AU3471700A - Herbicidal oxadiazolidines - Google Patents

Herbicidal oxadiazolidines Download PDF

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Publication number
AU3471700A
AU3471700A AU34717/00A AU3471700A AU3471700A AU 3471700 A AU3471700 A AU 3471700A AU 34717/00 A AU34717/00 A AU 34717/00A AU 3471700 A AU3471700 A AU 3471700A AU 3471700 A AU3471700 A AU 3471700A
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phenyl
formula
compound
oil
alkyl
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AU776425B2 (en
Inventor
Gary David Annis
George Chih-Shu Chiang
David Raymond Forney
Kanu Maganbhai Patel
Morris Padgett Rorer
William Francis Smith Iii
Thomas Martin Stevenson
King-Mo Sun
Chi-Ping Tseng
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University of California
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EI Du Pont de Nemours and Co
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Assigned to REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE reassignment REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE Alteration of Name(s) of Applicant(s) under S113 Assignors: E.I. DU PONT DE NEMOURS AND COMPANY
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/38—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the group >N—CO—N< where at least one nitrogen atom is part of a heterocyclic ring; Thio analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
    • C07C271/66—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/653—Five-membered rings
    • C07F9/65306—Five-membered rings containing two nitrogen atoms
    • C07F9/65318—Five-membered rings containing two nitrogen atoms having the two nitrogen atoms in positions 1 and 3

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Wood Science & Technology (AREA)
  • Agronomy & Crop Science (AREA)
  • Biochemistry (AREA)
  • Plant Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

WO 00/43377 PCT/USOO/01283 TITLE HERBICIDAL OXADIAZOLIDINES BACKGROUND OF THE INVENTION This invention relates to certain oxadiazolidines, processes for their preparation, their 5 N-oxides, agriculturally suitable salts and compositions, and methods of their use for controlling undesirable vegetation. This invention also relates to mixtures of herbicides that have a synergistic effect on weeds or have a safening effect on crops while retaining or increasing weed control. The control of undesired vegetation is extremely important in achieving high crop 10 efficiency. Achievement of selective control of the growth of weeds especially in such useful crops as rice, soybean, sugar beet, corn (maize), potato, wheat, barley, tomato and plantation crops, among others, is very desirable. Unchecked weed growth in such useful crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of undesired vegetation in noncrop areas is also important. Many 15 products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different modes of action. Arch. Pharm. (1974), 307, 7-12 discloses the chemical structures of NN-disubstituted 4-aryloxazolidindiones. However, it does not disclose the compounds of the present invention. 20 SUMMARY OF THE INVENTION This invention is directed to compounds and processes to prepare compounds of Formula 1 including all geometric and stereoisomers, N-oxides, and agriculturally suitable salts thereof, agricultural compositions containing them and their use for controlling undesirable vegetation: 25 X2 X3
Q--(CR
6
R
7 ) q-N O R2 xl I wherein Q is H; or C 1
-C
12 alkyl, C 3
-C
10 cycloalkyl, C 6
-C
14 bicycloalkyl, C 3
-C
1 2 alkenyl,
C
3
-C
10 cycloalkenyl, C 6
-C
14 bicycloalkenyl or C 3
-C
12 alkynyl, each optionally 30 substituted with one or more R 2 1 ; or WO 00/43377 PCT/USOO/01283 2 Q is a 3- to 7-membered fully saturated or 5- to 7-membered partially saturated heterocyclic ring containing one or two X, provided that (a) when X is other than o or S(O)n, then only one X may be present and (b) when two X are present in the ring, they cannot be bonded directly to each other; or 5 Q is a 5- or 6-membered aromatic heterocyclic ring system containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that the heterocyclic ring system contains no more than one oxygen and no more than one sulfur, and each heterocyclic ring system is optionally substituted with one or more R 16 ; and when Q is a 5- or 6 10 membered aromatic heterocyclic ring system containing a nitrogen, then Q is bonded through any available carbon or nitrogen atom by replacement of a hydrogen on said carbon or nitrogen atom; or Q is phenyl optionally substituted with one or more substituents independently selected from the group consisting of R 16 , phenoxy and Z; or 15 Q is
(R
1 2 )t(I
(R'
2 )t or ;or Q is -C(R1 4
)(=NOR
15 ), -C(O)RI 9 , -C(O)OR1 9 , -C(O)SR1 9 , -C(S)R1 9 , -C(S)OR 19 , -C(S)SR1 9 , -C(O)NR 23
R
24 , -C(S)NR 23
R
24 , -OR1 9 , -NR 19
R
20 , -S(O),R' 9 or -S(O)nNR1 9
R
20 ; 20 each X is -0-, -S(O)n-, -N=, -NRIO- or -Si(RIl )2-; Y is, together with the carbons to which it is attached, a fully or partially saturated 5-, 6- or 7-membered carbocyclic ring optionally substituted with one or more
C
1
-C
4 alkyl groups; or Y is, together with the carbons to which it is attached, a fully or partially saturated 5-, 25 6- or 7-membered heterocyclic ring which contains one or two X and is optionally substituted with one or more R 12 , provided that when said heterocyclic ring contains two X, then one X is other than 0; Z is phenyl or a 5- or 6-membered aromatic heterocyclic ring system containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, 10 oxygen and sulfur, provided that the heterocyclic ring system contains no more than one oxygen and no more than one sulfur, and each phenyl and heterocyclic ring system is optionally substituted with one or more R16; WO 00/43377 PCT/USOO/01283 3
R
1 is C 1
-C
6 alkyl, C 1
-C
6 haloalkyl, C 3
-C
6 alkenyl, C 3
-C
6 haloalkenyl, C 3
-C
6 alkynyl,
C
3
-C
6 haloalkynyl, C 1
-C
6 alkoxy, C 2
-C
6 alkoxyalkyl or C 2
-C
6 haloalkoxyalkyl; or RI is C 3
-C
7 cycloalkyl or C 3
-C
7 cycloalkenyl, each optionally substituted with one or more R 5 ; or 5 RI is phenyl optionally substituted with one or more R 1 3 ; or
R
1 is a 5- or 6-membered aromatic heterocyclic ring system containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that the heterocyclic ring system contains no more than one oxygen and no more than one sulfur, and each heterocyclic ring system 10 is optionally substituted with one or more R16;
R
2 is CI-C 6 alkyl, C 1
-C
6 haloalkyl, C 3
-C
7 cycloalkyl, C 3
-C
6 alkenyl, C 3
-C
6 haloalkenyl,
C
3
-C
6 alkynyl, C 3
-C
6 haloalkynyl,
C
1
-C
6 alkoxy, C 2
-C
6 alkoxyalkyl, C 2
-C
6 haloalkoxyalkyl or NR 3
R
4 ; or
R
2 is 15 -(CR17R18 (R 8 )m; or RI and R 2 are taken together as -CH 2
CH
2 -, -CH 2
CH
2
CH
2 -, -CH 2
CH
2
CH
2
CH
2 -,
-CH
2
CH
2
CH
2
CH
2
CH
2 - or -CH 2
CH
2 0CH 2
CH
2 -;
R
3 is Ci-C 6 alkyl, CI-C 6 haloalkyl, C 3
-C
6 alkenyl, C 3
-C
6 haloalkenyl, C 3
-C
6 alkynyl,
C
3
-C
6 haloalkynyl; or 20 R 3 is C 3
-C
7 cycloalkyl or C 3
-C
7 cycloalkenyl, each optionally substituted with one or more R 5 ; or
R
3 is a saturated or partially saturated 5-, 6- or 7-membered heterocyclic ring containing 1 to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, and each heterocyclic ring is optionally 25 substituted with one or more R 5 ; or
R
3 is phenyl optionally substituted with one or more R 26 groups; or
R
1 and R 3 are taken together with the two nitrogen atoms to which they are attached to form a saturated or partially saturated 5-, 6- or 7-membered heterocyclic ring containing an optional third heteroatom selected from the group consisting of 30 oxygen, sulfur and nitrogen, and said heterocyclic ring is optionally substituted with one or more R 9 ; or
R
2 and R 13 , together with the two atoms to which they are attached and the atom between them, form a fully saturated 5-, 6- or 7-membered carbocyclic or heterocyclic ring containing one oxygen, one sulfur or one or two nitrogen WO 00/43377 PCTIUSOO/01283 4 atoms, said heterocyclic ring is optionally substituted with one or more R12, provided that when said heterocyclic ring contains two nitrogen atoms, they are other than bonded directly to each other;
R
4 is H or CI-C 4 alkyl; or 5 R 3 and R 4 are taken together with the nitrogen atom to which they are attached to form a saturated or partially saturated 5-, 6- or 7-membered heterocyclic ring containing an optional second heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and said heterocyclic ring is optionally substituted with 1-4 R 9 ; 10 each R 5 is independently halogen, CI-C 4 alkyl or CI-C 4 alkoxy; or when two R 5 are attached to the same carbon, then said two R 5 groups are taken together as (=0); each R 6 and R 7 are independently H or C 1
-C
4 alkyl;
R
8 is independently CI-C 4 alkyl, CI-C 4 haloalkyl or CI-C 4 alkoxy; each R 9 is independently CI-C 4 alkyl or CI-C 4 alkoxy; or when two R 9 are attached to 15 the same carbon, then said two R 9 groups are taken together as (=0); W is, together with the carbons to which it is attached, a fully or partially saturated 5-, 6- or 7-membered heterocyclic ring containing one or two X, provided that (a) when X is other than 0 or S(O)n, then only one X may be present; (b) when two X are present in the ring, they cannot be bonded directly to each other; and (c) 20 said heterocyclic ring is bonded to the group (CRI 7 R1 8 )q through other than X;
R
10 is H, Ci-C 4 alkyl, C 1
-C
4 haloalkyl, C 3
-C
4 alkenyl, C 3
-C
4 alkynyl, C 2
-C
4 alkoxycarbonyl or C 2
-C
4 alkylcarbonyl; or R 10 is phenyl optionally substituted with C 1
-C
3 alkyl, halogen, cyano, nitro or C 2
-C
4 alkoxycarbonyl; each R I I is CI-C 4 alkyl; 25 each R 12 is independently halogen, CI-C 4 alkyl, CI-C 4 haloalkyl, C 1
-C
4 alkoxy,
CI-C
4 haloalkoxy, CI-C 4 alkylthio, CI-C 4 haloalkylthio, Ci-C 4 alkylsufinyl,
CI-C
4 alkylsufonyl or C 2
-C
4 alkoxycarbonyl; each R 13 is independently halogen, CI-C 3 alkyl, CI-C 3 haloalkyl, CI-C 3 alkoxy, Ci-C 3 haloalkoxy, C 3
-C
6 alkenyloxy, C 3
-C
6 alkynyloxy, CI-C 4 alkylthio, C 1
-C
4 30 haloalkylthio, Ci-C 4 alkylsufinyl, CI-C 4 alkylsufonyl, cyano, amino, nitro or
C
2
-C
4 alkoxycarbonyl;
R
14 is H, Ci-C 6 alkyl, Ci-C 6 haloalkyl or C 2
-C
6 alkoxyalkyl; or
R
1 4 and R 6 , together with the carbon atoms to which they are bonded, form a 5- or 6 membered saturated carbocyclic ring optionally substituted with one or more 35 Ci-C 4 alkyl groups;
R
15 is H, Ci-C 6 alkyl, C 1
-C
6 haloalkyl, C 3
-C
4 alkenyl or C 3
-C
4 alkynyl; WO 00/43377 PCTIUSOO/01283 5 each R 16 is independently halogen, nitro, cyano, Ci-C 4 alkyl, C 1
-C
4 haloalkyl, C 3
-C
4 alkenyl, C 3
-C
4 alkynyl, OR 22 , NR 23
R
24 or S(O)nR19; each R 17 and R 18 are independently H or Ci-C 4 alkyl; each R 19 and R 20 are independently C 1
-C
12 alkyl, C 3
-C
8 cycloalkyl, C 3
-C
12 alkenyl, 5 C 3
-C
8 cycloalkenyl or C 3
-C
12 alkynyl, each optionally substituted with one or more R21; each R 2 1 is halogen, C 4
-C
8 trialkylsilylalkyl, CN, NO 2 , -OR 22 , -NR 23
R
24 , -S(O)nR 22 , -S(O)nNR 23
R
24 , -C(O)R 22 , -C(S)R 22 , -C(O)OR 22 , -C(S)OR 22 , -C(S)SR 22 ,
-C(O)NR
23
R
24 , -C(S)NR 23
R
24 , -CHR 25
COR
22 , -CHR 25
P(O)(OR
22
)
2 , 10
-CHR
25
P(S)(OR
22
)
2 , -CHR 25
C(O)NR
23
R
24 , -CHR 25
C(O)NH
2 ,
-CHR
25
CO
2
R
22 , phenyl optionally substituted with one or more R 26 groups or benzyl optionally substituted with one or more R 26 groups; each R 22 is CI-C 8 alkyl, C 3
-C
8 cycloalkyl, C 3
-C
8 alkenyl, C 3
-C
8 alkynyl, CI-C 8 haloalkyl, C 2
-C
8 alkoxyalkyl, C 2
-C
8 alkylthioalkyl, C 2
-C
8 alkylsulfinylalkyl, 15 C 2
-C
8 alkylsulfonylalkyl, C 4
-C
8 alkoxyalkoxyalkyl, C 4
-C
8 cycloalkylalkyl,
C
4
-C
8 alkenoxyalkyl, C 4
-C
8 alkynyloxyalkyl, C 6
-C
8 cycloalkoxyalkyl, C 4
-C
8 alkenyloxyalkyl,
C
4
-C
8 alkynyloxyalkyl,
C
3
-C
8 haloalkoxyalkyl,
C
4
-C
8 haloalkenoxyalkyl, C 4
-C
8 haloalkynyloxyalkyl, C 6
-C
8 cycloalkylthioalkyl,
C
4
-C
8 alkenylthioalkyl, C 4
-C
8 alkynylthioalkyl, CI-C 4 alkyl substituted with 20 phenoxy or benzyloxy, each ring optionally substituted with halogen, C I-C 3 alkyl or CI-C 3 haloalkyl, C 4
-C
8 trialkylsilylalkyl,
C
3
-C
8 cyanoalkyl, C 3
-C
8 halocycloalkyl,
C
3
-C
8 haloalkenyl, C 5
-C
8 alkoxyalkenyl,
C
5
-C
8 haloalkoxyalkenyl,
C
5
-C
8 alkylthioalkenyl,
C
3
-C
8 haloalkynyl, C 5
-C
8 alkoxyalkynyl, C 5
-C
8 haloalkoxyalkynyl, C 5
-C
8 alkylthioalkynyl, C 2
-C
8 alkyl 25 carbonyl, C 2
-C
8 alkoxy carbonyl, phenyl optionally substituted with halogen, CN, CI-C 2 haloalkyl and CI-C 2 haloalkoxy or benzyl optionally substituted with halogen, CI-C 3 alkyl and Ci-C 3 haloalkyl; each R 23 is H or CI-C 4 alkyl; each R 24 is C 1
-C
4 alkyl or phenyl optionally substituted with one or more R 26 groups; 30 R 23 and R 24 may be taken together as -(CH 2
)
5 -, -(CH 2
)
4 - or -CH 2
CH
2
OCH
2
CH
2 -, each ring optionally substituted with CI-C 3 alkyl, phenyl or benzyl; each R 25 is H or CI-C 4 alkyl; each R 26 is C 1
-C
3 alkyl, Ci-C 3 haloalkyl, Ci-C 3 alkoxy, Ci-C 3 haloalkoxy, CI-C 3 alkylthio, C 2
-C
5 alkylcarbonyl, C 2
-C
5 alkoxycarbonyl, halogen, amino, cyano or 35 nitro;
R
28 is H or Ci-C 4 alkyl; WO 00/43377 PCT/USOO/01283 6 XI and X 2 are independently 0 or S;
X
3 is 0, S or NR 28 ; m is 0, 1, 2, 3 or 4; each n is independently 0, 1 or 2; 5 p is 0 or 1; each q is independently 0, 1 or 2; and t is 0, 1 or 2; provided that when Q is unsubstituted phenyl, XI, X 2 and X 3 are 0, q is 0 and R 2 is methyl, then RI is other than methyl. 10 In the above recitations, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl or hexyl isomers. The term "1-2 alkyl" indicates that one or two of the available positions for that substituent may be alkyl. "Alkenyl" includes straight-chain or branched alkenes such as 1-propenyl, 2-propenyl, and 15 the different butenyl, pentenyl and hexenyl isomers. "Alkenyl" also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes straight-chain or branched alkynes such as 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, 20 isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkoxyalkyl" denotes alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CH 3 0CH 2 ,
CH
3 0CH 2
CH
2 , CH 3
CH
2 0CH 2 , CH 3
CH
2
CH
2
CH
2
OCH
2 and CH 3
CH
2
OCH
2
CH
2 "Alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. 25 "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "Saturated Carbocyclic" ring denotes a ring having a backbone consisting of carbon atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms. The term "halogen", either alone or in compound words such as "haloalkyl", includes 30 fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" include F 3 C, CICH 2 , CF 3
CH
2 and
CF
3 CC1 2 . The terms "haloalkenyl", "haloalkynyl", "haloalkoxy", and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkenyl" include (Cl) 2
C=CHCH
2 35 and CF 3
CH
2
CH=CHCH
2 . Examples of "haloalkynyl" include HC=CCHC1, CF 3
C=C,
WO 00/43377 PCTIUSOO/01283 7 CCl 3 CaC and FCH 2
C=CCH
2 . Examples of "haloalkoxy" include CF 3 0, CC1 3
CH
2 0,
HCF
2
CH
2
CH
2 0 and CF 3
CH
2 0. The total number of carbon atoms in a substituent group is indicated by the "Ci-Cj" prefix where i and j are numbers from I to 12. For example, C 1
-C
3 alkylsulfonyl designates 5 methylsulfonyl through propylsulfonyl; C 2 alkoxyalkyl designates CH 3 0CH 2 ; C 3 alkoxyalkyl designates, for example, CH 3
CH(OCH
3 ), CH 3 0CH 2
CH
2 or CH 3
CH
2
OCH
2 ; and C 4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including
CH
3
CH
2
CH
2
OCH
2 and CH 3
CH
2
OCH
2
CH
2 . In the above recitations, when a compound of 10 Formula 1 contains a heterocyclic ring, all substituents are attached to this ring through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen. When a group contains a substituent which can be hydrogen, for example R 3 , then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted. 15 Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to 20 separate, enrich, and/or to selectively prepare said stereoisomers. Accordingly, the present invention comprises compounds selected from Formula 1, N-oxides and agriculturally suitable salts thereof. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form. One skilled in the art will appreciate that not all nitrogen containing heterocycles can 25 form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary 30 amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethydioxirane. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist in Comprehensive Organic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed., 35 Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and WO 00/43377 PCT/USOO/01283 8 B. R. T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, 5 pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press. The salts of the compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. 10 Preferred compounds for reasons of better activity and/or ease of synthesis are: Preferred 1. Compounds of Formula 1 wherein Q is H; or CI-C 12 alkyl, C 3
-C
8 cycloalkyl, C 3
-C
1 2 alkenyl, C 3
-C
8 cycloalkenyl or
C
3
-C
12 alkynyl, each optionally substituted with one or more R 2 1 ; or Q is a 3- to 7-membered fully saturated or 5- to 7-membered partially saturated 15 heterocyclic ring containing one or two X, provided that (a) when X is other than 0 or S(O)n, then only one X may be present and (b) when two X are present in the ring, they cannot be bonded directly to each other; or Q is a 5- or 6-membered aromatic heterocyclic ring system containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, 20 oxygen and sulfur, provided that the heterocyclic ring system contains no more than one oxygen and no more than one sulfur, and each heterocyclic ring system is optionally substituted with one or more R 16 ; and when Q is a 5- or 6 membered aromatic heterocyclic ring system containing a nitrogen, then Q is bonded through any available carbon or nitrogen atom by replacement of a 25 hydrogen on said carbon or nitrogen atom; or Q is phenyl optionally substituted with one or more substituents independently selected from the group consisting of R 16 , phenoxy and Z. Preferred 2. Compounds of Preferred 1 wherein Q is C 1
-C
12 alkyl, C 3
-C
8 cycloalkyl, C 3
-C
12 alkenyl, C 3
-C
8 cycloalkenyl or 30 C 3
-C
12 alkynyl, each optionally substituted with one or more R 21 . Preferred 3. Compounds of Preferred 1 wherein Q is a 3- to 7-membered fully saturated or 5- to 7-membered partially saturated heterocyclic ring containing one or two X, provided that (a) when X is other than 0 or S(O)n, then only one X may be present and 35 (b) when two X are present in the ring, they cannot be bonded directly to each other; or WO 00/43377 PCT/USOO/01283 9 Q is a 5- or 6-membered aromatic heterocyclic ring system containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that the heterocyclic ring system contains no more than one oxygen and no more than one sulfur, and 5 each heterocyclic ring system is optionally substituted with one or more
R
16 ; and when Q is a 5- or 6-membered aromatic heterocyclic ring system containing a nitrogen, then Q is bonded through any available carbon or nitrogen atom by replacement of a hydrogen on said carbon or nitrogen atom. 10 Preferred 4. Compounds of Preferred I wherein Q is phenyl optionally substituted with one or more substituents independently selected from the group consisting of R 16 , phenoxy and Z. Preferred 5. Compounds of Preferred 2 wherein Q is C 1
-C
6 alkyl optionally substituted with one or more R 2 1 , C 5
-C
7 15 cycloalkyl, C 3
-C
7 alkenyl or C 3
-C
6 alkynyl. Preferred 6. Compounds of Preferred 3 wherein Q is a 5- or 6-membered aromatic heterocyclic ring system containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that the heterocyclic ring system 20 contains no more than one oxygen and no more than one sulfur, and each heterocyclic ring system is optionally substituted with one or more
R
16 ; and when Q is a 5- or 6-membered aromatic heterocyclic ring system containing a nitrogen, then Q is bonded through any available carbon or nitrogen atom by replacement of a hydrogen on said carbon or 25 nitrogen atom. Preferred 7. Compounds of Preferred 4 wherein Q is phenyl optionally substituted with one or more substituents independently selected from the group consisting of R 16 . Preferred 8. Compounds of Preferred 2, Preferred 3 or Preferred 4 wherein XI, X 2 and 30 X 3 are O. Preferred 9. Compounds of Preferred 7 wherein Q is phenyl with substituents on the 2-, and 6-position independently selected from the group consisting of R 16 . Preferred 10. Compounds of Preferred 5 wherein 35 q is 0 or 1. Preferred 11. Compounds of Preferred 6 wherein WO 00/43377 PCTIUSOO/01283 10 q is 0 or 1. Preferred 12. Compounds of Preferred 7 wherein q is 0 or 1. Preferred 13. Compounds of Preferred 1 wherein 5 RI is phenyl substituted with one or more R 13 . Preferred 14. Compounds of Preferred I wherein
R
2 is C 2
-C
6 alkyl, C 2
-C
6 haloalkyl or C 2
-C
6 alkoxyalkyl. Most preferred is the compound of Formula 1 which is selected from the group consisting of: 10 (a) N-(4-fluorophenyl)-N-(1 -methylethyl)-4-(2-methylphenyl)-3,5-dioxo 1,2,4-oxadiazolidine-2-carboxanide; (b) 4-(2,6-dimethylphenyl)-N-(4-fluorophenyl)-N-(1-methylethyl)-3,5-dioxo 1,2,4-oxadiazolidine-2-carboxamide; (c) 4-(2,6-dimethylphenyl)-N-(1-methylethyl)-3,5-dioxo-N-phenyl-1,2,4 15 oxadiazolidine-2-carboxamide; (d) 4-cyclohexyl-N-(1 -methylethyl)-3,5-dioxo-N-phenyl- 1,2,4-oxadiazolidine 2-carboxamide; (e) 4-cyclohexyl-N-(4-fluorophenyl)-N-(1 -methylethyl)-3,5-dioxo- 1,2,4 oxadiazolidine-2-carboxamide; 20 (f) N,4-bis(1 -methylethyl)-3,5-dioxo-N-phenyl- 1,2,4-oxadiazolidine-2 carboxamide; (g) N-(4-fluorophenyl)-N-(1 -methylethyl)-3,5-dioxo-4-(cyclopropyl)- 1,2,4 oxadiazolidine-2-carboxamide; and (h) N-(4-fluorophenyl)-N,4-bis(1 -methylethyl)-3,5-dioxo- 1,2,4 25 oxadiazolidine-carboxamide. The oxadiazolidines of Formula 1 are useful as herbicides. The present invention also relates to processes for preparing an oxadiazolidine of Formula 1. The present processes for preparing the oxadiazolidines of Formula 1 provided herein are characterized by employing a process sequence selected from process sequences A, B, C, D or E as 30 described below. PROCESS SEQUENCE A A process for preparing a compound of Formula 1 WO 00/43377 PCTIUSOO/01283 11 X2 X3
Q-(CR
6 R7)q-N O R2 xi 1 wherein Q, R 6 , R 7 , q, XI, X 2 , X 3 , RI and R 2 are as defined above, comprising: (a) contacting a compound of Formula 5 H X2R27 XI.: N 5 5 wherein R 27 is -(CR 6
R
7 )q-Q, with a compound of Formula 4 Q- (CR 6 R7)q- X4 4 wherein X 4 is halogen or mesylate, in the presence of a base to provide a compound of Formula 3 R27X 2
Q-(CR
6
R
7 )q-N 3 X 1 , and 10 (b) contacting the compound of Formula 3 with a carbamoyl or thiocarbamoyl chloride of Formula 2 R1 X3 Rr R2/ 2 PROCESS SEQUENCE B 15 WO 00/43377 PCT/USOO/01283 12 A process for preparing a compound of Formula 1 X2 X3 /UQ%R
Q-(CR
6
R
7 )q-NI O R2 xi wherein Q, R 6 , R 7 , q, XI, X 2 , X 3 , R I and R 2 are as defined above, comprising: (a) contacting a compound of Formula 5 H X2R27 5 5 wherein R 27 is -(CR 6
R
7 )q-Q, with an alcohol of Formula 6 Q- (CR 6 7 )q - OH 6 under reaction conditions involving a tertiary phosphine and an azo compound to provide a 10 compound of Formula 3 R27X2
Q-(CR
6
R
7 )q-N I 3 XI , and (b) contacting the compound of Formula 3 with a carbamoyl or thiocarbamoyl chloride of Formula 2 R1 X3 R2/ 2 WO 00/43377 PCT/USOO/01283 13 PROCESS SEQUENCE C A process for preparing a compound of Formula 1 X2 X3 X IA NO RI
Q-(CR
6
R
7 )q-N I I O R2 XI 1 5 wherein Q, R 6 , R 7 , q, XI, X 2 , X 3 , RI and R 2 are as defined above, comprising: (a) contacting a compound of Formula 5 HX2R27 HR 5 wherein R 27 is -(CR 6
R
7 )q-Q, with a carbamoyl or thiocarbamoyl chloride of Formula 2 I X3 Ri\NjI-a R2/ 2 10 in the presence of a base to provide the compound of Formula 1 X2 X3 R27-N Z-A -1R O 12 XI directly or a compound of Formula 7 WO 00/43377 PCT/USOO/01283 14 X2 X3 H-N N XI 7 ,and (b) contacting the compound of Formula 7 with an alcohol of Formula 6 Q- (CR 6 R7)q-- OH 6 5 under reaction conditions involving a tertiary phosphine and an azo compound or with a compound of Formula 4
Q--(CR
6
R
7 )q- X 4 4 in the presence of a base. 10 PROCESS SEQUENCE D A process for preparing a compound of Formula 1 X2 X3
Q-(CR
6
R
7 )q-N O R2 xi wherein Q, R 6 , R 7 , q, X 2 , X 3 , R 1 and R 2 are as defined above, and XI is 0, comprising: 15 (a) contacting a compound of Formula 19 Q-
(CR
7 )q- H
OR
1 19 X1 with phosgene or thiophosgene to provide a compound of Formula 20 WO 00/43377 PCTIUSOO/01283 15 X2 Q- (CR 6 R7)q - O 1 RI 20 (b) contacting the compound of Formula 20 with hydroxylamine, following by treatment with a base, and then an acid, to provide a compound of Formula 8 x 2
Q-(CR
6
R
7 )q-N O 8 , and 5 (c) contacting the compound of Formula 8 with a compound of Formula 2 R1 X3 RkL \N Cl R2/ 2 PROCESS SEQUENCE E 10 A process for preparing a compound of Formula 1 X2 X3 RI
Q-(CR
6
R
7 )q-N O R2 xl wherein Q, R 6 , R 7 , q, XI, X 2 , X 3 , RI and R 2 are as defined above, comprising: (a) contacting a compound of Formula 2 RI X3 R2/ 2 WO 00/43377 PCT/USOO/01283 16 with hydroxylamine in the presence of a base to provide a compound of Formula 22 X3 OH R2H 22 (b) contacting the compound of Formula 22 with a compound of Formula 23 xi II C- C--N= C=X 2 23 5 in the presence of a base to provide a compound of Formula 7 X2 X3 H-N N X1 7 ,and (c) contacting the compound of Formula 7 with an alcohol of Formula 6 Q- (CR 6
R
7 )q-OH 6 10 under reaction conditions involving a tertiary phosphine and an azo compound or with a compound of Formula 4 Q- (CR 6
R
7 )q- X4 4 in the presence of a base. 15 PROCESS SEQUENCE F A process for preparing a compound of Formula 1 WO 00/43377 PCTIUSOO/01283 17 X2 X3 Q--(CR R7)q--N I I O R2 xi wherein Q, R 6 , R 7 , q, XI, X 2 , X 3 , R I and R 2 are as defined above, comprising contacting a compound of Formula 7 X2 X3 H-N / N O 0 2 X1 7 5 with an orthoformate of Formula 24 (R2 7 0)3CH 24 wherein R 27 is -(CR 6
R
7 )q-Q, in the presence of a base. PROCESS SEQUENCE G 10 A process for preparing a compound of Formula 1 X2 X3
Q-(CR
6
R
7 ) q-N O R2 xl wherein Q, R 6 , R 7 , q, XI, X 2 , X 3 , RI and R 2 are as defined above, comprising: (a) contacting a compound of Formula 8 WO 00/43377 PCTIUSOO/01283 18 X2
Q-(CR
6
R
7 )q-N xi 8 with a compound of Formula 26 X3 26 to provide a compound of Formula 25 Q--(CR6R7)q- N XI 5 25 or a compound of Formula 27 X2 X 3
X
2 Q- (CR6R7) N N) N- (CR 6
R
7 )q- Q )q-~ x x 27 in the presence of a catalyst such as hexamethylguanidinium chloride; and (b) contacting the compound of Formula 25 or Formula 27 with an amine of Formula 10 13 RIg NH R2/ 13 in the presence of a base.
WO 00/43377 PCT/USOO/01283 19 The present invention also relates to an intermediate compound of Formula 5 H X 2 R27 N Xi N 5 wherein
R
27 is -(CR 6
R
7 )q-Q; R 6 , R 7 , q, Q, XI and X 2 are as defined above for Formula 1; 5 provided that when XI and X 2 are 0 and q is 0, then Q is other than unsubstituted benzyl. The present invention also relates to intermediate compounds of Formula 8 and Formula 20 2 X2
Q-(CR
6
R
7 )q-N Q-(CR6R7)q X O XI O 8 20 wherein 10 R 6 , R 7 , q, Q and X 2 are as defined above for Formula 1; and XI is 0; provided that when X 2 is 0 and q is 0, then Q is other than unsubstituted benzyl. The oxadiazolidines of Formula 1 can be used alone or in combination with other commercial pesticides. The present invention also relates to certain rare combinations that surprisingly give greater-than-expected or synergistic effect, or give a less-than-additive or 15 safening effect on crops while retaining or increasing synergistically weed control. The mixtures of compounds of Formula 1 and certain sulfonylureas have now been discovered to synergistically control weeds. Also, the mixtures of compounds of Formula 1 and safeners such as dichlormid or naphthalic anhydride have now been discovered to exhibit a crop safening effect while retaining or synergistically increasing weed control. 20 This invention also relates to a herbicidal composition comprising a herbicidally effective amount of a compound of Formula 1 and at least one of a surfactant, a solid diluent or a liquid diluent. The preferred compositions of the present invention are those which comprise the above preferred compounds. This invention also relates to a method for controlling the growth of undesired 25 vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of Formula 1.
WO 00/43377 PCT/USOO/01283 20 DETAILS OF THE INVENTION Compounds of the Formula 1 can be readily prepared by one skilled in the art by using the reactions and techniques described in Scheme 1 to Scheme 10 below. In cases where a substituent of the starting material is not compatible with the reaction conditions 5 described for any of the reaction schemes, the substituent can be converted to a protected form prior to the described reaction scheme and then deprotected after the reaction using commonly accepted protection/deprotection techniques (see Green, T. W and Wuts, P. G., Protecting Groups in Organic Transformations, 2nd Edition, John Wiley and Sons, New York, 1991). Otherwise, alternative approaches known to one skilled in the art are available. 10 The definitions of Q, X1, X 2 , X 3 , Ri, R 2 , R 6 , R 7 , and q in compounds of Formulae 1-21 below are as defined in the Summary of the Invention. As shown in Scheme 1, compounds of Formula 1 can be obtained by the reaction of oxadiazolidines of Formula 8 with carbamyl chlorides of Formula 2. The preferred solvent for the carbamoylation reaction is an inert solvent such as tetrahydrofuran, toluene, benzene 15 or dioxane. The presence of a tertiary amine base such as triethylamine or diisopropylethylamine is preferable. Use of an acylation catalyst such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine in a catalytic or stoichiometric amount is preferred. Other bases such as alkali hydroxide, carbonates or hydrides may also be employed. The reaction can be carried out at temperatures between 20 to 150 *C. 20 SCHEME 1 X2 X3 X2 X3 6 XINH Rl_ AIm/ -JN RI Q- (CR6RI)q -N I + Ra Base Q- (CR,6R7)q- N I R2
X
1 X 0 8 2 Oxadiazolidines of Formula 8 can be prepared by methods known in the literature. Zinner reported the preparation of a wide variety of oxadiazolidines. See, for example: Arch. Pharm. (1965), 298, 580-587; Arch. Pharm. (1971), 303, 139-144, German patent 25 application, DE 2010396 (1971). As shown in Scheme 2, a hydroxyurea or hydroxythiourea of Formula 9 is reacted with an activated carbonyl or thiocarbonyl compound of Formula 10 in the presence of a base to give compounds of Formula 8. Examples of suitable activated carbonyl compounds are ethyl chloroformate, phenyl chloroformate, carbonyl diimidazole, phosgene, diphosgene or triphosgene. Examples of suitable activated thiocarbonyl WO 00/43377 PCT/USOO/01283 21 compounds are carbon disulfide, thiophosgene and thiocarbonyldiimidazole. Suitable bases include alkali carbonates, tertiary amines such as triethylamine and alkali hydroxides. The reaction can be carried out in a variety of solvents including tetrahydrofuran, toluene, dichloromethane, chloroform, acetonitrile or dioxane. The reaction may also be carried out 5 in two-phase mixtures of water and an organic solvent such as dichloromethane, ethyl acetate or toluene. Depending on the reactivity of the carbonyl or thiocarbonyl compound, the reaction may be carried out at temperatures from 0 to 150 *C. SCHEME 2 X2 Xi Q--(CR6R7)q OH + M) M2 Bas 8 I I H H 9 10 M1, M 2 is halogen, phenoxy, OCH 3 , OC 2
H
5 or imidazole 10 As shown in Scheme 3, compounds of Formula 8a wherein XI and X 2 are 0 can be made via the method of Zinner, Arch. Pharm. (1981), 314, 294-302. The reaction of isocyanates of Formula 11 with hydroxyurethanes of Formula 12 gives compounds of Formula 8a. The cyclization can be carried out in a variety of solvents such as acetone, dichloromethane, tetrahydrofuran, dioxane, ethyl acetate, and other solvents inert to 15 isocyanates. The presence of a base such as triethylamine or sodium hydroxide is also useful. The reaction may be carried out at temperatures from 20 to 150 *C. SCHEME 3 X2 Q- (CR 6
R
7 )q - NCX 2 + HO I OR Q-(CR 6
R
7 )q- NH 11 12 X (R is alkyl, allyl or aryl) 8a (wherein X1 and X 2 are O) Carbamyl chlorides of Formula 2a (which are compounds of Formula 2 wherein X 3 20 is 0) are well known in the literature and can be made by the reaction of amines of Formula 13 with phosgene or a phosgene equivalent such as di- or triphosgene as shown in Scheme 4. The presence of a base is useful and the use of hindered tertiary amines such as WO 00/43377 PCTIUSOO/01283 22 diisopropylethyl amine is preferred. The reaction can be carried out in a variety of solvents such as toluene or benzene that are inert to phosgene and its equivalents. The reaction can be carried out at temperatures from 0 to 120 *C. SCHEME 4 Phosgene 0 RI ~ or R NH equivalent R R2/ Base 2 5 13 2a As shown in Scheme 5, hydroxyureas and thioureas of Formula 9 can be prepared from the reaction of hydroxylamine with isocyanates or isothiocyanates of Formula 11. The reaction is carried out in a two-phase reaction medium consisting of water and an organic solvent such as toluene, benzene, dichloroethane, dichloromethane, ethyl acetate or 10 chlorobutane. The hydroxylamine employed can be a commercially available aqueous solution or can be prepared in situ from the reaction of an acid addition salt of hydroxylamine with an alkali hydroxide or carbonate. The reaction is generally carried out at temperatures between 0 and 40 *C. SCHEME 5 X2 Q- (CR 6
R
7 )q- NCX 2 NH2OH (CR6R )q OH H H 11 9 15 Isocyanates of Formula 11 a are commercially available or can be prepared from amines of Formula 14 as shown in Scheme 6. The reaction of phosgene or its equivalents (such as di- and triphosgene) with amines or amine hydrochlorides of Formula 14 gives the isocyanates of Formula 11 a. This reaction is well known in the literature and can be carried out in a variety of solvents such as toluene, benzene, ethyl acetate or dichloroethane which 20 are inert to phosgene. Depending upon the reactivity of the amine of Formula 14, the reaction may be carried out at temperatures from 0 to 200 *C.
WO 00/43377 PCTUSOO/01283 23 SCHEME 6 Phosgene or Q- (CR 6
R
7 )q - NH 2 equivalent Q- (CR7)q- N= CX2 14 11a(wherinX 2 is0) As shown in Scheme 7, isocyanates of Formula 1 la can also be formed from activated acids of Formula 15. Acid halides, anhydrides, imidazolides and the like can be reacted with various azides to provide, after a Curtius rearrangement, the isocyanates of 5 Formula 11 a. The azide used may be an alkali azide, trialkylsilyl azide or trialkylstannyl azide. The reaction may be carried out in solvents such as toluene, tetrahydrofuran, ethyl acetate, dioxane, benzene, or methyl tert-butyl ether. When an alkali azide is employed, biphasic aqueous solvents or miscible aqueous containing mixtures are preferred in the formation of the acyl azide intermediate. For further examples of Curtius rearrangements, 10 see: March, J. Advanced Organic Chemistry, 3rd edition; John Wiley & Sons, 1985; pp 984 985 and 380. See also Kim, World Patent Application 98/51683 (1998) and Larock, Comprehensive Organic Transformations, VCH, 1989, pp 931-932. SCHEME 7 Q- (CR 6
R
7 )q - COT M-N3 (CR 6
R
7 )q - N= C=X2 15 1la (wherein X 2 is O) T is halogen, imidazole, etc. M is alkali metal, trialkylsilyl or trialkylstannyl 15 As shown in Scheme 8, compounds of Formula 9 can also be made by the reaction of compounds of Formula 16 with hydroxylamine. The reaction may be carried out in a number of different solvents including tetrahydrofuran, dioxane, acetonitrile, dimethylformamide and dimethylsulfoxide. Temperatures from 0 to 160 *C may be employed in this transformation. Many compounds of Formula 16 are known, and can be 20 made by the reaction of commercially available chloroformates and chlorothioformates with compounds of Formula 14.
WO 00/43377 PCT/USOO/01283 24 SCHEME 8 W Q-(CR)q N O
NH
2 OH H 16 (W is H, halogen or NO2) As shown in Scheme 9, compounds of Formula 9 can also be made by the reaction of activated hydroxylamines of Formula 17 with amines of Formula 14. The reaction may be carried out in a number of different solvents including tetrahydrofuran, dioxane, acetonitrile, 5 dimethylformamide and dimethylsulfoxide. In some cases lower alcohols or even mixtures of water and alcohols may also be employed. Temperatures from 0 to 160 *C maybe employed in this transformation. Compounds of Formula 17 are known in the literature and can be made from hydroxylamine and activated esters or thioesters (See Oesper and Broker, J. Am. Chem. Soc., 1925, 47, 2607; Defoin et. al., Helv. Chim. Acta., 1992, 75, 109-123; and 10 Stewart and Brooks, J Org. Chem., 1992, 57, 5020-5023). SCHEME 9 W 14 + HO N O9 H 17 (W is H, halogen orNO2) Compounds of Formula 2b (which are compounds of Formula 2 wherein X 3 is
NR
2 3 ) can be made by the chlorination of ureas of Formula 18 as shown in Scheme 10. The 15 chlorination may be carried out with a wide variety of reagents such as phosphorus oxychloride, thionyl chloride, phosphorous pentachloride, or triphenylphosphine reagents with carbon tetrachloride or chlorine. A variety of solvents may be used including halogenated solvents such as dichloromethane, dichloroethane, or trichloroethane. A preferred solvent of the transformation is dimethylformamide. The reaction may be carried 20 out from 0 to 150 *C. Some known chloroamidine compounds and their synthesis may be found in Reid, Chem. Ber., 1975, 108, 2290-2299.; Kuehle et al.; Angew. Chem.; 1969; 81; 18; and Shevchenko,V.I. et al.; J. Gen. Chem. USSR (Engl.Transl.); 1976; 46; 535-539.
WO 00/43377 PCT/USOO/01283 25 SCHEME 10 0 Chlorinating R N NRR2 Agent R N NR 1
R
2 H 18 2b Wherein X 3 is NR23 Many isothiocyanates of Formula 1 la are commercially available. Amines of Formula 13 are commercially available or can be prepared by methods disclosed in the 5 literature. See the following references and references cited therein for synthesis of these materials: Kim, World Patent Application 98/51683 (1998); Dhar, World Patent Application 98/35961 (1998); Rorer, World Patent Application 98/25912 (1998); and Morita et. al., World Patent Application WO 98/11079 (1998). Amines of Formula 14 are commercially available or can be synthesized by methods 10 known in the art. See the following references and references cited therein for synthesis of these materials: Kim, World Patent Application 98/51683 (1998); Dhar, World Patent Application 98/35961(1998); Rorer, World Patent Application 98/25912 (1998), Goto et. al., European Patent Application EP 695748 (1996); Goto et. al., European Patent Application EP 771,797 (1997); and Goto et. al. US patent 5,589,439 (1996). 15 Activated carboxylic acids of Formula 10 are commercially available or can be prepared by methods disclosed in the literature. See the following references and references cited therein for the synthesis of these materials: Kim, World Patent Application 98/51683 (1998); Dhar, World Patent Application 98/35961(1998); Rorer World Patent Application 98/25912 (1998); and Goto et. al., European Patent Application EP 695748 (1996). See also 20 Larock, Comprehensive Organic Transformations, VCH, 1989, p 821 for a list of comprehensive references for the synthesis and chemistry of carboxylic acids and activated derivatives. This invention is further directed to processes for the preparation of compounds of Formula 1 using process sequences described below. 25 30 WO 00/43377 PCTIUSOO/01283 26 PROCESS SEQUENCE A STEP 1 H-, N X2R27 Q-(CR 6
R
7 )q X2R27 X1 N + Q-(CR 6
R
7 )q-X4 Se N O SolventXO 5 4 3 Step 1 forms compounds of Formula 3 by contacting compounds of Formula 5 with 5 compounds of Formula 4 in the presence of a suitable base either neat or in a suitable solvent. Compounds of Formula 5 may be prepared, for example, by methods described in Synthesis, 1991, 265. For Step 1, the reaction temperature is generally from -10 to 250 "C, preferably from 10 0 to 100 *C. The reaction times are generally from 0.25 to 48 h, preferably from 0.25 to 24 h. Generally, the pressure is in the range of 1.013 x 102 to 2.026 x 102 KPa, preferably ambient pressure. Suitable solvents include typical organic solvents in which the reactants can be dissolved and the process of Step 1 can proceed without interference. Examples of such reactants include aromatics such as benzene, toluene, xylene, chlorobenzene and 15 dichlorobenzene, ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, ethyl acetate, dichloromethane, dichloroethane, and polar aprotic solvents such as dimethylformamide and dimethylsulfoxide. Suitable bases include organic trialkylamines such as trimethylamine, triethylamine, diisopropylethylamine, tributylamine and the like, dimethylaniline, NN-dimethylamino 20 pyridine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4 diazabicyclo[2.2.2]octane and 1,5-diazabicyclo[4.3.0]non-5-ene. 1,8-Diazabicyclo[5.4.0] undec-7-ene is a particularly useful organic base for this reaction. Inorganic bases include, but are not limited to, potassium carbonate, sodium carbonate, potassium hydride, sodium hydride, lithium carbonate and cesium carbonate. !5 A phase transfer catalyst can accelerate the reaction in the presence of inorganic bases. Phase transfer catalysts include tetraalkylammonium halides, crown ethers, phosphonium salts, silicon analogs of crown ethers and acyclic analogs of crown ethers. Particularly useful as a base is the combination of potassium carbonate and a phase transfer catalyst. 0 Generally at least an equimolar amount of the Formula 4 compound is used in respect to the Formula 5 compound, and preferably at least a small molar excess of the Formula 4 compound is used. More particularly, the molar ratio of the Formula 4 compound to the WO 00/43377 PCT/USOO/01283 27 Formula 5 compound is usually in the range of 1.05:1 to 10:1. In most cases, the molar ratio of the Formula 5 compound to the Formula 4 compound is preferably in the range of 1.1:1 to 1.5:1. Generally at least an equivalent of base is used in respect to the Formula 5 compound, and preferably at least a small equivalent excess of the base is used. More particularly, the 5 ratio of the number of equivalents of base to number of moles of the Formula 5 compound is usually in the range of 1.05:1 to 10:1. In most cases, the ratio of the number of equivalents of base to number of moles of the Formula 5 compound is preferably in the range of 1.1:1 to 1.5:1. The equivalent amount of base may be similar to the molar amount of the Formula 4 compound, but this is not necessary. 10 The compound of Formula 4 is preferably added to the reaction mixture containing the compound of Formula 5 and a base either neat or in a solvent. The reaction temperature is maintained during and after the addition and until the reaction reaches completion. Isolation of product of Step 1 can be accomplished by standard workup procedures or the resultant mixture can be used directly in Step 2. 15 STEP 2 X3 Q- (CR6R7)q X2 RI\A Bae NR R2/ Solvent XI O N N 2 2 X3 1 Step 2 forms compounds of Formula 1 from the reaction of compounds of Formula 3 with compounds of Formula 2 in the presence of a suitable base in a suitable solvent. For Step 2, the general and preferred reaction conditions are the same as the ones 20 described above for Step 1. Alternatively, the processes of Step 1 and 2 can be combined without isolating product of Step 1 and preferably, the reaction conditions (e.g. temperature, mole ratio, reaction time etc) are balanced to achieve a high yield of compound of Formula 1. The compound of Formula 1 can be isolated by standard procedures. 25 PROCESS SEQUENCE B STEP 1 H X2R27 X + Q (CR6R7)q OH Mitsunobu 3 5 6 WO 00/43377 PCTUSOO/01283 28 Step 1 forms the compounds of Formula 3 from the reaction of compounds of Formula 5 with compounds of Formula 6 under Mitsunobu reaction conditions involving a tertiary phosphine and an azo compound. One skilled in the art can find a variety of the tertiary phosphine and azo compounds as well as solvents useful for this transformation in 5 Synthesis, 1981, 1 and Org. Reactions, 1992, 42, 335. For the process of Step 1, the reaction temperature is generally from about -40 to 250 *C, preferably from -20 to 80 *C. The reaction times are generally from about 0.20 to 24 h, preferably from 0.5 to 12 h. Generally, the pressure is from 1.013 x 102 to 5.065 x10 2 KPa; preferably ambient pressure. 10 Generally at least an equimolar amount of the Formula 5 compound is used in respect to the Formula 6 compound, and preferably at least a small molar excess of the Formula 6 compound is used. More particularly, the molar ratio of the Formula 6 compound to the Formula 5 compound is usually in the range of 1.05:1 to 10:1. In most cases, the molar ratio of the Formula 6 compound to the Formula 5 compound is preferably in the range of 1.1:1 to 15 1.5:1. Isolation of product of Step 1 can be accomplished by standard workup procedures. STEP 2 Compounds of Formula 1 are then obtained by the reaction of the compounds of 20 Formula 3 prepared in Step 1 and compounds of Formula 2 under the same reaction conditions as already described in Step 2 for Sequence A. PROCESS SEQUENCE C STEP Ia
X
2
R
27 X2 X3 HN + 2 Q- (CR 6
R
7 R N N R1 0 0 N + 2-Bae 7)q 5 X 25 wherein R 27 is (CR 6
R
7 )q Step la forms the compounds of Formula 1 by contacting compounds of Formula 5 with compounds of Formula 2 in the presence of a suitable base either neat or in a suitable solvent. For the process of Step 1 a, the general and preferred reaction conditions are the same 30 as the ones described above for Step 1 in Process Sequence A.
WO 00/43377 PCT/USOO/01283 29 A solution of compound of Formula 2 can be added to a solution/suspension of compound of Formula 5 and a base in a solvent. Reaction temperature is maintained during and after the addition and until the reaction reaches completion. Isolation of product of Step la can be accomplished by standard workup procedures. 5 STEP lb HX2R27 H2 N2 Base ON/ N 2 X+ Np N--.R 0 lo iiY R Xj3 5 7 Step lb forms the compounds of Formula 7 from the reaction of compounds of Formula 5 and compounds of Formula 2 in the presence of a base either neat or in a suitable 10 solvent. For the process of Step lb, the general and preferred reaction conditions are the same as the ones described above for Step 1 in Process Sequence A. The product of Step lb can be isolated by standard workup procedures. 15 STEP2a 7 + Q- (CR 6
R
7 )q-OH Mitsunobu 1 6 Step 2a forms the compounds of Formula 1 from the reaction of compounds of Formula 7 and compounds of Formula 6 under Mitsunobu reaction conditions involving a tertiary phosphine and an azo compound. One skilled in the art can find a variety of the 20 tertiary phosphine and azo compounds as well as solvents useful for this transformation in Synthesis, 1981, 1 and Org. Reactions, 1992, 42, 335. For the process of Step 2a, the reaction temperature is generally from about -40 to 250 *C, preferably from -20 to 80 *C. The reaction times are generally from about 0.20 to 24 h, preferably from 0.5 to 12 h. Generally, the pressure is from 1.013 x 102 to 5.065 x102 25 KPa; preferably ambient pressure. Generally at least an equimolar amount of the Formula 7 compound is used in respect to the Formula 6 compound, and preferably at least a small molar excess of the Formula 6 compound is used. More particularly, the molar ratio of the Formula 6 compound to the Formula 7 compound is usually in the range of 1.05:1 to 10:1. In most cases, the molar ratio WO 00/43377 PCT/USOO/01283 30 of the Formula 7 compound to the Formula 6 compound is preferably in the range of 1.1:1 to 1.5:1. Isolation of product of Step 2a can be accomplished by standard workup procedures. 5 STEP 2b 7 + Q-(CR 6
R
7 )q-X 4 Base 4 Step 2b forms compounds of Formula 1 by contacting compounds of Formula 7 with compounds of Formula 4 in the presence of a suitable base either neat or in a suitable solvent. 10 For the process of Step 2b, the general and preferred reaction conditions are similar to the ones described above for Step I in Process Sequence A. Isolation of product of Step 2b can be accomplished by standard workup procedures. PROCESS SEQUENCE D 15 Compounds of the Formula 8 can be readily prepared by one skilled in the art by using the reactions and techniques described in Steps 1 and 2. In cases where a substituent of the starting material is not compatible with the reaction conditions described for any of the reaction schemes, the substituent can be converted to a protected form prior to the described reaction scheme and then deprotected after the reaction using commonly accepted 20 protection/deprotection techniques (see Green, T. W. and Wuts, P. G., Protecting Groups in Organic Transformations, 2nd Edition, John Wiley and Sons, New York, 1991). Otherwise, alternative approaches known to one skilled in the art are available. STEP 1 X2
Q(RH
7 ) Base <Ja Q-(CR6R7q- ORI Phos gene qQ- (Rl OR or 19 X Thiophosgene 20 (wherein X 1 is O) 25 Step 1 forms compounds of Formula 20 from the reaction of compounds of Formula 19 with phosgene or thiophosgene in the presence of a base. For general reaction conditions for this transformation, see: U.S. Patent Number 5,602,251. Compounds of Formula 19 are well known in the literature. See: for example, J. Chem. Soc. Perkin I(1997), 1041.
WO 00/43377 PCT/USOO/01283 31 STEP 2 X2 _ Hydroxylamnine NHOH 1. Base 20a Q- (CR6R7)q- N OR .AcdI Q--(CR6R7)q-N L 21 8 X (wherein X 2 is or S and X1 is O) Step 2 forms compounds of Formula 8 in the form of a salt by treatment of compounds of Formula 20 with hydroxylamine and a base. The salt is then converted to compound of 5 Formula 8 by treatment with an acid. The reaction is conducted in a suitable organic solvent such as, but not limited to, tetrahydrofuran, dioxane or toluene at a temperature between - 20 and 100 *C with 10-50 *C being the preferred temperature. Hydroxylamine may be generated from one of its salts by use of a suitable base such as, but not limited to, potassium carbonate, potassium hydroxide 10 or sodium hydroxide. Alternatively, hydroxylamine in water may be used. Judicious use of an appropriate co-solvent such as water or a phase transfer catalyst may be effective in facilitating the reaction. Further amounts of the base (vide supra) can be added to scavenge the HCI formed in the reaction. Alternatively, an excess amount of hydroxylamine can be used to achieve the same purpose. 15 The intermediate compound of Formula 21 is not usually isolated, but converted directly to compounds of Formula 8 by addition of further quantities of base. It is apparent to one skilled in the art that salts of compounds of Formula 8 generated from this reaction may be used directly in the preparation of compounds of Formula 1 as described in Scheme 1. To facilitate the transformation, it may be desirable to adjust the solvent composition by 20 removal of co-solvents such as water prior to the reaction. Alternatively, compounds of Formula 8 may be isolated from their salts by addition of an appropriate mineral acid such as, but not limited to, HCI before being subjected to the reaction conditions as described in Scheme 1 to produce compounds of Formula 1. 25 PROCESS SEQUENCE E Compounds of the Formula 7 can be readily prepared by one skilled in the art by using the reactions and techniques described in Steps 1 and 2. Since hydroxylamine is unstable upon heating, this sequence allows a safe and efficient route to the compounds of the Formula 7 under mild conditions. 10 WO 00/43377 PCT/USOO/01283 32 STEP 1
X
3 R \ Base R1NJ X3 OH N-- C + NH 2 OH N R2/ H 2 H 22 Step 1 forms the compounds of Formula 22 by contacting a compound of Formula 2 with hydroxylamine in the presence of a suitable base in a suitable solvent. Hydroxylamine 5 may be generated from one of its salts or hydroxylanmine in water may be used. For Step 1, the reaction temperature is generally from -10 to 150 *C, preferably from 0 to 100 *C. The reaction times are generally from 0.10 to 24 h, preferably from 0.10 to 2 h. Generally, the pressure is in the range of 1.013 x 102 to 2.026 x 102 KPa; preferably ambient pressure. Suitable solvents include typical organic solvents in which the reactants can be 10 dissolved and the process of Step 1 can proceed without interference. Examples of such solvents include aromatics such as benzene, toluene, xylene, chlorobenzene and dichlorobenzene, ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, ethyl acetate, dichloromethane, dichloroethane, and polar aprotic solvents such as dimethylformamide and dimethylsulfoxide. Judicious use of an appropriate co-solvent 15 such as water or a phase transfer catalyst may be effective in facilitating the reaction. Suitable bases include organic trialkylamines such as trimethylamine, triethylamine, diisopropylethylamine, tributylamine and the like, dimethylaniline, NN-dimethylamino pyridine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4 diazabicyclo[2.2.2]octane and 1,5-diazabicyclo[4.3.0]non-5-ene. Trialkylamines is a 20 particularly useful organic base for this reaction. When an excess quantity of hydroxylamine is employed, the excess hydroxylamine can also serve as a base. Inorganic bases include, but are not limited to, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate. Generally at least an equimolar amount of the Formula 2 compound is used in respect 25 to hydroxylamine, and preferably at least a small molar excess of hydroxylamine is used. More particularly, the molar ratio of the Formula 2 compound to hydroxylamine is usually in the range of 1:1.05 to 1:10. In most cases, the molar ratio of the Formula 2 compound to hydroxylamine is preferably in the range of 1:1.1 to 1:1.5. Generally at least an equivalent of base is used in respect to the Formula 2 compound, and preferably at least a small 0 equivalent excess of the base is used. More particularly, the ratio of the number of equivalents of base to number of moles of the Formula 2 compound is usually in the range of 1.05:1 to 10:1. In most cases, the ratio of the number of equivalents of base to number of WO 00/43377 PCT/USOO/01283 33 moles of the Formula 2 compound is preferably in the range of 1.1:1 to 1.5:1. The equivalent amount of base may be similar to the molar amount of the Formula 2 compound, but this is not necessary. Isolation of product of Step 1 can be accomplished by standard workup procedures. 5 In the scenario that the reaction is carried our in an aqueous solution, a filtration can be employed to collect compounds of Formula 22. STEP 2 x1 22 + a-c-N= C=X 2 Ba 7 23 10 Compounds of Formula 7 are synthesized by contacting compounds of Formula 22 with chlorocarbonyl isocyanate (XI and X 2 are 0) or chlorocarbonyl isothiocyanate (XI is 0 and X 2 is S) or chlorothiocarbonyl isocyanate (XI is S and X 2 is 0) or chlorothiocarbonyl isothiocyanate (XI and X 2 are S) in the presence of a base to scavange the HCl byproduct. Similar examples of such reactions using N-alkyl-N-hydroxylamine and chlorocarbonyl 15 isocyanate have been reported in Syn., 1982, 781-2 and in WO 9741097 but there is no example of compound like 22 and chlorocarbonyl isocyanate in the literature. Compounds of Formula 23 are either commercially available or may be prepared by one skilled in the art using methods known in the art (or slight modification of these methods); for example, see: Chem. Ber. 1981, 114, 1746-51, Chem. Ber. 1973, 106, 1487-95, 20 and Chem. Ber. 1966, 99, 3572-81. For Step 2, the reaction temperature is generally from -10 to 150 *C, preferably from 0 to 100 *C. The reaction times are generally from 0.10 to 24 h, preferably from 0.10 to 2 h. Generally, the pressure is in the range of 1.013 x 102 to 2.026 x 102 KPa; preferably ambient pressure. Suitable solvents include typical organic solvents in which the reactants can be 25 dissolved and the process of Step 1 can proceed without interference. Examples of such reactants include aromatics such as benzene, toluene, xylene, chlorobenzene and dichlorobenzene, ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, ethyl acetate, dichloromethane, dichloroethane, and polar aprotic solvents such as dimethylformamide and dimethylsulfoxide. 30 Suitable bases for Step 2 are similar to the ones described above for Step 1. Generally at least an equimolar amount of the Formula 22 compound is used in respect to the Formula 23 compound, and preferably at least a small molar excess of the Formula 23 compound is used. More particularly, the molar ratio of the Formula 22 WO 00/43377 PCT/USOO/01283 34 compound to the Formula 23 compound is usually in the range of 1:1.05 to 1:10. In most cases, the molar ratio of the Formula 22 compound to the Formula 23 compound is preferably in the range of 1:1.1 to 1:1.5. Generally at least an equivalent of base is used in respect to the Formula 22 compound, and preferably at least a small equivalent excess of the 5 base is used. More particularly, the ratio of the number of equivalents of base to number of moles of the Formula 22 compound is usually in the range of 1.05:1 to 10:1. In most cases, the ratio of the number of equivalents of base to number of moles of the Formula 22 compound is preferably in the range of 1.1:1 to 1.5:1. The equivalent amount of base may be similar to the molar amount of the Formula 22 compound, but this is not necessary. 10 Isolation of product of Step 2 can be accomplished by standard workup procedures. Compounds 7 can be readily converted into alkali salts when treated with potassium carbonate or sodium carbonate in water. The salts may be useful in alkylation reactions. Compounds of Formula 1 are then obtained by the reaction of compounds of Formula 7 under the same reaction conditions as already described in Step 2a/2b in Sequence C. 15 PROCESS SEQUENCE F Compounds of the Formula 1 can be readily prepared by one skilled in the art by using the reactions and techniques described in the scheme below. X2 X3 X2 X3 H-N / N + (R270)3CH O Q- (CR 6
R
7 )q-N N I \..-0 0 R // 24 I X1 7 X1 wherein R 27 is -(CR 6
R
7 )-Q 20 The compounds of Formula 1 are formed by contacting a compound of Formula 7 with an orthoformate of Formula 24 either neat or in the presence of a suitable solvent. The reaction temperature is generally from -10 to 150 *C, preferably from 0 to 100 *C. The reaction times are generally from 0.10 to 24 h, preferably from 0.10 to 2 h. Generally, the pressure is in the range of 1.013 x 102 to 2.026 x 102 KPa; preferably ambient 25 pressure. Suitable solvents include typical organic solvents in which the reactants can be dissolved and the process can proceed without interference. Examples of such reactants include aromatics such as benzene, toluene, xylene, chlorobenzene and dichlorobenzene, ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, ethyl acetate, dichloromethane, dichloroethane, and polar aprotic solvents such as 30 dimethylformamide and dimethylsulfoxide.
WO 00/43377 PCT/USOO/01283 35 Generally at least an equimolar amount of the Formula 24 compound is used in respect to the Formula 7 compound, and preferably at least a small molar excess of Formula 24 compound is used. More particularly, the molar ratio of the Formula 7 compound to the Formula 24 compound is usually in the range of 1:1.05 to 1:10. In most cases, the molar 5 ratio of the Formula 7 compound to the Formula 24 compound is preferably in the range of 1:1.1 to 1:1.5. PROCESS SEQUENCE G Compounds of the Formula 1 can be readily prepared by one skilled in the art by using the reactions and techniques described in Steps 1 and 2. 10 STEP 1 X2 X2 X3
Q-(CR
6
R
7 )q- N N + X Q-(C6R)q N 0 aI a X 8 26 X 25 Catalyst
X
2
X
3
X
2 Q-(c 6 7)- (N6 N (N% 6
R
7 )q-Q X1 27 Step 1 forms the compounds of Formula 25 by contacting a compound of Formula 8 with a compound of Formula 26 either neat or in a suitable solvent. For Step 1, the reaction temperature is generally from -10 to 150 *C, preferably from 15 0 to 100 'C. The reaction times are generally from 0.10 to 24 h, preferably from 0.10 to 2 h. Generally, the pressure is in the range of 1.013 x 102 to 2.026 x 102 KPa; preferably ambient pressure. Suitable solvents include typical organic solvents in which the reactants can be dissolved and the process of Step 1 can proceed without interference. Examples of such reactants include aromatics such as benzene, toluene, xylene, chlorobenzene and 20 dichlorobenzene, ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, ethyl acetate, dichloromethane and dichloroethane. Generally at least an equimolar amount of the Formula 26 compound is used in respect to the Formula 8 compound, and preferably at least a small molar excess of the Formula 26 compound is used. More particularly, the molar ratio of the Formula 8 WO 00/43377 PCT/USOO/01283 36 compound to the Formula 26 compound is usually in the range of 1:1.05 to 1:10. In most cases, the molar ratio of the Formula 8 compound to the Formula 26 compound is preferably in the range of 1:1.1 to 1:1.5. In the presence of a catalyst such as hexamethylguanidinium chloride, the reaction of 5 compounds of Formula 8 and compounds of Formula 26 produces compounds of Formula 27. For general and preferred conditions, see Tet. Lett. 1987, 5823-5826. Isolation of product of Step 1 can be accomplished by standard workup procedures. STEP 2 25 + NH R2/ R I \ Base X 27 + R2/NH1 13 10 Compounds of Formula 1 are synthesized by contacting compounds of either Formula 25 or Formula 27 with amines of Formula 13 in the presence of a suitable base in a suitable solvent. For Step 2, the general and preferred reaction conditions are the same as the ones described above for Step 1 in Process Sequence A. 15 One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula 1. One skilled in the art will also recognize that it may be necessary 20 to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula 1. One skilled in the art will also recognize that compounds of Formula 1 and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify 25 existing substituents. Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following WO 00/43377 PCT/USOO/01283 37 Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. 1 H NMR spectra are reported in 5 ppm downfield from tetramethylsilane; s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, br s = broad singlet. EXAMPLE 1 Step A: Preparation of N-(2,4-dichlorophenvl)-N'-hydroxyurea 10 A solution of 14.2 g (75 mmol) of 2,4-dichlorophenylisocyanate in 50 mL of toluene was added to a mixture of 8.26 g (120 mmol) of hydroxylamine hydrochloride and 4.8 g (120 mmol) of sodium hydroxide in a two-phase solvent mixture consisting of 50 mL of water and 50 mL of toluene. The resulting mixture was stirred at 25 *C for 30 minutes and filtered. The solid thus obtained was washed with water and then dissolved in 200 mL of 15 ethyl acetate. The solution was dried over magnesium sulfate and the solvent was removed under reduced pressure to yield 12.7 g of the title compound of Step A as a white solid melting at 157-158 *C. It was used directly in the next step without further purification. Step B: Preparation of 4-(2,4-dichlorophenvl)-1,2,4-oxadiazolidine-3,5-dione A solution of 4.2 g (19 mmol) of the compound of step A in tetrahydrofuran (20 mL) 20 was treated with carbonyldiimidazole (3.2 g, 19 mmol). The mixture was stirred at 25 *C for 16 h. Some precipitated imidazole was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between IN HCl (20 mL) and ethyl acetate (50 mL). The organic layer was dried over magnesium sulfate and concentrated to an oil which solidified to give 3.8 g of the title compound of Step B as a solid melting at 104-107 25 *C. It was used directly for the next step without further purification. Step C: Preparation of 4-fluoro-N-propvlbenzenamine A 3L three neck round bottom flask equipped with a nitrogen inlet, a thermometer, an overhead stirrer and a solid addition funnel was charged with 250 mL acetic acid, 50 mL absolute ethanol and 29.5 g (0.27 mol) of 4-fluoroaniline. To this mixture was added 30 acetone (23 mL, 0.31 mol) in one portion followed by the portion-wise addition of sodium acetate trihydrate over 5 min. This vigorously stirred mixture was cooled to 0 *C (dry ice/acetone) and 4.5 g of sodium borohydride (1.2 mol) was added portion-wise via a solid addition funnel over 50 min while keeping the internal temperature below 10 *C. During this addition, acetic acid (100 mL) and absolute ethanol (50 mL) were added to facilitate 35 stirring. After the addition, the mixture was allowed to warm to room temperature, and then stirred at ambient temperature for 12 h. Sufficient ammonium hydroxide (30% aqueous) was WO 00/43377 PCT/USOO/01283 38 added to adjust the pH to -8 while maintaining the internal temperature below 30 *C using an ice/water bath. The mixture was extracted with ether (4 x 400 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, then concentrated under reduced pressure to give the desired product as a black/brown oil (38 g). 5 IH NMR: (300 MHz, CDCl 3 ) 5 6.8-6.9 (t, 2H), 6.5 (m, 2H), 3.5 (m, lH), 1.2 (d, 6H). Step D: Preparation of 4 -(fluorophenvl)propylcarbamic chloride A IL three neck round bottom flask equipped with a nitrogen inlet, a thermometer and two addition funnels was charged with 600 mL of toluene and 36.0 g (0.22 mol) of the compound of Step C. This stirred mixture was cooled to 3 *C, and then 116 mL (0.22 mol) 10 of a 20% solution of phosgene in toluene was added dropwise over 15 min while maintaining the temperature below 10 *C. Ten min after the addition, diisopropyl ethylamine (39 mL, 0.22 mol) was added dropwise over 15 min while maintaining the temperature below 7 *C. The reaction mixture was allowed to warm to room temperature and stirred for 14 hours. The resulting brown solution was flooded with CH 2 Cl 2 (700 mL), 15 and then saturated NaHCO 3 solution. The organic layer was separated and washed with saturated NaHCO 3 solution (3 x 500 mL), dried over MgSO 4 , and filtered. The solvent was removed under reduced pressure, then in vacuo, during which time the resulting oil slowly crystallized. This solid was triturated with hexanes to give 36 g (78%) of a gray solid melting at 50-55 *C. 20 1 H NMR: (300 MHz, CDCl 3 ) 8 7.1-7.2 (m, 4H), 4.68 (m, 1H), 1.1-1.2 (d, 6H). Step E: Preparation of 4-(2,4-dichlorophenvl)-N-(4-fluorophenvl)-N-(I methylethyl)-3.5-dioxo- 1.2,4-oxadiazolidine-2-carboxamide A solution of 0.6 g (2.4 mmol) of the compound of Step B in toluene (25 mL) was treated with 0.42 g (1.9 mmol) of the compound of Step D and 0.35 g (2.9 mmol) of 4 25 dimethylaminopyridine. The resulting mixture was heated at 80 *C for 1 hour, and subsequently diluted with IN hydrochloric acid (20 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with saturated brine solution (30 mL). It was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel with 85:15 hexanes-ethyl acetate as 30 eluent. Appropriate fractions were combined and concentrated to give 0.32 g of the title compound of Step E, a compound of this invention, as an oil which solidified on standing to give a solid melting at 57-60 *C. 1 H NMR (CDCl 3 ) 8 1.22 (m, 6H), 4.7 (m, IH), 7.04-7.17 (m, 2H), 7.2-7.3 (m, 3H), 7.39 (d, IH), 7.58 (s, lH). 35 EXAMPLE 2 Step A: Preparation of N-(2.6-dimethylphenvl)-N'-hydroxylurea WO 00/43377 PCT/USOO/01283 39 A 500 mL side arm flask equipped with a thermometer and an addition funnel with a nitrogen inlet was charged with 100 mL of toluene and 2.00 g (0.10 mol) of 50% hydroxylamine in water. A solution of 4.41 g of 2,6-dimethylphenyl isocyanate (0.03 mol) dissolved in 50 mL of toluene was added dropwise over 15 min. External cooling was used 5 to maintain the internal reaction temperature below 25 *C. Stirring was continued at room temp for 18 h. The solvent was removed under reduced pressure to give a white solid. The residual solvent was further co-evaporated twice with toluene, then oven dried overnight to give the desired product (5.25 g) as a white solid melting at 192-193 *C. 1 H NMR: (300 MHz, DMSO-d 6 ) 8 8.85 (d, lH), 8.58 (s, lH), 8.14 (s, lH), 7.00-7.08 10 (m, 3H), 2.15 (s, 6H). Step B: Preparation of 4-(2,6-dimethvlphenvl)-1,2,4-oxadiazolidine-3.5-dione A 300 mL flask with side arm equipped with a nitrogen inlet and a thermometer was charged with 25 mL of tetrahydrofuran followed by 5.00 g (0.0277 mol) of 2,6 dimethylphenyl hydroxyurea. To this stirred suspension was added portion-wise 4.41 g 15 (0.0277 mol) of carbonyl diimidazole over 5 min. While stirring at room temperature, the suspension turned into a solution before precipitate started to form slowly. After 18 h, the mixture was quenched with 50 mL of IN HCl which caused the suspension to turn into a solution. It was partitioned between ethyl acetate (250 mL) and IN HCI (50 mL). The organic layer was separated and washed with brine, then dried over MgSO 4 and filtered. 20 The solvent was removed under reduced pressure to give the title compound as a red oil (5.20 g) which slowly crystallized upon standing at room temperature to give a solid melting at 90-100 *C. 1 H NMR: (300 MHz, CDCl 3 ) 8 7.30 (t, lH), 7.20 (d, 2H), 2.24 (s, 6H). Step C: Preparation of 4-(2,6-dimethylphenyl)-N-(4-fluorophenvl)-N-(I -methylethvl) 25 3.5-dioxo- 1,2,4-oxadiazolidine-2-carboxamide To a 500 mL two neck round bottom flask equipped with a thermometer and a reflux condenser with nitrogen inlet was charged sequentially 30 mL of toluene, 1.50 g (0.0072 mol) of the compound of Step B, 1.60 g (0.0074 mol) of the compound of Step D in Example 1, and lastly 0.90 g of 4-dimethylaminopyridine (0.072 mol). The reaction became 30 homogeneous upon heating to 85 *C. Heating was continued at 85 *C for 2 h during which time a precipitate was formed. The reaction mixture was then cooled to room temperature, filtered and the solid was washed with toluene (2 x 25 mL). The toluene was removed under reduced pressure to give a tan solid. The product was washed with cool isopropyl alcohol (2 x 10 mL) to give 2.16 g of the title compound, a compound of the invention, as a white solid 35 melting at 134-136 *C.
WO 00/43377 PCTUSOO/01283 40 1 H NMR: (300 MHz, DMSO-d 6 ) 5 7.20-7.47 (m, 7H), 4.52-4.65 (m, 1H), 2.03 (s, 6H). EXAMPLE 3 Step A: Preparation of 4-(2-propenvl)-1,2,4-oxadiazolidine-3,5-dione 5 To a 500 mL round-bottom flask were added acetone (300 mL), allyl isocyanate (12.0 g, 0.145 mol), N-hydroxyurethane (6.1 g, 0.058 mol) and triethylamine (11.7 g, 0.116 mol) respectively at room temperature under nitrogen with efficient stirring. The reaction mixture was allowed to stir at room temperature for 6 d. The solvent was removed under reduced pressure. The residue was suspended in 100 mL of IN HCl, extracted with ethyl 10 acetate (3 x 150 mL). The organic solution was washed with water, brine, dried over MgSO 4 and concentrated to a clear yellow oil. The crude product was dried under high vacuum for 4 h to give the title compound as an oil (13.1 g) which was used in the next step without further purification. IH NMR: (300 MHz, CDCl 3 ) 8: 5.87 (m, 1H), 5.27 (m, 2H), 4.17 (m, 1H), 3.82 15 (bs, 1H). Step B: Preparation of N-(4-fluorophenvl)-N-(1 -methylethvl)-3,5-dioxo-4-(2 propenyl)-1,2,4-oxadiazolidine-2-carboxamide A dry 100 mL round-bottom flask was changed with dry tetrahydrofuran (20 mL), the compound of step A (1.0 g, 7.0 mmol), the compound of Step D in Example 1 (1.5 g, 7.0 20 mmol), triethylamine (1.0 g, 10.0 mmol) and 4-dimethylaminopyridine (0.2 g, 1.6 mmol) respectively at room temperature under nitrogen atmosphere with stirring. The reaction mixture was heated at reflux for 1.5 h during which time a white solid precipitated out. The reaction mixture was cooled to room temperature and diluted with 150 mL of ethyl acetate. The organic layer was washed with IN HCl, water, brine, and dried over MgSO 4 . Upon 25 concentration, a yellow syrup (1.8 g) was obtained. The crude product was purified by flash chromatography on silica gel with ethyl acetate/hexanes 1:9 as eluent to provide 1.22 g of the title compound, a compound of the invention, as a white solid melting at 65-66 *C. 1 H NMR: (300 MHz, CDCl 3 ) 8 7.22 (m, 2H), 7.11 (m, 2H), 5.78 (m, 1H), 5.26 (m, 2H), 4.42 (m, 1H), 4.07 (d, 2H), 1.20 (d, 6H). 0 EXAMPLE 4 Step A: Preparation of phenylhydroxvcarbamate To a stirred solution of NaHCO 3 (60.5 g) in water (200 mL) in a 2 L beaker was added portion-wise over 15 min 27.5 g of hydroxylamine hydrochloride. Once the bubbling subsided, dichloromethane (200 mL) was added to the reaction mixture and cooled to 5 *C. 5 Phenyl chloroformate (50 g) was then added at a steady rate to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. Ethyl acetate WO 00/43377 PCT/USOO/01283 41 (100 mL) was employed to bring the reaction mixture to a transparent solution. The organic layer was separated, washed with brine (200 mL) and dried over MgSO 4 . The organic solvent was removed under reduced pressure to give the title compound (38.20 g) as a white solid melting at 104-107 *C. 5 Step B: Preparation of N-hydroxv-2.2-dimethvlhvdrazinecarboxamide To a solution of 37.3 g of the compound of Step A in tetrahydrofuran (200 mL) at room temperature under nitrogen was added 22 mL of 1,1 -dimethylhydrazine. The reaction mixture was then heated at reflux overnight. The solvent was removed under reduced pressure to afford an oil which was purified by column chromatography with 9:1 ethyl 10 acetate-methanol as eluent to give a semi-solid. Triturating of the residue with dichloromethane gave the title compound (7.25 g) as a white solid melting at 115-118 *C. 1 H NMR (DMSO-d 6 ) 5 8.5 (brs, 1H), 8.27 (brs, lH), 7.4 (brs, lH), 2.4 (s, 6H). Step C: Preparation of 4-(dimethylamino)- 1,2,4-oxadiazolinedine-3,5-dione The compound of Step B (4.25 g, 29 mmol) was suspended in tetrahydrofuran 15 (25 mL) at 5 *C under nitrogen. To the mixture was added portion-wise 1,1' carbonyldiimidazole (5.78 g, 29 mmol) while maintaining the reaction temperature under 10 *C. The reaction was partitioned between ethyl acetate (125 mL) and IN HCl (60 mL). The organic layer was separated. The aqueous layer was further extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over MgSO 4 and concentrated under 20 reduced pressure to afford the title compound as an oil (2.9 g). 1 H NMR (CDCl 3 ) 5 5.1 (br s, 1H), 2.9 (s, 6H). Step D: Preparation of 4-(dimethvlamino)-N-(4-fluorophenvl)-N-(1-methylethyl) 3,5-dioxo-1,2,4-oxadiazolidine-2-carboxamide The compound of Step D, Example 1 (1.48 g, 6.9 mmol), 4-dimethylaminopyridine 25 (0.84 g, 6.9 mmol), and the compound of Step C (1.00 g, 6.9 mmol) were combined in toluene (25 mL) at room temperature. The reaction mixture was heated to 80 *C for 3 h. Acetonitrile (20 mL) and silica gel (5 g) were added and the solvent was removed under reduced pressure. After column chromatography with 8:2 hexanes-ethyl acetate as eluent, the title compound, a compound of the invention, was isolated as a white solid (1.23 g) 30 melting at 69-71 *C. 1H NMR (CDCl 3 ) 5 7.2 (m, 2H), 7.1 (m, 2H), 4.6 (m, 1H), 2.9 (s, 6H), 1.2 (d, 6H). EXAMPLE 5 Step A: Preparation of 4-[(2-methvlphenvl)methyll-3-(phenylimethoxy)-1.2.4 oxadiazol-5(4H)-one 35 A 50 mL round bottom flask equipped with a thermometer, a stirrer, and a nitrogen inlet was charged with 3-(phenylmethoxy)-1,2,4-oxadiazol-5(4H)-one (Synthesis, (1991), WO 00/43377 PCT/USOO/01283 42 265 0.5 g, 2.6 mmol), potassium carbonate (0.5 g, 3.6 mmol), tetrabutylammonium bromide (0.022 g, 0.1 mmol), 2-methylbenzyl bromide (0.6 g, 3.2 mmol) and acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into water (25 mL) and extracted with dichloromethane (3 x 20 mL), dried over 5 MgSO 4 and concentrated under reduced pressure to provide a solid. The solid was further purified by flash chromatography on silica gel using 9:1 hexane-ethyl acetate to provide 0.3 g (40%) of the title compound as a white solid melting at 77-78 *C. 1 H NMR (CDCl 3 ): 8 7.39 (m, 3H), 7.27 (m, 3H), 7.17 (m, 3H), 5.26 (s, 2H), 4.69 (s, 211), 2.31 (s, 3H). 10 Step B: Preparation of N-(4-chlorophenvl)-N-(1 -methylethyl)-4-[(2 methylphenyl)methyll-3,5-dioxo-1,2,4-oxadiazolidine-2-carboxamide A 50 mL round bottom flask equipped with a stirrer, a thermometer, and a nitrogen inlet was charged with the compound of Step A (0.6 g, 2.05 mmol), (4-chlorophenyl)(1 methylethyl)carbamic chloride (0.5 g, 2.155 mmol), N, N'-dimethylaminopyridine (0.26 g, 15 2.13 mmol) and tetrahydrofuran (20 mL). The mixture was heated to reflux for 3 hours, then cooled to room temperature and poured into IN HCl (50 mL). The mixture was extracted with diethyl ether (3 x 25 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure to provide a thick oil. The oil was purified by flash chromatography on silica gel using 9:1 hexane-ethyl acetate to provide 0.22 g (28%) of the title compound as 20 a white solid melting at 90-91 *C. 1 H NMR (CDCl 3 ): S 7.5-7.0 (m, 8H), 4.63 (s, 2H), 4.6 (m, 1H), 2.36 (s, 3H), 1.18 (d, 6H). EXAMPLE 6 Step A: Preparation of 4-methyl-3-(phenvLmethoxv)-1,2,4-oxadiazol-5(4H)-one 25 A 50 mL round bottom flask equipped with a thermometer, a stirrer and a nitrogen inlet was charged with 3-(phenylmethoxy)-1,2,4-oxadiazol-5(4H)-one (1 g, 5.2 mmol), iodomethane (0.916 g, 6.5 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (1 g, 6.5 mmol) and acetonitrile (10 mL). The mixture was stirred at room temperature for 18 h. The entire reaction mixture was flash chromatographed (silica gel, 8:2 hexane-ethyl acetate) to provide 30 1 g (37.5%) of the title compound as a white solid melting at 80-83 *C. 1H NMR (CDCl 3 ): 8 7.43 (m, 5H), 5.32 (s, 2H), 3.09 (s, 3H). Step B: Preparation of N-(4-fluorophenvl)-4-methyl-N-(1 -methylethyl)-3,5-dioxo 1.2.4-oxadiazolidine-2-carboxamide A 50 mL round bottom flask equipped with a thermometer, a stirrer and a nitrogen inlet 35 was charged with 4-methyl-3-(phenylmethoxy)-1,2,4-oxadiazol-5(4H)-one (0.55 g, 2.66 mmol), (4-fluorophenyl)(1-methylethyl)carbamic chloride (0.581 g, 2.7 mmol), WO 00/43377 PCT/USOO/01283 43 N, N'-dimethylaminopyridine (0.329 g, 2.7 mmol) and acetonitrile (10 mL). The reaction mixture was heated to reflux 2 h, and allowed to cool to room temperature. The entire mixture was flash chromatographed (silica gel, 9:1, then 8:2 hexane-ethyl acetate) to provide 0.6 g (76%) of the title compound as a white solid melting at 135-136 *C. 5 1 H NMR (CDCl 3 ) 8 7.29 (m, 2H), 7.11 (m, 2H), 4.64 (m, 1H), 3.05 (s, 3H), 1.18 (d, 6H). EXAMPLE 7 Step A: Preparation of N-(4-chlorophenvl)-4-methyl-N-(1-methylethvl)-3,5-dioxo 1.2.4-oxadiazolidine-2-carboxamide 10 A 50 mL round bottom flask, equipped with a thermometer, a stirrer and nitrogen inlet was charged with 3-(phenylmethoxy)-1,2,4-oxadiazol-5(4H)-one (0.5 g, 2.6 mmol), 1,8-diazabicyclo[5.4.0]unded-7-ene (0.5 g, 3.28 mmol), iodomethane (0.5 g, 3.54 mmol) and acetonitrile (5 mL). The mixture was stirred at room temperature for 18 h. To the mixture was added (4-chlorophenyl)(1 -methylethyl)carbamic chloride (0.7 g, 3 mmol) and N, 15 N'-dimethylamino-pyridine (0.367 g, 3 mmol), and the resulting mixture was heated to reflux for 2 h. It was then cooled to room temperature and flash chromatographed (silica gel, 9:1 hexane-ethyl acetate) to provide 150 mg (18 %) of the title compound as a white solid melting at 121-123 *C. 1 H NMR (CDCl 3 ): 5 7.36 (m, 2H), 7.2 (m, 2H), 4.6 (m, 1H), 3.05 (s, 3H), 1.21 (d, 20 6H). EXAMPLE 8 Step A: Preparation of 4-(2-methylpropvl)-3-(phenvimethoxv)-1.2,4-oxadiazol-5(4H) one A 50 mL round bottom flask equipped with a thermometer, a stirrer, addition funnel 25 and nitrogen inlet was charged with 3-(phenylmethoxy)-1,2,4-oxadiazol-5(4H)-one (1 g, 5.2 mmol), 2-methyl propanol (0.45 g, 6 mmol), triphenylphosphine (1.57 g, 6 mmol) and tetrahydrofuran (5 mL). The mixture was cooled to 0 *C and a solution of diethyl azodicarboxylate (1.04 g, 6 mmol) in tetrahydrofuran (2 mL) was added dropwise over a period of 10 min. The reaction mixture was allowed to warm to room temperature, and 30 stirred for 18 h. The entire mixture was flash chromatographed (silica gel, 8:2 hexane-ethyl acetate) to provide 1.1 g (84 %) of the title compound as a white solid melting at 53-60 *C. 1 H NMR (CDCl 3 ): 8 7.42 (m, 5H), 5.31 (s, 2H), 3.34 (d, 2H), 2.01 (m, 1H), 0.897 (d, 6H). Step B: Preparation of N-(4-fluorophenvl)-N-(1-methylethyl)-4-(2-methylpropyl)-3.5 35 dioxo-1,2,4-oxadiazolidine-2-carboxamide WO 00/43377 PCT/USOO/01283 44 A 50 mL round bottom flask equipped with a stirrer, a thermometer and a nitrogen inlet was charged with 4-(2-methylpropyl)-3-(phenylmethoxy)-1,2,4-oxadiazol-5(4H)-one (0.25 g, I mmol), (4-fluorophenyl)(1-methylethyl)carbamic chloride (0.24 g, 1.1 mmol), N, N'-dimethylaminopyridine (0.14 g, 1.1 mmol) and acetonitrile (10 mL). The mixture was 5 heated to reflux for 2 h and allowed to cool to room temperature. The entire mixture was flashed chromatographed (silica gel, 9:1 hexane-ethyl acetate) to provide 0.18 (53 %) of the title compound as a white solid melting at 80-81 *C. 1 H NMR (CDCl 3 ): 8 7.24 (m, 2H), 7.11 (m, 2H), 4.65 (m, 1H), 3.29 (d, 2H), 2.0 (m, 1H), 1.2 (d, 6H), 0.89 (d, 6H). 10 EXAMPLE 9 Step A: Preparation of N-(4-fluorophenvl)-N-(1 -methylethy)-3,5-dioxo-4 (phenvlmethyl)- 1,2,4-oxadiazolidine-2-carboxamide A 50 mL round bottom flask equipped with a thermometer, a stirrer and a nitrogen inlet was charged with 3-(phenylmethoxy)-1,2,4-oxadiazol-5(4H)-one (0.5 g, 2.6 mmol), 15 (4-fluorophenyl)(1-methylethyl)carbamic chloride (0.58 g, 27 mmol), N, N'-dimethylaminopyridine (0.33 g, 2.7 mmol) and acetonitrile (5 mL). The mixture was heated to reflux for 3 h and allowed to cool to room temperature. The mixture was flash chromatographed (silica gel, 9:1 hexane-ethyl acetate) to provide 0.24 g (25 %) of the title compound as a white solid melting at 95-96 *C. 20 1 H NMR (CDCl 3 ): 8 7.22 (s, 5H), 7.2 (m, 2H), 7.06 (m, 2H), 4.6 (m, 1H), 4.59 (s, 2H), 1.17 (d, 6H). EXAMPLE 10 Step A: Preparation of N-(4-fluorophenvl)-N-(1 -methylethyl)-3,5-dioxo- 1,2.4 oxadiazolidine-2-carboxamide and N-(4-fluorop~henyl)-4-methyl-N-( 1 25 methylethvl)-3,5-dioxo-1,2,4-oxadiazolidine-2-carboxamide A 50 mL round bottom flask equipped with a thermometer, a stirrer and nitrogen inlet was charged with 3-methoxy-1,2,4-oxadiazol-5(4H)-one (1.16 g, 0.01 m), (4 fluorophenyl)(1-methylethyl)carbamic chloride (2.4 g, 0.011 m), N, N'-dimethylaminopyridine (1.35 g, 0.011 m) and acetonitrile (20 mL). The mixture was 30 heated to reflux for 18 h. The mixture was allowed to cool to room temperature, poured into IN HCl (20 mL) and extracted with ethyl acetate (3 x 25 mL). The organic phase was dried over MgSO 4 and concentrated under reduced pressure to provide a thick oil. The oil was flash chromatographed (silica gel, 7:3 dichloromethane-ethyl acetate) to provide two fractions. Fraction A contained 0.42 g (15%) of N-(4-fluorophenyl)-4-methyl-N-(1 35 methylethyl)-3,5-dioxo-1,2,4-oxadiazolidine-2-carboxamide as a white solid melting at 135-136 *C. 1 H NMR (CDCl 3 ): 8 7.26 (m, 2H), 7.11 (m, 2H), 4.6 (m, 1H), 3.05 (s, 3H), WO 00/43377 PCT/USOO/01283 45 1.17 (m, 6H). Fraction B contained 1.1 g (40 %) of N-(4-fluorophenyl)-N-(1-methylethyl) 3 ,5-dioxo-1,2,4-oxadiazolidine-2-carboxamide as a solid melting at 55-60 *C. IH NMR (CDCl 3 ): 8 7.24 (m, 2H), 7.19 (m, 2H), 4.6 (m, 1H), 1.2 (d, 6H). IR
(CH
2 Cl 2 ); 3200, 3300, 1776, 1715 cm- 1 . MS (M + 1): 281, 257. 5 Stp B: Preparation of N-(4-fluorophenvl)-N-(1 -methylethyl)-4-(2-methylpropyl)-3.5 dioxo-1,2 ,4 -oxadiazolidine-2-carboxamide A 50 mL round bottom flask equipped with a thermometer, a stirrer, an addition funnel, and a nitrogen inlet was charged with N-(4-fluorophenyl)-N-(1-methylethyl)-3,5 dioxo-1,2,4-oxadiazolidine-2-carboxamide (5.5 g, 0.019 m), 2-methyl-1-propanol (3 g, 0.04 10 mol), triphenylphosphine (6.3 g, 0.021 mol) and tetrahydrofuran (60 mL). The reaction solution was cooled to 15 *C and diethyl azodicarboxylate (4.2 g, 0.024 mol) in tetrahydrofuran (10 mL) was added dropwise over a period of 10 min. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was flash chromatographed (silica gel, 9:1 hexane-ethyl acetate) to provide 15 the title compound as a white solid (5.6 g, 88%). The solid has a melting range of 80-81 *C, and was identical to the material prepared in Example 8, Step B. EXAMPLE 11 Step A: Preparation of methyl (chlorocarbonvl)(2.6-dimethylphenvl)carbamate A mixture of toluene (150 mL), biphenyl (0.2 g) and sodium methoxide in methanol 20 (23.76 g, 0.11 mol, 25% by weight) was heated at reflux, and the methanol-toluene azeotrope was removed. The mixture was allowed to cool to 80 *C, and toluene (80 mL) was added. To the resulting mixture was added in five portions methyl (2,6 dimethylphenyl)carbamate (17.9 g, 0.1 mol). The methanol formed in the reaction was removed as the above azeotrope. When most of the methanol had been removed, ethylene 25 glycol dimethyl ether (8 mL) was added, and the mixture was distilled until the head temperature reached 110 *C. The mixture was allowed to cool to 25 *C, and ethylene glycol dimethyl ether (3 mL) was added. The mixture was then added to phosgene in toluene (22.5 g, 0.56 mol, 25% by weight). When the addition was complete, excess phosgene was removed by distillation. The mixture was allowed to cool to 25 *C, and then washed with 30 sodium bicarbonate solution (40 mL, saturated). The organic layer was dried and the volatiles removed by evaporation to give 17.21 g (64.5%) of the title compound as a solid. An analytical sample was prepared by column chromatography on silica gel using 1:3 ethyl acetate-hexanes as the eluent. M.P. 84.5-86 *C; IR (Nujol): 1814, 1437, 1252, 1229, 1209, 1182, 1013, 982, 845 35 cm-1; IH NMR (CDCl 3 ): 5 7.28-7.12 (m, 3H), 3.82 (s, 3H), 2.23 (s, 6H).
WO 00/43377 PCTIUSOO/01283 46 Step B: Preparation of 4-(2.6-dimethvlphenvl)-2-methyl-1,2,4-oxadiazolidine-3.5 dione A portion of the compound from Step A (3.72 g, 15.4 mmol) in dioxane (15 mL) was added to a mixture of aqueous hydroxylamine (2.03 g, 30.7 mmol, 50% by weight) in 5 dioxane (15 mL). When the addition was complete, a solution of potassium hydroxide (2.22 g, 33.6 mmol, 85 %) in water (5 mL) was added dropwise to the mixture so that the temperature did not rise beyond 30 *C. When the addition was complete, the solvent was removed until the volume was reduced to about 5 mL. The mixture was poured into water (100 mL), and the aqueous mixture was extracted with ethyl acetate (2 x 50 mL). The 10 aqueous mixture was acidified with HCI and further extracted with ethyl acetate (2 x 50 mL). The combined organic extracts from the second extraction were dried and evaporated to give the title compound as a solid (2.34 g, 73.7%). The solid has a melting point range of 92-93.5 *C after crystallization from ether/hexanes, and was identical to material prepared in Example 2, Step B. 15 EXAMPLE 12 Step A: Preparation of N'-hydroxv-N-(1-methvlethyl)-N-phenvlurea A solution of 50% aqueous hydroxylamine (16.8 g, 0.25 mol) was added dropwise to a solution of (I-methylethyl)phenylcarbamic chloride (20.0 g, 0.1 mol) in 200 mL of THF in an ice bath so that the reaction temperature was kept below 30 *C. Precipitate began to form 20 halfway through the addition. The resulting slurry was stirred overnight. The mixture was filtered, and the solids collected were first washed with water and then with hexane/ether. After air-drying, 14.56 g of the title compound was obtained. Its structure was confirmed by an analysis of the NMR spectra. The filtrate was stripped down to afford a residue which was washed sequentially with IN HC, water and hexane/ether to yield a second crop of the 25 title compound (5.38 g) melting at 165-166 *C. The combined yield was 100%. IH NMR (300 MHz, DMSO-d 6 ): 5 8.10 (br s, IH), 7.74 (s, 1H), 7.38 (m, 3H), 7.12 (m, 2H), 4.55 (m, 1H), 0.97 (d, 6H) Step B: Preparation of N-( 1-methylethyl)-3,5-dioxo-N-phenvl- 1,2,4-oxadiazolidine-2 carboxamide 30 A solution of chlorocarbonyl isocyanate (5.0 g, 0.047 mol) was added dropwise to a slurry of the title compound of Step A (9.2 g, 0.047 mol) and triethylamine (5.3 g, 0.052 mol) in 200 mL of THF while maintaining the reaction temperature below 30 *C using an ice bath. After 2 hours, TLC showed the presence of starting material. Another 0.5 g of chlorocarbonyl isocyanate was added, and the reaction mixture was stirred for another hour. 35 At that point, TLC showed still the presence of starting material. The reaction mixture was filtered to remove solids, and the filtrate was stripped to dryness and then extracted with IN WO 00/43377 PCT/USOO/01283 47 HCl and ether. Upon evaporation of volatiles, a gummy product was obtained which was taken into methylene chloride and potassium carbonate solution. Solids were collected by a filtration, washed with methylene chloride and air dried. The solids (5.3 g) were found to be the potassium salt of the title compound. The basic aqueous filtrate was acidified with 5 concentrated HC1 and extracted with methylene chloride to afford 4 g of the title compound, an intermediate useful for the preparation of the compounds of the present invention, melting at 116-7 *C. From the methylene chloride used to wash the solids, 2.6 g of the title compound of Step A was recovered. This represented a 71.7% conversion. The combined yield was therefore 96% based on the 71.7% conversion. 10 1 H NMR (300 MHz, DMSO-d 6 ): 5 9.60 (brs, 1H), 7.37 (m, 3H), 7.23 (m, 2H), 4.60 (m, 1H), 1.19 (d, 6H). EXAMPLE 13 Step A: Preparation of N-(4-fluorophenvl)-N-(1 -methylethyl)-3,5-dioxo- 1,2,4 oxadiazolidine-2-carboxamide 15 A 1 L three neck round bottom flask equipped with nitrogen inlet, thermometer and water condenser was charged with dioxanes (400 mL), 1,2,4-oxadiazole-3,5-dione (30 g 0.29 moles, prepared according to Srivastava, P. and Robins, R., J. Med. Chem. 1981, 24, 1172 1177), 4-dimethylaminopyridine (36 g, 0.29 mole), and N-isopropyl-4 flourophenylcarbamoyl chloride (63 g, 0.29 moles) at room temperature. The yellow 20 mixture was heated at reflux for 4 hours. When no starting material was detected by thin layer chromatography, heat was tuned off and mixture was cooled to room temperature. The solvent was removed under reduced pressure and the resulting solids were suspended in ethyl acetate. The mixture was washed with IN HCl, and the aqueous layer was extracted twice with ethyl acetate. The combined organic solutions were washed with brine, dried 25 over anhydrous magnesium sulfate, and concentrated under reduced pressure. The product was crystallized from chlorobutane and hexanes, and filtered to give 47 g (57%) of the title compound as a white solid melting at 94-95 *C. 'H NMR: (300 MHz, CDCl 3 ) 8 7.24 (m, 2H), 7.09 (m, 2H), 4.63 (m, IH), 1.18 (d, 6H). Step B: Preparation of N-(4-fluorophenvl)-N4-bis(1 -methylethyl)-3,5-dioxo- 1.2.4 30 oxadiazolidine-2-carboxamide A solution of the compound of Step A (1.0 g, 3.6 mmol) in 20 mL of triisopropylorthoformate was heated at 145 *C for 2 h and then allowed to stir at ambient temperature overnight. The volatiles were removed under reduced pressure, and the residue recrystallized from methanol to give 0.99 g (86%) of the title compound, a compound of this 35 invention, as a solid melting at 78-80 *C.
WO 00/43377 PCTIUSOO/01283 48 IH NMR (300 MHz, CDCl 3 ): a 7.26(m, 2H), 7.1 1(m, 2H), 4.62(m, 1H), 4.18(m, 1H), 1.40(d, 6H), 1.20(d, 6H). EXAMPLE 14 Step A: Preparation of 2.2'-carbonylbisr4-(1-methylethyl)-1,2,4-oxadiazolidine-3.5 5 dionel To a solution of 4 -(1-methylethyl)-1,2,4-oxadiazolidine-3,5-dione (20 g, 139 mmol) and hexamethylguanidinium chloride (0.25 g, 1.39 mmol) in 150 mL of toluene was added phosgene (6.88 g, 69 mmol, 20% by weight in toluene). The resulting mixture was heated at reflux for 1.5 h with the use of a dry ice/acetone condenser. The volatiles were removed 10 under reduced pressure, and the residue recrystallized from 150 mL of n-BuCI to give 14 g (64%) of the title compound as a white solid melting at 150 *C. IH NMR (300 MHz, CDCl 3 ): a 1.52 (d, 6H), 4.36 (m, 1H). Step B: Preparation of N4-bis(1 -methylethyl)-3,5-dioxo-N-phenvl- 1.2.4 oxadiazolidine-2-carboxamide 15 A solution of the compound of Step A (0.5 g, 1.6 mmol), N-phenyl-N-(2 methylethyl)amine (0.215 g, 1.6 mmol) and 4- dimethylaminopyridine (0.19 g, 1.6 mmol) in 10 mL of acetonitrile was heated at reflux under a nitrogen atmosphere. The resulting mixture was allowed to cool to ambient temperature and poured into 25 mL of water. It was then extracted with ethylacetate (4 x 25 mL). Condensation gave an oil which was purified 20 by flash chromatography using 1:3 EtOAc-Hexanes as the eluant to give the title compound, a compound of this invention, as a white solid melting at 83-84 *C. IH NMR (300 MHz, CDCI 3 ): 8 1.20 (d, 6H), 1.38 (d, 6H), 4.16 (m, IH), 4.63 (m, lH), 7.26 (m, 2H), 7.39 (m, 3H). EXAMPLE 15 25 Sten A: N-(4-fluorophenyl)-4-(methoxvmethyl)-N-(1-methylethyl)-3,5-dioxo-1,2,4 oxadiazolidine-2-carboxamide To a solution of 308 uL of bromomethyl methyl ether (1 eq, 90% tech.) in 8 mL dry acetonitrile was added 995 mg of the title compound of Step A in Example 13. To this mixture was then addede 508 uL (1 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The 30 resulting solution was heated at reflux under a nitrogen atomsphere for 3 h. The reaction mixture was allowed to cool to room temperature and the volatiles removed under reduced pressure. The residue was dissolved in 1 mL of dichloromethane and loaded onto a 70 mL solid phase extraction (SPE) cartridge containing 10 g of silica gel (230-400 mesh). The title compound (260 mg), a compound of this invention, was obtained after elution using a 20% 35 ethyl acetate/hexane solution.
WO 00/43377 PCT/USOO/01283 49 IH NMR (300 MHz, CDCl 3 ): 6 7.22(m, 2H),7.09 (m, 2H), 4.89 (s, 2H), 4.65 (m, lH), 3.39 (s, 3H), 1.2 (d, 6H). By the procedures described herein together with methods known in the art, the following compounds of Tables 1 to 3 can be prepared. The following notations have been 5 used in Tables. Q-1 Ph Q-36 2-SCH 3 -Ph Q-2 2-Cl-Ph Q-37 2-Me-6-(i-Pr)-Ph Q-3 3-Cl-Ph Q-38 2-Cl-4-Me-Ph Q-4 4-Cl-Ph Q-39 2-CN-Ph Q-5 2-Br-Ph Q-40 4-Cl-2-Me-Ph Q-6 2-F-Ph Q-41 2-CI-6-Me-Ph Q-76 2,4-di-F-Ph Q-42 2-Me-5-Cl-Ph Q-8 2,6-di-F-Ph Q-43 2-Cl-5-Me-Ph Q-9 2,3-di-Cl-Ph Q-44 2-Cl-3-Me-Ph Q-10 2,4-di-Cl-Ph Q-45 2-NO 2 -Ph Q-1 I 2,6-di-Cl-Ph Q-46 1-tetrahydronaphthyl Q-12 2,6-di-Et-Ph Q-47 4-(2,3-dihydro-1H-indene) Q-13 2,6-di-OMe Q-48 7-(2,3-diH-2,2-di-Me-7-benzofuran) Q-14 2-C-4-F-Ph Q-49 2-Vinyl-Ph Q-15 2-Cl-6-F-Ph Q-50 2-Ph-Ph Q-16 2-Me-Ph Q-51 1-(2-Me-tetrahydronaphthyl) Q-17 3-Me-Ph Q-52 3-(2-Cl-Pyridine) Q-18 4-Me-Ph Q-53 4,6-di-Me-Pyrimidin-5-yl Q-19 2-Et-Ph Q-54 4,6-di-OMe-Pyrimidin-5-yl Q-20 2-Pr-Ph Q-55 PhCH 2 Q-21 2,5-di-Me-Ph Q-56 PhC(CH 3
)
Q-22 4-OMe-Ph Q-57 (2-CI-Ph)CH 2 Q-23 2-C1-6-Me-Ph Q-58 (2,6-di-Cl-Ph)CH 2 Q-24 2,6-di-Me-Ph Q-59 (2,3-di-Cl-Ph)CH 2 Q-25 2,4-di-Me-Ph Q-60 (2-Me-Ph)CH 2 Q-26 2,5-di-Me-Ph Q-61 (2-OCH 3 -Ph)CH 2 Q-27 2,3-di-Me-Ph Q-62 (2,4-di-Cl-Ph)CH 2 Q-28 2-Me-6-Et-Ph Q-63 (2-CF 3 -Ph)CH 2 Q-29 2-CF 3 -Ph Q-64 (2-OCF 3 -Ph)CH 2
-
WO 00/43377 PCTIUSOO/01283 50 Q-30 4-CF 3 -Ph Q-65 (2-CN-Ph)CH 2 Q-31 2-OCF 2 H-Ph Q-66 (2-Cl-Ph)CH(CH 3
)
Q-32 2-OCF 3 -Ph Q-67 (2-Me-Ph)CH(CH 3
)
Q-33 2,4,6-tri-Me-Ph Q-68 PhCH 2
CH
2 Q-34 4-CI-2,6-di-Me-Ph Q-69 (2-C1-Ph)CH 2
CH
2 Q-35 2-OPh-Ph Q-70 (2-Me-Ph)CH 2
CH
2 H 3 H 3 H 3 Gil C 3
C
2
H
5 / G\N, l 3 Q-71I Q-72 Q-73 Q-74
CH
3
H
3 H3 H 3 al / N_ \ / N\ 1o \ 1 ~s Hss Q-75 Q-76 Q-77 Q-78 Cf! 3
H
3 abl H 3
H
3 CA% s
CH
3 NN a Q-79 CHn 3 II Q-80 CL- 3 CHt 3 Q-81 Q-82 a
H
3 Cf! 3 Q-84 Q-85 Q-86 Q-83 / \CH 3
H
3 aQ-88 H3 Q-87 Q-89 Q-90 WO 00/43377 PCTIUSOO/01283 51 H3 a / \- l / Q-91 Q-92 S Q-93 Q-94 Q-95 n-Pr Q-121 c-Butyl Q-96 n-Bu Q- 122 EtC(Me) 2 Q-97 i-Bu - Q-123 CF 3
CH
2 Q-98 n-hex Q-124 4-(1-Butenyl) Q-99 c-Pr Q-125 3-Me-Propargyl Q-100 Allyl Q-126 1-(3-Me-1-Propenyl) Q-101 Propargyl Q-127
NCCH
2 Q-102 3-(2-Cl-Propenyl) Q-128 (i-C 3
H
7 )0 Q-103 Cyclohexyl Q-129 (Allyl)O Q-104 1-cyclohexenyl Q-130 (Me) 2
N
Q- 105 2-Me-i -cyclohexenyl Q-13 1 1-piperidino Q-106 MeOCH 2
CH
2 - Q-132 Me0 2
S
Q-107 MeOCH 2 - Q-133 MeSCH 2
CH
2 Q-108 3-Cl-Pr Q-134 Me 2 NS(0) 2 Q- 109 4-( 1, -di-F-butenyl) Q- 135 0 2
NCH
2 Q-1 10 3-(1, 1-di-Cl-propenyl) Q-136 MeC(=O) Q-1 11 i-Pr Q-137 (i-Pr)OC(=O) Q-1 12 2-OMe-Ph Q-138 EtOC(=O) Q-1 13 2-Me-6-OMe-Ph Q-139 Me 2
NC(=O)
Q-1 14 2-Ci-Et Q-140 EtOC(=O)CH 2 Q-1 15 3-(2-Me-Propenyl) Q-141 (MeO) 2
P(=-O)CH
2 Q-1 16 t-Bu Q-142 Me 2
NC(=O)CH
2 Q-1 17 MeC(=NOMe)CH 2 - Q-143 2-(Tetrahydropyranyl) Q-1 18 2-Me-(c-Hex) Q-144 (Oxirane)-CH 2 Q-119 Et Q-120 c-Pentyl ______________________ WO 00/43377 PCT/USOO/01283 52
H
3 C Q-145 Q-146 Q-148 Q-147 K N Oa Q-150 Q-149 Q-151 Q-152
CF
3
F
3 C H 3 C CF3 Q-153 Q-154 Q-155 Q-156 Q-157 Me 2
NCH
2
CH
2 - Q-167 2-(SF 5 )-Ph Q-158 Me 2
NCH
2 - Q-168 1-(Morpholino) Q-159 Me 3 SiCH 2 - Q-169 EtCH(Me) Q-160 Me 2 NC(=S)- Q-170 Me 3
CCH
2 Q-161 3-oxetanyl Q-171 (Et) 2
N
Q-162 NCCH 2
CH
2 Q-172 MeS Q-163 MeOC(=O)CH(CH 3 )- Q-173 MeSC(=S) Q-164 MeOC(=O)CH(i-Pr)- Q-174 4-(2-Butynyl) Q-165 MeNH Q-175 F 3
CS
Q-166 2-(NMe 2 )-Ph
I
WO 00/43377 PCT/USOO/01283 53 0 0 B-1 B-2 B-3 B-4
CH
3 B-6
,CH
3 B-5 B-7 B-8 i-C 3 H-j C 2
H
5 06 B-1 IB-12 B-9 B-10 co) N B-13 B-14 B-15 B-16 Allyl Propargyl B-17 B-18 TABLE 1 ~42 0 WO 00/43377 PCT/USOO/01283 54 R2 is i-C3H7, R 1 3 is 4-F Q Q Q Q Q Q Q Q Q Q-1 Q-2 Q-3 Q-4 Q-5 Q-6 Q-7 Q-8 Q-9 Q-10 Q-11 Q-12 Q-13 Q-14 Q-15 Q-16 Q-17 Q-18 Q-19 Q-20 Q-21 Q-22 Q-23 Q-24 Q-25 Q-26 Q-27 Q-28 Q-29 Q-30 Q-31 Q-32 Q-33 Q-34 Q-35 Q-36 Q-37 Q-38 Q-39 Q-40 Q-41 Q-42 Q-43 Q-44 Q-45 Q-46 Q-47 Q-48 Q-49 Q-50 Q-51 Q-52 Q-53 Q-54 Q-55 Q-56 Q-57 Q-58 Q-59 Q-60 Q-61 Q-62 Q-63 Q-64 Q-65 Q-66 Q-67 Q-68 Q-69 Q-70 Q-71 Q-72 Q-73 Q-74 Q-75 Q-76 Q-77 Q-78 Q-79 Q-80 Q-81 Q-82 Q-83 Q-84 Q-85 Q-86 Q-87 Q-88 Q-89 Q-90 Q-91 Q-92 Q-93 Q-94 Q-95 Q-96 Q-97 Q-98 Q-99 Q-100 Q-101 Q-102 Q-103 Q-104 Q-105 Q-106 Q-107 Q-108 Q-109 Q-110 Q-111 Q-112 Q-113 Q-114 Q-115 Q-116 Q-117 0-118 Q-119 Q-120 Q-121 Q-122 Q-123 Q-124 Q-125 Q-126 Q-127 Q-128 Q-129 Q-130 Q-131 Q-132 Q-133 Q-134 Q-135 Q-136 Q-137 Q-138 Q-139 Q-140 Q-141 Q-142 Q-143 Q-144 Q-145 Q-146 Q-147 Q-148 Q-149 Q-150 Q-151 Q-152 Q-153 Q-154 Q-155 Q-156 Q-157 Q-158 Q-159 Q-160 Q-161 Q-162 Q-163 Q-164 Q-165 Q-166 Q-167 Q-168 Q-169 Q-170 Q-171 Q-172 Q-173 Q-174 Q-175
R
2 is i-C 3 H7, R 1 3 is 2,4-di-F Q Q Q Q Q Q Q Q Q Q-1 Q-2 Q-3 Q-4 Q-5 Q-6 Q-7 Q-8 Q-9 Q-10 Q-11 Q-12 Q-13 Q-14 Q-15 Q-16 Q-17 Q-18 Q-19 Q-20 Q-21 Q-22 Q-23 Q-24 Q-25 Q-26 Q-27 Q-28 Q-29 Q-30 Q-31 Q-32 Q-33 Q-34 Q-35 Q-36 Q-37 Q-38 Q-39 Q-40 Q-41 Q-42 Q-43 Q-44 Q-45 Q-46 Q-47 Q-48 Q-49 Q-50 Q-51 Q-52 Q-53 Q-54 Q-55 Q-56 Q-57 Q-58 Q-59 Q-60 Q-61 Q-62 Q-63 Q-64 Q-65 Q-66 Q-67 Q-68 Q-69 Q-70 Q-71 Q-72 Q-73 Q-74 Q-75 Q-76 Q-77 Q-78 Q-79 Q-80 Q-81 Q-82 Q-83 Q-84 Q-85 Q-86 Q-87 Q-88 Q-89 Q-90 WO 00/43377 PCTUSOO/01283 55 Q-91 Q-92 Q-93 Q-94 Q-95 Q-96 Q-97 Q-98 Q-99 Q-100 Q-101 Q-102 Q-103 Q-104 Q-105 Q-106 Q-107 Q-108 Q-109 Q-110 0-111 Q-112 0-113 Q-114 Q-115 Q-116 Q-117 Q-118 Q-119 Q-120 Q-121 Q-122 Q-123 Q-124 Q-125 Q-126 Q-127 Q-128 Q-129 Q-130 Q-131 Q-132 Q-133 Q-134 Q-135 Q-136 Q-137 Q-138 Q-139 Q-140 Q-141 Q-142 Q-143 Q-144 Q-145 Q-146 Q-147 Q-148 Q-149 Q-150 Q-151 Q-152 Q-153 Q-154 Q-155 Q-156 Q-157 Q-158 Q-159 Q-160 Q-161 Q-162 Q-163 Q-164 Q-165 Q-166 Q-167 Q-168 Q-169 Q-170 Q-171 Q-172 Q-173 Q-174 Q-175
R
2 is i-C 3
H
7 , R 13 is 4-Cl Q Q Q Q Q Q Q Q Q Q-1 Q-2 Q-3 Q-4 Q-5 Q-6 Q-7 Q-8 Q-9 Q-10 Q-11 Q-12 Q-13 Q-14 Q-15 Q-16 Q-17 Q-18 Q-19 Q-20 Q-21 Q-22 Q-23 Q-24 Q-25 Q-26 Q-27 Q-28 Q-29 Q-30 Q-31 Q-32 Q-33 Q-34 Q-35 Q-36 Q-37 Q-38 Q-39 Q-40 Q-41 Q-42 Q-43 Q-44 Q-45 Q-46 Q-47 Q-48 Q-49 Q-50 Q-51 Q-52 Q-53 Q-54 Q-55 Q-56 Q-57 Q-58 Q-59 Q-60 Q-61 Q-62 Q-63 Q-64 Q-65 Q-66 Q-67 Q-68 Q-69 Q-70 Q-71 Q-72 Q-73 Q-74 Q-75 Q-76 Q-77 Q-78 Q-79 Q-80 Q-81 Q-82 Q-83 Q-84 Q-85 Q-86 Q-87 Q-88 Q-89 Q-90 Q-91 Q-92 Q-93 Q-94 Q-95 Q-96 Q-97 Q-98 Q-99 Q-100 Q-101 Q-102 Q-103 Q-104 Q-105 Q-106 Q-107 Q-108 Q-109 Q-110 0-111 0-112 Q-113 Q-114 Q-115 0-116 Q-117 0-118 Q-119 Q-120 Q-121 Q-122 Q-123 Q-124 Q-125 Q-126 Q-127 Q-128 Q-129 Q-130 Q-131 Q-132 Q-133 Q-134 Q-135 Q-136 Q-137 Q-138 Q-139 Q-140 Q-141 Q-142 Q-143 Q-144 Q-145 Q-146 Q-147 Q-148 Q-149 Q-150 Q-151 Q-152 Q-153 Q-154 Q-155 Q-156 Q-157 Q-158 Q-159 Q-160 Q-161 Q-162 Q-163 Q-164 Q-165 Q-166 Q-167 Q-168 Q-169 Q-170 Q-171 Q-172 Q-173 Q-174 Q-175 WO 00/43377 PCT/USOO/01283 56
R
2 is i-C3H7, R13 is H Q Q Q Q Q Q Q Q Q Q-1 Q-2 Q-3 Q-4 Q-5 Q-6 Q-7 Q-8 Q-9 Q-10 Q-11 Q-12 Q-13 Q-14 Q-15 Q-16 Q-17 Q-18 Q-19 Q-20 Q-21 Q-22 Q-23 Q-24 Q-25 Q-26 Q-27 Q-28 Q-29 Q-30 Q-31 Q-32 Q-33 Q-34 Q-35 Q-36 Q-37 Q-38 Q-39 Q-40 Q-41 Q-42 Q-43 Q-44 Q-45 Q-46 Q-47 Q-48 Q-49 Q-50 Q-51 Q-52 Q-53 Q-54 Q-55 Q-56 Q-57 Q-58 Q-59 Q-60 Q-61 Q-62 Q-63 Q-64 Q-65 Q-66 Q-67 Q-68 Q-69 Q-70 Q-71 Q-72 Q-73 Q-74 Q-75 Q-76 Q-77 Q-78 Q-79 Q-80 Q-81 Q-82 Q-83 Q-84 Q-85 Q-86 Q-87 Q-88 Q-89 Q-90 Q-91 Q-92 Q-93 Q-94 Q-95 Q-96 Q-97 Q-98 Q-99 Q-100 Q-101 Q-102 Q-103 Q-104 Q-105 Q-106 Q-107 Q-108 Q-109 Q-110 Q-111 Q-112 Q-113 Q-114 Q-115 Q-116 Q-117 Q-118 Q-119 Q-120 Q-121 Q-122 Q-123 Q-124 Q-125 Q-126 Q-127 Q-128 Q-129 Q-130 Q-131 Q-132 Q-133 Q-134 Q-135 Q-136 Q-137 Q-138 Q-139 Q-140 Q-141 Q-142 Q-143 Q-144 Q-145 Q-146 Q-147 Q-148 Q-149 Q-150 Q-151 Q-152 Q-153 Q-154 Q-155 Q-156 Q-157 Q-158 Q-159 Q-160 Q-161 Q-162 Q-163 Q-164 Q-165 Q-166 Q-167 Q-168 Q-169 Q-170 Q-171 Q-172 Q-173 Q-174 Q-175 Q R2 R13 Q R2 R13 Q R2 R13 Q-2 CH3 4-F Q-2 CH 3 2,4-di-F Q-2 CH 3 4-Cl Q-16 CH3 4-F Q-16 CH 3 2,4-di-F Q-16 CH 3 4-Cl Q-24 CH3 4-F Q-24 CH 3 2,4-di-F Q-24 CH 3 4-Cl Q-29 _ _ 4-F Q-29 CH 3 2,4-di-F Q-29 CH 3 4-Cl Q-57 CH3 4-F Q-57 CH 3 2,4-di-F Q-57 CH3 4-Cl Q-71 - HI 4-F Q-71 CH 3 2,4-di-F Q-71 CH 4-Cl Q-100 CH3 4-F Q-100 CH 3 2,4-di-F Q-100 CH 3 4-Cl Q-119 .H3 4-F Q-119 CHI 2,4-di-F Q-119 CH 3 4-Cl Q-120 4-F Q-120 CH 2,4-di-F Q- 120 CH 3 4-Cl Q-126 CH3 4-F Q-126 CH3 2,4-di-F Q-126 CH 3 4-Cl Q-130 CH3 4-F Q-130 CH3 2,4-di-F Q-130 CH 3 4-Cl WO 00/43377 PCT[USOO/01283 57 Q-144 Gil 3 4-F Q-144 CH,; 2,4-di-F Q-144 Gil 3 4-Cl Q-162 Gil 3 4-F Q-162 Gil 3 2,4-di-F Q-162 Gil 3 4-Cl Q- 169 Gil 3 4-F Q- 169 Gil 3 2,4-di-F Q- 169 CH 3 4-Cl Q-2 C 2
H
5 4-F Q-2 C 2
H
5 2,4-di-F Q-2 IC 2
H
5 4-Cl Q-16 C 2
H
5 4-F Q-16 C 2
H
5 2,4-di-F Q-16 C 2
H
5 4-Cl Q-24 C 2
H
5 4-F Q-24 C 2
H
5 2,4-di-F Q-24 C 2
H
5 4-Cl Q-29 C 2
H_
5 4-F Q-29 C 2
H_
5 2,4-di-F Q-29 C 2
H
5 j 4-Cl Q-57 C 2
H
5 4-F Q-57 C 2
H
5 2,4-di-F Q-57 C 2
H
5 4-Cl Q-71 C2H 4-F Q-71 C 2
H
5 2,4-di-F Q-71 C 2 il 5 4-Cl Q-100 C2H 4-F Q- 100 CASl 2,4-di-F Q- 100 C 2 il 5 4-Cl Q-1 19 C2H 4-F Q-119 C 2
H
5 2,4-di-F Q-119 C 2 il 5 4-Cl Q- 120 C 2 il 5 4-F Q- 120 ClH, 5 2,4-di-F- Q- 120 C 2 il 5 4-Cl Q- 126 C2H 4-F Q-126 CASl 2,4-di-F Q- 126 C 2
H
5 j 4-Cl Q-130 C2H 4-F Q-130 C 2
H
5 2,4-di-F Q-130 C 2 Hl 5 4-Cl Q-144 C2H 4-F Q-144 C 2
H
5 2,4-di-F- Q-144 C 2 il 5 4-Cl Q-162 C 2
H
5 4-F Q-162 C2~ 2,4-di-F Q-162 C 2 il 5 4-Cl Q-169 C2H 4-F Q-169 C2H 2,4-di-F Q-169 C 2 il 5 4-Cl Q-2 i-4H 4-F Q-2 i-C 4 il 9 2,4-di-F Q-2 i-C 4 il 9 4-Cl Q- 16 i-49 4-F Q-1 6 i-C 4 il 9 2,4-di-F Q- 16 i-C 4 H9 I 4-Cl Q-24 i-C 4 il 9 4-F Q-24 i-C 4 il 9 2,4-di-F IQ-24 i -C 4 il 9 I4-Cl Q-29 i-4H 4-F Q-29 i-C 4
H
9 2,4-di-F Q-29 i-C 4
H
9 4-Cl Q-57 i-4H 4-F Q-57 i-C 4 Ho 2,4-di-F Q-57 i-C 4 il 9 4-ClI Q-71 i-4H 4-F Q-71 i-C 4 il 9 2,4-di-F Q-71 i-C 4 ilg 4-Cl Q-100 i-C 4
H
9 4-F Q-100 i-CAil 9 2,4-di-F Q-100 i-C 4 il 9 4-Cl Q-119 i-4H 4-F Q-119 i-4H 2,4-di-F Q-119 i-C 4 il 9 4-Cl Q-120 i-4H 4-F Q-120 i-4H 2,4-di-F Q-120 i-4H 4-Cl Q-126 i-4H 4-F Q-126 i-4H 2,4-di-F Q-126 i -4H 4-Cl Q-130 i-C 4 il 9 4-F Q-130 i-C 4
H
9 2,4-di-F Q-130 i-4H 4-Cl Q-144 i-4H 4-F Q-144 i-4H 2,4-di-F- Q-144 i-4H 4-Cl Q-162 i-4H 4-F Q-162 i-4H 2,4-di-F Q-162 I -CH 4-Cl Q-169 i-4H 4-F Q-169 i-C 4 il 9 2,4-di-F Q-169 i-4H 4-Cl Q-2 n-3H 4-F Q-2 n-3H 2,4-di-F Q-2 n-3H 4-Cl Q-16 n-3H 4-F Q-16 I -CH 2,4-diF IQ-16 n-IH 4-Cli Q-24 I -3H 4-F IQ-24 I -CH 2,4-di-F IQ-24 I n -H 4-Cl WO 00/43377 PCT/USOO/01283 58 Q-29 n-C 3
H
7 4-F Q-29 n-C 3
H
7 2,4-di-F Q-29 n-C 3
H
7 4-Cl Q-57 n-C 3
H
7 4-F Q-57 n-C 3
H
7 2,4-di-F Q-57 n-C 3
H
7 4-Cl Q-71 n-C 3
H
7 4-F Q-71 n-C 3
H
7 2,4-di-F Q-71 n-C 3
H
7 4-Cl Q-100 n-C 3
H
7 4-F Q-100 n-C 3
H
7 2,4-di-F Q-100 n-C 3
H
7 4-Cl Q-119 n-C 3
H
7 4-F Q-119 n-C 3
H
7 4-F Q-119 n-C 3
H
7 4-F Q-120 n-C 3
H
7 4-F Q-120 n-C 3
H
7 4-F Q-120 n-C 3
H
7 4-F Q-126 n-C 3
H
7 4-F Q-126 n-CIH 7 4-F Q-126 n-CIH 7 4-F Q-130 n-C 3
H
7 4-F Q-130 n-C 3
H
7 4-F Q-130 n-C 3
H
7 4-F Q-144 n-C 3
H
7 4-F Q-144 n-C 3
H
7 4-F Q-144 n-C 3
H
7 4-F Q-162 n-C 3
H
7 4-F Q-162 n-C 3
H
7 4-F Q-162 n-C 3
H
7 4-F Q-169 n-C 3
H
7 4-F Q-169 n-C 3
H
7 4-F Q-169 n-C 3
H
7 4-F Q-2 Cyclopropyl 4-F Q-2 Cyclopropyl 2,4-di-F Q-2 Cyclopropyl 4-Cl Q-16 Cyclopropyl 4-F Q-16 Cyclopropyl 2,4-di-F Q-16 Cyclopropyl 4-Cl Q-24 Cyclopropyl 4-F Q-24 Cyclopropyl 2,4-di-F Q-24 Cyclopropyl 4-Cl Q-29 Cyclopropyl 4-F Q-29 Cyclopropyl 2,4-di-F Q-29 Cyclopropyl 4-Cl Q-57 Cyclopropyl 4-F Q-57 Cyclopropyl 2,4-di-F Q-57 Cyclopropyl 4-Cl Q-71 Cyclopropyl 4-F Q-71 Cyclopropyl 2,4-di-F Q-71 Cyclopropyl 4-Cl Q-100 Cyclopropyl 4-F Q-100 Cyclopropyl 2,4-di-F Q-100 Cyclopropyl 4-Cl Q-119 Cyclopropyl 4-F Q-1 19 Cyclopropyl 2,4-di-F Q-119 Cyclopropyl 4-Cl Q-120 Cyclopropyl 4-F Q-120 Cyclopropyl 2,4-di-F Q-120 Cyclopropyl 4-Cl Q-126 Cyclopropyl 4-F Q-126 Cyclopropyl 2,4-di-F Q-126 Cyclopropyl 4-Cl Q-130 Cyclopropyl 4-F Q-130 Cyclopropyl 2,4-di-F Q-130 Cyclopropyl 4-Cl Q-144 Cyclopropyl 4-F Q-144 Cyclopropyl 2,4-di-F Q-144 Cyclopropyl 4-Cl Q-162 Cyclopropyl 4-F Q-162 Cyclopropyl 2,4-di-F Q-162 Cyclopropyl 4-Cl Q-169 Cyclopropyl 4-F Q-169 Cyclopropyl 2,4-di-F Q- 169 Cyclopropyl 4-Cl Q R2 R13 Q R2 R13 Q R2 R13 Q-2 -3H 4-OCF 3 Q-2 3H_ 4-COOCH Q-2 -C3H7 3,5-di-F Q-16 i-C3H7 4-OCF 3 Q-16 i-C3H7 4-COOCH Q-16 i-C3H7 3,5-di-F Q-29 i-C3H7 4-OCF 3 Q-29 i-C3H7 4-COOCH Q-29 i-C3H7 3,5-di-F Q-57 i-C3H7 4-OCF 3 Q-57 i-C3H7 4-COOCH Q-57 i-C3H7 3,5-di-F Q-71 i-C3H7 4-OCF 3 Q-71 i-C3H7 4-COOCHI Q-71 i-C3H7 3,5-di-F Q-100 i-C3H7 4-OCF 3 Q-100 i-C3H7 4-COOCH Q-100 i-C3H7 3,5-di-F WO 00/43377 PCT/USOO/01283 59 Q-119 i-C 3
H
7 4-OCF 3 Q-119 i-C 3
H
7 4-COOCH Q-119 i-C 3
H
7 3,5-di-F Q-120 i-C 3
H
7 4-OCF 3 Q-120 i-C 3
H
7 4-COOCH Q-120 i-C 3
H
7 3,5-di-F Q-126 i-C 3
H
7 4-OCF 3 Q-126 i-C 3
H
7 4-COOCH Q-126 i-C 3
H
7 3,5-di-F Q-130 i-C 3
H
7 4-OCF 3 Q-130 i-C 3
H
7 4-COOCH Q-130 i-C 3
H
7 3,5-di-F Q-144 i-C 3
H
7 4-OCF 3 Q-144 i-C 3
H
7 4-COOCH Q-144 i-C 3
H
7 3,5-di-F Q-162 i-C 3
H
7 4-OCF 3 Q-162 i-C 3
H
7 4-COOCH Q-162 i-C 3
H
7 3,5-&-F Q-169 z-C 3
H
7 4-OCF 3 Q-169 i-C 3
H
7 4-COOCH Q-169 i-C 3
H
7 3,5-di-F Q-2 i-C3H7 4-CF 3 Q-2 - 4-CH 3 Q-2 i 2,4,6-ni Q-16 i 4-CF 3 Q-16 i-C 3
H
7 4-CH 3 Q-16 i-C 3
H
7 2,4,6-tn-F Q-24 i-C3H7 4-CF 3 Q-24 i 4-CH 3 Q-24 i 2,4,6-ni-F Q-29 i-C3H7 4-CF 3 Q-29 i-CiH 7 4-CH 3 Q-29 i 2,4,6-tn Q-57 i-C3H7 4-CF 3 Q-57 i-C 3
H
7 4-CH 3 Q-57 i-C 3
H
7 2,4,6-tn-F Q-71 i-C3H7 4-CF3 Q-71 H 4 Q-71 H 2,4,6-tn-F Q-100 i-C3H7 4-CF 3 Q-100 i 4-CH 3 Q-100 i 2,4,6-tn Q-119 i 4-CF 3 Q-119 i 4-CH 3 Q-119 i 2,4,6-ni-F Q-120 i 4-CF 3 Q-120 J-3L 4-CH 3 Q-120 - 2,4,6-ni-F Q-126 i-C3H7 4-CF 3 Q-126 jH 4-CH 3 Q-126 I 2,4,6-ni-F Q-130 i-C3H7 4-CF 3 Q-130 I 4-CH 3 Q-130 i 2,4,6-ni-F Q-144 i-C3H7 4-CF 3 Q-144 i 4-CH 3 Q-144 i 2,4,6-ni-F Q-162 i-C3H7 4-CF 3 Q-162 i 4-CH 3 -162 i 2,4,6-ni-F Q- 169 i-C3H7 4-CF 3 Q-169 i 4-CH 3 Q-169 i L 2,4,6-ni-F Q-2 i L 4-OCH 3 Q-2 i L 2,4-di-Ci -2 i 2,5-di-F Q-16 i-C3H7 4-OCH Q-16 H 2,4-di-CI Q-1 I H 2,5-di-F Q-24 i-C 3
H
7 4-OCH 3 Q-24 i 2,4-di-Ci 0-0 i 2,5-di-F Q-29 i-C 3
H
7 4-OCH 3 Q-29 i L 2,4-di-Cl Q-29 i 2,5-di-F Q-57 i-C3H7 4-OCH3 Q-57 CI7 2-i- Q5 CH ,-dF Q-71 i-C3H7 4-OCH3 Q-71 -37 2-i-l Q1 iCH ,5dF Q-100 i-C 3
H
7 4-OCH 3 Q-100 - 2,4-di-Ci Q-100 & 2,5-di-F Q-119 i-C3H7 4-OCHg; Q-119 iCH ,-iC - 9 iC47 25d Q-120 i-C3H7 4-OCH3 Q-120 iCH ,-iC -2 -37 25d Q-126 i-C3H7 4-OCH3 Q-126 iCH ,-iC -2 -37 25d Q-130 i-C 3
H
7 4-OCH 3 Q-130 i 2,4-di-Ci Q-130 2,5-di-F Q-144 i-C 3
H
7 4-OCH 3 Q- 144 i-C 3
H
7 2,4-di-C Q-144 1 2,5-di-F Q-162 i-C 3
H
7 4-OCH 3 H 162 i-C 3
H
7 2,4-di-Ci Q-162 - 2,5-di-F WO 00/43377 PCT/USOO/01283 60 Q-169 i-C 3
H
7 4-OCH 3 Q-169 i-C 3
H
7 2,4-di-Cl Q-169 i-C 3
H
7 2,5-di-F Q-2 i-C 3
H
7 4-CN Q-2 i-C 3
H
7 2-F, 4-Cl Q-2 i-C 3
H
7 4-OCF 2 H Q-16 i-C 3
H
7 4-CN Q-16 i-C 3
H
7 2-F, 4-Cl Q-16 i-C 3
H
7 4-OCF 2 H Q-24 i-C 3
H
7 4-CN Q-24 i-C 3
H
7 2-F, 4-Cl Q-24 i-C 3
H
7 4-OCF 2 H Q-29 i-C 3
H
7 4-CN Q-29 i-C 3
H
7 2-F, 4-Cl Q-29 i-C 3
H
7 4-OCF 2 H Q-57 i-C 3
H
7 4-CN Q-57 i-C 3
H
7 2-F, 4-Cl Q-57 i-C 3
H
7 4-OCF 2 H Q-71 i-C 3
H
7 4-CN Q-71 i-C 3
H
7 2-F, 4-Cl Q-71 i-C 3
H
7 4-OCF 2 H Q-100 i-C 3
H
7 4-CN Q-100 i-C 3
H
7 2-F, 4-Cl Q-100 i-C 3
H
7 4-OCF 2 H Q-119 i-C 3
H
7 4-CN Q-119 i-C 3
H
7 2-F, 4-Cl Q-1 19 i-C 3
H
7 4-OCF7H Q-120 i-C 3
H
7 4-CN Q-120 i-C 3
H
7 2-F, 4-Cl Q-120 i-C 3
H
7 4-OCF 2 H Q-126 i-C 3
H
7 4-CN Q-126 i-C 3
H
7 2-F, 4-Cl Q-126 i-C 3
H
7 4-OCF 2 H Q-130 i-C 3
H
7 4-CN Q-130 i-C 3
H
7 2-F, 4-Cl Q-130 i-C 3
H
7 4-OCF7H Q-144 i-C 3
H
7 4-CN Q-144 i-C 3
H
7 2-F, 4-Cl Q-144 i-C 3
H
7 4-OCF 2 H Q- 162 i-C 3
H
7 4-CN Q-162 i-C 3
H
7 2-F, 4-Cl Q-162 i-C 3
H
7 4-OCF 2 H Q-169 i-C 3
H
7 4-CN Q-169 i-C 3
H
7 2-F, 4-Cl Q-169 i-C 3
H
7 4-OCF 2 H Q-2 iH_ 4-NO 2 Q-2 _ 3,4-di-F Q-2 i- 3
H
7 _4-SCH 3 Q-16 4-NO 2 Q-16 H 3,4-di-F Q-16 1-C 3
H
7 4-SCH 3 Q-24 i-C3H7 4-NO 2 Q-24 i-C3H7 3,4-di-F Q-24 i-C3H7 4-SCH 3 Q-29 i-C3H7 4-NO 2 Q-29 i-C 3
H
7 3,4-di-F Q-29 i-C3H7 4-SCH 3 Q-57 i-C3H7 4-NO 2 Q-57 i-C 3
H
7 3,4-di-F Q-57 i-C3H7 4-SCH 3 Q-71 i-C3H7 4-NO 2 Q-71 i-C3H7 3,4-di-F Q-71 i-C3H7 4-SCH 3 Q-100 i-C3H7 4-NO 2 Q-100 i-C3H7 3,4-di-F Q-100 i-C 3
H
7 4-SCH 3 Q-119 i-C3H7 4-NO 2 Q-119 i-C3H7 3,4-di-F Q-119 i-C3H7 4-SCH 3 Q-120 i-C3H7 4-NO 2 Q-120 i-C3H7 3,4-di-F Q-120 i-C3H7 4-SCH 3 Q-126 i-C3H7 4-NO 2 Q-126 i-C3H7 3,4-di-F Q-126 i- 3H7 4-SCH 3 Q-130 i-C3H7 4-NO 2 Q-130 i-C3H7 3,4-di-F Q-130 i-C3H7 4-SCH 3 Q-144 - 3H 4-NO 2 Q-144 i- 3H 3,4-di-F Q-144 H 4-SCH 3 Q-162 igHL 4-NO 2 Q-162 H 3,4-di-F Q-162 HC SCH Q-169 i-C3H7 4-NO 2 Q-169 i-C3H7 3,4-di-F Q-169 i-C3H7 4-SCH 3 Q R2 R13 Q R2 R13 Q R2 R13 Q-2 Allyl 4-F Q-2 Allyl 2,4-di-F Q-2 Allyl 4-Cl Q-16 Allyl 4-F Q-16 Allyl 2,4-di-F Q-16 Allyl 4-Cl WO 00/43377 PCT/USOO/01283 61 Q R2 R13 Q R2 R13 Q R2_R13 Q-24 Alyl 4-F Q-24 Alyl 2,4-di-F Q-24 Allyl 4-Cl Q-29 Allyl 4-F Q-29 Allyl 2,4-di-F Q-29 Allyl 4-Cl Q-57 Allyl 4-F Q-57 Allyl 2,4-di-F Q-57 Allyl 4-Cl Q-71 Allyl 4-F Q-71 Allyl 2,4-di-F Q-71 Allyl 4-Cl Q-100 Alyl 4-F Q-100 Allyl 2,4-di-F Q-100 Allyl 4-Cl Q-119 Allyl 4-F Q-119 Allyl 2,4-di-F Q-119 Allyl 4-Cl Q-120 Allyl 4-F Q-120 Allyl 2,4-di-F Q-120 Allyl 4-Cl Q-126 Allyl 4-F Q-126 Allyl 2,4-di-F Q-126 Allyl 4-Cl Q-130 Allyl 4-F Q-130 Allyl 2,4-di-F Q-130 Allyl 4-Cl Q-144 Alyl 4-F Q-144 Allyl 2,4-di-F Q-144 Allyl 4-Cl Q-162 Allyl 4-F Q-162 Allyl 2,4-di-F Q-162 Allyl 4-Cl Q-169 Allyl 4-F Q-169 Allyl 2,4-di-F Q-169 Allyl 4-Cl Q-2 OCH 3 4-F Q-2 OCH 3 2,4-di-F Q-2 OCH 3 4-Cl Q-16 OCH 3 4-F Q-16 OCH 3 2,4-di-F Q-16 OCH 3 4-Cl Q-24 OCH 3 4-F Q-24 OCHI 2,4-di-F Q-24 OCH 3 4-Cl Q-29 OCH 3 4-F Q-29 QCH 3 2,4-di-F Q-29 OCH 3 4-Cl Q-57 OCH 3 4-F Q-57 OCH 3 2,4-di-F Q-57 OCH 3 4-Cl Q-71 OCH 3 4-F Q-71 OCH 3 2,4-di-F Q-71 OCH 3 4-Cl Q-100 OCHa 4-F Q-100 OCH 3 2,4-di-F Q-100 OCH 3 4-Cl Q-119 OCH 3 4-F Q-119 OCHI 2,4-di-F Q-119 OCH 3 4-Cl Q-120 OCH 3 4-F Q-120 OCH 3 2,4-di-F Q-120 OCH 3 4-Cl1 Q-126 OCH 3 4-F Q-126 OCH 3 2,4-di-F Q-126 OCH 3 4-Cl Q-130 OCH 3 4-F Q-130 OCHI 2,4-di-F Q-130 OCH 3 4-Cl Q-144 OCH 3 4-F Q-144 OCH 3 2,4-di-F Q-144 OCH 3 4-Cl Q-162 OCH 3 4-F Q-162 OCH 3 2,4-di-F Q-162 OCH 3 4-Cl Q-169 OCH 3 4-F Q-169 OCHI 2,4-di-F Q-169 OCH 4-Cl Q-2 N(CH 3
)
2 4-F Q-2 N(CH 3
)
2 2,4-di-F Q-2 N(CH 3
)
2 4-Cl Q-16 N(CH 3
)
2 4-F Q-16 N(CH 3
)
2 2,4-di-F Q-16 N(CH 3
)
2 4-Cl Q-24 N(CH 3
)
2 4-F Q-24 N(CH 3
)
2 2,4-di-F Q-24 N(CH 3
)
2 4-Cl Q-29 N(CH 3
)
2 4-F Q-29 N(CH 3
)
2 2,4-di-F Q-29 N(CH 3
)
2 4-Cl Q-57 N(CH 3
)
2 4-F Q-57 N(CH 3
)
2 2,4-di-F Q-57 N(CH 3
)
2 4-Cl Q-71 N(CH 3
)
2 4-F Q-71 N(CH 3
)
2 2,4-di-F Q-71 N(CH 3
)
2 4-Cl Q-100 N(CH 3
)
2 4-F Q-1 N(CH 3
)
2 2,4-di-F Q-100 N(CH 3
)
2 4-Cl WO 00/43377 PCTUSOO/01283 62 Q R2 R 13 Q R2_R13 Q R2__R13 Q-1 19 N(CH 3
)
2 4-F Q-1 19 -N(CH- 3
)
2 2,4-di-F Q-1 19 N(CH 3
)
2 4-Cl Q-120 N(CH 3
)
2 4-F Q-120 N(CHI) 2 2,4-di-F Q-120 N(CH 3
)
2 4-Cl Q-126 N(CH 3
)
2 4-F Q-126 N(CH 3
)
2 2,4-di-F -Q-126 N(CH 3
)
2 4-Cl Q-130 N(CH 3
)
2 4-F Q-130 -N(CH 3
)
2 2,4-di-F Q-130 N(CH 3
)
2 4-Cl Q-144 N(CH 3
)
2 4-F Q-144 N(CH- 3
)
2 2,4-di-F Q-144 N(CH 3
)
2 4-Cl Q-162 N(CH 3
)
2 4-F Q- 162 -N(CH 3
)
2 - 2,4-di-F Q-162 IN(CH 3
)
2 4-Cl Q- 169 N(CH 3
)
2 4-F Q- 169 -N(CH 3
)
2 ) 2,4-di-F Q-169 N(CH 3
)
2 4-Cl Q-2 CH 2
OCH
3 4-F Q-2 CH 2
OCH
3 2,4-di-F Q-2 CH 2
)OCH
3 4-Cl Q-16 CH 2
OCH
3 4-F Q-16 C# 2
OCH
3 2,4-di-F Q-16 ICH 2
OCH
3 4-Cl Q-24 CH 2
OCH
3 4-F Q-24 CH170CHI 2,4-di-F Q-24 CH 2
OCH
3 ; 4-Cl Q-29 CH 2
OCH
3 4-F Q-29 CH 2
OCH
3 2,4-di-F Q-29 CH 2
OCH
3 4-Cl Q-57 CH 2
OCH
3 4-F Q-57 CH 2
OCH-
3 2,4-di-F Q-57 CH 2
OCH
3 4-Cl Q-71 CH 2
OCH
3 4-F Q-71 CH 2 0CHI 2,4-di-F Q-71 CII 2
OCH
3 4-Cl Q-100 CH 2 OAH 4-F Q-100 CH 2
)OCH
3 2,4-di-F Q-100 CH 2
OCH
3 4-Cl Q-l119 CH 2 0CH 3 4-F Q-1 19 CH 2 )OCH-A 2,4-di-F Q-1 19 CH 2 0CHI 4-Cl Q-120 CH 2
OCH
3 4-F Q-120 -,CH 2
OCH
3 2,4-di-F IQ-120 CH 2 0CHI 4-Cl Q-126 CH 2
OCH
3 4-F Q-126 CH 2 )OCHI 2,4-di-F Q-126 CH 2
OCH
3 4-Cl Q-130 CH 2
OCH
3 4-F Q-130 CH 2 )OCHI 2,4-di-F Q-130 CH 2
OCH
3 4-Cl Q-144 CH 2
OCH
3 4-F Q-144 CH 2 0CHI 2,4-di-F Q-144 CH 2 0CHI 4-Cl Q-162 CH 2
OCH
3 4-F Q-162 CH 2 0CHI 2,4-di-F Q-162 CH 2
OCH
3 4-Cl Q- 169 CH 2
OCH
3 4-F Q-169 CHI 2 OCH-A 2,4-di-F Q-169 CH 2 0CH 3 4-Cl Q-2 CH 2
CF
3 j 4-F Q-2 CH 2
CF
3 2,4-di-F Q-2 CH 2
)CF
3 4-Cl Q-16 CH 2
CF
3 4-F Q-16 CH 2
CF
3 2,4-di-F Q-16 CH 2
CF
3 4-Cl Q-24 CH 2
CF
3 4-F Q-24 CH 2
)CF
3 2,4-di-F Q-24 CH 2
CF
3 j 4-Cl Q-29 CH 2
CF
3 4-F Q-29 CH 2
CF
3 2,4-di-F Q-29 CH 2
CF
3 4-Cl Q-57 CH 2
CF
3 4-F Q-57 CH 2
CF
3 2,4-di-F Q-57 CHCF 4-Cl Q-71 CH 2
CF
3 4-F Q-71 CH9CFj 2,4-di-F Q-71 CH 2
CF
3 j 4-Cl Q-100 CH 2
CF
3 j 4-F Q-100_ CH 2
CF
3 2,4-di-F Q-100 CH 2
CF
3 4-Cl Q-119 CH 2
CF
3 4-F Q-1 19 CH 2
CF
3 2,4-di-F Q-1 19 CH 2
CF
3 4-Cl Q-120 CH 2
CF
3 4-F Q-120 CHI)CF; 2,4-di-F Q-120 CH 2 )CF; 4-Cl Q-126 CH 2
CF
3 j 4-F Q-126 CH 2
CF
3 2,4-di-F Q-126 CH 2
CF
3 4-Cl Q-130 CH 2
CF
3 4-F Q- 130 CH 2
CF
3 l 2,4-di-F IQ-130 CH 2
CF
3 4-Cl Q- 144 CH 2
CF
3 4-F Q- 144 CH 2
CF
3 2,4-di-F IQ-144 CH 2
CF
3 I4-ClI WO 00/43377 PCTIUSOO/01283 63 1 QR2 R13 Q R 2
R
13 Q R2 R13! Q-12 CH 2
CF
3 A 4- Q-162 CH 2 )CFA ,-d- Q-162 CH 2
)CF
3 4-Cl Q-169 CH2CF3 4-F Q-169 CH2CF 3 2,4-di-F Q-l169 CH2CF3 4-Cl TABLE 2 0- 0 0 RI is C 2 Hj, R 2 isB-1 ________ Q Q Q Q Q Q Q Q Q Q-1 Q-2 Q-3 Q-4 Q-5 Q-6 Q-7 Q-8 Q-9 Q-10 Q-11 Q-12 Q-13 Q-14 Q-15 Q-16 Q-17 Q-18 Q- 19 Q-20 Q-21I Q-22 Q-23 Q-24 Q-25 Q-26 Q-27 Q-28 Q-29 Q-30 Q-3 1 Q-32 Q-33 Q-34 Q-35 Q-36 Q-37 Q-38 Q-39 Q-40 Q-41 Q-42 Q-43 Q-44 Q-45 Q-46 Q-47 Q-48 Q-49 Q-50 Q-51 Q-52 Q-53 Q-54 Q-55 Q-56 Q-57 Q-58 Q-59 Q-60 Q-61 Q-62 Q-63 Q-64 Q-65 Q-66 Q-67 Q-68 Q-69 Q-70 Q-71 Q-72 Q-73 Q-74 Q-75 Q-76 Q-77 Q-78 Q-79 Q-80 Q-81 Q-82 Q-83 Q-84 Q-85 Q-86 Q-87 Q-88 Q-89 Q-90 Q-91I Q-92 Q-93 Q-94 Q-95 Q-96 Q-97 Q-98 Q-99 Q-100 Q-101 Q-102 Q-103 Q-104 Q-105 Q-106 Q-107 Q-108 Q-109 Q-110 Q-11l Q-112 Q-113 Q-1 14 Q-115 Q-116 Q-117 Q-1 18 Q-119 Q-120 Q-121 Q-122 Q-123 Q-124 Q-125 Q-126 Q-127 Q-128 Q-129 Q-130 Q-131 Q-132 Q-133 Q-134 Q-135 Q-136 Q-137 Q-138 Q-139 Q-140 Q-141 Q-142 Q-143 Q-144 Q-145 Q-146 Q-147 Q-148 Q-149 Q-150 Q-151 Q-152 Q-153 Q-154 Q-155 Q-156 Q-157 Q-158 Q-159 Q-160 Q-161 Q-162 Q-163 Q-164 Q-165 Q-166 Q-167 Q-168 Q-169 Q-170 Q-171 Q-172 Q- 173 Q-174 Q-175 I____ I________ ________ WO 00/43377 PCT/USOO/01283 64 RI is i-C 3
H
7 , R 2 is B4 Q Q Q Q Q Q Q Q Q Q-1 Q-2 Q-3 Q-4 Q-5 Q-6 Q-7 Q-8 Q-9 Q-10 Q-11 Q-12 Q-13 Q-14 Q-15 Q-16 Q-17 Q-18 Q-19 Q-20 Q-21 Q-22 Q-23 Q-24 Q-25 fQ-26 Q-27 Q-28 Q-29 Q-30 Q-31I Q-32 Q-33 Q-34 Q-35 Q-36 Q-37 Q-38 Q-39 Q-40 Q-41 Q-42 Q-43 Q-44 Q-45 Q-46 Q-47 Q-48 Q-49 Q-50 Q-51 I -52 Q-53 Q-54 Q-55 Q-56 Q-57 Q-58 Q-59 Q-60 Q-61 Q-62 Q-63 Q-64 Q-65 Q-66 Q-67 Q-681 Q-69 Q-70 Q-71 Q-72 Q-73 Q-74 Q-75 Q-76 Q-77 Q-78 Q-79 Q-80 Q-8 1 Q-82 Q-83 Q-84 Q-85 Q-86 Q-87 Q-88 Q-89 Q-90 Q-9 1 Q-92 Q-93 Q-94 Q-95 Q-96 Q-97 Q-98 Q-99 Q-100 Q-101 Q-102 Q-103 Q-104 Q-105 Q-106 Q-107 Q-108 Q-109 Q-110 Q-111 Q-1 12 Q-113 Q-1 14 Q-115 Q-116 Q-1 17 Q-118 Q-1 19 Q-120 Q-121 Q-122 Q-123 Q-124 0-125 Q-126 Q-127 Q-128 Q-129 Q-130 Q-131 Q-132 Q-133 Q-134 Q-135 Q-136 Q-137 Q-138 Q-139 Q-140 Q-141 Q-142 Q-143 Q-144 Q-145 Q-146 Q-147 Q-148 Q-149 Q-150 Q-151 Q-152 Q-153 Q-154 Q-155 Q-156 Q-157 Q-158 Q-159 Q-160 Q-161 Q-162 Q- 163 Q-164 Q- 165 Q- 166 Q- 167 Q-168 Q-169 Q-170 Q-171 Q-172 Q-173 Q-174 Q-175 ____ ________ ________
R
1 is C 2 Hj, R 2 is B-4 __________ ___ _____ Q-1 Q-2 Q-3 Q-4 Q-5 Q-6 Q-7 Q-8 Q-9 Q-10 Q-11 Q-12 Q-13 Q-14 Q-15 Q-16 Q-17 Q-18 Q-19 Q-20 Q-2 1 Q-22 Q-23 Q-24 Q-25 Q-26 Q-27 Q-28 Q-29 Q-30 Q-31I Q-32 Q-33 Q-34 Q-35 Q-36 Q-37 Q-38 Q-39 Q-40 Q-41 Q-42 Q-43 Q44 Q-45 Q-46 Q-47 Q-48 Q-49 Q-50 Q-51 Q-52 Q-53 Q-54 Q-55 Q-56 Q-57 Q-58 Q-59 Q-60 Q-61 Q-62 Q-63 Q-64 Q-65 Q-66 Q-67 Q-68 Q-69 Q-70 Q-71 Q-72 Q-73 Q-74 I -75 Q-76 I -77 Q-7J8 Q-79 Q-80 Q-81 Q-82 Q-83 IQ-84 Q-85 IQ-86 IQ-87 Q-88 Q-89 0 -90 WO 00/43377 PCT[USOO/01283 65 Q-91I Q-92 Q-93 Q-94 Q-95 Q-96 Q-97 Q-98 Q-99 Q-100 Q-101 Q-102 Q-103 Q-104 Q-105 Q-106 Q-107 Q-108 Q-109 Q-110 Q-111 Q-112 Q-113 Q-114 Q-115 Q-1 16 Q-117 Q-118 Q-119 Q-120 Q-121 Q-122 Q-123 Q-124 Q-125 Q-126 Q-127 Q-128 Q-129 Q-130 Q-131 Q-132 Q-133 Q-134 0Q-135 Q-136 Q-137 Q-138 Q-139 Q-140 Q-141 Q-142 Q-143 Q-144 Q-145 Q-146 Q-147 Q-148 Q-149 Q-150 Q-151 Q-152 Q-153 Q-154 Q-155 Q-156 Q-157 Q-158 Q-159 Q-160 Q-161 Q-162 Q- 163 Q-164 Q- 165 Q-166 Q-167 Q-168 Q-169 Q-170 Q-171 Q-172 ,Q-173 Q-174 Q-175 ____ ________ ________ RIis C 2 Hj, R 2 is ]3b_1 ____ ____ Q Q Q Q Q Q Q Q Q Q-1 Q-2 Q-3 Q-4 Q-5 Q-6 Q-7 Q-8 Q-9 Q-10 Q-11 Q-12 Q-13 Q-14 Q-15 Q-16 Q-17 Q-18 Q- 19 Q-20 Q-21I Q-22 Q-23 Q-24 Q-25 Q-26 Q-27 Q-28 Q-29 Q-30 Q-3 1 Q-32 Q-33 Q-34 Q-35 Q-36 Q-37 Q-38 Q-39 Q-40 Q-41 Q-42 Q-43 Q-44 Q-45 Q-46 Q-47 Q-48 Q-49 Q-50 Q-51 Q-52 Q-53 Q-54 Q-55 Q-56 Q-57 Q-58 Q-59 Q-60 Q-61 Q-62 Q-63 Q-64 Q-65 Q-66 Q-67 Q-68 Q-69 Q-70 Q-71 Q-72 Q-73 Q-74 Q-75 Q-76 Q-77 Q-78 Q-79 Q-80 Q-8 1 Q-82 Q-83 Q-84 Q-85 Q-86 Q-87 Q-88 Q-89 Q-90 Q-91 Q-92 Q-93 Q-94 Q-951 Q-96 Q-97 Q-98 Q-99 Q-100 Q-101 Q-102 Q-103 Q-104 Q-105 Q-106 Q-107 Q-108 Q-109 Q-1 10 Q-111 Q-1 12 Q-113 Q-114 Q-115 Q-1 16 Q-117 Q-118 Q-119 Q-120 Q-121 Q-122 Q-123 Q-124 Q-125 Q-126 Q-127 Q-128 Q-129 Q-130 Q-131 Q-132 Q-133 Q-134 Q-135 Q-136 Q-137 Q-138 Q-139 Q-140 Q-141 Q-142 Q-143 Q-144 Q-145 Q-146 Q-147 Q-148 Q-149 Q-150 Q-151 Q-152 Q-153 Q-154 Q-155 Q-156 Q-157 Q-158 Q-159 Q-160 IQ-161 Q-162 Q-163 Q-164 Q-165 Q-166 Q-167 Q-168 Q-169 Q-170 Q-171 Q-172 Q-173 Q-174 Q-175 ____ ________ ________ WO 00/43377 PCT/USOO/01283 66
R
1 is i-C3H 7,R 2 isB-10 Q Q Q Q Q Q Q Q Q Q-1 Q-2 Q-3 Q-4 Q-5 Q-6 Q-7 Q-8 Q-9 Q-10 Q-11 Q-12 Q-13 Q-14 Q-15 Q-16 Q-17 Q-18 Q-19 Q-20 Q-21 Q-22 Q-23 Q-24 Q-25 Q-26 Q-27 Q-28 Q-29 Q-30 Q-31 Q-32 Q-33 Q-34 Q-35 Q-36 Q-37 Q-38 Q-39 Q-40 Q-41 Q-42 Q-43 Q-44 Q-45 Q-46 Q-47 Q-48 Q-49 Q-50 Q-51 Q-52 Q-53 Q-54 Q-55 Q-56 Q-57 Q-58 Q-59 Q-60 Q-61 Q-62 Q-63 Q-64 Q-65 Q-66 Q-67 Q-68 Q-69 Q-70 Q-71 Q-72 Q-73 Q-74 Q-75 Q-76 Q-77 Q-78 Q-79 Q-80 Q-81 Q-82 Q-83 Q-84 Q-85 Q-86 Q-87 Q-88 Q-89 Q-90 Q-91 Q-92 Q-93 Q-94 Q-95 Q-96 . Q-97 Q-98 Q-99 Q-100 Q-101 Q-102 Q-103 Q-104 Q-105 Q-106 Q-107 Q-108 Q-109 Q-110 Q-111 Q-112 0-113 Q-114 Q-115 Q-116 0-117 Q-118 Q-119 Q-120 Q-121 Q-122 Q-123 Q-124 Q-125 Q-126 Q-127 Q-128 Q-129 Q-130 Q-131 Q-132 Q-133 Q-134 Q-135 Q-136 Q-137 Q-138 Q-139 Q-140 Q-141 Q-142 Q-143 Q-144 Q-145 Q-146 Q-147 Q-148 Q-149 Q-150 Q-151 Q-152 Q-153 Q-154 Q-155 Q-156 Q-157 Q-158 Q-159 Q-160 Q-161 Q-162 Q-163 Q-164 Q-165 Q-166 Q-167 Q-168 Q-169 Q-170 Q-171 Q-172 Q-173 Q-174 Q-175 Q RI R2 Q RI R 2 Q RI R2 Q-2 Cyclopropyl B-10 Q-2 Allyl B4 Q-2 Cyclohexyl B-18 Q-16 Cyclopropyl B-10 Q-16 Allyl B-4 Q-16 Cyclohexyl B-18 Q-24 Cyclopropyl B-10 Q-24 Allyl B-4 Q-24 Cyclohexyl B-18 Q-29 Cyclopropyl B-10 Q-29 Allyl B4 Q-29 Cyclohexyl B-18 Q-57 Cyclopropyl B-10 Q-57 Allyl B4 Q-57 Cyclohexyl B-18 Q-71 Cyclopropyl B-10 Q-71 Allyl B-4 Q-71 Cyclohexyl B-18 Q-100 Cyclopropyl B-10 Q-100 Allyl B4 Q-100 Cyclohexyl B-18 Q-119 Cyclopropyl B-10 Q-119 Allyl B4 Q-119 Cyclohexyl B-18 Q-120 Cyclopropyl B-10 Q-120 Allyl B4 Q-120 Cyclohexyl B-18 Q-126 Cyclopropyl B-10 Q-126 Allyl B4 Q-126 Cyclohexyl B-18 Q-130 Cyclopropyl B-10 Q-130 Allyl B4 Q-130 Cyclohexyl B-18 WO 00/43377 PCTIUSOO/01283 67 Q-144 Cyciopropyl B-10 Q-144 Allyl B4 Q-144 Cyciohexyl B-18 Q-162 Cyciopropyl B-10 Q-162 All B4 Q-162 Cyclohexyl B-18 Q-169 Cyclopropyl B-10 Q-169 Allyl B4 Q-169 Cyclohexyl B-i8 Q-2 n-C 4
H
9 B-10 Q-2 Cyciopropyl B4 Q-2 i-C3H7 B-18 Q-16 n-C 4
H
9 B-10 Q-16 Cyciopropyl B4 Q-16 i-C 3
H
7 B-i8 Q-24 B-10 Q-24 Cyciopropyl B-4 Q-24 1-C 3
H
7 B-18 Q-29 n-C4H9 B-10 Q-29 Cyclopropyl BA Q-29 i-C 3
H
7 B-18 Q-57 n-C4H9 B-10 Q-57 Cycopropyl BA Q-57 i-C 3
H
7 B-18 Q-71 n-C4H B-10 Q-71 Cyclopropyl BA Q-71 i-C3H7 B-i8 Q-100 n B-10 Q-100 Cyciopropyl BA Q-100 i-C 3 H B-18 Q-119 n j B-10 Q-119 Cyclopropyl BA Q-119 1-C 3
H
7 B-18 Q-120 n-C 4 H B-10 Q-120 Cyclopropyl BA Q-120 i-C3H7 B-18 Q-126 n B-10 Q-126 Cyclopropyl B4 Q-126 f-C 3
H
7 B-18 Q-130 n-4H B-10 Q-130 Cyclopropyl B-4 Q-130 i-C3117 B-18 Q-144 B-10 Q-144 Cyclopropyl B-4 Q-144 i-C 3
H
7 B-18 Q-162 B-10 Q-162 Cycopropyl B-4 Q-162 i-C3H7 B-18 Q-169 n-C4H9 B-10 Q-169 Cyclopropyl B4 Q-169 i-C 3
H
7 B-18 Q-2 CH 2
CH
2
CH
3 B-10 Q-2 0 B4 Q-2 Cyclohexyl B-17 Q-16 CH 2
CH
2
CH
3 B-10 Q-16 CH B4 Q-16 Cyclohexyl B-17 Q-24 CH 2
CH
2
OCH
3 B-10 Q-24 C B4 Q-24 Cyclohexyl B-17 Q-29 CH 2
CH
2
CH
3 B-10 Q-29 CH B4 Q-29 Cyclohexyl B-17 Q-57 CH 2
CH
2
OCH
3 B-10 Q-57 C B4 Q-57 Cyclohexyl B-17 Q-71 CH 2
CH
2
CH
3 B-10 Q-71 9B Q-71 Cycohexyl B-17 Q-100 CH 2
CH
2
CH
3 B-10 Q-100 H B4 Q-100 Cyclohexyl B-17 Q-1619 CH 2
CH
2
CH
3 B-10 Q-119 H B4 Q-119 Cycbohexyl B-1 Q-120 CH 2
CH
2 0CH 3 B-10 Q-1204 CH B4 Q-120 Cyclohexyl B-17 Q-126 CH 2
CH
2
CH
3 B-10 Q-126 CH B4 Q-126 Cycohexyl B-17 Q-130 CH 2
CH
2
CH
3 B-10 Q-130 CH 3 B4 Q-130 Cyclohexyl B-17 Q-144 CH 2
CH
2 OCHI B-10 Q-144 CH3 B4 Q-144 Cyclohexyl B-17 Q-162 CH 2
CH
2
CH
3 B-10 Q-162 CH 3 B-4 Q-162 Cyclohexyl B-17 Q-169 CH 2
CH
2
OCH
3 B-10 Q-169 C 3 BA Q-169 Cyclohexyl B-17 Q-2 0 13 B-10 Q-2 CH 3 B Q-2 C 2
H
5 B-17 Q-16 CH 3 B-10 Q-16 CH 3 BA Q-16 2
H
5 B-17 Q-24 CI B-10 Q-24 C 3 BA Q-24 C 2
H
5 B-17 WO 00/43377 PCTIUSOO/01283 68 Q-29 CH3 B-10 Q-29 CH3 B4 Q-29 C 2
H
5 B-17 Q-57 CH3 B-10 Q-57 CH3 B-4 Q-57 C 2
H
5 B-17 Q-71 CH3 B-10 Q-71 CH3 B4 Q-71 C 2
H
5 B-17 Q-100 CH3 B-10 Q-100 I CH 3 B-4 Q-100 C 2
H
5 B-17 Q-119 CH3 B-10 Q-119 C3 B4 Q-119 C 2
H
5 B-17 Q-120 CH3 B-10 Q-120 CH3 B4 Q-120 C 2
H
5 B-17 Q-126 CH3 B-10 Q-126 CH3 B4 Q-126 C 2
H
5 B-17 Q-130 CH3 B-10 Q-130 CH3 B4 Q-130 C 2
H
5 B-17 Q-144 CH3 B-10 Q-144 CH B4 Q-144 C 2
H
5 B-17 Q-162 CH3 B-10 Q-162 CH3 B4 Q-162 C 2
H
5 B-17 Q-169 CH3 B-10 Q-169 CH3 B4 Q-169 C 2
H
5 B-17 Q-2 n-C6HI3 B-10 Q-2 CH 2
CF
3 B4 Q-2 n-C 3
H
7 B-6 Q-16 n-C 6
H
1 3 B-10 Q-16 CH 2
CF
3 B4 Q-16 n-C 3
H
7 B-6 Q-24 n-C 6
HI
3 B-10 Q-24 CH 2
CF
3 B4 Q-24 n-C 3
H
7 B-6 Q-29 n-C 6
H
1 3 B-10 Q-29 CH7CF 3 B4 Q-29 n-C 3
H
7 B-6 Q-57 n-C 6
H
1 3 B-10 Q-57 CH 2
CF
3 B4 Q-57 n-C 3
H
7 B-6 Q-71 n-C 6
H
1 3 B-10 Q-71 CH 2
CF
3 B4 Q-71 n-C 3
H
7 B-6 Q-100 n-C 6
H
13 B-10 Q-100 CH 2
CF
3 B4 Q-100 n-C 3
H
7 B-6 Q-119 n-C 6 H 13 B-10 Q-119 CH 2
CF
3 B4 Q-119 n-C 3
H
7 B-6 Q-120 n-C 6
H
1 3 B-10 Q-120 CH 2
CF
3 B-4 Q- 120 n-C 3
H
7 B-6 Q-126 n-C 6
H
1 3 B-10 Q-126 CH7CF 3 B4 Q-126 n-C 3
H
7 B-6 Q-130 n-C 6
H]
3 B-10 Q-130 CH 2
CF
3 B4 Q-130 n-C 3
H
7 B-6 Q-144 n-C 6
H
1 3 B-10 Q-144 CH 2
CF
3 B4 Q-144 n-C 3
H
7 B-6 Q-162 n-C 6
H
13 B-10 Q-162 CH 2
CF
3 B4 Q-162 n-C 3
H
7 B-6 Q-169 n-C 6
H
1 3 B-10 Q-169 CH 2
CF
3 B-4 Q-169 n-C 3
H
7 B-6 Q RI R2 Q RI R2 Q RI R2 Q-2 C7H5 B-2 Q-2 C7H5 B-5 Q-2 C 2
H
5 B-8 Q-16 C7H5 B-2 Q-16 C7H5 B-5 Q-16 C 2
H
5 B-8 Q-24 C2H5 B-2 Q-24 C2H5 B-5 Q-24 C 2
H
5 B-8 Q-29 C7H5 B-2 Q-29 C7H5 B-5 Q-29 C 2
H
5 B-8 Q-57 2H5 B-2 Q-57 C B-5 Q-57 C 2
H
5 B-8 Q-71 C2HS B-2 Q-71 C7H B-5 Q-71 C 2
H
5 B-8 Q-100 C2H5 B-2 Q-100 C2H5 B-5 Q-100 C 2
H
5 B-8 WO 00/43377 PCT/USOO/01283 69 Q-119 C 2
H
5 B-2 Q-119 C 2
H
5 B-5 Q-119 C 2
H
5 B-8 Q-120 C 2
H
5 B-2 Q-120 C 2
H
5 B-5 Q-120 C 2
H
5 B-8 Q-126 C 2
H
5 B-2 Q-126 C 2
H
5 B-5 Q-126 C 2
H
5 B-8 Q-130 C 2
H
5 B-2 Q-130 C 2
H
5 B-5 Q-130 C 2
H
5 B-8 Q-144 C 2
H
5 B-2 Q-144 C 2
H
5 B-5 Q-144 C 2
H
5 B-8 Q-162 C 2
H
5 B-2 Q-162 C 2 B-5 Q-162 C 2
H
5 B-8 Q-169 C 2
H
5 B-2 Q-169 C 2
H
5 B-5 Q-169 C 2
H
5 B-8 Q-2 C 3
H
7 B-2 Q-2 i-C 3 H7 B-6 Q-2 Cyclopropyl B-8 Q-16 C 3
H
7 B-2 Q-16 i-C 3 H7 B-6 Q-16 Cyclopropyl B-8 Q-24 C 3
H
7 B-2 Q-24 i-C 3
H
7 B-6 Q-24 Cyclopropyl B-8 Q-29 C 3
H
7 B-2 Q-29 i-C 3
H
7 B-6 Q-29 Cyclopropyl B-8 Q-57 C 3
H
7 B-2 Q-57 i-C 3
H
7 B-6 Q-57 Cyclopropyl B-8 Q-71 C 3
H
7 B-2 Q-71 i-C 3
H
7 B-6 Q-71 Cyclopropyl B-8 Q-100 C 3
H
7 B-2 Q-100 i-CiH 7 B-6 Q-100 Cyclopropyl B-8 Q-1 19 C 3
H
7 B-2 Q-119 i-C 3
H
7 B-6 Q-119 Cyclopropyl B-8 Q-120 C 3
H
7 B-2 Q-120 i-C 3
H
7 B-6 Q-120 Cycloprpyl B-8 Q-126 C 3
H
7 B-2 Q-126 i-C 3
H
7 B-6 Q-126 Cyclopropyl B-8 Q-130 C 3
H
7 B-2 Q-130 i-C 3
H
7 B-6 Q-130 Cyclopropyl B-8 Q-144 C 3
H
7 B-2 Q-144 i-C 3
H
7 B-6 Q-144 Cyclopropyl B-8 Q-162 C 3
H
7 B-2 Q- 162 i-C 3
H
7 B-6 Q-162 Cyclopropyl B-8 Q- 169 C 3
H
7 B-2 Q-169 i-C 3
H
7 B-6 Q-169 Cyclopropyl B-8 Q-2 C 2
H
5 B-3 Q-2 C 2
H
5 B-6 Q-2 C 2
H
5 B-9 Q-16 C 2
H
5 B-3 Q-16 C 2
H
5 B-6 Q-16 C 2
H
5 B-9 Q-24 C 2
H
5 B-3 Q-24 C 2
H
5 B-6 Q-24 C 2
H
5 B-9 Q-29 C 2
H
5 B-3 Q-29 CIH 5 B-6 Q-29 C 2
H
5 B-9 Q-57 C 2
H
5 B-3 Q-57 C 2
H
5 B-6 Q-57 C 2
H
5 B-9 Q-71 C 2
H
5 B-3 Q-71 C 2
H
5 B-6 Q-71 C 2
H
5 B-9 Q-100 C 2
H
5 B-3 Q-100 C 2
H
5 B-6 Q-100 C 2 HS B-9 Q-119 C 2
H
5 B-3 Q-119 C 2
H
5 B-6 Q-119 C 2
H
5 B-9 Q-120 C2H5 B-3 Q-120 C 2
H
5 B-6 Q-120 C 2
H
5 B-9 Q-126 C2H5 B-3 Q-126 C 2 H B-6 Q-126 C 2
H
5 B-9 Q-130 C2H5 B-3 Q-130 C 2
H
5 B-6 Q-130 C 2
H
5 B-9 Q-144 CL B-3 Q-144 I C2H B-6 Q-144 C 2
H
5 B-9 Q-162 C B-3 Q- 162. 5 B-6 Q-162 C 2
H
5 B-9 WO 00/43377 PCT/USOO/01283 70 Q-169 C 2
H
5 B-3 Q-169 C 2
H
5 B-6 Q-169 C 2
H
5 B-9 Q-2 i-C 3
H
7 B-3 Q-2 C 2
H
5 B-7 Q-2 i-C 3
H
7 B-9 Q-16 i-C 3
H
7 B-3 Q-16 C 2
H
5 B-7 Q-16 i-C 3
H
7 B-9 Q-24 i-C 3
H
7 B-3 Q-24 C 2 HS B-7 Q-24 i-C 3
H
7 B-9 Q-29 i-C3H7 B-3 Q-29 C 2
H
5 B-7 Q-29 i-C 3
H
7 B-9 Q-57 i-C 3
H
7 B-3 Q-57 C 2
H
5 B-7 Q-57 i-C 3
H
7 B-9 Q-71 i-C 3
H
7 B-3 Q-71 C 2
H
5 B-7 Q-71 i-C 3 H7 B-9 Q-100 i-C 3
H
7 B-3 Q-100 C 2
H
5 B-7 Q-100 i-C 3
H
7 B-9 Q-119 i-C 3
H
7 B-3 Q-119 C 2
H
5 B-7 Q-119 i-C 3
H
7 B-9 Q-120 i-C 3
H
7 B-3 Q-120 C 2
H
5 B-7 Q-120 i-C 3
H
7 B-9 Q-126 i-C 3
H
7 B-3 Q-126 C 2
H
5 B-7 Q-126 i-C 3
H
7 B-9 Q-130 i-C 3
H
7 B-3 Q-130 C 2
H
5 B-7 Q-130 i-C 3
H
7 B-9 Q-144 i-C 3
H
7 B-3 Q-144 C 2
H
5 B-7 Q-144 i-C 3
H
7 B-9 Q-162 i-C 3
H
7 B-3 Q-162 C 2
H
5 B-7 Q-162 i-C 3
H
7 B-9 Q-169 i-C 3
H
7 B-3 Q-169 C 2
H
5 B-7 Q-169 i-C 3
H
7 B-9 Q-2 C 2
H
5 B4 Q-2 i-C 3
H
7 B-7 Q-2 C 2
H
5 B-11 Q-16 C 2
H
5 B4 Q-16 i-C 3
H
7 B-7 Q-16 C 2
H
5 B-11 Q-24 C7H5 B4 Q-24 i-C 3
H
7 B-7 Q-24 C 2
H
5 B-11 Q-29 C7H5 B4 Q-29 i-C 3
H
7 B-7 Q-29 C 2
H
5 B-11 Q-57 C2HS B4 Q-57 i-C 3
H
7 B-7 Q-57 C 2
H
5 B-11 Q-71 C7HS B4 Q-71 i-C 3
H
7 B-7 Q-71 C 2
H
5 B-1I Q-100 C7H5 B4 Q-100 i-C 3
H
7 B-7 Q-100 C 2
H
5 B-11 Q-119 C7H5 B4 Q-119 i-C 3
H
7 B-7 Q-119 C 2
H
5 B-11 Q-120 C2H5 B4 Q-120 i-C 3
H
7 B-7 Q-120 C 2 HS B-11 Q-126 C7H5 B4 Q-126 i-C 3
H
7 B-7 Q-126 C 2
H
5 B-11 Q-130 C2H5 B4 Q-130 i-C3H B-7 Q-130 C 2
H
5 B-11 Q-144 C7HS B4 Q-144 i-C 3
H
7 B-7 Q-144 C 2 HS B-11 Q-162 C 2
H
5 B4 Q-162 i-C 3
H
7 B-7 Q-162 C 2
H
5 B-11 Q- 169 69BA i-C3H7 B-7 Q-169 C 2
H
5 B-1I Q RI R2 Q RI R2 Q RI R2 Q-2 Cyclopropyl B-Il Q-2 C 2
H
5 B-14 Q-2 i-C3H7 B-16 Q-16 Cyclopropyl B-I1 Q-16 C 2
H
5 B-14 Q-16 i-C3H7 B-16 Q-24 ICyciopropyl B- II Q-24 C 2
H
5 B- 14 Q-24 i-C3H B- 16 WO 00/43377 PCTUSOO/01283 71 Q-29 Cyclopropyl B-Il Q-29 C L B-14 Q-29 i-C 3
H
7 B-16 Q-57 Cyclopropyl B-11 Q-57 C L B-14 Q-57 i-C 3
H
7 B-16 Q-71 Cyciopropyl B-11 Q-71 C L B-14 Q-71 i-C 3
H
7 B-16 Q-100 Cyclopropyl B-11 Q-100 C2HS B-14 Q-100 b-C 3
H
7 B-16 Q-119 Cyclopropyl B-11 Q-19 C2H B-14 Q-119 i-C 3
H
7 B-16 Q-120 Cyclopropyl B-11 Q-120 2 B-14 Q-120 i-C 3
H
7 B-1 Q-126 Cyciopropyl B-il Q-126 C B-14 Q-126 b-C 3
H
7 B-16 Q-130 Cyciopropyl B-11 Q-130 C L B-14 Q-130 i-C 3
H
7 B-16 Q-144 Cyciopropyl B-11 Q-144 C B-14 Q-144 i-C 3
H
7 B-16 Q-162 Cyclopropyl B-11 Q-162 Cj B-14 Q-162 i-C 3
H
7 B-16 Q-169 Cyciopropyl B-11 Q-169 C L B-14 Q-169 i-C 3
H
7 B-16 Q-2 C 2
H
5 B-12 Q-2 - B-14 Q-2 t-C 4
H
9 B-1 Q-16 C B-12 Q-16 i B-14 Q-16 t-C 4
H
9 B-1 Q-24 C B-12 Q-24 i B-14 Q-24 t-C 4
H
9 B-1 Q-29 C B-12 Q-29 i-C3H7 B-14 Q-29 t-C 4
H
9 B-1 Q-57 C B-12 Q-57 i-C3H B-14 Q-57 t-CH B-1 Q-71 C B-12 Q-71 -C;H7 B-14 Q-71 t-C 4 H9 B-1 Q-100 C B-12 Q- i-C3H7 B-14 Q-100 t B-1 Q-119 C B-12 Q-119 i B-14 Q-119 t B-1 Q-120 C 2
H
5 B-12 Q-20 i-C3H7 B-14 Q-120 t B-10 Q-126 C B-12 Q-126 H B-14 Q-126 t-C 4
H
9 B-1 Q-130 C B-12 Q-130 i-C 3
H
7 B-14 Q-130 t B-1 Q-144 C B-12 Q-144 i-CIH 7 B-14 Q-144 t B-1 Q-162 C B-12 Q-162 i-C 3
H
7 B-14 Q-162 t-C 4
H
9 B-1 Q-169 C2H5 B-12 Q-169 i-CIH 7 B-14 Q-169 t j B-10 Q-2 - B-12 Q-2 CH B-15 Q-2 i j B-1 Q-16 i B-12 Q-16 C B-15 Q-16 i j B-1 Q-24 i-C3H7 B-12 Q-24 C B-15 Q-24 i B-1 Q-29 i B-12 Q-29 C2H B-15 Q-29 i j B-10 Q-57 i B-12 Q-57 C B-15 Q-57 i B-1 Q-71 B-12 Q-71 C2H B-15 Q-71 i j B-1 Q-100 i B-12 Q-100 C L B-15 Q-100 - B-10 Q-119 i B-12 Q-119 C 2 Hq B-15 Q-119 i B-1 Q-120 1i-C H B-12 1Q-20 CH B-15 Q-120 i-CH B- WO 00/43377 PCT/USOO/01283 72 Q-126 i-C 3
H
7 B-12 Q-126 C2H5 B-15 Q-126 i-C 4
H
9 B-10 Q-130 i-C 3
H
7 B-12 Q-130 C2H B-15 Q-130 i-C 4
H
9 B-10 Q-144 i-C 3
H
7 B-12 Q-144 C B-15 Q-144 i-C 4
H
9 B-10 Q-162 i-C 3
H
7 B-12 Q-162 C2H B-15 Q-162 i-C 4 Hq B-10 Q-169 _ -C 3
H
7 B-12 Q-169 C2H B-15 Q-169 1-C 4 H9 B-10 Q-2 C 2
H
5 B-13 Q-2 i-C 3
H
7 B-15 Q-2 CHCFj B-10 Q-16 CAS B-13 Q-16 i-C3H7 B-15 Q-16 CH 2
CF
3 B-10 Q-24 C 2
H
5 B-13 Q-24 i-C3H7 B-15 Q-24 CH 2
CF
3 B-10 Q-29 C 2
H
5 B-13 Q-29 i-C3H7 B-15 Q-29 CH 2
CF
3 B-10 Q-57 C 2
H
5 B-13 Q-57 i B-15 Q-57 CH 2
CF
3 B-10 Q-71 C 2
H
5 B-13 Q-71 i-CIH7 B-15 Q-71 CHCFA B-10 Q-100 C 2
H
5 B-13 Q-100 i-C3H7 B-15 Q-100 CH 2
CF
3 B-10 Q-119 C 2 HS B-13 Q-119 i-C37 B-15 Q-119 CH 2
CF
3 B-10 Q-120 C 2
H
5 B-13 Q-120 i-C3H7 B-15 Q-120 CH 2
CF
3 B-10 Q-126 C 2
H
5 B-13 Q-126 3 B-15 Q-126 CH 2
CF
3 B-10 Q-130 C 2
H
5 B-13 Q-130 - B-15 Q-130 CH 2
CF
3 B-10 Q-144 j H B-13 Q-144 H B-15 Q-144 CH 2
CF
3 B-10 Q-162 C2H5 B-13 Q-162 i-C H7 - Q-162 CII 2 CFI B-10 Q-169 C2H5 B-13 Q-169 i 2 B-15 Q-169 CH 2
CF
3 B-10 Q-2 i-C 3
H
7 B-13 Q-2 C2H5 B-16 Q-2 n-C 3
H
7 B-10 Q-16 &C 3
H
7 B-13 Q-16 C B-16 Q-16 n-C 3
H
7 B-10 Q-24 &C 3
H
7 B-13 Q-24 C L B-16 Q-24 n-C 3
H
7 B-10 Q-29 i-C 3
H
7 B-13 Q-29 C2HS B-16 Q-29 n-C 3
H
7 B-10 Q-57 i-C 3
H
7 B-13 Q-57 C B-16 Q-57 n B-10 Q-71 i-C3H7 B-13 Q-71 C2H5 B-16 Q-71 n B-10 Q-100 - B-13 Q-100 C L B-16 Q-100 n-C 3
H
7 B-10 Q-119 i-37 B-13 Q-1 19 C25 B-16 Q-119 n-C3H7 B-10 Q-120 i B-13 Q-120 C B-16 Q-120 n-C3H7 B-10 Q-126 i B-13 Q-126 C2HS B-16 Q-126 n-C3H7 B-10 Q-130 i-C3H7 B-13 Q-130 C B-16 Q-130 B-10 Q-144 i-C3H7 B-13 Q-144 C2H5 B-16 Q-144 n-C3H7 B-10 Q-162 i-C3H7 B-13 Q-162 C2H5 B-16 Q-162 n-C3H7 B-10 Q-169 i B-13 Q-169 C2H5 B-16 Q-169 n-C3H7 B-10 WO 00/43377 PCT/USOO/01283 73 TABLE 3
X
2
X
3 Q X1 X2 X R _ R2 i-Pr S 0 0 i-Pr 4-F-Phenyl i-Pr 0 S 0 i-Pr 4-F-Phenyl i-Pr 0 0 S i-Pr 4-F-Phenyl i-Pr NMe 0 0 i-Pr 4-F-Phenyl i-Pr 0 NMe 0 i-Pr 4-F-Phenyl i-Pr 0 0 NMe i-Pr 4-F-Phenyl i-Pr NCN 0 0 i-Pr 4-F-Phenyl i-Pr 0 NCN 0 i-Pr 4-F-Phenyl i-Pr 0 0 NCN i-Pr 4-F-Phenyl i-Pr S S 0 i-Pr 4-F-Phenyl i-Pr S 0 S i-Pr 4-F-Phenyl i-Pr 0 S S i-Pr 4-F-Phenyl i-Pr S S S i-Pr 4-F-Phenyl c-Pr S 0 0 i-Pr 4-F-Phenyl c-Pr 0 S 0 i-Pr 4-F-Phenyl c-Pr 0 0 S i-Pr 4-F-Phenyl c-Pr NMe 0 0 i-Pr 4-F-Phenyl c-Pr 0 NMe 0 i-Pr 4-F-Phenyl c-Pr 0 0 NMe i-Pr 4-F-Phenyl c-Pr NCN 0 0 i-Pr 4-F-Phenyl c-Pr 0 NCN 0 i-Pr 4-F-Phenyl c-Pr 0 0 NCN i-Pr 4-F-Phenyl c-Pr S S 0 i-Pr 4-F-Phenyl c-Pr S 0 S i-Pr 4-F-Phenyl c-Pr 0 S S i-Pr 4-F-Phenyl c-Pr S S S i-Pr 4-F-Phenyl i-Pr 0 0 0 i-Pr 2-Cl-Pyridin-5-yl i-Pr O 0 0 i-Pr 2-F-Pyridin-5-yl WO 00/43377 PCT/US0O/01283 74 i-Pr 0 O O i-Pr 2-Br-Pyridin-5-yl i-Pr 0 0 0 i-Pr 2-Me-Pyridin-5-yl i-Pr 0 0 0 i-Pr 2-CF-Pyridin-5-yl i-Pr 0 0 0 i-Pr 2-Cl-Pyrimidin-5-yl i-Pr 0 o o i-Pr 2-F-Pyrimidin-5-yl i-Pr 0 o o i-Pr 2-Br-Pyrimidin-5-yl i-Pr 0 0 0 i-Pr 2-Me-Pyrimidin-5-yl i-Pr 0 0 0 i-Pr 2-CF-Pyrimidin-5-yl i-Pr 0 0 0 i-Pr 2-Cl-Thien-5-yl i-Pr 0 0 0 i-Pr 2-F-Thien-5-yl i-Pr 0 0 0 i-Pr 2-Me-Thien-5-yl i-Pr 0 0 0 i-Pr Thien-2-yl i-Pr 0 0 0 i-Pr Pyrimidin-5-yl i-Pr 0 0 0 i-Pr 2-Cl-Pyridazin-5-yl i-Pr 0 0 0 i-Pr 2-C-1,3,4-Thiadiazol-5-yl i-Pr 0 0 0 i-Pr 2-CFrl,3,4-Thiadiazol-5-yl i-Pr 0 0 0 i-Pr 2-Cl-Thiazol-5-yl i-Pr 0 0 0 i-Pr 5-Cl-Thiazol-2-yl c-Pr 0 0 1 0 i-Pr 5-lTin-2-yl c-Pr 0 0 0 i-Pr Thien-2-yl Et 0 0 0 i-Pr Thien-2-yl n-Pr 0 0 0 i-Pr Thien-2-yl i-Bu 0 0 0 i-Pr Thien-2-yl Allyl 0 0 0 i-Pr Thien-2-yl Alleyl 0 0 0 1 i-Pr Tlbien-2-yI c-Hexyl 0 0 0 i-Pr Thien-2-yl c-Pr 0 0 0 i-Pr 2-Cl-Pyridin-5-yl Et 0 0 0 i-Pr 2-Cl-Pyridin-5-yl n-Pr 0 0 0 i-Pr 2-Cl-Pyridin-5-yl Me 0 0 0 i-Pr 2-Cl-Pyridin-5-yl i-Bu 0 0 0 i-Pr 2-Cl-Pyridin-5-yl Allyl 0 0 0 i-Pr 2-Cl-Pyridin-5-yl c-Hexyl 0 0 0 i-Pr 2-Cl-Pyridin-5-yl s-Bu 0 0 0 i-Pr 2-Cl-Pyridin-5-yl s-Bu 0 0 0 i-Pr Thien-2-yl WO 00/43377 PCT/USOO/01283 75 Formulation/Utility Compounds of this invention will generally be used as a formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant. The formulation or composition ingredients are selected to be 5 consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature. Useful formulations include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like which optionally can be thickened into gels. Useful formulations further include solids such as dusts, 10 powders, granules, pellets, tablets, films, and the like which can be water-dispersible ("wettable") or water-soluble. Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or "overcoated"). Encapsulation can control or delay release of the active ingredient. Sprayable formulations can be extended in suitable media and used 15 at spray volumes from about one to several hundred liters per hectare. High-strength compositions are primarily used as intermediates for further formulation. The formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight. Weight Percent Active Ingredient Diluent Surfactant Water-Dispersible and Water-soluble 5-90 0-94 1-15 Granules, Tablets and Powders. Suspensions, Emulsions, Solutions 5-50 40-95 0-15 (including Emulsifiable Concentrates) Dusts 1-25 70-99 0-5 Granules and Pellets 0.01-99 5-99.99 0-15 High Strength Compositions 90-99 0-10 0-2 20 Typical solid diluents are described in Watkins, et al., Handbook ofInsecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon's Detergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, New Jersey, as well as Sisely and Wood, Encyclopedia ofSurface Active Agents, Chemical Publ. 25 Co., Inc., New York, 1964, list surfactants and recommended uses. All formulations can WO 00/43377 PCT/USOO/01283 76 contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth and the like, or thickeners to increase viscosity. Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl 5 sulfates, alkylbenzene sulfonates, organosilicones, NN-dialkyltaurates, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, and polyoxyethylene/polyoxypropylene block copolymers. Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium 10 sulfate. Liquid diluents include, for example, water, N,N-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, tung, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols 15 such as methanol, cyclohexanol, decanol and tetrahydrofurfuryl alcohol. Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by blending and, usually, grinding as in a hammer mill or fluid-energy mill. Suspensions are usually prepared by wet-milling; see, for example, U.S. 3,060,084. Granules and pellets can be prepared by spraying the active 20 material upon preformed granular carriers or by agglomeration techniques. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp 147-48, Perry's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and WO 91/13546. Pellets can be prepared as described in U.S. 4,172,714. Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, 25 U.S. 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030. Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566. For further information regarding the art of formulation, see U.S. 3,235,361, Col. 6, line 16 through Col. 7, line 19 and Examples 10-41; U.S. 3,309,192, Col. 5, line 43 through 30 Col. 7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182; U.S. 2,891,855, Col. 3, line 66 through Col. 5, line 17 and Examples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp 81-96; and Hance et al., Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989.
WO 00/43377 PCT/USOO/01283 77 In the following Examples, all percentages are by weight and all formulations are prepared in conventional ways. Compound numbers refer to compounds in Index Tables A-D below. Example A 5 High Strength Concentrate Compound 2 98.5% silica aerogel 0.5% synthetic amorphous fine silica 1.0%. Example B 10 Wettable Powder Compound 2 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% 15 montmorillonite (calcined) 23.0%. Example C Granule Compound 2 10.0% attapulgite granules (low volatile matter, 20 0.71/0.30 mm; U.S.S. No. 25-50 sieves) 90.0%. Example D Extruded Pellet Compound 2 25.0% anhydrous sodium sulfate 10.0% 25 crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%. Test results indicate that the compounds of the present invention are highly active preemergent and postemergent herbicides or plant growth regulants. Many of them have 30 utility for broad-spectrum pre- and/or postemergence weed control in areas where complete control of all vegetation is desired such as around fuel storage tanks, industrial storage areas, parking lots, drive-in theaters, air fields, river banks, irrigation and other waterways, around billboards and highway and railroad structures. Some of the compounds are useful for the control of selected grass and broadleaf weeds with tolerance to important agronomic crops 5 which include but are not limited to alfalfa, barley, cotton, wheat, rape, sugar beets, corn (maize), sorghum, soybeans, rice, oats, peanuts, vegetables, tomato, potato, perennial WO 00/43377 PCT/USOO/01283 78 plantation crops including coffee, cocoa, oil palm, rubber, sugarcane, citrus, grapes, fruit trees, nut trees, banana, plantain, pineapple, hops, tea and forests such as eucalyptus and conifers (e.g., loblolly pine), and turf species (e.g., Kentucky bluegrass, St. Augustine grass, Kentucky fescue and Bermuda grass). Those skilled in the art will appreciate that not all 5 compounds are equally effective against all weeds. Alternatively, the subject compounds are useful to modify plant growth. A herbicidally effective amount of the compounds of this invention is determined by a number of factors. These factors include: formulation selected, method of application, amount and type of vegetation present, growing conditions, etc. In general, a herbicidally 10 effective amount of compounds of this invention is 0.001 to 20 kg/ha with a preferred range of 0.004 to 1.0 kg/ha. One skilled in the art can easily determine the herbicidally effective amount necessary for the desired level of weed control. Compounds of this invention can be used alone or in combination with other commercial herbicides, insecticides or fungicides. Compounds of this invention can also be 15 used in combination with commercial herbicide safeners such as benoxacor, dichlormid and furilazole to increase safety to certain crops. A mixture of one or more of the following herbicides with a compound of this invention may be particularly useful for weed control: acetochlor, acifluorfen and its sodium salt, aclonifen, acrolein (2-propenal), alachlor, ametryn, amidosulfuron, amitrole, ammonium sulfamate, anilofos, asulam, atrazine, 20 azafenidin, azimsulfuron, benazolin, benazolin-ethyl, benfluralin, benfuresate, bensulfuron-methyl, bensulide, bentazone, bifenox, bispyribac and its sodium salt, bromacil, bromoxynil, bromoxynil octanoate, butachlor, butralin, butroxydim (ICIA0500), butylate, caloxydim (BAS 620H), carfentrazone-ethyl, chlomethoxyfen, chloramben, chlorbromuron, chloridazon, chlorimuron-ethyl, chlornitrofen, chlorotoluron, chlorpropham, chlorsulfuron, 25 chlorthal-dimethyl, cinmethylin, cinosulfuron, clethodim, clomazone, clopyralid, clopyralid-olamine, cyanazine, cycloate, cyclosulfamuron, 2,4-D and its butotyl, butyl, isoctyl and isopropyl esters and its dimethylammonium, diolamine and trolamine salts, daimuron, dalapon, dalapon-sodium, dazomet, 2,4-DB and its dimethylammonium, potassium and sodium salts, desmedipham, desmetryn, dicamba and its diglycolammonium, 30 dimethylammonium, potassium and sodium salts, dichlobenil, dichlorprop, diclofop-methyl, 2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-5-methyl-3 pyridinecarboxylic acid (AC 263,222), difenzoquat metilsulfate, diflufenican, dimepiperate, dimethenamid, dimethylarsinic acid and its sodium salt, dinitramine, diphenamid, diquat dibromide, dithiopyr, diuron, DNOC, endothal, EPTC, esprocarb, ethalfluralin, 35 ethametsulfuron-methyl, ethofumesate, ethoxysulfuron, fenoxaprop-ethyl, fenoxaprop-P-ethyl, fenuron, fenuron-TCA, flamprop-methyl, flamprop-M-isopropyl, WO 00/43377 PCTUSOO/01283 79 flamprop-M-methyl, flazasulfuron, fluazifop-butyl, fluazifop-P-butyl, fluchloralin, flufenacet, flumetsulam, flumiclorac-pentyl, flumioxazin, fluometuron, fluoroglycofen-ethyl, flupoxam, flupyrsulfuron-methyl and its sodium salt, fluridone, flurochloridone, fluroxypyr, fluthiacet-methyl, fomesafen, fosamine-ammonium, glufosinate, glufosinate-ammonium, 5 glyphosate, glyphosate-isopropylanimonium, glyphosate-sesquisodium, glyphosate-trimesium, halosulfuron-methyl, haloxyfop-etotyl, haloxyfop-methyl, hexazinone, imazamethabenz-methyl, imazamox, imazapyr, imazaquin, imazaquin-ammonium, imazethapyr, imazethapyr-ammonium, imazosulfuron, ioxynil, ioxynil octanoate, ioxynil-sodium, isoproturon, isouron, isoxaben, isoxaflutole, lactofen, 10 lenacil, linuron, maleic hydrazide, MCPA and its dimethylammonium, potassium and sodium salts, MCPA-isoctyl, mecoprop, mecoprop-P, mefenacet, mefluidide, metam-sodium, methabenzthiazuron, methylarsonic acid and its calcium, monoammonium, monosodium and disodium salts, methyl [[[1-[5-[2-chloro-4-(trifluoromethyl)phenoxy]-2 nitrophenyl]-2-methoxyethylidene]amino]oxy]acetate (AKH-7088), methyl 5-[[[[(4,6 15 dimethyl-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]-1-(2-pyridinyl)-1H-pyrazole-4 carboxylate (NC-330), metobenzuron, metolachlor, metosulam, metoxuron, metribuzin, metsulfuron-methyl, molinate, monolinuron, napropamide, naptalam, neburon, nicosulfuron, norflurazon, oryzalin, oxadiazon, oxasulfuron, oxyfluorfen, paraquat dichloride, pebulate, pendimethalin, pentoxazone (KPP-314), perfluidone, phenmedipham, picloram, 20 picloram-potassium, pretilachlor, primisulfuron-methyl, prometon, prometryn, propachlor, propanil, propaquizafop, propazine, propham, propyzamide, prosulfuron, pyrazolynate, pyrazosulfuron-ethyl, pyridate, pyriminobac-methyl, pyrithiobac, pyrithiobac-sodium, quinclorac, quizalofop-ethyl, quizalofop-P-ethyl, quizalofop-P-tefuryl, rimsulfuron, sethoxydim, siduron, simazine, sulcotrione (ICIA005 1), sulfentrazone, sulfometuron-methyl, 25 TCA, TCA-sodium, tebuthiuron, terbacil, terbuthylazine, terbutryn, thenylchlor, thiafluamide (BAY 11390), thifensulfuron-methyl, thiobencarb, tralkoxydim, tri-allate, triasulfuron, triaziflam, tribenuron-methyl, triclopyr, triclopyr-butotyl, triclopyr-triethylammonium, tridiphane, trifluralin, triflusulfuron-methyl, and vernolate. In certain instances, combinations with other herbicides having a similar spectrum of 30 control but a different mode of action will be particularly advantageous for preventing the development of resistant weeds. Certain combinations of compounds of this invention with other herbicides may provide synergistic herbicidal effects on weeds or may provide enhanced crop safety. Preferred for better control of undesired vegetation in corn (e.g., lower use rate, 35 broader spectrum of weeds controlled, or enhanced crop safety) or for preventing the development of resistant weeds in corn are mixtures of a compound of this invention with WO 00/43377 PCT/USOO/01283 80 one or more of the herbicides selected from the group rimsulfuron, nicosulfuron, thifensulfuron, prosulfuron, halosulfuron, naphthalic anhydride, flurazole, dichlormid, fenchlorazole ethyl, naphthalic anhydride, MG-191 (2-dichloromethyl)-2-methyl-1,3 dioxolane), dicyclonon, benoxacor, cyometrinil, furilazole, oxabetrinil, cloquintocet mexyl, 5 fluxofenim, fenclorim, menfenpyr diethyl, and R-29148 (3-(dichloroacetyl)-2,2,5 trimethyloxazolidine). Specifically preferred mixtures for use in corn are selected from the group consisting of: a) Compound 113 (Index Table C, mixture partner A, generally applied at a rate of 10 10 to 1000 g/ha, preferably applied at a rate of 50 to 500 g/ha) in combination with: Combination Number Mixture partner B 1 rimsulfuron 2 nicosulfuron 3 dichlormid 4 benoxacor 5 naphthalic anhydride 6 rimsulfuron (B 1) in combination with dichlormid (B2) 7 nicosulfuron (B3) in combination with dichlormid (B4) Combination 1 is generally used in a ratio of A to B of 3:1 to 50:1, preferably 5:1 to 30:1, with B being applied at a rate of 1 to 100 g/ha, preferably 5 to 50 g/ha. Combination 2 15 is generally used in a ratio of A to B of 2:1 to 20:1, preferably 4:1 to 10:1, with B being applied at a rate of 1 to 100 g/ha, preferably 20 to 70 g/ha. Combination 3 is generally used in a ratio of A to B of 1:10 to 10:1, preferably 1:2 to 2:1, with B being applied at a rate of 10 to 1000 g/ha, preferably 50 to 500 g/ha. Combination 4 is generally used in a ratio of A to B of 1:10 to 10:1, preferably 1:2 to 4:1, with B being applied at a rate of 1 to 1000 g/ha, 20 preferably 20 to 500 g/ha. Combination 5 is generally used in a ratio of A to B of 1:500 to 50:1, preferably 1:20 to 10:1, with B being applied at a rate of 10 to 1000 g/ha, preferably 50 to 500 g/ha. Combination 6 is generally used in a ratio of A to B1 of 3:1 to 50:1, preferably 5:1 to 30:1, and a ratio of A to B2 of 1:10 to 10:1, preferably 1:2 to 2:1, with BI being applied at a rate of 1 to 100 g/ha, preferably 5 to 50 g/ha, and B2 being applied at a rate of 10 25 to 1000 g/ha, preferably 50 to 500 g/ha. Combination 7 is generally used in a ratio of A to B3 of 2:1 to 20:1, preferably 4:1 to 10:1, and a ratio of A to B4 of 1:10 to 10:1, preferably WO 00/43377 PCT/USOO/01283 81 1:2 to 2:1, with B3 being applied at a rate of 1 to 100 g/ha, preferably 20 to 70 g/ha, and B4 being applied at a rate of 10 to 1000 g/ha, preferably 50 to 500 g/ha. b) Compound 131 (Index Table C, mixture partner A, generally applied at a rate of 10 5 to 1000 g/ha, preferably applied at a rate of 50 to 500 g/ha) in combination with: Combination Number Mixture partner B 1 rimsulfuron 2 nicosulfuron 3 dichlormid 4 benoxacor 5 naphthalic anhydride 6 rimsulfuron (B 1) in combination with dichlormid (B2) 7 nicosulfuron (B3) in combination with dichlormid (B4) Combination 1 is generally used in a ratio of A to B of 3:1 to 50:1, preferably 5:1 to 30:1, with B being applied at a rate of 1 to 100 g/ha, preferably 5 to 50 g/ha. Combination 2 10 is generally used in a ratio of A to B of 2:1 to 20:1, preferably 4:1 to 10:1, with B being applied at a rate of 1 to 100 g/ha, preferably 20 to 70 g/ha. Combination 3 is generally used in a ratio of A to B of 1:10 to 10:1, preferably 1:2 to 2:1, with B being applied at a rate of 10 to 1000 g/ha, preferably 50 to 500 g/ha. Combination 4 is generally used in a ratio of A to B of 1:10 to 10:1, preferably 1:2 to 4:1, with B being applied at a rate of I to 1000 g/ha, 15 preferably 20 to 500 g/ha. Combination 5 is generally used in a ratio of A to B of 1:500 to 50:1, preferably 1:20 to 10:1, with B being applied at a rate of 10 to 1000 g/ha, preferably 50 to 500 g/ha. Combination 6 is generally used in a ratio of A to B 1 of 3:1 to 50:1, preferably 5:1 to 30:1, and a ratio of A to B2 of 1:10 to 10:1, preferably 1:2 to 2:1, with BI being applied at a rate of 1 to 100 g/ha, preferably 5 to 50 g/ha, and B2 being applied at a rate of 10 20 to 1000 g/ha, preferably 50 to 500 g/ha. Combination 7 is generally used in a ratio of A to B3 of2:1 to 20:1, preferably 4:1 to 10:1, and a ratio of A to B4 of 1:10 to 10:1, preferably 1:2 to 2:1, with B3 being applied at a rate of I to 100 g/ha, preferably 20 to 70 g/ha, and B4 being applied at a rate of 10 to 1000 g/ha, preferably 50 to 500 g/ha. 25 c) Compound 242 (Index Table C, mixture partner A, generally applied at a rate of 10 to 1000 g/ha, preferably applied at a rate of 50 to 500 g/ha) in combination with: WO 00/43377 PCTIUSOO/01283 82 Combination Number Mixture partner B 1 Rimsulfuron 2 Nicosulfuron 3 Dichlormid 4 Benoxacor 5 naphthalic anhydride 6 rimsulfuron (B 1) in combination with dichlormid (B2) 7 nicosulfuron (B3) in combination with dichlormid (B4) Combination 1 is generally used in a ratio of A to B of 3:1 to 50:1, preferably 5:1 to 30:1, with B being applied at a rate of 1 to 100 g/ha, preferably 5 to 50 g/ha. Combination 2 5 is generally used in a ratio of A to B of 2:1 to 20:1, preferably 4:1 to 10:1, with B being applied at a rate of 1 to 100 g/ha, preferably 20 to 70 g/ha. Combination 3 is generally used in a ratio of A to B of 1:10 to 10:1, preferably 1:2 to 2:1, with B being applied at a rate of 10 to 1000 g/ha, preferably 50 to 500 g/ha. Combination 4 is generally used in a ratio of A to B of 1:10 to 10:1, preferably 1:2 to 4:1, with B being applied at a rate of 1 to 1000 g/ha, 10 preferably 20 to 500 g/ha. Combination 5 is generally used in a ratio of A to B of 1:500 to 50:1, preferably 1:20 to 10:1, with B being applied at a rate of 10 to 1000 g/ha, preferably 50 to 500 g/ha. Combination 6 is generally used in a ratio of A to BI of 3:1 to 50:1, preferably 5:1 to 30:1, and a ratio of A to B2 of 1:10 to 10:1, preferably 1:2 to 2:1, with B1 being applied at a rate of 1 to 100 g/ha, preferably 5 to 50 g/ha, and B2 being applied at a rate of 10 15 to 1000 g/ha, preferably 50 to 500 g/ha. Combination 7 is generally used in a ratio of A to B3 of 2:1 to 20:1, preferably 4:1 to 10:1, and a ratio of A to B4 of 1:10 to 10:1, preferably 1:2 to 2:1, with B3 being applied at a rate of I to 100 g/ha, preferably 20 to 70 g/ha, and B4 being applied at a rate of 10 to 1000 g/ha, preferably 50 to 500 g/ha. 20 d) Compound 146 (Index Table C, mixture partner A, generally applied at a rate of 10 to 1000 g/ha, preferably applied at a rate of 50 to 500 g/ha) in combination with: Combination Number Mixture partner B 1 Rimsulfuron WO 00/43377 PCTIUSOO/01283 83 2 Nicosulfuron 3 Dichlormid 4 Benoxacor 5 naphthalic anhydride 6 rimsulfuron (B 1) in combination with dichlormid (B2) 7 nicosulfuron (B3) in combination with dichlormid (B4) Combination 1 is generally used in a ratio of A to B of 3:1 to 50:1, preferably 5:1 to 30:1, with B being applied at a rate of 1 to 100 g/ha, preferably 5 to 50 g/ha. Combination 2 is generally used in a ratio of A to B of 2:1 to 20:1, preferably 4:1 to 10:1, with B being 5 applied at a rate of 1 to 100 g/ha, preferably 20 to 70 g/ha. Combination 3 is generally used in a ratio of A to B of 1:10 to 10:1, preferably 1:2 to 2:1, with B being applied at a rate of 10 to 1000 g/ha, preferably 50 to 500 g/ha. Combination 4 is generally used in a ratio of A to B of 1:10 to 10:1, preferably 1:2 to 4:1, with B being applied at a rate of I to 1000 g/ha, preferably 20 to 500 g/ha. Combination 5 is generally used in a ratio of A to B of 1:500 to 10 50:1, preferably 1:20 to 10:1, with B being applied at a rate of 10 to 1000 g/ha, preferably 50 to 500 g/ha. Combination 6 is generally used in a ratio of A to BI of 3:1 to 50:1, preferably 5:1 to 30:1, and a ratio of A to B2 of 1:10 to 10:1, preferably 1:2 to 2:1, with B1 being applied at a rate of 1 to 100 g/ha, preferably 5 to 50 g/ha, and B2 being applied at a rate of 10 to 1000 g/ha, preferably 50 to 500 g/ha. Combination 7 is generally used in a ratio of A to 15 B3 of 2:1 to 20:1, preferably 4:1 to 10:1, and a ratio of A to B4 of 1:10 to 10:1, preferably 1:2 to 2:1, with B3 being applied at a rate of 1 to 100 g/ha, preferably 20 to 70 g/ha, and B4 being applied at a rate of 10 to 1000 g/ha, preferably 50 to 500 g/ha. The following Tests demonstrate the control efficacy of the compounds of this 20 invention against specific weeds. The weed control afforded by the compounds is not limited, however, to these species. See Index Tables A-D for compound descriptions. The abbreviation "dec" indicates that the compound appeared to decompose on melting. The abbreviation "Ex." stands for "Example" and is followed by a number indicating in which example the compound is prepared. !5 WO 00/43377 PCT/USOO/01283 84 INDEX TABLE A R16 R1 Cmpd No. R' R 2 R16 MP(*C) I Et Et 4-OCH 3 113-116 2 Et Et 2,6-dimethyl 90-93 3 Et Et 4-F 71-76 4 i-Pr 4-F-Phenyl 2-CH 3 122-124 5 i-Pr 4-F-Phenyl 4-OCH 3 145-148 6 i-Pr 3, 6-dihydro-2H-pymn 4-OCH 3 98-100 7 (Ex. 1) i-Pr 4-F-Phenyl 2,4-di-Cl 57-60 8 i-Pr 4-F-Phenyl 2-Cl 80-83 9 i-Pr 3, 6-dihydro-2H-pyran 3,5-di-Cl 137-139 10 i-Pr 3, 6-dihydro-2H-pyran 2-CH 3 143-145 11 Et Et 3,5-di-CI oil* 12 Et Et 4-OCF 3 oil* 13 i-Pr 3, 6-dihydro-2H-pyran 4-OCF 3 oil* 14 i-Pr 4-F-Phenyl 2-OCF 3 129-131 15 i-Pr 4-F-Phenyl 2-CF 3 131-134 16 i-Pr 4-F-Phenyl 2, 5-di-Cl 120-122 17 i-Pr 4-F-Phenyl 1, 4-di-Me 154-156 18 i-Pr 4-F-Phenyl 2,6-di-Me 103-105 19 i-Pr 4-F-Phenyl 2,6-di-Cl 130-132 20 i-Pr 4-F-Phenyl 4-C1-2-CF 3 128-131 21 i-Pr 4-F-Phenyl 3-C1-2-Me 170-172 22 i-Pr 2,4-di-F-Phenyl 2,4-di-F 108-110 23 Et c-Hex 2,4-di-F oil* 24 i-Pr 2,4-di-F-Phenyl 2,4-di-Me 103-106 25 i-Pr 2,4-di-F-Phenyl 2-Me 85-89 26 Et c-Hex 2,4-di-Me 118-120 27 Et c-Hex 2,6-di-Me 120-122 WO 00/43377 PCT/USOO/01283 85 28 i-Pr 2,4-di-F-Phenyl 2,6-di-Me 129-131 29 Et c-Hex 2-OMe 111-114 30 i-Pr 4-F-Phenyl 2-OMe 109-111 31 i-Pr 2,4-di-F-Phenyl 2-OMe 55-60 32 i-Pr 2,4-di-F-Phenyl 2,4-di-OMe 134-137 33 i-Pr 4-F-Phenyl 2,4-di-OMe 175-177 34 i-Pr 4-F-Phenyl 2-Et 94-97 35 i-Pr 4-F-Phenyl 2-Me-4-OMe 112-115 36 i-Pr Phenyl 2-Me 148-150 37 c-Pr 4-F-Phenyl 2-Me oil* 38 i-Pr 4-F-Phenyl H oil* 39 i-Pr 4-CF 3 -Phenyl 2-Me 85 40 i-Pr 4-Me-Phenyl 2-Me 128 41 i-Pr 4-Cl-Phenyl 2-Me 139-141 42 i-Pr 2,4-di-C1-5-0-i-Pr-Phenyl 2-Me 68-70 43 i-Pr 4-F-Phenyl 2,4-di-Cl-5-0-i-Pr 148-150 44 i-Pr 4-N0 2 -Phenyl 2-Me 148 45 i-Pr 2,4-di-F-Phenyl 2-Et 93-97 46 (Ex.2) i-Pr Phenyl 2,6-di-Me 146-148 47 i-Pr 4-Cl-Phenyl 2,6-di-Me 143-147 48 i-Pr 3,4-di-F-Phenyl 2-Me 124 49 i-Pr 4-OMe-Phenyl 2-Me 95 50 c-Pr 2,4-diF-Phenyl 2-Me oil* 51 i-Pr 4-CN-Phenyl 2-Me 205 52 i-Pr 4-F-Phenyl 2-Et-6-Me oil* 53 i-Pr 4-F-Phenyl 2-CI-6-Me oil* 54 i-Pr 4-Cl-Phenyl 2-Cl-6-Me oil* 55 i-Pr Pyrrolidinyl 2,4-di-Cl 120-122 56 i-Pr Pyrrolidinyl 2-OCF 3 oil* 57 i-Pr Pyrrolidinyl 2-CF 3 120-122 58 i-Pr Pyrrolidinyl 2, 5-di-Cl 139-140 59 i-Pr Pyrrolidinyl 2-Me 103-106 60 i-Pr 4-F-Phenyl 2,4, 6-tri-Me 181-183 61 i-Pr 4-Cl-Phenyl 2,4, 6-tri-Me 121-122 WO 00/43377 PCT/USOO/01283 86 62 i-Pr 4-F-Phenyl 2-Me-6-OMe 100-102 63 Et c-Hex 2,4, 6-tri-Me 122-123 64 i-Pr 4-Cl-Phenyl 2-i-Pr, 6-Me oil* 65 i-Pr 4-F-Phenyl 2-i-Pr, 6-Me oil* 66 i-Pr Phenyl 2-i-Pr, 6-Me oil* 67 i-Pr 3,5-di-F 2-Me 120 68 i-Pr 2, 5-di-F 2-Me 98 69 i-Pr Benzyl 2,6-di-Me oil* 70 Et Benzyl 2,6-di-Me oil* 71 Et Benzyl 2-Me oil* 72 i-Pr Benzyl 2-Me oil* 73 i-Pr Phenyl 2-OMe, 6-Me 132-134 74 i-Pr 2,4-di-F-Phenyl 2-OMe, 6-Me 107-109 *see Index Table B for 1 H NMR data. INDEX TABLE B Cmpd No. 'H NMR Data (CDC1 3 solution unless indicated otherwise)a 11 8 1.25 (t, 6H), 3.40 (m, 4H), 6.96 (s, 1H), 7.55 (s, 1H), 8.59 (s, 1H). 12 8 1.26 (t, 6H), 3.58 (m, 4H), 7.36 (d, 2H), 7.61 (d, 2H). 13 8 1.33 (d, 6H) 2.3-2.4 (m, 2H), 3.86 (t, 2H), 4.2-4.3 (m, 2H), 4.38-4.45 (m, 1H), 5.83-5.90 7.38 (m, 2H), 7.60 (m, 2H). 23 8 7.5-7.4 (m, IH), 7.1 (t, 2H), 4.2-3.8 (m, 111), 3.5-3.2 (m, 2H), 2.0-1.8 (m, 3H), 1.8-1.0 (n 37 8 7.3-7.4 (m, 6H), 7.0-7.1 (t, 2H), 3.4 (m, 1H), 2.21 (s, 3H), 0.9 (m, 2H), 0.7-0.8 (m, 2H). 38 8 7.4-7.6 (m , 4H), 7.3 (m, 111), 7.0-7.2 (m, 2H), 4.7 (m, 1H), 1.2 (d, 6H). 50 8 7.3-7.4 (m, 4H), 7.2 (d, IH), 6.8-7.0 (q, 2H), 3.4 (m, 1H), 2.2 (s, 3H), 0.9 (d, 2H), 0.8 (d, 52 5 7.2-7.4 (m, 3H), 7.0-7.2 (m, 4H), 4.7 (m, 1H), 2.3-2.4 (q, 2H), 2.1 (s, 3H), 1.2 (d, 6H), 1. (t, 3H). 53 8 7.3 (m, 3H), 7.2 (m, 2H), 7.1 (t, 2H), 4.6-4.7 (m, 1H), 2.19 (s, 3H), 1.2 (d, 6H). 54 8 7.3-7.4 (q, 4H), 7.2 (im, 3H), 4.6-4.7 (m, 1H), 2.198 (s, 3H), 1.2 (d, 611). 69 8 7.4-7.1 (m, 8H), 4.68 (s, 2H), 4.5 (bs, 1H), 2.23 (s, 6H), 1.27 (d, 6H). 70 8 7.4-7.1 (m, 8H), 4.74 (s, 2H), 3.6-3.4 (bs, 2H), 2.26 (s, 6H), 1.2 (m, 311). 71 8 7.5-7.3 (m, 9H), 4.74 (m, 2H), 3.6-3.4 (bm, 211), 2.30 (s, 3H), 1.2 (bt, 311). 72 8 7.5-7.1 (m, 9H), 4.67 (s, 2H), 4.5 (bs, 1H), 2.27 (s, 3H), 1.28 (d, 6H). a 1H NMR data are in ppm downfield from tetramethylsilane. Couplings are designated by (s)-singlet, (d)-doublet, (t)-triplet, (q)-quartet, (m)-multiplet, (dd)-doublet of doublets, (dt)-doublet of triplets, 5 (br s)-broad singlet.
WO 00/43377 PCTIUSOO/01283 87 INDEX TABLE C 0 0 Q, N)JL NA W R Cmpd. Q RI___R2_ U________ MPC 75 1,3,5-Trimethylpyrazol-4-yl i-Pr 4-F-Phenyl 152-154 76 1 ,3,5-Trimethylpyrazol-4-yl i-Pr 2,4-diF-Phenyl 45-50 77 2-Thienylmethyl Et Et oil* 78 (Ex.9) Benzyl i-Pr 4-F-Phenyl 95-96 79 Benzyl i-Pr 2,4-diF-Phenyl 93-95 80 2-Thienyhmethyl i-Pr 4-F-Phenyl oil* 81 2-Thienylmethyl i-Pr 2-Dihydropyranyl oil* 82 2-Thienylmethyl -Et c-Hexyl oil* 83 2-Thlienylmethyl Me Phenyl oil* 84 2-Methylbenzyl Et Et oil* 85 2-Methylbenzyl Me Ph oil* 86 2-Thienylmethyl i-Pr 2,4-di-Ph 77-80 87 2-Methylbenzyl i-Pr 2,4-diF-Phenyl oil* 88 2-Methylbenzyl i-Pr 4-F-Phenyl 118-120 89 5-Tetahydronaphthyl Et Et oil* 90 5-Tetrahydronaphthyl i-Pr 4-F-Phenyl oil* 91 n-Propyl i -Pr 4-F-Phenyl oil1* 92 n-Propyl i-Pr Phenyl oil* 93 Allyl i-Pr Phenyl 68-70 94 Benzyl i-Pr Phenyl 90-94 95 1,3-Dimethyl-5-chloropyrazol- i-Pr 4-F-Phenyl 109-112 __ _ __ _ l _ _ __ _ _ __ __ _ _ __ _ __A_ _ 96 1,3-Dimethyl-5-chloropyrazol- i-Pr 2,4-diF-Phenyl 55-59
A
1 _ _ _ _ _ _ _ _ _ _ _ _ 97 I-Methyl-5-chloropyrazol-4-yl i-Pr 4-F-Phenyl 55-60 98 I-Methylpyrazol-4-yl i-Pr 4-F-Phenyl 145-146 99 2-Trifluoromethylcyclohexyl i-Pr 4-F-Phenyl oil* 100 3-Phenyl-5-mehylisoxazol4-yl i-Pr 4-F-Phenyl =206-209 WO 00/43377 PCT/USOO/01283 88 101 3-Ethyl-5-methylisoxazol-4-yl i-Pr 4-F-Phenyl oil* 102 3-Ethyl-5-ethylisoxazol-4-yl i-Pr 4-F-Phenyl 74-77 103 2-Thienylmethyl i-Pr Phenyl 90-95 104 2-Methoxybenzyl i-Pr Phenyl 115-117 105 Allyl i-Pr 4-Ci-Phenyl oil* 106 Benzyl i-Pr 4-Ci-Phenyl oil* 107 Ethyl i-Pr 4-F-Phenyl 78-81 108 Ethyl i-Pr 4-Ci-Phenyl 83-86 109 Isopropyl i-Pr 2,4-diF-Phenyl 82-85 110 c-Hexyl i-Pr 4-F-Phenyl 128-131 111 c-Hexyl i-Pr 4-CI-Phenyl 126-130 112 c-Hexyl i-Pr Phenyl 136-139 113 (Ex. 14) Isopropyl i-Pr Phenyl 82-86 114 Isopropyl i-Pr 4-Cl-Phenyl 76-80 115 c-Hexyl i-Pr 2,4-diF-Phenyl 88-90 116 Ethyl i-Pr 2,4-diF-Phenyl 75-77 117 Ethyl i-Pr Phenyl 74-76 118 t-Bu i-Pr 4-CI-Phenyl 88-90 119 n-Pr i-Pr 4-CI-Phenyl oil* 120 1,3,5-Trimethylpyrazol-4-yl i-Pr Phenyl 48-52 121 1,3-Dimethyl-5-chloropyrazol-4- i-Pr Phenyl 54-56 y 122 1-Methyl-5-chloropyrazol-4-yl i-Pr Phenyl 94-97 123 1-Methylpyrazol-4-yl i-Pr Phenyl 111-112 124 1-Methylpyrazol-5-yl i-Pr 4-F-Phenyl 52-59 125 1, 4-Dimethylpyrazol-5-yl i-Pr 4-F-Phenyl 45-49 126 3,5-di-Me-isoxazol-4-yl i-Pr 2-Dihydropyranyl oil* 127 Allyl c-Pr 2,4-F-Phenyl oil* 128 CH 2
CO
2 Et i-Pr 4-F-Phenyl oil* 129 t-Bu i-Pr Phenyl oil* 130 n-Pr i-Pr 2,4-diF-Phenyl oil* 131 (Ex.13) i-Pr i-Pr 4-F-Phenyl 78-80 132 i-Pr i-Pr 4-Me-Phenyl 68-71 133 a-Me-Benzyl i-Pr 4-Cl-Phenyl oil* WO 00/43377 PCTIUSOO/01283 89 134 a-Me-Benzyl i-Pr 4-F-Phenyl oil* 135 3,5-Diisopropylisoxazol-4-yl i-Pr 4-F-Phenyl oil* 136 (Ex.5) 2-Methylbenzyl i-Pr 4-Cl-Phenyl oil* 137 (Ex.7) Methyl i-Pr 4-Cl-Phenyl 121-123 138 (Ex.6) Methyl i-Pr 4-F-Phenyl 135-136 139 2-Methylallyl i-Pr 4-F-Phenyl oil* 140 2-Chlorobenzyl i-Pr 4-F-Phenyl oil* 141 2-Chlorobenzyl i-Pr Pyrrolidinyl oil* 142 2-Methoxybenzyl i-Pr Pyrrolidinyl oil* 143 2-Methoxybenzyl i-Pr 4-F-Phenyl 104-106 144 2-Chlorobenzyl i-Pr 2-Dihydropyranyl oil* 145 2-Chlorobenzyl i-Pr c-Hexenyl oil* 146 (Ex.3) Allyl i-Pr 4-F-Phenyl 65-66 147 Allyl i-Pr 2-Dihydropyranyl oil* 148 2-Chloroethyl i-Pr 4-F-Phenyl oil* 149 2-Chloroethyl i-Pr 2-Dihydropyranyl oil* 150 Allyl Et Pyrrolidinyl oil* 151 Allyl i-Pr 2,4-diF-Phenyl oil* 152 Benzyl Et Et oil* 153 Benzyl Me Phenyl oil* 154 Allyl c-Pr 4-F-Phenyl oil* 155 3,5-Dimethylisoxazol-4-yl i-Pr 4-F-Phenyl 133-136 156 3,5-Dimethylisoxazol-4-yl i-Pr 2,4-diF-Phenyl 175-178 157 3,5-Dimethylisothiazol-4-yl i-Pr 4-F-Phenyl oil* 158 3,5-Dimethylisothiazol-4-yl i-Pr 2,4-di-F-Phenyl 158-161 159 3,5-Dimethylisothiazol-4-yl i-Pr 4-Cl-Phenyl 124-127 160 2, 5-Dichlorothiazoly-4-yl i-Pr 4-F-Phenyl oil* 161 2-Me-c-Hex i-Pr 4-F-Phenyl 78-81 162 2-Me-c-Hex i-Pr Phenyl oil* 163 CF 3
CH
2 i-Pr 4-F-Phenyl 122-124 164 H i-Pr 4-F-Phenyl 55-60 165 i-Pr i-Pr Benzyl oil* 166 i-Pr Et Benzyl oil* 167 a-Me-Benzyl (S) i-Pr 4-F-Phenyl oil* WO 00/43377 PCT/USOO/01283 90 168 a-Me-Benzyl (S) i-Pr Phenyl oil* 169 (Ex.8) i-Bu i-Pr 4-F-Phenyl 80-81 170 (Ex.4) NMe2 i-Pr 4-F-Phenyl 69-71 171 2-Methylphenyl i-Pr 2, 3-DiF-Phenyl 88 172 2-Methyl-c-hexyl i-Pr 2,4-DiF-Phenyl oil* 173 a-Methylbenzyl (S) i-Pr Phenyl 72-74 174 a-Methylbenzyl (S) i-Pr 4-Cl-Phenyl oil* 175 2-Methylphenyl i-Pr 4-Br-Phenyl 117 176 2-Methylphenyl i-Pr 2,6-di-F-Phenyl 91 177 Phenyl (Me)N i-Pr 4-F-Phenyl 62-64 178 a-Methylbenzyl (R) i-Pr 4-Cl-Phenyl oil* 179 a-Methylbenzyl (R) i-Pr 4-F-Phenyl 64-67 180 2,6-DiMe-Phenyl i-Pr 4, 6-Dimethoxy-1,3,5- oil* Triazine-2-yl 181 2-Me-Phenyl i-Pr 4, 6-Dimethoxy- 1,3,5- oil* Triazine-2-yl 182 i-Propyl i-Pr 4, 6-Dimethoxy-1,3,5- oil* Triazine-2-yl 183 Phenyl (Me)N Et c-Hexyl oil* 184 3-Trifluoromethylcyclohexyl i-Pr 4-F-Phenyl oil* 185 2-Methylphenyl i-Pr 2,4-DiCi-Phenyl 54 186 2-Methylphenyl i-Pr 2-Cl, 4-F-Phenyl 48-51 187 2-Methylphenyl i-Pr 4-Ph-Phenyl 63 188 Oxiranylmethyl i-Pr 4-F-Phenyl oil* 189 i-Propyl Et 4-Pyridylmethyl oil* 190 i-Propyl Et 1,3,4-Thiadiazol-2-yl oil* 191 (2,4-Dimethylthiazol-5- i-Pr 4-Cl-Phenyl oil* yl)methyl 192 (2,4-Dimethylthiazol-5- i-Pr 4-F-Phenyl oil* yl)methyl 193 2-Methylphenyl 3-Pentyl 4-F-Phenyl 142-145 194 Allyl c-Bu 4-F-Phenyl 61-63 195 2-Methylphenyl i-Pr 4-Cl, 2-F-Phenyl 50 196 2,4-Dimethylthiazol-5-yl i-Pr 4-Cl-Phenyl oil* 197 2,4-Dimethylthiazol-5-yl i-Pr Phenyl oil* WO 00/43377 PCTIUS00/01283 91 198 2,4-Dimethylthiazol-5-yl i-Pr 4-F-Phenyl oil* 199 1-(3-Methyl-3-Butenyl) i-Pr 4-F-Phenyl 77-78 200 2-Methylphenyl c-Bu 4-F-Phenyl 108-110 201 2-Et-6-Me-Phenyl i-Pr 4-F-Phenyl oil* 202 4-Trifluoromethoxyphenyl i-Pr 4-F-Phenyl 88-92 203 2-Methylphenyl i-Pr 4-Methylsulfonyiphenyl 153 204 2-Methylphenyl i-Pr 2-F-Phenyl 42 205 2-Methyiphenyl i-Pr 4-Methyithiophenyl 104 206 2-Furanylniyl I .- Pr 4-Ci-Phenyl oil* 207 2-Furanylmethyl i-Pr 4-F-Phenyl oil* 208 2-Furanyhuethyl i-Pr 2,4-diF-Phenyl oil* 209 2-Furanylmethyl i-Pr Phenyl 67-70 210 Cinnamyl i-Pr 4-F-Phenyl oil* 211 4-Acetoxybutyl i-Pr 4-F-Phenyl 93-95 212 Propargyl i-Pr 4-F-Phenyl 74-75 213 3-Trimethylsilylpropargyl i-Pr 4-F-Phenyl oil* 214 1-(3-Ethoxycarbonyl-2- i-Pr 4-F-Phenyl oil* __________ Propenyl)________ ____ _____ 215 MeO 2
CCH
2 i-Pr 4-F-Phenyl oil* 216 t-BuCOCH 2 i-Pr 4-F-Phenyl oil* 217 MeCOCH 2 i-Pr 4-F-Phenyl oil* 218 1-(3,4,4-Trifluoro-3-Butenyl) i-Pr 4-F-Phenyl oil* 219 2-(1,3-Dioxolan-2-yl)ethyl i-Pr 4-F-Phenyl 94-96 220 CH 3
OCH
2
CH
2
OCH
2 i-Pr 4-F-Phenyl oil* 221 -- n-Butyl i-Pr 4-F-Phenyl oil* 222 2,4-DiMe-6-OMe-Phenyl i-Pr 4-F-Phenyl oil* 223 2,4-DiMe-6-OMe-Phenyl i-Pr 2,4-diF-Phenyl oil* 224 2-Br-4, 6-diMe-Phenyl i-Pr 4-F-Phenyl 141-144 225 Me 2 N i-Pr Phenyl oil* 226 3-Methyl-3-oxetanylmethyl i-Pr 4-F-Phenyl 65-77 227 1-(3,3,3-Trifluoro-2- i-Pr 4-F-Phenyl 80-105 methoximino)propyl_________________ 228 Methyl Et c-Hex 65-74 229 2-Methyiphenyl i-Pr 4-n-Bu-Phenyl oil* 230 2-Methyiphenyl i-Pr 4-Et-Phenyl oil* WO 00/43377 PCT/USOO/01283 92 231 2-Methylphenyl i-Pr 4-i-Pr-Phenyl 94 232 (2,4-DiMe-Thiazol-5-yl)methyl i-Pr 4-F-Phenyl oil* 233 (2,4-DiMe-Thiazol-5-yl)methyl i-Pr 2,4-diF-Phenyl oil* 234 3-Pyridyl i-Pr 4-F-Phenyl 109-112 235 3-Pyridyl i-Pr Phenyl 116-118 236 2-Methylphenyl i-Pr 2-Me-Phenyl oil* 237 2-Methylphenyl i-Pr 4-Dimethylamino-Phenyl 115 238 a-Me-Benzyl (R) i-Pr 2,4-diF-Phenyl oil* 239 2-Methylphenyl s-Bu 4-F-Phenyl 79-82 240 2-Methylphenyl 1-c-Pr-ethyl 4-F-Phenyl 90-93 241 c-Propyl i-Pr 4-Cl-Phenyl oil* 242 c-Propyl i-Pr 4-F-Phenyl 65-67 243 c-Propyl i-Pr Phenyl 70-74 244 2,6-DiMe-Phenyl 1-Ethoxy 4-F-Phenyl 97-99 carbonylethyl 245 D 3 C i-Pr 4-F-Phenyl 141-143 246 Neopentyl i-Pr 4-F-Phenyl 106-108 247 2-Methylphenyl 1-Ethoxy 4-F-Phenyl 97-99 carbonylethyl 248 Ethyl 1-Ethoxy 4-F-Phenyl oil* carbonylethyl 249 Allyl c-Heptyl 4-F-Phenyl 72-79 250 2-Phenethyl i-Pr 4-F-Phenyl 95-96 251 c-Propylmethyl i-Pr 4-F-Phenyl oil* 252 CH 3
CH
2
C(O)CH
2 i-Pr 4-F-Phenyl oil* 253 n-CI 9
H
39 i-Pr 4-F-Phenyl oil* 254 1-(2-Octynyl) i-Pr 4-F-Phenyl oil* 255 2-(1,3-Dioxan-2-yl)ethyl i-Pr 4-F-Phenyl 82-83 256 1-(2-Trimethylsilylmethyl-2- i-Pr 4-F-Phenyl oil* propenyl) 257 2-Cyclohexylethyl i-Pr 4-F-Phenyl oil* 258 CH 3 0CH 2
CH
2
OCH
2 i-Pr 4-F-Phenyl 119-120 259 (3,5-dimethylisoxazol-4- i-Pr 4-F-Phenyl oil* yl)methyl I 1___ 260 PhC(O)CH(Me) i-Pr 4-F-Phenyl oil* WO 00/43377 PCTJUSOO/01283 93 261 PhCH 2
OCH
2 i-Pr 4-F-Phenyl 110-112 262 Geranyl i-Pr 4-F-Phenyl oil* 263 1-(3-Methoxycarbonyl-2- i-Pr 4-F-Phenyl oil* Propenyl)____________ 264 Et 2
NC(O)CH
2 i-Pr 4-F-Phenyl oil* 265 t-BUO 2
CCH
2 i-Pr 4-F-Phenyl oil* 266 MeO 2
CCH
2
CH
2
CH
2 i-Pr 4-F-Phenyl oil* 267 2-Pyridylmethyl i-Pr 4-F-Phenyl oil* 268 2-Methyiphenyl i-Pr 4-Phenoxy-Phenyl 51 269 2-Methylphenyl i-Pr 3-F-Phenyl 128 270 2-Methyiphenyl i-Pr 4-t-Bu-Phenyl oil* 271 c-Pentyl i-Pr 4-F-Phenyl 79-80 272 3-Thienyl i-Pr 4-F-Phenyl 125-128 273 2,6-DiMe-Phenyl i-Pr 2-Cyclohexenyl 105-112 274 Me 2 N Et c-Hex oil* 275 Neopentyl Et c-Hex oil* 276 Neopentyl i-Pr Phenyl 116-1 18 277 Neopentyl i-Pr 2,4-DiF-Phenyl oil* 278 2-Methylphenyl i-Pr 5-Indanyl 115 279 Allyl I-Ethoxy 4-F-Phenyl oil* carbonylethyl_____ 280 c-Hexyl 1-Ethoxy 4-F-Phenyl oil* _________ _____________________ carbonylethyl ____ 281 2, 3-Dihydro-2-Me-benzofuran- i-Pr 4-F-Phenyl 148-150 _________ ~ 7 -y 1 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 282 c-Pentyl i-Pr 4-Ci-Phenyl 104-106 283 c-Pentyl i-Pr Phenyl oil* 284 c-Pentyl i-Pr 2,4-DiF-Phenyl oil* 285 1-(3-Chlorobutenyl) i-Pr 4-F-Phenyl oil* 286 1-(2-Pentenyl) i-Pr 4-F-Phenyl oil* 287 3-Fluoropropyl i-Pr 4-F-Phenyl oil* 288 1-(3-Methyl-2-butenyl) i-Pr 4-F-Phenyl oil*" 289 1-(4-Fluorobutyl) i-Pr 4-F-Phenyl oil* 290 n-Pentyl i-Pr 4-F-Phenyl oil* 291 1-(4-Pentenyl) i-Pr I 4-F-Phenyl Ioil* WO 00/43377 PCTIUSOO/01283 94 292 Acetoxymethyl i-Pr 4-F-Phenyl oil* 293 (Ex. 15) Methoxymethyl i-Pr 4-F-Phenyl oil* 294 Trimethylsilylmethyl i-Pr 4-F-Phenyl oil* 295 Ethoxymethyl i-Pr 4-F-Phenyl oil* 296 i-Propyl i-Pr 2-Pyrazinyl oil* 297 c-Propyl Et Et oil* 298 c-Propyl Et c-Hex oil* 299 c-Propyl i-Pr 2,4-DiF-Phenyl 83-85 300 2-Methylphenyl i-Pr 4-CF 3 0-Phenyl 109 301 2-Methylphenyl i-Pr 4-Pyridinyl 152-154 302 i-Propyl 1-Ethoxy 4-F-Phenyl oil* carbonylethyl 303 2-t-Bu-6-Me-Phenyl i-Pr Phenyl oil* 304 2,6-DiEt-Phenyl i-Pr 4-F-Phenyl oil* 305 2,6-DiEt-Phenyl i-Pr Phenyl 77-83 306 2-Methylphenyl i-Pr 2-Naphthyl 49 307 Allyl Et c-Hex 62-65 308 c-Hexyl Et c-Hex oil* 309 i-Propyl Et c-Hex oil* 310 4-Tetrahydropyranyl i-Pr 4-F-Phenyl 101-103 311 2-Tetrahydropyranyl i-Pr 4-F-Phenyl 103-105 312 2-Furanylmethyl Et c-Hex oil* 313 2-Biphenylylmethyl i-Pr 4-F-Phenyl 113-126 314 1-(2-Methylthioethyl) i-Pr 4-F-Phenyl 101-106 315 2,6-DiMe-Phenyl i-Pr 2-Dihydropyranyl 122-124 316 2-(3-Methylbutyl) i-Pr 4-F-Phenyl 62-64 317 1-(2,2-Dimethoxyethyl) i-Pr 4-F-Phenyl oil* 318 2,6-DiMe-Phenyl c-Bu 2,4-DiCI-Phenyl 127-131 319 i-Propyl c-Bu 2,4-DiCI-Phenyl 103-106 320 (5-Cl-1,2,3-thiadiazol-4- i-Pr 2,4-DiF-Phenyl 103-108 yl)methyl 321 (5-C-1,2,3-thiadiazol-4- i-Pr Phenyl 128-131 yl)methyl 322 Cyclopentylmethyl i-Pr 4-F-Phenyl 83-90 323 1-(3-Dimethylaminopropyl) i-Pr 4-F-Phenyl oil* WO 00/43377 PCT/USOO/01283 95 324 2-Methyiphenyl 2-(3-OMe-propyl) 4-F-Phenyl 115-121 325 Allyl 1-c-Pr-ethyl 4-Ci-Phenyl oil* 326 [2.2.1]-Bicyclohept-2-yI i-Pr 2,4-DiF-Phenyl 103-105 327 [2.2.1]-Bicyclohept-2-yl i-Pr 4-F-Phenyl 90-94 328 [2.2.1]-Bicyclohept-2-yl i-Pr Phenyl 90-91 329 2-Naphthyl i-Pr 4-F-Phenyl 150-15 1 330 2-Methyiphenyl 1-c-Pr-ethyl 4-Ci-Phenyl 111-115 331 2-MeO-6-Me-Phenyl 1-Ethoxy 4-F-Phenyl oil* __________ ~~~~~carbonylethyl ____________ ____ 332 2-Naphthyl i-Pr Phenyl 134-135 333 2-Naphthyl i-Pr 4-CI-Phenyl 142-143 334 2-Naphthyl i-Pr 4-Me-Phenyl 172-173 335 2-Naphthyl i .- Pr 2,4-DiF-Phenyl oil* 336 1-Me-2-Naphthyl i-Pr 4-Ci-Phenyl oil* 337 1-Me-2-Naphthyl i-Pr 2,4-DiF-Phenyl oil* 338 I-Me-2-Naphthyl i-Pr 4-F-Phenyl oil* 339 c-Heptyl i-Pr 4-Ci-Phenyl 125-135 340 c-Heptyl i-Pr 4-F-Phenyl 104-105 341 c-Heptyl i-Pr Phenyl 100-102 342 c-Heptyl i-Pr 2,4-DiF-Phenyl 87-90 343 2-Tetrahydrofuranylmethyl i-Pr 4-F-Phenyl 95-96 344 1-Me-2-Naphthyl i-Pr Phenyl oil* 345 2-Teftrahydrofuranyl i-Pr 4-F-Phenyl oil* 346 (3,5-Dimethylpyrazol-1- i-Pr Phenyl 138-148 __________ yl)methyl ________ ___________ 347 (3,5-Dimethylpyrazol-1- i-Pr 4-F-Phenyl 140-144 yl)methyl________________ 348 c-Butyl i-Pr Phenyl 70-72 349 c-Butyl i-Pr 4-CI-Phenyl 64-68 350 c-Butyl i-Pr 4-F-Phenyl 97-100 351 c-Butyl i-Pr 2,4-diF-Phenyl 65-67 352 MeOCH 2 CH(Me) i-Pr 2,4-diF-Phenyl oil* 353 3-Pentyl i-Pr 2,4-diF-Phenyl 72-75 354 3-Pentyl i-Pr Phenyl oil* 355 2-(3-Methylbutyl) i-Pr Phenyl oil* WO 00/43377 PCTUSOO/01283 96 356 2-(3-Methylbutyl) i-Pr 2,4-diF-Phenyl oil* 357 MeOCH 2 CH(Me) i-Pr 2,4-diF-Phenyl 8 1-85 358 3-Pentyl i-Pr 4-F-Phenyl oil* 359 2-t-Bu-6-Me-Phenyl i-Pr 4-F-Phenyl oil* 360 1-(1-Me-c-propyl) i-Pr Phenyl 82-83 361 1-(1-Me-c-propyl) f-Pr 4-Cl-Phenyl oil* 362 1-(1-Me-c-propyl) i-Pr 4-F-Phenyl oil* 363 1-(1-Me-c-propyl) i-Pr 2,4-di-Phenyl oil* 364 2-Methylphenyl Et Et oil* 365 Methyl 1-Ethoxy 4-F-Phenyl oil* carbonylethyl ____ 366 3-Pyridylinethyl i-Pr 4-F-Phenyl oil* 367 2-(3-Chloropropyl) i-Pr 4-F-Phenyl oil* 368 Methyl i -Pr 2,4-diF-Phenyl oil* 369 1-(2-Me-c-propyl) i-Pr 4-Ci-Phenyl oil* 370 1-(2-Me-c-propyl) i-Pr Phenyl oil* 371 1-(2-Me-c-propyl) i-Pr 4-F-Phenyl 95-97 372 1-(2-Me-c-propyl) i-Pr 2,4-diF-Phenyl oil* 373 (5-CI-3-Me-isothiazol-4- i-Pr 4-F-Phenyl 126-129 yl)methyl ___________________ 374 (5-CI-3-Me-isothiazol-4- i-Pr Phenyl 133-136 yl)methyl____________ ____ 375 3-Tetahydrofuirylmethyl i-Pr 4-F-Phenyl 84-86 376 Chioromethyl i-Pr 4-F-Phenyl 83-86 377 H i-Pr 4-Cl-Phenyl 137-138 378 (4-Methyl-1,2,3-thiadiazol-5- i-Pr Phenyl 109-113 yl)methyl____________ ____ 379 (2-Ethoxy-4-CF 3 -tbiazol-5- i-Pr Phenyl oil* yl)methyl ____________ 380 (4-Methyl-1,2,3-thiadiazol-5- i-Pr 4-F-Phenyl 54-55 __________ yl)methyl ___________________ 381 (2-Ethoxy-4-CF 3 -thiazol-5- i-Pr 4-F-Phenyl oil* __________ yl)methyl____________ ____ 382 1-(2,6-Dimethylpiperidine) i-Pr 4-F-Phenyl 97-100 383 t1-(2,6-Dimethylpiperidine) i-Pr 2,4-diF-Phenyl 81-84 WO 00/43377 PCTUSOO/01283 97 384 4-(Morpholino) i-Pr 2,4-diF-Phenyl 62-68 385 4-(Morpholino) i-Pr 4-F-Phenyl 173-175 386 H i-Pr Phenyl 116-117 387 2-(2-Gyanoediyl) i-Pr 4-F-Phenyl 0i1* 388 1-(2-Cyanoethyl) i-Pr 4-F-Phenyl 125-128 389 n-Hexyl i-Pr 4-F-Phenyl oil* 390 2-(1,3-Difluoropropyl) i-Pr 4-F-Phenyl 99-101 391 H i-Pr 2,4-dI-Phenyl 110-112 392 Trans- I-(2-Me-c-propyl) i-Pr 4-F-Phenyl 90-91 393 1-(1-Chloroethyl) i-Pr 4-F-Phenyl 70-73 394 i-Butyl i-Pr 2,4-diF-Phenyl oil* 395 Cyanomethyl i-Pr 4-F-Phenyl 120-123 396 1-(2-Ethoxy-3-ethoxycarbonyl- i-Pr 4-F-Phenyl 112-114 2-propenyl) ____________ 397 1-(3,3,3-trifluoropropyl) i-Pr 4-F-Phenyl 99-100 398 1-(4,4,4-trifluorobutyl) i-Pr 4-F-Phenyl 7 1-72 399 1-(3,4,4, 4-Tetrafluoro-3- i-Pr 4-F-Phenyl oil* trifluoromethylbutyl) ___________________ 400 CH 3
C(O)CH(CH
3 ) i-Pr 4-F-Phenyl oil* 401 1-(2-C1-4-Me-thiazol-5-yl)ethyl i-Pr 4-F-Phenyl oi1* 402 2-Methyl-c-propyhnethyl i -Pr 4-F-Phenyl 8 1-83 403 c-Butylmethyl i-Pr 4-F-Phenyl 74-76 404 1-(c-Propylethyl) i-Pr 4-F-Phenyl 97-99 405 l-(2-C14-Me-thiazol-5-yl)ethyl i-Pr 2,4-iff-Phenyl 122-125 406 1-(2-CI-4-Me-thiazol-5-yl)ethyl i-Pr 4-Ci-Phenyl 128-131 407 1-(2-C14-Me-thiazol-5-yl)ethyl i-Pr Phenyl 128-131 408 2-(3-Chloropropyl) i-Pr 2,4-diF-Phenyl 0i1* 409 Methyl i-Pr Phenyl 105-114 410 i-Butyl i-Pr Phenyl 55-67 411 2-(3-Chloropropyl) i-Pr Phenyl 95-105 412 1-(2-Butenyl) i-Pr 4-F-Phenyl oil* 413 2-(3-Butenyl) i-Pr 4-F-Phenyl 0i1* 414 Allyldimethylsilylmethyl i-Pr 4-Ci-Phenyl oil* 415 1-(2-Bromoethyl) i-Pr Phenyl 90-92 416 4-Tetahydropyranyl i-Pr Phenyl 80-93 WO 00/43377 PCT/USO0/01283 98 417 i-Butyl i-Pr 4-Cl-Phenyl oil* 418 1-(3-Methyl-3-Butenyl) i-Pr Phenyl oil* 419 1-(2-Methylthioethyl) i-Pr Phenyl oil* 420 (3-Methyl-3-oxetanyl)methyl i-Pr Phenyl oil* 421 2-(1,3-difluoropropyl) i-Pr Phenyl 95-107 422 Chloromethyl i-Pr 4-CI-Phenyl 75-77 423 Chloromethyl i-Pr Phenyl 75-77 424 Phenyldimethylsilylmethyl i-Pr 4-CI-Phenyl oil* 425 Vinyldimethylsilylmethyl i-Pr 4-CI-Phenyl oil* 426 Allyldimethylsilylmethyl i-Pr 4-F-Phenyl oil* 427 c-Heptyl i-Pr 3, 6-dihydro-2H-pyran oil* 428 c-Heptyl i-Pr 1-Cyclohexenyl oil* 429 c-Heptyl Et c-Hexyl oil* 430 (5,6-Dihydro-1,2-Oxazin-3- i-Pr Phenyl 95-97 yl)methyl 431 Cyanomethyl i-Pr 2,4-diF-Phenyl 123-126 432 1-(1-Cyanoethyl) i-Pr 2,4-diF-Phenyl oil* 433 1-(2-Cyanoethyl) i-Pr 2,4-diF-Phenyl 112-114 434 Cyanomethyl i-Pr Phenyl 90-91 435 1-(1-Cyanoethyl) i-Pr Phenyl oil* 436 1-(2-Cyanoethyl) i-Pr Phenyl 74-77 437 Chloromethyl i-Pr 2,4-diF-Phenyl 69-71 438 1-(1-Chloroethyl) i-Pr Phenyl 73-75 439 1-(1-Methoxyethyl) i-Pr 4-F-Phenyl 77-79 440 Me 2
NC(O)CH
2 i-Pr 2,4-diF-Phenyl 111 441 1-(1-Methoxyethyl) i-Pr Phenyl oil* 442 1-(2,4-Dimethylthiazol-5- i-Pr Phenyl oil* yl)ethyl 443 1-(2,4-Dimethylthiazol-5- i-Pr 2,4-diF-Phenyl oil* yl)ethyl 444 1-(2-Cyanoethyl) i-Pr 4-Cl-Phenyl 139-142 445 PhCONHCH 2 i-Pr 4-F-Phenyl 161-163 446 1-(1,2-Dimethoxyethyl) i-Pr 4-F-Phenyl oil* 447 (EtO) 2
P(O)CH
2 i-Pr Phenyl oil* 448 (EtO) 2
P(O)CH(CH
3 ) i-Pr Phenyl oil* WO 00/43377 PCT/USOO/01283 99 449 1-(2-Ethyl-4-methylthiazol-5- i-Pr 4-F-Phenyl 106-109 __________ yl)ethyl ________ ___________ 450 (5,6-Diliydro-1,2-Qxazin-3- i-Pr 4-CI-Phenyl 105-108 yl)methyl ___________ 451 1-(1-Cyanoethyl) i-Pr 4-Ci-Phenyl 117-127 452 1-(1-Methoxy-2-propenyl) i-Pr 4-F-Phenyl oil* 453 1-(2-Methylsulfonylethyl) i-Pr 4-F-Phenyl oil* 454 1-(2-Pentenyl) i-Pr Phenyl oil* 455 3-(4-Pentenyl) i-Pr Phenyl oil* 456 2-(3-Chloropropyl) i-Pr 4-CI-Phenyl oil* 457 Hydroxymethyl i-Pr 4-CI-Phenyl oil* 458 1-(2-Chloro- I1-methoxyethyl) i-Pr 4-Ci-Phenyl oil* 459 Ethyldimethylsilylmethyl i-Pr 4-F-Phenyl 54-55 460 Ethyldimethylsilylniethyl i-Pr 4-CI-Phenyl 68-7 1 461 1-(3-Trimethylsilylpropyl) i-Pr 4-F-Phenyl oil* 462 t-BuC(O)OCH 2 i-Pr 4-F-Phenyl 87-90 463 CH 3
O
2
CCH(CH
3 ) i-Pr 2,4-di-Phenyl oil* 464 CH 3
O
2
CCH(CH
3 ) i-Pr Phenyl oil* 465 EtO 2 cCH 2
CH(CQ
2 Et) i-Pr 2,4-diF-Phenyl oil* 466 (3,4-Dihydroisoxazol-3- i-Pr 4-F-Phenyl 93-95 __________ yl)methyl ________ ___________ 467 Me 3 SiCH 2
CH
2
OCH
2 i-Pr 4-Cl-Phenyl oil* 468 2-(1,3-Difluoropropyl) i-Pr 4-CI-Phenyl 93-96 469 1-(2-Chloroethyl) i-Pr Phenyl 80-831 470 Hydroxymethyl i-Pr 4-F-Phenyl 89-95 471 2-(3, 3-Dimethoxypropyl) i-Pr 4-F-Phenyl 60-63 472 2-(3, 3-Dimethoxypropyl) i-Pr 2,4-diF-Phenyl oil* 473 MeCQNHCH 2 i-Pr 4-F-Phenyl 150-168 474 1-(2-Chloroethyl) i-Pr 4-Ci-Phenyl 100-101 475 1-(2-Chloroethyl) i-Pr 2,4-di-Phenyl 70-72 476 Cyanomethyl i-Pr 4-Ci-Phenyl 173-179 477 Me 2
NC(O)CH
2 i-Pr 4-Ci-Phenyl 152-153 478 Me 2
NC(O)CH(CH
3 ) i-Pr 4-F-Phenyl oil* 479 1 Me 2
NC(O)CH(CH
3 ) i-Pr Phenyl oil* 40Me 2
NC(O)CH(CH
3 ) i-Pr 4-Ci-Phenyl 102 WO 00/43377 PCTIUSOO/01283 100 481 Me 2
NC(O)CH(CH
3 ) i-Pr 2,4-Mi-Phenyl oil* 482 (2-Chlorothiazol-5-yl)methyl i-Pr 4-F-Phenyl 69-70 483 1-(2-nitroethyl) i-Pr 4-CI-Phenyl 119-122 484 i-PrC(CO)CH 2 i-Pr 4-F-Phenyl 79-8 1 485 z-PrC(CQ)CH 2 i-Pr Phenyl oil* 486 i-PrC(CO)CH 2 i-Pr 2,4-diF-Phenyl oil* 487 i-PrC(co)CH 2 i-Pr 4-CI-Phenyl oil* 488 c-PrC(CO)CH 2 i-Pr 4-F-Phenyl oil* 489 c-PrC(CO)CH 2 i-Pr Phenyl 87-89 490 c-PrC(CO)CH 2 i-Pr 2,4-diF-Phenyl oil* 491 HC(O)CH 2 i-Pr 4-F-Phenyl oil* 492 C1CH 2
C(O)NHCH
2
CH
2 i-Pr Phenyl oil* 493 C1CH 2
C(O)NHCH
2
CH
2
CH
2 i-Pr Phenyl oil* 494 (5,6-Dihydro- 1,3-oxazin-2- i-Pr Phenyl oil* __________ yl)methyl________ 495 (3,4-Dihydrooxazol-2- i-Pr Phenyl oil* _________ yl)methyl ___________ 496 (1-Cyclohexenyl)methyl i-Pr Phenyl oil* 497 (I-Methyl-1,2,5,6- i-Pr Phenyl oil* _________tetrahydropyridin-3-yl)methyl ____________ 498 l-(2-(3-Pyridyl)-2-propenyl) i-Pr Phenyl oil* 499 1-(2-Ethyl-4-methylthiazol-5- i-Pr 4-Ci-Phenyl 103-104 yl)ethyl ___________ 500 1-(3-Fluoropropyl) i-Pr 2,4-diF-Phenyl oil* 501 2-(1 ,3-Dioxolan-2-yl)ethyl i-Pr 2,4-diF-Phenyl oil* 502 2-(1,3-Dioxan-2-yl)ethyl i-Pr 2,4-diF-Phenyl oil* 503 Methoxymethyl i-Pr 2,4-di-Phenyl oil* 504 Ethoxymethyl i-Pr 2,4-di-Phenyl oil* 505 CH 3
OCI{
2
CH
2
OCH
2 i-Pr 2,4-diF-Phenyl oil* 506 .1-(4-Acetoxybutyl) i-Pr 2,4-diF-Phenyl oil* 507 1-(3,4,4-Trifluoro-3-butenyl) i-Pr 2,4-diF-Phenyl oil* 508 1-(2-Phenylethyl) i-Pr 2,4-diF-Phenyl oil* 509 Cyclopropyhnethyl i-Pr 2,4-diF-Phenyl oil* 510 (3,5-Dimethyloxazol-4- i-Pr 2,4-diF-Phenyl oil* __________ yl)methyl________ _______ _____ _ _ _ _ WO 00/43377 PCT/USOO/01283 101 511 PhCOCH(CH 3 ) i-Pr 2,4-diF-Phenyl oil* 512 Et 2
NC(O)CH
2 i-Pr 2,4-diF-Phenyl oil* 513 MeO 2
CCH
2
CH
2
CH
2 i-Pr 2,4-diF-Phenyl oil* 514 1-(3-Chloro-2-butenyl) i-Pr 2,4-diF-Phenyl oil* 515 1-(3-Methyl-2-butenyl) i-Pr 2,4-diF-Phenyl oil* 516 1-(4-Pentenyl) i-Pr 2,4-diF-Phenyl oil* 517 CH 3
C(O)CH(CH
3 ) i-Pr 2,4-diF-Phenyl oil* 518 Trimethylsilylmethyl i-Pr 2,4-diF-Phenyl oil* 519 1-(2-Ethoxy-3-ethoxycarbonyl- i-Pr 2,4-diF-Phenyl oil* 2-propenyl) 520 PhCH 2
OCH
2 i-Pr 2,4-diF-Phenyl oil* 521 Cyclobutylmethyl i-Pr 2,4-diF-Phenyl oil* 522 1-(4-Fluorobutyl) i-Pr 2,4-diF-Phenyl oil* 523 1-(2-Pentenyl) i-Pr 2,4-diF-Phenyl oil* 524 CH 3
CH
2
C(O)CH
2 i-Pr 2,4-diF-Phenyl oil* 525 1-(3,3,3-Trifluoropropyl) i-Pr 2,4-diF-Phenyl oil* 526 1-(4,4,4-Trifluorobutyl) i-Pr 2,4-diF-Phenyl oil* 527 n-Butyl i-Pr 4-Cl-Phenyl oil* 528 n-Pentyl i-Pr 4-Cl-Phenyl oil* 529 n-Hexyl i-Pr 4-Cl-Phenyl oil* 530 1-(3-Fluoropropyl) i-Pr 4-Cl-Phenyl oil* 531 2-(1,3-Dioxolan-2-yl)ethyl i-Pr 4-Cl-Phenyl oil* 532 2-(1,3-Dioxan-2-yl)ethyl i-Pr 4-Cl-Phenyl oil* 533 Methoxymethyl i-Pr 4-Cl-Phenyl oil* 534 Ethoxymethyl i-Pr 4-Cl-Phenyl oil* 535 CH 3 0CH 2
CH
2 0CH 2 i-Pr 4-Cl-Phenyl oil* 536 1-(4-Acetoxybutyl) i-Pr 4-Cl-Phenyl oil* 537 1-(3,4,4-Trifluoro-3-butenyl) i-Pr 4-Cl-Phenyl oil* 538 1-(2-Phenylethyl) i-Pr 4-Cl-Phenyl oil* 539 Cyclopropylmethyl i-Pr 4-Cl-Phenyl oil* 540 (3,5-Dimethyloxazol-4- i-Pr 4-Cl-Phenyl oil* yl)methyl 541 PhCOCH(CH 3 ) i-Pr 4-Cl-Phenyl oil* 542 Et 2
NC(O)CH
2 i-Pr 4-Cl-Phenyl oil* 543 MeO 2
CCH
2
CH
2
CH
2 i-Pr 4-Cl-Phenyl oil* WO 00/43377 PCT/US0O/01283 102 544 1-(3-Chloro-2-butenyl) i-Pr 4-Cl-Phenyl oil* 545 1-(3-Methyl-2-butenyl) i-Pr 4-Cl-Phenyl oil* 546 1-(4-Pentenyl) i-Pr 4-Cl-Phenyl oil* 547 CH 3
C(O)CH(CH
3 ) i-Pr 4-Cl-Phenyl oil* 548 Trimethylsilylmethyl i-Pr 4-Cl-Phenyl oil* 549 1-(2-Ethoxy-3-ethoxycarbonyl- i-Pr 4-Cl-Phenyl oil* 2-propenyl) 550 Cyclobutylmethyl i-Pr 4-Cl-Phenyl oil* 551 1-(4-Fluorobutyl) i-Pr 4-Cl-Phenyl oil* 552 1-(2-Pentenyl) i-Pr 4-Cl-Phenyl oil* 553 CH 3
CH
2
C(O)CH
2 i-Pr 4-Cl-Phenyl oil* 554 1-(3,3,3-Trifluoropropyl) i-Pr 4-Cl-Phenyl oil* 555 1-(4,4,4-Trifluorobutyl) i-Pr 4-Cl-Phenyl oil* 556 n-Butyl i-Pr Phenyl oil* 557 n-Pentyl i-Pr Phenyl oil* 558 n-Hexyl i-Pr Phenyl oil* 559 1-(3-Fluoropropyl) i-Pr Phenyl oil* 560 2-(1,3-Dioxolan-2-yl)ethyl i-Pr Phenyl oil* 561 2-(1,3-Dioxan-2-yl)ethyl i-Pr Phenyl oil* 562 Methoxymethyl i-Pr Phenyl oil* 563 Ethoxymethyl i-Pr Phenyl oil* 564 CH 3 0CH 2
CH
2 0CH 2 i-Pr Phenyl oil* 565 1-(4-Acetoxybutyl) i-Pr Phenyl oil* 566 1-(3,4,4-Trifluoro-3-butenyl) i-Pr Phenyl oil* 567 1-(2-Phenylethyl) i-Pr Phenyl oil* 568 Cyclopropylmethyl i-Pr Phenyl oil* 569 (3,5-Dimethyloxazol-4- i-Pr Phenyl oil* yl)methyl 570 PhCOCH(CH 3 ) i-Pr Phenyl oil* 571 Et 2
NC(O)CH
2 i-Pr Phenyl oil* 572 MeO 2
CCH
2
CH
2
CH
2 i-Pr Phenyl oil* 573 1-(3-Chloro-2-butenyl) i-Pr Phenyl oil* 574 1-(3-Methyl-2-butenyl) i-Pr Phenyl oil* 575 1-(4-Pentenyl) i-Pr Phenyl oil* 576 CH 3
C(O)CH(CH
3 ) i-Pr Phenyl oil* WO 00/43377 PCTIUSOO/01283 103 577 Trimethylsilylmethyl i-Pr Phenyl oil* 578 1-(2-Ethoxy-3-ethoxycarbonyl- i-Pr Phenyl oil* 2-propenyl) ________ ____ 579 PhCH 2
OCH
2 i-Pr Phenyl oil* 580 Cyclobutylmethyl i-Pr Phenyl oi1* 581 1-(4-Fluorobuty1) i-Pr Phenyl 0il* 582 1-(2-Pentenyl) i-Pr Phenyl oil* 583 CH 3
CH
2
C(O)CH
2 i-Pr Phenyl oi1* 584 1-(3,3,3-Trifluoropropyl) i-Pr Phenyl 0il* 585 1-(4,4,4-Trifluorobutyl) i-Pr Phenyl oil* 586 Me 2
NC(O)CH
2 i-Pr 4-F-Phenyl 117 587 (EtOh2P(O)CH 2 i-Pr 4-F-Phenyl oil* 588 Me 2
NC(O)CH
2 i-Pr Phenyl 152 589 1-(2-Ethyl-4-methylthiazol-5- i-Pr 2,4-diF-Phenyl 87-90 yl)ethyl ____________ 590 1-(2-Ethyl-4-methylthiazol-5- i-Pr 4-Cl-Phenyl 93-97 __________ yl)ethyl________ 591 1-(2-Nitroethyl) i-Pr 2,4-dI-Phenyl 92-98 592 1-(1-Methoxyethyl) i-Pr 4-Ci-Phenyl oi1* 593 1-(1-Methoxyethyl) i-Pr 2,4-diF-Phenyl 0il* 594 2-(3-Bromopropyl) i-Pr 2,4-diF-Phenyl 0i1* 595 2-(1,3-Difluoropropyl) i-Pr 2,4-diF-Phenyl 91-96 596 2-(3-Acetoxy-1I-cbloropropyl) i-Pr 4-F-Phenyl 0i1* 597 F 3
CC(O)CH
2 i-Pr 4-Ci-Phenyl 0i1* 598 F 3
CC(O)CH
2 i-Pr 2,4-diF-Phenyl oi1* 599 (EtO) 2
P(O)CH
2 i-Pr 4-CI-Phenyl 0il* 600 Allyl 2-(3-OMe-propyl) 2,6-DiMe-Phenyl oi1* 601 (5,6-Dihydro-1 ,2-Oxazin-3- i-Pr 4-F-Phenyl 108-112 __________ yl)methyl ____________ 602 (5,6-Dihydro- 1,2-Oxazin-3- i-Pr 2,4-dI-Phenyl 87-95 y1)methyl ___________________ 603 1-(2-Nitropropyl) i-Pr 2,4-diF-Phenyl 0i1* 604 1-(2-Nitropropyl) i-Pr Phenyl oil* 605 1-(2-(6-Cbloro-2-pyridyl)-2- i-Pr Phenyl oil* __ __ __ _propenyl) I________ I ___________ I___ I_ WO 00/43377 PCT/US0O/01283 104 606 1-(2-(4-Fluorophenyl)-2- i-Pr Phenyl oil* propenyl) 607 1-(2-Methyl-2-propenyl) i-Pr Phenyl oil* 608 1-(2-Chlorol-2-propenyl) i-Pr Phenyl oil* 609 2-(3-Butynyl) i-Pr Phenyl oil* 610 s-Butyl (R) i-Pr Phenyl 53-55 611 s-Butyl (S) i-Pr Phenyl 55-57 612 s-Butyl (S) i-Pr Phenyl 41-43 613 s-Butyl (R) i-Pr 4-F-Phenyl 41-43 614 EtO 2
CCH
2
CH(CO
2 Et) i-Pr Phenyl oil* 615 EtO 2
CCH
2
CH(CO
2 Et) i-Pr 4-F-Phenyl oil* 616 MeO 2
CCH(CH
3 ) i-Pr 4-F-Phenyl oil* 617 (EtO) 2
P(O)CH(CH
3 ) i-Pr 4-F-Phenyl oil* 618 Thiocyanatomethyl i-Pr 4-F-Phenyl 125-127 619 PhC(O)NHCH 2 i-Pr 2,4-diF-Phenyl 120-123 620 PhC(O)NHCH 2 i-Pr Phenyl 145-146 621 MeC(O)NHCH 2 i-Pr Phenyl 122-126 622 MeC(O)NHCH 2 i-Pr 2,4-diF-Phenyl 173-175 623 MeO 2
CCH(CH
3 ) i-Pr 4-Cl-Phenyl oil* 624 (2-Tetrahydropyranyl)methyl i-Pr 4-F-Phenyl 80-82 625 CH 3
C(O)N(CH
3
)CH
2
CH
2 i-Pr 4-F-Phenyl 112-126 626 1-(2-Fluoroethyl) i-Pr 4-F-Phenyl 95-96 627 1-(2-Methoxyethyl) i-Pr 4-F-Phenyl oil* 628 1-(2-Methoxyethyl) i-Pr 2,4-diF-Phenyl 94-97 629 1-(2,2-Diethoxyethyl) i-Pr 4-F-Phenyl oil* 630 1-(2,2-Diethoxyethyl) i-Pr 2,4-diF-Phenyl 84-88 631 1-(2-Methoxyethyl) i-Pr Phenyl oil* 632 1-(2,2-Diethoxyethyl) i-Pr Phenyl oil* 633 1-(2,2-Diethoxyethyl) i-Pr 4-Cl-Phenyl 73-75 634 1-(2-Chloro-2-propenyl) i-Pr 2,4-diF-Phenyl oil* 635 n-Butyl i-Pr 2,4-diF-Phenyl oil* 636 n-Pentyl i-Pr 2,4-diF-Phenyl oil* 637 n-Hexyl i-Pr 2,4-diF-Phenyl oil* 638 Me 2
NC(O)CH
2
CH
2 i-Pr 4-F-Phenyl 100 WO 00/43377 PCTUSOO/01283 105 639 c-PrC(O)CH 2 i-Pr 4-Cl-Phenyl -oil* 640 c-BuC(Q)CH 2 i-Pr 4-F-Phenyl -Oil* 641 c-BuC(O)CH 2 i-Pr Phenyl 115-117 642 c-BuC(O)CH 2 i-Pr 2,4-di-Phenyl oil* 643 c-BuC(O)CH 2 i-Pr 4-Ci-Phenyl oil* 644 (EtO) 2
P(O)CH(CH
3 ) i-Pr 4-CI-Phenyl oil* 645 (2-Chloro-1 ,3,4-thiadiazol-5- i-Pr 2,4-diF-Phenyl 106-109 _________ yl)methyl ____________ 646 (2-Cliloro-1,3,4-thiadiazol-5- i-Pr 4-F-Phenyl 110-112 __________ yl)methyl________ 647 1-(3-Cyanopropyl) i-Pr 4-F-Phenyl oil* 648 1-(2-t-Butyl-2-propenyl) i-Pr Phenyl oil* 649 1-(2-i-Propyl-2-propenyl) i-Pr Phenyl oil* 650 1-(2-Benzyl-2-propenyl) i-Pr Phenyl oil* 651 2-(3-Carbomethoxy-3-butenyl) i-Pr Phenyl oil* 652 1-(1-Ethynyl-3-methyl-2- i-Pr Phenyl oil* butenyl) ___________ 653 (2-Chloro-1 ,3,4-thiadiazol-5- i-Pr 4-Ci-Phenyl oil* ymethyl________________ 654 (2-Chloro-1,3,4-thiadiazol-5- i-Pr Phenyl oil* __________ yl)methyl________ 655 2-(4-Ethynyl-2-methyl-3- i-Pr Phenyl oil* butenyl)________________ 656 2-(5,6-Dihydro-1,2-Oxazin-3- i-Pr 4-F-Phenyl oil* yI)ethyl________________ 657 2-(3-Butynyl) i-Pr 2,4-di-Phenyl oil* 658 2-(3-Butynyl) i-Pr 4-CI-Phenyl oil* 659 (2-Tetrahydropyranyl)methyl i-Pr Phenyl 97-100 660 (2-Tetrahydropyranyl)methyl i-Pr 4-Ci-Phenyl 82-84 661 (3,4-Dihydroisoxazol-3- i-Pr 4-Ci-Phenyl 105-107 yl)methyl____________ ____ 662 (MeO) 2
P(O)CH
2
CH
2 &-P 4-F-Phenyl 79-85 663 i-propyl i-Pr 4-Pyridyl 85-89 664 s-Butyl (5) i-Pr 4-Ci-Phenyl 53-56 665 s-Butyl (R) i-Pr 4CI-Phenyl 54-56 66S-Butyl (S) i-Pr 2,4-di-Phenyl 59-6 1 WO 00/43377 PCTUSOO/01283 106 667 s-Butyl (R) i-Pr 2,4-diF-Phenyl 5 8-60 668 1-(2-Fluoroethyl) i-Pr 4-Ci-Phenyl 120-12 1 669 1-(2-Fluoroethyl) i-Pr Phenyl 88-89 670 1-(2-Fluoroethyl) i-Pr 2,4-diF-Phenyl 90-91 671 Me 2
NC(O)CH
2
CH
2 i-Pr Phenyl 91 672 2-(1,3-Dichloropropyl) i-Pr 4-F-Phenyl oil* 673 1-(2,2-Dichloroethyl) i-Pr 2,4-di-Phenyl 121-122 674 1-(3-Cyanopropyl) i-Pr Phenyl 89-92 675 1-(3-Cyanopropyl) i-Pr 2,4-diF-Phenyl oil* 676 (3,4-Dihydroisoxazol-3- i-Pr 2,4-diF-Phenyl 66-68 __________ yl)methyl ________ ____ 677 PhCH(CQ 2 Me) i-Pr 4-F-Phenyl oil* 678 HOCH 2
CH
2
CH(CO
2 Me) i-Pr Phenyl 120-123 679 HOCH 2
CH
2
CH(CO
2 Me) i-Pr 4-Ci-Phenyl 107-110 680 HOCH 2
CH
2
CH(CO
2 Me) i-Pr 4-F-Phenyl 102-106 681 EtO 2 cCH 2
CH(CO
2 Et) i-Pr 4-Ci-Phenyl oil* 682 (1-Ethyl-5-Chloropyrazol-4- i-Pr 2,4-diF-Phenyl oil* yl)methyl ____________ 683 (1-Ethyl-5-Chloropyrazol-4- i-Pr Phenyl oil* __________ yl)methyl ___________________ 684 (l-Ethyl-5-Chloropyrazol-4- i-Pr 4-Ci-Phenyl oil* yl)methyl____________ ____ 685 (l-Ethyl-5-Chloropyrazol-4- i-Pr 4-F-Phenyl oil* __________ yl)methyl ____________ 686 1-(1-Ethyl-5-Chloropyrazol-4- i-Pr 4-F-Phenyl oil* yl)ethyl ________ ___________ 687 Me 2
NC(O)CH
2
CH
2 i-Pr 2,4-diF-Phenyl oil* 688 i-Propyl s-Butyl (S) 4-F-Phenyl 59-6 1 689 i-propyl s-Butyl 4-F-Phenyl 74-75 690 i-Propyl s-Butyl (R) 4-F-Phenyl 64-65 691 i-Propyl i-Pr 4-Br-Phenyl 75-76 692 3-Cyclohexenyl i-Pr 4-F-Phenyl 80-82 693 HC(O)CH(CH 3 ) i-Pr Phenyl oil* 694 3-Cyclohexenyl i-Pr 2,4-diF-Phenyl oil* 695 3-Cyclohexenyl i-Pr 4-CI-Phenyl 87-89 WO 00/43377 PCTUSOO/01283 107 696 3-Cyclohexenyl i-Pr Phenyl oil* 697 (MeO) 2
P(O)CH
2
CH
2 i-Pr Phenyl oil* 698 (MeO) 2
P(O)CH
2
CH
2 i-Pr 4-Ci-Phenyl oil* 699 1-(Cyclopropyl)ethyl i-Pr Phenyl 65-67 700 1-(Cyclopropyl)ethyl i-Pr 4-Cl-Phenyl 52-54 701 1-(Cyclobutyl)ethyl i-Pr 4-CI-Phenyl oil* 702 1-(Cyclobutyl)ethyl i-Pr 2,4-diF-Phenyl oil* 703 1-(Morpholinocarbonyl)ethyl i-Pr 4-CI-Phenyl 163 704 Me 2
NC(S)CH(CH
3 ) i-Pr Phenyl 141 705 l-(Morpholinocarbonyl)ethyl i-Pr 4-F-Phenyl oil* 706 (3,4-Dihydroisoxazol-3- i-Pr Phenyl oil* __________ yl)methyl ________ ___________ 707 2-(l -Chloro-3-fluoropropyl) i-Pr 4-F-Phenyl 85-8 6 708 2-(l-Acetoxy-3-chloropropyl) i-Pr 2,4-diF-Phenyl oil* 709 Fluoromethyl i-Pr 4-F-Phenyl 126-127 710 2,2-Difluoroethyl i-Pr 4-F-Phenyl 94-96 711 2,2-Difluoroethyl i-Pr 2,4-diF-Phenyl 105-108 712 1-(4-Chlorobutyl) i-Pr 4-F-Phenyl oil* 713 1-(3-Chloropropyl) i-Pr 4-F-Phenyl oil* 714 1-(2-Chloropropyl) (S) i-Pr 2,4-diF-Phenyl oil* 715 (2-Tetahydropyranyl)methyl i-Pr 2,4-di-Phenyl oil* 716 (2-Phenyl- 1,3,4-oxadiazol-5- i-Pr Phenyl 130-132 yl)mediyl________ 717 1-(Cyclobutyl)ethyl i-Pr Phenyl oil* 718 1-(Cyclobutyl)ethyl i-Pr 4-F-Phenyl oil* 719 Me 2
NC(O)CH
2
CH
2 - i-Pr 4-Ci-Phenyl 82-83 720 l-(Cyclopropyl)ethyl i-Pr 2,4-di-Phenyl oil* 721 1-(3,4-Dihydroisoxazol-3- i-Pr 4-F-Phenyl oil* __________ yl)ethyl ________ ___________ 722 (5-Phenyl- 1, 2, 5-oxadiazol-2- i-Pr Phenyl 120-12 1 yl)methyl____________________ ____ 723 PhCH(CO 2 Me) i-Pr Phenyl oil* 724 PhCH(CO 2 Me) i-Pr 4-Ci-Phenyl oil* 725 l-(2-Chloro-l-methoxyethyl) i-Pr 4-Cl-Phenyl oil* 726 1-(1,2-Dimethoxyethyl) i-Pr 4-Cl-Phenyl oil* I WO 00/43377 PCT IUSOO/01283 108 727 CH 3
C(O)NHCH
2
CH
2 i-Pr 4-F-Phenyl oil* 728 Me 2
NC(S)CH(CH
3 ) i-Pr 4-F-Phenyl 130 729 1-(3,4-Dihydroisoxazol-3- i-Pr Phenyl oil* yl)ethyl________ 730 1-(3,4-Dihydroisoxazol-3- i-Pr 2,4-diF-Phenyl oil* __________ yl)ethyl ___________ 731 1-(2-(6-Chloro-2-pyridyl)-2- i-Pr Phenyl oil* propenyl) ___________ 732 1 -(2-Carbomethoxy-2-propenyl) i-Pr 4-F-Phenyl oil* 733 Me 2
NC(S)CH(CH
3 ) i-Pr 4-Ci-Phenyl 136 734 1-(1,2-Diimethoxyethyl) i-Pr Phenyl oil* 735 1-(2-Chloro- I1-methoxyethyl) i-Pr Phenyl oil* 736 (EtO) 2
P(O)CH
2 i-Pr 2,4-diF-Phenyl 113-115 737 1-(2-Chloro- 1-methoxyethyl) i-Pr 2,4-diF-Phenyl oil* 738 1-(1 ,2-Dimethoxyethyl) i-Pr 2,4-diF-Phenyl oil* 739 Me 2
NC(S)CH(CH
3 ) i-Pr 2,4-diF-Phenyl 107 740 (5,6-Dihydro- 1,2,4-Dioxazin-3- i-Pr 4-CI-Phenyl 107 __________ yl)methyl________ 741 PhCON(CH 3
)CH
2
CH
2 i-Pr 4-F-Phenyl 141-146 742 1-(1-Ethoxypropyl) i-Pr 4-F-Phenyl oil* 743 Propargyl i-Pr 4-F-Phenyl oil* 744 1-(3-Butynyl) i-Pr 2,4-diF-Phenyl oil* 745 2,2-Difluoroethyl i-Pr 4-Ci-Phenyl 104-107 746 2,2-Difluoroethyl i-Pr Phenyl oil* 747 1-(2-Chloropropyl) (S) i-Pr Phenyl oil* 748 1-(2-Chloropropyl) (S) i-Pr 4-CI-Phenyl oil* 749 1-(3-Chloropropyl) i-Pr 4-CI-Phenyl 68-72 750 1-(3-Chloropropyl) i-Pr Phenyl oil* 751 s-Butyl i-Pr 4-F-Phenyl 42-44 752 1-(3-Bromo-2-methylpropyl) i-Pr 4-F-Phenyl 96-100 753 3-(4mPentynyl) i-Pr 4-F-Phenyl oil* 754 Propargyl i-Pr Phenyl 75-76 755 Bromomethyl i-Pr Phenyl 82-841 756 1-(4,5-Diniethylthiazol-2- i-Pr Phenyl 101-104 __________ yl)ethyl ________ ___________ ____ WO 00/43377 PCT[USOO/01283 109 757 1-(4,5-Dimethylthiazol-2- i-Pr 4-F-Phenyl 103-105 __________ yl)ethyl ____________ 758 (5,6-Dihydro-1 ,2,4-Dioxazin-3- i-Pr 2,4-diF-Phenyl oil* yl)methyl ___________ 759 1-(3,4-Dihydroisoxazol-3- i-Pr 4-CI-Phenyl 0il* yl)ethyl 760 (5,6-Diliydro-6-OMe-1,2- i-Pr 4-Cl-Phenyl 107-109 __________ oxazin-3-yl)methyl ____________ 761 PhCON(CH 3
)CH
2
CH
2 i-Pr Phenyl 124-127 762 PhCON(CH 3
)CH
2
CH
2 i-Pr 2,4-diF-Phenyl 106-108 763 2-(3-Butynyl) i-Pr 4-F-Phenyl oil* 764 Propargyl i-Pr 2,4-diF-Phenyl 0il* 765 (5,6-Dihydro- I ,2,4-Dioxazin-3- i-Pr 4-F-Phenyl oil* yl)methyl ____________ 766 (Dihydro-6-OMe- 1,2-oxazin-3- i-Pr 4-F-Phenyl oil* __________ yl)methyl________ 767 1-(3-Butynyl) i-Pr 4-F-Phenyl oil* 768 1-(3-Butynyl) i-Pr Phenyl oil* 769 (5-i-Propyl- 1, 2, 5-oxadiazol-2- i-Pr Phenyl oil* yl)methyl____________ ____ 770 (5-c-Hexyl- 1, 2, 5-oxadiazol-2- i-Pr Phenyl 106-108 __________ yl)methyl ____________ 771 i-propyl i-Pr 2-C1-5-Pyiidiyl 0i1* 772 1-(1-Ethoxypropyl) i-Pr 4-CI-Phenyl oil* 773 1-(1-Ethoxypropyl) i-Pr Phenyl oil* 774 1-(1-Ethoxypropyl) i-Pr 2,4-diF-Phenyl oi1* 775 CH 3
O
2
CN(CH
3
)CH
2
CH
2 i-Pr Phenyl oi1* 776 (EtO) 2
P(O)CH(CH
3 ) i-Pr 2,4-dI-Phenyl 0il* 777 (CH 3
O)
2
P(O)CH
2
CH
2 i-Pr 2,4-dI-Phenyl oil* 778 CH 3
O
2
CN(GH
3
)CH
2
CH
2 i-Pr 2,4-dI-Phenyl oil* 779 CH 3
O
2
CN(CH
3
)CH
2
CH
2 i-Pr 4-Ci-Phenyl oi1* 780 i-Propyl i-Pr 4-OMe-Phenyl 93-94 781 1-(3-Methyl-3-nitropropyl) i-Pr 2,4-diF-Phenyl 118-120 782 1-(3, 3-Dichloro-2-propenyl) i-Pr 4-F-Phenyl oi1* 783 3-(4-Pentynyl) I i-Pr f 2,4-diF-Phenyl 011i'* WO 00/43377 PCT/USOO/01283 110 784 Propargyl i-Pr 4-Cl-Phenyl oil* 785 1-(4,5-Dimethylthiazol-2- i-Pr 2,4-diF-Phenyl oil* yl)ethyl____________ _ ___ 786 Pyrrolidinothiocarbonylmethyl f-Pr 2,4-diF-Phenyl 68 787 Pyrrolidinothiocarbonylmethyl i-Pr 4-Ci-Phenyl 144 788 Pyrrolidinothiocarbonylmethyl i-Pr Phenyl 117 789 Pyrrolidinodhiocarbonylmethyl i -Pr 4-F-Phenyl 142 790 2-(3-Methoximinopropyl) i-Pr Phenyl 82-87 791 1-(4-Chlorobutyl) i-Pr 4-Ci-Phenyl 103-109 792 1-(4-Chlorobutyl) i-Pr Phenyl oil* 793 4-Cyclohexenyl i-Pr 4-F-Phenyl 107-108 794 1-(2-Bromoethyl) i-Pr 4-F-Phenyl 105-106 795 1-(2-Bromoethyl) i-Pr 2,4-diF-Phenyl 77-80 796 1-(2-Bromoethyl) i-Pr 4-Cl-Phenyl 85-87 797 (Pinenyl)methyl i-Pr Phenyl oil* 798 i-Propyl i-Pr (3,5-Dimethylisoxazol-4- oil* _________ yl)methyl ____ 799 1-(2,2-Dimethylcyclopropyl) i-Pr 4-F-Phenyl 69-72 800 1-(2,2-Dimethylcyclopropyl) i-Pr Phenyl oil* 801 1-(2,2-Dimethylcyclopropyl) i-Pr 4-CI-Phenyl oil* 802 1-(2,2-Dimethylcyclopropyl) i-Pr 2,4-diF-Phenyl oil* 803 3-(4-Pentynyl) i-Pr Phenyl oil* 804 1-(3-Butynyl) i-Pr 4-Ci-Phenyl oil* 805 2-(1,3-Dibromopropyl) i-Pr 4-F-Phenyl oil* 806 1-(3-Bromo-2,2- i-Pr 4-F-Phenyl 122-126 __________ dimethyipropyl) ________ ____ 807 (5,6-Diydro-6-methoxy-1,2- i-Pr 2,4-diF-Phenyl 110-115 oxazin-3-yl)methyl ________ 808 3-(4-Pentynyl) i-Pr 4-Ci-Phenyl oil* 809 (5,6-Diliydro-6-methoxy-1,2- i-Pr Phenyl 96-98 oxazin-3-yl)methyl _______________ 810 1-(4,5-Dihydro-5- i-Pr 4-F-Phenyl oil* methoxyisoxazol-3-yl)ethyl ____________ 811 1-(4,5-Diliydroisoxazol-5- i-Pr 4-F-Phenyl oil* _________ ~yl)ethyl ________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ WO 00/43377 PCTUSOO/01283 812 1-(4,5-Dihydro-5- i-Pr Phenyl oil* _________ methoxyisoxazol-3-yl)ethyl ____________________ 813 i-Pr c-PrCH 2 4-F-Phenyl 76-77 814 1-(4,5-Dihydroisoxazol-5- i-Pr 4-Ci-Phenyl oi1* _________ ~yl)ethyl________ 815 1-(4,5-Dihydroisoxazol-5- i-Pr 2,4-di-Phenyl oil* yl)ethyl ___________ 816 1-(4,5-Dihydroisoxazol-5- i-Pr Phenyl oi1* yl)ethyl ___________ 817 2-(1 .1, 1-Trifluoropropyl) i-Pr 2,4-diF-Phenyl oil* 818 3-( 1-Trimethylsilylpropyl) i-Pr 4-F-Phenyl oil 819 l-(2,3-Epoxy-2-methylpropyl) i-Pr 4-F-Phenyl oil* _____ ~~(R) _ _ _ _ _ _ 820 l-(2,3-Epoxy-2-methylpropyl) i-Pr 4-F-Phenyl 78 -80 __________ ~(S) ________ ____ 821 (MeO 2
Q)
2 CH i -Pr Phenyl oil 822 1-(3-Chloropropyl) i-Pr 2,4-di-Phenyl 0il* 823 1-(4-Chlorobutyl) i-Pr 2,4-diF-Phenyl oil* 824 2-(3-Chloro-3-methoxypropyl) i-Pr Phenyl 0il*1 825 2-(3-Chloro-3-methoxypropyl) i-Pr 4-F-Phenyl oil* 826 1-(2,2-Dichloroethyl) i -Pr 4-F-Phenyl 95 -98 827 1-(2-Butynyl) i-Pr 2,4-diF-Phenyl 131 -132 828 1-(2-Butynyl) i-Pr 4-F-Phenyl 115 ____ ___ ____ ___ ___ 116.5 829 i-Pr i-Pr (5-t-Butyl-1,2,4-oxadiazol- 0i1* ________________3-yl)methyl_____ 830 1-(2-Butynyl) i-Pr 4-Ci-Phenyl 24-25 831 l-(2-Cyclopropylethyl) i-Pr 4-F-Phenyl 70- 72 832 1-(2-Cyclopropylethyl) i-Pr Phenyl 70- 72 833 1-(2-Butynyl) i-Pr Phenyl 90.5 -92 834 1-(1,3-Dioxolan-2-yl)ethyl i-Pr 4-F-Phenyl 104 -107 835 1-(1,3-Dioxan-2-yl)ethyl i-Pr 4-F-Phenyl 94- 96 836 1-(5,5-Dimethyl-1,3-dioxan-2- i-Pr 4-F-Phenyl 90- 93 __________ yl)ethyl ____________ 837 1 -( 1,3-Dioxepin-5-en-2-yl)ethyl i-Pr 4-F-Phenyl oil* WO 00/43377 PCT[USOO/01283 112 838 i-Pr i-Pr 2,6-DiF-Phenyl 80-83 839 i-Pr i-Pr 2,3-DiF-Phenyl oil* 840 i-Pr Et 4-F-Phenyl oil* 841 2-(3-Butenyl) i-Pr 4-Ci-Phenyl oil* 842 2-(3-Butenyl) i-Pr 2,4-diF-Phenyl oil* 843 2-(3-Butenyl) i-Pr Phenyl oil* 844 1-(3-Methylenecyclobutane) i-Pr 4-F-Phenyl 60- 61 845 1-(3-Methylenecyclobutane) i-Pr 2,4-diF-Phenyl oil* 846 1-(3-Methylenecyclobutane) i-Pr Phenyl oil* 847 1-(3-Methylenecyclobutane) i-Pr 4-CI-Phenyl 81 -84 848 3-Cyclopentene i-Pr 4-F-Phenyl 71 -74 849 HC(O)CH(CH 3 ) i-Pr 4-Ci-Phenyl oil* 850 HC(O)CH(CH 3 ) i -Pr Phenyl oil* 851 (3-Chioro- 1-methylpyrazol-4- i-Pr 4-F-Phenyl 105 -107 __________ yl)methyl ____________ 852 (3-Chloro-l-methylpyrazol-4- i-Pr 4-Ci-Phenyl oil* yl)methyl ___________ 853 (3-Chloro-1-methylpymaol-4- i-Pr Phenyl oil* yl)methyl_________________ 854 (3-Chloro- 1-methylpyrazol-4- i-Pr 2,4-diF-Phenyl oil* __________ yl)methyl ____________ 855 (I-Methyl-5-chloro-3- i-Pr Phenyl 152 -154 trifluoromethylpyrazol-4 yl)methyl ___________________ 856 (1-Methyl-5-chloro-3- i-Pr 4-F-Phenyl 148 -149 trifluoromethylpyrazol-4 __________ yl)methyl ____ 857 (1-Methyl-5-chloro-3- i-Pr 2,4-diF-Phenyl 112 -114 trifluoromethylpyrazol-4 __________ yl)methyl________ 858 (1-Methyl-5-chloro-3- i-Pr 4-Ci-Phenyl 132 -136 trifluoromethylpyrazol-4 _________ yl)methyl ___________ 859 (1-Methyl-4-bromopyrazol-3- i-Pr Phenyl 161 -165 __________ yl)methyl ___________________ WO 00/43377 PCTIUSOO/01283 113 860 (1-Methyl-4-bromopyrazol-3- i-Pr 4-F-Phenyl 124 -132 __________ yl)methyl ________ ____ 861 1-(1-Methyl-4-bromopyrazol-3- i-Pr Phenyl 123 -124 yl)ethyl ___________ 862 1-(1-Methyl-4-bromopyrazol-3- i-Pr 4-F-Phenyl 122 -124 yl)ethyl ____________ 863 (1-Methyl-4-bromopymwzl-3- i-Pr 4-Ci-Phenyl 147 -150 __________ yl)methyl ____________ 864 1-(1-Methyl-4-bromopyrazol-3- i-Pr 4-Ci-Phenyl 119 -121 yl)ethyl ___________ 865 (I-Methyl-4-bromopyrazol-3- i-Pr 2,4-diF-Phenyl 116- 117 yl)methyl ____________ 866 1-( 1-Methyl-4-bromopyrazol-3- i-Pr 2,4-Mi-Phenyl oil* __________ yl)ethyl ____________ 867 Cyclooctyl i-Pr 4-F-Phenyl 81 -84 868 i-Pr 2-(3-MeQ-propyl) Phenyl 73 -77 869 i-Pr 2-(3-MeO-propyl) 4-F-Phenyl 119 -125 870 i-Pr 2-(3-MeO-propyl) 4-CI-Phenyl 76- 81 871 2-(3-Chloro-3-methoxypropyl) i-Pr 4-CI-Phenyl oil* 872 2-(3-Cbloro-3-methoxypropyl) i-Pr 2,4-di-Phenyl oil* 873 1-(2,2-Dichloroethyl) i-Pr 4-CI-Phenyl 80- 88 874 1-(2,2-Dichloroethyl) i-Pr Phenyl 95 -96 875 1-(2-Chloropropyl) (S) i-Pr 4-F-Phenyl 55 -60 876 2-( , 1, 1-Trifluoropropyl) i-Pr 4-Ci-Phenyl _____ 877 Cyclooctyl i-Pr Phenyl 50- 58 878 i-Pr Allyl Phenyl 58 -60 879 Cyclooctyl i-Pr 4-Ci-Phenyl 99 -103 880 Cyclooctyl i-Pr 2,4-di-Phenyl 89-93 881 Me 2
NC(O)OCH
2
CH
2 i-Pr 4-F-Phenyl 94-96 882 3-(1-Hexynyl) i-Pr Phenyl oil* 883 i-Pr (CD 3
)
2 CH 4-F-Phenyl 66- 68 884 1-(3-Allyloxy-2- i-Pr 4-F-Phenyl oil* __________ methoximinopropyl) __________________________ 885 1-(3-Allyloxy-2- i-Pr Phenyl oil* __________ methoximinopropyl) __________________________ WO 00/43377 PCTIUSOO/01283 114 886 1-(3-Allyloxy-2- i-Pr 2,4-diF-Phenyl oil* __________ methoximinopropyl) ________ ___________ ____ 887 1-(3-Aflyloxy-2- i-Pr 4-Ci-Phenyl oil* methoximinopropyl)____________ 888 i-Pr 2-(1-Chloropropyl) 4-Ci-Phenyl oil* 889 (1,3-Dioxolan-4-yl)mediyl f-Pr 4-F-Phenyl 75 -78 890 (2,2-Dimnethyl-1,3-dioxolan-4. i-Pr 4-F-Phenyl 110 -113 __________ yl)methyl ____________ 891 (1 ,3-Dioxolan-4-yl)methyl i-Pr Phenyl 91 -96 892 2-Methoxymethylpyrrolidin-l- i-Pr 4-F-Phenyl oil* 89 -(-etybty)i-rPenl63A6 894 1-(3-Methylbutyl) i-Pr 4-iPhenyl 64- 66 895 1-(3-Methylbutyl) i-Pr 4-Fl-Phenyl 884-691 896 1-(3-Methylbutyl) i-Pr 24-dF-Phenyl 54-956 897 3-(l-Hexynyl) i-Pr 2,4-diF-Phenyl 63 -64 898 1-(1 ,3-Dioxepin-2-yl)ethyl i-Pr 4-F-Phenyl oil* 899 (1,3-Dioxolan-2-yl)methyl i-Pr 4-F-Phenyl 84- 87 900 1-(3-Benzyloxy-2- i-Pr 4-F-Phenyl oil* methoximinopropyl) ________ ____ 901 1-(3-Benzyloxy-2- i-Pr Phenyl oil* __________ methoximinopropyl) _________ 902 1-(3-Methoxy-2- i-Pr 4-F-Phenyl oil* methoximinopropyl) ________ ___________ 903 1-(3-Methoxy-2- i-Pr Phenyl oil* methoximinopropyl)____________ 904 1-(3-Methoxy-2- i-Pr Phenyl oil* __________ methoximinopropyl) ________ 905 i-Pr 2-(1,1- 4-Cl-Phenyl oil* ________ _____________________Dimethoxypropyl)____________ 906 i-Pr 2-(1-Cbloropropyl) Phenyl 92- 94 907 i-Pr 2-(1-Chloropropyl) 4-F-Phenyl 95 -97 908 i-Pr 2-(3-Chlorobutyl) Phenyl oil* 909 i-Pr- 2-(3-Chlorobutyl) 4-F-Phenyl oil* 910 i-Pr n-Bu 4-F-Phenyl 72-73 WO 00/43377 PCT/USOO/01283 115 911 i-Pr n-Pr 4-F-Phenyl 63 -64 912 i-Pr i-Bu 4-F-Phenyl 66-67 913 CH 3
C(O)CH
2
CH
2 i-Pr Phenyl oil* 914 HC(O)CH 2
CH
2 i-Pr 4-F-Phenyl oil* 915 CH 3
C(O)CH
2
CH
2
CH
2 i-Pr 2,4-diF-Phenyl oil* 916 CH 3
C(O)CH
2
CH
2
CH
2 i-Pr 4-Cl-Phenyl oil* 917 3-(1-Hexynyl) i-Pr 4-Cl-Phenyl oil* 918 i-Pr 2-(1,1,1- Phenyl 92-94 Trifluoropropyl) 919 i-Pr 2-(1,1- Phenyl oil* Dimethoxypropyl) 920 i-Pr 2-(1,1- 4-F-Phenyl oil* Dimethoxypropyl) 921 i-Pr 1-(1-Cyanoethyl) 4-F-Phenyl 80- 82 922 1-(3-Methoxy-2- i-Pr 4-Cl-Phenyl oil* methoximinopropyl) 923 1-(3-Methoxy-2- i-Pr 2,4-diF-Phenyl oil* methoximinopropyl) 924 i-Pr Allyl 4-F-Phenyl 57-59 925 i-Pr c-Hexyl 4-F-Phenyl 126 - 131 926 i-Pr c-Pentyl 4-F-Phenyl 93 - 95 927 3-(Cyclopentene) i-Pr 2,4-diF-Phenyl oil* 928 3-(Cyclopentene) i-Pr 4-Cl-Phenyl 100 - 103 929 3-(Cyclopentene) i-Pr Phenyl oil* 930 1-(3-Oxocyclobutyl) i-Pr 4-F-Phenyl oil* 931 1-(3-Oxocyclobutyl) i-Pr 2,4-diF-Phenyl 95 - 97 932 1-(3-Oxocyclobutyl) i-Pr Phenyl 148 - 150 933 1-(3-Oxocyclobutyl) i-Pr 4-Cl-Phenyl 120 - 122 934 CH 3
C(O)CH
2
CH
2 i-Pr 4-F-Phenyl 94-95 935 CH 3
C(O)CH
2
CH
2 i-Pr 2,4-diF-Phenyl oil* 936 CH 3
C(O)CH
2
CH
2 i-Pr 4-Cl-Phenyl 111 - 113 937 1-(3-Butenyl) i-Pr 4-F-Phenyl 40-42 938 1-(3-Butenyl) i-Pr 2,4-diF-Phenyl 58 - 60 939 1-(3-Butenyl) i-Pr Phenyl 43 -45 940 1-(3-Butenyl) i-Pr 4-Cl-Phenyl 50- 51 WO 00/43377 PCT/USOO/01283 116 941 i-Pr Neopentyl 4-F-Phenyl 88-89 942 i-Pr (CH 3
)
3
CCH
2
CH
2 4-F-Phenyl 79- 80 943 2-(l-Chloro-3-Fluoropropyl) i-Pr 4-Cl-Phenyl 87-90 944 2-(1,3-Dichloropropyl) i-Pr 4-Cl-Phenyl 79- 82 945 4-(2,3,5,6- i-Pr 4-F-Phenyl 163 -165 Tetrahydrothiopyranyl) 946 4-(2,3,5,6- i-Pr Phenyl 145 -148 Tetrahydrothiopyranyl) 947 4-(2,3,5,6- i-Pr 2,4-diF-Phenyl oil* Tetrahydrothiopyranyl) 948 4-(2,3,5,6- i-Pr 4-Cl-Phenyl 153 - 157 Tetrahydrothiopyranyl) 949 3-(2,3,4,5-Tetrahydrothienyl) i-Pr 4-F-Phenyl 67-70 950 2-(1-Chloro-3-Fluoropropyl) i-Pr Phenyl 100- 103 951 i-Pr 3-(2,3,4,5- 4-F-Phenyl 114 -117 Tetrahydrothienyl) 952 i-Pr N=CHMe Phenyl oil* 953 i-Pr N=CMe 2 Phenyl oil* 954 PyrrolidinoC(O)OCH 2
CH
2 i-Pr Phenyl 100-104 955 i-Pr 2-(1,3-DiCl-propyl) Phenyl oil* 956 i-Pr 2-(1,3-DiCl-propyl) 4-F-Phenyl oil* 957 i-Pr 3-(2-Me-butyl) 4-F-Phenyl 109 - 110 958 c-Pr (CD 3
)
2 CH 4-F-Phenyl 69 -70 959 3-(2-Methyl-4-pentynyl) i-Pr Phenyl oil* 960 EtOC(O)OCH 2
CH
2 i-Pr 4-F-Phenyl 105-108 961 i-Pr 3-Pentyl 4-F-Phenyl 55 -57 962 CH 3
C(O)CH
2
CH
2
CH
2 i-Pr 4-F-Phenyl oil* 963 CH 3
C(O)CH
2
CH
2
CH
2 i-Pr Phenyl oil* 964 HC(O)CH 2
CH
2 i-Pr 2,4-diF-Phenyl oil* 965 HC(O)CH 2
CH
2 i-Pr Phenyl oil* 966 HC(O)CH 2
CH
2 i-Pr 4-Cl-Phenyl 98 - 100 967 4-(1-Hexynyl) i-Pr 4-F-Phenyl oil* *see Index Table D for 1 H NMR data.
WO 00/43377 PCT/USOO/01283 117 INDEX TABLE D Cmpd No. IH NMR Data (CDC1 3 solution unless indicated otherwise)a 77 8 7.30 (d, 1H), 7.20 (d, 1H), 6.99 (m, 1H), 4.89 (s, 2H), 3.50 (q, 4H), 1.24 (t, 6H). 80 8 7.22 (m, 4H), 7.09 (m, 2H), 6.96 (m, 1H), 4.78 (s, 2H), 4.42 (m, 1H), 1.20 (d, 6H). 82 8 7.32 (d, 1H), 7.20 (d, 111), 7.00 (m, 111), 4.90 (s, 2H), 3.95 (m, 1H), 3.40 (m, 2H), 1.82 (m, 4H), 1.70-1.50 (m, 2H), 1.40-1.20 (m, 7H). 83 8 7.3 (d, 1H), 7.19 (d, 1H), 6.96 (m, 1H), 4.88 (s, 2H), 4.38 (m, 1H), 4.20 (s, 2H), 3.80 (t, 2H) 2.30 (br.s, 2H), 1.28 (d, 6H). 84 8 7.41 (d, 1H), 7.10 (m, 4H), 4.75 (s, 2H), 3.50 (q, 4H), 3.45 (s, 3H), 1.24 (t, 6H). 85 8 7.41-7.14 (m, 9H), 4.66 (s, 2H), 3.44 (s, 311), 2.37 (s, 3H). 87 8 7.38 (m, 1H), 7.10 (m, 4H), 6.92 (m, 211), 4.64 (m, 3H), 2.36 (s, 3H), 1.10 (m, 6H). 90 8 7.10 (in, 8H), 5.20 (m, 1H), 4.60 (m, 1H), 2.80 (m, 3H), 2.20 (m, 2H) 1.20 (d, 6H). 91 5 7.22 (m, 2H), 7.08 (m, 2H), 4.62 (m, 1H), 3.42 (t, 211), 1.62 (m, 2H), 1.20 (d, 6H), 0.90 (t, 3H). 92 8 7.40 (m, 2H), 7.12 (m, 2H), 4.64 (m, 1H), 3.42 (t, 2H), 1.62 (m, 2H), 1.20 (d, 6H), 0.90 (t, 3H). 99 8 7.3 (m, 211), 7.1 (m, 2H), 4.7 (m, 1H), 4, 1 (m, 1H), 2.4-2.7 (m, 2H), 2.2 (m, 1H), 2.0 (m, 1H), 1.3-1.8 (m 5H), 1.2 (d, 6H). 101 8 6.87 (t, 2H), 6.52 (dd, 2H), 3.57 (m, 1H), 2.91 (q, 2H), 2.70 (s, 3H), 1.32 (t, 3H), 1.19 (d, 6H). 105 8 7.40 (d, 2H), 7.20 (d, 2H), 5.80 (m, 1H), 5.30 (m, 2H), 4.04 (d, 2H), 1.20 (d, 6H). 106 8 7.40-7.08 (m, 9H), 4.40 (m, 3H), 1.20 (d, 6H). 115 8 7.40 (d, 2H), 7.10 (d, 2H), 4.62 (m, 1H), 3.42 (t, 2H), 1.64 (q, 2H), 1.20 (d, 6H), 0.92 (t, 3H). 126 8 5.87 (br m, 1H), 4.41 (m, 1H), 4.27 (m, 2H), 3.86 (t, 211), 2.41 (s, 3H), 2.35 (br m, 2H), 2.25 (s, 3H), 1.32 (d, 611). 127 8 7.3 (m, 1H), 6.8-7.0 (m, 2H), 5.7-5.9 (m, 111), 5.2-5.4 (t, 2H), 4.1 (d, 2H), 3.3 (m, 1H), 1.3 (m, 2H), 0.7 (d, 2H). 128 8 7.2-7.4 (m, 4H), 7.1 (t, 2H), 4.8 (m, 111), 4.2 (g, 4H), 4.0 (s, 2H), 1.3 (t, 6H), 1.1 (d, 6H). 129 8 7.40-7.20 (m, 511), 4.62 (m, 1H), 3.42 (t, 2H), 1.58 (s, 9H), 1.20 (d, 6H). 130 8 7.38 (m, 1H), 6.94 (m, 2H), 4.64 (m, 1H), 3.43 (t, 2H), 1.62 (m, 2H), 1.20 (m, 6H), 0.90 (t, 311). 133 8 7.40-7.18 (m, 9H), 5.18 (q, 1H), 4.40 (m, 1H), 1.80 (d, 3H), 1.18 (d, 6H). 134 8 7.40-7.10 (m, 9H), 5.18 (q, 1H), 4.42 (m, 1H), 1.80 (d, 3H), 1.18 (d, 6H). 135 8 7.27 (m, 2H), 7.11 (t, 2H), 4.69 (m, 1H), 2.92 (m, 1H), 2.76 (in, 111), 1.32-1.14 (m, 18H). 144 8 7.40-7.27 (m, 8H), 5.80 (s, 1H), 4.86 (s, 2H), 4.40 (m, 1H), 4.22 (s, 2H), 3.80 (t, 2H), 2.30 (s, 2H), 1.28 (d, 6H). 145 8 7.40-7.27 (m, 4H), 5.80 (br.s, 1H), 4.86 (s, 2H), 4.30 (m, 1H), 2.38 (m, 1H), 2.16 (m, 411), 1.90 (m, 1H), 1.70 (m, 2H), 1.26 (d, 611). 147 8 5.8 (m, 2H), 5.38 (m, 2H), 4.4 (m, 1H), 4.22 (s, 2H), 4.08 (m, 2H), 3.83 (t, 2H), 2.30 (br.s, 2H), 1.26 (d, 6H).
WO 00/43377 PCT/USOO/01283 118 148 6 7.22 (m, 2H), 7.10 (m, 2H), 4.40 (m, 1H), 3.80-3.50 (m, 4H), 1.21 (d, 6H). 149 5 5.72 (s, 1H), 4.40 (m, IH), 4.28 (s, 2H), 4.16 (m, 2H), 7.10 (m, 2H), 4.40 (m, 1H), 3.80-3.50 (m, 4H), 1.21 (d, 6H). 150 6 5.82 (s, 1H), 5.38 (m, 2H), 4.18 (d, 2H), 3.72 (br.s, 2H), 3.54 (br.s, 2H), 1.96 (br.s, 4H). 151 6 7.30 (m, 1H), 6.92 (m, 2H), 5.80 (m, 1H), 5.26 (m, 2H), 4.42 (m, 1H), 4.06 (d, 2H), 1.2 (m, 6H). 152 6 7.40 (m, 5H), 4.71 (s, 2H), 3.50 (q, 4H), 1.24 (t, 6H). 153 6 7.31 (m, 10H), 4.61 (s, 2H), 3.43 (s, 3H). 172 6 7.40 (m, 1H), 6.94 (m, 2H), 4.62 (m, 1H), 4.02 (m, 1H), 3.40 (m, 1H), 1.20 (m, 6H), 0.78 (d, 3H). 174 8 7.20-7.40 (m, 4H), 5.02 (m, 1H), 4.62 (m, 1H), 1.80 (d, 3H), 1.18 (d, 6H). 178 8 7.40-7.20 (m, 4H), 4.62 (i, 1H), 3.40 (m, 1H), 1.20 (d, 6H), 0.78 (d, 3H). 180 6 7.3 (m, IH), 7.2-7.1 (d, 2H), 5.1-5.0 (m, 1H), 3.99 (s, 6H), 2.22 (s, 6H), 1.46 (d, 6H). 181 8 7.5-7.1 (m, 4H), 5.1-5.0 (m, 1H), 4.00 (s, 6H), 2.26 (s, 3H), 1.5 (d, 6H). 182 6 5.0 (m, IH), 4.3 (m, 1H), 3.97 (s, 6H), 1.5-1.4 (m, 12H). 183 6 7.3 (m, 2H), 7.0 (m, 1H), 6.8 (m, 2H), 3.9 (m, 1H), 3.4 (m, 5H), 1.9-1.1 (m, 13H). 184 6 7.2 (m, 2H), 7.1 (m, 2H), 4.6 (m, 1H), 4.1-3.8 (m, 1H), 2.2-1.7 (m, 9H), 1.2 (d, 6H). 188 8 7.25 (m, 2H), 7.10 (m, 2H), 4.65 (m, IH), 3.65 (m, 2H), 3.20 (m, 1H), 2.80 (t, 1H), 2.62 (m, 11), 1.21 (d, 611). 189 6 8.6 (m, 2H), 7.2 (m, 2H), 4.69 (s, 2H), 4.3 (m, 1H), 3.5 (bm, 2H), 1.50 (d, 6H), 1.22 (t, 3H). 190 6 8.97 (s, 1H), 4.6 (q, 2H), 4.4 (m, 1H), 1.5 (m, 9H). 191 6 7.37 (d, 2H), 7.19 (d, 2H), 4.70 (s, 2H), 4.55-4.67 (m, 1H), 2.61 (s, 3H), 2.42 (s, 3H), 1.20 (d, 6H). 192 6 7.20-7.25 (m, 2H), 7.04-7.10 (m, 2H), 4.70 (s, 2H), 4.58-4.67 (m, 1H), 2.61 (s, 3H), 2.42 (s, 3H), 1.19 (d, 6H). 196 6 7.38-7.41 (m, 2H), 7.20-7.23 (m, 2H), 4.62-4.71 (m, 1H), 2.66 (s, 3H), 2.21 (s, 3H), 1.23 (d, 6H). 197 6 7.41-7.43 (m, 3H), 7.25-7.28 (m, 2H), 4.61-4.74 (m, 1H), 2.65 (s, 3H), 2.19 (s, 3H), 1.24 (d, 6H). 198 6 7.24-7.28 (m, 2H), 7.11 (t, 2H), 4.61-4.74 (m, 1H), 2.66 (s, 3H), 2.21 (s, 3H), 1.23 (d, 6H). 201 8 7.4 (m, 3H), 7.2-7.25 (m, 3H), 7.1-7.2 (t, 2H), 4.6-4.8 (m, IH), 2.3-2.4 (q, 2H), 2.07 (s, 3H), 1.2 (d, 6H), 1.0 (t, 3H). 206 6 7.40-7.20 (m, 5H), 6.40 (m, 1H), 6.36 (m, IH), 4.60 (m, 3H), 1.20 (d, 6H). 207 8 7.40 (s, 11) 7.20 (m, 2H), 7.18 (m, 2H), 4.60 (m, 3H), 1.20 (d, 6H). 208 8 7.40 (m, 2H), 6.94 (t, 2H), 6.38 (m, 1H), 6.36 (m, 1H), 4.62 (m, 3H), 1.20 (d, 6H). 210 6 7.29 (m, 7H), 7.17 (m, 2H), 6.65 (d, 1H), 6.1 (m, 1H), 4.65 (m, IH), 4.22 (d, 211), 1.2 (d, 6H). 213 8 7.23 (m, 2H), 7.09 (m, 2H), 4.65 (m, 11H), 4.24 (s, 2H), 1.2 (d, 6H), 0.14 (s, 9H). 214 6 7.24 (in, 2H), 7.1 (m, 2H), 6.75 (m, 1H), 5.92 (in, 1H), 4.65 (m, 1H), 4.2 (m, 4H), 1.28 (t, 3H), 1.2 (d, 6H). 215 8 7.23 (m, 2H), 7.09 (m, 2H), 4.65 (m, 1H), 4.21 (s, 2H), 3.77 (s, 3H), 1.2 (d, 6H).
WO 00/43377 PCT/USOO/01283 119 216 5 7.27 (m, 2H), 7.08 (m, 2H), 4.65 (m, 1H), 4.38 (s, 2H), 1.21 (m, 15H). 217 8 7.2 (m, 2H), 7.1 (m, 2H), 4.65 (m, 1H), 4.25 (s, 2H), 2.22 (s, 3H), 1.2 (d, 6H). 218 8 7.23 (m, 2H), 7.11 (m, 2H), 4.65 (i, 1H), 3.7 (t, 2H), 2.65 (m, 2H), 1.2 (d, 6H). 220 8 7.23 (m, 2H), 7.09 (i, 2H), 4.65 (i, 1H), 3.68 (m, 4H), 3.55 (m, 2H), 3.44 (m, 2H), 3.31 (s, 3H), 1.2 (d, 6H). 221 8 7.22 (in, 2H), 7.09 (m, 2H), 4.65 (m, 1H), 3.47 (t, 211), 1.6 (m, 2H), 1.3 (n, 2H), 1.2 (d, 6H), 0.9 (t, 3H). 222 8 7.40 (i, 1H), 6.90 (m, 2H), 4.70 (m, 1H), 3.71 (s, 3H), 2.31 (s, 3H), 2.10 (s, 3H), 1.20 (m, 6H). 223 8 7.26 (m, 2H), 7.15 (m, 4H), 6.70 (m, LH), 2.33 (s, 3H), 2.15 (s, 3H), 1.20 (m, 6H). 225 5 7.40 (m, 3H), 7.30 (m, 2H), 4.65 (m, 1H), 2.80 (s, 6H), 1.20 (s, 6H). 229 8 7.20 (m, 8H), 4.66 (i, 1H), 2.64 (t, 2H), 2.13 (s, 3H), 1.59 (m, 2H), 1.35 (m, 2H), 1.23 (m, 6H), 0.94 (t, 3H). 230 8 7.40-7.13 (m, 8H), 4.68 (I, 1H), 2.69 (q, 2H), 2.14 (s, 3H), 1.26 (m, 9H). 232 8 7.37 (m, 3H), 7.20-7.30 (m, 2H), 4.68 (s, 2H), 4.61 (m, 1H), 2.61 (s, 3H), 2.41 (s, 3H), 1.20 (d, 6H). 233 8 7.37 (dd, 1H), 6.92 (dd, 1H), 4.69 (s, 2H), 4.61 (m, 1H), 2.61 (s, 3H), 2.41 (s, 3H), 1.21 (d, 6H). 236 8 7.28 (m, 8H), 4.53 (m, 1H), 2.33 (s, 3H), 2.20 (s, 1.5H), 2.07 (s, 1.5H), 1.44 (d, 3H), 1.16 (d, 3H). 238 5 7.40 (m, 3H), 5.05 (m, 1H), 4.60 (m, 1H), 1.80 (d, 3H), 1.20 (m, 6H). 241 8 7.37 (d, 2H), 7.19 (d, 2H), 4.61 (m, IH), 2.65 (m, 1H), 1.119 (d, 6H), 0.97 (m, 4H). 248 8 7.40 (i, 2H), 7.05 (m, 2H), 4.80 (q, 1H), 4.25 (q, 2H), 3.55 (q, 2H), 1.43 (d, 3H), 1.30 (m, 12H). 251 8 7.23 (m, 2H), 7.11 (m, 2H), 4.65 (i, 1H), 3.34 (d, 2H), 1.22 (m, 7H), 0.55 (m, 2H), 0.35 (m, 2H). 252 8 7.22 (m, 2H), 7.08 (m, 2H), 4.65 (i, 1H), 4.25 (s, 2H), 2.48 (q, 2H), 1.19 (d, 6H), 1.1 (t, 3H). 253 8 7.22 (m, 2H), 7.08 (m, 2H), 4.65 (i, 1H), 3.4 (m, 4H), 1.9-1.19 (m, 34H), 0.88 (m, 7H). 254 8 7.23 (m, 2H), 7.09 (m, 2H), 4.65 (i, 1H), 4.22 (m, 2H), 2.13 (m.2H), 1.45 (in, 2H), 1.29 (m, 4H), 1 0.88 (m, 3H). 256 5 7.2 (m, 2H), 7.04 (m, 2H), 4.61 (m, 3H), 3.88 (s, 2H), 1.43 (s, 2H), 0.04 (m, 9H). 257 8 7.23 (m, 2H), 7.1 (m, 2H), 4.65 (m, 1H), 3.46 (mn, 3H), 1.67-0.9 (m, 18H). 258 8 7.23 (in, 2H), 7.08 (m, 2H), 4.98 (s, 2H), 4.65 (m, 1H), 3.71 (m, 2H), 3.45 (m, 2H), 3.28 (s, 3H), 1.2 (d, 6H). 260 8 7.75 (d, 2H), 7.6 (t, 1H), 7.45 (t, 2H), 7.2 (m, 2H), 7.05 (m, 2H), 5.38 (q, 1H), 4.65 (m, 1H), 1.73 (d, 3H), 1.19 (d, 6H). 262 8 7.23 (mn, 2H), 7.08 (m, 2H), 5.17 (m, 1H), 5.02 (m, 1H), 4.65 (mn, 1H), 4.06 (d, 2H), 2.02 (m, 4H), 1 1.65 (s, 3H), 1.57 (s, 3H), 1.19 (d, 6H). 263 8 7.22 (m, 2H), 7.1 (m, 2H), 6.75 (m, 1H), 6.92 (m, 1H), 4.65 (m, 1H), 4.22 (m, 2H), 3.74 (s, 3H), 1.2 (d, 6H). 264 8 7.22 (m, 2H), 7.08 (m, 2H), 4.65 (m, 1H), 4.07 (s, 2H), 3.38 (m, 4H), 1.24-1.14 (m, 12H).
WO 00/43377 PCT/USOO/01283 120 265 8 7.23 (, 211), 7.08 (m, 211), 4.65 (m, IH), 4.09 (s, 2H), 1.43 (s, 911), 1.19 (d, 6H). 266 .7.21 (m, 2H), 7.08 (m, 2H), 4.65 (m, 11H), 3.66 (s, 3H), 3.55 (t, 2H), 2.33 (t, 2H), 1.96 (m, 2H), 1.2 267 8 8.53 (I, 1), 7.76 (m, 11H), 7.25 (m, 611), 7.08 (t, 2H), 4.76 (s, 2H), 4.66 (in, 1H), 1.19 (d, 6H). 274 3 3.90 (i, 1H), 3.40 (q, 2H), 2.97 (s, 6H), 1.50 (bm, 15H). 275 3 3.90 (m, 1H), 3.45 (m, 411), 1.70 (bm, 10H), 1.00 (s, 9H), 277 8 7.30 (m, 1H), 6.90 (m, 2H), 4.70 (m, 11H), 3.20 (s, 2H), 1.20 (m, 6H), 0.90 (s, 9H). 279 8 7.4 (m, 211), 7.05 (m, 2H), 5.80 (m, 1H), 5.30 (m, 1Hl), 5.25 (m, 111), 4.80 (q, 1H), 4.25 (m, 2H), 4.6 (m, 211), 1.42 (d, 311), 1.30 (m, 6H). 280 8 7.4 (m, 211), 7.05 (m, 2H), 4.80 (q, 1H), 4.25 (q, 211), 3.75 (m, 11H), 1.00-2.00 (m, 19H). 283 3 7.40-7.20 (m, 511), 4.6 (m, 1H), 4.10 (m, 1H), 1.80 (m, 8H), 1.20 (d, 6H). 284 8 7.40 (m, 11H), 6.80 (m, 211), 4.6 (m, 1H), 4.10 (m, 11H), 1.80 (m, 8H), 1.20 (d, 6H). 285 5 7.23 (m, 211), 7.08 (m, 211), 5.5 (t, 1H), 4.65 (m, 11H), 4.2 (d, 2H), 2.12 (s, 3H), 1.2 (d, 6H). 286 3 7.23 (m, 211), 7.11 (m, 2H), 5.8 (m, 1H), 5.4 (m, 11H), 4.65 (m, 11H), 4.0 (d, 2H), 2.05 (m, 211), 1.2 (d, 6H), 0.96 (t, 311). 287 8 7.21 (m, 211), 7.09 (m, 211), 4.65 (m, 11H), 4.54 (t, 1H), 4.38 (t, 1H1), 3.65 (t, 2H), 2.05 (m, 211), 1.2 (d, 6H). 288 8 7.21 (m, 2H), 7.08 (m, 2H), 5.2 (n, 11H), 4.65 (m, 1H), 4.05 (d, 211), 1.73 (d, 6H), 1.2 (d, 611). 289 3 7.23 (m, 211), 7.09 (m, 211), 4.65 (m, 11H), 4.52 (t, 1H), 4.36 (t, 1H), 3.53 (t, 2H), 1.8-1.6 (m, 4H), 1.2 (d, 6H). 290 3 7.23 (m, 211), 7.08 (m, 211), 4.65 (m, 1H), 3.46 (t, 211), 1.6 (m, 2H), 1.3 (m, 4H), 1.19 (d, 6H), 0.87 (t, 3H). 291 8 7.22 (m, 211), 7.09 (m, 2H), 5.72 (m, 1H), 4.99 (m, 211), 4.65 (m, 11H), 3.48 (t, 2H), 2.05 (q, 211), 1.1 1.2 (d, 611). 292 5 7.38-7.35 (m, 2H), 7.21-7.18 (m, 2H), 4.65 (m, 1H), 2.93 (s, 211), 1.2 (d, 6H), 0.08 (s, 9H). 293 3 7.22 (m, 2H), 7.09 (m, 211), 4.89 (s, 211), 4.65 (m, 1H), 3.39 (s, 311), 1.2 (d, 6H). 294 3 7.23 (m, 211), 7.08 (m, 2H), 4.65 (m, 1H), 2.93 (s, 211), 1.2 (d, 611), 0.08 (s, 9H). 295 3 7.23 (m, 211), 7.09 (m, 2H), 4.92 (s, 211), 4.65 (m, 1H), 3.58 (q, 2H), 1.2 (m, 9H). 296 8 8.59 (s, 11H), 8.51 (s, 211), 4.7 (m, 1Hl), 4.2-4.1 (m, 11H), 1.4-1.3 (m, 12H). 297 3 3.49 (m, 1H), 2.77 (m, 1H), 1.25 (,6H), 1.05 (m, 4H). 298 8 3.9 (m, 1H), 3.41 (q, 2H), 2.79 (m, 11H), 2-1 (m, 1711). 302 8 7.4 (m, 211), 7.1 (in, 2H), 4.8 (m, 1H), 4.3 (m, 311), 1.5-1.2 (m, 12H). 303 3 7.4 (m, 4H), 7.2-7.3 (m, 1Hl), 7.1-7.2 (in, 2H), 4.7-4.8 (m, 1H), 2.306 (s, 3H), 1.3-1.4 (m, 9H), 1.2 (m, 3H), 1.1 (m, 3H). 304 8 7.40 (t, 1H), 7.26 (m, 1H), 7.15 (d, 2H), 7.10 (m, 2H), 4.70 (in, 11H), 2.38 (q, 411), 1.20 (d, 6H), 1.10 (t, 611) ). 308 5 3.95 (m, IlH), 3.40 (m, IlH), 2.10 (m, 1H1), 1.80 ( (m, 3H1), 1.70-1.20 (m, 6H).
WO 00/43377 PCT/USOO/01283 121 309 8 4.28 (m, 1H), 3.80 (m, 1H), 3.40 (m, 2H), 1.8 (m, 2H)1.25 (d, 6H), 1.20 (t, 311). 312 8 7.40 (m, 1H), 6.42 (s, 1H), 6.40 (s, 1H), 4.74 (s, 2H), 3.84 (M, 1H), 3.40 (m, 2H), 1.80 (4H), 1.20 (t, 3H). 317 8 7.20 (m, 2H), 7.10 (m, 2H), 4.70 (m, 1H), 3.50 (d, 2H), 3.30 (s, 6H), 1.20 (d, 6H). 323 8 7.22 (m, 2H), 7.07 (m, 2H), 4.6 (m, 1H), 3.55 (t, 2H), 2.26 (t, 2H), 2.11 (s, 6H), 1.8 (t, 2H), 1.2 (d, 6H) 325 8 7. 4 (m, 2H), 7.3 (m, 2H), 5.9-5.7 (m, IH), 5.3-5.2 (m, 2H), 4.1 (d, 2H), 3.7 (q, 1H), 1.3 (d, 311), 0.7-0.4 (m, 4H), 0.3 (m, 1H). 331 8 7.4 (m, 2H), 7.30 (t, 1H), 7.05 (t, 2H), 6.95 (d, 1H), 6.90 (d, 1H), 4.80 (q, 1H), 4.25 (q, 2H), 3.75 (s, 3H), 2.12 (s, 3H), 1.45 (s, 3H), 1.30 (t, 6H). 335 8 8.18 (d, 1H), 8.08 (d, 1H), 7.82 (d, 11), 7.62-7.44 (n, 6H), 7.20 (n, 1H), 4.60 (m, 1H), 1.20 (br. s, 6H) (In DMSO). 336 8 8.18-8.00 (m, 2H), 7.60-7.43 (m. 8H), 4.62 (m, 1H), 2.24 (s, 3H), 1.20 (m, 6H) (in DMSO). 337 8 8.14-8.00 (m, 2H), 7.60-7.20 (m, 7H), 4.62 (m, 1H), 2.20 (s, 3H), 1.20 (s, 6H) (in DMSO). 338 8 8.12-8.00 (m, 2H), 7.60-7.22 (m, 8H), 4.60 (m, 1H), 2.24 (s, 3H), 1.19 (d, 6H) (in DMSO). 344 8 8.10-8.00 (m, 2H), 7.60-7.22 (m, 9H), 4.62 (m, 1H), 2.22 (s, 3H), 1.20 (m, 6H) (in DMSO). 345 8 7.40-7.20 (m, 4H), 5.60 (m, 1H), 5.02 (m, IH), 4.60 (m, IH), 4.00 (m, 1H), 3.60 (m, IH), 3.40 (m, 1H), 1.20 (d, 6H). 352 8 7.30 (m, 1H), 6.90 (m, 2H), 4.65 (m, 1H), 4.20 (m, 1H), 3.75 (t, 1H), 3.40 (q, 1H), 3.20 (s, 3H), 1.30 (d, 3H), 1.20 (m, 6H). 354 8 355 8 7.30 (m, 1H), 6.90 (m, 2H), 4.70 (m, 1H), 3.60 (m, 1H), 2.20 (m, 1H), 1.35 (s, 3H), 1.20 (m, 6H), 0.90 (d, 3H), 0.80 (d, 3H). 356 8 7.40 (m, 3H), 7.28 (m, 2H), 4.70 (m, 1H), 3.60 (m, IH), 2.20 (m, 1H), 1.35 (s, 3H), 1.20 (d, 6H), 0.90 (d, 3H), 0.80 (d, 3H). 358 8 7.20 (m, 2H), 7.10 (m, 2H), 4.70 (m, IH), 1.90 (m, 2H), 1.70 (mn, 2H), 1.20 (d, 6H), 0.80 (t, 6H). 359 8 7.2-7.4 (m, 2H), 7.15 (m, 2H), 7.0-7.1 (t, 3H), 4.7-4.8 (m, 1H), 2.308 (s, 3H), 1.3-1.4 (m, 12H), 1.16 (s, 3H). 361 8 7.37 (d, 2H), 7.18 (d, 2H), 4.64 (m, 1H), 1,39 (s, 3H), 1.19 (d, 6H), 1.02 (m, 2H), 0.86 (m, 2H). 362 8 7.24 (d, 2H), 7.18 (d, 2H), 4.64 (m, 1H), 1,39 (s, 3H), 1.19 (d, 6H), 1.02 (m, 2H), 0.86 (m, 2H). 363 8 7.37 (d, 1H), 6.92 (m, 2H), 4.64 (m, 11), 1,39 (s, 3H), 1.19 (d, 6H), 1.02 (m, 2H), 0.86 (mn, 2H). 364 8 7.40 (in, 3H), 7.28 (m, 2H), 4.70 (m, 1H), 3.60 (m, 11), 1.90 (m, 2H), 1.70 (mn, 2H), 1.20 (d, 6H), 0.80 (d, 6H). 365 8 7.4 (m, 2H), 7.2 (in, 2H), 4.8 (m, 1H), 4.2 (m, 2H), 3.0 (s, 3H), 1.4 (d, 3H), 1.3 (t, 3H). 366 8 8.61 (m, 2H), 7.70 (br d, 1H), 7.27 (m, 3H), 7.07 (t, 1H), 4.73 (m, 1H), 4.62 (s, 2H), 1.19 (d, 6H). 367 8 7.23 (in, 2H), 7.11 (m, 2H), 4.67 (m, 1H), 4.2 (in, 1H), 3.93 (m, 1H), 3.6 (m, 1H), 1.48 (d, 3H), 1. 18 (d, 6H).
WO 00/43377 PCTIUSOO/01283 122 369 6 7.37 (q, 1H), 7.19 (d, 2H), 4.64 (m, 1H), 2.31 (b, 1H), 1.4-0.77 (m, 12H). 370 8 7.39 (m, 3H), 7.24 (m, 2H), 4.64 (m, 1H), 2.28 (m, 1H), 1.3-1 (m, 11H), 0.78 (m, 1H). 372 8 7.37 (q, 1H), 6.92 (m, 2H), 4.64 (m, 1H), 2.31 (m, 1H), 1.4-1.0 (m, 11H), 0.78 (m, 1H). 379 6 7.38 (m, 3H), 7.22 (m, 2H), 4.83 (s, 2H), 4.62 (m, 1H), 4.46 (q, 2H), 1.41 (t, 3H), 1.21 (d, 6H). 381 6 7.22 (m, 3H), 7.06 (m, 3H), 4.85 (s, 2H), 4.63 (m, 1H), 4.48 (m, 2H), 1.42 (t, 3H), 1.19 (d, 6H. 387 6 7.3 (m, 2H), 7.1 (m, 2H), 4.93 (m, 1H), 4.65 (m, 1H), 1.8 (d, 3H), 1.2 (d, 6H). 389 8 7.23 (m, 2H), 7.08 (m, 2H), 4.65 (m, 1H), 3.46 (t, 2H), 1.6 (m, 2H), 1.26 (m, 6H), 1.2 (d, 6H), 0.86 (t, 3H). 394 6 7.28 (m, 1H), 6.91 (m, 2H), 4.65 (m, IH), 3.29 (d, 2H), 2.11 (i, 1H), 1.21 (b, 6H), 0.87 (D, h 399 6 7.24 (m, 2H), 7.1 (m, 2H), 4.64 (m, 1H), 3.77 (mn, 2H), 2.45 (m, 2H), 1.21 (d, 6H). 400 6 7.21 (m, 2H), 7.09 (m, 2H), 4.65 (m, 1H), 4.47 (q, 1H), 2.19 (s, 3H), 1.67 (d, 3H), 1.2 (d, 6H). 401 6 7.05-7.24 (m, 4H), 5.37-5.44 (m, 1H), 4.58-4.67 (m, 1H), 2.33 (s, 3H), 1.78 (d, 3H), 1.19 (d, 6H). 408 6 7.27 (m, 1H), 6.89 (m, 2H), 4.62 (m, IH), 4.2 (m, 1H), 3.98 (m, 1H), 3.6 (m, 1H), 1.45 (d, 3H), 1.21 (d, 6H). 412 6 7.20-7.10 (m, 4H), 5.80 (m, 1H), 5.40 (m, 1H), 4.60 (m, 1H), 4.05 (d, 1H), 4.00 (d, 1H), 1.70 (m, 2H), 1.20 (d, 6H). 413 6 7.20 (m, 2H), 7.10 (m, 2H), 6.00 (m, 1H), 5.20 (m, 2H), 4.60 (m, 2H), 1.50 (d, 3H), 1.20 (d, 6H). 414 6 7.36 (m, 2H), 7.19 (m, 2H), 6.02 (m, 2H), 5.69 (m, 1H), 4.64 (septet, J = 6.8 Hz, 111), 2.97 (s, 2H), 1.20 (d, J = 6.8 Hz, 8H), 0.17 (s, 6H). 417 6 7.38 (m, 2H), 7.17 (im, 2H), 4.65 (m, 1H), 3.29 (d, 2H), 2.01 (m, 1H), 1.21 (d, 6H), 0.88 (d, 6H). 418 6 7.38 (m, 2H), 7.25 (m, 2H), 4.75 (s, 1H), 4.63 (m, 1H), 4.6 (m, 1H), 3.57 (t, 2H), 2.31 (t, 2H), 1.71 (s, 3H), 1.2 (d, 6H). 419 6 7.38 (m, 2H), 7.25 (m , 2H), 4.62 (m, 1H), 3.68 (t, 2H), 2.73 (t, 2H), 2.06 (s, 3H), 1.2 (d, 6H). 420 6 7.38 (m, 3H), 7.25 (m, 2H), 4.53 (d, 2H), 4.31 (d, 2H), 3.67 (s, 3H), 1.27 (s, 3H), 1.2 (d, 6H). 424 6 425 6 7.23 (m, 2H), 7.08 (m, 2H), 6.01 (m, 2H), 5.70 (dd, J = 16.5 Hz, J = 7.3 Hz, 1H), 4.65 (septet, J= 6.8 Hz, 1H), 2.97 (s, 2H), 1.19 (d, J = 6.8 Hz, 6H), 0.17 (s, 6H). 426 6 7.23 (m, 2H), 7.05 (m, 2H), 5.69 (m, 1H), 5.29 (s, 2H), 4.85 (m, 2H), 4.65 (septet, J = 6.8 Hz, 1H), 2.95 (s, 2H), 1.58 (d, J =8.1 Hz, 2H), 1.19 (d, J = 6.8 Hz, 6H). 427 6 5.82 (s, 1H), 4.25 (m, 1H), 4.20 (s, 1H), 4.00 (t, 2H), 2.25 (s, 1H), 1.20 (m, 6H). 428 6 5.78 (s, 1H), 4.25 (m, 1H), 4.00 (m, 1H), 2.25 (in, 1H), 2.20 (m, 4H), 1.20 (d, 6H). 429 6 4.00 (m, 111), 3.50 (m, 2H), 3.00 (m, 1H), 2.20 (m, 2H), 1.80 (n, 4H), 1.20 (t, 3H). 432 6 7.35 (m, 2H), 7.0 (m, IH), 4.9 (m, 1H), 4.6 (m, 1H), 1.8 (d, 3H), 1.2 (br, 6H). 435 6 7.4-7.2 (m, 5H), 4.9 (m, 1H), 4.62 (m, 1H), 1.7 (d, 3H), 1.2 (d, 6H). 441 6 7.3 (m, 3H), 7.2 (m, 3H), 5.0 (m, 1H), 4.6 (m, 1H), 3.2 (s, 3H), 1.6 (d, 3H), 1.1 (d, 6H).
WO 00/43377 PCT/USOO/01283 123 442 8 7.37 (i, 3H), 7.20 (m, 2H), 5.40 (q, 1H), 4.61 (m, 1H), 2, 62 (s, 3H), 2.30 (s, 3H), 1.76 (d, 3H), 1.20 (d, 6H). 443 8 7.30 (m, 1H), 6.90 (t, 2H), 5.40 (q, IH), 4.60 (m, 1H), 2.62 (s, 3H), 2.32 (s, 3H), 1.77 (d, 3H), 1.20 (m, 6H). 446 8 7.2 (m, 2H), 7.1 (m, 2H), 5.1 (m, 1H), 4.7 (m, 11H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (s, 3H), 3.3 (s, 3H), 1.2 (s, 6H). 447 8 7.4 (m, 3H), 7.3 (m, 2H), 4.6 (m, 1H), 4.1 (m, 4H), 3.8 (d, 2H), 1.2 (mn, 12H). 448 8 7.4 (m, 3H), 7.3 (m, 2H), 4.6 (m, 1H), 4.3 (m, 1H), 4.1 (m, 4H), 1.6 (m, 6H), 1.2 (m, 1211). 452 8 7.2 (m, 2H), 7.1 (m, 2H), 6.1-5.2 (m, 3H), 4.7 (m, 1H), 3.6 (m, 1H), 3.4 (s, 3H), 3.4 (s, 3H), 1.2 (d, 6H). 453 8 7.21 (m, 2H), 7.08 (m, 2H), 4.6 (m, 1H), 3.99 (t, 2H), 3.36 (t, 2H), 2.97 (s, 3H), 1.18 (d, 6H). 454 8 7.39 (m, 3H), 7.26 (m, 2H), 5.8 (m, 1H), 5.38 (m, 1H), 4.68 (m, 1H), 3.99 (d, 2H), 2.0 (m, 2H), 1.2 (d, 6H), 0.95 (t, 3H). 455 8 7.39 (m, 3H), 7.26 (m, 2H), 6.0 (m, 1H), 5.2 (dd, 2H), 4.65 (m, 1H), 4.2 (m, 1H), 1.9 (m, 2H), 1.21 (d, 6H), 0.83 (t, 3H). 456 8 7.39 (m, 2H), 7.20 (m, 2H), 4.65 (m, 1H), 4.2 (m, 1H), 3.91 (m, 11), 3.6 (dd, 1H), 1.46 (d, 3H), 1.21 (d, 6H). 457 8 7.4 (m, 3H), 7.2 (m, 2H), 5.0 (s, 2H), 4.5-4.0 (br, 1H), 1.6 (m, 1H), 1.2 (d, 6H). 458 8 7.3 (m, 2H), 7.1 (m, 2H), 5.1 (m, 1H), 4.7 (m, 1H), 4.1 (m, 11H), 3.8 (m, 1H), 3.4 (s, 3H), 1.2 (d, 6H). 461 8 7.27 (m, 2H), 7.11 (m, 2H), 4.68 (m, 1H), 3.46 (t, 2H), 1.64 (m, 2H), 1.22 (d, 6H), 0.44 (m, 2H), 0.00 (s, 9H). 463 5 7.3-7.4 (q, 1H), 6.8-7.0 (m, 211), 4.6-4.7 (m, 2H), 3.73 (s, 311), 1.6 (d, 3H), 1.2 (d, 6H). 464 8 7.4 (m, 3H), 7.2 (m, 2H), 4.6-4.7 (m, 2H), 3.727 (s, 3H), 1.6 (d, 6H), 1.3 (d, 3H). 465 8 7.3-7.4 (m, 1H), 6.8-7.0 (m, 211), 4.6-4.7 (m, 1H), 4.1-4.3 (m, 3H), 3.5-3.9 (m, 1H), 3.0-3.3 (m, 1H), 2.2-2.5 (m, 1H), 1.2 (m, 12H). 467 8 7.39 (m, 2H), 7.22 (m, 2H), 4.93 (s, 2H), 4.66 (septet, J = 6.8 Hz, 11H), 3.62 (apparent t, J= 8.3 Hz, 2H), 1.22 (d, J = 6.8 Hz, 611), 0.93 (apparent t, J = 8.3 Hz, 211), 0.00 (s, 9H). 472 8 7.35 (m, IH), 7.00 (m, 2H), 4.70 (m, 1H), 4.00 (m, 1H), 3.38 (s, 3H), 3.23 (s, 3H), 1.35 (d, 3H), 1.20 (m, 6H). 478 8 1.18 (d, 6H), 1.68 (d, 311), 2.95 (s, 3H) 2.98 (s, 3H), 4.64 (m, 1H), 4.83 (q, 1H) 7.05 (m, 2H), 7.22 (m, 2H). 479 8 1.20 (d, 6H), 1.66 (d, 3H), 2.94 (s, 3H), 2.96 (s, 3H), 4.65 (m, 3H), 4.82 (q, 111), 7.21 (mn, 2H), 7.38 (m, 2H). 481 5 1.20 (n, 6H), 1.68 (d, 311), 2.94 (s, 3H), 2.99 (s, 311), 4.64 (m, 1H), 4.82 (q, 1H), 6.89 (m, 211), 7.33 (m, 1H). 485 8 7.39 (m, 3H), 7.24 (m, 2H), 4.64 (m, 1H), 4.3 (s, 2H), 2.64 (m, 1H) 1.21 (d, 6H), 1.16 (d, 6H). 486 8 7.34 (q, 1H), 6.93 (m, 2H), 4.64 (m, 1H), 4.3 (s, 2H), 2.64 (m, IH), 1.22 (b, 6H), 1.16 (d, 6H).
WO 00/43377 PCTIUSOO/01283 124 487 5 7.37 (d, 2H), 7.18 (d, 2H), 4.64 (m, 1H), 2.65 (m, 111), 1.19 (m, 12H). 488 5 7.20 (m, 2H), 7.09 (m, 2H), 4.64 (m, 1H), 4.43 (s, 2H), 1.92 ( m, 1H), 1.19 (m, 8H), 1.04 (m, 2H). 490 8 7.34 (I, 1H), 6.95 (m, 2H), 4.64 (m, 1H), 4.42 (s, 2H), 1.92 (m, 1H), 1.22 (m, 8H), 1.03 (m, 2H). 491 5 9.53 (s, 1H), 7.24 (m, 2H), 7.1 (m, 2H), 4.64 (m. 1H), 4.35 (s, 2H), 1.2 (b, 6H). 492 8 7.3-7.2 (m, 2H), 7.1 (m, 2H), 6.1 (bs, 1H), 4.7 (m, 1H), 4.14 (s, 2H), 3.7-3.6 (m, 4H), 1.20 (d, 6H). 493 5 7.3-7.2 (m, 2H), 7.1 (m, 2H), 5.9 (bs, 1H), 4.7-4.6 (m, 1H), 4.09 (s, 2H), 3.6-3.5 (t, 2H), 3.5 (dt, 2H), 2.0 (m, 2H), 1.20 (d, 6H). 494 5 7.4 (m, 3H), 7.3-7.2 (m, 2H), 4.7 (m, 1H), 4.14 (t, 2H), 4.02 (s, 2H), 3.3 (t, 2H), 1.9-1.8 (m, 2H), 1.21 (d, 6H). 495 5 7.4 (m, 3H), 7.3-7.2 (m, 2H), 4.7-4.6 (m, 1H), 4.3 (t, 2H), 4.24 (s, 2H), 3.9-3.8 (t, 2H), 1.21 (d, 6H). 496 8 7.4-7.3 (m, 3H), 7.2-7.1 (m, 2H), 5.6 (bs, 1H), 4.7-4.6 (m, 1H), 3.9 (s, 2H), 2.0 (bs, 2H), 1.9 (bs, 2H), 1.6-1.4 (m, 4H), 1.2 (d, 6H). 497 8 7.3 (m, 3H), 7.2 (m, 2H), 5.8 (s, 1H), 4.7-4.6 (m, 1H), 3.94 (s, 2H), 2.7 (m, 2H), 2.4 (m, 2H), 2.2 (b, 2H), 1.2 (d, 6H). 498 5 8.7-8.6 (bs, 1H), 8.5 (bs, 1H), 7.7 (m, 1H), 7.4-7.2 (m, 6H), 5.5 (s, 1H), 5.3 (s, 1H), 4.7-4.6 (m, 1H), 4.45 (s, 2H), 1.2 (d, 6H). 500 5 7.3 (m, 1H), 6.9 (m, 2H), 4.64 (m, 1H), 4.48 (d of t, 2H), 3.65 (t, 2H), 2.42 (m, 2H), 1.2 (m, 6H). 501 8 7.3 (m, 1H), 6.9 (in, 2H), 4.87 (m, 1H), 4.64 (m, 1H), 3.86 (m, 2H), 3.77 (m, 2H), 3.64 (t, 2H), 2.05 (i, 2H), 1.2 (m, 6H). 502 8 7.4 (i, 1H), 6.9 (m, 2H), 4.64 (m, 1H), 4.57 (m, 1H), 3.97 (m.2H), 3.63 (m, 4H), 1.97 (m, 3H), 1.2 (m, 7H). 503 8 7.3 (m, 1H), 6.9 (m, 2H), 4.88 (s, 2H), 4.64 (m, 1H), 3.93 (s, 3H), 1.2 (m, 6H). 504 5 7.4 (m, 1H), 6.9 (m, 2H), 4.92 (s, 2H), 4.65 (m, 1H), 3.59 (q, 2H), 1.2 (m, 9H). 505 5 7.4 (m, 1H), 6.9 (m, 2H), 4.97 (s, 2H), 4.63 (m, 1H), 3.72 (m, 2H), 3.45 (m, 2H), 3.30 (s, 3H), 1.2 (n, 6H). 506 5 7.4 (m, 1H), 6.9 (m, 2H), 4.63 (m, 1H), 4.05 (m, 2H), 3.51 (m, 2H), 2.04 (s, 3H), 1.67 (m, 4H), 1.2 (m, 6H). 507 5 7.35 (m, 2H), 6.92 (m, 211), 4.64 (m, 1H), 3.7 (t, 2H), 2.65 (m, 2H), 1.23 (br s, 6H). 508 5 7.3 (m, 4H), 7.1 (m, 2H), 6.9 (m, 2H), 4.62 (m, 1H), 3.69 (m, 2H), 2.92 (m, 2H), 1.2 (m, 6H) 509 5 7.3 (m, 1H), 6.9 (m, 2H), 4.65 (m, 1H), 3.33 (m, 2H), 1.2 (n, 7H), 0.54 (m, 2H), 0.33 (m, 2H) 510 8 7.3 (m, 1H), 6.9 (m, 2H), 4.63 (m, 1H), 4.37 (s, 2H), 2.43 (s, 3H), 2.24 (s, 3H), 1.2 (m, 6H). 511 5 7.75 (d, 2H), 7.6 (t, 1H), 7.45 (t, 2H), 7.3 (m, 1H), 6.89 (m, 2H), 5.37 (q, 1H), 4.65 (m, IH), 1.72 (d, 3H), 1.2 (br s, 6H). 512 8 7.3 (m, 1H), 6.9 (m, 2H), 4.65 (m, IH), 4.23 (s, 2H), 3.36 (q, 2H), 3.26 (q, 2H), 1.21 (m, 9H), 1.11 (t,3H). 513 8 7.35 (m, 1H), 6.92 (m, 2H), 4.65 (m, 1H), 3.66 (s, 3H), 3.53 (t, 2H), 2.31 (t, 2H), 1.96 (m, 2H), 1.22 (br s, 6H).
WO 00/43377 PCTUSOO/01283 125 514 8.35 (m, 1H), 6.92 (m, 2H), 5.55 (t, 1H), 4.65 (m, 1H), 4.2 (d, 2H), 2.12 (s, 3H), 1.21 (br s, 6H). (3:1 cis/trans mix.) 515 8 7.35 (m, IH), 6.92 (m, 2H), 5.2 (t, 1H), 4.65 (m, IH), 4.04 (d, 2H), 1.72 (m, 6H), 1.21 (br s, 6H). 516 8 7.35 (m, 1H), 6.92 (m, 2H), 5.73 (m, 1H), 5.0 (m, 2H), 4.65 (m, 1H), 3.48 (t, 2H), 2.04 (q, 2H), 1.74 1.22 (br s, 6H). 517 8 7.32 (m, 1H), 6.91 (m, 2H), 4.65 (m, 1H), 4.48 (q, 1H), 2.19 (s, 3H), 1.65 (d, 3H), 1.22 (br s, 6H). 518 8 7.35 (m, 1H), 6.89 (m, 2H), 4.65 (m, 1H), 2.93 (s, 2H), 1.21 (br s, 6H), 0.08 (m, 9H). 519 8 7.37 (m, 1H), 6.92 (m, 2H), 5.1 (s, 1H), 4.87 (s, 2H), 4.65 (m, 1H), 4.13 (q, 2H), 3.78 (q, 2H), 1.231 520 8 7.3 (m, 6H), 6.9 (m, 2H), 4.98 (s, 2H), 4.6 (m, 3H), 1.21 (br s, 6H). 521 8 7.35 (m, 1H), 6.9 (m, 2H), 4.64 (m, 1H), 3.5 (d, 2H), 2.65 (m, 1H), 2.0-1.7 (mn, 6H), 1.21 (br s, 6H). 522 8 7.35 (m, IH), 6.92 (m, 2H), 4.65 (m, 1H), 4.52 (t, 1H), 4.36 (t, IH), 3.53 (t, 2H), 1.85-1.6 (m, 4H), 1.22 (br s, 6H). 523 8 7.35 (m, 1H), 6.9 (m, 2H), 5.8 (m, 1H), 5.4 (m, IH), 4.65 (m, 1H), 4.0 (d, 2H), 2.03 (m, 2H), 1.21 (br s, 6H), 0.94 (t, 3H) 524 8 7.32 (m, 1H), 6.92 (m, 2H), 4.65 (m, 1H), 4.24 (s, 2H), 2.47 (q, 2H), 1.21 (br s, 6H), 1.1 (t, 3H). 525 8 7.33 (in, 1H), 6.93 (m, 2H), 4.65 (m, 1H), 3.75 (t, 2H), 2.48 (m, 2H), 1.22 (br s, 6H). 526 8 7.33 (m, 1H), 6.93 (m, 2H), 4.65 (m, 1H), 3.55 (t, 2H), 2.1 (m, 2H), 1.92 (m, 2H), 1.23 (br s, 6H) 527 8 7.39 (m, 2H), 7.22 (m, 2H), 4.93 (s, 2H), 4.66 (septet, J = 6.8 Hz, 1H), 3.62 (apparent t, J = 8.3 Hz, 2H), 1.22 (d, J = 6.8 Hz, 6H), 0.93 (apparent t, J = 8.3 Hz, 2H), 0.00 (s, 9H). 528 8 7.3 (d, 2H), 7.1 (d, 2H), 4.6-4.7 (m, 1H), 3.5 (t, 2H), 1.6 (m, 2H), 1.3 (m, 4H), 1.1 (d, 6H), 0.875 (t, 3H). 529 8 7.3 (d, 2H), 7.1 (d, 2H), 4.64.7 (m, 1H), 3.4 (t, 2H), 1.6 (m, 2H), 1.26 (brd s, 6H), 1.1 (d, 6H), 0.865 (t, 3H). 530 8 7.3 (d, 2H), 7.1 (d, 2H), 4.64.7 (m, 1H), 4.5 (t, 1H), 4.4 (t, 1H), 3.6 (t, 2H), 1.9-2.1 (m, 2H), 1.2 (d, 6H). 531 8 7.3 (d, 2H), 7.1 (d, 2H), 4.875 (m, 1H), 4.6-4.7 (m, 1H), 3.7-3.9 (m, 4H), 3.648 (t, 2H), 2.046 (m, 2H), 1.1 (d, 6H). 532 8 7.3 (d, 2H), 7.1 (d, 2H), 4.6-4.7 (m, 1H), 4.561 (in, 1H), 3.9-4.0 (m, 2H), 3.6 (m, 4H), 1.9-2.0 (m, 3H), 1.3 (brd s, 1H), 1.1 (d, 6H). 533 8 7.3 (d, 2H), 7.1 (d, 2H), 4.886 (s, 2H), 4.6-4.7 (in, 1H), 3.394 (s, 3H), 1.2 (d, 6H). 534 8 7.4 (d, 2H), 7.2 (d, 2H), 4.922 (s, 2H), 4.64.7 (m, 1H), 3.6 (q, 2H), 1.1-1.2 (m, 9H). 535 8 7.3 (d, 2H), 7.1 (d, 2H), 4.977 (s, 2H), 4.6-4.7 (m, 1H), 3.708 (m, 2H), 3.470 (m, 2H), 3.277 (s, 3H), 1.2 (d, 6H). 536 8 7.3 (d, 2H), 7.1 (d, 2H), 4.6-4.7 (m, 1H), 4.056 (t, 2H), 3.508 (t, 2H), 2.039 (s, 3H), 1.6-1.8 (m, 4H), 1.2 (d, 6H). 537 8 7.3 (d, 2H), 7.1 (d, 2H), 4.6-4.7 (m, 1H), 3.7 (t, 2H), 2.6-2.8 (m, 2H), 1.2 (d, 6H).
WO 00/43377 PCT/USOO/01283 126 538 8 7.3 (d, 2H), 7.238 (m, 2H), 7.166 (m, 1H), 7.0-7.1 (m, 4H), 4.6-4.7 (m, 1H), 3.7 (t, 2H), 2.9 (t, 2H), 1.2 (d, 6H). 539 8 7.3 (d, 2H), 7.1 (d, 2H), 4.6-4.7 (m, 1H), 3.3 (d, 2H), 1.2 (d, 611), 1.1-1.2 (m, 1H), 0.56 (q, 2H), 0.3 (q, 2H). 540 8 7.3 (d, 2H), 7.1 (d, 2H), 4.6-4.7 (m, 1H), 4.369 (s, 2H), 2.436 (s, 3H), 2.245 (s, 3H), 1.1 (d, 6H). 541 8 7.77 (d, 2H), 7.6 (t, 1H), 7.4 (t, 2H), 7.3 (d, 2H), 7.1 (d, 2H), 5.3-5.4 (q, 1H), 4.6-4.7 (m, 1H), 1.7 (d, 3H), 1.1 (d, 6H). 542 8 7.3 (d, 2H), 7.1 (d, 2H), 4.6-4.7 (m, 1H), 4.230 (s, 2H), 3.4 (q, 2H), 3.2-3.2 (q, 2H), 1.239 (t, 3H), 1.2 (d, 6H), 1.1 (t, 3H). 543 8 7.3 (d, 2H), 7.1 (d, 2H), 4.6-4.7 (m, 1H), 3.658 (s, 3H), 3.5 (t, 2H), 2.3-2.4 (t, 2H), 1.9-2.0 (m, 2H), 1.3 (d, 6H). 544 8 7.3 (d, 2H), 7.1 (d, 2H), 5.5 (t, 1H), 4.6-4.7 (m, 1H), 4.2 (d, 2H), 2.1 (s, 3H), 1.1 (d, 6H) (3:1 cis/trns mixture). 545 8 7.3 (d, 2H), 7.1 (d, 2H), 5.2 (t, 1H), 4.6-4.7 (n, 1H), 4.0 (d, 2H), 1.735 (s, 3H), 1.719 (s, 3H), 1.1 (d, 6H). 546 8 7.3 (d, 2H), 7.1 (d, 2H), 5.6-5.8 (m, 1H), 4.9 (m, 2H), 4.6-4.7 (m, IH), 3.4 (t, 2H), 2.0-2.1 (q, 2H), 1.7-1.8 (m, 2H), 1.2 (d, 6H). 547 8 7.4-7.37 (m, 2H), 7.19-7.16 (m, 2H), 4.65 (m, 1H), 4.48 (q, 1H), 2.19 (s, 3H), 1.66 (d, 3H), 1.2 (d, 6H). 548 8 7.38-7.35 (m, 2H), 7.21-7.18 (mn, 2H), 4.65 (m, 1H), 2.93 (s, 2H), 1.2 (d, 6H), 0.08 (s, 9H). 549 8 7.4 (d, 2H), 7.2 (d, 2H), 5.1 (s, 1H), 4.9 (s, 2H), 4.6-4.7 (m, 1H), 4.1-4.2 (q, 2H), 3.7-3.8 (q, 2H), 1.3 (t, 3H), 1.1-1.2 (m, 9H). 550 8 7.3 (d, 2H), 7.1 (d, 2H), 4.6-4.7 (m, 1H), 3.4-3.5 (d, 2H), 2.6-2.7 (m, 1H), 2.0-2.1 (in, 2H), 1.8-1.9 (q, 2H), 1.1 (d, 6H). 551 8 7.3 (d, 2H), 7.1 (d, 2H), 4.6-4.7 (m, IH), 4.5 (t, 1H), 4.3-4.4 (t, 1H), 3.5 (t, 2H), 1.6-1.8 (m, 4H), 1.2 (d, 6H). 552 8 7.3 (d, 2H), 7.1 (d, 2H), 5.7-5.9 (mn, 1H), 5.3-5.5 (m, 1H), 4.6-4.7 (m, 1H), 4.0 (d, 2H), 2.0-2.1 (mn, 2H), 1.1 (d, 6H), 0.9 (t, 3H). 553 8 7.4 (d, 2H), 7.2 (d, 2H), 4.6-4.7 (n, 1H), 4.244 (s, 2H), 2.4 (q, 2H), 1.2 (d, 6H), 1.087 (t, 3H). 554 8 7.4 (d, 2H), 7.2 (d, 2H), 4.64.7 (m, 1H), 3.7 (t, 2H), 2.4-2.6 (m, 2H), 1.2 (d, 6H). 555 5 7.4 (d, 2H), 7.2 (d, 2H), 4.6-4.7 (m, 111), 3.5 (t, 2H), 2.0-2.2 (m, 2H), 1.8-2.0 (mn, 2H), 1.1 (d, 6H). 556 8 7.39 (in, 3H), 7.3 (n, 2H), 4.6-4.7 (in, 1H), 3.45 (t, 2H), 1.56 (m, 2H), 1.3 (n, 2H), 1.2 (d, 6H), 0.9 (t, 3H). 557 8 7.38 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (m, 1H), 3.44 (t, 2H), 1.6 (m, 2H), 1.3 (m, 4H), 1.2 (d, 6H), 0.86 (t, 3H). 558 8 7.387 (m, 3H), 7.38 (m, 2H), 4.6-4.7 (m, 1H), 3.44 (t, 2H), 1.6 (m, 2H), 1.25 (d, 6H), 1.2 (s, 6H), 0.859 (t, 3H). 559 8 7.4 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (m, 1H), 4.53 (t, 1H), 4.37 (t, 1H), 3.61-3.66 (t, 2H), 1.9-2.1 (m, 2H), 1.2 (d, 6H).
WO 00/43377 PCTUSOO/01283 127 560 5 7.37 (m, 3H), 7.26 (m, 2H), 4.87 (t, 1H), 4.6-4.7 (m, 1H), 3.8-3.9 (m, 2H), 3.7-3.8 (m, 2H)m 3.63 (t, 2H), 2.045 (m, 2H), 1.2 (d, 6H). 561 8 7.3 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (m, 1H), 4.56 (t, 1H), 3.9-4.0 (m, 2H), 3.6 (m, 4H), 1.9 (m, 3H), 1.259 (t, 1H), 1.2 (d, 6H). 562 8 7.39 (m, 3H), 7.26 (m, 2H), 4.87 (s, 2H), 4.6-4.7 (m, 1H), 3.377 (s, 3H), 1.2 (d, 6H). 563 8 7.3 (m, 3H), 7.27 (m, 2H), 4.886 (s, 2H), 4.6-4.7 (m, 1H), 3.547-3.571 (q, 2H), 1.2 (d, 6H), 1.129 1.15 (t, 3H). 564 8 7.38 (m, 3H), 7.26 (m, 2H), 4.966 (s, 2H), 4.6-4.7 (m, 1H), 3.7 (t, 2H), 3.4 (t, 2H), 3.257 (s, 3H), 1.2 (d, 6H). 565 5 7.39 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (m, 1H), 4.046 (t, 2H), 3.495 (t, 2H), 2.033 (s, 3H), 1.6-1.8 (m, 4H), 1.2 (d, 2H). 566 5 7.38 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (m, 1H), 3.66-3.707 (t, 2H), 2.6-2.7 (m, 2H), 1.2 (d, 6H). 567 8 7.38 (m, 3H), 7.24 (m, 5H), 7.12 (d, 2H), 4.63 (m, 1H), 3.67 (t, 2H), 2.9 (t, 2H), 1.2 (d, 6H). 568 5 7.39 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (m, IH), 3.3 (d, 2H), 1.2 (d, 6H), 1.1 (m, 1H), 0.5 (q, 2H), 0.3 (q, 2H). 569 8 7.38 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (m, IH), 4.353 (s, 2H), 2.422 (s, 3H), 2.225 (s, 3H), 1.2 (d, 6H). 570 5 7.759 (d, 2H), 7.438 (t, 1H), 7.374 (t, 3H), 7.37 (m, 2H), 7.26 (m, 2H), 5.3-5.4 (q, 111), 4.6-4.7 (mn, 1H), 1.7 (d, 3H), 1.2 (d, 6H). 571 5 7.37 (m, 3H), 7.25 (m, 2H), 4.6-4.7 (m, 1H), 4.2 (s, 2H), 3.2-3.3 (q, 2H), 3.3-3.4 (q, 2H), 1.2 (in, 9H), 1.1 (t, 3H). 572 5 7.39 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (m, 1H), 3.6 (s, 3H), 3.54 (t, 2H), 2.3 (t, 2H), 1.9 (m, 2H), 1.2 (d, 6H). 573 8 7.39 (m, 3H), 7.26 (m, 2H), 5.5 (t, 1H), 4.6-4.7 (m, 11H), 4.2 (d, 211), 2.1 (s, 3H), 1.2 (d, 6H). 574 5 7.39 (m, 3H), 7.26 (m, 211), 5.1-5.2 (t, 1H), 4.6-4.7 (m, 1H), 4.01-4.039 (d, 2H), 1.7 (d, 6H), 1.2 (d, 6H). 575 8 7.39 (m, 3H), 7.26 (m, 2H), 5.6-5.8 (m, 1H), 4.9-5.1 (m, 2H), 4.6-4.7 (m, 1H), 3.44-3.49 (t, 2H), 2.0-2.1 (q, 2H), 1.7-1.8 (m, 2H), 1.2 (d, 6H). 576 5 7.39 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (mn, 1H), 4.4-4.5 (q, 1H), 2.166 (s, 3H), 1.6 (d, 2H), 1.2 (d, 6H). 577 8 7.37 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (m, 1H), 2.9 (s, 2H), 1.2 (d, 6H), 0.6-0.8 (m, 9H). 578 5 7.4 (m, 311), 7.26 (m, 2H), 5.1 (s, 1H), 4.862-4.866 (s, 2H), 4.6-4.7 (m, 1H), 4.1-4.2 (q, 2H), 3.7 3.8 (q, 2H), 1.17-1.28 (m, 12H). 579 5 7.4-7.2 (m, 10H), 4.97 (s, 2H), 4.63 (m, 1H), 4.58 (s, 2H), 1.2 (d, 6H). 580 8 7.38 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (m, 1H), 3.47-3.49 (d, 2H), 2.6-2.7 (m, 1H), 1.9-2.1 (m, 2H), 1.8-1.9 (q, 2H), 1.7-1.8 (q, 2H), 1.2 (d, 6H). 581 5 7.39 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (m, 1H), 4.5 (t, 1H), 4.3-4.4 (t, 1H), 3.5 (t, 2H), 1.7-1.8 (m, 3H), 1.6-1.7 (m, 1H), 1.2 (d, 6H).
WO 00/43377 PCT/USOO/01283 128 582 8 7.38 (mn, 3H), 7.26 (m, 2H), 5.7-5.9 (m, 1H), 5.3-5.4 (m, 1H), 4.6-4.7 (m, 1H), 4.0 (d, 2H), 1.9-2.1 (m, 2H), 1.2 (d, 6H), 0.9-1.0 (t, 3H). 583 8 7.39 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (m, IH), 4.23 (s, 2H), 2.45-2.48 (q, 2H), 1.2 (d, 6H), 1.1 (t, 3H). 584 8 7.39 (m, 3H), 7.26 (m, 2H), 4.6-4.7 (m, 1H), 3.7 (t, 2H), 2.4-2.6 (m, 2H), 1.2 (d, 6H). 585 8 7.3 (m, 2H), 7.1 (=, 2H), 4.6-4.7 (m, 1H), 3.5 (t, 2H), 2.0-2.2 (m, 2H), 1.8-2.0 (m, 2H), 1.2 (d, 6H). 587 8 7.4 (m, 3H), 7.3 (m, 2H), 4.6 (m, 1H), 4.1 (m, 4H), 3.8 (d, 2H), 1.2 (m, 12H). 592 a 7.4 (m, 2H), 7.2 (m, 2H), 5.1 (m, 1H), 4.7 (m, 1H), 3.3 (s, 3H), 1.7 (d, 3H), 1.2 (d, 6H). 593 8 7.3 (m, 1H), 6.9 (m, 2H), 5.1 (m, IH), 4.7 (n, 1H), 3.3 (s, 3H), 1.7 (d, 3H), 1.2 (m, 6H). 594 8 7.28 (m, 1H), 6.92 (m, 2H), 4.6 (m, 1H), 4.2 (m, 1H), 3.8 (m, 1H), 3.4 (mn, IH), 1.31 (d, 3H), 1.26 (d, 6H). 596 8 7.22 (m, 2H), 7.09 (m, 2H), 4.65 (m, lh), 4.4 (m, 2H), 4.2-3.6 (m, 3H), 2.04 (s, 3H), 1.21 (d, 6H). 597 8 7.39 (m, 2H), 7.16 (m, 2H), 4.6 (m, 1H), 4.2-3.6 (m, 2H), 1.22 (d, 6H). 598 8 7.28 (m, IH), 6.9 (m, 2H), 4.63 (m, IH), 3.8 (s, 2H), 1.26 (b, 61). 599 8 7.4 (d, 2H), 7.20 (d, 2H), 4.65 (m, 1H), 4.12 (q, 4H), 4.80 (d, 2H), 1.30 (m, 12H). 600 8 7.11 (m, 3H), 5.80 (m, 1H), 5.22 (m, 3H), 4.03 (d, 2H), 3.90 (m, 2H), 3.26 (s, 3H), 2.35 (d, 6H), 1.41 (d, 3H). 603 8 7.38-7.41 (m, 3H), 7.21-7.25 (m, 2H), 4.82-4.89 (m, 1H), 4.594.68 (m, 1H), 4.08-4.16 (m, 1H), 3.68-3.74 (m, 1H), 1.57 (d, 3H), 1.21 (d, 6H). 604 8 7.29-7.37 (m, 1H), 6.90-6.96 (m, 2H), 4.83-4.90 (m, 1H), 4.58-4.67 (m, 1H), 4.09-4.17 (m, 1H), 3.68-3.74 (m, 1H), 1.58 (d, 3H), 1.22 (br s, 6H). 605 8 7.6 (m, 1H), 7.48 (m, 1H), 7.3 (m, 3H), 7.2 (m, 3H), 5.94 (s, 1H), 5.3 (s, 1H), 4.6 (m, 3H), 1.2 (d, 6H). 606 8 7.4-7.2 (m, 7H), 6.9 (m, 2H), 5.4 (s, 1H), 5.1 (s, 1H), 4.7-4.6 (m, 1H), 4.4 (s, 2H), 1.2 (d, 6H). 607 8 7.4 (m, 3H), 7.3-7.2 (m, 2H), 4.9 (s, 1H), 4.8 (s, 1H), 4.7-4.6 (m, 1H), 3.9 (s, 2H), 1.7 (s, 3H), 1.2 (d, 6H). 608 8 7.4 (m, 3H), 7.2 (m, 2H), 5.4 (s, 2H), 4.7-4.6 (m, 1H), 4.2 (s, 2H), 1.2 (d, 6H). 609 8 7.39 (m, 3H), 7.26 (m, 2H), 4.82 (m, 1H), 4.64 (m, 1H), 2.41 (s, 1H), 1.60 (d, 3H), 1.22 (d, 6H). 614 8 7.4 (m, 3H), 7.2 (m, 2H), 4.6-4.7 (m, 1H), 4.04.2 (4H), 5.0 (in, 1H), 3.9 (n, 1H), 3.0-3.2 (q of q, 2H), 1.2 (m, 16H). 615 8 7.2 (m, 2H), 7.0-7.1 (t, 2H), 5.7 (m, 1H), 4.6 (m, 1H), 4.2 (m, 2H), 3.9 (mn, 2H), 3.0-3.2 (im, 2H), 1.1-1.3 (m, 14H). 616 8 7.2-7.3 (m, 2H), 7.0-7.1 (m, 2H), 4.6-4.7 (m, 2H), 3.7 (s, 3H), 1.66 (d, 3H), 1.2 (d, 6H). 617 8 7.3 (m, 2H), 7.1 (m, 2H), 4.6 (m, IH), 4.3 (m, 1H), 4.1 (m, 4H), 1.6 (m, 6H), 1.2 (m, 12H). 623 8 7.4 (d, 2H), 7.2 (d, 2H), 4.6-4.7 (m, 2H), 3.742 (s, 3H), 1.6 (d, 3H), 1.2 (d, 6H).
WO 00/43377 PCT/USOO/01283 129 627 8 7.20 (m, 2H), 7.10 (m, 2H), 4.70 (i, 2H), 3.70 (m, 2H), 3.60 (t, 2H), 3.55 (t, 2H), 3.30 (s, 3H) 1.20 (d, 6H). 629 8 7.20 (m, 2H), 7.10 (i, 2H), 4.70 (i, 2H), 3.70 (m, 2H), 3.60 (d, 2H), 3.45 (m, 2H), 1.20 (d, 6H), 1.10 (t, 6H). 631 8 7.35 (m, 3H), 7.28 (m, 2H), 4.70 (I, 1H), 3.65 (t, 2H), 3.54 (t, 2H), 3.30 (s, 3H), 1.22 (d, 6H). 632 8 7.35 (m, 3H), 7.28 (m, 2H), 4.70 (m, 2H), 3.65 (m, 2H), 3.55 (d, 2H), 3.48 (m, 2H), 1.20 (d, 6H), 1.10 (d, 6H). 634 8 7.3 (m, 1H), 6.92 (m, 2H), 5.43 (s, 2H), 4.65 (m, 1H), 4.23 (s, 2H), 1.21 (bs, 6H). 635 8 7.3 (m, 1H), 6.9 (m, 2H), 4.62 (m, 1H), 3.46 (t, 2H), 1.56 (m, 2H), 1.2 (m, 8H), 0.91 (t, 3H). 636 8 7.3 (m, 1H), 6.9 (m, 2H), 4.64 (m, 1H), 3.45 (t, 2H), 1.64 (m, 2H), 1.2 (m, 10H), 0.87 (t, 3H). 637 8 7.3 (m, 1H), 6.9 (m, 2H), 4.63 (m, 1H), 3.45 (t, 2H), 1.6 (m, 2H), 1.2 (mn, 12H), 0.86 (t, 3H). 639 8 7.37 (d, 2H), 7.17 (d, 2H), 4.64 (m, 1H), 4.43 (s, 2H), 1.91 (m, 1H), 1.2 (m, 8H), 1.04 (m, 2H). 640 8 7.21 (m, 2H), 7.09 (m, 2H), 4.65 (m, 1H), 4.19 (s, 2H), 3.3 (m, 1H), 2.4-1.8 (m, 6H), 1.21 (d, 6H). 642 8 7.34 (in, IH), 6.94 (m, 2H), 4.65 (m, 1H), 4.19 (s, 2H), 3.3 (m, 11), 2.4-1.8 (m, 6H), 1.21 (d, 6H). 643 8 7.37 (d, 2H), 7.17 (d, 2H), 4.65 (m, 1H), 4.19 (s, 2H), 3.3 (m, 1H), 2.4-1.8 (m, 6H), 1.21 (d, 6H). 648 8 7.3 (m, 2H), 7.2 (m, 3H), 5.0 (s, 1H), 4.8-4.6 (m, 1H), 4.5 (s, 1H), 4.0 (s, 2H), 1.2 (d, 6H). 649 8 7.3 (m, 3H), 7.2 (m, 2H), 4.9 (s, 1H), 4.8 (s, 1H), 4.7-4.6 (m, 1H), 4.0 (s, 2H), 2.3-2.1 (m, 1H), 1.2 (d, 6H), 1.0 (d, 6H). 650 8 7.4-7.0 (m, 10H), 5.0 (ABm, 2H), 4.7-4.6 (m, 1H), 3.9 (s, 2H), 3.3 (s, 2H), 1.2 (d, 6H). 651 8 7.3 (m, 3H), 7.2 (m, 2H), 6.5 (s, 1H), 5.9 (s, 1H), 5.0 (m, 1H), 4.74.6 (m, 1H), 3.66 (s, 3H), 1.5 (d, 3H), 1.2 (d, 6H). 652 8 7.3 (m, 3H), 7.2 (m, 2H), 5.6 (m, IH), 5.4 (m, 1H), 4.7-4.6 (m, 1H), 2.4 (s, 1H), 1.73 (s, 3H), 1.69 (s, 3H), 1.2 (d, 6H). 655 8 7.4 (m, 3H), 7.2 (m, 2H), 6.4-6.3 (m, 1H), 5.6-5.5 (m, 1H), 4.7-4.6 (m, IH), 2.9 (s, 1H), 1.6 (s, 6H), 1.2 (d, 6H). 656 8 7.22 (m, 2H), 7.09 (m, 2H), 4.63 (m, 2H), 3.95 (m, 2H), 2.07 (m, 2H), 1.94 (m, 2H), 1.60 (d, 3H), 1.18 (d, 6H). 657 8 7.40 (m, 1H), 6.94 (m, 2H), 4.82 (m, 1H), 4.64 (m, 1H), 2.40 (m, 1H), 1.60 (d, 3H), 1.20 (d, 6H). 658 8 7.39 (m, 2H), 7.20 (m, 2H), 4.80 (m, 1H), 4.64 (m, 1H), 2.42 (m, 1H), 1.64 (d, 3H), 1.21 (d, 6H). 672 8 7.26 (in, 2H), 7.09 (m, 2H), 4.67 (m, 1H), 4.4 (m, 1H), 3.9 (in, 2H), 3.8 (m, 2H), 1.22 (d, 6H). 675 8 7.35 (n, 1H), 6.93 (t, 2H), 4.6 (m, 1H), 3.62 (t, 2H), 2.39 (t, 2H), 2.05 (m, 2H), (br, 6H) 677 8 7.39 (m, 5H) 7.20 (m, 2H), 7.10 (m, 2H), 5.60 (s, 1H), 4.60 (m, 1.20 (d, 6H), 3.78 (s, 3H), 1.19 (d, 6H). 681 8 7.3 (d, 2H), 7.2 (d, 2H), 5.0 (m, 1H), 4.6-4.7 (m, 1H), 4.0-4.2 (m, 4H), 3.0-3.3(m, 2H), 1.2-1.3(m, 1211). 682 8 7.56 (s, 1H), 7.36 (m, 1H), 6.91 (m, 2H), 4.60 (m, 1H), 4.47 (s, 2H), 4.15 (q, 2H), 1.41 (t, 3H), _____1.21 (brs, 6H).
WO 00/43377 PCT/USOO/01283 130 683 5 7.54 (s, 1H), 7.38 (m, 3H), 7.24 (m, 2H), 4.63 (m, 1H), 4.59 (s, 2H), 4.14 (q, 211), 1.41 (t, 3H), 1.21 (d, 6H). 684 5 7.56 (s, 1H), 7.36 (m, 2H), 7.19 (m, 2H), 4.63 (m, 1H), 4.48 (s, 2H), 4.15 (q, 2H), 1.41 (t, 3H), 1.19 (d, 6H). 685 5 7.56 (s, 1H), 7.22 (m, 2H), 7.07 (n, 2H), 4.63 (m, 1H), 4.48 (s, 2H), 4.15 (q, 2H), 1.41 (t, 3H), 1.19 (d, 6H). 686 5 7.68 (s, 1H), 7.22 (m, 2H), 7.07 (m, 2H), 5.12 (q, 1H), 4.63 (m, 111), 4.14 (q, 2H), 1.73 (d, 3H), 1.41 (t, 311), 1.18 (d, 6H). 687 5 7.37 (m, 1H), 6.92 (m, 2H), 4.62 (m, 1H), 3.81 (t, 2H), 2.94 (s, 3H), 2.92 (s, 3H), 2.66 (t, 2H), 1.22 (m, 6H). 693 8 9.52 (s, IH), 7.22 (m, 3H), 7.1 (m, 2H), 4.64 (m, 1H), 4.44 (q, 1H), 1.6 (d, 3H), 1.2 (d, 6H). 694 8 7.37 (m, 11H), 6.92 (m, 211), 5.99 (m, 1H), 5.44 (m, 1H), 4.64 (m, 1H), 4.57 (m, 1H), 2.2-1.6 (m, 6H), 1.21 (br, 6H). 696 8 7.37 (d, 2H), 7.17 (d, 2H), 5.99 (m, 1Hl), 5.44 (m, 1H), 4.64 (m, 1H), 4.57 (m, 1H), 2.2-1.6 (m, 6H), 1.21 (d, 6H). 697 5 7.4 (m, 3H), 7.15 (m, 2H), 4.65 (m, 1H), 3.90 (m, 8H), 2.20 (m, 2H), 1.22 (d, 6H). 698 5 7.4 (d, 211), 7.20 (d, 2H), 4.65 (m, 11H), 3.90 (m, 8H), 2.20 (m, 2H), 1.22 (d, 6H). 701 5 7.35 (d, 2H), 7.20 (d, 2H), 4.65 (m, 1H), 3.90 (m, 1H), 2.85 (m, 1H), 1.40-2.00 (m, 6H), 1.20 (d, 9H). 702 8 7.40 (m, 1H), 6.92 (m, 2H), 4.65 (m, 111), 3.90 (m, IH), 2.85 (m, 1H), 1.40-2.00 (m, 6H), 1.25 (mn, 9H). 705 5 7.22 (m, 2H), 7.06 (m, 2H), 4.78 (q, 1H), 4.62 (m, 1H), 3.64 (m, 8H), 1.66 (d, 3H), 1.19 (d, 6H). 708 5 7.29 (m, 1Hl), 6.92 (m, 2H), 4.65 (m, 1H), 4.4-3.5 (m, 5H), 2.04 (s, 311), 1.23 (bs, 6H). 712 5 7.28 (m, 211), 7.08 (m, 2H), 4.62 (m, 1H), 3.52 (m, 4H), 1.8 (m, 4H), 1.18 (d, 6H). 713 5 7.23 (m, 2H), 7.08 (m, 211), 4.61 (m, 11), 3.66 (t, 2H), 3.5 (t, 2H), 2.11 (m, 2H), 1.21 (d, 6H). 714 8 7.3 (m, 11H), 6.92 (m, 2H), 4.65 (m, 1H), 4.25 (m, 1H), 3.71 (m, 2H), 1.49 (d, 3H), 1.23 (bs, 6H). 715 5 7.40 (m, 1H), 6.92 (m, 2H), 4.65 (m, 1H1), 3.90 (m, 1H), 3.56 (q, 2H), 3.30 (m, 2H), 1.82 (m, 1H), 1.50 (m, 5H), 1.20 (m, 6H). 717 5 7.40 (m, 3H), 7.25 (m, 2H), 4.65 (m, 1H), 3.90 (m, 1H), 2.85 (m, 1H), 1.50-2.00 (m, 6H), 1.25 (d, 3H), 1.20 (d, 6H) 718 5 7.25 (m, 2H), 7.10 (m, 2H), 4.65 (m, 1H), 3.90 (m, 1H), 2.85 (m, 1H), 1.50-2.00 (m, 6H), 1.25 (d, 3H), 1.20 (d, 6H). 720 5 7.3 (m, 111), 6.9 (m, 2H), 4.6 (n, 1H), 3.1 (n, 1H), 1.5 (m, 3H), 1.4 (mn, 1H), 1.2 (m, 6H), 0.6-0.3 (m, 4H). 721 5 7.22 (m, 2), 7.09 (m, 2H), 4.92 (m, 1H), 4.65 (m, 1H), 4.39 (m, 2H), 2.91 (n, 2H), 1.68 (d, 3H), 1.19 (d, 6H). 723 5 7.39 (m, 7H) 7.20 (m, 2H), 7.10 (m, 2H), 5.60 (s, 1H), 4.60 (m, 1H), 3.78 (s, 3H), 1.19 (d, 6H). 724 8 7.40 (m, 7H), 7.15 (d, 2H), 5.60 (s, 1H), 4.60 (m, 1H1), 3.79 (s, 3H), 1.20 (d, 6H).
WO 00/43377 PCT/USOO/01283 131 725 8 7.4 (m, 2H), 7.2 (i, 2H), 5.1 (i, 1H), 4, 6 (IM, 1), 4.1 (m, 1H), 3.8 (m, 1H), 3.4 (s, 3H), 1.2 (d, 6H). 726 8 7.4 (m, 2H), 7.2 (i, 2H), 5.1 (i, 1H), 4, 6 (i, 1H), 4.1 (m, 1H), 3.9 ([, 1H), 3.4 (s, 3H), 3.3 (s, 3H), 1.2 (d, 6H). 727 8 7.2 (m, 2H), 7.1 (m, 2H), 5.97 br, IH), 4.65 (m, 1H), 3.65 (m, 2H), 3.45 (m, 2H), 1.91 (s, 3H), 1.19 (d, 6H). 729 6 7.39 (m, 3H), 7.25 (m, 2H), 4.91 (q, 1H), 4.64 (m, IH), 4.37 (m, 2H), 2.92 (in, 211), 1.67 (d, 3H), 1.20 (d, 6H). 730 8 7.35 (m, 1H), 6.93 (m, 2H), 4.93 (q, 1H), 4.65 (m, 1H), 4.39 (m, 2H), 2.94 (m, 2H), 1.68 (d, 3H), 1.20 (d, 6H). 731 8 8.4 (s, 11), 7.6 (m, 1H), 7.5 (m, 1H), 7.4 (m, 3H), 7.2 (m, 2H), 5.84 (s, 1H), 5.3 (s, 1H), 4.7 (m, 1H), 4.6 (s, 2H), 1.2 (d, 6H). 732 8 7.3-7.2 (m, 3H), 7.1-7.0 (m, 2H), 6.4 (s, 1H), 5.7 (s, 1H), 4.7-4.6 (m, 1H), 4.3 (s, 2H), 3.75 (s, 3H), 1.2 (d, 6H). 734 . 8 7.4 (m, 3H), 7.2 (m, 2H), 5.1 (m, 1H), 4,6 (m, 1H), 4.1 (m, 1H), 3.9 (m, 1H), 3.4 (s, 3H), 3.3 (s, 3H), 1.2 (d, 6H). 735 8 7.4 (m, 3H), 7.2 (i, 2H), 5.1 (m, 1H), 4, 6 (m, 1H), 4.1 (m, 1H), 3.8 (m, 1H), 3.4 (s, 3H), 1.2 (d, 6H). 737 8 7.3 (i, 1H), 6.9 (m, 2H), 5.1 (m, 1H), 4, 6 (m, 1H), 4.1 (in, 1H), 3.8 (m, 1H), 3.4 (s, 3H), 1.2 (d, 6H). 738 8 7.3 (m, 1H), 6.9 (m, 2H), 5.1 (m, 1H), 4, 6 (m, IH), 4.1 (mn, 1H), 3.9 (m, 1H), 3.4 (s, 3H), 3.3 (s, 3H), 1.2 (d, 6H). 742 8 7.3 (m, 1H), 6.9 (m, 2H), 4.9 (m, IH), 4.7 (m, 1H), 3.4-3.6 (m, 2H), 2.1 (m, 1H), 1.9 (m, lh), 1.2 (m, 9H), 0.9 (t, 3H). 744 8 7.40 (m, 1H), 6.92 (m, 2H), 4.66 (m, IH), 3.67 (m, 2H), 2.56 (m, 2H), 1.95 (m, 1H), 1.60 (d, 6H). 746 8 7.41 (m, 3H), 7.39 (m, 2H), 5.60 (m, 1H), 4.62 (m, 1H), 3.82 (m, 2H) 1.20 (d, 6H). 747 8 7.38 (m, 3H) 7.25 (m, 2H), 4.66 (m, 1H), 4.25 (m, 1H), 3.65 (m, 2H), 1. 49 (d, 3H), 1.20 (d, 6H). 748 8 7.39 (mn, 2H) 7.17 (m, 2H), 4.62 (m, 1H), 4.25 (mn, 1H), 3.65 (m, 2H), 1. 49 (d, 3H), 1.20 (d, 611). 750 8 7.39 (m, 3H) 7.26 (m, 2H), 4.63 (m, 1H), 3.65 (m, 2H), 3,48 (in, 2H), 2.10 (m, 211), 1.20 (d, 611). 753 8 7.22 (in, 2H), 7.11 (m, 2H), 4.64 (m, 1H), 4.58 (m, IH), 2.42 (m, IH), 2.04 (m, 1H), 1.94 (m, 11), 1.20 (d, 6H), 0.99 (t, 3H). 758 8 1.20 (m, 611), 4.07 (m, 2H), 4.17 (s, 2H), 4.32 (m, 2H), 4.62 (m, 1H), 6.92 (m, 2H), 7.36 (m, 1H). 759 8 7.38 (d, 2H), 7.18 (d, 2H), 4.92 (q, 1H), 4.62 (m, 1H), 4.39 (n, 2H), 2.91 (m, 2H), 1.68 (d, 3H), 1.20 (d, 6H). 763 8 7.40 (m, 1H), 6.92 (m, 2H), 4.66 (m, 1H), 3.67 (m, 2H), 2.56 (m, 2H), 1.95 (n, 1H), 1.60 (d, 6H). 764 8 7.38 (m, 1H), 6.93 (m, 2H), 4.62 (m, 1H), 4.25 (s, 2H), 2.37 (m, IH), 1.25 (d, 6H) 765 8 1.20 (m, 6H), 4.24 (S, 2H), 4.25 (M, 2H), 4.38 (M, 2H), 4.63 (M, 1H), 7.09 (M, 2H), 7.24 (M, 2H).
WO 00/43377 PCTIUSOO/01283 132 766 8 7.25 (m, 2H), 7.15 (m, 1H) , 4.95 (brs, IH), 4.65 (m, 1H), 4.16 (m, 2H), 3.39 (s, 3H), 2.19 (m, 1H), 1.92 (m, 3H), 1.19 (d, 6H). 767 8 7.26 (mn, 2H), 7.11 (m, 2H), 4.64 (m, 1H), 3.67 (t, 2H), 2.56 (m,2H), 1.96 (mi,1H), 1.21 (d, 6H). 768 8 7.38 (m, 3H), 7.26 (m, 2H), 4.64 (m, 1H), 3.66 (t, 2H), 2.54 (m, 2H), 1.92 (m,1H), 1.22 (d, 611). 769 8 7.39 (m, 3H), 7.24 (m, 2H), 4.74 (s, 2H), 4.62 (m, 1H), 3.18 (m, 1H), 1.35 (d, 6H), 1.21 (d 6H). 771 8 8.3 (d, 1H), 7.6 (dd, 1H), 7.4 (d, 1H), 4.7 (septet, 1H), 4.2 (septet, 1H), 1.40 (d, 3H), 1.21 (d, 3H). 772 8 7.4 (m, 2H), 7.2 (m, 2H), 4.9 (m, 1H), 4.7 (m, 1H), 3.4-3.6 (mn, 2H), 2.1 (m, 1H), 1.9 (in, 1H), 1.2 (m, 9H), 0.9 (t, 3H). 773 8 7.4 (m, 2H), 7.2 (m, 2H), 4.9 (m, 1H), 4.7 (m, 1H), 3.4-3.6 (m, 2H), 2.1 (mn, 1H), 1.9 (m, 1H), 1.2 (m, 9H), 0.9 (t, 3H). 774 8 7.3 (m, 1H), 6.9 (m, 2H), 4.9 (m, 1H), 4.7 (m, 1H), 3.4-3.6 (m, 2H), 2.1 (i, 1H), 1.9 (m, 1H), 1.2 (m, 9H), 0.9 (t, 3H). 776 8 7.3 (m, 1H), 6.90 (m, 2H), 4.65 (m, IH), 4.20 (m, 5H), 1.70 (m, 3H), 1.25 (m, 12H). 778 8 7.4 (m, 1H), 6.90 (m, 2H), 4.65 (m, 1H), 3.60 (m, 7H), 2.85 (m, 3H), 1.21 (m, 6H). 779 8 7.4 (d, 2H), 7.2 (d, 2H), 4.65 (m, 1H), 3.60 (m, 7H), 2.85 (m, 3H), 1.21 (m, 6H). 782 8 7.22 (m, 2H), 7.09 (t, 2H), 5.93 (t, 1H), 4.62 (m, 1H), 4.21 (d, 2H), 1.2 (d, 6H). 783 8 7.38 (i, 1H), 6.96 (m, 2H), 4.60 (m, 2H), 2.40 (m, 1H), 2.10-1.80 (m, 2H), 1.22 (m, 1H), 0.94 (mn, 3H). 784 8 7.39 (m, 2H), 7.20 (m, 2H), 4.64 (m, 1H), 4.25 (m, 2H), 2.33 (m, 1H), 1.21 (d, 6H). 785 8 7.35 (m, 1H), 6.92 (m, 2H), 5.32 (q, 1H), 4.62 (m, 1H), 2.31 (s, 3H), 2.24 (s, 3H), 1.83 (d, 3H), 1.22 (br, 6H). 792 8 7.39 (m, 3H) 7.25 (m, 2H), 4.61 (m, 1H), 3.52 (m, 4H), 1.80 (m, 4H), 1.20 (d, 6H). 797 8 7.4 (m, 3H), 7.3-7.1 (m, 2H), 5.5 (bs, 1H), 4.7-4.6 (m, 1H), 3.94 (bs, 2H), 2.35 (s, 2H), 2.3-2.2 (n, 2H), 2.0 (m, 2H), 1.2 (d, 6H), 1.2 (s, 6H). 800 8 7.38 (m, 3H), 7.25 (m, 2H), 4.64 (m, 1H), , 2.35 (m, IH), 1.21 (d, 6H), 1.15 (s, 3H), 1.05 (m, 1H), 0.94 (m, 4H). 801 8 7.37 (d, 2H), 7.19 (d, 2H), 4.64 (m, 1H), 2.37 (m, 1H), 1.19 (m, 9H), 1.07 (m, 1H), 0.96 (m, 4H). 802 8 7.37 (m, 1H), 6.91 (m, 2H), 4.64 (m, 1H), 2.37 (m, 1H), 1.19 (m, 9H), 1.07 (m, 1H), 0.96 (m, 411). 803 8 7.39 (m, 3H), 7.26 (m, 2H), 4.64 (m, 1H), 4.52 (m, 1H), 2.40 (m, 1H), 2.04 (n, 1H), 1.92 (m, 1H), 1.44 and 0.98 (t, 3H), 1.22 (d, 6H). 804 8 7.38 (n, 2H), 7.21 (m, 2H), 4.64 (m, 1H), 3.67 (t, 2H), 2.56 (m, 2H), 1.96 (n, 1H), 1.22 (d, 6H). 805 8 7.25 (m, 2H), 7.08 (m, 2H), 4.65 (m, 1H), 4.40 (m, 1H), 3.70 (m, 4H), 1.20 (d, 6H). 808 8 7.39 (m, 2H), 7.20 (m, 2H), 7.64 (m, 1H), 4.58 (m, 1H), 2.43 (m, 1H), 2.40 (n, 1H), 1.92 (m, 1H), 1.21 (d, 6H), 0.97 (t, 3H). 810 8 7.22 (i, 2H), 7.09 (m, 2H), 4.46 (m, 1H), 4.95 (m, 1), 4.64 (m, 1H), 3.02 (mn, 1H), 2.76 (m, 1H), 1.68 (d, 3H), 1.20 (d, 6H).
WO 00/43377 PCT/USOO/01283 133 811 8 7.21 (m, 2H) , 7.11 (m, 2H), 4.98 (m, 1H), 4.64 (m, 1H), 3.89 (m, 1H), 2.98 (dd, 1H), 2.69 (dd, 1H), 1.5 (d, 3H), 1.20 (d, 6H). 812 8 7.42 (m, 3H), 7.40 (m, 2H), 5.44 (m, 1H), 4.93 (m, 1H), 4.64 (m, 1H), 2.80 (m, 111), 2.70 (m, 1H), 1.28 (d, 3H), 1.22 (d, 6H). 814 8 7.39 (d, 2H), 7.17 (d, 2H), 7.11 (brs, 1H), 4.92 (m, 1H), 4.64 (m, 1H), 3.89 (m, 1H), 3.02 (m, 1H), 2.70 (m, 1H), 1.52 (d, 3H), 1.20 (d, 6H). 815 8 7.32 (m, LH), 7.11 (brs, 1H), 6.94 (m, 2H), 4.88 (m, 1H), 4.64 (m, 1H), 3.90 (m, 1H), 3.01 (m, 1H), 2.70 (m, 1H), 1.51 (d, 3H), 1.23 (br, 6H). 816 8 7.40 (m, 3H), 7.23 (m, 2H), 7.09 (brs, IH), 4.91 (m, 1H), 4.66 (m, 1H), 3.88 (m, 1H), 3.00 (m, 1H), 2.70 (m, 1H), 1.50 (d, 3H), 1.21 (d, 6H). 817 8 7.28 (m, 1H), 6.91 (m, 2H), 4.63 (m, 1H), 4.11 (m, 1H), 1.28 (d, 3H), 1.22 (d, 6H). 819 8 7.22 (m, 2H), 7.08 (m, 2H), 4.62 (m, 1H), 3.78 (d, 1H), 3.50 (d, 1H), 2.70 (d, 1H), 2.60 (d, 1H), 1.33 (s, 3H), 1.18 (d, 6H). 822 6 7.40 (m, 2H), 6.92 (m, 2H), 4.60 (m, 1H), 3.66 (m, 2H), 3.50 (m, 2H), 2.05 (m, 2H), 1.26 (d, 6H). 823 8 7.40 (m, 2H), 6.92 (m, 2H), 4.61 (m, 1H), 3.54 (m, 4H), 1.80 (m, 4H), 1.22 (d, 6H). 824 8 7.39 (m, 3H), 7.24 (m, 2H), 4.62 (m, IH), 4.30 (m, 1H), 3.90 (in, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 3.30 (s, 3H), 1.22 (d, 6H). 825 8 7.21 (m, 2H), 7.08 (m, 2H), 4.62 (m, 1H), 4.30 (m, 1H), 3.90 (m, 1H), 3.71 (m, 1H), 3.60 (m, 1H), 3.30 (s, 3H), 1.22 (d, 6H). 829 8 4.66 (s, 1H), 4.5 (m, 1H), 4.3 (m, 1H), 1.48 (d, 6H), 1.42 (s, 9H), 1.28 (d, 6H). 837 8 7.20 (m, 2H), 7.10 (m, 2H), 5.65 (m, 2H), 5.05 (d, 1H), 4.65 (m, 1H), 4.20 (m, 4H), 1.45 (d, 3H), 1.20 (d, 6H). 839 8 7.12-7.2 (m, 3H), 4.62 (m, 1H), 4.17 (m, 1H), 1.39 (d, 6H), 1.25 (d, 6H). 840 8 7.23 (m, 2H), 7.1 (m, 2H), 4.2 (m, 1H), 3.80 (q, 2H), 1.40 (d, 6H), 1.27 (t, 3H). 841 8 7.38 (d, 2H), 7.18 (d, 2H), 6.0 (m, 1H), 5.25 (m, 2H), 4.6 (m, 2H), 1.5 (d, 3H), 1.2 (d, 6H). 842 8 7.38 (d, 2H), 6.93 (m, 2H), 5.98 (m, 1H), 5.24 (m, 2H), 4.6 (m, 2H), 1.49 (d, 3H), 1.22 (br, 6H). 843 8 7.4 (m, 3H), 7.25 (m, 2H), 6.0 (m, 1H), 5.22 (m, 2H), 4.6 (n, 2H), 1.48 (d, 3H), 1.2 (d, 6H). 845 8 7.38 (d, 2H), 6.93 (m, 2H), 4.9 (s, 2H), 4.64 (m, 1H), 4.41 (m, 1H), 3.45 (m, 2H), 2.95 (m, 2H), 1.21 (d, 6H). 846 8 7.4 (m, 3H), 7.25 (m, 2H), 4.89 (s, 2H), 4.64 (m, 1H), 4.41 (in, 1H), 3.45 (m, 2H), 2.95 (m, 2H), 1.21 (d, 6H). 849 8 9.53 (s, 1H), 7.39 (d, 2H), 7.19 (d, 2H), 4.64 (m, 1H), 4.44 (q, 1H), 1.6 (d, 3H), 1.21 (d, 6H). 850 8 9.51 (s, 1H), 7.4 (d, 3H), 7.25 (m, 2H), 4.64 (m, IH), 4.42 (q, 1H), 1.58 (d, 3H), 1.21 (d, 6H). 852 8 7.42 (s,1H), 7.37 (m, 2H), 7.18 (m, 2H), 4.63 (m, 1H), 4.48 (s, 2H), 3.81 (s, 3H), 1.20 (d, 6H). 853 8 7.44 (s, IH), 7.38 (m, 2H), 7.24 (m, 3H), 4.63 (m, 1H), 4.47 (s, 2H), 3.80 (s, 3H), 1.20 (d, 6H).
WO 00/43377 PCTUSOO/01283 134 854 8 7.47 (s, 1H), 7.37 (m, 1H), 6.93 (m, 2H), 4.62 (m, 1H), 4.49 (s, 2H), 3.81 (s, 3H), 1.21 (brs, 6H). 866 8 7.34 (m, 2H), 6.91 (m, 2H), 5.33 (m, 1H), 4.62 (m, 1H), 3.92 (s, 21), 1.91 (m, 3H), 1.21 (brs, 6H). 871 8 7.40 (m, 2H), 7.19 (m, 2H), 4.65 (m, 1H), 4.30 (m, 1H), 3.95 (dd, 1H), 3.75 (m, 1H), 3.60 (m, 1H), 3.30 (s, 3H), 1.22 (d, 6H). 872 8 7.30 (m, 1H), 6.92 (m, 2H), 4.62 (m, 1H), 4.30 (m, 1H), 3.90 (m, 1H), 3.73 (m, 2H), 3.60 (m, 1H), 3.30 (s, 3H), 1.26 (d, 6H). 876 8 7.36 (m, 2H), 7.17 (m, 2H), 4.60 (m, 1H), 4.12 (m, 1H), 1.20 (d, 3H), 1.19 (d, 6H). 882 8 7.38 (m, 3H), 7.25 (m, 2H), 4.62 (m, 2H), 2.40 (m, 1H), 2.00-1.80 (m, 2H), 1.50-1.30 (m, 2H), 1.20 (d, 6H), 0.92 (t, 3H). 884 8 7.23 (m, 2H), 7.08 (m, 2H), 5.75 (m, 1H), 5.21 (m, 2H), 4.65 (i, 1H), 4.41 (s, 1H), 4.32 (s,1H), 4.25 (s, 1H), 3.98 (s, 1H), 3.91 (d, 1H), 3.86 (s, 1.5H), 3.78 (d, 1H), 3.74 (s, 1.5H), 1.20 (d, 6H). syn/anti mixture 885 8 7.37 (m, 3H), 7.26 (m, 2H), 5.75 (m, 1H), 5.20 (m, 2H), 4.63 (m, 1H), 4.39 (s, 1H), 4.31 (s, 1H), 4.24 (s, 1H), 3.94 (s, 1H), 3.89 (d, 1H), 3.84 (s, 1.5H), 3.75 (d, 1H), 3.73 (s, 1.5H), 1.20 (d, 6H). syn/anti mixture 886 8 7.36 (m, 1H), 6.91 (m, 2H), 5.80 (m, 1H), 5.21 (m, 2H), 4.63 (m, 1H), 4.40 (s, 1H), 4.32 (s, 1H), 4.25 (s, 1H), 3.96 (s, 1H), 3.92 (d, 1H), 3.85 (s, 1.5H), 3.80 (d, 1H), 3.73 (s, 1.5H), 1.20 (br, 6H) syn/anti mixture 887 8 7.36 (d, 2H), 7.20 (d, 2H), 5.76 (m, 1H), 5.19 (m, 2H), 4.64 (m, IH), 4.41 (s, 1H), 4.32 (s, 1H), 4.25 (s, 1H), 3.95 (s, 1H), 3.91 (d, 1H), 3.86 (s, 1.5H), 3.78 (d, 1H), 3.74 (s, 1.5H), 1.20 (d, 6H). syn/anti mixture 888 8 7.4 (d, 2H), 7.29 (d, 2H), 4.63 (m, 1H), 4.15 (m, 1H), 3.58 (m, 2H), 1.49-1.27 (m, 9H). 892 8 7.20 (m, 2H), 7.08 (t, 2H), 4.65 (m, IH), 3.70 (m, 1H), 3.42 (m, 2H), 3.30 (m, 2H), 3.12 (s, 3H), 1.90 (m, 3H), 1.50 (m, 1H), 1.20 (m, 6H). 898 8 7.20 (m, 2H), 7.08 (t, 2H), 4.97 (d, 1H), 4.65 (n, 1H), 3.90 (m, 2H), 3.80 (m, 1H), 3.62 (m, 1H), 3.47 (m, 1H), 1.50 (m, 4H), 1.40 (d, 3H), 1.20 (m, 6H). 900 8 7.30 (m, 9H), 4.63 (m, 1H), 4.44 (s, 1H), 4.39 (s, 1H), 4.34 (s, 1H), 4.29 (s, 1H), 4.25 (s, 11), 3.96 (s, 1H), 3.83 (s, 1.5H), 3.71 (s, 1.5H), 1.21 (m, 6H). syn/anti mixture 901 8 7.30 (m, 10H), 4.63 (m, 1H), 4.44 (s, 1H), 4.39 (s, 1H), 4.34 (s, 1H), 4.29 (s, 1H), 4.25 (s, 11H), 3.96 (s, 1H), 3.83 (s, 1.5H), 3.71 (s, 1.5H), 1.21(m,6H). syn/anti mixture 902 8 7.23 (m, 2H), 7.08 (m, 2H), 4.65 (m, 1H), 4.39 (s, 1H), 4.29 (s, IH), 4.20 (s, 1H), 3.91 (s, 1H), 3.86 (s, 1.5H), 3.74 (s, 1.5H), 3.28 (s, 1.5H), 3.14 (s, 1.5H), 1.20 (d, 6H). syn/anti mixture 903 8 7.37 (m, 3H), 7.26 (m, 2H), 4.64 (m, 1H), 4.38 (s, 1H), 4.28 (s, 1H), 4.19 (s, 1H), 3.89 (s, 1H), 3.85 (s, 1.5H), 3.74 (s, 1.5H), 3.27 (s, 1.5H), 3.10 (s, 1.5H), 1.20 (d, 6H). syn/anti mixture 904 8 7.37 (m, 3H), 7.26 (m, 2H), 4.64 (m, 1H), 4.38 (s, 1H), 4.28 (s, 1H), 4.19 (s, 1H), 3.89 (s, 1H), 3.85 (s, 1.5H), 3.74 (s, 1.5H), 3.27 (s, 1.5H), 3.10 (s, 1.5H), 1.20 (d, 6H). 4:1 syn/anti mixture WO 00/43377 PCT/USOO/01283 135 905 8 7.35 (d, 2H), 7.27 (d, 2H), 4.39 (m, 2H), 4.15 (m, 11), 3.40 (s, 3H), 3.38 (s, 3H), 1.39 (d, 6H), 1.26 (d, 3H). 908 5 7.36 (m, 3H), 7.26 (m, 2H), 4.35 (m, 2H), 4.15 (m, 1H), 1.70 (d, 3H), 1.38 (m, 6H). 909 8 7.28 (m, 2H), 7.09 (m, 2H), 4.38 (m, 2H), 4.18 (m, 1H), 1.68 (d, 3H), 1.38 (m, 6H). 913 8 7.4 (m, 3H), 7.25 (m, 2H), 4.64 (m, 1H), 3.71 (t, 2H), 2.84 (t, 2H), 2.14 (s, 3H), 1.21 (d, 6H). 914 8 9.73 (s, 1H), 7.22 (m, 2H), 7.09 (m, 2H), 4.64 (m, 1H), 3.81 (t, 2H), 2.88 (t, 2H), 1.2 (d, 6H). 915 8 7.35 (m, 1H), 6.92 (m, 2H), 4.63 (m, 1H), 3.51 (t, 2H), 2.45 (t, 2H), 2.11 (s, 3H), 1.89 (m, 2H), 1.22 (br, 6H). 916 8 7.37 (m, 2H), 7.18 (m, 2H), 4.64 (m, 1H), 3.51 (t, 2H), 2.45 (t, 2H), 2.11 (s, 3H), 1.89 (m, 2H), 1.22 (br, 6H). 917 8 7.37 (m, 2H), 7.21 (m, 2H), 4.62 (m, 2H), 2.40 (m, IH), 2.00-1.80 (m, 2H), 1.50-1.30 (m, 2H), 1.20 (d, 6H), 0.92 (t, 3H). 919 8 7.34 (m, 5H), 4.42 (m, 2H), 4.18 (m, 1H), 3.74 (s, 3H), 3.42 (s, 3H), 1.37 (d, 6H), 1.27 (m, 3H). 920 8 7.30 (m, 2H), 7.09 (m, 2H), 4.38 (m, 2H), 4.18 (m, 1H), 3.41 (s, 3H), 3.38 (s, 3H), 1.39 (d, 6H), 1.27 (m, 3H). 922 8 7.36 (d, 2H), 7.20 (d, 2H), 4.64 (m, 1H), 4.39 (s, 1H), 4.29 (s, 11), 4.20 (s, 111), 3.91 (s, 1H), 3.86 (s, 1.5H), 3.74 (s, 1.5H), 3.28 (s, 1.5H), 3.14 (s, 1.5H), 1.20 (d, 6H). syn/anti mixture 923 8 7.38 (m, 1H), 6.91 (m, 2H), 4.64 (m, 1H), 4.39 (s, 1H), 4.29 (s, 1H), 4.19 (s, 1H), 3.91 (s, 1H), 3.86 (s, 1.5H), 3.74 (s, 1.5H), 3.29 (s, 1.5H), 3.15 (s, 1.5H), 1.20 (br, 6H). syn/anti mixture 927 8 7.37 (m, 2H), 6.91 (m, 2H), 6.15 (m, IH), 5.55 (m, 1H), 5.00 (m, 1H), 4.64 (m, 1H), 2.7 (m, IH), 2.30 (m, 2H), 1.98 (m, 1H), 1.2 (br, 6H). 929 8 7.4 (m, 3H), 7.25 (m, 2H), 6.17 (m, 1H), 5.55 (m, 1H), 5.00 (m, IH), 4.64 (m, 1H), 2.7 (m, 1H), 2.3 (m, 2H), 1.99 (m, IH), 1.2 (d, 6H). 930 8 7.24 (m, 3H), 7.10 (m, 2H), 4.65 (m, 2H), 3.8 (m, 2H), 3.39 (m, 2H), 1.21 (d, 6H). 935 8 7.35 (m, 1H), 6.91 (m, 2H), 4.63 (m, 1H), 3.74 (t, 2H), 2.85 (t, 2H), 2.15 (s, 3H), 1.21 (br, 6H). 947 8 7.31 (m, 1H), 6.89 (m, 2H), 4.6 (m, 1H), 3.75 (m, IH), 2.72 (m, 4H), 2.4 (m, 2H), 2.00 (m, 2H), 1.23 (m, 6H). 952 8 7. 51 (m, 3H), 7.24 (m, 2H), 6.86 (q, 1H), 4.31 (m, 1H), 1.97 (d, 3H), 1.49 (d, 6H). 953 8 7.34 (in, 5H), 4.22 (m, 1H), 2.14 (s, 3H), 1.92 (s, 3H), 1.44 (d, 6H). 955 8 7.43 (m, 5H), 4.64 (m, 1H), 4.17 (m, 1H), 3.79 (d, 4H), 1.38 (d, 6H). 956 8 7.44 (m, 2H), 7.12 (m, 2H), 4.19 (m, IH), 4.13 (m, 2H), 3.78 (d, 4H), 1.40 (d, 6H). 959 8 7.38 (m, 3H), 7.26 (m, 2H), 4.64 (m, 1H), 4.26 (m, 1H), 2.41 (m, 2H), 1.22 (m, 6H), 1.10 (d, 3H), 0.85 (d, 3H). 962 8 7.22 (m, 2H), 7.10 (m, 2H), 4.64 (m, 1H), 3.51 (t, 2H), 2.45 (t, 2H), 2.11 (s, 3H), 1.90 (m, 2H), 1.2 (d, 6H).
WO 00/43377 PCT/USOO/01283 136 963 8 7.39 (m, 3H), 7.26 (m, 211), 4.64 (m, 1H), 3.50 (t, 211), 2.43 (t, 2H), 2.11 (s, 3H), 1.89 (m, 2H), 1.2 (d, 6H). 964 5 9.73 (s, 1H), 7.37 (m, 1H), 6.93 (m, 2H), 4.63 (m, 1H), 3.81 (t, 211), 2.89 (t, 211), 1.22 (br, 6H). 965 5 9.72 (s, 1H), 7.39 (m, 3H), 7.25 (m, 2H), 4.64 (m, 111), 3.79 (t, 2H), 2.87 (t, 2H), 1.21 (br, 6H). 967 5 7.22 (m, 2H), 7.08 (m, 2H), 4.64 (m, 1H), 3.94 (m, 1H), 2.78 (m, 1H), 2.58 (m, 1H), 2.00-1.70 (m, 3H), 1.26 (m, 2H), 1.20 (m, 6H), 0.90 (m, 3H). a H NMRdata are in ppm downfield from tetramethylsilane. Couplings are designated by (s)-singlet, (d)-doublet, (t)-triplet, (q)-quartet, (m)-multiplet, (dd)-doublet of doublets, (dt)-doublet of triplets, (br s)-broad singlet. 5 TEST A Seeds of barnyardgrass (Echinochloa crus-galli), crabgrass (Digitaria spp.), morningglory (Ipomoea spp.), and velvetleaf(Abutilon theophrasti) were planted into a sandy loam soil and treated preemergence by soil drench with test chemicals formulated in a non-phytotoxic solvent mixture which includes a surfactant. At the same time, these crop 10 and weed species were also treated postemergence sprayed to runoff, with test chemicals formulated in the same manner. Plants ranged in height from two to eighteen cm and were in the one to two leaf stage for the postemergence treatment. Treated plants and untreated controls were maintained in a greenhouse for approximately eleven days, after which all treated plants were compared to 15 untreated controls and visually evaluated for injury. Plant response ratings, summarized in Table A, are based on a 0 to 10 scale where 0 is no effect and 10 is complete control. Table A COMPOUND Rate 2000 g/ha 1 2 3 10 42 43 52 53 99 114 127 128 136 137 177 183 Pre-emergence Barnyardgrass 9 9 9 10 0 0 9 8 9 10 9 0 9 10 9 9 Crabgrass 9 2 3 9 0 1 10 9 10 10 8 0 10 10 9 5 Morningglory 0 0 0 1 0 0 0 0 2 6 0 0 0 3 0 0 Velvetleaf 0 0 0 2 0 0 0 0 3 6 0 0 0 5 1 0 Table A COMPOUND Rate 2000 g/ha 184 225 377 386 Pre-emergence Barnyardgrass 9 10 0 0 Crabgrass 9 10 0 0 Morningglory 0 8 0 0 Velvetleaf 0 7 0 0 Table A COMPOUND Rate 1000 g/ha 1 2 3 10 42 43 52 53 99 114 127 128 136 137 177 183 Barnyardgrass 8 8 6 9 0 0 5 3 7 8 6 0 4 8 0 0 Crabgrass 5 0 0 8 0 0 8 6 7 7 7 0 6 8 3 1 Morningglory 0 0 0 0 0 0 1 0 2 10 0 0 9 10 0 0 Velvetleaf 0 0 0 4 0 0 1 1 2 5 0 0 2 2 2 0 WO 00/43377 PCTIUSOO/01283 137 Table A COMPOUND Rate 1000 g/ha 184 225 377 386 Postemergence Barnyardgrass 2 9 0 0 Crabgrass 1 9 0 0 Morningglory 10 10 0 0 Velvetleaf 2 3 0 0 TEST B Seeds of bedstraw (Galium aparine), blackgrass (Alopecurus myosuroides), surinam grass (Brachiaria decumbens), cocklebur (Xanthium strumarium), corn (Zea mays), 5 crabgrass (Digitaria sanguinalis), giant foxtail (Setariafaberii), morningglory (Ipomoea hederacea), pigweed (Amaranthus retroflexus), rape (Brassica napus), soybean (Glycine max), sugar beet (Beta vulgaris), velvetleaf (Abutilon theophrasti), wheat (Triticum aestivum), wild oat (Avenafatua) and purple nutsedge (Cyperus rotundus) tubers were planted and treated preemergence with test chemicals formulated in a non-phytotoxic solvent 10 mixture which included a surfactant. At the same time, these crop and weed species were also treated with postemergence applications of test chemicals formulated in the same manner. Plants ranged in height from 2 to 18 cm (1- to 4-leaf stage) for postemergence treatments. Plant species in the flood test consisted of rice (Oryza sativa), smallflower flatsedge (Cyperus difformis), duck salad 15 (Heteranthera limosa) and barnyardgrass (Echinochloa crus-galli) grown to the 2-leaf stage for testing. Treated plants and controls were maintained in a greenhouse for twelve to sixteen days, after which all species were compared to controls and visually evaluated. Plant response ratings, summarized in Table B, are based on a scale of 0 to 10 where 0 is no effect and 10 is complete control. A dash (-) response means no test result. 20 WO 00/43377 PCTIUSOO/01283 138 -4 M~ 0000 -4 r-4 -4 col O000 -4 00 -4 cn 0000 -4 M C CDo0a MA 0000a co M C)oor 0 C 000 M 000 CN0 1.0 OOCO N 0 0 N a4 00 0 :n 0C qr 1.C0c 1.0 000 L 0 0 r, 0 1 1 0 I0 I OL OO 1- D I I C0 CC )CDC -I Cl CD 0 0 0 r 0N 01 I1.00 10C 1.-41c1C1 I 0 N- 0 000C C C'q LA () U) u a a ) U) . Q ) U) 10 (L) ) U) U .) 0 4)(aL C) U M) M100 l 3) a)4) ) 't) -I) U) 4)U 0 1 0 0 J)( 0 ) 4 r- 4 a) 4 '0 4 Q) 0) U4 f ( I4 M4) 4-)) * '0 a) -1 (L) >U) 4i ) 0) > 1 U) 4q ) a) -r , 4 4 - 0) D) 4) ,1) 0 H 0 4 W 4)4) 1 ,14 a) rX4 r- ) I r, S4 ) r14 H ()4) U) r U) OU 4 0 Q14 r 0 U) 4) 4 a)~r 44Q ( WO 00/43377 PCTUSOO/01283 139 C-4 C14~ 0 0 r-I m 00 m')0 0 i 0C>00 N 000 00 0C)00 wO 01-400 N- 0 000 C 1-4 0 -4 m C) -Io 0 iD 0000 0)I 00 D00 O 0000 0 N 0o CNC DC m C Lfl 000)C C 0 D 0 00 Ln 0aC l 000 Q 0 00CD 0 0 0 o4 0cD 0Dooa o 00aaa 0n 0 00 0 Orl C)j CD0000u m 0000D 0 00 00 00 -1 In wD 0 c 0 0 H ai 0000 wD 000 D 0l0 in Coco in CDooo C 0 0000C m 1 n CN0C) C00C) .Na 00 0 0o C m en * 00CD0 OHN 00000 o r m 0000 I Iz - a a) a )c )C ) 0 l C lcn a 0 C 0) OQ). U)- C)r- Q 0I U) N~d a 0 l r.) 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4 J a)I4UO U 4- a I4U U ~Q4- a) 4 U ~4-) I4 U ~Q4- W O WO 00/43377 PCTUSOO/01283 146 M~ Ln 0) 10111110111110011111 co 0000000000 (Nq Ln 00 1 01 1 11 1~ III m111 n l 1 11 1 r, OOOOOOOOOH (N -1 V- Ln r- I 0 I I I I 1 01 1 1 I 1(d' I~ 0) 1 1 1 W . 000000000H' (Nq Ln 110 10111110111110011111 LA oocOooO~ooel (N Ln LA (NCNcor -Ln 0 0)0 00N I a -- 0 rnNm 0 0 0N C> r ON N NOAmOCDAmN (N LA H OO'o 0r- (NN C ~ o0a CD0 0 -r- 0o (NC HO 1 00-0 a zpH (N LO 0: C O LA(NOCDONO 11 0 0 0 (N w-:m0 00 H 0 010C)0 c~r0 M H (N LA 0', o o" ic 00-N0 I0H N o0oLn c c rLA0o o 0 101 I I I 1 01 1 H- LA 00 c o (N 0m "o )r-r m "o H w LAOm %.o L (0 0',o 0 1 1I0000' 1iO)m H Hi -0j N- 0 m r-Ln m0C)'m0 LAn0r D0 wC m,0 i mC aC00 CD 0 I C0(NQ0 0 0m H IH '0 C I~ n0 00 OO (N OO ~00 , 0 CDN% Oc 01C I w (N0 m I(% LA 1 O - (n0 0 0N 0001mw( wII 1 0qLA 00 1.0 r 0 1 0n 0 rn 0 .(n e 0 Ir.n nD o ooo-;000000000 r-c) H00oo(aN oa oa 0 c oo 00c 0 0 OH OOOCD OOa OOOOOOOO 0OOOOOO U( OOamIOC OOOOOH 0N 0 0 00N~H 0 1 ' 0 0 ' -I0 )0 C 0 (0 000C)00I 00 CD0 00CD000 0 00I1 0O0ON0 mN HH co 00m 1 0 0 0 N N01 0 C)0(N L'.C CD 0 0 LA ) 00 0L0-0 1 mH W noc -c)cL DL ' Doc o, Dc N00 0 . 0 OO O OO r- 0 01NOH0 fn1 0 m o w CD *H 0 >k 0r 00C CO'- 0 ~ 0 co q ) oc 0tq t W0 W0X 0 Q0w Dr aC 0 C1 40J 0 00- 0O m CwI II 01 H r- 0 0 o Dc C% c'd D 0 - 0 C)C N Ic l 01 1. >IJ, H ~ Cl4.H1 H 1 ~ 4J 0) 01 H>4J H J~flM rd *rd0~~ H~ 1 0 - ul~ 1 O0 ~ 4 )mU WO 00/43377 PCTUSOO/O 1283 147 001 H OOOOOHOOOO wO H~ODACI~oiIIN 00 H 00 H H 00 H H 00 H OOO0OO H c0o0000o0 a r- 000oHo0o0o oo o m o qo o H) 000 000 -000 0~~, 0. 0 0CA 00 00ooHooooHlq roo H nvC nNr Ho H H0 co 0 00 0 000111 a) 00 oc 0N O H000 m -: 0 M-'vrn0clq1ooM o r- ~ HH r- 0 N H N 0 H )0 0 0 q D IrJ 0 0 ~fn m Dr Nc tl )100C nC 0~00 N- H 0 CII I N -I0 00 0) 1 10 0C)0001 400 000 1 1I1 0cq0 0 Ol w 00 N Y CD A0~ CD C 0 0 H qC D r )000H0 0 CDw 00004:p0 0 10000CD0 CD -0 w H) 001 I I -M 10 0 OLi I O C1 O C I Ir 0 '0 ~ 00Na)0 ILAO O CD0 - 0010C 0o00mD 0000C0CD-4lC)0 0 rN %D 0) %D0 ONI 1 I110 01 11 11 H H 0I1N-H a a C Dm0 m-1oo Am a00 0 M) I 4 M1 0) a) 41( )0)W H40 ) E - 04 - c ~0) 0 0C Q 0) .L-Ji O Ht ra 2 0) a) (Ot0(aI 4 a) 0 U- W] 0 4a) Q - > 4) '4- ( 4 H H) W] 4-0 )O a c 10 4a Q4- ) O ( A( 04 4J a T$ U >1d 0) ~-A 0)r 0 (d 0) -H - 0 ) X l 0( 0 0 Q 00 :JHI4~ -C4* 0 0 H(3a i .0 :1 ) 4 r 0 0 Z~ d PI Y H0 H Q4 U Z C4i)U)E :::: q Z a M M V M U r) Z Z P 4 J( U ::J E Wa WO 00/43377 PCTUSOO/01283 148 co I r IInQ ~ 4 ~ NON OO~ 0~ r~ oN-10. mo r~ i 0L-d ooi0No0-c~ r, 0r- o 00 m0 a%00 ) r rn0 0 L m cq M H ~~- 1l ( j I H O I r40 r-I -4 Hn c -- z'Iv O % m 1, 0) ChH ,0%10,0 CQ0 H o 01c 0 l 0* 1r~~~ I 0 mCD ,D H co~~ ~ ~ ~ 1oooomwooooooowooo ii n ,rooo r ~ O O 0~00~ N 0000000000000 r- m ":vCD C) CD0 C w C CD-i CN c) D (N r-H 1 ww r 0 0 100 D C 00000I0000(n n 0N0001 H r 0 00a V 00 (N LA 0 (N (0 00 0 0 0 00 CI a fl LA o i r- ri c 0o) c a ( oNqcN 0 C LA 0 C0 C) i LA0 N0CDC) mA A0 0 (Nl 00I00 A0 q0 (N (N H CD0000 CDN 0 m 0 m~ (N 000 CD C Hqm 00C l0 0 m 0 N m 1 ;J m0 m0m I0C r 0N L A i ) 0c0oo oi cocc av r' II I~ COM 0 IM NW n iN0w00% HH coN ic na oI m GI NDL co i LA w D '~Ln H) N i )L -a c ,o )c o~~~ ~ ~ ~ HDioL z - ; o ar vm ic ~I I ~ A0 I~ .OI 0~I LA~I DL -4 Ha U) 4 to4)0 .0)U 40 4 iJ0 -40 U)H f ()r rA a41( 0) C) M cl1 0)CO 4 Eao 0 4 o (d -1-4 0) M *' 4)r 0-I f roU )Wl o I 0- -4 0)~- CO 4 HO(d U)CO ( O1)X 4( o 0 ( ( QJ) 0 0) 4Jd Cfl 0)HO )~ C Z z aH -ri> i 4- )E 4OUO) 0 ) 0 - ) a)) 0)0 1) )-rI> 4 S r- 0) to 4) 0() 0 U) ~ ~ rTi 0) U ZE a j-L 4 0 ror 0). o) 9i)U ) 9ii 0 .0( ) *H 4 r (, H ( OU (d J.H0) 0 H ) r0)4-) 0) o 41rn $( 0)*H( 1 40J(0 tJU 4 4J rO Q)ri0 0 j- l -- *0 0 ) 4 * ( (o0 - ( ) 0 0 - J a WO 00/43377 PCTIUSOO/01283 149 i i o .o Ln koLn H- r o v ~ m oo) - ,: N 0 Ln i I Z44 - D0O 0 M Cl 00 n ODCN 0 r 0 00000000000000000000 eq 0 10 00eM0000 0) 0 0 0 0 ~ 0 o o o o 010 LA 0 I I H c v0 00 oo 00Lnoo - oLn cq o o :,oo Lno ooo 0 0 10 I I M rq L o N 0 - 00 1 N 0r iH0-O00o 0.300 0 CAi 01 0 Ln N- H -4 LA i iALn.; U o O (N 0 OCDCN 0 m m D O o0HooCDo -10 C 0 0 O inN I I "vOD0 N N C H li r ot )c )c okDL -c o- nL oo LA 0D10C 0000000C 0 cD00oc)00oLA0 0 0 00n0 0 cz ooaoc oc 0 1 1 LA HH 00C 00 00 co m~ 00L0A0LL 00 0,10 0 0 00LA0000C14W M MA W O~ M00(N WMMr-MMWW -0 uN H o C)C Dr o nc )oa ok no vc zrr f ioa m00 W o )0 N 00c 00l WOO O m(N-0C Oc O( rn NO I* nWC400 r I0 ,N~ 0 Ii w VMmw(- Dm1 000 0 C>a% 0Wl)0 N -0 H 0 0 n I c M~ w H1 1-1 0~~ ~ ~ H)C)c C C C C nMr -M Ia -C)I I Or C D c 0 1% a) 4JIOUC0 0 rA0) E k U 10 Xr4 - O A (dC EQ 0'p- 00 4-) N ~ a) N I ( Q N 4( 4Q (0 rI 4I IM LAC 1,0 4- 4- 1.i M 0 r. I aj f 1041 0 r=;M f 4 4) 4 d r. o 0 d (d a 1 0 ) (1 0 u > 0 H ))f 4 ) 4 0ZU 4dU(dH4 ard 1t) H a)- 4) U) U)r - U) 0 ) , r f (d0 -( a)H 0 0 4 $- 0 0 a)~ -r- -)O 0 0) 0)0) 4 -4 (0( 0 W 0 W > 3: 0 Ew, ~ 0,a Q0 2 Wc)U n>3 R P , C WO 00/43377 PCT/USOO/01283 150 0000 IOCNOOOI lc0000 r- 0 1Ln :: en0 I1 N en0 CN 0 1 ILf 0000100000i 100000 o i00000i0Lfl000l I4 C'.4 00001000001 100000 LA 0I10 0 4 0 -1 0 CV10 0 C1'14 C..' ODO M I :PO NW I 10000.0O (Y 01 000---0CD I COOC00 I 1IN C). C.4 1 0CC'.N I N m CD OON I1I CN CD0C.10 C'. 0 1 -- 10C '0~ ji1 C4 0) 0 N I 11 C. 0 -4 0rno00I 0,000OI I.-IOMM~O c 0 1 10000j000 11-4CDI -4 mm OCO I -iL0C'.'.o I I~ W 0 N 0 1I000C .'CNI mo0000I I10 aN -4 cq.c'.'0co 10 0 0 I:)'LA000 i '.lm aD k0 0100000:> OCD10000001 1 0 H-4 -4 'A -4 0 0I N-C')o' 1 MOCCO I I c'~)0H-I00 r-4 H 1 I m m C'.0 C IcoCD00CD I Iq H4 0, -4 Lcq ico.'0O',I> r- i ILflo cqo0c 0 0IOCO000O00000 IC 0, -1 CC) D ) 0 l10 cq 0 1 I I'.M'.r 4m CN 0) c I CDlo-',Dom I c)CD0cCD I 1C", -4 -4 '0C'.0 DI-CN 0 '0 0I00NC I~~ 0 C r4' 0I'.oo-Ic.'c'.lN0'.N I -4o -4 co) m~ o) m 1c o2) mL oL n L 0 N 0 IfIH C ) H c )*-o l~)0 U) E ) )4J H ' -A u (d (d0 4( WO 00/43377 PCT[USOO/O 1283 151 (I N(N0O rn - i ILn L c,4 o wcO0k oo0( o O iL mcc 0 1 1lO(Cn0 M LA 0000 (N 001C r I 0 (NI m co0 N - 11 I~mco0O 0 00 0r en Ln C>0000 .- l 0 1000041 0,0000g 11 ~00D0 r- 0 1 0 1900 M LA (N C(4 0 (i0 0 0 o0i oo o0oN i - -00c0oi IL o oOaO LA 01 00 ~IOC w M LA 0000 m1 0 100000 1000001 1I(N a (l0 0 44 0 1-*00 0 (N LA v 0C 0 C o CD CN 0 1 0 0) a CDC141 ~'A .00a0M 0 10000 C(4 LA (N (N ,;:vm 00 r- c io -N )f o1 r~0 0 - i ILnLn fnLAN I-i (NI a% 0 r-)0 (N H- LA (N (N c,4L~ W;j o ~ w %i r o,4 tooo ir-~ r- rwo i i D ,4c)om M~ 0 10000 (N (N 000DC)0 LA 0 1' iC 0 0 o 00 0 wC%4N(Nl I I vC ro N 00 010000CDO (N (N (N 0000 m - NI 04m0I H W0 CD MI I V m i'0 N 0 q1 000 % 0 (N (Nd (N
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C D o oo nw0 0 00VV IIr-C 4% NQ M )I nor (N (N 0 0 000 r- zo -:44L~ I0 N r C IN.C~N O~IC0N. 0 N 0 (N u u LA :rC)000 r- c Ico VC) 100I 0 II r 11 - 0 CN r-i 1rm '.IO-f C (N (N 0 0 . 0 C 0 1 1 co mm r I w 0 CD m I I (l N( 0 N 0 0l C CD o I Ln Ln - c 000CD0 LA m i oo L o c(c4N ILA m0 o wI iric o 00com 0) 0) I m MH0 (N (N ,-- (n (N (N3 C1 CNC d 0 1I 4-DIm C 001.-0 11C 0 1 0 COdX - 0C o 0) JC14 CO 0011C 1 0000 w .n m c% 0 m iL r--H>>.4 oem- 01O-i -H0)c)0 iic c-~)0)- i ) c o v >D I C C-4 C ~r 01~-1)~-04CO U~ 0~Cd ~ d~-J odu 0-I.~ CO 'd70 ~0 ~ U)d d *CU0).0 C a. 0~) ~ ~ ~ 0 * d)-0 WO 00/43377 PCT[USOO/0 1283 152 e1In mI il,, 0 0 q0wm C q1 00 00 D0 10r n0 00-I 00 1 0OOOm (N Olc4Oo o Ln w iN ( 0 o nrio 1C DC 01o oI, 0 a0wNI I mO0 rI0 1OI 0 to m00 1 100000H c 0 0I1 OODI00I a CDDCD I I L0(N0C CN 0 1IC 0) a00 wI I cqr-(N C 0(0 1 N 0 0I C0' D I q cq0m~l C) N 11 a 0 0 1 0C:)Ooo0 I 1 00(000 00 a 0 n 0 0 1C 10 C) 0 N I I N(NOlcq0 0) 10c m0001I I w NI0 000 r- 0m 0 0 I oooo00ow0,-) Dm ni i Io Ln -i0o CN 0 m I(0 0 I10J cq0 00 mo 0 1 m00 0 0m I1 (N00 ac I- N 00 0 )C 0 C) C> I I H0C)0 0 (N 0 1 CO,-I00 I0N00C~r I I L-000 CN (N In 1 00 r n I 10 ~Lfn r c -0C 0 100000 100C000 I I (N9000 0 a) I m co 0nc o i wc -c o a D1 r-Lf(N0C) H I (N r 00> > I I fn CDrn w I) 1 C) o OwON: I I -zm~,N( Nn H mcq c I I 0m 0 1 N0 N~ l I (N I N ~Da 0 0r I I m 0 0 m (N IcqN0 f cIN m 1r-c e') -1 -c NNP l I I w -* m (N W~ I W nL 0~D f I r- (1 1 0m(DNm 0 C f) to ~ 00 c4i% oc4D i r-c~0I- - I I)r- 0 (N Oni cqLOOao m ig I c0N0c0 n o .C CD CI I f0 ( I C)0 0m0;ri I -0(M n CD 00 C)%D0 00mII- l N00 r D Iof (N 01 0000 C41mr I0 0 l0 1 - I 0(N0N (N OI1o wNOODOI 100C)m00 N 0 D CD CI ILA 1-C)0II0 0 v I I -zra q 0 I0C(N-C)000 1 1 .- l0000 0 0 1 1000 Iq CD10 w 0 0 I IqqC 1C (N r. 4 d (d 0 (d r-O4-4 0) U)- j0 A 0C L . 0)0)Q fOr- 44 U Ot. MU) 4 0 w r 4 U0 0 $-O 0 . >1 M a'r-I 4 4- U) U rO . (d U 4 () 0 4 ) a k U Q >1 u) rI IdU l -4 J0M ) A 0 a) r- 0M t )rA J J-rU0)%0 Q -r-I - 0 4 0.'d ) HQ U )0z :P .Wc o>2 R 4P 4OQmmP 4I4I )U n>: WO 00/43377 PCTIUSOO/01283 153 0 M CI 1 0000I N 0 j 1Ir- OC 11 :0000 r- o 0I0 10 0 10 o N w1100000 c00 . 010000010 0 4 0 D NI flO0 0 C l10 1 1cc.OA M I C.DccccN 01-0000010O 0 Mi ci 0 - ic %r oo oinr oo - l o o l 0 a 0I00000ocI O(OOODI I Mco 0 0000 0 1 0I 0 fn (N 0 1CD0 0000D I OC OO In I ci OO DC -I 0 0 0 10 oIC 0 Mi 0D w. 0 10aCD0000 1IC OLflOOO I I (N 0 00C0 0 0 1 10000D1 0 0 Mi 0 (N CD cq 0 M1 0 1 0 ~00CD I(N..D00'. I ILA(N000 cc 0 11 IU 0 0( 1,1 0 (N 0 Noc ztc oi O O O O OO cq i imO C Nnc 0 1 1IN4cq00MI0C 0 (N 90 cl 0 0N 0 H 04 D C I 1D000 10000 I CI000 0C00D0C)fl M (N I I Coco 1 0 zo ) E C4 I a) coci i m I-:P n icco cccc i ir- -r r -,v l (N c It3Cc:POL I %: () cq ~' cc 0 1 1 0000o I Cr1000 I I vo o~ i 0) I I :Zpoo0co I co m (N (N N- 0110000100000 IiooCOC) 0 0 1IC0 0ClrI en 0) (N 0 C) 0 I ) OcC)0 CN I -Vm 1:" z I I w.COD(Nc M ' Ch C I I M 0 0 M 1 0 (N ci 0 fnrcicim m NI CcO'I' O,C'owi ILnci'.Nco N cci I 1-icHicMc co (N Mi O (N CI100000I10(N000oI I -I00C w. (NI 1 NOCC 0 ci (N Mi CD 1.0 (N i w oco ow Iicc ' o w(NNr- fi i c , nr n v i i co oLn Ln INr cc 1 ccq (N rn ld Cl) 0 12 o U)4 ) ld Cl) r C)0 E ] W1 4-J H a) 4 rdI ClD M A4)W A r 41i o 401 d: cl)dO0OM ) In] W19W 4-) C I d 10 :d~ ;J M do0 0O 0 (d t40) W I 4M r.d 0 d .4 -W J 0 P MW (Id a)1 ) -4 >1 41 IS4 O-A 0 U) .- 0 0 ~- a J4W 0) a) a) -4>,. 4-) -4 M *OHd a) WO W~Hdd W*IWdO4FO ! W4 Q0>(dr 4 - WUH r- 1M O M U P0 U ( 4 r U > )- - - a O 0 U WO 00/43377 PCTUSOO/01283 154 000 00 NOOO 0q NN N N 0 l Owm I 1 OL A10-Vr L . qo %D co 00001 ~ ~ 0 000N000-4000Oc 00 0~c 010 ,N0 lmLAN LO 0 000011040000 N0 N(N I LoA o-ooo r-10o'n~n. M LA 0 MA M 0000110*0000 LA r nr-c nL c,40c Ic ooN 0,0moc,4 co m 0 - ' LA 0 mM 0000 11 COCCO000 CN 01 ICH0 %. l0C1 00000C00 m CI lD 4' en'L CZ LA 0 N 000 01I ICNOOHDO mH )H oIc 0LI 0 0 -* w I I wwc~LA LAC H LA N, M M mOOO I I wCN0 0 c C n 1r n0r )C Nf)0c n0k0NL i 0 0 M ~00IO 1 1 LCNCCO11 LA 000000r-qm 00)00000000000 H--Vflk ;rr l MCC0I I mWOCOC -z 000000000000N00N0000 0 M 0m r I I ";v w 0 0 0 ( ,cqmw- )0 n0 m M CILn-0 0 ,;:V0 00 1I : I 0 moCo CN - 0 HOL zl Cm00 -m C *0 cc0 C INOOOa O co c 0 C%3Ln I 1 1i0 arn 'rIV 0 0 1IC coo c'. I C 1%D000w I I I enDm00 LA r H wD M I N1 9z I ~0 mm CC) 0 1 Looco N C0 0 0 1 1 C\ 000 m rn t) i CU (VU ) 0) 0 4 o U)4 ~)C U H) U)U - .4E o 0H H~ to)4- W)I CI 4 4 0 *l X i4- (d E0 H. :) (b rO 4-)I (d Ot d Ea ()dX 0. 0)a)w a)~ 4-) 0 M ) 4- -) a) Wa) om na)r . J (~d dId c4Q (5ri 44 OO) ) C)) 41J 0 I ( 0d 0 (d 4-) 0 ul (a ) ) C d rl o (0 d r,04.) 0 0 r-q0 W U) W 4J (1) a) _1> 4) N4r- 0)La) )4.H ) 0 -1 ) U ) 4- 0) CI) EO ) 4 Q) 4 4 > Idd H W4J WCI) S 4' ZI r: W W CI) W) 44 U z (d > Md dH a 4 -)04O U > tm HU Hw,04C1 ( ) r (V d U Cd 0 (d I.4-)0 O U 6)HUi )H.0I4 4 0 :J d Q)-H *0 :J ) .1H. (o r0 (a 41) 00O$4 :J-H-0 l(a ) -r-4 -0 aO~ ) 0 H M dd r: WP nC O> : E 1 4r uuur P 4U nm> R 0 WO 00/43377 PCT/USOO/0 1283 155 ooi o Q m o n o oo i i ~ c,4 o L n 0 r -0,1 01 00'.D0 r-10 10c0 n00 10 11mQ0m C m 1L 0C0 ~ r 01 ~- ~ r - mI moo I o Oicco0 -* i w a ci noooc 0 io ar0 r m~ o a% i o) r- r1c0 4 10 c iL C O r- 01 -ia :>ooL omao L i Ln coo i no r 0 1 00000 1 0r-CD0 D\H II q CD 0 0 0Ii DmH00 1D 0) 100 C) O N I I I H C) I CO0 00Lfl I I H0q 0 L 0 1 w ~ O ic ccoa)iaoor 0 110 0 000c 0I C) C) 000 1 a ' n omO c )oor 10 0 0 I1 -IC C I w O 0 mc I I C IQ C)0 Im O I 0DO) a 0)cc0 0 . w0 t 0 z0 Cr1 H m I IOLA-C I m'I-O0 m r- 1 1L m1-'m r- . 0 1 1ICOOC) C I O' 0C I a% I I CO CN 0CO I C)r 1 r I I1 ~r- 1'OCO H- 010 0 0 001 00 00 o l l o c o l a c o I I N c o o CD CO r- n r c C I D Cn I C CO Ani m c N wa% ia)0mo NLA i Ir m w %D - CO C)I w 00o )I1OmL w.0 COH w) Il Hza)ww tu (d h -4U d Q)0) I$- w 4- r *H ) (l44 01 t 4 CO 4 0) H 0) U 4 (n1 CJ IX-I 10 a) .I) I U) 0t -q 0 n) U) 24En10x -4 a) r.O O) CO ( 0) 0) 4-1 4j r:a -1 ( L )r Od Q (d- 4 0) 0 E m (1 3 a 4(d r 0 (dfi - 0 E tmr 40 L) d 0r a) -H >1 41 -1 r- M U)4-1.-11 ) 0 '-4 W )4 ) . Ia) Q) .Hi> .-I ) ~C 4-) 1 4J U) r: U U ' ' .r 4Wr4 Z > 0r 14W4)W r 4F: % U2C ' O~ U 4 d Zk4 J-) a O U >,0- ) -4 QAj CA 4r 4Z 4 0o 1 1 - 00 - Z a) -H- *0 a X -HI (0 O 0 da - A: H00( WO 00/43377 PCTJUSOO/01283 156 m -r N1.0 c 1 Ln m0 0 o0 0 o0 0 M0C 0 0 m 00 C)rn 0) 0 1 MI LO C I 1 1.0 0 LA * 00 0 0-Z)400o-o:v 00om m LA LA i i L o or- -o m %D 0 -00 mOm0 00 -0 m o o~ 0 >Na0 q 0 1 N 1 -;: k 4 1.D C'.m N 00 1 -0 O 1 0 w00 c o . o . C\J 1 en LA 0 CNJOc'O0 -i N LA0 10 0 c ~ c o LA LA I m LA 0 1 ICN~0000 0 v~ e~0 m p o CN. I fn LA C imo~co o a) ~ i or0000w~ o ommocNOC) M'~ LAI CN LA N I I r- v 10 M00 ) OLA I - 0lHC)MLCDm 0 0 0' NN) ( Dr C D N 0 1 (N LA (N I I1 0 D rLn t- 00 C I ":v N0 0 C )-~ D0 0 CDC)N 0 N 0 CD l H N I (N LA NI I~N 1o -0C 1.0 ooc o oc 0 la DcNo vwc )r 00 iN c'j "~ 0) (N I I r-I C M ,00 LA 00 I ( Ocn 0 n00 C 0 %. m r~ cqw 0 0 1 CN H (N 0 0 ~00.0Z A~ N 00 I O 0 00 0 o*00A 0 u u 01C )wr I- 0 C 1 mr 0%0 -m 0 N0LAW00 N'0000 0 w 00L (N 0 (N r-i H NDI I AA qrn n r 0i w' 0 OO c00 0 0) 0 CD0 CD 00 - I 1-I r-I 0 1 100000 N o 0qC ~o ~c000 0 -I(N 0'1wl1oo 00 0~ cI I )C D0 r . D0C a) N0NN m1.0 % OI N IL N I O N N( I0N 0 0 ) 01I H m N I ImO C LA Dc V0k 1r 1 0 m0 D DI m 0N0amN0 N W o 0 0) ~ ~ ( to2U 1 l 0)r ( Zl4 m 0 0) . Cd -1 0 C) 4 a 1) Lo 41 00)r Q 40 ) 10 ) 4J( 0) )0 ) ) co rcl xOH)0 a ) 4-) ( 0 U)- 3 o ( d Q -) 40 ) 0 4 M ) 4(d 0 , 0 (13 d Q 4-) 0 E0)( ro () >4 0) 4J ) j) U) H >.- ( U 4(C ) (d J H ) 0 M r-0)i a) 0iQ) M 4> WO 00/43377 PCTUSOO/01283 157 ~00~I 100 ~ I N ~ oo 10 I0000I00000l IN.0000 CN~ 01 I000rMIN000(mi i oc00or-iom o ~ro w0I10C 00 lr0'A0 Ni N0 1 N0 'C 00O0 I I 1 0) 00 I 0) 1m I N0 1 1~0 0 en 0 N In I I r- 0'v0) 1 N00 0 0 f II 11 f0 0 )1 0) 00 ko I I en 0 M 0 0 0.0 OD I c)0 m10)0~0 0 wI I I~~~~~~ 0000. 0I Nm00 a I) 1-00~ 00 IN 000 - IN w II I I m 0 CN I rM ornl"If I I c\)nomc~ mn 0 1 1 00000 I NO.4000 I I I C'00000 I Ior 000 00;poo r-4 I'D01 IN-000) oLom~n I I 0 I ca 0 r-1ON I o ~ 0 N v 1 I (N 0 Ln 0 0 1.0n - I w 0 m ma I l O0. C1 W I I I10a000D I o"000 I I 0.20000 N- 0 1 1r NLACDw 1 I:1 1 a ww I I 1.0 1000000 000C)I 100000 w. N-I 1 0) C\30 0) '3C0 0N -1 1.0 I100001 l00CD00D I 10CD0 000 rl) 0 1 1 C,4 N o0C4 I %D .Q0 0 0 1 I I c'.2lim OI I 0. D000>0 1 11w.a00000C CN. 011000010010011 I a0r-CDm 1 NO'mtOOOC I I N C a00m H- 0 I I m cc'. CD I 0 c D00 I 1 ID Id U) I Ea0)0 rA o C - 0) 0) 4 c A)0 ) d 0 0) a) ) W 4 a) ) -) A W(drOId ; U d H0b) () 4u ~00) as4I s: a d 4 0 01~ (Id 40) Id 4(r r 0 0 (d 4.), S4 0) co 41 -1 ) 0 -1 ) 4 ) 4J D -1 0)j l t:)a w -.HW 0 r-i U) U S4 Q rd , WQ) 4(1 0 d> d r-j a)4. 4J-) M r EO U S4 4 dU 0$-:EnQ) 0 rOMU dU( - War 1M- )ri 4-) EO -HrO (d *I 0 4 (d U 0 4 0 0 L Q)_ 4 : , : 1 ) - j Q , d r 1 L - 4 0 C )- WO 00/43377 PCTUSOO/01283 158 Ln Ln L o oLA -o 1- mliiNoc )ia lCnOo0Il0r- o 4N * ICc\0 c, Co 0 1 100 H m LA LA r- 0 C0 0 0 w. I I %D 0'0 0) 1 0I. ONI I. 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LA LA LA LA 0 0 1 m LAD r ) i IL cqL cD c)0 mI I N 0 C 0 I0O q0 1 0C, , LA 00 10' Ic,4o i ILcm o N ' I ICD0 N -,: I w o 0 0 C I I C ) , H LA LA N 0 00 r, CN 1Iv I I m 0 00 a w 0 N I wa "W A 1 0 D0 C 10 1I 00 LA LA LA LA LA 0 10 q0 M 0~ 1 1 .0 t LA Ln ll' m %Ir )1c ,C I I n c LA LA %D oI cD e m i IL 0 o icqgm LA i r-r-cq o o INrO IIa I I I cNqI 0 Ln m i m aLA c o )ii, w rI '. '.n r N 0 1 CD 0a I, v NN)1 0N -a m I Im ,e ~Ln 0 LA H LA LA ma 1 0 0 C) m0 I r I o ' .0 0 0 e.N 1 0 cq CN I I 0 C 13m 0 I I M LACN H LA LA LA -zvm I0) N 10 I o wv wN' L LA ('. No w 0' LA c o r-oi r in v IC Ln N LA LA Lo) i 0',No 0 ni r-mcco vNA A i Mn iI M CD , I0(n cI I r f"I1mNrnC LA un cD l) - c cc)cc)i ir nL m~N.O . 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N o o I o CO m i m0 D i 00n. > 4 o o 0) O D I I CO M r-1 LA t.0 LA :r In N-1 I - I - N Lf M I m C)0 LAn r I M r-L CO 0 0 I 0 0 0 I 00~- 0 1-1 r-c 0 0 1r 0- 1~ I1 M M~O I) O m , I I -IV 00 0N N N-r I I r-O0c\JOM I 00 w . q (N M I I r,10~ D MN I rN o '0 0 Inr n -0 r 01-00 1 00 1-4 0 M LA -f o i- O o ml O w' m N )o i -mi I LAo oo o vLn Ln 0 I 1I C>oo>M I I0 'A0 00C o r 0 CO 1 00 0 oo I I COO COO- C I 10~ 0 0 000 I 00 C m, (N I LAC C I N 001 I 1 MM I 110 0 00 CD 0 C I I100001 LN w M IN CO 01 I (N00 O I 000 %vM I ~ 0 (NJ N-I I0 ,00OMI In to0 (NICNI N m I 1 0 ' e I I co OOODOC C I i In 1000o .-i N I co 00 I a I w Iq 1'.- 0 m 1 0'N0 t0 v 1O~ I -V I I '1'000 0 Da C 0 1I )C 0 C)0 r I LN w m(No L c, g p n N c', a, o101 r- I I w C nc (N0 0 0 1 1 00001 o 0 mmAn04-zv 0 i i Iq CIc' Iq CO f ooocr ni I r-0 CV C0q C40 CD I 10 0 00CD M L er) 0 I I cD 0O m o0 a% ('I m o '.0 ('10 r-'.0 N 0 1 1IC 00C> . I LA LA C)rn~ ('1 0 I 1I OC)0co 1 0 1 CDI;p0 1 I NONCOr LA w.0I I m (N(M1 ) I LA LA CI c 'H- LA I 1I00 0 n I M 0000CD I I I'000 i' ml ILA O *,om i In LA NN 'Ho l oc LA LA 00 0) :1 1 1 M mJN " w I I 0 0 v I I -Ir0Dmn0 0 ('1 0 1 I o ~e I LA LA 0>rq co r CO N m w O,.Lno m i mo00renc,4i w cI co ' C Ln .o i-I 0 1 1 00 D D01 LA LA C1 N 0- ID 0 CDq0 co 1 0CD00D0 1 1W '00(NICD0 0 0 11 ID 0CD(' I LA LA 0 c M. 0I I W n II)1OM0 0 M LnI I W0LA L l 0 ~ -l 0) n IM 0(11 n LA LA fd U) (d w 0 M r. -4d 0 4 0 0- 0) -A 0) U)i -l c 10 tC, -4 0 04 aH) J- 4 )4 0a 01-H i4-J r--I CJI f 4-) Q) -JC ) -rI> J 4 - ) )4)-- ) 0 H a - a ) 'H 4 C 4j a )-i> . 4- )( (dr - ).- )0 -4 r 4 r :C ) ) ,0 d > ( C )4 ) O L 5 ' , WO 00/43377 PCT[USOO/01283 161 Chcom m 0 1100C i t1 n c- LO 0011 n NI I Ch o~ r- 10)r- 111 - w CN in m m mwo0LA- 1 l0'or-mm n0I 00 ml Q I N0 M10),N 0OmlI I IOC> VO(NI m t.0 14 m acDr-o n i i in'.0O'. v N -o - 01 1 cO 00l I n0 1 OIOHwI I I 00I r-r M 1 0 10 N I I 1 0Lf~~ m C0 0 I0(0)~ m01 IC'. 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H(N H4 H4 r ( N H- I00LmA0 C)0 C)0 r-oococ~moooooooooo 'Zl 0 ~LA0 0 0 r-I(N 0 Ln00CDLr)m 0 %D LA) % '.0N 0 0C)10 (D0(N0 0 ( N CD0)0CI10 ) 0~ 1 W000DaLA1 (n m0 00C IN 0 0r- 0 0 m M N O 0 oo00aLn r-0 H) H1 (1N HHI H- MO.OOo'ooO m- coocor-WOOCOoooooo 0) oll 0)CD Cor-oC H (N 0)) EllOH *d W0- ( (( ML)H WXH M 0)0) -)40 J (d E ) H U) H U) x -A0 O0 4)) ) CD H4a) H EO 4 E a) (10) - 4 0) (0 a: )a ) 4 d :: E 0) - :a - n iz( q 04 :)U 41HO~ H 0WOa) 1- Hr(d Mrf r (0 )HOO 10 0 ( Q4) 0 a ) )a 4 zr aQ4) 0 ()0 40 ) WO 00/43377 PCTIUSOO/01283 169 a0LA0O 0) W zzvOO.o oooLo0o 00 00 0 0 0 00 0 0 0000 H- H -4 O-A w a r CN C 00I0000cqoo me 00m0 -0mm0 N 00 Q 0100 N WN q Hq %.0 H 0n H w3 01% 00 00 0o~ C'Q 00 ' 0m 0 0 00 0 q 0 0 0010000000N HI OCD.00LAOC00000000 N 00N0 cq N 000 I00000O00 0- r -,inm000,00 o ooo tD0 0 co ~0 -0 0 C 000 ) 0 O N 0 C v nmcDoc : 0ioo c~~ Ol000 c00o0L 0 co 0 C H n HHH co H (N 00 qI 0n0c 000 co r-0D D0)i) oo 0 mr-c o~ r N - cNI a)o Nc nc0MO O in L H H r-I Ho H cn D 0D0,0 00CDCDo c- mo 0co C i00C 0rn r- -ooorC c4 00 0 ac - 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00000000m0a 000000o N0 00 H H H 00 000 0 CD 00000 ) -qCC 00000000000 in ci HH 0 D00C )a 0 0 o HoL -oo ,L or )c CD 0 0 0~0 v oCI 0OC D0 C : C0400 C 00 0 0 0 0 4)0 0oo oCo QC.C)C) 4 0 1 HH 0 m mONO 0C> r ;Vr r- 0l0N m 00 r I'o.0'Ic 0 0 0O0 0 0 0 0 )N 140 0 I C 0 H~ A 0 m H (N C m e a mN 0(NWOO MO OOON ml ODIO001omo o ooDDO O N- N-I m m w0 Nr,0 0 0H CD(N0 0 l 0 C m0I: 00NO)CD00 r D01 ) N q00i C .0 Nf D I H -4 0 (NC1 m m 0)a0 00 00C0 00 00 H 000OI 000000000000~c In) 00C 0 (N m r 0t.0 I0 C) 01 0 Nv 0CD C C3 0 DI0CN- )00C)C)00 00C(Nm m 0 1 0 H ( 0)~~a ((d2 )I ~ 0 H0) L) H4 () .4 b 02 4J 30 -1 U 44 02 t3 j-) 0 UH 044m 02XH x 4.)(d U) 0D0)H r-4 U) 4 n x H Ea CDU a) 00 to d 0 0) a ()a) - C b d 0fo: in 0 ' Ot.1 Q04 u)( t2.1r.-H0 0 (a -1)j 0 ) H4 0) ( 4J. 0 0 (a 0 41 0 0) 0-H 4 d 0 4 -) 4 O > M 1 () - j ) rO( U 0( O ' d>1 bH) 4-) ) 0 4 -H00)d a Q H ( ( 4 -a - 4''0 (1 )0 :JQ H ( d WO 00/43377 PCTUSOO/01283 171 00 ' 00100Iooo 0H L 100 h0 0e 0 0 C r-1 .D O '0 14 H4 r-.-- r- o14H mn m 0-00M-COCOCC M000 0o MO C C MO O C O M H~' o -i H 4 H '--4 4H I - 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R Wa WO 00/43377 PCTUSOO/01283 172 Ln i L a 0Do o oo ooo 0 o o -: - 1H 0 0I 00 0O0 >0 0 000Oho CN -i ~ -H rHHH r O00oom(oN,.0000oooo Ch 0 N0~0 L ~ N L H H- HH - H H H- H r4HHH H rHH H- - H H - 1-4 -I H- H- H H HH wrW COOCOO 1 m0o~l-D-I o C MOlO Q>OQ) o a C) C 0CDN -i Hirq - H H- H HHI I NO0 M OO0OMO(Nmncr H 0-1 c0OO O00ONCOHWWOO H Hi H HH HHA H HHHH H H H HH H 0H HHHH H H 0 H HH H H Hl1 0 0 0l( Nl0 n0 D0O0 C)0 0 0 L a4 OIOOIODWoOOOOOOOoaa Z 0 HH 0 1 N 0I 'no 000o 000c l-4 '44 00O o I00LA0DO0M oNLA0 o HH4-1H H-4H H- H 0 0CD000 0 000 4". NCO C COO I 0'. I w 0C0 0 r- 0) (NLAOW c 0100000000000000 (N C3)0 0 )Ch0 0 C130 D 00Hm w coCD0 0 -0 0 0a c0ND 0r- m 0 H 0 1 (NCDC)00co D0 0 M D C >0 LA I WOM 'oo0NI C 0 000 CD CD 4 0NI0000'4 4 co olcN00o H 0 HH HHH-4ri - H 0'.14 H H H4H HH 020) 0) 0U 0 S02 Q ( 414t)0) -WH 02-4 0 nL 4 d 02 (13 0) U) 0 (d w 0)C 0 )d4 r 0 dIQ4 020 0) 0)) .0) 4 0 00 0)0 0 (a ~-r 4 0) -14 r- ) ).Ia 0 a) 4 W 0 a) ~ '0 -r 4-3 r- 0)40- 1 () )4 -H40~ (0 Uk ( M 4) 0 T >10)1--1 Q 0IiQ) 4) 4-~ rO d k(d d 4) 0 0) H.1-4 0) Q) r-4 0 0k 02 :J(5C JQ rI( 0k -Q - 4 0 04 a 4( M QMUUU 2 7 Q OC 9 -,0 a QMUL - 414U )>.:::E WO 00/43377 PCTUSOO/01283 173 N 0 N w 0 m 0 a - m N r -OiOOOOOOOOcoOOO wOOOOeO4 wO -4-i -4 oh 01 0 00 0 0 00 0mOOO "OOOCtCOC.t-O A LAOcC ooNIA O O IOOOCOIOcN0ot0om (NJ OOCOOOOOOOooOOO N OIomoorCQooomrooo 0 OIMOOOMMOO00000 H H H r-I r- 1 k LA) r- -4 0 DO CO't CCOO O -I CNI 0m mO r- I w O0C00OOOC0 NO 0 o0o (I Ln 4 ~~~IL -IO,- o c o ~ o o r-4 H Ln LA MH Oe Om ~ r~ O O ( J Ln O-I I- NO Olai~ C 0 ~L vi ~I m CC O0O CC OO fl)o kD tI Ln)C)mNr-CDfnI fnOL0 t) W c%4 .- -I LA)r- 'AI co ml) IN 00 oC 0 ) 0 C 00 0C (N 0 1 Noom - oo 00OO C14 LA) N1 0 tOO.cO WOOOO%.onw (3) C) OnOO M OOOOm C4 OC (N -4 -4-4 1-4-4 I I- )10C 0C 000000 r ClOO OO O O O N OOOComcoOoOOOCoO N v IVj Cl) H) (D rl) ri (d a-~) (dr ~0) En) 4J 0 ' 4 r.4- t) Cl 4) -4 U)44 O0)r-i E0~ Cl) Eaxri 0 4J(d U) O0a) - U) 4 ca x-4 4 4)( )0)) e .13 (o r )a )Q - 0 0) (v)1 0)0j) ) I-i 0)O a) a) a) ol 4 4a) 0) C: 0 (d Q 4-) 0) Q) M ,5 4 4-0) a)O P a 0 Z 4 4 Ei- 1 , 4 0 - r 4 ) 1 - ) r; A4 4 )4)-- a) 0 )H) 4 Q))O J a)()V )0-4 V4 r U )P Q (l> ( 0r- 1 1 )U ' : :r U ) d> ( WO 00/43377 PCTIUSOO/01283 174 N- LA 0I00000000000000 a% co0IZV000000000 LO 0- m 0000c00000coo000000 %Dor 00~~000 0a0Lar LA m (N 00 0 m ~ 0 0 0 $ 0 LA mm o mmoio0000ON a% q -4 -1 IZIO LA m r-i r-I r4i -4H I 10 LA o )0 ) 10C IO LA0D0D0-ICDM0 m LAn oa M m cm,; C 0 L o 0n o-oLn o LO O - L 0) 0I0fCD0CD0 0 0 00 C 0 0 (H 0m00 D D D0 C CCDCD0OLCD 00 r4 H- H- 1-4 H- '-'4 .:Zv LA LA o Lo CO IM0C 1-000-:p )oN 0(Nm n 0 % o c CoL wo c0Lmo oac i0 -0 LA 00A C ~ N 0~ ( a 0 N L~ 0 HL~ O ~ 0 IN ,4 co 1-1 H0 H -l -0 LA 0o 0 r- H 4 -4 -4 z-4 0o o0L (No C r- 10r 00 D0C o CD COOO 00N N - M 0C) C m0) a%0 -CN 00LC ra) N 'I- 0 -' CD I.0 0, CI 00000*0CD00 (N C0O)~0 I0r DmC Dx rI o m )mmC 0 o co N- 0 ~- H -4 LA o D0r -C 0 N0 0 CD00.0 NO 00Co , 0 ~~~~0 LAO0 00 co 0 N- H- 0 1- H 1- - H 1414 o Nr )c>L zi Dmwr Dc ) c H 0I'~ 0 N0 O 0 0 0 0 ( co 0 C)0 0C 0 N -44 0q r4.- M- -~ o M C.0 I C)0 I ) - ', 0000 r ID0 10 c Nq 0 0000mCh000000 0 0 Ul to 4-) 00)1 U 4rh- i t to C D I C i ) - I 0 4- d E ) a - )U U) - 1 04 a) E UrI-- 4 0) -JO a 0H a) 'I)4- a = r -S4 HU 0 4jO -1 a) 101- (1) a U U U -4 4 : S)-4 W (1)I U) Z Mr 0 W M U) -Z 4 Z Z- M 0 .f0( HO d ) 0~~0 )-4 -40 U d a) 0~ 0 0J Cl) 4)-r-4 (dd Odd.O()ri0 4-10 : 0 )0 0) MMUUU 40 )U ] 3:-)H &1aJ- Z) 0-4~4 MP P -H U0) En WO 00/43377 PCTUSOO/0 1283 175 000 m' OLAI1 000000 1 omnoc~ H m 0o 00 m 0CNCA Ln LA M kD LA -. CNI M0000000 IONNOM0r 0 000000OMOOOO H r-I r- H LA LA H~ Hr- %.0 H- H LA LA w ON, 0) -0 0 C 0 00 000,1 0*0 ov00 m 00 C 0) O w -00W N LA LA L~ -o W q0'.01 h0o 0 1cq1 00 - ) r N 0 0Ln ONo) o oo o LA LA ON r- -I L M CN II00000000N~MLA w. a)OOOONOOOOOO H 1-4 H wH- LA LA 0 %D0 0O h0CN 0 000r 0;V000 LA 0 0 0 0 0 N9a0 0 1 H ~'H HH4 H LA LA 00C o 00000 NO~ loooomoo000 - N0a 0 C mm ) IM LA LA '0O0N LA D O 0 C 0 D 0 0 1 10 CD D 0 0 0) C 0)0 f 10) 0) m H H or-i 1-4H LA LA ODr-0) 1$ 1 1 CD oo In 0 l0 111 I N CD CD1 0 0 CN m CD0 00CDD MH r-I w. H Hi H HH LA LA 0 C'N r- M )C O~00 w CD0 0 00 0 t-LA0 a H m o 0noLA0oNr--*iOcn a M H H k-0 LA LA Q0clq CN 00D 00C 0 0 0C l0 0 mv D D 00 0 0 DL a0CD0m0 00 0 MH4H w. HH H4 LA LA HM H H- ~Ln I H H1 H 0 0 0 0 0a4co I I I cc 0CDmoC I 1 0 10 1 a m %D '0 00)0 0 00 )CD N H -1::C - - ZH ~LA u 0 co~' Nom r I I I m 0 0 0N 0 1 v CD w CN 1 1 I - N - N0 o00C)0C00 CD .o qH H LA H H LA LA CC)r-0 w. I I I CDC140 0 CN I 1 0 co I I w 0) O0 )0 00CDCD00 CO H- CN H H LA H rqH LA LA LA co0 LA m O 0~0 c D0 w0 v n0 m lf ln LA 0 C0 m aN N 0 00 D0N H CN H H LA- H LA LA 0 c D 01 CN 0 CD ICCN0 vI 1I0 1 I 1 10 00CN0-C NCDCD00 M 0 H H N~ H H LA H HH H LA LA 0 00 m L 0 r-0 ~0)0 D0OCN-0) CD mLA v C rn c ~00 C)m 0C) C N0I 1 (N H rH LA - H H HH LA LA (Nq H HH- H HH LA H LA LA LA LA 000 C 0 0000 00 000 000 0 0 C D DCDC 0C l )m D0 0 0 0WONC (N H4H LA H H H H LA LA M H 0) u) H4 4 m4- C)a U) 4 n O r -4 U41-d r )4 U) iO U)*H 0d m) 04 d) .1: U) H , b)J W) WW () 0 c)3 ( d;j w 00H a H 0P f 4r d 4 (d 4tM 0 4-) 0a - ( r H .0 4 (d 44 ) M 4..) 0 a) 0 t40a s-l z 10 0 ( - 0 ()0) 4 ) 5- 4 r.d 0 a)42).) a) E -H 4 -1 t3 O4 -4) 0 a) 4 a) 0) ri 1411 S*H 4J.M ~J4) -- ) 0 > fl 011a )E .U ) d> dr 4Q )w ()( 1 :4 r aa WO 00/43377 PCTUSOO/01283 176 o)o)oo:; a or--, o) ~o ~ - ~ oor qm 0 00oo Ooc 0oo -A H LA 0cN00O M 0I00ON0O00ooo000 N- mok'o0oWom0L Ln k 0m~1cl 0100Oo0oooo00000 %D H0ooo~-1cV00 ) o -LAn 00r- 0100000000000o00c LA o0 00N0 m H CD \lq0 00 0 0 100ODN000000~OOO m Omi 0mm00cDO 0c1 H H H 0 .0 C\N 0 m~ OIO00a'CDoO~OOOOOO cq. oooomooom H- 00 H H1 1114 H r4 H 0A 1- . 0 r 0000 w o c 0 a 0 0 Q L ' 0~ o - 0 H ' 0 ' 0 \ H~~~ ~ ~ 1- 0 r4 H H - i H 14 aD N0 a)0 0- m 00 0 NL0n~ o)c om oc nc r ) 0 0 1 0m CD H 0 0 . HH 00 H H -1 H H 0 H- H 4 H LA w. coH 0D H m r-Lnco r N 1 wC DC c.1 0 0 co C,3 C m mCDoo oo0 w C I. im CDCDcoocn o Q OD H H- 0) 0 O CN0 CNN a 3 -r r O O 000m) rn00 c oon nLna ,w 010 0 0 --00 N0 HrI2 0 Ln H 0 HH N H 0 -4H LAnw - r 'A 0 1()0 MW wC 10m O0) )0 C0C O 0 OO'.Dmcoc 0 0 0 000000C CD00 N- H- 0 m I N I I LA )N0MC 1 1c DC4( ' (n f) e~0 W 0 00co000 LA) LA CDLn 0 -: o0' )C CC N0 )0C ()C C4C 00 CD a 00 0000CCD00 -;P% l M 0 0 tD 00 (o~c~00()C Dm()C Nr C '. D 00D0 0 w 0 CD0 LA LA CD001 C 0 N C)C 00 0 00Nr-000>c)Ln c0cc, 0 LA aO000'.0OI'.0 LA LA (0 U) H0 ~U EO4 .1b i 4-)O0 Q (44 0) Ea 4. 0 4J) a) 00CD0)H (d~ COXH (d 4J) 0U)0 ) 4) 00) tm (dCOXH: ) ) (0 1041~ 0 Q) 4 0) 4 rz V 0 (d Q 4 0 W0) 4 ) a) .1 0) W )IJ r:) ~-H,A - ' i 0 4J-H ) 0 Q) 4 J ) 4-dJJ,- H 1 14J-4 ) >1 olH a)H0 Q41J Q) 'rO 4( MI 4 - 010> t)) - () H Q 4- 0) rO M 0 4 d (l 4 0 ;1 Q)*.Z Z 1 4- :J( )0 , dI 4 0) A00O 4-r-H0 : W O> : E 4a QC Qr - . z w w>:: - a WO 00/43377 PCT/USOO/0 1283 177 0000000 0H Ln w ioooo 10H -I -4 m00 C 0 r- HA H H -0Hm10 kD wD 1 --4 1~-4 s-I H n10H' H- H H - qH %DH 0 r .or-0 L ) ncooooo o w-- ~-qpo o4 ar 1% 0 -D M ID %D 0 0 co o C 1 V DIMrOCDC Dr 0C 1 r- o 0 o 0 ~ I 00DOiC0C '' 'H H M 'H -1 H 'H In 'H 1 10 wD oo0 - 00 m -10 t r-0 ao o 0 oi CN 0)C D0Qz -llaCC DL 0 O I ro0Cq M CD 'H H 'H4 M 'H Ln 'HI r- r- --: - )w ON 1 I 00 L 0 lLAO zil0 0 0 N-0m r- 0 i Nc4omm Hm 'H 'H 'H H LA ' %10 10 OOOOODC)m Q - mm0N 0 00LAm r000c' c 00 1 r- N0N-0 0 ChM 'H -4 Ln 0 0 coCD0 0000. c C D0 -c C D- )0 00NOO'0NN0cc CN c'0 Nm 0 m ) z CN - 1-1H HH'-1'H r- r- -4 LA 0I 01 C)0000000C -0 )r )a oc nmoL Nn C 0 fm 0 0 0C 'H 'H H''H 'H - LA 'H H ~ 'Hq 'H 1 000000 0 mn (N I 1 00 1 m 0 0 (0D0CDN Q0cq N 0 1 Oromlo (N (Nq -4'H 0000000c 'H 0 0C)00CD00 00 00 m 000CD0 LA CIOLAN 10 1 IV 0000000 0 00CD0 a0 w0)0 OOOOODOOCOO0 Mw co 10 CD000 (NH HD 10HH 0 u I a) 0)U 24( .r )4 : 0) U) 4.) 0 1 C-4v 3 4 -) 02- w oM L 4 .r 4 ( 44J 10 H ) 0214 ( n : - d4 0 C4 - ) )a 4 r 0 0(C - 40 ) 0 ) 4 ) 4J -,-1 aI 4-O) -' W M4 r ) 0 Q a) 0-) -1 -4 r- 0204 (da 0 Q -- ( 10 a)() - 0 4 -l-H 0 a) 0 ) -i (a)d ~ - 0)r- 0 H P0% ) ) 3 5 E P 0 MM V U L) L) 0 Z Z C4 134 W 3 :E 34a WO 00/43377 PCT/USOO/01283 178 rn100 i o00 rv-a- ch 0 0r 0 O0 m 0 0 Io m 0 - 0r-0 m c D ch0O'D r-A~ C ~ N N- 00l 0~ O 0~ r4O-i C'i lLflO' 0 w ' I c -r-1 0 - 0Ln 0 0cqm 0r- c ' N0)r N o no N0 10 NC m M0 , 0) L0 CIO00 -4 I 0N0OL00. 0~ 00000co L 000 00~ 00000 CNI r 0 00 C C V0~L N a 0 CC0m c o NC 0 aI0c m00NC 000r0,0- 0 -- 0 C 0 O N 0 co "DO 00 mNLfl 0-r ) 0 00c 0 0 0000%.oo 1V O~00C H H co 0 H 00 w wC e 0)C - o m C O00C0C,-A00 0 0 H0 0 C M00 N co Co' N 0 o0o00rn >o o cN 0w oo i co oLDr occ0w.o mco rL ,;i0 cD o oo 0 0 0 r-.H) C.) 4 0 0 000000000zl oW CM r CO 00(r- 0) 0 m OD 0 coN LflC o C0 N -,1 40 ooc0o o (N 0 NC0C q c 0 1C0C(N Ccoc0c o '0 w "0 - D 00 o0oLn r- 1 0oC H co o 0 -4 ma-, ia)i 0 0 o co0w o~o m n co A LA w 0 0)0m C00 00C00 00 0 o a%0c c )o o ooo c C co) o a o) c IC0 %.0 w. C0ow0n oC0 CH00m0 C~ 0 0a%0co C -,o,.ooC croco N C n i O C 0 O 0 C0) L OO O- co 0 a "r r- 0 1 C00 OLCAw OO'.0 0 r-Co, 0 (N 1C0r '. 0 -4 M 0 ' 0'.0W44m4- -4 Wr ,44 -) U -4 , -1 CL 0)j I0 H U4w x'A4 )wc) ) zoa -H UIQ 0 Q)M1 t2 W) 4 10 0H( 04-4 0 M U)W W , 0 J~ W - ) 00)-4 -w-4(f i 4 UX-,1 a) 0 w - 4 1J~ ) -H-4J -)4 020)0 a 0>iM0- ) r-i Q 020W0 W 0()0 ( o 1 o5 ) -i a) -AQ J W '00 0 jr d 0 0Id )4 ri( 4--a)rI 0)p2-1200 $- 0 w 0 dw, rqrdm-] 0- 0) 0 0 0 z*: PO z mO~ ~ 0) a-4 u- u 0.HI zW W- 0) ZH44-J >:: 3 E 4 4PQr 4 WO 00/43377 PCTUSOO/01283 179 a c c coo o m o Ln Cr% I c0 0 ( 0 00 N 0 0 ,vm~ Hn - mOO C en 14 ~H -4H H- t.0 O0 000 Cn 0'.o 00 wO0~0 ~ ~ o 0 00'00%D'( H M -- H '.0 H H H H H m H rfLA m - HH H H In H r H H H - LA 0)0 w0 0'.0 00 .00 CD MOcc c o n i i Lnr-ccHo o '.0 0N H - - HH HH H H Ln a) . 00 0 W'0 o COOC ,Tr or -r-o N c DCDN0 00 H00 C) lAr 000l rH Hq M Ln o oH i Ln 0 cLn c %o o) m10 0 )0 ) -C m O-w0 n )m M ml H H H H1 LA HHr C'N H H H H HH1- H Ln HH 1 c o0a0a NLAn~'.0' c m O 0 OCON-wN l~0 v C0N0 H- 1 00 HHa H H Ln H H H H C'3 H H LO HHl N N4 0 0 HH H - 4C'4 ri H0 I u U) r- N
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0 0 0 0 o oooD cN H a C'C.00 ) )L - 0C 0C I I I CN N4r4rIri - - - C)00 1 m 00CDw 1 0 0 0001C) IooC) ooN ) CoC 0 MLnm Ul OLn c 0 0o Ln CO CDW w. 0) )c : OL00 a) o 0m c) coo cin o) C)000 H- H4 H H- H4 H-fH H H HH 00(N 0w (M 0 m -10 o LA )0 c 0 00 .0 1 I D 0 00N' .00 Hq C14 U) -4 H- H- H- H-I H HHI H r-' C0C0 D00 N0~a c 0C)m 0 C 1 o 0) CD D 0 Co(ooooCD'C o'%DC)'W 0 1 00) fa a~~I) (a CJ2 H- 0)) -4 H 0 (L) rd i >1 fa .0J 0 H VfII- 44 0 2E 4-1 0 H U) 44 b) u t.oX - 4- ( Ca3 0 wr4 nH4 U x~ -01< 4-) (o 0) C 1 U w 0 ' O)w d L W 4) :) ( - 0j 0 0 0)d3 0) (L 4) 41 0 )( :( 0) J-)-f W 0 W () -W a) F j - 4 -1 r 0 ) 3HO) 0 () ) -W 0) - -4.) _S ,Q r r Oa 44 ( 0r IQ 1 )C X 9 !C ) 0r - Q) U) H WO 00/43377 PCTUSOO/O 1283 180 00 D OC 000000000 0o 0 0D ll' 0 00C0 LA 0) 0 W. 0 M 1 0N 0 00 C) 0 0 0 0 ' 0 LA 020 co 0 0 m 000 0 0 002 No N-r 0) o % ) n Do n4 -4 00a 0'. CA. 000 a' 00CD0 r0 LA 0) 0 -1 r-l 0DC0) 0) 1 0 N o 00000 0'. 0nMm rA iiic Docoo iiL 0 0 0 00000C >C naC q0 00 0. Iq o) IN o)1 O0 o c101o%. LA a) a% m 0 -' 4-l-4 0 00 na0mr 0 002 '. NL C'o' 0-. 1 o D100 o00001 n )-- CDA 10 00 N 0 0' 0 (o Ozpo o NOq r c)cD r- ".0.c 0,t C 00000 0 0 D0 0 0 C)CD 0 La40 0 00 0 0L 0 m ', O 2 0 N C 0'0( m 0 A'0'. r' u- U2 ,4 0 omD00o '. I 1 LA INr I I N 0 0 0 0C )C ) OOL 0 ( C0 0 )0.0 0' -Is-I cc cov n ic i i CN sC I 0 DCD -0IDC 0 00-4 C)~~ ~ ~ ~ Nq 0 nr )C Vt0C o r o00L DC )C qa q h m C H0 w 0n o- U(N 0 00'. O N I I I '. I I ~ '. 0 0 0 0 0 0 0 0 0 0 0 0 0 H N l N 0CI 0m AN0d)00 N o 10 0 L 0 00 0 N '( LA ' ' 4-I 00 .- I COs- 44s- r:b "0. U 4 co x 1- 1 1 U a -A E l 4) ca C NlU w~~~~~~~ ~ ~ ~ ~ ~ 0 3 )a ) 4 )( :( j r )()a 0 L 4r H ) -1- 1Q ) )4) a E. -I 41s-- 1 4-s1 a ) 4 Q -) a 14~~ ~ ~ ~ r.Q r .U )L t> (5r - )Q ) OL " :r OZ U D O r4a 0 0 0 0(d( - 0 00 1 LA ' LA N02(0'.04 ) O dU (N0 000 War i0) -N020'. j 0s - 40-I0 )0 : ) , (0 ( 4 -Q - 0- W4 s-H- 0- :W Q)0 : ) f 0 0 U~~~ ~ ~ U .
mWU 9 I0 24P Ur)r)0: Z o oc 3 0 4C WO 00/43377 PCTUSOO/01283 181 000 Nn 000 C'c0 0 1 0 0 10 00 0 m 1 000 I'D 0000 H 000DCD0 m 0000 LA 0000 c'q O't0 00H M1h0 000 Ln 0000 0 0000 (N 0000 CD 0 00 H- -ZV 0 0 00 IIZ 0 0 00 00 000>0 H1 0000 t'1 0000 0 00 co0 M ~ inA0 H- (N (N N (N 000 M 0000 N, CO00 C 0 0000 (N 0 000 C i 00 c co0 m1 Ln N H- (9 (N (N (Nq 00CD0 (N 0 00D0 I'D 000 0 0C )0 0 0 HA 000 00 c -I (N (N (NQ (N 00CD0 H1 000DCD0 LA 000CD0 00 0CD00 0 0000 N- H CN 00 (N LA N H- (N N (N (Nq 00C)0 0 0 000 CD 0000 CDN 0 00 O) 0000 1.0O ICD H (N (N4 (N (N 000 NC 0 000 Ci) 0 000 CDw0 00C 000 C 0 00 0 N 01 (N 4 00 1.0 D 0000 (N )0000 C LA C 000 N C C 0 00 M v %.0 0 (N
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H HV C%4 ( N 000 (N 000CD0 H4 0 D000 LA 000 a0 N-C 0 000 0) 00 (N a% H mi LA Hi H (N (N (Nq 000 HqC 0000 0 000 a 0CDC 0 00 CD 000)0 DCDcC 0 (N 0) H mi LA 00C)0 H4 H (N4 e4q ( 01 DC 000 a 01 000 C) im C C 000 LA C 000 N- 00 00Q0 H C)H en LA HH (Q cq (N Cd Cd d Cdfu 'v a) mUu ~~ a) U) 0 U O 0) -uc U) ) uoi U) a) C1) C 01t o ) C 0)~C m 01 0 0) 01a) C 01C m 01Q) C 0) tCd wd V2 LA rO d WC L 4 U 0 m CC) 1AC0 d C) LA 4'0 M U) Ln 4 rO zd ad rCd o d rd o (a r::(v(o 0 d (d~ d d 0( (Cdd U) H a) a) > 1 Ci HOr ) 0>1 U) H 0) a)i H) 1w A>, to HO) O>1 Ea ab ) H 0 - ) 1 I S W 4JFXH a) i : a) 94H a) 1 % Q) rX 0) 1 Z A4 ~ 0 ~ - ) I r Cu .) aJ) 4U U , 4-Q) 4U U Q4 . 4C )U U .Q- W )4 U . 4J W 4U -,AH (Cdd 0 -Cd -- (Cd $-4 (0:J-Hi *CMd( d4 d :1 -H *Cdd 4 d -1 ICd (d d : WO 00/43377 PCT[USOO/01283 182 '0000 0) 0000 00 0000 N 0 0 00 Ln 000 0q0 M m r 00 c 1. 000 a0 Lf 00 CD0 L 00 r- 00D CD ) D1 000C C 0 o 0 LA w 0 mm 00C zr C Q~ 0 0 0~ 000 a0 L' 0 D00 N 000 10 N~ 000Q 00 Hn C l0 L 0000 0 00 m 0 0 LA 000 C O - 0 00C 0q LA 00 m ~ Mm 00 C 0 0000 C'1C 0000 r- 0000 N 000 0 lLA co en mm MM 00 a0 CD o 0 0000q - 0 00 000 0 )C :" C c - C 00 00 0) 000 0 0 0000 0 000CD0 CD Al C 0 00 0 CDl ml CO Hn0 00C N HOm O 0 0 H O 00 ' 0 0 O O m m 00 w C 0 0 00 CD 0 00 0 0 0 0 C 0 000DC)0 00 000 aNH H co 0 0 0 0 00 00 m M~m LA 0 C )OO MO N D 0000 CDa 00 00C>0 a4 D 0 H i2 m NE 0,zC 0C40m m n m0.* 00 H ~ 0 0 00 o Da0 uO 000 LAo 000)CD0 u On coo Hq mN0 00 0 CDi 0 0 000 LA 000D 0 C) V 0000 q4 M '.10 H) m N- 0 0D0 0CD 1OH C) 000 C 0 0 00C0 m* C)C 000> AM CN CD cn H m N- 0 00 CO a% 00 HN 0 0 0 C l0 CD 00 0 m 0000 H 00 0 wO H mn N 0 Alq m m M z 00 co a 0000 0 qCD0 00 Ml 0000 HN 0000 LA 00 CO HA m N- 0 Al en M m m0 00 % C LA N CO 0 000 H 000~ 0 0 0C i C >00 Ln CD.Om l en m m 00 1 C) CD0 0a0 C D 00 0 0 0000 0 l 000 m 0 00C co 0 M. w0(n Al m (1 M M (~(d G) N ~l a) OW -co 0 ) '-.uw 0) ~u 0) ft 0) od) ' r_0)t 0 ' 0) o0tm m0 0) mO z 0' 02 ) tm'd 02 ro'd w) LA 'd m) 0) Uow C m1 mM ) 0 )tmr H )O - ) a) i HG, W~U) H ) a) >1U) HGi ) a) >1U) H1G) w >1 O a) H G- ) r! a) 4, 0) 1 I -% a) H G - ) I r , a) r4H a) I r: G),4 ~ w l 0- ) I r.- 4) -W a~!) G) U Q4J) ) u .4 - ) 4U U Q -W W )4U U .Ja) 4U U WO 00/43377 PCT/USOO/01283 183 o 0o OOOO0 v 0000 0 0000 %D oooO mi 0oo N)r 0 (N '.0 'n 0w O O O Lo wO L O OO 0 rI 0000 O0 0000 0- 0000 mN 0000 L 0000 %D0 c %.0 0 O 0 (n 0 0 0 O 0000 ( C)O O OO O a O O n 0000 0 OO LA 0 OO 0 HN 0CD0 00 N 000 ' 00 0 010 I 000D0 CD(n 0000 w. CO LA 0> (N - 0LA w. w. 0 0 00003 . 0000 (N 00c0 0 0000 C1 0000 110 0O LA (NCl c4 0LA LA %.0 0 N 0OO Lo 0OO 0 0000 CO 0oo 0 0000 LA co LA O% OO -I 0LA LA w. 0' CO 0C)00 mn C 000 '.C) 0 000 c 0 000 O' 0000 LA co Ln 0) C1 v -0LA LA %.0 (N N00 (N00 000CD0 w~ 000D10 LA 0000 0) 00 00C LALCO o Ln~L 0000m iLn in w 0 or0 00 00 0 C L 0000O 000 CD 0o 0 N o 0000 LA 0n m LA LA wD 0w o O D O O O O O O co O O CD L0 CD O O 3 0000O vOn Ln 000 0 0 0 0 0 CDa'T C 0C40C 000 1C) 0CDCD04N 000DLn 0000 Ln L L 0 MC 0 000 - 000 0 C) 0010 -1 0 000 C)-I 0000 Ln NN H 1o1 -zlLA LA '. CO (N 000 .C 0 000 CO)C 0010C 0 C0 00 m C C 00 LA Ln Ow0 0 H- 0 0 00 vC 0000 H 000 0' 000 D D0 CDN1 0000 - wLA LA %.0 0 0 0Oo0o m 0000 O Co0 CCO 0O0OO H 0000 LA N- 0 0O H1 V 0LA LA w. 0 0 C 0 000 (N 000) C0 aC 0 000 N 0000 0 0 0CN 0 L0 LO H 0 C 000 H 0000 CO 0 0 0 0 w 00 0 m 0 0 0 N LC LO 0O LLA CO N- C 0000 0 00 CD.0 0 C 000 0 000 C O C) C 0000D NLO CO 0 0 w. 000DC 0 CC 0 000 LA 000>0 N 0 D00 N- 00 00C LLA (d md faCdC OOOQ Oo w O OO O O O 0) OU m) b)W 0) 0- c 0) d 0) '-d0 0) O 4 0 k O) O$4d OO 10 O 0 a) 00)m10 Q 0mm 00 mmj t mr a)~ C:) M 0) L 4r wU)~ 0) o rO M oul 0n a( ) Ln 04r ( ) on 4 0 d CO A~d~ CO LA-1dO O OO O OIC O OO O Od~ O O) OA-C OO J-)mN Q) $4r 4 Cq N0) -1 4J PQCq ) 4H 4j ~N 0) - . C 4 mN a) H 4r4 Cd r=;(a d Cd fCdd d a E d Cdd Cd0 ( = lid fd Cd Ha) a)>U) HO)q O O O O O O O HO Oa) OO HO O-4 )O H O Cz- 0 - 4 0 m 0- I , r4 a) 0 4 ) r0 I 4 41w uu 4 W 4 U 4 W 4 U U -W W 4 U W 4U 0 0 0100 .0 -O En0U0 ~4O 00 O en O)e 0 O 4J ) 0 ((d d H0 ( d ( d C fd d - d (d 4 (d :J -, - (d fd r (d :d fd : ,QE- 0 aM W u) , a4 P Q Q P4 c E WO ,WQWt , P M Q O4 ,n Q a C4 M WO 00/43377 PCT[USOO/01283 184 kD 0000 04 0)1m010) In 0) 0) 0 0 00 0 0 In 0000 I-q 0000 00 000c D m 0 m0 -rCNO0 Ln 00 4 LD wD 14 0000 0 0CD00 04i LA c wD %DD 0 00 0CD0 A 0 0m 0 0 0 000 0 0 00CD0 LA N- LA 0OC r D 040 m0I CN00 0) C 0 0 00 C) 0 000 -V m0o,-10O(.0r100 I'D tD N 000 ND0a C 0 000 LA 000CD0 04 w ~~~ w -IDq0;pm n0vC wD 0 000 C)w D 0 00 0000 r- ID N- o 0oc4noc>oc qoc In 0000 Ln C 0 000 -40000 0 0 0 :t0 0 0m 0 H r w w4 ~~r 000 . 0000 C 0 00 0-C N -N MD CD N 0 00H C- CDCD 0000 cq 0 00C0 c-4 000CD0 r- 0000 04 0000n CD 0000 -I 000 c.D 00 O 00 w 0 0 000 r CD0 DD 0 C 10 wD N ko~L w00 D00L0000D00D 0- 000D a0 N 000CD0 0n 0 0 00 i 1D w H N o4 000000000Ln c% c0o 00 0 0 POm000C 4L N0C OU w 00 0-4LC 000000000000O 0 0000 w 000 LA 0400 u~ ~~I 0- - - D D00000C 0D ID 0 D v 0C ) L CN 0 H N 00 0 0 0 0 0 0 w~ WD 0 C) 0 000zH00()0001q0 C mD wD N) C )C D )C )C IC wD 0 ko~~~~ ~ ~ 00 0 00 H~ 1010 N C )00 H 00 10 c O N O O C I ~10000 l-i 0C)00 (3 D 3 ~0Ln cr C%4 000 0 000 N) 00000 c I M 0 0 0 0C) 000 CD 000DC)0 CD O~NAI00m0 m~~~~~~ 00000)0 0C 0L L )w0 r-1000 OD 00 0000 LA 0000 LA o WD wD ID 000vo00l00N000 0 0000 N- 0000 ~10000 (d (aCd U . u0) ) I- uU) a) I-4la) U f i (1~d M) tm r Cd 0) 0)~C $: a 0) 0)iC0 (d 4 aj4 (L) )4 0) 4 0c ) ol U) 4.) C00) 0)10 0) 00)0)~ 0o() 0 OlM 0 0) 0 0) H ) U)k U) a clx H Ln -4 10I (a LA r d U) In 4 '0d Ci) LA -4Cd o (a Id E U)1 0 )0)a CN ) 4 H 4- N Q) 4 -I 4- C040 ) 4 -4 J) 04 C ( Q (d A4.4 010) Ei 0 d (d r=; d d Id E C ( d t~l (d 401) 4 d z rc a) 0>1 rIU) -40) (LiU ) a) >1 n H ) - 0. >44-) '4r- 0) E)J-) -H0I) H- 0) 1 -1 (L) r- E 0H() I % )F4 0 4 0) I rI A a) F4 r- ) a) 4J ) r U) U~ -4 Q C E 0) ,Q -) () OU u 4J-) Q)~ 4U0 44-) ) 4 u u ,Q 4J) ri 4r 0() 4 0 M d d 4 T d --I - TJ( d d-4 Ad 3-r-H ( *Id R :$ 0 d (d~d Q) OO4 0 4 - 4 0 d WO 00/43377 PCT/USOO/01283 185 00CCN 00oo 00 O 0 0 0o o o o ooN 0 LA c NCN c0 m oo 0 0CD0 0 0 000 -4 0 0or-40 00C0 %D00 LA LA co 0 0 c 0 0 o LA Ln 0 LA LA ~.O 00 'l000 m ~ NI0 0 LA LA 000 '~1 00 0 101 co 0 o 0 m In o m00 H o o o 0i 0 0 LA 'A m OLn 1 0 0 C0 000A0 ~ I ~ 0 0 I ~ 0 0 CN C)0 -0 0 C 1 0 c 0 Lo o I 1C 3 0cI 1. LAO10 0q00rWm10 H0 0-000LA CO c 0 o oo o,00oo w ' 0 ON0)C0CD000 C) 0 C -00-00-o 0 C o0 CDC0 -0 0 0 C 00 N C00C'~qoooo mq C OOOOO0 D00 ~0 0 0 )0 4: 0 C', 0, o 0 CD0 D0 0 C)0D 0 O I 0L 0 0 00 0 000 0 o0 0 r 000r10000) m 0 1Ioco m I o:Oooi: I I00o 0 o 00 00 0 C ;P0 0 )0 r D100 0 I 00 DI~ 1100000C IICCC,0 C:, 00 m t.0 000t) 10000 LA ODC)M H-j 0 -4 0 000, l o 0l 000 : Cj- C ) N0 L -oLo -4 -- I C: C O 'D W 0 a MC')oCNL 0a w 0 CD 0 0 cq 0 m 00 000.HOODOO C-I 00co0 0OCDCkm0 o w0 0 0 00cqq0 0 0 0 00C m w. H CD000 0 OOC m 000)(n 0-;: m 0D0o 0 0 0o0 a 0 0 0 LA U) 44 d)U 4 m . 4-) 0N ) 0 4(d ) WQ (fld - 0 4) F: r Q) 0 (O -)1 0 0 )) L A (d 1 d C Oo4wC 0 )0 (L) 4 ( d M ) o -4 d a4-) 0 ) r. ~ 0 fd( - 0 1 o4 -r >, 4)~~ . r- tm iOj--H0 0 r- a) 4) 4-) a) 0. >1 Vclu )- Q) -4 JC 4.),4-C U) O f 4 0U r 4r 0) *r * 0 1 ) 4 -' o( 0 -(da 0 0 4 - : :j aO~) 4 -Hrd- (o 0 WO 00/43377 PCTIUSOO/01283 186 r--4 W -4 c 0 Ln0 m r 0 C14Ln 0 (N m0 0 0 -4 0r-L N m O e 0 0) c 0 0) 00 0: 0 00 CD 0) 0 0D 00 0 00 0 CD-0o00c0000 )0coo 0cq 00 0000 OoOCOC0000 oo 000 0o H 0 N-0 00 cc0 wcqoN 00 00-4000 r- o i o ccnc fo i o mLn mLnl i r-4 0 r00o-0 O 0 -4 0)C 0 0 0 0 0 000 00 0 CDl 00C 0 0 0 m DIz a '0WD I mOO. -1 c' I I -4 L cc>00 D oo oHo : c3 o~000 ~ 0 (N 000000000-400000D 0 OOO. 00 IN 0 N '0 00 0 I 0 C>O'~ 0 ( 0 O OOOCDlfOOOODCi 10 00 0 OIO OOgco o I 0 00000 100000 I I 00000Oa O~CJ\30Lf 0 MfOOCD-i I100000C I I NCDO0000um oom I O000 Iq. c'4oooCD C cWo 0)i OOOODOOO-100000-4oMoo :I0f0cLl0co Ch-4 000000000000000000O m ccIWN0a C00.a-diN0 m ~ qC C )0C9C n CN r- I I r--(N CDCA I ) O'0 0 I I I 0 ~0 O0 CD 0 m 0 VN0 0O 0 0 I m c J~ 0 I 0 aOaOOO1C) 0N -0 0 000)CD m000a0 mc oc~c o N c o OOm000ml I 00 f) ) a I) U) (d U)9 11 (d 0) 0) 40t r) I- 0 - ' A 44 (L) 0) ~ (1) 4JO 0 * U)( 0 0 ) o a (DX- 41 4-nl (0 4 00 03 Co cn: (a 0)( b )( (0 -44 0 ) 1 - 0d 0) IlidQ -i dr qQ aJ 0d -f 44 0) l 410 .- '-q t))(1)4-) -4) 0 -1 () ) 4J a) a) -,q> 1 4-) -4 r 0) w 4- .H0 ) 0 (D A-l rOCO(1 .HO)FZ 4 M ( ID- 1OI . -1~ Q)J)C .U )- - 4r ) )4 '0 f 4 ( d J ar$U > )14()-44 4 ) 0 ( 40 U ( 44- 4r WO 00/43377 PCTUSOO/O 1283 187 rn Ol0o0 coc IH0cc0 w 00000 mn LA Hq H LnmOH ri 13 CN C 0 0 a m ~1 0 0 .0 0r q mcc 0 L 0 00C'0 C M Ln H H~ r- %DW -n 0 1-4 co I C'00LnW00 n0 cI O ~r00 1 1 00 m t 00 0 0 0 M LA H H L ND O A H 0 -110r DCa0 %C40 1e I m AO'i M mC 0 00a D0 M Ln HH LACLnr0 m 0r en M 'D0 C19O I0 1~~ m 0I at C N 1 QC 0 0000 c H H H 0 C\N0 C) 00CD0000000000000 00000o 0 00C D00 CIO LA rn~c' C)( C C- 00000C)a D0 00D0 00000)C)CD00 000 C'i 00000 H H L ri 0 000000.00CD 0CD0 0CD0 0000 ) 00000 0 L 0 wr- 0 CN. HH 04 1 C\ C00 LA -0010000oc~co )D C.CO )) 0000o 00 0 H H 0000 aCD0 OCD 10 0 0 0 0 0 0 ~ 0 , -10 ODH r- 00m H rH 10 CD0 0 N )01v (1 w 0-mc4c LA O C Lo N H0 0 0 H 0000 1-4 -4CDC)C C 0C -O I OMN00000'410CD CDNOo) C'] OCN m0 0 CNq HO0CN 0 0 H H m1 M I V r000 IDC 0 C']0CC'Q I I ,r0(1Mrn m H C)0CD'N00C H H N~00 cq m" I ON oC I) O' LA 0 cn r- r-~00 0qc nmww- 0 'LA r, nmc) H H H 1 H H m C. D m LA 0 0 H0' 0 A . 0 0 0 ~ ( 0 0 N L 0 H H H r-C D 1 (d rA LA OOC ] 41(d m C)MH 1 q4 0 rID 0O. ) n 41I- IDn I U] .1-1 0 0 *H 0 U24- a) a) 4)CI] ' : 4-) 0] r=1H; M] (]T)J I40 L 4(a zr d 4J 4-) 0 t~ t E m (d $-I Q) 4 ) ) 4.)] 1 LA i~' ~ d >14. -4-A 0)U 4 - ) 0 n -4 11) 4-J (1 )- J-4 Id. (d >0r H W4JW rM U 4 0 Q -. 4I Z 0 M 0 4 f ( dr - ). )L 0 I ) X -ri(d Z 0 - (d () -400 0 4 :J ori :d a).H- *0 D).Cj-ri (d 0 *I WHO) 4 WO 00/43377 PCTUSOO/01283 188 OOo0o o - o o 0 oi oo0~o C04CCD00 rI 0 0 0 0 0 0 O 0 1 I(\OO q o OOOOO wO N OO 00r- 000 OOMOON~OC.CoOCO)ONOO a H O c co o o 1-4 0 1aaN00NC coOOoOOOCOOOOOC LA OI0O C4001oiMDOoog Hon -4 OCD No OOOOO r 0OO 0 CC ;r C I 110 C ( 0 - ID OLAO I 0 11C . OCDN NOO0 0OOO, o)oo N. C I oLnocad I OMClomI IMCC) N, H H 110 -401 t .0T 0 C) 0C D0 )0 00 m o o 0n V CNO) 0 CDOO~ I r- oio C'J ni D omiimo o OH H 0 0 H CD- )N D00 N CD M.0 N0C "v CC C COIC C0 0 0 0Coco000000 0 :v 0 0 M C D cq C CD M C CD 0 0 M L i - w m c co coLn D c m i -'l , CD0 C 41c D CQ 0 D l0 1 D a C 0 w ICl > > 0 -z H-: n0 C0 Nn LA C~~ I ~ ~ OC CC C ~ COO~wC LA H Ln H (0 0)0 0 H- 0 2 H a U 4 )0) ) H- 0 C 4 (1 0oxri 0 ) 41U~~f Rs to C) 12)10) E l x .1--14 t)0 1 - - w a) Cl-1 4C )F: 4Q ( r-0 44 0)0 -) 4J C: 4 (04~ co r 0 ) (a (1 =;t d) 0)H a1) ()d PH 0. (a z 0) U) J- -H0I) 0 -1QW) 4 ) 4.) a) (L) -H->1-1 4.) 1 )ED1-) -H () 0 H0f ) ) 4 (tU ( 00- r 10) -4 a) Id> Id 4 4.) U -1 r ( 0 U (1d O4 4J 00 0 4 I-0 T) M Cd o0 5-H0io j d ). -r 0o a 0-H (d0o *Cd a)Hio00 H0 ::1(a ) H *0 0) u R R 414 4MMMWUUUZP WO 00/43377 PCTUSOO/O 1283 189 00 0 OO0CONI OCNiOOOI I Na-400 0m 0IcJ4M Cl . I c.lJ (N 00 co 0 1 00000 1 ac,4000 I I1000 C I00 1 0)I Ch C0 0O I 0 0 r- 0 100000100000 l c~co I 10 00 1~ 000 LA r H CN H (N 00 a 0D I CD N CNO C I 0 1 NHOO Cl0 I 1CD0 000 N- N- 1 C CD00M I 00 C) m C C 0100000 1O O 1 IHOOCO ,fl 1 I(N 0 c I w en (N 0D I00(NO4c:H I ow0(Nm I I momoo in m I W Jl0 0 N 1 0'1 CN 00 C H 0- I CD0( l ) v 0 (N00C)0 1 I maCN 0o 0 cz 0 I (N400m I 0) H 00 0 0 IC)0 00CD0 0CD0CD0I1 1CD0 00CD0 M C m NrC'Ja0N I HH 00 0 CD OIOO) OOO I OOooO I10000O O CN r1cqk0 (N 0 co (J0 I H (N 001 1~oo I N o o I(N 000o0 H 0 11 I10 0 0HI o H (Nm 0 9HN 0 10 0 0 0 0 0 m 0000 0' C, r000 I ' a 0H 0( 00Q m r 0 I 000N I0(N(OOC I I CD 000CD0 a4C 0 10Va00CD01 u (N 00 LA 0 Imoo )C 1 I0 H00 N ICDmoo o N DC 0C C 0 ILA(N00(N I 00 rn 0n C I mmCD ooC I10 -10CDm I I mL H O 0 0DC1000001 n D c 00 m~ 001 CD tOO0 I 0,-bOO I I rn0U)00 q0 LA 0) I CD HO CDI0 H (Nq 00 Cl M 01c- o:C IOIO HO CO I 10 00 clo ~ o 'n 01 0I -1 0 NI co 0 00 Hl OI O OO O OO I1000001 CO ) I (o c 1 0 100 i00'41 co 0 00 r- 0 D 0I00000I0 0~ 100000C I(NCO CC 0I1 ac\I0H I 00C C C D 0I OADC00cNI0Ifl00CI IH O O Hl 01000001oi-* L ,4c No 0 C) 0 0 1 n V di 0 N 1 00 0 -iC n H o 100 0 r-4 - In.-O * d 14IQ) ~ ~ I a) M Id rti 0 I-d) 0 tI~t0 ro U 4 )M fd 4.) 01) 0-H >,4A -) i 01C ~ I 4-) -- ) 0 r-I ) Q(D4J (1) a)--H >4J A4r- 0 (d Ho In U~d ~ ~ 4 Q~ >,nJ 0))4~ (1 Q .1 4 :r U L 4 )r4do>f - )j) dpw u 4 z4 Q) -4 4JU) 4 O * d ) 0 .0 0 d d Id-.)04 '0 t)~) r-H ~ d *Id01)H0O O d ( 4 r 0 ( I - 4 J-q 0 d a)-- ) ( d 0 .( 1 - 4 WO 00/43377 PCT/USOO/01283 190 0o 0ooom IrCnNC 0 LA OIC 0~- LAoo 000OC,40 1 -ocvDfLn 0rn000l Imoc~oo ~401000001000001100000 cJ wwo0 mml rNN N~' 0 0 01r - j 0 0 ~0 0 o r I-:v--iI 1 10 H -00 4 *j N00 -00 1 1 r -:p0Nr- tv H 1r0 - 0 oL 0 O0 Mlm 0C I m0 e0 IH cj0 CN r-000 r IH00. 0 C1 NCH 01M 0 - ~0 0 N 1 0 0 CD0 I I N-I0 rI0 0 r-0000 I I H00oolc\1 N 0 1 IN 100a0 I Hen 0Ca.m I I HOM DC CN 0;: r-0 0 -1I I H0 0 C0 00 0100CD0 00,O1inMCDooog 11 Ic\JH0 0 m m CD0 k I I H 00 tD CN r C) 0 140 000D0 1 COt.M00 I 100 ) 00 0 . D m00H I ImOCO rn0 C 0 1000 0000IO0ooI I100000DC m .0C~0~ -4 CD H0 J0D~C I ~ C~0 I I m 0 Cn 000 00 u u 0m N )0 IC 1 1 O O NN0- )CD C 0 NC 00 I) 0 CN0LflC I I -Zif 0 CDC)0 C.' 0)CN000 m 0 00 I W C DC CDI OOOC00 I O N000I I lc>C0ON0 CN. CN. CN. OH O In 0 0 11I 0m 0 1- C r o N( 1 I cm0 C. 0 ~' f 0 0 I I -- v o0 n0 C... 4-J 00C H W II (-T a33 (0 0 n L C-3)cl )1cok 0 1 L Md (0 - m O0 3000 11CNmHC (0 m30 4-3 LA rd U d (rn O 0 (0 o30 4-3 * pro 4--0 0 rq 3o a 4-J 0) M3H,43~ 0 -. 0 .43 0 H3044J 0 X U3q 0 a) 4.)~ (0r~ H 04( U) CD M~b -1 U) 03 -I co~z rd x 4 a 0 r44 3 )) 4- . aU) -4 (d r-3C0 L i dc O rd( d ( 4 4- 30 4- 4) (L) ) 3om -HO 10 0 ( ( 0 - 0*r.-M (d.H Uda) O (d03 OO . Or 0 3 0 (d 3.4 4J d WO 00/43377 PCTIUSOO/01283 191 N, OI 0 O 0fn I CN r0 0 0 11M I' -I M C-4 ri NIe0)C 0 ) 100 cc0 w 01 w3 co (N (N -0 0 I1 koM 0 0QC IC 100CD00 D I I (n -lOO CDaCD 0 0 1 0 CN,-~ Iq CDr)10OD w3 H 00 (N (Nq 13 co (N 0 1 10000CD l0 LA00CmI I m 0 -10O LA o01r-r-00or-i0o Ao (N (N H- OS 1 OOODOI10 %D00HI4 l1 'O O CD 0 1 ko (N0H~rI N0 (N (N4 0) 0 I 1 00 00 1 I mo 0CDm I I HICQ -40 0 m~ 0 I LAr N C) H 1I 00 3) 0C I 10 N 0 CI C)r-0 0 wI I -r q1m 0 (N cDi r-Ln cq o oi0oN0 (N (N 00 1 -r-C ~ N 0 (NI1 41r0CDa NII I LA00 1 HD V01 -4 C ICo co I omo: LAq cca N- 0 10 -10 CD N 100(Ncq01 ICN 000 0C 0I100000 1000O C14 cci Ln (N (N 0 1' 0 31 00 0 C)1 OO0 0 N I I (N00D0C0a r r- i occ) o io Ln i -,;vcoa LA r (N ( N (N (N N 0Ic nc)0 3 N 0 C~ o~0 0 mo OIvOCcNoO.-i ) c o CIOO(N100 (N C14 01 0 1r 0C W 1r rIO'C)HQ0I0131 1 ION1'O,00 mN 0 loCD C oC olH o C c (N (Nq 0 0 10 N-100 0 0I o ~ , 1 10 Dti0011 004c o H1 0 1 CCN1 C) CD1 0rcc0 (N (N 0) C OIOOOo oi C10C )C l0C 00000D 0 l 00000-I1 000c CN (N (N (N (N] 13 0O1 % H0 0 1LO 0) o(N I I M0 0CN0 cc 0 OIOOOOCOCDIO1( N 0 -H 'd ~I ( 4- 0)d U). 4) ) 4 f)4. 0 r- 0~ ) 44I b)HU M -1 0 CD~C2O~0 (52 52)0 n mr x 4 ) ) (d t D0)2i0 E) o X 0) 0)(d 40)() 4 0 : d 0 (~d ( 44-) 0 Ej ) ( t4M ) 4( z1 a) L.) 1 4 )H 0) w 41 -4 ) 0 r-q ) W J 0ja - ) 4) -H> 4 4-1 ?CO4-) -H ) fo0 -Id (1) r40 0 :5-H 0 : d a) H - 0 ;J ) -H (d (d0 (Id 1- 00 4 -ri0 WO 00/43377 PCTUSOO/01283 192 0 N I I C Mcqr-m LA oi . 0 DLn o -vL i * 0o o, IrICoOC N oo 0 H OCD~ I I - 1 00 00~ 4= 0 1 L OO H 00oc .141m m I Iti 0O C 0 LN A 0 qr- 1 1IO-0 0 ror-M 0 0000000 C 00ONI I moooo n C0 Mm LA~I IC~~e. H 0100000l0c000I lir1000 m' 0 HM 001 -ChC )1 0r mrH0 0 I If CN o m N~ 0 M M ~OI I~Ll~0 Cm 0IO00000I0C 000I lC' 000 H 0 0M VMLAI IL NHOO 00 00D0 C)~0 1 0 0 m en 001 Io-oo r- 01 000000 0 000I IN0000 N 0 MM 001 I H0000 %D 0 1 00000DICD IOO~CCD I I NO0000o 0 0 0 C 0c' I I McoOCOl dn N 1 I ao I CoLDDONW I I .00I. C H- 0 m 0 NI IHO C N C) 10 0 I0~0 0 am O oiioocoiomoon iLooooo %0 0 00 1 OC' : m aii Io Iil~0 Nco c 01 I0 0 l00 Im Oc~o p~ 0 001 ' I . 0 004 ND OIoooOOIOHI IHacl 1 n-OOCO a i 0 001 o000D0 0 H C 0I o 0 I OO0(N0I1I00000 . 0 O CC) M C M M IDCh CN D d U CN M ON I I HOCDO 0o2 O c o oc12VXH oo lm oc 0, IDD o Id o.aco r- 01C00CV 0 rdal.04-3 0 m o)I HIDI 4 Ioca w 0 1 COD ID-~4 ~ 01C4.-10 0a HI D- ID -lo aD-H 0 d ID- M0cDrn-H n n ivmd0o *IdI H00:-H0 I I -H .Oi ID.cnHd d WO 00/43377 PCTUSOO/01283 193 Ic.3OmOi o oo oo ol 11 00 Ln. r- o00CI tr o i I100000 1000001 100000 0 nwc DwL >coc %D I 0000OO I 0000mc I I CNOOOCO 0 C C 000D'. CD-'0 0 00 0 LA m I 10000 1000001 100000 0A 0-i a% o coo0o v 0nco -o0Nv00 LA I0 0 0 0 0 0 1lo o - -IO O jO O O to00 c 0~ r 0o N0oo) o o10 LA m I I0000D 1 00000 1 1 C-.3000 mn C>0 0 % CI '0cqC I~ - 0 CD~ I LA LA Ln I 00('.300 I100000q I I wo0000 r-I cm I CD 0D0O.O OWO('.n0 I r-0 0 0 -1 I C)N00riv I I Lna 0q00 01 0000 D000 M00 0000C)cqC I ~0 0C'. I -~ 00 I ('~ A000 ri 00LA .30 ~ 0~ 0 30m 1 COLAOO I OmOOOD I I r-ic000 04c *w C 0 C)'~l0 N 000.'.D 013 I I ~ I C)00 D10 0 1Id1 N - 0 CD CD~ 0 n O > aco o a o >I -V3- 0N-1 rC4 -H 0 M IIlvC000 tv 0 0 )0 04- CD 0)H 4)- tCl4-CD 0 C 0 i o o o o c - oc D- n o nc4 o m c o- qc I 1O W~-~~ 0 )r q000 C nNcoc Ne nc
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WO 00/43377 PCTUSOO/01283 194 i Ln L o0oD Ln w I0 04000)I 1 0001o I C' 000e 0) coICQc 000 -::p 0O0 N 0 ,rr DI COC\ Oo I O)OCO I I mooco 00 0110m 00 0 rl) -0 0c Ln 0 cq mLn H 0 1I0000O I.ooco I Zcoooo wn 0 11 0 000 0 NmO m 0 En H I o000o o~ L o o I 1H000I0qoo L 1 1 l 0 00 0 rlM0 0 Mm 01 0 OIOO0 100 ) ' CD0 oI IHO O -- 0 ml 1 0 00 0 IH 00 - Hi000 C) 0 c oo Ir~~o I OOOOO>mOOOO, 00 0 r- O I I I %D rn N0 CD 01 1 0000 10000c) I100000o H Of 1 O r- ~ ~ O4 0000m r C C 'qc I e 0 oe Ic.N00 .0 11;pH Da r C4 0 1 m N 01 N, m' 00L m m~ -4. M I W D0 coI C) -O 00 I m C N O m a'.0 0 0 0 0 0m N- H- 0). M m C) ~ ~ . HN C00C )C I'.D0C N"C)0C DC 0C ) m C w Ch m M N'.w0 0 0 0 0 1 1I I00 acoI co.0 0 0 1 IH CD N0 HCD1 I "OHOO LA 01 0 1000001o oc o licJ00 0 LAI 101 I. 0'M000C 00NC DC D D0C Dmo0 DC % oi. '.00 I N 0 00 C H I -- N N \ cN Ln I m i OcD '4q I w .m m LA -i co c I I I rn M b m 0 mu0b -&- (dt~ ca *'-. 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I'D 0 vw I I oW LnWI1 0 c) oc,4 o0oL i o Ln LA LA LA LA LA LA LA LA on c4 o\ o I O cr% i c i mo i IL zvL 0 c),r r I I I I cq0 m I Oh r LA LA co m iik )l ic or lW ' O Ii0 N ILn co-I oc Clq o0i0a0oc\ Nr-i -oLn 0 M LA LA Wo 01 1ILA C14 0N-I en0 CN0I11vk ItCqcIQ0 I-q 01 00 CN 0 m ICh 0 r LA LA 0) CO ! 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Iq c, cI i oo '0 in ito I L c) o m 0 n0I 11 110C)00CD LA 01 1I0C .1q00CI C) -00'.0gw I 0 00 q*CDC O0 LA LA C)r I I - W C) 0 CD -. m I I q~p000 1 r- N0 0 c I i L C Ij rq N LA LA )0 011 l%:v 00CD00 fne - - o oc ) AI I0'OC0LLn i i rn 1c'10 '. o LA LA 0001 '.0000 (N L i q n -r - JNi co0oLn0 a )i i -o w r- LA LA LA LA LA 0111II q I V I 1 0 w Dr ~ nir Nc)"o IN 00 c" m ' e LA LA LA LA 0).. ZOl d U) 0) 0) 44 a 0 Ea~O U) .)r- 0 ~ .1 0) 4 4- d U 0 ) ) ( CU 0)0 ro x 41 O0 0 CD 0) A 1 0 (d ldQ -- ) 0 E m d 4 M ) ld (0 r. 0 (d (a 4- 0 0) 0 -1 d) - W4J W) 0.1-1>1 - S q D ~c 41 -4 0 r-0~0J W) 0) Z) P0 4) CO CO~. >d :9 Ed-A C4 IiMM U) U U) C) 0 : zP U) En V) 0)xQ > 2: UR I E-4 P WO 00/43377 PCTUSOO/0 1283 200 01~~~~L CN010 Irooooo 1c40000 L I N 0 l A. O O m mN L ncooo"i o N o0o Cn I i n o o oo m 0I I CO O0 INC r 0 OOa O C 01 ,ooLnir o00cIo4Io i i~0 0 LI 01oc oaI110001 IO-C'CD00 I'D 01 10000 1000001 100000 C 0 01 10001 1I0.CNOO0 01 I0000I00,i0oi c-40000 a- 11ca IIO O-404000 I'I I~(~~O 0(~ ~ OcJ~0110000100000loco 0 1 0 1I N O CV 0 11 o I ccA(I01 N4 0 0~ 1 I IL4 CmoO m 01 I00000 1I0-l100 0' I I 0000 000 I 100000qr I' rr qc D CD4 I1 0000I 1 m)CO ~O '-4 01 i 0 0 10 40 0 -4 00 LAoa -c oc m iiiL noo r 0 1 1ICD0a0CII Dr-00 0 -I 0 1 1 0000I10 04~000 11I co o L lC000 1' O CmO OLAq4 W-000 0DI1 0000 1IcmoOODI I enccoom00 oa~,4 o i' I 0 Io~coqmnr 0 0D11VC C) I4 10 D OLA 1 0 cq I I m0CDLA0 0 Oc rN I to 0 0 0 0)1 I O 0 0 . 0I'w 0D I I rn0 0 1 1 0 kDCooO I I WD0000 0> N I -vaO.c~on I MO~LnmI' -i %'D 0 ~ o o m i co o oo I m (~0 0 i' LA v v~N ' v qc o iiic -i r-0cc)Ic '. H 0 %'D N I D' NC'.I'D I O'L o r-(' I i c namcc) N C) I I IDO00M I cc I000 -40 '-A N I I n ~' LAn r or -c I iN -q r, w -v ~ ~ Ln LA 0 1 I 0 0 0 - I CD M Q0 0 C'D -40 4 c 0 >4r4 a a - 0) I -A Mo Ii)4 U r x (d ro -4 U) (do~ 0 -)EI1 ) 4- r 4dr) ( l E d 0 b 0)o (a 0) a)' a 0 0 ac 4 4) 0M 1 4 3 ) 4( >10 t-H Co- - 0) 4-)-1 a) 0 d -40) o(4-) a -rt- i4 q 0 En 4-10 -H ) Z M-'4 r Co Q Co'4 . X M L 4 ( (d r) r-4 Co 00-43 M ::M 4 Z Q '4 ! 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N r, 00100 ) I cn %p0 1 InI I N~~ in CI r- OI N 1 0mmN 11 a0 m II m co0 0 m I w0 m wI I -v0 w0I N4 N NI I COON I 00comI 1 0 N 1-4 mN a in r-i ILA Ln o w' NI I ) a) I r-N inAo0)I 1 1 0 000c)D l l~ o I ImooCo mn InI I r m nI cn-0 %. aI LAi 0000Icma~OOoI NO cio,- N o I I inrn dnI m , vw I ILAn MC';O n I L000(n I I vo000,-I w- DI tN(N00MI %mc'.1o)I LAI 0 rNC0"*W 'COO IO0N I I LA0W00: a 031M I1 0 00 W I CO 14 ) C C I Im 0 r co v H a I r n r-Nm I I I ;i0 v 0 N H 0 10 0 000C 1 00 0 0N I 1 0 co w O0)0 0coIo m N 00I 1 1CO4 OCO 0 0I10 0 0 0 -4IOHOOOCI00 1 0 co w oo0o coI IaCl (Nen I I N O C O 0) 0 1O0000 I O00 0I I-IH 00001CIHaO1O0I 1 00000 r- 0 10a000 0 1N 0 0 0i I 11 0000I(1- II 1 00000 N 0- 1 woo0II WNO0m I I1 N0000I o 0 N0 0 1 1v 0 a000 Wn NoI %DWOOI 0 I m C400r' I I In H 17N w U) I~ U) w) U) 4.)0 14)Ul M 4 ) U 4 El 4 wrlXr4 0 ) - d () 0 0 Ab U) O4 U) U0x1- ) fa; nf )a o a ) 41 '-4 V4 fu(fl4(a0 n a U)tI- Q) U-O) U) q - 4)X- 0) U) J 1) 0 4-A (d CO r~t U)l w U VmXq(d-444 tMt - 4U) b~) a) I 4(3 z10 0 3( 10 .- 0 E 0)(13 O U ) (L 4II :V 0 (df A4 -q tU)En4.-IH) 0 r-i ) 4 )J U-) (D a rI 4 - t)l En4j -1- () 0 .- 1 U) UO-4 F! rQ 9 :r U) (L) 4 (L)~ rx Q ( > 111'0-1 Q) 4J) ul U) u 9 U r E) U - ) rl Q)z M ) C d 4)0 O U > mr 4)1-4-jU En ' d - ,r >1 WO 00/43377 PCTIUSOO/01283 203 Ic'pm0C - CNI 0 1CD0000C0 1000D0, C)aooIIoDoDa '0oOmLAO0 0 N v kI 0O I m Q 10 %DI 1 '0 N rn cn C w 10 cq 0 0~ -0 CN I I W NO ON 1 00 100 I r, 1 LAOMN0 cq 0CN~~0 CNr N C r' I co I CNI0 0 wI 1 '0 %D m o1 0CD OC' - 10 CO I [I cLA-I O 0N 0 wC I I r')MC) 0 0 OC 10 0 0 1" 0 C) rOO I r- m0 CN10 I1 0 o0 a0 00to CN -1 4 0) w 10000- C C I CO mNaO DC I I rn 0 wCD0 10 NCI~ w o 0 w 0 co 1 0)' v N~ 0 0 c' I I Ln W 00' 10 0CNI m-I r- o I a N 0 m ~0O Iq o nr n i i o WO Na LA Ln C zLA 0 r o0r 0 0 W) r C ILA 0 0 "D I co c 1001 I ;:p n 0[AD0 0- 0-1 C) LA0CD ~LA 0r100 CI (N ICN loc l00W CI CD V I I w m N J00 0 LN I 1 f0 0 LA In 0000 ) mWI mIwC';Pa0Oi Io)L O wNlL~ v i inomoogD ai ncq o0o N Ni 0 0 0 0 6l C I~l ~ 0OI ~ .L 010~ IL ~ rl0 ~ W OI~lNa) 0000 w tm I- ca 00 4I W0 W I I0 EOW 00 f 44 I M N $ J 0w (d A >1or - 0 W I r-O 0C J~ M~I UC4l 4W X 1 - 1 0100001 tmr- ri Q W ) 4rO (1 U iM U 15 4-W rO U tmr- a rA 0 a 4 0 N J ~ N 1 d0 -M W - 4 10 :1(dW-- a H ( d0 fJa M :E P 4 QPQC C UUM Z0 4 nCnE > : p14 2 MMM WO 00/43377 PCTUSOO/0 1283 204 m 0 0CN 0Or- nO0DLA 0 00 00 m~ N LA r- 0000000000000000
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C9 LA cq LA LA r-owoooooooocooooko LA CN LA LA (NN w0~ 0 w -0 00m0m00-10O cq N Ln -fI oooo0(N -WNO( L or-o-oo 1-1 (NI LA (N 0) N ( 0 c r- 1 00 0 CN ) -C0a0 co -4 iv -4 v4 I~. I0CA00CaN-rw0I0I 00000W LA H M CNL 00CD011 IOlDO Ln0 DC D0C )0 C -1 ~0" 0 r-i cocc OOIO'.OCOOCOOOCO 0 N o co~0 I) Io ICC Im 00 00 00 (n ~ ~ ~ 0 00 0 0 00 0 0 0 '3cc)IICDC lC NIr ccccoo~cco w c)C) r, 1 Iooo %3 10NI' 1 C.mencio Nq ICN I CD 0 q C I I '.0cq 0 m' mc c o 0 ~ w c c 0 . a 0 Cn C00M0D'D mco0N0 00000 a , D 1 01 00 0 100000IC OC OO C OO-4D IO I OccDooo ooo M a) I~ U)a) .H >1 a ) d4 a)j rd 0) U) I I 0 )lL 4- 0 -i Vc U)'I4 ) U) 4.) 0 -1 U) 44r U) r0 Ox a- ) 4-)(1 U) aW - a) U)Ea U)X x, -1 0 )1 ( U) C)a) (n a 00) ) U) a) a) 4-) LA 0) (d :rd E U)0 )a ) Q)a) 4-) LAO)m 4( V c 0 (dt (04 4) 0 a) 0) W -i MV Q) 4 0 o r -) 0 a 0) ul4.) -A a 0 r-I (1) 4 4) a) E H- ). -4 -I t)4- -Ha() 0 () a) -) a) (a U) Z a4 ) 0410 u~~ >1 0) r '0 )) rq ) r (0 0~ P M Al U4 ) 04r -1 0) -1>I~ 0) Q4- ) -O:J 4 .0 V 0 1( Q H - 0 )4 1 0d a) .0-Ja V 0 0 ~4 0 CO a)0 ::a) 4 0 (13a) WO 00/43377 PCT[USOO/01283 205 OOOOO000000000o0o o CO.OOOOOOOOOWOOO co OOCOOOCCCO 000O0o wo ~ ~ O O O o ~ o coI OOOOO00000000000 Ln 0'OLAOOOOOO0 coO0O coO-oo r-mmOOOOO0000 Cl 0 OOOOOOOO0oOOOOO OOOOOOOO000 000 0 CO 'CO coOO 0v r-C 01eq0 -4 -I N OCDN0CDc 0 C Coo N D -0 C 0000C 9 D D0 0(0 0m0D0D0D0D0 IV coo 000000oa moo 000 Ln C -000mC D0r.0000c H r-- N 0000000000000000OC v 0a 0 00 LnCD 0 00 0N 0 0 0 0000000000000000 ml 0000ocoo-00000 Ooo 0000000000000000OO 0 00 0CD0 0 0 C\a 00CDDCDDCD0 0 o 0 0 0 a 0CD0 0m I CD0CD0CD0 00C00 0 C:) 00C0CD00CNo0C)0 000 0 C C Hi H H 't0 H H 0C)0 C)C0m CN 0 )00OCDC>CD0 N- CON.)O0 W a000om0 D0 0 rnCDI' 00C0 000OC ' DC)C : D DC ) qD ) C '0 q 00 0 ~ 00 NC) 0 0Da0 rH to N000 N I r-i 0 0 00 - w1 0 0 0 c ~ 0 0 0 c 0 W0 c) 0 ~ o0 ~ ( 0 0~ H ul -400 O 00 ,40 A (d 1 '0 fdr UO U) 41 0O H )4 .0 )4)0 - )4 CO w HU - 0 g. (d W C )H )CO)x - d u 4 (04 t)t3 .).r40 - dM N -H CO4. Qe (O 44-M0) *LH 0 a)-i d d34 0) 1-i r a 0 IQ 41J 0 a) M W40) Q) .r (d Q ,4 4 0 .H -W -1 0 O41-,A 0) 0 ) 1- ) 4-) )w K 4 - -- H 4 r4 03).H ) 001-l a) 4J a) MO COU Z Q .F:M 4 0)~ > 0 rOH )C O W W WO W U 1 r w d>A (d U 4( d J0 O > )H Q - ) rO ( 4( d 0 0 C mria r- 4- 1 ( )0 : )4 -i( d 40 0 r ( )0 ) ( WO 00/43377 PCTUSOO/01283 206 LA MOOOOOOOOOO-0OOOO M CV MOOOONOOO- o o.:a H M- H M HHHrI rA- H -qr- 0 C\I IN 0ON-qC o~~0 000000000000000tOLA H -- 4 'A w 000000000000000 Hv 0n 0 w0 H 00 0 Oi 00 0 0 HH o Hn 00 0 0 CD O O N OOOOC~OCC\3)O000LAOO0o H OO OO0ONOOecooOco co m oH nmoooL nmL 00 H a4' N 00ooao mo) oooo0o0o0 o C..' 0 00 OO .0 0 0 000 0 00 00 H 0 H- -00 0 00 0 0 0 00H qr 00 o0r H0 H 0C.' 000 0 00 0Ln0 ) q O O0) H H m 0 .OOOOOOOONCOOC. H4 H ": 14 0 M% c 0 0 l 0 0 0-;r H - -1H H H H '0 000 n0 H O0 r0 00 0% 00 r m ON~~~ ~ ~ ~ HHHH HL 0 -m0 LA m '~j'0Co 0O 0 .. '0 C ri H0 no ic c )oaa0 )r wo H Hm u 4 H H H4 H H HH HH HH4 w W 4 X - 4 ( ( 0 0 rq O 4 OX 4 4 -)H m l 00 O O L o0 t a0wa) .0 L 1 ( ( :s w 0 a 0a N 4r 44 04 )tD 4 df 4 H. H4 HQ Hd LA O0 O 'O0 'sOCW H a)M 4 W 4 r r 0 (0IQ--) 0 ) 1 4M r H H H- 4- OLA 41 -,1l0 0 w .~j0 H) - - 1 - 3 W-4w 0 £d U4 ) H 12 10 Jf ) 0 ~ U3Q 4 d ) rI6 q 4-H 0 cid )0 )4 iX a4OQ DQM U UU 0 X2; P W W W> -c R: E C O CI QMUUU02 ZWWU )> WO 00/43377 PCTUSOO/01283 207 0q w No0no00r00000000 00 IooocOOaI00eoIoO in N v r-I v-I CN V OO0m00%DO000OO0000 r- om0000 o000c00 Ln r- 00, -* 00MOO0WC'0000000.0 wN N O 00 0) 0 0 0 0 000 L-A N v 0 M1 o0m 000o000o00o '.O 00ch 00d,0000000 v-4 Ln
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v-I v-I r- m r- H w. v-i L 0 0 Cn0A0 0CD0 0m 00a0 0 ( maCD0CD o Ch0 0 0 00C o C a 00CD0 Lnm 0 CD00 CD0 00 CN~ L m c>c)00o00o0 oooLv C> O) 0CD000CD00 000CD00CD00D0 v-A mooooDOO ILMOO N qvI ~ IvI .I o w. 00 00C oc 0 c 00 C 00 C)00 C q C\0 C00 -0N000000" Q4 i ' v-v-,- v-I T-4v- vi r -I ko. v-1 w ~ r-4r v-Iv 0 0 0Or-I 0 v-I u u LA M~ c4o L I 00ocom jD D o-oa m0Doin LA )0 0 0 0 C 0 0 z mv w w 0 N CDC 0C O000 CN LAO0CDCD0O0O0 O0 0 0 a000CD00CD00a00D00 %D0 v-I CD ooo m moooCDomom 0 DC 000C M*1 1 , o C 0I 00N w 0 ' '.0 -1 'A. 0 - 00 wocic - Do- Dc 0 00C DC Oi M~ H ~ 0 0 ~ 00 1 A . H- A N 0 ~ ,l 0 H- - . 0 - r-r h0C D0 D000- -Inm c D00 DC 0h w n N NNG,00-0coo00m oa~ co 000 00 00 00 M-U -4 M-u LA r. m'l.0 0 00 0 00 0 & 00 44 OOIOw -10 0 ~ W C M) l MC W Cr)o0( . ) )W 4 z1 aI w = -f41 MC -wv ia 4w 4)r H. S -I 0) .0 CCq C W CC M M 4 - )r- 0 C - 0J~ CC( ) : 4.1 0C -I )- CC4 C - 0 aW0: :R: E v4~C C)C CJ CA)Q~I CCOQC UC) > 9 R - .0 C UUU0ZZ WO 00/43377 PCTUSOO/01283 208 000 H OOD 'O~ 0ooooom 00 qrofom00o~o 1 00 0 00 0 C)- -4 - rIC 0 n00 co 0 00000 00 C D0 0 00 Pr D00 tnco, co 0 H C 000 r.D 0000000000000000 D Co o 00 0IOO IDC 0) N H H~ 000 11 Ol 00OOC 0CD00 0 C 0 a0 Ch- 0cc00cc00 ko 0) H H 0 0 n C m 0000 0In00 0 CD00CD0 C0 CD o 00 %D D0 aN r-i rH H CN H) HH 0 HH H c 0 Dc Hn C )0 om0C 0 CD 0 0000 0000e w' 0m0C>0 cor-0I0 0 D H H wOmOH 1 0 000000000 00 q0 0 000e -0 00~cooi~ o u O H C 00 0a oc0cD 00rl000000oo ~ o oN LAON oOmLvOIOio L O 0 H cH HN 0c 0 r-CN f 00000N00000)C000 0 00~t0COMO0CO.1 Ho Hc H 0 00i CD CD C 0CD0 w0)001C000D0 N0 m00000 OO O OOOOO cc 0 000 cQ - i 0 0 0o o oo ~ c, 0s ccn0CD0CD0a 0 ro00-00 CmCAooooo C cc 0H H CNJ 000 H 000000000000000ao D c c oo a >0 m 0000 00 00 Ho HCD cc 0 H w ) 0)~wU H U)H ) C 00 0 C) C o oo Hc> 1 DD O O CN c wn ow - c 4I4 0) .- 0 -1 U) 4-4 r.) tm t 41J 0 *H (d EO C) a H U) (1) H -q 04 J0 U) c0U) HI CO U) n UXHr a) 4-) Lr )( 1 d U) 0 0) (1)WU) 41 - 0)s :( j E 0 b)O a) (d) 0 (1)M ) U) Q r d Z O ) 4 (3 d UH Q)Q E 1 4r 0 C: 0 U) ) 0 U- ) -i a) rO.-J~ (d k 0 ( dU4) Q4O$U )U. -4a UqQ La) '0 (d 4(d 4 4-) 0 r Q) '- d d )H 0 0 40 : (Sa a H ( 4 Q - 4- : d a WO 00/43377 PCTIUSOO/01283 209 00000 I'D MOW000000oooooVO'. co 000000000 OOOOcN un co 0) 0 Noo. I-m0 0 0 cq oor- 0 00eCONeON Ha%0o 0 0 0 r-I -4OO O O o o o 1. 0rO400LAI% 0000' I'i 0000 00 00 N00o, % 0 00 )0 0 C W0 0 0 %D0 CN. 0 0r-0 0 ;rr - oo . ow' en~0 00LA 0MI o .o' 0' L 0 O0m00 -4 l r w. N~ - ,-00 l 0 0c: 00m0 0000000.~n N 00C q0000q 10 0 0 ''000nCON 0 00000-000 0~ C.. 00C1.DCccc'00C..'I0-io0 L mo 0000~' 1 ~ 0 0 O00D.0- OC CO O COlm O 01 O -l00LflO O CN. 00000 r- OOOCOOOOOOO mOOOO 0 mocqoo. oo 0 C0C\ N 00000COCOICO1000000 0i C000l I O0 m Ln LA C..' 00 000 L a 00w00C00m00aI0 -0-di N C0000mo cor'.co.' o 0 M Un 00 c C. C .. 'A 0-0~ 0 0 0A00CD M OD O OD rn 000000'.00 rn LA C..4 CV. 00000 0 .- i ~ r co oo oo m 000100001 M LA 0 0 0 0 0C00a0CNC00Ca0 C0C0 00 C.H 00amo0mo0 I C.. C.. 00000 co 0 00000r M0 0 000a000 a -a COCOI000l01 C..4 LA C..' CV. O O m r 1a o oaoooom Nor 0I 0 0 0h0'o 0 001OOO OOMOO N..H v-4 T -I H CO0 C000 LA mooC 00w 0 mLA.0- N 000LCCA c C 00.'C.00 N'. C..'lr -Hi M 44P J0 ri U 40M E 4J 0 4.) ~ ~ ~ 2O0 rd U ) )1U0 aXr- 4 4) (d E ) - ) U O 0) 4~~~~~ ~ ~ -0 0 Q U 40)()) .r 0 .'.QSJa) 0 W 0)0pC1 ) a) 4 0r W 4 0 - L -- J 1 - 1 H 4 L 4 a .) 4 t H 4)A - m- rIa WO 00/43377 PCT[USOO/01283 210 0000000 1 roD O DO 0 0m n N0 0 ooo o o )O Om 0 000 CD 0) 1 -4 0 N~f a CC )0C N 00 -00N 0 0 000 00 0 r 00 m C4 O00000 0000 000 -.1 O 0 0 0 0Ic ( 00 00 (NM 0 00000- , NL 0 W0 In O~n 0 0 00Cm 0 rCDm 0 n N C ~0 CD0c 0 0 0 0CD00 0 0 -C I I0 C 0C 0 mN C) D m0 0 - C 0 0( 0N(0 (N (N CNM C) 0 00 00 D M C) 0 C-4 0' ( 0 10 00C0N0 00 N O 000 0 00CD CN M' 000000 0 00 00 0 00 00 0 Inc )wcao -r Doc n r 0000N'coo 00 (N m0000Nm0m " 000 OW 0 0'D 0000Coco0000w C 000 CDC.0 0 OD 0 0 0 c. C)ok n- n 0 )0 0C )C N D0 0C )0 C 40 0C N 0- N- C)4 0 D r DNr 0000000C w. O O '0 0- c.0 o ~ s I 0 0 0 t')~ ~ ~ .- 4 0 (1 N11e 00C r4W( 00C )C 0 00C 0O CN 0n H- 1--I i H 1- r N- r-i -4 1-4 ~ -4r-1 0000000 C 0 0 00CC 0 0000 0 00) 0 0 0 W CD0 00 0 00 0000 0 -0 W0 M 00 0 M 0 .~c c I )-z n 00C) OOOONO C W -4 0' 1M (d V a) lt ) HO Ea Cla) (d a) aIC)j o 0H0 )44 r Cl) to4J~e- 4J~1J-04M 0 1 4-)4. 0) 0) U) 4 C 00 4 J) )0) 4 3) ) d r.4 * W 0aH 0 (04 -W 0 a) 0) 4 0)00 -,4 0 ) 4 )4- W Eu uI 1A4H ) J Zr Q Q c 4) ) , A) ci M - WO 00/43377 PCT/USOO/01283 211 oI,,JoO~m.w 00 0000000000000000 c'q tr-00ooc OIONO0H0ON O00C0000.00O0O000 H IM00 OOOOOOQC0o '0 OOOOONOCOOOOOO O~ 0n Naoc:I M MA 000000000 m' 0000000000000000 r- WLDa000 M Ln H w0a0cq0r MDO COl"000000000k. mn IO~ o oo o o o aN ' O0 m Mn m L 000000000 ) C ) D0C 0 0aC D L Q 00 LA m Am en LA m m 000000000c 0 0000000000 0000 I O CO 'lr L 0r-0mr CN Ln mm 000000000 r- - 0I0000000I0r-0000 I o LAIN M > C14 Ln Mm 00000'0000 o'0 mi I NloO c0a0'000 0e' 0 C')0 o 0 0 o 0 000O000000 ,Ln 0 0 c)0 0 H o0 0 0 0 0 0 CD0 CD I I *1 0 0 m 0 m m r 00 00000 C) CCDDm 000000I10000000O LA DC 000 C') 00CD0 000C)00 c'q H I Ln00CLn M 0oCD oc00 oC., 0 0 10Ca0 a I00 ~ wH)c G o - flI w 0omao o o o o (I '0cq M wImoo0 000000000o 0 c,4 i IAi moM'00000000 CN C C)0m I C C") m rn 000 0000 00 C CCD m cNC 00 cqCYN 00 00 0 00a0 Hq 0I0woo H a) (A Cl a 4 l H 04 4- 0 Cl) 0 a) H wl) Cl)A EaX' 4 - ) C) 1- 1) Ol0 )a) - Ln 0 (a :R:(d 0) Q a) 0 ) 01 Lo o 0 14(a0 -Ha 0(d) -~) ~ 0 ) ) )a -H4JP: rd-)HQ O0 (a )i4 0) a)- ). 0 a -4 0 Q 4()4 ) E 14j-4H M4. 1Q 4w 4 ) E - J - WO 00/43377 PCT[USOO/01283 212 co C>%Dr . % ow0 - H 1 I 00 M 0O 0'. o ,40o 0 N- I c m -- z OO O O . N 0 '-Ie10IO .00000,-4c'Ojw Ln r, Ia co 0 rn 10 en 10 0 0 mC rC 0LA Ln H0) 0 M 0 0 0 LON 0 0 0 0CD00C0C0 -. 0 01C)0 H H co 0 m a000o ooo n cn aH 0 000 0 m n0CD0 0 CD0 0 00 Ln C 1 0 HH co 0 H HH HN0 m~ 0 0 0 . cD o0 o c ooow D o 0ooooooocc oDO N v ~IOm ,A H N- H0 Hr-I -4 04C q- qv w 0 1C O a CC O D O ~ i C H H H N -r- 0 M 0 Co 0000wo 00~o. .. 000 00I400000Lfl00~o 4 o 00 %D Ic en m HH H H r-H Ha% N - H H -4H H 0r0000Co mo000 oi N i (',4 o ~ cooDn,4 n C 0 0 r- H H C I0IC)0 0 0 CD0OI0 ) CCo C 00 m00 CD 0 N 0 N0 CD0 mN CD10 H H w r- HH H1 H H-4 H -i a% H H H w Ch No o oo o o C) 0000000000000000 0 O Li H w0 co00r0 000cam D CD 4 0C>H 0acN Moa0 0CD0a00 000 m C 0I W H %D0 co CN m 0 0 DO 0CDoo a0oooooa m~ t OO r-No Ao m r-oNr- o0 o co m iLn H. HH H4 H co 0) (d k2 0)Id 0 4)0 - Q4. 02 cc 41 0 q W 4ol c Hl X2= 4J0 04 (d r) 0 a - U 4 U 4 4J( a C H t 00r. 0 00020J0 a U 0b)a 4 .22 0( _ b 40 bi 4)-l4a) 0 W 4 4-2 ) F=;-H-4-) ' r- 0) 4- -40 W 0 W 40)~ W 00 ) r:;-A -)'4 1=-4 0 :3 d a) 0 :J (L) C.4 d (d 4 a) - 00 s--HOI 0 ) 0 :j a) ,: H (d (d $4 - ) 1 WO 00/43377 PCTIUSOO/01283 213 0 k00 0am r .0 C') 0 1 00 toooooooooo '4' '4Z LA 0 0 co a) 00 a0 0 0CD0 0n 0I0000000o0o~0c~ O- 0 Q0N0 ,0-*000 a0000L *0 .0 agoIocoo oaoooo oo 0- 0n 0 M 0 0 r4'0 V)00 C M MAn0 ko 0I0Co0 00 0 o00000 0z N Nco c 0 C o000 CD %D0D N0 a a mI 00a.,oooooloooco w' 0 a0n0 N0 ,0 0 0 0 00o LA, r, ~0 0 0 co" 1:1 10N oo'000 0'0o. c")oooq '4' a, 1 0 000 10 comNr L -a r H14- HU c'44'Hr- -1 H '410 aooooo0 004'0 Mo r OloLo o o o LAO CUr ,aac L z , Nac 0N 1 m w0000 ON 'C N)000 wc n w1M 0 0CAa000 0~~~ w '-wN4 r H 0 10O0~ 0 0 C~ H~ Q 0 rn a % a 00a 0La a 00N0c, ,4 0 -i tMU p- '4'l rlr X4 -4 a'-4'r) a d - ) l E 4-1)t ) a () U)'4 0')WQ4)' n M u ( : a0 0 w4 L J L i( 00 44b)0t0 410 4)0 0dCO0 P '0 IN0CU0004 00l )) 0CU)LrA 0(0 C 0 a) 4 010 0 0 Q41 0 4) 0)kM'4' .r 0 ( -) 0 a ~ 0 00 001 . 1 ) 0 (1 4 a - 1 -04)-4r4 U 4N -l0 O 0 0 4~ 0 ~ ~ c. (1 0 a 4W- j q l c a p q o > rdro- 4 a)a o(,-S40 Q r oa)p Q ( a'04f()0 U ( ( - 0 r > 0 rI ) '14 '4)Q d0 J ar 1MrAQ - 4' 0 ~ ~ ~ ~ ~ ~ ~ ~ ~ - 0- ,-lr- : 0Q 0 )4 H( d 4 -10 , 0 )0-4 Q r ( d U UU ZZ P WM :: '4' M UUU0ZZO E n> :: P 4 WO 00/43377 PCTIUSOO/01283 214 1- 0 -1 0 In I~~r 14 0i W O'0t0 W cH L Ln -4 r- H- 0 0 Ln 10 Ln I(00LH V 0o 00OOcc 0 r maoo Wnc 0I 0 0 0 0~ o cDo 0 c N- H ID c> oo )o 0o c oo oc0 o0D m 0IIONODOOOOOMMOW r 0000~ 0o oooo o c cvi 0oCO 00000C (.,(0 00 LN 0000NM 000oooooo-m HN 0IOmowc ooo~oawwo '0 ND H H ~- H H 1 O H H H HHH O 0 H r000w - 0N10 z0ON I 000o oo oooo D CO~ '0 m i w o 000000q~r- r-ON H HO I 0000000O0000000 M~ 0 I cqoo00c\ oo000000000 co '00H i ooco0~o00n0-o0Loom cN OOOOOOaCOOOoOoDOoo N, H HiH CD OOOOCCoOCCOoOOo H 0000000000000000 0w '0o aOcQ c0o0ma o D oLn o oLA0HD 0 0 1 0CO0'0O 000000COo LA 100000000000000O co -;: I o oh cc wD n CN LA H c v 10 CD) 0 J 0- %Dm 0 0 v C 4 0 l - 00C CD 0 0 00 *H0 Cfl I D I-t0) 0 11 M - 0d tp~ (a W41 - ~ 0 0 W4 4-J,0 a w 4JH 0) 4 0 ::1 00I.0)- 0) M-4~ w~1a0 O ) 0~ 4J (d 44 ( W 0 - i ( q r 44 ( 4t M w 0wr4 ( r.r aA - M$ t 4 01 oA .
WO 00/43377 PCTIUSOO/01283 215 0 0 00 An Qn OrH r-0 H ODW . w' 0 rOooo-oc H -4 14 CN H- (NI An W;om0mw - w ooooooooDc. o.0 H TH Iq H rIH An L n 1I0 O010 00 0oI I IM11 H H r H4 Hq H Cq v-1H An H- H H (N An fnm mor000ooo~ooC-oN0oo HH HH HH CN HHIr An 00000000)000000000 CN aoa -ooc4o.z no)c4 CN H H-IH H- H An o i ooonfA 00000000 H 00000O0000N00rC100 (N HH4r An 0000000000000000 0 00000000 CN H An HA I (N CI IO o oCIcc0o~o O 00t)00 10000000I ~co~o An An An An OO000om(N000oooooo~a n Ho0L Dmr 0wa l nr 0 CLn An H HH H- H HH An 0010 CD 0 )0 0 0 CI O00 A H) w C 00 00 0 0a)rNm00m00 00-rnr H0H H H An 0I00000000CI00c0 w~~~0~0I-n An 0 HHI An 0i H o H) t - 4 U)4 4I 0 H1 U)4 1-1 CO 4 U)x r4J) d ) 0) a x r- )( i 0 d it :3U) H )() ) 4) L 0) 0 (a HjW 0 0 ) )Q 4 ( 4 d4 U) M *H)r a) -I (dM C 4r d 04 ) tU) .J) *H a)L-i ( Q) 4 0) Q) -4 P:1 d4 4 0 W0) 40) a) 4 rl1 d4 4 0 Ej -4 4)J l M - -IJH a) 0 ) .4 ) 4-) () E-f , 0) ~- 4. H d4- 4) O0a) W4J 0MWUXr:4r .W0 > J dtA 0H 40 rOrAWWMMU-4r Q0r 4Q0>0 a) *0 HO (d U 4( d - O > )rAQ - Q 4 ) rC 1 4( d J 0 O ) - L - WO 00/43377 PCTUSOO/01283 216 Ln LA Ln Ln LA 'IV Moo I H~ q w w0k )m00C 1 LA LA M CAq ,C OO0 CDCD maN D n C 0m LA 0Or-oo 0a% ooo0CN C, oo LA H1-4 H r- r LA LA LA H N H H LA LA LA r-4r- H N LA LA o )ar DaC O00w000)0 0 ACq N C CN C 00 0 0 0 C D0 00 0 0 LA H-I 1r LA LA 0' ~r- HL' O O OO ~ o j H LA LA Hz - H H N LA LA 1 1HH w0 LA LA LA LA -0 r '0C a0 0 0 mmC 0OC I N 0 00 0)0a 0OCD00 00 0 %.0 4 HH LA LA 0 0 0~ CCD0MC CD0CmCDCCDo Cq 0 W ~ oo cy)qIOf-M LA LA w 00000C D0C C DC 0 0o o o C, CNQ00 M c)oa D )ooa LA LA m H '01 H H H H H LA LA ~~- H H iL o .oo mHH '0 1 LA LA LA LA A H -I Hi LA LA LA LA U) to) r-U)( U 4 20)4(0 r.ol U) 4-)O0 -H U) L-i b0) U) J0 -*H 0 U4.4 0)H -4 W 4 U)X x - 0 4.) ( U) 00J -1 W 4 EnX x Q, 41( Cq U)rO ( 40) 0) 4j d0)C 4.J L 0 (dg 44 ( 4 t)O)t) 43 0a)0) (1) ul)40) ) 4 c'0 ra 0 (1 0 a) 0) t) ) 4 0 10 0 (a Q 4 r0) -rI4 0) 41-H ) 0 a) ) J a) 1 -H 4- 1.4H 0) 4-) -1-1) 0 a) 0) a)E ) %40 Qr U 1 .H 10 rIa )WL 1 . *00 0 - 0 W 4) 04 d) a) T dU d0 Jar 10 - )rAQ4)Q O f 4T C 44 4' 1M- WO 00/43377 PCT/USOO/01283 217 O (V CN ' >w NO . O O0 0 0Do ncoo-zlw 0In w 0 CO O NM0 CD 0 4 en 0D0 H co ~0 0 0 0I O co' C)C )m )io nL v 0 i10 C C 0 00o 0 00m 0 CD ~ o oo 0o o CD CD00 I D D 0 0 01m )r- a% cooc)o o In ' 0)0 00 0000D000000000000 0 a00 0D0CDcq 0 0C)0 In '3 0 C 0 H 0 CD 0 0 0CD00 00 a a .,C ) (00O0a 0 0 0 In w3 00 In 0 -Z OO aN, C) N vr.0 o N 0 c C00 I OCNo I1000 In ' In w3 00 M 0 0 0C)000DCD0 000000000 '3 0 0 -*00CoC r C Coo00 In w3 OD w H 0 1 000 0 00 C DC D0C D0CD00C -0 0C)m 0C a0~0 CDC C 0 a%H In %3 00 0 01C>OOODCN O O O O O r' 0 oaI C 0c'a. m I N D0 -0 0 0 a In w3 %D~~~~~~~~~~~~ 00 00 1 (Cra)IacoloNC Dac DC N 0 c 0 (N 0 0 co0. 0 Inn 0 00 a o n noN q0 1 a4 0 0mOC) C0m 0 o0 Z~ ODH-4 11 H1 o Ln 0 w .) w. m~ N InC I '3ooc)O HO0rIOo,-4N 0m . O 0 3 N 0 In w3 '3 Ln Ia O Oo0ooa, 0 ~ ' In ' W .'.o Z I m 0N n M ;: Om 0 a N D mN 0 - c I co 000ma0 0 rN In ' W In CI N o cc 0 c '0c 'oom- o 0O. .D N D ~I 00or OM o Nc In ' H c4 r 0. O0 ,00omoo, c40aoL oinc,o U3 oIao oOa n O.,o00a0o In ' In w3 In ' r.0N .41- 0 i w44. W CD )r 4 U) x - 1 II4 4J( )) 4 w x -I Dm :( :1 w0tmwa 4J *H En rDd tf:3 w0 )w w U) En 2 .1-JOM H 02- O U -X -10 4.) OI4- (d Cf ~4 4 )J 4,r )-ld (12 '0D~ 0 U 4 Cfa r4 4 0 0 df 0DtI 4-14 0V ::j d .4 0 J 0 ID0I 44W 00 -4 0 J d O)l0 2:3:E- W. 0-4~-4MPQmUUU0: ZWP uM>2 tI.-)HI E-4ID~ ID .Hjr-4 tpqJI OID0zzP4W WO 00/43377 PCT/USOO/01283 218 1 0D' t- On 0) 0 a 0 r- 1 I 00 H ~ C 0q 0d'0 co 000) 00mo m t.0H H '0 W H 0000 q~z CN I OC00ernDmn I C'4000000 r- 0 1 I0 ~0 r 00 me 0000 mn NI O M 0 0 0 CO w rlmIODO~oco o %D A H ID %D 0 0 00 C19 Ln U, 100C N0000N L oIc 00 D0 0 -1H wO H kD %.D 0000 H oor' UI'D000~000 L ,H IDJ HH. V.0 W. 0000 M~ LnIN00c ~lr ' C%4 M I-: 100 0 0 v0 m kD %D kD 0000 00 0 Mq: 1 O0 DCN qUOD0 t.0 Unrn 0 H1 e'I 0 0 r 00 0 0000 r- 00CqO 0C)0 0 o r amo 0 C> 0 W0 a0~0CD0 am HH H U, L %D w. iDNUCr , H H) Q n MC Dar ,C,00 n( 0 I r-C'JC ' 00 0 , m Hi I- L- 0 0n' 01.0 :H U, n 0 ko D CDc n r o n0CIa D0 lHCI 0C w im H oo oI 0 c 00o o m H- H U ID VD 0000 a% L omwmooL )mwr N NC 0 0o0 00 00 0 r0 0 Q00 co oC)C ,D~.IV.a r-a),C00nko0c--Um , w 0CD 0 00CD0 0,0 ,00 C (Nq H H- Hnr 0000 U, C 1r 0IN0 OCN0C140 0H ~p c ' r- OOnco 00CNI1OO'a) ,00co (NH %D I 4 UI) HL). ~ ) H W ~~~> ' -0 )Ict4) 0-1 t i- : ) w (44.(d U C)()r E (42 Ea O *d H Q4 4-4 a c D 4 A E (4 U 4-) 0 n tm~ 0 (d 'd (d 0J cc0 ul() )a) 410) (0 d: )00 1 4-j 04 0) k 0) (1) ~l--0 ) O0 (d 4-) 0) a) -I~ t) p0 ( . iJ.0 a) J-) ) -~o,A e -'4 - ) J - L ) )4J a . r . 1 0 . 4 a 0) Hq ) -1 4-)J0o 40 -) 0 r ' >1 M -4 ) , 4J) Q) ' 4(d( 4J) WO 00/43377 PCT[USOO/01283 219 0~O OO M 00 CD 00NM000CD0C > Dn w C OOOOOO 0 0 0 L0 0 - CD 00 O0 C) 0 C) oIooo 0 qL NC N n 0000 00 H00 H HH4 H H4 HH 0- c oLl H n w r 0 00 00I D c o c r ocvo o o -4 %D 000 CDLAOO 0r NN O CD ~ 0~0 0 0 m N C-) C )cfa ooocDa oH ic, n Dr- )c 00na)0 oc Ho H H H H w
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co HH HH HH H HH 14 N 0 00m 0 010 0C 0 In O~00 0 a 0 C\f0 C a0 0 Lfa C)000O0r H00 00H 100 0C C,: r- N C)0 O~0 0 N0r m w 1 0\wr H0 0IH00(\:Oc) .00000000oo 0l C.0 ~0)0CD0 0 C C) 0- H CN1. N )0C ) r c w o o - c ~ o Iq C DC m CI 0 C)0 Co) 0o I OOOwoo00m000mo*Nm 0 ~0 M00 1C>0 C) H HD HH N- 0rq H NH 0- mH -0 00000 Cl M r,1 c 0) C 0lv D 00 N rN0 0 m m m r CD 0 000C D00LfI N- H H0qH H N (3H a)0 1.0l(d U N O O O O rm N1-100 00 ~ 0 ' 0 C 0 ~ L~ Nd rj H 1.0 U1.0( 000000- _:o u .. -1 WOc O O O N O m L 44D r 0 N0Ea 0' )0 0) rQ ( 0a - )0 U) U)U-4r 0 !C ) IQ ( ( OrA4)Q 0 U -4Z40) ro ~ ~ >10 q4 UI - ) HO ( 4( d . O 0) a 44 4- ) HO ( 4( d Od) - 0 Q ,- 0 0 U) - Q ) 400 ~-H : dW0; a) O ~ Jl 0H( d a 100 0 nW > 4 04 a4 J-~ PQ.H OaQW PQ S.Ju~ u t) ZzE E ::3 J 4Mp C WO 00/43377 PCT/USOO/01283 220 0 0CO0 C' 0 0OM 0 00 00 0 0)m0 0 LnM CD m0 0 CN - W0 r-0 0 10000000 ornc0 NMO00O'c0c\Nc0O Hi 0 0 0 0L 0 coo or kom l a) 00 o00oor-0N ca N-, c w %D Lno 0 0 C) o l0 0 14M H- rH ~ -4 H kW H- r M LA 14 HH rAH LA 0 r h0 0 0 )NNOo o mo m o0 0 0~LA000N oooLAn oo w C 000000m H LA 00 C DmC -r 0) 0 0 0 N 00 C)0 0) N0MnC C r 0 CD~0 CD O0 0CD rii M LA Nl
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r-4H -fN -1 H IH H- LA 11 r H (N H LA n CN H N 0H 0 "l0 C'Dc N N0 r- r ,00 C i 0 H A0 0 CO0 0I) 0 0 :21CN H H CNN o w rm o (N Hoc a ~ ~ o o a t no , r N N4 (NQ H H (N H H-A 4 H H 00(' CNW 0 i N 0rqm 0 N0 it00 00 a) 0 (1 Q4) 0 )MO )Q) :1 Id 4 CW0 a O 4M ) -) CO)- 4 CO M-' > d' 4Q ) 0E -' . . r )a 4 CO4- 0 1 O r- )Q COU -1 4J04rO > 0) rA) ~-1 -J () (Ar~ d~ 0 O Oa a)O Z J 4TI> ) -4 I a) ~ d~~ CO -)Q O (dU (d a) -. 0 : CO O (L il. -0rdM 4 -Q)- , r 0 :5(ba J 0)'.-- Z ( 4 -Q a) i 0 0 4 13aC) Ua~ ) > :-i IP4P PQ 1-4~ () ) 0 : 0 3 ) U) J ) :-dJ :? 0) a Q WO 00/43377 PCTIUSOO/01283 221 m~ 0D0 0 mn 0 lcz 0 0 0 0- 0000 000000000Cm 00 Ch '-4 0' 0 00 0 0 00 mn 0 113 Cm n N0000 0~~~~ ~ ~ ~ 00001 0 -. Z n 0c 0) 0 00 CN 000 C in ooCoo rn 0000 0 0000000 a C flm -00 CD 0 -0 000C )k 0 NOOOOO-mL LA LOin 0) r ChCD, H Im 00 0 0 oClm oow c 00 o o q- MLA m0 00 OI00NO~l0,-1 CD 0 a 000 ~ L ~ ccOo r, oo oo N Ln r-0 00 o m m - o Lnr Dc AnoN 00W 0 0C N N 0 ' 00 0 0 0 C 0 0 0 0 C C N IN it00000,-fC 'b0 ICOOOm) 1 ~-4 ND 0- 0 rn 0D CDO -N C 0 r- r- ND In N 00 coo OC CD 0 oo 0o CDoC) C)C 000 O) OA 0000 ON H C~) C'..O 0000 OOOCOCCHIOHCH 000000 0 0 0 0 0~ r-1 0 )0m (d ~ ~ - N4 U 4. 0 -4 M44tm E 4 0 rq M44aN x ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ' 0000- 0 - ) ( JM ni mr 0000) ~ C N .0 Inmr oC:JO w00C 0 N ( IL i N ) 41 C 4r 440 1 .0( q 400 -Q (d ~ -~4 ) M 4 - 0M H Q 4H 4 N. v-0I J l fm 4 01 0( q4 0 000 r 41 H ) W 4 4 0 -q J) 4 4 4 -4a) 0 W -J>1torN O0 M 0 d4 M0>0m ifl -4 WMUA r 400>0r - 4-4W 4~~~~~ ~ ~ ~ ~ 0000O 0 - . ) r dU W ar iM14Q)- Q-JW -ri~ ~ ~ 0NdW 0 : )r H ( d 40 0 4-r : dQ 5a l 4( l 0 Z P4 P3 En cn 3:lm 6q0La MMM LA NC 0 0 0 0 C ~ N Z 0 ;:: i 0000 MM WO 00/43377 PCTUSOO/01283 222 %.0 0000 00 0000 ~ 0000 - 000 0 0 D0 l0 CN CN (N (N Ln 000 NCD 0000 m D ) 000 w '. 0 0 0 C D 000 -q m ~ Zn co0 (N CN (N CNm '000 0 D D 0 000 C)c 0000 LA lC 00 C)c D 000 (N CN (N (Nm CN )0 000 Ln 0CD000 N- 0000 14 HOO Q N 0000 -q LA 0 0 (N (N (9 CNm -1 0000 -V 0000 -10 0000 m MOODC w. 0000 4m LO c 0 (N (N (N CNm 0 0000 rn C 000 0 LA 0000 (N NOOD D LA 0000 r4M Ln 0 0 (N (N (N N m S00 )0 0 CDN 0C>00 CD 000 0 I-q 000 a DCD'C 0 00 0D m LA 0 (N ((N (NM r- C 000D0 1-1 000 CDCC 0 D000D 0 000 C)0 m~ 00C)0 0) Zr LA 00C (N (N cq (Nm '.0 000 0 000 C . C 0000C C 0) 000CD0 (N 0D0 0 (N N (N (N LA 000 C 0 000 r-I 000DC,0 co 000DCD0 l0 000 CD (N LA N CD (N N CN (N S0000 00 0 CC)0a000)C)0 N- CN CN 0 0 CCD00 0> N LA N- 0 (N N (N (N fri 000)C 0 N 0 00)0 O0) 0000 w'w0 '000 0) (NCO 0 (N v' N (N (N (N (N (N 00 0 0 0 0 0 cq 0 ol 0 (N 0 C40 1 0 0 0000 OO'D 00 0 'D 0000 (N 0000 '.o 0000O 0 C(4 a)' (N (N (N( N m 0000 r 0 000 Zn C)000 -1 m 0oO LA 0000 ()N r- m -1 (N (N (N N- 000C)0 (N 0000 0' 0000 0 C 0000 rn ~0 00C H4 (N (N (N3 (N w. 000D0 C) -C 0000 CD 000 C 0 0C>00D m 00CD0 M ~ (N v w a (- N (N (N (Nq LA 0 0 00 0 000 0 CD(N 0000 m 0000 H -0 C0 Ch(N w' m. -4 (N (Ni (N (N -0 000 0000 0 000 '.0 r 000 O C -0000C m ~ -f v' w m H(N (N (N (N (N 0 000 N 000>C)C0 m~ 00 00C LA 0 000 CDm: '00 0 H4 (N (N (V (N ww~ u co w~c ,r)M ~-.-UC 0) N Ou a) OC a) UO0)4C 0)n M m 0 a) ) mL 0) ' 0)10 '0 m) Im'0a nmMr H A~' a) LA i0' H) 41~' 0oH - W 1 ) l ) LA-0I ' 04- I) M A~' 0) H 4 E fd(d d ( to (N(d0 CO i 0 ('0) Cd ( d (d00 M Cd ( 4 0 (a a) 0>1C w H ) w >1 o -q0w a) >1 U ,-10 0>1 w w) 0>1 -10 - r0 -4 a) 0)F4 0 ) I r: r- W ) 44 -4 w),- 10 W) I r - a) .4 H ) W -'4 W 4 . J) 4 u u 40 W 4 U U ,Q-0 W 4 U U ~4J W )4 U ~4J W C)O .U WO 00/43377 PCTJUSOO/01283 223 (D 00 0 rH 0000 H C)000 0 00 0000 H- 000 0 - 0000C 0 0000 LA 0000 N CO 0000o w0 0 0 0 000 COia 0000 m 000 0 00CD0 0 m~ 000 C0 LA m~ 0000 00 0000 (N )0 000 Ln 0C)0 000 C 000 IZ co 0 0 00 N 0 0 00 -1C 0 000 v 0000 N C 0000 M (N w. m ~ ~ . m rn N- C 0 000 110 CD0000 0 LAOH c-fa M 0000 w. 0000 (N m~ m' cn w. 0000 LA 000CD0 O'i 0 010 CDC 0000 LA 000D 0 (N w. 000 v m rnm m i 1 LA 000 C) 0 oC) C co C) o H 1 C 000)0 M 000CD0 C) (N LA .j' -zp 0 M mM-i V I~ C 0000C ~' 000CD0 N- 0 000 CD ) C 0 00 (N 0 )00 co (N LA co n0 00 m M M m 00 00C m a0 0N LA 0000 00 0CD000 Hi 0000 N (N LA co m %D 00 mn m n (Nq mO0 o H 0000 Iti 0000 N 000D 0 000 0 C '.w (N LA 00 w' . 00 H 0000 0) 0000 M 000D0 a' 0000 Coo 000CD0 LA (N LA co LA 00 0N 0000 n (n :D0 D ,0 ooown ooool co oo c 000o0 0 0 0 0 0 0 m C) 0 0C)a4 H CO C C "Pa4 r 0000 040 ~00 4r C >C 0000 c H X C)Z qzLn A C m 0m Cn0m 0.- 0v 00 C 0C C ) C) C C D u ) CDC C) u D C D0 C u H -V 0C LA co N 000 ) 0CD0 0 o)o CD 000)0 co 0 00C0 LA 0 000 C 0 w. '.00 0 c 0 0 D00 0 000>0 N- 0000 1 000 0 c H m 0 LA LA 000 NC)r 0000 W. 0000 w'C. C 000 m 0 000 N H mN0LA 01 000 CD 000 LA 0CD00 LA 000DC>0 (N C 0000 C .0 H m N0 LA mm N 0000 LA 000C0 m' 0000 rn V'HO H C 0 D000 M1 Hm N 0> LA N (N 0 0 00 m' 000 mN C 0 00C H0 m i0 0 0 000 mN H Now uu a a a 0 LA N) - M a 0 d m )r_(a z m z' (o M r r 0 ) 0 0 Hn 0 00 , a L 0 00 (N) 00 a) LAOH M' 000 (o a np mr n6 )r N Hq ( ) C 4r d U N 4r d t 4r d I CN 4 O N 4-0) ) 41 -W 0) r- C a) 4C H W04H 4) CQ - O W 4- 0 ' (d di fa( o r:0 ( a : a( 00 r LAQ O ) LA0 ca H0 1w - a) A to H) w ~ ~ ' a)5 0 ) La)~~ 0) L 0 ) C O) O)IU HO 4 ) O)4C O ) O)4C HO 1(v u ) a) iU HO) 4 0) 4 I -4 O)Z- (0)( I 3 -1 O - (0)( - (d l -r~ M) k ;I - H 0) (d Z k) ~ (0 H -( 0 WO 00/43377 PCTIUSOO/01283 224 00 000 00 mi 0000 CN 0000 0) C'000 w, co 0 MLn 000 0 0 D0 00 C 0 000 H- HOO 0 CO0 0000 LA 00 0 cnLA n %0 LAw LA o t ) D r D0C C D r 0 CD 10 -0 0000 0 000D10 o0C>00 0) 000 a C 0% 0000 CN N, 0 CNLA 0) 0 000 C O OOH01- C LA 000 C 0000 0 CLA 0000 1 w0 0 LA 00 000 0 00 >a D0 ":v 00 0 C 0 Q 000 0 000D0 0 w0 0 LA 00 0000O H 0000O m' 0000 LA 0000O 0 0000 m~ 000 0 0 00 CDC )0 C 0000 Coco 000 CD 000 CD CO 000 Dco 00 10 H- 000a0 CDm 0000 N-C 0000 Nr LA 0 ri 1 00 10 0 D00C0 0 000 N 000)C)0 10 0 00D0 w0 LA 0 Nq-Vr 0 000 (N 000 0 C nC 0 000 H1 000C0 LA 0 00Q0 LA LA Ch N
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LA LA w0 % 0 000 0 000 CO 0000 0 0000 C) 000 CDC 0Z10I0 - C c LA LA w0101 CD0000 00wCDC I C)1 00 0 C 000o m j 00 00H 00 0 0 0 0000 14 ooO c a 0000Q CD 00C)0 m0 D C 0ooN 00C0a0 04co OLA OL 01 010t 01w 000CD0 CCO 0 010 C-VC 0 000 N- 0 a00 H- 000CD0 N mn 0) 1 LA LA 01 000)C)0 CN OCOCO 00 0 0 000 DCDw D0 0 0 00C)0 10 D M )H 10 LA LA w0 ww C)000D0 H- 000a0 CD(N 0CD00 LA C 0000 CD 0000 DD LA dl H fn0 LA LA w %D 10 0000 0 C 001 0 H- 0000 10 0000 CO 0000 1:31 (N m~ H10 LA LA w0 Ww C0 000 COc 01 0 0 CD0000 rn 0 00 0 N 00 10 rn LA LA 10 10 000 a DHC 000 OD 000m 0 CD 00 10000CDwaC 001 (N (N CO H w 1 LA LA w0 %01 0 000 0) 000CD0 CO 0CD00 HiC 0000 CD 000a0 .
0 co 10M LA LA to %D w0 000 0 ' 000aNCD0 N 0000 C 0 000 D0 m1 0000 0 u U) wd U r.0u 0( 0 ~(d ) 0 ) z 0w 0) M- 0 ( 0) M r. (d 0) tp 0 0) m d 0 L m010 a) m U1IO 0w Ln p tm ro 0) L tm M rO 0) LA 0) A (0 Ea (~' CN 4 af to CN 4 rO wO (N V(U0 (d m Cq (U rO (0 C4 -1~ .0 CJ H Q) - j H ) .(mH i~ -W -4 ) H 4J H Q) H $4 -1)mHOI ) rd m U (a rdU~ EU U( r=; (a (a (t rd (d (d O>1 w - HO O>1C HO4 ) 5, wU HOa) a)I H) >1 >U-1HO) 0) I ) I 4 ) A 0) I 9 S4 a) H fZ ) I r 14 0) D 4 H 1) I S4 Q) H 0)r- I r , a) H 0) -fC W 4 U U - a) 4uu - Q4J ) UU Q a4J ) - u 4- O~0 W .. UU JO)W WO 00/43377 PCTUSOO/01283 225 0 0CD0 d 00000000000000OC\0000 co in cN LA VN 000000000COOOOOO,-00ooo kD 0 00D0 NLA k.o Q 000000000OH00D00CDC>,-100CDC0 Ln Ln CN LA 000D0 CD M 0 fn 01C C o00 c qa 00(mOlCDOO rn (N LA rn OO0 0 'Aa (co0 00 0 0m 0 00 CD N 0 00 (Nq LA (N 0N0 0 l0(N " a00HC)00m 0 0 D0 .- 4 (N LA H- 0 0 0CD0 0 00DC N 00 0 CDCDN 000 0 LA 0 00 rn ONONC)r 0 oornoco000N00rno00m0000 m~ am ookoooooOooCOoooomDOooo 00 CD000 In CD0000 H N- 00 OOr-i 0H 0 0 0 0 0aC)00 CD 00l0 N- H r 00C>CD0 H 0000 w caooooooooHo~oooo,-oooo3 LA 0000 0 0 0 00 Cl -I 1 Coco 0: 0000 0 00 oooo~-iooooc~ 000000000000N ON 00 000 0q 000 a ) .- 00CD00 0CDc D0 C N 0 CD0000 C) 0 CD 0 oooo q CD 0i C000000 00tC000a a N ODOOOOO)OOOI oooooCOooo w 000 In0 COO O O DCO O o WO 000 (N 0000 00ci0 1CDC DC n D 0) LA 00 LA r 0,44 'J0L N00L 00 0000 r c 0 1 0 o 0 Ln v ,4 aL cDL A(00~N cNc tvc D *c4rnoc 0 D00C DC 0aQ00000C (Ni 000 0 00DCD00aCD00CD0a0C0CD0 0 H 000 N 000 0 D00 >0000 , ,,0 U0) 0) - UU 0) U 0 caI 0)q 4 m~ 0 LA t 0 m m H~ M U 2 w0X H ~ ) 4J (0 (A LA (0( a CQ 41 d ~ (0 4 - d1 1 d: (a b0 ) (0 W0)0) 41 (N 0 ( : 0 o ( 0)4o 0) w ~ 4( 01 0 (ard q41 0 >1 (0 w0 0>1 [ 1- H0 0).- 1 W 4 r4 0 (a f41-H ) 0 H W )40 4J] 0 (d :J 14 ( 0 I4 (d -q - 0 J 0 - (0 a)H 4 ;J -4 0 ) (d Cx W -4 (~ 00)Q1-1 d( PQQ 4 n -iA aQ4 M Q Z u) E- )a( C 1)0Z0 C C CO u~H) 3:3 4 P4 WO 00/43377 PCTIUSOO/01283 226 OOO O00000 00010 000~oo r- 0000000C - n0N -00 O 0 0 0 0 0 0 ~ 0 0 0 0~ 0 0 0 ~ 1 0 1 1 1 1I00 CooOCDCooOc~iOoo0ooHooca ko 0 0 0 0 l0m0000a0 0 0 ~ o o ~ s o o o ~ , o o o CN 0 0 0 0 0 0000 C10 C 0 0 C 101 0 ri 0 I 1001 I I I I 1~ 0 0 0 10 1 1 00 COCCOCCOM0000000~0000 N 000000000000 00 CI0 0 0-*0 rnrq Cm 00 IC\ 00C0 N. c 000r 1 O1 O1110 1111100 11111 0 OOOOOO -0O NMOO C I C C 0 -I 1 0 C 0 I I C 0 0 CO c o m ~ ~oNo CI C C 0 0 I 0C 0 0 0 0 C I 0 000 0 C M acco000 10000 01 IOC OOO ciO O 00 q 0M I 0 C0 CI 00N0 C000c000 OICOOC OOaC0 o00o0 C 10C0 C00 H C:00I00000001 0 00 0 0 C IC10 C 10 w0 0 N0qINI0 C0 0 0 u C) 00 0 0C000)00 0 kD CO1O 00 C0 C C0 C0CI010 C 0 00 w 0000I00000C'i00 %D 000000oo,-looo-oc.1oooc -;:p o000000000,-l c1d o0)noCc4c oooc r , iCo 0dm 0 0 aC0 C C) 0C N ar-0 0 C:) dN a 0 rA C n 0C0 0 0 0 q4 C) rq a -i ) 0CriC C 0) 0)4 0 r- 0HC C J 0-1 04)Cl4-*H Cl)Id0 Id ~ d ~~' 0 04, 4-)l)1d0 Id~ d~.w o (o )ro~o04o H oo~oo0).HC *00). Ndd *Id 0-l0CO-Ha4I
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WO 00/43377 PCTUSOO/0I 283 227 c,'~~ m0~ 0~o 0 0 0 * Na000 Cl 0I H~~m O -1 0 0- N N L m r 0C>0 0 ~0 o H> CO 0'1 c L ~ ~ 0 ~ 0 O m 0 0l 0C 0m C L 0~ C 'e) C 0' 0 mi0 M0 000-M0 00 r- H ' H- H 000H qN00 n N olo rO N O 0-0000 - c N NN N r m c 0 Ai ~ 0 0 OOO0Hq C 000 0 H -H 0 000O NA COCDO OCDO0000~~~o o o o N0 00 0 4 H' 001 I OOICOOOO ILAOOO M 00 0 H OOOHOOCOOHO 0 01 IH01 IHOOOO c~000 InCC)C 00 00 001000 0O4 0 00 )NV 0M000 0 00C C C 0 0C C ~ C 0 1-4 0 0 0 OOONOO 0 OI COOOCCOHOOOI I00000~ HN0 O 0 000rA 0 I CC 0O0 %0 000 00H 0 C C( C m C0 N 4 00 H 0 COLOCDH0 CO N o OOOCO(\IOOHCCCCOCOOqc4OO HC H 0 OOHO0 00 mOn LA COor-*oO-oHCnmOcHLnmomo 1 01 HN N l C40000 nN0 00 001 0 r 0C1 0 OM 0 0N0C 0 t 00 H a%1%i 0'l0 0COC0H 0O 0CO) Ho N I Co Lo 0 I C) 000 mt I I ( 1.DoH0 N LA CO 00i 004 b) tM r. 0) (iI 0 .rl )4- )W H) U) 4-)0 r U)4 04 'd 04-1 d E n t ) U 4 u 0)1- 02 4-O *H a) 4 (a n-40 -40 a)a . N) 4J( (0 rO (dHOj 01)- (2d H 0Ma)r) a)~ a) 4- La 021(d 02) 4.) ) -A J (N (do ~d m 024 i 4ruOQ(dr4 4M0) 4-) 0-)V ) r- (jM (N-4 0I O - H) 4 W 4j a) Q) -R->1 4-I 14r4 2 ( 0-Ha) 0 -4 ) ) 4-) 0o ) a) -H4>1 4 (D i~ Id 4 Z> MddH - 4 I 4- U)r.U U F F: EO a2.) -i Q)~z r C d > (d rH Q) 4J 0) 0 10 > 0t)H0 ()Hr4 4-) r2 O (d( 4( 0 ( - - J~0 U > 0),-4 )H-. 4-) W )-4 a)-H *O ) r H (d(dO0 - Id0)HOO 00 -HOJ 0 d )HrI *O0 ). *H dl X3*Ida( 0 -( WO 00/43377 PCTIUSOO/01283 228 LA -4 OCNI C'N OOO I I M0000 Ln O~coO CD'N r-MOOO coo In In oo o n anr-io -cvo l f i ir r- m m m cooo cOOOOCOCo Coo Ln -4 i Lno o o )d Noc IOiOe~ IcN o mH cq CN OOOOOOOOOO00 oooo in -4 OOCOO.;pI wlooo I I NOOOO 1-I ;do co oco o o In -4 ooocooOOOoooooooolo 0 O00000000000000~ In -4 00OOOOOOO0OO0OOOO~c 0) OOOoOODODOcCDOOOO IO O OOOO0OOC)OOO a oo 00 O ~ ~ '~0 - r O I OCOO C0LflOO O I OM1OOc40 wA O ~ ~ O~ , C ~ IW O CM cD c V O O L CDWNHO aO~f ~ w~\ONOcO 0 0.
w m 0 0m m -z -00C 0 wm 0 r c I- CN (m00 .:r mC>0m0m0mN00m .0 -4 0~ 0r I n , oo CI": nC 140m0 00C - -00 0 0000-40-HC>o I -zv 0 M4 O d ~ ~ o ~ o ~ o ~ i (~ c (No~ a~ a, n~c~H w " 0 C) lz 0 mCN orn m o o o cLn ci D c4 c~v o o o o IV N0 a,0O OO) e O0 10 0OLA0(NO( 0 O0 ' D)4 1 1 l4 a) 0 000Ea0,- 0 0 0 C 4 U a x ri 0 a) 4-) (d fU) ) - ) U 4 ar$x 0) )J O *H (d 11'c a COIQ 41 M 0 4 Cl ) 4 (d 0 *H (d 41I4H )c CO .O) ) HQ) l) 0) 4 14 S - ) 41. -4Id a-i aO~ O ) 0 Cl) '0 (d U 4 (d U (J .04) a 0 .- 1) b )) 0, 4U) O ( 4f U ZC0 P 4-) 0 T$ CI) -4 0 - J- (3Q 1 0 : ) Z ( 04 C ~ O , (d ()rI0 0 - ( ) m cQO0u-u .H0a) 0 ;Q().H U *OU)~ Hd~ > & w04OOmPQ uu 0z z)H WO 00/43377 PCT/USOO/0 1283 229 N400 0 NlCN C'0000 W. OO00cN0000cqO00000OO0OO 00 01000 00 0 00 UIl 0 10 0 01 HOOOCOIO-o oII-0 O N 0 1000 H- m 0a0000 C ' 0 1 0 CH0Co 0 10L 00C rI I C0 0 00 W. 0 1000 Nc H H aL H0000 -4 C r OOCHe~I i lOOCCO-100 0 Ml OIOOH 000m Nm H0 0 0 m0 0 0 000I H00 00 o o 0 m -ICC( 0 1000 -40 a I 0CH:)( 0 R COl OIOOH0 H H m WN a I 0m C C 0 Iz01C\ m0 0 00 11 0H00 H - l , 0 0 0 t.0 c H H en - 00 C CC CC O c0 0 a C000HI0 C0 l CHOO 0 : 01 000 H Ho 1.0H H H m 000 q 0 01 0C00 C 00 O C O HOOOCOCCO0000 N 0 1 0 00 O 00 WmC' 0 0q0) H 0 I 0 0 N 00 CI en00. a a 00C' 0 1000 1.0 ~000 a 0 1 COO-000CON OONCOMOCC I aC 0 IA 0 c00 H4 H mOOq C 00 r 0I10)000CDI' oo o H -i00 'om0HClC 0 C, a) OInNHC 1n.0 a) (D 4) C 40 0 0 0 0 0 0 0 0 0 0 0 0 0000 0)()U 4 ) 4 N 01000 ' (1 1 dM - a - 4 IJr444 t) ) A) 4 0 4 rq (f -1.0 4 0 4H H10t)( 4M a 4II r c$ 0 f o .) 00 0 1. 04 0 0 04) 4-)0 0 0 00-I 01- 4-) H 0)w .- riQ 0 -4 4W 4J- 1 000 S (0 > ( r )4- Q : )0 r4 .4 9 Z U ) 4a X4 ( 0 C 4I)4 Qr.E tM ~ H - 4, O -l0 d U 4(d U d k 4- ,0 U 1 )-1a 1r -h 4'J ( U 0 )0H000 d - 0Q - 0 H000 0C : r- J 00 0)m-10 4- (0d 0 0-( 10 I00 U)M>:3 E- 4 l P QU 2 14I MM>3:3 I 4M WO 00/43377 PCTUSOO/01283 230 0~rq 100000l 1 c100 1 0INOOOOoo ,~ rn CN O CN0 CN *f0 0 0 0 0CN 0 (N 0 1 0000lo I -foool IIMOO C'4 (N 001000001100>000 r- n1r mION 0 0 w 1 r- 0 00 1I IC v (N 0010 f 0 100000 IOO CD 0 r-i co-0cq.L i wLfoo-li ILfoo CN (N 00100000 1I100000 a% CN 1 . rt- H0-I1O -w r I I In CN 001-0 00110 00 0-1 Im oo OO C I CN OO I 1 -00 CN 00 I00-000 11-11 0000 1 - C- 1 0 -zr00 CN I (NJcvOOOOC I I 'A a C (NI 001000001 IMO DO "r 1~.0 0 '.0Zv or (N 0 0 ( I am 0ooI Il o00 (N 0oo.If mo,-.4I ~ o o en 0 0C I0( 0 aA OI O o I CDw C CNrI I' M0 (NI 0(N IOCCDCOOO IlmOODOoD N oic . Nok i$ 0o0r00a omoo i i N0o 'H CN 00100000 II N100000 m I m0000 I 'ZVNO- I ~ -I RN 0 00 1000C00 I I 00O000 Q40 0 1 (NOOCO0 I 0(N000 I 1 -400 0 C CC)4 I 0'H00- I I HO0000 00 0 1 0CD.JoOO I 0(N000~ I I (N0O-l CN 00 I0'OCI I I NOC>0CN0 '. 0 1000CN0 0 l0C N0 00 1I 1 0 H00 (N 00 00 0 I c" ON0 0I 000N (D 0I00H00DC:)I00000)D I I H00C (N 00)1 00000 1100 0 HOD C n 01 Ds 0l000CDoCDo1o l-40CD-I 0 (N 00C1 00000 1 1 00000 -:4 OIOOOOOIOOOO1 m 0i 1000- C 001000001C I1 00000 (NI 0 1C))0001 000,- 1 1 000 (N ac IOCfOOOODI 1 - 0 a .D 4 N C 01000mCD0 0 1 ( 'H00r 0 1 1I'Hn0 0 -H U) En (d 4 r4 0) 41 0)0 4-O - H '0 U44 Q)0 U) 4O '0 14E -4 U)dX -4 a ) J-)I( (d l Ln 6) A ) U) 4 '0 <' r- 0 4- ( U) (a 0 0) W aU ) a)) CN4-(1r ;( ca (J)d 0 m ) U) ) 4(d r.0 0 (d (~4 41 0 E 0) 0 )U) W 0 4Z 0 0 (d (0 0 4 M M I4. H) 0 r-AQ)W U4 W J (D a) -- H >j 4-) -' q U) .)IH a) 0 r-I W .4 0 0 .4 l-H 0 0co() -H- *0 U ) -H(U(d0 -I(d (L)--10 0 4 :$-H 0 :dMU) -1 *0 ) U : 4Q MM>::::E NMMMMUUUQ0MZZ14O OV WO 00/43377 PCTIUSOO/01283 231 00 in -tl 0 I 0 Ivr O i I m )0 0 o I Im~~~ Nn 01000001r- Oi~o c CN. 00o -0 01000001000001100000 k.o OlOinooCI 0 %D0 c.0 N oim olC') C'.) i r- - a0o v i li '0cN .p r- 0 CD 0I ko CN 0C0 1 CN. CN. w n ' ) mr lL0A0 Im 0 011 N0 lMt. CD 0'0C00CDI '.cc 00 MH C'. -4 N0N a i a n o N i i r-00o -A0oCc 0 1 00000 1 NCD) O) 0 Ir '0 I-0 0 1 0 c'.0 CD0 1 1 r-ICD -I0D0 .-I 0D I 1 0000 1 CN. C') 00 CD r-' ~ o oi c 0 o Co)~o 0 ol0 ON C IrAO m 01oCDo o I m '.0 c'.) CN. co w C) OIOOOOOO VoooI I iol0000 C 1i 0I00 C> CD00 m LA 00 CD 0 0n C 100000oc I o0lq000 I I .- I0000 r 0 1 OtLA0COO I rn LA CN. C.) 00 LA0 oIoOOcooIoc.oco looi w00 01000001 M LA 00 1 OI O O IO O O 10 00 o '.oo 0 0 o 000001o oo rn LA 0DC,0 C 0 ,IC 0C'i 0m C' ) C, , 0I C 3 0 L 0" C, 0C' 0 I 0 0 cc C) 0D 1 0 CN.C.0 N 0 10 oCD .3 I I rnNCQCD 0 0.v 0 1 -i0000 1 00 r-.) 0 1 00 000 1 C 0C'0 00 1 I HOD000 f C D0 CD I000 m LA 0 0 0 0 1 00000 1 0CC.)o00 1 100000CD'C ) 0 NC I 0C0 00C I '1 LA N'. CN. 00 COi C 0I00000CI00ooo I1I00000D C> 0I w ) 0 01 N'. LA CN. C'. 0D0 m 0 100000 lOOCODl 00000 0 0 100000Oo1 CN. LA CD0 r N N D010-I 0I0 CN I0I0m 0 0 0 mm o CD 010 000D 0 1 00 C'.w C'.) I en L 0 0 1r-0C) I NNO a I C'.00 co 0 1 00000 1 C'.) CN. 00 LA1I00')lc00 iO'0')N 0000 C'.9 C'.) 00C 114 0C) I D0 000C'.0 D0 I I MCN CD0 0 w OI r-CN 0 OOO CN. N'. C'.) (d (dU)c U) w~ toU)U U) r.A (a U) U U) dU r. >1 (d (0 '- 0 r. ( a) 0)~ U) c 4- 0 .1 1 EG 44I- a) 0) U) En L 0p) r-i ) (1) a) ra -A Q4 a) J- (a U) L 0)r-q M U)~. U)Ta r 4-) C4 )4 (a10 '3:(0 ::J Ea (d0 0) ) U) a) ) 4-) CN a1 : d ; )( 0 : 0 0)I 0)U W 4(d z d 0 ad044 0 (d)4 0 ) a) 4M 4-) a) U)H >1 41 14 -I 0) E ) -H ) 0 rHUW) 4 W 4J a) U. >1 -I-) 4 01W (d H d~ T$ r- Q0J Qr )U 4rQS r;: )Q) Q 4 0 > o1 1a)-- o U) u 0 4 IQ - 4r ) 0 U (J . O U 0 - )riI - ) 0 0 WO 00/43377 PCTUSOO/01283 232 OHOOO I I(NO000 0CD0 00 0 0 0 I'00 0)~ CN 000ll l 0Lf 0 0) m n ) - ol(~ 0Lflh Ln kDo N Ln i moo I 0 Ll CN OOOOCNI lmoooo co 00 1 o oOCoO(NO I I CNOOOO (N (N O(N000I 100000 '0 0I 00 CN0OOOI (no(qn I li"OM0 (N (N ovoo0 n I I rno0000 L' 0 i In nO 0 IN oN~~ o en i 'm00o0 N No (N 0(N 0 N100001 o co -l o nN D- ro m -o N0 I O' m i i v m 00o0 (N 0 N C C C I I rmI0 CD 0 (Nm 0 1rI W CAN00CD I m0) CDm :z I 1 I10 N0 00 (N Iro r 100( I I o -I c N'00 H O 0 a 0 0 1 0 %.00CDm I I M0H D0 0 0N (N I0k00HNI I ( 0 0 H~ O11OOO DOOI1O C 0aC II 1000 CD0 CN 0 co 0CN0m I I m 00 0 0 0 0 0 0 I000 0 IIH 0 0 o00 (N0 000001H 10 00 I0 OINCDOr-400D10H000I ILAOO CN cn'(CN00 I I %D0000 O CD0 1 0 00 0 0 0 I 0 0 CN 0'0(0 (0000(N IOOOOUw CI 1I O IOH OoooI I HoocoO
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(N 000001C)C: I 1m DO D " 0000 1 0I'0 00HC(N mOn I I M (N00 CN 00000~oo1 10C10000 0n C: 0000CDCD01CD0 00 0 1 0mD0 00 CN OWONO 1 100 0 CN O Cq, 0 1 00 DI OH00OOI I rH:OooO (N 0)C0O(OI I OOOO coD 0I 0000I000 I100000CDO '0 (N C) 00 aa)N1 1HC )C 0 0 10 00 1 D0C HL a) ~U) U) H a 4-)O 0 H 0) )44 (L) ) U ( 4J 0 H lqCO4 X, a) 4-I (d If Ln b)-1) U) () rdX H Q a) 4.)I fd 0Otma) Q) () 41.I- aJ a;s w ( 0 0)O )a() U a) w .0~ z 1 0 z f 0 E M d 401 ) fdl r. U) 0 (d( 44 0 4l -Ha) 0 r-iW 4 i 01) () Q) W-H > ,4 , -i M U) 4- -Ha) 0 -- 1)W a4 W4 a) 0 V4 ) a) 4 (D)r4 40 > (d H T$ J ( U4) COC U) U.e 91 Q U4r, )1 a) -I Q) P4Q (d > Z ro) (d 4 4) a rOU > 0) - ) W 4-1U) Cd'0ZU ZU CO 4 -W "'0U > 0 Aa) -4 *Hq0 :1(0 ) H *0 a) -H d (0 0 *CdWH) -A0 0 $ ~-H0i (aa)H .o sa) .H (o WO 00/43377 PCTUSOO/01283 233 (' mI O 0 I 0 ~ , i" 0 0 zzp r-oomOlOn nooiivo n-rm c 1 0000I000 H fn Hn 0I000:A00 0' 0 1 000000 10co 00 0I0000 100001-4iooo: ('00 H 01000001000 0m mn M 1N C0I10000 0 1 C>C,40 0 1 C14000 0 a~ 0I0rqri0 0 00 00 C Ln C 0I00000D I0O 0OOMI I('4000 O OIHD HOOOC a 01cO0OC 0 (' A 0 0 0c)00 1 c0m0 0 C I I zvC: )000 No o 0 3N000 i orcD 0 ('4 mN C 0I0000C=O I COH I I C'40000 LA 0)IC)O0000 0 O0 m en ('4 0O1OCOOO 1 OH 0000 1 000C m1 0100000:000 0 0C 0 00 I :00000IDO I I (4000 Q 4 01 0 0 ) D0 00 0)O n1r-0 cq N O '0 m Ir NLfl0m m I I 1 nC)ma34ri 0 IZPC>C)CD0 10 r C Wrl 0~ 03m00 co 0:00000 C>omocoj I moc)CO C CDIC)C 0300 1 CDHO rN 0 13 O 100000 1 10 Imocoo Chi aO1OOCDOO aO(C'4oC a%. H ('4 m .O0 0300C000100Co0 l C 300000 CDCC) 000Cl0 00C310 00 N' m C) 1 0iw0 oo 1C)1. 00 1m C C>.O o t.0 0 1 '4H10C0Dl10 V 0 0). H ('4 m 0). H ('4 0 1OOODOODIOHOOO00 I300000o V 1' 0 .0 0 0 I'4N0 0CA 1 .,q U) 0) U) (a 3df rdm M 4 (d w~: 4.) 0 H 10 U) 44 0) M u] 4-0 LA H pi ~ r-4d~ tp W 0E 0 ) 4-) f U) L t3H 1-4m o U) 10x 1 ('4p (o 1 t : d E (~d 0 ))) U) 0L) () 4-) C4q (a'cl : d~ : Ea(a 0 0) a F: M3 M 4b)a ' I dzr 0 (d (aQ -) 0 (0 4 tD ) p d z' Q)- 1 - - 0) U) 4) .H0) 0 r-4W 4 ) ~ 0) HrI> 1 4- 14H- 0)Ea41.H 4JU) F: EO L4 r Q 9 j r! O Q C ) E4 .C)7'>0)HO -i ) 4J O r EOU 914 9 il E 41 o 3 ( 00)H(d . 4.3d0 O0 .t) H ) - *O-0).a.HPdrd *3 0 0 OO(0U MHO (I 0 Q - 4 Z - ( )-A -0 J Q rI( 1 d 4 - J-i0 : WO 00/43377 PCT[USOO/01283 234 001 IC4000o No 0 C W'D0 0 0 9 00 00rn0 0 c40 t cq m 1~ 0 Ln c 0,O1IC'.I000 1.0 OOO 1 .
00000 0000 4 0N0 NMIr; 0 0 LA c LM M Mm 00110~0000 L$ 0o Ia 00 o LA00rO,0ccLAH000 C 0 mm 001 1HOO00 rI 01 I,4 000Irlm0C'.2t mm-fo Ic00 0 0 LA 000 I HO000 m~ oi cc:OO(1000cqmlNC\: O m0o w 0 LA OLAn I I .00 CNOOO 0(1 Nmom 00m H0Niw oo or-Noooo Ln 0 LA M 0;iiiiLAoooo 0 00I-z00 oHNW00O 00O 0000 (1 0 LA mm 00 II NOOOO an ONM00000LA00OOO MNc OaO o N' c'q 001 r-ioo000 co lAN 00c'.M McO lOOWNo NoMM r- 0 001II-I0000 LA 00000000000000000000 0 C'N Orli moooo~ rv00000000000000cON0oo0 m 0 V 0o 01. om.0 III OCNOOO fct m ~ A 0 0 0 0 c 0 L 0 0 N 0 001IlM 0000 N- CDIOmOOOOCDCDIONO aN l~pmI I '0000 LA 0 00 110H0000 rq C1 00C 0 00 0 -0 0CDI I qC)CD 0 0 Ln 0D 0ol oooo cc 0I 0o o 0 00 1 0000 " LACNO cc:O 00 1 1 00oo-o0 N ) 0 ,I c ocooOI ONO H I I r-o000 m- 0 CD019 Im000lC)0 1.0 0I00NC0oI 0000OO I -I0000 0q 0 01 1I qOOOO LA Ol0 000o1OOCIOog I r-40000 0 0 m1 LA 101 U) .U)(U U))U( U) ) 4a t) UO ( *'4.) 0 -4 aU) 44 V 4- 4 c f 0)t A U olJ CO V4 c o xrIa . (0 w4-4 (U 4)) 4.) C'4 (d V~ 0 (otU ) (U )a U) U () 4-3 Cq 4 ( o1 4 )H ( Qria)r 4 0rI4 0) 00 4(U U 41 j a) ~ 0 -i 0dP 4a o 4 a) k () 4-) U1) a) -H> 4- 4 -i b 4(U -H ) 0 -U)W 4 -) U) (L) .H k) a)(z r3 d > (d d -i Q)4J (u c: wU r-) -,4 4 4 r. (U U) ) 4 a)~, 4 Ip d ~> fo q -i a).i 4J 0,dou).H 0 - *O ) .HId 0 Q 41 w OO V (d U)-H d 44J0 00 > *0 U)-q ( rq 4) WO 00/43377 PCT/UISOO/01283 235 lO0000I0C\000g IN'00O0 LA 01 0000 ION000I o - O O N ~Ln oa c i i r- oo0co 1* c"1 I I I c C)m I Ch w0 M C I -0 100000 10r0 1-OI0 MHOC CN I q0 Imw0r -0 I 10000100-000j 100000 Hqc 01 000m010 n 0 10 1 i ILA00:jti WHocol IHooCo 0 CO1 00I 000H0000 0 I 1 0 0 0010L 1 10H I N CDoc 0 00o I k a0 00~f 0 0 00C0C I I OC -A0~ I mNN000 I I MO0000 r- 0 0 00o I WO'I0000 IO~ cn m I I N%-j0 C Izr1- C Q ~ 0 1 I H LA0 CD0Ac. LA I 0 C'D 0c I a'r-OOO I H CH Cm I I 00 c.~Ic 1LAD O 0000 Rm C I I H0Clq H 0r- I o 00 0 1 01 0m I010 CD0 NIMoooo00 CDoo a' iC N00u C 011C 000m CD m0I0 m 10 00100ooo0 o10Co00 0 OniOO ioo r-iOmenooOLni CD H C DmC 0) CD 0 h )0)1C rJ2n I ( co o w C H O O * I Ln q . k r- ' r c o c H O C12 ~ U2~< ~ . 0) JJ~ 12 L~ IHO C1~ 11~do ~ ~ d 0 Id. 4~) ~~ I 1~t 0) ~~fn >,iJ r-r-cJ.H0) 0 vcqorn4J 0) i) H J~ -*LnoocH0 0n f o r-IM i o ~c WO 00/43377 PCTUSOO/01283 236 1riHocoO 0 -f 0 n00( 0N0 N 0 11 0 M Ln l(N0000 m~ OODI CNooH-(NHHOOOc:O0(cNO00 H 0 1 00 (N Ln 1 -01000 ~ 0 I0 0 0 H 0 0 H 00 0 0 I 1 0 CN In IILACNOOOD r cC, LA I CD 00I.DN N00000D HO000 m~ 0DI10 (N I -HOOCO LA (NO Ir'oroNONLoooaoOH(iN00 r- 01 10C (N C) m000 n D1 00000 0000CDN0 00 0 000000 CD CI CDL omOC LnooooC 00 I000000c00000(NM0000 LA 0 1 10C (N 1LACC CD0 C 0 0 N0 0 0CD00 ;: C C C CD0 N 00 CD 0 1 (N (N 0(000 O0O00N0OOO00(N000D000 H 0 11 0 10C,000 DRC; >0 0 (N0(DN)0 0N0 'n00 ,00(n0C000 goo 0110 0 0 1I C)0C0r- a4 00 00 0C D0 0 M00CDCD D W CD000 O 0a4M C I 1 0 100000) wD IDO 00olo(0 ID 0 (~0 0 I N(NO LA 00) D I N0 0 m0 1r-0 0 0 1 CD0 a0 NoC 010 0 1 0 000 Of D I (N00rIOI INCO0 (O OC D D 00 1 N a 0 0 H c 1 I IH0:D~oI Mw0.Dr I I N00Cr 0 LA C 0000Cl 10000 0 CDC01r Io a I 10iIO0I0I I A 0 0 0 C) 1 c 0 0 wd a2) 4 02wE w L w-. old 02 -W 0~ .14 M 44d 02 E 4J (Zm0ni rj U)01- 02 w 10 H '0i 04 d E n-4 m)1 w2 Ea ) 4 -) cqk(d 02 LA0 HO (a:3 U)( 02' m H U) a) ) J Cd 0d 'A1 0 02 40-20Mr- U)U 4 4 c. Id0 4 Q (d00413)U -)0 Q)) r-I (a (N4 Id r. I d,4-) 0 E 15 p 0U) a) 4 d F: 0 0 fa(IQ 4-) 0 r:;0) d0 1 HU) U4- UJ ) a) - > -) '4- 0) w 4-) -HU ) 0 H a) 4 a) 4 U) a) -4 >1 4% I ( >(dU O H Ia)-W l E ~'IU 14r.' -4 .s: w a a -J0O( > (d1 >-i a) H) U)0r. coIU U) U) O ::E- P l M P UU0 . d ) 0~ -0 Id ) - Z*Z0 PU)X W> R: -1Pd04 MIdUM WO 00/43377 PCT/USOO/O1 283 237 C0o I Or0oool I r-Icoo0 W 00 0 oo w-0000-q1 1-00 00 lfn0 0 I00 r 1 1 I00 0Ccq I N ,- 000I 1 r 001 lOnC l ooo i i -40 00o0 CN 0 1 1 CD0 0Nl 1 c'Ml o0 C I CNI a 0000 001ooo I 0000 O H 0 1 IC' 0 0 M 1- M 0 0 0I1 I0 0 00C 10 CN 00CDI 1 1-400 0oC 0 0 1CD00 00 1 0C)0 001I 0 0 00 0) 1 aMOC100 I I N 0000 N 1 C0 CD w 1 NO). ) d d0 0 0 1 I r-I 0 OO C A10N z CI 00 \ 1 1 .- DI 0 N 0 1 000 O 10 I In o0C'imr oo" i w CD000 I -0 000N I I H 0CD0 0 0 1 1 CN I I 0 O I C r 10 0 I I0 C 001 )I Dr 0 1 0 )I I1r400000 C) 0 I I 1' 00CD I I CNIC 0a0 I 1 1-0 0 00T CD CD1 OCICDC I I100CD00 M~ 0 1 I CDI00O 1 00000 1 1I-4 IV 00C N00100000 00000- 0 0 '.0aC2 0D10I00I Ic00000l mo Coo0i1 00000 110H0000 fl, 0 110CD0 010 IC) -0 C0 ICNIMO ~~ w) 0a) I-v I Ln O 0 0 D0 C 0 C 01 1 0 1 D W Io -o c)1 1M oo1 O~2 -foooa 0 I-a~)- a)co M CDI I 0 0r-q tJ C> co CD 0 1 r 00M~- 0~dW H *O a)~- I~~o~ *0 WO 00/43377 PCT/USOO/01283 238 OO 0 An i O n c nI jc I t l0 LA CN I I %DCN 0l Ln LA 000 O) 01 ) 0 > ooooooomoooi I I oooo 1 0 1 CN 0 N 0 -0 LA 000 000100 QIO Ie~0ocoi 4~0000 m~ 0 1 0 0 C0CO LA a000 r- 0O 000001000001 ICDOOO C'2 L 1OC00m m 0 zv LA CN CD00 w 0 1Imnooo COOOOlI I rooCo - 0 1 No 00-I~ CN LA 000 LA n1 0 0 I H C I 1 0 0 0 011IOo rel 0) (N LA 00 t0100000001a000 % 011 000(N LA 000 mn 0 11 0000 100000 1 1000 oco 0 I r-1r-OOcN LA LA 0 D0 - ,r0 0 w1'0o0oIC 0 0 0 ILAOOOLAa 0 1 C :Zr M0 n LA LA 000 CO ~I NCo00NrI OONO000 I ~ '0 0 I$ 01DO ) v I m-i 0 0) LA 00 0 - C I CNDOO r I CNO:OO(N I 1~ .00O00 m fnIIl d 0 'o0 0 rII 0 0 C)0CD w 0 1 H 1O 0M I r-1-OCOO0 1 I ~00 0O .c0 0 H I I M NO(> N 0 LA C)000 LA )10rC OI N O I O I -00 1v I 0 00D0 uH O MCOO rn co H H 000 mn 01 I IOOoDI OooOO I 1 00000 0 -o iILn no co LO 00CD0 H 01 IIOOM(N I(NO I1>0 1 1 'T 00D CD 01)co C I m H 0 h co 0 -0 LA 000 C 0 m i cm00w ILvc000 i i m0000 W 0 bOomD co LA 000 co C I0Co00CDCDm I WoooCcl I I ol a o LA D 0 Mi I or-m Nqc LA 000 D0 )C NI l ,C CO 0I0(1NoomDl0 CDoo wI I(0 0 w. mIDO ( co N 0 LA N 0 ) 4dU 4 0) 0 U 4 f) 4-4 0)- I 4J 0 riH Md I44 a)0) ~ ( (d wI L!)O) m En 4 U) tr)'XH r- a) 41 (d wI Ln tm A ) mI~- w w2 41 (N ~ ~ d CI)IdO ( :5 m 00 ) CI) a)12) 41 (N 4 (o j d ~ UI) H- 0 M - W 0I4 4 Q (dH 44t))O3 J) 4 ) r-0) IC -i(V0 4Id 4 Id 4.) 0 E )f 40 1 4 (d 0 d 0 (d d -) 0 (d 40)Q) i W J-) a) (1) -1>1 .13 I M 0~) )-W.H0 ) 0 r-0)W 4 W J 0) 0) H 41)~ rS 1 0 > V O j A : nU 44r:CI-4r-r E~OI O d 4 JO Q 4a r4C MT a) 4-J (n r. UCIU -'4 r. Q4I A -A 43 U) O 'I0)HCO 4(dU 0 44J0, O > *O0 r- Q)H~d d *Id)0))HOTOd a) -- d 0 -( 1 4 :$- : ( ) 0 : ) - d ( d ()ri0 0 WO 00/43377 PCT/USOO/01283 239 i C~0c oNi IL omC' N i O Ln m o aii%. I \0OLAI I N 0 0OC Ln Ln 1 00N 1 0 1 10 00C0 cn 0(1 0I0 I on1 O0%.00I INCO 10IO Ln Ln I N en 0 Q NI I LA0 0 C N 0100 L o o Co In t-10.D o ko C nC o0a0o Ln LA i c ,pCo-~ i~ I o w . Ln o -,i r-I 0 1 0 r-0 0w I I N I r- 0 1 I n c m0o0 LA LA LA LA I -:r0 C0 aI I f)0 N 0 0 0 oioo n O 0 0 Ic o o I o i i N 0C0o LA i o' 00 In o -o i mc' 0 N ~ 0 N w CL 101000 I I-z lo 11-0000 LA 1 00 N C 0v I I w 0~C 0 CJ Wn 0 I C 00rn I N 1 10-IC I I H 0 n0 0 LA i Ln oo Ir C w0zi, LA *ac4 0 1 N0M C 00 1 C~ -1 00N I I N-0 0 00 LA I M NC v I I v rnVaC) M C : 0 1 0 N C 0 I I N 0 C C LA I Ocn r-0 w I I r- n N0o C m 0100001 I OC3000 I No coO LA I On M0 V D 14 1 r VM c\JV0 a- 0 1 I0000nI O0 CNOI I 00000 LA 0 i rn LA 1 01r-> v o ~000 01 o COOOL I 0C\N 00 I I Z110000 OLA I n 4 0 Hw I I -zlf0 H C LA 0 I : C ~t 0 1 1 N \0 00C I I w COOO0 LA I wDLA0.;P> 1 1 > 0 r-*.' 0 1N C I0LA I M N N C m I I ~1CN 0 0 LA 11>10001 lM0V00 c'q 01 1IN N 0 oI oo 0C )1 I~0 0 LA i c 000 m I C\L00 r-ii ori-i 0 1 0000w J I *MO0 O I I OOC O LA I 1 0 0 p0 I IC3ACC\ 0 1 0 C00 c I c lv OO 0 I0 0 o LA lO0i co>~e~ 1>NCCiiN nCNN M 0 1 COCOM I fnr oaOI I 0Cv00 LA icoctoc4- i0 ' i Iq mLA o 0 i . C %D I I wOC'N M I M' w.0 0 0 1 I M0 ,000 LA -0 4 0) 4 0) 4-)O -iq V) 044M 4 w 4.) 0J If ) Cl4-4 ro X rI a, a) 4.I 0 w LEt r- t MO COdX- w 0) x- (12a 1 4-40) M1 .00 4-) W H CO4W 4 O d 4 0) mO 4)0 (d rd r_ 1 0 (d ~0 4 4 0 1 M fd d d zr 0 to ( 'Q-lj 0 M 4--H ) 0 -1W 4 0 w) a).d- ,J4J %4 -1 )E 4--) J-0w 0 -1 - l 0 .0 WO 00/43377 PCTUSOO/01283 240 1. 0 CD D O0 m I fncq 0 0 a 1 C0 0O0a 0 0 1 1 CoCH- 100 LA CD LA 0 1 C NIC : I L mOOO 0) 0)II D1 I 0 -I LA LA w N0CN1r 01 IIDcl CCI0I0 I I N C' CD CO 0 100000)O1 00 LA LA (n 0 1 00 0 r 0) D iQC % lc'.D0000 w 0 110000100c LA LA cq 0O 1 1C)0000D I C)m OMCD I I enc0000 LA 0 1 I- NO C 0 1 LA LA H- 0C O 1 10 0 a00000 a 1 c1 oo C% C) 0 1 1 LAOON r I r-clq N- H LA LA m' 0: I 1I0N o )0 m 0 oooDo i i LAO o )c , cq 0 1 10000O I OH LA LA 00 1 cIO -OH0 00 10) ooo i ILnA00~,4c- H 0 1 10000 100 LA LA N 1 0IC O I00 c)r 100- c 1 4pc:,0 000 0 0 1 10C )00) I0 (n LA LA w 0 1O I ICNCN0 CO I m LAOO 0LA I I ;:r j0 C 0). 0 1 10c) 000 I0 LA LA LA ,C C OIOOOOO oo ooo I r- n CD co 0 1 1I0 0 0 CN 1I0 1.0 CC) LA LA 0 L0 C. I IC) ~ L IN 100)'.c)k c D : I Imm A I LA ) : ) ) 0 1 COI-A OO0LA I C,4 wD COD LA LA H 01i ILAOn ' Dc)m i c-,t I I LAo c) 0 lqr m I LANr-C.)cq r ICOm LA LA 0 v I'I I LA00 m ~e i LA I c4(: ) oo co NCo1r C', 0IN 0 aOI 0 LA LA LA LA O I I0C a000>0DI NO0 00 DI I OOO 0 N 1 1 %ID m m I wN LA LA LA L LA N LA LA LA LA) 10) m1 W a)10u co)11 H ) U (d EO 10(1 10 ( Ln U ti m rO 10 ) 1 dX -4 4- ()I d 10 LA )-f 0) U)10 a)r X -qX 4( 1-1 44 010) 10 a)) rI ( Q 0 T r-I 44 00 ) (a0)0 0)H>.I4 13 V: 0) 0 Z Q 41~ 0) 0) dHk..1- a) H 4)(d4J a) (1 *OW>HI, 4- *I4 - ) -i())Ha 4) a) aO- ,43-4 - M U 0 a)4 ar O1 OW )4 0 > (l' 4a . O5:U ' 34 S WO 00/43377 PCTIUSOO/O1 283 241 0001I I C COO H 0 1 0000(fl I O OO I I LO0 0 0 D L k.00 0001 100000 001I0 I0 00 -000' 0001 Ic'.000 0) 0 0 0 0 -l O I I O O 00 I 0 m -0 0 C)0 0 1 1 0100100000DOO I 1 00000 N'. 0001 IOLMMOO r- 0D110000 100000 I I r- Da0 00 .- q 00 1 1 0 0 la0H0 ~ m0~ 1 0 0 10 0001 II -4000 LA OI1ooooOqI MCoOOI I HO O I C',C 00 I-000 000~o L 0I0000~0o0H0ooI I -q0 000 CDa 000D I I HC-D0000 ": 0 m 0 0 11C)lo c I I M'c~0' 0r o CI I L ~ 0 00a 0001 IH0C'00 M C iia)Nc ml a)00r-C', )00c' i ILn oc>~~ LA 0001C: I I 0000 D I ml I 1 0) 0 0 0 I0 o 00CI I I r-Orm lqc w L 0001) I '0 0 O D C l.Ore I I cr I ,0 I N 0 II 1r O CD I H 0 O mo ) I I -40 00CDRo % 0 I 1 0)~ o 'A I0 -c )c -C (nr0L H Il 0'A I n 0 0 0QC I I m CD 0CD0 M - 0) I C) -10 I) 1 0) Q C C:0C I I WI00 0 )C a 1 0 C) -I M'~ 0 %D W 0 m C I~ L ~ L LA 01 N0 0 I l~ O O mCJ0-~- N D m o iiwoc>m ir r nL oL 0m 0lDaL I I i :C.)Oo I'D 0 110001 IC'O 000 1 H OO 1 I- )0 D 0 N.. 0o% 1001 I C'.Q 000 m- 0i 1 I10CDO C - I l00CDC)()I I ~ 00 OOmo L 0 C 0) C) N. Od Uw *H ) tM S: Id Ud) -1 rd U) 44 a) Wtm I U)] 4-0 -q'-I U)i W~44 (10) 41 (d Cl] L 0r) w ) 4 m1 u r)-i 04 a) 4.) d Cl] Lnim co Ql) a.) 41 c 4(J a rdd' ;s wd 0 0 0003 ) U) a)0) 41 -4 'e 0 (a d d. 41 0 (t~d O () 4 d r. d 0 rd (d Q -0 0 E 0) - 0 -0A 0) w >14-) r-l ) U) I- H0I) 0 r-4 0 4 WA-) 0) 0) CO)O Q)~ r3 4 d > (dd O rqa).I 4J ) EQ U) EO U ~ I S4 Z Cir ) a) 4 a) FX4 4 Id ~> 0 rO 4 0) Id 0) -H 0 :J0) 4 -i ( d 0 *Id -0 0 :I H 0 :$ 0 ) -r *0 0 ) V -ri M Z WO 00/43377 PCTJUSOO/01283 242 01 I0000I0000CN II-l000 0 NI 1 I0 I 0 n n 0w IOO0I00ci 1~0 0 I0~0 I0 0 1co-10 01 IOOO0looomI10N00004 LN oI Iiroo'tCN0woL CI 00 0I~ l 00 I0000-4 '.0 rl0 0I I -lCo CI 10 000N 1 0roo00I I000 oono 01 I00001'00000 0D I I1000C I I o0moo-O I I COC0)H c.q 01 100001 oN-oc~o vi z o ~'c,4Ln Io '.c L o oi H o -lc. o-f - 0H O 00OONI MO COD 0D 1IN- 0'n 0N I r-CN C0'w C I I NCNmo 0 0 C 0 1 0 0 CC I q ci0 0 .J %.0 LA 0 0D0 0CD1 0 N0C Ic0oo 0 1 > D0 r CI I c00Clq1- 0 100 '.M0NC LA 0 0 0 1" ~ m .0 r H N 0 00 I I N C>C000 '0 W N Iq 1 N1 O I-C 0 .qCD OC Z LA 0'.w u mi I 0L o IO C0 Io ILC'0 LA 01a )00 11 nC oNC n C I C0 0 IN C 1r I0 CNC14 LA 0 I I) OCD0Ln I I-N .0 0C I I 1 0 -I0C)0 0l C I 100001D C 000 LA H I LA CO0 mm I CC) C4 C)0 1 w I '.OOLACO M C) I I1)00001C C H 0 CD LA co I CO-I. co H w i Nc4icDm I i I cD w qwm (N C I 1 0000 1 Mc0 1 0 LA N 1 Io 0 e CC I I %D0 I CM I V '0 vm N 0 0 1 I CO -I I NocN3C' LA r-I 1 n C0CDI- -1 CC CD I M C0COC CC) 1 Ic Cooc I N000o '0
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CU AJ(d U) id CU (I M 4 4 0 -4 1 -I ) LW )C U M- U) J r- o) E U UA 0 4- (HU)> b H m U)i ul U) X UrCU r: C d U 4 0rI44 )0 4JO - r. (Lri ( )z p a4 Q CU -4 4-U3 M 0) d 401 ) 4 d r3 d 0 (a d Q 41 0 EU3I U0 ) Id 4MW ( . 0 *H-i>4- 4 -I t)) O4- 4 ) 0 r-4 Q) ) J a) a) -4 > 4J.--4 ) 4-) 4J-H ) 0 MU VQ MU PQ U U U : ::ZW UE U) U) I> 3: 'd -4 P4- P4 M M M U~ u U C ) 0 E: D iC WO 00/43377 PCTUSOO/0 1283 243 i Ic~cq)L 0 li 0 100001 I Iol-00N- I lqcD' O00 Ln NI I 0 CD0000 0 0 1 CM000OI rm00co I I MODooO 1 i' O Ln I MOW0. m~ Oq IMm ci 0O m a 1 01 11 I I m nin C)0 in in 1 0 0 ~0 CN 0 0 11O 01 1 bD0 -0 mI cq w0 0 '. 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C) m0m00 o0 0 C) I COC C 0C CO -4 01 .0 CD C *0 1aH ) N 0 -C)c C C) CNC-4 CD C)0 *H z 0 C D -40C C 00 C 0~~- 0N C)4 ) 0) C 0 0C)C C CZ' r- 0 D ) 0 C ) C w 0 00) W . w) CD4Jr- H)J.0 OJi00 C) H4-H- (00 (Y CN0% )C 0 )0C )Qr) rIHrI He WO 00/43377 PCTIUSOO/01283 248 NODOO000o00 00 Clo0000-aI0oo0000ooo H 000 ooo0oooI00000 r- 00 WM00000 oo 0 HOCDC rq i-I 000o0N00000 1.0 00000Coo00ooocoo 00 0000 r 000 000 00 n 0 400 w c- ooo ooo N 0000 H H 0OCOOOOOOCD C 0 ro Iq 00CD0 0 r -0 aC)0 CD0 0 00 1.0 0000 H HHa M00C 0 a0 0CD 0 0 r, n > 000 1 mDc0 0 k N 0 o In 0 m IoOHo H N 01 MOO MOC OO~o On I H 0M0 C - l.CD.0 0 C)o;z oo0 u - C 0CD CD rH -A 0D000)CD00C>00CD0 lz 0HC 0C H0000 CD00 000CD00a0 k 0000 N O H H N- H -I 0 c0 NC>C)00 C N1 CN C mQ0 0 co -0 ) N o C ) Il n 00m00 H H O~~ 0 0 0 0 ol N~~rl Co (N H O 0 0 0 0 0 0 0 H HHD0 On 00 ( U) Q (d 0 00 0 I In t)H m0U)N0U00 1H0 l N 000 .1 0 )4 l o4 . ( 4r ) E X rI 4- ( to LO a)H w 4 to - 04 -W (d ul n ) rA )H '0 0 00 U)a )a) 4) C 0 000 00000000000)0 a)0 0000) C O a :fo 44 ~ ~ ~ ~ . tnt) 4 Co0m H r 0 d4 )t) 4 : Q - dm rA o r. ~ ~ Ho0( Q4 )0 40 ) 91 sQ4 )0 40 L 00 0 0 0 Q 4Q - 14 rIq C' 0 00I4 - Q 00a)0 4 c a) 0000 , 4)h4 4 ~ ~ .
CoC drjW U X rlI lr )a (3 d1 )w r)( 1 a~ ~ ~ Ho> )- )- O U 0M J O t)r4a - 1a 0( -40 :J(OaO;OO O O - ( () - 0 . - 0" ;'.2 0(dN 0CQ) 00() -H f d 4 ) r-A I e 0 :R: ~ ~ '. Co 4u O>: R E a nMM up ::: 4a WO 00/43377 PCT/USOO/01283 249 CN2 WOCD0 00C'0N0LMa 0N CN~ 000. L OO O O O C 0 0000 00O 000000 r- LA r-000 o 00cic m LA 00 0 00 0 00 0c0OOqI L C.lq~ 00m0 D )0 0 00oDo C wo cD o o oo 0oi0'c v o-o0~ w0nL - l 0 CN OO OONO o-:COCNIC N 00CDW 0C0C zv0000LA0 0 H m0 m~ co 'H onoo IOIDOOOo w C>00N~o~o oL 0 000000o 00co M H~ 0 DC 0 a0 q0 0a 0L 0 1 0 CI L 00C 0 0 00 000DCD00C0 000C 0 0000C D D00 00CD0 00000C0 CDNIc 00 0q0 OW AO O OO O w m0 0 0 00 0 0 0 0D000C D00C C O C>n o o ~ o c 00 0 e 0 (NMIC D D D wm C CDI (N 0 (NI 0 (NI (NI co 0 )a )a 1 l ) d M w 0 )0 () 4) o 0) (0 44 t) H (0-41J) 4--1r0)rA ( O - 4 r d r 1 4 tlt -,-I l a (1-1(Q - 4 . 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Cfl u - H U) 44t w) U) 4 An)a)H 02qU)4 0xH r- a -)(d ca An a)H11 U) 02 ) 0XH -1 4 a C, d ( j c 0 0 ) a) a) a) A.)- 3) (j :(d :J c 0 0 ) a) a) ) a) tm 1 b)a) -i r.0 ra 0 ($ 0 a) 0) 40)a) 4 r. 0 as .Q41 a) W U S4 . 0 r. UH) 0a) )4 ( >(i o f) a) 0 H4-uJ 14 04 z - toa) 0a)Q ()> ( 4-)a) 0 0 U~ 4( 0 . 4r 3 - )rI 0 a) r 4( d - 4r 1tlri (dP a)- 0 0a4- 0 : a) ~44 '>0 ::s a) 4 W ro( 4C )ri0 0 , J0 a JQ WO 00/43377 PCTUSOO/01283 253 0 '0Oor-0 0ooooo 00o N 00000 000coc oo 000 CD H' 0I 00OOoo oo oo W 000000000000 l o ~ o o a H 00 M o- H OOO)CoOmocoO ooo~oo -: LA NC 0I00OCD CO ooOO0 N) 0 (DC H D1- C r qC 00H1 (1 10 c 00000 M 000000000 cq nMr 0C 0N0OO-OOO CN0 0 0f L 0L00) 000 ~o~ 0- 0I000aOW00o0oo N- -I4 - C m on M C -c CNI OO \ O 0 0 (D m ncoo r w. OIOOONOOOO CD n OOO N H H 0' HN , LA , oc noo , nor 000000-0000000 0M C oc'o0000:Po mw. O LA I 0000O0OcN00'00 H h -I H 0 0 0 a) 0 1 D0 0 r'(r 0 00 0 0 CDV00000a n oi ooc Na 000 o'c040c o0c'4 0 mH (n0 0 0 N - O ON 0 D%0d 00 1-oC'QCD HN ODr-IO OO)O O 0 0 () a0o>0 w. -H rH r i mM 0 - 0C -0aMC D0m00vr Dr LA 000 0Cogo oC), 0 CDCD0 0C. D 0 0 '.0 0) mm 0 L 0C)CCD 0 C 00 0 0 CD 1000CD 0 C) CD ) C . o om n m 00c40)0 r '.0) 0 C C) (l~O 00 0 0 CD0 LA a C)0 D0 a C) I H00ON0000000 0) r 0' O 0r-oc) r- o-,r.0Lna 0 0 N- 0 0 00 OD 0CD0 0 00 '.00H 0 0) w ia )r c. 0n c)0c A00 c)0,o0.'., w -: 0 100~ I k.00000000 '. 0 EaH ~ wf U)f J. U) U) (13 j U) -, a ( , b) LUH 024 (dX 4 4J)t u2 LAU) CJro 0 - U 41I U 0 IU q U) 4 .mU) 41 0 .14~U U) o) L a) -I U) 4 U) X -I_ 0 ca Ln ) I to 4 c x - 0 4 -) ~- 4- % r U 1 -1H ) 0 Q) 4 ) 4 a)rU - -) lk4 JJ.0 d 41 If ) 0 a) U)U )4r - C ) M 0r - )Q W *U A4 : Q r. W )O4 r- 0 Q O ( 4 f 4 4 ,r )rI()r- - ) T 4 (l(5 P 4) 14T ,0 WO 00/43377 PCTIUSOO/01283 254 000 -1 0100010000000000 m (NI000k.OMlOOO-z: m Ln 000 0 NIrnoooooooooocqoo (Nq o0i o00LAn000 00 ~0000000 00H01000000000 CN Ln 1- 0I co co ooor-c-000000000 0 H I N00N-w000 (N LA c00-,Z t- 0I 0 a 0 0 0 0 0 c~ 000c0m'.ooooo 00~O~000 t000mo ov0m(NOt- 0 00 a0 0 qlCNCD0 00 000 Ln 0 0 iO 000 C>CDCN 00 0oo r- 0icco0nmoooo 000 r- 0- 00 0 0 0 0 0 0 -V Ir ~ ~ o o o (N( 00000Izv0 0000000000 LAo 0oI000CO00000. CN 000 0 mN cooo000(N0CD0000 (N 0otoocooloocoo (N L H %oma) 0 1 0 0 0 HH -i0O0C)0 0 )0 0 0 01I000000000 0 0 ooo C) 40 m I IV C oo0 D 4cq cDC : I ko 0 r-I' 0C) -: ren)O r- Ii I00COM0 00 0 C0 0D c) CODum 1000 000000 H e H -I H m C) 0 cq LA m I LAQ0(NcO00lo 000(ork C) I 000000000o C>0Cq ) qv a o0 C 11 OCDr ) DU m Cq I qC C )CDC 000 co C DC 000CD a 0o o o o C 0 0 )-z l N oi000000000c~c fdH d U ( co~ Hn cu r -0 N0p co X o- 4-L (0 LA a) Oi EOO( (to 0X0.
4J~ Oi i -W I 4 -q t3) 0( I) po a)o La) 4- a ) (N -ri 4J 4 - 003)0.000I () > df O0-4 U) ) 4Q ( o _ )a U) 0)L Z4 0 0 0 -1 a)- 4 - ) rO 0 U H d 4)ar 1)- 0) r- U) H- o (3u p o( W 0) 4 -r-I(d d 4 * Q)r-j 0 0 -rI 0 l (d a) :j ) 4 -H ( (a ) r4 0 4-1H ( > :::E Y4NmmmuC)c z P P4 co u)~- > :'& - 4M 4P U U -1 U*DHZC WO 00/43377 PCT/USOO/01283 255 00000 N- c Ho ok o HO o o o o of L -i oH ) 0 \n0 m m LA 00000 W0000000000000000 0 mmdo~0LAcom0LA N 04 LA 00000 CN I(MOOMOO000(0000m 0)000 . OOOLAOO 00000 m 0I0O00c oooooo Co OI00OCNCOO 00000 Cq o) N omooo~nm 010000000 00000clooo10 0000000o0 L. 010000000 00 0 0, mI O ~ oo o o o LAL -10 C N00 0L N : 010000000 -. 4 -:v* 00000 00 CN I V000~0oo-00ooo m 000000rn00 w P 00000 N- 0OOCWowr0oo0NN0000 CN 00 00 00 00 0 w Ch1 00 00a0 w D L o 0o 0co00cr-Nqo a ooo 0 LAI1 00 0 000 '0r -0,1 00000c 0n C I M000a010 0 m0 00m NI) - 00Dc0 00 0 10- -- * Co 0- 0 01 C.) U 0 00 00C H- 01000000ocaccoooo w LAIa 0o'm00 0000 C)0 C) 0 )C) 000 0 14w C0 0C0C0 c 0C)C Ln L i o 0N cr-ooo0 w 0 0000 C)0 m, coo carNOIDC0000000 M )CDC 0000 000 LA 0 00000 OD ~I~ o~oo 0oc0rI00 0CN r(N 0I1000DO'000 LA 0 00000 N- 0I100000000000000 ,c -I 0 0 w0 00D0) 0I 0 0 0'0 0 w C 0I(N c0' w0 0 00 N 0 N0 0 0 C) vi Ln c00oo 0c LA ,-f s-I N 0 0 c0 0C)10C m) 0 1 0000I (N 00 0 00 00 WWW0OM000 W4-r4 -1o ~ O * O' ]41 4J1 (d E L a) -4 ) 4 U] Cf~-1 4- (0 (0) LA)a)r-4 U0) C(nx H ~4.) 0 a)0) 4 0) a) 40- (dd O IQ041 0 ()0) -4t 0) (L -f z (1.4 ) 4-) 0) Hj-44--J.5S4r-i M4-) -1 () 0 Q) 4) 4J 0) ; H -A ' ) 04J--H0) 0o (dro I a)(L U *0) u-1 F 0 r .0) a) o >(0 r-H-I a ) aU (0) -%40 . 0 >1t)- )- 1 a O ( 4M ( 4- ,r ,6 - )riQ 4 ) r d U 44 WO 00/43377 PCTIUSOO/01283 256 00 CM N. lq - -14 c ,so aCoaooacqo o m m Lna) m 0) O0 rO0 0 m LA LA C0OM 0 d 00 VD 0) M 0 (z zo0)0*N0 N 000000 0)0 Ln LA 00 0 0000 (N 0 D0r ooc Nc oL ooc co r4 ~ 0 0 a%0 (N 14LA LA LA 0C0 00C00 0 00C00oCoCoCoCooo0 0 m c(N C0 0Om LA LA 0000000 0 0C0C0O)0OCCO0o00 ch 00-v00t-0 UA LA 0000000 C CCco OC O CO C 00 0c0o 0 o 0 cq ( 00 C)0 ) m LA LA 000 C 0nc ('0 m0 C0 C0 0 C N0CN 0 N ww I 1 0 0C r1 LA LA LA LA LA LA 0 - 0 C OON a' V) C ( 00tr- 0 0 .0 m0 -v0 04 .-I OOOOOLAC O V li r-I ;* LA LA LA LA -C O ' (-N C1 0 m ~0 1'-V0C 0 W0I0qr, 00( (0 C 0 0 00C00CAm 0 ~ 00 0 -4 -00 ' 00w 00 0 L 0 0 0 n Ul 0 00O0 0 0r 0 r- NO W a0I' I 00O'00( w CD C 4L O',00'0000 0'0O0C0 0 C m 0 Cl0O 00CMO'.00000 a 0N (u"v MOM0 CO00 LA LA LA LA 0000000 w0 000 0 LA0 0 000 00(Nk cq11 Ia (N0,0 0 0 LA LA 00000C ',' LA IOC'wO(N'004'w0a% C 0 , (Nv( C ir i c 0 00 (n 0 0 r-I .- q (N LA LA 0I0000 N I~v 0Lco0LLn w c o 00o0o00'0LA D r- (NI (N0 C0 0 0 r-q -4l- H(3N C0m C0 00av co ~Ln 0,o L c m ,4 c0o am kso( 'o w 0 0000 00C 0 C14 -I (NI LA LA H 00,- 0 C( - N a% I00 C00(C 0 m01 m h v 4 L en 0)' LA 1I0r- 0 C h0 LA LA a) (0) I1 b U ) U)) 4 U) En 0)) 0 ri U)44r:4l ID4 4J(d Ea Ln W -i U) 4 U)X - 4 4 d W Ia)H E U) -) 101:: w H (0)M I 4 : 0 - d4 )0 -4 - d Orq .( Q ( 0 J 0M )Q 4 r d 0( 1 0 a ~ 40 ) WO 00/43377 PCTUSOO/01283 257 m0 0~ 0 00 in nO WO OODOI00COO0000 d0) NOO000 Ln LA Ln Ln 0 0 m '0 C10 0 m M N0000OMO0ONOONOOO to 00 0 00 Ln Ln O0CO 000CONO N OQ000oOOoooooooo in %D o m 0o in LA in LA 000000000 0 000Ol00000 01000 in LA OO 0mO~o o0 0 )a n0 0 C>a )00 0 o0 0 0 N 00000 0. 0 D0000 o w 10 ov0mwo ln in in in in 000 ~ 0%0 Nr000 -4 0 0 0o o 0 0 00 in in 0O N in 0 000 0 0 0 000 , 00 0 0 0 a 0 0 0 -4 01m00 in LA 00 00 00 0 00 Nivn n oo ooc a NoNowoo r- e I0 0 W 00 00 0 0 ,00 0 O(o0 00 0 '. inn I N o 0 00 NN0O- 0 0 0 o co 0o oOmwa a 0 oc o a) o) 04 n co co cooc'N w co in in oOc0o o in 0oO0 0 N-0w0 0 a)0 0 m m0 0'N in 0 0 0 000 w. H c in in Cl0 0 0 0 N0 0 )0 0. 0 0m 0 0 C14 1o) a Nw Zo p o H 0 0)0 0 N~ in H H HH H in LA 0 00 0 0 :v0 00 0 N C0 ',h0 0 0 0 0 00 0 0 w-0 m00a LA c io LA 000000000 Nl wow0 000NOCOMO~c ON a 00000 LA LA 000.0.* N O 000 mc o '. a0 NO~O 00co 000cOO in
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Ln LA 00VI0 w N 0 m in IOOO0O 000000in00 N m 0 Q0C4 LA H N LA LA 000C)0 0 COe m 10 rl' N0zp 000aO 000Io OO N m0 m 0 0 in LA 0 2 rl Uf ) 0 0EO440 a) ~ ~ ~ 1~ wl 41O C, a 0: a lwa ) 4- z omt 1r W~- COL-i dM4I r 44 4- 0 4 WH (f 1 -A -4 . r: Ord. 4 .1 0 0) 4 0) w - 4 fi1 0(IQ 41 0 a) tMO40) Q *d12) 0 rO >1 M -i a) 12) Ja r dU 4( (dHJ~ tlJ 4H J-)a r > M 4-) 12) Q J ) O d H 0 COW (0I d 0)) O OO~~ a)0 3 ) 0)M d 4 - 00 4 40 1 d 0 W4 4 d d 4 - ) j Z Z 0dW0 0 *Hdd m m .1 : 2)HOmO 0zzzP m >: 3:E 3 4 WO 00/43377 PCTUSOO/O1 283 258 0 0 000 0 00CDCD00000D0000N 10000 m ococa CN I1O 000 000 000 0~00000I-lr000000000) 0N NI0 OO000COC>O-4o to 000000(OioOIOOOOOCD O 0- 0 10C CD 0 o0 00 o o 0oD - ooooowv'ooooooooo 0- r (NIM -A0)000CD000000 '0 0 0000 r 1 0 CDC 0 r D000 - n0 00 010 w 0 00oooo C 00oo0o - r-_ mi omo~o ooooo~w r - Ln 0ow 0 0 0 00W COM0000 na O c ) Dooi nco- m '4H 0 O'lA 0 0w CD -4 CD n0 00c: 0 0 0 0C> D w0 CC) N O 0 1 0000 (NOCCN m' Lla O' w w w a C C m0 0 0( N 0 ) I C D N00 O00000 0 0- m0C~ C r-Ln a0 0 00 0 0 '0 0 10001'0000000000 Ci (0 1 0 (N '0 '0 0 wN w wN 00 0 C)'n0 0 w0 0(N ~i0'000e000N00 00mO C a' '0w 0 ( 01 0- ,-l 4- 4 W44( '0 '0 I)( ~ n 4 W toX- 0 W L f u 0 W U4W. A) -4 M4 4 0 W ~ U)W4 - 0 S 0 J- W 0 5W 0. -H4- Z (UP ) r- 4 -10 HJ( 04- :J W 1U0Z k - ) Z P4 , P j)r inW>W3 ::E1 a-MM U)r 0, :E Z~ in04- 0UW() R: :E P a WO 00/43377 PCTIUSOO/01283 259 O OIC'.JOOOOOOOO N L I O 0D -0o-owC o-Wr'lON H- c OOCO CO OOOOo o o LA r, aO I'f 0 CD0 0'. Cor )00C NC ) n o o c co ~ o c o n r 0o0 00LALA00'.OLOCD N OICno1000'.00O0O000 ;:4 0 000) 00 CD 0 0 0CD0 C C) r-I 1'.CD0 r0oO,0 0 L )0 000 CD 0N w. t.0 CDICD a) 0 Ow o n o . Co Og O NO A ~ N 0 . 0 0 0 0% I Ic om o ko o c 4 C 0000 oDO0000N oOCOOc., 0 '.0 I 00 NI >0 -4C)m 00 00 o mo 0 H 00 )C N w C 0000 C -0 0 0 Iv0 C r0 0 00 ~LA H LA 0 0 0 w 0w 0co0 0CDCkm D 0 A D r 0 ) 0 C 10 " Co0 1CCDCDCDC)0 0 CL( w. H LA mO1ONo 0 0 00 CoWCQa D ;vImC 00000 co C C0e0a00C0C0CD00 H w. 0 0 CD000 )0 OO' r r 1mo No NID 0000 CCCow0co 0 m HHHN '. Q'D.0o ) 0 0 0 0 CD w C O D 0 C 0 C DC DC h c '.0d 4tF '0 a) mU X 4J)( A ) ) MU 4 u - . (3 t ) Hjw 0 0 w()a 4-) .N 3 H 0)0 ::j U)0 U )U)) - N I fd4 3 M 4) a ( Q qO r. (0- rQ as 4.40)P -- S-:a) -4 dM H r 4 U)0 a0 0 a ) d)4- 0)U~ U U)0f 0)a 0).0 (S4 4) 0~ a)( 0) a 0U J a~ ) H ( U H ( U , Wt O 41 a 4H J% - 0 1 -q a) 0 Q a) H 4-) 4 : aa $-4 rQ 0 (. 0 or - )0WMU 4 W~ a 4 Qd (dU > 0 r H) i( (3 -t)4) 4H rO W 4 >1U - 01)1 4 ) W .H ( Ui, d H J). -) a 0WO 41 0) r- ) - 4 HQ 0 0 4 -, 0 :J (d Q)0 J a).c-H (d (d 4 a)H- 0 0 4 - 0 4) (U 0 J Q). -H (d (d P U U 0 :: :E- m 4M Mrr' U 0 4Q EU)W> : 04C WO 00/43377 PCTUSOO/0 1283 260 cnc )0 0 1m mCqC - LA 00 00 O)rq00 h0LnL n 0 Mo~ojW~otoM~aw m OO OOnN~ A L CN I' r-No o a %o'o o vo o o o m -4 N m OO0c~h q I W rNOaW o W r LA -4 rAI Om O a OO oo0 n )00C 00C 00 o coor-coco moo ccoa N N CN 10 000O000OO OoOoO Ln 0c '~0 N O ~ 0 O w or L nooo 0 N CN N CN Nq N C D00C L D0C D0i o0 1~~~~ ~ ~ 0 0 000CCD0CDC W CDM i >c qc Dco Dicaoooc Da N O 0 r CN~O m Dr -00C l -Nm ( l o o~ o M N O N H Ch- 1 i ) ~ o~ a i ~ w CN 1 r OC O O'~N O~ I comr l ~ l0 0C N 0 00100 0000000000 C0 m 04 C'q w rN co a) c00Noor n %c na o rnmc o AaNoN )ot0 -vmo o o0 aI a'IH r- ~ ~ ~ ~ ~ .
NDoa )mo i-voc oc na r DQ000C >00 0 0 c toI -4 M. N- 1 U 4U w4)0 H ()4 N000I Oc a f0 J) 0 4) M I 0 ) a)000 r00o 0 004-) 0 41 H- 0-I 4- H a0 ) a J Q) E - - 1 b - - ) 0 a 4 Q M ~ ~ ~ ~ ~ ~ ~ . NJ9 0Qr ,MW ar$rf()()U )U_404 r E ) d>(391ria IC$((jU 4 ( Z 4 -) r 0- A (1 HN 4-J L O ( i d( 44 04-t O O O>s-0) - 0 0~~~- 0- 4 0 ; 1 )0 :JQ ' dM 1 4- 0 7 0a JQ rI( M ~ ~ ~ ~ ~ ~ ~ .
N )U ZZWr O( : E4A 4C )uU0ZZC 4WW>- :E 3 WO 00/43377 PCTUSOO/01283 261 m na nr Dri- ) 0 e H OOOO CA 0OCOOOO0 m0 ooC H H '0 Ln ~00 0 D0CD0 1 I r 0 .ON0C\ 00~ N- OC 00,00 oo 00 0D00o H HH ' LA O~ 0)0L )0C >C r Nmr 0 w aocNooa 0O \0 O,~ 0 0 0 o co H4 LA w c r c oLn wH oo c cDo o c) . LA O0000000I00oooOOo Ln O0000OO0DOI OCCIOOOC ' m )0C %0m 000HM LA H Ln H- H LA 11 1 LA H H 0 -V HH H H NO0O00000 .I D OOoCDO LA c OcD o o00c4oIoAc oto mo c HH 4 H H )4 . n4 W 4 i x rI -)fl n U) a)H En E x 4)(Nt (0 j 100 )(D4. 0 ( a j in o 0) CN 0 4 H4 H d4 n0 1)0( 44 ( - 1I ( 0)Q) k : 0 0 d () 4 ) ) 4 . 0 a N 'A 0) -W H00N a) 0 , Jf- rI4J r- - , (N) 00 0 0 0 0 0 k0w00 Q)C E -4r.4 r.r U ) 4 (o> (dr Q ) nCo _4 : 0 !W 4 > MN a) O ( 0P 0 ( 4 J0, O u 1(1 - a 0(1 4 d HJ-)C0O4AC' O0)HmQ) 4 -a - ri o : a ) o ) 4 r. 4 -(H Hi 4 0 : d ) 0 : 1 a P P uL U0: : X 4cnE > :3:E a MMU ZP P ) n>N:: WO 00/43377 PCTUSOO/01283 262 N' 0000 00 0 0000 H - m al 0000 r 0) 000 N -0 000 0 C H 00 000 N m -4 r0 0 00C0 H1f r- O0 000 N H: )m - 000 .0 0 0C 000 00 N '.3oH 0000 M - No 000 H N0 N. (N H 0 C 0NCC0000CNON3OM H00 0 C 00 000 H 00 1 0co(No 0000ro(NNCO0 0 000 0 C '. In 000 N-.N N 0N N(NJ - 0CN0C00 D C c t-~ l0 0 0 00 ( 0 .. ( . 0 li 000 H0 0 N~~0 HHcq00 D 1 oC 1000000 IC C0 0 0 N : 000 0 0 N- HH 0000 0 N- (NJC 0 (NJ N- I0 ' 0 0 H0 ( J O 0 c0 000 N~ N 0H 1 00 0 00N 10 10 C0100C0 C 000(NC 0 a CIen 000 C cC 3 N H- 000 0 N 0CN N cq (N N H r- i o 0 n 00 C 0 00 0 D c woCk L : 00C0C0 n o D HH 4 r-0: w -4000 0 00 0 0 cI.1 r00000 n 0 1 Ln I C00 0 1 C 1-0 1 1 0 coca~ H(N ko 010 0('3 0N00 , h w HH U-4a C ~~~~~~ 00 0 0 00 0 0 0 C 000 In N In% no m CiLnn~~-o ,U 0000 0)(. N 10 C '. 0 HN 0N 000 C0 00C00a0000CC0000 H 0000 00 N 10 000 0 ( ril H N [A00 0 01 0 0I1 0 000 M 4 ) 14 m, H) HHi HO H4 000- 4 -) ( C m 0 00 )rCN ) a)6 1 ma 40 0 (dN00 4-J00 0u10 no NdcC d00 00 ' -44 - ) 1-- ) 4W 4 H) O'i Nco m -4 ~ a)(O 0 o' )-j00. 1 HH r )0 %Q j-i( Z - (d'44 d l 0 0 0 Oa ('4 N N a 4c y )E R 3 P 4P 4WE 4MiP H P4 a WO 00/43377 PCTUSOO/01283 263 0000 00 0000 10 0000 e'i 0000 %.0 0000 0 (N (N m(N C 0000 N- 0000 mn 0000 14 0000 00 0000 m~ 0 w. M N n co (N (NMmm 0000 '.0 0000 r-4 (N000 0 0000 -0 0000 co 0 w. ONN in co (N C9 mM 0000 in 0000 0 MO000 m~ 0000 m*. 0000 N- 0 w. a%, -Ln 00 CD0000 ' 0000 0 m 0000 C 000 00 C)iC 0 000 in o W. co i- n CO (N (N m mm 000D0 CD a 0 000 Co 0 0000 w m r'000 0 0 0 0C0 10 0 in co in co 0000 co 0000 N- 0000 in '1000 %.D 0000 m 0 in co Co (N (N r 0000 N- 0000 w. 0CD000 01 000D0 .-4 (N 00 r- (N 0 in 00 Coi 0 (N (N mr 000DCl0 Lo0 0 000 in 000D0 CDI 0 0 0 C 0 0 OC 1-1 0 C9 (N mm 0000 in 000oco00 (NCC 0000D m~ (N0 0 0 in Co 4 co (N (Nrnrnr 0000 CD 000D0 m~ 0C>00 1-1 000CD0 Co 000DC)0 0) 0 in Co Nqrnr (N (N e mm a000 0 M 000 a0 (N NOOO0 C 0 CD0000 N- 000CD0 Co 0 in Co N- mr (N (N MMm 0CD0 00c 00000H c3 00 o0 0 o0 0 0 noagwoc on 0o 0m 00 00CD0--1C 0 00 co 0000 a . 0000 a4 n 0 0 00C04n 0 Lin r- 0 ZmZr 0 ol0 0 Cm 0r' en 0 0000 0 CD0000 r N H a-Ia0 rM 0 00Q0 ll1 0000 ' 0: C In N- 0 M N, (N (N rn m 000DCD0 m' 000 .D0 ~0 0 0 CD 0000 0 000 m 0 N- 0 MI (N (N m m m 000 '0 0 0 C) 0000 0 000 Q',v Da 0Coo0 0 000 CD(N 0 'I' N, 0 N N (%4N en mM 0CD000 in CD0000D m 000CD0 0a) 0CD00 Co 000CD0 H4 0 N0 (-mN N, (NQ (N (%4 CM 000 CD0 mCC 0000 (N C>0000 C o 0 000 N-C 0000> 0 0 N 0', (N NI (N (N4 (N nn 000 (N D 1 0 000 CD li 00v0 N r 0000 w. 0000 m' 0 (N (l N en m' 000DCD0 H- 0000 0 000 C 0 o0CD000 in 000DC)0 Co 0 -:4 0', m N w. (N (N N C14 , 0000D C 0 000 CD , 0)m 000 i n C>0000 czv 000DCD0 N 0 N~~f C14O)Um U) w) '-1cf a) M-C~ w) 1O w 0) m U) (1) - l z (a (N)l z) (N~ d a) 0) ri (a ) ol r. (d 0))z( (a U) a)~ I U) 10 (1) Id o (1) Id rcl a '.o 'l C/ ) 4 >1 i r- () a) > 1 ri r-ia) a) > 1 ) r-Ia) a) > 1 U)12 Wa Q) > 1 11 U) -a) Q)> r -4 W Z4H )I r:-4 a) f4 aq() I aj_4() 'HaI ) I r a_4() l-j () 1I S a) f.,-q ) 1 WO 00/43377 PCTIUSOO/01283 264 OH (NI 000 C c D0 CD 00 0 t 0000 00 0 0 rI0 00 00 wa Ch D 0> -* n '.0 0 10 1-4 00 '0 0 00 (N 00 0 N 000 0 r- 0 CDaCD 00C 10 0 OL '0 000 0) 0 0CDa 0000 CDoo o 0000 r-I D0 00 w. 00 MA w'O.t 0o0 00 0000 01 C 0000 C) 0 00)0 0 0000 LA 00 '.0 vo '0 0 000 N- 0 n000 (N 0000 Co 00 Co 00 CD1 0 co 0 w 0. C Ln 0 a0v n V.0 CD000 C) 0 00 H 0>CD000 N- 0000 w'. 0 000 mn 00 H'0co Ln 0 an w. 000 rH 000 0 0 000 a 'w. C 000D0 CN 00C210 (Nq 00 H .0C Ln 0 0 00C 0 0 0 m 0', 0 00C0 LA 0 00D0 0 000CD0 H 00 11 an 00 an 0) 000 0) rHOOD oC000 a C 0 0CD0 w 0'. O 1O Co 00 C Ln LA 00 Co C 00 D0 0 N- 0000 (N 000CD0 O) 000 C0 00C w c 0 an C0or 0) a0 n an 00 0 Nr 0000 w. 0000 0 0CD0 000 0010 C LA 00 0 LA co en 0 -; n an 000 '.0~ 0000 LA C 0 00 0) 000 )0 ( 0 C0a 0) 00 0 Ln Nn 000L CD000l v 0o0 o 00 0000 H m0 0~ 00C 00 ~ 000~' 000N 0 0 0 0 0 "~a 0 0 " 0( 0 0 U o CD ~ ~ L CN C~( rn C D00 C 00C )uw 0 D0C o 0010uH 0C 0a can-CI 0 000 CD 1 (N00 (NC) C 000 ' 00 Co l H C 00C20 H 00C 0D Ln N N 0) qvj ~ LA Ln Coo 0 an0, 1 D0 D0 C 0CD000 M' C) o H ) 0000 0) c0 o Ln N- (N m~ va n an 00C)0 H 00 0 0 D0 ) 0 )0 0 q C 0r 000 C> 000C) 0 0 ', C 0 0 LAN0 Co 00 an 000IV CD 0 0',v C 0 000 (N 0 000 CD i 000 Cc 00c 00 CD e2 aC 00 0 000)CD0 H 00 C o 000C w 0 .0 0CD 0a 000 a CD 0000 CD 000 0 000Ch 0 '0 0 n a00C0 0- 00 M an 0 00 _q 0 00C0 m$ 000 0 ' 000 anc 0000 N 00C 0 0 c 000 H 000 ) 0 0 C 0 0 0 0 0 0 0) ~* '. fa Nd a) ' 0.U) a) am- a) -u m a) -- QU tm r.a (0 ol 0)0 d 0) 0)r ( ma r. ~a 0) 0) r a rda) c 4' 13 ) (N 4)t) a) (N )' 13) QN)ta'U 0 a) t2 H .3 m Q) H- 4~ a) 4H Jm 0JH J~a) 4- 4 H 4-m W 4HI ad ad r::it d ad r:; a d aa om (a (a d ad (ad d wo Ha ) (D>,Ci Ha)- a) >1 Ea Ha) 4) >1u Hw a) w >, ) Ha) a>CI 9 W 44 r-4 Iap Wfa)H44 3) a r.- a) rX4 r a) a Z % a) f4H a) a z (Dx9 w ) I r ; -4 *aad it0 4 0 JH (a 0 ad (0ad $*H *fd (d -4 (d a. ri- *ad d 4 d 7J - *ad $4 -a WO 00/43377 PCTJUSOO/01283 265 00 -;v 0000 rH 0000 0 0000 m w N N 0 10 00 C) n 0000 0~ 000 .0 0 0 00 Mc o 00 C 0000 m 0000 LA 0000 to to L 000 00 r- 0 000 N 00 0 C . n 0000 1 0 l wA 0 00 C D00 0 r 0000 '.0 0000 v 0010 1 M. CD 0 00 N 0000 w 0000o N- 0000 0 00 CN LA CDC o o o.n 0C 0. '0) n w 00 LA 000 0- 000 0. 000 wA w w 00 r- C 0000 -4 000D0 LA 0C)0 00 C C CN~~ 000n '.m 0. 0CD c o 0 '.0 C o o C 0C 0 C w 00L 00Ln C-" 00 C >C 0 0LaN 00 0aC D0 D0 w w0 C coQO 00 0A C>0>a0D0- oc - 0 C )0w000 OO ow ow o 00 -4 CC 000 w m 0 00 C 00ONQ00 c CN 0N w zl0 0 0 .' 0D0 LA 00 C CD L 000CD0 H 000 a 0 . o'oo. HN NJ' N- m' 00 0' '.0 %0 W. N H 0 0 0 N 00CDa CN. 0000 0 000 q D Da0 N, 000 Coc 000 H, Z -i z. .0zt A:c 00 w. 000 000 000 H 00 00 H Oui' LA 000 00 Ho 000CD0 m 0 00C0 LA 0000 000 ' 000 rH -0. '. U ' w. %D0 w. N) C 00 0n 000DCD0 N D 00 1)0 ~ 0000 m' 000 0 k -4 H. v. '0 N) 0 0 00C 00 0M 0000 '0 0 010 C 0 0C)0 0 HoC 0 0 0 0 C'. N. 0' 000D a DCD00 w 0C 0 - D0C H. M. 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O (d C. rQ 4J W 4 U 4- k u u ,Q .0 W )4 U Q ji ) U U rQ4JM '0r .H *C- dC (00 M :H *C(d (~d l 1 (Cd (d 4 (d ;J- (Cd(d fd :J r- (CdO (Cda) WO 00/43377 PCTUSOO/01283 266 0000 CO )O l mo o O 10000010 0 mCc 00 0 O0 0 0O 00 0 -1 w 0000 0000 1 10 000 .0 0 00O0 0000 000 000000-1000000040000D M 0000000000000000 %.0 0 C 00CDC)0 0 0CD0 00C)ICD0000 C) 0000000001-000O00" 000000000000cDNO000 0 0 0CD1 0 0 00 0 0 0\ 0 C C 1.0 LA) LA) LA) 0D0CD CD 000 ) D()0 CD0 mCDC LA 00 co000C00) H0C H0 0m LA 0LA LA 0 LA) OOO C>0 CD 0 0 C> m0 Cn0 00 C C 0 0 100000 1I-l0000) I 1Irl 0 0 00 CD0 -10 0 -f0C14CDC)0o 0 - C01 00000 10-1000I 1 1c 0 00 C 0) C0()00 C1-.C0 0 C )riC DL D0 m0 000 CD0 0 0CD0 0 0 0CD0 00 0 N 0 0 CD0CD 00CD0 CO 000000000000000 0>(D0 0 0 0 -i C00 C c'00 00 mn 00C00)0 0 C) 0CCD00 NC DIC DN 0 0 0 0 0Ca000CDCD)00CD0 00 c.q 000 D D00 00 00 0 0D0 00 a)I ga w 2-I _1>, a) -1 a) (d m )r 0) 0) to -)O rq 0 W 44 41) 0i ri) *H ' U) 4 co aX~ r- 0 a) 4.)c (a w l0) r-40M C 4 ulr c'X - a~ a) (d ~ U d0 0) a) U) a) a) 4-j W (Id ' : :: c C)d0 Ma) Ci) 0) a) kI (0 : 0 0 Id (d 4 41 0 ~0) Z d40) a W (ad 0 0 0 d 1-1 m L 0U41-H a) 0 rH W 4 4 a) -1 >1 4-)Mr-i b) U) 4-) --Ha) 0 H-ia) (0 (d U d U 4 a CO4 U M -1 Q) I - a)Q 4 U) 4 O ( 4 (b (d U) a) -4 - 0 0 4 J-10 l d (D-rI *0 3 ) H d dO0 (Id Q) rI0 0-4 -H0 : d ) 0 PQL )1 0ZZP )MW>3 : - 4a QP OC )UUQ0XZ9 4P )U WO 00/43377 PCTUSOO/01283 267 Cl' 0l0 000 0 0 0 Cco oio OCO 000 Lfl OO0 0 0 0 0 C140 0 cq00a, CD0o H 0r1Co I' 00l00 m0 oor-.ooolcooo N %D000000 0 p000 m r10I 0 r~n 0' o . o o o o w'-4NCN00,f q0 1.0 co 0 0)0 O mO ' C m nI I r-0 0 WI OD r- 0CN CI I 'n H0o0 H 0 L~n ooo gz oo 00 0 H "I I 1 0InN O 0 ( 4 I l m0H H- om H 000 0 OCD 00A0HA00m00o N0 0,V0000 -V oomoco m H 0000C0 0, o oH C 00o00ooooooCcoo 0 0o 000 0 C 0a mco I ~ O I H m 0 00 H 00 00 0 0 C0 0 0 0 N OO0 0 C Na0 040 00 C0N 000 H 00 H 0 C000 w. 00N0 OCON OV COO N 0000 H- c OLn oCoO co H 0 Q0C' 00H 0 0 0 1 I I 10 II I00 I I I I I 1 1 1 1 H 0000~0 r'- 0000 000 0000 000 00 0000 N o0 . a00 oo0oo o o0 00 a c 0 0 0 1*o o 00 0 co r -1( -CC 0 0. 00 00 z Ho 0 0w 0 C N 0. 0 o 0Ca010CnCr NCCIqNNC0 L 0 100 0000 CCC C CC O 00 c 0m o o oo00 H 0 00c)0 -V COOCCCO 004H0c) CDCOC0000 0 ~ 0 0 0 0000 en OO0000 0C C ' a omoo o . 0 00 000000I NA 0 N H 001000 0 0000 1 IOO OOI OoOI 1 00000 H r 0000 0000 H) 0 1000001 00000 11000000 0 lc 0 0 0 No H 0000 0 0 1 0 0 0 0 0 1 0 0 0 00 1 0 0 O m o H. 0 f E W 4- (0 0) w 13) 0(i r wL) tm w) U-W o U4 1)t U) m-) Ea '4 x )1 131- w UM) m C w313 w -) w 40r ( ( U Otm3 wU ) w31 4-1 kO 0 :( : W 4 fa 0 4 z Q 0-144 'tM .0 w ~0 w -q a 0 ~4 0 13) ~w4 a3) ri > 4 S4 i w4- 13w 0 H134 w 134 . ) w -rq>1 04 ) -i M > :3:' :H W 4) U) U U Z C4Z U) En > : E P4 a40 M- M) Q M) U, U WO 00/43377 PCT/USOO/0I 283 268 0 00rV 0 0 00 a0-1 C)0 0O0o0 n oo CN~ ~ ~ I0O0000 0 I I-I 0 C ,qI H,-o0 0I 1H 0o00 IH m~ N O I" cIO vD C f C H c c Ol000 0C.~o C.~0 m a)~ 0 l0N0CN0 r co000 c o H no"r oomaivor 4e M 0 0 0 N 0C . 0 L l 0 M0 M V)0 C0 0 rn cv 'o H N~ ~ 0 l. 10 0 rO-4C 0 MIHOOC mC 0 1 m ": 0 10-oC o0C0 i o Ln co oi -i HoCo C C4OoC CN"C0 -0 N 0 C H C- 0 41:vCm(,C C 00m00Co0 H N~~ Cl m 0 nl c 0 0 C IfHNOOOCm0 l mo0Ln0000oo-ooo H ~~- iimo C me~0'4 o~ 000c~I00 n o "ooaiHiioaoC CN 0~~~4 C C0 0 0 0 0 0 0 1 0 0 000 C 0 _ 0- 00 0 C C 0 0 0 0 0C 0 00 0 C CN 1 0" 1 O 0000H0000 H k' :) 00C00C000000 0CCC)C0 0 0 I M1000H- I I V0000 I-q vf CC0I OC00000000oo0000 CIC 0 0CaC000 '0 0 0 H MOO O OO o o Co I"aHlOC C ~ N o C~ ~ ~ 00 0IC CC000CC0000C0C CC 0 0~~N 1O0I00C0C0C1 1 0 0C0Co00 r (N 0 C C HH00 040m0C 0Hcq0 0900 0000 000H0(NCOC-10000 N 0) r. 4 0 ~ (a 4-- 0O -d EQ 044 a) ) 02 41 0 *q (A 044 ro~X x, -- )( 41 0 (NJJH 0)020) m 4 (a 'oXH -4 04 4 ( 0r~o 0 0) W2 m )a 4-V (D 02ra :(d0 ) a ) 02 a)a) (dI H 04 0)J 0) 4. 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m OLCI OOO a Cf)I00I lO 0C~c a) 01 1 0000) l0C10COO I I -i 00000CCDI0 '00OO I CCD000 00 0 1UOOOOCDIOCDCOOOI II 000001 wo o l NCOO C--D I Iqoo c I0 0 0 10 00 1 0001 II cD0nccDoiLnr-co i IH00Lrc'2 0 l1Lf00 C -- I 0 C-.O00I I 0-00CD0l0C:ID00O I I OOD000 C 1i 0 C00C 00 C 1 0 0 0 I c-mOooD Ior-O,-l I I 1-0CO0 -0 0 1000001000001 I I 0DOC.C 0I 0-;0o~oI I COOI00 M0 LO0C 0 0 0 01C-.3C>0 CD II 0 m 0Lfl00CDM c e a0 CDI I " 00 In CD 01C ICOOCO IOO)COO OI I 0 C)CD000I 10 r-00HCDI 1C'0 00C))C H DI CD 0 00 0 0 0 1rD)0 0 I 0 e 0000 iN r NwoDo, I H000 m 01100II~i D00C)1000I N0 0 1 1 CDD m co30 * CD ID I 4.4DC 0 00 1H 1 CDtIqI c 1I OCON~ V C 0 0dd~. 0 CD Id d CD CId Cd 0 Id1 4-rH t~I4-.HD 0 ID 4D4) D IDH>43.r- ~ Cl4JHI 0a m m U U U ~ >U U U~en WO 00/43377 PCTIUSOO/01283 274 00000 0) ONC'NC-i 00000Lfl00 o~ioooo M~ 01100 00000 00 ON I N~arHl mcl0000 0lCNc' CNN 00 1 -00 H0000O IL O O o o o o o o o o H 011NO~ N0000o ;If0 00 0 0 oo c o o 0 O0C)I 0N 0 CD 000 m Noa - 0000CriaaN 0) 00100c 00000 CN 00- O O O0 00-0 a a00M 0 00 0 00 OIONOr 0 0000 01MC a0C 0 NIOaOONON NI I HO N 011C ) 14 0 000 a O CO 0 0I 0000lC OCOO I I Hocao M I'w4 00 0 m mooc 0 0 r 0 1 ao 00j IC)CD0o I I HOODOCl r, I Lna0 ,-A O 0 0 ; 01000001000001 40 0c IHOOa N~ a' ILn m Ln 0 0 HO O 0 0I 0 0 I0 0 0 I O O 0 m C OL u u C)N I000 m 0 100 0 100000o c co I I NH 0000O 0e'o0o'40 ~LA Cmq C)00a N 01C CC C C m 1amC M Ln M m CH 0000 0~ c 10000aOoOcoIll-0000 '0 0 1-oaM C M Ln cocoa 0) OIooooOlooooaj IHooaoOL oHomo M M IH0 0000 00, aa c OI OOrl oO oIN IH OO 1 1OOc M 0 1 H00C0 r- Ol O 0 I00a 11 00 r-aac -aa"iim )ac 0110 o0 N LA M M M 0 0 00 N 0 1 0000oaI0On00mI IL OO moc:a - 00100 M M (~q0 0 00 '0 01 aaa 1 IOOOOIOLAO 11 0 a0 c I -:v 0 0 N LA M M .1d U2 0d I W w 4-4 0) H4 E 1)0U 0)- a0) M 02 4- dN 0 qM E co do 2 r-q> P4 ) J- (d U) 02 F- )ri (dM Q 4(d4 ( -440 t)~~l 2) 41O r. 'd 02-i d 0 4 402 .is Q-1-) 0 F=dH0) (0 ~ 024 ~ 0) 0) 4( o 0 ( 004 0 0) (d wla >1t)0)IW - 4 .) ' CdCO 4V ( U dr (2 d k J-) 04 V010) H ) -1 041E 10 (~d 0d4~ ; a)4 -- 0 (d 0 - (d () A0 0 C % 4 l-10 : 0 a) d~.~ 0 : a d( (n U)4- > ) w )H IJ~ a4 o MPQJ-H0)i z 0 H0) U)4 >) 12L4 4..
WO 00/43377 PCTIUSOO/01283 275 00DI 0000c' I I 00o 0o r 0*0 1 IW00C10C>000000CMO0 a% m OoN o Ln ooc qoooooocDc)o m k C 0C DC lo o L oo o I-0 0 Ch M oO IOLArocoOI I100000 -Ln 0100 000100000I 1000 Ch 000fn000 k DC D00C A0 ooo 1f 1 O CI I 0 0 NII CD0 CD IOm 0 0 aN m 00 1 o N0 0 CI 1 . 0 0 00 CN rq i 00 0 C O 0 i -~ "irLo o i -io M 00m Iom-0cc\o I I oc-com -1 ,- I I 1I00 0 1N 1001O I I COO 0 C 0 1-0 C C C 00I C I '0 0 0 N I m 0I00 0 I 1 0 m m OH00000000000000o C 0 1 10m00) I ocq00I0C I I c-400 CD00mm000IC) > I VC - N m 0 r- I 1000 0 1000010 CDI I I00 cm Un H r-4 000 qIIc 1 CN 0,C1 - C C nC DC l 0 IO 0CDCD0 0I11C I-0 0 0 0 00 0C0c0 CD m0 0 o C : a' O OMOOHIo nOOCO I I r-l00 C)0 H0 mm000 0 ' o H 'D0-0C NCNC 1 0 1 1l0000OI0000 0IO 1 000NO CD000mcocl000 0 C 04N00N00 LA 0 1I 0 0CD0 10C 0CD00 1 1 - 0C 00 1 Olflmocoo I -I0000 -1 01 I0000I0IC1000I ICO0 No M~ 0 N N0C 0C >a) 0 0 c Icd ca r-~c]) io o 0) ~GJWco 0)n 0 I -4C>N D 0 Idd0- N qC00 0 ko olI~l0) c Id oo 0 dldoQo CD00 n ) D -- D H00 C 1 CD Q 04a4~ 1) 0)H 5 - r~)~-i ) 00 11r-i 0 k~dUd~4 Q 4 VO0)~,Q4ca I O~I O~d 4-J~ O >~I 0~4~0~d .H *0 O).~dd0 *I 0-H 0~-H~ d0.H .0 0 0 4c n mc >c ic O D D0 0 1 1C WO 00/43377 PCTUSOO/O1 283 276 00(N00100000000o 0N0000 ~0 OON CN 0)0 1 cI 00 00-OO~oN00H00 -;Vo00 rn c 0100000 1 (N 1 0 Q 0 OO 0 0 0 N r-Z00 C) 0 C 0 N(NC 0 0 1000001 (Nv 00 0) co 0 00 o00000 c00000NC0000 0 001l1 00co0 00 r- ocooOO000 rn0000(Nma00 0) 01100001 00 1. CN c1 .0C>0 (N C -ql 0 0 1-0 0L 0 000 0 0 10000C'1I 00 1 4 CD I10 0 C) H I m i0 0 0 11qC ( 0 000 %D 00000000 0 H Om r 0 0 A 0 0 0 0 00 0 0 11 1 00-0 1 0 (N0)qoI 1~ 0 0 c 000 0 )00 00 m~ m I0CD w0 C) w 1 0 C>0 I rC I ' 000 M 00I(NooCNo 0 e o 0 0 R co ,,oc 00cm , a -o oo I I A 0 0o c' 00100000)I c c 0 0 O0 04 r 0 1 10000o I 0%,00CO I I O00000~ aH 00100000OO 00 k. 0 1 10000100000cI1 I.-0000 0 00 1 N00cO 0 0 0 LA 0) I 1 0000 1 O0(N000 I I (N0000 0) 00 1 00000 0 (Nq 0 (N 0 C 0 1 I0 D00(N4I l(No(No4 I I ' 0 0 r- 0010000 0 (N 00 (N Oc I 10 0 mI Co rna rI N I1 r-4 00c0 w C4C ( lm0C)0D-40 0 (NQ 00 H- 01 I O OOOI 1OMOOO)I 1 00000 LA 00I1(N00lo0 0 (N -0 qo CD0 0~ ccOi o00(Noen(N000 cloo o (,0 00100000 0 (N Clq (d)(( En a) R50)flw U1 fo 0) w ) 4 U) 4 J 0 *H r ) /44 W)- tm t w C%4 /~~0 01-4 0) M d , 44- E 0 , t ~ 0 -1 ) Ii 0) M 0) d i4Ib. a)- 4 t(d4- z-H) 0 0 0 4 -1-) 0) EM( 0).->4JM5W' 4 (d( w )r 14 4H m C .)- 4W 4 ) w.I> . - WO 00/43377 PCTUSOO/01283 277 004~0001 1 .- COO 00 0 1 I oo rn I c1000 IlH-0000 I'D 0CZ00000Lfl0000 LA 0 1 I000HI c r000 I I I C OOO %'D 000001I 1 00000 m 0 1 1 COCO1 00000I1 1 -00CO Ll j 0 0 zzrOO C' oOIii -ioO Cc, C 0 1o00 0oo000 ,I 100000O %'D 000 011 000 I HCO - 0 1 1 0000 1OmCOC0 I I C'0000 000000000000 0: 01 Ie400mI0N000I IeO000 CDI-0000000000 c'. 01 0000 10I'D0001m0000 LA 000000000000 co 01 1ICOON I r0000I I100000 LA v$C'C0000H0000 N 0I00000I00000l 100000 In o 0 00000 a0 C0 0 0 aQ C 0 0 1 I'D00 v I NC1.0C CO I I H0000A R 2:Ln 010I 0 WHO-l0000 10000 v 01 I000eNICN000I IHOOOO In CH O OO O O rI C0ria 01 1 I0000I m0000I I HO CO In Ln 00c 0 00C00 00 00 H O:)IOCOOCOOIOHOOOI , 00 10C0 C00 LA m .0 C0 0 00 0 a000 0D 0 1 10000c\ 10000 I I rOOC OO Ln WcNJ00000,-ic, o0CDC '0 01 I0000Ial clq000 100000 0CO00000 0 COo mA 01 1I00CO0CI orn000I I -I0000 b) rl u2 0) ( 0 0) a))W 1 wH ) 4J w ar t: mwa ) 4- O U > m11WrqQ- ) O ( 0)M U d 44 4.4~ rOHU U1~< 0) -I W 0 oa H -00W -H0( d - 0 4 ;ri~ 0 d W q 0 :J a~4) 0H( Z 4P 14r (120 M- >)z 3: 2: I E'd P4-1 A4 PQM U. u L ) C zI4P 0 ) U) U) > Id: EH WO 00/43377 PCTIUSOO/01283 278 In rn 0 1 1I00 010 00 I 10000 DCO 0 ti i II IL00 0 n o In CN 0 1 100001000001~oo 1 00000 N- C 1- 0I 0 00 r Ic N0 10 In 110 e 10 0 LA I D 00 ICn In 00 a 0 0 10 0 1 Ln - 0 00I1 I1 00 00 0 v 0 1 1 000NI- 1 W20 00 -1 1* In N, 0 1 000O001I ONlOo I I MID 00O C ID 0I 0 4I I M0 Ino 1 0 0 0 0 1CN- I n a0 C I I zfC) CD0n0 C-l 0o i 0 0 i NooN i N 4 co In fn CD I o o o o o 10 00 0001CODD O OD C CNl I I n 0 M10 I CNC) I oOcooIOI )n~oooI I.-0000D 0) CI I CNa00M I mI0C co 0 In a- 0I0000OCDI COOCDog I 1 0 0 VOOC 01 o i000 oo aioo m i co 0 10 In 10 OI 0 0C I C J0 0 r- Z a co 0 1 00CDCD0 C41 m 0- 1N C 1 N ~0 00CDa 0 I 1 w NO0 o I co '0O CDO OIOCD0 0 HI N 0C0C 01 - I(No0D0 Ht 01 I m C)0 -I CO 0 In w 0 1 1 000D I C'O 000c I ICD 0 0C>CD0 .- (n I I M en N W O I I N- 0 0 01 10000C1 100r-0001 I 00000 0 D I I CO~C~O I on o0 N- 0 CN 0 1 1 a CDn r-1 -MCD0O I o1 oo40 00 El CD 0110000101 C 00 (N 0 1 1 OOOaN- I a ~ O m I 0O 0 10C'0000 IIN00CD1 000 C - 01 0 D00CDI l0 aO00aI I ONOO00 LD 01I I OOOODIOC O NO Ud fa MI -4 0 W 0) d~ r 4M1M. ) Id 0 Q) M 4 w .)0 *H 10 I~ W~ 44 W~ M 4 J tm 0 4)0 tmw 4d r. to 0 (d (a10.0- 0 r=; 0 d4 MW ) I Z 1 W H> 4 r-I tn MJJ-H a 0 r- 4W4 ) a q w.->J- -'4 O- MW 4J-H W W M r.W 0U S Q-4r : ~0 W 40JF rX OH4 0w 404-4r w - 4 " (IdOU 4Id U Z 4 -0 OdO )- W r-4 J. M2 jr (A~d 4U d 4 4-) M 0 W - 4: r 1 ( 1 0 : ) 1 , a 0 .f )ri0 0 J.10 WO 00/43377 PCT[USOO/01283 279 001 lCO040O c 0100001 IOLI 101 100000 0 0 001 I~0IO0 .0 OIOOOOH0 0oI ,I0000 0'i 00 11 00000 Ln CD 100000 1010o0o1I IHOCOOO co T -01.W ,- dfI I C)0mrCD0 C) OI a0r M0 01CDm0Qa0Do I0DC)0 00 r- 0 1m I I rn CN00 0 c OIOOOOODI oHO:OoI 30 00 CDDO0C w 04 LA LA w CD0I I w m N000 H CDI00DCD0DCD0 10 a CD0 0 1CD00000 LA I 0 LA LA 0 M I I -I CN m mo 0 C0I C000LAI004000lO IHO O r-00' - 0 CD AI 110 0 l0 w 0 11C C DC)IC DI 000 0 40 01 10"CD0 000 M 0D c') w. OLAr-I 1 H OO LA NIvCD 0 1 00 D IA I C) CD0 11 I 000CD0 04 CD CD:)I I -i 4 C 00 rn 0 110 1 104 Ic i0 00111 ;r000CD0 0 0 00 1 1 N0O OR0 r 1 Oil )O l0 0 I O000O I I~0 0 0OCO C 0 0.0 0 0 1H m CD CD .-o 010 01000400N 01)> IM 0000 4 r 0 on 0 L 00- 1r In H H 000 01 O0 0c c00 1001~c I r10000QII m moo I' 0 N~ cD I i vI ) I I M 0 0 w I nt )0 0 1 1 N 0 ' D I m - 1 NI DC n : ImLAHOOk I 0 0 0 I Lncr co c,4I I MC01C00 10 0 0401o I0A0 4 1. 1 1ImOCDOC)0 I t1v 0 1000 1 1 r 0 0 LA 0)C n C 0011HOODO LA 0 1 ocoom01.I LAC4000 I I 1*00400 CN 0 00 10 00 I1 01DC~ (N C I 0 o D00mI c m00 0 im OO 1 VmIQ0C 0 0 0 11C DC l 0IHOOO 1 OI O-.000 30 0 11* ~0 0 00 0 0 LA LA 00CDI110C)0 00 CD04 I 0 00D0 CII e ma0 C> I1 40 en0 a 0 t mm04 LA(d 001100000 a 0 01 104 I 4 ~ 0 I 1 0 0 M4 0) w) w ~ J-) LO l4 (dU):110 )a) 4 4 4- 1 A D IIUSU) ID 0 q (0--1 4b m - 0 lwH 0 0 r W - ) 54 4 0 Udr - .)M r : - ) U)W 4 1 IJr - )J a ID uJ >,t ) 0 4 4 )U) 4 O ZU (d U X (d ID 4.J 04r Um- ) r- .3 I odW-4 0 W - I Z rI 044 5-J 0 ::S~)I (IJ W - 0 :JW " 0 0 o P I 4I4 ID coincn> : r a MM MU U Q 0 Z P4 r4 0 o HIn~D. ID IDR-E-HP a WO 00/43377 PCTUSOO/01283 280 1 IOoOO IC)O~OOC 1 00000 -I oii of IO LnI C iwooo i Ln 100000 I0MC)00I 00000 0110000 1000001 Ln 1 000-40 co I - 0 0oI lzv0 0 0 0 0 1 O0OOCl0I oi000I In I 0000C I00 I O l I100000 Hl 01 100001000001 Ln I I OOC CN oI oL 00ml I 1 ~ 0 0 0 1 10000C IOCNO)000l LA IOaO 0oo0 0m I C 01 IC1r0 00 a% 01 looool0moooi LA IOO0~ I~L 00~I 1000 0 00 LA 1 0000) IkolI000 I I LAOOCoO kW 0 000C\)IC'W000 I 00 LA 1 1M 0N 1~ r- I 100' 1 1 M~M 0 LA 01 0t 00 I l .D00 I co LA I 0C\)00N I NHOVC0 ) I I N'0000 v en I LA Ln00C) H I r- -40 rn C I co LA LA i r-oc I 0 Lnl ~ O 0 0 i l )00Co i -: oa NcN 1-4 L 10 vC Nm 1 N vCD0LAnI co LA I10000IC I ('20000 I I M~OOOCD o 0 1 m CN r 0 0 1) 0 0 CD I -4 c 0 100000 1 OLACDO I I DO0000aoi 0 1000001001001 C) OLA 100000 o.'Zp0 I I 0000c-.2 aD 01 10000 I 0O ooI LA I ('0 0 00 IC r-i 0 0 C>tI 1 40 000 CD N 0 1 10000C I 0NC,000 I LA I LA0000nI OHOC000 I I~ 0 0 C1CDOD 0 )11C >0 1000C13 0 .000CDI LA I100000 I N00c' o 1 1 -14a0 CD00 LA 0 1 100>00 I ofn 1001 LA 1 000004 I0Q-0 1 0C) 0 ('0 00CD0 H' 01 1IC\O OOIC1200000 1 LA 41 H00~ Im 104 iw 0 1 W ('2 10 L -4 0 -i >1 0 0 4 l t ( 0- 0 O I P) rO ZI U 4( ZW Wa OU 0 11w- I) U) '-' 4 4J O (1 )rU 0 0 r j( H 0 :1W 9 H ( a)r4 0 :-. U - :J W m. CQ coJ u,- u zzP zP U)4- >0~- U) 4.2q0 a C uuQ 0 Z -H C WO 00/43377 PCT[USOO/01283 281 100000 H 1-1 I 1 0 000 10-1000 1 1 -0000 ko 0 10 0 CN 10 0 00 0 0 a0I0000H-fI0ON000I I,-40000 Ln 0 100 %D w 1H0000 m, 0I000001OOOO0js1 .- OOOO 10 0110 Hv I H~oO o co 01 I 0 1 0 o o 00000 :C: M 0 11 0 H I NOOOO ' 01 10000O lONOOOI I MOOOO H 01I1 0 Ic 0OOO N HI 0 I fl 0H i~0 0 0ro - -n~:c)ii-O O 0 11 0 H e Ho w 0 ID I Dm 00q 0H 01I INzv0 0 mI Ln C)00 MI IL O o m n - 0110N Q en 0 0 I C 0OO0O 0 0C0 0 0 C) 000 10I 1 L O O 10 HOIN00aON 0 0 0 ID 0 m INOmmc O 0f m1 I C00m ILAOOOO I 0000CD 0' 0 100 0 m o %. I MO0000O N 0 1100 000 I H0D0 0 q I I ma00 0 c 0 100w 0 N1 0 C14 w w1 c1 oo C1 m 0C 0110000D1 00000 1100 OOO C n C 0 1m o~ C1 )0 01 1l O000IH0000r- I H 0 0 00 q* q'~p 0I 0d 0 '0M IAM00 0 4 0l0 0 o o~~ 10 00 LA 0100 4CN OO W' 4Mr t( J w0 0 00 000 0 wH O (D' w 4Iw0 ( 0-I ca W 0( 4N rI4 Mt 1 4) 1 0m Q 4 LA E aID)w 40 r o 0 d( W 0 wC O O LA 0 H> 0-4 - 0 J-Ia -1mOOa)cD ooo a)ONO -W 0100 0 7 )4 r d0 - (0 ) -00 4J-H0 MWH 0:3a4 -H0) ( ~0 (aw co~~~~~~~~~~~~~~~~~ cn>t :E 4a QCQC 0UUU(10:: 4p E ou l:3 l1414WC WO 00/43377 PCTUSOO/01283 282 0 000 0 10000 O O 1-4 Of1 I0 0 0-f ILnr- 0I l 11CN 0 00010000011,1-0000 0 cI I CN 4r )1C o0Io',I0 I m lCD 0001001 0CN~I 100000 c H - I I Nloo' 1Io -j cr I I N 0001000101ICD I~0 0 Nqo c> 0 10 koC WDI Ln C'.1C D NI I CN 0 000 100000 I IC.1000-i %D 01 1IW Q00m I C D0 0 01 I-0 000 00 01 10 00 ILACIO IIOCO D 0 1 010000 1 N IOeQI I mo1 coo 00 00 10 00 C D ~ .CO 1 r 0 101 DO00I CDCD000 I I 1 o o c c i n D o o D i i i c D r- 0 1 1 0 0 0 1 " D C C 0 'H0 00(q nIL OI CNI00- .-I 01N0 11N" )0 0 C I 000ooI m' oo00 I N-O cq ) I c HN0 CN 0 1 1 mO CD'0 0 0N c io -a~- 01 0 0 Im,- 0cc i i cN1 Ln %0 r-a00I ,-I00,-1I I c)C00 0 00 0 1 1IOOOOI1oNoO'0l C1'NO LA 000 I Or4000 I I Noo0000 rN 0 1I W '00H m I MACN 1 0 01 1-l 0 0 0 01 fn C)CD0 1 I - CD H0 0 CD a 0 1I W '000D0 1 M r-400lCD0 1 1 z LA 0 ko LA CD0H I N CDCD0 1 c4C I 0000 CD ": 0 1 1 0 00C0 1 C M00a0 I 1 00 LA 0IH MC ,000 1 ;v oD3 n CDI I~ 0 C) 01 0000 10C a00001l 10 0 LA CocoI co-fo00mI I l0.D00C CN1 CD I OODOOI (nIOCO I 1 00 LA CD00 I 0\I nmn N1 V I0 m cq 0 0 0 1 1 0000 1I0-O'O0Cq I IC'No LA ao.DI oro cDo 1 1000 DCDa D00 0 10 >C D1 0 I0 koCD0 0 1 C00 '0 00C') N 100000o I 1. '0 0 00 N - I 0'%D0OON-1 I ) 0 00 I I N a)q w U) a)I (d a4 ) a)W (dl (0 (1 41) 0 .1 10 En4-4 0) (12U 4-)O 0 112$ U I-i Ea 1 x -4 a) 4-)~ (13 c ,lO M -1 (flO' w10x -4 4J) U ~ 1) ( ()c a) a) 4-) w 4( 0 d; r (210OM)a) (2 a a) 3 rz rd 0 M d Q -) 0 r: U) (a 0 ) df $; 0 roro M co41 -H a) 0 1-4 () 4 ) 4- a) (1) -- 4.) S4 -1 0 O C14-r.A () 0 -4 4) 004 H : *0a !H~ W 0).0)f4 ( ( - )4)U O 4r Q !EnQ - )P4 U 4f d - 0 u 0 A() 4 4)U 4 ( 4( d - O U 0 WO 00/43377 PCT[USOO/0 1283 283 000 0) cq I M L 0 0 -IrlfnCN 0CN -flI I M -OO 0 0) c ~I O o~m In0ao00C IL Ln a 0cq Ieq0 0 0 I I moCoooD 1.0 1aN I0C\1O N Nn N D m iiL -ik vo Noc o 000 LN CZl I ~I nC)0 IV I CNm0 I I m N0 000 CN 0 1 0 0 000 CD e en o o0 cN 0-0.o oi ia o o o a w 0 100000 00C)0 CD 0 1 I Inooo I Wcq\q 00 I I c'q 0 000 N C') I Nmo'c o. N N D 0 )IM 0 C . -k )0 D0 0 M 0 1 1L )C 00C ) CN 110 0 0I v0cCD n 0c~ 000 D 0 0CI c 0000 N0 - N~ -o o o iwo oL n iic qoo CN000 111 V-4 OI O 0~0iC - N090 C mor c' 0 0 0 n 1i i OOm N N N LN N N 00 C ') 0 1 n IO1000zrI0LOCN0 0 m IIrqrI D c r I00 I en 0 000N C'I '0 0 0~ CD c 1 0~ I00~I O 0 n n C0'00 1 01000111m c o - NooL 0 0n 0CD0 wc 0 1 1 N00 o CDnp1100C 0 C I I N 0 0 0 M 01 10 Coco LIn 0 0 0 C)I11 DC r 9C ) A m 1Q o r- In 000 iioooL im-i >o -iic w0 In ICD0I so~ Im~ O Nn 01 0 0 0 In Nd N 0 Inm -U 000 . 4 OI OOdO O O Mmoc 0 I'0 n 000 W. 014 m - IC ) 0 I00 I IC\ 0 M 4 0110000w ( m N In- m M )1 l 0 J)( qt q0 ) w i 0 N4f 0 d: )0U D 1 - 4M' 1 a:s t 000CA S: In I0 0 WI d - l 00~ 4-) 4 00 C')fa 0 1000CM4 ( N1 In)( A 0 1 4(1 .r d' .) 00 4O ) '.) N1 a )-- 14 14- )4)-- ) 0 rA W - 1 H > - 4rA b 000 -i 4 C 4r U (I I- '0I a NC' 00 U I 1 C 00) - )rIr -W k Ic 0 u O N) In( d a - 1 j ( L 4 0 : )4 -i a (j0 -( )rI0 0 >. N WC4MMMMUUU 0:jZP P c )E - rE4%a WO 00/43377 PCTIUSOO/0 1283 284 I CN r-0ONCN I I c~Cm00 1000001100000 100000 II00000 I OC a00aLD I 1 0\0000 1 00 0 110 1 I - I O 0 0 I0to(N0 \0CDI I N0 0 00 1 00 C> CD I I CN a CD00 1 C D0 CD I I CNN0 0 CD I C n0 C0I 1 1 f0 000 1 0 0 0 C I I CN 0 0 00 0 I 0 c Ic o m0 I ' 00 I Icq 0 C0C I I -:f0n0C0C 0 I D10 00 0 -4 l0mC(lcq I 1-0aC13 0 C 0 1 oc ~' 0 C I 1 C en ' 0 D00Cw0 CN I 0D--l0 0 m I mcliCo 000 1 1I > r-II fa) 0) 0 (a) 41J 0 If 10 2O4-4 ) ~ U)4. .1-JO 0 U) 0244 o -A 0. 01) 4) (d En N M-4O 0) T 2 o c r2X -4 a. a) 4-~ 02 U (d0 ) a 02) a)) 4-) 1.0 4 ( ro d : (2d 00J ) 0)0()U ()() 4-) ri 4 t 4-) 413 0) -1 (13 fn ) r Id 4Q ( -A 4-4 t)) t W- .I4J )(D-4 ( (d r_ 1 0 (d (d 4 -- 0 r~ 0)I (b )4 Vl( i1 10Id(d Q 4-) 0 024 -). ) 0 -1 a) 0).(1) 12 ) a) -H > 1,4 -4 t0 a4-) -H ) 0 1- a) ) 4 r. 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Id b u I4 4 00Ud Id 0a' 1t Ht~$t0 W-I H' 0 -0d0- 0 OId4 W M I U) -r o 0 0 -0 0)-p>4:jr -))JH 0 0j (a-a).14 $4Q)! 0 0 00dQ ->1 1 0r 0 ClW.ME) P a MMM Uj- 11 0 :: Z~ % ll C4 W W W I> Eddr 134- rn M WO 00/43377 PCTUSOO/01283 303 1000001 100000 1000001il0000 1000001 100000 10,10001 100000 i r-moco i I 0000 I Lloooo I I %V0 0 00 1000001 100000 1000001100000 10CD0 000 1 100000 1 0 r- OO 1 ri b0 a0 0 1 0100001 I,-0 00C0C 1 (N ( a000D I 1 00000 1 0 m 0001 10C)00CD0 I(CNC"NL0CDI I H oro m qi 00ocm n (oN3c, Oi c,40mI f ~ l0 ~ IcN c,4 oO I00 00CI 1 00000 .o 0I10 CN 0 0 (N qIN 0 0 0 1114C CD0' 0 I 0D000 I1CD00000 C> e 0 1 ooOO))I OMOO 1 000004 I0 O0 0 ImO O kD 0 1 1 IoD000 I CD 000DI I -10000O Lf I0 q0 0 0I1 Ir-0 0O 0~ 'IV CD IO 00 I 0Lfl00 I I O0l00 Ln 0 N C C Ir- C 0 0C) co M I"r C C 10Ln 0 D > Iif0 0C 4-J - $: U14- 0) d (0 4 H V ( 4-) J0 r o E 4 )M) Ea 0)0) 0flIiO U) 440 (d 0 1 0 (a M 4 4 0 (d 4 b) Q) d r. 1 0 (d (J Q4-) 0 (D 43 -4 ) 0 1-1 ) ) 4J a) a)-q 4-J % -1 0 n4-) -r () 0 -1 ) 4 )4J -N4r.r. n ) 4 a 4VO d> ( 0 -(4.)C MQ5 4 - . .U 0)~ dU j JJ 4 V a) rX- 0)( > (d -)" r 1b 1()rI4 - ) r d U d U ( 44 ,r 1M ria WO 00/43377 PCT/USOO/01283 304 ~ ooooO o i ooo oo oi.0o000 000 Ln LA clq 000000M010000000 ~'0l00OC'0O000000 Ln 0000000r-OloO0ooo .0 00000000000000 LA c'.0 10 0000000000000000 00 0o,000ooo0'0o00o0 cq LA LA 0l00O~CN000OW00O000 00 00110o000000CNC000 CN LA H- cqo~Ln i cLA000N0000c\oc m 0000000C0000000 Nq 0000'0 0 00 0 -~ 00 c ~ 0 0 r- 0000000D O C OD r- 00 00 0 0 n CD 000000 a0C)00 00 10 00 0 0 0 0 0 0 0 00 I O L O O O O '.0 0000000000000 00COC CD 01 0 ~0 0 ODCD0 00C,0OCD LA H wA 0000000000000000 (N 0N ~ 0 CDIOCDODco0C)CD m(NC 0C 01 co0O000000000O000~ 01 N o00 0000000000cncMC 10 10 CD, 00001 00000000'0 0 000000000001CCCCOD OD C 00 HE 00000z00 00m H 00 0 C 3 0 0 0 0 C19 rn (n mC rC q0 0N 0 00 00( -4CDO O OO 0D CD CD00D 0 00a00 m (N (NN C)~ 000000000000000 (N (Nq w OOOOOmOOO OOOm (Ni LAOoOO O O t 0 C) CD I0 m) (3)0 )0 0 0 0) U -)0 r U) 4 r: 0) c -)0 r U) 4 -q E 4 m x -14)( ) H a)rI U 4 U Xri 0 1( m~ ID(3 I: :r : )0 b )Q ) 1 m t a ( )0 0 )a m Z fQrb44 t) J wH (ap i k (d4 )0 4J r4Q)H 4 -1 ol t4- -dI1 a) Q 44)4-) 4) ~-H 4J -' r tn 41 .HI 0 a OD 4 Q) 0I d 9 r.. IDZ M O Oz > r .I Ow u 14 0 I DO. W WO 00/43377 PCT/USOO/01283 305 0c 00 0 CNa4a 00 , 0 0C D0C D0C D00ur DC DC 0 C'o NI 00o 00 k0 r a b 00m U - r Q4 ) 00 )r4 U 4 U 4 - d U D 0 )r 00 )( :M :I w 0 0)Wa ) 4) 4 ( 00m : 4Q 1 40 - Q - aP ) 0 40 )( 4 s:: Iro~ ' oo 0odoo 4oo 0roo N. r 1 - )4 rI a ) )4)() > N0rIrq()Q )U 4 r r O ) d > f O rf()1 r 4a Z 00r Q . Q) IO O(0U04flu- 4 1-)0a00 0 ) 4 ) i J ) j N'.-- O 0 ) - 4 -i 0 : f 3 J Q r O ( 4 ( J N:::Eir 4M M P :Z 0 XU )> ::3 14a Q1)14E WO 00/43377 PCT/USOO/01283 306 0) 0 0 ~ 1 0 0 0 0 N 00 000000DCN coo000000O ~C 0 uN- oDO~ WO000000Ho 0) U)4-0 A M 4 r-A EO 4 X r a J)H (d E 0)4 0) ru 1: 0(,aJ 0j E 1a)4 ) a) E. -44.)-4 m -)JH ) 0 0) 4 ) 4J (d 0) -1 0 0 rA 0 :J d Q) 0 :: )4 - CN 0 0 D1 00CD0 01 0(n0 0 0 1 1 'AOOCOO C 0 r- 0 10 000CD0 1I0C C aC)I I HOOCO0 U) U) 0)(dd0 a) Cl) U4 U .)0 - 1 ) 11-0 tm 110 O )r - 4 a ( U) a) 0l 4 4 d - 4~ U) < t ~ 4 0 ) a)( r-i r: l(d ) )4 (d U 0 )0) Cl) 00)0d ) 0i a) a)-i 4 1I -1, -1 0 1- 0 r- 0) a 0- )4 r ) U -4r.H r~4 0 : 4 tJU) J40 0 () 0 > d ' 10 41U) 4' dL 4(0U (1 - >I 0) a) H Cd (d0 - ( Q) rj0 0 J-- ~. 0 : (0) -rH *0 ;1 ) 4 WO 00/43377 PCTIUSOO/01283 307 TEST C Compounds evaluated in this test were formulated in a non-phytotoxic solvent mixture which included a surfactant and applied to plants that were grown for various periods of time before treatment (postemergence application). A mixture of sandy loam soil and greenhouse potting mix in a 60:40 ratio was used for the postemergence test. Plantings of these crops and weed species were adjusted to produce plants of appropriate size for the postemergence test. All plant species were grown using normal greenhouse practices. Crop and weed species include arrowleaf sida (Sida rhombifolia), bamyardgrass (Echinochloa crus-galli), cocklebur (Xanthium strumarium), common ragweed (Ambrosia elatior), corn (Zea mays), cotton (Gossypium hirsutum), eastern black nightshade (Solanum ptycanthum), fall panicum (Panicum dichotomiflorum), field bindweed (Convolvulus arvensis), giant foxtail (Setariafaberii), hairy beggarticks (Bidenspilosa), ivyleaf morningglory (Ipomoea hederacea), johnsongrass (Sorghum halepense), ladysthumb smartweed (Polygonum persicaria), lambsquarters (Chenopodium album), large crabgrass (Digitaria sanguinalis), purple nutsedge (Cyperus rotundus), redroot pigweed (Amaranthus retroflexus), soybean (Glycine max), surinam grass (Brachiaria decumbens), velvetleaf (Abutilon theophrasti) and wild poinsettia (Euphorbia heterophylla). Treated plants and untreated controls were maintained in a greenhouse for approximately 14 to 21 days, after which all treated plants were compared to untreated controls and visually evaluated. Plant response ratings, summarized in Table C, were based upon a 0 to 100 scale where 0 was no effect and 100 was complete control. A dash response (-) means no test result. Table C COMPOUND Rate 1120 g/ha 80 93 94 103 107 109 113 116 117 131 132 138 146 242 Postemergence Arrowleaf sida 30 60 80 - 85 95 95 90 50 60 80 70 90 90 Barnyardgrass 20 95 65 80 95 95 95 90 90 95 95 85 95 95 Cocklebur 50 - - 0 - - 50 50 0 10 0 0 70 20 Common ragweed 5 20 5 5 50 20 20 0 50 0 0 - 30 80 Corn 0 45 0 0 60 55 60 20 85 40 10 60 50 20 Cotton 40 85 80 80 90 70 80 - 60 65 40 70 70 70 E. blacknightsh 60 85 95 0 95 95 95 50 80 80 0 70 85 90 Fall panicum 10 90 70 30 85 95 85 90 80 90 50 90 90 90 Field bindweed 0 50 0 0 60 10 50 50 40 60 70 50 0 0 Giant foxtail 20 95 40 40 95 85 80 85 80 80 0 85 85 85 H. beggarticks 10 70 20 5 95 85 50 - 0 70 - 80 85 90 I. morningglory 50 70 - 10 95 70 50 20 0 50 0 0 50 0 Johnsongrass 0 90 0 0 90 95 95 80 85 70 60 90 90 90 Ladysthumb 70 - 90 10 - 95 85 - - - - - - Lambsquarters 20 40 30 20 40 70 50 0 0 0 0 20 50 0 Large crabgrass 10 95 - 10 95 90 95 90 80 85 80 85 80 85 Purple nutsedge 0 10 0 0 10 0 10 10 80 80 0 70 0 80 Redroot pigweed 80 85 0 85 80 85 90 20 30 30 30 70 20 50 Soybean - 85 55 35 85 85 85 40 60 45 40 40 85 65 Surinam grass 10 85 10 5 95 95 90 90 90 90 30 90 95 90 WO 00/43377 PCT/USOO/01283 308 Velvetleaf 20 70 40 45 75 75 75 80 60 70 0 80 60 60 Wild poinsettia 5 70 85 60 80 90 95 - 0 80 0 70 70 85 Table C COMPOUND Rate 560 g/ha 80 93 94 103 107 109 113 116 117 131 132 138 146 242 Postemergence Arrowleaf sida - 60 80 0 75 85 70 85 0 30 10 - 85 70 Barnyardgrass 20 90 30 10 90 85 85 90 90 95 80 85 85 90 Cocklebur 50 40 - 0 - 60 50 0 0 0 0 0 70 0 Common ragweed 5 10 5 05010 - 020 0 0 03080 Corn 0 0 0 055 5451540 5 050 5 0 Cotton 40 70 70 40 80 70 50 50 30 40 20 40 65 45 E. blacknightsh 50 -75 070 - -107050 0708560 Fall panicum 0 9010 085808585409050609090 Field bindweed 0 0 0 03010505030 040 0 0 0 Giant foxtail 0 80 10 0 95 80 80 60 75 60 0 80 80 80 H. beggarticks 10 5 5 0 70 70 30 90 - 40 - - 85 I. morningglory 30 10 90 0 30 50 50 0 0 20 0 0 20 0 Johnsongrass 0 85 0 0 90 60 60 60 40 60 0 60 60 60 Ladysthumb 70 80 85 10 30 30 85 - - - - - 85 Lambsquarters 20 10 10 5 40 30 20 0 0 - 0 10 10 0 Large crabgrass 10 50 70 0 95 90 95 30 60 70 40 85 60 85 Purple nutsedge 0 0 0 010 0 01010 0 050 010 Redroot pigweed 50 10 0708070 0 0 020 -40 -10 Soybean 60 80 30 35 85 85 85 30 40 30 30 30 60 25 Surinam grass 0 50 0 0 80 50 90 - 40 85 0 85 50 85 Velvetleaf 20 40 20 10 70 50 60 40 20 10 0 70 40 40 Wild poinsettia 5 306010405080 0 030 0 050 0 Table C COMPOUND Rate 280 g/ha 80 93 94 103 107 109 113 116 117 131 132 138 146 242 Postemergence Arrowleaf sida 5 1010 0307040 - 010 0 -4530 Barnyardgrass 10 90 0 0 85 85 80 85 80 70 50 70 80 85 Cocklebur 10 35 0 0 50 30 50 - 0 0 0 0 40 0 Common ragweed 0 10 0 05010 5 0 0 0 0 0 -10 Corn 0 0 0 0 5 040 0 0 0 020 0 0 Cotton 35 30 70 20 60 50 15 50 10 10 10 30 65 20 E. blacknightsh 5 4040 0508050 0 010 0103040 Fall panicum 0 80 0 0 60 50 80 60 - 40 30 0 60 85 Field bindweed 0 0 0 0 0 0 0 0 30 0 0 0 0 Giant foxtail 0 55 0 0708070606040 0154060 H. beggarticks - 0 0 0 60 5 30 - - - 0 10 20 I. morningglory 10 10 10 0 30 50 50 0 0 0 0 0 20 0 Johnsongrass 0 5 0 0 50 10 20 40 35 40 0 20 30 45 Ladysthumb 10 010 0 -10 0 - - - - -10 Lambsquarters 15 10 5 5 010 - - 0 0 0 0 5 0 Large crabgrass 0 30 0 0 85 60 85 0 20 20 10 10 60 30 Purple nutsedge 0 0 0 0 0 010 0 0 0 0 0 0 0 Redroot pigweed 0 - -607540 0 0 0101010 - 0 Soybean 20 60 15 30 70 70 70 10 35 25 20 30 50 25 Surinam grass 0 45 0 0 70 5 40 0 0 80 0 40 5 40 Velvetleaf 5 5 5 5 60 20 0 0 - 0 0 60 40 0 Wild poinsettia 0 0 0 0 15 30 50 0 0 10 0 0 40 0 Table C COMPOUND Rate 140 g/ha 80 93 94 103 107 109 113 116 117 131 132 138 146 242 Postemergence Arrowleaf sida 0 - - 0 - 60 30 0 0 - 0 0 40 10 Barnyardgrass 0 70 0 0 70 60 80 55 70 70 50 40 60 80 WO 00/43377 PCT/USOO/01283 309 Cocklebur 5 0 0 0 0 30 5 0 0 0 0 0 40 0 Common ragweed 0 5 0 0 0 5 5 0 0 0 0 0 10 0 Corn 0 0 0 0 0 0 0 0 0 0 0 - 0 0 Cotton 20 15 20 0 45 10 10 10 5 10 5 5 40 0 E. blacknightsh 0 10 0 0 50 50 50 0 0 0 0 0 0 0 Fall panicum 0 0 0 0 50 50 60 10 0 0 0 0 50 30 Field bindweed 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Giant foxtail 0 10 0 0 - 50 20 - 0 10 0 0 0 40 H. beggarticks 0 - 0 0 5 - 5 80 - 0 0 - 10 I. morningglory 0 5 0 0 10 0 10 0 0 0 0 0 0 0 Johnsongrass 0 0 0 0 35 0 0 10 10 15 0 0 0 45 Ladysthumb 10 0 5 0 0 - 0 - - - - - 0 Lambsquarters 0 10 0 0 0 10 0 0 0 0 0 0 0 0 Large crabgrass 0 0 0 0 70 10 0 0 0 0 0 0 0 10 Purple nutsedge 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Redroot pigweed - 5 - 0 - 0 0 0 0 10 0 0 0 0 Soybean 5 40 15 30 45 35 40 10 10 20 5 10 40 20 Surinam grass 0 0 0 0 10 0 0 0 0 0 0 10 0 0 Velvetleaf 5 0 5 0 5 10 0 0 0 0 0 0 0 0 Wild poinsettia 0 0 0 0 0 10 10 0 0 0 0 0 0 0 TEST D Seeds, tubers, or plant parts of Alexandergrass (Brachiariaplantaginea), bermuda grass (Cynodon dactylon), common purslane (Portulaca oleracea), common ragweed (Ambrosia elatior), common groundsel (Senecio vulgaris), dallisgrass (Paspalum dilatatum), goosegrass (Eleusine indica), guineagrass (Panicum maximum), itchgrass (Rottboellia exaltata), Johnson grass (Sorghum halepense), large crabgrass (Digitaria sanguinalis), pitted morningglory (Ipomoea lacunosa), purple nutsedge (Cyperus rotundus), sandbur (Cenchrus echinatus), sourgrass (Trichachne insularis), Spanishneedles (Bidens bipinnata), surinam grass (Brachiaria decumbens) and tall mallow (Malva sylvestris) were planted into green house pots of flats containing greenhouse planting medium. Plant species were grown in separate pots or individual compartments. Preemergence applications were made within one day of planting the seed or plant part. Test chemicals were formulated in a non-phytotoxic solvent mixture which included a surfactant and applied preemergence to the surface of the pot containing seeds in a sandy loam soil. Untreated control pots and treated pots were placed in the greenhouse for growth and visually evaluated for injury 14 to 21 days after herbicide application. Plant response ratings, summarized in Table C, are based on a 0 to 100 scale where 0 is no injury and 100 is complete control. A dash (-) response means no test result. Table D COMPOUND Table D COMPOUND Rate 500 g/ha 146 147 299 Itchgrass 65 65 100 Postemergence Johnsongrass 65 70 100 Alexandergrass 65 75 100 Large crabgrass 65 60 100 Bermudagrass 35 40 100 P. morninglory 65 30 0 C. purslane 20 10 0 Purple nutsedge 35 60 100 C. ragweed 40 0 100 Sandbur 80 90 100 Com. groundsel 0 0 100 Sourgrass 80 80 Dallisgrass 80 85 100 Spanishneedles 20 20 100 Goosegrass 80 65 100 Surinam grass 80 70 100 Green foxtail - - 100 Tall Mallow 50 20 100 Guineagrass 60 60 100 WO 00/43377 PCTUSOO/01283 310 In 0 0 C 00OO0O0 0 CN -0 10 0 OD H. r- -I H H r- - -IH H H -0 0 0 0 0f O00 CO 0 0 H HH H - - - q 1 jl 00 r-0 0 0000 N0000OoO00 H HH HH H H H IH 'A H H HHH 1 00 co ooooc00 o00oLo nco iL o o m 00co o0co00 Cow~ Noo OC0 H HHqH H HH HH H HH 1 H H
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HH HH- HHH H H H 1 H 00 -10 OOOCOOOLI aOLAOOODICO1 O O1 cc oO O nn Ll OW k C") m e - Hm rn cI v mH H4 moQC o 00 w 00 H 00l0 CDCDC0CDCD0 0 0 0 0 00 00CD0 c~ oDoooCDI COCO Io m c o oc w 00dO O O O ro N0 m0 0 c mC' 0)1 H H H-IH HHH H 41 4 H H H (a ) U) >1 M U) l~ U U)W ) to ( w w 0) 1rd w)U r ( U) 0) HAc ( U)- nM f da)Z U) X d-(dU)10J HO H a) .. W 4 (d a) -H U m ) E *HE ) ) O 0 r)*H 0) 0) b)M0 dH 4G J U0r 40 )w0)~0 Q) ( HOM-1 a)0)U)~ a) 0 SI0 I H0 a i d90( HOw r a -ia &- 4 A r . t - 4 9 -i- 4a A -- WO 00/43377 PCTIUSOO/0I 283 314 0 LA 0 LA LA Ln i o LA 0 0 000 0 01000 14 H4 11 0 LA 0 00 Co 1 0 LA 0 Iq Ln00D00D0 1 0 L -4 00000 LA 1 0 LA 0 Cq 0 CN o r- -4 0000001I000 0 0 o 1m0 0m w0 LA LA r A 00 0 -A en 0 NO H C0 0) H LA 0 1-4 m r M0000 0 0 N 0NaC n C H li m 000000400 LA ON 0D 00 LA 0 0 v 000 11 10 0 0 Ln 0 00 I 000 00 0 LA LA 00 0C 0 4000 c 0n C mN 10 -4O0
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m -4n 00000014000 0 00 4 0 0r 0) C 00 0 00 0 CN C\10 m O 0~ ONWCO CO) 0l O 0 ~ CD Nr 19 CD -4 CD m- -4 4Zr -4) 00 0 0I 0 N LA O OO O O OL L 0 00 0 A 0)0 1)oo8c ooc N H0 0 0 -4 -4 - 4 -4 -4 CI2-4 Hn H-qH H-H4W ~ ~ 4 C ~ t -4 )~ ~ W 4 4- ~ W ~ - 0M aH W~ 0 D000a000 - oc oooocL n r 4- 0l C1 a * n n0 o a c 8 8 o L nC ~d ~ r- d Cr 0 4I WO 00/43377 PCTIUSOO/01283 315 0 o ~i oa% h O r~lM M a) ~000n 00 0O0 a 00 0 -0 oc ~00 00 0 0 a0 0 Lf0 nOa0 en O~o M 00 0 00 0 0 "-I H4 1- qH N4 0 a D 0O0I~ 0 00*Om 0 In o oo co n a n o ooLn oo o 00000000000000 1000C m co000o00o00a00o00o0Io n 0 M 0 000a 0 In 0t H- 0)0 00 0 o fSoLn coo HcN r 001I00000000000 1000 N I00LAn000 0 0 0 0C. 0 0 In H o -0l0 N 10 000000000000001000 000 0 0 00 0 w 0 r-4 CN 0 m 0 r-q OC O N 0 0r-r-0 -ir4 H- H~ 1- H 14 H-H 0 0 00 0 00000 Ca01 00000 L noo oo a c0~~0o~o0 0 N In 00 0cN 0 N- m m 0 000 OD0 m 0 Mm No m 00 1 0 0 0 0 01c o - aocoo N 00 0 00 0 n0 0oo0oIn 0 n~ 0 0 laC, 0 0 00 M 0mNt. 0 00 000 0000000oo 1 0 00 Ln OOO nLA 000 0OOO U, Lna an cq ~0 co0)chC ~ 0 ONN H H 1~~'4 H1 4 H ~ 0H 0:C00100Co0 00C0C000 1 00Ca aC0 C~ O 000w 000 C0w0C0 n 0) -0 cq XOm mO mN N0~O m CCC' 0 h 00 C0 0 0 00C00CaCo0 1 0 00 co oa 0000n Ln Ln Ln C0Co 0o ON C : 0 00 0~' 0 CN c: m nm N- r m r-- U ODONw 0 1-1 NOO 0 M In m m -0 1 c'n rNn m 0 0 Vj 0 coI000~n I000CC000 0 m cn 00 ' jo I O- -: n BCLn M c, a% co r, co 0 0' lfl C,-I0 0 U, C 0'O 1n~~ co ooooop noooL r-Is- H -i 0 w OnO 0 U, a 0 N- co w C3 a) 1--i 1 - -I 0000 100100000D0000 10 co OMnOOOOM~O OQfl000 s- I M - N~ C14O mn NL' HN4 c oc oM a 0 0 C 0 0 NmoC 0 10 co ONON LAN r a% L to a U) a)0) ( 0) E '-1 ri U0)I D( n 1 a ul a) -H n du to 0)O1w o z I L0)m t t4E o r - d U) Ea 0 ) tO) 0 O r:E QJ)E O )4) Q 40 r 3 dr 0 z E Ea 41 En~w (at o 0o ) -1 4( ):$( )X ( O 0r J U D0 toe -s -1Q 4 0Q ( n X ( ) dr 0)- ) . 4( *o o 4Jo Ul b)~ jJ4c -A11* - W t)a D -IQ m( d D0 4- WO 00/43377 PCTIUSOO/01283 316 I 0D 0 0 t0 co 0 In 000 0 CO 0 1 0000 1 0 In 0 1 000 0 0000100 0 0, ~ I1000) CO 0000000 I 0 0rn 0 0 4 0 0 0 0 LA o N D0 00C)000 00 LA wOcom 000 0'i 0000100 CN Itl N 10 00 CN OfLOOI cl 0Ln Ocoo c DoOcO 0Ln0o orn 0 000CD10 0 C) o0 0 (3)ON.C m r 10 C)H(N0I~ l LAO0) (N .- i .-4 H -4 10L, 0 CD- 0 c ) o COC-o~ 0o cDo oc o1 0a0 Ul CD 0 C)0 0O C 00 m- CDOO OD000U-0CD m 0 (N 0 ;p 00 000O VA 00 LALAOOOOCOIAOOCOOOO-:*1O0 0O 000000000 00wV -0)0 a 0 i CON 0)0 - 1 D LACob 0 -I (N 000 C n nc oo ooooc OO OO OLn o oLno0 ( N 0000000O 0D r-l 0 .4f Ch(M(AC O'DO O O0 M W C0 'OCD 0 WLA) 1 LAOc ( r'0 0 r U rqH-4 (N1rI 1 I ' ON to M 0C U 0C)a )) - C >U ) lo( 10 H-10 m L ) koC a)) m U) UQ) -I (0U 4 rO U) H EO 1 4U) rU) to -1 0) O0U) -4 to ~ U L)Ud)O t U) d 0 A )a aU o ) U )H u -4 (d U) i: 0) U)wU)i-4 )w wIH 0) r- W *H) ) -Aa 0U4(d0 U) O,--HF! O . U) A M *HU) 1 )0 4( (04 r 4r 0C : * U )) - 0F:U a4 ( aH ) ro (d O ) WO 00/43377 PCTUSOO/01283 317 -n (AOO0 Co 0 0 00% 000I0m L-A r- QI '-4 ko L oooc oi fl 0c0o o c0Ln co Lnqo r-I Iq 1 On O~ 0LA0 mmAL LAL ooo woosoo H L0w m w 00 - r00LH a% -4 oq c ' c o LnaI0 0 c 000000001 100 0 N 00 0 A A 0ALAL coo001OL0 C NO0 0) 0 Cn CA0N .0 H N 0 C-lN,- 0 n r n0 oC 40t 14 H 1 0 0 C )0 c0 1 1 O 0-C 0~ON' r- oc oL nc nL noo co i '-I 0 00000000 co or 1000 CO O AOOO OLAO oOoo0 100 m00H00 0I00 H 0 OLA OO OO OOO OCOM ~.0 ~0 0 0 D0 C 10C C'4 Co cO Cl ocoooLoc c cccc icc r- CC) 14 r-ClC4 10 0) 0000 a0I00c 0 tD 0L c 00o 00a 10o 0 c c00o000 o0 0 rN LC'JC M' Co CO ' 0 00 0DIc o 0 0L 00 0 (' .I ClL CD N C) 1 0 Q m-- ko- -4 C4 N r-4 CN' , , 0 oMC 00000000c 1 000 CD 00 0 cAL In cO O OO f o o 00iac c)c0 'C) aa 0 0 ) DC)0 C c a cooc co oc Q C 0 0 N O04 w N C ID wl w 9 0D U)i M O 0 1-1 U)) (d u E Ul) Cfl4O 0 -lU) (dU) U 0l) -1 D 0 a 3 Ol 1U WI 'dc a cl ) (15 U Ca l d-4U)(d n O4.)R D)Cl 3)- ) 40 r ~l0 0 a 0 1m (d' )4- )l 0 D*HO 0 4 riS - (0r_ r4-I D M- O DH , 0) a)0 0) r- Q 0k 0-4C.-4ID- Z to ~4 4 J t) *..U0 ( j dQ Or ( O : k440 O0rU r. O4 d tv (0 #0 1 1 l )q r )M U 40 ): 4 U WO 00/43377 PCT/USOO/01283 318 O 00001I0000000C 00 0000000000000O Ln r- 0000100000000 mA 0r,0-I CN 0001000000000 LA 0 0000100000000 00 0000000000000 m L M0000000000000 0 m N ' N 03. 0000000000000 al LA '.0) m' L LaCOi Ln L o L L ao oOiOaLA c H 000000CC00C0C00 0 w c oc 0 0 co W vi0 o qw Hi H 14 l (U ) w i a 0 )m r 0 0 w - UU t)) 4- a)( ,40 )t) W( r r U) HO4)0 q b a) 4 ( a (U U * d U O -~( (d SH0 t )M - D b 4 a():IM u ) (0 0 4 O f W4CUU 0))44 0(U (($ CUO)U . 04 E :da O ) :d4M 44 IM( r (VU r. Q)Zr 4MME ) ( 4 4W: 4M0Z r;r (Uo H4 0~) H ) OdO a ) d 240 ri ; rIa la a a 1 0 4 ) 0 o 0 ; d - ) r ) 0 ) a (1 4 -iUU) ) r..9 U )O E: 04U 4 -) X , 4 rIE aH ) r. 4 r. UU)O a)rI0 a rIU4 4 0 ( 4- J E ) - 1 1U4 WO 00/43377 PCT/USOO/01283 319 CV LAoOO I LALAOOLAOOOO 1I0O 34 w CO 0 tor O r%-4a% (N (Nq % a~ 00000OlflLA00oo000I00 N4 0000000IO000C0000000 'v Ln H 1. tIL O AO wIO0LAOOOO0OwO)OOO0 1 H H r- Hl H -1 w N mN CO N011 00 iC V-i 00)1 000 (N 0000000000000001I0co H~ w - H 00 1000 0) aopc c~ O 0 0LA opo 0cLn oo0aico o H 00I I HLA00N00000LA0:0w1v00 0 000 CO M 000- N LALO o 000m O HH -4 00 1000 M 0 000C)00C0)0C)0 0 0 0cIc0 0 0 M H N- N H (Nq H Ln 10 w. (N 001000c 0 000000000000000I0i0 m* 000 (N M LA M M(CN 10 C n 00 ( N H H 00 C 00 I 00 0 00 0 00 0 1000 ONoo c o c acIc o 0r LAOO H04 - N H 0 (q NN (Nq 0 LA v n 1 H H U) w (d 10 (D HM)~U -4U D ) 0 ) H OU) Ea)U (a t)) L) - o a 1 U) (a I U) t QI ) HU)o0 0 4E :j En ~ (Dt3 UI Q k) ( ) ;J 10 ) XU (d )U) 'dl4 0 . S ) L)0 - c 0 Ok ) r: ED~ H - )Q )rI4 4(J0 )M -H 0 U)~ H - ) 4Q ) 4(a E a 4 O d : 40O W4L- ) U . -4 ( n a4J ) q (6t :j dz a .r 4t ~ D d 1 5 i Nf .
WO 00/43377 PCTUSOO/01283 320 H- o0000D0000000000 IOC Un 0 0 CN aCDC00 0 0 0 CD , D Hl HH 14 -4-4-4-1 , -1 -1 r- o ao ooOOIOaLAc LAo o aLflDoOa co c C 00 00 0 ~ 0 oC H- HHH H- r- H .:: CC OO -foooCOCfOOOOOO s00 00 0000000O~0C\n00I00 H - 11HH H - -4 HH H HHH'1H oM-000000000000O r-. H - - - I-4 H H H H H H- H.- li'A4iH H r- cooc DOO DOOOO OOOOI1O H 0.0 cqo00o00S00006) -10 H H1 H 111 - HH -H HH4 IN 000000000000000I0l H 0D 00D l~H 0 HDao n8H H HH H- ri-iH I H1 0 0 0 0C)0 0 00 00CDn0 00001 0 H C0 N0D, HO C)f"00 0 H H 0c 000 C > 0 C C D 0 H H4H 4 - AH 1 iH H 0 C 00 LA 0D0 0C)00o0 m 0 H HHr- - H-4H r-A HH H q 0 00 00C000000r0 C0 H- H H 4H HH HH H H H1 0 c 00 00 00 00 o %0 r 0 H- HH HH H H H H H4 I m C 0 00 aoo~o~ r-o c fl H HHH H H 00 CD 0 0 000 (D j1 HO CNC L H H H H H HH H H4 00 0000000000)00000 I0C 0i 0 C) 00 00 C~ LC4 o Hl HH H H4l 4 r 01 00 0 0 000l ~ 0 CDwr- D 1 HH1 HHHHH H H H C 000000000000000OI0 H- 00 i O000C4\HCI -I0 000000C)O' co co0m 000 H..Do 11 rI H H 4 1 Hr- - 1414-1H HHH H414r c ~~ ~ ~ c)d nioLnaoc ~oa c - o0C 0 00ccI0c0 L 0 0 HD H HHHHHr- H H4l a0o00o q000n00000nc oa C00O o 0O 00000D 0 D 00C)0 0 0 0 000000000w wm 00 0 00 U) O0 00o 00I m0 00 H H H H H -4 Hd wO 4 m) H C aU) U MH -O4OQ) HdC( 0~)~ C CU *H MO O0 H)rlE 1 ) U )rI ' J (13 X (d O 4 a . - E a 0) H 0 L)O4 (C~ d (L) J (Z -)C X ( U 4fd -J c () IZ0 O0 4- El) t H C0)0) (1 0C4( 4U ) 1 o) a)O r O C C -H 0O 0 4 C(a 3 40 - 40 Sr . 4( 4( n OC Q 0) 4 L*HW 0) d r4 )O r q C t4 Ea 0) (0 4 0 - ): 4 E 0 ! a d 4 (): -1 Oa ) H~ a)W . U 0) M Q) 0 - ) )E ) 0 d ) * O - H In ( L) 4 -r. r.C dU) Edad d C 4 H 0 CO~ O a) r. 4 * U) ::O r: - 0 4 H 4H4Z ( U 1HQA)W 4' 0 1U 4: WO 00/43377 PCTUSOO/01283 321 0D LA 0 co -4 0 N -4 Q0 00 H4 -4 CD0 l0 00C 00 -4 -4 00 C 00 00 0 0 0D)00000C000 m~ C\I -.0 00C m 00CDooc rn~ -4-4 r-4-4-H 44 1 00 LN 0000- 00 a00 0D0 r- 0,0 0 0 CDOOO 0 C en cc Ln 000 000 0 a% LA 00 000000 -4 M,. -- 4 -- 44H -4-4-4 00) m 000000000 00 CDI m'0 CL ho) cD0v rl-4-m -4 -4 0 LA co 000000000o ON r- 00C CD 0 000O H- M H H14 00 0 00 00) D00 Ch CN010 O 0 0 CD 0 0 0~ co 00 uc, 000000000 oo mN O OOOO OOOoQ - 4 -4 H-4-4-4r no C 000000000 OD~~ 00 CDoDocco00 ('4 H - ~ l l 0~~~~' .- q- liH - i 1 a-4 O 1-4 -4 H ~ H-- -4 -44H 1 H HH HH11l H olH 0WWf (I d a) : dU dM J E 0) rA C 0)U 04 f ) ;J0 ) IH C )M 1W - 4 W O0 -4M U4- - n ) 0 *H(00 Ln 4 0 d M 444tMfOr:U 4 ( A E a c 0ro (dto)4M 4 4 0) r )49)mwOm 0 2 . 4 O0 z 9i2 1A 0 )0) m w tm w ~ ~ ~ O~4J~ *dO ( rA0 r m 0 1QIm-1 0 -qO WO 00/43377 PCT/USOO/01283 322 -i OOOCOooooooooLo IOoLA LA 00 Oq O0O0 0 0 L0 wO0 00 -i H l Hv4H HH-I H -I Hi r- coOoOooIOi oma~oOLAoooo ~i 0~000 o'o 100.-IOM 10 00O'i k C~O0Oc 0 NOOOOO£ 0c 0 H Hi -41- HH H - -4H H M 0 0 W 0000%D cWoroc. -O m m ) N HH H H H-H-4-1HH rn C 00 0010CDcc0 cC c00 ~00 0 Nr-0Cn H4 rH -4 qrIH-4£H HH H H- H H 0D0 0 0) 0 0 0) r0 0 H 0) H HH1- H VHH1- H H Ln L 0oc0co0p oo0o oLn co c ci cLn c H- 000 C4 -40 c o mLAn LA HNr H H HHr H 0 0 000 0 1 C)00 CN 0o0000occ0000000 1000 mN-0 H C 0) C CD 0)~ H CO0m 0 0 Ch0) 0 Hi H- H Hi AHH H 000C c00) 1 0 c0 C = D 0 C 0 00 0 acCD DCDc00oo1 0 00C 000 c H-401 LA 0 H 00 c 0N N D01 l % r HHH -il H H141 HHH H LOaCD LAOS CNO 0 C 0CD - C0 D 0 0 0 00r0 m o0a% H H- H-IH H H H HHHH 1 11 iHH- H H t.0OD0 0 M 0 C~q C C 0 0cC)0)000O-i Ha% Cn H H H - H HHf HH v4HH H a ~ 00 0. ) CD0 00 0 0 0c c m0 r-0 0 0) Hi H HHl HHHHH H H H HHrI H l 0 00000-1 o R n ooc oo o 00 0Ln L000coo0opALA0o0op0 L C)01 CD 0 0D -z C 00 000 ca00 r0 0) r H Hi H HH H HH H H 0 )0 0 000 I coo0 m LA 0 00 c 0000C)0 CO0 0 L 1000 £10C)0 LA cN 0m 0 CO0 0) M 0 m 0) N- C19 HHH 0OH H H 000000I 10 00C m OOCD0CD0 0 00 0 0 Ln 0 ) 00 Oa 0) - 1 1-1 m C 0 0 0 0 £ce1C0 C H H H HHH riH H4 H4 0 0 00CD0 1 000 CO LA0o000)n o o o o o c aLAio Lno L c0 0 Cq0N N- NOr-0 0)0 0He CN0 N- C H-4H H H H H HH- H CD0 0 0D0 00a w NO 00O aNC)w 0 HH H HH-IH HH H H -HrA i H Hq 00000c0ICDCD0 co co1 00 0 0 I M000000000 CO 'n0 0D0 000 £1 %0O 0O m 0Nm O v0 H H HHf HH 11H H H H4 H 00000 £ )000 0 o0coo 0o LA0moco ocooo o OLna 0 0 a) - H0 m C C) C CO ~0 0) 0) 0i H- H Hi H 00 o ioLA LAO O o ( o C L c 0000ai m0oc o c a L o LA w mm 0 C C.1 NO C 0 0 0) 0 ONN r OOOOOLAOr-4 1-4 LA 0 0 r £ 0 A 0oo C1 0 LA LA LALA COCH C'N wO 00O m h h 0 0 CN 0 H -Z 0 H H H 0~ HN1 00 0 000 WO 0'0 O'00 C) - cmc c o acc o o m 0i o C HHHHHH HH H H H O c U) >1 ) 02 a riI 0 fl r2 Ca 02 0 H) U)02 02 (dQ 1 J ) 4 Hr. ~)0 0a r. 02r.E U 4OnUd ) 4 H10 p 0 Ir 4 0 0Q : 4U) z a r A )0Hi rS 4a OW 4 0W z aU) H0 U O t- O£H a) a4 UH)0 ~ 2U O U)-d U) EnE1E49 44 P - 4 )U )V P J.a WO 00/43377 PCT/USOO/01283 323 w0 C 00 m0a0 0 000"000C) C 00 000010000000000c U) m' 0 tl- 0000 0 0D M -4HH ,I -4 -l H r r- CDo a CDCD Doo0 o0 Doo0 In 0 0 000 a0 rm to0 m~ r-4H H -,i H Hr CN co00000000000000O In 0 0 C D c')0 00 cq "0 0 m HH HH.- T1-IH H- H- aI 000 0 00 C C D0 0 D0 00 -0 r-o 0 CN k.D0 c HOC CN m ~ H Hlr 00 000000000000000 IZ 00 0000DCD0 CN 0 w. e H H H HH 1 en CD 0 0 ID0000CD CD 0 D0 0 mC HH1 H, rI -4- H H oa% 00 amoc0000liwa 0 cli H 1 - r-~ H H-I 1 H000000000000000D D 00 1- D010 0 001f 0 0 r C") H H H - HHHH H H Clq In000 D0I0 0 000DD0 0 0v 0 000 ~ l e o ,-Io mf 0~~ CDCDCDcoM C H~ H- r-4,- Hq H- H1 H1 1 000 n0 00I 00 n~n 1 00 H 000000000000000Oo 0 ~ ~ ~ ~ ~ ~ c o0O.00 $00W Wo ~1~ ~) 0 1 0 0 0 . 0 l'0 q H4 -4 H H HH HHH H H H- WU) -W W HH14 H Hr4rIrIri I M) U) 0 W HU) VU ) U) M o H U) 4 0 SU) H w - a r Mr 4W( 0w ( rd rir )E 1w ( 1 w 0 w w~( W w U04 M -W 4 0 ) ( 0X 0 W $ w 0 0 - n t 4 0M 4( 0) r 4( *O O 44J r W *OO). O 4- 1 " Mr4W0 4M0 4-iC Z O 40 44 )00Ur q0 f )rI0' tM 4M 4M( ! WO 00/43377 PCTUSOO/01283 324 00 O0oo 0oco oo o Uno n j L o Ln rH - I H H H H H4 0000000000000001000o m DC ma0C 000 0 0000W 0 kfl '0 c ,qH H 4HHHHI-H H q H H m 0 omo~0omr-o 0) H c H H H1 -1 Hq H H HHH H NO 0 HH ~ '0 u o N 0 r H1 H H H Ml W000000000000001o000 1 ~ ~ 000 m 0 cDc Do o o c uop0 m o nc )i o Ln H1 - H HHHH H H- H- 1 0 O DC ) D0C 0C )C 0 00 H OO 0NDO~ H a I fl CD00 r 000 00 0O0 OD 0 HG 0 )001 H H100L 0 ) 0 0u0 0 0CD0 C)(n0) ( %D0) CN HOL 0 CDC n 00 -c 0-00 0 0 C0f~ o Co aio o 100r 0m 4 LA CO 0 0~~0 10I 0 v 1000 CD 000 ko ODC) OD 0)L O 0I H H1 I 00 3 L 0 0 Lf0o ~ o 1-0 0 % L 4 000 N 0) 00 H I m CD0) 0NNr0 w H 0) m 0 H- HHH4 U 10DDO00 M LC1)0000C LOOoOOo)Iooc Cl Nr C) 0a 0 0 C ( H- H H 0O 0* 'l 0w0 CD 00 V n 0 H Hq 1 0 0 C 0 0 )C 0000 LA I LA 0 000cCD00CD000D 0\0 Ch 0O co C\4 CDO H- H H H I1)000 0D C 0~0 )0C)D r L r 000 CAO o) o CD 1 N 00 100 0 C)0) Ml Ln~ m D 0 N0r-r 0) -0 v' 0) 0 0 0) 0 H HN H- 100D 00 0 00C0CDCDLA 0 1LA0o0aODCDooO0 0 0 L o oo L Ln Ln O H CN w0 a 0 01 N- 0 aN' N- w - 0 O . o H H H4 H H H1 0000 -I C 00 ) 000 1I00000000000) -c H ~00 )a0 0 Cl CN cNi 1-f m ~ O CA 0) 0 H Ln 0) 0 a00 HH OH H- HHH- rI L H H m O 0 co 0 0 C'N 0~ Np~ co A 0 H H- H- UHr 1 00 0 -0 00 0 =IOD000) )000 0 0 D0 00 ~0CD0 L 0 0 r,00 0 Q'CA 0) 0 ml~O a' -oaN10OO r IH H H- H H (d U) w >1U 0) r d u co) l4 wi H 1 (d > 1 COa)) l4 Ul)H IEn2 (d Ci) U) H- U) d 12C1 0 Q)Cl ) 0) Hra (d U) Ea ) a to rdt Ea CJ) _qU) H ( i) 0 -U )I U) ) c$ E CO ) M- H n Q~) HU( )O :J( O) 0U)fl - H U) a H L QN ) ) HU ( ) OSM (0 (d S1ZI1 r- 4 O (dU U)4 4 4U) (0 0 U r 4(dOHfdC r COH U) 4 *H) 4 10 40) ) Oa ) 0. 40HoW J Ma V: r$ 4 0) )HO 0) H z :j - Q)H: ) LOO 4 O~ a) 0 O ~ d d ~ U *1O rqz Q - a : O r A r rIri- ) a 4 g Ii U )r r )J 4 1 - - )( 4 -- WO 00/43377 PCTIUSOO/01283 325 -4 -4 -4 '-4 -4 CD CCD00 0000 0000 100 ko L 0 r C) 0 0 0 L'- 4 00 000O000000000001000 CN kO LAO r 0 00N0 0 L O -1 -Ar- 4 r-4-4-4 H 1 Ln C 0001 0 00CD0w 0CD 001 00 CN LA 00 OOO'i 0- -1 LA ri -4 LA 00 C NnoOSo q 0 r- 4m m 0 M~ -4- - --4-4 -4 -4 C'4 00000100000C00000 1 0a0 r 00 ooooooooooooco Iooo LA r' NO L (A 0 0 CN CN 0 -4 -4 -4-44 M A~ 00C 10 (N 40 0 0 N 000 10000000000C~cO I coo co (NNO 00 Um' w~~OO ~ ( ~ CN CDO - O 0 C) CD~r 0 D000 )000 DC (N A- r-i 1 1l CDC o co Ccq 0 .- 0 m .4 -410 (N LAO. -10 0 (N w. ml r-I~~~.- .- -IA l H I CD lN~ i N -C) 4 Vm 1.0 w.00 w.00c 0 C) D (N -4-4i -4 -i 4 -4 -4- -4 o oLAOcOD)ocOi oOcLA N- 0000000IO000000C00lO ' 0O- LA COI ON 1fl (N H 0) wco0O Ml 0 .- i H4 H- .-m NCNm LA- HI -4 -4 -4 000000000000 H- OOOO00000000000lC>ooO 0 0 oCD r ) 0 W0c DC qe 0w-C M 0W H4( w u 0 wW Ci) C 40 W -4( w w U MHU) 0 ( 0) 0~~1 HWW-WO - m~ w aw m0) 0 o ~4 U)O( * dQ1d d d 0 *.O&- W 4 Owtmd r JOw d m 1dW 01dkd0 X 40r : Dw0 - M 40W: 4 0; )t WO 00/43377 PCTIUSOO/01283 326 ~)00 0 00 O CO 0 LA 0 LA 0 0 0 0> 1 000 11 H HA mo 000LA 00000 LA 000LA i 0 In 0 a% o0 m~o o o o 0 )V 00 - OC 11 H H A 1 a) 000 00000 LA 0 %D 00 kI 00 0A H -f H H HiI q LA 0000o Ln m 0 LA 0 LA co 00c LA i 000 rO 0o m a%6) mLAnO~ 1.0) LA H H 0 00 0 00 LA 0 LA 0 00 0A 0 00 1 0 LA 0 CA 00000000 0000 -:r M 0) CO 0 C'0 ~ ~ 1 OO O L -I HC , r 0LA 000 LAA LA M 0 1 00000 I 00 (no ODOOOMNOH r M~C HO. H- H r- H rI H 000 r- 000 LA 0000 LA 00 00 ' 0 CD0 0 r- r- a 1.0 M 100 LA co 00 cO c 0 1 00 0 0 0 c0 0 ~ I0C OM M 00 r 0000 MOO CO 0 00OM0 LNW 0 0 r-fr- -1"4rH H -V1 00000 A L LALA00mcO 000I 00
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1 0 Mi m M' Mc 0) CDIOI0:"CMC14w0 H' H HH C) ID C OOLAM L C) ooc m ooooo1 oo 0 O O O A A c O O en Mr- 00 00 0 M- CN O OC C. LA~~cO4 cO i LA CIIoo o - f OOOOOLA0A I- 00 M 0 0LA 0 LA A OO c In 0 0 r00) CD 0 nr Vv00 I.Zp MI M0. a) 0~ cO C cOC'-C\IOI 0 ~ r- LA N' 0) C0 H 0 . El 0) 0'0 0 00I1.N00 o naccL Lcoomo cc i o o cI MI 1C 0C CD0C m V) 0 0 0 00r-O MIC LANIC N00 w. MI CO 1--VaM H 0C 0cr M lzz1a Ea t U) MU ) (a E H IU-) U)C 0 a ) H4( a wW U)ISC M O Q)OU HCO U)ITC M M a' - a 1 0 Mu )w r w ( o E 0)OU 0 W zC 10HC 0 w~~CU wdU 41SC M CqMJ- 40 l0 0 .r i Qw dA 4 d Q ( ) 4Z 9 : aO)0)H r- )k d a ( d C 4( 4) MO H4 W 4( 4W 0 4- . w r - O t )- - 00 ) 4 ( n - 44 *H ) 0) (d 0 U C OH f .l f E : 4M 4440 U) 0 HU ~ C U Q) *H )tMC )COU) -d H )UX4 0*HCOU 4 O 40)01M 0 C4U Q O~ 4 O T a) .. 19 a f iF WO 00/43377 PCTUSOO/01283 327 r-I 00000 -4 10 L00 0 mz CO 0 H4 -4 H~ 0L00O~ -4 LA 0 Ln00 0 H L %D O ON (n 000A00 0 -4 C 0n O'iOC)a H 0~0 0 k -4 1 N0 0.0 L0N c 0 0 N H ~~C OO O O O O O o i o LA 0 000L LA (NO 0' N 00 )0 r 0(N c 000C00)00C)0 000000 1 00 C)c L 0 00 00 LA '0) N en -0 0C, M O C) m MN H 00 I0LA0 000010 000000co 1000 10 OLAO0 N 0 ~ .( V ' aHC01 00 00 00OC)00 0000000 0000CO 1 0 00 a4 M OLACC OOI LA w 0000 00M00 0o0 0 OLAzmCO1D0 O0)o A CD1 CD 00 .00001C0IC o cC D 0CD0 00 0 C) OLn cO LACOLAC (N 00 0 00 0 0 00 l 0 l OL OO 00 00 o- 00 nc o 00000 00o O000ooo1 o00 w C co 0000 (N -4C n Nw ;4 C '0 m-I m LA OD 0.00.( 0 O (NM V en C C)0 C) 00 c O.U1CU U) -H C) O00 Cc0 -0) CDU)0 al r,~ -)0 U) w UU Ln 0 ) U)UI.-IU) rdr q ~CJ ) CO CN Ln o Umc C c oc oc cc cc o 00 ) JX oLnc WO 00/43377 PCT/USOO/O 1283 328 LO LO 0 0 00 CO 0 00 CD 0 00C -i 0 LA I 000 CO000 LA 000 0 00 1 LA 00 000c LA CO LA 0 0 1-1 LACO 00000000 0 OLA0 m m 0 0 Ln 0 0 w r ne WCONN14 0i LA LA 000 LA 00 c 000cc i o r-CO 1 r LA 0 Cn 00 00 LA c 000w -A 00 00 00 -- 00 CO CO 0D0 Iln 00000D 000D MMCDO CD rI m c LA 0 LA 0 0 000 cc 0 LA 0 LA o 0 LA LA LA o 00 o 0 LA 0 CO CO LA LA 00 CO 00CD0 1 00 0 0) 'C 0CO m 0000000000 I Cl000 o o LA LA 00 cO 000 000cic 0)~ N k 0)r - ' H r- CN ' 00 CI 0 00 LA 00 0 CO 000c CN CN 00 00 000 M 0 00 I 000 LA 0000000 m COi 00 00 I00000000000 en LA w.~i N C 1 -4 o000c000 00 00 1 Q000 NLA L o o iLn L o L L o o ooai o Ln o R q* 000O wCO 0 CO wCO :vD CD CO CO CO ~N 0 w0 0ON C m w r '0 CO CO C13 r-i-U -4 o 1 w Awaw .r - 0 a iw 0 U ) -1 C 4 0 ) riu M ~ ~ ~ cOt- fa CdEacX dw C~ U)mC E o(a 0 Q o ) ( U OUl-I(1 O( mt m d~ 41~u Cd w (d~ 4 3 4) () 40 )0 Dr 0wm 1w (dQb)4) a) 0 lX r O 4 f 1 U Q) 0) CN Q 4 ff ): d E ( ) 0 0 :l U )t) rH(0 0J4E. 0 H -- r w r rC~ - Z J W m )0 )OWa. 4( )k-q i 0) O4 4)O j d E0 4' dE : b 44 ) dr r. *O d 4~ ~dJ.' d EAU - : 4M dZ a .r p t)O nt) ( 4a : 4U WO 00/43377 PCT/USOO/01283 329 (N Ln 000o L L o pLA o ": w~ 0 0 .0 r- CNO -4 (N 0 00CQ0C000C)Ln0 00 LnI -00001% 0A0 0O W 00 m0 CA000 M q0 -00r OO)OfnALA000 I LrA ,-A 0L 0000 00n0H '-A acco ooco ccoo loc LAQ 0 000000LA00 0n 00 0 0 0 0 0 0 1 0 ( h 00000 00 000 O m ri LA mm- 0 r- H-Z c CN O w1 : 0 (N 000D I 1 0 00C000 0000 1 000 ca r OLA coOcOm cL o o CO 0000I00000000001000o LA 00AOOOOLALAO rn L Clq0 aD 1 mH aD 00000000000000000 00 000000000oo n n n 0' LAi vN 0 00 w ww 0 CN 0001 I000000000o 1 00C0 CO OLAOccoo coo o o V (N r- -4 ' LA v' w (N (N 000000000000000j10 c C 0 00000000000o 0N LA w O alm N rn LA I) CN (N 14 o c 0C )0 D00 a0000oooooCDoo CD cDC0000000000 U) C)i .14U CO -l 0~' a) )) U) 0 U) ri 0)UIU r4 *.-I f U U) M-AWi (d4U ~0~U ) W U) -H U w~ )U tm0r d .U) Ea J) rA d b) 4-) a) Id r t~~)) rd0 Ca U) Ea41U) (1 W ) 4Z Q : dE 1 Q . ) m 1- ) 4( Q 1Z ( U~WO ~) z 00 0 lt 0) (H~ Cd 40 )C );,- 4 Ca .H 01 En 0H ) (0 t 0 z m j 0 -H Q)raH0mMQ)0r- 0 -i0 13crIa)r.a WO 00/43377 PCTIUSOO/01283 330 0000 I 000 O0000 I 000 o 000 I 000 C00000000 00000000 00001I000 0 n00 I 000 On 000 0 n 0 00001I000 Lq In000 000% 000 I00 000 I00 000 m 000 00001I000 00001I000 000010I00 0000 I 00LO 00000000 0C O In O CDC0 M M 0C a wcn (a O Om O OO O4 O a) O 1 OEOn O OIO O OI 0) O- W p O co O ) O i a) O 0 t -I d4' 0 (d ,.Q :). 3 4 U) O w 0 -1 0) - 1 i 0) E r-I ,O -H C i d - ; (d 0 Q4 :j (a WO 00/43377 PCTIUSOO/01283 331 TEST E Compounds evaluated in this test were formulated in a non-phytotoxic solvent mixture which included a surfactant and applied to plants that were in the 1- to 4-leaf stage (postemergence application). A mixture of sandy loam soil and greenhouse potting mix in a 60:40 ratio was used for the postemergence test. Plantings of these crops and weed species were adjusted to produce plants of appropriate size for the postemergence test. All plant species were grown using normal greenhouse practices. Crop and weed species include annual bluegrass (Poa annua), blackgrass (Alopecurus myosuroides), black nightshade (Solanum nigra), chickweed (Stellaria media), common poppy (Papaver rhoeas), deadnettle (Lamium amplexicaule), downy brome (Bromus tectorum), field violet (Viola arvensis), galium (Galium aparine), green foxtail (Setaria viridis), Italian ryegrass (Lolium multiflorum), jointed goatgrass (Aegilops cylindrica), kochia (Kochia scoparia), lambsquarters (Chenopodium album), littleseed canarygrass (Phalaris minor), rape (Brassica napus), redroot pigweed (Amaranthus retroflexus), Russian thistle (Salsola kali), scentless chamomile (Matricaria inodora), spring barley (Hordeum vulgare), sugar beet (Beta vulgaris), sunflower (Helianthus annuus), ivyleaf speedwell (Veronica hederaefolia), spring wheat (Triticum aestivum), winter wheat (Triticum aestivum), wild buckwheat (Polygonum convolvulus), wild mustard (Sinapis arvensis), wild oat (Avenafatua), windgrass (Apera spica-venti) and winter barley (Hordeum vulgare). Treated plants and untreated controls were maintained in a greenhouse for approximately 21 to 28 days, after which all treated plants were compared to untreated controls and visually evaluated. Plant response ratings, summarized in Table E, are based upon a 0 to 100 scale where 0 is no effect and 100 is complete control. A dash response (-) means no test result.
WO 00/43377 PCT/USOO/01283 332 '-I I CN I m -4 a) r-f N -w 4 H -) (d Ea 4 (U 0 Q)w'0 W CN 00 I- 0) I- r. ID w1 w 0 v 0 0 (a I 0) 0) 0 1 A 01 w4r EN o ' 0 0 N_ >14)- )(d 0 - - 4 44) 04-4 -4 O 02- ~0)0 H 0)~ 0 02 ~ 4 ~ ~ =CD £ ~ 0 0 -I 0 022 0)~) II0 ~ 4- *H -~ ~ 2~00~-~ )0)h 01O0~ ~ 4 00) ~ 0)~ O~-HU~-~ I-~4 0 ~~0)~-40 IH ko I Co rd 10 W 0'( (d ( 4 (1) -l a Q)r-Ip - -) dco J' . 4 ror-i ) a CA (1) J > Q) 4 ( 4 ) A L) 0 4- (a 1 4) .11 4 4 Cl l 4 ) 4) a)Q)N r. 1.1 04 ) Q (d w ( a)p H L) -I a 4) 4 4 l N -r-IU) E 04Q) E r-I -W E) 0 4-) 3) ci a)0 (da)0 CD 0 r-I U) 4) ro 0 rq 0 x c tm 4 >1 4.)CO f 4 11 4 ca 0 o a -) 02- u 0'004-H )Z r ). U0)0 r.-A- d440C 0rO' )4 0 J- Iu 4 0) p d$4 A ( 3 ) -4a 0 4 O - P)- Q) r.4 - i . a W c rd0) 0 r:(5 '0ri 0 )0- 0 0202 0d ) a 4; a) 4 - r 4rq f 00 (0C4 4 J L)UClC f24 .s- *,- 4 P4 ~02W U) M ) U) )0' U)> -. U01 3 4 4 I 0)- 00 0) - -00 L0 Hi 4)~ WO 00/43377 PCT[USOO/01283 333 I~~~~~~~~ I I I l 1 1 1 1 In I I I I (N C14 1 1 I 1 1 I I 1 1 I 1 1 1 1 1 1 1 I 1 1 0 1D I I I m I I I I Ln 00 (N I I I I I I I I I I I I I I I I I I I I I ILA)I I 1I 1 C 1 1 1 1 C14 (N 1 1 1 I 1 1 1 1 1 1 1 1 I I 1 1 1 I 1 1 1 I LA I I I I r- I I I I CO N L(N LA I I I I I I I I I I I I I I I I I I 0 1 I i- I I I LA N (N I I I I I I I I I I I I I I I I I I I I I1 1 0 1n I I I %D II I I I I I I I I I I I I I I I I I I I I I I A I I I I O D I I I '.04 I I I I I I I I I I I I I I I I I 110 1 1 I 1O 1 411II 1 0(N I I I I I I I I I I I I I I I I I I I I I 1 0 1 1 1 I C.N' I CV 1 I 1 I 1 1 1 1 1 I 1 I 1 1 I 1 1 I 1 1 1 1 1 0C 1 I I 1 1 (N 1 1 I 1 (N I I I I I I I I I I I I I I I I I I I I I1 0) 1 I I 1 0N 1 1 1 1 (N N 0N I 1 II I 1 1 1 1 1 I II I I 11 1 11 1 1 1 0 1 1 I 1111 N1 0 I4 a)I I4 U) a) I I I I II I I 4 11 1 J I (N (d I I 0) r$ m CA n 0).0 1 a (d : W 40 4-) 0 > J- ri 1 (d : ) Ic 4)4-) 10 D a)ra ) 4)(N 4 aI a) I ) II d I d a)I I4 I ) I r UI I- Io Q) 4I . 10 IN > 0) a) r4~~Id ~ 0 .) 0d Hd ) 0 0 >, >1-4 00)0 (i 0: Z - )(d 0-- 4>Z1 .1- *HI Z~ $41 0) a-O)4 Q 4r -i() L)@24 -4rL r OU )H4U)O -rit -H4> d0) *d.4- 0 COrOr O a) 4) :J r- i 0 -i 4 4 0-l ( 0 0 C/0 Od ) U Pt :: 0- Q) 4 - -- i-H-i )d*H( M L) U Q l44004C P )CO U)CJ)W >2::R:3: t HW 4J P WO 00/43377 PCTUSOO/01283 334 I I I I I I I I I I I I I I I I I I I I I LA I I I I LA I I I I I I I I I I I I I I I I I 1 0 I I I I I I I I I I I I I I I I I I I I I I I I I 1 0r I I I 1 II I I I I I I II I II I I I LA I I I LAm I I I I I I II I I 0 1111 11 1 I ~~~ ~ ~ t I I I I I Nl I '.0 I I I I I I I I I I I I I I I I A I I I I 0 I I I NC I~~ ~ I I 1 1 1 1 1 1 CD I 0 I I 1 0 I 1 1 1 1 1 1 I a) 00 4 ul r- 4 4-)(d ( m Ea Ea a) 4I I1 a) Id I 0 II w II I I I I lclI iI >1 4 ri 41 4 (d : n 4 a) 4 ra a) LA I:--L 0 J) (d > a) a)I I) 0 (a I- I) Il 0 -I 0I kI I I- I I) ILA r.1 0 14 0 0 > rci-H ) 0 0 -44J 4J0) ) () 0 A4r.0 Q) Z C: ) k ) 0 -H r-i t 44 0 d ' ' .i (I I ~ a) H u a IO W I) k I I I IM r 4 10) r I r i r i 4- U I I4 ( I S4 4 0 a 0 -1M 4 0 U (d Q ::I 01 0 ;:J:3 Q) -r-' 4 'H (d NI U ~ ~ ~ ~ I UO) Q r Id4 . mwmww> :3 : :::EiZ0 QL WO 00/43377 PCTUSOO/0I 283 335 0 CI I I I I I I I -4 O'n 1lOLC I I IlIl I I wD LALA r-4 CN 1 0 0L I I I11 I I 1-4 rLA 1 0 0L I I I I I 1 1 C%4 L O iLn IC 1 0 1 I 1 1 1 1 ID LALA CD 0 1 1 1 1 Ch-4k I I I I I I I I I I I I Ln I I I w I CD Ln I I I I I I I I~~~~~~ ~ ~ ~ 100 I I I n ic n i i i i i LA wCO I ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ 1 IO II I II I IIIII LA 1 0 I I I 1 I I I I I I I I I I I 10 1 1 C 1 0 0 1 1 1 1 1 1 I 0- LAN Ln m 0 1 I- M11 I I I I I I I I I I I I I I I I I 1 0C I I I f 1 0 0 C L I I I I I I I rw QX) 0NID I4 a) -A 5 I4 - 4. (0 (0 I 0 I L4O A I I I -i ~ ~ ~ ~ I N) ulID)W > L - a - ) r E 1 I- U) 0 I. 0I rq I. I 4 W 4I I0 I: I I D 0 I V) U I a I E r I w w II v r: 0I I C I - I ) I n 0 I L I 0 100 a) I- r. a) >1 ~ ~ ~ ~ ~ ~ ~ ~ L rO -4Z( W--4U 0 0- 4)r .1 i J la r;( 1 I H a) II En r, Ir- I II 44 0 (d IC IO 1101 T3 r- lOL Q) IJ -I U r- 0 r W a) 4 4 U)r Q r4 -ir- ZN ~ -W a) LA( -i 0 I, (0 I 0 0 (d En (d a) : ) 04 a 3 I ) 10 r -rI Ir -H M I 100 4 (a I o 0 a) 0 Q r40 Ht- l4 p u c U mc > R 5: E:3: :E1 4 m u-40 Q4 WO 00/43377 PCTIUSO01 283 336 C o II I I I II I I I I 1 0 1 1 0 1 1$ 00 1I 1I 1 1 I l LA I I 001 11 1 1 11 1 1 1 1 01 1 0 M 1 OL I I I I I I 1 lo~ I I C00M LA co 00O 0O'M H N 1 LAO I 1 1 1 II 1 1 I LA I 1 01 (N 1 0 01 1 1 1 1 1 10 01 1 0 ON10 'IV 00I r. - ONr C 011 1 1 1 I I II 1 I 1 01 1 01 H 1 001 I II I I 1 0 01 1 0 0m LA 0 00 ~L 01.0 LAO II 1 I 1 1 1 1 1 I 1 01 10 a N r 1 0 0 1 1 1 1 1 >001 1 t.0 r- N- r, LAO 00 (N 1-1 0 01I I I I I I I I I I LA I I0 a I ILA LA I I I I I I 10 0 1 1 0D.w LA N - N n kf.0 'LA LAOC I I I I I I I I I I I I 0 101 IC) I 1 0 0 1 I I I I I 1 0 0 00~( r-w r-c 0t o LA i i i i i i i i i i i i LA i 10 o i H 10 0 1 1 1 1 1 1 1 0 0 1 1 1.0c - N- 100 0 0 (N H H 001DI I I I I I I I I I 110 1 1 01 0i 1 001D I I I I I 1 00 1 1 LA LA LA k w. 1.0I ON 001D I I I I I I I I I I 1 0 1 LA I 1.0 1 00 11 I II 10 0 11 . LA (N LA -0 w00 00 (N 11 H 0 0 1 1 I 1 1 1 1 1 10 1 1 01 co OLA i iI i i i io LA i i Ch 0 CIQ 1.0 m n r)0 (NH 0 0 1 1 I I 1 1 1 1 1 1 1 I 10 1 w ' oo0 100 I I I D I LAI i ON N-rn m LN r OLA CD01 I 1 1 1 1 1 1 1 1 1 101) 1 01 rn 1 OLA I I I I I I 10 01 1 010 w' LA m 1.w 01.0 k 0 LAOC I I I I I I I I I I I 10CD1 1 0 1 0 pCN. I LAO0 1 1 I 1 1 1 CD LA I I coLA H- (N :2 m LA LA OL 0 0: i i i i i i i i i i i i LA i i 0D i (NI 1 0 LA I I I I I I 1 0 0 I 1 010 w. N r H LA1. ON r (N 0 0 i i i i i i i i i i LA co 10 IX O LA I I I I I I 1lO LA I f w 0LA w. I-l 0 LA or-0 0 0 1 1 1 1 1 1 1 1 I 1 1 1 0 1 1 0 I r N o LA i i i i i i 10 Q o i w OLA (N LA 0 c o0r (N 0 1 1 I f II I I I I 1 01 1 01 qq ic OLA I I I oI OLA i i c -LA N- 0 m0 01.0l (N ' 0 1 1 1 I 1 1 1 1 01 10 C (N ~ 1 0 01 1 1 1 1 1 1 001 1 (N 0 01 I 1 1 1I I 1 1 I 1 01 1 01 N- 100 pI oi i i LAO )i i 1. LA (N N- N1. to co 0 01) I I I I I I I I I I110 1 101I W 1. OLA I I I I I I 1 0 CD I NN (NC1 LA N, LN r o LA i i i i i I I i i I 10 10 c 1 1 0 OLA I I I I I II LAO 1 O IXo LA r N ~ -LA o wA 0)-E ~ .~ d I~0 - 4 rI(( )-Jid -I 4-) (d j (0 1 -Hq 4-) 40 : ) () 41 a) 0) r a '- 0 ) 4- d >1 4-) -1 4-) fa D) a 4 O uH( 40d~)-. 4 4 w0 0~ 0 4 a a) a) X(d I( x (a0) I 1a . ) d4a) r 0Idr-)4t0 a r- W 4J '~~0) 0)00)xIa 0 4 (d 4 U CO :a) Q '3 U M 4.)U) D t3 Q (d a)" 4 4 -H 0 a0) a)r v; (d -- Id4- M d E0~0 0)0- () r-I >1 m H~ z a) ) a)H( Pi ~ ~ ~ r (0 40) -1 U-i rd 0 0)- 4-) - 4 r-I 4. 0) () 0) a) -I Id 0 r. >14 r WO 00/43377 PCTIUSOO/01283 337 iii a a a 00 101 00 N, I II I I I 11 0 1 I llI II f I 1 0 1101n LA L II 1 1 1 -4 10 101 1 1L n I r- Itz In oo I .0f 0 0 1 00 1 0 I 1 1 1 10 101 0 1 1 1 1I C I II I I I I 10 IL I LA LA) C40)U d I I II IU I CI I 0 0 ~ 1 0 I I I I 1 0 0 1 1 1 l 1 I w o % o NL oNa I I I I I I I I I 1 I 10 1 0- 1 0 0L I I I I I I I LALA 0 I 1 1 1 I LA 0.0 0)o r- ) 0 0 I I I I 1 0 1 Io 10 1 0 0 O L I 1 1 1 1 I lO L 1 1 1 1 1 I '.N N-1c 0 I 0 I 1 0 I Lo 1 0 0C I I I I I I I100a 1 I I I I I U) r- (d ( 4 I IO I4 ul m I : II w 1 0 w 10m 10 1001 II -I ( a)0 J I 10 1 I 0 I N a) a) rd~L zO 0 I ) I 4 CO r, -H I I (I 4 01 101 0 lOLA IO IO I- a) (D ; -I riL Q) Z r, I U a a ~ ~ L rO kO M !()- r - ) 4( oi : )r- ) r (d I4 (d -4 I II W 10 .01 (a p0 0 II (o V) (d01 LA : LA 4 C4 P4 MC. 0 ) n4 0 '.0 4 40 WO 00/43377 PCTUSOO/01283 338 C1 1 1 1 1 1 1 1 I 1 1 I 1 1 1 I 1 1 1 1 1-1 '-I 00 ~ I 1 1 1 1 1 1 1 1 I 1 1 1 1 1 -A U , I I I I I I I I I I I I I I I I I I I I I I v-i '-I 0 m, '.0v w -I -4 C ow nLlr %U, fl '0 -i v-i C.), '-i U, I I I I I I I I I 1 I I I I I I I I I I -I 00 1 I 1 1 1 1I 1 1 1 1 1 1I 1 1 1 1 1 0 II 1 1I I 1 1 Ill l i 0' i i f n I C I flo %.D I I I I I I I I I I I I I I I I I I I I I I 0 I 1 0 1 IL I Qn. I I I II I I I I I I I I I I f I I I III I I ) I 1 1 0 1 U, I I I I I I I I I I I I I I I I I I I I I 1 0 1 1 0 N C I I I I 101 0'D rn I N 1 1 C 1. '0 I n i i a i C I I I I 1 1 0 I I I I I I I I I I I I I I I I I I 1 I I I 10 c 0 I 1 II 1 l I I l 1 1 '.0 0'a) I I 1 0 11 0 I 11dI l II a) I4 I ) (DI rI rd 4.) k , 1 0 0) r I l a) I I a) (a U) (a I Q) I4 -H 1 ( (d ( I ) ) a)~ -W > 4- ) 04j r -1 ~ 01 ) 0 4 1) rl >j ) 0d d Im -4 -Jgjz w i J 3)a) (1 ( a 0-S~4 J . r: -N :jr 1--IU 0 0-, J0 r CO 4 O 0H (d4 O9 O9 - ( - l 0 r o r r- -r- 4) :4 U Q ) nf' U) 4 4 ) a rI -Ar- r Q -W CO k 1514 H s * ) 4 ) H U 04rJ )Q) :: 0 4 0 H-H-i l (d(d0 ( rjr- !I 1 ~ O 0 -rI ( *00 (a a :3 ) a A ~ ~ EnM( )V :3 : :3 - C QuuC 4 Dr)U WO 00/43377 PCTUSOO/01283 339 00 0 00 0 0 00 1 1 1 1 1 1 1I 1 1I 11 1 11 1I 1 1 1 I 1 1 I 0-I r'I 0 0 0 0iI I I I II I 1 00 1 1 1I 1I 1 1 1 1 1I 1 1I Cl N N - 00 C (N 0 0 0 0 0 0 0 N 1 1 I I 1 I 1 1 1 1 1 1 1 I 1I 1 1 1 1 1 1 I (N I 0 0 1 n 0 D I I I I I I I I I I I I I I I I I I I I I I I I I I (N 0 1 ~ 0 0 0 1 C'I I I t I I I I I I I I I I I I I I I I I I I I I I I I I flI~ c m I' I OI Lnr-4 O O O O O O O L Ai ~- I I II I I I I I I I i I I I I I I I I I I 1 0 I N I I I I I I I I I III I I I I I II r-4 I I 1 0 1 1 1 1 I I I I I I I I I II I I I I I I I I I I I I I II I I I I 0 III I I I I I I II I I I I I I I I I I I II I I I I -I C 14 1 1 1 1 1 1 1 1 1 11) I I I L A I I I I co I I I I I I I I I I I I I I I I I I I I I I I I I I I Q 0 I I I I N I I I I I I I I I I I I I I I 'L0 Ea-w4 I 4 - 1 0 1 Io M I4 LA I4 I) I I I I I I I I I N) '.f0 ) 4a 00) D o 4 a) a) ro ~~~- U 0 j 0 > 1 q . 40 w . Z I4 10 0 a) r. I a~ w a) (d m z 4) I4 I '.0 3-qm 4w F;rq 0 m 0 4)M 4 ) 4 4j C tm-1 w 1 o 0rH0 x (d > 0 4 CO('-4 z : 10 (n I- w C) I4 I Id 4 W I4 4J I4 -H 0 I4 I d I 4 m m :R w I I u - Z o L a t a 4 > -4?M :j m J . ) .0: 0 -1 E - 1 -q ) 5 a) v 0 0 rA )'-4-1 I A I ! 01 I ) a) w z- a) II r. 011 r.I Z I I 4 I -II I) Z 0 -44JZ Z 44 0 Z rO r rO ra -4 a) 0 u u 0r i- iw r ) )S:-i- 0) r 4 r-Ar-i 3 Q -W4 ! 4 H M )- ) -iU 0 0 W Q 4 : w I ILA -4 IH iH (z Io 0 I 0 1 I 0 I w 0 -4I (a I4 I 0I 0 nz J1110 :j: > . iL: : : - 4a44MMMUU11Q4 H D4 q ZP40WWWWW> WO 00/43377 PCT/UJSOO/01283 340 '0) 0 1 I I I 1 I 1 1 1 I 1 1 I 1 1 1 I 1 1 I I I 1 1 I I I 1 I 1 0 1 1 NN 0 1 1 I 1I L I I I I I I I I I I I I I I I I I I I I I I I I 1 0 1 1 CN 0 1 I I I -qp I I I I I I I I I I I I I I I I I I I I I I I I 1 0 1 1 (N I0f 1 1 I 1 I n I I I I I I I I I I I I I I I I I I I I I I I I 1 0 1 I m 00 cc (N 0n I i i i I I I I I I I I I I I I I I I I I I I I I I I 1 0CD I I (N 01 I4 1 1 N I I I I I I I I I I I I I I I I C) I 0 I (N (N 01 I I I n I I I I I I I I I I I I I I I I I I I I I I I I 1 0 1 1 Ifl N LA (N 0 1 1I 1 1 4C I I I I I I I I If II I II I I 1 I I I I I I l C lIl (N 0D I1 I I w I I I I I I I I I I I I I I I I I I I I I I I I 1 0 1 I Ocq 0n I I I I N I I I I I I I I I I I I I I I I I I I I I I I 1 0 1 1 .~CjQ ILfI I I I I k 1 I I I I I I I I I f I I I I I I I I I I I I I I 1 0 1 I (N (N 0 1 1 1 1 I I I I I I I I I I I I I I I I I I 1 I I I I I I l 0 l l (n LA (N LA I I I '0 I I II I 1 1 1 I I I I I1 1 1 1 1 1 0 (4 Q 4 fu 40 0 -q 0) U)ri a 4(N 0 1 IV Io U I) 41 (d III 4-) .14 I I 4 (a m w 4-) I I I I 4J 4 4 0) :: a)0 a) 0 Ea (0 Cl 4 -- f u q rda4 4 0 :(0a rI a En 0 ) - 4) I 0 4) ) --i4 4 Q J(N :( q 0 4 0 1 3Ir.Q 0 0 s:I 0) U2dI Wa-4 0) 0 41 ' tm a) a) (0) C-H4 9 , 4.J-H )( ri4 r 4 ir -q (D0 .W. Ua) 4 M~ r-4-H M 44 0 a)*H0 4 o -) ( 14) Q 0t)I U)-~0~0 "I0 r>I u4) C) r4 CHL) ,C: -r--I - )) (0 (0 0d - Id M j 0- 0 0 a )Z Q)- CI) 0 0 :J .H H d I 4I -40 :R: ~ ~ ~ ~ ~ ~ ~ ~ W H - : : t : : P P 4 4 M O C ) Q P 0 0 H O t - C) a 4 W ) U) V)I U)~ >- W:: WO 00/43377 PCTJUSOO/01283 341 1 1 00 1 1 1 1 1 1 1I 1I 1 1 1 1 1 1 I 1 1 1 1 LA I I I I co k I I LA I I I I I I I I I I I I I I I I1 0 1 I I I r- Ln I I I I I I I I I I I I I I I I I I I I I I I I I 0 1 I I I I~~ ~ ~~~~~~~~ I 1- In I I I I I I I I I 0 I I I IN I I I I I I I I I I I I I I I I I I I I I I I I 1 0 1 I I I I I I I I I I I I I I I I I I I I I I I > I 0 I I I LA LA I I I I I I I I I I I II I II I I I II II I II 1 0 1 I 1 I LA A ~ - I I I I I I I 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ILA iI i 00 I o~ 0 1 1 I 1 I I I I I I I I I I 1 1 I 0Om 0 I II I I I I I I I I I I I I I I I I I I I I LA I I I I I I 0 1 I I I 1 I 1 I 1 1 1 1 1 I 1 1 1 I 1 1 I 1 1 I LA I I I I LA I I co I I I I I I I I I I II I I I I fI I I I I I I 1 0 1 1 1 clq I M -I mI I A I I I I I I I I I I n1 I 0 I I I 0£ I I I I I I I I I I I I I I I I I I I I I I I I 1 0 1 1 I I 0 N M I I I I I I I I I I I I I I I I I I I I101 I I I m. '.0 CN En - fd Q 0 .fo Q ( d -I a) CJ)L to -i 0 J wm aU 0~ 4-W -H H~ 4 CI) W J 4 0 0' w 0 1 a 1ro0 , 0 0 xwc fa tVHrH 0)4-)X- M( 4W 4 rA -.. U) C)0 -f Q 0 4 Q) a4O I40 -4 0 -H04cam m--) 13) (a (a wLn w 4 b)W> l 4-t)m ra -W 0 : d Q - U)0 4 MS4H ~0 0) a w a)0 rO MW -4 0) 0H 4a SO A r (a -H 0~ (d 0 iri40a r d dW lUa0 j: HHH.A &4 a MPQ UU ( 040 0 H- b4 % U) ml En w) mu) ~> 3: :R : - WO 00/43377 PCTUSOO/01 283 342 N- ILA L i i iI i i LA o i i I i1 1 110 10 i D i io i c I LA v %DLf N- -1 k HiC k' OL O O 0 AOL0 A O 0 0 0 0 L I p noooL )ooo no cq 1 0 -z -or ' . nmoc N 0 0 A n r- o o w o m N oSo S o H 1-1 H- - - H1 Hq 1 Hi H A H -iH H N CN 0 IO III 1 1 0 01 11 1 11 11 1 11 101 IULnI H- 1 0 m 0 00 w0 '0 H- H o L ooa~ oooono o o~o a ~o o inoo oo 00 1 C H - HHHH " H H H 4 HHH H HHHH N 00 001 11 1ILACI 1 11 1 11 11 1 110 11 01 N 1 0 H- LAO '1 ND N 0 N H 0 00 0 0 D 0 - NO0 o0'0r-N OBoOSLA C 0ChO - C)0) w0~0 CD 0 zp H4 H- r HH -4 H1 ' - "q -. IH -qH H H C4 111 1 001D I I I I I 1 0 0 1 1 1 1 1 I II 1 10CD1 1 01 -q 1 0 H N 3LA NLA H LA 0 N' ll1 00000 c oc m O OL L O O O O O O A O O cDac D )moooo ( N 1 0 H H H- H1 H H H1 a) L LA o o0c oc o 0LAOp 0000) oLAOO D )o c0 c)LAO O H 10oo D 0 N- 0 ,4c or -c cIO) 0 N 0LA'o 8 m LnLAn r- A ) 000 0) (N H- H- H H4H H- H4 H LA 10 0CD I I I I I I QOLA I I I I I I I I II I1I01 I LAI N- I10 0 H4Ln 0~ HDr LA N ' H4 HA H 1~ 0011110 0 11 1 1111 11 11 101101 'I0 1 0 ~ O A I I I I I A I I I I I I I I I 110 1 10 CD I0 0 '0 1 OLA) I I I I I I I LAO I I 1 1 1 1 1 I I I I 1 0 1 0 1 U ) 1 0 -4 LA 100 I )C I I I I1 0 1 I I I I I I I 1 1 1 1 0 1r 1 0 '0 z ClN L m H .0 V' 'LA 00 w '-10 '.0 LA 0) 1 00 1 1 1 CD 0 100 1 I II I I I I 1 01 1 01 I1 1 0 co ic OLA i i iI i i 100o1o 1 I II o I I aI 110 lCN f O 0 101 C I I I I I 100 I I I I I 110 1 10C)1 H 1 0 00 1 OLn iic I I II a I00 I c11 1 I 110 101 10 H n mN LA'w H 10 LA mn H 01 C OLA C3 LA H 4 ~) H 0) c uco2 4) 41 (a>1 0 4 a0) '-0 4-1 I0 >1 4-) -*H 4 a 9 E .4 (Dd 04-) 0) a) d--4 M4 0A (1)0 r- 3:4U~ w 1r 0II0 d d> 4j~0 CO( ) 4 4) a ( -1 > 1 0- :: . ) rz b, l ( Id 0 0 d 00E 0 4 w- 0) >1 (da ,4r 1 o, 0) o ri l( 0) 0 *HUI W r.r. 4r H4 H 0H 4) E ft WO 00/43377 PCTUSOO/0 1283 343 O0 1 1 I 1 I LAO o i I I I f I I I I 1 0 1 10 1 0 1 0 0 1 1 1 0or Ln r- aI wr 0,1 1 1 1 1 1 LA o i i i I o I I c, 01 01 00 ILA 0 1 1 LA -m r co .- LA LA I Il I I I110 01 I II I I I II I I 10 a 10 Ln loall I I Ln lqlim c - en 01 I I I I An I I a I 111 I 01 1 0 1 (\r 1 0 01 1 1I 0 1 1 1 I LO I I I I I I i I I I I 1 0 1 1 0 CDI 101 L I I I 0CD I I I I I 0 In I> I I 1 0 I II I I I0 0 I1 0 I I en ODe LA LA N LALAo 0) I I In o I- 1 0 0 I I I I I I I I 1 1 0 I1 0 1 1 1 0 1: I I n I 0 1 1 1 I 1 I IcI Ii L r I In 1 0 01 1I 1O I I LAw 'D en LA N 0CD a I 1 0 1 I I I I I I I I 01 1 0 1 ko 1 0 01 I I LA MA' LA Nn r i L 01 D I 1 0 I LA I III I I II 0 L ~ ~ 1 0 I orIQ C-) 0P I n I 0 0 I I I I i i i i i i 1 0 o0 I Ii 1 0 0 I p m i q o i ZZP Nn w LAOm O I I I I L LA I I I I I I I I 1 0 1 0 e~ 1 0 I 0 1 1 I I 1 1 1 00 I I I 1 0I I I I 1 0 1 ko- 1 I0 I 1 1 01 In In i t i iL L I II I I I I I) ILAD I 01 'C 1 0 0 I I 0 1 1 I nI I I I l L I I I I I I 1 I 1 0 1 1 0 1 eN CD001c L I I LA LN' NLn LA' ;v 0 c O 1 I I I~ i O I I I I I I I I I I I I o I N 1 0011 0 1 I 1 1 I 1 1 0 0 1 1 1 1 1 1 1I 1 1 01 1 1 - 1 0 01o I I o 'en %n encINN (N CN, ID U) 1e- 1 1.j 1 I 1 1 1 1 1 1 1 C 1 a I CD I I ~~~~ m Ira) rCn ID rH-4I O D m~IDI~n4.u o~-jCw S 4 (du-t t) 0lQ 0 0)ID~ m ca a w > S d$,a WO 00/43377 PCT/USOO/01283 344 1 1 1 1 0C,0 1 1 1 f I I I I I I1 0 1 101 %o n fn r I I I 1 00 CD 3 I I I I I I I I I I I LA I 10 3 I I I too 0 1 1 1 1 1 33 1 1 1 I 11 03 1 0 1 0 01D I I I II I I00 I I I I I II I I I I LO I11 0 1 LA OLn iI i 31 3 i I fI D01 33 1 1 1 1 1 1 1 3 1 01 10 1 N 1 00 1 1 1I 1 1 I~~~~ 1 1 0 3 I 3 3 3 LA I I LA I I-3 0 3 3 3 I 1 0 O LA I I I I I I I I I I I 130 1 1 LA) I 0D I 0 C 3 C I 1 1. 1 1 I I I 100 CD I I I I I I I I I I 3 310 3 11 at 1 0 0 C) I I I I I I a% LA LA) wo w LAN I I I 10 CD CD I I I I I I I f I 3 0 1 1 0 1 1 0 0 C) I I I I I MLA LA LA I 1 3 OLA I I I I I I I I I I 130 11 0 1 en c OLA 3 i i 1111 I I I IlO)LA I I I3 I I I I I I 3 110 1 LAU I H I( 1 0011 11 11 1 0 0LA wO LA C00 I I 330 C0 3 1 1 1 1 1 1 1 1 1 3 D I C 10 30 I 0 1 LA 3D I 3 I I I I 0 0 1 1 10 1 1 1 1 1 1 1 1 1 33 30 1 )Ia4 1 30 0 1 1 1 1 1311 0 at :E .ow% I I I 3 0 0 3 1 1 1 1 1 1 1 1 1 1 1 LA I 10 3 300 3 0 0 1 1 1 3 -1%Ar4r- - - -3,-i H H -i -iH 1 m I I 331003 1 1 1 1 1 1 1 I I 1 1 0 1 LA I LA OLA 33 i 1331 i I I I3 )0 1001 1 3 1 1 1 3 30 1 1 01 at 1 0 033 1 1311 CD m- 0 cNIO% H4 M II I 1 3 0 3 3 I I I I I I I I I 1 1I0 N ) I IC) I r LAOC I I I I3 I3I3 o LA LA W (A LAcN I 33 00 I I )C I I I I I I 3 1 33 30311C a 1 00 1 1 331 331 cn Ln M LA at LA LA I-I CI)~ rc )H 0=.3'U~ 0 r- 0) CInU L) 41 (t> 1 3U (d 4 ) rcl 4-) -1 4-3 'U (d I)ED a)4J a) ()d -0)Om 4j (0 >1 4-) a)~ rd W w - (d ) - 0)~-WC -10rI( 4- 40 0 . 4 a ) a) H0 xO 0t JU (dUO a)i )i 4J CI) O0a) rH U) 4- ro0 r- 0 4-) > 440) '0 0 J O' Qt) 3 0 : :S j a f r O -4H40) ) 1 Q) a) M ;:, 0J (d) -i0) t3) 0) 00 )- :%:a >1~ 10 1:: >1 H--Hd0- 4 lr 4r- 10 ) r~ d 0 4 d - r a F 4 Q)) ,-4- (CW )) ~044( Or O ) (V t0-U U 'U0 r4 Q)14a) - 4 O E Q -H 0 )r- - r49 -)Q U (d 'r- 'U H 0 0 - W - WO 00/43377 PCTUSOO/01283 345 Cq I I I I I II h I -4 Ln i i i i i i i i I I c I Cl I I I I I I I I I I I I I I 0 ~ ~ ~ ~ ~ ~ ~ ~ I In II I Ii I 0 1101 m o o o oo no I 0LO I I I I I I I I 110 1 1 01 0 o In o o o op o In oI o o LA c I1 11 11 1 11 1 1 0 1 Oniio i r- oc nc oL 00000o00oA0L 000) D L 0 ~-coh w -4 CLnI- m t nH r-4 OLAI 1 1 1 11 1 11 110o I1 01 Ln ILA 00I00I0 0 01 0)-4L CD L A i i i i i i i i i n i i pi I I I I I I I I I I I I I I O A 0 A O 0 L 0 L 1-4 0 0 1 1 1 I 1 1 1 I I I I 1 0 1 1 0 1 cot I I I I I I I I I I I I I 00) -0 m 0L 0) 00 001 c i o I I a I M II I I 00 10 CD I I I I II 0I I I 0 0 1L I I I I I i i i i i 1 0 i o i LIn i I I I I I I I I I I I I I I 00' co Ln w 0 Nn df) LA r zL0 0 L~L ~ I I I I I I I I I o I 0 10 I O Li' I I I I I I I I I I I I I I wAL LA) Lr) r 0 0Lf I I I I I I I I I I I 1 0 I 1 0 1 I tw I I I I I I I I I I I I I I CD00 0A LA v o L I 1 1 1 1 1 1 1 1I 1 1 1 0i i 1 00 1 1 1 1 1 1 1 1I 0~~' 4. n r-4 OLA) I I I I I I I I I I I LAC I 10 0)I C I I I I I I I I I I I I I I 0 0C 1 I I II I I L I 0 I II I I I I I C) O I I OD0 a'0 LA -4 (dL '0 'D 0 I ) lOL LA LA - -4J( D *H -) (d a $HU-1 d 4)4 a a ) f n( x 0 0) W4> 04 I-HO U)f4 (1 W-W44-) w 0 r )4 O - o0 0-U) 4Jt (d4 U)J U) CO3 ( U U J HWU ( ) 04 4) -4 -1 i0 lO X4D r H(d44d t aarOrI( 4- U) 0t - A U u i'tO-4 a -4 04 U ) m4 4 U) ) -1)- U H 4-OO d-S ri ( R Q - D H 4 0 U d L :lL)aaO $4-H-4-j-H( ( f 1 0 0 ~ - , )~ W 0 r dp 00 0 F.) 4 l0 Z Z W U U EnCf 9 3::R : :: E1 P 0 m m uC)mCD40 34 WO 00/43377 PCT/USOO/01283 346 I I I I IQ I I I I I I I I I I I I I II I I I I I I I w rq I I I I I I 0 1 I I I I I I I I I I I I I I I I I I o o oL o00o0oLn o o Lno oo C I I I I I I I I I I I I I I I I I 0C)0 000CDLn 0 CDLA00)0 000 r-i I I I I I I I I I I I I I I I I I CNINLr-q -1co . L 0 0 >0 00~0 0 0CD0 0 0 0 OD I I I i I I I I I I I I I I I I I -4 I I I II I I I I I1 0D 1 I I I N- I I I I I I I I I I I I I I I I I H Ln I I I II I I I I I1 0 1 I I 1 0 I 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 I I I I I ID I 0 I I I N- I I I I I I I I I I I I I I I I I LA 00000000000000 00 00 0000000C\CO000000000 I i I In i i I c-4I L I I I I I I I I I I I I I I I I I I i LA 0 -I I 0 I I I H O OI D 0 0 IDC I IC CDC C) I I I I CN (N I II I I CD 1 0 I I 1 0) 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 '-I I I II I I a I I I 1 00 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 II I I 1 0 1 1 1 1 NL I I I I I I I I I I I I I I I I1 -4I H -cLCI ~ ' I I I I LA I I I I LA) I I I I II I I I I I I I1I11I1 '-I I C 0-I I I "d..l Id Id 00 0 0 0( DC 4I (0 ~ 4~ 'dc )J- 0) 0) a I ' d 4 (d >1 .11 * 4-) 4 M Q) 4 b)-1U r-4 (a a *4-) Ci) Q)f 4 l' O - O r.Xia 0)Q ow a w (0 4-40 .1 U l M0WC MQ - 4-4 D 1 ( r.d 0O*H)ol0ri 0 4 F b -- 4 a a a o Ea M 21 4 V 4rA r 4 )a) a d (1 1 0 zI,> i H W ( WO 00/43377 PCTUSOO/01283 347 I~~ 1 1 co I I I II - I I I I I I I I I I I I I I I I I I I I I I I I f110 1 I I I I I I I I I I I I I I I I I I I I I I I~~ 1 I I I 1 1 I I I I I I I I I I I I I I I I I I I I I~~ I f O I 1 1 I I I I I I I I I I I I I I I I I I 1 I C'N I I 1 1 II I N 1 1 1 1 1 I 1 1 1 1 I 1 I 1 I 1 II1 00 -I (-4 OOO O ~ ooo L H 1 1 1 1 11 1 1 1 1 H-H4 - - M O 10H 0 0 (-4 m I I I 1 I I D 1 0 1 a I I I I I I I I I I I I I I I I I I I I I I oC4 0 O O C O C1OC11 N I I I I I I I I I I i I I I I I I I I I I (-40 C'O q CI CD I CI CD I Il I CD I CD C a I I I I I I I I I I I I I I I I I I I i i i i i i i i li i I I I10 I I I 1 I I I I I I I I I I I I I I -4 I~ rI I I I I I I I I 1 I I I I II I I I I I I CN (3N I I I I I I I LA I I I I Il I I I l I I I I I IO O O O A L I I I I I C) II I I I I I I1 I CD0 0 C IIa 0 C C D II I 110I I I I I II I I I II I I I 1 wO O L o o L 0 111d11 1W11 101 -H U) -4 (04 4r. 4()a ( d 4JW 4H i n 0)~4) -4 Ea41ro0 CO0 O( 0) .I J &0 0 fo r- m 0) 4 >1b) -H a)0 ) (O ) 0 0 (ar 0H -14 ! 4J r HC C S::~ 4-4O -i -Wb ) d a 5H0 J-H U , 4 U)~4 r,-i-- 4 dr O CO -1 ) . O :J-1u o o -1H ) ",4 W-~ 1 0 rO C ) 4b : )rAr4- : JW r kA (I0 -) =;d 4. L)r- W.H "~ IS EO a W : U a 4 J V r.-A r- -4 0 0 (d0 ) I -Hq( 0 V ) a : E W 0 U COU)W U > :2::R: 2:E-49404 uC:)1: 4 0 0 f-HO 4C4141 Qr O ) WO 00/43377 PCTUSOO/01283 348 1 I 0 I I n I I I I I I I I I I I I I I lIl I I 1 1.1 1 l LO 0 1 1 1 00 10 1 1 1 1 1i i 1 1 1 1 1 1 1 1 1 1 1 1I LA 0 I 1 0 I I 0 1 1 I I 0n I I I I I I I I I I I I I I I I I I I I I I I 00~ CNI CNI N co (NI 101 L(N I I 10 1 04 %. 1 1 I I I I I I I I I I I I I I I I I I I I I LA II 1 1 I I I I I I I I I II I I I 11 I I I I I I I C14 I I I I I I I r- I I I I I I I I I I I I I I I I I I I I I I I LA r II C I I I 1 I1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 OcNI 0 1I I I f1 0 1 I 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 I CN I I 1 1 f I I ko ~ I I I I I I I I I I I I I I I I I I I I I I I Ln V I I I l o l lI I I m I II I I I I I I1I 1 1I1 I I I I I I I I I (NI Io I 0vII I 0 IH rI -1 In I 1 I 1 M M t. 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( 0 0) l . 10 0 A 0 z tm 4 1 4 r(a, a 4 M : k - - -1 Q J OdI- I4 d H >, a 4-q *)H U- aI rOCO a) 4 0 a J: )4-H( o0 ( 0 w 0 owi (d d 0) En(da):OU a: >dUj. 3: 02: :R:C 4~d O E-4 Z a4 4lC: r1 00 D x.44 WO 00/43377 PCTIUSOO/01283 349 Ln MA co I 10 1 I II LA I I I II I 1 1 I I II I ILA 1 0 I I I I I I I I I I I I I I I I I I I I I I I I I I 1 0 i 1 0 In I I I I I I I1 0 I~0 10 1 1 1 C) I I I I I I I 1 1 1 I 1 1 ko LA ("1 LA r m I 1 0L I I I I Q O f I I I I I I I I I I I I I I I I I I I I I I I I I C0 ~Ln rn I~~~~~ ~~~~ 10 f I I I I I I I I I I I I 1 0 M I 0 1 I I II I I I I III I CD I I I I I i i i i i i i i i I LA I 0 1 1 1 I 1 1 1 1 1 I I I I I 1 1 1 I l LA m 0 II I LA I I I 0) 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1I 1 0 LA L N- .- I N~ N l 0 N 0 LA0 a) I I (d' W14 tm c ) 1 0 >10)d 10 (L) 0 bo )~ 41 d >1 4-) -1 4-) 4Ea Q) 4 En.4- Cl 0 ) q w 4- r ~o '<00 c d ) 4 044 EO a - 0-H (1 4 M Q)0 4J >' 4- 0)l 0 rd C) V ~ H- )~ ,Q U 4-1 CO H H~ 4 4~ r-I 4- tm(1) a) z a) 0 >1r-H0z) -H (0 Z 1 - C 0 z 0) q r 0 Q) -H -H -H-H fo Id 0 0 dI 11 ' 00a) 0 -H- Id p- O0 0 1 ) z () :j u j0 )I.
WO 00/43377 PCTIUSOO/01283 350 mq 1 I 1 1 1 1o I I I I I I I I I I I 1 1 0 1 Hi - HL Ln (N I 0 1 1 1 100 1 1 1 0 0 1011 1 111 1I I 1 01 10 1 H4r I 1 II 0 LA i i i i i i LAO o I I II i i I i I I 1 0 1 i c i i ) i H HH H H H H- H- fHHrI 1 I I I LA 1 0 01) I I I I I 1 0 0 1 1 1 1 1 1 1 1 1 1 1 0 1 1 01D 0n LA LA) I~~~~~~ ~~~~~ 1 I= I 100 0 I 0 1 I I I I I I I I I I 1 11 0 r NLn (N l~ I I 1 00 1 0 01 1 1 1 1 I 10 011 1 1 111 1 1 1 110 1 10 1 0) H N W.DLo I11 IIIM L oL c colLnooo ioloooooooloLamoooooo H1 H H H H 1 1 1 ~ 11001 IC C I I I I I 1 00 1 1 1 1 1 1 1 1 1 I 1 0 1 10 1 I I I I LA 10CD0 1 1 1 1 1 1 1 0 0 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 0 N- H (N w.( H1 I I I I N- 1 0 0 I 1 1 1 1 1 1 0 0 I 1 1 1 1 1 1 1 1 1 1 1 0 1 1 01D w N H n 0H m II I 'D I1 >0 1 1 1 1 1 1 f 0 C I I I I I10 1 I I I I I I I1C01 I LA I M v WLn LA 0 I II010 I I I I I 1 0 01 1 1 1 1 11 1 I I11 0 1 101 I I I OD ic OLA i i i i iI 10 1 I aI cD i II I 10 101 i i i io M v0) N (N a 1 I 0D I00 I I I I I 1 0 0 11 1 1 I I 1 1 1 10 11 01 M Hm In MN H1 I I I I co 1 00 1 1 1 1 1 1 0C I I I I I I00 I I I I I 110 1 101) AHLA LA(CN (N I-I - (d a) 0W Id£~~ W(a O C l a)- U4 H 1 -4 O1 4. 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I CD00 1 1 1 1 1 1 1 a I I I I I 100 I1 1 I I I I 1 0 1 1 0 1 0N co 100 In a I I I 100iLna I I I I II I I I I 1 0 1 1 0 1 w 1- wL co 1, D mn r 1 LAO 1 1 1 10 L I I I I ILA I I I I I I )I 10 10 1 -0 H -4V111 HHI - - -i H H1 HN0. 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U.0 CO Nn (N oiL i i iLn oI I I I I O I II I I o I I cI I 101 10 C 1 0 1 1 iniLn r-in i n r- in o C1 -I 0 001D I I I I I I1001 I I I I I I I I I I 10 1 10C I w 1 1 (NC' m r m in in r-N rL)n 0)0 I I 1 I 1 I 1 0 0 I 1 I 1 1 I I 1 1 I I 1 0 1 1 0 I 1 0 0 1 1 MiniLn in N- in 0 01> I I I I I 1 00 11 1 1 1 1 1 1 1 1 I 1 0 1 1 0 1 m loinLr I I r w0 r ON) in r- N - in H (N 001C1I I I I I 1 0 01)I I I I I II I I C)I 101 0 1 -1 nO If I I") *Cl N- q~ (N ' 0011I I I I I 1 00 1 1 1 1 1 1 1 1 I 1 0 110C1 0) 1 D01 in n n (N 'n .0 m0 (N 0 0 1 1 1 1 1 1 1 00) I I I I I I I I I I I 10D I 10 I N- 1 0 0 m. i o n k0 miLn (N 001 i i i i i i niLn iI II il I i i i i io i i I 0a C) 100 I miL) n C~mN in 10 -0k (V 0 0 1 1 1 I I I 1 0 I I I I I I I I I01 101 1 IC l LnI I qo in %Dom H- m1 -ci wco (N OiLn I I I I I I 1 )0 1 1 1 1 1 1 1C I I CD II CN ID 1 0 1 0 (N O n I -~ (N .-I 4) 1 .) a) I-) Ealc a) -i24-) (o) (d~- ~ c 4- ( 0 l - ( Q.4- W d,0 ~ H~ Q) 40) (1 -)1r r. , r. a) a) H 01En cd - ) 4 HU rmI z 4-)4-C in -c.4 U)O J J cd ' 41001 0 1 1 4>, a11E 1 ) 0 - 4-OI Or4 1 tH 4- .4 -r- 00- 0 lE ) - l L )Q -W 44 rj J d J ) b d C O W -1 m -- 0i 0-cd- z (Da)a)m r 0(d-H c dc0 A 0 14r- > a)-1 r -4 zr. >141-1U)(d 0 -rI 0 ! : 4 4 W ) a -1 WO 00/43377 PCTIUSOO/01283 353 I0 II 1 00> I co 1 0 11 1 1 01 Hm 11 1 00II 1 1I1 0 1 10 1 r, ILn o 11111ii r-LA Ln H- o 1- ~ m i i i i i Lnl p i i i i i i i i i i i n o I 1 0 1 0 1 0 1 1 I I I I WW r- m NN N m I i i i 1 0 0 L o i I I I I I I I I I 1 0 1 1 0 1 0 0 Il I 1 1 I I 1 1 LA I 1 I 1 1 I 1 1 1 0 1 1 0 1 r-4 1 OLA I I I I I I M 1-4 I I I I 1 0 01 1 I 1 1 1 I 1I 1 I 1 01 10C)1 0 1 00 1 1 1 111 0)~ N LA w r. LA i t I i cD O LA I i iI i i i i i i i i i o i i p 10 I C0 0 I I I I I I -4 M) r- Nmw n mN ~ L I I I 10 1 1 I I 1 I 1 I I 11 1 0 1 1 0 1 Nl 1001> I I I I I Ho - Ir I Hnc4 0L r- NN w NWr rI,, 1 II 1I 1 0 0 11 1 1 1 I 1 II I 1 LA 1 0 1 1 1 00 1 1 1 11 1 I I I I 1 00 1 II I 1 1 1 1 11 1 10 CO I I )1 0 1C 0 1 1 1 11 cq~~L LA Hl nL HM N LA 0 LAW 11 CH CDH n H H H (n H I ~ ~ ~ ~ / I) HI I- 4 I~ CD~ CD I I I I I I I I f I I I0)IIC n 1 0 C H tI w/( r--2> r- r- w0 OHOO X~O ~ ~ ~(0 O )H~ 04J' OHm ij J . 0i (0i) ) ~ W J L c i i i i i i Q i iLn 1 D I I I S~ 4-4)n Id .In0 r- wI~~1N Ld0) 4 0)0)d O~~t~t 0 Q 0~ 0H>It.H ~~H-H) ~~~ 10~ C ~ H H d a d' H0)0) HO H I 0 H0 -HO Ln Id -i 1-O. 1d M0 d H ~ 0 O WO 00/43377 PCTJUSOO/01283 354 1 00 11 11 11 1 1 111 1 0 1 101 t. 0oLAOOOOO00OOOOCLA -4 cq '~A mne \C q C% icl 1 a01 1 1 1 II I I 1C I I CI 1014101 1 II 1 1 1 1 1 11 1 r, LA 1 -4 -4 -> 0 0 r -4 1 0 0 o o I i i i I I I i 1 0 I i o i LA i 1'' I I I I I I I f I I I I I -4 1 D01 1 1 1 I 1 1 1 1 1 1 1 0 11 01 k.0 0DCD00CD00CD0 000000 LAWt LA r-i LA-1-0Ln :pr ~ 1 Ln cs -4 1001 i i i I I iI I i I cI I 10 ILA i M I I I I I I 1 1 C0) Id LA 1 0 1 1 1 1 1 1 1 1 1 1 1C I I D I l I I I I I I10 1 1 I I I I I I I 1 ON~~ t. % i LA o i I I i i I I I o i i c0 I g 0l - i i l I II i i i I I I I LA m' - 1,0ko 0 i L A O q i i i i i i i i i i 1 0 I 1 0 I i o i I I I I I I I I I I I I I 0-4q I oLA I I I I I I I I I I I 0 I 10 1 00 0 0 0 0 0 0 0 0L LA0 0 rqI m ~ 1lr4 1-4-4 O1 N 0 - Ln I I I I LA 0 -lc\3mLrr I 0011CD I I I I I I I I 1 0I1 I II I C)1 I 1I I n a 0 0 C DC D0 C ON N-r- 0 C ) i c LL i i i i i i i i i i i 1 0 I 1 0 i p i Q I I I I I I I I I I I I H0011111 ) 111 1 11 r k0 1 - 000 00 0 0 ON N1- N4 (dI ('I Ea4 a W am)r$- )4) ( 1 . -4 U o ()k 0 H ( i( 1) 4t )a d r)r ILA1 En 0 1 0 I H 4 I 4 w 41 (010 I I :II -H E n a 1 11114- E xL N0 p 4 4 jU dV )k-H LA c L )H E - 1 - a H 0) -AU 0,rO U ( 40 Z 1 - J AF d4( 4~- -H () -1 H) H ( 4.0J 0 (d O ;:l UH, 0A4 Q J : 4- d d0 f W rH-I 2i4 0 L -Wr-1 r k 0 0 0 - .1 P WP W m)En l WEn U) R 3 -4W P MUU )0 X 0~~-i - O -; WO 00/43377 PCT/USOO/01283 355 I~ 1 1 1 1 I I I I I I I I I I I I I I I I I NC o o o Do oOoOpoo o o oc no mn I I I I I I I I I I I I I I I I L 0 0 0 0 0 o0 0 0 oN a ia a o a o I I I I I I I I I I I I I I I I I I I I I I I 1 0 1 1 1 1 LA I I I I I I I I I I I I I I I I -4 0 I I I I II I I 101 I I N I III II I II I I I I NN 0 CD CD I 0 IC 0 I 0 0 0 C C 0 0 0 w I I I I I I I I I I I I I I I I CN CN I I I I I I I I I I I 1 0 1 1 1 1 LA I I I I I I I I I I I I I I I I 0000C)0 00CD0 00C0CD0000 M I I I I I I I I I I I I I I I I OaoLALocoOOOOOOOLAoL Al 0000000000000000C CN m LA - Al-i m H H H CN '4 CN r * f %D Nl en0r W. r 1 1 I I 1 1 1I I 0 0 1 1I 1 1 -I I I I I I I I I I I I I I I I I I I II I I I I I I I 1 0 1 1 1 1 I I I I I I I I I I I I I 1 1 1 Al Al I I I I I I I I I I f I 1 0 1 I I I 1 0 1 1 1 1 1 1 1 1 1 1 1 1 0 I I I I I I I I I I 1 0 1 1 1 1 I4 00 1 1 1 1 1 1 1 1 1 1 1 1 1 I o oLA o po oO)o o oOcOmo ao 1-I I I I I I I I I I I I I I I I I 1-4 o LA DoOcO)o oOLAo oOOO c ccLAO AlN I I I I I I I IIII IIII C14 H CNA m 1- - N M 0)s M' -4 I I I I I I I I I I I 1 0 1 1 1 I H- I I I I I I I I I I I I I I I I s-A 0)s -l I I I I I I I I I I I I101 I I 1 0 I 11 1 1 I 1 I 1 1 1 1 -4 LA I~ 1 1 1 1 I0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 H OW -~~> U)4 (d)$0 (d s-I 0) ((ED U)E - 1Q)o d4 a 4 a) 410 a - . r> ' 01tm a O4 (0 C 0. Q) 4- r 4 a 1 - L t 4 ( - 1 -)0 0' (d 4) 0))r 4 4 a) -I 01 4 0 fo a) j 1-4U I w & 4 Q) r= 44- ) co 4 0 o4 IdU1~ 4) U) (d 0)CHH- a)Id- 4) r 0) H U-Is-4g000)- 0H 0d~ x d)l WO 00/43377 PCT[USOO/01283 356 I II I I I3I0>3 I I I I~ ~ 1I 1 0 1 1 1 0 D I I I I I III I I I I I I I 1 0 I I I I ~~ 1 1 1 1 I I 1 1 I I I I I I I I I I f I I I I I I I I I CD CD 0 I 0 a 1 CDa 0 m C I I I I I I I I I I I I I I I I I I I CN w 0 0 0 0 0 I0 0 U f' f1 1 1 3 n i 4 I I I I I II I II II 3 II I 3 3 0 I H II I III II I I II 1 3 1 I CD I I I I CDI I I I I I I I I I I I I I I I I I mG I I I I I 1 3 0 3 1 1 1 1 C ) I I I I I I I I I I I I I I I I I I3 II I I I I I 1 3) 1I 0 13 1 1 I 1 1 1 1 1 1 1 I 1 31 1 1 1 0) I4 ) (d ( H I I I I I I) Id I II U) WI a HI 0) I) co W II I I co~ ~ ~ a)4Ha ( )r )4 c > .) - 1 d I )-r I I - 0 a) J I I4 3 ) r. 0) I 4' a a) () Id Il (d () pI M 1 4 ~~ ~ ~ H4a 1 9 d0 r nt 0 - - )0 4 ) _ J E0 (d I ) PI 101 41 wI 0 b) I M 4- 110 1 0I -I 0I 0l x 0I)I M~ ~ ~ MH:WW :UW4 N ( Q - 4- 4 ( 0 (d -A t m 0 H 0 0)r;ri> t ri9 0 ( Q)I Id4 UI) F:r l 4 driQ .): -I: rIria U ) 4W 0, O M W P4 A0)J 40 ) - 14 1 4-- EO Id >a 4a)-1 a) -H U a aU) (d Q ;IU 10 a :$ a 4 r z1 HQ)I(d( 0 ( -40Q 4J-I 0 'ROI'I(d 0 0 Il d 4 W. 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H- LA L a r- C4 H CD0m (N CNL m f m M) I I I I I 101 I I I 1 10 0 1 11 II 1 1 1 01 1 1 II I 1 1I I I II I 101C I I C 1 0 01 I I I I I 1 0 0 1 II II 1 1 1 1 1 1 40 10 C I I I 10 I I I CD0 10 1 1 I 1 0 1 1 1 II I 1 1I L-) IIIII 1 01 1 1 I 0) >i DOLA o iooc IO O Ln o pc)c Do OOc>oLmAo 111111011111 N 000mLAl00000mo000000000LAO H1 H- H H I I I I 1 0 1 1 LA 1 00 11 1 1 1 ILA 1 1 1 1 I 1 1 11 NN 0 Lm I I I I I 1 0 1 1 I I 0 1 00 0 N-a C %D lLA I1I11I1 I LAI I II Ml )c 00 LA0p 1000DcDLA0op0p000000c 0100i ) %.0 01 LA Ln r.0- w H'.0 w H 4 r r OD 0 H LA 1 1 1 0I 1 0 OLA I I I I I I11 0 0 1 1 I I 1 1 1 11 I I I C) I 0 I I I 1 0 0 1 I 1 1 1 1 1 0 0 1 1 1 1 1 1 1 1 I I 0 j) - (d Id (d~ 4 $4 U) WH >1 HL 4 (dW a ) U) t Q) 4.)I d) .) o a a)Ol -) a > 41) -1 J-) $4 (d r) Q)4 4D 4-)(0r ;J ~ -4U) U) 04~ f U) 4.) - ) 4Hc I-ll fo4 a) *H 1J CI) LWr-4 E Z)Jro o io o (0 ) 4e 04> 4.-U)Id(0 LO N 0 d $4 ) 044) A 1 4 (0co :R a) - ~ q- O V Q~ ) H 0 - 40 () 4)4 4t 1 0 4 zH~~ (1$~ ) rA mH) -HO H0U ))W 10 4 :r 1 ww0&S ( - )0 JJ r 4r J0 E (d 1) 140Z-H-14 r.0 11 : 14- ,1E d 0 -,A -J Z r WO 00/43377 PCTUSOO/01283 358 I I101 1 0 1 In I 00C I I I I I I 1 0 0a1I I I I I I I I I I 10 1 (Nq (h N Lfln -4 (Ni .- I (Nq 110 11 01 LA 1 0 0111 1 11 100 11 1 11 1 111 1 1 101 (N (N ( (N(N C')1 r (N OO AO OO '0 1 0 01 1 f I I I 1 00 111 1 I II 1 1 10 1 MNMMWA N- Lnm me' (N -4 10 1 1 1 LA I 1 I II I 0 1 1 II 1 I I 1 1 I 1 0 1 (N m- N em N-W en) 10 0 1 LA foo I 0 1 1 I 1 00 1 1 1 1 1 1 1 I I 1 1 1 0 1 W N N-LA 0'.w LA (N ~-4 (N s-i r-I -4 I 101D 1 01 s-1 100 oI o i i i LA o i i l I I II I 1101i io (N 1 1 01 1 01 LA 1001D I I I I I 10 0 1 11 1 1 1 I ILA 1 (N LA w LA LA n (N I 01 1 I O 100 In o Il I A I I I I I I I I i i ILA i 0 I 1 1 10 C> L I III c o n i f i i I o l LA iI i I I II I I i I 101i i Ze1-0wmLA LA 0 (q CD00 0000o0 s-i 100 1 1 1 I 1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1 01 m( N M mO0 H s4 LA '-I (N 0C)0 0 0000 m i OLA i i i i i i 10 1 oI o I i II I 1101i ii H' 0M m 0 0s% NW Ow CDCOO0LAC ( N 1 00 11 1 1 I II 10 01 11 1 1 I II 1 1 10 1 H -4 I 01 1 1 0 1 0 0 1 1 1 1 I 1 0 0 1 111 I Il 1 1 10 1 m LA N- '.w ON N)r 4~- r'W O LA (( -I( I -4 r-I 1 0 sI I io LAI 1111110011111111111101 i i i o -4 I 1 1 1 1 CC 1 00 1 1 1 1 11 1 0 0 1 11 1 1 1 1 I 1 1 10 1 r-4 I-II (0 14W 'd-I U) WU) Ea J-) 0 >1 i( a) a) 1 ' t 4I rd >1 4-) -1 &-) 4 (d WUl.) 4 aD) a WO ~ 4-) c, ) () _ r 4 ) ( l( ()Nd r u)~ J - O-q (d~ 4W)U 0 a0 :;- ni ,()E - 1En 0 4- t))-~~ -r 0 s4 d t 04 Q)4 _ 0LI Idd 5 dd- U9 0 4) W ) d -. W " 4- ) 09 -H 0~H 4- (d 4 c )0) E : ~ ~ ~ - ; (a (d WJ0 'AC) W4 ) ) - 4d)' ( .a W WO 00/43377 PCTUSOO/01283 359 I n 0 0 In C M I- 0 C 1 A IC 0 I 1 0 0C I I 1 I F o o l I I I I I $ I I I IC I 1 C I LA r- %m L 14 m HO 1 1 0 n I I I I I I1 0 0 1 I I I I I I I I I I 0 10 LA LA 1 1 1 n I I 1 0 0 I i i 1 1 i i i I I o L I N~~ ic LAL m n L LAO CD~ 001 1 1 1 01 I I I 110 1 10 1 0 rn 1 0 1 I lOLA I I I I I I CDAo I I I I I I I I I f I 1 0 1 1 0 1I LA LN LOLA N i LA M I0 I I 1 1 0 cD In II II I I I 10 LA oI r- 0ne nL r0 10 10 0 1 1 1 1 1 CD II I LA I I I I II I I I 1 0 1 1 0 1A NoL C'Ln CDA w m C0 0 1 1 0 1 1 1 1I C I I I I I I I I I I I n I 1 I 1 0 I IC IIO I CD I aL In I I I I I o o I I 10 I 1 0 1 CN LA4 Nw co 0rL L N m r 101 i 0 LAO I I I I I I LA I II II I I I I 1 1 10I 1 L m LA ; LADr-L m4 4 H'L -~ LA 101 LA LAO I 1 4I rq 41 d IR COL W 4II I I I A L LA 4 a)r4 m H LA 0 a Oa w. N 1 0 1~ 0 lOL I) I) I I I 1 0 1 I I I I I I 1 10 1 10 1 LA I- a) 100 rO W I) I4 I4 000 r. a) r- Ii ri r. I 0 L (d 4 0 ONI -1 Q U0-ii ' .0W: U a a j4 H_ 1( (N EHO : ~ : X - 4 4 4w 0 :::::3 R - WO 00/43377 PCTIUSOO/01283 360 Ln I I I I I I I I I I I I I I I I I I I I I I I I 0 I I I 00 1 i 1 1 1 I 1 1 1I 1 1 1I 1 1 1 1 1I 1 0 1p I I I Ln 00 1i I I I I I I I I I I I I I II I I I I I 1 0 1 II I -0 cc 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 C) I 0 I I I r' m '-4 re) Lf) mmk0-. nmk mc Lm~ m-V LH -fLn 4- LAL V mn O ml I I f I I I I I I I I I I I I I I I I I I I I I 1 0 1 I 1.1 -I rn I I I I I I I I I I I I I I I I I I I I I I I I 101) I I I C) I I I I I I I I I I I I I I I I I I I I I I I I 1 0 1 1 1 '-I 0 -I I N I - -1 I H I N H I N 'A ID ' I rI H I 1 0I H ~~ CN I1 H 14 N H -1 C IV I I I I I I I ci I I -4I 1 0 OI 0 H- I H0 '-44 0 j (I Io a) 0 I I I II it1 1 I fa ( 4- il a I 4 - o r O 4 ( )0 W -, 0N H H- C-l d:: u. wH 41 cc '-D4 a)N ) - 4Mr 0L0 a:00000L 0;000 0d00(d0 wjw 0 (Ni >1 0) -4~e Hc': f- Ha ()r H dH 0 ) 0.4 4 E H L d a 4 r 1 1' > 1- n ( H 4 !F 4I - )a )( 0)J.) s -i( U 0 ri r- ) Y4 r,4 U Q U r - - d 4 ( r r O O -IQ)0 4JWr 4M - dm: )- 1 - = 040 00 0900 00U000000 O 00r00o)1- - - r4 J (0 0 (0 Hj -4f )0 - d( 0 )M WN 40 : : Q l 1 4'- d f Q a M M UU QQ rX 0 tD 4 4 9 W M M > : : R: 2:E- c 12 WO 00/43377 PCTUSOO/01283 361 Un I1001 Cq LA Ln O'l 100 -4 r- 1 001n LOU,:Z -4 .- 4 ICD0 I -4 -1 4 M 00 0-H CD 100 1 r-4 Chm 100 1 -4 c r-4 0 -4 0 1001 C w 0 I l I I)I I U) w ID 4I >1 w A I A I a) 0 0 0 4-1 ra 1 4 ri 4.) 4 d ) 4 a) I-)w w ro 1 a 0 C\ 4.) (d r. 4 a a (V d m (d ) - -H u (d .. )4 0) a)r-4 U)1 111O1 1 aI 1w1 1 1 1 1 Fi 0- - f - ) -- . or j -000a (o~~~~ ~ ~ ~ ~ 0 a)0 1Nf-i 0 4 r :() ( ) aJjrl w b d 00 0L 0 000- 00iLa) 00LU)Z -rI -- I(l 4 (d flO O OO Q-I (1 0 1 (d 0) 14 0 )0 - (J U) (d )-I I :sa)r: rlr o ( 4 T--- - - A 0) PQMM0) Q0P 't - 0 ) 4U 4U) V) U U)~-C >~ :R0) '03 E 4Q WO 00/43377 PCT/USOO/01283 362 1 1 1 1 I 100~ I I I I I I I I I I I 1 0 I 10a I I I I I I 1 0 0Q I I I I I I I I I I I 1 0 1 1 0C I I I I n 0 100 1 1 1 1 1 1 I 1 1 I 1 0 I 1 01n r-H LA I I I I I 1 D00 1 1 1 1 1 1 1 1 I II 1 0 1 10 1 I I I I I I1 )00 1 1 1 I I I 1 I I 1 I 1 0C I 1 0 1 I I I I I Lt 0 I 1 1 1 I 1 I 1 1 1 I 1 0 1 1lQt I 'w LAm I I I I I I1 0n 0 I 1 1 1 1 1 1 1 1 I I 1 0C I 1 0 1 v ON LA L I I I I I 1 0 0 1 1 I 1 1 1 1 1 1 I I 1 0C I 1 0 I I 1 1 I 1 1 LAO I I I I I I I I I I I 10a I 10 1 CDL I 10 I I I I I I LAO I I I I 0 1 0 L I I I I I I 1 0 I 0 I o H II ri a% f~ w IN m n co G r- In I- I wI DL 101 10 11 Ln I 1 I0 0 O 0 0 0 I n 100 I I I I I I I) aI In 101 1011 1 I I I I I 1 0 0 1 1 1 1 1 1 1 1 1 1 1 1 0 1 10 1 C C 00( vN V. mr 0100 A~ fl A000 0000 0000 00LA 0 l~flI 111 m HrIHO~O (mA3 ~ 1 LAHH a)AH 0 4 U) ( r-4 H (d 0- 0) (nOL O O O O O O O O O Nl 100 1 Id I I4 a) >1 4J r LA A L ~ A4 A LA Nm N( L WO A M )(N - a )r ,a)0 . d > 04 ~ ~ ~ H) Hd co( 1 4 b)-q( - (l L N ) )r . 10 0 ~ HNLA 0~ 0 m H0mL 0 LAW 1 Q - )M ) 4 J) rl C Q q M4 a0 I) I4 1 I- -I 1 0 1 I4 Io IA I I q :3 I 1 ( I, E0 101 M ' 10)4 0 I I) , 4J k -1 : (1) -- 1 Q) q al r -I EQ I) Id4 0)0 Q - -Iri r - ) . d _ r 4~ ~ ~ 0 )0- 0 0 ( n( (): 0 4~> 04 ::1 'd4 - 4-q-r d U - 44 0 Q u l 2 4 0 -H D 4J P4I ~00 )4J U)U WW )0 R ): :3:&P a~4J Im m >uu WO 00/43377 PCTIUSOO/01283 363 N0 100 fn I I I CN LA 1 00C1II I I I 110 C'N 1lOLA I I I 11 0 cr enLA LA LA 1 001 1I 1I1I 10C 100 I- fn 111 0 04 kD 1 0 01 1 1 11 11 0 Z 0 CIQ C1 LA 0 -q r- t o ol i i i 1110 L I- 0 0) I I I I I I 1 0 I..-t ) 'f m~ .. Iu w, 4..4 *4 0) ~ ~ ~ (a0 4 )0 .Jk d 0) W4-Id~O Ul()4)Q> 4 >1 0)ia:0 a a) I S4 0) - 0 r. )0)0)-4U U u V o -HA 0) J- -) 0) 0 4 (13 4 -1 fo I a~) -4 0D NQ fa I4 fo I 1 0 a) 011 (d LA I I I I I I I I I I CN' I I I I I I I I I I I C%2 Ln I I I I I I I I I I I I 1 D0 1 1 1 1 1 1 1 1 1 1 1 1C I I CD 1 0 % I I I I I I 1 0 1 1 U I I I I I 1 '.OL r 0. Z -4 I 0 I I I I I I I I I I l 0 1 0 1 .-I I I I I I I I I I N 14 w 0) Id r a)O 0n 112) ( 0- 41.~ (a (0 4 0) -A 0) E En0 a) 4-i 1( (1) 4 ) rtS 4) -H 4.) k (d U) Q) 4.) 4)) V .0CUOm-) Ia >1 4.4 0) ( u a) k -H U C d .) 4r a)~ r_ . 14 0)0) Id r - EO 0 41 3) 1 kH, a0) 4- r (d a) s-riU)1 U) P40)E -- i 4J) 0o a0 XJdt CO> (2d 4 ) 4-r-f4. 4 U) b)rj U ) 14J $0 r-40O0 X *Hj 0 $. T C a:~ WmQ) a) :U U4J M m4 ~It 4 ) 4 4J -1 0 5 a0) (D0' 0 (d -4L 0 IQ 0 lx) r4>0) H a) ra j . > 4) -- IU) - 4J - r. 4r-i4J0) ) ) -4 r.-40 o 9 r WO 00/43377 PCTIUSOO/01283 364 0 I I I I I10 ICD I 0 1 1 I 1 1 1 I 1 01 1CD I 10 1 Ln II I I I I I I I I I 1 0 1 1 0C I In n (N 0 11 1 I 1 1l I 1 I 1 1 1 I 10 1 011~1 1 I 1 01 10 1 LA ( 0) I I I I I I I I I I I I10 I 1 0 1 m w toC1 O4 > 1 d J-) 4 (0 En.~~ 4 a 4 a a 1 En 0) 41 4-I rA4U) W r.9 ( C)0) $-I1 U) (dH ,- Id 4-H I 4 - V 3)1 :M 0 r. a) :Je 0- (d )4~ 00 Od r. 0 to -1 0) tm 0 0 -d- l-H. I H I a o w a) 4 I 4 m I l a) I I 10 I r I I z I I I I I I I I I I I I I I LA I I I I I I I I I I I I I I I I I1 0 1 I I I I LA II I I I I I I I I I I I 10C I I I I I I I I I I III I I I 1 0 1 1I 1 I LA I I I I I I I I I I I I I 1 0Q I I I I Id a0)0 I I-i U) i 0)4 4 (d 0) . -w a)41 dV m H C) Q 4 U ) k U)) m -410 - ~ w*0 0 1 Md H/ Id 0) 4 0) -W f ).0 H* - WO 00/43377 PCT/USOO/01283 365 Test F Protocol Abutilon theophrasti (ABUTH), Chenopodium album (CHEAL), Amaranthus rudis (AMATA), Setariafaberii (SETFA), Panicum dichotomiflorum (PANDI), and Digitaria 5 sanguinalis (DIGSA) were grown from seed in pots of an artificial potting mixture in a greenhouse. Compounds of the present invention were applied at 70 and 105 g ai/ha preemergence. Rimsulfuron was applied at 8.8 and 17.5 g ai/ha. Mixtures of the compounds of the present invention and rimsulfuron were also applied. Following application, the plants were maintained by watering as needed. A fertilizer 10 solution of Peter's 20-20-20 (10 pounds/5 gallons of water) plus Sprint 330, a Iron Chelate micronutrient, (113.5 grams/5 gallons of water) was injected into the water with an Anderson fertilizer injection system to provide approximately 218 ppm of nitrogen with each watering. Artificial lighting was used to supplement natural light to produce a 14 hour photoperiod and an additional one hour light period was used between 1:00 am to 2:00 am 15 for a night interruption. Greenhouse temperatures were targeted for 27 *C in the day and 21 *C at night. At 21 days after treatment, all plants were evaluated for injury as compared to control plants that were sprayed only with non-phytotoxic solvent. Mean plant response ratings, summarized in Table F, are based upon a 0 to 100 scale where 0 is no effect and 100 is complete control. 20 Colby's equation was used to calculate the expected additive herbicidal effect of the mixtures of Compound 21 and the mixture partners listed above. Colby's equation (Colby, S. R. "Calculating Synergistic and Antagonistic Responses of Herbicide Combinations," Weeds, 15(1), pp 20-22 (1967)) calculates the expected additive effect of herbicidal mixtures, and for two active ingredients is of the form: 25 Pa+b ~ Pa + Pb - (Pafb / 100) wherein Pa+b is the percentage effect of the mixture expected from additive contribution of the individual components, Pa is the observed percentage effect of the first active ingredient at the same use rate as in the mixture, and 30 Pb is the observed percentage effect of the second active ingredient at the same use rate as in the mixture. Combinations of Compound 113, Compound 131, and Compound 242 with rimsulfuron are surprisingly found to provide better control of certain weeds than expected by calculation from the Colby's equation, thus demonstrating synergism. Weeds other than 35 those specifically listed are also controlled by mixtures of compounds of the present invention and rimsulfuron. Different ratios of compounds of the present invention with rimsulfuron, and different formulation types, also provide useful weed control from the combination of the two herbicides.
WO 00/43377 PCT/USOO/01283 366 TABLE F ABUTH CHEAL Cmpd. 113 Rimsulfuron Observed Expectedt Observed Expectedt Alone 70 0 45 - 15 105 0 65 - 35 0 8.8 20 - 25 0 17.5 40 - 60 Mixtures 70 8.8 75 56 60 36 70 17.5 85 67 95 66 105 8.8 90 72 100 51 105 17.5 80 79 100 74 AMATA SETFA Cmpd. 113 Rimsulfuron Observed Expectedt Observed Expectedt Alone 70 0 35 - 60 105 0 25 - 65 0 8.8 10 - 75 0 17.5 15 - 90 Mixtures 70 8.8 15 23 95 90 70 17.5 70 45 100 96 105 8.8 25 33 100 91 105 17.5 90 36 100 97 PANDI DIGSA Cmpd. 113 Rimsulfuron Observed Expectedt Observed Expectedt Alone 70 0 100 - 95 105 0 95 - 70 0 8.8 75 - 95 0 17.5 95 - 100 - WO 00/43377 PCT/USOO/01283 367 Mixtures 70 8.8 90 100 100 100 70 17.5 100 100 100 100 105 8.8 100 99 90 99 105 17.5 85 99 100 100 ABUTH CHEAL Cmpd. 131 Rimsulfuron Observed Expectedt Observed Expectedt Alone 70 0 40 - 60 105 0 60 - 95 0 8.8 20 - 25 0 17.5 40 - 60 Mixtures 70 8.8 50 52 95 70 70 17.5 85 64 100 84 105 8.8 80 68 95 96 105 17.5 75 76 100 98 AMATA SETFA Cmpd. 131 Rimsulfuron Observed Expectedt Observed Expectedt Alone 70 0 50 - 35 105 0 40 - 65 0 8.8 10 - 75 0 17.5 15 - 90 Mixtures 70 8.8 95 54 85 84 70 17.5 100 58 100 93 105 8.8 95 46 95 91 105 17.5 85 49 100 97 WO 00/43377 PCTIUSOO/01283 368 PANDI IDIGSA Cmpd. 131 Rimsulfuron Observed Expectedt Observed Expectedt Alone _ 70 0 100 - 100 105 0 95 - 100 0 8.8 75 - 95 0 17.5 95 - 100 Mixtures 70 8.8 75 100 100 100 70 17.5 95 100 100 100 105 8.8 100 99 100 100 105 17.5 100 100 100 100 ABUTH CHEAL Cmpd. 242 Rimsulfuron Observed Expectedt Observed Expectedt Alone 70 0 50 - 30 105 0 70 - 100 0 8.8 20 - 25 0 17.5 40 - 60 Mixtures 70 8.8 85 60 100 48 70 17.5 80 81 85 72 105 8.8 85 76 100 100 105 17.5 80 82 100 100 AMATA SETFA Cmpd. 242 Rimsulfuron Observed Expectedt Observed Expectedt Alone 70 0 20 - 60 105 0 55 - 75 0 8.8 10 - 75 0 17.5 15 - 90 - WO 00/43377 PCTUSOO/01283 369 Mixtures 70 8.8 70 28 90 90 70 17.5 85 32 100 96 105 8.8 35 60 75 94 105 17.5 65 62 100 97 PANDI DIGSA Cmpd. 242 Rimsulfuron Observed Expectedt Observed Expectedt Alone 70 0 60 - 100 105 0 80 - 100 0 8.8 75 - 95 0 17.5 95 - 100 Mixtures 70 8.8 95 90 100 100 70 17.5 100 98 100 100 105 8.8 100 85 100 100 105 17.5 100 99 100 100 * Data are reported as percent control. t Expected from the Colby Equation 5 Test G protocol In soil-containing pots were planted seeds of maize hybrid P33G26 that was previously treated with dichlormid, fenchlorazole-ethyl, and naphthalic anhydride (or no safener). The soil surface was then treated with several rates of Compound 131 or Compound 146 10 dissolved in a non-phytotoxic solvent using a flat-fan sprayer calibrated to deliver 310 L/ha. Treatments were replicated 4 or 5 times. The treated and untreated plants were allowed to grow in a greenhouse using supplementary artificial lighting with a day-length of 14 hours, with the temperature maintained at about 27 *C during the day and 24 *C during the night. Plants were kept watered with a dilute balanced fertilizer solution. 5 At 28 days after application, the treated plants were compared with untreated controls and visually evaluated. Mean plant response ratings, summarized in Table G, are based upon a 0 to 100 scale where 0 is no effect and 100 is complete control.
WO 00/43377 PCTIUS0O/01283 370 TABLE G* Safener Compd Rate None Dichlormid Fenchlorazole- naphthalic (g ai/ha) ethyl anhydride 131 560 95 40 96 NDt 131 280 91 3 92 NDt 131 140 88 3 91 0 131 70 80 3 85 NDt 146 1120 85 4 85 35 146 560 80 4 78 NDt 146 280 73 1 74 NDt 146 140 49 1 3 0 * Data are reported as percent control. t naphthalic anhydride treatment severely inhibited corn germination. Where corn 5 did satisfactorily emerge, it was safened against the herbicide damage. As can be seen from Table F, in the absence of any safener, both Compound 131 and Compound 146 at rates ranging from 70 to 560 g/ha, and 140 to 1120 g/ha respectively, were severely injurious to maize. With the exception of Compound 131 at the rate of 560 g/ha (entry 1 in Table F), the presence of dichlormid reduced the injury to an insignificant level 10 from which the corn would be expected to recover with no long-term deleterious effects. The presence of fenchlorazole-ethyl, however, did not provide safening effects except for low rate of Compound 146 (Entry 8 in Table F). The dramatic safening effects observed here were unexpected and surprising. Based on this discovery, it is anticipated that other compounds known to safen herbicides on corn, soybeans or other crops are useful in 15 safening compounds of the present invention on corn, soybeans or other crops. Test H protocol Mixtures of the herbicide and safeners were applied to pots of a soil mixture previously sown with corn. Pioneer hybrid P33G26 corn was sown in pots containing a 20 sterile mix of 60% sassafras soil and 40% Metro Mix 360 @ growing medium (pH 6.7, O.M. 2%). Test compounds were dissolved in AGWT (a mixture of 0.25% Tween 20 surfactant, 5% water, 5% glycerin and 89.75% acetone) and sprayed on the soil as pots passed under a stationary 8002E nozzle. Treatments were applied at a 33 gal/acre rate of the AGWT carrier. After treatment, the test pots were placed in the greenhouse and watered. There were two 25 replications for each treatment. Each pot contained eight corn seeds. The pots within each WO 00/43377 PCT/USOO/01283 371 replication were placed in random positions on greenhouse benches. Test plants were fertilized as they were watered with approximately 200 ppm of N (as water soluble 20-20-20 fertilizer) which was metered into the water lines with a fertilizer injector. Daytime temperature was 23-30 C* and night time temperature was 18-25 C*. The test plants were 5 supplemented with artificial lighting. The lights were activated whenever the natural light intensity dropped below the programmed threshold. Day length was maintained for approximately 14 hours. The test was evaluated approximately 12 days after treatment. Treated plants were visually compared to untreated controls and rated on a scale from 0 to 100 where 0 is no 10 effect and 100 is plant death. The results summarized in Table H are the averages from the two replications for each treatment. TABLE H Compd Rate None Dichlormid Dichlormid Dichlormid (g ai/ha) 70 g/ha 140 g/ha 280 g/ha 113 70 18 0 0 0 113 140 25 20 0 0 113 280 53 35 28 33 Compd Rate None Benoxacor Benoxacor Benoxacor (g ai/ha) 70 g/ha 140 g/ha 280 g/ha 113 70 18 0 0 0 113 140 25 0 0 8 113 280 53 38 18 20 15 As shown in Table H, both dichlormid and benoxacor functioned very effectively as safeners for Compound 113. Without safener, Compound 113 at rates from 70 to 280 g/ha produced corn injury of 18 to 53%. In the presence of dichlormid or benoxacor at rates from 70 to 280 g/ha, corn injury was reduced to from 0 to 38%. The dramatic and unexpected 20 safening by dichlormid and benoxacor demonstrates the potential utility of mixtures of these compounds with Compound 113, or other similar compounds of this invention, for the control of undesired vegetation in corn production.

Claims (20)

  1. 6- or 7-membered carbocyclic ring optionally substituted with one or more CI-C 4 alkyl groups; or Y is, together with the carbons to which it is attached, a fully or partially saturated 5-, 6- or 7-membered heterocyclic ring which contains one or two X and is 10 optionally substituted with one or more R 12 , provided that when said heterocyclic ring contains two X, then one X is other than 0; Z is phenyl or a 5- or 6-membered aromatic heterocyclic ring system containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that the heterocyclic ring system contains no more 15 than one oxygen and no more than one sulfur, and each phenyl and heterocyclic ring system is optionally substituted with one or more R16; RI is CI-C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 haloalkenyl, C 3 -C 6 alkynyl, C 3 -C 6 haloalkynyl, CI-C 6 alkoxy, C 2 -C 6 alkoxyalkyl or C 2 -C 6 haloalkoxyalkyl; or RI is C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkenyl, each optionally substituted 20 with one or more R 5 ; or R 1 is phenyl optionally substituted with one or more R 13 ; or RI is a 5- or 6-membered aromatic heterocyclic ring system containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that the heterocyclic ring system contains no more 25 than one oxygen and no more than one sulfur, and each heterocyclic ring system is optionally substituted with one or more R16; R 2 is Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 haloalkenyl, C 3 -C 6 alkynyl, C 3 -C 6 haloalkynyl, CI-C 6 alkoxy, C 2 -C 6 alkoxyalkyl, C 2 -C 6 haloalkoxyalkyl or NR 3 R 4 ; or 30 R 2 is - (CR17R18 )q o (R;) or R 1 and R 2 are taken together as -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH 2 0CH 2 CH 2 -; WO 00/43377 PCTUSOO/01283 374 R 3 is Ci-C 6 alkyl, CI-C 6 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 haloalkenyl, C 3 -C 6 alkynyl, C 3 -C 6 haloalkynyl; or R 3 is C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkenyl, each optionally substituted with one or more R 5 ; or 5 R 3 is a saturated or partially saturated 5-, 6- or 7-membered heterocyclic ring containing 1 to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, and each heterocyclic ring is optionally substituted with one or more R 5 ; or R 3 is phenyl optionally substituted with one or more R 26 groups; or 10 R 1 and R 3 are taken together with the two nitrogen atoms to which they are attached to form a saturated or partially saturated 5-, 6- or 7-membered heterocyclic ring containing an optional third heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and said heterocyclic ring is optionally substituted with one or more R 9 ; or 15 R 2 and R 13 , together with the two atoms to which they are attached and the atom between them, form a fully saturated 5-, 6- or 7-membered carbocyclic or heterocyclic ring containing one oxygen, one sulfur or one or two nitrogen atoms, said heterocyclic ring is optionally substituted with one or more R12, provided that when said heterocyclic ring contains two nitrogen atoms, they are 20 other than bonded directly to each other; R 4 is H or CI-C 4 alkyl; or R 3 and R 4 are taken together with the nitrogen atom to which they are attached to form a saturated or partially saturated 5-, 6- or 7-membered heterocyclic ring containing an optional second heteroatom selected from the group consisting of 25 oxygen, sulfur and nitrogen, and said heterocyclic ring is optionally substituted with 1-4 R 9 ; each R 5 is independently halogen, CI-C 4 alkyl or CI-C 4 alkoxy; or when two R 5 are attached to the same carbon, then said two R 5 groups are taken together as (=0); each R 6 and R 7 are independently H or CI-C 4 alkyl; 30 R 8 is independently CI-C 4 alkyl, CI-C 4 haloalkyl or CI-C 4 alkoxy; each R 9 is independently CI-C 4 alkyl or CI-C 4 alkoxy; or when two R 9 are attached to the same carbon, then said two R 9 groups are taken together as (=0); W is, together with the carbons to which it is attached, a fully or partially saturated 5-, 6- or 7-membered heterocyclic ring containing one or two X, provided that (a) 35 when X is other than 0 or S(O)n, then only one X may be present; (b) when two WO 00/43377 PCT/USOO/01283 375 X are present in the ring, they cannot be bonded directly to each other; and (c) said heterocyclic ring is bonded to the group (CRI 7 R18)q through other than X; R 10 is H, Ci-C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkynyl, C 2 -C 4 alkoxycarbonyl or C 2 -C 4 alkylcarbonyl; or R 10 is phenyl optionally substituted 5 with CI-C 3 alkyl, halogen, cyano, nitro or C 2 -C 4 alkoxycarbonyl; each RII is C 1 -C 4 alkyl; each R 12 is independently halogen, C 1 -C 4 alkyl, CI-C 4 haloalkyl, CI-C 4 alkoxy, Ci-C 4 haloalkoxy, CI-C 4 alkylthio, Ci-C 4 haloalkylthio, CI-C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl or C 2 -C 4 alkoxycarbonyl; 10 each R 13 is independently halogen, CI-C 3 alkyl, CI-C 3 haloalkyl, CI-C 3 alkoxy, Ci-C 3 haloalkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, CI-C 4 alkylthio, C 1 -C 4 haloalkylthio, CI-C 4 alkylsulfinyl, CI-C 4 alkylsulfonyl, cyano, amino, nitro or C 2 -C 4 alkoxycarbonyl; R 1 4 is H, CI-C 6 alkyl, C 1 -C 6 haloalkyl or C 2 -C 6 alkoxyalkyl; or 15 R 14 and R 6 , together with the carbon atoms to which they are bonded, form a 5- or 6 membered saturated carbocyclic ring optionally substituted with one or more C 1 -C 4 alkyl groups; R 15 is H, Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 3 -C 4 alkenyl or C 3 -C 4 alkynyl; each R 16 is independently halogen, nitro, cyano, Ci-C 4 alkyl, CI-C 4 haloalkyl, C 3 -C 4 20 alkenyl, C 3 -C 4 alkynyl, OR 22 , NR 23 R 24 or S(O)nRl 9 ; each R 17 and R 18 are independently H or CI-C 4 alkyl; each R 1 9 and R 20 are independently CI-C 12 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 12 alkenyl, C 3 -C 8 cycloalkenyl or C 3 -C 12 alkynyl, each optionally substituted with one or more R21; 25 each R 2 1 is halogen, C 4 -C 8 trialkylsilylalkyl, CN, NO 2 , -OR 22 , -NR 23 R 24 , -S(O)nR 22 , -S(O)nNR 23 R 24 , -C(O)R 22 , -C(S)R 22 , -C(O)OR 22 , -C(S)OR 22 , -C(S)SR 22 , -C(O)NR 23 R 24 , -C(S)NR 23 R 24 , -CHR 25 COR 22 , -CHR 25 P(O)(OR 22 ) 2 , -CHR 25 P(S)(OR 22 ) 2 , -CHR 25 C(O)NR 23 R 24 , -CHR 25 C(O)NH 2 , -CHR 25 CO 2 R 22 , phenyl optionally substituted with one or 30 more R 26 groups or benzyl optionally substituted with one or more R 26 groups; each R 22 is Ci-C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, CI-C 8 haloalkyl, C 2 -C 8 alkoxyalkyl, C 2 -C 8 alkylthioalkyl, C 2 -C 8 alkylsulfinylalkyl, C 2 -C 8 alkylsulfonylalkyl, C 4 -C 8 alkoxyalkoxyalkyl, C 4 -C 8 cycloalkylalkyl, C 4 -C 8 alkenoxyalkyl, C 4 -C 8 alkynyloxyalkyl, C 6 -C 8 cycloalkoxyalkyl, C 4 -C 8 35 alkenyloxyalkyl, C 4 -C 8 alkynyloxyalkyl, C 3 -C 8 haloalkoxyalkyl, C 4 -C 8 haloalkenoxyalkyl, C 4 -C 8 haloalkynyloxyalkyl, C 6 -C 8 cycloalkylthioalkyl, WO 00/43377 PCTUSOO/01283 376 C 4 -C 8 alkenylthioalkyl, C 4 -C 8 alkynylthioalkyl, C 1 -C 4 alkyl substituted with phenoxy or benzyloxy, each ring optionally substituted with halogen, CI-C 3 alkyl or CI-C 3 haloalkyl, C 4 -C 8 trialkylsilylalkyl, C 3 -C 8 cyanoalkyl, C 3 -C 8 halocycloalkyl, C 3 -C 8 haloalkenyl, C 5 -C 8 alkoxyalkenyl, C 5 -C 8 5 haloalkoxyalkenyl, C 5 -C 8 alkylthioalkenyl, C 3 -C 8 haloalkynyl, C 5 -C 8 alkoxyalkynyl, C 5 -C 8 haloalkoxyalkynyl, C 5 -C 8 alkylthioalkynyl, C 2 -C 8 alkyl carbonyl, C 2 -C 8 alkoxy carbonyl, phenyl optionally substituted with halogen, CN, CI-C 2 haloalkyl and CI-C 2 haloalkoxy or benzyl optionally substituted with halogen, CI-C 3 alkyl and CI-C 3 haloalkyl; 10 each R 23 is H or C 1 -C 4 alkyl; each R 24 is CI-C 4 alkyl or phenyl optionally substituted with one or more R26 groups; R 23 and R 24 may be taken together as -(CH 2 ) 5 -, -(CH 2 ) 4 - or -CH 2 CH 2 OCH 2 CH 2 -, each ring optionally substituted with Ci-C 3 alkyl, phenyl or benzyl; each R 25 is H or CI-C 4 alkyl; 15 each R 26 is CI-C 3 alkyl, Ci-C 3 haloalkyl, C 1 -C 3 alkoxy, Ci-C 3 haloalkoxy, Ci-C 3 alkylthio, C 2 -C 5 alkylcarbonyl, C 2 -C 5 alkoxycarbonyl, halogen, amino, cyano or nitro; R 2 8 is H or CI-C 4 alkyl; XI and X 2 are independently 0 or S; 20 X 3 is 0, S or NR 28 ; m is 0, 1, 2, 3 or 4; each n is independently 0, 1 or 2; p is 0 or 1; each q is independently 0, 1 or 2; and 25 t is 0, 1 or 2; provided that when Q is unsubstituted phenyl, X1, X 2 and X 3 are 0, q is 0 and R 2 is methyl, then R I is other than methyl. 2. The compound of Claim 1 wherein 30 Q is H; or C 1 -C 12 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 bicycloalkyl, C 3 -C 12 alkenyl, C 3 -C 10 cycloalkenyl, C 6 -C 14 bicycloalkenyl or C 3 -C 12 alkynyl, each optionally substituted with one or more R 2 1 ; or Q is a 3- to 7-membered fully saturated or 5- to 7-membered partially saturated heterocyclic ring containing one or two X, provided that (a) when X is other than 35 0 or S(O)n, then only one X may be present and (b) when two X are present in the ring, they cannot be bonded directly to each other; or WO 00/43377 PCT/USOO/01283 377 Q is a 5- or 6-membered aromatic heterocyclic ring system containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that the heterocyclic ring system contains no more than one oxygen and no more than one sulfur, and each heterocyclic ring system 5 is optionally substituted with one or more R 16 ; and when Q is a 5- or 6 membered aromatic heterocyclic ring system containing a nitrogen, then Q is bonded through any available carbon or nitrogen atom by replacement of a hydrogen on said carbon or nitrogen atom; or Q is phenyl optionally substituted with one or more substituents independently 10 selected from the group consisting of R 16 , phenoxy and Z. 3. The compound of Claim 2 wherein Q is H; or C 1 -C 12 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 bicycloalkyl, C 3 -C 12 alkenyl, C 3 -C 10 cycloalkenyl, C 6 -C 14 bicycloalkenyl or C 3 -C 1 2 alkynyl, each optionally 15 substituted with one or more R 2 1 . 4. The compound of Claim 2 wherein Q is a 3- to 7-membered fully saturated or 5- to 7-membered partially saturated heterocyclic ring containing one or two X, provided that (a) when X is other than 20 0 or S(O)n, then only one X may be present and (b) when two X are present in the ring, they cannot be bonded directly to each other; or Q is a 5- or 6-membered aromatic heterocyclic ring system containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that the heterocyclic ring system contains no more 25 than one oxygen and no more than one sulfur, and each heterocyclic ring system is optionally substituted with one or more R 16 ; and when Q is a 5- or 6 membered aromatic heterocyclic ring system containing a nitrogen, then Q is bonded through any available carbon or nitrogen atom by replacement of a hydrogen on said carbon or nitrogen atom. 30 5. The compound of Claim 2 wherein Q is phenyl optionally substituted with one or more substituents independently selected from the group consisting of R 16 , phenoxy and Z. 35 6. The compound of Claim 3 wherein WO 00/43377 PCT/USOO/01283 378 Q is CI-C 6 alkyl optionally substituted with one or more R 2 1 , C 3 -C 7 cycloalkyl, C 3 -C 7 alkenyl or C 3 -C 6 alkynyl.
  2. 7. The compound of Claim 4 wherein 5 Q is a 5- or 6-membered aromatic heterocyclic ring system containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that the heterocyclic ring system contains no more than one oxygen and no more than one sulfur, and each heterocyclic ring system is optionally substituted with one or more R 16 ; and when Q is a 5- or 6 10 membered aromatic heterocyclic ring system containing a nitrogen, then Q is bonded through any available carbon or nitrogen atom by replacement of a hydrogen on said carbon or nitrogen atom.
  3. 8. The compound of Claim 5 wherein 15 Q is phenyl optionally substituted with one or more substituents independently selected from the group consisting of R 1 6 .
  4. 9. The compounds of Claim 3, Claim 4 or Claim 5 wherein XI, X 2 and X 3 are 0. 20 10. The compound of Claim 8 wherein Q is phenyl with substituents on the 2-, and 6-position independently selected from the group consisting of R 16 .
  5. 11. The compound of Claim 6 wherein q is 0 or 1. 25
  6. 12. The compound of Claim 7 wherein q is 0 or 1.
  7. 13. The compound of Claim 8 wherein q is 0 or 1. 30 14. The compound of Claim 1 wherein R 1 is phenyl substituted with one or more R 13 .
  8. 15. The compound of Claim 1 wherein R 2 is C 2 -C 6 alkyl, C 2 -C 6 haloalkyl or C 2 -C 6 alkoxyalkyl. 35
  9. 16. The compound of Claim 1 which is selected from the group consisting of: WO 00/43377 PCT/USOO/01283 379 (a) N-(4-fluorophenyl)-N-(1 -methylethyl)-4-(2-methylphenyl)-3,5-dioxo 1,2,4-oxadiazolidine-2-carboxamide; (b) 4-(2,6-dimethylphenyl)-N-(4-fluorophenyl)-N-(1-methylethyl)-3,5-dioxo 1,2,4-oxadiazolidine-2-carboxamide; 5 (c) 4-(2,6-dimethylphenyl)-N-(1 -methylethyl)-3,5-dioxo-N-phenyl- 1,2,4 oxadiazolidine-2-carboxamide; (d) 4-cyclohexyl-N-(1 -methylethyl)-3,5-dioxo-N-phenyl- 1,2,4-oxadiazolidine 2-carboxamide; (e) 4-cyclohexyl-N-(4-fluorophenyl)-N-(1 -methylethyl)-3,5-dioxo- 1,2,4 10 oxadiazolidine-2-carboxamide; (f) N,4-bis(1 -methylethyl)-3,5-dioxo-N-phenyl- 1,2,4-oxadiazolidine-2 carboxamide; (g) N-(4-fluorophenyl)-N-(1 -methylethyl)-3,5-dioxo-4-(cyclopropyl)- 1,2,4 oxadiazolidine-2-carboxamide; and 15 (h) N-(4-fluorophenyl)-N,4-bis(I -methylethyl)-3,5-dioxo- 1,2,4 oxadiazolidine-carboxamide.
  10. 17. A compound of Formula 5 H X 2 R27 1N 0~ 5 20 wherein R 27 is -(CR 6 R 7 )q-Q; R 6 , R 7 , q, Q, XI and X 2 are as defined above for Formula 1; provided that when XI and X 2 are 0 and q is 0, then Q is other than unsubstituted benzyl.
  11. 18. A compound of Formula 8 or Formula 20 2 3X2 Q-(CR 6 R 7 )q-N Q--(CR 6 R 7 )q- ORI Z5 8 20 wherein R 6 , R 7 , q, Q and X 2 are as defined above for Formula 1; and XI is 0; WO 00/43377 PCTIUSOO/01283 380 provided that when XI and X 2 are 0 and q is 0, then Q is other than unsubstituted benzyl.
  12. 19. A process for preparing a compound of Formula 1 X 2 X3 Nu1 W R1 Q-(CR6 7 )q-N O R2 xi 5 wherein Q, R 6 , R 7 , q, XI, X 2 , X 3 , RI and R 2 are as defined for Formula 1 in Claim 1, comprising: (a) contacting a compound of Formula 5 H X2R 5 10 wherein R 27 is -(CR 6 R 7 )q-Q, with a compound of Formula 4 Q- (CR 6 R 7 )q- X4 4 wherein X 4 is halogen or mesylate, in the presence of a base to provide a compound of Formula 3 R27X2 Q-(CR 6 R 7 )q-N I 3 X 1 , and 15 (b) contacting the compound of Formula 3 with a carbamoyl or thiocarbamoyl chloride of Formula 2 WO 00/43377 PCT/USOO/01283 381 R1 X3 RkI R2'/ 2
  13. 20. A process for preparing a compound of Formula 1 X2 X3 Q--(CR6R7)q--N 1 O R2 X1 5 wherein Q, R 6 , R 7 , q, XI, X 2 , X 3 , RI and R 2 are as defined for Formula 1 in Claim 1, comprising: (a) contacting a compound of Formula 5 H X2R27 1N 5 wherein R 27 is -(CR 6 R 7 )q-Q, with an alcohol of Formula 6 Q- (CR 6 R 7 )q - OH 10 6 under reaction conditions involving a tertiary phosphine and an azo compound to provide a compound of Formula 3 R27X2 Q-(CR 6 R 7 )q-N 3 XI , and (b) contacting the compound of Formula 3 with a carbamoyl or thiocarbamoyl 15 chloride of Formula 2 WO 00/43377 PCT/USOO/01283 382 R1 X3 R2' 2
  14. 21. A process for preparing a compound of Formula 1 X2 X3 Q-(CR 6 R 7 )q-N 1 1 O R2 xi wherein Q, R 6 , R 7 , q, XI, X 2 , X 3 , RI and R 2 are as defined for Formula 1 in Claim 1, 5 comprising: (a) contacting a compound of Formula 5 H X2R iN 5 wherein R 27 is -(CR 6 R 7 )q-Q, with a carbamoyl or thiocarbamoyl chloride of Formula 2 1I X3 RKJ R2' 2 10 in the presence of a base to provide the compound of Formula 1 X2 X3 R 2 7 -N RI O 2 xd 1 directly or a compound of Formula 7 WO 00/43377 PCT/USOO/01283 383 X2 X3 H- N O R2 X, and (b) contacting the compound of Formula 7 with an alcohol of Formula 6 Q- (CR 6 R 7 )q- OH 6 5 under reaction conditions involving a tertiary phosphine and an azo compound or with a compound of Formula 4 Q- (CR 6 R 7 )q- X4 4 in the presence of a base. 10
  15. 22. A process for preparing a compound of Formula I X2 X3 N I Q-(CRR 7 )q--N O R2 xi wherein Q, R 6 , R 7 , q, X 2 , X 3 , RI and R 2 are as defined for Formula 1 in Claim 1, and XI is 0, comprising: 5 (a) contacting a compound of Formula 19 H Q- (CR6R7)q- N: R ~ N~ OR 1 19 X with phosgene or thiophosgene to provide a compound of Formula 20 WO 00/43377 PCT/USOO/01283 384 X 2 Q-(CR6R7)q-N) "F OR' 20 , (b) contacting the compound of Formula 20 with hydroxylamine, following by treatment with a base, and then an acid, to provide a compound of Formula 8 Q- (CR 6 R 7 )q-N O 8 , and 5 (c) contacting the compound of Formula 8 with a compound of Formula 2 R1 X3 RN rC R2/ 2
  16. 23. A process for preparing a compound of Formula 1 X2 X3 Q-(GR 6 R 7 )q-N A NIR X1 10 wherein Q, R 6 , R 7 , q, XI, X 2 , X 3 , RI and R 2 are as defined for Formula 1 in Claim 1, comprising: (a) contacting a compound of Formula 2 R1 X3 R2/ 2 with hydroxylamine in the presence of a base to provide a compound of Formula 22 WO 00/43377 PCT/USOO/01283 385 X 3 R1 <J_ OH I I R2 H 22 (b) contacting the compound of Formula 22 with a compound of Formula 23 xi I a-c-N=c= x 2 23 in the presence of a base to provide a compound of Formula 7 X2 X3 R1 H--N 5 X1 , and (c) contacting the compound of Formula 7 with an alcohol of Formula 6 Q- (CR 6 R 7 )q- OH 6 under reaction conditions involving a tertiary phosphine and an azo compound or with a 10 compound of Formula 4 Q- (CR 6 R 7 )q- X4 4 in the presence of a base.
  17. 24. A process for preparing a compound of Formula 1 WO 00/43377 PCTIUSOO/01283 386 X 2 X3 N RI Q-(CR6R7)q--N I I O R2 xi wherein Q, R 6 , R 7 , q, X1, X 2 , X 3 , RI and R 2 are as defined for Formula 1 in Claim 1, comprising contacting a compound of Formula 7 X2 X3 H-NN XI 7 5 with an orthoformate of Formula 24 (R 7 0) 3 CH 24 wherein R 2 7 is -(CR 6 R 7 )q-Q, in the presence of a base.
  18. 25. A process for preparing a compound of Formula 1 X2 X3 N I Q-(R 6 R 7 )q--N O R2 xl 10 wherein Q, R 6 , R 7 , q, XI, X 2 , X 3 , RI and R 2 are as defined for Formula 1 in Claim 1, comprising: (a) contacting a compound of Formula 8 WO 00/43377 PCT/USOO/01283 387 X 2 Q- (CR 6 R 7 )q- N xi 8 with a compound of Formula 26 X 3 C C1 26 to provide a compound of Formula 25 X 2 X Q-(CR6R7)q - N xl 5 25 or a compound of Formula 27 X2 X 3 X 2 Q- (CR6R7)q N /N N N- (CR 6 R 7 )q - Q X I xl xi 27 in the presence of a catalyst such as hexamethylguanidinium chloride; and (c) contacting the compound of Formula 25 or Formula 27 with an amine of Formula 10 13 RIg NH R2/ 13 in the presence of a base. WO 00/43377 PCTIUSOO/01283 388
  19. 26. A herbicidal composition comprising a herbicidally effective amount of a compound of Claim 1 and at least one of a surfactant, a solid diluent or a liquid diluent.
  20. 27. A method for controlling the growth of undesired vegetation comprising 5 contacting the vegetation or its environment with a herbicidally effective amount of a compound of Claim 1.
AU34717/00A 1999-01-25 2000-01-20 Herbicidal oxadiazolidines Ceased AU776425B2 (en)

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US15636299P 1999-09-28 1999-09-28
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