DESCRIPTION

PYRIDOPYRIMIDONES, QUINOLINES AND FUSED N-HETEROCYCLES AS BRADYKININ ANTAGONISTS

Technical Field

This invention relates tc new heterocyclic compounds and pharmaceutically acceptable salts thereof.

More particularly, it relates to new heterocyclic ccmpounds and pharmaceutically acceptable salts thereof which have activities as bradykinin antagonists, zo processes for preparation thereof, to a pharmaceutical composition comprising the same, and tc methods of using the same therapeutically in the prevention and/or the treatment of bradykinin or its analogues mediated diseases such as allergy, inflammation, autoimmune disease, shock, pain, or the like, in human being or animals.

One object of this invention is to provide new and useful heterocyclic compounds and pharmaceutically acceptable salts thereof which possess activities as bradykinin antagonists.

Another object of this invention is tc provide processes for the preparation of said compounds and salts thereof. A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said heterocyclic compounds and pharmaceutically acceptable salts thereof.

Still further object of this invention is to provide a therapeutical method fcr the prevention and/or the treatment of bradykinin or its analogues mediated diseases such as allergy, inflammation, autoimmune disease, shock, pain, or the like, using said heterocyclic compounds and pharmaceutically acceptable salts thereof.

Background Art

- 2 -

Some heterocyclic compounds have been known as described, for example, in EP-A-224, 086, EP-A-261, 539, Chemical Abstracts 90:34849g (1979), or Chemical Abstracts 97:18948c (1982) . However, it is not known that said compounds have activities as bradykinin antagonists.

Heterocyclic compounds having activities as bradykinin antagonists have been known as described in EP-A.-596, 406 and EP-A-622, 361.

Disclosure of the Invention

The object heterocyclic compounds of this invention are new and can be represented by the following general formula [I] :

Z-

wherein

Z is a group of the formula

in which X ¹ is N or C-R ¹ ,

X ² is N or C-R ⁹ ,

X ³ is N or C-R ² ,

R ¹ is lower alkyl,

R ² is hydrogen; lower alkyl; halogen; aryl; hydroxy(lower)alkyl; lower alkoxy(lower)alkyl; carboxy; esterified carboxy; carbamoyl optionally substituted with lower alkyl; cyclo(lower) alkoxy; lower alkoxy optionally substituted with a substituent selected from the group consisting of lower alkoxy, lower alkylamino, hydroxy, carboxy, esterified carboxy and carbamoyl optionally substituted with lower alkyl; halo(lower)alkoxy; lower alkylamino optionally substituted with a substituent selected from the group consisting of lower alkoxy, lower alkylamino and esterified carboxy; lower alkenylamino; or an N-containing heterocyclic-N-yl group optionally substituted with lower alkyl, q R is hydrogen or lower alkyl,

R ^J is hydrogen, lower alkyl, lower alkoxy or halogen, R ⁴ is lower alkyl, lower alkoxy or halogen, R is hydroxy; nitro; lower alkoxy optionally substituted with a substituent selected from the group consisting of amino, acvlamino and lower alkoxy; piperazinyl substituted with acyl (lower)alkyl and oxo; or a group of the formula :

^ _R 6

-N

R ⁷ ,

in which R° is hydrogen or lower alkyl, and

R ⁷ is hydrogen; aryloxycarbonyl; aroyl optionally substituted with a substituent selected from the group consisting of acyl-ar (lower) alkenyl, acyl-ar (lower) alkoxy, acyl-aryloxy(lower) alkyl and acyl-ar(lower) alkyl; heterocycliccarbonyl optionally substituted with acyl- ar (lower) alkenyl; acyl (lower) alkanoyl; hydroxy(lower)alkanoyl; acyloxy(lower) alkanoyl; carbamoyl optionally substituted with acyl (lower) alkyl; or a group of the formula :

- (AA) -CO-Q-R ⁸ or -(AA)-R ¹⁰ ,

⁸ is arylthio, aryloxy or arylamino, each of which is optionally substituted with substituent(s) selected from the group consisting of acyl, heterocyclic(lower) alkyl, heterocyclic(lower)alkenyl, nitro, amino and acylamino; heterocyclicthio or heterocyclicamino, each of which is optionally substituted with substituent (s) selected from the group consisting of acyl, acylamino, amino and lower alkoxy; halogen; tri (lower) alkylphosphonio; aryl substituted with substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, acyl (lower)alkenyl, heterocyclic(lower) alkenyl, nitro, acyl, acyl (lower) alkoxy, guanidino, amino, acylamino, N-acyl- - [heterocyclic(lower) - alkyl]amino and an N-containing heterocyclic- N-yl group substituted with oxo; or a heterocyclic group optionally substituted with substituent (s) selected from the group

- _) - consisting of oxo, lower alkyl, lower alkoxy, nitro-aryl, acyl, acylamino, amino, N-acyl-N- (lower)alkylamino, lower alkylamino, halogen, heterocyclic(lower)alkyl, heterocyclic(lower)alkenyl and an N-containing heterocyclic-N-yl group substituted with oxo;

R ¹⁰ is hydrogen or acyibiphenyl, (AA) is amino acid residue, and

Q is lower alkylene, lower alkenylene or single bond, A is lower alkylene, and i i i

Y is 0 or N-R , in which R ^_J - is hydrogen or an N-protective σroup

The object compound [I] or its salt can be prepared by processes as illustrated in the following reaction schemes.

Process 1

or its salt

Z - YH

[II] or its salt

- o -

[I] or its salt

Process 2

⁸ -Q-COOH [Vj

or its reactive

Z derivative at the carboxy group or a salt thereof

[IV] [la] or its salt or its salt

Process 3

[VI] [lb] or its salt cr its salt

wherein R° is arylthio optionally substituted with substituent (s) selected from the group consisting of acyl, amino and acylamino; or heterocyclicthio optionally substituted with substituent(s) selected from the group consisting of acyl, acylamino, amino and lower alkoxy; Q _a is lower alkylene, X is a leaving group, and R ³ , p. ⁴ , R ⁵ , R ⁶ , R ⁸ , A, Y, Z , (AA) and Q are each as defined above.

In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.

The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided. In this respect, the term "lower" in lower alkenyl moiety, heterocyclic(lower)alkenyl moiety, acyl (lower)alkenyl moiety and ar(lower)alkenyl moiety in the various definitions is intended to mean a group having 2 to 6 carbon atoms.

Further, the term "lower" in ar(lower)alkenoyl moiety and heterocyclic(lower)alkenoyl moiety in the various definitions is intended to mean a group having 3 to 6 carbon atoms.

Suitable "lower alkyl" and lower alkyl moiety such as in the terms "heterocyclic(lower)alkyl", "acyl (lower)alkyl", "lower alkylthio", "N-acyl-N- (lower) alkylamino",

"hydroxy(lower) lkyl", "lower alkoxy(lower)alkyl", "tri (lower)alkylphosphonio", "lower alkylamino", etc., may be straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyi, pentyl, hexyl or the like, in which preferable one is ^~ I~ ^~ _Δ alkyl such as methyl,

- δ - ethyl, propyl, isobutyl or τ_erτ.-butyl.

Suitable "cyclo (lower) alkoxy" may be cyclo ^-Cg) alkox such as cyclopropyloxy, cyclobutyloxy, cyciopentyloxy, cyclohexyloxy or the like. Suitable "lower alkoxy" and lower alkoxy moiety such a in the terms "acyl (lower) alkoxy", "lower alkoxy(lower) alkyl etc., may be straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy pentyloxy, hexyloxy or the like, in which preferable one is ^c ι~ ^c 4 alkoxy such as methoxy, ethoxy or isopropoxy. Suitable "esterified carboxy" may be lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isopropoxycarbonyl, tert- butoxycarbonyi, etc.], ar(lower) alkoxycarbonyl [e.g. benzyloxycarbonyl, etc.] or the like.

Suitable "halo(lower)alkoxy" may be chloromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy or the like.

Suitable lower alkenyl moiety such as in the terms "lower alkenylamino", "heterocyclic (lower) alkenyl", etc., may be a straight or branched one such as vinyl, allyl, 1- propenyl, isooropenyl, butenyl, isobuτ_er.yl, pentenyl, hexeny or the like.

Suitable "halogen" may be fluorine, chlorine, bromine and iodine.

Suitable "acyl" and acyl moiety such as in the terms "acylamino", "acyl (lower) alkyl", "acyl (lower) alkoxy", "acyl-ar(lower)alkenylaroyl", "N-acyl-N- (lower)alkylamino", etc., may be lower alkanoyl [e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl 3, 3-dimethylbutyryl, etc.], halo (lower) alkanoyl [e.g. chioroacetyi, trifluoroacetyl, bromoacetyl, bromobutyryl, heptafluorobutyryl, etc.], heterocyclic (lower) alkanoyl optionally substituted with lower alkyl [e.g. pyridylacetyl, ethylpyridylacetyl, ethylpyridylacetyl, etc.], lower

alkoxy(lower)alkanoyl [e.g. methoxyacetyl, methoxypropionyl, ethoxyacetyl, etc.], carboxy, esterified carboxy such as lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.], aryloxycarbonyl [e.g. phenoxycarbonyl, etc.], heterocycliccarbonyl optionally substituted with lower alkyl, lower alkoxy or lower alkylthio [e.g. pyridylcarbonyl, pyrazinylcarbonyl, isoquinolylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl, methylpyridylcarbonyl, methylpyrazolylcarbonyl, methoxypyridylcarbonyl, methylthiopyridylcarbonyl, etc.], carbamoyl, lower alkylcarbamoyl [e.g. methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl, etc.], lower alkylamino(lower)alkylcarbamoyl [e.g. methylaminomethylcarbamoyl, methylaminoethylcarbamoyl, dimethylaminoethylcarbamoyl, etc.], N-[lower alkylamino(lower)alkyl]-N- (lower alkyl)carbamoyl [e.g. N- (methylaminoethyl) -N-methylcarbamoyl, N- (di ethylaminoethyl)-N-methylcarbamoyl, etc.] , arylcarbamoyl optionally substituted with lower alkylcarbamoyl [e.g. phenylcarbamoyl, naphthylcarbamoyl, tolylcarbamoyl, methylcarbamoylphenylcarbamoyl, dimethylcarbamoylphenylcarbamoyl, etc. ] , heterocycliccarbamoyl optionally substituted with lower alkyl, lower alkoxy, lower alkylthio or oxo [e.g. pyridylcarbamoyl, or its oxide, pyrazinylcarbamoyl, isoquinolylcarbamoyl, thiazolylcarbamoyl, oxazolylcarbamoyl, methyloxazolylcarbamoyl, methylpyrazolylcarbamoyl, methylpyridylcarbamoyl, methoxypyridylcarbamoyl, methylthiopyridylcarba oyl, etc.], ar(lower)alkylcarbamoyl [e.g. benzylcarbamoyl, phenethylcarbamoyl, etc.].

heterocyclic (lower) alkylcarbamoyl [e.g. pyridylmethy1carbamoyl, pyrazinylmethy1carbamoyl, pyrimidinylmethylcarbamoyl, etc. ] , lower alkylsulfonylcarbamoyl [e.g. methylsulfonylcarbair.oyl, ethylsulfonyicarbamoyl, etc.], aryi≤ulfonylcarbamoyl [e.g. phenylsulfonylcarbamoyl, tolyisulfonylcarbamoyl, etc.], ar(lower) alkenoyl substituted with lower alkylcarbamoyl [e. methylcarbamoylcinnamoyi, dimethylcarbamoylcinnamoyl, etc.] ar (lower) alkenoyl substituted with lower alkanoylamino [e.g acetylaminocinnamoyl, etc.], heterocyclic (lower) alkenoyl substituted with lower alkylcarbamoyl [e.g. methylcarbamoylpyridylacryloyi, dimethylcarbamoylpyridylacryioyl, etc. ] , heterocyclic (lower)alkenoyl substituted with lower alkanoylamino [e.g. acetylaminopyridylacryloyl, etc.], lower alkylsulfonyl [e.g. methylsuifonyl, ethyisulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, etc.], phthaloyl, or the like.

Suitable "aryl" and aryl moiety such as in the terms "aryloxycarbonyl", "arylthio", "aryloxy", "arylcarbamoyl", "aryloxy(lower) alkyl", "arylamino", "nitro-aryl", "ar(lower) alkenoyl", etc., may be phenyl, naphthyl, phenyl or naphthyl substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di (tert-butyl)phenyl, methylnaphthyl, etc. and the like, in which preferable one is phenyl, naphthyl a tolyl.

Suitable "aroyl" may be benzoyl, toluoyl, xyloyl, naphthoyl or the like.

Suitable "ar(lower)alkyl" may be benzyl, phenethyl, phenylpropyl, naphthylmethyl, benzhydryl, trityl or the like Suitable "ar (lower) alkoxy" may be benzyioxy, phenethyloxy, phenylprcpoxy, naphthyl ethoxy or the like.

Suitable "ar(lower)alkenyl" may be phenylvinyl, naphthylvinyl, phenylpropenyl or the like. Suitable lower alkanoyl moiety in the terms

"acyl (lower)alkanoyl", "hydroxy(lower)alkanoyl" and "acyloxy(lower) alkanoyl" may be formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl or the like.

Suitable "heterocyclic group" and heterocyclic moiety such as in the terms "heterocyclic(lower) alkyl", "heterocyclic(lower)alkenyl", "heterocyclic(lower)alkanoyl", "heterocycliccarbonyl", "heterocycliccarbamoyl", "heterocyclic(lower)alkylcarbamoyl", "heterocyclic(lower) alkenoyl, "heterocyclicthio",

"heterocyclicamino", etc., may be saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur and/or nitrogen atom such as : -unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, triazolvl, tetrazolyl, dihydrotriazinyl, etc.; -saturated 3 to 8-membered, preferably 4 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, etc.;

-unsaturated condensed 7 to 12-membered heterocyclic group containing 1 to 5 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinlolyl, isoquinolyl, tetrahydroquinolyl, indazolyl, benzotriazolyl, imidazopyridyl, etc.;

-unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic group containing an oxygen atom, for example, furyi, etc.;

-unsaturated condensed 7 to 12-membered heterocyclic group containing 1 to 2 oxygen atom(s), for example, benzofuryl, piperonyl, etc.; -unsaturated 3 to 8-membered, preferably 5 or 6-membered

heteromonocyclic group containing a sulfur atom, for exampl thienyl, etc.;

-unsaturated condensed 7 to 12-membered heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, etc.;

-unsaturated 3 to 8-membered, preferably 5 cr 6-member heteromonocyclic group containing I to 2 oxygen atom(s) and to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, cxadiazolyl, etc.; -saturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and to 3 nitrogen atom(s), for example, morpholinyl, etc.;

-unsaturated condensed 7 to 12-membered heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;

-unsaturated 3 to 8-membered, preferably 5 or 6-membere heteromonocyclic group containing 1 to 2 sulfur atom(s) and to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiazolinyl, thiadiazolyl, etc.; -saturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;

-unsaturated condensed 7 to 12-membered heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, benzothiazinyl, benzothiazolinyl, etc., or the like.

Suitable "N-containing heterocyclic-N-yl group" may be morpholino, thiomorpholino, pyrrolidin-1-yl, piperidino, 1, 2, 3, 6-tetrahydropyridin-l-yl, 1,2-dihydropyridin-l-yl, piperazin-1-yl, or the like.

Suitable "amino acid residue" may include natural or artificial ones, and such amino acid may be glycine, sarcosine, alanine, β-alanine, valine, norvaline, leucine, isoleucine, norleucine, serine, threonine, cysteine,

methionine, phenylalanine, phenylglycine, tryptophan, tyrosine, proline, hydroxyproline, glutamic acid, aspartic acid, glutamine, asparagine, lysine, arginine, histidine, ornithine, or the like, in which more preferable one is glycine, sarcosine, alanine, β-alanine and proline, and the most preferable one is glycine.

Suitable "lower alkylene" may be a straight or branched one such as methylene, ethylene, trimethylene, methylmethylene, tetramethylene, ethylethylene, propylene, pentamethylene, hexamethylene or the like, in which the most preferable one are methylene and ethylene.

Suitable "lower alkenylene" may be a straight or branched C2~ alkenylene such as vinylene, methylvinylene, propenylene, 1,3-butadienylene or the like, in which the most preferable one is vinylene.

Suitable examples of Z may be a group of the formula

wherein R ¹ , R ² and R ⁹ are each as defined above.

Suitable "N-protective group" may be ar (lower) alkoxycarbonyl [e.g. benzyloxycarbonyl, etc.], lowe alkoxycarbonyl [e.g. tert-butoxycarbonyl, etc.] or the like. Suitable "a leaving group" may be a conventional acid residue such as halogen [e.g. fluoro, chloro, bromo and iodo], arenesulfonyloxy [e.g. benzenesulfonyloxy, tosyloxy, etc.], alkanesulfonyloxy [e.g. mesyloxy, ethanesulfonyloxy, etc.], and the like.

Suitable pharmaceutically acceptable salts of the objec compound [I] are conventional non-toxic salts and include a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, oxalate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], a salt with an amino acid [e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.], an intramolecular salt and the like.

With respect to the salts of the compounds [la] and [lb] in the Processes 2 and 3, it is to be noted that these compounds are included within the scope of the compound [I], and accordingly the suitable examples of the salts of these compounds are to be referred to those as exemplified for the object compound [I] .

Preferred embodiments of the object compound [I] are as follows :

a) a compound of the formula :

wherein

X ¹ is N or C-R ¹ ,

X is N or C-R , l b X- s N or C-R ² ,

R- is lower alkyl, R^ is hydrogen; lower alkyl; aryl; hydroxy(lower)alkyl; lower alkoxy(lower)alkyl; carboxy; esterified carboxy; carbamoyl optionally substituted with lower alkyl; 0 cyclo(lower)alkoxy; lower alkoxy optionally substituted with a substituent selected from the group consisting of lower alkoxy, lower alkylamino, hydroxy, carboxy, esterified carboxy and carbamoyl optionally substituted with lower alkyl; halo (lower)alkoxy; lower alkylamino 5 optionally substituted with a substituent selected from the group consisting of lower alkoxy, lower alkylamino and esterified carboxy; lower alkenylamino; or an N-containing heterocyclic-N-yl group,

R ³ is hydrogen, lower alkyl, lower alkoxy or halogen, 0 R is lower alkyl, lower alkoxy or halogen,

P. is hydroxy; lower alkoxy optionally substituted with a substituent selected from the group consisting of amino, acylamino and lower alkoxy; piperazinyl substituted with acyl (lower)alkyl and oxo; or a group of the formula : 5

- 1 6 -

R ⁶

-N

R ⁷

in which R ⁶ is hydrogen or lower alkyl, and

₇

R is aryloxycarbonyl; acyi-ar(lower) alkenylaroyl; carbamoyl optionally substituted with acyl (lower) alkyl; or a group of the formula

- (AA) -CO-Q-R ⁰

p in which R° is arylthio, aryloxy or arylamino, each of which is optionally substituted with substituent (s) selected from the group consisting of acyl, amino and acylamino; heterocyclicthio or heterocyclicamino, each of which is optionally substituted with substituent (s) selected from the group consisting of acyl, acylamino, amino and lower alkoxy; halogen; tri (lower)alkyiphosphonio; aryl substituted with substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, nitro, acyl, acyl (lower) alkoxy, amino, acylamino and an N-containing heterocyclic-N- yl group substituted with oxo; or a heterocyclic group optionally substituted with substituent (s) selected from the group consisting of oxo, lower alkyl, lower alkoxy, nitro-aryl, acyl, acylamino, amino, N-acyl-N-

(lower) alkylamino, lower alkyl, lower alkylamino, halogen, lower alkoxy, heterocyclic(lower) alkyl, heterocyclic(lower) alkenyl and an N-containing heterocyclic-N-yl group substituted with oxo;

(AA) is amino acid residue, and

Q is lower alkylene, lower alkenylene or single bond, R^ is hydrogen or lower alkyl, and A is lower alkylene, and

b) a compound of the formula :

wherein R ¹ is lower alkyl,

R ^ώ is hydrogen; cyclo (lower) alkoxy; lower alkoxy optionally substituted with a substituent selected from the group consisting of lower alkoxy, lower alkylamino, hydroxy, carboxy, esterified carboxy and carbamoyl optionally substituted with lower alkyl; halo(lower)alkoxy; lower alkylamino optionally substituted with a substituent selected from the group consisting of lower alkoxy, lower alkylamino and esterified carboxy; lower alkenylamino; or an N-containing heterocyclic-N-yl group,

R ³ is hydrogen, lower alkyl or halogen,

R is lower alkyl or halogen,

R ⁵ is hydroxy; lower alkoxy optionally substituted with a substituent selected from the group consisting of amino, acylamino and lower alkoxy; piperazinyl substituted with

acyl (lower) alkyl and oxo; or a group of the formula

R ⁶

-N

in which R is hydrogen or lower alkyl, and

R' is aryloxycarbonyl; carbamoyl optionally substituted with acyl (lower) alkyl; or a group of the formula :

- (AA)-CO-Q-R ⁸

p in which R° is arylthio, aryloxy or arylamino, each of which is optionally substituted with substituent (s) selected from the group consisting of acyl, amino and acylamino; heterocyclicthio or heterocyclicamino, each of which is optionally substituted with substituent (s) selected from the group consisting of acyl, acvlamino, amino and lower alkoxy; halogen; tri (lower) alkylphosphonio; aryl substituted with substituent(s) selected from the group consisting of acyl, acyl (lower) alkoxy, amino and acylamino; or a heterocyclic group optionally substituted with substituent (s) selected from the group consisting of nitro-aryl, acyl, acylamino, amino, N-acyl-N- (lower)alkylamino, lower alkyl, lower alkvlamino, halogen, lower alkoxy, heterocyclic (lower)alkyl and an

N-containing heterocyclic-N-yl group substituted with oxo;

(AA) is amino acid residue, and

Q is lower alkylene, lower alkenylene or single

bond, q

R^ is hydrogen or lower alkyl, and A is lower alkylene.

The processes for preparing the object compound [I] are explained in detail in the following.

Process 1

The object compound [I] or its salt can be prepared by reacting a compound [II] or its salt with a compound [III] or its salt.

Suitable salts of the compounds [II] and [III] may be the same as those exemplified fcr the compound [I] .

The reaction is preferably carried out in the presence of a base such as alkali metal [e.g. lithium, sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof [e.g. sodium hydroxide, potassium carbonate, potassium bicarbonate, etc.], alkali metal alkoxide [e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.], or the like.

This reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, N,N-dimethylformamide, acetone, or the like.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 2

The object compound [la] or its salt can be prepared by reacting a compound [IV] or its salt with a compound [V] or its reactive derivative at the carboxy group or a salt thereof.

Suitable reactive derivative at the carboxy group of the compound [V] may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive derivatives may be an acid

chloride; an acid azide; a mixed acid anhydride with an acid such as dialkylphosphoric acid, sulfuric acid, aliphatic carboxylic acid or aromatic carboxylic acid; a symmetrical acid anhydride; an activated amide with imidazole; or an activated ester [e.g. p-nitrophenyl ester, etc.]. These reactive derivatives can optionally be selecte from them according to the kind of the compound [V] to be used.

Suitable salts of the compound [IV] can be referred to the organic or inorganic acid addition salts as exemplified for the compound [II.

Suitable salts of the compound [V] and its reactive derivative can be referred to the ones as exemplified for the compound [I] . The reaction is usually carried out in a conventional solvent, such as methylene chloride, chloroform, pyridine, dioxane, tetrahydrofuran, N,N-dimethylformamide, or the like.

In case that the compound [V] is used in the free acid form or salt form, it is to carry out the reaction in the presence of a conventional condensing agent such as l-ethyl-3- (3- dimethylaminopropyl)carbodiimide,

N,N ¹ -dicyclohexylcarbodiimide or the like.

The reaction temperature is not critical and the reaction can be carried out under cooling, at ambient temperature, or under heating.

This reaction is preferably carried out in the presence of a conventional inorganic base or in the presence of a conventional organic base.

Process 3

The object compound [lb] or its salt can be prepared by reacting a compound [VI] or its salt with a compound [VII] or its salt.

Suitable salts of the compound [VI] can be referred to the organic or inorganic acid addition salt as exemplified

for the compound [I] .

Suitable salts of the compound [VIII can be referred to the ones as exemplified for the compound [I] .

This reaction can be carried out in substantially the same manner as Process 1. and therefore the reaction mode and reaction condition of this reaction are to be referred to those explained in Process 1.

The object compound [I] and the starting compounds can also be prepared by the methods of Examples and Preparations mentioned below or similar manners thereto or conventional manners.

The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, chromatography, reprecipitation or the like.

It is to be noted that the compound [I] and the other compounds may include one or more stereoisomers and geometrical isomers due to asymmetric carbon atoms and double bonds, and all of such isomers and mixture thereof are included within the scop of this invention.

The object compound [I] and pharmaceutically acceptable salts thereof possess strong activities as bradykinin antagonists, and are useful for the treatment and/or the prevention of bradykinin or its analogues mediated diseases such as allergy, inflammation, autoimmune disease, shock, pain, or the like, and more particularly for the prevention and/or the treatment of asthma, cough, bronchitis, rhinitis, rhinorrhea, obstructive pulmonary disease [e.g. pulmonary emphysema, etc.], expectoration, pneumcnitis, systemic inflammatory response syndrome (SIRS) , septic shock, endotoxin shock, anaphylactic shock, adult respiratory distress syndrome, disseminated intravascular coagulopathy, arthritis, rheumatism, osteoarthritis, lumbago, inflammation- induced bone resorption, conjunctivitis, vernal

conjunctivitis, uveitis, iritis, iridocyclitis, headache, migraine, toothache, backache, superficial pain, cancerous pain, postoperative pain, tenalgia, trauma [e.g. wound, burn, etc.], rash, erythema, eczema or dermatitis [e.g. contact dermatitis, atopic dermatitis, etc. ¹ , urticaria, herpes, itching, psoriasis, lichen, inflammatory bowel disease [e.g. ulcerative colitis, Crohn's disease, etc.], diarrhea, e esis, hepatitis, pancreatitis, gastritis, esophagitis, food allergy, ulcer, irritable bowel syndrome, nephritis, angina, periodcntitis, edema, hereditary angioneurotic edema, cerebral edema, low blood pressure, thrombosis, myocardial infarction, cerebral vasospasm, congestion, coagulation, gout, central nervous system injury, premature labor, arteriosclerosis (hyperlipidemia, hypercholesterolemia) , postgastrectomy dumping syndrome, carcinoid syndrome, altered sperm mobility, diabetic neuropathy, neuralgia, graft rejection in transplantation, or the like, in human being or animals.

And further, it is known that bradykinin relates to the release of mediators such as prostaglandins, leukotrienes, tachykinins, histamine, thromboxanes, or the like, so the compound [I] is expected to be useful for the prevention and/or the treatment of such mediators mediated diseases.

In order to illustrate the usefulness of the object compound [I], the pharmacological test data of some representative compounds of the compound [I] are shown in the following.

^J H-Bradykinin receptor binding

(i) Test Method :

(a) Crude ileum membrane preparation Male Hartly strain guinea pigs were sacrificed by

decapitation. The ileum was removed and homogenized in buffer (50 mM trimethylaminoethanesulfonic acid (TES) , 1 mM 1, 10-phenanthroline pK 6.8). The homogenate was centrifuged (1000 xg, 20 minutes) to remove tissue clumps and the supernatant was centrifuges (100,000 xg, 60 minutes) to yield a pellet. The pellet was resuspended in buffer (50 mM TES, 1 mM 1, 10-phenanthroline, 140 mg/C bacitracin, 1 M dithiothreiol, 0.1s bovine serum albumin pK 6.8) and homogenized with a glass-teflon homogenizer to yield suspension which was referred to as crude membrane suspension. The obtained membrane suspension was stored at -80°C until use.

(b) ^J H-Bradykιr_in binding to the membrane The frozen crude membrane suspension was thawed. In binding assays, ³ H-Bradykinin (0.06 nM) and drug (1 x 10 ^~6 M) were incubated with 50 μl of the membrane suspension at room temperature for 60 minutes in a final volume of 250 μl. Separation of receptor-bound from free ^J H-Bradykinin is achieved by immediate filtration under vacuum and washed three times with 5 ml of ice-cold buffer (50 mM Tris-KCl pH 7.5). Non-specific binding was defined as binding in the presence of 0.1 μM Bradykinin. The radioactivity retained on rinsed filters was determined by a liquid-scintillation counter.

(ii) Test Results

Inhibition % of

-3

Test Compound (Example No.) "H-Bradykinin binding (concen¬ tration: 1 x 10 ^" )

2-cu: 96

10- (9) dihydrochloride 99

25- (2) dihydrochloride 96

34-(3) 100

37- (5) hydrochloride 100

73-(4) 95

90-(2: 98

The effects of the compound [I] on bradykinin-induced bronchoconstriction and carrageenin-induced paw edema were measured according to similar manners described in British Journal of Pharmacology, 102. 774-777 (1991) .

For therapeutic purpose, the compound [I] and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral, parenteral such as intravenous, intramuscular, subcutaneous or intraarticular, external such as topical, enteral, intrarectal, transvaginal, inhalant, ophthalmic, nasal of hypoglossal administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, suppositories, solution, lotion, suspension, emulsion, ointment, gel, cream, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or

emulsifying agents, buffers and other commonly used additives.

While the dosage of the compound [I] will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 100C mg of the compound [I] may be effective for preventing and/or treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.

Examoles

- to be contined on the next page -

- 26 -

The following Preparations and Examples are given for the purpose of illustrating this invention.

Preparation 1 To a suspension of 4-formylbenzoic acid (1.00 g) in dry tetrahydrofuran (15 ml) was added methyl (triphenylphosphoranylidene)acetate (2.50 g) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 hour at the same temperature, poured into aqueous sodium bicarbonate solution, and washed with ethyl acetate. lN-Hydrochloric acid was added to the aqueous layer until the layer was adjusted to pH 2. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, dried ever magnesium sulfate and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give methyl 4-carboxycinnamate (1.21 g) as colorless powder. p : 243°C

NMR (DMSO-d ₆ , δ) : 3.74 (3H, s), 6.76 (IH, d, J=16Hz), 7.73 (IH, d, J=16Hz), 7.85 (2H, d, J=8Hz) , 7.96

(2K, d, J=8Hz)

Preparation 2

To a solution of methyl 4-carboxycinnamate (160 mg) in methylene chloride was added methylamine hydrochloride (58 mg) and l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (140 mg) at ambient temperature, and the mixture was stirred for 2 hours. To this suspension was added 1-hydroxybenzotriazole (137 mg) and dimethylformamide (2 ml) , and the mixture was stirred for 14 hours at same temperature. The reaction mixture was poured into water, and extracted with dichloromethane. The organic layer was washed with aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give methyl

4- (methylcarbamoyl)cinnamate (82 mg) as a colorless powder, mp : 210.5°C

NMR (DMSO-D ₆ , δ) : 2.79 (3H, d, J=5Hz), 3.74 (3H, s) , 6.74 (IH, d, J=16Hz), 7.69 (IH, d, J=16Hz), 7.80 (2H, d, J=8Hz), 7.87 (2H, d, J=8Hz), 8.51 (IH, q-like)

Preparation 3

To a solution of methyl 4- (methylcarbamoyl) cinnamate (75 mg) in methanol (3 ml) was added IN aqueous sodium hydroxide solution (0.5 ml) at 40°C. The mixture was stirred at same temperature for 3 hours. lN-Hydrochloric acid (0.5 ml) was added to the reaction mixture and evaporated in vacuo. Water was added to the residue, the mixture was filtered and the residue was washed with diethyl ether to give 4-

(methylcarbamoyl)cinnamic acid (56 mg) as a colorless powder, mp : >250°C NMR (DMSO-d ₆ , δ) : 2.78 (3H, d, J=5Hz) , 6.62 (IH, d,

J=16Hz), 7.61 (IH, d, J=16Hz), 7.77 (2H, d, J=8Hz) , 7.85 (2H, d, J=8Hz), 8.51 (IH, q-like)

Preparation 4

A mixture of 2-acetylamino-5-formylpyridine (241 mg) and malonic acid (168 mg) in pyridine (0.12 ml) and ethanol (0.36 ml) was refluxed for 2 hours. After cooling the mixture, the precipitate was collected by filtration, and washed with ethyl acetate to give (E) -3- (6-acetylamino-3-pyridyl) acrylic acid (248 mg) as a colorless powder, mp : 291-292°C NMR (DMSO-d ₆ , δ) : 2.10 (3H, s) , 6.55 (IH, d, J=16Hz),

7.58 (IH, d, J=16Hz), 8.07-8.21 (2H) , 8.59 (IH, br s)

Prepa_.at_._Q.- 5 (E) -3- (6-Ethoxycarbonyl-3-pyridyl) acrylic acid (from

ethyl 5-formyl-2-pyridinecarboxylate) was obtained according to a similar manner to that of Preparation 4. mp : 201-202°C

NMR (DMSO-d ₆ , δ) : 1.33 (3H, t, J=7Hz), 4.36 (2H, q, J=7Hz), 6.80 (IH, d, J=16Hz), 7.69 (IH, d, J=16Hz) ,

8.07 (IH, d, J=9Hz), 8.33 (IH, dd, J=9, 2Hz) , 9.00 (IH, d, J=2Hz)

Preparation 6 To a mixture of sodium hydride (40° in oil, 2.64 g) and N,N-dimethylformamide (100 ml) was added 8-hydroxy-2- methylquinoline (10 g) in an ice-water bath. The mixture was stirred for 30 minutes at the same temperature and then 2,6- dichloro-3-nitrobenzyl chloride (15.1 g) and tetrabutylammonium iodide (100 mg) were added therein. The reaction mixture was stirred at ambient temperature for 1 hour. To this mixture was added water (100 ml) in an ice- water bath. The precipitates were collected by vacuum filtration and washed with water (60 ml) to give 8- (2, 6- dichloro-3-nitrobenzyloxy)-2-methylσuinoline (20.36 g) as a powder.

NMR (CDC1 ₃ , δ) : 2.76 (3H, s) , 5.70 (2H, s) , 7.21-7.57 (5H), 7.76 (IH, d, J=8Hz) , 8.02 (IH, d, J=8Hz)

Preparation 7

The following compounds were obtained according to a similar manner to that of Preparation 6.

(i) 4-Chloro-8- (2, 6-dichloro-3-nitrobenzyloxy) -2- methylquinoline

NMR (CDCI3, δ) : 2.70 (3H, s), 5.67 (2H, s),

7.23-7.92 (6H)

(2) 8- (2, 6-Dichloro-3-nitrobenzyloxy) -4-methoxy-2- methylquinoline

NMR (CDCI3, δ) : 2.70 (3H, s) , 4.02 (3H, s) , 5.68 (2H, S), 6.67 (IH, s), 7.25 (IH, dd, J=8, 1Hz), 7.34 (IH, t, J=8Hz), 7.50 (IH, d, J=8Hz) , 7.75 (IH, d, J=8Hz), 7.84 (IH, dd, J=8, 1Hz)

Preparation 8

To a mixture of 8- (2, 6-dichloro-3-nitrobenzyloxy) -2- methyiquinoline (1.0 g) , concentrated hydrochloric acid (5.2 ml) and methanol (5.2 ml)) was added iron powder (666 mg) . The mixture was heated under reflux for 2 hours and stirred in an ice-water bath for 1 hour. The precipitate was collected by vacuum filtration and washed with IN hydrochloric acid and water to give 8- (3-amino-2,6- dichlorobenzyloxy) -2-methylσuinoline dihydrochloride (635 mg) as a brownish powder.

NMR (DMSO-d ₆ , δ) : 2.93 (3H, s), 5.50 (2H, s) , 6.98 (IH, d, J=8Hz), 7.23 (IH, d, J=8Hz), 7.80-8.02 (4H), 9.03 (IH, d, J=8Hz)

Preparation 9

To a mixture of 8-(3-amino-2, 6-dichlorobenzyloxy) -2- methylquinoline dihydrochloride (4.06 g) ,

4-dimethylaminopyridine (120 mg) , N-methylpyrrolidone (30 ml) and pyridine (10 ml) was added phthalimidoacetyl chloride (3.35 g) at ambient temperature. The mixture was stirred at 50°C for 1.5 hours and cooled in an ice-water bath. Water (40 ml) was added therein and the mixture was stirred for 30 minutes in an ice water bath. The precipitate was collected by vacuum filtration and washed with water and ethyl acetate to give 8-[2, 6-dichloro-3- (phthalimidoacetyla ino)benzyloxy]- 2-methylquinoline (4.45 g) as a yellowish powder.

NMR (CDC1 ₃ , δ) : 2.86 (3H, s), 4.74 (2H, s), 5.51 (2H, s), 7.20-7.50 (5H), 7.63-7.93 (4H) , 8.03 (IH, d, J=8Hz), 8.29 (IH, d, J=8Hz)

Preparation 10

To a mixture of 8- [2, 6-dichloro-3- (phthalimidoacetylamino)benzyloxy]-2-methylquinoline (4.44 g and N,N-dimethylformamide (44 ml) was added sodium hydride (60> in oil, 375 mg) in an ice-water bath. After stirring for 30 minutes in an ice-water bath, methyl iodide (0.6 ml) was added thereto and the mixture was stirred at ambient temperature for 1 hour. To this mixture was added water (88 ml) in an ice-water bath and the mixture was stirred at the same temperature for 1.5 hours. The precipitate was collected by vacuum filtration and washed with water and methanol to give 8- [2, 6-dichioro-3- [N- (phthalimidoacetyl) -N- methylamino]benzyloxy]-2-methylquinoline (3.99 g) as a yello powder. NMR (CDC1 ₃ , δ) : 2.76 (3H, s) , 3.23 (3H, s), 4.08 (2H, s), 5.68 (IH, d, J=12Hz), 5.75 (IH, d, J=12Hz) , 7.24-7.59 (6H), 7.66-7.91 (4H), 8.03 (IH, d, J=8Hz)

Preparation 11 A mixture of 8- [2, 6-dichloro-3- [N- (phthalimidoacetyl) -N methylamino]benzyloxy]-2-methylquinoline (3.98 g) , hydrazine monohydrate (0.72 ml) and ethanol (40 ml) was heated under reflux for 1 hour. The precipitate was removed by vacuum filtration and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane and the precipitate was removed by vacuum filtration. The filtrate was evaporated in vacuo to give 8- [3- (N-glycyl-N-methylamino)- 2, 6-dichlorobenzyloxy]-2-methylσuinoline (2.99 g) as a yello amorphous powder. NMR (CDC1 ₃ , δ) : 2.76 (3H, s), 2.96 (IH, d, J=16Hz) ,

3.10 (IH, d, J=16Hz), 3.21 (3H, s), 5.66 (2H, s), 7.20-7.50 (6H), 8.02 (IH, d, J=8Hz)

Preparation 12 A mixture of 4-chloro-8-hydroxy-2-methylquinoline (9 g),

1, 3-dimethyl-2-imidazolidinone (100 ml) and 28 ^' . solution of sodium methoxide in methanol (135 ml) was stirred at 150°C for 4 hours. The reaction mixture was cooled to ambient temperature followed by partition into ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The crystalline residue was washed with n-hexane to give 8- hydroxy-4-methoxy-2-methylquinoline (5.57 g) . mp : 110.5-112°C NMR (CDCI ₃ , δ) : 2.67 (3K, s), 4.01 (3H, s), 6.63 (IH, s), 7.11 (IH, d, J=8Hz), 7.31 (IH, t, J=8Hz) , 7.56 (IH, d, J=8Hz)

Preparation 13 The following compounds were obtained according to a similar manner to that of Preparation 12.

(1) 4-Ethoxy-8-hydroxy-2-methylquinoline mp : 85-86°C NMR (CDC1 ₃ , δ) : 1.56 (3H, t, J=6Hz), 2.66 (3H, s),

4.23 (2H, q, J=6Hz) , 6.60 (IH, s), 7.10 (IH, d, J=8Hz), 7.31 (IH, t, J=8Hz), 7.60 (IH, d, J=8Hz)

(2) 8-Hydroxy-4- (2-methoxyethoxy)-2-methylquinoline NMR (CDCI3, δ) : 2.40 (3H, s), 3.52 (3H, s), 3.91 (2H, t, J=6Hz), 4.32 (2H, t, J=6Hz), 6.64 (IH, s) , 7.12 (IH, d, J=8Hz), 7.32 (IH, t, J=8Hz), 7.62 (IH, d, J=8Hz)

(3) 8-Hydroxy-2-methyl-4- (2-dimethylaminoethoxy)quinoline mp : 94-96°C

NMR (CDCI3, δ) : 2.40 (6H, s), 2.67 (3H, s), 2.91 (2H, t, J=6Hz), 4.29 (2H, t, J=6Hz) , 6.63 (IH, s), 7.12 (IH, d, J=8Hz), 7.31 (IH, t, J=8Hz), 7.59 (In, d, J=8Hz)

(4) 8-Hydroxy-4-isopropoxy-2-methylquinoline

NMR (CDC1 ₃ , δ) : 1.48 (6H, d, J=7.5Hz), 2.64 (3H, s), 4.75-4.86 (IH, m) , 6.60 (IH, s) , 7.10 (IH, d, J=8Hz) , 7.29 (IH, t, J=8Hz), 7.59 (IH, d, J=8Hz)

(5) 4-Cyclopentyloxy-8-hydroxy-2-methylquinoline

NMR (CDCI3, δ) : 1.56-2.07 (8H, ) , 2.66 (3H, s), 4.94- 5.02 (IH, in) , 6.60 (IH, s), 7.10 (IH, d, J=8Hz), 7.29 (IH, t, J=8Hz), 7.55 (IH, d, J=8Hz)

Preparation 14

A mixture of 4-chloro-8- (2, 6-dichloro-3-nitrobenzyloxy) 2-methylσuinoline (200 mg) and N,N-dimethylformamide (3 ml) was heated under reflux for 18 hours. The reaction mixture was partitioned into ethyl acetate and saturated aqueous solution of sodium bicarbonate. The organic layer was washe with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol) to give 8-hydroxy- 2-methyl-4-dimethylaminoquinoline (26 mg) as a brownish powder.

NMR (CDCI3, δ) : 2.62 (3H, s) , 3.03 (6H, s), 5.29 (IH, br s), 6.63 (IH, s), 7.07 (IH, d, J=8Hz) , 7.28 (IH, t, J=8Hz), 7.46 (IH, d, J=8Hz)

Preparation 15

(1) To a suspension of 8- (2, 6-dichloro-3-nitrobenzyloxy) -4- methoxy-2-methylquinoline (1.75 g) in methanol (17 ml) was added tin (II) chloride (3.37 g) at ambient temperature. The mixture was refluxed for 1 hour. After cooling, the mixture was adjusted to pH 10 with IN sodium hydroxide solution. To this mixture was added dichloromethane (50 ml) and the precipitate was removed by filtration. The filtrate was extracted with dichloromethane twice. The organic layer was washed with water and brine. After dried over magnesium

sulfate, the solvent was removed in vacuo to give 8-(3-amino- 2, 6-dichlorobenzyloxy) -4-methoxy-2-methylquinoline (1.16 g) as a colorless powder, p : >250°C NMR (DMSO-d ₆ , δ) : 2.58 (3H, s), 4.00 (3H, s) , 5.31

(2H, s), 5.68 (2H, br s), 6.90 (IH, d, J=8Hz), 7.23 (IH, d, J=8Hz), 7.31-7.46 (2H) , 7.68 (IH, dd, J=8, 2Hz)

(2) 8- [2, 6-Dichioro-3- (phthalimidoacetylamino)benzyloxy] -4- methoxy-2-methylquinoline was obtained according to a similar manner to that of Preparation 9. p : 184-185°C NMR (CDC1 ₃ , δ) : 2.62 (3H, s), 4.27 (3H, s) , 4.78-5.02 (2H) , 5.10-5.79 (2H) , 6.60 (IH, br d, J=9Hz) , 7.19-

7.38 (2H), 7.58 (IH, t, J=9Hz) , 7.70-7.99 (7H)

(3) 8- [2, 6-Dichloro-3-[N- (phthalimidoacetyl) -N- methylamino]benzyloxy] -4-methoxy-2-methylquinoline was obtained according to a similar manner to that of Preparation 10. mp : 209-210°C

NMR (CDCI3, δ) : 2.70 (3H, s) , 3.22 (2H, s) , 3.99 (3H, s), 4.02 (2H, s), 5.65 (IH, d, J=10Hz) , 5.72 (IH, d, J=10Hz), 6.63 (IH, s), 7.21-7.40 (2H) , 7.46 (IH, d, J=9Hz), 7.53 (IH, d, J=9Hz) , 7.68-7.91 (5H)

(4) 8- [3- (N-Glycyl-N-methylamino) -2, 6-dichlorobenzyloxy] -4- methoxy-2-methylquinoline was obtained according to a similar manner to that of Preparation 11.

NMR (CDCI3, δ) : 2.70 (3H, s), 2.95 (IH, d, J=17Hz), 3.10 (IH, d, J=17Hz), 3.21 (3H, s) , 4.01 (3H, s), 5.62 (2H, s), 7.18-7.29 (2H) , 7.33 (IH, t, J=8Hz) , 7.46 (IH, d, J=9Hz), 7.32 (IH, d, J=8Hz)

Preparation 16

A mixture of 4-chloro-8-hydroxy-2-methyIquinoline (500 mg) , N,N-dimethylethylenediamine (341 mg) and phenol (486 m was heated at 125°C for 18 hours. After cooling the reactio mixture, acetone (5 ml) was added thereto. The precipitates were collected by filtration and recrystallized from acetonitrile to give 4- (2-dimethylaminoethyIamino) -8-hydrox 2-methylquinoline hydrochloride (415 mg) ) as brown crystals, mp : 248-250°C NMR (DMSO-d ₆ , δ) : 2.45 (6H, s), 2.63 (3H, s) , 3.81-

2.92 (2H, ) , 3.58-3.70 (2H, m) , 6.72 (IH, s), 7.2 (IH, d, J=8Hz), 7.39 (IH, t, J=8Hz) , 7.63 (IH, d, J=8Hz) , 8.43 (IH, br s)

Preparation 17

The following compounds were obtained according to a similar manner to that of Preparation 16.

(1 ) 4-Ethoxycarbonylmethylamino-8-hydroxy-2-methylquinoline (from 4-chloro-8-hydroxy-2-methylquinoline and ethyl aminoacetate hydrochloride) mp : 227-229°C

NMR (DMSO-d ₆ , δ) : 1.23 (3H, t, J=7Hz) , 2.59 (3H, s),

4.18 (2H, q, J=7Hz), 4.29 (2H, br d, J=6Hz) , 6.50 (IH, s), 7.15 (IH, d, J=7.5Hz) , 7.36 (IH, t,

J=7.5Hz), 7.69 (IH, d, J=7.5Hz), 8.35 (IH, br s)

(2) 4-Allylamino-8-hydroxy-2-methylquinoline (from 4-chloro 8-hydroxy-2-methylquinoline and allylamine) mp : 263-264°C

NMR (DMS0-d _β , δ) : 2.66 (3H, s) , 4.11-4.09 (2H, m) ,

5.18-5.30 (2H, ) , 5.88-6.02 (IH, m) , 6.67 (IH, s), 7.38 (IH, d, J=7.5Hz), 7.47 (IH, t, J=7.5Hz), 7.91 (IH, d, J=7.5Hz), 9.29 (IH, br t, J=6Hz)

(3) 8-Hydrcxy-4- (2-methoxyethylamino) -2-methylσuinoline hydrochloride (from 4-chloro-8-hydroxy-2-methylquinoline and 2-me hoxyethylamine) mp : 235.8-239°C NMR (DMSO-d ₆ , δ) : 2.65 (3H, s), 3.29 (3H, s), 3.59-

3.61 (4H, ) , 6.79 (IH, s) , 7.31 (IH, d, J=8Hz) , 7.43 (IH, t, J=8Hz), 7.89 (IH, d, J=8Hz) , 8.90 (IH, br s)

( ) 4- [Bis (2-methoxyethyl) amino] -8-hydroxy-2-methylquinoline

(from 4-chloro-8-hydroxy-2-methylquinoline and bis (2- methoxyethyl) amine) NMR (CDC1 ₃ , δ) : 2.63 (3H, br s) , 3.29 (6H, s) , 3.50-

3.80 (8H, m) , 6.85 (IK, br s), 7.06 (IH, d, J=8Hz) , 7.29 (IH, br t, J=8Hz) , 7.49 (IH, br d, J=8Hz)

(5) 8-Hydroxy-2-methyl-4- (piperidino) quinoline (from 4- chloro-8-hydroxy-2-methylquinoline and piperidine)

NMR (CDCI3, δ) : 1.63-1.74 (2H, m) , 1.79-1.89 (4H, ) , 2.64 (3H, s), 3.15-3.22 (4H, m) , 6.70 (IH, s) , 7.06

(IH, d, J=8Hz), 7.28 (IH, t, J=8Hz) , 7.39 (IH, d, J=8Hz)

(6) 8-Hydroxy-2-methyl-4- (morpholino) quinoline (from 4- chloro-8-hydroxy-2-methylquinoline and morpholine)

NMR (CDC1 ₃ , δ) : 2.66 (3H, s) , 3.24 (4H, t, J=5Hz) , 3.98 (4H, t, J=5Hz), 6.74 (IH, s), 7.09 (IH, d, J=7.5Hz), 7.31 (IH, t, J=7.5Hz), 7.39 (IH, d, J=7.5Hz)

Preparation 18

(1) To a solution of 2, 6-dichloro-3-nitrobenzyl alcohol (5.0 g) in N,N-dimethylformamide (25 ml) were added imidazole (1.69 g) and tert-butyldiphenylsilyl chloride (6.0 ml) at ambient temperature with stirring. After 8 hours, the

mixture was diluted with water (25 ml) and was extracted wit ethyl acetate twice. The organic layer was washed with wate and brine, dried over magnesium sulfate. The solvent was removed in vacuo tc give 1- (tert-butyldiphenylsilyloxy- methyl) -2, 6-dichloro-3-nitrobenzene (11.5 g) as an oil.

NMR (CDC1 ₃ , δ) : 1.05 (9H, s), 4.96 (2H, s), 7.27-7.51

(7H, m) , 7.58-7.81 (5H, m)

(2) To a stirred mixture of 1- (tert-butyldiphenylsilyloxy- methyl)-2, 6-dichloro-3-nitrobenzene (433 mg) , ferric chlorid hexahydrate (17.5 mg) and activated carbon (17.5 mg) in a mixture of methanol (2.78 ml) and water (0.69 ml-) was added hydrazine onohydrate (0.135 ml) dropwise at 60-70°C. After the addition was finished, the mixture was refluxed for half an hour. The mixture was allowed to cool and filtered. The filtrate was concentrated in vacuo. The residue was extracted with dichloromethane and the organic phase was dried over anhydrous magnesium sulfate. After being filtered, the filtate was concentrated in vacuo and the resulting residue was washed with n-hexane to give 3-amino-l- (tert-butyldiphenylsilyloxymethyl) -2, 6-dichlorobenzene (348 mg) as a white mass.

NMR (CDCI3, δ) : 1.05 (9H, s), 4.07 (2H, br s), 4.87

(2H, s), 6.66 (IH, d, J=9Hz), 7.08 (IH, d, J=9Hz) , 7.30-7.50 (6H, m) , 7.70-7.84 (4H, m)

(3) 1- (tert-Butyldiphenylsilyloxymethyl)-2, 6-dichloro-3- (phthalimidoacetylamino)benzene was obtained according to a similar manner to that of Preparation 9. mp : 198.1°C

NMR (CDCI3, δ) : 1.04 (9H, s), 4.57 (2H, s), 4.90 (2H, s), 7.25-7.50 (7H, m) , 7.55-7.83 (6H, ) , 7.85-8.07 (2H, m) , 8.00 (IH, br s), 8.25 (IH, d, J=8Hz)

(4) 1- (tert-Butyldiphenylsilyloxymethyl)-2, 6-dichloro-3- [N-

methyl-N- (phthalimidoacetyl) amino]benzene was obtained according to a similar manner to that of Preparation 10. mp : 167-172°C

NMR (CDC1 ₃ , δ) : 1.06 (9H, s), 3.20 (3H, s), 4.04 (2H, S), 4.98 (2H, s), 7.31-7.51 (9H, ) , 7.65-7.79 (6H, m) , 7.80-7.92 (2H, m)

(5) 3- (N-Giycyl-N-methylamino) -1- (tert-butyldiphenyl- silyloxymethyl) -2, 6-dichlorobenzene was obtained according to a similar manner to that of Preparation 11.

NMR (CDCI3, δ) : 1.05 (9H, s), 2.94 (IH, d, J=17Hz) ,

3.09 (IH, d, J=I7Hz), 3.20 (3H, s) , 4.93 (2H, s) ,

7.18 (IH, d, J=8Hz), 7.35-7.49 (7H, m) , 7.69-7.77 (4H, m)

(6) 1- (tert-Butyldiphenylsilyloxymethyl) -2, 6-dichloro-3- [N- methyl-N- [4- (methylcarbamoyl) cinnamoylglycyl]amino] - benzene was obtained by reacting 3- (N-glycyl-N- methylamino) -1- (tert-butyldiphenylsilyloxymethyl) -2, 6- dichlorobenzene with 4- (methylcarbamoyl) cinna ic acid according to a similar manner to that of Example 1. mp : 219-222°C NMR (CDCI3, δ) : 1.05 (9K, s) , 3.C2 (3H, d, J=5Hz) ,

3.21 (3H, s), 3.56 (IH, dd, J=17.4Hz), 3.93 ( (IH, dd, J=17, 5Hz), 4.91 (IH, d, J=10Hz) , 4.98 (IH, d,

J=10Hz), 6.15 (IH, br d, J=5Hz) , 6.51 (IH, d, J=15Hz), 6.63 (IH, br s), 7.19-7.28 (2H, m) , 7.32- 7.48 (6H, m) , 7.50-7.60 (3H, m) , 7.68-7.78 (6H, m)

(7) To a suspension of 1- (tert-butyldiphenylsilyloxymethyl) - 2, 6-dichloro-3- [N-methyl-N- [4- (methylcarbamoyl) - cinnamoylglycyl]amino]benzene (17.6 g) in tetrahydrofuran (138 ml) was added 1M tetrabutylammonium fluoride in tetrahydrofuran (38.4 ml) at ambient temperature. The reaction mixture was stirred for 1 hour. The mixture was

concentrated and diluted with dichloromethane. The organic layer was washed with IN hydrochloric acid, saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated in vacuo to give 2, 6-dichloro-l-hydroxymethyl 3- [N-methyl-N- [4- (methylcarbamoyl) cinnamoylglycyl]amino]- benzene (8.14 g) . mp : 207-2Il°C

NMR (DMSO-d ₆ , δ) : 2.79 (3H, a, J=5Kz), 3.11 (3H, s) ,

3.47 (IH, dd, J=17, 4Hz), 3.77 (IH, dd, J=17, 5Hz) , 4.74 (IH, d, J=5Hz), 5.34 (IK, t, J=5Hz), 6.87 (IH, d, J=15Hz), 7.40 (IH, d, J=15Hz), 7.59-7.68 (4H, m) , 7.85 (2H, d, J=8Hz), 8.29 (IH, t, J=5Hz) , 8.48 (IH, d, J=5Hz)

(8) To a mixture of 2, 6-dichloro-l-hydroxymethyl-3- [N- methyl-N-[4- (methylcarbamoyl) cinnamoylglycyl]amino]benzene (8.10 g) in dichloromethane (81 ml) was added triphenylphosphine (5.66 g) and carbon tetrabromide (8.95 g) at 0°C. After 15 minutes the reaction mixture was stirred at ambient temperature for 3 hours. To the mixture was added triphenylphosphine (1.42 g) and carbon tetrabromide (2.39 g) and stirred for another 2 hours. The reaction mixture was washed with saturated sodium hydrogen carbonate, water and brine. After dried over anhydrous magnesium sulfate, the mixture was filtered and evaporated in vacuo. The residue was purified by flash column chromatography eluting with dichloromethane:ethyl acetate (1:1, V/V) and dichloromethane:methanol (20:1, V/V) followed by crystallizing from ethyl acetate to give 2, 6-dichloro-3- [N- methyl-N- [4- (methylcarbamoyl) cinnamoylglycyl] amino]benzyl bromide (6.40 g) as pale yellow crystals, mp : 211.6-216.5°C NMR (CDC1 ₃ , δ) : 3.02 (3H, d, J=5Hz) , 3.27 (3H, s),

3.62 (IH, dd, J=17, 4Hz). 3.92 (IH, dd, J=17, 5Hz) , 4.78 (1.2H, s), 4.90 (0.8H, s), 6.15 (IH, br d,

/13485

- 39 -

J=5Hz), 6.51 (IH, d, J=15Hz), 6.67 (IH, br t, J=5Hz), 7.29 (IH, overlapped with H ₂ 0) , 7.45-7.62 (4H, ) , 7.76 (2H, d, J=8Hz)

Preparation 19

(1) 3- [N- [ (E) -3- (6-Acetamidopyridin-3-yl) acryloylglycyl]-N- methylamino] -1- [tert-butyldiphenylsilyloxy ethyl] -2, 6- dichlorobenzene was obtained by reacting 3- (N-glycyl-N- methylamino) -1- (tert-butyldiphenylsiiyloxymethyl) -2, 6- dichiorobenzene with (E) -3- (6-acetamidopyridin-3-yl) acrylic acid according to a similar manner to that of Preparation 18- (6) . mp : 194-196°C

NMR (CDC1 ₃ , δ) : 1.06 (9H, s) , 2.22 (3H, s), 3.23 (3H, s) , 3.57 (IH, dd, J=17, 4Hz) , 3.94 (IH, dd, J=17,

5Hz), 4.92 (IH, d, J=10Hz) , 4.98 (IH, d, J=10Hz) , 6.44 (IH, d, J=15Hz), 6.63 (IH, br s) , 7.22 (IH, d, J=8Hz), 7.35-7.48 (6H, m) , 7.52 (IH, d, J=15Hz) , 7.70-7.77 (4H, m) , 7.83 (IH, dd, J=8, 3Hz) , 8.05 (IH, br s), 8.22 (IH, d, J=8Hz) , 8.36 (IH, d,

J=3Hz)

(2) 3-[N-[ (E)-3- (6-Acetamidopyridin-3-yl) acryloylglycyl]-N- ethy1amino]-l-hydroxymethyl-2, 6-dichlorobenzene was obtained according to a similar manner to that of Preparation 18- (7) . mp : 207-209°C NMR (DMSO-d ₆ , δ) : 2.10 (3H, s) , 3.10 (3H, s) , 3.47

(IH, dd, J=17, 4Hz), 3.76 (IH, dd, J=17, 5Hz) , 4.74 (IH, d, J=5Hz), 5.35 (IH, br s) , 6.79 (IH, d, J=15Hz), 7.37 (IH, d, J=15Hz) , 7.61 (IH, d, J=8Hz) ,

7.65 (IH, d, J=8Hz), 7.98 (IH, dd, J=8, 3Hz), 8.11 (IH, d, J=8Hz), 8.21 (IH, t, J=5Hz) , 8.47 (IH, s)

(3) 3-[N-[ (E)-3- (6-Acetamidopyridin-3-yl) acryloylglycyl]-N- methylamino]-2, 6-dichlorobenzyl bromide was obtained

- 40 - according to a similar manner to that of Preparation 18- (8) . mp : 222-223°C NMR (CDCI3-CD3OD, δ) : 2.22 (3H, s), 3.27 (3H, s),

3.60 (IH, dd, J=17, 3Hz), 3.94 (IH, dd, J=17, 3Hz) , 4.78 (2H, s), 6.49 (IH, d, J=15Hz) , 7.31 (IH, d,

J=8Hz), 7.49 (IH, d, J=8Hz), 7.51 (IH, d, J=15Hz) , 7.88 (IH, dd, J=8, 3Hz), 8.23 (IH, br d, J=8Hz), 8.33 (IH, d, J=3Hz)

Preparation 20

(1) To a solution of 4-hydroxybenzaldehyde (10 g) and potassium carbonate (17 g) in dimethylformamide (100 ml) was added ethyl bromoacetate (15 g) under ice-cooling, and the mixture was stirred for 2 hours at ambient temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (ethyl acetate :n-hexane, 1:4, V/V) to give 4- (ethoxycarbonylmethoxy) benzaldehyde (16 g) . mp : 39°C

NMR (CDCI3, δ) : 1.32 (3H, t, J=7.5Hz), 4.28 (2H, q, J=7.5Hz) , 4.71 (2H, s) , 6.98 (2H, d, J=9Hz), 7.83 (2H, d, J=9Hz), 9.88 (IH, s)

(2) 4- (Ethoxycarbonylmethoxy) cinnamic acid was obtained according to a similar manner to that of Preparation 4. p : 154.2°C

NMR (CDCI3, δ) : 1.30 (3H, t, J=7.5Hz), 4.28 (2H, q, J=7.5Hz), 4.66 (2H, s), 6.34 (IH, d, J=15Hz) , 6.91

(2H, d, J=9Hz) , 7.50 (2H, d, J=9Hz) , 7.73 (IH, d, J=15Hz)

Preparation 21 4-Acetamidocinnamic acid (80 mg) was suspended in

/134

- 41 - methanol (5 ml) and 10% palladium cn carbon (15 mg) was added thereto. The mixture was stirred under hydrogen atmosphere at 25°C for 3 hours. Catalyst was removed and the solution was concentrated to give 3- (4-acetamidophenyl)propionic acid (69 mg) as a solid. mp : 127.1-137.8°C

NMR (DMSO-d ₆ , δ) : 2.00 (3H, s), 2.47 (2H, t, J=7.5Hz), 2.74 (2H, t, J=7.5Hz), 7.12 (2H, d, J=8Hz) , 7.45 (2H, d, J=8Hz), 9.85 (IH, s)

Preparation 22

The following compounds were obtained according to a similar manner to that of Preparation 21.

(1) 3- [4- (Methylcarbamoyl)phenyl]propionic acid mp : 171.2°C

NMR (DMSO-d ₆ , δ) : 2.63 (2H, t, J=7.5Hz), 2.76 (3H, d, J=5Hz), 2.85 (2H, t, J=7.5Hz), 7.30 (2H, d, J=8Hz) , 7.73 (2H, d, J=8Hz), 8.35 (IH, q-like)

(2) 4- [2- (Methoxycarbonyl) ethyl]benzoic acid

NMR (DMS0-d ₆ , δ) : 2.67 (2H, t, J=7.5Hz), 2.93 (2H, t, J=7.5Hz), 3.59 (3H, s) , 7.35 (IH, d, J=8Hz) , 7.85 (IH, d, J=8Hz)

(3) 3-[6-Acetamidopyridin-3-yl]propionic acid

NMR (DMSO-d ₆ , δ) : 2.06 (3H, s), 2.49 (2H, t, J=7.5Hz), 2.76 (2H, t, J=7.5Hz), 7.63 (IH, dd, 3=2 , 8Hz) , 7.96 (IH, d, J=8Hz), 8.15 (IH, d, J=8Hz) ■.

Preparation 23

(1) Methyl 3- [4- (2-pyridylmethylcarbamoyl)phenyl]propionate was obtained from 4-[2- (methoxycarbonyl) ethyl]benzoic acid and 2-pyridylmethylamine according to a similar manner to that of Example 7.

- 42 -

NMR (CDCI3, δ) : 2.65 (2H, t, J=7.5Hz) , 3.00 (2H, t, J=7.5Hz) , 3.67 (3H, s) , 4.76 (2H, d, J=5Hz) , 7.22 (IH, dd, J=5, 8Hz), 7.25-7.36 (3H, m) , 7.55 (IH, brpeak) 7.68 (IH, td, J=8, 2Hz), 7.80 (2H, d, J=8Hz) , 8.57 (IH, d, J=5Hz)

(2) 3- [4- (2-Pyridylmethylcarbamoyl)phenyljpropionic acid wa obtained according to a similar manner to that of Preparation 3. mp : 83.8°C

NMR (DMSO-d ₆ , δ) : 2.57 (2H, t, J=7.5Hz), 2.88 (2H, t, J=7.5Hz), 4.56 (2H, d, J=5Hz), 7.25 (IH, dd, J=5, 8Hz), 7.28-7.37 (3H, m) , 7.74 (IH, td, J=8, 2Hz) , 7.83 (2H, d, J=8Hz), 8.50 (IH, d, J=5Hz), 9.05 (IH, t, J=5Hz)

Preparation 24

To a suspension of (E) -3- (6-acetylaminopyridin-3-yl) - acrylic acid (460 mg) in ethanol (5.4 ml) was added IN sodium hydroxide (5.4 ml) at ambient temperature, and the mixture was stirred for 3 hours at 50°C. The reaction mixture was adjusted to pH 7, and the resulting precipitate was collected by filtration and dried to give (E) - (6-aminopyridin-3- yl) acrylic acid (295 mg) . mp : 243.6-246.4 ^β C

NMR (DMSO-d ₆ , δ) : 6.21 (IH, d, J=15Hz) , 6.45 (IH, d, J=8Hz), 6.52 (2H, s), 7.42 (IH, d, J=15Hz) , 7.75 (IH, d, J=8Hz), 8.11 (IH, s)

Preparation 25

(1) To a suspension of 4-amino-N-methylbenzamide (500 mg) in tetrahydrofuran (5 ml) was added di-tert-butyi dicarbonate (799 mg) and the mixture was stirred for 18 hours at 50°C. The mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was stirred under ice-cooling,

and the resulting precipitates were collected by filtration to give N- (tert-butoxycarbonyl)-4-methylcarbamoylaniline (500 mg) . mp : 185.2°C NMR (CDC1 ₃ , δ) : 1.54 (9K, s) , 3.00 (3H, d, J=6Hz), 6.12 (IH, br s), 6.69 (IH, br s), 7.43 (2H, d, J=9Hz), 7.70 (2H, d, J=9Hz)

(2) Sodium hydride ( 60% dispersion in mineral oil, 41.9 mg) was added to a solution of N- (tert-butoxycarbonyl)-4- methylcarbamoylaniline (250 mg) in dimethylformamide (2.5 ml) in ice water bath under nitrogen and stirred for 30 minutes under same condition. To the mixture was added tert- butylbro oacetate (234 mg) and stirred at ambient temperature for 20 hours. The reaction mixture was poured into water and extracted with chloroform. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethyl acetate - n-hexane to give N- (tert-butoxycarbonyl) -N- (tert-butoxycarbonyl ethyl)-4-methylcarbamoylaniline (280 g) . p : 163.7-165.9°C

NMR (CDCI3, δ) : 1.46 (9H, s), 1.49 (9H, s) , 3.00 (3H, d, J=5Hz), 4.19 (2H, s) , 6.11 (IH, br q, J=5Hz) , 7.33 (2H, br q, J=9Hz) , 7.71 (2H, d, J=9Hz)

(3) Trifluoroacetic acid (3.3 ml) was added to a solution of N- (tert-butoxycarbonyl)-N- (tert-butoxycarbonylmethyl)-4- methylcarba oylaniline (250 mg) in ice water bath and stirred for 20 hours at ambient temperature. The solvent was evaporated under reduced pressure. The residue was pulverized with diethyl ether to give N-(4- methylcarbamoylphenyl)glycine (125 mg) . mp : 233.5°C NMR (DMSO-d ₆ , δ) : 2.72 (3H, d, J=5Hz), 3.85 (3H, s) ,

6 . 55 ( 2H, d, J=9Hz ) , 7 . 60 ( 2H, d, J=9Hz ) , 7 . 99 ( I br q, J=5Hz )

Preparation 26 To a mixture of naphthalene-2, 6-dicarboxylic acid (5 g) methylamine hydrochloride (1.64 g) and 1-hydroxybenzotriazo (3.75 g) in dimethylformamide (50 ml) was added l-ethyl-3- ( dimethylaminopropyl) carbodiimide (3.79 g) under ice-cooling. The mixture was stirred for 1 hour at the same temperature and then at ambient temperature overnight. The mixture was diluted with water, and the precipitates were collected by filtration to give 6- (methylcarbamoyl)naphthalene-2- carboxylic acid (4.07 g) . mp : >275.7°C NMR (DMSO-d ₆ , δ) : 2.82 (3H, d, J=5Hz), 7.90-8.14 (3H, m) , 8.20 (IH, d, J=7.5Hz), 8.45 (IH, br d, J=7.5Hz), 8.58-8.74 (2H, m)

Preparation 27 (1) To a mixture of 2, -dichlorophenol (3.20 g) and imidazole (2.67 g) in dimethylformamide (30 ml) was added triisopropylsilyl chloride (3.97 g) in water bath under nitrogen atmosphere, and the mixture was stirred for 3 hours under the same condition. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate an concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane) tc give 1, 3-dichloro-4- triisopropylsilyloxybenzene (5.12 g) . NMR (CDC1 ₃ , δ) : 1.12 (18H, d, J=7.5Kz), 1.23-1.39 (3H, m) , 6.83 (IH, d, J=8Hz), 7.06 (IH, d, J=8Hz) , 7.34 (IH, d, J=2Hz)

(2) To a solution of 1, 3-dichloro-4- triisopropylsilyloxybenzene (6.00 g) in tetrahydrofuran (50

ml) at -60°C was added dropwise n-butyllithium, 1.6M solution of hexane (12.9 ml) over 30 minutes under nitrogen and the mixture was stirred for 1 hour at the same temperature. A solution of ethyl chloroformate in tetrahydrofuran {20 ml) was added dropwise to the mixture over 20 minutes at -60°C. The resulting mixture is stirred for 1 hour at -60"C, the cooling bath was removed, and temperature was allowed to rise to 20°C. A solution of ammonium chloride (2 g) in water (37 ml) was then added over 5 minutes followed by ethyl acetate ( 40 ml) and brine (40 ml) . The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:10 to 1:6) to give ethyl 2, 6-dichloro-3- triisopropylsilyloxybenzoate (1.59 g) as an oil.

NMR (CDC1 ₃ , δ) : 1.12 (18H, d, J=7.5Hz), 1.23-1.38 (3H, m) , 1.41 (3H, t, J=7.5Hz), 4.46 (2H, q, J=7.5Hz), 6.85 (IH, d, J=8Hz), 7.15 (IH, d, J=8Hz)

(3) Ethyl 2, 6-dichloro-3-hydroxybenzoate was obtained according to a similar manner to that of Preparation 18- (7). NMR (CDCI3, δ) : 1.42 (3H, t, J=7.5Hz), 4.45 (2H, q,

J=7.5Hz), 7.01 (IH, d, J=8Hz), 7.23 (IH, d, J=8Hz)

(4) To a suspension of sodium hydride (60% in oil, 474 mg) in N,N-dimethylformamide (2 ml) was added a solution of ethyl 2, 6-dichloro-3-hydroxybenzoate (2.42 g) in N,N- dimethylformamide (10 ml) under nitrogen at ambient temperature and the mixture was stirred for 1 hour at the same temperature. Chloro ethyl methyl ether (1.15 ml) was added thereto and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on

- 4 6 - silica gel eluting with a mixture of ethyl acetate and hexan (1:8, V/V) to give ethyl 2, 6-dichlcro-3- (methoxy ethoxy)benzoate (2.58 g) as an oil.

NMR (CDC1 ₃ , δ) : 1.42 (3H, t, J=7.5Hz), 3.50 (3H, s), 4.46 (2H, q, J=7.5Hz), 5.23 (2H, s), 7.16 (IH, d,

J=8Hz), 7.25 (IH, d, J=8Hz)

(5) To a suspension of lithium aluminum hydride (347 mg) in tetrahydrofuran was dropwise added a solution of ethyl 2,6- dichloro-3- (methoxymethoxy)benzoate (2.55 g) in tetrahydrofuran at 0°C under nitrogen atmosphere, and the mixture was stirred for 30 minutes at the same temperature and for 18 hours at ambient temperature. Water was dropwise added thereto at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (n-hexane:ethyl acetate = 6:1, V/V) to give 2, 6-dichloro-3- (methoxymethoxy)benzyl alcohol. NMR (CDCI3, δ) : 2.14 (IH, t, J=7.5Hz), 3.51 (3H, s),

4.47 (2H, d, J=7.5Hz), 5.23 (2H, s), 7.11 (IH, d, J=8Hz), 7.26 (IH, d, J=8Hz)

(6) To a solution of 2, 6-dichloro-3- (methoxymethoxy)benzyl alcohol (1.1 g) and triethylamine (563 mg) in dichloromethane was added a solution of methanesulfonyl chloride (585 mg) in dichloromethane at -20°C over 5 minutes under nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes and under ice-cooling for 30 minutes. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 1,3-dichloro-2- methanesulfonyloxymethyl-4- (methoxymethoxy)benzene.

NMR (CDCI3, δ) : 3.10 (3H, s), 3.52 (3H, s), 5.25 (2H, s), 5.53 (2H, s), 7.23 (IH, d, J=8Hz) , 7.32 (IH, d,

J=8Hz )

Preparation 28 (I) To a suspension of (E)-3- (6-acetylaminopyridin-3- yl)acrylic acid (200 mg) in a mixture of dichloromethane (3 ml) and methanol (3 ml) was added a solution of 10% trimethylsilyldiazomethane (3 ml) at ambient temperature and the mixture was stirred for 3 hours. The reaction mixture was evaporated in vacuo, poured into water and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was collected by vacuum filtration and washed with diisopropyl ether to give methyl (E)-3-(6- acetylaminopyridin-3-yl) crylate (197 mg) as a powder. p : 17I.5-200°C

NMR (CDC1 ₃ , δ) : 2.22 (3H, s), 3.80 (3H, s) , 6.41 (IH, d, J=16Hz), 7.64 (IH, d, J=16Hz) , 7.89 (IH, dd, J=2, 8Hz), 8.07 (IH, br s) , 8.25 (IH, d, J=8Hz), 8.38 (IH, d, J=2Hz)

(2) To a suspension of sodium hydride (60°- in oil, 20.6 mg) in N,N-dimethylformamide (1 ml) was added dropwise a solution of methyl (E)-3-(6-acetylaminopyridin-3-yl)acrylate (180 mg) in N,N-dimethylformamide (2 ml) at 0°C under nitrogen and the mixture was stirred for 1 hour. Methyl iodide (116 mg) was added to the mixture under the same condition and the mixture was stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was collected by vacuum filtration and washed with diisopropyl ether to give methyl (E)-3- [6- (N-methyl-N-acetylamino)pyridin-3- yl]acrylate (115 mg) as a powder, mp : 94.3°C NMR (CDCI3, δ) : 2.20 (3H, s) , 3.44 (3H, s), 3.82 (3H,

s ) , 6 . 48 ( IH, d, J=16Hz ) , 7 . 48 ( IH , br d , J=8Hz ) , 7 . 67 ( IH, d, J=16Hz ) , 7 . 87 ( IH, dd, J=2 , 8Hz ) , 8 . ( IH, d, J=2Hz )

(3) To a solution of methyl (E) -3- [ 6- (N-methyl-N- acetylamino)pyridin-3-yl] acrylate (110 mg) in methanol (3 m was added IN sodium hydroxide solution (1.1 ml) at ambient temperature and the mixture was stirred at 50°C for 4 hours. The reaction mixture was evaporated in vacuo and was dissolved in water. The solution was adjusted to pH 6 with IN hydrochloric acid, and the precipitate was collected by vacuum filtration to give (E) -3- [6- (methylamino) pyridin-3- yl] acrylic acid (72 mg) as a powder, mp : 227°C NMR (CDC1 ₃ , δ) : 2.80 (IH, d, J=5Hz), 6.23 (IH, d,

J=16Hz), 6.47 (IH, d, J=8Hz) , 7.09 (IH, q, J=5Hz), 7.45 (IH, d, J=16Hz), 7.76 (IH, dd, J=2, 8Hz) , 8.2 (IH, d, J=2Hz)

Preparation 29

(1) To a solution of 2-methyInicotinic acid (470 mg) in dichloromethane (6 ml) were dropwise added oxalyl chloride (522 mg) and dimethylformamide (1 drop) at 0°C under nitroge atmosphere, and the mixture was stirred for 1 hour at the same condition. The mixture was concentrated and the residu was pulverized with diethyl ether to give 2-methylnicotinoyl chloride hydrochloride (671 mg) as a solid.

NMR (CDC1 ₃ , δ) : 3.23 (3H, s) , 7.96 (IH, dd, J=6, 8Hz) , 8.93 (IH, d, J=6Hz), 9.08 (IH, d, J=8Hz)

(2) To a mixture of 10% trimethylsilyldiazomethane in hexan (4.2 ml) and triethylamine (527 mg) in tetrahydrofuran- acetonitrile (1:1, 10 ml) was added dropwise 2- methylnicotinoyl chloride hydrochloride (500 mg) in an ice water bath. The mixture was stirred for 7 hours in an ice

96/13485

- 49 - water bath and allowed to stand for 18 hours at 0"C, then evaporated in vacuo. Saturated aqueous sodium bicarbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. Evaporation of the solvent gave crude 3-diazoacetyl-2- ethylpyridine as an yellow oil.

Benzyl alcohol (2 ml) and 2, , 6-trimethylpyridine (2 ml) were added to the residue. The mixture was stirred at 180°C- 185°C for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent, 2,4, 6-trimethylpyridine and excess benzyl alcohol were evaporated in vacuo to give crude benzyl 2- (2-methyl-3-pyridyl)acetate as an oil.

NMR (CDC1 ₃ , δ) : 2.50 (3H, s) , 3.67 (2H, s) , 5.14 (2H, s), 7.10 (IH, dd, J=8, 6Hz) , 7.23-7.40 (5H, m) , 7.49 (IH, dd, J=8, 2Hz) , 8.49 (IH, dd, J=6, 2Hz)

(3) The residue including benzyl 2- (2-methyl-3- pyridyl)acetate obtained in Preparation 29-(2) was dissolved in methanol (5 ml), and 10% palladium on carbon was added thereto. The mixture was stirred under hydrogen atmosphere for 3 hours. The reaction mixture was diluted with water and washed with ethyl acetate. The solvent was removed in vacuo to give 2- (2-methyl-3-pyridyl)acetic acid (90 mg) .

NMR (DMSO-d ₆ , δ) : 2.40 (3H, s), 3.62 (2H, s) , 7.15

(IH, dd, J=6, 8Hz), 7.55 (IH, d, J=8Hz) , 8.30 (IH, d, J=6Hz)

Preparation 30

(1) 6-Methylnicotinoyl chloride hydrochloride was obtained by reacting 6-methyl nicotinic acid with oxalyl chloride according to a similar manner to that of Preparation 29- (1) . NMR (CDCI3, δ) : 3.13 (3H, s) , 7.84 (IH, d, J=8Hz),

8 . 82 ( IH, dd, J=2 , 8Hz ) , 9 . 35 ( IH, d, J=2Hz )

(2) Benzyl 2- ( 6-methyl-3-pyridyl) acetate was obtained according to a similar manner to that of Preparation 29-(2) .

NMR (CDC1 ₃ , δ) : 2.54 (3H, s), 3.63 (2H, s) , 5.14 (2H, s), 7.12 (IH, d, J=8Hz), 7.19-7.46 (5H, m) , 7.53 (IK, dd, J=8, 2Hz) , 8.40 (IH, d, J=2Hz)

(3) 2- (6-Methyl-3-pyridyl) acetic acid was obtained accordin to a similar manner to that of Preparation 29- (3) . NMR (DMSO-d ₆ , δ) : 2.43 (3H, s) , 3.56 (2H, s) , 7.20

(IH, d, J=8Hz), 7.55 (IH, dd, J=2, 8Hz) , 8.30 (IH, d, J=2Hz)

Preparation 31

(1) 2- (tert-Butoxycarbonylamino)benzothiazole was obtained by reacting 2-aminobenzothiazole with di-tert-butyl dicarbonate according to a similar manner to that of Preparation 25- (1) .

NMR (CDCI3, δ) : 1.59 (9H, s) , 7.22-7.30 (IH, ) , 7.40 (IH, t, J=8Hz), 7.79 (8H, d) , 7.85 (8H, d)

(2) 2- (N-tert-Butoxycarbonyl-N-tert- butoxycarbonylmethylamino)benzothiazole was obtained according to a similar manner to that of Preparation 25-(2) .

NMR (CDCI3, δ) : 1.46 (9H, s), 1.57 (9H, s) , 4.86 (2H, S) , 7.24 (IH, t, J=8Hz) , 8.38 (IH, t, J=8Hz) , 7.71 7.78 (2H, iu)

(3) 2- (Carboxymethylamino)benzothiazole was obtained according to a similar manner to that of Preparation 25-(3) . NMR (DMSO-d ₆ , δ) : 4.10 (2H, d, J=6Hz) , 7.04 (IH, t,

J=8HZ ) , 7 .22 ( IH, t , J=8Hz ) , 7 . 40 ( IH, d, J=8Hz ) , 7 . 68 ( IH, d, J=8Hz ) , 8 . 32 ( IH, t , J=6Hz )

Preparation 32 (1) A mixture of p-toluidine (10 g) and diethyl 2-methyl-3- oxosuccinate (18.9 g) in dichloromethane (50 ml) was refluxed for 2 days. The reaction mixture was poured into 0.5N hydrochloric acid (200 ml) and extracted with dichloromethane. The organic layer was washed with water, 0.5N sodium hydroxide solution and brine, dried over magnesium sulfate, and concentrated. The obtained residue was added to heated diphenyl (80 g) and the mixture was refluxed for 15 minutes. The reaction mixture was allowed to stand at ambient temperature, ana the resulting precipitates were collected by filtration to give ethyl 1,4-dihydro-3, 6- dimethyl-4-oxoquinoline-2-carboxylate (16.3 g) . p : 190.1-192.7°C

NMR (CDC1 ₃ , δ) : 1.47 (3H, t, J=7Hz) , 2.15 (3H, s) , 2.47 (3H, s), 4.51 (2H, σ, J=7Hz) , 7.30 (IH, d, J=8Hz), 7.45 (IH, dd, J=2, 8Hz) , 8.13 (IH, s-like) ,

9.20 (IH, br s)

(2) To a mixture of ethyl 1, -dihydro-3, 6-dimethyl-4- oxoquinoline-2-carboxylate (4.0 g) and phosphoryl chloride (10 g) was added N,N-dimethylaniline (3.95 g) at ambient temperate and the mixture was stirred for 1 hour. The solvent was removed in vacuo, and the residue was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-hexane-dichloromethane) to give ethyl 4- chloro-3, 6-dimethylσuinoline-2-carboxylate (3.17 g) as an oil. NMR (CDC1 ₃ , δ) : 1.49 (3H, t, J=7Hz) , 2.61 (3H, s) ,

2 . 68 ( 3H, s ) , 4 . 55 ( 2H, q, J=7Hz ) , 7 . 59 ( IH, d, J=8Hz ) , 8 . 00 ( IH, s- l i ke ) , 8 . 06 ( IH, dd, J=2 , 8Hz )

(3) A mixture of ethyl 4-chloro-3, 6-dimethylquinoline-2- carboxylate (3.0 g) , triethylamine (2.4 ml) and 10% palladium on carbon (300 mg) in ethyl acetate (30 ml) was stirred for 4 hour at ambient temperature under hydrogen atmosphere. After filtration the filtrate was concentrated in vacuo and diluted with dichloromethane. The mixture was washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (dichloromethane-ethyl acetate) to give ethyl 3, 6-dimethylquinoline-2-carboxylate.

NMR (CDC1 ₃ , δ) : 1.47 (3H, t, J=7Hz) , 2.55 (3H, s), 2.66 (3H, s), 4.53 (2H, q, J=7Hz) , 7.49-7.55 (2H, m) , 7.92 (IH, s) , 8.06 (IH, d, J=8Hz)

(4) To a solution of ethyl 3, 6-dimethylquinoline-2- carboxylate (1.0 g) in tetrachloromethane (10 ml) were added N-bromosuccimide (815 mg) and 2,2'-azobis (2, 4-dimethyl-4- methoxyvaleronitrile) at ambient temperature under nitrogen atmosphere, and the mixture was heated at 90°C for 1 hour. The reaction mixture was poured into 5% sodium thiosulfate solution and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (n-hexane - ethyl acetate) to give ethyl 6- bromomethyl-3-methylquinoline-2-carboxylate (802 mg) as a solid. NMR (CDCI3, δ) : 1.49 (3H, t, J=7.5Hz), 2.66 (3H, s),

4.54 (2H, q, J=7.5Hz), 4.65 (3H, s), 7.71 (IK, d, J=8Hz), 7.77 (IH, d, J=2Hz) , 8.00 (IH, s-like), 8.16 (IH, d, J=8Hz)

(5) To a solution of ethyl 6-bromomethyl-3-methylquinoline-

2-carboxylate (700 mg) in dimethylformamide (7 ml) was added sodium acetate (373 mg) at ambient temperature, and the mixture was stirred for 24 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The. organic layer was washed with water, sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (n-hexane:ethyl acetate = 1:2, V/V) to give ethyl 6-acetoxymethyl-3- methylquincline-2-carboxylate (452 mg) as an oil.

NMR (CDC1 ₃ , δ) : 1.48 (3H, t, J=7.5Hz), 2.15 (3H, s) , 2.67 (3H, s), 4.53 (2H, q, J=7.5Hz), 5.29 (2H, s) , 7.66 (IH, dd, J=2, 8Hz) , 7.75 (IH, s-like), 8.01 (IH, s-like), 8.18 (IH, d, J=8Hz)

(6) A mixture of ethyl 6-acetoxymethyl-3-methylquinoline-2- carboxylate (420 mg) and potassium carbonate in methanol was stirred for 30 minutes under ice-cooling. After filtration the filtrate was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with water, dried over magnesium sulfate and concentrated to give methyl 6-hydroxymethyl-3-methylquinoline-2-carboxylate (20 mg) . mp : 84.3 ^β C

NMR (CDCI3, δ) : 2.70 (3H, s) , 4.05 (3H, s) , 4.90 (2H, s), 7.68 (IH, dd, J=2, 8Hz), 7.76 (IH, s-like),

8.01 (IH, s-like,) 8.17 (IH, d, J=8Hz)

(7) To a mixture of methyl 6-hydroxymethyl-3- methylquinoline-2-carboxylate (193 mg) , triethylamine (422 mg) dimethyl sulfoxide (2 ml) and dichloromethane (2 ml) was added portionwise sulfur trioxide pyridine complex (266 mg) in water bath and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and

- 54 - evaporated in vacuo. The residue was purified by preparativ thin-layer chromatography (n-hexane:ethyl acetate = 1:1, V/V to give methyl 6-formyl-3-methylquinoline-2-carboxylate (149 mg) . mp : 117.8-120.7°C

NMR (CDC1 ₃ , δ) : 2.71 (3H, s) , 4.08 (3H, s) , 8.15-8.28 (2H, m) , 8.28-8.35 (2H, m) , 10.20 (IH, s)

(8) To a mixture of water (0.8 ml) and tert-butyl alcohol ( ml) were added methyl 6-formyl-3-methylquinoline-2- carboxylate (140 mg) , 2-methyl-2-butene (190 mg) and sodium dihydrogenphosphate (105 mg) in water bath. To -the mixture was added dropwise sodium chlorite (244 mg) and the mixture was stirred for 1 hour at the same temperature. The reactio mixture was cooled in an ice bath, adjusted to pH 4 with 1M hydrochloric acid and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporate in vacuo. The residue was purified by preparative thin-laye chromatography (dichloromethane:methanol = 10:1, V/V) followed by crystallization from methanol-isopropyl ether to give 2-methoxycarbonyl-3-methylquinoline-6-carboxylic acid (121 mg) as crystals, mp : 215°C

NMR (CDCI3, δ) : 2.57 (3H, s) , 3.96 (3H, s) , 8.11 (IH, dd, J=2, 8Hz), 8.21 (IH, dd, J=2, 8Hz) , 8.53 (IH, d, J=2Hz), 8.62 (IH, d, J=2Hz)

Example 1

To a mixture of 8- [3- (N-glycyl-N-methylamino)-2, 6- dichlorobenzyloxy]-2-methylquinoline (1.65 g) , (E)-3-(6- ethoxycarbonyl-3-pyridyl) acrylic acid (1.04 g) and dimethylformamide (25 ml) were added l-ethyl-3- (3- dimethyla inopropyl)carbodiimide hydrochloride (939 mg) and 1-hydroxybenzotriazole (717 mg) . After being stirred for 4 hours at ambient temperature, the mixture was poured into

/13485

- 55 - water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane - methanol) to give 8-[2, 6-dichloro-3-[N-[ (E)-3- (6-ethoxycarbonylpyridin- 3-yl)acryloylglycyl]-N-methylamino]benzyloxy]-2- methylquinoline (2.07 g) as an amorphous powder.

NMR (CDC1 ₃ , δ) : 1.45 (3K, t, J=7.5Hz), 2.72 (3H, s) , 3.27 (3H, s), 3.70 (IH, dd, J=18, 4Hz) , 3.94 (IH, dd, J=18, 4Hz), 4.49 (2H, q, J=7.5Hz), 5.59-5.70

(2H, m) , 6.66 (IH, d, J=16Hz) , 6.80 (IH, t-like) , 7.22-7.35 (3H, m) , 7.37-7.53 (3H, m) , 7.60 (IH, d, J=16Hz), 7.88-7.94 (IH, ) , 8.02 (IH, d, J=8Hz) , 8.12 (IH, d, J=8Hz), 8.81-8.86 (IH, )

Example 2

The following compounds were obtained according to a similar manner to that of Example 1.

(l) 8-[3-[N-[ (E)-3-(6-Aminopyridin-3-yl)acryloylglycyl]-N- methylaminoj-2, 6-dichlorobenzyloxy]-2-methylquinoline NMR (CDCI3, δ) : 2.73 (3H, s), 3.27 (3H, s), 3.65 (IH, dd, J=17, 4Hz), 3.94 (IH, dd, J=17, 5Hz) , 4.75 (2H, s), 5.64 (2H, s), 5.84 (IH, d, J=10Hz) , 6.30 (IH, d, J=15Hz), 6.48 (IH, d, J=8.5Hz), 6.62 (IH, br t,

J=4Hz), 7.23-7.35 (3H) , 7.39-7.52 (4H) , 7.60 (IH, dd, J=8.5, 1.5Hz), 8.02 (IH, d, J=8.5HZ), 8.16 (IH, d, J=1.5HZ)

(2) 8-[2,6-Dichloro-3-[N-[4-(methoxycarbonyl)cinnamoyl¬ glycyl]-N-methylamino]benzyloxy]-2-methylquinoline NMR (CDCI3, δ) : 2.74 (3H, s), 3.27 (3H, s) , 3.64 (IH, dd, J=18, 4Hz), 3.87-4.00 (4H, m) , 5.60-5.70 (2H, ), 6.57 (IH, d, J=16Hz), 6.75 (IH, t-like), 7.24- 7.63 (11H, m) , 7.99-8.05 (IH, m)

(3) 8- [2, 6-Dichloro-3- [N- [4- (ethoxycarbonylmethoxy) - cinnamoylglycyl] -N-methylamino]benzyloxy] -2- methylquinoline

NMR (CDC1 ₃ , δ) : 1.31 (3H, t, J=7.5Hz), 2.75 (3H, s), 3.26 (3H, s), 3.65 (IH, dd, J=18, 4Hz) , 3.95 (IH, dd, J=18, 5HZ), 4.29 (2H, q, J=7.5Hz), 4.64 (2H, s), 5.64 (IH, d, J=9Hz), 5.67 (IK, d, J=9Hz) , 6.35 (IH, d, J=15Hz), 6.57 (IH, br t, J=5Hz) , 6.85-6.93 (2H, m) , 7.21-7.34 (3H, m) , 7.37-7.58 (6H, m) , 8.03 (IH, d, J=8Hz)

(4) 8- [3- [N- [3- (4-Acetamidophenyl)propionylglycyl] -N- methylamino] -2, 6-dichlorobenzyloxy] -2-methylquinoline NMR (CDCI3, δ) : 2.04 (3H, s) , 2.51 (2H, t, J=7.5Hz), 2.68 (3H, s), 2.88 (2H, t, J=7.5Hz), 3.21 (3H, s),

3.44 (IH, dd, J=4, 18Hz) , 3.70 (IH, dd, J=5, 18Hz) ,

5.59 (2H, s-like), 6.38 (IK, t-like), 7.06 (2H, d, J=8Hz), 7.13 (IH, d, J=8Hz) , 7.21-7.34 (3H, m) , 7.34-7.49 (4H, m) , 8.04 (IH, d, J=8Hz) , 8.15 (IH, s)

its hydrochloride

NMR (DMSO-d ₆ , δ) : 2.01 (3H, s) , 2.39 (2H, t, J=7.5Hz), 2.70 (2H, t, J=7.5Hz), 2.90 (3H, s) , 3.12 (3H, s) , 3.41 (IH, dd, J=5, 18Hz), 3.73 (IH, dd, J=5, 18Hz) ,

5.60 (IH, d, J=10Hz), 5.66 (IH, d, J=10Hz) , 7.08 (2H, d, J=8Hz), 7.44 (2H, d, J=8Hz), 7.76-7.99 (6H, m) , 8.10 (IH, t, J=8Hz), 8.98 (IH, brpeak)

(5) 8- [2, 6-Dichloro-3- [N-methyl-N- [3- [4- (methylcarbamoyl) - phenyl]propionylglycyl] amino]benzyloxy]-2- methylquinoline NMR (CDCI3, δ) : 2.51 (2H, t, J=7.5Hz), 2.71 (3H, s) ,

2.93-3.01 (5H, m) , 3.23 (3H, s) , 3.46 (IH, dd, J=4, 18Hz), 3.78 (IH, dd, J=4, 18Hz) , 5.63 (2H, s) , 6.17

- 57 -

(IH, q-like) , 6. 36 ( IH, t-like) , 7 .20-7 . 33 (5H, m) , 7 . 37-7 . 50 ( 3H, m) , 7 . 66 (2H, d, J=8Hz ) , 8 . 03 ( IH, d, J=8Hz )

its hydrochloride

NMR (DMSO-d ₆ , δ) : 2.46 (2H, t, J=7.5Hz), 2.76 (3H, d, J=5Hz), 2.82 (3H, t, J=7.5Hz), 2.90 (3H, s) , 3.13 (3H, s), 3.43 (IH, dd, J=5, 16Hz), 3.73 (IH, dd, J=5, 16Hz), 5.60 (IH, d, J=10Hz) , 5.66 (IH, d, J=10Hz), 7.26 (2H, d, J=8Hz) , 7.72 (2H, d, J=8Hz) ,

7.77-8.01 (6H, m) , 8.13 (IH, t-like), 8.38 (IH, q-like), 8.94-9.04 (IH, )

(6) 8-[2, 6-Dichloro-3-[N-methyl-N-[3- [4- (2- pyridylmethylcarbamoyl)phenyl]propionylglycyl]amino]- benzyloxy]-2-methylquinoIine

NMR (CDC1 ₃ , δ) : 2.54 (2H, t, J=7.5Hz), 2.73 (3H, s) , 3.00 (2H, t, J=7.5Hz), 3.22 (3H, s) , 3.47 (IH, dd, J=4, 17Kz), 3.79 (IH, dd, J=5, 17Hz) , 4.75 (2H, d, J=6Hz), 5.64 (2H, s) , 6.38 (IH, t-like), 7.17-7.57

(11H, ) , 7.68 (IH, td, J=8, 2Hz) , 7.79 (2H, d, J=8Hz), 8.03 (IH, d, J=8Hz) , 8.56 (IH, d, J=5Hz)

its dihydrochloride NMR (DMSO-d ₆ , δ) : 2.47 (2H, t, J=7.5Hz), 2.83 (2H, t,

J=7.5Hz), 2.90 (3H, s) , 3.13 (3H, s) , 3.43 (IH, dd, J=4, 16Hz), 3.73 (IH, dd, J=4, 16Hz) , 4.78 (2H, d, J=5Hz), 5.60 (IH, d, J=10Hz), 5.65 (IH, d, J=10Hz) , 7.32 (2H, d, J=8Hz), 7.75-8.00 (10H, m) , 8.15 (IH, t, J=5Hz), 8.40 (IH, t, J=8Hz) , 8.78 (IH, d,

J=5Hz), 8.95 (IH, d-like) , 9.40 (IH, t, J=5Hz)

(7) 8-[2, 6-Dichloro-3-[N-methyl-N-TN-[4- (methylcarbamoyl)- phenyl]glycylglycyl]amino]benzyloxy]-2-methylquinoline mp : 280.1°C

NMR (DMSO-d ₆ , δ) : 2.59 (3H, s), 2.74 (3H, d, J=5Hz), 3.12 (3H, s), 3.40 (IK, dd, J=17, 4Hz), 3.65 (IH, dd, J=17, 5Hz), 3.71 (2H, d, J=6Hz) , 5.46 (IH, d, J=9Hz), 5.52 (IH, d, J=9Hz) , 6.44-6.60 (3H, m) , 7.32-7.69 (6H, m) , 7.75 (2H, s) , 7.94-8.10 (2H, m) ,

8.20 (IH, d, J=8Hz)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.97 (3K, s), 3.04 (3H, s), 3.21 (3H, s), 3.80 (2H, s), 3.93 (IH, d, J=17Hz) , 4.00

(IH, d, J=17Hz), 5.60 (IH, d, J=9Hz), 5.65 (IH, d, J=9Hz), 6.86-6.95 (2H, d, J=9Hz) , 7.45-7.68 (5H, m) , 7.70-7.90 (3H, m) , 8.80 (IH, d, J=8Hz)

(8) 8- [2, 6-Dichloro-3- [N-methyl-N-[ [6- (methylcarbamoyl)- naphthalene-2-carbonyl]glycyl] amino]benzyloxy]-2- methylquinoline

NMR (CDCI3, δ) : 2.70 (3K, s), 3.04 (3H, d, J=4.5Hz), 3.27 (3H, s), 3.75 (IH, dd, J=17, 4Hz) , 4.03 (IH, dd, J=17, 5Hz), 5.64 (2H, s), 6.59 (IH, br q,

J=4.5Hz), 7.26-7.50 (6H, ) , 7.36 (IH, br t, J=4.5Hz), 7.84-7.95 (4H, m) , 8.03 (IH, d, J=8Hz) , 8.31 (2H, br d, J=8Hz)

(9) 8- [2, 6-Dichloro-3-[N-[ (2-methoxycarbonyl-3- methylquinoline-6-carbonyl)glycyl]-N- methylamino]benzyloxy]-2-methylquinoline

NMR (CDCI3, δ) : 2.70 (3H, s), 2.75 (3H, s) , 3.30 (3H, s), 3.79 (IH, dd, J=4, 18Hz) , 4.01-4.11 (5H, m) , 5.67 (2H, s), 7.25-7.55 (7H, m) , 8.00-8.15 (3H, m) ,

8.24 (IH, d, J=8Hz), S.29 (IK, d, J=2Hz)

(10) 8- [2, 6-Dichloro-3-[N-methyl-N-[4-

(methylcarbamoyl) cinnamoylglycyl]amino]benzyloxy]-4- methoxy-2-methylquinoline

NMR (CDCI3, δ) : 2.67 (3H, s) , 3.00 (3H, d, J=5Hz) ,

3.26 (3H, s), 3.15 (IH, dd, J=17, 4Hz) , 3.92 (IH, dd, J=17, 5Hz), 4.02 (3H, s) , 5.59 (IH, d, J=10Hz), 5.63 (IK, d, J=10Hz), 6.38 (IH, br d, J=5Hz) , 6.52 (IH, d, J=15Hz), 6.65 (IH, s) , 6.76 (IH, br s), 7.21-7.31 (2H, m) , 7.38 (IH, t, J=8Hz) , 7.43-7.61 (4H, m) , 7.75 (2H, d, J=8Hz) , 7.83 (IH, d, J=8Hz)

its hydrochloride

NMR (CDCI3-CD3OD, δ) : 2.99 (3H, s) , 3.00 (3H, br s) ,

3.29 (3H, s), 3.89 (IH, c, J=17Hz) , 4.10 (IH, d,

J=17Hz), 4.36 (3H, s) , 5.51 (IK, d, J=10Hz) , 5.68 (IH, d, J=10Hz), 6.63 (IH, d, J=15Hz) , 7.35-7.43

(2H, ) , 7.48-7.59 (6H, m) , 7.70-7.81 (4H, m) , 7.95 (IH, d, J=8Hz)

(11) 8-[3-[N-[ (E)-3-(6-Acetylaminopyridin-3- yl) acryloylglycyl]-N-methylamino]-2, 6- dichlorobenzyioxy]- -methoxy-2-methylquinoline NMR (CDCI3, δ) : 2.21 (3H, s) , 2.69 (3H, s) , 3.27 (3H, s), 3.67 (IH, dd, J=17, 4Hz) , 3.94 (IH, dd, J=17, 5Hz), 4.01 (3H, s), 5.59 (IH, d, J=10Hz) , 5.64 (IH, d, J=10Hz), 6.48 (IH, d, J=15Hz) , 6.65 (IH, s) , 6.74 (IH, br t, J=5Hz) , 7.23 (IH, d, J=8Hz) , 7.30 (IH, d, J=8Hz), 7.38 (IH, t, J=8Hz) , 7.48 (IH, d,

J=8Hz), 7.51 (IH, d, J=15Hz) , 7.81 (IH, br d, J=8Hz), 8.11 (IH, br s), 8.19 (IH, br d, J=8Hz) , 8.32 (IH, br s)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.42 (3H, s) , 3.04 (3H, S), 3.28 (3H, s), 3.90 (IH, d, J=17Hz), 4.26 (IH, d, J=17Hz), 4.38 (3H, s) , 5.48 (IH, d, J=10Hz) , 5.68 (IH, d, J=10Hz), 6.92 (IH, d, J=15Hz) , 7.34-7.41 (2H, ), 7.51-7.59 (2H, m) , 7.62 (IH, d, J=8Hz) ,

7 . 74 ( IH, t , J=8Hz ) , 7 . 96 ( IH, d, J=8Hz ) , 8 . 09 ( IH d, J=8Hz ) , 8 . 52 ( IH, br d, J=8Hz ) , 8 . 87 ( IH, br s )

(12) 8- [2, 6-Dichloro-3- [N-methyl-N- [ (E) -3- [6- (methylamino) pyridin-3-yl] acryloylglycyl] amino] - benzyloxy] -2-methylquinoline NMR (CDC1 ₃ , δ) : 2.73 (3H, s), 2.96 (3H, d, J=5Hz),

3.27 (3H, s), 3.63 (IK, dd, J=4, 17Hz), 3.94 (IK, dd, J=4, 17Hz), 4.83 (IH, q-like), 5.59-5.70 (2H, m) , 6.27 (IH, d, J=16Hz) , 6.38 (IH, d, J=8Hz) , 6.5

(IH, t-like), 7.23-7.34 (3H, m) , 7.36-7.51 (4H, m) 7.60 (IH, dd, J=8, 2Hz), 8.01 (IH, d, J=8Hz) , 8.20 (IH, d, J=2Hz)

(13) 8- [3- [N- [3- (6-Acetamidopyridin-3-yl) propionylglycyl] -N- methylamino] -2, 6-dichlorobenzyloxy] -2-methylquinoline NMR (CDCI3, δ) : 2.20 (3H, s) , 2.46 (2H, t, J=7.5Hz), 2.73 (3H, s), 2.88 (2H, t, J=7.5Hz), 3.23 (3H, s) , 3.50 (IH,- dd, J=4, 17Hz), 3.84 (IH, dd, J=5, 17Hz) , 5.56-5.69 (2H, ) , 6.96 (IH, t-like), 7.16-7.33

(3H, m) , 7.33-7.56 (4H, m) , 7.95-8.05 (2H, m) , 8.11 (IH, d, J=8Hz), 8.69 (IH, s)

(14) 8- [3- [N-[2- (2-Benzothiazolylamino)acetylglycyl]-N- methylamino] -2, 6-dichlorobenzyloxy]-2-methylquinoline

NMR (CDCI3, δ) : 2.64 (3H, s) , 3.21 (3H, s) , 3.91 (2H, t, J=5Hz), 4.10 (IH, d, J=16Hz), 4.20 (IH, d, J=16Hz), 5.58 (2H, s) , 6.85-7.35 (7H, ) , 7.40-7.61 (5H, m) , 8.05 (IH, d, J=8Hz)

Example 3

To a solution of 8- [2, 6-dichloro-3- [N- [ (E) -3- (6- ethoxycarbonylpyridin-3-yl) acryloylglycyl]-N- methylamino]benzyloxy] -2-methylquinoline (2.07 g) in ethanol (20 ml) was added IN sodium hydroxide solution (3.75 ml) at

ambient temperature. The mixture was stirred for 3 hours at 60°C. The reaction mixture was adjusted to pH 4 with IN hydrochloric acid and concentrated. The residue was purified by flash chromatography (dichloromethane - methanol) to give 8-[3-[N-[ (E) -3- (6-carboxypyridin-3-yl)acryloylglycyl]-N- methylamino]-2, 6-dichlorobenzyloxy]-2-methylquinoline (1.71 g) as an amorphous powder.

NMR (DMSO-d ₆ , δ) : 2.58 (3H, s), 3.13 (3H, s) , 3.50

(IH, dd, J=4, 16Hz), 3.80 (IH, dd, J=4, 16Hz), 5.46 (IH, d, J=10Hz), 5.53 (IH, d, J=10Hz) , 6.95 (IH, d,

J=16Hz), 7.30-7.57 (5H, m) , 7.78 (2H, s-like), 8.02 (IH, d, J=8Hz), 8.10 (IH, d, J=7.5Hz), 8.20 (IH, d, J=8Hz), 8.45 (IH, t-like), 8.85 (IH, s-like)

Example 4

8- [3-[N- (4-Carboxycinnamoylglycyl)-N-methylamino]-2, 6- dichlorobenzyloxy]-2-methylquinoline was obtained according to a similar manner to that of Example 3. mp : 237.8-240.9°C NMR (DMSO-d ₆ , δ) : 2.61 (3H, s) , 3.15 (3H, s) , 3.51

(IH, dd, J=4, 18Hz), 3.81 (IH, dd, J=4, 18Hz) , 5.48 (IH, d, J=10Hz), 5.54 (IH, d, J=10Hz) , 6.90 (IH, d, J=16Hz), 7.32-7.60 (5H, ) , 7.64-7.75 (2H, m) , 7.75-7.85 (2H, ) , 7.96 (2H, d, J=8Hz) , 8.21 (IH, d, J=8Hz), 8.35-8.44 (IH, m)

Example 5

To a mixture of 8-[3-[N-[ (E) -3-(6-aminopyridin-3- yl) acryloylglycyl]-N-methylamino]-2, 6-dichlorobenzyloxy]-2- methylquinoline (90.0 mg) , 2-pyrazinecarboxylic acid (24.3 mg) and dimethylformamide (0.9 ml) were added l-ethyl-3- (3- dimethylaminopropyl)carbodiimide hydrochloride (43.9 mg) and 1-hydroxybenzotriazole (35.4 mg) . After being stirred for 37 hours at ambient temperature, the mixture was poured into saturated sodium bicarbonate solution and extracted with

chloroform. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform -methanol) to give 8- [2, 6- dichloro-3- [N-methyl-N- [ (E) -3- [6- (2-pyrazinecarboxamido) - pyridin-3-yl] acryloylglycyl] amino]benzyloxy] -2- methylquinoline (43.7 mg) as a solid, mp : 220-231°C

NMR (CDC1 ₃ , δ) : 2.72 (3H, s) , 3.28 (3H, s), 3.69 (IH, dd, J=16.5, 4.5Hz), 3.96 (IH, dd, J=16.5, 4.5Hz),

5.64 (2K, s), 6.52 (IH, d, J=16.0Hz), 6.73 (IH, br t, J=4.5Hz), 7.22-7.51 (7K, m) , 7.56 (IH, d, J=16.0Hz), 7.92 (IH, dd, J=8.5, 1.0Hz), 8.03 (IK, d, J=8.5Hz), 8.42 (IH, d, J=8.5Hz), 8.47 (IK, d, J=1.0Hz), 8.62 (IH, d, J=1.0Hz), 8.83 (IH, d,

J=1.0Hz), 9.51 (IH, s)

its trihydrochloride mp : 190-193°C NMR (DMSO-d ₆ , δ) : 2.92 (3H, s), 3.17 (3H, s), 3.60

(IH, dd, J=16.5, 4.5Hz), 3.91 (IH, dd, J=16.5, 4.5Hz), 5.62 (IH, d, J=11.0Hz), 5.68 (IH, d, J=11.0Hz), 6.88 (IH, d, J=16.0Hz), 7.43 (IH, d, J=16.0Hz), 7.80-8.00 (5H, ) , 8.14 (IH, dd, J=8.5, 1.0Hz), 8.31 (IH, d, J=8.5Hz), 8.37 (IH, t,

J=4.5Hz), 8.61 (IH, d, J=1.0Hz), 8.86 (IH, m) , 8.95-9.03 (2K, m) , 9.35 (IH, s)

Example 6 The following compounds were obtained according to a similar manner to that or Example 5.

(1) 8- [2, 6-Dichloro-3- [N-methyl-N- [ (E)-3-[6-(6- methylpyridine-3-carboxamido)pyridin-3-yl]- acryloylglycyl] amino]benzyloxy] -2-methyIquinoline

485

- 63 - p : 167-177°C

NMR (CDCI3, δ) : 2.65 (3H, s), 2.73 (3H, s), 3.27 (3H, s), 3.67 (IH, dd, J=16.5, 4.5Hz), 3.96 (IH, dd, J=16.5, 4.5Hz), 5.62 (IH, d, J=11.0Hz), 5.69 (IH, d, J=11.0Hz), 6.51 (IH, d, J=16.0Hz), 6.72 (IH, br t, J=4.5Hz), 7.23-7.33 (4H, m) , 7.38-7.46 (2H, rc) , 7.49 (IH, d, J=8.5Hz), 7.55 (IH, d, J=16.0Hz), 7.90 (IH, dd, J=8.5, l.OHz), 8.03 (IH, d, J=8.5Hz), 8.13 (IH, dd, J=8.5, l.OHz), 8.38 (IH, d, J=8.5Hz), 8.40 (IH, d, J=1.0Hz), 8.71 (IH, s) , 9.04 (IH, d,

J=l.OHz)

its trihydrochlcride mp : 198-213°C NMR (DMSO-d ₆ , δ) : 2.72 (3H, s) , 2.93 (3H, s) , 3.17

(3H, ε), 3.62 (IH, dd, J=16.5, 4.5Hz), 3.91 (IH, dd, J=16.5, 4.5Hz), 5.66 (2H, s) , 6.88 (IH, d, J=16.0Hz), 7.44 (IH, d, J=16.0Hz), 7.75-8.01 (8H, m), 8.08-8.18 (IH, ) , 8.26 (IH, d, J=8.5Hz), 8.32- 8.42 (IH, m), 8.59-8.70 (2H, m) , 8.93-9.07 (IH, m) ,

9.20 (IH, s)

(2) 8-[2, 6-Dichloro-3-[N-methyl-N-[ (E)-3-[6-(2- methylthiopyridine-3-carboxamido)pyridin-3-yl]- acryloylglycyl]amino]benzyloxy]-2-methylquinoline

NMR (CDCI3, δ) : 2.61 (3K, s), 2.73 (3H, s), 3.26 (3H, s), 3.68 (IH, dd, J=5, 18Hz), 3.95 (IH, dd, J=5, 18Hz), 5.65 (2H, s-like), 6.51 (IH, d, J=16Hz), 6.79 (IH, t-like), 7.13 (IH, dd, 3=6, 8Hz) , 7.24- 7.35 (3H, m), 7.35-7.61 (4H, m) , 7.90 (IH, dd, J=2,

8Hz), 7.95 (IH, dd, 3=2 , 8Hz) , 8.03 (IH, d, J=8Hz), 8.35-8.45 (2H, m) , 8.58 (IH, dd, 3=2 , 6Hz), 8.89 (IH, s)

its trihydrochloride

- 64 -

NMR (DMSO-d ₆ , δ) : 2.49 (3H, s), 2.91 (3H, s),

3.16 (3H, s), 3.60 (IH, d, J=18Hz), 5.57-5.71 (2H, m) , 6.86 (IH, d, J=16Hz), 7.23 (IH, dd, 3=6 , 8Hz) , 7.41 (IH, d, J=16Hz), 7.75-8.03 (7H, m) , 8.03-8.15 (IH, m) , 8.22 (IH, d, J=8Hz) , 8.29-8.40 (IH, m) ,

8.51-8.65 (2H, m) , 8.98 (IH, brpeak)

(3) 8- [2, 6-Dichloro-3- [N-methyl-N- [ (E)-3-[6-[ (2- pyridyl) acetamido]pyridin-3-yl] acryloylglycyl] amino] - benzyloxy]-2-methylquinoline

NMR (CDC1 ₃ , δ) : 2.74 (3H, s), 3.26 (3H, s), 3.65 (IH, dd, 3=4 , 18Hz), 3.86-4.00 (3K, m) , 5.68-5.70 (2H, m) , 6.44 (IH, m, J=16Hz) , 6.64 (IH, t-like), 7.20- 7.35 (6H, ) , 7.35-7.55 (4H, m) , 7.70 (IH, td, J=8, 2Hz), 7.80 (IH, dd, J=8, 2Hz) , 8.03 (IH, d, J=8Hz),

8.21 (IH, d, J=8Hz), 8.39 (IH, d, J=2Hz) , 8.70 (IH, d, J=6Hz)

its trihydrochloride NMR (CDCI3, δ) : 2.86 (3H, s) , 3.14 (3H, s), 3.57 (IH, dd, 3=4 , 16Hz), 3.87 (IH, dd, 3=4 , 16Hz) , 4.32 (2H, s), 5.55-5.66 (2H, m) , 6.81 (IH, d, J=16Hz) , 7.38 (IH, d, J=16Hz), 7.71-7.95 (10H, m) , 7.95-8.10 (IH, m) , 8.31 (IH, t, J=6Hz), 8.40 (IH, t, J=8Hz) , 8.53 (IH, d, J=2Hz), 8.83 (IH, d, J=6Hz) , 8.90 (IH, brpeak)

(4) 8- [2, 6-Dichloro-3- [N-methyl-N- [ (E)-3-[6-[ (3- pyridyl) acetamido]pyridin-3-yl] acryloylglycyl]amino] - benzyloxy] -2-methylquinoline

NMR (CDCI3, δ) : 2.73 (3H, s), 3.27 (3K, s), 3.66 (IH, dd, J=4, 18Hz), 3.75 (2H, s), 3.94 (IH, dd, J=4, 18Hz), 5.59-5.70 (2H, m) , 6.46 (IH, d, J=16Hz) , 6.67 (IH, t-like), 7.20-7.36 (4H, m) , 7.36-7.55 (4H, m) , 7.70 (IH, d, J=8Hz) , 7.83 (IH, dd, 3=2 ,

8Hz ) , 7 . 97-8 . 06 (2H, m) , 8 . 19 ( IH, d, J=8Hz ) , 8 . 33 ( IH, d, J=2Hz ) , 8 . 54- 8 . 62 ( 2H, m)

its trihydrochloride NMR (DMS0-d ₆ , δ) : 2.88 (3H, s), 3.15 (3K, s) , 3.57

(IH, dd, J=4, 16Hz), 3.89 (IH, dd, 3=4 , 16Hz), 4.09 (2H, s), 5.57-5.70 (2H, m) , 6.81 (IH, d, J=16Hz), 7.38 (IH, d, J=16Hz), 7.75-7.95 (8H, m) , 7.95-8.10 (2H, m) , 8.30 (IH, t, J=6Hz), 8.49 (IH, d, J=8Hz) , 8.53 (IH, d, J=2Hz), 8.83 (IH, d, J=6Hz) , 8.88 (IH, s-like), 8.93 (IH, brpeak)

(5) 8-[2, 6-Dichloro-3-[N-methyl-N-[ (E)-3-[6-(2- pyridinecarboxamido)pyridin-3-yl]acryloylglycyl]amino]- benzyloxy]-2-methylquinoline

NMR (CDC1 ₃ , δ) : 2.75 (3H, s) , 3.27 (3H, s) , 3.68 (IH, dd, J=5, 18Hz), 3.95 (IH, dd, 3=5, 18Hz) , 5.60-5.70 (2H, ) , 6.51 (IH, d, J=16Hz), 7.23-7.30 (3H, m) , 7.33 (IH, d, J=8Hz), 7.38-7.61 (5H, m) , 7.87-7.96 (2H, m) , 8.03 (IH, d, J=8Hz) , 8.30 (IH, d, J=8Hz) , 8.41-8.49 (2H, m) , 8.65 (IH, d, J=5Hz)

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.93 (3H, s) , 3.15 (3H, s), 3.60 (IH, dd, J=5, 16Hz), 3.92 (IH, dd, J=5, 16Hz), 5.63

(IH, d, J=10Hz), 5.70 (IH, d, J=10Hz) , 6.86 (IH, d, J=16Hz), 7.43 (IH, d, J=16Hz), 7.70-8.03 (8H, m) , 8.09-8.19 (2H, m) , 8.24 (IH, d, J=8Hz) , 8.30-8.40 (2H, ) , 8.58 (IH, d, J=2Hz) , 8.78 (IH, d, J=5Hz) , 9.03 (IH, br d, J=8Hz)

(6) 8-[2, 6-Dichloro-3-[N-methyl-N-[ (E)-3-[6-(3- pyridinecarboxamido)pyridin-3-yl]acryloylglycyl]- amino]benzyloxy]-2-methylquinoline NMR (CDCI3, δ) : 2.71 (3H, s), 3.26 (3H, s) , 3.68 (IH,

dd, J=4, 18Hz), 3.93 (IH, dd, 3=4, 18Hz) , 5.56-5.70 (2H, m) , 6.52 (IH, d, J=16Hz), 6.72 (IH, t-like), 7.21-7.56 (10H, m) , 7.89 (IH, dd, 3=2, 8Hz) , 8.00-8.10 (2H, m) , 8.41 (IH, d, J=2Hz) , 8.71 (IH, d, J=6Hz), 8.92 (IH, d, J=2Hz)

its trihydrochloride

NMR (CDC1 ₃ , δ) : 2.92 (3H, s), 3.15 (3H, s), 5.59-5.72 (2H, m) , 6.86 (IH, d, J=16Hz), 7.43 (IH, d, J=16Hz), 7.60-8.01 (6K, m) , 8.10 (IH, dd, J=2,

8Hz), 8.25 (IH, d, J=8Hz) , 8.31-8.49 (2H, m) , 8.53- 8.65 (2H, m) , 8.88 (IH, d, J=6Hz) , 8.95-9.04 (IH, m) , 9.13 (IH, s-like), 9.23 (IH, s-like)

(7) 8- [2, 6-Dichloro-3-[N-[ (E)-3-[6- (2-methoxypyridine-3- carboxamido)pyridin-3-yl]acryloylglycyl]-N- methylamino]benzyloxy]-2-methylquinoline

NMR (CDCI3, δ) : 2.71 (3H, s), 3.26 (3H, s) , 3.67 (IH, dd, 3=4, 16Hz), 3.94 (IH, dd, 3=4, 16Hz) , 4.23 (3H, s), 5.57-5.70 (2H, m) , 6.50 (IH, d, J=16Hz) , 6.74

(IH, t-like), 7.12 (IH, dd, J=8, 6Hz) , 7.20-7.35 (4H, m) , 7.35-7.50 (3H, m) , 7.55 (IH, d, J=16Hz) , 7.87 (IH, dd, 3=2, 8Hz) , 8.03 (IH, d, J=8Hz) , 8.35 (IH, dd, J=6, 2Hz), 8.38-8.48 (2H, m) , 8.57 (IH, dd, J=8, 2Hz)

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.95 (3H, s) , 3.16 (3H, s) , 3.60

(IH, dd, 3=4, 16Hz), 5.55-5.72 (2H, m) , 6.60 (IH, t, J=8Hz), 6.85 (IK, d, J=16Hz) , 7.40 (IH, d,

J=16Hz), 7.65-8.01 (8H, m) , 8.01-8.12 (IH, m) ,

8.20-8.41 (2H, m) , δ.43-8.60 (2K, m) , 8.99 (IH, brpeak)

(8) 8- [2, 6-Dichloro-3- [N-methyl-N- [ (E)-3-[6- (2-

methylpyridine-3-carboxamido)pyridin-3- yl]acryloylglycyl]amino]benzyloxy]-2-methylquinoline NMR (CDCI3, δ) : 2.71 (IH, s), 2.76 (3H, s) , 3.25 (3H, s), 3.69 (IH, dd, 3=4 , 18Hz) , 3.95 (IH, dd, J=5, 18Hz), 5.63 (3H, s) , 6.48 (IH, d, J=16Hz), 6.87 (IH, t-like), 7.18-7.37 (4H, m) , 7.37-7.57 (4H, m) , 7.85 (IH, dd, J=2, 8Hz), 7.89 (IH, dd, J=2, 8Hz) , 8.04 (IH, d, J=8Hz), 8.20 (IH, d, J=2Hz) , 8.37 (IH, d, J=8Hz), 8.63 (IH, d, J=6Hz) , 8.93 (IH, s)

(9) 8-[2, 6-Dichloro-3-[N-methyl-N-[ (E) -3-[6-[2- (6-methyl-3- pyridyl)acetamido]pyridin-3-yl]acryloylglycyl]amino]- benzyloxy]-2-methylσuinoline

NMR (CDCI3, δ) : 2.57 (3H, s) , 2.73 (3H, s), 3.26 (3H, s), 3.66 (IH, dd, 3=4 , 18Hz) , 3.72 (2H, s) , 3 . 94

(IH, dd, 3=4 , 18Hz), 5.58-5.70 (2H, m) , 6.46 (IH, d, J=16Hz), 6.68 (IH, t-like) 7.18 (IH, d, J=8Hz) , 7.23-7.62 (8H, ) , 7.81 (IH, dd, J=2, 8Hz) , 7.98- 8.05 (2H, m) , 8.19 (IH, d, J=8Hz) , 8.32 (IH, d, J=2Hz), 8.45 (IH, d, J=2Hz)

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.74 (3H, s) , 2.89 (3H, s) , 3.14 (3H, s), 3.57 (IH, dd, J=4, 16Hz) , 3.88 (IH, dd, J=4, 16Hz), 4.04 (2H, s) , 5.56-5.70 (2H, m) , 6.81

(IH, d, J=16Hz), 7.40 (IH, d, J=16Hz), 7.78-8.13 (10H, m) , 8.32 (IH, t-like), 8.42 (IH, dd, 3=2, 8Hz), 8.53 (IH, d, J=2Hz) , 8.75 (IH, d, J=2Hz) , 8.94 (IH, brpeak)

(10) 8-[2, 6-Dichloro-3-[N-methyl-N-[ (E) -3-[6-[2- (2-methyl-3- pyridyl)acetamido]pyridin-3-yl]acryloylglycyl]amino]- benzyloxy]-2-methylquinoline

NMR (CDCI3, δ) : 2.58 (3H, s), 2.73 (3H, s) , 3.26 (3H, S), 3.65 (IH, dd, J=4, 18Hz), 3.77 (2H, s) , 3.93

- 68 -

(IH, dd, J=5, 18Hz), 5.60-5.70 (2H, m) , 6.47 (IH, d, J=16Hz), 6.68 (IH, t-like), 7.18 (IH, dd, 3=6, 8Hz), 7.22-7.35 (3K, m) , 7.35-7.59 (5H, m) , 7.80- 7.90 (2H, m) , 8.02 (IH, d, J=8Hz), 8.21 (IH, d, J=8Hz) , 8.32 (IH, d, J=2Hz) , 8.50 (IH, d, J=6Hz)

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.74 (3H, s) , 2.90 (3H, s), 3.15 (3H, s), 3.56 (IH, dd, J=5, 16Hz), 4.11 (2H, s) , 5.56-5.69 (2H, m) , 6.31 (IH, d, J=16Hz) , 7.38 (IH, d, J=16Hz), 7.76-8.10 (10H, m) , 8.31 (IH, t-like), 8.47 (IH, d, J=8Hz), 8.53 (IH, d, J=2Hz) , 8.71 (IH, dd, 3=2, 6Hz), 8.95 (IH, br s)

Example 7

To a mixture of 8- [3-[N-[ (E)-3- (6-carboxypyridin-3-yl)- acryloylglycyl]-N-methylamino]-2, 6-dichlorobenzyloxy]-2- methylquinoline (100 mg) , 2-aminopyrazine (19.7 mg) and N,N- dimethylformamide (2 ml) were added l-ethyl-3- (3- dimethylaminopropyl)carbodiimide hydrochloride (43 mg) and 1- hydroxybenzotriazole (35 mg) , and the mixture was stirred for 36 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride - methanol) to give 8- [2, 6-dichloro-3-[N-methyl-N-[ (E)-3-[6- (2-pyrazinylcarbamoyl)- pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2- methylquinoline (21 mg) as an amorphous powder.

NMR (CDC1 ₃ , δ) : 2.71 (3H, s) , 3.30 (3H, s), 3.76 (IH, d, J=16Hz), 4.02 (IH, d, J=16Hz), 5.64 (2H, s) , 6.71 (IH, d, J=16Hz), 7.22-7.43 (3H, m) , 7.43-7.58 (3H, m) , 7.64 (IH, d, J=16Hz) , 7.99 (IH, dd, J=2, 8Hz), 8.09 (IH, d, J=8Hz) , 8.23 (IH, d, J=8Hz) ,

8 . 33-8 . 47 (2H, m) , 8 . 71 ( IH, s-like ) , 9. 25 ( IH, s )

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.85 (3H, s), 3.15 (3H, s) , 3.91 (IH, dd, J=5, 18Hz), 5.55-5.69 (2H, m) , 7.08 (IH, d, J=16Hz), 7.55 (IH, d, J=16Hz), 7.68-7.93 (8H, m) , 8.21-8.33 (2H, m) , 8.41-8.53 (2H, m) , 8.85 (IH, brpeak), 8.94 (IH, s-like), 9.49 (IH, s-like)

Example ^'

The following compounds were obtained according to a similar manner to that of Example 7.

(1) 8-[2, 6-Dichloro-3-[N-methyl-N-[ (E)-3-[6-(2- thiazolylcarbamoyl)pyridin-3-yl]acryloylglycyl]amino]- benzyloxy]-2-methylquinoline mp : 144-155°C

NMR (CDC1 ₃ , δ) : 2.73 (3H, s) , 3.30 (3H, s), 3.72 (IH, dd, J=16.5, 4.5Hz), 3.97 (IH, dd, J=16.5, 4.5Hz), 5.67 (2H, s), 6.70 (IH, d, J=16.0Hz), 6.83 (IH, br t, J=4.5Hz), 7.08 (IH, d, J=3.0Hz), 7.23-7.37 (4H, ) , 7.39-7.57 (4H, m) , 7.63 (IH, d, J=16.0Hz), 7.96-8.09 (2H, m) , 8.27 (IH, d, J=8.5Hz), 8.73 (IH, s)

its trihydrochloride mp : 161-165°C

NMR (DMSO-d _β , δ) : 2.93 (3H, s), 3.16 (3H, s) , 3.61 (IH, dd, J=16.5, 4.5Hz), 3.91 (IH, dd, J=16.5, 4.5Hz), 5.62 (IH, d, J=11.0Hz), 5.68 (IH, d,

J=11.0Hz), 7.10 (IH, d, J=16.0Hz), 7.37 (IH, d, J=2.5Hz), 7.54 (IH, d, J=16.0Hz), 7.59 (IH, d, J=2.5Hz), 7.80-7.99 (5H, m) , 8.21 (IH, d, J=7.5Hz), 8.27 (IH, dd, J=7.5, l.OHz), 8.49 (IH, t, J=4.5Hz), 8.91-9.03 (2H, m)

(2) 8- [2, 6-Dichloro-3-[N-[ (E)-3-[6- (1-isoquinolylcarbamoyl) pyridin-3-yl]acryloylglycyl]-N-methylamino]benzyloxy] -2 methylquinoline mp : 127-135°C NMR (CDC1 ₃ , δ) : 2.72 (3H, s) , 3.28 (3H, s), 3.72 (IH, dd, J=16.5, 4.5Hz), 3.98 (IH, dd, J=16.5, 4.5Hz), 5.64 (2H, s), 6.70 (IH, d, J=16.0Hz), 6.87 (IH, br t, J=4.5Hz), 7.23-7.47 (6H, m) , 7.51 (IH, d, J=8.5Hz), 7.57 (IH, d, J=5.5Hz), 7.60-7.70 (2H, ml 7.73 (IH, t, J=7.5Hz), 7.86 (IH, d, J=7.5Hz), 8.00

(IH, dd, J=7.5, 1.0Hz), 8.03 (IH, d, J=8.5Hz), 8.1 (IH, d, J=7.5Hz), 8.32 (IH, d, J=7.5Hz), 8.43 (IH, d, J=5.5Hz), 8.76 (IH, s)

its trihydrochloride mp : 143-145°C

NMR (DMSO-d ₆ , δ) : 2.93 (3H, s), 3.17 (3H, s) , 3.63 (IH, dd, J=16.5, 4.5Hz), 3.94 (IH, dd, J=16.5, 4.5Hz), 5.63 (IH, d, J=11.0Hz), 5.70 (IK, d, J=11.0Hz), 7.13 (IH, d, J=16.0Hz), 7.61 (IH, d,

J=16.0Hz), 7.78-8.02 (9H, m) , 8.13 (IH, d, J=8.5Hz), 8.25-8.37 (3H, m) , 8.41 (IH, d, J=7.0Hz), 8.53 (IH, t, J=4.5Hz), 8.93-9.07 (2H, m)

(3) 8-[2, 6-Dichloro-3-[N-methyl-N- [4- [ (l-oxo-3-pyridyl- methyl)carbamoyl]cinnamoylglycyl]amino]benzyloxy]-2- methylquinoline mp : 142-163°C

NMR (CDCI3, δ) : 2.70 (3H, s) , 3.25 (3H, s) , 3.63 (IH, dd, J=16.5, 4.5Hz), 3.97 (IH, dd, J=16.5, 4.5Hz),

4.51-4.62 (2H, m) , 5.64 (2H, s) , 6.56 (IH, d, J=16.0Hz), 7.03 (IH, br t, J=4.5Hz), 7.13-7.37 (6H, m) , 7.40-7.51 (5H, m) , 7.56 (IH, d, J=16.0Hz), 7.77-7.90 (3H, m) , 7.99-8.07 (2H, ) , 8.11 (IH, s)

(4) 8-[2, 6-Dichloro-3-[N-[ (E) -3-[6- (6-methoxypyridin-3- ylcarbamoyl)pyridin-3-yi]acryloylglycyl]-N- methylamino]benzyloxy]-2-methylquinoline mp : 168-183°C NMR (CDC1 ₃ , δ) : 2.73 (3H, s) , 3.27 (3H, s) , 3.70 (IH, dd, J=16.5, 4.5Hz), 3.96 (3H, s), 3.98 (IH, dd, J=16.5, 4.5Hz), 5.66 (2H, s), 6.68 (IH, d, J=16.0Hz), 6.78-6.83 (2H, m) , 7.24-7.37 (3H, m) , 7.39-7.48 (2H, ) , 7.51 (IK, d, J=8.5Hz), 7.64 (IH, d, J=16.0Hz), 7.97-8.07 (2H, m) , 8.18 (IH, dd,

J=8.5, l.OHz), 8.26 (IH, d, J=8.5Hz), 8.44 (IH, d, J=1.0Hz), 8.69 (IH, s) , 9.82 (IH, s)

(5) 8-[2, 6-Dichloro-3-[N-methyl-N-[ (E)-3-[6- (4-methyloxazol- 2-ylcarbamoyl)pyridin-3-yl]acryloylglycyl]amino]- benzyloxy]-2-methylquinoline mp : 128-139°C

NMR (CDCI3, δ) : 2.19 (3H, s) , 2.72 (3H, s) , 3.28 (3H, s) , 3.73 (IH, dd, J=16.5, 5.5Hz), 3.97 (IH, dd, J=16.5, 5.5Hz), 5.64 (2H, s), 6.69 (IH, d,

J=15.0Hz), 6.88 (IH, br t, J=5.5Hz), 7.21-7.35 (5H, m), 7.40-7.53 (3H, m) , 7.61 (IH, d, J=15.0Hz), 7.98 (IH, dd, J=8.5, l.OHz), 8.03 (IH, d, J=8.5Hz), 8.25 (IH, d, J=8.5Hz), 8.68 (IH, d, J=1.0Hz)

(6) 8-[2,6-Dichloro-3-[N-methyl-N-[ (E)-3-[6- (2-methyl-2H- pyrazoI-3-ylcarbamoyl)pyridin-3-yl]acryloylglycyl]- amino]benzyloxy]-2-methylquinoline

NMR (CDCI3, δ) : 2.74 (3H, s), 3.27 (3H, s), 3.70 (IH, dd, J=4, 18Hz), 3.85 (3H, s) , 3.95 (IH, dd, J=4,

18Hz), 5.60-5.70 (2K, ) , 6.65 (IH, d, J=16Hz), 6.75 (IH, t-like), 6.83 (IH, d, J=2Hz) , 7.20-7.36 (5H, m) , 7.36-7.54 (3H, m) , 7.62 (IH, d, J=16Hz) , 7.97 (IH, dd, J=2, 8Hz) , 8.03 (IH, d, J=8Hz) , 8.24 (IH, d, J=8Hz), 8.68 (IH, d, J=2Hz)

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.92 (3H, s), 3.15 (3H, s), 3.80 (3H, s), 3.91 (IH, dd, J=5, 16Hz), 5.61 (IH, d, J=10Hz), 5.68 (IH, d, J=10Hz) , 6.61 (IH, d, J=2Hz) , 7.06 (IH, d, J=16Hz), 7.54 (IH, d, J=16Hz) ,

7.59-7.76 (2H, ) , 7.76-8.01 (6K, m) , 8.15 (IH d, J=8Hz), 8.24 (IH, dd, J=8, 2Hz) , 8.45 (IH, t-like), 8.88 (IH, d, J=2Hz), 8.99 (IH, brpeak)

Example ^'

To a solution of 3- [N- [4- (methylcarbamoyl) - cinnamoylglycyl]-N-methylamino]-2, 6-dichlorobenzyl bromide (60 mg) and 4-ethoxy-8-hydroxy-2-methylquinoline (24.9 mg) in dimethylformamide (0.6 ml) was added potassium carbonate (48.5 mg) , and the mixture was stirred for 5 hours at ambient temperature. Water was added thereto, and the mixture was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography (dichlormethane:methanol = 15:1, V/V) to give 8-[2, 6- dichloro-3- [N-methyl-N- [4- (methylcarbamoyl) cinnamoylglycyl]- amino]benzyloxy]-4-ethoxy-2-methylquinoline (67 mg) as an amorphous powder.

NMR (CDC1 ₃ , δ) : 1.56 (3H, t, J=7.5Hz), 2.66 (3H, s) , 3.00 (3H, d, J=5Hz) , 3.26 (3H, s) , 3.65 (IH, dd,

J=17, 4Hz), 3.93 (IH, dd, J=17, 5Hz) , 4.22 (2H, q, J=7.5Hz), 5.59 (IH, d, J=10Hz) , 5.64 (IH, d, J=10Hz), 6.31 (IH, br d, J=5Hz) , 6.52 (IH, d, J=15Hz), 6.61 (IH, s), 6.73 (IH, br s) , 7.21-7.31 (2H, m) , 7.37 (IH, t, J=8Hz) , 7.43-7.61 (4H, ) ,

7.74 (2H, d, J=8Hz), 7.87 (IH, d, J=8Hz)

its hydrochloride

NMR (CDCI3-CD3OD, δ) : 1.68 (3H, br t, J=7.5Hz), 2.98 (3H, s), 3.00 (3H, s), 3.29 (3H, s), 3.88 (IH, d,

J=17Hz), 4.10 (IH, d, J=17Hz) , 4.60 (2H, q, J=7.5Hz), 5.52 (IH, d, J=10Hz) , 5.69 (IH, d, J=10Hz), 6.63 (IH, d, J=15Hz) , 7.29-7.32 (IH, overlapped with H ₂ 0) , 7.41 (IH, d, J=15Hz), 7.50- 7.60 (5H, m) , 7.72 (IK, d, J=8Hz), 7.79 (2H, d,

J=8Hz), 7.98 (IH, d, J=8Hz)

Example 10

The following compounds were obtained according to a similar manner to that of Example 9.

(1) 8- [2, 6-Dichloro-3- [N-methyl-N-[4- (methylcarbamoyl)- cinnamoylglycyl]amino]benzyloxy]-4-isopropoxy-2- methylquinoline NMR (CDC1 ₃ , δ) : 1.48 (6H, d, J=7Hz) , 2.64 (3H, s),

3.00 (3H, d, J=5Hz), 3.25 (3H, s) , 3.66 (IH, dd, J=17, 4Hz), 3.93 (IH, dd, J=17, 5Hz) , 4.75-4.85 (IH, ) , 5.59 (IH, d, J=10Hz), 5.62 (IH, d, J=10Hz), 6.32 (IH, br d, J=5Hz) , 6.52 (IH, d, J=15Hz), 6.61 (IH, s) , 6.75 (IH, br s), 7.20-7.38

(3H, m) , 7.42-7.60 (4H, m) , 7.74 (2H, ά, J=8Hz) , 7.83 (IH, d, J=8Hz)

its hydrochloride NMR (CDCI3-CD3OD, δ) : 1.60 (6H, br d, J=7Hz), 2.98

(3H, s), 2.99 (3H, s) , 3.28 (3H, s) , 3.88 (IH, d, J=17Hz), 4.15 (IH, d, J=17Hz) , 5.15-5.26 (IH, m) , 5.50 (IH, d, J=10Hz), 5.67 (IH, d, J=10Hz) , 6.64 (IH, d, J=15Hz), 7.25 (IH, br s), 7.39 (IH, d, J=15Hz), 7.49-7.61 (5H, m) , 7.71 (IH, t, J=8Hz) ,

7.79 (2H, br d, J=8Hz), 7.95 (IK, d, J=8Hz)

(2) 8-[2, 6-Dichloro-3-[N-methyl-N-[4- (methylcarbamoyl)- cinnamoylglycyl]amino]benzyloxy]-4- (2-methoxyethoxy)-2- methylquinoline

NMR (CDCI3, δ) : 2.66 (3H, s), 3.00 (3H, d, J=5Hz) , 3.24 (3H, s), 3.50 (3H, s), 3.63 (IH, dd, J=17, 4Hz), 3.87-3.98 (3H, ) , 4.29-4.33 (2H, m) , 5.61 (2H, br s), 6.31 (IH, br d, J=5Hz) , 6.52 (IH, d, J=15Hz), 6.63 (IH, s) , 6.73 (IH, br s), 7.21-7.61

(7H, ) , 7.74 (2H, d, J=8Hz) , 7.98 (IH, d, J=8Hz)

its hydrochloride

NMR (CDCI3-CD3OD, δ) : 2.99 (3H, s) , 3.00 (3H, s) , 3.28 (3H, s), 3.49 (3H, s) , 3.78 (IH, br d, J=17Hz) ,

3.92-4.00 (2H, ) , 4.13 (IH, br d, J=17Hz), 4.68- 4.75 (2H, m) , 5.52 (IH, d, J=10Hz) , 5.67 (IH, d, J=10Hz), 6.65 (IH, d, J=15Hz) , 7.32-7.60 (7H, m) , 7.69-7.82 (3H, m) , 8.00 (IH, d, J=8Hz)

(3) 8-[2, 6-Dichloro-3-[N-methyl-N-[4- (methylcarbamoyl)- cinnamoylglycyl]amino]benzyloxy]-4- (2- dimethylaminoethoxy)-2-methylquinoline

NMR (CDCI3, δ) : 2.41 (6H, s), 2.66 (3H, s), 2.91 (2H, t, J=6Hz), 3.00 (3H, d, J=5Hz) , 3.25 (3H, s) , 3.64

(IH, dd, J=17, 4Hz) 3.92 (IH, dd, J=17, 5Hz) , 4.29 (2H, t, J=6Hz), 5.59 (IH, d, J=10Hz) , 5.64 (IH, d, J=10Hz), 6.29 (IH, br d, J=5Hz), 6.52 (IH, d, J=15Hz), 6.63 (IH, s) , 6.73 (IH, br t, J=5Hz) , 7.21-7.29 (3H, m) , 7.33-7.60 (4H, m) , 7.74 (2H, d,

J=8Hz), 7.83 (IH, d, J=8Hz)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.87-3.00 (8H, m) , 3.06 (6H, br s), 3.29 (3H, s) , 3.79-3.99 (4H, m) , 5.02-5.14 (2H, m) , 5.49 (IH, d, J=10Hz) , 5.69 (IH, d, J=10Hz) , 6.59 (IH, d, J=15Hz), 7.38-7.61 (7H, m) , 7.71-7.82 (3H, m) , 8.42 (IH, d, J=8Hz)

(4) 4-Cyclopentyloxy-8- [2, 6-dichloro-3- [N-methyl-N- [4-

(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-2- methylquinoline

NMR (CDC1 ₃ , δ) : 1.62-2.06 (8H, m) , 2.64 (3H, s), 3.00 (3H, d, J=5Hz), 3.24 (3H, s) , 3.66 (IH, dd, J=17, 4Hz), 3.92 (IH, dd, J=17, 5Hz), 4.94-5.00 (IH, m) ,

5.59 (IH, d, J=10Hz), 5.62 (IH, d, J=10Hz) , 6.36 (IH, br d, J=5Hz), 6.52 (IK, d, J=15Hz), 6.61 (IH, s), 6.76 (IH, br ε), 7.20-7.38 (3d' , m) , 7.42-7.60 (4H, m) , 7.73 (2H, br d, J=8Hz) , 7.80 (IH, d, J=8Hz)

its hydrochloride

NMR (CDCI3-CD3OD, δ) : 1.76-2.26 (8H, m) , 2.99 (6H, s), 3.28 (3H, s), 3.88 (IK, d, J=17Hz) , 4.20 (IH, d, J=17Hz), 5.30-5.38 (IH, ) , 5.51 (IH, d, J=10Hz) ,

5.63 (IH, d, J=10Hz), 6.67 (IH, d, J=15Hz) , 7.15 (IH, br s), 7.37 (IH, d, J=15Hz), 7.45-7.60 (5H, m) , 7.67-7.79 (3H, ) , 7.89 (IH, d, J=8Hz)

(5) 8- [2, 6-Dichloro-3-[N-methyl-N-[4- (methylcarbamoyl)- cinnamoylglycyl]amino]benzyloxy]-4-dimethylamino-2- methylquinoline

NMR (CDCI3, δ) : 2.66 (3H, br s), 3.00 (3H, d, J=5Hz) , 3.09 (6H, br s), 3.25 (3H, s), 3.72 (IH, br dd, J=17, 4Hz), 3.99 (IH, br dd, J=17, 5Hz), 5.09 (2H, s), 6.48 (IH, br s) , 6.57 (IH, br d, J=15Hz) , 6.67 (IH, s), 7.20-7.56 (8H, m) , 7.68-7.74 (3H, m)

its dihydrochloride NMR (CDCI3-CD3OD, δ) : 2.71 (3H, s) , 2.99 (3H, s) , 3.28

(3H, s), 3.50 (6H, s), 3.87 (IH, d, J=17Hz) , 4.19 (IH, d, J=17Hz), 5.47 (IK, d, J=10Hz) , 5.62 (IH, d, J=10Hz), 6.63 (IH, d, J=15Hz) , 6.72 (IH, br s), 7.33 (IH, d, J=15Hz), 7.41-7.61 (6H, m) , 7.77-7.82 (3H, m)

(6) 8- [2, 6-Dichloro-3- [N-methyl-N-[4- (methylcarbamoyl)- cinnamoylglycyl] amino]benzyloxy]-4- ethoxycarbonylmethylaminc-2-methylquinoline NMR (CDCI3-CD3OD, δ) : 1.32 (3H, t, J=7.5Hz), 2.54 (3H, s), 2.98 (3H, s), 3.25 (3H, ε), 3.73 (IH, d,

J=17Hz), 3.97 (IH, d, J=17Hz) , 4.15 (2H, br s) , 4.30 (2H, q, J=7.5Hz), 5.50 (IH, d, J=10Hz) , 5.56 (IH, d, J=10Hz), 6.21 (IH, s), 6.52 (IH, d, J=15Hz), 7.26 (IH, br d, J=7.5Hz), 7.36-7.52 (6H, m) , 7.62-7.78 (3H, m)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 1.30 (3H, t, J=7.5Hz), 2.66 (3H, s), 2.99 (3H, s), 3.29 (3H, s), 3.91 (2H, br s) , 4.25 (2H, q, J=7.5Hz), 4.41 (2H, br s) , 5.46 (IH, d, J=10Hz), 5.62 (IH, d, J=10Hz) , 6.24 (IH, s) , 6.58 (IH, d, J=15Hz), 7.38 (IH, d, J=15Hz) , 7.42- 7.48 (3H, m) , 7.50 (IH, d, J=7.5Hz), 7.58 (IH, d, J=7.5Hz), 7.66 (IH, t, J=7.5Hz), 7.78 (2H, d, J=7.5Hz), 8.35 (IH, br d, J=7.5Hz)

(7) 4-Allylamino-8-[2, 6-dichloro-3- [N-methyl-N-[4-

(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-2- methylquinoline NMR (CDCI3-CD3OD, δ) : 2.54 (3H, s), 2.98 (3H, ε) , 3.25

(3H, ε), 3.79 (IK, d, J=17Hz) , 3.94 (IH, d, J=17Hz), 4.08 (2H, br d, J=6Hz) , 5.20-5.33 (2H, m) , 5.48 (IH, d, J=10Hz), 5.57 (IH, d, J=10Hz) , 5.88- 6.02 (IH, m) , 6.29 (IH, s) , 6.56 (IH, d, J=15Hz) , 7.29 (IH, d, J=8Hz) , 7.39-7.54 (6H, m) , 7.69 (2H, d, J=8Hz), 7.88 (IH, br d, J=8Hz)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.61 (3H, s) , 2.99 (3H, ε) , 3.28 (3H, s), 3.91 (2H, br ε), 4.22 (2H, br d, J=6Hz) ,

5.20-5.31 (2H, m) , 5.44 (IH, d, J=10Hz), 5.61 (IH, d, J=10Hz), 5.83-5.98 (IH, m) , 6.29 (IH, s) , 6.58 (IH, d, J=15Hz), 7.32-7.47 (4H, m) , 7.50 (IH, d, J=8Hz), 7.66 (IH, d, J=8Hz) , 7.63 (IH, t, J=8Hz), 7.78 (2K, d, J=8Hz), 8.42 (IK, br d, J=8Hz)

(8) 8-[2, 6-Dichloro-3-[N-methyl-N-[4- (methylcarbamoyl)- cinnamoylglycyl]amino]benzyloxy]-4- (2- dimethylaminoethylamino)-2-methylquinoline NMR (CDC1 ₃ , δ) : 2.31 (6H, s) , 2.57 (3H, s) , 2.69 (2H, br t, J=6Hz), 2.99 (3H, d, J=5Hz), 3.21-3.33 (5H, m) , 3.69 (IH, br dd, J=17, 4Hz) , 3.93 (IH, br dd, J=17, 5Hz), 5.57 (IH, d, J=10Hz) , 5.61 (IH, d, J=10Hz), 5.79 (IH, br s), 6.31 (IH, ε), 6.45 (IH, br ε), 6.53 (IH, d, J=15Hz), 6.88 (IH, br s), 7.19

(IH, br d, J=8Hz), 7.25-7.37 (2H, m) , 7.40-7.60 (5H, m), 7.73 (2H, br d, J=8Hz)

its trihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.75 (3H, br ε) , 2.99 (9H, br

8), 3.18-3.27 (3H, overlapped with H ₂ 0) , 3.57-3.68 (2H, m) , 3.81 (IH, d, J=17Hz) , 3.95 (IH, d, J=17Hz), 4.10-4.20 (2H, ), 5.46 (IH, d, J=10Hz), 5.67 (IH, d, J=10Hz), 6.59 (IH, d, J=15Hz) , 7.40- 7.70 (8H, m) , 7.80 (2H, br d, J=8Hz) , 8.33 (IH, br d, J=8Hz)

(9) 8-[2, 6-Dichloro-3-[N-methyl-N-[4- (methylcarbamoyl)- cinnamoylglycyl]amino]benzyloxy]-4- (2- methoxyethylamino) -2-methylquinoline

NMR (CDCI3-CD3OD, δ) : 2.53 (3H, s) , 2.98 (3H, ε), 3.26 (3H, ε), 3.41 (3H, ε) , 3.55 (2H, br t, J=6Hz), 3.70-3.80 (3H, m) , 3.97 (IH, br d, J=17Hz), 5.49 (IH, d, J=10Hz), 5.56 (IH, d, J=10Hz) , 6.39 (IH, s), 6.54 (IH, d, J=15Hz), 7.22 (IH, br d, J=7.5Hz),

7.38-7.53 (6H, m) , 7.64-7.71 (3H, m)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.63 (3H, s), 2.99 (3H, s), 3.29 (3H, s), 3.38 (3H, s) , 3.78 (4H, ε), 3.92 (2H, br

S), 5.45 (IH, d, J=10Hz), 5.61 (IH, d, J=10Hz) , 6.53-6.63 (2K, m) , 7.36-7.68 (7H, m) , 7.79 (2H, br d, J=7.5Hz), 8.31 (IH, d, J=7.5Hz)

(10) 4- [Bis (2-methoxyethyl)amino]-8-[2, 6-dichloro-3- [N- methyl-N- [4- (methylcarbamoyl) cinnamoylglycyl] amino] - benzyloxy] -2-methylquinoline

NMR (CDCI3, δ) : 2.68 (3H, br s), 3.00 (3H, d, J=5Hz) , 3.25 (3H, ε), 3.30 (6H, ε), 3.50-3.74 (9H, m) , 3.98 (IH, br dd, J=17, 5Hz) , 5.60 (2H, ε) , 6.36 (IH, br s), 6.57 (IH, d, J=15Hz) , 6.88 (IH, s), 7.21 (IH, br d, J=8Hz), 7.30-7.60 (6H, ) , 7.73 (2H, br d, J=8Hz), 7.79 (IH, d, J=8Hz)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.71 (3H, s), 2.99 (3H, ε) , 3.28 (3H, s) , 3.38 (6H, ε) , 3.24-3.71 (4H, m) , 3.88 (IH, d, J=17Hz), 4.00-4.08 (4H, m) , 4.19 (IK, d, J=17Hz), 5.47 (IH, d, J=10Hz) , 5.64 (IH, d, J=17Hz), 6.65 (IH, d, J=15Hz) , 6.97 (IH, br ε) ,

7.38 (IH, d, J=15Hz), 7.44 (IH, α, J=8Hz) , 7.49- 7.61 (5H, ) , 7.81 (2H, d, J=8Hz), 7.94 (IH, d, J=8Hz)

(11) 8- [2, 6-Dichloro-3- [N-methyl-N- [4-

(methylcarbamoyl) cinnamoylglycyl]amino]benzyloxy]-2- methyl-4- (piperidino)quinoline

NMR (CDCI3, δ) : 1.64-1.90 (6H, m) , 2.63 (3H, ε) , 2.99 (3H, d, J=5Hz), 3.10-3.28 (7H, ) , 3.70 (IH, br d, J=17Hz), 3.96 (IH, br d, J=17Hz), 5.58 (IH, d,

J=10Hz), 5.62 (IH, d, J=10Hz) , 6.36 (IH, br d, J=5Hz), 6.55 (IH, d, J=15Hz) , 6.72 (IH, s) , 7.20 (IH, d, J=8Hz), 7.28-7.59 (7H, m) , 7.64 (IH, d, J=8Hz), 7.73 (2K, br d, J=8Hz)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 1.81-1.96 (6H, m) , 2.78 (3H, br ε), 2.99 (3H, s), 3.27 (3H, s) , 3.69-3.79 (4H, m) , 3.87 (IH, br d, J=17Hz) , 4.28 (IH, br d, J=17Hz) , 5.48 (IK, br d, J=10Hz) , 5.61 (IH, br d, J=10Hz) ,

6.68 (IH, br d, J=15Hz), 6.85 (IH, br ε) , 7.32 (IH, br d, J=15Hz), 7.39-7.62 (7H, m) , 7.78 (2H, br d, J=8Hz)

(12) 8- [2, 6-Dichloro-3-[N-methyl-N- [4- (methylcarbamoyl) - cinnamoylglycyl]amino]benzyloxy]-2-methyl-4- (morpholino) quinoline

NMR (CDCI3, δ) : 2.67 (3H, br ε) , 3.00 (3H, d, J=5Hz) , 3.15-3.28 (7H, m) , 3.68 (IH, br dd, J=17, 4Hz), 3.88-4.02 (5H, m) , 5.62 (2H, br ε) , 6.37 (IH, br ε), 6.53 (IH, br d, J=15Hz), 6.72-6.80 (2H, m) , 7.20-7.70 (8H, ) , 7.75 (2H, br d, J=8Hz)

its dihydrochloride NMR (CDC1 ₃ -CD30D, δ) : 2.80-2.90 (3H, overlapped with

H ₂ 0) , 2.98 (3H, s), 3.28 (3H, s), 3.74-3.82 (4H, ) , 3.88 (IH, d, J=17Hz), 3.97-4.03 (4H, m) , 4.12 (IH, d, J=17Hz), 5.49 (IH, d, J=10Hz) , 5.65 (IH, d, J=10Hz), 6.65 (IH, d, J=15Hz) , 7.07 (IH, br s) , 7.38 (IH, d, J=15Hz) , 7.46-7.69 (7H, m) , 7.79 (2H, br d, J=8Hz)

Example 11 (1) 8-[3-Glycylamino-2, 6-dichlorobenzyloxy]-2- methylquinoline waε obtained from 8- [2, 6-dichloro-3-

(phthalimidoacetylamino)benzyloxy]-2-methylquinoline according to a εimiiar manner to that of Preparation 11. NMR (CDC1 ₃ , δ) : 2.73 (3K, ε) , 3.52 (2H, ε), 5.62 (2H, ε), 7.20-7.45 (5H, m) , 8.01 (IK, d, J=8.5Hz), 8.51 (IH, d, J=8.5Hz)

(2) 8-[3- [ (E)-3- (6-Acetamidopyridin-3-yl) acryloylglycyl- amino]-2, 6-dichlorobenzyloxy]-2-methylquinoline waε obtained according to a εimiiar manner to that of Example 1. mp : 272-282°C

NMR (DMSO-d ₆ , δ) : 2.11 (3H, s), 2.60 (3H, s), 4.14 (2H, d, J=5.5Hz), 5.47 (2H, ε) , 6.76 (IH, d, J=16Hz) , -7.34-7.57 (5H, m) , 7.60 (IH, d, J=9Hz) , 7.92 (IH, d, J=9.0Hz), 8.00 (IH, d, J=9.0Hz), 8.11

(IH, d, J=9.0Hz), 8.20 (IH, d, J=9.0Hz), 8.45-8.60 (2H, m) , 9.80 (IH, ε), 10.67 (IH, s)

Example 12 (1) 8- [2, 6-Dichloro-3- (N-ethyl-N-phthalimidoacetylamino)- benzyloxy]-2-methylquinoline waε obtained by reacting 8- [2 , 6-dichloro-3- (phthalimidoacetylamino)benzyloxy]-2- methylquinoline with ethyl iodide according to a εimiiar manner to that of Preparation 10. NMR (CDCI3, δ) : 1.23 (3H, t, J=6Hz) , 2.73 (3H, s) ,

3.39 (1.2H, q, J=6Hz) , 3.95-4.10 (2.8Hz), 5.70 (IH, d, J=12Hz), 5.75 (IH, d, J=12Hz) , 7.24-7.47 (5H) , 7.53 (IH, d, J=8Hz), 7.70-7.76 (2H) , 7.83-7.89 (2H) , 8.02 (IH, d, J=8Hz)

(2) 8- [2, 6-Dichloro-3- (N-ethyl-N-glycylamino)benzyloxy]-2- methylquinoline was obtained according to a similar manner to that of Preparation 11.

NMR (CDCI3, δ) : 1.13 (1.5H, t, J=6Hz) , 1.14 (1.5H, t, J=6Hz), 2.74 (3H, ε), 2.94 (IH, d, J=18Hz) , 3.04

( IH, d, J=18Hz ) , 3 . 33 ( IH, q, J=6Hz ) , 4 . 10 ( IH, q, J=6Hz ) , 5 . 67 (2H, ε ) , 7 . 16-7 . 48 ( 6H) , 8 . 02 ( IH, d, J=8Hz )

⁽ 3 ⁾ 8-[3-[N-[ (E) -3- (6-Acetamidopyridin-3-yl) acryloylglycyl]- N-ethylamino]-2, 6-dichlorobenzyloxy]-2-methylquinoline was obtained according to a similar manner to that of Example 1.

NMR (CDC1 ₃ , δ) : 1.18 (3H, t, J=6Hz), 2.23 (3H, s) , 2.74 (3H, s), 3.38 (IH, q, J=6Hz) , 3.64 (IH, dd,

J=18, 4Hz), 3.92 (IH, dd, J=18, 4Hz) , 4.15 (IH, q, J=6Hz), 5.67 (2H, ε), 6.47 (IH, d, J=15Hz) , 6.71 (IH, t, J=4Hz), 7.23-7.56 (7H) , 7.83 (IH, dd, 3=8 , 2Hz), 8.02 (IH, d, J=8Hz) , 8.10 (IH, ε) , 8.20 (IH, d, J=8Hz), 8.35 (IH, d, J=2Hz)

itε dihydrochloride

NMR (CDCI3-CD3OD, δ) : 1.20 (3H, t, J=6Hz) , 2.42 (3H, s), 3.12 (3H, s), 3.67 (IH, q, J=6Hz) , 3.86 (IH, d, J=18Hz), 3.96 (IH, q, J=6Hz) , 4.23 (IH, d, J=18Hz) ,

5.56 (IH, d, J=10Hz), 5.76 (IH, d, J=10Hz) , 6.86 (IH, d, J=15Hz), 7.42 (IH, d, J=15Hz) , 7.56-7.70 (3H), 7.80-8.02 (4H) , 8.53 (IH, d, J=8Hz) , 8.81 (IH, s ) , 8.90 (IH, d, J=8Hz)

(4) 8-[2, 6-Dichloro-3-[N-ethyl-N-[4- (methylcarbamoyl) - cinnamoylglycyl]amino]benzyloxy]-2-methylquinoline was obtained according to a similar manner to that of Example I. NMR (CDCI3, δ) : 1.17 (3H, t, J=6Hz) , 2.72 (3H, s) ,

3.02 (3H, d, J=4Hz), 3.37 (IH, q, J=6Hz) , 3.64 (IH, dd, J=18, 4Hz), 3.90 (IH, dd, J=18, 4Hz), 4.15 (IH, q, J=6Hz), 5.67 (2H, s) , 6.25 (IH, q, J=4Hz), 6.52 (IH, d, J=15Hz), 6.71 (IH, t, J=4Hz) , 7.23-7.62 (9H), 7.75 (2H, d, J=8Hz) , 8.03 (IK, d, J=8Hz)

itε hydrochloride

NMR (CDCI3-CD3OD, δ) : 1.21 (3H, t, J=6Hz) , 2.99 (3H, ε), 3.11 (3H, ε), 3.60 (IH, q, J=6Hz), 3.85-4.07 (3H), 5.60 (IH, d, J=12Hz) , 5.75 (IH, d, J=12Hz) , 6.64 (IH, d, J=15Hz), 7.44 (IH, d, J=15Hz) , 7.50-

7.98 (10H), 8.94 (IH, d, J=8Hz)

Example 13

To a εolution of 8- [3- (N-glycyl-N-methylamino) -2, 6- dichlorobenzyloxy]-2-methylquinoline (404 mg) and triethylamine (120 mg) in dichloromethane (8 ml) was added bromoacetyl bromide (220 mg) at 5°C. After stirring for 30 minutes at the same temperature, the mixture was waεhed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (dichloromethane - methanol) to give 8- [3- [N- (bromoacetylglycyl)-N-methylamino]-2, 6- dichlorobenzyloxy]-2-methylquinoline (327 mg) as an amorphouε powder. NMR (CDC1 ₃ , δ) : 2.77 (3H, ε) , 3.27 (3H, s) , 3.55 (IH, dd, J=14, 4Hz), 3.83 (IH, dd, J=14, 4Hz) , 3.89 (2H, s), 5.68 (2H, s), 7.23-7.47 (5H, m) , 7.50 (IH, d, J=7.5Hz), 8.06 (IH, d, J=7.5Hz)

Example 14

A mixture of 8- [3- [N- (bromoacetylglycyl)-N-methylamino]- 2, 6-dichlorobenzyloxy]-2-methylquinoline (200 mg) and tri-n- butylphoεphine (140 μl) in tetrahydrofuran (4 ml) waε εtirred for 2 hourε at ambient temperature. The mixture was concentrated, and the residue was purified by flash chromatography (dichloromethane - methanol) to give 8- [3- [N- [2- (tri-n-butylphosphonio)acetylglycyl]-N- methylamino]-2, 6-dichlorobenzyloxy]-2-methylquinoline bromide (128 mg) aε an amorphouε powder. NMR (DMSO-d _δ , δ) : 0.91 (9H, t, J=7.5Hz), 1.31-1.56

(12H, m) , 2.20-2.31 (6H, m) , 2.61 (3H, s) , 3.15 (3H, s), 3.43-3.58 (3H, m) , 3.72 (IH, dd, J=15, 4Hz), 5.52 (2H, ε), 7.37-7.57 (4H, m) , 7.78 (2H, ε), 8.22 (IH, d, J=7.5Kz), 8.74 (IH, t, J=4Hz)

Example 1

A mixture of 8-[3-[N-(bromoacetylglycyl) -N-methylamino] - 2, 6-dichlorobenzyloxy]-2-methylquinoline (80 mg) , 5-amino- 1,3,4-thiadiazole-2-thiol (24 mg) , potassium carbonate ( 42 mg) in dimethylformamide (2 ml) was stirred for 30 minutes at ambient temperature. To the mixture was added water, and the mixture was extracted with ethyl acetate twice. Combined organic layers were washed with water three times, dried over magnesium sulfate and concentrated. The residue was pulverized from diethyl ether to give 8-[3-[N-[2- (5-amino- 1,3,4-thiadiazol-2-ylthio)acetylglycyl]-N-methylamino]-2, 6- dichlorobenzyloxy]-2-methylquinoline (25 mg) as a solid, mp : >120°C NMR (DMSO-d ₆ , δ) : 2.61 (3H, s) , 3.14 (3H, s) , 3.38 (IH, dd, J=18, 4Hz), 3.68 (IK, dd, J=18, 4Hz) , 3.75

(2H, ε), 5.47 (IH, d, J=9Hz) , 5.55 (IH, d, J=9Hz) , 7.30 (2H, ε), 7.37-7.57 (4H, m) , 7.77 (2H, ε) , 8.22 (IH, d, J=7.5Hz), 8.40 (IH, t, J=4.5Hz)

Example 16

The following compounds were obtained according to a similar manner to that of Example 15.

(1) 8-[3-[N-[2- (2-Benzoxazolylthio)acetylglycyl]-N- methylamino]-2, 6-dichlorobenzyloxy]-2-methylquinoline NMR (DMSO-d ₆ , δ) : 2.59 (3H, s) , 3.15 (3H, s) , 3.43

(IH, dd, J=15, 4Hz), 3.71 (IH, dd, J=15, 4Hz) , 4.20 (2H, ε), 5.46 (IH, d, J=12Hz), 5.55 (IH, d, J=12Hz), 7.30-7.66 (8H, m) , 7.77 (2H, ε) , 8.20 (IH, d, J=7.5Hz), 8.58 (IH, t, J=4Hz)

(2) 8-[3-[N-[2- (2-BenzimidazoIylthio) acetylglycyl]-N- methylamino]-2, 6-dichlorobenzyloxy]-2-methylσuinoline mp : >120°C

NMR (DMSO-d ₆ , δ) : 2.61 (3H, s), 3.13 (3H, s) , 3.42 (IH, dd, J=15, 4Hz), 3.70 (IH, dd, J=15, 4Hz), 4.0

(2H, s), 5.46 (IH, d, J=15Hz) , 5.53 (IH, d, J=15Hz), 7.09-7.16 (3H, m) , 7.33-7.55 (5H, m) , 7.7 (2H, s), 8.19 (IH, d, =7.5Hz), 8.58 (IH, t, J=4Hz

(3) δ- [3-[N- [2- (2-Benzothiazolylthio) acetylglycyl]-N- methylamino]-2, 6-dichlorobenzyloxy]-2-methylquinoline mp : 174-175°C

NMR (DMSO-d ₆ , δ) : 2.60 (3H, s), 3.15 (3H, s), 3.45

(IH, dd, J=14, 4Hz), 3.72 (IH, dd, J=14, 4Hz) , 4.2 (2H, s), 5.47 (IH, d, J=14Hz) , 5.54 (IH, d,

J=14Hz), 7.33-7.56 (6H, m) , 7.76 (2H, ε) , 7.86 (IH, d, J=7.5Hz), 8.02 (IH, d, J=7.5Hz), 8.21 (IH, d, J=7.5Hz), 8.57 (IH, t, J=5Hz)

(4) 8-[2, 6-Dichloro-3-[N-[2-(6-ethoxybenzothiazol-2-ylthio) acetylglycyl]-N-methylamino]benzyloxy]-2-methylquinolin NMR (DMSO-d ₆ , δ) : 1.36 (3H, t, J=7.5Hz), 2.59 (3H, s) , 3.14 (3H, s), 3.44 (IH, dd, J=15, 4Hz) , 3.71 (IH, dd, J=15, 4Hz), 4.06 (2H, q, J=7.5Hz), 4.15 (2H, ε), 5.46 (IH, d, J=15Hz) , 5.53 (IH, d, J=15Hz) ,

7.05 (IH, dd, J=7.5, 2Kz) , 7.34-7.70 (6H, m) , 7.73 (2H, s), 8.21 (IH, d, J=7.5Hz), 8.54 (IH, t, J=4Hz)

(5) 8- [3-[N- [2- (4-Aminophenylthio) acetylglycyl]-N- methylamino]-2, 6-dichlorobenzyloxy]-2-methylquinoline

NMR (CDC1 ₃ , δ) : 2.75 (3K, ε) , 3.26 (3H, ε), 3.47 (2H, s), 3.51 (IH, dd, J=14, 4Hz) , 3.80 (IH, dd, J=14, 4Hz), 5.62 (2H, s) , 6.60 (2H, ά, J=7.5Hz), 7.22- 7.32 (5H, m) , 7.39-7.49 (3H, m) , 7.62 (IH, t, J=4Hz), 8.02 (IH, d, J=7.5Hz)

Example

A mixture of 8-[3-[N-[2- (4-aminophenylthio) - acetylglycyl]-N-methylamino]-2, 6-dichlorobenzyloxy]-2- methylquinoline (56 mg) , triethylamine (15 mg) and acetic anhydride (15 mg) in dichloromethane (2 ml) was stirred for 4 hours at ambient temperature. The resulting precipitates were collected by filtration to give 8- [3-[N-[2- (4- acetamidophenylthio)acetylglycyl]-N-methylamino]-2, 6- dichlorobenzyloxy]-2-methylquinoline (30 mg) as a colorleεs crystal. mp : 179-180°C

NMR (DMSO-d ₆ , δ) : 2.04 (3H, s), 2.62 (3H, s), 3.16

(3H, s), 3.35 (IH, m) , 3.66 (2H, s) , 3.69 (IH, m) , 5.49 (IH, d, J=14Hz), 5.57 (IH, d, J=14Hz) , 7.28- 7.59 (7H, m) , 7.78 (2H, s) , 8.20-8.35 (2H, m)

Example 18

To a suspension of 8-[3-(N-glycyl-N-methylamino)-2, 6- dichlorobenzyloxy]-2-methylquinoline (100 mg) in tetrahydrofuran were added triethylamine (18.8 mg) and 4- methoxycarbonylphenyl chloroformate (39.8 mg) at 0°C under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed, and ethyl acetate and water were added to the residue. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography (ethyl acetate:n-hexane = 2:1, V/V) to give 8-[2, 6-dichloro- 3- [N-[ (4-methoxycarbonylphenoxycarbonyl) glycyl]-N- methylamino]benzyloxy]-2-methylquinoline (30 mg) as an amorphous powder.

NMR (CDC1 ₃ , δ) : 2.74 (3H, s), 3.26 (3H, s), 3.54 (IH, dd, J=4, 16Hz), 3.81 (IH, dd, J=4, 16Hz) , 3.89 (3H, s), 5.65 (2H, ε), 5.95 (IH, t-like) 7.19 (2H, d, J=8Hz), 7.22-7.35 (2H, m) , 7.35-7.52 (4H, m) , 7.97- 8.08 (3H, in)

Example 19

To a solution of 8- [3- (N-glycyl-N-methylamino) -2.6- dichlorobenzyloxy]-2-methylquinoline (80 mg) and triethylamine (40 mg) in dimethylformamide was added phenyl 2-benzothiazolylcarbamate (56.2 mg) under nitrogen atmoεphere, and the mixture waε εtirred for 2 hours at 80°C. The reaction mixture was poured into water and extracted wit ethyl acetate. The organic layer was washed with water and brine, dried over magneεiu εulfate and evaporated in vacuo to give 8- [3- [N- [N'- (2-benzothiazolyl)ureidoacetyl]-N- methylamino]-2, 6-dichlorobenzyloxy]-2-methylquinoline (85 mg) as a powder.

NMR (DMSO-d ₆ , δ) : 2.61 (3H, s), 3.17 (3H, s), 3.51

(IH, dd, 3=4 , 16Hz), 3.77 (IH, dd, J=4, 16Hz) , 5.48 (IH, d, J=10Hz), 5.56 (IH, d, J=10Hz) , 7.10 (IH, t- like), 7.21 (IH, t, J=8Hz) , 7.31-7.66 (7H, m) , 7.80 (2H, s-like), 7.88 (IH, d, J=8Hz) , 8.21 (IH, d, J=8Hz)

Example 20

To a solution of methyl 2-aminoisonicotinate (500 mg) and triethylamine (549.6 μl) in dichloromethane (5 ml) waε added phenyl chloroformate (433 μl) at 0°C under nitrogen atmoεphere. After stirring for 2.5 hours at 0°C, the reaction mixture was concentrated. The residue waε disεolved in dimethylformamide (13 ml), and 8- [3- (N-glycyl-N- methylamino)-2, 6-dichlorobenzyloxy]-2-methylquinoline (1.33 g) and triethylamine (917 μl) were added thereto at ambient temperature under nitrogen atmoεphere. The mixture waε stirred for 91 hours, and chloroform was added thereto. The organic solution was washed with water, εaturated εodium bicarbonate solution and brine and dried over magnesium sulfate. The solvent was removed, and the reεidue waε cryεtallized from ethyl acetate to give 8- [2, 6-dichloro-3- [N- [N'- (4-methoxycarbonylpyridin-2-yl)ureidoacetyl]-N-

methylamino]benzyloxy]-2-methylquinoline (916 mg) . mp : 217-220 ^β C

NMR (DMSO-d ₆ , δ) : 2.61 (3H, s), 3.16 (3H, s) , 3.53 (IH, dd, J=16.5, 5.5Hz), 3.77 (IH, dd, J=16.5, 5.5Hz), 3.87 (3H, ε) , 5.48 (IH, d, J=10.0Hz), 5.55 (IH, d, J=10.0Hz), 7.33-7.58 (4H, m) , 7.47 (IH, t, J=8.5Hz), 7.78 (IH, d, J=8.5Hz), 7.80 (IH, d, J=8.5Hz), 7.99 (IH, s) , 8.11 (IH, m) , 8.21 (IH, d, J=8.5Hz), 8.37 (IH, d, J=6.0Hz), 9.69 (IH, s)

itε dihydrochloride p : 168-173°C

NMR (DMSO-d ₆ , δ) : 2.11 (3H, ε) , 2.92 (3H, s) , 3.12 (3H, ε), 3.66 (IH, dd, J=16.5, 4.5Hz), 3.86 (IH, dd, J=16.5, 4.5Hz), 5.57 (IH, d, J=11.5Hz), 5.61

(IH, d, J=11.5Hz), 6.88 (IH, d, J=8.5Hz) 7.46 (IH, d, J=8.5Hz), 7.66 (IH, t, J=3.5Hz), 7.73 (IH, d, J=8.5Hz), 7.77 (IH, d, J=8.5Hz), 7.83-8.00 (4H, m) , 8.57 (IH, br s), 9.01 (IH, br d, J=8.5Hz), 9.48 (IH, br ε)

Example 21

8-[3- [N-[N'- (6-Acetamidopyridin-2-yl)ureidoacetyl]-N- methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline waε obtained according to a similar manner to that of Example 20. mp : 129-134°C

NMR (CDC1 ₃ , δ) : 2.16 (3H, s), 2.71 (3H, ε) , 3.23 (3H, ε), 3.72 (IH, dd, J=16.5, 4.5Hz), 3.93 (IH, dd, J=16.5, 4.5Hz), 5.56 (IH, d, J=10.0Hz), 5.61 (IH, d, J=10.0Hz), 6.40 (IH, d, J=8.5Hz), 7.22-7.34 (5H, m) , 7.40-7.52 (3H, m) , 7.70 (IH, d, J=8.5Hz), 7.90 (IH, br ε), 8.03 (IH, d, J=8.5Hz), 8.90 (IH, ε)

Example 22 (l) To a stirred solution of N,N'-carbonyldiimidazole (7.14

g) in 1,4-dioxane (250 ml) was added 3-ethoxycarbonylaniline (7.28 g) at 0°C and the solution was stirred at ambient temperature for 15 hours and then at 40°C for 5 hours. To the mixture was added 8- [2, 6-dichloro-3- (N-glycyl-N- methylamino)benzyloxy]-2-methylquinoline (14.84 g) at ambient temperature and the reεulting mixture was heated at 100°C for 4 hours. After cooling, the mixture was concentrated in vacuo and the residue waε purified by flash chromatography (methanol-chloroform) to afford N,N'-bis [ [N- [2, 4-dichloro-3- (2-methylquinolin-8-yloxymethyI)phenyl]-N-methylamino]- carbonylmethyl]urea (17.63 g) .

NMR (CDC1 ₃ , δ) : 2.71 (3H x 2, ε) , 3.19 (3H x 2, s), 3.44 (IH x 2, dd, J=15, 4Hz) , 3.72 (IH x 2, dd, J=15, 5Hz), 5.45-5.78 (6H, ) , 7.13-7.60 (12H, m) , 8.00 (IH x 2, d, J=9Hz)

(2) A mixture of N,N'-bis[ [N-[2,4-dichloro-3- (2- methylquinolin-8-yloxymethyl)phenyl]-N-methylamino]- carbonylmethyl]urea (16 g) , IN εodium hydroxide εolution (40 ml) in dioxane (200 ml) waε εtirred for 4 hourε at 80°C. The εolvent was removed in vacuo, and water was added to the residue. The resulting precipitates were collected by filtration and washed with water to give 8- (2 , 6-dichloro-3- methylaminobenzyloxy)-2-methylquinoline (7.20 g) aε a solid. NMR (CDCI3, δ) : 2.73 (3H, s), 2.90 (3H, d, J=6Hz) ,

4.50 (IH, q-like), 5.60 (2H, s), 6.61 (IH, d, J=8Hz), 7.20-7.32 (3H, m) , 7.33-7.43 (2H, m) , 8.00 (IH, d, J=8Hz)

(3) 8- [2, 6-Dichloro-3- (N-methyl-N-phenoxycarbonylamino) - benzyloxy]-2-methylquinoline was obtained by reacting 8-(2,6- dichloro-3-methylaminobenzyloxy) -2-methylquinoline with phenyl chloroformate according to a similar manner to that of Example 18. NMR (CDCI3, δ) : 2.71 (3H, s), 3.30 (3H, ε), 5.64 (IH,

d, J=10Hz ) , 5 . 70 ( IH, d, J=10Hz ) , 7 . 00- 7 . 06 (2H, m) , 7 . 03-7 . 50 ( 9H, m) , 8 . 00 ( IH, d, J=8Hz )

(4) To a solution of bis (trichloromethyl)carbonate (232 mg) , pyridine (273 mg) in dichloromethane was added 8- (2, 6- dichloro-3-methylaminobenzyloxy)-2-methylquinoline (800 mg) at 0°C under nitrogen atmosphere, and the mixture was stirred for 1 hour at ambient temperature. To the mixture were added glycine ethyl ester hydrochloride (289 mg) and triethylamine (582 mg) , and the mixture was stirred for 3 hours at ambient temperature. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (chloroform) to give 8-[2, 6-dichloro-3- (N'- ethoxycarbonylmethyl-N-methylureido)benzyloxy]-2- methylquinoline (512 mg) as a powder.

NMR (CDC1 ₃ , δ) : 1.24 (3H, t, J=7.5Hz), 2.73 (3H, s) ,

3.22 (3H, ε), 3.85 (IH, brpeak), 4.04 (IH, brpeak), 4.16 (2H, q, J=7.5Hz), 4.80 (IH, t-like), 5.61 (2H, s), 7.21-7.35 (2H, m) , 7.35-7.51 (4H, m) , 8.03 (IH, d, J=8Hz)

Example 23 8-[2, 6-Dichloro-3-[N ^? -(ethoxycarbonylmethyl)ureido]- benzyloxy]-2-methylquinoline was obtained from 8- (2, 6- dichloro-3-aminobenzyloxy)-2-methylquinoline and glycine ethyl ester hydrochloride according to a similar manner to that of Example 22-(4). NMR (CDC1 ₃ , δ) : 1.06 (3H, t, J=7.5Hz), 2.21 (3H, s) ,

3.89-4.06 (4H, m) , 5.36 (2H, s) , 7.13 (IH, dd, J=8, 2Hz), 7.24-7.42 (3H, m) , 7.56 (IH, t-like), 8.01 (IH, d, J=8Hz), 8.39 (IH, d, J=8Hz) , 8.50 (IH, s)

Example 24

The following compounds were obtained according to a similar manner to that of Example 3.

(1) 8- [3- [N- [4- (Carboxymethoxy) cinnamoylglycyl] -N- methylamino] -2, 6-dichlorobenzyloxy] -2-methylquinoline mp : 286.6-290.6°C

NMR (DMSO-d ₆ , δ) : 2.60 (3H, s), 3.14 (3H, s), 3.49

(IH, dd, J=17, 4Hz), 3.79 (IH, dd, J=17, 5Hz) , 4. (2H, s), 5.47 (IH, d, J=9Hz) , 5.54 (IH, d, J=9Hz)

6.62 (IH, d, J=15Hz), 6.87 (2H, d, J=9Hz) , 7.27- 7.58 (7H, m) , 7.75 (IH, d, J=9Hz) , 7.79 (IH, d, J=9Hz), 8.16 (IH, m) , 8.20 (IH, d, J=9Hz)

(2) 8- [3- [N- [ (2-Carboxy-3-methylquinoline-6-carbonylglycyl] N-methylamino]-2, 6-dichlorobenzyloxy] -2-methylquinolin NMR (DMSO-d ₆ , δ) : 2.57 (3H, s), 2.61 (3H, s) , 3.17 (3H, s), 3.63 (IH, dd, J=16, 5Hz) , 3.92 (IH, dd, J=16, 5Hz), 5.50 (2H, ε) , 7.33-7.66 (4H, m) , 7.75 7.88 (2H, m) , 8.06-8.36 (3H, m) , 8.36-8.55 (2H, m)

8.96 (IH, t-like)

(3) 8-[3-[N-[N'- (4-Carboxypyridin-2-yl) ureidoacetyl] -N- methylamino] -2, 6-dichlorobenzyloxy] -2-methylquinoline mp : 201-207 ^β C

NMR (DMSO-d ₆ , δ) : 2.61 (3H, ε) , 3.16 (3H, s) , 3.54 (IH, dd, J=16.5, 5.5Hz), 3.78 (IH, dd, J=16.5, 5.5Hz), 5.47 (IH, d, J=10.0Hz), 5.53 (IH, d, J=10.Hz), 7.30-7.58 (4H, ) , 7.47 (IH, t, J=8.5Hz) 7.77 (IH, d, J=8.5Hz) , 7.80 (IH, d, J=8.5Hz), 7.9

(IH, s), 8.21 (IH, d, J=8.5Hz), 8.30 (IH, m) , 8.34 (IH, d, J=6.0Hz), 9.66 (IH, s)

(4) 8- [3- (N' -Carboxymethylureido) -2, 6-dichlorobenzyloxy] -2- methylquinoline

NMR (DMSO-d ₆ , δ) : 2.60 (3H, ε), 3.86 (IH, d, J=6Hz) , 5.42 (2H, ε), 7.35-7.55 (6H, m) , 8.20 (IH, d, J=8Hz), 8.26 (IH, d, J=8Hz) , 8.50 (IH, ε)

(5) 8- [3- (N'-Carboxymethyl-N-methylureido)-2, 6- dichlorobenzyloxy]-2-methylquinoline

NMR (DMSO-dg, δ) : 2.61 (3H, s), 3.10 (3H, s) , 3.61 (2H, d, J=6Hz), 5.46 (2H, ε) , 6.46 (IH, brpeak), 7.38-7.58 (5K, m) , 7.67 (IH, d, J=8Hz), 8.21 (IH, d, J=8Hz)

Example 25

The following compoundε were obtained according to a εimiiar manner to that of Example 7.

(1) 8-[2, 6-Dichloro-3-[N-methyl-N-[4- (methylcarbamoyl- ethoxy)cinnamoylglycyl]amino]benzyloxy]-2- methylquinoline (from 8-[3- [N-[4- (carboxymethoxy) - cinnamoylglycyl]-N-methylamino]-2, 6-dichlorobenzyloxy]- 2-methylquinoline and methylamine hydrochloride)

NMR (CDC1 ₃ , δ) : 2.74 (3H, ε), 2.90 (3H, d, J=5Hz) ,

3.27 (3H, s), 3.65 (IH, dd, J=17, 4Hz) , 3.94 (IH, dd, J=17, 5Hz), 4.50 (2H, s) , 5.63 (IH, d, J=9Hz) , 5.66 (IH, d, J=9Hz), 6.36 (IH, d, J=15Hz) , 6.55 (IH, br s), 6.61 (IH, br t, J=5Hz), 6.88 (2H, d,

J=9Hz), 7.22-7.34 (3H, m) , 7.37-7.58 (6H, ) , 8.02 (IH, d, J=9Hz)

its hydrochloride NMR (DMSO-d ₆ , δ) : 2.90 (3H, s) , 3.16 (3H, s), 3.29

(3H, s), 3.87 (IH, d, J=17Hz) , 4.02 (IH, d, J=17Hz), 4.50 (2H, ε) , 5.60 (IH, d, J=9Hz) , 5.70 (IH, d, J=9Hz), 6.46 (IH, d, J=15Hz) , 6.84-6.97 (2H, m) , 7.36-7.67 (7H, m) , 7.75-7.95 (4H, m) , 8.88 (IH, br d, J=7.5Hz)

- 92 -

(2) 8- [2, 6-Dichloro-3- [N-methyl-N- [ [2- (methylcarbamoyl) -3- methylquinoline-6-carbonyl]glycyl]amino]benzyloxy] -2- methylquinoline (from 8- [3- [N- [ (2-carboxy-3- methylquinoline-6-carbonyl) glycyl] -N-methylamino] -2, 6- dichlorobenzyloxy] -2-methylquinoline and methylamine hydrochloride)

NMR (CDC1 ₃ , δ) : 2.74 (3K, ε) , 2.83 (3H, s), 3.07 (3H, d, J=5Hz), 3.31 (3H, s), 3.79 (IH, dd 3=4 , 17Hz) , 4.08 (IH, dd, 3=5 , I7Hz) , 5.66 (2H, ε), 7.23-7.48 (6H, ) , 7.51 (IH, d, J=8Hz) , 8.03 (IH, d, J=8Hz),

8.05-8.11 (2H, m) , 8.19 (IH, q-like), 8.28 (IH, s-like)

its dihydrochloride NMR (DMSO-d ₆ , δ) : 2.61 (3H, s), 2.85 (3H, d, J=5Hz) ,

2.90 (3H, s), 3.17 (3H, s) , 3.70 (IH, dd, J=5, 16Hz), 2.98 (IH, dd, 3=5, 16Hz) , 5.60 (IH, d, J=10Hz), 5.66 (IH, d, J=10Hz), 7.78-7.98 (6H, m) , 8.05-8.18 (2H, m) , 8.33 (IH, s-like), 8.45 (IH, s- like), 8.70 (IH, q-like), 8.92-9.07 (2H, m)

(3) 8- [2, 6-Dichloro-3- [N- [N'- [4- (dimethyicarbamoyl)pyridin- 2-yl] reidoacetyl]-N-methyiamino]benzyloxy]-2- methylquinoline (from 8- [3-[N- [N ¹ - (4-carboxypyridin-2- yl)ureidoacetyl] -N-methylamino] -2 , 6-dichlorobenzyloxy]- 2-methylquinoline and dimethylamine hydrochloride) mp : 118-123°C

NMR (DMSO-d ₆ , δ) : 2.60 (3H, s), 2.83 (3H, s) , 2.97 (3H, s), 3.16 (3H, s), 3.53 (IH, dd, J=16.5, 5.5Hz), 3.78 (IH, dd, J=16.5, 5.5Hz), 5.47 (IH, d,

J=10.0Hz), 5.53 (IH, d, J=10.0Hz), 6.91 (IH, d, J=5.5Hz), 7.30-7.58 (4H, m) , 7.47 (IH, t, J=8.5Hz), 7.76 (IK, d, J=8.5Hz), 7.80 (IK, d, J=8.5Hz), 8.21 (IH, d, J=8.5Hz), 8.26 (IH, d, J=5.5Hz), 8.32 (IH, m) , 9.59 (IH, s)

- 93 - its dihydrochloride mp : 166-173°C

NMR (DMSO-d ₆ , δ) : 2.85 (3H, s) , 2.93 (3H, s) , 2.97 (3H, s), 3.13 (3H, s) , 3.60 (IH, dd, J=16.5, 5.5Hz), 3.82 (IH, dd, J=16.5, 5.5Hz), 5.61 (2H, s) ,

6.96 (IH, d, J=6.0Hz), 7.33 (IH, s), 7.78-7.99 (6H, m) , 8.23 (IH, d, J=6.0Hz), 8.29 (IH, m) , 9.00 (IH, br d, J=8.5Hz) , 9.87 (IH, s)

(4) 8-[2,6-Dichloro-3-[N ^, -(phenylcarbamoylmethyl)- ureido]benzyloxy]-2-methylquinoline (from 8-[3-(N'- carboxymethylureido)-2,6-dichlorobenzyloxy]-2- methylquinoline and aniline)

NMR (DMSO-d ₆ , δ) : 2.60 (3H, s) , 4.01 (IH, d, J=6Hz) , 5.44 (2H, ε), 7.05 (IH, t, J=8Hz) , 7.27-7.55 (9H, m), 7.61 (2H, d, J=8Hz), 8.21 (IH, d, J=8Hz) , 8.28 (IH, d, J=8Hz), 8.58 (IH, s)

(5) 8-[2, 6-Dichloro-3-[N'~(phenylcarbamoylmethyl)-N- methylureido] enzyloxy]-2-methylquinoline (from 8-[3- (N*-carboxymethyl-N-methylureido)-2, 6- dichlorobenzyloxy]-2-methylquinoline and aniline) NMR (CDC1 ₃ , δ) : 2.50 (3H, s) , 3.27 (3H, s) , 5.59 (2H, s) , 6.08 (IH, t-like), 6.83-6.98 (3H, m) , 7.10 (IH, d, J=8Hz), 7.20-7.30 (3H, m) , 7.38-7.55 (4H, m) ,

7.91 (IH, d, J=8Hz), 8.46 (IH, s)

(6) 8- [3- [N'- (Benzvlcarbamoylmethyl) -N-methylureido]-2, 6- dichlorobenzyloxy] -2-methylquinoline (from 8-[3-(N'- carboxymethyl-N-methylureido) -2, 6-dichlorobenzyloxy] -2- methylquinoline and benzylamine)

NMR (CDC1 ₃ , δ) : 2.65 (3H, ε) , 3.20 (3H, ε), 3.70-4.48 (4H, brpeak), 5.41-5.60 (2H, brpeak), 5.65 (IH, t- like), 6.65 (IH, brpeak), 6.97-7.13 (4H, m) , 7.20- 7.35 (4H, m) , 7.42-7.50 (3H, n) , 8.05 (IH, d.

- 94 - J=8Hz)

Example 26

To a mixture of 8- [2, β-dichloro-3- [N-methyl-N- [ (Ξ) -3- (6 methylaminopyridin-3-yl) acryloylglycyl]amino]benzyloxy]-2- methylquinoline (100 mg) and triethylamine (23.3 mg) in dichlcromethane was added acetyl chloride (15.3 mg) under nitrogen in ice water bath and the mixture was stirred for 3 hours at εame temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparativ thin-layer chromatography (dichloromethane:methanol = 20:1, V/V) to give 8-[2, 6-dichloro-3-[N-methyl-N-[ (E)-3-[6- (N- methylacetamido)pyridin-3-yl]acryloylglycyl]amino]benzyloxy] - 2-methylquinoline (50 mg) as an amorphous powder.

NMR (CDC1 ₃ , δ) : 2.17 (3H, s) , 2.71 (3H, s) , 3.29 (3H, ε), 3.41 (3H, ε), 3.70 (IH, dd, 3=4 , 16Hz) , 3.95 (IH, dd, 3=4 , 16Hz) , 5.60-5.69 (2H, m) , 6.52 (IH, d, J=16Hz), 6.72 (IH, t-like), 7.22-7.52 (7H, m) , 7.56 (IH, d, J=16Hz), 7.83 (IH, dd, J=2, 8Hz) , 8.03 (IH, d, J=8Hz), 8.54 (IH, d, J=2Hz)

its dihydrochloride

NMR (DMSO-d ₆ , δ) : 2.10 (3H, s) , 2.88 (3H, s) , 3.13 (3H, ε), 3.31 (3H, s) , 3.89 (IH, dd, 3=4 , 16Hz), 5.56-5.70 (2H, m) , 6.87 (IH, d, J=16Hz) , 7.42 (IH, d, J=16Hz), 7.61 (IH, d, J=8Hz) , 7.66-7.97 (6H, m) , 8.03 (IH, d, J=8Hz), 8.35 (IH, t-like), 8.61 (IH, d, J=2Hz), 8.91 (IH, brpeak)

Example 7

(1) A εolution of 8-hydroxy-2-methylquinoline (737 mg) in dimethylformamide was dropwise added to a solution of sodium

6/13485

- 95 - hydride (60% in oil, 185 mg) in dimethylformamide under ice- bath cooling, and the mixture was stirred for 1 hour at the same temperature. To the mixture was added 2 , 6-dichloro-l- methylsulfonyloxymethyl-3- (methoxymethoxy)benzene (1.46 g) under ice-bath cooling, and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue waε purified by εilica gel column chromatography (ethyl acetate - n-hexane) to give 8-[2, 6-dichloro-3- (methoxymethoxy)- benzyloxy]-2-methylquinoline as an oil.

NMR (CDC1 ₃ , δ) : 2.75 (3H, s) , 3.53 (3H, s), 5.26 (2H, s), 5.63 (2H, s), 7.15 (IH, C, J=8Hz) , 7.23-7.45 (5H, m) , 8.00 (IH, d, J=8Hz)

(2) To a solution of 8-[2,6-dichloro-3- (methoxymethoxy)benzyloxy]-2-methylquinoline (1.57 g) in methanol was dropwise added cone, hydrochloric acid (2.7 ml) at 0°C, and the mixture was stirred for 5 minutes. The solvent was removed, and water was added thereto. The mixture was neutralized with saturated sodium bicarbonate solution, and the resulting precipitates were collected by filtration to give 8- (2, 6-dichloro-3-hydroxybenzyloxy)-2- methylquinoline (734 mg) as a solid.

NMR (DMSO-d ₆ , δ) : 2.73 (3H, s), 5.44 (2H, s) , 7.10

(IH, d, J=8Hz), 7.34 (IH, d, J=8Hz), 7.53-7.76 (4H, ) , 8.48-8.64 (IH, brpeak)

(3) 8-[2, 6-Dichloro-3-(2-phthalimidoethoxy)benzyloxy]-2- methylquinoline was obtained by reacting 8-(2, 6-dichloro-3- hydroxybenzyloxy)-2-methylguinoline with 2-phthalimidoethyl bromide according to a similar manner to that of Preparation 27-(4) . NMR (CDC1 ₃ , δ) : 2.70 (3H, s) , 4.16 (2H, t, J=5Hz) ,

- 96 -

4.28 (2H, t, J=5Hz) , 5.55 (2H, s), 6.95 (IH, d, J=8Hz), 7.20 (IH, dd, 3=2 , 8Hz) , 7.23-7.31 (2H, m) , 7.31-7.43 (2H, m) , 7.67-7.76 (2K, ) , 7.79-7.91 (2H, ) , 7.99 (IH, d, J=8Hz)

(4) 8- [3- (2-Aminoethoxy) -2, 6-dichlorobenzyloxy] -2- methylquinoline was obtained according to a similar manner to that of Preparation 11.

NMR (CDC1 ₃ , δ) : 2.72 (3K, s) , 3.17 (2H, t, J=5Hz) , 4.08 (2H, t, J=5Hz), 5.60 (2H, s), 5.90 (IH, d,

J=8Hz), 7.20-7.30 (3H, m) , 7.30-7.46 (2H, m) , 8.03 (IH, d, J=8Hz)

(5) To a solution of 8- [3- (2-aminoethoxy) -2, 6- dichlorobenzyloxy] -2-methylquinoline (11 mg) in dichloromethane were added pyridine (3.46 g) and acetic anhydride (4.47 mg) , and the mixture was stirred for 30 minutes. The mixture waε concentrated, and the reεidue was purified by preparative thin-layer chromatography (dichloromethane :methanol = 10:1, V/V) to give 8- [3- (2- acetamidoethoxy) -2, 6-dichlorobenzyloxy] -2-methylquinoline ( 6 mg) as an amorphous powder.

NMR (CDCI3, δ) : 1.97 (3H, s) , 2.71 (3H, ε) , 3.61 (2H, q, J=5Hz), 4.10 (2H, t, J=5Hz) , 5.56 (2H, s) , 6.83 (IH, d, J=8Hz), 6.99 (IH, t-like), 7.20-7.28 (2H, m) , 7.31 (IH, d, J=8Hz) , 7.41 (2.2H, d-like) , 8.04 (IH, d, J=8Hz)

(6) 8- [2, 6-Dichloro-3- [2- [4- (methylcarbamoyl) cinnamamido] - ethoxy]benzyloxy] -2-methylquinoline was obtained from 8- [3-

(2-aminoethoxy) -2, 6-dichlorobenzyloxy] -2-methylquinoline and 4- (methylcarbamoyl) cinnamic acid according to a similar manner to that of Example 1.

NMR (CDCI3, δ) : 2.42 (3H, s) , 2.78 (3H, d, J=5Hz) , 3.75 (2H, q, J=5Hz) , 4.14 (2H, t, J=5Hz) , 5.49 (2H,

- 97 - ε), 6.66 (IH, d, J=8Hz), 6.72 (IH, d, J=16Hz), 6.99 (IH, d, J=8Hz), 7.21-7.29 (IH, m) , 7.35-7.51 (4H, m) , 7.55 (IH, d, J=16Hz), 7.77 (2H, d, J=8Hz) , 7.97 (IH, q-like), 8.00-8.07 (2H, m)

Example 29

(1) 8-[2, 6-Dichloro-3-[N-ethoxycarbonylmethyl-N- (phthalimidoacetyl)amino]benzyloxy]-2-methylquinoline waε obtained by reacting 8-[2, 6-dichloro-3- (phthalimidoacetyl- amino)benzyloxy]-2-methylquinoline with ethyl bromoacetate according to a εimiiar manner to that of Preparation 10. mp : 211-213°C

NMR (CDC1 ₃ , δ) : 1.28 (3H, t, J=7.5Hz), 2.73 (3H, s) , 3.68 (IH, d, J=17Hz), 4.03 (IH, d, J=17Hz) , 4.13- 4.30 (3H), 5.00 (IH, d, J=17Kz) , 5.65 (IH, d,

J=10Hz), 5.70 (IH, d, J=10Hz), 7.23-7.31 (2H) , 7.36-7.49 (3H), 7.69-7.75 (2H) , 7.81-7.91 (3K) , 8.01 (IH, d, J=8Hz)

(2) To the solution of 8- [2 , 6-dichloro-3-[N-ethoxy- carbonylmethyl-N-(phthalimodoacetyl)amino]benzyloxy]-2- methylquinoline (527 mg) in dichloromethane (5.3 ml) was added 30% solution of methylamine in methanol (2 ml) at ambient temperature. After stirring for 24 hours, the reaction mixture was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel 50 ml) eluting with dichloromethane:methanol (20:1, V/V) and by crystallizing from isopropyl ether to give 8-[2, 6-dichloro-3- (2, 5-dioxopiperazin-l-yl)benzyloxy]-2-methylquinoline (187 mg) as colorless crystalε. mp : 211-213 ^β C

NMR (CDCI3, δ) : 2.74 (3H, ε) , 4.09-4.21 (3H) , 4.40 (IH, d, J=17Hz), 5.62 (2H, s), 6.38 (IH, br ε) , 7.21-7.51 (6H), 8.01 (IH, d, J=8Hz)

(3) 8- [2, 6-Dichloro-3- (4-ethoxycarbonylmethyl-2, 5- dioxopiperazin-1-yl)benzyloxy] -2-methylquinoline waε obtained by reacting 8- [2, 6-dichloro-3- (2, 5- dioxopiperazin-1-yl)benzyloxy] -2-methylquinoline with ethyl bromoacetate according to a εimiiar manner to that of Preparation 10. NMR (CDCI ₃ , δ) : 1.31 (3H, t, J=7.5Hz), 2.74 (3H, s),

4.11-4.36 (7H), 4.48 (IH, d, J=17Hz) , 5.61 (2H, s), 7.21-7.32 (3H), 7.36-7.51 (3H), 8.02 (IH, d, J=8Hz)

(4) 8- [2, 6-Dichloro-3- (4-carboxymethyl-2, 5-dioxopiperazin-l- yl)benzyloxy] -2-methylquinoline waε obtained according to a εimiiar manner to that of Example 3.

NMR (DMSO-d ₆ , δ) : 2.61 (3H, s) , 4.00-4.37 (5H, m) , 4.50 (IK, d, J=16Hz), 5.46 (2H, s), 7.37-7.56 (4H, m) , 7.69 (IH, d, J=8Hz) , 7.74 (IH, d, J=8Hz) , 8.21 (IH, d, J=8Hz)

(5) 8- [2, 6-Dichloro-3-[4-[4- (methylcarbamoyl) - phenylcarbamoylmethyl] -2 , 5-dioxopiperazin-l- yl]benzyloxy] -2-methylquinoline was obtained from 8- [ 2 , 6-dichloro-3- (4-carboxymethyl-2, 5-dioxopiperazin-l- yl)benzyloxy] -2-methylquinoline and 4-amino-N- methylbenzamide according to a similar manner to that of Example 7.

NMR (CDC1 ₃ -CD ₃ 0D, δ) : 2.62 (3H, s), 3.89 (3H, ε) , 4.07 (IH, d, J=16Hz), 4.18 (IH, d, J=16Hz) , 4.27-4.41 (4H, m) , 5.50 (2H, ε), 7.19-7.30 (4H, m) , 7.37-7.44 (3H, m) , 7.56 (2H, d, J=8Hz) , 7.70 (2H, d, J=8Hz) , 8.02 (IH, d, J=8Hz)

Preparation 33

The following compoundε were obtained according to a similar manner to that of Preparation 12.

(1) 8-Hydroxy-2-methyl-4- (2,2,2-trifluoroethoxy) quinoline mp : 117-119°C

NMR (CDC1 ₃ , δ) : 2.69 (3H, ε) , 4.56 (2H, q, J=7.5Hz), 6.60 (IH, ε), 7.17 (IH, d, J=8Hz) , 7.38 (IH, t, J=8Hz), 7.60 (IH, d, J=8Hz)

(2) 8-Hydroxy-4-propoxy-2-methylquinoline mp : 60-62 ^' C

NMR (CDCI3, δ) : 1.13 (3H, t, J=7.5Hz), 1.89-2.03 (2H, m) , 2.65 (3H, ε) , 4.12 (2H, t, J=8Hz) , 6.61 (IH, ε), 7.11 (IH, d, J=8Hz), 7.3C (IH, t, J=8Hz), 7.60 (IH, d, J=8Hz)

Example 29 The following compoundε were obtained according to a similar manner to that of Example 9.

(1) 8-[3-[N-[ (E)-3-(6-Acetylaminopyridin-3- yl) acryloylglycyl]-N-methylamino]-2, 6-dichloro- benzyloxy]-4-dimethylamino-2-methylquinoline

NMR (CDCI3, δ) : 2.21 (3H, s) , 2.72 (3H, br s) , 3.11

(6H, br s), 3.26 (3H, ε), 3.76 (IH, br d, J=17Hz), 4.00 (IH, dd, J=17.5Hz), 5.59 (2H, s) , 6.53 (IH, br d, J=15Hz), 6.67 (IH, s), 7.21-7.52 (5H, m) , 7.70 (IH, d, J=8Hz), 7.78 (IH, br d, J=8Hz), 8.10 (IH, br d, J=8Hz), 8.20 (IH, s) , 8.31 (IH, s)

its trihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.44 (3H, s) , 2.77 (3H, br ε) , 3.27 (3H, s), 3.51 (6H, s), 3.85 (IH, d, J=17Hz),

4.42 (IH, d, J=17Hz), 5:42 (IH, d, J=10Hz) , 5.62 (IH, d, J=10Hz), 6.75 (IH, br ε) , 6.94 (IH, br d, J=15Hz), 7.27 (IH, br d, J=15Hz), 7.43 (IH, d, J=8Hz), 7.50-7.68 (3H, m) , 7.82 (IH, d, J=8Hz) , 8.14 (IH, br d, J=8Hz), 8.35 (IH, br d, J=8Hz) ,

8 . 90 ( IH, br s )

(2) 8- [3- [N- [ (E) -3- (6-Acetylaminopyridin-3-yl) acryloyl¬ glycyl] -N-methylamino] -2, 6-dichiorobenzyloxy] -4-ethoxy- 2-methylquinoline

NMR (CDC1 ₃ , δ) : 1.55 (3H, br t, J=7.5Hz), 2.20 (3K, ε), 2.66 (3H, ε), 3.25 (3H, s), 3.66 (IH, dd, J=17, 4Hz), 3.93 (IH, dd, J=17, 5Hz) , 4.16-4.29 (2H, m) , 5.59 (2H, br ε), 6.47 (IH, d, J=15Hz), 6.61 (IH, ε), 6.73 (IK, br s) , 7.19-7.55 (5K, m) , 7.76-7.89

(2H, m) , 8.08-8.21 (2H, m) , 8.32 (IH, br s)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 1.63-1.72 (3H, m) , 2.42 (3H, s), 3.02 (3H, br s) , 3.28 (3H, s) , 3.89 (IH, d,

J=17Hz), 4.29 (IH, d, J=17Hz), 4.56-4.66 (2H, ) , 5.48 (IH, d, J=10Hz), 5.67 (IH, d, J=10Hz) , 6.92 (IH, br d, J=15Hz), 7.16-7.63 (5H, m) , 7.72 (IH, t, J=8Hz), 7.98 (IH, d, J=8Hz) , 8.10-8.16 (IH, m) , 8.44-8.51 (IH, m) , 8.84-8.92 (IH, m)

(3) 8- [2, 6-Dichloro-3- [N-methyl-N- [4- (methylcarbamoyl) - cinnamoylglycyl] amino]benzyloxy]-2-methyl-4- (2,2,2- trifluoroethoxy) quinoline NMR (CDCI3, δ) : 2.69 (3H, s), 3.01 (3H, d, J=5Hz) ,

3.25 (3H, s), 3.63 (IH, dd, J=4, 18Hz) , 3.92 (IH, dd, 3=4 , 18Hz), 4.55 (2H, q, J=8Hz) , 5.60 (IH, d, J=10Hz), 5.65 (IH, d, J=10Hz) , 6.23 (IH, q-iike) , 6.53 (IH, d, J=16Hz), 6.62 (IH, s-like), 6.70 (IH, t-like), 7.27-7.35 (2H, m) , 7.39-7.63 (5H, m) , 7.75

(2H, d, J=8Hz), 7.85 (IH, d, J=8Hz)

its hydrochloride

NMR (DMSO-d ₆ , δ) : 2.79 (3H, d, J=3Hz) , 2.88 (3H, s), 3.13 (3H, ε), 3.60 (IH, dd, J=5, 16Hz) , 5.36 (2H,

- 101 - q, J=8Hz), 5.60 (IH, d, J=10Hz) , 5.66 (IH, d, J=10Hz), 6.88 (IH, d, J=16Hz), 7.41 (IH, d, J=16Hz), 7.55-7.67 (2H, m) , 7.73 (IH, s-like), 7.80-8.01 (7H, m), 8.38 (IH, t-like), 8.51 (IH, q-like)

(4) 8-[3-[N-[ (E)-3- (6-Acetylaminopyridin-3-yl)acryloyl¬ glycyl]-N-methylamino]-2, 6-dichlorobenzyloxy]-2-methyl- 4- (2, 2,2-trifluoroethoxy)quinoline NMR (CDC1 ₃ , δ) : 2.21 (3H, s) , 2.70 (3H, s) , 3.26 (3H, ε), 3.65 (IH, dd, J=17 and 4Hz) , 3.94 (IH, dd, J=17 and 5Hz), 4.55 (IH, σ, J=7.5Hz), 5.59 (IH, d, J=9Hz), 5.64 (IH, d, J=9Hz) , 6.45 (IH, d, J=15Hz) , 6.61 (IH, s), 6.71 (IH, br t, J=4Hz) , 7.29 (IH, d, J=9Hz), 7.30 (IH, d J=8Hz) , 7.42 (IH, d, J=9Hz) ,

7.48 (IH, t, J=8Hz), 7.52 (IH, d, J=15Hz), 7.81 (IH, dd, 3=9 and 1Hz), 7.85 (IH, d, J=9Hz), 8.14 (IH, br ε), 8.20 (IH, d, J=9Hz) , 8.35 (IH, d, J=lHz)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.41 (3H, s) , 3.09 (3H, br s) , 3.28 (3H, s), 3.92 (IH, d, J=17Hz), 4.15 (IH, d, J=17Hz), 5.10 (2H, br q, J=9Hz) , 5.49 (IH, d, J=9Hz), 5.68 (IH, d, J=9Hz) , 6.89 (IH, br d,

J=15Hz), 7.41 (IH, d, J=15Hz) , 7.53-7.64 (3H, m) , 7.70-7.84 (2H, m) , 7.99 (IH, d, J=9Hz), 8.04 (IH, d, J=8Hz), 8.59 (IH, br d, J=8Hz), 8.88 (IH, br s)

(5) 8-[2,6-Dichloro-3-[N-methyl-N-[4-(methylcarbamoyl) - cinnamoylglycyl]amino]benzyloxy]-4-propoxy-2- methylquinoline

NMR (CDCI3, δ) : 1.13 (3H, t, J=7.5Hz), 1.91-2.02 (2H, m) , 2.66 (3H, br s), 3.00 (3H, d, J=5Hz) , 3.25 (3H, s), 3.64 (IH, dd, J=17, 4Hz) , 3.93 (IH, dd, J=17,

- 102 -

5Hz), 4.13 (2H, br t, J=7.5Hz), 5.60 (IH, d, J=10Hz) , 5.65 (IH, d, J=10Hz) , 6.33 (IH, br d, J=5Hz), 6.53 (IH, d, J=15Hz), 6.63 (IH, s) , 6.72 (IH, br s), 7.22-7.32 (2H, m) , 7.37 (IH, br t, J=8Hz), 7.47 (IH, d, J=8Hz), 7.51 (2H, d, J=8Hz) ,

7.58 (IH, d, J=15Hz), 7.75 (2H, d, J=8Hz) , 7.88 (IH, d, J=8Hz)

its hydrochloride NMR (CDCI3-CD3OD, δ) : 1.18 (3H, t, J=7.5Hz), 2.00-

2.13 (2H, m) , 2.98 (3H, s), 3.00 (3H, s), 3.29 (3H, s), 3.88 (IH, d, J=17Hz), 4.15 (IH, d, J=17Hz) , 4.49 (2H, br t, J=7.5Hz), 5.51 (IH, d, J=10Hz) , 5.68 (IH, d, J=10Hz) , 6.65 (IH, d, J=15Hz) , 7.26 (IH, br s), 7.39 (IK, d, J=15Hz) , 7.48-7.60 (5H, m) , 7.69-7.81 (3H, m) , 7.97 (IH, br d, J=8Hz)

(6) 8-[3- [N- [ (E)-3- (6-Acetylaminopyridin-3-yl)acryloyl¬ glycyl]-N-methylamino]-2, 6-dichlorobenzyloxy]-4-propoxy- 2-methylσuinoline

NMR (CDCI3, δ) : 1.15 (3H, t, J=7.5Hz), 1.91-2.02

(2H, m) , 2.21 (3H, s) , 2.68 (3H, s) , 3.28 (3H, s) , 3.67 (IH, dd, J=17, 4Hz) , 3.96 (IH, dd, J=17, 5Hz) , 4.13 (2H, br t, J=7.5Hz), 5.61 (IH, d, J=10Hz) , 5.68 (IH, d, J=10Hz) , 6.48 (IH, d, J=15Hz) , 6.63

(IH, s), 6.73 (IH, br s) , 7.21-7.40 (3H, m) , 7.45- 7.58 (2H, m) , 7.79-7.90 (2H, m) , 8.12-8.23 (2H, m) , 8.34 (IH. br s)

itε dihydrochloride

NMR (CDCI3-CD3OD, δ) : 1.18 (3H, t, J=7.5Kz), 2.00-

2.13 (2H, m) , 2.42 (3H, s), 3.00 (3H, br s) , 3.28

(3H, s), 3.88 (IH, d, J=17Hz) , 4.29 (IH, d,

J=17Hz), 4.49 (2H, br t, J=7.5Hz), 5.47 (IH, d, J=10Hz), 5.66 (IH, d, J=10Hz), 6.90 (IH, br d,

J=15Hz), 7.25 (IH, br s) , 7.36 (IH, br d, J=15Hz) , 7.50-7.64 (3H, m) , 7.73 (IH, t, J=8Hz) , 7.97 (IH, d, J=8Hz), 8.13 (IH, br d, J=8Hz), 8.48 (IH, br d, J=8Hz) , 8.90 (IH, br s)

(7) 8-[3-[N-[ (E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]- N-methylamino]-2, 6-dichlorobenzyloxy]-4-isopropoxy-2- methylquinoline

NMR (DMSO-d ₆ , δ) : 2.19 (3H, s ) , 2.66 (3H, s), 3.26 (3K, s), 3.69 (IK, dd, 3=4 , 18Hz) , 3.95 (IH, dd,

J=4,18Hz), 4.80 (IH, m) , 5.5C-5.65 (2H, m) , 6 . 46 (IH, d, J=16Hz), 6.61 (IK, s-like), 6.96 (IH, brpeak), 7.17-7.58 (5H, m) , 7.72-7.90 (2H, m) , 8.16 (IH, d, J=8Hz), 8.30 (IH, s-like), 8.60 (IH, brpeak)

its dihydrochloride

NMR (DMSO-d ₆ , δ) : 1.49 (6H, d, J=7Hz) , 2.11 (3H, s) , 2.85 (3H, s), 3.14 (3H, ε) , 3.59 (IH, dd, J=4, 16Hz), 3.90 (IH, dd, 3=4 , 16Hz) , 5.24 (IH, m) , 5.60

(IH, d, J=10Hz), 5.66 (IH, d, J=10Hz) , 6.79 (IH, d, J=16Hz), 7.37 (IH, d, J=16Hz) , 7.60 (IH, s-like), 7.75-8.05 (7H, m) , 8.11 (IH, d, J=8Hz), 8.31 (IH, t-like), 8.48 (IH, d-like)

(8) 8-[3-[N-[ (E)-3- (6-Acetamidopyridin-3-yl)acryloylglycyl]- N-methylamino]-2, 6-dichlorobenzyloxy]-4- (2- methoxyethoxy)-2-methylquinoline

NMR (CDC1 ₃ , δ) : 2.21 (3H, s) , 2.67 (3H, s) , 3.25 (3H, s), 3.50 (3H, s), 3.65 (IH, dd, 3=4 , 18Hz) , 3.85-

4.02 (3H, m) , 4.32 (2H, t, J=5Hz) , 5.62 (2H, s-like), 6.47 (IH, d, J=16Hz), 6.65 (IH, s-like), 6.71 (IH, brpeak), 7.19-7.41 (3H, m) , 7.41-7.57 (2H, m) , 7.78-7.92 (2H, m) , 8.07 (IH, s-like), 8.19 (IH, d, J=8Hz), 8.34 (IH, d, J=2Hz)

its dihydrochloride

NMR (DMSO-dg, δ) : 2.10 (3H, s), 2.85 (3H, ε) , 3.14 (3H, ε), 3.37 (3H, s), 3.59 (IH, dd, J=4, 16Hz), 3.84-3.96 (3H, m) , 4.61-4.63 (2H, ) , 5.60 (IH, d, J=10Hz), 5.66 (IH, d, J=10Kz) , 6.79 (IH, d,

J=16Hz), 7.37 (IH, d, J=16Hz) , 7.60 (IH, s-like), 7.78-8.03 (7H, m) , 8.11 (IH, d, J=8Hz), 8.31 (IH, t-like), 8.47 (IH, d, J=2Hz)

Example 30

(1) Methyl (E)-3- (indol-5-yl)acrylate was obtained by reacting indole-5-carbaldehyde with methyl (triphenylphosphoranilidene)acetate according to a similar manner to that of Preparation 1. mp : 139.6-142.2°C

NMR (CDC1 ₃ , δ) : 3.80 (3H, s) , 6.44 (IH, d, J=15Hz) , 6.59 (IH, d-like), 7.20-7.27 (2H, m) , 7.33-7.46 (2H, m) , 7.75-7.88 (2H, ) , 8.27 (IH, brpeak)

(2) ⁽ E ) -3- (Indol-5-yl)acrylic acid was obtained according to a εimiiar manner to that of Preparation 3. mp : >185°C (dec.) NMR (DMSO-d ₆ , δ) : 6.39 (IH, d, J=16Hz) , 6.49 (IH, t-like), 7.36-7.50 (3H, m) , 7.69 (IH, d, J=16Hz) , 7.83 (IH, ε-like)

(3) 8-[2, 6-Dichloro-3-[N-methyl-N- [ (E)-3- (indol-5-yl)- acryloylglycyl]amino]benzyloxy]-2-methylquinoline waε obtained according to a εimiiar manner to that of Example 1.

NMR (CDCI3, δ) : 2.71 (3H, s) , 3.22 (3H, s), 3.62 (IH, dd, 3=4 , 18Hz), 3.93 (IH, dd, 3=4 , 18Hz) , 5.63 (2H, ε-like), 6.43 (IH, d, J=16Hz) , 6.50-6.59 (2H, m) , 7.17-7.22 (IH, m) , 7.22-7.50 (8H, m) , 7.70 (IH, d, J=16Hz), 7.76 (IH, ε-like), 8.03 (IH, d, J=8Hz) ,

8 . 55 ( IH, br s )

its dihydrochloride

NMR (DMSO-d ₆ , δ) : 2.90 (3H, s) , 3.15 (3H, s) , 3.59 (IH, dd, J=4,16Hz), 3.88 (IH, dd, J=4, 16Hz) , 5.54-

5.69 (2H, m) , 6.47 (IH, s-like), 6.66 (IH, d, J=16Hz), 7.29-7.52 (4H, m) , 7.71 (IH, s-like), 7.76-8.02 (6H, m) , 8.19 (IH, t-like), 8.95 (IH, brpeak)

Example 31

(1) 4-Acetamido-3-methylcinnamic acid was obtained by reacting 4-acetamido-3-methylbenzaldehyde with malonic acid according to a similar manner to that of Preparation 4. mp : 262-263°C (dec.)

NMR (DMSO-d ₆ , δ) : 2.09 (3H, s) , 2.23 (3H, s) , 6.43 (IH, d, J=16Hz), 7.43-7.61 (4H) , 9.33 (IH, ε)

(2) 8-[3-[N- (4-A.cetamido-3-methylcinnamoylglycyl)-N- methylamino]-2, 6-dichlorobenzyloxy]-2-methylσuinoline waε obtained according to a similar manner to that of Example 1.

NMR (CDC1 ₃ , δ) : 2.22 (3H, s) , 2.27 (3H, s) , 2.73 (3H, s), 3.25 (3H, s) , 3.63 (IH, dd, J=18, 4Hz) , 3.94

(IH, dd, J=18, 4Hz), 5.64 (2H, s) , 6.41 (IH, d, J=16Hz), 6.62 (IH, br ε) , 7.05 (IH, br s) , 7.22- 7.55 (9H), 7.89-8.06 (2H)

its hydrochloride

NMR (DMSO-d ₆ , δ) : 2.09 (3H, s) , 2.22 (3H, s) , 2.91 (3K, ε), 3.15 (3H, s) , 3.59 (IK, dd, J=18, 4Hz) , 3.89 (IH, dd, J=18, 4Hz), 5.64 (2H, s) , 6.72 (IH, d, J=16Hz), 7.26-8.00 (10H), 8.28 (IH, t, J=4Hz) , 8.97 (IH, br ε) , 9.38 (IH, s)

Example 32

(1) (E) -3- (6-Ethoxypyridin-3-yl) acrylic acid was obtained b reacting 6-ethoxypyridine-3-carbaldehyde with malonic acid according to a εimiiar manner to that of Preparation 4. mp : 171-172'C

NMR (CDC1 ₃ -CD ₃ 0D, δ) : 1.40 (3H, t, J=6Hz) , 4.37 (2K, q, J=6Hz), 6.36 (IH, d, J=16Hz) , 6.80 (IH, d, J=8Hz), 7.63 (IH, d, J=16Hz) , 7.89 (IH, dd, J=8, 1Hz), 8.23 (IH, d, J=lHz)

(2) 8- [2, 6-Dichloro-3- [N- [ (Ξ) -3- (6-ethoxypyridin-3- yl) acryloylglycyl] -N-methylamino]benzyloxy] -2- methylquinoline waε obtained according to a similar manner to that of Example 1.

NMR (CDC1 ₃ , δ) : 1.40 (3H, t, J=6Hz) , 2.73 (3H, s),

3.27 (3H, ε), 3.65 (IH, dd, J=16, 4Hz) , 3.94 (IH, dd, J=16, 4Hz), 4.38 (2H, q, J=6Hz) , 5.66 (2H, ε) , 6.38 (IH, d, J=16Hz), 6.62 (IH, t, J=4Hz) , 6.72 (IH, d, J=8Hz), 7.23-7.56 (7H) , 7.73 (IH, dd, J=8,

2Hz), 8.03 (IH, d, J=8Hz) , 8.23 (IH, ε)

itε dihydrochloride

NMR (DMSO-d ₆ , δ) : 1.33 (3H, t, J=6Hz) , 2.92 (3H, s) , 3.16 (3H, s), 3.58 (IH, dd, J=16, 4Hz) , 3.89 (IH, dd, J=16, 4Hz), 4.33 (2H, q, J=6Hz), 5.65 (2H, s) , 6.73 (IH, d, J=16Hz), 6.87 (IH, d, J=8Hz) , 7.32- 7.99 (8H), 8.23-8.36 (2H) , 8.98 (IH, br s)

Example 33

(1) To a solution of 2, 6-dimethylbenzoic acid (20 g) in cone, sulfuric acid (100 ml) was dropwise added under ice- cooling a mixture of 70% nitric acid and cone, sulfuric acid (21.6 ml), which was prepared by dropwise adding cone. sulfuric acid (10.8 ml) to 70% nitric acid (15.1 ml) under

- 107 - ice-cooling, and the mixture was stirred for 1 hour at the same temperature. Ice-water was added to the reaction mixture, and the resulting precipitates were filtered off. The filtrate was concentrated, and the residue was purified by flash chromatography (dichloromethane : methanol = 20 : 1 including 1% acetic acid) to give 2, 6-dimethyl-3-nitrobenzoic acid (7.0 g) as a colorless crystal. mp : 109-112°C

NMR (CDC1 ₃ , δ) : 2.48 (3H, s) , 2.57 (2H, s) , 7.22 (IH, d, J=8Hz), 7.87 (IH, d, J=8Hz)

(2) To a solution of 2, 6-dimethyl-3-nitrobenzoic acid (3.09 g) in tetrahydrofuran (5 ml) was added borane-methyl sulfide complex (2.41 g) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature, for 1 hour at ambient temperature, and then for 4 hours under heating. To the mixture was added IN hydrochloric acid under ice-cooling, and the mixture was allowed to stand overnight. The mixture was extracted with ethyl acetate twice, and the combined organic layer was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. The residue was recrystallized with diisopropyl ether to give 2, -dimethyl-3-nitrobenzyl alcohol (2.296 g) as a pale yellow crystal. mp : 99-101°C

NMR (CDCI3, δ) : 1.45 (IH, t, J=5Hz) , 2.50 (3H, s) , 2.56 (3H, s), 4.80 (2H, d, J=5Hz) , 7.15 (IH, d, J=8Hz), 7.64 (IH, d, J=8Hz)

(3) To a εolution of 2,6-dimethyl-3-nitrobenzyl alcohol (1.5 g) and triethylamine (1.01 g) in dichloromethane (15 ml) waε dropwise added methanesulfonyl chloride (1.04 g) under ice- cooling, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed with saturated sodium bicarbonate solution and water, dried over

magnesium sulfate and concentrated in vacuo to give a mixtur of 2, 6-dimethyl-3-nitrobenzyl methanesulfonate and 2,6- dimethyl-3-nitrobenzyl chloride, which was used as a startin compound at the following example without further purification.

(4) 8- (2, 6-Dimethyl-3-nitrobenzyloxy) -2-methylquinoline was obtained by reacting 8-hydroxy-2-methylquinoline with a mixture of 2, 6-dimethyl-3-nitrobenzyl methanesulfonate and 2, 6-dimethyl-3-nitrobenzyl chloride obtained above according to a similar manner to that of Preparation 6. mp : 150-152°C

NMR (CDC1 ₃ , δ) : 2.58 (3K, s) , 2.65 (3H, s), 2.73 (3H, ε) , 5.39 (2H, s), 7.18-7.33 (3H, ) , 7.38-7.50 (2H, m) , 6.60 (IK, s), 7.72 (IH, d, J=8Hz) , 8.04 (IH, d,

J=8Hz)

(5) To a suεpension of 8- (2, 6-dimethyl-3-nitrobenzyloxy) -2- methylquinoline (2.34 g) , ferric chloride (70.6 mg) and carbon (70.6 mg) in methanol (35 ml) was added hydrazine monohydrate (1.09 g) at 65°C, and the mixture was refluxed for 2 hours. Methanol (20 ml) was added thereto, and the mixture waε refluxed for 1 hour. After cooling chloroform waε added thereto, and the reεulting precipitates were filtered off. The filtrate was concentrated and the residue was diεsolved in chloroform. The solution waε washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. The residue waε cryεtallized with ethyl acetate to give 8- (3-Amino-2, 6- dimethylbenzyloxy) -2-methylquinoline (1.67 g) as a pale brown crystal . mp : 204-205°C

NMR (CDCI3, δ) : 2.27 (3H, s) , 2.37 (3H, s) , 2.72 (3H, s), 3.57 (2H, br s) , 5.32 (2H, s), 6.67 (IH, d, J=8Hz), 6.91 (IH, d, J=8Hz) , 7.18-7.31 (2H, m) ,

7 . 36-7 . 42 (2H, m) , 8 . 00 ( IH, d, J=8Hz )

(6) 8- [2, 6-Dimethyl-3- (phthalimidoacetylamino)benzyloxy] -2- methylquinoline was obtained according to a similar manner to that of Preparation 9. mp : 266-268°C NMR (CDCI3-CD3OD, δ) : 2.22 (3H, s), 2.42 (3H, s),

2.68 (3H, ε), 4.58 (2H, ε) , 5.28 (2H, s) , 7.08 (IH, d, J=8Hz), 7.23-7.51 (5H, m) , 7.73- 7.80 (2H, m) , 7.87-7.95 (2H, m) , 8.08 (IH, d, J=8Hz)

(7) 8- [2, 6-Dimethyl-3- [N- (phthalimidoacetyl) -N- methylamino]benzyloxy] -2-methylquinoline was obtained according to a similar manner to that of Preparation 10. mp : 102-110°C

NMR (CDCI3, δ) : 2.51 (3H, s), 2.57 (3H, ε), 2.73 (3H, s), 3.22 (3H, s), 3.96 (IH, d, J=17Hz) , 4.19 (IH, d, J=17Hz), 5.38 (IH, d, J=10Hz) , 5.43 (IH, d, J=10Hz), 7.17-7.32 (4H, m) , 7.37-7.48 (2H, m) , 7.67-7.74 (2H, m) , 7.80-7.89 (2H, m) , 8.02 (IH, d,

J=8Hz)

(8) 8- [3- (N-Glycyl-N-methylamino) -2, 6-dimethylbenzyloxy] -2- methylquinoline was obtained according to a εimiiar manner to that of Preparation 11.

NMR (CDCI3, δ) : 2.32 (3H, s) , 2.53 (3H, s) , 2.72 (3H, ε), 2.93 (IH, d, J=17Hz), 3.93 (IH, d, J=17Hz) , 3.22 (3H, s), 5.36 (2H, ε) , 7.03 (IH, d, J=8Hz), 7.14 (IH, d, J=8Hz), 7.20-7.32 (2H, m) , 7.37-7.48 (2H, m) , 8.03 (IH, d, J=8Hz)

(9) 8- [2, 6-Dimethyl-3- [N-methyl-N- [4- (methylcarbamoyl) - cinnamoylglycyl] amino]benzyloxy] -2-methylquinoline was obtained according to a similar manner to that of Example 1.

NMR (CDC1 ₃ , δ) : 2.37 (3H, ε), 2.52 (3H, ε), 2.72 (3H, s), 3.00 (3H, d, J=5Hz), 3.26 (3H, s), 3.63 (IH, dd, J=17, 4Hz), 3.88 (IH, dd, J=17, 5Hz) , 5.35 (2H ε), 6.22 (IH, br d, J=5Hz) , 6.52 (IH, d, J=15Hz), 6.75 (IH, br ε), 7.08 (IH, d, J=8Hz) , 7.18 (IH, d, J=8Hz), 7.22-7.32 (2H, m) , 7.41-7.61 (5H, m) , 7.73 (2H, d, J=8Hz), 8.04 (IH, d, J=8Hz)

itε hydrochloride

NMR (CDCI3-CD3OD, δ) : 2.30 (3H, s), 2.48 (3H, s),

2.99 (3H, ε), 3.12 (3H, br s), 3.28 (3H, s), 3.80 (IH, d, J=17Hz), 3.88 (IH, d, J=17Hz) _r 5.39 (IH, d J=10Hz), 5.49 (IH, d, J=10Hz) , 6.61 (IH, d, J=15Hz), 7.19-7.28 (2H, m) , 7.40-7.53 (3H, m) , 7.6 (IH, d, J=8Hz), 7.75-7.97 (5H, m) , 8.90 (IH, d,

J=8Hz)

(10) 8-[3-[N-[ (E)-3-(6-Acetylaminopyridin-3-yl)- acryloylglycyl]-N-methylamino]-2, 6-dimethylbenzyloxy]-2 methylquinoline was obtained according to a εimiiar manner to that of Example 1.

NMR (CDCI3, δ) : 2.21 (3H, ε), 2.36 (3H, ε), 2.52 (3H, s), 2.72 (3H, ε), 3.26 (3H, s) , 3.63 (IH, dd, J=17, 4Hz), 3.89 (IH, dd, J=17, 5Hz) , 5.36 (2H, s) , 6.45 (IH, d, J=15Hz), 6.72 (IH, br t, J=5Hz) , 7.08 (IH, d, J=8Hz), 7.17 (IH, d, J=8Hz) , 7.22-7.32 (2H, m) , 7.39-7.47 (2H, m) , 7.50 (IH, d, J=15Hz) , 7.83 (IH, dd, J=8, 3Hz), 8.00-8.08 (2H, m) , 8.20 (IH, br d, J=8Hz) , 8.34 (IH, br s)

itε dihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.30 (3H, ε), 2.44 (3H, s) ,

2.46 (3H, ε), 3.20 (3H, ε), 3.27 (3H, s) , 3.88 (IH, d, J=17Hz), 3.96 (IH, d, J=17Hz), 5.36 (IH, d, J=10Hz), 5.48 (IK, d, J=10Hz), 6.88 (IH, d,

- Ill -

J=15Hz), 7.21-7.31 (2H, m) , 7.48 (IH, d, J=15Hz) , 7.65 (IH, d, J=8Hz), 7.78 (IH, d, J=8Hz), 7.87 (IK, t, J=8Hz), 7.99 (IH, d, J=8Hz) , 8.15 (IH, d, J=8Hz), 8.44 (IH, d, J=8Hz), 8.80-8.90 (2H, m)

Example 34

The following compounds were obtained according to a similar manner to that of Example 20 .

(1) 8-[3-[N-[N'-(6-Methoxycarbonylpyridin-2-yl)- ureidoacetyl] -N-methylamino] -2, 6-dichlorobenzyloxy] -2- methylquinoline

NMR (DMSO-d _β , δ) : 2.60 (3H, ε), 3.13 (3H, s) , 3.53 (IH, dd, J=16.5, 5.5Hz), 3.77 (IH, dd, J=16.5, 5.5Hz), 3.88 (3H, s) , 5.46 (IH, d, J=10.5Hz), 5.52

(IH, d, J=10.5Hz), 7.33-7.59 (4H, m) , 7.62 (IH, d, J=8.5Hz), 7.67-7.76 (IK, m) , 7.77 (IK, d, J=8.5Hz), 7.80 (IH, d, J=8.5Hz), 7.80-7.91 (IH, m) , 7.97 (IH, m) , 8.20 (IH, d, J=8.5Hz), 9.87 (IH, s)

(2) 8- [3- [N-[N'~ (2-Acetamidopyridin-4-yl) ureidoacetyl]-N- methylamino]-2, 6-dichlorobenzyloxy]-2-methylσuinoline

(3) 8- [2, 6-Dichloro-3- [N- [N'~ (5-methoxycarbonylpyridin-3- yl) ureidoacetyl] -N-methylamino]benzyloxy] -2- methylquinoline mp : 177-187°C NMR (DMSO-d ₆ , δ) : 2.63 (3H, ε) , 3.17 (3H, s) , 3.47

(IH, dd, J=16.5, 4.5Hz), 3.69 (IH, dd, J=16.5, 4.5Hz), 3.87 (3H, s) , 5.50 (IH, d, J=10.0Hz), 5.57

(IH, d, J=10.0Hz), 6. 62 (IH, t, J=4.5Hz), 7.38-7.79

(6H, m) , 8.27 (IH, m) , 8.49 (IH, d, J=3.0Hz), 8.63

(2H, t, J=3.0Hz), 9.37 (IH, ε)

Example 35

The following compoundε were obtained according to a εimiiar manner to that of Example 3.

(1) 8- [3- [N- [N'- (6-Carboxypyridin-2-yl) ureidoacetyl] -N- methylamino] -2, 6-dichlorobenzyloxy] -2-methylquinoline mp : 233-236°C

NMR (DMSO-d ₆ , δ) : 2.60 (3H, ε), 3.11 (3H, ε),

3.54 (IH, dd, J=16.5, 5.5Hz), 3.76 (IH, dd, J=16.5, 5.5Hz), 5.46 (IH, d, J=10.0Hz), 5.51 (IK, d,

J=10.0Hz), 7.36-7.63 (6H, m) , 7.66-7.86 (3H, m) , 8.20 (IK, m) , 8.22 (IH, d, J=8.5Hz), 9.77 (IH, m)

(2) 8- [3- [N- [N'- (5-Carboxypyridin-3-yl) ureidoacetyl] -N- methylamino] -2, 6-dichlorobenzyloxy] -2-methylquinoline

Example 36

The following compounds were obtained according to a similar manner to that of Example 7.

(1) 8- [2, 6-Dichloro-3- [N- [N'- [6- (dimethylcarbamoyl)pyridin- 2-yl]ureidoacetyl] -N-methylamino]benzyloxy] -2- methylquinoline (from 8- [3- [N- [N ¹ - (6-carboxypyridin-2- yl) ureidoacetyl] -N-methylamino] -2, 6-dichlorobenzyloxy] - 2-methylquinoline and dimethylamine hydrochloride) mp : 110-130°C

NMR (CDC1 ₃ , δ) : 2.71 (3H, s), 3.03 (3H, s) , 3.16 (3H, ε), 3.23 (3H, ε), 3.84 (IH, dd, J=16.5, 5.5Hz), 4.11 (IH, dd, J=16.5, 5.5Hz), 5.56 (IH, d, J=10.0Hz), 5.62 (IH, d, J=10.0Hz) , 6.83 (IH, d,

J=8.5Hz), 7.13 (IH, d, J=7.5Hz), 7.21-7.35 (3H, m) , 7.38-7.49 (3H, m) , 7.59 (IH, t, J=8.5Hz), 8.05 (IH, d, J=8.5Hz), 8.72 (IK, ε), 9.16 (IH, m)

itε dihydrochloride

mp : 169-174°C

NMR (DMSO-d ₆ , δ) : 2.93 (6H, s) , 3.00 (3H, ε), 3.15

(3H, ε), 3.58 (IH, dd, J=16.5, 5.5Hz), 3.82 (IH, dd, J=16.5, 5.5Hz), 5.63 (2H, s) , 7.06 (IH, d, J=7.5Hz), 7.46 (IH, d, J=δ.5Hz), 7.77 (IH, t,

J=7.5Hz), 7.81-7.99 (6H, m) , 8.13 (IH, m) , 8.98 (IH, m) , 9.62 (IH, s)

(2) 8-[2, 6-Dichloro-3-[N-[N'-[5- (dimethylcarbamoyl)pyridin- 3-yl]ureidoacetyl]-N-methylamino]benzyloxy]-2- methylquinoline (from 8-[3-[N-[N'~ (5-carboxypyridin-3- yl)ureidoacetyl]-N-methylamino]-2, 6-dichlorobenzyloxy] - 2-methylquinoline and dimethylamine hydrochloride)

Example 37

(1) 8- (2-Chloro-5-nitrobenzyloxy)-2-methylquinoline was obtained according to a similar manner to that of Preparation 6.

NMR (DMS0-d ₆ , δ) : 2.69 (3H, ε) , 5.48 (2H, s), 7.32 (IK, d, J=7.5Hz), 7.43 (IH, d, J=7.5Hz), 7.46 (IH, d, J=7.5Hz), 7.53 (IH, d, J=7.5Hz), 7.83 (IH, d, J=7.5Hz), 8.22 (2H, dd, J=7.5, 2.0Hz), 8.77 (IH, d, J=2.0Hz)

(2) 8- (5-Amino-2-chlorobenzyloxy)-2-methylquinoline waε obtained according to a similar manner to that of Preparation 8. mp : 176-178°C

NMR (DMSO-d ₆ , δ) : 2.67 (3H, s) , 5.22 (2H, ε), 5.31 (2H, ε), 6.55 (IH, dd, J=7.5, 2.0Hz), 6.80 (IH, d,

J=2.0Hz), 7.10-7.16 (2H, m) , 7.37-7.48 (3H, m) , 8.19 (IK, d, J=7.5Hz)

(3) 8-[2-Chloro-5-[N-methyl-N- (phthalimidoacetyl)amino]- benzyloxy]-2-methylquinoline was obtained according to a

similar manners to those of Preparations 9 and 10. mp : 120-124°C

NMR (DMSO-d ₆ , δ) : 2.67 (3H, ε), 3.18 (3K, bs), 4.06

(2H, bε), 5.42 (2H, bs) , 7.29 (IK, d, J=7.5Hz), 7.41-7.96 (10H, m) , 8.19 (IH, d, J=7.5Hz)

(4) 8- [5- (N-Glycyl-N-methylamino) -2-chlorobenzyloxy] -2- methylquinoline was obtained according to a similar manner to that of Preparation 11. mp : 82-87°C

NMR (CDC1 ₃ , δ) : 2.83 (3H, s), 2.94 (2H, s), 3.19 (3H, s), 5.53 (2H, ε), 6.95 (IH, d, J=7.5Hz), 7.07 (IH, bd, J=7.5Hz), 7.30-7.44 (3H, m) , 7.46 (IH, d, J=8.5Hz), 7.56 (IH, d, J=1.5Hz) , 8.05 (IH, d, J=8.5Hz)

(5) 8- [2-Chloro-5- [N-methyl-N- [4- (methylcarbamoyl) - cinnamoylglycyl] amino]benzyloxy] -2-methylquinoline was obtained according to a similar manner to that of Example 1. mp : 221-228°C

NMR (CDCI3-CD3OD, δ) : 2.79 (3H, s) , 3.00 (3H, ε) ,

3.24 (3H, ε), 3.76 (2H, s) , 5.52 (2H, s), 6.52 (IH, d, J=15.0Hz) , 7.03 (IH, dd, J=7.5, 1.5Hz), 7.19 (IH, dd, J=7.5, 1.5Hz), 7.33-7.44 (3H, m) , 7.49-

7.60 (4H, m), 7.68 (IH, d, J=1.5Hz) , 7.76 (2H, d, J=7.5Hz) , 8.07 (IH, d, J=7.5Hz)

its hydrochloride mp : 161-171°C

NMR (DMSO-d ₆ , δ) : 2.79 (3H, d, J=4.5Hz), 2.96 (3H, s), 3.20 (3H, bs), 3.42-4.00 (2H, m) , 5.58 (2H, s) , 6.85 (IH, d, J=15.0Hz), 7.35 (IH, d, J=15.0Hz), 7.51 (IH, dd, J=7.5, 1.5Hz), 7.61-7.85 (5H, m) , 7.63 (2H, d, J=8.5Hz), 7.87 (2H, d, J=8.5Hz) , 7.91

- 11 c _

( IH, d, J=7 . 5Hz ) , 8 . 29 ( IH, t , J=5 . 5Hz ) , 8 . 53 ( IH, q, J=4 . 5Hz ) , 8 . 91 ( IH, d, J=7 . 5Hz )

(6) 8-[5-[N-[ (E)-3- (6-Acetamidopyridin-3-yl) acryloylglycly] - N-methylamino]-2-chlorobenzyloxy]-2-methylquinoline waε obtained according to a εimiiar manner to that of Example 1. mp : 204-205°C

NMR (CDCI3-CD3OD, δ) : 2.22 (3H, s), 2.81 (3H, s), 3.24 (3H, s), 3.76 (2H, d, J=4.0Hz), 5.52 (2H, s) ,

6.45 (IH, d, J=16.0Hz), 6.82 (IH, bt, J=4.0Hz), 7.03 (IH, dd, J=7.0, 1.5Hz), 7.17 (lK,- dd, J=8.5, 1.5Hz), 7.33-7.41 (3H, m) , 7.45-7.53 (2H, m) , 7.66 (IH, d, J=1.5Hz), 7.85 (IH, dd, J=8.5, 1.5Hz), 8.06 (IH, d, J=8.5Hz), 8.21 (IH, d, J=8.5Hz), 8.33 (IH, d, J=1.5Hz)

itε dihydrochloride mp : 151-160°C NMR (DMSO-d ₆ , δ) : 2.11 (3K, s) , 2.99 (3H, s) , 3.20

(3H, bs), 3.62-3.82 (2H, m) , 5.60 (2H, s) , 6.77 (IH, d, J=16.0Hz), 7.31 (IH, d, J=16.0Hz), 7.52 (IH, dd, J=8.5, 1.5Hz), 7.64-7.73 (2H, m) , 7.77- 7.89 (3H, m) , 7.95-8.03 (2H, m) , 8.10 (IH, d, J=8.5Hz), 8.24 (IH, t, J=5.5Hz), 8.47 (IH, d,

J=1.5Hz), 9.01 (IH, d, J=8.5Hz)

Example 38

(1) (E) -3- (2-Acetamidopyridin-4-yl) acrylic acid was obtained by reacting 2-acetamidopyridine-4-carbaldehyde with malonic acid according to a similar manner to that of Preparation 4. mp : 281-282°C

NMR (DMSO-d ₆ , δ) : 2.10 (3H, s), 6.63 (IH, d, J=16.0Hz), 7.39 (IH, d, J=5.5Hz), 7.51 (IH, d,

J=l 6 . 0Hz ) , 8 . 20 ( IH, s ) , 8 . 34 ( IH, d, J=5 . 5Hz )

(2) 8-[3-[N-[ ⁽ E) -3-(2-Acetamidopyridin-4-yl)acryloylglycyl] - N-methylamino]-2, 6-dichlorobenzylcxy]-2-methylquinoline was obtained according to a similar manner to that of Example 1. mp : 115-131°C

NMR (DMS0-d ₆ , δ) : 2.11 (3H, s), 2.60 (3H, s), 3.13 (3H, s), 3.52 (IH, dd, J=I6.5, 6.0Hz), 3.82 (IH, dd, J=16.5, 6.0Hz), 5.49 (IH, d, J=10.5Hz), 5.54

(IH, d, J=10.5Hz), 6.98 (IH, d, J=16.0Hz), 7.23 (IH, d, J=5.5Hz), 7.34 (IH, d, J=l6.0Hz), 7.35-7.50 (3H, m) , 7.54 (IH, d, J=7.5Hz), 7.78 (IH, d, J=8.5Hz), 7.81 (IH, d, J=8.5Hz), 8.21 (IH, d, J=7.5Hz), 8.26 (IH, s), 8.32 (IH, d, J=5.5Hz), 8.57

(IH, t, J=6.0Hz)

its dihydrochloride mp : 166-171°C NMR (DMSO-d ₆ , δ) : 2.12 (3H, ε), 2.91 (3H, s) , 3.16

(3H, s), 3.61 (IH, dd, J=16.5, 6.0Hz), 3.90 (IH, dd, J=16.5, 6.0Hz), 5.62 (IH, d, J=11.5Hz), 5.68 (IH, d, J=11.5Hz), 7.02 (IH, d, J=16.0Hz), 7.28 (IH, d, J=5.5Hz), 7.34 (IH, d, J=16.0Hz), 7.81 (IH, d, J=8.5Hz), 7.85 (IH, d, J=8.5Hz), 7.86-7.93 (3H, m) , 7.97 (IH, d, J=8.5Hz), 8.18 (IH, s), 8.33 (IH, d, J=5.5Hz), 8.64 (IH, t, J=6.0Hz), 9.02 (IH, d, J=8.5Hz)

Example 39

A mixture of 8-[3- [N- (bromoacetylglycyl) -N-methylamino]- 2, 6-dichlorobenzyloxy]-2-methylquinoline (90 mg) , 4-nitro-l- (1-piperazinyl)benzene (48 mg) and potassium carbonate (94 mg) in dimethylformamide (2 ml) was stirred at ambient temperature for 1 hour and water added thereto. The mixture

waε extracted with ethyl acetate twice, and the combined organic layer waε waεhed with water, dried and concentrated. The residue was purified by preparative thin-layer chromatography (10% methanol in dichloromethane) to give 8- [2, 6-dichloro-3-[N-methyl-N-[2-[4- (4-nitrophenyl)piperazin-1- yl]acetylglycyl]amino]benzyloxy]-2-methylquinoline (44 mg) . mp : 178-181°C

NMR (CDC1 ₃ , δ) : 2.66-2.78 (4K, m) , 2.75 (3H, s), 3.06 (IH, d, J=l5Hz), 3.12 (IH, d, J=15Hz), 3.26 (2H, ε), 3.43-3.54 (4H, s) , 3.55 (IH, dd, J=18 and 4Hz) ,

3.91 (IH, dd, J=18 and 4Hz) , 5.66 (2H, s), 6.84 (2H, d, J=7.5Hz), 7.25-7.34 (4H, m) , 7.38-7.53 (3H, m) , 7.88 (IH, t, J=4Hz) , 8.03 (IH, d, J=7.5Hz), 8.13 (2H, d, J=7.5Hz)

Example 40

(1) To methanol (5 ml) in dry ice-acetone bath was added thionyl chloride (0.41 ml) dropwise over 5 minutes. After (E) -3-(6-Aminopyridin-3-yl)acrylic acid (700 mg) waε added to the mixture, the reaction mixture waε heated at reflux for 1 hour, and the εolvent was removed under reduced pressure. The reaction mixture was adjusted to pH 8 with saturated εodiu bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The precipitate was collected by vacuum filtration and washed with isopropyl ether to give methyl (E)-3- (6-aminopyridin-3- yl)acrylate (725 mg) as a εolid. mp : 173-175°C NMR (DMSO-d ₆ , δ) : 3.67 (3H, s), 6.32 (IH, d, J=16Hz),

6.45 (IK, d, J=8Hz), 6.57 (2H, s) , 7.51 (IH, d, J=16Hz), 7.79 (IH, dd, 3=2 , 8Hz), 8.15 (IH, d, J=2Hz)

(2) To a mixture of methyl (E)-3- (6-aminopyridin-3-

yl) acrylate (700 mg) and triethylamine (477 mg) in dichloromethane (6 ml) was added dropwise 4-bromobutyryl chloride (801 mg) under nitrogen in ice water bath and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water, saturated sodium bicarbonate aqueouε εolution and brine, dried over magnesium sulfate and evaporated in vacuo. the reεidue waε chromatographed on εilica gel eluting with chloroform and purified by preparative thin-layer chromatography (n-hexane:ethyl acetate=l:l, v/v) to give methyl (E)-3- [6- (4-bromobutyramido)pyridin-3-yl]acrylate (101 mg) . mp : 155.8-172.7°C NMR (CDC1 ₃ , δ) : 2.27 (2H, quint, J=7.5Hz), 2.62 (2H, t, J=7.5Hz), 3.53 (2H, t, J=7.5Hz), 3.81 (3H, s) , 6.43 (IH, d, J=16Hz), 7.64 (IH, d, J=16Hz) , 7.87 (IH, dd, J=2, 8Hz), 8.12 (IK, br s), 8.23 (IH, d, J=8Hz), 8.39 (IH, d, J=2Hz)

(3) To a εolution of methyl (E) -3- [6- (4-bromobutyramido) - pyridin-3-yl]acrylate (90 mg) in dimethylformamide was added sodium hydride (6.93 mg) at 0°C under nitrogen atmosphere, and the mixture waε stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give methyl (E) -3- [6- (2-oxopyrrolidin-l-yl)pyridin-3-yl]acrylate (65 mg) . mp : 151-160°C NMR (CDCI3, δ) : 2.16 (2H, quint, J=7.5Hz), 2.69 (2H, t, J=7.5Hz), 3.81 (3H, ε), 4.11 (2H, t, J=7.5Hz), 6.43 (IH, d, J=16Hz), 7.65 (IH, d, J=16Hz) , 7.87 (IH, dd, 3=2 , 8Hz), 8.44-8.50 (2H, m)

(4) (E) -3-[6- (2-Oxopyrrolidin-i-yl)pyridin-3-yl]acrylic acid

waε obtained according to a similar manner to that of

Preparation 3. mp : >233°C (dec.)

NMR (CD ₃ OD, δ) : 2.14 (2H, quint, J=7.5Hz), 2.66 (2H, t, J=7.5Hz), 4.11 (2H, t, J=7.5Hz), 6.52 (IH, d,

J=16Hz), 7.65 (IH, d, J=16Hz), 8.06 (IH, d, J=8Kz), 8.39 (IH, d, J=8Hz), 8.51 (IH, s-like)

(5) 8-[2, 6-Dichloro-3-[N-methyl-N-[ (E) -3-[6- (2-oxo- pyrrolidin-l-yl)pyridin-3-yl]acryloylglycyl]- amino]benzyloxy]-2-methylquinoline was obtained according to a similar manner to that of Example 1. NMR (CDCI3, δ) : 2.15 (2H, quint, J=7.5Hz), 2.69 (2H, t, J=7.5Hz), 2.74 (3H, s), 3.27 (3H, s) , 3.68 (IH, dd, J=4, 18Hz), 3.95 (IH, dd, 3=4 , 18Hz), 4.12 (2H, t, J=7.5Hz), 5.60-5.71 (2H, m) , 6.48 (IH, d, J=16Hz), 6.66 (IH, t-like), 7.22-7.36 (2H, m) , 7.36-7.59 (5H, m) , 7.84 (IH, d, J=8Hz) , 8.03 (IH, d, J=8Hz), 8.39-8.48 (2H, n)

its dihydrochloride

NMR (DMSO-d ₆ , δ) : 2.05 (2H, quint, J=7.5Hz), 2.59

(2H, t, J=7.5Hz), 2.91 (3H, s) , 3.15 (3H, s) , 3.59 (IH, dd, 3=4 , 16Hz), 3.89 (IH, dd, 3=4 , 16Hz) , 4.00 (2H, t, J=7.5Hz), 5.56-5.72 (2H, m) , 6.81 (IH, d,

J=16Hz), 7.39 (IH, d, J=16Hz) , 7.77-8.08 (7H, m) , 8.29-8.40 (2H, m) , 8.55 (IH, d, J=2Hz) , 8.97 (IH, brpeak)

Example 41

(1) A mixture of 2-methcxyaniline (10 g) , acetic acid (1 ml) and ethyl 2-acetylpropionate (12.3 g) in benzene (30 ml) waε refluxed for 24 hourε, and then the εolvent waε removed to give crude ethyl 3-(2-methoxyanilino) -2-methyl-2-butenoate, which waε uεed as a starting compound at the following

example without further purification.

(2) A mixture of biphenyl (15 g) and dipher.yl ether (15 ml) waε heated at 250-270°C, and 3- (2-methoxyanilino) -2-methyl-2 butenoate obtained above waε added thereto. The mixture waε stirred at the same temperature for 1 hour. During cooling n-hexane (30 ml) was added to the mixture, and the reεulting precipitateε were collected by filtration. The residue was recrystallized with acetonitrile to give 2, 3-dimethyl-4- hydroxy-8-methoxyquinoline (4.49 g) . mp : 299.2°C NMR (DMSO-d ₆ , δ) : 1.95 (3H, s) , 2.43 (3H, s) , 3.97

(3H, s), 7.13 (IH, d, J=9Hz), 7.16 (IH, d, J=9Hz), 7.56-7.66 (IH, m)

(3) To a suspenεion of 2, 3-dimethyl-4-hydroxy-8- ethoxyquinoline (3.0 g) in phoεphoryl chloride was dropwise added N,N-dimethylaniline (3.58 g) under ice-cooling, and th mixture was εtirred for 15 minuteε at the same temperature, for 30 minutes at ambient temperature and then for 1 hour at 70°C. The solvent was removed, and saturated sodium bicarbonate solution and 10% solution of methanol in dichloromethan were added to the residue. The organic layer was dried over magnesium sulfate and concentrated. The reεidue was purified by flash chromatography (ethyl acetate:n-hexane = 1:2 v/v) to give 4-chloro-2, 3-dimethyl-8- ethoxyquinoline (3.02 g) . mp : 134.4-137.6°C

NMR (CDC1 ₃ , δ) : 2.55 (3H, s) , 2.78 (3H, s), 4.06 (3H, ε), 7.02 (IH, d, J=9Hz), 7.45 (IH, t, J=9Hz) , 7.74

(IH, d, J=9Hz)

(4) To a solution of 4-chloro-2, 3-dimethyl-8- methoxyquinoline (2.5 g) in dichloromethane (5 ml) was added boron tribromide (22.6 ml) under ice-cooling, and the mixtur

was stirred for 3 hours. The reaction mixture waε extracted with 10% εolution of methanol in chloroform, and the organic layer was dried over magnesium sulfate and concentrated. The residue was disεolved in acetonitrile under heating, and the mixture waε allowed to cool. The reεulting precipitates were collected by filtration to give 4-chloro-2, 3-dimethyl-8- hydroxyquinoline (1.50 g) . mp : 120.5°C

NMR (CDC1 ₃ , δ) : 2.54 (3H, s), 2.71 (3H, s) , 7.11 (IH, d, J=9Hz), 7.44 (IK, t, J=9Hz) , 7.59 (IH, d, J=9Hz)

(5) 4-Chloro-8-[2, 6-Dichloro-3-[N-methyl-N-[4- (methyl¬ carbamoyl)cinnamoylglycyl]amino]benzyloxy]-2,3- dimethylquinoline was obtained according to a εimiiar manner to that of Example 9.

NMR (CDCI3, δ) : 2.54 (3H, s) , 2.72 (3H, s), 2.98 (3H, d, J=5Hz), 3.24 (3H, s) , 3.62 (IH, dd, J=17, 4Hz) , 3.91 (IH, dd, J=17, 5Hz), 5.60 (IH, d, J=9Hz) , 5.65 (IH, d, J=9Hz), 6.25 (IH, br q, J=5Hz) , 6.51 (IH, d, J=15Hz), 6.68 (IH, t, J=5Hz) , 7.24-7.34 (3H, m) ,

7.43-7.57 (4H, m) , 7.57 (IH, d, J=15Hz) , 7.74 (2H, d, J=9Hz), 7.86 (IH, d, J=9Hz)

itε hydrochloride NMR (CDCI3-CD3OD, δ) : 2.74 (3H, ε), 2.99 (3H, s) ,

3.13 (3H, br s) , 3.29 (3H, s) , 3.85 (IH, d, J=17Hz), 4.18 (IH, d, J=17Hz), 5.59 (IH, d, J=9Hz) , 5.73 (IH, d, J=9Hz), 6.65 (IH, d, J=15Hz) , 7.40 (IH, d, J=15Hz), 7.45-7.70 (5H, m) , 7.77 (2H, d, J=9Hz), 7.94 (IH, t, J=9Hz) , 8.08 (IH, d, J=8Hz)

Example 42

(1) Ethyl 3- (2-benzyloxyanilino)-2-butenoate was obtained by reacting 2-benzyloxyaniline with ethyl acetoacetate according to a similar manner to that of Example 41-(1).

NMR (CDCI3, δ) : 1.28 (3H, t, J=7Hz), 1.99 (3H, s) ,

4.16 (2H, q, J=7.0Hz), 4.73 (IH, s) , 5.11 (2H, s) , 6.88-6.99 (2H, ) , 7.03-7.15 (2H, m) , 7.26-7.40 (3H, m) , 7.47 (2H, d, J=8.5Hz)

(2) 8-Benzyloxy-4-hydroxy-2-methylquinoiine was obtained according to a similar manner to that of Example 41- (2) . mp : 155-164°C

NMR (DMSO-d ₆ , δ) : 2.40 (3H, s) , 5.38 (2H, s) , 5.90 (IH, ε), 7.13 (IH, t, J=8.5Hz) , 7.22 (IH, d,

J=8.5Hz), 7.28-7.43 (3H, ) , 7.53 (2H, d, J=8.5Hz),

7.57 (IH, d, J=8.5Hz)

(3) 8-3enzyloxy-4-ethoxycarbonylmethoxy-2-methylquinoline waε obtained by reacting 8-benzyloxy-4-hydroxy-2- methylquinoline with ethyl bromoacetate according to a similar manner to that of Preparation 20- (1) . mp : 138-140°C

NMR (CDCI3, δ) : 1.31 (3K, t, J=7.5Hz), 2.74 (3H, ε) , 4.31 (2H, q, J=7.5Hz), 4.81 (2H, s) , 5.43 (2H, ε),

6.53 (IH, ε), 7.02 (IH, d, J=8.5Hz), 7.22-7.40 (4H, m) , 7.51 (2H, d, J=8.5Hz), 7.79 (IH, d, J=8.5Hz)

(4) A mixture of 8-benzyloxy-4-ethoxycarbonylmethoxy-2- methylquinoline (1.30 g) and palladium on carbon (130 mg) in a mixture of ethanol (8 ml) and dioxane (7 ml) waε εtirred for 3 hourε at ambient temperature under hydrogen atmoεphere. The reaction mixture waε filtered, and the filtrate waε concentrated in vacuo to give 4-ethoxycarbonylmethoxy-8- hydroxy-2-methylσuinoline (539 mg) . mp : 97-98°C NMR (DMSO-d ₆ , δ) : 1.23 (3H, t, J=7.5Hz), 2.60 (3H, ε), 4.22 (2H, q, J=7.5Hz), 5.07 (2H, ε), 6.92 (IH, ε), 7.04 (IH, d, J=8.5Hz), 7.34 (IH, t, J=8.5Hz), 7.52 (IH, d, J=8.5Hz)

(5) 8-[2, 6-Dichloro-3- [N-methyl-N- [4- (methylcarbamoyl) - cinnamoylglycyl]amino]benzyloxy]-4-ethoxycarbonylmethoxy-2- methylquinoline waε obtained according to a εimiiar manner to that of Example 9. mp : 134-147°C

NMR (DMSO-d ₆ , δ) : 1.22 (3H, t, J=7.5Hz), 2.53 (3H, ε), 2.79 (3H, d, J=5.5Hz), 3.15 (3H, ε), 3.51 (IH, dd, J= 16.5, 5.5Hz), 3.81 (IH, dd, J=16.5, 5.5Hz), 4.21 (2H, q, J=7.5Hz), 5.07 (2H, s) , 5.47 (IH, d, J=11.5Hz), 5.53 (IH, d, J=11.5Hz), 6.88 (IH, d,

J=15Hz), 6.91 (IH, s), 7.34-7.49 (3H, m) , 7.61-7.68 (2K, m) , 7.72-7.80 (3H, m) , 7.86 (2H, d, J=8.5Hz), 8.33 (IH, t, J=5.5Hz), 8.49 (IH, q, J=5.5Hz)

itε hydrochloride mp : 147-158°C

NMR (DMSO-d ₆ , δ) : 1.28 (3H, t, J=7.5Hz), 2.79 (3H, d, J=4.5Hz), 2.83 (3H, s), 3.15 (3H, s), 3.60 (IH, dd, J= 16.5, 4.5Hz), 3.91 (IH, dd, J=16.5, 4.5Hz), 4.24 (2H, q, J=7.5Hz), 5.37 (2H, ε) , 5.62 (IH, d,

J=10.5Hz), 5.67 (IH, d, J=10.5Hz), 6.89 (IH, d, J=16Hz), 7.42 (IH, d, 16Hz) , 7.57-7.70 (3H, m) , 7.79-8.00 (7H, m) , 8.39 (IH, t, J=4.5Hz), 8.52 (IH, q, J=4.5Hz)

(6) 4-Carboxymethoxy-8-[2, 6-dichloro-3-[N-methyl-N-[4- (methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-2- methylquinoline waε obtained according to a similar manner to that of Example 3. mp : 233-257°C

NMR (DMSO-d _β , δ) : 2.54 (3H, s) , 2.78 (3H, d,

J=4.5Hz), 3.17 (3H, s), 3.51 (IH, dd, J=16.5, 4.5Hz), 3.82 (IH, dd, 3=16. 5, 4.5Hz), 4.96 (2H, s), 5.47 (IH, d, J=10Hz), 5.53 (IH, d, J=10Hz), 6.89 (IH, d, J=16.5Hz), 6.93 (IH, s) , 7.33-7.50 (3H, m) ,

7.60-7.70 (2H, ) , 7.73-7.81 (3H, m) , 7.85 (2H, d, J=8.5Hz), 8.32 (IH, t, J=4.5Hz), 8.49 (IH, q, J=4.5Hz)

(7) 8- [2, 6-Dichloro-3- [N-methyl-N- [4- (methylcarbamoyl) - cinnamoylglycyl] amino]benzyloxy] -4-dimethylcarbamoylmethoxy- 2-methylquinoiine was obtained from 4-carboxymethoxy-8- [2, 6- dichloro-3- [N-methyl-N- [4- (methylcarbamoyl) cinnamoylglycyl] - amino]benzyloxy] -2-methylquinoline and dimethylamine hydrochloride according to a similar manner to that of Example 7.

NMR (DMS0-d ₆ , δ) : 2.53 (3H, s), 2.76 (3H, d,

J=4.5 Hz), 2.86 (3H, s) , 3.04 (3H, s), 3.15 (3H, s), 3.50 (IH, dd, J= 16.5, 4.5Hz), 3.80 (IH, dd, J=16.5, 4.5Hz), 5.10 (2H, ε), 5.45 (IH, d, J=9Hz) ,

5.51 (IH, d, J=9Hz), 6.87 (IH, d, J=15Hz) , 6.88 (IH, ε), 7.32-7.48 (3H, ) , 7.61-7.69 (2H, m) , 7.73-7.81 (3H, m) , 7.87 (2H, d, J=8.5Hz), 8.33 (IH, t, J=4.5Hz), 8.48 (IH, q, J=4.5Hz)

itε hydrochloride mp : 157-172°C

NMR (DMSO-d ₆ , δ) : 2.78 (3H, d, J=4.5Hz), 2.83 (3H, s) , 2.90 (3H, ε), 3.03 (3H, s) , 3.15 (3H, s) , 3.60 (IH, dd, J=16.5, 4.5Hz), 3.91 (IH, dd, J=16.5,

4.5Hz), 5.49 (2H, s), 5.61 (IH, d, J=11.5Hz), 5.66 (IH, d, J=11.5Hz), 6.88 (IH, d, J=16.0Hz), 7.42 (IH, d, J=l6.0Hz), 7.53 (IH, s) , 7.63 (2H, d, J=8.5Hz), 7.79-7.89 (5H, m) , 7.91-7.99 (2H, m) , 8.38 (IH, t, J=4.5Hz), 8.52 (IH, q, J=4.5Hz)

Preparation 34

(1) 1- (tert-Butyldiphenylsiiyloxymethyl) -2, 6-dimethyl-3- nitrobenzene was obtained by reacting 2, 6-dimethyl-3- nitrobenzyl alcohol with tert-butyldiphenylsilyl chloride

according to a similar manner to that of Preparation 18- (1) . NMR (CDC1 ₃ , δ) : 1.03 (9H, s), 2.20 (3H, s) , 2.38 (3H, s), 5.73 (2H, s), 7.06 (IH, d, J=8Hz) , 7.33-7.49 (6H, m) , 7.58-7.73 (5H, π)

(2) To a suspension of 1- (tert-butyldiphenylsilyloxymethyl) - 2, 6-dimethyl-3-nitrobenzene (42 g) and ammonium chloride (4.2 g) in ethanol (378 ml) -water (42 ml) was added iron (7.0 g) , and the mixture was refluxed for 6 hours, during which iron (7.0 g) was added thereto twice. Inεoluble materials were filtered off, and the filtrate was concentrated. To the residue was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to give 3-amino-l- (tert- butyldiphenylsilyloxymethyl) -2, 6-dimethylbenzene (42.8 g) as pale yellow oil.

NMR (CDCI3, δ) : 1.04 (9H, s) , 2.09 (3H, s), 2.11 (3H, s), 3.48 (2H, br s), 4.70 (2H, s) , 6.58 (IH, d, J=8Hz), 6.71 (IH, d, J=8Hz) , 7.33-7.48 (6H, m) , 7.66-7.73 (4H, m)

(3) 1- (tert-Butyldiphenylsilyloxymethyl) -2, 6-dimethyl-3- (phthalimidoacetylamino)benzene waε obtained according to a εimiiar manner to that of Preparation 9. mp : 207-210°C

NMR (CDC1 ₃ , δ) : 1.02 (9H, s) , 2.12 (3H, s), 2.19 (3H, s), 4.52 (2H, s), 4.70 (2H, s) , 6.95 (IH, d, J=8Hz), 7.25-7.50 (7H, m) , 7.63-7.80 (6H, m) , 7.86- 7.96 (2H, m)

(4) 1- (tert-Butyldiphenylεilyloxymethyl) -2, 6-dimethyl-3- [N- methyl-N- (phthalimidoacetyl) amino]benzene was obtained according to a similar manner to that of Preparation 10. mp : 180-182°C NMR (CDCI3, δ) : 1.04 (9H, s) , 2.21 (3H, s), 2.27 (3H,

s), 3.17 (3H, s), 3.82 (IH, d, J=17Hz) , 4.12 (IH, d, J=17Hz), 4.78 (2H, s) , 7.09 (IH, d, J=8Hz) , 7.1 (IH, d, J=8Hz), 7.34-7.49 (6H, m) , 7.65-7.73 (6H, m) , 7.80-7.88 (2H, m)

(5) 3- (N-Glycyl-N-methylamino) -1- (tert- butyldiphenylsilyloxymethyl) -2, 6-dimethylbenzene was obtained according to a similar manner to that of Preparation 11.

NMR (CDC1 ₃ , δ) : 1.03 (9H, s), 2.02 (3H, s), 2.22 (3H, s), 2.82 (IH, d, J=17Hz), 3.09 (IH, d, J=17Hz) ,

3.15 (3H, 8), 4.72 (2H, ε), 6.92 (IH, d, J=8Hz), 7.01 (IH, d, J=8Hz), 7.32-7.49 (6H, m) , 7.62-7.70 (4H, m)

(6) 1- (tert-Butyldiphenylεilyloxymethyl) -2, 6-dimethyl-3- [N- methyl-N- [4- (methylcarbamoyl) cinnamoylglycyl] amino]benzene was obtained according to a similar manner to that of Preparation 18- (6) . mp : 204-208°C NMR (CDCI3, δ) : 1.05 (9H, s), 2.05 (3H, s) , 2.26 (3H, s), 3.02 (3H, d, J=5Hz), 3.20 (3K, s) , 3.52 (IH, dd, J=17, 5Hz), 3.87 (IH, dd, J=17, 5Hz) , 4.73 (2H, ε), 6.16 (IH, br d, J=5Hz) , 6.51 (IH, d, J=15Hz) , 6.69 (IH, br t, J=5Hz) , 6.98 (IH, d, J=8Hz), 7.06 (IH, d, J=8Hz), 7.35-7.48 (6H, m) , 7.51-7.60 (3H, m) , 7.65-7.80 (6H, m)

(7) 2, 6-DimethyI-l-hydroxymethyl-3- [N-methyl-N- [4- (methylcarbamoyl) cinnamoylglycyl] amino]benzene waε obtained according to a εimiiar manner to that of Preparation 18- (7) . mp : 261-263°C NMR (DMSO-d ₆ , δ) : 2.27 (3H, s) , 2.40 (3H, s) , 2.79

(3H, d, J=5Hz), 3.08 (3H, ε), 3.43 (IH, dd, J=17, 5Hz), 3.65 (IH, dd, J=17, 5Hz) , 4.53 (2H, d, J=5Hz), 4.88 (IH, t, J=5Hz), 6.89 (IH, d, J=15Hz) ,

7.15 (2H, s), 7.41 (IH, d, J=15Hz), 7.64 (2H, d, J=8Hz), 7.85 (2H, d, J=8Hz) , 8.21 (IH, br t, J=5Hz), 8.48 (IH, br d, J=8Hz)

(8) To a solution of 2, 6-dimethyl-l-hydroxymethyl-3-[N- methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzene (2.00 g) in N,N-dimethylformamide (100 ml) was added methanesulfonyl chloride (784 mg) under ice-cooling, and the mixture was stirred for 2 hours at the same temperature and overnight at ambient temperature. To the mixture was added water and extracted with chloroform. The organic layer was washed with brine, dried over magnesium εulfate and concentrated. The residue was pulverized with diethyl ether to give l-chloromethyl-2, 6-dimethyl-3- [N-[4- (methylcarbamoyl) cinnamoylglycyl]-N-methylamino]benzene (2.00 g) as white powder, mp : 232°C

NMR (CDC1 ₃ , δ) : 2.29 (3H, s) , 2.46 (3H, s) , 3.03 (3H, d, J=5Hz), 3.24 (3H, ε) , 3.59 (IH, d, J=17, 5Hz) , 3.82 (IH, dd, J=17, 4Hz) , 4.67 (2H, ε), 6.20 (IH, m) , 6.50 (IH, d, J=15Hz), 6.70 (IH, d, J=5Hz) , 7.04 (IH, d, J=9Hz), 7.14 (IH, d, J=9Hz) , 7.50-7.60 (3H, m), 7.75 (2H, d, J=9Hz)

Preparation 35

(1) 2, 6-Dimethyl-l-hydroxymethyl-3-[N-methyl-N- (phthalimidoacetyl) amino] benzene waε obtained from l-(tert- butyldiphenylsilyloxymethyl) -2, 6-dimethyl-3- [N-methyl-N- ( phthalimidoacetyl) amino] benzene according to a εimiiar manner to that of Preparation 18- (7). mp : 241-243°C

NMR (CDCI3, δ) : 2.47 (3H, ε), 2.48 (3H, ε) , 3.20 (3H, s), 3.81 (IH, d, J=17Hz), 4.18 (IH, d, J=17Hz), 4.83 (2H, s), 7.14 (IH, d, J=8Hz) , 7.19 (IH, d, J=8Hz), 7.68-7.75 (2H, m) , 7.80-7.88 (2H, m)

(2) A. mixture of 2, 6-dimethyl-l-methanesulfonyloxymethyl-3- [N-methyl-N- (phthalimidoacetyl) amino] enzene and 1- chloromethyl-2, 6-dimethyl-3- [N-methyl-N-

(phthalimidoacetyl) amino]benzene v/as obtained according to a similar manner to that of Example 33- (3) .

Preparation 36

(1) 1- (tert-Butyldiphenylsilyloxymethyl) -2, , 6-trimethyl-3- nitrobenzene was obtained by reacting 2, 4, 6-trimethyl-3- nitrobenzyl alcohol with tert-butyldiphenylsilyl chloride according to a similar manner to that of Preparation 18- (1) . mp : 81-83°C

NMR (CDC1 ₃ , δ) : 1.02 (9H, s), 2.13 (3H, ε) , 2.18 (3H, ε), 2.23 (3H, ε), 4.67 (2H, s), 6.88 (IH, s) , 7.35- 7.48 (6H, m) , 7.65 (4H, d, J=8Hz)

(2) 3-Amino-l- (tert-butyldiphenylεilyloxymethyl) -2, 4, 6- trimethylbenzene waε obtained according to a εimiiar manner to that of Preparation 34- (2) . NMR (CDCI3, δ) : 1.03 (9H, s), 2.08 (3H, s), 2.13 (3H, ε), 2.16 (3H, ε), 3.48 (2H, br s) , 4.68 (2H, s) , 6.72 (IH, s), 7.33-7.47 (6H, m) , 7.70 (4H, d, J=8Hz)

(3) 1- (tert-Butyldiphenylsilyloxymethyl) -3-

(phthalimidoacetylamino) -2, 4, 6-trimethylbenzene waε obtained according to a similar manner to that of Preparation 9. mp : 218-220°C

NMR (CDCI3, δ) : 1.01 (6H, s), 1.04 (3H, ε), 2.11 (2H, s), 2.15 (2H, ε), 2.18 (2H, s) , 2.21 (IH, s) , 2.31

(IH, s) , 2.39 (IH, s) , 3.94 (0.7H, s) , 4.5 (1.3H, s), 4.64 (1.3H, ε), 4.72 (0.7H, ε), 6.71 (0.4H, ε), 6.86 (0.6H, ε), 6.93 (0.6H, s) , 6.99 (0.4H, s), 7.32-7.46 (6H, m) , 7.83-7.88 (0.6H, m) , 7.90-7.94 (1.4H, m)

(4) 1- (tert-Butyldiphenylsilyloxymethyl) -3- [N-methyl-N- (phthalimidoacetyl) amino] -2, 4, 6-trimethylbenzene was obtained according to a similar manner to that of Preparation 10. mp : 146.5-149.7°C

NMR (CDC1 ₃ , δ) : 1.04 (9H, s), 2.19 (3H, s), 2.23 (3H, s), 2.32 (3H, s), 3.12 (3H, s), 3.85 (IH, d, J=17Hz), 3.92 (IH, d, J=17Hz) , 4.72 (2H, s) , 7.00 (IH, ε), 7.33-7.48 (6H, m) , 7.63-7.73 (6H, m) , 7.80-7.88 (2H, m)

(5) l-Hydroxymethyl-3- [N-methyl-N- (phthalimidoacetyl) amino] 2, 4, 6-trimethylbenzene waε obtained according to a εimiiar manner to that of Preparation 18- (7) . mp : 254-256°C NMR (CDCI3, δ) : 2.33 (3H, ε), 2.44 (6H, s) , 3.26 (3H, s), 3.95 (2H, ε), 4.78 (2H, ε), 7.05 (IH, ε) , 7.67- 7.74 (2H, m) , 7.80-7.88 (2H, m)

(6) A mixture of l-methanesulfonyloxymethyl-3- [N-methyl-N- (phthalimidoacetyl) amino] -2 , 4 , 6-trimethylbenzene and 1- chloromethyl-3- [N-methyl-N- (phthalimidoacetyl) amino] -2 , 4 , 6- trimethylbenzene was obtained according to a similar manner to that of Example 33- (3) .

Preparation 37

(1) 2 , 6-Dimethoxy-3-nitrobenzyl alcohol was obtained from 2 , 6-dimethoxy-3-nitrobenzoic acid according to a similar manner to that of Example 33- (2) . mp : 71-73°C NMR (CDCI3, δ) : 2.31 (IH, t, J=7.5Hz), 3.96 (3H, s) ,

3.98 (3H, s), 4.78 (2H, d, J=7.5Hz), 6.75 (IH, d, J=8Hz), 7.99 (IH, d, J=8Hz)

(2) A mixture of 2, 6-dimethoxy-3-nitrobenzyl methanesulfon- ate and 2, 6-dimethoxy-3-nitrobenzyl chloride waε obtained

according to a similar manner to that of Example 33- (3) .

Preparation 38

(1) 1- (tert-Butyldiphenylsilyloxymethyl) -2, 6-dimethyl-3- [N- ethyl-N- (phthalimidoacetyl) amino]benzene was obtained by reacting 1- (tert-butyldiphenylsilyloxy ethyl) -2, 6-dimethyl-3- (phthalimidoacetylamino) benzene with ethyl iodide according to a εimiiar manner to that of Preparation 10. mp : 146-150°C NMR (CDC1 ₃ , δ) : 1.04 (9H, s), 1.12 (3H, t, J=7.5Hz),

2.22 (3H, s), 2.28 (3H, s), 3.21 (IH, q, J=7.5Hz) , 3.78 (IH, d, J=17Hz) , 4.01-4.12 (2H, m) , 4.78 (2H, s), 7.10 (2H, s), 7.33-7.47 (6H, m) , 7.65-7.73 (6H, m) , 7.80-7.88 (2H, m)

(2) 2 , 6-Dimethyl-l-hydroxymethyl-3- [N-ethyl-N- (phthalimidoacetyl) amino]benzene was obtained according to a similar manner to that of Preparation 18- (7) . mp : 205-207°C NMR (CDCI3, δ) : 1.12 (3H, t, J=7.5Hz), 1.50 (IH, br ε), 2.46 (3H, ε), 2.49 (3K, s) , 3.24 (IH, m) , 3.88 (IH, d, J=17Hz), 4.03-4.19 (2H, m) , 4.73 (2H, br ε), 7.15 (2H, s) , 7.68-7.75 (2H, m) , 7.80-7.88 (2H, m)

(3) A mixture of 2, 6-dimethyl-l-methanesulfonyloxymethyl-3- [N-ethyl-N- (phthalimidoacetyl) amino]benzene and 1- chloromethyl-2, 6-dimethyl-3- [N-ethyl-N- (phthalimidoacetyl) amino)benzene waε obtained according to a similar manner to that of Example 33- (3) .

Preparation 39

(1) To a stirred solution of 8-benzyloxy-4-hydroxy-2- methylquinoline (5.00 g) and 2,6-lutidine (3.03 g) and 4- dimethylaminopyridine (230 mg) in dichloromethane (80 ml) was

added trifluoromethanesulfonic anhydride (5.85 g) dropwise in an ice bath. The reaction mixture was stirred at the same temperature for half an hour and then at ambient temperature for an hour. The mixture was poured into saturated ammonium chloride (100 ml), extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residual εolid was crystallized from 90% aqueous acetonitrile (100 ml) and collected to give 8- benzyloxy-2-methyl-4- (trifluoromethanesulfonyloxy)quinoline (6.58 g) as white powder, mp : 158°C

NMR (CDC1 ₃ , δ) : 2.86 (3H, s), 5.46 (2H, ε), 7.10 (IH, d, J=7.5Hz), 7.25-7.60 (8H, m)

(2) A. mixture of 8-benzyloxy-2-methyl-4- (trifluoromethane¬ sulfonyloxy) quinoline (300 mg) , vinyltributyltin (263 mg) , tetrakis (triphenylphoεphine)palladium(0) (43.6 mg) and lithium chloride (96 mg) in 1,4-dioxane (6 ml) was refluxed for three hours and then left at ambient temperature overnight. The mixture was diluted with ethyl acetate and was added silica gel (70-230 meεh, 5 g) and stirred at ambient temperature for half an hour. The silica gel was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed on a silica gel column eluting with ethyl acetate - n-hexane (1:4, V/V) to give a solid. This solid was crystallized from diisopropyl ether to give 8-benzyloxy-2-methyl-4-vinylquinoline (110 mg) as pale yellow solid, mp : 114.2°C NMR (CDCI3, δ) : 2.80 (3H, s), 5.45 (2H, ε), 5.60 (IH, d, J=10Hz), 5.91 (IH, d, J=16Hz), 6.98 (IH, d, J=7.5Hz), 7.20-7.40 (5H, m) , 7.44-7.53 (2H, m) , 7.59 (IH, d, J=7.5Hz)

(3) To a stirred solution of 8-benzyloxy-2-methyl-4-

vinylquinoline (200 mg) in 1,4-dioxane - water (3:1, V/V, 1 ml) waε added catalytic amount of osmium tetroxide in tert- butanol in an ice bath. Sodium periodate (342 mg) was added to the reaction mixture portionwise and the resulting suspenεion was vigorously stirred overnight at ambient temperature. The mixture was extracted with ethyl acetate and washed with water and brine. The organic layer was drie over anhydrous magnesium sulfate and concentrated in vacuo t give a brown oil. This was purified by a silica gel column eluting with ethyl acetate - n-hexane (1:3, V/V) to give 8- benzyloxy-4-formyl-2-methylquinoline as a yellow solid (123 mg) . mp : 129.1°C

NMR (CDC1 ₃ , δ) : 2.90 (3K, s) , 5.46 (2H, s), 7.10 (IH, d, J=7.5Hz), 7.24-7.40 (3H, m) , 7.41-7.55 (3H, m) ,

7.71 (IH, ε), 8.46 (IH, d, J=8.0Hz), 10.49 (IH, ε)

(4) To a εtirred solution of εodium dihydrogenphosphate dihydrate (788 mg) and 2-methyl-2-butene (885 mg) in tert- butanol (12 ml) and water (3 ml) was added 8-benzyloxy-4- formyl-2-methylquinoline (700 mg) and sodium chloride (79% purity, 457 mg) succesεively at ambient temperature. After being stirred for one and half an hour, the reaction was quenched with water (12 ml), then the pH of the mixture was adjuεted to about 3-4 by addition of IN hydrochloric acid. The mixture was extracted with chloroform and dried over anhydrous magnesium εulfate. The organic phaεe waε concentrated in vacuo and the residual solid was triturated with diethyl ether to give 8-benzyloxy-4-carboxy-2- methylquinoline (729 mg, 98.5%) aε a pale yellow powder, mp : 241.3°C NMR (CDCI3-CD3OD, δ) : 2.82 (3H, s), 5.41 (2H, s),

7.07 (IH, d, J=7.5Hz), 7.24-7.53 (6H, m) , 7.84 (IH, s), 8.26 (IH, d, J=7.5Hz)

(5) To a stirred mixture of 8-benzyloxy-4-carboxy-2- methylquinoline (700 mg) , potasεium carbonate (659 mg) and N,N-dimethylformamide (0.3 ml) waε dropwise added ethyl iodide (409 mg) under ice-cooling and the mixture was εtirred for 30 minuteε at the same temperature and for 1 hour at ambient temperature. To the mixture was added water and extracted with ethyl acetate. The organic layer was washed I with water and brine, dried over magnesium sulfate, dried over magneεium sulfate. The solvent waε removed, and the reεidue was crystallized from diisopropyl ether to give 8- benzyloxy-4-ethoxycarbonyl-2-methylquinoline (686 mg) as solid. mp : 134.5°C

NMR (CDC1 ₃ , δ) : 1.46 (3H, t, J=7.5Hz), 2.85 (3H, s) , 4.48 (2H, q, J=7.5Hz), 5.45 (2H, s), 7.04 (IH, d,

J=7.5Hz), 7.26-7.43 (4H, m) , 7.46-7.55 (2H, m) , 7.79 (IH, s), 8.19 (IH, d, J=7.5Hz)

(6) A mixture of 8-benzyloxy-4-ethoxycarbonyl-2- methylquinoline (663 mg) and palladium(II) hydroxide (60 mg) in a mixture of ethanol (6 ml) and dioxane (6 ml) was stirred for 3 hours at ambient temperature under hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The residue was pulverized with n-hexane to give 4-ethoxycarbonyl-8-hydroxy-2-methylquinoline (370 mg) as pale yellow εolid. mp : 71.8°C

NMR (CDCI3, δ) : 1.46 (3H, t, J=7.5Hz), 2.77 (3H, s) , 4.49 (2H, q, J=7.5Hz), 7.16 (IH, d, J=7.5Hz), 7.46 (IH, t, J=7.5Hz), 7.83 (IH, s) , 8.11 (IH, d,

J=7.5Hz) , 8.35 (IH, br s)

Preparation 40

A mixture of 8-benzyloxy-2-methyl-4-vinylquinoline (200 mg) and palladiu (II) hydroxide (40 mg) in a mixture of

ethanol (1.5 ml) and dioxane (1.5 ml) was εtirred for 9 hour at ambient temperature under hydrogen atmoεphere. The reaction mixture waε filtered, and the filtrate was concentrated. The reεidue waε purified by flash chromatography (ethyl acetate : n-hexane = 1:2, V/V) to give 4-ethyl-8-hydroxy-2-methylquinoline (66 mg) as brown oil.

NMR (CDC1 ₃ , δ) : 1.36 (3H, t, J=7.5Hz), 2.68 (3H, s), 3.04 (2H, q, J=7.5Hz), 7.10 (IH, d, J=9Hz) , 7.15 (IH, 8), 7.36 (IH, t, J=9Hz), 7.44 (IH, d, J=7.5Hz)

Preparation 41

(1) To a εuεpenεion of 8-benzyloxy-4-formyl-2- methylquinoline (300 mg) in a mixture of methanol (3 ml) and tetrahydrofuran (2 ml) waε added εodium borohydride (20.6 mg) portionwise in an ice bath. The suεpension was stirred for half an hour, then quenched with saturated sodium chloride. The mixture was extracted with chloroform and the organic layer was dried over anhydrous magnesium sulfate. After being concentrated in vacuo the residue was chromatographed on silica gel eluting with ethyl acetate - n-hexane to give an amorphous solid which was εolidified with diisopropyl ether to afford 8-benzyloxy-4-hydroxymethyl-2-methylquinoline (250 mg) as a colorless solid, mp : 137.0-140.7°C NMR (CDCI3, δ) : 2.79 (3H, s), 5.12 (2H, br s) , 5.45

(2H, s), 6.99 (IH, d, J=8Hz) , 7.21-7.45 (6H, m) , 7.53 (2H, d, J=9Hz)

(2) 4-Hydroxymethyl-8-hydroxy-2-methylquinoline was obtained according to a similar manner to that of Preparation 39- (6) . NMR (CDCI3-CD3OD, δ) : 2.71 (3H, s), 5.10 (2H, s), 7.11 (IH, d, J=8Hz), 7.29-7.43 (2H, m) , 7.51 (IH, s)

Preparation 42

(1) To a solution of 8-benzyloxy-4-hydroxymethyl-2- methylquinoline (148 mg) in N,N-dimethylfσrmamide (1.5 ml) was added sodium hydroxide (60% in oil, 23.3 mg) under ice- cooling, and the mixture was stirred for 15 minutes at the same temperature. To the mixture waε added methyl iodide

(82.7 mg) under ice-cooling, and the mixture waε εtirred for 15 minuteε at the same temperature and then overnight at ambient temperature. To the mixture was added εaturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water twice, dried over magneεium sulfate and concentrated in vacuo. The residue waε purified by flaεh chromatography (ethyl acetate:n-hexane = 1:3, V/V) to give 8-benzyloxy-4- methoxymethyl-2-methyIσuinoline (123 mg) as pale yellow solid. mp : 73.7-76.3°C

NMR (CDC1 ₃ , δ) : 2.80 (3H, s), 3.51 (3H, ε) , 4.86 (2H, ε), 5.45 (2H, s), 6.99 (IH, d, J=9Hz) , 7.24-7.54 (8H, m)

(2) 8-Hydroxy-4-methoxymethyl-2-methylσuinoline was obtained according to a similar manner to that of Preparation 39- (6). NMR (CDCI3, δ) : 2.70 (3H, s) , 3.53 (3H, s) , 4.86 (2H, s), 7.12 (IH, d, J=8Hz), 7.29-7.44 (3H, )

Preparation 43

A mixture of 2-hydroxyaniline (2 g) , crotonoylbenzene (8.03 g) and concentrated hydrochloric acid (8 ml) waε refluxed for 24 hourε. The mixture waε neutralized with concentrated ammonia water under ice-cooling, and extracted with chloroform. The organic layer waε waεhed with brine, dried over magneεium sulfate and concentrated in vacuo. The residue was purified according to a conventional manner to give 8-hydroxy-2-methyl-4-phenylquinoline (2.4 g) as an oil. NMR (CDCI3, δ) : 2.75 (3H, ε), 7.14 (IH, m) , 7.27-7.36

- i J ~ O

( 2H, m) , 7 . 40- 7 . 61 ( 6H, m) , 7 . 95 ( IK, d, J=8Hz )

Preparation 44

The following compounds were obtained according to a similar manner to that of Preparation 27- (5) .

(1) 6-Hydroxymethyl-3, 4-dihydro-2 (IH) -quinoline (from methyl 3, 4-dihydro-2 (IH) -σuinolinone-6-carboxylate) mp : 148-173°C NMR (CDC1 ₃ , δ) : 2.61 (2K, t, J=7.5Hz) , 2.96 (2H, t,

J=7.5Hz), 4.61 (2H, s), 6.74 (IH, d, J=8Hz) , 7.14- 7.22 (2H, m)

(2) 5-Hydroxymethyl-2- [ (E) -2- (4-pyridyl) vinyl]pyridine (from methyl 2- [ (E) -2- (4-pyridyl) vinyl]pyridine-5-carboxylate) mp : >198.9°C

NMR (CDCI3, δ) : 4.73 (2H, s), 7.34 (IH, d, J=16Hz),

7.40-7.49 (3H, m) , 7.53 (IH, d, J=16Hz), 8.53-8.65 (3H, m)

Preparation 45

(1) To a εolution of methyl 3, 4-dihydro-2 (IH) -quinolinone-6- carboxylate (500 mg) in tetrahydrofuran waε dropwiεe added 2M solution of borane-methyl sulfide complex in tetrahydrofuran (2.5 ml) under ice-cooling, and the mixture waε refluxed for 45 minutes. After cooling, methanol (1 ml) was dropwise added thereto, and the mixture was stirred for 1 hour. The solvent was removed, and ethyl acetate and water were added to the reεidue. The organic layer waε washed with water, saturated sodium bicarbonate εoiution and brine, dried over magneεium sulfate and concentrated in vacuo. The residue was pulverized with diisopropyl ether - n-hexane to give methyl 1, 2, 3, 4-tetrahydroquinoline-6-carboxylate (385 mg) as solid, mp : 75-84°C NMR (CDCI3, δ) : 2.93 (2H, quint, J=7Hz), 2.76 (2H, t,

J=7Hz), 3.33 (2H, t, 3= ^~ Hz ) , 3.83 (3H, s), 4.29 (IH, br ε), 6.39 (IH, d, J=6Hz) , 7.59-7.68 (2H, m)

(2) 6-Hydroxymethyl-l,2, 3, 4-tetrahydroσuinoIine was obtained according to a similar manner to that of Preparation 27- (5). NMR (CDC1 ₃ , δ) : 1.53 (IH, t, J=6Hz) , 1.90 (2H, quint, J=7Hz), 2.73 (2H, t, J=7Hz) , 3.28 (2H, t, J=7Hz), 4.49 (2H, d, J=6Hz), 6.44 (IH, d, J=8Hz) , 6.90-7.00 (2H, m)

(3) To a solution of 6-hydroxymethyl-l,2,3,4- tetrahydroquinoline (314 mg) in methanol (4 ml) was dropwise added acetic anhydride (589 mg) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed in vacuo, and ethyl acetate and saturated sodium bicarbonate solution was added to the residue. The organic layer was waεhed with water and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (n-hexane:ethyl acetate = 1:2, V/V) to give l-acetyl-6-hydroxymethyl-l,2,3,4- tetrahydroquinoline (227 mg) aε powder, mp : 95-106°C

NMR (CDCI3, δ) : 1.70 (IH, t-like), 1.96 (2H, quint, J=7Hz), 2.24 (3H, s) , 2.75 (2H, t, J=7Hz) , 3.80 (2H, t, J=7Hz), 4.67 (2H, d, J=6Hz) , 6.96-7.36 (3H, m)

Preparation 46 (1) A mixture of 3-methoxy-4-nitrobenzyl alcohol (1.0 g) and 10% palladium on carbon (100 mg) in methanol waε εtirred for 2 hourε under 3 atmoεpheric preεεure of hydrogen. After filtration, the filtrate waε concentrated in vacuo to give 4- amino-3-methoxybenzyl alcohol (910 mg) as an oil.

NMR (CDC1 ₃ , δ) : 3.77 (2H, br s), 3.84 (3H, s) , 4.56 (2H, s), 6.66 (IH, d, J=8Hz), 6.76 (IH, d, J=8Hz) ,

6 . 81 ( IH, s )

(2) To a solution of 4-amino-3-methoxybenzyl alcohol (900 mg) in methanol waε added acetic anhydride (1.8 g) under ice cooling, and the mixture waε stirred for 1 hour at the same temperature. After evaporation, the residue waε diεεolved in ethyl acetate, and the solution was washed with sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated in vacuo to give 4-acetamido-3- methoxybenzyl alcohol (840 mg) aε εolid. mp : 104°C NMR (CDC1 ₃ , δ) : 1.69 (IH, t, J=5Hz) , 2.20" (3H, ε) ,

3.90 (3H, s), 4.65 (2H, d, J=5Hz) , 6.88-6.97 (2H, m) , 7.74 (IH, br s) , 8.32 (IH, d, J=8Hz)

Preparation 7

The following compounds were obtained according to a similar manner to that of Preparation 32- (7).

(1) 6-Formyl-3,4-dihydro-2 (IH)-quinoline mp : 207°C NMR (CDCI3, δ) : 2.70 (2H, t, J=7.5Hz), 3.07 (2H, t,

J=7.5Hz), 6.90 (IH, d, J=8Hz) , 7.68-7.75 (2H, m) ,

9.89 (IH, s)

(2) l-Acetyl-6-formyl-l,2,3, 4-tetrahydroquinoline

NMR (CDCI3, δ) : 2.01 (2H, quint, J=7Hz) , 2.29 (3H, s), 2.82 (2H, t, J=7Hz), 3.81 (2H, t, J=7Hz) , 7.46- 7.60 (IH, brpeak), 7.65-7.74 (2H, m) , 9.93 (IH, s)

(3) 4-Acetamido-3-methoxybenzaldehyde mp : 145°C

NMR (CDCI3, δ) : 2.25 (3H, s) , 3.97 (3H, s) , 7.41 (IH, d, J=2Hz), 7.48 (IH, dd, 3=2 , 8Hz) , 7.99 (IH, br s), 8.59 (IH, d, J=8Hz) , 9.88 (IH, s)

(4) 5-Formyl-2- [ (E) -2- (4-pyridyl) vinyl]pyridine mp : 131-136°C

NMR (CDC1 ₃ , δ) : 7.40 (IH, d, J=16Hz) , 7.47 (2H, d,

J=6Hz), 7.56 (IH, d, J=8Hz), 7.78 (IH, d, J=16Hz), 8.19 (IH, dd, J=2, 8Hz), 8.65 (2H, d, J=6Hz) , 9.07

(IH, d, J=2Hz), 10.12 (IH, s)

(5) 5-Formyl-2- [ (E) -2- (3-pyridyl) vinyl]pyridine (from 5- hydroxymethyl-2- [ (E) -2- (3-pyridyl) vinyljpyridine) NMR (CDCI3, δ) : 7.29 (IH, d, J=16Hz) , 7.35 (IH, dd,

J=5, 8Hz), 7.54 (IH, d, J=8Hz) , 7.85 (IH, d, J=16Hz), 7.93 (IH, ddd, J=2, 2, 8Hz) , 8.18 (IH, dd, 3=2 , 8Hz), 8.58 (IH, d, J=5Hz) , 8.83 (IH, d, J=2Hz), 9.06 (IH, d, J=2Hz), 10.10 (IH, s)

Preparation 48

The following compounds were obtained according to a similar manner to that of Preparation 1.

(1) Methyl (E) -3- (2-oxo-l,2, 3, -tetrahydroquinolin-6- yl) acrylate NMR (CDCI3, δ) : 2.66 (2H, t, J=7.5Hz), 3.00 (2H, t,

J=7.5Hz), 3.80 (3H, s) , 6.35 (IH, d, J=16Hz) , 6.75 (IH, d, J=8Hz), 7.31-7.39 <2H, ) , 7.80 (IH, br s)

(2) Methyl (E) -3- (1-acetyl-l, 2, 3, 4-tetrahydroquinolin-6- yl) acrylate

NMR (CDCI3, δ) : 1.97 (2H, quint, J=7Hz) , 2.25 (3H, s), 2.75 (2H, t, J=7Hz), 3.79 (2H, t, J=7Hz) , 3.80 (3H, s), 6.38 (IH, d, J=16Hz) , 7.27-7.33 (4H, m)

(3) Methyl 4-acetamido-3-methoxycinnamate mp : 137°C

NMR (CDCI3, δ) : 2.21 (3H, s) , 3.80 (3H, s) , 3.93 (3H, s), 6.36 (IH, d, J=16Hz) , 7.01 (IH, s) , 7.14

( IH, d, J=8Hz ) , 7 . 63 ( IH, d, J=16Hz ) , 7 . 83 ( IH, br s ) , 8 . 40 ( IH, d, J=8Hz )

(4) Methyl (E) -3- (3-quinolyl) acrylate (from 3- quinolinecarbaldehyde) mp : 122°C

NMR (CDC1 ₃ , δ) : 3.87 (3H, s) , 6.68 (IH, d, J=16Hz) ,

7.60 (IH, t, J=8Hz), 7.78 (IH, t, J=8Hz) , 7.81-7.90 (2H, m) , 8.12 (IH, d, J=8Hz), 8.25 (IH, d, J=2Hz) , 9.10 (IH, d, J=2Hz)

(5) Methyl (E) -3- [6- [ (E) -2- (4-pyridyl) vinyl]pyridin-3- yl] acrylate mp : >143.2°C NMR (CDCI3, δ) : 3.83 (3H, s) , 6.53 (IH, d, J=16Hz) ,

7.34 (IH, d, J=16Hz), 7.40-7.47 (3H, m) , 7.64 (IH, d, J=16Hz), 7.70 (IH, d, J=16Hz) , 7.87 (IH, d, J=8Hz), 8.63 (2H, d, J=6Hz), 8.75 (IH, d, J=2Hz)

(6) Methyl (E) -3- [6- [ (E) -2- (2-pyridyl) vinyl]pyridin-3- yl] acrylate (from 5-formyl-2- [ (E) -2- (2-pyridyl) vinyl] - pyridine)

NMR (CDCI3, δ) : 3.83 (3H, s) , 6.52 (IH, d, J=16Hz) ,

7.22 (IH, dd, J=5, 8Hz), 7.45 (2H, d, J=8Hz) , 7.65- 7.77 (4H, ) , 7.84 (IH, dd, J=2, 8Hz) , 8.64 (IH, d,

J=5Hz), 8.75 (IH, d, J=2Hz)

(7) Methyl (E) -3- [6- [ (E) -2- (3-pyridyl) vinyl]pyridin-3- yl] acrylate NMR (CDCI3, δ) : 3.82 (3H, s), 6.51 (IH, d, J=16Hz) ,

7.23 (IH, d, J=16Hz), 7.32 (IH, dd, J=5, 8Hz), 7.41 (IH, d, J=8Hz), 7.60 (IH, d, J=16Hz) , 7.61 (IH, d, J=16Hz), 7.85 (IH, dd, 3=2 , 8Hz) , 7.90 (IH, ddd, 3=2 , 2 , 8Hz), 8.54 (IH, d, J=5Hz), 8.73 (IH, d, J=2Hz), 8.81 (IH, d, J=2Hz)

Preparation 49

The following compounds were obtained according to a similar manner to that of Preparation 3.

(1) (E) -3- (2-Oxo-l,2,3, -tetrahydroquinolin-6-yl) acrylic acid mp : >250°C

NMR (DMSO-d ₆ , δ) : 2.46 (2H, t, J=7.5Hz), 2.90 (2H, t, J=7.5Hz), 6.40 (IH, d, J=16Hz), 6.86 (IH, d, J=8Hz), 7.41-7.57 (3H, )

(2) (E)-3- (1-Acetyl-l,2,3, -tetrahydroquinolin-6-yl)acrylic acid

NMR (DMS0-d ₆ , δ) : 1.85 (2H, quint, J=7Hz) , 2.17 (3H, s), 2.73 (2H, t, J=7Hz) , 3.68 (2H, t, J=7Hz) , 6.46

(IH, d, J=16Hz), 7.41-7.63 (4H, m)

, ^' 3) 4-A.cetamido-3-methoxycinnamic acid mp : 221.5-230°C

NMR (DMS0-d ₆ , δ) : 2.10 (3H, s) , 3.89 (3H, s) , 6.52 (IH, d, J=16Hz), 7.20 (IH, d, J=8Hz) , 7.38 (IH, s-like), 7.53 (IH, d, J=16Hz) , 8.07 (IH, d, J=8Hz) , 9.26 (IH, s)

(4) (E) -3- (3-Quinolyl) acrylic acid

NMR (DMS0-d ₆ , δ) : 6.85 (IH, d, J=16Hz) , 7.66 (IH, t, J=8Hz), 7.72-7.86 (2H, m) , 7.96-8.06 (2H, m) , 8.69 (IH, d, J=2Hz), 9.23 (IH, d, J=2Hz)

(5) (E)-3-[6-[ (E) -2- (4-Pyridyl)vinyl]pyridin-3-yl]acrylic acid mp : >250"C

NMR (DMSO-d ₆ , δ) : 6.71 (IH, d, J=16Kz) , 7.56-7.77 (6H, m) , 8.20 (IH, dd, J=2, 8Hz) , 8.59 (2H, d, J=6Hz), 8.88 (IH, d, J=2Hz)

(6) (E) -3- [6- [ (E) -2- (2-Pyridyl) vinyl]pyridin-3-yl] acrylic acid

NMR (DMSO-d ₆ , δ) : 6.70 (IH, d, J=16Hz) , 7.33 (IH, dd J=5, 8Hz), 7.59-7.72 (3H, m) , 7.78 (IH, d, J=2Hz) 7.83 (2H, ddd, 3=2 , 8, 8Hz) , 8.19 (IH, dd, J=2,

8Hz) , 8.62 (IH, d, J=5Hz) , 8.88 (IH, d, J=2Hz)

(7) (E)-3-[6-[ (E)-2- (3-Pyridyl) vinyl]pyridin-3-yl] acrylic acid NMR (DMSO-d ₆ , δ) : 6.69 (IH, d, J=17Hz) , 7.43 (IH, dd

J=5, 8Hz), 7.49 (IH, d, J=16Hz), 7.60 (IH, d, J=8Hz), 7.64 (IH, d, J=16Hz), 7.78 (IH, d, J=17Hz) 8.09-8.22 (2H, m) , 8.50 (IH, d, J=5Hz) , 8.85 (IH, s-like)

Example 43

(1) 2, 4-Dimethyl-8- [2, 6-dimethyl-3- [N- (phthalimidoacetyl) - methylamino] enzyloxy] quinoline was obtained by reacting 8- hydroxy-2, 4-dimethylquinoline with a mixture of 2 , 6-dimethyl l-methanesulfonyloxymethyl-3- [N-methyl-N-

(phthali idoacetyl) amino]benzene and l-chloromethyl-2, 6- dimethyl-3- [N-methyl-N- (phthalimidoacetyl) amino]benzene according to a εimiiar manner to that of Preparation 6. mp : 123-125°C NMR (CDC1 ₃ , δ) : 2.50 (3H, s) , 2.58 (3H, s) , 2.65 (3H, s), 2.68 (3H, s), 3.22 (3K, s) , 3.94 (IH, d, J=17Hz) , 4.19 (IH, d, J=I7Hz) , 5.38 (IH, d, J=10Hz), 5.42 (IH, d, J=10Hz) , 7.15 (IH, br s) , 7.19-7.28 (3H, ) , 7.42 (IH, t, J=8Hz) , 7.61 (IH, d, J=8Hz), 7.67-7.74 (2H, ) , 7.80-7.88 (2H, m)

(2) 8- [3- (N-Glycyl-N-methylamino) -2, 6-dimethylbenzyloxy] - 2, 4-dimethylquinoline waε obtained according to a εimiiar manner to that of Preparation 11. mo : 145-148°C

NMR (CDCI3, δ) : 2.32 (3H, s), 2.52 (3H, s), 2.65 (3H, s), 2.68 (3H, s) , 2.93 (IK, d, J=17Hz), 3.15 (IH, d, J=17Hz), 3.21 (3H, s) , 5.34 (2H, s) , 7.02 (IH, d, J=8Hz), 7.10-7.18 (2H, m) , 7.22 (IH, d, J=8Hz) , 7.42 (IH, t, J=8Hz), 7.61 (IK, d, J=8Hz)

(3) 2, 4-Dimethyl-8-[2, 6-dimethyl-3- [N-methyl-N- [N'-[3- [ (4- pyridyl) carbamoyl]phenyl]ureidoacetyl]amino] enzyloxy]- quinoline waε obtained by reacting 8-[3- (N-glycyl-N- methylamino)-2, 6-dimethylbenzyloxy]-2, 4-dimethylquinoline with phenyl 3-[ (4-pyridyl) carbamoyl]phenylcarbamate according to a similar manner to that of Example 19.

NMR (CDCI3, δ) : 2.32 (3H, s), 2.53 (3H, s) , 2.64 (3H, s), 2.68 (3H, s), 3.23 (3H, s) , 3.93 (2H, br s) , 5.09 (IH, br d, J=10Hz) , 5.25 (IH, d, J=10Hz), 6.66

(IH, br s), 6.72 (IH, br s) , 6.98-7.08 (3H, m) , 7.15 (IH, br s), 7.20 (IH, br d, J=8Hz), 7.29 (IH, br d, J=8Hz), 7.46-7.55 (2H, m) , 7.65 (IH, d, J=8Hz), 7.90 (2H, d, J=7.5Hz), 8.43 (2H, d, J=7.5Hz), 8.51 (IH, br s) , 9.75 (IH, br s)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.32 (3H, s) , 2.47 (3H, s) , 2.93 (6H, br s), 3.27 (3H, s), 3.80 (2H, br s) , 5.39 (IH, br d, J=10Hz) , 5.50 (IH, br d, J=10Hz) ,

7.19-7.30 (3H, m) , 7.53 (IH, br d, J=8Hz) , 7.63 (2H, br d, J=8Hz) , 7.71 (IH, br s) , 7.78-7.89 (2H, m) , 7.91 (IH, br s) , 8.42-8.52 (4H, )

Example 44

(1) 2-Methyl-8-[2-methyl-3-nitrobenzyloxy]quinoline was obtained according to a similar manner to that of

Preparation 6. mp : 184-188 ^β C NMR (CDCI3, δ) : 2.56 (3H, s) , 2.80 (3H, s) , 5.48 (2H,

s), 7.00 (IH, d, J=8Hz) , 7.28-7.44 (4H, m) , 7.74 (IH, d, J=8Hz), 7.82 (IH, d, J=8Hz), 8.04 (IH, d, J=8Hz)

(2) 8- [3-Amino-2-methylbenzyloxy] -2-methylquincline was obtained according to a εimiiar manner to that of Preparation 8. mp : 223-227°C

NMR (CDC1 ₃ , δ) : 2.23 (3H, s) , 2.79 (3H, s), 3.66 (2H, br s), 5.41 (2H, ε) , 6.68 (IH, br d, J=8Hz) , 6.92-

7.05 (3H, m) , 7.24-7.38 (3H, ) , 8.00 (IH, d, J=8Hz)

(3) 2-Methyl-8- [2-methyl-3- (phthalimidoacetylamino) - benzyloxy] quinoline waε obtained according to a similar manner to that of Preparation 9. mp : 283-285°C NMR (DMSO-d ₆ , δ) : 2.27 (3H, s) , 2.65 (3H, ε) , 4.48

(2H, ε) , 5.30 (2H, ε), 7.20 (IH, t, J=8Hz) , 7.26- 7.34 (4H, m) , 7.85-7.98 (4H, m) , 8.20 (IH, d,

J=8Hz) , 9.85 (IH, br ε)

(4) 2-Methyl-8- [2-methyl-3- [N- (phthalimidoacetyl) -N- methylamino] enzyloxy] quinoline was obtained according to a similar manner to that of Preparation 10. mp : 158-161°C

NMR (CDCI3, δ) : 2.47 (3H, s), 2.80 (3H, s) , 3.26 (3H, s), 3.92 (IH, d, J=17Hz), 4.19 (IH, d, J=17Hz) , 5.46 (2H, ε) , 7.06 (IH, br d, J=8Hz) , 7.23-7.42 (5H, m) , 7.65-7.75 (3H, m) , 7.81-7.89 (2H, m) , 8.0

(IH, d, J=8Hz)

(5) 8- [3- (N-Glycyl-N-methylamino) -2-methylbenzyloxy] -2- methylquinoline waε obtained according to a εimiiar manner to that of Preparation 11.

NMR (CDCI3, δ) : 2.29 (3H, s), 2.80 (3H, ε), 2.90 (IH, d, J=17Hz), 3.13 (IH, d, J=17Hz) , 3.24 (3H, s) , 5.40 (2H, s), 7.01 (IH, br d, J=8Hz) , 7.09 (IH, br d, J=8Hz), 7.21-7.43 (4H, m) , 7.60 (IH, br d, J=8Hz), 8.03 (IH, d, J=8Hz)

Example 45

(1) 2, 4-Dimethyl-8- [3- [N- (phthalimidoacetyl) -N-methylamino]- 2, 4, 6-trimethylbenzyloxy] quinoline was obtained by reacting 8-hydroxy-2, 4-dimethylquinoline with a mixture of l-methanesulfonyloxymethyl-3-[N-methyl-N- (phthalimidoacetyl)- amino]-2, , 6-trimethylbenzene and l-chloromethyl-3- [N-methyl- N- (phthalimidoacetyl)amino]-2,4, 6-trimethylbenzene according to a εimiiar manner to that of Preparation 6. mp : 204-206°C

NMR (CDCI3, δ) : 2.37 (3H, s) , 2.47 (3K, s) , 2.51 (3H, s), 2.64 (3H, s), 2.68 (3H, s) , 3.18 (3H, s) , 3.98 (2H, s), 5.32 (IH, d, J=10Hz) , 5.39 (IH, d, J=10Hz), 7.10 (IH, s), 7.15 (IH, s) , 7.14 (IH, d, J=8Hz), 7.41 (IH, t, J=8Hz) , 7.60 (IH, d, J=8Hz) ,

7.68-7.74 (2H, m) , 7.81-7.89 (2H, m)

(2) 8-[3- (N-Glycyl-N-methylamino)-2, 4, 6-trimethylbenzyloxy]- 2,4-dimethylquinoline was obtained according to a εimiiar manner to that of Preparation 11.

NMR (CDCI3, δ) : 2.18 (3H, s) , 2.29 (3H, s) , 2.49 (3H, s) , 2.65 (3H, ε), 2.68 (3H, s), 2.95 (2H, s) , 3.16 (3H, 8), 5.31 (2H, s), 7.02 (IH, s) , 7.13 (IH, s), 7.21 (IH, d, J=8Hz), 7.41 (IH, t, J=8Hz) , 7.60 (IH, d, J=8Hz)

Example 46

(1) 8- [2, 6-Dimethoxy-3-nitrobenzyloxy]-2-methylquinoline waε obtained by reacting 8-hydroxy-2-methylquinoline with a mixture of 2, 6-dimethoxy-3-nitrobenzyl methaneεulfonate and

2, 6-dimethoxy-3-nitrobenzyl chloride according to a similar manner to that of Preparation 6. mp : 192-196°C

NMR (CDC1 ₃ , δ) : 2.68 (3H, s), 3.91 (3H, s), 4.08 (3H, s), 5.40 (2H, ε), 6.78 (IH, d, J=8Hz) , 7.22-7.31

(2H, m) , 7.37-7.46 (2H, ) , 8.00 (IH, d, J=8Hz) , 8.09 (IH, d, J=8Hz)

(2) To a mixture of 8- [2, 6-dimethoxy-3-nitrobenzyloxy]-2- methylquinoline (2.28 g) , ferric chloride (68 mg) , carbon (6 mg) and methanol (34 ml) was added hydrazine monohydrate (1.25 ml) at 60°C, and the mixture was refluxed for 4 hours. Ferric chloride (68 mg) , carbon (68 mg) , hydrazine monohydrate (1.25 ml) and methanol (10 ml) was further added, and the mixture was refluxed overnight. Inεoluble materials were filtered off, and the filtrate was concentrated. The residue was dissolved in chloroform, and the solution was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography

(chloroform-methanol) and crystallized with methanol to give 8- [3-amino-2, 6-dimethoxybenzyloxy]-2-methylquinoline (1.33 g) as pale brown crystalε. mp : 208-210°C NMR (CDCI3, δ) : 2.27 (3H, S) , 2.37 (3H, s) , 2.72 (3H,

8), 3.57 (2H, br s) , 5.32 (2H, s) , 6.67 (IH, d, J=8Hz), 6.91 (IH, d, J=8Hz), 7.18-7.31 (2H, m) , 7.36-7.42 (2H, m) , 8.00 (IH, d, J=8Hz)

(3) 8- [ 2 , 6-Dimethoxy-3- (phthalimidoacetylamino)benzyloxy]-2- methylquinoline was obtained according to a similar manner to that of Preparation 9. mp : 229-231°C

NMR (CDCI3, δ) : 2.70 (3H, s) , 3.79 (3H, s) , 3.94 (3H, s), 4.55 (2H, s) , 5.36 (2H, s), 6.66 (IH, d,

J=8Hz) , 7.22-7.30 (2H, m) , 7.32-7.42 (2H, m) , 7.71- 7.79 (2H, m) , 7.86-7.92 (2H, m) , 7.99 (IH, d, J=8Hz), 8.08 (IH, br s) , 8.19 (IH, d, J=8Hz)

(4) 8- [2, 6-Dimethoxy-3-[N- (phthalimidoacetyl)-N- methylamino]benzyloxy]-2-methylquinoline was obtained according to a similar manner to that of Preparation 10. mp : 184-185°C

NMR (CDC1 ₃ , δ) : 2.70 (3H, s) , 3.29 (3H, ε), 3.90 (3H, s), 4.01 (3H, ε), 4.22 (IH, d, J=17Hz) , 4.32 (IH, d, J=17Hz), 5.44 (2H, s) , 6.79 (IH, d, J=8Hz) , 7.24-7.44 (5H, m) , 7.69-7.75 (2H, m) , 7.81-7.89 (2H, m) , 8.00 (IH, d, J=8Hz)

(5) 8- [3- (N-Glycyl-N-methylamino)-2, 6-dimethoxybenzyloxy]-2- methylquinoline was obtained according to a similar manner to that of Preparation 11.

NMR (CDCI3, δ) : 2.69 (3H, s) , 3.10 (IH, d, J=17Hz) , 3.22 (IH, d, J=17Hz), 3.30 (3H, s) , 3.85 (6H, s) , 5.33 (IH, d, J=10Hz), 5.44 (IH, d, J=10Hz) , 6.72

(IH, d, J=8Hz), 7.12 (IH, d, J=8Hz) , 7.21-7.45 (4H, m) , 8.00 (IH, d, J=8Hz)

Example 7 (1) 2,4-Dimethyl-8-[2,6-dimethyl-3-[N-ethyl-N-

(phthalimidoacetyl) amino]benzyloxy]quinoline was obtained by reacting 8-hydroxy-2,4-dimethylquinoline with a mixture of 2, 6-dimethyl-l-methanesulfonyloxymethyl-3-[N-ethyl-N- (phthalimidoacetyl) amino]benzene and l-chloromethyl-2, 6- dimethyl-3-[N-ethyl-N- (phthalimidoacetyl)amino]benzene according to a εimiiar manner to that of Preparation 6.

NMR (CDC1 ₃ , δ) : 1.15 (3H, t, J=7.5Hz), 2.50 (3H, s) ,

2.58 (3H, ε), 2.65 (3H, s) , 2.68 (3H, ε), 3.28 (IH, m) , 3.90 (IH, d, 3=11 Hz) , 4.05-4.19 (2H, m) , 5.40 (2H, ε), 7.14 (IH, br ε), 7.20 (2H, s), 7.25 (IH,

d, J=8Hz ) , 7 . 42 ( IH, t , J=8Hz ) , 7 . 61 ( IH, d, J=8Hz ) , 7 . 67-7 . 73 ( 2H, m) , 7 . 80-7 . 88 ( 2H, )

(2) 8-[3- (N-Glycyl-N-ethylamino) -2, 6-dimethylbenzyloxy]-2,4 dimethylquinoline waε obtained according to a εimiiar manner to that of Preparation 11.

NMR (CDC1 ₃ , δ) : 1.15 (3H, t, J=7.5Hz), 2.32 (3H, s),

2.52 (3H, ε), 2.65 (3H, s), 2.67 (3H, s), 2.89 (IH d, J=17Hz), 3.11 (IH, d, J=17Hz) , 3.25 (IH, m) , 4.14 (IH, ) , 5.35 (2H, s) , 6.99 (IH, d, J=8Hz),

7.10-7.17 (2H, m) , 7.22 (IH, d, J=8Hz) , 7.42 (IH, t, J=8Hz), 7.61 (IH, d, J=8Hz)

Example 48 (1) 8- [2, 6-Dimethyl-3-[N- (phthalimidoacetyl)-N- methylamino]benzyloxy]-2-methylquinoxaline was obtained by reacting 8-hydroxy-2-methylquinoxaline with a mixture of 2, 6-dimethyl-l-methanesulfonyloxymethyl-3- [N-methyl-N- (phthalimidoacetyl) amino]benzene and l-chloromethyl-2, 6- dimethyl-3-[N-methyl-N- (phthalimidoacetyl)amino]benzene according to a similar manner to that of Preparation 6. p : 124-127 ^β C

NMR (CDCI3, δ) : 2.50 (3H, s) , 2.54 (3H, s) , 2.76 (3H, S), 3.22 (3H, s), 3.96 (IK, d, J=17Hz) , 4.20 (IH, d, J=17Hz), 5.37 (IH, d, J=10Hz) , 7.20-7.35 (3H, m) , 7.61-7.77 (4H, m) , 7.81-7.89 (2H, ) , 8.74 (IH, s)

(2) 8-[3- (N-Glycyl-N-methylamino)-2, 6-dimethylbenzyloxy]-2- methylquinoxaline was obtained according to a similar manner to that of Preparation 11.

NMR (CDCI3, δ) : 2.32 (3H, s) , 2.51 (3H, s) , 2.78 (3H, s), 2.68 (3H, s), 2.93 (IH, d, J=17Hz) , 3.16 (IH, d, J=17Hz), 3.22 (3H, s), 5.34 (2H, s) , 7.06 (IH, d, J=8Hz), 7.16 (IH, d, J=8Hz), 7.29 (IH, d,

J=8Hz), 7.65 (IH, t, J=8Hz), 7.76 (IH, d, J=8Hz) , 8.74 (IH, s)

Example 49 The following compounds were obtained according to a similar manner to that of Example 9.

(1) 8-[2, 6-Dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)- cinnamoylglycyl]amino]benzyloxy] -2 ,4-dimethylquinoline NMR (CDC1 ₃ , δ) : 2.65 (3H, s), 3.00 (3H, d, J=5Hz) ,

3.26 (3H, ε), 3.66 (IH, dd, J=17, 4Hz), 3.93 (IH, dd, J=17, 5Hz), 5.61 (IH, d, J=10Hz) , 5.66 (IH, d, J=10Hz), 6.32 (IH, br d, J=5Hz) , 6.52 (IH, d, J=15Hz), 6.72 (IH, br s), 7.14 (IH, s) , 7.22-7.32 (2H, ) , 7.39-7.66 (6H, m) , 7.74 (2H, d, J=8Hz)

itε hydrochloride

NMR (CDC1 ₃ -CD ₃ 0D, δ) : 2.95 (3H, ε), 2.99 (3H, s) ,

3.07 (3H, br s) , 3.28 (3H, s) , 3.89 (IH, d, J=17Hz), 4.20 (IH, d, J=17Hz) , 5.58 (IH, d,

J=10Hz), 5.67 (IH, d, J=10Hz) , 6.68 (IH, d,

J=15Hz), 7.35 (IH, d, J=15Hz), 7.40-7.62 (5H, m) ,

7.67-7.76 (3H, m) , 7.79-7.90 (2H, )

(2) 8- [2 , 6-Dichloro-3-[N-methyl-N-[4- (methylcarbamoyl)- cinnamoylglycyl]amino]benzyloxy] -2 ,3-dimethylσuinoline NMR (CDC1 ₃ , δ) : 2.43 (3H, s) , 2.66 (3H, s) , 3.00 (3H, d, J=5Hz), 3.27 (3H, ε) , 3.65 (IK, dd, J=17, 4Hz) , 3.94 (IH, dd, J=17, 5Hz), 5.63 (2H, s) , 6.27 (IH, br d, J=5Hz), 6.52 (IH, d, J=15Hz) , 6.69 (IH, br ε), 7.17-7.32 (2H, ) , 7.36-7.41 (2H, m) , 7.45-7.62 (4H, m) , 7.74 (2H, d, J=8Hz) , 7.81 (IH, br ε)

itε hydrochloride NMR (CDCI3-CD3OD, δ) : 2.63 (3H, br ε), 3.00 (3H, s) ,

3.10 (3H, br s) , 3.29 (3H, s) , 3.89 (IH, d, J=17Hz), 4.22 (IH, d, J=17Hz) , 5.60 (IH, d, J=10Hz), 5.69 (IH, d, J=10Hz) , 6.69 (IH, d, J=15Hz) , 7.34-7.61 (7H, m) , 7.67-7.89 (3H, m) , 8.6 (IH, br s)

(3) 8- [2, 6-Dichloro-3- [N-methyl-N- [4- (methylcarbamoyl) - cinnamoylglycyl] amino]benzyloxy] -2, 3-dimethyl-4- ethoxyquinoline NMR (CDC1 ₃ , δ) : 1.52 (3H, t, J=7.5Hz), 2.35 (3H, s) ,

2.65 (3H, s), 3.00 (3H, d, J=5Hz) , 3.27 (3H, ε) ,

3.66 (IH, dd, J=17, 4Hz) , 3.94 (IH, dd, J=17, 5Hz) 4.09 (2H, q, J=7.5Hz), 5.62 (2H, ε), 6.28 (IH, br d, J=5Hz), 6.52 (IH, d, J=15Hz) , 6.71 (IH, br t, J=5Hz), 7.19 (IH, d, J=8Hz) , 7.30 (IH, d, J=8Hz) ,

7.39 (IH, t, J=8Hz), 7.45-7.62 (4H, ) , 7.69 (IH, d, J=8Hz), 7.74 (2H, d, J=8Hz)

its hydrochloride NMR (CDCI3-CD3OD, δ) : 1.61 (3H, t, J=7.5Hz), 2.41-

2.51 (3H, overlapped with H ₂ 0) , 2.98 (3H, s) , 3.01 (3H, s), 3.28 (3H, s) , 3.86 (IH, d, J=17Hz) , 4.26 (IH, d, J=17Hz), 4.42 (2H, q, J=7.5Hz), 5.54 (IH, d, J=10Hz), 5.68 (IH, d, J=10Hz) , 6.68 (IH, d, J=15Hz), 7.38 (IH, d, J=15Hz) , 7.48-7.62 (5H, m) ,

7.73-7.90 (4H, )

(4) 8- [2, 6-Dimethyl-3- [N- [4- (methylcarbamoyl) - cinnamoylglycyl] -N-methylamino]benzyloxy]-4- ethoxycarbonyl-2-methylquinoline

NMR (CDCI3-CD3OD, δ) : 1.47 (3H, t, J=7.5Hz), 2.35

(3H, s), 2.52 (3H, s) , 2.77 (3H, s) , 3.00 (3H, d, J=5Hz), 3.25 (3H, s) , 3.62 (IH, dd, J=17 and 5Hz) , 3.86 (IH, dd, J=17, 4Hz) , 4.00 (2H, a, J=7.5Hz), 5.34 (2H, s), 6.20 (IH, br q, J=5Hz) , 6.52 (IH, d,

J=17Hz), 6.71 (IH, br t, J=5Hz) , 7.06 (IH, d, J=8Hz), 7.16 (IH, d, J=8Hz), 7.20 (IH, d, J=8Hz), 7.48-7.62 (4H, m) , 7.70-7.80 (3H, m) , 8.31 (IH, d, J=8Hz)

itε hydrochloride

NMR (CDCI3-CD3OD, δ) : 1.51 (3H, t, J=7.5Hz), 2.32

(3H, s), 2.49 (3H, s) , 2.97 (3H, s) , 3.17 (3H, s) , s), 3.27 (3H, s), 3.81 (2H, s), 4.60 (2H, q, J=7.5Hz), 5.41 (IH, d, J=9Hz) , 5.51 (IH, d, J=9Hz) ,

6.60 (IH, d, J=15Hz), 7.24 (2H, s), 7.46 (IH, d, J=15Hz), 7.53 (2H, d, J=8Hz) , 7.70 (IH, d, J=8Hz) , 7.80 (2H, d, J=8Hz), 7.92 (IH, t, J=3Hz) , 8.20 (IH, ε), 8.42 (IH, d, J=8Hz)

(5) 8- [2, 6-Dimethyl-3-[N-[4- (methylcarbamoyl)- cinnamoylglycyl]-N-methylamino] enzyloxy]-4-ethyl-2- ethylquinoline

NMR (CDCI3, δ) : 1.39 (3H, t, J=7.5Hz), 2.36 (3H, s) , 2.52 (3H, ε), 2.67 (3H, s), 2.98 (3H, d, J=7.5Hz),

3.06 (2H, q, J=7.5Hz), 3.25 (3H, s) , 3.62 (IH, dd, J=17, 5Hz), 3.86 (IH, dd, J=17, 4Hz) , 5.33 (2H, s) , 6.25 (IH, br q, J=7.5Hz), 6.51 (IH, d, J=17Hz) , 6.72 (IH, t, J=5Hz), 7.04 (IH, d, J=8Hz), 7.11-7.18 (2H, m), 7.24 (IH, d, J=8Hz) . 7.44 (IH, t, J=8Hz) ,

7.51 (2H, d, J=9Hz), 7.55 (IH, d, J=17Hz) , 7.66 (IH, d, J=8Hz), 7.74 (2H, d, J=9Hz)

itε hydrochloride

NMR (CDCI3-CD3OD, δ) : 1.50 (3H, t, J=7.5Hz), 2.30

(3H, ε), 2.48 (3H, s), 2.98 (3H, ε), 3.05 (3H, br d) , 3.28 (3H, ε), 3.34 (2H, q, J=7.5Hz), 3.80 (IH, d, J=15Hz), 3.86 (IH, d, J=15Hz) , 5.39 (IH, d, J=9Hz), 5.50 (IH, d, J=9Hz) , 6.63 (IH, d, J=17Hz) , 7.20-7.28 (2H, m) , 7.45 (IH, d, J=17Hz) , 7.53 (2H,

d, J=9Hz ) , 7 . 61-7 . 76 ( 2H, m) , 7 . 81 ( 2H, d, J=9Hz ) , 7 . 84 -7 . 95 ( 2H, m)

(6) 8-[2, 6-Dimethyl-3-[N-[4- (methylcarbamoyl) - cinnamoylglycyl]-N-methylamino]benzyloxy]-4- hydroxy ethyl-2-methylquinoline NMR (CDCI3-CD3OD, δ) : 2.32 (3H, s) , 2.50 (3H, s),

2.66 (3H, s), 2.96 (3H, s) , 3.24 (3H, s), 3.65 (IH d, J=17Hz), 3.92 (IH, d, J=17Hz) , 5.10 (IH, d, J=9Hz), 5.16 (IH, d, J=9Hz) , 5.31 (2H, s) , 6.56

(IH, d, J=16Hz), 7.13 (IH, d, J=7.5Hz), 7.20 (IH, d, J=7.5Hz), 7.26 (IH, d, J=8Hz) , 7.39-7.58 (6H, m) , 7.64 (2H, d, J=9Hz)

its hydrochloride

NMR (CDCI3-CD3OD, δ) : 2.20 (3H, s) , 2.50 (3H, s) ,

2.97 (3H, s), 3.04 (3H, s) , 3.28 (3H, s) , 3.74 (IH, d, J=17Hz), 3.91 (IH, d, J=17Hz) , 5.34 (2H, s) , 5.37 (IH, d, J=9Hz), 5.51 (IH, d, J=9Hz) , 6.66 (IH, d, J=15Hz), 7.25 (IH, d, J=8Hz) , 7.30 (IH, d,

J=8Hz) , 7.48 (IH, d, J=15Hz), 7.52-7.62 (2H, m) , 7.67-7.93 (2H, m) , 8.15 (IH, s)

(7) 8-[2, 6-Dimethyl-3-[N-[4- (methylcarbamoyl)- cinnamoylglycyl]-N-methylamino]benzyloxy]-4- methoxymethy1-2-methylquinoline

NMR (CDCI3, δ) : 2.35 (3H, s) , 2.52 (3H, ε) , 2.70 (3H, ε), 2.98 (3H, d, J=5Hz), 3.24 (3H, s) , 3.51 (3H, s), 3.62 (IH, dd, J=17, 5Hz) , 3.86 (IH, dd, J=17, 4Hz), 4.87 (2H, s) , 5.34 (2H, s) , 6.24 (IH, br q,

J=5Hz), 6.50 (IH, d, J=15Hz) , 6.73 (IH, m) , 7.05 (IH, d, J=8Hz), 7.15 (IH, d, J=8Hz) , 7.22-7.29 (IH, m) , 7.38 (IH, ε), 7.45 (IH, t, J=8Hz) , 7.49-7.60 (4H, ) , 7.74 (2H, d, J=9Hz)

itε hydrochloride

NMR (CDCI3-CD3OD, δ) : 2.30 (3H, ε), 2.49 (3H, s) ,

2.96 (3H, ε), 3.08 (3H, s) , 3.28 (3H, s) , 3.66 (3H, s), 3.80 (IH, d, J=17Hz), 3.86 (IH, d, J=17Hz) , 5.13 (2H, s), 5.49 (IH, d, J=9Hz) , 5.50 (IH, d, J=9Hz), 6.62 (IH, d, J=15Hz) , 7.24 (2H, s), 7.44 (IH, d, J=15Hz), 7.51 (2H, d, J=9Hz) , 7.66-7.74 (2H, m) , 7.80 (2H, d, J=9Hz) , 7.90 (IH, d, J=9Hz) , 7.99 (IH, s)

(8) 8-[2, 6-Dimethyl-3-[N-[4- (methylcarbamoyl)- cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methyl-4- phenylquinoline

NMR (CDCI3, δ) : 2.39 (3H, s) , 2.55 (3H, s), 2.74 (3H, s), 2.99 (3H, d, J=5Hz) , 3.26 (3H, s) , 3.64 (IH, dd, J=17, 4Hz), 3.88 (IH, dd, J=17, 5Hz) , 5.37 (2H, s), 6.25 (IH, br q, J=5Hz) , 6.50 (IK, d, J=15Hz) , 6.73 (IH, br t, J=5Hz) , 7.07 (IH, d, J=7.5Hz), 7.16 (IH, d, J=7.5Hz), 7.20-7.30 (3H, m) , 7.38 (IH, t, J=7.5Hz), 7.44-7.60 (8H, m) , 7.74 (2H, d, J=9Hz)

its hydrochloride

NMR (CDCI3-CD3OD, δ) : 2.32 (3H, s) , 2.50 (3H, s) ,

2.96 (3H, s), 3.12 (3H, s) , 3.29 (3H, s), 3.80 (IH, d, J=17Hz), 3.87 (IH, d, J=17Hz) , 5.42 (IH, d,

J=9Hz), 5.55 (IH, d, J=9Hz) , 6.64 (IH, d, J=15Hz) , 7.33 (IH, s), 7.40-7.88 (15H, m)

(9) 8- [2, 6-Dimethyl-3-[N-methyl-N-[4- (methylcarbamoyl)- cinnamoylglycyl]amino]benzyloxy]-2-methylquinoxaline

NMR (CDCI3, δ) : 2.34 (3H, s) , 2.51 (3H, s) , 2.77 (3H, ε), 3.02 (3H, d, J=5Hz) , 3.27 (3H, ε), 3.65 (IH, dd, J=17, 4Hz), 3.88 (IH, dd, J=17, 5Hz) , 5.35 (2H, ε), 6.17 (IH, br d, J=5Hz) , 6.53 (IH, d, J=15Hz) , 6.71 (IH, br t, J=5Hz) , 7.09 (IH, d, J=8Hz) , 7.19

(IH, d, J=8Hz), 7.30 (IH, d, J=8Hz) , 7.51-7.61 (3H m) , 7.67 (IH, t, J=8Hz) , 7.72-7.79 (3K, ) , 8.75 (IH, ε)

(10) 8-[3-[N-[ (E)-3-(6-Acetylaminopyridin-3- yl)acryloylglycyl]-N-methylamino]-2, 6- dimethylbenzyloxy]-2-methylquinoxaline

NMR (CDC1 ₃ , δ) : 2.22 (3H, s) , 2.35 (3H, ε), 2.51 (3H, s), 2.77 (3H, s), 3.27 (3H, s) , 3.64 (IH, dd, J=17, 5Hz), 3.87 (IH, dd, J=17, 5Hz), 5.35 (2H, s), 6.47

(IH, d, J=15Hz), 6.71 (IK, br t, J=5Hz) , 7.10 (IH, d, J=8Hz), 7.19 (IH, d, J=8Hz), 7.31 (IH, d, J=8Hz), 7.51 (IH, d, J=15Hz), 7.67 (IH, t, J=8Hz) , 7.76 (IH, d, J=8Hz), 7.85 (IH, d, J=8Hz) , 8.07 (IH, br s), 7.21 (IH, br d, J=8Hz) , 8.36 (IH, br s) ,

8.74 (IH, ε)

Example 50

The following compoundε were obtained according to a similar manner to that of Example 1.

(1) 8- [2, 6-Dichloro-3-[N-methyl-N-[ (E)-3- (2-oxo-l,2,3,4- tetrahydroquinolin-6-yl)acryloylglycyl]amino]benzyloxy]- 2-methylquinoline NMR (CDCI3, δ) : 2.63 (2H, t, J=7.5Hz), 2.72 (3H, s) ,

2.97 (2H, t, J=7.5Hz), 3.26 (3H, s), 3.64 (IH, dd, 3=4, 18Hz), 3.94 (IH, dd, J=4, 18Hz) , 5.60-5.66 (2H, m) , 6.39 (IH, d, J=16Hz) , 6.60 (IH, t-like), 6.71 (IH, d, J=8Hz), 7.18-7.54 (9H, m) , 7.71 (IH, br s), 8.02 (IH, d, J=8Hz)

its hydrochloride

NMR (DMSO-d ₆ , δ) : 2.48 (2H, t, J=7.5Hz), 2.90 (2H, t,

J=7.5Hz), 2.92 (3H, s) , 3.15 (3H, s), 3.58 (IH, dd, 3=4, 16Hz), 3.87 (IH, dd, J=4, 16Hz) , 5.56-5.70

- 155 -

(2H, m) , 6.65 (IH, d, J=16Hz) , 6.87 (IH, d, J=8Hz) , 7.29 (IH, d, J=16Hz), 7.31-7.42 (2H, m) , 7.75-8.00 (6H, m) , 8.21 (IH, t-like) 8.96 (IH, brpeak), 10.26 (IH, s)

(2) 8-[3-[N-[ (E)-3- (l-Acetyl-1,2, 3, 4-tetrahydroquinolin-6- yl)acryloylglycyl]-N-methylamino]-2, 6- dichlorobenzyloxy]-2-methylquinoline

NMR (CDC1 ₃ , δ) : 1.97 (2H, quint, J=7Hz) , 2.24 (3H, s), 2.68-2.77 (5H, ) , 3.26 (3H, s), 3.64 (IH, dd,

3=4 , 16Hz), 3.78 (2H, t, J=7Hz) , 3.94 (IH, dd, 3=4 , 16Hz), 5.59-5.70 (2H, m) , 6.42 (IH, d, J=16Hz) , 6.60 (IH, t-like), 7.21-7.36 (6H, ) , 7.36-7.56 (6H, ) , 8.03 (8H, d)

itε hydrochloride

NMR (DMSO-d ₆ , δ) : 1.86 (2H, quint, J=7Hz) , 2.19 (3H, ε), 2.72 (2H, t, J=7Hz), 2.91 (3H, s) , 3.15 (3H, s), 3.59 (IH, dd, 3=4 , 16Hz) , 3.67 (2H, t, J=7Hz) , 3.89 (2H, t, J=7Hz), 5.57-5.77 (2H, m) , 6.73 (IH, d, J=16Hz), 7.27-7.43 (2H, m) , 7.50-7.61 (IH, brpeak), 7.77-8.00 (7H, m) , 8.27 (IH, t, J=6Hz) , 8.90-9.03 (IH, )

(3) 8-[3-[N-(4-Acetamido-3-methoxycinnamoylglycyl)-N- methylamino]-2, 6-dichlorobenzyloxy]-2-methylquinoline NMR (CDCI3, δ) : 2.20 (3H, s) , 2.73 (3H, s) , 3.26 (3H, s), 3.84-4.00 (4H, ) , 5.60-5.71 (2H, m) , 6.40 (IH, d, J=16Hz), 6.60 (IH, brpeak), 6.98 (IH, s-like), 7.12 (IH, d, J=8Hz), 7.20-7.34 (3H, m) , 7.34-7.55

(4H, m) , 7.81 (IH, br s) , 8.02 (IH, d, J=8Hz) , 8.37 (IH, d, J=8Hz)

itε hydrochloride NMR (DMSO-d ₆ , δ) : 2.09 (3H, s) , 2.89 (3H, ε), 3.15

- 156 -

(3H, s), 3.86 (3H, s), 5.56-5.69 (2H, m) , 6.75 (IH d, J=16Hz), 7.10 (IH, d, J=8Hz) , 7.21 (IH, s-like) 7.32 (IH, d, J=16Hz), 7.72-7.96 (6H, m.) , 8.03 (IH, d, J=8Hz), 8.20 (IH, t-like), 8.93 (IH, brpeak), 9.23 (IH, s-like)

(4) 8- [2, 6-Dichloro-3- [N-methyl-N- (3-methyl-4- nitrocinnamoylglycyl) amino]benzyloxy] -2-methylquinoline NMR (CDC1 ₃ , δ) : 2.59 (3H, s) , 2.72 (3H, s), 3.25 (3H, ε), 3.68 (IH, dd, 3=4, 16Hz) , 3.94 (IH, dd, 3=4,

16Hz) , 5.60-5.70 (2H, m) , 6.58 (IH, d, J=16Hz) , 6.71 (IH, t-like), 7.22-7.33 (3H, m) , 7.35-7.51 (5K, ) , 7.55 (IH, d, J=16Hz) 7.98 (IH, d, J=8Hz) , 8.03 (IH, d, J=8Hz)

(5) 8- [2, 6-Dichloro-3- [N-methyl-N- [ (E) -3- (3-quinolyl) - acryloylglycyl] amino]benzyloxy] -2-methylquinoline NMR (DMSO-d ₆ , δ) : 2.73 (3H, s) , 3.28 (3H, s) , 3.72

(IH, dd, J=5, 16Hz), 3.96 (IH, dd, J=5, 16Hz) , 5.59-5.71 (2H, ) , 6.66-6.80 (2H, m) , 7.21-7.36

(3H, ) , 7.36-7.61 (4H, ) , 7.67-7.86 (3H, ) , 8.0 (IH, d, J=8Hz), 8.09 (IH, d, J=8Hz) , 8.20 (IH, s-like), 9.07 (IH, d, J=2Hz)

its dihydrochloride

NMR (DMSO-d ₆ , δ) : 2.91 (3H, s) , 3.17 (3H, s) , 3.62

(IH, dd, J=5, 17Hz), 3.92 (IH, dd, J=5, 17Hz) , 5.6 (IH, d, J=10Hz), 5.69 (IH, d, J=10Hz) , 7.13 (IH, d, J=16Hz), 7.63 (IH, d, J=16Hz) , 7.69-8.01 (8H, m) , 8.07-8.17 (2H, m) , 8.45 (IH, t, J=6Hz) , 8.74 (IH, s-like), 8.90-9.02 (IH, m) , 9.24 (IH, s-like)

(6) 8- [2, 6-Dichloro-3- [N-methyl-N- [ (E)-3-[6-[ (E)-2-(4- pyridyl) vinyl]pyridin-3-yl] acryloylglycyl] amino] - benzyloxy] -2-methylquinoline

- 157 -

NMR (CDCI3, δ) : 2.74 (3H, s) , 3.28 (3H, s) , 3.68 (IH, dd, 3=4, 16Hz), 3.95 (IH, dd, 3=4, 16Hz) , 5.61-5.71 (2H, m) , 6.58 (IH, d, J=16Hz) , 6.72 (IH, t-like), 7.23-7.66 (12H, m) , 7.82 (IH, dd, J=2, 8Hz) , 8.03 (IH, d, J=8Hz), 8.62 (2H, d, J=6Hz) , 8.73 (IH, d,

J=2Hz)

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.90 (3H, s), 3.15 (3H, s), 3.59 (IH, dd, J=4, 16Hz), 3.60 (IH, dd, 3=4, 16Hz) ,

5.58-5.70 (2H, m) , 7.01 (IH, d, J=16Hz) , 7.48 (IH, d, J=16Hz), 7.68-7.98 (8H, m) , 8.05 (IH, d, J=16Hz), 8.12 (IH, dd, 3=2, 8Hz) , 8.31 (2H, d, J=6Hz), 8.44 (IH, t-like), 8.85-8.93 (3H, ) , 8.69 (IH, brpeak)

(7) 8- [2, 6-Dimethyl-3-[N-methyl-N- [4- (2-oxopyrrolidin-l- yl)cinnamoylglycyl]amino]benzyloxy]-2-methylquinoline NMR (CDCI3, δ) : 2.11-2.25 (2H, m) , 2.38 (3H, s) , 2.54 (3H, s), 2.63 (2H, t, J=7.5Hz), 2.74 (3H, ε) , 3.27

(3H, ε), 3.63 (IH, dd, J=17, 4Hz) , 3.82-3.94 (3H, ) , 5.38 (2H, ε) , 6.42 (IH, d, J=15Hz) , 6.67 (IH, br ε), 7.08 (IH, d, J=8Hz) , 7.18 (IH, d, J=8Hz) , 7.23-7.32 (2H, m) , 7.40-7.59 (5H, ) , 7.67 (2H, d, J=8Hz), 8.04 (IH, d, J=8Hz)

its hydrochloride

NMR (CDCI3-CD3OD, δ) : 2.12-2.26 (2H, n) , 2.32 (3H, s), 2.50 (3H, s), 2.65 (2H, t, J=7.5Hz), 3.19 (3H, br s), 3.30 (3H, s) , 3.80-3.93 (4H, m) , 5.42 (IH, br d, J=10Hz), 5.51 (IH, br d, J=10Hz) , 6.50 (IH, d, J=15Hz), 7.20 (IH, d, J=8Hz) , 7.26 (IH, d, J=8Hz), 7.45-7.53 (3H, m) , 7.59-7.68 (3H, ) , 7.77- 7.94 (3H, ) , 8.90 (IH, br d, J=8Hz)

8) 8- [3- [N- (4-Acetamido-3-methylcinnamoylgiycyl) -N- methylamino] -2, 6-dιπtethylbenzyloxy] -2-methylquinoline NMR (CDC1 ₃ , δ) : 2.22 (3H, br s), 2.29 (3H, s) , 2.54

(3H, s), 2.74 (3H, s), 3.27 (3H, s) , 3.63 (IK, dd, J=17, 5Hz), 3.89 (IH, dd, J=17, 5Hz) , 5.37 (2H, s) , 6.41 (IH, d, J=15Hz) , 6.67 (IH, br ε) , 7.02 (IH, b s), 7.09 (IK, d, J=8Hz), 7.19 (IH, d, J=8Hz) , 7.23 7.55 (7H, m) , 7.93 (IH, br d, J=8Hz) , 8.05 (IH, d, J=8Hz)

its hydrochloride

NMR (CDCI3-CD3OD, δ) : 2.24-2.38 (9H, overlapped with H ₂ 0) , 2.50 (3H, s), 3.13 (3H, br s), 3.28 (3H, s) , 3.78 (IH, br d, J=17Hz) , 3.87 (IH, br d, J=17Hz) , 5.41 (IH, d, J=10Hz), 5.50 (IH, d, J=10Hz) , 6.45

(IH, d, J=15Hz), 7.19-7.30 (4H, ) , 7.39 (IH, d, J=15Hz), 7.64 (IH, d, J=8Hz) , 7.70 (IH, d, J=8Hz) , 7.76-7.93 (3H, m) , 7.93 (IH, br d, J=8Hz) , 8.05 (IH, d, J=8Hz)

(9) 8- [3- [N- (4-Acetamido-3-methoxycinnamoylglycyl) -N- methylamino] -2, 6-dimethylbenzyloxy] -2-methylquinoline NMR (CDCI3, δ) : 2.21 (3H, s) , 2.38 (3H, s), 2.53 (3H, s), 2.72 (3H, s), 3.25 (3H, s) , 3.62 (IH, dd, J=17, 5Hz), 3.82-3.93 (4H, ) , 5.37 (2K, ε), 6.40 (IH, d,

J=15Hz), 6.65 (IH, br ε), 6.98 (IH, br s) , 7.04- 7.20 (3H, m) , 7.22-7.32 (2H, ) , 7.40-7.54 (3H, m) , 7.81 (IH, br ε), 8.02 (IH, d, J=8Hz) , 8.38 (IH, br d, J=8Hz)

itε hydrochloride

NMR (CDCI3-CD3OD, δ) : 2.21 (3H, s) , 2.26-2.45 (3H, overlapped with H ₂ 0) , 2.50 (3H, s) , 3.18 (3H, br s), 3.29 (3H, s), 3.82 (2H, br s), 3.95 (3H, ε), 5.38-5.55 (2H, m) , 6.49 (IH, br d, J=15Hz), 7.00-

- 1 60 - its hydrochloride

NMR (CDCI3-CD3OD, δ) : 2.24 (3H, s) , 2.50 (3H, ε),

2.94 (3H, ε), 3.06 (6H, br s) , 3.14 (3H, s), 3.30 (3H, s), 3.84 (2H, br s), 5.42 (IH, d, J=10H∑), 5.50 (IH, d, J=10Hz), 6.61 (IH, d, J=15Hz), 7.21

(IH, d, J=8Hz), 7.26 (IH, d, J=8Hz) , 7.40 (2H, br d, J=8Hz), 7.49-7.58 (3H, ) , 7.61 (IH, br d, J=8Hz), 7.70 (IH, br s) , 7.78-7.90 (2H, m)

(12) 2,4-DimethyI-8-[2, 6-dimethyl-3-rN-methyl-N-[4-(2- oxopyrrolidin-1-yl) cinnamoylglycyl] amino]benzyloxy]- quinoline

NMR (CDCI3, δ) : 2.11-2.23 (2H, m) , 2.37 (3H, s), 2.53 (3H, s), 2.59-2.70 (8H, m) , 3.26 (3H, s), 3.61 (IH, dd, J=17, 4Hz), 3.83-3.93 (3K, m) , 5.35 (2H, s),

6.42 (IH, d, J=15Hz), 6.65 (IH, br s) , 7.07 (IH, d, J=8Hz), 7.14-7.19 (2H, m) , 7.22-7.28 (IH, overlapped with CDCI3), 7.41-7.57 (4H, m) , 7.60- 7.67 (3H, m)

itε hydrochloride

NMR (CDC1 ₃ -CD ₃ 0D, δ) : 2.13-2.26 (2H, ) , 2.32 (3H,

8), 2.49 (3H, s), 2.63 (2H, d, J=7.5Hz), 2.95 (3H, s), 3.11 (3H, s), 3.29 (3H, s), 3.81 (2H, s) , 3.89 (2H, d, J=7.5Hz), 5.42 (IH, d, J=10Hz) , 5.50 (IH, d, J=10Hz) 6.50 (IH, d, J=15Hz) , 7.20 (IH, br d, J=8Hz), 7.26 (IH, br d, J=8Hz) , 7.44-7.52 (3H, ) , 7.59-7.66 (3H, m) , 7.70 (IH, br s) , 7.79-7.90 (2H, m)

(13) 2 , 4-Dimethyl-8- [2, 6-dimethyl-3- [N-methyl-N- [4-

(propionamido) cinnamoylglycyl] amino]benzyloxy] quinoline NMR (CDC13, δ) : 1.22 (3H, t, J=7.5Hz), 2.31-2.42 (5H, m) , 2.51 (3H, s), 2.66 (6H, s), 3.24 (3H, s) , 3.61 (IH, dd, J=17, 5Hz), 3.86 (IK, dd, J=I7, 5Hz) , 5.32

- 159 -

7.10 (2H, m) , 7.20-7.32 (2H, m) , 7.46 (IH, br d, J=15Hz) , 7.64 (IH, br s) , 7.75-7.97 (3H, ) , 8.29 (IH, d, J=8Hz), 8.90 (IH, br s)

(10) 8- [3- [N- (4-Acetamido-3-methoxycinnamoylglycyl) -N- methylamino] -2, 6-dimethylbenzyloxy] -2, 4- dimethy1quinoline

NMR (CDC1 ₃ , δ) : 2.20 (3E, s), 2.35 (3H, s), 2.50 (3H, s), 2.64 (3H, s), 2.66 (3H, s), 3.24 (3H, s), 3.60 (IH, dd, J=17, 5Hz), 3.82-3.92 (4H, m) , 5.33 (2H, s), 6.39 (IH, d, J=15Hz), 6.64 (IK, br t, J=5Hz), 6.98 (IH, br s) , 7.03-7.26 (5H, ) , 7.40-7.52 (2H, m) , 7.61 (IH, d, J=8Hz), 7.80 (IH, br ε), 8.36 (IH, d, J=8Hz)

itε hydrochloride

NMR (CDCI3-CD3OD, δ) : 2.21 (3H, s) , 2.33 (3H, ε) ,

2.49 (3H, ε), 2.95 (3H, ε), 3.12 (3H, ε), 3.29 (3H, s), 3.82 (2H, br s), 3.93 (3K, s), 5.42 (IH, d, J=10Hz), 5.50 (IH, d, J=10Hz) , 6.50 (IH, d,

J=15Hz), 7.01-7.08 (2H, m) , 7.20 (IH, d, J=8Hz), 7.26 (IH, d, J=8Hz), 7.45 (IH, d, J=15Hz) , 7.61 (IH, br d, J=8Hz), 7.70 (IH, br s), 7.78-7.92 (2H, m) , 8.28 (IH, d, J=8Hz)

(11) 2, 4-Dimethyl-8- [2, 6-dimethyl-3- [N- [4- (dimethylcarbamoyl) cinnamoylglycyl] -N- methylamino]benzyloxy] quinoline

NMR (CDCI3, δ) : 2.37 (3H, s), 2.52 (3H, s), 2.65 (3H, ε), 2.67 (3H, s), 2.99 (3H, br s), 3.11 (3H, br s),

3.26 (3H, s), 3.63 (IH, dd, J=17, 5Hz), 3.89 (IH, dd, J=17, 5Hz), 5.33 (2H, ε) , 6.50 (IH, d, J=15Hz) , 6.71 (IH, br s) , 7.07 (IH, d, J=8Hz) , 7.11-7.28 (3H, m) , 7.37-7.64 (7K, m)

(2K, s), 6.39 (IH, d, J=15Hz), 6.64 (IH, br t, J=5Hz), 7.05 (IH, d, J=8Hz,, 7.14 (2K, d, J=8Hz), 7.25 (IH, d, J=8Hz), 7.40-7.56 (7H, m) , 7.62 (IH, d, J=8Hz)

itε hydrochloride

NMR (CDCI3-CB3OD, δ) : 1.20 (3H, t, J=7.5Hz),

2.31 (3H, ε), 2.40-2.50 (5H, m) , 2.93 (3H, s), 3.05 (3K, br s), 3.27 (3H, s) , 3.85 (2H, br s) , 5.40 (IH, br d, J=10Hz), 5.48 (IH, br d, J=10Hz) , 6.42

(IH, br d, J=15Hz), 7.18-7.39 (3H, ) , 7.58-7.65 (3K, m) , 7.69 (IH, br s), 7.76-7.89 (2H, m)

(14) 2, 4-Dimethyl-8-[2, 6-dimethyl-3-[N-methyl-N- [4- (methyl- carbamoyl)cinnamoylglycyl]amino]benzyloxy]quinoline

NMR (CDCI3, δ) : 2.36 (3H, ε), 2.52 (3H, s) , 2.65 (6H, ε), 3.01 (3H, d, J=5Hz), 3.26 (3H, s), 3.63 (IH, dd, 3=4, 17Hz), 3.88 (IH, dd, 3=4, 17Hz) , 5.35 (2H, ε), 6.21 (IH, q-like), 6.53 (IH, d, J=16Hz) , 6.72 _ (IH, t-like), 7.07 (IK, d, J=8Hz) , 7.12-7.19 (2H,

IP.) , 7.22-7.29 (IH, ) , 7.46 (IH, t, J=8Hz) , 7.50- 7.65 (4H, m) , 7.75 (2H, d, J=8Hz)

itε hydrochloride NMR (DMSO-d ₆ , δ) : 2.27 (3H, s) , 2.47 (3H, ε), 2.79

(3H, d, J=4Hz), 2.90 (6H, s) , 3.12 (3H, ε), 3.57 (IH, dd, 3=4, 16Hz), 3.63-3.85 (IH, ) , 5.41-5.55 (2H, m) , 6.90 (IH, d, J=16Hz) , 7.28-7.44 (3H, m) , 7.63 (2H, d, J=8Hz), 7.82-8.0C (6H, m) , 8.28 (IH, t-like), 8.50 (IH, q-like)

(15) 8- [3- [N- (4-Acetamido-3-methylcinnamoylglycyl) -N- methylamino] -2, 6-dimethylbenzyloxy] -2, 4- dimethyl quinoline NMR (CDCI3, δ) : 2.22 (3H, ε), 2.26 (3H, s), 2.35 (3H,

ε), 2.52 (3H, ε), 2.65 (3H, ε) , 2.67 (3K, ε) , 3.25 (3H, ε) , 3.61 (IK, dd, 3=4, 18Hz) , 3.87 (IH, dd, 3=4, 18Hz), 5.35 (2H, s), 6.40 (IH, d, J=16Hz) , 6.64 (IH, brpeak), 6.99 (IH, brpeak), 7.06 (IH, d, J=8Hz) , 7.11-7.19 (2H, m) , 7.22-7.28 (IH, m) , 7.28-

7.40 (2H, ), 7.40-7.54 (2H, ) , 7.62 (IH, d, J=8Hz) , 7.93 (IH, br d, J=8Hz)

its hydrochloride NMR (DMSO-d ₆ , δ) : 2.07 (3H, s), 2.21 (3H, s), 2.29

(3H, s), 2.46 (3H, s), 2.90 (6H, ε) , 3.11 (3H, s), 3.54 (IH, dd, 3=4, 18Hz), 3.70 (IK, dd, 3=4, 18Hz), 5.43-5.55 (2H, m) , 6.73 (IH, d, J=16Hz), 7.22-7.42 (5H, m) , 7.54 (IH, d, J=8Hz), 7.86-8.00 (4H, m) , 8.18 (IH, t, J=6Hz), 9.36 (IK, s)

(16) 8-[3-[N-[ (Ξ)-3- (l-Acetyl-l,2,3,4-tetrahydroσuinolin-6- yl) acryloylglycyl] -N-methylamino] -2, 6- dimethylbenzyloxy] -2, 4-dimethylquinoline NMR (CDC1 ₃ , δ) : 1.96 (2H, quint, J=7Hz) , 2.25 (3H, ε), 2.36 (3H, ε), 2.53 (3H, s), 2.65 (3H, s), 2.68 (3H, ε), 2.74 (2H, t, J=7Hz), 3.25 (3H, ε), 3.61 (IH, dd, 3=4, 18Hz), 3.77 (2H, t, J=7Hz) , 3.88 (IH, dd, 3=4, 18Hz), 5.34 (2H, ε), 6.42 (IH, d, J=16Hz) , 6.65 (IH, t-like), 7.07 (IH, d, J=8Kz) , 7.13-7.20

(2H, m) , 7.21-7.35 (4H, m) , 7.41-7.56 (2H, m) , 7.63 (IH, d, J=8Hz)

its hydrochloride NMR (DMSO-d ₆ , δ) : 1.84 (2H, quint), 2.16 (3H, s),

2.25 (3H, s), 2.45 (3H, s) , 2.70 (2H, t, J=7Hz),

2.87 (6H, s), 3.53 (IH, dd, 3=4, 16Hz), 3.61-3.73

(3H, m) , 5.41-5.53 (2H, ) , 6.73 (IH, d, J=16Hz),

7.23-7.38 (5H, m) , 7.46-7.59 (IH, brpeak), 7.84- 7.98 (4H, m) , 8.16 (IH, t, J=6Hz)

(17) 2,4-Dimethyl-8-[2, 6-dimethyl-3- [N- [4- (ethylcarbamoyl) - cinnamoylglycyl] -N-methylamino]benzyloxy] quinoline NMR (CDC1 ₃ , δ) : 1.25 (3H, t, J=7.5Hz), 2.36 (3H, s),

2.52 (3H, ε), 2.65 (3H, ε), 2.66 (3H, s), 3.26 (3H, s), 3.50 (2H, quint, J=7.5Hz), 3.62 (IK, dd, 3=4 ,

18Hz), 3.87 (IH, dd, 3=4 , 18Hz) , 5.34 (2H, ε), 6.09 (IH, t-like), 6.53 (IK, d, J=16Hz) , 6.71 (IH, t-like), 7.06 (IH, d, J=8Hz), 7.11-7.18 (2H, m) , 7.22-7.27 (IH, m) , 7.45 (IH, t, J=8Hz) , 7.50-7.64 (4H, m) , 7.74 (2H, d, J=8Hz)

itε hydrochloride

NMR (DMSO-d ₆ , δ) : I.11 (3H, t, J=7.5Hz), 2.28 (3H, ε), 2.46 (3H, s), 2.88 (6H, s), 3.12 (3H, s), 3.28 (2H, quint, J=7.5Hz), 3.56 (IH, dd, 3=4 , 18Hz) ,

3.73 (IH, dd, J=4, 18Hz) , 5.43-5.55 (2H, m) , 6.90 (IH, d, J=16Hz), 7.31 (IH, d, J=8Hz) , 7.35-7.44 (2K, ) , 7.63 (2H, d, J=8Hz) , 7.82-8.00 (6H, m) , 8.28 (IH, t-like), 8.52 (IH, t-like)

(18) 2, 4-Dimethyl-δ- [2, 6-dimethyl-3- [N-methyl-N- [4- (iso- nicotinamido) cinnamoylglycyl] amino]benzyloxy] quinoline NMR (CDCI3, δ) : 2.26 (3H, s) , 2.42 (3H, s), 2.59 (3H, s), 2.66 (3H, s), 3.19 (3H, s), 3.59 (IH, dd, 3=4 , 18Hz), 3.80 (IH, dd, 3=4 , 18Hz), 5.30 (2H, s), 6.40

(IH, d, J=16Hz), 7.00 (IH, d, J=SHz) , 7.07 (IH, d, J=8Hz), 7.14 (IH, s), 7.26 (IH, d, J=8Hz) , 7.40- 7.53 (4H, m) , 7.59-7.60 (3H, m) , 7.75 (2H, d, J=5Hz), 8.67-8.75 (3H, )

its dihydrochloride

NMR (DMSO-d ₆ , δ) : 2.28 (3H, s) , 2.45 (3H, s), 2.88 (6H, s), 3.11 (3H, s), 3.55 (IK, dd, 3=4 , 16Hz), 5.42-5.55 (2H, m) , 6.75 (IH, d, J=16Hz), 7.28-7.43 (3K, m) , 7.59 (2H, d, J=8Hz), 7.81-7.99 (6H, m) ,

7.99-8.06 (2H, m) , 8.21 (IH, t-like, , 8.87 (2H, d, J=5Hz), 10.82 (IK, s)

(19) 2,4-Dimethyl-8-[2, 6-dimethyl-3- [N- [ (E)-3-(6- ethoxycarbonylpyridin-3-yl) acryloylglycyl] -N- methylamino]benzyloxy] quinoline

NMR (CDC1 ₃ , δ) : 1.46 (3H, t, J=7.5Hz), 2.37 (3H, s), 2.53 (3H, s), 2.65 (3H, s) , 2.68 (3H, s), 3.27 (3H, s), 3.62 (IH, dd, J=17, 5Hz), 3.90 (IH, dd, J=17, 5Hz), 4.49 (2H, q, J=7.5Hz), 5.35 (2K, s), 6.62

(IH, d, J=15Hz), 6.79 (IH, br t, J=5Hz), 7.07 (IH, d, J=8Hz), 7.13-7.20 (2H, m) , 7.22-7.28 (2H, m) , 7.44 (IH, t, J=8Hz), 7.54-7.66 (3H, ) , 7.91 (IH, dd, 3=8, 3Hz), 8.12 (IK, d, J=8Hz), 8.84 (IH, br s)

(20) 8- [3- [N- [ (E) -3- (6-Acetamidopyridin-3-yI) acryloylglycyl] - N-methylamino] -2, 6-dimethylbenzyloxy] -2, 4- dimethylquinoline

NMR (CDCI3, δ) : 2.20 (3H, s) , 2.36 (3H, s), 2.52 (3H, s), 2.66 (3H, s), 2.69 (3H, s), 3.25 (3H, s), 3.63

(IH, dd, 3=4, 18Hz), 3.88 (IH, dd, 3=4, 18Hz) , 5.33 (2H, s), 6.45 (IH, d, J=16Hz), 6.72 (IH, t-like), 7.07 (IH, d, J=8Hz), 7.12-7.19 (2H, m) , 7.22-7.26 (IH, m) , 7.40-7.56 (2H, ) , 7.62 (IH, d, J=8Hz) , 7.81 (IH, dd, 3=2, 8Hz) , 8.07 (IH, ε), 8.20 (IH, d,

J=8Kz), 8.34 (IK, d, J=2Hz)

itε dihydrochloride

NMR (DMSO-d ₆ , δ) : 2.11 (3H, ε) , 2.28 (3H, s) , 2.46 (3H, s), 2.89 (6H, s), 3.11 (3H, s) , 3.54 (IH, dd,

3=4, 16Hz), 3.71 (IH, dd, J=4, 16Hz), 5.42-5.55 (2H, m) , 6.81 (IH, d, J=16Hz), 7.29-7.42 (3H, ) , 7.86-8.04 (5H, m) , 8.11 (IH, d, J=8Hz), 8.23 (IH, t-like), 8.48 (IH, d-like)

(21) 8- [3- [N- [ (E) -3- (6-Aminopyridm-3-yl) acryloylglycyl] -N- methylamino] -2, 6-dimethyIbenzyIoxy] -2, 4- dimethylquinoline

NMR (CDC1 ₃ , δ) : 2.33 (ΞH, s), 2.52 (3H, s), 2.65 (3K, 3), 2.67 (3H, s), 3.25 (3K, s), 3.61 (IH, dd, 3=4 ,

18Hz), 3.86 (IH, αc, 3=4 , 18Kz) , 4.66 (2K, br s), 5.33 (2H, ε), 6.29 (IH, ά, J=16Hz) , 6.48 (IH, d, J=8Hz), 6.59 (IH, -likej , 7.05 (IK, d, J=8Hz) , 7.10-7.19 (2H, ) , 7.21-7.28 (IH, m) , 7.40-7.50 (2H, ) , 7.56-7.65 (2H, ) , 8.17 (IH, d, J=2Hz)

(22) 2,4-Dimethyl-8-[2, 6-dimethyI-3- [N-methyl-N- [ (E)-3-[6- [ (E) -2- (4-pyridyl) vinyl]pyridin-3-yl] acryloylglycyl] - amino]benzyloxy] quinoline NMR (CDCI3, δ) : 2.36 (3K, ε ) , 2.53 (3H, s), 2.65 (3H, ε), 2.68 (3H, ε), 3.25 (3H, s), 3.64 (IK, dd, 3=4 , 18Hz), 3.90 (IH, dd, 3=4 , 18Hz) , 5.35 (2H, s), 6.56 (IH, d, J=16Hz), 6.73 (IH, t-like) , 7.07 (IH, d, J=8Hz), 7.12-7.20 (2H, ) , 7.20-7.32 (IH, ) , 7.32- 7.50 (6H, m) , 7.53-7.65 (2H, m) , 7.82 (IH, dd, 3=2 ,

8Hz), 8.61 (IH, d, J=6Hz), 8.73 (IK, d, J=2Hz)

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.27 (3H, ε), 2.45 (3H, s) , 2.89 (6H, s), 3.11 (3H, s) , 3.56 (IH, dd, J=4, 16Hz) ,

3.75 (IK, dd, J=4, 16Hz), 5.44-5.55 (2H, m) , 7.02 (IH, d, J=16Hz) , 7.29-7.41 (2H, m) , 7.45 (IH, d, J=16Hz), 7.75 (IH, d, J=8Hz) , 7.86-8.14 (8H, m) , 8.25-8.40 (3H, m) , 8.85-3.93 (3H, m)

(23) 2,4-Dimethyl-8-[2, 6-dimethyl-3- [N-methyl-N- [ (E)-3-[6- [ (E) -2- (2-pyridyl) vinyl]pyridin-3-yl] acryloylglycyl] - amino]benzyloxy] quinoline

NMR (CDCI3, δ) : 2.37 (3H, ε), 2.53 (3H, s), 2.65 (3K, ε), 2.66 (3H, s), 3.27 (3H, s), 3.64 (IH, dd, 3=4 ,

- 166 -

18Hz), 3.89 (IH, dd, 3=4, 18Hz), 5.35 (2H, s), 6.55 (IH, d, J=16Hz), 6.75 (IH, t-like), 7.08 (IH, d, J=8Hz), 7.13-7.28 (4H, m) , 7.37-7.75 (8H, m) , 7.80 (IH, dd, 3=2, 8Hz) , 8.65 (IH, d, J=5Hz) , 8.73 (IH, d, J=2Hz)

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.28 (3H, s) , 2.46 (3H, s), 2.91 (6H, s), 3.12 (3H, s), 3.57 (IH, dd, 3=4, 16Hz), 3.75 (IH, dd, 3=4, 16Hz), 5.44-5.55 (2H, ) , 7.02

(IH, d, J=16Hz), 7.31 (IH, d, J=8Hz), 7.39 (IH, d, J=8Hz), 7.46 (IH, d, J=16Hz), 7.71 (IH, dd, J=5, 8Hz), 7.79 (IH, d, J=8Hz) , 7.89-8.06 (6K, ) , 8.12 8.21 (2H, ) , 8.26-8.40 (2H, ) , 8.77 (IH, a, J=5Hz), 8.49 (IH, s-like)

(24) 2,4-Dimethyl-δ-[2, 6-dimethyl-3-[N-methyl-N-[ (E)-3-[6- [ (E) -2- (3-pyridyl)vinyl]pyridin-3-yl]acryloylglycyl]- amino]benzyloxy]quinoline NMR (CDC1 ₃ , δ) : 2.37 (3K, s) , 2.54 (3H, s) , 2.65 (3K, s), 2.68 (3H, s), 3.27 (3K, s), 3.64 (IH, dd, 3=4, 18Hz), 3.89 (IH, dd, 3=4, 18Hz) , 5.35 (2H, ε), 6.55 (IH, d, J=16Hz), 6.73 (IH, t-like), 7.06 (IH, d, J=8Hz), 7.12-7.27 (4H, m) , 7.31 (IH, dd, 3=5, 8Hz) , 7.39 (IH, t, J=8Hz), 7.45 (IH, d, J=8Hz) , 7.52-7.71

(3H, ) , 7.80 (IH, dd, 3=2, 8Hz), 7.89 (IH, ddd, 3=2, 2, 8Hz), 8.53 (IH, d, J=5Hz) , 8.70 (IH, d, J=2Hz), 8.80 (IH, d, J=2Hz)

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.27 (3H, s), 2.46 (3H, s), 2.89 (6H, s), 3.12 (3H, ε), 3.55 (IH, dd, 3=4, 16Kz) , 3.74 (IH, dd, 3=4, 16Hz), 5.43-5.56 (2H, m) , 6.99 (IH, d, J=16Hz), 7.29-7.50 (3H, ) , 7.64-7.76 (2H, m) , 7.82-8.00 (6H, m) , 8.09 (IH, d, J=8Hz), 8.32

( IH, t-like ) , 8 . 20 ( IH, dd, 3=2 , 8Kz ) , 8 . 76 ( IH, d, J=5Hz ) , 8 . 83 ( IH, ε- like ) , 9. 13 ( IK, ε-like )

(25) 2-Methyl-8-[2-methyl-3- [N-methyl-N- [4- (methylcarbamoyl) - cinnamoylglycyl]amino]benzyloxy] quinoline

NMR (CDC1 ₃ , δ) : 2.32 (3H, ε), 2.79 (3H, ε), 3.02 (3H, d, J=5Hz), 3.28 (3H, s), 3.67 (IH, dd, J=17, 5Hz) , 3.88 (IH, dd, J=17, 4Hz) , 5.38 (IK, d, J=10Hz), 5.46 (IH, d, J=10Hz), 6.18 (IH, br d, J=5Hz), 6.52 (IK, d, J=15Hz), 6.70 (IH, br s) , 7.06 (IH, dd,

J=8, 3Hz), 7.12 (IH, br d, J=8Hz) , 7.24-7.43 (4H, ) , 7.50-7.66 (4H, ) , 7.75 (2H, d, J=8Hz) , 3.04 (IH, d, J=8Hz)

(26) 2, 4-Dimethyl-8- [3- [N-methyl-N- [4- (methylcarbamoyl) - cinnamoylglycyl] amino] -2, 4, 6-trimethylbenzyloxy] - quinoline mp : 213-215°C

NMR (CDCI3, δ) : 2.20 (3K, s), 2.32 (3K, s) , 2.48 (3H, s), 2.65 (3H, s), 2.67 (3H, s), 3.02 (3H, d,

J=5Hz), 3.21 (3H, s), 3.57-3.78 (2H, m) , 5.30 (2H, s), 6.22 (IH, br d, J=5Hz) , 6.53 (IH, d, J=15Hz) , 6.72 (2H, br t, J=5Hz), 7.05 (IH, s) , 7.15 (IH, s) , 7.21-7.28 (IH, overlapped with H ₂ 0) , 7.44 (IH, t, J=8Hz), 7.50-7.65 (4H, m) , 7.75 (2H, d, J=8Hz)

its hydrochloride

NMR (CDCI3-CD3OD, δ) : 2.28 (3H, s), 2.30 (3H, br s) ,

2.43 (3H, ε), 2.93 (3H, s) , 2.99 (3H, ε), 3.08 (3H, br ε), 3.22 (3H, s) , 3.70 (IK, br d, J=17Hz) , 3.88

(IH, br d, J=17Kz), 5.38 (IH, br d, J=10Hz) , 5.45 (IH, d, J=10Hz), 6.63 (IH, br d, J=15Hz), 7.11 (IH, s), 7.40-7.52 (3H, m) , 7.60 (IH, br d, J=8Hz) , 7.69-7.89 (5H, m)

- 163 -

(27) 8- [2, 6-Dimethoxy-3- [N-methyl-N- [4- (methylcarbamoyl) - cinnamoylglycyl] amino]benzyloxy] -2-methyiquinoline NMR (CDC1 ₃ , δ) : 2.26 (3H, s), 2.99 (3H, d, J=5Hz) , 3.32 (3K, s), 3.82-3.92 (7H, m) , 3.98 (IH, dd, J=17, 5Hz), 5.31 (IK, d, J=10Hz), 5.47 (IH, d, J=10Hz), 6.28 (IH, br d, J=5Hz), 6.51 (IH, d, J=I5Hz), 6.70 (IH, br t, J=5Hz), 6.75 (IH, d, J=8Hz), 7.19 (IH, d, J=8Hz), 7.22-7.59 (7H, m) , 7.74 (2H, d, J=8Hz), 7.99 (IH, d, J=8Hz)

its hydrochloride

NMR (CDCI3-CD3OD, δ) : 3.00 (3H, s), 3.12 (3H, s),

3.37 (3K, s), 3.79 (3H, s), 3.84 (3H, s), 3.96 (IH, d, J=17Hz), 4.18 (IH, d, J=17Hz) , 5.33 (IH, d, J=10Hz), 5.54 (IH, d, J=10Hz), 6.63 (IH, d,

J=15Hz), 6.82 (IH, d, J=8Hz) , 7.39 (2H, d, J=8Hz), 7.48-7.91 (8H, m) , 8.83 (IH, d, J=8Hz)

(28) 2, 4-Dimethyl-8- [2, 6-dimethyl-3- [N-ethyl-N- [4- (methylcarbamoyl) cinnamoylglycyl] amino]benzyloxy] - quinoline

NMR (CDCI3, δ) : 1.18 (3H, t, J=7.5Hz), 2.35 (3H, s) , 2.54 (3H, s), 2.66 (6H, ε), 3.01 (3K, d, J=5Hz) , 3.29 (IH, m) , 3.60 (IH, dd, J=17, 5Hz) , 3.86 (IH, dd, J=17, 5Hz), 4.19 (IH, ) , 5.32 (IH, d, J=10Hz),

5.38 (IK, d, J=10Hz), 6.20 (IH, br d, J=5Hz) , 6.52 (IH, d, J=15Hz), 6.76 (IH, br t, J=5Hz) , 7.04 (IH, d, J=8Hz), 7.13-7.20 (2H, m) , 7.22-7.30 (IH, overlapped with H ₂ 0) , 7.46 (IH, t, 8Hz) , 7.50-7.65 (4H, m) , 7.75 (2K, d, J=8Hz)

itε hydrochloride

NMR (CDCI3-CD3OD, δ) : 1.18 (3H, t, J=7.5Hz), 2.32

(3H, ε), 2.48 (3H, s), 2.95 (3H, ε), 2.99 (3H, ε), 3.07 (3H, ε), 3.43 (IH, m) , 3.80 (2H, br s), 4.09

(IH, m) , 5.40 (IH, d, J=10Kz) , 5.50 (IH, d, J=10Hz), 6.60 (IH, d, J=15Hz), 7.17-7.28 (2H, m) , 7.40-7.53 (3H, ) , 7.62 (IH, d, J=8Hz), 7.71-7.90 (6H, m)

(29) 2,4-Dimethyl-8-[2, 6-dimethyl-3- [N-methyi-N- [3- [4- [ (2- pyridylmethyl)carbamoyl]phenyl]propionylglycyl]amino]- benzyloxy]quinoline

NMR (CDC1 ₃ , δ) : 2.32 (3H, s), 2.48-2.57 (5H, ) , 2.65 (3H, s), 2.67 (3H, ε), 2.99 (2H, t, J=7.5Hz), 3.45

(IH, dd, 3=4 , 18Hz), 3.72 (IH, dd, 3=4 , 18Hz) , 4.75 (2H, d, J=5Hz), 5.33 (2H, ε), 6.43 (IH, t-like), 7.02 (IH, d, J=8Hz), 7.11-7.34 (7H, m) , 7.44 (IK, t, J=8Hz), 7.50 (IH, t-like), 7.59-7.71 (2H, ) , 7.77 (2H, d, J=8Hz), 8.55 (IH, d, J=5Hz)

itε dihydrochloride

NMR (DMSO-d ₆ , δ) : 2.23 (3H, s), 2.38-2.52 (3H, m) ,

2.78-2.94 (8H, ) , 3.09 (3H, s) , 3.40 (IH, dd, J=4, 16Hz), 3.58 (IH, dd, J=4, 16Hz) , 4.75 (2H, d,

J=6Hz), 5.42-5.53 (2H, ) , 7.26-7.37 (4H, m) , 7.71- 7.99 (8H, m) , 8.06 (IH, t-like), 8.29-8.37 (IH, m) , 8.76 (IH, d, J=5Hz), 9.35 (IH, t-like)

(30) 8- [2, 6-Dimethyl-3-[N-methyl-N-[4- (2-oxopyrrolidin-l- yl)cinnamoylglycyl]amino]benzyloxy]-2-methylquinoxaline NMR (CDC1 ₃ , δ) : 2.11-2.23 (2H, ) , 2.34 (3H, s), 2.50 (3H, s), 2.62 (2H, t, J=7.5Hz), 2.77 (3H, s) , 3.26 (3H, s), 3.64 (IH, dd, J=17, 5Hz) , 3.81-3.91 (3H, m) , 5.35 (2H, s), 6.42 (IH, d, J=15Hz) , 6.64 (IH, br s), 7.10 (IH, d, J=8Hz) , 7.19 (IH, d, J=8Hz), 7.30 (IH, d, J=8Hz), 7.48-7.57 (3H, m) , 7.62-7.70 (3H, in), 7.75 (IH, d, J=8Hz), 8.74 (IH, s)

(31) 8-[2, 6-Dimethyl-3- [N-methyl-N- [4- (propionamido)-

cinnamoylglycyl] amino]benzyloxy] -2-methylσuinoxaline NMR (CDCI3, δ) : 1.24 (3H, t, J=7.5Hz), 2.34 (3H, s), 2.39 (2H, q, J=7.5Hz), 2.77 (3K, ε), 3.27 (3K, s) , 3.63 (IH, dd, J=17, 5Hz) , 3.87 (IH, dd, J=17, 4Hz), 5.32 (2H, s), 6.40 (IH, d, J=15Hz), 6.63 (IH, br t,

J=5Hz), 7.09 (IH, d, J=8Hz), 7.18 (IH, d, J=8Hz) , 7.29-7.33 (2H, m) , 7.42-7.57 (5H, m) , 7.68 (IH, t, J=8Hz), 7.75 (IH, d, J=8Hz) , 8.73 (IH, br ε)

(32) 8- [2, 6-Dimethyl-3-[N-[4- (dimethylcarba oyl) - cinnamoylglycyl] -N-methylamino] enzyloxy] -2- methylquinoxaline

NMR (CDCI3, δ) : 2.31 (3H, s) , 2.50 (3H, s), 2.73 (3H, S), 2.98 (3H, br s), 3.11 (3H, br s), 3.26 (3H, s), 3.63 (IH, dd, 3=4, lβHz) , 3.87 (IH, dd, 3=4, 18Hz) ,

5.34 (2H, s), 6.50 (IH, d, J=16Hz) , 6.68 (IH, t- like), 7.08 (IH, d, J=8Hz) , 7.18 (IH, d, J=8Hz) , 7.30 (IH, d, J=8Hz), 7.41 (2H, d, J=8Hz) , 7.48-7.60 (3H, m) , 7.65 (IH, t, J=8Hz), 7.75 (IH, d, J=8Hz) , 8.73 (IH, s)

(33) 8- [2, 6-Dimethyl-3- [N- [4- (ethylcarbamoyl) - cinnamoylglycyl] -N-methylamino] benzyloxy] -2- methylquinoxaline NMR (CDCI3, δ) : 1.25 (3H, t, J=7.5Hz), 2.34 (3H, s),

2.51 (3H, s), 2.76 (3K, s), 3.27 (3H, s), 3.45-3.56 (2H, m) , 3.63 (IH, dd, J=17, 5Hz), 3.88 (IH, dd, J=17, 4Hz), 5.35 (2H, s), 6.09 (IH, br t, J=7Hz),

6.52 (IH, d, J=15Hz), 6.71 (IH, br t, J=5Hz) , 7.10 (IH, d, J=8Hz), 7.18 (IH, d, J=8Hz), 7.30 (IH, d,

J=8Hz), 7.51-7.61 (3K, m) , 7.66 (IH, t, J=8Hz), 7.72-7.79 (3H, m) , 8.74 (IH, br s)

(34) 8- [2, 6-Dimethyl-3-[N-[ (E)-3- (6-ethoxycarbonylpyridin-3- yl) acryloylglycyl] -N-methylamino]benzyloxy] -2-

methylquinoxaline

NMR (CDCI3, δ) : 1.45 (3H, t, J=7.5Hz), 2.33 (3H, s),

2.51 (3H, s), 2.77 (3H, s), 3.27 (3H, s) , 3.64 (IH, dd, J=17, 5Hz), 3.89 (IH, dd, J=17, 4Hz) , 4.49 (2H, q, J=7.5Hz), 5.35 (2H, S ) , 6.63 (IH, d, J=15Hz) ,

6.78 (IH, br t, J=5Hz) , 7.10 (IH, d, J=8Hz) , 7.20 (IK, d, J=8Hz), 7.31 (IH, d, J=8Hz) , 7.60 (IH, d, J=15Hz), 7.67 (IH, t, J=8Hz), 7.76 (IH, d, J=8Hz) , 7.92 (IH, dd, J=8, 3Hz), 8.14 (IH, d, J=8Hz) , 8.74 (IH, br s), 8.85 (IH, d, J=3Hz)

(35) 8-[3-[N-[ (E)-3- (6-Aminopyridin-3-yl)acryloylglycyl]-N- methylamino]-2, 6-dimethylbenzyloxy]-2-methylquinoxaline NMR (CDCI3, δ) : 2.33 (3H, s) , 2.50 (3H, s) , 2.85 (3H, s), 3.25 (3H, s) , 3.63 (IH, d, 3=4 , 18Hz) , 3.85

(IH, dd, J=4, 18Hz), 4.69 (2H, s), 5.33 (2H, s), 6.30 (IH, d, J=16Hz), 6.49 (IH, d, J=8Hz) , 6.61 (IH, t-like), 7.10 (IH, d, J=8Hz), 7.18 (IH, d, J=8Hz), 7.31 (IH, d, J=8Hz) , 7.47 (IK, d, J=16Hz), 7.57-7.71 (2H, m) , 7.75 (IH, d, J=8Hz) , 8.17 (IH, s-like), 8.74 (IH, s-like)

Example 51

8-[3-[N- (4-Amino-3-methylcinnamoylglycyl)-N- methylamino]-2, 6-dichlorobenzyloxy]-2-methylquinoline was obtained from 8- [2, 6-dichloro-3-[N-methyl-N- (3-methyl-4- nitrocinnamoylglycyl)amino]benzyloxy]-2-methylσuinoline according to a similar manner to that of Preparation 15-(1). NMR (CDCI3, δ) : 2.16 (3H, s) , 2.73 (3H, s), 3.26 (3H, s), 3.61 (IH, dd, 3=4 , 16Kz) , 3.82 (2H, br s) , 3.93

(IH, dd, 3=4 , 16Hz), 5.60-5.70 (2H, ) , 6.27 (IH, d, J=16Hz), 6.48 (IH, t-like), 6. 64 (IH, d, J=8Hz) , 7.17-7.35 (5H, m) , 7.35-7.51 (4H, ) , 8.02 (IH, d, J=8Hz)

Example 52

To a solution of 8- [3- [N- (4-amino-3- methylcinnamoylglycyl) -N-methylamino] -2, 6-dichlorobenzyloxy] 2-methylquinoline (200 mg) and triethylamine (35.9 g) in dichloromethane was dropwiεe added iεobutyryl chloride (41.6 mg) at 0°C under nitrogen atmosphere, and the mixture was stirred for 30 minutes at the same temperature. The mixture waε concentrated, and the residue was dissolved in methanol (3 ml) . To the solution was added saturated sodium bicarbonate solution (1 ml), and the mixture was stirred for 2 hours at ambient temperature and concentrated. To the residue were added ethyl acetate and water, and the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried and concentrated. The residue was purified by preparative thin-layer chromatography

(dichloromethane:methanol = 15:1, V/V) to give 8- [2, 6- dichloro-3- [N-methyl-N- (4-isobutyramido-3- methylcinnamoylglycyl) amino]benzyloxy] -2-methylquinoline (195 mg) as an amorphous powder. NMR (CDC1 ₃ , δ) : 1.28 (6H, d, J=7.5Hz), 2.25 (3H, s),

2.56 (IH, m) , 2.72 (3H, ε), 3.26 (3H, s), 3.63 (IH, dd, J=4, 18Hz), 3.93 (IH, dd, 3=4 , 18Hz) , 5.62 (IH, d, J=10Hz), 5.68 (IH, d, J=10Hz) , 6.41 (IH, d, J=16Hz), 6.58 (IH, t-like), 7.02 (IH, br s) , 7.23- 7.55 (9H, m) , 7.95-8.07 (2H, )

its hydrochloride

NMR (DMSO-d ₆ , δ) : 1.10 (6H, d, J=7Hz), 2.21 (3H, s),

2.69 (IH, m) , 2.89 (3H, s), 3.15 (3H, s), 3.58 (IH, dd, 3=4 , 16Hz), 3.88 (IH, dd, 3=4 , 16Hz) , 5.57-5.69

(2H, ) , 6.72 (IH, d, J=16Hz), 7.26-7.52 (4H, m) , 7.77-7.99 (6H, ) , 8.26 (IH, t, J=6Hz) , 3.95 (IH, br s) , 9.27 (IH, s)

Example 53

The following compounds were obtained according to a similar manner to that of Example 52.

(1) 8- [2, 6-Dichioro-3- [N-methyl-N- [3-methyl-4- (isonicotinamido) cinnamoylglycylJ amino]benzyloxy] -2- ethylquinoline

NMR (CDC1 ₃ , δ) : : 2.33 (3H, s), 2.72 (3H, s) , 3.25 (3H, s), 3.63 (IK, dd, 3=4 , 13Hz) , 3.93 (IH, dd, 3=4 , 18Hz), 5.58-5.63 (2H, ) , 6.43 (IH, d, J=16Hz), 6.61 (IH, t-like), 7.21-7.33 (3H, m) ,

7.33-7.57 (6H, m) , 7.70 (2H, d, J=6Hz) , 7.77 (IH, s), 7.96-8.05 (2H, ) , 8.80 (2H, d, J=6Hz)

its dihydrochloride NMR (DMSO-d ₆ , δ) : 2.28 (3H, s), 2.93 (3H, s) , 3.16

(3H, s), 3.60 (IH, dd, 3=4 , I6Hz), 3.90 (IH, dd, 3=4 , 16Hz), 5.59-5.70 (2H, ) , 6.79 (IK, d, J=16Hz), 7.37 (IH, d, J=16Hz) , 7.41-7.53 (3H, m) , 7.79-7.99 (6K, m) , 8.01 (2H, d, J=6Hz), 8.31 (IH, t, J=6Hz), 8.91 (2H, d, J=6Hz), 8.98 (IH, d,

J=8Hz), 10.44 (IH, s)

(2) 2,4-Dimethyl-8-[2, 6-dimethyl-3- [N-methyl-N- [ (E)-3-(6- propionamidopyridin-3-yl) acryloylglycyl] amino]- benzyloxy] quinoline

NMR (CDCI3, δ) : 1.25 (3H, t, J=7.5Hz), 2.36 (3H, s) , 2.44 (2H, q, J=7.5Hz), 2.65 (3H, s), 2.66 (3H, ε), 3.25 (3H, ε), 3.63 (IH, dd, 3=4 , 18Hz) , 3.88 (IH, dd, 3=4 , 18Hz), 5.35 (2H, s), 6.55 (IH, d, J=16Hz), 6.70 (IH, t-like), 7.06 (IH, d, J=8Hz) , 7.12-7.19

(2H, m) , 7.21-7.28 (IH, m ¹ - , 7.45 (IH, t, J=8Kz), 7.51 (IH, d, J=16Hz), 7.82 (IK, da, 3=2 , 8Hz) , 7.98 (IK, s), 8.22 (IH, a, J=8Hz) , 8.44 (IH, d, J=2Hz)

- 174 - its dihydrochloride

NMR (DMSO-d ₆ , δ) : 1.07 (3H, t, J=7.5Hz), 2.26 (3H, s), 2.42 (2H, q, J=7.5Hz), 2.46 (3H, s), 2.90 (6H, s), 3.11 (3K, s), 3.54 (IH, dd, 3=4 , 16Hz), 3.71 (IH, dd, J=4, 16Hz), 5.54-5.55 (2H, ) , 6.81 (IH, d,

J=16Hz), 7.28-7.41 (3H, m) , 7.89-8.06 (6H, in), 8.13 (IH, d, J=8Hz), 8.23 (IK, t-like), 8.48 (IH, a, J=2Hz)

(3) 2,4-Dimethyl-8-[2, 6-dimethyl-3- [N-methyl-N- [ (E)-3-[6- (2 methylpyridine-3-carboxamido)pyridin-3- yl] acryloylglycyl] amino]benzyloxy] quinoline NMR (CDC1 ₃ , δ) : 2.37 (3H, s) , 2.53 (3H, s) , 2.65 (3H, S), 2.67 (3H, s), 2.75 (3H, s), 3.25 (3H, s) , 3.63 (IH, dd, 3=4 , 18Hz) , 3.89 (IH, dd, 3=4 , 18Hz), 5.3

(2H, s), 6.49 (IH, d, J=16Hz), 6.73 (IH, t-like), 7.07 (IK, d, J=8Hz), 7.13-7.20 (2H, ) , 7.20-7.27 (2K, m) , 7.45 (IH, t, J=8Hz) , 7.52 (IH, d, J=16Hz),

7.62 (IH, d, J=8Hz), 7.83 (IH, d, J=8Hz), 7.90 (IH, dd, 3=2 , 8Hz), 8.31-8.39 (2H, ) , 8.40 (IH, s) ,

8.63 (IH, d, J=6Hz)

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.27 (3H, s) , 2.47 (3H, ε), 2.75 (3H, s), 2.90 (6H, s), 3.12 (3H, ε), 3.55 (IH, dd,

3=4 , 16Hz), 3.73 (IH, dd, 3=4 , 16Hz) , 5.43-5.56 (2H, m) , 6.88 (IH, d, J=16Hz), 7.28-7.45 (3H, m) , 7.81 (IH, dd, 3=6, 8Hz), 7.89-8.00 (4H, m) , 8.10 (IK, dd, 3=2 , 8Hz), 8.20-8.31 (2H, m) , 8.46 (IH, d, J=8Hz), 8.56 (IH, d, J=2Hz), 8.80 (IK, d, J=6Hz),

11.44 (IH, s)

(4) 2,4-Dimethyl-8-[2, 6-dimethyl-3- [N-methyl-N- [ (E)-3-[6-(4- pyridylacetamido)pyridin-3-yl] cryloylglycyl] amino] - benzyloxy] quinoline

NMR (CDCI3, δ) : 2.35 (3H, ε), 2.51 (3H, ε), 2.65 (3H, ε), 2.67 (3H, s), 3.25 (3H, s), 3.62 (IK, dd, J=4, 18Hz), 3.74 (2H, s), 3.87 (IK, dd, 3=4 , 13Hz), 5.33 (2H, s), 6.45 (IH, d, J=16Hz), 6.74 (IH, t-like), 7.06 (IH, d, J=8Hz), 7.12-7.19 (2H, m) , 7.22-7.30 (3H, m) , 7.44 (IH, t, J=8Hz) , 7.50 (IH, d, J=16Hz) , 7.62 (IH, d, J=8Hz), 7.80-7.86 (IH, m) , 8.08 (IH, 8), 8.18 (IH, d, J=8Hz), 8.33 (IH, d, J=2Hz) , 8.62 (2H, d, J=7Hz)

itε trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.26 (3H, s), 2.45 (3H, s), 2.89

(6H, s), 3.11 (3H, s), 3.47-3.59 (IK, ) , 3.66-3.77 (IH, m) , 4.17 (2H, s), 5.42-5.55 (2H, m) , 6.83 (IH, d, J=16Hz), 7.27-7.41 (3H, ) , 7.85-8.10 (8H, m) ,

8.22 (IH, t-like), 8.51 (IH, ε-like), 8.86 (2H, d, J=6Hz)

(5) 8-[2, 6-Dimethyl-3-[N-methyl-N- [ (E)-3-[6-(2- methylpyridine-3-carboxamido)pyridin-3- yl]acryloylglycyl]amino]benzyloxy]-2-methylquinoxaline NMR (CDCI3, δ) : 2.33 (3H, s) , 2.50 (3H, s) , 2.75 (6H, s), 3.25 (3H, ε), 3.63 (IH, dd, 3=4 , 18Hz) , 3.87 (IH, dd, J=4, 18Hz), 5.34 (2H, s) , 6.48 (IH, d, J=16Hz), 6.72 (IH, t-like), 7.09 (IH, d, J=8Hz) ,

7.14-7.17 (2H, m) , 7.31 (IH, d, J=8Hz) , 7.54 (IH, d, J=16Hz), 7.67 (IH, t, J=3Hz), 7.75 (IH, d, J=8Hz), 7.83 (IH, d, J=8Kz) , 7.92 (IH, dd, 3=2 , 8Hz), 8.32-8.44 (3H, ) , 8.64 (IH, d, J=5Hz) , 8.74 (IH, s)

Example 54

To a εolution of 8- [3-[N- (4-amino-3- methylcinnamoylglycyl) -N-methylamino]-2, 6-dichlorobenzyloxy]- 2-methylquinoline (200 mg) and triethylamine (35.9 mg) in

dichloromethane was dropwise added methanesulfonyl chloride (0.03 ml) at 0°C under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature. Methanesulfonyl chloride (0.C3 ml) and triethylamine (36 mg) were further added thereto, and the mixture was stirred for 1 hour at the same temperature. The εolvent was removed in vacuo, and the residue was diεsolved in methanol. To the solution was added IN sodium hydroxide solution (0.5 ml), an the mixture was stirred for 3 hours at ambient temperature and concentrated. To the residue were added dichloromethane and water, the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1, V/V) to give 8- [2, 6-dichloro-3- [N- (4-methanesulfonamido-3- methylcinna oylglycyl)-N-methyi mino]benzyloxy]-2- methylσuinoline (185 mg) aε an amorphous powder.

NMR (CDC1 ₃ , δ) : 2.29 (3H, s) , 2.73 (3H, ε), 3.05 (3H, ε), 3.26 (3H, s), 3.64 (IH, dd, 3=4 , 18Hz) , 3.95 (IH, dd, 3=4 , 18Hz) , 5.65 (2H, s-like), 6.27 (IH, s), 6.43 (IH, d, J=16Hz), 6.62 (IH, t-like), 7.22- 7.57 (10H, m) , 8.03 (IH, d, J=8Hz)

its hydrochloride NMR (DMSO-d ₆ , δ) : 2.30 (3H, s), 2.88 (3H, s) , 3.02

(3H, s), 3.58 (IH, dd, 3=4 , 16Hz) , 5.56-5.69 (2H, m) , 6.75 (IH, d, J=16Hz), 7.28-7.47 (4K, m) , 7.75- 7.97 (6H, m) , 8.29 (IH, t, J=6Hz), 8.91 (IH, br ε), 9.19 (IH, ε)

Example 55

2, 4-Dimethyl-8- [2, 6-dimethyl-3- [N- [ (E) -3- (6- methanesulfonamidopyridin-3-yl) acryloylglycyl]-N- methylamino]benzyloxy]quinoline waε obtained according to a εimiiar manner to that of Example 54.

NMR (CDCI3, δ) : 2.35 (3H, s) , 2.51 (3H, s) , 2.62 (3H, s), 2.64 (3H, s), 3.19 (3H, s) , 3.25 (3H, s) , 3.62 (IH, dd, 3=4, 16Hz), 3.87 (IH, dd, 3=4, 16Hz) , 5.33 (2K, s), 6.41 (IH, d, J=16Kz), 6.73 (IH, t-like), 7.06 (IH, d, J=8Hz), 7.10-7.27 (5H, m) , 7.38-7.50

(2K, ) , 7.62 (IH, a, J=8Hz), 7.80 (IH, d, J=8Hz) , 8.29 (IH, d, J=2Hz)

itε dihydrochloride NMR (DMSO-d ₆ , δ) : 2.27 (3H, s), 2.46 (3H, s) , 2.89

(6H, s), 3.11 (3H, s), 3.29 (3H, s), 3.53 (IH, dd, 3=4, 16Hz), 3.71 (IK, dd, 3=4, 16Hz),_ 5.43-5.55 (2H, m) , 6.75 (IH, d, J=16Hz), 7.02 (IH, d, J=8Hz), 7.27-7.40 (3H, m) , 7.86-8.00 (5H, ) , 8.23 (IK, t- like), 8.40 (IH, ε-like)

Example 56

To a εolution of 8- [3-[N- (4-amino-3- methylcinnamoylglycyl)-N-methylamino]-2, 6-dichlorobenzyloxy]- 2-methylquinoline (200 mg) and triethylamine (35.9 mg) in dichloromethane waε dropwiεe added methyl isocyanate (0.023 ml) at 0°C under nitrogen atmosphere, and the mixture was stirred for 1 hour at the εame temperature and for 2 hourε at ambient temperature. Methyl isocyanate (0.03 ml) was further added thereto, and the mixture was stirred overnight at ambient temperature. The mixture was partitioned between dichloromethane and water, the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography

(dichloromethane.methanol = 15:1, V/V) to give 8-[2, 6- dichloro-3-[N-methyl-N-[3-methyl-4- (N'-methylureido)- cinnamoylglycyl]amino]benzyloxy]-2-methylquinoline (150 mg) aε an amorphouε powder. NMR (CDCI3, δ) : 2.07 (3H, ε), 2.69 (3H, s) , 2.78 (3H,

- 178 - d, J=5Hz), 3.24 (3H, s), 3.63 (IH, dd, 3=4, 18Hz) 3.90 (IH, dd, 3=4, 18Hz), 5.31 (IH, q-like), 5.61 (2H, s-like), 6.38 (IH, d, J=16Hz) , 6.50 (IH, s), 6.64 (IH, t-like), 7.21-7.35 (5H, ) , 7.39-7.51 (4H, m) , 7.69 (IH, d, J=8Hz), δ.05 (IH, d, J=8Hz)

its hydrochloride

NMR (DMSO-d ₆ , δ) : 2.20 (3K, s), 2.66 (3K, ε) , 2.92 (3H, ε), 3.15 (3H, s), 3.58 (IH, dd, 3=4, 16Hz), 3.68 (IH, ad, 3=4, 16Hz), 5.57-5.69 (2H, m) , 6.63

(IH, d, J=16Hz), 7.21-7.34 (3H, m) , 7.78-8.00 (8H, m) , 8.19 (IH, t-like), 9.00 (IH, brpeak)

Example 57 2,4-Dimethyl-8-[2, 6-dimethyl-3-[N-[ (E) -3- [6- (N*- etnylureido)pyridin-3-yl]acryloylglycyl]-N-raethy1amino]- benzyloxy]quinoline waε obtained according to a εimiiar manner to that of Example 56.

NMR (CDC1 ₃ , δ) : 1.25 (3H, t, J=7.5Hz), 2.36 (3H, ε), 2.52 (3H, ε), 2.65 (3H, s) , 2.66 (3H, ε) , 3.25 (3H ε), 3.42 (2H, quint, J=7.5Hz), 3.64 (IH, dd, 3=4, 18Hz), 3.88 (IH, dd, J=4, 18Hz), 5.35 (2H, s) , 6.4 (IH, d, J=16Hz), 6.70-6.78 (2H, m) , 7.07 (IH, d, J=8Hz), 7.13-7.19 (2H, m) , 7.22-7.27 (IH, m) , 7.40 7.52 (2H, m) , 7.63 (IH, d, J=8Hz) , 7.73 (IH, d,

J=8Hz), 7.86 (IH, ε), 8.25 (IH, d, J=2Hz) , 9.15 (IH, brpeak)

itε dihydrochloride NMR (DMSO-d ₆ , δ) : 1.09 (3H, t, J=7.5Hz), 2.27 (3H, ε), 2.45 (3H, ε), 2.88 (IH, ε, J=6Hz) , 3.11 (3H, ε), 3.13-3.25 (2H, ) , 3.54 (IK, dd, 3=4, 17Hz) , 3.71 (IH, dd, 3=4, 17Hz), 5.42-5.56 (2K, m) , 6.74 (IH, d, J=16Hz), 7.27-7. 0 (3K, ) , 7.46 (IH, d, J=8Hz), 7.85-8.02 (6H, m) , 8.20 (IH, t, J=6Hz) ,

8 . 33 ( IH, d, J=2Hz ) , 9 . 72 ( IH, br s )

Example 58 (1) 8- [3- [N- [4- (4-3romobutyra-r.ido) -3-methylcinnamoylglycyi]- N-methylamino]-2, 6-dichlorobenzyloxy]-2-methylquinoline was obtained from 8- [3-[N- (4-amino-3-methylcinnamoylglycyl) -N- methylamino]-2, 6-dichlorobenzyIoxy]-2-methylquinoline and 4- bromobutyric acid according to a similar manner to that of Example 5. NMR (CDC1 ₃ , δ) : 2.14-2.30 (5H, m) , 2.61 (2H, t,

J=7Hz), 2.73 (3H, s) , 3.26 (3K, ε), 3.59-3.71 (3H, m) , 3.94 (IH, dd, 3=4 , 18Hz) , 5.60-5.70 (2H, ) , 6.41 (IH, d, J=16Hz), 6.60 (IH, brpeak), 7.07 (IH, br s), 7.21-7.55 (9H, ) , 7.95 (IH, d-like) , 8.03 (IH, d, J=8Hz)

(2) To a solution of 8-[3-[N-[4-(4-bromobutyramido)-3- methylcinnamoylglycyl]-N-methylamino] -2 , 6-dichlorobenzyloxy]- 2-methylquinoline (110 mg) in N,N-dimethylformamide was added potasεium carbonate (64 mg) and the mixture waε εtirred for 2 hourε at 50°C. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated in vacuo. The residue waε purified by preparative thin-layer chromatography (dichloromethane-methanol) to give 8- [2, 6-dichloro-3-[N- methyl-N- [3-methyl-4- (2-oxopyrrolidin-l-yl) cinnamoylglycyl]- amino]benzyloxy]-2-methylquinoline (72 mg) aε an amorphous powder.

NMR (CDCI3, δ) : 2.15-2.29 (5H, m) , 2.58 (2H, t, J=7.5Hz), 2.73 (3H, s) , 3.26 (3H, ε), 3.64 (IH, dd,

3=4 , 18Hz), 3.73 (2K, t, J=7.5Hz), 3.93 (IH, dd, 3=4 , 18Hz), 5.60-5.70 (2H, m) , 6.43 (IH, d, J=16Hz), 6.63 (IH, brpeak), 7.21-7.58 (9H, m) , 8.02 (IH, d, J=8Hz)

its hydrochloride

NMR (DMSO-d ₆ , δ) : 2.05-2.18 (5H, m) , 2.41 (2H, t,

J=7.5Hz), 2.90 (3H, s), 3.15 (3H, ε), 3.58 (IH, d 3=4 , 16Hz), 3.68 (2H, t, J=7.5Hz), 3.90 (IH, dd, 3=4 , 16Hz), 5.58-5.69 (2K, m) , 6.79 (IH, d,

J=16Hz), 7.26 (IH, d, J=8Hz), 7.35 (IH, d, J=16Hz) 7.39-7.50 (2H, m) , 7.77-7.98 (6H, m) , 8.30 (IK, t- like), 7.96 (IK, brpeak)

Example 59

The following compounds were obtained according to a similar manner to that of Example 58-(l) and (2) .

(1) 2, 4-Dimethyl-8-[2, 6-dimethyl-3- [N-methyl-N- [ (E) -3- [6- (2 oxopyrrolidin-1-yl)pyridin-3-yl] acryloylglycyl] amino] - benzyloxy] quinoline

NMR (CDC1 ₃ , δ) : 2.15 (2K, quint, J=7.5Hz), 2.36 (3H, s), 2.53 (3H, s), 2.61-2.72 (8H, m) , 3.25 (3H, ε), 3.63 (IH, dd, J=4, 18Hz) , 3.87 (IH, dd, 3=4 , 18Hz) 4.11 (IH, t, J=7.5Hz), 5.35 (2H, ε), 6.46 (IH, d,

J=16Hz), 6.69 (IH, t-like), 7.07 (IK, d, J=8Hz) , 7.13-7.19 (2H, m) , 7.23-7.28 (IH, m) , 7.45 (IH, t, J=8Hz), 7.52 (IH, d, J=16Hz) , 7.63 (IH, d, J=8Hz), 7.82 (IH, dd, J=2, 8Hz) , 8.38-8.45 (2H, )

its dihydrochloride

NMR (DMSO-d ₆ , δ) : 2.05 (2H, quint, J=7.5Hz), 2.28

(3H, s), 2.47 (3H, s), 2.59 (2H, t, J=7.5Hz), 2.90 (6H, s), 3.11 (3H, s), 3.54 (IH, dd, 3=4 , 16Hz), 3.72 (IH, dd, 3=4 , 16Hz), 4.00 (2H, t, J=7.5Hz),

5.43-5.56 (2H, m) , 6.82 (IH, d, J=16Hz), 7.27-7.41 (3H, m) , 7.86-8.05 (5H, ) , 8.25 (IH, t-like), 8.3 (IH, d, J=8Hz), 8.53 (IH, d-like)

(2) 8- [2, 6-Dimethyl-3- [N-methyl-N- [ (E)-3-[6- (2-

oxopyrrolidin-l-yl)pyridin-3-yl]acryloylglycyl]amino]- benzyloxy]-2-methylquinoxaline

NMR (CDCI3, δ) : 2.14 (2H, quint, J=7.5Hz), 2.34 (3H, s), 2.51 (3H, s), 2.68 (2H, t, J=7.5Hz), 2.76 (3H, s), 3.25 (3H, s), 3.63 (IH, άd, 3=4 , 18Hz) , 3.87

(IK, dd, J=4, 18Hz), 4.11 (2H, t, J=7.5Hz), 5.34 (2H, s), 6.46 (IH, a, J=16Hz), 6.67 (IK, t-like), 7.10 (IH, d, J=8Hz), 7.19 (IH, d, =8KZ) , 7.30 (IH, d, J=8Hz), 7.53 (IH, d, J=16Hz) , 7.67 (IH, t, J=8Hz), 7.75 (IH, d, J=8Hz), 7.84 (IH, dd-like,

J=8Hz), 8.41-8.46 (2K, m) , 8.74 (IH, s)

Example 60

The following compounds were obtained according to a similar manner to that of Example 3.

(1) 8-[3-[N- [ (E) -3- (6-Carboxypyridin-3-yl)acryloylglycyl]-N- methylamino]-2, 6-dimethylbenzyloxy]-2, 4- dimethylquinoline NMR (DMSO-d ₆ , δ) : 2.30 (3H, s), 2.42 (3H, ε), 2.51

(3H, ε), 2.59 (3H, s), 3.09 (3H, s), 3.49 (IH, dd, J=17, 5Hz), 3.68 (IH, dd, J=17, 5Hz), 5.28 (2H, br s), 7.00 (IH, d, J=15Hz), 7.20-7.31 (3H, m) , 7.39 (IH, d, J=8Hz), 7.42-7.60 (3H, ) , 7.61 (IH, d, J=8Hz), 8.03 (IH, d, J=8Hz) , 8.11 (IH, dd, J=8,

2Hz), 8.31 (IH, br t, J=8Hz) , 8.85 (IH, br ε)

(2) 8-[3-[N-[ (E)-3-(6-Carboxypyridin-3-yl)acryloylglycyl]-N- methylamino] -2, 6-dimethylbenzyloxy]-2-methylquinoxaline NMR (CDCI3, δ) : 2.36 (3H, s), 2.51 (3H, s) , 2.78 (3H, ε), 3.28 (3H, s), 3.66 (IH, dd, J=17, 5Hz) , 3.90 (IH, dd, J=17, 5Hz), 5.35 (2H, s), 6.68 (IH, d, J=15Hz), 6.83 (IH, br t, J=5Hz) , 7.10 (IH, d, J=8Hz), 7.20 (IH, a, J=8Hz) , 7.31 (IH, d, J=8Hz) , 7.58-7.70 (2K, m) , 7.77 (IH, d, J=8Hz) , 8.02 (IH,

dd, J=8 , 2Hz ) , 3 . 21 ( IH, d, J=8Hz ) , 8 . 70 ( IH, br d J=2Hz ) , 8 . 75 ( IH, s )

Example 61 The following compounds were obtained according to a similar manner to that of Example 7.

(1) 2, 4-Dimethyl-8- [2, 6-dimethyl-3- [N-methyi-N- [ (E) -3- [6- (4 pyridylcarbamoyl)pyridin-3-yl] acryloylglycyl] amino] - benzyloxy] quinoline

NMR (CDC1 ₃ , δ) : 2.39 (3H, s), 2.55 (3K, s), 2.66 (3H, s), 2.68 (3H, s), 3.28 (3H, ε), 3.67 (IH, dd, J=17 5Hz), 3.91 (IH, dd, J=17, 4Hz) , 5.36 (2H, ε), 6.67 (IH, d, J=15Hz), 6.82 (IH, br ε), 7.08 (IH, br d, J=8Hz), 7.13-7.30 (4H, rc) , 7.45 (IH, t, J=8Hz) ,

7.60-7.68 (2H, ) , 7.71 (2H, d, J=7Hz) , 8.01 (IH, br d, J=8Hz), 8.29 (IH, d, J=8Hz), 8.58 (2H, d, J=7Hz) , 8.70 (IH, br s)

its trihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.36 (3H, s), 2.49 (3H, s),

2.97 (3H, s), 3.12 (3H, br s), 3.30 (3H, s), 3.84 (IK, br d, J=17Hz), 3.95 (IH, br d, J=17Hz), 5.39 (IH, br d, J=10Hz), 5.49 (IH, br d, J=10Hz), 6.91 (IH, br d, J=15Hz), 7.22-7.31 (2H, m) , 7.52 (IH, br d, J=15Hz), 7.62 (IH, br d, J=8Hz) , 7.74 (IH, br s), 7.80-7.90 (2H, ) , 8.16 (IH, br s), 8.37 (IH, br s), 8.42-8.51 (2H, m) , 8.61-8.70 (2H, m) , 8.95 (IH, br ε)

(2) 2, 4-Dimethyl-8- [2, 6-dimethyl-3- [N-methyl-N- [ (E) -3- [6- [ (2-pyridylmethyl) carbamoyl]pyridin-3-yl] - acryloylglycyl] amino]benzyloxy] quinoline

NMR (CDCI3, δ) : 2.38 (3H, ε), 2.53 (3H, s), 2.65 (3H, s), 2.67 (3H, s), 3.27 (3H, s), 3.64 (IH, dd, J=17,

5Hz), 3.90 (IH, dd, J=17, 4Hz) , 4.80 (2H, d, J=7Kz), 5.35 (2H, s), 6.61 (IH, d, J=15Hz), 6.78 (IH, br t, J=5Hz), 7.08 (IH, d, J=8Hz), 7.13-7.28 (4H, ) , 7.34 (IH, br d, J=8Hz), 7.45 (IH, t, J=8Hz), 7.57-7.70 (3H, m) , 7.94 (IH, dd, J=8, 2Hz) ,

8.20 (IH, d, J=8Hz), 8.60 (IK, br d, J=7Hz) , 8.68 (IH, d, J=2Hz), 3.89 (IH, br t, J=7Hz)

its trihydrochloride NMR (CDCI3-CD3OD, δ) : 2.32 (3H, s) , 2.46 (3H, s) ,

2.97 (3H, s), 3.10 (3H, br s), 3.26 (3H, s) , 3.84 (IH, d, J=17Hz), 3.92 (IK, a, J=17Hz), 5.16 (2H, s), 5.39 (IH, br a, J=10Hz), 5.49 (IK, br d, J=10Hz), 6.99 (IH, br d, J=15Hz), 7.19-7.28 (2H, m) , 7.50 (IH, br d, J=15Hz) , 7.61 (IH, br d,

J=8Hz), 7.72-7.92 (4H, m) , 8.15 (IH, br d, J=8Hz) , 8.34-8.58 (3H, m) , 8.78 (IH, br d, J=7Hz) , 9.07 (IH, br s)

(3) 2, 4-Dimethyl-8-[2, 6-dimethyl-3-[N-methyl-N-[ (E)-3-[6- (methylcarbamoyl)pyridin-3-yl]acryloylglycyl]amino]- benzyloxy]quinoline

NMR (CDCI3, δ) : 2.37 (3H, s) , 2.53 (3H, s) , 2.65 (3H, s), 2.68 (3H, s), 3.04 (3H, d, J=5Hz) , 3.27 (3H, s), 3.64 (IH, dd, J=I7, 5Hz) , 3.90 (IH, dd, J=17,

5Hz), 5.34 (2H, s) , 6.61 (IK, d, J=15Hz) , 6.79 (IH, br t, J=5Hz), 7.08 (IH, d, J=8Hz), 7.15-7.20 (2H, m) , 7.25 (IH, d, J=8Hz), 7.45 (IH, t, J=8Hz) , 7.56- 7.66 (2H, ), 7.90-8.00 (2H, m) , 8.19 (IH, d, J=8Hz), 8.61 (IH, d, J=2Hz)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.31 (3H, s) , 2.40 (3H, s) ,

2.97 (3K, s), 3.06 (3H, s), 3.11 (3H, br s) , 3.28 (3H, s), 3.88 (IH, d, J=17Hz), 4.06 (IH, d,

J=17Hz) , 5.34 (IH, d, J=10Hz), 5.46 (IH, d, J=10Hz), 7.10 (IH, br d, J=15Hz) , 7.19-7.32 (2H, m) , 7.49 (IH, br d, J=15Hz), 7.60 (IH, br d, J=8Hz), 7.72-7.89 (3H, m) , 8.74 (IH, br d, J=8Hz), 8.88 (IH, br d, J=8Hz), 9.42 (IH, br s)

(4) 8- [2, 6-Dimethyl-3- [N-methyl-N- [ (Ξ) -3- [6-

(methylcarbamoyl)pyridin-3-yl] acryloylglycyl] amino] - benzyloxy] -2-methylquinoxaline NMR (CDC1 ₃ , δ) : 2.34 (3H, s), 2.52 (3H, s), 2.77 (3H, s), 3.04 (3H, d, J=5Hz), 3.28 (3H, s), 3.64 (IH, dd, J=17, 5Hz), 3.89 (IH, dd, J=17, 5Hz), 5.34 (2H ε), 6.61 (IH, d, J=15Hz) , 6.76 (IH, br t, J=5Hz), 7.10 (IK, d, J=8Hz), 7.19 (IH, d, J=8Hz) , 7.31 (IH d, J=8Hz), 7.60 (IH, d, J=15Hz) , 7.67 (IH, t,

J=8Hz), 7.75 (IH, d, J=8Hz) , 7.91-8.00 (2H, m) , 8.20 (IH, d, J=8Hz), 8.61 (IH, d, J=2Hz), 8.73 (IH s)

Example 62

(1) 4-Carboxy-8-[2, 6-dimethyl-3- [N- [4- (methylcarbamoyl) - cinnamoylglycyl] -N-methylamino]benzyloxy] -2-methylquinoline waε obtained from 8- [2, 6-dimethyl-3- [N- [4- (methylcarbamoyl) - cinnamoylglycyl] -N-methylamino]benzyloxy] -4-ethoxycarbonyl-2 methylquinoline according to a εimiiar manner to that of Example 3. mp : 178.2-184.2°C

NMR (DMSO-d ₆ , δ) : 2.30 (3H, s), 2.45 (3H, s), 2.70 (3H, s), 2.76 (3H, d, J=5Hz), 3.10 (3H, s), 3.50 (IH, dd, J=17, 5Hz) , 3.69 (IH, dd, J=17, 4Hz) , 5.34

(2H, s), 6.87 (IH, d, J=15Hz) , 7.27 (IH, d, J=8Hz), 7.34 (IH, a, J=8Hz) , 7.40 (IH, a, J=15Hz), 7.53- 7.71 (4H, m) , 7.80-8.04 (3H, m) , 8.18 (IH, d, J=8Hz), 8.27 (IH, br t, J=5Hz) , 8.52 (IH, br q, J=5Hz)

(2) 8-[2, 6-Dimethyl-3-[N-[4- (methylcarbamoyl) - cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methyl-4- (methylcarbamoyl) quinoline was obtained from 4-carboxy-8- [2, 6-dimethyl-3- [N-[4- (methylcarbamoyl) cinnamoylglycyl]-N- methylamino]benzyloxy]-2-methylquinoline and methylamine hydrochloride according to a εimiiar manner to that of Example 7.

NMR (CDC1 ₃ , δ) : 2.36 (3H, s), 2.52 (3K, ε), 2.64 (3H, s), 2.99 (3H, d, J=5Hz), 3.06 (3H, d, J=5Hz) , 3.23 (3H, s), 3.47 (IH, dd, J=17, 5Hz) , 3.79 (IH, dd,

J=17, 4Hz), 5.36 (2H, s) , 6.27 (IH, br q, J=5Hz) , 6.50 (IH, d, J=15Hz), 6.58 (IH, br q, J=5Hz) , 6.71- 6.80 (IH, m) , 7.04 (IH, d, J=9Hz) , 7.15 (IH, d, J=9Hz), 7.21-7.30 (2H, ) , 7.50-7.60 (3H, ) , 7.51 (IH, d, J=15Hz), 7.67 (IH, d, J=9Hz) , 7.75 (IH, d,

J=8Hz)

its hydrochloride

NMR (CDCI3-CD3OD, δ) : 2.30 (3H, s), 2.50 (3H, ε) , 2.96 (3H, ε), 3.06 (3H, s), 3.08 (3H, s), 3.28 (3H, ε), 3.74 (IH, d, J=17Hz) , 3.89 (IH, d, J=17Hz), 5.36 (IH, d, J=9Hz), 5.49 (IH, d, J=9Hz), 6.60 (IH, d, J=15Hz), 7.20-7.31 (2H, m) , 7.49 (IH, d, J=15Hz), 7.55 (2H, d, J=9Hz) , 7.65 (IH, d, J=8Hz) , 7.78 (2H, d, J=9Hz) , 7.85 (IH, t, J=8Hz) , 8.00 (IH, ε), 8.05 (IH, d, J=8Hz)

Example 63

A mixture of 3-[ (Z) -2- (4-methylcarbamoylphenyl)vinyl]- benzoic acid (281 mg) and thionyl chloride (10 ml) waε refluxed for 2 hourε and then the mixture waε concentrated in vacuo. The reεidue was dissolved in dichloromethane (10 ml), and triethylamine (0.3 ml) and 8-[2, 6-dichloro-3- (methylamino)benzyloxy]-2-methylquinoline (347 mg) were added thereto with stirring under ice-bath cooling. The mixture

was stirred for 12 hours at ambient temperature. Chlorofor and brine were added thereto, and the organic layer was dri over magnesium sulfate and concentrated in vacuo. The reεidue waε purified by flash chromatography (chloroform- methanol) to give 8- [2, 6-dichloro-3- [N-methyl-N- [3- [ (Z) -2- (4 methylcarbamcylphenyl) vinyl]benzoyl] amino]benzyloxy] -2- methylquincline (110 mg) as an amorphous powder.

NMR (CDC1 ₃ , δ) : 2.73 (3H, s) , 3.02 (3H, d, J=6Hz), 3.40 (3H, s), 5.48 (IK, d, J=10Hz) , 5.54 (IH, d, J=10Hz), 6.23 (IH, br s), 6.98-7.63 (14H), 7.70

(IH, d, J=8Hz), 8.02 (IH, d, J=8Hz)

Example 64

8- [2, 6-Dichloro-3- [N-methyl-N- [3- [ (E) -2- (4- methylcarbamoylphenyl)vinyl]benzoyl] amino]benzyloxy] -2- methylquinoline was obtained from 3- [(E) -2- (4- methylcarbamoylphenyl) vinyl]benzoic acid and 8- [2, 6-dichloro 3- (methylamino)benzyloxy] -2-methylquinoline according to a similar manner to that of Example 63. NMR (CDCI3, δ) : 2.67 (2.4K, s), 2.69 (0.6H, ε), 2.78

(3H, d, J=6Hz), 3.29 (2.4H, br ε), 3.40 (0.6H, br s), 5.58 (2H, br s), 6.41 (0.4H, br s), 6.58 (1.6H br s), 6.98-7.73 (15H), 8.03 (IH, d, J=8Hz)

Preparation 50

The mixture of 4-chloro-8-hydroxy-2-methylquinoline (60 mg) , piperidine (6.13 ml) and tetrabutylammonium iodide (10 mg) was refluxed for 18 hourε. The cooled reaction mixture waε concentrated in vacuo and to the residue was added chloroform and aqueouε sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and evaporate in vacuo. The residue was recrystallized from n-hexane to give 8-hydroxy-2-methyl-4-piperidinoquinoline (712 mg) as pale brown crystalε. mp : 115-118°C

NMR (CDCI3, δ) : 1.63-1.74 (2H, m) , 1.79-1.89 (4H, ) , 2.64 (3H, ε) , 3.15-3.22 (4H, m) , 6.70 (IH, s), 7.06 (IH, d, J=8Hz), 7.28 (IH, t, J=8Hz), 7.39 (IH, d, J=8Hz)

Preparation 51

The following compounds were obtained according to a similar manner to that of Preparation 6.

(1) 8- [2, 6-Dichloro-3- [N-methyl-N- (phthalimidoacetyl) amino] - benzyloxy] -4-dimethylamino-2-methylquinoline NMR (CDCI3, δ) : 2.66 (3H, s) , 2.96 (3H, s), 3.21 (3H, s), 4.07 (2H, s), 5.63 (IH, d, J=10Hz), 5.71 (IH, d, J=10Hz), 6.99 (IH, s) , 7.20 (IH, d, J=8Hz) , 7.30 (IH, d, J=8Hz), 7.46 (IH, d, J=8Hz) , 7.53 (IH, d,

J=8Hz), 7.65-7.75 (3H, m) , 7.82-7.90 (2H, m)

(2) 8- [2, 6-Dichloro-3- (N-phthalimidoacetyl-N-methylamino) - benzyloxy]-2-methyl-4-piperidinoquinoline mp : 223-226°C

NMR (CDCI3, δ) : 1.59-1.72 (2H, m) , 1.78-1.88 (4H, m) , 2.65 (3H, s), 3.07-3.19 (4H, m) , 3.22 (3H, s) , 4.08 (2H, ε), 5.64 (IH, d, J=10Hz) , 5.71 (IH, d, J=10Hz), 6.73 (IH, ε) , 7.20 (IH, br d, J=8Hz) , 7.30 (IH, t, J=8Hz), 7.46 (IH, d, J=8Hz) , 7.51 (IH, d,

J=8Hz), 7.64 (IH, br d, J=8Hz) , 7.70-7.76 (2H, m) , 7.82-7.89 (2H, m)

(3) 8- [2, 6-Dichloro-3- (N-phthalimidoacetyl-N- methylamino)benzyloxy] -2-methyl-4-morpholinoquinoline NMR (CDCI3, δ) : 2.69 (3H, s), 3.19 (4H, t, J=6Hz) , 3.21 (3H, s), 3.96 (4H, t, J=5Kz) , 4.06 (2H, s) , 5.65 (IK, d, J=10Hz), 5.72 (IH, d, J=10Hz) , 6.76 (IH, s), 7.22 (IH, d, J=8Hz), 7.32 (IH, t, J=8Hz) , 7.47 (IH, d, J=8Kz) , 7.53 (IH, d, J=8Hz), 7.66 (IH,

d, J=8Hz ) , 7 . 72 ( 2H, dd, J=8 , 2Hz ; , 7 . 84 ( 2H , dd, J=8 , 2Hz )

Preparation 52 The following compounds were obtained according to a similar manner tc that of Preparation 11.

(1 ) 8- [3- (N-Glycyl-N-methylamino) -2, 6-dichlorobenzyloxyj -4- dimethylamino-2-methylquinoline NMR (CDC1 ₃ , δ) : 2.66 (3K, s) , 2.91-3.13 (8H, ∑a) , 3.21

(3H, s), 5.61 (2K, ε) , 6.70 (IK, s) , 7.12-7.36 (3K, m) , 7.45 (IH, a, J=8Hz) , 7.70 (IH, d, J=8Hz)

(2) 3- [3- (N-Glycyl-N-methylamino) -2, 6-dichIorcbenzylcxy] -2- methyl-4-piperidinoquinolir.e

NMR (CDCI3, δ) : 1.57-1.90 (6H, ) , 2.65 (3H, s), 2.97 (IH, d, J=17Hz), 3.02-3.18 (4K, m) , 3.20 (3H, s) , 5.60 (2H, s), 6.72 (IH, s), 7.15 (IH, br d, J=8Hz) , 7.19-7.34 (2H, m) , 7.43 (IH, d, J=8Hz) , 7.64 (IH, br d, J=8Hz)

(3) 8- [ 3- (N-Glycyl-N-methylamino) -2, 6-aichlorobenzyioxy] -2- methyl-4-morpholinoquinoline

NMR (CDCI3, δ) : 2.69 (3H, s), 2.98 (IH, d, J=17Hz) , 3.09 (IH, d, J=17Hz), 3.13-3.22 (4H) , 3.20 (3H, s) ,

3.92-4.00 (4H), 5.62 (2K, s) , 6.77 (IH, s) , 7.16- 7.26 (2H), 7.33 (IH, t, J=8Hz) , 7.44 (IH, d, J=8Hz), 7.66 (IH, d, J=8Hz)

Preparation 53

The following compoundε were obtained according to a similar manner to that of Preparation 2.

(1) Methyl 4- [N- (2-dimethylaminoethyl) carbamoyl] cinnamate mo : 104-106°C

NMR (CDCI3, δ) : 2.27 (6H, s), 2.51 (2H, t, J=7Hz) ,

3.51 (2H, br q, J=7Hz) , 3.81 (3H, s), 6.49 (IH, d, J=15Hz), 6.85 (IH, br s), 7.58 (2H, br d, J=8Hz) , 7.70 (IH, d, J=15Hz), 7.81 (2H, br d, J=8Hz)

(2) Methyl 4-[N- (2-dimethylaminoethyl) -N-methylcarbamoyl]- cinnamate NMR (CDCI3, δ) : 2.09 (3H, br s), 2.31 (3H, br s) ,

2.36-2.64 (2K, m) , 2.94-3.14 (3H, m) , 3.32 (IH, br s), 3.65 (IH, br ε), 3.80 (3H, s), 6.47 (IH, d,

J=15Hz), 7.42 (2H, br d, J=8Hz) , 7.55 (2H, br d, J=8Hz), 7.69 (IH, d, J=15Hz)

Preparation 54 The following compoundε were obtained according to a similar manner to that of Preparation 3.

(1) 4- [N- (2-Dimethylaminoethyl) carbamoyl]cinnamic acid mp : 219-223 ^β C NMR (DMSO-d ₆ , δ) : 2.33 (6H, s), 2.62 (2H, br t,

J=7Hz), 3.43 (2H, br q, J=7Hz) , 6.59 (IH, d, J=15Hz), 7.57 (IH, d, J=15Hz) , 7.75 (2H, d, J=8Hz), 7.86 (2H, d, J=8Hz), 8.54 (IH, br t, J=7Hz)

(2) 4- [N- (2-Dimethylaminoethyl) -N-methylcarbamoyl]cinnamic acid mp : 171-I74°C

NMR (DMSO-d ₆ , δ) : 1.98 (3H, br s), 2.28-2.60 (5H, m) , 2.84-3.00 (4H, m) , 3.07-3.75 (IH, overlapped with H ₂ 0), 6.59 (IH, d, J=15Hz) , 7.40 (2H, d, J=8Hz) ,

7.61 (IH, d, J=15Hz), 7.74 (2H, d, J=8Hz)

Preparation 55

The following compounds were obtained according to a similar manner to that of Preparation 46- (1).

(1) N- (3-Aminobenzoyl)methanesulfonamide (from N- (3-nιtrobenzoyl)methanesulfonamide) mp : 153-155°C

NMR (DMSO-d ₆ , δ) : 3.32 (3H, ε), 6.73 (IH, dd, J=3, 2Kz), 7.01-7.17 (3H, )

(2) N- (3-Aminobenzoyl ) -4-methylbenzene≤ulfonamide

(from N- (3-nitrobenzoyl ) -4-methylbenzenesulfonamide) NMR (DMSO-d ₆ , δ) : 2.39 (3H, s), 6.74 (IH, br da, 3=8, 2Hz), 6.92-6.99 (2H, ) , 7.08 (IH, t, J=8Kz), 7.41

(2H, d, J=8Hz), 7.84 (2H, d, J=8Hz)

Preparation 56

To a solution of N- (3-aminobenzcyl)methaneεulfonamide (400 mg) in dioxane (4 mi) and IN εodiuir. hydroxide solution (3.73 ml) was added phenyl chloroformate (351 mg) under ice- cooling, and the mixture was stirred for 2.5 hourε at ambient temperature. Water waε added thereto, the mixture was adjusted pH 3 with hydrochloric acid. The mixture waε extracted with chloroform-methanol, and the extract waε dried over magnesium sulfate and concentrated in vacuo to give phenyl 3- (methanesulfonylaminocarbonyl)phenylcarbamate (600 mg) as colorlesε crystals, mp : 201-202°C NMR (DMSO-d _β , δ) : 3.22 (3H, s) , 7.22-7.30 (3H, m) ,

7.47-7.57 (3H, m) , 7.62 (IH, a, J=8Hz), 7.70 (IH, br d, J=8Hz), 8.07 (IH, br ε)

Preparation 57 Phenyl 3- (4-methylbenzenesulfonylaminocarbonyl) - phenylcarbamate waε obtained according to a εimiiar manner to that of Preparation 55.

NMR (CDC1 ₃ , δ) : 2.38 (3H, br s), 7.11-7.43 (10H, m) , 7.51 (IH, br d, J=8Hz) , 7.66 (IH, br d, J=8Hz) , 7.87 (IH, br s), 7.99 (2H, br a, J=8Kz)

Preparation 58

(1) A mixture of 2-hydroxypyridine (2.40 g) , ethyl 4-iodobenzoate (6.97 g) , potaεsium carbonate (3.83 g) and copper (253 mg) in N,N-dimethylformamide (12 ml) waε εtirred for 4 hourε at 175°C under nitrogen atmoεphere. Inεoluble material was filtered off, and the filtrate was concentrated in vacuo. To the residue was added ethyl acetate and IN hydrochloric acid, the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give ethyl 4- (2-oxo-l,2-dihydropyridin-l-yl)benzoate (2.18 g) as brown powder.

NMR (CDC1 ₃ , δ) : 1.40 (3K, t, J=7.0Hz), 4.40 (2H, q, J=7.0Hz), 6.26 (IH, t, J=7.5Hz), 6.67 (IH, d,

J=7.5Hz), 7.32 (IH, d, J=7.5Hz), 7.41 (IH, t, J=7.5Hz), 7.47 (2H, d, J=8.5Hz), 8.17 (2H, d, J=8.5Hz)

(2) 4- (2-Oxo-l,2-dihydropyridin-l-yl)benzyl alcohol waε obtained according to a εimiiar manner to that of Preparation 27- (5). NMR (CDC1 ₃ , δ) : 4.71 (2H, ε) , 6.23 (IH, t, J=7.5Hz),

6.66 (IH, d, J=7.5Hz), 7.29-7.51 (2H, m) , 7.33 (2H, d, J=8.5Hz), 7.46 (2H, d, J=8.5Hz)

(3) 4- (2-0xo-l,2-dihydropyridin-l-yl)benzaldehyde waε obtained according to a εimiiar manner to that of Preparation 32- (7). NMR (CDCI3, δ) : 6.31 (1H, t, J=7.5Hz), 6.68 (IH, d,

J=7.5Hz), 7.33 (IH, d, J=7.5Hz), 7.42 (IH, t, J=7.5Hz), 7.61 (2H, d, J=3.5Hz), 8.03 (2H, d, J=8.5Hz), 10.08 (IH, s)

(4) 4- (2-Oxo-l,2-dihydropyridin-l-yl)cinnamic acid was

obtained according to a εimiiar manner to that of Preparation 4. mp : 279-282°C

NMR (CDCI3-CD3OD, δ) : 6.37 (IH, t, J=7.5Hz), 6.47 (IH, d, J=16.0Hz), 6.68 (IH, d, J=7.5Hz), 7.33-7.54

(4H, m) , 7.67 (2H, d, J=8.5Hz), 7.71 (IH, d, J=l6.0Hz)

Example 65 (1) 8-Hydroxy-2-methyl-4- (pyrrolidin-1-yl) quinoline waε obtained from 4-chloro-8-hydroxy-2-methylquinoline and pyrrolidine according to a εimiiar manner to that of Preparation 16. mp : 135-137°C NMR (CDCI3, δ) : 1.99-2.10 (4K, m) , 2.56 (3H, ε),

3.65-3.76 (4H, m) , 6.32 (IH, ε), 7.03 (IH, d, J=7.5Hz), 7.16 (IH, t, J=7.5Hz), 7.65 (IH, d, J=7.5Hz)

(2) 8- [2, 6-Dichloro-3-[N-methyi-N- [4- (methylcarbamoyl) - cinnamoylglycyl] amino]benzyloxy] -2-methyl-4- (pyrrolidin- 1-yl) quinoline waε obtained according to a εimiiar manner to that of Example 9.

NMR (CDCI3, δ) : 1.98-2.06 (4H, ) , 2.54 (3H, ε), 2.99 (3H, d, J=5Hz), 3.24 (3H, s) , 3.59-3.72 (5H, m) ,

3.93 (IH, dd, J=17, 5Hz) , 5.56 (IH, d, J=10Hz) , 5.60 (IH, d, J=10Hz), 6.33-6.41 (2H, m) , 6.52 (IH, a, J=15Hz), 6.85 (IH, br ε), 7.11-7.30 (3H, m) , 7.41-7.50 (3H, m) , 7.55 (IH, d, J=15Kz) , 7.71 (2H, br d, J=8Hz), 7.84 (IH, br d, J=8Hz)

itε dihydrochloride mp : 203-206°C

NMR (CDCI3-CD3OD, δ) : 2.14-2.26 (4H, ) , 2.67 (3H, ε), 2.99 (3H, s), 3.29 (3H, s), 3.87 (IH, d,

J=17Hz), 3.89-4.08 (4H, m) , 4.13 (IH, d, J=17Hz), 5.48 (IH, a, J=10Hz) , 5.65 (IH, d, J=10Hz) , 6.51 (IH, s), 6.62 (IH, d, J=15Hz), 7.33-7.64 (7H, m) , 7.81 (2K, d, J=8Hz), 8.02 (IH, d, J=8Hz)

Example 66

(1) S-Hydroxy-2-methyl-4- (4-methylpiperazin-i-yl) quinoline hydrochloride was obtained from 4-chloro-8-hydroxy-2- methylquinoline and 1-methylpiperazine according to a similar manner to that of Preparation 16. mp : >300°C NMR (DMSO-d ₆ , δ) : 2.66 (3H, s), 2.46 (3H, br s),

3.10-3.60 (8H, overlapped with H ₂ 0) , 7.01-7.11 (2H, ) , 7.30-7.42 (2K, m)

(2) 3- [2, 6-Dichioro-3- [N-methyl-N- [4- (methylcarbamoyl) - cinnamoylglycyl] amino]benzyloxy]-2-methyI-4- (4- methylpiperazin-1-yi) quinoline was obtained according to a εimiiar manner to that of Example 9. NMR (CDC1 ₃ , δ) : 2.42 (3H, ε), 2.66 (3H, s) , 2.67-2.75

(4H, ) , 3.01 (3H, d, J=5Hz) , 3.19-3.29 (7H, m) , 3.68 (IK, dd, J=17, 4Hz), 3.94 (IH, dd, J=17, 5Hz) , 5.59 (IH, d, J=10Hz), 5.65 (IH, d, J=10Hz) , 6.25 (IH, br a, J=5Hz) , 6.53 (IH, d, J=15Hz) , 6.70-6.79 (2H, m) , 7.18-7.68 (8H, m) , 7.75 (2H, br d,

J=7.5Hz)

its trihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.84 (3H, br s), 2.99 (3H, s) , 3.04 (3H, br s) , 3.30 (3H, s), 3.50-3.59 (2H, m) ,

3.86-4.02 (4H, m) , 4.19-4.29 (4H, m) , 5.50 (IH, d, J=10Hz), 5.68 (IH, d, J=10Hz), 6.59 (IH, d, J=15Hz), 7.37-7.81 (11H, !

Example 67

(1) 4-Hexamethyleneimino-8-hydroxy-2-methylσuinoline was obtained from 4-chloro-8-hydroxy-2-methylquinoline and hexamethyleneimine according to a similar manner to that of Preparation 16. NMR (CDC1 ₃ , δ) : 1.70-1.80 (4H, m) , 1.87-1.99 (4H, m) ,

2.59 (3H, s), 3.49-3.58 (4H, m) , 6.63 (IH, ε), 7.03 (IH, d, J=8Hz), 7.21 (IK, t, J=8Hz), 7.46 (IH, d, J=8Hz)

(2) 4-Hexamethyleneimino-8- [2, 6-dichloro-3- [N-methyl-N- [4- (methylcarbamoyl) cinnamoylglycyl]amine]benzyloxy]-2- methylquinoline waε obtained according to a εimiiar manner to that of Example 9.

NMR (CDCI3, δ) : 1.59-1.80 (4H, ) , 1.86-1.97 (4H, m) , 2.60 (3K, br ε), 2.99 (3H, d, J=5Hz), 3.24 (3H, ε),

3.43-3.53 (4H, m) , 3.70 (IH, dd, J=17, 4Hz) , 3.95 (IH, dd, J=17, 5Hz), 5.57 (2H, s) , 6.35 (IH, br s), 6.54 (IH, d, J=15Hz), 6.70 (IH, br s), 7.19 (IH, br d, J=8Hz), 7.27-7.35 (2H, m) , 7.41-7.50 (3H, m) , 7.54 (IH, d, J=15Hz), 7.67-7.75 (3H, m)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 1.69-1.79 (4H, ) , 2.00-2.11

(4H, m) , 2.69 (3H, s), 2.99 (3H, ε), 3.28 (3H, ε) , 3.86 (IH, d, J=17Hz) , 3.90-4.00 (4H, ) , 4.24 (IH, br d, J=17Hz), 5.46 (IH, d, J=10Hz) , 5.62 (IH, d, J=10Hz), 6.65(1H, d, J=15Hz) , 6.69 (IH, br ε), 7.33 (IH, d, J=15Hz), 7.42 (IH, br d, J=8Hz), 7.48-7.61 (5H, m) , 7.76-7.84 (3H, m)

Example 68

The following compounds were obtained according to a similar manner to that of Example 1.

(l) 8- [2, 6-Dichloro-3- [N- [4- (dimethylcarbamoyl) -

cinnamoylglycyl]-N-methylamino] enzyloxy]-4- dimethylamino-2-methylquinoline

NMR (CDC1 ₃ , δ) : 2.69 (?H, br s), 2.92-3.15 (12H, m) ,

3.28 (3H, s), 3. ^" 70 (IH, br d, J=17Kz), 3.96 (IH, br 5 d, J=17Hz), 5.62 (2K, br si, 6.53 (IH, br d,

J=15Hz), 6.69 (IH, s), 7.18-7.60 (10H, m) , 7.71 (IH, br d, J=8Hz)

its dihydrochloriαe 0 NMR (CDCI3-CD3OD, δ) : 2. 8 (3H, br s), 2.95-3.15 (6H, m) , 3.28 (3K, s), 3.49 (6H, s), 3.85 (IH, a,

J=17Hz), 4.09 (IH, d, J=17Hz), 5.50 (IH, d,

J=10Hz), 5.61 (IH, a, J=10Hz) , 6.64 (IH, d,

J=15Hz), 6.71 (IH, br s), 7.32-7.61 (9H, m) , 5 7.79 (IH, br d, J=8Hz)

(2) 8- [2, 6-Dichloro-3-[N-methyi-N- [4-[N- (2-pyridylmethyi) - carbamoyl]cinnamoylglycyl]amino]benzyloxy]-4- aimethylamino-2-methylquinoline 3 NMR (CDCI3, δ) : 2.67 (3H, ε), 3.05 (6H, s) , 3.27 (3K, s), 3.66-3.77 (IH, m) , 3.91-4.05 (IH, m) , 4.76 (2H, d, J=6Hz), 5.61 (2H, s ) , 6.57 (IH, d, J=16Hz) , 6.67 (IH, s), 7.16-7.74 (13H, m) , 7.78-7.85 (2H, m) , 8.53-8.60 (IH, m) b its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.63 (3H, ε), 3.13 (3H, ε), 3.42 (6H, ε), 3.57 (IH, dd, J=4, 16Hz), 3.90 (IH, dd, 3=4 , 16Kz), 4.74 (2H, d, J=6Hz), 5.50-5.63 (2H, m) , 0 6.85-6.97 (2H, m) , 7.43 (IH, d, J=16Hz), 7.59 (IH, t, J=8Hz), 7.64-7.90 (7H, m) , 7.90-8.03 (3H, m) , 8.23 (IH, t, J=8Hz), 8.40 (IH, t, J=6Hz) , 8.71 (IH, d, J=6KZ), 9.43 (IK, t, J=8Hz), 12.75 (IH, s)

(3) 8- [2, 6-Dichloro-3-[N-[4-[N- (2-dimethylaminoethyl) -

carbamoyl] cinnamoylglycyl] -N-methylamino]benzyloxy] -4- dimethylamino-2-methylquinoline

NMR (CDC1 ₃ , δ) : 2.30 (6H, s), 2.56 (IH, br t, J=7Hz), 2.65 (3H, s), 3.00 (6H, ε), 3.26 (3K, s), 3.54 (IH, br q, J=7Hz), 3.69 (IH, dd, J=17, 4Hz), 3.95 (IH, dd, J=17, 5Hz), 5.59 (IH, d, J=10Hz), 5.64 (IK, d, J=10Hz), 6.53 (IH, a, J=15Hz), 6.69 (IH, s), 6.78 (IH, br s), 6.98 (IH, br ε), 7.20 (IH, br d, J=8Hz), 7.28-7.38 (2H, m) , 7.45-7.55 (3H, m) , 7.58 (IH, d, J=15Hz), 7.70 (IK, br d, J=8Hz), 7.80 (2H, br d, J=8Hz)

its trihydrochloride

NMR (CDC1 ₃ -CD ₃ 0D, δ) : 2.72 (3H, s), 2.95 (6H, ε), 3.00 (6H, s), 3.27 (3H, s) , 3.39-3.51 (8H, m) ,

3.82-3.92 (3H, m) , 4.15 (IH, d, J=17Hz) , 5.48 (IH, d, J=10Hz), 5.62 (IH, d, J=10Hz) , 6.62 (IH, d,

J=15Hz), 6.70 (IH, ε), 7.33 (IH, d, J=15Hz) , 7.40-

7.61 (6H, m) , 7.80 (IH, br d, J=8Hz), 7.96 (2H, br a, J=8Hz)

(4) 8- [2, 6-Dichloro-3- [N- [4- [N- (2-dimethylaminoethyl) -N- methylcarbamoyl] cinnamoylglycyl] -N-methylamino] - benzyloxy] -4-dimethylamino-2-methylquinoline NMR (CDCI3, δ) : 2.09 (3H, br ε), 2.24-2.46 (4H, m) ,

2.53-2.70 (4H, m) , 2.91-3.13 (9H, m) , 3.26 (3H, s), 3.34 (IH, m) , 3.60-3.73 (2H, m) , 3.96 (IH, dd, J=17, 5Hz), 5.60 (IH, d, J=10Hz) , 5.65 (IH, d, J=10Hz), 6.50 (IH, d, J=15Hz), 6.69 (IH, s), 6.73 (IH, br ε), 7.20 (IH, d, J=8Hz) , 7.28-7.60 (9H, m) ,

7.70 (IH, br d, J=8Hz)

its trihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.74 (3H, br s), 2.97 (6H, br s), 3.10 (3H, br ε), 3.28 (3H, br ε), 3.38-3.52

(8H, m) , 3.88 (IH, br d, J=17Hz), 3.95-4.02 (2H, m) , 4.15 (IH, d, J=17Hz), 5.49 (IH, d, J=10Hz), 5.62 (IH, d, J=10Kz), 6.67 (IH, d, J=15Hz), 6.72 (IH, br ε), 7.31-7.62 (9H, ) , 7.79 (IH, br d, J=8Hz)

(5) 8-[2, 6-Dichloro-3-[N-methyl-N-[4- (4-pyridylcarbamoyl) - cinnamoylglycyl]amino]benzyloxy]-4-dimethylamino-2- methylquinoline NMR (CDC1 ₃ , δ) : 2.45 (3H, s) , 3.01 (6H, s), 3.15 (3H, s), 3.61 (IH, dd, 3=4, 16Hz), 3.81 (IH, dd, J=4, 16Hz), 5.51 (2H, ε), 6.48 (IH, d, J=16Hz) , 6.63 (IH, s), 6.87 (IH, br peak), 7.13-7.40 (6H, m) , 7.46 (IH, d, J=16Hz), 7.64-7.76 (3H, m) , 7.90 (2H, d, J=8Hz), 8.43 (2H, d, J=6Hz) , 9.65 (IH, s)

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.65 (3K, s) , 3.15 (3H, s) , 3.42 (6H, ε), 3.60 (IH, dd, 3=4, 16Hz), 3.93 (IH, dd, J=4, 16Hz), 5.51-5.63 (2H, m) , 6.92 (IH, ε) , 6.97

(IH, d, J=16Hz), 7.49 (IH, d, J=16Hz), 7.55-7.63 (IH, m) , 7.72-7.85 (5H, m) , 7.95 (IK, d, J=8Hz), 8.13 (2H, d, J=8Hz), 8.35-8.50 (3H, m) , 8.77 (2H, d, J=6Hz), 11.76 (IH, ε)

(6) 8-[2, 6-Dichloro-3-[N-[3-methoxy-4- (methylcarbamoyl)- cinnamoylglycyl]-N-methylamino]benzyloxy] -4- dimethylamino-2-methylquinoline

NMR (CDCI3, δ) : 2.67 (3H, s) , 2.93-3.14 (9H, m) , 3.25 (3H, s), 3.66-3.78 (IH, m) , 3.89-4.02 (4H, m) ,

5.55-5.66 (2H, m) , 6.52-6.63 (IH, m) , 6.68 (IH, s) , 7.04 (IH, s), 7.11-7.42 (5H, m) , 7.46 (IH, d, J=8Hz), 7.52 (IH, d, J=16Hz) , 7.70 (IH, d, J=8Hz) , 7.74-7.83 (IH, m) , 8.09-8.20 (IH, br peak)

its dihydrochloride

NMR (DMSO-d ₆ , δ) : 2.61 (3H, s), 2.79 (3H, s) , 3.14

(3H, s), 3.40 (6K, s), 3.47-3.65 (IK, m) , 3.80-3.96 (4K, m) , 5.50-5.63 (2H, m) , 6.83-6.97 (2H, ) , 7.21 (IH, a, J=8Kz) , 7.31 (IH, s), 7.41 (IH, d, J=16Hz),

7.53-7.63 (IH, ) , 7.67-7.87 (4H, n) , 7.93 (IH, a, J=8Hz), 8.14 (IH, q-like), 8.31 (IH, t-like)

(7) 8- [2, 6-Dichloro-3- [N-methyl-N- [3- [4-[N- (2- pyridylmethyl) carbamoyl]phenyl]propionylglycyl] amino] - benzyloxy] -4-dime hyiamino-2-methylquinoline NMR (CDC1 ₃ , δ) : 2.52 (2H, br t, J=7.5Hz) , 2.65 (3H, s), 2.92-3.06 (8H, ) , 3.22 (3H, s) , 3.49 (IH, br d, J=17Hz), 3.80 (IH, dd, J=17, 4Hz), 4.74 (2H, a, J=5Hz), 5.60 (2H, ε) , 6.68 (IH, br ε), 7.17-7.36

(8H, m) , 7.43-7.55 (2H, ) , 7.63-7.80 (4H, m) , 8.56 (IH, br a, J=5Hz)

itε trihydrochloride NMR (CDCI3-CD3OD, δ) : 2.50-2.63 (4K, m) , 2.90 (IH,

IT.) , 3.25 (3H, s), 3.51 (6H, s), 3.69 (IH, d, J=17Hz), 3.78 (IH, d, J=17Hz), 4.99 (2K, ε), 5.48 (IH, d, J=10Hz), 5.63 (IK, d, J=10Hz), 6.80 (IH, br s), 7.18 (2H, d, J=8Hz), 7.40-7.61 (4H, m) , 7.79- 7.90 (4H, ) , 8.11 (IH, br d, J=8Hz) , 8.39 (IH, br t, J=8Hz), 8.73 (IK, br d, J=5Hz)

(8) 8- [2, 6-Dichloro-3- [N-methyl-N- [4- (methanesulfonamido) - cinnamoylglycyl] amino]benzyloxy] - -dimethylamino-2- methylquinoline

NMR (CDCI3, δ) : 2.64 (3H, s) , 3.01 (6H, s), 3.26 (3H, s), 3.68 (IH, dd, 3=4 , 18Hz) , 3.95 (IK, dd, 3=4 , 18Hz), 5.53-5.64 (2K, m) , 6.41 (IH, a, J=16Hz), 6.67 (IK, ε), 6.81 (IH, br peak), 7.11-7.38 (6H, m) , 7.38-7.53 (4K, m) , 7.70 (IH, d, J=8Hz)

its dihydrochloride

NMR (DMSO-d ₆ , δ) : 2.63 (3K, s), 3.03 (3K, s), 3.13 (3H, s), 3.41 (6H, __), 3.55 (IH, dd, 3=4 , 18Hz) , 3.90 (IH, dd, J=4, 18Hz), 5.53 (IK, d. J=10Hz) , 5.59 (IH, d, J=10Hz), 6.68 (IH, d, J=16Hz), 6.92 (IH, s), 7.23 (2H, d, J=8Hz), 7.32 (IH, d, J=16Hz), 7.52 (2H, d, J=8Hz), 7.53 (IH, t, J=8Hz) , 7.72-7.83 (3H, m) , 7.94 (IH, d, J=8Hz), 8.29 (IH, t-like), 10.03 (IH, s) ι π

(9) 8- [2, 6-Dichloro-3- [N-methyl-N- [ 4- (isonicotmamido) - cinnamoylglycyl] amino]benzyloxy] -2-methyl-4- dimethylaminoquinoline NMR (CDCI3-CD3CD, δ) : 2.58 (3K, s), 3.04 (6H, br) ,

3.25 (3K, s), 3.39 (IH, ir.) , 3.69 (2K, m) , 4.00 (IH, d, J=15Hz), 5.54 (2K, m) , 6.48 (IH, d, J=15Hz) , 6.69 (IH, s), 7.20 (IH, d, J=8Hz) , 7.36-7.52 (6H, m) , 7.70 (3H, m) , 7.83 (2H, d, J=8Hz), 8.70 (2H, d, J=8Hz) 0 itε trihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.70 (3H, s) , 3.29 (3H, s) , 3.52 (6K, s), 3.88-4.04 (4H, m) , 5.49 (IH, d, J=15Hz), 5.68 (IH, d, J=15Hz), 6.51 (IH, d, 5 J=15Hz), 6.70 (IH, s) , 7.36-7.64 (7H, m) , 7.84 (IH, d, J=8Hz), 7.92 (2H, d, J=8Hz) , 8.66 (2H, d, J=8Hz), 3.99 (2H, d, J=8Hz)

(10) 8- [2, 6-Dichloro-3- [N-methyl-N- [4- (2-oxopyrrolidin-I- 0 yl) cinnamoylglycyl] amine]benzyloxy] -4-dimethylamino-2- methylquinoline NMR (CDCI3, δ) : 2.10-2.23 (2H, m) , 2.61 (2H, t,

J=7.5Hz), 2.67 (3H, s), 3.03 (6H, s), 3.26 (3H, S ) , 3.63-3.75 (IH, ) , 3.36 (2H, t, J=7.5Hz), 3.90-4.02 5 (IH, m) , 5.60 (2H, ε), 6.45 (IH, d, J=16Hz), 6.67

(IH, s) , 7.16-7.28 (2H, m) , 7.28-7.41 (2H, m) , 7.41-7.56 (4H, m) , 7.62 (2K, d, J=8Hz), 7.70 (IH, d, J=8Hz)

its dihydrochloride

NMR (DMSO-d ₆ , δ) : 2.00-2.13 (2H, m) , 2.62 (3H, s), 3.13 (3H, ε), 3.41 (6K, ε), 3.46-3.61 (IH, m) , 3.80-3.97 (3H, ) , 5.53 (IH, a, J=10Hz}, 5.60 (IH, a, J=10Hz), 6.71 (IH, a, J=16Hz), 6.92 (IH, ε), 7.33 (IH, d, J=16Hz), 7.52-7.63 (2H, m) , .67-7.86

(5H, m) , 7.93 (IH, d, J=8Hz), 8.30 (IH, t, J=6Hz), 12.75 (IH, s)

(11) 8- [2, 6-Dichloro-3- [N- [4- [N- (2-methoxyacetyl) -N- (3- pyridylmethyl) amino] cinnamoylglycyl] -N-methylamino] - benzyloxy] -2-methyl-4-dimethylaminoquinoline NMR (CDC1 ₃ , δ) : 2.68 (3H, s), 3.07 (6H, s), 3.26 (3H, s), 3.36 (3H, ε), 3.63-4.00 (2K, m) , 3.78 (2K, ε), 4.88 (2H, ε), 5.59 (2H, ε), 6.50 (IK, d, J=15Hz), 6.67 (IH, ε), 6.93 (2H, a, J=8Hz), 7.20 (2H, m) ,

7.30 (2H, m) , 7.41-7.52 (4H, m) , 7.63 (IH, d, J=8Hz), 7.68 (IH, d, J=8Hz), 8.34 (IK, br) , 8.50 (IH, d, J=7Hz)

itε trihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.70 (3H, br) , 3.28 (3H, s) , 3.36 (3H, s), 3.53 (6H, br) , 3.83-4.10 (2H, m) , 3.88 (2H, br), 5.09 (2H, br) , 5.49 (IH, d, J=15Hz), 5.68 (IH, d, J=15Hz), 6.63-6.79 (2H, m) , 7.17 (2H, br), 7.40 (IH, m) , 7.48 (IH, d, J=8Hz) , 7.58 (4H, br), 7.83 (IH, d, J=8Hz), 8.04 (IH, br) , 8.57 (IH, br) , 8.75 (IH, br) , 8.80 (IH, br)

(12) 8- [3- [N- (4-Acetamido-3-methylcinnamoylglycyl) -N- methylamino] -2, 6-dichlorobenzyloxy] -2-methyl-4-

dimethyla inoquinoline

NMR (CDCI3, δ) : 2.20 (3H, s), 2.27 (3H, s), 2.65 (3H, s), 3.00 (6H, ε), 3.25 (3H, s), 3.65 (IH, dd, 3=1, 15Hz), 3.94 (IH, dd, J=7, 15Hz) , 5.61 (2H, ) , 6.40 (IH, a, J=15Hz), 6.68 (2H, s), 7.06 (IK, br) , 7.20

(IH, d, J=8Hz), 7.27-7.36 4H, ) , 7.44-7.52 (2H, m) , 7.69 (IH, d, J=8Hz) , 7.90 (IH, d, J=8Hz)

its dihydrochloride NMR (CDCI3-CD3OD, δ) : 2.22 (3H, s) , 2.28 (3H, s) ,

2.70 (3H, ε), 3.28 (3H, s), 3.49 (6H, s) , 3.91 (2H, m) , 5.48 (IH, d, J=8Hz) , 5.67 (IH, d, J=8Hz), 6.47 (IH, d, J=15Hz), 6.70 (IH, s) , 7.27-7.38 (3H, m) , 7.47-7.63 (6H, ) , 7.83 (IH, d, J=8Hz)

(13) 8- [3-[N-[ (E)-3- (l-Acetyl-1,2,3,4-tetrahydroquinoIin-6- yl)acryloylglycyl]-N-methylamino]-2, 6- dichlorobenzyloxy]-4-dimethylamino-2-methylquinoline NMR (CDCI3, δ) : 1.96 (2H, quint, J=7Hz) , 2.26 (3H, ε), 2.68 (3H, s), 2.72 (2H, t, J=7Hz), 3.02 (6H, s), 3.27 (3H, s), 3.67 (IH, dd, J=4, 18Hz) , 3.77 (2H, t, J=7Hz), 3.95 (IH, dd, J=5, 18Hz) , 5.55-5.67 (2H, ), 6.45 (IH, d, J=16Hz), 6.69 (IH, ε), 6.80 (IH, br peak), 7.22 (IH, d, J=8Hz) , 7.25-7.39 (5H, m) , 7.47 (IH, d, J=8Hz) , 7.52 (IH, d, J=16Hz), 7.70

(IH, d, J=8Hz)

its dihydrochloride

NMR (DMSO-d ₆ , δ) : 1.87 (2H, quint, J=7Hz), 2.20 (3H, s), 2.63 (3H, s) , 2.72 (2H, t, 3=1 Hz ) , 3.15 (3H, s), 3.42 (6H, s) , 3.51-3.81 (3H, m) , 3.91 (IH, dd, J=5, 16Hz), 5.52-5.63 (2H, m) , 6.72 (IK, d, J=16Hz), 6.93 (IH, ε), 7.26-7.41 (3H, m) , 7.50-7.65 (2H, m) , 7.75 (IH, d, J=8Hz), 7.81 (2H, ε-like), 7.94 (IH, d, J=8Hz) , 8.27 (IH, t-like)

(14) 8- [2, 6-Dichloro-3- [N- [ (E) -3- (6-ethoxycarbonylpyridin-3- yl) acryloylglycyl] -N-methylaminojbenzyloxy] -4- dimethylamino-2-methylquinoline

NMR (CDC1 ₃ , δ) : 1.45 (IH, t, J=7.5Hz), 2.62 (3H, ε), 3.00 (6H, br ε) , 3.28 (3H, s) , 3.72 (IH, br dd,

J=17, 4Hz), 3.95 (IH, br dd, J=17, 5Hz) , 4.49 (2H, a, J=7.5Hz), 5.60 (IK, d, J=10Hz), 5.65 (IH, d, J=10Kz), 6.63-6.72 (2H, m) , 6.88 (IK, br s), 7.20 (IH, br d, J=8Hz), 7.29-7.38 (2H, ) , 7.48 (IH, d, J=8Hz), 7.60 (IH, d, J=15Hz), 7.70 (IK, d, J=8Hz) ,

7.90 (IH, dd, J=8, 2Hz) , 8.10 (IK, br d, J=8Hz) , 8.83 (IH, br s)

(15) 8- [3- [N- [ (E) -3- (6-Aminopyridin-3-yl) acryloylglycyl] -N- methylamino] -2, 6-dichIorobenzyloxy] -4-dimethylamino-2- methylquinoline

NMR (CDCI3, δ) : 2.63 (3H, s) , 2.98 (6H, s), 3.24 (3H, s), 3.64 (IH, dd, J=4, 17Hz) , 3.93 (IH, dd, J=4, 17Hz), 4.67 (2H, s), 5.55-5.67 (2H, m) , 6.29 (IH, d, J=16Hz), 6.46 (IH, d, J=8Hz) , 6.55 (IH, t-like), 6.69 (IH, s), 7.18 (IH, d, J=8Hz), 7.22- 7.36 (2H, m) , 7.40-7.50 (2H, m) , 7.58 (IH, d, J=8Hz), 7.69 (IH, d, J=8Hz) , 8.16 (IH, s)

(16) 8- [2, 6-Dichloro-3- [N-methyl-N- [ (E)-3-[6-[ (E) -2- (pyridin- 4-yl) vinyl]pyridin-3-yl] acryloylglycyl] amino]benzyloxy] - -dimethyiamino-2-methylquinoline

NMR (CDCI3, δ) : 2.67 (3H, s), 3.03 (6H, s), 3.27 (3H, s), 3.66-3.80 (IH, m) , 3.91-4.05 (IH, m) , 5.56-5.68 (2H, in) , 6.61 (IH, d, J=16Hz), 6.70 (IH, s), 7.15-

7.66 (11H, m) , 7.66-7.77 (IK, m) , 7.77-7.85 (IH, m) , 8.61 (2H, d, J=6Hz), 8.69-8.75 (IH, m)

its tetrahydrochloride NMR (DMSO-d ₆ , δ) : 2.63 (3K, s), 3.15 (3H, s), 3.43

(6H, s), 3.91 (IH, dd, 3=4, 18Hz) , 5.51-5.64 (2H, m) , 6.93 (IH, s), 7.00 (IH, d, J=16Hz), 7.47 (IH, d, J=16Hz), 7.59 (IK, t, J=8Hz), 7.73-8.15 (8K, m) , 8.29 (2K, a, J=6Hz), 8.44 (IH, t-like), 8.85-8.93 (3H, m)

(17) 3- [2, 6-Dichloro-3- [N- [4- (dimethvlcarbamoyi) - cinnamoylglycyl] -N-methyl mi o]benzyloxy] -2-methyi-4- piperidinoquinoline NMR (CDC1 ₃ , δ) : 1.60-1.75 (2H, overlapped with H _? 0) ,

1.79-1.90 (4H, m) , 2.68 (3H, br s), 2.98 (3H, br ε), 3.06-3.29 (10H, ) , 3.70 (IK, br d, J=17Hz) , 3.97 (IH, br d, J=17Kz) , 5.60 (2H, br s), 6.52 (IH, br d, J=15Hz), 6.71 (IH, s) , 7.20 (IH, br d, J=8Hz), 7.27-7.60 (9H, ) , 7.62 (IH, br d, J=8Hz)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 1.82-1.94 (6H, m) , 2.84 (3H, br ε), 3.00 (3H, br s) , 3.10 (3H, br s), 3.39 (3H, s), 3.67-3.76 (4H, ) , 3.89 (IH, br a, J=17Hz) , 4.12

(IH, br d, J=17Kz), 5.51 (IH, d, J=10Hz), 5.61 (IH, d, J=10Hz), 6.68 (IH, d, J=15Hz) , 6.84 (IH, br s),

7.32-7.61 (10H, )

(18) 8- [2, 6-Dichloro-3- [N-methyl-N- [4- [N- (2-pyridylmethyl) - carbamoyl] cinnamoylglycyl] amino]benzyloxy] -2-methyl-4- piperidinoquinoline

NMR (CDCI3, δ) : 1.24 (2H, t, J=7Hz), 1.80 (4H, br) , 2.66 (3H, s), 3.17 (4H, br) , 3.25 (3K, s) , 3.70 (IK, m) , 3.96 (IH, dd, 3=1, 15Hz) , 4.75 (2H, d,

J=7Hz), 5.58 (2H, m) , 6.55 (IK, a, J=15Hz) , 6.72 (IH, s), 7.20 (2K, m), 7.29-7.38 (3H, m) , 7.44-7.77 (7H, ) , 7.80-7.91 (2H, m) , 8.55 (IK, d, J=7Hz)

its trihydrochloride

NMR (CD3OD, δ) : 1.67 (6H, br) , 2.49 (3H, s) , 3.07 (3K, s), 3.53 (4K, br) , 3.60-3.33 (2H, ) , 4.65 (2H, br (overlap) ), 5.4? (IH, d, J=8Hz), 5.50 (IH, d, J=8Hz) , 6.58 (IH, d, J=15Hz) , 6.83 (IH, s) , 7.31 (IH, d, J=15Hz) , 7.40-7.5S (6H, m) , 7.19-7.83 (4H, ) , 8.30 (2H, IT.) , 8.52 (2H, br;

(19) 8- [2, 6-Dichiorc-3- [N- [3-methoxy-4- (methylcarbamoyl) - cinnamoylglycyl] -N-methylamino]benzyloxy] -2-methyl-4- piperidinoquinoline

NMR (CDCI3, δ) : 1.57-1.74 (2K, overlapped with H ₂ 0) , 1.79-1.90 (4H, m) , 2.65 (3K, br s), 3.00 (3H, d, J=5Hz), 3.19-3.22 (4H, m) , 3.26 (3H, s), 3.70 (IH, br d, J=17Hz., 3.90-4.01 (5K, ) , 5.53 (IH, d, J=10Hz), 5.64 (IH, d, J=10Hz), 6.57 (IH, br a,

J=15Hz), 6.70-6.80 (2H, m) , 7.04 (IH, br s) , 7.16- 7.39 (4H, m) , 7.48 (IK, d, J=8Hz), 7.52 (IH, br d, J=15Hz), 7.64 (IH, br d, J=8Hz), 7.79 (IH, br d, J=5Hz) , 8.19 (IH, br s)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 1.81-1.95 (6H, n) , 2.82 (3K, br s), 3.00 (3H, s), 3.28 (3H, s), 3.69-3.78 (4H, m) , 3.88 (IH, br d, J=17Hz) , 4.04 (3H, s) , 4.20 (IH, br d, J=17Hz), 5.50 (IH, br a, J=10Hz), 5.61 (IH, br d, J=10Kz), 6.73-6.86 (2H, m) , 7.04 (IK, d, J=8Hz), 7.21 (IH, br s), 7.33-7.61 (6H, m) , 8.01 (IH, br d, J=8Hz)

(20) 8- [2, 6-Dichloro-3- [N-methyl-N- [4- (isonicotinamidc) - cinnamoylglycyl] amino]benzyloxy] -2-methyl-4- piperidinoquinoline

NMR (CDCI3, δ) : 1.58-1.90 [6 ^' ή, m) , 2.51 (3H, br s) , 3.14-3.27 (7H, m) , 3.62 (IH, br d, J=17Hz) , 3.89 (IH, br dd, J=17, 5Hz) , 5.52 (2H, s), 6.41 (IH, d.

J=15Hz), 6.70 (IH, s), 7.18-7.31 (4H, m) , 7.37-7.44 (3H, ) , 7.49 (IH, br d, J=15Kz), 7.64 (IH, br a, J=18Hz), 7.72 (2H, a, J=8Kz) , 7.73 (2H, a, J=5Hz) , 8.63 (2K, d, J=5Hz), 9.35 (IH, br s)

its trihydrochloride

NMR (CDCI3-CD3OD, δ) : 1.81-1.96 (6H, ) , 2.76 (3H, br s), 3.28 (3H, s), 3.70-3.80 (4K, ) , 3.88 (IH, br d, J=17Hz), 4.11 (IH, br d, J=17Hz), 5.48 (IH, d, J=10Hz), 5.66 (IH, d, J=10Hz), 6.50 (IH, br a,

J=15Hz), 6.86 (IH, br s), 7.24-7.63 (8K, i ) , 7.92 (2K, br d, J=8Hz), 8.70 (2H, a, J=5Hz) _. , 8.95 (2H, d, J=5Hz)

(21) 3- [2 , 6-Dichloro-3- [N-methyl-N- [4- (2-oxopyrrolidm-l- yl) cinnamoylglycyl] amino]benzyloxy] -2-methyl-4- piperidinoquinoline

NMR (CDCI3, δ) : 1.25 (2H, t, J=7Hz) , 1.84 (4H, br) , 2.15 (2H, m) , 2.60 (2H, t, J=7Hz) , 2.65 (3H, s), 3.16 (4H, br), 3.27 (3H, s) , 3.65 (IH, dd, J=7,

15Hz), 3.87 (2K, t, J=7Hz) , 3.93 (IH, ad, 3=1 , 15Hz), 5.60 (2H, m) , 6.44 (IH, d, J=15Hz) , 6.72 (IH, s), 6.80(1K, br) , 7.18 (IH, a, J=8Hz) , 7.30- 7.37 (2H, m) , 7.46-7.66 (7H, )

itε dihydrochloride

NMR (CD3OD, δ) : 1.84 (6K, br) , 2.19 (2H, m) , 2.58-

2.66 (2H, m) , 2.69 (3H, ε), 3.27 (3H, ε) , 3.73 (4H, br), 3.85-4.03 (2H, m) , 5.60 (IH, d, J=8Hz) , 5.72 (IH, d, J=8Hz), 6.60 (IH, d, J=15Hz), 7.06 (IH, s) ,

7.46 (IH, a, J=15Hz), 7.54 (2K, m) , 7.62-7.75 (7H, m)

(22) 8-[3-[N-[ (E)-3- (1-Acetyl-l, 2, 3, 4-tetrahydroquinolin-6- yl) acryloylglycyl] -N-methylamino] -2, 6-

dichlorobenzyloxy] -2-methyi-4-piperidinoσuinoline and its dihydrochloride

(23) 3- [2, 6-Dichloro-3- [N- [ (E) -3- ( 6-ethoxycarbor.ylpyricir.-3- yl) acryloylglycyl] -N-methylamino]benzyloxy] -2-methyl-4- piperidincquincline

NMR (CDC1 ₃ , δ) : 1.43 (IH, t, J=7.5Hz), 1.59-1.74 (2H, overlapped with H ₂ 0) , 1.78-1.90 (4H, m) , 2.65 (3H, br s), 3.09-3.22 (4H, m) , 3.27 (3K, s), 3.74 (IH, br a, 3.97 (IK, br d, J=17Hz) , 4.48 (2H, q, J=7.5Hz), 5.60 (IK, s), 6.64-6.75 (2H, ) , c.89 (IH, br s), 7.16-7.40 (3K, ) , 7.47 (IH, br d, J=8Hz), 7.52-7.67 (2H, m) , 7.90 (IH, br d, J=8Hz), 8.08 (IH, br d, J=8Kz), 8.70 (IH, br ε)

(24) 8-[3-[N-[ (E)-3-[6- (Acetamido)pyridin-3-yl] - acryloylglycyl] -N-methylamino] -2, 6-dichlorobenzyIoxy] -2- methyl-4-piperidinoquinoline NMR (CDCI3, δ) : 1.10-1.26 (2H, m) , 1.82 (4H, br) ,

2.19 (3H, ε), 2.63 (3H, s), 3.15 (4H, br) , 3.24 (3H, ε), 3.68 (IH, dd, J=7, 15Hz) , 3.94 (IH, dd, 3=1 , 15Hz), 5.60 (2H, ) , 6.47 (IH, d, J=15Hz) , 6.72 (IH, s), 6.83 (IH, br) , 7.18 (IH, d, J=8Hz) , 7.27-7.39 (2H, m) , 7.46 (IH, d, J=8Hz) , 7.52 (IH, a, J=15Hz), 7.63 (IK, d, J=8Hz), 7.80 (IH, dd, J=4, 8Hz), 8.17 (IH, a, J=8Hz), 3.26 (IH, br) , 8.32 (IH, s)

(25) 8- [3- [N- [ (E) -3- (6-Aminopyridin-3-yl) acryloylglycyl] -N- methylamino] -2, 6-dichlorobenzyloxy] -2-methyI-4- piperidinoquinoline

NMR (CDCI3, δ) : 1.55-1.72 (2H, m) , 1.77-1.88 (4H, m) , 2.64 (3K, ε), 3.07-3.18 (4H, m) , 3.24 (3H, s), 3.64 (IH, da, J=4, 18Hz) , 3.93 (IH, dd, 3=4 , 18Hz) ,

4.66 (2K, s), 5.57 (IH, d, J=10Hz) , 5.63 (IH, d, J=10Hz), 6.29 (IH, d, J=15Hz) , 6.47 (IH, d, J=8Hz) , 6.59 (IH, t-like), 6.73 (IK, s; , 7.13 (IH, d, J=8Hz), 7.23-7.37 (2H, m) , 7.40-7.50 (2H, m) , 7.59 (IH, dd, 3=2, 8Hz), 7.64 (IH, a, J=8Hz) , 8.16 (IH, d, J=2Hz)

(26) 8- [2, 6-Dichloro-3-[N-[4- (dimethylcarbamoyl)- cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methyl-4- morpholinoσuinoline

NMR (CDC1 ₃ , δ) : 2.69 (3H, s) , 2.99 (3H, br s), 3.11 (3H, br s), 3.17-3.24 (4H, m) , 3.28 (3H, s), 3.67 (IH, br dd, J=17, 4Hz), 3.90-4.01 (5H, m) , 5.60 (IH, d, J=10Hz), 5.65 (IH, d, J=10Hz), 6.50 (IH, d, J=15Hz), 6.69 (IH, br s), 6.78 (IH, ε), 7.19-7.53

(8H, m) , 7.58 (IK, d, J=15Hz), 7.68 (IK, br d, J=8Hz)

itε dihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.91 (3H, 8), 2.97-3.14 (6H, m) , 3.29 (3K, ε), 3.72-3.81 (4H, m) , 3.88 (IH, br d, J=17Hz), 3.96-4.05 (5H, ) , 5.53 (IH, d, J=10Hz), 5.64 (IH, d, J=10Hz) , 6.65 (IH, d, J=15Hz), 7.06 (IH, br s) , 7.37 (2H, d, J=8Hz) , 7.42-7.68 (8H, m)

(27) 8- [2, 6-Dichloro-3-[N-methyl-N- [4-[N- (2-pyridylmethyl) - carbamoyl]cinnamoylglycyl]amino]benzyloxy]-2-methyl-4- morpholinoquinoline NMR (CDCI3, δ) : 2.68 (3H, s), 3.22 (4H, m) , 3.28 (3H, s), 3.64-3.77 (2H, m) , 3.95 (4H, m) , 4.74 (2H, d, J=7Hz), 5.60 (2H, m) , 6.54 (IH, a, J=15Hz) , 6.78 (IH, s), 7.00 (IH, br), 7.20-7.25 (2H, m) , 7.29- 7.42 (3H, m) , 7.45-7.73 (7H, m) , 7.76-7.90 (2H, m)

its trihydrochloride

NMR (CD3OD, δ) : 2.74 (3H, s) , 3.26 (3H, s), 3.78-3.87 (6H, m) , 3.95 (4H, m) , 4.90 (2H, ε), 5.65 (IH, d, J=8Hz), 5.73 (IH, d, J=8Kz) , 6.79 (IK, d, J=15Hz) , 7.13 (IK, s), 7.54 (IH, d, J=15Hz), 7.66-7.79 (8H, m) , 7.93-8.05 (4H, ) , 8.09 (IH, d, J=8Hz), 8.60 (IH, t, J=8Hz), 8.78 (IH, d, J=8Hz)

(28) 3- [2, 6-Dichloro-3- [N- [3-methoxy-4- (methylcarbamoyl) - cinnamoylglycyl] -N-methylamino]benzyloxy] -2-methyl-4- mcrpholinoquinoline

NMR (CDCI3, δ) : 2.67 (3H, br s), 3.00 (3H d, J=5Hz) , 3.16-3.22 (4H, m) , 3.27 (3H, s), 3.69(1H, br dd, J=17, 4Hz), 3.89-4.01 (7H, ) , 5.59 (IH, d, J=10Hz), 5.64 (IH, d, J=10Hz), 6.55 (IH, d,

J=15Hz), 6.72 (IH, br s), 6.78 (IH, s) , 7.21 (IH, br a, J=8Hz), 7.30 (IH, d, J=8Hz) , 7.37 (IH, t, J=8Hz), 7.48 (IH, d, J=8Hz), 7.53 (IH, d, J=15Hz) , 7.66 (IH, br d, J=8Hz) , 7.79 (IH, br d, J=5Hz) , 8.20 (IH, d, J=8Hz)

itε dihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.90 (3H, br s) , 2.99 (3H, s) , 3.28 (3H, ε), 3.73-3.81 (4H, m) , 3.87 (IH, d, J=17Hz), 3.97-4.07 (7H, m) , 4.15 (IH, d, J=17Hz) ,

5.52 (IH, d, J=10Hz), 5.62 (IH, d, J=10Hz), 6.76 (IH, d, J=15Hz), 7.00-7.09 (2H, ) , 7.18 (IH, ε) , 7.37-7.68 (6H, m) , 7.98 (2H, d, J=8Hz)

(29) 8- [2, 6-Dichioro-3- [N-methyl-N- [4- (isonicotinamido) - cinnamoylglycyl] amino]benzyloxy] -2-methyl-4- morpholinoquinoline NMR (CDCI3, δ) : 2.52 (3H, br s) , 3.13-3.25 (7H, m) ,

3.60 (IH, dd, J=17, 4Hz) , 3.85 (IH, dd, J=17, 5Hz), 3.93-4.02 (4H, m) , 5.56 (2H, s), 6.40 (IH, d,

J=15Hz), 6.63 (IH, br s), 6.72 (IK, s), 7.17-7.34 (3H, m) , 7.38-7.47 ( 3H, ) , 7.50 (IH, d, J=15Hz) , 7.63-7.77 (5K, ) , 8.66 (2H, br d, J=8Hz), 9.11 (IH, br s)

its trihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.33 (3H, br s), 3.28 (3H, ε), 3.70-3.87 (5H, ) , 3.92-4.03 (4H, m) , 4.16 (IH, br d, J=17Hz), 5.48 (IH, br d, J=10Hz), 5.67 (IK, br a, J=10Hz), 6.54 (IH, br ≤), 7.07 (IH, br s) , 7.24-

7.68 (8H, ) , 7.89-7.99 (2H, m) , 8.71-8.93 (4H, )

(30) 8-[2, 6-Dichloro-3-[N-methyi-N-[4- (2-oxopyrrolidin-l- yl) cinnamoylglycyl]amino]benzyloxy]-2-methyl-4- morpholinoσuinoline

NMR (CDCI3, δ) : 2.18 (2H, ) , 2.62 (2H, t, J=7Hz) , 2.67 (3H, ε), 3.22 (4H, br) , 3.26 (3H, ε), 3.60- 3.73 (2H, m) , 3.87 (2H, ) , 3.96 (4H, m) , 5.60 (2H, m) , 6.40 (IH, d, J=15Hz) , 6.76 (2H, br) , 7.19 (IH, d, J=8Hz), 7.29-7.38 (2H, m) , 7.46-7.50 (4H, m) ,

7.59-7.68 (3H, )

itε dihydrochloride

NMR (CD3OD, δ) : 2.19 (2K, m) , 2.61 (2H, t, J=7Hz) , 2.74 (3H, s), 3.28 (3H, s) , 3.79 (4K, ) , 3.88-3.98

(8H, m) , 5.63 (IH, a, J=8Hz) , 5.72 (IH, d, J=8Hz) , 6.60 (IH, d, J=15Hz), 7.12 (IH, s), 7.44 (IH, d, J=15Hz), 7.54 (2H, d, J=8Hz), 7.60-7.78 (7H, m)

(31) 8- [3-[N-[ (E)-3- (1-Acetyl-l,2, 3, 4-tetrahydroquinolin-6- yl)acryloylglycyl]-N-methylamino]-2,6- aichlorobenzyloxy]-2-methyi-4-mcrphclinoquinoline and its dihydrochloride

(32) 8- [2, 6-Dichloro-3- [N- [ (E) -3- (6-ethoxycarbonylpyridin-3- yl) acryloylglycyl] -N-methylamino]benzyloxy] -2-methyl-4- morpholinoquinoline

NMR (CDC1 ₃ , δ) : 1.45 (IH, t, J=7.5Hz), 2.66 (3H, s), 3.17η3.25 (4H, m) , 3.29 (3H, s) , 3.73 (IH, br dd,

J=17, 4Hz), 3.90-4.02 (5H, m) , 4.50 (2H, q, J=7.5Hz), 5.60 (IH, d, J=10Hz), 5.66 (IH, d, J=10Hz), 6.67 (IH, d, J=15Hz) , 6.78 (IK, s), 6.83 (IH, br s), 7.20-7.28 (IH, overlapped with CDCI3), 7.31 (IH, d, J=8Hz), 7.39 (IH, t, J=8Hz), 7.60 (IH, d, J=15Hz), 7.68 (IH, br d, J=8Hz), 7.91 (IH, br d, J=8Hz), 8.11 (IH, br d, J=8Hz), 8.73 (IH, br s)

(33) 8-[3-[N-[ (E)-3-[6- (Acetamido) pyridin-3-yl] - acryloylglycyl] -N-methylamino] -2, 6-dichlorobenzyloxy] -2- methyl-4-morpholinoquinoline

NMR (CDCI3, δ) : 2.21 (3H, s), 2.67 (3H, s) , 3.15- 3.23 (4H, m) , 3.36 (3H, s), 3.70 (IH, dd, J=17, 4Hz), 3.88-4.01 (5H, m) , 5.58 (IH, d, J=10Hz), 5.63 (IH, d, J=10Hz), 6.47 (IH, d, J=15Hz), 6.39-6.79

(2H, m) , 7.19-7.28 (IH, overlapped with CDCI3), 7.30 (IH, d, J=8Hz), 7.37 (IH, t, J=8Hz) , 7.47 (IH, d, J=8Hz), 7.51 (IH, d, J=15Hz), 7.65 (IH, d, J=8Hz), 7.80 (IH, br d, J=8Hz), 8.09 (IH, br s), 8.19 (IH, br d, J=8Hz) , 8.33 (IH, br s)

(34) 8- [3- [N- [ (E) -3- (6-Aminopyridin-3-yl) acryloylglycyl] -N- methylamino] -2, 6-dichlorobenzyloxy] -2-methyl-4- morpholinoquinoline NMR (CDCI3, δ) : 2.67 (3H, s), 3.19 (4H, m) , 3.28 (3H, s), 3.73 (2H, m) , 3.98 -(4H, m) , 4.71 (2H, br) , 5.61 (2H, m) , 6.29 (IH, d, J=15Hz), 6.47 (IH, d, J=8Hz), 6.60 (IH, m) , 6.77 (IH, s), 7.21 (IH, m) , 7.28-7.39 (2H, m) , 7.43-7.49 (2K, m) , 7.60 (IH, d, J=8Hz), 7.66 (IH, d, J=8Hz), 8.18 (IH, s)

(35) 8- [2, 6-Dichloro-3- [N-methyl-N- [4- [ (E) -2- (pyridin-4- yl) vinyl] cinnamoylglycyl] amino]benzyloxy] -2- methylquinoline

NMR (CDC1 ₃ , δ) : 2.73 (3H, s), 3.23 (3H, s), 3.67 (IH, dd, J=17, 4Hz), 3.96 (IH, d, J=14, 5Kz), 5.64 (2H, ε), 6.50 (IH, d, J=15Hz), 6.67 (IH, br s), 7.04 (IH, d, J=16Hz), 7.23-7.61 (14K, m) , 3.02 (IH, a, J=8Hz), 8.59 (2H, d, J=7Hz)

its dihydrochloride

NMR (CDCI3-CD3OD, δ) : 3.23 (3K, br s), 3.31 (3H, s), 3.91 (IH, d, J=17Hz), 4.09 (IH, d, J=17Kz) , 5.62 (IH, d, J=I0Hz), 5.70 (IH, a, J=10Hz), 6.68 (IK, br d, J=I5Kz), 7.14 (IH, br d, J=15Hz), 7.43 (IK, br d, J=15Hz), 7.50-7.64 (8H, ) , 7.77 (IH, a, J=8Hz) ,

7.82-7.98 (4H, m) , 8.64-8.73 (2H, m) , 8.82 (IH, br d, J=8Hz)

(36) 8- [2, 6-Dichloro-3- [N- [3-methoxy-4- (methylcarbamoyl) - cinnamoylglycyl] -N-methylamino]benzyloxy] -2- methylquinoiine NMR (CDCI3, δ) : 2.72 (3H, s) , 3.01 (3H, d, J=5Hz) ,

3.28 (3K, s), 3.63 (IH, dd, J=4, 18Hz) , 3.89-4.02 (4H, ) , 5.60-5.70 (2H, ) , 6.55 (IH, d, J=16Hz) , 6.70 (IH, t-like), 7.04 (IH, s-like), 7.18-7.36

(5H, ) , 7.38-7.60 (3H, m) , 7.78 (IH, q-like), 8.03 (IH, a, J=8Hz) , 8.21 (IH, d, J=8Hz)

its hydrochloride NMR (DMSO-d ₆ , δ) : 2.79 (3H, d, J=5Kz) , 2.92 (3H, s),

3.16 (3H, s), 3.60 (IK, dd, J=4, 16Hz), 3.83-3.96

(4H, m) , 5.58-5.71 (2H, ) , 6.93 (IH, d, J=16Hz), 7.23 (IH, d, J=8Hz), 7.30-7.46 (2H, m) , 7.73-8.01

(7H, m) , 8.16 (IH, q-like), 8.32 (IH, t-like), 8.94-9.06 (IK, br peak)

(37) 8- [2, 6-Dichloro-3- [N-methyl-N- [4- (2-oxo-l,2- dihydropyridin-1-yl) cinnamoylglycyl] amino]benzyloxy] -2- methylquinoline mp : 160.5-172°C NMR (CDC1 ₃ , δ) : 2.73 (3H, s), 3.26 (3H, s) , 3.64 (IH, dd, J=17.5, 4.0Hz), 3.94 (IH, dd, J=17.5, 5.5Hz), 5.63 (IH, d, J=11.5Hz), 5.68 (IH, d, J=11.5Hz), 6.23 (IH, t, J=7.5Hz), 6.50 (IH, d, J=16.0Hz), 6.66 (IH, d, J=7.5Hz), 6.67 (IH, m) , 7.22-7.34 (4H, ) , 7.36-7.52 (6H, m) , 7.60 (IH, d, J=16.0Hz), 7.61

(2H, d, J=8.5Hz), 8.01 (IH, a, J=7.5Hz)

(38) 8- [2, e-Dimethyl-3- [N-methyi-N- [ (E)-3-[6-[ (E)-2- (pyridin- 4-yl) vinyl]pyridin-3-yl] acryloylglycyl] amino]benzyloxy] - 2-methyIquinoline

NMR (CDCI3, δ) : 2.36 (3H, s), 2.53 (3H, ε), 2.73 (3H, s), 3.27 (3H, s), 3.6c (IH, dd, 3=4 , 18Hz) , 3.90 (IH, dd, 3=4 , 18Hz), 5.37 (2H, s) , 6.56 (IH, d, J=16Hz), 6.75 (IH, t-like), 7.09 (IH, d, J=8Hz) , 7.19 (IH, d, J=8Hz), 7.22-7.33 (2H, m) , 7.33-7.48

(6H, ) , 7.53-7.67 (2K, ) , 7.81 (IH, d, J=8Hz) , 8.04 (IH, d, J=8Hz), 8.62 (2H, d, J=5Hz), 8.74 (IH, s-like)

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.30 (3H, s), 2.47 (3H, s) , 2.84 (3H, s), 3.12 (3H, s), 3.55 (IH, dd, 3=4 , 16Hz), 3.74 (IH, dd, 3=4 , 16Hz), 5.44 (2K, s), 7.01 (IH, d, J=16Hz), 7.30 (IH, d, J=8Hz) , 7.38 (IH, d, J=8Hz), 7.47 (IH, d, J=16Hz), 7.70-7.95 (6H, m) ,

8.02 (IH, d, J=8Hz), 8.11 (IH, dd, 3=2 , 8Hz), 8.23- δ.29 (2H, m) , 8.35 (IH, t-like), 8.76-8.91 (4H, m)

(39) 8- [3- [N- [ (E) -3- (6-Aminopyridin-3-yl) acryloylglycyl] -N- methylamino] -2, 6-dimethyIbenzyloxy] -2-methylquinoline

NMR (CDCI3, δ) : 2.36 (3H, ε) , 2.53 (3H, s) , 2.73 (3H, ε), 3.26 (3H, s), 3.62 (IK, dd, 3=4, 18Hz) , 3.87 (IH, dd, 3=4, 18Hz) , 4.66 (2K, br s) , 5.35 (2H, ε) , 6.30 (IH, d, J=16Hz), 6.49 (IH, d, J=8Hz) , 6.60 (IH, t-like) , 7.06 (IH, d, J=8Hz) , 7.17 (IH, d,

J=8Hz), 7.22-7.33 (2H, m) , 7.40-7.50 (3H, m) , 7.60 (IH, dd, 3=2, 8Kz), 8.03 (IH, d, J=8Hz) , 8.17 (IH, d, J=2Hz)

(40) 8- [2, 6-Dimethyl-3- [N- [ (E) -3- (6-ethoxycarbonylpyridin-3- yi) acryloylglycyl]-N-methylamino]benzyloxy]-2- methylquinoline NMR (CDCI3, δ) : 1.45 (3H, t, J=7.5Hz), 2.38 (3H, s) ,

2.53 (3K, ε), 2.72 (3H, s), 3.26 (3K, s) , 3.64 (IH, dd, 3=4, 18Hz), 3.90 (IH, dd, 3=4, 18Hz) , 4.49 (2H, q, J=7.5Hz), 5.36 (2H, s) , 6.64 (IK, d, J=16Hz) , 6.78 (IH, t-like), 7.08 (IH, d, J=8Hz) , 7.18 -(IH, d, J=8Hz), 7.23-7.33 (2H, m) , 7.39-7.49 (2H, m) , 7.61 (IH, a, J=16Hz), 7.92 (IH, da, 3=2, 8Hz) , 8.03 (IH, d, J=8Hz), 8.13 (IH, d, J=8Hz) , 8.84 (IK, d,

J=2Hz)

(41) 8- [2, 6-Dichloro-3- [N-methyl-N- [4- (4-pyridylcarbamoyl) - cinnamoylglycyl] amino] benzyloxy] -2-methyl-4- piperidinoquinoline

NMR (CDCI3, δ) : 1.65-1.76 (2H, m) , 1.79-1.90 (4K, m) ,

2.54 (3H, br ε), 3.18 (3H, s) , 3.20-3.30 (4H, m) , 3.64 (IH, br dd, J=17, 4Hz) , 3.91 (IH, br d, J=17Hz), 5.52 (2H, s), 6.51 (IH, d, J=15Hz), 6.71 (IH, ε), 7.21-7.45 (7H, m) , 7.64 (IH, br a, J=8Hz) ,

7.75 (2H, br d, J=7Hz), 7.90 (2H, d, J=8Hz) , 8.45 (2H, a, J=7Hz) , 9.59 (IH, br s)

itε trihydrochloride NMR (CDCI3-CD3OD, δ) : 1.78-2.04 (6H, ) , 2.78 (3H, br

ε), 3.29 (3H, s) , 3.62-4.00 (5H, m) , 4.21 (IH, br s), 5.49 (IH, d, J=10Hz), 5.66 (IH, d, J=10Hz) , 6.60 (IH, br ε), 6.87 (IH, br s) , 7.22-7.70 (8H, m) , 8.06-8.20 (2H, m) , 8.41-8.55 (2H, m) , 8.60-8.77 (2K, m)

(42) 8-[2, 6-Dichloro-3- [N-methyl-N-[4- (4-pyridylcarbamoyl) - cinnamoylglycyl] amino]benzyloxy]-2-methyl-4- orpholinoquinoline NMR (CDC1 ₃ , δ) : 2.55 (3H, s), 3.17-3.24 (7H, m) , 3.62

(IH, dd, J=17, 4Hz), 3.85 (IH, dd, J=17, 5Hz), 3.95-4.01 (4K, m) , 5.57 (2H, ε) , 6.50 (IK, d, J=15H∑), 6.70-6.76 (2H, m) , 7.20-7.28 (2H, m) , 7.33-7.56 (5H, m) , 7.61-7.71 (3H, ) , 7.89 (2H, d, J=8Hz), 8.49 (2H, a, J=7Hz), 8.99 (IH, br ε)

its trihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.87 (3K, br s), 3.29 (3H, ε),

3.68-4.25 (10H, m) , 5.50 (IH, br d, J=10Hz) , 5.69 (IH, br d, J=10Hz), 6.61 (IH, br s) , 7.07 (IK, br ε), 7.28-7.74 (8H, m) , 8.01-8.16 (2H, m) , 8.45-8.70

(4H, m)

Example 69 The following compoundε were obtained according to a εimiiar manner to that of Example 3.

(1) 8- [3- [N- [ (E) -3- (6-Carboxypyridin-3-yl) acryloylglycyl]-N- methylamino]-2, 6-dichlorobenzyloxy]-4-dimethylamino-2- methylquinoline

NMR (DMSO-d ₆ , δ) : 2.60 (3H, ε), 3.13 (3H, ε),

3.20-3.42 (6H, overlapped with H ₂ 0) , 3.58 (IH, br dd, J=17, 4Hz), 3.90 (IH, br dd, J=17, 5Hz) , 5.51 (IH, d, J=10Hz), 5.58 (IK, d, J=10Hz), 6.90 (IH, br ε), 7.01 (IH, d, J=15Hz), 7.44-7.93 (6H, m) , 8.07

( IH, d, J=8Hz ) , 8 . 14 ( IH, br d, J=8Hz ) , 8 . 45 ( IH, br t , J=5Hz ) , 8 . 88 ( IH, br ε )

(2) 8- [3- [N- [ (E) -3- (6-Carboxypyriain-3-yl) acryloylglycyl] -N- methylamino] -2, 6-dichIorobenzyloxy] -2-methyl-4- piperidinoquinoline

NMR (DMSO-d ₆ , δ) : 1.59-1.83 (6H, ) , 2.55 (3H, br ε), 3.00-3.60 (8H, overlapped with H ₇ 0) , 3.86 (IH, br d, J=17, 4Hz), 5.50 (2H, br ε), 6.87-7.08 (2H, ) , 7.30-7.67 (4H, m) , 7.79 (2H, s), 8.03-8.51 (4H, ) ,

8.59 (0.5H, br s), 8.89 (0.5H, br s)

(3) 8- [3- [N- [ (E) -3- (6-Carboxypyridin-3-yl) acryloylglycyl] -N- methylamino] -2, 6-dichlorobenzyloxy] -2-methyl-4- morpholinoquinoline

NMR (CDCI3-CD3OD, δ) : 2.67 (3H, br s), 3.25 (3H, s),

3.30-3.45 (4H, m) , 3.77 (IH, br d, J=17Hz) , 3.92-

4.11 (5H, m) , 5.45-5.62 (2H, ) , 6.64-7.00 (2H, m) ,

7.24-7.68 (6H, m) , 7.90 (IH, br d, J=8Hz) , 8.04 (IH, br s) , 8.70 (IH, br s)

(4) 8- [3-[N-[ (E)-3- (6-Carboxypyridin-3-yl) acryloylglycyl] -N- methylamino] -2, 6-dimethylbenzyloxy] -2-methylquinoline NMR (DMSO-d ₆ , δ) : 2.33 (3H, s) , 2.46 (3H, s) , 2.61 (3H, s), 3.13 (3H, s) , 3.51 (IH, dd, J=5, 16Hz),

3.71 (IH, dd, J=5, I6Hz) , 5.25-5.37 (2H, m) , 7.00 (IH, d, J=16Hz), 7.25 (IH, d, J=8Hz), 7.37 (IH, d, J=8Hz), 7.37-7.57 (5K, ) , 8.00 (IH, d, J=8Hz) , 8.08 (IH, d, J=8Hz), 8.21 (IK, d, J=8Hz) , 8.33 (IH, t-like), 8.78 (IH, s-like)

Example 70

The following compounds were obtained according to a similar manner to that of Example 7.

(1) 8- [2, 6-Dichloro-3- [N-methyl-N- [ (E)-3-[6-

(methylcarbamoyl)pyridin-3-yl]acryloylglycyl]amino]- benzyloxy]-2-methy1-4-dimethylaminoquinoline NMR (CDC1 ₃ , δ) : 2.62 (3H, s), 2.98 (6H, s), 3.04 (3H, d, J=7Hz), 3.26 (3H, s) , 3.74 (IH, ad, 3=1 , 15Hz),

3.95 (IK, ad, J=7, 15Hz), 5.58 (2H, ) , 6.59-6.68 (2H, m) , 6.94 (IH, br) , 7.19 (IH, d, J=8Kz) , 7.28- 7.36 (2H, ) , 7.48 (IH, a, J=δHz), 7.53 (IH, d, J=15Hz), 7.70 (IH, d, J=8Hz), 7.84-8.01 (2H, m) , 8.08 (IH, d, J=10Hz), 8.56 (IH, s)

itε trihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.74 (3H, s), 3.07 (3H, s),

3.28 (3H, br), 3.51 (6H, s), 3.87 (IH, d, J=15Ez) , 4.30 (IH, d, J=15Hz), 5.45 (IH, d, J=8Hz) , 5.65

(IH, d, J=8Hz), 6.77 (IH, br) , 6.98 (IH, d, J=15Hz), 7.37-7.47 (2H, ) , 7.51-7.64 (3H, m) , 7.81 (IH, d, J=8Hz), 8.49 (IH, br) , 3.64 (IH, br) , 9.23 (IH, br)

(2) 8- [2, 6-Dichloro-3-[N-[ (E)-3- [6- (dimethylcarbamoyl) - pyridin-3-yl]acryloylglycyl]-N-methylamino]benzyloxy]-4- dimethylamino-2-methylquinoline

NMR (CDCI3, δ) : 2.66 (3H, br s) , 3.03 (6H, br s) , 3.13 (3H, ε), 3.26 (3H, s) , 3.75 (IH, br d,

J=18Hz), 3.98 (IH, br d, J=18Hz) , 5.54-5.65 (2H, ) , 6.58-6.71 (2H, ) , 7.15-7.41 (4H, m) , 7.48 (IH, d, J=8Hz), 7.51-7.64 (2H, ) , 7.70 (IH, d, J=8Hz) , 7.89 (IH, dd, 3=2 , 8Hz), 8.64 (IK, s)

its trihydrochloride

NMR (DMSO-d ₆ , δ) : 2.63 (3H, s), 2.95 (3H, s),3.01

(3H, ε), 3.14 (3H, ε), 3.42 (6H, ε), 3.59 (IH, dd, 3=4 , 16Hz), 3.92 (IK, dd, 3=4 , 16Hz) , 5.53 (IH, d, J=10Hz), 5.60 (IH, d, J=10Hz), 6.90-7.00 (2H, m) ,

- 217 -

7.45 (IH, d, J=16Hz), 7.53-7.65 (2H, m) , 7.72-7.89 (3H, m) , 7.95 (IH, ά, J=8Hz) , 8.09 (IK, C, J=8Hz), 8.43 (IH, t-like), 8.75 (IH, s)

(3) 8- [2, 6-Dichloro-3- N-methyI-N-[ (E)-3-[6- (2- pyridylmethylcarbamoyl)pyridin-3-yl1 acryloylglycyl]- amino]benzyloxy] -4-dimethylamino-2-methylq inoline NMR (CDC1 ₃ , δ) : 2.65 (3H, br s) , 3.03 (6H, br ε) ,

3.26 (3H, s), 3 . 13 (IH, br d, J=17Hz), 3.97 ( H, br d, J=17Hz), 4.79 (2K, d, J=5Hz), 5.60 (2H, br s),

6.67 (IH, br s) , 6.85 (IH, broad), 7.17-7.36 (5H, m) , 7.46 (IH, d, J=8Hz) , 7.59 (IH, d, J=15Hz) , 7.62-7.72 (3H, ) , 7.90 (IH, br d, J=8Hz), 8.15 (IH, ) , 8.57-8.65 (2H, ir.) , 8.88 (IH, m)

itε tetrahydrochloride

NMR (CDCI3-CD3OD, δ) : 2.62-2.88 (3H, overlapped with H ₂ 0) , 3.27 (3H, 8), 3.50 (6H, s) , 3.87 (IH, d, J=17Hz), 4.25 (IH, d, J=17Hz) , 5.12 (2H, br s) , 5.46 (IH, d, J=10Hz) , 5.62 (IH, d, J=10Hz) , 6.74

(IH, br s), 6.95 (IH, br d, J=15Hz) , 7.37-7.65 (5H, m) , 7.81 (IH, br d, J=8Hz) , 7.89 (IH, br t, J=7Hz) , 8.11 (IH, br d, J=8Hz), 8.27 (IH, m) , 8.34 (IH, ) , 8.44 (IH, br t, J=8Hz) , 8.78 (IH, br d, J=5Hz) , 8.92 (IH, )

(4) 8- [2, 6-Dichloro-3-[N-methyl-N- [ (E) -3- [6- [N- (4- pyridyl) carbamoyl]pyridin-3-yl]acryloylglycyl]amino] - benzyloxy] -2-methyl-4-dimethylaminoquinoline NMR (CDCI3, δ) : 2.63 (3H, s), 3.00 (6H, s), 3.28 (3H, s), 3.79 (IH, dd, J=7, 15Hz) , 3.99 (IH, dd, 3= ^~ , 15Hz), 5.60 (2H, m) , 6.68 (IH, s) , 6.73 (IH, d, J=15Hz), 7.19-7.28 (3H, ) , 7.31-7.42 (2H, m) , 7.48 (IH, d, J=8Hz), 7.62 (IK, d, J=15Hz) , 7.66-7.75 (3H, m) , 7.95 (IH, άd, 3=4 , 8Hz), 8.17 (IH, d.

J=8Hz), 8.57 (2H, d, J=8Hz) , 8.62 (IH, s)

its tetrahydrochloride

NMR (CD ₃ OD, δ) : 2.68 (3H, ε), 3.28 (3H, s), 3.49 (6H, s), 3.82 (IH, d, J=15Hz), 4.02 (IH, d, J=15Hz) ,

5.65 (IK, d, J=8Hz) , 5.71 (IH, a, J=8Hz), 6.87 (IH, s), 6.97 (IH, d, J=15Hz), 7.54-7.71 (6H, m) , 7.97

(IH, d, J=8Hz), 8.28 (2H, ) , 8.53 (2H, d, J=8Hz),

8.70 (2H, d, J=8Hz) , 8.91 (IH, s)

(5) 8- [2, 6-Dichloro-3- [N-methyi-N- [ (E)-3-[o- (2- cyridylmethylcarbamoyl)pyridin-3-yl] acryloylglycyl] - amino]benzyloxy] -2-methyl-4-piperidinoquinoiine NMR (CDCI3, δ) : 1.59-1.74 (2H, overlapped with H ₂ 0) , 1.79-1.89 (4H, ) , 2.63 (3H, br s) , 3.09-3.20 (4H, ) , 3.26 (3H, s), 3.73 (IH, br d, _ 17Hz), 3.95 (IK, br d, J=17Hz), 4.79 (2K, d, J=5Hz) , 5.60 (2H, s), 6.63 (IH, br d, J=15Hz), 6.72 (IH, br s), 6.85 (IH, br ε), 7.17-7.39 (5H, m) , 7.48 (IH, d, J=8Hz) , 7.56-7.71 (3H, ) , 7.91 (IH, br d, J=8Hz) , 8.16

(IH, br d, J=8Hz), 8.61 (IH, d, J=5Hz) , 8.65 (IH, br s), 8.89 (IH, br t, J=5Hz)

itε tetrahydrochloride NMR (CDCI3-CD3OD, δ) : 1.81-1.93 (6H, ) , 2.80 (3H, br ε), 3.27 (3H, ε) , 3.69-3.79 (4H, ) , 3.89 (IH, br d, J=17Hz), 4.40 (IH, br d, J=17Hz) , 5.16 (2H, br ε), 5.48 (IH, br d, J=10Hz) , 5.63 (IH, br d, J=10Hz), 6.89 (IH, br s) , 7.04 (IH, br d, J=15Hz) , 7.33-7.70 (6H, m) , 7.89 (IH, br s) , 8.15 (IH, br s), 8.39-8.50 (2H, m) , 8.53 (IH, br s), S.79 (IH, br ε) , 9.04 (IH, br s)

(6) 8- [2, 6-Dichloro-3- [N-methyl-N- [ (E)-3-[6-(2- pyridylm.ethylcarbamoyl)pyridin-3-yl]acryloylglycyl] -

- 219 - amino]benzyloxy]-2-methyl-4-morpholinoquinoiine and itε tetrahydrochloride

(7) 8-[2, 6-Dimethyl-3-[N-methyl-N-[ (E)-3- [6-

(methylcarbamoyl)pyridin-3-yl]acryloylglycyl]- amine]benzyloxy]-2-methylquinoline

NMR (CDC1 ₃ , δ) : 2.37 (3H, ε), 2.53 (3H, s) , 2.74 (3K, s), 3.05 (3H, d, J=5Hz), 3.27 (3H, s) , 3.64 (IH, dd, 3=4 , 16Hz), 3.90 (IH, ad, 3=4 , 16Hz), 5.36 (2H, s), 6.61 (IH, d, J=16Hz), 6.77 (IH, t-like), 7.07 (IH, a, J=8Kz), 7.18 (IH, d, J=8Hz) , 7.22-7.33 (2H, m) , 7.40-7.49 (2H, m) , 7.60 (IH, d, J=16Hz), 7.90- 8.00 (2H, ) , 8.03 (IH, a, J=8Hz) , 8.20 (IH, d, J=8Hz), 8.63 (IH, d, J=2Hz)

itε dihydrochloride

NMR (DMSO-d ₆ , δ) : 2.29 (3H, s) , 2.48 (3H, s) , 2.82 (3K, d, J=5Hz), 2.92 (3H, s) , 3.13 (3H, s) , 3.55 (IH, dd, J=4, 16Hz), 3.75 (IH, dd, 3=4 , 16Hz),

5.41-5.54 (2H, ) , 7.05 (IK, d, J=16Hz), 7.31 (IH, d, J=8Hz), 7.39 (IH, a, J=8Hz) , 7.49 (IH, d, J=16Hz), 7.81-8.00 (4H, m) , 8.05 (IH, d, J=8Hz) , 8.15 (IH, dd, J=2, 8Hz), 8.35 (IH, t-like), 8.74- 8.84 (2H, m) , 8.98 (IK, br peak)

(8) 8-[2, 6-Dichloro-3-[N-methyl-N-[ (E)-3-[6-

(methylcarbamoyl)pyridin-3-yl]acryloylglycyl]amino]- benzyloxy]-2-methyl-4-piperidinoquinoline NMR (CDCI3, δ) : 1.69 (2H, br s), 1.84 (4H, br s) ,

2.63 (3H, s}, 3.05 (3H, a, J=5Hz) , 3.18 (4H, br ε), 3.26 (3H, ε), 3.72 (IH, dd, J=17, 4Kz) , 3.96 (IH, dd, J=17, 4Hz), 5.59 (2H, ε), 6.65 (IH, d, J=16Hz), 6.72 (IH, ε), 7.00-7.70 (7H) , 7.83-8.21 (3H) , 8.58 (IH, s)

its trihydrochloride

NMR (CD3OD, δ) : 1.37 (6K, br s) , 2.71 (3H, ε), 2.98 (3H, s), 3.27 (3H, ε), 3.78 (4H, br s) , 3.82 (IH, d, J=17Hz), 4.02 (IH, d, J=17Hz) , 5.64 (IH, d, J=llHz), 5.72 (IK, d, J=liHz) , 6.82-8.30 (10K) ,

8.79 (IH, br s)

(9) 8- [2, 6-Dichloro-3-[N-methyl-N- [ (E)-3-[6-

( ethylcarbamoyl)pyridir.-3-yl]acryloylglycyl]amino]- benzyloxy]-2-methyl-4-morpholinoquinoline

NMR (CDCI3, δ) : 2.67 (3K, ε) , 3.04 (3H, d, J=5Hz),

3.18-3.24 (4H, m) , 3.28 (3H, s) , 3.70 (IH, br dd, J=17, 4Hz), 3.90-4.01 (5H, ) , 5.60 (IH, d, J=10Hz), 5.67 (IH, a, J=10Hz) , 6.62 (IH, br d, J=15Hz), 6.78 (2H, s), 7.22 (IH, br d, J=8Hz), 7.30

(IH, d, J=8Hz), 7.38 (IH, t, J=8Kz), 7.49 (IH, d, J=8Hz), 7.60 (IH, d, J=15Hz) , 7.67 (IH, br d, J=8Hz), 7.90-8.00 (2H, ) , 8.18 (IH, d, J=8Hz) , 8.61 (IH, br ε)

its trihydrochloride

NMR (CDC1 ₃ -CD ₃ 0D, δ) : 2.86 (3H, br s) , 3.07 (3H, s) ,

3.29 (3H, s), 3.73-3.90 (5H, m) , 3.98-4.06 (4H, m) , 4.48 (IH, br d, J=17Hz), 5.44 (IH, d, J=10Hz), 5.63 (IH, d, J=10Hz), 6.99-7.09 (2H, m) , 7.30-7.69 (6H, ) , 8.68-8.80 (2H, m) , 9.44 (IH, br s)

Example 71

The following compounds were obtained according to a similar manner to that of Example c

(1) 8-[2, 6-Dichloro-3-[N-methyi-N-[ (E)-3-[6-(4- pyridylacetamido)pyridin-3-yl]acryloylglycyl]amino]- benzyloxy]-4-dimethylamino-2-methylquinoline NMR (CDCI3, δ) : 2.66 (3H, s), 3.02 (6H, s), 3.26 (3H,

s), 3.63-3.79 (3H, m) , 3.96 (IH, br d, J=I8Hz), 6.55-6.67 (2K, m) , 6.49 (IH, d, J=16Hz), 6.68 (IH, s), 7.16-7.40 (6H, m) , 7.40-7.55 (2H, m) , 7.71 (IH, d, J=8Hz), 7.82 (IH, d, J=8Kz), 8.10-8.21 (2H, m) , 8.32 (IH, ε-like), 8.62 (2H, d, J=6Hz)

(2) 3-[2, 6-Dichloro-3-[N-methyl-N-[ (E)-3-[6-(2- methylnicotinamido)pyridin-3-yl]acryloylglycyl]amino]- benzyloxy]- -dimethylamino-2-methylquinoline NMR (CDC1 ₃ , δ) : 2.64 (3H, ε), 2.77 (3H, s), 2.99 (6H, s), 3.27 (3H, s), 3.64-3.77 (IH, m) , 3.94 (IH, dd, 3=4, 18Hz), 5.56-5.67 (2H, m) , 6.51 (IH, d, J=16Hz), 6.69 (IH, s), 6.76 (IH, br peak), 7.15- 7.38 (4H, m) , 7.45-7.48 (2H, ) , 7.66-7.74 (IH, m) , 7.83 (IK, d, J=8Hz), 7.80 (IH, d, J=8Hz) , 8.30-8.40

(3H, m) , 8.64 (IK, d, J=6Hz)

(3) 8- [2, 6-Dichioro-3- [N-methyl-N- [ (E)-3-[6- (isonicotinamido)pyridin-3-yl] acryloylglycyl] amino] - benzyloxy] -4-dimethylamino-2-methylquinoline

NMR (CDCI3, δ) : 2.66 (3H, s) , 3.04 (6H, ε), 3.27 (3H, ε), 3.76 (IH, br d, J=18Hz) , 3.98 (IH, br d, J=18Hz), 5.60 (2H, ε), 6.65 (IH, d, J=16Hz) , 6.69 (IH, s), 7.17-7.42 (4H, ) , 7.48 (IH, d, J=8Hz) , 7.54 (IH, d, J=16Hz), 7.71 (IH, d, J=8Hz) , 7.78

(2H, d, J=6Hz), 7.90 (IH, dd, J=2, 8Hz) , 8.33 (IH, d, J=8Hz), 8.41 (IH, d, J=2Hz) , 8.76 (IH, s) , 8.84 (2H, d, J=6Hz)

(4) 8- [2, 6-Dichloro-3- [N-methyl-N- [ (E)-3-[6- (4- pyridylacetamido)pyridin-3-yl]acryloylglycyl]amino]- benzyloxy]-2-methyl-4-piperidinoquinoline NMR (CDCI3, δ) : 2.61-2.90 (6H, ) , 2.68 (3H, br s), 3.20 (4H, br peak), 3.25 (3H, s) , 3.65-3.80 (3H, m) , 3.98 (IH, br d, J=18Hz) , 5.59 (2H, s), 6.52

(IH, d, J=16Hz), 6.72 (IH, s), 7.21 (IH, d, J=8Hz), 7.25-7.41 (5H, m) , 7.45 (IH, d, J=8Hz), 7.49 (IH, d, J=16Hz), 7.63 (IH, d, J=8Hz), 7.81 (IH, dd, 3=2 , 8Hz), 8.08-8.19 (IH, m) , 8.23-8.33 (2H, ) , 8.61 (2H, d, J=6Hz)

(5) 8-[2, 6-Dichloro-3-[N-methyl-N- [ (E)-3-[6- (4- pyridylacetamido)pyridin-3-yl]acryloylglycyl]amino]- benzyloxy]-2-methyl-4-morpholinoquinoline NMR (CDC1 ₃ , δ) : 2.67 (3H, s), 3.22 (4H, br) , 3.27

(3H, s), 3.66-3.76 (4K, m) , 3.98 (4H, m) , 5.68 (2H, m) , 6.47 (IH, d, J=15Hz), 6.78 (IK, s), 6.94 (IH, br) , 7.22 (IH, d, J=8Hz), 7.28-7.50 (6H, ) , 7.66 (IH, d, J=8Hz), 7.79 (IH, dd, J=4, 8Kz), 8.16 (IH, d, J=8Hz), 8.30 (IH, br) , 8.60 (2H, d, J=7Hz) , 8.68

(IH, s)

Example 12

The following compounds were obtained according to a similar manner to that of Example 19.

(1) 8- [2, 6-Dichloro-3- [N-methyl-N-[N'- [3- [N- (4-pyridyl)- carbamoyl]phenyl]ureidoacetyl]amino]benzyloxy]-2-methyl- 4-dimethylaminoquinoline NMR (CDCI3, δ) : 2.50 (3H, s) , 3.01 (6H, s), 3.19 (3H, s), 3.92 (2H, m) , 5.40 (2H, m) , 6.32 (IH, br) , 6.65 (IH, ε), 7.03 (IH, m) , 7.14 (2H, m) , 7.28-7.42 (4H, m) , 7.64 (IH, m) , 7.70 (IH, d, J=8Hz), 7.78 (2H, m) , 8.40-8.52 (2H, m) , 8.69 (IH, br) , 9.47 (IH, br)

itε trihydrochloride

NMR (CD3OD, δ) : 2.41 (3H, s) , 3.07 (3K, ε), 3.27 (6H, s), 3.42-3.70 (2H, ) , 5.40 (IH, d, J=15Hz), 5.52 (IH, d, J=15Hz), 6.62 (IH, ε), 7.18-7.48 (9H, m) , 7.72 (IH, d, J=8Hz) , 7.86 (IH, ) , 8.10-8.20 (3H,

m) , 8 . 44 ( 2H, m)

(2) 8- [2, 6-Dichloro-3- [N-methyl-N- [N' - (3-nitrophenyl) - ureidoacetyl] amino]benzyloxy] -4-dimethylamino-2- methylquinoline

NMR (CDC1 ₃ , δ) : 2.44 (3H, s), 3.06 (6H, s), 3.23 (3H, ε), 3.77 (IH, dd, J=3, 18Hz), 4.70 (IH, dd, J=10, 18Hz), 5.32 (IH, d, J=10Hz), 5.44-5.53 (IH, ) , 5.56 (IH, d, J=10Hz), 7.68 (IK, s), 7.10-7.21 (2H, m) , 7.21-7.29 (IH, ) , 7.29-7.48 (3H, m) , 7.63-7.74

(2H, m) , 8.20 (IH, s), 9.90 (IH, s)

(3) 8- [2, 6-Dichloro-3- [N-methyl-N- [N ¹ - [3- [ (E) -2- (pyridin-4- yl) vinyl] phenyl] ureidoacetyl] amino]benzyloxy] -2-methyl- 4-dimethylaminoquinoline

NMR (CDCI3, δ) : 2.48 (3H, s), 3.04 (6H, ε), 3.22 (3H, ε), 3.65-3.87 (2H, m) , 5.41 (IH, d, J=8Hz) , 5.61 (IH, d, J=8Hz), 5.63 (IH, br) , 6.68-6.80 (2H, m) , 7.00-7.22 (7H, ) , 7.29-7.36 (2H, m) , 7.45 (IH, t, J=8Hz), 7.57 (IH, s) , 7.70 (IH, d, J=8Hz) , 8.52

(2H, d, J=7Hz), 8.86 (IH, br)

its trihydrochloride

NMR (CD3OD, δ) : 2.57 (3H, s) , 3.27 (3H, s) , 3.46 (6H, ε), 3.70 (IH, d, J=15Hz), 3.90 (IH, d, J=15Hz) ,

5.63 (IH, d, J=8Hz), 5.76 (IH, d, J=8Hz) , 6.75 (IH, m) , 6.80 (IH, s), 7.15 (IH, m) , 7.30-7.45 (4H, m) , 7.58 (IH, m) , 7.66-7.99 (6H, m) , 8.12 (2H, d, J=8Hz) , 8.68 (2H, d, J=8Hz)

(4) 8- [2, 6-Dichloro-3- [N-methyl-N- [N'- [3- [N- (4-pyridyl) - carbamoyl] phenyl] ureidoacetyl] amino]benzyloxy] -2-methyl- 4-piperidinoquinoline

NMR (CDCI3, δ) : 1.65-1.90 (6H, m) , 2.54 (3H, s) , 3.11-3.29 (7H, m) , 4.00 (2H, br ε), 5.49 (2H, br

s), 6.32 (IH, br s), 6.70 (IH, br s), 7.06 (IH, t, J=8Hz), 7.19 (2H, br d, J=8Hz) , 7.23-7.48 (5H, ) , 7.63 (IH, br d, J=8Hz), 7.75 (2H, br d, J=6Hz) , 8.49 (2H, br d, J=6Hz), 8.88 (IH, br s), 9.35 (IH, br ε)

itε trihydrochloride

NMR (CDCI3-CD3OD, δ) : 1.81-1.94 (6H, ) , 2.57 (3H, br s), 3.24 (3H, s), 3.67-3.77 (4H, m) , 3.82 (IH, br d, J=17Hz), 4.19 (IH, br d, J=17Hz) , 5.48 (IH, d,

J=10Hz), 5.67 (IH, d, J=10Hz), 6.73 (IH, br s),

7.18 (IH, br t, J=8Hz) , 7.39-7.65 (7H, ) , 7.92

(IH, br s), 8.45-8.54 (4H, m)

(5) 8- [2, 6-Dichloro-3- [N-methyl-N- [N'- [3- [N- (4-pyridyl) - carbamoyl]phenyl]ureidoacetyl]amino]benzyloxy] -2-methyl-

4-morpholinoquinoline

NMR (CDCI3, δ) : 2.59 (3H, s) , 3.17-3.26 (7H, m) ,

3.91-4.01 (4H, m) , 5.41 (IH, d, J=10Hz) , 5.49 (IH, d, J=10Hz), 6.45 (IH, br ε) , 6.76 (IH, s) , 7.00-

7.10 (2H, m) , 7.19 (IH, br d, J=8Hz) , 7.22-7.48 (5H, m) , 7.68 (IH, br d, J=8Hz) , 7.82 (2H, br d, J=7Hz), 8.51 (2H, br d, J=7Hz) , 8.58 (IH, br s) , 9.51 (IH, br s)

its trihydrochloride

NMR (CDCI3-CD3OD, δ) : 2.66 (3H, s) , 3.25 (3H, s) ,

3.68-4.07 (9H, m) , 4.19 (IH, br ε), 5.49 (IH, d, J=7.5Hz), 5.69 (IH, d, J=7.5Hz), 6.92 (IH, br s) , 7.16 (IH, br ε), 7.41-7.70 (7H, m) , 7.91 (IH, br ε), 8.40-8.59 (4H, )

(6) 8- [2, 6-Dichloro-3- [N-methyl-N- [N'-[4- [N- (4- pyridylmethyl) carbamoyl]phenyl]ureidoacetyl]amino]- benzyloxy]-2-methylσuinoline

NMR (CDCI3, δ) : 2.56 (3H, s) , 3.17 (3H, br) , 3.49- 3.82 (2K, m) , 4.54 (2H, br) , 5.47 (IH, d, J=8Hz) , 5.57 (IH, m) , 7.15 (2H, br) , 7.23-7.33 (5H, m) , 7.46 (2H, br) , 7.60 (2H, d, J=8Hz), 8.08 (IH, m) , 8.46 (2H, br), 8.93 (IH, br)

itε dihydrochloride

NMR (CD3OD, δ) : 3.00 (3H, s), 3.28 (3H, s), 3.80

(2H, m) , 4.84 (2H, br) , 5.70 (IH, d, J=8Hz) , 5.84 (IK, d, J=8Hz), 7.49 (2H, a, J=8Hz), 7.73 (2H, d,

J=4Hz) , 7.84 (2H, m) , 7.91 (4H, m) , 8.04 (2H, d, J=8Hz), 3.78 (2H, d, J=8Hz), 9.03 (IH, m)

(7) 8- [2, 6-Dichloro-3- [N- [N'- [3- (me hanesulfonylamino- carbonyl) phenyl] ureidoacetyl] -N-methyiamino]benzyloxy] - 2-methylquinoline p : 239-242°C NMR (CDCI3-CD3OD, δ) : 2.64 (3H, s), 3.22 (3H, s) ,

3.28 (3H, s), 3.79 (IH, br d, J=17Hz), 3.90 (IH, br a, J=17Hz), 5.52 (IH, d, J=10Hz) , 5.60 (IH, d,

J=I0Hz), 7.13-7.19 (2H, ) , 7.22-7.60 (7H, m) , 7.81 (IH, br ε), 8.09 (IH, d, J=8Hz)

(8) 8-[2, 6-Dichloro-3-[N-[N'-[3-(4- methylbenzeneεulfonylaminocarbonyl) phenyl] ureidoacetyl] - N-methylamino]benzyloxy] -2-methylσuinoline mp : 235-240°C NMR (CDCI3-CD3OD, δ) : 2.37 (3H, s) , 2.61 (3H, s) ,

3.21 (3H, ε), 3.80 (IH, br d, J=17Hz), 3.90 (IH, br d, J=17Hz), 5.51 (IH, d, J=10Hz) , 5.69 (IK, d,

J=10Hz), 6.99-7.13 (2H, m) , 7.18-7.49 (9K, m) , 7.70 (IH, br ε), 7.97 (2H, d, J=8Hz), 8.05 (IH, d, J=8Hz)

(9) 8- [2, 6-Dichloro-3- [N-methyl-N- [N'- [3- [ (E) -2- (pyridin-4-

yl) vinyl]phenyl]ureidoacetyl]amino]benzyloxy]-2- methylquinoline

NMR (CDC1 ₃ , δ) : 2.62 (3H, s), 3.22 (3H, ε), 3.63-3.88

(2H, ) , 5.49 (IH, d, J=8Hz), 5.63 (IH, d, J=8Hz), 5.67 (IH, br), 6.78-6.88 (2H, m) , 7.03-7.25 (7H, m) , 7.33 (2H, ) , 7.48 (IH, ) , 7.59 (IH, br) , 8.02

(IH, br), 8.03 (IH, d, J=8Hz), 3.41 (IH, br) , 8.51

(2K, d, J=7Hz)

itε dihydrochloride

NMR (CD3OD, δ) : 2.93 (3H, s), 3.28 (3H, s), 3.77 (IH, d, J=15Hz), 3.89 (IH, d, J=15Hz), 5.65 .(IH, m) , 5.72 (IK, d, J=8Hz), 5.84 (IH, d, J=8Hz), 7.29-7.40 (3H, m) , 7.59-8.00 (9K, m) , 8.13 (2H, d, J=8Hz), 8.69 (2H, d, J=8Hz), 9.00 (2H, m)

(10) 8- [2, 6-Dichloro-3- [N-methyl-N-[N'- [3- [ (Z) -2- (pyridin-4- yl)vinyl]phenyl] reidoacetyl]amino]benzyloxy]-2- methylquinoline NMR (CDCI3, δ) : 2.61 (3H, ε), 3.17 (3H, ε), 3.76 (IH, dd, 3=4 , 16Hz), 4.01 (IH, dd, J=5, 16Hz), 5.47 (IH, d, J=10Hz), 5.60 (IH, d, J=10Hz) , 5.73 (IH, t- like), 6.35 (IH, d, J=llHz), 6.64 (IH, d, J=llHz) , 6.74 (IH, d, J=8Hz), 6.94-7.19 (5H, m) , 7.19-7.37 (4H, m) , 7.37-7.51 (2H, m) , 8.05 (IH, d, J=8Kz) ,

8.23-8.58 (3H, m)

(11) 8- [2, 6-Dichloro-3- [N-methyl-N-[N'- [3- [2- (pyridin-4- yl) ethyl]phenyl]ureidoacetyl]amino]benzyloxy]-2- methylquinoline

NMR (CDC1- ₃ , δ) : 2.61 (3H, s), 2.66-2.80 (4H, m) , 3.22

(3H, s), 3.80 (IH, da, 3=4 , 17Hz) , 4.23 (IH, dd, J=5, 17Hz), 5.47 (IH, d, J=10Hz) , 5.53 (IH, t-like), 5.63 (IK, d, J=I0Hz), 6.71 (IH, d, J=8Hz) , 6.90-7.13 (4H, m) , 7.19 (IH, ε-like), 7.21-7.35

( 4K, ) , 7 . 42- 7 . 50 ( 2H, m) , 3 . 02 ( IH, s-l i ke ) , 8 . 08 ( IH, d, J=8Hz ) , 3 . 43 ( 2H, d, J=6Hz )

its dihydrochloride NMR (DMSO-d _β , δ) : 2.82-2.97 (5H, m) , 3.06-3.21 (5H, m) , 3.40-3.90 (2K, m, (overlap in H ₂ 0) ) , 5.61 (2H, s), 6.48 (IH, br ε), 6.77 (IH, d, J=8Hz), 7.11 (IH, t, J=8Hz), 7.16-7.31 (2H, m) , 7.67-7.88 (6H, m) , 7.93 (2H, d, J=6Hz), 8.75-8.89 (3H, m) , 8.96 (IH, s)

Example 73

(1) 8- [N-tert-Butoxycarbonyl-N- [2, 6-dichloro-3- [N-methyl-N- (phthalimidoacetyl) amino]benzyl] amino] -2-methylquinoline waε obtained from 8-tert-butoxycarbonylamino-2-methylquinoline and 2, 6-dichloro-3- [N-methyl-N- (phthalimidoacetyl) amino] - benzyl bromide according to a similar manner to that of Preparation 6.

NMR (CDCI3-CD3OD, δ) : 1.24, 1.66 (9H, s) , 2.72, 2.78 (3H, ε) , 2.96, 3.04 (3H, s) , 3.16-3.22, 3.56-3.66

(2H, m) , 5.18-5.38, 5.50-5.69 (2H, m) , 6.83-8.08 (11H, m)

(2) 8- [N- [3- (N-Glycyl-N-methylamino) -2, 6-dichlorobenzyl] -N- tert-butoxycarbonylamino] -2-methylquinoline waε obtained according to a εimiiar manner to that of Preparation 11. NMR (CDCI3, δ) : 1.20, 1.63 (3H, s) , 2.14-2.20, 2.59- 2.88 (2H, m) , 2.19, 2.23 (3H, ε), 5.07-5.22, 5.54- 5.70 (2H, m) , 6.83-7.88, 7.66, 8.00 (7H, )

(3) 8- [N-tert-Butoxycarbonyl-N- [2, 6-dichloro-3- [N-methyl-N- [4- (methylcarbamoyl) cinnamoylglycyl] amino]benzyl] amino] - 2-methylquinoline waε obtained according to a εimiiar manner to that of Example 1. NMR (CDCI3, δ) : 1.24, 1.60 (9H, ε), 2.74 (3H, s) ,

3.05 (3H, s), 3.08 (3H, s), 2.84, 2.90, 3.30, 3.86 (2H, ) , 5.00-5.16, 5.62-5.72 (2H, m) , 6.16 (IH, br) , 6.48 (IH, m) , 6.56 (IH, m) , 6.60-6.98 (IH, ) , 7.10 (IH, ) , 7.46 (IH, ; , 7.50-7.65 (4H, m) , 7.75 (2H, m) , 7.96 (IH, )

(4) To a solution of 8- [N-tert-butoxycarbonyl-N- [2, 6- dichloro-3- [N-methyl-N-[4- (methylcarbamoyl) cinnamoylglycyl]- amino]benzyl]amino]-2-methylquinoline (32.3 mg) in ethyl acetate (0.5 ml) was added 4N solution of hydrogen chloride in ethyl acetate (0.5 ml) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature and for 2 hours at ambient temperature. The mixture was concentrated in vacuo to give 8- [2, 6-dichloro-3-[N-methyl-N-[4- (methylcarbamoyl)cinnamoylglycyl]amino]benzylamino]-2- methylquinoline dihydrochloride (22.0 mg) as amorphous powder.

NMR (CDC1 ₃ , δ) : 3.00 (3H, s), 3.20 (3H, s), 3.31 (3H, s), 3.84-4.06 (2H, ) , 4.71-4.35 (2H, m) , 6.25 (IH, m) , 6.55 (IK, ) , 7.07 (IH, ) , 7.16 (IH, d,

J=8Hz), 7.27-7.31 (2H, ) , 7.42-7.58 (4H, ) , 7.64- 7.74 (3H, m) , 8.57 (IH, )

Example 74 To a εuspension of sodium hydride (601 in oil, 38 mg) in anhydrous dimethylformamide (2.0 ml) was added 8- [2, 6- dichloro-3-[N-methyl-N- [4- (methylcarbamoyl) cinnamoylglycyl]- amino]benzyloxy]-2-methylquincline (189 mg) under nitrogen atmosphere in an ice-water bath. After stirring for 40 minutes, methyl iodide (0.06 ml) was added thereto and the mixture was stirred for additional 2 hours. The reaction mixture waε partitioned between ethyl acetate and water and organic layer waε iεolated. The aqueous layer was extracted with ethyl acetate. The combined crganic phases were washed with water twice, dried over magnesium sulfate and evaporated

in vacuo. The residue was pulverized with diethyl ether to give 8- [2, 6-dichloro-3-[N-methyl-N- [N-methyl-N-[4- (dimethylcarbamoyl) cinnamoyl]glycyl]amino]benzyloxy]-2- methylquinoline (160 mg) as a pale yellow powder.

NMR (CDC1 ₃ , δ) : 2.72 (3H, s), 2.98 (3H, br s), 3.11 (3H, br s), 3.23 (6H, s), 3.41 (IH, a, J=16Hz), 4.36 (IK, d, J=16Hz), 5.66 (2H, s), 6.97 (IH, d, J=15Hz), 7.14-7.59 (10H), 7.66 (IK, a, J=15Kz; , 8.03 (IH, d, J=8Kz)

Example 75

(1) To a mixture of 8- (3-aminc-2, 6-dichlorobenzyloxy)-2- methyiquinoline (1.67 g) , triethylamine (0.9 ml) and anhydrouε dichloromethane (84 ml) was added ^' 3-methoxycarbonylpropionyl chloride (0.7 ml). After stirring at ambient temperature for 9 hourε, triethylamine (1.8 ml) and 3-methoxycarbonylpropionyl chloride (1.4 ml) were added thereto and the mixture waε stirred for additional 30 minutes. The reaction mixture was waεhed with water and saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a εilica gel column chromatography eluted with chloroform to give 8- [2, 6-dichloro-3- (3- methoxycarbonylpropionylamino)benzyloxy]-2-methylquinoline (2.04 g) aε a pale yellow oil.

NMR (CDCI3, δ) : 2.63-3.05 (4H) , 2.74 (3H, s), 3.69

(3H, s), 5.68 (2K, s), 7.18-7.46 (6H), 8.03 (IH, d, J=8Hz) , 8.27 (IH, br s)

(2) To a mixture of 8- [2, 6-dichloro-3- (3- methoxycarbonylpropionylamino)benzyloxy]-2-methylquinoIine (447 g) , iodomethane (0.1 ml) and dimethylformamide (5.0 ml) was added sodium hydride (60% in oil, 44 mg) under ice-water cooling. After stirring for 2 hours at the εame temperature, the reaction mixture waε diluted with ethyl acetate and

waεhed with water twice. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The reεidue was purified by a column chromatography eluted with chloroform to give 8- [2, 6-dichloro-3- [N- (3-methoxycarbonylpropionyl) -N- methylamino]benzyloxy] -2-methylquinoline (310 mg) as a pale yellow oil.

NMR (CDC1 ₃ , δ) : 2.15 (IK, dt, =16, 7Ez) , 2.30-2.55 (2H), 2.65-2.78 (IH), 2.75 (3H, s), 3.19 (3H, s) , 3.68 (3H, s), 5.67 (2H, s) , 7.21-7.49 (6H), 8.03 (IH, d, J=8Hz)

(3; To a solution of 8- [2, 6-dichloro-3- [N- (3- methoxycarbonylpropionyl) -N-methylamino]benzyloxy] -2- methylquinoline (303 mg) in methanol (3 ml) was added IN aqueous solution of sodium hydroxide (1.0 ml) at ambient temperature. The mixture waε εtirred for 1 hour and neutralized to pH 4 with IN hydrochloric acid. The reaction mixture was diluted with chloroform and washed with water. The aqueous layer was saturated with sodium chloride and extracted with chloroform. The combined organic layers were dried over magnesium εulfate and evaporated in vacuo to give 8- [3- [N- (3-carboxypropionyl) -N-methylamino] -2, 6- dichlorobenzyloxy] -2-methylquinoline (242 mg) aε an off-white powder. NMR (CDCI3, δ) : 2.32 (IH, m) , 2.53-2.69 (3H) , 2.67

(3H, s), 3.23 (3H, s), 5.44 (IK, d, J=10Hz), 5.62 (IH, d, J=10Hz), 7.18-7.53 (6H), 8.08 (IH, d, J=8Hz)

(4) To a mixture of 8- [3- [N- (3-carboxypropionyl) -N- methylamino] -2, 6-dichlorobenzyloxy] -2-methylquinoline (139 mg) , 3-amino-N-methylbenzamide (51.3 mg) and anhydrouε dichloromethane (4 ml) were added l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (71.5 mg) and 1-hydroxybenzotriazole (54.6 mg) . The mixture was stirred

96/13485

- 231 - for 12 hours at ambient temperature and washed with water. The organic layer waε dried over magneεium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol) followed by pulverization with diethyl ether to give 8- [2 , 6-dichloro-3- [N- [3- [N- (3-methylcarbamoylphenyl) carbamoyl]propionyl] -N- methylaminc]benzyloxy]-2-methylquinoline (103 mg) as an amorphous powder.

NMR (CDC1 ₃ , δ) : 2.32 (IK, m) , 2.48-2.69 (2H) , 2.72 (3H, s), 2.82 (IH, ) , 2.97 (3H, d, J=6Hz) , 3.19

(3H, s), 5.64 (2K, ε), 6.74 (IH, br ε), 7.20-7.50 (8H), 7.57-7.67 (2H) , 8.04 (IH, d, J=8Hz) , 9.17 (IH, s)

Example 76

(1) 8-[3-(N-Acetoxyacetyl-N-methylamino)-2, 6- dichlorobenzyloxy]-2-methylquinoline was obtained from 8-hydroxy-2-methylquinoline and 3- (N-acetoxyacetyl-N- methylamino) -2, 6-dichlorobenzyl bromide according to a similar manner to that of Example 9. mp : 104-105 ^β C

NMR (CDCI3, δ) : 2.22 (3H, s) , 2.72 (3H, s) , 3.20 (3H, s), 4.12 (IH, d, J=15Hz), 4.45 (IH, d, J=15Hz) , 5.62 (IH, d, J=10Hz), 5.68 (IH, d, J=10Hz) , 7.20-7.50 (6H, ) , 8.02 (IH, d, J=8Hz)

(2) To a solution of 8- [3- (N-acetoxyacetyl-N-methylamino) - 2, 6-dichlorobenzyloxy] -2-methylquinoline (640 mg) in methanol ( 6. 4 ml) was added potassium carbonate (395 mg) , and the mixture was stirred for 2 hours at ambient temperature. To the mixture was added chloroform and water, the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (chloroform:ethyl acetate = 3:1, V/V) to give 8-[2, 6-dichloro-3- (N-hydroxyacetyl-N-

methylamino)benzyloxy]-2-methylσuinoline (580 mg) as colorlesε amorphouε.

NMR (CDC1 ₃ , δ) : 2.74 (3K, s), 3.20-3.29 (4H, m) , 3.62 (IH, dd, J=15, 4Hz), 3.80 (IH, dd, J=15, 5Hz) , 5.62 (IH, d, J=10Hz), 5.69 (IH, 0, J=10Hz), 7.20-7.50

(6H, m) , 8.02 (IH, d, J=8Hz)

(3) To a solution of 8-[2, 6-dichloro-3- (N-hydroxyacetyl-N- methylamino)benzyloxy]-2-methylquinoline (200 mg) and triethylamine (99.9 mg) in dry dichloromethane (2 ml) was added methanesulfonyl chloride (62.2 ml) under ice-cooling, and the mixture was εtirred for 30 minuteε. The mixture waε waεhed with water, saturated εodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give 8-[2, 6-dichloro-3-(N-methaneεuifonyloxyacetyl-N- methylamino)benzyloxy]-2-methylquinoline (220 mg) aε colorleεε amorphous.

NMR (CDCI3, δ) : 2.73 (3H, s), 3.22 (3H, ε), 3.24 (3H, s), 4.30 (IH, d, J=15Hz), 4.50 (IH, d, J=15Hz) , 5.63 (IH, d, J=10Hz), 5.69 (IH, d, J=10Hz) , 7.21-

7.53 (6H, ) , 8.03 (IH, d, J=8Hz)

(4) Tc a mixture of dimethylamine hydrochloride (2.79 g) and triethylamine (6.92 g) in dichloromethane (50 ml) was added 4-bromobenzoyl chloride (5 g) was added εlowly under ice- cooling, and the mixture waε εtirred for 20 minutes at the same temperature and for 2 hours at ambient temperature. The mixture was waεhed with water, saturated sodium bicarbonate solution and brine, dried over magnesium εulfate and concentrated in vacuo to give 4- (dimethylcarbamoyl) -1- bromobenzene (5.20 g) aε brown oil.

NMR (CDCI ₃ , δ) : 2.97 (3K, br s), 3.10 (3H, br ε) , 7.30 (2H, a, J=8Hz), 7.54 (2H, d, J=8Hz)

(5) To the mixture of 3-aminophenylboronic acid hemiεulfate

(4.88 g) in toluene (57 ml) were added tetrakis (triphenylphosphine)palladium(0) (659 mg) , a solution of εodium carbonate (6.04 g) in water (28.5 ml), 4- (dimethylcarbamoyl) -1-bromobenzene (5.2 g) and methanol (14.3 ml) at ambient temperature, and the mixture waε heated at 8C°C. After 90 minuteε, the cooled reaction mixture was extracted with chloroform and the organic layer was washed with aqueous sodium bicarbonate solution and brine. The organic layer waε dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from n-hexane-ethyl acetate to give 4- (3-aminophenyl) -N,N-dimethylbenzamide (4.7 g) aε brown crystalε. mp : 139-141°C

NMR (CDC1 ₃ , δ) : 3.04 (3H, br s), 3.13 (3H, br ε) , 3.75 (2K, br ε), 6.69 (IK, d, J=8Hz), 6.89 (IH, s) ,

6.98 (IH, d, J=8Hz), 7.22 (IH, ι, J=8Hz) , 7.47 (2H, d, J=8Hz), 7.59 (2H, d, J=8Hz)

(6) A mixture of 8- [2, 6-dichioro-3- (N- methanesulfonyloxyacetyl-N-methylamino)benzyloxy]-2- methylquinoline (110 mg) , 4- (3-aminophenyl)-N, - dimethylbenzamide (60.2 mg) and potassium carbonate (94.2 mg) in N,N-dimethylformamide (1 ml) was stirred for 12 hourε at 60°C and ethyl acetate and water were added thereto. The organic layer waε waεhed with water and brine, dried over magneεium εulfate and concentrated in vacuo. The reεidue was purified by preparative thin-layer chromatography (chloroform:methanol = 20:1, V/V) to give 8- [2, 6-aichloro-3- [N- [2- [4'- (dimethylcarbamoyl)biphenyl-3-ylamino]acetyl]-N- methylamino]benzyloxy]-2-methylquinoline (30 mg) as colorless amorphous.

NMR (CDCI3, δ) : 2.70 (3H, s) , 3.01 (3H, br ε) , 3.12 (3H, br s), 3.27 (3H, s) , 3.51 (IH, br dd, J=17, 4Hz), 3.67 (IH, br dd, J=17, 5Hz), 4.81 (IH, br s) , 5.66 (IH, d, J=10Hz), 5.71 (IH, d, J=10Hz), 6.49

(IH, br da, J=8, 3Hz) , 6.70 (IH ε) , 6.91 (IH, br d, J=8Hz), 7.17-7.59 (UK, ) , 8.02 (IK, d, J=8Kz)

Example 77 The following compounds were obtained according to a εimiiar manner to that of Example 63.

(1) 8- [2, 6-Dichloro-3- [N-methyl-N- [3- [4- (methylcarbamoyl) - benzyloxy]benzoyl] amino]benzyloxy] -2-methylquinoline NMR (CDC1 ₃ , δ) : 2.70 (3H, s), 2.98 (3H, m) , 3.33 (3H, s), 5.03 (2H, ) , 5.60 (2H, m) , 6.40 (IH, br) , 6.80-8.10 (15H, m)

(2) 8- [2, 6-Dichloro-3- [N-methyi-N- [ 3- [4- (methyicarbamcyl) - phenoxymethyi]benzoyl] amino]benzyloxy] -2-methylquinoline

NMR (CDCI3, δ) : 2.70 (3H, s) , 2.90 (3K, m) , 3.33 (3H, s), 5.00 (2H, m) , 5.55 (2H, m) , 6.15 (IH, br) , 6.80-8.10 (15H, rr.)

(3) 3- [2, 6-Dichloro-3- [N-methyl-N- [3- [2- [4-

(methylcarba oyl) phenyl] ethyl]benzoyl] amino]benzyloxy] -

2-methylquinoline

NMR (CDCI3, δ) : 2.70 (3H, s), 2.80 (3K, br) , 2.90

(3H, d, J=7Hz), 3.33 (3H, br) , 5.60 (2H, d, J=8Hz), 6.20 (IH, br), 6.90-8.10 (15H, )

(4) 8- [2, 6-Dichloro-3- [N-methyl-N- [6- [ (E)-2-(4- methylcarbamoylphenyl) vinyl]pyridin-2-yIcarbonyl] - amino] benzyloxy] -2-methylquinoline NMR (CDCI3, δ) : 2.69 (3H, s) , 3.02 (3H, d, J=6Hz) ,

3.45 (3H, s) , 5.48 (IH, a, J=12Hz) , 5.55 (IH, d, J=12Hz), 6.25 (IK, br s), 6.83 (IH, d, J=15Hz) , 7.02 (IH, d, J=8Hz), 7.10-7.73 (14H), 7.98 (IH, d, J=8Hz)

Exampl e 78

(1) To a solution of 8- [2, 6-dichloro-3- [N-methyl-N- (4- aminocinnamoylglycyl)amino]benzyloxy]-2-methyIquinoline (50 mg) in ethanol (2 ml) were added N,N-bis (tert- 5 butoxycarbonyl) -S-methoxyisothiourea (28 mg) and mercury(II) oxide (21 mg) at ambient temperature and stirred for 1 hours at 40°C. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by ^p reparative thin-layer chromatography (8°. εolution of C methanol in chloroform) to give 8- [2, 6-dichloro-3- [N-[4- [2, 3- bis (tert-butoxycarbonyl) guanidinoj-cinnamoylglycyl]-N- methylamino]benzyloxy]-2-methylquinoline (60 mg) aε an amorphous powder.

NMR (CDC1 ₃ , δ) : 1.50 (9H, s), 1.53 (9H, ε), 2.73 (3H, ε), 3.26 (3H, s), 3.64 (IH, dd, 3=4 , 18Hz), 3.94

(IH, dd, 3=4 , 18Hz), 5.60-5.71 (2H, m) , 6.40 (IH, d, J=16Hz), 6.58 (IH, t-like), 7.21-7.35 (5H, ) , 7.35-7.60 (6K, m) , 7.64 (2H, d, J=8Hz) , 8.03 (IH, d, J=8Hz)

(2) To a solution of 8- [ 2 , 6-dichloro-3- [N- [4- [2 , 3-bis (tert- butoxycarbonyl)guanidino]cinnamoylglycyl]-N-methylamino]- benzyloxy]-2-methylquinoline (51 mg) in ethyl acetate and methanol was added 4N solution of hydrogen chloride in methanol (0.5 ml), and the mixture was stirred for 2 days at ambient temperature. The mixture was concentrated in vacuo, and the residue was disεolved in methanol. The solution was adjusted to pH 7 to 8 with aqueous ammonia and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol-aqueous ammonia) to give 8- [2, 6-dichlcro-3- [N- (4-guanidinocinnamoylglycyl)-N- methyla ino]benzyloxy]-2-methylquinoline (12 mg) aε amorphouε powder.

NMR (CDCI3-CD3OD, δ) : 2.67 (3H, s) , 3.21 (3H, ε) , 3.48 (IH, br d, J=16Hz) , 3.71 (IH, br d, J=16Hz),

5.50 (IH, d, J=10Hz), 5.65 (IH, d, J=10Hz), 6.26 (IK, d, J=16Hz), 6.97-7.12 (3H, m) , 7.21-7.36 (4H, m) , 7.42-7.58 (3H, m) , 7.80 (IH, d, J=8Hz), 8.08 (IH, d, J=8Hz)

Example 79

8- [2, 6-Dimethyl-3- [N-methyl-N- [ (E) -3- [6- (2- oxopyrrclidin-l-yl)pyridin-3-yl] acryloylglycyl] amino] - benzyloxy] -2-methyiσuinoline waε obtained according to a similar manner to that of Examples 58- (1) and (2) .

NMR (CDC1 ₃ , δ) : 2.13 (2H, quint, J=7.5Hz), 2.36 (3H, s), 2.52 (3H, s), 2.68 (2H, t, J=7.5Kz), 2.72 (3H, s), 3.25 (3H, ε), 3.63 (IH, dd, 3=4 , 18Hz), 3.89 (IH, dd, 3=4 , 18Hz), 4.11 (2H, t, J=7.5Hz), 5.36 (2H, s), 6.47 (IH, d, J=16Hz), 6.70 (IH, t-like),

7.06 (IH, a, J=8Hz), 7.16 (IH, d, J=8Hz) , 7.22-7.32 (2H, m) , 7.38-7.48 (2H, m) , 7.53 (IH, d, J=16Hz), 7.83 (IH, dd, 3=2 , 8Hz), 8.03 (IK, d, J=8Hz) , 8.39- 8.46 (2K, m)

its dihydrochloride

NMR (DMSO-d ₆ , δ) : 2.04 (2H, quint, J=7.5Hz), 2.28

(3H, s), 2.48 (3H, s ) , 2.60 (2H, t, J=7.5Hz), 2.93 (3H, ε), 3.11 (3H, s), 3.54 (IH, dd, J=4, 16Hz), 3.71 (IH, dd, 3=4 , 16Hz) , 4.00 (2H, t, J=7.5Hz),

5.41-5.53 (2H, ) , 6.83 (IH, d, J=16Hz) , 7.28-7.41 (3H, m) , 7.31-8.06 (5H,m), 3.25 (IH, t-like), 8.35 (IH, d, J=8Hz), 8.54 (IH, d, J=2Hz) , 8.98 (IK, br s)

Example 80 (1) 4- (Methoxycarbonyl) -N-methylcinnamamide was obtained from 4-methoxycarbonylcinnamic acid and methylamine hydrochloride according to a similar manner to that of Preparation 2.

mp : 180-182°C

NMR (DMSO-d ₆ , δ) : 2.71 (3H, d, J=4.0Hz), 3.87 (3H, ε), 6.71 (IH, d, J=16.5Hz), 7.47 (IH, d, J=16.5Hz), 7.70 (2H, d, J=8.5Hz), 7.98 (2H, d, J=8.5Hz), 8.14 (IH, q, J=4.0Hz)

(2) 4-Carboxy-N-methylcinnamamide was obtained according to a similar manner to that of Preparation 3. mp : 270-273°C NMR (DMSO-d ₆ , δ) : 2.72 (3H, d, J=4.0Hz), 6.70 (IK, d,

J=16.0Hz), 7.47 (IH, d, J=16.0Hz), 7.69 (2H, d, J=8.5Hz), 7.96 (2H, a, J=8.5Hz), 8.14 (IH, q, J=4.0Hz)

(3) 8-[2, 6-Dichloro-3-[N-methyl-N- [4- [ (E)-2-

(methylcarbamoyl)vinyl]benzoylglycyl]amino]benzyloxy]-2- methylquinoline was obtained according to a εimiiar manner to that of Example 1. mp : 143-150°C NMR (DMSO-d ₆ , δ) : 2.61 (3H, s) , 2.73 (3H, d,

J=5.5Hz), 3.16 (3H, ε) , 3.57 (IH, dd, J=16.5, 5.5Hz), 3.85 (IH, dd, J=16.5, 5.5Hz), 5.50 (2H, s) , 6.70 (IH, d, J=15.0Hz) ,7.35-7.57 (5H, ) , 7.67 (2H, d, J=8.5Hz), 7.79 (2H, s) , 7.87 (2H, dd, J=8.5, 1.0Hz), 8.11 (IH, q, J=5.5Hz), 8.22 (IH, d,

J=3.5Hz), 8.72 (IH, t, J=5.5Hz)

its hydrochloride mp : 160-168°C NMR (DMSO-d ₆ , δ) : 2.72 (3H, d, J=4.0Hz), 2.89 (3H, s), 3.16 (3H, ε), 3.46-3.79 (IH, ) , 3.93 (IH, dd, J=16.5, 5.5Hz), 5.59 (IH, d, J=10.5Hz), 5.65 (IH, d, J=10.5Hz), 6.70 (IH, d, J=16.0Hz), 7.45 (IH, d, J=16.0Hz), 7.64 (2H, d, J=8.5Hz), 7.77-7.97 (8H, m) , 8.18 (IH, q, J=4.0Hz), 8.76 (IH, t, J=5.5Hz),

8.94 (IH, m)

Example 81

8- [2, 6-Dichloro-3- [N- [4- [ (E) -2- (methoxycarbonyl)vinyl]- benzoylglycyl]-N-methylamino]benzyloxy]-2-methylquinoline waε obtained from 8-[3- (N-giycyl-N-methylamino) -2, 6- dichlorobenzyloxy]-2-methylquinoline and methyl 4-carboxycinnamate according to a εimiiar manner to that of Example 1. NMR (CDC1 ₃ , δ) : 2.73 (3H, s), 3.27 (3H, ε), 3.70 (IK, dd, J=16.5, 4.5Hz), 3.81 (3H, ε), 4.00 (IH, dd, J=16.5, 4.5Hz), 5.63 (2K, s) , 6.50 (IH, d, J=l6.0Hz), 7.19 (IH, t, =4.5Hz), 7.23-7.34 (3K, m) , 7.37-7.51 (3H, m) , 7.57 (2H, d, J=8.5Hz), 7.69 (IH, d, J=16.0Hz), 7.82 (2H, d, J=8.5Hz), 8.02 (IK, d, J=8.5Hz)

itε hydrochloride mp : 171-175°C NMR (DMSO-d ₆ , δ) : 2.88 (3H, ε), 3.17 (3H, s) , 3.64

(IH, dd, J=16.5, 5.5Hz), 3.76 (3H, s) , 3.92 (IH, dd, J=16.5, 5.5Hz), 5.59 (IH, d, J=11.5Hz), 5.66 (IH, d, J=11.5Hz), 6.76 (IH, d, J=16.0Hz), 7.71 (IH, d, J=16.0Hz), 7.78-7.97 (10H, m) , 8.82 (IH, t, J=5.5Hz), 8.92 (IH, m)

Example 32

8-[3-[N-[ (E)-3-[6- (Acetamido)pyridin-3- yi]acryloylglycyl]-N-methylamino]-2, 6-dichlorobenzyloxy]-2- methyl-4-morpholinoquinoline was obtained from 8-hydroxy-2- methyl-4-morpholinoquinoline and 3- [N- [ (E) -3- [6- (acetamido)pyridin-3-yl]acryloylglycyl]-N-methylamino]-2, 6- dichlorobenzyl chloride according to a similar manner to that of Example 9. NMR (CDCI3, δ) : 2.21 (3H, s), 2.67 (3H, s), 3.15-

3.23 (4H, ) , 3.36 (3H, ε), 3.70 (IH, dd, J=17, 4Hz), 3.88-4.01 (5H, m) , 5.58 (IH, d, J=10Hz) , 5.63 (IH, d, J=10Hz), 6.47 (IH, d, J=15Kz) , 6.39-6.79 (2K, ) , 7.19-7.28 (IH, overlapped with CDCI ₃ ) , 7.30 (IK, d, J=3Hz), 7.37 (IH, t, J=8Hz), 7.47 (IH, d, J=8Hz), 7.51 (IH, d, J=15Hz), 7.65 (IH, a, J=8Hz), 7.80 (IH, br d, J=8Hz) , 8.09 (IH, br ε), 8.19 (IH, br d, J=8Hz) , 8.33 (IH, br s)

Example 83

(1) 8- [N-tert-Butoxycarbonyl-N- [2, 6-dichloro-3- [N-methyl-N- [N'~ (4-pyridyl)ureidoacetyl] amino]benzyl] amino] -2- methylquinoline waε obtained by reacting 3- [N- [3- (N-glycyl-N- merhyla ino) -2, 6-dichlorobenzylj-N-tert-butoxycarbonylamino] - 2-methylσuinoline with phenyl 4-pyridylcarbamate according to a εimiiar manner to that of Example 19.

NMR (CDCI3, δ) : 1.21, 1.72 (9H, s), 2.72 (3H, s),

3.08, 3.12 (3H, s), 2.80, 3.26, 3.60-3.80 (2H, m) , 5.03-5.18, 5.58-5.70 (2H, m) , 6.20 (IH, m) , 6.83, 6.95 (IH, ) , 7.18 (4H, br) , 7.36 (IH, m) , 7.60

(IH, m) , 7.90-8.05 (2H, ) , 8.29 (2H, br)

(2) 8- [2, 6-Dichloro-3- [N-methyl-N- [N*- (4-pyridyl) - ureidoacetyl] amino]benzylamino]-2-methylquinoline trihydrochloride waε obtained according to a similar manner to that of Example 73- (4) . NMR (CDCI3-CD3OD, δ) : 2.85 (3H, s), 3.29 (3H, ε),

3.40, 3.61-3.71, 3.84, 3.90 (2H, m) , 4.86 (2H, m) , 7.13 (IH, m) , 7.28 (IH, m) , 7.46-7.60 (5H, m) , 7.97 (2H, m) , 8.48 (2H, d, J=8Hz)

Example 84 (1) 8- [2, 6-Dichloro-3-[ (phthaloyl-DL-alanyl) amino] - benzyloxy] -2-methylquinoline waε obtained from 8- (3- amino-2, 6-dichlorobenzyloxy) -2-methylσuinoline and 2-

- 240 - phthalimidopropionyl chloride according to a εimiiar manner to that of Preparation 9. mp : 98-100°C (dec.)

NMR (CDC1 ₃ , δ) : 1.75 (3H, d, J=6Hz), 2.72 (3H, ε), 5.14 (IH, q, J=6Hz) , 5.60 (2K, ε), 7.20 (IH, d, 7.23-7.43 (4H) , 7.76 (2H, dd, J=8, 2Hz) , 7.89 (2H, dd, J=8, 2Kz) , 8.00 (IK, d, J=8Hz) , 8.32-8.39 (2H)

(2) 8-[2, 6-Dichloro-3-[N-methyl-N- (phthaloyl-DL-alanyl)- amino]benzyloxy]-2-methylquinoline waε obtained according to a similar manner to that of Preparation 10. p : 169-171°C

NMR (CDCI3, δ) : 1.56 (0.9H, d, J=6Hz), 1.59 (2.1H, d, J=6Hz), 2.70 (0.9H, ε), 2.73 (2.1H, s), 3.21

(3H, s), 4.77-4.92 (IH), 5.00 (0.3H, d, J=10Hz) , 5.28 (0.3H, d, J=10Hz), 5.64 (0.7H, d, J=10Hz) , 5.70 (0.7H, a, J=10Hz), 7.00-8.06 (11H)

(3) 8-[3- (N-DL-Alanyl-N-methylamine)-2, 6-dichIorobenzyloxy]-

2-methylquinoline was obtained according to a similar manner to that of Preparation 11.

NMR (CDCI3, δ) : 1.08-1.16 (3K), 2.73 (0.9H, ε), 2.75 (2.1H, ε), 3.14 (0.7H, q, J=6Hz), 3.21 (3H, ε) , 3.35 (0.3H, q, J=6Hz) , 5.60-5.72 (0.6H), 5.66

(1.4H, s), 7.22-7.51 (6H), 8.03 (IH, d, J=8Hz)

(4) 8-[2, 6-Dichloro-3-[N-methyl-N-[4-(methylcarbamoyl) - cinnamoyl-DL-alanyl]amino]benzyloxy]-2-methylquinoline waε obtained according to a εimiiar manner to that of Example 1.

NMR (CDCI3, δ) : 1.20 (1.8H, d, J=7Hz) , 1.27 (1.2H, d, J=7HZ), 2.70 (1.2H, s), 2.72 (1.8H, s), 2.95-3.03 (3H, in) , 3.23 (3H, s), 4.43-4.51 (0.4H, m) , 4.51- 4.63 (0.6H, m), 5.53-5.73 (2H, m) , 6.17-6.30 (IH,

- 241 - ) , 6.40-6.70 (2H, m) , 7.18-7.35 (2H, ) , 7.35-7.63 (7H, ) , 7.63-7.80 (2H, m) , 8.02 (IH, d, J=8Hz)

Example 85 (1) 8-[3-[ (3-Bromopropionyl)amino]-2, 6-dichIorobenzyloxy]-2- methylquinoline waε obtained from 8- (3-amino-2, 6- dichlorobenzyloxy) -2-methylquinoline and 3- bromopropionyl chloride according to a εimiiar manner to that of Preparation 9.

NMR (CDC1 ₃ , δ) : 2.70 (3H, s) , 2.99 (0.4H, t, J=6Hz) , 3.11 (1.6H, t, J=6Hz), 3.68 (1.6H, t, J=6Hz), 3.86 (0.4H, t, J=6Hz), 5.53 (2H, br s), 7.20-7.48 (6H), 8.00-8.09 (IH), 8.30-8.50 (IK)

(2) To a solution of 8- [3-[ (3-bromoproρionyl)amino]-2, 6- dichlorobenzyloxy]-2-methylquinoline (2.08 g) in anhydrous dimethylformamide (21 ml) was added potassium phthalimide (905 mg) and the mixture was stirred at 100°C for 1.5 hours. To this reaction mixture were added ethyl acetate (105 ml) and water (105 mi) and the mixture was stirred for 1 hour under ice-water cooling. The precipitate waε collected by filtration and waεhed with ethyl acetate and water to give 8-[2, 6-dichloro-3- [ (3-phthalimidopropionyl)amino]benzyloxy]- 2-methylquinoline (1.49 g) aε a grey powder. NMR (CDCI3, δ) : 2.70 (3H, s), 2.90 (2H, t, J=6Hz) ,

4.12 (2H, t, J=6Hz), 5.53 (2H, ε), 7.18-7.45 (6H), 7.72 (2H, dd, J=8, 2Hz) , 7.86 (2H, dd, J=8, 2Hz) , 8.03 (IH, d, J=8Hz), 8.15-8.22 (IH)

(3) 8-[2, 6-Dichloro-3-[N-methyl-N- (3-phthalimidopropionyl)- amino]benzyloxy]-2-methylquinoline waε obtained according to a similar manner to that of Preparation 10. mp : 176-177°C NMR (CDCI3, δ) : 2.25-2.52 (2K) , 2.70 (3H, s), 3.18 (3H, s), 3.86-4.04 (2H) , 5.61 (2H, ε), 7.20-7.46

- 242 -

( 6H) , 7 . 68 (2H, dd, J=8 , 2Hz ) , 7 . 80 ( 2H, dd, J=8 , 2Hz ) , 8 . 00 ( IH, d, J=8Hz )

(4) 8- [3- [N- (3-Aminopropionyl) -N-methylamino]-2, 6- dichlorobenzyloxy] -2-methylquinoline waε obtained according to a εimiiar manner to that of Preparation 11. NMR (CDC1 ₃ , δ) : 1.96-2.21 (2K, ) , 2.73 (3H, ε), 2.81-2.98 (2H, m) , 3.18 (3H, s) , 5.64 (2H, s), 7.20-7.33 (3H, m) , 7.33-7.50 (3H, n) , 8.02 (IH, d, J=8Hz)

(5) 8- [2, 6-Dichloro-3- [N-methyl-N- [3- [4- (methylcarbamoyl) - cinnamoylamino]propionyl] amino]benzyloxy] -2- methylquinoline was obtained according to a similar manner to that of Example 1.

NMR (CDCI3, δ) : 2.03-2.18 (IH, m) , 2.18-2.33 (IH, ) , 2.67 (3H, s) , 2.98 (3H, d, J=6Hz) , 3.17 (3H, s), 3.51-3.64 (2H, m) , 5.62 (2H, s) , 6.32-6.42 (IH, ) , 6.42 (IH, d, J=15Hz) , 6.73 (IH, t-like), 7.17- 7.31 (3H, m) , 7.34-7.51 (5H, m) , 7.55 (IH, d,

J=15Hz), 7.73 (2H, d, J=8Hz), 8.01 (IH, d, J=8Hz)

(6) 8- [2, 6-Dichloro-3- [N- [3- [N'- [3- (4-pyridylcarbamoyl) - phenyl]ureido]propionyl] -N-methylamino]benzyloxy] -2- methylquinoline was obtained according to a similar manner to that of Example 19. NMR (CDCI3, δ) : 2.23-2.33 (IH, m) , 2.33-2.45 (IH, m) , 2.53 (3H, s) , 3.10 (3H, s) , 3.21-3.41 (IH, m) ,

3.41-3.57 (IH, m) , 5.46 (IH, d, J=10Hz), 5.57 (IH, d, J=10Hz), 5.82 (IH, br peak), 7.03-7.17 (IH, m) ,

7.17-7.34 (4H, ) , 7.43-7.52 (3H, ir.) , 7.67 (2H, d, J=6Hz), 7.79 (IH, br ε), 8.08 (IH, a, J=8Hz) , 8.45 (2H, d, J=6Hz), 8.53 (IK, br s), 9.37 (IH, br s)

Example 86

8- [3- [N- [N'- (3-Aminophenyl) ureidoacetyl] -N-methylamino] • 2, 6-dichlcrobenzyloxy] -4-dimethylamino-2-methylquinoline waε obtained from 8- [2, 6-dichloro-3- [N-methyl- [N- [N*- (3- nitrophenyl) ureidoacetyl] amino]benzyloxy] -4-dimethylamino-2- methylquinoline according to a similar manner to that of Preparation 15.

NMR (CDC1 ₃ , δ) : 2.43 (3H, ε), 3.10 (6H, br peak), 3.20 (3H, ε), 5.43 (IH, d, J=10Hz) , 5.61 (IH, d, J=10Hz), 6.22 (IH, d, J=8Hz), 6.49 (IH, d, J=8Hz) , 6.61 (IH, s-like), 6.75-6.88 (2H, m) , 7.15-7.47

(7K, m) , 7.63-7.71 (2H, m)

Example 87

8- [2, 6-Dichloro-3- [N- [N'~ (3-isonicotinamidophenyl) - ureidoacetyl] -N-methylamino]benzyloxy] -4-dimethylaminc-2- methylquinoline waε obtained from 8- [3- [N- [N ^? - (3- aminophenyl)ureidoacetyl] -N-methylamino] -2, 6- dichlorobenzyloxy]-4-dimethyiamino-2-methylquinoline and iεonicotinoyl chloride hydrochloride according to a εimiiar manner to that of Example 52.

NMR (CDCI3, δ) : 2.43 (3H, ε), 3.03 (6H, s) , 3.11

(3H, ε), 3.74-4.08 (2H, ) , 5.43 (IH, a, J=10Hz) , 5.53 (IK, d, J=10Hz), 6.61 (IH, s) , 6.89 (IH, br peak), 7.03 (IH, t-like), 7.08-7.33 (4H, m) , 7.40 (IH, t, J=8Hz), 7.44-7.55 (IH, m) , 7.55-7.88 (5H, m) , 8.65 (2H, d, J=6Hz) , 8.90 (IH, br s)

its trihydrochloride

NMR (DMS0 ₆ , δ) : 2.65 (3H, s) , 3.14 (3H, s) , 3.41 (6K, s), 3.75 (IH, br d, J=18Hz) , 5.56 (2H, s) ,

6.48 (IH, br s) , 6.91 (IH, s), 7.18-7.25 (2H, ) , 7.25-7.33 (IH, ) , 7.58 (IH, t, J=8Hz) , 7.75 (IH, d, J=8Hz), 7.81 (2H, s-like), 7.88 (IH, s-like), 7.93 (IH, d, J=8Hz), 8.03 (2H, d, 3=6Hz ) , 8.88 (2K, d, J=6Hz), 9.08 (IH, s) , 10.61 (IH, s)

Example 88

8- [2, 6-Dichloro-3- [N-methyl-N- [N'- [4- [N- (4- pyridyl) carbamoyl]phenyl]ureidoacetyl] amino]benzyloxy] -2- ethylquinoline and its dihydrochloride was obtained from 8- [2, 6-dichloro-3- [N-methyl-N- [N'~ (4- carboxyphenyi)ureidoacetyl] amino]benzyloxy] -2-methylquinoline and 4-aminopyridine according to a similar manner to that of Example 7.

Example 89

3- [2, 6-Dichloro-3-[N-methyI-N-[N'-[4-[N- (4- pyridylmethyl) carbamoyl]phenyl] reidoacetyl] amino]benzyloxy] - 2-methylquinoline was obtained from 8- [2, 6-dichlorc-3- [N- methyl-N- [N'~ (4-carboxyphenyl) ureidoacetyl] amino]benzyloxy] - 2-methylquinoline and 4-aminomethylpyridine according to a similar manner to that of Example 7.

NMR (CDC1 ₃ , δ) : 2.56 (3H, s), 3.17 (3H, br) , 3.49- 3.82 (2H, si), 4.54 (2H, br) , 5.47 (IH, d, J=8Hz) , 5.57 (IH, ) , 7.15 (2H, br) , 7.23-7.33 (5H, m) , 7.46 (2H, br), 7.6C (2H, a, J=8Kz) , 8.08 (IH, ) ,

8.46 (2H, br), 8.93 (IK, br)

its dihydrochloride

NMR (CD ₃ OD, δ) : 3.00 (3H, s) , 3.28 (3H, ε), 3.80 (2H, m) , 4.84 (2H, br) , 5.70 (IH, d, J=8Hz) , 5.84

(IH, d, J=8Hz), 7.49 (2H, d, J=8Hz) , 7.73 (2H, d, J=4Hz), 7.84 (2H, m) , 7.91 (4H, m) , 8.04 (2H, d, J=8Hz), 8.78 (2H, d, J=8Hz), 9.03 (IH, m)

Example 90

(1) To a εuspension of 2-amino-3-benzyloxypyridine (5.01 g) in polyphosphoric acid (40 ml) was dropwise added ethyl acetoacetate (6.51 g) at 6C°C, and the mixture was warmed at 100°C for 3 hours. The mixture was poured into ice water, neutralized with sodium hydroxide and extracted with

chloroform. The extract waε washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (methanol-chloroform) to give 9-hydroxy-2-methyl-4H-pyrido [1, 2-a]pyrinidin-4-one (880 mg) . p : 146.3°C

NMR (CDC1 ₃ , δ) : 2.46 (3H, s), 6.30 (IH, s), 7.00

(IH, t, J=8Hz), 7.13 (IH, d, J=3Hz), 8.51 (IH, d, J=8Hz)

(2) 9- [2, 6-Dimethyl-3- [N-methyl-N- [4- (methylcarbamoyl) - cinnamoylglycyl] amino]benzyloxy] -2-methyl-4H-pyrido- [1, 2-a]pyrimidin-4-one waε obtained according to a εimiiar manner to that of Example 9. NMR (CDCI3, δ) : 2.31 (3H, s) _. 2.45 (3H, s), 2.49

(3K, s), 3.00 (3H, d, J=5Hz), 3.25 (3H, s) , 3.63 (IH, dd, J=17, 5Hz), 3.82 (IH, dd, J=17, 4Hz) , 5.27 (2H, s), 6.23 (IH, br q, J=5Hz) , 6.36 (IH, s) , 6.51 (IH, d, J=15Hz), 6.73 (IH, br t, J=5Hz), 7.05 (IH, z , 3=8Hz ) , 7.10 (IH, d, J=9Hz), 7.17 (IH, d,

J=9Hz), 7.21 (IH, d, J=8Hz), 7.51 (2K, d, J=9Hz) , 7.55 (IH, d, J=15Hz), 7.74 (2H, d, J=9Hz) , 8.74 (IH, d, J=8Hz)