WO1999061021A1

WO1999061021A1 - Drug-sensitivity recovering agents for resistant pathogenic microorganisms

Info

Publication number: WO1999061021A1
Application number: PCT/JP1999/002596
Authority: WO
Inventors: Takashi Nakamura; Yoshinori Yamano; Syujiro Seo
Original assignee: Shionogi & Co., Ltd.
Priority date: 1998-05-26
Filing date: 1999-05-19
Publication date: 1999-12-02

Abstract

Drug-sensitivity recovering agents capable of overcoming resistance acquired by pathogenic microorganisms and recovering the efficacy of antipathogenic microbial agents to such a level as exerted on drug-sensitive strains which contain compounds represented by general formula (I), salts thereof or metal complexes of the same; and medicinal compositions containing the above drug-sensitivity recovering agents and antimicrobial agents.

Description

Description Agent for restoring drug susceptibility to resistant pathogenic microorganisms TECHNICAL FIELD

The present invention relates to an agent for restoring the susceptibility of a pathogenic microorganism exhibiting multidrug resistance to an antibacterial agent, particularly a Pseudomonas aeruginosa, to a drug.

Conventional technology

Since the discovery of penicillin, humans have continually developed new antibiotics or antipathogenic microbial agents and established treatments for infections caused by pathogenic microorganisms. However, due to the emergence of resistant pathogenic microorganisms, even new antipathogenic microorganisms usually have a short life span. Also, increasing multidrug resistance of pathogenic microorganisms is an important issue, and overcoming it is an important issue. Among these infections, Pseudomonas aeruginosa infections tend to be refractory, and the infectious bacteria have become more resistant to ^ ij, making treatment difficult.

The mechanism of drug resistance in Pseudomonas aeruginosa includes a decrease in membrane permeability (mutation of LPS and porin), a change in the site of action (change in drug affinity of penicillin binding protein PBP: peptide glycan biosynthetic enzyme), Drug inactivating enzymes (production of 3-lactamase and aminoglycoside modifying enzymes), mutation of DNA gyrase, elimination of intracellular drugs by drug efflux system, etc. are known. In recent years, the production of drug efflux systems, that is, drug transporters, has been attracting attention as a mechanism for multidrug resistance, and research on the molecular level has been actively conducted. It has been clarified that Pseudomonas aeruginosa simultaneously obtains moderate to low resistance to several antibacterial agents by this action, and that this action also contributes to the natural resistance of this bacterium. Was

(J. Bacterid. 175: 7363-7372, 1993) (Biochera. Biophys. Res. Commun. 210: 356-362, 1995). If an inhibitor against this drug efflux transporter is developed, the antibacterial activity of the antibacterial agent can be restored to the same level as the susceptible strain against Pseudomonas aeruginosa, which has low sensitivity to the drug, and the therapeutic effect can be improved Therefore, its development was desired.

As a compound having such an action, there is a compound L-phenylalanyl-L-arginyl-J3-naphthylamide described in WO96 / 332885. this is, Decreases MICs for nov. quinolone such as chloramphenicol ^ tetracycline, ofloxacin, piramacillin, and ceftazidime in laboratory strains with high production of Op r M (K 385) and standard strain (PA01) in vitro It is a dipeptide compound having an action.

Problems to be solved by the invention

The present invention has been made in view of such circumstances, and provides a drug susceptibility recovery agent capable of overcoming the resistance acquired by a pathogenic microorganism and restoring the action of an antipathogenic microbial agent to the level of a drug-sensitive strain. Things.

Means for solving the problem

Means for Solving the ProblemsThe present inventors have conducted intensive research on a novel drug sensitivity-restoring agent, and as a result, have found that a compound represented by the following general formula (I), a salt thereof or a metal complex thereof has this effect, and Completed. That is, the present invention relates to a drug sensitivity restoring agent comprising the compound of the general formula (I), a salt thereof, or a metal complex thereof.

[Wherein R ¹ is (1) COXR ⁴ (X is O or S, and R ⁴ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted aralkyl , heteroarylalkyl to which may be Teroari Ichiru or substitution of optionally ^{substituted), (2) CONR5R 6 (} R 5, R 6 are identical or different and are a hydrogen atom, hydroxyl, optionally substituted Optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted Represents teroarylalkyl, provided that one of R ⁵ and R ⁶ is hydroxyl or Or in the case of optionally substituted alkoxyl, the other is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted aralkyl. ) Or (3) CO—R ⁷ —OR (R ⁷ is an α-amino acid residue; R is a hydrogen atom or alkyl);

R ² is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, COR ¹³ (R ¹³ is Hydrogen atom, alkyl which may be substituted, aryl which may be substituted, aralkyl which may be substituted, heteroaryl which may be substituted or heteroalkyl which may be substituted, COOR ¹⁴ (R ¹⁴ is alkyl which may be substituted, aryl which may be substituted, aralkyl which may be substituted, heteroaryl which may be substituted or heteroarylalkyl which may be substituted) , CONR ¹⁵ R ¹⁶ (R ¹⁵ and R ¹⁶ are the same or different and are a hydrogen atom, an optionally substituted alkyl, an optionally substituted Optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl);

R ³ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, COR ¹⁷ (R ¹⁷ is a hydrogen atom An optionally substituted alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl or an optionally substituted heteroarylalkyl), COOR ¹⁸ ( R ¹⁸ is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl or an optionally substituted heteroarylalkyl) or CON R ¹⁹ R ²⁰ (R ¹⁹ and R ² ° are the same or different and each may be a hydrogen atom, an optionally substituted alkyl, or an optionally substituted Aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl)

^{^{^{R 2, R 4, R 5}}} , R 6, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, ^{^{^{R 16, R 17, R 18}}} , R 19, R 2. And R ³ , which may be substituted, include alkyl having 1 to 10 carbon atoms, preferably alkyl having 1 to 4 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, n-butyl and isobutyl. , Sec-butyl, tert-butyl and the like. Of these, methyl, ethyl and propyl are preferred, and methyl is particularly preferred.

When these alkyls are substituted, examples of the substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine); an alkoxy having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms (eg, methoxy, Ethoxy, propoxy, etc.); alkylthio having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms (eg, methylthio, ethylthio, propylthio, etc.); having alkoxyl having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms Alkoxycarbonyl (eg, methoxy / levonyl, ethoxy canoleboninole, propoxy norebonyl, etc.); carboxy; hydroxy; substituted by alkyl or alkanol having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms. May be amino (eg, amino, monomethylamino, dimethylamino, acetylamino, etc.); Kanoiruokishi (e.g., such as Asetokishiru) and the like. Of these, a halogen atom, alkoxy and hydroxy are preferred, and chlorine, fluorine, methoxy, ethoxy and hydroxy are particularly preferred.

These substituents may be bonded to any substitutable position of the alkyl, preferably 1 to 3, and more preferably 1 to 2.

^{^{^{R 2, R 4, R 5}}} , R 6, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15,

^{^{^{R 16, R 17, R 18}}} , R 19, R 2. And optionally substituted aralkyl represented by R ³ ′ include, for example, benzyl, phenethyl, (α- or —) naphthylmethyl and the like. When these aralkyls are substituted, examples of the substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine); an alkyl having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms (eg, methyl, ethyl, Propyl, etc.); C1-C5, preferably C1-C3 alkoxy (eg, methoxy, ethoxy, propoxy, etc.); C1-C5, preferably C1-C3 halogenated alkyl ( Examples are fluoromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, dichloroethyl, etc.); nitro; cyano and the like. These substituents may be bonded to any substitutable position of the aralkyl, preferably 1 to 3, more preferably 1 to 2.

^{^{^{R 2, R 4, R 5}}} , R 6, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 2 The optionally substituted heteroaryl represented by ° and R ³ is optionally selected from heteroaryl containing one or more oxygen, sulfur or nitrogen atoms in the ring, for example, pyridyl, pyrimidinyl, furyl , Cenyl, pyrrolyl, quinolyl, oxazolyl, isoxazolyl, indolyl and the like. When the heteroaryl is substituted, examples of the substituent include a halogen atom (eg, fluorine, chlorine, bromine, and iodine); an alkyl having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms (eg, methyl). , Ethyl, propyl, etc.); alkoxy having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms (eg, methoxy, ethoxy, propoxy, etc.); halogenation having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms Alkynoles (eg, fluoromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, dichloroethyl, etc.); nitro; cyano. These substituents may be bonded to substitutable or shifted positions of the heteroaryl, preferably 1 to 3, more preferably 1 to 2. Further, the heteroaryl may be further condensed with another heteroaryl or carbocycle.

^{^{^{R 2, R 4, R 5}}} , R 6, R 8, R 9, R 10, R 1 R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 2. And the optionally substituted heteroarylalkyl represented by R ³ , and the heteroaryl as exemplified above, and an alkyl having 1 to 5 carbon atoms, preferably 1 to ² carbon atoms (eg, methyl, ethyl, etc.) Heteroarylalkyl, specifically, picolyl, pyridylethyl, pyrimidinylethyl, tulle, furfuryl and the like. Examples of the substituent when the heteroarylalkyl is substituted include the same substituents as those described above for the heteroarylalkyl.

Examples of the optionally substituted alkoxy represented by R ⁵ and R ⁶ include: To 5, preferably alkoxy having 1 to 3 carbon atoms, specifically, methoxy, ethoxy, propoxy, isopropoxy and the like. When the alkoxy is substituted, examples of the substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine). An alkoxy having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms (eg, methoxy, ethoxy, propoxy, etc.); an optionally substituted phenyl (eg, chlorophenyl, tolyl, methyl And nitrophenyl). These substituents may be bonded to any substitutable position of the alkoxy, preferably 1 to 3, and more preferably 1 to 2.

^{^{^{R 5, R 6, R 9}}} , R 10, and scale ^{^{^{11, R 12, R 13,}}} R 14, R 15, R 16, R 17, R 1 8, substituted represented by R ¹⁹ or R ² ° Examples of good aryl include aryl having 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, and specific examples include phenyl, α-naphthyl, and] -naphthyl. When the aryl is substituted, the substituent is a halogen atom (eg, fluorine, chlorine, bromine, iodine); an alkyl having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms (eg, methyl, ethyl, Alkoxy having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms (eg, methoxy, ethoxy, propoxy, etc.); alkyl halide having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms (Eg, fluoromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, dichloroethyl, etc.); nitro; and cyano. These substituents may be bonded to any substitutable position of the aryl, preferably 1 to 3, and more preferably 1 to 2.

Α-amino acid residues represented by R7 include cysteine (Cys) residues, dalysin (G1y) residues, serine (Ser) residues, and alanine (A1a) residues. Can be

Examples of the alkyl represented by R include the same groups as the groups exemplified as the alkyl of the optionally substituted alkyl represented by R ² and the like.

R ¹ is preferably COOR ^4, wherein R ⁴ is preferably a hydrogen atom, an optionally substituted alkyl or an optionally substituted benzyl, or CO NR ⁵ R ⁶ (where R ⁵ and R ⁶ are each independently preferably a hydrogen atom, a hydroxy, an alkoxy, an alkyl, a carboxyalkyl, an alkoxycarbonylalkyl or a hydroxyalkyl), and more preferably a carboxy group. , Alkoxy force bonyl, alkoxyalkoxycarbonyl, t-doxyalkoxycarbonyl, benzyloxycarbonyl, nodogenated benzene Ziroxycarbonyl, dicarbamoyl, monoalkylcarbamoyl, dialkyldirubamoyl, hydroxycarbamoyl, N-alkylhydroxycarbamoyl, carboxyalkyldirubamoyl, and alkoxycarbonylalkyldirubamoyl.

R ² is preferably a hydrogen atom, an optionally substituted alkyl, an optionally substituted benzyl or alkanol, and more preferably a hydrogen atom, an alkyl, an alkoxyalkyl, an alkyl halide, a benzyl halide, Al power Noil.

R ³ is preferably an oxygen atom or OR ³ ′ (where R ³ ′ is preferably a hydrogen atom, an optionally substituted alkyl, an optionally substituted benzyl or alkanoyl) And more preferably an oxygen atom, an alkoxy, an alkoxyalkoxy, a nodogenated alkoxy, a halogenated benzyloxy, and an alkanoyloxy.

“Drug susceptibility restorer” refers to a substance that has the effect of restoring the drug susceptibility of a drug-resistant pathogenic microorganism when used in combination with an antibacterial agent. The agent for restoring the drug sensitivity of the present invention includes a substance having an effect of restoring the drug sensitivity of Pseudomonas aeruginosa, which has become less sensitive to the drug due to overproduction of OprM.

“OprM” is one of the Pseudomonas aeruginosa drug efflux pumps that provide drug resistance for Pseudomonas aeruginosa, and OprJ and OprN are also known.

The metal complex of the compound represented by the general formula (I) can be represented by, for example, the following formula (1).

Where M is Zn, Cu, Co, Ni or Fe. "

—The compound represented by the general formula (I), a salt or a metal complex thereof has an anti-mycoplasma activity It has been known for some time that it has sex, anticoccidial activity, antifungal activity and immunosuppressive activity, but it is not known to have a drug sensitizing effect. Specific examples of the compound of the general formula (I), a salt thereof, and a metal complex include the compounds exemplified in Tables 1 and 2 below. These Mika Koshidin

All the (icacocidin) derivatives can be obtained by the methods disclosed in WO 96/042 62 (PCT / JP95 / 01552) and WO 97/29096 (PCT / JP97 / 00266). it can.

table 1

Compound number

1 C00H Η Ac

2 C00H Η C0CF3

3 C00H Η C0CH2C1

4 C00H Η C0CH2F

δ C00H Η COEt

6 C00H Η CO-iPr

7 C00H Η COPh

8 CO0H Η C0CH2Ph

9 C00H Η CO-2-Py

10 C00H Η CONHMe

11 C00H Η CONHEt

12 C00H Η COPr

13 C00H Η CONH-iPr

14 C00H Η CONHPh

15 CO0H Η C0NH-2-Py

16 C00H Η CO Marauder e2

17 C00H Η C0NEt2

18 C00H Η COOMe

19 CO0H Η COOEt

20 CO0H Η COOPh 3W½24635897021345C1 COOH HH COOH H Me COOH H CH2F COOH Me H COOH Me Ac COOH Me C0CF3 COOH Me C0CH2C1 COOH Me COCH2F COOH Me COEt COOH Me CO-iPr COOH Me COCH2Ph COOH Me CO-2-Py COOH Me CONMe2 COOH Me CONEt COOMe COOH Me COOEt COOH Me COOPh COOH Me CONHMe COOH Me CONHEt COOH Me CONHPr COOH Me CONH-iPr COOH Me CONHPh COOH Me Me COOH Me C ^ F COOH CH20Me Ac COOH CH20Me COCF3 COOH CH20Me C0CH2C1 COOH CH20Me COCH2E COOH CH20E αι ι ο

00 '~ J 05 J1 co O tO OO --J CTS On

8d 3 H003 Οΐ

aWOOD ZdDOD HOOD 90ΐ

S ring 03 CdDOD HOOD 90T

HOOD Μ) ΐ

CilDOD H003 εοτ Ζ

MdHNOD il D HOOO ΖΟΐ • idT-HNOO £ JOOD HOOD ΤΟΐ

• ¾03 CJDOD HOOD ΟΟΐ

ΪΞΗΝ03 HOOO 66

HOOD 16

H003 96 qdOD Cd300 HOOD 96

• idT-OD HOOO ^ 6

SHDOD HOOD ε6 9ΐ CdDOD HOOD Ζ6

Ϊ32Η300 H003 16

CilDOO HOOO 06

HOOD 68

³ V HOOD 88 01 3V HOOD IS

MdOOD ³ V HOOD 98

3V HOOD 98

3V HOOO 8

H003 98

³ V H003 28

^ d-2-HN03 HOOO 18

MdH OD ³ V HOOD 08 • idT-HNOD 3V HOOD 6 ΐ ΐ

96SZ0 / 66df / IDd 019/66 OM OAV

o

〇

H08

Ϊ32Η08 H08

Ϊ32Η§ ciEt CO 【2ph 〇

§HOEt C cotBUl

co <Et CO COiPr- σ¾ αι αι αι

rf ^ O Ο O 00 CJ1 ^

co-COEt

COOH COEt: 0 / 6S1 o

«3 oo cn o e

U5 to to to t ^ t-- t ^ t- t— t— 00 00 00 00 00 00 00 00 0O 00 O5 CJ5 O¾ OS o in in

cm

195 C00H CO-iPr H

196 C00H CO-iPr Me

197 C00H CO-iPr CH2F

198 COOH COPh Ac

199 COOH COPh C0CF3

200 COOH COPh C0CH2C1

201 COOH COPh C0CH2F

202 COOH COPh COEt

203 COOH COPh CO-iPr

204 COOH COPh COPh

205 COOH COPh CONHMe

206 COOH COPh CONHEt

207 COOH COPh CONH-iPr

208 COOH COPh CONHPh

209 COOH COPh C0NMe2

210 COOH COPh C0NEt2

211 COOH COPh COOMe

212 COOH COPh COOEt

213 COOH COPh COOPh

214 COOH COPh H

215 COOH COPh Me

216 COOH COPh CH2F

217 COOH CONHMe Ac

218 COOH CONHMe C0CF3

219 COOH CONHMe C0CH2C1

220 COOH CONHMe C0CH2F

221 COOH CONHMe COEt

222 COOH CONHMe CO-iPr

223 COOH CONHMe COBu 224 C00H CONHMe COPh 225 C00H CONHMe C0CH2Ph 226 C00H CONHMe CO-2-Py 227 COOH CONHMe CONHMe 228 COOH CONHMe CONHEt 229 COOH CONHMe COPr 230 COOH CONHMe CONH-iPr 231 COOH CONHMe C0NEt COOH COH CONH COH CONHCOH COH CONHCOH COH CONHCOH 235 COOH CONHMe H 236 COOH CONHMe Me 237 COOH CONHMe CH2F 238 COOH C0NMe2 Ac 239 COOH C0NMe2 C0CF3 240 COOH C0NMe2 C0CH2C1 241 COOH C0NMe2 C0CH2F 242 COOH C0NMe2 CO-2-Py2 COOH C0N2 COOH C0NCO2 COPh 246 COOH C0NMe2 CONHMe 247 COOH C0NMe2 CONHEt 248 COOH C0NMe2 CONH-iPr 249 COOH C0NMe2 CONHPh 250 COOH C0NMe2 C0NMe2 251 COOH C0NMe2 C0NEt2 252 COOH C0NMe2 COOMe 253 C00H C0NMe2 COOEt 254 C00H C0N e2 COOPh 255 C00H C0NMe2 H 256 COOH C0NMe2 Me 257 COOH C0NMe2 CH2F 258 COOH COOMe Ac 259 COOH COOMe C0CF3 260 COOH COOMe C0CH2C1 COO COOM CO263 COOH COOMeCOH COOM COOCOOM COO COOMCOH COBu 265 COOH COOMe COPh 266 COOH COOMe C0CH2Ph 267 COOH COOMe CO-2-Py 268 COOH COOMe CONHMe 269 COOH COOMe CONHEt 270 COOH COOMe COPr 271 COOH COOMe C0NMe2 272 COOH COOMe C0NEt COE COe COOM CO273 COOH COOMe H 277 COOH COOMe Me 278 COOH COOMe CH2F 279 CONMeOH COOMe COMe 280 CONMeOH COOMe C0CF3 281 CONMeOH COOMe C0CH2C1 282 CONMeOH COOMe C0CH2F 283 CONMeOH COOMe C0-2-Py 284 CONMeOH COOMe COEt 285 CONMeOH COOMe CO-iPr 286 CONMeOH COOMe COPh 287 CONMeOH COOMe CO wake e 288 CONMeOH COOMe CO HEt 289 CONMeOH COOMe CONH-iPr 290 CONMeOH COOMe CONHP C0 Me2 292 CONMeOH COOMe C0NEt2 293 CONMeOH COOMe COOMe 294 CONMeOH COOMe COOEt 295 CONMeOH COOMe COOPh 296 CONMeOH COOMe H 297 CONMeOH COOMe Me 298 CONMeOH COOMe CH2F 299 CONMeOH H Ac 300 CONMeOH H C0CF3 301 CONMeOH H C0CH2C1H2 304 CONMeOH H CO-iPr 305 CONMeOH H COBu 306 CONMeOH H COPh 307 CONMeOH H C0CH2Ph 308 CONMeOH H CO-2-Py 309 CONMeOH H CONHMe 310 CONMeOH H CONHEt 311 CONMeOH H COPr

312 CONMeOH H CONMe2

313 CONMeOH H CONEt2

314 CONMeOH H COOMe

315 CONMeOH H COOEt

316 CONMeOH H COOPh

317 CONMeOH H H

318 CONMeOH H Me

319 CONMeOH H CH2F

320 CONMeOH Me Ac

321 CONMeOH Me C0CF3

322 CONMeOH Me COCH2C1

323 CONMeOH Me COCH2F

324 CONMeOH Me CO-2-Py

325 CONMeOH Me COEt

326 CONMeOH Me CO-iPr

327 CONMeOH Me COPh

328 CONMeOH Me CONHMe

329 CONMeOH Me CONHEt

330 CONMeOH Me CONH-iPr

331 CONMeOH Me CONHPh

332 CONMeOH Me C0NMe2

333 CONMeOH Me CONEt2

334 CONMeOH Me COOMe

335 CONMeOH Me COOEt

336 CONMeOH Me COOPh

337 CONMeOH Me H

338 CONMeOH Me Me

339 CONMeOH Me CH2F 340 CONMeOH CH20Me Ac

341 CONMeOH CH20Me COCF3

342 CONMeOH CH20Me C0CH2C1

343 CONMeOH CH20Me C0CH2F

344 CONMeOH CH20Me COEt

345 CONMeOH CH20Me CO-iPr

346 CONMeOH CH20Me COBu

347 CONMeOH CH20Me COPh

348 CONMeOH CH20Me COCH2Ph

349 CONMeOH CH20Me CO-2-Py

350 CONMeOH CH20Me CONHMe

351 CONMeOH CH20Me CONHEt

352 CONMeOH CH20Me COPr

353 CONMeOH CH20Me CONH-iPr

354 CONMeOH CH20Me CONHPh

355 CONMeOH CH20Me CONH-2-Py

356 CONMeOH CH20Me CONMe2

357 CONMeOH CH20Me CONEt2

358 CONMeOH CH20Me COOMe

359 CONMeOH CH ed e COOEt

360 CONMeOH CH20Me COOPh

361 CONMeOH CH20Me H

362 CONMeOH CH20Me Me

363 CONMeOH CH2F CH2F

364 CONMeOH Ac Ac

365 CONMeOH Ac C0CF3

366 CONMeOH Ac COCH2C1

367 CONMeOH Ac COCH2F

368 CONMeOH Ac CO-2-Py 369 CONMeOH Ac COEt 370 CONMeOH Ac COPi 371 CONMeOH Ac COPh 372 CONMeOH Ac CONHMe 373 CONMeOH Ac CO HEt 374 CONMeOH Ac CONH-Pr 375 CONMeOH Ac CONHPh 376 CONMeOH Ac CONMe2 377 CONMeOH Ac CONEt2 378 CONMeOH Ac COOMe 379 CONMeOH Ac COOEt 380 CONMeOH Ac COOPh 381 CONMeOH Ac H 382 CONMeOH Ac Me 383 CONMeOH Ac CH2F 384 CO e eCOCF3 Ac 385 CONHMe COCF3 COCF3 386 CONHMe COCF3 COCH2C1 387 CONHMe COCF3 COCH2F 388 CONHMe C0CF3 COEt 389 CONHMe COCF3 CO-iPC 390 COPh 392 CONHMe COCF3 COCH2Ph 393 CONHMe COCF3 CO-2-Py 394 CONHMe COCF3 CONHMe 395 CONHMe COCF3 CONHEt 396 CONHMe COCF3 COPr 397 CONHMe C0CF3 CONMe2 398 CONHMe C0CF3 C0NEt2

399 CONHMe C0CF3 COO e

400 CONHMe C0CF3 COOEt

401 CONHMe C0CF3 COOPh

402 CONHMe C0CF3 H

403 CONHMe C0CF3 Me

404 CONHMe C0CF3 CH2F

405 CONHMe C0CH2F Ac

406 CONHMe C0CH2F COCF3

407 CONHMe C0CH2F COCH2C1

408 CONHMe C0CH2F COCH2F

409 CONHMe C0CH2F COEt

410 CONHMe C0CH2F CO-iPr

411 CONHMe C0CH2F COPh

412 CONHMe C0CH2F CONHMe

413 CONHMe C0CH2F CONHEt

414 CONHMe C0CH2F CONH-iPr

415 CONHMe C0CH2F CONHPh

416 CONHMe C0CH2F CONMe2

417 CONHMe C0CH2F CONEt2

418 CONHMe C0CH2F COOMe

419 CONHMe C0CH2F COOEt

420 CONHMe C0CH2F COOPh

421 CONHMe C0CH2F H

422 CONHMe C0CH2F Me

423 CONHMe C0CH2F CH2F

424 CONHMe COEt Ac

425 CONHMe COEt COCF3

426 CONHMe COEt COCH2C1 427 CONHMe COEt C0CH2F

428 CONHMe COEt COEt

429 CONHMe COEt CO-iPr

430 CONHMe COEt COBu

431 CONHMe COEt COPh

432 CONHMe COEt C0CH2Ph

433 CONHMe COEt CO-2-Py

434 CONHMe COEt CONHMe

435 CONHMe COEt CONHEt

436 CONHMe COEt COPr

437 CONHMe COEt C0NMe2

438 CONHMe COEt C0NEt2

439 CONHMe COEt COOMe

440 CONHMe COEt COOEt

441 CONHMe COEt COOPh

442 CONHMe COEt H

443 CONHMe COEt CH2F

444 CONHMe C0CH2C1 Ac

445 CONHMe C0CH2C1 C0CF3

446 CONHMe C0CH2C1 C0CH2C1

447 CONHMe C0CH2C1 C0CH2F

448 CONHMe C0CH2C1 COEt

449 CONHMe C0CH2C1 CO-iPr

450 CONHMe C0CH2C1 COPh

451 CONHMe C0CH2C1 CONHMe

452 CONHMe C0CH2C1 CONHEt

453 CONHMe C0CH2C1 CONH-iPr

454 CONHMe C0CH2C1 CONHPh

455 CONHMe C0CH2C1 C0N e2 456 CONHMe C0CH2C1 C0NEt2

457 CONHMe C0CH2C1 COO e

458 CONHMe C0CH2C1 COOEt

459 CONHMe C0CH2C1 COOPh

460 CONHMe C0CH2C1 H

461 CONHMe C0CH2C1 Me

462 CONHMe C0CH2C1 CH2F

463 CONHMe COPr Ac

464 CONHMe COPr C0CF3

465 CONHMe COPr C0CH2C1

466 CONHMe COPr C0CH2F

467 CONHMe COPr COEt

468 CONHMe COPr CO-iPr

469 CONHMe COPr COBu

470 CONHMe COPr COPh

471 CONHMe COPr C0CH2Ph

472 CONHMe COPr CO-2-Py

473 CONHMe COPr CONHMe

474 CONHMe COPr CONHEt

475 CONHMe COPr COPr

476 CONHMe COPr C0NMe2

477 CONHMe COPr C0NEt2

478 CONHMe COPr COOMe

479 CONHMe COPr COOEt

480 CONHMe COPr COOPh

481 CONHMe COPr H

482 CONHMe COPr CH2F

483 CONHMe COPh Ac

484 CONHMe COPh C0CF3 485 CONHMe COPh C0CH2C1 486 CONHMe COPh C0CH2F 487 CONHMe COPh COEt 488 CO HMe COPh CO-iPr 489 CONHMe COPh COPh 490 CONHMe COPh CONHMe 491 CONHMe COPh CONHEt 492 CONHMeHP COH OH 496 CONHMe COPh COOMe 497 CONHMe COPh COOEt 498 CONHMe COPh COOPh 499 CONHMe COPh H 500 CONHMe COPh Me 501 CONHMe COPh CH2F 502 CONHMe CONHMe Ac 503 CONHMe CONHMe C0CF3 504 CONHMe CONHMe C0Me2C1H COHH 508 CONHMe CONHMe COBu 509 CONHMe CONHMe COPh 510 CONHMe CONHMe C0CH2Ph 511 CONHMe CONHMe CO-2-Py 512 CONHMe CONHMe CONHMe 513 CONHMe CONHMe CONHEt 514 CONHMe CONHMe COPr 515 CONHMe CONHMe C0NMe2 516 CONHMe CONHMe C0NEt2 517 CONHMe CONHMe COOMe 518 CONHMe CONHMe COOEt 519 CONHMe CONHMe COOPh 520 CONHMe CONHMe H 522 CONHMe C0NMe2 Ac 523 CONHMe C0NMe2 C0CF3 524 CONHMe C0NMe2 C0CH2C1 525 CONHMe C0NMe2 C0CH2F 526 CONHMe C0NMe2 COEt 527 CONHMe C0NMe2 CO-iPr 528 CONHMe C0NMe2 COPh 529 CONHMe C0NMe2 CONHMe 530 CONHMe C0NMe2 CONHEt 531 CONHMe C0NMe2 CONH-iPr 532 CONHMe C0NMe2 CONHPh 533 CONHMe C0NMe2 C0NMe2 534 CONHMe C0NMe2 C0NEt2 535 CONHMe C0NMe2 COOMe 536 CONHMe C0NMe2 COOEt 537 CONHMe C0NMe2 COOPh 538 CONHMe C0NMe2 H 539 CONHMe C0NMe2 Me 540 CONHMe C0NMe2 CH2F 541 CONHMe COOMe Ac 542 CONHMe COOMe COCF3 543 CONHMe COOMe C0CH2C1 544 CONHMe COOMe C0CH2F 545 CONHMe COOMe COEt 546 CONHMe COOMe CO-iPr 547 CONHMe COOMe COBu 548 CONHMe COOMe COPh 549 CONHMe COOMe C0CH2Ph 550 CONHMe COOMe CO-2-Py 551 CONHe COHME COHME COHe MEH CONHMe COOMe 552 555 CONHMe COOMe C0NEt2 556 CONHMe COOMe COOMe 557 CONHMe COOMe COOEt 558 CONHMe COOMe COOPh 559 CONHMe COOMe H 560 CONHMe COOMe CH2F 561 CONHMe COOEt Ac 562 CONHMe COOEt C0CF3 COHCOECOH COEtCOHCOE COHCO 567 CONHMe COOEt COPh 568 CONHMe COOEt CONHMe 569 CONHMe COOEt CONHEt 570 CONHMe COOEt CONH-iPr 571 CONHMe COOEt CONHPh 572 CONHMe COOEt CONMe2 t

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622 C0NHCH20H Me Me 623 C0NHCH20H Me CH2F 624 C0NHCH2CH20H H Ac 625 CONHCH2CH20H H C0CF3 626 CONHCH2CH20H H COCH2C1 627 CONHCH2CH20H H C0CH2F 628 CONHCH2CH20H H COEt 629 CONHCH2CH20H H CO-iPr 630 CONHCH2CH20H H COBu dHNOO aW H0CHD2H3H 03 699idT-HN03 9W H02HD2H3HN0D 8S9

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730 C0NHCH20H Ac Me 731 C0NHCH20H Ac CH2F 732 C0NHCH20H C0CF3 Ac 733 C0NHCH20H C0CF3 COCF3 734 C0NHCH20H C0CF3 C0CH2C1 735 C0NHCH20H C0CF3 C0CH2F 736 C0NHCH20H C0CF3 COEt 737 C0NHCH20H C0CF3 CO-iPr 738 C0NHCH20H C0CF3 COBu 739 C0NHCH20H C0CF3 COPh 740 C0NHCH20H C0CF3 COCH2Ph 741 C0NHCH20H C0CF3 CO -2-Py 742 C0NHCH20H C0CF3 CO married e 743 C0NHCH20H C0CF3 CONHPr 744 C0NHCH20H C0CF3 CONH-iPr 745 C0NHCH20H C0CF3 CONHPh 746 C0NHCH20H C0CF3 CONH-2-Py ο

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841 C0NHCH20H COPr Me 842 C0NHCH20H COPr CH2F 843 C0NHCH20H COPh Ac 844 C0 HCH20H COPh COCF3 845 C0NHCH20H COPh COCH2C1 846 C0NHCH20H COPh COCH2F 847 C0NHCH20H COPh CO-2-Py 848 C0NHCH20H COPh COEt 849 C0NHCH20H COPh CO-iPr 850 C0NHCH20H COPh COBu 851 C0NHCH20H COPh COPh 852 C0NHCH20H COPh CONH e 853 C0NHCH20H COPh CONHEt 854 C0NHCH20H COPh CONHPr 855 C0NHCH20H COPh CONH-iPr 856 C0NHCH20H COPh CONHPh 857 C0NHCH20H COPh CONH20P0CONCOHCOHCOPCOHCOHCOPCH COHCOHCOHCOHCOHCOHCOHCOHCOHCOHCOHCOHOH t

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96S: 0/66 <ir / lDd 019/66 ΟΛ \ 949 C0NHCH20H COOEt CONMe2 950 C0NHCH20H COOEt CONEt2 951 C0NHCH20H COOEt COOMe 952 C0NHCH20H COOEt COOEt 953 C0NHCH20H COOEt COOPh 954 C0NHCH20H COOEt H

955 C0NHCH20H COOEt Me 956 C0NHCH20H COOEt CH2F 957 CONHCHMeOH H Ac 958 CONHCHMeOH H COCF3 959 CONHCHMeOH H COCH2C1 960 CONHCHMeOH H COCH2F 961 CONHCHMeOH H COEt 962 CONHCHMeOH H CO-iPrCH MeOH HCO-CHPCHH MeOH -2-Py 967 CONHCHMeOH H CONHMe 968 CONHCHMeOH H CO HEt 969 CONHCHMeOH H COPr 970 CONHCHMeOH H CONH-iPr 971 CONHCHMeOH H CONHPh 972 CONHCHMeOH H CONH-2-Py 973 CONHCHMeOH H C0 Me2 974 CONHCHMeOH H CONEt2 975 CONHCHMeOH H COOEt 977 CONHCHMeOH H COOPh 978 CONHCHMeOH HH

979 CONHCHMeOH H Me

980 CONHCHMeOH H CH2F

981 CONHCHMeOH Me Ac

982 CONHCHMeOH Me C0CF3

983 CONHCHMeOH Me C0CH2C1

984 CONHCHMeOH Me C0CH2F

985 CONHCHMeOH Me C0-2-Py

986 CONHCHMeOH Me COEt

987 CONHCHMeOH Me CO-iPr

988 CONHCHMeOH Me COPh

989 CONHCHMeOH Me CONHMe

990 CONHCHMeOH Me CONHEt

991 CONHCHMeOH Me CONHPr

992 CONHCHMeOH Me CONH-iPr

993 CONHCHMeOH Me CONHPh

994 CONHCHMeOH Me CO H-2-Py

995 CONHCHMeOH Me CONMe2

996 CONHCHMeOH Me CONEt2

997 CONHCHMeOH Me COOMe

998 CONHCHMeOH Me COOPh

999 CONHCHMeOH Me H

1000 CONHCHMeOH Me Me

1001 CONHCHMeOH Me CH2F

1002 CONHCHMeOH COOPh COCH2C1

1003 CONHCHMeOH COOPh C0CH2F

1004 CONHCHMeOH COOPh COEt

1005 CONHCHMeOH COOPh CO-iPr

1006 CONHCHMeOH COOPh COBu 1007 CONHCHMeOH COOPh COPh 1008 CONHCHMeOH COOPh COCH2Ph 1009 CONHCHMeOH COOPh CO-2-Py 1010 CONHCHMeOH COOPh CONHMe 1011 CONHCHMeOH COOPh CONHEt 1012 CONHCHMeOH COOPh COPr 1013 CONHCHMeOH COOPh CONHCHHCOPhCOPh CONH-CHPOH10H e2 1017 CONHCHMeOH COOPh CO Et2 1018 CONHCHMeOH COOPh COOMe 1019 CONHCHMeOH COOPh COOEt 1020 CONHCHMeOH COOPh COOPh 1021 CONHCHMeOH COOPh H

1022 CONHCHMeOH COOPh Me 1023 CONHCHMeOH COOPh CH2F 1024 CONHCHMeOH COCH2F Ac 1025 CONHCHMeOH COCH2F COCF3 1026 CONHCHMeOH COCH2F COCH2F 1027 CONHCHMeOH COCH2F COCH2C1 1028 CONHCHMeOH COCH2FCO-2-FCH10CH2CHFCO-2-CHFCO-2-CHFCO-2-CHOCHFCH COCH2F CO-iPr 1033 CONHCHMeOH C0CH2F COPh 1034 CONHCHMeOH COCH2F CONHMe 1035 CONHCHMeOH COCH2F CONHEt 1036 CONHCHMeOH C0CH2F CONH-iPr

1037 CONHCHMeOH C0CH2F CONHPh

1038 CONHCHMeOH C0CH2F CONMe2

1039 CONHCHMeOH C0CH2F CONEt2

1040 CONHCHMeOH C0CH2F COOMe

1041 CONHCHMeOH C0CH2F COOEt

1042 CONHCHMeOH C0CH2F H

1043 CONHCHMeOH C0CH2F Me

1044 CONHCHMeOH Ac Ac

1045 CONHCHMeOH Ac COCF3

1046 CONHCHMeOH Ac COCH2C1

1047 CONHCHMeOH Ac COCH2F

1048 CONHCHMeOH Ac COEt

1049 CONHCHMeOH Ac CO-iPr

1050 CONHCHMeOH Ac COBu

1051 CONHCHMeOH Ac COPh

1052 CONHCHMeOH Ac COCH2Ph

1053 CONHCHMeOH Ac CO-2-Py

1054 CONHCHMeOH Ac CONH e

1055 CONHCHMeOH Ac CONHEt

1056 CONHCHMeOH Ac COPr

1057 CONHCHMeOH Ac CONH-iPr

1058 CONHCHMeOH Ac CONHPh

1059 CONHCHMeOH Ac CONH-2-Py

1060 CONHCHMeOH Ac CO Me2

1061 CONHCHMeOH Ac CONEt2

1062 CONHCHMeOH Ac COOMe

1063 CONHCHMeOH Ac COOEt

1064 CONHCHMeOH Ac COOPh 1065 CONHCHMeOH Ac H 1066 CONHCHMeOH Ac Me 1067 CONHCHMeOH Ac CH2F 1068 CONHCHMeOH COCH2C1 Ac 1069 CONHCHMeOH C0CH2C1 C0CF3 1070 CONHCHMeOH C0CH2C1 COCH2C1 1071 CONHCHMeOH COCH2C1 COCH2F1 CO2CH1CO2CH1CO2C1CO2C1CH2 COH2CH1CO2C1CH2COHCOMeOH 1076 CONHCHMeOH COCH2C1 CONHMe 1077 CONHCHMeOH COCH2C1 CONHEt 1078 CONHCHMeOH COCH2C1 CONH-iPr 1079 CONHCHMeOH COCH2C1 CONHPh 1080 CONHCHMeOH C0CH2C1 CONMe2 1081 CONHCHMeOH COCH2C1 CONEt2 1082 CONHCHMeOH COCH2C1 COOMe 1083 CONHCHMeOH C0CH2C1 COOEt 1084 CONHCHMeOH COCH2C1 COOPh 1085 CONHCHMeOH COCH2C1 H 1086 CONHCHMeOH C0CH2C1 Me 1087 CONHCHMeOH C0CH2C1 CH2F 1088 CONHCHMeOH COCF3 Ac 1089 CONHCHMeOH COCF3 C0CF3 1090 CONHCHMeOH C0CF3 COCH2C1 1091 CONHCHMeOH COCF3 COCH2F 1092 CONHCHMeOH COCF3 COEt 1093 CONHCHMeOH COCF3 CO-iPr 1094 CONHCHMeOH C0CF3 COBu 1095 CONHCHMeOH C0CF3 COPh 1096 CONHCHMeOH C0CF3 C0CH2Ph 1097 CONHCHMeOH C0CF3 C0-2-Py 1098 CONHCHMeOH C0CF3 CO ban e 1099 CONHCHMeOH C0CF3 CONHEH 1100 CONHCHMeOH C0C3CHPH1COHCHMeOH -Py 1104 CONHCHMeOH C0CF3 C0 Me2 1105 CONHCHMeOH C0CF3 C0NEt2 1106 CONHCHMeOH C0CF3 COOMe 1107 CONHCHMeOH C0CF3 COOEt 1108 CONHCHMeOH C0CF3 COOPh 1109 CONHCHMeOH C0CF3 H

1110 CONHCHMeOH C0CF3 Me mi CONHCHMeOH C0CF3 CH2F

1112 CONHCHMeOH COEt Ac

1113 CONHCHMeOH COEt C0CF3 1114 CONHCHMeOH COEt C0CH2C1 1115 CONHCHMeOH COEt C0CH2F 1116 CONHCHMeOH COEt CO-2-Py 1117 CONHCHMeOH COEt COEt 1118 CONHCHMeOH COEt CO-iPr 1119 CONHCHMeOH COEt COHCOEH COEt COHCOEH 1123 CONHCHMeOH COEt CONH-iPr 1124 CONHCHMeOH COEt CONHPh 1125 CONHCHMeOH COEt CONMe2 1126 CONHCHMeOH COEt CONEt2 1127 CONHCHMeOH COEt COOMe 1128 CONHCHMeOH COEt COOEt 1129 CONHCHMeOH COEt COOPh 1130 CONHCHMeOH COE

1131 CONHCHMeOH COEt Me 1132 CONHCHMeOH COEt CH2F 1133 CONHCHMeOH COPr Ac 1134 CONHCHMeOH COPr C0CF3 1135 CONHCHMeOH COPr C0CH2C1 1136 CONHCHMeOH COPr C0CH2F 1137 CONHCHMeOH COPr COEt1PHCOPCOHCOPCOCOPCOHCOPCOCOHCOPCOH COPr CO-2-Py 1143 CONHCHMeOH COPr CO band e 1144 CONHCHMeOH COPr CONHEt 1145 CONHCHMeOH COPr CONH-iPr 1146 CONHCHMeOH COPr CONHPh 1147 CONHCHMeOH COPr CONH-2-Py 1148 CONHCHMeOH COPr CONMe2 1149 CONHCHMeOH COPrCOHCOECOPCOHCOPCOH 1152 CONHCHMeOH COPr COOPh

1153 CONHCHMeOH COPr H

1154 CONHCHMeOH COPr Me

1155 CONHCHMeOH COPr CH2F

1156 CONHCHMeOH COPh H

1157 CONHCHMeOH COPh Ac

1158 CONHCHMeOH COPh C0CF3

1159 CONHCHMeOH COPh C0CH2F

1160 CONHCHMeOH COPh CO-2-Py

1161 CONHCHMeOH COPh COEt

1162 CONHCHMeOH COPh CO-iPr

1163 CONHCHMeOH COPh COBu

1164 CONHCHMeOH COPh CONHMe

1165 CONHCHMeOH COPh CONHEt

1166 CONHCHMeOH COPh CONHPr

1167 CONHCHMeOH COPh CONH-iPr

1168 CONHCHMeOH COPh CONHPh

1169 CONHCHMeOH COPh CO H-2-Py

1170 CONHCHMeOH COPh C0NMe2

1171 CONHCHMeOH COPh C0NEt2

1172 CONHCHMeOH COPh COOMe

1173 CONHCHMeOH COPh COOEt

1174 CONHCHMeOH COPh COOPh

1175 CONHCHMeOH COPh Me

1176 CONHCHMeOH COPh CH2F

1177 CONHCHMeOH CONHMe Ac

1178 CONHCHMeOH CONHMe C0CF3

1179 CONHCHMeOH CONHMe C0CH2C1

1180 CONHCHMeOH CONHMe C0CH2F 1181 CONHCHMeOH CO ban e COEt 1182 CONHCHMeOH CONHMe CO-iPr 1183 CONHCHMeOH CO ban e COBu 1184 CONHCHMeOH CONHMe COPh 1185 CONHCHMeOH CONHMe C0CH2Ph 1186 CONHCHMeOH CONHMe CO-2-Py 1187 CONHCHMeOH CONHMe CONHMe 1188 CONHCHMeOH CONHMeH 1H CONHCHMeOH CONHMe CONHPh 1191 CONHCHMeOH CONHMe CONH-2-Py 1192 CONHCHMeOH CONHMe C0N e2 1193 CONHCHMeOH CONHMe C0NEt2 1194 CONHCHMeOH CONHMe COOMe 1195 CONHCHMeOH CONHMe COOPh 1197 CONHCHMeOH CONHMeCONHMe

1198 CONHCHMeOH CONHMe Me 1199 CONHCHMeOH CONHMe CH2F 1200 CONHCHMeOH C0NMe2 Ac 1201 CONHCHMeOH C0NMe2 C0CF3 1202 CONHCHMeOH C0NMe2 C0CH2F 1203 CONHCHMeOH C0NMe2 CO-2-Py 1204 CONHCHMeOH C0NMe2 COEt 1205 CONHCHMeOH C0NMe2 COPr 1206 CONHCHMeOH C0NMe2 CQ-iPr 1207 CONHCHMeOH C0NMe2 COPh 1208 CONHCHMeOH C0N e2 CONHMe 1209 CONHCHMeOH C0NMe2 CONHEt 1210 CONHCHMeOH C0NMe2 CONHPr

1211 CONHCHMeOH C0NMe2 CONH-iPr

1212 CONHCHMeOH C0NMe2 CONHPh

1213 CONHCHMeOH C0NMe2 CONH-pyridine

1214 CONHCHMeOH C0 Me2 CONMe2

1215 CONHCHMeOH C0NMe2 CONEt2

1216 CONHCHMeOH C0NMe2 COOMe

1217 CONHCHMeOH C0 e2 COOEt

1218 CONHCHMeOH C0NMe2 COOPh

1219 CONHCHMeOH C0NMe2 H

1220 CONHCHMeOH C0NMe2 Me

1221 CONHCHMeOH C0NMe2 CH2F

1222 CONHCHMeOH COOEt Ac

1223 CONHCHMeOH COOEt COCF3

1224 CONHCHMeOH COOEt COCH2C1

1225 CONHCHMeOH COOEt C0CH2F

1226 CONHCHMeOH COOEt COEt

1227 CONHCHMeOH COOEt CO-iPr

1228 CONHCHMeOH COOEt COBu

1229 CONHCHMeOH COOEt COPh

1230 CONHCHMeOH COOEt COCH2Ph

1231 CONHCHMeOH COOEt CO-2-Py

1232 CONHCHMeOH COOEt CONHMe

1233 CONHCHMeOH COOEt CONHEt

1234 CONHCHMeOH COOEt COPr

1235 CONHCHMeOH COOEt CONH-iPr

1236 CONHCHMeOH COOEt CONHPh

1237 CONHCHMeOH COOEt CONH-2-Py

1238 CONHCHMeOH COOEt CON e2 1239 CONHCHMeOH COOEt C0NEt2 1240 CONHCHMeOH COOEt COOMe 1241 CONHCHMeOH COOEt COOEt 1242 CONHCHMeOH COOEt COOPh 1243 CONHCHMeOH COOEt H

1244 CONHCHMeOH COOEt Me 1245 CONHCHMeOH COOEt CH2F 1246 CONHCHMeOH COOMe Ac 1247 CONHCHMeOH COOMe C0CF3 1248 CONHCHMeOH COOMe C0CH2F 1249 CONHCHMeOH COOMe CO-2-Py 1250 CONHCHMeOH COOMe COEt 1251 CONHCHMeOH COHHCOMeOH COHHCOMeOH COHH COOMe CONH-iPr 1256 CONHCHMeOH COOMe CONHPh 1257 CONHCHMeOH COOMe CONH-2-Py 1258 CONHCHMeOH COOMe C0NMe2 1259 CONHCHMeOH COOMe C0 Et2 1260 CONHCHMeOH COOMe COOMe 1261 CONHCHMeOH COOMe COOEt 12262 CONHCHMeOH COOMeCOOPH

1264 CONHCHMeOH COOMe Me 1265 CONHCHMeOH COOMe CH2F 1266 CONHCHMeCOOH H Ac 1267 CONHCHMeCOOH H C0CF3 1268 CONHCHMeCOOH H COCH2C1 1269 CONHCHMeCOOH H C0CH2F 1270 CONHCHMeCOOH H COEt 1271 CONHCHMeCOOH H CO-iPr 1272 CONHCHMeCOOH H COBu 1273 CONHCHMeCOOH H COPh 1274 CONHCHMeCOOH H COCHHMECOHHOH COHCHOHHCOHCHOHHCOHCHOHHCOHCHOHHOH H COPr 1279 CONHCHMeCOOH H CONH-iPr 1280 CONHCHMeCOOH H CONHPh 1281 CONHCHMeCOOH H CONH-2-Py 1282 CONHCHMeCOOH H CONMe2 1283 CONHCHMeCOOH H CO Et2 1284 CONHCHMeCOOH H COOMe 1285 CONHCHMeCOOH HCOOEtCOHCOHCOHCOHCOHCOHCOHCOHCOHCOHCOHHCOHCOHCOHHCOHCOHCOHHCOHCOHCOHCOHHCOHCOHHCOHCOHCOHCOHHCOHCOHOH

1288 CONHCHMeCOOH H Me 1289 CONHCHMeCOOH H CH2F 1290 CONHCHMeCOOH Me Ac 1291 CONHCHMeCOOH Me C0CF3 1292 CONHCHMeCOOH Me COCH2C1 1293 CONHCHMeCOOH Me C0CH2F 1294 CONHCHMeCOOH Me CO-2-Py 1295 CONHCHMeCOOH MeCOPCOE 1297 CONHCHMeCOOH Me COPh 1298 CONHCHMeCOOH Me CONHMe 1299 CONHCHMeCOOH Me CONHEt 1300 CONHCHMeCOOH Me CONHPr 1301 CONHCHMeCOOH Me CONH-iPr 1302 CONHCHMeCOOH Me CONHPh 1303 CONHCHMeCOOH Me CONH2-Py 1304 COHCHMECOOH MeCOHCOMeCOOH COOPh 1308 CONHCHMeCOOH Me H

1309 CONHCHMeCOOH Me Me 1310 CONHCHMeCOOH Me CH2F 1311 CONHCHMeCOOH COOPh COCH2C1 1312 CONHCHMeCOOH COOPh C0CH2F 1313 CONHCHMeCOOH COOPh COEt 1314 CONHCHMeCOOH COOPh CO-iPr 1315 CONHCHMeCOOH COOPh COBu 1316 CONHCHMeCOOH COOPh COPh 1317 CONHCHMeCOOH COOPh COCH2Ph 1318 CONHCHMeCOOH COOPh CO-2-Py 1319 CONHCHMeCOOH COOPh CONHMe 1320 CONHCHMeCOOH COOPh CONHEt 1321 CONHCHMeCOOH COOPh COPr 1322 CONHCHMeCOOH COOPh CONH-iPr 1323 CONHCHMeCOOH COOPh CONHPh 1324 CONHCHMeCOOH COOPh CONH-2-Py 1325 CONHCHMeCOOH COOPh CONMe2 1326 CONHCHMeCOOH COOPh C0NEt2

1327 CONHCHMeCOOH COOPh COO e

1328 CONHCHMeCOOH COOPh COOEt

1329 CONHCHMeCOOH COOPh COOPh

1330 CONHCHMeCOOH COOPh H

1331 CONHCHMeCOOH COOPh Me

1332 CONHCHMeCOOH COOPh CH2F

1333 CONHCHMeCOOH C0CH2F Ac

1334 CONHCHMeCOOH C0CH2F C0CF3

1335 CONHCHMeCOOH C0CH2F C0CH2F

1336 CONHCHMeCOOH C0CH2F C0CH2C1

1337 CONHCHMeCOOH C0CH2F CO-2-Py

1338 CONHCHMeCOOH C0CH2F COEt

1339 CONHCHMeCOOH C0CH2F CONH-2-Py

1340 CONHCHMeCOOH C0CH2F COEt

1341 CONHCHMeCOOH C0CH2F CO-iPr

1342 CONHCHMeCOOH C0CH2F COPh

1343 CONHCHMeCOOH C0CH2F CO Bandana e

1344 CONHCHMeCOOH C0CH2F CONHEt

1345 CONHCHMeCOOH C0CH2F CONH-iPr

1346 CONHCHMeCOOH C0CH2F CONHPh

1347 CONHCHMeCOOH C0CH2F C0NMe2

1348 CONHCHMeCOOH C0CH2F C0NEt2

1349 CONHCHMeCOOH C0CH2F COOMe

1350 CONHCHMeCOOH C0CH2F COOEt

1351 CONHCHMeCOOH C0CH2F H

1352 CONHCHMeCOOH C0CH2F Me

1353 CONHCHMeCOOH Ac Ac

1354 CONHCHMeCOOH Ac C0CF3 1355 CONHCHMeCOOH Ac C0CH2C1

1356 CONHCHMeCOOH Ac C0CH2F

1357 CONHCHMeCOOH Ac COEt

1358 CONHCHMeCOOH Ac CO-iPr

1359 CONHCHMeCOOH Ac COBu

1360 CONHCHMeCOOH Ac COPh

1361 CONHCHMeCOOH Ac COCH2Ph

1362 CONHCHMeCOOH Ac CO-2-Py

1363 CONHCHMeCOOH Ac COO e

1364 CONHCHMeCOOH Ac CONHEt

1365 CONHCHMeCOOH Ac COPr

1366 CONHCHMeCOOH Ac CONH-iPr

1367 CONHCHMeCOOH Ac CONHPh

1368 CONHCHMeCOOH Ac C0NH-2-Py

1369 CONHCHMeCOOH Ac C0 Me2

1370 CONHCHMeCOOH Ac C0NEt2

1371 CONHCHMeCOOH Ac COOMe

1372 CONHCHMeCOOH Ac COOEt

1373 CONHCHMeCOOH Ac COOPh

1374 CONHCHMeCOOH Ac H

1375 CONHCHMeCOOH Ac Me

1376 CONHCHMeCOOH Ac CH2F

1377 CONHCHMeCOOH C0CH2C1 Ac

1378 CONHCHMeCOOH C0CH2C1 C0CF3

1379 CONHCHMeCOOH COCH2C1 C0CH2C1

1380 CONHCHMeCOOH C0CH2C1 C0CH2F

1381 CONHCHMeCOOH C0CH2C1 CQ-2-Py

1382 CONHCHMeCOOH COCH2C1 COEt

1383 CONHCHMeCOOH C0CH2C1 CO-iPr 1384 CONHCHMeCOOH C0CH2C1 COPh

1385 CONHCHMeCOOH C0CH2C1 CONHMe

1386 CONHCHMeCOOH C0CH2C1 CONHEt

1387 CONHCHMeCOOH C0CH2C1 CONH-iPr

1388 CONHCHMeCOOH C0CH2C1 CONHPh

1389 CONHCHMeCOOH C0CH2C1 C0N e2

1390 CONHCHMeCOOH C0CH2C1 C0NEt2

1391 CONHCHMeCOOH C0CH2C1 COOMe

1392 CONHCHMeCOOH C0CH2C1 COOEt

1393 CONHCHMeCOOH C0CH2C1 COOPh

1394 CONHCHMeCOOH C0CH2C1 H

1395 CONHCHMeCOOH C0CH2C1 Me

1396 CONHCHMeCOOH C0CH2C1 CH2F

1397 CONHCHMeCOOH C0CF3 Ac

1398 CONHCHMeCOOH C0CF3 C0CF3

1399 CONHCHMeCOOH C0CF3 C0CH2C1

1400 CONHCHMeCOOH C0CF3 C0CH2F

1401 CONHCHMeCOOH C0CF3 COEt

1402 CONHCHMeCOOH C0CF3 CO-iPr

1403 CONHCHMeCOOH C0CF3 COBu

1404 CONHCHMeCOOH C0CF3 COPh

1405 CONHCHMeCOOH C0CF3 C0CH2Ph

1406 CONHCHMeCOOH C0CF3 CO-2-Py

1407 CONHCHMeCOOH C0CF3 CONHMe

1408 CONHCHMeCOOH C0CF3 CONHEt

1409 CONHCHMeCOOH C0CF3 COPr

1410 CONHCHMeCOOH C0CF3 CONH-iPr

1411 CONHCHMeCOOH C0CF3 CONHPh

1412 CONHCHMeCOOH C0CF3 CONH-2-Py 1413 CONHCHMeCOOH C0CF3 C0NMe2 1414 CONHCHMeCOOH C0CF3 C0NEt2 1415 CONHCHMeCOOH C0CF3 COOMe 1416 CONHCHMeCOOH C0CF3 COOEt 1417 CONHCHMeCOOH C0CF3 COOPh 1418 CONHCHMeCOOH C0CF3 H 1419 CONHCHMeCOOH C0CF3 Me 1420 CONHCHMeCOOH C0CF3 CH2F 1421 CONHCHMeCOOH COEt Ac 1422 CONHCHMeCOOH COEt C0CF3 1423 CONHCHMeCOOH COEt C0CH2C1 1424 CONHCHMeCOOH COEt C0CH2F 1425 CONHCHMeCOOH COEt CO-2-Py 1426 CONHCHMeCOOH COEt COEt 1427 CONHCHMeCOOH COEt CO-iPr 1428 CONHCHMeCOOH COEt CO-tBu 1429 CONHCHMeCOOH COEt COPh 1430 CONHCHMeCOOH COEt CO wake e 1431 CONHCHMeCOOH COHTCOHCOHCOHCOH COHCOHCOH C0NMe2 1435 CONHCHMeCOOH COEt C0NEt2 1436 CONHCHMeCOOH COEt COOMe 1437 CONHCHMeCOOH COEt COOEt 1438 CONHCHMeCOOH COEt COOPh 1439 CONHCHMeCOOH COEt H 1440 CONHCHMeCOOH COEt Me 1441 CONHCHMeCOOH COE 1442 CONHCHMeCOOH COPr Ac 1443 CONHCHMeCOOH COPr C0CF3 1444 CONHCHMeCOOH COPr C0CH2C1 1445 CONHCHMeCOOH COPr C0CH2F 1446 CONHCHMeCOOH COPr COEt 1447 CONHCHMeCOOH COPr CO-iPr 1448 CONHCHMeCOOH COPr CO-tBu 1449 CONHCHMeCOOH COPr COPh 1450 CONHCHMeCOOH COPr C0CH2Ph 1451 CONHCHMeCOOH COPr CO-2-Py 1452 CONHCHMeCOOH COPR CO negation e 1453 CONHCHMeCOOH COPr CONHEt 1454 CONHCHMeCOOH COPr CO H-iPr 1455 CONHCHMeCOOH COPr CONHPh 1456 CONHCHMeCOOH COPr CONH-2-Py 1457 CONHCHMeCOOH COPr C0NMe2 1458 CONHCHMeCOOH COPr C0NEt2 1459 CONHCHMeCOOH COPr COOMe 1460 CONHCHMeCOOH COPr COOEt 1461 CONHCHMeCOOH COPr COOPh 1462 CONHCHMeCOOH COPr H

1463 CONHCHMeCOOH COPr Me 1464 CONHCHMeCOOH COPr CH2F 1465 CONHCHMeCOOH COPh H

1466 CONHCHMeCOOH COPh Ac 1467 CONHCHMeCOOH COPh C0CF3 1468 CONHCHMeCOOH COPh C0CH2F 1469 CONHCHMeCOOH COPh CO-2-Py ί470 CONHCHMeCOOH COPh COEt 1471 CONHCHMeCOOH COPh CO-iPr

1472 CONHCHMeCOOH COPh COBu

1473 CONHCHMeCOOH COPh CONHMe

1474 CONHCHMeCOOH COPh CONHEt

1475 CONHCHMeCOOH COPh CONHPr

1476 CONHCHMeCOOH COPh CONH-iPr

1477 CONHCHMeCOOH COPh CONHPh

1478 CONHCHMeCOOH COPh CONH-2-Py

1479 CONHCHMeCOOH COPh C0NMe2

1480 CONHCHMeCOOH COPh C0NEt2

1481 CONHCHMeCOOH COPh COOMe

1482 CONHCHMeCOOH COPh COOEt

1483 CONHCHMeCOOH COPh COOPh

1484 CONHCHMeCOOH COPh Me

1485 CONHCHMeCOOH COPh CH2F

1486 CONHCHMeCOOH CONHMe Ac

1487 CONHCHMeCOOH CONHMe C0CF3

1488 CONHCHMeCOOH CONHMe C0CH2C1

1489 CONHCHMeCOOH CONHMe C0CH2F

1490 CONHCHMeCOOH CONHMe COEt

1491 CONHCHMeCOOH CONHMe CO-iPr

1492 CONHCHMeCOOH CONHMe COBu

1493 CONHCHMeCOOH CONHMe COPh

1494 CONHCHMeCOOH CONHMe C0CH2Ph

1495 CONHCHMeCOOH CONHMe CO-2-Py

1496 CONHCHMeCOOH CONHMe CONHMe

1497 CONHCHMeCOOH CONHMe CONHEt

1498 CONHCHMeCOOH CONHMe CONH-iPr

1499 CONHCHMeCOOH CONHMe CONHPh 1500 CONHCHMeCOOH CONHMe CONH-2-Py

1501 CONHCHMeCOOH CO Marauder e CONMe2

1502 CONHCHMeCOOH CONHMe CONEt2

1503 CONHCHMeCOOH CONHMe COOMe

1504 CONHCHMeCOOH CONHMe COOEt

1505 CONHCHMeCOOH CONHMe COOPh

1506 CONHCHMeCOOH CONHMe H

1507 CONHCHMeCOOH CONHMe Me

1508 CONHCHMeCOOH CONHMe CH2F

1509 CONHCHMeCOOH CO Me2 Ac

1510 CONHCHMeCOOH CONMe2 COCF3

1511 CONHCHMeCOOH CONMe2 C0CH2F

1512 CONHCHMeCOOH CONMe2 CO-2-Py

1513 CONHCHMeCOOH CONMe2 COEt

1514 CONHCHMeCOOH C0NMe2 COPr

1515 CONHCHMeCOOH CONMe2 CO-iPr

1516 CONHCHMeCOOH C0NMe2 COPh

1517 CONHCHMeCOOH CONMe2 CONHMe

1518 CONHCHMeCOOH CONMe2 CONHEt

1519 CONHCHMeCOOH C0NMe2 CO HPr

1520 CONHCHMeCOOH CON e2 CONH-iPr

1521 CONHCHMeCOOH CONMe2 CONHPh

1522 CONHCHMeCOOH C0NMe2 CONH-pyridine

1523 CONHCHMeCOOH CON e2 CONMe2

1524 CONHCHMeCOOH CONMe2 CONEt2

1525 CONHCHMeCOOH CONMe2 COOMe

1526 CONHCHMeCOOH CON e2 COOEt

1527 CONHCHMeCOOH CONMe2 COOPh

1528 CONHCHMeCOOH CONMe2 H 1529 CONHCHMeCOOH CO Me2 Me

1530 CONHCHMeCOOH CONMe2 CH2F

1531 CONHCHMeCOOH COOEt Ac

1532 CONHCHMeCOOH COOEt COCF3

1533 CONHCHMeCOOH COOEt C0CH2C1

1534 CONHCHMeCOOH COOEt C0CH2F

1535 CONHCHMeCOOH COOEt COEt

1536 CONHCHMeCOOH COOEt CO-iPr

1537 CONHCHMeCOOH COOEt COBu

1538 CONHCHMeCOOH COOEt COPh

1539 CONHCHMeCOOH COOEt COCH2Ph

1540 CONHCHMeCOOH COOEt CO-2-Py

1541 CONHCHMeCOOH COOEt CONHMe

1542 CONHCHMeCOOH COOEt CONHEt

1543 CONHCHMeCOOH COOEt COPr

1544 CONHCHMeCOOH COOEt CONH-iPr

1545 CONHCHMeCOOH COOEt CO HPh

1546 CONHCHMeCOOH COOEt C0NH-2-Py

1547 CONHCHMeCOOH COOEt C0NMe2

1548 CONHCHMeCOOH COOEt CONEt2

1549 CONHCHMeCOOH COOEt COOMe

1550 CONHCHMeCOOH COOEt COOEt

1551 CONHCHMeCOOH COOEt COOPh

1552 CONHCHMeCOOH COOEt H

1553 CONHCHMeCOOH COOEt Me

1554 CONHCHMeCOOH COOEt CH2F

1555 CONHCHMeCOOH COOMe Ac

1556 CONHCHMeCOOH COOMe COCF3

1557 CONHCHMeCOOH COOMe C0CH2F 1558 CONHCHMeCOOH COOMe CO-2-Py

1559 CONHCHMeCOOH COOMe COEt

1560 CONHCHMeCOOH COOMe COBu

1561 CONHCHMeCOOH COOMe CO bandits e

1562 CONHCHMeCOOH COOMe CONHEt

1563 CONHCHMeCOOH COOMe CONHPr

1564 CONHCHMeCOOH COOMe CONH-iPr

1565 CONHCHMeCOOH COOMe CONHPh

1566 CONHCHMeCOOH COOMe CONH-2-Py

1567 CONHCHMeCOOH COOMe C0NMe2

1568 CONHCHMeCOOH COOMe C0NEt2

1569 CONHCHMeCOOH COOMe COOMe

1570 CONHCHMeCOOH COOMe COOEt

1571 CONHCHMeCOOH COOMe COOPh

1572 CONHCHMeCOOH COOMe H

1573 CONHCHMeCOOH COOMe Me

1574 CONHCHMeCOOH COOMe CH2F

1575 COO e H Ac

1576 COOMe H COCF3

1577 COOMe H C0CH2C1

1578 COOMe H COCH2F

1579 COOMe H COEt

1580 COOMe H CO-iPr

1581 COOMe H COBu

1582 COOMe H COPh

1583 COOMe H COCH2Ph

1584 COOMe H CO-2-Py

1585 COOMe H CONHMe

1586 COOMe H CONHEt 1587 COOMe H COPr

1588 COOMe H CONH-iPr

1589 COOMe H CONHPh

1590 COOMe H CONH-2-Py

1591 COOMe H C0NMe2

1592 COOMe H C0NEt2

1593 COOMe H COOMe

1594 COOMe H COOEt

1595 COOMe H COOPh

1596 COOMe H H

1597 COOMe H Me

1598 COOMe H CH2F

1599 COOMe Me Ac

1600 COOMe Me C0CF3

1601 COOMe Me C0CH2C1

1602 COOMe Me C0CH2F

1603 COOMe Me CO-2-Py

1604 COOMe Me COEt

1605 COOMe Me CO-iPr

1606 COOMe Me COBu

1607 COOMe Me COPh

1608 COOMe Me CONHEt

1609 COOMe Me CONHPr

1610 COOMe Me CONH-iPr

1611 COOMe Me CONHPh

1612 COOMe Me CONH-2-Py

1613 COOMe Me C0NMe2

1614 COOMe Me C0NEt2

1—615 COOMe Me COOMe 1616 COOMe Me COOPh

1617 COOMe Me H

1618 COOMe Me Me

1619 COOMe Me CH2F

1620 COOMe Ac Ac

1621 COOMe Ac COCF3

1622 COOMe Ac COCH2C1

1623 COOMe Ac COCH2F

1624 COOMe Ac COEt

1625 COOMe Ac CO-iPr

1626 COOMe Ac COBu

1627 COOMe Ac COPh

1628 COOMe Ac COCH2Ph

1629 CobMe Ac CO-2-Py

1630 COOMe Ac CONHMe

1631 COOMe Ac CONHEt

1632 COOMe Ac COPr

1633 COOMe Ac CONH-iPr

1634 COOMe Ac CONHPh

1635 COOMe Ac CONH-2-Py

1636 COOMe Ac CONM02

1637 COOMe Ac CONEt2

1638 COOMe Ac COOMe

1639 COOMe Ac COOEt

1640 COOMe Ac COOPh

1641 COOMe Ac H

1642 COOMe Ac Me

1643 COOMe Ac CH2F

1644 COOMe C0CH2C1 Ac

1674 COOMe C0CF3 CONHMe

1675 COOMe COCF3 CONHEt

1676 COOMe C0CF3 COPr

1677 COOMe C0CF3 CONH-iPr

1678 COOMe C0CF3 CONHPh

1679 COOMe COCF3 CONH-2-Py

1680 COOMe C0CF3 C0NMe2

1681 COOMe COCF3 C0NEt2

1682 COOMe COCF3 COOMe

1683 COOMe COCF3 COOEt

1684 COOMe COCF3 COOPh

1685 COOMe COCF3 H

1686 COOMe C0CF3 Me

1687 COOMe COCF3 CH2F

1688 COOMe COEt Ac

1689 COOMe COEt COCF3

1690 COOMe COEt COCH2C1

1691 COOMe COEt COCH2F

1692 COOMe COEt CO-2-Py

1693 COOMe COEt COEt

1694 COOMe COEt CO-iPr

1695 COOMe COEt CO-tBu

1696 COOMe COEt COPh

1697 COOMe COEt CONHMe

1698 COOMe COEt CONHEt

1699 COOMe COEt CONH-iPr

1700 COOMe COEt CONHPh

1701 COOMe COEt CONMe2

1702 COOMe COEt CONEt2 1703 COOMe COEt COOMe

1704 COOMe COEt COOEt

1705 COOMe COEt COOPh

1706 COOMe COEt H

1707 COOMe COEt Me

1708 COOMe COEt CH2F

1709 C00CH20Me H Ac

1710 COOCH rinse e H C0CF3

1711 C00CH20Me H C0CH2C1

1712 COOCH spirit e H C0CH2F

1713 C00CH20Me H COEt

1714 C00CH20Me H CO-iPr

1715 COOCH spirit e H COBu

1716 COOCH e H COPh

1717 COOCH spirit e H C0CH2Ph

1718 C00CH20Me H CO-2-Py

1719 COOCH H e CO Awakening e

1720 C00CH20Me H CONHEt

1721 C00CH20Me H COPr

1722 COOCH Fiber e H CONH-iPr

1723 C00CH20Me H CONHPh

1724 C00CH20Me H CONH-2-Py

1725 C00CH20Me H C0N e2

1726 C00CH20Me H C0NEt2

1727 C00CH20Me H COOMe

1728 C00CH20 e H COOEt

1729 C00CH20 e H COOPh

1730 C00CH20Me H H

1731 C00CH20Me H Me αι o

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SrO / 66Jf / I3d ΪΖ0Ι9 / 66 OAV 1848 COSMe C0CF3 CO-iPr 1849 COSMe C0CF3 COBu 1850 COSMe C0CF3 COPh 1851 COSMe C0CF3 C0CH2Ph 1852 COSMe C0CF3 CO-2-Py 1853 COSMe C0CF3 CONHMe 1854 COSMe C0CF3 CONHEC 1CF COSMe C0CF1857 COSMe C0CF3 C0CF3 CONH-2-Py 1859 COSMe C0CF3 C0NMe2 1860 COSMe C0CF3 C0NEt2 1861 COSMe C0CF3 COOMe 1862 COSMe C0CF3 COOEt 1863 COSMe C0CF3 COOPh 1864 COSMe C0CF3 H

1865 COSMe C0CF3 Me 1866 COSMe C0CF3 CH2F 1867 COSMe COEt Ac 1868 COSMe COEt C0CF3 1869 COSMe COEt C0CH2C 1870 COSMe COEt C0CH2F 1871 COSMe COEt C0-2-P 1872 COSMe COEt COEE 1873 COSMe COEt 1873 COSMe 1876 COSMe COEt CONHEt 1877 COSMe COEt CONH-iPr

1878 COSMe COEt CONHPh

1879 COSMe COEt CONMe2

1880 COSMe COEt C0NEt2

1881 COSMe COEt COOMe

1882 COSMe COEt COOEt

1883 COSMe COEt COOPh

1884 COSMe COEt H

1885 COSMe COEt Me

1886 COSMe COEt CH2F

1887 COSMe H Ac

1888 COSMe H COCF3

1889 COSMe H C0CH2C1

1890 COSMe H C0CH2F

1891 COSMe H COEt

1892 COSMe H CO-iPr

1893 COSMe H COBu

1894 COSMe H COPh

1895 COSMe H C0CH2Ph

1896 COSMe H CO-2-Py

1897 COSMe H CONHMe

1898 COSMe H CONHEt

1899 COSMe H COPr

1900 COSMe H CONH-iPr

1901 COSMe H CONHPh

1902 COSMe H C0NH-2-Py

1903 COSMe H C0NMe2

1904 COSMe H CONEt2

1905 COSMe H COOMe 1906 COSMe H COOEt 1907 COSMe H COOPh 1908 COSMe HH 1909 COSMe H Me 1910 COSMe H CH2F 1911 COSMe Me Ac 1912 COSMe Me COCF3 1913 COSMe Me COCH2C1 1914 COSMe Me COCH2F 1915 COSMe Me CO-2-Py 1916 COSMe Me COE19 CO-iPr 1918 COSMe Me COPh 1919 COSMe Me CONHMe 1920 COSMe Me CONHEt 1921 COSMe Me CONH-iPr 1922 COSMe Me CONHPh 1923 COSMe Me CONMe2 1924 COSMe Me CONEt2 1925 COSMe Me COOMe 1926 COSMe Me COOEt 1927 COSMe MeOP COSMe Me Me 1930 COSMe Me CH2F 1931 COSMe Ac Ac 1932 COSMe Ac COCF3 1933 COSMe Ac COCH2C1 1934 COSMe Ac COCH2F 1935 COSMe Ac COEt 1936 COSMe Ac CO-iPr 1937 COSMe Ac COBu 1938 COSMe Ac COPh 1939 COSMe Ac C0CH2Ph 1940 COSMe Ac CO-2-Py 1941 COSMe Ac CONHMe 1942 COSMe Ac CONHEt 1943 COSMe Ac COPr 1944 COSMe Ac CONI-iPr Ac CONHPh 1946 COSMe Ac CONH-2-Py 1947 COSMe Ac C0NMe2 1948 COSMe Ac C0NEt2 1949 COSMe Ac COOMe 1950 COSMe Ac COOEt 1951 COSMe Ac COOPh 1952 COSMe Ac H

1953 COSMe Ac Me 1954 COSMe COMe CH2F 1955 COSMe C0CH2C1 Ac 1956 COSMe C0CH2C1 C0CF3 1957 COSMe C0CH2C1 C0CH2C1 1958 COSMe C0CH2C1 C0CH2F 1959 COSMe C0CH2C1 CO-2-Py 1960 COSMe C0CH2C1 COEt 1961 COSMe C0CH2C1 CO-iPr 1962 COSMe C0CH2C1 COPh 1963 COSMe C0CH2C1 CONHMe 1964 COSMe C0CH2C1 CONHEt 1965 COSMe C0CH2C1 CONH-iPr 1966 COSMe C0CH2C1 CONHPh 1967 COSMe C0CH2C1 C0NMe2 1968 COSMe C0CH2C1 C0NEt2 1969 COSMe C0CH2C1 COOMe 1970 COSMe C0CH2C1 COOEt 1971 COSMe C0CH2C1 COOPh 1972 COSMe C0CH2C1 H

1973 COSMe C0CH2C1 Me 1974 COSMe C0CH2C1 CH2F 1975 COSMe C0CF3 Ac 1976 COSMe C0CF3 C0CF3 1977 COSMe C0CF3 C0CH2C1 1978 COSMe C0CF3 C0CH2F 1979 COSMe C0CF3 COEt 1980 COSMe C0CF3 CO-iPr 1981 COSMe C0CF3 COBu 1982 COSMe C0CF3 COPh 1983 COSMe C0CF3 C0CH2Ph 1984 COSMe C0CF3 CO -2-Py 1985 COSMe C0CF3 CONHMe 1986 COSMe C0CF3 CONHEt 1987 COSMe C0CF3 COPr 1988 COSMe C0CF3 CONH-iPr 1989 COSMe C0CF3 CONHPh 1990 COSMe C0CF3 CONH-2-Py 1991 COSMe C0CF3 C0MeMe2CF 1993 COSMe C0CF3 COOMe 1994 COSMe C0CF3 COOEt 1995 COSMe C0CF3 COOPh 1996 COSMe C0CF3 H

1997 COSMe C0CF3 Me 1998 COSMe C0CF3 CH2F 1999 COSMe COEt Ac 2000 COSMe COEt C0CF3 2001 COSMe COEt C0CH2C1 2002 COSMe COEt C0CH2F 2003 COSMe COEt CO-2-Py 2004 COSMe COEt COEt 2005 COSMe COECOECOT CO-iECOE COEt CO-iE COEt CO-iECOE COEt CO-iECO 2008 COSMe COEt CONHEt 2009 COSMe COEt CONH-i-Pr 2010 COSMe COEt CONHPh 2011 COSMe COEt C0NMe2 2012 COSMe COEt C0NEt2 2013 COSMe COEt COOMe 2014 COSMe COEt COOEt 2015 COSMe COEt COOPh 2016 COSMe COEt H

2017 COSMe COEt Me 2018 COSMe COEt CH2F 2019 COSMe COPr Ac 2020 COSMe COPr C0CF3 2021 COSMe COPr C0CH2C1 2022 COSMe COPr C0CH2F 2023 COSMe COPr COEt 2024 COSMe COPr CO-iPr 2025 COSMe COPr COBu 2026 COSMe COPr COPh 2027 COSMe COPr C0CH2Ph 2028 COSMe COPr CO-2-Py 2029 COSMe COPCOCOP COPCO COPCO CONPMe COPOS -iPr 2033 COSMe COPr CONHPh 2034 COSMe COPr CONH-2-Py 2035 COSMe COPr CONMe2 2036 COSMe COPr CONEt2 2037 COSMe COPr COOMe 2038 COSMe COPr COOEt 2039 COSMe COPr COOPh 2040 COSMe COPr H

2041 COSMe COPr Me 2042 COSMe COPr CH2F 2043 COSMe COPh Ac 2044 COSMe COPh COCF3 2045 COSMe COPh COCH2C1 2046 COSMe COPh C0CH2F 2047 COSMe COPh CO-2-Py 2048 COSMe COPh COEt 2049 COSMe COPh COPh COPh COPm 2051 COSMe COPh CONHMe 2052 COSMe COPh C0NMe2 2053 COSMe COPh C0 Et2 2054 COSMe COPh COOMe 2055 COSMe COPh COOEt 2056 COSMe COPh COOPh 2057 COSMe COPh H

2058 COSMe COPh Me 2059 COSMe COPh CH2F 2060 COSMe CONHMe Ac 2061 COSMe CONHMe C0CF3 2062 COSMe CONHMe C0CH2C1 2063 COSMe CONHMe C0CH2F 2064 COSMe CONHMe COEt 2065 COSMe CONHMe CO-COSMECH COH MeCOPH 2066 COSMeCOSH -2-Py 2070 COSMe CONHMe CONHMe 2071 COSMe CONHMe CONHEt 2072 COSMe CONHMe COPr 2073 COSMe CONHMe CONH-iPr 2074 COSMe CONHMe CONHPh 2075 COSMe CONHMe CONH-2-Py 2076 COSMe CONHMe C0N e2 2077 COSMe CONHMe COSMe CONHMe COSMe CONHMe COOEt 2080 COSMe CONHMe COOPh 2081 COSMe CONHMe H 2082 COSMe CONHMe Me 2083 COSMe C0 Me2 CH2F 2084 COSMe C0NMe2 Ac 2085 COSMe C0NMe2 C0CF3 2086 COSMe C0NMe2 C0CH2C1 2087 COSMe C0N2 C0Me2 C0N2 C0Me2 C0N2 -iPr 2091 COSMe C0NMe2 COPh 2092 COSMe C0NMe2 CONHMe 2093 COSMe C0NMe2 CONHEt 2094 COSMe C0NMe2 CONH-Pr 2095 COSMe C0NMe2 CO HPh 2096 COSMe C0NMe2 C0NMe2 2097 COSMe C0NMe2 C0NEt2 2098 COSMe C0NMe2 COOMe 2099 COSMe C0NMe2 COOEt 2100 COSMe C0NMe2 COOPh 2101 COSMe C0NMe2 H 2102 COSMe C0N e2 Me 2103 COSMe C0NMe2 CH2F 2104 COSMe CONHEt Ac 2105 COSMe CONHEt C0CF3 2106 COSMe CONHEt C0CH2C1 2107 COSMe CONHEt C0CH2F 2108 COSMe CONHEt COEt 2109 COSMe CONHEt CO-iPr

2110 COSMe CONHEt COBu

2111 COSMe CONHEt COPh

2112 COSMe CONHEt C0CH2Ph

2113 COSMe CONHEt CO-2-Py

2114 COSMe CONHEt CONHMe

2115 COSMe CONHEt CONHEt

2116 COSMe CONHEt COPr

2117 COSMe CONHEt CONH-iPr

2118 COSMe CONHEt CONHPh

2119 COSMe CONHEt CONH-2-Py

2120 COSMe CONHEt C0NMe2

2121 COSMe CONHEt C0NEt2

2122 COSMe CONHEt COOMe

2123 COSMe CONHEt COOEt

2124 COSMe CONHEt COOPh

2125 COSMe CONHEt H

2126 COSMe CONHEt Me

2127 COSMe C0NEt2 CH2F

2128 COSMe C0NEt2 Ac

2129 COSMe C0NEt2 C0CF3

2130 COSMe C0NEt2 C0CH2C1

2131 COSMe C0NEt2 C0CH2F

2132 COSMe C0NEt2 CO-2-Py

2133 COSMe C0NEt2 COEt

2134 COSMe C0NEt2 CO-iPr

2135 COSMe C0NEt2 COPh

2136 COSMe C0NEt2 CONHMe

2137 COSMe C0NEt2 CONHEt 2138 COS e C0NEt2 CONH-Pr

2139 COSMe C0NEt2 CONHPh

2140 COSMe C0NEt2 C0NMe2

2141 COSMe C0NEt2 C0NEt2

2142 COSMe C0NEt2 COOMe

2143 COSMe C0NEt2 COOEt

2144 COSMe C0NEt2 COOPh

2145 COSMe C0NEt2 H

2146 COSMe C0NEt2 Me

2147 COSMe C0NEt2 CH2F

2148 COSMe COOMe Ac

2149 COSMe COOMe COCF3

2150 COSMe COOMe C0CH2C1

2151 COSMe COOMe C0CH2F

2152 COSMe COOMe COEt

2153 COSMe COOMe CO-iPr

2154 COSMe COOMe COBu

2155 COSMe COOMe COPh

2156 COSMe COOMe C0CH2Ph

2157 COSMe COOMe CO-2-Py

2158 COSMe COOMe CONHMe

2159 COSMe COOMe CONHEt

2160 COSMe COOMe COPr

2161 COSMe COOMe CONH-iPr

2162 COSMe COOMe CONHPh

2163 COSMe COOMe CONH-2-Py

2164 COSMe COOMe CO Me2

2165 COSMe COOMe CONEt2

2166 COSMe COOMe COOMe

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2250 COSPh H CONHPh

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2253 COSPh H CONEt2 2254 COSPh H COOMe 2255 COSPh H COOEt 2256 COSPh H COOPh 2257 COSPh HH 2258 COSPh H Me 2259 COSPh H CH2F 2260 COSPh Me Ac 2261 COSPh Me C0CF3 2262 COSPh Me COCH2C1 2263 COSPh Me COCH2F 2264 MeSPy Me-2-h COEt 2266 COSPh Me CO-iPr 2267 COSPh Me COPh 2268 COSPh Me CONHMe 2269 COSPh Me CONHEt 2270 COSPh Me CONH-iPr 2271 COSPh Me CONHPh 2272 COSPh Me C0NMe2 2273 COSPh Me C0NEt2 2274 COSPh Me COOMe 2275 COSPe COSPh Me H 2278 COSPh Me Me 2279 COSPh Me CH2F 2280 COOPh H Ac 2281 COOPh H COCF3 2282 COOPh H COCH2C1 MdOD MdOOD

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SrO / 66Jf / X3d 019/66 OM 2457 COSPh CONHMe COPh 2458 COSPh CONHMe C0CH2Ph 2459 COSPh CONHMe CO-2-Py 2460 COSPh CONHMe CONHMe 2461 COSPh CONHMe CONHEt 2462 COSPh CONHMe COPr 2463 COSPh CONHMe CONH-iPr 2464 COSPh CONHMe COPhCOH 2H 2468 COSPh CONHMe H 2469 COSPh CONHMe Me 2470 COSPh CONHMe CH2F 2471 COSPh C0NMe2 Ac 2472 COSPh C0NMe2 C0CF3 2473 COSPh C0NMe2 C0CH2C1 2474 COSPh C0NMe2 C0CH2F 2475 COSPh CO0y2CO2 C2N2 CO2 C2N2 CO2 C2N2CO2 2479 COSPh C0NMe2 CONHMe 2480 COSPh C0NMe2 CONHEt 2481 COSPh C0NMe2 CONH-iPr 2482 COSPh C0NMe2 CONHPh 2483 COSPh C0NMe2 C0 Me2 2484 COSPh C0NMe2 C0NEt2 2485 COSPh C0NMe2 COOM 2486 COSPh C0NMe2 COOEt 2487 COSPh C0NMe2 COOPh 2488 COSPh C0NMe2 H 2489 COSPh C0NMe2 Me 2490 COSPh C0NMe2 CH2F 2491 COSPh COOMe Ac 2492 COSPh COOMe C0CF3 2493 COSPh COOMe C0CH2COM CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2 2498 COSPh COOMe COPh 2499 COSPh COOMe C0CH2Ph 2500 COSPh COOMe CO-2-Py 2501 COSPh COOMe CONHMe 2502 COSPh COOMe CONHEt 2503 COSPh COOMe COPr 2504 COSPh COOMe C0NMe2 2505 COSPh COOMe C0NEt2 2506 COSPh COOMe COOMe 2507 COSPh COOMe COOEt 2508 COSPh COOMe COOPh 2509 COSPh COOMe H 2510 COSPh COOMe Me 2511 COSPh COOMe CH2F 2512 COSPh COOPh Ac 2513 COSPh COOPh C0CF3 2514 COSPh COOPh C0CH2C1 2515 COSPh COOPh C0CH2F

2516 COSPh COOPh CO-2-Py

2517 COSPh COOPh COEt

2518 COSPh COOPh CO-iPr

2519 COSPh COOPh COPh

2520 COSPh COOPh CONHMe

2521 COSPh COOPh CO HEt

2522 COSPh COOPh CONH-iPr

2523 COSPh COOPh CO HPh

2524 COSPh COOPh CONMe2

2525 COSPh COOPh CONEt2

2526 COSPh COOPh COOMe

2527 COSPh COOPh COOEt

2528 COSPh COOPh COOPh

2529 COSPh COOPh H

2530 COSPh COOPh Me

2531 COSPh COOPh CH2F

2532 COS-tBu COO e Ac

2533 COS-tBu COOMe COCF3

2534 COS-tBu COOMe C0CH2C1

2535 COS-tBu COOMe COCH2F

2536 COS-tBu COOMe COEt

2537 COS-tBu COOMe CO-iPr

2538 COS-tBu COOMe COBu

2539 COS-tBu COOMe COPh

2540 COS-tBu COOMe C0CH2Ph

2541 COS-tBu COOMe CO-2-Py

2542 COS-tBu COOMe CONHMe

2543 COS-tBu COOMe CONHEt 2544 COS-tBu COOMe COPr 2545 COS-tBu COO e C0NMe2 2546 COS-tBu COOMe C0NEt2 2547 COS-tBu COOMe COOMe 2548 COS-tBu COOMe COOEt 2549 COS-tBu COOMe COOPh 2550 COS-tBu COOMe H 2551 COS COS-tBu COOMe CH2F 2553 COS-tBu COOPh Ac 2554 COS-tBu COOPh C0CF3 2555 COS-tBu COOPh C0CH2C1 2556 COS-tBu COOPh C0CH2F 2557 COS-tBu COOPh CO-2-Py 2558 COS-tBu COOPt COEt 2559 CO-iPr 2560 COS-tBu COOPh COPh 2561 COS-tBu COOPh CONH e 2562 COS-tBu COOPh CO concealed t 2563 COS-tBu COOPh CONH-iPr 2564 COS-tBu COOPh CONHPh 2565 COS-tBu COOPh C0NMe2 2566 COS0-tBu COOP 2567 COS-tBu COOPh COOMe 2568 COS-tBu COOPh COOEt 2569 COS-tBu COOPh COOPh 2570 COS-tBu COOPh H 2571 COS-tBu COOPh Me 2572 COS-tBu COOPh CH2F 2573 COO-tBu CONHMe Ac 2574 COO-tBu COS e C0CF3 2575 COO-tBu CONHMe C0CH2C1 2576 COO-tBu CONHMe C0CH2F 2577 COO-tBu CONHMe COEt 2578 COO-tBu CONHMe CO-iPr 2579 COO-tBu COHMe COBu 2580 CONHMe COPh 2581 COO-tBu CONHMe C0CH2Ph 2582 COO-tBu CONHMe CO-2-Py 2583 COO-tBu CONHMe CONHMe 2584 COO-tBu CONHMe CONHEt 2585 COO-tBu CONHMe COPr 2586 COO-tBu CONHMe C0 Me2 2587 COO-tBu CONHMe COO-tBu CONHMe COOMe 2589 COO-tBu CONHMe COOEt 2590 COO-tBu CONHMe COOPh 2591 COO-tBu CONHMe H 2592 COO-tBu CO HMe Me 2593 COO-tBu CONHMe CH2F 2594 COO-tBu C0NMe2 Ac 2595 COO-tBuC3N2CO2 -tBu C0NMe2 C0CH2C1 2597 COO-tBu C0NMe2 C0CH2F 2598 COO-tBu C0NMe2 CO-2-Py 2599 COO-tBu C0NMe2 COEt 2600 COO-tBu C0NMe2 CO-iPr 2601 COO-tBu C0NMe2 COPh 2602 COO-tBu C0NMe2 CONHMe

2603 COO-tBu C0NMe2 CONHEt

2604 COO-tBu C0NMe2 CONH-iPr

2605 COO-tBu C0NMe2 CONHPh

2606 COO-tBu C0 Me2 C0 Me2

2607 COO-tBu C0NMe2 C0NEt2

2608 COO-tBu C0NMe2 COOMe

2609 COO-tBu C0NMe2 COOEt

2610 COO-tBu C0 Me2 COOPh

2611 COO-tBu C0NMe2 H

2612 COO-tBu C0NMe2 Me

2613 COO-tBu C0 Me2 CH2F

2614 COO-tBu C0CF3 Ac

2615 COO-tBu C0CF3 COCF3

2616 COO-tBu C0CF3 COCH2C1

2617 COO-tBu C0CF3 COCH2F

2618 COO-tBu C0CF3 COEt

2619 COO-tBu C0CF3 CO-iPr

2620 COO-tBu C0CF3 COBu

2621 COO-tBu C0CF3 COPh

2622 COO-tBu C0CF3 C0CH2Ph

2623 COO-tBu C0CF3 CO-2-Py

2624 COO-tBu C0CF3 CONHMe

2625 COO-tBu C0CF3 CONHEt

2626 COO-tBu C0CF3 COPr

2627 COO-tBu C0CF3 C0NMe2

2628 COO-tBu C0CF3 C0NEt2

2629 COO-tBu C0CF3 COOMe

2630 COO ~ tBu C0CF3 COOEt 2631 COO-tBu COCF3 COOPh 2632 COO-tBu COCF3 H 2633 COO-tBu COCF3 Me 2634 COO-tBu COCF3 CH2F 2635 COO-tBu COCH20 e Ac 2636 COO-tBu C0CH20Me COCF3 2637 COO-tBu COCH20Me COCH2C1 2638 COOt026 COO-tBu C0CH20Me COEt 2640 COO-tBu COCH20Me CO-iPr 2641 COO-tBu COCH20Me COPh 2642 COO-tBu C0CH20 e CO HMe 2643 COO-tBu C0CH20Me CONHEt 2644 COO-tBu COCH20 e CONH-iPr 2645 COO-OhCOH -tBu COCH20Me CONMe2 2647 COO-tBu COCH20Me CONEt2 2648 COO-tBu COCH20Me COOMe 2649 COO-tBu COCH20Me COOEt 2650 COO-tBu COCH20Me COOPh 2651 COO-tBu C0CH20Me H 2652 COO-tBu COCH20-MeCO 26TCOOt-CO2 CO-iPr Ac 2655 COO-tBu CO-iPr COCF3 2656 COO-tBu CO-iPr C0CH2C1 2657 COO-tBu CO-iPr C0CH2F 2658 COO-tBu CO-iPr COEt 2659 COO ~ tBu CO-iPr CO-iPr 2660 COO-tBu CO-iPr COBu 2661 COO-tBu CO-iPr COPh 2662 COO-tBu CO-iPr C0CH2Ph 2663 COO-tBu CO-iPr CO-2-Py 2664 COO-tBu CO-iPr CONH e 2665 COO-tBu CO -iPr CO thigh 2666 COO-tBu CO-iPr COPr 2667 COO-tBu CO-iPr C0NMe2 2668 COO-tBu CO-iPr C0NEt2 2669 COO-tBu CO-iPr COOMe 2670 COO-tBu CO-iPr COOEt 2671 COO-tBu CO -iPr COOPh 2672 COO-tBu CO-iPr H 2673 COO-tBu CO-iPr Me 2674 COO-tBu CO-iPr CH2F 2675 COO-tBu COPh Ac 2676 COO-tBu COPh C0CF3 2677 COO-tBu COPh C0CH2C1 2678 COO-tBu C0CH2F 2679 COO-tBu COPh COEt 2680 COO-tBu COPh CO-iPr 2681 COO-tBu COPh COPh 2682 COO-tBu COPh CONHMe 2683 COO-tBu COPh CO Foreign t 2684 COO-tBu COPh CONH-iPr 2685 COO-tBu COP 2686 COO-tBu COPh C0NMe2 2687 COO-tBu COPh C0NEt2 2688 COO-tBu COPh COOMe 2689 COO-tBu COPh COOEt

2690 COO-tBu COPh COOPh

2691 COO-tBu COPh H

2692 COO-tBu COPh Me

2693 COO-tBu COPh CH2F

2694 COS-tBu COEt Ac

2695 COS-tBu COEt C0CF3

2696 COS-tBu COEt C0CH2C1

2697 COS-tBu COEt C0CH2F

2698 COS-tBu COEt COEt

2699 COS-tBu COEt CO-iPr

2700 COS-tBu COEt COBu

2701 COS-tBu COEt COPh

2702 COS-tBu COEt C0CH2Ph

2703 COS-tBu COEt CO-2-Py

2704 COS-tBu COEt CO Marauder e

2705 COS-tBu COEt CONHEt

2706 COS-tBu COEt COPr

2707 COS-tBu COEt C0N e2

2708 COS-tBu COEt C0NEt2

2709 COS-tBu COEt COOMe

2710 COS-tBu COEt COOEt

2711 COS-tBu COEt COOPh

2712 COS-tBu COEt H

2713 COS-tBu COEt Me

2714 COS-tBu COEt CH2F

2715 COS-tBu COEt Ac

2716 COS-tBu C0CH2C1 C0CF3

2717 COS-tBu C0CH2C1 C0CH2C1 2718 COS-tBu C0CH2C1 C0CH2F 2719 COS-tBu C0CH2C1 COEt 2720 COS-tBu C0CH2C1 CO-iPr 2721 COS-tBu C0CH2C1 COPh 2722 COS-tBu C0CH2C1 CONHMe 2723 COS-tBu C0C2C1C2C1C2C1C2T1 C0CH2C1 CONHPh 2726 COS-tBu C0CH2C1 CONMe2 2727 COS-tBu C0CH2C1 C0NEt2 2728 COS-tBu C0CH2C1 COOMe 2729 COS-tBu C0CH2C1 COOEt 2730 COS-tBu C0CH2C1 COOPh 2731 COSC2C1C2C2C2C1 2734 COO-tBu Ac Ac 2735 COO-tBu Ac COCF3 2736 COO-tBu Ac C0CH2C1 2737 COO-tBu Ac C0CH2F 2738 COO-tBu Ac COEt 2739 COO-tBu Ac CO-iPr 2740 COO-tBu Ac COBu 2741 COO-tBu Ac COPh 2742 COO-tBu Ac C0CH2Ph 2743 COO-tBu Ac CO-2-Py 2744 COO-tBu Ac CONHMe 2745 COO-tBu Ac CONHEt 2746 COO-tBu Ac COPr 2747 COO-tBu Ac CONMe2 2748 COO-tBu Ac CO Et2 2749 COO-tBu Ac COOMe 2750 COO-tBu Ac COOEt 2751 COO-tBu Ac COOPh 2752 COO-tBu Ac H 2753 COO-tBu Ac Me 2754 COO-tBu Ac CH2F 2755 COO-tBu COCH2F Ac 2756 COO-tBu C0CH2F COCF3 2757 COO-tBu C0CH2F C0CH2C1 2758 COO-tBu COCH2F COCH2F 2759 COO-tBu C0CH2F COEt 2760 COO-tBu C0CH2F CO-iPr 2760 COOFt CO2F e 2763 COO-tBu COCH2F CONHEt 2764 COO-tBu COCH2F CONH-iPr 2765 COO-tBu C0CH2F CONHPh 2766 COO-tBu COCH2F CO Me2 2767 COO-tBu C0CH2F C0NEt2 2768 COO-tBu C0CH2F COOMe 2769 COOe 2769 COOe 2769 COOe 2769 C0CH2F COOPh 2771 COO-tBu C0CH2F H 2772 COO-tBu COCH2F Me 2773 COO-tBu C0CH2F CH2F 2774 COO-tBu H Ac 2775 COO-tBu H COCF3 2776 COO-tBu H COCH2C1

2777 COO-tBu H COCH2F

2778 COO-tBu H COEt

2779 COO-tBu H CO-iPr

2780 COO-tBu H COBu

2781 COO-tBu H COPh

2782 COO-tBu H C0CH2Ph

2783 COO-tBu H CO-2-Py

2784 COO-tBu H CO marauder e

2785 COO-tBu H CONHEt

2786 COO-tBu H COPr

2787 COO-tBu H CONMe2

2788 COO-tBu H CONEt2

2789 COO-tBu H COO e

2790 COO-tBu H COOEt

2791 COO-tBu H COOPh

2792 COO-tBu H H

2793 COO-tBu H Me

2794 COO-tBu H CH2F

2795 COO-tBu Me Ac

2796 COO-tBu Me C0CF3

2797 COO-tBu Me COCH2C1

2798 COO-tBu Me COCH2F

2799 COO-tBu Me COEt

2800 COO-tBu Me CO-iPr

2801 COO-tBu Me COPh

2802 COO-tBu Me COface e

2803 COO-tBu Me CONHEt

2804 COO-tBu Me CONH-iPr W

105

2805 COO-tBu Me CONHPh

2806 COO-tBu Me CONMe2

2807 COO-tBu Me C0NEt2

2808 COO-tBu Me COOMe

2809 COO-tBu Me COOEt

2810 COO-tBu Me COOPh

2811 COO-tBu Me H

2812 COO-tBu Me Me

2813 COO-tBu Me CH2F

2814 COS-tBu H Ac

2815 COS-tBu H COCF3

2816 COS-tBu H C0CH2C1

2817 COS-tBu H C0CH2F

2818 COS-tBu H COEt

2819 COS-tBu H CO-iPr

2820 COS-tBu H COBu

2821 COS-tBu H COPh

2822 COS-tBu H C0CH2Ph

2823 COS-tBu H CO-2-Py

2824 COS-tBu H CONHMe

2825 COS-tBu H CONHEt

2826 COS-tBu H COPr

2827 COS-tBu H C0NMe2

2828 COS-tBu H CONEt2

2829 COS-tBu H COOMe

2830 COS-tBu H COOEt

2831 COS-tBu H COOPh

2832 COS-tBu H H

2833 COS-tBu H Me 2834 COS-tBu H CH2F

2835 COS-tBu Me Ac

2836 COS-tBu Me COCF3

2837 COS-tBu Me C0CH2C1

2838 COS-tBu Me COCH2F

2839 COS-tBu Me COEt

2840 COS-tBu Me CO-iPr

2841 COS-tBu Me COPh

2842 COS-tBu Me CO Marauder e

2843 COS-tBu Me CONHEt

2844 COS-tBu Me CONH-iPr

2845 COS-tBu Me CONHPh

2846 COS-tBu Me CONMe2

2847 COS-tBu Me CONEt2

2848 COS-tBu Me COOMe

2849 COS-tBu Me COOEt

2850 COS-tBu Me COOPh

2851 COS-tBu Me H

2852 COS-tBu Me Me

2853 COS-tBu Me CH2F

2854 COS-tBu Ac Ac

2855 COS-tBu Ac C0CF3

2856 COS-tBu Ac COCH2C1

2857 COS-tBu Ac C0CH2F

2858 COS-tBu Ac COEt

2859 COS-tBu Ac CO-iPr

2860 COS-tBu Ac COBu

2861 COS-tBu Ac COPh

2862 COS-tBu Ac COCH2Ph 2863 COS-tBu Ac CO-2-Py

2864 COS-tBu Ac CONHMe

2865 COS-tBu Ac CONHEt

2866 COS-tBu Ac COPr

2867 COS-tBu Ac CONMe2

2868 COS-tBu Ac C0NEt2

2869 COS-tBu Ac COOMe

2870 COS-tBu Ac COOEt

2871 COS-tBu Ac COOPh

2872 COS-tBu Ac H

2873 COS-tBu Ac Me

2874 COS-tBu Ac CH2F

2875 COS-tBu COCH2F Ac

2876 COS-tBu COCH2F COCF3

2877 COS-tBu COCH2F COCH2C1

2878 COS-tBu COCH2F C0CH2F

2879 COS-tBu C0CH2F COEt

2880 COS-tBu COCH2F CO-iPr

2881 COS-tBu COCH2F COPh

2882 COS-tBu COCH2F CONHMe

2883 COS-tBu C0CH2F CONHEt

2884 COS-tBu C0CH2F CONH-iPr

2885 COS-tBu C0CH2F CONHPh

2886 COS-tBu C0CH2F CONMe2

2887 COS-tBu C0CH2F C0NEt2

2888 COS-tBu COCH2F COOMe

2889 COS-tBu C0CH2F COOEt

2890 COS-tBu COCH2F COOPh

2891 COS-tBu C0CH2F H 2892 COS-tBu C0CH2F Me 2893 COS-tBu C0CH2F CH2F 2894 COS-tBu COEt Ac 2895 COS-tBu COEt C0CF3 2896 COS-tBu COEt C0CH2C1 2897 COS-tBu COEt C0CH2F 2898 COS-tBu COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt COEt 2900 COS-tBu COEt COBu 2901 COS-tBu COEt COPh 2902 COS-tBu COEt C0CH2Ph 2903 COS-tBu COEt CO-2-Py 2904 COS-tBu COEt CO band e 2905 COS-tBu COEt CONHEt 2906 COS-tBu COEt COPr 2907 -tBu COEt C0NMe2 2908 COS-tBu COEt C0NEt2 2909 COS-tBu COEt COO e 2910 COS-tBu COEt COOEt 2911 COS-tBu COEt COOPh 2912 COS-tBu COEt H 2913 COS-tBu COEt Me 2914 COS-tBu COEt tBu C0CH2C1 Ac 2916 COS-tBu C0CH2C1 C0CF3 2917 COS-tBu C0CH2C1 C0CH2C1 2918 COS-tBu C0CH2C1 C0CH2F 2919 COS-tBu C0CH2C1 COEt 2920 COS-tBu C0CH2C1 CO-iPr 2921 COS-tBu C0CH2C1 COPh

2922 COS-tBu C0CH2C1 CONHMe

2923 COS-tBu C0CH2C1 CONHEt

2924 COS-tBu C0CH2C1 CONH-iPr

2925 COS-tBu C0CH2C1 CONHPh

2926 COS-tBu C0CH2C1 C0NMe2

2927 COS-tBu C0CH2C1 C0NEt2

2928 COS-tBu C0CH2C1 COO e

2929 COS-tBu C0CH2C1 COOEt

2930 COS-tBu C0CH2C1 COOPh

2931 COS-tBu C0CH2C1 H

2932 COS-tBu C0CH2C1 Me

2933 COS-tBu C0CH2C1 CH2F

2934 COS-tBu C0CF3 Ac

2935 COS-tBu C0CF3 COCF3

2936 COS-tBu C0CF3 C0CH2C1

2937 COS-tBu C0CF3 C0CH2F

2938 COS-tBu C0CF3 COEt

2939 COS-tBu C0CF3 CO-iPr

2940 COS-tBu C0CF3 COBu

2941 COS-tBu C0CF3 COPh

2942 COS-tBu C0CF3 C0CH2Ph

2943 COS-tBu C0CF3 CO-2-Py

2944 COS-tBu C0CF3 CONHMe

2945 COS-tBu C0CF3 CONHEt

2946 COS-tBu C0CF3 COPr

2947 COS-tBu C0CF3 CONMe2

2948 COS-tBu C0CF3 CONEt2

2949 COS-tBu C0CF3 COOMe 2950 COS-tBu C0CF3 COOEt 2951 COS-tBu C0CF3 COOPh 2952 COS-tBu C0CF3 H 2953 COS-tBu C0CF3 Me 2954 COS-tBu C0CF3 CH2F 2955 COS-tBu C0CH20Me Ac 2956 COS-tBu C0CH20 C0C2C2958COS COS-tBu C0CH20Me C0CH2F 2959 COS-tBu C0CH20Me COEt 2960 COS-tBu C0CH20 e CO-iPr 2961 COS-tBu COCH20 e COPh 2962 COS-tBu C0CH20Me CO med e 2963 COS-tBu C0CH20 e CONHEt 2964 COS-tCOS-tBus 2965 COS-tBu C0CH20Me CONHPh 2966 COS-tBu C0CH20Me C0 Me2 2967 COS-tBu C0CH20Me C0NEt2 2968 COS-tBu COCH20 e COOMe 2969 COS-tBu C0CH20Me COOEt 2970 COS-tBu C0CH20 e COOPh 2971 COS-tCOT 2971 COS-t C0CH20Me Me 2973 COS-tBu C0CH2 (Me CH2F 2974 COS-tBu COOMe Ac 2975 COS-tBu COO e C0CF3 2976 COS-tBu COOMe C0CH2C1 2977 COS-tBu COOMe C0CH2F 2978 COS-tBu COOMe COEt 2979 COS-tBu COOMe CO-iPr 2980 COS-tBu COOMe COBu 2981 COS-tBu COOMe COPh 2982 COS-tBu COOMe C0CH2Ph 2983 COS-tBu COOMe CO-2-Py 2984 COS-tBu COOMe CONH e 2985 COS-tBu COOMe CONHEt 29 COS-tBu COOMe COPr 2987 COS-tBu COOMe CONMe2 2988 COS-tBu COOMe C0NEt2 2989 COS-tBu COOMe COOMe 2990 COS-tBu COOMe COOEt 2991 COS-tBu COOMe COOPh 2992 COS-tBu COOMe H 2993 COS-tBu COOMe tBu COOMe CH2F 2995 COS-tBu COOPh Ac 2996 COS-tBu COOPh C0CF3 2997 COS-tBu COOPh C0CH2C1 2998 COS-tBu COOPh C0CH2F 2999 COS-tBu COOPh CO-2-Py 3000 COS-tBu COOPh COEt 3001 COS-t CO iPr 3002 COS-tBu COOPh COPh 3003 COS-tBu COOPh CONHMe 3004 COS-tBu COOPh CONHEt 3005 COS-tBu COOPh CONH-iPr 3006 COS-tBu COOPh CONHPh 3007 COS-tBu COOPh C0 Me2 3008 COS-tBu COOPh C0NEt2 3009 COS-tBu COOPh COOMe 3010 COS-tBu COOPh COOEt 3011 COS-tBu COOPh COOPh 3012 COS-tBu COOPh H 3013 COS-tBu COOPh Me 3014 COS-tBu COOPh CH2F 3015 COS-tBu CONS -tBu CO band e C0CF3 3017 COS-tBu CONHMe C0CH2C1 3018 COS-tBu CONHMe C0CH2F 3019 COS-tBu CONHMe COEt 3020 COS-tBu CONHMe CO-iPr 3021 COS-tBu CONHMe COBu 3022 COS-tBu CONHMe COPh 30P 3024 COS-tBu CONHMe CO-2-Py 3025 COS-tBu CONHMe CONHMe 3026 COS-tBu CONHMe CONHEt 3027 COS-tBu CONHMe COPr 3028 COS-tBu CONHMe C0 Me2 3029 COS-tBu CONHMe C0NEt2 3030 COS-tBu CONHMe COOMe 3031 tBu CONHMe COOEt 3032 COS-tBu CONHMe COOPh 3033 COS-tBu CONHMe H 3034 COS-tBu CONHMe Me 3035 COS-tBu CONHMe CH2F 3036 COS-tBu C0NMe2 Ac 3037 COS-tBu CONMe2 COCF3 3038 COS-tBu CONMe2 C0CH2C1 3039 COS-tBu CONMe2 C0CH2F 3040 COS-tBu CONMe2 CO-2-Py 3041 COS-tBu CONMe2 COEt 3042 COS-tBu C0NMe2 CO-iPr 3043 COS-tBu CONMe -tBu CONMe2 CO image e 3045 COS-tBu CONMe2 CONHEt 3046 COS-tBu CONMe2 CONH-iPr 3047 COS-tBu CON e2 CONHPh 3048 COS-tBu C0NMe2 CONMe2 3049 COS-tBu CONMe2 CONEt2 3050 COS-tBu CONMe2 COOMe 3051 COS COOEt 3052 COS-tBu CONMe2 COOPh 3053 COS-tBu CO Me2 H 3054 COS-tBu C0NMe2 Me 3055 COS-tBu CONMe2 CH2F 3056 COS-tBu CO-iPr Ac 3057 COS-tBu CO-iPr C0CF3 3058 COS-tBu CO-iPr C0CH 3059 COS-tBu CO-iPr COCH2F 3060 COS-tBu CO-iPr COEt 3061 COS-tBu CO-iPr CO-iPr 3062 COS-tBu CO-iPr COBu 3063 COS- tBu CO-iPr COPh 3064 COS-tBu CO-iPr C0CH2Ph 3065 COS-tBu CO-iPr CO-2-Py 3066 COS-tBu CO-iPr CONHMe 3067 COS-tBu CO-iPr CONHEt 3068 COS-tBu CO-iPr COPr 3069 COS-tBu CO-iPr C0N e2 3070 COS-tBu CO-iPr C0NEt2 3071 COS-tBu CO-iPr COOMe 3072 COS-tBu CO-iPr COOEt 3073 COS-tBu CO-iPr COOPh 3074 COS-tBu CO-iPr H 3075 COS-tBu CO-iPr Me 3076 COS-tBu CO-iPr CH2F 3077 COS-tBu COPh Ac 3078 COS-tBu COPh C0CF3 3079 COS-tBu COPh C0CH2C1 3080 COS-tBu COPh C0CH2F 3081 COS-tBu COPh COEt 3082 COS-tBu COPh CO-iPr 3083 COS-tBu COPh COPh 3084 COS-tBu COPh CONHMe3085 COS-tBuCOS CONH-iPr 3087 COS-tBu COPh CONHPh 3088 COS-tBu COPh C0NMe2 3089 COS-tBu COPh C0NEt2 3090 COS-tBu COPh COOMe 3091 COS-tBu COPh COOEt 3092 COS-tBu COPh COOPh 3093 HOS-tBu COP Py: pyridyl group

Ac: acetyl group

Ph: phenyl group

-Metal complexes of compounds of general formula (I):

[Where M is Zn, Cu, Co, Ni or Fe]

Compound number M

3095 Z n

3096 C u

3097 C o

3098 N i

3099 F e

The compound represented by the general formula (I), its salt or metal complex has an excellent susceptibility-recovery activity against drug-resistant pathogenic microbial strains and high safety as shown in Examples described later. Useful as a sensitizer.

The antibacterial agent used in combination with the sensitizing agent of the present invention is not particularly limited, but preferred examples thereof include aztreonam (AZT), ceftazidime (CAZ), cefpirome (CPR), cefsulodin (CFS), and ratamoxef ( Β-lactam agents such as LM0X), new quinolones such as norfloxacin (NFLX) and ofloxacin (0FLX), tetracycline (TC), and chloramphenicol (CP).

Example

Hereinafter, the present invention will be described in more detail with reference to Production Examples, Reference Examples and Examples. The present invention is not limited by these.

Production Example 1

WO 96/04262 (PCT / JP95 / 01552) and WVO 97/29096

(PCT / JP97 / 00266) by the method disclosed in Pseudomonas sp.

(Pseudomonas sp.) No. 57-250, 54 mg of mica coccidin (compound 3095) obtained as a culture product was dissolved in 7 ml of methanol, a diazomethane ether solution was added, and the mixture was reacted at room temperature for 1 hour. After the reaction, the mixture was concentrated under reduced pressure and dried to dryness, and the compound 22 (5. Omg) in Table 1 was isolated and purified by preparative TLC and preparative HPLC.

In addition, Pseudomonas sp. No. 57-250 strain was deposited under the accession number FERM P-14235 with the Institute of Biotechnology and Industrial Technology, the Ministry of International Trade and Industry at 1-3 1-3 Higashi, Tsukuba, Ibaraki Prefecture. Date: March 17, 1994), was transferred to an international deposit based on the Budapest Treaty on June 22, 1995 (Accession No. FE RM BP-5143).

Compound 22:

Molecular _{_{_{formula: C 28 H 41 N 3 0}}} 4 S 3

FAB MS m / z = 580 [M + H] +

¹ H_NMR (CDC 13: 0.90 ppm (3H, t, J = 7.1 Hz), 1.28 ppm (3H, s), 1.30 ppm (3H, s), 1.32-1.39 ppm (4H, m), 1.53 ppm (3H, s), 1.59-1.67ppm (2H, m), 2.64ppm (3H, s), 2.92-3.02ppm (4H, m), 3.13ppra (1H, m), 3.21ppm (1H, d, J = 11.7Hz) ), 3.22ppm (1H, dd, J = ll.2Hz, 8.8Hz), 3.37ppm (1H, d, J = 7.8Hz), 3.40ppm (1H, dd, J = l 1.2Hz, 8.8Hz), 3.62 ppm (1H, d, J = 11.7Hz), 4.15ppm (1H, d, J = 8, 1Hz), 4.75ppm (lH'dt, J = 8.1Hz, 8.8Hz), 6.70ppm (1H, dd, J = 7.6Hz, 1.2Hz), 6.84ppm (1H, dd, J = 8.3Hz, 1.2Hz), 7.20ppra (1H, dd, J = 8. (3Hz, 7.6Hz).

^{1 3 C - NMR (CDC 1} 3): 14. 06ppra, 22. 48ppra, 22. 51ppra, 23. 66ppm, 26. 04ppm, 31. 92ppm, 32. 34ppm, 34. 67ppm, 34. 86ppm, 35. 55ppm , 40.62ppm, 45.50ppm, 46.61ppm, 61.96ppm, 74.59ppm, 78.55ppm, 78.92ppm, 83.71ppm,

90.43ppm, 115.49ppm, 116.02ppm, 121.34ppm, 132.15ppm, 143.85ppm,

160.38ppm, 171.68ppm, 174.67ppm, 181.71ppm.

Reference example 1

Single dose safety

Compound (I) of the Zn complex (Compound No.: ³ 0 ⁹ 5) to dissolve the 1% aqueous methyl cellulose solution, the highest dose administered orally as 300 mg / Kg in 6-week-old CD-I mice, single The administration safety was examined. The observation was performed for 14 days after the administration. No deaths were observed even at the highest dose, and the compound is highly safe! /,it is conceivable that.

Example 1

Pseudomonas aeruginosa OprM overproducing resistant strains restore drug sensitivity

The experimentally produced mutants (nalB3 strain) which were made drug-insensitive by overproduction of OprM showed various antibacterial activities in the presence and absence of the sensitizing agent of the present invention (compounds shown in Table 1). The minimum inhibitory concentration (MIC) of the agent was determined. That is, the test bacteria were cultured in Mueller Hinton Broth (MHB) at 37 ° C. for 24 hours, and the number of bacteria was adjusted to 5 × 10 ⁴ cells / ml. The MICs of various antibacterial agents were measured by a liquid microdilution method using MHB (final concentrations of Caion 25 mg / L and Mgion 12.5 mg / L were separately added to MHB). The sensitizing agent of the present invention was dissolved in dimethyl sulfoxide at a concentration of 25 μg / ml and added to the medium. Each antibacterial agent was serially diluted 2-fold, and the MIC was determined as the final concentration at which the growth of the bacteria was completely eliminated. Aztreonam (AZT), norfloxacin (NFLX), and ofloxacin (0FLX) were used as antibacterial agents. Table 2 shows the results of the preferred compounds among the obtained results. As is clear from the table, all the compounds of the present invention restored the drug sensitivity of OprM overproduction-resistant Pseudomonas aeruginosa. These compounds of the present invention, was not the yarn at all antimicrobial activity at a concentration of 1 0 0 / i _g / mL, such as in na 1 B strains and later of OFR 5 0 4 strains. The compound numbers in Table 2 correspond to the compound numbers in Table 1. You.

Table 2

MIC (ug / ml)

Compound number AZT 0FLX NFLX

1 6.25 3.13 0.78

21 6.25 1.56 0.78

22 3.13 1.56 0.39

24 6.25 3.13 0.78

69 6.25 3.13 0.78

317 6.25 3.13 1.56

645 0 0.> 3 1.00

1287 6.25 NT 1.56

1730 12.5 3.13 3.13

3094 6.25 1.56 0.78

3095 12.5 3.13 1.56

3096 12.5 3.13 1.56

3097 12.5 3.13 1.56

In the absence of presence 25-12.5 6.25 3.13-1.56

Example 2

The same experiment as in Example 1 was carried out by further increasing the kinds of antibacterial agents for Compound No. 22. Antibacterial agents include Aztreonam (AZT), norfloxacin

In addition to (NFLX) and ofloxacin (0FLX), ceftazidime (CAZ), cefpirom (CPR), ratamoxef (LM0X), tetracycline (TC), and chloramphenicol (CP) were used. Table 3 shows the results. As is clear from the table, Compound No.:22 restored the drug sensitivity of Pseudomonas aeruginosa to any drug. This result indicates that the compound of the present invention has a susceptibility-recovery effect on a drug involved in the reduction of sensitivity due to OprM overproduction.

Table 3

No agent added in the presence of 25 " _g / ml Ceftazidime (CAZ) 3.13 0.78

Cefpirome (CPR) 3.13 0.78

Latamoxef (LM0X) 50 6.25

Aztreonam (AZT) 12.5 3.13

Norfloxacin (NFLX) 1.56 0.78-0.39

Ofloxacin (0FLX) 6.25-3.13 1.56

Tetracycline (TC) 50 25

Chloramphenicol (CP) 200 100

Example 3

The activity of Compound No. 22 (in the presence of 25 μg _/ mL) against various Pseudomonas aeruginosa strains was tested as described in Example 1. The strains used were Pseudomonas aeruginosa marker 'P AO1 strain, which is widely used for genetic experiments, and OFR504 strain, a mutant strain of Pseudomonas aeruginosa laboratory (Three kinds of Pseudomonas aeruginosa drug efflux pumps (Opr M, Op r J And OprN), which express Op r J, which show CPR, OFLX, NFLX and CP resistance) and SLR-09 strain (/ 3-lactamase) , CPR and LMOX resistance). Table 4 shows the properties of the test strains.

Table 4

NALB3 0FR504 SLR09 PA01

Opr ++-+

OprJ-++

—Lactamaze + + +++ +

1: No activity Soil: Detectable Ten to +++: Shows the intensity of activity

Table 5 shows the results.

Table 5

NALB3 SLR09 0FR504 PA01

Compound No. 22 (25ug / mL. Added: 10, no added—)

+ One + one + — — + — —

CAZ 0.78 3.13 12.5 12.5 0.78 0.78 0.78 0.78 AZT 3.13 12.5 6.25 6.25 0.2 0.2 0.78 3.13 CPR 0.78 3.13 12.5 12.5 12.5 12.5 0.78 1.56

LMOX 6.25 50 100 100 NT NT NT NT

OFLX 1.56 6.25-3.13 0.2 0.39 12.5 12.5 0.78 0.78 FLX 0.78--0.39 1.56 0.39 0.39 12.5 12.5 0.39 0.78 TC 25 50 400 400 NT NT 25 50

CP 100 200 25 25 100 200 25 50 As shown in Table 5, in the na1B3 strain rendered resistant by OprM overproduction, the recovery of MIC was observed by adding Compound No. 22. That is, the compound had a drug sensitivity restoring action. O !, which is an Op r J-resistant strain! ¾ 504 shares? There was no effect of restoring CAZ, CPR and LMOX resistance of 1 ^, OF LX and NF LX resistance, and of the S LRO 9 strain, which is a highly resistant strain of] 3-lactamase. This indicates that this compound is considered to be selective for the drug efflux pump OprM inhibition, which is essentially different from the additive and synergistic action of antibiotics.

Claims

The scope of the claims

General formula (I)

[Wherein R ¹ is (1) COXR ⁴ (X is O or S, and R ⁴ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted aralkyl , Optionally substituted heteroaryl or optionally substituted heteroarylalkyl), (2) CONR ⁵ R ⁶ (R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, hydroxy, substituted Alkyl which may be substituted, alkoxyl which may be substituted, aryl which may be substituted, arylalkyl which may be substituted, heteroaryl which may be substituted or heteroaryl which may be substituted Represents reel alkyl, provided that when one of R ⁵ and R ⁶ is hydroxyl or optionally substituted alkoxyl, the other is a hydrogen atom, an optionally substituted alkyl, or a substituted Or an optionally substituted aralkyl.) Or (3) CO—R ⁷ —OR (R ⁷ is an α-amino acid residue; R is a hydrogen atom or alkyl);

R ² is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, COR ¹³ (R ¹³ is hydrogen Atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroalkyl), COOR ¹⁴ (R ¹⁴ is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted hetero. Aryl or an optionally substituted heteroarylalkyl), CONR ¹⁵ R ¹⁶ (R ¹⁵ and R ¹⁶ are the same or different and are a hydrogen atom, an optionally substituted alkyl, an optionally substituted An optionally substituted aralkyl, an optionally substituted heteroaryl or an optionally substituted heteroarylalkyl);

R ³ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroalkyl, COR ¹⁷ (R ¹⁷ is hydrogen An atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl or an optionally substituted heteroalkyl), COOR ¹⁸ (R ¹⁸ is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl or an optionally substituted (Terarylalkyl) or CONR ¹⁹ R ²⁰ (R ¹⁹ , R ² ° may be the same or different, and may be a hydrogen atom, an optionally substituted alkyl, or an optionally substituted Aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl).

Or a salt thereof or a metal complex thereof.

2. The compound according to claim 1, wherein R ¹ is COOR ⁴ , and R ⁴ is a hydrogen atom, an optionally substituted alkyl, or an optionally substituted benzyl, a salt thereof, or a metal thereof. A drug sensitivity recovery agent containing a complex.

3. R ¹ is CONR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a hydroxyloxy group, an anoreoxy group, an anole carbonyl group, a canoleboxy ano quinole group, an alkoxyl phenol group, or 2. The agent for restoring drug sensitivity comprising the compound according to claim 1, which is hydroxyalkyl, a salt thereof, or a metal complex thereof.

4. R ² is a hydrogen atom, including alkyl substituted compound according to any one of claims 1 to 3 is good benzyl or Arukanoiru be substituted, its salt or metal complex thereof, Drug sensitivity recovery agent.

5. R ³ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted 5. A drug sensitivity restoring agent comprising the compound according to any one of claims 1 to 4, which is benzyl or alkanol, a salt thereof, or a metal complex thereof.

6. The drug-sensitive remedy according to any one of claims 1 to 5, which is for Pseudomonas aeruginosa.

7. The drug sensitivity-restoring agent according to any one of claims 1 to 6, which reduces drug resistance due to overproduction of OpRM.