AU2003204342B8 - Piperazine derivatives and process for the preparation thereof - Google Patents

Description

Our Ref:7823543 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Samjin Pharmaceutical Co., Ltd.

338-8, Seokyo-dong Mapo-ku Seoul 121-739 Republic of Korea (South) Address for Service: DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Invention Title: Piperazine derivatives and process for the preparation thereof The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 P:\WPDOCS\CAB\SPECI\7823543.doc-22/05/03 -1- Piperazine derivatives and process for the preparation thereof This application is a divisional of parent application No. 29461/00. The ensuing description is substantially identical to the description of the specification of the parent application. The "parent" description has been readopted to facilitate identification of the parent/divisional relationship. The scope of the invention of this divisional application is set forth in the claims of this specification.

The present invention relates to a new piperazine derivative of the general formula or its pharmaceutically acceptable acid addition salt, and process for the preparation thereof.

R3 R4

Y

R2 Xi N= C-N\ N R Ri X 2 Z

R

Z R

(I)

wherein R, and R 2 are independently hydrogen, CI-C 4 alkyl, Ci-C 4 alkylcarboxyl, Ci-C 4 alkylcarbonyl, Ci-C 4 alkoxy, Ci-C 4 hydroxyalkyl, CI-C 4 aminoalkyl or C i

C

4 hydroxyiminoalkyl, or R, and R are fused to form C 3

-C

4 unsaturated ring;

R

3

R

4

R

6 and R 7 are independently hydrogen, halogen, hydroxy, nitro, amino, Ci-C 4 alkyl, C,-C 4 alkylcarboxyl, C-C 4 alkylcarbonyl, C-C 4 alkoxy or C i

C

4 thioalkoxy; Rs isCl-C 4 alkyl;

I_

P:\WPDOCS\CAB\SPECI\7823543.doc-22/05/03 -2- Y is oxygen, sulphur, amino, substituted amino or C-C 4 thioalkyl; Z is C 1

-C

4 alkoxy, C,-C 4 alkyl, C 1

-C

4 alkylamino or C-C 4 thioalkoxy; X, and X 2 are independently CH or nitrogen; and and may form a single bond or a double bond provided that if forms a single bond, forms a double bond, and if forms a single bond, forms a double bond and R 8 is nonexistent.

In the above definitions, C-C 4 alkyl means methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

CI-C

4 alkylcarboxyl means carboxyl esterified with a lower alkyl such as methylcarboxyl and ethylcarboxyl.

CI-C

4 alkylcarbonyl means carbonyl ketonized with a lower alkyl such as methylcarbonyl and ethylcarbonyl.

C

1

-C

4 alkoxy means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy.

C,-C

4 thioalkoxy means methyithio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio or tert-butylthio.

C,-C

4 aminoalkyl means aminomethyl, aminoethyl, aminopropyl, aminobutyl or the like.

C-C

4 kydroxyalkyl means hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or the like.

C,-C

4 hydroxyiminoalkyl means C 1

-C

4 alkyl substituted with P:\WPDOCS\CAB\SPECI\7823543.doc-22/05/03 -3hydroxyimino such as hydroxyiminoethyl.

Substituted amino means hydroxyamino, C 1

-C

4 alkylamino, Ci-C 4 alkoxyamino or the like.

The present inventors had studied for a long time to find compounds having intensive antitumor activity. As a result, now we have finally found out the facts that the present compounds of the general formula and acid addition salts thereof have not only prominent antitumor activities but very low toxicities.

Accordingly, one aspect of the present invention seeks to provide novel compounds of the general formula and acid addition salts thereof having not only prominent antitumor activities but very low toxicities.

Another aspect of the present invention seeks to provide a process for the preparation of the compounds of general formula and acid addition salts thereof.

The compounds of the present invention can be mixed with pharmaceutically acceptable vehicles by a known method to give pharmaceutical compositions and thus the pharmaceutical compositions can be used for the prevention or treatment of human or mammalian tumors.

Therefore, another aspect of the present invention seeks to provide pharmaceutical compositions containing the compound of the general formula or an acid addition salt thereof as an active ingredient.

P:\WPDOCS\CAB\SPECI\7823543.doc-2205/03 -3A- In a particularly preferred aspect of the invention compounds of the formula are based on pyridine derivatives, i.e. where X, is CH and X 2 is nitrogen. Thus, according to an aspect of the present invention as claimed there is provided a compound of the general formula (Ib) R3 R4 2 X, N=C-N N- R R ,X 2 Z R7 R6 (Ib) wherein R, and R 2 are independently hydrogen, C 1

-C

4 alkyl, C 1

-C

4 alkylcarboxyl,

C

1

-C

4 alkylcarbonyl, C 1

-C

4 alkoxy, C 1

-C

4 hydroxyalkyl, C 1

-C

4 aminoalkyl or C-

C

4 hydroxyiminoalkyl, or R, and R 2 are fused to form C 3

-C

4 unsaturated ring;

R

3 R, R, R, R and R, are independently hydrogen, halogen, hydroxy, nitro, amino, CI-C 4 alkyl, C 1

-C

4 alkylcarboxyl, C 1

-C

4 alkylcarbonyl, C 1

-C

4 alkoxy or C 1

C

4 thioalkoxy; Rs is C 1

-C

4 alkyl; Y is amino, substituted amino or C1-C4 thioalkyl; Z is C 1

-C

4 alkoxy, C 1

-C

4 alkyl, C 1

-C,

4 alkylamino or C 1

-C

4 thioalkoxy; and X 1 is CH and X 2 is nitrogen; or pharmaceutically acceptable acid addition salts thereof.

Furthermore, the present invention provides a process for the preparation of compound of general formula (Ib) comprising reacting a compound of the general formula (II) with an alkylating agent in the presence of a base to give a compound of the general formula and reacting the compound of the formula with a substituted or unsubstituted amine in the presence of a base to give a compound of the general formula (Ib).

P:\WPDOCS\CAB\SPECI\7823543.do-22/05/03 -3B-

R

3 R4

IS

R X 1

N

-C-

N N Rs K-6

R

1

X

2

ZR

R" R3 R4 (ir)

R

2

X

1 N=C-N N RI X 2 z R! R 6 R3, ,R4 R2 X N R j l/ (Ib) wherein R2, R 3 R4, R 5 R6, R 7

X

2 Y and Z are as defined above and R' is

C,-C

4 alkyl.

Acids which can be reacted with the compounds of the general forrmula to form acid addition salts are pharmaceutically acceptable inorganic or organic acids; for example, inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid; organic acids such as formic acid, acetic acid, propionic acid, succinic acid, citric acid, maleic acid, malonic acid, glycolic acid, lactic acid; amino acids such as glycine, alanine, valine, leucine, isoleucine, seine, cysteine, cystine, asparaginic acid, glutamic acid, lysine, arginine, tyrosine, proline; sulfonic acids such as methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid; or the like.

Vehicles which can be used in the preparation of pharmaceutical compositions containing the compound of the general formula as the active P:\WPDOCS\CAB\SPECI\7823543.doc-22/05/03 -3Cingredient may include a sweetening agent, binding agent, dissolving agent, aids for dissolution, wetting agent, emulsifying agent, isotonic agent, adsorbent, degrading agent, antioxident, antiseptics, lubricating agent, filler, perfume or the like; such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, calcium stearate, magnesium aluminum silicate, starch, gelatine, tragacanth gum, glycine, silica, alginic acid, sodium alginate, methyl cellulose, sodium carboxy methyl cellulose, agar, water, ethanol, polyethylenglycol, polyvinyl pyrrolidone, sodium chloride, potassium chloride, orange essence, strawberry essence, vanila aroma or the like.

I

-4- Daily dosage of the compound of the general formula may be varied depending on age, sex of a patient, degree of disease, etc. and generally 1.0mg to 5,000mg per day may be administered one to several times.

The compounds of the general formula according to the present invention wherein forms a single bond and forms a bouble bond, may be prepared by the following scheme I.

Scheme I

R

2 Xi NH 2

R

1

X

2

Z

Y

Lie Providing agent

Y

H

R

2 X N-C-Providing agent

R

1

X

2

Z

(3) R3 R4 H-N N R5

R

7 R6 (4) (3) Base Alkylating gent, arylating agent Base R3 R4 R Y

R

2

X

1 N-C-N N _R

R

1

X

2 Z R (la) wherein R 1 R2, R3, R4, Rs, Re, R 7 Rs, X 1

X

2 Y and Z are as defined above, and Lie is a conventional leaving group such as halogen, sulfonyl or the like.

The above process comprises reacting a compound of the general formula with a Lie-C(=Y)- group-providing agent in an organic solvent to obtain a compound of the general formula and successively reacting the compound of the formula with a compound of the general formula to give the compound of the general formula Then, the compound of the formula may be reacted with an alkylating agent or an arylating agent in the presence of a base to give a compound of the general formula (Ia).

The -C(=X)-group-providing agent used in the above reaction may include 1,1-carbonyldiimidazole, 1,1-carbonylthiodiimidazole, phosgene, thiophosgene, carbonyldiphenoxide and phenylchloroformate, and it may be used in an amount of 1 1.5 equivalent, preferably 1-1.1 equivalent to the starting compound.

The reaction may be carried out in a conventional organic solvent such as, for example, tetrahydrofuran, dichloromethane, acetonitrile, chloroform and dimethylformamide.

And also the reaction is preferably carried out in the presence of a coupling agent such as a conventional inorganic or an organic base.

Such conventional inorganic or organic bases used in the reaction may include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and

DBU.

The reaction may be carried out at a temperature between 3°C and boiling point of the solvent used, preferably at 50'C-100C and for 5 48 hours, preferably for 10 24 hours.

The reaction of the compound with the compound to give the compound may be carried out in the presence of a conventional organic solvent at the temperature of 50-100°C for 5-48 hours. The compound may be used by 1-1.5 equivalent.

-I

-6- And also the reaction is preferably carried out in the presence of a conventional inorganic or organic base, such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, DBU or the like.

Then, the compound of the formula may be reacted with an alkylating agent or an arylating agent in the presence of a conventional organic or inorganic base to give a compound of the general formula (Ia).

10 The alkylating agent and arylating agent used in the above step may include C 1

-C

8 alkylhalide, C 1

-C

8 alkylsulfonate, substituted or unsubstituted C 3

-C

8 cycloalkyl halide, arylhalide, and substituted or unsubstituted C 3

-C

8 cycloalkyl sulfonate.

Ci-Cs alkyl halide means methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl chloride, propyl bromide, propyl iodide, butyl chloride, butyl bromide, butyl iodide, pentyl chloride, pentyl bromide, pentyl iodide, bromo ehtylacetate or the like.

C

1

-C

8 alkylsulfonate means methyl sulfonate, ethyl sulfonate, propyl sulfonate, butyl sulfonate, pentyl sulfonate or the like.

Substituted or unsubstituted C 3

-C

8 cycloalkyl halides mean cyclopropyl chloride, cyclopropyl bromide, cyclopropyl iodide, cyclobutyl chloride, cyclobutyl bromide, cyclobutyl iodide, cyclopentyl chloride, cyclopentyl bromide, cyclopentyl iodide, cyclohexyl chloride, cyclohexyl bromide, cyclohexyl iodide, cyclopropyl methyl chloride, cyclopropyl methyl bromide, cyclopropyl methyl iodide, cyclobutyl methyl chloride, cyclobutyl methyl bromide, cyclobutyl methyl iodide, cyclopentyl methyl chloride, cyclopentyl methyl bromide, cyclopentyl methyl iodide, cyclohexyl methyl chloride, cyclohexyl methyl bromide, cyclohexyl methyl iodide, or the like.

Aryl halides may include benzyl chloride, benzyl bromide, benzyl iodide, benzoyl chloride, benzoyl bromide, benzoyl iodide, toluyl chloride,

I_

-7toluyl bromide and toluyl iodide.

Substituted or unsubstituted C 3

-C

8 cycloalkyl sulfonate may include cyclopropyl sulfonate, cyclobutyl sulfonate, cyclopentyl sulfonate, cyclohexyl sulfonate, cyclopropyl methyl sulfonate, cyclobutyl methyl sulfonate, cyclopentyl methyl sulfonate and cyclohexyl methyl sulfonate.

Aryl sulfonate may include benzyl sulfonate, benzoyl sulfonate, toluyl sulfonate, or the like.

The reaction may be carried out in a conventional organic solvent as 10 such as, for example, tetrahydrofuran, dichloromethane, chloroform, dimethyl sulfoxide, acetonitrile and dimethylformamide.

The conventional inorganic or organic base used in above step may include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and

DBU.

In the above reaction process, if any acid material is formed, a basic material may be added as a scavenger in order to eliminate the acid material from the reaction phase. Such basic material may be alkali metal hydroxide, alkali earth metal hydroxide, alkali metal oxide, alkali earth metal oxide, alkali metal carbonate, alkali earth metal carbonate, alkali metal hydrogen carbonate, alkali earth metal hydrogen carbonate such as for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium bicarbonate, calcium bicarbonate or the like, and organic amines.

The compounds of the general formula and the formula are known compounds, or may be prepared by a known method described in, for example, Farmaco(pavia) Ed, Sci., 18(8), 557-65(1963) or by a similar method thereto.

-8- A compound of the general formula wherein forms a single bond and forms a double bond may be prepared by the following scheme II Scheme II.

R3 R4 H Ii

R

2 Xi N-C-N N- R 5 Alkylating agent R X2 Z R Base

R

1 I X 2 I z R R 6 10

(II)

S

R

2 XI N=C-N Rs 5 Amination R X

R

7 R Base R3 R4 R2 X1 N=C-N N_

R

1 2 Z R R6 (Ib) wherein Ri, R 2

R

3 R4, Rs, R6, R7, X 1

X

2 Y and Z are as defined above, and R' is lower alkyl such as methyl and ethyl.

A compound of the general formula which may be prepared by a known method, is reacted with an alkylating agent in the presence of a base to give a compound of the general formula Then, the compound of the formula is reacted with a substituted or unsubstitued amine in the presence of a base to give a compound of the general formula (Ib).

The reaction may be carried out at a temperature between 3"C and

_L

-9boiling point of the solvent used, preferably at 50°C-100°C for 5 48 hours, preferably for 10 24 hours.

The alkylating agent may be used in an amount of 1 1.5 equivalent to the compound The alkylating agent may include Ci-C 8 alkyl halide, C 1

-C

8 alkylsulfonate, substituted or unsubstituted C 3 -C8 cycloalkyl halide, aryl halide and substituted or unsubstituted C 3

-C

8 cycloalkyl sulfonate.

The reaction may be carried out in a conventional organic solvent as described above.

10 The conventional inorganic or organic base as described above may be used in the above process.

The compound of the formula is reacted with a substituted or unsubstitued amine in the presence of a conventional base to give a compound of the general formula (Ib).

The reaction also may be preferably carried out in a conventional organic solvent as decribed above.

The conventional inorganic or organic base described above may be used in the above reaction step.

In the above reactions, if any acid material is formed, any basic material may be preferably added as a scavenger in order to eliminate the acid material from the reaction phase. Such basic material may be the organic or inorganic bases as described in the scheme I above.

The compound of the general formula (II) is a known compound, or may be prepared by a known method described in, for example, USP 5,780,472, PCT/KR97/00128 or by a similar method thereto.

Hereinafter the present invention will be described in more details with reference to following examples but it is not intended to limit the scope of the invention thereinto.

Compounds of the general formula (Ia) were prepared in following examples according to the above-mentioned process.

R

3

R

R

8

Y

R

2

X

1 N-C-N N R I R R

R

1

X

2 z R (Ia) wherein R 1

R

2

R

3 R,4, R5, 116, 17, R8, XI, X 2 Y and Z are as defined above.

Fx R2 I R3 I R4 N I l1 X 2 Sz 1 CH 3

CH

3 H H H H H H N N OOCH 3 2 CH3 CH3 OCH 3 H H H H H N N OOCH3 3 CI 3

CH

3 H OCH 3 H OCH 3 H H N N OOCH 3 4 CH3 CH 3 Et H H H H H N N OOCH 3 b

CH

3

CH

3 H H n-Bu H H H NNOOCH 3 6 Cf-H Cf 3 iPr H H H H H N N OOCH 3 7 CFb CH 3 H Ci 3 H CH3 H H N N OOCH 3 8 CH3 C 3

CH

3 GiL 3 H CH 3 Gi 3 H N N OOCH 3 9 GH- 3

CH

3 F H H H H H N N OOCHS

GH

3

CH

3 H Br H H H H N N OOCL-b 11 CH 3

CH

3 H Cl H C1 H H N N OCH 3 12 GIl3CH 3 H F H F H H N N OOCIL 13 CH3 CH3 H CF 3 H H H- H N N OOCH 3 14. C3 CH 3

SCH

3 H H H H H N N OOCH3

CH

3

CH

3 H NO 2 H NO 2 H H N N OOCH 3 11 Ek Ri R2 R3 R4 15 16 17 R 8 XI X 2 Y Z 16 CH3 CH 3 H NH 2 H Nil 2 H H N NOOCH 3 17 CH3 CH3 H H Ac H H H N N OOCH 3 18 CH 3

CH

3

OCH

3 H H H H CH3 N N OOCH 3 19 CH3 CH 3 H OCH 3 H OCH 3 H CH3 N N OOCH 3

CH

3

CH

3 H CIL H Gl 3 H N N

OOCH

3 21 CH 3

CH

3 H Cl H Cl H CH 3 N N O0OCH 3 22 CH 3 CH3 H F H F H Cb N N OOCH 3 23 CIH3CH 3

SCH

3 H H H H CH3 N N OOCH 3 24CH3 CH H NO 2 H NO 2 H CH3 N N OOCH 3

CH

3 CH3 H NH 2 H NH 2 H C 3 N N OOCH 3 26 CH 3 CHs H OCH 3 H OCH 3 H Et N N OOCH 3 27 CH 3

CH

3 H CH 3 H C113 H Et N N OOCH 3 28 Cl3 CH 3 H OCH 3 H OCH 3 H H N N S OCH3 29 CH 3

C

3 Et H H H H H N N S OCH3 C-b CH3 H CFb H Cit H H N N S OCItb 31 Cit CHb H Br H H H H N N S OCH3 32CICH CH3 H Cl H Cl H H N N S OCH 33 CIH CtbSCI-b H H H H H N N S OCH3 34 Et Et H CH3 H CH3 H H NNOOCH3 Et Et H OCI-b H OCH3 H H NNO OCH3 Fx R 1

R

2

R

3 R14 R 5 R16 R17 R 8 XI X 2 1Y IZ 36 CHG1H-UI=CHH H H H H H N NO0OH 3 37 EG-UH=fRlOGH 3 H H H H H N N 0 OGH 3 38 G+C-U H 0GWb H 0GW3 H H N N 0 0GW3 39 CH=Fl-UHEt H H H H H N N OGW CHrGI-UH&G iPr H H H H H N N 0 0GW- 41lC(H=CHCHCH H nBu H H H N N OGW 42 CH=CG{ H GH3 H Gl 3 b H H N NO0OH3 43C C1-U-GbH 3 Fb H Gil 3 Gi 3 H N N OGWb 44 CHGI-CU-PM F H H H H H N N 0 OG Gm1C-HmlH Br H H H H N N OGW 46 HG1-CHLCH H F H F H H N N OGW 47 azC-MC~HG H CF 3 H H H H N N 0 0GW3 48 CH=H~-CHzG H NO 2 H NO 2 H H N N 0 0GW- 49 CmHzalC=C H NH 2 H NH 2 H H N N 0 0GW3 H-HZGhi H H Ac H H H N N OGW 51 CHzG+1-~I-SGW H H H H H N N OGW 52 mCJU~aM Ph H H H H H N N OGW 53 (ThI-(h& H 0GW3 H 0GW3 H GW3 N N 0 0GW3 54 Cnz0-UmI OGW H H H H GW3N N OGW MCRA-MzH G113 H GW- H GHSbN N OGW 13 Ek, Ri R 2 R13 114 R 5

R

6 R7 18Xl X 2 Y Z 56 CH=CH-HK1HH F H F H CH1 3 N NO0OCH3 57 GWahU7I1 H NO 2 H NO 2 H CU 3 N N 0 OCH 3 58 alzUH-CH l H NH 2 H NH 2 H C11 3 N N 0 OCFL 59 CEPH-CH-UKH H OCH3 H OCH 3 H Et N N 10 OCH3 iUa+CHm H CH 3 H CH 3 b H Et N N 0 OCH3 61l~C~HG z H Cl H Cl H EtN NO0OCL 62 a=I-G-1Mi H 0C11 3 H OCH 3 b H iTr N N 0 OCH 3 b 63 CH-mi-umiliOCH 3 b H H H H H N N S OCI-b 64 +CH~-ami F OCH 3 b H OCH3 H H N N S OCH 3 b C=CH-CLIH Et H H H H H N N SOC3 66 CH=CHIIH=GH CH 3 b H CHL H H N N SOCH3 67 C1IO1-G-f-MH Br H H H H N N SOC3 68 CRh-C+ mlCHH F H F H H NN S OCH 69 Ura-UmIHSCH 3 b H H H H H N N SOC3 CRHc-HGmiH H Ac H H H N N SOC3 71c11zCf-UIOH H nBu H H H N N S OU 72 ammmi-C H OCH 3 H OC~b H H N N 0 GEt 73 G-iR:hGIOEt H H H H H N NO0OEt 74 Gmmmi H Cl-b H Gil 3 H H N N 0 OEt am=H-CuCH Cl-b CH3 H H H H N N 0 GEt 14 Ex. Ri R12 R 3 R4 115 116 117 R 8

XIX

2 Y IZ 76 CH1C-CTHz&1Et H H H H H N NO0OEt 77 ChaCH-R=CH H Cl H Cl H H N NO0O-t 78 GIGEWUIH Br H H H H N NO0OEt 79 CHmC-CGlzHH F H F H H N N0OEt GIU+C-uM SCH 3 H H H H H N N 0 GEt 81 G1TCH-UG1 H OCH 3 H OCH 3 b H CH 3 b N N 0 GEt 82 CII=GI-CH=CH H Cl H Cl H CFL- N N 0 GEt 83 +cmammi H 0GWf H OCH 3 H Et N N 0 GEt 84 Cm~lCHam H Cl H Cl H Et N N 0 OEt GmCH-fa H CH 3 b H CH 3 b H Et N N 0 OEt 86 mI-amlGiH CH 3 H CH 3 b H H CGO 0OCH3 87 Cmui-&m H 0GW- H 0GW3 H H C C 0 0GW3 88 CHzCH&1H~a4H F H F H H C CO0OCH3 89 CmC-CHmCH H Cl H Cl H H C CO0OCH3 CHma-CHlmlH CH3 H CW- H CW-bC CO0GGW 9lCHHru-CHIZUH F H F H CbC CO0OCIW 92 GkzGf~l&1 H Cl H Cl H CH3 C C 0 0GW3 93 G-&I Q H 0GW- H 0GW3 H CW- C 0 0GW3 94 GCHu-um H 0GWb H 0GW- H Et G G 0 0GW- ECHEH-UI=GI H GW- H GW- H Et G G 0 0GW3 I I 15 The compounds of the general formula (Ib) were prepared in the following examples according to the above-described process.

R

3

R

4

Y

R

2 X N=C-N N

R

1

X

2 Z R7 (Ib) wherein, R 1 R2, R 3

R

4

R

5

R

6

R

7 X, Y and Z are as defined above.

Ex R 1 R2 R 3 R4 R5 R6 R 7

X

1

X

2 Y Z 96 CH 3 CIt H H H H H C N NHOH OCH 3 97 CH 3 CH3 H H CH3 H H C N NHOH OCH 3 98 CH3 CH 3 H H nBu H H C N NHOH OCH 3 99 CH 3

CH

3 H CH3b H CH H C N NHOH OCH 3 100 CH3 CH3 OCH 3 H H H H C N NHOH OCH 3 101 CH 3 CH3 H OCH 3 H OCH H C N NHOH OCI-Hs 102 CH3 Ci3 H F H F H C N NHOH OCH 3 103 CH3 CH3 H C1 H Cl H C N NHOH OCI1 104 CH3 CH3 H Br H H H C N NHOH OCHs 105 CH3 CH H NO 2 H NO 2 H C N NHOH OCI-3 o 0 106 CHi CiH3 H AOEt H H C N NHOH OCH3 107 CH3 CH3 H H ^oH H C N NHOH OCH3 108 CH3 Et OCH3 H H H H C N NHOH OCH 3 109 CH3 Et H OCI- H OCH3 H C N NHOH OCH- 110 CH 3 Et Et H H H H C N NHOH OCI-b 16 111 112 113 114 115 116.

117 118 119 120 121 122 123 124 125 126 127 128 129 130 Ri CR3 CH3 CR3 CH3

CH

3

CH

3 CI-1 3 CI-1 3 GH3 Gil 3

CH

3 Gil 3 CH3

CH

3

CH

3

CH

3 C1R3 CH3 CH3 Gil 3 R12 Et Et Et Et Et Et Et 0

AOCH

3 0 A0CH3

AOCH

3 0 0OCH 3 0 AOCH3

A~OCH

3 0OCH 3

-"OH

OH

-"OH

'OH

R13

H

SCH

3

H

H

H

Ph

H

H

H

H

OCH

3

H

H

H

H

H

H

0CH 3

H

H

114

H

H

CR3

F

R15

H

H

H

H

R16

H

H

CR3b

F

H

H

H

H

Y

NHOH

NHOH

NHOH

NilOi z

OCR

3 b

OCH

3 OC113

OCH

3 1 4 1 en

H

N02 OCI-1 3

CIL

F

H

H

H

H

H

H

H

H

CI

H

N02 0GW3 CR3

F

H

H

H

H

H

H

NHOH

NHOH

NUH

NHOH

NilOi

NHOH

0GW- OCH3 0GW- 0GW3 0GW3 0GW3 I I H IH NHOHIOCH3 I L -I-

H

H

Cl OCH3 CR3b

F

H

H

H

H

CR3

H

H

H

H

H

H

CR3b

H

H

H

OC1H 3 CR3

F

H

FH

H

H

H

H

H

H

H

H

C

C

C

C

C

C

C

C

N

N

N

N

N

N

N

N

NHOH

NHOH

NHOH

NilOi

NHOH

MIH

NHOH

NHOH

OCW3 OCW3 OC1W 0CH3

OCW-

OCW-

OCW3 OCW3 OCW- HIlH N INHOH I I L I 1 1 II I 17 Ex R 1 R2 R 3

R

4

R

5

R

6

R

7

XIX

2 Y Z 131 CH 3 -OH H Cl H H H C N NHOH OCH 3 132 CH3 H GCL 3 H Gl- 3 H C N NHOH OCJLb 133 Cls t H OCH 3 H OCH 3 H C N NHOH OCH 3 134 Cl 3 1 H H H H H C N NHOH CH 3 135 CH 3 b H H CH 3 H H C N NHOH OCH 3 136 CH3 H F H F H C N NHOH OCH 3 137 CH 3

SCH

3 H H H H C N NHOH OCH 3

OH

138 C113 H CH 3 H CH 3 H C N NHOH OCH 3

OH

139 CH 3 H OCH 3 H OCH 3 H C N NHOH OCH 3

OH

140 CH3 H H H H H C N NHOH OCH 3

OH

141 CH 3 H H CH 3 H H C N NHOH OCH 3

OH

142 CH3 H F H F H C N NHOH OCHa

OH

143 CH3 SCH 3 H H H H C N NHOH OCH 3

NHOH

144 CH 3 H CH3 H CH 3 H C N NHOH OCH3 145 CH3NHOH 145 CH 3 HH OC143 H OCHs H C N NHOH OCH 3

NHOH

146 CH3 )LOH H F H F H C N NHOH OCH 3 147 CH3NHOH 147 CH 3 SCH3 H H H H C N NHOH OCIH 3 148 I_13

NHOH

148 CH 3 JH NO 2 H NO 2 H C N NHOH OCH 3

NHOH

149 CH 3 H H CH3 H H C N NHOH OCH 3 150 Cl-S

NH

2 H CE--b H CIL H C N NHOH OCH3 18 Ek 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 E R2 R 3 4 R5 R6 R 7

XIX

2 Y Z CH3NH 2 H OCH 3 H OCH 3 H CN NHOH OCH 3

CH

3 N2H F H F H CN NHOH OCH 3

CH

3 NH SCH 3 H H H H C N NHOH OCH 3

CH

3 N2H

NO

2 H NO 2 H C N NHOH OCH 3

CH

3 N2H Cl H Cl H C N NHOH OCH3 0 Et OCH H CH 3 H H C N NHOH OCH 3 0 Et A F t H H H H C N NHOH OCH3 qlCH, Et OCH3 H CH 3 b H CIL H C N NHOH OCH 3 Ft OCH3 H OCH 3 b H 0C1W H C N NHOHOCWH, Et OCH H CI H CI H C N NHIOHCCW Ft AOCH SCH 3 H H H H C N NHOH OCW- Ft ~OCH H CFth H CH 3 H C N NHOH OCW3 Ft AO OCH 3 H FOCHF H C N NHOH OCH3 Ft "OH H Cl H CH H C N NHOH OCH3 Ft OH EtH H H H H C N NHOH OCH3 Ft "OH H COH H Cl H C N NHOH OCfb 19 Ex Ri R 172 CH=CH-CH=CI 173 CH=CH-~CH=C1 174 CH=CH-CH=CI 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 CH=CH-CH=Cl CH=CH-CH=Cf

CH

3 Cil1 3 Gil 3 Gi 3 Gil 3 Cl-b3 Gil 3 CH1 3 Cl-b CH 3 Gil 3 Cl-1 3 Gil 3

GH

3 Gil 3 Cl-b3 CH3 CH3 Gil 3 Cil3 R3

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OGH

3 L H OGH 3 H C C NHOH OGU3 F H F H C CGNHOH OGj3 C il il H C CGNHOH OGU3 Br il H H C C NHOH OGU3

OGH

3 H OGH 3 H C N NHOCHb OGH 3 20 u 21

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JIR

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5 OC3 H H 211 212 213 CHL3 Clb

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3 Et H OC13 H r, L r- i t H HC 214j CH3 I Et

N

NJ

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SCH

3

SCH

3 215 216 CH3 Cl-b Et Et H I F I H I F IHICIN

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3

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3 OCH3

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3 H Cl H CitH C N SCH3 I 1 I 217 218 CH3 C143 EtIPh H H H I" C I NCH JOCH 219__ CH3 220 221

CH

3 Gl- 3 222_j CH3 223 224 225 226

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3 0 0OCH 3 0CH

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3 H SCH 3 H1 N0 2 IH INO2IH C I SCH3

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OCH

3 HICINISCIoCH3 H H H I H IC IN H H Cl-b H H C HfC1 H i H C 227 CH3 228 CH 3 230 CH 3 H I CH3

IH

N

N

N

Cl-b OC143

H

H

L~1 SCH3b SCH3

SCHI

SCH3 SCIb SC13 SCH3 OCH-3

OCH

3 OCl-b OCH3

OCH

3 OCH3

OCHW

OCH

3 OCl-b

OCH

3 H OC113 H H H H

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H

CH3

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H H C

N

CN

22 Bc. R 1 R R 3 R14 R15 R6 R 7

XIX

2 Y Z 231 CH 3 H

C

3

OH

232Ci CH 3 F H H H C N SCH 3 b OCH3 234 CHt 0% H t H H H H t O 23,EkC SH3 CH H CH H C N SCH 3

OCH

3 236 Et CH, H H~i H ObiH H C N SCH 3 OCI-b 238 Et OCH3 ECt H H H H C N SCH 3 OCI-b 0 240 Et ACH, H CF H Fl- H C N SCit OCH 3 241 Et=C COCH H OCItb H OCit H C N SCH 3 OCit 2437 Et CACCH H Fl H Fl H C N SCIt1 OCit 245 E CH=C-HCH HC- CH H H H C N SCItb OCItb 239CEt ACt H HO~ H HO H CCNSCIL OCH3 247 Cit ACt H H Ci H H C C SCit OCit 248 Cit Cit= PtI- H H H H C C SCit OCit 249 Cit Citb H Cit3 H Cit H C C SCitb OCit 250 Cit Cit H OCit H OCit H C C SCitb OCit 23 EX~ Ri R2 R 3 R14 R 5 R16 [R 7

XIX

2 Y Z 251 CH3 CH3 H F H F H C C ISGH 3 0GW3 252 Cl-3 CH 3 H Cl H H H C C SCH 3 0GW3 253 CH 3

CH

3 H Br H H H C C SCH 3 0GW3 254 CH 3

CH

3 b SCH3 H H H H C C SCHW 0GW Example 1) 1- 6 -Dimethyl-2-methoxypyrazin-3-yl)aminocar-bonyl] -4-p henylpiperazi ne a) Phenyl N- (5, 6 -dimethyl-2-methoxypyrazin-3-yI )carbamate: 3 -Amino-5,6-dimethyl-2-methoxypyrazine(l1.O0g, 6.53nimol) and phenylchloroformate(1 .02g, 6.53mmol) were dissolved in dichioromethane and stirred at room temperature for 2 hours. The resulting mixture was concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.

yield: 98 101 -1031C b) 1- 6 -Dimethyl-2-methoxypyrazin-3-yl)aniinocarbonyl] -4-phenyl piperazine: Phenyl N- (5,6-di'methyl-2-methoxypyrazin-3-yl )carbamate (350mg, 1.28mmol) and 1-phenylpiperazine(208mg, t.28mmol) were dissolved in anhydrous tetrahydrofuran and thereto DBU(195mg, 1.28mmol) was added. The resulting mixture was stir-red at room temperature for 2 hours and concentrated under the reduced pressure to remove the solvent, and purified by column chromatography to obtain the titled compound.

yield :78.5% m.p. :185-1871C 24 Example 2) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminocarbonyl] -4- (2-methoxyphenyl)piperazine Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl )carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 82.0% 184 -1851"C Example 3) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl)anuinocarbonyl] -4- Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 85.0% 136 -137 IC Example 4) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl)armnocarbonyl] -4- (2-ethylphenyl)piperazine Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(2-ethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 70.4% 197-1991C Example 5) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (4-butylphenyl)piperazine Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(4-butylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 68.5% 121-1231C Example 6) 1- [(5,6-Dimethyl-2-methoxyp~yrazin-3-yl)aminocarbonyl] -4- (2-isopropylphcnyl)piperazine Phenyl N- (5,6-dimethyl-2-methoxypyrazin3yl)carbamate and 25 1- (2-isopropylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 73.0% 165 -167 IC Example 7) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-y)am-inocarbonyl] -4- Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl )carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 84.0% 162 1641"C Example 8) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminocarbonyl] -4- (2,3,5,6-tetramethylphenyl)piperazine Phenyl N- (5,6-dimethyl-2-methoxypyrazin3yl)carbamate and 1-(2,3,5,6,-tetramethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 65.5% 202 -2041C Example 9) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl)am-inocarbonyl] -4- (2-fluorophenyl)piperazine Phenyl N- (5,6-di'methyl-2-methoxypyrazin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 74.5% 170- 172"C Example 10) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl) anilnocarbonyll-4- (3-bromophenyl)piperazine Phenyl N- (5,6-dimethyl-2-methoxypyrazin3yl )carbamnate and 1-Q(bromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 70.0% 26 Example 11) 1-[I(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminhocarbonyll -4- Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-y1)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 80.5% 180 -181 IC Example 12) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl)amnocarbonyl -4- Phenyl N- (5,6-dimethy-2-methoxypyrazin3yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 78.0% 153 154 *C Example 13) 1- [(5,6-Dimethyl-2-methoxypyrazin-3yl)aminocarbonyll -4- (3-trifluorotolyl)piperazine Phenyl N- (5,6-dimethyl-2-methoxypyrazin3yl)carbamate and 1-(3-trifluorotolyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 69.5% 168-170*C Example 14) 1- [(5,6-DimethylP2-methoxypyrazin-3-yI )aminocarbonyl] -4- (2-methylthiophenyl)piperazine Phenyl N- (5,6-dimethyl-2-methoxypyrazin3yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 71.0% 202 -204 *C Example 15) 1- [(5,6-Dimethyl-2-methoxypyrazin3yl) arninocarbonyl] -4- 27 Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-dinitrophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 64.5% 192-194"C Example 16) (5,6-Dimethyl-2-methoxypyrazin-3-yl)aminocarbonyl] -4- 1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminocarbonyll-4was dissolved in ethanol(30ml) and thereto 10 10% palladium/carbon(10mg) was added. The resulting mixture was hydrogenated for 4 hours, and then filtered to remove the palladium/carbon. The filtrate was concentrated and purified by column chromatography to obtain the titled compound.

yield 45.0% >1001C(decomposed) Example 17) 1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminocarbonyl]-4- (4-acetylphenyl)piperazine Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

Yield 71.5% 166-168 0

C

Example 18) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl] -4-(2-methoxyphenyl)piperazine 1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminocarbonyl] -4- (2-methoxyphenyl)piperazine(200mg, 0.54mmol) was dissolved in dimethylformamide (15ml) and thereto 60% sodium hydride (21.5mg, 0.54mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes, and thereto methyl iodide(76.6mg, 0.54mmol) was added. The resulting mixture was stirred at room temperature for 6 hours, concentrated under the reduced pressure to remove the solvent, 28 and purified by column chromatography to obtain the titled compound.

yield: 92.5% 140 -142 IC Example 19) 1- [(5,6-Dimethyl-2-methoxypyrazin73-yl) N-methylaminocarbonyl] 1- [(5,6-Dimnethyl-2-methoxypyrazin-3-yl)aminocarbonyl] -4was reacted by the same way with the example 18 to obtain the titled compound.

yield: 90.5% 80 -82 0

C

Example 20) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl] 1-Il(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminocarbonyl] -4was reacted by the same way with the example 18 to obtain the titled compound.

yield: 88.4% 94-961C Example 21) 1- [(5,6-Dimethyl-2--methoxypyrazin-3-yl) N-methylaminocarbonyl] 1- [(5,6-Dimethyl-2-methoxypyrazin-3yl)ami nocarbonyl] -4was reacted by the same way with the example 18 to obtain the titled compound.

yield: 95.2% 97 -991C Example 22) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl] 1- [(5,6-Dimnethyl-2-methoxypyrazin-3yl)aminocarbonyl -4was reacted by the same way with the example 18 to obtain the titled compound.

yield: 94.0% 104 -1061C 29 Example 23) 1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl] (2-methylthiophenyl)piperazine 1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminocarbonyll-4- (2-methylthiophenyl)piperazine was reacted by the same way with the example 18 to obtain the titled compound.

yield: 89.5% 133-134 0

C

Example 24) 1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl] -4-(3,5-dinitrophenyl)piperazine 1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminocarbonyl] -4was reacted by the same way with the example 18 to obtain the titled compound.

yield: 80.0% 133-1351C Example 25) 1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl]l-4-(3,5-diaminophenyl)piperazine 1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl)N-methylaminocarbonyl]-4was reacted by the same way with the example 18 to obtain the titled compound.

yield: 58.5% >100 0 C (decomposed) Example 26) 1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl) N-ethylaminocarbonyl] -4-(3,5-dimethoxyphenyl)piperazine 1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminocarbonyl] -4- (3,5-dimethoxyphenyl)piperazine(250mg, 0.62mmol) was dissolved in and thereto 60% sodium hydride(24.9mg, 0.62mmol) was added. The mixture was stirred at room temperature for minutes, and thereto methyl iodide(96.7mg, 0.62mmol) was added.

The resulting mixture was stirred at room temperature for 6 hours, concentrated under the reduced pressure to remove the solvent used, and purified by column chromatography to obtain the titled compound.

30 yield: 89.5% 78 -801C Example 27) 1-lI(5,6-Dimethyl-2-methoxyvpyrazin -3-yl) N-ethylamninocarbonyll -4-(3,5-dimethylphenyl)piperazine 1-[I(5,6-Dimethyl--2-methoxypyrazin -3-yl )aminocarbonyl] -4was reacted by the same way with the example 26 to obtain the titled compound.

yield: 92.0% 68 -70 IC Example 28) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminothlocarbonyll -4a) Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate: 3-Amino-5,6-dimethyl-2-methoxypyrazine(500mg, 3.26mmol) was dissolved in dichloromethane and thereto phenyl thiochloroformate (564mg, 3.26mmol) was slowly added. The mixture was stir-red at room temperature for 24 hours, concentrated under the reduced pressure to remove the solvent, and purified by column chromatography to obtain the titled compound.

yield: 78.5% 71 -73 IC b) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminothiocarbonyl] -4- Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate (200mg, 0.69m-mol) and 1- (3,5-dimethoxyphenyl )piperazine( 154mg, 0.69mmol) were dissolved in anhydrous tetrahydrofuran(25m1l) and thereto .69mmol) was added. The mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.

yield :71.5% m.p. :183-1841C 31 Example 29) 1- [(5,6-Dimethyl-2-methoxypyrazin-3-yl)amn othiocarbonyll -4- (2-ethylphenyl)piperazine Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate and 1-(2-ethylphenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.

yield: 64.0% 197 -199"C Example 1- [(5,6-Dimethyl-2-methoxypyrazin-3yl)aminothiocarbonyl] -4- Phenyl N- (5,6-dimethyP2-methoxypyrazin-3yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.

yield: 68.4% 160 -162 IC Example 31) 1-[I(5,6-Dimethyl-2-methoxypyrazin-3yl)aminothiocarbonyl] -4- (3-bromophenyl )piperazine Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3yl)thiocarbamate and 1- (3-bromophenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.

yield: 62.5% 136 -1381C Example 32) 1- [(5,6-Dirnethyl-2-methoxypyrazin-3yl)anuothlocarbonyl] -4- Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3yl)thiocarbamate and 1- (3,5-dichlorophenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.

yield: 70.8%o 32 182 -1841C Example 33) 1- 15,6-Dimethyl-2-methoxypyrazin-3-yl)aminothiocarbonyl] -4- (2-methylthiophenyl)piperazine Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl)thocarbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.

yield: 61.4% 181-1831C 10 Example 34) 1- [(5,6-Dichloroethyl-2-methoxypyrazirn-3-yl)aminocarbonyl] -4- Phenyl N- (5,6-diethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 77.5% 118-1201C Example 1- [(5,6-Dichloroethyl-2-methoxypyrazin-3-yl)aminocarbonyl] -4- Phenyl N- (5,6-diethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 78.9% 90 -92 *C Example 36) 1- [(2-Methoxyquinoxalin-3-yl)aminocarbonyl] -4-phenylpiperazine a) Phenyl N- (2-methoxyquinoxalin-3-yl)carbamate: 3-Arnino-2-methoxyquinoxaline (1 .Og, 6.53mmol) and phenylchloroformate (1.02g, 6.53mmol) were dissolved in dichloromethane and stirred at room temperature for 2 hours. The resulting mixture was 33 concentrated under the reduced pressure to remove the solvent, and purified by column chromatography to obtain the titled compound.

yield: 75.5% 147-149°C b) 1-[(2-Methoxyquinoxalin-3-yl)aminocarbonyl]-4-phenylpiperazine: Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate(378mg, 1.28mmol) and 1-phenylpiperazine(208mg, 1.28mmol) were dissolved in anhydrous tetrahydrofuran and thereto DBU(195mg, 1.28mmol) was added. The mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent, and purified by column chromatography to obtain the titled compound.

yield 76.5% m.p. 156-158°C Example 37) 1-[(2-Methoxyquinoxalin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)piperazine Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 72.4% m.p. 177-178°C Example 38) 1-[(2-Methoxyquinoxalin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl) piperazine Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxy-phenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 81.2% m.p. 140--141°C Example 39) 1-[(2-Methoxyquinoxalin-3-yl)aminocarbonyl]-4-(2-ethylphenyl)piperazine 34 Phenyl N- (2-methoxyquinoxalin-3-yl)carbamate and 1-(2-ethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 75.0% mp. 191-193 0

C

Example 1- [(2-Methoxyquinoxalin-3yl)aminocarbonyl] (2-isoprop-ylphenyl) piperazine Phenyl N- (2-methoxyQuinoxalin-3-yl)carbamate and 10 1-(2-isopropylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 77.5% m.p. 147-1491C Example 41) 1- [(2-Methoxyquinoxain-3yl)aminocarbonyll (4-butylph-enyl) piperazine Phenyl N- (2-methoxyquinoxalin3yl)carbamate and 1-(4-butylphenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 65.4% m.p. 124- 1261C Example 42) 1- [(2-Methoxyquinoxalin-3-yl)aminocarbonyll piperazine Phenyl N- (2-methoxyquinoxalin3yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 79.3% m.p. 155- 1571C7 Example 43) 1- [(2-Methoxyquinoxalin-3-y)aminocarbonyl] (2,3,5,6-tetramethylV 35 phenyl)piperazine Phenyl N- (2-methoxyquinoxalin3yl)carbamate and 1-(2,3,5,6-tetramethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 64.0% m.p. 237-2391C Example 44) 1- [(2-Methoxyquinoxalin-3-yl)aminocarbonyl] (2-fluorop-henyl) piperazine 10 Phenyl N- (2-methoxyquinoxalin-3-yl)carbamate and 1- flu orophenyl) -piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 67.5% m.p. 142-1441C Example 1- [(2-Methoxyquinoxalin-3-yl)aminocarb onyl] (3-bromop-henyl) piperazine Phenyl N- (2-methoxyquinoxalin3yl)carbamate and 1- (3-bromophenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 69.5% m.p. 148- 1501C Example 46) 1- [(2-Methoxyquinoxalin-3-yl)aminocarbonyl] piperazine Phenyl N- (2-methoxyquinoxalin3yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 74.5%~ m.p. 172-173 0

C

Example 47) 36 1- (2-Methoxyquinoxalin-3-yl )amninocarbonyll (2-trifluorotolyl) piperazine Phenyl N- (2-methoxyquinoxalin-3-yl)carbamate and 1-(2-trifluorotolyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 70.7% m.p. :132 1341C Example 48) 1- [(2-Methoxyquinoxalin-3-yl)aminocarbonyl] 1 piperazine Phenyl N- (2-methoxyquinoxalin-3-yl)carbamate and.

1-(3,5--dinitrophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield :54.5% m.p. :216-218*C Example 49) 1- [(2-Methoxyquinoxalin-3-yl)aminocarbonyll piperazine 1- [(2-Methoxyquinoxalin-3-yl)aminocarbonyl] piperazine(200mg, 0.44mmol was dissolved in ethanol(30m1) and thereto palladiuni/carbon(l0mg) was added. The mixture was hydrogenated for 4 hours, and then filtered to remove the 10% palladium/carbon. The filtrate was concentrated and purified by column chromatography to obtain the titled compound.

Yield 42.5% >1001C (decomposed) Example 1- [(2-Methoxyquinoxalin-3yl)aminocarbonyl] (4-acetylp-henyl) piperazine Phenyl N- (2-methoxyquinoxalin-3yl)carbamate and 1- (4-acetylphenyl)-piperazine were reacted by the same way with the 37 example 36 to obtain the titled compound.

yield 71.0% m.p. 198-200"C Example 51) 1-[(2-Methoxyquinoxalin-3-yl)aminocarbonyll -4-(2-methylt-hiophenyl) piperazine Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

10 yield 69.8% m.p. 180-1821C Example 52) 1-[(2-Methoxyquinoxalin-3-yl)aminocarbonyl]-4-(2-biphen-yl)piperazine Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(2-biphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 59.0% m.p. 162-165 0

C

Example 53) 1-[(2-Methoxyquinoxalin-3-yl) N-methylaminocarbonyl] -4-(3,5-dimethoxyphenyl)piperazine 1-[(2-Methoxyquinoxalin-3-yl)aminocarbonyll-4-(2-methoxyphenyl) piperazine(229mg, 0.54mmol) was dissolved in and thereto 60% sodium hydride(21.5mg, 0.54mmol) was added. The mixture was stirred at room temperature for 15 minutes, and thereto ehtyl iodide (76.6mg, 0.54mmol) was added. The mixture was stirred at room temperature for 6 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.

yield 92.5% m.p. 143-144C Example 54) 1-[(2-Methoxyquinoxalin-3-yl) N-methylaminocarbonyll]-4- 38 (2-methoxyphenyl)piperazine 1- [(2-Methoxyquinoxalin-3-yl)aminocarbonyll -4t-(2-methoxyphenyl) piperazine was reacted by the same way with the example 53 to obtain the titled compound.

yield 83.8% m.p. 128- 1301C Example 55) 1- [(2-Methoxyquinoxalin-3-yI) N-methylaminocarbonyl] -4- 1-[I(2-Methoxyquinoxalin-3-yl)ami'nocarbonyl] piperazine was reacted by the same way with the example 53 to obtain the titled compound.

yield 86.5% m.p. 142-1441C Example 56) 1- [(2-Methoxyquinoxalin-3-yl) N-methylaminocarbonyl] -4- 1- [(2-Methoxyquinoxalin-3-yl)aminocarbonyl] piperazine was reacted by the same way with the example 53 to obtain the titled compound.

yield 84.7% m.p. 197-199*C Example 57) 1-[I(2-Methoxyquinoxalin-3-yl) N-methylaminocarbonyl] -4- 1- [(2-Methoxyquinoxalin-3-yl)aminocarbonyll piperazine was reacted by the same way with the example 53 to obtain the titled compound.

yield 56.5% m.p. 197- 1991C Example 58) 1- [(2-Methoxyquinoxalin3yl) N-methylarmnocarbonyl] -4- To 1- [(2-methoxyquinoxalin3yl) N-methylaminocarbonyl] -4dissolved in ethanol (30m1 39 palladium/carbon (10mg) was added. The mixture was hydrogenated for 4 hours, and then filtered to remove the 10% palladium/carbon. The filtrate was concentrated and purified by column chromatography to obtain the titled compound.

Yield 44.5% >100 0 C (decomposed) Example 59) 1-[(2-Methoxyquinoxalin-3-yl) N-ethylaminocarbonyll-4- To 1-[(2-methoxyquinoxalin-3-yl)aminocarbonyll -4- 10 (3,5-dimethoxyphenyl)piperazine(263mg, 0.62mmol) dissolved in dimethylformamide (20ml), 60% sodium hydride(24.9mg, 0.62mmol) was added and stirred at room temperature for 15 minutes, and thereto methyl iodide (96.7mg, 0.62mmol) was added. The resulting mixture was stirred at room temperature for 6 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.

yield 85.4% m.p. :129-130 0

C

Example 60) 1-[(2-Methoxyquinoxalin-3-yl) N-ethylaminocarbonyl] -4- 1-[(2-Methoxyquinoxalin-3-yl)aminocarbonyl] -4-(3,5-dimethylphenyl) piperazine was reacted by the same way with the example 59 to obtain the titled compound.

yield 87.6% m.p. 145- 1470 Example 61) 1-[(2-Methoxyquinoxalin-3-yl) N-ethylaminocarbonyl]-4- 1-[(2-Methoxyquinoxalin-3-yl)aminocarbonyll-4-(3,5-dichlorophenyl) piperazine were reacted by the same way with the example 59 to obtain the titled compound.

yield 80.6% 40 m.p. 146-1481C Example 62) 1- [(2-Methoxyquinoxalin-3-yl) N-isopropylaminocarbonyll- 4- To 1-[I(2-methoxyquinoxalin-3-yl)aminocarbonyl] -4- (3,5-dimethoxyphenyl)piperazine(216mg, .5lmmol) dissolved in dimethylformarmde(20m1), 60% sodium hydride(20.4mg, 0.5lmmol) was added and stirred at room temperature for 15 minutes, and thereto propyl iodide (86.7mg, .lmmol) was added. The resulting mixture was stirred at room temperature for 6 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.

yield 82.0% m.p. 110-1121C Example 63) 1- [(2-Methoxyquinoxalin-3yl)aminothiocarbonyll (2-met--hoxyphenyl) piperazine a) Phenyl N- (2-Methoxyqluinoxalin3yl)thiocarbamate: To 3-Amino-2-Methoxyquinoxaline(571mg, 3.26mmol) dissolved in dichloromethane, phenylthiochloroformate(564mg, 3.2Gmmol) were added slowly and stirred at room temperature for 24 hours. The resulting :Th mixture was concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.

yield: 60.5% 160 -162 0

C

b) 1- [(2-Methoxyquinoxalin-3yl)aminothiocarbonyl] (2-methoxyphenyl) piperazine: Phenyl N- (2-methoxyquinoxalin-3yl)thiocarbamate( 2 l5mg, 0.69mmol) and 1- (2-methoxyphenyl)piperazine( 154mg, 0.69mmol) were dissolved in anhydrous tetrahydrofuran(25m1) and thereto DBU(lO5mg, 0.69mmol) 41 was added. The mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.

yield :62.4% m.p. 177-179 C Example 64) 1-[(2-Methoxyquinoxalin-3-yl)aminothiocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 10 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.

yield 64.5% m.p. 141-143°C Example 1-[(2-Methoxyquinoxalin-3-yl)aminothiocarbonyl]-4-(2-ethylphenyl) piperazine Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(2-ethylphenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.

yield 60.7% m.p. 141-143°C Example 66) 1-[(2-Methoxyquinoxalin-3-yl)aminothiocarbonyl]-4-(3,5-di-methylphenyl)piperazine Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.

yield 65.0% m.p. 193-195°C Example 67) 1-[(2-Methoxyquinoxalin-3-yl)aminothiocarbonyl]-4-(3-bro-mophenyl) 42 piperazine Phenyl N- (2-methoxyquinoxalin-3-yl)thiocarbam~ate and 1-(3-bromophenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.

yield 57.5% m.p. 195--1971C Example 68) 1- [(2-Methoxyquinoxalin-3-yl)am-inothiocarbonyl] piperazine Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.

yield :59.0% m.p. 280-2811C Example 69) 1- [(2-Methoxyquinoxalin-3yl)aminothiocarbonyl] (2-methylthiophenyl~piperazine Phenyl N- (2-methoxyquinoxalin-3yl)thiocarbamate and 1- (2-methylthiophenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.

yield: 64.5% m.p. :148-1501C Example 1- [(2-Mcthoxyquinoxalin-3-y)aminothiocarbonyl] (4-acetyiphenyl) piperazine Phenyl N- (2-methoxyqui'noxalin-3-yl)thiocarbamate and 1- (4-acetylphenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.

yield :56.9% m.p. :235 -237 0

C

Example 71) 43 1- [(2-Methoxyquinoxalin3yl )aminothiocarbonyll--4- (4-but-ylphenyl) piperazine Phenyl N- (2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(4-butylphenyl)piperazine w ere reacted by the same way with the example 63 to obtain the titled compound.

yield 62.5% m.p. 163-1651C Example 72) 1- [(2-Ethoxyquinoxalin-3-y)aminocarbonyl] piperazine Phenyl N- (2-ethoxyquinoxalin3-yl )carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 74.7% m.p. 149-150'C Example 73) 1-[I(2-Ethoxyquinoxain-3yl)aminocarbonyl1 (2-ethoxyphenyl) piperazine Phenyl N- (2-ethoxyquinoxalin-3yl)carbamate and 1-(2-ethoxyphenyl)>iperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 76.5% m.p. 120-1221C Example 74) 1- [(2-Ethoxyquinoxalin-3yl)aminocarbonyll piperazine Phenyl N- (2-ethoxyquinoxalin-3yl)carbamate and 1- (3,5-dimethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 82.0% m.p. 152-1541C 44 Example 1-[l(2-Ethoxyquinoxalin-3-yl)aminocarbonyl] (2,3-dimethyiphenyl) pi perazine Phenyl N- (2-ethoxyquinoxalin-3-yl)carbamate and 1-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 78.7% m.p. 108-1101C Example 76) 10 1- [(2-Ethoxyquinoxalin-3-yl)aminocarbonyl] (2-ethylphenyl)piperazine Phenyl N- (2-ethoxyquinoxalin-3yl)carbamate and 1-(2-ethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 77.5% m.p. 152-15 0

C

Example 77) 1- [(2-Ethoxyquinoxalin-3-y)aminocarbonyl] piperazine Phenyl N- (2-ethoxyquinoxalin-3yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 81.3% m.p. 157--1591C Example 78) 1- [(2-Ethoxyquinoxalin-3-yl)aminocarbonyll (3-bromophenyl)piperazine Phenyl N- (2-ethoxyquinoxalin-3-yl)carbamate and 1-(3--bromophenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 80.6% m.p. 164- 166 0

C

Example 79) 45 1- [(2-Ethoxyquinoxalin-3-yl)aminocarbonyll piperazine Phenyl N- (2-ethoxyquinoxalin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 78.6% m.p. :146-148,C Example 1- [(2-Ethoxyquinoxalin-3-yl)aminocarbonyll (2-methyithiophenyl) piperazine Phenyl N- (2-ethoxyquinoxalin-3-yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.

yield 71.4% m.p. 139-141'C Example 81) 1- [(2-Ethoxyquinoxalin-3-yl) N-methylaminocarbonyll -4- 1- [(2-Ethoxyquinoxalin-3-yl)aminocarbonyl] (3,5-dimethoxyphenyl) piperazine was reacted by the same way with the example 53 to obtain the titled compound.

yield 92.8% m.p. :159-1611C Example 82) 1- [(2-Ethoxyquinoxalin-3-yl) N-methylaminocarbonyl]-4- 1- [(2-Ethoxyquinoxalin-3yl)aminocarbonyl] piperazine was reacted by the same way with the example 53 to obtain the titled compound.

yield 94.5% m.p. :129-1311C Example 83) 1- [(2-Ethoxyquinoxalin-3-yl) N-ethylaminocarbonyl] -4- )piperazine 46 1- [(2-Ethoxyquinoxalin-3-yl)armnocarbonyll (3,5-dimethoxyphenyl) piperazine was reacted by the same way with the example 61 to obtain the titled compound.

yield 82.80% m.p. 144- 1460(3 Example 84) 1- [(2-Ethoxyquinoxalin3yl) N-ethylaminocarbonyl] -4- 1- [(2-Ethoxyquinoxalin-3-yl)aminocarbonyll piperazine was reacted by the same way with the example 61 to obtain 10 the titled compound.

yield 80.7% Example 85) 1- [(2-Ethoxyquinoxalin-3-yl) N-ethylaminocarbonyll -4- 1- [(2-Ethoxyquinoxalin-3-yl)aminocarbonyl] (3,5-dimethyiphenyl) piperazine was reacted by the same way with the example 61 to obtain the titled compound.

yield :78.8% m.p. :142-~1441C 1) 20 Example 86) 1- [(2-Methoxynaphth-3-yl)aninocarbonyl] (3,5-dimethylphenyl) piperazine a) Phenyl N- (2-methoxynaphth-3-yl)carbamate: 3-Amino-2-methoxynaphthalene(1. 13g, 6.53mmol) and phenylchloroformate(1.02g, 6.53mmol) were dissolved in dichloromethane.

The mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent'and purified by column chromatography to obtain the titled compound.

yield: 75.0% 105-~107*C b) 1- [(2-Methoxynaphth-3-yl)aminothocarbonyl] 47 piperazine: Phenyl N-(2-methoxynaphth-3-yl)carbamate(375mg, 1.28mmol) and 1-(3,5-dimethylphenyl)piperazine(208mg, 1.28mmol) were dissolved in anhydrous tetrahydrofuran(25ml) and thereto DBU(195mg, 1.28mmol) was added, and then stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.

yield 72.0% m.p. 117-119°C 10 Example 87) 1-[(2-Methoxynaphth-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl) piperazine Phenyl N-(2-methoxynaphth-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 86 to obtain the titled compound.

yield 74.5% m.p. 191-193°C Example 88) 1-[(2-Methoxynaphth-3-yl)aminocarbonyl]-4-(3,5-difluorophenyl) piperazine Phenyl N-(2-methoxynaphth-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 86 to obtain the titled compound.

yield 78.5% m.p. 160-161°C Example 89) 1-[(2-Methoxynaphth-3-yl)aminocarbonyl]-4-(3,5-dichlorophenyl) piperazine Phenyl N-(2-methoxynaphth-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 86 to obtain the titled compound.

48 yield 76.7% m.p. 182- 1841C Example 90) 1-[I(2-Methoxynaphth-3-yl) -N-methylaminocarbonyl] -4- To 1- [(2-methoxynaphth-3-yl)aminocarbonyll (3,5-dimethyiphenyl) piperazine(210mg, 0.54mmol) dissolved in dimethylforrramide( 15m1), sodium hydride(21.5mg, 0.54mmol) was added, stir-red at room temperature for 15 minutes, and thereto methyl iodide (76.6mg, 0.54rnmol) was added. The resulting mixture was stirred at room temperature for 6 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.

yield 86.4% m.p. :134- 1361C Example 91) 1- [(2-Methoxynaphth3yl) -N-methylaminocarbonyl] -4- 1- [(2-Methoxynaphth-3-y)aminocarbonyll (3,5-difluorophenyl) piperazine was reacted by the same way with the example 90 to obtain the titled compound.

yield :85.0% Example 92) 1- [(2-Methoxynaphth-3-y1-N-methylaminocarbonyll -4- 1- [(2-Methoxynaphth-3y) aminocarbonyl] (3,5-dichlorophenyl) piperazine was reacted by the same way with the example 90 to obtain the titled compound.

yield 89.8% m.p. :165-1671C Example 93) 1- [(2-Methoxynap~hth-3-y)-N-methylaminocarbonyll -4- 1- [(2-Methoxynaphth-3yl)ainocabofyl] (3,5-dimethoxyphenyl) 49 piperazine was reacted by the same way with the example 90 to obtain the titled compound.

yield 92.5% m.p. 83-85"C Example 94) (2-Methoxynaphth-3-yl)-N-ethylaminocarbonyl] -4- To 1-[(2-methoxynaphth-3-yl)aminocarbonyl] -4-(3,5-dimethylphenyl) piperazine(210mg, 0.54mmol) dissolved in dimethylformamide(15ml), sodium hydride(21.5mg, 0.54mmol) was added, stirred at room 10 temperature for 15 minutes, and thereto methyl iodide (84.2mg, 0.54mmol) was added. The mixture was stirred at room temperature for 6 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.

yield 70.2% Example 95) 1-[(2-Methoxynaphth-3-yl)-N-ethylaminocarbonyl]-4- 1-[(2-Methoxynaphth-3-yl)aminocarbonyl] -4-(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 94 to obtain the titled compound.

yield 85.0% Example 96) N-Hydroxy-N'-(5,6-dimethyl-2-methoxypyridin-3-yl) (4-phenylpiperazin-1-yl)carboxyimidamide To methyl N-(5,6-dimethyl-2-methoxpyridin-3-yl)-(4-phenylpiperazin-1-yl)iminothiorate (0.50g, 1.35mmol) dissolved in chloroform (30ml), hydroxylamine hydrochlroride (0.25g, 3.60mmol) and triethylamine (0.41g, 4.05mmol) were added and stirred at room temperature for hours, and then thereto water(30ml) was added to stop reaction. The resulting mixture was extracted with methylene chloride. The organic layer was concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.

50 yield 64.5% m.p. 173-1751C Example 97) N-Hydroxy-N' -(5,6-dimethyl-2-methoxypydn-3-yl)- (4-methylphenyl)piperazin-1 -yllcarboxyimidamide Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl) (4-methyiphenyl) piperazin-1-yllirninothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 55.2% m.p. 187- 1891C Example 98) N-Hydroxy-N' -(5,6-dimethyl-2-methoxypyridin3yl) (4-n-butylphenyl)piperazin-1 -yllcarboxyimidamide Methyl N- (5,6-dimethyl-2-methoxypyridin-3 yl) (4-n-butylphenyl) piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 60.1 m.p. 153-1551C Example 99) N-Hydroxy-N' -(5,6-dimethyl-2-methoxypyridin3yl) (3,5-dimethylphenyl)piperazin-1 -yl] carboxyimidamide Methyl N- (5,6-dmethyP2-methoxypyridin3yl> [4-(3,5-dimethylphenyl) piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 67.5% m.p. 125-1281C Example 100) N-Hydroxy-N' -(5,6-dimethyl-2-methoxypyridin3yl) (2-methoxyphenyl)piperazin-1-yllcarboxyimidamide Methyl N- (5,6-dimethyl-2-methoxypyridin3-yl) (2-methoxyphenyl) piperazin-1-y1]iminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

51 yield 62.0%o m.p. 134-1361C Example 101) N-Hydroxy-N' -(5,6-dimethyl-2-methoxypyn dn-3-yl) (3,5-dimethoxyphenyl)piperazin-1 -yllcarboxyiidamide Methyl N- (5,6-dimethyl-2methoxypyridin3y[) phenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 57.2% m.p. 188-1901C 10 Example 102) N-Hydroxy-N' -(5,6-dimethyl-2-methoxypyridin3yl) (3,5-difluorophenyl)piperazin- 1 -yllcarboxyim-idaMide Methyl N- (5,6-dimethyF2methoxypyridin3yl> phenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 60.7% m.p. 177-1781C Example 103) N-Hydroxy-N' -(5,6-dimethyl-2-methoxypyridin3yl) (3,5-dichlorophenyl)piperazin-1 -yllcarboxyimidamide Methyl N- (5,6-dimethyl-2-methoxypyridin-3-y1)-[4- phenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 65.4% m.p. 185-1871C Example 104) N-Hydroxy-N'- (5,6-dimethyl-2-methoxypyridin3yl) (3-bromophenyl)piperazin- 1-yllcarboxyimidamide Methyl N- (5,6-dimethyl-2-methoxypyridin3yl) (3-bromophenyl) piperazine-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 68.1 m.p. 174-1761C 52 Example 105) N-Hydroxy-N' -(5,6-dimethyl-2-methoxypyridin-3-yl) 1-yllcarboxyimidamide Methyl N- (5,6-dimethyl-2-methoxypyridin-3-Yl) phenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 45.2% m.p. 193-1951C Example 106) N-Hydroxy-N' -(5,6-dimethyl-2-methoxypyridn-3-yl) (3,5-diethylisophthal-l1-yl)piperazin- 1-yllcarboxyimidamide 10 Methyl N- (5-methoxycarbonyl-2-methoxy-6-methylpyfldin- 3 -yl) (3,5-diethylisophthal- 1-yl)piperazin- 1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 64.1 m.p. 166-1681C Example 107) N-Hydroxy-N' -(5,6-dimethyl-2-methoxypyridin-3-yl (hydroxymethyl)phenyllpiperazin- 1-yl~carboxyimidamide To N-hydroxy-N' -(5,6-dimethyl-2-methoxypyridin-3-yl)- (3,5-diethylisophthal-l1-yl)piperazin- 1-yllcarboxyimidarmde (500mg, 1.Ommol) dissolved in tetrahydrofuran(20m), lithium alumrinium hydride (57mg, 1.5mmol) were added slowly, and stirred at 20'C for 1 hours, and then thereto water(0.5m1) was added to stop reaction. The resulting mixture was concentrated under the reduced pressure to remove the solvent and extracted with methylene chloride with addition of water.

The organic layer was dried with magnesium sulfate and purified by column chromatography to obtain the titled compound.

yield 42.1 m.p. 184 1861C Example 108) N-Hydroxy-N' -(5-ethyl-2-methoxy6methylpyidin3yl) (2-methoxyphenyl )piperazin-1 -yllcarboxyimidamide 53 Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) (2-methoxyphenyl)piperazin- 1-yliliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 69.4% m.p. 134-135*C Example 109) N-Hydroxy-N' -(5-ethyl-2-methoxy6methylpyhidin3yl) methoxyphenyl)piperazin-1-yllcarboxyimidamide Methyl 10 N- (5-ethyl-2-methoxy-6-methylpyridin3yl) yphenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 68.2% Example 110) N-Hydroxy-N' -(5-ethyl-2-methoxy-6-methylpyridin-3-yl) (2-ethylphenyl)piperazin- 1-yllcarboxyimidamide Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) (2-ethylphen-yl) piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 70.2% m.p. 157-1601C Example 111) N-Hydroxy-N' -(5-ethyl-2-methoxy-6-methylpyridin-3-yl) -(4-phenylpiperazin- 1-yl~carboxyimidamide Methyl N- (5-ethyl-2-methoxy-6-methylpyridin -3-yl) -(4-phenylpiperazin-1-yl)i-minothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 72.2% m.p. 178-1801C 54 Example 112) N-Hydroxy-N' -(5-ethyl-2-methoxy-6-methylpyn'din-3-yl) (2-methylthiophenyl)piperazin- 1-yllcarboxyimidamide Methyl N- (5-ethyl- 2-methoxy-6-methylpyridin-3-yl) (2-methylthiophenyl)piperazin-1-yllimrinothiolate was reacted by the same way wit the example 96 to obtain the titled compound.

yield 69.3% m.p. 178 -1791C Example 113) N-Hydroxy-N'-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)- (3,5-dimethylphenyl)piperazin- 1-yllcarboxyimidarmde Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) phenyl)piperazin-1-yllin-inothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 64.7% m.p. 155- 1571C Example 114) N-Hydroxy-N' -(5-ethyl-2-methoxy-6-methylpyridin-3-yl)-[4-(3,5-difluorophenyl)piperazin-1 -yllcarboxyimidamide Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) phenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 51.8% m.p. 150-152 0

C

Example 115) N-Hydroxy-N' -(5-ethyl-2-methoxy-6-methylpyridin-3-yl)-[4- 1-yllcarboxyim-idamide Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) phenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

55 yield 72.2% m.p. 172-1741C Example 116) N-Hydroxy-N' -(5-ethyl-2-methoxy-6-methylpyridin-3-y)-[4- (2-biphenyl)piperazin- 1-yllcarboxyimidamide Methyl N- (5-ethyl-2-methoxy-6-methylpyridin.-3-yl) (2-biphenyl) piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 53.4% m.p. 195-197C Example 117) N-Hydroxy-N (5-ethyl-2-methoxy-6-methylpyridin-3-yl)- [4- (3,5-dinitrophenyl)piperazin-1 -yllcarboxyimidamiude Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) phenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 44.3% m.p. 193-1951C Example 118) N-Hydroxy-N' -(5-methoxycarbonyl-2-methoxy-6methylpyridn-3-yl) (3,5-dimethoxyphenyl)piperazin-1 -yllcarboxyimidamide Methyl N- (5-methoxycarbonyl-2-methoxy-6-methylpyriclin-3-yl) (3,5-dimethoxyphenyl)piperazin- 1-yllliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 61.6%o m.p. 192-1941C Example 119) N-Hydroxy-N' -(5-methoxycarbonyl-2-methoxy6methylpyridin-3'yl) (3,5-dimethylphenyl)piperazin-1 -yllcarboxyimidam-ide Methyl N- (5-methoxycarbonyl-2-methoxy6methylpyrdin3yl) (3,5-dimethylphenyl)piperazin-1 -yllirmnothiolate was reacted by the 56 same way with the example 96 to obtain the titled compound.

yield 63.00% m.p. 195-1971C Example 120) N-Hydroxy-N' -(5-methoxycarbonyl2methoxy-6methylpyn'dil 3 -yl) (3,5-difluorophenyl)piperazin-1 -yllcarboxyimidamide Methyl N- (5-methoxycrbonyl2methoxy-6methylpyridil3-y) difluorophenyl)piperazin-1iyliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 57.4% m.p. 170-1721C Example 121) N-Hydroxy-N' -(5-methoxycarbonyl2methoxy-6methylpyridne-3-yl) (2-methoxyphenyl)piperazin-1 -yllcarboxyimidamide Methyl N- (5-methoxycarbony2methoxy6methylpyidn 3 yl) (2-methoxyphenyl)piperazin-1 -yllirmnothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 65.1 m.p. 176-178 0

C

Example 122) N-Hydroxy-N' -(5-methoxycarbonyl-2-methoxy6methylpyridin3yl) (4-phenylpiperazin- 1-yl)carboxyimidamide Methyl N- (5-methoxycarbony2methoxy6methylpyridin 3 yl) (4-phenylpiperazin-1-yl)iminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 69.5%o m.p. 194--1961C Example 123) N-Hydroxy-N' -(5-methoxycarbonyl2methoxy-6methylpyridlfl3-yl) (4-methylphenyl)piperazin- 1 -yllcarboxyimidamide 57 Methyl N- (5-methoxycarbonylF2-methoxy-6-methylPYridll- 3 -yl) (4-methylphenyl)piperazin-1 -yllim-inothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 73.2% m.p. 190-192 0

C

Example 124) N-Hydroxy -(5-methoxycarbonyl-2-methoxyH-iflethylpyridine- 3 -yl) (3-chlorophenyl)piperazin- 1-yllcarboxyimidamide Methyl N- (5-methoxycarbony2-methoxy6-methylpyfdn 3 yl) [4-(3-chlorophenyl)piperazin-1-yliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 60.2%o m.p. 91 -93 IC Example 125) N-Hydroxy-N' -(5-hydroxymethyl-2-methoxy-6-methylpyfldin-3-yl) (3,5-dimethoxyphenyl)piperazin-1 -yllcarboxyimidamide To N-hydroxy-N' -(5-methoxycarbony2methoxy6methylF pyridin-3-yl)-[(4- (3,5-dimethoxyphenyl)piperazin-1 -yllcarboxyimidamide (300mg, .65mmol) dissolved in tetrahydrofuran(20m1), lithium aluminium hydride(37mg, 0.98mmol) was added slowly and stirred at 201C for 1 hours. Then, water(0.5m1) was added thereto to stop reaction. The resulting mixture was concentrated under the reduced pressure to remove the solvent, and extracted with methylene chloride with addition of water. The organic layer was dried with magnesium sulfate, and purified by column chromatography to obtain the titled compound.

yield 45.8% m.p. 185- 1871C Example 126) N-Hydroxy-N' -(5-hydroxymethy2methoxy-6methylpyr-ldine- 3 yl) (3,5-dimethylphenyl)piperazin-1 -yllcarboxyiniidamide Methyl N- (5-hydroxymethyl 2-methoxy6methylpyridin3yl) 58 (3,5-dimethylphenyl)piperazin- 1-yliiiminothiolate was reacted by the same way with the example 125 to obtain the titled compound.

yield 47.3% m.p. 127- 1291C Example 127) N-Hydroxy-N' -(5-hydroxymethyl-2-methoxy-6-methylpyridin-3-yl) (3,5-difluorophenyl)piperazin-1 -yllcarboxyimidamide Methyl N- (5-hydroxymethyl-2-methoxy6methylpyridin3yl) (3,5-difluorophenyl)piperazirn-1-yllimninothiolate was reacted by the 10 same way with the example 125 to obtain the titled 'compound.

yield 42.3% m.p. 179-1811C Example 128) N-Hydroxy-N' -(5-hydroxymethyl-2-methoxy-6-methylpy idn-3-yl) (2-methoxyphenyl)piperazin-1 -yllcarboxyimid-amide Methyl N- (5-hydroxymethyl-2-methoxy6methylpyridin3yl) (2-methoxyphenyl)piperazin-1 -yllirmnothiolate was reacted by the same way with the example 125 to obtain the titled compound.

yield 57.5% m.p. 129-131'C Example 129) N-Hydroxy-N' -(5-hydroxymethyl-2-methoxy-6-methylpyridine3yl) (4-phenylpiperazin-1 -yl)carboxyimidaniide Methyl N- (5-hydroxymethyl2methoxy6methylpyridin3yl) (4-phenylpiperazin-1-yl)iminothiolate was reacted by the same way with the example 125 to obtain the titled compound.

yield 61.6% m.p. 167-1691C Example 130) N-Hydroxy-N' -(5-hydroxymethyF2-methoxy-6-ethylpyn'din-3-yl) (4-methylphenyl)piperazin-1 -ylllcarboxyimida-mde 59 Methyl N- (5-hydroxymethyl-2-methoxy-6-methylpyn'din-3-yl) (4-methyiphe nyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 125 to obtain the titled compound.

yield 66.7% m.p. 157-1591C Example 131) N-Hydroxy-N' -(5-hydroxymethyl-2-methoxy-6-methylpyidin3yl) (3-chlorophenyl)piperazin-1 -yllcarboxyimidamide Methyl N- (5-hydroxymethyl-2-methoxy-6-methylpyridn-3-yl) (3-chlorophenyl)pipcrazin- 1-yljiminothiolate was reacted by the same way with the example 125 to obtain the titled compound.

yield 56.2% m.p. 171-1731C Example 132) N-Hydroxy-N' (5-acetyl-2-methoxy-6-methylpy idn-3-yl) (3,5-dimethylphenyl)piperazin- 1-yllcarboxyimidarm'de Methyl N- (5-acetyl-2-methoxy-6-methylpyridin-3-yl) phenyl)piperazin-1-ylliniinothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 35.1 m.p. 174- 1761C Example 133) N-Llydroxy-N' -(5-acetyl-2-methoxy-6-methylpyridin-3yl) methoxyphenyl)piperazin- 1-yllcarboxyimidamide Methyl N- (5-acetyl-2-methoxy-6-methylpyridin-3y) methoxyphenyl)piperazin-1-yllirmnothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 32.4%o m.p. 143-1451C 60 Example 134) N-Hydroxy-N' -(5-acetyl-2-methoxy-6-methylpyridifl-3-yl) (4-phenylpiperazin-1-yl)carboxyimidamide Methyl N- (5-acetyl-2-methoxy-6-methylpynldll- 3 -yl) -(4-phenylpipcrazin-1-yl,)iminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 40.5% m.p. 169-1701C Example 135) N-Hydroxy-N' -(5-acetyl-2-methoxy6methylpyridin-3-yl) (4-methylphenyl)piperazin-1 -yllcarboxyimidami~de Methyl N- (5-acetyl2methoxy-6methylpyidln 3 -yl) (4-methylphenyl)piperazinlylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 55.2% m.p. 164-1661C Example 136) N-Hydroxy-N' -(5-acetyl-2-methoxy6methylpyridin3yl) (3,5-difluorophenyl)piperazin-1 -yllcarboxyimidamide Methyl N- (5-acetyl-2-methoxy6methylpyridin3yl) phenyl)piperazin-1-yllirninothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 33.2% m.p. 184-185 0

C

Example 137) N-Hydroxy-N' -(5-acetyl-2-methoxy6methylpyidin 3 yl) (2-methylthiophenyl)piperazin-1 -yllcarboxyimidamide Methyl N- (5-acetyl-2methoxy6methylpyidifl 3 -yl (2-methylthiophenyl)piperazin-1yliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

61 yield 39.8% m.p. :178 -1791C Example 138) N-Hydroxy-N' (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] (3,5-dimethylphenyl)piperazin-1 -yllcarboxyimiclam-ide To N-hydroxy-N' -(5-acetyl-2-methoxy-6-methylpyridin-3-yl)- (3,5-dimethyiphenyl )piperazin-1 -yllcarboxyimidamide (150mg, 0.36mmol), ethanol(20m1) and then sodium borohydride(l7mg, 0.4Smmol) were added slowly. The resulting mixture was stirred at 20 'C for 4 hours, concentrated under the reduced pressure to remove the solvent, and extracted with methylene chloride with addition of water. The organic layer was dried with magnesium sulfate and purified by column chromatography to obtain the titled compound.

yield :75.6% m.p. :94 -96 *C Example 139) N-Hydroxy-N' (1-hydroxyethyl) -2-methoxy-6-methylpyridin3yll (3,5-dimethoxyphenyl)piperazin-1 -yllcarboxyimi damide Methyl N- (1-hydroxyethyl) -2-methoxy-6-methylpyridin3yl] (3,5-dimethoxyphenyl)piperazin-1ylliminothiolate was reacted by the ~iD same way with the example 138 to obtain the titled compound.

yield :65.6% m.p. :123-1251C Example 140) N-Hydroxy-N' (1-hydroxyethyl) -2-methoxy-6methylpyridin-3-ylI- (4-phenylpiperazin-1 -yl)carboxyimidamide Methyl N- (1-hydroxyethyl) -2-methoxy-6-methylpyridin3yl] (4-phenylpiperazin-liyl)iminothiolate was reacted by the same way with the example 138 to obtain the titled compound.

yield :72.3%o m.p. :154 -155 0

C

Example 141) 62 N-Hydroxy-N' (1-hydroxyethyl)-2-methoxy-6-methylpyridin-3-yl] (4-methylphenyl)piperazin-1 -yllcarboxyimi damide Methyl N- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] (4-methylphenyl)piperazin-1 -yllliminothiolate was reacted by the same way with the example 138 to obtain the titled compound.

yield 62.1 m.p. 187-1891C Example 142) N-Hydroxy-N' (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] 10 (3,5-difluorophenyl)piperazin-1 -yllcarboxyimi damide Methyl N- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] (3,5-difluorophenyl)piperazin-1 -yllirmnothiolate was reacted by the same way with the example 138 to obtain the titled compound.

yield 63.8% m.p. 156-157*C Example 143) N-Hydroxy-N' (1-hydroxyethyl)-2-methoxy-6-methylpyridin3yl] (2-methylthiophenyl)piperazin- 1-yllcarboxyimidaniide Methyl N- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] [4-(2-methylthiophenyl)piperazin-1iyllimnothiolate was reacted by the same way with the example 138 to obtain the titled compound.

yield 70.2% m.p. 162-1631C Example 144) N-Hydroxy-N' (1-hydroxyiminoethyl) -2-methoxy-6-methylpyridin-3-yll (3,5-dimethylphenyl)piperazin- 1-ylllcarboxyimidamide Methyl N- (5-acetyl-2-methoxy-6-methylpydin3yl) 1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield :23.2% Example 145) 63 N-Hydroxy-N' (1-hydroxyiminoethyl) -2-methoxy-6-methylpyridin-3yl] (3,5-dimethoxyphenyl)piperazin- 1-yljcarboxyimidaniide Methyl N-(5-acetyl-2-methoxy-6-methylpydn-3-yl)-[4-(3,5dimethoxyphenyl)piperazin-1Py]iminothiolate was reacted by th same way with the example 96 to obtain the titled compound.

yield :35.6% Example 146) N-Hydroxy-N' (1-hydroxyiminoethyl) -2-methoxy-6-methylpyridin-3yl]- (3,5-difluorophenyl)piperazin- 1-yllcarboxyirm'daniide 10 Methyl N- (5-acetyl-2-methoxy-6-methylpyridin-3-yl difluorophenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield :33.3% Example 147) N-Hydroxy-N' (1-hydroxyiminoethyl) -2-methoxy-6-methylpyridin-3yl]- (2-methylthiophenyl)piperazin- 1-ylllcarboxyim-idamide Methyl N- (5-acetyl-2-methoxy-6-methylpyridin3yl) (2-methylthiophenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield :30.2% Example 148) N-Hydroxy-N' (1-hydroxyirminoethyl)-2-methoxy-6-methylpyridin-3yll (3,5-dinitrophenyl)piperazin- 1-yllcarboxyim-idamide Methyl N- (5-acetyl-2-methoxy-6-methylpyridin3yl) dinitrophenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield :29.5% Example 149) N-Hydroxy-N' (1-hydroxyiminoethyl) -2-methoxy-6-me-thylpyridin-3 -yl] (4-methylphenyl)piperazin-1 -yllcarboxyimidamide Methyl N- (5-acetyl-2-methoxy-6-methylpyr dn-3-yl)- (4- 64 methylphenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield :25.0% Example 150) N-Hydroxy-N' (1-am-inoethyl) -2-methoxy-6-methylpyridin-3-yl] 1-yllcarboxyitnidamide Methyl N- (1-am-inoethyl) -2-methoxy-6-methylpyriclin-3-yl] (3,5-dimethylphenyl)piperazin- 1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

10 yield :45.6% Example 151) N-Hydroxy-N' (1-aminoethyl) -2-methoxy-6-methylpyridin-3-yll (3,5-dimethoxyphenyl)piperazin- 1-yllcarboxyimidamide Methyl N-ES- (1-aminoethyl) -2-methoxy-6-methylpyridi-3-yl] (3,5-dimethoxyphenyl)piperazin- 1-ylliniinothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield :42.2% Example 152) N-Hydroxy-N' (1-aniinoethyl) -2-methoxy-6-methylpynidin-3-yll 20 (3,5-difluorophenyl)piperazin-1 -yllcarboxyinii~damide Methyl N-ES- (1-aminoethyl) -2-methoxy-6-methylpyridin-3-yl] (3,5-difluorophenyl)piperazin- 1-yllimninothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 53.1 Example 153) N-Hydroxy-N' (1-am-inoethyl) -2-methoxy-6-methylpyridin-3-yl] (2-methylthiophenyl)piperazin-1 -yllcarboxyimidamide Methyl N- (1-aminoethyl) -2-methoxy-6-methylpyridin-3-yl] (2-methylthiophenyl)piperazin -1 -yllimninothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield :44.7% 65 Example 154) N-Hydroxy-N' (1-aminoethyl) -2-methoxy-6-methylpyridin-3-yl] (3,5-dinitrophenyl )piperazin- 1-yllcarboxyimidarni'de Methyl N-ES- (1-amninoethyl) -2-methoxy-6-methylpyridin-3-yl] dinitrophenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield :52.1% Example 155) N-Hydroxy-N' (1-aminoethyl) -2-methoxy-6-methylpyridin-3-yl] (3,5-chlorophenyl)piperazin- 1-yllcarboxyimidamide Methyl N-ES- (1-aminoethyl) -2-methoxy-6-methylpyridin-3-yl] (3,5-chlorophenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield :47.6% Example 156) N-Hydroxy-N' -(6-ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) (4-methylphenyl)piperazin- 1-yllcarboxyimidamide Methyl N- (6-ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) [4-(4-methylphenyl)piperazin-1iylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 71.2% m.p. 176-1781C Example 157) N-Hydroxy-N' -(6-ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) (2-ethylphenyl)piperazin- 1-yl] carboxyimidamide Methyl N- (6-ethyl-5-methoxycarbonyl -2-methoxypyridin-3-yl) (2ethylphenyl)piperazin- 1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 65.0% m.p. 182-1841C 66 Example 158) N-Hydroxy-N' 6 -ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) (3,5-dimethylphenyl)piperazin-1 -yllcarboxyimidamide Methyl N- 6 -ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) (3,5-dimethylphenyl)piperazin- 1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 59.1 m.p. 152-1551C Example 159) N-Hydroxy-N' 6 -ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) 1-yllcarboxyimidam-ide Methyl N- 6 -ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) dimethoxyphenyl)piperazin-1-yli-inothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 55.6% m.p. 156-1571C Example 160) N-Llydroxy-N' 6 -ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) (3,5-dichlorophenyl)piperazin- 1-yllcarboxyimidamide Methyl N- 6 -ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) 3 ,5-dichlorophenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 54.4% m.p. 158- 160'C Example 161) N-Hydroxy-N' -(6-ethyl-5-methoxycarbonyl-2-methoxypyn'din-3-yl) (2-methylthiophenyl)piperazin- 1-ylllcarboxyimidamide Methyl N- 6 -ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) (2-methylthiophenyl)piperazin- 1-yl] iminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

67 yield 50.1% m.p. 168- 1701C Example 162) N-Hydroxy-N' -(6-ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) (3,5-diethylisophthalate- 1-yl)piperazin- 1-yllcarboxyiidam-ide Methyl N- (6-ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) 1-yl)piperazin- 1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 57.3% m.p. 101-103'C Example 163) N-Hydroxy-N' -(6-ethyl-5-methoxycarbonyl-2-methoxypyrildin-3-yl) 1-yllcarboxyimid-aniide Methyl N- (6-ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) (3,5-difluorophenyl)piperazin- 1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 45.0% m.p. 143-1451C Example 164) N-Hydroxy-N' -(6-ethyl-5-hydroxymethyl-2-methoxypyridin-3-yl) (4-methylphenyl)piperazin- 1-yllcarboxyimidamide Methyl N- (6-ethyl-5-hydroxymethyl-2-methoxypyridin-3-yl) (4-methylphenyl)piperazin-1-ylliminothiolate was reacted by the same way with the example 125 to obtain the titled compound.

yield 66.6%o m.p. 170-1721C Example 165) N-Hydroxy-N' -(6-ethyl-5-hydroxymethyl-2-methoxypyridin-3-yl) (2-ethylphenyl)piperazin- 1-yllcarboxyimidamide Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) (2-ethylphenyl)piperazin-1-ylliminothiolate was reacted by the same way with 68 the example 125 to obtain the titled compound.

yield 60.4% M.P. 185-1871C Example 166) N-Hydroxy-N' -(6-ethyl-5-hydroxymethyV2-methoxypyridin3-yl) (3,5-dimethylphenyl)piperazin-1-yl] carboxyimidam-ide Methyl N- (6-ethyl-5-hydroxymethyF2methoxypyridin3yl) (3,5-dimethylphenyl)piperazin-1 -yl] im-inothiolate was reacted by the same way with the example 125 to obtain the titled compound.

10 yield 65.1% m.p. 75 -771C Example 167) N-Hydroxy-N' -(6-ethyl-5-hydroxymethylV2-methoxypyn'din3yl) (3,5-dimethoxyphenyl)piperazin-1-yllcarboxyirnidamide Methyl N- (6-ethyl-5-hydroxymethyP2methoxypyridin3yl) dimethoxyphenyl)piperazin-1iylliminothiolate was reacted by the same way with the example 125 to obtain the titled compound.

yield 61.2% m.P. 67 -691C Example 168) N-Hydroxy-N' -(6-ethyl-5-hydroxymethy2methoxypyridin3-yl) (3, 1-yllcarboxyimidamide Methyl N- (6-ethyl-5-hydroxymethyl2methoxypyridin-3y) dichlorophenyl)piperazin-1iyliminothiolate was reacted by the same way with the example 125 to obtain the titled compound.

yield 70.1% m.p. 75 -77 0

C

Example 169) N-Hydroxy-N' -(6-ethyl-5-hydroxymethyl -2-methoxypyridin-3-yl) [4-(2-methylthlophenyl)piperazin-1 -yllcarboxyimidarnide Methyl N- (6-ethyl-5-hydroxymethyb2-methoxyPyridin3yl) (2- 69 methylthiophenyl)piperazin- 1-ylliminothiolate was reacted by the same way with the example 125 to obtain the titled compound.

yield 67.2% m.p. 163- 1651C3 Example 170) N -Hydroxy-N'- (6-ethyl-5-hydroxymethyl-2-methoxypyridin-3-yl)- {4- -bis (hydroxymethyl)phenyllpiperazin- 1-yl Icarboxyimidamide Methyl N- (6-ethyl-5-hydroxymethyl-2-methoxypyridin-3-yl) his (hydroxymethyl)phenyllpiperazin- 1-ylliminothiolate was reacted by the 10 same way with the example 125 to obtain the titled compound yield :59.4% Example 171) N-Hydroxy-N' -(6-ethyl-5-hydroxymethyl-2-methoxypyridin-3-yl) 1-yllcarboxyirmdaniide Methyl N- (6-ethyl-5-hydroxymethyl-2-methoxypyridin-3-yl) difluorophenyl)piperazin-1-yllimi nothiolate was reacted by the same way with the example 125 to obtain the titled compound.

yield 48.7% m.p. 68 701C Example 172) N-Hydroxy-N' -(2-methoxyquinolin-3-yl) (3,5-dimethoxyphenyl) piperazin- 1-yllcarboxyimidamnide Methyl N- (2-methoxyquinolin-3-yl) (3,5-dimethoxyphenyl) piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 41.0% m.p. 215-~2171C Example 173) N-Hydroxy-N' -(2-methoxyquinolin-3-yl) (3,5-dimethyiphenyl) piperazin- 1-ylllcarboxyimidamide Methyl N- (2-methoxyquinolin-3-yl) (3,5-dimethiylphenyl) 70 piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 44.2% m.p. 182-1841C Example 174) N-Hydroxy-N' -(2-methoxyquinolin-3-yl)-[4- (3,5-difluoro-phenyl) piperazin-1 -yl~carboxyim-idamide Methyl N- (2-methoxyquinolin-3-yl)- (3,5-difluorophenyl) piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 38.1 m.p. 163-1651C Example 175) N-Hydroxy-N' -(2-methoxyquinolin-3-yl) (2-methoxyphenyl) piperazin- 1-yllcarboxyirnidamide Methyl N- (2-methoxyquinolin-3-yl)- (2-methoxyphenyl) piperazin-1-ylliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 43.2% m.p. 210-212'C Example 176) N-Hydroxy-N' -(2-methoxyquinolin-3-yl) (3-chlorophenyl) piperazin- 1-yllcarboxyimidamide Methyl N- (2-methoxyquinolin-3-yl) (3-chlorophenyl)piperazin -1 -yl] iminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 45.2%o m.p. 162-1641C Example 177) N-Hydroxy-N' -(4,5-dimethyl-2-methoxyphenyl- 1-yl) -(4-phenyl- 71 piperazin-1 -yl)carboxyimidamide Methyl N- 4 ,5-dimethyl-2-methoxyphenyl- 1-yl) 4 -phenylpiperazin- 1yl~iminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield :62.7% m.p. 160-1621C Example 178) N-Hydroxy-N' 4 ,5-dimethyl-2-methoxyphenyl- I.-yl) (4-methylphenyl)piperazin- 1-yllcarboxyimidamide 10 Methyl N- 4 ,5-dimethyl-2-methoxyphenyl 1 -yl) (4-methylphenyl) piperazin-1-ylliminothjolate was reacted by the same way with the example 96 to obtain the titled compound.

yield :60.1% m.p. :181 -183 "C Example 179) N-Hydroxy-N' 4 ,5-dimethyl-2-methoxyphenyl- 1-yl) (2-ethylphenyl)piperazin-1 -yllcarboxyimidan-ide Methyl N- 4 ,5-dimethyl-2-methoxyphenyl 1 -yl) (2-ethylphenyl) piperazin-1I-yliminothiol ate was reacted by the same way with the example 96 to obtain the titled compound.

yield :65.4% m.p. :194-1961C Example 180) N-Hydroxy-N' 4 ,5-dimethyl-2-methoxyphenyl- 1-yl) 3 ,5-dimethylphenylpiperazin- 1-yllcarboxyimidamide Methyl N- 4 ,5-dimethyl-2-methoxyphenyl 1 -yl) (3,5-dimethyiphenyl) piperazin-1-yllininothjolate was reacted by the same way with the example 96 to obtain the titled compound.

yield :64.1 m.p. :184 -186'C Example 181) N-Hydroxy-N' 4 ,5-dimethyl-2-methoxyphenyl- 1-yl 72 3 ,5-dimethoxyphenyl)piperazin -1 yllcarboxyimidamide Methyl N- 4 ,5-dimethy-2-methoxyphenyp 1 -yl) 3 phenyl)piperazin-1-yllinnothjolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 65.5% M.P. 189-1911C Example 182) N-Hydroxy-N' 4 ,5-dimethyl-2-methoxyphenyj 1 -yl) 3 ,5-difluorophenyl)piperazin 1 -yllcarboxyirnidarrjde Methyl N- 4 ,5-dimethyl-2-methoxyphenyj-1-yl) 3 phnl-ieai-1ylmntilt was reacted by the same way with the example 96 to obtain the titled compound.

yield 60.0% m.p. 179-181*C Example 183) N-Hydroxy-N' 4 ,5-dimethyl-2-methoxyphenyl-1 -yl) (3-chlorophenyl)piperazin-1 -yllcarboxyirnidamide Methyl N- 4 ,5-dimethyl-2-methoxyphenyl-1 -yl) 3 -chlorophenyl) piperazin-l-yinjnothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 58.7% m.p. 174-1761C Example 184) N-Hydroxy-N' 4 ,5-dimethyl-2-methoxyphenyl-1 -yl) (3-bromophenyl)piperazin- 1-yllcarboxyimjidan-lide Methyl N- 4 ,5-dimethyl-2-methoxyphenyl-1 -yl) 44- 3 bromophenyl)piperazin-1-yliminothiolate was reacted by the same way with the example 96 to obtain the titled compound.

yield 61.2% m.p. 178-1801C Example 185) N-Hydroxy-N 4 ,5-dimethyl-2-methoxyphenyl-1 -yl) 2 -methyl- 73 thiophenyl)piperazin- 1-yllcarboxyimidamide Methyl N- (4,5-dimethyl-2-methoxyphenyl- 1-yl)-114- (2-methylthiophenyl)piperazin-1-ylliminothiolate was reacted by the same way with the ex-ample 96 to obtain the titled compound.

yield 60.5% m.p. 194- 1961C Example 186) N-Methoxy-N'- (5,6-dimethyl-2-methoxypyridin-3-yl) phenylpiperazin- 1-yl)carboxyimidamide To N-hydroxy-N' -(5,6-dimethyl-2-methoxypyridin-3-yl)- (4-phenyl- 10 piperazin-1-yl)carboxyimidamide (0.5g, 1.4lmmol) dissolved in dimethylformamide (i5nmi), sodium hydride(60%, 57.8mg, 1.45mmuol) and methyl iodide (0.20g, 1.4lmmol) were added and stirred for 4 hours and then water(20m1) was added thereto to stop reaction. The resulting mixture was extracted with ethylether. The organic layer was concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.

yield :89.1 Example 187) N-Methoxy-N' -(5,6-dimethyl-2-methoxypynidin-3-yl) (4-methylphenyl)piperazin-1 -yllcarboxyimiidami de N-Hydroxy-N' -(5,6-dimethyl-2-methoxypyridin-3-yl) (4-methylphenyl)piperazin-1-yllcarboxyimida-ide was reacted by the same way with the example 186 to obtain the titled compound.

yield :92.2% Example 188) N-Methoxy-N' -(5,6-dimethyl-2-methoxypyridin-3-yl) phenyl)piperazin- 1-ylllcarboxyimidamide N-Hydroxy-N' -(5,6-dimethyl-2-methoxypyridin-3-yl) dimethylphenyl)piperazin- 1-yllcarboxyimidamide was reacted by the same way with the example 186 to obtain the titled compound.

yield :90.0% 74 Example 189) N-Methoxy-N' -(5,6-dimethyl-2-methoxypyridin-3-yl) methoxyphenyl)piperazin- 1-yllcarboxyim-idamide N-Hydroxy-N' -(5,6-dimethyl-2-methoxypyridin-3-yl) methoxyphenyl)piperazin-1-yllcarboxyimidamide was reacted by the same way with the example 186 to obtain the titled compound.

yield :92.2% Example 190) N-Methoxy-N' -(5,6-dimethyl-2-methoxypyridin-3-yl) phenyl)piperazin- 1-yllcarboxyimidamide N-Hydroxy-N' -(5,6-dimethyl- 2-methoxypyridin-3-yl phenyl)piperazin-1-yllcarboxyimidamide was reacted by the same way with the example 186 to obtain the titled compound.

yield :85.2% Example 191) N-Methoxy-N' -(5,6-dimethyl-2-methoxypyridin-3-yl) (2-methylthiophenyl)piperazin- 1-yllcarboxyimidamide N-Hydroxy-N' -(5,6-dimethyl-2-methoxypyridin -3-yl) (2-methylthiophenyl)piperazin- 1-yllcarboxymidamide was reacted by the same way with the example 186 to obtain the titled compound.

yield :89.2% Example 192) N-Methoxy-N' -(5,6-dimethyl-2-methoxypyridin-3-yl) (3,5-dini trophenyl)piperazin- 1-yllcarboxyimidam-ide N-Hydroxy-N'- (5,6-dimethyl-2-methoxypyridin-3-yl) phenyl)piperazin-1-yllcarboxyimidamide was reacted by the same way with the example 186 to obtain the titled compound.

yield :79.5% Example 193) N-Methoxy-N' -(5-ethyl-6-methyl-2-methoxypyridin-3-yl) chlorophenyl)piperazin- 1-yllcarboxyimidamide 75 N-Hydroxy-N' (-ethyl-6-methyl-2-methoxypyridin-3-yl) dichlorophenyl)piperazin-1-yllcarboxyimidamide was reacted by the same way with the example 186 to obtain the titled compound.

yield 84.2%o m.p. 163-165 0

C

Example 194) N-Methoxy-N (6-ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) (3,5-difluorophenyl)piperazin- 1-yllcarboxyimid-amide N-Hydroxy-N' -(6-ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) 10 (3,5-difluorophenyl)piperazin- 1-yllcarboxyimidaumde was reacted by the same way with the example 186 to obtain the titled compound.

yield :91.3% Example 195) N-Methoxy-N' -(6-ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) (3,5-diethylisophthal- 1-yl)piperazin- 1-yllcarboxyimidamide N-Hydroxy-N' -(6-ethyl--5-methoxycarbonyl-2-methoxypyridin-3-yt) (3,5-diethylisophthal- 1-yl)piperazin- 1-yllcarboxyimidarmde was reacted by the same way with the example 186 to obtain the titled compound.

yield :94.0% Example 196) N-Methoxy-N' -(6-ethyl-5-hydroxymethyi -2-methoxypyridin-3-yl) (hydroxymethyl)phenyl- 1-yllpiperazin- 1-yl Icarboxyimidamide N-methoxy-N' -(6-ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl) [4-(3,5-diethylisophthal- 1-yl )piperazin- 1-yllcarboxyimidamide was reacted by the same way with the example 186 to obtain the titled compound.

yield :68.0% Example 197) N-MethoxyN' -(4,5-dimethyl-2-methoxyphenyl- 1-yl) (4-methyl phenyl)piperazin- 1-yl] carboxyimidami de I U1 76 N-Hydroxy-N'- (4,5-dimethyl-2-methoxyphenyl-1-yl)-[4- (4-methylphenyl)piperazin-1-yl]carboxyimidamide was reacted by the same way with the example 186 to obtain the titled compound.

yield 86.7% Example 198) N-Methoxy-N'-(4,5-dimethyl-2-methoxyphenyl-1-yl)- (3,5-dimethylphenyl)piperazin- 1 -yl]carboxyinidamide N-Hydroxy-N' -(4,5-dimethyl-2-methoxyphenyl-1-yl)-[4-(3,5-dimethylphenyl)piperazin-1-yllcarboxyimidamide was reacted by the same way with the example 186 to obtain the titled compound.

9 10 yield 87.0% Example 199) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)-(4-phenylpiperazin-1-yl)iminothiolate To 1-[(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-phenylpiperazine (0.5g, 1.4Ommol) dissolved in sodium hydride 56.1mg, 1.4Ommol) and methyl iodide (0.20g, 1.4lmmol) were added. The resulting mixture was stirred for 2 hours and then water(20ml) was added thereto to stop reaction. The resulting mixture was purified by column chromatography to obtain the titled compound.

yield 92.4% Example 200) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (4-et-hylphenyl) piperazin- 1 -ylliminothiolate 1- [(5,6-Dimethyl-2-methoxypyridin-3-yl)aminotiocarbonyl] (4methylphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield 95.2% Example 201) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl) (4-nbutylphenyl)piperazin- 1 -yl]iminothiolate 1- [(5,6-Dimethyl-2-methoxypyridin-3-yl)aminothiocarbonyl]

U_

77 butylphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield 93.4% Example 202) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)-[4-(3,5-dimethyiphenyl)piperazin-1 -ylliminothiolate 1-L(5,6-Dimethyl-2-methoxypyridin-3-yl)ainothiocarbonyl-4-(3,5-dimethylphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield 97.2% Example 203) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)- (2-methoxyphenyl)piperazin-1 -yl]iminothiolate 1-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminothiocarbonyl methoxyphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield 97.4% Example 204) Methyl N- (5.6-dimethyl-2-methoxypyridin-3-yl)-[4-(3,5-dimethoxyphenyl)piperazin-1 -ylliminothiolate 1- [(5,6-Dimethyl-2-methoxypyridin-3-yl)ariinothiocarbonyl] dimethoxyphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield 95.2% Example 205) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl) (3,5-di-fluorophenyl) piperazin-1 -ylliminothiolate 1- [(5,6-Dimethyl-2-methoxypyridin-3-yl) aminothiocarbonyl] difluorophcnyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield 90.1% 78 Example 206) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl) (3,5-di-chiorophenyl) piperazin- 1-ylliminothiolate 1- [(5,6-Dimethyl-2-methoxypyridin-3-yl)ami'nothiocarbonyl] (3,5-di chlorophenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :92.5% Example 207) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl) -14- (3-bromophenyl) piperazin-1-ylliminothiolate 1- [(5,6-Dimethyl-2-methoxypyridin-3-yl)ami nothiocarbonyl (3bromophenyl~piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :89.5% Example 208) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)- (3,5-di-nitrophenyl) piperazin- 1-ylliminothiolate 1- [(5,6-Dimethyl-2-methoxypyridin-3-yl)aminothiocarbonyll-4- dinitrophenyl~piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :92.9% Example 209) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl) -14- (3,5-di-ethylisophthal-l1-yl) piperazin-1 -ylliminothiolate 1- [(5,6-Dimethyl-2-methoxypyridin-3-yl)aminoth-iocarbonyl] diethylisophthal-1-yl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :92.9% Example 210) Methyl N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)-(4phenyl)piperazin-1 -yllliminothiolate 1- [(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)aminothlocarbonyl -4- 79 phenylpiperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :92.2% Example 211) Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl (2-methoxyphenyl)piperazin- 1-ylliminothiolate 1- [(5-Ethyl-2-methoxy-6-methylpyidin-3-yl)aminothiocarbonyl] -4- (2-methoxyphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :87.2% Example 212) Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) (3,5-dimethoxyphenyl) piperazin- 1-ylliminothiolate 1- [(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl -4was reacted by the same way with the example 199 to obtain the titled compound.

yield :92.4% Example 213) Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) (2-ethylphenyl)piperazin- 1-ylliminothiolate 1- [(5-Ethyl-2-methoxy-6-methylpynidin-3-yl)aminothiocarbonyl -4- (2-ethylphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :93.6% Example 214) Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl)- (3,5-dimethylphenyl)piperazin-l1-yllim-inothiolate 1- [(5-Ethyb2-methoxy6methylpyridin-3-yl)aminothocarbonyl] -4was reacted by the same way with the example 199 to obtain the titled compound.

yield :96.2% Example 215) Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) (3,5-difluorophenyl) piperazin- 1-yllliminothiolate 80 1- [(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)amrinothiocarbonyl -4was reacted by the same way with the example 199 to obtain the titled compound.

yield :92.5% Example 216) Methyl N- (5-ethyl- 2-methoxy--6-methylpyridin-3-yl) (3,5-dichiorophenyl) piperazin-1 -ylliminothiolate 1- [(5-Ethyl-2-methoxy-6-methylpynidin-3-yl)a-inothocarbonyl] -4was reacted by the same way with the example 199 to obtain the titled compound.

yield :93.2% Example 217) Methyl N- (5-ethyl-2-metho~xy-6-methylpyridin-3-yl [4- (2-phenylphenyl)piperazin- 1-ylliminothiolate 1- [(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl] -4- (2-phenylphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :91.4% Example 218) Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) (3,5-dinitrophenyl) piperazin- 1-yllirninothiolate 1- [(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl] -4was reacted by the same way with the example 199 to obtain the titled compound.

yield :94.2% Example 219) Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl) (2-methylthiophenyl)piperazin-l1-ylliminothiolate 1- [(5-Ethyl-2-methoxy-6-methylpyridin-3-yl)aninothocarbonyl] -4- (2-methylthiophenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :90.5%~ Example 220) Methyl 81 N- (5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl) dimethoxyphenyl)piperazin- 1-ylliminothiolate 1- [(5-Methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl] (3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :93.2% Example 221) Methyl N- (5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl) -14- dimethylphenyl)piperazin- 1-ylliminothiolate 1- [(5-Methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl] (3,5-dimethylphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :92.9% Example 222) Methyl N- (5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl) difluorophenyl)piperazin- 1-ylliminothiolate 1- [(S-Methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)am-inothiocarbonyl]-4-(3,5-difluorophenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :88.5% Example 223) Methyl N- (5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl) (2methoxyphenyl)piperazin- 1-ylliminothiolate 1- [(5-Methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl]-4-(2-methoxyphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :90.2% Example 224) Methyl N- (5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl) -(4-phenylpiperazin- 1-y~irminothiolate 1- [(5-Methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl )aminothio- 82 carbonyl]-4-phenylpiperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :93.5% Example 225) Methyl N- (5-methoxycarbonyl-2-methoxy-6-methylpynidin-3-yl) -[4-(4-methylphenyl)piperazin-1 -ylliminothiolate 1- [(5-Methoxycarbonyl-2-methoxy-6-methylpyriclin-3-yl)aminothiocarbonyl]-4-(4-methylphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :97.5% Example 226) Methyl N- (5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl) (2-chlorophenyl)piperazin- 1-ylliminothiolate 1- [(5-Methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl]-4-(2-chlorophenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :95.5% Example 227) Methyl N- 2 -methoxy-5-methylcarbonyl-6-methylpyridin- 3-yl) (3,5-dlimethylphenyl)piperazin- 1-ylliminothiolate 1- [(5-Methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl]-4-(3,5-dimethylphenyl)piperazine was reacted by. the same way with the example 199 to obtain the titled compound.

yield :96.2% Example 228) Methyl N- 2 -methoxy-5-methylcarbonyl-6-methylpynidin- 3-yl) (3,5-dimethoxyphenyl)piperazin- 1-ylliminothiolate 1- [(5-Methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl )aminothiocarbonyll dimethoxyphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :95.4% Example 229) Methyl N- 2 -methoxy-5-methylcarbonyl-6-methylpyridin- 3-yl) -(4-phenylpiperazin- 1-yl)imninothiolate 83 1- [(5-Methoxycarbonyl-2-methoxy-6-methylpyridin-3-ylaminothiocarbonylj-4-phenylpiperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :90.1 Example 230) Methyl N- 2 -methoxy-5-methylcarbonyl-6-methylpyridin- 3-yl) (4-methylphenyl)piperazin- 1-yllimninothiolate 1- [(5-Methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyll-4-(4-methylphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :92.2% Example 231) Methyl N- 2 -methoxy-5-methylcarbonyl-6-methylpyridin 3-yl) (3,5-difluorophenyl)piperazin- 1-ylliniinothiolate 1- [(5-Methoxycarbonyl-2-methoxy-6-methylpyridin-3-y)am-inothiocarbonyl]-4-(3,5-difluorophenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :93.1 Example 232) Methyl N- 2 -methoxy-5-methylcarbonyl-6-methylpyridin- 3-yl) (2-methylthiophenyl)piperazin- 1-yljimninothiolate 1- [(5-Methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyll-4-2-methylthiophenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :90.0% Example 233) Methyl N- 6 -ethyl-5-methoxycarbonyl-2-methoxypyridin- 3-yl) (4-methylphenyl)piperazin- 1-ylliminothiolate 1- [(6-Ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl)aminothiocarbonyll-4-(4-methylphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :91.1% Example 234) Methyl N- 6 -ethyl-5-methoxycarbonyl-2-methoxypyridin- 3-yl) (2-ethylphenyl)piperazin- 1-ylliminothiolate 1- [(6-Ethyl-5-methoxycarbonyl-2-methoxypynidin -3-yl)aminothio- 84 carbonyl]-4-(2-ethylphenyl)pperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :90.4% Example 235) Methyl N- (6-ethyl-5-methoxycarbonyl-2-methoxypyridjn- 3-yl) (3,5-dimethylphenyl)piperazin- 1-ylliminothiolate 1- [(6-Ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl)aminothiocarbonyl] (3,5-dimethylphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :95.5% Example 236) Methyl N- 6 -ethyl-5-methoxycarbonyl-2-methoxypyridin- 3-yl) (3,5-dimethoxyphenyl)piperazin- 1-yllirninothiolate 1- [(6-Ethyl-5-methoxycarbonyl-2-methoxypyridin-3-y)aminothiocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :95.4% Example 237) Methyl N- (6-ethyl-5-methoxycarbonyl-2-methoxypyridin- 3-yl) (3,5-dichlorophenyl)piperazin- 1-ylliminoth-iolate 1- [(6-Ethyl-5-methoxycarbonyl-2-methoxypyricjjn-3-yl)aninofiiocarbonyll-4-(3,5-dichlorophenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :90.5% Example 238) Methyl N- (6-ethyl-5-methoxycarbonyl-2-methoxypyridin- 3-yl) (2-methylthiophenyl)piperazin- 1-ylliminothiolate 1- 6 -Ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl)aminothiocarbonyl]-4-(2-methylthiophenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :92.0% Example 239) Methyl N- (6-ethyl-5-methoxycarbonyl-2-methoxypyridin- 3-yl) (3,5-diethylisophthalate- 1-yl)piperazin- 1-ylliminothi-olate 1- [(6-Ethyl-5-methoxycarbonyl-2-methoxypynidin-3-yl)aminothiocarbonyll (3,5-diethylisophthalate- 1-yl)piperazine was reacted by the 85 same way with the example 199 to obtain the titled compound.

yield :93.2% Example 240) Methyl N- (6-ethyl-5-methoxycarbonyl-2-methoxypyridin- 3-yl) (3,5-difluorophenyl)piperazin- 1-ylliminothiolate 1- [(6-Ethyl-5-methoxycarbonyl-2-methoxypyridin-3-yl)aminothiocarbonyll-4-(3,5-difluorophenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :95.2% Example 241) Methyl 10 N- (2-methoxyquinolihn-3-yl (3,5-dimethoxyphe-nyl)piperazin- 1-yl] iminothiolate 1- [(2-Methoxyquinolin-3-yl)ami'nothocarbonyl] phenyl~piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :90.3% Example 242) Methyl N- (2-methoxyquinolin-3-yl (3,5-dimethylphenyl)piperazin- 1-yl] iminothiolate 1- [(2-Methoxyquinolin-3-yl )aminothiocarbonyl] phenyl~piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :91.1% Example 243) Methyl N- (2-methoxyquinolin-3-yl) -14- phenyl)piperazin- 1-ylllimnothiolate 1- [(2-Methoxyquinolin-3yl)aminothiocarbonyl] 4-(3,5-difluorophenyl) -piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :94.2%o Example 244) Methyl N- (2-methoxyquinolin-3-yl)- (2-methoxyphenyl) piperazin- 1-yl] iminothiolate 86 1-[(2-Methoxyquinolin-3-yl)aminothiocarbonyl]-4-(2-methoxyphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield 92.4% Example 245) Methyl N-(2-methoxyquinolin-3-yl)-[4-(3-chlorophenyl)pi-perazine-1-yl]iminothiolate 1-[(2-Methoxyquinolin-3-yl)aminothiocarbonyl]-4-(3-chlorophenyl)piperazine was reacted by the same way with the example 199 to obtain 10 the titled compound.

yield 90.3% Example 246) Methyl N-(4,5-dimethyl-2-methoxyphenyl-l-yl)-(4-phenyl-piperazin-1-yl)iminothiolate 1-[(4,5-Dimethyl-2-methoxyphenyl-1-yl)aminothiocarbonyl]-4-phenylpiperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield 95.4% Example 247) Methyl N-(4,5-dimethyl-2-methoxyphenyl-1-yl)-[4-(4-methylphenyl)piperazin -1 -yl]iminothiolate 1-[(4,5-Dimethyl-2-methoxyphenyl-1-yl)aminothiocarbonyl]-4-(4methylphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield 94.4% Example 248) Methyl N-(4,5-dimethyl-2-methoxyphenyl-1-yl)-[4-(2ethylphenyl)piperazin-l-yl]iminothiolate 1-[(4,5-Dimethyl-2-methoxyphenyl-1-yl)aminothiocarbonyl]-4- (2-ethylphenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield 96.2% 87 Example 249) Methyl N- (4,5-dimethyl-2-methoxyphenyl- 1-yl) (3,5-di-methyiphenyl) piperazin- 1-ylliminothiolate 1- [(4,5-Dimethyl-2-methoxyphenyl- 1-yl)aminothiocarbonyl] dimethylphenyl~piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :96.8% Example 250) Methyl N- (4,5-dimethyl-2-methoxyphenyl- 1-yl) 10 phenyl)piperazin- 1-yllliminothiolate 1- 4 ,5-Dimethyl-2-methoxyphenyl- 1-yl)aminothiocarbonyl] -4was reacted by the same way with the example 199 to obtain the titled compound.

yield :95.7% Example 251) Methyl N- (4,5-dimethyl-2-methoxyphenyl- 1-yl) -14- (3,5-difluorophenyl) piperazin- 1-ylliminothiolate 1- [(4,5-Dimethyl-2-methoxyphenyl- 1-yl)aminothiocarbonyl] -4was reacted by the same way with the example 199 to obtain the titled compound.

yield :90.4% Example 252) Methyl N- (4,5-dimethyl-2-methoxyphenyl- 1-yl) (3-chlorophenyl) piperazin-1 -yllim-inothiolate 1- [(4,5-Dimethyl-2-methoxyphenyl- 1-yl)aminothiocarbonyl] -4- (3-chlorophenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :94.2% Example 253) Methyl N- (4,5-dimethyl-2-methoxyphenyl- 1-yl) (3-bromophenyl) piperazin- 1-ylliminothiolate 88 1- [(4,5-Dimethyl-2-methoxyphenyl- 1-yl )aminothiocarbonyl] -4- (3-bromophenyl)piperazine was reacted by the same way with the example 199 to obtain the titled compound.

yield :94.4% Example 254) Methyl N- (4,5-dimethyl-2-methoxyphenyl- 1-yl) (2-inethylthiophenyl) piperazin-1 -ylliminothiolate 1- [(4,5-Dimethyl-2-methoxyphenyl- 1-yl)aminothiocarbonyl] -4- (2-methylthiophenyl)piperazine was reacted by* the same way with the example 199 to obtain the titled compound.

yield :93.5% Physical data of the compounds prepared in the above examples are as follows Example I1 H NMR(CDC1 3 8 2.37(3H,s), 2.39(3H,s), 3.27(4H,t), 3.74(4H,t), 3.97(3H,s), 6.97(2H,m), Example 2 '11 NMR(CDC3) 8 3.75(4H,t), 3.89(3H,s), 3.97(3H,s), Example 3 1H NMR(CDCl 3 8' 3.71 3.79(6H,s), 3.97(3H,s), Example 4 '1H NMIR(CDCl 3 2.74(2H,q), 2.94(4H,t), 3.68(4H,t), 7.19(1H,t), 7.25(1H,s) Example 5 'H NMR(CDC3) 8' 2.37(3H,s), 2.39(3H,s), 2.56(2H,t), 6.95(2H,brs), 7.14(2H,m) Example 6 1H NlVR(CDCl 3 6'8 2.95(4H,t), 3.53(1H,m), 3.72(4H,t), Example 7 1H NMR(GDC 3 8 7.31 (2H,t) 2.36(3H,s), 2.40(3H,s), 3.13(4H-,t), 6.95(3H,m), 7.05(2H,m) 2.37(3H,s), 2.39(3H,s), 3.25(4H,t), 6.10(3H,m) 1 .26(3H,t), 3.97(3H,s), 0.92(3H,t), 3.25(4H,t), l.23(6H,d), 3.98(3H,s), 2.30(6H,s), 2.37(3H,s), 2.41(3H,s), 6.72(lH,brs), 7.08(2H,m), 1.35(2H,m), 1.57(2H,m), 3.78(4H,t), 3.97(3H,s), 2.38(3H,s), 2.42(3H,s), 7.11(1H,m), 7.29(1H,m) 2.37(3H,s), 2.40(3H,s), 3.25(4H,t), 3.75(4H,t), 3.97(3H,s), 6.62(3H,m) 89 Example 8 'H NMR(CDC1 3 ):8 2.43(3H,s), 3.17(4H,t), 3.67(4H,t), Example 9 'H NMR(CDC13):8 3.73(4H,t), 3.98(3H,s), 6.99(2H,m), Example 10 'H NMR(CDC 3 ):8 2.21(6H,s), 2.22(6H,s), 4.O0(3H,s), 6.84(IH,s) 2.37(3H,s), 2.40(3H,s), 7.07(2H,m) 2.37(3H,s), 2.39(3H,s), 2.38(3H,s), 3. 14(4H,t), 3.26(4H,t), 7.13(1H,t) 3.27(4H,t), 3.70(4H,t), 3.98(3H,s), 6.85(1H,m), 7.01 (1H,d), Example 11 'H NMR(CDC1 3 2.37(3H,s), 3.69(4H,t), 3.98(3H,s), 6.75(2H,s), 6.84( 1H,s) Example 12 'H N1VR(CDCI 3 2.37(3H,s), 3.69(4H,t), 3.97(3H,s), 6.30(1H,t), 6.37(2H,d) Example 13 'H NMR(CDC 3 2.38(3H,s), 3.73(4H,t), 3.98(3H,s), 7.09( 1H,d), 7.13(2H,m), Example 14 'H NMR(CDC 3 2.38(3H,s), 7.05( 1H,s), 2.39(3H,s), 2.39(3H,s), 3.27(4H,t), 2.40(3H,s), 7.38( 1H,t) 2.42(3H,s), 3.31 (4H,s), 2.43(3H,s), 3.57(4H,t), 3.05(4H,t), 3.73(4H,t), 3.99(3H,s), 7.05(1H,brs), 7.13( 1H,s) Example 15 'H NMR(CDC1 3 2.39(3H,s), 2.45(3H,s), 3.88(4H,t), 4.08(3H,s), 7.98(2H,s), 8.45( 1H,s) Example 16 'H NMR(CDC 3 2.38(3H,s), 2.40(3H,s), 3.70(4H,t), 3.98(3H,s), 6.35( 1H,s), 6.42(2H,s) Example 17 'H NMR(CDC 3 2.38(3H,s), 2.40(3H,s), 3.46(4H,t), 3.74(4H,t), 3.99(3H,s), 6.88(2H,d), 7.90(2H,d) Example 18 'H NMR(CDC1 3 2.39(3H,s), 2.40(3H,s), 3.22(3H,s), 3.46(4H,t), 3.85(3H,s), 3.95(3H,s), 6.89(3H,m), Example 19 'H NMR(CDCb3) 2.39(3H,s), 2.40(3H,s), 3.21 3.40(4H,t), 3.75(6H,s), 3.92(3H,s), 6.03(3H,s) 3.26(4H,t), 2.54(3H,s), 2.91 (4H,t), 7.02( 1H,m) 3.01 (4H,t), 2.40(3H,s), 3.03(4H,t), 3.03 (4H,t), Example 20 'H NMR(CDC1 3 2.26(6H,s), 2.39(3H,s), 2.99(4H,t), 3.22(3H,s), 3.40(4H,t), 3.93(3H,s), 6.52(3H,m) Example 21 1H NMR(CDCb3) 2.40(3H,s), 2.41(3H,s), 3.21(3H,s), 3.38(4H,t), 3.93(3H,s), 6.68(2H,s), 6.81(1H,s) Example 22 'H NMR(CDC1 3 2.40(3H,s), 2.41(3H,s), 3.21 3.39(4H,t), 3.93(3H,s), 6.27(3H,m) Example 23 'H NMR(CDC 3 2.40(9H,s), 2.87(4H,t), 3.22 (3H,s), 90 3.46(4H,t), 3.96(3H,s), 7.02( 1H,brs), 7.11 (3H,s) Example 24 'H NMR(CDCb3) 2.43(6H,s), 3.24(3H,s), 3.27(4H,t), 3.45(4H,t), 3.95(3H,s), 7.89(2H,d), 8.40(1H,s) Example 25 'H NMR(CDC1 3 2.38(3H,s), 2.39(3H,s), 2.95(4H,t), 3.21 3.37(4H,t), 3.92(3H,s), 5.62(1H,s), 5.65(2H,s) Example 26 'H NMR(CDC13) 1.65(3H,t), 2.39(3H,s), 2.40(3H,s), 2.96(4H,t), 3.35(4H,t), 3.74(2H,q), 3.75(6H,s), 3.92(3H,s), 6.02(3Hl,s) Example 27 1H NMR(CDC 3 1.17(3H,t), 2.25(6H,s), 2.39(3H,s), 2.40(3H,s), 2.95(4H,t), 3.36(4H,t), 3.74(2H,q), 3.92(3H,s), 6.50(3H,m) Example 28 'H NMR(CDC1 3 :6 2.32(3H,s), 2.34(3H,s), 3.34(4H,t), 3.78(6H,s), 3.98(3H,s), 4.07(4H,t), 6.12(3H,m) Example 29 'H N1VR(CDGI 3 1.26(3H,t), 2.35(3H,s), 2.37(3H,s), 2.74(2H,q), 3.02(4H,t), 3.97(3H,s), 4.02(4H,t), 7.09(2H,q), 7. 19(1H,t), 7.55(1H,s) Example 30 'H NMR(CDC 3 6 2.29(6H,s), 2.32(3H,s), 2.35(3H,s), 3.31 3.98(3H,s), 4.04(4H,t), 6.59(3H,brs) Example 31 1 NMR(CDC1 3 2.32(3H,s), 2.35(3H,s), 3.33(4H,t), 3.98(3H,s), 4.06(4H,t), 6.82( 1H,d), 7.01 7.13( 1H,t) Example 32 'H NMR(CDCl 3 6 2.44(3H,s), 2.49(3H,s), 3.48(4H,t), 4.05(3H,s), 4.25(4H,t), 6.98(3H,m) Example 33 1H NMR(CDC 3 6 2.35(3H,s), 2.36(3H,s), 2.43(3H,s), 3. 12(4H,t), 3.97(3H,s), 4.05(4H,t), 6.87( 1H,d), 7.05(1H,brs), 7. 13(2H,m) Example 34 'H NMR(CDC 3 6 1.26(6H,m), 2.30(6H,s), 2.70(2H,t), 2.78(2H,t), 3.25(4H,t), 3.74(4H,t), 3.99(3H,s), 6.65(3H,m) Example 35 'H NMR(CDC 3 6 1.24(6H,m), 2.69(2H,t), 2.78(2H,t), 3.24(4H,t), 3.71 3.78(6H,s), 3.98(3H,s), 6.07( 1H,s), 6.11 (2H,brs) Example 36 1H N1\R(CDC13) 6 3.34(4H,t), 3.88(4H,t), 4.15(3H,s), 7.05(3H,m), 7.35(3H,m), 7.43(2H,m), 7.70(1H,brs) Example 37 'H NMR(CDC 3 6 3.17(4H,t), 3.83(4H,t), 3.90(3H,s), 4.16(3H,s), 6.99(4H,m), 7.49(2H,m), 7.75(2H,m) Example 38 'H N1\R(CDCl 3 6 3.22(4H,t), 3.30(4H,t), 3.79(6H,s), 91 4.11 7.20( 1H,d), 7.33(2H,m), 7.50(2H,m), 7.62(1H,d), 7.76( 1H,m), 7.83(1H,m) Example 39 'H NMR(CDC 3 1.28(3H,t), 2.78(2H,q), 3.02(4H,t), 3.89(4H,t), 4. 15(3H,s), 7. 13(2H,m), 7.21 7.28( 1H,m), 7.43(3H,m), 7.70(1H,d) Example 40 'H NMR(CDC 3 1.24(6H,d), 2.98(4H,t), 3.56(1H,m), 3.82(4H,t), 4.15(3H,s), 7. 16(3H,m), 7.30(1H,d), 7.43(2H,brs), 7.69(2H,d) Example 41 'H NMR(CDC 3 0.93(3H,t), 1.35(2H,m), 1.57(2H,m), 2.56(2H,t), 3.35(4H,t), 3.88(4H,t), 4. 15(3H,s), 7. 19(3H,brs), 7.43(3H,brs), 7.70(2H,brs) Example 42 'H N1VR(CDC1 3 2.30(6H,s), 3.26(4H,t), 3.78(4H,t), 4.14(3H,s), 6.60(3H,s), 7.30(2H,m), 7.50(1H,s), 7.55(1H,m) Example 43 'H NMR(CDC 3 2.21(6H,s), 2.34(6H,s), 3.20(4H,t), 3.83(4H,t), 4.17(3H,s), 6.85(1H,s), 7.46(2H,m), 7.61(1H,brs), 7.72(1H,d) Example 44 'H NMR(CDCl 3 3.20(4H,t), 3.91(4H,t), 4.15(3H,s), 7.07(4H,m), 7.42(3H,m), 7.70(1H,d) Example 45 'H N1VR(CDCI 3 8 3.30(4H,t), 3.90(4H,t), 4.16(3H,s), 6.95(1H,d), 7.05( 1H,d), 7.15(2H,m), 7.42(2H,m), 7.53(1H,s), 7.69(1H,d) Example 46 1H NMR(CDC1 3 3.27(4H,t), 3.78(4H,t), 4.16(3H,s), 6.39(3H,m), 7.52(2H,m), 7.74(2H,m) Example 47 11H NMR(CDC 3 3.34(4H,t), 3.90(4H,t), 4.16(3H,s), 7. 15(3H,m), 7.40(3H,m), 7.52(1H,brs), 7.70(1H,d) Example 48 1H NMR(CDCb3) 3.55(4H,t), 3.98(4H,t), 4.19(3H,s), 7.46(3H,m), 7.73(1H,m), 8.00(2H,s), 8.44(1H,s) Example 49 'H NMR(CDC1 3 3.25(4H,t), 3.73(4H,t), 4.13(3H,s), 5.68(1H,brs), 5.79(2H,brs), 7.49(2H,m), 7.74(2H,m) Example 50 'H NMR(CDC1 3 2.54(3H,s), 3.49(4H,t), 3.92(4H,t), 4. 16(3H,s), 6.95(2H,d), 7.43(2H,m), 7.51 (1H,brs), 7.71 7.92(2H,d) Example 51 'H NMR(CDC1 3 2.47(3H,s), 3.30(4-H,t), 4.04(4H,t), 4.19(3H,s), 7.20(3H,brs), 7.47(2H,m), 7.60(2H,m), 7.76(1H,m) Example 52 'H NMR(CDCl 3 2.92(4H,t), 3.57(4H,t), 4.11(3H,s), 92 7.15(1H,d), 7. 12(1H,t), 7.30(4H,m), 7.41 7.54(1H,m), 7.64(3H,m) Example 53 'H NMR(CDC1 3 8 3.19(4H,t), 3.38(3H,s), 3.68(4H,t), 3.78(6H,s), 4.07(3H,s), 6.09(3H,brm), 7.50(2H,m), 7.80(2H,m) Example 54 1H NMR(CDC1 3 3.08(4H,t), 3.39(3H,s), 3.73(4H,t), 3.88(3H,s), 4.09(3H,s), 6.92(4H,m), 7.50(2H,m), 7.80(2H,m) Example 55 1H NT\R(CDCI 3 8 2.30(6H,s), 3.19(4H,t), 3.39(3H,s), 3.70(4H,t), 4.08(3H,s), 6.59(3H,brs), 7.52(2H,s), 7.80(2H,m) Example 56 'H NIVR(CDC1 3 8 3.20(4H,t), 3.39(3H,s), 3.66(4H,t), 4.07(3H,s), 6.35(3H,m), 7.52(2H,m), 7.82(2H,m) Example 57 'H NMR(CDCb3) 8 3.41(3H,s), 3.43(4H,t), 3.71(4H,t), 4.09(3H,s), 7.55(2H,m), 7.79(1H,m), 7.88( 1H,m), 7.96(2H,s), 8.44( 1H,s) Example 58 'H NIVR(CDC1 3 8 3.13(4H,t), 3.37(3H,s), 3.65(4H,t), 3.94(3H,s), 5.59(2H,m), 5.61U(H,s), 7.50(2H,m), 7.77( 1H,m), 7.82(1H,m) Example 59 'H NMR(CDCS) 8 1.33(3Rt, 3.15(4H,t), 3.65(4H,t), 3.77(6H,s), 3.91(2H,q), 4.08(3H,s), 6.09(3H,brs), 7.52(2H,m), 7.80(2H,m) Example 60 'H NMR(CDC 3 :6 1.34(3H~t), 2.28(6H,s), 3.12(4H,t), 3.62(4H,t), 3.91 4.08(3H,s), 6.55(3H,brs), 7.51 7.80(2H,m) Example 61 'H NMR(CDC1 3 8 1.33(3H,t'), 3.15(4H,t), 3.61(4H,t), 3.91 4.08(3H,s), 6.77(2H,s), 6.87(1H,s), 7.53(2H,m), 7.78(1H,m), 7.85(1H,m) Example 62 'H NMR(CDC 3 :68 1.43(6H,d), 2.98(4H,t), 3.48(4H,d), 3.74(6H,s), 4.06(3H,s), 4.71(1H,m), 5.99(2H,s), 6.01(1H,s), 7.53(2H,m), 7.77(1H,m), 7.84(1H,m) Example 63 'H NIN'R(CDCI 3 :6 3.49(4H,t), 3.96(3H,s), 4.15(3H,s), 4.31(4H,t), 7.06(3H,m), 7.44(3H,m), 7.71(2H,d) Example 64 'H NIVR(CDC1 3 3.40(4H,t), 3.80(6H,s), 4.15(3H,s), 4.30(4H,t), 6. 16(3H,brs), 6.84(1H,d), 7.23( 1H,t), 7.44(2H,brs), 7.70(1H,brs) Example 65 H NMR(CDC1 3 6'8 1.27(3H,t), 2.76(2H,q), 3.05(4H,t), 4. 15(3H,s), 4.39(4H,t), 7.10(2H,m), 7.19( 1H,s), 7.40(3H,m), 7.75( 1H,m), 8.01(1H,s) Example 66 'H NMR(CDCb3) 2.31(6H,s), 3.36(4H,t), 4.14(3H,s), 93 4.38(4H,t), 6.64(3H,brs), 7.45(2H,m), 7.72(2H,m) Example 67 'H NMR(CDCI 3 3.34(4H,t), 4.16(3H,s), 4.38(4H,t), 6.85( 1H,d), 7.01 7.06(1H,s), 7. 15( 1H,m), 7.42(3H,m), 7.68( 1H,brs) Example 68 'H NMR(CDG13) 3.42(4H,t), 4.16(3H,s), 4.30(4H,t), 6.39(3H,m), 7.20(1H,t), 7.43(1H,m), 7.69(2H,m) Example 69 'H NMR(CDC1 3 :68 2.46(3H,s), 3.20(4H,t), 4.15(3H,s), 4.30(4H,t), 6.90(1H,m), 7.15(3H,m), 7.45( 1H,m), 7.65( 7.73(1H,m), 8.01 (1H,d) Example 70 'H NMR(CDC1 3 :68 2.56(3H,s), 3.60(4H,t), 4.15(3H,s), 4.30(4H,t), 6.96(2H,d), 7.44(1H,m), 7.59(1H,m), 7.74(2H,m), 7.95(2H,m) Example 71 1H NMR(CDCh3) :68 0.92(3H,t), 1.35(2H,m), 1.57(2H,m), 2.56(2H,t), 3.34(4H,t), 4.11 4. 19(3H,s), 6.91 7.14(2H,m), 7.60( 1H,t), 7.68(1H,t), 7.98(1H,d), 8.02(1H,d) Example 72 'H NMR(CDC13) :68 1.52(3H,t), 3.32(4H,t), 3.79(6H,s), 3.80(4H,t), 4.60(2H,q), 6.14(3H,m), 7.44(2H,brs), 7.69(2H,brs) Example 73 'H N1VR(CDC13) :68 1.50(3HRt, 3.26(4H,t), 3.86(4H,t), 4.11 4.62(2H,q), 6.95(2H,m), 7.07(1H,brs), 7.55(3H,m), 7.80(2H,m) Example 74 'H NMR(CDCb3) 1.52(3H,t), 2.30(6H,s), 3.30(4H,t), 3.80(4H,t), 4.61(2H,q), 6.62(3H,brs), 7.48(2H,m), 7.76(2H,m) Example 75 'H NMR(CDCI 3 6'8 1.52(3H,t), 2.98(4H,t), 3.78(4H,t), 4.60(2H 6.94(2H,m), 7.47(2H,brs), 7.74(1H,brs) Example 76 'H NMR(CDC1 3 6'8 1:28(3H,t), 3.06(4H,t), 3.89(4H,t), 4.61 7. 14(2H,m), 7.44(2H,m), 7.69(2H,m) Example 77 'H NIVR(CDC1 3 6'8 1.54(3H~t), 4.63(2H,q), 6.88(2H,s), 6.90( 1H,s), 7.47(2H,m), Example 78 'H N1\R(CDC1 3 1.52(3H,t), 4.60(2H,q), 6.90(1H,d), 7.03(1H,d), 7.10(1H,s), 7.69(1H,brs) Example 79 'H NMR(CDCbs) 1.52(3H,t), 2.27(3H,s), 2.29(3H,s), 7.10(iH,m), 7.30(1H,brs), 1.52(3H,t), 2.79(2H,q), 7.22(1H,t), 7.28(1H,d), 3.36(4H,t), 3.91(4H,t), 7.59( 1H,brs), 7.71(1H,m) 3.30(4H,t), 3.83(4H,t), 7.15(1H,t), 7.43(2H,brs), 3.33(4H,t), 3.77(4H,t), 94 3.78(4H,t), 4.68(2H,q), 6.31 6.40(2H,d), 7.47(2H,m), 7.54(1H,m), 7.72 H,t) Example 80 1H NMR(CDCl 3 6'1.52(3H,t), 2.44 3.13(4H,t), 3.89(4H,t), 4.61 7.15(4H,brs), 7.45(2H,m), 7.69(2H,br-m) Example 81 'H NMR(CDC1 3 8 1.44(3H,t), 3.22(4H,t), 3.38(3H,s), 3.71 3.78(6H,s), 4.53(2H,q), 6.09( 1H,brs), 6.13(2H,brs), 7.50(2H,m), 7.75(1H,m), 7.82(1H,m) Example 82 1H N1VR(CDC13) 1.43(3H,t), 3.22(4H,t), 3.38(3H,s), 3.66(4H,t), 4.54(2H,q), 6.76(2H,s), 6.86( 1H,s), 7.51 7.76( 1H,m), 10 7.83(1H,m) Example 83 1H NMR(CDC 3 6'8 1.34(3H,t), 1.44(3H,t), 3.15(4H,t), 3.62(4H,t), 3.77(6H,s), 3.91 4.53(2H,q), 6.06(3H,brs), 7.51 (2H,m), 7.75(1H,m), 7.81(1H,m) Example 84 1H NMR(CDC13) :68 1.33(3H,t), 1.44(3H,t), 3.16(4H,t), 3.59(4H,t), 3.91(2H,q), 4.54(2H,q), 6.74(2H,s), 6.85(1H,s), 7.52(2H,m), 7.76(1H,m), 7.82(1H,m) Example 85 'H NMR(CDC13) 1.34(3H,t), 1.45(3H,t), 2.28(6H,s), 3. 15(4H,t), 3.63(4H,t), 3.91 4.53(2H,q), 6.56(3H,brs), 7.50(2H,m), 7.75(1H,d), 7.82(1H,d) Example 86 'H NMR(CD'CI 3 :6 2.30(6H,s), 3.27(4H,t), 3.73(4H,t), 4.03(3H,s), 6.60(3H,brs), 7.13( 1H,s), 7.33(2H,t), 7.45( 1H,s), 7.67(1H,m), 7.75(1H,m) Example 87 'H N1VR(CDCl 3 6'S 3.20(4H,t), 3.40(4H,t), 3.75(6H,s), 3.99(3H,s), 6.10(3H,brs), 7.12(1H,s), 7.31(2H,t), 7.44(1H,s), 7.65(1H,m), 7.70(1H,m) Example 88 'H NMVR(CDCI 3 3.32(4H,t), 3.73(4H,t), 4.03(3H,s), 6.32(1H,t), 6.41(2H,d), 7.13(1H,s), 7.34(2H,t), 7.43(1H,s), 7.67(1H,m), 7.75( 1H,m) Example 89 1H NMR(CDCl 3 6'8 3.34(4H,t), 3.77(4H,t), 4.03(3H,s), 6.84(1H,m), 6.92(2H,m), 7.13(1H,s), 7.34(2H,m), 7.43(1H,s), 7.68(1H,m), 7.75( 1H,m) 95 Example 90 'H NMR(CDCJ 3 :6 2.20(6H,s), 2.85(4H,t), 3.18(3H,s), 3.32(4H,t), 3.99(3H,s), 6.39(2H,s), 6.47(1H,s), 7.20(1H,s), 7.35(1H,t), 7.43( 1H,t), 7.53(1H,s), 7.69(1H,d), 7.73( 1H,d) Example 91 1H NMR(CDC 3 6 2.91(4H,t), 3.18(3H,s), 3.33(4H,t), 4.O(3H,s), 6.24(3H,brm), 7.21 7.37(1H,t), 7.45( 1H,t), 7.53( 1H,s), 7.70(1H,d), 7.74(1H,d) Example 92 1H NMR(CDC13) 3.03(4H,t), 3.18(3H,s), 3.52(4H,t), 4.01 6.82(3H,brmn), 7.12( 1H,brs), 7.37( 1H,m), 7.46(1H,m), 7.56( H,m), 7.72(2H,m) 10 Example 93 1H NMR(CDC 3 6 2.88(4H,t), 3.18(3H,s), 3.33(4H,t), 3.71 3.99(3H,s), 5.92(2H,brs), 5.97( 1H,brs), 7.20( 1H,s), 7.36( 1H,t), 7.43( 1H,t), 7.52(1H,s), 7.69( 7.73( 1H,d) Example 94 'H NMR(CDC13) 1.34(3H,t), 2.21(6H,s), 2.88(4H,t), 3.32(4H,t), 3.91 3.99(3H,s), 6.39(2H,s), 6.47(1H,s), 7.20( 1H,s), 7.35(1H,t), 7.46(1H,t), 7.56(1H,s), 7.71(1H,d), 7.73(1H,d) Example 95 1H NMR(CDC1 3 :6 1.35(3H,t), 2.90(4H,t), 3.33(4H,t), 3.70(6H,s), 3.92(2H,q), 3.99(3H,s), 5.92(2H,brs), 5.97(1H,brs), 7.25( LH,s), 7.36(1H,t), 7.43(1H,t), 7.52(1H,s), 7.72(1H,d), 7.73(1H,d) Example 96 'H NMR(CDC1 3 :6 2.14(3H,s), 2.33(3H,s), 3.19(4H,s), 3.20(4H,s), 3.98(3H,s), 6.84(1H,s), 6.87(1H,t), 6.93(2H,d), 7.25(1H,d), 7.55(1H,s) Example 97 'H N1VR(CDCl 3 6 2.13(3H~s), 2.27(3H,s), 2.32(3H,s), 3. 13(4H,d), 3. 19(4H,d), 3.98(3H,s), 6.81 6.83(2H,d), 7.07(2H,d), 7.54(1H,s) Example 98 'H NMR(CDC 3 6 0.91(3H,t), 1.30(2H,m), 1.54(2H,m), 2.13(3H,s), 2.32(3H,s), 2.53(2H,t), 3.14(4H,d), 3.19(4H,d), 3.98(3H,s), 6.80(1H,s), 6.85(2H,d), 7.08(2H,d), 7.55(1H,s) Example 99 'H NMR(CDC 3 6 2.13(3H,s), 2.27(6H,s), 2.32(3H,s), 3.12(4H,s), 3.13(4H,s), 3.89(3H,s), 6.56(3H,s), 6.81(1H,s), 7.54(1H,s) Example 100 'H NMR(CDC1 3 6 2.16(3H,s), 2.33(3H,s), 3.08(4H,t), 3.25(4H,t), 3.85(3H,s), 3.98(3H,s), 6.87( 1H,t), 6.93(2H,d), 7.02( 1H,m), 96 7.57(1H,s) Example 101 'H NMR(CDC 3 2.14(3L1,s), 2.32(3H,s), 3.17(8H,s), 3.77(6H,s), 3.98(3H,s), 6.04( 1H,s), 6.08(2H,s), 6.81 7.53( 1H,s) Example 102 1H NMR(CDGI 3 2.15(3H,s), 2.33(3H,s), 3.17(8H,s), 3.98(3H,s), 6.28(1H,t), 6.35(2H,d), 6.78(1H,s), 7.50(IH,s) Example 103 H NMR(CDC1 3 2.16(3H,s), 2.39(3H,s), 3.18(4H,s), 3.20(4H,s), 3.98(3H,s), 6.69(3H,s), 6.78(1H,s), 7.45(1H,s) Example 104 'H NMR(CDC 3 2.15(3H,s), 2.33(3H,s), 3.18(8H,s), 3.98(3H,s), 6.78(1H,s), 6.82(1H,d), 6.97(1H,d), 7.03(1H,s), 7.11(1H,t), 10 7.51(1H,s) Example 105 1H N1\R(CDCl 3 2.16(3H,s), 2.34(3H,s), 3.20(4H,s), 3.37(4H,s), 3.90(3H,s), 6.78( 1H,s), 7.47(1H,s), 7.97(2H,s), 8.42( 1H,s) Example 106 'H NI\/R(CDC13) 1.40(6H,t), 2.17(3H,s), 2.30(3H,s), 3.29(4H,s), 3.33(4H,s), 3.98(3H,s), 4.38(4H,q), 7.41(1H,s), 7.72(2H,s), 8.16(1H,s) Example 107 'H N1VR(CDC1 3 2.14(3H,s), 2.33(3H,s), 3.21(8H,s), 3.98(3H,s), 4.66(4H,s), 6.82( 1H,s), 6.88(3H,s), 7.52( 1H,s) Example 108 'H NMR(CDC 3 1.19(3H,t), 2.36(3H,s), 2.52(2H,q), 3.07(4H,s), 3.30(4H,s), 3.84(3H,s), 3.97(3H,s), 6.85-7.03 7.51(1H,s) Example 109 'H NMR(CDC 3 1.14(3H,t), 2.36(3H,s), 2.50(2H,q), 3. 17(8H,d), 3.77(6H,s), 3.98(3H,s), 6.04( 1H,s), 6.07(2H,s), 6.80( 1H,s), 7.56( lH,s) Example 110 'H NMR(CDC 3 1.22(6H,m), 2.36(3H,s), 2.54(2H,q), 2.68(2H,q), 2.90(4H,s), 3.20(4H,s), 3.98(3H,s), 6.80( 1H,s), 7.08(2H,m), 7.17(lH,t), 7.22(1H,d), 7.62(1H,s) Example 111 'H N1VR(GDCI 3 1.14(3H,t), 2.36(3H,s), 2.50(2H,q), 3. 18(4H,s), 3.25(4H,s), 3.98(3H,s), 6.89(4H,m), 7.27(2H,m), 7.52(1H,s) Example 112 'H NMR(CDC1 3 8l.20(3H,t), 2.36(3H,s), 2.38(3H,s), 2.54(2H,q), 3.00(4H,s), 3.27(4H,s), 3.97(3H,s), 7.00(I.H,brs) 7.01(1H,s), 7.10(3H,s), 7.55(1H,s) Example 113 'H NMR(CDC 3 1.14(3H,t), 2.27(6H,s), 2.36(3H,s), 97 2.49(2H,q), 3.17(4H,s), 3.18(4H,s), 3.98(3H,s), 6.55(3H,s), 6.81(1H,s), 7.57( 1H,s) Example 114 'H NMR(CDC1 3 6 1.15(3H,t), 2.36(3H,s), 2.50(2H,q), 3.17(8H,s), 3.98(3H,s), 6.28(1H,t), 6.35(2H,d), 6.65(1H,brs), 6.78(1H,s), 7.52(1H,s) Example 115 'H NMR(CDCb3) :6 1.15(3H,t), 2.36(3H,s), 2.50(2H,ql), 3. 17(8H,s), 3.98(3H,s), 6.17( 1H,brs), 6.74(3H,m), 6.82( 1H,s), 7.51 (1H,s) Example 116 1H N1\'R(CDC13) :6 1.15(3H,t), 2.32(3H,s), 2.48(2H,q), 2.84(4H,s), 2.94(4H,s), 3.94(3H,s), 6.73(1H,s), 7.O(IH,s), 7.09(1H,t), 7.24(2H,m), 7.29(1H,t), 7.35(2H,t), 7.51(1H,s), 7.58(2H,d) Example 117 1H NMR(CDC 3 6 1.15(3H,t), 2.37(3H,s), 2.51(2H,q), 3.28(4H,s), 3.39(4H,s), 3.98(3H,s), 6.84(1H,brs), 7.47(1H,s), 7.96(2H,s), 8.42( H,s) Example 118 'H NTVR(CDCI 3 :6 2.69(3H,s), 3.20(8H,s), 3.77(6H,s), 3.80(3H,s), 4.06(3H,s), 6.04(1H,s), 6.09(2H,s), 6.93(1H,s), 8.39(1H,s) Example 119 1H NMR(CDC1 3 :6 2.28(6H,s), 2.70(3H,s), 3.20(8H,s), 3.80(3H,s), 4.06(3H,s), 6.56(3H,s), 6.94(1H,s), 8.40(1H,s) Example 120 'H NMR(CDC 3 6 2.69(3H,s), 3.19(4H,d), 3.22(4H,d), 3.80(3H,s), 4.07(3H,s), 6.29( 1H,t), 6.36(2H,d), 6.75( 1H,brs), 6.93( 1H,s), 8.36(1H,s) Example 121 1H NMR(CDC 3 6 2.70(3H,s), 3.13(4H,s), 3.28(4H,s), 3.83(3H,s), 3.86(3H,s), 4.06(3H,s), 6.94(5H,m), 8.42( 1H,s) Example 122 1H NMR(CDC1 3 6 2.70(3H,s), 3.23(8H,s), 3.78(3H,s), 4.07(3H,s), 6.89( 1H,t), 6.94(2H,d), 6.99(1H,brs), 7.27(2H,d), 8.38( 1H,s) Example 123 'H NIVR(CDCl 3 6 2.27(3H,s), 2.69(3H,s), 3.17(4H,d), 3.22(4H,d), 3.78(3H,s), 4.06(3H,s), 6.84(2H,d), 6.98(1H,brs), 7.09(1H,d), 8.38 H,s) Example 124 'H NMR(CDC 3 6 2.70(3H,s), 3.22(8H,s), 3.80(3H,s), 4.06(3H,s), 6.78(1H,d), 6.84(1H,d), 6.88(1H,s), 6.98(1H,brs), 7.17(1H,t), 8.35(1H,s) Example 125 'H NMR(CDC 3 6 2.39(3H,s), 3.17(8H,s), 3.76(6H,s), 98 4.00(3H,s), 4.59(2H,s), 6.03(1H,s), 6.07(2H,d), 6.88(1H,s), 7.79(1H,s) Example 126 'H N1VR(CDCI 3 2.27(6H,s), 2.40(3H,s), 3.18(8H,s), 4.01 4.59(2H,s), 6.55(3H,s), 6.87(1H,s), 7.80(2H,s) Example 127 'H NMR(CDC1 3 8 2.40(3H,s), 3.19(8H,s), 4.00(3H,s), 4.61(2H,s), 6.27(1H,t), 6.35(2H,d), 6.86(1H,s), 7.79(IH,s) Example 128 1H NMR(CDC 3 2.40(3H,s), 3.08(4H,s), 3.31(4H,s), 3.84(3H,s), 3.99(3H,s), 4.61 6.92(5H,m), 7.77( 1H,s) Example 129 1H N1\'R(CDCI 3 2.39(3H,s), 3.20(8H,d), 4.00(3H,s), 4.58(2H,s), 6.90(4 7.27(2H,d), 7.79( 1H,s) Example 130 1H NMR(CDCI.

3 8 2.17(3H,s), 2.39(3H,s), 3.13(4H,d), 3.22(4H,d), 3.99(3H,s), 4.58(2H,s), 6.82(2H,d), 7.O0(1H,brs), 7.06(2H,d), 7.78( 1H,s) Example 131 'H NMR(GDC1 3 2.39(3H,s), 3.19(8H,d), 4.00(3H,s), 4.60(2H,s), 6.76(1H,d), 6.82(1H,d), 6.85(1H,s), 6.95(1H,brs), 7.16(1H,t), 7.77(1H,s) Example 132 'H NMR(CDC 3 8 2.27(6H,s), 2.50(3H,s), 2.64(3H,s), 3.19(8H,d), 4.07(3H,s), 6.55(2H,s), 6.56(1H,s), 6.88(1H,s), 7.39(1H,brs), 8.19(1H,s) Example 133 'H NMR(CDC 3 8 2.50(3H,s), 2.64(3H,s), 3.16(4H,s), 3.25(4H,s), 3.76(6H,s), 4.06(3H,s), 6.05(1H,s), 6.07(2H,s), 7.05(1H,brs), 8.13(1H,s) Example 134 'H N1VR(CDC1 3 8 2.50(3H,s), 2.65(3H,s), 3.20(4H,s), 3.26(4H,s), 4.06(3H,s), 6.91 7.27(2H,m), 8.15( 1H,s) Example 135 1H NMR(CDC 3 6'8 2.18(3H,s), 2.42(3H,s), 2.57(3H,s), 3. 15(4H,s), 3.30(4H,s), 4.07(3H,s), 6.84(2H,d), 7.07(3H,d), 8.13( 1H,s) Example 136 'H N1VR(CDCl 3 6'8 2.52(3H,s), 2.66(3H,s), 3.22(4H,s), 3.28(4H,s), 4.07(3H,s), 6.30(3H,m), 8.07( 1H,s) Example 137 'H NMR(CDC 3 6'8 2.39(3H,s), 2.58(3H,s), 2.66(3H,s), 3.04(4H,s),,3.33(4H,s), 4.07(3H,s), 7.02(1H,d), 7.10(3H,s), 8.14(1H,s) Example 138 'H NTVR(GDC1 3 6'8 1.40(3H,d), 2.26(6H,s), 2.39(3H,s), 3.19(8H,s), 3.99(3H,s), 5.04(1H,q), 6.54(3H,s), 6.86(1H,s), 7.93(1H,s) 99 Example 139 '1l NMR(CDC 3 8 1.40(3H,d), 2.39(3H,s), 3.20(8H,m), 3.76(6H,s), 3.99(3H,s), 5.03(1H,q), 6.03(1H,s), 6.06(2H,s), 7.04(1H,brs), 7.89 H,s) Example 140 1H NMR(CDC13) 8 1.40(3H,d), 2.39(3H,s), 3.19(4H,m), 3.30(4H,s), 3.97(3H,s), 5.08(1H,q), 6.89(3H,m), 7.24(2H,m), 7.87(1H,s) Example 141 'H NMR(CDCls) :6 1.40(3H,d), 2.26(3H,s), 2.39(3H,s), 3.15(4H,s), 3.35(4H,s), 3.97(3H,s), 5.02(1H,q), 6.82(2H,d), 7.06(2H,d), 7.84(1H,s) Example 142 1H NMR(CDC1 3 1.40(3H,d), 2.39(3H,s), 3.20(4H,m), 3.28(4H,s), 3.98(3H,s), 5.04(1H,q), 6.27(3H,m), 7.85(1H,s) Example 143 'H NMR(CDC 3 1.45(3H,d), 2.38(3H,s), 2.39(3H,s), 3.02(4H,m), 3.31 3.98(3H,s), 5.07(1H,q), 7.03(1H,brs), 7.09(4H,s), 7.91(1H,s) Example 144 1H NMR(CDC1 3 2.18(3H,s), 2.27(6H,s), 2.41(3H,s), 3.19(4H,brs), 3.22(4H,brs), 4.00(3H,s), 6.55(2H,s), 6.56(1H,s), 7.50( 1H,s) Example 145 'H NMR(CDC13) 2.18(3H,s), 2.41(3H,s), 3.16(4H,brs), 3.25(4H,s), 3.76(6H,s), 4.00(3H,s), 6.05(1H,s), 6.03(2H,s), 7.49(1H,s) Example 146 'H N1VR(CDC1 3 6 2.18(3H,s), 2.40(3H,s), 3.18(4H,brs), 3.27(4H,brs), 4.00(3H,s), 6.27(3H,m), 7.50(IH,s) Example 147 'H NTVR(CDCI 3 6 2.18(3H,s), 2.39(3H,s), 2.40(3H,s), 3.04(4H,s), 3.33(4H,s), 4.01 7.02(1H,d), 7. l0(3H,s), 7.50(4H,s) Example 148 'H NMR(GDC 3 :6 2.10(3H,s), 2.31(3H,s), 3.20(4H,s), 3.37(4H,s), 3.95(3H,s), 7.42( 1H,s), 7.96(2H,s), 8.40( 1H,s) Example 149 'H NMR(CDC 3 6 2.09(3H,s), 2.26(3H,s), 2.31(3H,s), 3.11 (4H,brs), 3.25(4H,brs), 4.00(3H,s), 6.80(2H,d), 7.06(2H,d), 7.42( 1H,s) Example 150 'H NMR(CDCb3) :6 1.74(3H,d), 2.28(9H,s), 3.12(2H,brs), 3.27(4H,brs), 3.65(4H,brs), 4.02(3H,s), 4.15(1H,q), 6.54(3H,s), 8.37(1H,s) Example 151 1'H NMR(CDC 3 6 1.74(3F1,d), 2.28(3H,s), 3.05(2H,brs), 3.26(4H,m), 3.67(4H,m), 3.82(6H,s), 4.01 4. 15( 1H,q), 6.06( 1H,s), 6.09(2H,s), 8.37(1H,s) Example 152 'H NMR(CDC 3 1.74(3H,d), 2.28(3H,s), 3.15(2H,brs), 100 3.22(4H,s), 3.29(4H,s), 4.0O(3H,s), 4. 15(1H,q), 6.30(3H,m), 8.37( 1H,s) Example 153 1H NMR(CDC 3 8 1.74(3H,d), 2.28(3H,s), 2.39(3H,s), 3. 10(2H,brs), 3.04(4H,s), 3.34(4H,s), 4.07(3H,s), 4. 15( 7.02( 1H,d), 7.10(3H,s), 8.37(1H,s) Example 154 'H NMR(CDC1 3 8 1.74(3H,d), 2.28(3H,s), 3.07(2H,brs), 3.20(4H,s), 3.35(4H,s), 3.90(3H,s), 4.15(1H,q), 7.97(2H,s), 8.35(1H,s), 8.42(1H,s) Example 155 1H NMR(CDC1 3 1.74(3H,d), 2.28(3H,s), 3.11(2H,brs), 3.20(8H,s), 4.0O(3H,s), 4.15( 1H,q), 6. 17(lH~s), 6.74(2H,m), 8.37( 1H,s) Example 156 1H NMR(CDC1 3 1.26(3H,t), 2.28(3H,s), 3.08(2H,q), 3.17(4H,s), 3.24(4H,s), 3.78(3H,s), 4.07(3H,s), 6.85(2H,d), 7.00( 1H,brs), 7.07(2H,d), 8.05(1H,s) Example 157 'H N1VR(CDCI 3 1.25(6H,m), 2.70(2H,q), 2.95(4H,t), 3.08(2H,q), 3.26(4H,brs), 3.90(3H,s), 4.07(3H,s), 7.08(2H,m), 7. 18( 1H,t), 7.24(1H,d), 8.40(1H,s) Example 158 1H N1VR(CDCI 3 1.26(3H,t), 2.27(6H,s), 3.08(2H,q), 3.20(8H,s), 3.79(3H,s), 4.07(3H,s), 4.22(3H,s), 6.56(1H,s), 6.57(2H,s), 6.94(1H,s), 8.38(1H,s) Example 159 'H NMR(CDCh3) 8 1.26(3H,t), 3.07(2H,q), 3.21(8H,s), 3.77(6H,s), 3.79(3H,s), 4.07(3H,s), 6.05(1H,s), 6.09(2H,s), 6.95(1H,s), 8.37(1H,s) Example 160 'H NMR(CDC 3 1.27(3H,t), 3.07(2H,q), 3.24(8H,s), 3.81 4.08(3H,s), 6.75(2H,s), 6.83(1H,s), 7.05(1H,brs), 8.29( 1H,s) Example 161 'H NMR(CDC1 3 1.27(3H,t), 2.40(3H,s), 3.07(6H,m), 3.28(4H,brs), 3.88(3H,s), 4.07(3H,s), 7.05(2H,m), 7. 12(3H,m), 8.38( 1H,s) Example 162 1H NMR(CDC 3 1.27(3H,t), 1.40(6H,t), 3.07(2H,q), 3.26(4H,s), 3.34(4H,s), 3.77(3H,s), 4.08(3H,s), 4.39(4H,q), 7.00( 1H,brs), 8.17(1H,s), 8.35(1H,s) Example 163 'H NMR(CDCl 3 1.27(3H,t), 3.07(2H,q), 3.22(8H,d), 3.80(3H,s), 4.08(3H,s), 6.29(1H,t), 6.36(2H,d), 6.99(1H,brs), 8.32(1H,s) Example 164 'H NMR(CDC 3 1.25(3H,t), 2.27(3H,s), 2.69(2H,q), 101 3.14(4H,d), 3.22(4H,d), 4.01 4.60(2H,s), 6.82(2H,d), 6.96(1H,brs), 7.06(2H,d), 7.78(1H,s) Example 165 'H NMR(CDC1h) :6 1.21(3H,t), 1.26(3H,t), 2.67(4H,m), 2.91 3.27(4H,s), 4.01 4.66(2H,s), 7.06(2H,m), 7. 16(1H,t), 7.21(1H,d), 7.82(1H,s) Example 166 'H1 NMR(CDC13) :6 1.26(3H,t), 2.27(6H,s), 2.69(2H,q), 3.19(8H,d), 4.02(3H,s), 4.60(2H,s), 6.55(3H,s), 6.90(1H,s), 7.80(1H,s) Example 167 1H N1\'R(CDC1 3 :6 1.26(3H,t), 2.69(2H,q), 3.19(8H,s), 3.76(6H,s), 4.02(3H,s), 4.60(2H,s), 6.03(1H,s), 6.08(2H,d), 6.88( 1H,s), 7.79(1H,s) Example 168 'H NMR(CDC1 3 :6 1.26(3H,t), 2.69(2H,q), 3.20(8H,s), 4.01(3H,s), 4.62(2H,s), 6.73(2H,s), 6.84(1H,s), 6.95(1H,brs), 7.77(1H,s) Example 169 'H NI\'R(CDC13) :6 1.26(3H,t), 2.39(3H,s), 2.70(2H,q), 3.03(4H,d), 3.28(4H,s), 4.01 4.65(2H,s), 7.03( 2H,m), 7.10(3H,m), 7.80(1H,s) Example 170 'H N1VR(CDCI 3 1.20(3H,t), 2.61(2H,q), 3.09(4H,s), 3.23(4H,s), 3.97(3H,s), 4.45(4H,s), 4.46(2H,s), 6.77( 1H,s), 6.81 (2H,s), 6.99(1H,brs), 7.90(1H,s) Example 171 1H NMR(CDC1 3 6 1.25(3H,t), 2.68(2H,q), 3.21(4H,s), 3.22(4H,s), 4.01(3H,s), 4.62(2H,s), 6.27(1H,t), 6.33(2H,d), 7.05(1H,brs), 7.76(1H,s) Example 172 'H NMR(CDC13) 6 3.24(8H,s), 3.76(6H,s), 4.15(3H,s), 6.00( 1H,s), 6.08(2H,d), 7.31 7.35(1H,s), 7.43( 1H,t), 7.57(1H,d), 7.71(LH,d), 8.06(1H,s) Example 173 'H NMR(CDC 3 6 2.28(6H,s), 3.25(4H,s), 3.26(4H,s), 4.18(3H,s), 6.33(1H,brs), 6.56(1H,s), 6.58(2H,d), 7.33(1H,t), 7.47(1H,t), 7.57(1H,d), 7.78( 8.05( 1H,s) Example 174 'H NT\'R(CDCl 3 6 3.26(8H,s), 4.18(3H,s), 6.29(1H,t), 6.36(2H,d), 7.25( 1H,brs), 7.34( 1H,t), 7.49( 1H,t), 7.50( 1H,d), 7.79( H,d), 8.02(1H,s) Example 175 'H NMR(CDC 3 6 3.16(4H,s), 3.36(4H,s), 3.84(3H,s), 102 4.18(3H,s), 6.86(1H,d), 6.95(2H,m), 7.02(1H,m), 7.34( 1H,t), 7.48( 1H,t), 7.60(1H,d), 7.78(1H,d), 8.04( H,s) Example 176 'H NMVR(CDCI 3 :6 3.25(4H,d), 3.32(4H,s), 4.18(3H,s), 6.77( 1H,d), 6.85(2H,m), 7. 17(1H,t), 7.35(1H,t), 7.50(1H,t), 7.59(1H,d), 7.79(1H,d), 7.99(1H,s) Example 177 'H NMR(CDC1 3 2.14(3H,s), 2.20(3H,s), 3.18(4H,d), 3.23(4H,d), 3.84(3H,s), 6.65(1H,s), 6.87(1H,t), 6.91 6.93(1H,brs), 7.25(2H,m), 7.36(1H,s) Example 178 'H N1VR(CDCl 3 2.14(3H,s), 2.20(3H,s), 2.27(3H,s), 3.12(4H,d), 3.22(4H,d), 3.84(3H,s), 6.64(1H,s), 6.83(2H,d), 6.96(1H,brs), 7.07(2H,d), 7.35(1H,s) Example 179 'H NIVR(CDC1 3 :6 1.21(3H,t), 2.20(3H,s), 2.21(3H,s), 2.67(2H,q), 2.90(4H,t), 3.26(4H,s), 3.85(3H,s), 6.65(1H,s), 7.07(3H,m), 7.17(1H,t), 7.21(1H,d), 7.36(1H,s) Example 180 'H NMR(CDC 3 :6 2.14(3H,s), 2.20(3H,s), 2.27(6H,s), 3.16(4H,d), 3.20(4H,d), 3.85(3H,s), 6.54(1H,s), 6.56(2H,s), 6.64(1H,s), 6.89(1H,brs), 7.37(1H,s) Example 181 1H NMR(CDC 3 :6 2.14(3H,s), 2.20(3H,s), 3.17(4H,s), 3.19(4H,s), 3.77(6H,s), 3.85(3H,s), 6.03(1H,s), 6.08(2H,d), 6.64(1H,s), 6.90(1H,brs), 7.36(1H,s) Example 182 'H NMR(CDC 3 :6 2.14(3H,s), 2.20(3H,s), 3.22(8H,s), 3.85(3H,s), 6.28(1H,t), 6.36(2H,d), 6.64(1H,s), 6.89(1H,brs), 7.36(1H,s) Example 183 1H NMR(CDC 3 6 2.15(3H,s), 2.20(3H,s), 3.17(4H,d), 3.21(4H,d), 3.85(3H,s), 6.65(1H,s), 6.78(1H,d), 6.81(1H,d), 6.86(1H,s), 6.94(1H,brs), 7.16(1H,t), 7.33(1H,s) Example 184 'H NMR(CDC 3 6 2.15(3H,s), 2.20(3H,s), 3.17(4H,d), 3.21(4H,d), 3.85(3H,s), 6.65(1H,s), 6.81(1H,d), 6.96(2H,brd), 7.02(1H,s), 7.10(1H,t), 7.33(1H,s) Example 185 1H NMR(CDC1 3 6 2.19(3H,s), 2.21(3H,s), 2.39(3H,s), 3.00(4H,d), 3.28(4H,s), 3.85(3H,s), 6.64(1H,s), 6.99(1H,brs), 7.03(1H,d), 7.10(3H,m), 7.36(1H,s) 103 Example 186 1H NMR(CDC 3 2.14(3H,s), 2.33(3H,s), 3.19(4H,s), 3.20(4H,s), 3.78(3H,s), 3.98(3H,s), 6.84(1H,s), 6.87(IH,t), 6.93(2H,m), 7.24(1H,d), 7.56(1H,s) Example 187 'H NMR(CDC1 3 8 2.13(3H,s), 2.27(3H,s), 2.32(3H,s), 3.13(4H,d), 3.19(4H,d), 3.77(3H,s), 3.98(3H,s), 6.81 6.83(2H,d), 7.07(2H,d), 7.54(1H,s) Example 188 'H NMR(CDC 3 2.13(3H,s), 2.28(9H,s), 3.17(4H,brs), 3.78(3H,s), 3.98(3H,s), 6.56(3H;s), 6.70(1H,s), 7.53(1H,s) Example 189 1H NMR(CDC 3 :6 2.14(3H,s), 2.32(3H,s), 3.17(8H,s), 3.77(9H,s), 3.98(3H,s), 6.04(1H,s), 6.08(2H,s), 6.81(1H,s), 7.53(1H,s) Example 190 1H NMR(CDC 3 2.15(3H,s), 2.33(3H,s), 3.17(8H,s), 3.78(3H,s), 3.98(3H,s), 6.28( 1H,t), 6.35(2H,d), 6.78(1H,s), 7.50( 1H,s) Example 191 1H NMVR(CDCl 3 2.15(3H,s), 2.34(3H,s), 2.38(3H,s), 3.00(4H,s), 3.28(4H,s), 3.78(3H,s), 3.90(3H,s), 7.01( 1H,s), 7.10(3H,s), 7.55(1H,s) Example 192 1H NT\'R(CDC1 3 2.16(3H,s), 2.34(3H,s), 3.20(4H,s), 3.37(4H,s), 3.78(3H,s), 3.90(3H,s), 6.78(1H,s), 7.47(1H,s), 7.97(2H,s), 8.42( 1H,s) Example 193 'H NMR(CDC 3 6 1.15(3H,t), 2.37(3H,s), 2.50(2H,Q), 3. 18(4H,brs), 3.23(4H,brs), 3.82(3H,s), 3.97(3H,s), 6.72(2H,s), 6.88( 1H,s), 7.45(1H,s) Example 194 1H NMR(CDC 3 1.26(3H,t), 3.07(2H,Q), 3.22(8H,s), 3.79(3H,s), 3.86(3H,s), 4.07(3H,s), 6.29(1H,t), 6.36(2H,d), 8.29( 1H,s) Example 195 'H NMR(CDCl 3 6 1.26(3H,t), 1.40(6H,t), 3.06(2H,q), 3.27(4H,brs), 3.38(4H,brs), 3.77(3H,s), 3.81 4.07(3H,s), 4.38(4H,q), 7.76(2H,s), 8.17(1H,s), 8.30(1H,s) Example 196 'H NMR(CDC 3 6 1.24(3H,t), 2.67(2H,q), 3.21(8H,s), 3.78(3H,s), 4.01 4.59(2H,s), 4.63(4H,s), 6.84(2H,m), 6.88(2H,s), 7.78(1H,s) Example 197 'H NMR(CDC 3 6 2.14(3H,s), 2.20(3H,s), 2.27(3H,s), 3. 13(4H,brs), 3.24(4H,brs), 3.78(3H,s), 3.84(3H,s), 6.64( 1H,s), 6.84(2H,brs), 104 7.07(2H,d), 7.27(1H,brs) Example 198 'H NI\R(GDC13) :68 2.14(3H,s), 2.20(3H,s), 2.25(6H,s), 3.16(4H,brs), 3.22(4H,brs), 3.79(3H,s), 3.83(3H,s), 6.54(2H,s), 6.64(1H,s), 6.81(1H,brs), 7.27(1H,brs) Example 199 1 H N1\'R(CDCI 3 :68 2.11(3H,brs), 2.16(3H,s), 2.36(3H,s), 3.24(4H,t), 3.80(4H,s), 3.92(3H,s), 6.85( 1H,brs), 6.89( 1H,t), 6.95(2H,d), 7.28(2H,t) Example 200 111 NMR(CDCI 3 :68 2.36(3H,s), 3.19(4H,t), 3.80(4H,brs), Example 201 'H NMR(CDC 3 2. 10(3H,brs), 2. 16(3H,s), 2.36(3H,s), 3.92(3H,s), 6.87(3H,brd), 7.09(2H,d) Example 202 'H NMVR(CDCl 3 6'8 2.36(3H,s), 3.21(4H,t), 3.78(4H,brs), 6.84(3H,brs) Example 203 1H NMR(GDC13) 6'8 3.22(4H,t), 3.79(7H,brs), 3.92(3H,s), Example 204 'H NIVR(CDC1 3 :68 2.11(3H,brs), 2.16(3H,s), 2.28(3H,s), 3.92(3H,s), 6.86(3H,brd), 7.08(2H,d) 0.92(3H,t), 1.35(2H,m), 1.55(2H,m), 2.54(2H,t), 3.20(4H,t), 3.80(4H,brs), 2.10(3H,brs), 2.16(3H,s), 2.89(6H,s), 3.92(3H,s), 6.56(1H,s), 6.59(2H,S), 2.10(3H,brs), 6.84(1H,brs), 2.10(3H,brs), 2. 16(3H, s), 6.95(4H,s) 2. 16(3H, s), 2.36(3H,s), 2.36(3H,s), 3.24(4H~brs), 3.78( 1OH,s), 3.92(3H,s), 6.05( IH,s), 6.11 6.84(3H,brs) Example 205 1H N]\'R(CDC1 3 6'8 2.10(3H,brs), 2.16(3H,s), 2.36(3H,s), 3.24(4H,t), 3.78(4H,t), 6.28( 1H,t), 6.39(2H,d), 6.84( 1H,s) Example 206 'H NMR(GDCI 3 :68 2.10(3H,s), 2.16(3H,s), 2.36(3H,s), 3.25(4H,t), 3.78(4H,t), 3.92(3H,s), 6.77(2H,s), 6.84(2H,s) Example 207 'H NIVR(CDCl 3 6'8 2.10(3H,brs), 2.17(3H,s), 2.36(3H,s), 3.25(4H,brs), 3.79(4H,brs), 3.92(3H,s), 6.84(2H,m), 7.00( 1H,d), 7.06( 1H,brs), 7.13(1H,t) Example 208 1H NIVR(CDCl 3 6'8 2.12(3H,s), 2.17(3H,s), 2.37(3H,s), 3.50(4H,t), 3.88(4H,brs), 3.93(3H,s), 6.87( 1H,brs), 8.00(2H,d), 8.43( 1H,s) Example 209 1H NMR(CDC1 3 :68 1.41(6H,t), 2.11(3H,brs), 2.15(3H,s), 2.37(3H,s), 3.36(4H,brs), 3.83(4H,brs), 3.92(3H,s), 4.40(4H,q), 6.85( 1H,brs), 7.78(2H,s), 8.18(1H,s) 105 Example 210 'H NMR(CDC1 3 1.67(3H,t), 2.1O(3H,s), 2.39(3H,s), 2.51 3.25(4H,t), 3.80(4H,t), 3.92(3H,s), 6.90(2H,t), 6.95(2H,d), 7.29 (2H,t) Example 211 'H NMR(CDC1 3 1.17(3H,t), 2.10(3H,brs), 2.39(3H,s), 2.52(2H,q), 3.13(4H,brs), 3.84(4H,brs), 3.88(3H,s), 3.93(3H,s), 6.89(2H,brd), 6.93(2H,m), 7.04(1H,m) Example 212 'H NMVR(CDC1 3 1.16(3H,t), 2.09(3H,s), 2.39(3H,s), 2.51 3.23(4H,t), 3.79( 1OH,s), 3.92(3H,s), 6.05(1H,s), 6.11 (2H,d), 6.87( 1H,s) 10 Example 213 'H NMR(CDC 3 1.18(3H,t), 1.25(3H,t), 2.11(3H,brs), 2.40(3H,s), 2.52(2H,q), 2.72(2H,q), 2.96(4H,brs), 3.79(4H,brs), 3.94(3H,s), 6.88(1H,brs), 7.09(2H,m), 7.18( 1H,t), 7.24( 1H,d) Example 214 'H NMR(CDC13) 1.16(3H,t), 2.09(3H,s), 2.29(6H,s), 2.39(3H,s), 2.51 3.22(4H,t), 3.78(4H,t), 3.92(3H,s), 6.56(1H,s), 6.59(2H,s), 6.87(1H,s) Example 215 'H NMR(CDC13) 1.16(3H,t), 2.11(3H,brs), 2.40(3H,s), 2.51 3.27(4H,s), 3.80(4H,s), 3.92(3H,s), 6.28( 1H,t), 6.39(2H,d), 6.84(1H,s) Example 216 'H NIVR(CDC13) 1.17(3H,t), 2.12(3H,brs), 2.40(3H,s), 2.52(2H,q), 3.27(4H,s), 3.80(4H,s), 3.92(3H,s), 6.77(2H,d), 6.84(1H,s), 6.90(1H,brs) Example 217 'H NMR(CDC1 3 1.15(3H,t), 2.03(3H,brs), 2.38(3H,s), 2.50(2H,q), 2.90(4H,brs), 3.51(4H,brs), 3.90(3H,s), 6.82( 1H,d), 7.03( 1H,d), 7. 10( 1H,t), 7.27(3H,m), 7.39(2H,t), 7.61 (2H,d) Example 218 'H NMR(CDC1 3 1.15(3H,t), 2.13(3H,brs), 2.41(3H,s), 2.52(2H,Q), 3.52(4H,brs), 3.93(7H,s), 6.87( 1H,brs), 7.99(2H,d), 8.44( 1H,s) Example 219 'H NI\R(CDCJ 3 1.17(3H,t), 2.10(3H,brs), 2.39(3H,s), 2.42(311,s), 2.52(2H,q), 3.06(4H,s), 3.83(4H,s), 3.93(3H,s), 6.88(1H,brs), 7.05(1H,m), 7.12(3H,s) Example 220 1H NI\'R(CDC1 3 2.10(3H,brs), 2.73(3H,s), 3.23(4H,brs), 3.86(1OH,s), 3.89(3H,s), 6.05(1H,s), 6.11(211,s), 7.62(1H,brs) 106 Example 221 'H NMR(CDC1 3 :6 2.10(3H,brs), 2.29(6H,s), 2.73(3H,s), 3.23(4H,brs), 3.82(4H,brs), 3.86(3H,s), 3.99(3H,s), 6.57(3H,m), 7.62( 1H,brs) Example 222 1H NMR(CDC1 3 6 2.1O(3H,s), 2.73(3H,s), 3.27(4H,t), 3.83(4H,s), 3.86(3H,s), 4.00(3H,s), 6.30(1H,t), 6.40(2H,d), 7.64( 1H,brs) Example 223 1H NMR(C'DC13) 2.10(3H,brs), 2.73(3H,s), 3.14(4H,brs), 3.86(7H,s), 3.89(3H,s), 4.00(3H,s), 6.89( 1H,d), 6.95(2H,m), 7.04(1H,brm), 7.62(1H,brs) Example 224 'H NIN'R(CDCl 3 6 2.11(3H,brs), 2.73(3H,s), 3.26(4H,t), 3.85(7H,s), 4.O0(3H,s), 6.91 6.95(2H,d), 7.30(2H,t), 7.63( 1H,brs) 10 Example 225 'H N1VR(CDC1 3 :6 2.1O(3H1,s), 2.27(3H,s), 2.72(3H,s), 3.20(4H,t), 3.83(4H,s), 3.85(3H,s), 4.00(3H,s), 6.87(2H,d), 7.09(3H,d), 7.63(1H,brs) Example 226 111 NMR(CDCb3) :6 2.11(3H,brs), 2.73(3H,s), 3.27(4H,brs), 3.86(7H,s), 4.O0(3H,s), 6.81 6.85( 1H,d), 6.90( 1H,s), 7.19( 1H,t), 7.63(1H,brs) Example 227 1H NMR(CDC] 3 :6 2.12(3H,brs), 2.29(6H,s), 2.53(3H,s), 2.67(3H,s), 3.24(4H,brs), 3.83(4H,brs), 4.00(3H,s), 6.58( 1H,s), 6.60(2H,s), 7.47( 1H,brs) Example 228 'H NMR(CDC1 3 6 2.12(3H,brs), 2.53(3H,s), 2.68(3H,s), 3.25(4H,t), 3.79(6H,s), 3.82(4H,brs), 4.00(3H,s), 6.06(1H,s), 6.12(2H,d), 7.46(1H,brs) Example 229 1H NMR(CDCb3) :6 2.12(3H,s), 2.53(3H,s), 2.68(3H,s), 3.26(4H,t), 3.77(4H,t), 4.00(3H,s), 6.89(3H,d), 7. 19(2H,d), 7.46( 1H,s) Example 230 'H NMR(CDCl 3 6 2.12(3H,brs), 2.12(3H,s), 2.53(3H,s), 2.68(3H,s), 3.22(4H,s), 3.85(3H,brs), 4.00(3H,s), 6.87(2H,d), 7.10(2H,d), 7.45( 1H,s) Example 231 'H NMR(CDC13) 6 2.12(3H,s), 2.55(3H,s), 2.68(3H,s), 3.32 (4H,brs), 3.86(4H,brs), 4.01 6.38(3H,m), 7.47( H,brs) Example 232 'H NMR(CDC3) 6 2.12(311,s), 2.43(3H,s), 2.54(3H,s), 2.68(3H,s), 3.07(4H,brs), 3.86(4H,brs), 4.00(3H,s), 7.06( 1H,m), 7.13(3H,m), 7.46(1H,brs) 107 Example 233 1H NMR(CDC1 3 1.28(3H,t), 2.13(3H,brs), 2.29(3H,s), 3.11 3.21 (4H,brs), 3.85(7H,brs), 4.0O(3H,s), 6.89(2H,brs), 7.08(2H,d), 7.62(1H,brs) Example 234 'H NMR(CDG1 3 1.24(3H,t), 1.28(3H,t), 2.12(3H,brs), 2.72(2H,q), 2.96(4H,brs), 3. 1O(2H,q), 3.81 (4H,brs), 3.86(3H,s), 4.00(3H,s), 7.09(2H,m), 7.19( 7.24( 7.60(1H,brs) Example 235 'H NMR(CDCl 3 1.28(3H,t), 2.1O(3H,brs), 2.29(6H,s), 3.11 3.23(4H,brs), 3.82(4H,brs), 3.85(3H,s), 4.00(3H,s), 6.57(1H,s), 6.59(2H,s), 7.59(1H,brs) Example 236 'H N1\'R(CDCl 3 1.28(3H,t), 2.10(3H,brs), 3.10(2H,q), 3.24(4H,brs), 3.79(6H,s), 3.81 (4H,brs), 3.85(3H,s), 4.00(3H,s), 6.06(1H,s), 6.11(2H,s), 7.59(1H,brs) Example 237 'H NMR(CDC 3 1.28(3H,t), 2.10(3H,brs), 3.11(2H,q), 3.28(4H,brs), 3.82(4H,brs), 3.85(3H,s), 4.00(3H,s), 6.77(2H,d), 6.85( 1H,s), 7.60(1H,brs) Example 238 1H NMR(CDC1 3 1.28(3H,t), 2.1O(3H,brs), 2.43(3H,s), 3.06(6H,m), 3.86(7H,brs), 4.01 7.06( 7. 12(3H,s), 7.60(1H,brs) Example 239 'H NMR(CDC1 3 1.28(3H,t), 1.43(6H,t), 2.11(3H,brs), 3. 12(2H,q), 3.37(4H,brs), 3.86(7H,s), 4.01Hs, 4.41 (4H,cq), 7.60( 1H,brs), K) 20 7.79(2H,s), 8.18(1H,s) Example 240 1H NIVR(CDCl 3 1.28(3H,t), 2.10(3H,brs), 3.10(2H,q), 3.28(4H,brs), 3.82(4H,brs), 3.86(3H,s), 4.00(3H,s), 6.30(1H,t), 6.39(2H,d), 7.60( 1H,brs) Example 241 'H NMR(CDC1 3 2.07(3H,s), 3.27(4H,t), 3.79(6H,s), 3.86(4H,t), 4.10(3H,s), 6.06(1H,m), 6.12(2H,d), 7.32(1H,t), 7.36(1H,s), 7.48(1H,t), 7.61(1H,d), 7.80(1H,d) Example 242 'H NMR(CDC 3 2.07(3H,s), 2.30(6H,s), 3.25(4H,s), 3.86(4H,s), 4.10(3H,s), 6.58(1H,s), 6.60(2H,s), 7.32(1H,t), 7.36(1H,s), 7.49(1H,d), 7.80(1H,d) Example 243 'H NMR(CDCl 3 2.09(3H,brs), 3.27(4H,s), 3.87(4H,s), 4. 10(3H,s), 6.29( 1H,t), 6.39(2H,d), 7.32(1H,t), 7.37( 1H,s), 7.49(1H,t), 108 7.80( 1H,d) Example 244 'H NMR(CDC1 3 :6 2.09(3H,brs), 3.15(4H,t), 3.89(4H,s), 4.11 6.89( 1H,d), 6.96(2H,m), 7.04( 1H,m), 7.32( 1H,t), 7.38( 1H,brs), 7.48(1H,t), 7.62(1H,d), 7.80(1H,d) Example 245 1 NMR(CDC1 3 2.1O(3H,brs), 3.29(4H,t), 3.88(4H,brs), 4.10(3H,s), 6.82(1H,dd), 6.88( 1H,d), 6.92( 1H,s), 7.20( 1H,t), 7.33(1H,t), 7.40(1H,brs), 7.49(1H,t), 7.62( 1H,d), 7.80( 1H,d) Example 246 1H NMR(CDC1 3 :6 2.14(3H,brs), 2.17(3H,s), 2.22(3H,s), 3.25(4H,t), 3.78(7H,s), 6.60(1H,brs), 6.66( 1H,s), 6.89( 1H,t), 6.95(2H,t), 7.29(2H,t) Example 247 1H NMR(CDC 3 6 2.14(3H,brs), 2.17(3H,s), 2.22(3H,s), 2.28(3H,s), 3.19(4H,t), 3.77(7H,s), 6.60(1H,brs), 6.66( 1H,s), 6.86(2H,d), 7.08(2H,d) Example 248 'H NMR(CDC1 3 :6 1.25(3H,t), 2.14(3H,brs), 2.18(3H,s), 2.23(3H,s), 2.72(2H,q), 2.96(4H,brs), 3.75(4H,brs), 3.79(3H,s), 6.60(1H,brs), 6.67(1H,s), 7.08(2H,t), 7.18(1H,t), Example 249 1'H NMR(CDC 3 2.29(6H,s), 3.21 3.74(4H,t), 6.65( 1H,s) Example 250 'H NMR(CDCI 3 3.23(4H,t), 3.74(4H,t), 3.77(3H,s), 6.59(1H,s), 6.65(1H,s) Example 251 'H NMR(CDC1 3 3.25(4H,t), 3.74(4H,t), 3.77(3H,s), 6.66(1H,s) Example 252 'H NMR(CDC1 3 7.24( 1H,m) 8 2.12(3H,s), 2.16(3H,s), 2.22(3H,s), 3.77(3H,s), 6.55(1H,s), 6.59(3H,s), 8 2.12(3H,s), 2.16(3H,s), 2.22(3H,s), 3.78(6H,s), 6.04(1H,s), 6.12(2H,d), 8 2.11(3H,s), 2.16(3H,s), 2.22(3H,s), 6.28(1H,t), 6.39(2H,d), 6.59(1H,s), 6 2.14(3H,brs), 2.17(3H,s), 2.22(3H,s), 3.25(4H,t), 3.76(4H,brs), 3.78(3H,s), 6.61 H,brs), 6.66( 1H,s), 6.83(2H,m), 6.90(1H,s), 7.18(1H,t) Example 253 'H NMR(CDCl 3 6 2.14(3H,brs), 2.17(3H,s), 2.23(3H,s), 3.25(4H,t), 3.78(7H,s), 6.61 (1H,brs), 6.66( 1H,s), 6.85( 1H,d), 6.98( 1H,d), 7.06(1H,s), 7.12(1H,t)

U_

109 Example 254 'H NMR(CDCl 3 8 2.14(3H,brs), 2.17(3H,s), 2.22(3H,s), 2.42(3H,s), 3.06(4H,t), 3.78(7H,s), 6.60(1H,brs), 6.66(1H,s), 7.06(1H,m), 7.12(3H,s) Antitumor activities of the compounds of the present invention were tested in vitro against 5 kinds of human tumor cell lines and a leukemia tumor cell line. The method and result of the in vitro tests is as follows.

10 Experimental 1 In vitro antitumor effect against human tumor cell lines.

A. Tumor cell line A549 (human non-small lung cell) SKOV-3 (human ovarian) HCT-15 (human colon) XF 498 (human CNS) SKMEL-2 (human melanoma) B. SRB Assay Method.

a. Human solid tumor cell lines, A549(non-small lung cell), SKMEL-2(melanoma), HCT-15(colon), SKOV-3(ovarian), XF-498(CNS) were cultured at 37°C in 5% CO 2 incubators using RPMI 1640 media containing 10% FBS, while they were transfer-cultured successively once or twice per week. Cell cultures were dissolved in a solution of 0.25% trypsin and 3 mM CDTA PBS(-) and then cells were separated from media which the cells were sticked on.

b. 5x 103-2x 104 cells were added into each well of 96-well plate and cultured in 5% CO 2 incubator, at 37 C, for 24 hours.

c. Each sample drug was dissolved in a little DMSO and diluted with the used medium to a prescribed concentration for experiments, wherein the final concentration of DMSO was controlled below 110 d. Medium of each well cultured for 24 hours as above b. was removed by aspiration. Each 200/1l of drug samples prepared in c. was added into each well and the wells were cultured for 48 hours. Tz(time zero) plates were collected at the point of time drugs were added.

e. According to the SRB assay method, cell fixing with TCA, staining with 0.4% SRB solution, washing with 1% acetic acid and elution of dye with 10mM Tris solution were carried out on Tz plates and culture-ended plates, whereby OD values were measured at 520 nm.

10 C. Calculation of result a. Time zero(Tz) value was determined with measuring the SRB protein amounts of the Tz plates collected at the point of time drugs were added.

b. Control value(C) was determined with the OD values of wells untreated with a drug.

c. Drug-treated test value(T) was determined with the OD values of drug-treated wells.

d. Effects of drugs were estimated with growth stimulation, net growth inhibition, net killing etc., being calculated from Tz, C and T.

e. If T Tz, cellular response function was calculated by 100x(T-Tz)/(C-Tz), and if T Tz, by 100 x (T-Tz)/Tz. The results are shown in the next table 1.

REFERENCE

1) P. Skehan, R. Strong, D Scudiero, A. Monks, J. B. Mcmahan, D. T.

Vistica, J. Warren, H. Bokesh, S. Kenny and M. R. Boyd Proc. Am.

Assoc. Cancer Res., 30, 612(1989) 2) L. V. Rubinstein, R. H. Shoemaker, K. D. Paull, R. M. simon, S.

Tosini, P. Skehan, D. Scudiero, A. Monks and M. R. boyd. J. Natl.

Cancer Inst., 82, 1113(1990) 3) P. Skehan, R. Strong, D. Scudiero, A. monks, J. B. Mcmahan, D. T.

I 111 Vistica, J. Warren, H. Bokesh, S. Kenny and M. R. Boyd.;J, Natl.

Cancer Ins., 82, 1107(1990) D. Results.

It was found that all the tested compounds of the present invention have superior antitumor activities to the control, cisplatin.

Table 1.

EDso= g/m 0 Example Example A 549 SK-OV-3 SK-MEL-2 XF-498 HCT No.

2 0.032 0.088 0.029 0.084 0.019 3 0.0016 0.0064 0.0015 0.0022 0.0020 4 0.047 0.251 0.042 0.089 0.038 7 0.0024 0.0072 0.0023 0.0027 0.0028 12 0.008 0.069 0.008 0.017 0.001 14 0.204 0.677 0.283 0.340 0.067 0.079 0.184 0.038 0.096 0.071 19 0.0064 0.143 0.043 0.093 0.080 0 0.323 0.904 0.211 0.970 0.295 21 0.038 0.093 0.024 0.097 0.008 28 0.0001 0.0006 <0.0001 0.0001 0.0001 0.0006 0.0007 <0.0001 0.0005 0.0007 34 0.0023 0.0038 0.0003 0.0021 0.0021 0.0001 0.0007 <0.0001 0.0001 0.0001 37 0.01 0.02 0.02 0.003 0.009 38 0.00003 0.00009 0.00004 0.00011 0.00013 39 0.10 0.33 0.07 0.14 0.06 3 40 0.41 1.01 0.37 0.81 0.39 42 0.0018 0.0043 0.0012 0.0057 0.0026 0 112 Example A 549 SK-OV-3 SK-MEL-2 XF-498 HCT No.

0.0001 0.0002 <0.0001 0.0002 0.0001 46 0.002 0.007 0.003 0.001 0.002 48 0.001 0.007 0.0003 0.004 0.002 51 0.37 0.68 0.28 0.63 0.18 53 0.17 0.21 0.93 0.27 0.05 0.34 0.49 0.22 0.41 0.33 64 0.019 0.057 0.011 0.014 0.032 66 0.005 0.008 0.002 0.008 0.003 68 0.38 0.86 0.34 0.47 0.31 72 0.0001 0.0007 <0.0001 0.0001 0.0001 74 0.0020 0.038 0.003 0.024 0.028 86 0.04 0.08 0.03 0.04 0.06 87 0.01 0.03 0.66 0.08 0.008 89 0.04 0.20 0.03 0.04 0.05 0.38 0.35 0.90 0.68 0.20 99 0.012 0.008 0.006 0.010 0.003 101 0.0003 0.0003 0.0003 0.0002 0.0001 107 0.032 0.013 0.005 0.008 0.009 118 0.057 0.032 0.019 0.017 0.0002 120 0.64 0.73 0.28 0.82 0.30 125 0.0009 0.0008 0.0001 0.0001 0.0001 127 0.013 0.011 0.005 0.006 0.002 132 0.011 0.007 0.001 0.002 0.001 133 0.0001 0.0001 0.0001 0.0001 0.0001 138 0.074 0.030 0.016 0.018 0.006 139 0.0007 0.0007 0.0002 0.0003 0.0004 I 113 Example A 549 SK-OV-3 SK-MEL-2 XF-498 HCT No.

159 0.029 0.010 0.002 0.006 0.0006 172 0.07 0.08 0.02 0.03 0.02 173 0.40 0.86 0.15 0.21 0.18 176 0.0012 0.0009 0.0003 0.0001 0.0001 177 0.0006 0.0008 0.0003 0.0004 0.0001 180 0.28 0.16 0.31 0.24 0.16 181 0.13 0.06 0.11 0.04 0.02 182 0.292 0.081 0.033 0.103 0.006 1 Cisplatin 0.91 1.32 0.87 0.77 3.17 Experimental 2.

In vitro antitumor effects against animal leukemia cells.

A. Material: Tumor cell line P388 (mouse lymphoid neoplasma cell) B. Method Dye Exclusion Assay.

1) Concentrations of P388 cells being cultured in RPMI 1640 media containing 10% FBS were regulated to 1 106 cells/ml.

2) Sample drugs of respective concentrations diluted in the ratio of log doses were added into each cell culture and cultured at 37 C, for 48 hours, in 50% CO 2 incubator, and then viable cell numbers were measured by dye exclusion test using trypan blue.

3) Concentrations of sample compounds showing 50 cell growth inhibition compared with the control(ICso) were determined and listed in the table 2 below.

REFERENCE

1) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T.

Vistica, J. Warren, H. Bokesh, S. Kenney and M. R. Boyd. Proc. Am.

I 114 Assoc. Cancer Res., 30, 612(1989).

2) L. V. Rubinstein, R. H. Shoemaker, K. D. Paull, R. M. Simon, S.

Tosini, P. Skehan, D. Scudiero, A. Monks, J. Natl. Cancer Inst., 82, 1113(1990) 3) P. Skehan, R. Strong, D. Scudiero, J. B. Mcmahan, D. T. Vistica, J.

Warren, H. Bokesch, S. Kenney and M. R. Boyd. J. Natl. Cancer Inst., 82, 1107(1990) C. Results 10 As the results of measurement of antitumor activities of compounds of the present invention against P388 mouse leukemia cells, it was found that all the compounds tested have equal to or higher antitumor activities than those of the control drug, mitomycin C.

S 115 Example P388 Example P388 P388 P388 No. No.

2 0.3 46 0.2 3 0.01 48 0.39 7 0.02 64 0.34 11 0.02 66 0.2 12 0.1 72 0.10 0.70 74 0.68 19 0.2 99 0.04 10 20 1.2 101 0.002 21 0.8 107 0.04 28 0.04 118 0.3 0.07 138 0.1 34 0.14 139 0.03 0.01 173 0.4 37 0.3 180 0.05 38 0.01 181 0.03 42 0.03 182 0.2 45 0.15 Mitomycin C 1.1 Experimental 3.

Acute toxicity test (LDso) A. Method Litchfield-Wilcoxon method.

6 weeks old ICR mice(male 30±2.0g) were fed freely with solid feed and water at room temperature, 23±1+C at humidity 60±5%. Sample drugs were injected into abdominal cavities of mice, while each group comprises 6 mice. Observed during 14 days, external appearances and life or death were recorded, and then, visible pathogenies were observed from dead animals by dissection. LDso value was calculated by P:\WPDOCS\CAB\SPECI\7823543.doc-22/05/03 -116- Litchfiled-Wilcoxon method.

B. Result The results are shown at the next Table 3.

Table 3 Example No.

LD

5 s(mg/kg) P.O. i.v. i.p.

7 38 410 97 99 >200 104 212 Cisplatin 9.7 As described above, it was found that the compounds of the present invention are more safer than cisplatin, whereby the present compounds may solve problems of known drugs by the prior art such as restriction of dosage, toxicity, etc.

Comparative Examples Representative compounds of the present invention (Samjin or S) and from prior art documents D1 (WO 98/00402) and D2 (WO 96/21648) were subjected to comparative tests for in vitro antitumor effects against various human tumor cell lines and animal leukemia cells and for acute toxicity.

P:\WPDOCS\CAB\SJ'ECI\7823543.do.-22/05/03 -117- The representative compounds are as follows:

OCH

3 OH 0 H 11- N-C-N N N OCH 3

OCH

3 compound 1-1 (Ex. 56 of DI)

OCH

3 OH S H II N-C-N \N0 N OCH 3 I OCH 3 compound 1-2 (Ex. 63 of Dl) OH HN OHOCH 3 N OCH 3

OCH

3 compound 1-3 (Samjin, Ex. 139) OH 0 H 11/ N OCH 3 compound 2-1 (Ex. 57 of Dl) OH S H Ii /I N OCH 3 compound 2-2 (Ex. 64 of Dl) OH

HN'OH

N=C-N N N OCH 3 compound 2-3 (Samjin, Ex. 99) P:\WPDOCS\CAB\SPECI\7823543.doo-22/05/03 118

OCH

3 o 0 H 11-ii N-C-N N N OCH 3

OCH

3 compound 3-1 (Ex. 46 of D1)

OCH

3 0 S H II N-C-N \,N0 N OCH 3

OCH

3 compound 3-2 (Ex. 53 of DI) 0 HN' OH

OCH

3 N=C-N N0 N OCH 3

OCH

3

OCH

3 0 H 11 N N-C-N N N OCH 3 OH compound 4-1 (Ex. 1 10 of D2) HN'OH

OCH

3 N= NC-N

N

N OCH 3 OH compound 4-2 (Samjin, Ex. 101) compound 3-3 (Samjin, Ex. 133) Experimental 4: In vitro antitumor effect against human tumor cell lines and an animal (mouse) leukemia cell line.

The representative compounds were subjected to the in vitro human and animal cell line tests as described in Experimental 1 (page 109) and Experimental 2 (page 113). The results are shown below in Table 4.

P:\WPDOCS\CAB\SPECI\7823543doc-22/05/03 119- Table 4

ED

5 0 (pg/ml) on human solid tumor cell lines ED 50 (pg/ml) compound on mouse leukemia cell A549 SK-OV-3 SK-MEL-2 XF-498 HCT-15 P388 1-1 (D1) 0.017 0.0027 0.01 0.013 0.045 0.2 1-2 (D1) 0.04 0.1 0.11 0.03 0.07 0.3 1-3 0.0007 0.0007 0.0002 0.0003 0.0004 0.03 2-1 (D1) 0.27 0.15 0.18 0.22 0.25 1.2 2-2 (D1) 0.42 0.56 0.52 0.23 0.37 1.4 2-3 0.012 0.008 0.006 0.010 0.003 0.04 3-1 (D1) 0.21 0.12 0.08 0.14 0.16 1.9 3-2 (D1) 0.47 0.47 0.63 0.67 0.71 3-3 0.0001 0.0001 0.0001 0.0001 0.0001 0.04 4-1 (D2) 0.038 0.0011 0.0046 0.0042 0.0024 0.06 4-2 0.0003 0.0003 0.0003 0.0002 0.0001 0.002 The results depicted in Table 4 show that the EDso values for the representative compounds of the invention (compounds 1-3, 2-3, 3-3 and 4-2) are lower than, those of D1 and D2. The compounds of the present invention have higher antitumor activities than those of the corresponding compounds of D1 and D2.

Experimental 5. Acute toxicity test (LD 5 0 The representative compounds were subjected to the acute toxicity test as: described in Experimental 3 (page 115). The results are shown below in Table y-_ P:\WPDOCS\CAB\SPECI\7823543.doc-2205/03 -120- Table compound adminstration path LD 50 (pg/ml) 3-1 (D1) i.p 410 3-2 (D1) i.p 455 4-1 (D2) i.p 182.8 3-3 p.o >2000 2-3 i.v >200 The results depicted in Table 5 show that the LD 5 o values for the representative compounds of the invention are higher than the prior art compounds of D1 and D2. The compounds of the invention may be regarded as being less toxic as compared to the prior art compounds from D1 and D2.

Experimental 6. Solubility The compounds of the invention where Y is amino, substituted amino or thioalkyl are generally found to have increased solubility and hence better affinity to cell protein increase than those prior art compounds where Y is carbonyl or sulfonyl.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

P:\WPDOCS\CAB\SPECI\7823543.do-22/05/03 121 The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Claims (6)

1. A compound of the general formula (Ib) Y x 2 (Ib) wherein R, and R 2 are independently hydrogen, CI-C 4 alkyl, C 1 -C 4 alkylcarboxyl, Cl-C 4 alkylcarbonyl, CI-C 4 alkoxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 aminoalkyl or C- C 4 hydroxyiminoalkyl, or R, and R 2 are fused to form C 3 -C 4 unsaturated ring; R 3 R 4 R 5 R 6 and R 7 are independently hydrogen, halogen, hydroxy, nitro, amino, CI-C 4 alkyl, CI-C 4 alkylcarboxyl, CI-C 4 alkylcarbonyl, C 1 -C 4 alkoxy or C- C 4 thioalkoxy; R s is CI-C 4 alkyl; Y is amino, substituted amino or C 1 -C 4 thioalkyl; Z is C 1 -C 4 alkoxy, C,-C 4 alkyl, CI-C 4 alkylamino or C 1 -C 4 thioalkoxy; and X, is CH and X 2 is nitrogen; or pharmaceutically acceptable acid addition salts thereof.

2. A process for the preparation of compound of the general formula (Ib) comprising reacting a compound of the general formula (II) with an alkylating agent in the presence of a base to give a compound of the general formula and reacting the compound of the formula with a substituted or unsubstituted amine in the presence of a base to give a compound of the general formula (Ib) P:\WPDOCS\CAB\SPECI\7823543.doc-22/05/03 -123- K-II N-C-N NR SR3. 4 S Ri 2 z R 6 (II) R' R3, .R4 K2 Xi N=C-N N Rs, 10 RR x 2 R (F) R3, ,.4 zI- 1( z (Ib) wherein R 2 R 3 R 4 R 5 R 6 R 7 X 2 Y and Z are as defined in claim 1, and R' is C 1 -C 4 alkyl.

3. Pharmaceutical compositions comprising a compound of general formula (Ib) as defined in claim 1 or pharmaceutically acceptable acid addition salts thereof together with pharmaceutically acceptable vehicles.

4. Method for the prevention or treatment of tumours which comprises administering to a subject in need of such prevention or treatment a prophyl- actically or therapeutically effective amount of a compound of the general formula (Ib) as defined in claim 1 or pharmaceutically acceptable acid addition salts thereof optionally together with pharmaceutically acceptable vehicles.

P:\WPDOCS\CAB\SPECI\7823543.doc-22/05/03 -124- Use of a compound of the general formula (Ib) as defined in claim 1 for the manufacture of a medicament for the prevention or treatment of tumours.

6. Compounds of the general formula (Ib) as defined in claim 1, processes for their preparation or pharmaceutical compositions or methods/uses involving/ containing same, substantially as hereinbefore described with reference to the Examples. DATED this 2 3 rd day of May 2003. SAMJIN PHARMACEUTICAL CO., LTD. By its Patent Attorneys DAVIES COLLISON CAVE