CA2150345A1 - Quinoxaline derivative as antidiabetic agent - Google Patents

Quinoxaline derivative as antidiabetic agent

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Publication number
CA2150345A1
CA2150345A1 CA002150345A CA2150345A CA2150345A1 CA 2150345 A1 CA2150345 A1 CA 2150345A1 CA 002150345 A CA002150345 A CA 002150345A CA 2150345 A CA2150345 A CA 2150345A CA 2150345 A1 CA2150345 A1 CA 2150345A1
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Prior art keywords
group
lower alkyl
optionally
alkyl group
formula
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Abandoned
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CA002150345A
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French (fr)
Inventor
Makoto Komatsu
Hideaki Sato
Shinichi Taira
Masahiro Miyake
Kiyohiko Magata
Hidehiro Yoshida
Atsunori Ueyama
Takao Nishi
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Otsuka Pharmaceutical Co Ltd
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Individual
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Publication of CA2150345A1 publication Critical patent/CA2150345A1/en
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Endocrinology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
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  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Quinoxaline derivatives of formula (1), and salts thereof, which have excellent antidiabetic activity, and an antidiabetic agent comprising as an active ingredient the quinoxaline derivative or a pharmaceutically acceptable salt thereof.

Description

DEMANDES OU BREVETS VOLUMINEUX

LA PRÉSENTE PARTIE DE CETTE DEMANDE OU CE BREVET
COMPREND PLUS D'UN TOME.

CECI EST LE TOME _ L DE ,~

NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets ~ 1 5 0 JUMBO APPLICATIONS/PATENTS

THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE
THAN ONE VOLUME

NOTE: For additional volumes please contact the Canadian Patent Offics wo 95/09159 2 1 5 0 3 4 5 PCT/JP94/OlSS9 DESCRI PTION

QUINOXALINE DERIVAlIVE AS ANTIDIA~ElIC AGENT
Technical Field The present invention relates to an antidiabetic agent.
Background Art Various quinoxaline derivatives have been known. For example, BE-764998 (= JP-A-46-4377) discloses that the following sulfonylureas are useful as hypoglycemic agents.
/=\
R-CO-NH-CH2CH2 ~ SO2NHCONHR2 wherein R is a group of the formula:

~X ~
and R2 is alkyl, alkenyl, cycloalkyl, etc. Said compounds are similar to the compounds of this invention in the basic structure and also in the pharmacological activity but are distinguished from the compounds of this invention in the substituent on the phenyl ring in the substituent -CoNR3R4 at 2 -20 position of quinoxaline ring.
DD-273254-A discloses selective reduction of quinoxaline-di-N -oxide derivatives of the formula:
0~

R ~ ~N COR2 o wherein R1 is H, Cl, methyl, or methoxy, and R2 is OH, alkoxy or ~ -hydroxyethylamino, to give the corresponding N-4-monoxides which are useful 30 as an intermediate for pharmaceuticals and pesticides.
DT-2410852 (= JP-A-50-29583) discloses N-tetrazolyl -quinoxaline-2-carboxamides of the formula:

WO 95/09159 o ~ 45 PCT/JI'94/01559 R6~C ~CONH~/ "N

wherein A is -N=CR2- etc., R2 is H, halogen, alkyl, OR3, NR4R5, etc., and R6 and R7 are H, halogen, alkyl, OR3, NR4R5, etc., which are useful for treating disorders such as asthma, hay-fever, urticaria, eczema or atopic dermatitis.
EP-23785 discloses substituted alkoxy-phenoxy-quinoxaline(s), N -oxide(s) thereof of the formula:
A ()k Y ~ X--CR1R2--(CH2)n W

()m 1 5 wherein A, B, D, E, J, U and V are H, halogen, nitro, CN, amino, mono- or di -substituted amino, alkyl, alkoxy, carbamoyl, etc.; Y and X are O or S; R1 and R2are H, alkyl, alkenyl, etc.; and W is CN, CSNH2, etc., which are useful as pre-and post-emergence selective herbicides. EP-26622 discloses also similar quinoxalinyl-amino-phenoxyalkanoic acids which are useful as pre- and post-20 emergence selective herbicides.
Heterocycles, Vol. 26, No. 3, 1987, pp. 699-711 discloses substituted 2-quinoxalinecarboxamides and their N-oxides of the formula:
()I

~N CONH(CH2)n~
()m wherein R is H or methyl, n is 0 or an integer of 1 to 4,1 and m are 0 or 1, but no 30 pharmacological activity of these compound is mentioned.
J. Chem. Eng. Data, vol. 29, No. 2, pp. 229-231 (1984) discloses quinoxaline compounds of the formula:

WO 95/09159 ~ t 5 ~ 3 4 5 PCI/JP94/01559 (~)1 [~N CO NH (CH2)2- R
( )m wherein I and m are 0 or 1, and R is 2-imidazolyl, 3-indolyl, etc. which have antibacterial activity.
DD-284585-A discloses quinoxaline-1,4-di-N-oxides of the formula:

[~ R2 wherein R1 is H or optionally substituted alkyl, and R2 is H, optionally substituted alkyl, or hydroxyethylcarbamoyl, which are useful as a medicinal feedstuff to protect piglets from gastro-intestinal disorders.
BE-721725 discloses 3-carboxamidoquinoxaline-di-N-(1,4) -oxides of the formula:

~NXCON--~N CH2XCOR4 wherein R1 is H, alkyl, alkoxy, or Cl; R2 and R3 are H, optionally substituted alkyl, or may form with N a 5- or 6- membered heterocyclic ring; X is O or S; and R4 is optionally substituted alkyl or optionally substituted phenyl, which have antibacterial activity. Similar compounds are also disclosed in many literaturessuch as BE-721726, BE-721728, BE-738246, BE-742970, DT-2012743, NL -7305048, BE-846532, GB-1308370, JP-B-46-23264, JP-B-45-24988, and JP-B-45-24989.

2lSo345 WO 95tO9159 PCI/JP94/OlS59 NL-7206031 discloses 2-formyl-3-carbamoyl-quinoxaline 1,4-dioxides of the formula:
0~ .

~N XC i l-Z
o wherein R1 and R2 are H, optionally substituted aliphatic or cycloaliphatic group, or form a 5- to 7-membered ring optionally containing O or S, Z is NOH
or NNHC(Y)R3, which have antimicrobial activity. Similar compounds are also disclosed in many literatures such as BE-856771, DT-2639429, DT-2656783, EP-1618, EP-73390, DE-3230273-A, BE-824065, DT-2501492, BE-828745, US-3948911, US-4039540, DD-268127, DD-268942-A, JP-A-62-120371, JP-A-62-123178, EP-288628-A, JP-A-60-120815, BE-856771, and BE-753582.
DE-3324908-A discloses 2-(N-(2-hydroxyethyl)carbamoyl)-3 -methylquinoxaline 1,4-di-N-oxide of the formula:
o ~N~CONHCH2CH20H

~ N"~CH

which is useful as animal growth promoters. Similar compounds are also disclosed in other many literatures such as EP-142093-A, DT-2907174, JP-A -50-082217, GB-2038824, JP-A-62-174061, and JP-A-62-149670.
NL-7206601 discloses 2,3-disubstituted quinoxaline-1,4-dioxides of the formula:
o ~ ~`X R~

wherein R1 is phenyl optionally substituted by alkyl, alkoxy, halogen or CF3, and R2 is -CoNR3R4 where R3 and R4 are H or alkyl or form together alkylene wo gs/ogls9 2 1 5 0 ~ 4 ~ PCI1JP94/01559 optionally containing O, S or N heteroatom, which are useful as bactericides and amoebicides. Similar compounds are also disclosed in BE-763377, DT -2228802, and BE-904482.
EP-12725 discloses quinoxaline di-N-oxides of the formula:
O

~N CH2CH2N R2R3 wherein R1 is H or alkyl; R2 and R3 are alkyl or NR2R3 forms 4-5C heterocyclic ring optionally substituted by alkyl, and R4 is H, methoxy, methylthio, OH, F, Cl, Br or CN, which are useful as broad-spectrum antimicrobial agents, esp. as veterinary medicaments, and animal growth promoters. Similar compounds are also disclosed in DT-2701707.
CH-619456 discloses 6-phenylthio-quinoxaline-1,4-dioxide derivatives of the formula:
O+

wherein one of A and B is methyl, and the other is -CONHCH2CH2OH, which are useful as animal growth stimulants. Similar compounds are also disclosed in CH-619457 and CH-630908.
DT-2052359 discloses quinoxaline 1,4-dioxides of the formula:

,~ O

R2 ~X ~'X ~ R3 wherein Rl and R2 are each H, alkyl or alkoxy, or form together methylenedioxy; R3 is H, optionally unsaturated aliphatic residue (optionally substituted by CN, COOH, carbamoyl, alkylamino, etc.), a 5- or 6-membered WO 9~;/09159 PCT1JP94/01559 ~S~3 45 cycloaliphatic residue (optionally substituted by alkyl), arylalkyl or furfuryl; R4 is H, or NR3R4 is optionally unsaturated 5- or 6-membered heterocyclic ring optionally substituted by alkyl; and R5 is optionally substituted and optionallyunsaturated aliphatic, cycloaliphatic, araliphatic aromatic or heterocyclic 5 residue, which have antiprotozoal and antibacterial activity. Similar compounds are also disclosed in DT-2052279.
DT-2120501 discloses 3-substituted quinoxaline-2-carboxamido-1,4-dioxides of the formula:
o X~¢ 1~1 CO N R' R "

wherein X is H, methyl, methoxy, CF3, F, Cl, or Br; Y is alkylthio, alkylsulfinyl, or alkylsulfonyl; R' is H or alkyl; and R" is H or alkyl optionally substituted by amino alkylamino, dialkylamino, pyrrolidino, piperidino, etc., which are useful as broad spectrum antibacterial agents, growth stimulants especially for pigs and poultry. Similar compounds are also disclosed in BE-764088, BE-773396, and DT-2212932.
US-3185688 discloses quinoxaline derivatives of the formula:
X~N~COZ

H2N J~N NH2 wherein Z is NR(CH2)nNR1R2, NR(CH2)nOalkyl, NR(CH2)nSalkyl; X and R are H or alkyl; R1 and R2 are alkyl, or NR1 R2 is morpholino, piperidino, pyrrolidino;
and n is 2 - 4, which are useful as tranquilizers. Similar compounds are also disclosed in US-3192212 and FR-2211006.
Disclosure of Invention The antidiabetic agent of the present invention comprises as an active ingredient at least one of quinoxaline derivatives of the formula (1):

WO 95/091592 1 5 0 3 ~ ~ PCT1Jr94/01559 ( l)m ~NXR2 (1) (R1) ~ ~ R4 ()n wherein R1 is hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, a lower alkyl group having optionally a halogen substituent, phenyl group, a morpholino-substituted lower alkyl group or an imidazolyl-substituted lower alkyl group, nandmareeachOor1, ris 1 or2, R3 and R4 are the same or different and each a) hydrogen atom; b) a lower alkyl group; c) a phenyl-lower alkoxycarbonyl group; d) a lower alkanoyloxy-substituted lower alkyl group; e) a lower alkanoyl group; f) a loweralkoxycarbonyl group; g) a lower alkoxy-lower alkyl group; h) a phenoxycarbonyl group; i) a lower alkanoyl-substituted lower alkyl group; j) a 20 lower alkoxycarbonyloxy-substituted lower alkyl group; k) a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring; I)a group of the formula: -E-N(R52)(R53) (in which R52 and R53 are the same or different and each hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or phenyl group, or R52 and R53 may combine together with the nitrogen 25 atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom, E is a lower alkylene group, a group of the formula: -CO-, or a group of the formula: -CO-A- (in which A is a lower alkylene group)); m) a group of the formula:

WO 95/09159 ~ S ~3 ~S PCI/JP94/01559 A Rs4 0~0 5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); n) a group of the formula:
(Rs)p A~

10 (in which A is the same as defined above, p is an integer of 1 to 3, R5 is hydrogen atom, a lower alkoxy-substituted lower alkoxy group, a lower alkoxy group, an amino group having optionally a lower alkyl substituent, a halogen atom, nitro group, hydroxy group, a lower alkyl group having optionally a hydroxy substituent, a lower alkenyloxy group, a carboxyl-substituted lower 15 alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a lower alkoxycarbonyl group, a halogen-substituted lower alkoxy group, a hydroxy -substituted lower alkoxy group, a phenyl-lower alkoxy group having optionally a substituent selected from a lower alkyl group and a lower alkoxy group on the phenyl moiety, a 1,3-dioxolanyl group having optionally a lower alkyl 20 substituent, a lower alkanoyl group, a morpholino-substituted lower alkoxy group, a morpholino-substituted lower alkyl group, a morpholinocarbonyl group or a group of the formula: -Y-A1-CONR6R7 (in which A1 is a lower alkylene group, Y is a group of the formula: -O- or a group of the formula: -NH-, R6 and R7 are the same or different and each hydrogen atom, a lower alkyl group 25 having optionally a hydroxy substituent, a phenyl-lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, a furyl-substituted lower alkyl group, or a lower alkoxy-substituted lower alkyl group, or R6 and R7may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being 30 intervened with nitrogen atom or oxygen atom, said heterocyclic group having optionally 1 to 3 substituents selected from hydroxy group, a lower alkyl group and a phenyl-lower alkyl group)); o) a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an WO 95/09159 2 1 5 0 3 ~ 5 PCTIJP94/01559 amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula: -O -A4-CO-NR40R41 (in which A4 is a lower alkylene group, R40 and R41 are the same or different and each hydrogen atom or a lower alkyl group, or R40 and R41 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety; p) an alkenyl group; q) a cycloalkyl-lower alkyl group; r) a naphthyl-lower alkyl group; s) a phenylthio-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; t) a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; u) a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; v) a phenoxy-substituted lower alkyl group; w) a group of the formula:
(R8)q ~
(in which q is an integer of 1 to 3, a group of the formula:

is a lower alkyl group substituted by a 5- to 1 4-membered saturated or 25 unsaturated heteromonocyclic, heterobicyclic or heterotricyclic group having 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, R8 substitutes on the above heterocyclic group, and is hydrogen atom, oxo group, a lower alkyl group having optionally a hydroxy substituent, a halogen atom, nitro group, a lower alkoxy group, cyano group, a lower alkoxycarbonyl group, 30 a phenyl-lower alkoxy group having optionally an amino group having optionally a lower alkanoyl substituent on the phenyl moiety, a carboxyl -substituted lower alkoxy group, carboxyl group, a lower alkoxycarbonyl -substituted lower alkoxy group, hydroxy group, a lower alkoxy-substituted lower ,2150345 alkoxy group, a lower alkenyloxy group, a lower alkanoyloxy-substituted lower alkyl group, a halogen-substituted lower alkyl group, a lower alkanoyl group, a phenyl group having optionally a substituent selected from a lower alkyl group, a lower alkoxy-substituted lower alkoxy group, hydroxy group, a halogen atom 5 and a lower alkoxy group on the phenyl moiety, a lower alkenyl group, a morpholinocarbonyl-lower alkoxy group, a lower alkylsufinyl group, an amino -substituted lower alkyl group having optionally a substituent selected from a lower alkylsulfonyl group and a lower alkanoyl group, a lower alkylthio group, alower alkylsulfonyl group, a lower alkanoyloxy group, a 1,3-dioxolanyl -10 substituted lower alkyl group having optionally a lower alkyl substituent, alower alkanoyl-substituted lower alkyl group, an aminocarbonyl-substituted lower alkyl group having optionally a lower alkyl substituent, a lower alkoxycarbonyl-substituted lower alkenyl group, an aminocarbonyl-substituted lower alkenyl group having optionally a lower alkyl substituent, a carboxyl -15 substituted lower alkenyl group, benzoyl group, a lower alkoxy-lower alkyl group, a group of the formula:
(R45)s 20 (in which s is an integer of 1 to 3, a group of the formula:

is a 5- to 6-membered saturated or unsaturated heterocyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, R45 25 bonds to said heterocyclic group and is hydrogen atom, a lower alkyl group, alower alkoxy-substituted lower alkyl group, phenyl group or oxo group), a group of the formula:
(R46) ~<
~) (in which t is an integer of 1 to 3, a group of the formula:

WO 95/09159 2 1 5 0 3 ~ ~ PCI/JP94/01559 is a lower alkyl group substituted by a 5- to 6-membered saturated or unsaturated heterocyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, R46 bonds to said heterocyclic group and is hydrogen atom, a lower alkyl group or oxo group), or a group of the formula: -(C=O)INR9R10 (in which I is 0 or 1, R9 and R10 are the same or different and each hydrogen atom, a lower alkanoyl group, a lower alkyl group, a morpholinocarbonyl-lower alkyl group, a cycloalkylcarbonyl group, a phenyl -lower alkenylcarbonyl group, a lower alkyisulfonyl group, an aminocarbonyl group having optionally a lower alkyl substituent, a phenylsulfonyl group having optionally a lower alkyl substituent on the phenyl moiety, a phenyl-loweralkenyl group, a benzoyl group having optionally 1 to 3 substituents selected from a halogen atom, a lower alkoxy group, an amino group having optionally a lower alkanoyl substituent and hydroxy group on the phenyl moiety, an amino -substituted lower alkanoyl group having optionally a lower alkanoyl substituent,an amino-substituted sulfonyl group having optionally a lower alkyl substituent,a phenyl-lower alkyl group, phenyl group, or an amino group having optionally a lower alkanoyl substituent, or R9 and R10 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom)); x) a group of the formula: -AS-CR42R43R44 (in which A5 is a lower alkylene group, R42 and R43 combine together to form a group of the formula: =O, or =N-OH or a lower alkylenedioxy group, and R44 is a phenyl group having optionally a lower alkoxy substituent on the phenyl moiety); y) a 2,3-dihydro-1H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring; or z) a group of the formula:
(R47) (in which u is an integer of 1 to 3, a group of the formula:

t ~1.S34S

{~

is a lower alkenyl group substituted by a 5- to 1 4-membered saturated or 5 unsaturated, heteromonocyclic, heterobicyclic or heterotricyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, R47 bonds on said heterocyclic group and is hydrogen atom, a halogen -substituted lower alkyl group, oxo group, a halogen atom, a lower alkoxy group, a lower alkyl group, a lower alkoxycarbonyl group, carboxyl group, an 10 aminocarbonyl group having optionally a lower alkyl substituent, an amino group having optionally a lower alkanoyl substituent, a phenyl group having optionally a substituent selected from a lower alkoxy group and a halogen atom on the phenyl moiety, or a group of the formula:
(R45)s ~

(in which A6, R45 and s are the same as defined above)), or R3 and R4 may combine together with the adjacent nitrogen atom to which they bond to form 1,2,3,4-tetrahydroisoquinolyl group, said heterocyclic 20 group having optionally a lower alkoxy substituent, or a salt thereof.
The present invention provides also novel quinoxaline derivatives of the formula (1 ) as described above wherein all the symbols are the same as defined above except that n is 0 and the group R5 excludes hydrogen atom and 25 further provided that when R1 is hydrogen atom, R2 is methyl group, R3is hydrogen atom, and m is 0, then R4is not 2-(imidazol-2-yl)ethyl, 2-(indol-3 -yl)ethyl, or sec-butyl, and a salt thereof.
According to the diseases determination by WHO, diabetes is 30 caused by the absolute lack of the secretion of insulin and arises either acutely or subacutely, and includes, insulin dependent diabetes mellitus (IDDM) which requires the insulin-treatment, non insulin dependent diabetes mellitus (NIDDM) which does not always require insulin-treatment, malnutrition-related WO 95/OglS9 2 1 5 0 3 4 5 PCT/JP94/01559 diabetes mellitus (MRDM), other complications accompanied with other diseases.
Among the above, a cause of IDDM is estimated to be the destruction of pancreatis 13-cells by auto-immune system. The pancreatis ~ -5 cells are considered to be destroyed by HLA antigen, cytokine virus, etc. (cf.Koji NAKANISHI, Tetsuro KOBAYASHI, Mitsuru HARA; Tonyobyogaku (Diabetology) 1989: edited by Mikinori KOSAKA, Yasuo AKANUMA, Shindan-to-Chiryo sha, 1989, pages 226-244). On the other hand, the cause of NIDDM
is estimated to be (i) congenital anomaly in pancreatin, i.e. anomaly in 10 adaptability to the increase in insulin consumption, or (ii) disorder in insulin activity induced by various factors such as aging, obesity, stress, etc. (Hiroo IMURA; Tonyobyogaku-no-Shinpo (Progress in Diabetology) 1989, No. 23, edited by Japan Diabetology Association, Shindan-to-Chiryo sha, 1989, pages 1 to12).
However, the crisis of diabetes is not simple but happens in complicated situation, such as hereditary factors, environmental factors, etc., and it has not been clarified yet.
In viewpoint of the tissue of the patient of NIDDM, the important causes of hyperglycemia is considered to be the decrease in the uptake of glucose at the peripheral tissue, especially at the muscle, and the increase in glucose secretion at the liver. Hitherto, the most common drug therapy for diabetes is treatment with insulin or sulfonylurea agent (agent for promotion ofinsulin secretion), which are both based on the supplement of insulin, but thesetreatment have difficulty in strict blood glucose level control, and sometimes they induce hyperinsulin serum or hypoglycemia. Accordingly, it has been considered that a compound which promotes the uptake of glucose at the muscle without promoting the secretion of insulin would be a new kind of hypoglycemic agent without hyperinsulinism nor hypoglycemia and would be useful for treatment of diabetes.
The quinoxaline derivatives of the above formula (1 ) and salts thereof (hereinafter referred to as the compounds of the present invention) promote the uptake of 2-deoxyglucose (2DG) against L6 cells, cell line of rat WO 95tO91S9 PCT/JP94101559 ?t~503 ~5 striated muscle (muscular cells) and also promote the consumption of glucose by which they show hypoglycemic activity. Especially, the compounds of the present invention show hypoglycemic activity in db/db mice and KK-Ay mice, which are diabetic animal model (L. Herberg, D.L. Coleman: Metabolism, vol.
26, No. 1 (January), 1977, pp. 59-99). The compounds of the present invention promote the uptake of glucose at the muscle and do not affect the insulin secretion and the glucose release at the liver so that they do not show acute hypoglycemic activity and do not affect oral glucose tolerance test.
Accordingly, the antidiabetic agent of the present invention is useful for treatment of diabetes and diabetic complications such as diabetic blood vessel disorder, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, etc.
Each group in the above formula (1 ) specially means the following groups.
The lower alkyl group includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl,butyl, tert-butyl, pentyl, hexyl, etc.
The halogen atom is fluorine atom, chlorine atom, bromine atom or iodine atom.
The lower alkyl group having optionally a halogen substituent includes, for example, in addition to the above mentioned lower alkyl groups, a straight chain or branched chain alkyl group having 1 to 6 carbon atoms having optionally 1 to 3 halogen substituents, such as trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromo -methyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2 -methylpropyl, 5-bromohexyl, 5,6-dichlorohexyl, 5-bromohexyl, 5,6-dichloro-hexyl, etc.
The morpholino-substituted lower alkyl group includes a morpholino-substituted alkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, morpholinomethyl, 2-morpholinoethyl, 1-morpholinoethyl, 3-(2-morpholinyl)-propyl, 4-(3-morpholinyl)butyl, 1,1-dimethyl-2-(2-morpholinyl)ethyl, 5-WO 95109159 2 1 ~ O ~ 4 ~ PCTIJP94101559 morpholinopentyl, 6-morpholinohexyl, 2-methyl-3-morpholinopropyl, etc.
The imidazolyl-substituted lower alkyl group includes an imidazolyl-substituted alkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, (1 -imidazolyl)methyl, 2-(1-imidazolyl)ethyl, 1-(2-imidazolyl)ethyl, 3-(4-imidazolyl)-propyl, 4-(5-imidazolyl)butyl, 1,1-dimethyl-2-(2-imidazolyl)ethyl, 5-(4-imidazolyl)pentyl, 6-(1-imidazolyl)hexyl, 2-methyl-3-(1-imidazolyl)propyl, etc.
The lower alkylene group includes a straight chain or branched chain alkylene group having 1 to 6 carbon atoms, for example, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1 -methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene, etc.
The lower alkoxy group includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.
The amino group being optionally substituted by a lower alkyl group includes an amino group which may optionally be substituted by 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino, and the like.
The lower alkyl group having optionally a hydroxy substituent includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which may optionally have 1 to 3 hydroxy substituents, for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyisopropyl, 3-hydroxy-propyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4 -trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 2-methyl-3-hydroxypropyl, 2,3-dihydroxyethyl, 3,4-dihydroxybutyl, 5,6-dihydroxyhexyl, and the like.
The lower alkenyloxy group includes a straight chain or branched chain alkenyloxy group having 2 to 6 carbon atoms, for example, allyloxy, 2 -butenyloxy, 3-butenyloxy, 1-methylallyloxy, 2-pentenyloxy, 2-hexenyloxy, and W095/09159 . 215~1~4S pCTlJP94/01559 the like.
The carboxy-substituted lower alkoxy group includes a carboxy -alkoxy group wherein the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, carboxymethoxy, 2 -carboxyethoxy, 1-carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy, 5 -carboxypentyloxy, 6-carboxyhexyloxy, 1,1-dimethyl-2-carboxyethoxy, 2-methyl -3-carboxypropoxy, and the like.
The lower alkoxycarbonyl-substituted lower alkoxy group includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, methoxy -carbonylmethoxy, 3-methoxycarbonylpropoxy, ethoxycarbonylmethoxy, 3-ethoxycarbonylpropoxy, 4-ethoxycarbonylbutoxy, 5-isopropoxycarbonyl-pentyloxy, 6-propoxycarbonylhexyloxy, 1,1-dimethyl-2- butoxycarbonylethoxy, 2-1 5 methyl-3-tert-butoxycarbonylpropoxy, 2-pentyloxycarbonylethoxy, hexyloxy - carbonylmethoxy, and the like.
The lower alkoxycarbonyl group includes a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like.
The halogen-substituted lower alkoxy group includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which has 1 to 3 halogen substituents, for example, trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3 -chloropropoxy, 2,3-dichloropropoxy, 4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5 -chloropentyloxy, 3-chloro-2-methylpropoxy, 5-bromohexyloxy, 5,6-dichloro-hexyloxy, 5-bromohexyloxy, 5,6-dichlorohexyloxy, and the like.
The hydroxy-substituted lower alkoxy group includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by 1 to 3 hydroxy groups, for example, hydroxymethoxy, 2-hydroxy -ethoxy, 1-hydroxyethoxy, 1-hydroxypropoxy, 3-hydroxypropoxy, 2,3-dihydroxy-WO 95/09159 2 1 5 0 3 ~ 5 PCT/JP94101559 propoxy, 4-hydroxybutoxy, 1,1-dimethyl-2-hydroxyethoxy, 5,5,4-trihydroxy-pentyloxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy, 1-hydroxyisopropoxy, 2-methyl-3-hydroxypropoxy, 2,3-dihydroxyethoxy, 3,4-dihydroxybutoxy, 5,6 -dihydroxyhexyloxy, and the like.
The phenyl-lower alkoxy group having optionally a substituent selected from a lower alkyl group and a lower alkoxy group on the phenyl moiety includes a phenylalkoxy group wherein the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which may optionally have 1 to 3 substituents selected from a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms and a straight chain or branched chain alkyl group having 1 to 6 carbon atoms on the phenyl moiety, for example, benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4 -phenylbutoxy, 1,1-dimethyl-2-phenylethoxy, 5-phenylpentyloxy, 6-phenyl-hexyloxy, 2-methyl-3-phenylpropoxy, 2-(3-methoxyphenyl)ethoxy, 1-(4-methoxyphenyl)ethoxy, 2-methoxybenzyloxy, 3-(2-ethoxyphenyl)propoxy, 4-(3-ethoxyphenyl)butoxy, 1,1-dimethyl-2-(4-ethoxyphenyl)ethoxy, 5-(4-isopropoxy-phenyl)pentyloxy, 6-(4-hexyloxyphenyl)hexyloxy, 3,4-dimethoxybenzyloxy, 3,4,5-trimethoxybenzyloxy, 2,5-dimethoxybenzyloxy, 3-methoxybenzyloxy, 4 -methoxybenzyloxy, 2,4-diethoxybenzyloxy, 2,3-dimethoxybenzyloxy, 2,4 -dimethoxybenzyloxy, 2,6-dimethoxybenzyloxy, 2-methylbenzyloxy, 4-ethyl -benzyloxy, 2-(3-methylphenyl)ethoxy, 1-(4-methylphenyl)ethoxy, 3-(2-ethyl -phenyl)propoxy, 4-(3-ethylphenyl)butoxy, 1,1-dimethyl-2-(4-ethylphenyl)ethoxy, 5-(4-isopropylphenyl)pentyloxy, 6-(4-hexyphenyl)hexyloxy, 3,4-dimethyl-benzyloxy, 3,4,5-trimethylbenzyloxy, 2,5-dimethylbenzyloxy, 2-methoxy-3 -methylbenzyloxy, and the like.
The 1,3-dioxolanyl group having optionally a lower alkyl substituent includes a 1,3-dioxolanyl group which may optionally be substituted by 1 to 3 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms, for example, 1,3-dioxolanyl, 2-methyl-1,3-dioxolanyl, 4-ethyl-1,3 -dioxolanyl, 2-propyl-1,3-dioxolanyl, 4-butyl-1,3-dioxolanyl, 2-pentyl-1,3-dioxolanyl, 4-hexyl-1,3-dioxolanyl, 2,4-dimethyl-1,3-dioxolanyl, 2,4,5-trimethyl -1,3-dioxolanyl, and the like.
The lower alkanoyl group includes a straight chain or branched WO 95tO91S9 PCTIJP94/OlS59 2~,~o3~s chain alkanoyl group having 1 to 6 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, t-butylcarbonyl, hexanoyl, and the like.
The morpholino-substituted lower alkoxy group includes a morpholino-substituted alkoxy group wherein the alkoxy moiety is a straight 5 chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, morpholinomethoxy, 2-morpholinoethoxy, 1-morpholinoethoxy, 3-(2-morpholinyl)propoxy, 4-(3-morpholinyl)butoxy, 1,1-dimethyl-2-(2-morpholinyl) -ethoxy, 5-morpholinopentyloxy, 6-morpholinohexyloxy, 2-methyl-3-morpholino-propoxy, and the like.
The phenyl-lower alkyl group includes a phenyl-alkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1,1-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl, and the like.
The phenyl-lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety includes a phenyl-alkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and may optionally have 1 to 3 straight chain or branched chain alkoxy substituents having 1 to 6 carbon atoms on the phenyl moiety, for example, in addition to the above mentioned phenyl-lower alkyl group, 2-(3 -methoxyphenyl)ethyl, 1-(4-methoxyphenyl)ethyl, 2-methoxbenzyl, 3-methoxy-benzyl, 4-methoxybenzyl, 3-(2-ethoxyphenyl)propyl, 4-(3-ethoxyphenyl)butyl, 1,1-dimethyl-2-(4-ethoxyphenyl)ethyl, 5-(4-isopropoxyphenyl)pentyl, 6-(4-hexyl-oxyphenyl)hexyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 3,4,5-trimethoxy-benzyl, and the like.
The furyl-substituted lower alkyl group includes a furyl-substituted alkyl group wherein the alkyl moiety is a straight chain or branched chain alkylgroup having 1 to 6 carbon atoms, for example, (2-furyl)methyl, 2-(3-furyl)ethyl, 1-(2-furyl)ethyl, 3-(2-furyl)propyl, 4-(3-furyl)butyl, 5-(2-furyl)pentyl, 6-(3-furyl) -hexyl, 1,1-dimethyl-2-(2-furyl)ethyl, 2-methyl-3-(3-furyl)propyl, and the like.
The lower alkoxy-lower alkyl group includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for ,, example, methoxymethyl, 2-ethoxyethyl, 1-methoxyethyl, 3-methoxypropyl, 4 -ethoxybutyl, 6-propoxyhexyl, 5-isopropoxypentyl, 1,1-dimethyl-2-butoxyethyl, 2-methyl-3-tert-butoxypropyl, 2-pentyloxyethyl, hexyloxymethyl, and the like.
The phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl -lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety includes a phenylalkenyl group wherein the alkenyl moiety is a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms and having 1 to 2 double bonds, and the phenyl moiety may opitionally be substituted by 1 to 3 groups selected from a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, a halogen atom, an amino group having optionally 1 to 2 substituents selected from a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms and a phenylalkenylcarbonyl group wherein the alkenylcarbonyl moiety is a straight chain or branched chain alkenylcarbonyl group having 3 to 6 carbon atoms in the alkenylcarbonyl moiety, a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, a tetrazolyl group having optionally a straight chain or branched chain alkyl group having 1 to 6 carbon atoms on the tetrazole ring, hydroxy group, a group of the formula: -O-A4-Co-NR4R41 (A4 is a straight chain or branched chain alkylene group having 1 to 6 carbon atoms, R40 and R41 are the same or different and each hydrogen atom or a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, or R40 and R41 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6 -membered saturated heterocyclic ring with or without being intervened with another nitrogen atom or oxygen atom), a straight chain or branched chain alkylenyloxy group having 2 to 6 carbon atoms, nitro group, and a straight chain or branched chain alkyl group having 1 to 6 carbon atoms having WO9S/09159 , ~,,,ts~34S PCT/JP94/01559 optionally 1 to 3 halogen substituents, for example, styryl, cinnamyl, 4-phenyl-3 -butenyl, 4-phenyl-2-butenyl, 5-phenyl-4-pentenyl, 5-phenyl-3-pentenyl, 5-phenyl-2-pentenyl, 6-phenyl-5-hexenyl, 6-phenyl-4-hexenyl, 6-phenyl-3-hexenyl, 6-phenyl-2-hexenyl, ~-methyl-4-phenyl-3-butenyl, ~-methyl-cinnamyl, ~-methyl-cinnamyl, 5-phenyl-2,4-pentadienyl, 4-phenyl-1,3-butadienyl, 6-phenyl-2,4-hexadienyl, 6-phenyl-2,4-hexadienyl, 6-phenyl-3,5-hexadienyl, 6-phenyl-1,3-hexadienyl, 5-phenyl-1,3-pentadienyl, 3-methoxycinnamyl, 4-methoxycinnamyl, 2-methoxycinnamyl, 4-methoxystyryl, (2-ethoxyphenyl)-2 -butenyl, 5-(3-ethoxyphenyl)-4-pentenyl, a,a-dimethyl-4-ethoxycinnamyl, 5-(4-isopropoxyphenyl)-2,4-pentadienyl, 6-(4-hexyloxyphenyl)-2-hexenyl, 3,4-dimethoxycinnamyl, 3,4,5-trimethoxystyryl, 2,5-dimethoxystyryl, 3-methoxy -styryl, 4-methoxystyryl, 2,4-diethoxystyryl, 2,3-dimethoxycinnamyl, 2,4 -dimethoxycinnamyl, 2,6-dimethoxycinnamyl, 2-nitrocinnamyl, 3-nitrocinnamyl, 4-nitrocinnamyl, 4-(2-nitrophenyl)-3-butenyl, 4-(3-nitrophenyl)-2-butenyl, 5-(2-nitrophenyl)-2-pentenyl, 6-(3-nitrophenyl)-3-hexenyl, 3,4-dinitrocinnamyl, 3,4,5-trinitrocinnamyl, 2-nitrostyryl, 3-nitrostyryl, 4-nitrostyryl, 3-methylcinnamyl, 2 -methylstyryrl, 4-methylcinnamyl, 2-ethylcinnamyl, 4-isopropylcinnamyl, 4-(3 -ethylphenyl)-3-butenyl, a-methyl-4-isopropylcinnamyl, 5-(4-isopropylphenyl)-2-pentenyl, 6-(4-hexylphenyl)-2-hexenyl, 3,4-dimethylcinnamyl, 3,4,5-trimethyl-cinnamyl, 2,5-dimethylcinnamyl, 2-chlorocinnamyl, 3-chlorostyryl, 2-fluoro-cinnamyl, 4-chlorocinnamyl, 2-fluorostyryl, 4-(3-fluorophenyl)-2-butenyl, 5-(4 -fluorophenyl)-2-pentenyl, a,a-dimethyl-2-bromocinnamyl, 6-(3-bromophenyl)-2-hexenyl, 4-bromostyryl, 2-iodocinnamyl, 3-iodostyryl, 3,4-dichlorocinnamyl, 3,5 -dichlorocinnamyl, 2,6-dichlorostyryl, 2,3-dichlorocinamyl, 2,4-dichlorostyryl, 3,4-difluorocinnamyl, 3,5-dibromocinnamyl, 3,4,5-trichlorocinnamyl, 2-methoxy-3-chlorocinnamyl, 3-(4-acetylaminophenyl)-2-butenyl, 3-(2-trifluoromethylphenyl)-2-butenyl, 3-[4-(1-methyltetrazol-5-yl)phenyl]-2-butenyl, 3-(4-cinnamoylamino-phenyl)-2-butenyl, 3-(3-methoxymethoxyphenyl)-2-butenyl, 3-(2-methoxy-phenyl)-2-butenyl, 3-(3-methoxyphenyl)-2-butenyl, 3-(4-trifluoromethylphenyl)-2-butenyl, 3-(3-trifluoromethylphenyl)-2-butenyl, 3-(3-acetylaminophenyl)-2-butenyl, 3-(3-hydroxyphenyl)-2-butenyl, 3-(3-morpholinocarbonylmethoxy-wo 9S/O9lS9 ~ 1 5 0 3 ~ ~ PCT/JP94/OlSS9 .. _ phenyl)-2-butenyl, 3-(3-diethylaminocarbonylmethoxyphenyl)-2-butenyl, 3-[3-(2-methyl-2-propenyloxy)phenyl]-2-butenyl, 4-chloromethylstyryl, 3-bromomethyl-cinnamyl, 4-(2-iodomethylphenyl)-3-butenyl, 4-[4-(2,2,2-trichloroethyl)phenyl]-2-butenyl, 5-(4-aminophenyl)-4-pentenyl, 5-(3-propionylaminophenyl)-2-pentenyl, 6-(2-butyrylaminophenyl)-5-hexenyl, 6-(4-pentanoylaminophenyl)-4-hexenyl, 6-(3-hexanoylaminophenyl)-3-hexenyl, 6-(2,4-diaminophenyl)-2-hexenyl, 2,4,6-triaminocinnamyl, 4-(3-butenoylamino)styryl, 3-(2-pentenoyl -amino)cinnamyl, 4-[2-(4-hexenoylamino)phenyl]-3-butenyl, 4-[4-(4-ethoxy-butoxy)phenyl]-2-butenyl, 3-[4-(N-acetyl-N-cinnamoylamino)phenyl]-2-butenyl, 1 0 5-[2-(6-propoxyhexyloxy)phenyl]-4-pentenyl, 6-[3-(2-pentyloxyethoxy)phenyl]-2 -pentenyl, 6-(4-hexyloxymethoxyphenyl)-5-hexenyl, 6-[2-(1,1-dimethyl-2-butoxy-ethoxy)phenyl]-3-hexenyl, 3-(2,4-dimethoxymethoxyphenyl)-2-butenyl, 3-(2,4,6-trimethoxyphenyl)-2-butenyl, 3-[4-(1-ethyltetrazol-5-yl)phenyl]-2-butenyl, 3-[3-(2-propyltetrazol-5-yl)phenyl]-2-butenyl, 3-[2-(1-butyltetrazol-5-yl)phenyl]-2-butenyl, 3-[4-(2-pentyltetrazol-5-yl)phenyl]-2-butenyl, 3-[3-(1-hexyltetrazol-5-yl)-phenyl]-2-butenyl, 2-hydroxycinnamyl, 3-hydroxycinnamyl, 4-hydroxycinnamyl, 4-(2-hydroxyphenyl)-3-butenyl, 5-(2-hydroxyphenyl)-2-pentenyl, 6-(3-hydroxy-phenyl)-3-hexenyl, 2,4-dihydroxycinnamyl, 3,4,5-trihydroxycinnamyl, 4-hydroxy-cinnamyl, 4-allyloxystyryl, 3-(2-butenyloxy)cinnamyl, 4-[2-(3-butenyloxy)phenyl] -3-butenyl, 5-[3-(2-pentenyloxy)phenyl]-2-pentenyl, 6-[4-(2-hexenyloxy)phenyl]-4-hexenyl, 2,4-diallyloxycinnamyl, 2,4,6-triallyloxystyryl, 3-(2-dimethylamino-carbonylethoxyphenyl)-2-butenyl, 4-[4-(3-butylaminocarbonylpropoxy)phenyl]-3-butenyl, 5-[2-(4-pentylaminocarbonylbutoxy)phenyl]-3-pentenyl, 6-[3-(5-hexyl-aminocarbonylpentyloxy)phenyl]-5-hexenyl, 4-[6-(N-methyl-N-propylamino)-carbonylhexyloxy]styryl, 4-methylaminocarbonylmethoxycinnamyl, 4-(1 -piperidinyl)carbonylmethoxycinnamyl, 3-(1-piperazinyl)carbonylmethoxystyryl, 4-[3-(1-pyrrolidinyl)carbonylmethoxyphenyl]-3-butenyl, 3-(2-methoxy-5-chloro-phenyl)-2-butenyl, 3-(2-methoxymethoxy-5-chlorophenyl)-2-butenyl, 3-(2-hydroxy-5-chlorophenyl)-2-butenyl, and the like.
The alkenyl group includes a straight chain or branched chain alkenyl group with 1 to 3 double bonds having 2 to 12 carbon atoms, for example, vinyl, allyl, 3-methyl-2-butenyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2 -pentenyl, 2-hexenyl, 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 3 ~ PCTJJ~94tO1559 wo gS/oglS9 2~ ~

2-dodecenyl, 2-heptenyl, 3-heptenyl, 3-methyl-4-heptenyl, 2-methyl-5-heptenyl, 4-methyl-2-heptenyl, 3-methyl-1-heptenyl, 1,3-heptadienyl, 1,4-heptadienyl, 1,5-heptadienyl, 1,6-heptadienyl, 2,4-heptadienyl, 2-methyl-2,4-heptadienyl, 2,6-dimethyl-2,4-heptadienyl, 2,5-dimethyl-1,3-heptadienyl, 2,4,6-trimethyl-2,4-heptadienyl, 2-octenyl, 3-octenyl, 4-octenyl, 2-methyl-5-octenyl, 3-methyl-6 -octenyl, 2-methyl-7-octenyl, 1,3-octadienyl, 1,4-octadienyl, 1,5-octadienyl, 1,6 -octadienyl, 1,7-octadienyl, 2,4-octadienyl, 3,7-octdienyl, 4,8-dimethyl-3,7 -octadienyl, 2,4,6-trimetyl-3,7-octadienyl, 3,4-dimethyl-2,5-octadienyl, 3,7 -dimethyl-2,6-octadienyl, 4,8-dimethyl-2,6-octadienyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 2-methyl-5-nonenyl, 2-methyl-6-nonenyl, 2-methyl-7-nonenyl, 2 -methyl-8-nonenyl, 1,3-nonadienyl, 1,4-nonadienyl, 1,5-nonadienyl, 1,6-nonadienyl, 1,7-nonadienyl, 1,8-nonadienyl, 2,4-nonadienyl, 3,7-nonadienyl, 4,8-dimethyl-3,7-nonadienyl, 2,4,6-trimethyl-3,7-nonadienyl, 3,4-dimethyl-2,5-nonadienyl, 4,8-dimethyl-2,6-nonadienyl, 2-decenyl, 3-decenyl, 4-decenyl, 5 -decenyl, 2-methyl-6-decenyl, 3-methyl-7-decenyl, 4-methyl-8-decenyl, 5-methyl -9-decenyl, 1,3-decadienyl, 1,4-decadienyl, 1,5-decadienyl, 1,6-decadienyl, 1,7-decadienyl, 1,8-decadienyl, 1,9-decadienyl, 2-methyl-2,4-decadienyl, 3-methyl -2,5-decadienyl, 4,8-dimethyl-2,6-decadienyl, 2,4,6-trimethyl-3,7-decadienyl, 2,9-dimethyl-3,7-decadienyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undeceyl, 2-methyl-6-undecenyl, 3-methyl-7-undecenyl, 4-methyl-8-undecenyl, 5-methyl-9-undecenyl, 2-methyl-10-undecenyl, 1,3-undecadienyl, 1,4-undecadienyl, 1,5-undecadienyl, 1,6-undecadienyl, 1,7-undecadienyl, 1,8-undecadienyl, 1,9-undecadienyl, 1,10-undecadienyl, 2-methyl-2,4-undecadienyl, 3-methyl-2,5-undecadienyl, 4,8-dimethyl-2,6-undecadienyl, 2,4,6-trimethyl-3,8-undecadienyl, 2,9-dimethyl-3,8-undecadienyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 2-methyl-7-dodecenyl, 3-methyl-8-dodecenyl, 4-methyl-9-dodecenyl, 5-methyl-10-dodecenyl, 6-methyl-11-dodecenyl, 2-methyl-2,4-dodecadienyl, 3-methyl-2,5-dodecadienyl, 4,8-dimethyl-2,6-dodecadienyl, 2,4,6-trimethyl-2,7-dodecadienyl, 2,10-dimethyl-2,8-dodecadienyl, 2,5-dimethyl-3,7-dodecadienyl, 4,8,12-trimethyl-3,7,11-dodeca-trienyl, 1,3,5-heptatrienyl, 2,4,6-octatrienyl, 1,3,6-nonatrienyl, 2,6,8 -dodecatienyl, 1,5,7-undecatrienyl, and the like.
The cycloalkyl-lower alkyl group includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, which is substituted by a cycloalkyl group having 3 to 8 carbon atoms, for example, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 2,2-dimethyl-3-cycloheptylpropyl, 5-cyclooctylpentyl, 6-cyclohexylhexyl, and 5 the like.
The naphthyl-lower alkyl group includes a naphthyl-alkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, a-naphthylmethyl, ~-naphthylmethyl, 2-(a-naphthyl)ethyl, 1-(~-naphthyl)ethyl, 3-(~-naphthyl)propyl, 4-(a-naphthyl)-10 butyl, 2-methyl-3-(a-naphthyl)propyl, 5-(~-naphthyl)pentyl, 6-(a-naphthyl)hexyl, 1,1-dimethyl-2-(~-naphthyl)ethyl, and the like.
The phenylthio-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety includes a phenylthio-alkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group 15 having 1 to 6 carbon atoms and may optionally have 1 to 3 substituents of straight chain or branched chain alkoxy group having 1 to 3 carbon atoms on the phenyl moiety, for example, phenylthiomethyl, 2-phenylthioethyl, 1 -phenylthioethyl, 3-phenylthiopropyl, 4-phenylthiobutyl, 5-phenylthiopentyl, 6-phenylthiohexyl, 1,1-dimethyl-2-phenylthioethyl, 2-methyl-3-phenylthiopropyl, 20 (2-methoxyphenylthio)methyl, (3-methoxyphenylthio)methyl, 2-(4-methoxy-phenylthio)ethyl, 1-(2-ethoxyphenylthio)ethyl, 3-(4-isopropoxyphenylthio)-propyl, 4-(3-pentyloxyphenylthio)butyl, 5-(4-hexyloxyphenylthio)pentyl, 6-(2-butyloxyphenylthio)hexyl, (3,4-dimethoxyphenylthio)methyl, (3-ethoxy-4-methoxyphenylthio)methyl, 2-(2,3-dimethoxyphenylthio)ethyl, 1-(2,6-dimethoxy-25 phenylthio)ethyl, 2-(3,4,5-trimethoxyphenylthio)ethyl, and the like.
The phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety includes a phenylsulfinylalkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl grouphaving 1 to 6 carbon atoms, and may optionally have 1 to 3 substituents of 30 straight chain or branched chain alkoxy group having 1 to 6 carbon atoms on the phenyl moiety, for example, phenylsulfinylmethyl, 2-phenylsulfinylethyl, 1-W095/O91S9 o~4S PCTtJP94/015S9 phenylsulfinylethyl, 3-phenylsulfinylpropyl, 4-phenylsulfinylbutyl, 5-phenyl-sulfinylpentyl, 6-phenylsulfinylhexyl, 1,1-dimethyl-2-phenylsulfinylethyl, 2-methyl-3-phenylsulfinylpropyl, (2-methoxyphenylsulfinyl)methyl, (3-methoxy-phenylsulfinyl)methyl, 2-(4-methoxyphenylsulfinyl)ethyl, 1-(2-ethoxyphenyl-5 suflinyl)ethyl, 3-(4-isopropoxyphenylsulfinyl)propyl, 4-(3-pentyloxyphenyl-sulfinyl)butyl, 5-(4-hexyoxyphenylsulfinyl)pentyl, 6-(2-butyloxyphenylsulfinyl)-hexyl, (3,4-dimethoxyphenylsulfinyl)methyl, 3-ethoxy-4-methoxyphenylsulfinyl)-methyl, 2-(2,3-dimethoxyphenylsulfinyl)ethyl, 1-(2,6-dimethoxyphenylsulfinyl)-ethyl, 2-(3,4,5-trimethoxyphenylsulfinyl)ethyl, and the like.
The phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety includes a phenylsulfonyl-alkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, which may optionally have 1 to 3 substituents of straight chain or branched chain alkoxy group 15 having 1 to 6 carbon atoms on the phenyl moiety, for example, phenylsulfonyl -methyl, 2-phenylsulfonylethyl, 1-phenylsulfonylethyl, 3-phenylsulfonylpropyl, 4-phenylsulfonylbutyl, 5-phenylsulfonylpentyl, 6-phenylsulfonylhexyl, 1,1-dimethyl-2-phenylsulfonylethyl, 2-methyl-3-phenylsulfonylpropyl, (2-methoxy-phenylsulfonyl)methyl, (3-methoxyphenylsulfonyl)methyl, 2-(4-methoxyphenyl-20 sulfonyl)ethyl, 1-(2-ethoxyphenylsulfonyl)ethyl, 3-(4-isopropoxyphenylsulfonyl)-propyl, 4-(3-pentyloxyphenylsulfonyl)butyl, 5-(4-hexyloxyphenylsulfonyl)pentyl, 6-(2-butyloxyphenylsulfonyl)hexyl, 3,4-dimethoxyphenylsulfonylmethyl, 3-ethoxy-4-methoxyphenylsulfonyl)methyl, 2-(2,3-dimethoxyphenylsulfonyl)ethyl, 1-(2,6-dimethoxyphenylsulfonyl)ethyl, 2-(3,4,5-trimethoxyphenylsulfonyl)ethyl, 25 and the like.
The 5- to 14-membered saturated or unsaturated hetero -monocyclic, heterobicyclic or heterotricyclic group having 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyridyl, thienyl, 30 quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazinyl, pyrimidyl, pyridazinyl, pyrrolyl, carbostyril, 3,4-dihydrocarbostyril, 1,2,3,4-tetrahydroquinolyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, benzoxazolyl, imidazolidinyl, isoquinolyl, quinazolidinyl, quinoxalinyl, cinnonyl, phthalazinyl, chromanyl, isoindolinyl, 21~03~

isochromanyl, pyrazolyl, imidazolyl, pyrazolidinyl, 2,3-dihydrobenzofuryl, perhydrobenzofuryl, benzofuryl, benzothienyl, 4H-chromenyl, 1,3,4 -oxadiazolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, 1,3,4-triazolyl, 1,2,4-oxadiazolyl, 2,3-dihydrobenzofuryl, perhydrobenzofuryl, 5-1H-indazolyl, furyl, pyrrolinyl, 5 nolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolidinyl, 1,2,3,5-oxathiadiazolyl, isothiazolyl, pyranyl, pyrazolidinyl, quinuclidinyl, 1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithia-2,4-dihydronaphthalenyl, 1,4-dithianaphthalenyl, furo[3,2-c]pyridyl, furo[2,3-g~quinolyl, 3,4-dihydrofuro[2,3-g]quinolyl, 1,2,3,4-tetrahydrofuro[2,3-g]quinolyl, 1,4-benzodioxanyl, 1,2,4-triazinyl, naphtho[2,1-b]furyl, imidazo[1,2-a]pyridyl, and the like.
The lower alkyl group which is substituted by a 5- to 14 -membered saturated or unsaturated heteromonocyclic, heterobicyclic or heterotricyclic group having 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom includes, for example, pyrrolidinylmethy, 2 -piperidinylethyl, 3-piperazinylpropyl, 4-morpholinobutyl, (2-pyridyl)methyl, (3-pyridyl)methyl, (2-thienyl)methyl, (3-quinolyl)methyl, 5-(6-quinolyl)pentyl, 6-(1,4-dihydro-2-quinolyl)hexyl, (2-benzothiazolyl)methyl, 2-(3-pyrazinyl)ethyl, 1-(2-pyrimidyl)ethyl, 3-(3-pyridazinyl)propyl, 4-(2-pyrrolyl)butyl, 5-(3-carbostyril) -pentyl, 6-(3,4-dihydrocarbostyril-6-yl)hexyl, (1,2,3,4-tetrahydroquinolyl-8-yl)methyl, (2-indolyl)methyl, (3-indolyl)methyl, 2-(3-indolyl)ethyl, (4-isoindolyl)-methyl, 2-(3-indolinyl)ethyl, (2-benzoimidazolyl)methyl, 3-(5-benzoxazolyl)-propyl, 4-(4-imidazolidinyl)butyl, 5-(1-isoquinolyl)pentyl, 6-(7-quinazolidinyl)-hexyl, (8-quinoxalinyl)methyl, 1-(4-cinnolinyl)ethyl, 3-(5-phthalazinyl)propyl, 4-(6-chromanyl)butyl, 5-(4-isoindolinyl)pentyl, 6-(7-isochromanyl)hexyl, (3-pyrazolyl)methyl, 2-(2-imidzolyl)ethyl, 3-(3-pyrazolidinyl)propyl, (2-benzofuryl)-methyl, (3-benzofuryl)methyl, 4-(6-benzofuryl)butyl, (2-benzothienyl)methyl, (3-benzothienyl)methyl, 5-(5-benzothienyl)pentyl, [6-(4H-chromenyl)]methyl, (2,3-dihydro-2-benzofuryl)methyl, (2-perhydrobenzofuryl)methyl, (5-1H-indazolinyl)-methyl, thienylmethyl, 1-(5-isoindolinyl)ethyl, 3-(2-imidazolinyl)propyl, 4-(2 -pyrrolinyl)butyl, (2-furyl)methyl, (4-oxazolyl)methyl, (5-oxazolyl)methyl, 5-(4-oxazolyl)pentyl, 6-(3-isoxazolyl)hexyl, (4-thiazolyl)methyl, (2-thiazolyl)methyl, 2-(3-isothiazolyl)ethyl, (2-pyranyl)methyl, 3-(3-pyrazolidinyl)propyl, 4-(2-,2lso345 pyrazolinyl)butyl, 5-(2-quinuclidinyl)pentyl, (1,4-benzoxazin-6-yl)methyl, (3,4-dihydro-2H- 1 ,4-benzoxazin-2-yl)methyl, ( 1 ,4-benzothiazin-5-yl)methyl, ( 1 ,2,3,4 -tetrahydroquinoxalinyl-6-yl)methyl, (1,3-dithia-2,4-dihydronaphthalen-6-yl)-methyl, (1,4-dithianaphthalen-7-yl)methyl, (5-thiazolyl)methyl, (1,3,4-oxadiazolin-5-yl)methyl, (1,2,4-triazol-5-yl)methyl, (1,2,3,4-tetrazol-5-yl)methyl, (1,3,4-triazol-5-yl)methyl, (1,2,4-oxadiazol-5-yl)methyl, (1,2,4-triazin-3-yl)-methyl, (thiazolidin-5-yl)methyl, (1,2,3,5-oxathiazolin-4-yl)methyl, (3-furyl)-methyl, (2-furyl)methyl, (2-imidazolyl)methyl, 2-(5-thiazolyl)ethyl, 1-(1,3,4-oxadiazolin-2-yl)ethyl, 3-(1,2,4-triazol-3-yl)propyl, 4-(1,2,3,4-tetrazol-5-yl)butyl, 6-(1,3,4-triazol-2-yl)hexyl, 2-(1,2,4-oxadiazol-3-yl)ethyl, 1-(1,2,4-triazin-5-yl) -ethyl, 3-(thiazolidin-2-yl)propyl, 4-(1,2,3,5-oxathiadiazolin-4-yl)butyl, 5-(furo[3,2-c]pyridin-2-yl)pentyl, 6-(furo[2,3-g]quinolin-7-yl)hexyl, (3,4-dihydrofuro[2,3-g] -quinolin-8-yl)methyl, 2-(1,2,3,4-tetrahydrofuro[2.3-g]quinolin-4-yl)ethyl, (1,4-benzodioxan-2-yl)methyl, 1-(1,4-benzodioxadin-3-yl)ethyl, (2,3-dihydrobenzo-furan-2-yl)methyl, (perhydrobenzofuran-2-yl)methyl, naphtho[2,1-b]furylmethyl, 4-(naphtho[2,1-b]furyl)pentyl, imidazo[1,2-a]pyridylmethyl, 2-(imidazo[1,2-a] -pyridyl)ethyl, 1-(imidazo[1,2-a]pyridyl)ethyl, and the like.
The phenoxy-substituted lower alkyl group includes a phenoxyalkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, phenoxymethyl, 2 -phenoxyethyl, 1-phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl, 5-phenoxy-pentyl, 6-phenoxyhexyl, 1,1-dimethyl-2-phenoxyethyl, 2-methyl-3-phenoxy-propyl, and the like.
The phenyl-lower alkoxy group which may optionally have an amino substituent having optionally a lower alkanoyl substituent on the phenyl moiety includes a phenylalkoxy group, wherein the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, which may optionally have 1 to 3 substituents of amino group having optionally a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4 -phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1,1-dimethyl-2-phenyl-ethoxy, 2-methyl-3-phenylpropoxy, 4-acetylaminobenzyloxy, 2-(2-propionyl -aminophenyl)ethoxy, 1-(3-butyrylaminophenyl~ethoxy, 3-(4-pentanoylamino-WO 95/09159 2 1 5 0 3 4 ~ PCT/JP94/01559 phenyl)propoxy, 4-(3-tert-butylcarbonylaminophenyl)butoxy, 5-(4-hexanoyl -aminophenyl)pentyloxy, 6-(3,4-bisacetylaminophenyl)hexyloxy, 3,4,5-triacetyl-aminobenzyloxy, 2,4-bisacetylaminobenzyloxy, 4-aminobenzyloxy, 2,3-diaminobenzyloxy, 2,4,6-triaminobenzyloxy, 2-(3-aminophenyl)ethoxy, 3-(2 -5 aminophenyl)propoxy, and the like.
The lower alkoxy-substituted lower alkoxy group includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methoxymethoxy, 3-methoxypropoxy, 4 -ethoxybutoxy, 6-propoxyhexyloxy, 5-isopropoxypentyloxy, 1,1-dimethyl-2-butoxyethoxy, 2-methyl-3-tert-butoxypropoxy, 2-pentyloxyethoxy, hexyloxy-methoxy, and the like.
The lower alkanoyloxy-substituted lower alkyl group includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkanoyloxy group having 2 to 6 carbon atoms, for example, acetyloxymethyl, 2,2-dimethylpropionyloxy -methyl, propionyloxymethyl, 2-propionyloxyethyl, 1-acetyloxyethyl, 1-butyryl -oxyethyl, 3-acetyloxypropyl, 4-isobutyryloxybutyl, 5-pentanoyloxypentyl, 6-tert -butylcarbonyloxyhexyl, 1,1-dimethyl-2-hexanoyloxyethyl, 2-methyl-3-acetyloxy-propyl, and the like.
The halogen-substituted lower alkyl group includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by 1 to 3 halogen atoms, for example, trifluoromethyl, trichloro -methyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloro-pentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dichlorohexyl, 5-bromo -hexyl, 5,6-dichlorohexyl, and the like.
The tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring includes a tetrazolyl group having optionally a straight chain or branched chain alkyl group having 1 to 6 carbon atoms on the tetrazole ring, for example, tetrazolyl, 1-methyltetrazolyl, 2-methyltetrazolyl, 5-ethyltetrazolyl, 5 -propyltetrazolyl, 1-butyltetrazolyl, 2-pentyltetrazolyl, 1-hexyltetrazolyl, and the 2,~5a34s like.
The phenyl group having optionally a substituent selected from a lower alkyl group, a lower alkoxy-substituted lower alkoxy group, hydroxy group, a halogen atom and a lower alkoxy group includes a phenyl group which may optionally have 1 to 3 substituents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, hydroxy group, a halogen atom and a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, phenyl, 2-methylphenyi, 3 -methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 3 -isopropylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 2,5-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-pentyl -oxyphenyl, 2,4-dimethoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3-ethoxy-4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,5 -dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dipentyloxy-phenyl, 3,4,5-trimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chloro-phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromophenyl, 3,4,5-trichlorophenyl, 2 -methoxy-5-chlorophenyl, 3-chloro-4-methoxyphenyl, 3-methoxy-5-iodophenyl, 3,4-dimethoxy-5-bromophenyl, 3,5-diiodo-4-methoxyphenyl, 2-hydroxy-5-chlorophenyl, 2-methoxymethoxy-5-chlorophenyl, 2-hydroxyphenyl, 3-hydroxy-phenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, 2-methoxymethoxyphenyl, 3-(3-methoxypropoxy)phenyl, 4-(4-ethoxybutoxy)phenyl, 2-(6-propoxyhexyloxy)phenyl, 3-(5-isopropoxypentyloxy)-phenyl, 4-(1,1-dimethyl-2-butoxyethoxy)phenyl, 2-(2-methyl-3-tert-butoxy-propoxy)phenyl, 3-(2-pentyloxyethoxy)phenyl, 4-hexyloxymethoxyphenyl, 2,3-dimethoxymethoxyphenyl, 3,4,5-trimethoxymethoxyphenyl, and the like.
The lower alkenyl group includes a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms, for example, vinyl, allyl, 2-WO 95/09159 ~ 1 S 0 3 4 5 PCI/JP94/01559 butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl, and the like.
The morpholinocarbonyl-lower alkoxy group includes a morpholinocarbonylalkoxy group wherein the alkoxy moiety is a straight chain or branched chain alkoxyl group having 1 to 6 carbon atoms, for example, 5 morpholinocarbonylmethoxy, 2-morpholinocarbonylethoxy, 1-morpholino-carbonylethoxy, 3-(2-morpholinocarbonyl)propoxy, 4-(3-morpholinocarbonyl)-butoxy, 1,1-dimethyl-2-(2-morpholinylcarbonyl)ethoxy, 5-morpholinylcarbonyl-pentyloxy, 6-morpholinocarbonylhexyloxy, 2-methyl-3-morpholinocarbonyl-propoxy, and the like.
The morpholinocarbonyl-lower alkyl group includes a morpholinocarbonylalkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, morpholinocarbonylmethyl, 2-morpholinocarbonylethyl, 1-morpholinocarbonyl-ethyl, 3-(2-morpholinocarbonyl)propyl, 4-(3-morpholinocarbonyl)butyl, 1,1 -dimethyl-2-(2-morpholinocarbonyl)ethyl, 5-morpholinocarbonylpentyl, 6-morpholinocarbonylhexyl, 2-methyl-3-morpholinocarbonylpropyl, and the like.
The cycloalkylcarbonyl group includes a cycloalkylcarbonyl group having 3 to 8 carbon atoms in the cycloalkyl moiety, for example, cyclopropyl -carbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, and the like.
The phenyl-lower alkenylcarbonyl group includes a phenylalkenyl -carbonyl group wherein the alkenylcarbonyl moiety is a straight chain or branched chain alkenylcarbonyl group having 3 to 6 carbon atoms in the alkenylcarbonyl moiety, for example, cinnamoyl, 4-phenyl-2-butenoyl, 4-phenyl -3-butenoyl, 5-phenyl-4-pentenoyl, 5-phenyl-3-pentenoyl, 5-phenyl-2-pentenoyl, 6-phenyl-5-hexenoyl, 6-phenyl-4-hexenoyl, 6-phenyl-3-hexenoyl, 6-phenyl-2-hexenoyl, 2-methyl-4-phenyl-3-butenoyl, 2-methyl-cinnamoyl, 1 -methyl-cinnamoyl, and the like.
The 5- to 6-membered saturated heterocyclic group which is formed by combining R6 and R7, R9 and R10, R40 and R41 or R52 and R53 together with the adjacent nitrogen atom with or without being intervening with nitrogen atom or oxygen atom, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, and the like.

WO 9S/09159 PCI/JI'94/OlS59 ~S03~5 The above heterocyclic group having 1 to 3 substituents selected from hydroxy group, a lower alkyl group and a phenyl-lower alkyl group includes the above mentioned heterocyclic groups having 1 to 3 sustituents selected from hydroxy group, a straight chain or branched chain alkyl group 5 having 1 to 6 carbon atoms, and a phenylalkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, 3-hydroxypyrrolidinyl, 2-hydroxypyrrolidinyl, 4-hydroxypiperidinyl,3-hydroxypiperidinyl, 2-hydropiperidinyi, 3-hydroxypiperazinyl, 2-hydroxy-piperazinyl, 3-hydroxymorpholino, 2-hydroxymorpholino, 4-benzylpiperazinyl, 3-(2-phenylethyl)pyrrolidinyl, 2-(3-phenylpropyl)pyrrolidinyl, 4-(4-phenylbutyl)-piperidinyl, 3-(5-phenylpentyl)morpholino, 2-(6-phenylhexyl)piperazinyl, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propyl-pyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 2-hexylpiperazinyl, 3-methyl-4-benzylpiperazinyl, 3-ethyl-4-hydroxypiperidinyl, 3-methyl-4-benzylpyrrolidinyl, and the like.
The amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group includes an amino group having optionally 1 to 2 substituents selected from a straight chainor branched chain alkanoyl group having 1 to 6 carbon atoms and a phenylalkenylcarbonyl group wherein the alkenylcarbonyl moiety is a straight chain or branched chain alkenylcarbonyl group having 3 to 6 carbon atoms in the alkenylcarbonyl moiety, for example, amino, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pentanoylamino, t-butyl -carbonylamino, hexanoylamino, cinnamoylamino, 4-phenyl-3-butenoylamino, 4-phenyl-2-butenoylamino, 5-phenyl-4-pentenoylamino, 5-phenyl-3-pentenoyl-amino, 5-phenyl-2-pentenoylamino, 6-phenyl-5-hexenoylamino, 6-phenyl-4-hexenoylamino, 6-phenyl-3-hexenoylamino, 6-phenyl-2-hexenoylamino, 2-methyl-4-phenyl-3-butenoylamino, 2-methyl-cinnamoylamino, 1-methyl-cinnamoylamino, N-acetyl-N-cinnamoylamino, and the like.
The amino group having optionally a lower alkanoyl substituent includes an amino group having optionally a substituent of a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, amino, formylamino, acetyamino, propionylamino, butyrylamino, isobutyryl-WO 95/09159 2 1 5 0 3 1 5 PCT1JP94/OlS59 amino, pentanoylamino, tert-butylcarbonylamino, hexanoylamino, and the like.
The alkylsufinyl group includes a straight chain or branched chain alkylsulfinyl group having 1 to 6 carbon atoms, for example, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, 5 hexylsulfinyl, and the like.
The lower alkylthio group includes a straight chain or branched chain alkylthio group having 1 to 6 carbon atoms, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, hexylthio, and the like.
The lower alkylsulfonyl group includes a straight chain or branched chain alkylsulfonyl group having 1 to 6 carbon atoms, for example, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, butysulfonyl, tert-butysulfonyl, pentylsulfonyl, hexylsulfonyl, and the like.
The lower alkanoyloxy group includes a straight chain or branched chain alkanoyloxy group having 1 to 6 carbon atoms, for example, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert -butylcarbonyloxy, hexanoyloxy, and the like.
The amino-substituted lower alkyl group having optionally a substituent selected from a lower alkylsulfonyl group and a lower alkanoyl group includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by an amino group having optionally 1 to 2 groups selected from a straight chain or branched chain alkylsulfonyl group having 1 to 6 carbon atoms and a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, aminomethyl, 2-aminoethyl, 1 -aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1 -dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, formylaminomethyl, 1-acetyl -aminoethyl, 2-propionylaminoethyl, 3-butyrylaminopropyl, 4-pentanoylamino-pentyl, 5-hexanoylaminohexyl, 6-isobutyrylaminohexyl, 1,1-dimethyl-2-acetyl-aminoethyl, 2-methyl-3-formylaminopropyl, methylsulfonylaminomethyl, 2-ethylsulfonylaminoethyl, 1-isopropylsulfonylaminoethyl, 3-butylsulfonylamino-propyl, 4-tert-butylsulfonylaminobutyl, S-pentylsulfonylaminopentyl, 6-hexyl -sulfonylaminohexyl, 1,1-dimethyl-2-methylsulfonylaminoethyl, 2-methyl-3-ethylsulfonylaminopropyl, N-methylsulfonylamino-N-acetylaminomethyl, and WO 9S/09159 ~ 4~ pCI/JP94/01559 the like.
The 1,3-dioxolanyl-substituted lower alkyl group having optionally a lower alkyl substituent includes a 1,3-dioxolanyl-substituted alkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group 5 having 1 to 6 carbon atoms, which may optionally have 1 to 3 substituents of astraight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-4-yl)ethyl, 1-(1,3-dioxolan-2-yl)ethyl, 3-(1,3-dioxolan-4-yl)propyl, 4-(1,3-dioxolan-2-yl)butyl, 2-(1,3-dioxolan-2-yl)propyl, 5-(1,3-dioxolan-2-yl)pentyl, (4-hexyl-1,3-dioxolan-2-yl)-10methyl, (2,4-dimethyl-1,3-dioxolan-2-yl)methyl, 6-(1,3-dioxolan-3-yl)hexyl, 4-(2-propyl-1,3-dioxolan-2-yl)butyl, 5-(4-butyl-1,3-dioxolan-2-yl)pentyl, 6-(2-pentyl-1,3-dioxolan-2-yl)hexyl, 1,1-dimethyl-2-(1,3-dioxolan-2-yl)ethyl, 2-methyl-3-(1,3-dioxolan-2-yl)propyl, (2-methyl-1,3-dioxolan-2-yl)methyl, 2-(4-ethyl-1,3-dioxolan-2-yl)ethyl, 3-(2,4,5-trimethyl-1,3-dioxolan-2-yl)propyl, and the like.
15The alkanoyl-substituted lower alkyl group includes an alkanoylalkyl group wherein the alkanoyl moiety is a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms and the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, formylmethyl, acetylmethyl, 2-propionylethyl, 1-butyrylethyl, 3 -20 isobutyrylpropyl, 4-pentanoylbutyl, 5-hexanoylhexyl, 6-tert-butylcarbonylhexyl, 1,1-dimethyl-2-acetylethyl, 2-methyl-3-acetylmethyl, and the like.
The aminocarbonyl-substituted lower alkyl group which may optionally have a lower alkyl substituent includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by an 25 aminocarbonyl having optionally 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, aminocarbonylmethyl, 2-aminocarbonylethyl, 1-aminocarbonylethyl, 3-aminocarbonylpropyl, 4-aminocarbonylbutyl, 5-aminocarbonylpentyl, 6-aminocarbonylhexyl, 1,1-dimethyl-2-aminocarbonylethyl, 2-methyl-3-amino-30 carbonylpropyl, methylaminocarbonylmethyl, 1-ethylaminocarbonylethyl, 2-propylaminocarbonylethyl, 3-isopropylaminocarbonylpropyl, 4-butylamino-carbonylbutyl, 5-pentylaminocarbonylpentyl, 6-hexylaminocarbonylhexyl, dimethylaminocarbonylmethyl, 2-diethylaminocarbonylethyl, 2-dimethylamino-carbonylethyl, (N-ethyl-N-propylamino)carbonylmethyl, 2-(N-methyl-N-hexyl-amino)carbonylethyl, and the like.
The lower alkoxycarbonyl-substituted lower alkenyl group includes a straight chain or branched chain alkenyl group having 2 to 6 carbon 5 atoms which is substituted by a straight chain or branched chain alkoxy -carbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, 2 -methoxycarbonylvinyl, 2-ethoxycarbonyvinyl, 3-propoxycarbonylallyl, 4-butoxy-carbonyl-2-butenyl, 4-pentyloxycarbonyl-3-butenyl, 3-hexyloxycarbonyl-1-methylallyl, 5-isopropoxycarbonyl-2-pentenyl, 6-tert-butoxycarbonyl-2-hexenyl, 10 and the like.
The aminocarbonyl-substituted lower alkenyl group which may optionally have a lower alkyl substituent includes a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms which is substitued by an aminocarbonyl group having optinally have 1 to 2 substituents of a straight 15 chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, 2 -aminocarbonylvinyl, 3-aminocarbonylallyl, 4-aminocarbonyl-2-butenyl, 4-aminocarbonyl-3-butenyl, 3-aminocarbonyl-1-methylallyl, 5-aminocarbonyl-2-pentenyl, 6-aminocarbonyl-2-hexenyl, 2-methylaminocarbonylvinyl, 3-ethyl-aminocarbonylallyl, 4-propylaminocarbonyl-2-butenyl, 4-isopropylamino-20 carbonyl-3-butenyl, 3-butylaminocarbonyl-1-methylallyl, 5-pentylamino-carbonyl-2-pentenyl, 6-hexylaminocarbonyl-2-hexenyl, 2-dimethylamino-carbonylvinyl, 2-diethylaminocarbonylvinyl, 3-(N-ethyl-N-propylaminocarbonyl)-allyl, 4-(N-methyl-N-hexylaminocarbonyl)-2-butenyl, and the like.
The carboxy-substituted lower alkenyl group includes a straight 25 chain or branched chain alkenyl group having 2 to 6 carbon atoms, for example, 2-carboxyvinyl, 3-carboxyallyl, 4-carboxy-2-butenyl, 4-carboxy-3-butenyl, 3-carboxy-1-methylallyl, 5-carboxy-2-pentenyl, 6-carboxy-2-hexenyl, and the like.
The aminocarbonyl group having optionally a lower alkyl 30 substituent includes an aminocarbonyl group which may optionally have 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, aminocarbonyl, methylaminocarbonyl, ethyl -aminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butyl-~ts~34~

aminocarbonyl, tert-butylaminocarbonyl, pentylaminocarbonyl, hexyl -aminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, dipropyl-aminocarbonyl, dibutylaminocarbonyl, dipentylaminocarbonyl, dihexyl -aminocarbony!, N-methyl-N-ethylaminocarbonyl, N-ethyl-N-propylamino-carbonyl, N-methyl-N-butylaminocarbonyl, N-methyl-N-hexylaminocarbonyl, and the like.
The phenylsulfonyl group having optionally a lower alkyl substituent includes a phenylsulfonyl group having optionally 1 to 3 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, phenylsulfonyl, 2-methyl phenylsulfonyl, 3 -methylphenylsulfonyl, 4-methylphenylsulfonyl, 2-ethylphenylsulfonyl, 3-ethylphenylsulfonyl, 4-ethylphenylsulfonyl, 3-isopropylphenylsulfonyl, 4-hexylphenylsulfonyl, 3,4-dimethylphenylsulfonyl, 2,5-dimethylphenylsulfonyl, 3,4,5-trimethylphenylsulfonyl, and the like.
The phenyl-lower alkenyl group includes a phenylalkenyl group wherein the alkenyl moiety is a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms, for example, styryl, cinnamyl, 4-phenyl-3-butenyl, 4 -phenyl-2-butenyl, 5-phenyl-4-pentenyl, 5-phenyl-3-pentenyl, 5-phenyl-2-pentenyl, 6-phenyl-5-hexenyl, 6-phenyl-4-hexenyl, 6-phenyl-3-hexenyl, 6-phenyl-2-hexenyl, 2-methyl-4-phenyl-3-butenyl, 2-methyl-cinnamyl, 1-methyl -cinnamyl, and the like.
The benzoyl group which may optionally have 1 to 3 substituents selected from a lower alkoxy group, a halogen atom, an amino group having optionally a lower alkanoyl substituent, and hydroxy group on the phenyl moiety includes a benzoyl group which may optinally have 1 to 3 substituents selected from a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, a halogen atom, an amino group having optionally a straight chain or branched chain alkanoyl substituent having 1 to 6 carbon atoms and hydroxy group on the phenyl moiety, for example, benzoyl, 2-chlorobenzoyl, 3 -chlorobenzoyl, 4-chlorobenzoyl, 2-fluorobenzoyl, 3-fluorobenzoyl, 4-fluoro-benzoyl, 2-bromobenzoyl, 3-bromobenzoyl, 4-bromobenzoyl, 2-iodobenzoyl, 4-iodobenzoyl, 3,5-dichlorobenzoyl, 2,6-dichlorobenzoyl, 3,4-dichlorobenzoyl, 3,4-difluorobenzoyl, 3,5-dibromobenzoyl, 3,4,5-trichlorobenzoyl, 2-methoxy-WO 9S/09159 PCItJP94/OlS59 benzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxy-benzoyl, 4-ethoxybenzoyl, 4-isopropoxybenzoyl, 4-hexyloxybenzoyl, 3,4-dimethoxybenzoyl, 3,4-diethoxybenzoyl, 3,4,5-trimethoxybenzoyl, 2,5 -dimethoxybenzoyl, 3-methoxy-4-chlorobenzoyl, 2-chloro-6-methoxybenzoyl, 2-5 methoxy-5-chlorobenzoyl, 2-aminobenzoyl, 3-aminobenzoyl, 4-aminobenzoyl, 2-hydroxybenzoyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, 2,5-diaminobenzoyl, 3,4,5-triaminobenzoyl, 2-formylaminobenzoyl, 3-acetyaminobenzoyl, 4-acetyl-aminobenzoyl, 2-acetylaminobenzoyl, 3-propionylaminobenzoyl, 4-butyryl-aminobenzoyl, 2-isobutyrylaminobenzoyl, 3-pentanoylaminobenzoyl, 3-tert-10 butylcarbonylaminobenzoyl, 4-hexanoylaminobenzoyl, 2,6-diacetylamino-benzoyl, 2,4-dihydroxybenzoyl, 2,4,6-trihydroxybenzoyl, 2-hydroxy-5-chloro-benzoyl, and the like.
The amino-substituted lower alkanoyl group having optionally a lower alkanoyl substituent includes a straight chain or branched chain alkanoyl 15 group having 2 to 6 carbon atoms which is substitued by an amino group having optionally 1 to 2 substituents of a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, 2-aminoacetyl, 3 -aminopropionyl, 2-aminopropionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 2,2-dimethyl-3-aminopropionyl, 2-methyl-3-aminopropionyl, 2-20 acetylaminoacetyl, 2-acetylaminopropionyl, 3-propionylaminopropionyl, 3-isopropionylaminopropionyl, 4-butyrylaminobutyryl, 5-pentanoylamino-pentanoyl, 6-hexanoylaminohexanoyl, 2-formylaminoacetyl, and the like.
The amino-substituted sulfonyl group having optionally a lower alkyl substituent includes an aminosulfonyl group which may optionally have 1 25 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, aminosulfonyl, methylaminosulfonyl, ethylamino -sulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, butylaminosulfonyl, tert-butylaminosulfonyl, pentylaminosulfonyl, hexylaminosulfonyl, dimethylamino-sulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, dibutylaminosulfonyl, 30 dibutylaminosulfonyl, dipentylaminosulfonyl, dihexylaminosulfonyl, N-methyl-N-ethylaminosulfonyl, N-ethyl-N-propylaminosulfonyl, N-methyl-N-butylamino-sulfonyl, N-methyl-N-hexylaminosulfonyl, and the Iike.
The lower alkeneldioxy group includes a straight chain or WO 9S/09159 I'CT1JP94/OlS59 3 4~ 36 -branched chain alkylenedioxy group having 1 to 4 carbon atoms, for example, methylenedioxy, ethylenedioxy, trimethylenedioxy, tetramethylenendioxy, and the like.
The phenyl group having optionlly a lower alkoxy substituent 5 includes a phenyl group which may optionally have 1 to 3 substituents of a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-pentyl -oxyphenyl, 2,4-dimethoxyphenyl, 4-hexyloxyphenyl, 3-ethoxy-4-methoxy-phenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dipentyloxy-phenyl, 3,4,5-trimethoxyphenyl, and the like.
The 2,3-dihydro-1 H-indenyl-substituted lower alkyl group which may optionall have a substituent selected from oxo group, hydroxy group and silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a 2,3-dihydro-1 H-indenyl group having optionally 1 to 3 substituents selected from oxo group, hydroxy group and a silyloxy group having 3 substituents of a straight chain or branched chain alkylgroup having 1 to 6 carbon atoms, for example, (2,3-dihydro-1 H-inden-2-yl) -methyl, 2-(2,3-dihydro-1 H-inden-1 -yl)ethyl, 1 -(2,3-dihydro-1 H-inden-3-yl)ethyl, 3-(2,3-dihydro-1H-inden-4-yl)propyl, 4-(2,3-dihydro-1H-inden-5-yl)butyl, 5-(2,3-dihydro-1 H-inden-6-yl)pentyl, 6-(2,3-dihydro-1 H-inden-7-yl)hexyl, (1 -oxo-2,3 -dihydro-1H-inden-2-yl)methyl, (1-hydroxy-2,3-dihydro-1H-inden-2-yl)methyl, (1 -dimethyl,tert-butylsilyloxy-2,3-dihydro-1H-inden-2-yl)methyl, (1,3-dihydroxy-2,3-dihydro-1H-inden-2-yl)methyl, [1,3-bis(trimethylsilyloxy)-2,3-dihydro-1H-inden-2-yl)methyl, (1,3,7-trihydroxy-2,3-dihydro-1H-inden-2-yl)methyl, [1,3,4-tri-(dimethyl,ethylsilyloxy)-2,3-dihydro-1H-inden-2-yl)methyl, and the like.
The silyloxy group having a lower alkyl substituent includes a silyloxy group being substituted by three straight chain or branched chain alkylgroups having 1 to 6 carbon atoms, for example, trimethylsilyloxy, triethyl -silyloxy, triisopropylsilyloxy, tributylsilyloxy, tri-tert-butylsilyloxy, tripentylsilyloxy, trihexylsilyloxy, dimethyl,tert-butylsilyloxy, and the like.

-The phenyl group having optionally a substituent selected from a lower alkoxy group and a halogen atom on the phenyl ring includes a phenyl group which may optionaly be substituted by 1 to 3 groups selected from a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms and 5 a halogen atom, for example, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4 -methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-pentyloxyphenyl, 2,4-dimethoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3-ethoxy-4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxy-phenyl, 3,4-dipentyloxyphenyl, 3,4,5-trimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-difluorocphenyl, 3,5-dibromophenyl, 3,4,5-trichlorophenyl, 2-methoxy-5-chlorophenyl, 3-chloro-4-methoxyphenyl, 3-methoxy-5-iodophenyl, 3,4-dimethoxy-5-bromophenyl, 3,5-iodo-4-methoxy-phenyl, and the like.
The saturated or unsaturated 5- to 6-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom 20 and sulfur atom includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyridyl, thienyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolidinyl, pyrazolyl, imidazolyl, pyrazolidinyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, 1,3,4-triazolyl, 1,2,4-oxadiazolyl, furyl, pyrrolinyl, oxazolyl, isoxazolyl, thiazolyl, thiazolidinyl, 1,2,3,5-oxathiadiazolyl, isothiazolyl, 25 pyranyl, pyrazolidinyl, 1,2,4-triazinyl, and the like.
The lower alkyl group substitued by a 5- to 6-membered saturated or unsaturated heterocyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by 30 the above mentioned heterocyclic group, for example, pyrrolidinylmethyl, 2 -piperidinylethyl, 3-piperazinylpropyl, 4-morpholinobutyl, (2-pyridyl)methyl, (3-pyridyl)methyl, (2-thienyl)methyl, 2-(3-pyrazinyl)ethyl, 1-(2-pyrimidyl)ethyl, 3-(3-pyridazinyl)propyl, 4-(2-pyrrolyl)butyl, 4-(4-imidazolidinyl)butyl, (2-imidazolyl)-21503~5 methyl, (3-pyrazolyl)methyl, 2-(2-imidazo!yl)ethyl, 3-(3-pyrazolidinyl)propyl, thienylmethyl, 3-(2-imidazolinyl)propy~1, 4`-(2-pyrrolinyl)butyl, (2-furyl)methyl, (4-oxazolyl)methyl, (5-oxazolyl)methyl, 5-(4-oxazolyl)pentyl, 6-(3-isooxazolyl)-hexyl, (4-thiazolyl)methyl, (2-thiazolyl)methyl, 2-(3-isothiazolyl)ethyl, (2-pyranyl) -5 methyl, 3-(3-pyrazolidinyl)propyl, 4-(2-pyrazolinyl)butyl, (5-thiazolyl)methyl, (1,3,4-oxadiazolin-5-yl)methyl, (1,2,4-triazol-5-yl)methyl, (1,2,3,4-tetrazol-5-yl)-methyl, (1,3,4-triazol-5-yl)methyl, (1,2,4-oxadiazol-5-yl)methyl, (1,2,4-triazin-3-yl)methyl, (thiazolidin-5-yl)methyl, (1,2,3,5-oxathiadiazolin-4-yl)methyl, (2-furyl)-methyl, (3-furyl)methyl, 2-(5-thiazolyl)ethyl, 1-(1,3,4-oxadiazolin-2-yl)ethyl, 3-(1,2,4-triazol-3-yl)propyl, 4-(1,2,3,4-tetrazol-5-yl)butyl, 6-(1,3,4-triazol-2-yl) -hexyl, 2-(1,2,4-oxadiazol-3-yl)ethyl, 1-(1,2,4-triazin-5-yl)ethyl, 3-(thiazolidin-2 -yl)propyl, 4-(1,2,3,5-oxathiadiazolin-4-yl)butyl, and the like.
The lower alkenyl group substituted by a 5- to 14-membered saturated or unsaturated heteromonocylic, heterobicyclic or heterotricyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom includes the above mentioned heterocyclic group-substituted alkenyl group wherein the alkenyl moiety is a straight chain or branched chain alkenyl group with 1 to 2 double bounds having 2 to 6 carbon atoms, for example, 2-benzofurylvinyl, 3-benzofuryl-2-propenyl, 4-benzofuryl-3-butenyl, 3-benzofuryl-2-butenyl, 2-methyl-3-benzofuryl-2-propenyl, 5-benzofuryl-4-petenyl, 5-benzofuryl-2-pentenyl, 4-benzofuryl-3-pentenyl, 6-benzofuryl-5 -hexenyl, 6-benzofuryl-4-hexenyl, 6-benzofuryl-3-hexenyl, 6-benzofuryl-2-hexenyl"B-methyl-4-benzofuryl-3-butenyl, 5-benzofuryl-2,4-pentadienyl, 4-benzofuryl-1,3-butadienyl, 6-benzofuryl-2,4-hexadienyl, 6-benzofuryl-3,5-hexadienyl, 6-benzofuryl-1,3-hexadienyl, 5-benzofuryl-1,3-pentadienyl, 2-benzothienylvinyl, 3-benzothienyl-2-propenyl, 4-benzothienyl-3-butenyl, 3-benzothienyl-2-butenyl, 2-methyl-3-benzothienyl-2-propenyl, 5-benzothienyl-4-petenyl, 5-benzothienyl-2-pentenyl, 6-benzothienyl-5-hexenyl, 6-benzothienyl-4-hexenyl, 6-benzothienyl-3-hexenyl, 6-benzothienyl-2-hexenyl, ~-methyl-4-benzothienyl-3-butenyl, 5-benzothienyl-2,4-pentadienyl, 4-benzothienyl-1,3-butadienyl, 6-benzothienyl-2,4-hexadienyl, 6-benzothienyl-3,5-hexadienyl, 6-benzothienyl-1,3-hexadienyl, 5-benzothienyl-1,3-pentadienyl, 2-(furo[3,2-c]-pyridyl)vinyl, 3-(furo[3,2-c]pyridyl)-2-propenyl, 4-(furo[3,2-c]pyridyl)-3-butenyl, 3 -(furo[3,2-c]pyridyl)-2-butenyl, 2-methyl-3-(furo[3,2-c]pyridyl)-2-propenyl, 5 -(furo[3,2-c]pyridyl)-4-petenyl, 5-(furo[3,2-c]pyridyl)-2-pentenyl, 6-(furo[3,2-c]pyridyl)-5-hexenyl, 6-(furo[3,2-c]pyridyl)-4-hexenyl, 6-(furo[3,2-c]pyridyl)-3-hexenyl, 6-(furo[3,2-c]pyridyl)-2-hexenyl"B-methyl-4-(furo[3,2-c]pyridyl)-3 -butenyl, 5-(furo[3,2-c]pyridyl)-2,4-pentadienyl, 4-(furo[3,2-c]pyridyl)-1,3-butadienyl, 6-(furo[3,2-c]pyridyl)-2,4-hexadienyl, 6-(furo[3,2-c]pyridyl)-3,5-hexadienyl, 6-(furo[3,2-c]pyridyl)-1,3-hexadienyl, 5-(furo[3,2-c]pyridyl)-1,3-pentadienyl, 2-quinolylvinyl, 3-(1,4-dihydroquinoly)1-2-propenyl, 4-benzo-thiazolyl-3-butenyl, 3-carbostyril-2-butenyl, 2-methyl-3-(3,4-dihydrocarbostyril)-2-propenyl, 5-(1,2,3,4-tetraquinolyl)-4-petenyl, 5-indolyl-2-pentenyl, 6-indolinyl-5-hexenyl, 6-indolinyl-4-hexenyl, 6-benzoimidazolyl-3-hexenyl, 6-benzoxazolyl-2-hexenyl, ~-methyl-4-isoquinolyl-3-butenyl, 5-quinazolidinyl-2,4-pentadienyl, 4-cinnolyl-1,3-butadienyl, 6-quinoxalinyl-2,4-hexadienyl, 6-phthalazinyl-3,5-hexadienyl, 6-chromanyl-1,3-hexadienyl, 5-isoindolinyl-1,3-pentadienyl, 2-(4H-chromenyl)vinyl, 3-(2,3-dihydro-2-benzofuryl) -2-propenyl, 4-(2-perhydrobenzo-furyl)-3-butenyl, 3-(1,4-benzoxadinyl)-2-butenyl, 2-methyl-3-(3,4-dihydro-2H -1,4-benzoxazinyl)-2-propenyl, 5-(1,4-benzothiazinyl)-4-pentenyl, 5-(1,2,3,4-tetrahydroquinoxalinyl)-2-pentenyl, 6-(1,3-dithia-2,4-dihydronaphthalenyl)-5-hexenyl, 6-(1,4-dithianaphthalenyl)-4-hexenyl, 6-(1,4-benzodioxanyl)-3-hexenyl, 2-pyrrolidinylvinyl, 3-pyrrolidinyl-2-propenyl, 4-pyrrolidinyl-3-butenyl, 3-pyrrolidinyl-2-butenyl, 2-methyl-3-pyrrolidinyl-2-propenyl, 5-pyrrolidinyl-4-pentenyl, 5-pyrrolidinyl-2-pentenyl, 6-pyrrolidinyl-5-hexenyl, 6-pyrrolidinyl-4-hexenyl, 6-pyrrolidinyl-3-hexenyl, 6-pyrrolidinyl-2-hexenyl, ~-methyl-4-pyrrolidinyl-3-butenyl, 5-pyrrolidinyl-2,4-pentadienyl, 4-pyrrolidinyl-1,3-butadienyl, 6-pyrrolidinyl-2,4-hexadienyl, 6-pyrrolidinyl-3,5-hexadienyl, 6-pyrrolidinyl-1,3-hexadienyl, 5-pyrrolidinyl-1,3-pentadienyl, 2-piperidinylvinyl, 3-piperidinyl-2-propenyl, 4-piperidinyl-3-butenyl, 3-piperidinyl-2-butenyl, 2-methyl-3-piperidinyl-2-propenyl, 5-piperidinyl-4-pentenyl, 5-piperidinyl-2-pentenyl, 6-piperidinyl-5-hexenyl, 5-piperidinyl-2-pentenyl, 6-piperidinyl-5-hexenyl, 6-piperidinyl-4-hexenyl, 6-piperidinyl-3-hexenyl, 6-piperidinyl-2-WO 95/09159 2 ~S O 3 ~S PCI/JP94/015S9 hexenyl, ~-methyl-4-piperidinyl-3-butenyl, 5-piperidinyl-2,4-pentadienyl, 4-piperidinyl-1,3-butadienyl, 6-piperidinyl-2,4-hexadienyl, 6-piperidinyl-3,5-hexadienyl, 6-piperidinyl-1,3-hexadienyl, 5-piperidinyl-1,3-pentadienyl, 2-piperazinylvinyl, 3-piperazinyl-2-propenyl, 4-piperazinyl-3-butenyl, 3-piperazinyl-2-butenyl, 2-methyl-3-piperazinyl-2-propenyl, 5-piperazinyl-4-pentenyl, 5-piperazinyl-2-pentenyl, 6-piperazinyl-5-hexenyl, 6-piperazinyl-4-hexenyl, 6-piperazinyl-3-hexenyl, 6-piperazinyl-2-hexenyl, ~-methyl-4-piperazinyl-3-butenyl, 5-piperazinyl-2,4-pentadienyl, 4-piperazinyl-1,3-butadienyl, 6-piperazinyl-2,4-hexadienyl, 6-piperazinyl-3,5-hexadienyl, 6-piperazinyl-1,3-hexadienyl, 5 piperazinyl-1,3-pentadienyl, 2-morpholinovinyl, 3-pyridyl-2-propenyl, 4-thienyl-3-butenyl, 3-pyradinyl-2-butenyl, 2-methyl-3-pyrimidyl-2-propenyl, 2-pyridazinylvinyl, 3-pyrrolyl-2-propenyl, 4-imidazolyl-3-butenyl, 3-imidazolyl-2-butenyl, 2-methyl-3-imidazolyl-2-propenyl, 5-imidazolyl-4-pentenyl, 5-imidazolyl-2-pentenyl, 6-imidazolyl-5-hexenyl, 6-imidazolyl-4-hexenyl, 6-imidazolyl-3-hexenyl, 6-imidazolyl-2-hexenyl, ~-methyl-4-imidazolyl-3-butenyl, 5-imidazolyl-2,4-pentadienyl, 4-imidazolyl-1,3-butadienyl, 6-imidazolyl-2,4-hexadienyl, 6-imidazolyl-3,5-hexadienyl, 6-imidazolyl-1,3-hexadienyl, 5-imidazolyl-1,3-pentadienyl, 2-imidazolidinylvinyl, 3-pyrazolyl-1,3-pentadienyl, 2-imidazolidinylvinyl, 3-pyrazolyl-2-propenyl, 4-pyrazolidinyl-3-butenyl, 3-perhydrobenzofuryl-2-butenyl, 2-methyl-3-(1,3,4-oxadiazolyl)-2-propenyl, 5-(1,2,4-triazolyl)-4-petenyi, 5-(1,2,3,4-tetrazolyl)-2-pentenyl, 6-(1,3,4 -triazolyl)-5-hexenyl, 6-(1,2,4-oxadiazolyl)-4-hexenyl, 6-(2,3-dihydro-2-benzofuryl)-3-hexenyl, 6-pyrrolinyl-2-hexenyl, ,B-methyl-5-nonyl-3-butenyl, 5-isoxazolyl-2,4-pentadienyl, 4-thiazolyl-1,3-butadienyl, 6-thiazolidinyl-2,4-hexadienyl, 6-(1,2,3,5-oxathiadiazolyl)-3,5-hexadienyl, 6-isothiazolyl-1,3-hexadienyl, 5-pyranyl-1,3-pentadienyl, 2-oxazolylvinyl, 3-oxazolyl-2-propenyl, 4-oxazolyl-3-butenyl, 3-oxazolyl-2-butenyl, 2-methyl-3-oxazolyl-2-propenyl, 5-oxazolyl-4-pentenyl, 5-oxazolyl-2-pentenyl, 4-oxazolyl-3-pentenyl, 6-oxazolyl-5-hexenyl, 6-oxazolyl-4-hexenyl, 6-oxazolyl-3-hexenyl, 6-oxazolyl-2-hexenyl, ,B-methyl-4-oxazolyl-3-butenyl, 5-oxazolyl-2,4-pentadienyl, 4-oxazolyl-1,3-butadienyl, 6-oxazolyl-2,4-hexadienyl, 6-oxazolyl-3,5-hexadienyl, 6-oxazolyl-Wo 9S/O9lS9 2 1 5 0 3 4 ~

1,3-hexadienyl, 5-oxazolyl-1,3-pentadienyl, 2-pyrazolylvinyl, 3-quinuclidinyl-2-propenyl, 4-benzothiazolyl-3-butenyl, 3-carbostyril-2-butenyl, 2-methyl-3-(3,4-dihydro[2,3-g]quinolyl)-2-propenyl, 5-(1,2,3,4-tetrahydrofuro[2,3-g]quinolyl)-4-pentenyl, 2-(naphtho[2,1-b]furyl)vinyl, 3-(naphtho[2,1-b]furyl)-2-propenyl, 4 -(naphtho[2,1-b]furyl)-3-butenyl, 3-(naphtho[2,1-b]furyl)-2-butenyl, 2-methyl-3-(naphtho[2,1-b]furyl)-2-propenyl, 5-(naphtho[2,1-b]furyl)-4-pentenyl, 5-(naphtho-[2,1-b]furyl)-2-pentenyl, 4-(naphtho[2,1-b]furyl)-3-pentenyl, 6-(naphtho[2,1-b] -furyl)-5-hexenyl, 6-(naphtho[2,1-b]furyl)-4-hexenyl, 6-(naphtho[2,1-b]furyl)-3-hexenyl, 6-(naphtho[2, 1 -b]furyl)-2-hexenyl"~-methyl-4-(naphtho[2, 1 -b]furyl)-3 -butenyl, 5-(naphtho[2,1-b]furyl)-2,4-pentadienyl, 4-(naphto[2,1-b]furyl)-1,3-butadienyl, 6-(naphtho[2,1-b]furyl)-2,4-hexadienyl, 6-(naphtho[2,1-b]furyl)-3,5-hexadienyl, 6-(naphtho[2,1-b]furyl)-1,3-hexadienyl, 5-(naphtho[2,1-b]furyl)-1,3-pentadienyl, 2-(imidazo[1,2-a]pyridyl)vinyl, 3-(imidazo[1,2-a]pyridyl)-2-propenyl, 4-(imidazo[1,2-a]pyridyl)-3-butenyl, and the like.
The phenyl-lower alkoxycarbonyl group includes a phenylalkoxy -carbonyl group wherein the alkoxycarbonyl moiety is a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, benzyloxycarbonyl, 2-phenylethoxycarbonyl, 1-phenyl -ethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, 5-phenyl-pentyloxycarbonyl, 6-phenylhexyloxycarbonyl, 1,1-dimethyl-2-phenylethoxy-carbonyl, 2-methyl-3-phenylpropoxycarbonyl, and the like.
The lower alkoxycarbonyloxy-substituted lower alkyl group includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, which is substituted by alkoxycarbonyloxy group wherein the alkoxy moiety is a a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methoxycarbonyloxymethyl, ethoxycarbonyloxy -methyl, 2-ethoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 3-methoxy-carbonyloxypropyl, 4-ethoxycarbonyloxybutyl, 6-propoxycarbonyloxyhexyl, 5-isopropoxycarbonyloxypentyl, 1,1-dimethyl-2-butoxycarbonyloxyethyl, 2-methyl-3-tert-butoxycarbonyloxypropyl, 2-pentyloxycarbonyloxyethyl, hexyloxy-carbonyloxymethyl, and the like.
The benzoyl-substituted lower alkyl group having optionally a WO 95/09159 PCTIJP94/OlSS9 2~s0345 halogen substituent on the phenyl ring includes a straight chain or branched chain alkyl group having 1 to 6 carbon atom, which is substituted by a benzoyl group wherein the phenyl ring may opti~nally have 1 to 3 halogen substituents, for example, benzoylmethyl. 1-(2-chlorobenzoyl)ethyl, 2-(3-chlorobenzoyl) -ethyl, 3-(4-chlorobenzoyl)propoyl, 4-(2-fluorobenzoyl)butyl, 1,1-dimethyl-2-(3-fluorobenzoyl)ethyl, 5-(4-fluorobenzoyl)pentyl, 6-(2-bromobenzoyl)hexyl, 2-methyl-3-(3-bromobenzoyl)propyl, (4-bromobenzoyl)methyl, 2-(2-iodobenzoyl)-ethyl, 1-(4-iodobenzoyl)ethyl, (3,5-dichlorobenzoyl)methyl, 2-(2,6-dichloro-benzoyl)ethyl, 1-(3,4-dichlorobenzoyl)ethyl, 3-(3,4-difluorobenzoyl)propyl, (3,5-dibromobenzoyl)methyl, (3,4,5-trichlorobenzoyl)methyl, and the like.
The amino group having optionally a lower alkanoyl substituent includes an amino group which may optionally have a substituent of a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, amino, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pentanoylamino, t-butylcarbonylamino, hexanoylamino, and the like.
The present invention specifically includes the following compounds.
(1 ) A quinoxaline derivative of the formula (1 ) wherein R1 is hydrogen atom and R2, R3, R4, m, n and r are the same as defined above, or a salt thereof.
(2) A quinoxaline derivative of the formula (1 ) wherein R1 is a halogen atom and R2, R3, R4, m, n and r are the same as defined above, or a salt thereof.
(3) A quinoxaline derivative of the formula (1 ) wherein R1 is a lower alkyl group and R2, R3, R4, m, n and r are the same as defined above, or a salt thereof.
(4) A quinoxaline derivative of the formula (1 ) wherein R2 is hydrogen atom and R1, R3, R4, m, n and r are the same as defined above, or a salt thereof.
(5) A quinoxaline derivative of the formula (1) wherein R2 is a lower alkyl group having optionally a halogen substituent, and R1, R3, R4, m, n and r are the same as defined above, or a salt thereof.

WO 95/O91S9 2 I 5 0 3 ~ 5 PCT/JP94/OlS59 (6) A quinoxaline derivative of the formula (1 ) wherein R2 is phenyl group and R1, R3,R4, m, n and r are the same as defined above, or a salt thereof.
(7) A quinoxaline derivative of the formula (1 ) wherein R2 is a 5 morpholino-substituted lower alkyl group and R1, R3,R4, m, n and r are the same as defined above, or a salt thereof.
(8) A quinoxaline derivative of the formula (1 ) wherein R2 is an imidazolyl-substituted lower alkyl group and R1, R3,R4, m, n and r are the same as defined above, or a salt thereof.
10 (9) A quinoxaline derivative of the formula (1 ) wherein R3iS hydrogen atom, R4is a group of the formula:
(R5)p A~

15 (wherein A, R5 and p are the same as defined above), and R1, R2 and r are the same as defined above, or a salt thereof.
(10) A quinoxaline derivative of the formula (1 ) wherein R3iS a lower alkyl group, R4is a group of the formula:
(R5)p A ~

(wherein A,R5 and p are the same as defined above), and R1, R2 and r are the same as defined above, or a salt thereof.
(11) A quinoxaline derivative of the formula (1 ) wherein R3is hydrogen 25 atom, R4iS a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower 30 alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula:
-O-A4-Co-NR40R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and R1, R2, m, n and r are the same as defined above, or 9 ~ 1 S 3 4 5 PCT/JP94/01559 a salt thereof.
(12) A quinoxaline derivative~of the formula (1) wherein R3iS a lower alkyl group, R4is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen 5 atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula:
-O-A4-Co-NR40R41 (in which A4, R40 and R41 are the same as defined above), 10 a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(13) A quinoxaline derivative of the formula (1), wherein R3is hydrogen atom, R4is a lower alkenyl group, and R1, R2, m, n and r are the 15 same as defined above, or a salt thereof.
(14) A quinoxaline derivative of the formula (1), wherein R3is a lower alkyl group, R4is a lower alkenyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(15) A quinoxaline derivative of the formula (1), wherein R3is hydrogen atom, R4is a cycloalkyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(16) A quinoxaline derivative of the formula (1), wherein R3is a lower alkyl group, R4is a cycloalkyl-lower alkyl group, and R1, R2, m, n and r are thesame as defined above, or a salt thereof.
25 (17) A quinoxaline derivative of the formula (1), wherein R3is hydrogen atom, R4is a naphthyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(18) A quinoxaline derivative of the formula (1), wherein R3is a lower alkyl group, R4is a naphthyl-lower alkyl group, and R1, R2, m, n and r are the 30 same as defined above, or a salt thereof.
(19) A quinoxaline derivative of the formula (1), wherein R3is hydrogen atom, R4is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, 21503~
WO 9S/09159 - PCI~/JP94/OlS59 n and r are the same as defined above, or a salt thereof.
(20) A quinoxaline derivative of the formula (1), wherein R3is a lower alkyl group, R4is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, 5 n and r are the same as defined above, or a salt thereof.
(21 ) A quinoxaline derivative of the formula (1), wherein R3is hydrogen atom, R4is a phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
10 (22) A quinoxaline derivative of the formula (1), wherein R3is a lower alkyl group, R4is a phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(23) A quinoxaline derivative of the formula (1), wherein R3is 15 hydrogen atom, R4is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(24) A quinoxaline derivative of the formula (1), wherein R3is a lower alkyl group, R4is a phenylsulfonyl-substituted lower alkyl group which may 20 optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(25) A quinoxaline derivative of the formula (1), wherein R3is hydrogen atom, R4is a phenoxy-substituted lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
25 (26) A quinoxaline derivative of the formula (1), wherein R3is a lower alkyl group, R4is a phenoxy-substituted lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(27) A quinoxaline derivative of the formula (1), wherein R3is hydrogen atom, R4is a group of the formula:
(R8)q (wherein the symbols are the same as defined above), and R1, R2, m, n and r WO 95/O91S9 PCI`/JP94/OlS59 ~ls~34s are the same as defined above, or a salt thereof.
(28) A quinoxaline derivative of the formula (1), wherein R3is a lower alkyl group, R4is a group of the formula:
(R8)q ~

(in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(29) A quinoxaline derivative of the formula (1), wherein R3is hydrogen atom, R4is a group of the formula: -A5-CR42R43R44(A5,R42,R43 and R44 are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(30) A quinoxaline derivative of the formula (1), wherein R3is a lower alkyl group, R4is a group of the formula: -A5-CR42R43R44 (A5,R42,R43 and 15 R44 are the same as defined above), and R1,R2, m, n and r are the same as defined above, or a salt thereof.
(31) A quinoxaline derivative of the formula (1), wherein R3is hydrogen atom, R4is a 2,3-dihydro-1 H-indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, 20 hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3 -dihydro-1 H-indenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(32) A quinoxaline derivative of the formula (1), wherein R3is a lower alkyl group, R4is a 2,3-dihydro-1 H-indenyl group-substituted lower alkyl group 25 which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro -1 H-indenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(33) A quinoxaline derivative of the formula (1), wherein R3is hydrogen atom, R4is a group of the (R47)uformula:
{~

WO 95tO9159 2 1 5 0 3 ~ 5 PCT/JP94/OlSS9 (in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(34) A quinoxaline derivative of the formula (1), wherein R3 is a lower 5 alkyl group, R4 is a group of the formula:
(R47)u (in which the symbols are the same as defined above), 10 and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(35) A quinoxaline derivative of the formula (1), wherein R3 and R4 combine together with the nitrogen atom to form 1,2,3,4-tetrahydroisoquinolyl group which may optionally have a lower alkoxy group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
15 (36) A quinoxaline derivative of the formula (1), wherein R1 is a halogent atom or a lower alkyl group, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R5) A~
(in which A, R5 and p are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(37) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkenyl group, R2 is hydrogen atom, R3 is hydrogen 25 atom or a lower alkyl group, R4 is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having 30 optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and m, n and r are the same as 2~50345 defined above, or a salt thereof.
(38) A quinoxaline derivative of thQ formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is hydrogen atom, R3is hydrogen atom or a lower alkyl group, R4is a lower alkenyl group, and m, n and r are the same 5 as defined above, or a salt thereof.
(39) A quinoxaline derivative of the formula t1), wherein R1 is a halogen atom or a lower alkyl group, R2 is hydrogen atom, R3is hydrogen atom or a lower alkyl group, R4is a cycloalkyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
10 (40) A quinoxaline derivative of the formula (1), wherein R1is a halogen atom or a lower alkyl group, R2 is hydrogen atom, R3is hydrogen atom or a lower alkyl group, R4is a naphthyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(41 ) A quinoxaline derivative of the formula (1), wherein R1 is a 15 halogen atom or a lower alkyl group, R2is hydrogen atom, R3is hydrogen atom or a lower alkyl group, R4is a naphthyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(42) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is hydrogen atom, R3is hydrogen atom 20 or a lower alkyl group, R4iS a phenylthio-substitued lower alkyl group which may optinally have a lower alkoxy substituent on the phenyl moiety, and m, n, and r are the same as defined above, or a salt thereof.
(43) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is hydrogen atom, R3is hydrogen atom 25 or a lower alkyl group, R4is a phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(44) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is hydrogen atom, R3is hydrogen atom 30 or a lower alkyl group, R4is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(45) A quinoxaline derivative of the formula (1), wherein Rlis a WO 95/09159 2 1 5 0 3 4 5 PCT1JP94/OlS59 ^ 49 -halogen atom or a lower alkyl group, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a phenoxy-substituted lower alkyl group, and m, n - and r are the same as defined above, or a salt thereof.
(46) A quinoxaline derivative of the formula (1), wherein R1 is a 5 halogen atom or a lower alkyl group, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R8)q 10 (in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(47) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula: -A5-CR42R43R44 (A5, R42, 15 R43 and R44 are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(48) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a 2,3-dihydro-1 H-indenyl group-substituted lower 20 alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3 -dihydro-1 H-indenyl ring, and m, n and r are the same as defined above, or a salt thereof.
(49) A quinoxaline derivative of the formula (1), wherein R1 is a 25 halogen atom or a lower alkyl group, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R47)u 30 (in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(50) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is hydrogen atom, R3 and R4 combine 2~503~S

together with the nitrogen atom to form 1,2,3,4-tetrahydroisoquinolyl group which may optionally have a lowenalkoxy group), and m, n and r are the same as defined above, or a salt thereof.
(51 ) A quinoxaline derivative of the formula (1), wherein R1 is a 5 halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R5)p A~

(in which A, R5 and p are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(52) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionally15 a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy 20 group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and m, n and r are the same as defined above, or a salt thereof.
25 (53) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionallya halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a loweralkenyl group, and m, n and r are the same as defined above, or a salt thereof.
(54) A quinoxaline derivative of the formula (1), wherein R1 is a 30 halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a cycloalkyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.

WO 95/09159 2 1 5 0 3 4 ~ PCT/JP94/01559 (55) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionallya halogen substituent, R3is hydrogen atom or a lower alkyl group, R4is a naphthyl-lower alkyl group, and m, n and r are the same as defined above, or a 5 salt thereof.
(56) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionallya halogen substituent, R3is hydrogen atom or a lower alkyl group, R4is a phenylthio-substituted lower alkyl group which may optionally have a lower 10 alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(57) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionallya halogen substituent, R3is hydrogen atom or a lower alkyl group, R4is a 15 phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety and m, n and r are the same as defined above, or a salt thereof.
(58) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionally20 a halogen substituent, R3is hydrogen atom or a lower alkyl group, R4is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(59) A quinoxaline derivative of the formula (1), wherein R1 is a 25 halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionally a halogen substituent, R3is hydrogen atom or a lower alkyl group, R4is a phenoxy-substituted lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(60) A quinoxaline derivative of the formula (1), wherein R1 is a 30 halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionally a halogen substituent, R3is hydrogen atom or a lower alkyl group, R4is a group of the formula:

WO 95/09159 PCT/JP94/OlSS9 ~ls~345 (R8) (in which the symbols are the same as defined above), and m, n and r are the 5 same as defined above, or a salt thereof.
(61 ) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionallya halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula: -A5-CR42R43R44 (A5, R42, R43 and R44 are the same as 10 defined above), and m, n and r are the same as defined above, or a salt thereof.
(62) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionallya halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a 2,3 -15 dihydro-1 H-indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n and r are the same as defined above, or a salt thereof.
(63) A quinoxaline derivative of the formula (1), wherein R1 is a 20 halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R47)u ~<
~J
(in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(64) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a lower alkyl group having optionally30 a halogen substituent, R3 and R4 combine together with the nitrogen atom to form 1,2,3,4-tetrahydroisoquinolyl group which may optionally have a lower alkoxy group, and m, n and r are the same as defined above, or a salt thereof.
(65)A quinoxaline derivative of the formula (1), wherein R1 is a 21~03 1~

halogen atom or a lower alkyl group, R2 is phenyl group, R3is hydrogen atom or a lower alkyl group, R4is a group of the formula:

A~ (R5)p (in which A,R5 and p are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(66) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is phenyl group, R3is hydrogen atom 10 or a lower alkyl group, R4is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a 15 lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and m, n and r are the same as defined above, or a salt thereof.
(67) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is phenyl group, R3is hydrogen atom or a lower alkyl group, R4is a lower alkenyl group, and m, n and r are the same as defined above, or a salt thereof.
(68) A quinoxaline derivative of the formula (1), wherein R1 is a 25 halogen atom or a lower alkyl group, R2 is phenyl group, R3is hydrogen atom or a lower alkyl group, R4is a cycloalkyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(69) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is phenyl group, R3is hydrogen atom 30 or a lower alkyl group, R4is a naphthyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(70) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is phenyl group, R3is hydrogen atom 2lso34s or a lower alkyl group, R4 is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(71 ) A quinoxaline derivative of the formula (1), wherein R1 is a 5 halogen atom or a lower alkyl group, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety and m, n and r are the same as defined above, or a salt thereof.
(72) A quinoxaline derivative of the formula (1), wherein R1 is a 10 halogen atom or a lower alkyl group,R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(73) A quinoxaline derivative of the formula (1), wherein R1 is a 15 halogen atom or a lower alkyl group, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenoxy-substituted lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(74) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is phenyl group, R3 is hydrogen atom 20 or a lower alkyl group, R4 is a group of the formula:
(R8)q {~
(in which the symbols are the same as defined above), and m, n and r are the 25 same as defined above, or a salt thereof.
(75) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula: -A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and m, n and r are the same as 30 defined above, or a salt thereof.
(76) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a 2,3-dihydro-1 H-indenyl group-substituted lower WO 95/09159 PCI~/JP94/01559 21503~5 alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3 -dihydro-1 H-indenyl ring, and m, n and r are the same as defined above, or a salt thereof.
5 (77) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R47) ~<
~) (in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(78) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is phenyl group, R3 and R4 combine 15 together with the nitrogen atom to form 1,2,3,4-tetrahydroisoquinolyl group which may optionally have a lower alkoxy group), and m, n and r are the same as defined above, or a salt thereof.
(79) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl 20 group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R5)p A~

(in which A, R5 and p are the same as defined above), 25 and m, n and r are the same as defined above, or a salt thereof.
(80) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected 30 from a lower alkoxy group, a halogen atom, an amino group having optionally asubstituent selected from a lower alkanoyl group and a phenyl-lower alkenyl -carbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy PCT/~4101559 2~S o3 4S -56-group, a group of the formula: -O-A4-CO-NR40R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and m, n and r are the same as defined above, or a salt thereof.
5 (81) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl group, R3is hydrogen atom or a lower alkyl group, R4is a lower alkenyl group, and m, n and r are the same as defined above, or a salt thereof.
(82) A quinoxaline derivative of the formula (1), wherein R1 is a 10 halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl group, R3is hydrogen atom or a lower alkyl group, R4is a cycloalkyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(83) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl 15 group, R3is hydrogen atom or a lower alkyl group, R4iS a naphthyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(84) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl group, R3iS hydrogen atom or a lower alkyl group, R4is a phenylthio -20 substituted lower alkyl group which may optionally have a lower alkoxysubstituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(85) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl 25 group, R3iS hydrogen atom or a lower alkyl group, R4is a phenylsulfinyl -substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety and m, n and r are the same as defined above, or a salt thereof.
(86) A quinoxaline derivative of the formula (1), wherein R1 is a 30 halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl group, R3is hydrogen atom or a lower alkyl group, R4 is a phenylsulfonyl -substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined 21503~

above, or a salt thereof.
(87) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenoxy-substituted 5 lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(88) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
1 0 (R8)q (in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(89) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:-A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(90) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a 2,3-dihydro-1 H -indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n and r are the same as defined above, or a salt thereof.
(91 ) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula: (R47) ~, (in which the symbols are the same as defined above), and m, n and r are the WO 95/O91S9 2~S o3 45 PCT/JP94101559 same as defined above, or a salt thereof.
(92) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is a morpholino-substituted lower alkyl group, R3 and R4 combine together with the nitrogen atom to form 1,2,3,4 -5 tetrahydroisoquinolyl group which may optionally have a lower alkoxy group),and m, n and r are the same as defined above, or a salt thereof.
(93) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkylgroup, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:1 0 (R5)p A~

(in which A, R5 and p are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
15 (94) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkylgroup, R3 is hydrogen atom or a lower alkyl group, R4 is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a 20 substituent selected from a lower alkanoyl group and a phenyl-lower alkenyl -carbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxygroup, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a 25 lower alkyl group having optionally a halogen substituent, and m, n and r are the same as defined above, or a salt thereof.
(95) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkylgroup, R3 is hydrogen atom or a lower alkyl group, R4 is a lower alkenyl group, 30 and m, n and r are the same as defined above, or a salt thereof.
(96) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkylgroup, R3 is hydrogen atom or a lower alkyl group, R4 is a cycloalkyl-lower alkyl WO 95/09159 2 1 5 0 3 ~ 5 PCI/JP94/01559 _ group, and m, n and r are the same as defined above, or a salt thereof.
(97) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkylgroup, R3 is hydrogen atom or a lower alkyl group, R4 is a naphthyl-lower alkyl 5 group, and m, n and r are the same as defined above, or a salt thereof.
(98) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkylgroup, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylthio -substituted lower alkyl group which may optionally have a lower alkoxy 10 substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(99) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkylgroup, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylsulfinyl -15 substituted lower alkyl group which may optionally have a lower alkoxysubstituent on the phenyl moiety and m, n and r are the same as defined above, or a salt thereof.
(100) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkyl20 group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylsulfonyl -substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(101 ) A quinoxaline derivative of the formula (1), wherein R1 is a 25 halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenoxy-substituted lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(102) A quinoxaline derivative of the formula (1), wherein R1 is a 30 halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:

WO 9S/09159 PCT/JP94/OlS59 2l503~

(R8)q ~-,.
(in which the symbols are the same as defined above), and m, n and r are the 5 same as defined above, or a salt thereof.
(103) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkylgroup, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:-A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and m, 10 n and r are the same as defined above, or a salt thereof.
(104) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkylgroup, R3 is hydrogen atom or a lower alkyl group, R4 is a 2,3-dihydro-1 H -indenyl group-substituted lower alkyl group which may optionally have a 15 substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n and r are the same as defined above, or a salt thereof.
(105) A quinoxaline derivative of the formula (1), wherein Rl is a halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkyl20 group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R47)u ~<

(in which the symbols are the same as defined above), and m, n and r are the 25 same as defined above, or a salt thereof.
(106) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group, R2 is an imidazolyl-substituted lower alkylgroup, R3 and R4 combine together with the nitrogen atom to form 1,2,3,4 -tetrahydroisoquinolyl group which may optionally have a lower alkoxy group), 30 and m, n and r are the same as defined above, or a salt thereof.
(107) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom, R3 is hydrogen atom, R4 is a group of the formula:

WO 95/09159 2 1 ~ 0 3 ~ 5 PCT/JP94/01559 A ~ (R5)p (wherein A,R5 and p are the same as defined above), and R2, m, n and r are the same as defined above, or a salt thereof.
(108) A quinoxaline derivative of the formula (1), wherein R1is hydrogen atom, R3is a lower alyl group, R4is a group of the formula:
(Rs jp A
(wherein A,R5 and p are the same as defined above), and R2, m, n and r are the same as defined above, or a salt thereof.
(109) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom, R3is hydrogen atom, R4is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -o-A4-Co-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and R2, m, n and r are the same as defined above, or a salt thereof.
(110) A quinoxaline derivative of the formula (1), wherein R1is hydrogen atom, R3iS a lower alkyl group, R4is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenyl -carbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxygroup, a group of the formula: -O-A4-CO-NR40R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and R2, m, n and r WO gS/Ogl59 2 ~S O 3 45 PCT/JPg4/01559 are the same as defined above, or a salt thereof.
(111 ) A quinoxaline derivative of the formula (1), wherein R1is hydrogen atom, R3is hydrogen atom, R4is a lower alkenyl group, and R2, m, n and r are the same as defined above, or a salt thereof.
(112) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom, R3is a lower alkyl group, R4is a lower alkenyl group, and R2, m, n and r are the same as defined above, or a salt thereof.
(113) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom, R3is hydrogen atom, R4is a cycloalkyl-lower alkyl group, and R2, m, n and r are the same as defined above, or a salt thereof.
(114) A quinoxaline derivative of the formula (1), wherein R1is hydrogen atom, R3is a lower alkyl group, R4is a cycloalkyl-lower alkyl group, and R2, m, n and r are the same as defined above, or a salt thereof.
(115) A quinoxaline derivative of the formula (1), wherein R1is hydrogen atom, R3is hydrogen atom, R4is a naphthyl-lower alkyl group, and R2, m, n and r are the same as defined above, or a salt thereof.
(116) A quinoxaline derivative of the formula (1), wherein R1is hydrogen atom, R3is a lower alkyl group, R4is a naphthyl-lower alkyl group, and R2, m, n and r are the same as defined above, or a salt thereof.
(117) A quinoxaline derivative of the formula (1), wherein R1is hydrogen atom, R3is hydrogen atom, R4is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R2, m, n and r are the same as defined above, or a salt thereof.
(118) A quinoxa ine derivative of the fornula (1), wherein R1is hydrogen atom, R3is l lower alkyl group, R4is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R2, m, r. and r are the same as defined above, or a salt thereof.
(119) A quinoxaline derivative of the formula (1), wherein R1is hydrogen atom, R3 is hydrogen atom, R4is a phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R2, m, n and r are the same as defined above, or a salt thereof.
(120) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen ator " R3is a lower alkyl group, R4is a phenylsulfinyl-substituted WO 95/09159 2 1 5 0 3 ~ 5 PCI/JP94/OlS59 lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R2, m, n and r are the same as defined above, or a salt thereof.
(121) A quinoxaline derivative of the formula (1), wherein R1 is 5 hydrogen atom, R3 is hydrogen atom, R4 is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R2, m, n and r are the same as defined above, or a salt thereof.
(122) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom, R3 is a lower alkyl group, R4 is a phenylsulfonyl-substituted 10 lower alkyl group which may optionally have a lower alkoxy substituent on thephenyl moiety, and R2, m, n and r are the same as defined above, or a salt thereof.
(123) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom, R3 is hydrogen atom, R4 is a phenoxy-substituted lower alkyl 15 group, and R2, m, n and r are the same as defined above, or a salt thereof.
(124) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom, R3 is a lower alkyl group, R4 is a phenoxy-substituted lower alkyl group, and R2, m, n and r are the same as defined above, or a salt thereof.
(125) A quinoxaline derivative of the formula (1), wherein R1 is 20 hydrogen atom, R3 is hydrogen atom, R4 is a group of the formula:
(Ra)q (wherein the symbols are the same as defined above), and R2, m, n and r are 25 the same as defined above, or a salt thereof.
(126) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom, R3 is a lower alkyl group, R4 is a group of the formula:
(R8)q ~
(wherein the symbols are the same as defined above), and R2, m, n and r are the same as defined above, or a salt thereof.
(127) A quinoxaline derivative of the formula (1), wherein R1 is wo gs/ogl592 15 03 4~ PCT/JP94/01559 hydrogen atom, R3is hydrogen atom, R4is a group of the formula:
-A5-CR42R43R44(A5,R42,R43 and R44 are the same as defined above), and R2, m, n and r are the same as defined above, or a salt thereof.
(128) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom, R3is a lower alkyl group, R4is a group of the formula:
-A5-CR42R43R44(A5,R42,R43 and R44 are the same as defined above), and R2, m, n and r are the same as defined above, or a salt thereof.
(129) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom, R3is hydrogen atom, R4is a 2,3-dihydro-1 H-indenyl group -substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and R2, m, n and r are the sameas defined above, or a salt thereof.
(130) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom, R3is a lower alkyl group, R4is a 2,3-dihydro-1 H-indenyl group -substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and R2, m, n and r are the sameas defined above, or a salt thereof.
(131) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom, R3is hydrogen atom, R4is a group of the formula:
(R47)u ,~
,~, (in which the symbols are the same as defined above), and R2, m, n and r are the same as defined above, or a salt thereof.
(132) A quinoxaline derivative of the formula (1), wherein Rlis hydrogen atom, R3is a lower alkyl group, R4is a group of the formula:
(R47)u ~

(in which the symbols are the same as defined above), and R2, m, n and r are the same as defined above, or a salt thereof.

WO95109159 2 1 5 ~ 3 4 ~ PCT/JP94101559 (133) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom, R3 and R4 combine together with the nitrogen atom to form 1,2,3,4-tetrahydroquinolyl group which may optionally have a lower alkoxy group), and R2, m, n and r are the same as defined above, or a salt thereof.
5 (134) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group and R2, R3,R4, m, n and r are the same as defined above, or a salt thereof.
(135) A quinoxaline derivative of the formula (1),wherein R1 is an amino group having optionally a lower alkyl substituent and R2, R3,R4, m, n and r are 10 the same as defined above, or a salt thereof.
(136) A quinoxaline derivative of the formula (1),wherein R1 is an aminocarbonyl group having optionally a lower alkyl substituent and R2, R3,R4, m, n and r are the same as defined above, or a salt thereof.
(137) A quinoxaline derivative of the formula (1),wherein R3is a phenyl -15 lower alkoxycarbonyl group and R4is a group of the formula:
(R5)p A~

(in which A, R5 and p are the same as defined above), and R1, R2, m, n and r 20 are the same as defined above, or a salt thereof.(138) A quinoxaline derivative of the formula (1),wherein R3is a lower alkanoyloxy-substituted lower alkyl group and R4is a group of the formula:

A~ (R5)p (in which A, R5 and p are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(139) A quinoxaline derivative of the formula (1),wherein R3is a phenyl -lower alkoxycarbonyl group and R4is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl ring selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having WO 95/09159 PCT/JP94/OlSS9 ~2l~03~

optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -o-A4-Co-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(140) A quinoxaline derivative of the formula (1),wherein R3is a lower alkanoyloxy-substituted lower aikyl group and R4is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl ring selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenyl -carbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxygroup, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and R1,R2, m, n and r are the same as defined above, or a salt thereof.
(141) A quinoxaline derivative of the formula (1),wherein R3is a phenyl -lower alkoxycarbonyl group and R4is a lower alkenyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(142) A quinoxaline derivative of the formula (1),wherein R3is a lower alkanoyloxy-substituted lower alkyl group and R4is a lower alkenyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(143) A quinoxaline derivative of the formula (1),wherein R3is a phenyl -lower alkoxycarbonyl group and R4is a cycloalkyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(144) A quinoxaline derivative of the formula (1),wherein R3is a lower alkanoyloxy-substituted lower alkyl group and R4is a cycloalkyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(145) A quinoxaline derivative of the formula (1),wherein R3iS a phenyl -lower alkoxycarbonyl group and R4is a naphthyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(146) A quinoxaline derivative of the formula (1),wherein R3is a lower alkanoyloxy-substituted lower alkyl group and R4is a naphthyi-lower alkyl wogs/ogl59 2 1 S 0 3 4 ~ PCT/JP94/OlSS9 group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(147) A quinoxaline derivative of the formula (1),wherein R3is a phenyl -lower alkoxycarbonyl group and R4is a phenylthio-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl ring, and R1, 5 R2, m, n and r are the same as defined above, or a salt thereof.
(148) A quinoxaline derivative of the formula (1),wherein R3is a lower alkanoyloxy-substituted lower alkyl group and R4 is a phenylthio-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(149) A quinoxaline derivative of the formula (1),wherein R3is a phenyl -lower alkoxycarbonyl group and R4is a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(150) A quinoxaline derivative of the formula (1), wherein R3is a lower 15 alkanoyloxy-substituted lower alkyl group, R4is a phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(151) A quinoxaline derivative of the formula (1), wherein R3is a phenyl -20 lower alkoxycarbonyl group, R4is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.(152) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyloxy-substituted lower alkyl group, R4is a phenylsulfonyl-substituted 25 lower alkyl group which may optionally have a lower alkoxy substituent on thephenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(153) A quinoxaline derivative of the formula (1), wherein R3is a phenyl -lower alkoxycarbonyl group, R4is a phenoxy-substituted lower alkyl group, and 30 R1, R2, m, n and r are the same as defined above, or a salt thereof.
(154) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyloxy-substituted lower alkyl group, R4is a phenoxy-substituted lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt WO 95/09159 PCI/JP94/OlS59 2~so3 ~

thereof.
(155) A quinoxaline derivative of the formula (1), wherein R3is a phenyl -lower alkoxycarbonyl group, R4is a group of the formula:
(R8)q ~

(wherein the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(156) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyloxy-substituted lower alkyl group, R4is a group of the formula:
(R8)q (in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(157) A quinoxaline derivative of the formula (1), wherein R3is a phenyl -lower alkoxycarbonyl group, R4is a group of the formula: -A5-CR42R43R44 (A5, R42,R43 and R44 are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(158) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyloxy-substituted lower alkyl group, R4is a group of the formula:
-A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(159) A quinoxaline derivative of the formula (1), wherein R3is a phenyl -lower alkoxycarbonyl group, R4is a 2,3-dihydro-1 H-indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1H-indenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(160) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyloxy-substituted lower alkyl group, R4is a 2,3-dihydro-1 H-indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower WO 95/09159 2~ 1 5 0 3 4 ~i PCI/JP94/01559 alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(161 ) A quinoxaline derivative of the formula (1), wherein R3is a phenyl -lower alkoxycarbonyl group, R4is a group of the formula:
(R47) (in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(162) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyloxy-substituted lower alkyl group, R4is a group of the formula:
(R47) (in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(163) A quinoxaline derivative of the formula (1) wherein R3is a lower alkanoyl group, R4is a group of the formula:
(R5)p A ~

(wherein A,R5 and p are the same as defined above), and R1, R2 and r are the same as defined above, or a salt thereof.
(164) A quinoxaline derivative of the formula (1) wherein R3is a lower alkoxycarbonyl group, R4is a group of the formula:
(R5)p A~

(wherein A, R5 and p are the same as defined above), 30 and R1, R2 and r are the same as defined above, or a salt thereof.
(165) A quinoxaline derivative of the formula (1) wherein R3is a lower alkanoyl group, R4is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a WO95/09159 rcT/Jrg4/olssg 2~a3~s halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -o-A4-CO-NR40R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and R1, R3,R4, m, n and r are the same as defined above, or a salt thereof.
(166) A quinoxaline derivative of the formula (1) wherein R3is a lower alkoxycarbonyl group, R4is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula:
-O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and R1, R3,R4, m, n and r are the same as defined above, or a salt thereof.
(167) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyl group, R4is a lower alkenyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(168) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyl group, R4is a lower alkenyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(169) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyl group, R4is a cycloalkyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(170) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyl group, R4is a cycloalkyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(171) A quinoxaline derivative of the formula (1), wherein R3is a lower WO 95/O91S9 PCI~/JP94/OlSS9 - 21~0345 alkanoyl group, R4is a naphthyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(172) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyl group, R4is a naphthyl-lower alkyl group, and R1, R2, m, n and 5 r are the same as defined above, or a salt thereof.
(173) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyl group, R4is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(174) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyl group, R4is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(175) A quinoxaline derivative of the formula (1), wherein R3 is a lower alkanoyl group, R4is a phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(176) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyl group, R4is a phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(177) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyl group, R4is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(178) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyl group, R4is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(179) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyl group, R4is a phenoxy-substituted lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(180) A quinoxaline derivative of the formula (1), wherein R3is a lower WO 95tO9lS9 PCI/JP94/01559 ~5~3~ - 72 -alkoxyca nyl group, R4is a phenoxy-substituted lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(181) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyl group, R4is a group of the formula:
(R8) (wherein the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(182) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyl group, R4is a group of the formula:
(R8)q (in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(183) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyl group, R4is a group of the formula: -A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(184) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyl group, R4is a group of the formula: -A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(185) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyl group, R4iS a 2,3-dihydro-1H-indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3 -dihydro-1 H-indenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(186) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyl group, R4is a 2,3-dihydro-1H-indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, WO 95/09159 2 1 5 0 3 ~ ~ PCT/JP94/01559 hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3 -dihydro-1 H-indenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(187) A quinoxaline derivative of the formula (1), wherein R3is a lower 5 alkanoyl group, R4is a group of the formula:
(R47)u ~, (in which the symbols are the same as defined above), 10 and R1,R2, m, n and r are the same as defined above, or a salt thereof.
(188) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyl group, R4is a group of the formula:
(R47)u ~
(in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(189) A quinoxaline derivative of the formula (1) wherein R3is a lower alkoxy-lower alkyl group, R4is a group of the formula:
(R5)p A~

(wherein A, R5 and p are the same as defined above), and R1, R2 and r are the same as defined above, or a salt thereof.
(190) A quinoxaline derivative of the formula (1 ) wherein R3is phenoxycarbonyl group, R4is a group of the formula:
(R5)p A~
\=J
(wherein A, R5 and p are the same as defined above), and R1, R2 and r are the same as defined above, or a salt thereof.
(191) A quinoxaline derivative of the formula (1) wherein R3is a lower alkoxy-lower alkyl group, R4is a phenyl-lower alkenyl group which may WO95/09159 PCT/JPg4/olSS9 2~S o3 4S

optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having 5 optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula:
-O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and R1, R3,R4, m, n and r are the same as defined 10 above, or a salt thereof.
(192) A quinoxaline derivative of the formula (1) wherein R3is phenoxycarbonyl group, R4is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent 15 selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula:
-O-A4-Co-NR4R41 (in which A4, R40 and R41 are the same as defined above), 20 a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and R1, R3,R4, m, n and r are the same as defined above, or a salt thereof.
(193) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxy-lower alkyl group, R4is a lower alkenyl group, and R1, R2, m, n and r are25 the same as defined above, or a salt thereof.
(194) A quinoxaline derivative of the formula (1), wherein R3is phenoxy carbonyl group, R4is a lower alkenyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(195) A quinoxaline derivative of the formula (1), wherein R3iS a lower 30 alkoxy-lower alkyl group, R4is a cycloalkyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above.
(196) A quinoxaline derivative of the formula (1), wherein R3 is phenoxycarbonyl group, R4 is a cycloalkyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(197) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxy-lower alkyl group, R4is a naphthyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(198) A quinoxaline derivative of the formula (1), wherein R3is phenoxycarbonyl group, R4is a naphthyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(199) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxy-lower alkyl group, R4is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and Rl, R2, m, n and r are the same as defined above, or a salt thereof.
(200) A quinoxaline derivative of the formula (1), wherein R3is phenoxycarbonyl group, R4is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(201 ) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxy -lower alkyl group, R4is a phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(202) A quinoxaline derivative of the formula (1), wherein R3is phenoxycarbonyl group, R4is a phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(203) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxy-lower alkyl group, R4is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(204) A quinoxaline derivative of the formula (1), wherein R3is phenoxycarbonyl group, R4is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and Rl, R2, m, n and r are the same as defined above, or a salt thereof.
(205) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxy-lower alkyl group, R4is a phenoxy-substituted lower alkyl group, and 2l5034s - ~6 -R1, R2, m, n and r are the same as defined above, or a salt thereof.
(206) A quinoxaline derivative of the formula (1), wherein R3is phenoxycarbonyl group, R4is a phenoxy-substituted lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(207) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxy-lower alkyl group, R4is a group of the formula:
(R8)q (wherein the symbols are the same as defined above), and R1,R2, m, n and r are the same as defined above, or a salt thereof.
(208) A quinoxaline derivative of the formula (1), wherein R3is phenoxycarbonyl group, R4is a group of the formula:
tR8)q ~

(in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(209) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxy-lower alkyl group, R4is a group of the formula: -A5-CR42R43R44 (A5, R42,R43 and R44 are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(210) A quinoxaline derivative of the formula (1), wherein R3is phenoxycarbonyl group, R4is a group of the formula: -A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(211 ) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxy-lower alkyl group, R4is a 2,3-dihydro-1 H-indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1H-indenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(212) A quinoxaline derivative of the formula (1), wherein R3is phenoxy-WO 9S/09159 2 1 5 0 3 4 S PCI~/JP94/01559 carbonyl group, R4 is a 2,3-dihydro-1 H-indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3 -dihydro-1 H-indenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(213) A quinoxaline derivative of the formula (1), wherein R3 is a lower alkoxy-lower alkyl group, R4 is a group of the formula:
(R47)u (in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(214) A quinoxaline derivative of the formula (1), wherein R3 is phenoxy -carbonyl group, R4 is a group of the formula:
1 5 (R47)u (in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(215) A quinoxaline derivative of the formula (1) wherein R3 is a lower alkanoyl-substituted lower alkyl group, R4 is a group of the formula:
(R5)p A~

(wherein A, R5 and p are the same as defined above), and R1, R2 and r are the same as defined above, or a salt thereof.
(216) A quinoxaline derivative of the formula (1) wherein R3 is a lower alkoxycarbonyloxy-substituted lower alkyl group, R4 is a group of the formula:
(R5)p A~
\=/
(wherein A, R5 and p are the same as defined above), and R1, R2 and r are the same as defined above, or a salt thereof.

WOgS/09159 PCT/~4/01559 (217) A quinoxaline derivative of the formula (1) wherein R3is lower alkanoyl-substituted lower alkyl group, R4is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a 5 substituent selected from a lower alkanoyl group and a phenyl-lower alkenyl -carbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxygroup, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a 10 lower alkyl group having optionally a halogen substituent, and R1,R3,R4, m, n and r are the same as defined above, or a salt thereof.
(218) A quinoxaline derivative of the formula (1) wherein R3is a lower alkoxycarbonyloxy-substituted lower alkyl group, R4is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected 15 from a lower alkoxy group, a halogen atom, an amino group having optionally asubstituent selected from a lower alkanoyl group and a phenyl-lower alkenyl -calbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxygroup, a group of the formula: -O-A4-Co-NR4R41 (in which A4, R40 and R41 20 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and R1, R3,R4, m, n and r are the same as defined above, or a salt thereof.
(219) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyl-substituted lower alkyl group, R4is a lower alkenyl group, and R1, R2, 25 m, n and r are the same as defined above, or a salt thereof.
(220) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyloxy-substituted lower alkyl group, R4is a lower alkenyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(221) A quinoxaline derivative of the formula (1), wherein R3iS a lower 30 alkanoyl-substituted lower alkyl group, R4is a cycloalkyl-lower alkyl group, and R1, R2, m, n and r are the same as the same, or a salt thereof.
(222) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyloxy-substituted lower alkyl group, R4is a cycloalkyl-lower alkyl WO 95/09159 2 1 ~ 0 3 4 5 PC~IJP94/OlS~9 group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(223) A quinoxaline derivative of the formula (1), wherein R3 is a lower alkanoyl-substituted lower alkyl group, R4 is a naphthyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
5 (224) A quinoxaline derivative of the formula (1), wherein R3 is a lower alkoxycarbonyloxy-substituted lower alkyl group group, R4 is a naphthyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(225) A quinoxaline derivative of the formula (1), wherein R3 is a lowe 10 alkanoyl-substituted lower alkyl group, R4 is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.(226) A quinoxaline derivative of the formula (1), wherein R3 is a lower alkoxycarbonyloxy-substituted lower alkyl group, R4 is a phenylthio-substituted 15 lower alkyl group which may optionally have a lower alkoxy substituent on thephenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(227) A quinoxaline derivative of the formula (1), wherein R3 is a lower alkanoyl-substituted lower alkyl group, R4 is a phenylsulfinyl-substituted lower20 alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.(228) A quinoxaline derivative of the formula (1), wherein R3 is a lower alkoxycarbonyloxy-substituted lower alkyl group, R4 is a phenylsulfinyl -substituted lower alkyl group which may optionally have a lower alkoxy 25 substituent on the phenyl moiety, and Rl, R2, m, n and r are the same as defined above, or a salt thereof.
(229) A quinoxaline derivative of the formula (1), wherein R3 is a lower alkanoyl-substituted lower alkyl group, R4 is a phenylsulfonyl-substituted loweralkyl group which may optionally have a lower alkoxy substituent on the phenyl 30 moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(230) A quinoxaline derivative of the formula (1), wherein R3 is a lower alkoxycarbonyloxy-substituted lower alkyl group, R4 is a phenylsulfonyl -substituted lower alkyl group which may optionally have a lower alkoxy WO 9S/09lS9 ~ 3 ~s~ PCT/JP94/OlSS9 substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(231) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyl-substituted lower alkyl group, R4is a phenoxy-substituted lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(232) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyloxy-substituted lower alkyl group, R4is a phenoxy-substituted lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
1 0 (233) A quinoxaline derivative of the formula (1), wherein R3iS a lower alkanoyl-substituted lower alkyl group, R4is a group of the formula:
(R8)q (wherein the symbols are the same as defined above), and R1,R2, m, n and r are the same as defined above, or a salt thereof.
(234) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyloxy-substituted lower alkyl group, R4is a group of the formula:
(R8)q ~
~, (in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(235) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyl-substituted lower alkyl group, R4is a group of the formula:
-A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(236) A quinoxaline derivative of the formula (1), wherein R3is a lower alkoxycarbonyloxy-substituted lower alkyl group, R4iS a group of the formula:
-A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(237) A quinoxaline derivative of the formula (1), wherein R3is a lower alkanoyl-substituted lower alkyl group, R4is a 2,3-dihydro-1H-indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1H-indenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
5 (238) A quinoxaline derivative of the formula (1), wherein R3 is a lower alkoxycarbonyloxy-substituted lower alkyl group, R4 is a 2,3-dihydro-1 H -indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and R1, R2, m, n 10 and r are the same as defined above, or a salt thereof.
(239) A quinoxaline derivative of the formula (1), wherein R3 is a lower alkanoyl-substituted lower alkyl group, R4 is a group of the formula:
(R47)u ,7<
15 ~) (in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(240) A quinoxaline derivative of the formula (1), wherein R3 is a lower alkoxycarbonyloxy-substituted lower alkyl group, R4 is a group of the formula:
(R47)u ~, (in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(241 ) A quinoxaline derivative of the formula (1 ) wherein R3 is a benzoyl-substituted lower alkyl group which may optionally have a halogen substituent on the phenyl ring, R4 is a group of the formula:
(R5) A~
(wherein A, R5 and p are the same as defined above), and R1, R2 and r are the same as defined above, or a salt thereof.
(242) A quinoxaline derivative of the formula (1 ) wherein R3 is a group WO 95/09159 PCT/JP94/OlS59 2,~S~3 4S - 82 -of the formula: -E-NR52R53 (in which E, R52 and R53 are the same as defined above), R4is a group of the formula:
(R5)p A ~

(wherein A,R5 and p are the same as defined above), and R1, R2 and r are the same as defined above, or a salt thereof.
(243) A quinoxaline derivative of the formula (1 ) wherein R3is a benzoyl-substituted lower alkyl group which may optionally have a halogen substituent on the phenyl ring, R4is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and R1, R3,R4, m, n and r are the same as defined above, or a salt thereof.
(244) A quinoxaline derivative of the formula (1) wherein R3is a group of the formula: -E-NR52R53 (in which E, R52 and R53 are the same as defined above), R4iS a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula:
-O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and R1, R3,R4, m, n and r are the same as defined above, or a salt thereof.
(245) A quinoxaline derivative of the formula (1), wherein R3is a benzoyl-substituted lower alkyl group which may optionally have a halogen wo gS/oglS9 2 1 ~ 0 3 4 ~ PCT/JP94/01559 substituent on the phenyl ring, R4is a lower alkenyl group, and R1, R2, m, n andr are the same as defined above, or a salt thereof.
(246) A quinoxaline derivative of the formula (1), wherein R3is a group of the formula: -E-NR52R53 (in which E, R52 and R53 are the same as defined above), R4is a lower alkenyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(247) A quinoxaline derivative of the formula (1), wherein R3is a benzoyl-substituted lower alkyl group which may optionally have a halogen substituent on the phenyl ring, R4is a cycloalkyl-lower alkyl group, and R1, R2,m, n and r are the same as defined above, or a salt thereof.
(248) A quinoxaline derivative of the formula (1), wherein R3is a group of the formula: -E-NR52R53 (in which E, R52 and R53 are the same as defined above), R4is a cycloalkyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(249) A quinoxaline derivative of the formula (1), wherein R3is a benzoyl-substituted lower alkyl group which may optionally have a halogen substituent on the phenyl ring, R4is a naphthyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(250) A quinoxaline derivative of the formula (1), wherein R3is a group of the formula: -E-NR52R53 (in which E, R52 and R53 are the same as defined above), R4is a naphthyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(251) A quinoxaline derivative of the formula (1), wherein R3is a benzoyl-substituted lower alkyl group which may optionally have a halogen substituent on the phenyl ring, R4is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(252) A quinoxaline derivative of the formula (1), wherein R3is a group of the formula: -E-NR52R53 (in which E, R52 and R53 are the same as defined above), R4is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(253) A quinoxaline derivative of the formula (1), wherein R3is a WO9S/09159 PCT1~4/01559 ~S~3~5 benzoyl-substituted lower alkyl group which may optionally have a halogen substituent on the phenyl ring, R4is a phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.(254) A quinoxaline derivative of the formula (1), wherein R3is a group of the formula: -E-NR52R53 (in which E, R52 and R53 are the same as defined above), R4is a phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
1 0 (255) A quinoxaline derivative of the formula (1), wherein R3is a benzoyl-substituted lower alkyl group which may optionally have a halogen substituent on the phenyl ring, R4is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
1 5 (256) A quinoxaline derivative of the formula (1), wherein R3is a groupof the formula: -E-NR52R53 (in which E, R52 and R53 are the same as defined above), R4is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(257) A quinoxaline derivative of the formula (1), wherein R3is a benzoyl-substituted lower alkyl group which may optionally have a halogen substituent on the phenyl ring, R4is a phenoxy-substituted lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(258) A quinoxaline derivative of the formula (1), wherein R3is a group of the formula: -E-NR52R53 (in which E, R52 and R53 are the same as defined above), R4is a phenoxy-substituted lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(259) A quinoxaline derivative of the formula (1), wherein R3is a benzoyl-substituted lower alkyl group which may optionally have a halogen substituent on the phenyl ring R4is a group of the formula:

WO 95/09159 2 1 5 0 3 ~ 5 PCTIJP94/01559 (R8)q {~
(wherein the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(260) A quinoxaline derivative of the formula (1), wherein R3is a group of the formula: -E-NR52R53 (in which E, R52 and R53 are the same as defined above), R4is a group of the formula:
(R8)q (in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(261 ) A quinoxaline derivative of the formula (1), wherein R3is a benzoyl-substituted lower alkyl group which may optionally have a haiogen substituent on the phenyl ring, R4is a group of the formula: -A5-CR42R43R44 (A5,R42,R43 and R44 are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(262) A quinoxaline derivative of the formula (1), wherein R3is a group of the formula: -E-NR52R53 (in which E, R52 and R53 are the same as defined above), R4is a group of the formula: -A5-CR42R43R44 (A5,R42,R43 and R44 are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(263) A quinoxaline derivative of the formula (1), wherein R3is a benzoyl-substituted lower alkyl group which may optionally have a halogen substituent on the phenyl ring, R4is a 2,3-dihydro-1 H-indenyl group-substitutedlower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and R1, R2, m, n and r are the same as definedabove, or a salt thereof.
(264) A quinoxaline derivative of the formula (1), wherein R3is a group of the formula: -E-NR52R53 (in which E, R52 and R53 are the same as defined above), R4is a 2,3-dihydro-1 H-indenyl group-substituted lower alkyl group 3~

which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro -1 H-indenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
5 (265) A quinoxaline derivative of the formula (1), wherein R3 is a benzoyl-substituted lower alkyl group which may optionally have a halogen substituent on the phenyl ring, R4 is a group of the formula:
(R47)u ~
(in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(266) A quinoxaline derivative of the formula (1), wherein R3 is a group of the fomula: -E-NR52N53 (in which E, R52 and R53 are the same as defined 15 above), R4 is a group of the formula:
(R47)u ~, (in which the symbols are the same as defined above), 20 and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(267) A quinoxaline derivative of the formula (1 ) wherein R3 is a group of the formula:
A~R54 `n' (in which A and R54 are the same as defined above), R4 is a group of the formula:
(R5)p A~

(in which A, R5 and p are the same as defined above), and R1, R2 and r are the same as defined above, or a salt thereof.

WO9S/09159 2l~n345 PCI/JP94/01559 (268) A quinoxaline derivative of the formula (1) wherein R3is a group of the formula:
- --A~R54 O~O
o (in which A and R54 are the same as defined above), R4is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having 10 optionally a substituent selected from a lower alkanoyl group and a phenyl -lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -O-A4-CO-NR40R41 (in which A4,R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group 15 and a lower alkyl group having optionally a halogen substituent, and R1,R3, R4, m, n and r are the same as defined above, or a salt thereof.
t269) A quinoxaline derivative of the formula (1), wherein R3iS a group of the formula:

~

`n' o (in which A and R54 are the same as defined above), R4is a lower alkenyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(270) A quinoxaline derivative of the formula (1), wherein R3is a group of the formula:

0~,~0 O
(in which A and R54 are the same as defined above), R4is a cycloalkyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.

WO95/09159 ~ 34'j PCT/JP94/01559 (271 ) A quinoxaiine derivative of the formula (1), wherein R3 is a group of the formula:
A Rs4 S O~lfO

(in which A and R54 are the same as defined above), R4 is a naphthyl-lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(272) A quinoxaline derivative of the formula (1), wherein R3 is a group of the formula:
A Rs4 0~,0 O
(in which A and R54 are the same as defined above), R4 is a phenylthio -substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(273) A quinoxaline derivative of the formula (1), wherein R3 is a group of the formula:

0~0 O
(in which A and R54 are the same as defined above), R4 is a phenylsulfinyl -substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(274) A quinoxaline derivative of the formula (1), wherein R3 is a group of the formula:

WO 95/09159 ~ 2 1 5 0 3 ~ S PCT/JP94/01559 --A Rs4 ~1' O
(in which A and R54 are the same as defined above), R4 is a phenylsulfonyl -substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(275) A quinoxaline derivative of the formula (1), wherein R3 is a group of the formula:
A Rs4 O O

(in which A and R54 are the same as defined above), R4 is a phenoxy -substituted lower alkyl group, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(276) A quinoxaline derivative of the formula (1), wherein R3 is a group of the formula:

`n' o (in which A and R54 are the same as defined above), R4 is a group of the 25 formula:
(R8)q ~<

(wherein the symbols are the same as defined above), and R1, R2, m, n and r 30 are the same as defined above, or a salt thereof.
(277) A quinoxaline derivative of the formula (1), wherein R3 is a group of the formula:

WO 95tO9159 PCT1JP94101559 3 ~

A Rs4 0~0 O

5 (in which A and R54 are the same as defined above), R4is a group of the formula: -A5-CR42R43R44 (A5,R42,R43 and R44 are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(278) A quinoxaline derivative of the formula (1), wherein R3is a group of the formula:
A Rs4 0~0 o (in which A and R54 are the same as defined above), R4is a 2,3-dihydro-1 H -15 indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(279) A quinoxaline derivative of the formula (1), wherein R3is a group 20 of the formula:

`n' o 25 (in which A and R54 are the same as defined above), R4is a group of the formula:

(R47)u 30 (in which the symbols are the same as defined above), and R1, R2, m, n and r are the same as defined above, or a salt thereof.
(280) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an WO 95/09159 2 1 ~ 0 3 ~ ~ PCT/JP94101559 aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, R3is hydrogen atom or a lower alkyl group, R4is a group of the formula:
(R5)p A ~

(in which A, R5 and p are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(281) A quinoxaline derivative of the formula (1), wherein R1 is a lower 10 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, R3is hydrogen atom or a lower alkyl group, R4is a phenyl -lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and m, n and r are the same as defined above, or a salt thereof.
(282) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, R3is hydrogen atom or a lower alkyl group, R4is a lower alkenyl group, and m, n and r are the same as defined above, or a salt thereof.
(283) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is 30 hydrogen atom, R3is hydrogen atom or a lower alkyl group, R4iS a cycloalkyl -lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(284) A quinoxaline derivative of the formula (1), wherein R1 is a lower 3 ~

alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower aikyl substituent, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a naphthyl -lower alkyl group, and m, n and r are the same as defined above, or a salt 5 thereof.
(285) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a naphthyl -10 lower alkyl group, and m, n and r are the same as defined above, or a saltthereof.
(286) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is 15 hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylthio -substitued lower alkyl group which may optinally have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(287) A quinoxaline derivative of the formula (-i ), wherein R1 is a lower 20 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylsulfinyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as 25 defined above, or a salt thereof.
(288) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a 30 phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(289) A quinoxaline derivative of the formula (1), wherein R1 is a lower WO 95/09159 2 1 ~ o 3 4 5 PCT/JP94/01559 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a phenoxy -substituted lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(290) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the 1 0 formula:
(R8)q (in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(291 ) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula: -A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(292) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a 2,3-dihydro -1H-indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n and r are the same as defined above, or a salt thereof.
(293) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the WO gS/O9159 PCI`/JI'94tO1559 34~

formula:
(R47) 5 (in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(294) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is 10 hydrogen atom, R3 and R4 combine together with the nitrogen atom to form 1,2,3,4-tetrahydroisoquinolyl group which may optionally have a lower alkoxy group), and m, n and r are the same as defined above, or a salt thereof.
(295) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an 15 aminocarbonyl group having optionally a lower alkyl substituent, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R5)p A~
(in which A, R5 and p are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(296) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an 25 aminocarbonyl group having optionally a lower alkyl substituent, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a 30 lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -o-A4-Co-NR4R41 (in which A4, R40 and R41 are the same as defined wo 9S/09159 2 1 5 0 3 9 ~ PCT/JPg4/OlSS9 above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and m, n and r are the same as defined above, or a salt thereof.
(297) A quinoxaline derivative of the formula (1), wherein R1 is a lower 5 alkoxy group, an amino group having optionally a lower alkyl substituent or anaminocarbonyl group having optionally a lower alkyl substituent, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a lower alkenyl group, and m, n and r are the same as defined above, or a salt thereof.
(298) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a cycloalkyl-lower alkyl group, and m, n and r are the 15 same as defined above, or a salt thereof.
(299) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a 20 lower alkyl group, R4 is a naphthyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(300) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a lower 25 alkyl group having optionally a halogen substituent, R3 is hydrogen atom or alower alkyl group, R4 is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and are the same as defined above, or a salt thereof.
(301 ) A quinoxaline derivative of the formula (1), wherein R1 is a lower 30 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylsulfinyl-substituted lower alkyl group which WO gS/O9159 PCT/JP94/OlS59 3 4~

may optionally have a lower alkoxy substituent on the phenyl moiety and m, n and r are the same as defined above, or a salt thereof.
(302) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an 5 aminocarbonyl group having optionally a lower alkyl substituent, R2 is a loweralkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(303) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a phenoxy-substituted lower alkyl group, and m, n and rare the same as defined above, or a salt thereof.
(304) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R8)q (in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(305) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula: -A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(306) A quinoxaline derivative of the formula (1), wherein R1 is a lower 21503~
WO 95/09159 - PCI`/JP94101559 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a 2,3-dihydro-1 H-indenyl group-substituted lower alkyl5 group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3 -dihydro-1 H-indenyl ring, and m, n and r are the same as defined above, or a salt thereof.
(307) A quinoxaline derivative of the formula (1), wherein R1 is a lower 10 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a lower alkyl group having optionally a halogen substituent, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R47)u /~

(in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(308) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a lower alkyl group having optionally a halogen substituent, R3 and R4 combine together with the nitrogen atom to form 1,2,3,4-tetrahydroisoquinolyl group which may optionally have a lower alkoxy group, and m, n and r are the same as defined above, or a salt thereof.
(309) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula: (R5)p A~

(in which A, R5 and p are the same as defined above), W095/0915;~3~ PCI/JP94/01559 and m, n and r are the same as defined above, or a salt thereof.
(310) A quinoxaline derlvative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenyl -carbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxygroup, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and m, n and r are the same as defined above, or a salt thereof.
(311 ) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a lower alkenyl group, and m, n and r are the same as defined above, or a salt thereof.
(312) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a cycloalkyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(313) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a naphthyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(314) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylthio-WO 95tO9159 2 1 5 0 3 4 ~ PCT/JP94/01559 substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(315) A quinoxaline derivative of the formula (1), wherein R1 is a lower 5 alkoxy group, an amino group having optionally a lower alkyl substituent or anaminocarbonyl group having optionally a lower alkyl substituent, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylsulfinyl -substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety and m, n and r are the same as defined 10 above, or a salt thereof.
(316) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylsulfonyl -15 substituted lower alkyl group which may optionally have a lower alkoxysubstituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(317) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an 20 aminocarbonyl group having optionally a lower alkyl substituent, R2 is phenylgroup, R3 is hydrogen atom or a lower alkyl group, R4 is a phenoxy-substituted lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(318) A quinoxaline derivative of the formula (1), wherein R1 is a lower 25 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
~ (R8)q ~) (in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(319) A quinoxaline derivative of the formula (1), wherein R1 is a lower WO95/09159 ~ 3~ PCI/Jl'94/01559 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:-A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and m, S n and r are the same as defined above, or a salt thereof.
(320) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a 2,3-dihydro-1 H -10 indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n and r are the same as defined above, or a salt thereof.
(321 ) A quinoxaline derivative of the formula (1), wherein R1 is a lower 15 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is phenyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:(R47) ~) (in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(322) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an 25 aminocarbonyl group having optionally a lower alkyl substituent, R2 is phenylgroup, R3 and R4 combine together with the nitrogen atom to form 1,2,3,4 -tetrahydroisoquinolyl group which may optionally have a lower alkoxy group), and m, n and r are the same as defined above, or a salt thereof.
(323) A quinoxaline derivative of the formula (1), wherein R1 is a lower 30 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:

WO 95/09159 2 1 5 0 3 ~ ~ PCT/JP94/OlS59 ~, (R5)p (in which A, Rs and p are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(324) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula:
-O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and m, n and r are the same as defined above, or a salt thereof.
(325) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a lower alkenyl group, and m, n and r are the same as defined above, or a salt thereof.
(326) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a cycloalkyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(327) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an :.
WO 9S/09159 PCT/JP94/OlS59 ~3~

aminocarbonyl group having optionally a lower alkyl substituent, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a naphthyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
5 (328) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylthio-substituted lower alkyl group which may optionally 10 have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(329) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a 15 morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylsulfinyl-substituted lower alkyl group which may optionallyhave a lower alkoxy substituent on the phenyl moiety and m, n and r are the same as defined above, or a salt thereof.
(330) A quinoxaline derivative of the formula (1), wherein R1 is a lower 20 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r 25 are the same as defined above, or a salt thereof.
(331 ) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl 30 group, R4 is a phenoxy-substituted lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(332) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R8)q ~

(in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(333) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula: -A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(334) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a 2,3-dihydro-1H-indenyl group-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro -1 H-indenyl ring, and m, n and r are the same as defined above, or a salt thereof.
(335) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a morpholino-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R47) (in which the symbols are the same as defined above), and m, n and r are the ? ~3 - 104 -same as defined above, or a salt thereof.
(336) A qulnoxa!ine derivative of the formula t1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is a 5 morpholino-substituted lower alkyl group, R3 and R4 combine together with the nitrogen atom to form 1,2,3,4-tetrahydroisoquinolyl group which may optionally have a lower alkoxy group), and m, n and r are the same as defined above, or a salt thereof.
(337) A quinoxaline derivative of the formula (1), wherein R1 is a lower 10 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is an imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R5)p A~

(in which A, R5 and p are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(338) A quinoxaline derivative of the formula (1), wherein R1 is a lower 20 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is an imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen 25 atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula:
-O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), 30 a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, and m, n and r are the same as defined above, or a salt thereof.
(339) A quinoxaline derivative of the formula (1), wherein R1 is a lower WO 95/09159 2 1 5 ~ 3 ~ ~ PCT/JP94/01559 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is an imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a lower alkenyl group, and m, n and r are the same as defined above, or a salt thereof.
(340) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is an imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a cycloalkyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(341 ) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is an imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a naphthyl-lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(342) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is an imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r are the same as defined above, or a salt thereof.
(343) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is an imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylsulfinyl-substituted lower alkyl group which may optionallyhave a lower alkoxy substituent on the phenyl moiety and m, n and r are the same as defined above, or a salt thereof.
(344) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an WO95/09159 ~ 34~ PCT/JPg4/015S9 aminocarbonyl group having optionally a lower alkyl substituent, R2 is an imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and m, n and r 5 are the same as defined above, or a salt thereof.
(345) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is an imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl 10 group, R4 is a phenoxy-substituted lower alkyl group, and m, n and r are the same as defined above, or a salt thereof.
(346) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is an 15 imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
(R8)q 20 (in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(347) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is an 25 imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula: -A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(348) A quinoxaline derivative of the formula (1), wherein R1 is a lower 30 alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is an imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a 2,3-dihydro-1H-indenyl group-substituted lower alkyl group 21S03~S

which may optionally have a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro -1 H-indenyl ring, and m, n and r are the same as defined above, or a salt thereof.
5 (349) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is an imidazolyl-substituted lower alkyl group, R3 is hydrogen atom or a lower alkyl group, R4 is a group of the formula:
1 0 (R47)u (in which the symbols are the same as defined above), and m, n and r are the same as defined above, or a salt thereof.
(350) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is an imidazolyl-substituted lower alkyl group, R3 and R4 combine together with the nitrogen atom to form 1,2,3,4-tetrahydroisoquinolyl group which may optionally 20 have a lower alkoxy group), and m, n and r are the same as defined above, or a salt thereof.

Wo95/09159 ?,~a3~ PCT/JP94/01559 (351 ) A quinoxaline derivative of the forrnula (1), wherein R1 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower 5 alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
1 0 A~R54 0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 15 defined above); R4 is a group of the formula:
(R47)u .~

(in which the group {~), R47 and u are as defined above), and R2, m, n, 20 and r are as defined above, or a salt thereof.
(352) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower 25 alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

,.

2.......................................... 1 '~ O 3 4 S

A~=~R54 `n' o 5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:

(R5)p --A~

10 (in which A, R5 and p are as defined above), and R2, m, n, and r are as defined above, or a salt thereof.

(353) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl 15 group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:

-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of 20 the formula:

A~R54 0~,~0 o 25 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy 30 group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula: -O-A4-Co-NR4R41 (in which A4, R40 and R41 are as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the WO 95/09159 ? ~ 3 45 PCT/JP94101559 phenyl moiety, and R2, m, n, and r are as defined above, or a salt thereof.
(354) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl 5 group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of 10 the formula:
A Rs4 0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a lower alkenyl group; and R2, m, n, and r are as defined above, or a salt thereof.
(355) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

--A~
0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 iS a cycloalkyl-lower alkyl group; and R2, m, n, and r are asdefined above, or a salt thereof.

WO 95/09159 ~ 1 S (1 3 ~ S PCTIJP94/01559 (356) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower 5 alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 15 defined above); R4 is a naphthyl-lower alkyl group; and R2, m, n, and r are as defined above, or a salt thereof.
(357) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl 20 group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of 25 the formula:

A Rs4 - 0~0 o 30 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety; and R2, m, n, and r are as defined above, or a salt thereof.

W095/09159 21 S03~5 PCI/JP94/01559 (358) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower 5 alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
1 0 A~R54 0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; and R2, m, n, and r are as defined above, or a salt thereof.
(359) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~ R54 0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; and R2, m, n, and r WO9S/09159 ~1 S 0 ~ 4 5 PCI1JP94/OlS59 are as defined above, or a salt thereof.
(360) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~ R54 O O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenoxy-substituted lower alkyl group; and R2, m, n, and r are as defined above, or a salt thereof.
(361 ) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
- A Rs4 0~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:

WO 95/09159 PCI'1JP94/01559 O~S

(R8)q (in which the group ~), R3 and q are as defined above); and R2, m, n, 5 and r are as defined above, or a salt thereof.
(362) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower 10 alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula: -A5-CR42R43R44 (in which A5, R42, R43 and R44 are as defined above); and R2, m, n, and r are as defined above, or a salt thereof.
(363) A quinoxaline derivative of the formula (1), wherein R1 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

wo 9S/O9lS9 2 1 5 0 3 ~ ~

0~0 O
5 tin which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a 2,3-dihydro-1 H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and R2, m, n, and r are as defined above, or a salt thereof.
(364) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl 15 group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~
0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R47)u (in which the group {~), R47 and u are as defined above), and m, n, and r are as defined above, or a salt thereof.
(365) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl 5 group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-NtR52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:

O~O
o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R5)p A~

(in which A, R5 and p are as defined above), and m, n, and r are as defined above, or a salt thereof.
(366) A quinoxaline derivative of the formula (1), wherein R1 is a 20 halogen atom or a lower alkyl group; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl 25 group, a benzoyl-substituted lower alkyl group having otionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

O~O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenyl-lower alkenyl group having optionally a WO 95/O91S9 2 1 ~ 0 3 4 5 PCT/JP94/OlSS9 substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-iower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the 5 tetrazole moiety, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(367) A quinoxaline derivative of the formula (1), wherein R1 is a 10 halogen atom or a lower alkyl group; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl 15 group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:
A~R54 ~

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a lower alkenyl group, and m, n, and r are as defined above, or a salt thereof.
(368) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:

~ 21~03~5 A~R54 0~0 5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a cycloalkyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(369) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is hydrogen atom; R3 is a lower 10 alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen 15 substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A>=~R54 O O
~
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a naphthyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(370) A quinoxaline derivative of the formula (1), wherein R1 is a 25 halogen atom or a lower alkyl group; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl 30 group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:

wo gS/oglS9 ~ ~ ~ o ~ 4 ~ PCT/JP94/01559 A Rs4 - 0~0 O
5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(371 ) A quinoxaline derivative of the formula (1), wherein R1 is a 10 halogen atom or a lower alkyl group; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl 15 group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:
A~ R54 O~O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are 25 as defined above, or a salt thereof.
(372) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower 30 alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which WO 9S/O91S9 PCT/JP94/OlSS9 ~o3 45 E, R52 and R53 are as defined above), or a group of the formula:
A~R54 0~,~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(373) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~( 0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenoxy-substituted lower alkyl group, and m, n, and r 25 are as defined above, or a salt thereof.
(374) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxy -30 carbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and WO 9S/09159 2 1 ~ 0 3 4 ~ PCI/JP94/01559 R53 are as defined above), or a group of the formula:

0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R8)q f~<
10 ~J

(in which the group ~, R8 and q are as defined above), and m, n, and r are as defined above, or a salt thereof.
(375) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxy -carbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) ~in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula: -A5-CR42R43R44 (in which A5, R42, R43 and R44 are as defined above), and m, n, and r are as defined above, or a salt thereof.
(376) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is hydrogen atom; R3 is a lower W095'09l59 2 1 5 ~3 ~ pCI/JP94/01559 aikanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxy -carbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a 5 benzoyl-substituted lower alkyl group having a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 1 0 0~,0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a 2,3-dihydro-1 H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n, and r are as defined above, or a salt thereof.
(377) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a lower alkyl group having optionallya halogen substituent; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~=~
0~,0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:

WO 95/O91S9 2 1 ~ 0 3 4 ~ PCI/JP94/01559 (R47)u (in which the group ~3, R47 and u are as defined above), and m, n, and r 5 are as defined above, or a salt thereof.
(378) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a lower alkyl group having optionallya halogen substituent; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower 10 alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of 15 the formula:
A~R54 0~,0 o 20 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R5)p A~

25 (in which A, R5 and p are as defined above), and m, n, and r are as defined above, or a salt thereof.
(379) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a lower alkyl group having optionallya halogen substituent; R3 is a lower alkanoyloxy-substituted lower alkyl group, 30 a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a 21S03~

lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

O O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(380) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a lower alkyl group having optionallya halogen substituent; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E -N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

O O
~f W095/09159 2l5n31l5 PCI/JP94/01559 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a lower alkenyl group, and m, n, and r are as defined above, or a salt thereof.
(381 ) A quinoxaline derivative of the formula (1), wherein R1 is a 5 halogen atom or a lower alkyl group; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -10 substituted lower alkyl group, a benzoyl-substituted lower alkyl group havingoptionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~
0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a cycloalkyl-lower alkyl group, and m, n, and r are as 20 defined above, or a salt thereof.
(382) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a lower alkyl group having optionallya halogen substituent; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower 25 alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of 30 the formula:

WO 95/09159 PCI`/JP94/01559 215~3~5 0~0 O ~
5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a naphthyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(383) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a lower alkyl group having optionally10 a halogen substituent; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having 15 optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~R54 ~

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety, and m, n, and r are 25 as defined above, or a salt thereof.
(384) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a lower alkyl group having optionallya halogen substituent; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower 30 alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:

_ WO 95/09159 2 1 5 0 3 4 ~ PCr/JP94/OlS59 -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~R54 O~O
o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are 10 as defined above, or a salt thereof.
(385) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower 15 alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of 20 the formula:

A~R54 0~0 o 25 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(381 ) A quinoxaline derivative of the formula (1), wherein R1 is a 30 halogen atom or a lower alkyl group; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a WO 95tO9lS9 2 1 S 0 3 ~ S pCT/Jp94/OlSS9 lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of 5 the formula:
A~R54 0~0 o 10 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenoxy-substituted lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(387) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a lower alkyl group having optionally15 a halogen substituent; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having 20 optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:

(R8)q ~<

(in which the group ~), R8 and q are as defined above), and m, n, and r WO 95/09159 2 1 5 0 3 ~ 5 PCT/JP94101559 are as defined above, or a salt thereof.
(388) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a lower alkyl group having optionallya halogen substituent; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 O~fO

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula: -A5-CR42R43R44 (in which A5, R42, R43 and R44 are as defined above), and m, n, and r are as defined above, or a salt thereof.
(389) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a lower alkyl group having optionallya halogen substituent; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

A Rs4 0~0 o 5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a 2,3-dihydro-1 H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n, and r are as defined above, or a salt thereof.
(390) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~
0~,~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R47)u ~ , (in which the group {~, R47 and u are as defined above), and m, n, and r are as defined above, or a salt thereof.
(391 ) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is phenyl group; R3 is a lower WO 95/O91S9 2 1 5 0 ~ 4 5 PCI/JP94/01559 alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl 5 group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:
A Rs4 1 0 0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(Rs)p --A~

(in which A, R5 and p are as defined above), and m, n, and r are as defined above, or a salt thereof.
(392) A quinoxaline derivative of the formula (1), wherein R1 is a 20 halogen atom or a lower alkyl group; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl 25 group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

O~O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenyl-lower alkenyl group having optionally a WO 95/09159 PCI'1JP94/01559 2~ 03 4S

substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the 5 tetrazole moiety, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(393) A quinoxaline derivative of the formula (1), wherein R1 is a 10 halogen atom or a lower alkyl group; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl 15 group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:
A~ R54 ~f (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a lower alkenyl group, and m, n, and r are as defined above, or a salt thereof.
(394) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:

_ WO 95/09159 2 1 ~ 0 3 4 ~ PCI/JP94/01559 A Rs4 0~,~0 5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a cycloalkyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(395) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is phenyl group; R3 is a lower 10 alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen 15 substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~R54 0~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a naphthyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(396) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:

WO 9S/09159 PCIIJP94/OlSS9 z~so34s A Rs4 O O
~ .

5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(397) A quinoxaline derivative of the formula (1), wherein R1 is a 10 halogen atom or a lower alkyl group; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl 15 group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are 25 as defined above, or a salt thereof.
(398) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower 30 alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and Rs3 are as defined above), or a group of the formula:

0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(399) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~
0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenoxy-substituted lower alkyl group, and m, n, and r 25 are as defined above, or a salt thereof.
(400) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower 30 alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which 2l~03~5 E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 - O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R8)q ~

(in which the group ~), R8 and q are as defined above), and m, n, and r are as defined above, or a salt thereof.
(401 ) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is phenyl group; R3 is a lower 15 alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen 20 substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula: -A5-CR42R43R44 (in which A5, R42, R43 and R44 are as defined above), and m, n, and r are as defined above, or a salt thereof.
(402) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is phenyl group; R3 is a lower WO 95/09159 2 1 ~ 0 3 ~ S PCT/JP94/01559 alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl 5 group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in whichE, R52 and R53 are as defined above), or a group of the formula:
A Rs4 1 0 0~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a 2,3-dihydro-1 H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a 15 silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1H-indenyl ring, and m, n, and r are as defined above, or a salt thereof.
(403) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower 20 alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) 25 (in which E, R52 and R53 are as defined above), or a group of the formula:

0~0 o 30 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:

WO 95/O91S9 PCT/JP94/OlS~9 (R47)u ~ .
(in which the group {~, R47 and u are as defined above), and m, n, and r 5 are as defined above, or a salt thereof.
(404) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, 10 a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
1 5 A~R54 `n' o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 20 defined above); R4 is a group of the formula:
(R5)p A~
\=/
(in which A, R5 and p are as defined above), and m, n, and r are as defined 25 above, or a salt thereof.
(405) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, 30 a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower WO 95/09159 2 ~ 5 0 3 4 5 PCT/JP94/01559 alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~
0~.~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenyl-lower alkenyl group having optionally a 10 substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula: -o-A4-CO-NR4R41 (in which A4, R40 and R41 are as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(406) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a morpholino-substituted lower alkyl 20 group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a 25 halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a lower alkenyl group, and m, n, and r are as defined above, or a salt thereof.

WO 95/09159 2~5 03 ~S PCT1JP94/015S9 (407) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-subs-tituted lower alkyl group, a lower alkoxy -carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a 5 phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
~
0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 15 defined above); R4 is a cycloalkyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(408) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower 20 alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) 25 (in which E, R52 and R53 are as defined above), or a group of the formula:

A Rs4 0~0 o 30 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a naphthyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(409) A quinoxaline derivative of the formula (1), wherein R1 is a WO 95/09159 2 1 ~ 0 3 4 S PCTtJP94/01559 halogen atom or a lower alkyl group; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -5 lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
--A Rs4 O O
~f (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylthio-substituted lower alkyl group having 15 optionally a lower alkoxy-substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(410) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower 20 alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) 25 (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 - ' ~
0~0 O

30 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.

wo 95/09l59 2l5 03 4S PCT/JP94/01559 (411 ) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, 5 a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 15 defined above); R4 is a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(412) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a morpholino-substituted lower alkyl 20 group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a 25 halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenoxy-substituted lower alkyl group, and m, n, and r are as defined above, or a salt thereof.

WO 95/O91S9 2 I 5 0 3 ~ S PCTIJP94/OlSS9 (413) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, 5 a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
~=~

O O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as 15 defined above); R4 is a group of the formula:
(R8)q .~

(in which the group ~), R3 and q are as defined above~, and m, n, and r 20 are as defined above, or a salt thereof.
(414) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, 25 a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

~so34~

A~R54 0~0 O -5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula: -A5-CR42R43R44 (in which A5, R42, R43 and R44 are as defined above), and m, n, and r are as defined above, or a salt thereof.
(415) A quinoxaline derivative of the formula (1), wherein R1 is a 10 halogen atom or a lower alkyl group; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower 15 alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

A>=~R54 ~f (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a 2,3-dihydro-1 H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a 25 silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n, and r are as defined above, or a salt thereof.
(416) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is an imidazolyl-substituted lower alkylgroup; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower 30 alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a WO 9StO9159 2 15 l) 3 ~ 5 PCTIJP94/01559 halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

5 ~n~
O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R47)u f~<

(in which the group ~), R47 and u are as defined above), and m, n, and r are as defined above, or a salt thereof.
(417) A quinoxaline derivative of the formula (1), wherein R1 is a 15 halogen atom or a lower alkyl group; R2 is an imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower 20 alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 .~
0~0 O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R5)p A~

WO95/09159 2lso345 PCT/JP94/01559 (in which A, R5 and p are as defined above), and m, n, and r are as defined above, or a salt thereof.
(418) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is an imidazolyl-substituted lower alkyl5 group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a 10 halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and 20 a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxygroup, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula: -O-A4-Co-NR4R41 (in which A4, R40 and R41 are as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the 25 phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(419) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is an imidazolyl-substituted lower alkylgroup; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, 30 a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) WO 95/09159 21 ~ 0 3 4 ~ PCT/JP94/01559 (in which E, R52 and R53 are as defined above), or a group of the formula:
X
0~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a lower alkenyl group, and m, n, and r are as defined above, or a salt thereof.
(420) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is an imidazolyl-substituted lower alkylgroup; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~R54 V
o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a cycloalkyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(421) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is an imidazolyl-substituted lower alkylgroup; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

WO 9S/09159 2 I S ~3 4S PCT/JP94/OlSS9 A~R54 O~O
o 5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a naphthyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(422) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is an imidazolyl-substituted lower alkyl10 group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a 15 halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~R54 O~.~O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(423) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is an imidazolyl-substituted lower alkylgroup; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

21S034~

A Rs4 0~0 O

5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(424) A quinoxaline derivative of the formula (1), wherein R1 is a 10 halogen atom or a lower alkyl group; R2 is an imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower 15 alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~R54 ~

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are 25 as defined above, or a salt thereof.
(425) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is an imidazolyl-substituted lower alkylgroup; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, 30 a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) WO 95/09159 ~34~ PCI/JP94/015S9 (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~,0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenoxy-substituted lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(426) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is an imidazolyl-substituted lower alkylgroup; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R8)q ~

(in which the group ~, R8 and q are as defined above), and m, n, and r are as defined above, or a salt thereof.
(427) A quinoxaline derivative of the formula (1), wherein R1 is a 30 halogen atom or a lower alkyl group; R2 is an imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy-WO 95/09159 ~ 1 5 0 3 1 5 PCT/JP94/01559 carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a 5 halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53)(in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~,~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula: -A5-CR42R43R44 (in which A5, R42, R43 and R44 are as defined above), and m, n, and r are as defined above, or a salt thereof.
(428) A quinoxaline derivative of the formula (1), wherein R1 is a halogen atom or a lower alkyl group; R2 is an imidazolyl-substituted lower alkylgroup; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -20 lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~( `n' O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a 2,3-dihydro-1 H-indenyl-substituted lower alkyl group 30 having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n, and r are as defined above, or a salt thereof.
(429) A quinoxaline derivative of the formula (1), wherein R1 is a lower 3 4~

alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl 5 group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E -N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the 1 0 formula:
A~R54 0~0 o 15 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R47)u 20 (in which the group ~, R47 and u are as defined above), and m, n, and r are as defined above, or a salt thereof.
(430) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is 25 hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having 30 optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of WO 95/09159 21 ~ 0 3 4 ~ PCT/JP94/01559 the formula:
A Rs4 0~,~0 O
- (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R5)p - A~
1 0 \~/
(in which A, R5 and p are as defined above), and m, n, and r are as defined above, or a salt thereof.
(431 ) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an 15 aminocarbonyl group having optionally a lower alkyl substituent; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -20 substituted lower alkyl group, a benzoyl-substituted lower alkyl group havingoptionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~
0~0 - O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenyl-lower alkenyl group having optionally a 30 substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the 2lS0~5 tetrazole moiety, hydroxy group, a group of the formula: -O-A4-Co-NR4R41 (in which A4, R40 and R41 are as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
5 (432) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl 10 group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of 15 the formula:
A~R54 0~0 o 20 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a lower alkenyl group, and m, n, and r are as defined above, or a salt thereof.
(433) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an 25 aminocarbonyl group having optionally a lower alkyl substituent; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -30 substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

wo 9S/O9lS9 21 ~ 0 3 4 5 PCTtJP94/OlSS9 A~R54 `n' O

5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a cycloalkyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(434) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an 10 aminocarbonyl group having optionally a lower alkyl substituent; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -15 substituted lower alkyl group, a benzoyl-substituted lower alkyl group havingoptionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~
0~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a naphthyl-lower alkyl group, and m, n, and r are as 25 defined above, or a salt thereof.
(435) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a 30 lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkylgroup, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having 2~034s optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

~
`n' O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylthio-substituted lower alkyl group having 10 optionally a lower alkoxy-substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(436) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is 15 hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having 20 optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~R54 `r~
O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(437) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is WO 95/09159 2 1 S 0 3 ~ 5 PCT/JP94/01559 hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -5 substituted lower alkyl group, a benzoyl-substituted lower alkyl group having - optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

A Rs4 0~,0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfonyl-substituted lower alkyl group having 15 optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(438) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is 20 hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having 25 optionally a halogen substituent on the phenyl ring, a group of the formula: -E -N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

``n' 2~5~3~

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenoxy-substituted lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(439) A quinoxaline derivative of the formula (1), wherein R1 is a lower 5 alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower 10 alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
1 5 A~R54 O O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as 20 defined above); R4 is a group of the formula:
(R8)q {~

(in which the group ~3, R3 and q are as defined above), and m, n, and r 25 are as defined above, or a salt thereof.
(440) A quinoxaline derivative of the formula (1), wherein Rl is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a 30 lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkylgroup, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of 5 the formula:

0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula: -A5-CR42R43R44 (in which A5, R42, R43 and R44 are as defined above), and m, n, and r are as defined above, or a salt thereof.
(441 ) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is hydrogen atom; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl -substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula:
-E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~R54 - `n' O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as 30 defined above); R4 is a 2,3-dihydro-1 H-indenyl-substituted lower alkyl grouphaving optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n, and r are as defined above, or a salt thereof.

2l50345 (442) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy -substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy -carbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxy -carbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl -substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

--A~
0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R47) ~

(in which the group ~, R47 and u are as defined above), and m, n, and r are as defined above, or a salt thereof.
(443) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an 25 aminocarbonyl group having optionally a lower alkyl substituent; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy -substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxy -carbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a 30 phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent WO 95/09159 2 1 ~ 0 3 4 ~ PCT/JP94/01559 on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

`n' O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(Rs)p A~

(in which A, R5 and p are as defined above), and m, n, and r are as defined above, or a salt thereof.
(444) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy -substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy -carbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxy -carbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl -substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

0~,0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 30 defined above); R4 is a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy WO 9S/09159 2 1 5 3 4 5 PCI/JP94/OlS59 group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula: -o-A4-Co-NR4R41 (in which A4, R40 and R41 are as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(445) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy -substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy -carbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxy -carbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl -substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A>~R54 0~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a lower alkenyl group, and m, n, and r are as defined above, or a salt thereof.
(446) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy -substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy -carbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxy -carbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl -substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 WO 9S/09159 21 5 0 3 ~ 5 PCTtJP94/01559 are as defined above), or a group of the formula:

0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a cycloalkyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(447) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy -substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy -carbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxy -carbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl -substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~,0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 25 defined above); R4 is a naphthyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(448j A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a lower 30 alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy -substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy -carbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxy-carbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl -substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

`n' o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 10 defined above); R4 is a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(449) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an 15 aminocarbonyl group having optionally a lower alkyl substituent; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy -substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy -carbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxy -20 carbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl -substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfinyl-substituted lower alkyl group having 30 optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(450) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an WO 95/09lS9 2 1 5 0 ~ 4 5 PCT/JP94/01559 aminocarbonyl group having optionally a lower alkyl substituent; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy -substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy -carbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl 5 group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxy -carbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl -substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 O~fO
o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 15 defined above); R4 is a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(451 ) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an 20 aminocarbonyl group having optionally a lower alkyl substituent; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy -substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy -carbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxy -25 carbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl -substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

~
`n' 215034~

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenoxy-substituted lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(452) A quinoxaline derivative of the formula (1), wherein R1 is a lower 5 alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy -substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy -carbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl 10 group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxy -carbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl -substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
1 5 A~R54 0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 20 defined above); R4 is a group of the formula:
(R8)q ,~
~, (in which the group ~, R8 and q are as defined above), and m, n, and r 25 are as defined above, or a salt thereof.
(453) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy -30 substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy -carbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl wo gS/oglS9 2 1 5 û 3 ~ ~ PCT/JP94/01559 group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxy -carbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl -substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 5 are as defined above), or a group of the formula:
A Rs4 0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula: -A5-CR42R43R44 (in which A5, R42, R43 and R44 are as defined above), and m, n, and r are as defined above, or a salt thereof.
(454) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a lower alkyl group having optionally a halogen substituent; R3 is a lower alkanoyloxy -substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy -carbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxy -carbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl -substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as 30 defined above); R4 is a 2,3-dihydro-1 H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n, and r are as defined above, or a salt thereof.

WO 95/09159 PCT/JP94/OlS59 ~2,iS 03 Q~S - 168 -(455) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy -5 carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) 10 (in which E, R52 and R53 are as defined above), or a group of the formula:
A~R54 0~,~0 o 15 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R47)u 20 (in which the group {~), R47 and u are as defined above), and m, n, and r are as defined above, or a salt thereof.
(456) A quinoxaline derivative of the formula (1), wherein Rl is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is phenyl 25 group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy -carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a 30 halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

WO 95/09159 21 5 0 3 ~ ~ PCT/JP94/01559 A Rs4 O~fO
O

5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R5)p A~

10 (in which A, R5 and p are as defined above), and m, n, and r are as defined above, or a salt thereof.
(457) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is phenyl 15 group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy -carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a 20 halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are as defined above), a lower alkenyloxy group, nitro ~,~S~34S

group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(458) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an 5 aminocarbonyl group having optionally a lower alkyl substituent; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy -carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower 10 alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~ R54 1 5 `n' o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a lower alkenyl group, and m, n, and r are as defined above, or a salt thereof.
(459) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy -carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
0 A Rs4 0~0 WO 9S/09159 2 1 ~ 0 3 4 ~ PCTIJP94/01559 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a cycloalkyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(460) A quinoxaline derivative of the formula (1), wherein R1 is a lower 5 alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy -carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -10 lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~
O O
~f (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a naphthyl-lower alkyl group, and m, n, and r are as 20 defined above, or a salt thereof.
(461 ) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy -25 carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) 30 (in which E, R52 and R53 are as defined abovej, or a group of the formula:

~S~34~

A Rs4 0~0 o 5 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(462) A quinoxaline derivative of the formula (1), wherein R1 is a lower 10 alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy -carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -15 lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~
O O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfinyl-substituted lower alkyl group having 25 optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(463) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is phenyl 30 group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy -carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower WO 95/09159 ~ 1 5 0 3 4 ~ - PCT/JP94/01559 alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~
0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfonyl-substituted lower alkyl group having 10 optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(464) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is phenyl 15 group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy -carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a 20 halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenoxy-substituted lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(465) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy -carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a 2~So3 4S

phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) 5 (in which E, R52 and R53 are as defineq ~above)~ or a group of the formula:
--A~R54 `n' o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R8)q {~

(in which the group ~), R8 and q are as defined above), and m, n, and r are as defined above, or a salt thereof.
(466) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy -carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 `n' O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as WO 95/09159 2 1 5 0 3 4 5 PCTtJP94/01559 defined above); R4 is a group of the formula: -A5-CR42R43R44 (in which A5, R42, R43 and R44 are as defined above), and m, n, and r are as defined above, or a salt thereof.
(467) A quinoxaline derivative of the formula (1), wherein R1 is a lower 5 alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is phenyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxy -carbonyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy -10 lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~
0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a 2,3-dihydro-1 H-indenyl-substituted lower alkyl group 20 having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n, and r are as defined above, or a salt thereof.
(468) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an 25 aminocarbonyl group having optionally a lower alkyl substituent; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a 30 lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

2~5~1345 - 176-A Rs4 0~,0 O
5 (in which R54 is hydrogen atom or a iower alkyi group and A is the same as defined above); R4 is a group of the formula:
(R47)u 10 (in which the group ~, R47 and u are as defined above), and m, n, and r are as defined above, or a salt thereof.
(469) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a 15 morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl 20 group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

O~O
o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R5)p A~

WO 9S/09159 2 1 ~ 0 3 4 ~ PCT/JP94101S59 (in which A, R5 and p are as defined above), and m, n, and r are as defined above, or a salt thereof.
(470) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an 5 aminocarbonyl group having optionally a lower alkyl substituent; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a 10 lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(471 ) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower WO 95/09159 ~ S ~3 ~S PCT/JP94/01559 alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or 5 a group of the formula:

A~
0~0 o 10 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a lower alkenyl group, and m, n, and r are as defined above, or a salt thereof.
(472) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an 15 aminocarbonyl group having optionally a lower alkyl substituent; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a 20 lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

--A~
0~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a cycloalkyl-lower alkyl group, and m, n, and r are as 30 defined above, or a salt thereof.
(473) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a WO 95/09159 2 1 5 0 3 4 5 PCT/JP94/OlS59 morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a 5 lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~( 0~,0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a naphthyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(474) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

A Rs4 O~f O
O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety, and m, n, and r are ~,~So3~S

as defined above, or a salt thereof.
(475) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a 5 morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl 10 group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 1 5 O~O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(476) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

WO 95/09159 2 1 5 0 3 ~ 5 --A~=~R54 - `n' O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(477) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 25 defined above); R4 is a phenoxy-substituted lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(478j A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a 30 morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a ~3 ~JS

lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

0~,~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R8)q (in which the group ~), R3 and q are as defined above), and m, n, and r are as defined above, or a salt thereof.
(479) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as 21503~5 defined above); R4 is a group of the formula: -A5-CR42R43R44 (in which A5, R42, R43 and R44 are as defined above), and m, n, and r are as defined above, or a salt thereof.
(480) A quinoxaline derivative of the formula (1), wherein R1 is a lower 5 alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is a morpholino-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower 10 alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
--A~= ~R54 O O
~f (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 20 defined above); R4 is a 2,3-dihydro-1 H-indenyl-substituted lower alkyl grouphaving optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n, and r are as defined above, or a salt thereof.
(481 ) A quinoxaline derivative of the formula (1), wherein R1 is a lower 25 alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is an imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower 30 alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or WO gS/O9159 PCT/JP94/01559 ~3~

a group of the formula:
--A~= ~RS4 0~0 O
(in which Rs4 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R47)u ~

(in which the group ~, R47 and u are as defined above), and m, n, and r are as defined above, or a salt thereof.
(482) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an 15 aminocarbonyl group having optionally a lower alkyl substituent; R2 is an imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a 20 lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

~
0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R5)p A~

WO 95/09159 _ 2 1 S 0 3 ~ S PCT/JP94101~59 (in which A, R5 and p are as defined above), and m, n, and r are as defined above, or a salt thereof.
(483) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an 5 aminocarbonyl group having optionally a lower alkyl substituent; R2 is an imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a 10 lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~( 0~,~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(484) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is an imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower 3 ~ -186-alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or 5 a group of the formula:
A Rs4 0~0 o 10 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a lower alkenyl group, and m, n, and r are as defined above, or a salt thereof.
(485) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an 15 aminocarbonyl group having optionally a lower alkyl substituent; R2 is an imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a 20 lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~( O~.~O
o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a cycloalkyl-lower alkyl group, and m, n, and r are as 30 defined above, or a salt thereof.
(486) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is an WO 9S/09159 2 t ~ 0 3 ~ 5 PCT/JP94/01559 imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a 5 lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 ~
0~0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same.as defined above); R4 is a naphthyl-lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(487) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is an imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(488) A quinoxaline derivative of the formula (1), wherein R1 is a iower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is an 5 imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl 10 group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~ R54 1 5 ~n' o (in which R54 is hydrogen atom or a lower alkyl group ànd A is the same as defined above); R4 is a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(489) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is an imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

WO 95109159 21 5 0 3 ~ 5 PCT/JP94/01559 A Rs4 O O

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, and m, n, and r are as defined above, or a salt thereof.
(490) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is an imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

0~,0 o (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 25 defined above); R4 is a phenoxy-substituted lower alkyl group, and m, n, and r are as defined above, or a salt thereof.
(491 ) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is an 30 imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a WO 95/09159 PCT/JP94/OlS59 ~34~j lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:

0~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); R4 is a group of the formula:
(R8)q .~

(in which the group ~, R3 and q are as defined above), and m, n, and r are as defined above, or a salt thereof.
(492) A quinoxaline derivative of the formula (1), wherein R1 is a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is an imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower alkanoy! group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A Rs4 0~0 O
(in which R54 is hydrogen atom or a lower alkyl group and A is the same as WO 95/09159 2 1 5 0 3 ~ S PCT/JP94/01559 defined above); R4 is a group of the formula: -A5-CR42R43R44 (in which A5, R42, R43 and R44 are as defined above), and m, n, and r are as defined above, or a salt thereof.
(493) A quinoxaline derivative of the formula (1), wherein R1 is a lower 5 alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent; R2 is an imidazolyl-substituted lower alkyl group; R3 is a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy -substituted lower alkyl group, a phenyl-lower alkoxycarbonyl group, a lower 10 alkanoyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which E, R52 and R53 are as defined above), or a group of the formula:
A~ R54 0~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as 20 defined above); R4 is a 2,3-dihydro-1 H-indenyl-substituted lower alkyl grouphaving optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring, and m, n, and r are as defined above, or a salt thereof.

3~'j The compound of the present invention also inciudes the compounds of the formula (1 ) wherein both m and n are simultaneously 1, or m is 1 and n is 0, or m is O and n is 1, or both m and n are simultaneously 0, butthe more preferable compounds are compounds of the formula (1) wherein m is 1 andnisO.
The heterocyclic group represented by the formula:

includes, for example, pyridyl, thiazolyl, furyl, benzimidazolyl, benzothiazolyl, oxazolyl, quinolyl, indolyl, 1,4-benzodioxanyl, 3,4-dihydrofuro[2,3-g]quinolyl, 1,2,3,4-tetrahydrofuro[2,3-g]quinolyl, furo[3,2-c]pyridyl, furo[2.3-g]quinolyl, benzofuryl, benzothienyl, 2,3-dihydrobenzofuryl, perhydrobenzofuryl, imidazolyl, 1,2,3,4-tetrazolyl, imidazo[1,2-a]pyridyl, and the like.
The heterocyclic group represented by the formula:

includes, for example, 1,2,3,4-tetrazolyl, thiazolyl, pyridyl, oxazolyl, 1,2,3,5 -oxathiadiazolyl, 1,3,4-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazinyi, imidazolyl, 1,3,4-oxadiazolyl, pyrimidinyl, 1,2,3,4-tetrazolyl, 3,4-dihydrofuro[2,3-g]quinolyl, 1,2,3,4-tetrahydrofuro[2,3-g]quinolyl, naphtho[2,1-b]furyl, oxazolyl, furo[2,3 -g]quinolyl, and the like.
The heterocyclic group represented by the formula:

includes, for example, thiazolyl, 1,2,3,4-tetrazolyl, thiazolidinyl, and the like.
The heterocyclic group represented by the formula:

includes, for example, benzofuryl, benzothiazolyl, carbostyril, 3,4 -dihydrocarbostyril, furo[3,2-c]pyridyl, benzothienyl, and the like.
The compounds of the present invention of the formula (1 ) may be prepared by various processes, but preferably prepared by the following 21~U34~

processes.
Reaction Scheme-1 (f )m ~ R3 ~l )m R2 HN 4 (3) ~; R2 ()n ()n (2) (1) [wherein R1, R2, R3, R4, r, m and n are the same as defined above]
The reaction of the compound (2) and the compound (3) is carried out by a conventional amido bond producing reaction. The amido bond producing reaction can be carried out under the same conditions as those of 15 the conventional amino bond producing reaction, for example, (a) a mixed acid anhydride process, i.e. a process of reacting the carboxylic acid compound (2) with an alkyl halocarbonate to form a mixed acid anhydride and reacting the resultant with the amine compound (3), (b) an activated ester process, i.e. a process of converting the 20 carboxylic acid compound (2) into an activated ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and reacting the resultant with the amine compound (3), (c) a carbodiimide process, i.e. a process of condensing the carboxylic acid compound (2) and the amine compound (3) in the presence of 25 an activating agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc., (d) other processes, i.e. a process of converting the carboxylic acid compound (2) into a carboxylic anhydride by treating it with a dehydrating agent such as acetic anhydride, and reacting the resultant with the amine 30 compound (3); a process of reacting an ester of the carboxylic acid compound (2) with a lower alcohol and the amine compound (3); a process of reacting an acid halide compound of the carboxylic acid compound (2), i.e. a carboxylic WO 9S/09159 PCT/JP94/OlSS9 3~ej acid halide, with the amine compound (3); a process of activating the carboxylicacid (2) with a phosphorus compound such as triphenylphosphine, diethyl chlorophosphate, etc., and reacting the resultant with the amine compound (3);
a process of converting the carboxylic acid compound (2) into a N -5 carboxyamino anhydride with a phosgene or chloroformic acid trichloromethylester, and reacting the resultant with the amine compound (3); a process of activating the carboxylic acid compound (2) with an acetylene compound such as trimethylsilylethoxyacetylene, etc., and reacting the resultant with the amine compound (3), and the like.
The mixed acid anhydride used in the above mixed acid anhydride process (a) is obtained by the known Schotten-Baumann reaction, and the reaction product is used without isolating from the reaction mixture forthe reaction with the amine compound (3) to give the desired compound (1 ) of the present invention. The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. The basic compound is any conventional compounds used for the Schotten-Baumann reaction and includes, for example, organic basic compounds such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc., and inorganic basic compounds such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc. The reaction is usually carried out at a temperature from about -20C to about 1 00C, preferably at a temperature of 0C to about 50C, for about 5 minutes to about 10 hours, preferably for 5 minutes to about 2 hours.
The reaction between the mixed acid anhydride thus obtained and the amine compound (3) is usually carried out at a temperature of -20C to about 1 50C, preferably at a temperature of 1 0C to about 50C, for 5 minutes to about 10 hours, preferably for about 5 minutes to 5 hours. The mixed acid anhydride process is usually carried out in a solvent or without a solvent, and the solvent may be any conventional solvents which are usually used in the mixed acid anhydride process and includes, for example, halogenated hydrocarbons (e.g. methylene chloride, chloroform, dichloroethane, etc.), WO 95/09159 21 ~ 0 3 4 ~ PCT/JP94/01559 aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. diethyl ether, dioxane, diisopropyl ether, tetrahydrofuran, dimethoxyethane, etc.), esters (e.g. methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g.
1,1,3,3-tetramethylurea, N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), or a mixture of these solvents. The alkyl halocarbonate used in the mixed acid anhydride process includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. In said process, the carboxylic acid compound (2), the alkyl halocarbonate ester and the amine compound (3) are usually used in each equimolar amount, but preferably, the alkyl halocarbonate ester and the amine compound (3) are used each in an amount of about 1 to 1.5 mole to 1 mole of the carboxylic acid compound (2).
The activated ester process (b), for example, a process using N -hydroxysuccinic acid imide ester is carried out in a suitable solvent which doesnot affect the reaction, in the presence or absence of a basic compound.
Besides, the reaction may be carried out with addition of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, 1-ethyl-3-(3'-dimethyl -aminopropyl)carbodiimide, etc. The basic compound may be any basic compounds for the above mentioned Schotten-Baumann reaction, and alkali metal carboxylates (e.g. sodium acetate, sodium benzoate, sodium formate, potassium acetate, lithium benzoate, cecium acetate, etc.), alkali metal halides(e.g. potassium fluoride, cecium fluoride, etc.), and the like. The solvent includes, for example, halogenated hydrocarbons (e.g. methylene chloride, chloroform, dichloroethane, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, etc.), esters (e.g. methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, dimethylsulfoxide, hexamethyl -phosphoric triamide, etc.), or a mixture of these solvents. The reaction is carried out at a temperature of 0 to 1 50C, preferably at a temperature of 10 to 100C for 5 to 30 hours. The amine compound (3) and N-hydroxysuccinic acid imide ester are used each at least in equimolar amount, preferably in an amount of 1 to 2 moles to 1 mole of the carboxylic acid compound (2).
Besides, the amido bond producing reaction in Reaction Scheme-wogs/ ~ts~3~S

1 may also be carried out by reacting the carboxylic acid compound (2) and the amine compound (3) in the presence of a condensing agent such as phosphorus compounds (e.g. triphenylphosphine, triphenylphosphine-2,2' -dipyridyldisulfide, diethyl chlorophosphate, diphenylphosphinyl chloride, 5 phenyl-N-phenylphosphoramide chloridate, diethyl cyanophosphate, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, etc.). The reaction is usually carried out in the presence of the solvent and the basic compound. The basic compound includes, for example, in addition to the basic compounds used for the above mentioned Schotten-Baumann reaction, sodium hydroxide, potassium 10 hydroxide, etc. The solvent includes, for example, in addition to the solvents used in the mixed acid anhydride process (a), pyridine, acetone, acetonitrile, or a mixture of two or more above solvents. The reaction is usually carried out at a temperature of -20C to about 1 50C, preferably at a temperature of 0C to about 1 00C, for about 5 minutes to about 30 hours. The condensing agent 15 and the amine compound (3) are used at least in equimolar amount, preferably in an amount of about 1 to 2 moles, to 1 mole of the carboxylic acid compound (2).
The amido bond producing reaction is also carried out by reacting the amine compound (3) and the carboxylic acid compound (2) in the presence 20 of a condensing agent. The reaction is carried out in a suitable solvent in the presence or absence of a catalyst. The solvent includes, for example, halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), acetonitrile, dimethylformamide, etc. The catalyst includes, for example, organic bases such as dimethylaminopyridine, 4 -25 piperidinopyridine, etc., salts such as pyridinium tosylate, etc., camphorsulfonicacid, mercury oxide, and the like. The condensing agent includes, for example, acetylene compounds such as trimethylsilylethoxyacetylene, etc., and is used in an amount of 1 to 10 moles, preferably in an amount of 2 to 6 moles, to 1 mole of the amine compound (3). The carboxylic acid compound (2) is usually 30 used at least in equimolar amount, preferably in an amount of 1 to 2 moles, to 1 mole of the amine compound (3). The reaction is usually carried out at a temperature of 0 to about 150C, preferably at a temperature of room temperature to about 100C, for about 1 to about 10 hours.

WO 95/09159 2 1 ~ 0 3 ~ ~ PCT/JP94/01559 Among the above other processes (d), in case of the process of reacting the carboxylic acid halide with the amine compound (3), the reaction isusually carried out in the presence of a de-hydrogen halogenating agent in an appropriate solvent. The de-hydrogen halogenating agent is any conventional 5 basic compounds and includes, for example, in addition to the basic compounds used for the above mentioned Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, and the like. The solvent includes, for example, in addition to the solvents used in the mixed acid anhydride process, alcohols (e.g. methanol, ethanol, 10 propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve, methylcellosolve, etc.), pyridine, acetone, acetonitrile, or a mixture of two or more these solvents, and the like. The amount of the amine compound (3) and the carboxylic acid halide is not critical, but the amine compound (3) is usually used at least in equimolar amount, preferably about 1 to 5 moles, to 1 mole of the carboxylic 15 acid halide. The reaction is usually carried out at a temperature of about -20C to about 1 80C, preferably at a temperature of about 0C to about 1 50C,for about 5 minutes to about 30 hours.
The carboxylic acid halide used in the above reaction may be prepared, for example, by reacting the carboxylic acid compound (2) with a 20 halogenating agent in a solvent or without a solvent. The solvent may be any one which does not affect the reaction, for example, aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g.
chloroform, methylene chloride, carbon tetrachloride, etc.), ethers (e.g. dioxane, tetrahydrofuran, diethyl ether, etc.), dimethylformamide, dimethylsulfoxide, and25 the like. The halogenating agent may be any conventional one which convert the hydroxy group in carboxyl group into a halogen, for example, thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, etc. The amount of the carboxylic acid compound (2) and the halogenating agent is not critical, but the 30 halogenating agent is usually used in an excess amount to the carboxylic acidcompound (2) when the reaction is carried out without a solvent, and when the reaction is carried out in a solvent, the hydrogenating agent is usually used atleast in equimolar amount, preferably in an amount of 2 to 4 moles, to 1 mole of WO 95109159 ~3 ~ PCT1JP94/01559 the carboxylic acid compound (2). The reaction temperature and the reaction period are not necessarily specified, but the reaction is usually carried out at a temperature of room temperature to about 1 00C, preferably at a temperature of 50 to 80C, for 30 minutes for about 6 hours.
In the process of reacting the amine compound (3) with an ester of the carboxylic acid compound (2) and a lower alcohol, the reaction is carried out in a suitable solvent or without a solvent. The solvent may be any ones which are used in the above mentioned reaction of the carboxylic acid halide and the amine compound (3). The amine compound (3) is usually used at least in equimolar amount, preferably in an amount of 1 to 15 moles, to 1 mole of the ester of the carboxylic acid compound (2) and a lower alcohol. The reaction is usually carried out at a temperature of room temperature to 1 50C, preferably at a temperature of room temperature to about 1 20C, for one to about 20 hours.
Reaction Scheme-2 (t)m (t)m j~ ~X R3bX (4a) or ~N`X R

y CoNHR3a R3CCoR3d (4b) (R1) CO ~ R3b ()n ()n (1a) (1 b) [wherein R1, R2, r, m and n are the same as defined above, X is a halogen 25 atom, R3a is hydrogen atom, a lower alkyl group, a phenyl-lower alkoxy -carbonyl group, a lower alkanoyloxy-substituted lower alkyl group, e) a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkoxy-lower alkyl group, a phenoxycarbonyl group, a lower alkanoyl-substituted lower alkyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a benzoyl -30 substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-NR52R53 (in which R52 and R53 are the same or different and each hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or phenyl group, or R52 and R53 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom, E is a lower alkylene group, a group of the 5 formula: -CO-, or a group of the formula:
-CO-A- (in which A is a lower alkylene group)), a group of the formula:
A Rs4 0~0 (in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above), a group of the formula:
(R5)p A~
(in which A, R5 and p are the same as defined above), a phenyl-lower alkenyl group which may optionally have a substituent on the phenyl moiety selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower 20 alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (in which A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent, an alkenyl 25 group, a cycloalkyl-lower alkyl group, a naphthyl-lower alkyl group, a phenylthio-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, a phenylsulfinyl-substituted lower alkyl grouphaving optionally a lower alkoxy substituent on the phenyl moiety, a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy 30 substituent on the phenyl moiety, a phenoxy-substituted lower alkyl group, a group of the formula:

WO 9S/O91S9 PCIIJP94/OlSS9 (R8)q ~A ~ -(in which a group of the formula: ~, R3 and p are the same as defined above), a group of the formula: -A5-CR42R43R44 (in which A5, R42, R43 and R44 are the same as defined above), a 2,3-dihydro-1 H-indenyl-substituted lower alkyl group having optionally a substituent on the 2,3-dihydro-1 H-indenyl ring selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent, or a group of the formula:
1 0 (R47)u .~

(in which a group of the formula: ~, R47 and u are the same as defined above, R3b is the same groups for the above mentioned R3a except hydrogen atom, and R3C and R3d are each hydrogen atom or a lower alkyl group]
The reaction of the compound (1a) and the compound (4a) is usually carried out in the presence or absence of a basic compound in a suitable inert solvent. The inert solvent includes, for example, aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, etc.), alcohols (e.g. methanol, ethanol, isopropanol, butanol, etc.), ethyl acetate, acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, or a mixture of these solvents. The basic compound includes, for example, an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), sodium hydride, potassium, sodium, sodium amide, an alkali metal alcoholate (e.g. sodium methylate, sodium ethylate, etc.), organic basic compounds (e.g. pyridine, N -ethyldiisopropylamine, dimethylaminopyridine, triethylamine, DBN, DBU, WO 95/09159 5 0 3 4 S ~CT/~4/01559 DABCO, etc.), and the like. The amount of the compound (1a) and the compound (4a) is not critical, but the compound (4a) is used at least in equimolar amount, preferably in an amount of 1 to 10 moles, to 1 mole of the compound (1 a). The reaction is usually carried out at a temperature of 0 to about 200C, preferably at a temperature of 0 to about 1 70C, for 30 minutes to30 hours. The reaction may be carried out by adding an alkali metal halide compound such as sodium iodide, potassium iodide, etc., into the reaction system. Further, the reaction may be carried out by adding a halogenated ammonium such as tetra-n-butylammonium iodide, tetra-n-butylammonium bromide, n-butyl triethyl ammonium iodide, tetraethylammonium iodide, tri-n -butyl methyl ammonium iodide, etc., into the reaction system.
The reaction of the compound (1a) and the compound (4b) is usually carried out in the presence of a reducing agent in a suitable solvent orwithout a solvent. The solvent includes, for example, water, alcohols (e.g.
methanol, ethanol, isopropanol, butanol, etc.), acetonitrile, formic acid, acetic acid, ethers (e.g. dioxane, diethyl ether, diglyme, tetrahydrofuran, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), or a mixture of these solvents. The reducing agent includes, for example, formic acid, alkali metal salts of fatty acid (e.g. sodium formate, etc.), hydrogenating-reducing agents (e.g. sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, etc.), catalytic reducing agents (e.g. palladium-black, palladium -carbon, platinum oxide, platinum black, Raney-nickel, etc.), and the like.
When formic acid is used as a reducing agent, the reaction is usually carried out at a temperature of room temperature to about 200C, preferably at a temperature of ~0 to about 1 50C, for 1 to about 10 hours. The formic acid is used in an excess amount to the compound (1a).
When a hydrogenating agent is used, the reaction is usually carried out at a temperature of -30 to about 1 00C, preferably at a temperatureof 0 to about 70C, for 30 minutes to about 15 hours. The reducing agent is used in an amount of 1 to 20 moles, preferably in an amount of 1 to 6 moles, to 1 mole of the compound (1a). When lithium aluminum hydride is used as an reducing agent, the solvent may preferably ethers (e.g. diethyl ether, dioxane, tetrahydrofuran, diglyme, etc.) and aromatic hydrocarbons (e.g. benzene, ,a~ 202-toluene, xylene, etc.).
When a catalytic reducing agent is used, the reaction is usually carried out under atmospheric pressure or 20 atms. of hydrogen gas, preferably under atmospheric pressure or about 10 atms. of hydrogen gas, or in the 5 presence of a hydrogen-donor such as formic acid, ammonium formate, cyclohexene, hydrazine hydrate, etc., at a temperature of -30 to about 1 00C, preferably at a temperature of 0 to about 60C, for 1 to 12 hours. The catalyticreducing agent is usually used in an amount of 0.1 to 40 % by weight, preferably 1 to 20 % by weight, to the compound (1a).
The compound (4b) is usually used at least in equimolar amount, preferably in an amount of 1 to excess amount, to 1 mole of the compound (1 a).
Reaction Scheme-3 o 5~N~X O ~R3 ~N'X ,R3 (Rl)r ~ ~ R4 (R1)r ~ ~ R4 ()n ()n (1c) (1 d) ~l )m ( j~ )m X ~X _R '5~:7X ,R3 (1e) (1f) [in which R1, R2, R3, R4, r, m and n are the same as defined above]
The reaction of converting the compound (1c) into the compound (1d), and the reaction of converting the compound (1e) into the compound (1f) are carried out in the presence of an oxidizing agent in a suitable solvent. The 21503~

solvent includes, for example, water, organic acids (e.g. formic acid, acetic acid, trifluoroacetic acid, etc.), alcohols (e.g. methanol, ethanol, etc.), halogenated hydrocarbons (e.g. chloroform, dichloromethane, etc.), or a mixture of these solvents. The oxidizing agent includes, for example, peracids (e.g. performic 5 acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloro -perbenzoic acid, p-carboxyperbenzoic acid, etc.), hydrogen peroxide, sodium metaperiodate, dichromic acid, dichromates (e.g. sodium dichromate, potassium dichromate, etc.), permanganic acid, permanganates (e.g.
potassium permanganate, sodium permanganate, etc.), lead salts (e.g. Iead 10 tetraacetate, etc.), and the like. The oxidizing agent is usually used at least in equimolar amount, preferably in an amount of 1 to 2 moles, to 1 mole of the starting compound. The above reaction is usually carried out at a temperature of -10 to 40C, preferably at a temperature of -1 0C to room temperature, for about 1 to 100 hours.

3~

Reaction Scheme-4 ~l )m ~N~XR (R~)ql ()n (C)IN H R9a (19) \R OH (5) ()m R10bX (6a) \ ~N~xR

Rl0CcoR10d (6b) ~N CON_~
(1h) ~;'XCO N~ ~ (R8)q/Rgb 2û ()n lCI )IN~R~ob (1i) [wherein R1, R2, R3a~ R8, a group of the formula: ~, r, m, n, X and I are the same as defined above, R9a is hydrogen atom, a lower alkanoyl group, a lower alkyl group, a morpholinocarbonyl-lower alkyl group, a cycloalkyl -25 carbonyl group, a phenyl-lower alkenylcarbonyl group, a lower alkylsulfonyl group, an aminocarbonyl group which may optionally have a lower alkyl substituent, a phenylsulfonyl group which may optionally have a lower alkyl substituent on the phenyl moiety, a phenyl-lower alkenyl group, a benzoyl group which may optionally have 1 to 3 substituents on the phenyl moiety 30 selected from a halogen atom, a lower alkoxy group, an amino group having optionally a lower alkanoyl substituent and hydroxy group, an amino-WO 95/09159 2 1 5 0 3 ~ 5 PCT/JP94/01559 substituted lower alkanoyl group which may optionally have a lower alkanoyl substituent, an amino-substituted sulfonyl group which may optionally have a - lower alkyl substituent, a phenyl-lower alkyl group, phenyl group and an amino group which may optionally have a lower alkanoyl substituent, R10a is a lower alkanoyl group, a cycloalkylcarbonyl group, a phenyl-lower alkenylcarbonyl group, a benzoyl group which may optionally have 1 to 3 substituents on the phenyl moiety selected from a halogen atom, a lower alkoxy group, an amino group having optionally a lower alkanoyl substituent and hydroxy group, and an amino-substituted lower alkanoyl group which may optionally have a lower alkanoyl substituent, R10b is a lower alkyl group, a morpholinocarbonyl-lower alkyl group, a lower alkenylsulfonyl group, an aminocarbonyl group which may optionally have a lower alkyl substituent, a phenylsulfonyl group which may optionally have a lower alkyl substituent, a phenyl-lower alkenyl group, an amino-substituted sulfonyl group which may optionally have a lower alkyl substituent, or a phenyl-lower alkyl group, q' is 1 or 2, R10C and R10d are eachhydrogen atom or a lower alkyl group]
The reaction of the compound (1g) and the compound (5) is carried out under the same conditions as those of the reaction of the compound (2) and the compound (3) in the above mentioned Reaction Scheme-1.
The compound (1h) wherein R10a is a lower alkanoyl group may be derived from the compound (19) by subjecting the compound (19) to lower alkanoylization with using a compound of the formula: (R11)2O (7) or R11X (8) (in which R1 l is a lower alkanoyl group, and X is the same as defined above).
The lower alkanoylization reaction is carried out in the presence or absence of a basic compound. The basic compound includes, for example, an alkali metal (e.g. sodium, potassium, etc.), hydroxides, carbonates and hydrogen carbonates of these alkali metals, or organic basic compounds (e.g. N,N -dimethylaminopyridine, pyridine, piperidine, etc.), and the like. The reaction is carried out in a solvent or without a solvent. The solvent includes, for example, ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e.g. diethyl ether, dioxane, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), water, pyridine, and the like. The compound (7) or the compound (8) is used at WO9S/09159 2~Sa34S PCT/JP94/01559 least in equimolar amount, preferably in an amount of 1 to excess amount, to 1 mole of the starting compound (19). The reaction is carried out at a temperature of 0 to 200C, preferably at a temperature of 0 to 1 50C, for about5 minutes to about 5 days.
The reaction of the compound (19) and the compound (6a) or the compound (6b) is carried out under the same conditions as those of the reaction of the compound (1a) and the compound (4a) or the compound (4b) in the above mentioned Reaction Scheme-2.
Reaction Scheme-5 (~ )m ~)n (cRo)oRl2 (1 j) \
~drolysis ()m 5~ 'X _R~ COOH

( ~~)m R HN\ (9) (1k) ~N'XCON'~ (R8)q, ()n CON\

(1 I) [wherein R1, R2, R8, R3a~ m, n, q', R9, R10, r and the group of the formula:

- ~ 2lso3~s ~) are the same as defined above, and R12 is a lower alkyl group]
The hydrolysis of the compound (1j) is carried out in the presence of an acid or a basic compound in a suitable solvent or without a solvent. The solvent includes, for example, water, lower alcohols (e.g. methanol, ethanol, 5 isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e.g.
dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g.
acetic acid, formic acid, etc.), dimethylformamide, or a mixture of these solvents.
The acid includes, for example, inorganic acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), and organic acids (e.g. formic acid, acetic acid,10 aromatic sulfonic acid, etc.). The basic compound includes, for example, alkali metal salts (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal or alkaline earth metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), and the like. The reaction is usually carried out at atemperature of room temperature to about 200C, preferably at a temperature of room temperature to about 1 50C, for 10 minutes to about 25 hours.
The reaction of the compound (1 k) and the compound (9) is carried out under the same conditions as for the reaction of the compound (2) and the compound (3) in the above mentioned Reaction Scheme-1.

34~

Reaction Scheme-6 ()m X N`X R (RR1a) q~

(10) \ (t )m R2 X)x R3 OH
15 (t )m R13X (10) (1 m) ~ N`X R2 ()n oR13 (1 n) [wherein R1, R2, R3a~ R8, m, n, q', X and the group of the formula: ~3 are the same as defined above, R13 is a lower alkyl group, a phenyl-lower alkyl 25 group which may optionally have an amino substituent having optionally a lower alkanoyl substituent on the phenyl moiety, a carboxy-substituted lower alkyl group, a lower alkoxycarbonyl-substituted lower alkyl group, a lower alkoxy-substituted lower alkyl group, a lower alkenyl group, a lower alkanoyl group, or a morpholinocarbonyl-lower alkyl group, and Rl4 is a lower alkoxy 30 group, a phenyl-lower alkoxyl group which may optionally have an amino substituent having optionally a lower alkanoyl substituent on the phenyl moiety, WO 9S/09159 PCI/JP94/OlSS9 21~034~

a lower alkanoyloxy group or a lower alkoxy-substituted lower alkoxy group]
The reaction of converting the compound (10) into the compound (1m) is carried out by reducing the compound (10) when R14 is a phenyl-lower alkoxy group. The reduction reaction is carried out by subjecting the 5 compound (1 m) to catalytic hydrogenation in the presence of a catalyst in a suitable solvent . The solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane,cyclohexane, etc.), ethers (e.g. dioxane, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.),10 aprotic polar solvents (e.g. dimethylformamide, etc.), or a mixture of these solvents. The catalyst is, for example, palladium, palladium-black, palladium -carbon, platinum, platinum oxide, copper chromite, Raney-nickel, etc. and used in an amount of 0.02 to 1 part by weight to 1 part by weight of the compound (7). The reaction is usually carried out at a temperature of -20 to 1 00C, preferably at a temperature of 0 to about 80C, under 1 to 10 atms of hydrogen gas, for 0.5 to 20 hours.
The reaction of converting the compound (1 O) into the compound (1m) is carried out by subjecting the compound (10) to hydrolysis when R14 is a lower alkoxy group or a lower alkoxy-substituted lowre alkoxy group. The hydrolysis is carried out in the presence of an acid in a suitable solvent. The solvent includes, for example, water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ethers (e.g. dioxane, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride, etc.), polar solvents (e.g. acetonitrile, etc.), or a mixture of these solvents. The acid includes, for example, inorganic acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), fatty acids (e.g. formic acid, acetic acid, etc.), Lewis acids (e.g. boron trifluoride, aluminum chloride, boron tribromide, etc.), iodides (e.g. sodium iodide, potassium iodide, etc.), a mixture of the above Lewis acid and a iodide, and the like. The reaction is usually carried out at a temperatureof 0 to 150C, preferably at a temperature of room temperature to 100C, for 0.5to about 50 hours.
The reaction of converting the compound (1 O) into the compound WO 95/09159 3 ~ PCT/JP94/OlS59 (1 m) is carried out in the same manner as in the hydrolysis of the compound (1j) in the above mentioned Reaction Scheme-5, when R14 is a lower alkanoyloxy group.
The reaction of the compound (1 m) into the compound (10) is 5 carried out under the same conditions as those of the reaction of the compound(19) and the compound (6) in the above mentioned Reaction Scheme-4. The compound (1 n) wherein R13 is a lower alkanoyl group is also prepared by reacting the compound (1m) and the compound (7) under the same conditions as those of the reaction of the compound (19) and the compound (7) in the 10 above mentioned Reaction Scheme-4.
Reaction Scheme-7 ~l )m ~l )m ~, N~ R Halogenation ~N`y R2 CON--R (R8) ~ ~N CON~ (R8) ()n ()n X
(1 p) (1q) ~l )m ~l )m ~N~R Halogenation ~N~R2 ~N CON (R5)p~ ~N CON (R5)p~
(R1), ~ `A~ (R1)r ~ A~
()n ()n X

(1E) (1F) [wherein R1 R2, R3a, R5, R8, m, n, q', A, X, r and the group of the formula:

are the same as defined above, and p' is 1 or 2]
The halogenation reaction of the compound (1p) or the compound 30 (1 E) is carried out in the presence of a conventional halogenating agent. The halogenating agent may be any conventional ones, for example, a halogen WO 95tO9159 _ 2 1 ~ O ~ ~ S PCTIJP94tO1559 atom (e.g. bromine, chlorine, etc.), or halogenating agents such as iodine monochloride, sulfuryl chloride, N-halogenosuccinimides (e.g. N-bromo-succinimide, N-chlorosuccinimide, etc.). The halogenating agent is used at least in equimolar amount, preferably in an amount of 1 to 1.5 mole, to 1 mole o5 the compound (1 p) or the compound (1 E). The solvent includes, for example, halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), acetic acid, propionic acid, water, or a mixture ofthese solvents. The reaction is carried out at a temperature of 0C to a boilingpoint of the solvent to be used, preferably at a temperature of 0 to 100C, for 1 10 to about 10 hours.

~3~
? i - 21 2 -Reaction Scheme-8 ()m ( l)m (R )q ~ N,XcoN~(~(Rh) (1u) (1r) (R~ ~ ~N~(Rh)q, ~N~R ()n R16 ~N~ CON_~(R8)ql (1s) ()n C= C H- R18a ¦ R MgX (11 ) (1v) R18b (l)m ~N~X ,R3a (RH)q, ()n C- R17 (1t) R
~wherein R1, R2, R3a~ R8, m, n, q', X, r, and the compound of the formula:

~ are the same as defined above, R15 is a lower alkyl group having a hydroxy substituent, R16 is a lower alkanoyl group, R17 and R13 are each a lower alkyl group, R19 is a lower alkanoyloxy-substituted lower alkyl group, R18a is a hydrogen atom or a lower alkyl group, R13C is phenyl group, and R13b is a lower alkyl group]
The reaction of converting the compound (1 r) into the compound (1 s) is carried out in the presence of an oxidizing agent in a suitable solvent.

wo 95/og1S9 2 1 5 0 3 4 5 PCT/JP94/01559 The oxidizing agent includes, pyridinium chromates (e.g. pyridinium chloro -chromate, pyridinium dichlorochromate, etc.), dimethylsulfoxide-oxazolyl -chloride, manganese dioxide, DDQ, chromic acid, chromites (e.g. sodium chromite, potassium chromite, etc.), permanganic acid, permanganates (e.g.
5 potassium permanganate, sodium permanganate, etc.), and the like. The solvent includes, for example, water, organic acids (e.g. formic acid, acetic acid, trifluoroacetic acid, etc.), alcohols (e.g. methanol, ethanol, etc.), halogenated hydrocarbons (e.g. chloroform, dichloromethane, etc.), ethers (e.g.
tetrahydrofuran, diethyl ether, dioxane, etc.), dimethylosulfoxide, dimethyl -10 formamide, or a mixture of these solvents. The oxidizing agent is usually usedat least in equimolar amount, preferably in an amount of 1 to 30 moles, to 1 mole of the starting compound. The reaction is carried out at a temperature of 0to 150C, preferably at a temperature of 0 to 100C, for 1 to about 10 hours.
The reaction of converting the compound (1 r) into the compound 15 (1s) is carried out by reacting the compound (1r) with an oxidizing agent in the presence of a co-oxidizing agent in a suitable solvent. The solvent includes, pyridine, ethers (e.g. dioxane, tetrahydrofuran, diethyl ether, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), 20 esters (e.g. ethyl acetate, etc.), water, alcohols (e.g. methanol, ethanol, isopropanol, t-butanol, etc.), or a mixture of these solvents. The co-oxidizing agent used therein includes, for example, N-oxides of organic amine such as pyridine N-oxide, N-ethyldiisopropylamine N-oxide, N-methylmorpholine N -oxide, trimethylamine N-oxide, triethylamine N-oxide, etc. The oxidizing agent 25 includes, for example, tetra(n-propyl)ammonium perruthenate, and the like.
The co-oxidizing agent is used at least in equimolar amount, preferably in an amount of 1 to 5 moles, to 1 mole of the starting compound. The oxidizing agent is used in a catalytic amount. The reaction is carried out at a temperature of -20 to 1 50C, preferably at a temperature of 0 to 1 00C, for 1 to about 20 30 hours. The reaction may proceed more advantageously by adding Molecular Shieves into the reaction system.
The reaction of converting the compound (1s) into the compound (1 r) is carried out by a reduction reaction using a hydrogenating agent. The WO 95/O91S9 ~ c~ j PCT/JP94/01559 hydrogenating agent includes, for example, lithium aluminum hydride, diboran, aluminum diisobutyl hydride, sodium borohydride, lithium borohydride, tetrabutylammonium borohydride, calcium borohydride, aluminum hydride, and the like, and is used at least in 0.1 mole amount, preferably in an amount of 0.1 5 to 15 moles, to 1 mole of the starting compound. The reduction reaction is usually carried out in a suitable solvent, for example, water, lower alcohols (e.g.
methanol, ethanol, isopropanol, etc.), ethers (e.g. tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, etc.), aromatic hydrocarbons (e.g. benzene, toluene,xylene, etc.), or a mixture of these solvents, at a temperature of -60 to 1 50C, preferably at a temperature of -30 to 1 00C, for about 10 minutes to about 20 hours.
The reaction of the compound (1s) and the compound (11) is carried out in a suitable solvent. The solvent includes any solvents used for the Grignard reaction, and preferable ones are, for example, ethers (e.g. diethyl ether, dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (e.g. benzene, toluene, etc.), saturated hydrocarbons (e.g. pentane, hexane, heptane, cyclohexane, etc.), and the like. The compound (11 ) is usually used at least inequimolar amount, preferably in an amount of 1 to 2 moles, to 1 mole of the compound (1s). The reaction is carried out at a temperature of -70 to 1 00C, preferably at -30 to about 70C, for 1 to about 50 hours.
The reaction of converting the compound (1 r) into the compound (1 u) is carried out by reacting the compound (1 r) with the compound (7) or thecompound (8) under the same conditions as those of the reaction of the compound (1 h) and the compound (7) or the compound (8) in the above mentioned Reaction Scheme-4.
The reaction of converting the compound (1 u) into the compound (1 r) is carried out under the same conditions as those of the hydrolysis of thecompound (1j) in the above mentioned Reaction Scheme-5.
The reaction of the compound (1s) and the compound (11a) is carried out in the presence of a basic compound in a suitable solvent. The basic compound includes, for example, inorganic bases such as metal sodium, metal potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen ,_ ~ 2~S03~

carbonate, and organic bases such as alkali metal alcoholates (e.g. sodium methylate, sodium ethylate, potassium t-butoxide, etc.), an alkyl lithium, aryl - lithium or lithium amide (e.g. methyl lithium, n-butyl lithium, phenyl lithium, lithium diisopropylamide, etc.), pyridine, piperidine, quinoline, triethylamine,- 5 N,N-dimethylaniline, and the like. The solvent may be any one which does not affect the reaction, for example, ethers (e.g. diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aromatic hydrocarbons (e.g.
benzene, toluene, xylene, etc.), aiiphatic hydrocarbons (e.g. n-hexane, heptane, cyclohexane, etc.), amines (e.g. pyridine, N,N-dimethylaniline, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), alcohols (e.g. methanol, ethanol, isopropanol, etc.), or a mixture of these solvents. The reaction is usually carried out at a temperature of -80 to 1 50C, preferably at a temperature of -80 to about 120C, for 0.5 to about 15 hours. The compound (1 1a) is used at least in equimolar amount, preferably in an amount of 1 to 10 moles, to 1 mole of the compound (1s).
Reaction Scheme-9 (l )m ()m ~N XR2 (R5)p ~ NXR2 (R5)p N CON ~ N CON /~/
(R )r ~ A~R21 (R )r ~ `A~`OH
()n ()n (1x) / (1xl) ()m / R20X (12) `X (R5)p~

1w) WO 95/09159 2 1 ~; 0 3 ~5 PCT/JP94/01559 [wherein R1, R2, R3a~ R5, m, n, p', A, r and X are the same as defined above, R20 is a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a lower alkenyl group, a lower alkoxycarbonyl-substituted lower alkyl group, a hydroxy -substituted lower alkyl group, a carboxy-substituted lower alkyl group, a phenyl -5 lower alkyl group which may optionally have a substituent selected from alower alkyl group and a lower alkoxy group on the phenyl moiety, a morpholino -substituted lower alkyl group, or a group of the formula: -A1-CO-NR6R7 (in which A1, R6 and R7 are the same as defined above), and R21 is a lower alkoxy group, a lower alkoxy group-substituted lower alkoxy group, or a phenyl-lower 10 alkoxy group which may optionally have a substituent selected from a lower alkyl group and a lower alkoxy group on the phenyl moiety]
The reaction of converting the compound (1x) into the compound (1x') is carried out under the same conditions as those of the reaction of converting the compound (10) into the compound (1m) in the above mentioned 15 Reaction Scheme-6.
The reaction of the compound (1x') and the compound (12) is carried out under the same conditions as those of the reaction of the compound (1m) and the compound (10) in the above mentioned Reaction Scheme-6.

Reaction Scheme-10a (l )m (t )m (R3)q ~ R (R3)q (1Y) /' (1z) (1A) Reaction Scheme-10b (1 )m ()m ~ N CON (R )p ~ 5~ ~X ~ R3a (R5)p ~1, A~ R22 ( )r ~1, A~ R23 (1B) ~ (1C) 25()m / ~ R7 ~ NXR2 (R5)p (R )r J~ A~R25 ()n 30(1D) [wherein R1, R3a' R8, m, n, q', R5, p', r and the group of the formula:

are the same as defined above, R22 is a lower alkoxycarbonyl-substituted lower alkoxy group, R23 is a carboxy-substituted lower alkoxy group, R24 is a morpholinocarbonyl-lower alkoxy group, R25 is a group of the formula:
-O-A1-CO-NR6R7 (in which A1, R6 and R7 are the same as defined above)]
The reaction of converting the compound (1y) into the compound (1z) and the reaction of converting the compound (1B) into the compound (1C) are carried out under the same conditions as those of the hydrolysis of the compound (11) in the above mentioned Reaction Scheme-5.
The reaction of the compound (1z) and the compound (13) and 10 the reaction of the compound (1C) and the compound (14) are carried out under the same conditions as those of the reaction of the compound (2) and the compound (3) in the above mentioned Reaction Scheme-1.
Reaction Scheme-11 ()m ()m l 2 l ~ ~X ~R (Ra)q ~ ~ ~X ~R (Ra)q~
()n COOR12 ()n CH2OH

(1i) (1G) (l )m (l )m ~ NXR2 (R5)p ~ NX R3a (R5) (R1)r ~ `A~ (R1)r ~ A~
()n COOR1 ()n CH2OH
(1 H) (11) [wherein R1, R2, R8, R3a~ m, n, q', R12, R5, p', A, r and the group of the formula:
~ are the same as defined above]

The reaction of converting the compound (1j) into the compound (1 G) and the compound of converting the compound (1 H) into the compound (11) are carried out under the same conditions as those of the reaction of converting the compound (1s) into the compound (1r) in the above mentioned Reaction Scheme-8.
5 Reaction Scheme- 12 (~)m (l)m ça~ N CON ~' ~ ~X (R5)p 10 (R )r ~ A~o BCOOR12 (R )r ~ A~O--B--CH20H

(lJ) / (1K) ()m (t)m ~

~N CON ()p (R )r '1, A~(R )p (~n A~O--B--CH2X ()n O-B-CH2N~ O
(1 M) (1L) [wherein R1, R2, R3a~ R5, A, m, n, p', R12, r and X are the same as defined above and B is a lower alkylene group]
The reaction of converting the compound (1J) into the compound 25 (1 K) is carried out under the same conditions as those of the reaction of converting the compound (1s) into the compound (1r) in the above mentioned Reaction Scheme-8.
The reaction of converting the compound (1 K) into the compound (1 L) is carried out by reacting the compound (1 K) with a halogenating agent in30 a suitable solvent or without a solvent. The halogenating agent includes, forexample, inorganic acids (e.g. hydrochloric acid, hydrobromic acid, etc.), N,N -diethyl-1,2,2-trichlorovinylamide, phosphorus pentachloride, phosphorus .~.

pentabromide, phosphorus oxychloride, thionyl chloride, mesyl chloride, tosyl chloride, etc., and a basic compound, carbon tetrachloride or carbon tetrabromide and triphenylphosphine. The basic compound may be the same as the above mentioned basic compounds for the reaction of the carboxylic 5 halide and the amine compound in Reaction Scheme-1. The solvent includes, for example, ethers (e.g. dioxane, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g. chloroform, methylene chloride, carbon tetrachloride, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), and the like.
When a phenyl-lower alkyl halide (e.g. tosyl chloride, etc.) and a basic 10 compound are used as a halogenating agent, the halogenating agent is used at least in equimolar amount, preferably in 1 to 2 moles, to 1 mole of the compound (1K). When other halogenating agents are used, the halogenating agent is used at least in equimolar amount, preferably in an excess amount, to 1 mole of the compound (1 K). The reaction is usually carried out at a 15 temperature of room temperature to 1 50C, preferably at a temperature of room temperature to 80C, for 1 to about 80 hours.
The reaction of the compound (1L) and the compound (13) is carried out under the same conditions as those of the reaction of the compound (1a) and the compound (4a) in the above mentioned Reaction Scheme-2.

WO 95/09159 2 1 5 0 3 ~ 5 PCT/JP94/01559 Reaction Scheme-13 ()m ()m t 5~ N~X , R3a ~ NXR2 (R )r ~ ~R26 (R )r ~ ~R27 ()n \ ()n (1N) \ (10) ~)m \,~ ~ NXR2 (R1) ¦ `R28 1 5 ()n (1P) [wherein R1, R2, R3a~ r, m and n are the same as defined above, R26 is a phenylthio-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, R27 is a phenylsulfinyl-substituted 20 lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, and R28 is a phenylsulfonyl-substituted lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety]
The reaction of converting the compound (1 N) into the compound (10) and the reaction of converting the compound (10) into the compound (1 P) 25 are carried out under the same conditions as those of the reaction of converting the compound (1c) into the compound (1d) in the above mentioned Reaction Scheme-3.
- The reaction of converting the compound (1 N) into the compound (1 P) is carried out under the same conditions as those of the reaction of 30 converting the compound (1 N) and the compound (10) except that the oxidizing agent is used at least in an amount of 2 moles, preferably in an amount of 2 to 4 moles, to 1 mole of the compound (1 N).

2150~5 WO 95/09159 PCI'1JP94101S59 Reaction Scheme-14 (t )m S ~[CON' ~Y--A~-(1a) R6bX ~, 5~z RBC_I_R6d (15b) (R~ CON ~Y--A~--CON

~t)m (1 R) 1 5 ~ NXR ( R5)p (R1)r ~ A~NHR2g ()n (lS) \ (~)m R30X (1 6a)~, N~ R2 R30a_C_R30b (16b) (R ), ~ CON ~(RR52)9p~

()n \ R30 (1~) [wherein R1, R2, R3a~ R5, m, n, p', X, A, A1, r and Y are the same as defined 25 above, R6a is hydrogen atom, a lower alkyl group which may optionally have a hydroxy substituent, a phenyl-lower alkyl group which may optionally have a lower alkoxy substituent on the phenyl moiety, a furyl-lower alkyl group, or a lower alkoxy-substituted lower alkyl group, R6b is the same groups for the above mentioned R6a except hydrogen atom, R6C and R6d are each hydrogen 30 atom or a lower alkyl group, R29 is hydrogen atom or a lower alkyl group, R30 is a lower alkyl group or a group of the formula: -A1 CONR6R7 (in which A1, R6 WO 95/09159 2 1 S 0 3 9 ~ PCr/JP94/01559 and R7 are the same as defined above), R30a and R30b are each hydrogen atom or a lower alkyl group, provided that when R30 is a group of the formula:
-A1CoNR6R7, R29 is hydrogen atom]
The reaction of the compound (1Q) and the compound (15a) and 5 the reaction of the compound (1S) and the compound (16a) are each carried out under the same conditions as those of the reaction of the compound (1 a) and the compound (4a) in the above mentioned Reaction Scheme-2 The reaction of the compound (1Q) and the compound (15b) and the reaction of the compound (1 S) and the compound (1 6b) are each carried out under the same 10 conditions as those of the reaction of the compound (1 a) and the compound (4b) in the above mentioned Reaction Scheme-2.
The starting compound (2) or (3) may be prepared by the following processes.
Reaction Scheme-15 R3bCH2N~3 ~ R3bCH2NH2 (17) (3a) [wherein R3b is the same as defined above, provided that the total number of carbon atoms of no-cyclic parts of a group of the formula: R3bCH2- in the compound (3a) is not over 6]
The reaction of converting the compound (17) into the compound 25 (3a) is carried out by reacting the compound (17) with hydrazine in a suitable solvent or by subjecting the compound (17) to hydrolysis. The solvent used for the reaction of the compound (17) and hydrazine includes, for example, in addition to water, the same solvents for the reaction of the compound (2) and the compound (3) in the above mentioned Reaction Scheme-1. The reaction is 30 usually carried out at a temperature of room temperature to about 1 20C, preferably at a temperature of 0 to about 1 00C, for 0.5 to about 10 hours.
Hydrazine is used at least in equimolar amount, preferably in an amount of 1 to WO 95/Ogl59 2 1 5 0 3 4 5 PCT/JP94101559 5 moles, to 1 mole of the compound (17).
The hydrolysis is carried out in the presence of an acid or a basic compound in a suitable solvent or without a solvent. The solvent includes, for example, water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g. aceticacid, formic acid, etc.), or a mixture of these solvents. The acid includes, forexample, inorganic acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acids (e.g. formic acid, acetic acid, aromatic sulfonic acid, etc.), and the like. The basic compound includes, for example, alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal or alkaiine earth metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), and the like. The reaction is usually carried out at atemperature of room temperature to about 200C, preferably at a temperature of room temperature to about 1 50C, for 10 minutes to about 25 hours.
Reaction Scheme-16 R3e--C--R31 R32NH4 (19) R3e--C H--R3 (18) (3b) [wherein R31 is hydrogen atom, a lower alkyl group or a lower alkenyl group, R3e is hydrogen atom, a lower alkyl group, a group of the formula: -(D)r'-R33 (Dis a lower alkylene group, r' is 0 or 1, R33 is a group of the formula:

(R5)p (R5 and p are the same as defined above), a lower alkanoyloxy -substituted lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkanoyl-substituted lower alkyl group, a lower alkoxycarbonyloxy-substituted lower alkyl group, a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring, a group of the formula: -E-N(R52)(R53) (in which R52 and R53 are the same as defined above, and E is a lower alkylene group), a group of the formula:

A Rs4 0~0 O

5 (in which Rs4 is hydrogen atom or a lower alkyl group and A is the same as defined above), a cycloalkyl group; naphthyl group; a group of the formula:

(R8)q (R8 and q are the same as defined above, a group of the .~

formula: ~ is a 5- to 14-membered saturated or unsaturated heteromonocyclic, heterobicyclic or heterotricyclic group having 1 to 4 10 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom); a phenyl group which may optionally have a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having 15 optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -o-A4-CO-NR4R41 (A4, R40 and R41 are the same as defined above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl ring; a phenyl-lower alkenyl group which may optionally have a substituent selected from a lower alkoxy 20 group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula: -O-A4-CO-NR4R41 (A4, R40 and R41 are the same as defined 25 above), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl ring; a phenyltio-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl ring; a phenylsulfinyl-substituted lower alkyl group having optionally a lower wo gs/09159 2 1 S 0 3 4 5 PCTIJP94/015S9 alkoxy substituent on the phenyl ring; a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl ring; a phenoxy-substituted lower alkyl group, a group of the formula: -A5-CR42R43R44 (A5, R42, R43 and R44 are the same as defined above); a 2,3-dihydro-1 H -5 indenyl-substituted lower alkyl group which may optionally have a substituent selected from oxo group, hydroxy group a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1 H-indenyl ring; a group of the formula:

(R47) ( ~, R47 and u are the same as defined above), a group of the formula: (R47)u (R47 and u are the same as defined above, a group 10 oftheformula: ~ isa5-tol4-memberedunsaturated heteromonocyclic, heterobicyclic or heterotricyclic group having 1 to 4 hetero -atoms selected from nitrogen atom, oxygen atom and sulfur atom), provided that wherein R3e is a phenyl group which may optionally have a substituent selected from a lower alkoxy group, a halogen atom, an amino group having 15 optionally a substituent selected from a lower alkanoyl group and a phenyl -lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole ring, hydroxy group, a group of the formula:
-o-A4-Co-NR4R41 (A4, R40 and R41 are the same as defined above), a lower 20 alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl ring, or a group of the formula:
(R47)u~ then R31 is a lower alkenyl group, and that the total number of wo 9S/O9lS9 2 1 S 0 3 4 5 PCT/JP94/01559 carbon atoms in non-cyclic part of the group of the formula: (R3e)(R31)CH- in the compound (3b) is not over 6, and R32 is a lower alkanoyloxy group]
The reaction of the compound (18) and the compound (19) is carried out under the same conditions as those of the reaction of the compound 5 (1a) and the compound (4b) in the above Reaction Scheme-2.
The starting compound (17) is prepared by the following processes.
Reaction Scheme-17 R3b - CH3 (20) M N~ (22a) R3b--CH2X

~ R3~-CH2N~,3 ~ (1~
R3b- CH2O H ~
(24) H N~J (22b) ~ ~ O (22a) R3b cHo R3b-CooR12 R(236)H
(23) (25) 25 [wherein R3b, R12 and X are the same as defined above, M is an alkali metal such as potassium, sodium, etc., provided that the total number of carbon atoms of non-cyclic part of the group of the formula: -CH2R3b in the compound (17) is not over 6]
The reaction of converting the compound (20) into the compound 30 (21) is carried out in the same manner as in the halogenation reaction of thecompound (1p) in the above mentioned Reaction Scheme-7, but it is preferably carried out by adding to the reaction system a radical initiator such as 2-(4-WO 95/09159 2 1 S 0 3 4 ~i PCT/JP94101559 biphenylyl)-5-phenyloxazole, azobisisobutyronitrile perbenzoic acid, etc., and asuitable amount of water (e.g. 3 mole %).
The reaction of the compound (21 ) and the compound (22a) is carried out under the same conditions as thosè of the reaction of the compound 5 (1a) and the compound (4a) in the above Reaction Scheme-2.
The reaction of converting the compound (23) into the compound (24) is carried out under the same conditions as those of the reaction of converting the compound (1s) into the compound (1r) in the above Reaction Scheme-8.
The reaction of the compound (24) and the compound (22b) is carried out in a suitable solvent in the presence of an azodicarboxylic acid derivative such as dialkyl azodicarboxylate (e.g. diethyl azodicarboxylate, dibutyl azodicarboxylate, etc.) and a dialkylazodicarboxyamide (e.g. 1,1' -azodicarbonyldipiperidine, etc.), and a phosphorus compound such as a 15 trialkylphosphine (e.g. trimethylphosphine, etc.) and a triarylphosphine (e.g.
triphenylphosphine, etc.). The solvent may be the same solvents for the reaction of the compound (1a) and the compound (4a) in the above Reaction Scheme-2 except lower alcohols. The azodicarboxylic acid derivative, phosphorus compound and the compound (22) are each used at least in 20 equimolar amount, preferably in an amount of 1 to 1.5 mole, to 1 mole of the compound (24). The reaction is usually carried out at a temperature of 0 to 1 00C, preferably at a temperature of 0 to about 70C, for 1 to about 15 hours.The reaction of converting the compound (25) into the compound (24) is carried out under the same conditions as those of the reaction of 25 converting the compound (1s) into the compound (1 r) in the above Reaction Scheme-8.
The reaction of the compound (26) and the compound (22a) is carried out in a suitable solvent in the presence of formaldehyde and an acid.
The solvent includes, for example, halogenated hydrocarbons (e.g.
30 dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), water, alcohols (e.g. methanol, ethanol, isopropanol, etc.), alkanoic acids (e.g. acetic acid, propionic acid, etc.), acid anhydrides (e.g. acetic anhydride, etc.), polar soivents (e.g. acetone, dimethylformamide, etc.), or a mixture of these solvents.

The acid includes, for example, inorganic acids such as hydrogen chloride gas, hydrochloric acid, hydrobromic acid, etc. Formaldehyde includes, for example, an aqueous 20 to 40 % by weight formaldehyde solution, trimer of formaldehyde, polymer of formaldehyde, i.e. para-formaldehyde, and the like.
- 5 The compound (22a) is usually used at least in equimolar amount, preferably in an amount of 1 to 2 moles, to 1 mole of the compound (26). Formaldehyde is usually used at least in equimolar amount, preferably in an excess amount, to 1 mole of the compound (26). The reaction is carried out at a temperature of 0 to about 200C, preferably at a temperature of room temperature to 150C, for 0.5 to about 24 hours.
Reaction Scheme-18 R3b-C N . R3b-CH2NH2 (27) (3c) 15 [wherein R3b is the same as defined above]
The reaction of converting the compound (27) into the compound (3c) is carried out under the same conditions as those of the reaction of converting the compound (1s) into the compound (1 r) in the above Reaction Scheme-8.
20 Reaction Scheme-19 R3sH
R34--A--X ~R34--A- R35 H2N--A- R35 (28) (30) (3d) 25 [wherein R34 is a group of the formula:

--N~

or a group of the formula: -NR36R37 (in which R36 and R37 are each a phenyl -lower alkyl group), R35 is a phenylthio group having optionally a lower alkoxy substituent on the phenyl ring, and A is the same as defined above]

WO 95/09159 2 1 ~ 0 3 ~ 5 PCT/JP94/01559 The reaction of the compound (28) and the compound (29) is carried out under the same conditions as those of the reaction of the compound (1 a) and the compound (4a) in the above Reaction Scheme-2.
The reaction of converting the compound (30) into the compound 5 (3d) is carried out under the same conditions as those of the reaction of converting the compound (17) into the compound (3a) in the above Reaction Scheme-15, when R34 of the compound (30) is a group of the formula:

--N~
o When R34 of the compound (30) is a group of the formula:
-NR36R37 the reaction of converting the compound (30) into the compound (3d) is carried out under the same conditions as those of the reduction of the compound (10) into the compound (1m) in the above Reaction Scheme-6 wherein R14 is a phenyl-lower alkoxy group.
Reaction Scheme-20 o o ~,N~ R2 CH2CO2Rl2 ~NXR2 N (32) N C02R
(R )r ~ (R )r ,' ~

~N C02R12 ~NXco2R12 ~N'xco R12 (R1)r (R1)r (R1)r (33d) (33c) (33b) [wherein R1, R2, R12 and r are the same as defined above]
The reaction of the compound (31 ) and the compound (32) is carried out in the presence of a basic compound. The basic compound includes the same basic compounds as used for the reaction of the compound - 5 (1a) and the compound (4a) in the above Reaction Scheme-2. The compound (32) is used at least in equimolar amount, preferably in an amount of 1 to 5 moles, to 1 mole of the compound (31). The reaction is carried out at a temperature of 0 to 1 00C, preferably at a temperature of 0 to about 70C, for 1 hour to about 5 day.
The reaction of converting the compound (33a) into the compound (33b) is carried out in the presence of a halogenated phosphorus compound such as phosphorus tribromide, phosphorus trichloride, etc. in a suitable solvent. The solvent includes, for example, ethers (e.g. dioxane, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g. chloroform, methylene chloride, carbon tetrachloride, etc.), and the like. The halogenated phosphorus compound is used in an amount of 1 to 2 moles, to 1 mole of the compound (33a). The reaction is usually carried out at a temperature of 0 to 1 00C, preferably at a temperature of 0 to about 70C, for 0.5 to 5 hours.
The reaction of converting the compound (33a) into the compound (33c) is carried out by reacting the compound (33a) with sodium hydrosulfate in the presence of an acid in a suitable solvent. The solvent includes, for example, alcohols (e.g. methanol, ethanol, propanol, butanol, 3 -methoxy-1-butanol, ethylcellosolve, methylcellosolve, etc.), water, and the like.
The acid includes, for example, mineral acids such as hydrochloric acid, etc.
Sodium hydrosulfate is used at least in equimolar amount, preferably in an amount of 1 to 5 moles, to 1 mole of the compound (33a). The reaction is usually carried out at a temperature of 0 to 1 00C, preferably at a temperatureof 0 to abol~t 70C, for 1 to about 10 hours.
The reaction of converting the compound (33c) into the compound (33d) is carried out under the same conditions as those of the reaction of converting the compound (1c) into the compound (1d) in the above Reaction Scheme-3.

WO 9S/09159 2 1 5 0 3 4 5 pCTtJP94/01559 The reaction of converting the compound (33a) into the compound (33d) is carried out under the same conditions as those of the above mentioned reaction of converting the compound (33a) into the compound (33d) except a trialkylphosphite such as trimethylphosphite is used instead of a 5 halogenated phosphorus compound, and the solvent used therein may be an alcohol such as 1-propanol, etc., and the reaction is carried out at a temperature of 0 to 1 50C, preferably at a temperature of 0 to 1 00C.
Reaction Scheme-21 ()m ()m t ~N~y R Hydrolysis ~N~, R2 ~NlCOOR12 ~ ~N COOH
(R )r ~ Csl~ nfica~l~ tR1)r ()n ()n (33) (2) [wherein R1, R2, R12, r, m and n are the same as defined above]
The hydrolysis of the compound (33) is carried out under the same conditions as those of the hydrolysis of the compound (1j) in the above Reaction Scheme-5.
The esterification of the compound (2) is carried out by reacting the starting compound with an alcohol (e.g. methanol, ethanol, isopropanol, etc.) in the presence of an inorganic acid (e.g. hydrochloric acid, sulfuric acid, etc.) and a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, etc., at a temperature of 0 to 1 50C, preferably at a temperature of 50 to 1 00C, for 5 minutes to about 10 hours.
The intermediate compound (24a) is prepared by the following Reaction Scheme-22.

WO 95tO9159 PCT/JP94/01559 -- 21503~5 Reaction Scheme-22 (R8)q~ (R8)q~

- 5 \~CH3 ~CH3 (20a) (20b) (R8)q~ (R8)q~

1 0 ~`CH2OCOR12 ~CH2OH

(20c) (24a) [wherein R8, q' and R12 are the same as defined above]
The reaction of converting the compound (20a) into the compound (20b) is carried out in the presence of an oxidizing agent in a suitable solvent. The solvent and the oxidizing agent used therein are the same solvents and oxidizing agents as used for the reaction of the converting the compound (1c) into the compound (1d) in the above Reaction Scheme-3, 20 respectively. The oxidizing agent is usually used in an excess amount to the compound (20a). The reaction is usually carried out at a temperature of room temperature to 150C, preferably at a temperature of room temperature to about 120C, for 1 to about 20 hours.
The reaction of converting the compound (20b) into the 25 compound (20c) is carried out by heating the compound (20b) in the presence of a compound of the formula: R12COOCOR12 (R12 is the same as defined above) at a temperature of room temperature to about 200C, preferably at a temperature of room temperature to 150C, for 1 to 10 hours.
The reaction of converting the compound (20c) into the compound 30 (24a) is carried out under the same conditions as those of the hydrolysis of the compound (1j) in the above Reaction Scheme-5.
The compound (1) wherein R5 or R8 is an amino group is WO 95/09159 2 ~ 5 3 4 5 PCT/JP94/OlSS9 prepared by reducing the corresponding compound (1) wherein R5 or R8 is nitro group.
The reduction reaction is carried out, for example, (a) by using a catalyst in a suitable solvent, or (b) by using ~as a reducing agent a mixture of a metal or a metal salt with an acid, a mixture of a metal or a metal salt and an alkali metal hydroxide, an alkali metal sulfite or an alkali metal ammonium saltin an inert solvent.
When the above (a) is employed, the solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane, cyclohexane, etc.), ethers (e.g. dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, etc.), esters (e.
ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g. N,N -dimethylformamide, etc.), or a mixture of these solvents. The catalyst includes,for example, palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney-nickel, and the like. The catalyst is used in an amount of 0.02 to 1 mole, to 1 mole of the starting compound. The reaction is carried out at a temperature of -20 to 1 50C, preferably, at a temperature of 0 to 1 00C, under 1 to 10 atms of hydrogen gas, for 0.5 to 10 hours. An acid (e.g.
hydrochloric acid) may be added to the reaction system.
When the method (b) is employed, there is used as a reducing agent a mixture of iron, zinc, tin or stannous chloride and a mineral acid (e.g.hydrochloric acid, sulfuric acid, etc.), or a mixture of iron, iron sulfide, zinc or tin and an alkali metal hydroxide (e.g. sodium hydroxide, etc.), sulfide (e.g.
ammonium sulfide, etc.), aqueous ammonia, ammonium salt (e.g. ammonium chloride, etc.). The inert solvent includes, for example, water, methanol, ethanol, dioxane, acetic acid, and the like. The conditions for reduction can beselected according to the kinds of the reducing agent to be used. For example, when a mixture of stannous chloride and hydrochloric acid is used as a reducing agent, the reaction is preferably carried out at a temperature from 0Cto about room temperature, for 0.5 to about 10 hours. The reducing agent may be used at least in equimolar amount, usually in an amount of 1 mole to 5 moles, to 1 mole of the starting compound.

Reaction Scheme-23 ()m S ~N'Xco ~(RB)q (R )r ~ CHO

(1 U) ~ ()m (R48)2PCH2(D),,R49 N~ R2 1 0 (34) ~ --l ~ R3a (R8) ()n ~ CH=CH(D)r'R49 (~)m R / (1V) 15~N~XcO ~R (R8) (R1 ~
()n ~~ CH=CH(D)~'COOH

()m R50 ,~ t ~Rs~ ,~N CO ~( )q ~Rso ()n CH=CH(D)r CON~
(1 [wherein R1 R2 R3a~ R8, R39, m, n, q', D, r, r' and the group of the formula:
are the same as defined above, R48 is a lower alkoxy group, R49 is a lower alkoxycarbonyl group, and R50 and R51 are the same or different and each hydrogen atom or a lower alkyl group]
The reaction of the compound (1 U) and the compound (34) is 30 carried out in the presence of a basic compound in a suitable solvent. The basic compound includes, for example, inorganic bases (e.g. metal sodium, metal potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc.), organic bases such as an alkali metal alcoholate (e.g. sodium methylate, sodium ethylate, potassium t-butoxide, etc.), an alkyl lithium, aryl lithium or lithium amide (e.g. methyl lithium, n-butyl lithium, phenyl lithium, lithium diisopropylamide, etc.), pyridine, piperidine, quinoline, triethylamine,N,N-dimethylaniline, and the like. The solvent may be any one which does not affect the reaction, and includes, for example, ethers (e.g. diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), aliphatic hydrocarbons (e.g. n-hexane, heptane, cyclohexane, etc.), amines (e.g. pyridine, N,N-dimethylaniline, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, etc.), alcohols (e.g. methanol, ethanol, isopropanol, etc.), and the like. The reaction is usually carried out at a temperature from -80C to 1 50C, preferably at a temperature from -80 to about 120C, for 0.5 to about 15 hours.
The reaction of converting the compound (1V) into the compound (1 W) can be carried out under the same conditions as those of the hydrolysis ofthe compound (1j) in the above Reaction Scheme-5.
The reaction of the compound (1W) and the compound (35) can be carried out under the same conditions as those of the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.
Reaction Scheme-24 ()m ()m ~ R2 ~X R3CoH (38) ~ XN~ 3a CoNHR3a N CON
(Rl)r ~ (Rl)r ~ ~ R3 ()n ()n (1 a) (1 y) [wherein R1, R2, m, n, r and R3a are the same as defined above, R3C' is a phenyl -lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxycarbonyl WO 95/09159 21~ 0 3 4 S PCT/JP94/01559 group, a phenoxycarbonyl group, or a group of the formula: -Co-A-NRs2R53 (in which A, R52, R53 are the same as defined above)]
The reaction of the compound (1a) and the compound (38) is carried out under the same conditions as those of the reaction of the compound 5 (2) and the compound (3) in Reaction Scheme-1. In said reaction, when the compound (38) is used in the form of an acid anhydride, the reaction of the carboxylic acid anhydride and the amine compound is carried out in the same manner as in the reaction of the compound (2) and the compound (3) when the active ester method is employed, i.e. in the presence of a basic compound in a 1 0 solvent at a temperature of 0 to 1 50C, preferably at a temperature of 10 to 100C, for 5 to 30 hours. The carboxylic acid anhydride compound is used at least in equimolar amount, preferably in an amount of 1 to 2 moles, to 1 mole ofthe compound (1a).
The compound (1 ) wherein R3 is a lower alkanoyl group is 15 prepared by reacting the corresponding compound (1 ) wherein R3 is cyano group with a compound of the formula: R17MgX (11 ) (wherein R17 and X are the same as defined above), followed by subjecting the resultant to hydrolysis.
The reaction of the compound (1 ) and the compound (11 ) is carried out under the same conditions as those of the reaction of the compound (1s) and the 20 compound (11 ) in the above Reaction Scheme-8. The subsequent hydrolysis is carried out under the same conditions as those of the hydrolysis of the compound (1j) in the above Reaction Scheme-5. The reaction is preferably carried out in the presence of an acid.
The compound (1) wherein R5 is a 1,3-dioxolanyl group having 25 optionally a lower alkyl substituent or R8 is a 1,3-dioxolanyl-substituted lower alkyl group having optionally a lower alkyl substituent is prepared by reacting the corresponding compound (1 ) wherein R5 is a lower alkanoyl group or R8 is a lower alkanoyl-substituted lower alkyl group with a compound of the formula:
(R38)v ,L, (36) HO OH

WO 95/09159 2 1 ~ 0 3 4 5 PCI/JP94/01559 (wherein R33 is a lower alkyl group, v is 0 or an integer of 1 to 3). The reaction is carried out in the presence of an acid in a suitable solvent. The solvent includes, for example, in addition to the same solvents for the above mentioned reaction of the compound (1a) and the compound (4a) in the above mentioned Reaction Scheme-2, halogenated hydrocarbons (e.g. methylene chloride, dichloroethane, chloroform, etc.). The acid includes, for example, mineral acids(e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acids (e.g.
p-toluenesulfonic acid, etc.), and the like. The compound (36) is used at least in equimolar amount, preferably in an amount of 1 to 10 mole, to 1 mole of the starting compound. The reaction is usually carried out at a temperature of room temperature to 1 50C, preferably at a temperature of room temperature to about 1 00C, for 1 to about 24 hours.
The compound (1 ) wherein R5 is a lower alkanoyl group or R3 is a lower alkanoyl-substituted lower alkyl group is prepared by hydrolysis of the corresponding compound (1 ) wherein R5 is a 1 ,3-dioxolanyl group having optionally a lower alkyl substituent, or R3 is a 1,3-dioxolanyl-substituted lower alkyl group having optionally a lower alkyl substituent. The hydrolysis is carried out in the presence of an acid in a suitable solvent. The solvent includes, for example, water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), or a mixture of these solvents. The acid includes, for example, inorganic acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.) and organic acids (e.g. p-toluenesulfonic acid, etc.). The reaction is carried out at a temperature of 0 to 70C, preferably at a temperature of 0C toroom temperature, for 1 to 10 about hours.
The compound (1 ) wherein R3 is a tetrazolyl group having a substituent selected from a lower alkyl group and a lower alkoxy-lower alkyl group is prepared by reacting the corresponding compound (1 ) wherein R3 is a tetrazolyl group with a compound of the formula: R39X (37) (wherein R39 is a lower alkyl group or a lower alkoxy-lower alkyl group, and X is the same as defined above) in the same manner as in the reaction of the compound (10) with the compound (4a) in the above mentioned Reaction Scheme-2.
The compound (1 ) wherein R8 is unsubstituted tetrazolyl group is prepared by subjecting the compound (1) wherein R8 is a tetrazolyl group having a lower alkoxy-lower alkyl substituent, to hydrolysis in the same manner as in the hydrolysis of the compound (10) wherein R14 is a lower alkoxy -substituted lower alkoxy group in the above mentioned Reaction Scheme-6.
The compound (1) wherein R2 is a morpholino-substituted lower alkyl group or an imidazolyl-substituted lower alkyl group is prepared by reacting the corresponding compound (1 ) wherein R2 is a lower alkyl group having a halogen substituent with morpholine or imidazole in the same manner as in the reaction of the compound (1a) and the compound (4a) in the above mentioned Reaction Scheme-2.
The compound (1) wherein R2 is a halogen-substituted methyl group is prepared by reacting the corresponding compound (1) wherein R2 is methyl group in the same manner as in the reaction of converting the compound (20) into the compound (21) in the above mentioned Reaction Scheme-17. Further, the compound (1) wherein R2 is a halogen-substituted methyl group (in which halogen atom is fluorine atom ) is also prepared by reacting the corresponding compound (1) wherein R2 is a halogen-substituted methyl group (in which halogen atom is other than fluorine atom) with silver fluoride.
Among the desired compounds (1 ) of the present invention, the compounds having a basic group can easily be converted into acid addition salts thereof by treating them with a pharmaceutically acceptable acid. The acid includes, for example, inorganic acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc.), and organic acids (e.g. oxalic acid, acetic acid, succinic acid, malonic acid, methanesulfonic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, etc.). These salts show as well excellent antidiabetic activity as the free compounds (1).
Besides, among the desired compounds (1 ) of the present invention, the compounds having an acidic group can easily be converted into WO 95tO9159 2 l S O 3 4 ~ PCT/JP94/01559 salts by treating them with a pharmaceutically acceptable basic compound.
The basic compound includes, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, and the like.
The desired compound of each process can easily be isolated and purified by conventional isolation methods. The isolation methods are, for example, extraction with solvent, dilution method, recrystallization method, column chromatography, preparative thin layer chromatography, and the like.
In addition, the compounds (1 ) of the present invention include stereoisomers and optical isomers, and these isomers are also useful as antidiabetic agents.
The desired compounds (1 ) of the present invention and salts thereof are useful as antidiabetic agent and are used in the form of a conventional pharmaceutical preparation. The preparation is prepared by using conventional diluents or carriers such as fillers, thickening agents, binders, wetting agent, disintegrators, surfactants, lubricants, and the like. The pharmaceutical preparations can be selected from various forms in accordance with the desired utilities, and the representative forms are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), and the like. In order to form in tablets, there are used carriers such as vehicles (e.g. Iactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.), binders (e.g. water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinyl -pyrrolidone, etc.), disintegrators (e.g. dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, starches, lactose, etc.), disintegration inhibitors (e.g. white sugar, stearin, cacao butter, hydrogenated oils, etc.), absorption promoters (e.g.
quaternary ammonium base, sodium laurylsulfate, etc.), wetting agents (e.g.
glycerin, starches, etc.), adsorbents (e.g. starches, lactose, kaolin, bentonite, colloidal silicates, etc.), lubricants (e.g. purified talc, stearates, boric acid WO95/09159 21 $ o 3~ S PCT/JP94/01559 powder, polyethylene glycol, etc.), and the like. Moreover, the tablets may alsobe in the form of a conventional coated tablet, such as sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film coating tablets, or double or multiple layer tablets. In the preparation of pills, the carriers may be conventional ones, and include, for example, vehicles (e.g. glucose, lactose, starches, cacao butter, hydrogenated vegetable oils, kaolin, talc, etc.), binders (e.g. gum arabic powder, tragacanth powder, gelatin, ethanol, etc.), disintegrators (e.g. Iaminaran, agar, etc.), and the like. In the preparation ofsuppositories, the carriers may be conventional ones, and include, for example, polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides, and the like. Capsules can be prepared by charging a mixture of the compound of the present invention and the above carriers into hard gelatin capsules or soft capsules in usual manner.
In the preparation of injections, the solutions, emulsions and suspensions are sterilized and are preferably made isotonic with the blood. In the preparation of these solutions, emulsions and suspensions, there are used conventional diluents, such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the pharmaceutical preparations may also be incorporated with sodium chloride, glucose, or glycerin in an amount sufficient to make them isotonic, and may also be incorporated with conventional solubilizers, buffers, anesthetizing agents. Besides, the pharmaceutical preparations may optionally be incorporated with coloring agent, preservatives, perfumes, flavors, sweetening agents, and other medicaments, if required.
The amount of the desired compound of the present invention to be incorporated into the pharmaceutical preparation is not specified but may be selected from a broad range, but usually, it is preferably in the range of 1 to 70 % by weight.
The pharmaceutical preparation of the present invention containing as an active ingredient the compounds (1) of the present invention or a salt thereof may be administered in any method, and suitable method for administration may be determined in accordance with various forms of 2~s0~4~

preparations, ages, sexes and other conditions of the patients, the degree of severity of diseases, and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. The injections are intravenously administered à~one or together with a conventional 5 auxiliary liquid (e.g. glucose, amino acid solutions), and further are optionally administered alone in intramuscular, intracutaneous, subcutaneous, or intraperitoneal route, if required. Suppositories are administered in intrarectal route.
The dosage of the pharmaceutical preparation of the present 10 invention may be selected in accordance with the usage, ages, sexes and other conditions of the patients, the degree of severity of the diseases, and the like, but it is usually in the range of about 0.2 to 200 mg of the active compound of the present invention per 1 kg of body weight of the patient per day.

wo gS/oglS9 2 1 5 0 ~ 4 S ~Cr/JP94101S59 Best Mode for CarryinQ Out the Invention Examples The present invention is illustrated in more detail by the following Preparations of antidiabetic agent, Reference Examples of processes for 5 preparing the starting compounds to be used for preparing the desired compounds of the present invention, and Examples of processes for preparing the desired compounds, and Experiments of the activities of the desired compounds of the present invention.
Preparation 1 Tablets are prepared from the following components.
Components Amount 2-(2-Benzofuranylmethylaminocarbonyl)-3-methylquinoxalin-4-oxide 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Totally 200 mg In the conventional manner, these are obtained tablets each containing the above components.
Preparation 2 Film coated tablets are prepared from the following components.
Components Amount 2-[3-(4-Methoxyphenyl)propylaminocarbonyl]-3-methylquinoxalin-4-oxide 150 mg Avicel (trade name of microcrystalline cellulose manufactured by Asahi Chemical Industry, Co., Ltd. Japan) 40 9 Corn starch 30 9 Magnesium stearate 2 9 Hydroxypropyl methylcellulose 10 g Polyethylene glycol-6000 3 9 Castor oil 40 9 Methanol 40 9 The active compound of the present invention, Avicel, corn starch 35 and magnesium stearate are mixed and kneaded and the mixture is tabletted W095/09159 2 lS 03 45 pCI/JP94/01559 using a conventional pounder (R 10 mm) for sugar coating. The tablets thus obtained are coated with a film coating agent consisting of hydroxypropyl methylcellulose, polyethylene glycol-6000, castor oil and methanol to give film coated tablets.
Reference Example 1 A solution of 2-ethoxycarbonyl-3-methylbenzofuran (5.0 9) in anhydrous diethyl ether (10 ml) is added dropwise to a suspension of lithium aluminum hydride (0.93 9) in diethyl ether (30 ml) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. The mixture is cooled, and decomposed with saturated aqueous sodium sulfate solution. The mixture is filtered through celite, and dried over anhydrous sodium sulfate, and the residue is evaporated to remove the solvent to give 2-hydroxymethyl-3 -methylbenzofuran (3.7 9) as white powder.
1 H-NMR (CDCI3) ~ ppm: 1.82 (1 H, t, J=6 Hz), 2.27 (3H, s), 4.76 (2H, d, J=6 Hz), 7.20-7.55 (4H, m) Reference Example 2 In tetrahydrofuran (40 ml) are suspended 2-hydroxymethyl-3 -methylbenzofuran (3.7 9), triphenylphosphine (6.6 9) and phthalimide (3.7 9), and thereto is added dropwise a solution of diethyl azodicarboxylate (4.4 9) in tetrahydrofuran (10 ml) under ice-cooling. The mixture is stirred at room temperature overnight, and evaporated to remove the solvent, and the resulting residue is purified by silica gel column chromatography (solvent; methylene chloride), and crystallized from diethyl ether. The crystals ~re collected by filtration, and dried to give 3-methyl-2-phthalimidomethylbenzofuran (4.6 9) as white powder.
1H-NMR (CDCI3) ~ ppm: 2.40 (3H, s), 4.97 (2H, s), 7.10-7.30 (2H, m), 7.40 (1 H, d, J=7 Hz), 7.48 (1 H, d, J=7 Hz), 7.65-7.75 (2H, m), 7.80-7.90 (2H, m) Reference Example 3 To methanol (80 ml) is added 3-methyl-2-phthalimidomethyl -benzofuran (4.6 9), and thereto is added hydrazine hydrate (1.2 9), and the mixture is refluxed for three hours. The mixture is evaporated to remove the solvent, and to the residue is added diluted aqueous sodium hydroxide solution, and then the mixture is extracted with chloroform. The chloroform WO 95/09159 2 1 5 0 3 ~ 5 pcrt~4/0l559 layer is washed with saturated brine solution, and dried over anhydrous sodium sulfate. The residue is evaporated to remove the solvent to give 2 -aminomethyl-3-methylbenzofuran (3.0 9) as colorless transparent liquid.
1H-NMR (CDCI3) ~ ppm: 1.55 (2H, brs), 2.21 (3H, s), 3.93 (2H, s), 7.15 -7.30 (2H, m), 7.35-7.50 (2H, m) Reference Example 4 To carbon tetrachloride (50 ml) are added 2-methylbenzo -thiophene (4.0 9), N-bromosuccinimide (4.8 9) and azobisisobutyronitrile (0.3 g), and the mixture is refluxed for five hours. After cooling, the insoluble 1 0 materials are removed by filtration, and the filtrate is concentrated to give 2 -bromomethylbenzothiophene (6.7 g) as brown powder.
1H-NMR (CDCI3) ~ ppm: 4.79 (2H, s), 7.30-7.45 (2H, m), 7.36 (1 H, s), 7.70-7.85 (2H, m) Reference Example 5 1 5 In dimethylformamide (40 ml) is dissolved 2-bromomethyl -benzothiophene (6.7 9), and thereto is added potassium phthalimide (5.0 9), and the mixture is stirred at 60C for two hours. The mixture is evaporated to remove the dimethylformamide, and the residue is extracted with chloroform.
The extract is washed with water and saturated brine solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent. To the residue is added diethyl ether, and the precipitated crystals are collected by filtration, and dried to give 2-phthalimidomethylbenzothiophene (4.5 9) as pale brown powder.
1H-NMR (CDCI3) ~ ppm: 5.10 (2H, s), 7.20-7.40 (3H, m), 7.70-7.80 (4H, m), 7.80-7.95 (2H, m) Reference Example 6 3-Formylbenzofuran (4.3 9) is dissolved in methanol (50 ml), and thereto is added gradually sodium borohydride (1.1 g) under ice-cooling. The mixture is stirred at the same temperature for one hour, and evaporated to remove the methanol. The residue is extracted with chloroform, and the extract is washed with water, and dried over anhydrous sodium sulfate. The residue is evaporated to remove the solvent to give 3-hydroxymethylbenzofuran (4.1 9) as WO 95/09159 2 1 5 0 3 4 5 PCI`/JP94/01559 pale yellow liquid.
1H-NMR (CDCI3) ~ ppm: 1.62 (1H, t, J=5 Hz), 4.85 (2H, d, J=5 Hz), 7.20 -7.45 (2H, m), 7.53 (1 H, d, J=8 Hz), 7.62 (1 H, s), 7.68 (1 H, d, J=8 Hz) Reference Example 7 ~
A solution of ethyl 2-benzofuranacrylate (3.46 g) in dry toluene is cooled to -50C, and thereto is added dropwise alminum diisobutyl hydride (1 M
toluene solution, 37 ml). The mixture is stirred at -20C for one hour, and thereto is added methanol (30 ml), and the mixture is stirred at room temperature overnight. The precipitates are removed by filtration, and the filtrate is concentrated. The residue is dissolved in ethyl acetate, and filtered through Florisil (an activated magnesium silicate), and concentrated to give 2 -(3-hydroxy-1-propenyl)benzofuran (2.6 9) as colorless liquid.
1H-NMR (CDCI3) ~ ppm: 4.39 (2H, brs), 6.60 (3H, m), 7.17-7.32 (2H, m), 7.43 (1 H, d, J=7 Hz), 7.52 (1 H, d, J=7 Hz) Reference Example 8 Into a mixture of benzothiophene (13.4 9) and 37 % aqueous formaldehyde solution (15 ml) is blown hydrogen chloride gas for about 20 to 30 minutes under ice-cooling. The mixture is stirred at room temperature for two hours. The reaction mixture is poured into ice-water, and extracted with diethyl ether. The extract is washed with saturated sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The resultant is evaporated to remove the solvent. and the resulting residue and potassium phthalimide (18.5 9) are dissolved in diemthylformamide (100 ml). The mixture is heated at 60C for 1.5 hour, and after cooling, the mixture is poured into ice-water. The precipitated crystals are collected by filtration, washed with diisopropyl ether to give 3-phthalimidomethylbenzothiophene (13.4 9) as pale brown crystals.
1H-NMR (CDCI3) ~ ppm: 5.08 (2H, s), 7.3-7.5 (2H, m), 7.61 (1 H, s), 7.6 -7.9(5H,m),8.15(1H,d,J=8Hz) Reference Example 9 2-Acetylbenzofuran (3.2 9) is dissolved in methanol (60 ml), and thereto are added ammonium acetate (15 9) and sodium cyanoborohydride (1.26 9). The mixture is stirred at room temperature overnight, and thereto is WO95/09159 21 5 03 ~ S ` ~ PCT/JP94/01559 added diluted aqueous hydrochloric acid solution to make the solution acidic.
The mixture is washed with ethyl acetate, and the aqueous layer is basified with aqueous sodium hydroxide solution, and extracted with chloroform. The chloroform layer is washed with water, dried over anhydrous sodium sulfate, 5 and evaporated to remove chloroform to give 2-(1-aminoethyl)benzofuran (1.8 g) as colorless liquid.
1 H-NMR (CDCI3) ~ ppm: 1.52 (3H, d, J=6 Hz),1.83 (2H, brs), 4.20 (1 H, q, J=6 Hz), 6.50 (1H, s), 7.15-7.30 (2H, m), 7.43 (1H, d, J=8 Hz), 7.51 (1H, d, J=8Hz) Reference Example 10 5-Ethyl-2-methylpyridine (25 9) is dissolved in acetic acid (200 ml), and thereto is added 30 % aqueous hydrogen peroxide solution (25 ml), and the mixture is heated at 100C. Four hours later, to the mixture is added 30% aqueous hydrogen peroxide solution (25 m), and the mixture is heated with 1 5 stirring at the same temperature for 14 hours. After cooling, the mixture is concentrated several times with adding water thereto. The final residue is neutralized with saturated aqueous potassium carbonate solution, and extracted with chloroform. The extract is dried over anhydrous potassium carbonate, and evaporated to remove the solvent. The resulting residue is dissolved in acetic anhydride (200 ml), and the mixture is heated at 120C for 4hours. The mixture is evaporated to remove the solvent, and thereto is added saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate, and evaporated to remove the solvent. The residue is dissolved in methanol (200 ml), and thereto is added potassium carbonate (57 g), and the mixture is stirredat room temperature for 12 hours. The mixture is evaporated to remove the solvent, and thereto is added water. The mixture is extracted with chloroform, - and dried over anhydrous potassium carbonate. The resultant is evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; ethyl acetate: n-hexane=1: 4) to give 5-ethyl-2 -hydromethylpyridine (20.4 9) as pale brown liquid.
1H-NMR (CDCI3) ~ ppm: 1.26 (3H, t, J=8 Hz), 2.66 (2H, q, J=8 Hz), 3.67 (1H, br), 4.73 (2H, s), 7.18 (1H, d, J=8 Hz), 7.52 (1H, d, J=8 Hz), 8.41 (1H, s) ~ 2150~45 Reference Example 11 4-(2-Methyl-1,3-dioxolan-2-yl)benzonitrile (1.9 9) is dissolved in diethyl ether (20 ml), and thereto is added lithium aluminum hydride (400 mg) at 0C. The mixture is reacted at room ternperature for 14 hours, and thereto 5 are added water (1 ml) and 8M aqueous sodium hydroxide solution (3 ml). To the mixture is added magnesium sulfate, and the insoluble materials are removed by filtration. The filtrate is concentrated to give [4-(2-methyl-1,3 -dioxolan-2-yl)benzyl]amine (2.1 9) as colorless oil.
1H-NMR (CDCI3) ~ ppm: 7.45 (2H, d, J=8 Hz), 7.29 (2H, d, J=8 Hz), 4.04 (2H, m),3.87 (2H, s), 3.77 (2H, m),1.77 (2H, br),1.65 (3H, s) Reference Example 12 N-Bromoethylphthalimide (13 9) and p-methoxythiophenol (7.9 9) are dissolved in dimethylformamide (70 ml), and thereto is added potassium carbonate (10 9). The mixture is stirred at 70C overnight, and evaporated to 15 remove the solvent. The residue is extracted with diethyl ether, washed with water, and dried over anhydrous sodium sulfate. The residue is evaporated to remove diethyl ether, and crystallized from n-hexane. The crystals are collected by filtration, and dried to give N-[2-(4-methoxyphenylthio)ethyl] -phthalimide (13.9 9) as white powder.
1H-NMR (CDCI3) â ppm: 3.14 (2H, t, J=7 Hz), 3.75 (3H, s), 3.89 (2H, t, J=7 Hz), 6.80 (2H, d, J=8 Hz), 7.42 (2H, d, J=8 Hz), 7.65-7.75 (2H, m), 7.75-7.90 (2H, m) Reference Example 13 N-(2-Chloroethyl)dibenzylamine hydrochloride (25 9) and phenol (8.0 9) are dissolved in dimethylformamide (100 ml), and thereto is added potassium carbonate (30 9). The mixture is stirred at 70C for 6 hours, and evaporated to remove dimethylformamide. The residue is extracted with diethyl ether, and the extract is washed with water, and dried over anhydrous sodium sulfate. The residue is evaporated to remove diethyl ether to give N-(2 -phenoxyethyl)dibenzylamine (25.5 9) as colorless oil.
1H-NMR (CDCI3) ~ ppm: 2.90 (2H, t, J=6 Hz), 3.72 (4H, s), 4.03 (2H, t, J=6 Hz), 6.80 (2H, d, J=8 Hz), 6.85-7.00 (1H, m), 7.15-7.45 (12H, m) WO 95/O91S9 2 1 5 0 3 ~ 5 PCI~/JP94/015S9 Reference Example 14 N-(2-Phenoxyethyl)dibenzylamine (25.5 9) is dissolved in ethanol (500 ml), and thereto is added 10 % palladium-carbon (3.0 g). The mixture is subjected to hydrogenation at 50C under 1 atm of hydrogen gas. The catalyst 5 is removed by filtration, and the filtrate is evaporated to remove ethanol to give 2-phenoxyethylamine (11.0 g) as colorless oil.
1H-NMR (CDCI3) ~ ppm: 1.47 (2H, brs), 3.08 (2H, t, J=5 Hz), 4.01 (2H, t, J=5 Hz), 6.85-7.00 (3H, m), 7.25-7.35 (2H, m) Reference Example 15 To triethylamine (1.5 liter) are added benzofuroxane (216 g) and ethyl acetoacetate (207 g), and the mixture is stirred at room temperature for four days. The precipitated crystals are collected by filtration, washed with water, dried, and crystallized from ethyl acetate to give 2-ethoxycarbonyl-3 -methylquinoxaline-1,4-dioxide (115 g) as pale yellow needles.
M.p. 137-138C
Reference Example 16 2-Ethoxycarbonyl-3-methylquinoxaline-1,4-dioxide (77 g) is dissolved in ethanol (3.5 liters) and conc. hydrochloric acid (200 ml), and to the mixture is added dropwise aqueous solution of sodium hydrosulfite (200 g) in 20 water (1 liter) with stirring at room temperature. The mixture is stirred at the same temperature for four hours, and the reaction mixture is neutralized with sodium hydrogen carbonate, and evaporated to remove ethanol. To the residue is added water, and the precipitated crystals are collected by filtration, washed with water, dried, and recrystallized from n-pentane to give 2-ethoxy -25 carbonyl-3-methylquinoxaline (67 9) as colorless needles.
M.p. 74-75C
Reference Example 17 2-Ethoxycarbonyl-3-methylquinoxaline (64 g) is dissolved in methylene chloride (700 ml), and thereto is added gradually m-chloro -30 perbenzoic acid (70 g) under ice-cooling. The mixture is stirred at room temperature overnight, and the reaction solution is washed successively with diluted aqueous sodium thiosulfate solution, saturated sodium hydrogen carbonate solution, and water, and dried over anhydrous sodium sulfate. The WO 95/09159 2 1 5 0 3 ~ 5 PCTIJP94/01559 resultant is evaporated to remove the solvent, and to the residue is added n -hexane. The precipitated crystals are collected by filtration, dried, and recrystallized from n-hexane/diethyl ether to give 2-ethoxycarbonyl-3 -methylquinoxalin-4-oxide (45 9) as colorless needles.
M.p. 91 -93C
Reference Example 18 2-Ethoxycarbonyl-3-methylquinoxaline-1,4-dioxide (105 9) is dissolved in chloroform (500 ml), and thereto is added dropwise gradually phosphorus tribromide (44 ml) under ice-cooling. The mixture is stirred at room temperature for one hour, and evaporated to remove the solvent. The residue is poured into ice-water, and neutralized with potassium carbonate. The mixture is extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate. The resultant is evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; n -hexane: ethyl acetate = 2: 1), and recrystallized from ethyl acetate/n-hexane togive 2-ethoxycarbonyl-3-methylquinoxalin-1-oxide (35 9) as colorless prisms.
M.p. 85-87C
Reference Example 19 2-Ethoxycarbonyl-3-methylquinoxalin-4-oxide (4.0 9) is suspended in methanol (80 ml) and 5N aqueous sodium hydroxide solution (10 ml), and the mixture is stirred at room temperature for three hours. The mixture is evaporated to remove the solvent, and the residue is dissolved in water. The aqueous layer is washed with ethyl acetate, and acidified with hydrochloric acid. The precipitated crystals are collected by filtration, washedwith water, and dried to give 2-carboxy-3-methylquinoxaline-4-oxide (3.2 9) as white powder.
M.p. 143-145C (decomposed) Reference Example 20 2-Carboxyquinoxaline (2.0 9) is dissolved in methanol (20 ml), and thereto is added dropwise thionyl chloride (1.3 ml) under ice-cooling. The mixture is refluxed for 15 minutes, and evaporated to remove the solvent. The residue is extracted with chloroform, and the extract is washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The residue is evaporated to remove the solvent, and the resulting 2-methoxycarbonylquinoxaline is dissolved in methylene chloride (40 ml). To the mixture is added m-chloroperbenzoic acid (2.9 9) with stirring at room temperature, and the mixture is stirred at room temperature overnight.
5 The reaction solution is washed with diluted aqueous sodium thiosulfate solution and saturated sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The resultant is evaporated to remove the solvent, and to the residue is added n-hexane. The precipitated crystals are collected by filtration, and dried to give 2-methoxycarbonylquinoxalin-4-oxide (2.0 9) as 10 yellow powder.
M.p. 154-1 55C
Reference Example 21 2-Ethoxycarbonyl-3-methylquinoxaline (2.2. 9) is dissolved in carbon tetrachloride (40 ml), and thereto are added N-bromosuccinimide (2.7 9) and perbenzoic acid (0.2 9), and the mixture is refluxed for 8 hours. The mixture is evaporated to remove the solvent, and thereto is added water. The mixture is extracted with dichloromethane, and the extract is dried over anhydrous sodium sulfate, and evaporated. The residue is dissolved in isopropanol (50 ml), and thereto is added imidazole (2.8 9). The mixture is 20 refluxed for 10 hours, and evaporated to remove the solvent. To the residue is added water, and the mixture is extracted with chloroform, and dried over anhydrous sodium sulfate. The resultant is evaporated to remove the solvent, and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane: methanol = 16: 1) to give 2-ethoxycarbonyl-3-(1 -25 imidazolyl)methylquinoxaline (1.33 9) as yellow powder.
1H-NMR (CDCI3) â ppm: 1.47 (3H, t, J=7 Hz), 4.55 (2H, q, J=7 Hz), 5.82 (2H, s), 7.04 (2H, d, J=5 Hz), 7.70 (1 H, s), 7.8-8.0 (2H, m), 8.0-8.1 (1 H, m), 8.2 8.3 (1 H, m) By using the suitable starting compounds, there are obtained the 30 following compounds as listed in Table 1 in the same manner as in Reference Examples 3, 9, 11 and 14.

2150~S

Table 1 M.p. ~;rystalline No.Structure C Forrr~ ~ 1H-NMR (CDCI3) ~ ppm:

H3C Colorless 1.55 (2H, brs), 2.21 (3H, s), H2N`~)~ oil 3.93 (2H, s), 7.15-7.30 (2H, m), O 7.35-7.50 (2H, m) 2 Cl Yellow 1.31 (2H, brs), 4.14 (2H, s), H2N~J~ powder 7.07 (1H, s), 7.2-7.3 (1H, m), 7.6-7.7 (2H, m) 1.61 (2H, brs), 4.15 (2H, s), 3 ~ 65 Yellow 7.14 (1 H, s), 7.25-7.40 (2H, m), H2NJ~s~ powder 7.72 (1H, d, J=8 Hz), 7.82 (1H, d, J=8 Hz) 1.2/ (2H, brs), 4.01 (2H, s), 4 o~, Pale yelow 7.20-7.40 (2H, m), 7.50 (1 H, d, H2NJ~J oil J=8 Hz), 7.55 (1H, s), 7.60 (1H, d, J=8 Hz) 1.56 (2H, brs), 3.9/ (2H, s), 5~,~CI Pale yellow 6.48 (1 H, s), 7.20 (1 H, d, J=8 H2NJ~o~ oil Hz) 7.34 (1H, d, J=8 Hz), 7.48 1.54 (2H, brs), 3.95 (2H, s), 6 O Pale yellow 6.74 (1 H, d, J=2 Hz), 7.25 (1 H, H2N~ oil d, J=8 Hz), 7.49 (1H, d, J=8 Hz), 7.54 (1H, s), 7.63 (1 H, d, J=2 Hz) 1.58 (2H, brs), 4.04 (2H, s), 7 NO2 Yellow 6.69 (1 H, s), 7.50 (1 H, d, J=9 H2N~J~ powder Hz) 8.21 (1H, d, J=9 Hz), 8.46 8 ~ Pale yellow 1.61 (2H, brs), 4.01 (2H, s), H2NJ~J oil 6.58 (1H, s), 7.13 (1H, m), 7.25 Cl (1H, d, J=8 Hz), 7.42 (1H, d, J=8 Hz) WO 95/O91S9 2 1 5 0 3 4 ~ PCT/JP94/01559 1.5~ (~H, ~rs), ~ H, s)~
9 _ ~,OCH3 Pale yellow 3.94 (2H, s), 6.46 (1 H, s), H2N~ 3~ oil 6.84 (1H, d, J=8 Hz), 6.98 (1 H, s), 7.31 (1 H, d, J=8 Hz) Yellow 1.49 (2H, brs), 3.75 (3H, s), J~ powder 4.03 (2H, s), 6.38 (1 H, s), H2N N 7.04-7.24 (2H, m), 7.30 (1 H, CH3 d, J=8 Hz), 7.58 (1 H, d, J=8 Hz) 1.58 (2H, brs), 4.06 (2H, s), 11 ~ Yellow 6.32 (1 H, s), 7.03-7.20 (2H, H2NJ~N~J powder m), 7.34 (2H, d, J=8 Hz),H 7.54 (2H, d, J=8 Hz), 8.50 (1H, brs) 12 OCH3 Pale yellow 1.54 (2H, brs), 3.9 1(3H, s), H2N~J~ powder 3.94 (2H, s), 6.46 (1H, s), Br 7.01 (1H, s), 7.63 (1H, s) 1.51 (2H, brs), 3.56 (2H, 13~NH2 Yellow brs), 3.91 (2H, s), 6.36 (1H, H2NJ~o~J powder s), 6.62 (1H, d, J=8 Hz), 6.79(1H,s),7.22(1H,d, J=8 Hz) 14 ~ Pale yellow 1.57 (2H, brs), 3.98 (2H, s), H2NJ~oJ~ oil 4.01 (3H, s), 6.52 (1H, s), OCH3 6.74-6.83 (1 H, m), 7.08-7.18 (2H, m) 15CN Pale yellow 4.02 (2H, s), 6.61 (1H, s), H2NJ~ powder 7.52 (2H, brs), 7.86 (1H, brs) 3.94 (3H, s), 4.00 (2H, s), 16CO2CH3 Yellow 6.60 (1H, s), 7.45 (1H, d, H2N~ powder Hz) 8 26 (r1H s) WO 95/091592 1 5 0 3 4 ~ pCT/JP94/01559 H, ~rs), ~-Y;~ ~H, S), 17 ,CH3 Pale 3.93 (2H, s), 6.42 (1H, s), ~N~CH3 yel!ow oil 6.80 (1 H, d, J=8 Hz), 6.85 H2N O ~ (1 H, s), 7.34 (1 H, d, J=8 Hz) . 1.42 (3H, t, J=/ Hz), 1.53 18 ' Pale (2H, brs), 4.00 (2H, s), 4.40 ~CO2C2Hs yellow oil (2H, q, J=7 Hz), 6.60 (1 H, H2N~o~ s), 7.47 (1 H, d, J=8 Hz), 8.00(1H,d,J=8Hz),8.26 (1H, s) 1.5/ (2H, brs), 3.9/ (2H, s), 19 Pale 7.15-7.30 (2H, m), 7.44 (1H, H2N J~ yellow oil d, J=7 Hz), 7.52 (1 H, d, J=7 1.52 (2H, brs), 2.18 (2H, s), H3C Pale 3.05 (3H, s), 3.89 (2H, s), H ~)~:l yellow oil 5.20 (2H, s), 6.95 (1 H, d, 2N O OCH2OCH3 J=8 Hz), 7.14 (1H, s), 7.32 (1H, d, J=8 Hz) 1.51 (2H, brs), 2.34 (2H, s), 21 OCH2OCH3 Pale 3.52 (3H, s), 3.89 (2H, s), H3C ,~ yellow oil 5.28 (2H, s), 6.81 (1H, d, H2NJ~o~J J=8 Hz), 7.05-7.16 (2H, m) 0.92 (3H, t, J=/ Hz), 1.08 -22 H3C Colorless 1.18 (2H, m), 1.40-2.05 (9H, H2N`~ oil m), 2.45-2.62 (1 H, m), 2.62 -2.90 (2H, m), 3.80-3.95 (2H, m) 1.92 (2H, m), 2.82 (2H, t, J=
23 ~ Pale Hz), 2.84 (2H, t, J=7 Hz), H2N J~O~ yellowoil 6.41 (1H, s), 7.13-7.25 (2H, m), 7.35-7.50 (2H, m) 24 Pale 1.83 (2H, brs), 3.56 (3H, s), H2N~_J~ yellow oil 3.40 (2H, s), 5.37 (2H, s), OCH2OCH3 6.55 (1H, s), 7.04 (1H, d, J=8 Hz), 7.05-7.21 (2H, m) 2 1 5 0 3 4 S pCTJJP94101559 ._ ~

H3C White 1.51 (2H, brs), 2.17 (3H, s), ~q powder 3.89 (2H, s), 5.10 (2H, s), H2N~o~OCH2~ 6.94 (1H, d, J=8 Hz), 7.02 (1 H, s), 7.27-7.50 (6H, m) 1.26 (3H, t, J_/ Hz). 2.92 Pale (2H, q, J=7 Hz), 3.95 (3H, 26 CH3CH2~,CO2CH3 yellow s), 4.24 (2H, s), 7.41 (1H, d, H2N~'`o oil J=9 Hz), 8.00 (1H, d, J=9 Hz), 8.25 (1 H, s) 27 S Yellow 1.89 (2H, brs), 4.13 (2H, s), H2N~)~ dl 7 2-7.5 (3H, m), 7.7-7.9 (2H, Pale 1.97 (2H, brs), 4.05 (2H, s), H~ yellow 7.2-7.6 (9H, m) 1.59 (2H, brs), 4.10 (2H, s), Brown 7.54 (1 H, dd, J=8 Hz, 8 Hz), ~ oil 7.69 (1 H, dd, J=8 Hz, 8 Hz), H2N~ 7.80 (1H, d, J=8 Hz), 8.0-8.2 (2H, m), 8.89 (2H, s) 2.2/ (3H, s), 3.9/ (3H, s), 30 H3C CO2CH3 Pale 4.52 (2H, d, J=6 Hz), 7.42 ~ yellow (1 H, d, J=8 Hz), 7.98 (1 H, d, H2N~O~ oil J=8 Hz~, 8.20 (1 H, s), 1.52 (3H, d, J=6 Hz), 1.83 31 Color - (2H, brs), 4.20 (1 H, q, J=6 ~q less oil Hz), 6.50 (lH, s), 7.15-7.30 H2N~o ~ (2H, m~, 7.43 (1 H, d, J=8CH3 Hz), 7.51 (1H, d, J=8 Hz) 2.20 (3H, brs), 4.00 (2H, s), Pale 5.08 (1H, s), 5.34 (1H, brs), H2N ~CCH--3CH2 oil 7 56 (lH, s) WO 95/091S9 2 1 5 0 3 4 5 pCT/JP94/01559 Wttlte l.W (~H, ~rS), ;~.Y~ H, S), 33~CO2CH3 powder 4.17 (2H, s), 7.21 (1H, s), H2N~J~S~ 7.84 (1H, d, J=8 Hz), 7.94 (1 H, d, J=8 Hz), 8.40 (1 H, s) 1.60 (2H, brs), 2.18 (3H, s), 34H3C~OCH2OCH3 Pale 3.51 (3H, s), 3.91 (2H, s), H2N~o~W yellow 5.20 (2H, s), 6.95 (1H, d, oil J=8 Hz), 7.10 (1H, s), 7.29 (1H, d, J=8 Hz) 35CH3 Yellow 1.14 (3H, s),1.44(3H, s), 2.8 -H3C~ oil 3.1 (2H, m),4.2-4.3 (1H, m), H2N ~o ~ 6.7-7.2 (4H, m) 1.35 (2H, brs), 2.8-3.1 (3H, 36~, Yellow m), 3.2-3.4 (1 H, m),4.7-4.9 H2N~J~o~ oil (1H, m), 6.7-6.9 (2H, m), 7.0 -7.2 (2H, m) 1.5/ (3H, d, J=8 Hz). 1.~9 37R Pale (2H, brs), 2.07 (3H, s), 3.97 OCCH3 yellow (2H, s), 5.97 (1 H, q, J=8 ~CH3 oil Hz), 6.52 (1 H, s), 7.25 (3H, H2N~o~ d, J=8 Hz), 7.40 (1H, d, J=8 Hz), 7.52 (1 H, s) 1.45 (3H, t, J=/ Hz), 1.74 38~ Pale (2H, s), 4.05 (2H, s), 4.46 H2N~o~fJ brown (2H, q, J=7 Hz), 6.58 (1H, CO2C2Hs oil s), 7.20- 7.35 (1 H, m), 7.70 (1 H, d, J=8 Hz), 7.89 (1 H, d, J=8 Hz) 39~ Pale 1.60 (2H, brs), 4.03 (2H, s), H2NJ~oJ~J brown 6.61 (1 H, s), 7.20-7.35 (1 H, CF3 oil m), 7.48 (1 H, d, J=8 Hz), 7.69 (1 H, d, J=8 Hz) 40CF3 Pale 1.56 (2H, brs), 4.01 (2H, s), H2N~J~ brown 6.60 (1H, s), 7.50 (2H, s), oil 7.81 (1H, s) wo gS/oglS9 2 1 5 0 3 ~ 5 ~.14 (;~H, S), ;~.4;~ 11, S), 41 H3C ,~, Pale 6.39 (1H, brs), 6.59 (1H, s), H2N~J;~o~J yellow 7.15-7.25 (2H, m), 7.40-7.50 oil (2H, m) 2.04 (3H, s), 3.54 (2H, d, 42~ Pale J=7 Hz), 6.44 (1H, t, J=7 H2N ~O~ yellow Hz), 6.60 (1 H, s), 7.1 5-7.30 CH oil (2H, m), 7.46 (1H, d, J=73 Hz), 7.51 (1 H, d, J=7 Hz) 43N-N Pale 3.53 and 3.60 (3H, s), 4.02 - ~N,' yellow and4.04 (2H, s), 5.89 and H2NJ~o~ CH20CH3 oil 5.72 (2H, s), 6.62and 6.66 (1H,s),7.54and7.62(1H,d, J=9 Hz), 8.00 and 8.02 (1 H, (1- or 2-rrlethoxymethyl group ) d, J=9 Hz), 8.37 (1 H, s) 44~ Pale 3.54 (2H, d, J=5 Hz), 6.43 -H2N~o~ yellow 6.63 (3H, m), 7.13-7.30 (2H, oil m), 7.40-7.55 (2H, m) 1.39 (2H, brs), 1.67-1.80 45OCH3 Pale (2H, m), 2.60 (2H, t, J=6 Hz), H2N~ yellow 2.72 (2H, t, J=6 Hz), 3.79 oil (3H, s), 6.82 (2H, d, J=8 Hz), 7.09 (2H, d, J=8 Hz) 1.28 (2H, brs), 1.15-1.30 46/CH3 Pale (2H, m), 2.56 (2H, t, J=7 Hz), ~ N\ yellow 2.72 (2H, t, J=7 Hz), 2.91 H2N ~,!J CH3 oil (6H, s), 6.69 (2H, d, J=8 Hz), 7.07 (2H, d, J=8 Hz) - 1.2/ (2H, brs), 1.61 (3H, s), 47 Pale 1.63 (3H, s), 1.71 (3H, s), - H2N~ ~CH3 brown 1.95-2.15 (4H, m), 3.27 (2H, CH3 CH3 oil d, J=7 Hz), 5.05-5.15 (1H, m), 5.20-5.31 (1 H, m) 21503~5 48 CH3 N Brown 2.50 (3H, s), 3.90 (2H, s), H2N~S>~ ` ' 7 3-7.5 (3H, m), 7.8-8.0 (2H, ~ 1.26 (2H, br), 3.49 (2H, d, OCH Yellow J=6 Hz), 3.88 (3H, s), 3.90 1~ oil (3H, s), 6.2-6.3 (1 H, m), 6.42 H2N~ `OCH3 (1H, d, J=16 Hz), 6.82 (1H, d, J=8 Hz), 6.9-7.0 (2H, m) Yellow 1.30 (2H, br), 3.53(2H, d, ~ oil J=6 Hz), 6.2-6.4 (1 H, m), H2N~ 6.90 (1H, d, J=16 Hz), 7.1 -Cl 7.3 (2H, m), 7.3-7.5 (2H, m) 51 Pale 1.53 (2H, brs), 4.03 (2H, s), 1~1 brown 7.35-7.50 (3H, m), 7.70-7.92 H2N~ powder (4H, m) 1.18 (2H, brs), 4.31 (2H, s), 52 Brown 7.30-7.50 (2H, m), 7.88 (1 H, H2N~J`~I oil d, J =7 Hz), 7.97 (1H, d, J=7 1.30 (2H, brs), 3.45 (2H, d, 53 Yellow J=6 Hz), 3.81 (3H, s), 6.0 -OCH3 oil 6.2 (1 H, m), 6.48 (1 H, d, H2N~J J=16 Hz), 6.82 (2H, d, J=8 Hz), 7.20 (2H, d, J=8 Hz) 1.25 (2H, br), 3.48 (2H, d, 54 Yellow J=6 Hz), 3.86 (3H, s), 6.3 -~ oil 6.5 (1 H, m), 6.7-6.9 (3H, m), H2N ~ 7.20 (1 H, m), 7.42 (l H, d, OCH3 J=8 Hz) Brown 1.36 (2H, brs), 3.54 (2H, d, ~jl oil J=6 Hz), 6.2-6.4 (lH, m), H2N~J 6.98 (1H, d, J=16 Hz), 7.37 NO2 (1H, m), 7.5-7.7 (2H, m), 7.90 (1H, d, J=8 Hz) WO 95/O91S9 2 1 5 0 ~ 4 S PCr/JP94/0l55 56 White 2.37 (3H, s), 3.74 (2H, s), CH3~_o ~=\ powder 7.4-7.5 (3H, m), 7.95-8.05 H2N ~N>~ (2H, m) 1.23 (2H, t, J=8 Hz), 1.49 57,~CH2CH3 Yelllow oil (2H, brs), 2.63 (2H, q, J=8 H2N~ Hz), 3.82 (2H, s), 7.16 (2H, d, J=8 Hz), 7.22 (2H, d, J=8 Hz) 1.39 (2H, brs), 3.40 (2H, d, 58 ~ Pale yellow J=6 Hz), 5.85-6.00 (1 H, m), H2N ~1~ oil 6.32 (1 H, dd, J=16 Hz, 10 Hz),6.52(1H,d,J=16Hz), 6.78 (1H, dd, J=16 Hz, 10 Hz). 7.15-7.42 (5H, m) 1.24 (3H, t, J=8 Hz), 1.91 59 ,~ C2H5 Brown oil (2H, brs), 2.64 (2H, q, J=8 H2NJ~ ~ Hz), 3.94 (2H, s), 7.19 (1H, N d, J=8 Hz), 7.48 (1 H, d, J=8 Hz), 8.40 (1 H, s) /.24 (2H, d, J=8 Hz), /.20 CH3 Colorless oil (2H, d, J=8 Hz), 3.83 (2H, ~CH3 bp.80C/ s), 2.90 (1H, sep, J=7 Hz), H2N ~ 0.3 mmHg 1.40 (2H, br), 1.25 (6H, d, J=7 Hz) 61CH3 N White 2.22 (3H,s), 3.92 (2H, s), 7.4 -H2N ~0>~ powder 7 5 (3H, m), 8.00-8.05 (2H, /.45 (2H, d, J=8 Hz), /.29 62 ~ Colorless oil (2H, d, J=8 Hz), 4.04 (2H, m), 3.87 (2H, s), 3.77 (2H, CH3 m), 1.77 (2H, br), 1.65 (3H, H2N ~ S) WO 95/09159 2 15 0 3 ~ 5 PCT/JP94/01559 1.~() (;~H, t, J=~ HZ), ~
63 CH3 o Pale (3H,s),2.65(2H,q,J=8 ~ \ ~ C2H5 yellow Hz),2.82(2H, brs), 3.58 H2N~ N powder (2H,s),7.33(2H, d, J=8 Hz),8.06(2H, d, J=8 Hz) 1.62(2H, brs), 1.l-1.9(2H, 64 ~ r_~ Yellow m), 2.3-2.5(6H,m),2.63(2H, H2N'~ N~_~O oil t, J=8 Hz),3.72(4H, t, J=5 Hz),3.83(2H,s),7.15(2H, d, J=8 Hz),7.23(2H, d, J=8 Hz) /.29(2H,d,J=8 Hz),/.16 CH3 Color - (2H,d,J=8 Hz),6.48(1H, d, ~CH3 less oil J=16 Hz),6.28(1H, dt, J=16 H2N ~ Hz,6 Hz),3.47(2H, d, J=6 Hz),2.88(1H, sep, J=7 Hz), 1.72(2H, br), 1.23(6H, d, J=7 Hz) /.15(2H,d,J=8 Hz),/.11 66CH3 Color - (2H,d,J=8 Hz),2.88(1H, ~CH3 less oil sep, J=7 Hz),2.74(2H, t, H2N ~ J=7 Hz),2.63(2H, t, J=7 Hz),1.77(2H,qui,J=7 Hz), 1.24(6H, d, J=7 Hz),1.55 (2H, br) 2.//(2H,t,J=6 Hz),3.12 67 OCH3 Pale (2H,t,J=6 Hz),3.78(3H,s), HN~ yellow 3.95(2H,s),6.63(1H, brs), oil 6.69(1H, brd, J=8Hz),6.92 (1H, d, J=8 Hz) /.20(4H,s),6.41(1H, brs), 68 CH3 Color - 3.39(2H,s),2.90(1H,sep, CH ~ lessoil J=7 Hz),2.09(2H, br), 1.91 H2N~ CH3 (3H, brs), 1.25(6H,d,J=7 1.38(2H, brs), 2.80-2.95 69~,OCH3 Color - (4H,m),3.80(3H,s),6.84 H2N S~ less oil (2H, d, J=8 Hz),7.38(2H,d, WO 95/09159 2 1 S 0 3~4 5 PCTIJP94/OlSS9 H, ~rs), Z.~ U
,~, Color - (2H, m), 2.90-3.05 (2H, m), H2N S~ less oil 7.10-7.40 (5H, m) 1.4~ (2H, brs), 3.08 (2H, t, 71 ~ Color - J=5 Hz), 4.01 (2H, t, J=
H2N o,l~ lessoil 5Hz), 6.85-7.00 (3H, m), 7.25 -7.35 (2H, m) 72 S~ Pale 7.9-8.0 (2H, m), 7.4-7.5 (3H, H2N-CH2~N yellow m), 7.08 (1 H, s), 4.05 (2H, s) 73 CH3 S Pale 7.85-7.95 (2H, m), 7.4-7.5 ~ ~>~ yellow (3H, m), 3.88 (ZH, s), 2.45 H2N-CH2 N oil (3H, s) /.5-/.6 (1H, m), /.4-/.5 (1H, 74 Yellow m), 7.2-7.3 (2H, m), 6.69 (1H,l~q oil s), 5.gO (1 H, s), 5.23 (1 H, s), H2N ~f o ~ 2.98 (2H, t, J-6.0 Hz), 2.62 CH2 (2H, t, J=6.0 Hz) N--N Pale 7.58 (5H, brs), 4.17 (2H, s~
H2NCH2 ~N ' yellow 76 CH Pale 3.88 (2H, s), 2.59 (3H, s~, ~S yellow 2.53 (3H, s) 77 ,N Pale 4.16 (2H, s), 4.23 (3H, s) N~ N yellow H2N-CH2 , oil WO 95/O91S9 21 S ~ 3 ~ 5 PCT/JP94/015S9 ~ H,~r),~.U4(~H, 78 ~ Pale s), 3.55(2H, d, J=7 Hz), yellow 6.51(1H, t, J=7 Hz), o C,=CH-CH2NH2 oil 6.62(1H, d, J=3 Hz), F CH3 6.90-7.15(2H,m),7.40-7.60(2H,m) 1.41(2H, br), 2.04(3H, 79 White s), 3.56(2H, d, J=7 Hz), solid 6.46(1H, t, J=7 Hz), S ~ 6.64(1H,s),7.30(1H, =cHcH2NH2 d, J=3 Hz),7.46(1H, d, CH3 J=9 Hz),7.85(1H, d, J=2 Hz),7.86(1H, dd, J=9 Hz,3 Hz),8.13 (1H, d, J=2 Hz) 1.30(3H, t, J=/Hz), C2H5 Pale 1.56(2H, br), 2.02(3H, O N~ yellow s), 2.64(2H, t, J=7 Hz), ll oil 2.96(2H, t, J=7Hz), ~`o ~ C,=CHCH2NH2 3.54(2H, d, J=7 Hz), CH3 4.04(2H,q,J=7 Hz), 6.41(1H, t, J=7Hz), 6.56(1H,s),7.12(1H, s),7.21(1H,s) 2.13(3H,s),3.41(2H, 81 Yellow d, J=7 Hz),6.05(1H, dt, powder J=15 Hz,7 Hz),6.57 ~`O C,=CH-CH-CHCH2NH2 (1H, dd, J=15 Hz,12 CH3 Hz),6.65(1H,s),6.97 (1H, d, J=12 Hz),7.15-7.42(2H,m),7.43(1H, d, J=8 Hz),7.51(1H, d, J=8 Hz) 2.05(3H,s),2.52(3H, 82 CH S CH3 Pale s), 2.69(3H,s),3.56 yellow (2H, d, J=7 Hz),6.46 N~ powder (1H, t, J=7 Hz),6.62 O ~ C=cHcH2NH2 (1H,s),7.45(1H, d, J=8 CH3 Hz),7.51(1H,d,J=8 Hz),7.73(lH,s) 83 N~ Yellow 2.07 (3H, s), 3.58(2H, N ~ /N powder d, J=7 Hz), 4.20 (3H, s), / ~ ~ 6.52 (1 H, t, J=7 Hz), CH3 ~O C=cHcH2NH2 6.68 (1H, s), 7.59 (2H, CH s), 7.89 (1 H, s) 2.11 (3H, s), 3.~/ (2H, 84 Pale d, J=7 Hz), 6.47 (1 H, t, yellow J=7 Hz), 7.10 (1H, s), powder 7.43-7.62 (3H, m), 7.69 (1 H d, J=8 Hz), 7.93 O/c=cHcH2NH2 (1H d, J=8 Hz), 8.11 CH3 (1H, d, J=8 Hz) Yellow 1.78 (2H, brs), 2.23 (3H, oil s), 2.52 (3H, s), 2.70 s~NI CH3 (3H, s), 3.96 (2H, s), 7.4 -~( 7.5 (2H, m), 7.70 (1 H, s) CH3 ~o CH2NH2 1.53 (2H, brs), 2.3/ (3H, 86 CH3 Yellow s), 2.43 (3H, s), 3.48 )~N powder (3H, s), 3.97 (2H, s), CH3--N _~ 6.52 (1H, s), 7.4-7.6 (2H, m), 7.72 (1 H, s) CH3 ~O CH2NH2 87 CH3 Yellow 1.56 (2H, brs), 2.47 (3H, kN oil s), 2.51 (3H, s), 3.98 ~ (2H, s), 6.54 (1H, s), 7.4 -CH3 ~O CH2NH2 7 6 (2H, m), 7.77 (1 H

1.56 (2H, brs), 2.54 (3H, 88 CH3 Color - s), 2.71 (3H, s), 4.17 )~ less oil (2H, s), 7.33 (1 H, s), S~,S~ CH2NH2 7.61 (1 H, d, J=8 Hz), CH3 ~ ~ 7.90 (1 H, d, J=8 Hz), S 8.01 (1 H, s) 89 OC2H5 White 1.46 (3H, t, J=7 Hz), 1.57 ~N powder (2H, brs), 3.98 (2H, s), 4.57 (2H, q, J=7 Hz), 6.57 (1 H, d, J=6 Hz), 6.59 (1 H, s), 7.49 O CH2NH2 (1H, d, J=9 Hz), 8.38 (1H, d, J=9 Hz), 8.48 (1 H, d, J=6 Hz), 8.61 (1H, s) ~N Brown 1.62 (2H, brs), 4.03 (2H, s), ~CH H oil 6.75 (1 H, dd, J=7 Hz, 7 Hz), N 2N 2 7.15(1H,dd,J=7Hz,8Hz), 7.48 (1 H, s), 7.54 (1 H, d, J=8 Hz), 8.07 (1 H, d, J=7 Hz) 91 CH3 Pale 1.29 (2H, brs), 2.06 (3H, s), yellow 2.50 (3H, s), 3.50 (2H, d, J=7 N~c:cH_cH2NH2 powder Hz), 6.05 (1H, t, J=7 Hz), 7.4 -CH3 7.5 (3H, m), 7.9-8.1 ( 2H, m) -92 CH3 Color - 1.2-1.5 (2H, br), 2.27 (3H, s), ~\N~ less oil 3.71 (3H, s), 3.88 (2H, s), 7.3 -H2NCH2 N--\~Y 7.7 (5H, m) 93 CH3 ,CH3 Pale 1.55 (2H, brs), 2.26 (3H, s), ~N ~ yellow 3.56 (3H, s), 3.78 (2H, s), 7.3 -H2NCH2--~N~<~ oil 7.6 (5H, m) 1.25 (2H, brs), 2.01 (3H, s), 94 F~ Pale 3.54 (2H, d, J=7 Hz), 6.43 L 11 ~J~ yellow (1 H, t, J=7 Hz), 6.55 (1 H, s), o Ç=CHCH2NH2 powder 6.9-7.0 (1H, m), 7.15 (1H, d, CH3 J=9 Hz), 7.2-7.4 (1H, m) wo 9S/O9lS9 215 0 3 ~ 5 PCT/JP94101SS9 CH3 Paie 1.65 (2H, brs), 2.48 (3H, s), J~N yellow 2.51 (3H, s), 4.03 (2H, s), 7.4 -~ oil 7.6 (3H, m), 7.87 (1 H, s) CH3 ~ ~CH2NH2 b~`oli Pale DMSO-d6:
C=O yellow 1.96 (3H, s), 2.04 (3H, s), N H powder 3.36 (2H, d, J=7 Hz), 6.31 (1H, t, 7 Hz), 6.82 (1 H, s), 7.31 (1H, dd, J=2 Hz, 9 Hz), --o C, =CHCH2NH2 7.42 (1 H, d, 9 Hz), 7.90 (1 H, CH3 d, J=2 Hz), 9.91 (1H, s) 97 F~_ Yellow 1.31 (2H, brs), 2.02 (3H, s), powder 3.55 (2H, d, J=7 Hz), 6.51 -- o C, =CHCH2NH2 (1 H, t, J=7 Hz), 6.58 (1 H, d, F CH3 J=3 Hz), 6.77 (1 H, dd, J=10 Hz, 10 Hz), 6.97 (1H, d, J=8 Hz) Using suitable starting compounds, there are obtained the compounds as listed in Table 2 in the same manner as in Reference Examples 15-21 .

Table 2 m.p. Crystalline No.Structure C Form 1H-NMR (CDCI3) ~ pm:

N CF3 Pale 1.48 (3H, t, J=7 Hz), 4.58 [~ ~X yellow (2H, q, J=7 Hz), 7.95-8.05 N CO2C2Hs powder (2H, m), 8.20-8.32 (2H, m) 2 ~ 64- Pale 1.18 (3H, t, J=7 Hz), 4.34 N J~ 65 yellow (2H, q, J=7 Hz), 7.45-7.55 `~ powder (3H, m), 7.70-7.80(2H, m), ~N~CO2c2Hs 7.80-7.90 (2H, m), 8.15-8.25 (2H, m) 3 o 154- Yellow 4.12 (3H, s), 7.80-7.95 (2H, N 155 powder m), 8.34 (1H, d, J=8 Hz), 8.61 ~NlCO2CH3 (1 H, d, J=8 Hz), 9.04 (1 H, s) 4 O Pale 1.48 (3H, t, J=7 Hz), 1.52 N J~ yellow (6H, d, J=8 Hz), 3.6-3.8 (1H, CH3 powder m), 4.54 (2H, q, J=7 Hz), 7.7 -~N CO2C2Hs 7.9 (2H, m), 8.0-8.2 (1 H, m), 8.5-8.6 (1 H, m) o Yellow 1.38 (3H, t, J=7 Hz), 3.27 powder (2H, q, J=7 Hz), 4.09 (3H, s), ~,N~C2Hs 7.7-7.9 (2H, m), 8.1-8.3 (1H, ~NJ`CO2CH3 m), 8.5-8.7 (1H, m) 6 CH3 Yellow 1.42 (3H, d, J=7 Hz), 1.49 ~~N~J`cH powder (3H, t, J=7 Hz), 3.6-3.8 (1 H, -l m), 4.56 (2H, q, J=7 Hz), 7.7 -N CO2C2Hs 7.9 (2H, m), 8.0-8.2 (2H, m) wo 95/og1S9 2 15 0 3 ~ 5 PCT/JP94/01559 1.4~ H, t, J=/ HZ), ;~.~U
7 ~ N~C2Hs Pale brown (2H, q, J=7 Hz), 4.09 (3H, s), 'l powder 7.7-7.9 (2H, m), 8.09 (1 H, dd, 2CH3 J=2Hz,8Hz),8.18(1H,dd, J=2 Hz, 8Hz) L~MS~-d6:
8 O ,~ Pale yellow 7.45-7.60(5H, m), 7.85-8.05 N~J~J powder (2H, m), 8.21 (1H, d, J=8 Hz), ~NlCO2H 8.48 (1H, d, J=8 Hz) 9 O 106 - Pale yellow 1.03 (3H, t, J=7 Hz), 4.18 108 powder (2H, q, J=7 Hz), 7.45-7.60 ~,N~ (5H, m), 7.75-7.95 (2H, m), ~NJ~CO2C2Hs 8 25 (1 H, d, J-8 Hz), 8.64 O Yellow 1.49 (3H, t, J=7 Hz), 2.78 N CH3 flakes (3H, s), 4.56 (2H, q, J=7 Hz), ~ `~' (diisopropyl 7.73 (1 H, dd, J=2 Hz, 9 Hz), CI~N~CO2C2Hs ether) 8.18 (1H, d, J=2 Hz), 8.53 (1 H, d, J=9 Hz) 11 o Yellow oil 1.49 (3H, t, J=7 Hz), 3.0-3.2 ~ ~ (4H, m), 3.8-4.0 (4H, m),4.56 N J (2H, q, J=7 Hz), 4.56 (2H, s), 7.8-7.9 (2H, m), 8.0-8.1 (1H, ~N CO2C2Hs m), 8.2-8.3 (1 H, m) 12 ~N Yellow 1.47 (3H, t, J=7 Hz), 4.55 N~ powder (2H, d, J=7 Hz), 5.82 (2H, s), N J 7.04 (2H, d, J=5 Hz), 7.70 "~ (1H,s),7.8-8.0(2H,m),8.0-~N'~CO2C2Hs 8.1 (1H, m), 8.2-8.3 (1H, m) ;~ ~;olorless 13 O '` 91-93 needles 1.49 (3H, t, J=7 Hz), 2.81 CH (n-hexane/ (3H, s), 4.56 (2H, q, J=7 Hz), -X diethyl 7.75-7.85 (2H, m), 8.15-8.25 ~N CO2C2Hs ether) (1 H, m), 8.55-8.65 (1 H, m) 1.50 (3H, t, J=/ Hz), 2.96 14 ~N CH3 74-75 Colorless (3H, s), 4.57 (2H, q, J=7 Hz), 1 1~ needles 7.70-7.90 (2H, m), 8.05 (1H, --N~CO2C2Hs (n-pentane) d, J=8 Hz), 8.19 (1H, d, J=8 Hz) O 137 - Pale yellow 1.48 (3H, t, J=7 Hz), 2.60 138 needles (3H, s), 4.59 (2H, q, J=7 Hz), ~N~,CH3 (ethyl 7.30-7.46 (2H, m), 8.53-8.67 ~N~CO2C2Hs acetate) (2H, m) o 16 O 143 - White 2.87 (3H, s), 7.75-7.90 (2H, 145 powder m), 8.15-8.25 (1H, m), 8.54 -~NXCH3 (dec) 8.65 (1H, m) Colorless 1.50 (3H, t, J-/ Hz), 2.68 17 N CH3 85-87 prisms (3H, s), 4.58 (2H, q, J=7 Hz), 'X (n-hexane/ 7.6S-7.90 (2H, m), 8.04 (1 H, --N~ CO2C2Hs ethyl d, J=8 Hz), 8.53 (1H, d, J=8 O acetate) Hz) 18 /~ Yellow 3.0-3.2 (4H, m), 3.9-4.0 (4H, ~,N~CH2-N~JO powder m), 4.56 (2H, s), 7.8-7.9 (2H, ~NlCOOH m), 8.0-8.1 (1H, m), 8.2-8.3 (1 H, m) 21503~5 19 O Yellow 1.48 (3H, t, J=7 Hz), 2.56 N CH3 powder (3H, s), 4.00 (3H, s), 4.59 ~ `~' (2H, q, J=7 Hz), 7.46 (1 H, CH3O~N~`CO2C2Hs dd, J=3 Hz, 10 Hz), 7.86 - O (1H, d, J=3 Hz), 8.51 (1 H, d, J=10 Hz) O Yellow 1.49 (3H, t, J=7 Hz), 2.78 N CH3 powder (3H, s), 3.96 (3H, s), 4.56 ~ `~' (2H, q, J=7 Hz), 7.3-7.5 (2H, CH3O~N~`CO2C2Hs m), 8.48 (1 H, d, J=9 Hz) 21 O Brown 1.26 (6H, t, J=7 Hz), 1.47 N CH3 powder (3H, t, J=7 Hz), 2.52 (3H, s), ~ `~' 3.52(4H,q,J=7Hz),4.57 (C2Hs)2N~N~CO2C2Hs (2H, q, J=7 Hz), 7.27 (1H, O dd, J=3 Hz, 10 Hz), 7.42 (1H,d,J=3Hz),8.39(1H,d, J=10 Hz) 22 o Brown 1.25 (6H, t, J=7 Hz), 1.47 N CH3 powder (3H, t, J=7 Hz), 2.73 (3H, s), ~ `~ 3.50 (4H, q, J=7 Hz), 4.53 (C2H5)2N~N~CO2C2Hs (2H, q, J=7 Hz), 7.08 (1 H, d, J=3 Hz), 7.29 (1 H, dd, J=3 Hz,10Hz),8.38(1H,d, J=10 Hz) 23 O Brown 1.0-1.4 (6H, br),1.48 (3H, t, - (c2Hs)2N--C N~ CH3 powder J=7 Hz), 2.60 (3H, s), 3.1 -~ ' 3.7 (4H, br), 4.59 (2H, q, J=7 ~N CO2C2Hs Hz), 7.8-7.9 (1 H, m), 8.5-8.6 O (2H, m) W095/09159 2~SO~ PCT1JP94/01559 :
O Brown 1.0-1.4 (6H, br), 1.49 (3H, t, Il ~ powder J=7 Hz), 2.81 (3H, s), 3.2 -(C2Hs)2N--C~ ~X 3.8 (4H, br), 4.56 (2H, q, J=7 ~N CO2C2Hs Hz), 7.80 (1 H, dd, J=2 Hz, 9 Hz), 8.24 (lH, d, J=9 Hz), 8.58(1H,d,J=2Hz) Using the suitable starting compounds, there are obtained the compounds as listed in Table 3 in the same manner as in Reference Example 3,9,11 adn14.
Table 3 Crystalline No. Structure Form 1H-NMR (CDCI3) ~ppm:

CH3 ~,Co2cH3 Pale 1.61 (2H, br), 2.23 (3H, s), 3.95 ,~ J yellow (5H, s), 4.05 (3H, s), 7.50 (1 H, H2NCH2 ~f solid s), 7.85 (1H, s) 2 /CH3 Pale 1.56 (2H, br), 2.87 (3H, s), 3.36 ~,N\ orange (3H, s), 3.98 (2H, s), 6.53 (1 H, ll I SO2CH3 solid s), 7.24 (1 H, d, J=9 Hz), 7.43 H2NCH2 (1 H, d, J=9 Hz), 7.54 (1 H, s) 3 H2NCH2 CF3 Pale 1.43 (2H, br), 2.47 (3H, s), 3.95~ yellow oil (2H, s), 7.40-7.60 (2H, m), 7.85 CH3 O~~ (1H, s) 4H2NCH2 Pale 1.44 (2H, br), 2.50 (3H, s), 3.94~ yellow oil (2H, s), 7.20-7.35 (1 H, m), 7.45 CH3--o-`f (1H, d, J=9 Hz), 7.75 (1H, d, CF3 J=9 Hz) &OCH3 Pale 1.12 (3H, t, J=7 Hz), 1.67 (2H, ~ N~ yellow oil br), 1.82 (3H, s), 3.77 (2H, q, H NCH ~ C2H5 J=7 Hz), 4.01 (2H, s), 6.56 (1H, 2 2 S), 7.03 (1 H, d, J=9 Hz), 7.30 (1 H, s), 7.46 (1 H, d, J=9 Hz) WO 95/09159 2 1 5 0 3 4 5 PC'r/JP94/OlSS9 VM~ 6 6 Cl Yellow 2.18 (3H, s), 4.13 (2H, s), 7.43 )~ powder (1H, d, J=9 Hz), 7.63 (1 H, d, H2NCH2 S NHCOCH3 J=9 Hz), 8.38 (1H, s), 9.42 (1H, br) - 1.60 (2H, br), 2.21(3H, s), 4.13 7NHCOCH3 White (2H, s), 7.09 (1H, s), 7.15-7.30 ~ powder (2H, m), 7.70 (1 H, d, J=9 Hz), H2NCH2 S 8.03 (1H, s) 8 Pale 1.56 (2H, br), 2.83 (2H, t, J=7 H2N(CH2)2~ brown Hz), 3.05 (2H, t, J=7 Hz), 7.20 o~ oil 7.40 (2H, m), 7.40-7.65 (3H, m) 9 ~ Pale 1.58 (2H, br), 3.97 (2H, s), 4.00 O O brown 4.25 (4H, m), 5.89 (1 H, s), 6.53 ~H oil (1 H, s), 7.37 (1 H, d, J=8 Hz), H2NCH2 7 44 (1 H, d, J=8 Hz), 7.65 (1 H, O Pale 1.54 (2H, br), 4.04 (2H, s), 7.45 H2NCH2 C~ yellow 7.70 (5H, m), 7.75-7.90 (3H, m), ~ oil 8.12(1H,s) 11 H2NCH2 Cl White 1.48 (2H, br), 2.27 (3H, s), 3.97 powder (2H, s), 7.31 (1 H, s), 7.55 (1 H, ``f s), 7.61 (1H, br), 8.25 (1H, s) 12 H2NCH2 CN Pale 1.48 (2H, br), 4.04 (2H, s), 7.50 yellow 7.65 (2H, m), 7.68 (1 H, s), 8.01 0~~ powder (1H, s) 13 CH3 Br Orange 1.58 (2H, br), 2.17 (3H, s), 3.92 ,~ solid (2H, s), 7.20-7.40 (2H, m), 7.57 H2NCH2 (1H, s) WO9S/09159 215 0 3 4 5 PCT/JP94/OlSS9 14 CH3 ~,CI Pale 1.58 (2H, br), 2.17 (3H, yellow s), 2.27 (3H, s), 3.95 H2NCH2 ~ - powder (2H, s), 7.15 (1H, s), NHCOCH3 7.70 (1H, br), 8.21 (1H, s) H2NCH2 Br Pale 1.51 (2H, br), 3.97 (2H, yellow s),7.30-7.45 (2H, m), ~~ oil 7.55 (1 H, s), 7.75 (1 H, s) 16 ~,Br Pale 1.58 (2H, br), 3.97 (2H, ~ ~J yellow s), 6.53 (lH, s), 7.20 -H2NCH2 oil 7.60(3H, m) 17 O Pale 1.61 (2H, br),4.00(2H, Br~ ~NHCCH=CH~ brown s), 6.58 (1H, d, J=16 J~ 1 1 oil Hz), 7.30-7.90 (10H, m) 18 Br NHCOCH3 Pale 1.61 (2H, br), 2.20 (3H, ~ brown s), 4.00 (2H, s), 7.35 H2NCH2 O solid (2H, s), 7.46 (1H, br), 7.68 (1 H, s) 19 O Pale 1.61 (2H, br),2.75 (3H, yellow s), 4.01 (2H, s), 6.62 ~SCH3 solid (1 H, s),7.49 (1 H, d, H2NCH2 J=9 Hz), 7.57 (1 H, d, J=9 Hz), 7.89 (1H, s) 1 ~/ (;~H, S), ~./4 (~H~
~ Pale red s), 3.94 (2H, s), 4.78 & \=/ oil (2H, s), 6.46 (1H, s), ~[~ SO2N(CH3)2 7.00 (1 H, d, J=9 Hz), H2NCH2 7.15-7.32 (5H, m), 7.32 (1H, d, J=9 Hz), 7.41 (1H, s) 1.5/ (2H, s), 3.95 (3H, 21 H2NCH2 CO2CH3 Pale s), 4.03 (2H, s), 4.05 yellow (3H, s), 7.53 (1 H, s), ~ oil 7.62 (1 H, s), 7.97 (1 H, OCH3 s) 1.35 (3H, t, J=/ Hz), 22 White 1.60 (2H, br), 3.99 (2H, ~,CH=CH-CO2C2H5 solid s), 4.27 (2H, q, J=7 H2NcH2 Hz), 6.41 (1 H, d, J=16 Hz), 6.55 (1H, s), 7.40 (2H, m), 7.68 (1 H, s), 7.77 (1H, d, J=16 Hz) 1.00-1.20 (6H, m), 1.58 23 CH2CON(C2H5)2 Pale (2H, br), 3.20-3.45 (4H, ~f brown m), 3.76 (2H, s), 3.96 H2NCH2--O--~ oil (2H, s), 6.47 (1H, s), 7.13 (1H, d, J=8 Hz), 7.37 (2H, d, J=8 Hz), 7.41 (1 H, s) 1.5/ (2H, br), 2.45 (3H, 24 CH3 N Brown s), 2.69 (3H, s), 3.96 ~ \~CH3 oil (2H, s), 6.47 (1H, s), J~ S 7.10 (1H, d, J=8 Hz), H2NCH2 0--~ 7.30-7.55 (2H, m) 1.32 (3H, s), 1.5/ (2H, ~CH~2 CH3 Color - br), 2.99 (2H, s), 3.70 -J~ ~ X lessoil 3.95 (4H, m), 3.96 (2H, H2NCH2 O q 1 s), 6.48 (1H, s), 7.16 CH2--CH2 (1H, d, J=8 Hz), 7.34 (1 H, d, J=8 Hz), 7.41 (1H, s) r PCr/JP94/015S9 WO 9S/091592 1 5 0 3 4 ~

l .~U (~H, ~r), ;~-U~ H, 26 SO2CH3 White s), 4.04 (2H, s), 6.67 ~[~ powder (1H, s), 7.58 (1H, d, H2NCH2 J=9 Hz), 7.84 (1 ff, d, J=9 Hz), 8.16 (1H, s) 1.5/ (2H, brl, 2.51 (3H, 27 SCH3 White s), 3.97 (2H, s), 6.47 ~ solid (1 H, s), 7.22 (1 H, d, H2NCH2 O J=9 Hz), 7.35 (1 H, d, J=9 Hz), 7.47 (1 H, s) UM~ d6:
28 CH2NHSO2CH3 Pale 2.84 (3H, s), 4.24 (4H, ,1~ yellow s), 7.04 (1 H, s), 7.33 H2NCH2 powder (1H, d, J=9 Hz), 7.57 (HCI) (1H, d, J=9 Hz), 7.64 (1H, s), 8.78 (1H, br) 1.54 (2H, br), 1.59 (3H, 29 /OCOCH3 Pale d, J_8 Hz), 2.07 (3H, H2NCH2 CH yellow s), 4.02 (2H, s), 6.00 CH3 oil (1 H, q, J=8 Hz), 7.32 (1 H, d, J=1 0 Hz), 7.45 (1H, d, J=10 Hz), 7.56 (1H, s), 7.60 (1H, s) 1.53 (2H, br), 4.0/ (2H, N--N White s), 4.41 (3H, s), 7.57 H2NCH2~~ (1 H, s), 8.11 (1 H, d, O J=9 Hz), 8.41 (1H, s) 1.52 (2H, br), 3.95 (3H, 31 Pale s), 4.05 (2H, s), 7.50 H2NCH2~,CO2CH3 yellow (1H, d, J=10 Hz), 7.62 O~ powder (1H, s), 8.04 (1H, d, J=10 Hz), 8 35 (1 H, s) wo gS/oglS9 2 I 5 0 3 ~ S PCT/JP94/OlSS9 ~) ~4 (;~H, t, J=/ HZ), 32 ~ (CH2)2CH3 Pale yellow 1.50-1.62(2H,m),2.40-/ oil 2.60(2H, m), 3.55(2H, ~`O C=CHCH2NH2 - d,J=7 Hz),5.70(1H,t, J=7 Hz),6.63(1H,s), 7.17-7.29(2H, m), 7.40-7.56(2H, m) 33 o Pale yellow 4.02(2H,s),6.61(1H, oil s),7.46-7.63(4H, m), 7.77-8.01(3H, m), 8.01 ~`O CH2NH2 (1H,s) 0.88(3H,t,J=/ Hz), 34 OCOCH3 Pale yellow 1.80-2.00(2H, m), 2.07 C2H5 - CH amorphous (3H,s),3.96(1H,s), 5.73(1H,t,J=7 Hz), ~`o CH2NH2 6.51(1H,s),7.23(1H, dd,J=8 Hz,2 Hz),7.39 (1H,d,J=8 Hz),7.48 (1H,d,J=2 Hz) 1.4/(3H,d,J=/ Hz), OCH3 Colorless oil 3.22(3H,s),3.96(2H, CH3 - CH s), 4.37(1H,q,J=7 Hz),6.51(1H,s),7.20 o CH2NH2 (1H,dd,J=8 Hz,2 Hz), 7.40(1H,d,J=8 Hz), 7.45(1H,d,J=2 Hz) 1.53(3H,d,J=/ Hz), 36 NHCOCH3 Yellow 1.99(3H,s),3.96(2H, CH3 - CH amorphous s), 5.21(1H,qui,J=7Hz),5.7(1H, br), 6.65 ~'`O CH2NH2 (1H,s),7.23(1H,d, J=8 Hz),7.40(1H,d, J=8 Hz),7.50(1H,s) ~.U;~ H, s), ~.4~ H, 37 CH3~ Pale s), 3.53 (2H, d, J=7 yellow Hz), 6.41 (1H, t, J=7 --o C=CHCH2NH2 oil Hz), 6.52 (1H, s), 7.04 CH3 (1H, d, J=8 Hz), 7.28 (1H,s),7.30(1H,d, J=8 Hz) 2.04 (3H, s), 2.52 (3H, 38 ~ Pale s), 3.55 (2H, d, J=7 yellow Hz), 6.47 (1H, t, J=7 --0 C=CH-CH2NH2 oil Hz), 6.58 (1H, s), 7.04 CH3 CH3 (1H, d, J=8 Hz), 7.08 (1 H, t, J=8 Hz), 7.33 (1H, d, J=8 Hz) 39 ~ Pale 3.99 (2H, s), 6.57 (1 H, yellow s), 7.30-7.48 (5H, m), ~3~ powder 7.59-7.62 (2H, m), 7.71 o CH2NH2 (1H, s) 4.02 (2H, s), 6.60 (1H, 40 ~ Pale s), 7.34-7.55 (3H, m), N~ yellow 7.72 (1H, d, J=5 Hz), T 1~ powder 7.90 (1 H, d, J=7 Hz), --0 CH2NH2 8.58 (1H, d, J=5 Hz), 8.87(1H,s) 41 N CH3 Pale 2.39 (3H, s), 2.49 (3H, CH3~/--~ yellow s), 4.00 (2H, s), 6.56 ~ powder (1H, s), 7.47 (2H, s), ~o~cH2NH2 7.70 (1 H, s) _ Wo95/09159 2 1 5 0 3 4 5 PCT/JP94/OlS59 ~.~U~H,S),~.4~(~H,~, 42 ~ Pale yellow J=7 Hz),3.82(3H,s), C=CHCH2NH2 oil 5.55(1H,t,J=7Hz),6.85-OCH3 CH3 6.93(2H,m),7.13(lH, dd,J=8 Hz,2 Hz),7.22 (1H,dd,J=8 Hz,2 Hz) 2.04(3H,s),3.49(2H,d, 43 ~ Colorless J=7 Hz),3.82(3H,s), CH3O~C=CHCH2NH2 oil 5.86(1H,t,J=7 Hz),6.79 CH3 (1 H,dd,J=8 Hz,2 Hz), 6.93(1H,t,J=2 Hz),6.99 (1H,d,J=8 Hz),7.23 (1H,t,J=8 Hz) 44 Colorless 2.06(3H,s),3.52(2H,d, F3C~CI=CHCH2NH2 oil J=7 Hz),5.92(1H,t,J=7 CH3 Hz),7.47-7.61(4H,m) 2.0/(3H,s),3.52(2H,d, ~ Colorless J=7 Hz),5.90(1H,t,J=7 ~ C~=CHCH2NH2 oil Hz),7.39-7.58(3H,m), F3C CH3 7.63(1H,s) 46 ~ Colorless 2.06(3H,s),3.49(2H,d, Cl=CHCH2NH2 oil J=7 Hz),5.85(1H,t,J=7 CH3 Hz),7.21-7.42(5H,m) 2.04(3H,s),2.18(3H,s), 47 ~ Pale yellow 3.48(2H,d,J=7 Hz), ~ Cl=CHCH2NH2 oil 5.86(1H,t,J=7Hz),7.15 CH3CONH CH3 (1H,d,J=8 Hz),7.26 (1H,t,J=8 Hz),7.39(1H, d,J=8 Hz),7.51(1H,s), 7.20(1 H, br) 48 o Yellow DMSO-d6:
CH3O2C ~ ~ amorphous 2.05(3H,s),3.38(2H,d, =CHCH2NH2 J=7 Hz),3.90(3H,s), H 5 86(1 H, t,J=7 Hz), 7.50-C 3 7.78(4H,m) PCT/JI'94101559 WO95/09159 2lS03 ll~

H, s~ .5~ ~H, ~, 49 N-N White J=7 Hz),4.40(3H,s),5.96 ' ~C=CHCH2NH2 powder (1 H,t,J=7 Hz),7.53(2H,d, I CH3 J=8 Hz),8.09t2H,d,J=8 CH3 Hz) 1.9/(3H,s~,3.44(2H,d, Colorless J=7 Hz),5.41(1H,t,J=7 C=CHCH2NH2 oil Hz),7.22(1H,d,J=8 Hz), CH 7.37(1H,t,J=8 Hz),7.48 CF3 3 (1H,t,J=8 Hz),7.63(1H,d, J=8 Hz) 2.03(3H,s),2.1/(3H,s), Colorless 3.48(2H,d,J=7 Hz),5.83 CH3CONH ~ Cl=CHCH2NH2 oil (1H,d,J=7 Hz),7.35(2H, CH3 d,J=8 Hz),7.45(2H,d, J=8 Hz),7.30(1H, br) 2 09(3H,s),2.44(3H,s), 52 Colorless 3 50(2H,d,J=6Hz),5.82 CH3 O~ oil (1H,t,J=6 Hz),6.34(1H, ,C=CHCH2NH2 s),7.25(1H;dd,J=8 Hz, 7.46(1H,d,J=2 Hz) 2.31(2H,t,J=/Hz~,2./2 Colorless (2H,t,J=7 Hz),3.82-3.91 53 ~ oil (2H,m),3.88(3H,s),3.98-~ CH2CH2NH2 4.07(2H,m),6.90(1H,t, CH30 q q J=8 Hz),6.93(1H,t,J=8 CH2-CH2 Hz),7.29(1H,t,J=8 Hz), 7.47(1H,d,J=8 Hz) 54 Pale 3.86(2H,s),6.47(1H,s), yellow 7.20-7.55(5H,m),7.64~1H, needles s) -WO 95/09159 2 1 5 0 ~ 4 5 PCI/JP94/01559 O Pale yellow 2.03 (3H, s), 3.49 (2H, d, ~CH-CHCNH-- oil J=7 Hz), 5.84 (1H, t, J=7 Hz), 6.59 (lH, d, J=16Hz), ~C=CHCH2NH2 7.35-7.68 (10H, m), 7.75 CH3 (1H, d, J=16 Hz) 2.14(3H,s),3.54(2H,d, 56 Yellow J=7 Hz), 5.96 (1H, t, J=7 ~<N~ solid Hz), 7.45-7.60(4H, m), 7.91 \=/ S~c=cHcH2NH2 (1H, d, J=2 Hz), 8.00 (1H, CH3 d, J=8 Hz), 8.07-8.11 (2H, m) 57 OCH3 Pale yellow 2.43 (3H, s), 3.99 (3H, s), h~<N_~ 3 powder 4.05 (2H, s), 6.93 (1 H, d, W S~ J=8 Hz), 7.28 (1H, dd, J=8 Cl CH2NH2 Hz, 3 Hz), 8.32 (1H, d, J=3 Hz) 2.14(3H,s),3.54(2H,d, 58 OCH3 Yellow J=7 Hz), 4.06 (3H, s), 5.96 ~<,N~ amorphous (1H, t, J=7 Hz), 7.00 (1H, d, Cl S~,C=CHCH2NH2 J--8 Hz), 7.39 (1H, dd, J=8 J=8 Hz, 2 Hz), 7.92 (1 H, d, J=2 Hz), 8.0 1(1H, d, J=8 Hz), 8.53 (1 H, d, J=3 Hz) 59 Brown oil 3.97 (2H, s), 6.52 (1 H, d, ~ J=2 Hz), 7.25-7.55 (6H, m) o CH2NH2 WO 95/09159 2 1 5 0 ~ 4 ~ PCr/JP94/01559 H, s)~ H, t, H Yellow J=7 Hz), 2.98 (2H, t, J=7 O~,N~ amorphous Hz), 3.53 t2H, d, J=7 Hz), ~J~ 5.94 (1H, t, J=7 Hz), 6.72 ,C=CHCH2NH2 (1 H, d, J=8 Hz), 7.23 (2H, CH3 m), 8.06 (1 H, br) 2.44 (3H, s), 3.52 (3H, s), 61 OCH OCH Yellow oil 4.06 (2H, s), 5.35 (2H, s), 2 3 7.17 (1H, d, J=8 Hz), 7.26 ~<N~CH3 (1 H, dd, J=8 Hz, 2 Hz), S CH2NH2 8.34 (1H, d, J=2 Hz) Cl 2.04 (3H, s), 3.48 (2H, d, 62 ~ Colorless J=7 Hz), 3.49 (3H, s), 5.19 ~,C=CHCH2NH2 oil (2H, s), 5.86 (1 H, t, J=7 CH3 Hz), 6.93 (1H, dd, J=8 Hz, OCH2OCH3 3 Hz), 7.05 (1H, dd, J=8 Hz, 3 Hz), 6.95 (1 H, s), 7.23 (1 H, t, J=8 Hz) 2.98 (2H, dd, J=6 Hz, 2Hz), 63 Colorless 4.01 (1 H, dd, J=11 Hz, 7 ~~ oil Hz),4.13(1H,m),4.27(1H, ~OlCH2NH2 dd, J=11 Hz, 2 Hz), 6.81 -1.84 (3H, s), 2.04 (3H, s), ~ Colorless 3.49 (2H, d,J=7 Hz), 4.44 ~f=CHCH2NH2 oil (2H, s), 4.99 (1H, s), 5.10 CH2= ICCH2O CH3 (1 H, s), 6.82 (1 H, d, J=8 CH3 Hz), 6.97 (1 H, s), 6.99 (1 H, d, J=8 Hz), 5.86 (1 H, t, J=7 Hz), 7.22 (1 H, t, J=8 Hz) - WO 95/09lS9 2 1 S 0 3 4 5 PCT/JP94/015S9 ~.11(~H,S),~ H,S), 66 N~ Colorless 3.52(2H, d, J=7 Hz),5.91 CH3~/ 11 1 amorphous (1H,t,J=7 Hz),7.50(1H, S~ `c=cHcH2NH2 dd, J=8 Hz,2Hz),7.82(1H, CH3 d, J=2 Hz),7.87(1H, d, J=8 Hz) 67O~ ,CH3 Pale yellow 3.41(3H,s,),3.96(2H,s), S-N oil 7.06(1H, d, J=2 Hz),7.14 `N~Br (1H, dd, J=8 Hz,2 Hz), ~ o ~ CH2NH2 7.43(1H, d, J=8 Hz) 68 \\S ,CH3 Pale yellow 3.35(3H,s),3.97(2H,s), ~\ oil 6.68(1H,s),7.03(1H, dd, `N~ J=8 Hz,2 Hz),7.17(1H,d, oJ~cH2NH2 J=2 Hz),7.41(1H,d,J=8 Hz) 69 ~ Yellow 1.59(2H, brs), 3.92(2H, powder brs), 3.96(2H,s),6.48(1H, o CH2NH2 s),6.61(1H, d, J=7 Hz), NH2 6.9-7.1(2H,m) Br Yellow 1.61(2H, brs), 4.14(2H,s), powder 7.06(1H,s),7.37(1H,d, S CH2NH2 J=8 Hz),7.64(1H,d,J=8 Hz),7.82(1H,s) WO95/09159 5034~ PCI`/JP94/01559 71 CH3 Yellow 1.51 (2H, brs), 2.34 (3H, s), ~( powder 4.09 (2H, s), 7.2-7.4 (2H, S CH2NH2 m), 7.63 (1 H, d, J=8 Hz), 7.79 (1 H, d, J=8 Hz) 72 CH2NH2 Yellow oil 1.46 (3H, t, J=7 Hz), 1.68 (2H, brs), 4.25 (2H, s), 4.48 o CO2C2Hs (2H, q, J=7 Hz), 7.3-7.5 (2H, m), 7.58 (1 H, d, J=8 Hz), 7.77 (1H, d, J=8 Hz) 73 CH2NH2 Pale yellow 1.46 (2H, brs), 2.44 (3H, s), [~ oil 3.91 (2H, s), 7.1-7.3 (2H, O CH3 m), 7.3-7.4 (1 H, m), 7.5-7.6 t1H, m) 74 NH2 Yellow 1.53 (2H, brs), 3.87 (2H, ,~ powder brs), 3.95 (2H, s), 6.45 (1H, J~ s), 6.49 (1 H, d, J=8 Hz), O CH2NH2 6.90 (1 H, d, J=8 Hz), 7.05 (1 H, dd, J=8 Hz, 8 Hz) Yellow 1.54 (2H, brs), 3.71 (2H, ,~ powder brs), 3.90 (2H, s), 6.38 (1H, H2N O CH2NH2 s), 6.60 (1H, d, J=8 Hz), 6.77 (1 H, s), 7.26 (1 H, d, J=8 Hz) 76 H2N CH2NH2 Orange 1.44 (2H, brs), 2.38 (3H, s), ~( powder 3.56 (2H, brs), 3.83 (2H, s), o CH3 6.59 (1 H, d, J=8 Hz), 6.83 (1H, s), 7.17 (1H, d, J=8 Hz) -WO 95/09159 2 1 ~ 0 3 ~ 5 PCT/JP94/01559 77 SCH3 Orange 1.57 (2H, brs), 2.35 (3H, s), ~( oil 4.10 (2H, s), 7.2-7.3 (2H, o CH2NH2 m), 7.4-7.5 (1H, m), 7.6-7.7 (1H, m) - 78 CH3 White 1.64 (2H, brs), 2.52 (3H, s), ~=N powder 2.69 (3H, s), 3.99 (2H, s), S~ 6.55 (1H, s), 7.4-7.6 (2H, CH3 ~oJ`cH2NH2 m), 7.74 (1 H, s) 79 ~ Orange 1.59 (2H, brs), 4.00 (2H, s), \~N powder 6.60 (1 H, s), 7.3-7.5 (5H, m), 7.9-8.1 (3H, m), 8.22 S ~ (1H, s) ~ 0 CH2NH2 ~ White 1.61 (2H, brs), 2.61 (3H, s), ~=~S ~,CH3 powder 4.00 (2H, s), 6.58 (1 H, s), N~ 7.3-7.6 (4H, m), 7.61 (1 H, d, J=8 Hz), 7.85 (1 H, s), 7.9 -o CH2NH2 8.0 (2H, m) L1MSO-d6:
81 O S CH Brown 3.0-3.1 (1H, m), 3.4-3.6 ~-- >'~ 2~ powder (1H, m), 4.09 (2H, s), 4.7 -HN ~ ~0 CH2NH2 4.8 (1H, m), 6.85 (1H, s), 7.18 (1H, d, J=9 Hz), 7.4 -7.6 (2H, m) wo gs~0925~ 5 o 3 4 5 PCIIJP94/OlSS9 ~

82 CH3 S Yellowoil 1.58(2H, brs), 2.79(3H,s), ~NI ~ 3.99(2H,s),6.56(1H,s), 7.26(1H,s),7.45(1H,d, H2NH2 J=8 Hz),7.75(1H,d,J=8 Hz),8.06(1H,s) 83 ~ N Brown 1.53(2H, brs), 4.00(2H,s), ~S~ powder 6.59(lH,s),7.30(1H, d, ~ J=3 Hz),7.48(1H,d,J=9 i~,~o CH2NH2 Hz),7.8-7.9(2H,m),8.14 (1H,s) 84 CH3 ~S CH3 Yellow oil 1.56(2H, brs), 2.52(3H,s), N ~ CH2NH2 2.70(3H,s),4.03(2H,s), ~ 74-7.6(3H,m),7.85(1H, N~N Yellow oil 1.57(2H, brs), 3.95(2H,s), N /~ CH2 4.29(3H,s),4.30(2H,s), CH3' N ~ 6.47(1H,s),7.21(1H,d, '`o CH2NH2 J=8 Hz),7.36(1H,d,J=8 Hz),7.46(1H,s) 86 CH2NH2 Yellow oil 1.49(2H, brs), 4.05(2H,s), 7.33(1H,dd,J=8 Hz,8 Hz),7.56(1H,d,J=8 Hz), CF3 7.66(1H,s),7.81(1H,d, J=8 Hz) 87 CH3 Yellow oil 1.61(2H, brs), 2.24(3H,s), 3.97(2H,s),7.28(1H,dd, o CH2NH2 J=8 Hz,8 Hz),7.49(1H,d, CF3 J=8 Hz),7.63(1H,d,J=8 Hz) 215034~

88 I N Yellow 1.45 (2H, brs), 4.06 (2H, s), ~S ~ CH2NH2 powder 7.32 (1 H, d, J=3 Hz), 7.52 (1 H, d, J=9 Hz), 7.60 (1 H, s), 7.8-8.0 (2H, m), 8.24 (1H, s) 89 ~N Yellow 1.57 (2H, brs), 3.96 (2H, s), CH2 powder 4.42 (2H, s), 6.49 (1 H, s), 7.1-7.3 (2H, m), 7.49 (1H, d, --0 CH2NH2 J=8 Hz), 7.46 (1 H, s), 7.70 (1 H, d, J=3 Hz) CH3 Yellow 1.54 (2H, brs), 2.51 (3H, s), \~ly powder 3.99 (2H, s), 6.57 (1 H, s), S'~ 6.84 (1 H, s), 7.45 (1 H, d, ~o ~CH2NH2 J=9 Hz), 7.83 (1 H, d, J=9 Hz), 8.11 (1 H, s) 91 CH2NH2 Yeilow oil 1.53 (2H, brs), 4.05 (2H, s), ,~ 7.52 (1 H, d, J=8 Hz), 7.6 -F3C O 7.8 (3H, m) 92 CH3 Yellow 1.56 (2H, brs), 2.24 (3H, s), ~( powder 3.97 (2H, s), 7.4-7.6 (2H, F3C~--0 CH2NH2 m), 7.67 (1 H, s) 93 CH3~ Yellow 1.54 (2H, brs), 3.97 (3H, s), N--N powder 3.98 (2H, s), 6.58 (1 H, s), ~N~ 7.48 (1H, d, J=9 Hz), 8.01 H2NH2 s), 8.26 (1H, s) WO 95tO9159 2 ~S O 3 4~ PCrlJP94101559 94 ,CH3 Yellow 1.61 (2H, brs), 4.01 (3H, s), N--N powder 4.02 (2H, s), 6.62 (1 H, s), N ~ 7.5-7.6 (2H, m), 7.83 (1 H, H2NH2 s), 7.95 (1H, s) S Brown oil 1.37 (2H, brs), 2.34 (3H, s), / ~ 2.71 (3H, s), 3.54 (2H, s), CH3~N 7.15 (1H, d, J=7 Hz), 7.33 ~CH2NH2 (1H, dd, J=7 Hz, 8 Hz), ~ 750(1H,d,J=8Hz),7.55 96 ~ Yellow oil 1.54 (2H, brs), 2.54 (3H, s), J~ 2.69 (3H, s), 3.99 (2H, s), ~ O CH2NH2 6.54 (1 H, s), 7.4-7.6 (2H, CH3 S CH3 m), 7.67 (1 H, s) CH3 N~N Pale 1.54 (2H, brs), 2.61 (3H, s), ll yellow 2.72 (3H, s), 4.01 (2H, s), CH3 N--~ powder 6.63 (1 H, s), 7.54 (1 H, d, O CH2NH2 J=9 Hz), 8.46 (1 H, d, J=9 Hz), 8.70 (1 H, s) 98 CH3 Yellow oil 1.49 (2H, brs), 2.47 (3H, s), S~ 2.71 (3H, s), 3.97 (2H, s), ~N 6.69 (1 H, s), 7.2-7.5 (3H, CH3 l m) (~CH2NH2 - wo 95/09159 2 1 5 0 3 4 5 PcrtJps4lol5ss 99 ,~ Yellow 0.16 (3H, s), 0.20 (3H, oil s), 0.95 (9H, s), 1.61 --`CH2NH2 (2H, brs), 2.3-2.4 (1H, OSi(t-C4Hg)(CH3)2 m), 2.5-2.6 (1 H, m), 2.7 -2.9 (1 H, m), 3.0-3.2 (2H, m), 4.94 (1 H, d, J=7 Hz), 7.1-7.3 (4H, m) 100 ~ ,CH2NH2 Yellow 1.50 (2H, brs), 2.54 ll ll oil (3H, s), 2.70 (3H, s), CH3~ ~'' 4.04 (2H, s), 7.5-7.7 S CH3 (3H, m), 7.73 (1 H, s) 101 Cl White 2.17 (3H, s), 3.88 (2H, ~ powder d, J=6.8 Hz), 6.51 (1 H, H2NCH2CH=C\ O t, J=6.8 Hz), 6.63 (1H, CH3 s), 7.20 (1 H, d, J=8.7 Hz), 7.33 (1 H, d, J=8.7 Hz), 7.49 (1 H, s) 102 CONHCH3 Yellow 2.97 (3H, s), 4.00 (2H, J~ oil brs), 6.27 (1 H, brs), H2NCH2 O' 7.42 (1 H, brd, J=8 Hz), 7.65 (1 H, brs), 7.76 (1 H, brd, J=8 Hz), 8.05 (1H, brs) - 103 CH3 Yellow 2.39 (3H, s), 2.42 (3H, J~,COOCH3 oil s), 3.92 (3H, s), 4.05 J~ (2H, s), 6.65 (1 H, s), H2NCHz O ~ CH3 7.12 (1H, s) 2~5034s 104 ,CH3 Pale 1.27 (6H, d, J=6.9 Hz), ~,,CH~ ~ ~ yellow 2.99 (1H, sept. J=6.9 ~ ~ CH3 oil Hz), 3.99 (2H, s), 6.52 H2NCH2 (1H, s), 7.12 (1H, d, J=8.7 Hz), 7.34 (1H, d, J=8.7 Hz), 7.36 (1 H, s) 105 ~ Yellow 2.13 (3H, brs), 3.53 J~ ~ oil (2H, d, J=6.6 Hz), 6.10 H2NCH2CH=C\ S (1H, t, J=6.6 Hz), 7.19 CH3 (lH, s), 7.2-7.4 (2H, m), 7.6-7.8 (2H, m) 106 ~ Yellow 1.55 (3H, d, J=7.4 Hz), ~ ~J oil 4.44 (1H, q, J=7.4 Hz), H2N-CH S 7.13 (1H, s), 7.2-7.4 CH3 (2H, m),7.68(1H,d, J=7.3 Hz), 7.80 (1H, d, J=7 3 Hz) 107 H2N(CH2)2 ~ Yellow 2.92 (2H, t, J=6.5 Hz), ~J oil 3.10 (2H, t, J=6.5 Hz), 6.46 (1H, s), 7.1-7.3 (2H, m), 7.4-7.6 (2H, m) 108 CO2CH3 Yellow 2.19 (3H, s), 3.91 (2H, ,[~ oil d, J=6.5 Hz), 3.94 (3H, H2NCH2CH=C\ O s), 6.54 (1H, t, J=6.5 CH3 Hz), 6.74 (1H, s), 7.43 (1 H, d, J=8.6 Hz), 8.00 (1 H, d, J=8.6 Hz), 8.27 (1H, s) 109 NHCOCH3 Yellow 2.21 (3H, s), 4.01 (2H, ~ oil s), 6.59 (1H, s), 7.42 H2NCH2 ~f (1H, s), 8.06 (1H, s) 2tS03~5 110 ~ Yellow 4.02 (2H, s), 4.15 (3H, ~ oil s), 6.69 (1 H, s), 7.40 H2NCH2 ~f (1H, t, J=8.1 Hz), 7.58 N~N~CH3 . (1H, d, J=8.1 Hz), 7.76 N N (1 H, d, J=8.1 Hz) 111 Yellow 4.10 (2H, s), 4.49 (3H, ,~q oil s), 6.64 (1 H, s), 7.34 H2NCH2 ~f (1 H, t, J=7.7 Hz), 7.65 N~N (1H, d, J=7.7 Hz), 8.05 N--N (1 H, d, J=7.7 Hz) CH3~

112 ~OCH3 Pale 2.02 (3H, brs), 3.54 J~ ~J yellow (2H, d, J=6.8 Hz), 3.84 H2NCH2CH=C\ O powder (3H, s), 6.41 (1H, t, CH3 J=6.8 Hz), 6.54 (1H, s), 6.84 (1 H, dd, J=8.8 Hz, 2.5Hz),6.98(1H,d, J=2.5 Hz), 7.30 (1 H, d, J=8.8 Hz) 113 CH3 Yellow 2.12 (3H, brs), 2.35 ~q oil (3H, s), 3.55 (2H, d, H2NCH2CH=C~`O~ J=6.7 Hz), 6.11 (1H, t, CH3 J=6.7 Hz), 7.2-7.3 (2H, m), 7.4-7.5 (2H, m) 114 Yellow 2.05 (3H, brs), 3.56 ,~q oil (2H, d, J=7.1 Hz), 6.53 H2NCH2CH=C\ O~ (1H, t, J=7.1 Hz), 6.64 CH3 CF3 (1 H, s), 7.25 (1 H, t, J=6.9 Hz), 7.48 (1H, d, J=6.9 Hz), 7.68 (1 H, d, J=6.9 Hz) WO 9S/09159 ~3 45 PCT/JP94/OlS59 115 ,N N, Yellow 4.03 (2H, s), 4.20 (3H, N~ N~ oil s), 6.69 (1 H, s), 7.4-7.5 r CH3 (2H, m), 7.6-7.7(1H, m) 116 ,CH3 Yellow 4.05 (2H, s), 4.45 (3H, ,N, N, oil s), 7.33 (1 H, s), 7.37 N~N (1 H, t, J=7.6 Hz), 7.55 ~ (1H, d, J=7.6 Hz), 8.06 H2NCH2 (1H, d, J=7.6 Hz) 117 H Yellow 2.44 (2H, t, J=7.5 Hz), ~ ~ oil 2.96 (2H, t, J=7.5 Hz), H2NCH2 4.00 (2H, s), 6.68 (1 H, s), 7.00 (1 H, s), 7.37 (1H, s), 10.11 (1H, s) 118 CH3 Yellow 2.42 (3H, s), 3.95 (2H, ~ oil s), 6.45 (1 H, s), 7.0-7.2 H2NCH2 (1H, m), 7.3-7.5 (2H, m) 119 , ~, Yellow 2.51 (3H, s), 3.98 (2H, J~ ~ d oil s), 6.51 (1H, s), 7.06 H2NCH2 1' (1H, d, J=7.3 Hz), 7.10 CH3 (1 H, t, J=7.3 Hz), 7.34 (1 H, d, J=7.3 Hz) 120 N Yellow 4.02 (2H, s), 6.61 (1H, ,~ oil s), 7.39 (1 H, d, J=5.7 H2NCH2 0 Hz), 8.46 (1 H, d, J=5.7 Hz), 8.86 (1H, s) - wo 95/09159 2 ~ 5 o ~ 4 ~ PCr,JP94,0l559 121 ~N Yellow 2.05 (3H, s), 3.56 (2H, J~ ~J oil d, J=6.6 Hz), 6.50 (1H, H2NCH2CH=C\ O t, J=6.6 Hz), 6.64 (1H, CH3 s), 7.37 (1 H, d, J=5.7 Hz), 8.45 (1 H, d, J=5.7 Hz), 8.84 (1H, s) 122 Cl 2H5 Yellow 1.29 (3H, t, J=7.1 Hz), ,~N~ ~O oil 2.64 (2H, t, J=8.2 Hz), 2.97 (2H, t, J=8.2 Hz), H2NCH2 4.04 (2H, q, J=7.1 Hz), 4.12 (2H, s), 6.71 (1H, s), 7.16 (1H, s), 7.27 (1H, s) 123 N=N Yellow 2.21 (3H, s), 3.91 (2H, ~N,N~CH3 oil d, J=6.6 Hz), 4.41 (3H, ll I ~ s), 6.54 (1H, t, J=6.6 H2NCH2CH=C\ O Hz), 6.76 (1H, s), 7.52 CH3 (1 H, d, J=8.5 Hz), 8.06 (1H, d, J=8.5 Hz), 8.33 (1H, s) 124 ~_CH2 Yellow 2.39 (3H, s), 2.61 (3H, ~ I ~S oil s), 3.98 (2H, s), 4.12 H2NCH2 CH3--N--CH3 (2H, s), 6.47 (1H, s), 7.07 (1H, d, J=8.4 Hz), 7.30 (1 H, s), 7.47 (1 H, d, J=8.4 Hz) 125 ~ Yellow 2.41 (3H, s), 2.72 (3H, J~ ~J oil s), 3.97 (2H, s), 6.58 H2NcH2 T (1H, s), 7.3-7.7 (3H, m) ~N

WO 9S/09159 ` PCT/JP94/01559 ~5~ - 292 -126 H2NCH2 Yellow 2.41 (3H, s), 2.72 (3H, oil s), 4.04 (2H, s), 7.3-7.7 O~ (4H, m) ~N
H3C--~S~CH3 Using the suitable starting compounds, there are obtained the compounds as listed in Table 4 in the same manner as in Reference Examples 15-21.
Table 4 m.p. Crystalline No. Structure C Form 1H-NMR (CDCI3) ~ppm:

o Yellow 1.47 (3H, t, J=7 Hz), 2.51 powder (3H, s), 2.53 (3H, s), 2.57 CH3 ~N`~XcH3 (3H, s), 4.58 (2H, q, J=7 CH3~N co2c2Hs Hz), 8.31 (1H, s), 8.36 (1H, O s) 2 CH3 ~,~N CH3 Orange 1.49 (3H, t, J=7 Hz), 2.48 ll ~X powder (3H, s), 2.50 (3H, s), 2.93 CH3~--N CO2C2Hs (3H, s), 4.55 (2H, q, J=7 Hz), 7.78 (1 H, s), 7.91 (1 H, s) 3 O Pale yellow 1.48 (3H, t, J=7 Hz), 2.48 powder (3H, s), 2.53 (3H, s), 2.80 CH3~N~,CH3 (3H, s), 4.54 (2H, q, J=7 CH3~NJ`CO2c2Hs Hz), 7.93 (1H, s), 8.34 (1H, s) 2 1 S 0 3 4 S PCr/JP94/01559 ~;rystalllne ~orm No. Structure m.p. C (solvent for recystal.) 4 N ,CH2Br 83-95 Colorless needles (dichloro -, ~ methane/
`N~ `CO2C2Hs n-hexane) NMR analysis:

,~ N CH2F 96-97 White powder (dichlor~."~elhane/
~N~C02C2H5 n-hexane) 6 O 109-1 10 Colorless flakes (dichloromethane/

~NXco2c2Hs n-hexane) 7 O 140-141 Brown powder (chlorofor"~) ~N XCH2F

~: 1H-NMR (CDCI3) ppm:

1.53 (3H t J=7 Hz) 4.61 (2H d J=7 Hz) 5.14 (2H s) 7.81-7.93 (2H m) 8. 1 1 (1 H, m) 8.23 (1 H m) ~ ,~5~ 4S ~ 294 -Example 1 2-Ethoxycarbonyl-3-methylquinoxalin-4-oxide (1.5 9) is mixed with 3-aminomethylbenzofuran (1.9 9) under nitrogen atmosphere, and the mixture is stirred at 60C overnight. The reaction mixture is purified by silica5 gel column chromatography (solvent; n-hexane: ethyl acetate = 3: 1), and recrystallized from ethanol to give 2-[(3-benzofuranyl)methylaminocarbonyl]-3 -methylquinoxalin-4-oxide (1.3 9) as colorless needles.
M.p. 143-1 44C
Example 2 2-Carboxy-3-methylquinoxalin-4-oxide (0.8 9) and 2-aminomethyl -5-dimethylaminobenzofuran (0.9 9) are dissolved in dimethylformamide (10 ml), and thereto are added dropwise successively diethyl cyanophosphate (0.8 g) and triethylamine (0.8 9) under ice-cooling. The mixture is stirred at room temperature overnight, extracted with ethyl acetate, and washed with water.
The mixture is dried over anhydrous sodium sulfate, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 1: 1), and recrystallized from acetonitrile to give 2-[(5-dimethylamino-2-benzofuranyl)methylaminocarbonyl]-3-methylquinoxalin-4-oxide (0.6 9) as yellow plates.
M.p. 155-1 57C
Example 3 2-Quinoxalinecarboxylic acid (0.5 9) is dissolved in dichloromethane (10 ml), and thereto is added dicyclohexylcarbodiimide (0.7 9). The mixture is stirred for 30 minutes, and thereto is added 2 -aminomethylbenzofuran (0.5 9), and the mixture is stirred overnight. The insoluble materials are removed by filtration, and the organic layer is washed with saturated sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The resultant is evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; n -hexane: ethyl acetate = 3: 1), and recrystallized from n-hexane/ethyl acetate togive 2-[(2-benzofuranyl)methylaminocarbonyl]quinoxaline (0.43 9) as colorless flakes.
M.p. 155-1 56C

- WO 9S/09159 2 1 5 0 3 4 ~ PCT/JP94/01559 Example 4 2-[(4-Morpholinocarbonylmethoxybenzyl)aminocarbonyl]-3 -methylquinoxaline (2.2 9) is dissolved in methylene chloride (30 ml), and thereto is added m-chloroperbenzoic acid (1.3 9) at room temperature, and the mixture is stirred for one day. To the mixture is added chloroform, and the organic layer is washed successively with aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution, and water, and dried over anhydrous sodium sulfate. The mixture is evaporated to remove the solvent, and the residue is purified by silica gel column chromatography 1 0 (solvent; ethyl acetate), and recrystallized from acetonitrile to give 2-[(4 -morpholinocarbonylmethoxybenzyl)aminocarbonyl]-3-methylquinoxalin-4 -oxide (1.5 9) as colorless needles.
M.p. 142-143C
Using the suitable starting compounds, there are obtained the compounds of Examples 28-103, 125, 126, 128, 130-135, 137, 138, 141, 143 -146, 148,150, 152, 154-157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177-184, 187-189, 191, 192, 194, 196-201, 203-205, 207, 209-213, 216, 21g, 220, 224, 226, 228-230, 233, 235, 236, 239, 240 and the following Examples 435 -440, 442-479 and 484-487 in the same manner as in Example 4.
Example 5 2-Cinnamylaminocarbonyl-3-methylquinoxaline (1.b 9) is dissolved in dimethylformamide (15 ml), and thereto is added sodium hydride (160 mg) under ice-cooling. The mixture is stirred at the same temperature for 30 minutes, and thereto is added methyl iodide (0.52 g), and the mixture is stirred at room temperature for two hours. The mixture is poured into ice-water,- and extracted with diethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate. The resultant is evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; n -hexane: ethyl acetate = 2: 1) to give 2-(N-cinnamyl-N-methylaminocarbonyl)-3 -methylquinoxaline (0.8 9) as pale yellow liquid.
1H-NMR (CDCI3) ~ ppm: 2.78, 2.79 (3H, s), 2.92, 3.24 (3H, s), 3.98, 4.43 (2H, d, J=6 Hz), 6.10-6.40 (1H, m), 6.40, 6.70 (1H, d, J=16 Hz), 7.20-7.50 (5H, WO 95tO9159 PCT/Jl'94/01559 ~,~S~3 4S ~ 296 -m), 7.70-7.85 (2H, m), 8.00-8.15 (2H, m) Using the suitable starting compounds, there are obtained the compounds of Examples 44, 66, 107, 110, 135, 138,150, 151, 152, 153,175, 176,178, 186, 187, 191 and 192 in the same manneras in Example 5.
Example 6 2-[(5-Aminobenzofuran-2-yl)methylaminocarbonyl]-3 -methylquinoxalin-4-oxide (0.4 9) is suspended in pyridine (6 ml), and thereto isadded dropwise with stirring acetic anhydride (0.26 9) under ice-cooling. The mixture is stirred at room temperature for one day, and poured into ice-water.
The precipitated crystals are collected by filtration, washed with water, and the resulting crude crystals are recrystallized from acetonitrile to give 2-[(5 -acetylaminobenzofuran-2-yl)methylaminocarbonyl]-3-methylquinoxalin-4-oxide (0.4 9) as pale yellow needles.
M.p. 183-184C
Using the suitable starting compounds, there are obtained the compounds of Examples 84 and 85 in the same manner as in Example 6.
Example 7 2-[(5-Aminobenzofuran-2-yl)methylaminocarbonyl]-3-methyl -quinoxalin-4-oxide (0.8 g) is dissolved in dimethylformamide (15 ml), and thereto are added potassium carbonate (0.5 9) and N-chloroacetylmorpholine (0.37 9). The mixture is stirred at 70C for four hours, and evaporated to remove the solvent. To the residue is added water, and the mixture is extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate.
The resultant is evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; ethyl acetate), to convert the resultant to an oxalate thereof, and recrystallized from ethanol to give 2-[(5 -morpholinocarbonylmethylaminobenzofuran-2-yl)methylaminocarbonyl]-3 -methylquinoxalin-4-oxide (40 mg) as pale brown granules.
M.p. 159-167C (decomposed) 1 H-NMR (CDCI3) ~ ppm: 3.09 (3H, s), 3.40-3.55 (2H, m), 3.55-3.85 (6H, m), 3.90 (2H, s), 4.78 (2H, d, J=6 Hz), 6.60 (1 H, s), 6.65 (1 H, d, J=7 Hz),6.67 (1H, s), 7.28 (1H, d, J=7 Hz), 7.75-7.85 (2H, m), 8.05-8.15 (lH, m), 8.47 (1H, brs), 8.50-8.60 (1 H, m) Example 8 2-[(5-Ethoxycarbonylbenzofuran-2-yl)methylaminocarbonyl]-3 -methylquinoxalin-4-oxide (4.2 9) is added to a solution of sodium hydroxide (1.4 9) in methanol (50 ml) and water (14 ml), and the mixture is stirred at room temperature overnight. The mixture is evaporated to remove methanol, and to the resultant is added water and acidified with hydrochloric acid, and the precipitated crystals are collected by filtration, washed with water, and dried to give 2-[(5-carboxybenzofuran-2-yl)methylaminocarbonyl]-3-methylquinoxalin-4-oxide (3.8 9) as white powder.
M.p. 251-252C (decomposed) Example 9 2-[(6-Methoxymethoxy-3-methylbenzofuran-2-yl)methylamino -carbonyl]-3-methylquinoxalin-4-oxide (2.1 g) is dissolved in tetrahydrofuran (20ml) and methanol (20 ml), and to the mixture is added 6N hydrochloric acid (10 ml), and the mixture is refluxed for one hour. The mixture is evaporated to remove the solvent, and the residue is extracted with chloroform. The extract iswashed with saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated to remove the solvent, and the residue is recrystallized from dimethyl -formamide/water to give 2-[(6-hydroxy-3-methylbenzofuran-2-yl)methylamino -carbonyl]-3-methylquinoxalin-4-oxide (1.6 9) give as yellow needles.
M.p. 222-223C (decomposed) Example 10 2-[(4-Hydroxy-3-methylbenzofuran-2-yl)methylaminocarbonyl]-3-methylquinoxalin-4-oxide (0.55 9) is dissolved in dimethylformamide (4 ml), and to the mixture are added potassium carbonate (0.41 9) and methyl iodide (0.19 ml), and the mixture is stirred at 60C for four hours. To the mixture is added water, and the precipitated crystals are collected by filtration, and washed with water. The crude crystals are recrystallized from ethyl acetate/n -hexane to give 2-[(4-methoxy-3-methylbenzofuran-2-yl)methylaminocarbonyl] -3-methylquinoxalin-4-oxide (0.41 9) as yellow prisms.
M.p. 196-1 97C

WO 95/09159 PCI~1JP94/OlS59 2~S03 4~ - 298 -Example 1 1 2-[(Benzofuran-2-yl)methylaminocarbonyl]-3-methylquinoxalin-4 -oxide (0.8 9) is dissolved in chloroform (10 ml), and thereto is added N -bromosuccinimide (0.47 9), and the mixture is refluxed for 7 hours. The mixture 5 is evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 2: 1), and recrystallized from ethyl acetate/n-hexane to give 2-[(3-bromobenzofuran-2 -yl)methylaminocarbonyl]-3-methylquinoxalin-4-oxide (0.44 g) as colorless needles.
1 0 M.p. 170-171 C
Using the suitable starting compounds, there are obtained the compounds of Examples 31, 34, 38, 88, 93, 98, 119, 124, 125, 131 and 139 in the same manner as in Example 11.
Example 12 2-[(4-Methoxybenzyl)aminocarbonyl]-3-methylquinoxaline (10.5 g) is dissolved in dry methylene chloride (150 ml), and thereto is added dropwise a 1M solution of boron tribromide in methylene chloride (105 ml) under ice-cooling. The mixture is stirred at room temperature for two days, cooled, decomposed with methanol, and evaporated to remove the solvent. To the residue is added water, and the mixture is neutralized with sodium hydrogen carbonate, and the precipitated crystals are collected by filtration, washed with water, and dried. The residue is recrystallized from ethanol to give 2-[(4-hydroxybenzyl)aminocarbonyl]-3-methylquinoxaline (10.0 g) as colorless needles.
M.p. 21 1-21 4C
Example 13 2-{[5-(1 -Acetoxyethyl)benzofuran-2-yl]methylaminocarbonyl}-3 -methylquinoxalin-4-oxide (4.5 g) is dissolved in methanol (90 ml), and thereto is added potassium carbonate (1.8 9), and the mixture is stirred at room temperature overnight. The mixture is evaporated to remove the solvent, and to the residue is added water. The mixture is extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate. The mixture is evaporated to remove the solvent, and the crude crystals are recrystallized from - WO 95/09159 2 1 5 û 3 4 S PCT/JP94/01559 ethyl acetate/n-hexane to give 2-{[5-(1-hydroxyethyl)benzofuran-2-yl]methyl -aminocarbonyl}-3-methylquinoxalin-4-oxide (3.4 9) as colorless granules.
M.p. 112-114C
Example 14 - 5 2-{[5-(1-Hydroxyethyl)benzofuran-2-yl]methylaminocarbonyl}-3-methylquinoxalin-4-oxide (0.8 9) is dissolved in chloroform (30 ml), and theretois added manganese dioxide (3.6 9), and the mixture is refluxed for 6 hours.
The reaction solution is filtered through celite, and concentrated. The residue is recrystallized from ethyl acetate/n-hexane to give 2-[(5-acetylbenzofuran-2 -yl)methylaminocarbonyl]-3-methylquinoxalin-4-oxide (0.5 9) as pale yellow granules.
M.p. 205-206C
Example 15 2-[(5-Acetylbenzofuran-2-yl)methylaminocarbonyl]-3 -methylquinoxalin-4-oxide (0.7 9) is dissolved in anhydrous tetrahydrofuran (20 ml), and thereto is added dropwise a 1 M solution of methylmagnesium bromide in diethyl ether (2.5 ml) under ice-cooling. The mixture is stirred at room temperature for three hours, and poured into ice-aqueous ammonium chloride solution. The mixture is extracted with chloroform, and the extract is washed with water and brine, and dried over anhydrous sodium sulfate. The resultant is evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 1: 1), and recrystallized from n-hexane/ethyl acetate to give 2-{[5-(1-hydroxy-1 -methylethyl)benzofuran-2-yl]methylaminocarbonyl}-3-methylquinoxalin-4-oxide (0.1 9) as pale yellow prisms.
- M.p. 147-1 50C
Example 16 2-{[5-(5-Tetrazolyl)benzofuran-2-yl]methylaminocarbonyl}-3 -methylquinoxalin-4-oxide (1.4 9) is dissolved in dimethylformamide (15 ml), and thereto are added potassium carbonate (0.97 9) and methyl iodide (0.44 9), and the mixture is stirred at room temperature for four hours. The reaction solution is poured into ice-water, and the precipitated crystals are collected by filtration, and recrystallized from dimethylformamide/ethanol to give 2-{[5-(2-2~so34~

methyl-5-tetrazolyl)benzofuran-2-yl]methylaminocarbonyl}-3-methylquinoxalin -4-oxide (0.48 9) as white powder.
M.p. 206-209C
Using the suitable starting compounds, there are obtained the compounds of Examples 36 and 161-164 in the same manner as in Example 16.
Example 17 2-[(4-Methoxycarbonylmethoxybenzyl)aminocarbonyl]-3 -methylquinoxaline (3.65 9) is dissolved in methanol (50 ml), and thereto is added 2N sodium hydroxide (6 ml), and the mixture is stirred at room temperature for two hours. The mixture is evaporated to remove the solvent, and to the resultant is added water. The mixture is acidified with hydrochloric acid, and the precipitated crystals are collected by filtration, washed with water, and dried to give 2-[(4-carboxymethoxybenzyl)aminocarbonyl]-3-methyl -quinoxaline (3.40 9) as white powder.
1H-NMR (DMSO-d6) ~ ppm: 2.83 (3H, s), 4.48 (2H, d, J=6 Hz), 4.66 (2H, s), 6.91 (2H, d, J=9 Hz), 7.33 (2H, d, J=9 Hz), 7.8-8.0 (2H, m), 8.0-8.2 (2H, m), 9.33 (1 H, t, J=6 Hz) Using the suitable starting compounds, there is obtained the compound of Example 49 in the same manner as in Example 17.
Example 1 8 2-[(4-Carboxymethoxybenzyl)aminocarbonyl]-3 -methylquinoxaline (1.05 9) is dissolved in dimethylformamide (10 ml), and thereto is added furfurylamine (0.35 9), and thereto are added dropwise successively diethyl cyanophosphate (0.6 9) and triethylamine (0.6 9) under ice -cooling. The mixture is stirred at room temperature overnight, and poured into ice-water, and the precipitated crystals are collected by filtration. The crystals are recrystallized from acetone/n-hexane to give 2-[(4-furfurylaminocarbonyl -methoxybenzylaminocarbonyl]-3-methylquinoxaline (0.92 9) as white powder.
M.p. 175-1 76C
Example 19 2-[(4-Methoxycarbonylmethoxybenzyl)aminocarbonyl]-3-DEMANDES OU BREVETS VOLUMINEUX

LA PRÉSENTE PARTIE DE C~TTE DEMANDE OU CE BREVET
COMPREND PLUS D'UN TOME.

CECI EST LE TOME / DE_ ~

NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets ~ ~ S ~c~t5 JUMBO APPLICATIONS/PATENTS

THIS SECTION OF THE APPLlCATlON/PATENT CONTA1NS MORE
THAN ONE VOLUME

THIS IS VOLUME ¦ OF *~

NOTE: For additional volumes please contact the Canadian Patent Offic~

Claims

1. A quinoxaline derivative of the formula:

wherein R1 is hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, a lower alkyl group having optionally a halogen substituent, phenyl group, a morpholino-substituted lower alkyl group or an imidazolyl-substituted lower alkyl group, n is 0, m is 0 or 1, r is 1 or 2, R3 and R4 are the same or different and each a) hydrogen atom; b) a lower alkyl group; c) a phenyl-lower alkoxycarbonyl group; d) a lower alkanoyloxy-substituted lower alkyl group; e) a lower alkanoyl group; f) a loweralkoxycarbonyl group; g) a lower alkoxy-lower alkyl group; h) a phenoxy -carbonyl group; i) a lower alkanoyl-substituted lower alkyl group; j) a lower alkoxycarbonyloxy-substituted lower alkyl group; k) a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring; 1) a group of the formula: -E-N(R52)(R53) (in which R52 and R53 are the same or different and each hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or phenyl group, or R52 and R53 may combine together with the nitrogen atom to which they bond to form a 5 or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom, E is a lower alkylene group, a group of the formula: -CO-, or a group of the formula: -CO-A- (in which A is a lower alkylene group)); m) a group of the formula:

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); n) a group of the formula:

(in which A is the same as defined above, p is an integer of 1 to 3, R5 is a lower alkoxy-substituted lower alkoxy group, a lower alkoxy group, an amino group having optionally a lower alkyl substituent, a halogen atom, nitro group, hydroxy group, a lower alkyl group having optionally a hydroxy substituent, a lower alkenyloxy group, a carboxyl-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a lower alkoxycarbonyl group, a halogen-substituted lower alkoxy group, a hydroxy-substituted lower alkoxy group, a phenyl-lower alkoxy group having optionally a substituent selected from a lower alkyl group and a lower alkoxy group on the phenyl moiety, a 1,3 -dioxolanyl group having optionally a lower alkyl substituent, a lower alkanoyl group, a morpholino-substituted lower alkoxy group, a morpholino-substituted lower alkyl group, a morpholinocarbonyl group or a group of the formula:
-Y-A1-CONR6R7 (in which A1 is a lower alkylene group, Y is a group of the formula: -O- or a group of the formula: -NH-, R6 and R7 are the same or different and each hydrogen atom, a lower alkyl group having optionally a hydroxy substituent, a phenyl-lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, a furyl-substituted lower alkyl group, or a lower alkoxy-substituted lower alkyl group, or R6 and R7 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen atom or oxygen atom, said heterocyclic group having optionally 1 to 3 substituents selected from hydroxy group, a lower alkyl group and a phenyl -lower alkyl group)); o) a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula: -O-A4-CO-NR40R41 (in which A4 is a lower alkylene group, R40 and R41 are the same or different and each hydrogen atom or a lower alkyl group, or R40 and R41 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6 -membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety; p) an alkenyl group; q) a cycloalkyl-lower alkyl group; r) a naphthyl -lower alkyl group; s) a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety; t) a phenylsulfinyl -substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; u) a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; v) a phenoxy -substituted lower alkyl group; w) a group of the formula:

(in which q is an integer of 1 to 3, a group of the formula: is a lower alkyl group substituted by a 5- to 14-membered saturated or unsaturated heteromonocyclic, heterobicyclic or heterotricyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, R8 substitutes on the above heterocyclic group, and is hydrogen atom, oxo group, a lower alkyl group having optionally a hydroxy substituent, a halogen atom, nitro group, a lower alkoxy group, cyano group, a lower alkoxycarbonyl group, a phenyl-lower alkoxy group having optionally an amino group having optionally a lower alkanoyl substituent on the phenyl moiety, a carboxyl -substituted lower alkoxy group, carboxyl group, a lower alkoxycarbonyl-substituted lower alkoxy group, hydroxy group, a lower alkoxy-substituted lower alkoxy group, a lower alkenyloxy group, a lower alkanoyloxy-substituted lower alkyl group, a halogen-substituted lower alkyl group, a lower alkanoyl group, a phenyl group having optionally a substituent selected from a lower alkyl group, a lower alkoxy-substituted lower alkoxy group, hydroxy group, a halogen atom and a lower alkoxy group on the phenyl moiety, a lower alkenyl group, a morpholinocarbonyl-lower alkoxy group, a lower alkylsufinyl group, an amino -substituted lower alkyl group having optionally a substituent selected from a lower alkylsulfonyl group and a lower alkanoyl group, a lower alkylthio group, alower alkylsulfonyl group, a lower alkanoyloxy group, a 1,3-dioxolanyl -substituted lower alkyl group having optionally a lower alkyl substituent, a lower alkanoyl-substituted lower alkyl group, an aminocarbonyl-substituted lower alkyl group having optionally a lower alkyl substituent, a lower alkoxycarbonyl-substituted lower alkenyl group, an aminocarbonyl-substituted lower alkenyl group having optionally a lower alkyl substituent, a carboxyl -substituted lower alkenyl group, benzoyl group, a lower alkoxy-lower alkyl group, a group of the formula:

(in which s is an integer of 1 to 3, a group of the formula: is a 5- to 6 -membered saturated or unsaturated heterocyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, R45 bonds to said heterocyclic group and is hydrogen atom, a lower alkyl group, a lower alkoxy-substituted lower alkyl group, phenyl group or oxo group), a group of theformula:

(in which t is an integer of 1 to 3, a group of the formula: is a lower alkyl group substituted by a 5- to 6-membered saturated or unsaturated heterocyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, R46 bonds to said heterocyclic group and is hydrogen atom, a lower alkyl group or oxo group), or a group of the formula:
-(C=O)1NR9R10 (in which 1 is 0 or 1, R9 and R10 are the same or different and each hydrogen atom, a lower alkanoyl group, a lower alkyl group, a morpholinocarbonyl-lower alkyl group, a cycloalkylcarbonyl group, a phenyl -lower alkenylcarbonyl group, a lower alkylsulfonyl group, an aminocarbonyl group having optionally a lower alkyl substituent, a phenylsulfonyl group having optionally a lower alkyl substituent on the phenyl moiety, a phenyl-loweralkenyl group, a benzoyl group having optionally 1 to 3 substituents selected from a halogen atom, a lower alkoxy group, an amino group having optionally a lower alkanoyl substituent and hydroxy group on the phenyl moiety, an amino -substituted lower alkanoyl group having optionally a lower alkanoyl substituent,an amino-substituted sulfonyl group having optionally a lower alkyl substituent,a phenyl-lower alkyl group, phenyl group, or an amino group having optionally a lower alkanoyl substituent, or R9 and R10 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom)); x) a group of the formula: -A5-CR42R43R44 (in which A5 is a lower alkylene group, R42 and R43 combine together to form a group of the formula: =O, or =N-OH or a lower alkylenedioxy group, and R44 is a phenyl group having optionally a lower alkoxy substituent on the phenyl moiety); y) a 2,3-dihydro-1 H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1H-indenyl ring; or z)a group of the formula:

(in which u is an integer of 1 to 3, a group of the formula: is a lower alkenyl group substituted by a 5- to 14-membered saturated or unsaturated, heteromonocyclic, heterobicyclic or heterotricyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, R47 bonds on said heterocyclic group and is hydrogen atom, a halogen-substituted lower alkyl group, oxo group, a halogen atom, a lower alkoxy group, a lower alkyl group, a lower alkoxycarbonyl group, carboxyl group, an aminocarbonyl group having optionally a lower alkyl substituent, an amino group having optionally a lower alkanoyl substituent, a phenyl group having optionally a substituent selected from a lower alkoxy group and a halogen atom on the phenyl moiety, or a group of the formula:

(in which , R45 and s are the same as defined above)), or R3 and R4 may combine together with the adjacent nitrogen atom to which they bond to form 1,2,3,4-tetrahydroisoquinolyl group, said heterocyclic group having optionally a lower alkoxy substituent, provided that when R1 is hydrogen atom, R2 is methyl group, R3 is hydrogen atom, and m is 0, then R4 is not 2-(imidazol-2-yl)ethyl, 2-(indol-3 -yl)ethyl, or sec-butyl, or a salt thereof.
2. A quinoxaline derivative according to claim 1, wherein m is 1, or a salt thereof.
3. A quinoxaline derivative according to claim 1, wherein m is 0, or a salt thereof.
4. A quinoxaline derivative according to claim 1, wherein R1 is hydrogen atom, or a salt thereof.
5. A quinoxaline derivative according to claim 1, wherein R1 is a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent, or a salt thereof.

6. A quinoxaline derivative according to claim 4, wherein R2 is a lower alkyl group having optionally a halogen substituent, or a salt thereof.
7. A quinoxaline derivative according to claim 4, wherein R2 is hydrogen atom, phenyl group, a morpholino-substituted lower alkyl group or an imidazolyl-substituted lower alkyl group, or a salt thereof.
8. A quinoxaline derivative according to claim 5, wherein R2 is a lower alkyl group having optionally a halogen substituent, or a salt thereof.
9. A quinoxaline derivative according to claim 5, wherein R2 is hydrogen atom, phenyl group, a morpholino-substituted lower alkyl group or an imidazolyl-substituted lower alkyl group, or a salt thereof.
10. A quinoxaline derivative according to claim 6, wherein R3 is hydrogen atom, a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, or a lower alkoxycarbonyloxy-substituted lower alkyl group; and R4 is a group of the formula:

(wherein the group , R3 and q are as defined in claim 1), or a group of the formula:

(wherein the group , R47 and u are as defined in claim 1), or a salt thereof.
11. A quinoxaline derivative according to claim 6, wherein R3 is hydrogen atom, a lower alkyl group, a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, or a lower alkoxycarbonyloxy-substituted lower alkyl group; and R4 is a group of the formula:

(in which A, R5 and p are as defined in claim 1); a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula:
-O-A4-CO-NR40R41 (in which A4 is a lower alkylene group, R40 and R41 are the same or different and each hydrogen atom or a lower alkyl group, or R40 and R41 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety; an alkenyl group; a cycloalkyl-lower alkyl group; a naphthyl-lower alkyl group; a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety; a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; a phenylsulfonyl-substituted lower alkyl grouphaving optionally a lower alkoxy substituent on the phenyl moiety; a phenoxy -substituted lower alkyl group; a group of the formula: -A5-CR42R43R44 (in which A5 is a lower alkylene group, R42 and R43 combine together to form a group of the formula: =O, or =N-OH or a lower alkylenedioxy group, and R44 is a phenyl group having optionally a lower alkoxy substituent on the phenyl moiety); a 2,3 dihydro-1 H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1H-indenyl ring, or a salt thereof.12. A quinoxaline derivative according to claim 6, wherein R3 is a phenyl-lower alkoxycarbonyl group; a lower alkanoyl group; a lower alkoxy -lower alkyl group; a phenoxycarbonyl group; a lower alkanoyl-substituted lower alkyl group; a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring; a group of the formula: -E-N(R52)(R53) (in which R52 and R53 are the same or different and each hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or phenyl group, or R52 and R53 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom, E is a lower alkylene group, a group of the formula: -CO-, or a group of the formula: -CO-A- (in whichA is a lower alkylene group)); or a group of the formula:

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above), and R4 is a group of the formula:

(in which A, R5 and p are as defined in claim 1 ); a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula:
-O-A4-CO-NR40R41 (in which A4 is a lower alkylene group, R40 and R41 are the same or different and each hydrogen atom or a lower alkyl group, or R40 and R41 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety; alkenyl group; a cycloalkyl-lower alkyl group;a naphthyl-lower alkyl group; a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety; a phenylsulfinyl -substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; a phenoxy -substituted lower alkyl group; a group of the formula:

(in which the group , R8 and q are as defined in claim 1 ); a group of the formula: -A5-CR42R43R44 (in which A5 is a lower alkylene group, R42 and R43 combine together to form a group of the formula: =O, or =N-OH or a lower alkylenedioxy group, and R44 is a phenyl group having optionally a lower alkoxy substituent on the phenyl moiety); a 2,3-dihydro-1H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3 -dihydro-1H-indenyl ring; or a group of the formula:

(in which the group , R47 and u are as defined in claim 1), or a salt thereof.
13. A quinoxaline derivative according to claim 6, wherein R3 and R4 combine together with the adjacent nitrogen atom to which they bond to form 1,2,3,4-tetrahydroisoquinolyl group, said heterocyclic group having optionally a lower alkoxy substituent, or a salt thereof.
14. A quinoxaline derivative according to claim 7, wherein R3 is hydrogen atom, a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, or a lower alkoxycarbonyloxy-substituted lower alkyl group; and R4 is a group of the formula:

(wherein the group , R8 and q are as defined in claim 1), or a group of the formula:

(wherein the group , R47 and u are as defined in claim 1), or a salt thereof.
15. A quinoxaline derivative according to claim 7, wherein R3 is hydrogen atom, a lower alkyl group, a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, or a lower alkoxycarbonyloxy-substituted lower alkyl group; and R4 is a group of the formula:

(in which A, R5 and p are as defined in claim 1 ); a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula:
-O-A4-CO-NR40R41 (in which A4 is a lower alkylene group, R40 and R41 are the same or different and each hydrogen atom or a lower alkyl group, or R40 and R41 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety; an alkenyl group; a cycloalkyl-lower alkyl group; a naphthyl-lower alkyl group; a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety; a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; a phenylsulfonyl-substituted lower alkyl grouphaving optionally a lower alkoxy substituent on the phenyl moiety; a phenoxy -substituted lower alkyl group; a group of the formula: -A5-CR42R43R44 (in which A5 is a lower alkylene group, R42 and R43 combine together to form a group of the formula: =O, or =N-OH or a lower alkylenedioxy group, and R44 is a phenyl group having optionally a lower alkoxy substituent on the phenyl moiety); or a 2,3-dihydro-1H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1H-indenyl ring, or a salt thereof.
16. A quinoxaline derivative according to claim 7, wherein R3 is a phenyl-lower alkoxycarbonyl group; a lower alkanoyl group; a lower alkoxy -lower alkyl group; a phenoxycarbonyl group; a lower alkanoyl-substituted lower alkyl group; a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring; a group of the formula: -E-N(R52)(R53) (in which R52 and R53 are the same or different and each hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or phenyl group, or R52 and R53 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom, E is a lower alkylene group, a group of the formula: -CO-, or a group of the formula: -CO-A- (in whichA is a lower alkylene group)); or a group of the formula:

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above), and R4 is a group of the formula:

(in which A, R5 and p are as defined in claim 1 ); a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula:
-O-A4-CO-NR40R41 (in which A4 is a lower alkylene group, R40 and R41 are the same or different and each hydrogen atom or a lower alkyl group, or R40 and R41 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety; alkenyl group; a cycloalkyl-lower alkyl group;a naphthyl-lower alkyl group; a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety; a phenylsulfinyl -substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; a phenoxy -substituted lower alkyl group; a group of the formula:

(in which the group , R3 and q are as defined in claim 1); a group of the formula: -A5-CR42R43R44 (in which A5 is a lower alkylene group, R42 and R43 combine together to form a group of the formula: =O, or =N-OH or a lower alkylenedioxy group, and R44 is a phenyl group having optionally a lower alkoxy substituent on the phenyl moiety); a 2,3-dihydro-1H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3 -dihydro-1H-indenyl ring; or a group of the formula:

(in which the group , R47 and u are as defined in claim 1), or a salt thereof.
17. A quinoxaline derivative according to claim 7, wherein R3 and R4 combine together with the adjacent nitrogen atom to which they bond to form 1,2,3,4-tetrahydroisoquinolyl group, said heterocyclic group having optionally a lower alkoxy substituent, or a salt thereof.
18. A quinoxaline derivative according to claim 8, wherein R3 is hydrogen atom, a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, or a lower alkoxycarbonyloxy-substituted lower alkyl group; and R4 is a group of the formula:

(wherein the group , R3 and q are as defined in claim 1), or a group of the formula:

(wherein the group , R47 and u are as defined in claim 1), or a salt thereof.
19. A quinoxaline derivative according to claim 8, wherein R3 is hydrogen atom, a lower alkyl group, a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, or a lower alkoxycarbonyloxy-substituted lower alkyl group; and R4 is a group of the formula:

(in which A, R5 and p are as defined in claim 1); a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula:
-O-A4-CO-NR40R41 (in which A4 is a lower alkylene group, R40 and R41 are the same or different and each hydrogen atom or a lower alkyl group, or R40 and R41 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety; an alkenyl group; a cycloalkyl-lower alkyl group; a naphthyl-lower alkyl group; a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety; a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; a phenylsulfonyl-substituted lower alkyl grouphaving optionally a lower alkoxy substituent on the phenyl moiety; a phenoxy -substituted lower alkyl group; a group of the formula: -A5-CR42R43R44 (in which A5 is a lower alkylene group, R42 and R43 combine together to form a group of the formula: =O, or =N-OH or a lower alkylenedioxy group, and R44 is a phenyl group having optionally a lower alkoxy substituent on the phenyl moiety); or a 2,3-dihydro-1H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1H-indenyl ring, or a salt thereof.
20. A quinoxaline derivative according to claim 8, wherein R3 is a phenyl-lower alkoxycarbonyl group; a lower alkanoyl group; a lower alkoxy -lower alkyl group; a phenoxycarbonyl group; a lower alkanoyl-substituted lower alkyl group; a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring; a group of the formula: -E-N(R52)(R53) (in which R52 and R53 are the same or different and each hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or phenyl group, or R52 and R53 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom, E is a lower alkylene group, a group of the formula: -CO- , or a group of the formula: -CO-A- (in whichA is a lower alkylene group)); or a group of the formula:

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above), and R4 is a group of the formula:

(in which A, R5 and p are as defined in claim 1 ); a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula:
-O-A4-CO-NR40R41 (in which A4 is a lower alkylene group, R40 and R41 are the same or different and each hydrogen atom or a lower alkyl group, or R40 and R41 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety; alkenyl group; a cycloalkyl-lower alkyl group;a naphthyl-lower alkyl group; a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety; a phenylsulfinyl -substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; a phenoxy -substituted lower alkyl group; a group of the formula:

(in which the group , R8 and q are as defined in claim 1 ); a group of the formula: -A5-CR42R43R44 (in which A5 is a lower alkylene group, R42 and R43 combine together to form a group of the formula: =O, or =N-OH or a lower alkylenedioxy group, and R44 is a phenyl group having optionally a lower alkoxy substituent on the phenyl moiety); a 2,3-dihydro-1H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3 -dihydro-1H-indenyl ring; or a group of the formula:

(in which the group , R47 and u are as defined in claim 1), or a salt thereof.
21. A quinoxaline derivative according to claim 8, wherein R3 and R4 combine together with the adjacent nitrogen atom to which they bond to form 1,2,3,4-tetrahydroisoquinolyl group, said heterocyclic group having optionally a lower alkoxy substituent, or a salt thereof.
22. A quinoxaline derivative according to claim 9, wherein R3 is hydrogen atom, a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, or a lower alkoxycarbonyloxy-substituted lower alkyl group; and R4 is a group of the formula:

(wherein the group , R8 and q are as defined in claim 1), or a group of the formula:

(wherein the group , R47 and u are as defined in claim 1), or a salt thereof.
23. A quinoxaline derivative according to claim 9, wherein R3 is hydrogen atom, a lower alkyl group, a lower alkanoyloxy-substituted lower alkyl group, a lower alkoxycarbonyl group, or a lower alkoxycarbonyloxy-substituted lower alkyl group; and R4 is a group of the formula:

(in which A, R5 and p are as defined in claim 1); a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula:
-O-A4-CO-NR40R41 (in which A4 is a lower alkylene group, R40 and R41 are the same or different and each hydrogen atom or a lower alkyl group, or R40 and R41 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety; an alkenyl group; a cycloalkyl-lower alkyl group; a naphthyl-lower alkyl group; a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety; a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; a phenylsulfonyl-substituted lower alkyl grouphaving optionally a lower alkoxy substituent on the phenyl moiety; a phenoxy -substituted lower alkyl group; a group of the formula: -A5-CR42R43R44 (in which A5 is a lower alkylene group, R42 and R43 combine together to form a group of the formula: =O, or =N-OH or a lower alkylenedioxy group, and R44 is a phenyl group having optionally a lower alkoxy substituent on the phenyl moiety); or a 2,3-dihydro-1H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1H-indenyl ring, or a salt thereof.24. A quinoxaline derivative according to claim 9, wherein R3 is a phenyl-lower alkoxycarbonyl group; a lower alkanoyl group; a lower alkoxy -lower alkyl group; a phenoxycarbonyl group; a lower alkanoyl-substituted lower alkyl group; a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring; a group of the formula: -E-N(R52)(R53) (in which R52 and R53 are the same or different and each hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or phenyl group, or R52 and R53 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom, E is a lower alkylene group, a group of the formula: -CO-, or a group of the formula: -CO-A- (in whichA is a lower alkylene group)); or a group of the formula:

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above), and R4 is a group of the formula:

(in which A, R5 and p are as defined in claim 1); a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula:

-O-A4-CO-NR40R41 (in which A4 is a lower alkylene group, R40 and R41 are the same or different and each hydrogen atom or a lower alkyl group, or R40 and R41 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety; alkenyl group; a cycloalkyl-lower alkyl group;a naphthyl-lower alkyl group; a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety; a phenylsulfinyl -substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; a phenoxy -substituted lower alkyl group; a group of the formula:

(in which the group , R3 and q are as defined in claim 1); a group of the formula: -A5-CR42R43R44 (in which A5 is a lower alkylene group, R42 and R43 combine together to form a group of the formula: =O, or =N-OH or a lower alkylenedioxy group, and R44 is a phenyl group having optionally a lower alkoxy substituent on the phenyl moiety); a 2,3-dihydro-1H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3 -dihydro-1H-indenyl ring; or a group of the formula:

(in which the group , R47 and u are as defined in claim 1), or a salt thereof.
25. A quinoxaline derivative according to claim 9, wherein R3 and R4 combine together with the adjacent nitrogen atom to which they bond to form 1,2,3,4-tetrahydroisoquinolyl group, said heterocyclic group having optionally a lower alkoxy substituent, or a salt thereof.
26. A quinoxaline derivative according to claim 10, wherein the saturated or unsaturated heterocyclic group in the lower alkyl group substitutedby a 5- to 14-membered saturated or unsaturated heterocyclic groups represented by the group of in the group of the formula:

is a member selected from the group consisting of benzofuryl, benzothienyl, indolyl, 2,3-dihydrobenzofuryl, perhydrobenzofuryl, quinolyl, benzimidazolyl, benzothiazolyl, imidazo[1,2-a]pyridyl, 1,4-benzodioxanyl, furo[3,2-c]pyridyl, 1,2,3,4-tetrahydrofuro[2,3-g]quinolyl, furo[2,3-g]quinolyl, 3,4-dihydrofuro[2,3-g]quinolyl, thiazolyl, pyridyl, furyl, imidazolyl, 1,2,3,4-tetrazolyl, and oxazolyl, or a salt thereof.
27. A quinoxaline derivative according to claim 26, wherein the saturated or unsaturated heterocyclic group in the lower alkyl group substitutedby a 5- to 14-membered saturated or unsaturated heterocyclic groups represented by the group of is benzofuryl or oxazolyl, or a salt thereof.
28. A quinoxaline derivative according to claim 10, wherein the saturated or unsaturated heterocyclic group in the lower alkenyl group substituted by a 5- to 14-membered saturated or unsaturated heterocyclic groups represented by the group of in the group of the formula:

is a member selected from the group consisting of benzofuryl, benzothienyl, carbostyril, 3,4-dihydrocarbostyril, benzothienyl, furo[3,2-c]pyridyl, furo[2,3-g] -quinolyl, 3,4-dihydrofuro[2,3-g]quinolyl, 1,2,3,4-tetrahydrofuro[2,3-g]quinolyl,naphtho[2,1-b]furyl, and oxazolyl, or a salt thereof.
29. A quinoxaline derivative according to claim 28, wherein the saturated or unsaturated heterocyclic group in the lower alkenyl group substituted by a 5- to 14-membered saturated or unsaturated heterocyclic groups represented by the group of is benzofuryl, or a salt thereof.

30. A quinoxaline derivative according to claim 1, which is a member selected from the group consisting of 2-[3-(benzofuran-2-yl)-2 -butenylaminocarbonyl]-3-methylquinoxalin-4-oxide, 2-[(3-methyl-7-trifluoro-methylbenzofuran-2-yl)methylaminocarbonyl]-3-methylquinoxalin-4-oxide, 2-[(2-phenyl-5-methyloxazol-4-yl)methylaminocarbonyl]-3-methylquinoxalin-4 -oxide, 2-{[5-(2,5-dimethylthiazol-4-yl)benzofuran-3-yl]methylaminocarbonyl}-3-methylquinoxalin-4-oxide, 2-{3-[5-(2-methyl-1,2,3,4-tetrazol-5-yl)benzofuran-2-yl]-2-butenylaminocarbonyl}-3-methylquinoxalin-4-oxide, 2-[5-(benzofuran-2-yl)-2,4-hexadienylaminocarbonyl]-3-methylquinoxalin-4-oxide, 2-{3-[5-(2,5-dimethylthiazol-4-yl)benzofuran-2-yl]-2-butenylaminocarbonyl}-3-methyl -quinoxalin-4-oxide, 2-{3-[5-(thiazol-2-yl)benzofuran-2-yl]-2-butenylamino-carbonyl}-3-methylquinoxalin-4-oxide, 2-[3-(5,7-difluorobenzofuran-2-yl)-2-butenylaminocarbonyl]-3-methylquinoxalin-4-oxide, 2-{N-[3-(benzofuran-2-yl)-2-butenyl]-N-methoxycarbonylaminocarbonyl}-3-methylquinoxalin-4-oxide, 2-{N-[3-(benzofuran-2-yl)-2-butenyl]-N-propanoyloxymethylaminocarbonyl}-3 -methylquinoxalin-4-oxide, 2-{N-[3-(benzofuran-3-yl)-2-butenyl]-N-acetyloxy-methylaminocarbonyl}-3-methylquinoxalin-4-oxide, 2-{N-[3-(benzofuran-2-yl)-2-butenyl]-N-ethoxycarbonyloxymethylaminocarbonyl}-3-methylquinoxalin-4 -oxide, 2-{N-[3-methyl-7-trifluoromethylbenzofuran-2-yl)methyl]-N-acetoxy -methylaminocarbonyl}-3-methylquinoxalin-4-oxide, and 2-{N-[2-phenyl-5 -methyloxazol-4-yl)methyl]-N-acetoxymethylaminocarbonyl}-3-methylquinoxalin -4-oxide, or a salt thereof.
31. An antidiabetic agent which comprises as an active ingredient a compound as set forth in claim 1.

32. An antidiabetic agent which comprises as an active ingredient a quinoxaline derivative of the formula:

wherein R1 is hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group having optionally a lower alkyl substituent, or an aminocarbonyl group having optionally a lower alkyl substituent, R2 is hydrogen atom, a lower alkyl group having optionally a halogen substituent, phenyl group, a morpholino-substituted lower alkyl group or an imidazolyl-substituted lower alkyl group, n and m are each 0 or 1, r is 1 or 2, R3 and R4 are the same or different and each a) hydrogen atom; b) a lower alkyl group; c) a phenyl-lower alkoxycarbonyl group; d) a lower alkanoyloxy-substituted lower alkyl group; e) a lower alkanoyl group; f) a loweralkoxycarbonyl group; g) a lower alkoxy-lower alkyl group; h) a phenoxy -carbonyl group; i) a lower alkanoyl-substituted lower alkyl group; j) a lower alkoxycarbonyloxy-substituted lower alkyl group; k) a benzoyl-substituted lower alkyl group having optionally a halogen substituent on the phenyl ring; 1) a group of the formula: -E-N(R52)(R53) (in which R52 and R53 are the same or different and each hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or phenyl group, or R52 and R53 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom, E is a lower alkylene group, a group of the formula: -CO-, or a group of the formula: -CO-A- (in which A is a lower alkylene group)); m) a group of the formula:

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); n) a group of the formula:

(in which A is the same as defined above, p is an integer of 1 to 3, R5 is hydrogen atom, a lower alkoxy-substituted lower alkoxy group, a lower alkoxy group, an amino group having optionally a lower alkyl substituent, a halogen atom, nitro group, hydroxy group, a lower alkyl group having optionally a hydroxy substituent, a lower alkenyloxy group, a carboxyl-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a lower alkoxycarbonyl group, a halogen-substituted lower alkoxy group, a hydroxy -substituted lower alkoxy group, a phenyl-lower alkoxy group having optionally a substituent selected from a lower alkyl group and a lower alkoxy group on the phenyl moiety, a 1,3-dioxolanyl group having optionally a lower alkyl substituent, a lower alkanoyl group, a morpholino-substituted lower alkoxy group, a morpholino-substituted lower alkyl group, a morpholinocarbonyl group or a group of the formula: -Y-A1-CONR6R7 (in which A1 is a lower alkylene group, Y is a group of the formula: -O- or a group of the formula: -NH-, R6 and R7 are the same or different and each hydrogen atom, a lower alkyl group having optionally a hydroxy substituent, a phenyl-lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, a furyl-substituted lower alkyl group, or a lower alkoxy-substituted lower alkyl group, or R6 and R7may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen atom or oxygen atom, said heterocyclic group having optionally 1 to 3 substituents selected from hydroxy group, a lower alkyl group and a phenyl-lower alkyl group)); o) a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy-substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula:
-O-A4-CO-NR40R41 (in which A4 is a lower alkylene group, R40 and R41 are the same or different and each hydrogen atom or a lower alkyl group, or R40 and R41 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety; p) an alkenyl group; q) a cycloalkyl-lower alkyl group; r) a naphthyl-lower alkyl group; s) a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety; t) a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; u) a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; v) a phenoxy-substituted lower alkyl group; w) a group of the formula:

(in which q is an integer of 1 to 3, a group of the formula: is a lower alkyl group substituted by a 5- to 14-membered saturated or unsaturated heteromonocyclic, heterobicyclic or heterotricyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, R8 substitutes on the above heterocyclic group, and is hydrogen atom, oxo group, a lower alkyl group having optionally a hydroxy substituent, a halogen atom, nitro group, a lower alkoxy group, cyano group, a lower alkoxycarbonyl group, a phenyl-lower alkoxy group having optionally an amino group having optionally a lower alkanoyl substituent on the phenyl moiety, a carboxyl -substituted lower alkoxy group, carboxyl group, a lower alkoxycarbonyl -substituted lower alkoxy group, hydroxy group, a lower alkoxy-substituted lower alkoxy group, a lower alkenyloxy group, a lower alkanoyloxy-substituted lower alkyl group, a halogen-substituted lower alkyl group, a lower alkanoyl group, a phenyl group having optionally a substituent selected from a lower alkyl group, a lower alkoxy-substituted lower alkoxy group, hydroxy group, a halogen atom and a lower alkoxy group on the phenyl moiety, a lower alkenyl group, a morpholinocarbonyl-lower alkoxy group, a lower alkylsufinyl group, an amino -substituted lower alkyl group having optionally a substituent selected from a lower alkylsulfonyl group and a lower alkanoyl group, a lower alkylthio group, alower alkylsulfonyl group, a lower alkanoyloxy group, a 1,3-dioxolanyl -substituted lower alkyl group having optionally a lower alkyl substituent, a lower alkanoyl-substituted lower alkyl group, an aminocarbonyl-substituted lower alkyl group having optionally a lower alkyl substituent, a lower alkoxy -carbonyl-substituted lower alkenyl group, an aminocarbonyl-substituted lower alkenyl group having optionally a lower alkyl substituent, a carboxyl-substituted lower alkenyl group, benzoyl group, a lower alkoxy-lower alkyl group, a group of the formula:

(in which s is an integer of 1 to 3, a group of the formula: is a 5- to 6 -membered saturated or unsaturated heterocyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, R45 bonds to said heterocyclic group and is hydrogen atom, a lower alkyl group, a lower alkoxy-substituted lower alkyl group, phenyl group or oxo group), a group of theformula:

(in which t is an integer of 1 to 3, a group of the formula: is a lower alkyl group substituted by a 5- to 6-membered saturated or unsaturated heterocyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, R45 bonds to said heterocyclic group and is hydrogen atom, a lower alkyl group or oxo group), or a group of the formula:
-(C=O)1NR9R10 (in which I is 0 or 1, R9 and R10 are the same or different and each hydrogen atom, a lower alkanoyl group, a lower alkyl group, a morpholinocarbonyl-lower alkyl group, a cycloalkylcarbonyl group, a phenyl -lower alkenylcarbonyl group, a lower alkylsulfonyl group, an aminocarbonyl group having optionally a lower alkyl substituent, a phenylsulfonyl group having optionally a lower alkyl substituent on the phenyl moiety, a phenyl-loweralkenyl group, a benzoyl group having optionally 1 to 3 substituents selected from a halogen atom, a lower alkoxy group, an amino group having optionally a lower alkanoyl substituent and hydroxy group on the phenyl moiety, an amino -substituted lower alkanoyl group having optionally a lower alkanoyl substituent,an amino-substituted sulfonyl group having optionally a lower alkyl substituent,a phenyl-lower alkyl group, phenyl group, or an amino group having optionally a lower alkanoyl substituent, or R9 and R10 may combine together with the adjacent nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom)); x) a group of the formula: -A5-CR42R43R44 (in which A5 is a lower alkylene group, R42 and R43 combine together to form a group of the formula: =O, or =N-OH or a lower alkylenedioxy group, and R44 is a phenyl group having optionally a lower alkoxy substituent on the phenyl moiety); y) a 2,3-dihydro-1H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1H-indenyl ring; or z)a group of the formula:

(in which u is an integer of 1 to 3, a group of the formula: is a lower alkenyl group substituted by a 5- to 14-membered saturated or unsaturated, heteromonocyclic, heterobicyclic or heterotricyclic group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, R47 bonds on said heterocyclic group and is hydrogen atom, a halogen-substituted lower alkyl group, oxo group, a halogen atom, a lower alkoxy group, a lower alkyl group, a lower alkoxycarbonyl group, carboxyl group, an aminocarbonyl group having optionally a lower alkyl substituent, an amino group having optionally a lower alkanoyl substituent, a phenyl group having optionally a substituent selected from a lower alkoxy group and a halogen atom on the phenyl moiety, or a group of the formula:

(in which agroup of the formula: , R45 and s are the same as defined above)), or R3 and R4 may combine together with the adjacent nitrogen atom to which they bond to form 1,2,3,4-tetrahydroisoquinolyl group, said heterocyclic group having optionally a lower alkoxy substituent, or a pharmaceutically acceptable salt thereof.
33. A process for preparing a quinoxaline derivative as set forth in claim 1, which comprises (a) reacting a quinoxaline compound of the formula:

(wherein R1, R2, m, n, and r are as defined in claim 1 ) or a reactive derivative thereof with an amine of the formula: HNR3R4 (wherein R3 and R4 are as defined in claim 1), (b) reacting a quinoxaline compound of the formula:

(1a) (wherein R3a is hydrogen atom; a lower alkyl group; a phenyl-lower alkoxycarbonyl group; a lower alkanoyloxy-substituted lower alkyl group; a lower alkanoyl group; a lower alkoxycarbonyl group; a lower alkoxy-lower alkyl group; a phenoxycarbonyl group; a lower alkanoyl-substituted lower alkyl group; a lower alkoxycarbonyloxy-substituted lower alkyl group; a benzoyl -substituted lower alkyl group having optionally a halogen substituent on the phenyl ring; a group of the formula: -E-N(R52)(R53) (in which R52 and R53 are the same or different and each hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or phenyl group, or R52 and R53 may combine together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with another nitrogen atom or oxygen atom, E is a lower alkylene group, a group of the formula: -CO-, or a group of the formula: -CO-A- (in which A is a lower alkylenegroup)); a group of the formula:

(in which R54 is hydrogen atom or a lower alkyl group and A is the same as defined above); a group of the formula:

(wherein A, R5 and p are as defined in claim 1); a phenyl-lower alkenyl group having optionally a substituent selected from a lower alkoxy group, a halogen atom, an amino group having optionally a substituent selected from a lower alkanoyl group and a phenyl-lower alkenylcarbonyl group, a lower alkoxy -substituted lower alkoxy group, a tetrazolyl group having optionally a lower alkyl substituent on the tetrazole moiety, hydroxy group, a group of the formula:
-O-A4-CO-NR40R41 (in which A4, R40 and R41 are as defined in claim 1), a lower alkenyloxy group, nitro group and a lower alkyl group having optionally a halogen substituent on the phenyl moiety; an alkenyl group; a cycloalkyl-lower alkyl group; a naphthyl-lower alkyl group; a phenylthio-substituted lower alkyl group having optionally a lower alkoxy-substituent on the phenyl moiety; a phenylsulfinyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety; a phenylsulfonyl-substituted lower alkyl grouphaving optionally a lower alkoxy substituent on the phenyl moiety; a phenoxy -substituted lower alkyl group; a group of the formula:

(in which . R8 and q are as defined in claim 1); a group of the formula:
-A5-CR42R43R44 (in which A5, R42, R43, and R44 are as defined in claim 1); a 2,3-dihydro-1H-indenyl-substituted lower alkyl group having optionally a substituent selected from oxo group, hydroxy group and a silyloxy group having a lower alkyl substituent on the 2,3-dihydro-1H-indenyl ring; or a group of the formula:

(in which , R47 and u are as defined in claim 1), and R1, R2, m, n, and r are as defined in claim 1) with a compound of the formula: R3bX or R3cCOR3d (wherein R3b is the same as R3a other than hydrogen atom, and R3c and R3d are each hydrogen atom or a lower alkyl group), to give a quinoxaline compound of the formula:

(1b) (wherein R1, R2, m, n, and r are as defined in claim 1, and R3a and R3b are as defined above), c) oxidizing a quinoxaline compound of the formula:

(1c) (wherein R1, R2, R3, R4, n, and r are as defined in claim 1) with an oxidizing agent to convert into a compound of the formula:

(1d) (wherein R1, R2, R3, R4, n, and r are as defined in claim 1), d) oxidizing a quinoxaline compound of the formula:

(1N) (wherein R26 is a phenylthio-substituted lower alkoxy group having optionally a lower alkoxy substituent on the phenyl moiety, R1, R2, m, n, and r are as defined in claim 1, and R3a is as defined above) with an oxidizing agent to convert into a compound of the formula:

(1O) (wherein R27 is a phenylsulfinyl-substituted lower alkyl group having optionallya lower alkoxy substituent on the phenyl moiety, R1, R2, m, n, and r are as defined in claim 1, and R3a is as defined above), and further to convert into a compound of the formula:

(1P) (wherein R23 is a phenylsulfonyl-substituted lower alkyl group having optionally a lower alkoxy substituent on the phenyl moiety, R1, R2, m, n, and r are as defined in claim 1, and R3a is as defined above), e) oxidizing a quinoxaline compound of the formula:

(1N) (wherein R1, R2, m, n, and r are as defined in claim 1, and R3a and R26 are as defined above) with an oxidizing agent to convert into a compound of the formula:

(1P) (wherein R1, R2, m, n, and r are as defined in claim 1, and R3a and R23 are as defined above), or f) reacting a quinoxaline compound of the formula:

(1a) (wherein R1, R2, m, n, and r are as defined in claim 1, and R3a is as defined above) with a compound of the formula: R3cOH (in which R3c is as defined above) to give a compound of the formula:

(1Y) (wherein R1, R2, m, n, and r are as defined in claim 1, and R3a is as defined above, and R3c' is a phenyl-lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a phenoxycarbonyl group, or a group of the formula: -CO-A-NR52R53 (in which A, R52, R53 are the same as defined above).
CA002150345A 1993-09-28 1994-09-22 Quinoxaline derivative as antidiabetic agent Abandoned CA2150345A1 (en)

Applications Claiming Priority (4)

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JP24114093 1993-09-28
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AU674613B2 (en) 1997-01-02
WO1995009159A1 (en) 1995-04-06
KR100196356B1 (en) 1999-06-15
TW284760B (en) 1996-09-01
KR950704269A (en) 1995-11-17
AU7666094A (en) 1995-04-18
EP0670831A1 (en) 1995-09-13

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