was prepared by the same method as that described in Example 14, using 2,3-difluorobenzoic acid (0.3159 g, 2.00 mmol). 0187 1H-NMR(270 MHz, CDCl3) 7.76 (ddt, 1H, J8.1, 6.6, 1.6 Hz), 7.33-7.22 (m, 1H), 7.17 (tdd, 1H, J8.1, 4.8, 1.6 Hz), 6.43 (br, 1H), 1.48 (s, 9H)

Example 23 0188 N-t-Butyl-2-thiophenecarboxamide 0189 The title compound (0.3700 g; >99%) was prepared by the same method as that described in Example 1, using 2-thiophenecarbonyl chloride (0.2939 g, 2.00 mmol). 0190 1H-NMR(270 MHz, CDCl3) 7.43 (dd, 1H, J5.0, 1.0 Hz), 7.40 (dd, 1H, J4.0, 1.0 Hz), 7.04 (dd, 1H, J5.0, 4.0 Hz), 5.80 (br, 1H), 1.46 (s, 9H)

Example 24 0191 N-t-Butyl-4-phenylbenzamide 0192 The title compound (0.4869 g; 95%) was prepared by the same method as that described in Example 14, using 4-phenylbenzoic acid (0.3982 g, 2.01 mmol). 0193 1H-NMR(270 MHz, CDCl3) 7.80 (d, 2H, J9.2 Hz), 7.66-7.59 (m, 4H), 7.49-7.37 (m, 3H), 5.98 (br, 1H), 1.50 (s, 9H)

Example 25 0194 N-t-Butyl-2,5-difluorobenzamide 0195 The title compound (0.3921 g; 91%) was prepared by the same method as that described in Example 14, using 2,5-difluorobenzoic acid (0.3173 g, 2.01 mmol). 0196 1H-NMR(270 MHz, CDCl3) 7.78-7.71 (m, 1H), 7.14-7.03 (m, 2H), 6.60 (br, 1H), 1.47 (s, 9H)

Example 26 0197 N-(2-Fluoro-1,1-dimethylethyl)-2,4-difluorobenzamide 0198 WSC HCl (1.15 g, 6 mmol) was added to a mixture of 2,4-difluorobenzoic acid (0.95 g, 6 mmol), 2-fluoro-1,1-dimethylethylamine hydrochloride (J. Med. Chem., 34, 29-37(1991): 0.77 g, 6 mmol), HOBt (0.81 g, 6 mmol) and triethylamine (0.91 g, 9 mmol) in methylene chloride (15 ml), and stirred at room temperature for 3 hours. The reaction mixture was concentrated, diluted with ethyl acetate and washed with saturated aqueous NaHCO3, 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively, dried over MgSO4 and concentrated under a reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate20/1) to give the title compound (0.61 g; 44%). 0199 1H-NMR(270 MHz, CDCl3) 8.07 (1H, td, J8.9, 6.6 Hz), 6.95-7.02 (1H, m), 6.86 (1H, ddd, J12, 8, 3 Hz), 6.57 (1H, br), 4.56 (2H, d, J47.5Hz), 1.47 (6H, d, J2 Hz)

Example 27 0200 N-(2-Hydroxy-1,1-dimethylethyl)-2,4-difluorobenzamide 0201 WSC HCl (7.68 g, 40 mmol) was added to a mixture of 2,4-difluorobenzoic acid (6.32 g, 40 mmol), 2-amino-2-methyl-1-propanol (3.56 g, 40 mmol) and HOBt (5.40 g, 40 mmol) in methylene chloride (150 ml), and stirred at room temperature for 3 hours. The reaction mixture was concentrated, diluted with ethyl acetate and washed with saturated aqueous NaHCO3, 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively, dried over MgSO4 and concentrated under a reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate3/1) to give the title compound (6.20 g; 68%). 0202 1H-NMR(270 MHz, CDCl3) 8.08 (1H, td, J8.8, 6.6 Hz), 6.96-7.04 (1H, m), 6.87 (1H, ddd, J12, 8, 2 Hz), 6.76 (1H, br), 4.43 (1H, t, J6 Hz), 3.69 (2H, J6 Hz), 1.42 (6H, s)

Example 28 0203 N-(1-Cyano-1-methylethyl)-2,4-difluorobenzamide 0204 The title compound was prepared by the same method as that described in Example 27, using 2-amino-2-methylpropionitrile (J. Med. Chem., 37, 1810-1822(1994)). 0205 1H-NMR(270 MHz, CDCl3) 8.18 (1H, td, J9.2, 6.6 Hz), 7.00-7.07 (1H, m), 6.86 (1H, ddd, J12, 8, 2 Hz), 6.71 (1H, br), 1.82 (6H, s)

Example 29 0206 N-(1-Carbamoyl-1-methylethyl)-2,4-difluorobenzamide 0207 The title compound was prepared by the same method as that described in Example 26, using 2-amino-2-methylpropanamide hydrochloride. 0208 1H-NMR(270 MHz, CDCl3) 8.09 (1H, td, J8.9, 6.6 Hz), 7.28 (1H, br), 6.96-7.04 (1H, m), 6.88 (1H, ddd, J12, 8, 2 Hz), 6.34 (1H, br), 5.54 (1H, br), 1.70 (6H, s)

Example 30 0209 N-(1-Methoxycarbonyl-1-methylethyl)-2,4-difluorobenzamide 0210 The title compound was prepared by the same method as that described in Example 26, using methyl 2-amino-2-methylpropionate hydrochloride. 0211 1H-NMR(270 MHz, CDCl3) 8.10 (1H, td, J9.2, 6.6 Hz), 7.22 (1H, br), 6.95-7.03 (1H, m), 6.88 (1H, ddd, J12, 8, 2 Hz), 3.79 (3H, s), 1.67 (6H, s)

Example 31 0212 N-(2-Methoxy-1,1-dimethylethyl)-2,4-difluorobenzamide 0213 A solution of 2M trimethylsilyldiazomethane in hexane (3.9 ml, 7.8 mmol) was added dropwise to a solution of N-(2-hydroxy-1,1-dimethylethyl)-2,4-difluorobenzamide obtained in Example 27 (0.59 g, 2.6 mmol) and boron trifluoride diethyl etherate (43 mg, 0.3 mmol) in methylene chloride (6 ml), and stirred at room temperature overnight. To the reaction mixture was added IN hydrochloric acid (5 ml) dropwise, and the resulting mixture was concentrated and extracted with ethyl acetate. The extract was washed with brine, dried over MgSO4 and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate10/1) to give the title compound (0.38 g; 60%). 0214 1H-NMR(270 MHz, CDCl3) 8.07 (1H, td, J8.9, 6.6 Hz), 6.93-7.00 (1H, m), 6.88 (1H, br), 6.83 (1H, ddd, J12, 8, 3 Hz), 3.44 (2H, s), 3.41 (3H, s), 1.47 (6H, s)

Example 32 0215 N-(1-Formyl-1-methylethyl)-2,4-difluorobenzamide 0216 To a solution of N-(2-hydroxy-1,1-dimethylethyl)-2,4-difluorobenzamide obtained in Example 27 (6.2 g, 27 mmol) and triethylamine (8.2 g, 81 mmol) in DMSO (60 ml) was added a solution of pyridine sulfur trioxide complex (12.9 g, 81 mmol) in DMSO (60 ml) dropwise with cooling in an ice-bath and stirred for 2 hours. The reaction mixture was poured over a mixture of ice and water, and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively dried over Na2SO4, concentrated under a reduced pressure and the residue was crystallized from hexane/ethyl acetate to give the title compound (5.05 g; 82%). 0217 1H-NMR(270 MHz, CDCl3) 9.47 (1H, s), 8.11 (1H, td, J8.9, 6.6 Hz), 7.14 (1H, br), 6.98-7.04 (1H, m), 6.90 (1H, ddd, J12, 8, 2 Hz), 1.51 (6H, s)

Example 33 0218 N-(2-Hydroxy-1,1-dimethylpropyl)-2,4-difluorobenzamide 0219 To a solution of N-(1-formyl-1-methylethyl)-2,4-difluorobenzamide obtained in Example 32 (1.14 g, 5 mmol) in THF (10 ml) was added 0.9 M methyl magnesium bromide in THF (13 ml, 12 mmol) dropwise at 20 C. The reaction mixture was warmed gradually to room temperature over 2 hours and added to 10% aqueous ammonium chloride (100 ml). The resulting mixture was extracted with ethyl acetate, washed with saturated aqueous NaHCO3 and brine,dried over MgSO4, concentrated under a reduced pressure and the residue was crystallized from hexane/ethyl acetate to give the title compound (1.05 g; 86%). 0220 1H-NMR(270 MHz, CDCl3) 8.08 (1H, td, J8.8, 6.6 Hz), 6.97-7.04 (1H, m), 6.87 (1H, ddd, J12, 8, 2 Hz), 6.73 (1H, br), 4.55 (1H, br d, J6 Hz), 3.80 (1H, m), 1.49 (3H, s), 1.37 (3H, s), 1.20 (3H, d, J6.33 Hz)

Example 34 0221 N-(2-Oxo-1,1-dimethylpropyl)-2,4-difluorobenzamide 0222 To a solution of N-(2-hydroxy-1,1-dimethylpropyl)-2,4-difluorobenzamide obtained in Example 33 (0.30 g, 1.2 mmol) and triethylamine (0.37 g, 3.7 mmol) in DMSO (3 ml) was added pyridine sulfur trioxide complex (0.59 g, 3.7 mmol) portionwise and stirred at room temperature for 3 hours. The reaction mixture was added to a mixture of ice and water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively dried over Na2SO4 and concentrated under a reduced pressure. The residue was crystallized from hexane/ethyl acetate to give the title compound (0.24 g; 81%). 0223 1H-NMR(270 MHz, CDCl3) 8.08 (1H, td, J8.9, 6.6 Hz), 7.47 (1H, br), 6.96-7.03 (1H, m), 6.89 (1H, ddd, J12, 8, 2 Hz), 2.25 (3H, s), 1.61 (6H, s)

Example 35 0224 N-(1-Carboxy-1-methylethyl)-2,4-difluorobenzamide 0225 To a solution of N-(1-methoxycarbonyl-1-methylethyl)-2,4-difluorobenzamide obtained in Example 30 (1.51 g, 5.9 mmol) in methanol (10 ml) was added 4N aqueous NaOH (10 ml), and stirred at room temperature for 30 min. The methanol was evaporated and the resulting mixture was acidified with 4N hydrochloric acid and extracted with ethyl acetate. The extract was dried over Na2SO4 and the solvent was evaporated under a reduced pressure to give the title compound (1.42 g; 99%). 0226 1H-NMR(270 MHz, CDCl3) 12.35 (1H, br), 8.44 (1H, br), 7.64 (1H, td, J8.7, 6.5 Hz), 7.33 (1H, ddd, J11, 9, 2 Hz), 7.13-7.20 (1H, m), 1.44 (6H, s)

Example 36 0227 N-(1,1-Dimethyl-2-propynyl)-2,4-difluorobenzamide 0228 The title compound was prepared by the same method as that described in Example 27, using 1,1-dimethylpropargylamine. 0229 1H-NMR(270 MHz, CDCl3) 8.15 (1H, td, J8.9, 7.0 Hz), 6.96-7.02 (1H, m), 6.85 (1H, ddd, J12, 8, 2 Hz), 6.76 (1H, br), 2.40 (1H, s), 1.75 (6H, s)

Example 37 0230 N-(1,1-Dimethyl-2-propenyl)-2,4-difluorobenzamide 0231 Five percent Pd/BaSO4 (100 mg) was added to a solution of N-(1,1-dimethyl-2-propynyl)-2,4-difluorobenzamide obtained in Example 36 (1.0 g, 4.5 mmol) and quinoline (100 mg) in methanol (20 ml), and stirred under a hydrogen atmosphere at room temperature for 1.5 hours. The catalyst was removed by filtration and the filtrate was concentrated under a reduced pressure. The residue was diluted with ethyl acetate and washed with 1N hydrochloric acid (3), saturated aqueous NaHCO3 and brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate15/1) to give the title compound (0.95 g; 94%). 0232 1H-NMR(270 MMHz, CDCl3) 8.09 (1H, td, J8.9, 6.6 Hz), 6.94-7.01 (1H, m), 6.85 (1H, ddd, J12, 8, 2 Hz), 6.66 (1H, br), 6.10 (1H, dd, J17.5, 11 Hz), 5.18 (1H, d, J17.5 Hz), 5.10 (1H, d, J11 Hz), 1.55 (6H, s)

Example 38 0233 N-(1,1-Dimethylpropyl)-2,4-difluorobenzamide 0234 To a solution of t-amylamine (0.35 ml, 3.0 mmol) and triethylamine (0.56 ml, 4.0 mmol) in methylene chloride (3 ml) was added a solution of 2,4-difluorobenzoyl chloride (0.36 g, 2.0 mmol) in methylene chloride (2 ml) with cooling in an ice-bath, and stirred for 1 hour. The reaction mixture was poured over saturated aqueous NaHCO3 and extracted with ethyl acetate. The extract was washed with saturated aqueous NaHCO3 and dried over MgSO4. The solvent was evaporated to give the title compound (0.47 g; >99%). 0235 1H-NMR(270 MHz, CDCl3) 8.07 (td, J9.1, 6.6 Hz, 1H), 7.01-6.93 (m, 1H), 6.84 (ddd, J11.9, 8.6, 2.6 Hz, 1H), 6.40 (br, 1H), 1.82 (q, J7.6 Hz, 2H), 1.41 (s, 6H), 0.91 (t, J7.6 Hz, 3H)

Example 39 0236 N-t-Butyl-6-chloro-3-pyridazinecarboxamide 0237 1) 6-Chloro-3-vinylpyridazine 0238 Pd(PPh3)4 (0.42 g, 0.37 mmol) was added to a suspension of tributyl(vinyl)tin (7.67 g, 24.2 mmol) and 3,6-dichloropyridazine (3.57 g, 24.0 mmol) in toluene (30 ml), and stirred at 50 C. for 8 hours. The reaction mixture was added to aqueous ammonium fluoride (100 ml), and ethyl acetate (30 ml) was added thereto and stirred for 1 hour. The white precipitates were removed by filtration. The organic layer was separated from the filtrate and the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined and dried over MgSO4. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane/ethyl acetate3/1) to give the title compound (1.03 g; 31%). 0239 2) 6-Chloro-3-pyridazinecarboxylic Acid 0240 AD-mix- (Aldrich Chemical Company: 1.39 g) was added to a mixture of t-butanol and water (1:1, 10 ml) and stirred. The mixture was cooled in an ice-bath and 6-chloro-3-vinylpyridazine (0.14 g, 1.0 mmol) was added thereto. The resulting mixture was warmed to room temperature gradually and stirred overnight. After the reaction mixture was cooled in an ice-bath, sodium sulfite (1.53 g) was added thereto and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate and the extract was dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel chromatography (chloroform/methanol10/1) to give the diol (0.14 g; 81%). The diol was dissolved in chloroform (3 ml), and saturated aqueous NaHCO3 (0.12 ml) and sodium per iodate (0.35 g, 1.6 mmol) were added thereto and stirred for 1 hour. Na2SO4 was added thereto and filtered off, after stirring for 1 hour. The solvent was evaporated under a reduced pressure to give 6-chloro-3-pyridazinecarboxyaldehyde (0.10 g; 90%). To an aqueous solution (2 ml) of disodium hydrogen phosphate dodecahydrate (50 mg), were added acetnitrile (3 ml), 6-chloro-3-pyridazinecarboxyaldehyde (0.10 g, 0.70 mmol), 31% aqueous hydrogen peroxide (0.12 g, 1.1 mmol) and sodium chlorite (0.10 g, 1.1 mmol), and stirred for 3 hours. The precipitated solid was removed by filtration. Water (20 ml) was added to the filtrate and the resulting mixture was extracted with ethyl acetate (30 ml3) and the extracts were dried over Na2SO4. The solvent was evaporated to give the title compound (0.043 g; 39%). 0241 1H-NMR(270 MHz, DMSO-d6) 8.23 (d, J9.0 Hz, 1H), 8.09 (d, J9.0 Hz, 1H) 0242 3) N-t-Butyl-6-chloro-3-pyridazinecarboxamide 0243 To a solution of 6-chloro-3-pyridazinecarboxylic acid (0.12 g, 0.76 mmol) in methylene chloride (15 ml) were added t-butylamine (0.21 ml, 2.0 mmol) and N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.24 g, 0.93 mmol), and stirred overnight. The reaction mixture was added to saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane/ethyl acetate2/1) to give the title compound (0.080 g; 49%). 0244 1H-NMR(270 MHz, CDCl3) 8.27 (d, J8.8 Hz, 1H), 7.97 (br, 1H), 7.67 (d, J8.8 Hz, 1H), 1.51 (s, 9H)

Example 40 0245 N-t-Butyl-5-chloro-2-pyridinecarboxamide 0246 1) 5-Chloro-2-vinylpyridine 0247 Pd(PPh3)4 (0.46 g, 0.4 mmol) was added to a solution of tributyl(vinyl)tin (6.33 g, 20.0 mmol) and 2,5-dichloropyridine (2.96 g, 20.0 mmol) in toluene (30 ml), followed by heating under reflux for 3 hours. The reaction mixture was added to aqueous ammonium fluoride (100 ml), and ethyl acetate (30 ml) was added thereto and stirred for 1 hour. The white precipitates were removed by filtration. The organic layer was separated from the filtrate and the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined and dried over Na2SO4. Purification through silica gel chromatography (hexane/ethyl acetate10/1 to 2/1) followed by evaporation of the solvent at an atmospheric pressure gives the title compound (3.6 g) as an oil containing a solvent. 0248 1H-NMR(270 MHz, CDCl3) 8.52 (d, J2.4 Hz, 1H), 7.62 (dd, J8.5, 2.4 Hz, 1H), 7.29 (d, J8.5 Hz, 1H), 6.78 (dd, J17.5, 10.7 Hz, 1H), 6.18 (dd, J17.5, 1.3 Hz, 1H), 5.51 (dd, J10.7, 1.3 Hz, 1H) 0249 2) 5-Chloro-2-pyridinecarboxylic Acid 0250 Potassium carbonate (0.29 g, 2.1 mmol) was added portionwise to an aqueous solution (10 ml) of sodium periodate (2.13 g, 9.98 mmol) and potassium permanganate (0.065 g, 0.41 mmol). After t-butanol (5 ml) was added, 5-chloro-2-vinylpyridine obtained above (0.34 g, ca. 2 mmol) was added portionwise followed by stirring for 1 hour. Then ethylene glycol (1 ml) was added thereto and stirred for another hour. The reaction mixture was added to 5% aqueous KHSO4, extracted three times with ethyl acetate and the extracts were dried over Na2SO4. The solvent was evaporated to give the title compound (0.31 g). 0251 1H-NMR(270 MHz, DMSO-d6) 8.76 (dd, J2.3, 0.5 Hz, 1H), 8.12 (dd, J8.3, 2.3 Hz, 1H), 8.04 (dd, J8.3, 0.5 Hz, 1H) 0252 3) N-t-Butyl-5-chloro-2-pyridinecarboxamide 0253 The title compound was prepared by the same method as that described in Example 27, using 5-chloro-2-pyridinecarboxylic acid and t-butylamine. 0254 1H-NMR(270 MHz, CDCl3) 8.46 (dd, J2.4, 0.6 Hz, 1H), 8.13 (dd, J8.4, 0.6 Hz, 1H), 7.85 (br, 1H), 7.80 (dd, J8.4, 2.4 Hz, 1H), 1.49 (s, 9H)

Example 41 0255 N-t-Butyl-1-oxido-5-chloro-2-pyridinecarboxamide 0256 Thirty-one percent aqueous hydrogen peroxide (1.0 ml) was added to a solution of N-t-butyl-5-chloro-2-pyridinecarboxamide obtained in Example 40 (0.35 g, 1.65 mmol) in trifluoroacetic acid (5 ml), and heated under reflux for 1.5 hours. The reaction mixture was added portionwise into an ice-cooled 1N aqueous NaOH and extracted three times with ethyl acetate and the extracts were dried over MgSO4. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate5/1 to 2/1) to give the title compound (0.24 g, 65%). 0257 1H-NMR(270 MHz, CDCl3) 10.90 (br, 1H), 8.35 (d, J8.5 Hz, 1H), 8.27 (d, J1.6 Hz, 1H), 7.43 (dd, J8.5, 1.6 Hz, 1H), 1.47 (s, 9H)

Example 42 0258 N-t-Butyl-3-fluoro-2-pyridinecarboxamide 0259 1) 1-Oxido-3-fluoropyridine 0260 Thirty-one percent aqueous hydrogen peroxide (22.2 g, 196 mmol) was added to a solution of 3-fluoropyridine (9.5 g, 98 mmol) in acetic acid (100 ml), and heated under reflux for 5 hours. The reaction mixture was allowed to cool and concentrated under a reduced pressure to about one third of its volume. Ethanol (10 ml) and water (50 ml) were added thereto and the mixture was concentrated again. The residue was basified with conc. aqueous NaOH and extracted with chloroform. The solvent was evaporated to dryness under a reduced pressure to give the title compound (9.0 g; 81%). 0261 1H-NMR(270 MHz, CDCl3) 8.16 (m, 1H), 8.07 (d, J7 Hz, 1H), 7.26 (q, J7 Hz, 1H), 7.07 (t, J7 Hz, 1H) 0262 2) N-t-Butyl-3-fluoro-2-pyridinecarboxamide 0263 Dimethyl sulfate (1.01 g, 8 mmol) was added to 1-oxido-3-fluoropyridine (0.9 g, 8 mmol) and stirred at 100 C. for 2 hours. The reaction mixture was allowed to cool and concentrated to dryness under a reduced pressure. Water (10 ml) was added to the residue and cooled in an ice-bath. Sodium cyanide (1.18 g, 24 mmol) was added to the mixture and stirred for 30 min. followed by stirring at room temperature for 30 min. Aqueous NaOH (1N) was added thereto and extracted with chloroform. The extract was dried over Na2SO4 and the solvent was evaporated under a reduced pressure to give a mixture of regio-isomers of fluorocyanopyridine (0.9 g). Aqueous NaOH (4N, 10 ml) was added to the mixture of regio-isomers and heated under reflux for 2.5 hours. The mixture was allowed to cool, acidified with conc. hydrochloric acid and concentrated to dryness under a reduced pressure. The residue was suspended in DMF (10 ml), and t-butylamine (1.46 g, 20 mmol), WSC HCl (3.1 g, 16 mmol) and HOBt (2.2 g, 16 mmol) were added thereto and stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaHCO3 and dried over Na2SO4. The solvent was evaporated under a reduced pressure and the residue was purified by silica gel chromatography (hexane/ethyl acetate5/1) to give the title compound (0.19 g; 12%). 0264 1H-NMR(270 MHz, CDCl3) 8.34 (dt, J4, 1.3 Hz, 1H), 7.77 (br, 1H), 7.53 (ddd, J10.5, 8.5, 1.3 Hz, 1H), 7.44 (dt, J8.5, 4 Hz, 1H), 1.49 (s, 9H)

Example 43 0265 N-t-Butyl-5-fluoro-2-pyridinecarboxamide 0266 1) 5-Fluoro-2-pyridinecarboxylic Acid 0267 To water (100 ml) were added 5-fluoro-2-methylpyridine (J. Med. Chem., 32, 1970(1989): 2.2 g, 20 mmol) and potassium permanganate (19.1 g, 120 mmol), and heated under reflux for 4 hours. The reaction mixture was filtrated and the filtrate was concentrated, acidified with KHSO4, extracted with ethyl acetate and the extract was dried over Na2SO4. The solvent was evaporated to give the title compound (0.80 g; 28%). 0268 1H-NMR(270 MHz, DMSO-d6) 8.70 (d, J2.8 Hz, 1H), 8.14 (dd, J8.7, 4.6 Hz, 1H), 7.89 (td, J8.7, 2.8 Hz, 1H) 0269 2) N-t-Butyl-5-fluoro-2-pyridinecarboxamide 0270 The title compound was prepared by the same method as that described in Example 39-3), using 5-fluoro-2-pyridinecarboxylic acid and t-butylamine. 0271 1H-NMR(270 MHz, CDCl3) 8.35 (d, J2.8 Hz, 1H), 8.21 (dd, J8.6, 4.5 Hz, 1H), 7.82 (br, 1H), 7.52 (td, J8.6, 2.8 Hz, 1H), 1.49 (s, 9H)

Example 44 0272 N-t-Butyl-2,4,5-trifluorobenzamide 0273 The title compound was prepared by the same method as that described in Example 26, using 2,4,5-trifluorobenzoic acid and t-butylamine. 0274 1H-NMR(270 MHz, CDCl3) 7.91 (ddd, J11, 9, 7 Hz, 1H), 6.97 (ddd, J11, 10, 6 Hz, 1H), 5.53 (br, 1H), 1.46 (s, 9H)

Example 45 0275 N-t-Butyl-1-oxido-5-fluoro-2-pyridinecarboxamide 0276 The title compound was prepared by the same method as that described in Example 41, using N-t-butyl-5-fluoro-2-pyridinecarboxamide obtained in Example 44. 0277 1H-NMR(270 MHz, DMSO-d6) 10.92 (br, 1H), 8.77 (dd, J4.9, 2.3 Hz, 1H), 8.25 (dd, J9.2, 7.0 Hz, 1H), 7.63 (ddd, J9.2, 7.0, 2.3 Hz, 1H), 1.38 (s, 9H)

Example 46 0278 N-t-Butyl-6-chloro-3-pyridinecarboxamide 0279 The title compound was prepared by the same method as that described in Example 26, using 6-chloronicotinic acid and t-butylamine. 0280 1H-NMR(270 MHz, CDCl3) 8.67 (d, J2.6 Hz, 1H), 8.03 (dd, J8.3, 2.6 Hz, 1H)), 7.39 (dd, J8.3, 0.7 Hz, 1H), 5.88 (br, 1H), 1.48 (s, 9H)

Example 47 0281 N-(2-Hydroxy-1,1-dimethylethyl)-5-chloro-2-pyridinecarboxamide 0282 The title compound was prepared by the same method as that described in Example 26, using 5-chloro-2-pyridinecarboxylic acid obtained in Example 40-2) and 2-amino-2-methyl-1-propanol. 0283 1H-NMR(270 MHz, CDCl3) 8.49 (dd, J2.4, 0.7 Hz, 1H), 8.14 (dd, J8.6, 0.7 Hz, 1H), 8.05 (br, 1H), 7.83 (dd, J8.6, 2.4 Hz, 1H), 4.70 (t, J6.4 Hz, 1H), 3.73 (d, J6.4 Hz, 2H), 1.43 (s, 6H)

Example 48 0284 N-t-butyl-2-fluorobenzamide 0285 The title compound (380 mg, 97%) was prepared by the same method as that described in Example 14, using 2-fluorobenzoic acid (280 mg, 2 mmol) in place of 4-chloro-2-fluorobenzoic acid. 0286 1H-NMR(270 MHz, CDCl3) 8.05 (td, J7.9, 2.0 Hz, 1H), 7.48-7.38 (m, 1H), 7.24 (td, J7.9, 1.0 Hz, 1H), 7.09 (ddd, J12, 8, 1 Hz, 1H), 6.60 (br, 1H), 1.48 (s, 9H)

Example 49 0287 N-t-butyl-4-bromo-2-fluorobenzamide 0288 1) 4-Bromo-2-fluorobenzoic Acid 0289 To a mixture of water (3 ml) and acetonitrile (5 ml) were added Na2HPO4.12H2O (0.11 g),31% aqueous hydrogen peroxide (0.34 g, 3.1 mmol), 4-bromo-2-fluorobenzaldehyde (0.41 g, 2.0 mmol) and sodium chlorite (0.27 g, 3.0 mmol), successively, and stirred at room temperature for 1 hour. The reaction solution was poured into 5% KHSO4, extracted three times with ethyl acetate and the combined extracts were dried over MgSO4. The solvent was evaporated under a reduced pressure to give the title compound (0.42 g; 96%). 0290 1H-NMR(270 MHz, CDCl3) 7.91 (dd, J8.4, 7.8 Hz, 1H), 7.44-7.36 (m, 2H) 0291 2) N-t-butyl-4-bromo-2-fluorobenzamide 0292 The title compound (0.51 g, 96%) was prepared by the same method as that described in Example 14, using 4-bromo-2-fluorobenzoic acid (0.42 g, 1.9 mmol) in place of 4-chloro-2-fluorobenzoic acid. 0293 1H-NMR(270 MHz, CDCl3) 7.94 (t, J8.3 Hz, 1H), 7.40 (dd, J8.3, 1.8 Hz, 1H), 7.29 (dd, J11, 2 Hz, 1H), 6.50 (br, 1H), 1.46 (s, 9H)

Example 50 0294 N-t-butyl-1-oxide-2-pyridinecarboxamide 0295 N-t-butyl-2-pyridinecarboxamide was prepared by the same method as that described in Example 14, using picolinic acid in place of 4-chloro-2-fluorobenzoic acid. To a solution of the obtained carboxamide (1.78 g, 10 mmol) in acetic acid (10 ml), 31% aqueous hydrogen peroxide (2.27 g, 20 mmol) was added and refluxed under heating for 4 hours. After cooling, the reaction mixture was evaporated under reduced pressure, made alkali with 2N aqueous NaOH, extracted with chloroform and dried over Na2SO4. The solvent was evaporated under a reduced pressure to give the title compound (1.61 g; 83%). 0296 1H-NMR (270 MHz, CDCl3) 11.30 (br, 1H), 8.42 (dd, J8, 2 Hz, 1H), 8.23 (dd, J6.1 Hz, 1H), 7.46 (td, J8, 1 Hz, 1H), 7.37 (ddd, J7, 6, 2 Hz, 1H), 1.49 (s, 9H)

Example 51 0297 N-(2-hydroxy-1,1-dimethyethyl)-2-pyrazinecarboxamide 0298 WSC HCl (1.94 g, 10 mmol) was added to a mixture of 2-pyrazinecarboxylic acid (0.99 g, 8 mmol), 2-amino-2-methyl-1-propanol (0.80 g, 9 mmol) and HOBt (1.36 g, 10 mmol) in methylene chloride (30 ml), and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine, successively, dried over Na2SO4 and concentrated under a reduced pressure. The residue was suspended in methanol (10 ml), added 2N aqueous NaOH to and stirred for 30 minutes. Methanol was evaporated under a reduced pressure, diluted with saturated aqueous NaHCO3 and extracted with chloroform. The extract was washed with with saturated aqueous NaHCO3 and brine, successively, dried over Na2SO4. After the solvent was evaporated, the obtained crystal was washed with hexane and dried to give the title compound (0.27 g; 18%). 0299 1H-NMR(270 MHz, CDCl3) 9.40 (d, J1.5 Hz, 1H), 8.77 (d, J2.5 Hz, 1H), 8.53 (dd, J2.5, 1.5 Hz, 1H), 7.93 (br, 1H), 4.42 (t, J6.3 Hz, 1H), 3.75 (d, J6.3 Hz, 2H), 1.44 (s, 6H)

Example 52 0300 N-(2-hydroxy-1,1-dimethyethyl)-4-pyridazinecarboxamide 0301 The title compound (0.31 g; 35%) was prepared by the same method as that described in Example 14, using 4-pyridazinecarsoxylic acid in place of 4-chloro-2-fluorobenzoic acid and purifying the obtained crude product by silica gel chromatography (chloroform/methanol/triethylamine100/10/1). 0302 1H-NMR(270 MHz, CDCl3) 9.47 (dd, J2.3, 0.9 Hz, 1H), 9.36 (dd, J5.3, 0.9 Hz, 1H), 7.80 (dd, J5.3, 2.3 Hz, 1H), 6.52 (br, 1H), 3.72 (s, 2H), 1.36 (s, 6H)

Example 53 0303 N-(2-hydroxy-1,1-dimethyethyl)-4-pyrazolecarboxamide 0304 A solution of DMF (2 drops) and oxalyl chloride (0.88 g, 4.5 mmol) in methylene chloride (4 ml) was added to a suspension of 4-pyrazolecarboxylic acid (0.50 g, 4.5 mmol) in methylene chloride (6 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated and dried under a reduced pressure. To a suspension of the obtained solid in methylene chloride (5 ml) cooled in an ice-bath, 2-amino-2-methyl-1-propanol (1.33 g, 15 mmol) was added. The mixture was stirred at room temperature for 1 hour, added saturated aqueous NaHCO3 to, and concentrated and dried under a reduced pressure. The residue was extracted with warm chloroform and the solvent was evaporated under a reduced pressure. The residue was subjected to silica gel chromatography (chloroform/methanol/triethylamine100/10/1) to give the title compound (0.37 g, 45%). 0305 1H-NMR(270 MHz, DMSO-d6) 13.0 (br, 1H), 8.1 (br, 1H), 7.9 (br, 1H), 7.14 (s, 1H), 4.93 (t, J5.9 Hz, 1H), 3.47 (d, J5.9 Hz, 2H), 1.27 (s, 6H)

Example 54 0306 N-(2-hydroxy-1,1-dimethyethyl)-5-bromo-2-pyrimidinecarboxamide 0307 The title compound was prepared by the same method as that described in Example 14, using 5-bromo-2-pyrimidinecarboxylic acid, which was given by the methods described in J. Chem. Soc., 3129 (1953) and Collect. Czech. Chem. Commun.,37, 1721 (1972), in place of 4-chloro-2-fluorobenzoic acid. 0308 1H-NMR(270 MHz, CDCl3) 8.92 (s, 2H), 8.0 (br, 1H), 4.32 (t, J6.3 Hz, 1H), 3.75 (d, J6.3 Hz, 2H), 1.44 (s, 6H)

Example 55 0309 N-(2-hydroxy-1,1-dimethyethyl)-4-bromo-2-fluorobenzamide 0310 The title compound was prepared by the same method as that described in Example 14, using 4-bromo-2-fluorobenzoic acid in place of 4-chloro-2-fluorobenzoic acid. 0311 1H-NMR(270 MHz, CDCl3) 7.94 (t, J8.3 Hz, 1H), 7.42 (dd, J8.3, 1.8 Hz, 1H), 7.33 (dd, J11.4, 1.8 Hz, 1H), 6.7 (br, 1H), 4.22 (t, J6.3 Hz, 1H), 3.70 (d, J6.3 Hz, 2H), 1.41 (s, 6H)

Example 56 0312 N-(2-hydroxy-1,1-dimethyethyl)-2-chloro-4-fluorobenzamide 0313 The title compound was prepared by the same method as that described in Example 14, using 2-chloro-4-fluorobenzoic acid in place of 4-chloro-2-fluorobenzoic acid. 0314 1H-NMR(270 MHz, CDCl3) 7.68 (dd, J8.6, 6.0 Hz, 1H), 7.15 (dd, J8.4, 2.6 Hz, 1H), 7.06 (ddd, J8.6, 7.8, 2.6 Hz, 1H), 6.2 (br, 1H), 4.20 (t, J6.2 Hz, 1H), 3.71 (d, J6.2 Hz, 2H), 1.42 (s, 6H)

Example 57 0315 N-(2-hydroxy-1,1-dimethyethyl)-2-fluoro-4-(3-hydroxy-1-propynyl) benzamide 0316 To a solution of N-(2-hydroxy-1,1-dimethylethyl)-4-bromo-2-fluorobenzamide (0.29 g, 1.0 mmol) in triethylamine (5 ml), dichlorobis(triphenylphosphine)palladium(II) (0.035 g, 0.05 mmol), copper(I) iodide (0.009 g, 0.05 mmol) and 2-propyn-1-ol (0.085 g, 1.5 mmol) were added and stirred at 50 C. for 3.5 hours. The reaction mixture was poured into water, extracted with ethyl acetate and dried over Na2SO4. After the solvent was evaporated under a reduced pressure, the residue was subjected to silica gel chromatography (hexane/ethyl acetate1/2) to give the title compound (0.30 g, 94%). 0317 1H-NMR(270 MHz, CDCl3) 8.00 (t, J8.2 Hz, 1H), 7.31 (dd, J8.2, 1.5 Hz, 1H), 7.18 (dd, J12.6, 1.5 Hz, 1H), 6.8 (br, 1H), 4.51 (d, J6.4 Hz, 2H), 4.34 (t, J6.2 Hz, 1H), 3.60 (d, J6.2 Hz, 2H), 1.78 (t, J6.4 Hz, 2H), 1.41 (s, 6H) 0318 The structures of the compounds obtained in Example 1 to 57 are as follows: 1

Example 1Example 2

Example 3Example 4

Example 5Example 6

Example 7Example 8

Example 9Example 10

example 11

Example 12

Example 13

Example 14

Example 15

Example 16

Example 17

Example 18Example 19

Example 20Example 21

Example 22Example 23

Example 24

Example 25

Example 26X CH2FExample 27X CH2OHExample 28X CNExample 29X CONH2Example 30X CO2MeExample 31X CH2OMeExample 32X CHOExample 33X CH(OH)CH3Example 34X C(O)CH3Example 35X CO2HExample 36X CCHExample 37X CHCH2Example 38X CH2CH3

Example 39Example 40

Example 41Example 42

Example 43Example 44

Example 45Example 46

Example 47

Example 48

Example 49Example 50

Example 51Example 52

Example 53

Example 54

Example 55

Example 56

Example 57

Formulation Example 1 0319 Aqueous Eye Drops 0320 The compound of Example 50 (0.3 g), sodium dihydrogenphosphate (0.56 g), disodium hydrogenphosphate (0.284 g), benzethonium chloride (0.02 g) and sodium chloride (0.28 g) are dissolved in sterile purified water to make the total 100 ml to give aqueous eye drops.

Formulation Example 2 0321 Aqueous Eye Drops 0322 The compound of Example 50 (0.5 g), boric acid (2.0 g), dried sodium sulfite (0.1 g), phenylmercuric nitrate (0.001 g) and citric acid (0.01 g) are dissolved in sterile purified water to make the total 100 ml to give aqueous eye drops.

Formulation Example 3 0323 Aqueous Eye Drops 0324 The compound of Example 50 (1.0 g), boric acid (1.24 g), potassium chloride (0.74 g), thimerosal (0.002 g) and sodium bicarbonate (suitable amount) are dissolved in sterile purified water to make the total 100 ml to give aqueous eye drops.

Formulation Example 4 0325 Aqueous Eye Drops 0326 The compound of Example 50 (1.0 g), boric acid (1.7 g), zinc sulfate (0.1 g) and benzethonium chloride (0.01 g) are dissolved in sterile purified water to make the total 100 ml to give aqueous eye drops.

Formulation Example 5 0327 Oily Eye Drops 0328 The compound of Example 1 (1.0 g) is dissolved or dispersed in peanut oil to make the total 100 ml to give oily eye drops.

Formulation Example 6 0329 Oily Eye Drops 0330 The compound of Example 25 (1.0 g) is dissolved or dispersed in propylene glycol to make the total 100 ml to give oily eye drops.

Formulation Example 7 0331 Oily Eye Drops 0332 The compound of Example 48 (1.0 g), methylparaben (methyl 4-Hydroxybenzoate) (0.05 g), propylparaben (propyl 4-hydroxybenzoate) 0.01 g) and -octyldodecanol (suitable amount) are dissolved or dispersed in propylene glycol to make the total 100 ml to give oily eye drops.

Formulation Example 8 0333 Ophthalmic Ointment 0334 The compound of Example 49 (1.0 g) is dissolved or dispersed in liquid paraffin (5.0 g) and then mixed with white vaseline (petrolatum) (94.0 g) homogeneously to give ophthalmic ointment.

Formulation Example 8 0335 Ophthalmic Ointment 0336 The compound of Example 1 (1.0 g) is dissolved or dispersed in plastibase to make the total 100 g to give ophthalmic ointment. 0337 The compounds of formulae 1, 2 and 3 are useful as a medicament for treating retinal neurodegenarative disorders. The retinal neurodegenarative disorders include, for example, retinitis pigmentosa, senile macular degeneration, diabetic retinopathy, glaucoma, traumatic retinal detachment and the like. The compounds of formulae 2 and 3 are also useful as amedicament for treating neurodegenarative disorders (e.g. damage of central nervous system induced by stroke, hypoglycemia, cardiac arrest, perinatal asphyxia, medulla spinalis trauma and the like, and epilepsy, Huntington's chorea, Parkinson's disease, Alzheimer's disease, diabetic neuropathy and the like) and the like. 0338 Retinal outer nuclear cells have been known to be degenerated by the constant white light exposure to albino rats (L. M. Rapp, et al., New York: Plenum, 135 (1980)). Effectiveness of the compounds of formula 1, 2 or 3 or pharmaceutical acceptable salts thereof can be evaluated by their protective action against constant light exposure-induced retinal degeneration in rats. The present invention is embodied by the following experiment.

Experiment 1 0339 Pharmacological Effect Against Constant White Light-induced Retinal Damage 0340 Male Wistar rats (7 weeks old, Charles River Japan Inc.) were purchased and maintained in cyclic light/dark environment (8:00-20:00/light term) for one week, and then placed within the apparatus for constant white light exposure for two days. The constant white light exposure apparatus is a covered breeding box of 1020 mm in length, 425 mm in width, 520 mm in height, which is made of acryl boards and of which all inner side are covered with mirrors. Light was continuously irradiated all the day long (24 hours) using white fluorescent lamp attached to the ceiling of the apparatus. The average illuminance in the apparatus was 174.2 foot candle. After two days in the apparatus, the rats were moved to a darkroom and dark adapted for 1-4 hours. The rats were anesthetized with pentobarbital and placed in a stereotaxic frame. After topical mydriatica was given and electrodes were put on corneal surface, center of the forehead and the lower part of the lobe, the response in active potential of retina to the flash stimulation with fixed energy was determined from the recorded ERG (electroretinogram). The damage of retina was evaluated by the decrease in the amplitude of ERG a-wave which originated from retinal outer nuclear cells (photoreceptors). Test compounds were intraperitoneally injected just before placing the rats into the constant to light exposure apparatus and at the same time on the next day to investigate its protective effect. 0341 According to the experimental procedure described above, each test compound in the present invention, which was suspended or dissolved in 0.5% methylcellulose (MC) solution, was intraperitoneally administered twice to three rats in a group at the dose of 50 mg/kg. In the same way, 0.5% MC solution was intraperitoneally administered to the rats in MC group. The rats maintained in 12 hours cyclic light/dark environment were used for normal control group. The protection by the compounds against the retinal damage was represented as % recovery value, and the results were shown in Table 1. 0342 % recovery(xz)(yz)100 0343 x: a-wave amplitude in test compound group 0344 y: a-wave amplitude in normal control group 0345 z: a-wave amplitude in MC group 2TABLE 1Pharmacological effect of tested compounds% recoveryCompounds(Mean S.E.M.)NThe compound of Example 195.5 12.33The compound of Example 680.1 8.93The compound of Example 2745.7 10.13The compound of Example 4082.3 25.63The compound of Example 4758.2 2.73

Experiment 2 0346 Pharmacological Effect Against Constant White Light-induced Retinal Damage 0347 The protective effect of the compound of Examples by administration of eye drops was tested by the same method as Experiment 1. The tested compounds were administered immediately before rats were placed within the apparatus for constant white light exposure. Further, the eye drops were administered 3, 6, 9 and 24 hours after and the effect was evaluated. 0348 The compounds of the present invention were dissolved in 0.5% aqueous methylcellulose (MC) solution and each 50 l of the solution per once was dropped to both eyes of 5 rats, according to the method of Experiment 1. In o the same way, 0.5% MC solution was dropped to eyes of the rats in MC group. The rats maintained in 12 hours cyclic light/dark environment were used for normal control group. The protection against the retinal damage was represented as % recovery value, and the results were shown in Table 2. 3TABLE 2Protective effect of tested compounds% recoveryCompoundsConcentration(Mean S.E.M.)NThe compound of2 mg/ml11.6 2.65Example 1The compound of10 mg/ml19.1 7.55Example 50The compound of0.4 mg/ml5.1 1.85Example 49The compound of1.2 mg/ml16.2 3.25Example 25The compound of3.2 mg/ml15.0 3.75Example 48

Experiment 3 0349 Pharmacological Effect Against Constant White Light-induced Retinal Damage 0350 The compound of Example 50 was further tested by the same method as Experiment 2. 0351 The compound of the present invention was dissolved in 0.5% aqueous methylcellulose (MC) solution and each 50 l of the solution per once was dropped to both eyes of 5 rats, according to the method of Experiment 1. In the same way, 0.5% MC solution was dropped to eyes of the rats in MC group. The rats maintained in 12 hours cyclic light/dark environment were used for normal control group. The protection against the retinal damage was represented as % recovery value, and the results were shown in Table 3. 4TABLE 3Protective effect of tested compounds% recoveryCompoundsConcentration(Mean S.E.M.)NSolvent only0.0 5.75The compound of3 mg/ml2.3 3.85Example 50The compound of10 mg/ml6.9 5.75Example 50The compound of30 mg/ml17.4 3.9**5Example 50The compound of60 mg/ml35.6 2.7**5Example 50**significant difference from solvent only group (p < 0.01, Dunnett method)

0352 Industrial Applicability 0353 The present invention can provide a medicament for treating retinal neurodegenerative disorders and the like.