CA2065337A1 - Herbicidal oxabicyclo ethers - Google Patents

Abstract

The present invention relates to novel oxabicyclo ether derivative compounds, compositions containing these ether derivative compounds, and methods of using these compounds or compositions to control the growth of undesired vegetation. More particularly, the present invention relates to a variety of compounds, compositions, and methods of using them which are herbicidally active on a wide variety of weed species and exhibit safety to rice, cereals and broadleaf crops.

Description

2 ~ 3 ~
`W091/034~ ~.~. . ., PCT/US90/049~3 1 . ~ ~ i ; j ~ ,, . . ~E
HERBICIDAL OXABICYCLO ETHERS
~ROSS-REFERENCE.TO ~5L~E~ e~l~A~
This application is a continuation-in-part of copending application U.S. Serial No. 07~431,734 filed September 11, 1989.
- Field o~ .~h~ Lny~L~iL~
The present invention relates to novel o~a-bicyclo ether derivative compounds, to compositions containing these ether derivative compounds, and to - methods of using these compounds or compositions to control the growth of undesired vegetation. ~ore particularly, the present invention relates to a variety of compounds, compositions, and methods of using them which are herbicidally active on a wide variety of weed species and e~hibit safety to rice, cereals and broadleaf crops.
~ 20 Backqround of the Inven~iQn - Payne et al., U.S. Patent 4,567,283 and Payne ~- et al., U.S. Patent 4,670,041 disclose a variety of ~- herbicidal bicyclic ethers of the Formula -. R2 ~, ~- . 30 - Z I ~
X

. .
~:~ 35 ~-.
... .

W O 91/03464 2 ~ 6 ~ 3 3 7 PC~r/~'S90/04953 ~ :

U.S. 4,798,621 and WO 8,902,219 both disclose biryclic ethers and their method-of-use in rice.
U.S. 4,4B6,219 discloses bicyclic ethers of the formula:

I ~CH2 W

R I

It is an object of the present inventi:on to provide compounds and compositions which eshibit herbicidal activity on-a variety of economically important weed species. It is a further object of the present invention to provide compounds and compositions that are herbicidally safe to rice, cereals and broadleaf crops. It is a feature of the present invention to furnish novel o~abicyclo ethers that exhibit useful herbicidal activity. These and other objects, features and ad7antages will ~ecome apparent with respect to the following description of the invention.
SU~B~ OF TH~ INVEN~IO~
The present invention comprises compounds of the formulas selected from the group consisting of:

. .

- ~ .

WO 91/03464 2 ~ ~ ~3 3~ PCI/l,'S90/04~53 3 ~ .

II

, ~ :

R X

R~ ~2 :~ 25 R : R2 ` . III TV

~ 30 ~:
- , .

~.`'' ' ~ - -~: 35 `:
., ~ .
i `

4 ; ~.i PCl'/US90io49~
2 ~ 3 7 4 Q~X
~
R2 z V VI

. 20 x ~

~ ~ ~x 2 5 ~R2 VlI VIII
' .
'~ : , : and stereoisomers thereof, ~ ~ :
wherein X and Y are indepsndently H or C(R3)(R4) OR5;
Z is C(R3~(R4~ O~5; -:
: 35 Rl is H or a straight-ohain Cl-C3 ~lkyl;

: :
' ~WO91/03~ 2 ~ ~ ~ 3 3 7 PCT/US90io49~3 . ~ . " i . .

R2 is H, Cl-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or Cl-C4 alkyl substituted c 5 by Ph, OH, CN, oR8~ SO2R8, PhSO2, N3, CO2R8 or CO2H;
~ R3, R4, R9 and R10 a-e independently H, Cl~C4 -- alkyl, C2-C4 alkenyl, C2-C4 alkynyl or Cl-C3 :: alkyl substituted with OCH3 or OCH2CH3;
. 10 RS is Cl-C3 alkyl, C~-C4 alkenyl, C3-C4 alkynyl, benzyl or Cl-C4 alkyl substituted with oR8~ OCF3;
R8 lS Cl-C3 alkyl;
Q is WCH2 or ~- 15 :

~` ` R~ q :` :
~ ~ , w is~phenyl optiona:lly substituted with 1-3 ~substituents~selected~from F, Cl,~ ~r, Cl-C3 ;~
alkyl, Cl-C3~al~ko~y, OH, CN, Cl-C3 ~:: :: : haloalkyl, Cl-C3:~haloalko~y, Cl-C3 -~ ~ 30 ~ alkylthio, C2-C4 alkenyl and C2-C4 alkynyl, .
or W is a 5 or~6-membered heterocyclic ring containing 0-2~nitrogens, 0-2 osygens or 0-2 : sulfurs, each ring optionally substituted with 1-2 substituents selected from~F, Cl, ~r, CH3 and OCH3;

` :
. ., :
.

: . : .
.

.
: ; ' :

WO91/034~ PCT/US90/~49~3 ;
20~33~

zl is CH2, NRa, O, S or may be taken to form a double bond with an adjacent carbon;
Ra is H or Cl-C3 alkyl;
R6 is H, halogen, R5v oR8, 8R3 or CN;
R7 i H, F, Cl, CH3, OCH3, OH or oR8;
ql is 0, 1 or 2, and q is 0, 1 or 2.
proYided that 1) at least one of ~ and Y is C(R3)(R4)oR5;
2) R3, R9, R9 and R10 each contains no more than four carbon ~toms;
3) in Formula II, iF Rl is H then X is C(R3)(R4)oR5 and Y is H;
4~ the sum of q and ql is 0, 1 or 2; and 5) if the sum of q and ql is O then zl is CH2.
A representative esemplification of the aforementi:oned heterocycles includes but is not limited to pyrrole, furan, thiophene, tetrahydropyran, tetrahydrofuran, isoxazole, o~azole, pyrazole, imidazole, thiazole,:pyridine hnd pyrazines;

Pre~erred compounds of the invention for either their biological activity or ease of synthesis are:

- 1. Compounds o~ Formulas I, II, III, IV, V, YI, VII, or VIII wherein:
- W is~phenyl optionally substituted by 1-2 substituents selected from F, Cl, Br, CH3 -- and OCH3; or W is tetrahydropyran, - ^ - tetrahydrouran, thiophene, isosazole, - pyridine or pyrazine, each ring optio~ally substituted with 1-2 substituents selected from F, Cl, ~r, CH3 and OCH3;

2 ~ 3 7 6~ ' PCr/l,lS90/04953 Q is R~, R~, R~

0-~ Q z : ~3 - :

~: 15 :

. R~
R~ . R ~, Q-4 Q-5 Q_~, 25~

~ R / a R~

~ .

: .

WO 91/034642 U 1) ~ ~ 3 ~ P~/l'S90/04953 R~ R

Q-10 Q-ll Q-12 R~ R
R~ . ~ or ~ 14 Q- l s Ra is H or Cl-C3 alkyl; and : R5 is other than benzyl.
2. Compounds of P~~r~ wherein - R2 is H, Cl-C3. alkyl, C2-C3 alkenyl or~
C2-C~ alkynyl.
3. Compounds of P~ferr~L2 wherein R3 is H, Cl-C3 alkyl, C3-C4 alkenyl or C3-C4 alkynyl;
~R4 is H, Cl-C3 alkyl, C3-C4 alkenyl or C3-C4 alkynyl;
3~ R5 is H, Cl-C3 alkyl, C3-C9 alkenyl or C3-C4 alkynyl:

.

', ~ ' . ~ ' ,~ "

"WO91/034~ 2 ~ ~ ~ 3 3 ~ . . PCT/~S90/~49~3 R9 is H, Cl-C3 alkyl, C3-C4 alkenyl or C3-C4 alkynyl;
R10 is H, Cl-C3 alkyl, C3-C4 alkenyl or ~ C3-C4 alkynyl;
: . 4. Compounds of Pr~LL~-~ wherein Q is Q-l, Q-3,-Q 6, Q-7 cr Q-15.
5. Compounds of ~Lfe~ wherein the . 10 compound is of Formula I.
6. Compounds of El~ wherein the compound is of Formula II.

7. Compounds of r~~1l&l_3 wherein the compound is of Formula III.

8. Compounds of Preferred 4 wherein the compound is of Formula IV.

9. Compounds of P~e~err.ed 4 wherein the :~ ~ compound is of Formula V.
: 10. Compounds of Preferred 4 wherein the compound is of Formula VI.
~ 11. Compounds of Preferred 9 wherein.the -: compound is of Formula VII.
12. Gompounds of Pr~ferred ~ wherein the - compound is of Formula VIII.
Specifically Preferred for its biological activity and/or ease of synthesis is the compound of Preferred 5 which is: . -.
~ 2~ ethyl-1-metho~ypropyl)-6-~phenylmethosy)-7-o~abicyclor2.2.13heptane, (2-eso, 6-e~o);
and the ompound of Preferred 7 which is:
2-(etho~ymethyl)-5-methyl-4-(phenylmetho~y)-6-. o.~abicyclol3.2.1]octane, (2-endo, 4-endo).

~:~ 35 .

WO91/034~ ; PCT/US90/04953 i :L0 All may preferably be selected from the group consisting of pyrrole,-furan, thiophene, tetrahydro-pyran, tetrahydrofuran, isosazole, osazole, pyrazole,imidazole, triazole, pyridine, and pyrazine.
Compounds of Formula I-VIII that have the WCH2O
group ~xn with respect to the o~ygen-containing bridge are usually more herbicidally active than the ant~ form. The present invention contemplates all of the herbicidally active forms resulting from synthesis and from deliberately created mi~tures.
The compounds of the invention are prepared by treating the appropriately substituted o~abicyclo-alkanol (Ia-VIIIa) with a compound of the formula WCH2X in which X is a halogen atom or a mesyloxy, tosylo~y group-or the like. This reaction is carried out, as shown in Scheme 1, in the presence of a strong base, such as an alkali metal hydride, in an inert solvent, such as ethers, aromatic hydrocarbons, dimethyformamide and the like. Suitable temperatures for the reaction are preferably from 20C to 100C.
The product ethers are recovered and isolated by conventional technigues.
Compositions suitable for controlling the growth of undersired vegetation are also contemplated as within the scope of this invention. Such compositions comprise an effective amount of any of the compounds disclosed herein and at least one of the ~ollowing: surfactant, solid, or liquid diluent.
- Methods for controlling the growth of undesired - vegetation are similarly considered to be within the -scope of the invention. These methods comprise applying to the locus to be protected an effective amount of any of the compounds disclosed herein. Of particular importance is the method wherein the locus ~ to be protected is rice.
:: .

- . :' ' :

~' ' ;
, WO91/034~ ~ i7~ PCT/US90io4933 .
Scheme 1 S , Ia-VIIIa ~ VIII
base The alkylating agents WCH2X are prepared in the conventional manners known to those skilled in the art from the alcohols WCH2OH.
The alcohols, WCH2OH, are generally known in the art and are most conveniently prepared through - metal hydride (e.g., sodium borohydride~ reduction of the corresponding bicyclic ketones which can be derived by Friedel-Crafts type cyclization of derivatives of phenylalkylcarbo~ylic acid, 2D phenoxyalkylcarbo~ylic acids, phenylthioalkyl-carbo~ylic acids, benzylo~yalkylcarbo~ylic acids, and benzylthioalkylcarbo~ylic acids. Details may be found in a) T. Laird in Comprehen~iYe Or~a~
Chemistry, D. Barton and W. D. Ollis, ed., Vol. 1, pp. 116~-1168, Pergamon Press, New York (1979); b) M. H. Palmer and N. M.~Scollick, J. Chem. SQC. . C, (1968), 2633; c) C. E. Dalgliesch and Mann, J. ~h~m ~, (1945), 893; d~ C. D. Hurd and S. Hayao, J._am Che~, Soc., ~1954), 76, 4299 and 5056; and e) 30 - R. Lesser, Chem~ ~er,, ~1923$, 56, 1642.
Alternatively, the compounds of Formulas I-VIII
may be prepared by the coupling procedure described -- in ~cheme 2,-which is used in cases where the - standard Williamson ether synthesis prov~s problematic. This procedure uses a Lewis acidic metal o~ide wherein the metal can remove the halide WO91/034~ PCT/US90/049~3 ~~

ion by forming an insoluble precipitate. For example, Silver (I) oxide can be used and the silver halide is the co-product. Alternative metal o~ides that may be used are HgO, CaO, MgO. N,N-Dimethyl-formamide and ethereal solvents, such as diethyl ether, tetrahydrofuran, diosane, or 1,2-dimetho~y-ethane are the preferred solvents. Other sol~ents likely to provide good yields include dipolar aprotic solvents like dimethyl sulfoside, acetone and N,N'-dimethylpropyleneurea.

S~Leme 2 Hal la-VIIIa , ~ q (M9n, I-VIII ~ ~Ehl n i~ 1 or 2 . .
The oxabicycloalkanols (la-VIIIa) can be obtained generally by one or more of the following routes: ~directly by a) epo~idation-cyclization of - unsaturated cyclic alcohols, with or without isolation of the eposy alcohol intermediates;
indirectly by b) Diels-Alder reactions of furans with - dienophiles: or by c) Die~s-Alder reaction~ of other dienes with dienophiles.

2 ~ 3~-33 ~
-WO91/0~ ~ PCT/~'S90/049~3 .. .. ..

Non-limiting illustrations of the preparation of representative compounds follow.
The compounds of Formula Ia are synthesized through the sequence shown in Scheme 3. Diels-Alder adducts are formed from readily available furans and from dienophiles includin~ acrylate esters, acrolein, acryloyl chloride, and the like (see Murai ~et al.
J. Chem~ Soc. Ch~m. Comm 2 1 (1981); and ~otsuki et al., Bul L Che~, Soc. Jp~, 57, 3339 (1984); and Laszlo et al., ~Q~ L~l, 25, 4387 (1984) for Diels-Alder methodology). For example, the Diels-Alder adduct (2) is prepared from furan (3) and acryloyl chloride. Treatment of (2) with alcohol and -~- base at 0C to ambient temperature produces the corresponding ester. This intermediate is treated with the appropriate Grignard reagent or reducing agent (e.g, lithium aluminum hydride) as shown in Equation 3b. Optionally, treatment with an alkyl halide or alkyl sulfonate a~d a base (e.g., sodium hydride) in an inert solvent, such as tetrahydrofuran or N,N-dimethylformamide at ambient temperature to 150C produces (4). Alcohol (4a) or ether (4b) is o~idized with a pero~ide, such as hydrogen pero~id~
or m-chloroperbenzoic acid, in a suitable solvent, such as methylene chloride, to yield an epo~ide.
This intermediate is treated with a reducing agent, such as lithium triethylborohydride or lithium -aluminum hydride, to reductively open the epo~ide toproduce alcohol Ia, using the method of ~rishnamurthy et al., J~ Amer. ~hem.!~oc., 95, 8486 (1973), as shown in Equation 3c.
. .

WO 91/03464 2 0 g ~i 3 3 7 PCI~/US90/n49~3 r_ Scheme ~

~ .

(3? (2) 1 ) RO~ b~ ~ J~ ~1<
b) (2~ ~ ¦ OR
- 2) R3M
3 ) R~ X. ba ~ e R2 (4) a: ~5 = ~
b: R5 f H

: ~ ~ . . ' ' O
- ' ~;
:

:

: ' wo 91/03464 2 ~ 3 7 Pcr/~s90io49s3 ..

R1 R~
1) peroxlde HD ~ ~
c) (4) ~ r 5 2) redueing ~gent lr Ia Alternatively, compounds of Formula Ia may be synthesized through the seguence shown in Scheme 4, 20 in which groups R3 and R4 may be va:ried independently. The Diels-Alder adducts (5) prepared.
from fu:~an (3) and a vinyl car~onyl (Ç) a:re treated ~:
with the appropriate Grignard reagent or reduc:ing agent:to produce alcohol (7). Alcohol Ia can then be :~ 25 prepared via~the routes:previously described ln Equations~3b and 3c or modifications thereof.
: ~ :
Scheme 4 ~ ~ :
. . . ~ .

--~ ~
~ .
.~ . , R~
~3) ~ 5) `

.

WO~1/034~ ~ PCT/US90/049~3 ~ `~
2~5337 lS

~M ~
b) ~5) . ~ OH
R~
-: :

1 ) R~X, b~
c) (7) 2) p roxld~
3) r-d~ 9 W
2 0 ~ 94nt I~

Compounds of Formula Ia, especially where R~.
;` and/or R4 are alIylic or vinylic can be prepared : through the sequence shown in Scheme 5. The Diels-Alder adducts (8~ are treated with a pero~ide as described in Equation 3c. This intermediate is treated with the appropriate Grignard rea~ent such as ~: vinyl magnesium halide or allyl magnesium halide, to produce alcohol (9). Alcohol Ia can be prepared via ; the routes previously described in Equa~ions 3b and -- 3c, or modifications thereof.

. ' .
.

, " , .
.
, ~; W0 91/034~4 2 ~ PCr/US90~04953 . ; . . ~ .
, I : ', ! J ~ .

~heme ~ I

~ .
, R'~ r ~3) Y=OR, R3 ~e) R' OH

1~ ~B~

:
(9 :~ 25 ~: ~ R' o*
c~ C9) 1 ) b~e ~R~l 3 o . 2) r-duclr~g ~gcnt - ---~` - :
:

~ ` .

WO91/0~ ~ `` - PCT~US90/b4953 ~~~
2~33~
lB

Compounds of Formula Ia can also be synthesized through the sequence shown in Scheme 6. Diels-Alder adducts ~10) are formed from furan (3) and a .
dicarbonyl dienophile, such as maleic anhydride, using the methods o~ Hanessian et al., ~ Lett., ~7, 5071 (1986) or Woodward et al., ~J AmeLl_Che~, ~ lQ, 1161 (1948). Alcohol Ia can be prepared via the routes shown previously in Equations gb and 4c or 5b and 5c or modifications thereof.

Scheme 6 O R~ O
R ~

: l R~ o ~3) Y-OR, R~ (10) .

:

1 ) R~M 1 ) peroxld~ 4 2) R~X, b~ 2) R~M ~R
b) (10) ~ or - I O I ~R5 3) peroxide 3) R5X, b~se ~OR~
4) reduclng4) redul:lng ~2 /3~R~ A
~gent ~gent Ia : 35 :: :

`` WO 91/03464 2 0 6 3 ~ 3 7 Pcr/vs90/04953 Compounds of Formula IIa can be prepared by the method described in Scheme 7 or modifications thereof. Cyclohe~ene (11) can be prepared via a Diels-Alder reaction using the methods of Alder et al., Çhem. ~er., ~,-1312^(1953). Treatment of the diester with a Gri~nard reagent or a reducing agent yields the diol derivative. Monoalkylation, using methods described earlier, yield a mi~ture of ethers (12). Treatment of (12) with peroside and acid, as tau~ht in U.S. Patent Serial No. 4,542,244, yields alcohol IIa~.
In situations where the endo form is desired, it can be obtained by osidation of the 2-eso-IIa to the corresponding ketone, followed by reduction of `~ the ketone with a reducing agent, such as sodium borohydride.

R~ ~ 1? h~ t R' o2R
M ~2C ~ 2) ROH acld ~
R2 CC~R

.
' WO 91/03464 ~ ~ 5 3 3 7 PCl /US90/04953 b) ~ 11 ) ~ ~ ~N
2) El~X. ~9~

10 ' ~ ~
OH R~OR~

(1Z) .
~'~

1 ~ p~r xi~

IIa ~ 25 :~ :
: , .
;- ~
: Compounds of ~ormu}a IIIa can be prepared by ~he method described in Scheme B or modifications' thereof. Cyclohe~ene~(13) can be prepared via a Diels-Alder from readily available dienophiles, such.
3S maleic anhydride, and a diene component, such as - isoprene or butadiene, using the methods of Fieser et al., J. Amer. ~hem. ~oc., 6~, 802 (1942). Treatment of. ~13) with a Grignard reagent or reducing agent yields the diol derivati~e. Monoalkylation using ' - ' . ' ' : . . .
' , , - .

~ `wo 91/0~ 2 ~3 ~ ~ PCTtUS90/049;3 . :'`.`' i methods described earli~r yields ether ~14). ~, Treatment of (14) with pero~ide and acid as taught in U.S. Patent Ser. No. 4,542l244 yields IIIa.
In situations where the endo form is desired, it can be obtained by oxidation of the 2-e~o-IIIa to the corresponding ketone, followed by reduction of the ketone with a reducing aqent, such as sodium borohydride.
~cheme B

O OR~
,~ 1~ R~ ,~

Y=~.OR
- (13) . C14) .. .

W09ltO34~ - PCT/~S90/0495~ , s ~ j - 1 ) p~roxld~ o~?5 2) ~id~ R4 b) (14) Rl ~ R3 ;~ R4 IIIa :

Compounds of Formula IIIa can also be prepared by the method described in Scheme 9 or modifications thereof. Cyclohe~ene (15? can be prepared via a ; 20 Diels-Alder from diene (16) and a readily available dienophile, such as methylacrylate. Treatment of (15) with a Grignard reagent or reducing~agent ~ields ~;` the diol derivative. Monoalkylation using methods ~; described earlier yields ether (17). Treatment of (17) with peroside and a~id, as descri~bed earlier, ; yields lIIa. In situations where the endo form is - desired, it can be o~tained by o~idation of the 2-eso-II1a to the corresponding ketone, f~llowed by reduction of the ketone with a reducing agent, such - 30 as sodium borohydride.

.

.

`' ' ~' .

-= ` WO 91/03464 2 ~ ~ ~ $ ~ 7 Pcr/US90/04953 S~heme ~C2 R
1' C02R
l C ( ~ f ~c ~16) :

:~ 15 R3 ~OR~
1) R3M R1`'J~ OH3 ~b) (15) 2) El ~ . b~!l e V

~ C1 7~
~:

~ - .
~ R~

7) ~ roYld- R
~) ~o~d --~
,,.:. . _ .. ~II~

:
.

- .

W091/034~ 2 ~5 33 7 PCT/~'S90io4953 -`

Compounds of Formula IV can be prepared by the method described in Scheme 10. Hydrosylation of 1,5-cyclooctadiene with a catalytic amount of osmium tetroside and trimethylamine o~ide as stoichiometric osidant, adapted from a literature procedure [Ray et al., Tet. I~ , 21, 449 (1980)], followed by Williamson ether coupling reaction with the appropriate alkylating agent WCH2X, as described previously, yields ether (18). O~idation of this alcohol using Jones reagent, as described by Heap et al. J~ h~nL Soc. B, 164 (1966)~ yields ketone (19), which is alkylated with an appropriately substituted ketone using an amide base under conditions known in the art. Treatment of the resulting alcohol with an alkyl halide in the presence of a strong base, as described previously, yields (20). Addition of an appropriate Grignard reagent or reducing agent (such ~-: as sodium borohydride) to the carbonyl group produces :- -alcohol (21), which is cyclized to yield the desired ether lVa by means of the alko~ymercuration~
demurcuration sequence lBordwell et al., .J, AmeL
Chem Soc., Q~, 993 (1966)].

3~
-O O~E~W

2) ~l X b~

(18 ~: .

~`WO 91/03464 2 ~ 3 ~ PCIJUS90/049~3 i ~W
Jona~ oxid~t ion b) ( 1 8 ) ~=./

:. (19) , ' 1 ) M~ R~R3 0CH~W
2) R3R~ c= o) c) (l 9) ~ R~O
- a) R5X, b~ls~i~ ~=/
( 20) ~:
~ :~

R3 OH~0C~2W

d) (20) ~ o~) 3 0 ~ :
,.
, , ,, . (Zl) ~' `:
.
- -~~ -~ :

, .

,,.. , :

.. . .

W091/~34~ 2 0 ~ ~ 3 3 7 PCT/US90/049~3 ,~~~

~) ~g(OAc) ~ (21) ' R90 ¦ O
; 10 2~ N~

. IVa Compounds of Formula VIIa (where X . ~) and VIa can be prepared by the method described in S~heme ll ~- or modifications thereof. Diesters (22) and (23) ~an be prepared via a Diels-Alder reaction such as described by Ruden et al. (J. A~e~. Ch~mL Soo., 97, 68~2 ~1975)) using readily available diene ~ompo~ents, such as isoprene or butadiene and~a dialkylketomalonate. ~reatment of the esters with a Grignard~reagent or a reducing reagent, as described earlier,~yields the diols (24) and (2S).
Monoalkylation, USiD9 methods described earlier, followed:by treatment with peroside and àcid, as : des~ribed~earlier, yield alcohols V}Ia and Vla. In 3Q situations where the endo alcohol is desired, it can be obtained by oxidation of the eso-VIIa or e~o-VIa to the ~orresponding ketone ~ollowed by redu~tion of : the ketone with a reducing ngent, su~h as sodium borohydride.

.

~~~ WO 91/0346~ 2 ~ ~ 3 ~ ~ ~ PCl/US90/04953 Schem~ 1 1 lD R'`~ ,~ R'~

- t2Z) ~ ' '~ ' :

(b)~2z) 3rld (Z3) ,~ R

QH . OH 3 (24~ (25, .': ~ . .' ~'.

WO91/034~ 2 0 6 5 3 3 7- PCT/~'S90/04953 ,~'-I

1) ~ b~e ~
(c)~24) and (25) Z) peroxlde ~) ~cid ~ ~

; VII~ VIa : 15 Compounds of Formula VIla (where Y - H) and of Formula Va can be prepared by ~he method described in Scheme 12 or modifications thereof. Diene (26) can be prepared from the corresponding diene ester by addition of a Grignard reagen~t or a reduci:ng agent such as described by Corey et al. (Te~ Let., 30, 2537 (1975), followed by alkylation of the~resulting alcohol. Diels-Alder reaction of (26) with~
glyo~ylate using methods similar to Jurczak~ et al.,:
J. Ora. Chem,, 4~, 3397 (1979) yields (27) and (28).
Treatment of (27) and (28) with a Grignard re3gent or a reducing agent yields alcohols (29) and (30).
Treatment with pero~ide and acid as described earlier . yields alcohols VI~a and Va. The endo alcohol can be obtained as described in Scheme 11.

~' . . :

,~, :'~ :

-`-WO91/03464 2`~ PCr/US9~io4953 23 Rf R5 Rl COzCP~ `
( " ) ~ 1 ) . ~29 M t -- Z) ~5X, b~"o (26 R~ R~

2 0 R'~

~2~) :t27) ~2 3 ~R3 ~t~OR~
R3 ~ R~

R R~
R~
29~ ~ aO) .
- - -~ , WO91/034~2 0 6 5 3 3 7` PCT/US90/049~3 ~

1~ p-ro~:~d- ~ ~3 (d~ ~29) ~30) D I / ~ ORS
2) ~cld Rl~--R~
~ ~ 1~

VII~ Va :

- Compounds of Formula VIII can be prepared by the method described in Scheme 13. Treatment of compound (4) with a trialkylamine N-o~ide and catalytic osmium tetro~ide yields triol ~31).
Alkylation of (31) with a QX (such as benzyl bromide~, followed by treatment with R5X and a strong base, yields VIII.
Scheme 13 :

~ 3~
(4) ~31) - ~ WO 91/03464 2 ~ ~ ~ 3 3 ~ PCI /US90iO49a3 -.
.

1 ) QX, ba~ e 0~~
( b) C 31 ) ~ O ¦ R~
2) R5X. ba~e Rs -- VIII
.

: :

EX~E~E 1 - 20 SteD A: 7-o~abicyclo[2.2~1]hept-5-ene-2-carb~sylic acid, 1,4-dimethyl-, methyl ester, (endo and : e~o, racemic) Acryloyl chloride (32.8 ml, 0.40 mol) was . 25 cooled to 0C in an ice-water bath unde:r:a:nitrogen : atmosphere~. :Aluminum chl~ri:de ~1.60 9, 0:.012~mol) was added in 0.5 g portions with stirring. ~The ~ :
mi~ture was stirred at 5C for 10 minutes, then was:
cooled:to~-65C with an isopropanol-dry ice bath.
2,5-Dimethylfuran (38.4 g~, 0.40 mol) was added . dropwise a:é -65:C to -50C:over 1.5 hours.~:After addition was~complete, the misture was stirred for 1 hour. Methylene chloride ~250 ml) was added to the mi~ture. The misture was then cannulat~d to a stirring mix~ture o~ triethylamine (48.4 9, 0.48 mol) ~; and methanol ~60 ml) at -55C to -40C over 10 ., ~, : .

: ~
.

20~337 W091/0~ ~ PCT/VS90/049~3 r minutes. The mixture was stirred at -65C for 1.25 hours, then was allowed to warm to ambient temperature. The mi~ture was poured into 500 ml water. The phases were separated and the aqueous layer was e~tracted two times with methylene chloride. The combined organic layers were washed with saturated sodium bicarbonate and brine solutions, dried over magnesium sulfate and concentrated in vacuo to leave 35.12 9 of a yellow oil. Flash chromatography in 3:1 hesanes:ether on 800 9 of silica gel yielded 17.39 g of the endo isomer and 11.82 9 of the e~o isomer.
NMR (CDC13) endo isomer: 6.22 td, lH), 6.03 (d, lH), 3.61 (s, 3~), 2.88 (dd, lH), 1.91 (ddd, lH), 1.80 (ddd, lH), 1.70 (s, 3H), 1.56 ~2, 3H).
NMR (CDC13) e~o isomer: 6.18 (d, lH), 6.12 (d, lH), 3.69 ~s, 3H), 2.52 (dd, lH), 2.0 (dd, lH), 1.66 (dd, - 20 lH), 1.62 (s, 3H), 1.50 (s, 3H).

Step B 7-oxabicyclo[2.2.1]hept-5-ene-2-methanol, ~ dimethyl-, e20-, ( racemic-) Lithium aluminum hydride (2.3 g, 60.0 mmol~ was added under a nitrogen atmosphere to 100 ml dry tetrahydrofuran. The mixture was heated at reflu~
for 15 minutes, then cooled to OQC. A solution of 7-osabicyclo[2.2.1]hept-5-ene-2-carbosylic àcid, 30 1,4-dimethyl-, methyl ester, (e~o, racemic) (1~.3 9, 78.6 mmol) in 100 ml tetrahydrofuran was added dropwise over 1.5 hours. The mi~ture was then allowed to warm to a~bient température and stirred for another 4.0 hours. The mi~ture was cooled to 5C
in an ice-water bath and 2.3 ml of water, 2.3 ml of 10% sodium hydro~ide, and 2.3 ml of water were added ::

~~ WO91/034~ 2~33~ t~ PCT/US90/049~3 The solids were removed by suction filtration and washed with 40 ml of cold tetrahydrofuran. The - 5 filtrate was concentrated in vacuo to yield 9.5 g of a colorless oil.
NMR (CDC13): 6.22 (d, lH~, 6.12 (d, lH), 3.83 (m, lH), 3.74 (m, lH), 2.17 (dd, lH), 1.86 (m, lH), 1.68 (dd, lH), 1.59 (s, 3H), 1.58 (s, 3H~, l.Sl (dd, lH).
IR (CH2C12): 3520, 3480, 1385, 1330, 1190, 1140, 1120, 1075, 1035, 975, 365 cm~l.
MS (CI): 155 (~+1), 137, 109, 107, 96, 95, 93.

S~* C: 7-oxabicyclo[2.2.1]hept-2-ene, 1,4-dimethyl-2-[(phenyl metho~y)methyl]-, (exo-, racemic) Sodium hydride (1.54 g, 3.85 mmol of a 60% oil dispersion) was washed with he~anes, decanted, and suspended in 20 ml of dimethylformamide. A solution of 4.75 g ~30.8 mmol) of 7-o~abicyclo[2.2.1]hept-5-ene-2-methanol, 1,4-dimethyl-, eso (racemic) in 40 ml dimethylformamide was added dropwise at 20 o~er 4 minutes. Ths misture was stirred 45 minutes at ambient temperature. ~enzyl bromide (6.05 9, 35.4 mmol) was added dropwise in 30 ml dimethylformamide over 30 minutes. The mi~ture was - stirred 20 hours at ambient temperature. The mi~ture ` was poured into 350 ml of water and e~tracted three times with methylene chloride. The combined estracts were washed with brine, dried over magnesium sulfate - and concentrated-in vacuo to yield 7.83 g of a yellow oil. Flash chromatography in 3:1 he~anes:ether on - . 400 g of silica gel yielded 3.77 g of a light yellow oil.

.~

wo gl/o~ 2 0 6 ~ 3 3 7 PCT~US90/04953 -~;

NMR (CDC13): 7.40-7.26 (m, 5H), 6,12 (s, 2H), 4.51 (dg, 2H), 3.60 (dd, lH~, 3.43 (dd, lH), 1.97 (m, lH), 1.70 (dd, lH), 1.56 (s, 3H), 1.53 (s, 3H), 1.18 (dd, lH).
IR (CH~C12): 1595, 1450, 1380, 1360, 1330, 1195, 1140, 1120, 1090, 1035, 1025, ~60.
Anal. Calcd. for C16H20o2: C, 78.69; H, 8.20.
Found: C, 78.80; H, 8.37.

Step p: 3,8-dio~atricyclo[3.2.1.0 sup2, sup4~octane, 1,5-dimethyl-6-[(phenylmetho~y)methyl]-, (e~o, racemic-) To a stirring solution of 3.60 9 (15.Q mmol) of 7-oxabicyclot2.2.1] he pt-2 -ene, 1,4-dimethyl -2 -~(phenylmetho~y)methyl~- (e~o, racemic) in 50 ml methylene chloride was added 3.56 g (16.5 mmol) o~
80~ technical m-chloroperbe~zoic acid at 0C to 10C. The mixture was stirred at 0C to 10C for 1 hour, then at amibient t~mperature. ~fter 20 hours at ambient temperature, the mi~ture was cooled to 0C~
for 0.5 hour, filtered, and washed with cold methylene chloride. The filtrate was washed with 10%
sodium sulfite, sat. sodium bicarbonate, and brine and dried over magnesium sulfate and concentrated in vacuo to yield 4.05 g o~ a light yellow oil. Flash ~hromatography in 1:1 he~ane:ether on 150 g of silica gel yielded 3.30 9 of a colorless liquid.
NMR (CDC13~o 7.40-7.26 tm, 5H), 4.48 (dq, 2H), 3.52 (dd, lH), 3.26 (dd, lH),-3.17 (dq, 2H), 2.10-1.98 ~m, lH), 1.85 (dd, lH), 1.47 (s, 3H), 1.46 (s, 3H)j 1.18 (dd, lH).

, ': ' ,. .

WO91/034~ ~ 3 ~.i7` `~ PCT/US90/04953 IR (CH2C12): 1451, 1400, 1380, 1362, 1308, 1218, 1192, 1120, 1090, 1025, 968, 915, 880, 870, 830, B10 cm~l.
MS (CI): 261 (M~l), 183, 181, 169, 153, 139, 91.

St~p E: 7-o~abicyclo[2.2.1]heptan-2-ol, 1,4-dimethyl-6-t(phenylmetho~y)methyl]-, (e~o, racemic), mi~ed with -5-~(phenylmethosy)methyl]regio-isomer To a stirring lM solution o lithium triethyl-borohydride (25.4 ml) in tetrahydrofuran was added 3.30 9 (12.7 mmol) of 3,8-diosatricyclo[3.2.1.0 sup2, sup4]octane,1,5-dimethyl-6-[(phenylmethosy)methyl~-, ~e~o, racemic) in 10 ml tetrahydrofuran a~ ambient temperature. After 3 hours at reflu~, the mixture was cooIed to 0C and 10.2 g of a 10% sodium hydro~ide solution was added dropwise. The mi~ture was warmed to ambient temperature and 8.64 g of 30%
hydrogen pero~ide (76.2 mmol) was added dropwise.
The mi~ture was stirred at 4~C for 30 minutes, then was saturated with potassium c3rbonate crystals. The mi~ture was poured into 100 ml ether and the organic layer was separated. The agueous layer was extracted with ether three times. - The combined organic layers were washed with brine, dried over magnesium sul~ate and concentrated in ~acuo to yield 4.45 g of a light yellow oil. Flash chromatography in 3:1 ether:
he~anes on 150 9 of silica gel yielded 2.04 g of colorless oil containing a 2:1 misture of the 5-(phenylmethosymethyl)isomer: 6-(phenylmethosy) methyl isomer.

9n ~q WO91/0~ ~ ~ U ~J ~ 3 7 - PCT/US90/04953 .

NMR (CDC13): 7.32 (m, 5H), 4.98 (m, 2H), 3.77 (m, lH), 3.54 (m, lH), 3.20 (m, lH), 2.20 ~m, lH), 1.90 (m, lH~, 1.75 (m, lH), 1.66 (m, lH), 1.45, 1.43, 1,41 and 1.38 (s, 6H, total), 1.30 (m, lH), 1.12 (m, lH).
IR(CH2C12): 3580, 3460 (br), 1452, 1380, 1363, 1203, 1090, 1070, 1027, 860 cm~l.

559~ E: 7-o~abicyclo[2.2.1]heptane, 1,4-dimethyl-2-(phenylmethoxy)-6-[(phenylmetho~y)methyl]-, 2:1 with the -5-[(phenylmetho~y)methyl]-isomer, (exo, e~o, racemic~

Sodium hydride (0.39 9, 9.73 mmol) was washed with hexanes, decanted, and suspended in 10 ml of dimethylacetamide. To the suspension was added 2.04 9 (7.79 mmol) of 7-o~abicyclo[2.2.1]heptan-2-ol, 1,4-dimethyl-6-[(phenylmetho~y)methyl]-~exo, - 20 racemic~j mi~ed with -5-[(phenylmetho~y)methyl]
regioisomer in 20 ml dimethylacetamide at ambient temperature over 20 minutes. The mi~ture was stirred at 65C for 2 hours, theD 1.66 9 (9.73 mmol) of benzyl bromide in 10 ml dimethylacetamide was added at 0C. The mi~ture was warmed to ambient temperature. After 20 hours, the mixture was poured - into 100 ml-methylene chioride and 100 ml water. The phases were separated and the aqueous layer was e~tracted three times-with methylene chloride. The combined organic layers were washed with brine, dried, and concentrated in vacuo to yield 4.00 g of a light yellow oil. Flash chromatography in 2:1 he~anes:ether on 150 9 of silica gel yielded 1.97 9 of a light oil containing a 2:1 mixture of isomers.

WO91/03464 '`'2'd~ '7~ Pcr/usgo/oq9~3 i NMR (CDC13): 7.32.(m, lOH), 4.58-4.36 (m, 4H), 3.54 (m, 2H), 3.20 ~m, lH~, 2 . 02 (m, lH), 1.88 (m, 1~
.. 5 1.8-1.6 (m, lH), 1.47, 1.45 and 1.43 (s, 6H total), 1~2-1.05 (m, 2H).
- IR (CH2C12): 1605, 1587, 1~95, 1452, 1385, 1372, 1360, 1333, 1203, 1185, 1085, 1013, 860 cm~l.
~S (CI): 353 (M+l), 335, 261, 2~6, 24S, 244, 215, 181, 155, 137, 119, 91.

EXAM~E 2 ~ a: 7-osabicyclo[2.2.1]hept-5-ene-2-carbosylic acid, methyl ester (exo and endo, racemic) To a misture of 93.0 9 (1.37 mmol) of furan and 0.50 g (8.6 mmol) of propylene o~ide was added 47.0 g (0.52 mmol) acryloyl chloride at ambient temperature. The misture was stirred under a nitrogen atmosphere for three days in the dark. The -mi~ture was then added to a solution of 45.0 ml (0.556 mol) pyridine and 45.0 ml of methanol in 100 ml methylene chloride at 0C. The mi~ture was warmed to ambient temperature after the addition was - complete. After 1 hour, water was added to the .: misture.and the layers were separated. The aqueous ~ layer was e~tracted two:times with methyiené
- chloride. The combined organic layers were washed .with.water, brine and dried over magnesium sulfate and concentrated in vacuo-to yield 66.3 g of dark oil ; - -containing.a 2:1-ratio of eso:endo isomers. Flash chromatography of 4.0 9 in 20:1 hesanes:ethyl acetate on 320 9 of silica gel separated the endo and eso isomers.

WO91/034~ ~ 0 6 5 3 3 7 PCT/~'S90io4953 ~

NMR (CDC13) endo: 6.44 ~cld, lH), 6.21 ~dd, lH), 5.17 (dd, lH), 5.03 (dd, lH), 3.64 (s, 3H), 3.10 (ddd, lH), 2.10 (ddd, lH), 1.58 (dd, lH).
NMR (CDC13) e~o: 6.37 (dd, 2H), 5.10 (dd, 2H), 3.73 (s, 3H), 2.~4 (dd, lH), 2.18 ~dt, lH), l.S6 (dd, lH).

~tep ~: 7-03abicyclo[2.2.1]hept-5-ene, 2~ ethyl-1-metho~ypropyl), eso-, (racemic-) To 20 ml (40 mmol) of 2M ethylmagnesium bromide in tetrahydrofuran at 0C was added 3.0 9 (19.5 mmol) of 7-o~abicyclo[2.2.1]hept-5-ene-2-carbosylic acid, methyl ester (e~o, racemic) in 20 ml tetrahydro-furan. The mi~ture was warmed to reflus. After eight hours, the mi~ture was cooled to 0 and 20 ml water was added. The mi~ture was acidified to p~3 with 10~ hydrochloric acid, then e~tracted two times with ether. The combined organi~ layers were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield 2.3 9 of light yellow oil. This intermediate was dissolved in 50 ml tetrahydrofuran and added to 0.65 g t45.1 mmol) of 60% sodium hydride in oil at 0C. The solution was warmed to ambient temperature and stirred 10 minutes. Iodomethane (103 9, 40.0 mmol) was added and the mixture was reflu~ed. After 20 hours, the mi~ture was cooled and poured into 100 ml water. The layers were separated, and the aqueous layer was - e~tracted twice with ether. The organic layers were -combined and washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield 1.69 9 of yellow oil. Flash chromatography in 6:1 he~anes:
ethylacetate yielded 1.27 9 of a pale yellow oil.

:~ , , .

-~ - .. , ' : ' ' .

. , .

~-- WO91/034~ 2 ~;3rr~ Q '; PCT/US90io4953 NRM (CDC13): 6.40 (dd, lH), 6.28 (dd, lH), 4.95 (dd, 2H), 3.19 (s, 3H), 1.77 (dd, lH), 1.60 (m, 4H), 1.47 . 5 (dd, lH), 1.33 (dd, lH), 0.9 (dt, 5H).

Step~: 7-oxabicyclo[2.2.1]heptane 2-(1-ethyl-1-methosypropyl)-6~(phenylmethoxy~-, lexo-(2-alpha, 6-alpha)]
Following procedures similar to those described in Steps D, E and F in E~ample 1, reaction of 1.27 9 (6.48 mmol) of 7-oxabicyclo[2.2.1]heptane, 2~ ethyl-l-metho~y-propyl)(e~o, racemic) with 1.9 g (6.6 mmol) of m-chloroperbenzoic acid gave 0.75 g of a yellow oil. Consequent reaction with 10 ml (10 mmol) of lithium triethylbor~hydride yielded 0.9 9 of a pale yellow oil. Treatment with benzyl bromide; follow~ed by flash chromatography yielded 0.20 g of a colorless oil.
- NMR (CDC13): 7.33 (m, 5H), 4.55 (m, 4H), 3.64 (dd, lH), 3.16 (s, 3H), 1.85-1.31 (m, 9H~, 0.89 and 0.88 (t, t, 6H).

~ ELE_l SteD A: ~is-7-o~abicyclo~2.2.1]hept-5-ene-2,3-di-methanol, (e~o)-Furan (85.0 ml, 1.17 mol~ was added to maleic anhydride (81.0 g, 0.827 mol) in 100 ml ether at ambient temperature. After 20 hours, the precipitated solid was filtered off and washed with ether to give 104 g of white ~rystalline solid.
Reduction of 34.0 9 of the Diels-Alder adduct with lithium aluminum hydride, as described previously, yiel~ed 28.0 9 oil. The NMR spectrum was .

WO91/034~ ~ 0~ 5 3 3 7 PCT/US90/049i3 the same as that reported in the literature [Das et al., J. Me~L_Che~ 1, 930 (19~8)].
NMR (CDC13): 6.40 (s, 2H), 4.70 (s, 2H), 4.00 (br, - 2H), 3.80 (m, 4H), 1.95 (m, 2H).

Step B: 7-o~abicyclo[2.2.1]heptane, 2,3-bis(ethosy-methosy)-5-hydroxy-, [2 e~o-(2 alpha, 3 alpha, 5 alpha)]

Alkylation of 14.0 g (0.0897 mol) cis-7-o~a-bicyclo[2.2.1]-hept-5-ene-2,3-dimethanol using ethyl iodide and sodium hydride was accomplished as described previously to give 15.0 g of the bis-ether. Eposidation using m-chloroperbenzoic acid, followed by reductive opening with lithium triethylborohydride, as described previously, yielded 4.00 9 of oil.
: 20 NMR (CDC13): 4.49 (d, lH), 4.23 (s, lH), 3.96 (brt, . lH), 3.5-3.2 (m, 8H), 2.12 (brd, lH), 1.95 (m, 3H), . 1.55 (ddt, lH), 1.17 (t, 6H).
MS (Cl): 231 (M+l), 259, 185.

Step ~: 7-o~abicyclo[2.2.1~heptane, 2,3-bis(etho~y-~ metho~y)-5-~phenylmethosy)-, [2 e~o-(2 : alpha, 3 alpha, 5 alpha)~-Coupling of 7-oxabicyclo[2.2.1]heptane, 2,3-bis(ethosymethosy)-5-(phenylmethoxy)-, [2 eso-(2 alpha, 3 alpha, 5 alpha)] (0.5 g, 2.17 mmol) with benzy.lbromide in the presence of sodium hydride, as described earlier, yielded 0.40 g of colorless oil.
NMR (CDC13): . 7.33 (m, 5H), 4.52 (m, 4H), 3.75 (dd, lH), 3.5-3.2 (m, 8H), 2.0-1.7 (m, 4H~, 1.21 and 1.20 (t, t, 6H).

.

WO91/034~ 2 ~ 3 ~ PCT/US90/04953 .
(+)-4-methyl-4~cyclohesene 1,2-dicarbo2ylic anhydride .
To 50 ml (0.50 mol) of isoprene ~ooled to 0C
was added 25 g (0.26 mol) of maleic anhydride portionwise. The reaction mi~ture was warmed to ambient temperature and stirred for 4 hours. The excess isoprene was removed under vacuum to give 40.5 g of a white solid, m.p. 63-65C.
NMR (CDC13): 5.70 (brs, lH), 3.45 (m, 2H), 2.50 (m, 4~), 1.81 (s, 3H).
IR (KBr): 2900, 1840, 1770, 1445, 1235, 965, 920, 800.

St~p ~ cis-4-methyl-4-cyclohe~ene-1,2-dimethanol ' To 300 ml of tetrahydrofuran at 0C was added 16.0 g (0.42 mol) lithium a~uminum hydride portionwise keepin~-the reaction temperature between 0C and 5C. A solution:of 33.0 g ~0.20 mol) of 4-methyl-4-~yclohe~ene-1,2-dicarbo~ylic:anhydride in 2~ 100 ml of tetrahydrofuran was added-dropwise over 2 hours keeping the temperature between 0C~ and I0C.
The reaction mi~ture was warmed to ambient ~: temperature and stirred for 2~hours. The reaction was cooled to 0C and 35 ml of ethyl acetate was added dropwise, followed by dropwise addition of 35 ml isopropanol and 35 ml water. The reactio~ mi~ture was filtered through celite using acetone,~dried with ~gSO4 and concentrated to 33.0 g of oil. Flash chromatography in 3:1 he~anes:ethyl acétate, followed 3s by 1:1 hesanes:ethyl acetate and finally ethyl acetate alone yielded 18.2 q of oil.

. .
~' , ' ' ' ' ' ' ~

.

WO91/034~ 2 0 ~ 5 3 3 7 PCT/~IS90/049~3 NMR (CDC13): 5.35 (brs, lH, 3.68 (m, 2H), 3.60 (m, 2H), 3.10 (brs, 2H), 2.05 (brs, fiH), 1.64 ~s, 3H).
I~ (neat)- 3500-3100, 1730W, 1440, 1010.
MS (CI): 157 (M+l), 139, 121.

~p_~: 2-~ndo,4-eso~ 4-hydrosy-5-methyl-6-osabicyclo[3.2.1]octane-2-metha~ol To a suspensionn of 39.0 9 ~0.124 mol) of 55~
m-chloro-perbenzoic acid in 400 ml methylene chloride at 0C was added 19.4 9 (0.124 mol~ of (+)-cis-4-methyl-1,4-cyclohesene-1,2-dimethanol in 100 ml methylene chloride over 15 minutes keeping the temperature less than 8C. The reaction mi~ture was warmed to ambient temperature and stirred for 24 hours. The reaction was cooled to 0C and 30 ml of a saturated aqueous solution of ~a2S2O3 was added dropwise keeping the temperature less than 8C. The reaction mi~tura was dried wîth MgSO4, filtered and concentrated. Flash chromatography in 3:1 he~anes:ethyl acetate, 1:1 heYanes:ethyl acetate, then ethyl acetate alone yielded 6.1 9 oily solid.
NMR (CDC13): 3.80 (brd, 2H), 3.60 tbrd, lH), 3.45 (d, 2H), 2.70 (brs, 2H), 2.42 (brs, lH), 2.0 (m), 1.5 (m), 1.33 ~s, 3H).
I~ (neat): 3400-3200, 2900, 1450, 1400, 13B0, 1060, 1~00, 8~.
MS (CI): 173-(M+1), 213, 155.
.: :- . . .
Step D: ~+)-2-endo,4-e~o-4-hydro~y-2-(metho~ymethyl~-5-methyl-6-o~abicyclo~3.2.1]octane To 1.45 y (0.036 mol) of he~ane-washed 60~
sodium hydride was added 100 ml tetrahydrofuran. THe .::

WO91/0~ ~ 2 ~ ~ 3 ~ PCT/US90/049~3 ~3 reaction was cooled to 0C: and 6.1 g (0.035 mol) of (+)-2-endo,4-exo-4-hydro~y-5-methyl-6~o~abicyclo-[3.2.1]octan-2-methanol in 70 ml tetrahydrofuran was added dropwise oYer 4S minutes keeping the temperature between 0C and 5C. The reaction mi~ture was warmed to ambient temperature and 2.5 ml (0.04 mol) of methyliodide was added. An additional 1.0 9 (0.025 mol~ of 60% sodium hydride and 2.0 ml (0.03 mol) of methyliodide was added to the reaction. After 4B hours, thE reaction was csoled to 0C and 25 ml of water, was added dropwise. The reaction mixture was estracted with ether, and then with methylene chloride. The combined organic layers were dried with MgS04, filtered and concentrated to 7.26 g oil. Flash chromatography in 3:1 hesanes:ethyl acetate yielded 2.0 9 of oil.
NMR (CDC13): 3.80 ~m, 2H), 3.60 ~brs, lH)j 3.32 (s, 3H), 3.20 (m, 2H), 2.40 ~brs, lH~, 2.18 (m, lH), 2.10 (d, lH), 1.50 (m, 3H), 1.33 (s, ~H).
MS (CI): 187 (M~l), 204, 169, 155.

Step~ 2-endo-2-(methoxymethyl)-5-methyl-6-o~abicyclo[3.2.1]octan-4-one To 21.0 ml (0.042 mol) of 2M osalylchloride in methylene chloride at -78C was added 4.2 ml (~.06 mol) dimethyl sulfo~ide. The reaction mi~ture was stirred for 15 minutes, then 3.9 g ~0.021 mol) of (+)-2-endo,4-e~o-4-hydrosy-2-(methosymethyl)-5-methyl-6-o~abicyclot3.2.1~octane in 10 ml methylene chloride was added dropwise and the reaction misture was stirred for 45 minutes. Triethylamine ~16.5 ml, 0.12 mol) was added dropwise and the reaction mixture was warmed to ambient temperature. Water was added (50 ml) and the reaction mi~ture was e~tracted with .

W091/034~ PCT/~'S90/~49~3 methylene chloride, dried over MgS09, filtered and concentrated. Flash chromatography in 3:1 hezanes:ethyl acetate yielded 0.96 9 of oil.
NMR (CDC13): 4.10 (m, 2H), 3.34 (m, 5H), 2.69 (brs, lH), 2.5-2.0 (m, 4H), 1.80 (d, lH), 1.34 (s, 3H~.
IR (neat): 2920, 2870, 1720s, 149S, 1105, 975.
MS (CI): 185 (M~l), 202, 199, 216.
Step F: (+)-2-endo,4-endo-4-hydrosy-2-(metho~y-methyl)-5-methyl-6-osabicyclo[3.2.1]-octane I5 To 2.2 g (0.012 mol) of (+)-2-endo,4-endo-4-`
hydro~y-2-(metho~ymethyl)-S-methyl-5-osabicyclo-[3.2.1]octan-4-one in tetrahydrofuran at -78C was added a slight e~cess of 1 M lithium triethylborohydride in tetrahydrofuran. After 5 minutes 10 ml of water was added and the reaction~
mi~ture was warmed to ambieDt temperature. The reaction mi~ture was estracted with methylene chloride, dried over ~gS04, ~iltered and concentrated. Flash chromatography in 1:1 he~anes:ethyl acet~te yielded 1.2 g of oil.
NMR (CDC13): 3.83 (brd, 2H), 3.40 (m, lH), 3.32 (s, 3H), 3.20 (d, 2H), 2.45 ~brs, lH), 2.05-1.9 (m), 1.52 (d, lH), 1.34 (s, 3H~.
.
Step G: 2-endo,4-endo-2-(metho~ymethyl)-5-methyl-4-~phenylmetho~y)-6-o~abicyclo~3.2.1~-octane To 0.12 9 (3 mmol) of he~ane-washed sodium hydride in tetrahydrofuran was added 0.35 g (1.8 mmol~ of (t)-2-endo,4-endo-2-(methoxymethyl)-5-methyl-6-o2abicyclo~3.2.1]octan-~-ol in 2 ~ t~ .
wo 91to~ -i 1, J! ~J ~, PCT/US90~04953 tetrahydrofuran. The reaction misture was stirred at 60C for 24 hours. Water was added and the reaction mi~ture was e~tracted with ether, dried over MgS04, filtered and concentrat~d. Flash chromatography in 23:1 hesanes:ethyl acetat~ yielded an oil.
NMR (CDC13): 7.32 (m, 5H~, q.62 ~d, lH), 4.42 (d, lH), 3.82 (d~dd, 2~, 3.32 (s, 3H), 3.2-2.2 (m, 3H), 2.39 (brs, lH), 2.03 (dt, lH), 1.8 (m, 2H), 1.49 (d, lH), 1.37 ~s, 3H), 1.25 (m, lH).
IR ~neat): 2900, 1450, 1360, 1080, 1000, 960, 850, 730, 690.
MS (CI): 277 (M+l), 294.
~L

Step A: (+)-diethyl 3,6-dihydro-4-methyl-ZH-pyran-2,2-dicarbo~ylate To 50 9 (0.70 mol) isoprene was added 25 9 (0.14 mol) diethylketomalonate and 0.78 9 (2.4 mmol) zinc iodide. The reaction mi~ture was stirred at room temperature for 48 hours. The e~cess isoprene was removed under vacuum. Flash chromatography in 20:1 he~anes:ethyl acetate yielded 1.2 9 of oil.
NMR (CDC13~: S.40 (brs, lH), 4.34 (m, 2H), 4.Z8 (q, 4H~, 2.58 (brs, 2H), 1.75 (brs, 3H), 1.29 (t, 6H)o MS (CI): 243 (M+l), Z83, 225~ 169 Ste~ B: (~)-3,6-dihydro-4-methyl-2H-pyran-2,2-dimethanol .
To 200 ml tetrahydrofuran at O~C was added 4.0 9 (0.105 mol) lithium aluminum hydride portionwise.
A solution of 12.5 9 (0.052 mol) of (+)-diethyl 3,6-dihydro-4-methyl-2H-pyran-2,2-dicarboxylate in 60 ml WO91/034~ 2 0 6 5 3 3 7 PCT/US90/04953 ~~

tetrahydrofuran was added dropwise over 30 minutes.
The reaction mixture was warmed to ambient temperature. After 2 hours, the reaction was cooled to 0C and successively treated with 30 ml ethyl ; acetate, 30 ml isopropanol, 30 ml water dropwise keeping the temperature under 10C. The reaction mi~ture was filtered through celite with acetone, dried over MsSO4, filtered, and concentrated to an oil. Flash chromatography in 1:1 hesanes:ethyl acetate followed by ethyl acetate alone yielded 5~5 g oil.
NMR (CDC13~: 5.42 (brs, lH), 4.18 (brs, 2H~, 3.71 15 (d, 2H~, 3.65 (d, 2H~ 4 (brs, 2H), 1.7 (s, 3H).
IR (neat): 3300 broad, 2900, 1435, 1380, 1110, 1020.
; MS (CI): 159 (M~l), 173, 141, 127.

Step C~ e~o-4-hydro~y-5-methyl-2,6-dioxabicyclo-t3.2.1]octan-1-methanol - To a suspension of 11.0 g (0.035 mol) 55%
m-chloroperbenzoic acid in 100 ml methylene chloride at 0C, was added 5.5 g ~0.035 mol) of 25 (~)-3,6-dihydro-4-methyl-2H-pyran-2,2-dimethanol in 100 ml methylene chloride. The reaction mi~ture was warmed to ambient temperature. After 20 hours, the reaction mi~ture was cooled to 0C and 30 ml of a saturated aqueous solution of Na2S2O3 was added dropwise. The reaction miYture was dried over MgSO4, filtered, and concentrated. Flash chromatography in 1:1 hesanes:ethyl acetate followed by ethyl acetate yielded 1.7 g of oil.
NMR (CDC13): 4.13 ~dd, 1~), 4.08 (d, lH), 3.86 (m, 35 2H), 3.78 (d, lH), 3.62 (d, lH), 3.45 (d, lH), 2.22 (d, lH~, 1.40 (d, lH), 1.40 ~s, 3H).
MS (CI): 175 ~M+l), 192, 157.

:. ....... .

2 ~ 7 ` ` WO 91/03464 j;", ~ r~ P~/US90/04953 Step~ 4-exo-1-(etho~ymethyl)-4-hydrosy-5-methyl-2,6-dio~abicylco[3.2.1]octane To 0.3 9 (0.007 mol) of 60% sodium hydride in tetrahydrofuran was added 1.2 9 ~0.007 mol) of (+)-e~o-4-hydroxy-5-methyl-2,6-dio~abicyclo[3.2.1~-octan-l-methanol in tetrahydrofuran followed by 0.6 ml (0.013 mol) ethyliodide. After 24 hours at ambient temperature, water was added and the reaction mi~ture was extracted with methylene chloride, dried over MgSO4, filtered, and concentrated. Flash chromatography yielded an oil.
NMR (CDC13): 4.18 (dd, lH), 4.09 (dd, lH), 3.95 (d, lH),-3.81 (m, 2H), 3.65~3.4 ~m, 4H), 2.20 (d, lH), 1.50 (d, lH), 1.40 (s, 3H), 1.19 (t, 3H).
MS (CI): 203 (M+l), 220, 185.

Step E: (+)-l-(etho~ymethyl)-5-methyl-2,6-diosabicyclo[3.2.1~octan-4-one To 4 ml ~0.008 mol) of Z M o~alylchloride in methylene chloride at -78C was added successively 0.7 ml (0.01 mol) dimethylsulfoside, 1.2 g ~0.0058 mol) of (~)-4-e~o-1-(etho~ymethyl~-4-hydrosy-5-methyl-2i6-diosabicycloC3.2.1~octane and 2.79 ml (0.02 mol) triethylamine. The reaction mi~ture was warmed to ambient temperature,~and water was added.
- The reaction misture was extra~ted with~methyl chloride, dried over MgSO4-, filtered and concentrated. Flash chromatogarphy yielded 1.0 ~ oil.
NMR ~CDC13): 4.50 (d, 1~), 4.21 (m, 3H), 3.57 (m, 4H), 2.20 (d, lH), 2.10 (d, lH), 1.40 (s, 3H), 1.21 (t, 3H).

, WO91/03464 2 0 6 ~ 3 3 7 PCr/~'S90io49~3 ~`

Step F: (+)-4-endo-1-(ethosymethyl)-5-methyl-5-methyl-4-(phenylmethoxy)-2,6-dio~abi-cyclot3.2.1]octane To a slight e~cess o lithium triethylboro-hydride in tetrahydrofuran at -78C was added 1.0 g - ~0.0~49 mol) of (~)-1-(etho~ymethyl)-5-methyl-2,6-dio~abicyclo[3.2.11Octan-4-one. After 5 minutes water was added and the reaction mi~ture was warmed to ambient temperature. The reaction mi~ture was estracted with methylene chloride, dried over MgS04, filtered, and concentrated to give 0.5 9 of oil. To 0.2 g (0.97 mmol) of this oil was added 0.1 g (2.5 mmol) of 60% sodium hydride and 0.25 9 (1.5 mm~1) of benzylbromide in tetrahydrofu~ran. After 24 hours at 60C, water was added and the reaction mi~ture was e~tracted with ether, dried over MgS04, filtered, and concentrated. Flash chromato~graphy in 20:1 he~anes:ethyl acetate-yielded 0.38 9 oil.
- NMR (CDC13): 7.32 (brs, 5H), 4.55 (s, 2H), 4.00 (d+d dd, 3~), 3.68 (t, lH), 3.40 (m, 4H), 3.38 (dd, lH), 1.79 ~dd, 2Hj, 1.40 (s, 3H), 1.18 (s, 3H).

~k ~tep A~ e~o,e~o,e~o--diethyl-5,6-bishydrosy~
- 7-osabicyclo[2.2.1~heptane-2-methanol ~ ~
To 26.5 g (0.146 mol) of 2-~1-ethyl-1-hydrosy-propyl)-7-o~abicyclo[2.2.11hept-5-ene in lOO ml acetone~at 0C was added-17.6 g (0.15 mol) N-methyl morpholine N-o~ide and 10 ml of 4~ osmium tetroxide in water. The reaction misture was warmed to ambient temperature and stirred for 4 days. A saturated . ~ .
~ . .
' ' ~-- W091tO~ ~ ;.~ PCT/US90/049~3 aqueous solution of Na2S~03 was added. The reaction mi~ture was estracted with ethyl acetate twice and the combined extracts were washed with water and brine, and dried over MgS04, filtered, and concentrated. Flash chromatography yielded 12.0 g thick oil.
NMR tCDC13): 4.44 (s, lH~, 4.38 (d, lH), 3.85 (m~, 1.8-1.7 (m), 0.84 (t~t, 6H).
MS (CI): 217 (M+l), 234.

St~D B: (+)-e~o,eso,eso-a,~-diethyl-6-[(2-fluoro-phenyl)metho~y]-5-hydrosy-7-osabicyclo-[2.2.1]heptane-2 methanol To 1.2 g (0.03 mol) of 60% sodium hydride in tetrahydrofuran at 0C was added 6.0 g (0.028 mol) of (_)-eso,eso,e~o-diethyl-5,6-bishydrosy-7-osabicyclo-~2.2.1]heptan-2-methanol in tetrahydrofuran. The reaction mixture was warmed to ambient temperature and 3.4 ml (0.03 mol) of 2-fluorobenzylbromide was added. After 24 hours, water was added and the reaction misture was estracted with ether, dried over MgS04, filtered and concentrated. Flash ehromatography yielded 1.3 g oil.
NMR (CDC13): 7.5-7.0 (m, 4H), 4.69 (d~d, 2H), 4.S0 (s, lH), 4.40 (d, lH), 3.92 (dd, lH), 3.61 (d, lHj, 3.20 (d, lH), 1.2-2.0 (m), 0.80 (m).
MS ~CI): 324 (M~), 342.

Step C: (~)-eso,e~o,eso-5-~1-ethyl-1-metho~y-~ propyl)-3 ( ( 2 - f 1 uo rophenyl)methosy~-- 2-metho~y-7-osabicyclo[2.2.1]heptane To 1.3 g (9.0 mmol~ of (+)-e~o,eso,eso-~,-diethyl-6-[(2-fluorophenyl)me~hosy~-5-hydrosy-7-' ' :
.

. . ~

W O 91/03464 2 0 6 ~ 3 3 7 PC~r/~lS90/049;3 -~-o~abicyclo[2.2.1~e~ane-2--methanol in dimethyl-formamide was added exces~ sodiùm hydride and methyliodide. The reaction mi~ture was stirred at 70C for 12 hours. Following aqueous workup, flash chromatography yielded 0025 9 oil.
NMR (CDC13): 7.6-7.~ (m, 4H), 4.71 (brs, 2H), 4.45 (s~d, 2H), 3.66 ~d, lH), 3.52 (d, lH), 3.52 (d, lH), 3.42 ts, 3H), 3.15 (s, 3H), 1.8-1.2 (m), O.B0 (m, 6H).
MS (CI): 353 (M~l), 370, 33a.

Tables 1-5 present esamples of species of the present invention. It is understood that these enumerated e~amples are merely representative of the range of species contemplated by the present invention. The notation ~Ph~ connotes a phenyl group. Compounds in Tables 10-15 have the WCH20 group ~Yn with respect to the 02ygen-containing bridge. The endo/e~o notation refers to the configuration of the C(R3)~R4)oR5 group. The indicated ratios (TablelO) refer to cases where the compounds of invention (I) are formed in an inseparable mi~ture with compounds of Formula (18).
The ratio is given in the form (I:(18)).

3 o R~ ~/ R~
I~C*O~C~ )OR~ ~C*O~
H 8 -- 8 C( R~) C R~ 0 ~xo - C(~)(R~)OR~ C(R~ )OR~

.~ WO91/0~ ~ ~ ~ PCT/US90/04~53 R, R, WCH21~C( R3) ( R4) OR~ ~2~
~ ~:( ~3) ( R~) OR~

( 1 8 ) : 15 The species of Tables 1-8 correspond to the Formulas I-VIII of the compounds of the present invention. Thus, the first compound identified in 20 Table 1 (with Rl-H; R2~H; R3~CH3CH2; R4~CH3C~2;
R5-CH3; and W~2-FPh) is a species of the compound identified as Formula I.

: 25 : :-;~ 35 . :

~ , ~

.
;:

wo 91/03464 2 0 6~ 3 3 7 PCltUS90/049~3 - `

~: 52 Q~x - ~

X and Y are C(R3)(R4)oR5 (unlefis 6pecified) Rl=R2=H (unle~s 6pecified) ~3 ~4 ~5 Q y CH3CH2 CH3CH2 CH3 CH2( 2-FPh) H
CH3CH2 CH3CH2 CH3 CH2(3-FPh) H
CH3CH2 CH~CH2 CH3 CH2(4-FPh) H
CH3CH2 CH3CH2 CH3 - CH2(2~3-F2ph) H -3CH2 CH3CB2 CH3 CH2(2~4-~2ph) H
CH3CH2~ CH3CH2 CH3 CH2~2~5-F2ph) H
3CH2 CH3CH2 CH3 CH2(2~6-F2Ph) H
3CB2 CH3CH2 c~3 CH2(2-ClPh) H
CH3CH2 CH3CH2 CH3 CH2(3-ClPh) CH3CH2 C~3C~2 CH3 CH2(4-ClPh~ Y
CH3CH2 CH3CH2 CH3 CH2(2,4-C12Ph) H
~H3CH2 CH3CH2 CH3 CH2(2,6-C12Ph) H
CH3CH2 CB3CH2 CH3 CH2(2-~rPh) H
3CH2 C~3CH2 CH3 CH213-~rPh) H

CH3CH2 CB3CH2 CH3 CH2(4-~3rPh) H
3C~2 ~B3CH2 CH3 CH2~2,4-B~zPh) H
CH3C~2 CH3CH2 C~3 CH2~2,6-Br2Ph) H
CH3CH2 CH3CH2 CH3 CH~2-(OCH3)Ph) H
CH3CB2 CH3CB2 CH3 CH2(3-(OCH3)Ph) H
CH3CH2 C~3C~2 CH3 CH2(4-~OCH3)Ph) H
CH3C82 CH3CH2 C~3 C~2(2-(C~3)Ph) H
' .
, . .

:

. ' .

. WO 91 ~0346~ s 1,. PCl /us90io49 ~3 ~4 ~5 Q

CH3CH2 CB3CH2 CB3 CH2(2~3-(CF13)2Ph) H
CH3CH2 CH3CH2 CH3 CH2~2,4-~CH3)2Ph) H
CH3CH2 CH3CH2 CB3 ~82~2,5-~CH3)2Ph) H
CH3CH2 CH3CH2 CH3 CH2(2~6-~cH3)2ph) H
CH3CH2 CH3C~2 CH3 C~2~2-tcH3cH2)ph) H
CH3CH2 CB3CH2 CH3 CH2~4-~CH3CH2)Ph) H
C~3CH2 CH3CH2 CH3 CH2~2-~OH)Pb) H
CH3CH2 CH3CH2 CH3 CH2t2-~CN ? Ph) H
CH3CH2 CH3CH2 CH3 CH2~4-(CN)Ph) H
3CH2 CH3CH2 CH3 CH2~2-tCF3)Ph) H
CH3CH2 CH3CH2 CH3 CH2(4-(CF3)Ph) H
CH3CH2 CH3CH2 CH3 CH2(2-(OCF3)Ph) H
CH3CH2 CH3CH2 CH3 CH2(4-(OCF3)Ph) H
CH3CH2 CH3CH2 CH3 CH2(2-~SCH3)Ph) : H
3CH2 CH3CH2 CH3 CH2(4-(SCH3)Phj ~
CH3CH2 CH3CH2 CH3 CH2~2-~CH2CH~CH)Ph) H
CH3CH2 CH3CH2 CH3 CH2~4-~CH2CH~CH)Ph) H
CH3CH2 CH3CH2 CH3 CH2~2-~HC-C)Ph) H
CH3CH2 CH3CH2 CH3 CH2(4-(HC-C)Ph)~ H
CH3CH2 CH3CH2 CH3 CH2(2-pyridyl) H
CH3CH2 CH3CH2 CH3 CH2~3-pyridyl) H
3 2 3 2 3 CH2(3-fura~yl) H
CH3CH2 CH3CH2 CH3 ~CH2(2-(3-Cl)pyridyl) -H
CH3CH2 CH3C~2 CH3 CH2(3-(2-Cl )pyriayl ) H
CH3CH2 CH3CH2 CH3 CH2(2-(3-Pr)thiophe~yl) H
CH3CH2 C~3C~2 CH3 ~CH2(3-~2-Br)thiopheDyl) H
. : CH3CH2 CH3CH2: CH3 CH2~2-~5-CH3)furaDyl) ~3CH2 CH3CB2 CH3 CH2(2-thiophe~yl) ---.~ H
- 3CH2 CH3CH2 CH3 CH2(3-thiophenyl) H
CH3CH2 CH3CH2 C 3 CH2~2-thi~zolyl) H
3CH2 CH3CH2 CH3 CH2(2-imidazolyl) CH3CH2 C~3CH2 c~3 CH2~2-pyrazoyl) H
CH3C~2 CH3CH2 CH3 CH2~2-or3~olyl) ~ .
:;,~ ' : .

;: :
~:
` .
:. :
-WO 91/03464 2 0 6 5 3 3 7 PCI/VS90/0495~ ' ' ~3 ~4 ~5 Q y CH3CH2 CH3CH2 CH3 CH2(2-iso~az~lyl) H
3CH2 CB3CH2 CH3 CH2(2-pyrrolyl) H
CH3CH2 CH3CH2 CH3 CH2(2-pyrimidinyl) H
CH3CH2 CH3CH2 c~3 CH2(2-pyrazinyl) H
C~3C~2 CH3CH2 CH3 CH2(2-tetrahydropyr~uyl) H
CH3CH2 CH3CH2 c~3 CH2(2-tetr~hydrofur~nyl) H
CH3CH2 CH3C~2 CH3 0-1 H
C~3CH2 CH3CH2 CH3 Q-2 H
CH3CH2 CH3CH2 CH3 Q_3 H
CH3CH2 CH3CH2 CH3 Q_4 H
CH3CH2 CH3CH2 CH3 g-s H
.. 3 2 CH3CH2 CH3 0-6 H
CH3CB2 CH3CH2 CH3 Q_7 H
CB3CH2 CH3C~2 CH3 Q-8 H
CH3CH2 CH3CH2 CH3 o-9 H

CH3CH2 CH3CH2 CH3 Q-ll H

CH3~H2 CH3C~2 CH3 Q-13 H
C83~H2 CH3CH2 CH3 Q-14 H
CH3CH2 CH3CH2 c~3 Q-15 H
CH3CH2 CH3CB2 CH3 CH2(Ph) H
CH3CH2 CH3CH2 CH3CH2 CR2(2-FPh) - CH3CH2 CB3CH2 CH3CH2 CH2(2-ClPh) H
CH3CH2 CH3CH2 CH3CH2 CH2t2-BrPb) 8 CH3CH2 CH3CH2 CH3CH2 CH2(2-tCH3)Ph) H
3CH2 CH3CH2 CH3CH2 . CH2(2-(ocH3)ph) H
3CH2 C~3CH2 C~3CH2 CH2t2-(CN)Ph) H
3CH2 C~3CR2 CH3CH2 :CH2(2-(~F3)Ph) H
3CH2 CH3CH2 CH3CH2 CH2(2-(OCF3)Ph) H
CH3CH2 CH3CH2 CH3CH2 CH2(2-tSCH3)Ph) H
CH3CH2 ~H3CH2 C~3CH2 CH2(2-(SCH3)Ph) H
CH3CH2 CH3CH2 CH3CH2 CH2(2,~-(F)2P~) H

-.
:

:

-`- WO91/~346~ ~$~ ; PCI/US90/04953 ~3 ~34 B5 Q

CH3CH2 C~3C82 CH3CH2 CH2 ( 2, 6- ( Cl ) 2Ph ) H
CH3CH2 Q3CH2 CH3CH2 CH2 ( 2-pyridyl ) H
CH3CH2 C}~3CH2 CH3CH2 CH2(2-furanyl) H
CH3C~2 CH3C~2 ~B3CH2 CH2(2-tetrahydro~uran) H
CH3C~2 CH3C~2 CH3CH2 CH2(2-tetrahydropyran) H
CH3CH2 C~3CH2 CH3CH2 CH2(2-thiophenyl) 3~H2 CH3~2 Q3CH2 CH2(2-i60~azolyl) H
CH3CH2 CH3CH2 Q3CH2 CH2(2-pyra~inyl) . H
C~3CH2 CH3CH2 CH3CH2 CH2 (Ph) H
CH3CH2 CH3CH2 CH3CH2 Q-l CH3CH2 CH3CH2 CH3CB2 Q_3 El C~33CH2 CH3CH2 CH3CH2 Q-6 H
CH3CH2 CH3CH2 CH3CH2 Q~7. H
CH3C~2 CH3CH2 CH3CH2 Q-15 B
CH3~H2 CH3CH2 CH3CH2CH2 CH2(2-FPh) H
CH3CH2 C~3CH2 CH3CH2CH2 CH2(2-ClPh) . H
CH3CH2 CH3CH2 CH3CH2CH2 CH2(2-~rPh) H
CH3CH2 CH3CH2 CH3CH2CH2 CH2(2-(CH3)Ph) H
CH3CH2 CH3CH2 CH3CH2CH2 CH2(2-(OCH3)Ph) }I
CH3CH2 C~3CH2 CH3CB2CH2 CH2(2-(CN)Ph) H
CH3CH2 CH3CH2 CH3CH2CH2 CH2(2-(CF3~Ph) H
CH3C~2 CH3CH2 CR3CH2CH2 CHz(2-(OCF3)Ph) H
CH3CH2 CH3C~2 CH3CH2CH2 ~2(2-(SCH3)Ph) H
CH3CH2 CH3CH2 CH3CH2CH2 CH2(2,6-~F)zPh) CH3CH2 C~3C~2 CH3CH2CH2 CH2(2,6-(C1)2Ph) H
CH3C~2 CB3CH2 CH3CH2C~2 CH2(2-pyridyl) H
CE~3C~2 C~3CH2 CH3CH2CH2 CH2(2-fur~nyl) H
CH3C~2 C}l3CH2 CH3CHZC~12 CH2(2-tètr ~ ydro~uri~n) }I
C~3CH2 CH3C~2 CH3CH2CH2 CH2S2-tetrahydropyra~) . H
3CH2 CH3CH2 CH3CH2C~2 CH2(2-thiopheDyl) H
3CH2 CH3CH2 CH3CH2CN2~ CH2(2-i60~olYl) H
3CH2 CH3CH2 C~3CH2CB2 CH2~2-pyra~i~yl) H
H3CH2 C83C32 C33CH2CH2 CH2(Ph) H

`, ''~ ' : ' ~

WO 91/03464 2 0 6 5 3 3 7 PCr/US90/049;3 ' -~3 B4 B5Q y CH3CH2 CH3CH2 CR3CH2CH2 Q-l H
CH3CH2 CH3CH2 CH3CH2CH2 Q~3 H

C~3CH2 C~3~H2 CH3CH2CH2 0-15 H
3CH2 CH3CH2 CH2CH=CH2 CH2(2-FPh) H
CH3CH2 Q3CH2 CH2CH=CH2 CH2~2-CIPh) H
3CH2 CH3CH2 CH2CH=CH2 CH2(2-~rPh) H
CH3C~2 CH3CH2 CH2CH=CH2 CH2(2-(CH3)Ph) H
CH3CH2 C~3CH2 CH2CH=cH2 CH2(2-(OCH3)Ph) H
3CH2 CH3CH2 CH2CH=cH2 CH2(2-(CN)Ph) H
CH3CH2 CH3CH2 CH2CH=CH2 CH2(2-(CF3)Ph) H
CH3CH2 CH3CH2 CH2CH=CH2 CH2(2-(OCF3)Ph) H
CH3C~2 CH3CH2 CH2CH=CH2 CH2(2-(SCH3)Ph) H
Q 3C~2 CH3CH2 CH2cH=cH2 CH2(2,6-(F)2Ph) . H
CH3CH2 CH3CH2 CH2CH=CH2 CH2(2,6-(C1)2Ph) H
3CH2 CH3CH2 CH2CH=CH2 CH2~2-pyridyl) H
CH3CH2 CH3CH2 CH2CH=CH2 CH2(2-furaDyl) H
CH3CH2 CH3cH2 CH2CH=CH2 CH2(2-tetrahydrofuran) H
CH3CH2 CH3CH2 CH2CH=CH2 CH2(2-tetr~hydropyran) H
CH3CB2 CH3CH2 CH2 Q=CH2 CH2(2-thiophenyl) H
CH3CH2 CB3CH2 CH2CH_CH2 CE~2(2-i60r~2:01yl) H
CH3CH2 CHzcH-cH2 CH2(2-pyraziiyl) H
CH3CH2 CH3CH2 CH2cH=cH2 ~ CB2(Ph) 3CH2 CH3CH2 CH2CH=CH2 ~ H
CH3CH2 ~3 Q2 CH2CH=CH2 :Q-3 ` H
CH3CH2 C~3CH2 CH2CH=CH2 Q-6 H
3CH2 CH3CH2~--C82cH=cH2 0-7 H
C83CH2 CH3CB2 CH2CH=CH2 Q-15 H
3C~2 CH3CH2 CH2C-CH ;CH2t2-FPh) H
~3CH2 CH3CH2 CH2C_CH CH2(2-ClPh) H
CH3C~2 - C~3CH2 CH2C-CH CH2~2-BrPh) H
CH3CH2 CH3CH2 CH2C-CH CH2(2-~cR3)ph) H

. : ~

~~ W O 9~/03464 2 ~ 3 ~ PCT/~'S90/04933 : R3 R4 ~5 Q

CH3CH2 CH3CH2 CH2C-CH CH2(2-(~CH3)Ph) H
CH3CH2 CH3CH2 CH2c-cH CH2(2-(CN)Ph) H
CH3CH2 CH3CH2 CH2C-cH CH2(2-(C~3)Ph) 3CH2 CH3CH2 CH2C-CH CH2(2-(t)CF3)Ph) H
CH3CH2 CH3CH2 CH2C--CH CH2(2-~SCH3)E'h) }~
3CH2 CH3CH2 CH2c-cH CH2(2,6-(F)2Ph) H
CX3CH2 Q3CH2 CH2c-cH CH2(2,6-(C1)2Ph) H
CB3CH2 CH3C~2 CH2c-cH CH2(2-pyridyl) H
CH3CH2 CH3CH2 CH2c-cH CH2(2-pyridyl) H
Q 3CH2 CH3CH2 CH2C_CH CH2(2-furanyl) H
~:CH3CH2 CH3CH2 CH2c-cH CH2(2-tetrahydrofuran) H
H3cHz C~3CH2 CH2c-cH CH~(2-tetr~hydropyr~n) H
CB3tH2 CH3CH2 CH2C_CH CH2(2-thiophenyl) 3CH2 CH3CN2 CH2c-cH C~2(2-i~o~azolyl) H
: 3 2 CH3CH2 CH2c-cH CH2(2-pyrazinyl) 3CH2 CH3CH2 CH2C_CH CH2(Ph) H
CE~3CH2 CH3CH2 CH2C--CH g-l H
CH3 Q2 CH3CH2 CH2C_CH~ 0-3 H
3CH2 CH3CH2 CH2C_CH Q-6 H
CH3CH2~ C~3CH2 CH2C-CH O 7 H
CH3CH2 CH3CH2 CH2C_CH~ - 0-lS
3CH2 CH3CHz CH2Ph : CH2(2-FPh) H
`tH3CH2 CH3CH2 C~2Ph CH2(2-ClPh) H
~CH3CH2 : CH3CH2 CH2Ph CH2(2-BrPh) H
CH3CH2 CH3CH2 CH2P~ .~ CH2(2-(CH3)Ph) H
:~: . 3 2 ~CH3CH2 ~CH2Ph tH2(2-(OCH3)Ph) H
~ CH3CH2 CH3CH2 CH2Ph ~- - CH2(2-(CN)Ph) H
: CH3CH2 CH3CH2 CH2Ph.. : : CHz(2-(CF3)Phj H
- :CH3CH2 CH3CH2 CH2Ph : CH2(2-~OCF3)Phj -CH3CH2 CH3CH2 ~CH2Ph CH2~2-(scH3)ph~ H
- CH3CH2 CH3CH2 CH2Ph CH2(2,6-(F)2Ph) H
3CH2 3 2 2 CH2(2,6-(C1)2Ph) 3CH2 CH3CH2 CH2Ph CH2(2-pyridyl) H
~.
' ' ': ' - , : ' :

.

W 0 91/~3464 2 0 6 5 3 3 7 PCT/~$90/049~3 ~3 ~4 ~5 Q y CH3CX2 CH3CR2 CH2Ph CH2S2-~uraDyl) H
CH3C~2 CH3C~2 CHzPh CH2(2-tetrahydrofura~) H
CH3CH2 C~3CH2 C~2Ph CH2(2-tetrahydropyra~) H
CH3CH2 CH3CH2 CH2Ph. CA2S2-thiopherlyl) X
CH3CH2 CH3CH2 CH2Ph CH2(2-i60razolyl) H
CH3CH2 j eH3cH2 CH2Ph CH2(2-pyrazi~yl) CH3CH2 CH3CH2 CHzPh CH2(Ph) H
CH3CH2 CH3C~2 CH2Ph Q-l H
CH3CH2 CH3CH~ CH2Ph 0-3 CH3CH2 C~3CH2 CH2Ph Q-6 H
CH3CH2 CH3CH2 CH2Ph o_7 H
CH3CH2 CH3CH2 CH2Ph Q-15 H
CH2CH2 C~3CH2CH2OCH3 CH2(2-FPh) H
CH2CH2 CH3CH2CHzOCH3 CH2(2-ClPh) H
CHzCH2 CB3CH2CH2OCH3 CH2~2-BrPh) H
: CH2CH2 CH3CH2CH2ocH3 CH2S2-(CH3)Ph) . H
CH2CH2 CH3CH2CH20CH3 CH2(2-(OCE13)Ph) }i CH2 3 2 2 3 CH2~2-SCN)Ph) H
; CH2CH2 CH3CH2CH2OCH3 CH2S2-SCF3)Ph) H
~: CHzCH2 CH3CH2CH2OCH3 CH2S2-SOCF3)Ph) H
H2CH2 CH3CH2CH2OCH3 CH2S2-(SCH3)Ph) . H
Q2CH2 CH3CH2CH20CH3 CHz(2~6-(F)2Ph3 H
: ~ Cg2CH2 CH3CHz : CH2OCH3 CH2(2~6-(Cl)2Ph) H
CH2CH2 CH3CH2 CH2OC~3 CH2(2-pyridyl) H
CH2CH2 CH3CH2 CHzOCH3 CH2(2-furaDyl) H
2C~2 CH3CH2 ; CHzocH3 C~2(2-teerahydrofuran). H
~ CB2CH2 CH3CH2 CH2OCH3 CH2(2-tetr~hydropyr~) H
;: CH2CB2 C83CH2 CH20CH3 . CB2(2-thiophe~yI) C~ CHz CH3CH2 CH2OCH3 CH2~2-i~o~azolylj H
~- C82CH2 CIi3Q2 CB20CH3 CH2 ( 2-pyr~zinyl ) H
:~ CH2CH2 Q3CH2 CH2OCH3 CH2(Ph) H
!; CB2CHz CH3CH2 CH2OCH3 Q-l H
: CH2CH2 Q3CH2 CH2OCH3 0~3 `'~ ' `WO gl/03464 2 ~ ~ ~ 3 ~ Pcr/~s90/oq9~

. .

CH3CH2CH2 CH3CH2CH2 CH3 Q2(2-FPh) H
CH3CH2CH2 CH3CH2CH2 CH3 CH2(2-ClPh) H
CH3CH2CH2 CH3CH2CH2 CH3 CH2(2-BrPh) H
CH3CH2CH2 CH3CH2CH2 CH3 CH2(2-(CH3)Ph) H
CH3CH2cH2 CH3CH2CH2 CH3 CH2(2-(OCH3)Ph) H
CH3CH2CH2 CH3CH2CH2 CH3 CH2(2-(CN)Ph) H
CH3CH2CH2 CH3CH2CH2 CH3 CH2(2-(cF3~ph) H
CH3CH2CH2 CH3CH2CH2 CH3 CH2(2-tOCF3)Ph) H
CH3CH2CH2 CH3CH2CH2 CH3 CH2(2-~SCH3)Ph) H
CH3CH2CH2 CH3CH2CH2 CH3 CH2~2,6-(F)2Ph) H
CH3CH2CH2 CH3CH2CH2 CH3 CH2(2,6-(Cl)2Ph) H
CH3CH2CH2 CH3CH2CH2 CH3 CH2(2-pyridyl) H
CH3CH2CH2 CH3CH2CH2 C~3 CH2(2-fur~yl) H
3CH2CH2 CH3CH2CH2 CH3 CH2(2-tetrahydrofura~) H
CH3cH2cH2 CH3CH2CH2 C~3 CH2(2-tetrahydropyran) H
CH3cH2cH2 CH3CH2cH2 CH3 CH2~2-thiopheny~) H
CH3CH2CH2 CH3CH2CH2 CH3 CH2(2-ico~azolyl) H
CH~CH2CH2 CH3CH2CH2 CH3 CH2(2-pyr~zinyl) H
CH3CH2CH2 CH3CH2CH2 CH3 CR2(Ph) H
CH3cH2cH2 CH3CH2CH2 CH3 0-1 H

H3CHifH2 CH3CB2CH2 CH3 D-6 H
~3CH2CH2 CH3CH2CH2 ~ CH3 Q_7 H
3 2CH2 C~3CH2CH2 CH3 Q-15 H
H3cH2cH2 CH3CH2CH2 CH3C~2 CH2(Ph) H
3CH2CH2 CB3CH2CH2 CH3CH2 CH2(Ph) H
3CH2CH2 CH3CH2CH2 CH2Ph CH2(Ph) H
~3CH2CH2CH2 CH3CH2CH2CH2 CH3 CH212-FPh) H
:CH3CH2CH2CH2 CH3CH2CH2CH2 C~3 CH2(2-ClPh) CB3CH2cH2cHz CH3CZ2CB2C~2 CH3 CH2(2-BrPh) H

~:
.

. , .
: , . , . .

-W O 9l/03464 2 0 6 S 3 3 7 PCl/l_'S90/049~3 ~4 B5 Q

3CH2CH2C~2 CH3CH2CH2CH2 CH3 C~2(2-(CH3)Ph) H
3CH2CH2CH2 CH3CH2CH2CH2 c~3 CH2(2-(OCH3)ph) H
H2cH2 CH3CH2 Q2CH2 CH3 CH2~2-(CN)Ph) H
C~3CH2CH2CH2 CH3CH2CH2CH2 CH3 ~2~2-~CF3)Ph) H
CH3CH2CH2CH2 CH3CH2CM2CH2 CH3 C~2(2-(OCF3)Ph) H
CH3CH2CH2CH2 CH3C~2CB2CH2 CH3 CH2(2-(SCH3)Ph) H
CH3CH2CH2CH2 C~3CH2CH2CHz CH3 CH2(2,6-(F)2Ph) H
CH3CH2CH2CH2 CH3CH2CH2CH2 CH3 CH2(2,6-(C1)2Ph) .
Q 3CH2CH2CH2 CH3CH2CH2CH2 CH3 CH2(2-pyridyl) H
CH3CH2CH2CH2 CH3CH2CH2CH2 CH3 CH2(2-furanyl) H
CH3CH2CH2CH2 CH3CH2CH2 Q2 C~3 CH2(2-t~trahydrofuran) H
CH3CH2CH2CH2 Q3cH2cH2cH2 CH3 CH2(2-tetr~hydropyran) H
3CH2CH2CH2 C~3CH2CH2CH2 CH3 CH2(2-thiophenyl) H
CH3CH2~H2CH2 CH3CH2CH2CH2 CH3 CH2(2-i60~azolyl) H
CH3CH2C~2CH2 CH3cH2cH2cH2 CH3 CH2(2-pyrazinyl) H
3CH2CH2CH2 CH3CH2CH2CH2 CH3 CH2(Ph) H
CH3cH2c~2cH2 CH3CR2CH2CH2 CH3 Q-ll H
3CH2CH2CH2 CH3cHzcH2cH2 C~3 o_3 H2cH2cH2 CH3CH2CH2CH2 CH3 Q-6 H
CH3c~2cH2cH2 CH3CH2CH2CH2 CH3 ~_7 H
CH3CH2CH2CH2 CH3CH2CH2CH2 C~3 Q-15 H
CH3~H2CH2C~2 CH3CH2CH2CH2 CH3CH2 CH2(Ph) H
CH3 CH3CH2 CH3 CH2~2-FPh) H
CR3 CH3CH2 CH3 CH2(2-ClPh) H
CH3 CH3CH2 C83 CH2(2-(CH3)Ph) H
CH3 CH3CH2 CH3 CH2(2,6-Cl~Ph) H
3 CH3CH2 c~3 CH2(2_C~3ph) CH3 CH3CH2 c~3 CH2~2-tetr~hydropyran) H
CH3 CH3C~2 CR3 CH2(2-pyridyl) H

3 CH3~H2 ~R3 CH2(Ph) H
C~33 C~3CU~ C33 .

~ W O 91/03464 2~ g~ PCT/~'S90/04953 ~3 E~4 B5 Q Y

CH3 C83CH2 C~3 Q_3 ~ H

CH3 CH3CH2 C~3 o_7 H
CH3 CH3CHz C~3 0-15 - H
CH2cH=cH2 CHzCH=cH2 CB3 CH2(2-FPh) H
CH2cH=cH2 CH2cH=cH2 CH3 CH2t2-ClPh) H
CH2cH=cH2 CB2cH~cH2 CH3 CH2(2-(CH3)Ph) H
CH2cH=cH2 CH2cH=cH2 C~3 CH2(2,6-C12Ph) H
: CH2CH=CH2 CH2CH=cH2 CH3 CH2(2-CF3Ph) CH2cH=cH2 CH2cH=cH2 CH3 CH2(2-tetrahydropyran) H
CH2cH=cH2 CH2CH=CH2 CH3 CH2(2-pyridyl) H
CH2cH=cH2 CB2cH=cH2 CH3 CH2(Ph) H
CH2cH=cB2 CH2cH=cH2 CH3 Q-l H
~: CH2cH=cH2 CH2CH=CH2 CH3 Q_3 H
: CH2CH=CH2 CH2cH=cH2 CH3 Q-6 H
CH2CH=CH2 CH2cH=cH2 CH3 o_7 : H
~: CH2CH=CH2 CH2cH=c82 CH3 -Q-15 ~, CH=CH2 CH~CY2 CH3 CH2(2-FPh) H
CH=CH2 CM~CH2 CH3 CH2(2-ClPh) H
: CH=CH2 CB=CH2 CH3 CH2(2-~CH3)Ph) H
CH=CH2 CH=CH2 CH3 C~2(2,6 C12Ph) H
~; CH=CH2 CH=CH2 CH3 CH2~2-c~3ph) :- CH=CH2 CH=CH2 CH3 CH2(2-tetr~hydropjr~n) H
CH=CH2 CH=CH2 ~B3 CH2(2-pyridyl) .
: CH=CH2 CH=CH2 CH3 CH2(Ph) H
CH=CH2 CH=CH2 CB3 Q-l H
~ ~ CH=CH2 CH=CH2 CH ~ 3 H
.~ C~=CH2 CH=CH2 CH3 Q-6 - H

CH=CH2 CH=CH2 CH3 0-15 H
: CH2C-CH CH2C-CH CH3 CH2(2-FPh) H
: CH2C_CH CH2C_CH CH3 ~ CH2(2-ClPh) H
CH2C_cR CH2C_CH C~3 CH2(2-~cH3)ph) H

.

- . ` ' , " " ` ' ' . ' ;, . '" . ' ' ' ' ' , . . .
.

. . .

W O 91/03464 2 0 ~ ~ 3 3 7 PCT/US90/049s~ --- . 62 ~3 ~4 ~5 Q y CH2c-cH CH2C_CH CH3 CH2(2,6-Cl~Ph) H
CH2C_CH CH2c-cH C~3 CH2~2-cF3pb) H
CH2C_CH CH2C_CH CH3 CH2(2-tetr~hydropyran) H
CH C-CH CH2C_CH CH3 CH2(2-pyridyl) H
CH2C_CH CH2C-CH CH3 CH2(Ph) H
CH2c-cH CH C-CH CH3 Q-l 8 CH2C-CH CH2C-CH CH3 o~3 H
CH2c-cH CH2C_CH CH3 0-6 H
CH2c-cH CH2C_CH CH3 Q_7 H

CH20CH3 CH20CH3 CH3 CH2(2-FPh) H
CH20CH3 CH20CH3 CH3 CH2~2-ClPh) CH20CH3 CH20CH3 CH3 CH2(2-(CH3)Ph) H
CH20CH3 CH20CH3 CH3 CH2(2,6-C12Ph) H
20CH3 CH20CH3 CH3 CH2(2-CF3Ph) H
CH20CH3 CH20CB3 CH3 CH2(2-tetrahydropyran) H
CH20CH3 CH20CH3 CH3 CH2(2-pyridyl) H
CH20CH3 CH20CH3 CH3 CH2(Ph) H
CH2ocH3 CH20CH3 CH3 Q-l H
0CH3 CH20CH3 CH3 0_3 H
CH20CH3 CH20CH3 CH3 ~ 6 H
CH20CH3 CH20CH3 CH3 Q_7 H
CH2ocH3 CH20CH3 CH3 Q-15 R
CH3CH2 H CH3 CH2(2-FPh) 3CH2 H CH3 CH2~2-ClPh) H
CH3CH2 H CH3 CB2(2-(CH3)Ph) H
CH3CHz R CH3 CH2(2,5-C12Ph) : H
3CH2 H CH3 C~2t2-CF3P~) : H
C~3CH2 H CH3 CH2~2-tetrahydropyran) B
CH3CH2 ~ CH3 CH2t2-pyridyl) H
CH3CH2 H CH3 CH2~Ph) H
CH3CH2 H CH3 Q-1 . H

CH3CH2 8 ~ CH3 0-3 --`` W0 91/03464 2 ~ 3 7~ Vi PCI /l,'S90/04953 B3 ~4 R5 Q

CH3CB2 C83 o_7 H
~3CH2 N CH3 0-15 H
CH2CH2CB3 H CH3 CH2(2-FPh~ H
CH2CH2CH3 H CH3 CH2(2-ClPh) H
. CH2cH2cg3 B CH3 CH2(2-(CH3)Ph) H
CH2cH2cH3 H CB3 C~2(2~6-cl2ph H
: CH2CH2CH3 H CH3 C82(2-CF3Ph) H
CH2CH2CB3 ~ CH3 CH2(2-tetrahydropyran) H
: CH2CH2C83 H CH3 CH2(2-pyridyl) H
- CH2cH2cH3 H CH3 CH2(Ph) H
:CH2CH2cH3 ~ CH3 Q-l CH2cH2cH3 . H CH3 Q 3 :: CH2CH2CH3 ~ CH3 Q_~ H
: CH2CH2CH3 H CH3 Q-7 H
: CH2CH2C83 H CH H
3CH2CH2CH2 H CH3 CH2(2-FPh) H
CH3CH2CH2CH2 H CH3 ~ CH2(2-ClPh) H
3CH2CH2CH2 H CH3 C82(2-(CH3)Ph) H
~CH3CH2CH2CH2 H CH3 CH2(2,6-C12Ph) H
- CH3CH2CH2CH2 H CH3 CHz(2-CF3Ph) H
3CH2CH2CH2 H CH3 CH2(2-t~trahydropyr~) H
CH3CH2CH2CH2 H : CH3 -CH2(2-pyridyl) H
~ ~CH3CR2CH2CH2 H CH3 CH2(Ph) H
`~;CH3CH2CH2CH2 H CH3 0 1 H
~CB3cH2cH2cH2 C~3 o_3 R
-~. CH3cH2c~2cH2 H: CH3 o-6 H
: CH3CH2CH2CH2 H . CH3 Q-7 H

CH3 CH3 CH3 CH2(2-FPh~
CH3 CH3~ CH~ CH2(2-ClPh) CH3 CH3 CH, CH2(2-(CH3)Ph) ~ H

' ,~ ' .

~VO 91/03464 2 0 6 ~ 3 3 7 PCT/US90/049~3 ; ~

.23 ~4 ~5 Q

C~3 CH3 CH3 CH2(2~6-cl2ph) CH3 C~3 CH3 CH2(2-CF3ph) H
CH3CH3 CH3 CH2(2-tetrah~dropyran) H
C~3C~3 C83 CH2(2~pyridyl) H
CH3CH3 CH3 CH2(Ph) H
CH3C~3 CH3 Q-l H

CH3CH3 CH3 Q_7 H
. CH3 CH3 ~C83 g-15 : ~

B2 R3 ~4 ~5 Q Y
3CH3 H H CH3 CH2(2-FPh) H
3CH3 H H CH3 CH2(2-ClPh) H
CH3CH3 H H CH3 CH2(2-~rPh) K
: : CH3 H H ~; CH3 CH2(2-(CH3)Ph) H
3 3 H: ~ CH3 CH2(2-(OC~3)Ph) H
CH3CH3 H H CH3 CH2(2-(CN)Ph) H
~` CH3~CH3 ~ H H CH3 CH2(2-(CF3)Ph) H
CH3C~3 ~ H ~ CH3 CH2~2-(OC~3)Ph) H
CH3: CH3 H H CH3 C~2(2-(sc~3)ph) H-CH3CH3 H H CH3 CH2(2,6-(F)2Ph) C~3CH3 ~ H~ ~CH3 CH2 (2~ 6-(cl )2ph? H
3CH3 H H CH3 CH2(2-pyridyl) H
CH3CH3 H H C83 CH2~(2-fura~yl) CH3~H3 H :H CH3 CH2(2-tetrahydrofuran) :H
: ~ 3 C83 H H CH3 . C~2(2-tetrahydropyr~n) H
CH3CR3 H H CH3~ CH2(2-ehiophenylj H
CH3CH3 H H : C83 CH2~2-ico~rolyl~ H
3CH3 H CB3 CH2(2-pyra~inyl) H
CH3~ CH3 H H ;CH3 CH2(Ph)~ H

: ~ . .. . :
.
-:

--- wo gl/03464 2 ~ . pcr/~!s9o/o49~3 ~1 ~2 ~3 ~4 R5 Q Y

CH3 CH3 H H CB~ Q-3 H
C~3 CH3 H H CH3 0-6 H
CH3 CH3 H H CH3 Q_7 H
C~3 CH3 ~ H CH3 Q-15 H
CH3 CH3 H H CB3CH2 CH2(2-FPh) B
CH3 CH3 H CH3CH2 CH2~2-ClPh) CH3 CH3 B CH3CH2 CH2(2-(CH3)Ph) H
CH CH CH3CH2 CH2(2~6-F2ph) H
C83 CH3 H CH3CH2 CH2(2-~3rPh) B
CH3 CH3 H CH3CH2 CH2(2,6-C12Ph) H
CH3 CH3 H H CH3C82 CH2( 2-pyridyl ) H
CH3 CR3 H CH3CH2 CH2(Ph) H
CH3 CH3 H H CH3CH2 Q-l H
CH3 CH3 H H CH3CH2 o_3 H

~3 CH3 H C~3CH2 Q-15 H
CH3 CH3 H H CH2CH=CH2 CH2t2-FPh) H
CH3 H H CH2CH=CH2 CH2(2-ClPh) H
CH3 CH3 H R CH2CH=CH2 C~2(2-(CH3)Ph) H
CH3 CH3 H H CH2CH=CH2 ~H2(2~6-C12Ph) H
CH3 CH3 H H C~2CH=CH2 CH2(2-CF3Ph) H
CH3 c~3 H H CH2CH=CH2 CH2(2-tetr~hydropyran) H
C~3 CH3 H H CH2CH=CH2 CH2~2-pyridyl) H
CB3 ~H3 H H CH2CH=CH2 CH?(Ph) H
CH3 CH CH2CH=CH2 Q-l H
CH3 CH3 H H CH2CH=CH2 0-3 CH3 CH3 H H CH2CB=CH2 Q-6 H
CH3 CH3 H H CH2CH=CH2 Q-7 H

CH3 CH3 H H CH2Ph CH2(P~) H
C~3 CH3 H H CH2Ph CH2(2-FPh) WO 91/03464 2 0 ~ ~ 3 3 7 PCl /US9~/049~ -~1 ~2 ~3 ~4 ~5 - Q y C83 CH3 B H CH2Ph CH2(2-(cH3)ph) H
CH~ CH3 H . H CH2Ph CH2(2,6-C12Ph) H
CH3 CH3 H H CH2Ph 0-3 H
CH3 CH3 H H CH2CH-CH(CH3) CH2(Ph) H
3 CH3 H H CH2CH~CB(CH3) CH2(2-FPh) H
CH3 CH3 H H CH2~H=CH(CH3) CH2t2-(CH3)Ph) H
CH3 CH3 H H CH2CH=CH(CH3) CH2t2,6-C12Ph) 3 CH3 H H CH2CH=CH(CH3) 0-3 H
CH3 ~C~3 H H CH20CH3 CH2(Ph) CH3 CH3 H H CH20CH3 CH2(2-FPh) CH3 CH3 H H CH20CH3 CH2(2-(CH3)Ph) H
3 CH3 H H CH20 Q3 CH2(2~6-cl2ph) H
CH3 CH3 H ~ H CH20CH3 0-3 H
CH3 CH3 CH3 CH3 CB3 CH2(Ph) H
3 CH3 CH3 CH3 CH3 CH2(2-FPh) H
3 CH3 CH3 CH3 CH3 CH2(2-(CH3)Ph) H
CH3 CH3 CH3 CH3 CH3 CH2(2,6-C12Ph) H
3 CH3 CH3 CH3 CH3 o-3 H
CH3 CH3 CH3 CH3 CB2CB3 CH2(Ph) CH CH3 CH3 CH3 Q2CH3 CH2(2-FPh) H
CH3 CH3 CH3 ~ :CH3 CH2CH3 CH2(2-(CH3)Ph) CH3 CHj CH3 CH3 CB2CH3 CH2~2,6-C12Ph) CH3 CH3 CH3~ CH3 CH2CH3 0-3 H
CH3 CH3 CH2CH2CH3 CH3 CH3 CH2(Ph) H
~CH3 CH3 CH2CR2CH3 C~3 C~3 CB2~2-FPh) C~3 C~3 CH2CH2CH3~ CH3 CH3 CH2~2-lcH3)ph) H
~C~3 CH3 CH2CH2CH3 C~3 CH3 - CH2(2,6-C12Ph) CH CH3 CH2cH2cH3 CH3 CH3 -3 H
CH2CH3,CH2CH3 H H CH3 CH2~Ph) ~
CH2CH3 CH2CH3 H ~ CH3 CH2~2-FPh) H
3 CH2C~3 H H CH3 CH2(2-(CH3)Ph) H

C~2CH3 CH2FH3 H H ~C~3 CH2(2,6-C12Ph) H

:
:~ .
....~ ~ .

-` W O 91~03464 2 ~ ~ 3 3 ~ 7~ ~: PCT/~IS9O/0495~

Bl B2 ~3 ~4 B Q Y

3 C~2CH3 ~ CH3 Q-3 H
2CH3 CH2CH3 ~ CH2C~3 CH2tPh) H
CH2CH3 CH2CH3 H CH2C~3 CH2(2-FPh) H
CH2CH3 CH2CH3 H C~2C~3 CH2(2-(CH3)Ph) H
~2CH3 CH2CH3 H CH2CH3 CH2t2~6~cl2p~) ~
CH2CH3 CH2CH3 H H CHZcH3 o-3 H
CH2CH3 CH2CH3 H H CH2CH=CH2 CH2(Ph) H
CH2CH3 CB2CH3 H . H CH2CH=CH2 CH2tZ-FPh) H
CH2CH3 CH2CH3 H H CH2CH=CH2 CH2(2-(CH3)Ph) H
CH2CH3 CH2CH3 H H CH2CH=CH2 CH2(2,6-C12Ph) 2CH3 CH2CH3 H H CH2CH~CH2 Q-3 H
CH2CH3 CH2CH3 CH3 CB3 CH3 CH2(Ph) H
CH2CH3 CB2CH3 CH3 CH3 CH3 CH2(2-FPh) H
CH2CH3 C82CH3 CH3 CH3 CH3 CH2(2-tCH3jPh) H
CH2CH~ CH2CH3 CH3 CH3 ` CH3 CH2(2,6-C12Ph) H

~2CH3 CH2C83 CH2CH2CN3 CH~CH2CB3 CH3 CH2(Ph) H
CH2CH3 CH2CH3 CH2CH2CH3 CH2CH2C~3 CH3 CB2(2-FPh) H
CH2CH3 CH2CH3 CH2CH2CH3 CH2CH2CH3 CH3 CH2(2-(CH3)Ph) B
CH2CH3 CH2CH3 CH2CH2CH3 CH2CH2CH3 CH3 CH2(2,6-C12Ph) H
CH2CH3 CH2CH3 CH2CH2CH3 C~2C~2CH3 CH3 Q H
CH=CH2 CH2CH3 CH2CH3 CH3 CH2~Ph) H
- CH=CH2 CH2C~3 CH2CH3 CH3 CR2(2-FP~) H
H CH=CH2 CH2CR3 CH2CH3 CH3 CH2(2-(cH3)ph) H
N2~ CH2CH3 CH2CH3 CH3 CH2(2,6-C12Ph) H
H. . CH=CH2 CH2CH3 C~ZcH3 CH3 Q-3 H
HC_CH CH2CH3 CH2CH3 CH3 CH2~Ph) H
HC-CH . CH2CH3 CH2CH3 - CH3 CH2~2-FPh~ H
RC-CH. . CH2CH3 CH2CH3 CH3 CH2~2-~CH3)Ph) H
H C-CH CH2CH3 CH~CH3CH3 CH2(2,6-C12Ph) H
H C_CH CH2CH3 CH2CH3CH3 Q_3 H
~ Ph CH2C~3 C~2CH3C~3 CH2(Ph) H
.

,., ., , ~ :
' .

WO 91/03464 2 0 ~ ~ 3 3 7 PCI/~'S90/049~3 ~1 ~2 ~3 ~4 B5 Q Y

H Ph CH2CH3 CH2CH3 CH3 CH2(2-FPh) H
H Ph CH2CH3 CH2CH3 CH3 CH2(2-(cH3)ph) H
H Ph CHzCH3 C~2CH3 CH3 CH2(2~6-cl2ph) H
H Ph CH2CH3 CH2C~3 C~3 Q_3 H
H CH2OCH3 CH2CH3 CH2CH3 CH3 CH2(Ph) H-H CH20CH3 CH2CH3 ~HzCH3 CH3 CH2(2-FPh) H
~ CH20CH3 CH2CH3 CH2CH3 CH3 CH2(2-(CH3)Ph) H
H ~H20CH3 C~2CH3 CH2CH3 CH3 CH2(2~6-cl2ph) H
H CH2OCH3 CH2CH3 CH2CH3 CH3 o_3 H
H H CH2CH2CH3 CH2CH2CH3 CH2(2(cH3)ph CH2(2-(cH3)pA) H
H H CH2CHzCH3 CHzCH2CH3 (2-FPh) CB2( -FPh) H
CH3 CH3 H , H CH3 CH2(2-FPh) H
CH3 CH3 H H CH3 CH2(2-ClPh) H
CH3 CH3 H H CH3 CH2(2-BrPh) H
CH3 CH3 H H CH3 CH2(2-(CH3)Ph) H
CH3 CH3 H H CH3 CH2(2-(OCH3)Ph)- H
CH3 CH3 H H CH3 CH2(2-~CN)Ph) H
CH3 CH3 H H CH3 CH2(2-(CF3)Ph) H
CH3 CH3 H H CH3 C~2(2-~OCF3)Ph) X
CB3 CH3 H H CH3 CH2~2-~SCH3)Ph) CH3 CH3 H H CH3 CH2~2,6-~F)2PA) H
CH CH H H
3 3 CH3 CHz(2~6-(cl)2ph) H
CH3 CH3 H H CH3 CH2~2-pyridyl) H
CH3 CH3 H H CX3 CH2~2-furanyl) H
CH3 CH3 H H CH3 CH2(2-tetrahydrofur~n) H
CH3 CH3 H ~ CH3 CH2(2-tetrahydropyra~) H
CH3 CH3 H H CH3 CH2(2-th10pheDylj H
CH3 CH3 H H C~3 CH2(2-ioo~azolyi) H
CH3 CH3 H H CH3 CH2(2-pyraziDyl) H .
CH3 CH3 H H CH3 CH2(Ph) .
.

.
`: ~ , .

~ :' ; '; ~ . ', .

W O 91/03464 2 ~ PCT/USgO/04953 8~ 32 33 24 j35 CH3 CH3 H H CH3 Q-l H
CH3 CH3 H H CH3 0~3 H

CR3 CH3 H H CH3 Q_7 H
3 C~3 H H CH3 Q-15 H
C83 CH3 H H CH3CHz CH2(2-FPh) H
3 CH3 H H CH3CH2 CH2(2-ClPh) CH3 CH3 H H CH3CH2 CH2t2-(cH3)ph~ H
CH3 CH3 H CH3CH2 CH2(2~6-F2ph) H
3 CH3 H H CH3CH2 CH2(2-~rPh) H
CH3 CH3 H - CH3CH2 CH2(2~6-C12Ph) H
CH3 CH3 H H CH3CH2. CH2(2-pyridyl) H
CH3 CH3 H H CH3 CH2 CH2(Ph) CH3 CH3 H H CH3CH2 Q-l H
3 CH3 H H CH3CH2 0_3 H

CH3 CH3 H H CH3CH2 I Q_7 H

CH3 CH3 H H CH2CH=CH2 CH2(2-FPh) :H
CH3 CH3 H H CH2CH=CH2 CH2(2-ClPh) ~ H
CH3 CH3 H - H CH2CHeCH2 CH2(2-(CH3~ Phj H
3 H H CH2CH-CH2 CH2(2,6-C12Ph) B
CH3 CH3 H H CH2CH-CH2 CH2(2-CF3Ph) H
CH3 CH3 H H CH2CB=CH2 CH2(2-tetr~hydropyrAn) H
CH3 CH3 H ~: H ~ CH2CH=CH2~ CH2( 2-pyridyl) H
CH3~ CH3 H . H CHzCH=CH2 CH2(Ph) H
Q3 CH3 H H CH2CH=CH~ 0-1 CH3 CH3 H H CH2CH=CH, 0-3 H
CH3 CH3 H H CH2CH-CH~ 0-6 H
CH3 CH3 H H CH2cH=cH~ Q~7 CH3 CH3 H H CH2cH=cH2 Q-15 H

:~

~'' ~.
:

, , WO 91/03464 2 0 6 ~ 3 3 7 PCl /~,'S90/049~3 ~1 ~2 ~3 R ~5 Q y CH3 CH3 H H C~2Ph CH2~Ph) H
CH3 CH3 H H CH2Ph CH2~2-FPh) H
CH3 CH3 H H CH2Ph CH2~2-~CH3)Ph) HCH3 CH3 H H CH2Ph CH2t2.6-C12Ph) HCH3 CH3 H H CH2Ph o-3 H
CH3 CH3 H H CH2CH=CH~CH3) CH2(Ph) H
CH3 CH3 `H H CH2CH=CH(CH3) CH2~2-FPh) H
CH3 CH3 H H CH2CH=CH(CH3) CH2~2-~CH3)Ph) HCH3 CH3 H H CH2CH=CH(CH3) CH2~2,6-C12Ph) HCH3 CH3 H H CH2CH=CH~CH3) o-3 H
CH3 CH3 H H CH20CH3 CH2~Ph) H
C~3 CH3 H H CH20CH3 CHz~2-FPh) H
CH3 CH3 H H CH20CK3 CH2~2-(CH3)Ph) H
CH3 CH3 H ; CH20CH3 CH2~2,6-C12Ph) H

, ~ . . . : . :
::' ':~ ~ ~ ' : ~ .
~ ~ -:
:

~: .

W O 91/03464 2 ~ PCT/~'S90/049 ~1 ~2 ~3 ~4 ~5 W

3 CH3 H H CH2OCH3Q_3 H
CH3 CH3 CH3 CH3CH2~Ph) H
3CH3 CH3 CH3 CH3 CH2(2-FPh) H
~: CH CH3 CH3 CH3 CH3 CH2(2-(CH3)Ph) H
3CH3 CH3 CH3 CH3 CH2(2,6-C12Ph) H
~ 3CH3 CH3 CH3 CH3 0-3 H
: CH3 CH3 CH3 CH3 CH2CH3 CH2(Ph) H
CH3 CH3 CH3 CH3 C~2CH3 CH2(2-FPh) H
: CH3 CH3 CH3 CH3 CH2CH3 CH2(2-~cH3)ph) H
` CH3 CH3 CH3 CH2~2,6-C12Ph) H

3 CH3 CH2CH2CH3 CH3 CH3 CH2(Ph) H
CH3 CH3 CH2CH2cH3 CH3 CH3 CH2(2-FPh) H
CH3 CH3 CH;.H2CH3 CH3 C~3 CH2~2-(CH3)Phj H
CH3 CH3. CH2CH2CH3 CH3 CH3 CH2(2,6-C12Ph) H
:~ CH3 CH3 2CH2CH3 CH3 CH3 o-3 H
CH2CH3 CH2CH3 H H CH3 CH2(Ph) H
CH2CH3 CH2CH3 H H CH3 CH2(2-FPh) B
CH2CH3 CH2CH3 H H CH3 ~H2(2-(cH3~ph) CH2CH3 CH2CH3 H H CH3 CH2(2,6-C12Ph) H
CH2CB3 CH2CH3 H: H CH3 Q_3 H
2CH3 CH2CH3 :H CH2CH3 CH2(Ph) :CH2CH3 CH2H3 H H CH2CH3 ~ CH2(2-FPh) H
Q2CH3 CH2CH3 H H -CH2CH3 -CHz(2-(CH3)Ph) H
2CH3 CH2cH3 H H . :CH2CH3 CH2(2,6-C12Ph) H
* CH3 CH2C~3 H H .CH2CH3 o-3 H
CH2CH3 CH2CH3 H H CH2cH=cH2 CH2(Ph) H
CH2CH3 CH2CH3 H : H CB2cH=cH2 CH2(2-FPh) H
2C~3 CH2CH3 H H CH2cH=cH2 C~2(2-(CH3)Ph) H
CH2CH3 CH2CH3 H H CH2cH=cH2 CH2(2,6-C12Ph) H
2CH3 C~2CH3 H ~ H CH2CH~CR2 Q-3 H
~:CH2CH3 CH2CH3 CH3 CH3 CH3 CH2(Ph) H

`'"'~
.

, ~ ,....

WO91/03464 2065337 PCT/i'590/049~3 ~-~1 ~2 ~3 R4 ~5 ~ ~

CH,CH3 CB2CH3 CH3 CH3 CH3 CH2(2-FPh) H
CH2CH3 CH2CH3 CH3 CH3 CH3 CH2(2-(CH3)Ph) H
CH2CH3 CH2CH3 CH3 C~3 C~3 CH2(2,6-C12Ph) H
CH2CH3 C~2CH3 C~3 CH3 C H
CH2CH3 CH2CH3CH2CH2CH3 CH2CH2CH3 CH3 CH2(Ph) H
CH2CH3 CHzCH3C~2CH2CH3 CH2CH2CH3 CH3 CH2(2-FPh) H
CB2CH3 CH2CH3CH2CH2CH3 CH2CH2CH3 CH3 CH2(2-(cH3)ph) H
C~2CH3 CH2CH3CH2CH2CH3 CH2CH2CH3 CH3 CH2t2,6-C12Ph) H

: H CH=CH2 C~2CH3 CH2CH3 CH3 CH2(Ph) H
H CH=CH2 CH2C~3 CH2CH3 CB3 CH2(2-FPh) H
H CH=CH2 CH2CH3 CH2CH3 C~3 CH2(2-(CH3)Ph) H
H CH= Q 2CH2CH3 CH2CH3 CH3 CH2(2,6-C12Ph) H
H CH=CH2 CH2CH3 CH2CH3 CH3 o-3 H
H C_CHCH2CH3CH2CH3 CH3 CH2(Ph) H C-CHCH2CH3CH2CH3 CH3 CH2(2-FPh~ H
H C_CHCH2CH3CH2CH3 CH3 CHz(2-(CH3)Ph) H C-CHCH2CH3CH2CH3 C~3 CH2(2~6-cl2ph) H
H C_CHCH2CH3CH2CH3 CH3 o-3 H
H PhCH2CH3CH2CH3 CH3 ~ CH2(Ph) H
PhCBZcH3CH2CH3 CH3 CH2(2-FPh) H
H PhCH2CH3CB2C~3 C~3 CH2(2-(cH3)ph) H
H PhC~2CH3CH2CH3 CH3 CH2(2,6-C12Ph) B
H PhCH2CH3 2CB3 CH3 o-3 ~ I
H ~3~ 2 3CH2C~3 CH3 CH2(Ph) H
CH2C~3 C~2CH3 CRZcH3 C~3 CH2(2-FPh) C~20CB3 CH2CH3 CH2CH3 CH3 CH2(2-~CH~)Ph) H
H CH20CH3 CH2CR3 C~2C~3 . 3 CH2(2,6-C12Ph) H
H CH20CH3 CH2CH3 CH2C~3 CH3 0-3 H
H H CH2cH2cH3 C~2CH2CH3 CH2(Z~CH3)Ph CH2(2-(cH3)ph) H
H H CH2CH2CH3 CH2cH2cH3 ~2-FPh) Q 2(2-FPh) H

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:. W O 91/034~4 2 ~ ~ ~ 3 ~ ,7 ,~ ~ . pCT/~'S90/04953 ~1 ~2 ~3 . ~4 R5 Q

H H CH2C~3CH2CH3CH3 CH2(2-FPh) H . H CH2CH3CH2CH3CH3 CH2(2-ClPh) H
H H CH2CH3CH2CH3CH3 CH2~2-~r~h) H
H H C~2CH3CH2CH3CH3 CH2s2-(cH3)ph) H
N H CH2CH3CH2C~3CH3 CH2(2-(OCH3)Ph) H
H H CH2CH3CH2CH3CH3 CH2(2-(CN)Ph) H
H H CH2CH3CH2CH3CH3 CH2(2-(CF3)Ph) H
H H C~2CH3CH2CH3CH3 CH2(2-(OCF3)Ph). H
H H CB2CH3CH2CH3CH3 CH2t2-(SCH3)Ph) H
H H CH2CH3CH2C~3CH3 CH2t2,6-(F)2Ph) H
H H CH2C~3C~2CH3CH3 CH2(2,6-(C1)2Ph) H
H H CH2CH3CH2CH3CH3 CH2(2-pyridyl) H
H H CH2CH3C~2CH3CH3 CH2(2-furanyl) H
H H CH2CH3CH2CH3CH3 CH2t2-tetrahydrofura~) H
H H CH2CH3CH2C~3C~3 CH2(2-tetrahydropyran) H
H H CH2CH3CH2CH3CH3 CH2(2-thiophenyl)H
H:H CH2CH3CH2CH3CH3 CH2(2-i6Orazolyl) H H CH2CH3CH2CH3CH3 CH2(2-pyrazinyl) H
H H CH2CH3 CH2C~3 CH3 CH2(Ph) H
H H CH2CH3 CH2C~3 CH3 Q-l H
H H C~2CH3 CH2CH3 CH3 0-3 H
H: H C~2CH3 CH2CH3 CH3 Q-6 H H CH2CH3 CB2CH3 CH3 Q_7 H
H H CH2CH3CH2C~3 CH3 0-15 H
H H CH2CH3CH2CH3 C~2C~3 CH2(2-FPh) H
H H CH2C~3CH2CH3 CN2CH3 CH2(2-ClPh) H
H CH2CH3CHZcH3 CH2CH3 CH2(2-(cH3)ph) H H CH2CH3CH2CH3 CH2CH3 CH2~2,6-C12Ph) H H CH2CH3CH2CH3 CH2CH3 CH2(2-CF3Ph) H
H11 CH2Q3CH2CH3 C~}12C}~3CH2 ( 2-t~trahydropyran) H
H H CH2CH3~HzCH3 CH2CH3 CH2(2-pyridyl) H
H H CH2CH3:C~2CH3 C~2CH3 CH2(Ph) ``

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~': ~ : :

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,, . ~ '`

' W O 91/03464 2 0 ~ ~ 3 37 PCT/US90/049;~ ~

~1 R2 ~3 R ~5 Q

H N CH2C~3 CH2C~3 CH2CH3 0-1 H
H H C82C~3 C~2CH3 CH2CH3 o H

H H CH2CH3 CH2C~3 CH2CH3 o : H H C~2CH3 CH2CH3 CH2CH3 0-15 H
: H H C~2CH3 C~2CH3 CH2CH=CH2 CH2~2-FPh) H
H H CH2CH3 CH2CH3 CH2CH_CH2 CH2(2-ClPh) H
H H CH2CH3 CH2CH3 CH2CH=cH2 CH2(2-(CH3)Ph) H
H B CH2CH3 CH2CH3 CH2CN=CH2 CH2(2,6 C12 ) H
H H CH2CH3 CH2CH3 CH2cH=cH2 CH2(2-CF3Ph) H
H H CH2CB3 CH2CH3 CH2CH=cH2 CH2(2-tetr~hydropyran) H
H H CH2CH3 CH2CH3 CH2cH=cH2 CN2(2 pyridy ) H
H H CH2CH3 CH2CH3 CH2cH-cH2 CH2(Ph) H
H H CH2CH3 CH2CH3 CH2cH=cH2 Q 1 H H CH2CH3 CH2CH3 CH2cH=cH2 0 3 H
H H CH2CH3 CH2CH3 CH2CH=CH2 Q 6 H
H H CH2CH3 CH2CH3 CH2CH=CH2 ~ 7 H
H H CH2CH3 CH2CH3 CH,2CH=cH2 0 15 H
H H H H CH3 CH2(2-FPh) H
H H H H CH3 CH2(2-ClPh) H
H H H H CH3 CH2~2-(CH3)Ph) H
H H H H CH3 CH2(2,6-C12Ph) H
H H H H CH3 CH2(2-CF3Ph) H
R H H H CH3 CH2(2-tetrAhydropyran) H
H H H H~ CH3 : CH2(2-pyridyl) H
H H H CH3 CH2(Ph) H
H H H R CH3 Q-l H
H H H H CH3 0-3 . .. H

H H H ~ R .CH3 0-7 .
:

' :. :

-` WO 91/~3464 2 ~ 3 3 ~ PCr/~lS90/049~3 - I i ' , ." . ~

~1 ~2 ~3 ~4 ~5 Q

H H H H 2CH3 CH2t2-FPh) H
H H H H CH2CH3 CH2(2-ClPh) H
H H H H C~2CH3 CH2(Z-(CH3)Ph1 W
H ~ H H CHzCH3 CHz(2,6-Cl2Ph) H
H H H H C~2CH3 CB2(2-CF3Ph) H
H ~ H H CH2C~3 CH2(2-tetrahydropyran) H
H H H H CH2CH3 CH2(2-pyridyl) H
H B H H CH2CH3 CH2(Ph) H
H H H H CH2CH3 Q-1 . H
H H H ~ ~H - CH2CH3 Q_3 H

H H H H CH2CH3 Q_7 H

H H CH3 CH3 CH3 CH2(2-FPh) H H CH3 CH3 CH3 CH2(2-ClPh) H
H H CH3 CH3 CH3 CH2(2-(CH3)Ph~ H
H ~ CH3 CH3 CH3~ CH2~2,6-C12Ph) H
H~ H CH3 CH3 CH3 ~ CH2(2-CF3ph) H
H H .CH3~ :CH3: CH3~ CH2(2-tetrahydropyran) H
H. H CH3 CH3 CH3 CH2(2-pyridyl) H
H H CH3 ~CH3 CH3 CH2(Ph) H
H H CH3 CH3 ~H3 Q-l H

H : H ~ CH3 CH3 CH3 Q-6 i H
H CH3 CH3 CH3 0 7 ~ H
H H CH3 CH3CH3 : Q-15 H
CH3 CH3 CH2CH3CH2C~3 - 3 CH2(2-rPh) ~~ H
CH3 CH3 CH2C~3CH2CH3 CH3 CH2(2-ClPh) H
CH3 CB3 C~2CH3C~2CH3 CH3 CH2(2-(CH3)Ph~ c H
CR~ CH3 CH2CH3CH2C~3 C~3 CH2(2,6 C12Ph) X
CH3 CH3 CH2CH3CH2CH3 CH3 CH2(2-CF3Ph) H
CH3 CH3 CH2CH3CH2CH3 CH3 ~ cH2(2-tetrhhydropyran) H
, ::

WO 91~03464 . PCI`/l,'S90/04953 --2~5337 R2 B3 ~4 ~5 Q

CH3 CB3CH2CH3CH2CH3 CH3 CH2(2-pyridyl) H
CH3 CH3CH2CH3CH2CH3 CH3 CH2(Ph) H
~H3 CH3CH2CH3CH2CH3 CH3 Q 1 H
C~3 CH3C~2C~3CH2CH3 CH3 Q_3 H

CH3 CH3CH2CH3CH2CH3 CH3 g-7 H

CH3 CH3 3 3 CH3 CH2(2-FPh) H
CH3 CH3 CH3 CB3 CH3 CH2(2-ClPh) H
CH3 CH3CH3 CH3 CH3 . CH2(2-(CH3)Ph) H
CH3 CH3CH3 CH3 CH3 CH2t2~6-C12Ph) H
CH3 CH3 CH3 CH2(2-CF3Ph) H
CH3 CH3C~3 CH3 CH3 CH2(2-tetrahydropyrar~) H
CH3 CH3CH3 CH3 CH3 CH2(2-pyridyl) H
: CH3 CH3CH3 CH3 CH3 CH2(Ph) H
CH3 CH3 3 ~ 3 c~3 0-1 H
CH3 CH3CH3 CH3 CH3 0~3 H

CH3 CH3 CH3 ~ CH3~ CH 0 7 H
~3 CH3 CH3 CH3 CH3 Q-15 H
CH2CB3 cH2CH3 CH2CH3 CH2CH3 CH3 CHz(2 F ) H
CH2CH3 CH2CH3 CH2CH3 CH2CH3 CH3 CH2(2-ClPh) H
CH2CH3 CH2CH3 CH2CH3~ CH2CH3 CH3- CHz(2-(CH3)Ph) H
2CH3 CH2CH3 CH2CH3 CH2CH3 CH3 CH2(2,6-C12Ph) H
::cH2cH3 CH2CH3 CH2CH3 CH2CH3 CH3 CH2(2 CF3ph) H
CH2CH3 CH2CH3 CH2CH3 CH2C~3 CH3 CH2(2 tetra y py ~CH2~H3 CH2CH3 CH2CH3 CH2CH3 ~CH3 CH2(2-pyridyl) H
ZCH3 CR2CH3 CR2CH3 CH2CH3 CH3 CH2(Ph) : H
CH2C}~3 CH2CH3 CH2CH3 CH2CH3 CH3 9-1 H
~: ,CH2CH3 CH2CH3 CH2CH3 CH2C~3 CH3 0 H
CH2CH3 CH2CH3 C~2C~3 CH2CH3 C~3 0-6 H
~ CH2CH3 CH2CH3 CH2C~3 CH2CH3 CH3 0-7 H
; CH2CH3 CH2CH3 CH2CH3 CH2CH3 CH3 O-lS H
.

;~

, 2~33~
- W O 91/03464 ~ J ~ J~ . PCT/US90/049 2 B3 a4 ~5 Q

CH3 C~3 H H CB3 CH2~Ph) H
CH3 CH3 H H CH3 CH2t2-FPh) H
CH3 CH3 H H C83 CH2(2-(CH3)Ph) H
CB3 CH3 H H C~3 CH2(2,6-C12Ph) H
CH3 C~3 H H CH3 . Q_3 CH3 CH3 3 CH3 3 CH2(Ph) H
CH3 CH3 CH3 CH3 CH3 CH2(2-FPh) H
CH3 CH3 CH3 CH3 CH3 CH2(2-(CH3)Ph) H
CH3 CB3 CH3 CR3 CH3 CH2(2,6-C12Ph) H
CH3 CH3 CH3 CH3 CB3 Q_3 H
CH2CH3 CH2CH3 H H C~3 CH2(Ph) H
CH2CH3 CH2CH3 H H CH3 CH2(2-FPh) H
CH2CH3 CH2CH3 H ~ CH3 CH2(2-(CH3)Ph) CH2CH3 CH2CH3 H H ~H3 C82(2,6-C12Ph) CH2CH3 CH2CH3 H CH3 Q_3 H
CH2CH3 CH2CH3 CH3 CH3 ~3 CH2(Ph) H
CH2CH3 CH2CH3 CH3 CH3 CH3 CH2(2-FPh) H
CH2CN3 CH2CH3 CH3 CH3 CH3 CH2(2-(CH3)Ph) CH2CH3:~ CH2CH3 CH3 CH3 CH3 CH2(2,6-C12Ph) H
CH2CH3 CH2CH3 CH3 ~ CH3 CH3 ~_3 H CH3 CH2CH3 CH2CH3 CH3 CH2(Ph) H
CH3 ~ CH2CH3 CH2CH3 CH3 CH2(2 FPh) H
H CH3 CH2CH3 CHZcH3 C~3: CH2(2-(cH3)ph) H CH3 CH2CH3 . CH2CH3 CH3 CH2(2~6'C12Ph) H
H ~ CH3 CH2CH3 CH2CH3 CH3 g_3 H
- .
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~:' :. - :

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W O 91/03464 2 0 6 ~ 3 3 7 PcT~sgo/b4~3 -~

~1 ~2 ~3 R4 ~5 Q

H H CH2CH2CH3 CH2cH2cH3 CH3 CH2(2,5-(F)2Ph) H
H H CH2CH2CH3 CH2CH2cH3 CH3 CH2~2,4-tF)2Ph) H
H H CH2cH2cH3 CH2CH2CH3 CH3 CH2(4-FPh) H
H H CH2cH2cH3 CH2cH2cH3 CH3 CH2t3-FPh) H
H H CH2cHzcH3 CH2CH2CH3 CH3 CH2(3-ClPh) H
H H CH2CH(CH3)2 CH2CH(CH3)2 CH3 CH2(2,5-(F)2Ph) H
H H CH2CH~CH3)2 C~2CH(CH3)2 C~3 CH2(2,4-(F)2Ph) H
H H CH2CHtCH3)2 CH2CHtCH3)2 CH3 CH2t4-FPh) H H CH2CH(CH3)2 CH2C~(CH3)2 CH3 CH2(3-FPh) H
H H CH2CH(CH3)2 CH2C~(CH3)2 ` CH3 CH2(3-ClPh) H
H H CH2CH3 CH2CH3 C~3 CH2(2,5-(F)2Ph) H
H H C~2CH3 CH2CH3 CH3 CH2(2,4-(F)2Ph) H H CH2CH3 CH2CH3 CH3 CH2(4-FPh) H
CHZcH3 CH2CH3 C~3 CH2(3-FPh) H
H CH2CH3 CH2CH3 CH3 CR2(3-ClPh) H
H H CH=CH2 CH=CH2 CH3 CH2`(2,5-(F)2Ph) H
H H CH=CH2 . CH=CH2 CH3 CH2(2,~-~F)2Ph)- H
H H CH=CH2 CH_CH2 CH3 CH2(4-FPh) H H CH=CH2 CH=CH2 CH3 CH2(3-FPh) H
H H ~ CH=CH2 CH=CH2 CH3 CH2(3-ClPh) H
H H CH3 CH2CH2cH3 CR3 CH2(2~5-(F)2Ph) H
HH~ CH3 CH2CH2cH3 CH3 CH2(2,4-(F)2Ph) H
H H CH3 CH2cR2cH3 C~3 CH2(4 FPh) H
H H CH3 : CH2CR2CR3 CH3 CR2(3-FPh) H~H CH3 CH2cH2cH3 CH3 CH2(3-ClPh) ~ H
H ~ CH3 CH2c~2cH2cH3 CH3 CH2(2,5-(F~2Ph) H
H H CH3 CH2cH2cH2cH3 CR3 CH2(2,4-(F)2Ph) H
H H CH3 CH2cH2cH2cH3 CH3 CB2(4-FPh) H
H R CH3 CH2cH2cH2cH3 CH3 CH2(3-FPh) H
N N CN~ CNZ~N2~N2~N3 ~N3 CN2(3-CIPh) N

:

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:

`` WO 91/03464 2 ~ ~ ~ 3 3~ P~/US90/0495~

~1 ~2 B3 84 R5 Q

H H CH3 CH2CH3 CH3 CH2~2,5-~F)2Ph) H
H H CH3 CH2CH3 C~3 CH2(2,4-(F)2Ph) H
H H CH3 CHZcH3 CH3 CH2(4-rPb) H
H H ~H3 CHZcH3 C~3 CH2(3-FPh) H
~;~ H H CH3 CH2C~3 CH3 CH2(3-ClPh) H

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91/03464 2 0 6 ~ 3 3 7 PCT/~S90/04953 :~'.

TA~

Q'~o I I

X and Y are C(R3)(R4)o~5 (unle~s ~pecified) :81 ~2 ~3=B4B9=R10~5 Q

H H CH2CH3 CH2CH3 CH3 CH2(2-FPh) H
H H CH2C~3 CH2CH3 :C83 CH2(2-ClPh) H
H H CH2C~3 CH2CH3 CH3 CH2(2 i3rPh) H H CH2CH3 ~CH2CH3 CH3 CH2(2-(CH3~Ph) H H CH2CH3 CH2C~3 CH3 CH2(2 (OCH3)Ph) H
H H C~2CH3 CH2C~3 cH3 cH2t2 (CN)Ph) H
H H~ ~ CH2CH3 CH2CH3 CH3 Q2~2 (~CF3)P ) H ~ :
H~ N ~ CH2~H3CH2CH3 CH3 ~CH2(2 (OCF3) ) H
H~ H CH2CH3 ~CH2cH3 ~H;3 CH2~(2-(SCH3~)Ph) H
H ~ CH2CH3 CH2CH3 CH3 CH2(~2~,6-(F)2Ph) H; ~ CH2CH3~ CH2cH3 cH3 c~2(2~6-(cl)2ph) H
H :H CH2CH3~ C~2CH3 . CH3 ~ CH2(2-pyridyl~ H
H~ H CH2CH3 CH2CH3CH3 CH2(:2-fur~nyl) H
H ~ H C~2CH3 CH2CH3~ CH3 ~CH2(2-tetr~hydrofuran) H
H H CH2CH3 CN2CH3CH3 CH2(2-t~trahydropyran) H
H H . CH2C~3 ~ CH2CH3 CH3 CH2(2 thiopheuy ) HH H CH2CH3 CH2CH3 C~3 CH2(2-iso~azoljl) H
H H CH2CH3 CH2CH3 C~3 CH2 ( 2-pyraziDy~
H H CH2CH3 CH2C83 CH3 CH2(Ph) ~ H
: ~' :

' ' ,:

- W O 91/~3464 2~.6~3`~. Pcr/us90/oq953 ~1 ~2 ~3_~4 ~9=~10 ~5 Q y H H CH2C~3 CH2CH3 CH3 0-1. H

H H CH2CH3 CH2C83 CH3. Q-6 B H CH2CH3 CH2CH3 - CH2C~3CH2(2-FPh) H
H H CH2CH3 CH2CH3 CH2CH3CH2(2-ClPh) H
H H CH2CH3 CH2CH3 CH2CH3CH2t2-(CR3)Ph) H
H H CR2CH3 CH2CH3 CH2CH3~2(2~6-C12Ph) H
H~H CH2CH3 CH2CH3 ~ C~2CH3CH2(2-CF3Ph) H
H H CH2CH3 CH2CH3 CH2CH3CH2t2-tetrahydropyran) H
H H CH2CH3 CH2CH3 CH2CH3CH2(2-pyridyl) H
H H C~2CH3 CH2CH3 CHzCH3 CH2tPh) H

H CH2CH3 CH2CH3 CHzCH=CH2 CHzt2-FPh) H
H HCH2CH3 CH2CH3 CH2CH_cH2CH2(2-ClPh) H
H H~CH2CH3 CH2~H3 CH2CH-CH2CH2t2-tCH3)Ph) H
HCH2CH3 CH2CH3 CH2CH=CH2C~2(2~6 C12 ) H
H HCH2CH3 CH2CH3 CH2CH'CH2cH2(2-cF3ph) . ~
H H:~CH2CH3 CB2CH3 CH2CH=CH2CH2t2-tetr~hydropyrarl) H
H H:CH2CH3 CH2CH3 .CH2CH=CH2C~Zt2 pyridyl) H
H HCH2CH3 CH2CH3 CH2CH=CH2CH2tPh) H
H HCH2CH3 CH2CH3 CH2CH=CH2 0-1 ~ H
H HCH2CH3 CH2CH3 CH2CH=CH2 0-3 ~ H
H ~HCH2CH3 CH2CH3 CH2CH=CH2 0-6 . ~ H
H NCH2CH3 CH2CH3 CH2CH-cH2 o_7 - H
H HCH2CH3 CH2CH3 CH2CH=CH2 0-15 H
~ .

.,.. , ~,. .

WO 91/03464 2 0 6 ~ 3 3 7 PCr/US90/049;3 ~1 ~2 ~3=~4 ~9=~10 ~5 Q . y H H H H CH3 CH2t2-FPh) H
H H H H CH3 CH2(2-ClPh) H
H H H H CH3 CH2(2-(C~3)Ph) H
H H H H CH3 CH2(2~6-C12Ph) H
H H H H CH3 CH2t2-CF3Ph) H
H ~ H H CH3 CH2t2-tetrahydropyran) H H H H CH3 CH2(2-pyridyl) H
H ~ H H H 3 CH2(Ph) H
H H H H CH3 Q-l H
H H H H CH3 0-3 H.

H H CH3 CH3 CH3 CH2(2-FPh) H
H H CH3 CH3 CH3 CH2~2-ClPh) H
H CH3 CH3 CH3 CH2(2-tcH3)ph) H
H H CH3 CH3 CH3 CH2(2,6 C12Ph) H
H H CH3 CH3 CH3 CH2(2-cF3ph) H
H H CH3 CH3 CH3 CH2(2-tetrahydropyran) H
~ H CH3 CH3 CH3 CH2(2-pyridyl) H
H CH3 CH3 CH3 CH2(Ph) H
H H CH3 CH3 CH3 Q-l H
H H CH3 CH3 CH3 ~_3 .
H H CH3 CH3 C~3 ~-6 , H
H ; H CH3 3 Q3 0-7 - -Q3 H CH2CH3 CH2CB3 CB3 CH2(2 FPh) H
CH3 H CH2 Q3 , CH2CH3 CH3 - CH2(2 ClPh) H
CH3 H CH2CH3 CH2CH3 CH3 CH2t2-tCH3)Ph) H
CH3 H C~2C~3 CH2CH3 CH3 CH2t2~6-cl2ph) H
CH3 8 CH2CH3 CH2CH3 CH3 CH2t2-CF3Ph) H

.

.
." ' : '. ` .

91/03464 2~ ; PCT/US90/04953 ~1 ~2 ~3=R4~9=~10 ~5 Q y CH3 H CH2CH3C~2CH3 CH3 CH2(2-tetrahydropyran? H
CH3 H CH2CH3CH2CH3 CH3 CH2(2-pyridyl) H
CH3 H CH2CB3CH2CH3 CH3 CH2(Ph) H
CH3 H . CH2CH3 C~2CH3 CH3 Q-l H
CH3 2CB3C~2CH3 CH3 Q_3 H
CH3 CH2CH3CH2CH3 CH3 Q-6 = H

CH2CH3 H CH3 CH3 CH3 CH2(2-FPh) H
CH2CH3 H CH3 CH3 CH3 CH2~2-ClPh) H
CH2CH3 H CH3~ CH3 CH3 CH2(2-(CH3)Ph) H
~H2CH3 H CH3 CH3 CH3 CH2(2,6-C12Pb) H
CH2CH3 H 3 3 CH3 CH2(2_CF3ph) H
CH2CH3 H " CH3 CH3 CH3 CH2(2-tetrabydropyran) H
CH2CH3 H ~H3 CH3 CH3 CH2(2-pyridyl) H
CH2CH3 H CH3 CH3 CH3 CH2(Ph) H

H3 H C~3 CH3 ` H

CH2CH3 H CH3 ~CH3 CH3 0-7 H :
H3 H CH3 C~3 CH3 Q-15 H

. .
' ' ' ~' , ~:~

::

:

WO 91/01464 ~! 0 6 ~ 3 3 7 P~/US90/04953 ^`.

~4 ~1 ~2~3=~4 ~9=~10 ~5 Q ~ y CH3 H H H CH3 Q-l ~
CH3 H H H CH3 Q_3 H
CH3 H H H C~3 0-6 H
CH3 H H H CH3 Q_7 . . H

C~3 H H H CH3 CH2(2-FPh) H
CH3 H H H CH3 CH2(2-ClPh) H
CH3 H H H CH3 CH2(2-(CH3~Ph) H
CH3 H H ~ H CH3 C~2~2~6-cl2ph) H
CH3 H H H CH3 CH2(2-CF3Ph) H
CH3 H H ~ H CH3 CH2(2-tetrahydropyr~) H
CH3 H 8 H c~3 CH2(2-pyridyl) H
CH3 H H : H CH3 CB2(Ph) H

CH3 HCH3 CH3 CH3 Q_3 H

CH3: HCH3 CH3 CH3 Q_7 : H
CH3 H CH3 CH3 : CH3 Q-15 H
CH3 H~ ; CH3 ~ CH3 CH3 CH2~2 rph ) H
CH3 ~H ~ CH3 CH3 CH3 CH2~(2-ClPh) H
~CH3 ~H ~C~3 CH3 CN3 ~2~z~-(cH3)ph) H
CH3 H `CH3 :~ CH3 CH3 : Q 2~(2,;6 C12 ) H
: .~;`CH3: H CH3 CH3 : ~H3 ; CH2(2-CF3ph) H
CH3 H `:` CH3 CH3 ~C~3 Q2(2-t~trahydropyran) H
CH3 ~ 3~ 3 : CH3 ~ CH2~(2-pyridyl) H
CH3 R ~CH3 C83~ CH3 CH2~Ph) R
CH3~ CH3 CH3 ~H3~ CH3 Q-l CR3 CH3 CH3 CH3 : CH3 Q-3 H

CH3 CH3 C~3 CH3 CH3 Q_7 H
CH3 CH3 CH3 ~CH3~ CH3 Q-15 H

!

~ ~ ' .
~:. . ~ ' , ' , ' . , ', .

'.
.
':

~` W O 91/03464 PCT/~'S90io4953 2~$~

~1 ~2 ~3=~4 ~9_~10 ~5 Q y CH3 CH3 CH3 CH3 CH3 CH2(2-FPh) CH3 CH3 CH3 CH3 CB3 CH2t2-ClPh) H
CH3 CH3 CH3 CH3 CH3 C~2t2-tCB3)Ph) H
CH3 CH3 CH3 CH3 CH3 CH2(2 6-C12Ph) H
CH3 CH3 C83 CH3 CH3 CH2(2-CF3Ph) H
CH3 CH3 CH3 CH3 CH3 CH2(2-tetrahydropyr~n) H
CH3 CH3 CH3 C83 CH3 CH2(2-pyridyl) H
: CH3 CH3 C83 CX3 CH3 CH2(Ph) H
:: CH3 H H CH3 CH3 Q-l H
CH3 H H CH3 CH3 Q_3 H
. CH3 H H CH3 CH3 Q-6 H
:~ CH3 H H CH3 CH3 Q H
~: CH3 H H CH3 CH3 0-15 H
: CH3 H H CH3 CH3 C~2t2-FPh) H:
CH3 H H CH3 CH3 CH2~2-ClPh) H
` CH H CH3 CH3 CH2(2-(CH3) Ph ) H
`` CB3 H H CH3 CH3 CH2t2,6-C12Ph) H
:~ ~ CH3 H H CH3 CH3 CH2t2-CF3Ph) H
~: ~ CH3 H H CH3 CH3 CH2(2-tetrahydropyrar.) H3 H H CH3 CH3 CH2(2-pyridyl) H
CH3 H H CH3 CH3 CH2(Ph) H
~ CH3 H H C~?CH3 CH3 Q-l H
: CH3 H H CB2CH3 CH3 Q 3 H
:~ ~ CH3 H H CN2CH3 CH3 Q-6 H
CH3 ~ H CH2CH3 C~3 0-7 H

:- CH3 H H CH2CH3 CH3 CH2t2-FPh) H
:~ CH3 H H CH2CH3 CH3 CH2(2-ClPh?' H
CH3 H H CH2CH3 CH3 C~2(2-(C~3)P~) H
CH3 ~ H CH2CH3 CH3 C~2t2,6-C12Ph) H
:~ CH3 H H CH2CH3 CH3 CH2(2_C~3ph) H
.
,,.,. ~

wo 91/03464 2 0 6 5 3 3 7 - PCr/US90/04953 ~-~6 ~2 B3=Bg B9=~10 ~5 Q Y
CB3 H B C~2CH3 CH3 CB2(2-tetrahydropyran) H
CH3 H H CH2CH3 CH3 CHz(2-pyridyl) H
CH3 H H CH2CH3 CH3 CH2~Ph) H

~H3 H CH3 H CH3 Q-6 H
3 H CH3 H CH3 Q_7 CH3 H CH3 H CH3 CH2~2-FPh) H
: 3 H CH3 H CH3 CH2(2-ClPh) H
CH3 H CH3 : H CH3 CH2~2-~CH3)Ph) 3 CH3 : H CH3 CH2(2,6-C12Ph) H
CH3 H CH3 H CH3 CH2(2-CF3Ph) H
CH3 H CH3 H CH3 CH2~2-tetrahydropyran) H
CH3 H CH3 H CH3 CH2~2-pyridyl) CH3 H CH3 H CH3 CH2~Ph) H
' ~ :
B R2 ~3=~4 ~p9_B10 R~ Q

CH3 H CH2CH3 H CH2CH3 CH2(2-FPh) H
;CB3 H :CH2CH3 ~ H CH2CH3 CH2(2-ClPh) H
CH3 H CH2CH3 H CH2CH3 : CH2(2-~CH3)Ph) H
CH3~ H CH2CH3 H CH2C~3 CH2~2~6-C12Ph) CH H CH2CH3 H C~2CH3 CH2(2-CF3Ph) H
~ :~CH3 H CH2CH3 CH2C~3 ~CH3 CH2(Z-tetrahydropyran) H
-: CH3 ~ H CH2CH3 ~ CH2CH3 C~3 CH2~2-pyridyl) H
3 H CH2~H3 C~2CH3~ ~CH3 CH2(Ph) CH3 H CH2CH3 CH2CH3 C~3 0~3 3 H C~2CH3 ;C~2CH3 C~3 Q-6 H
C~3 H CH2C~3 CH2CH3 : CH3 Q_7 H
3 H CN2CH3 CH2C83 C~3 Q-15 H

`
` ~

.. ..

' WO 91/03464 ~ PCI/l~'S90/04953 2~-~333~

~1 R2 R3=~4 R9=glo R5 CH2CB3 H CH3 CH3 CH3 CH2(2-FPh) H
CH2CH3 H CH3 CH3 CH3 CH2(2-ClPh) H
CH2CH3 H CH3 CH3 CH3 CB2(-2-~CH3~ph) H
2CH3 H CH3 C~3 CH3 CB~(2,6-C12Ph) H
CH2CH3 H CH3 CH3 CH3 Q2(2-cF3Ph) H
CH2CH3 H CH3 C83 CB3 CH2(2-totr~hydropyr~n) H
CH2CH3 B CH3 CH3 CH3 CH2~2-pyridyl) H
CH2CH3 H CH3 CH3 CH3 CH2(Ph) H
CH2 Q3 H CH3 CH3 CH3 Q-l H
C~2CH3 H CH3 CH3 CH3 Q_3 H

2CH3 H CH3 CH3 CH3 Q_7 H
C~2CH3 H CH3 CH3 CH3 O-lS H
CH3 H H H CH3 ~ Q-l : H
CB3 H H H CH3 \ 0_3 H
CH3 H H H CH3 ) Q-6 3 H H H CH3~ Q_i H

CH3 H H H CH3 CH2(2-FPh) H
CH3 H H B CH3 CH2(2-ClPh) H
CH3 - H H H CH3 CH2~2-(CH3)Ph) H
CH3 H H H CH3 CH2(2,6-C12Ph) H
3 H H H CR3 CH2(2_CF3ph) H
3 H H H CB3 CH2(2-tetrahydropyra~) H
CH3: H H H CH3 CH2(2-pyridyl) H
CH3 H H H CH3 CH2~Ph) H
CR3 H CH3 CH3 CH3 ~ 0-1 H
CR3 H CH3 CH3 CH3 g_j H

CH3 H CH3 CR3 CH3 ~ ~_7 H
CU3 H CH3 CH3 CH3 Q-lS H

.

... .. .

W O 91/03464 2 0 6 5 3 3 7 PCT/~S90/0495~ ,^

~1 ~2 B3=~4Bg=~10 ~5 Q

CH3 H CH3 CH3 CH3 CH2(2-FPh) H
CH3 -H CH3 CH3 CH3 CH2(2-ClPh) H
CH3 H CH3 CH3 CH3 CHz(2-(CH3)Ph) . H
3 H CH3 CH3 CH3 CH2(2,6-C12Ph) H
~H3 H CH3 CH3 CH3 CH2~2-CF3Ph) H
CH3 H CH3 CH3 CH3 CH2~2-tetrahydropyran~ H
CH3 H CH3 CH3 CH3 CH2~2-pyridyl) H
CH3 H CH3 3 CH3 CH2~Ph) H

CH3 CH3 CH3 C~3 CH3 Q~3 H

CH3 CH3 CH3 CH3 CH3 Q_7 H

CH3 CH3 CH3 CH3 CH3 CH2~2-FPh) : H
CH3 CH3 CH3 CH3 CH3 CH2~2-ClPh) CH3 CH3 CH3 CH3 CH3 ~CH2~2-(CH3)Ph) H
3 CH3 CH3 C~3 CH3 I CH2~2 6-C12Ph) H
CH3 CH3 CH3 3 3 CH2~2-CF3Ph) CH3 CH3 CH3 CH3 CH3 CH2~2-tetrahydropyraD) H
3 CH3 CB3 CH3 CH3 CH2~2-pyridyl) H
CH CH~3 CH3 CH3 CH3 CH2~Ph) H
CH3 H H CH3 CH3 :0-1 H
CH3 H ~3 3 Q H
CH3 H H ~H3 CH3 0-6 H
CH3 ~ H CH3 CH3 0 7 CH3 ~ H C~3 c~3 Q-15 CH3 H H CH3 CH3 CH2~2-FPh) H
CH3 H H CH3 CH3 CH2~2-ClPh) H
CH3 H H CH3 CH3 CH2~2-tCH3)Ph) CH3 H H CH3 CH3 CH2~2,6-C12Ph) H
~'23 N h Ch3 C23 Ch2~2-CF3Ph) 2 .
.. ' .

:~ , ' , ' ' . , WO 91/034~4 `2 ~ 7 PCT/~'S9oio4g53 Rl ~2 ~3=~ ~9=R10 ~5 Q
: ~
~`` H H CH3 CH3 CH2(2-tetrahydropyran) H
CH3 H H CH3 CH3 CH2(2-pyridyl) - H
CH3 H H CH3 CH3 CH2(Ph) H
CH3 H H CH2CH3 CH3 Q-l H
,- H H CH2CH3 CH3 0-3 H

H H CH2CH3 CH3 Q_7 H
:~ CH3 H H CH2CH3 CH3 Q-15 H
CH3 H H CH2CH3 CH3 CH2(2-FPh) H
CH3 H H CH2CH3 CH3 CH2(2-ClPh) H
CH3 H. H CH2CH3 CH3 CH2(2-(CH3)Ph) : H
CH H H CH2CH3 CH3 CH2~2,6-C12Ph) H
:~ C H H CH2CH3 CH3 CH2(2-CF3Ph) H
CH3 H H CH2CH3 CH3 CH2(2-tetrahydropyran) H
. CH3 H H CH2CH3 CH3 CH2(2-pyridyl) H
. 3 H H CH2CH3 CH3 CH2(Ph) H
CH3 H CH3 H CH3 Q-l ~CH3 H CH3 H CH3 Q~6 H
CH3 H CH3 H CH3 . Q-7 H
~; CH3 H CH3 H CH3 Q-15 H
~: CH3 H C83 H CH3 CH2(2-FPh) H
` ~ CH H CH3 H CH3 CH2(2-ClPh) ~ ~ CH3 ~ H CH3 H CH3 CH2(2-(CH3)Ph) H
:~ CH3 H CH3 H CH3 ~-CH2(2,6_C12ph) H
C~3 H CH3 H CH3 CH2~2-CF3Ph) H
: 3 H C~3 H . CH3 CH2(2-tetrahydropyran) H
` CH X CH3 H CH3- CH2~2-pyridylJ H
C 3 HFH3 ~ K Ci33 CH2(Ph) H

, :

:~ ' , . ~ : ~ : , : : - ; :
:
~ ' ' ~ ' ' ' ,. .

WO 91 /03464 2 0 6 5 3 3 7 PCT/US9OtO49~3 ~ , .`

' ' X
~: Q ~
- R~ R2 o~R9 R' . III
X and Y are C(R3)(R4)oR5 (unless specified) 2~3=R4 R9~ 0~5 Q y : ::
H H CH2CH3 CH2CH3~ CH3 CH2t2-FPh) H
H H C~2C93 CH2CH3 CH3 CH2~2-ClPh) H
H H CH2CH3 CH2CH3 --CH3 CH2(2 BrPh) H
~` H H CH2CH3 CH2C~3 CH3 CH2~2-(CH3~Ph) H
: ~ :H H CH2CH3 C~2CH3 ~CH3 ~CH2(~2-~ocH3)ph) H~
H~ H~ CH2CH3 CH2CH3 CH3 ~ CH2~2 tCN)Ph) H
HB::CH2CH3 CH2 Q3 :CH3 CH2~2 ~CF3) j H
; ; HHCH2CH3; CH2CH3 CH3~ CH2(2-(OCF3)Ph) H
- ~: HH CH2CH3 ~ CH2CH3:C~3 ~ C~2~2-~scH3)ph) HH CH2CH3~ CH2CH3~:CH3~ CH2~2'6 ~)2 ) B
N H CH2CH3~ ~;CH2C;H~3 ~ cH3 ~cH2~2r6-~cl)2ph) H
H H CH2CH3:~ CH2cH3 - CH3 ~:~cH2~(2-pyridyl) H
~ : H ~;CH2CH3~ :~CH2CH3:- CH3 CH2~2-furanyl) H
:~ H H CHz~H3 ~ CH2C~3 CH3 CH2~2-tetrahydrofuran) H
.H: ~H ~CH2CH3 CH2CH3~ CH3 CH2(2-tétrahydropyr~n) H
~ ~ H H CH2CH3 CH2CH3:~C~3 CH2(Z-thiophenyl) H
:~ H H C~2CH3- CH2CH3.--CH3 , CB2~2-i~o~azolyl) ~~H H C~2CH3 ~H2CB3 CH3 CH2(2-pyr~zinyl) H
H H CH2CH3 CH2CH3 CH3 CH2(Ph) H

H H CH2CH3 CH2CH3 CH3 Q-l : H
H H CH2CB3 CH2CH3~ CH3 o_3 H
: .
.

: ~ -. . :
: :: ,` ,: ~ '- ', : , '', ~ '' ~, ": ' ' ` WO 91/03464 ~ '', '`; PCI /l,'S90/04953 ~1 ~2 ~3=B4 ~9=R10 ~5 52 y H H CH2CH3 ~HzCH3 CH3 Q-6 H
H H CH2CH3 CH2CH3 CH3 5?_7 H

H H C~2CH3 CH2CH3 CH2CH3 CH2(2-FPh) H
R H CH2CH3 CH2CH3 CH2CH3 CH2(2-ClPh) H H CH2CH3 CH2CH3 CH2CH3 CH2(2-(CH3)Ph) H
H H CH2CH3 C~zCH3 CHzCH3 CH2(2,6-C12Ph) H H CH2CH3 CH2CH3 CH2CH3 CH2(2-CF3Ph) H
H H CH2CH3 CH2CH3 CH2CH3 CH2(2-tetrahydropyran) H H CH2CH3 CH2CH3 CH2CH3 CH2(2-pyridyl) H
H H CH2CH3 CH2CH3 CH2CH3 CH2(Ph) H
H H CH2CH3 CH2CH3 CH2CH3 Q-l H
H H CH2CH3 CH2CH3 CH2CH3 g H H CHzCH3 CH2CH3 CH2CH3 Q-6 : ~

H H CH~CH3 CH2CH3 CH2CH3 0-15 H H C~2CH3 CHzCH3 CH2CH=CH2 CH2(2-FPh) H H CH2CH3 CH2CH3 CH2CH=CH2 CH2(2-ClPh) H
H H CH2C~3 CH2CH3 CH2CH=CH2 CH2~2 (CH3) ) . H
H H CH2CH3 CH2CH3 CH2CH=CH2 CH2~2,6 C12 H
H H CH2CH3 CH2CH3 CH2CH=CH2 CR2(2_CF3ph) H H CH2CH3 CH2CH3 CH2CH=CHz CH2(2-tetrahydropyr~n) H
H H CH2CH3 CH2C~3 CH2CH=CH2 CHz(2-pyridyl;
H H CHzCH3 CH2CB3 CH2CH=CH2 CH2(Ph) H
H H CH2C~3 CH2CH3 CH2CH=C82 ~ 1 H H CH2CH3 CH2CH3 C82CH=CH2 0 3 H
H H CH2CH3 C~2CH3. C~2CH=CH2 0 6 H
H H CHzCH3 CH2CH3 CH2CH=CH2 0 7 H
H H CH2CI13 CH2CE~3 CEI2CH_CB2 0 15 W O 9l/03464 2 0 6 ~ 3 3 7 PCT/~S90io4953 ~!
~2 .
~1 ~2 ~3=~4 ~9=~10 ~5 Q y H H H -CH3 CH2t2-FPh) . H
H H H CH3 CH2(2-ClPh) H
H H H H ~H3 CH2~2-~CH3)Ph~ ~
H H H H CH3 CH2~2,6-C12Ph) H
H H H H CH3 CH2(2-cF3ph) H
H H H CH3 CH2(2-tetrahydropyrnn) H
~ H H H CH3 CH2(2-pyridyl) H
H H H H CH3 CH2(Ph) . H
H H H H CH3 Q-l H

H H H H CH3 Q-7 ~ H
H H H H c~3 Q-15 H
H H CH3 CH3 CH3 CH2(2-FPb) H
H H CH3 CH3 CH3 CH2(2-ClPh) H
H H CH3 CH3 CH3 C~2(2-tcH3)ph) H
H H CH3 CH3 CH3 CH2(2,6-C12Ph) H ~:
H H .- CH3 CH3 CH3 CH2(2-CF3Ph) H
H CH3 CH3 CH3 CH2(2-tetrahydropyran) H
H H CH3 CH3 ~ ~CH~ CH2(2-pyridyl) H
H ; H CH3 ~ ;CH3 ~CH3 CH2(Ph) H
H: H CH3 CH3 ~CH3 Q 1 H
R H CH3 , CH3 CH3 Q-3 . ~H
H H CH3 CH3 CH3 Q 6 H ~ .
H ~ H CH3 CH3 CH3 Q_7 . H
H 3~ CH3 CH3 Q-15 H
~CH3 H ~ ~CH2CH3 CH2CH3 CH3CH2(2-FPh) ~ . H
CH3 H CH2CH3 CH2CH3 CH3 CH~(2-ClPh) H
CH3 H C~2CH3 CH2CH3 CH3 CH2(2-(CH3)Ph) H
3 CH2CH3 CH2~H3 CH3 CH2(2,6-C12Ph) H
3 CH2CH3~ CH2CH3 CH3CH2(2 CF3Ph) H

~ :
:
: ::

`:~ ' :
.~ , : ~ ',:: - :
::

- ::

, ~ W 0 91/03464 ~ 3~ 7 PCT/US90io49~3 .
~1 R2 ~3=~4 R9=~10 R5 Q

3 CH2CB3 CH2CH3 C~3 CH2~2-tetrahydropy~a~) ~
CH3 H CH2CH3 CH2CH3 CH3 CH2(2-pyridyl) H
CH3 H CH2CH3 CH2CH3 CH3 CH2(Ph) H
H CH2CH3 CH2CH3 ~H3 o 1 H
CX3 H CH2CH3 CH2CH3 C~3 0-3 H
CH3 H CH2CB3 CH2CH3 C~3 0-6 H
CH3 H CH2CH3 CH2CH3 CH3 0_7 H

CH2CH3 H CH2CH3 CH2CH3 CH3 CH2(2-FPh) H
CH2CH3 H CH2CH3 CX2CH3 CH3 CH2(2-ClPh) H
CH2CH3 H CH2CH3 CH2CH3 CH3 CH2(2-(CH3)Ph) H
CH2CH3 H CH2CH3 CH2CH3 CH3 CH2t2,6-C12Ph) H
CH2CH3 H CH2CH3 CH2CB3 CH3 CH2~2-cF3ph) H
CH2CH3 H CH2CB3 CH2CH3 CH3 CH2(2-tetr~hydropyra~) H
CH2CH3 H CH2CH3 CH2CH3 C~3 CH2(2-pyridyl) H
CH2CH3 H CX2CH3 CH2CH3 CH3 CH2~Ph) H
CH2CH3 H CH2CH3 CH2CH3 CH3 Q-l H
CH2CH3 H C82CH3 CH2C~3 C~3 0-3 H

H2cn3 H CH2CH3 CH2CH3 CH3 0-7 H CH3 CH2CH3 :CH2CH3 CH3 CH2(2-FPh) H
B CH3 CH2CH3 CH2CH3 CH3 CH2(2-ClPh) H
B CH3 CH2CH3 CH2CH3 ~3 : CH2~2 ~CH3)Ph3 H CB3 CH2CH3 CH2CH3 C~3 C~2(2~6-C12Ph) H CH3 CHzcx3 CH2CH3 .CH3 C~2(2-cF3ph) H
CH2CH3 CH2CH3 C~3 ~CH2~2-tetr~hydropyr~) H
CH3 CH2CH~ CH2C~3 C~3 CH2(2-pyr~dyl) H
CH3 CH2CH3 CH2CH3 CH3 CH2~Ph) R CH3 C~2CH3 CH2CH3 Q3 g l H
~ : CH3 CHzCH3 C~2CH3 CH3 ~ 3 ~ , ~:.

::
' ~
- .
~ ~ ' ~ , .

W O 91/03464 2 0 6 ~ 3 3 7 PCT/~S90/049~3 ~

Bl ~Z ~3=R4 R9=~10 R5 Q

H CH3 C~2CH3 CH2CH3 CH3 Q-6 H
H CH3 CH2CH3 CH2CH3 CH3 Q_7 H
H CH3 CHzCH3 CH2CH3 CH3 Q-i5 H
H N CH3 H CH3 CH2(2-FPh) H
H H CH3 H C83 CH2(2-ClPh) H
H H CH3 H CH3 CH2(2-(CH3)Ph) H
H H CH3 H CH3 CH2(2,6-C12Ph) H
H CH3 H CH3 CH2(2-CF3Ph) H
H H CH3 H CH3 CH~(2-tetr~hydropyran) H
H H CH3 H CH3 CH2(2-pyridyl) H
H H CH3 H CH3 CH2(Ph) H

H H C~3 H CH3 Q_3 H H C~3 CH3 0-7 CH3 H HCH3 CH3 CH2(2-FPh) H
CH3 H HCH3 CH3 CH2(2-ClPh) H
CH3 H HCH3 CH; CH2(2-(CH3)Ph) H
CH3 H HCH3 CH3 CH2(2,6-C12Ph) CH3 H HCH3 CB3 CH2(2-CF3ph) H
CH3 H HCH3 CH3 CH2(2-t0trnhydropyraD) H
CH3 H HCH3 CH3 CH2(2-pyridyl) B
CH3 H HCH3 ~ CH3 CH2(Ph) CH3 H HCH3 CH3 Q-l - H
CH3 H H: CH3 C~3 g_3 H
CH3 H ~-CH3 - C~3 0-6 H
CB3 ~ .CH3 CH3 :Q-7 - H
CH3 H - HCH3 c~3 Q-15 : . H

~
, ~' ' , . ' . ' ` :

:: , ~-W O 91/03464 '' ~ "i,6'i . PCT/~'S90/04953 ~1 R2 ~3=~4 p9=~10 ~5 n Y
.
CH3 H H H CH3 CH2(2-FPh) H
CH3 H H H CH3 CH2(2-ClPh) H
CH3 H ~ H CH3 CH2(2-(CH3)Ph) H
CH3 H H H CH3 CH2(2,6-C12Ph) H
CH3 H H H CH3 CH2(2-CF3Ph) H
CH3 H H H CH3 CH2(2-tetr~hydropyr~D) H
CH3- H H H CH3 CH2(2~pyridyl) H
CH3 H H CH3 CH2(Ph) H
CH3 H H H CH3 Q-l H

CH3 H H H CH3 Q_7 H
C~3 H H H CH3 Q-15 H
CH3 H CH3 CH3 CH3 CH2(2-FPh) H
CH3 H CH3 CH3 CH3 CH2(2-ClPh) H
CH3 H CH3 CH3 CH3 CH2(2-(CH3)Ph) H
CH3 H CH3 CH3 CH3 CH2(2,6-C12Ph) ' H
CH3 H CH3 CH3 CH3 CH2(2-CF3Ph) H
CH3 H CH3 CH3 CH3 CH2(2-tetr~hydropyran) CH3 H CH3 CH3 CH3 CH2~2-pyridyl) H
CH3 H ~H3 CH3 CH3 CH2(Ph) H
CH3 H CH3 CH3 CH3 Q-l H
C~3 H CH3 CH3 CH3 Q 3 H

CH3 H CH3 CH3 CH3 Q_7 H

~l ~2 B3=R4 E9=~10 ~5 Q X
' ' . .
H H CH2CH3 CH2CH3 CH3 CH2(2-FPh) H

H H CH2CH3 CH2CH3 CH3 CH2(2-ClPh) H

' .' ~' .
,~
,, WO 91/034~4 2 0 6 5 3 3 7 PC'r/l~'S90/04953 ~1 ~2 ~3=R4 ~9=R10 ~5 Q

H H C~2CH3 CH2C~3 CH3 CH2(2-BrPh) H
H H C~2CH3 CHzCH3 CH3 CH2t2-(CH3)Ph) H
H H CH2CH3 CBzCH3 CH3 CH2t2-(OCH3)Ph) H
H H CH2CH3 CH2CH3 CH3 CH2~Z-(CN)Ph) H
H H CH2CH3 C~2CH3 C~3 CH2~2-(cF3)ph) H
CH2CH3 C~2CH3 CH3 CH2~2-~OCF3)Ph) H
H CH2CH3 CHzCH3 CB3 CH2~2-~SCH3)Ph) H
H CB2CH3 CH2CH3 CH3 CH2~2,6-~F)2Ph) H
H CH2CH3 CHzCH3 CH3 CH2~2,6-(Cl)2Ph) H
H CH2CH3 CHzCH3 CH3 CH2~2-pyridyl) H
H H CH2CH3 CH2CH3 CH3 CH2(2-furaDyl) H
H H CH2CH3 CHzCH3 CH3 CH2(2-tetr~hydrofuran) H
H C~2CH3 CH2CH3 C~3 CH2(2-tetrahydropyr~n) H
H H CH2CH3 CH2CH3 CH3 CH2(2-thiophenyl) H
H C~2CH3 CB2CH3 CH3 CH2(2-i~os~olyl) H
H CH2C~3 CH2CH3 CH3 CB2(2-pyra~inyl) H
H CH2C~3 CH2CH3 CH3 CH2(Ph) H H C~2C~3 CH2CH3 CH3 0-1 H
H CH2CH3 C~2CH3 CH3 g 3 H
H CH2CH3 C~2CH3 CH3 Q-6 H CH2CH3 CH2CH3 C~3 0-7 H

H H CH2CH3 CH2CH3 CH2CH3 CH2(2-FPh) H
H H CH2CH3 CH2CH3 CH2CH3 CH2(2~ClPb) H
H H C~2CH3 CH2CH3 CHzCH3 CH2(2-(CH3)Ph) H
H CH2CB3 CH2C~3 CH2CH3 CB2(2,6-C12Ph) H
H CH2CH3 CH2CH3 CH2CH3 CH2(2_CF3ph) H
H CH2CH3 CH2CH3 CH2CH3 CH2(2-tetr~hydropyraa) H
H H CH2CH3 CH2CH3 CH2CH3 CH2(2-pyridyl) H
I H H CH2C~3 CB2CB3 CH2CH3 CH2(Ph) : H H CH2CH3 C~2CH3 CH2CH3 Q-l H
: ~ H CH2~H3 zCH3 C~2CH3 o_ "

:~:
.

` W O ~I/03464 ;~o.~`,.~7 PCT/Us90io40;~

~1 ~2 ~3=~4 ~9=~10 ~5 Q

H HCH2CH3 CH2CH3 C~2CH3 Q-6 H
2 3 CH2CH3 CH2CH3 g_7 H
HCH2CH3 CH2CH3 CH2CH3 0-lS H
H HCH2CH3 CH2CH3 CH2CH=CH2 CH2(2-FPh) H
H HCH2C~3 CH2CH3 CH2CH=CH2 CH2t2-ClPh) HCH2CH3 CH2CH3 CH2CH=CH2 CH2(2-~CH3~Ph) HCH2CH3 CH2CH3 CH2CH=C~2 CH2(2,6-C12Ph) H
HCH2CH3 CH2CH3 CH2CH=CH2 CH2(2-C~3Pb) H
H . HCH2C~3 CH2CH3 CH2CH=CH2 CH2(2-tetrahydropyra~) H
H HCB2CH3 CH2CH3 CH2CH=CH2 CH2~2-pyridyl) H
HCH2CH3 CH2CH3 CH2CH=CH2 CH2~Ph) H
H CH2CH3 CH2CH3 CH2CH=CH2 Q-l H H CH2CH3 CH2CH3 CH2CH=CH2 Q 3 H
H H CH2CH3 CH2CH3 CH2CH=CH2 Q-6 : H
H H CH2CH3 CH2C~3 CH2CH=CH2 Q H
H H CH2CH3 CH2CH3 CH2CH=CH2 Q-15 H
H H H H CH3 CH2~2-FPh) H
H H H H CH3 CH2(2-ClPh) H
H H H H CH3 CH2~2-(cH3)ph) H
H H H H CH3 CH2(2,6-C12Ph) H
H H H ~ H CH3 CH2(2-CF3Ph) H
H H H H CH3 CH2(2-tetr~hydropyra~) H
H H H H CH3 CN2(2-pyridyl) H
H H H H CH3 CH2(Ph) W 0 91/03464 2 0 ~ ~ 3 3 7 PCT/VS90/04953 ?

:- .
~1 ~2 ~3=R4 R9=~10 P5 Q

.
H H CB3 CH3 CH3 CH2(2~FPh) H
H B CB3 CH3 CH3 CH2(2-ClPh) H
H H CH3 CH3 CH3 CH2(2-(CH3)Ph) H
H C~3 CH3 CH3 CH2(2,6-ClzPh) H
H H CH3 CH3 CH3 CH2~2-cF3ph) %
H H CH3 CH3 CH3 CH2~2-tetrahydropyr~n) H
H H CH3 CH3 CH3 CH2(2-pyridyl) H
H H CH3 CH3 CH3 CH2(Ph) H
H H CB3 CH3 CH3 Q-l H
H H CH3 CH3 CH3 Q_3 H H CH3 CH3 CH3 o_7 H

H H CH3 CB3 CH3 - CH2(2,4-FPh) H
H H CB3 CH3 CH3 CH2(2,5-(F)2Ph) H
H H CH3 CH3 CH3 CH2(2,6-~F)2Ph) H
H H CH3 ~ CH3 CH3 CH2(2-BrPh) C83 H H H CH3 CH2(2-FPh) H
CH3 H H H CH3 CH2(2-ClPh) H
CH3 H H H CH3 CH2t2-BrPh) H
CH3 % H H CH3 : CH2l2-(CB3)Ph) H
H3 H H H CH3 CH2(2-(OC~3)Ph) H
CH3- H H H CH3 CH2(2-(CN)Ph) H
H3 ~B H H CH3 CH212-(CF3)Ph) CH3 H ~ H CH3 CH2(2-(OCF3)Ph) H
CH3 H H H CH3 ~ CH2(2-(SCH3)Ph) H
H3: H H H CH3 CH2(2~6-(Fj2ph) CH3 H H H C~3 CH2(2,6-(Cl)2Ph) H
CH3 H H H CH3 CH2(2-pyridyl) H
H H H CH3 CH2(2-fura~yl) H
CH3 H H H CH3 CH2(2-t~trahydrofur~) H

~' .

WO 91/03464 PCl/U~i90/049~3 ~1 ~2 ~3=~4~9=~10 ~5 CH3 H H - H CH3 CH2(2-tetrahydropyran) H
CH3 H B H CH3 CH2(2-thiophenyl) H
CH3 H H H CH3 CH2(2-iso~zolyl) H
CH3 H H H CH3 CH2~2-pyrazi~yl) H
CH3 H H H CH3 CH2(Ph) R
CH3 H H H ~H3 0-1 H
CH3 H H H CH3 Q_3 H
CH3 H H H ~H3 0-6 H

CH3 B H H CH3 CH2(2,4-~F)2Ph) H
CH3 H H: H CH3 CH2(2~5-(F)2ph~ H
CH3 H H H CH3 CH2(2-F,6-ClPh) H
CH3 H H H CH2CR3 CH2~2-FPh) H
CH3 H H H CH2C~3 CH2(2-ClPh) CH3 H H CH2CH3 CH2(2-(CH3)Ph) H
CH3 H H H CH2~H3 CH2(2,6-C12Ph) H
C~3 H H CH2C~3 CH2(2-CF3ph) H
CH3 H HH . CH2CH3 CH2(2-tetrahydropyran) B
CH3 H H H CH2CH3 CH2(2-pyridyl) H
CH3 H H H CH2CH3 CH2(Ph) H
CH3 H H H CH2CH3 Q-l H
C~3 H H - H CH2CH3 Q_3 H
Q3 H H ~ _ CH2CH3 Q-6 H
CH3 H ~ H CH2C~3 0-7 H
CH3 H H H CH2CH3: Q-15 H
-CH3 H H H CH2C~3 CH2(2,6-(F)2Ph) CH3 H H -H ~ - CH2CH=CH2 CH2(2-FPh) - H
CH3 H H :H CH2CH_CH2 CH2(2-ClPh) H -CH3 H H H C~2CH-CH2 CH2(2-(CH3)Ph) H
CH3 H H H CH2CH-CH2 CH2(2,6-C12Ph) H
: , ~' ' ' ~- .

20~337 WO 91/03464 P~/US90/04953 .' `' R1 ~2 ~3=~4 ~9=~10 ~5 Q

CH3 H H H - CH2CH=CH2 CH2(2-CF3ph) H
CH3 H H H CH2CH=CH2 CH2(2-tetrAhydropyraD) H
CH3 H H H CH2CH=CH2 CH2(2-pyridyl) H
CH3 H H H CH2CH=CH2 CH2(Ph) H
CB3 H H H CH2CH=CH2 Q-1 : CH3 H H H CH2CH-CH2 0-7 H
H H H CH2CH=CH2 Q-15 H
C~3CH2 H H H CH3 CH2(2-FPh) H
CH3CH2 H H H CH3 CH2t2-ClPh) H
3~H2 H H H CH3 CH2(2-~cH3)ph) H
CH3CH2 H H H CH3 CH2(2,6-C12Ph) H
CH3C~2 H H H CH3 CH2(2~CF3Ph) H
3CH2 H H H CH3 CH2(2-tetrahydropyran) H
CH3CH2 H H H CH3 CH2(2-pyridyl) H
CH3CH2 B H H CH3 CH2(Ph) H

3CH2 H H C~3 Q_3 H

3CH2: H H H ~H3 Q_7 H
CH3CH2 H H ~ H C~3 Q-15 H
CB3CH2 H H H CH3 CH2(2,6-(F)2Ph) H
CH3~ H CH3 CH3 CH3 CB2(2-FPh) `H
~CH3 ~ H CH3~ C~3 CH3 CH2(2-ClPh) : H
CH H CH3 CH3 CH3 C~2(2-(CH3)Ph) H
~ CH3 ~ CH3 CH3 CH3 CH2(2,6-C12Ph) H

3 H CH3 CH3 CH3 CH2(2_CF3ph) H
C~3 H CH3 CH3 . C~3 CH2~2-tetrahydr~pyran) H
3 H CH CH ~A3 C~2(2-pyridyl) H
3 CH3~ CH3 - C~2(Ph) H

., : .
:: .
. ' .
.

~ 2~$~`371 `
WO 91/03464 Pcr/l,~sso/n4ss3 3=~4 B9_~10 ~S

CH3 ~ C~3 CH3 CH3 Q_3 CH3 ~ CH3 CH3 CH3 Q-6 : H
CH3 H CH3 CH3 CH3 Q~7 CH3 H CH3 CH3 CH3 O-lS
CH3 H CH2CH3 CH2CH3 CH3 CH2(2-~Ph) CH3 H CH2CH3 CH2CH3 CH3 CH2t2-ClPh) H
CB3 H CH2CH3 CH2CH3 CH3 ~2(2-(CH3)Ph) H
~CH3 H CH2CH3 CH2CH3 CH3 CH2(2,6-C12Ph) H
CH3 H CH3 CH3 CH3 CH2(2,6-(F)2Ph) B
CH3 H CH3 : CH3 CH3 CH2(2,4-(F)2Ph) H
CH3 H CH2CH3 C~2CH3 CH3 CH2(2-tetrahydropyran) H
CH3 H CH2CH3 CH2CH3 CH3 CH2(2-pyridyl) H
CH H CH2CH3 CH2CH3 CH3 CH2~Ph) ~ H
CH H C~2CH3 CH2CH3 .H3 Q-l H
CH3 H C82CB~ CH2CH3 CH3 Q_3 H

CK3 H CH2CH3 CH2CH3 CH3 : Q_7 H
3 H CH2CH3~ CH2C~3 C~3 Q-lS H
CH3 H CH2CH3 CH2CH3 CN3 CH2(2,6-(F)2Ph) H
CH2CH3 H CH2CH3 CH2CH3 C83 CH2(2-FPh) H
CH2CH3 H CH2CH3 CH2CH3 ~H3 CH2(2-ClPh) H
CH2CH3 ~ H : CH2CH3 ~C82C~3 CH3 ~ CH2(2-(CH3)Ph) H
CH2CH3~ H CH2CH3 CHzCH3 C83 CH2(2~6-cl2phj CH2CB3~ H ~ ~CH2CH3 CH2CH3 CH3 CH2~2-CF3Ph) H
CH3 B ~CH2C~3 CH2C~3 CH3 CH2(2-tetr~hydr~pyran) H
CH2CH3 H CH2CH3 CH2CH3 ~H3 CH2(2-pyridyl) ~ H
CH3 R CH2CH3~ CH2CH3 ~ C~3 C82(Ph) H
C~2CH3 H C~2CB3 CB2CH3 C~3 Q-l ~ H
2 3 H CH2C~3 CH2CH3 CH3 Q 8 C8zCB3 B CH2CH3~ C82C83 C83 Q-6 : H

' :
, 20~337 W O 91/0346~ PCT/~S~0/04953 ~1 R2 ~3=R4 ~9=R10 R5 o X

CH2CH3 H CH2CH3 CH2CH3 CH3 Q_7 H
CH2CH3 H CH2CH3 CH2CH3 .CH3 Q-15 CH3 CH3 CH2CH3 CH2CH3 CH3 CH2(2 FPh) H
CH3 CH3 CH2CH3 C~2CH3 CH3 CH2~2-ClPh) H
CH3 CH3 CH2CH3 CH2CH3 CH3 C~2~2-(cH3)ph) H
CH3 CH3 CH2CH3 CH2CH3 CH3 CH2(2~5-cl2ph) H
CH3 CH3 CH2CH3 CH2CH3 CH3 CH2(2-CF3Ph) H
CH3 CH3 CH2CH3 CH2CH3 CH3 CH2(2-tetrahydropyran) H
CH3 CH3 CH2CH3 CH2CH3 CH3 CH2(2-pyridyl) H
CH3 CH3 CH2CH3 CH2CH3 CH3 CH2(Ph) HCH3 CH3 CH2CH3 CH2CH3 CH3 Q-l H
H 3 CH2CH3 CH2CH3 CH3 0~3 H

CH3 CH2CH3 CH2CH3 CH3 o_7 CH3 H CH3 H CH3 CH2(2-FPh) H
3 H CH3 H CH3 I CH2(2-ClPh) : H
3 H CH3 H CH3 CH2(2-(CH3)Ph) H
CH H CH3 H CH3 CH2(2,6-C12Ph) H
CH3 ~ CH3 H CH3 ' CH2(2-CF3ph) H
CH3 H CH3 ~ CH3 CH2(2-t~tr~hydropyranj . H
3 H CH3 N CH3 CN2(2-pyridyl) H~
CH3 H CH3 H CH3 CH2(Ph) :. H
CH3 H CH3 H CH3 Q-l H
3 ~ CH3 H Cff3 0 3 H

CH3 H ; CH3 CH3 Q_7 H
CH3 H CH3 B CH3 : - 0-15 . H
3 H CH3 ~ Cff3 CH2(2,6-(F)2Ph) ~ H
CH3 H H CH3 C~3 0-1 : H
3 H 8 CH3 Cff3 Q_3 H

- . : .
.
:, ~ `:, . .

.

'W 0 91/03464 2 0 ~ 3 3 3 ~ PcT/~s90/n49~3 . .
~1 B2 R3=~4 R9=R10 ~5 Q

CH3 H H CH3 CH3 Q_7 - H
CH3 ~ ~ CH3 CH3 Q-15 . H
CH3 H H CH3 CH3 CB2(2-FPh) CH3 H H CH3 CH3 CH2(2-ClPh) CH3 H H CH3 CH3 CHz(2-(C83)Ph) CH3 H H CH3 CH3 CH2(2~6-cl2ph) H
CH3 H H CH3 CH3 CH2(2-CF3Ph) H
CH3 H H CH3 CH3 CH2~2-tetrahydropyra~) H
CH3 H H CH3 CH3 CH2(2-pyridyl) H
CH3 H H CH3 CH3 CH2(Ph) H

3 H ~ CH3 CH3 Q_3 H
CH3 H H CH3 CH3 0-6 : H
CH3 H H CH3 C83 o_7 H

CH3 H H CH2CH3 CH3 CH2(2,6-(F)2Ph) H
CH H H C~2CH3 CH3 CH2(2-FPh) H
CH3 H H CH2CH3 CH3 CH2(2-ClPh) H
CH3 H H CH2C~3 C~3 CH2(2-(CH3)Ph) H
CH H H CH2CH3 CH3 CH2(2,6-C12Ph) H
3 H H CH2CH3 c~3 CH2t2-CF3Ph) H
CH3 H H CH2CH3 C~3 CB2(2-tetr~hydropyrA~) H
3 H H ~ C~2CH3 CH3 CH2(2-pyridyl) :Q3 H H CH2CH3 CHj CH2(Ph~ H
CH3 ~ ~ CH2CH3 CH3 0-1 . H
C83 H H CH2CH3 CB3 Q_3 H
3 H H CH2~H3 C~3 0-6 H
C~3 H h C~zCH3 CH3 Q_7 :. . ' .

206~337 WO 91/0346~ PCI`/US90/049S3 ~1 R2 ~3=~4 ~9=~10 RS Q

CH2C~3 H CH3 CH3 CH3 CH2(2-FPh) . H
2CH3 H CH3 CH3 CH3 CH2~2-ClPh) H
CH2CH3 H CH3 CH3 CH3 CH2~2-tCH3)Ph) H
CH2CH3 H CH3 C~3 CH3 CH2(2,6-C12Ph) 8 CH2CH3 H C~3 CH3 C83 CH2(2-CF3Ph) CH2CH3 H CH3 CH3 CH3 CH2(2-tetrahydropyran) H
CH2CH3 H CH3 CH3 CH3 CH2(2-pyridyl) H
CH2CH3 H CH3 CH3 CH3 CH2tPh) H
:: CH2CH3 H CH3 CH3 CH3 0-1 H
: CH2CH3 H CH3 CH3 CH3 o_3 2CH3 H CH3 CH3 CH3 g_7 H
~ CH2CH3 H CH3 CH3 CH3 0-15 H

: `

., ~'''~ ' ' - --': :

-- ' ' .

- ~ .

~ WO 91/03464 ~'2 ~ ~ 3 ~ ~ 7 PCT/us90io49~3 ~A~L~ 4 R~ X
~ Q ~

IV
:
X , C(R3)(R4)oR5 l R2 ~3 R4_5 Q
~:
- H H CH3CH2 CH3CH2 CH3 CH2(2-FPh) ~H H CH3CH2 CH3CH2 CH3 CH2~2-ClPh) H H CH3CH2 CH3CH2 CH3 CH2(2-BrPh) H H CH3CH2 C~3CH2 CH3 CH~2-tCH3)Ph) H H CH3CH2 CH3C~2 CH3 CB2(22-(OCH3)Ph) H ~ HCH3CH2 ~CH3CH2 CH3~ CH2~2-(cN)phj H HCH3CH2 ~H3CH2 CH3 CH2~2-~CF3)Ph) H H~CH3CH2 CH3CHz C~3 C~2~2-(ocF3) HCH3CH2 CH3CH2 CH3 CH2~2-(SCH3)Ph) H~ H CH3cH2 CH3CH2~ CH3 CH2(2,6 (F)2P 1 HH ~ CH3CH2~ ~C~3C~2 ~CH3 CH2(2,6-(Cl)zPh) H HCH3CH2 CE3CH2 CH3 CH2(2-pyridyl) H~H ~C~3CH2 CH3CH2 C~3 ~ CH2~2-fura~yl) HCH3CH2 ~H3CB2 CH3 ;c~2~2-tètr~hydro~ura~) 3CH2 CH3CH2 CH3 ~ C~2~2-tetrahydropyran) H HCH3CH2 CH3C~2 ~CH3~ CH2~2-thiophe~yl) :~ R HCH3CR2 CH3CH2 CH3 CH2(2-i60~azolyl) H HCH3CH2 CH3CH2 CH3 CH2~2-pyrazinyl) H H CH3CH2 CH3CH2 CH3 CH2(Ph) ' ;
~ ~ ' ~'..,... .. . ~.

W O 9l/03464 PCT/~'S90/049~3 i `

Bl ~2 ~3 ~4 ~5 Q

H H CH3CH2 CH3CH2 CH3 Q-l ~ D r~-- ~U t`~- r~o ~
~ ~3'--2 ~3'~2 ~n3 ~-J
~-. U r o r~
C~2 ~3'n2 H3 H H CH3cH2 CH3CH2 CH3 Q_7 H HCH3CH2 CH3CH2 CH3CH2 CB2(2-FPh) H HCH3CH2 C83CH2 CH3CH2 CH2(2-ClPh) H HCH3CH2 CH3CH2 CH3CH2 CH2(2-(CH3)Ph) H HCH3CH2 CH3C~2 CH3CH2 - CH2(2,6-C12Ph) H HCH3CH2 CH3CH2 CH3CH2 CH2(2-CF3Ph) H HCH3CH2 CH3CH2 CH3CH2 CH2(2-t~trahydropyraD) H HCH3CH2 CH3CH2 CH3CH2 CH2(2-pyridyl) H HCH3CH2 CH3CH2 CR3CH2 CH2(Ph) H H CH3CH2 CH3CH2 CH3CH2 Q-l H H CH3CH2 CH3CH2 CH3~H2 H H CH3~H2 CH3CH2 CH3CH2 Q

B HCH2CH3 CR2CH3 CH2C~=CH2 CH2(2-FPh) HCH2CH3 CH2CH3 CH2CH=CH2 CH2(2-ClPh) H HCH2 Q3 CH2CH3 CH2CHQC~2 CH2(2-(CH3)Ph) HCH2CH3 CH2C~3 CH2CH=CH2 CH2(2,6-C12Ph) H HCH2CH3 CH2CH3 CH2CH-CH2 CH2(2-CF3Ph) H HCH2CH3 CH2CH3 CH2CH=CH2 CY2(2-tetrahydropyra~) H HCH2CH3 CH2CH3 ~H2CH=CH2 CH2(2 pyridyl) H HCH2CH3 CH2CH3~ CH2CHCH2 ~ CH2(Ph) H H CH2CH3 CH2CH3 ~C~2CH=CH2 U-l H HCH2CH3 CH2CH3 CH2CH=CH2 Q~3 H H CH2CH3 C~2CH3 CB2CH=CH2 Q 6 H 2 3 C82CH3 CHzC~=C~2 g-7 B H CH2C~3 C~2C~3 CB2CH_CH2 Q 15 -O91/03464 2a~33.~3~; PCI/llS90/04953 ~1 B2 R3 R ~ Q

H H H H CH3 CH2(2-FPh) H H H H CH3 CH2(2-ClPh) H H B H C~3 CH~(2-(CH3)Ph) H H H CH3 CH2(2,S-Cl2Ph) H H H H CH3 CH2(2-CF3Ph) H H H H CH3 CH2(2-tetrahydropyran) ~ H H H CH3 CH2(2-pyridyl) H H H H CH3 CH2tPh) H H H . H CH3 0-1 H H H ~ H CH3 Q-3 H H H ~ H CH3 0-6 H CH3 CH3 CH3 CH2(2-FPh) H H - CH3 CH3 CH3 CH2(2-ClPh) H H CH3 CH3 CH3 CH2(2-(CH3)Ph) H H CH3~ CH3 CH3 CH2~2,6-C12Ph) H CH3CH3 CH3 CH2~2-CF3Ph) H H :CH3 CH~: CN3 CH2(2-tetrahydropyran) H H CH3 :CH3 ~ CH3 ~2(2-PYridyl)~
H : H CH3 CH3 ; CH3 C~2~Ph) H H CH3 ~CH3~ CH3~ 0-l H ~ H CH3 ~CH3 : CH3~Q-3 H CH3 CH3; CH3 : 0-6 H~ ~H ~ C83 ~C~3 CH3 0_7 H H CH3 :~CH3 ~ CH3 Q-15 CH3 CH3CH2CH3 CH2CH3 CH3 :CH ~2-FPh) - . ~ , ... .
CH3 CH3 CH2CH3 CH2CH3 CH3 CH2(2-ClPh) CH3 CH3 : CH2CH3 CH2CH3 CH3 CH2(Z-~CH3)Ph) ~:~ CH3 CH3 CH2CH3 CH2CH3 CH3: CH2~2~6-cl2ph) ~ : ~ CH3 CB3 CHzCH3 ~H2CN3 CH3 ~ CB2(Z-CF3Ph) `: :

.
:

' W O ~1/03464 2 ~ 6 5 3 3 7 PCT/US90/049;3 Bl ~2 ~3 ~4 ~5 Q

CH3 CH3 CH2CH3 CH2CH3 CH3 CH~(2-tetr~hydropyr~n) C~3 CH3 CH2CH3 CH2CH3 C~3 CH2(2-pyridyl) C~3 CH3 CH2CH3 CH2CH3 CH3 CH2~Ph) CX3 CH3 CH2CH3 CH2C~3 CH3 Q-l CH3 CH3 CH2C~3 CH2CB3 CH3 Q_3 CH3 CH3 CH2CH3 CH2C~3 CH3 Q-6 ~H3 CH3 CH2CH3 CH2CH3 CH3 a-7 CH3 CH3 CH2CH3 CHzCH3 CH3 Q-15 CH2CH3 CH2CH3 C~2C~3 CH2CH3 CH3 CH2(2-FPh) CH2CH3 CH2CH3 CH2CH3 CH2CH3 CH3 CH2(2-ClPh) 2CH3 C~2CH3 CH2CH3 CH2CH3 CH3 CH2(2-(cH3)ph) H2CH3 CHzC~3 CH2CH3 CH2CH3 CH3 CH2(2,6-C12Ph) ~2CX3 CH2C~3 CH2CH3 CH2CH3 CH3 CH2~2-CF3Ph) CH2CH3 CH2CH3 CH2CH3 CH2CH3 CH3 CH2~2 tetra y py 2CH3 CH2CH3 ~H2CH3 CH2CH3 CH3 CH2(2-pyridyl) CH2CH3 CH2C~3 CH2CH3 CH2CH3 CH3 C~2~Ph) CH2CH3 C~2CH3 CH2CH3 CH2CH3 CH3 Q-l CH2CH3 CH2CH3 CH2CH3 CH2CH3 CH3 ~_3 CH2CH3 CR2CH3 CH2CH3 C~2CH3 CH3 Q-15 CH3 CH2CH3~ CH2CH3 ~3 CH2~2-FPh) CH3 H CH2CH3 CH2CH3 CH3 CH2(Z-ClPh) CH3 H CH2CH3 C~2CH3 cg3 CB2(2 (CH3) CH3 CH2CH3 ~2CH3 CH3 CH2(2,6-C12Ph) CB3 H CH2CH3 : C~2CH3 CH3 ~2(2-CF3Ph) CH3 H CH2~H3 CH2CH3 C~3 CH2(2-tetrahydropyran) C~i H c~2cH3 CH2CH3 CH3 C~2(2-pyridyl) CH3 H CH2CH3 CH2CH3 CH3 CH2(Ph) - CH3 2C~3 CB2C~3 CH3 Q-l 2 ~
` `W O 91/03464 PCT/US90/049~3 ~1 ~2 R3 ~4 ~5.Q

CH2CH3 H CH2CH3 CH2CB3 CH3 CH2~2-FPh) CH2CH3 8 CH2CH3 CH2CH3 CH3 CH2(2-ClPh~
CH2CH3 H CH2CH3 CHZcB3 CH3 CH2~2-(CH3)Ph) CH2CH3 H CH2C~3 ~H2C~3 CH3 CH2(2,6-C12Ph) 2CH3 H CB2CH3 CH2CH3 CH3 CH2(2-CF3Ph) C~2CH3 H CH2CH3 CH2CH3 CH3 CH2(2-tetrahydropyra~) 3 H CH2CH3 CH2CH3 CH3 CH2(2-(pyridyl) C82CH3 H CH2CH3 CH2CH3 CH3 CH2(Ph) CH2CH3 H CH2CH3 CH2CH3 CR3 Q-l 2CH3 H C~2CH3 CH2CH3 CH3 0-i5 : ~ `

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H H CH2CH3 CH2CH3 CH3 CH2(2-FPh) : H H CB2CH3 CH2CH3 CH3 CH2(2-ClPh) ~`
H H CH2CH3 CHzC83 CH3: CH2(2_8rph) H H CH2CH3 CH2CH3 C83 C82(2 (CH3) ~: : B H CH2CH3 ;~CH2C83 CH3 C~2~2 (OCH3) H H CH2C83 CH2CH3 CH3~ CH2(2-~CN~Ph) H H CR2C~3 CK2C83 CH3 CB2(2-~CF3)Ph) H H ~CH2~C83 CH2CH3 C83 Q 2(2-(OCF3)Ph) :~ ~ H CH2CB3 ~C82cH3~ CH3 CB2(2-(SCH3)Ph) R ~H CHzCH3 CH2CH3 ~ CH3 CH2(2,6-(r12Ph) : H ~ ~CH2C~H~3 CN2CH3 ~ CH3 CN2~2.6-(Cl)2Ph) H H CB2CH3 CH2 Q3 CH3 CH2~2-pyridyl) H H CB2CH3 CHzCH3 CB3 CHz(2-~ur~nyl) H H CH2CB3 CH2C~3 CH3 CH2(2-tetr~hydrofur~n~
H: CB2C83 CH2CH3 CH3 CH2(2-tetrahy~ropyron) H H CH2CB3 CH2CH3 CH3 CH2(2-thiophenyl) :~ H H C82CH3 C82CH3 CH3 :CH2(2-isor~zolyl) N ~ Ca2CH3 CH2CH3 C~3 Ca2(2-p~razinyl) H a CH2C~3 CN2CH3 CN3 CH2(rh~

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H H CH2C~3 CH2cH3 CH3 Q 1 H H CH2CH3 C~2CH3 C~3 Q-6 H H CH2CH3 ~H2CH3 CH3 Q

H CH2CH3 C~2CH3 CH2CH3 C~2(2-FPh~
H H CH2CH3 CH2CH3 CH2CH3 CH2(2-ClPh) H H CH2CH3 CB2CH3 CHzC~3 CH2(2-~cH3)ph) H H CH2CH3 CH2CH3 CH2C~3 CH2(2,6-C12Ph) H H CH2CH3 C~2CH3 CH2CH3 CH2(2-CF3ph) H H CH2CH3 CH2CH3 CH2CH3 CH2(2-tetrahydropyran) H H CH2CH3 CH2CH3 CH2CH3 CB2(2-pyridyl) H B CH2CH3 CH2CH3 CH2C~3 CH2[Ph) H H CB2CH3 CB2CH3 CH2CH3 Q-l :

H H CH2cH3 CH2CH3 CH2CH3 0-15 H CH2CH3 CH2CH3 CH2CH~CH2 CH2t2-FPh) H H CH2CH3 CH2CH3 CH2CB=CH2 CH2(2-ClPb) H H CH2CH3 CHzCH3 CH2CH=C~2 CH2t2-(CH3)Ph) H H CH2CH3 CH2CH3 CH2CB=CH2 CH2(2,6 C12Ph) H H C~2CH3 CH2CH3 CH2CH=CH2 CH2(2 CF3Ph) H H CH2CH3 CH2CH3 CH2CH=CH2 CH2~2-tetrnhydropyran) H H CH2CH3 CH2CH3 CH2CH=CH2 CB2 ( 2-pyridyi ) H H CH2CH3 CH2CH3 C~2CH=C~2 CB2~Ph) H H CH2CH3 CH2CH3 CH2CH_CH2 Q 1 H H CH2CH3 CH2CH3 CH2CH=CH2 Q 6 ~ H CH2CH3 CH2CH3 CH2CH=CH2 Q 7 H H CH2CH3 CH2CH3 CH2CH-CH2 0 lS

W O 91/034~4 2 0 6 5 3 3 ~ PCTtUS90/049~3 ~--~1 ~2 ~3=B4 R9-~10 ~5 Q

H H H H CH3 CH2(2-FPh) H ~ H H CH3 CB2~2-ClPh) H H H H CH3 CH2(2-~CH3)Ph) H H H H CH3 CH2(2,6-C12Ph) H ~ H H H CH3 CH2(2-CF3Ph) H H H H CH3 CH2~2-t~trahydropyran) H H H H CH3 CH2(2-pyridyl) H H H H CH3 CH2~Ph) H~ H H H CH3 Q-3 H H CH3 C~3 c~3 CH2(2-FPh) H H CH3 CH3 CH3 CH2(2-ClPh) H H CH3 CH3 CH3 CH2~2-~CH3)Ph) H H CH3 CH3 CH3 CH2(2,6-C12Ph) H H CH3 CH3 CH3 CH2(2-cF3ph) H R CH3 CH3 CH3 CH2(2-tetrahydropyran) H H CH3 CH3 CH3 CH2~2-pyridyl) H ~ H CH3 CH3 CH3 CH2(Ph) 8 H CH3 CH3 CH3 Q-l H H CH3 CH3~ CH3 Q_3 H H CH3 CH3 CH3 0-6 - .
H H: CH3 CH3. CH3 Q_7 CH3 H CH2CH3 CH2CH3 C~3 CH2~2 FPh) CH3 H CH2CB3 CH2CH~ CH3 CH2~2-ClPh) ' `
CH3 H CHzCH3 CH2CH3 CH3 CH2(2 (CH3)P~) .
~H3 H ~H2CH3 CH2~H3 CH3 CH2(2,6-C12Rh) Q 3 A z 3 C32C33 C133 C32(2-Cr3rh~

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CH3 H ~ H CH3 Q-1 CH3 H H H C~3 Q_3 H3 H H H CH3 Q_7 CH3 H ~ H CH3 CH2~2-FPh) H3 H H H CH3 CH2(2-ClPh) CH3 H H H CH3 CH2(2-(CH3)Ph) CH3 H H H CH3 CH2(2,6-C12Ph) CH3 H H H C~3 CH2(2_OE3ph) CH3 H H H CH3 CH2(2-tetr~hydropyraD) CH3 H H H CH3 CH2(2-pyridyl) CH3 H H H CH3 CH2(Ph) CH3 H CH3 CH3 CH3 Q_3 CH3 H CH3 C~3 CH3 Q-6 CH3 H CH3 CH3 CH3 Q_7 C~3 H CH3 CH3 CH3 CH2(2-F~h) CH3 H CH3 CH3 CH3 CH2(2-ClPh) CH3 H CH3 CH3 CH3 CH2(2-(CH3)Ph) CH3 H CH3 ~H3 CH3 CH2(2i6-C12~h) ~CH3 H CH3 CH3 CH CH2~2-CF3Ph) CH3 H 3 3 CH3 CH2(2-tetrahydropyran) CH3 H CH3 CH3 CH3 CH2t2-pyridyl) CH3 H CH3 CH3 CH3 CH2(Ph) CH3 CH3 CH3 CH3 CN3 Q-l CH3 CH3 CH3 CH3 CH3 Q_3 CX3 CH3 CH3 ~H3 CH3 Q-6 C~3 CN3 CN3 CH3 : CH3 Q_7 ..,.

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W 0 91/03464 i~2 ~ ~3i~7 PCT/US90iO49a3 ~1 ~2 ~3=~ ~9=R10 ~5 Q

CH3 CH3 C~3 CH3 CH3 CH2(Z-FPh CH3 CH3 CH3 CH3 CH3 CH2l2-lPh) CH3 CH3 CH3 CH CH CH2(2-(CH3)Ph) CK3 CH3 CH3 CH3 CH3 CH2(2,6-C12Ph) CH3 CH3 CH3 CH3 CH3 CH2(2-CF3Ph) CH3 CH3 CH3 C~3 CH3 CH2(2-t~tr~hydropyran) CH3 CH3 CB3 CH3 CH3 CH2(2-pyridyl) CH3 CX3 CH3 CH3 CH3 CH2(Ph) CH3 H H CH3 CH3 Q-l CH3 H H CH3 CH3 CH2(2-FPh) CH3 H H CH3 CH3 CH2(2-ClPh) CH3 H H CH3 CH3 CH2(2-(c~3)ph~
CH3 H H CH3 CH3 CH2(2,6-C12Ph) CH3 H H CH3 CH3 CH2(2-CF3Ph) CH3 H H CH3 CH3 CH2(2-tetrahydropyr~n) CH3 H H CH3 CH3 CH2(2-pyridyl) CH3 H H CH3 CH3 CH2(Ph) CH3 H ~ CH2CH3 CX3 Q-l CH3 H CH2CH3 CH3 Q_3 CH3 ~ H CH2CH3 CH3 Q-6 CB3 H H CH2C~3 C~3 Q_7 C~3 H H C~2CH3 CH3 Q-15 ~3 H ~ C~2C~3 CH3 CH2(2-FPh) CH3 H H CH2CH3 C~3 CH2(2-ClPh) C~3 H H C~2CH3 C~3 CH2(2-(CH3)Ph) CH3 H H C~2CH3 CH3 CH2(2,6-Cl~Ph) CH3 H H CB2CH3 CH3 CB2(2-CF3Ph) W O 9l/0346~1 2 0 6 ~ 3 3 7 Pcr/~s90/n49~3 :; .
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Q3 ~ H CH2CB3 CH3 CH2(2-tetrahydropyran) CH3 H H CH2CH3 CH3 CH2(2-pyridyl) ~; CH3 H H CH2CH3 CH3 . CH2(Ph) 3 H CH3 H CH~ Q-l . CH3 H CH3 H C~3 0-3 :~ 3 H C~3 H CH3 Q-6 CH3 H CH~3 H CH3 Q-15 CH3 H CH3 H CH3 CH2~2-FPh) CH3 H CH3 H ~ CH3 CH2(2-ClPh) CH3 H CH3 : H CH3 CH2~2-(cH3)ph) CH3 H CH3~ H CH3 CB2(2,6-C12Ph) CH3 H CH3 H CH3 CH2(2-CF3Ph)`
~CH3 H CH3 H CH3 CH2(2-tetrahydr~pyran) :~ ~ CH3 H CH3 H CH3 CH212-pyridyl) ~ ~ H CH3 H CH3 CH2(Ph) ~ ' .

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HCH2CH3 CH2CH3 CH3 CH2~2 FPh) HCH2CH3 CH2CH3 CH3 CH2(2-ClPh) HCH2CH3 CHzCH3 CH3 CH2~2 3rPh) CH2CH3 CH2CH3 CH3 CH2~2-~CH3)Ph) CB2CH3 CH2CH3 CH3 ~ CH2;~2-tocH3)ph) HCH2CH3 CB2CH3 CH3 C~2(2-(C~)Ph) CH2CH3 CH2CH3:: CH3 C~2~2-~CF3)~h) : ~ HCH2CH3 CH2CH3 : CH3 CH2~2-~OCF3)Ph) CH2CH3 ~ CH2C~3 CH3 CH2(2-~SC~3)P~) 2CH3~ CB2C~3 ~ CH3 - CH2~2~6A(Fj2p~
2C~3~ C~2CH3 ~: CH3 c~2(2~6-~cl)2ph) : ~ ~ :CH2CH3 CH2CH3 CH3 CH2~2-pyridyl) :
H ~ CH2CH3 CH2CH3 CH3 CH2~2 f~r~nylj CH?CH3 CH2CH3 CH3 cH2~2-tetrahydrofuran) 2CH3 C~2CH3 C83 CH2~2-tetrahydropyran) 2C~3 CH2C~3 ~ C~3 CHz( -thiophenyl) ~ ~ CH2CH3 CH2C~3 CH3 CB2(2-i~o~olyl) : ~ H CH2CH3 CHZcH3 C83 CH2 ~ 2-pyrz~:inyl ) H C~2CH3 CHzCN3 CH3: C82~Pb) ~ :

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HCH2CH3 CH2CH3 CB3 Q~l ~CH2CB3 CH2CH3 CH3 o-3 HCH2CH3 CHzCH3 ~H3 o_7 HCH2C~3 CH2CH3 CH3 0-15 H~H2CH3 CH2CH3 CH2CH3 CH2(2-FPh) HCH2CH3 CH2CH3 CH2CH3 CH2(2-ClPh) HCH2CH3 CHzCH3 CH2CH3 CH2(2-(CH3)Ph) HCH2CH3 CH2C~3 CH2CH3 CH2(2,6-C12Ph) HC~2CH3 C~2CH3 C~2CH3 CH2(2-CF3ph) HCH2CH3 CH2CH3 CH2CH3 CH2t2-tetrahydropyr~n) ~CH2CH3 C~2CH3 CH2CH3 CH2(2-pyridyl) HCH2CH3 CH2CH3 CH2CH3 CH2(Ph) HC~2CH3 CH2CH3 CH2CH3 Q-l HCH2CH3 CH2CH3 CH2CH3 Q_3 HCH2CH3 C~2CH3 CH2CH3 Q-6 HCH2CH3 CH2CH3 CH2CH3 Q_7 ~CH2CH3 CHzCH3 C~2CH3 0-15 HCH2CH3 CH2CH3 CH2CH-CH2 CH2(2-FPh) HC~2CH3 CH2CH3 CH2CH=CH2 CH2(2-ClPh) BCH2CH3 CH2CH3 CH2CH=CH2 CH2(2-(cH3)ph) HCH2CB3 CH2CH3 CH2CH=CH2 CH2(2,6-C12Ph) HZCH3 CH2CH3 CH2CH-CH2 CB2(2-CF3ph) }ICB2CX3 CH2CH3 C~2CH=CH2 CH2(2-tctr~hydropyranj HCH2CH3 CH2CH3 CH2CH=CH2 CH2~2-pyridyl) HCH2CH3 CH2CH3 CH2CH=C~2 C~2(Ph) HCH2CH3 CH2CH3 CR2CH=CH2 0-3 -HCH2CH3 CH2C~3 CH2CH~CH2 Q 6 HCH2CH3 C~2CH3 CH2cH=cH2 0 7 I!CH2CH3 CH2CB3 CH2CH=CH2 0 15 . , .

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~VO 91/0346~ PCr/US90/049~3 ` ~ 119 Rl B3=~4 ~9=B10 E5 H H H CH3 CH2(2-FPh) H H H CH3 CH2~2-ClPh) H H H CH3 CH2(2-tCH3)Ph) H H H CH3 CH2t2~6-~l2ph) H H H CH3 CH2(2-CF3Ph) H H H CH3 CH2(2-t~trahydropyran) H H- H CH3 C82(2-pyridylj H H H . CH3 CH2(Ph) H H H CH3 ~-3 H H H CH3 o_7 CH3 CH3 CH3 CH2(2-FPh) H CH3 CH3 CH3 CH2(2-ClPh) H CH3 CH3 CH3 CH2(2-(CH3)Ph3 H CH3 CH3 CH3 CH2(2,6-cl2Ph?
H CH3 CH3 CH3 CE2(2-CF3ph) H CH3 CH3 CH3 CH2(2-tetrahydropyr~n) H CH3 CH3 CH3 CH~(2-pyridyl) H CH3 CH3 : CH3 C~2~Ph) ~ H CH3 CH3 CH3~ Q-l :~ ~H CH3 CH3 ~ ~H3 : 0 3 ~;H CH3 CH3 CH3 Q-6 : CH3 CH3 C~3 ~ ~_7-H CH3 CH3~ ~ ~CH3 U-15 CH3~ C~2CH3 CH2CH3 ~ C~3 ~ CH2~2-FPh3 CH3 CH2CH3 CH2CH3 C~3 `- CH2(2-clph)~
~ CH3 CH2CH3 C~2CH3 C~3 - CH2(2-(CH3)Ph) : CH3 CH2CH3 CH2CR3 CH3 CH2(2,6-C12Ph) -CH3 CH2CH3 C~2CH3 CH3 CH2(2-CF3ph ~; : , ' 20~337 91/03464 PCT/~'S90/0~9 ~1 ~3=R4 ~9=~10 ~5 Q

CH3 CH2CH3 CH2CH3 CH3 CH2(2-tetrahydropyran) CH3 CH2CB3 CB2CH3 CH3 CH2(2--pyridyl) CH3 CH2CH3 CH2CH3 C~3 CH2(Ph) CH3 C~CH3 C~2CH3 CH3 Q-l CH3 C~2CH3 CH2CH3 CH3 Q_3 CH3 CH2CH3 CH2C~3 CH3 9-6 CH3 CH2CH3 CH2CH3 CH3 ~-7 CH3 CH2CH3 C~2CH3 CH3 0-15 CH2CH3 CH3 CH3 CH3 CH2 2-FPh) CH2CH3 CH3 CH3 CH3 CH2(2-ClPh) CH2CH3 CH3 CH3 CH3 CH2(2-(C83)Ph) 2CH3 CH3 CH3 CH3 CH2(2,6-C12Ph) C~2C~3 CH3 CH3 CH3 CH2~2-CF3Ph) CH2CH3 CH3 C83 CH3 CH2(2-tetrahydropyran) CH2CH3 C~3 CH3 CH3 CH2(2-pyridyl) CH2CH3 CH3 CH3 CH3 CH2(Ph) CH2CH3 CH3 CH3 CH3 Q-l , 2C~3 CH3 CH3 CH3 Q_7 CH3 H H C~3 Q_3 CH3 H H CH3 Q_7 CH3 H H CH3 Q-15.
CH3 H H CH3 CH2(2-FPh) CH H H CH3 CH2~2-ClPh) - ..
CH3 ~ CH3 - CH2(2-(CH3)Ph) CH H H CH3 CH2~2~6-C12Ph) CH3 H H CH3 CH2(2-CF3Ph) CH3 ~ H C~3 CX2(2-tetr~hydrcpyran) :`:
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W O 91/03464 ~ " PCT/US90/n4953 ~1 ~3~B4 B9=glo ~5 Q

C83 H HCH3 CH2(2-pyridyl) CH3 H HCH3 CH2tPh) CH3 CH3 CH3CH3 Q-l CH3 CH3 CH3CH3 CH2(2-FPh~
CH3 CH3 ~H3CH3 CH2(2-ClPh) CH3 CH3 CH3CH3 CH2(2-tCH3)Ph) CH3 CH3 CH3. CH3 CH2(2,6-C12Ph) CH3 CH3 CH3CH3 CH2t2-CF3Ph) CH3 CH3 CH3CH3 CH2(2-tetr hydropyra~) CH3 : CH3 CH3CH3 CH2(2-pyridyl) CH3 CH3 CH3CH3 CH2(Ph) : : CH3 H CH3C~3 Q_7 CH3 H CH3CH3 CH2(2-FPh) CH3 H CH3CH3 CH2(2-ClPh) CH3 H CH3CH3 CH2t2-(CH3)Ph) CH3 H CH3CH3 CH2t2,6-U 2Ph) CH3 H CH3CN3 CH2(2-CF3Ph) CH3 H CH3CH3 C82(2-t~tr~hydropyra~) C~3 H CH3CH3 CH2(2-pyridyl) CH3 H CH3CH3 CH2(Ph) . 3 HCH2CH3 CH3 0-1 : H- CH2C~3 CH3 Q_3 ~H3 HCH2CH3 CH3 Q-6 CH3 H CH2CH~ CH3 ~ Q-7 ' : ' ~: ' WO91/03464 2065337 PCr/U590/64933 ~

~1 B3=B9 ~9=R10 ~5 CH3 H C82CH3 CH3 CH2(2-FPh) CH3 H C82CH3 CH3 CH2~2-ClPh) C~3 H CH2CH3 CH3 CH2(2-(CH3)Ph) CH3 H CH2CH3 CH3 CH2(2,6-C12Ph) CH3 H CH2CH3 CH3 CH2(2-CF3Ph) CX3 H CH2CH3 CH3 CH2(2-tetrahydropyr~n) CH3 H CH2CH3 CH3 CH2(2-pyridyl) C~3 H CH2CH3 CH3 C~2(Ph) : CH3 CH3 H C83 Q-1 CH3 CH3 H C~3 Q 3 I ! CH3 CH3 H CH3 Q-6 3~ CH3 H CH3 CH2(2-FPh) CH3 CH3 H CH3 CH2(2-ClPh) -` CH3 CH3 H CH3 CH2~2-~CH3)Ph) CH3 CH3 H CH3 CH2(2,6-C12Ph) CH CH3 H CH3 CH2(2-CF3Ph) ~ CH3 CH3 H CH3 CH2(2-tetrahydropyran) .~ 3 CB3 H CH3 CH2(2-pyridyl) - CB CX3 ~ CH3 CH2~Ph) ~:'- : - ' ' ' - ' ~: - . .. . .

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~ CN2CH3CHzCH3 CB3 CH2(2-13rPh) H
:.~ HC~2CH3: ~C~2C~3 ..CH3~:~cH2(2-~c~3)ph) H
HCH2CH3CH2CH3 CH3 ~2(2-(CH3)Ph) H
: ~ H ~CH2CH3CH2CH3: C~3 ~CH2~2-~C~)Ph) ; B
HCH2CH3~CH2CH3 : CH3 cN2(2-~cr3)ph) H;
-~ : HCH2cH3 ~~cH2c83~ cH3~; ~ CH2(2~(CF3)Ph) H
H~CH2CH3~~CH2CH3 C~3~ c~2(~2-~scH3)ph) H
:CB2CH3 ~~CH2cH3 ~ cH3 CH2~(2,6-(F)2~h) H
;:CH2CH3~~ CH2cH3~ cH3~ ~`c~2~2~6-~cl)2ph) H
H ~ CHzC~3~CH2CH3~ C~3 CH2(2 pyri~y ) : H
H ~ CH2C~3~C~2CH3 ~CH3 c~2(2-fura~yl~ H
B ~ CH2~3~CH2CH3 CH3 CH2(2-t~tr~hydrofur~n) X
H ~ CH2CH3 : :~HzCH3~ ~CH3 CHz(2-tetr~hydropyro~) H
H : CH2CH3 CH2CH3 ~ CH3 CH2S2-thiophenyl) H
H C~2cR3~ CH2CH3 :CX3;: CR2(2-i6o~zolyl) H
~H ~:CH2C~3 CH2CH3 CH3~ CH2~2-pyra~iDyl) H
H ; CH2CH3~ CH2CH3 : CH3 ~CH2(Ph) H
2CR3 CR2CH3 ~ CR3~: g l ~ H
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H CH2CH3 CHzCH3 C~3 Q-6 H
H CH2C~3 CH2CB3 CH3 ~_7 H CH2C~3 CH2CH3 CH2CH3 CH2(2-FPh) ~ C~2CR3 CH2CH3 CH2CH3 CH2(2-ClPh) H
H Q2CH3 CH2CH3 CH2CH3 C~2(2-(CH3)Ph) H
H CH2CH3 CH2C~3 CH2CH3 CH2(2,6-Cl2Ph) H
H C~2CH3 CH2CH3 CH2CH3 CH2(Z CF3ph) H
H CH2CH3 CH2CH3 CH2CH3 CH2(2-tetrahydr~pyran) H
H CH2CH3 C~2CH3 CH2CH3 CH2(2-pyridyl) H
H CH2C~3 CH2CH3 CHzCH3 cH2(p~) H
C~2CH3 CH2C83 C~2CH3 0-l H
H CH2CH3 CH2CH3 CH2CH3 Q_3 H
H CH2CH3 CH2CH3 CH2CH3 Q-6 : H
H CH2CH3 2CH3 CH2CH3 o_7 H CH2C~3 CH2CH3 CH2CH3 Q-15. H
CH2C~3 CH2CH3 CH2CH=CH2 CH2(2-FPh) H CH2CH3 CH2CH3 CH2CH=CH2 CH2(2-ClPh) H
H CH~CH3 C~2C~3 CH2CH=CH2 CH2(2-(CH3)Ph) H
2C~3 CH2CH3 CH2CH=CH2 CH2(2,6-Cl2Ph) H
H CH2CH3 C~2CH3 CH2CH=CH2 CH2(2-CF3Pb) H
2CH3 C~2CH3 CH2CH~CH2 CH2(2-tetrahydropyran) B
B CX2CH3 CH2CH3 CH2CH-C~2 CH2(2-pyridyl) H
CH2CH3CE~2CX3 CH2CH=C~2~ . C~2(Ph~ '' ' ~' HQ 2CH3C~2C~3 CH2CH=C~2 q 1 H
HCH2CH3CH2CH3 CR2CH=CH2 0 3 H
HC~2CH3C~2CH3 CN2C~-C~2 .0-6 HCH2CH3C~2CH3 CH~CH-CH2 0-7 H
HQzC~33CK~Ci33 C~,CH.C~3 Q--5 ~3 ~ .
`-:
~ .
~ . . .

~WO 91/03464 ' ~ PCr/US90/049~3 .
3=B4 B9=B10 ~5 Q

H H CH3 CH2(2-FPh) - H
H H CH3 CH2(2-ClPh) H
: ~ H B H C~3 CH2~2-(CH3)Ph) H
H H H CH3 CHz(2,6-Cl2Ph) H H H CH3 CH2(2-CF3Ph) H
H H H CH3 CH2~2-tetrahydropyran) H
H H H CH3 CH2(2-pyridyl) H
H H H CH3 CH2(Ph) H H H CH3 ~-1 H
H H H C~3 Q_3 H

HCH~ CH3 CH3 CH2(2-FPh) :H
HCH3 CH3 CH3 CH2~2-ClPh) H
HCH3 CH3 CH3 CH2(2-(CH3)Ph) H
.~ BCH3 C83 CH3 CH2(2,6-C12Ph) . H
HCH3 CH3 CH3 CHz(2-CF3Ph) HCH3 CH3 CH3 CH2(2-tetrahydropyra~) H
CH3 CH3 CH3 CH2(2-pyridyl) H
HCH3 CH3 C~3 : CH2(Ph) H

3 C~3 C83 ` 0 3 H
CH3 C~3 CH3 Q-6 H
~3 C~3 C~3 0_7 ~ CH3 CH3 CH3 0-15 H
:; CH3 ~CH2C~3 CH2CH3 CH3 CH2(2-FPh) H
: CH3 CHzCH3 CHzCB3 CH3 CH2(2-ClPh~ H
CH3 CHzCH3 CH2CH3 C 3 CHz~2-~CH3)Ph~ H
CH3 CH2CH3 CHzCH3 ~H3 CH2(2.6-C12Ph) CH3 CH2CH3 CH2CH3 CH3 CH2(2-CF3Ph) .
:~ .

: ' ~

:` . ~ ` ` ' , W O 91/03464 2 0 6 ~ 3 3 ~ PCT/~'S90/04953 ~

~1 ~3--R4 R9=~10 ~5 Q

CH3 CH2CH3 CH2CH3 c~3 CH2(2-tetrahydropyran) C~3 CH2CH3 CH2CH3 CH3 C'H2(2-pyridyl) H
CH3 CH2CH3 CH2CH3 CH3 C:H2(Ph) H
CH3 CH2~H3 C~B2CH3 CH3 Q-l CH3 CH2C~3 CH2CH3 C~3 Q_3 H

CH3 CHzCH3 CH2CH3 CH3 Q-15 CHzCH3 CH2C~3 CH2CH3 c~3 CH2(2-FP~) 2CH3 CH2CH3 C~2CH3 CHi CH2(2-ClPh) C~2CH3 CH2C~3 CH2CH3 CH3 CH2(2-(CH3)Ph) H
2CH3 CH2CH3 CH2C~3 CH3 CH2(2,6_C12ph) H
CH2CH3 CH2CH3 CH2CH3 CB3 CH2(2-cF3ph) H
CH2CH3 CH2CH3 CH2CH3 CH3 CH2(2-tetrahydropyran) H
CH2CH3 CH2CH3 C~2CH3 CH3 CH2(2-pyridyl) H
CH2CH3 CH2CH3 CH2CH3 CH3 CH2(Ph) - H
CHZCH3 CH2CH3 CH2CH3 CH3 Q-l H
2CH3 CH2C~3 CH2CH3 CH3 Q-3 H
2CH3 CH2CH3 ~ CH2CH3 CH3 Q-6 H
CH2CH3~ CH2CH3 CH2C~3 C~3 g 7 H
C~2~H3 CA2C~3 CHzCH3 C~3 0-15 H

.

~ :

,; . ' .

~ W O 91/03464 ;~PCT/US90/049~3 ~1 ~3=~4 ~9=B10 ~5 Q y CH3 H CH3 CH2~2-FPh) H
H CH3 H CH3 CH2~2-ClPh) H
. . H CH3 H CH3 CH2(2-(OEI3)Ph) H
H CH3 H CH3 CHz~2~6-Cl2Ph) H
H CH3 H CH3 C~2~2-cF3ph) H
~ CH3 ~ CH3 CH2(2-tetrahydropyra~) H
H CH3 H CH3 CH2(2-pyridyl) R
H CH3 CH3 CR2~Ph) H

H CH3 H CH3 Q_3 CH3 H CH3 c~3 CH2~2-FPh) : H
CH3 H CH3 CH3 CH2(2 -ClPh ) H
CH3 H CH3 . CH3 CH2(2-~CH3)Ph) H
C~3 H CH3 CB3 CH2(2,6-C12Ph) H
CH3 H CH3 c~3 CH2(2-CF3Ph) H
CH3 H CH3 CH3 CH2(2-t:~tr~hydropyran) H
- ~ CH3 H CH3 CH3 CH2~2-pyridyl) H
CH3 H ` CH3 C~3 C~2(Ph) H
CH3 H CH3 ~H3 O-l H
.~ CH3 H CY3 CH3 O-3 ~ .
~CH3 R CH3 C~3 Q-6 .

CH3 H CH3 c~3 Q-15 : ~ :
' .' , ' ` . ~ ' ~ ' ''.

W O 9t/03464 '~ 2 ~ 6`5 3 3 7 PCT/~S90/049;3 ~ ~

~1 ~3=R4 ~9=~10 ~5 Q y CH3 H H CH3. CH2(2-FPh) H
CH3 H H CH3 CH2~2-ClPh) H
CH3 B B CH3 C~2(2-~cH3)ph) H
CH3 H H c~3 CH2(2,6-C12Ph~ H
CH3 H H CH3 CH2(2-CF3Ph) H
CH3 H ~ C~3 ~ CH2(2-tetr~hydropyran) H
CH3 H HCH3 CH2(2-pyridyl) H
CH3 ~ HCH3 CH2(Ph) H
CH3 H Hc~3 Q-1 H
CH3 H HCH3 g 3 H
3 H ~: CH3 Q-6 H

CH3 CH3 CH3~ CH3 CH2(2-FPh) H
CH3 CH3 CH3CH3 ~CB2(2-ClPh) M
C83~ CH3 CB3CH3 CH2(2-(~CH3)Ph) H
CH3 CH3 CH3CH3 CH2(2~6-cl2~h) H
CH3 ~ CH3 C~3CH3~ CH2(2_CF3ph) H
CH2~(2-t~trahydropyran) H
CH3 CH3 CH3CH3 Q2(2-pyridy~
CH3 CH3 CH3 ~ CH3 CH2~(Ph) H
CH3 CH3 CB3 CH3 ~-1 : H
CH3 CH3 CH3 CH3 g_3: H
CH3~ CB3 CH3 CH3 ~ ~-6 H
3 C~3 CH3 o_7 C~3 C~3 CH3 CH3 Q~15 l ~3=~4 ~9=810 B5 Q X

CH3 H H CH3 CH2(2-FPhl H
CH3 H H CB3 CH2(2-CiPh) ' ' WO 91/03464 't ' ~ J' '`PCl/US90/04~53 Rl B3=~4~s=Rl ~s Q

CH3 H H CH3 c~H2(z-~rph) H
CH3 H H CH3 CX2~2-(CH3)Ph) H
CH3 ~ H CB3 CH2(2-(OCH3)Ph) H
CH3 H H CH3 CH2(2-(CN)Ph) H
CH3 H H CH3 C~2(2-(CF3)Ph) H
CH3 H H CH3 CH2~2-(OCF3)ph) CH3 H H CH3 CH2(2-~SCH3)Ph) H
~H3 H H CH3 CH2~2,6-(F)2Ph) H
CH3 H H CH3 CH2(2,6-(C1)2Ph) CH3 H H CH3 CH2~2-pyridyl) H
CH3 H H c~3 CX2~2-fura~yl) H
CH3 H H CH3 CH2~2-tetrahydrofuran) H
CH3 H H CH3 CH2~2-tetrahydropyrnn) H
CH3 H ~ CH3 CH2t2-thiophenyl) H
CH3 H H CH3 CH2( 2-i80~azolyl ) H
CH3 H H CH3 CH2( 2-pyrazi~yl ) - H
CH3 H H CH3 CH2(Ph) H

CH3 H H CH3 o 3 H
CH3 H~ H CH3 9-6 H
C~3 H CH3 Q 7 H

CH3 H . CH2CH3 CX2(2-FPh) H
CB3 H C~2CB3 CH2~2-ClPh) H
- CH3 H H CH2CH3 CH2~2-(CH3)Ph) H
CH3 H H CB2CH3 CH2(2,6-C12Ph) CB3 H H C~2CH3 C~2~2-cF3ph) H
C~3 H ~ C~2CH3 CH2~2-tetrahyaropyran) H
CH3 H ~ CB2C~3 CH2(2-pyridyl) CH3 H H CB2C~3 CH2(Ph) H
CH3 H CH2C~3 Q-l CH3 H H CH2Ch3 Q_3 H

, . .
,,~ .

WO 91/03464 ~2~ `7; ` PCT/~'S90/049~3 ~, ~1 ~3=~4 ~9=~10 ~5 Q . X

CH H H CH2CH3 o_7 H
CH3 H H C~2CH3 0-15 H
CH3 H HCH2CH=CH2 CH2~2-FPh) H
CH3 H H- CH2CH-CH2 CH2(2-ClPh) H
CN3 H HCH2cH=cH2 CM2(2-(CH3~Ph) B
CH3 H HCH2CH=CH2 CH2(2,6-C12Ph) CH3 H H .CH2CH=CH~ CH2t2-CF3Ph) . H
CH3 H HCH2CH=CH2 CH2(2-tetrahydropyran) H
CH3 H HCH2CH=CH2 CH2(2-pyridyl) H
CH3 H HCH2CH=CH2 C~2(Ph) H
CH3 H HCH2CH=CH2 0-1 H
CH3 H HCH2CH-C~2 ~_3 H
3 H HCH2CH=CH2 Q-6 : H
CH3 H . HCH2CH=CH2 Q-7 H
CH H HCH2CH=CH2 0-15 H
CH3CH2 H HCH3 C~2(2-FPh) H
CH3CH2 H HCH3 CH2(2-ClPh) H
CH3CH2 H HCH3 CH2~2-(CX3)Ph) CH3CH2 H HCH3 CH2t2~-cl2ph) H
3CH2 H HCH3 C~2~2-cF3ph) H
CH3CH2 H - HCH3 CH2t2-tetrahydropyran) H
~CH3c~H2 H HCH3 : . CH2(2-pyridyl) H
CH3CH2 H HCH3 ~2(Ph~ H
C~3CH2 R HCH3 Q-1 H
cH3cH2 H C~3 o_3 H
CH3CH2 H HC~3 . 0-6 3 2 : CH3 0-7.~. ~

..... . .

~`W O 91/03464 2 ~6~3 J~t"

~1 ~3=R4 ~9=~10B5 CH3 CH3 CH3CH3 CH2~2 FPh) H
CB3 CH3 CH3 CH3 CH2~2-ClPh) H
CH3 CH3 C~3 CH3 CH2(2- CH3)Ph) H
CH3 CH3 CH3 CH3 CH2¦2,6-C12Ph) - H
CH3 CH3 CH3 CH3 CH2(2-CF3Ph) H
CH3 C~3 C~3 CH3 CH2(2-tetrAhydropyran) H
CH3 CH3 CH3 CH3 CH2(2-pyridyl) H

CH3 CH3 CH3 CH3 Q_3 H

CH3 CH2C~3 CH2CH3 CH3 CH2(2-FPh) : H
CH3 CH2CH3 C~2~H3 CH3 CH2(2-ClPh) H
CH3 ~H2CH3 CH2C~3 CH3CH2(2-(CH3)Ph) H
CX3 C~2C~3 CH2CH3CH3 CH2(2,6-C12Ph) H
CH3 CH3 CH3 CH3 CX2(2,6-(F)2Ph) H
CH3 C~3 CH3 CH3 CH2(2,4-(F)2Ph) H
CH3 CH2CH3 CH2CH3CH3 CH2$2-totrahydropyran) H
CH3 :CH2CB3 CH2CH3 CH3CH2(2-pyridyl) CH3 CH2CH3 CH2CH3C~3 CH2(Ph) H
CH3 C~2CH3 CH2CH3 CH3. Q-l H
CH3 CH2CH3 CH2CH3.: CH3 Q_3 H
CH3 CH2CH3 C~2CH3CH3 Q-6 H
CH3 CH2CH3 CH2CH3CH3 0_7 CH3 CH2CB3 CH2CH3CH3^ Q-15 CH3 CH2C~3 CHZcH3 ~- CH3C~2(2,6_~F)2ph) H
CH2CX3 CH2CH3 CH2CH~CH3 CH2(2-FPh) H
CH2CH3 C~2C~3 CH2CH3- CH3- CHz(2-ClPh-) H
CH2CH3 CH2CH3 C~2CH3CH3 CH2(2-(CH3)Ph) H
CHzCN~~N3 ~Zz(2.6-ClzPh~ N

~; -: :
:
. .:

91/~3464 2`~ i PCT/~'S90/049;3 ~l ~3=~4 ~g=~10 ~5 CH2CH3 CH2CH3 C82 Q3 CH3 CH2~2-CF3Ph) H
CH2CH3 CH2CH3 CH2CH3 CH3 CH2~2-tetrahydropyran) H
CH2CH3 CH2CH3 CH2CH3 CH3 CH2(2-pyridyl) H
CH2CH3 CH2C83 CH2CH3 C~3 CH2~Ph) H

CH2CH3 CH2CH3 CH2CH3 CH3 Q_7 H
CH~CH3 CH2CH3 CH2C~3 CH3 Q-15 - H
C~3 CH3 H CH3 CH2(2-FPh) H
CH3 CH3 H CH3 CH2~2-ClPh) H
CH3 CH3 H CH3 CH2t2-~CH3)Ph) CH3 CH3 H CH3 CH2~2,6-C12Ph) H
CH3 CH3 H CH3 CH2~2-cF3ph) H
CH3 CH3 H CH3 CH2(2-tetr~hydropyra~) H
CH3 CH3 H CH3 CN2~2-pyridyl) H
3 CH3 H CH3 CH2~Ph) H
CH3 CH3 H CH3 Q-l H
CH3 H CH3 o_3 CH3 CH3 H : CH3 Q_7 H

CH3 H CH3 CH3 CH2~2-FPh) H
CH3 H CH3 ~H3. CH2(2 -ClPh ) :
CH3 ~ H CH3 CH3 - Q2(2-(C~3)ph) CH3 H CH3 CH3 CH2(2,6-C12Ph) H
CH3 H CH3 C~3 ~ CH2(2-CF3Ph) -CH3 H CB3 CH3 CH2(2-tetrahydropyr~
C~3 ~ H CR3 C~3 CH2~2-pyrldyl) - H
CH3 H CH3 ~ CH3 tH2 Ph) H
O33 H CH3 C~3 0-l H

.

:

W 0 91/03464 2 ~ 6 ~ ~ 3 7 PCT/~'S90/04953 ~1 ~3=B~ ~9=~10 ~5 Q

CH3 H CH3 C~3 g_3 H

CB3 H CH3 CH3 0~7 H
CH3 M CH3 CH3 Q-15:
CH3 H CH2CH3 CH3 CH2(2-FPh) c~3 CH2CH3 CH3 CH2(2-ClPh) H
CH3 CH2CH3 CH3 CH2(2-(CH3)Ph) H
CH3 CHzCH3 CH3 CH2(2,6-C12Ph) H
CH3 H CB2CH3 CH3 CH2(2-CF3Ph) H
CH3 CH2CH3 CH3~ CH2(2-tetrahydropyran) H
CH3 CH2CB3 2H3 CH2(2-pyridyl) CH3 CH2CH3 c~3 CB2(Ph) H

CH3 H CHzCH3 CH3 Q_3 : H

CH3 H CH2CH3 CH3 ~_7 CH3 CH2CH3 CH3 Q-lS H
CH2CH3 CH3 C~3 CH3 CH2~2-FPh) CH2CH3 CH3 CH3 CH3 CH2(2-ClPh) H
2CH3 CH3 CB3 CH3 C~2(2-(CH3)Ph) H
C~2C~3 CH3 CH3 CH3 CH2(2,6-C12Ph) H
CH2CH3 CH3 CH3 CH3 CH2(2-CF3ph) H
CH2CH3 CH3 CH3 CH3 CR2(2-tetrahydr~pyraD) H
C~2C~3 CH3 CH3 CH3 CH2(2-pyridyl) CH2CH3 CK3 CH3 C~3 C~2~Ph) C~2CH3 CH3 ~ CH3 CH3 Q-l CH2C~3 CH3 CH3 CH 0 3 ~2CH3 CH3 CH3 CH3 0-6 CH2CH3 CH3 CH3 CH3 ~_7 : H
CH2C~3 CH3 C~3 CB3 Q-15 H

. .

WO 91/03464 ~2 ~ ~ 3 ~1 ~ PCr/US90/049~3 -;

; 134 ~1 ~3=~4 ~9_R10 ~5 Q

H H CH3 CH2(2-FPh) H
H H H CH3 CH2t2-ClPh) :~ H H H CH3 CH2(2-(cH3?Ph) H
H H H CH3 CH2(2,~-C12Ph) H
~ H H H CB3 Cg2(2-CF3Ph) H
: ~ H ~ X CH3 CH2(2-tetr~hydr~pyr~) H
: H H H CH3 CH2(2-py~idyl) H
~: H H H CH3 CH2(Ph) B
: H H H CH3 Q-l ~
H H H CH3~ Q-3 ~ H
H ~ ~ CH3 Q-6 H
H H H CH3 Q_7 H
: - H CH3 Q-15 H
:....... : . :
: ~ :

.
' ^

- -- , ..~
:
. ' .

`:

- `-WO 91/03464 2 0 653 3 7 PCI/US90/049~3 13~

QO~X ' , -~ 2~0 : R
VIII

X = C(R3)~R4)oRS
:. Rl ~2 B3 R4 ~5 g ~8 H H CH2CH3 CH2CH3 CH3 CH2~2-FPh) CH3 H H CH2CH3 CH2CH3 CH3 . CH2~2 ClPh) CB3 :~ H H CH2CH3 CH2CH3 CH3 C~2(2-BrPh) CH3 H H CH2CH3;CH2CH3 CH3~ - CH2(2 (CH3) ) CH3 : H C~2CH3 Q2CH3 CH3 CH2(2-(OCH3)Ph) CH3 H H CH2CH3 CH2CH3 CH3 CH2(2-(CN)Ph) CH3 : H H CH2CB3 CH2CH3 CH3 CH2(2-(CF3)Ph) ~H3 H H CH2CH3 CHzCH3 CH3 C~2(2-(ocF3)ph) CH3 H H C~2C~3:CH2cH3 :~C~3 c~2(2 (sc~3) ) C~3 R H CH2CH3 : CH~CH3 c~3 C~2(2,6_(F)2ph) CH3 ~H- H CH2CH3 CH2CH3 CH3 CH2(2,6-(Cl?2Ph) CH3 . ..2~ 3 ~2C~3 CH3 . CH2~2-pyridyl) C~3.
. ~ CH2CH3 CH2CH3 CH3 CH2(2-furanyl) C~3 H C~H2CH3 CH2C~3 C~3 C~2(2-teerahydrofuraD) CH3 H H CH2CH3~ CH2CH3 CH3~ CH2(2-t~trahydr~pyran) CH3 H H CH2CH3 CH2CH3 CH3 .CH2(2-thiophenyl) CH3 H H CH2CH3 C~2CH3 CH3 CH2~2-i~o~azolyl) CH3 -::. H ~ CH2CH3 CH2CH3 C~3 CH2(2-pyrazinyl) CH3 ~ CH2CB3 , CH2CH3 C~3 CH2(Ph) CH3 : , ~;

. ~ .
: ' .

WO91/03464 ~ ,,G'~ PCI/l'S90/04953 ~ `

Bl ~2 ~3 B4 ~5 Q ~8 H H CH2CH3 cH2cH3 CH3 Q-l CH3 H HCH2C~3 CH2CH3 CH3 Q_3 CH3 HCH2CH3 CH2C~3 CH3 Q~7 CH3 HCH2CH3 CH2C~3 CH3 Q-15 CH3 H HCH2CH3 CH2C~3 C~2CH3 CH2~2-FPh1 CH2CH3 H HCA2CH3 CH2CH3 CH2CH3 CH2(2-ClPh) CH2CH3 H HCH2CH3 CH2CH3 CH2CH3 CH2~2-~CH3)Ph) CH2CH3 H HCH2CH3 CH2CH3 CH2CH3 CH2(2,6-C12Ph) CH2CH3 H HCH2CH3 CH2CH3 CH2CH3 CH2(2_C~3ph) CH2CH3 H H CH2CH3~ CH2CH3 CH2CH3 CH2(2-tetr~hydr~pyran) CH2CH3 H HCH2CH3 CHzCH3 CH2CH3 CH2(2-pyridyl) CH2CH3 H HCH2CH3 CH2CH3 CH2CH3 CH2(Ph) CH2CH3 H HCHzCH3 CH2CH3 CH2CH3 Q-l CH2CH3 H HCH2CH3 CH2CH3 CH2CH3 Q CHzCH3 HCH2~CH3 CH2CH3 CH2CH'CH2 CH2(2-FPh) CH2CH=cH2 H HCH2CH3 CHzCH3 ; CH2CN=CH2 CH2(2-ClPh) CH2CH-CH2 H HCH2CH3 CH2CH3 CH2CH=CH2 CH2(2 (CH3)Ph) CH2CH=cH2 H HCH2CH3 CH2C 3 CH2CH=CH2 CH2~2'6 C12 ) CH2CH=CH2 H HCHzCH3 CH2CH3 CH2CH'C~2 C~2(2 Cr3Ph) CH2CH=CH2 H HCH2CH3 CH2CH3 CH2CH=CH2 CH2(2-tetrahydropyr~) CH2CH=CH2 H HCH2CH3 CH2CH3 CH2CH=CH2 C~2(2 pyridyl) CH2CH-cH2 H HCH2CH3 CR2CH3 CH2CH=C~2 CH2(P ) CH2CH=CH2 H HCH2CR3 CH2CH3 CH2CH=CH2 0-1 CH2CR=CH2 2 3 C~2CH3 CH2CH_CH2 U-3 CH2cH=cH2 H HCH2CH3 CH2CH3 CH2CH=CH2 0-6 - CH2CH=CH2 H HCR?CH3 CH2CH3 ~H2CH-CH2 Q 7 CH2CH=CH2 H HCH2CH3 CH2CR3 C~2C~=CH2 Q 15 CH2cH=cH2 .
:
.

~` W O g1/03464 2 0 6 ~ PCT/~S90/0495 pl ~2 ~3 ~4 ~5 Q ~8 H H H H CH3 CH2(2-FPh) CH3 H H H H CB3 CH2~2-ClPh) CH3 H H H H CH3 CH2(2-(CH3)Ph) CH3 H H H H CH3 CH2(2,6-C12Ph) CH3 H H H H CH3 CH2(2-CF3Ph) CH3 H H H H CH3 CH2~2-tetrahydropyran) CH3 H H H H CH3 CH2~2-pyridyl) C93 H H H H CH3 CH2(Ph) CH3 H H H H CH3 Q-l CH3 H H H H CH3 0_3 CH3 : ~H H H H CH3 Q-6 CH3 H H H CH3 Q_7 CH3 H H H H CH2CH3 CH2(2-FPh) CH2CH3 H H CH2CH3 CH2(2-ClPh) CH2CH3 H H H H CH2CH3 CH2~2-icH3)ph) CH2CH3 H H H H : CH2CH3 CH2(2~6-cl2ph) CH2C~3 H H H H CH2C ~ CH2(2-CF3Ph) CH2CH3 H H H H CH2CH3 CH2(2-tetrahydr~pyran) CH2CH3 H H H H CH2CH3 CH2(2-pyridyl) C~2CH3 H H H H CH2CH3 CH2(Ph) CH2C~3 H H H- H CH2CH3 0-3 . CH2CH3 H H H H CH2CH3 Q-6 CH2~H3 : ~H H H CH2CH3 0-7 CH2CB3 H R CH3 CH3 CH3 CHz~2-FPh) CH3 ~- ~ H CH3 CH3 CH3 CH2(2-CiPh) CH3 H H CH3 CH3 CH3 CH2~2-(CH3)Ph) CH3 ~: H H CH3 CH3 CH3 CH2(2,6-C12Ph) CH3 H H CH3 CB3 CH3 :C82(2 CF3Ph) CH3 .

.

:~ :

~ ' ' 9l/03464 ~ 3~ PCT/~S90/04933 ' ?

13~

~1 ~2 E3 ~4 ~5 Q ~8 H H CH3 CH3 CH3 CH2(2-tetrahydropyran) CH3 H H CH3 CH3 CH3 CH2(2-pyridyl) CH
H H CB3 CH3 CH3 CN2(Ph) CH3 H H CH3 CH3 CH3 O-l CN3 H H CH3 CH3. CH3 Q_3 CH

H . H CH CH CH3 .Q_7 CH3 CH3 CH3 CH2CH3 CH2C~3 CH3 CH2(2-FPh) CH3 `CH3 CH3 CH2CH3 CH2CH3 CH3 CH2(2 ClPh) CH3 CH3 CH3 CH?CH3 CH2CH3 CH3 CH2(2-(CH3)Ph) 3 CH3 CH2CH3 CHzCH3 CH3 CH2(2,6-C12Ph) CH3 CH3 CH3 CH2CH3 CH2CN3 CH3 CH2(2-CF3Ph) CH3 CH3 CH3 ~CH2CH3 CH2CH3 CH3 CH2(2-tetrahydropyran) CH3 CH3 CH3 CH2CH3 CH2CH3 CH3 CH2(2 pyri Y ) CH3 ~H3 CH3 CH2CH3 CH2CH3 CH3 CH2(P ~ CH3 CH3 CH3 CH2CH3 CH2CH3 CH3 Q-l CH3 CH3 CH3~ CH2C~3~ CH2CH3~ CH3 o 3 CH3 CH3 CH3: CH2CH3 CH2CH3 CH3 Q 6 CH3 CH3 CH2CH3 CH2CH3 CH3 ~_7 CH

CH3~CH3 CH3 CH3 CH3 CH2(2-FPh) , CH3 CH3 CH3 CH3 - CH3 CH3 CH2(2-ClPh) CH3 CH3 CH3 CH3 CH3 CH3 CH2(2-lCN3)Ph) CH
CH3 CH3 CH3~ CH3 CH3 CH2(2,6-ClzPh) 3 CH3 CH3~ CH3 CB3 CB3 CH2(2-CF3Ph) CH3 C~3 CH3 CH3 CH3 CH3 CN2~2-tetrahydropyr~n) CH3 C~3 CH3 CH3 CH3 ~H3 ~2~2-pyridyl) CH3 CH3 CH3 CH3 CH3 CH3 CH2tPh) C~3 CH3 CH3 CB3 CH3CH3 Q-l C~3 :
~'~`' ' ~ , , , : ~, .:
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W O 91/03464 ,;, 2 0 ~ 5 3 3 7 PCT/~S90io4953 ~1 ~2 R3 ~4 ~5 Q R8 CH3 CH3 CH3 CH3 CH3 Q_3 CH3 CH3 CH3 C~3 CH3 CH3 0-15 CH3 CH2CH3 CH2CH3 ~H2CH3 CHzCH3 CH3 CH2~2-FPh) CH3 CH2CH3 CH2CH3 CH2CH3 CHzCH3 CH3 CH2(2-ClPh~ CH3 CH2CH3 Q 2CH3 CH2CH3 CH2CH3 CH3 CH2(2-(CH3)Ph) C~3 CH2CH3 CH2CH3 CH2CH3 CH2CH3 C~3 C~2~2'6-C12Ph) CH3 CHzCH3 CH2~H3 CH2CH3 CH2CH3 CH3 CH2(2-CF3Ph) CH3 CH2CH3 CH2CH3 CH2CH3 CH2CH3 CH3 CH2(2-tetrahYdrPYran~ CH3 CB2CH3 CH2CH3 CH2CH3 CH2CH3 CH3 CH2(2-PYridYl) CH3 CH2CH3 CH2CH3 CH2CH3 CH2CH3 CH3 CH2(Ph) CH3 CH2CH3 CH2CH3 CH2CH3 CH2CH3 CH3 Q-l CH3 CH2CH3 CH2CH3 CH2CH3 CH2CH3 CN3 Q_7 C~3 CH2CH3 CH2CH3 CH2CH3 CH2CH3 CH3 ti-l~ CH3 CH3 CH3 H H CH3 CH2IPh) CH3 CH3 CH3 H H CH3 CH2(2-~Ph) c~3 CH3 CH3 H H CH3 CH2(2-tCH3~Ph) CH3 CH3 CH3 H H CH3 CH2t2~6-cl2ph) CH3 CH3 c~3 H : H CH3 Q-3 CH3 : 3 C~3 C~3 CH3 CH3 CH2(Ph) CH3 CH3 CH3 CB3 CH3 CH3 CH2(2-FPh) c~3 CH3 CH3 C~3 . CH3 C~3 CH2(2-(cH3)ph) CH3 CH3 CH3 CH3 CH3 CH3 ~2(2~6-C12Ph) CH3 CH2CH3 C~2CH3 H CH3 CH2(Ph) CH3 CH2CH3 CH2CB3 H H CH3 CH2(2-FPh) c~3 CH2CH3 CH2CH3 H CH3 CH2t2-1CH3)Ph) CH3 CH2CH3 CH2C83 H H CH3 CH2t2~6-Cl2Ph) CH3 CH2CH3 CB2CH3 h H CH3 Q-3 Ch3 ~ .
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, WO 91/03464 ~ 3 7 PCl'tl,'S90/049S3 , -~1 B2 ~3 E~4 B5 Q ~3 CH2CH3 CH2CH3 CH3 CH3 CH3 CH2(Ph) CH3 CH2CH3 CH2CH3 CH3 C83 CH3 CH2(2-FPh) ~H3 :- CHZcH3 CH2CH3 ~H3 CH3 CH3 CH2(2-(~3)ph) CH3 CH2CH3 C~2C~3 CH3 CH3 CH3 CH2(2~6-cl2Ph? C~3 CHzCH3 CH2CH3 CH3 CH3 CH3 Q-3 CH3 H CH3 CH2CH3 CH2CH3 CH3 CHz(Ph) CH3 CH3 CH2CH3 CH2CH3 CH3 CH2(2 -FPh ) CH3 R CH3 CH2CH3 CH~CH3 CH3 CH2(2-(C~3)~h) CH3 H CH3 CH2C~3 C~2CH3 CH3 C~2(2,6-C12Ph) CH3 H CH3 CH2C33 CH2CH3 CH3 Q-3 CH~

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~ WO91/034f~ t ~6~37 PCT/~'S90i~49S~

FormulatiQ~
- Useful formulations of the compounds of Formula I can be prepared in conventional ways. They include dusts, granules, pellets, solutions, suspensions, emulsions, wettable powders, emulsifiable concentrates and the like. Many of these may be applied directly. Sprayable formulations can be estended in suitable media and used at spray volumes of from a few liters to several hundred liters per hectare. High strength compositions are primarily used as intermediates for further formulation. The formulations, broadly, CQntain about 0.1% to 99~ by weight of active ingredient(s) and at least one of (a) about 0.1% to 20% surfactant(s) and (b) about 1%
to 99.9% solid or liquid diluent(s). More specifically, they will contain these ingredients in the following appro~imate proportions:
Tabl~_~
Weight Percent*
Active Ing~aien~ Diluentf 5) S~ L~ L
`~ 25 Wettable Powders 5-60 39-94 1-10 Emulsifiable 3-80 20-95 0-20 Concentrates : - - - . .
Dusts 1-25 70-99 0-5 3 - Granules and Pellets 0.1-50 S0-99.9 0-15 - ~ ~ Active ingredient plus at least one of a Surfactant or a Diluent eguals 100 weight percent.
~ 35 Lower or higher levels of aetive ingredient can, of course, be present depending on the intended use .:
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:
: , ' :, W091/034~ ~ 7 PCT/~'S90/049 and the physical properties of the compound. Higher - ratios of surfactant to active ingredient are some-times desirable, and are achieved by incorporation into the formulation or by tank mi~ing.
Typical solid diluents are described in Watkins~
et al., ~Handbook of Inseeticide Dust Diluents and Carriers~, 2nd Ed., Dorland Books, Caldwell, New Jersey, but other solids, either mined or manufa~-tured, may be used. The more absorptive diluents are preferred for wettable powders and the denser ones for dusts. Typical liquid diluents and solvents are described in Marsden, ~Solvents Guide,~ 2nd Ed.`, Interscience, New York, 1950. Solubility under 0.1%
is preferred for suspension concentrates; solution concentrates are preferably stable against phase separation at O~C. ~McCutcheon's Detergents and Emulsifiers Annualn, MC Publishing Corp., Ridgewood, New Jersey, as well as Sisely and Wood, ~Encyclopedia of Surface Active Agents~, Chemical Publishing Co., Inc., New York, 1964, list surfactants and re~ommended uses. All formulations can contain minor amounts of additives to reduce foamin~, caking, corrosion, micro-; 25 biological growth, etc.
The methods of making su~h compositions are wellknown. Solutions are prepared by simply mi~ing the ingredients. Fine solid compositions are made by blending and, usually, grinding as in a hammer or ~30 fluid energy mill. Suspensions are prepared by wet milling (see, for e~ample, Littler, U.S. Patent 3,060,084). Granules and pellets may be made by spraying the active material upon preformed granular carriers or by agglomeration techniques. See J. E.
~rowning, ~Agglomeration~, Che~ical Engin~ri~y, ~ December 4, 1967, pp. 147ff. and ~Perry~s Chemical ,~ .. ..

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- WO91/0~ ~ 2`0~3~i PCT/~'S90io4953 Engineer's Handbook', 5th Ed., McGraw-Hill, New York, 1973, pp. 8-57ff.
For further information regarding the art of formulation, see for example:
H. M. Lou2, U.S. Patent 3,235,361, February 15, 1956, Col. 6, line 16 through Col. 7, line 19 and Esamples 10 through 41;
R. W. ~uckenbaugh, U.S. Patent 3,~09,192, March 14, 1967, Col. 5, line 43 through Col. 7, line 62 and E~amples 8, 12, 15, 39, 41, 52, 53, 58, 132, I38-140, 162-164, 166, 167 and 169-182;
H. Gysin and E. ~nu~li, U.S. Patent 2,891,~55, June 23, 1959, Col. 3, line 66 through Col. 5, line 17 and E~amples 1-4;
G. C. Rlingman, ~Weed Control as a Science", John Wiley and Sons, Inc., New York, 1961, pp. 81-96;
and J. D. Fryer and S. A. Evans, ~Weed Control Hand-book~, 5th Ed., Blackwell Scientific Publications, O~ford, 1968, pp. 101-103.
In the following e~amples, all parts are by ~ weight unless otherwise indicated.
- ~ 25 E~a~ A
Wettable P~wder 2-~1-ethyl-1-metho~ypropyl)-6-(phenylmetho~y)-7-o~abicyclo[2.2.1]heptane ~ 60%
.
sodium alkylnaphthalenesulfonate 2%
sodium ligninsulfonate 2%
synthetic amorphous silica 36%
- The active ingredient-is first sprayed onto the amorphous silica,:then-the ingredients~are blended, - hammer-milled until all the solias are essentially under 50 mi~rons, reblended, and pachaged.

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WO 91/03464 i~ 6~ 7 PCl/US90~049:~3 --, , ' lq4 Wettable Powder , ' 2~ ethyl-1-metho~ypropyl)-6-(phenylmetho~y)-7-o~abicyclot2.2.1]heptane 50% ' sodium alkylnaphthalenesulfon~ate 2%
low viscosity methyl cellulose 2%
diatomaceous earth 46~
The active ingredient is first sprayed onto the diatomaceous earth then,the ingredients are blended, coarsely hammer-milled and then air-milled to produce particles essentially all below 10 microns in - 15 diameter. The product is reblended before packaging.
E~ample C
Gra~lÇ
Wettable Powder of E~ample B 5%
attapulgite granules 95%
(V.S.S. 20-40 mesh; 0.84-0.42 mm) A slurry ~f wettable powder containing 25%
solids is sprayed on,the surface of attapulgite granules in a double-cone blender. The granules ~ are dried and packaged.
-~ 25 , , , ~moel~_~
~mulifiable Concen-t~e ; ~ 2-(1-ethyl~ metho~ypropyl)-6-~phenylmetho~yj-7-osabicyclot2.Z.l]heptane - 40%
Atlo~,3403F , 3~
~ 30Atlox 3404F , - 3%
; ~ sylene ,- , '' 54%
, ; ; ,,The active ingredient and Atlo~ emulsifiers are ,dissolved in the solvent, filtered and packaged.
Atlo~ 3403F and 3404F are blends of anionic and ionic ~ 35 emulsifiers from ICI~ Americas, Inc.
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' - WO 91/034~ '" ~J06~3 7 PCT/US90/04953 .
~ow Stren~th ~ran~le S 2~ ethyl-1-methoxypropyl)-6-(phenylmetho~y)-7-o~abicyclol2.2.1]heptane 5~
attapulgite granules 95%
(U.S.S. 20-40 mesh) The active ingredient is dissolved in a solvent and the solution is sprayed upon dedusted granules in a double-cone blender. After spraying of the solution - :has been completedi the material is warmed to e.vaporate the solvent. The material is allowed to cool and then packaged.
15E~m~le F
~L~
- 2~ ethyl-1-metho~ypropyl)-6-(phenylmetho~y)-7-o~abicyclo[2.2.1]heptane 50%
wetting agent 1~
crude ligninsulfonate salt 10%
(containing 5-20% of the natural ` sugars) attapulgite c13y 39~
The:ingredients are blended and milled to pass ~: 25 through a 100 mesh screen. This material is then added :~- . to a luid:bed granulator, the air flow is adjusted to ~ently fluidize the mate~ial,: and a fine spray of water - ~ : is: sprayed onto the fluidized~material. The fluidiza-tion and spraying-are continued until granules of the desired size range are made. The spraying is s~opped, ;;~ but fluidization is continued, optionally with heat, until the water content-is reduced to the deslred -~ level, generally less than 1%. The materiàl is then .~ discharged, screened to the~desired size range, ; 35 generally I4-100 mesh (1410-149 microns), and packaged for use.

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W091/034~ ~ X~ `3 7 PCT/US90/04953 1~6 :
E~m~le G
Concentrated Em~l~ion 2~ ethyl-1-metho~ypropy:L)-6-Sphenylmetho~y)-7-o~abicyclo[2.2.1]Aeptane 25%
~ylene 25%
Atlo~ 3904F 5 G128~ 5%
ethylene glycol 8%
water 32~
The active ingredient, solvent and emulsifiers are blended together. This solution is added to a mi~ture of the ethylene glycol and water with stirring.
E8~Q
Solution 2-(1-ethyl-1-methosypropyl)-6-(phenylmetho~y)-7-o~abicyclo[2.2.1]heptane : 5%
water 95%
The compound is added directly to the water with stirring to produce the solution, which may then be packaged for use.
ESample I
~1:~
2-(1-ethyl-1-methoxypropyl)-6-~phenylmethoxy)-7-oxabicyclo[2.2.1]heptane 10%
attapulgite ~ 10~
Pyrophyllite 80%
The active ingredient is sprayed onto the attapulgite and then passed through a hammer-mill to produce particles substantially all below 200 microns. The ground concentrate is then blended with . ... - -. . . .. . .
powdered pyrophyllite until homogeneous.

. WO~1/034~ ...................... 2~5j337 PCT/~'S9~/0~9~3 UTILITY
Test results indicate compounds of this - 5 invention are active postemergence and, in ~,-particular, preemergence herbicides. Many compounds in this invention are useful for the control of selected grass and broadl~af weeds with tolerance to important agronomic crops such as alfalfa (MedL~a~o I0 ~ativa), barley (~QL~ym vulaa~), corn (~ mays), cotton (Gossypium hirsutum), rape (~ ~i~ n~
rice (Ory~_ sati~a), soybean (Glvcine E~), sugar beet ~ eta vuly~Li~), and wheat (~Li5i~m aeS~ivum).
Grass and broadleaf weed species controlled include, but are not limited to, barnyardgrass (EchinQshl5 crus-~alli), blackgrass (Alopecu~u~ myosur~i~es), cra~grass (Diaitaria spp.), fo~tail (Setar~i~ spp.), lambsquarters (Cheno~odi~m spp.~, teaweed (~
5~iDQ~d), umbrella sedge (Cype~l~ di~cLmds)~ and waterchestnut (El~Q~ha~is spp.~. Several compounds in this invention are particularly use~ul for the control of barnyaldgrass and selected broadle f weeds ~; such as umbrella sedge and waterchestnut in upland and paddy rice.
These compounds also have utility for weed ~- control of selected vegetation in specified areas such as around storage tanks, parking lots, hiyhways, and railways; in~fallow crop areas; and in citrus and plantation crops such as banana, coffee, oil palm, and rubber. Alternatively, these compounds are useful to modify plant growth.
Rates of application for compounds of this invention are 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 terms, wo gl/o~ ~ 3~ PCT~US90/049~3 ~~, - the subject compounds should be applied at rates from 0.01 to 20 kg/ha with a preferred rate range of 0.03 to 1 kg~ha. Although a small number of compounds show no herbicidal activity at the rates tested, it is anticipated these compounds have herbicidal activity at higher application rates. One skilled in the art can easily determine application rates necessary for the desired level of weed control.
Compounds of this invention may be used alone or in combination with other commercial herbicides, insecticides, or fungicides. The following list e~emplifies some of the her~icides suitable for use in mi~tures. A combination of a compound from this invention with one or more of the following herbicides may be particularly useful for w~ed ~` control.

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::: WO91/034~ `; ,2,~ ,33 j Pcr/~s90io49i~

Csm~on Name Chemi~al-~am~
acetochlor 2-chloro-N-(etho~ymethyl)-N-. (2-ethyl-6-methylphenyl)acetamide acifluorfen 5-[2-chloro-4-(trifluoromethyl)-pheno~y]-2-nitrobenzoic acid acrolein 2-propenal 10 alachlor 2-chloro-N-(2,6-diethylphenyl)-N-(methosymethyl)acetamide anilofos S-4-chloro-N-isopropylcarbaniloyl-methyl-O,O-dimethyl phosphorodi-thioate ametryn N-ethyl-N'-(l-methylethyl)-6-(methylthio)-1,3,5-triazine-2,4-diamine - amitrole lH-1,2,4-triazol-3-amine AMS ammonium sulfamate 20 asulam methyl [(4-aminophenyl)sulfonyl]-carbamate ~:~ atrazine 6-chloro-N-ethyl-N'-~l-methylethyl)-1,3,5-triazine-2,4-diamine barban 4-chloro-2-butynyl 3-chlorocarbamate 25 benefin : N-butyI-N-ethyl-2,6-dinitro-4-(tri-fluoromethyl)benzenamine bensulfuron 2-[[t r [ ( 4,6-dimethosy-2-pyrimi-methyl . dinyl)amino]methylcarbonyl]-. . amino]sulfonyl]methyl3benzoic acid, methyl ester bensulide O,O-bis~l-methylethylj S-12-~(phenylsulfonyl)amino]-. . ethyl]phosphorodithioate bentazon 3-(1-methylethyl)-(lH)-2,1,3-benzothiadiazin-4(3H)-one, ,2-dioside , :- .

WO91/0~ ~ ~ 3 7 PCT/US90/049S~

Common N~m~ Chemical ~me benzofluor N-[4-(ethylthio)-2~(trifluoro-methyl)phenyl]methanesulonamide benzoylprop N-benzoyl-N-(3,4-dichlorophenyl)-DL-alanine bifenox methyl 5-(2,4-dichlorophenosy)-2-- . 10 nitrobenzoate bromacil 5-bromo-6-methyl-3-(1-methylpropyl)-2,4(1H,3H)pyrimidinedione bromo~ynil 3,5-dibromo-4-hydro~ybenzonitrile butachlor N-(buto~ymethyl)-2-chloro-N-(2,6-diethylphenyl)acetamide ~uthidazole 3-~5-(1,1-dimethylethyl)-1,3,4-thia-diazol-2-yl]~q-hydrosy-1-methyl-2-imidazolidinone butralin 4-(1,1-dimethylethyl)-N-(l-methyl-propyl ? -2,5-dinitrobenzenamine butyl-ate S-ethyl bist2-methylpropyl)-carbamothioate cacodylic dimethyl arsinic oside acid 25 CDAA 2-chloro-N,N-di-2-propenylacetamide CDEC 2-chloroallyl diethyldithiocarbamate CGA 142,46~- 3-(4,6-dimetho~y-1,3,5-triazin-2~yl)--. - l-t2-(2-metho~yetho~y)-pehnyl-sulfonyl]-urea : 30 chloramben 3-amino-2,5-di~hlorobenzoic acid ... . . . ~ ~
chlorbromuron 3-(4-bromo-3-chlorophenyl)-1-metho~y-1-methylurea chlorimuron 2-tt[[(4-chloro-6-metho~y-2-pyrimi-ethyl dinyl)ethylamino]carbonyl]-amino]sulfonyl]benzoic acid, ethyl ester WO91/034~ ' 2~ 6~S ~`~ 7 PCT/US90/04953 CommQn_~m~ ~'h~mi~al Na~

5 chlormetho~y- 2,4-dichloxophenyl 4-nitro-3-nil metho~yphenyl ether chlornitrofen 2,4,6-trichlorophenyl-4-nitro--- phenyl ether chloro~uron N'-[4-(4-chloropheno~y)phenyl]-N,N-dimethylurea - chlorpropham l-methylethyl 3-chlorophenylcarbamate chlorsulfuron 2-chloro-N-t[(4-metho~y-6-methyl-l~3 triazin-2-yl)amino]carbonyl~benzene-sulfonamide chlortoluron N~-(3-chloro-4-methylphenyl)-N,N-dimethylurea cinmethylin eso-l-methyl-4-(1-methylethyl)-2-[(2-methylphenyl)metho~y]-7-oxabicyclo-[2.2.1]heptane : 20 clethodim ~E,E)-(+)-2-tl-tt(3-chloro-2-propenyl) o2y]imino]propyl]-5-[2-(ethylthio)-propyl]-3-hydro~y-2-cyclohexen-1-one clomazone 2-[(2-ch1orophenyl)methyl]-4,4-dimethyl-~ 3-iso~azolidinone 25 clopro~ydim ~E,E)-2-[1-~t(3-chloro-2-propenyl)o~y)-imino]b~tyl]-5-[2-.(ethylthio)propyl~-3-hydroxy-2-cyclohe~en-1-one clopyralid 3,6~-dich1oro-2-pyridinecarboxylic acid CMA calcium salt of MAA
.
cyanazine 2-t[4-chloro-6-(ethylamino)-1,3,5-tri-azin-2-yl]amino]-2-methylpropanenitrile cycloate S-ethyl cyc'-hesylethylcarbamothioate cycluron 3-cycloocty~ l,l-dimethylurea cyperquat l-methyl-4-phenylpyridinium ' wo g~o~ ~ 5~ ~ PCT/US90/~4953 ~~.

~QmmQn ~ame .Chemic~l_Xam~

5 cyprazine 2-chloro-4-(cyclopropylamino)-6-(iso-propylamino)-~-triazine - cyprazole N-[5-(2-chloro~ dimethylethyl)-1,3,4-thiadiazol-2-yl]cyclopropanecarbo~-amide 10 cypromid 3~,4'-dichlorocyclopropanecarbo~anilide . dalapon 2,2-dichloropropanoic acid dazomet: tetrahydro-3,5-dimethyl-2H-1,3,5-thia-diazine-2-thione DCPA dimethyl 2,3,5,6-tetrachloro-1,9-benzene-dicarbosylate -~ . desmediphan ethyl [3-[l(phenylamino)carbonyl]o~y]-phenyl]carbamate desmetryn 2-(isopropylamino)-4-(methylamino)-6 (methylthio)--triazine : 20 diallate S-(2,3-dichloro-2-propenyl)bis(l-methylethyl)carbamothioate dicamba 3,6-dichloro-2-metho~ybenzoic acid dichlobenil 2,6-dichlorobenzonitrile 25 dichlorprop (_)-2-(2,4-dichloropheno~y)propanoic .
. dichlofop . .(~)-2-[4-~2,4-dichloropheno~y)pheno~y~-propanoic ac1d, methyl ester diethatyl N-~:chloroacetyl~-N-(2,6-diethylphenyl)-difenzoquat 1,2-dimethyl-3,5-diphenyl-lH-pyrazolium - dimepiperate ~ S-l-methyl-l-phenylethylpiperidine-carbothioate dinitramine N3,N3-diethyl-2,4-dinitro-6-(trifluoro-35methyl)-1,3-benzenediamine .

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WO91/034~ 2 0 6 ~ 3 3 7 PCT/~S90/04953 Common Nam~ Ch~m~al Na~ `

5 dinoseb 2-(1-methylpropyl)-4,6-dinitrophenol diphenamid N,N-dimethyl-a phenylbenzeneacetamide dipropetryn 6-(ethylthio)-N,N'-bis(l-methylethyl)-1,3,5-triazine-2,~-diamine diquat 6,7-dihydrodipyrido[1,2-a:2',1'-c]-pyrazinedium ion diuron N'-(3,4-dichlorophenyl)-N,N-dimethylurea DNOC 2-methyl-4,6-dinitrophenol DSMA disodium salt of MAA
d~mron N-(4-methylphenyl)-N~-(l-methyl-l-phenylethyl)urea endothall 7-oxabicyclo[2.2.1]heptane-2:,3-dicarbo~-~; ylic Acid 20 -EPTC S-ethyl dipropylcarbamothioate esprocarb S-benzyl-N-e~hyl-N-(1,2-dimethyl)-- (SC2957) propyl)thiolcarbamate etha lf luralin N-ethyl-N-(2-methyl-2-propenyl)-2,6-dinitro-4-(trifluoromethyl)-benzenamine ethofumesate (+)-2-ethosy-2, 3-dihydro-3,3-dimethyl-- 5-benzofuranyl methanesulfonate , fenac 2,3,6-trichlorobenzeneacetic acid feno~aprop (+)-2-[4-[(6-chloro-2-benzosazolyl)osy]-phenosy]propanoic acid fenuron N,N-dimethyl-N~-phenylurea fenuron TCA Salt;of fenuron and TCA
flamprop N-benzoyl-N-(3-chloro-4-fluorophenyl)-- D~-alanine r ~ ~ ~q~`~33 7 WO91/034~ i 1J ~ PCT/VS90/049~3 ~ ¦

Common Nam~. Chemi~1_~m~

5 fluazifop (+)-2-[4-[[5-(trifluoromethyl)-2-pyri-dinylJo~ylpheno~y]propanoic acid ~: fluazifop-P (R)-2-t4-[[5-(tri1uoromethyl)-2-pyri-dinyl~o~y~pheno~y]propanoic acid fluchloralin N-(2-chloroethyl)-2,6-dinitro-N-propyl-4-(trifluoromethyl)benzenamine fluometuron N,N-dimethyl-N~-~3-(trifluoromethyl)-phenyl]urea fluorochlor- 3-chloro-4-(chloromethyl)-1-[3_(tri-~: idon~ fluoromethyl)phenyl]-2-pyrrolidinone fluorodifen D-nitrophenyl ~,a,~-trifluoro-2-nitro-~-tolyl ether : fluorogly- carbo~ymethyl 5-~2-chloro-4-~tri-cofen fluoromethyl)pheno~y]-2-nitrobenzoate fluridone l-methyl-3-phenyl-5-[3-(trifluoro-methyl)phenyl3-4tlH)-pyridinone fomesafen 5-[2-chloro-4-(trifluoromethyl)phenoxy3-N-(methylsulfonyl~-2-nitrobenzamide fosamine ethyl hydrogen (aminocarbonyl)-phosphate 25 glyphosate N-(phosphonomethyl)glycine halo~yfop 2-[4-[13-chloro-5-(trifluQromethyl)-2-pyridinyl3Oxy~phenosy]propanoic acid -he~aflurate potassium hexafluoroarsenate 30 hesazinone 3-cyclohe~yl-6-(dimethylamino)-1-methyl- -I,3,5-triazine-2,4(1H,3H)-dione imazametha- 6-(4-isopropyl-4-methyl-5-oso-2-benz . imidazolin 2-yl)-m-toluic acid, methyl ester and 6-(4-isopropyl- . .
4-methyl-5-o~o-2-imidazolin-2-yl)-P-toIuic acid, methyl ester 1.

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~` WO9l/034~ ~ ; .2065337 pcT/us9o/n49s3 Common Name ChemLaL N2me imazapyr (~)-2-[4,5-dihydro-4-methyl-4-~1-methyl- !
- ethyl)-5-o~o-lH-imidazol-2-yl]-3--pyridinecarboxylic acid imazaquin 2-[4,5-dihydro-4-methyl-4-(1-methyl-ethyl)-5-oxo-lH-imidazol-2-yl]-3-quinolinecarbo~ylic acid imazethapyr (+)-2-[4,5-dihydro-4-methyl-4-(1-methyl-ethyl)-5-o~o-1~-imidazol-2-yl].-5-: ethyl-3-pyridinecarbo~ylic acid ioxynil 4-hydro~y-3,5-diiodobenzonitrile ~:~ isopropalin 4-(1-methylethyl~-2,6-dinitro-N,N-15: dipropylbenzenamine isoproturon N-(4-isopropylphenyl~-N~,N~-dimethylurea isouron N'-[5-(1,1-dimethylethyl)-3-iso~azolyl]-N,N-dimethylurea 20 iso~aben N-[3-(1-ethyl-1-methylpropyl~-5-iso~azolylJ-2,6-dimethoxybenzamide karbutilate 3-[[(dimethylamino)carbonyl]amino]-phenyl-(l,l-dimethylethyl)carbamate ~: lactofen (~)-2-etho~y-1-methyl-2-o~oethyl 5-[2- :
chloro-4-(trifluoromethyl)phenosy]-2-nitrobenzoate lenacil 3-cyclohe~yl-6,7-dihydro-lH-cyclopenta-pyr1midine-2,4~3H,5H)-dione linuron :N'-t-3,4-dichlorophenyl)-N-methoxy-N-methylurea 30 MAA. : methylarsonic acid . MAMA . monoammonium salt of MAA
MCPA (4-chloro-2-methylpheno~y)acetic acid MCPB 4-(4-chloro-2-methylphenoxy)butanoic ~: :
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WO 91/03464 ~'4 ~ ~' `J a ~i ~ Pcr/us90/n495~ .

Commvn Name Chemical N~m~

MON 7200 . S,S-dimethyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridinedicarbothionate mecoprop ~ 2-(4-chloro-2-methylpheno~y)-propanoic acid 10 mefenacet 2-(2-benzothi~azolylosy-N-methyl-N-phenylacetamide - mefluidide N-[2,4-dimethyl-5-[[(trifluoromethyl)-sulfonyl~amino]phenyl]acetamide methal-. N-(2-methyl-2-propenyl)-2,6-dinitro-N-propalin propyl-4~(trifluoromethyl)benzenamide thiazuron` 1,3-dimethyl-3-(2-benzothiazolyl)urea metham methylcarbamodithioic acid :
methazole 2-(3,4-dichlorophenyl)-4-methyl-1,2,4-osadiazoli~dine-3,5-dione methosuron N'-(3-chloro-4-methoxyphenyl)-N,N-dImethylurea metolachlor 2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-metho~y-1-methylethyl)acetamide metribuzin 4-amino-6-~(1,1-dimethylethyl)-3-(methyl-thio)-i,2,4-triazin-5(4H)-one metsulfuron :2-tt[t(4-metho~y-6-methyl-l~3~5-tri methyl azin-2-yl)amino]car~onyl~-amino]sulfonyl~benzoic acid, methyl ester 30 MH 1,2-dihydro-3,6-pyridazinedione molinate S-ethyl hesahydro-lH-azepine-l-carbo-thioate monolinuron 3~ chlorophenyl)-1-metho~y-1-methyl-urea ' ~, . .
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. -WO91/034~ 2 0 6 5 3 3 7 PCT/~90/049~ ' Common N~m~ ~'hemi~3 1 ~~m~ t .. I
5 monuron N~-(4-chlorophenyl)-N,N-dimethylurea monuron TCA Salt of monuron and TCA
~; MSMA monosvdium salt of MAA
. napropamide N,N-diethyl-2-(1-naphthalenylo~y)-' 10 ProPanamide naptalam 2-[(1-naphthalenylamino)carbonyl]-; benzoic acid neburon l-butyl-3-(3,4-dichlorophenyl)-1-methyl-urea 15 nitralin 4-(me~hylsulfonyl)-2,6-dinitro-N,N-dipropylaniline nitrofen 2,4-dichloro-1-(4-nitropheno~y)benzene nitrofluorfen 2-chloro~ 4-nitropheno~y)-4-(tri-fluoromethyl)benzene 20 norea N,N-dimethyl-N~-~octahydro-4,7-methano-lH-inden-5-yl)urea 3aa,-4~,5a,7,7a-isomer norflurazon 4-chloro-5-(methylamino)-2-~3-(tri-fluoromethyl)phenyl]-3(2H)-1 25 pyridazinone ` oryzalin 4-(dipropylamino~-3,5-dinitro-benzenesulfonamide o~adiazon 3-~2,4-dichloro-5-(1-methyletho~y)-: phenyl]-5-(1,1-dimethylethyl)-1,3,4-o~adiazol-2(3H)-one , `~ 30 osyfluorfen 2-chloro-1-(3-ethosy-4-nitropheno~y)-4-(trifluoromethyl)benzene paraquat l,1'-dimethyl-4,4'-dipyridinium ion L
~: pebùlate S-propyl butylethylcarbamothioate pendimethalin N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitrobenzenamine ,', .';: , I
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W09l/034~ ~ & ~d i~? ~` ' PCT/~IS90/049~3 i~ -CQ~m~ ~

perfluidone 1,1,1-trifluoro-N-~2-methyl-4-(phenyl-sulfonyl)phenyl]methanesulfonamide phenmedipham 3-[(metho~ycarbonyl)amino]phenyl ~3-methylphenyl)carbamate picloram 4-amino-3,5,6-trichloro-2-pyridine-: 10 carbo~ylic acid PPG-1013 5-[2-chloro-4-(trifluoromethyl)-phenoxy]-2-nitroacetophenone o~ime-O-acetic acid, methyl ester pretilachlor a-chloro-2,6-diethyl-N-(2-propo~y-ethyl)acetanilide procyazine 2-[r4-chloro-6-~cyclopropylamino)-1,3,5-triazine-2-yl]amino]-2-methylpropane-nitrile profluralin N-(cyclopropylmethyl)-2,6-dinitro-N-propyl-4-(trifluoromethyl)benzenamine prometon 6-metho~y-N,N'-bis(l-methylethyl)-1,3,5-triazine-2~,4-diamine prometryn N,N'-bis(l-methylethyl)-6-(methylthio)-1,3,5-triazine-2,4-diamine pronamide 3,5-dichloro-N-(l,l-dimethyl-2-propyn-yl)benzamide propachlor 2-chloro-N-(l-methylethyl)-N-. phenylacetamide propanil N-(3,4-dichIorophenyl)propanamide propazine 6-chloro-N,N'-bis(l-methylethyl)-: 3~ 1,3,5-triazine-2,4-diamine propham l-methylethyl phenylcarbamate prosulfalin N-t[4-(dipropylamino~-3,5-dinitro-phenyl~sulfonyl]-S,S-dimethylsulfil-imlne .prynachlor 2-chloro-N-(l-methyl-2-propynyl~ocet-, ~ WO91/034~ PCT/~lS90io49~3 20~5337 : Common ~ame IChemical N~am~

pyrazolate 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-pyrazol-5-yl-~-toluenesulphonate pyrazon 5-amino-4-chloro-2-phenyl-3(2H)-~ pyridazinone ;~ pyrazosulfuron ethyl S-[3 (4,6-dimetho~ypyrimidin-2-ethyl yl)ureadosulfonyl]-l-methylpyrazole-4-carboxylate quinclorac 3,7-dichloro-8-quinoline carbo~ylic acid quizalofop (+)-2-[4-~(6-chloro-2-quinoxalinyl)-ethyl o~y]phenosy]propanoic acid, ethyl ester secbumeton N-ethyl-6-metho~y-N~ methylpropyl)-1,3,5-triazine-2,4-diamine : setho~ydim 2-[1-(etho~yimino)butyl]-5-[:2-(ethyl-thio)propyl3-3-hydro~y-2-cyclohe~en-l-one . '' slduron N-~2-methylcyclohe~yl)-N'-phenylurea simazine 6-chloro-N,~'-diethyl-1,3,5-triazine-2,4-di;amine SK-233 1-(a,a-dimethylbenzyl)-3-(4-methyl-phenyl)urea . 25 sulfometuron 2-~[1[(4,6-dimethyl-2-pyrimidinyl)-methyl~ ~ amiho~carbonyl]amino]sulfonyl]-~ ~ benzoic acid, methyl ester TCA trichloroacetic acid :
~:: : tebuthiuron N-[5-(1,1'-dimethylethyl)-1,3,4-thiadi-azol-2-yl]-N,N~-dimethylurea .~ ~ terbacil 5-chloro-3-(1,1-dimethylethyl)-6-methyl-2,4(1H,3H)-pyrimidinedione terbuchlor N-(buto~ymethyl)~-2-chloro-N-[2-(1,1-~- - dimethylethyl)-6-methylphenyl]-acetamide .. -. . ..

:

~06533 7 WO9l/034~ PCT/~'S90/0495~ ~
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Comm.QL~Le Chemical.N~m~

terbuthyl- 2-(tert-butylamino)-4-chloro-6-(ethyl-azine ~amino)-~-triazine terbutol 2,6-di-ter~-butyl-D-tolyl methylcar-bamate terbutryn N-(l,l-dimethylethyl)-N~-ethyl-6-(methylthio)-1,3,5-triazine-2,4-diamine thifensulfuron 3-t[[[(4-methoxy-6-methyl-1,3,5-triazin-methyl - 2-yl)amino]carbonyl~amino]sulfonyl]-2-thiophenecarbosylic acid, methyl ester thiobencarb S-[(4-chlorophenyl)methyl] diethylcar-. bamothioate triallate S-(2,3,3-trichloro-2-propenyl) bis(l-methylethyl)carbamothioate tribenuron 2-[[[tN-(4-methosy-6-methyl-1,3,5-20methyl triazine-2-yl)-N-methylamino]-carbonyl~amino]sulfonyl]benzoic acid, methyl ester triclopyr [(3,5,6-trichloro-2-pyridinyl)-osy]acetic acid tridiphane 2-(3,5-dichlorsphenyl)-2-(2,2,2-2S trichloroethyl)osirane trifluralin 2,6-dinitro-N,N-dipropyl-4-(tri-fluoromethyl)benzenamine trimeturon ~ (D-chlorophenyl)-2,3,3-trimethylpseu-30 2,4-D (2,4-dichlorophenosy)acetic acid 2,4-DB .4-(2,4-dichlorophenosy)butanoic acid : ~ernolate S-propyl:.. dipropylcarbamothioate sylachlor ~ 2-chloro-N-(2,3-dimethylphenyl)-N-(l-methylethyl)acetamide ~~WO91/0~ ~ PCT/~'S90/049~
3 j; ~~5337 Herbicidal properties of the subject compounds were discovered in a number of greenhouse tests.
; 5 Test procedures and results follow.

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Rl R~

RZ . - ~z : (I) (18) Physical Properties Cmpd Rl R2 R3 R4 R5 Q Rat~o (I (18)) Parti~i 1 CH3 CH3 H H CH2Ph C~2(Phj ~ oil, e~o, 4.58-4.36 (m,2H), 2 3.54 (m,2H), : 3.20 (m,lH) 2 CH3 C83 H ~ ~CH2CH=CH2 CH2(2_Fph) oil, e30, 5.gO (m,lH) 2 5.32-5.06 (m,2H), . ~ 4.54 (dq,2H), 3.94 (m,2H), : 3.6-3.43 (m,2H), 3.16 (m,lH) 3~ CB3 CH3 ~ H~ C~2CH=CH2 CH2(2-(C~3)ph) oil, e~o,~ 5 90 (m,lH), 2 5.28-5.15 ~m,2H), 4.~4 ~q,2H), 3.84 (m,2~), 3.55-3.43 (m,2H), , 3 .15 (m, lH) : ' .
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W 0 91/03464 ,~ ,2Jo!6s 3 3 7 PCT/US9OtO49 Physical Properties Con~iguration Partial Cmpd Rl R2 R3 R4 R5 g Ratio (I:(18)) NMR(~) .: . . . . _ 4 CH3 CH3 H H CH2CH=CH2 CH2~Ph) oil, e~o, 5.90 (m,lH), 1:2 5.3-5.16 (m,2H) 4.49 (dq,2H), 3.94 (m,2H), 3.58-3.42 (m,2H), 3.16 (m,lH) 5 CH3 CH3 H H CH3 CH2(2-FPh) oil, eso 4.52 (dd,2H), 3.56 (dd,lH), 3.43 (dd,lH), 3.3 (s,3H), 3,12 (dd,lH) 6 CH3 CH3 H H CN2CH3 CH2(2~6-F2ph) oil, endo 3.3 (m,4H), 4.60 (d,lH), - 4.5 (d,lH), ~ 3.76 (dd,lH) 7 CH3 CH3 H H CH2CH3 CH2(2,6-C12Ph) oil, eDdo 4.76 (d,lH), 4.66 ~d,lH), ~` 3.74 ~dd,lH), 3.3 ~m,4H), 8 CH3 CH3 H H CH2CH3 CH2(2-FPh) oil, eso, 4.58 (d,lH), ~ 3:1 4.45 (d,~H), - ~ 3.56 (dd,lH), - 3.4-3.1 (m,4H) 9 CH3 CH3 H H CH2CH3 CH2~2,6-C12Ph) oil, e~o, 4.73 ~dd,lH), - 2:1 4.64 (dd,lH), ~: :
- 3.5 (m,2H), 3.4_3.1 (m,4H) 10 CH3 CH3 ~ H CH3 CH2(2,6-C12P~) oil, e~o, 4.73 (dd,lH), 1:1 4.64 (dd,lH), 3.5 (m,2H), 3.08 (dd~dd, :~
,lH-l:l ratio) : -.

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WO 91/03464 ~ ' C S~ PCr/l,'S90/04953 . ~
' ~2~ 3 3 ~ I

Physical Properties . Configuration P~rti~l Cmpd Rl R2 R3 R4 R5 Q Ratio (I:(18)) NMR(~) 11CH3CH3 H H Et CH2(2--~3rPh) oil, e~o, 4.56 (d,lH), .
- 2:1 4.43 (dd,lH), 3.60 (dd,lH), 3.5 (m,3H), 3.12 (dd~dd,lH), 12CH3CH3 ~ H CH3 CH2(2-PrPh) oil, e~o, 4.58 (d,lH), 1:1 4.42 (dd,lH), ` . 3.61 (dd,lH), 3.45 (m,lH) 3.3 (sls,3H), 3.1 (dd~dd,lH) 13CH3CH3 H H Et CH2(2-ClPh) oil, endo 4.61 (d,lH), 4.56 (d,lH), .82 (dd,lH), 3.35 ~m,4H) 14CH3CH3 H H Et CH2(2-8rPh) oil, ~ndo 4.59 (d,~lH), 4.43 (d,lH), 3.84 (dd,lH), ., 3.25 (m,4H), 15CH3CH3 H H CH2CH=CH(CH3) CH2~2-FPh) oil, e~o 5.61 (m,2H), ~ - 4,56 (d,lH), - 4.50 (d,lH), - 3.9 (d,d,2H) : 3.5 (dd~dd,2H), 3.14 ~dd,lH) 16 ; CH3CH3 R H C~2~CH3 CH2(2-FPh) oil, eDds 4.56 (dd~s,4H), I
3.81 (dd,lH), ~ ;

3.45 (dd,2H), 3.29 (s,3H) . ` --'~ '' ' : ' .

W O 91/03464 `, ~ 2~6`5~7 PCT/US90io4953 Physi~al Properties Configur~tio~ Partial Cmpd Rl R2 R3 R4 RS q R~tio (I:(18)) NMR(6) 17 CH3 CH3 H H CH2CH3 CH2(2-(CH3)Ph) oil, e~o 4.53 (d,lH), 4.35 (d,lH), 3.45 (m,4H), - 3.13 (dd,lH) 18 H H CH3 CH3 CH3 CH2(2-(CH3)Ph) oil, e~o 4.6 (br,lH), 4.50 (m,3H), 3.65 ~dd,lH), 3.1B (s,3H) ; 21 H H CH3 CB3 CH3 CH2(Ph) oil, e~o 4.55 (t,lH), 4.49 (m,3H), 3~64 (dd,lH), 3.16 (s,3~) - 22 CH3 CH3 CH3 CH3 ~H2CH3 CH2(2-FPh) oil, e~o 4.59 (d,lH), 4.45 (d,lH), 3.55 (dd,lH), ~ .
3.3B (dq,2H) ;~ 23 CH3 CH3 CH3 C83 CH2CH3 C~2(Ph) oil, e~o 4.52 ~dd,lH), 4.40 tdd,lH), 3.52 (dd,lH) 3.37 ~dq~2H) H H Et Et CH3 CH2(Ph) oil, e~o 4.65 (m,4H), 3.72 (dd,lH), 3.22 ~8,3~) -~ 26 H H Et Et CH3 CH2~2,6-C12Ph) oil, e~o 4.75 (dd,2H), 4.59 (m,2H), 3.75 tdd,lH), -~ 3.18 (s,3H) ~, 27 H H Et Et CH3 CH2(2-(CH3)-Ph) oil, e~o 4.7 (m,4H), 3.7 (dd,lH), 3.2 (6,3H) ;: ' - ~ -~ : . .
:. :

WO 91/03464 ~ i3~3 7 PCI~/US90/04953 Phy~ical - Properties ` 1 2 3 5 Configuration Partial Cmpd R R ~ ~4 R Q R~tio (I:(lB)) NMR(6) 28 M H Et Et CH3 CH2(2-FPh) - oil, e~o 4.7 ~m,4H), 3.73 (dd,lH), 3.2 (~,3H) 29 H H Et Et CH3 CH2(2-ClPh) oil, e~o 4.7 (m,4H), 3.72 (dd,lH), 3.2 (s,3H) H H Et Et CH3 CH2(2-BrPh) oil, ero 4.59 (brd,4H), 3.71 (dd,lH), 3.18 (s,3H) 31 H H Et Et CH3 CH2(2,6_F2ph) oil, exo 4.56 (m,4H), 3.68 (dd,lH), 3.17 (~,3H) 32 H H n-Pr n-Pr CH3 CH2(Ph) oil, e~o 4.52 (m,4H), 3.62 (dd,lH), 3.15 (s,3H), 33 H H n-Pr n-Pr CH3 CH2(2-(CH3)Ph) oil, ero ~ 4.50 (t,lH), - ~ 4.48 (~,lHj, 4.45 tdd,2H), 3.62 Sdd,lH), ., :
- 3.19 (~,3H) 34 H H ~-Pr n-Pr C~3 CH2(2-FPh) oil, exo 4.50 lm,4H), 3 . 6 5 ~ dd, lH ), ~ 3.16 (~,3~) H H D-Pr n-Pr CH3 ~ CH2~2-ClP~) oil, e~o 4.59 (m,4H), 3.68 (dd,lH), 3.17 (~,3Hj 36 R H n-Pr n-Pr CH3 - C82(2-DrPh) oil, e~o 4.50 ~m,4H), 3.69 (dd,lH), 3.1? (s,3H) . ~ .

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-: 5aaLE 11 WCH2O ~ (R3)(R~)oR5 ~ ~ l `C~ R3) ( R~) oR5 ( I ) :
.

Phy~ical Cmpd Rl R2 R3 R4 p5 W Config~ration NMR(~) . : . _ 43 H H H ~ H CH2CH3 2-FPh e~o, oil, e~o 4.5 (d,d,4H),~
3.78 (dd,lH), 3.45-3.28 tm,8H) 44 ~ H ~H H H CH3 ~Ph e~o, oil, e~o 4.52 (d,d,4H), 3.63 (m,5H), ` ~ : 3.5-3.3 (slG,6H) H H H~ H CH3~ ~2-FPh ~ e~o, oil, e~o 4.62 (d,lH), 3:.6-3.3 t~,13H) 46~ ~H H H H ~CH2CH3 ~2-(CH3)Ph e~o, oil, o~o 4.48 (d,d,4H) 3.75 (dd,lH), ~ : 3.4 (m,8H) 47 H H H H ~ CH2CH3~ Ph e~o,:oil, e~o 4.5 (m,4H), - - : 3.75 (dd,lH), . , :
3.4 (m,8H) ' . ' ~ . ' ", ': ' ., ., ' ., ' ' : ' '' --- ,WO 91/03464 2 e~ 5 3 3 7PCI /VS90/049;3 :`` , , . ...

. . .
QO~C( R~) ~ R~) OR~

~

~ III) - . ~hy~i~al Propertie6 Partial Cmpd R1 R3 R4 RJ R9 R10 Q ConfiguratioD NMR~ ~ ) :
.~ 118CH3 H H CH3 H H CH2(Ph) oil, eDdo 4.6S (d,lH) :~ ! 4.44 ld,lH), 3 . 82 (m, 2H), 3 . 3 2 ~ 6, 3H ), 3.21 ~m,3H) 19CH3 H ~ CH3 E~ H CH2(2 FPh~ oil, endo 4.6 ~m,lH) ~: ' .
3.8 lm,ZH), 3 . 31 t ~, 3H ), 3.2 (m,3~), 12DC~3 H ~ CH3 8 H CH2(2,6-~)2P~)oil, ~ndo ~.65 (~,lH) 8 l d, lH ), . . 3.78 (m,2H), 3.32 l~,3H), 3.2: Im,3H) '' . ~ -- : ~

, WO 91/03464 ~ -J' ~ PCl~US90/04953 ,--Physical - Properties Partial Cmpd Rl R3 R4 R5 R9 R10 Q Configuration ~MR(~) . _ . . .
.
121 ~ H H CH2CH3 H H CH2(Ph) oil, endo 4.36 ~d~d,lH), 4.40 ~d,lH), 3.91 (d,lH), 3.75 (dd,lH), 3.45 (m,3H), 3.25 (d,2H) 122 H H H CH3 H H CH2(Ph) oil, endo 4.40 (d,lH), 3,90 (d,lH~, 3.7 (dd,2H), 3.31 (s,3H), 3.3 (m,lH) 3.1 (m,2H) -~ 123 H B H CH3 H H CH2(2-FPh) oil, endo 4.62 (s,2H), ; 4.40 (d,lH), 3.90 (d,lH), 3.71 (dd,lH), 3.32 (s,3H), 3.21 (m,2H) ~- 124 H H H CH3 H H CH2(2-(CH3)Ph) oil, endo 4.53 (dd,2H), 4.39 (d,1H), 3.90 (d,lH), 3.7 (dd,lH), 3-31 (~,3H), 3.31 ~m,l~), 3.10 ~m,2H) : ~ . :
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~ W O 91/03464 \'' ~2.g 6t.. ~3 3 7 PCT/VS9o/6~953 . .
Phy ical Propcrties Partial Cmpd ~1 R3 R4 R5 R9 R10 Q Co~figuration NMR(~) .
125 H H H CH3 H H CH2~2-ClPh) oil, endo 4.64 (c,28), 4.40 (d,lH), 3.9 (d,lH), 3.72 (dd,lH), 3.4 (dd,lH), 3.32 (s,3H), 3.2 (m,2H) 126 H H H CH3 H H CH2(2,6-(F)2Ph) oil, e~do 4.61 (s,2H), 4.4 (d,lH)j 3.9 (d,lH), 3.7 (dd,lH), 3.38 (dt,lH), 3.32 (s,3H), 3.2 ~d~d,2H) 127 H H H CH3 H H CH2(2,4-(F)2Ph) oil, e~do 4.S6 (s,2H), i.3~ (d,lH), 3.89 (d,lH), 3.72 (dd,lH), 3.38 (m,lH), 3.31 (s,3H), 3.20 (d~d,2H) 128 H ~H R CH3 H ~H~ CH2~2,5-:(F)2Ph) oil, endo 4.59 (~,2Hj, 4.40 (d,lH), 3.90 (d,lH), .
. 3.75 ~dd,lH), ~; 3.38 (m,lH), 3.33 (8,3H), 3.2 (m.2~3 .

'`''' : ' " ' . , Wog1/03464 i c. 2~ 337 PCr/US90io49~3 Physi~al 1 3 5 9 1 Properties P~rti~l Cmpd R R R4 RR R Q ConfiguratioD NMR(~) -. . _ 129` H H H CH3 ~ H CH2(2,6-(Cl)2Ph)`oil, endo 4.78 (dd,2H), 4.43 (d,lH), 3.9 (d,lH), 3.7 (dd,lH), 3.4 (m,lH), 3.32 (~,3~), 3.2 (dd!2H) 130 CH3 H~ H C~3 H H CH2(2-(CH3)Ph) oil, e~do 4.63 (d,lH), 4.41 (d.lH), 3.84 (m,lH), 3.4-3.2, (m,6H) 131 CH3 H H CH2CH3 H H CH2(Ph) oil, endo 4.65 (d,lH), 4.45 (d,lH), 3.85 (dldd.lH), 3.44 (dq,6H), ~ ~ 3.26 (m,3H) ;~ 132 CH3 H H CH2CH3 H H CH2(2-FPh) oil, endo 4.7 (d,lH), 4.5 (d,lH~, 3.87 (d1dd.2H).
3.43 ~dg,ZH), 3.28 (d~m,3H) CH3 ~ H CH2CH3 ~ ~ C~2t2-(C~3)Ph) oil, endo 4.63 (d,lH) 4.40 ~d,lH), 3.83 (d~dd,ZH) - 3.42 (dg,2H), . ..
3.27 (d~m,3H) ~;

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.

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', ~ W O 91/~3464 ~ 2;~.6~.~.3,7, PCT/~'S90io495~

Phyfiical Properties P~rtial Cmpd Rl R3 R4 R5 R9 R10 0 Configur~tion NMRI~) _ _ 134 CH3 H H CH2CB3 H H CH2(2,6-tF)2Ph) oi , 4.71 ~d,lH~, ;
4.50 ~d,lH), 3.B (d~dd,2H), 3.42 (dq,2H), 3.27 ~d~m,3H) 135 CH3 H H CH2~H3 H H CH2(2-ClPh) oil, endo 4.72 (d,lH), 4.5 Id,lH), 3.82 (d~dd,2H), 3.45 Sdq,2H), 3.3 (m,3H) 136 CH3 H H CH3 H H CH2(2-ClPh) oil, endo 4.71 (d,lH), 4.54 Id,lH), 3.88 (m,2H), - 3.3 (m,6H) 137 CH3 H H CH3 H H CR2(2,6-(Cl)2Ph) oil, endo 4.83 (d,lH), ~ 4.72 Id,lH), - 3.9 (m,2H), 3.33 (s,3H), .~
3~33 (m,lH), 3.23 (m,2H) 138 H CH3 CH3 CH3 CH3 C83 CH2(Ph) ~Ddo 4.65 (d+d,2H), ~- - m.p. 78-80C 4.~0 (d,lH), ` 3.3 (t,l~), 3.15 (fi,3H) ~ 139-~H CH3 CH3 CH3 CH3 C~3 CR2(2-FPh) oDdo 4.65 (d~d,2X), - m.p. 84-86~C 4.39 (d,lH), 3.31 (t,lH), 3.15 (~,3H) :: :

. . .

WO 91/03464 ~ ' PCT/US90/0495~ ~ ' 2~33'7 Physical Propertie6 Parti~l Cmpd Rl R R4 R5 ~9 R10 Q Confiyuration NM~(6) . ~
. .
140 H C~3 CH3 CH3 CH3 CH3 CH2(2-clph~ ~do 4.65 (dld,2H), m.p. 50 S2C 4.42 (d,lH), 3.38 (t,lH), ~ 3.16 ~s,3H) 141 H CH3 CH3 CH3 CH3 CH3 CH2(2~6-(F)2ph) endo 4.66 (dld,2H), m.p. 102-104C g.39 (d,lH), 3.31 (t,lH), ; 3.14 (~,3H) 142 H CH3 CH3 CH3 CH3 CH3 CH2(2-(cH3)ph) 4.6 (dld,2H), .p. 49-50C 4.4 (d,lH), 3.29 (t,lH), 3.15 (s,3H) ` 143 H CH3 CH3 CH3 CH3 CH3 CH2(2~6-(Cl)2Ph) endo 4.82 (s,2H), ; ~ m.p. 100-101C 4.4 (d,lH), `~ 3.3 (t,l~), 3.14 (s,3H) 144 H CH3 CH3 CH3 CH3 CH3 CH2(2'4-(F)2Ph) e~do 4.6 (dld,2H), - m.p. 102-103C 4.39 (d,lH), 3,11 (t,lH), 3.15 (s,3H) 3, 3 3 2 ~) oil, endo 4.64 (d,lH), 4.46 (d,lH), 3.50 ~dd,lH), :
3.34 (s,3H), ~ 3.21 (~d,lH) - .
.

.

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~`W O 91/03464 '~ 3~7 PCT/US~0/0495 Phy~ i c al Properties P~rtial Cmpd Rl R3 R4 R5 R9 R10 Q Configuration NMR(~
~ ~ . . . _ . . .
146 CH3 H H CH3 C~3 CH3 CH2(2-F(Ph) oil, endo 4.69 ~d,lH), - 4.50 (d,lH), 3.5 (dd,lH), 3.4 ~dd,lH), - 3.35 ~s,3H) 3.25 ~dd,lH) 147 CH3 H H C~3 CH3 CH3 CH2(2r6~(F)2Ph) oil, endo 4.70 (d,lH), 4.50 (dilH), 3.50 (dd,lH), 3.40 ~dd,lH), 3.35 (s,3~) 3.21 ~dld,lH) 148 CH3 H H CH3 CH3 CB3 CH2(2-ClPh) oil, endo: 4.72 (d,lH), 4.52 (d,lH), 3.52 (dd,lH), 3.39 Idd,lH), 3.35 ~s,3H) 3.30 ~dd,lH) 149 CH3 H H CR3 CH2CH3 CH2C~3 CH2(Ph) oil, endo ~.64 (d,lH), 4.48 ~d,lH), 3.45 (dd,lH), 3.34 ~s,3H) 3.34 ~dd,lH) ` 3.20 (dd,lH) lS0 CH3 B H CH3 CHzCB3 C~2C~3 C~2(2 rPh) oil, endo 4.68 ~d,lH), .
; 4.52 ~d,lH), 3.45 (dd,lH), 3.34 ~s~dd,4H) -- .
3.24 ~dd,lH) -~ . ' W O 91/03464 ~ 0 6 ~;~ 3 7 PCT/US90/0~953 7~

Physical Properti~s Partial Cmpd R~ R3 R4 R5 R~ ~10 Q Configur~tion NMR(~) 151 CH3 H H C~3 CH2CH3 CH2CH3 CH2(2~6-(F)2Ph) oil~ endo 4,7 (d,lH), 4.5 (d,lH), 3.45 (6~dd,lH), 3.24 (dd,lH) 152 CH2CH3 ~ H CH3 H ~ CH2(Ph) oil, endo 4.65 td,lH), 4.40 (d,lH), - 3.9 (d,lH), 3.78 (dd,lH), 3.36 (dd,2H), 3.33 (s,3H),~
3.24 (dd~dd,ZHj 153 CH2CH3 H H CH3 ~ H CH2(2-FPh) oil, endo 4.7 (d,lH), 4.45 (d,lH), 3.9 (d,lH), 3.79 (dd,lH), . ~. -~ ~ 3.4 (dd,2H), -~ 3.33 (s,3H), 3.24 (dd~dd,~2H) 154 CH2CH3 H H CH3 H ~ H CH2(2,6-(F)2Ph) oil, endo 4.7 (d,1H), , 4.47 ~d,lH), 3.89 ~d,lH), , -~ 3.78 (dd,lH), 3.39 ~dd,2H), 3.36 (s,3H), 3.26 (dd~dd,2H) -`~ 155 ~CH2C~3 ~ H CH3 H H C~2(2-ClPh~ oil, endo 4~75 (d,lH), 4.46 (d,lH), 3.91 (d,lH) :
3.8 (dd,lH), 3.44 ~dd,2H), 3.34 (s,3H), 3.25 (dd+dd,2H) :

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` ~g~37 W O 91/03464 ~ PCT/US90io49~3 Physical Properties Partial Cmpd R R3 R4 R5 R9 X10 Q Configuration NMR(6) 156 CH2CH3 H H CH3 H H CH2~2,6-(Cl)2Ph) endo 4.82 ~d,lH), m.p. 77-77.5C 4.69 (d,lH), 3.89 ~d,lH), 3.79 (dd,lH'/, 3.4 (dd,2H), 3.34 ~s,3H), 3.24 (s~s,2~) 157 CH2CH3 H H CH3 H H CH2~2-(CH3)Ph) oil, endo 4.85 (d,lH), 4.38 ~d,lH), 3.9 (d,lH), 3.8 ~dd,lH), 3.39 (dd,2H), 3.34 (s,3H), ` 3.22 tm,2H) ~ 15B CH2CH3 H H CH3 H H CH2~2 PrPh) o~l, endo 4.71 (d,lH), .~
4.41 (d,lH), 3.92 (d,lH), 3.80 (dd,lH), 3.46 (dd,:2H), 3.33 (s,3H),-3.24 (m,2H) - : . -' ' : . - . . ~

`

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r2~ 3j7 TAB~.E

; . ....... ... ..... .

4,4~ R )CR~)oR5 R~
o~D
`~ Rl ~ ' (III) Physical Properti~
Cmpd Rl R3 R4 R5 R9 R10 Q Rat~o ~I~tl8)) P rt ~l 159 CH3 H H CH3 H H CU2tPh) oil, endo 4.64 (d,lH), 4.44 (d,l~), 3.88 (d,lH), 3.~2 (dd,lH), 3.32 (c,3H), 3.2 (m,3H) 160 CH3 H H CH3 H H C82Pt2-FPh) oil, endo 4.7 (d,IH), 4.52 (d,lH~, ~
; ~ 4.83 (d,lH), ~:
.81 (dd,lH), : ~ : 3-33 (~,3H), : : 3.3-3.2 (m,3B) 161 CH3- H H ~CH3 8 H ~ CH2P(Z~6-~F)2Ph~ oil~ e 4.7 (d,l~), : : 4.5 (~
.
3.35 (d,lH), 3.3 (dd,lH), 3.33 ~c,3H), - 3.Z2 (m,3H) ' , .:
. : ' ~ ~ . ', ' ' ' `
, ~ :
.

2~$~3g~
` ` W O ~1/03464 ' P~Ti~S9o/049~3 :~ 197 .

!
'.
'` ' ' . . , ' '': C( R3 ) ( R~) oR5 R1 ~
o~Re (III) `

F~hy~ic~l `1 3 4 Propertie~ P~rtial Cmpd R R R RS R9 :R10 0 CoDfiguratio~ ~MR(~) 162 H H H CH3 CH3 H CH2(Ph) oil, eDdo 4.62 ~d,lH), 4.52 Sd,lH), 4.35 (6,1~), 4.09 (q~lH)~
3.5 (t,lH), 3.4 tdd,lH), ;: 3.32 (ad,lH),:
~ : 3.36 (~,3~) ; :163 H H~ H CH3 CH3 H cH2(2-rph) oil, ~d~ 4.62 (d~d,2H), 4.36 (s,lH), .06 (q,~
~- 3.5 ~t,lN), 3.4 (~d,lH), 3.36 ~,3H?, 3.3S ~m,l~) ~64 H H H CH3 CH3 H CR2~Ph; : oil, endo 4.62 (d,2H), 4.54`(d,1H), ~ ~.23 (6~m,2H), : . 3.4 (~,2H~, ~ 3.35 (~,3H), :~ ~ 3.34 ~m,lH) ~: .

: : : - , . .; .
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WO 9l/03464 ~ . 1 P~/US90io4953 ~
..

E'hy6ical Cmpd Rl R3 P~4 R5 as R10 Q E'roperties Parti~l o~ igurat~on NMR ( ~ ) 165 H H H CH3 CH3 B CH2~2-FPh) c>il, e~do .63 (dla,2H3, 4 . 24 (m~, 2~
3.41 (~1,2H), 3 . 35 ( ~, 3E~ ), 3 . 34 (m, lH) ~, `WO91/03464 `~ 2~5~37 PCl/I~S90/049~

199 ,:

T~'~aLE~

:
~.

:. Q~ ~ , ~LCC R3~ C R4) OR~

Rl o Phy6ical Cmpd Rl R3 R4 R(~ ~9 R10 Propertiefi Partial Conf i gur at i on NMR ( ~ ) -166 CH3 H H CH2CB3~H H CB2(Ph) oil, endo 4.55;(6,2H), 4.0 (d~d,dd, 3H), 3.68 (t,lH), 3.4 ~ (~,4H), 3.38 167 CB3 H H CH2~H3 B B CH2(~2-FPh~ oil, endo (dd,lH) 4.07 (t~d,2H), 3.9 (d,~lH), 3.69 (dd,lH), 3.4 (m,4H), 168 CB3 B H CBzCB3 B H C~z~2-(CB3~)~h) oll, endo 4 55 ~d;d~2B)~
~ ~.05 (d,lH), ; 4.04 (dd,lH), 3.9 (d,lH), :
3 . 69 ~t, l~l), .
3.49 ~m,4H), 3 . 3 5 ( dd, lH ) :: ~

::: : ~ : :
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W O 91/~3464 `. 2 O~ ~i3~3 7 PC~/~'S90io49;3 i -~; , ~-`

::; R1 QD ~ (R3)CR~)ORs R5~ ~

(VIII) Phy~ic~l Cmpd Rl R2 R3 R~ ~5 Propertie~ Partial ~ O CoDfiguratioD NMR(~) 169 H H CH2CH3 CH2CH3 CH2(Ph) CH2~Ph) oil, endo 4.67 ~m,4H) 4.51 (~Id,2H), 3.65 (d~d,2H), 3.13:(~,3H) 170 H H CH2CH3 CH2 Q3 ~2(2~FPh) CH2(2 ~Ph) oi i 4.70 (d,4H), : 4.52 (6~d,2H), I ~ 3.7 (d d,2H), 3.15 (~,3H) 171 ~ H CH2CH3 CH2~H3~ CH3 CH2(2-FPh~ oil, endo 4.71 ~br6,2H)i~:
: 4.45 (s~d,2H), . 3.66 (d,lH), 3.52 ~d,lH), 3 . 42 ~ 6, 3H ~, 3 .15 ( 1;, 3H ) : - :

.~: . . i : - - ~: -.. ' ~ :

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-~WO91/034~ ~ 6 ~ 3 '3 7 PcT/usgo/n49s3 TEST A
Seeds of barley (~nL~Q~m ~1Q~L~
barnyardgrass (Echinochloa crus-~lli), cheatgrass (~ro~ s~~linus)~ cocklebur (Xanthium p~nsyl~ani~m)~ corn (~Q~ m~Y~), cotton ~Gossypium hirsutum), crabgrass (~i9i~Li~ spp.), giant foxtail (Set~ria $ab~i), morningglory ~1PQmQ8~ spp.), rice (Oryza ~ ), sorghum (~Lghym hi~QlQL), soybean (Gly~ine m~), sugar beet (~Q~Q Y~Qaris), velvetleaf (AbutilQD ~h~ophr~i), wheat (Triti~um aestivum), and wild oat (Avena fa~) and purple nutsedge (~YE~L~ rQtUndU~) tubers were planted and treated preemergence with test chemicals dissolved in a non~phytoto~ic solvent. At the same time, these crop and weed species were also treated with postemergence applications o~ test chemicals. Plants ran~ed in height from two to eighteen cm (two to three leaf stage) for postemergence treatments. Treated plants and untreated controls were maintained in a greenhouse for approximately si~teen days, a~ter which all species were compared to untreated controls and visually evaluated. Plant response ratings, summarized in Table A, are based on a scale of 0 to l0 where 0 is no effect and 10 is complete control.
A dash (-) response means no test result.

, WO 91/03464 ~ ~$ ~ 3 ~ ~¦ PCT/l,lS90iO4953 r Tnbl~ A

- COMPOUND CoMPOVND

:~ Rate (2000 g/ha) 43 ~4 45 46 47 Rate ~2000 g~ha) 43 44 45 46 47 POSTEMERGENCE PREEM~RGENCE
Barley 0 0 0 0 0 ~arley 0 0 0 0 0 8arnyardqrass 0 0 0 0 0 Barnyardgrass 0 2 2 0 0 Cheatgra~s 0 0 0 0 0 Cheatgrass 0 0 0 0 0 Coc~lebur 3 0 0 0 0 Coc~lebur 0 0 0 0 0 Corn 0 0 0 0 0 Corn 0 0 0 0 0 Cstton 0 0 0 0 0 Cotton 0 0 0 0 0 Crabgra~ 3 0 0 - 3 Crabgras6 4 0 0 0 2 Giant fo~tail 0 0 0 0 0 Giant fo~tail 5 2 3 5 3 Morningglory 0 0 0 0 0 Morningglory 0 0 0: 0 0 Nutsedge 0 0 - 0 0 Nut~edge - 0 0 - 0 ~ice 0 0 0 0 0 Rice 0 0 0 0 0 Sorghum 0 0 0 0 0 Sorghum 0 0 0 0 0 Soybean 0 0 0 0 0 Soybean 0 0 0 0 0 Sugar beet 0 0 0 0 0 Sugar beet - 0 0 0 0 0 Velvetleaf 0 0 0 0 0 Velvetleaf 0 0 0 0 0 Wheat 0 0 0 0 0 Wheat 0 0 0 0 0 ~ O~ o 0 O O O ~lld b.t o o o o o '~:
, ~ .

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:i-` WO 91/03464 `20l~Si31~ PCT'~l~'S9OtO495?l , COMPOUND

Rate ~400 g~ha) 1 2 3 4 5 6 7 8 9 lo 11 12 13 14 16 POSTEMERGENCE
Barley 0 O 0 O O O O 2 0 O 0 O 0 O O
Bar~yardgras6 6 0 O O 9 9 0 9 3 2 3 2 6 O O
Cheatgrass O O 0 0 O 0 0 0 O 0 0 0 0 3 D
Coc~lebur 2 1 2 1 4 1 o 3 2 3 2 1 2 0 O
CorD 0 0 O O 5 1 O 5 O O 0 O 2 O 0 CottoD 8 0 O O O 0 O 2 O 0 0 O O O 0 Crabgrass O 0 0 O 8 2 O 9 3 0 3 O 2 O
Giant fo~tail 0 0 0 O 8 4 O 9 2 O 0 O 0 2 4 Morningg~ory O O O O 0 O O O O 0 0 0 O 0 0 Nut6~dge O O O 9 O 0 0 O O 0 O - -Rice 1 1 O O O O O 6 O 0 O O O O 0 Sorghum 0 0 O O O O O: O O 0 O O O O O
~ybean 3 0 1 O 3 0 0 2 O 0 O O O O O
:,ugar beet 0 O O O 0 2 0 0 0 0 Q 0 1 2 0 Velvetleaf 1 O O O 0 O O O 0 6 O 2 O O 0 Wheat O
Wild Oat O O C O O C O O O O O O O O 0 ~''' .

WO 91/03464 ~ æ3 ~7 PCI /US90is)4953 .' ~

COMPOUND

Rat~ (400 g/ha) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 PREEMERGENCE
~arley 0 3 0 2 5 0 0 2 0 0 0 0 0 0 0 ~arny~rdgrass 10 10 9 10 10 9 0 10 7 8 9 8 8 0 7 Cheatgrass O O O 0 6 3 0 4 0 0 2 3 0 0 2 Cocklebur O O O 0 3 4 0 5 0 0 0 5 0 0 CorD O 3 0 3 6 4 0 4 0 0 0 0 0 0 2 Cotton O O O 0 2 0 0 3 0 0 0 0 0 0 0 CrabgraEs 9 9 7 9 9 6 0 9 7 8 7 7 0 3 0 Giant fo~tail 9 9 8 9 9 6 0 9 7 7 8 7 2 0 5 Morningglory O O O O O O O O 0 5 0 O O O O
Nut6~dge 0 0 0 0 0 4 0 2 0 0 0 0 0 0 0 Rice O O O O O O O O O O O O O O O
Sorghum O 9 0 8 7 0 0 5 0 0 O O O 0 6 Soybean O O O 1 6 0 0 3 2 0 0 0 0 0 0 Sugar beet O 1 0 0 2 4 0 3 0 0 0 0 0 0 0 Velvetleaf 1 1 1 1 7 0 0 6 2 5 2 6 0 0 Whe~t O O O 0 2 0 0 3 0 0 0 0 0 0 0 ~ild Oat O O O 0 3 2 0 0 0 0 2 0 0 0 0 .` , .
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;WO 91/03464 2~3;~` PCI /l 'S90/û4953 - .

o o o ~ o o I C~ o o o o ,1 o o ~1 0 0 0 _1 0 0 1 '_~ OI O C~ O O U~ O O
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Rate (200 g/ha) 167 168 POSTEMERGENCE
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- : ' W091/034~ ;''j~ ~0 6 5 3 3 7 PCT/~S901049~3 ~r , COMPOUND

Rate (50 g/ha) 155 156 157 158 166 167 168 POSTEMERGENCE
Barley 0 0 0 0 0 0 0 Barnyardgrass 4 0 6 2 0 0 0 Cheatgrass 0 0 0 0 0 O 0 Cocklebur 1 1 2 1 0 Corn 0 0 0 0 0 0 0 Cotton 0 0 3 0 0 0 0 Crabgrass 0 2 0 0 0 0 0 . Giant fo~tail 2 0 8 0 0 0 0 i Morningglory O O O O O O O
Nutsedge 0 0 0 - 0 0 0 Rice 0 0 0 0 0 0 0 Sorghum 2 0 0 0 0 0 0 Soybean 1 0 O O O 0 0 Sugar beet - 0 0 0 0 0 0 0 Velvetleaf 3 2 2 2 0 0 0 -Wheat O 0 0 0 0 0 0 Wild Oat O 0 0 0 0 0 0 - ~ :
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O O O O O O O O O O 1:~ 0 Q O O O O O
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V O O O O O O N O O O O O O O O O O
117 0 0 0 0 0 0 0 U~ O O O O O O O O O
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O O O O I O O '- N O N O O O O O O O
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el oo~o~--oo1`~oooooo~oo O O O ~1 0 0 ~ O O I O O .0 0 0 0 0 0 0 0 0 t`7 0 0 ~ N O O O ~ O O O . O O O
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WO91/03q64 ~65337 PCr/~sgo/o4953 s~

COMPOUND

Rate (5Q g/ha) 155 156 157 158 166 167 168 PREEMERGENCE
Barley0 0 0 0 0 0 0 ~arnyardgrass 10 9 10 10 5 0 Cheatgrass0 0 2 0 0 0 0 Cocklebur0 0 0 0 0 - 0 Corn 0 0 0 0 0 0 0 Cotton 0 0 0 0 0 0 0 Crabgrass 10 0 5 -9 3 0 0 Giant fo~tail 9 9 9 9 5 2 2 Morningylory 0 0 0 0 0 0 0 Nutsedge0 a a o - o o Rice 0 0 0 0 0 Sorghum 0 0 0 0 0 0 0 Soybean 1 0 0 0 0 0 0 Sugar beet 3 2 0 0 0 0 0 Velvetl-eaf 5 1 3 2 0 0 0 Wheat : 0 0 0 0 0 0 0 Wild Oat ' '' ~
- :

.

.

/ I~ WO 91/03464 ~ 2 Q 6 ~ 3 3 7 PCr/US90/049~3 ~EST ~
Seeds of barley ~QLdQ~m vu ln~L~), barnyardgrass (Echinochl.Qa ~gscg~lli), blackgrass (Alopecu~us myosurQides)~ cheat~rass (Bromu~
secalinus3, chickweed (~a~ m~), coeklebur (~hillm p~ani~m), corn (~. m~), ~otton (~ssyPil~m hi~m), crabgrass (Di~itaria spp.), Galium (~li~m ~Lln~), giant fo~tail (Setaria.
~ab~rii), lambsquarters (ChenQpodi~m ~l~m), morningglory (l~omoea hQ~S~~), rape (~ras~ica naPus), rice (Oryza sa~a~a)~ sorghum (~orgh~m ~i~QlQL)~ soybean (~ in~ m~), sugar beet (~
vul~a~i~), velvetleaf (A~utilQn theophrasti), wheat (Tritiçum aestivu-)~ wild buckwheat (Polyaonum ~onvolvuLu~), and wild oat (~Y~n~ f~Y~) and purple nutsedge (Cypel~s rotu~d~) tubers were plqnted and treated preemergence with test chemicals dissolved in 20 a non-phytoto~ic solvent. At the same time, these crop and weed species were also treated with :~ postemergence applications of test chemicals. Plants ranged in height from two to eighteen cm (one to four leaf stage) for postemergence treatments. Treated plants and untreated controls were maintained in a ~: greenhouse for appro~imately fifteen to twenty days, after which all treated plants wer~ compared to untreated controls and visually evaluated. Plant : response~ratings, summarized in Table B, are based on a scale of O to 10 where O is no effect and 10 is complete control. A dash (-) response means no test result.

WO91/0~ ~ ;'`'' ~io~ s3 PCT/US90/04953 !"~

COMPOUND . . COMPOUND

Rate ~400 g/ha) 169 170 Rate (400 g/ha) 169 170 Barley 0 0 8arley 0 0 Barnyardgrass0 0 ~arnyardgrass 0 0 Blackgrass 0 0 Blackgrass 0 0 Cheatgrass ~:0 0 Cheatgrass 0 0 Chickweed~ 0 0 Chickweed 0 0 Cocklebur 1 1 Cocklebur 0 0 Corn 0 0 Corn 0 0 Cotton 1 0 Cotton 0 0 Crabgrass 1 0 Crabgrass : 2 0 Galium 0 0 Galium 0 0 Giant fo~tail0 0 Giant fo~tail 1 0 La:mbsguarters 3 ~ 0 `Lambsquarters ~ 0 0 Morninggl~ory1 0 Morningglo:ry V :0 Nutsedge 0 0 ~ Nutsedge 0~ 0 Rape ~ 0 0 :Rape 0 0 Rice: 1 ~0 :~ ~lce 0:~ 0 Sorghum ~ 2 0 ~ Sorghum 0 0 Soybean ~ : 2 0 ~ Soybean 0 ~ 0 Sugar beet0 0 : ~ Sugar`beet - ~ 0 0 Velvetleaf ~-0 : Velvetleaf : 0. 0 Wheat ~ .0:~ 0 ~ : Wheat 0 0 :Wild buckwheat 0 0~ Wild buckwheat : 0 ~0 Wild oat~ 0~ 0 Wild oat - : 0 0 ::
: :

.

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-:;WO91/034~ ` '~ ^.,.g~ 5 3 3 7 PCT/~'S90/049i3 COMPOUND

Rate (200 g/ha) 162 163 164 165 171 POSTEMERGENCE
Barley 0 0 0 0 7 Barnyardgrass 0 0 0 0 10 Blackgrass 0 0 0 -0 5 Cheatgrass 0 0 0 0 5 Chickweed 0 2 0 0 5 Cocklebur 2 0 0 0 8 Corn 0 0 0 0 9 Cotton 0 0 0 0 2 Crabgrass 0 0 0 0 9 Galium 0 0 0 0 2 Giant fo~tail . 0 0 0 0 9 Lambsquarters 0 0 0 0 2 Morningglory 0 0 0 0 2 Nutsedge 0 0 0 0 9:
Rape 0 5 Rice 9 Sorghum 0 0 0 0 5 Soybean 0 0 0 0 7 Sugar beet 4 6 2 2 5 Velvetleaf 0 0 0 0 7 Wheat 0 0 0 0 8 Wild buckwheat 0 0 0 0 4 Wild oat 0 0 . 0 4 .

W O 91/034$4 ~ 'i 2 0 ~ 5 3 3 7 PC~r/US90/04953 ~ '. j COMPOUND

Rate ~200 g/ha) 162 163 164 165 171 PREEMERGENCE
Barley 2 0 0 3 0 Barnyardgrass 1 0 0 0 10 Blackgrass 3 2 3 2 10 Cheatgrass 2 2 2 0 10 Chickweed 2 6 0 10 10 Cocklebur 0 0 0 - 5 Corn 1 0 0 0 7 Cotton 0 0 0 0 7 Crabgrass 2 0 0 0 9 Galium 0 0 0 0 10 Giant fo~tail 3 3 2 0 9 Lambsquarters 0 2 - 0 10 Morningglory 0 0 0 0 4 Nutsedge 0 0 0 0 0 ~ape . 0 2 0 0 7 Rice 0 0 0 0 5 Sorghum 0 0 0 0 Soybean 0 0 0 0 8 Sugar beet 0 3 2 2 9 Velvetleaf 0 0 0 0 8 Wheat 0 0 . 2 0 Wild buckwheat 0 0 0 2 -10 Wild oat ; 2 0 2 2 9 ` .WO91/034~ - 2 0 6 ~ 3 3 7 PCT/US90/049;~

COMPOUND COMPOUND
f Rate (100 g/ha3 169 170Rate (100 g/ha) 169 170 POSTEMERGENCE PREEMERGEN~E f Barley 0 0 Barley 0 0 Barnyardgrass 0 0Barnyardgrass 0 0 Blackgrass 0 0 Blackgrass0 0 Cheatgrass 0 0 ~heatgrass0 0 Chickweed 0 0 Chickweed 0 0 Cocklebur 1 1 Cocklebur 0 0 Corn 0 0 Corn 0 0 Cotton 0 0 Cotton 0 0 Crabgrass 0 0 Crabgrass 0 0 Galium 0 0 Galium 0 0 Giant fostail 0 DGiant fostail 1 0 Lambsquarters 0 0Lambsquarters 0 0 Morningglory 0 0 Morningglory0 0 Nutsedge 0 0 Nutsedge 0 0 Rape 0 a Rape 0 0 Rice 0 0 Rice 0 0 Sorghum 0 0 Sorghum 0 0 Soybean 0 0 Soybean 0 0 Sugar beet 0 0 Sugar beet0 0 Velvetleaf 0 0 Velvetleaf0 0 Wheat 0 0 Wheat 0 0 Wild buckwheat 0 0Wild buckwheat 0 0 Wild oat 0 0 Wild oat 0 0 " "206~337 WO~I/03464 ~ ; PCr/US90/049;3 ,~

COMPOUND

Rate (50 g/ha) 162 163 164 165 171 POSTEMERGENCE
Barley 0 0 0 D O
Barnyardgrass 0 0 0 0 9 ~lackgrass 0 0 0 0 0 Cheatgrass 0 0 0 0 Chickweed 0 0 0 0 0 Cocklebur 0 0 0 0 4 Corn 0 0 0 0 7 Cotton 0 0 0 0 2 Crabqrass 0 D 0 0 S
Galium 0 0 0 0 0 Giant fo~tail 0 0 0 0 5 Lambsquarters 0 0 0 0 0 Morningglory 0 0 0 0 2 Nutsedge 0` 0 0 0 2 Rape 0 0 0 0 0 Rice 0 0 0 O 9 Sorghum 0 0 0 0 2 Soybean 4 Sugar beet 2 3 2 2 d Velvetleaf 0 0 0 0 5 Wheat ~
Wild buckwheat 0 D 0 0 O
Wild o~t , , .. ~. .

' ~ - .

06a337 W0 91/03464 ` `~ " `J -~ ` PCl`/VS901049~3 COMPOUND

Rate (50 g/ha) 162 163 164 165 171 PREEMERGENCE
8arley 0 0 0- 0 0 Barnyardgrass 0 ~ 0 0 0 9 ~lackgrass 2 2 2 2 5 Cheatgrass 2 0 0 0 2 Chic~weed 0 5 0 0 5 Cocklebur 0 0 - - -Corn 0 0 0 0 3 Cotton ~ 0 0 0 -0 2 Crabgrass 0 0 0 0 10 Galium 0~ 0 0 0 2 Giant foxtail 0 0 0 0 9 Lambsquarters 0 0 - 0 1 .
Morningglory 0 0 0 0 2 Nutsedge 0 0 0 0 Rape 0 ~0 0 0 Rice - 0 0 0 0 2 Sorghum 0 0 0 0 0 Soybean 0 ~0 0 0 2 Sugar~beet 0 2 2 2 0 Velvetleaf 0 0 0 0 4 Wheat ': -Wild~buckwheat` 0 0 0 0 0 Wild oat - 0 0 0 0 0 - . ~ , .

:~:
~.. ,,.. , -: ' .
~: ' ' ' ': ' ;,,. . ' ' '' W091/034~ `J ``~'~ 6 ~ 3 3 7 PCT/~S90/049~3 r T~T_~
Seeds of barley ~Q~m vulaare), barnyardgrass (E5hi~shl~ crus-gaili3, blackgrass ~ myQsurQid~ chickweed (st~ll~Li~
media), cocklebur ~8~n~hi~m ~~nsYlv~n~m), corn (~
m~Y~), cotton (Go~sy~i~m h~L~ rabgrass ( iqi~a~ia spp.), downy brome (~LQm~ c~QL~m)~
giant fostail (Se~a~ia faberi~, ~reen foxtail (Seta~ja viridi~), jimsonweed (DatuL~ st~a~onium), johnsongrass (sorq~um halepens~), lambsquarters (ChenopodL~m ~lk~m), morningglory (IDomo~ spp.), rape ~B~si~a napu~)i rice (Q~yz~ sativa), sicklepod 15 (CAS~1~ obtusi~olia), soybean ~lYin~ m~), sugar beet (~ vulga~is), teaweed (Si~ spinQ~a), velvetleaf (~butilon ~h~Q~h~a4$i), wheat ~I~iSisYm - ~ aes~u~), wild buckwheat (PolyPo~m s~n~Qlyyl~E) and wild oat (Avena~ fg~) and purple nutsedge (Cyperus LQ~nlg~) tubers were planted and treated preemergence with test chemicals dissolved in a non-phytoto~ic solvent. At the same time, these crop and weed species were also treated with postemergencé
applications o~ test chemicals. Plants ranged in height from two to eighteen cm (two to three leaf stage) for postemergence treatments. Treated plants and untreated controls were maintained in a gree~house for approsimately 24 days, after which all treated plants were compared to untreated controls and visually evaluated. Plant response ratings, summarized in Table C, are reported on a 0 to 10 scale where 0 is no effect and 10 is complete control. A dash (-) response means no test result.

.

W091/03464 ~"2~06~337 PCI/US90/049;3 Tabl~ C
.

COMPOUND COMPOUND

Rate (500 g~ha) 32 34`93Rate (500 g/ha) 32 34 93 POSTEMERGENCE PREEMERGENCE
Barley 0 0 0 Barley 0 0 Barnyardgrass10 7 7 Barnyardgrass10 10 10 Blackgrass0 0 4 ~lackgrass9 5 10 Chickweed0 0 0 Chickweed 4 9 6 Cocklebur0 0 3 Cocklebur 0 - 9 Corn 0 0 3 Corn 10 8 10 Cotton 0 0 0 Cotton 0 0 0 Crabgrass5 ~- 0 Crabgrass 9 9 9 Downy brome ~0 0 4 Downy brome4 0 0 Giant fo~tail7 5 7 Giant fo~tail10 10 10 Green fo~tail5 0 0 Green fostail10 10 10 Jimsonweed0 7 0 Jimsonweed0 0 0 Johnsongrass3 0 0 Johnsongrass10 10 9 Lambsguarters5 - - Lambsquarters- - -Morningglory0 0 0 Morningglory0 0 0 Nutsedge :0 3 3 Nutsedge 0 0 3 Rape 0 7 0 Rape 3 0 0 Rice 5 0 3 Rice 0 0 3 Slcklepod 0 - 0 Sicklepod Soybean ~0 0 :0 Soybean 0 0 0 Sugar: beet0: 5 3 Sugar beet0 0 5 Teaweedi ~: :0 0 7 Teaweed 3 5 6 Velvetleaf7 6 4 Velvetleaf 1~ 6 3 4 Wheat : 0 0 5 Wheat 0 0 8 Wild buckwheat 8 6 0Wild buckwhqzt 0 0 8 Wild oat 0 3 0 Wild oat 4 0 6 :

wo 91~03464 r ~ 2~0 6 ~ PCl /US90/049~3 ~

z40 .
.
:
~; COMPalND

Rate (250 g/ha)2 25 3234 93 94102118 120 130 131 132 133 134 135 . POSTE:MERGlSNCE
E~arl~y O 00 0 0 0 O O - 5 0 3 0 2 0 Bar~yardgra~6 6 8 10 7 52 8 10 10 10 10 8 7 10 8 Blaclcgra~ 0 3 0 0 3 3 7 8 10 9 6 6 4 6 4 ChiclLweed 0 0 0 0 0 0 0 7 6 7 4 4 4 5 3 Cocltlehur 0 6 0 0 0 5 0 0 Z O - - O 4 Corn 0 00 0 0 0 0 0 1 0 2 0 0 0 0 Cotton 0 00 0 0 0 0 0 0 0 0 2 4 0 0 Crabgra66 5 00 0 0 0 4 2 9 9 3 6 0 3 4 DO~rDY brome 0 0 0 0 3 0 0 1 4 B 3 4 3 3 0 Gi~mt fo~tail 0 3 3 3 45 5 10 10 9 6 7 6 7 6 Green fo~tail 0 0 0 0 0 2 0 10 10 80 6 0 6 3 Jim~onweed . 0 0 0 3 0 0 0 5 0 0 0 3 0- 4 2 John60Dgra~ 0 0 0 0 0 0 3: 4 6 6 0 3 0 6 6 Lrmb6guarter6 7 5 3 0 -:- 0 10 - 3 8 6 8 6 6 Morningglory 0 0 0 0 0 0 3 : 4 0 4 0 ~ 0 3 ~ 4 2 ~Nut6edge 0 00 0 0 0 0 0 0 0 0 6 0 7 5 Rape 4 0: 0 3 0 0 0 0 0 0 0 2 2 0 4 Rice 0 0:2 0 0 0 3 9 6 Z 6 6 5 7 3 Siclclepod 0 2 0 0 0 0 0 0 3 0 0 0 0 0 O
~: ~ SoybeaD 02 ` 0 0 0 ~ 0 0 3 3 0 0 0 0 2 0:
- 6ugar beet . 0 ~- 0 3 ; 3 4~ 6 2 6 0 7 6 3 6 6 'rea reed ~ 0: 0 0 0: 5 0 0: 6 4: 0 0 5 3 0 5 Velvetleaf - - 5 5 2 - 0 3 - 0 0- 5 6 4 6 W~eat 0 0 . O 03 0 3 0 6 5 ~ 0 3 4 0 ~W~ld buclnrheat - 3 3 5 O~ 0 3 10 10 97 9 7 7 7 Wild oat 0 0 0 00 0 0 3 - 7 0 0 :

:
.
~ .

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~ , : -` WO 91tO3464 ;` '. '~'5; ~3 ~: 2 0 6 5 3 3 7 PCT/~S90/0495~ , CoMPOUND

~ate (250 g/ha) 2 25 32 34 93 94 102 118 120 130 131 132 133-134 135 PR~EMERGENCE
~arley0 0 0 0 7 3 4 7 10 5 7 6 3 7 0 Barnyardgra~6 10 10 10 10 10 10 1010 10 1010 10 10 10 10 ~Iac~gra6~ 7 10 8 5 9 76 7 10 7 e 7 610 6 ~hic~eed 0 6 2 0 6 4 9 7 7 8 8 7 B 9 9 Go~lebur 0 7 0 0 7 10 3 4 3 6 010 7 3 0 Corn 2 3 3 0 8 0 210 10 4 6 5 3 8 0 Cotton 0 0 0 0 0 3 0 3 9 S 0 2 3 4 0 Crebgra6~ 8 9 2 8 9 101010 10 10 1010 10 1010 Do~ny brome 0 2 2 0 0 43 5 ~5 4 5 6 4 8 3 Giant fortail 10 10 10 10 10 10 1010 10 1010 10 10 10 10 Green fortail 10 9 10 10 10 9 7 10 1010 10 10 10 10 10 Jim60nweed 0 6 0 0 0 3 3 0 4 5 5 5 5 6 0 Johnsongra66 8 10 8 7 8 6 4 1010 9 1010 7 8 8 Lambsguarters 3 10 ~ 6 10 9 9 9 9 8 10 - 9 rniDgglory O 10 0 0 0 4 3 - - - 5 3 5 5 0 Nu~6edge 0 0 0 0 0 5 0 4 5 4 4 4 8 5 0 Rape 2 3 2 0 0 0 0 2 0 0 0 0 0 2 3 Rice 0 0 0 0 - 6 3 3 9 0 7 6 3 3 0 Sic~lepod 0 3 0 3 7 3 3 9 7 5 8 7 7 7 B
Soybean 0 0 0 0 0: 0 0 7 6 3 4 3 6 6 5 ~Sugar beet 0 4 0 0 0 0 6 9 6 5 7 8 7 9 6 Tea~eed 0 g 2 5 2 7 3 6 9 8 ô 7 7 510 :Velvetleaf 3 0 5 3 2 8 0 9 9 9 7 7 5 7 7 Wheat 0 0 0 0 5 3 4 2 - 4 2 4 4 6 0 Wild buc~hent 0 5 0 0 6 0 7 9 910 8 10 7 7 8 Wild ont 0 3 2: 0 2 4 3 6 4 2 3 4 06` 0 ~,~
`

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W0 91/03464 `; 7~ 3 1~ ~2 0 6 a 3 3 7 PCT/~S90/04953 ,~

COMPOUND
' i Rate ~125 g/ha) 2 25 32 34 94 102 118 119 120 130 131 132 133 134 135 POSTEMERGENCE
~arl~y O O O O O O 0 5 9 0 0 0 0 0 0 8arny~rdgra~ 2 4 g 7 0 610 9 10 9 5 7 4 8 7 Blac~gras6 0 0 0 0 0 3 0 9 9 9 ~ 3 3 4 3 Chic~weed O O O O O 0 5 6 6 7 4 3 4 4 0 Coc~lebur 0 5 0 0 0 - O O 1 - - O O O
Corn O O O O O O O O O O O O O O O
Cotton O - O O O O O 1 0 0 0 2- 3 0 0 Crabgra~s O O O O 0 3 2 5 9 0 0 3 0 0 3 Downy brome O O O O O O 0 7 4 3 0 0 o 0 0 Giant fortail O O O 0 2 3 7 9 10 9 6 5 4 6 5 Green fortail O O O O O O 9 4 10 0 0 2 o 3 o ~im60nweed 0 0 0 0 0 0 0 0 0 0 0 2 o 3 0 John60ngra66 0 0 0 0 0 0 4 0 - O O O 0 3 3 Lambbquarter~ 5 4 0 - O 5 9 8 3 5 4 ~ 3 5 Morningglory O O O O 0 2 0 1l 0 3 0 0 0 3 0 Nutcedge O O O O O O - O O O O O 0 5 5 Rape O O O O O O O O O O O O O 0 3 Rice O O O O O O 0 3 6 0 3 5 2 6 0 Sicklepod 0 2 0 0 0 O 0 3 0 0 0 0 0 0 0 ~Soyb~an O O O O O O O 0 3 0 0 0 0 2 0 Sugar beet 0 5 0 0 3 4 0 6 4 0 6 3 3 3 3 Teaweed O O O O - O 0 2 2 o o 3 o o 3 .Velvetleaf - 5 4 0 0 0 0 6 6 0 0 2 3 3 4 Wbeat O O O O 0 2 o 7 6 3 3 0 0 3 0 *ild buc~heat - O O O O O 9 9 10 7 6 6 5 7 -5 Wild oat O 7 5 3 ~' ~ ' ' .
:

WO 91/03464 ~ "' 2 ~ 6 ~ 3 3 7 PCltUS90/049~3 COMPOUND

Rate (125 g/ha) 2 25 32 3493 94 102 118 119lZ0:130 131132 133 134 135 PREEMERGENCE
Barley 0 0 0 0 3 0 0 2 7 5 0 4 4 3 7 0 9arnyardgrass 10 10 lû 10 1010 10 10 101010 10 10 10 1010 Blac~cgrass 3 10 6 3 7 3 3 6 610 4 7 7 3 7 3 Chic~weed 0 3 0 0 4 3 3 7 7 7 7 8 7 8 9 7 Coc~clebur 0 0 0 0 0 5 0 4 3 0 5 0 10 7 - O
Corn 0 2 3 0 2 0 0 5 310 3 2 5 0 3 0 Cotto~:. 0 0 0 0 0 2 0 3 3 5 5 0 0 0 3 0 Crabgra6s 2 7 2 3 8 9 7 10 101010 10 10 10 1010 Downy brome 0 0 0 0 0 3 2 5 7 4 3 3 4 3 5 0 Giant fo~tail 9 10 8 10 1010 8 10 101010 10 10 10 1010 Green fo~tail 7 6 7 10 10 6 5 10 101010 10 10 9 1010 Jimsonweed 0 3 0 0 0 0 0 0 0 3 2 5 5 4 6 0 Johnsongra6~ 5 7 8 7 5 5 2 10 810 8 10 9 5 7 7 Lambsquarter6 2 3 - - - - 5 3 9 9 0 8 8 8 7 7 Morningglory 0 6 0 0 0 4 0 - 4 - - 3 3 3 4 0 Nutsedge 0 0: 0 0 0 3 0 3 . 3 5 0 4 3 3 0 0 Rape 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0~2 Rice 0 0 0 0 3 0 0 2 7 - 0 6 5 3 0 0 Siclclepod 0 0 0 0 :- 0 0 5 8 5 5 6 6 5 7 3 Soybean 0 0 0 0 0 0 0 5 3 5 0 4 0 4 5 0 Sugar beet 0 3 0 0 0 0 3 7 6 5 4 6 6 6 7 6 Teaweed 0 5 0 2 0 6 0 - 3 9 6 5 7 6 3 3 Velvetlea~. 2 0- 1 0 0 3 0 8 6 8- S 6 7 4 6 6 Wh~t t 0 0 0 0 3 2 3 0 7 5 4 0 3 2 4 0 Wild bucl~wheat 0 0 0 0 3 0 5 9 8 8 9 7 8 - 7 7 7 Wild oat 0 0 0 0 0 3 0 0 6 2 0 3 3 0 4 0 , .:
:.
.
: ~ :
: .

, . , ' W O 91/03464 ';r~i-;`' d ~2~ ~ 5 3 3 7 PCT/US90/049O3 r-o CoMPOUND

: Rate (62 g~ha) 32 34 94 10Z 118 120 130 131 132 133 134 135 POSTEM~RGENCE
Barley 0 0 0 0 0 1 0 0 0 0 0 0 Barny~rdgra6s 0 3 0 0 9 10 0 5 5 3 7 6 Blac~grass 0 0 0 0 0 4 0 0 2 0 3 0 Chick~eed 0 0 0 0 0 3 3 3 0 0 3 0 Coc~lebur 0 0 0 - 0 0 0 - 0 0 0 Corn 0 0 0 - 0 0 0 0 0 0 0 0 Cotton 0 0 0 0 0 0 0 0 0 Z 0 0 Crabgrass 0 0 0 0 0 7 0 0 0 0 0 3 Do~ny brome 0 0 0 0 0 0 0 0 0 0 0 0 Giant ~ortail 0 0 0 0 5 10 0 3 3 3 5 4 Green fortail 0 0 0 0 8 5 0 0 0 0 0 0 Jim&onweed 0 0 0 0 0 0 0 0 0 0 3 :0 Johnsongrass 0 0 0 0 0 5 0 0 0 0 2 0 Lambsquarters 0 0 - 0 0 8 2 4 0 0 0 4 Morningglory 0 0 0 0 0 0 0 0 0 0 3 0 Nutsedge 0 0 0 0 0 0 0 0 0 0 3 3 Rape . 0 0 0 0 0 0 0 0 0 0 0 0 Rice 0 0 0 0 0 6 0 0 0 0 4 0 ~-Slc~lepod 0 0 - 0 0 0 0 0 0 0 0 0 Soybean 0 0: 0 0 0 2 0 0 0 0 0 0 Sugar beet 0 0 0 3 0 0 . 0 3 0 3 3 3 Tea~eed 0 0 0 0 0; 2 0 0 0 0 0 0 ~ VelvetIeaf 3 0 0 0 5 3 3 : Wh~at Wild buc~heat 0 -0 0 0 9 2 6 3 5 3 4 `0 ~ild oat 0 0 0 0 0 0 0 0 0 :: :

' WO 91/03464 ~ 2 0 6 ~ 3 3 7 PCl tUS90/049;3 ~.
CUMPOUND
: , , . I
Rate (62 g~h~) 2 25 32 34 93 94 102 118 119 120 130 131 132 133 134 135 PREEMERGENCE
~ar1eY 0 0 0 0 0 0 0 0 6 2 0 3 3 36 0 ~arDYard9raSS 8 10 10 10 107 910 10 10 10 10 10 7 10 10~1aC~gra~fi 0 7 2 3 0 0 3 5 5 7 3 57 0 5 o Chi~hreed 0 0 0 0 0 0 0 2 7 6 7 8 77 9 6 COC~1ebUr 0 0 0 0 - 3 0 4 0 0 - 0 56 - o COrn 0 0 0 0 0 0 0 0 0 2 0 a 2 03 0 Cotto~ 0 0 0 0 0 0 0 3 0 5 0 0 0 03 0 Cr~bgra~S 0 6 0 0 0 6 4 10 10 10 10 9 10 9 9 8 DOWDY brOme 0 0 0 0 0 0 0 0 5 3 2 02 2 3 0 Giant fost~il 7 10 7 7 2 g 7 10 . 910 10 8 10 7 9 9 Green fostail 5 S 7 7 2 4 5 10 1010 10 10 10 5 10 9 Jim80nWeed 0 3 0 0 0 0 0 0 0 2 2 45 3 S 0 JOhnSOngraSS 2 5 2 4 o o o 7 7 6 37 7 4 7 4 Lamb~quarters 0 0 8 - - - 3 0 9 8 o7 7 7 7 7 MOrnin9910rY 0 0 0 0 0 q 0 - 4 - - 3 3 0 3 0 NUtSedge - 0 0 0 0 0 0 3 3 0 0 4 00 0 0 R~pe O O - O O O O O O O O O O
Ri ce 0 0 0 0 0 0 0 0 5 8 0 0 3 20 0 SiC~IePOd 0 0 0 0 6 0 0 2 6 3 2 56 5 7 0 SOYbO~n 0 0: 0 0 0 0:0 0 3 3 0 3 03 3 0 ; :
. Sugar beet 0 0 0 0 0 0 0 4 5 5 4 5 6 5 6 4 T~a~eed 0 5 0 2 - 6 0 - 3 B 3 4 6 4 3 3 ~; - Volvetleaf - O O O O O 0 8 6 7 4 0 3 3 5 4 ~hea~ 0 0 0 0 0 0 0 0 4 3 0 0 2 0 -3 0 ~ild bUCkWheat 0 0 0 0 0 0 3 5 7 B 4 7 7 5 7 5 - Nild oat O O O O O O O 0 4 0 0 02 0 3 0 :

~ .
:
, wo 91/03464 ~ 2 0 6 ~ 3 3 7 PCI /l,~S90/0495~

.
CGMPOUND
Xate (31 g/ha) 94 102 118 120 130 131 132 133 134 135 POSTEMERGENCE
rley O O O O O O O O O O
~arnyardgra6s 0 0 4 10 0 3 3 0 6 4 Bl~c~gra66 0 0 0 0 0 0 0 O O O
Chickweed O O O O O O O O O O
Coc~lebur O - O O O O O O O
Corn O O O O O O O O O O
Cotton O O O O O O O O O O
Cr~bgrass O O O O Q O O O O O
Do~ny brome O O O O O O O O O O
Gi~nt ~o~tail O 0 2 B O O O 0 4 3 Green fo~tail O O 0 3 0 0 0 0 0 0 Jimsonweed 0 0 0 0 0 0 0 0 2 0 John60ngra66 0 0 0 0 0 0 0 0 0 0 L~mbsquarter6 - O - 2 - 3 0 0 0 0 Morningglory O O O O O O O D 3 0 Nut6edge 0 0 0 0 0 0 0 Rape O O
Rice O O O 0 0 0 0 0 3 0 Sic~lepod O O O O O O O O O O
Soybean O O O O O O O O O O
Sugar beet O O O O O O O 3 Tea~eed O O 0 2 0 0 0 0 0 0 Velvetle~ O O O O 3 3 Wb~at O O O O O O O O O O
Wild buc~wheat D 0 6 0 3 0 ~ 0 4 0 Wild oat .
i) .

' ,: :
' .~ ' .

`` W O 91/03464 ` t.. ~ PCr/US90/04953 20S~337 CoMPOUND
,:
Rate (31 g/ha) 2 25 94 102 118 119 120 130 131 132 133 134 135 PREEWE~GENCE :
8arley 0 0 0 0 0 2 0 0 0 0 2 3 0 ~arnyardgrass 3 10 54 10 1010 4 10 10 5 10 7 Llnc~grAs~ 0 0 0 0 4 3 4 0 4 3 0 4 0 Chick~eed 0 0 0 0 . 0 7 6 6 7 7 6 9 5 Coc~lebur 0 - 0 0 0 0 0 - 0 3 3 - 0 Corn 0 0 0 0 0 0 0 0 0 0 0 0 0 Cotto~ 0 0 0 0 0 4 Crab~rass 0 6 5 0 8 9 9 7 8 9 7 8 6 Do~ny brome 0 0 0 0 0 3 0 0 0 0 0 3 0 Giant fortail 2 9 3 5 6 8 10 2 6 7 5 8 7 Green fortail 3 6 3 4 9 9 6 2 5 8 ~ 5 7 Jimsonweed 0 3 0 0 0 0 0 0 4 5 0 4 0 Johnsongrass 0 5 0 0 S 4 4 0 4 7 3 5 3 Lamb6quarters O O - 3 O 9 0 0 5 7 7 5 6 Morningglory 0 0 4 0 - 3 - - - 0 3 0 0 0 Nut6edge 0 0 0 0 0 0 0 0 4 0 0 0 0 Rape 0 0 0 0 0 0 0 0 0 0 0 0 0 Rice ~ 0 0 0 0 0 ~ 2 0 0 0 3 0 0 0 Sic~l~pod 0 0 0 0 ~ 4 3 0 5 5 0 5 0 Soybean 0 0 0 0 0 0 0 0 0 0 2 0 0 Sugar beet 0 0~ 0 0 2 3 4 0 4 5 4 6 4 Tea~eed 0 5. 6 0 5 3 6 2 3 6 0 0 0 Velvetleaf 0 0 0 0.. 2. 5 3 0 0 0 2 4 3 Wheat 0 0 0 0 0 3 0 0 0 0 0 3 0 Wild buc}~heat 0 0. 0 2 -6 `` 6 3 6 6 5 7 3 Wild oat :: . 0 00 ` 0 0 3 - 0 0 `~' ~.' ' ~ . . ' `~

'~
.

.
' ' - ,.
.

wo g~ /03464 2 0 6 5 3 3 7 PCl /US90~04953 r~ ~ ~

.~E~ D
Compounds evaluated in this test were formulated in a non-phytoxic solvent and applied to the soil surface before plant seedlings emerged (preemergence application), to water that covered the , soil surface (paddy application), and to plants that were in the one-to-four leaf stage (postemergence application). A sandy loam soil was used for the preemergence and postemergence tests, while a ~ilt loam soil was used in the paddy test. Water depth was appro~imately 2.5 cm for the paddy test and was - maintained at this level for the duration of the test.
15Plant species in the preemerge~ce and - postemergence tests consisted of barley (~QL~m vul~aL~), blackgrass (Al~rQ~ myQ~u~
chickweed (S~lla~i~ m~ ), corn (~ m~Y~), cotton (Gos~ypium,, hirsutum)~ crab~rass (DiLL~Li~
20 sangu~ali~), downy brome (~ro~ tectQL~m)~ galium (Gali~m aparin~~, giant fostail.( ~ f~k~Lii)~
.lambsquarters (~hs~QQ~ilm ~l~m), morningglory (IDomoea he~race2), pigweed (Ama~anthus ret~QflgL~E), rape (~L~55i~ "~us~, ryegrass ~Lolium 25 multiflorum), sorghum ( ~ ~icolQ~)J soybean (Gly~ine m~), speedwell (Veroni~a P~l~i~), sugar . beet (~ vUl~aris)~ velvetleaf (Abutilon theophrasti.), wheat (Tri~ m aestivum), wild buckwheat (~Qlyg~LLm c~nvolv~lus), and wild oat 30 ~Avena ~ ). All plant pecies were planted one day before appli~ation of compounds for the preemergence portion of this test. Plantings of ' J
these species were adjusted to produce plants of appropriate size for the postemergence portion of the 35 test. Plant species in the paddy test consisted of : barnyardgrass (~chiDQchl:~a s~5t5311i), rice (Qryza ~ iY~), and umbrella sedge (Cyperu$ ~if~5~miE)-~ WO91/034~ ~ , PCT/~'S90/04953 ` - `2~65337 All plant species were grown using normal greenhouse practices. Visual evaluations of injury e~pressed on treated plants, when compared to untreated controls, were recorded appro~imately fourteen to twenty-one days after application vf test compounds. Plant response ratings, summarized in Table D, were recorded on a 0 to lO scale where 0 is no injury and lO is plant death. A dash (-) response means no test result.

., .
, ~' .

,. ' W O 9l/03464 ~ 3 3 7 P CT/ ~ S90/0495~ 1 ~able CoMPOUND

Rate (250 g~ha) 136 145 146 lg7 152 153 154 155 157 15B
POSTEMERGENCE
Barley 2 2 - 5 68 9 7 0 4 0 Blac~grass5 0 9 49 9 8 5 8 5 Chie~eed 9 0 4 09 8 8 8 9 6 Corn 2 2 2 38 7 7 3 6 0 Cotton 0 0 0 03 3 0 3 3 3 Crabgras~ 8 3 7 88 7 9 3 6 6 Dow~y brome 0 0 02 7 8 6 0 5 0 Galium 7 5 2 08 6 7 2 4 4 Giant fo~t~il 7 6 88 7 8 8 7 8 7 ~amb~guarters 9 0 00 8 9 6 5 8 6 Morningglory 0 3 03 2 0 2 0 0 0 Pig~eed 2 0 0 07 7 6 0 0 5 Rape . 5 0 0 00 0 0 - 3 0 2 Ryegras~ 4 8 7 68 9 8 0 7 0 Sorghum 3 0 3 46 8 6 0 6 0 Soybean :0 0 9 06 6 2 2 2 7 Speedwell 9 0:0 09 10 9 7 9 6 Sugar:beet8 0 0 010 10 8 9 910 Velvetle~f5 3 2 46 7 6 6 4 5 Wheat 3 4 4 68 - 7 Q 4 0 Wild buckw~eat 9 56 0 10 10 9 9 9 7 Wild oat 0 0 0 38 6 6 4 5 0 ' ' ' ' WO 91/03464 2 0 6 S 3 3 7 Pcr/usgo/049~3 COMPOVND
Raee (250 g~ha) 136 145146147 152153 154155 157 158 P~DDY
Baruyardgrass 9 9 8 8 10 10 10 10 10 10 Rice 8 7 7 7 9 9 9 B 9 7 Umbrella ~edge 9 4 8 8 10 9 10 9 9 9 COMPCXnlD

Rate (250 g/ha)136145146147 15Z153 154l5S 157 158 PREEMERGENCE
Barley 3 3 2 4 5 7 5 3 3 0 cl~gra6~ ~ 8 10 10 10 10 10 10 7 9 7 Chiclcweed 7 7 7 8 9 9 8 8 9 8 Corn 4 3 2 3 5 6 7 0 0 0 Cotton 0 3 2 3 5 5 4 2 3 2 Crabgra~ 10 9 10 10 10 10 10 10 10 10 DO~DY brome 3 3 0 0 5 6 7 0 4 3 Galium - 3 0 0 ~ 6 GiaDt fo~tail 10 10 10 10 10 10 10 10 10 10 Lamb6quart~r6 : 9 10 10 - 9 9 8 9 9 8 Morningglory 0 2 0 2 0 9 0 0 0 0 Pig~reed 7 3 0 2 8 8 7 7 7 7 Rape: 5 0 0 0 0 6 0 4 3 3 Ry~gras6 7 10 10 10 I0 10 10 3 7 5 Sorghum ~ 5 3 48 . 10 10 6 4 6 3 ~oybean 3 1 0 2 7 8 0 0 0 0 Spe-d~ell ~ - 9 B 10 7 8 7 Sugar beet 9 6 0 0 9 8 9 8 8 7 Velvetleaf0 - 75 7 : 8 8 B-8 7 8 heat 4 33 4 5 5 5 4 Wi'd buc~cwheat 9 5 5 4 9 9 - 8 7 8 6 Wiid oat 4 40 3 1010 6 - 0 0 ',~

. ~ .
; ~

WO 91/03464 ~' ~,,2,,~6;!~;3 3 7 PCI/US90/04953 ~.,.

R~lte ~125 g/ha) 136145 146147 152153154 155 157 158 POSTEMERGENCE
Barley o 0 2 5 5 4 6 0 4 0 Bl~lcl~gra66 4 0 2 - 8 6 6 3 7 0 Chiclnreed 9 0 0 0 7 7 8 5 7 2 Corn 0 0 0 2 6 6 6 0 6 0 Cotton 0 0 0 0 2 2 0 0 0 2 Crabgras~ 6 0 3 7 4 5 7 0 3 4 Downy brome0 0 0 0 5 5 5 0 4 0 G~lliwn 4 0 0 0 3 3 6 2 3 0 Giant fo~tail :5 5 ~ ~7 7 7 7 4 7 7 Lamb6quarter6 6 0 0 0 7 6 6 - 7 5 Morningglory 0 0 0 2 0 0 0 0 0 0 Pigweed 2 0 0 03 5 3 0 0 5 R~lpe 5 0 0 00 0 0 0 0 0 Ryegra66 0 0 5 64 7 7 0 4 0 Sorghum 2 0 0 33 3 2 0 0 0 Soybean 0 0 0 04 3 0 0 0 3 Spe~duell 7 0 0 06 9 B 7 9 4 Sugar beet 2 0 0 08 4 - 6 6 0 Velvetlea~ 5 2 0 33 5 5 5 0 3 ~eat 0 3 2 53 6 6 0 4 0 Wild:bucl~wheat9 0 4 .0 8 9 6 3 5 0 Wlld oat ~0 0 0 03 5 3 3 ~OMR0U21D

Rate (125 g/ha)-136145 146 147 152 153 154 155 157 158 PADDY
8a:rnyardgra6s 9 6 6 6 10 10 lQ 10 10 10 Rice 7 3 4 78 8 9 5 8 2 Umbrelln~odge 9~ 3 44 9 9 9 8 9 8 .

:

- W O 91/03464~ 2 9 6 5 3 3 7 PCT/VS90/04953 CCMPOUND

Rate ~125 g/ha) 136 145 146 147 152 153 154 155 157 158 PREEMERGENCE
~arley 2 0 0 3 5 4 3 0 2 0 Plac~gras6 8 7 7 8 1010 7 6 8 4 Chickweed 7 7 6 7 9 8 8 B B 8 Corr~ 1 1 0 2 3 2 3 0 0 0 Cotton 0 2 1 2 0 3 3 0 2 0 Crabgra6s 10 910 10 1010 10 1010 10 DQwny brome 2 0 0 0 3 4 5 0 3 0 Galium_ o O O - - 7 _ o O
Giant fostail10 9 10 9 10 10 10 10 10 10 L~mbfiquarters 8 10 10 - 9 9 8 9 8 B
Morningglory0 0 0 2 0 0 0 0 0 0 Pigweed7 2 0 0 7 7 6 6 3 6 Rape S O O O 0 3 0 3 0 2 Ryegrass 7 7 5 10 5 6 8 0 5 0 Sorqhu~ 4 1 2 1 10 10 3 3 3 0 Soybean 0 0 0 0 4 6 0 0 0 0 Speedwell 7 - - - 8 8 8 6 7 6 Sugar beet 9 5 0 0 8 7 8 8 6 6 Velvetleaf 7 3 5 5 7 8 8 7 6 6 Wheat 3 3 4 4 4 3 Wild buclcwheat 9 3 ~ 3 8 8 7 6 7 4 Wild o~t 3 0 0 2 3 10 3 - O O

~ .

91/03464 ~ O ~ ~ 3 3 7 PCT/US90/04953 COMPOUND

R~te (62 g/ha) 136 145 146 147 152 153 154 155 157 158 POSTEMERGENCE
~arl~y . 0 0 0 4 4 2 3 0 2 0 .
91ac~gr~66 4 0 0 0 5 4 4 0 2 0 Chic~eed 2 0 0 0 7 6 6 0 5 0 Corn 0 0 0 0 3 2 4 0 0 0 Cotto~ 0 0 0 0 0 2 0 0 0 2 Crabgra6s 2 0 2 0 3 3 6 0 3 2 Dow~y brome 0 0 0 0 4 0 3 0 3 0 Galium 0 0 0 0 0 2 5 0 0 Giant fo~tail 2 0 3 2 4 6 7 0 4 3 Lamb~quarterE 3 0 0 0 5 4 5 4 - 4 Morningglory 0 0 0 0 0 0 0 0 Pigweed 0 0 0 0 0 4 0 0 0 3 Rape 0 0 0 0 0 0 0 0 0 0 Ryegras6 . 0 0 0 4 3 0 4 0 4 0 Sorghum 0 0 0 2 0 0 1 0 0 0 Soybean 0 0 0 0 2 2 0 0 0 2 Speedw~ll 0 0 0 0 6 6 8 q 8 0 Sugar beet 0 0 0 0 0 - 5 2 3 0 Velvetle~f 2 0 0 0 3 4 3 3 0 0 Wheat 0 3 3 4 5 i Wild buckwhoat 4 O O O - 9 6 0 4 0 ild oat 0 0 0 0 0 2 2 C O O

' :

~ - WO 91/03464,2~0. 6 5 3 3 7 PCT/US90/0495?~

COMPOUND

R~te (62 g/ha)136 145 1~6 147 152 153 154 15S 157 158 PADI)Y
~ar~yardgra66 9 ~ S4 10 10 10 10 9 10 Rice 4 1 1 3 7 8 8 3 6 0 Umbrella 6edge 9 2 22 9 9 9 7 9 P

CoMPoUND

Rate (62 g/ha) 136 145 146 147 152 153 154 155 157 158 PREEMERGENCE
Barley O O O 0 3 3 2 o O o Blac~grass 7 3 3 6 7 7 6 ~ 6 0 Chic~weed 5 6 6 7 9 8 7 7 7 7 Corn O O O O O O O O O O
cotto~ . o O O o O o 2 o o o CrAbgrass 10 9 9 10 10 10 10 10 9' 9 DOWDY brome O O O O ~ 3 3 3 ~, .
Galium 8 0 0 0 - O 3 0 O O
Gia~t fostail 10 8 8 8 10 10 10 10 10 10 ,`, Lambsquarters 5 10 10 - 7 9 8 7 8 5 Morningglory - O O O O 0 0 0 0 O O
Pigweed 6 0 0 0 6 6 : 5 3 0 4 ~ R~pe 2 0 0 0 0 0 0 0 0 0 ; Ryegrass '4 3 0 7 q- 6 5 0 3 0 : Sorghum 2 0 0 0 6 3 2 0 0 0 ~ Soy~an O O O : 0 2 3 0 0 0 O
:~ Speed~ell 2 - - - 8 8 7 6 6 5 Sugar beet 8 3 0 0 7 6 6 6 6 5 - Velv~tle~f 5 Z 2 5 5 : 6 7 3 4 3 Wheat O O O 0 3 3 3 0 0 0 Wild buc~wheat 8 3 3 0 7 7 6 4 4 3 Wild oat2 0 0 0 O O O O O O

' 91/03464 . . 2 0 6 ~ 3 3 7 PCl'/US90/04953 .~--\

CGMPOUND

Rate /,31 g/ha) 136 145 14~ 147 152 153 154 155 157 158 POSTEMERGENCE
B~rley 0 O O 0 0 0 3 0 0 0 ~lsc~gr~6s 3 0 O O 0 O 0 O - O
Chic~eed 0 O O O O 2 3 O O O
corD O O O O 0 0 2 0 0 0 Cotton 0 0 O O 0 O `0 0 0 2 Crabgr~ss 0- O 0 O 2 2 3 O 3 O
DOWDY brome 0 0 O 0 0 O 2 O O O
Galium 0 O O O 0 O O O O O
Giant fostail 0 O O O O 4 4 0 3 O
l,~mbsquarter6 0 O O O 0 3 4 Morningglory 0 O 0 0 0 O O O O O
Pigweed 0 0 0 0 0 3 Rape 0 0 O 0 0 Ryegrass O O O 0 O 0 0 0 0 0 Sorghum O O O O 0 O O 0 O O
Soybean 0 O O O O O :O O O O
Speedwell 0 O O O O 3 4 O O O
Sugar beet O O O 0 - O 0 2 O O
Velvetleaf 2 O O O 2 0 O O O O
Wheat O O O 2 O 2 O 0 O O
Wild buc~wheat O O O O 6 O - O O O
0l~ a o o o o o a o o o : wo91/0346~ 337 PCT/US90/04953 CoMPOUND

R~te ( 31 g~ha) 136 145 146 147 152 153 154 155 157 158 PADDY
B~rDyardgr~6 6 3 43 9 9 10 10 9 9 Rice 2 0 1 1 4 2 4 2 2 0 Umbrell~ ~edge 7 0 0 0 9 9 - - - 2 CoMPOUND

Rate:(31 g/ha) 136 145 146 147 152 153 154 155 157 158 PREEMERGENCE
Barley 0 00 0 0 0 0 0 0 0 Blac~grass 5 00 3 5 6 3 3 3 0 Chic~weed 4 35 7 7 8 7 5 7 3 Corn 0 00 o 0 0 0 0 0 0 Cotto~ o 0 0 o ~ 0 0 0 0 o Crabgrass 8. 7 9 9 10 10 10 7 8 5 Downy brome 0 0 0 0 0 0 0 0 0 0 Galium 8 0 O O - O 0 0 0 O
Giant fo~tail 8 4 67 1010 10 9 10 8 L~mb~quArter6 0 1010 - - 3 5 5 8 3 Morningglory 00 0 00 0 0 0 0 0 Pig~eed 00 0 53 : 0 0 0 0 Rape 0 00 0 0 0 :
Ryegra~6 0 00 ; 3 3 3 3 0 0 0 ~Sorghum 0 0 0 ~ O 3 2 0 0 0 0 Soy~n 0 0 0 0 2 0 0 0 0 0 Speed~ell 2 - - - 6 6 6 4 6 3 Sug~r beet 7 0 0 0 6 5 i 4 2 4 Velvetleaf 3 2 2 0 3 0 4 0 3 0 ~heat 0 -W~ld buc~wheat 5 O 0 0 6 6 4 3 2 0 Wild oat 0 : 0 0 0 , .

W V 91/03464 ~ ~ 6 ~ 3 3 7 PCT/US9~/049~3 .

COMPOUND

R~te tl6 gf~a) lgS 146 147 152 153 154 155 157 158 POST~MERGENCE
Barley 0 0 0 0 0 2 0 0 0 Blac~grn6~ 0 0 0 C 0 0 0 0 0 Chic~woed 0 0 0 0 0 0 0 0 0 CorD O O O O o o o o o Cotton 0 0 0 0 0 0 0 0 2 Crabgra6 6 0 0 0 0 0 0 0 0 0 Downy brome 0 0 0 0 0 0 0 0 0 Galium 0 0 0 0 0 0 0 0 0 Gi~t ~o~tail 0 0 0 0 3 0 0 0 0 Lamb~quarter~ 0 0 0 0 O 0 0 0 O
Morningglory 0 0 0 0 0 0 0 0 0 Pigweed 0 0 0 Rape 0 0 0 0 0 0 Rysgra6g 0 0 0 0 O O O O O
: Sorghum -0 0 0 0 O 0 0 0 O
Soybean 0 0 0 0 0 0 0 0 0 Speedwell 0 0 0 0 0 2 0 0 0 Sugar beet 0 0 0 0 0 0 0 - 0 Velvetl-af 0 0 0 0 : Wheat 0 0 Wild buc~heat 0 0 0 0 0 5 ~
Wild ~at .

Rate (16 g/ha) 145 146 147 152 153 154 155 157 158 PADDY
Bsrnyardgra~ 9 2 . 3 9 8 8 9 8 - 9 Rice 0 0 1 2 1 2 0 0 0 Um~rella c-dge 0 O 0 ' ~ .
'~ . .

.
' ' - ' ' ~` W O 91/03464 i ; ~ :~`$337 PCT/~S90/04953 CoMPOUND
, R~te (16 g/ha~ 145 146 147 152 153 154 155 157 158 PREE~ERG~NCE
Larley 0 0 00 0 0 0 0 0 Ela~gra660 0 03 3 3 3 o O
Chic~weed3 3 4 - 6 7 3 0 0 Corn 0 0 00 0 0 0 0 0 Cotton 0 0 00 0 0 0 0 0 Crabgras64 7 510 8 8 6 3 4 Dow~y brome ~ 0 0 0 0 0 0 0 0 0 Galium 0 0 0 - 0 0 0 0 0 Giant fo~tail 2 22 8 10 10 6 10 5 Lambsquarter610 10 - O 0 3 3 3 0 Morningglory 0 00 0 0 0 0 0 0 Pig~eed 0 0 04 0 0 0 0 0 Rape 0 0 00 0 0 0 0 0 Ryeyra66 0 0 00 0 0 0 0 0 Sorghwm 0 0 0 O O O O 0 O
Soybean 0 0 0 0 0 0 0 0 0 Speed~ell - - -- 5 5 4 3 3 0 Sugar beet 0 0 0 3 3 3 3 0 3 Velvetleaf 0 2 0 0 0 0 0 0 0 Wheat 0 0 0 O O O O O O
Wild buchwheat 0 0 0 4 3 3 0 0 0 Wild oat 0 0 - .

~ .

, :

W091/034~ ~ 2 0 ~ 3 ~ 7 PCT/US90/0495 ~E~ .
Plastic pots were partially filled with silt loam soil. The soil was then saturated with water.
Indica and/or Japonica rice (Oryza sativa) seedlings at the 2.0 to 2.5 leaf stage; seeds of barnyardgrass ~Echinochloa crus-~a~ ulrush (Scirpus mucronatus), duck salad (~tcL~n~hc~ limQ~a), and umbrella sedge (Cyperus difformi~); and tubers of arrowhead (~ittari~ spp.) and waterchestnut (Eleo~haris spp.) were planted into this soil.
- Several days after planting, water levels were raised to 3 cm above the soil surface and maintained at this level throughout the test. Chemical treatments were formulated in a non-phytoto~ic solvent and applied directly to the paddy water. Treated plants and - untreated controls were maintained in a greenhouse for 21 days, after which all treated plants were compared to untreated controls and visually evaluated. Plant response ratings, summarized in Table E, are reported on a 0 to 10 scale where 0 is no effect and 10 is complete control. A dash (-) response means no test result.

.

, ,.

WO 91/034~ O ~ 5 3 3 7 PCI /US90/049;~

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U~ O O O I o o o ~ I t` Ir~
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,., WO g1/03464 ~ J d i2`~ 6 ~ 3 ~ 7 PC-r/l~'S90/04953 '~.

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D~ ~ U C1 v , c a U r~ U _ C ~: c 'I s WO91/034~ 2 0 6 ~ 3 3 7 PCT/US90/04953 ~ ' EST F
Seeds of spring and winter barley (Hor~a~m vulQ~L~), blackgrass (~lQPeaaC~r~s mvosuroid~), black nightshade ~Solanum niqr~m), bluegrass (Poa annua), cheatgrass (~romus secalin~ downy brome (~LQm~
~ect~rUm), field pennycress (~hlaspi arve~e), field violet tViol2 arvenSL~), galium ~alium aParin~
green fo~tail (Se~lia ~i~ ), ivyleaf speedwell (Veroni~ hederaefoli~), jointed goatgrass (~silQoe~
cYlind~i~a)~ kochia (~QC~i~ scoparL~), lambsquarters (~henopodium ~l~m), Persian speedwell (yQL~nia Dersica), rape (B~ssica n~ ), Russian thistle ( ~ k~li), ryegrass (~Qli~m multi~lQ~um), scentless chamomile (~atricaLia i~Q~Q~), sugar beet ~ vul~aris), spring and winter wheat (TritL~m aestivum~, wild buckwheat (PolyQQnum convQlvulu$)~
and wild oat (Avena f~ were planted and treated preemergence with the te~t chemical dissolved in a non-phytotosic solvent. At the same time, these crop and weed species were also treated with postemergen~e applications of the test chemical. Plants ranged in height from two to twenty-four cm for postemergence ~5 treatments. Blackgrass and wild oat were treated postemergence at two growth stages. The first growth stage (1) was at the 1-2 leaf stage while the second stage (2~ was at the four leaf stage. Treated plants and untreated controls were maintained in a greenhouse for appro~imately 21 days. All treated plants were then compared to untreated controls and visually evaluated for injury. Plant response ratings,-summarized in Table F, are based on a zero to ten scale where O is no effect and 10 is complete control.

206~337 WO91/034~ ~, ~ , PCT/ US90/0495 T~l QE

COMPOUND COMPOUND
.
Rate (500 g/ha) 25 Rate ~500 g/ha) 25 POSTEMERGENCE PREEMERGENCE
Barley (Spring) 5 Barley (Spring) Barley (Winter) 5 Barley tWinter) 4 Blackgrass (l) 3 Blackgrass 6 Blackgrass (2) 2 Blk. nightshade 0 BIk. nightshade 0 Bluegrass 8 Bluegrass 2 Cheatgràss 6 Cheatgrass 0 Downy brome 3 Downy brome 0 Fld. pennycress l0 Fld. pennycress 0 Fld. violet 2 Fld. violet 2 Galium 5 Galium 0 Green fostail l0 Green fo~tail 4 Ivylf speedwell 2 Ivylf speedwell 0 ~Jntd. goatgrass 3 Jntd. goatgrass l Xochia 3 Kochia 2 Lambsquarters 2 Lambsguarters 4 Prsn. speedwell 7 Prsn. speedwell 0 ~ape 3 Rape 4 Russian thistle 3 Russian thistle l Ryegrass 9 Ryegrass - 3 Snls. chamomile 7 Snls. chamomile 0 Sugar beet 5 Sugar beet 2 - Wheat (Spring) 3 Wheat tSpring) 7 Wheat ~Winter) 2 Wheat (Winter) 2~ Wild buckwheat 2 Wild buckwheat 0 Wild oat 2 Wild oat (l) -- l Wi}d oat ~2) .
.:~

::

~ .
.~ , , ~;
.

WO91/034~ 2 0 6 ~ ~ 3 7 PCT/~'S90/0~953 .~~.

COMPOUND COMPOVND

Rate (250 g/ha) 25 Rate (250 g/ha) 25 POSTEM~RGENCE PREEMERGENCE
Barley (Spring) 4 Barley (Spring) 3 Barley (Winter) 4 Barley (Winter) 2 -Blackgrass (l) l Blackgrass 3 Blackgrass (2) 0 Blk. ni~htshade 0 Blk. nightshade 0 Bluegrass 8 Bluegrass l Cheatgrass 6 Cheatgrass 0 Downy brome Downy brome 0 Fld. pennycress 7 Fld. pennycress 0 Fld. violet 0 Fld. violet 0 Galium 0 Galium 0 ~reen fostail l0 Green fogtail 2 Ivylf speedwell 0 Ivylf speedwell 0 Jntd. goatgrass Jntd. goatgrass 0 Rochia - l ~ochia 0 Lambsquarters Lambsquarters 3 Prsn. speedwell 7 Prsn. speedwell 0 Rape 3 Rape ~ 2 Russian thistle Russian thistle 0 Ryegrass 9 Ryegrass l Snls. chamomile Snls. chamomile 0 Sugar beet 3 Sugar beet: l Wheat (Spring) Wheat (Spring) 4 Wheat (Winter) Wheat (Winter) 2 Wild buckwheat 0 Wild buckwheat 0 Wild oat Wild oat ~l) 0 Wild oat (2) 0 ~'~
~ .

, , WO 91/03464 `\~ ' 2 0 6 5 3 3 7 P~/US90~4953 . COMPOVND COMPOUND

Rate~(125 g/ha) 25 Rate (125 g~ha) 25 POSTEMERGENCE PREEMERGENCE
Barley (Spring) 4 Barley (Spring) 2 Barley (Winter) 2 Barley (Winter) 1 Blackgrass tl) 0 ~lackgrass 2 Bla~kgrass (2) 0 Blk. nightshade 0 Blk. nightshade 0 Bluegrass 7 Bluegrass 0 Cheatgrass 5 Cheatgrass 0 Downy brome 0 Downy brome 0 Fld. pennycress Fld. pennycress 0 Fld. violet 0 Fld. violet 0 Galium 0 Galium 0 Green fo~tail 10 Green ~o~tail 1 Ivylf speedwell 0 Ivylf speedwell 0 Jntd. goatgrass 0 Jntd. goatgrass 0 ~ochia 0 Kochia . 0 Lambsquarters Lambsquarters 0 Prsn. speedwell 2 Prsn. speedwell 0 Rape 2 Rape 1 Russian thistle 0 Russian thistle 0 Ryegrass 9 Ryegrass 0 Snls. chamomile 0 Snls. chamomile .. 0 Sugar ~aet 3 i Sugar beet-: - 1 Wheat (Spring) Wheat (Spring). 2 Wheat (Winter) 0 Wheat (Winter) 1 Wild buckwheat 0 Wild buckwheat 0 Wild oat 0 Wild oat (1) 0 Wild oat (2~

WO91/034~ `~ 2;~ 3 7 PCT/~S90~049~3 ~' COMPOUND COMPOUND

~ate ~69 g~ha) 25 Rate ~64 g~ha) 25 POSTEMERGENCE PREEMERGENCE
Barley (Spring~ 2 Barley (Spring) Barley (Win$er) l Barley (Winter) 0 Blackgrass (l) 0 Blackgrass 0 Blackgrass (2) 0 Blk. nightshade 0 Blk. nightshade 0 Bluegrass 5 Bluegrass 0 Cheatgrass 3 Cheatgrass 0 Downy brome D
Downy br~me 0 Fld. pennycress 0 Fld. pennycress 0 Fld. violet 0 Fld. violet 0 Galium 0 ~alium 0 Green fo~tail Green fo~tail 0 Ivylf speedwell 0 Ivylf speedwell 0 Jntd. goatgrass 0 Jntd. goatgrass 0 Kochia 0 Kochia -O Lambs~uarters Lambsquarters 0 Prsn. speedwell 0 Prsn. speedwell 0 Rape 0 Rape 0 Russian thistle 0 Russian thistle 0 Ryegrass 7 Ryegrass 0 Snls. chamomile 0 Snls. chamomile 0 Sugar beet 2 Sugar beet - 0 Wheat (Spring) 0 Wheat (Spring) l Wheat ~Winter) 0 Wheat (Winter) 0 Wild buckwheat 0 Wild buckwheat - 0 Wild oat 0 Wild oat (l) 0 `~ Wild oat ~2) 0 -~

~ .
:

.

- WO91/034~ "'''`'' ``2 0 ~ ~ 3 3 7 PCTtUS90tO49;3 COMPOUND COMPOUND

Rate (32 g/ha) 25 Rate (32 g/ha) 25 POSTEMERGENCE PR~EMERGENCE
Barley ~Spring) l Barley ~Spring) Barley (Winter) 0 Barley (Winter) 0 Blackgrass (l) 0 Blackgrass 0 Blackgrass (2) D Blk. nightshade 0 Blk. nightshade 0 Bluegrass 2 Bluegrass 0 Cheatgrass 0 Cheatgrass 0 Downy brome 0 Downy brome 0 Fld. pennycress 0 Fld. pennycress 0 Fld. violet 0 Fld. violet 0 Galium 0 Galium 0 Green fostail 3 Green foxtail 0 Ivylf speedwell 0 Ivylf speedwell 0 Jntd. goatgrass 0 Jntd. goatgrass 0 ~ochia 0 Kochia ~ O Lambsquarters 0 Lambsquarters 0 Prsn. speedwell 0 Prsn. speedwell 0 Rape 0 Rape 0 Russian thistle 0 Russian thistle 0 Ryegrass 4 Ryegrass 0 Snls. chamomile 0 Snls. chamomile 0 Sugar beet 2 Sugar beet 0 Wheat (Springj O
Wheat (Spring? O Wheat (Wint~r) 0 Wheat (Winter) 0 Wild buckwheat 0 Wild buckwheat 0 Wild oat 0 Wild oat (l) 0 Wild o~t (2) 0 ' ~ .

WO91/03464 .~ 2 0 6 ~ 3 ~ 7 PCT/~S90/04953 ,~~.

TEST G
Seeds, rhizomes, or tubers of alfalfa (Medica~o sativa), barnyardgrass (EchinQchloa cr~s-g.alli), bermudagrass (~ynQ~Qn dactylQn), broadleaf signalgrass (~laçhi3~ ~L~3gin~a), field bindweed (Convolvul~ ar.vensis), guineagrass (~ m m~im~m3, johnsonyrass (SQI~h~m h~lsP~n~), large crabgrass (Dipi~ria s _ ), pitted morningglory (Ip~Qe.a 13~nQ5~), purple nutsedge (Cyperus ~Q~m g9~)~ purslane (~Q~ D~a ole~c~
ragweed (hmb~s~ia artemL~ifolia)~ sandbur (sQn~hL~5 echin~g~), smooth crabgrass (ri9i~d~i~ i~sh~mYm)~
lS Te~as panicum (P..~ni~um ~Q3~n~m), tropical kudzu -(Pueraria ~avani~a), and yellow nutsedge (~YE~
es~l~n~) were planted into greenhouse pots containing greenhouse planting medium. ~ach pot contained only one plant species. Test compounds ~o were dissolved in a non-phytoto~ic solvent and applied to the soil surface (~reemergence). These applications were made within one day of planting.
Control pots receiving no test treatments and treated pots were maintained under ~reenhouse conditions for 13 to 21 days after herbicide application. ~rowth of - treated plants was compared to that of untreated controls and visually e~aluated. Plant response ratings, summarized in Table B, are based on a zero to 10 scale where zero is no injury, and 10 is plant death. A dash (-) response means no test result.

~ , : 35 ' -: 2Q~337 -~ WO91/034~ PCT/US90/0~953 Table G

COMPOUND
.

Rate (250 g~ha) 118 I32 136 147 153 154 157 PREEMERGENCE
~lfalfa 2 5 3 0 2 4 3 3arnyardgrass10 10 10 10 10 10 10 Bermudagrass10 10 10 10 10 10 10 Brdlf sgnlgrass 10 10 10 10 10 10 10 Field bindweed 0 5 1 0 1 1 0 Guineagrass 10 10 9 10 10 10 10 Johnsongrass 8 lD 2 2 10 10 10 Large crabgrass 9 10 10 10 10 10 10 Pitted mrnglory 0 3 2 1 0 3 2 Purple nutsedge 10 10 10 7 10 3 Purslane 7 10 8 1 9 9 7 Ragweed 1 6 2 0 5 10 9 Sandbur - 10 Smooth crbgrass 10 10 10 10 10 10 10 Te~as panicum .6 10 5 9 10 10 9 Trop. kudzu 6 10 9 7 9 9 9 Yello~ nutsedge 6 10 2 D 8 2 ~ : . ' ;~ ' .

`~. 2a~ 337 W091/034~ PCT/US90io4953 ~-COMPOUND

Rate (125 y/ha) 118 132 136 147 153 154 157 PREEME~GENCE
Alfalfa 0 3 1 0 1 4 5 Barnyardgrass 10 10 10 10 1010 10 Bermudagrass 10 10 10 10 1010 10 Brdlf sgnlgrass 10 10 10 710 10 9 Field bindweed 0 0 1 0 1 1 0 Guineagrass 10 8 9 8 1010 10 Johnsongrass 4 10 2 0 9 9 10 Large crabgrass 9 10 10 1010 10 9 Pitted mrnglory 1 0 1 0 1 3 2 Purple nutsedge 10 8 10 0 7 1 3 Purslane S 7 3 0 10 6 2 Ragweed 0 3 0 G 1 9 9 Sandbur - 10 - - - - -: Smooth crbgrass 10 10 10 1010 10 10 Te~as panicum 1 9 2 8 10 9 8 Trop. kudzu 5 6 10 0 9 9 9 Yellow nutsedge 1 4 0 0 1 1 0 .

~`~ WO91/034~ - ~ -. 2 9 ~ 5 3 3 7 PCTt~'~90~0495 .
COMPOUND

Rate (69 g/ha) 118 132 136 147 153 154 157 PREEMERGENCE
Alfalfa ~ 3 1 0 0 2 Barnyardgrass10 10 8 010 10 10 ~ermudagrass 9 10 1 1010 10 10 Brdl~ sgnlgrass 2 10 4 2 9 10 9 Field bindweed 0 2 0 0 2 1 0 Guineagrass 9 9 10 1 9 9 lQ
Johnsongrass 1 3 0 010 6 8 Large crabgrass 3 10 4 3 10 10 9 Pitted mrnglory 0 0 0 0 1 1 2 Purple nutsedge 10 10 10 0 1 0 Purslane 3 2 2 0 2 6 ~agweed 0 0 0 0 - 8 6 Sandbur - 10 Smooth crbgrass 10 10 10 9 10 10 9 Te~as panicum 0 3 1 1 8 8 6 Trop. kudzu 0 4 0 0 9 9 9 Yellow nutsedge 0 3 0 0 1 0 0 ~..

~O91/034~ ~'~ 0:8 5 3 3 7 PCT/~'S90/04953 r~

COMPOUND

Rate (32 g/ha) 118 132 136-147 153 154 157 PREEMERGENCE
Alfalfa 0 2 0 0 1 0 ~arnyardgrass 0 10 7 0 10 10 10 Bermudagrass 2 9 910 10 10 9 Brdlf sgnlgrass 010 0 0 9 9 7 Field bindweed 0 0 0 0 1 0 0 Guineagrass 0 9 1 0 9 9 4 Johnsongrass 0 2 0 0 3 2 Large crabgrass 1 6 0 0 9 8 7 Pitted mrnglory 0 0 0 0 0 1 2 Purple nutsedge 1 0 0 - 1 0 0 Purslane 0 0 0 0 1 2 0 Ragweed 0 - 0 0 7 2 6:
Sandbur - 10 - - - - -Smooth crbgrass 3 10 7 2 9 8 7 ~e~as panicum 0 3 1 0 6 7 7 Trop. kudzu 0 0 0 D 6 8 9 Yellow nuts-dge 0 ~ O O 1 0 0 '..
i

Claims (45)

What is claimed is:

1. The compounds of the formulas selected from the group consisting of:

; ;
I II

; ;

III IV

; ;

V VI

; ;
VII VIII

and stereoisomers thereof, wherein X and Y are independently H or C(R3)(R4)OR5;
Z is C(R3)(R4) OR5;
R1 is H or a straight-chain C1-C3 alkyl;

R2 is H, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl or C1-C4 alkyl substituted by Ph, OH, CN, OR8, SO2R8, PhSO2, N3, CO2R8 or CO2H;
R3, R4, R9 and R10 are independently H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C1-C3 alkyl substituted with OCH3 or OCH2CH3;
R5 is C1-C3 alkyl, C2-C4 alkenyl, C3-C4 alkynyl, benzyl or C1-C4 alkyl substituted with OR8, OCF3;
R8 is C1-C3 alkyl;
Q is WCH2 or W is phenyl optionally substituted with 1-3 substituents selected from F, Cl, Br, C1-C3 alkyl, C1-C3 alkoxy, OH, CN, C1-C3 haloalkyl, C1-C3 haloalkosy, C1-C3 alkylthio, C2-C4 alkenyl and C2-C4 alkynyl, or W is a 5 or 6-membered heterocyclic ring containing 0-2 nitrogens, 0-2 oxygens or 0-2 sulfurs, each ring optionally substituted with 1-2 substituents selected from F, Cl, Br, CH3 and OCH3;

Z1 is CH2, NRa, O, S or may be taken to form a double bond with an adjacent carbon;
Ra is H or C1-C3 alkyl;
R6 is H, halogen, R8, OR8, SR8 or CN;
R7 is H, F, Cl, CH3, OCH3, OH or OR8;
q1 is 0, 1 or 2; and q is 0, 1 or 2.
provided that 1) at least one of X and Y is C(R3)(R4)OR5;
2) R3, R4, R9 and R10 each contains no more than four carbon atoms;
3) in Formula II, if R1 is H then X is C(R3)(R4)OR5 and Y is H;
4) the sum of q and q1 is 0, 1 or 2; and 5) if the sum of q and q1 is 0 then Z1 is CH2.

2. The compounds of Formulas I, II, III, IV, V, VI, VII, or VIII according to Claim 1 wherein:
W is phenyl optionally substituted by 1-2 substituents selected from F, Cl, Br, CH3 and OCH3; or W is tetrahydropyran, tetrahydrofuran, thiophene, isorazole, pyridine or pyrazine, each ring optionally substituted with 1-2 substituents selected from F, Cl, Br, CH3 or OCH3;

Q is , , , , , , , , , , , , , or ;

Ra is H or C1-C3 alkyl; and R5 is other than benzyl.

3. The compounds of Claim 2 wherein R2 is H, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl.

4. The compounds of Claim 3 wherein R3 is H, C1-C3 alkyl, C3-C4 alkenyl or C3-C4 alkynyl;
R4 is H, C1-C3 alkyl, C3-C4 alkenyl or C3-C4 alkynyl;
R5 is H, C1-C3 alkyl, C3-C4 alkenyl or C3-C4 alkynyl;

R9 is H, C1-C3 alkyl, C3-C4 alkenyl or C3-C4 alkynyl;
R10 is H, C1-C3 alkyl, C3-C4 alkenyl or C3-C4 alkynyl;

5. The compounds of Claim 4 wherein Q is Q-1, Q-3, Q-6, Q-7 or Q-15.

6. The compounds of Claim 5 wherein the compound is of Formula I.

7. The compounds of Claim 5 wherein the compound is of Formula II.

8. The compounds of Claim 5 wherein the compound is of Formula III.

9. The compounds of Claim 5 wherein the compound is of Formula IV.

10. The compounds of Claim 5 wherein the compound is of Formula V.

11. The compounds of Claim 5 wherein the compound is of Formula VI.

12. The compounds of Claim 5 wherein the compound is of Formula VII.

13. The compounds of Claim 5 wherein the compound is of Formula VIII.

14. The compound of Claim 6 which is:
2-(ethyl-1-methoxypropyl)-6-(phenyl-methoxy)-7-oxabicyclo[2.2.1]heptane, (2-exo, 6-exo).

15. The compound of Claim 8 which is:
2-(ethoxymethyl)-5-methyl-4-(phenyl-methoxy)-6-oxabicyclo[3.2.1]octane, (2-endo, 4-endo).

16. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 1 and at least one of the following:
surfactant, solid or liquid diluent.

17. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 2 and at least one of the following:
surfactant, solid or liquid diluent.

18. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 3 and at least one of the following:
surfactant, solid or liquid diluent.

19. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 4 and at least one of the following:
surfactant, solid or liquid diluent.

20. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 5 and at least one of the following:
surfactant, solid or liquid diluent.

21. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 6 and at least one of the following:
surfactant, solid or liquid diluent.

22. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 7 and at least one of the following:
surfactant, solid or liquid diluent.

23. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 8 and at least one of the following:
surfactant, solid or liquid diluent.

24. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 9 and at least one of the following:
surfactant, solid or liquid diluent.

25. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 10 and at least one of the following:
surfactant, solid or liquid diluent.

26. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 11 and at least one of the following:
surfactant, solid or liquid diluent.

27. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 12 and at least one of the following:
surfactant, solid or liquid diluent.

28. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 13 and at least one of the following:
surfactant, solid or liquid diluent.

29. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 14 and at least one of the following:
surfactant, solid or liquid diluent.

30. An agriculturally suitable composition for controlling the growth of undesired vegetation comprising an effective amount of the compound of Claim 15 and at least one of the following:
surfactant, solid or liquid diluent.

31. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 1.

32. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 2.

33. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 3.

34. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 4.

35. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 5.

36. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 6.

37. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 7.

38. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 8.

39. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 9.

40. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 10.

41. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 11.

42. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 12.

43. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 13.

44. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 14.

45. A method for controlling the growth of undesired vegetation which comprises applying to the locus to be protected an effective amount of a compound of Claim 15.