AU2005201160B2 - Endothelin antagonists - Google Patents

Description

I

S&F Ref: 493447D2

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Abbott Laboratories, of CHAD 0377/AP6D-2 100 Abbott Park Road, Abbott Park, Illinois, 60064-3500, United States of America Martin Winn Steven A. King Steven J. Wittenberger Gang Liu Kenneth J. Henry Bruce G. Szczepankiewicz Bryan K Sorensen Jeffrey A. Kester Thomas W. von Geldem Andrew S. Tasker Hwan-Soo Jae Charles W Hutchins Steven A. Boyd Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Endothelin antagonists The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c [R:\LIBT]21275.doc:STL I I WO 99/06397 PCT/US98/15479 ENDOTHELIN ANTAGONISTS This is continuation-in-part application of U.S. patent application Serial No. 08/905,913, filed August 4, 1997 which is a continuation-inpart of U.S. patent application Serial No. 08/794,506, filed February 4, 1997 which is a continuation-in-part of U.S. patent application Serial No. 08/600,625, filed February 13, 1996, which is a continuation-inpart of U.S. patent application Serial No. 08/497,998, filed August 2, 1995, which is a continuation-in-part of U.S. patent application Serial No. 08/442,575, filed May 30, 1995, which is a continuation-in-part of U.S. patent application Serial No. 08/334,717, filed November 4, 1994, which is a continuation-in-part of U.S. patent application Serial No.

08/293,349, filed August 19, 1994.

Technical Field The present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and compositions for antagonizing endothelin.

Background of the Invention Endothelin (ET) is a 21 amino acid peptide that is produced by endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val bond in the precursor peptide big endothelin (Big ET). This cleavage is caused by an endothelin converting enzyme (ECE). Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increase airway resistance in vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in vitro and in vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release of renin in vitro and stimulate release of gonadotropins in vitro.

It has been shown that vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 411 WO 99/06397 -2- PCT/US98/15479 (1988), FEBS Letters 231 440 (1988) and Biochem. Biophys. Res.

Commun. 154 868 (1988)). An agent which suppresses endothelin production or an agent which binds to endothelin or which inhibits the binding of endothelin to an endothelin receptor will produce beneficial effects in a variety of therapeutic areas. In fact, an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin. Invest. 83 1762 (1989)).

In addition, an anti-endothelin antibody attenuated the nephrotoxic effects of intravenously administered cyclosporin (Kon, et al., Kidney Int. 37 1487 (1990)) and attenuated infarct size in a coronary artery ligation-induced myocardial infarction model (Watanabe, et al., Nature 344 114 (1990)).

Clozel et al. (Nature 365: 759-761 (1993)) report that Ro 46- 2005, a nonpeptide ET-A/B antagonist, prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (SAH) in rats, and decreases MAP in sodium-depleted squirrel monkeys when dosed orally. A similar effect of a linear tripeptide-like ET-A antagonist, BQ-485, on arterial caliber after SAH has also been recently reported (S.ltoh, T. Sasaki, K. Ide, K.

Ishikawa, M. Nishikibe, and M. Yano, Biochem. Biophys. Res. Comm. 1 969-75 (1993). These results indicate that agents which antagonize ET/ET receptor binding will provide therapeutic benefit in the indicated disease states.

Agents with the ability to antagonize ET/ET receptor binding have been shown to be active in a number of animal models of human disease.

For example, Hogaboam et al (EUR. J. Pharmacol. 1996, 309, 261-269), have shown that an endothelin receptor antagonist reduced injury in a rat model of colitis. Aktan et al (Transplant Int 1996, 9, 201-207) have demonstrated that a similar agent prevents ischemia-reperfusion injury in kidney transplantation. Similar studies have suggested the use of endothelin antagonists in the treatment of angina, pulmonary hypertension, Raynaud's disease, and migraine. (Ferro and Webb, Drugs 1996, 51,12-27).

Abnormal levels of endothelin or endothelin receptors have also been associated with a number of disease states, including prostate WO 99/06397 PCT/US98/15479 cancer (Nelson et al, Nature Medicine 1995, 1, 944-949), suggesting a role of endothelin in the pathophysiology of these diseases.

Wu-Wong et al (Lfe Sciences 1996, 58, 1839-1847) have shown that both endothelin and endothelin antagonists bind tightly to plasma proteins, serum albumin. This plasma protein binding can decrease the effectiveness with which the antagonists inhibit endothelin's action. Thus, endothelin antagonists with reduced plasma protein binding may be more effective than highly bound congeners.

Disclosure of the Invention In accordance with the present invention there are compounds of the formula R2 Z.

R

3 (cH 2 n

R

1

(I)

wherein Z is -C(R 1 8

)(R

1 9 or wherein R 18 and R 1 9 are independently selected from hydrogen and loweralkyl; n is 0 or 1; R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group, -P0 3

H

2 -P(0)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl,

-CN,

-C(0)NHR1 7 wherein R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(0)NHS(0) 2

R

1 6 wherein R 16 is loweralkyl, haloalkyl, aryl or dialkylamino, WO 99/06397 PTU9/57 PCT/US98/15479 (in) -S(O) 2 NHC(O)Rl 6 wherein R 16 is defined as above, HO 0 0 ()HO 0,

OH

(p) 0

NH

0 (r) N"0%

H

MH ,or -a NHS0 2

CFS

Ri and R 2 are independently selected from hydrogen, loweralkyt, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyt, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl,. dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, WO 99/06397PCIS/157 PCTIUS98/15479 aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyi, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or a rylalkyl, Rbb is hydrogen or alkanoyl and RC 0 is alkylene, with the proviso that one or both of R, and

R

2 is other than hydrogen;

R

3 is R 4

-C(O)-R

5 R4-R~a- R 4

R

5

-N(R

6

R

6

-S(O)

2

-R

7 or R 26

-S(O)-R

27 wherein R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20

)-R

8 or -R 8 a-N(R 20

)-R

8 wherein R 8 and R~a are independently selected from the group consisting of alkylene and alkenylene and R 20 is hydrogen, loweralkyl, alkenyl, haloaikyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyi or -0-R 9 or -R 9 a-O-R 9 wherein R 9 and R9a are independently selected from alkylene; is alkylene or (ii) alkenylene;

R

7 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 21 )-RjO- or RlOa-N(R21)-Rlo- wherein RIO and RiOa are independently selected from the group consisting of alkylene and alkenylene and R 21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl;

R

4 and R 6 are independently selected from the group consisting of (Rll)(Rl 2 wherein R 11 and R 12 are independently selected from hydrogen, loweralkyl, haloalkyl, -alkoxyalkyl, haioalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, (11) heterocyclic,

I

r WO 99/06397 1PCTI9/U519 (12) arylalkyl, (13) (heterocyclic)alkyl, (14) hydroxyalkyl, alkoxy, (16) aminoalkyl, (17) trialkylaminoalkyl, (18) alkylaminoalkyl,.

(19) dialkylamninoalkyl, and carboxyalkyl, (i i) loweralkyl, (iii) alkenyl, (i v) alkynyl, cycloalkyl, (v i) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (i x) heterocyclic, (heterocyclic)alkyl, (x i) alkoxyalkyl, (xii) hydroxyalkyl, (xiii) haloalkyl, (xiv) haloalkenyl, (xv) haloalkoxyalkyl, (xvi) haloalkoxy, (xvii) alkoxyhaloalkyl, (xviii) alkylamninoalkyl, (xix) dial kylam in oalkyl, (xx) alkoxy, and

(CH

2 N 7a (Xxi) 0 wherein z is 0-5 and R7a is alkylene;

R

26 is loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, -7- WO 99/06397-- (ix) heterocyclic, (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy-substituted haloalkyl; and

R

27 is alkylene or alkenylene;

R

22

-O-C(O)-R

23 wherein R 22 is a carboxy protecting group or heterocyclic and R 23 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 24

)-R

25 wherein R 25 is alkylene and R 24 is hydrogen or loweralkyl, loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic, (heterocyclic)alkyl, (in) alkoxyalkyl, alkoxyalkoxyalkyl, or

R

13 -C(O)-CH(Rl 4 wherein R 13 is amino, alkylamino or dialkylamino and R 14 is aryl or R 15 wherein R 15 is amino, alkylamino or dial kylimin o; or a pharmaceutically acceptable salt thereof.

A preferred embodiment of the invention is a compound of formula

R

2 z~ ,R 3

N

O

(CH

2 )n

R

(11) WO 99/06397 -8- PCT/US98/15479 wherein the substituents -R 2 -R and -Ri exist in a trans,trans relationship and Z, n, R, R 1

R

2 and R 3 are as defined above.

Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 0 and Z is -CH 2 Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 1 and Z is -CH 2 Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R 3 is R 4

-C(O)-R

5 2

-R

7 or R 26

-S(O)-R

2 7 wherein R 4

R

5

R

6

R

7

R

26 and R 27 are as defined above.

Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R 3 is alkoxyalkyl or alkoxyalkoxyalkyl.

A more preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and Rs is R 4

-C(O)-R

5 wherein R 4 is (R 11 )(R1 2 as defined above and R 5 is alkylene or R 3 is Re-S(0) 2

-R

7 or R 2 6-S(O)-R 2 7 wherein R7 is alkylene, R 27 is alkylene and R 6 and R 26 are defined as above.

Another more preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R 3 is R4-C(O)-N(R 20

)-R

8 or R6-S(0) 2

-N(R

21 )-R1o- wherein R 8 and Rio are alkylene and R 4

R

6

R

20 and R 21 are defined as above.

An even more preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, R is tetrazolyl or -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is -C(O)-NHS(0) 2

R

16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH2-, R1 and R 2 are independently selected from loweralkyl, (ii) cycloalkyl, (iii) substituted aryl wherein aryl is phenyl substituted WO 99/06397 -PCT/US98/1 5479 with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted heterocyclic, alkenyl, (vi) heterocyclic (alkyl), (vii) arylalkyl, (viii) aryloxyalkyl, (ix) (N-alkanoyl-Nalkyl)aminoalkyl and alkylsulfonylamidoalkyl, and R 3 is R 4 5 wherein R4 is (Rll)(Rl 2 wherein R 11 and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl, and R 5 is alkylene; or R 3 is R 4

-C(O)-N(R

20

)-R

8 or

R

6

-S(Q)

2

-N(R

21 )-Rlo- wherein R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R 8 and R 10 are alkylene and R 20 and R 21 are loweralkyl; or R 3 is R 6

-S(O)

2

-R

7 or R 26

-S(O)-R

27 wherein R 6 is loweralkyl or haloalkyl, R 7 is alkylene, R 26 is loweralkyl and R 27 is alkylene.

A yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein

R

16 is loweralkyl, haloalkyl or aryl, Z is -OH 2

R

1 is loweralkyl, (ii) a Ike ny (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), arylalkyl, (xi) aryloxyalkyl, (xii) (N-al kanoyl-N-al kyl)a min oalkyl, or (xiii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, B-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimnethoxyphenyl, fluorophenyl or difluorophenyl and

R

3 is R 4

-C(O)-N(R

2 0)-Ra- or R 6

-S(O)

2

-N(R

21 )-Rl 0 wherein R 8 and R 1 0 are alkylene, R 20 and R 21 are loweralkyl, R 4 is loweralkyl, aryl, alkoxy, _inl WO 99/06397 PTU9/37 alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl.

Another yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or NHS(0) 2

R,

6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -OH 2

R

1 is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethyiphenyl, 4-methyiphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethyiphenyl, 3-fluoro-4methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and

R

3 is R 4 -C(0)-R 5 wherein R 5 is alkylene and R 4 is (R 11

)(R

12

)N-

wherein R 1 1 and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.

Another yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or NHS(0) 2

R,

6 wherein R 16 is loweraikyl, haloalkyl or aryl, Z is -OH 2 R1 is loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, arylalkyl, (vi) aryl, (vii) (N-alkanoyl-Nalkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1,4benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or 1 1 ~11~ DCTITS-021 54479 'WO 99/06397- -J difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R 4

-C(O)-R

5 wherein R 5 is alkylene and R 4 is (Rll)(Rl 2 wherein R 11 is loweralkyl and R 12 is aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.

Another yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or

NHS(O)

2

R

16 wherein 13 16 is loweralkyl, haloalkyt or aryl, Z is -CH 2

R

1 is loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, arylalkyl, (vi) (N-alkanoyi-N-alkyl)aminoalkyl, or (vii) alkylsulfonylamidoalkyl,(vii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3flu oro ph en y 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweraikyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1 ,3benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyi, B-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is

R

6

-S(O)

2

-N(R

21 )-Rlo- wherein R 10 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R 21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.

Another yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or NHS(0) 2

R

16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -OH 2

R

1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-rnethoxypheny[, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl o r 1 ,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) I n 17a WO099/06397-rL/oI'9 heterocyclic (alkyl), aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-Nalkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is alkoxycarbonyl or R 6

-S(O)

2

-N(R

2 1)-Rl 0 wherein R 10 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 21 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl.

Another yet more preferred embodiment of the invention is acompound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or NHS(0) 2

R

16 wherein R 16 is loweralkyl or haloalkyl, Z is -OH 2 Rl is loweralkyl,alkenyl, heterocyclic (alikyl), aryloxyalkyl, aryalkyl, aryl, (N-lkaoy-N-lky~ainolky,,or alkylsulfonylamidoalkyl, and R 3 is

R

4 wherein R,5 is alkylene and R4 is (Ril)(R 1 2 wherein R 11 and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.

A still more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(0) 2 -G wherein G is 'hydrogen or a carboxy protecting group, tetrazolyl or -C(0)-NHS(0) 2 Rl 6 wherein

R

16 is loweralkyl or haloalkyl, Z is -OH 2 Rl is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3benzodioxolyl, 1,4-benzodioxanyl or di hyd robe nzof uranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl ,or (ix) phenyl, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(0)-R 5 wherein R 5 is alkylene and R 4 is (Rll)(Rl 2 wherein WO 99/06397 -13- -13- PCTIUS98/15479

R

11 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.

Another still more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or

NHS(O)

2 Rl 6 wherein R 16 is loweralkyl or haloalkyl, Z is -OH 2

R

1 is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, arylalkyl, (Nalkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, phenyl, or alkoxyalkyl, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(0)-R 5 wherein R 5 is alkylene and R 4 is (R 11

)(R

12 wherein R 11 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.

A most highly preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4methyiphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy,

R

2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(0)-R 5 wherein R 5 is alkylene and R 4 is (Rii)(R 12 wherein RI, and R 12 are independently selected from loweralkyl.

Another most highly preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(0)2-G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3benzodioxolyl, 1 ,4-benzodioxanyl or di hyd robe nzof uranyl wherein the WO 99/06397 -14- -14- PCTIUS98/1 5479 substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 wherein R5 is alkylene and R4 is (Rll)(Rl 2 wherein Rjj is loweralkyl and R 12 is aryl.

Another most highly preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 Ri is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4methoxymethoxyphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy,

R

2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R6-S(O)2-N(R 2 l)-Rlo- wherein R10 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is loweralkyl, haloalkyl or alkoxyalkyl.

Another most highly preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 Rl is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy,

R

2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is R4-C(O)-R 5 wherein R 5 is alkylene and R4

I

WO 99/06397 -15- PCT/US98/15479 is (R11)(R12)N- wherein R 11 is alkyl and R 12 is selected from aryl, aminoalkyl, trialkylaminoalkyl, and heterocyclic.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, R is -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH2-, R 1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (Nalkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R 3 is

R

4

-C(O)-R

5 wherein R 5 is alkylene and R 4 is (R 1 1

)(R

1 2 wherein Rl and R 1 2 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R 1 1 and R 1 2 is alkyl.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R 3 is

R

4

-C(O)-R

5 wherein R 4 is (R11)(R12)N- as defined therein and R5 is alkylene.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is loweralkyl, and R 3 is R4-C(O)-R 5 wherein R4 is (R 1 1

)(R

12 as defined therein and R 5 is alkylene.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is alkenyl, and R 3 is R 4

-C(O)-R

5 wherein R 4 is (R11)(R12)N- as defined therein and

R

5 is alkylene.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is heterocyclic (alkyl), and R 3 is R4-C(O)-R 5 wherein R 4 is (R11)(R12)Nas defined therein and R 5 is alkylene.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is aryloxyalkyl, and R 3 is R4-C(O)-R 5 wherein R4 is (R11)(R 12 as defined therein and Rs is alkylene.

I i

IR-

WO 99/06397 PCT/US98/1547Y Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is arylalkyl, and R 3 is R4-C(O)-R 5 wherein .R 4 is (R 11

)(R

1 2 as defined therein and R 5 is alkylene.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH2-, R1 is aryl, and

R

3 is R 4

-C(O)-R

5 wherein R 4 is (R 11

)(R

12 as defined therein and R is alkylene.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is (Nalkanoyl-N-alkyl)aminoalkyl, and R 3 is R 4

-C(O)-R

5 wherein R 4 is (R11)(R 12 as defined therein and Rs is alkylene.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is alkylsulfonylamidoalkyl, and R 3 is R 4

-C(O)-R

5 wherein R 4 is

(R

11

)(R

12 as defined therein and R 5 is alkylene.

The present invention also relates to processes for preparing the compounds of formula and (II) and to the synthetic intermediates employed in these processes.

The present invention also relates to a method of antagonizing endothelin in a mammal (preferably, a human) in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula or (II).

The invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula or (II).

The compounds of the invention comprise two or more asymmetrically substituted carbon atoms. As a result, racemic mixtures, mixtures of diastereomers, as well as single diastereomers I I -17- njn rnn rr+ H mtn WO 99/06397 PCI/uyS9/13'/, of the compounds of the invention are included in the present invention.

The terms and configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 The term "carboxy protecting group" as used herein refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis" pp. 152-186 (1981), which is hereby incorporated herein by reference.

In addition, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo for example by enzymatic hydrolysis, to release the biologically active parent. T.

Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S.

Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. No. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference.

Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy protecting groups are C 1 to C 8 alkyl methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-

I

_1A- WO 99/06397 PCTIUS9/ 134 1 (propionyloxy)-1 -ethyl, 1 -(pivaloyloxyl)-1 -ethyl, 1-methyl-1- (propionyloxy)- -ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1methoxycarbonyl-1 -ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1ethoxycarbonyloxy-1 -ethyl, 1 -cyclohexyloxycarbonyloxy-1 -ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyi, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1 ,3dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4yl)methyl and the like; and (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)methyl and the like.

The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, (x-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,

I

_19- WO 99/06397 PCTUS98/15479 p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5trimethoxybenzyloxycarbony I, 1 -(p-biphenylyl)-1 -methylethoxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term "alkanoyl" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkanoyl include acetyl, propionyl and the like.

The term "alkanoylamino" as used herein refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the like.

The term "alkanoylaminoalkyl" as used herein refers to

R

43

-NH-R

44 wherein R 43 is an alkanoyl group and R4 4 is an alkylene group.

The term "alkanoyloxyalkyl" as used herein refers to R30-0-R31wherein R 30 is an alkanoyl group and R 31 is an alkylene group. Examples of alkanoyloxyalkyl include acetoxymethyl, acetoxyethyl and the like.

The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1methyl-2-buten-1-yl and the like.

I

on DrT I91oa/ -479 WO 99/06397 The term "alkenylene" denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond.

Examples of alkenylene include -CH=CH-, -CH 2 CH=CH-, -C(CH 3

CH

2

CH=CHCH

2 and the like.

The term "alkenyloxy" as used herein refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the like.

The term "alkoxy" as used herein refers to R 4 1 0- wherein R 4 1 is a loweralkyl group, as defined herein. Examples of alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the like.

The term "alkoxyalkoxy" as used herein refers to R 80 0-R 81 0wherein R 80 is loweralkyl as defined above and R 81 is alkylene.

Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.

The term "alkoxyalkoxyalkyl" as used herein refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical.

Representative examples of alkoxyalkoxyalkyl groups include methoxyethoxyethyl, methoxymethoxymethyl, and the like.

The term "alkoxyalkyl" as used herein refers to an alkoxy group as previously defined appended to an alkyl radical as previously defined.

Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.

The term "alkoxycarbonyl" as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.

The term "alkoxycarbonylalkenyl" as used herein refers to an alkoxycarbonyl group as previously defined appended to an alkenyl radical. Examples of alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.

The term "alkoxycarbonylalkyl" as used herein refers to

R

34 -C(0)-R 35 wherein R 34 is an alkoxy group and R 35 is an alkylene group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like.

I

-21- PCT/US98/15479 WO 99/06397 The term "alkoxycarbonylaminoalkyl" as used herein refers to

R

3 8

-C(O)-NH-R

39 wherein R 38 is an alkoxy group and R 39 is an alkylene group.

The term "alkoxycarbonyloxyalkyl" as used herein refers to

R

36 -C(0)-O-R 37 wherein R 36 is an alkoxy group and R 37 is an alkylene group.

The term "(alkoxycarbonyl)thioalkoxy" as used herein refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical. Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.

The term "alkoxyhaloalkyl" as used herein refers to a haloalkyl radical to which is appended an alkoxy group.

The terms "alkyl" and "loweralkyl" as used herein refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, nbutyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

The term "(N-alkanoyl-N-alkyl)aminoalkyl" as used herein refers to R85C(O)N(R86)R87- wherein R85 is an alkanoyl as previously defined, R86 is loweralkyl, and R87 is alkylene.

The term "alkylamino" as used herein refers to R 51 NH- wherein

R

5 1 is a loweralkyl group, for example, ethylamino, butylamino, and the like.

The term "alkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylamino group.

The term "alkylaminocarbonyl" as used herein refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl linkage. Examples of alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the like.

The term "alkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an alkylaminocarbonyl group.

The term "alkylaminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylaminocarbonyl group.

I -99- r rn~ t C APO WO 99/06397 ruavoi,, The term "alkylaminocarbonylaminoalkyl" as used herein refers to

R

40

-C(O)-NH-R

4 1- wherein R 40 is an alkylamino group and R 41 is an alkylene group.

The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to carbon atoms by the removal of two hydrogen atoms, for example -CH 2

-CH

2

CH

2

-CH(CH

3

-CH

2

CH

2

CH

2

-CH

2

C(CH

3 2

CH

2 and the like.

The term "alkylsulfonylamidoalkyl" as used herein refers R88S(0)2NHR89- wherein R88 is loweralkyl and R89 is alkylene.

The term "alkylsulfonylamino" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino 2 group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like.

The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynyl include H-C=C-CH 2

H-C=C-CH(CH

3 and the like.

The term "alkynylene" refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing from 2 to 15 carbon atoms and also containing a carbon-carbon triple bond. Examples of alkynylene include -C=C-CH 2

-C=C-CH(CH

3 and the like.

The term "aminoalkyl" as used herein refers to a -NH2, alkylamino, or dialkylamino group appended to the parent molecular moiety through an alkylene.

The term "aminocarbonyl" as used herein refers to H 2

N-C(O)-

The term "aminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an aminocarbonyl (NH 2 group.

The term "aminocarbonylalkoxy" as used herein refers to

H

2 appended to an alkoxy group as previously defined. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.

The term "aminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an aminocarbonyl (NH 2 group.

I

-014 rrrno II L Irln 'WO 99/06397 Pra4 The term "trialkylaminoalkyl" as used herein refers to (R90)(R91)(R92)N(R93)- wherein R90, R91, and R92 are independently selected from loweralkyl and R93 is alkylene.

The term "aroyloxyalkyl" as used herein refers to R 32

-C(O)-O-R

33 s wherein R 32 is an aryl group and R 33 is an alkylene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.

The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy, hydroxalkoxy, phenyl and tetrazolylalkoxy. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term "arylalkenyl" as used herein refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl and the like.

The term "arylalkoxy" as used herein refers to R 42 0- wherein R 42 is an arylalkyl group, for example, benzyloxy, and the like.

The term "arylalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the like.

The term "arylalkyl" as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.

The term "aryloxy" as used herein refers to R 45 0- wherein R 45 is an aryl group, for example, phenoxy, and the like.

The term "arylalkylcarbonyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkylcarbonyloxy group

R

62 C(0)O- wherein R 62 is an arylalkyl group).

-24- WO 99/06397 PCTUS98/15479 The term "aryloxyalkyl" refers to an aryloxy group as previously defined appended to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like.

The term "carboxaldehyde" as used herein refers to a formaldehyde radical, -C(O)H.

The term "carboxy" as used herein refers to a carboxylic acid radical, -C(O)OH.

The term "carboxyalkenyl" as used herein refers to a carboxy group as previously defined appended to an alkenyl radical as previously defined. Examples of carboxyalkenyl include 2-carboxyethenyl, 3carboxy-1-ethenyl and the like.

The term "carboxyalkoxy" as used herein refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and the like.

The term "cyanoalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a cyano group.

Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like.

The term "cycloalkanoyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended a cycloalkanoyloxy group

R

60 wherein R 60 is a cycloalkyl group).

The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.

The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.

The term "dialkylamino" as used herein refers to R 56

R

57

N-

wherein R 5 6 and R 57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.

I

WO 99/06397 -25- PCT/US98/15479 The term "dialkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended a dialkylamino group.

The term "dialkylaminocarbonyl" as used herein refers to a dialkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl linkage. Examples of dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.

The term "dialkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group.

The term "dialkylaminocarbonylalkyl" as used herein refers to

R

50 -C(0)-R 51 wherein Rso is a dialkylamino group and R 51 is an alkylene group.

The term "halo" or "halogen" as used herein refers to I, Br, Cl or F.

The term "haloalkenyl" as used herein refers to an alkenyl radical to which is appended at least one halogen substituent.

The term "haloalkoxy" as used herein refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like.

The term "haloalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended a haloalkoxy group.

The term "haloalkyl" as used herein refers to a lower alkyl radical, as defined above, to which is appended at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or pentafluoroethyl and the like.

The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 6- or 7membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized. The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or

I

9A_ WO 99/06397 PCIqIUS951" 547' another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.

X.

Heterocyclics also include compounds of the formula where X* is -OH 2 or and Y* is or where R" is hydrogen or 0 1 -C4-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Heterocyclics also include bicyclic rings such as quinuclidinyl and the like.

Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo alkylimino wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SO 3

H,

alkoxycarbonyl, nitro, cyano and loweralkyl. In addition, nitrogen containing heterocycles can be N-protected.

The term "(heterocyclic)alkoxy" as used herein refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above. Examples of (heterocyclic)alkoxy include 4pyridylmethoxy, 2-pyridylmethoxy and the like.

The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.

I

-27- WO 99/06397 PCT/US98/15479 The term "heterocycliccarbonyloxyalkyl" as used herein refers to

R

46

-C(O)-O-R

4 7 wherein R 4 6 is a heterocyclic group and R 47 is an alkylene group.

The term "hydroxy" as used herein refers to -OH.

The term "hydroxyalkenyl" as used herein refers to an alkenyl radical to which is appended a hydroxy group.

The term "hydroxyalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a hydroxy (-OH) group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4hydroxybutoxy and the like.

The term "hydroxyalkyl" as used herein refers to a loweralkyl radical to which is appended a hydroxy group.

The term "leaving group" as used herein refers to a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like).

The term "mercapto" as used herein refers to -SH.

The terms "methylenedioxy" and "ethylenedioxy" refer to one or two carbon chains attached to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a fused 5 membered ring is formed. In the case of ethylenedioxy, a fused 6 membered ring is formed. Methylenedixoy substituted on a phenyl ring results in the formation of a benzodioxolyl radical. .Ethylenedioxy substituted on a phenyl ring results in the formation of a benzodioxanyl radical The term "substantially pure" as used herein means 95% or more of the specified compound.

The term "tetrazolyl" as used herein refers to a radical of the formula

H,

N- N or a tautomer thereof.

I

-28- WO 99/06397 PCT/US98/15479 The term "tetrazolylalkoxy" as used herein refers to a tetrazolyl radical as defined above appended to an alkoxy group as defined above.

Examples of tetrazolylalkoxy include tetrazolylmethoxy, tetrazolylethoxy and the like.

The term "thioalkoxy" as used herein refers to R 7 0S- wherein R 7 0 is loweralkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.

The term "thioalkoxyalkoxy" as used herein refers to RsoS-R 81 0wherein Rso is loweralkyl as defined above and R 81 is alkylene.

Representative examples of alkoxyalkoxy groups include CH 3

SCH

2

O-,

t-BuSCH20- and the like.

The term "thioalkoxyalkoxyalkyl" as used herein refers to a thioalkoxyalkoxy group appended to an alkyl radical. Representative examples of alkoxyalkoxyalkyl groups include CH 3

SCH

2

CH

2

OCH

2

CH

2

CH

3

SCH

2 0CH 2 and the like.

The term "trans,trans" as used herein refers to the orientation of substituents (R 1 and R 2 relative to the central substituent R as shown

R

2 Z R 3 S~(CH 2 )n

RI

The term "trans,cis" as used herein refers to the orientation of substituents (R1 and R 2 relative to the central substituent R as shown

R

2 ZN 3 NR2 ZN 3

R

3 N N R (CH 2 )n R (CH) 1 or R. This definition encompasses both the case where R and R 2 are cis and R and R 1 are trans and the case where R 2 and R are trans and R and R 1 are cis.

The term "cis,cis" as used herein refers to the orientation of substituents (R 1 and R2) relative to the central substituent R as shown WNO 99/06397 -9 CIS8157 -29- PCTIUS98/15479 Preferred compounds of the invention are selected from the group consisting of: trans-trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 propyl-N-n-pentanesulfonylamino)propyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(4-Methoxymethoxyphenyl)-4-(1 (2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(3,4-Dimethoxyphenyl)-4-(1 ,3-benzodioxol -5-yl)-1 (N-propyl-N-n-pentanesulfonylamino)ethyllpyrrolidi ne-3carboxylic acid; trans, trans-2-(3,4-Dimethoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 (N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(4-Propoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -t2-(Npropyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3,4-DiflIuoropheny)-4-(1 ,3-benzodioxol-5-yl)- 1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(3,4-Dif luorophenyl)-4-(1 ,3-benzodioxol-5-yl)-1 propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-propyl-N-(3-chloropropanesulfonyl)amino)ethyl)pyrroiidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-isobutyI-N-(3chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; qn- WO 99/06397 i'L1/USywi8/y7 trans, trans-2-(3-Fluoro-4- met hoxypheny1) ,3 -ben 1 -[2-(N-propyl-N-(4methylbutanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxy-3-f IuorophenyI)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-l -[2-(N-propyl-N-(npentanesulfonyl)amino)ethyllpyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-be 1 -[2-(N-propyl-N-(2,2,3,3,3-pentafluoropropoxyethanesulfony).

amino)ethyljpyrrolidine-3-carboxylic acid; trans-2-(1 ,4-Benzodioxan-6-yI)-4-(7- methoxy- 1 ,3-be nzodi oxol- 1-[2-(N-propyl-N-(npentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-isobutyl-N-(pentanesulfonylamino)ethyl)pyrrolidine-3 carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-(2-methoxyethyl)-N-(3-chloropropanesu Ifonyt)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-(2-methoxyethyl)-N- (pentanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -[2-(N-propyl-N-((2,2,2-trifluoroethoxyethane)sulfonyl)amino).

ethyflpyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-(2-methoxyethyl)-N-(butanesulfonylamino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2- Flu oro-4- methoxyp henyl)-4- (1 ,3-benzod yI)-1 -[2-(N-propyl-N-(2methylpropanesulfony)amino)ethylpyrroidine-3-.carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl>4}1 1 -(2-(N-isobutyl-N-(butanesufonylamino))ethyl)pyrrolidine.3 carboxylic acid; trans, trans-2-(2-Methylpentyl)-4-(1 ,3-benzodioxol-5-yI)- 1 -(N,N-di (nbutyl)aminocarbonyimethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 di(n-butyl)aminocarbonylmethy)-pyrrolidine-3.carboxylic acid; -141- WO 99/06397 -ri~I~, trans, trans-2- (1 Dioxo-2 -y1) ethyl) (1 ,3-be nzod ioxol1-5-yI1) -1 N-d i(n -butyI) am in ocarbonyl methyI) -py rrol id ine-3-carboxy Iic acid; trans, trans -2-(2-(2-Tetrahydro-2 H-pyran)ethy1) be nzodioxolI- 5-y I) 1-(N,N-di(n-butyI) am inocarbonylImet hyI) -pyrro Iidine-3carboxylic acid; trans, trans-2-(2,2,4-Trimethyl-3-pentenyl)-4-(1 1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(1 ,3benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxo-2-yI)ethyl)-4-(1 ,3-benzodioxol-5-y!)- 1 [[N-4-heptyl-N(2 methyl-3-fluorophenyl)] amino carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxol-2-yI)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonyimethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)-4-( 1,3-be 1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl).

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-( 1,3-benzodioxol-5yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxol-2-yI)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxyljc acid; trans, trans-2-(2,2-Dimethylpenty)-4-(7-methoxy 1 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; trans, trans-2-(2,2-dimethylpentyI)-4-(2,3-dihydrobenzof 1 ,N-di(n-butyI)aminocarbonylmethyI)-pyrrolidine-3-carboxylic acid; -32- WO 99106397 -32- PCT/US98/1 5479 trans, trans-2- (2,2,-Di met hylI-2-(1 ,3-dioxolIan -2-y I) ethy1) methoxy-1 ,3-benzodioxoi-5-y1) -1 -(N,N-di(nbutyi)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy- 1,3benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-pyridyl)ethyl)-4- (1 ,3-benzodioxol-5-yI)- 1 Ndi(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyt)-pyrrolidine-3carboxylic acid; (2S, 3R?, 4S)-2-(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-(1 yI)-l -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxo-5-yI)-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphe nyl)-4-(1 ,3-benzod ioxo I-5-yI1) -1 butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyllpyrrolidine-3-carboxylic acid; (2R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI) 1- (2-(N-propyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpe ntyl) -4-(7-methoxy- 1,3-be yI)-1 -(N-4-heptyl-N-(4-fI uoro-3methyiphe nyl) )am i nocarbo nylmethyl) -py rro lid i ne-3-carboxyl ic acid; trans, trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1 yI)-1 -((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; -33- WO 99/06397 -33- PCTIUS98/15479 trans, trans-2-(2,2-Dimethylpent-3-enyl)-4-(1 ,3-benzodioxol-5-yI)- 1 (N-4-heptyl-N-(4-flIuoro-3-methylIph enyt)) am inocarbony ImethyI) pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpent-3-enyl)-4-(1 ,3-benzodioxol-5-yI)-1 ((N-butyl-.N-(4-dimethylamino)butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 N-di(n-butyl)aminocarbonyimethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1 ,3benzodioxol-5-yt)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy- 1,3benzodioxol-5-yI)-1 -((N-butyl-N-(4dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(1 1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(1 1 -((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy-1 ,3benzodioxol-5-yi)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -((N-butyl-N-(4dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; -34- WO 99/06397 -34- PCT/US98/1 5479 trans, trans-2-(2-(1 ,3-Dioxol-2-y I) ethy1) ben zodioxol-5-y1) -1 [(N-butyl-N-(4-di met hy lam inobutyI) am i no) carbo nyl methyI] pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxol-2-yI)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yl)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2- -Di met hy1-2- (1 Diox o -2-yI) ethyl1)-4- (1 ,3benzodioxol-5-yI)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(1 ,3dimethylaminobutyl)amino)carbonylmethyll-pyrrolidine-3carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-Dioxol-2-yI)ethyl)-4-(7methoxy-1 ,3-benzodioxol-5-yI)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(7methoxy-1 ,3-benzodioxol-5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrroiidine-3carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 1-(N-4-heptyl-N-(4-fluoro-3methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethy

I]-

pyrrolidine-3-carboxylic acid; trans, trans-2-(2- (2-Met hoxyphe nylI)-ethy1) met hoxy- 1 13benzodioxol-5-y)-1 (N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy- 1 3benzodioxol-5-yI)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; -35- WO 99/06397 WO 9906397-35-PCT/US98/15479 trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methcxy- 1,3benzodioxol-5-y)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine.3 carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methy)-4-(1 1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))amino)carbonylmethyl]-pyrrolidine-3.carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)-4-(1 1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphe noxy)-methy)-4-(7-methoxy- 1 ,3benzodioxol-5-yI)-1 (N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1,3benzodioxol-5-yl)-1 -(N-4-heptyl-N-(4-fiuoro-3methylphenyl))amino)carbonylmethyl]-pyrrolidine-3.carboxylic acid; trans, trans-2-(2-(2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(2-Oxo 1 ,2-dihydro pyridin-1 -yl)-ethyl)-4-(1 ,3- -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyridin-1 -yI)-ethyl)-4-(1 yI)-l1-[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyridin-1 -yI)-ethyl)-4-(1 yt)-1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethy].

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyridin-1 -yl)-ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-l1-(N ,N-di(N-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyridin-1 -yI)-ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3- -36- WO 99/06397 -6 CIS8157 PCT[US98/15479 m ethy lp hen yl) am ino)ca rbonyl methy I]-py rro Iid in e-.3-ca rboxy ic acid; trans, trans-2- (2-Oxopy rid in -1 -yI)-ethyl)-4-(7-methoxy-1 13benzodioxo!-5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyI)amino)carbonylmethyl]-pyrrouidine-3 carboxylic acid; trans, trans-2-(2(-2-Oxopiperidin-1 -yI) -ethyl) (1 ,3-be nzodioxo yl)-1 ,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin- 1 -yI)-ethyl)-4-(1 ,3-be yI)-l1-[(N-4-heptyl-N-(4-fluoro-3methyiphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin-1 -yI)-ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1-(N,N-di(N-butyl)aminocarbonylmethyl).

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin-1 -yI)-ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -(N,N-di(N-butyl)aminocarbonylmethyl)pyrro lid ine-3-carboxyl ic acid; trans, trans-2-(2-(2-Oxopiperidin-1 -yI)-ethyl)-4-(7-methoxy-1 13benzodioxol-5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonyl methyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin-1 -yl)-ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3.

carboxylic acid; trans, trans-2-(2-(2-Oxopyrrol id in- 1 -y1) ethyl) (1 ,3-benzod yI)- 1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl].

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(1 yI)-1 -[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidi ne-3carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(1 yl)-1-[(N-butyl-N-(4 dimethylaminobutyl) amino) carbonylmethyl..

pyrrolidine-3-carboxylic acid; -37- WO 99/06397 -37- PCTJUS98II 5479 trans, trans-2-(2-(2-OxopyrroIidin-1 -y I) ethyI) yl1) -1 -[(N-butylI-N-(4t ri met hylI am man iob utyl I) am ino) carbon yI met hyl] -p yr ro l id i n e-3carboxylic acid; trans, trans-2- (2-(2-Oxopyrrol idi n- 1 -y [)ethyl) meth oxy- 1,3be nzodioxol-5-yI)-1 -(N,N-di(N-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(7-methoxy-1 ,3- -[(N-butyl-N-(3hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy-i ,3benzodioxol-5-yl)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin- 1 -yl)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -[(N-butyl-N- (propoxy)amino)carbonylmethy]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yl)-1 -f(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethy]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(2-Oxopyrroidin-1 -yl)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yl)-1 -[(N-butyl-N-(4trimethylammoniobutyl)amino)carbonylmethyl]-pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(2-Qxopyrrol idi n- 1 -yl)ethyl)-4-(2,3-dihydrobenzofuran-5-yI)-1 -(N,N-di(N-butyI)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(2,3-dihydro- 1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyI)amino)carbonylmethyJ-pyrrolidine-3.carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(2,3-dihydrobenzofuran-5-yi)-1 -[(N-butyl-N-(4dimethylaminobuty)amino)carbonylmethyl]-pyrrolidine-3.

carboxylic acid; WO 99/06397-3-CTU8/47 -38- PCT/US98/15479 trans, trans-2-(2-(3,3-Dimethyl-2-oxopyrro lid in -1 -y I) ethy1) ,3be nzodioxo I-5-yl)- 1 -(N,N-di(N-butyI) am inocarbonylImethyI) yrrolidine-3-carboxylic acid; trans, trans-2-(2-(3,3-Dimethy-2-oxopyrroidin-.1 -yI)ethyl)-4-(1 ,3benzodioxol-5-yl)-l-[(N-4-heptyl-N..(4..fluoro-3 methylphenyl)amino)carbonylmethyl].pyrrolidi ne-3-carboxylic acid; trans, trans-2- D imethy 1-2-oxopy rro Iidi n-1 -yI) ethyl) (1 ,3- -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl-pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin. 1 -yI)ethyl)-4-(1 ,3benzodioxol-5-yi)-l1-(N ,N-di(N-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(4,4- Dimethyl-2-oxopyrrolidin..1 -yl)ethyl)-4-(1 ,3benzodioxol-5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methy Iphe nyl) ami no) carbonyl methyl]-pyrro lid ine-3-carboxyl ic acid; trans, trans-2-(2-(4,4- Dimethyl-2-oxopyrrol idin- 1 -yl)ethyl)-4-(1 ,3benzodioxol-5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine.3 carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(1 1 N-dibutylaminocarbonylmethyl).pyrrolidine-.3..carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(1 1 -[(N-4-heptyl-N-(4-fI uoro-3methy lphe nyl) amino) carbonylmethyl].pyrrolidi ne-3-carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(1 1 -[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pro panes ulta myI) ethyl)-4-(1 ben zodioxol-5-y I) 1 -[(N-butyl-N-(propoxy)amino)carbonylmethyl]pyrrolidine-3 carboxylic acid; WO 99/06397-3-PTU8I57 -39- PCT[US98/15479 trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(1 1 -[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylm ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2- (1 -pro pan esulIta myl)et hy1) methoxy-1, ,3benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2- -propanesultamyl)ethyl)-4-(7-meth oxy- 1, 3benzodioxol-5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2- (1 -p ropa nesulIta myl) ethyl) (7-meth oxy-1, ,3benzodioxol-5-yI)-1 N-butyl-N-(4dimethylaminobutyI)amino)carbonylmethy]-pyrroidine.3 carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(2,3-dihydrobenzofuran-5-yI)-1 N-di(n-butyl)aminocarbonyimethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(2,3-dihydrobenzof uran-5-yI)- 1 -[(N-4-heptyl-N-(4-fI uoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4- (2 ,3-dihydrobe nzofu ran-5-yI)- 1 N-butyl-N-(4dimethylaminobutyl)amino)carbonyimethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonymethyl].

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-y)-1 butyl-N-(3-hydroxypropy)amino)carbonylmethyl]-pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(1 ,3-benzodioxol-5-y)-1 butyl-N-(propoxy)amino)carbonylmethyl].pyrrolidine-.3-carboxylic acid; trans, trans-2-(2-(1 -py razo lyl)ethyl)-4-(1 ,3-benzodioxol-5-y)- 1 butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl].

pyrrolidine-3-carboxylic acid; WO 99/06397-4-CTS9/57 -40- PCT/US98/15479 trans, trans-2-(2-(1 -pyrazoIy I) ethyI) -4.(7-methoxy- 1 ,3-benzodioxo I- 5-yI)-1 -(N,N-dibutylaminocarbonylmethyl)-pyrrolidine.3 carboxylic acid; trans, trans-2-(2- (1 -py razo ly1) ethyl) met hoxy- 1 ,3-be nzod ioxolI- 5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)ami no)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans- 2- (1 -pyrazolyl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol- 1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yI).

1 -(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-.3..carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5y).

1 -[(N-4-heptyl-N-(4-fI uoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4-(2,3-di hydro-benzof uran 1 utyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-oxazolyl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1

,N-

di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2- (2-(Oxazol-2-y)ethyl)-4-(1 ,3-benzodioxol1-5-yI)- 1 4 -heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]pyrrolidine-3-carboxyiic acid; trans, trans-2-(2-(Oxazo-2-y)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(Oxazol-2-y)ethyl)-4-(1 ,3-benzodioxo!-5-yI)-1 butyl-N-(propoxy) amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Oxazol-2-y)ethy)-4.(1 ,3-benzodioxol-5-yI)-1 butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; WO 99/06397-4-PTU9159 -41- PCTfUS98/15479 trans, trans-2-(2-(Oxazol-2-y I) ethy1) met hoxy- 1,3 -be nzodioxol- 5-yI1) -1 N-di(n-butyI) am i no carbon ylImet hyl)-pyrrolIidine-3carboxylic acid; trans, trans-2-(2-(Oxazol-2-yI)ethyl)-4-(7-methoxy- 1,3-benzodioxol- 5-yI)-1-[(N-4-heptyl-N-(4-fluoro-3methy lphenyl) ami no)carbo nyl methyl]-pyrro lid ine-3-carboxylic acid; trans, trans-2-(2-(Oxazol-2-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol- 1 -[(N-butyl-N-(4di methy lam inob utylI)am ino) carbonyl methyl]-pyrrol idi ne-3carboxylic acid; trans, trans-2- Methyl oxazol1-2-yI) ethyl1)-4-(1 be nzod yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2- (5-M ethyl oxazol1-2-yI) ethyl)-4- (1 ,3-be nzod yI)-1 -I(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyll-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(5-Methyloxazol-2-yI)ethyl)-4-(1 yI)-1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2,5-D ioxopyrro lidin- 1 -y1) ethyl) ,3-benzodioxol- N-di(n-butyl)ami nocarbonyl methyl)-pyrro lid ine-3carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin-1 -yl)ethyl)-4-(1 ,3-benzodioxol- -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)ami no)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans,trans-2-(2-(2,5-Dioxopyrrolidin-1 -yI)ethyl)-4-(1 ,3-benzodioxol- 5 -yI)-1 -[(N-butyl-N-(3-hydroxypropyl) amino) carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin- 1 -yI)ethyl)-4-(1 ,3-benzodioxol- 1 -[(N-butyl-N-(propoxy) amino) carbo nylmethyl]-pyrro lidi ne- 3-carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin- 1 -yI)ethyl)-4-(1 ,3-benzodioxoI- 5-yI)-l1-[(N-butyl-N-(4-dimethylaminobutyl) amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;

-AO-

'WO 99/06397 -C/S1/3 191I~yI~~ trans, trans-2-(2-(2,5-Dioxopyrro lid in -1 -y I) ethy1) me thoxy-1 13benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin- 1 -yI)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-l-[(N-4-heptyi-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Pyridin-2-y)ethyl)-4-(1 ,3-benzodioxol-5-yI)- 1 4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Pyridin-2-y)ethyl)-4-(1 ,3-benzodioxol-5-yI)- 1 butyl-N-(3-hydroxypropyl)amirio)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(Pyridin-2-y)ethyl)-4-(1 ,3-benzodioxoi-5-yI)- 1 butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Pyridin-2-y)ethyl)-4-(1 ,3-benzodioxol-5-y)- 1 butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyljpyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Pyridin-2-yI)ethyl)-4-(7-methoxy- 1 ,3-benzodioxol- 5-yI)-l1-(N, N-di(n-butyl)ami nocarbonylmethyi)-pyrrol idine-3carboxylic acid; trans, trans-2-(2- (Pyridin-2-y I)ethyI)-4-(7-meth oxy- 1 3-be nzodioxol- 5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy- 1,3-benzodioxol- 1-[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(Pyrimidin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-y)- 1 (N ,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Pyrimidin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 (N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyllpyrrolidine-3-carboxylic acid; -43- WO 99/06397 -43- PCTIUS98/15479 trans, trans-2-(2-(Pyrimidin-2-y I) ethy1) ben zodioxol-5-y1) -1 utyl-N imet hylIam inobuty I)a m ino) carbon y methy I]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-benzodioxol-4-yI)ethyl)-4-(1 yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(1 ,3-be nzodioxol1-4-yl) ethyl) (1 ,3-benzodioxol- yI)-l1-[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; and trans, trans- 2- (1 ,3-be nzod ioxol1-4-y1) ethyl) (1 ,3-ben zod yl)-l1-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1 1 N-d i(n-b utyl)am inocarbonyl methyl) -pyrrol idi ne-3-carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1 ,3benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1 1 N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 (N N-di (n-butyl)am in ocarbonyl methyl)-py rro lid i ne-3-ca rboxyl ic acid; or a pharmaceutically acceptable salt.

Most preferred compounds of the invention are selected from the group consisting of: trans, trans-2-(2-(1 ,3-Dioxol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 N-di (n-butyl) amino carbo nyl methy I)-py rro lid in e-3-carboxyl ic acid;

AA-.

WO 99/06397 PCTIUS98/1 5479 trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yl)ethyl)-4-(1 ,3benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxol-2-yI)ethy!)-4-(1 -1 -[[N-4-heptyl-N-(2-methyl-3-fluorophenyl)] aminocarbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxol-2-yI)ethyl)-4-(7-methoxy-1 ,3- -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)'4-(1 1 ,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin- 1 -yI)ethyl)-4-(1 yl)-1 ,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxol-2-yI)ethyl)-4-(7-methoxy-1 1,3benzodioxol-5-yI)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2- (2,2-Dimethylpentyl)-4-(7-methoxy- 1,3-benzodioxol-5yI)-1 N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxoian-2-yI)ethyl)-4-(7methoxy-1 ,3-benzodioxol-5-y!)-1 -(N,N-di(nbutyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 1 -(N,N-di(n-butyl)aminocarbonylmethy!)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethy-3-(E)-penteny)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-pyridyl)ethyl)-4-(1 ,3-benzodioxol-5-yI)- 1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrro lid in-1 -yI)ethyl)-4-(1 ,3-benzodioxol1-5yI)-1 -(N,N-di(n-buty!)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1 ,3-benzodioxol-5-yl)-1I (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid; 0 ~(2S,3 R,4S)-2-(2-(2-oxopyrrolidin- 1-yI)ethyl)-4-(1I,3-benzodioxol-5-yl)- I-(N-4heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid; trans, trans-2-(2-( I -pyrazolyl)ethyl)-4-( 1,3 -benzodioxol-5-yl)- 1 -(N,N-di(n- IND butyl)aminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid; (2R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- propyl-N-pentanesulfonyl)amino)ethyl] -pyrrolidine-3 -carboxylic acid; (2S, 3R, 4S)-2-(2,2-Dimethylpentyl)-4-( 1,3-benzodioxol-5-yl)- 1 -(N,N-di(nbutyl)aminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3 -enyl)-4-( 1,3-benzodioxol-5-yl)- I-(N,Ndi(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3 -enyl)-4-(7-methoxy- 1,3-benzodioxol-5yl)-lI ,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; (2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1I,3-benzodioxol-5-yl)- I di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid; and (2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-( 1,3-benzodioxol-5-yl)- 1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid; or a pharmnaceutically acceptable salt thereof.

According to one embodiment of this invention there is provided [2S,3R,4S]-2- (2,2-Dimethylpentyl)-4-(7-methoxy-1I,3-benzodioxol-5-yl)-l-(N,N-di(nbutyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or [2S,3 R,4S11-2-(4methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1 -jj(N-butyl-N-(4-dimethylaminobutyl)amino) carbonylmethyl]-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt of either one thereof.

According to another embodiment of this invention there is provided a pharmaceutical composition comprising [2S,3R,4S]-2-(2,2-dimethylpentyl)-4-(7methoxy- 1,3 -benzodioxol-5-yl)-l-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid or [2S,3R,4S]-2-(4-methoxyphenyl)-4-(1I,3-benzodioxol-5-yl)- I butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl] -pyrrolidine-3 -carboxylic acid or a pharmaceutically acceptable salt of either one thereof together with a pharmaceutically acceptable carrer.

(1010754 I):KZA O According to a further embodiment of this invention there is provided a method N of treating bone pain due to bone cancer in a mammal comprising administering to a O mammal in need of such treatment a therapeutically effective amount of [2S,3R,4S]-2- (2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-l-(N,N-di(nbutyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or [2S,3R,4S]-2-(4methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -[(N-butyl-N-(4-dimethylaminobutyl)amino) C carbonylmethyl]-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt of either one thereof or of a pharmaceutical composition comprising [2S,3R,4S]-2-(2,2- N dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-l-(N,N-di(nbutyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or [2S,3R,4S]-2-(4- CN methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-I -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt of either one thereof together with a pharmaceutically acceptable carrier.

Is According to an additional embodiment of this invention there is provided a use of [2S,3R,4S]-2-(2,2-dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-l-(N,N-di(nbutyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or [2S,3R,4S]-2-(4methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-I-[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt of either one thereof in the preparation of a medicament for treating bone pain due to bone cancer in a mammal According to an additional embodiment of this invention there is provided [2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-l-(N,N-di(nbutyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or [2S,3R,4S]-2-(4methoxyphenyl)-4-(1,3-benzodioxol-5-yl)- I -[(N-butyl-N-(4-dimethylaminobutyl)amino) carbonylmethyl]-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt of either one thereof when used in a therapeutically effective amount to treat bone pain due to bone cancer in a mammal.

Methods for preparing the compounds of the invention are shown in Schemes I-

XV.

Scheme I illustrates the general procedure for preparing the compounds of the invention when n and m are 0, Z is -CH 2 and W is (1010754 I):KZA AS rf~iR'nrT IftO/1 C t WO 99/06397 tu- r i/uayor141I/ -C0 2 H. A P-ketoester 1, where E is loweralkyl or a carboxy protecting group is reacted with a nitro vinyl compound 2, in the presence of a base (for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium ethoxide or sodium hydride and the like) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol and the like. The condensation product 3 is reduced (for example, hydrogenation using a Raney nickel or platinum catalyst). The resulting amine cyclizes to give the dihydro pyrrole A. Reduction of 4 (for example, sodium cyanoborohydride or catalytic hydrogenation and the like) in a protic solvent such as ethanol or methanol and the like gives the pyrrolidine compound 5. as a mixture of cis-cis, trans,trans and cis,trans products.

Chromatographic separation removes the cis-cis isomer leaving a mixture of the trans,trans and cis,trans isomers which is further elaborated. The cis-cis isomer can be epimerized (for example, using sodium ethoxide in ethanol) to give the trans,trans isomer and then carried on as described below. The pyrrolidine nitrogen is acylated or sulfonylated with R 3 -X (R 3 is R 4 or Re-S(0)2- and X is a leaving group such as a halide (CI is preferred) or X taken together with R4-C(O)- or R6-S(0)2- forms an activated ester including esters or anhydrides derived from formic acid, acetic acid and the like, alkoxycarbonyl halides, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and the like) or alkylated with R 3 -X where X is a leaving group (for example, X is a halide (for example, CI, Br or I) or X is a leaving group such as a sulfonate (for example, mesylate, tosylate, triflate and the like)) in the presence of a base such as diisopropyl ethylamine or triethylamine and the like to give the N-derivatized pyrrolidine J which is still a mixture of trans,trans and cis,trans isomers. Hydrolysis of the ester 6 (for example, using a base such a sodium hydroxide in EtOH/H 2 0) selectively hydrolyzes the trans,trans ester to give a mixture of Z and 8, which are readily separated.

Scheme II illustrates a general procedure for preparing the compounds of the invention when n is 1, m is 0, Z is -CH 2 and W is -C0 2 H. A substituted benzyl chloride 9 is reacted with a lithio dithiane 1Q in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct 11. The anion of compound 11 is formed using a base such as n-butyllithium and then reacted with R 1

-CH

2 wherein X' is a

I

7- WO 99/06397 -PCTlUS98/1 479 leaving group such as a halide or sulfonate to give compound 12. The dithiane protecting group is cleaved (for example, using a mercuric salt in water) to give the keto compound 13. Reaction of ketone 13 with benzyl amine and formaldehyde gives the keto piperidine compound 14.

Treatment of compound 14 with an activated nitrile such as trimethylsilyl cyanide followed by a dehydrating agent such as phosphorous oxychloride provides the isomeric ene nitriles Reduction of the double bond (for example, using sodium borohydride) affords the piperidinyl nitrile 16. Hydrolysis of the nitrile using hydrochloric acid in the presence of a carboxy protecting reagent (for example, an alkyl alcohol) affords ester 17 (where E is a carboxy protecting group). Debenzylation by catalytic hydrogenation under acidic conditions affords the free piperidine compound 18. Compound 1 8 is further elaborated by the procedures described in Scheme I for compound 5 to give the final product compound 19.

Scheme III illustrates a general procedure for preparing the compounds of the invention when m and n are 0, Z is and W is -C02H. 3-Keto ester 20 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an a-haloester 21 (where J is lower alkyl or a carboxy protecting group and the halogen is bromine, iodine or chlorine) in the presence of a base such as NaH or potassium tertbutoxide or lithium diisopropylamide in an inert solvent such as THF or dimethoxyethane to give diester 22. Treating compound 22 with R 3

-NH

2 and heating in acetic acid gives the cyclic compound 23. The double bond is reduced (for example, by catalytic hydrogenation using a palladium on carbon catalyst or sodium cyanoborohydride reduction) to give pyrrolidone 24. Epimerization with sodium ethoxide in ethanol to give the desired trans,trans configuration, followed by sodium hydroxide hydrolysis of the ester, affords the desired trans,trans carboxylic acid Scheme IV illustrates a general procedure for preparing the compounds of the invention when n is 0, m is 1, Z is -CH 2 and W is -C0 2 H. The trans,trans compound Z, prepared in Scheme I, is homologated by the Arndt-Eistert synthesis. The carboxy terminus is activated (for example, by making the acid chloride using thionyl chloride) to give compound 52, where L is a leaving group (in the case of an acid chloride, L is CI). Compound 52 is treated with diazomethane to AQ <^m/TTCtrf\0/1 C WO 99/06397 to- r give the diazo ketone 53. Rearrangement of compound 53 (for example, using water or an alcohol and silver oxide or silver benzoate and triethylamine, or heating or photolysis in the presence of water or an alcohol) affords the acetic acid compound 54 or an ester which may be hydrolyzed. Compounds where m is from 2 to 6 can be obtained by repetition of the above described process.

A preferred embodiment is shown in Schemes V and VI. A benzoyl acetate 26 is reacted with a nitro vinyl benzodioxolyl compound 27 using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in toluene to give compound 28. Catalytic hydrogenation using Raney nickel leads to reduction of the nitro group to an amine and subsequent cyclization to give the dihydropyrrole 29. The double bond is reduced with sodium cyanoborohydride to give the pyrrolidine compound 30 as a mixture of cis-cis, trans,trans and cis,trans isomers. Chromatography separates out the cis-cis isomer, leaving a mixture of the trans,trans and cis,trans isomers (31).

Scheme VI illustrates the further elaboration of the trans,trans isomer. The mixture (31) of trans,trans and cis,trans pyrrolidines described in Scheme IV is reacted with N-propyl bromoacetamide in acetonitrile in the presence of ethyldiisopropylamine to give the alkylated pyrrolidine compound 2, still as a mixture of trans,trans and cis,trans isomers. Sodium hydroxide in ethanol-water hydrolyzes the ethyl ester of the trans,trans compound but leaves the ethyl ester of the cis,trans compound untouched, thus allowing separation of the trans,trans carboxylic acid 33 from the cis,trans ester 34.

Scheme VII illustrates the preparation of a specific piperidinyl compound. Benzodioxolyl methyl chloride 35 is reacted with lithio dithiane 36 to give the alkylated compound 37. Treatment of compound 37 with 4-methoxybenzyl chloride in the presence of lithium diisopropylamide gives compound 38. Cleavage of the dithiane protecting group using a mercuric salt in aqueous solution gives ketone 39. Treatment of 39 with benzylamine and formaldehyde gives the keto piperidine 40. Treatment of compound 40 with trimethylsilyl cyanide followed by phosphorous oxychloride gives the ene nitrile as a mixture of isomers 41. Sodium borohydride reduction of the double bond gives the piperidinyl nitrile 42. Hydrochloric acid hydrolysis in the presence of ethanol gives ethyl ester 43. The N-benzyl protecting group is I I -4q- WO 99/06397 PCI/US98/W4 /Y removed by catalytic hydrogenation to give the free piperidine compound 44. Compound 44 is further elaborated by the procedures described in Scheme V for compound 31 resulting in the formation of the N-derivatized carboxylic acid A preferred embodiment of the process shown in Scheme III is shown in Scheme VIII. 4-Methoxybenzoylacetate 4. (wherein E is loweralkyl or a carboxy protecting group) is reacted with an benzodioxolyl a-bromoacetate 47 (wherein E is lower alkyl or a carboxy protecting group) in the presence of NaH in THF to give diester 48.

Treating compound 48 with ethoxypropylamine and heating in acetic acid gives the cyclic compound 49. The double bond is reduced by catalytic hydrogenation using a palladium on carbon catalyst to give pyrrolidone jQ. Epimerization with sodium ethoxide in ethanol to give the desired trans,trans configuration is followed by sodium hydroxide hydrolysis of the ester to afford the desired trans,trans carboxylic acid 51.

Scheme IX illustrates the preparation of compounds where n is 0, Z is -CH 2 and W is other than carboxylic acid. Compound 55, which can be prepared by the procedures described in Scheme IV, is converted (for example, using peptide coupling condition, e.g. N-methylmorpholine, EDCI and HOBt, in the presence of ammonia or other amide forming reactions) to give carboxamide 56. The carboxamide is dehydrated (for example, using phosphorus oxychloride in pyridine) to give nitrile 57.

Nitrile 57 under standard tetrazole forming conditions (sodium azide and triethylamine hydrochloride or trimethylsilylazide and tin oxide) is reacted to give tetrazole 58. Alternatively nitrile 57 is reacted with hydroxylamine hydrochloride in the presence of a base (for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF, DMSO, or dimethylacetamide to give amidoxime 59. The amidoxime 59 is allowed to react with a methyl or ethyl chloroformate in a conventional organic solvent (such as, chloroform, methylene chloride, dioxane, THF, acetonitrile or pyridine) in the presence of a base (for example, triethylamine, pyridine, potassium carbonate and sodium carbonate) to give an O-acyl compound. Heating of the O-acyl amidoxime in an inert solvent (such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and the like) results in

I

_n orsTTCOI1 479 WO 99/06397 cyclization to compound 60. Alternatively reacting the amidoxime 59 with thionyl chloride in an inert solvent (for example, chloroform, dichloromethane, dixoane and THF and the like) affords the oxathiadiazole 61.

Scheme X illustrates the preparation of compounds in which R 3 is an acylmethylene group. A carboxylic acid 62 (where R 4 is as previously defined herein) is treated with oxalyl chloride in a solution of methylene chloride containing a catalytic amount of N,Ndimethylformamide to give the acid chloride. Treatment of the acid chloride with excess ethereal diazomethane affords a diazoketone, and then treatment with anhydrous HCI in dioxane gives the a-chloroketone 63. Pyrrolidine ester 5 where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the a-chloroketone 63 to provide alkylated pyrrolidine 64. Carboxy deprotection (for example, hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrrolidine acid Scheme XI illustrates the preparation of "reverse amides and sulfonamides". The carboxy protected pyrrolidine 5, prepared in Scheme I, is reacted with a difunctionalized compound X-R 8 -X where R 8 is alkylene and X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 66. Treatment of 6 6 with an amine (R20NH 2 affords secondary amine 67. This amine (72) can be reacted with an activated acyl compound (for example, R 4 and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford amide 68. Alternatively amine 67 can be reacted with an activated sulfonyl compound (for example, R 6 -S(0) 2 -CI) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide 69.

Scheme XII illustrates a method for synthesizing pyrrolidines by an azomethine ylide type [3+2]-cycloaddition to an acrylate. General structures such as compound 70 are known to add to unsaturated esters such as 71 to provide pyrrolidines such as compound 72 Tsuge, S.

Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), 0. Tsuge, S.

Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 52 2523-30 (1987), and S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn. 62 1960-68 (1989)). A specific example is also shown in Scheme XII. Silylimine 73 I I -51- WO 99/06397 PCT/US98/15479 is reacted with acrylate 74 in the presence of trimethylsilyl triflate and tetrabutylammonium fluoride to give the desired pyrrolidine 75 as a mixture of isomers. This method can be modified to provide the Nacetamido derivatives directly by reacting 73 and 74 with the appropriate bromoacetamide (for example, dibutyl bromoacetamide) in the presence of tetrabutylammonium iodide and cesium fluoride to give compound 76.

Scheme XIII illustrates a method for producing an enantiomerically pure pyrrolidine 80, which can be further elaborated on the pyrrolidine nitrogen. Intermediate racemic pyrrolidine ester 77 (for example, prepared by the procedure described in Scheme V) is Bocnitrogen protected (for example, by treatment with Boc20) and then the ester is hydrolyzed (for example, using sodium or lithium hydroxide in ethanol and water) to give t-butyl carbamoyl pyrrolidine carboxylic acid 78. The carboxylic acid is converted to its (+)-cinchonine salt, which can be recrystallized (for example from ethyl acetate and hexane or chloroform and hexane) to afford the diastereomerically pure salt. This diastereomerically pure salt can be neutralized (for example, with sodium carbonate or citric acid) to afford enantiomerically pure carboxylic acid 79. The pyrrolidine nitrogen can be deprotected (for example, using trifluoroacetic acid) and the ester reformed by the use of ethanolic hydrochloric acid to give salt 80. Alternatively one can use ethanol HCI to cleave the protecting group and form the ester in one step. The pyrrolidine nitrogen can be further elaborated (for example, by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 81. The use of (-)-cinchonine will give the opposite enantiomer.

Scheme XIV describes another procedure for preparation of pyrrolidines. Pyrrolidines may be synthesized by the use of an azomethine ylide cycloaddition to an acrylate derivative as described by Cottrell, I. et.al., J. Chem. Soc., Perkin Trans. 1, 5: 1091-97 (1991).

Thus, the azomethine ylide precursor 82 (where R 55 is hydrogen or methyl) is condensed with a substituted acrylate 83 (wherein R 2 is as described herein and R 56 is loweralkyl) under acidic conditions to afford the substituted pyrrolidine 84. The N-protecting group can be removed (for example, by hydrogenolysis of an N-benzyl group) to give 1 r2 0 rmflClO 11 C AflT WO 99/06397-

J

1I a l which can be alkylated under the conditions described above to provide the N-substituted pyrrolidine 86. Standard ester hydrolysis of 86 produces the desired pyrrolidine carboxylic acid 87.

A preferred process is shown in Scheme XV. Nitro vinyl compound (88) is reacted with beta-keto ester 89 in the presence of a base such as sodium ethoxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or methylene chloride and the like at a temperature of from about 0° C to about 1000 C for a period of time from about 15 minutes to ovemight to give compound 90. Reduction of the nitro group followed by cyclization was effected for example by catalytic hydrogenation with a hydrogen pressure of from about atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day of compound 90 in an inert solvent such as THF, ethyl acetate, toluene, ethanol, isopropanol, DMF or acetonitrile and the like, using a hydrogenation catalyst such as Raney nickel, palladium on carbon, a platinum catalyst, such as platinum oxide, platinum on carbon or platinum on alumina and the like, or a rhodium catalyst, such as rhodium on carbon or rhodium on alumina and the like, and the like affords intermediate nitrone 91a or a mixture of nitrone 91a and imine 91b.

The reaction mixture comprising the nitrone or nitrone/imine mixture is treated with an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the like, and the hydrogenation is continued to give pyrrolidine compound 92 as the cis,cis-isomer. Epimerization at C-3 is effected by treatment of compound 92 with a base such as sodium ethoxide, potassium t-butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the 3o like or an amidine such as DBU and the like in an inert solvent such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and the like at a temperature of from about -200 C to about 1200 C to give the trans,trans compound 93. Compound 93 itself can optionally be resolved into enantiomers prior to reacting with X-R 3 The substantially pure at least 95% of the desired isomer) optically active (+)-isomer of compound 93 is obtained by treatment of a mixture of the (+)-isomer and the (-)-isomer of 93 with S-(+)-mandelic acid, D-tartaric acid or

I

r- DnrfTQ1a/1 4A7 WO 99/06397 D-dibenzoyl tartaric acid and the like in a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol and the like.

The (+)-isomer of 93 selectively crystallizes as the salt, leaving the (-)-isomer of 93 in solution. Alternatively, the substantially pure at least 95% of the desired isomer) optically active (-)-isomer of compound 93 can be selectively crystallized by reaction of a mixture of the (+)-isomer and the (-)-isomer of 93 with L-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid and the like, leaving the desired (+)-isomer of compound 93 in solution.

Compound 93 (racemic or optically active) is reacted with X-R 3 (where X is a leaving group (for example, a halide or a sulfonate) and R 3 is as previously defined) using a base such as diisopropylethylamine, triethylamine, sodium bicarbonate or potassium carbonate and the like in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and the like at a temperature of from about 0° C to about 1000 C to give the intermediate ester 94. The ester can be isolated or converted in situ to the carboxylic acid (25) using hydrolysis conditions such as a base such as sodium hydroxide or lithium hydroxide or potassium hydroxide and the like in a solvent such as ethanol-water or THF-ethanol and the like.

A more detailed description of the preparation of some specific analogs is provided in Schemes XVI-XXI. Aliphatic P-ketoesters (Scheme XVI) may be prepared by copper-catalyzed addition of a Grignard reagent (for example, propylmagnesium bromide) to an unsaturated ester, for example, ethyl 3,3-dimethylacrylate. The resultant ester is hydrolyzed, for example with sodium hydroxide in aqueous alcohol, and is homologated in stepwise fashion to the corresponding P-ketoester, for example by activation using carbonyldiimidazole and condensation with magnesio-ethoxymalonate.

Alternatively, olefinic P-ketoesters may be prepared by Claisen rearangement of the corresponding allylic alcohols; hydrolysis and homologation as described above produce the desired P-ketoester.

N-alkyl,O-alkyl bromohydroxamates are prepared according to Scheme XVII. N-Boc-O-allyl hydroxylamine is alkylated with and alkyl halide, for example using sodium hydride as base; the double bond is selectively reduced, for example using hydrogen and a palladium -54- r/lTren s/1^ 479 WO 99/06397 catalyst. After removal of the Boc protecting group, for example with TFA, the resultant amine is acylated, for example using bromoacetyl bromide.

The P-ketoesters described in Scheme XVI may be converted to pyrrolidine derivatives as described in Scheme XVIII. Michael addition onto a nitrostyrene derivative can be catalyzed with base, for example DBU or potassium t-butoxide; the resultant adduct is hydrogenated, for example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under controlled pH. A mixture of isomers are generated, in which the transtrans is generally preferred.

Scheme XIX describes several strategies for resolving the racemic pyrrolidines described above. Treatment with a chiral acid, for example (S)-(+)-mandelic acid, may provide a crystalline derivative, which can be further enriched through recrystallization. The salt may be washed with base to extract the resolving agent and return the optically active pyrrolidine product. Alternatively, the amino ester can be N-protected (for example with Boc-anhydride) and hydrolyzed (for example with sodium hydroxide) to give the corresponding N-protected amino acid.

Activation of the acid, for example as the pentafluorophenyl ester, followed by coupling with a chiral nonracemic oxazolidinone anion, provides the corresponding acyloxazolidinone diastereomers, which may be separated chromatographically. Alcoholysis of one acyloxazolidinone diastereomer, followed by cleavage of the N-protecting group, returns an optically enriched amino ester. A similar transformation may be accomplished through coupling of the protected amino acid with a chiral nonracemic amino alcohol. After chromatographic separation of the resultant diastereomers, the amide is cleaved and the protecting group is removed to provide optically enriched product.

Optically active amino esters prepared as described above may be alkylated (Scheme XX) with a variety of electrophiles, for example dibutyl bromoacetamide, N-butyl,N-alkoxy bromoacetamide, N-(4heptyl)-N-(3-methyl-4-fluorophenyl) bromoacetamide, or N-(Qhydroxyalkyl)-N-alkyl haloacetamide. Hydrolysis of the resultant ester, for example using sodium hydroxide in aqueous alcohol, provides the product.

WO 99/06397 55- PCT/US98/15479 For one particular class of electrophile, N-(L-hydroxyalkyl)-Nalkyl haloacetamides, further transformations of the alkylation product are possible (Scheme XXI). Activation (for example using methanesulfonyl chloride) of the alcohol, followed by displacement with halogen (for example, using lithium bromide) provides the corresponding halide. Displacement of halide with an amine, for example dimethylamine, provides the corresponding amino ester, which may be hydrolyzed as previously described to provide product.

WO 99/06397 PTU9/57 PCTfUS98/15479 -56- Scheme I 0 C0 2

E

N/

H

C0 2

E

[H]

C 0 2

E

Mixture of Cis-Cis Trans-Trans Cis-Trans

R

3

R

2

R

S C0 2

E

Mixture of Trams-Trans Cis-Trans 1H 2 01 2

H

Trans-Trans

-R

3

R

2 Kj.R, C0 2

E

Cis-Trans WO 99/06397 PCTIUS98/15J479 -57- Scheme II

R

2 %CI

S

0

R

2 QQ -N

R

2 Rl 2l N R2

R,

ISOMER

r-2 N R2 C02E L C N

R

2 HN> R2

CO

2

E

Ri R3 NR 2 C02H WO 99/06397 PTU9/57 PCTIUS98/15479 -58- Scheme III Halo 0 0

R

1 4.,C2 Halo CI, Br, or I 0 *R 3 C0 2

E

C0 2

E

R

2 3 C 0 2

H

Trar&-Trarr.

WO 99/06397 WO 9906397PCTJUS98/1 5479 -59- Scheme IV R2-

R

1 2

H

R

3 0 L

CH

2

N

2

R

3

R

2 R 1 C0 2

H

N eR 3

R

2

KJ.R

0 C HN 2 53 WO 99/06397PCUS/157 PCTfUS98/15479 Scheme V C

H

3 0

G

EtO 2

C

kI NO0 2 b 1 DBU H2I

OC~{

3 OC14 3 COQEt .r NaCNBH 3 Mixture of Cis-Cis Trans-Trans Comatographic separation Cis-Trans

COOPE

Cis-Cis Mixture of Trans-Trans and Cis-Trans WO 99/06397 WO 9906397PCTIUS98/I 5479 -61- Scheme VI 0 C H 3 COOEt Cis-Trans and BrCH 2 C0NHC3H 7 iPr 2 NEt

*OCH

3 COQEt Trans-Trans and Cis-Trans Trans-Trans NaOH H 2 0, EtOH 00 0OC H 3 800H 0 rANHC 3

H

7 o~Y-o &OCH3 COOEt Cis-Trans Trans-Trans WO 99/06397 PTU9/57 PCT/US98/15479 -62- Scheme ViI Qocl

Q

0

YKAS)

0 e Qa'!"Cr"

I

ISOMER

OMe e OMe WO 99/06397 WO 9906397PCT/US98/15479 -63- Scheme VII cont.

0

N.>

M e 41 N 0 C0 2 Et OMe OMe WO 99/06397 PTU9/57 PCTIUS98/15479 -64- Scheme Vill 0 CH30-0--CC02E

CH

3 0.

/C

H

3 H 3 /C H 3 Trans-Trans WO 99/06397 PTU9/57 PCT/US98/15479 Scheme IX R 3

(CH

2 )m R 3

(CH

2 )m

N=N

(CH2)m HN 4 0,O /R 3

(CH

2 )m1 (CHaOM

CN

.I /,R 3 -No -(CH 2 )m

H

2 N NO H

(CH

2 )m H

N

'S-0

I

0 WO 99/06397PCUS8147 PCTIUS98/15479 -66- Scheme X

R

4 yOH 0 0 0 C0 2

E

WO 99/06397 WO 9906397PCTIUS98/1 5479 -67- Scheme XI

H

R2~ A R 1 C0 2

E

0 R4 C0 2

H

C0 2

E

,Rs-NHR 20

N

R2-?-R C0 2

E

WO 99/06397PC/S8157 PCTfUS98/15479 68- Scheme X11

R

1

R

3

CH

2 C0 2 Et R2(

R

3 ,N -0E 73 0:0,

CO

2 Et 74

QCH

3 00)H 3 0 WO 99/06397PCIS8I57 PCT/US98/15479 -69- Scheme X111 1. Boc 2 0 2. NaOH, EtOH

H

2 0

OCH

3 BocN -C0 2

H

ZZ

1. (+)-cinchonine 2. recrystallize fronj EtOAc/hexane 3. Na 2

CQ

3

OCH

3 HCI N -CO 2 Et -0

HCI

EtOH

OCH

3 BocN C2 -0

-C

(+)iQ Z2

BU

2 NC(0)CH 2 Br EtNiPr 2

CH

3

CN

OCH

3 0

CO

2 00 LI WO 99/06397 WO 9906397PCTIUS98/15479 Scheme XIV Rss Rh."N 1"OMe MeAi

H

2 Pd(QH) 2

/C

C0 2

R

56 TFA, CH 2

CI

2 HN _C0 2

R

56 NaOH or LIOH EIOH, H 2 0 Rss Fh~k NQ _C0 2

R

56

R

3 Br

BU

4 NI or Nal

CH

3

CN

R3,NQ _C 2

H

R

2 WO 99/06397 PTU9/57 PCTfUS98/15479 -71- Scheme XV

R

2 ~N02 0 0 OL R 0 C0 2 r= C0 2

E

0 2

N

C0 2

E

C0 2

E

92 C0 2

E

R 3 R2 R C0 2

H

/R

3 C0 2

E

94 WO 99/06397PCIS8157 PCT/US98/15479 -72- SCHEME XVI COOEt nPrMgBr NaOH cat CuCI OO CDI t 0 0 Etooc

OH

OEt OJ(Et OEt NaOH heat Li arm% CDI O4L OEt 0 EtOOC SCHEME XVII BocHN' NaH

R-X

F TFA BrCH2COBr BocN' Pd-C 0 SCHEME XVIII

DBU

H

2 Ra-Ni NaBH 3

CN

HN .,COQEt RO0 or cat. KOtBu EtOOC WO 99/06397 WO 9906397PCTIUS98/1 5479 -73- SCHEME XIX HN .'eCOOEt (racemic)

R

HN -AICOQEt

CH

3 0O 0 (racemic) mandelic: acid recrystallization neutralization R= 1 J 1. EDAC, 2. F 5 -pheno6 91 -N-k 1. NaOMe, I. Io 2 1 MeOH 2. NaOH 3. separate 2. TFA diastereomers

R'

HN .'ICQOEt (single enantiomer)

R

HN IdCOOMe

CH

3 0 0 (single enantiomer) 1. EDAC, HOOBt 1.2 ocOAOH 1. HCI, heat 2. NaQH 3. separate 2. HCI, EtOH diastereomers, (racemic) (racmic)(single enantiomer) WO 99/06397 WO 9906397PCT/US98/15479 -74- SCHEME XX 0 R 13 JiR, HN R 2 COE NaOH 'R 0~ Kiml D 2

R

R

1 ~NN ."iCOOH ~~0 'R 0 Pr1fl2- SCHEME XXI 0 HN "uCQOEt Br 1.MsC ICfO 2. LiBr 0

O~

0

(C

3 2 H0 'R 0 (C3)2NH R )0 NaC *.'iCOOH I 0 0 WO 99/06397 PCT/US98/15479 Compounds which are useful as intermediates for the preparation __of compounds of the invention are:

NH

(CH

2 )n

(CH

2 )m w wherein n is 0 or 1; m is 0 to 6; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3 1-2, -P(Q)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

-ON,

-C(O)NHR17 where R17 is loweralkyl, alkylaminocarbonyl, dial kylami nocarbo nYl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl6, HO 0 0

H

WO 99/06397 WO 9906397PCTIUS98/115479 -76-

OH

0 0, H o an R1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hiydroxyalkyl, haloalkyl, haloalkoxyalkyl., alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl.

cycloalkyt, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarboflylalkyl, dialkylaminocarbonylalkyl, aminocarbonylaikenyl, alkyl amino carbonylalkenyl, dialkylaminocarbonylalkelyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)amifloalkyl, alkylsulf onyl amid oa lkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and R C is alkylene, with the proviso that one or both of R, and

R

2 is other than hydrogen; or a salt thereof; or a compound of the formula:

I

WO 99/06397 PCTIUS98/1 5479 N _77- R2 Rz NH 2 N2

(CH

2 )n (CH2)n

(CH

2 )m (HM' ID W R 1 or W Rj (IV)

(V)

C) wherein n is 0 or 1; m is Oto 6; W is -C(O) 2 -G where G is hydrogen or a carbroxy protecting group, -P0 3 H2, -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

-CN,

-C(O)NHR17 where R 1 7 is loweralkyl, aikylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2R16 where R 1 6 is loweralkyl, haloalkyl, phenyl or dialkylamino,

-S(O)

2 NHC(O)Rie, HO 0 0 HO 0

OH

IN? WO 99/06397 WO 9906397PCT/US98/1 5479 -78- 0 D 0 (q) 0 A

N_

H0 H n R, and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dial kyl am inocarbonyl al kenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and R C is alkylene, with the proviso that one or both of R, and

R

2 is other-than hydrogen; or a salt thereof.

Preferred intermediates include compounds of formula (1ll), (IV) and wherein m is zero or 1, W is *C0 2 -G wherein G is hydrogen or a carboxy protecting group, and R1 and R 2 are as defined above; or the substantially pure or (+)isomer thereof.

WO 99/06397 PCT/US98/15479 c-I 79- Particularly preferred intermediates are compounds of formula (Ill1), (IV) and wherein n and m are both 0; SW is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; and Ri is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, S(vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4- Smethoxyphenyl, N- 4-fluorophenyl, 3..fluorophenyl' 4-ethoxyphenyl, 4-ethylphenyl, 4methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4m eth oxy pheny I, 3-fluoro-4-ethOXyphenyl, 2-f luoropheflyl, 4-methoxymethoxyphenyl, 4-hydroxypheflyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuraflyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkOXY and carboxyalkoxy (ix) aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-Nalkyl)aminoalkyl, and (xiii) alkylsulfoflylamidoalkYl, and R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy- 1,4-benzodioxaflyl, dihydrobelzofturaflyl, benzofurnayl, 4-methoxypheflyl, dimethoxyphenyl,, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure or (+)isomer thereof.

Other compounds which are useful as intermediates for the preparation of compounds of the invention are:

R

2 N R5b

(CH

2 )n (C H 2 6; W

R

(V 1) WO 99/06397 WO 9906397PCTIUS98/15479 wherein n is 0 or 1; m is 0 to 6; Rsb is alkylene; Q is a le aving group; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3

H

2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

-ON,

-C(O)NHR17 where R 1 7 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2Rl6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl6,

HO

/NH

0 (HO 0

OH

(p) 0 WO 99/06397 PCTIUS98/15479

N

'0

N-

c-I

H

N JLCF3 H ,or -KI"I

NHSO

2

CF

3 and Ri and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl1 haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylamiflocarbonylalkyl, dialkylamiflocarbonYlalkYl, amino carboflylal ke nyl, alkylaminocarbonylalkeyll dialkylaminocarboflylalkenyl, hydroxyalkenll aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyi-N-alkyl)amfinoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rc is alkylene, with the proviso that one or both of R, and

R

2 is other than hydrogen; or a salt thereof; or a compound of the formula: R2N' 0R2N R.Q

C

(C

(CH

2 )n

V(CH

2 )m2)n

(C

2 C2 W R or W

R

(VII1) (Vill) wherein n is 0 or 1; m is 0 to 6; WO 99/06397 WO 9906397PCT/US98/15479 N -82- Z Rsb is alkylene; Q is a leaving group; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3 1- 2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

-CN,

-C(O)NHR1 7 where R 17 is loweralkyl, alkylaminocarbonyt, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido,

-C(O)NHS(O)

2 Rl 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 HO 0

-NH

0 HO 0

OH

0 0 q) X 0 WO 99/06397 WO 9906397PCTIUS98/1 5479 -83- 0= H o

NHSO

2

CF

3 and R, and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbOflylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkYl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbOflylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkell dialkylaminocarbonylalkel hydroxyalkeflyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkYl)aminoalkyl, alkylsulf onyl amid oal kyl, heterocyclic, (heterocyclic) alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and RC is a Ikylene, with the proviso that one or both of R, and

R

2 is other than hydrogen; or a salt thereof.

Preferred intermediates include compounds of formula

(VII)

and (Vill) wherein m is zero or 1; Rsb is alkylene; Q is a leaving group; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group, and RI and R 2 are as defined above; or the substantially pure or (+)isomer thereof.

Particularly preferred intermediates are compounds of formula (VII) and (VilI) wherein n and m are both 0; Rsb is alkylene; Q is a leaving group; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; WO 99/06397PCIS8I47 PCT/US98/15479 -84- S and R 1 is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, S 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4- IN methyiphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4- N- methoxyphenyl, S 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, ci 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-Nalkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure or (+)isomer thereof.

Other compounds which are useful as intermediates for the preparation of compounds of the invention are: R2 NIR5b

(CH

2 )n

(CH

2 )m

(IX)

wherein n is 0 or 1; m is 0 to 6; Rsb is alkylene;

R

2 0a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3

H

2 WO 99/06397 WO 9906397PCT/US98/15479 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

-CN,

-C(O)NHR17 where R 1 7 is loweraikyl, alkytaminocarbonyl, dialkylaminocarboflyl, tetrazolyl, hydroxy, 0 alkoxy, c-i sulfonamido, -C(O)NHS(O)2Rl6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)R16, HO 0 0 HO 0

OH

0, 0 0 (q) H4 PCTIUS98/1 5479 WO 99/06397 -86- J CF, M H or

NHSO

2

CF

3 and R1 and R2 are independently selected from hydrogen, loweralkyl, o alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, Clhaloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dial kylam inocarbonyl al kenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arytalkoxyalkyl, (N-alkanoyi-N-alkyl)aminoalkyl, alkylsulfonytamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyt. Rbb is hydrogen or alkanoyl and R 0 C is alkylene, with the proviso that one or both of R, and

R

2 is other than hydrogen; or a salt thereof; or a compound of the formula:

R

2 NI 5 b -NHR 2 0a R2N .R5b N H R2, I

I

(W CH)m (CH 2 )m2) W or W R (X (Xl) wherein n is 0 or 1; m is 0 to 6; Rsb is alkylene: R 20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, halo alko xyal kyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3

H

2 .P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, -O N, WO 99/06397 WO 9906397PCTIUS98/15479 -87- -C(O)NHR17 where R 1 7 is loweralkyl, alkylaminocarboflI dialkylamilocarboflI tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2Rl6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamiflo, (in) -S(Q) 2 NHC(O)Rl6, HO 0 0 ()HO 0

OH

0 .0 N AI- N =0

H

~r-CF 3 (H ,or WO 99/06397 PCTIUS98/15479 -88- NHS0 2

CF

3 (M and R1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, D cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, I) alkylaminocarbolylalkYl, dialkylaminocarboflylalkYl, D aminocarbonylalkenyl, alkylaminocarbolalkenyl, dial kylaminocarbonylal kell hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)amiloalkYl, alkylsulfonylamidoalkyl, heterocyclic, (heter ocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rc is alkylene, with the proviso that one or both of R, and

R

2 is other than hydrogen; or a salt thereof.

Preferred intermediates include compounds of formula

(X)

and (XI) wherein mn is zero or 1; is alkylene; R2Oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group, and R 1 and R 2 are as defined above; or the substantially pure or (+)isomer thereof.

Particularly preferred intermediates are compounds of formula and (XI) wherein n and mn are both 0; Rsb is alkylene;

R

2 0a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; and R 1 is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylpherlyl, 4..pentafluoroethylphell 3-fluoro-4-methoxypherlyl, 3-fluoro-4- WO 99/06397 PCTIUS98/15479 -89ethoxypheflyl, 2-fluorophenyl, 4-methoxymfethoxyphefl 4hydroxyPhenyl, 4-t-butylphenyl, 1 ,3-benzodioxolYl, 1 ,4-benzodioxaflyl or dihydrobefizofUranyl wherein the substituefit is selected from 0 loweralkyl, haloalkyl, alkoxy, alkoxyalkoxY and carboxyalkoxy, (ix) aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-Nalkyl)amiloalkYl, and (xiii) alkylsulfoflylamlidoalkyl, and R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3- 0 benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy- 1,4-benzodioxaflyl, N- dihydrobenzouranYl, benzofurflayl, 4-methoxypheflyl, dimethoxyphenyl, fluoropherlyl or difluoropheflyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure or (+)isomer thereof.

The foregoing may be better understood by reference to the following examples which are provided for illustration and not intended to limit the scope of the inventive concept. The following abbreviations are used: Boc for tert-butyloxycarbonyl, Cbz for benzyloxycarborlyl,

DBU

for 1,8-diazabicyclo[5.4.0]undec- 7 en~e, EDOI for 1-(3dimethylamirlopropYl3ethYlcarbodiimide hydrochloride, EIOAc for ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybeflzotriazole, Et 3

N

for triethylamifle, TEA for trifluoroacetic acid and THF for tetrahydrofurari.

Eagmple_1 trans. trans- 24Methoxy h n 1- 4 1 -3-ben zodiYnI-Ylhl 1 ,(propyvlaminocapboflylmethYi)-pyrrolidine3ca apoxyWQc acid Examgle 1A Ethyl 2 (4m et h xbe ilOl 4 -nit rom ethyl-3- (1 .3ben zoi x To ethyl (4-metho xybe nzoyl) acetate (23.0 g, 0.104 mol), prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967), and 5-(2nitrovinyl)-1 ,3-benzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of toluene and heated to 80 00 was added 1 ,8-diazabicyclo[5, 4 undec-7ene (DBU, 0.65 g) with stirring. The mixture was heated until all the nitro starting material dissolved. The solution was stirred without heating for 30 minutes (min) and then an additional 0.65 g of DBU was added. After stirring an additional 45 minutes, thin layer I

I

WO 99/06397 PCT/US98/15479 chromatography ethyl acetate in methylene chloride) indicated the Sabsence of nitro starting material. Toluene (200 mL) was added, and the organic phase was washed with dilute hydrochloric acid and NaCI Ssolution. The organic phase was dried over sodium sulfate and then Q concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 3:1 hexane-ethyl acetate to c give 21.22 g of the desired product as a mixture of isomers and 9.98 g.

of recovered ethyl (4-methoxybenzoyl)acetate.

Examole 1B Ethyl 2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-4.5-dihydro-3H-Dyrrole-3carboxylate The compound resulting from Example 1A (21 g) in 500 mL of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure using a Raney nickel 2800 catalyst (51 (The Raney nickel was washed with ethanol three times before use.) The catalyst was removed by filtration, and the solution was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 8.5% ethyl acetate in methylene chloride to give 12.34 g of the desired product.

Example 1C Ethyl 2-(4-methoxyohenyl-4-(1.3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate) as a mixture of cis-cis: transtrans: and cis.trans-isomers The compound resulting from Example 1B (11.89 g, 0.324 mol) was dissolved in 27 mL of tetrahydrofuran and 54 mL of ethanol. Sodium cyanoborohydride (2.35 g, 0.374 mol) and 5 mg bromocresol green were added. To this blue solution was added dropwise a solution of 1:2 concentrated HCI in ethanol at such a rate that the color was kept at light yellow-green. After the yellow color persisted without additional HCI, the solution was stirred an additional 20 minutes. The solution was concentrated in vacuo and then partitioned between chloroform and an aqueous potassium bicarbonate solution. The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 85:15 ethyl acetate-hexane to give 5.96 g. of a mixture of 64% trans, trans-compound and 34% cis,trans-compound. Further elution I r WO 99/06397 PCT/US98/15479 S-91- Swith pure ethyl acetate gave 0.505 g of an unknown solid followed by 3.044 g of pure cis,cis-compound.

0 Example 1 D o trans, trans-2-(4-Methoxvyhenyl)- 4 -(1.3-benzodioxol-5-vl-1- (fprovylaminocarbonvlmethyl)-pyrrolidine-3-carboxlic acid N The mixture of 64% trans,trans- and 34% cis, trans-pyrrolidines o (the mixture resulting from Example 1C) (5.72 g, 15.50 mmol), S ethyldiisopropylamine (4.20 g, 32.56 mmol), and N-propyl bromoacetamide (3.42 g, 19.0 mmol), prepared by-the method of Weaver, W.E. and Whaley, J. Amer. Chem. Soc., 69: 515 (1947), in 30 mL of acetonitrile was heated at 50 °C for 1 hour. The solution was concentrated in vacuo. The residue was dissolved in toluene, shaken with potassium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give 7.16 g of product as a mixture of trans,trans- and cis,trans- ethyl esters.

This mixture was dissolved in a solution of 50 mL of ethanol and mL of water containing 5.00 g of sodium hydroxide and stirred for 3 hours at room temperature. The-solution was concentrated in vacuo and 60 mL of water added. The mixture was extracted with ether to remove the unreacted cis,trans- ethyl ester. The aqueous phase was treated with hydrochloric acid until slightly cloudy. It was then further neutralized with acetic acid to give the crude acid product. The crude product was filtered and purified by dissolving it in tetrahydrofuran, drying over sodium sulfate, concentrating in vacuo, and crystallizing from ether to give 3.230 g of the title compound. m.p. 151-153

'H

NMR (CD 3 OD, 300 MHz) 8 0.87 J 7 Hz, 3H), 1.49 (sextet, J 7 Hz, 2H), 2.84 d, J 16 Hz, 1H), 2.95-3.20 4H), 3.20 J 16 Hz, 1H), 3.34-3.42 1H), 3.58-3.66 1H), 3.78 3H), 3.88 J 10 Hz, 1H), 5.92 2H), 6.75 J 8 Hz, 1H), 6.86 (dd, J= 8 Hz, J 1 Hz, 1H), 6.90 J 9 Hz, 2H), 7.02 J 1 Hz, 1H), 7.40 J 9 Hz, 2H).

Example 2 tans.trns-.2(4-Methoxvphenl)-4-( 1.3-benzodioxol-5-yl-1 -(aminocarbonvlmethvl)pyrrolidine-3-carboxylic acid Using the method described in Example 1D, 300 mg of the mixture of 64% trans,trans- and 34% cis, trans-pyrrolidines (the mixture WO 99/06397 WO 9906397PCTIUS98/1 5479 N -92- Zresulting from Example 10), 220 mg of diisopropylethylamine and 184 mg iodoacetamide were reacted at 45 00 in 1 mL acetonitrile to give 291 mg of a mixture of trans, trans- and cis, trans- N-alkylated esters.

A portion (270 mg.) was hydrolyzed with 200 mg NaQH in 1 mL of water and 3 mL of ethanol; a chloroform extraction was used to remove the unreacted cis,trans- ethyl ester. The isolation and purification procedures described in Example 10D were used to give 134 mg of the title compound. m.p. 246-248 00. 'H NMR (DMSO-d6, 300 MHz) 5 2.61 (d, J 16 Hz, 1 2.71 J 9 Hz, 1 2.90 J 9 Hz, 1 2.98 J= 16 Hz, 1H),3.25-3.35 (in, 1H), 3.45-3.55 (in, 1H), 3-71 3H), 3.75 J= Hz, 1H), 6.00 2H), 6.81 2H), 6.90 J 8 Hz, 2H), 7.10 1H), 7.17 1 7.34 1 7.38 J 8 Hz, 2H).

Example 3 trans. trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yl)- 1 -(4-fluorobenzylpyrrolidine-3-carboxylic acid Using the method described in Example 1D, 300 mg of the mixture of 64% trans,trans- and 34% cis,trans- pyrrolidines (the mixture resulting from Example 1C), 220 mg of diisopropylethylamine and 185 mg of 4-fluorobenzyl bromide were reacted at room temperature for 3 hours in 1 mL of acetonitrile to give 387 mg of a mixture of trans,trans- and cis, trans- N-al kyl ated esters. A portion (360 mg) was hydrolyzed with 250 mng NaGH in 1 mL of water and 4 mL of ethanol to give 160 mg of the title compound as an amorphous powder. 1 H NMR (00013. 300 MHz) 8 2.74 J 9 Hz, 1H), 2.95 J 7 Hz, 1H), 2.98 J 14, 1 3.07 (dd, J 9 Hz, 1 Hz, 1 3.42-3.53 (in, 1 3.70 J 9 Hz, 1H), 3.78 J 14, 1H), 3.81 3H), 5.92 2H), 6.70 J 8 Hz, 1 6.77 (dd, J 8 Hz, 1 Hz, 1 6.91 J 9 Hz, 2H), 6.94 -7.00 (in, 3H), 7.20 7.25 1 7.44 J =9 Hz, 2H).

Example 4 trans, trans-2-(4 -Met ho xvohenvfl)-4- 1,3- ben zodioxol-5 1 (2-eth oxyethvL')- Dyrrolidine-3-carboxylic acid Using the method described in Example 11), 300 mng. of the mixture of 64% trans,trans- and 34% cis, trans-pyrrolidines (the mixture resulting from Example 10), 220 mng of diisopropylethylamine and 152 mng of 2-bromoethyl ethyl ether were refluxed in 1.5. mL acetonitrile for WO 99/06397 PCT/US98/15479 -93- S3 hours (bath temperature at 95 00) to give 346 mg of a mixture of r- trans,trans- and cis,trans-esters. Hydrolysis with 250 mg NaOH in 1 mL of water and 3 mL of ethanol afforded 14*0 mg of the title compound.

m.p. 88 90 1 H NMR (CDCI3, 300 MHz) 8 1.25 J 7 Hz, 3H), 2.21 S2.32 (in, 1H), 2.70-2.80 (in, 1H), 2.85-2,94 (mn, 2H), 3.38-3.55 (in, 6H), S3.67 J 10 Hz, 1H), 3.79 3H), 5.94 2H), 6.72 J 8 Hz, 1H), S6.84 (in, 1 6.84 J 9 Hz, 2H), 7.08 J 1 Hz, 1 7.33 J 9 tn Hz, 2H).

Exampl trans, trans-2-(4-Methoxychenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -(2-proooxYethYl)gyrrolidine-3-carboxylic acid Using the method described in Example 10, 520 mng of the mixture resulting from Example 10, 364 mg of dilsopropylethylamine, 50 mg potassium iodide and 350 mg 2-chloroethyl propyl ether were reacted at 125 00 in 0.5 mL acetonitrile for 4 hours to give 517 mg of a mixture of trans,trans- and cis,trans-esters. A portion (500 mg) was hydrolyzed with 315 mg NaQH in 1 mL of water and 4 mL of ethanol to give 225 mg of the title compound as an amorphous powder. 1 H NMR (CDC1 3 300 MHz) 5 0.87 J 7 Hz, 1.53 (sextet, J 7 Hz, 2H-), 2.28-2.41 (in, 1H), 2.71-2.83 (in, 1H), 2.92-3.08 (in, 2H), 3.30 J 7 Hz, 2H), 3.40-3.60 (in, 4H), 3.72-3.83 (in, 1H), 3.76 3H), 5.92 2H), 6.71 J 8 Hz, 2H), 6.74 (dd, J 8 Hz, 1 Hz), 6.71 J 9 Hz, 2H), 7.07 J 9 Hz, 2H), 7.73 J 9 Hz, 2H).

Example 6 trans, transg-2 Met hoxvoh en yl)-4- 3-ben zod ioxol-5 -yfl- 14-2- (2inethoxyethoxy)ethylI-pyrrolidine-3-carboX~lic acid Example 6A Ethyl trans. trans-2-( 4-inethoxyohenyl)-4- (1 .3-benzodioxol-5-yl) grrolidine-3carboxylate To the pure cis, cis-coinpound resulting from Example 10 (3.02 g) dissolved in 10 mL of ethanol was added 20 drops of a solution of 21% sodium ethoxide in ethanol. The reaction mixture was refluxed overnight, at which time thin layer chromatography in ethyl acetate indicated the absence of starting material. The NaQEt was neutralized WO 99/06397 PCT/US98/15479 CM .94with HCI in ethanol, and the solution was concentrated in vacuo. The residue was taken up in toluene and extracted with potassium bicarbonate in water. The toluene was dried over sodium sulfate and O concentrated under reduced pressure to give 2.775 of the title compound which was pure by TLC (ethyl acetate).

cN Example 6B O trans. trans-2-(4-Methoxyohenyl)-4- 1.3-benzodioxol-5-yI)-1-[2-(2- 0 methoxyethoxy)ethvll-pvrrolidine-3-carboxylic acid Using the method described in Example 1D, 250 mg of the compound resulting from Example 6A, 150 mg of 2-(2methoxyethoxy)ethyl bromide and 175 mg diisopropyl-ethylamine in 1 mL acetonitrile were heated at 100 °C for 3 hours to give 229 mg of the trans,trans-ester. A portion (200 mg) was hydrolyzed with 125 mg NaOH in 1 mL of water and 2 mL of ethanol to give 151 mg of the title compound as an amorphous powder. 'H NMR (CD30D, 300 MHz) 8 2.9-3.9 13H), 3.81 3H), 4.49 J 10 Hz, 1H), 5.94 2H), 6.79 J 8 Hz, 1H), 6.89 (dd, J 8 Hz, 1 Hz, 1H), 7.00 J 9 Hz, 2H), 7.05 J 1 Hz, 1H), 7.49 J 9 Hz, 2H).

Example 7 trans.trans-2-(4-Methoxyohenyl)-4-( 1.3-benzodioxol-5-vl)- 1 -2-(2-pyridvl)ethyl]pyrrolidine-3-carboxylic acid The compound resulting from Example 6A (250 mg), 2-vinyl pyridine (355 mg) and one drop of acetic acid were dissolved in 2methoxyethanol, and stirred at 100 °C for 2.5 hours. Toluene was added, and the solution was washed with potassium bicarbonate solution. The solution was dried over potassium bicarbonate and concentrated in vacuo. Toluene was added and the solution re-concentrated. This was done until the odor of 2-vinylpyridine was gone. The residue was taken up in hot heptane, filtered to remove a small amount of insoluble impurity, and concentrated in vacuo to give 225 mg of intermediate ester. The ester was hydrolyzed by the method described in Example 1D to give 202 mg of the title compound as the dihydrate. m.p. 77-80 OC.

1 H NMR (CD3OD, 300 MHz) 5 2.8 3.3 6H), 3.55-3.70 2H), 3.76 (s, 3H), 3.99 J 10 Hz, 1H), 5.92 J 1 Hz, 2H), 6.72 J 8 Hz, 1H), (dd. J 8 Hz. 1 Hz), 6.85 J 9 Hz, 2H), 6.92 J 1 Hz, 1H), WO 99/06397 PCT/US98/15479 1 7.20 J 9 Hz, 2H), 7.20-7.32 2H), 7.70-7.80 2H), 8.40 J 4 Hz, 1H).

Example 8 trans trans-2-(4-Methoxyphenvl)- 4 .3-benzodioxol-5-yl)-1 -(morpholin-4- Sylcarbonvl)-pyrrolidine-3-carboxylic acid STo the compound resulting from Example 6A (300 mg) and 164 mg Striethylamine dissolved in 2 mL of methylene chloride and cooled in an ice bath was added 146 mg 1-morpholinocarbonyl chloride. The mixture was stirred 3 hours at room temperature. Toluene was added and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to give the intermediate ester. The ester was hydrolyzed by the method described in Example 1D to give 288 mg of the title compound. m.p. 244-246 OC. 1 H NMR (DMSOd6, 300 MHz) 8 2.96 (dd, J 12,Hz, 13 Hz, 1H), 3.03-3.13 2H), 3.20- 3.30 2H), 3.40-3.60 5H), 3.74 3H), 3.70-3.85 3H), 5.10 (d, J 10 Hz, 1H), 5.99 J 1 Hz, 2H), 6.80-6.90 2H), 6.87 J 9 Hz, 2H), 7.07 1H), 7.25 J 9 Hz, 2H).

Example 9 transtrans-2-(4-Methoxyphenvl)- 4 1,3-benzodioxole-5-v)- 1 -(butylaminocarbony)pyrrolidine-3-carboxylic acid To the compound resulting from Example 6A (300 mg) dissolved in 2 mL tetrahydrofuran and cooled in an ice bath was added 88 mg of butyl isocyanate. After 40 minutes at room temperature, toluene was added, and the solution was concentrated in vacuo to give the intermediate ester. The ester was hydrolyzed by the method described in Example 1D to give 232 mg of the title compound. m.p. 220-221 OC. 1 H NMR (DMSOd6, 300 MHz) 8 0.78 J 7 Hz, 3H), 1.10 (sextet, J 7 Hz, 2H), 1.22 (quintet, J 7 Hz, 2H), 2.78-3.05 3H), 3.40-3.56 2H), 3.74 (s, 3H), 3.95-4.05 1H), 4.93 J 9 Hz, 1H), 5.80 broad, J 7 Hz, 1H), 5.99 2H), 6.78-6.86 2H), 6.88 J 9 Hz, 2H), 7.00 J 1 Hz, 1H), 7.12 J 9 Hz, 2H).

I

WO 99/06397 PCT/US98/15479 1 -96- Example trans.trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl- 1 methoxyphenylaminocarbonvl)-3-ovrrolidine-3-carboxylic acid The compound resulting from Example 6A (300 mg) was treated S with 133 mg of 4-methoxyphenyl isocyanate by the procedure described in Example 9. The resulting ester was hydrolyzed with NaOH using the S method described in Example 1D to give 279 mg of the title compound.

S m.p. 185-187 'H NMR (CDC13, 300 MHz) 5 3.23 (dd, J 12 Hz, 13 Hz, 1H), 3.55-3.68 2H), 3.72 3H), 3.83 3H), 4.50-4.65 1H), 5.06 J 10 Hz, 1H), 5.90 1H), 5.95 1H), 6.72 J 9 Hz, 2H), 6.7-6.8 3H), 6.92 J 9 Hz, 2H), 6.97 J 9 Hz, 2H), 7.37 J 9 Hz, 2H).

Example 11 trans,trans-2-(4-Methoxyvhenvl)-4-(1.3-benzodioxol-5-vl)-1-acetvlovrrolidine-3carboxylic acid The compound resulting from Example 6A (250 mg) in 0.5 mL of toluene was treated with 200 mg of acetic anhydride. After stirring 2 hours at room temperature, water was added and the acetic acid neutralized with potassium bicarbonate. The mixture was extracted with toluene to give 273 mg of the intermediate ester. A portion of the ester (200 mg) was hydrolyzed using the method of Example 1D to give 211 mg of the title compound. m.p. 248-250 Rotational isomers are seen in the NMR. 1 H NMR (DMSO-d6, 300 MHz) 5 1.55 and 2.00 3H), 2.94 and 3.03 (dd, J 12 Hz, 13 Hz, 1H), 3.3-3.6 2H), 3.72 and 3.76 3H), 4.12 and 4.28 (dd, J 12 Hz, 7 Hz, 1H), 4.95 and 5.04 J 1H), 6.00 2H), 6.75-6.87 3H), 6.95 and 7.04 J 9 Hz, 2H), 7.18 and 7.32 J 9 Hz, 2H).

Example 12 trans, trans-2-(4-Methoxyphenyl)- 4 1.3-benzodioxol-5-vl)-1 -(2-furovl)-pyrrolidine-3carboxylic acid To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL methylene chloride and cooled in an ice bath was added 138 mg of 2-furoyl chloride. The mixture was stirred minutes at room temperature and then worked up by the procedures described in Example 8 to give the intermediare ester. The ester was WO 99/06397 PCT/US98/15479 D -97- ~hydrolyzed by the procedure described in Example 1D to give 269 mg of _the title compound as an amorphous powder. 1 H NMR (DMVSO-d6., 300 MHZ) 5 3.06 (dd, J 12 Hz, 13 Hz, 1H), 3.3-3.6 (in, 2H), 4.25 (in, 1H), D5.19 d, J 10 Hz, 1 6.67.4 (in, 8H), 7.8-7.9 (in, 1 H).

Examole 13 "A -trans, trans-2-(4-Methoxylhenyl')- 4 (1 .3-benzodioxol-_5-yf- 1-- D ~(ghenvlaminocarbonylporr li in vuic^acid DK Starting with the compound resulting from Example 6A, phenyl isocyanate and the procedures described in Example 9, the title compound was prepared. m.p. 209-211 0C.' 1 H NMR (DMSO-d6, 300 MHz) 3.03 (dd, 1 3.55 (in, 1 3.70 (in, 1 3.72 3H), 4.15 (in, 1 H), 5.13 1H), 6.00 2H), 6.88 (mn, 5H), 7.07-7.20 (in, 3H), 7.30 2H), 7.38 2H), 8.20 (bs, 1 H).

Examgle 14 trans, trans-2-(4-Methoxylhenyl- 4 -(l.3-benzodioxol-5-yfl- 1allvlaininocarboflylmethylorrolidine3carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 138-140 00. I H NMR (CDCI 3 300 MHz) 8 2.84 (d, 1KH), 2.90-3.10 (dt, 2H), 3.2B 1H), 3.35 (dd, 1H), 3.62 (in, 1H), 3.72- 3.97 (in, 3H), 3.80 3H), 5.13 (bd, 2H), 5.80 (in, 1H), 5.97 2H), 6.74- 6.97 (in, 5H), 7.38 2H).

Example trans. trans-2 -(4-Methoxylheyl)-4-( 1.3.benzodioxol-5yl)-1 butylam inocarbonylmethyl)-1DYrrolidine3carbgxylic acid Using the procedures described in Example 1 the title compound was prepared. in.p. 105-107 OC. I H NMR (CDCI3, 300 MHz) 5 0.90 3H), 1.30 (in, 2H), 1.45 (in, 2H), 2.80 1KH), 2.87-3.35 (in, 6H), 3.62 (in, 11-H), 3.80 3H), 5.97 2K), 6.75-6.92 (in, 5K), 7.28 2H).

Example 16 trans. trans-2 -(4-MethoxyphenYlI-4-( 1. 3-benzodiox 1-5-Yl- 1 (n-propyl)-Nmethylam inocarboflylmethvl)-nvrrolidifle-"-,carh,~ic ai Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. Rotational isomers are seen in the WO 99/06397 WO 9906397PCT/US98/15479 -98- NMR. 'H NMR (CDCI3, 300 MHz) 8 0.73, 0.84 (2t, 3H), 1.49 (in, 2H), 2.80 (dd, 1 2.85 (2s, 3H), 2.95-3.20 (in, 3H), 3.20-3.40 (in, 1 3.40 (d, D 1 3.60 (in, 1KH), 3.79 3H), 5.93 2H), 6.73 1 6.86 (in, 2H), o 7.03 (in, I1H), 7.32 2H).

D Example 17 r)trans, trans-2-(4-Methoxyphenl)-4-(l .3-benzodioxol-5-yl)-1 -(pyrrolidin-1 D lcarbonylmethyl.Dyrrolidile-3-crboxylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. 1 H NMR (CECI3, 300 MHz) 6 1.40- 1.70 (in, 6H), 2.80 1H), 3.00 (mn, 2H), 3.24-3.43 (in, 5H), 3.60 (in, 2H), 3.73 1 3.80 3H), 5.95 2H), 6.74 1 6.80-6.90 (in, 3H), 7.04 1KH), 7.30 2H).

Examole 18 trans, trans-2-(4-Methoxypheflyl)- 4 (isobutylam in ocarbon ylinethl)- yrrolidi e-3carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 175-177 OC. 1 H NMR (CD3OD, 300 MHz) 8 0.87 (dd, 6H), 1.75 (septet, 1H), 2.85 1H), 2.90-3.10 (in, 4H), 3.23 1H), 3.40 (in, 1 3.58-3.67 (in, 1 3.78 3H), 3.89 1 5.92 2H), 6.76 1KH), 6.86 (dd, 1KH), 6.91 2H), 7.02 1 7.40 2H).

Examole 19 trans, trans-2-(4- Methoxyohenl)-4-( 1.3benzodioxol-5-yI)-1 (cyclooentylam inocarbonylmethyl)-yrrolidine-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 137-1390 'C 1H NMR (CDCI3, 300 MHz) 8 1.34 (in, 2H), 1.62 (in, 4H), 1.90 (in, 2H), 2.76 1H), 2.90 1H), 3.04 (dd, 1H), 3.2 2 1 3.2 8 (d d, 1KH), 3.4 0 1 3.8 0 3 4.15. (in, 1KH), 5.9 7 2H), 6.75-6.95 (in, 5K), 7.27 (in, 2H).

WO099/06397 PeT/US98/1 5479 Example2 trans, trans-2-(4-Methoxyphenfl)l 4 1.3-benzodioxol-5-y)- 1 -(moro~hotin-4ylaminocarbonylmethyl)-Dyrrolidile--caboxylic acid D Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 2.82 (d, 1H), 3.00 (in, 2H), 3.24 (in, 1H), 3.30-3.52 (in, 4H), 3.52-3.75 (in, 8H), 'A 3.80 3H), 5.95 2H), 6.75 1H), 6.84 3H), 7.00 1H), 7.28 (d, 2H).

Examole 21 trans. trans-2-(4-Methoxylhenfl)-4 (1 .3-benzodioxol-5-Vfl- 1 -(2-phenoxyethfl)pyrrolidine-3-carbO~yli ai Using the procedures described in Example 4 the title compound was prepared as an amorphous solid. IH NMIR (CD 3 OD, 300 MHz) 8 2.82 (in, 1 2.96 (dd, 1 3.13 (in, 1 3.32 (in, I1H), 3.51-3.70 (mn, 2H), 3.77 4.00 1H), 4.07 (in, 2H), 5.91 2H), 6.72 1H), 6.80-6.95 (in, 6H), 7.03 1 722 (dd, 2H), 7.39 2H).

Example 22 trans, trans-2-(4-MethoxygheflYl)- 4 .3-benzodi~xol-5-Yfl- 1 methoxyethylaminocarbonylm ethyfl)-yrrolidifle-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 107-1090 -C IH NMR (CD 3 OD, 300 MHz) 8 2.82 (d, 1 2.97 2H), 3.21 1H), 3.38 (in, 1H), 3.32 3H), 3.44 (mn, 4H), 3.62 (in, 1 3.79 3H), 3.86 I1H), 5.93 2H), 6.76 1 6.85 (dd, 1 6.91 2H), 7.01 1 7.38 2H).

Example 23 trans, trpns-2-(4-Methoxyphenyl)- 4 1. 3-benzodioxol-5-yfl- 1 -(2-butoxyethylI)gyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared. in.p. 53-55 0C. 1 H NMR (0D01 3 300 MHz) 5 0.88 J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 1.50 (pentet, J=7Hz, 2H), 2.27 (it, J=6Hz, 6Hz, 1H), 2.92 J=lOHz, 2H), 3.35 J=7Hz, 2H), 3.42-3.56 (in, 4H), 3.68 J=lOHz, 1H), 3.78 3H), 5.94 2H), 6.73 J=8Hz, 1H), 6.83 J=9Hz, 2H), 6.82-6.87 (in, 1H), 7.06 J=2Hz, 1H), 7.32 J=9Hz, 2H). MS in/e 442 WO 99/06397 WO 9906397PCTIUS98/1 5479 '4 -100- Example 24 trans, trans-2-( 1.3-Benzodioxol-5-fl)-4-(4-methoxyphenll-1 (oroylam inocarbonvim ethyfl-oyrrolidifle-3-carboxylic acid Using the procedures described in Example 1 and substituting ethyl (1 3benzodi oxol- 5-ylCarbOflyl) acetate for ethyl (4methoxybenzoyl) acetate and 4-(2-nitrovinyl)anisole for 5-(2- D nitrovinyl)-1 ,3-benzodioxol-5yi afforded the title compound. m.p. 97- 99 0 C. I H NMR (00013, 300 MHz) 8 0.78 J=7Hz, 3H), 1.39 (sextet.

J=7Hz, 2H), 2.72 J=l6Hz, 1H), 2.74 J=10Hz-l- 1H), 2.80-3.10 (in, 4H), 3.26-3.38 (in, 1H), 3.53 (in, 1H), 3.73 3H), 3.80 J=lOHz, 2H), 7.80 J=6Hz, 1H). MS (DGI/NH3) mle 441 Example trans, trans-2 41 .3 Ben zodio xoI- 5-yi-4- (4-m ethoxyphenl)l -(2-proooxyethylpyrrolidine-3-carboXylic aid Using the procedures described in Example 5 and substituting ethyl (1 ,3-benzodioxol-5-ylcarbOnYI)acetate for ethyl (4methoxybenzoyl) acetate and 4-(2-nitrovinyl)anisole for 5-(2nitrovinyl)-1 ,3-benzodioxol-5yi afforded the title compound. m.p. 67- 69 0C. 'H NMR (00013, 300 MHz) 5 0.89 J=7Hz, 3H), 1.56 (sextet, J=7Hz, 2H), 2.33 (in, 1H), 2.78-3.00 (in, 3H), 3.32 J=7Hz, 2H), 3.45- 3.57 (in, 4H), 3.73 (in, 1KH), 3.79 3H), 5.93 6.22 J=8Hz, 1 H), 6.85 J=8Hz, 3H), 6.98 1H), 7.37 J=8Hz, 2H). MS (DCI/NH 3 in/e 428 Example 26 trans, trans-2-( 1.3-Benzodioxol.5-yl)-4-(4-inethoxyghenyl)-1 -f2-2methoxyethoxy)ethvl)lOpyrrolidine-3carboxylic acid Using the procedures. described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2inethoxyethoxy)ethylbroinide to alkylate the pyrrolidine nitrogen afforded the title compound. in.p. 85-86 00. 1 H NMR (00300, 300 MHz) 8 3.18-3.90 (in, 15H), 3.79 3H), 4.57 J=lOHz, 1H), 6.02 2H), 6.91 J=8Hz, 1H), 6.95 J=9Hz, 2H), 7.06 (dd, J=8Hz, 1H), 7.12 (dd, J=lHz, 7.37 J=9Hz, 2H). MS (DCI/NH3) in/e 444 WO 99/06397 PCT/US98/15479 Example 27 trans. trans-2-( 1.3-Benzodioxol-5-yfl-4-(4-methoxyphenlI- 1-(butoxyethyflpyrrolidine-3-carboxy~cai 0 Using the procedures described in Example 4, substituting the starting materials described in Example 25 and using 2- ~1ethoxyethylbromide to alkylate the pyrrolidine nitrogen afforded the Stitle compound. m.p. 54-56 00. I H NMR (ODC1 3 300 MHz) 5 0.89 J- S 7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 1.52 (pentet, J=7Hz, 2H), 2.40 (in, 1H), 2.74-2.98 (mn, 3H), 3.46 J=7Hz, 2H), 3.42-3r.56 (in, 4H), 3.68 (d, J=lOHz, 1H), 3.80 3H), 5.93 (dd, J=6Hz, 1Hz, 2H), 6.72 J=8Hz, 1H), 6.74 (dd, J=9Hz, 3H), 6.96 1H), 7.36 J=9Hz, 2H).

Examlole 28 trans, trans-2 Methoxy~h envl)-4-( 1. 4-ben odioxal-6-y)- 1rooylam inoca rbonylImethyl)- yrrolidi ne3-carboxylic acid Using the procedures described in Example 1 and substituting 6- (2-nitrovinyl)-1 ,4-benzodiOxafle. for 5-(2-nitrovinyl)-l ,3-benzodioxole afforded the title compound. m.p. 80-81 I H NMR (CDCI3, 300 MHz) 0.89 J-7Hz, 3H), 1.49 (sextet, J=7Hz, 2H), 2.78 J=16Hz, 1H), 2.92 J=lOHz, 1H), 3.05-3.43 (in, 5H), 3.24 J=16Hz, 1H), 3.52-3.62 (in, IH), 3.80 3H), 3.80 J=lOHz, 1H), 4.27 4H), 6.74-6.93 (in, 51H), 7.29 J=9H-z, 2H). MS (DCI/NH 3 mle 455 Examnle 29 trans. trans-2-(4-Methoxyohenyl)-4 (1 .4-benzodioxan-6-yi)-1 -(N-methyl-Np2ropylaminocarbonylmethyfl-prrolidine3carboxylic acid Using the procedures described in Example 1, substituting 6-(2nitrovinyl)-1 ,4-benzodioxane for 5-(2-nitrovinyl)-1 ,3-benzodioxole and alkylating the pyrrolidine nitrogen with N-inethyl-N-propyl bromoacetamide afforded the title compound. m.p. 74-76 00.

Rotational isomers are seen in the NMR. 1 H NMR (CDCI3, 300 MHz) 6 0.73, 0.83 (2t, J=7Hz, 3H), 1.48 (in, 2H), 2.78 (dd, 1H), 2.85 (2s, 3H), 2.96-3.15 (in, 3H), 3.27-3.42 (in, 3H), 3.52-3.60 (mn, 1H), 3.75 1H), 3.78 4.22 4H), 6.80-6.98 (mn, 5H), 7.32 2H). MS (DCI/NH3) m/e 469 WO 99/06397 PCTIUS98/15479 0 -102- Ct E~xampl 3 trans. trans-2-(4-Mthoxylhenlyl)-4-( 1.3-benzodioxol-5-yi)l1-(N-methyl-Nbutylam inocarbonylmethy)-Dyrrolidile-3-caroxyic acid Using the procedures described in Example 1, the title compound O was prepared. Rotational isomers are seen in the NMR. 1 H NMR (CD 3 0D, 300 MHz) 8 0.86 (2t, 3H), 1.04-1.50 (in, 4H), 2.85 (2s, 3H), 2.93-3.20 (in, 54H), 3.40 (in, 2H), 3.52 (dd, I1H), 3.60 (in, 1 3.80 3H), 3.85 (in, 1 H), S5.91 2H), 6.74 1 6.83-6.95 (in, 3H), 7.03 (dd, I 7.35 (dd, 2H).

o xaml, 1 trans. trans-2-(4-Methoy-2-netho~yiethoXYihenyl- 4 -(1.3-benzodioxol-5-yfl- 1 methyl-N-butylamlinocarbonlmethl)-12Yrrolidile-3-carboXlic acid Examgle 31 A Ethyl 2(4-methoXy-2-mlethoxymfethoXyphpnfl- 4 (1 3-abxli~ Using the procedures described in Examples 1 A and 1 B and substituting ethyl (4-m ethoxy-2 metho xymnetho xyben zoyl) acetate for ethyl (4-inethoxyben zoyl) acetate afforded ethyl 2-(4-methoxy-2inethoxyinethoxyphenyl)- 4 -(l,3-benzodioxol-5-yl)-4,5-dihydro-3Hpyrrole-3-carboxylate.

The above dihydro, pyrrole carboxylate (3.0 g, 7.0 minol) was dissolved in 20 mL of methanol, treated with 500 mg of 10% Pd/C and placed under hydrogen atmosphere for 32 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure and chromatographed on silica gel eluting with ethyl acetate to afford the title compound (1.9 g, 63%) as the cis-cis isomer.

Example 31B tranits. 2 -ehoy2mtoMmtoyhey)4 .3-benzodioxol-5-Vi')- 1 methyl-N-butylam inocarbonylmethyl)-pyrrolidie-3-carboxylic acid The compound resulting from Example 31A was epiinerized by the procedure described in Example 6A. The resulting trans,trans compound (100 mg, 0.23 iniol) was then reacted by the procedures described in Example 1D substituting N-methyl-N-butyl broinoacetamide for Npropyl bromoacetainide to give the title compound (75 mg, m.p.

65-67 OC. Rotational isomers are seen in the NMR. 1 H NMR (CDC1 3 300 WO 99/06397 WO 9906397PCT/US98/15479 -103- MHz) 8 0.64, 0.68 (2t, J=7Hz, 3H), 1.14, 1.12 (2 sextet, J=7Hz, 2H), 1.40- 1.48 (in, 2H), 2.86, 2.89 (2s, 3H), 2.95-3.42 (in, 6H), 3.50 3H), 3.43- 3.65 (in, 2H), 3.78 3H), 4.30 J=7Hz, 1 5.09 J=7H-z, 2H), 5.92 S(s, 2H), 6.55 (dd, J=3Hz, 1 6.68 1 6.72 1 6.85 (2t, J=1lHz, 1 1H), 7.04 J=l Hz, 1 7.42 (dd, J=3Hz, 1 H).

Exam ole 32 trans, trans-2-(4-MethoxyphelYl)-4-( 1.3-benzod ioxol-5-U)-1- (3-ethoxY1or~vl)- 12yrrolidin-5-one-3-carboxylic acid Examole 32A Ethyl 2- (4-rn thoxybenzol-3-carbomethoXy- 1.3-benzodioxole- 5-c2rooionate To ethyl (4-methoxybeflzoyl) acetate (4.44 g, 0.02 mmol) dissolved in 20 mL of anhydrous THF was added in portions 480 mg of NaH-. The mixture was stirred for 30 minutes under nitrogen at ambient temperature. Methyl (1 ,3-benzodioxol-5-yl) bromoacetate (5.46 g, 0.02 mol) in. 5 mL of THF was added. The mixture was stirred overnight at ambient temperature, diluted with 200 mL of EtOAc, and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound (7.67 g, 92%) which was used without further purification.

Examole 32B Ethyl 1 -(3-ethoxvorgoyl)-2-(4-methoyghenyF)-4- 3-benzodioxol-5-yl-4.5-dihydro- 5-oxo- 1 H-pyrrole-3-carboxylate A mixture of the compound resulting from Example 32A (700 mg, 1.69 mmol), 3-ethoxypropylamine (348 mg, 3.38 inmol) and 1 mL of acetic acid in a sealed tube was heated for 18 hours at 125 OC. After cooling the contents of the tube to ambient temperature, 5 mL of water was added and the mixture extracted with ethyl acetate (2x100 mL).

The. combined organic extracts were washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 3:2 hexane-ethyl acetate to give 330 mg of the title compound.

WO 99/06397 PCTIUS98/1 5479 -104- Example 320 Ethyl 1 -(3-ethoXyopyll-2-(4-methoxypheflyl) 4 (l.3-benzodioxol-5-Yl)-pyrrolidifl-5on-abxyate 0 The compound resulting from Example 32B (300 mg, 0.64 mmol) in mL of methanol was reduced with 100 mg of 10% Pd/C under S hydrogen for 3 hours at ambient temperature. The catalyst was n removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound.

Example -32D trans. trans-2-(4-M gthoxyphenyl) 4 .3-benzodioxol-5-yi')- 1 -(3-ethoxyoropl) pyrro lid in-5-on e3-carboxylic acid To the compound resulting from Example 320 (100 mg, 0.21 mmol) dissolved in 1 mL of ethanol was added 3 drops of a solution of 21 sodium ethoxide in ethanol. The mixture was heated to 70-80 00 for 3 hours, and then a solution of sodium hydroxide (100 mg) in 1 mL of water was added and heating was continued for 1 additional hour. The reaction mixture was cooled to ambient temperature, the ethanol was removed under reduced pressure, and water was added to the residue which was washed with ether. The aqueous layer was neutralized with 3 M HCl and allowed to stand overnight. The white crystalline solid was collected by filtration to give the title compound (60 mg, mn.p.

134-140 00. 1'H NMR (DMSO-d6, 300 MHz) 6 1.04 J=7Hz, 3H), 1.55 (sextet, J=7Hz, 2.48-2.56 (in, 11H), 2.93 (dd, J=9Hz, 3.25 (t, J=7Hz, 2H), 3.28-3.40 (in, 2H), 3.48-3.57 (mn, 3.78 3H), 3.88 (d, J=lOHz, 1H), 4.72 J=lOHz, 11H), 6.02 2H), 6.74 (dd, J=8Hz, 1Hz, 1H), 6.87 J=8Hz, 2H), 6.98 J=BHz, 2H), 7.38 J=8Hz, 2H). MS (DC1/NH 3 m/e 442 Exam ole 33 trans. trans-2-(4-MethoXYphenyl) 4 (l.3-benzodioxol-5-VI')- 1 -(3-inethoxybenzylovrrolidin-5-one-3-carboxylic aid Following the procedures described in Example 32 and substituting 3-methoxybeflzylarnine for 3-ethoxypropylarnine afforded the title compound (123 mng, m.p. 150-152 00. 1 H NMVR (CD 3

OD,

300 MI-z) 8 2.96 (dd, J=8Hz, 10Hz, 1H), 3.72 3.80 3H), 4.06 (d, J- 1I ILIN A RQ Iri I=RH7 1H). 4.92 J=l6Hz, 2H)U, 5.92 2H'), WO 99/06397 WO 9906397PCTIUS98/1 5479 -105r-6.55-6.63 (in, 2H), 6.82 J=8Hz, 4H), 6.94 J=8HZ, 2H), 7.15-7.22 (in, 3H). MS (DCI/NH3) m/e 475 trans. trans 2-(4-Methoxyphefly 4 1.3-benzodioxol-5-yl)-l1-(N.

N-

di isoa myla minoearbplylm ethyl)-pyrro lid in e3carboxylic acid The title compound was prepared as an amorphous solid using the 0 procedures described in Example 1. 1H NMR (CDCI3, 300 MHz) 8 0.70 0.90 (in, 12H), 1.10-1.60 (in, 10H), 2.75 J=l3Hz, 1H), 2.90-3.10 (in, 4H), 3.15 3.30 (in, 2H), 3.40 J=l0Hz, 3.40 3.52 (in, 2H), 3.55 3.62 (in, 1H), 3.75 J=12 Hz, 1H), 3.79 3H), 5.93 (dd, J =1 Hz, 3 Hz, 2H), 6.72 J=8Hz, 1H), 6.82-6.90 (in, 3H), 7.03 J=2Hz, 1H), 7.30 J=9Hz, 2H).

3 trans. trans-2-(4-Methogypheflyl)- 4 1.3-benzodigol-5-yl)-.1

N-

diientylaminocarboflylinethyl)-pyrrolidie3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (CDCI3, 300 MHz) 8 0.82 J 7Hz, 6H), 0.95-1.03 (in, 2H), 1.10-1.30 (in, 8H), 1.40-1.51 (in, 2H), 2.72 J=l3Hz, 1H), 2.90-3.08 (in, 4H), 3.25-3.50 (in, 3H), 3.37 (d, J=l3Hz, 1H), 3.52-3,60 (in, 1H), 3.70 J=lOHz, 1H), 3.75 3H), 5.92 (dd, J=2Hz, 5Hz, 2H), 6.72 J=BHz, 1H), 6.80-6.88 (in, 3H), 7.03 (d, J=2Hz, 1H), 7.30 J=9Hz, 2H).

trans, trans-2-(4-Mehoxyghenyl).' 4 -(l.3-enzodioxol-5-yfl- 1 .N-di(2in ethox(Yethvl) amninoca rbonylni ethyl)- 1yrrolidile-3-ca rboXyl ic acid The title compound was prepared using the procedures described in Example 1. m.p. 120-122 0 C. 1 H NM R (00013, 300 MHz) 8 2.82 (d, J=13, 1H), 2.94-3.08 (in, 2H), 3.12 3H), 3.23 3H), 3.20-3.70 (in, 11H), 3.73 J=lOHz, 1H), 3.79 3H), 5.92 (dd, J= 2Hz, 2Hz, 2H), 6.72 J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.04 J=2Hz, 1H), 7.30 J=9Hz, 2H).

WO 99/06397 PCTIUS98/1 5479 -106- Example 3 trans. trns-_2 (4.Methoxygheflyl) 4 (1_3-bnodOl-yk 1 %-eynyl)-yrrglidifle- Using the procedures described in Example 4, 200 mg. of the pure Strans,traflS isomer, the compound resulting from Example 6A was Sreacted with 109 mg of 1-bromo-2-hexyfle, prepared by the method '~described. in Perkin 1, 2004 (1987), for 1 hour at 55 0 C, to give 226 mg 0 of the intermediate ester. The ester was hydrolyzed using NaQH in ethanol-water for 3 hours at room temperature to give 175 mg of the title compound. IH NMR (CDCI3, 300 MHz) 8 1.00-(t, J=7Hz, 3H), 1.54 (in, 2H1), 2.14-2.22 (in, 2H), 2.96 (dd, J=7Hz, 13Hz, 1H), 3.07 (dd, J=l8Hz, 2Hz, 1H), 3.15 (dd, J=9Hz, 2Hz, 1H), 3.26 J=9Hz, 1H), 3.36 (dd, J 18 Hz, 2Hz, 1H), 3.47-3.55 (in, 1H), 3.79 3H), 3.88 J=9Hz, 1H), 5.95 2H), 6.72 J=8Hz, 1H), 6.80-6.88 (mn, 3H), 7.03 J=2Hz, 1H), 7.22 J=9Hz, 2H).

trans. trans-2-(4 M ethoxvYhenyl 4 ben zod ioxol 1 (N -cyclo oDVfl'tL- N-D2rooylam inocarbonvlinethyl')-yrrOlidie3-carboxvlic aid The title compound was prepared using the procedures described in Example 1. m.p. 167-169 0 C. Rotational isomers were seen in the NMR. 1 H NMR (CDCI3, 300 MHz) 5 -0.1 0.05 0.12-0.25 0.32- 0.51 0.67 and 0.74 (2 triplets, 3H), 0.90-1.00 1.20-1.55 (in), 2.72 J=l3Hz, 1H), 2.85--3.29 (in, 4H), 3.30-3.50 (in, 3H), 3.52-3.62 (in, 1H1), 3.65-3.73 (2 doublets, J=lOHz, 2Hz, 1H), 3.78 3H), 5.95 (2 singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (mn, 3H), 7.00 and 7.05 (2 doublets, J=9Hz, 2H).

Examp~le 9 trans, trans-2-(4- Methoxyph enlYI- 4 (l3-ben zodioxol-5-YI)- 1 (N-rn ethyl- Ngentylami incarbonvlinethyl)-Oyrrolidine-3-carboxyliccid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. 1 H NMR (CDCI3, 300 MHz) 6 0.85 J=7Hz, 3H), 1.00-1.08 (in), 1.13-1.32 1.35-1,50 2.72-2.82 (2 doublets, J=l3Hz, 1H), 2.83 and 2.86 (2 singlets, 3H), 2.92-3.20 (in, 3H), 3.22-3.45 (mn, 3H), 3.52- 41 1% f) rAp-ihte 1W' 3.75 and 3.76 (2 singlets, 3H), 5.92 WO 99/06397 PCTIUS98/1 5479 2 -107- (2 singlets, 2H), 6.72 J=8Hz, 1H), 6.80-6.87 (in, 3H), 7.03 (2 doublets, J=2Hz, IH), 7.30 J=9Hz, 2H).

trans. trans-24(4 Methoxyphenfl)- 4 1.3-benzodioxol-5-yL- 1 .N- 0 ~~diisobutylam inocarb ofylm ethyl -1yrro i din e3carboxyl ic acid The title compound was prepared using the procedures described in Example 1. m.p. 141-143 0 C. 1 H NMVR (CDCI3, 300 MHz) 8 0.54 (d, SJ=7Hz, 3H), 0.70-0.90 (3 doublets, J=7Hz, 9H), 1.60-1.75 (in, 1H), 1.90- 2.02 (in, 1H), 2.67 J=l3Hz, iH), 2.70 J=l3Hz, 1H), 2.84 (dd, J=6Hz, 15Hz, 1H), 2.96-3.06 (mn, 2H), 3.20 (dd, J=9Hz, 15Hz, 1H), 3.35 (dd, J=2Hz, 10Hz, 1H), 3.44-3.60 (in, 4H), 3.70 J=9Hz, 1H), 3.79 (s, 3H), 5.94 (dd, J=2Hz, 2Hz, 2H), 6.72 J=9Hz, 1H), 6.82-6.90 (in, 3H), 7.03 J=2Hz, 1H), 7.31 J=9Hz, 2H).

Examgle 41 trans. trans-2-(4-M-ethoXyheyl').

4 1.3-belzodioxol-5-yl)I -(N-methvl-N-(2n ropynyl)pm inogrbonylmnethyl)-gyrro lid in e3carboXylic aid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. 1'H NMR (CDCI 3 300 MHz) 6 2.09 and 2.32 (2 triplets, J=2Hz, I1H), 2.80-3.10 (in, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (mn, 2H), 3.52-3.62 (in, IN), 3.78 3H), 4.03 J=13H-z, 1H), 4.00-4.30 (mn, 3H), 5.93 2H), 6.72 (2 doublets, J=8Hz, iN), 6.80-6.90 (in, 3H), 7.02 and 7.11 (2 doublets, J 2Hz, 1 7.30 (2 doublets, J=9Hz, 2H).

Example 42 trans, trans-2-(4-Meth oXYheflyl)- 4 (l.3-benzod ioxol-5-yl)- 1 (N-inethyl-N (fhexl~am inocarbonylmethyl)-Dyrrolidife3carboxlic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMVR (CDCI 3 300 MHz) 8 0.85 (2 triplets, J=7Hz, 3H), 1.00-1.50 (mn, 8H), 2.72-2.82 (2 doublets, J=l3Hz, 1H), 2.81 and 2.86 (2 singlets, 3H), 2.92-3.20 (mn, 3H), 3.22-3.45 (in, 3H), 3.52-3.62 (in, IH), 3.72 (2 doublets, 1H), 3.75 and 3.76 (2 singlets 3H), 5.94 (2 singlets, 6.72 J=BHz, 1H), 6.80-6.87 (in, 3H), 7.03 (2 doublets, J=2Hz, IH), 7.30 J=9Hz, 1H).

WO 99/06397 WO 9906397PCT[US98/15479 2 -108- Example43 trans trans-2-(4-Methoxyph enyl-4-( 1. 3-benzodioxol-5.!yl)-l1-(N. N-di~nbutyflaminocarbnylmethfl-yrrolidilG-3-carboX~ylic acid The title compound was prepared using the procedures described in Example 1. m.p. 123-125 OC. 1 H NMR (ODC1 3 300 MHz) 8 0.79 (t, S J=7Hz, 3H), 0.85 J=7Hz, 3H), 1.00-1.50 (in, 8H), 2.74 J=l3Hz, 1H), 2.90-3.09 (in, 4H), 3.23-3.50 (in, 3H), 3.38 J=l3Hz, 1H), 3.52-3.62 S (in, 11H), 3.75 J=10 Hz, 1H), 3.78 3H), 5.93 (dd, J=2Hz, 4Hz), 6.71 ci J=8Hz, 1H), 6.81-6.89 (in, 3H), 7.03 J=2Hz, 1H), 7.30 J=9 Hz, 2H1). MS (DCI/NH 3 in/e 511 Anal calcd for C 29

H

38

N

2 0 6

C,

68.21; H, 7.50; N, 5.49. Found: C, 68.07; H, 7.47; N, 5.40.

Exam ole 44 trans, trans-2-(4-Methoxyohelyl)-4-( 1.3-benzodioxol-5-vl)- 1 .Ndi ethylam inocarbonylm ethyl-gyrrol idi n e-3-ca rboxyl ic acid The title compound was prepared using the procedures described in Example 1. m.p. 132-134 0 C. 1 H NMR (CDC1 3 300 MHz) 8 0.98 (t, J=7Hz, 3H), 1.06 J=7Hz, 3H), 2.78 J=13 Hz, 1H), 2.95-3.20 (in, 4H), 3.30-3.50 (in, 4H), 3.55-3.65 (in, 1H), 3.76 J=12 Hz, 1H), 3.79 3H), 5.93 2H), 6.72 J=8H-z, 1H), 6.80-6.90 (in, 3H), 7.02 (d, J=2Hz, 1H), 7.32 J=9Hz, 2H).

Exampl~e trans, trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)- 1 -(N-methyl-Nohenylam inocarbonymethyl)-pyrrolidifle-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (CD 3 OD, 300 MHz) 8 2.75- 2.85 (in, 2H), 3.05-3.13 (mn, 1H), 3.18 3H), 3.40-3.58 (in, 2H), 3.78 3H), 3.88 J=l2Hz, 1H), 5.92 2H), 6.72 J=8Hz, 1H), 6.75- 6.85 (mn, 3H), 7.00-7.12 (mn, 5H), 7.82-7.92 (mn, 3H).

Example 46 trans2. trans-2-(4- Methoxyph eyl)-4-( 1.3-benzodioxol-5-yl- 1 (N-rn ethyl- Ncyclohexylaminocar~flylmethl)-pyrrolidile-3-caroxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the MFN4R. 1H NMR (rD2-.OD. 300 MHz) 5 1.00-1.85 (in, 10H), 2.72 and 2.78 (2 WO 99/06397 WO 9906397PCTIUS98/15479 -109singlets, 3H), 2.75-2.82 (2 doublets, J=l2Hz, 1H), 2.96-3.22 (in, 3H), 3.40-3.65 (in, 3H), 3.68 and 3.82 (2 doublets, J=lOHz, 11H), 3.77 and 3.78 (2 singlets, 3H), 5.92 2H), 6.72 (2 doublets, J=BHz, 1H), 6.82-6.88 S(in, 3H), 7.02 (2 doublets, J=2Hz, 11H), 7.30-7.40 (2 doublets, J=9Hz, 2H).

Examole 47 tns -2 4-ethoxvnheflvl) 4 (.3-benzodigoxl-5-Vi')-l .N-di (nprogy~pminocrbnylmethl-yrrolidine3carboUILic aid The title compound was prepared using the-procedures described in Example 1. m.p. 170-172 0 C. 1 H NMR (CDCI3, 300 MHz) 5 0.69 (t, J=7Hz, 3H), 0.85 J=7Hz, 3H), 1.20-1.55 (in, 4H1), 2.72 J=l3Hz, 11H), 2.90-3.10 (in, 4H), 3.25-3.47 (in, 3.35-3.62 (in, 1H), 3.72 J=9Hz, 1H), 3.79 3H), 5.94 2H), 6.72 d, J=8Hz, 1H), 6.80-6.90 (in, 3H-), 7.02 J=2Hz, 11H), 7.30 J=9Hz, 2H-).

Example-48 trans. trans-2-(4-Mthoxyh envl)-4-( 1. 3-benzodioxol-5-Yfl- 1 -(N-rnethyl-N isobutylaminocarb-onlmliethyl-pyrrolidine3carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. IH NMR (CD 3 OD, 300 MHz) 8 0.65-0.85 (4 doublets, J=7Hz, 6H), 1.75-1.95 (in, 1H), 2.80 and 2.90 (2 singlets, 311), 2.90-3.10 (in, 4H), 3.10-3.65 (in, 4H), 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, J=l OHz, 1 H), 5.93 2H), 6.72 J=8Hz, 6.80-6.90 (mn, 3H), 7.02 (2 doublets, J=2Hz, 1H), 7.80-7.90 (2 doublets, J=9Hz, 2H).

Example 49 Alternate Preration of Ethyl 2(4iethoxybe lzoy')4itroiethYl 3 3benzodioxole-a- Ibuty-rate Example 49A E~2~3.4~eth~enedO--henl I l -nitroethefle To a stirred solution of piperonal (75g, 500 inmol) in methanol (120 inL at 10 OC was added nitroinethane (27.1 mL, 500 inmol, 1 eq) followed by the dropwise addition of sodium hydroxide (21 g, 525 inmol, 1.05 eq) in sufficient water to achieve a total volume of 50 mL while

I

WO 99/06397 PCT/US98/15479 (C -110maintaining the temperature between 10-15 OC. The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for minutes upon completion of the addition, and the mixture was then 0 diluted with ice-water (-350 mL) maintaining the temperature below until solution was achieved. The resultant solution was poured in a narrow stream (such that it just failed to break into drops) into a N rapidly stirred solution of 36% hydrochloric acid (100 mL) in water 0 (150 mL). A yellow solid precipitated (nitrostyrene), and this was collected by filtration, washed with water (1.5 L) until the filtrate was neutral. The filter cake was air dried and then-recrystallized from hot ethanol (3 L) to yield E-2-(3,4-methylenedioxy)-nitrostyrene as yellow needles (53 g, 1H NMR (300MHz, CDCI3) 5 7.94 (1H, d, J=13.5Hz), 7.47 (1H, d, J=13.5Hz), 7.09 (1H, dd, J=7.5&2Hz), 7.01 (1H, d, J=2Hz), 6.87 (1H, d, J=7.5Hz), 6.06 (2H, MS (DCI/NH 3 m/e 194 (M+H) 211 (M+H+NH3) Example 49B Ethyl 2-(4-methoxvohenvl)oxo-4-nitro- 3 3 .4-methvlenedioxvyhenvl)butvrate To a stirred solution of the nitrostyrene resulting from Example 49A (14.17 g, 73.34 mmol, 1.2 eq) in a mixture of propan-2-ol (75 mL) and tetrahydrofuran (175 mL) at room temperature was added successively a solution of ethyl (4-methoxybenzoyl)acetate (11.5 g, 51.7 mmol) in THF (50 mL) followed by 1,8-diazabicyclo[5,4,0]undec-7ene (DBU) (0.45 mL, 3.0 mmol, 0.05 eq). The resultant mixture was stirred at room temperature for 1 hour, then additional DBU (0.45 mL, mmol, 0.05 eq) was added. The mixture was stirred a further 1 hour, then the volatiles were removed in vacuo and the residue purified by flash chromatography on 500 g silica gel, eluting with 20% ethyl acetate-hexanes changing to 25% ethyl acetate-hexanes as the product eluted. The solvents were removed in vacuo to yield the nitroketoester (19.36 g, 76%) as a viscous oil. Diastereomers were seen in the NMR.

1 H NMR (300 MHz, CDCI3,) 5 8.06 (2H, d, J=9Hz), 7.89 (2H, d, J=9Hz), 6.96 (2H, d, J=9Hz), 6.91 (2H, d, J=9Hz), 6.77 (1H, dd, J=9Hz,3Hz), 6.73 (1H, d, J=9Hz), 6.65 (1H, d, J=3Hz), 5.95 (2H, 5.89 (1H, d, J=4Hz), 5.88 (1H, d, J=4Hz), 4.90-4.60 (3H, 4.39 (1H, 4.18 (2H, q, J=7Hz), 3.94 (2H, WO 99/06397 PCT/US98/15479 -111 in,3.80 3.78 (3H, 1.19 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz),

MS

(DCI/NH3) m/e 416 433 (M+H+NH3)+.

trans, trans-2-(4-MethO~jheny) 4 a3-benzodioxgl-5-yl)- 1-(kbuttoxcaronvimethyl-Yrnliifl3cabxni ai nTo a stirred solution of the compound resulting from Example S (100 mg, 0.27 mmol) in acetonitrile (2 mL) was added successively 7,A diisopropylethYlamlifle (70 jiL. 0.40 mmol, 1.5 eq) and t-butyl bromoacetate (48 1 0.29 inmol, 1.1 eq). The mixture was stirred 2 hours, then the solvent was removed in vacuo to yield the crude diester.

To a stirred solution of the diester in ethanol (1 mL) at room temperature was added 50% w/w sodium hydroxide (300 mng, 3.75mmol) in water. The mixture was stirred 2 hours, then the volatiles were removed in vacuo. The residue was dissolved in water (5 mL), and the solution was washed with ether. The aqueous phase was acidified with acetic acid (300 jiL), and then extracted with ethyl acetate The combined organic extracts were dried (Na 2 SO4), filtered, and concentrated to yield the title compound (74 mg, 60%) as a white solid.

1 H NMR (300 MHz, CDCI3) 5 7.36 (2H, d, J=8Hz), 7.13 (1H, d, J=3Hz), 6.90 (OH, dt, J=3Hz, 8Hz), 6.88 (2H, d, J=8Hz)., 6.76 (1H, d, J=8Hz), 5.96 (2H, 3.96 (1H, d, J=9Hz), 3.81 (3H, 3.58 (1H, ddd, J=12, lOHz,3Hz), 3.52 dd, J=9H-z,3Hz), 3.32 (1H, d, J=l7Hz), 3.08 (111, t, J=lOHz), 2.92 (1H1, dd, J=9Hz,7Hz), 2.83 (1H, d, J=l7Hz). MS (TJCI/NH 3 m/e 456 Anal calc for C 29

H

2 9N07 0.3 H20: C, 65.07; H, 6.48; N, 3.04. Found:

C,

65.02; H, 6.42; N, 2.93.

Examlle 51 trans. trans.2-(4_-Methoxyphefyl) 4 1 -naghthyl)- 1 -(N-methyl-Ngropyl)ain inoca rbonyl m ethfl)-pvrro lid ine-3-carboXyl ic acid' The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthalene- 1 -carboxaldehyde for piperonyl in Example 49A. Rotational isomers are seen in the NMR. 1

H

NMR (300 MHz, CDCI3) 8 8.29 (1 H, bd, J=8Hz), 7.86 (2H, d, J=8Hz),7.75 (1H, d, J=BHz), 7.49 (3H1, in), 7.34 (2H, dd, J=3Hz,9Hz), 6.83 (2H1, dd, J=9Hz,2Hz), 4.50 (111, mn), 3.94 (1H1, dd, J=9Hz,2Hz), 3.78 (3H1, 3.65 WO 99/06397 PCTIUS98/15479 -112- (1H, in), 3.49 (111, d, J=l4Hz), 3.40-2.93 (5H, in), 2.91, 2.83 (3H, 1.48 S(2H, sept, J=7Hz), 0.83, 0.77 (3H, t, J=7Hz). MS (DCI/NH3) mle 461 Anal calcd for 0 29

H

29 N07 -0.5 HOAc: C, 71.00; H, 6.99; 5.71.

SFound: C, 70.95; H, 7.00; N, 5.46.

trans. trans.2-(4-MethoX heflyl).4-(2.3-dihydrobgnzofuran-5-Yll 1 -(N-methyl-Nprooyl'am ingcarbonylmethyl)PgYrrolidifle3-carboxylic acid Examl 2A 2.3-Dihydrobenzofurafl.5-carboKaldeh~yde To a stirred solution of a,a-dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40 00 was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH 2 CI2 mL) maintaining the temperature at or below -35 The mixture was warmed to 0 0 C, stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and the phases separated. The organic phase was concentrated in vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid. b.p. 119-121 0 C at 0.3 mm Hg.

Examp~le 52B trans, tos2(-ehxgey)4(.3dhdoezfrn5y) -(N-methyl-N- D ropyl)am inocarbonylmethyl)-pyrrolidine3-carbowxLic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 52A for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, CDCI 3 8 7.33 (1H, d, J=8Hz), 7.28 (1H, in), 7.19 (1H, in), 6.87 (1H, d, J=8Hz), 6.73 (1H, d, J=8Hz), 4.56 (1H, t, J=8Hz), 3.83 (1H, d, J=lOHz), 3.80 (3H, 3.63 (1H, in), 3.4-3.0 (9H, in), 2.87, 2.84 (3H, 1.51 (2H, septet, J=7Hi), 0.88, 0.78 (3H, t, J=7Hz). MS

(DCI/NH

3 m/e 453 Anal calc for C 26

H

32

N

2 Os 0.25 H 2 0: C, 68.33; H, 7.17; N, 6.13. Found: C, 68.60; H, 6.88; N, 5.80.

WO 99/06397 WO 9906397PCT/US98/1 5479 N -113trans, trans-2.4-Bis(4flethoXYpheflyfl- -(N-methyl-N-propyP~am inocarbonylmethyl)pyrrolidine-3-carboxylic aci The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-methoxybenzaldehyde for piperonal in 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDCI3) 8 7.37 (2H, d. J=7.5 Hz), 7.32 (2H, d, J=7.5 Hz), 6.86 (4H, in), 3.83 (1 H, in), 3.81 (3H, 3.79 (3H, 3.64 (1 H, mn), 3.48-2.97 (6H1, m), 2.87, 2.83 (3H, 2.85 (1H, in), 1.45 mn), 0.84, 0.74 (3H, t, J=7.5 Hz).

MS (DCI/NH 3 Wne 441 Anal calc for C 25 ki32N205 -0.5 H20: C, 66.80; H, 7.40; N, 6.23. Found: C, 67.15; H, 7.31; N, 6.00.

Exam Dle 54 trans. trans-2-(4-MethoXyghenl)f4-(3.4-dimethoxY~henyl)-1 -(N-methyl-Nproovflam inocarbonylm ethyl)-yrrg lid in e- 3-ca rboxyl ic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-dimethoxybeflzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, CDCI3) 8 7.33 (2H, d, J=7.5 Hz), 7.07 (1H, d, J=2.0 Hz), 6.98 (1 H, mn), 6.85 (1 H, d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (3H1, 3.86 (3H, 3.83 (1 H, in), 3.79 3.64 (1 H, in), 3.50-2.95 (6H, in), 2.87 (1 H, in), 2.85, 2.83 (3H, 1.45 (2H, in), 0.84, 0.74 (3H, t, J=7.5 Hz). MIS (DCI/NH3) Wne 471 Anal calc for G 26

H

3 4N206 -0.5 H 2 0: C, 65.12; H, 7.36; N, 5.84. Found: C, 65'.22; H, 7.27;, N, 5.59.

trans. trans.2-(4-Methoxypheflyl)-4-(3-methoXyphenyl)-l-(N-methylN Dropy)aiinocarbonylmethyl)pgyrrolidine 3 carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, CDCI3) 5 7.33 (2H, d, J=7.5 Hz), 7.24 (111, t, J=7.5 Hz), 7.05 (2H, in), 6.85 (2H, dd, J=7.5&2 Hz), 6.76 (1KH, in), 3.83 (1 H, in), 3.81 (3H1, 3.79 (3H, 3.64 (1 H, in), 3.48-2.97 (6H, in), 2.87, 2.83 2.85 (1 H, in), 1.45 (2H, in), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCI/NH 3 Wne 441

I

WO 99/06397 PCT/US98/15479 C-114- Anal calc for C 2 5

H

32

N

2 0 5 0.5 H 2 0: C, 66.80; H, 7.40; N, 6.23. Found: C, 66.76; H, 7.36; N, 6.05.

Examole 56 trans. trans-2-(4-MethoxvDhenvl)-4-(2-naDhthyl- 1-(N-methyl-N- DproDyl)aminocarbonylmethvl)-yvrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in 0 Examples 1 and 49 substituting naphthylene-2-carboxaldehyde for N piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 NMR (300 MHz, CDCI3) 8 7.82 (4H, 7.69 (1H, 7.47 (2H, 7.37 (2H, dd, J=7.5&2 Hz), 6.85 (2H, dd, J=7.5&2 Hz), 3.90 (1H, d, J=8 Hz), 3.78 (3H, 3.57 (1H, 3.52-2.97 (6H, 2.93, 2.85 (3H, 2.90 (1H, m), 1.52 (2H, 0.86, 0.76 (3H, t, J=7.5 Hz). MS (DCI/NH 3 m/e 461 (M+H) Anal calc for C 28

H

32

N

2 0 4 -0.5 H20: C, 71.62; H, 7.08; N, 5.97. Found: C, 71.58; H, 7.11; N, 6.01.

Example 57 trans.trans-2-(4-Methoxvohenyvl-4-(1.3-benzodioxol-5-vl)- 1-(-(ethvlsulfinvl)ethyl)pyrrolidine-3-carboxvlic acid To the compound resulting from Example 1C (100 mg, 0.27 mmol) and 2-chloroethyl ethyl sulfide (67.5 mg, 0.5 mmol, 2 equivalents) dissolved in 6 mL of acetonitrile was added 10 mg of KI and 0.5 mL of diisopropylethylamine. The mixture was refluxed for 4 hours and then concentrated in vacuo, The residue obtained was purified by flash chromatography on silica gel eluting with 4:1 hexane-ethyl acetate to afford 93 mg of the ethylthioethyl compound.

To the sulfide (90 mg, 0.2 mmol) dissolved in 5 mL of CH 2

CI

2 in an ice bath was added 68 mg of 3-chloroperoxybenzoic acid. The mixture was stirred for 40 minutes in the ice bath and for 3 hours at room temperature. A 10% solution of sodium hydroxide (2 mL) was added, and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was chromatographed on silica gel eluting with EtOAc and 10% MeOH in CH2CI2 to afford the sulfoxide (62 mg, The ethyl ester was hydrolyzed by the procedure described in Fyrmnlp 1D to afford the title compound as a diastereomeric mixture.

WO 99/06397 PCT/US98/15479 -115m.p. 61-63 00.- MS (DCI/NH3) mle 446 1 H NMR (CDCI3, 300 MHz) 8 1.25, 1.32 J=9Hz, 3H), 2.45-2.75 (in, 4H), 2.84-2.96 (in, 3H), 3.02- 3.08 (in, 1H), 3.32, 3.36 J=3Hz, 1H), 3,47-3.58 (in, 2H), 3.65, 3.68 (d, 1H), 3.76, 3.80 3H), 5.94 2H), 6.72 J=7.5Hz, 1H), 3.84- 3.89 (in, 3H), 7.02 J.=6Hz, 1 7.30, 7.34 J=7.5Hz, 2H).

Examgle-58, -trans. trans-2.(4-Methoxylhelyl)- 4 .3-benzodioxol-5-yl)- 1 (i sop rogylsu liofylainfg) ethyl-gyrrolidne3ca rbxvl ic acid To 2-bromoethylamifle hydrobromide (1 mmrrol) suspended in anhydrous CH3CN was added 1 equivalent of Et 3 N. The mixture was stirred for 30 minutes and then 1 equivalent of isopropyl sulfonyl chloride and 1 equivalent of Et3N were added. The resulting mixture was stirred for 2 hours at room temperature and then added to a solution of the compound resulting from Example 1C (185 mg, 0.5 minol) in 3 mL of CH 3 CN. The mixture was warmed at 50-60 00 for 2 hours, cooled to room temperature, treated with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried and concentrated in vacuo. The residue obtained was chroinatographed on silica gel eluting with 3:2 hexane-EtOAC to give 195 mg of the ethyl ester. The ethyl ester (160 mg, 0.31 mmol) was hydrolyzed by the procedure described in Example 1 D to afford the title compound (133 ing, m.p. 94-96 H NMR (CD3OD, 300 MHz) 8 1.26 J=6Hz, 6H), 1.97 1H), 2.38 (in, 1H), 2.77 (in, 1H), 2.88 J=9Hz, 1H), 3.04 (in, 1H), 3.14 J=7.5Hz, 2H), 3.35 (in, 2H), 3.46 (mn, 1 3.58 (in, 1 3.78 3H), 5.92 2H), 6.74 J=9Hz, 1 6.86 (dd, J=9Hz,3Hz, I1H), 6.92 J=9Hz, 2H), 7.00 J=3Hz, 1 7.36 J=9Hz, 2H). MS (DC l/NH3) in/e trans. trans-2-(4-Methoxy_ n 1'- 4 1 3-benzodiOxOl-=-y'I%- 1- (-(iouox'ety) pyrrolidine-3-carboXy&_Ca~id The title compound was prepared by the procedures described in Example 1D from the compound resulting from Example 1C and 2- (isobutoxy) ethyl bromide. m.p. 68-70 00. 1 H NMR (CDC13, 300 MHz) 0.88 J=6Hz, 6H), 1.82 (quintet, J=6Hz, 1H), 2.22 (in, 2H), 2.72-2.79 WO 99/06397 WO 9906397PCT/US98/15479 (in 2.86-2.95 (in, 2H), 3.13 J=6Hz, 2H), 3.45-3.56 (in, 4H), 3.68 J=9Hz, 1 3.79 3H), 5.94 2H), 6.72 J=7.5Hz, 1 6.85 (dd, J=9Hz, 7.5 Hz, 3H), 7.08 1IH), 7.34 J=9Hz, 2H). MS (DCI/NH3) mn/e 442 Exampole trans, trans-2-(4-M ethoxyphenyl)-4-( .3 3enzodioxol- 5-vt)-l1-(butvlsulfonvi)- Ki oyrrolidine-3-carbo~ylic acid To 100 mg (0.271 mmol) of the compound resulting from Example IC dissolved in 10 mL of THF was added 1-butanesulfoflyl chloride (46.7 mng, 1 .1 equivalents) and diisopropyl ethyl amine (53 mg, 1.5 equivalents).

The resulting mixture was stirred for 2.5 hours at room temperature and then the solvent evaporated. The crude product was purified by flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to afford 120 mng of the ethyl ester.

The ester (120 mg, 0.244 minol) was dissolved in 1 mL of EtCH, and a solution of 100 mng of NaCH in 1 mL of water was added. The mixture was stirred for 3 hours at room temperature and then concentrated under reduced pressure. Water (5 mL) was added and the solution was washed with ether to remove any unhydrolyzed trans-cis isomer. The aqueous solution was acidified to pH-6 with acetic acid and then extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the pure title compound (60 mg, 53%) as a white solid. m.p. 67-69 0 C. 1 H NMR (CDC1 3 300 MHz) 8 0.82 J=7.5Hz, 3H), 1.20-1.33 (in, 2H), 1.58-1.68 (nm, 2H), 2.48-2.69 (in, 2H), 3.28 (dd, J=9Hz, 1H), 3.49 J=l2Hz, 1H), 3.65 (dd, J=l2Hz, 1H), 3.82 311), 4.32 (dd, J=l2Hz, 1H), 5.17 J=9Hz, 2H), 5.95 2H), 6.70-6.78 (in, 3H1), 6.92 J=9Hz, 2H), 7.35 J=9Hz, 2H). MS (DCI/NH3) in/e 462 Examgle 61 trans. trans-2 Meth oxylhenl)' 4 1.3-be nzod io xol-5-vl) 1 (N-m ethyl-N isoorOnvlc-arbonvlamiflp)gthyl)-pvrrolidine-3carbo(lic acid WO 99/06397 PCT/US98/15479 -117- Example 61A trans.trans-2-(4-MethoxyDhenvl)-4-( 13-benzodioxol-5-vl)- -(2-bromoethyl)pyrrolidine-3-carboxylic acid ethyl ester 3 To the mixture of cis,trans and trans,trans pyrrolidines resulting S from Example 1C (400 mg) dissolved in 9 mL of 1,2-dibromoethane was D added 0.7 mL of diisopropylethylamine and 30 mg of sodium iodide. The resultant mixture was heated at 100 °C for 1 hour, and then the solvents were removed in vacuo. The residue was taken up in EtOAc and S washed sequentially with water and brine, dried and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 4:1 hexane-EtOAc to give 470 mg of the title product.

Example 61B trans.trans.2-4-.Methoxvohenvl)-4-(1.3-benzodioxol-5-yl)- 1 -(2-(methylamino)ethyl)pyrrolidine-3-carboxylic acid ethyl ester To the compound resulting from Example 61A (450 mg) dissolved in 10 mL of EtOH was added 0.5 mL of 40% aqueous methylamine and mg of sodium iodide. The mixture was heated at 80 °C for 1 hour, and then the solvents were removed in vacuo. The residue was taken up in EtOAc and washed sequentially with water and brine, dried and concentrated in vacuo. The resultant product was carried on without further purification.

Example 61C trans.trans-2-(4-Methoxyhenyl-4-(1.3-benzodioxol-5-vl)-1 -(2-(N-methyl-Nisobutvrvlaminoethyl)-pvrrolidine-3-carboxylic acid To the compound resulting from Example 61B (-150 mg) dissolved in 5 mL of 1,2-dichloroethane was added 0.3 mL of diisopropylethylamine. The solution was cooled to -40 OC, isobutyryl chloride (0.17 mL) was added, the bath was removed, and the solution was allowed to warm to ambient temperature and stirred for 15 hours.

The solvent was removed in vacuo; the residue was taken up in EtOAc and washed sequentially with 1:1 sodium bicarbonate solution/water and brine, dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel eluting with a gradient 1:1 EtOAchexanes going to EtOAc and finally using 10% MeOH-EtOAc.

WO 99/06397 WO 9906397PCTIUS98/1 5479 The ester was dissolved in 1.5 mL of EtOH; 0.75 mL of a 17% aqueous NaOH solution was added, and the resultant mixture was stirred at ambient temperature for 3 hours. The solvents were removed in vacuo; the residue was taken up in water and washed with ether. The aqueous phase was acidified with 1 N~ H 3 P0 4 to pH 3 and extracted twice with ether. The combined organic extracts were washed with brine and dried over Na2SO4. The solvents were removed in vacuo to provide 82 mg of the title compound as a white foam. Rotamers were seen in the NMR. I H NMR (CDCI3, 300 MHz) of the major rotamer 8 1.06 3H, J=lOHz), 1.12 3H, J=lOHz), 2.15 (in, 1H), 2.5-1~0 (in, 3H), 2.91 3H), 3.32 (mn, 2H), 3.50 (mn, 2H), 3.65 (in, 2H), 3.77 3H), 5.92 2H), 6.73 1H, J=8Hz), 6.75-6.9 (mn, 4H), 6.96 1H, J=2Hz), 7.29 (mn, 1H). MS

(DCI/NH

3 m/z 469 Analysis calcd for C 26

H

32

N

2 0 6 -0.3 TFA: C, 63.55; H, 6.48; N, 5.57. Found: C, 63.44; H, 6.71; N, 5.24.

Exam Dle 62 trans, trans-2- (4-M ethoxyoh enyfl-4- (1 .3-benzod ioxol 1 (2 ethyl- N Drooionylam ino~ethyl)-oyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 61 substituting propionyl chloride for isobutyryl chloride in Example 61C. 1 H NMR (CDCI 3 300 MHz) of the major rotainer 8 1.13 (t, 3H, J=8Hz), 2.19 (in, 1H), 2.30 (mn, 2H), 2.65-3.0 (in, 3H), 2.85 3H), 3.25-3.4 (in, 3.5-3.7 (in, 3.79 3H), 5.92 6.74 1H, J=8Hz), 6.75-6.9 (in, 4H), 7.00 (bd s, 1H), 7.29 (bd s, 1H). MS (DCI/NH 3 m/z 455 Analysis calcd for C 25

H

3 0

N

2 0 6 1.0 H 2 0: C, 63.55; H, 6.83; N, 5.93 Found: C, 63.55; H, 6.52; N, 5.73.

Exampg 6 trans, trans-2-(4- Methoxyphenyfl-4- (1 .3-benzodioxol-5-yl)- 1 -(N-rn ethyl-N benzylam inocarbonylmethyl)-pyrrolidine-3-carboxylic -acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMVR (CDCI3, 300 MHz) of the major rotainer 8 2.79 (s, 3H), 2.8-3.2 (in, 2H), 3.48 (in, 2H), 3.61 (in, 2H), 3.77 3H), 3.78 (in, 1H), 4.3-4.5 (in, 2H), 5.95 2H,, J=2Hz), 6.7-6.9 (mn, 4H), 7.00 (in, 1H), 7.15-7.35 (in, MS (FAB/NBA) m/z 503 Anal calcd for

C

29

H

30

N

2 06 0.5 H 2 0: C, 68.36; H,5.74; N, 5.50. Found: 0,68.41; H, 5.74; N, 5.36 WO 99/06397 PCT/US98/15479 Examole 64 0trans. trans-2-(4-Methoxyoheyl)-4-( 1.3-benzodioxol-5-yfl- 1 -(N-ethyl-Nbutylaminocarbonylethyl)-Dyrrolidifle-3-carboalic acid Using the procedures described in Example 1 the title compound O was prepared. 1H NMR (CDCI3, 300 MHz) of the major rotamer 8 0.88 (t, .fl3H, J=7Hz), 1.06 3H, J=7Hz), 1.27 (in, 2H), 1.45 (in, 2H), 2.8-3.6 (in, o11 3.79 3.80 (in, 1 5.92 (bd s, 2H), 6.75 1 H, J=8Hz), 6.85 1H, J=BHz), 6.92 2H, J=8Hz), 7.03 1H), 7.33 1H, J=8Hz). MS

(DCI/NH

3 mlz 483 Anal calcd for C 27

H

34

N

2 06 -0.5 HOAc: C, 65.61; H,7.08; N, 5.46. Found: C,65.51; H, 6.70; N, 5.66.- Examole trans. trans-2-(4-Methoxyohenl)-4-(1 .3-benzodioxol-5-yl'kl -(N-methyl-N-(2.2dim ethylp rogylaminocarbonyll'ethyl-Yrrolidile-3-carboyliC acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (CDC1 3 300 MHz) of the major rotamer 8 0.90 (s, 9H), 2.8-3.1 (in, 4H), 2.94 3H), 3.3-3.5 (in, 3H), 3.61 (in, 1H), 3.80 (s, 3H), 3.82 (in, 1H), 5.94 (bd s, 2H), 6.74 1H, J=8Hz), 6.86 2H, J=BHz), 6.87 (in, 1H), 7.03 1H, J=2Hz), 7.33 2H, J=8Hz). MS

(DCI/NH

3 m/z 483 Exampl~e 66 trans, trans-2-(4-Methoxyhenyl)-4-( 1.3-benzodioQxol-5-yl)- 1 -(2-(N-methyl-NbUtylsulfonylamino)ethyl-yrrolidile-3-carboxylic acid To the compound resulting from Example 61B (60 mg, 0.13 minol) dissolved in 5 mL of CH 3 CN was added 0.2 mL of Et 3 N and 22 mg (0.143 mmol, 1.1 equivalents) of 1-butanesulfonyl chloride. The mixture was stirred for 1 hour a t room temperature and then concentrated in vacua.

The crude product was purified by column chromatography on silica gel eluting with 1:1 EtOAc-hexane to yield 64 mg of the ester. Ester hydrolysis by the procedure described in Example ID afforded the title compound. m.p. 64-66 0 C. 1 H NMR (CDC13. 300 MHz) 8 0.92 3H), 1.39 (hexad, J=7.5Hz, 2H), 1.68-1.76 (in, 2H), 2.16-2.25 (in, 1H), 2.72 3H), 2.75-2.92 (in, 5H), 3.12-3.20 (in, 1H), 3.25-3.34 (in, 1H), 3.46-3.55 (in, 2H), 3.65 J=9Hz, 1H), 3.78 3H), 5.53 2H), 6.72 (d, WO 99/06397 WO 9906397PCT/US98/1 5479 -120- >J=7.SHz, 1 6.82 (dd, J=7.5Hz,3Hz, I1H), 6.86 J=9Hz, 2H), 7.02 (d, J=3Hz, 1H), 7.34 J=9Hz, 2H). MS (DCI/NH 3 m/e 519,(M+H)+.

IND Example 6 trans. trans-2(4-MetoXYhelyl)-4-(1 .3-benzodioxol-5-yl)-l1-(2-(N-methyl-N- N 1prgpylsu lfonylamino)ethyl)-pyrrolidile-3-carboaylic acid The title compound was prepared by the procedures described in S Example 66 substituting 1-propanesulfolyl chloride for 1butanesulfonyl chloride. m.p. 69-70 0 C. 1H NMR (CDC13, 300 MHz) 8 1.02 J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.18-2'26 (in, 1H), 2.72 (s, 3H), 2.75-2.95 (in, 6H), 3.13-3.22 (in, 1H), 3.25-3.35 (in, 1H), 3.47-3.58 (in, 2H), 3.66 J=9Hz, 1H), 3.80 3H), 5.96 2H), 6.74 1H), 6.84 J=7.5Hz, 3Hz, 1H), 6.87 J=9Hz, 2H), 7.04 J=3Hz, 1H), 7.43 J=9Hz, 2H). MS (DCI/NH 3 m/e 505 trans. trans-2-(4-MethoxV~henfl)-4-(l .3-benzodioxol-5-yfl-1 (orooylsulfoflylethyl)-Dyrrolidile-3-carbX~lic cid To 1-propanethiol (3.5 g, 46.05 mmol) dissolved in 10 mL of anhydrous THF was added 632 mg (26.32 mmol) of NaH in portions under a nitrogen atmosphere. The mixture was heated at 60-70 0 C for 1 hours.

To this mixture was added the compound resulting from Example 61A (180 mg, 0.38 mmol) in 2 mL THE. Heating was continued at 60-70 IIC for an additional.2 hours, and then the volatiles were removed under reduced pressure. The crude propylthioethyl adduct was purified by flash chromatography on silica gel eluting with 3:2 hexane-EtOAc to give 170 mng To a solution of 170 mg (0.36 minol) of the sulfide and 93 mng (0.8 inmol) of N-methylmorpholine N-oxide (NMO) in a mixture of 20 mL of acetone and 5 mL of H20 was added a solution of osmium tetroxide mng) in 0.3 mL of t-butanol. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was partitioned between EtOAc and H 2 0. The organic phase was washed with brine, dried over NS 2 SO4 and concentrated in vacuo. Flash chromatography afforded 177 mg of the ethyl ester which was hydrolyzed by the procedures described in Example 1D to afford the title I a WO 99/06397 PCT/US98/15479 -121- S compound. m.p. 73-75 1 H NMR (CDCI3, 300 MHz) 8 1.04 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.59-2.66 1H), 2.84-3.08 7H), 3.43 (dd, J=9Hz, 3Hz, 1H), 3.53-3.60 1H), 3.68 J=9Hz, 3.82 (s, S 3H), 5.96 2H), 6.75 J=7.5Hz, 1H), 6.82 (dd, J=7.5Hz, 3Hz, 1H), 6.88 J=9Hz, 2H), 6.99 J=3Hz, 1H), 7.32 J=9Hz, 2H). MS (DCI/NH3) m/e 476 (M+H) 3 Example 69 trans. trans-2- (4Methox

N

Vhenvl)-4-(1.3-benzodioxol-5-vl- 1 2-envl-Dvrrolidine-3-carboxylic acid Example 69A trans5-Methylhex-2-enoic acid ethyl ester Oil dispersion sodium hydride (0.85 g) was washed with hexanes and suspended in THF (20 mL), and the mixture was cooled in an ice bath to 0 OC. Diisopropyl(ethoxycarbonylmethyl) phosphonate (5.0 mL) was added slowly and the mixture stirred for 20 minutes at 0 °C.

Isovaleraldehyde (2.0 mL) in THF (5 mL) was added dropwise over five minutes. The ice bath was removed and the mixture stirred for 18 hours at ambient temperature. Saturated ammonium chloride solution (50 mL) was added and the mixture extracted with diethyl ether (3 x 50 mL).

The ether extracts were combined, dried with Na 2 SO4, and evaporated to give a colorless oil which was purified by flash chromatography on silica gel eluting with hexanes. The title compound was isolated as a colorless oil (2.1 g).

Example 69B trans.5-Methvlhex-2-en-1 -ol The compound resuting from Example 69A (2.0 g) was dissolved in toluene and cooled to 0 °C in an ice bath. Diisobutylaluminum hydride N in toluene, 20 mL) was added dropwise and the solution stirred at 0 'C for two hours. Citric acid solution (25 mL) was added very slowly to the cooled solution. The resulting mixture was stirred for 18 hours at ambient temperature. Diethyl ether (50 mL) was added, the solids removed by filtration and washed with additional ether (2 x 25 mL).

The filtrate was extracted with ether (2 x 25 mL). The ether C ;3 o ,nti wahinas were combined, dried, and evaported to give a WO 99/06397 WO 9906397PCT/U598/1 5479 122colorless oil which was purified by flash chromatography on Silica gel eluting with 25% EtOAc-hexafles. The title compound was isolated as a S colorless oil (1.25 g).

trans:- Bromo-5-Methylhex-2-efle The compound resulting from Example 69B (1.0 g) was dissolved in diethyl ether and cooled to 0 0 IC in an ice bath. Phosphorus tribromide g, 0.87 mL) was added dropwise and the solution stirred at 0 0 'C for two hours. The solution was poured onto ice, the-layers separated, and the aqueous layer extracted with additional ether (3 x 25 mL). The ether layers were combined, dried, and evaporated to give a colorless oil which was used without further purification (0.95 g).

Exam 2 trans. trans-2- Meth oxyhgnyl)-4- (1.3-ben zodioxol-5-yl) 1 N- (trans- 5-m ethyl he-x- 2-enyl)-pvrrolidin e-3-carboxylic acid The title compound was synthesized using the methods detailed in Example 1D but substituting the compound resulting from Example 69C for N-propyl bromoacetamide. 1 H NMR (CDCI 3 300 MHz) 8 0.84 6H, J=8Hz), 1.57 (heptet, 1H, J=8Hz), 1.87 2H, J=6Hz), 2.60 (dd, 1H, J=8Hz,l4Hz), 2.86 1H, J=lOHz), 2.96 (dd, 1H, J=8Hz,lOHz), 3.20 (dd, 1H-, J= 5Hz,l4Hz), 3.29 (dd, 1H, J=3Hz,lOHz), 3.50 (in, 1H), 3.70 1H.

J=lOHz), 3.78 3H), 5.47 (in, 2H1), 5.93 2H), 6.71 1H, J=BHz), 6.83 3H, J=9Hz), 7.05 1H), 7.32 2H, J=9H-z). MS (DCI/NH3) m/e 438 Anal calcd for C 26

H

3 1N05: C, 71.37; H, 7.14; N, 3.20. Found: C, 71.16; H, 7.24; N, 3.17.

trans. trans- -(4-Methoxyghefnyl')-4 4 1 .3-benzodioxol-5-y)-l1-N-( dim ethylhex-2-enyl)- pyrrol id ire-3ca rboxylic acid The title compound was prepared by the procedures described in Example 69 but substituting 4-methyl-2-pefltanone for isovaleraldehyde in Example 69A, which gave -7:1 mixture of trans/cis olefins. The crude product was purified by preparative HPLC (Vydac l.C18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA, The f ad f rat ere I~t~nhijji7Qd M~ nive, the Drdc adits WO 99/06397 PCT/US98/15479 -123t diastereomer) as a white solid. 1 H NMR of the major (trans) isomer: (CDCI3, 300 MHz) 5 0.83 6H, J=8Hz), 1.56 1.74 1H), 1.92 (d, S2H, J=6Hz), 3.3-3.5 3H), 3.6-3.8 3.78 3H), 3.9-4.0 1H), S5.22 1H), 5.90 2H, J=12Hz), 6.63 1H), 6.78 3H), 6.95 (s, 1H), 7.45 3H, J=8Hz). MS (DCI/NH3) m/e 438 Anal calcd for C C 27 H33NO5 1.0 TFA: C, 61.59; H, 6.06; N, 2.48. Found: C, 61.36; H, 6.10; o N, 2.34.

O

Example 71 trans. trans-2-(4-Methoxyhenyl)-4-(1.3-benzodioxol-5-vl)-1 heotvlcarbonvlmethvl)-.vrrolidine-3-carboxlic acid Example 71A 1 .Chloro-3-proDyl-2-hexanone is To 2-propylpentanoic acid (156.6 1i, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 pL, 4 mole and the solution was cooled to 0 °C under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 gL, 1.08 mmol) dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The mixture was cooled to 0 OC and excess -0.3 M ethereal diazomethane solution was added. The reaction mixture was stirred 18 hours while warming to ambient temperature. The reaction mixture was washed with 1 M aqueous sodium carbonate solution mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in ether (2 mL) and cooled to 0 °C under a nitrogen atmosphere. Hydrogen chloride as a 4 N solution in dioxane (275 iL, 1.10 mmol) was added dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The reaction mixture was concentrated under reduced pressure and the residual oil was used in the next step without further purification.

Example 71B trans.trans-Ethyl 2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yi)-l-(4heptvlcarbonvlmethvl-Dvrrolidine-3-carboxylate To the compound resulting from Example 71A (1.00 mmol, maximum theoretical yield) was added a solution of the trans,trans WO 99/06397 PCT/US98/15479 -124ethyl carboxylate from Example 1C (295 mg, 0.80 mmol as a 50 solution in toluene), diisopropylethylamine (700 iL, 4.00 mmol) and S acetonitrile (4 mL). To the resulting solution was added sodium iodide (12 mg, 10 mole and the reaction mixture was stirred 18 hours S under a nitrogen atmosphere at ambient temperature. Additional sodium S iodide (24 mg, 20 mole and acetonitrile (4 mL) were added, and the S reaction mixture was heated at 45-50 °C with stirring for 18 hours.

The reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel eluting with 1:9 ethyl acetate-hexane to give 237 mg of the title -compound as a yellow oil.

Example 71C trans trans-2-(4-Methoxyphenyl)- 4 -(1,3-benzodioxol-5-yl-1 heptvlcarbonylmethvl)-pyrrolidine-3-carboxylic acid To the compound resulting from Example 71B (231 mg, 0.4532 mmol) dissolved in ethanol (10 mL) was added a solution of lithium hydroxide (38 mg, 0.9065 mmol) in water (2.5 mL). The solution was stirred for 18 hours under a nitrogen atmosphere, additional lithium hydroxide (19 mg, 0.4532 mmol) in water (0.5 mL) was added, and stirring was continued 24 hours. The reaction mixture was concentrated under reduced pressure to remove the ethanol, and the aqueous residue was diluted with water (45 mL) and washed with ether mL). The aqueous layer was neutralized with 1 N hydrochloric acid to cloudiness and then 10% aqueous citric acid was added to adjust the pH to This solution was then extracted with 10% ethanol in chloroform (4 x 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel eluted with 1:1 ethyl acetate-hexane to give 86 mg of the title compound as an off white powder. 1 H NMR (CDCI3, 300 MHz) 8 0.73-0.97 6H), 1.03-1.33 6H), 1.36-1.58 2H), 2.46 1H), 2.80-2.98 3H), 3.38-3.64 3H), 3.75-3.90 1H), 3.79 3H), 5.94 2H), 6.75 1H), 6.86 2H), 6.92 1H), 7.12 1H), 7.32 2H). MS (FAB) m/e 482 Anal calcd for C 28

H

35

NO

6 C, 69.83; H, 7.32; N, 2.91. Found: C, 69.57; H, 7.41; N, 2.73.

WO 99/06397 WO 9906397PCT/US98/15479 -125- ExampDle 72 0 oyrrolidine-3-carb9yiCacid Exam~ple72A c-i 1 -Chloro-2-hexpflofle o Using the procedure described in Example 71A and substituting cI pentanoiC acid for 2-propylpentaloiC acid afforded the title compound as an oil which was used in the next step without further purification.

Exm~l 72 trans, trans-Ethyl 2-(4-methoxypahenyl)-4-(1 .3-benzodioxole,-5-yl)-l (valeryl methyl)-gyrrolid ine-3-cg rboxyl ate Substituting the compound resulting from Example 72A for 1- -chiloro-3- propyI-2 -hexa none and using the procedure described in Example 71B, except deleting the first addition of sodium iodide, stirring 18 hours at ambient temperature and purifying by silica gel chromatography eluting with 3:17 ethyl acetate-hexane, the title compound 305 mg was obtained as a yellow oil.

Examgle 72C trans, trans MethoxY~henyl)- 4 .3-benzodioxol-5-yfl-l1 .(valprylmethyflpyrrolidifle-3carboxylic acid By substituting the compound resulting from Example 726 for trans, trans-Ethyl 2-(4-methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-l heptylcarbonylmethyl)-pyrrol idin e-3-carboxyl ate and using the procedure described in Example 71C, except only one solution of lithium hydroxide (81.5 mg, 1.942 mmol) in water (3.5 mL) was added followed by stirring for 18 hours, the title compound 130 mg was obtained as an off white powder. 1 H NMR (CDC13, 300 MHz) 6 0.87 (t, 3H), 1.26 (in, 2H), 1.49 (in, 2H), 2.37 (in, 2H), 2.79-2.98 (mn, 3H), 3.31- 3.49 (m,2H1), 3.56 (mn, 1 3.77, 3.79 4H), 5.94 2H), 6.75 1 H), 6.81-6.93 (in, 3H), 7.09 1H), 7.33 2H). MS (FAB) m/e 440 Anal. calcd for C 25 H29N06: C, 68.32; H, 6.65; N, 3.19. Found: C. 67.95: H, 6.64; N, 3.05.

WO 99/06397 WO 9906397PCT/US98/15479 -126- D trans. trans-2-(4-Methoxvichenl)l' 4 (1-.benz.odioxo l-5-yfl-l 4- 0 dim ethoxyben Zyl'.N-m ethylam inocarbonyl methyl') 1yrroli dife 3 ca rboxylic acid D trans.trans- and cistrans2(4Me hoxyphenyl- 4 -i yf)l- 3 4 dimethoxybeflzyl)amiflocarbon Imeh lProlidine 3 carboxylic aid ethyl ester Using the procedure of Example 1ID, paragvaph 1, substituting 3,4dimethoxybelzyl bromoacetamide for dipropyl bromoacetamide, the desired product mixture was obtained as a white foam in 81% yield.

-trans.trans- and ci.trans-2(4Methoxyphenyl- 4 yl)-l .(N-(3.4-dimethI en -fNmethylaminocprbn Imethgy1 rrolidine3caro Iic acd thyl eter The resultant product from Example 73A (220 mg, 0.404 mmol) was dissolved in 2 mL dry THF and added dropwise to a stirred, cooled (0 OC) suspension of sodium hydride (23 mg of a 60% by weight mineral oil suspension, 16.5 mg, 0.69 mmol) in 0.2 mL THE, under an argon atmosphere. The resulting mixture was stirred at 0 OC for 1 hour, then methyl iodide (28 64 mg, 0.45 mmol) was added. The reaction mixture was stirred at 0 0 C for 45 minutes. TLC (Et 2 O) indicated incomplete reaction. An additional portion of methyl iodide (28 ptL, 64 mg, 0.45 mmol) and dry 1, ,3-dimethyl- 3,4,5,6tetrahyd ro- 2(1 H)pyrimidinone (50 iiL, 0.41 mmol) were added. The reaction mixture was stirred at ambient temperature for 2 days. The reaction was poured into 25 mL of 0.5 Mr aqueous citric acid and extracted with 2 x 25 mL EtOAc. The combined organic extrracts were washed sequentially with 30 rnmL water and 30 mL brine, then dried (Na2SO4), filtered and concentrated under reduced pressure to produce 270 mg of crude material. Flash chromatography on silica gel eluting with Et2O gave the title compounds as an inseparable mixture in 43% yield. 1

H

NMR (CDCI3, 300 MHz) 8 2.79 and 2.81 for the N-CH3 signals.

MS

m/z 591 WO 99/06397 PCT/US98/15479 -127- Examiple 73 trnstrns2-(4-Methoxyphenyvlj)- 4 -(l.3-benzodioxol-5-vl)-l dim ethoxybenl)l-Nmethyl am n ocarbonyl methyl) pyrrol idine- 3 0~ cabxylic cid To the resultant compound from Example 73B (98 mg, 0.17 mmol) dissolved in 1 mL EtOH and cooled to 000I was added a solution of S lithium hydroxide monohydroxide (17 mg, 0.41 mmol) in 0.5 mL H20. The S resulting solution was stirred under a nitrogen atmosphere for 16 hours. The solution was concentrated in vacuo, and the residue was partitioned between 15 mL H20 and 15 mL Et2O. The aqueous phase was extracted with 5 mL Et2O, then the aqueous phase was acidified with aqueous citric acid. The acidic aqueous phase was saturated with NaCI and extracted with 3 x 15 mL EtOAc. The EtOAc extracts were combined, dried (Na2SO4), then filtered and concentrated in vacuo to give 40 mg of the title compound as a white foam. 1H NMR

(CD

3 00, 300 MHz, two rotameric forms) 5 2.85 3H), 2.94-3.25 (br m, 3H), 3.35-3.70 (br m) and 3.64 4 H total), 3.70-3.97 (br in), 3.74 3.76 3.78 3.79 3.81 and 4.03 (br d, J=14 Hz, 8H total), 4.43 (AB, 1H), 5.91 and 5.93 2H total), 6.50-6.60 (in, 1H), 6.67- 7.02 (br m, 6H), 7.29 (br d) and 7.35 (br d, 2H total). HRMS calcd for

C

3 1

H

35 N208 563.2393. Found: 563.2385.

Examiole 74 -trans. trans-2-(4-Methoxvohenl)- 4 (l .3-benzodioxol-5-yl)-1 dim ethogybenzyl) aminocarbonylm ethvl)12yrrol idine3ca rb22aLc acd The procedure of Example 73C was used, with the substitution of the resultant compound from Example 73A for the resultant compound from Example 7383, to provide the title compound. 1 H NMR (CD 3 OD, 300 MHz) 8 2.85 J=1l6Hz, 1 2.92 (br t, J=9Hz, 1 2.98 (br t, J=1 OHz, 1 3.32-3.39 (br m, 2H), 3.54-3.65 (br m, 1 3.67 3H), 3.78 (s, 3H), 3.80 3H), 3.85 J=10 Hz, 1H), 4.21 J=l5Hz, 1H), 4.41.

J=

I1H), 5.91 2H), 6.67 J=8Hz, 1 6.75-6.95 (in, 7H), 7.33-7.40 (in, HRMS calcd for C3 0

H

32 N208 549.2237. Found: 549.2224.

I

WO 99/06397 PCT/S98/15479 -128- -4- Example R .thoxv4- hen-.4-(1.3-bnzodi-1-1)-1-(N.NdirooviaminocarboYi-1- butvl)oYrrolidine-3-carbxvlic acid Example Sltrans tns2 r -(4MethoX y r OhenYl'benzodiox--ol-5Y l-((1 SThe procedure of Fung, et. al., J. Med. Chem., 35(10): 1722-34 S (1992) was adapted. The resultant compound from Example 6A (103 mg, 0.279 mmol) was dissolved in 0.7 mL of nitromethane and 0.7 mL of and ammonium carbonate (34 mg, 0.35 mmol) and (2S)-benzyl 2bromopentanoate (78 mg, 0.30 mmol) were added. The reaction was refluxed for 24 hours. The reaction was partitioned between 15 mL of 1 M aqueous Na 2 CO3 and 25 mL of CH2CI2. The aqueous phase was extracted with 2 x 10 mL CH2C12, and the combined organic phases were washed with 15 mL brine, dried (Na2SO4), then filtered and concentrated under reduced pressure to a brown oil (169 mg). The crude product was purified by silica gel chromatography eluting with 3:1

CH

2 C1 2 -hexane to produce 106 mg of the title compound as a waxy solid. 1H NMR indicated the presence of two diastereomeric products.

Example trans. rans-2-(4-Methoxh enl-4-(1 .3-benzdioxol-5--1 1R-1-N dipro I ylaminocarbo n I- I but orr lidine-3-carboyli id h r The resultant compound from Example 75A (101 mg, 0.180 mmol) and 30 mg of 10% palladium on charcoal were stirred in 2 mL EtOAc under 1 atmosphere of H2 for 4 hours. The reaction mixture was filtered through a plug of Celite, using 15 mL MeOH to wash the catalyst., The combined filtrate and wash were concentrated in vacuo to give 81.4 mg of the crude acid as a white solid.

The above crude acid was combined with HOBt hydrate (41 mg, 0.27 mmol), dipropylamine (26 mg, 0.26 mmol), and 4-methylmorpholine (37 mg, 0.37 mmol) in 2 mL dry DMF. The solution was cooled to -15 0C, then 1-ethyl-3-( 3 -dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) was added. The mixture was stirred at -15 OC and allowed to warm slowly to room temperature overnight. The solvent was removed by distillation under reduced pressure, and the residue WO 99/06397 PCTIUS98/1 5479 ct;--4-129was partitioned between 20 mL EtOAc and 10 mL of 1 IA aqueous Na2003.

The organic phase was washed with 10 mL of brine, dried (Na2SO4), then 0 filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 1:2 Et 2 O-hexanle.

Further purification of overlap fractions by preparative TLC eluting Swith 1:2 Et 2 G-hexanle yielded 32 mg of a less polar product, and S44 mg of a more polar product.

Examial1 750 2 1R.LaRrn2-0Me hoxyphe yl- 4 -(l.3benzotoxoXl5i)'l-((1 (N .~diroPlamfloarbon I but I prrolidiecabxl ci The procedure of Example 730 was followed, with the substitution of the less polar isomer from Example 75B for the resultant product from Example 7313, to provide the title compound in 94% yield. tcxQo 520 (c--0.23 5

CH

3 OH). I1H NMR

(CD

3 OD, 300 MHz) 8 0.55 J=7Hz, 3H), 0.87 J=7Hz) and 0.87-0.94 (in, 6H total), 1.03-1.25 (br m, 2H), 1.25- 1.68 (br m, 4H), 1.90-2.07 (br m, 1H), 2.75-2.94 (br m, 2H), 2.94-3.02 (br mn, 2H), 3.20-3.40 (in, overlapping with

CD

2 HOD signal), 3.40-3.60 (br m, 2H), 3.79 3H), 4.04 (br d, J=9 Hz, 1 5.92 (dd, J=3,5 Hz, 2H), 6.72 J=8 Hz, 1H), 6.79 (dd, J=1.5,B Hz, 1H), 6.92-6.98 (br mn, 3H), 7.29-7.39 (mn, 2H). MS in/z 525 Example 76 (MS. 3

S

4 S)l-2 4Met oxy heni) 4 .3bn ixol-5Yvl) 1

R-

(N.N-dipropylmilcroll butylI rrolidine- arbox lic aid The procedure of Example 730 was followed, with the substitution of the more polar isomer from Example 75B for the resultant product from Example 73B3, to provide the title compound in 88% yield. EctIh +580 (c=0.37,

CH

3 OH). 1 H NMR

(CD

3 OD, 300 MHz) 650.57 (br t, J=7Hz, 3H), 0.88-0.98 (in, 6K), 1.08-1.35 (br in, 2H), 1.35-1.6B (br m, 4K), 1.75-1.90 (br mn, 2.75-2.86 (br m, 2H), 3.10-3.30 (br mn, 2H), 3.51-3.65 (br m, 2 3.69 3H1), .4.03-4.16 (br in, 2H), 5.91 2H), 6.71-6.83 (in, 2H), 6.86-6.97 (in, 3H), 7.32 (br d, J=9Hz, 2H). MS m/z 525 WO 99/06397 PCTIUS98/15479 -130- Examrle 77 (2S9.3S.4S)-2-(4-MethoXYhenlY)4-(1.3-benzodioxol-5-yl)-I 1 Ndip roovlam inocarbo 1 -butyl yrrolidine3carboui~c acid EixampleZ7A D trans, trans-2-(4-Methoxylhenl)- 4 -(l.3-benzodioxol-5Yfll S)-1 (N .N-dipropylamliflocarboflyl)-l butyl)oyrroidil~~abXlC ai (2R)-N,N-dipropyl 2-hydroxypentaflamide (106 mg, 0.528 mmol, made by standard procedure) was dissolved in 2 rnL THF under an argon atmosphere, diisopropylethYlamine (75 mg, 0.58 mmol) was added, then the solution was cooled to -20 00. TrifluoromethalesulfofliC anhydride iL-, 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 00 for 1 hour, and at room temperature for an additional 1 hour. The resulting slurry was recooled to 0 00, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and diisopropylethYlamiIe (101 .iL, 75 mg.

0.58 mmol) in 3 mL of CH2CI2 was added. The reaction was stirred at 0 00 for 3 hours and for an additional 2 days at room temperature.

TLC

(Et 2 O-hexanle 1:2) indicated starting materials remained, so the mixture was warmed to retlux for 4 hours. The reaction was cooled, then partitioned between 30 mL EtOAc and 15 mL of 1 M aqueous Na2003. The aqueous phase was extracted with 15 mL EtOAc, then the combined organic phases were washed with 20 mL brine, dried (Na2SO4), filtered and concentrated in vacua to a yellowish oil. Purification by flash chromatography on silica gel eluting with 1:2 Et 2 O-hexanle gave 19.9 mg of a less polar product and 20.1 mg of a more polar product.

1 H NMR spectra and MS were the same as those of Example 76B.

Exampl~e 77B (2S 3 S. 4S)-2- Methoxyh enyl)- 4 ben zodi x I- -YlI S-1-(N NNdigropylamilocarbgnl)-~1 bu yl)Dyrrolidife3-carbgndlic id The procedure of Example 730 was followed, with the substitution of the less polar isomer from Example 77A for the resultant product from Example 7313, to provide the title compound in 100% yield. 1 H NMR

(CD

3 OD, 300 MHz) and MS identical to those of Example WO 99/06397 PCT/US98/15479 -131- Examole 78 2 R.3R.4R-2.(4-Methovhel-(1 .3-benzodioxol-5-v- diDroovlamicarboflnvYlo--utvlovrrolidine-3-carbxvic acid OThe procedure of Example 73C was followed, with the substitution Sof the more polar isomer from Example 77A for the resultant product from Example 73B, to provide the title compound in 88% yield. 1H NMR

(CD

3 OD, 300 MHz) and MS identical to those of Example 76.

Example 79 trans. trans-2(4-MethoXvphenyl)- 4 -(1.3-benzodioxol-5-vi- 1- N. N-din- Carbonyldiimidazole (510 mg, 3.148 mmol) was added to 1.020 g (2.00 mmol) of the compound resulting from Example 43 in 2.7 mL THF, and the mixture was heated for 40 minutes at 50 The reaction mixture was cooled in an ice bath, and 25% solution of ammonia in methanol was added. After 30 minutes, the solid which had formed was filtered, washed with ethanol and finally with ether to yield 850 mg of the 3-carboxamide compound, m.p. 194-196

OC.

Phosphorus oxychloride (1.06 g) was added to this amide in 7 mL of pyridine, and the mixture was stirred 1 hour at room temperature.

Dichloromethane was added, and the solution was washed with potassium bicarbonate solution, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with 2:1 hexane-ethyl acetate to give 790 mg of the 3carbonitrile compound.

To this nitrile in 5 mL toluene was added 385 mg of trimethyl tin chloride and 126 mg sodium azide. The mixture was heated 20 hours at 125 °C (bath temp). After cooling, methanol (5 mL was added, and the solution was concentrated in vacuo. To the resulting residue was added 6 mL of methanol and 6 mL of water containing 0.2 g phosphoric acid. After stirring 1 hour at room temperature, water was added and the mixture extracted with dichloromethane. The combined organic extracts were dried and concentrated, and the resulting residue was crystallized from ether to give a solid. The solid was dissolved in sodium hydroxide solution, filtered from insoluble material and acidified with acetic acid to get 532 mg of the title compound.

m.p. 165-167 1H NMR (CDC13, 300 MHz) 8 0.85 J=7Hz, 3H), 0.87 WO 99/06397 PCTIUS98115479 -132- J=7Hz, 3H), 1.10-1.50 (in, 8H), 3.0-3.6 (in, 8H), 3.70 3H), 3.7-3.8 (in, 1H), 3.90 J=9Hz, 1H), 4.37 J=9Hz, 1H), 5.86 2H), 6.62 (d, J=8Hz, 1 6.65-6.73 (in, 3H), 6.95 J=2Hz, 11-H), 7.11 J=9Hz, 2H).

Exampil 8 tran~s. trans-2-(4-Fluoroghenfl)l 4 14zdil5yf- N N-dilnbutvI~aminocrboflnmtVIDrroidine3carboxvlic acid IThe title compound was prepared as an amorphous solid from methyl (4-flourobenzoyl) acetate and 5-(2-nitroviflyl)- 1 ,3-benzodioxole using the procedures described in Examples 1 and A43. I H NMR (CDCI3, 300 MHz) 8 0.81 J=7Hz, 0.90 J=7Hz, 3H), 1.0-1.55 (in, 8H), 2.81 J=13 Hz, 2.90-3.10 (in, 4H), 3.15-3.30 (mn, 1H), 3.32-3.45 (in, 3H), 3.55-3.65 (in, 1H), 3.86 J=lOHz, 1H), 5.94 (dd, J=2Hz, 4Hz, 2H), 6.72 J=8 Hz, 1 6.86 J= 8 Hz, 1 6.95-7.07 (in, 3H), 7.32- 7.45 (mn, 2H).

Examlole 81 trans, trans-2-(4-Methoxyphenvl)- 4 -(l.3-benzd ioxol-5Yvl)i -(N.N-di(flbutyfl)am in ocarbonlm iethyl) pyrrolidine3-car mxlc acid N,N-Dibutyl glycine (150 mng, 0.813 inmol), prepared by the method of Bowman, J. Chein. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mng (0.852 inmol) carbonyidjiinidazole and heated for minutes at 50 0 C. After cooling to room temperature, 250 mng (0.678 mmol) of ethyl trntas2(-etoyhnl--13 bezdoo--i-yrliie -abxlae the compound resulting from Example 6A, was added, and the mixture was heated at 45 00 for minutes. The product was chromatographed on silica gel, eluting with 1:1 hexane-ethyl acetate to give 306 mg of the intermediate ethyl ester.

The ester was hydrolyzed with sodium hydroxide in water and ethanol to give 265 mng of the title compound as a white powder. 1

H

NMR (CDC13, 300 MHz) 5 rotational isomers 0.75 and 0.85 (2 t, J=7Hz, 3H), 1.05-1.5 (mn, 8H), 2.65-3.20 (mn, 6H) 3.43-3.70 (mn, 3.72 3H-), 3.87 J=l5Hz, 4.49 (dd, J=l2Hz, 6Hz) and 5.23 (dd, J=l2Hz, 8Hz) 2H, 5.90 (dd, J=2Hz, 4Hz, 6.63-6.78 6.86 and 7.04 (d, J=9Hz, 2H), 7.22 J=9Hz, 2H).

PCT/US98/15479 WO 99/06397 -133- Fxampi~n trans. trans.!2-(4-Methogyphenl~) 4 1.3-benzodioxol-5-Yf)l1-(N-n-butyl)-N-(fl progyflam inocarbonylmethyl) pvrrolidifle-3-ca rboxylic acid The title compound was prepared using the procedures described Sin Example 1. m.p. 160-162 H NMR (CDC13, 300 MHz) rotational 0 isomers 8 0.69, 0.80, 0.84, 0.87 (four triplets, J=7Hz, 6H), 1.00-1.52 (in, 2.63 and 2.66 (two doublets, J=l3Hz, 1H), 2.90-3.10 (in, 4H), 3.23- S3.61 (in, 5H), 3.71 and 3.75 (two doublets, J=lOHz, 1H), 3.78 3H), S5.92-5.96 (in, 2H), 6.72 J=8Hz, 1H), 6.83-6.89 (mn, 3H), 7.03 J=2Hz, 1H), 7.81 J=9Hz, 2H).

trans. trans- 4-etOnyhel) 4 -11 .3-benzodioXn---l- -l2( -in prooyvl)aininocarbonl~feth IDrr li ine -Arolin aid The compound resulting from Example 6A (250 ing, 0.677 inmol), 205 mng (1.36 mmol) diallyl acrylamide (Polysciences, Inc.), and 10 ing acetic acid were heated at 85 OC in 0.75 mL of methoxyethalol for one hour. Toluene was added, and the solution was washed with bicarbonate solution, dried, and concentrated. Chromatography on silica gel eluting with 3:1 hexane-ethYl acetate gave 283 mg of the diallyl compound.

The diallyl compound was hydrogenated using 10% Pd/C catalyst (27 mg) in ethyl acetate (25 mL) under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated to afford the dipropyl ainide ethyl ester in 100% yield.

The ester was hydrolyzed to the title compound by the method of Example 1iD in 83% yield. 1'H NMR (CDCI3, 300 MHz) 6 0.82 and 0.83 (two triplets, J=7Hz, 6H), 1.39-1.54 (mn, 4H), 2.35-2.60 (in, 3H), 2.80-3.07 (in, 3.14-3.21 (in, 2H), 3.31-3.38 (mn, 1H), 3.51-3.61 (in, 1H), 3.73 (d, J=12H, 1H), 3.75.(s, 3H), 5.94 2H), 6,71 J=9Hz, 1H), 6.79-6.85 (in, 3H), 7.04. J=2Hz, 1H)< 7.32 J=9Hz, 2H1).

WO 99/06397 PCTIUS98/15479 2 -134- Example 4 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)-l1-(N. N-di(nbutyfam inocarbonvi) pyrrolidine-3-carboxylic acid C) The -title compound was prepared by the procedures described in Example 8 using dibutyl carbamoyl chloride, prepared by the method of Hoshino et al., Syn. Comm., 17: 1887-1892 (1987), as a starting Nl material. 1 H NMR (CDCI3, 300 MHz) 5 0.86 J=7Hz, 6H), 1.14-1.28 (in, S4H), 1.35-1.48 (mn, 4H), 2.81-2.94 (in, 2H), 3.11 J=l2Hz, IN, 3.30ci 3.41 (mn, 2H), 3.59-3.68 (in, 2H), 3.76 3H), 3.78-3.85 (in, 1H), 5.81 (d, J=9Hz, 1H), 5.94 2H), 6.73-6.86 (in, 5H), 7.24 0d, J=9Hz, 2H).

trans. trans-2-(4-MethoXyphenyl)-4-( 1.3-benzodioxol-5-y'1- 1 N-di(nbutyvliaminocarbon vlmethy_/loyrrol idine-3-carboxylic acid sodium salt Sodium hydroxide (48.2 mg of 98.3% pure, 1.184 mmol) in 2 mL of MeOH was added to the compound resulting from Example 43 (610 mg, 1.196 mmol.) in 5 mL MeOH. The solution was concentrated to dryness, and the resulting powder was stirred with heptane. The heptane was removed in vacuo to give a powder which was dried in the vacuum oven for 2 hours at 60 00 to yield 627.5 mng of the title compound.

Examgle 86 trans. trans-2-(4-Methoxyhely)-4-( 1 .3-benzodioxol-5-yl)- 1 N-di(nbutyl)aming)ethyl]pyrrolidifle-3-carboxylic acid A solution of the bromoethyl compound resulting from Example 61A (150 mng), dibutylainine (150 mg) and sodium iodide (18 mg) in 0.75 mL ethanol was heated at 80 00C for 1 hour. After cooling, toluene was added, and the solution was washed with potassium bicarbona te solution, dried over Na 2 SO4 and concentrated. More toluene was added, and the solution was again concentrated to get rid,*of excess dibutylamine. The residue was dissolved in wam)i heptane and filtered from a small amount of insoluble material. The hepane was removed in vacuo to give 143 mng of the intermediate ethyl ester.

The ester was hydrolyzed by the method of Example 1D to give the title compound as a white powder. 1 H NMR (CD 3 OD, 300 MHz) 8 0.89 (t, J=7Hz, 6H), 1.16-1.30 (in, 4H), 1.44-1.56 (mn, 4H), 2.48-2.57 (mn, 1H), 2.80-3.08 (in, 8H), 3.14-3.25 (in, 1H), 3.31-3.38 (in, 1H), 3.59-3.60 (in, WO 99/06397 PCT/US98/15479 -135- 1 1H), 3.74 3H), 3.75 (do J=lOHz, 1H), 5.89 2H), 6.71 J=9Hz, 1H), 6.81 (dd, J=9Hz, 2Hz, 1H), 6.90 J=lOHz, 2H), 6.96 J=2Hz, 1H), 7.37 J='lOHz, 2H).

ExaMu21e-8 0trans. trans-2-(4-Methoxyohenyfl-4-(1I.3-ben odioxol-5-yl)-l1-f2-lN-(N.N-difnbUtyl)aminocarbonyl)-N-methylam inolethyloyrrolidile-3-carboxlic acid Dibutyl carbamoyl chloride (135 mg) was added to the compound Sresulting from Example 61B (250 mg) and 150 mg triethylamine in 1 mL dichlorom ethanle. After stirring 1 hour at room jemperature, toluene was added, and the solution was washed with potassium bicarbonate solution, dried over Na2SO4 and concentrated. The residue was chromatographed on silica gel, eluting with a mixture of 38% EtOAc and 62% hexane to give 194 mg of the ethyl ester intermediate.

The ester was hydrolyzed by the method of Example 1 D to afford 141 mg of the title compound. 1 H NMR (GD 3 OD, 300 MHz) 8 0.92 (to J=7Hz, 6H), 1.21-1.32 (in, 4H), 1.42-1.53 (in, 4H), 2.62 3H), 2.65-2.76 (mn, 1H), 3.00-3.20 (in, 8H), 3.44-3.55 (in, 1H), 3.62-3.78 (in, 2H), 3.80 3H), 4.07 J=12 Hz, 1H), 5.93 2H), 6.75 J=9Hz, 1H), 6.87 (dd, J=9Hz, 2Hz, 1H), 6.94 J=10 Hz, 2H), 7.04 J=2Hz, 1H), 7.40 (do J=1lOHz, 2H).

Example 88 trans. trans-2-(4MethoXyghenvyl'-4-( 1. 3-benzodioxol-5-yfl- 1 N-di(nbutyl~aminocarbonyliethylyrrolidine3(NmethanesulfonvI')carboxamide Carbonyldiimidazole (75 mg, 0.463 mmol) was added to 150 mg (0.294 minol) of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran, and the solution was stirred at 60 0 C for. 2 hours.

After cooling, 50 mng (0.526 inmol) of methanesulfonamide and 68 mg (0.447 inmol) of DBU in 0.3 mL of THF were added. The mixture was stirred at 45 0 C for 2 hours. The solvents were removed in vacuo, and the residue was dissolved in water. A few drops of acetic acid were added, and the solution was lyophilized to give 121 mng of the title compound. m.p. 170-173 0 C. 1 H INMR (CDC13, 300 MHz) 8 0.82 (t, J=7Hz, 3H), 0.88 J=7Hz, 1.05-1.51. (in, 8H), 2.75-2.86 (in, 2H), 2.83-3.25 (in, 4H), 3.17 3H), 3.32-3.50 (mn, 3H), 3.70-3.78 (in, 1H), 3.80 3H), 3.87 J=lOHz, 1H), 5.96 (dd, J=2Hz, 4Hz, 2H), 6.74 (d, PCT/US98/15479 WO 99/06397 -136- J=9Hz, 1H), 6.84 (dd, J=9Hz, 2Hz, 1H), 6.90 J=10 Hz, 2H), 7.01 (d, J=2Hz, 1H), 7.34 J=lOHz, 2H).

Exam3PJe2 tras trns2(4-MethoXyheflyl) 44 .3-benzodioxol-5-yfl-l1-(N.N-din- 0 t~~utyflami n ocrboflyimethyl)1Dyrrolid ie3(N ben zen esu If onyfl arboxaml ide The compound resulting from Example 43 was converted to the Stitle compound by the method of Example 88 substituting Sbenzenesulfoflatfide for methanesulfoflamide. m.p. 169-171 0 C for a sample recrystallized from acetonitrile. 1 H NMR (CDCI3, 300 MHz) 8 0.81(t, J=7 Hz, 3H), 0.89 J=7Hz, 3H), 1.02-1.50 (in, 8H), 2.65-2.80 (in, 2H), 2.90-3.25 (in, 4H), 3.80-3.95 (in, 3H), 3.50-3.60 (in, 1H), 3.65 (d, J=lOHz, 1H), 3.81 3H), 5.94 2H), 6.70 2H), 6.81-6.90 (in, 3H), 7.17 J=lOHz, 2H), 7.55 J=7 Hz, 2H), 7.66 J=7Hz, 8.95 (d, J=7Hz, 2H).

Example trans. trans-2-(4-MethoXylhenlvl- 4 .3-enzodioxol-5-VO)- 1 -4N. N-di(n--buty_'j amnsulfonylm ethyl]-Dyrrolid in e-3-carboxVi c acid Chloromethyl sulfenyl chloride, prepared by the method of Brintzinger et. al., Chem. Ber. 455-457 (1952), is reacted with dibutylamine by the method of E. Vilsmaier described in Liebigs Ann.

Chem. 1055-1063 (1980) to give N,N-dibutyl chloromethyl sulfenyl chloride. Alternatively dimethyl(methylhio)sultOnium tetraf lou robO rate is reacted with dibutylainine to give N,N-dibutyl methylsulfenyl chloride which is chlorinated with N-chlorosucciIniiide to give chioromethyl sulfenyl chloride by the method of E. Vilsmaier, described in the above reference.

The N,N-dibutyl chloromethyl sulfenyl chloride is reacted with the compound resulting from Example 6A to give ethyl trans, trans-2-( 4 Methoxyphenyl)- 4 buy~mnsl nl ty]-proiine3c b yae This is oxidized with osmium tetroxide and N-methyl morpholine N-oxide by the method of S. Kaldor and M. Hammond, Tet. Lett. 32: 5043-5045 (1991) to give the title compound after hydrolysis of the ethyl ester.

WO 99/06397 PCTIUS98/15479 -137- Examglg 9 trans, trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yfl- 1 -r(N .N-di (nbutylaminocarbonyl-1 .(RS-ethyIlpyrrolidine-3-carboxylic acid Example 91A (±)-Dibutyl 2-bromopropanamide 2-Bromopropanoic acid (510 mg, 3.33 mmol) and 4-methylmorpholine (0.74 SmL, 6.73 mmol) were dissolved in 10 mL of CH 2 01 2 the solution was cooled to 0 0

C

N1 under a N 2 atmosphere, and then treated dropwise with isobutyl chioroformate (0.45 mL, 3.5 mmol). After 10 minutes at 0 00, dibutylamnjne (0.57 mL, 3.4 mmol) was added. The reaction was stirred at 0 00 for 1 hour and for an additional 16 hours at room temperature. The mixture was partitioned with 25 mL of 1.0 M aqueous Na 2 CO3 solution, then the organic phase was washed sequentially with mL of 1 M aqueous NaHSO4 and 25 mL brine, dried (Na 2 SO4), filtered, and concentrated under reduced pressure to afford 698 mg (2.64 mmol, 79 of the crude bromoamide as a colorless oil. H NMR (CDCI 3 300 MHz) 8 0.93 J=7Hz) and 0.97 J=7.5Hz, 6H total), 1.26-1.60 (in, 7H), 1.60-1.78 (mn, 1 1.82 J=6Hz, 3H), 3.04-3.27 (mn, 2H), 3.42-3.64 (in, 2H), 4.54 J=7H, 1 MS (DCI/NH3) Wne 264 and 266 Example- 91B trans. trans.- and is. trans-2-(4-Methoxylheflyfl-4-(I 1 3-benzodioxol-5-yl)- 1 .Ndi(n-butyl)am ino~carbonyl-l1-( RS)-ethyl)D2yrrolidine-3-carboxylic acid ethyl ester A solution of the resultant mixture of transtrans and cis,trans compounds from Example 10 (232 mg, 0.628 mmol) and the resultant compound from Example 91 A (183 mg, 0.693 mmol) in 2 mL of CH 3 CN was treated with diisopropylethylainine (0.22 inL, 1.3 iniol). The solution was stirred at 60-80 00 under a N 2 atmosphere for 16 hours. The reaction was concentrated under reduced pressure, then the residue was partitioned between 30 mL Et 2 O and 10 mL of 1 M aqueous Na2003 solution. The organic phase was washed with 20 mL water and 20 mL brine, dried over Na 2 SO4, filtered and concentrated under reduced pressure to afford the crude amino amide as a brown oil (339 ing, 98% crude). The product was obtained by flash chromatography on silica gel eluting with EtOAc-hexane to provide 224 mng of the title compounds as a mixture of 4 diastereoiners. IH NMR (CDCI 3 300 MHz) 850.66-1.55 (several in, 19H), 2.63- 3.00 (in, 3H), 3.05-3.39 (mn, 2H), 3.40-3.76 (in, 4H), 3.78-3.20 (4 s, 3H), 3.84-4.25 WO 99/06397 PCT/US98/15479 2 -138- (n,2.6H1), 4.38 J=1 0.51-z, 0.2H) and 4.58 J=1 0.5Hz, 0.211), 5.90-5.97 (in, 2H), 6.68-6.96 (in, 5H), 7.38-7.43 (in, 2H). MS (DCI/NH3) mle 553 Example 91C trans. trans-2-(4-Methoxyhenyfl-4-( 1.3-benzodioxol-5-yi-1

N-

dibutylam ino)carbonyl-1 .(RS)-ethyl)pyrrolidine-3-carboxylic acid The procedure of Example 73C was used, substituting the resultant 0 compound from Example 91 B for the resultant compound from Example 73B to give N- the title compound in 61% yield. I H NMR (CD 3 OD, 300 MHz) 8 0.70-1.05 (several m, 8H1), 1.14 J=6Hz, 2H1), 1.17-1.55 (mn, 611), 2.79-3.03Jin, 3.5H), 3.20-3.65 (br m, 4.6H- plus CID 2 HO10D), 3.70-3.78 (mn, 0.4H), 3.79 3.98 J=8Hz, 0.6H), 4.06 J=7.5Hz, 0.4H), 4.25 J=8Hz, 0.4H). 5.92 and 5.94 2H total 6H), 6.73 (d, and 6.75 J=3Hz, 1 H total), 6.78-6.85 (mn, 1 6.91 -7.00 (in, 3H), 7.30- 7.38 (mn, 2H1). MS (DCI/NH3) m/e 525 Anal calcd for C 3 0H 4 oN 2 06-0.5H20: 0, 67.52; H, 7.74; N, 5.25. Found: C, 67.63; H, 7.65; N, 5.21.

trans. trans-2-(Pentyfl-4-( 1.3-benzodioxol-5-yl)-l1-(N. N-di~nbutyflaminocarbonylnethyl)gyrrolidine-3-carboxvlic acid Example 92A Methyl 2-(4-hexenoyl)-4-n itro-3-( 1.3-benzodioxole-5-yl')butyrate A solution of methyl 3-oxo-6-octenoate (502 ing, 2.95 inmol) in 10 mL of isopropanol was added to a solution of 5.(2-nitrovinyl).1,3-benzodioxole (712 ing, 3.69 iniol) in 10 mnL THF, then DBU (22 gl-, 0. 15 iniol) was added. The resulting reddish solution was stirred at room temperature for 20 minutes. TLC (ethyl acetate-hexane, 1:3) indicated complete consumption of ke toester. The solution was concentrated in vacuo and flash chromatographed on silica gel eluting with 18% ethyl acetate in hexane to produce 879 mng (2.42 mmol, 82%) of the title compound as a mixture of diastereoiners in a 1:1 ratio. 1 H NMVR (CDCI3, 300 MHz) 8 1.55-1.66 (in, 2.02-2.17 (br mn, 1 2.20-2.37 (in, 1.5H1), 2.49-2.76 (in, 3.57 3.74 3.97 J=7.5H, 0.5H-) and 4.05 J =8H-z, 0.511), 4.10-4.20 (mn, 1 4.68-4.82 (in, 5.06-5.52 (in, 5.95 (2s, 2H), 6.65 (in, 1 H), 6.68 (br s, 1 6.75 7.51-z. I1H). MS (DCI/NH 3 Wne 381 (M+NH4) 4 Anal calcd for 0 1 8H 21 N07: C, 59.50; H, 5.82; N, 3.85. Found: 0, 59.32; H, 5.71; N, 3.72.

I

L

WO 99/06397 PCT/US98/15479 *-139- Example 92B Methyl trans. trans-2-(entvl)- 4 -(1.3.benzodioxol-5-vlYDvrrolidine-3-carboxvl ate The procedures of Example 1B and Example 1C were followed, with the Q substitution of the resultant compound from Example 92A for the resultant compound from Example 1A, and the substitution of the this resultant compound for O the resultant compound from Example 1 B, to provide the title compound in crude n form as a yellow oil. This crude compound was epimerized under the following conditions. A solution of the crude compound (660 mg, 2.07 mmol) in 3 mL C I methanol was treated with a solution of sodium methoxide (made by the addition of sodium metal (14 mg, 0.61 mmol) to 1 mL of methanol). The resultant solution was heated at reflux for 18 hours. The reaction was concentrated under reduced pressure, and the residue was partitioned between 25 mL saturated NaHCO3 diluted with 10 mL water and 30 mL of CH 2 CI2. The aqueous phase was extracted (2 x 30 mL CH 2 CI2), then the combined organic phases were washed with 20 mL brine, dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford the crude product. Purification by flash chromatography on silica gel eluting with 3.5% methanol in CH2CI2 gave 336 mg the title compound as a yellow oil. 1H NMR (CDCI3, 300 MHz) 5 0.90 (br t, 3H), 1.25-1.70 (br m, 8H), 1.83-2.02 (br s, 2H), 2.58 (dd, J=8,9Hz, 1H), 2.99 (dd, J=8,14Hz, 1H), 3.34-3.45 (m, 2H), 3.53 J=9Hz, 1H), 3.66 3H), 5.94 2H), 6.65-6.75 3H). MS (DCI/NH 3 mle 320 Anal calcd for C 18

H

25 N04: C, 67.69; H, 7.89; N, 4.39.

Found: C, 67.39; H, 7.84; N, 4.37.

Example 92C trans. trans-2-(Pentyl)- 4 (1.3-benzodioxol-5-vl-1 -(N.N-di(nbutvlyaminocarbonylmethyl)Dyrrolidine-3-carboylic acid The procedures of Example 1B-1D were used, with the substitution of the resultant compound from Example 92A for the resultant compound from Example 1B, to provide the title compound as a white foam. 1 H NMR (CDCI3, 300 MHz) 3o 0.87 (br t) and 0.89 (br t, 6H total), 0.97 J=7.5Hz, 3H), 1.21-1.42 (br m, 10), 1.43- 1.78 (br m, 6H), 2.76 J=7Hz, 1H), 3.02-3.30 (br m, 6H), 3.40-3.60 3H), 3.73 (d, J=14Hz, 1H), 5.98 (AB, 2H), 6.70 J=7Hz, 1H), 6.77 (dd, J=1.5,7Hz, 1H), 6.89 (d, 1H). MS (DCI/NH3) m/e 475 (M+H) Anal calcd for C 27

H

42

N

2 05-0.5H20: C, 67.05; H, 8.96; N, 5.79. Found: C, 67.30; H, 8.77; N, 5.68.

WO 99/06397 PCTIUS98/15479 -140trans, trans-2-(Pentyl)-4-( 1. 3-benzodioxol-5-yl)- 1 4l2-(N-Progyl-Npropylsufonylaminoethylliyrrolidile-3-carboxylic acid Examl~l 9A 0 Methyl trans, trans-2-(pentyl)-4-( 1.3-benzodioxol-5-yfl- 1 (-brom pethYI)oYrrolidine-.

3-carboxylate The procedure of Example 61 A was used, with the substitution of the CIresultant compound from Example 92B for the resultant compound from Example 1C, to provide the title compound as a yellow oil. 1 H NMR (C0013, 300 MHz)860.89 (br t, J=7Hz, 3H), 1.24-1.40 (br m, 6H), 1.60-1.80 (br m, 2H), 2.61-2.75 (in, 2H), 2.76- 2.91 (in, 2H), 3.1 0-3.22 (in, 2H), 3.36-3.47 (in, 2H), 3.68 3H), 5.92 2H), 6.69- 6.77 (mn, 2H), 6.90-6.94 (mn, 1H). MIS (DCI/NH 3 Wne 426, 428 Example 93B Methyl trans. trans-2-(Pentyl-4-( 1.3-benzodioxol-5-yl)- 1 -l 2-(N-oropyl-Ngrpylsulfonylamino'~ethyl1yrrolidine-3carboxylate A solution of the resultant compound from Example 93A (102 mg, 0.24 mmol) and tetrabutylainionium iodide (6 mng, 16 .imol) in 1 mL EtOH was treated with propylamine (60 0.73 minol). The solution was warmed to 80 00 for 4 hours.

The reaction was concentrated under reduced pressure, then the residue was dissolved in 35 mL ethyl acetate and extracted with 2 x 15 mL of 1 M aqueous Na 2 CO3. The organic phase was washed with 15 mL brine, then dried over Na 2 SO4, filtered and concentrated under reduced pressure to provide the crude secondary amine as a yellow oil (94.2 ing). The crude amine was dissolved in 1 mL of CH 2

CI

2 diiosopropylethylainine (65 0.373 minol) was added, followed by propylsulfonyl chloride (29 V.L, 0.26 minol). The solution was stirred at room temperature for 4 hours. The reaction was quenched with 10% aqueous citric acid (to pH and the mixture was extracted with 2 x 3 mL CH 2 CI2. The combined organic extracts were washed with 2 mL brine, then dried over Na2SO4, filtered, concentrated in vacuo. Purification by flash chromatography eluting with 20% ethyl acetate in hexane provided 65.0 mg of the title compound as a waxy solid. Rf 0.17 (20%EtOAc-hexane). MS (001/NH 3 m/e 511 WO 99/06397 PCT/US98115479 -141- Exampl 93 trans. trans-2-(PentylI-4-( 1.3-benzodioxol-5-yl)-lI-f2-(N-proo~yl-Nprpysulfonylpmino)ethyllgyrrolidine3carboxylic acid The procedure of Example 71C was followed, with the substitution of the resultant compound from Example 93B for the resultant compound from Example S7113, to provide the title compound as a white foam (47 mg, Rf 0.14 S(5%MeOH-CH2CI2). I H NMR (CDCI3, 300 MHz) 8 0.88 (br t) and 0.92 J=7Hz, 6H Stotal), 1.22-1.52 (br mn, 6H), 1.63 (sextet, J=8Hz, 2H), 1.75-2.10 (br m, 4H), 2.89-2.98 ci(in, 2H), 3.05 (br t, J=9Hz, 1 3.10-3.30 (in, 3H), 3.30-3.80 (br m, 7H), 5.94 2H), 6.71 J=BHz, 1H), 6.77 (dd, J=1.5,BHz, 1H), 6.89 J=1.5Hz, 1H). MS (DCI/NH3) W/e 497 E~ml trans, trans-2ropyl)- 4 .3-benzodiogol-5-yfl- 1 .N-di(nbtutyl)amlinocarbonylmfethylPrrolidine3carboxULic acid ExamI21e 94A Ethyl 2-(4butanoyl)-4-n itro-3-( 1. The procedure of Example 92A was followed, with the substitution of ethyl butyryl acetate for methyl 3.oxo-6-octenoate, to provide the title compound as a mixture of trans and cis isomers (47 mng, Rf 0.28 (25%EtOAc-hexafle). I H NMR (CDCI3, 300 MHz) 8 0.74 J=7.5Hz) and 0.91 J=7.5Hz, 3H total), 1.08 (t, J=7Hz) and 1.28 J=7Hz, 3H- total), 1.45 (sextet, J=7Hz, 1 1.63 (sextet, J=7Hz, approx. 1.5H), 2.17 J=7Hz) and 2.24 J=7Hz, 0.5H total)2.40-2.5 4 (in, 1iH), 2.60 J=7.5Hz) and 2.67 J=7.5Hz, 0.5H total), 3.93-4.09 (in, 2H), 4.10-4.20 (br mn, 1H), 4.23 J=7Hz, 1H), 4.67-4.85 9mn, 2H), 5.94 2H), 6.62-6.75 (mn, 3H). MVS (DCI/NH3) Wne 369 Anal calcd for C 17

H

21 N07: 0, 58.11; H, 6.02; N, 3.99. Found: C, 58.21; H, 5.98; N, 3.81.

4 Ethyl trans. transw2 -or 1 l- 4 1.3-benzodo;--YflDvroidne--crbxyat The procedure of Example 92B was followed, with the substitution of the resultant compound from Example 94A for the resultant compound from Example 92A, to afford the title compound. MS (DCI/NH3) inie 306 WO 99/06397 PCTIUS98/15479 -142- Example 4C trans. trans-2- (Propyfl)-4- 1.3- ben zodioxol- 5-yl)- 1 N-di(nb utylam inocarbonylm ethyfl)-gyrrolidine-3-ca rboxylic acid The procedure of Example 920 was followed, with the substitution of the resultant product from Example 94B for the resultant product from Example 92B3, to 0 give the title compound. 1 HNMR (00013, 300 MHz) 8 0.89 J=7.5Hz), 0.92 (t, and 0.97 J=7.5H, 9H total), 1.22-1.80 (br m, 12 2.83 J=7.5Hz, 1 H), 3.40-3.55 (br m, 2H), 3.55-3.68 (in, 1 3.78 J=l 5Hz, 1 5.92 J=1 Hz, 2H), Cl6.70 J=8Hz, 1 6.79 (dd, J= 1 Hz,8Hz, 1 6.90 J= 1 Hz, MS (001/NH 3 m/e 447 Anal calcd for C 25

H

38

N

2 050.5 H 2 0: C, 65.91; H, 8.63; N, 6.15.

Found: C, 65.91; H, 8.68; N, 5.94.

(2 R3R.4S)(+I-2-(4-Methoyphenl)f-4-( 1.3-benzodioxol-5-ylD-l1-(tertbutyloxycarbonyl-am inocarbofllm ethyl) -pyrrolidife- 3 -ca rboxylic acid Exam ole trans. trns-2-(4-Methoxy=heflyl)- 4 -3-benzodioxol-5-yl)- 1 -(ftertbutyloxycarbonylaminocarboflylrfethYlloYrrolidife 3 carboxYlig acid The resulting mixture of 64% trans,trans- and cis,transpyrrolidines resulting from Example 10 (3.01 g, 8.15 inmol) was dissolved in 50 mL of methylene chloride. To this was added dropwise a solution of di-tert-butyl dicarbonate (1.96 g, 8.97 mmol) in 20 mL methylene chloride under a nitrogen atmosphere, and the resulting solution was stirred 30 minutes at which point TLC (ethyl acetate:hexane, 1:1) indicated that all of the starting material was consumed. The reaction mixture was concentrated and dried under high vacuum to give 3.94 g of the ethyl ester as a yellow-brown oil. 1 H NMR (CDC L 3 300 MHz) 8 0.99, 1.07 (br t, br t, J=7 Hz, 3H), 1. 11-1.62 (several br m, 9H), 3.05 (br mn, 1 3,44-3.95 (in, 3H), 3.81 3H), 4.04 J=7 Hz, 1 4.14-4.28 (br m, I1H), 4.89-5.24 (br mn, 1 5.94 J=3 Hz, 2H), 6.69-6.90 (in, 5H), 7.06-7.20 (in, 2H). MS (DCI/NH3) in/e 470 To the ethyl ester dissolved in 170 mL of ethanol was added a solution of lithium hydroxide (1.06 g, 25.17 mmol) in 60 mL of water.

The reaction mixture was vigorously stirred for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated to remove ethanol, diluted with 250 mL of water and extracted three times with

I

WO 99/06397 PCT/US98/15479 -143- S250 mL of ether. The organic phase acidified to slight cloudiness (pH with 1 h hydrochloric acid, then to pH 4 with 10 citric acid and extracted with 5 ethanol in methylene chloride (3 x 100 mL). The combined organic layers dried (Na2SO4), filtered, concentrated and dried Son high vacuum to give the title compound as a white foam (2.19 g, 1 H NMR (CDCI3, 300 MHz) 5 1.16 (v br s, 9H), 3.11 (br m, 1H), 3.50- 3.64 2H), 3.81 3H), 4.24 (br m, 1H), 4.96 (br m, 1H), 5.94 2H), 6.71-6.79 3H), 6.84-6.91 2H), 7.19 J=9 Hz, 2H). MS (DCI/NH 3 m/e 442 ExamQle 955 (2R.3R.4S)-+)-2-(4-MethoxvDhenvl)-4-1 .3-benzodioxol-5-vl)-1 -(tertbutvloxvcarbonvlaminocarbonylmethyl)-ovrrolidine-3-carboxvlic acid The compound resulting from Example 95A (2.15 g, 4.86 mmol) and (+)-cinchonine (1.43 g, 4.86 mmol) were added to 100 mL of methylene chloride; this suspension was swirled with warming as necessary to get all solids to dissolve. The solution was then concentrated and dried on high vacuum to a white foam. This material was crystallized from a mixture of refluxing chloroform (64 mL) and hexane (360 mL). The resulting crystals were isolated by filtration and recrystallized under the same conditions seven additional times. Each time the resulting crystals and filtrate were monitored by 1H NMR and chiral HPLC. The amount of enantiomer decreased first in the crystals and then in the filtrate with the predetermined endpoint achieved when the enantiomer could no longer be detected in the filtrate. The pure enantiomer thus obtained was partitioned between 100 mL of 10% citric acid and 100 mL of ether.

The aqueous layer was further extracted twice with 100 mL of ether.

The combined ether layers were washed with brine, dried (Na 2 SO4), filtered, concentrated and dried on high vacuum to a white powder (550 mg, 55 of theoretical 50 maximum, >99.5 ee). 1H NMR (CDC13, 300 MHz) 6 1.05-1.50 (br m, 9H), 3.12 (br m, 1H), 3.50-3.65 2H), 3.81 (s, 3H), 4.24 1H), 4.96 (br m, 1H), 5.95 2H), 6.70-6.79 3H), 6.86 J=9 Hz, 2H), 7.19.(d, J=9 Hz, 2H). MS (DCI/NH 3 m/e 442 WO 99/06397 PCT/US98/15479 -144- Example 950 (2R.3R.4S)-(+)-Ethyl 2-(4-methoxyo~henyfl-4-(1 .3-benzodioxol-5-yl)-Pyrrolidine-3- The compound resulting from Example 95B (251 mg, 0.568 mmol) was dissolved in 20 mL of a saturated solution of anhydrous HCI(g) in Sanhydrous ethanol. The resulting solution was heated at 50 00. with v-r stirring for 18 hours at which point all of the precipitated solid had Sdissolved. The reaction mixture was concentrated to a solid which was Spartitioned between 0.8 M aqueous sodium carbonate (50 ml-) and methylene chloride (50 mL). The aqueous layer yvas further extracted with methylene chloride (2 x 50 mL). The combined organic layers were dried (Na 2 SO4), filtered, concentrated and dried under high vacuum to give the title compound as an almost colorless oil (158 mg, 1H NMR (CDC1 3 300MHz) 5 1.11 J=7 Hz, 3H), 2.18 (v br s, 1 2.93 J= 1s 9 Hz, 1H), 3.19,3.22 (dd, J=7 Hz, 1H), 3.50-3.69 (in, 3.80 3H-), 4.07 J=7 Hz, 4.49 J=9 Hz, 1 5.94 6.73 J=2 Hz, 2H), 6.81-6.92 (in, 3H), 7.34-7.41 (in, MS (DCI/NH3) m/e 370 L21.BflASL- -2-(4-Methoaohenyfl-4-( 1.3-benzodioxol-5-yl1-(tertbutyloxvcarbonyl-aminocarboflYlmethyl)-12yrrolidife3carboXylic acid To the resulting compound from Example 950 (131 mg, 0.355 iniol) was added, diisopropylethylainine (137 mng, 185 1.06 inmol), acetonitrile (2 inL), N,N-di-(n-butyl)broinoacetainide (133 mg, 0.531 minol), and the mixture was heated at 50 OC. for 1.5 hours. The reaction mixture was concentrated to a solid, dried under high vacuum, and purified by chromatography on silica gel eluting with 1:3 ethyl acetatehexane to give pure ester as a colorless oil. 1H NMR (ODC1 3 300MHz) 8 0.81 J=7 Hz, 3H), 0.88 J=7 Hz, 3H), 1.10 J=7 Hz, 3H), 1.00-1.52 (in, 8H), 2.78 J=14 Hz, 1H), 2.89-3.10 (in, 4H), 3.23-3.61 (in, 3.71 J=9 Hz, 3.80 3H), 4.04 J=7 Hz, 2H), 5.94 (dd, J=1.5 Hz, 2H), 6.74 J=9 Hz, 1 6.83-6.90 (in, 3H), 7.03 J=2 Hz. I1H), 7.30 J=9 Hz, MS (DCl/NH 3 mWe 539 To the ethyl ester dissolved in 7 mL of ethanol was added a solution of lithium hydroxide (45 mg, 1.06 mmol) in water (2.5 mL). The mixture was stirred for 1 hour at ambient temperature and then warmed

I

WO 99/06397 PCT/US98/15479 -145r- slowly to 40 over 2.5 hours at which point all of the starting material had been consumed. The reaction mixture was concentrated to remove the ethanol, diluted with 60 mL water and extracted with ether (3 x 40 mL). The aqueous solution was treated with 1 N aqueous hydrochloric acid until cloudy, and the pH was then adjusted to 0 with 10% aqueous citric acid. This mixture was extracted with 1:19 ethanol-methylene chloride (3 x 50 mL). The combined extracts were dried (Na 2 SO4), filtered, concentrated and dried under high vacuum to Sgive the title compound as a white foam (150 mg, 1 H NMR (CDCI 3 300MHz) 8 0.80 J=7 Hz, 3H), 0.88 J=7 Hz, 3H), 1.08 2H), 1.28 3H), 1.44 3H), 2.70-3.77 (svr br m, 12H), 3.79 3H), 5.95 (m, 2H), 6.75 J=8 Hz, 1H), 6.87 (br d, J=8 Hz, 3H), 7.05 br s, 1H), 7.33 (v br s, 2H). MS (DCI/NH3) m/e 511 [a] 22 +74.420. Anal calcd for C 29

H

38 N206 -0.5 H 2 0: C ,67.03; H, 7.56; N, 5.39. Found: C, 67.03; H, 7.59; N, 5.33.

Example Alternate Preparation of (2R.3R.4S)-(+)-2-(4-Methoxyphenyl)-4-(1 yl)1-.(tert-butyloxycarbonylaminocarbonylmethvl)-Drrolidine-3carboylic acid The product of Example 95A (2.858 g) was suspended in 10 mL of EtOAc. 0.7833 g of R alpha methyl benzylamine in 3 mL ethyl acetate was added. On swirling all of the solids were dissolved. The ethyl acetate was removed in vacuum. Ether (13 ml) was added to the residue. When all of the residue had dissolved, 5 mg of seed crystals were added and these crystals were crushed with a metal spatula while cooling in ice. The product crystallized very slowly. After 1 hour the solid was filtered and washed with ether giving 1.4213 g, m.p. 163- 1670. The filtrate was concentrated, cooled and scratched with a spatula to give a second crop 0.1313 g, m.p. 164-1680. The filtrate was concentrated again and put in the refrigerator and let stand overnight giving 1.6906 g, m.p. 102-110°. (HPLC of this showed the desired enantiomer and 80% of the unwanted enantiomer.) The first two batches of crystallized material were combined and suspended in 20 mL dichloromethane (Note: the unwanted isomer is more soluble in dichloromethane) and stirred for 2 minutes. The mixture was concentrated, but not to dryness, and ether (10 mL) was added. After WO 99/06397 PCTIUS98/15479 -146stirring for a few minutes the crystals were filtered. Yield: 1.401 g, m.p. 164-1720.

0Treatment of the crystalline product with 10% citric acid and ether according the method described in Example 95B provided the title compound.

trans. trans-2-(4-Methovhnyl)k4-( 1.3-benzodioxol-5-yfl- 1 -r2-(N-orooyl-Nbutvyyamino~ethyllpyrrolidine-3-carboXylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and butyryl chloride for isobutyryl chloride in Example 61C. The product was purified by preparative HPLC (Vydac gCl8) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were Iyophilized to give the product as a white solid. 1H NMR (CDCI 3 300 MHz) 8 0.80 (in, 3H), 0.90 3H-, J=8H-z), 1.42 (in, 2H), 1.58 (heptet, 2H, J=8Hz), 2.20 3H, J=8Hz), 2.94 (br m, 2H), 3.10 (br m, 2H), 3.48 (br m, 4H1), 3.76 (br m, 2H), 3.78 3H), 4.30 (br s, 1H), 5.95 2H), 6.75 (d, 1H-, J=8Hz), 6.84 (in, 1H), 6.85 2H, J=8H-z), 7.04'(d, 1H, J=1 Hz), 7.40 2H, J=8Hz). MS (DCI/NH3) m/e 497 Anal calcd for

C

2 sH 36

N

2 06 -1.0 TFA: C, 58.82; H, 6.42; N, 4.57. Found: C, 58.77; H, 6.30; N, 4.42.

ExamDile 97 trans. trans-2-(4-Methoxvheflyl)- 4 1.3-benzodioxol-5-yl)- 1 -r2-(N-Projyl-N- (ethyl am inocarbon yl)am ino) eth yllpDrrolid in e-3-ga oxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61B and ethyl isocyanate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether-hexane.

The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDC1 3 300 MHz) mixture of rotamers 8 0.80 J=8Hz) and 1.05 J=8Hz) and 1.20 (in) and 1.42 (in) total of 8H for the four peaks, 2.35 (br s, 111), 2.70 (in, 1H), 3.0 (mn, 31-), 3.2 (in, 3.25 (dq, 11H, J=1,8Hz), 3.42 (mn, 3.6 (in, 111), 3.75 (in, 111), 3.78 3H), 4.8 (br s, 5.95 2H1), 6.74 1H, J=8H-z), 6.85 (mn, 3H), 7.00 7.30 2H, J=8Hz). MIS (DCI/NH3) m/e 498 WO 99/06397 PCTIUS98/15479 -147- Anal calcd for C 27 H35N306 -0.75 H 2 0: C, 63.45; H, 7.20; N, 8.22. Found: C, 63.38; H, 7.29; N, 8.44.

trans. trans-2-(4-Methoxylhel)f- 4 .3-benzodioxol-5-yl)-1 1 2-(N-butyl-Nbutyrylamino~IethylUPyrrolidifle-3-carbox~ylic ai The title compound was prepared by the methods described in SExample 61, but substituting butylamine for methylamine in Example 61B and butyryl chloride for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1.:1 diethyl ether-hexane.

The resulting solid was dissolved in CH 3 CN and water and Iyophilized to give the product as a white solid. 1 H NMR (CDCI 3 300 MHz) 8 0.80 (in, 3H), 0.90 3H, J=8Hz), 1.45 (in, 4H), 1.6 (in, 2H), 2.20 3H, J=BHz), 2.94 (br m, 2H), 3.10 (br m, 3.5 (br m, 4H), 3.80 (br m, 2H), 3.82 (s, 3H), 4.30 (br s, 1 5.95 2H), 6.75 1 H, J=8Hz), 6.84 (in, 1 6.85 2H, J=8Hz), 7.04 1H, J=lHz), 7.40 2H, J=8Hz). MS (DCI/NH3) mWe 511 HRMS calcd for C 29

H

38 N206: 511.2808. Found: 511.2809 Example-99 trans. trans-2- (4-MethoKYvh flyI) 4 .3-benzodioxol-5-yU)- 1 .f-(Dr lethomycarboflylamnino')etIl rr li ifle-2Cabo-xYiqacid The title compound was prepared by the methods described in Example 61, but substituting propylainine for methylamine in Example 61B and ethyl chloroformate for isobutyryl chloride in Example 61C.

The crude product was purified by trituration with 1:1 diethyl etherhexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1H NMR (CDC13, 300 MHz) 8 0.80 3H, J=8Hz), 1.05 (in, 2H), 1.22 (in, 3H), 1.45 (mn, 3H), 2.08 (br s, 1 2.75 (mn, 1 2.88 (br q, 2H, J=8Hz), 3.08 (br mn, 2H), 3.27 (br mn, 2H), 3.44 (in, 1H), 3.54 (dt, 1H, J=1,8Hz), 3.63 1H, J=8Hz), 3.78 (s, 3H1), 4.02 (br d, 2H), 5.93 2H), 6.72 1KH, J=BHz), 6.81 (dd, I1H, J=1,8Hz), 6.85 2H, J=8Hz), 7.00 1K), 7.30 2H, J=8Hz).

MS

(DCI/NH

3 m/e 499 (M+H) 4 Anal calcd for C 27

H

34 N207 0.5 H 2 0: C, 63.89; H, 6.95; N, 5.52. Found: C, 84.03; H, 6.71; N, 5.30.

WO 99/06397 PCT/US98/15479 -'148- Example trans. trans-2-(4-Mathoxyphenyfl-4-( 1.3-benzodioxol-5-yfl- 1 -r2-(N -m ethyl- N-2ethylbutrlamino)ethyllyrrolidile-3-carbXylic acid To -the compound resulting from Example 61B (190 mg) dissolved in THF (2 mL) was added HOBt (60 mg), EDCI (85 mg), N- C) methylmorpholifle (50 tFL), and DMF (2 mL). 2-Ethylbutyric acid was Sadded and the solution stirred overnight at ambient temperature. Water S (10 mL) was added, and the mixture was extracted with EtOAc (2 x CI mL). The combined organic extracts were washed with saturated sodium bicarbonate solution, 1 h~i H 3 P04, and brine, dried with Na2SO4, and evaporated to give an oil which was purified by flash chromatography on silica gel eluting with 1:3 EtOAc-hexane. The resulting ethyl ester was saponified by the procedure described in Example 61C. The crude product was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) (mixture of rotamers) 8 0.66, 0.74, 0.80, 0.88 (all triplets, total of 6H, J=8Hz), 1.05 (in, 2H), 1.25-1.75 (in, 5H), 2.16 (in, 1H), 2.32 (in, 1H), 2.45 (mn, 1 2.70 (in, 1 2.86, 2.94 total 3H), 2.95 (in, 1 3.35 (mn, 1 3.52 (mn, 2H), 3.65 (in, 1 3.80 3H), 5.94, 5.96 total 2H), 6.73 (in, 1H), 6.84 (in, 3H), 6.97 (in, 1H), 7.30 (in, 2H). MS (DCI/NH3) m/e 497 Anal calcd for C 28

H

3 6N206 -0.25 H20: C, 67.11; H, 7.34; N, 5.59. Found: C, 67.13; H, 7.24; N, 5.56.

Examgle 101 trons. trans-2-(4-Methpovhenyfl-4 4 1. 3-benzodioxol-5-yi .2-(N-methyI-N-(2prolylvaleryl)amino'~ethyl1Dvyrrolidine3carboxylic acid The title compound was prepared by the procedure described in Example 100, but substituting 2-propylpentanoic acid for 2ethylbutyric acid. The crude product was purified by preparative HPLC (Vydac jiCiB) eluting with a 10-70% gradient of CH 3 CN in 0.1% TEA. The desired fractions were Iyophilized to give the product as a white solid.

1 H NMR (CDC13, 300 MHz) 8 0.79 3H, J=8Hz), 0.82 3H, J=8Hz), 1.10 (in, 4H), 1.2-1.5 (in, 4H), 2.55 (in, 1 2.96 3H), 3.15 (br in, I1H), 3.32 (br mn, 1H), 3.56 (in, 2H), 3.68 (in, 1H) 3.68 3H), 3.70 (in, 1H), 3.80 (in, 2H), 4.65 (br d, 1 5.92 2H), 6.75 1 H, J=8Hz), 6.84 (in, 1 6.85 2H, M~Hz), 7.05 1H), 7.42 2H, J=8Hz). MS (DCI/NH3) m/e 525 WO 99/06397 PCT/US98/15479 -149- Anal calcd for C 3 0H 4

ON

2 06 1.25 TFA: C, 58.51; H, 6.23; N, 4.20.

Found: C, 58.52; H, 6.28; N, 4.33.

Example102 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yi)- 1 -l2.(N-propyl-N-(tertbutyloxyca rbonylm ethyflam ino)ethyll pyrrolid in e-3-Ca rboxylic acid The title compound was prepared by the methods described in S Example,61, but substituting propylamnine for methylamine in Example S 61B and t-butyl bromoacetate for isobutyryl chloride in Example 61C.

The crude product was purified by trituration with 1:1 diethyl etherhexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 8 0.82 3H, J=8Hz), 1.18 (in, 2H), 1.19 9H), 2.12 (mn, 1H), 2.46 (in, 2H), 2.70 (mn, 3H), 2.85 (mn, 2H), 3.20 2H), 3.40 (dd, 1K, J=2,8Hz), 3.50 (dt, 1H, J=2,BHz), 3.62 1H, J=8Hz), 3.78 3H), 5.95 2H), 6.72 1 H, J=8Hz), 6.84 (in, 1KH), 6.85 2H, J=8Hz), 7.05 1KH), 7.16 2H, J=8Hz). MS (DCI/NH 3 m/e 541 Anal calcd for

C

30

H

4

ON

2 07 -1.0 H 2 0: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.75; H, 7.35; N, 4.86.

Example 103 trans. trans-2-(4-MethoxyphenYfl-4-( 1.3-benzodioxol-5-yfl- 1 -j2-(N-prgoyI-N-(nprolylam inocarbonylm ethyfl)am in o) ethyllpyrrol idin e-3-carboxylic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61 B and N-propyl bromoacetamnide for isobutyryl chloride in Example 610. The crude product was purified by preparative HPLC (Vydac jiCi8) eluting with a 10-70% gradient of CH 3 CN in 0.1% TEA. The desired fractions were lyophilized to give the product as a white solid. 1 H NMR

(CDCI

3 300 MHz) 8 0.78 3H, J=8Hz), 0.88 3H, J=8Hz), 1.45 (in, 21-), 1.48 (in, 31-, J=8Hz), 2.55-2.7 (in, 2H), 2.90 (mn, 1KH), 3.04 (mn, I1H), 3.15 (in, 3H), 3.28 1 H, J=8Hz), 3.45 1KH, J=8Hz), 3.60 (in, 2H), 3.70. (d, 2H, J=8Hz), 3.75 (in, 1KH), 3.80 3H), 4.25 1KH, J=8Hz), 5.95 2H), 6.75(d, III, J=8Hz), 6.86 (dt, 1H, J=1,BHz), 6.88 2H, J=8Hz), 7.04 (d, 111, J=lHz), 7.40 2H, J=8Hz). MS (DCI/NH 3 in/e 526 Anal calcd for C 29

H

39 N306 1.85 TEA: C, 53.32; H, 5.59; N, 5.70. Found: C, 53.45; H, 5.62; N, 5.63.

WO 99/06397 PCTIUS98/15479 -150- Examlfl14 trans. trans-2-(4-Methoxyhelyl)-4-( 1. 3-benzodioxol-5-yl)- 1 -r2-(N-QroQvl-N-(4methoxyghenoymprbonfl~familo)ethyllDyrrolidie3-carboXylic acid The title compound was prepared by the methods described in O Example 61, but substituting propylamine for methylamine in Example 61 B and 4.methoxyphelylchloroformate for isobutyryl chloride in o Example 610. The crude product was purified by trituration with 1:1 Cldiethyl ether-hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a why~e solid. 1H NMR

(CD

3 OD, 300 MHz) mixture of rotamers 8 0.88 1.57 (in, 2H), 2.45 (br s) and 2.60 (br s, total of 1 2.90-3.15 (in, 4H), 3.42-3.7 (in, 3.78 3.80 3.85 (in) and 4.0 (in, total of I1H), 5.95 and 5.98 total of 6.63(m, 6.72 1H, J=8Hz), 6.81 (in, 6.93 (in, 5H), 7.40 (in, 2H). MS (DCI/NH3) m/e 577 Anal calcd for

C

32 H36N2O8 1 .0 H20: C, 64.63; H, 6.44; N, 4.71. Found: C, 64.70; H, 6.38; N, 4.63.

Examgle 105 trans. trans-2-(4-Methoxyohel)- 4 (1 .3-benzodioxol-5-yfl- 1 -f2-(N-o~roo~yl-N-(4methoxybenzoyl)amilo)ethYllo~yrrglidie3-carboxlic acid The title compound was prepared by the methods described in Example 61, but substituting propylainine for methylamine in Example 61 B and anisoyl chloride for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1:1 diethyl ether-hexane.

The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H- NMR (CDC13, 300 MHz) mixture of rotamers 8 0.78 (in) and 0.98 J=8Hz) total of 3H, 1.47 (in) and 1.52 (q, J=8Hz) total of 2H, 2.25 (br s, 1H), 2.78 (br s, 1H), 2.90 (br t, 2H), 3.12- 3.68 (in, 7H), 3.80 3H), 3.82 3H), 5.94 2H), 6.75(d, 11H, J=8Hz), 6.83 (mn, 5H), 6.94 (in, 1 7.22 (mn, MS (FAB) m/e 561 Anal calcd for C 32

H

36 N207 0.75 H 2 0: C, 66.94; H, 6.58; N, 4.88. Found: C, 67.00; H, 6.38; N, 4.59.

WO 99/06397 PCTIUS98/15479 -trans. trans-2-(4-MethOx henlY.

4 .(l.3-benz.odioxoI-5-YI')-l1 2-(N-DroPYI-NbenzolaminOglthI P 'rldife3carboxYli acid The title compound was prepared by the methods described in SExample 61, but substituting propylamine for methylamine in Example 0 61 B and benzoyl chloride for isobutyryl chloride in Example 61 C. The VIr crude product was purified by trituration with 1:1 diethyl ether-hexane.

The resulting solid was dissolved in CH 3 CN and water and lyophilized to Sgive the product as a white solid. 1 H NMR (CDC13, 300 MHz) mixture of rotamers 8 0.65 and 0.9 (in, total of 3H) 1.4 and 1.55 (in, total of 2H), 2.05 and 2.15 (mn, total of 1 2.6 3.6 (mn, 8H), 5.92 2H), 6.70(d, I1H, J=BHz), 6.82 (in, 4H), 7.2 7.4 (in, 6H). MS (DCI/NH3) in/e 531 (M+H) 4 Anal calcd for C 31

H

3 4N2O6 -0.3 H 2 0: C, 69.46; H, 6.51; N, 5.23. Found:

C,

69.48; H, 6.19; N, 4.84.

Example 107 trans. trans-2-(4-MethoxV=henyl- 4 (l .3.benzodioxoi-5-Vl)-1 -r2-(N-QroI2Yl-Nbenylxyar~nan -ino~ethvlloyrrolidine-3-carboxlic aci The title compound was prepared by the methods described in Example 61, but substituting propylainfe for inethylamille in Example 61B and benzyl chioroformate for isobutyryl chloride in Example 61C.

The crude product was purified by preparative HPLC (Vydac jgC18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1H NMR (00013, 300 MHz) 8 0.8 (in, 3H) 1.45 (in, 2H), 2.20 (br m, 1H), 2.75 (in, 1H), 2.93 (in, 1H), 3.15 (in, 2H), 3.32 (in, 3H), 3.52 (mn, 2H), 3.66 (in, 1H), 3.78 3H), 5.00 (in, 2H), 5.94 2H), 6.72(d, 1H, J=8Hz), 6.82 (in, 3H), (br d, I1H, J= 15Hz), 7.2 4H), 7.30 (in, 3H). MS (FAB) ine 561 Anal calcd for C 32

H

3 6N2O7 1.0 TFA: C, 60.53; H, 5.53; N, 4.15.

Found: C, 60.66; H, 5.34; N, 4.28.

Exmple 108a trans, trans-2-(4-MethoXylhelyl')..

4 (.3benzodioxol-5- ylV 1 42-(N-Prol-N-(4- Methoxbn IXY rhnnv~am inon~thyl1Dvrroidfl" Crbxli ai The title compound is prepared by the methods described in Example 61, substituting propylainine for methylaine in Example 61 B WO 99/06397 PCTIUS98/15479 -152and 4-methoxybelzyl chioroformate for isobutyryl chloride in Example 610C.

trans. trans-2-(4-MethowYhen 1 4 3-be dioxol-S-yi)-i -r2-(-tyl-Nethoxyab llmilo~ethyl1Dvrrolidne3caerbgU~LtcaciQd The title compound was prepared by the methods described in I Example 61, but substituting butylamine for methylamine in Example 61B and ethyl chloroforniate for isobutyryl chloride in Example 610.

The crude product was purified by preparative HPLC (Vydac g.Cl 8) eluting with a 10-70% gradient of CH3CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) 8 0.82 3H, J=8H-z), 1.20 (in, 5H), 1.34 (mn, 2H), 3.08 (in, 2H), 3.17 (mn, 2H), 3.52 (mn, 2H), 3.75 (in, 2H), 3.78 3H), 4.06 (q, 2H1, J=B1-z), 4.35 (br s, I1H), 5.94 2H1), 6.76 1 H, J=8H-z), 6.92 2H, J=8Hz), 7.03 (br s, I1H), 7.17 (br s, 1 7.7 (br s, 21-1). MIS (FAB) m/e 513 Anal calcd for C 28

H

36 N207 -0.5 TFA; C, 61.15; H, 6.46: N, 4.92.

Found: C, 60.99; H, 6.80; N, 4.93.

Examgle 110 trans. trans-2-(4-MthXYhnY1- 4 1 3-benzdioxoL-5-yl)-1-42.(-Utyl-N p~p p~y pr ony pmi O~ eth l- vrr idine 3 ca x)Yfi acid The title compound was prepared by the methods described in Example 61, but substituting butylamine for methylaine in Example 61B and propyl chloroforTmate for isobutyryl chloride in Example 610.

The crude product was purified by triturationi with 1:1 diethyl etherhexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDC13, 300 MlHz) 8 0.80 (br s, 1H), 0.85 3H, J=8Hz), 0.92 (br s, 1H), 1.22 (mn, 3H), 1.40 (in, 3H), 1.62 (br m, I1H), 2.15 (br s, 1 2.72 (mn, 1 2.87 (in, 1 H), 3.1-3.45 (mn, 5H), 3.55 (in, 1 3.64 1 H, J=8Hz), 3.79 3H), 3.88 (br s, 1lH), 3.97 (br s, 1 5.95 2H), 6.73(d, 1 H, J=8Hz), 6.85 (mn, 3H, 7.30 2H, J=8Hz), MIS (FAB) m/e 527 Anal calcd for

C

29

H-

3 8N2O7 0.15 H20: C, 65.80;- H, 7.29; N, 5.29. Found: C, 65.79;

H,

7.30; N, 5.2 1.

WO 99/06397 PCT/US98/I 5479 -153- Example 111 trans. trans-2-(4-Methoxyphenyl)- 4 (l.3-benzodi~xl5y'- -2NDolyl-NoroD~y~rb~lylmiflo)eth 1* -lidincrhO~fyi acid D The title compound was prepared by the methods described in Example 61, but substituting propylamifle for methylamifle in Example DKl 61B and propyl chioroforniate for isobutyryl chloride in Example 61C.

SThe crude product was purified by trituration with 1:1 diethyl etherhexane. The resulting solid was dissolved in CH3CN and water and lyophilized to give the product as a white solid. 1H NMR (CDC13, 300 MHz) 8 0.80 3H, J=8Hz), 093 (in, 3H), 1.43 (m,3H1), 1.62 (in, 1H), 2.15 (br 1 2. 68-3.45 (mn, 8H), 3.54 (in, I1H), 3.66 (in, 11-H), 3.78 3H), 3.94 (in, 2H), 5.94 2H1), 6.72 1H, J=8Hz), 6.82 (in, 1H1), 6.84 211, J=BHz), 7.00 (br s, 1H), 7.33 (in, 2H1). MS (DCI/NH3) ine 513 Anal calcd for C 28

H

3 6N207 0.15 H 2 0: C, 65.26; H, 7.10; N, 5.44. Found: C, 65.22; H, 6.74; N, 5.06.

Examile11 -trans. trans-i I-(N Di(n-bi tyflamil0 bn I ehyl).4-di( 1 .3kbenzj ixl-

L

yl')-yrrolidine-3- rO~i acid Ethyl 3 4 -m ethylen~edio xybe n zoyl)acetate, prepared by the method of Krapcho et al., Org. Syn. AZ, 20 (1967) starting with 3,4m ethylened ioxyaCetophe none instead of 4-inethoxyacetophelone, was reacted by the procedures described in Example 1 to give the title compound as a white solid. m.p. 58-60 0 C. H NMR (CDC13, 300 MHz) 8 0.B7 (quintet, J=6Hz, 6H), 1.12 (sextet, J=6Hz, 2H), 1.24-1.51 (mn, 6H), 2.80 J=13H-z, 1H), 2.94-3.12 (in, 4H), 3.28-3.50 (mn, 4H), 3.58-3.62 (in, 1H), 3.78 J=9Hz, IH), 5.95 4H), 6.73 (dd, J=8Hz, 3Hz, 2H4), 6.84-6.89 (in, 2H), 6.92 J=lHz, 1H), 7.01 H=1Hz, 1H). MS (DCI/NH3) m/e 525 ExanipLe 113 trans.t trns-i. 2(N- (n-Butl)-N.DroD~ylSlf onvam ino-ehyLL.(4methOXYh n1 4 (1 3 enzo i~l5V'Pr~iine -a-boxylic aci Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 64-65 0C. 1 H NMR (CDC13, 300 MHz) 8 0.83 J=7Hz, 3H),.0.98 J=7Hz, 3H), 1.12-1.25 (in, 2H), 1.32-1.41 (in, 2H), 1.75 (sextet, J=7Hz, 2H), 2.2 3-2.31 (in, 2H), 2.72-3.32 (mn, 8H), WO 99/06397 PCTIUS98/15479 Ct -154- 3.43 (dd, J=9Hz, 3Hz, 1H), 3.53-3.59 (in, 1H), 3.65 J=9Hz, 1H), 3.80 (s, 3H), 5.95 2H), 6.73- J=8Hz, 1H), 6.83 (dd, J=BHz, 1 Hz, 1 6.88 (d, S J=9Hz, 2H), 7.02 J=1 Hz, 1 7.33 J=9Hz, 2H). MS (DCI/NH3) mie 547 (M+H)Y.

Example 114 trn.tans-i-(N. N-Di(n-butyflam'inocarbonvlmethyl1-2 -methoxYhenyl- 4 1 3bezdoo--lgrrldn--ab~i acid Using the procedures described in Examples 28 and 43, the title compound was prepared as a white solid. mn.p. 74-J6 0 C. 1 NMR (CDCI3, 300 MHz) 8 0.80 J=6Hz, 3H), 0.88 J=8Hz, 1.08 (sextet, J=8Hz, 2H), 1.21-1.48 (in, 6H), 2.75 J=l2Hz, 2.95-3.09 (in, 4H), 3.26-3.59 (in, 5H), 3.75 J=9Hz, 1H), 3.79 3H), 4.28 6.78 (d, J=9Hz, IH), 6.85 J=9Hz, 6.91 J=3Hz, 9Hz, 1H), 6.98 (d, J=3Hz, 1H), 7.32 J=9Hz, 2H). MS (DCI/NH3) m/e 525 Exgapl 11 trans. trans-i- Ovl.N-Dro~vui)-laf onvlam ino%)thv1').2(4meh Y venl- 4 (1 3 -benz dioXol-5VIl~pvrroi in -arb l ci d Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 72-73 1 NMVR (CDC13. 300 MHz) 8 0.79 J=8Hz, 3H), 0.98 J=8Hz, 3H), 1.43 (sextet, J=BHz, 1.75 (sextet, J=BHz, 2H), 2.22-2.32 (in, 1H), 2.69-3.32 (in, 9H), 3.42 (dci, J=3Hz, 12Hz, 3.52-3.58 (in, 1HI), 3.64 (di, J=l2H-z, 3.80 3H), 5.95 2H), 6.73 J=llHz, 6.83 (dd, J=lHz, 11H-z, IH), 6.87 (di, J=llHz, 7.0 (di, J=2Hz, 7.32 J=llHz, 2H). MS (DCI/NH3) mie 533 Exam-ale 116 tran. trans-i42 .(NBtYNbuyslvam ino eth 1 4.inethoxyghe iVft 4 (L1,3b noiXl.IDroiine3-carboxviic- acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 62-63 0 C. I H NMR (CDC13, 300 MHz) 0.82 J=6Hz, 3H), 0.91 J=6H-z, 3H), 1.20 (sextet, J=6Hz, 2H), 1.33- 351.42 (in, 4H), 1.68 (quintet, J=6Hz, 3H),2.23-2.3 2 (in, 1H), 2.70-3.28 (mn, 911), 3.41 (di, J=8Hz, 3.52-3.58 (in, iN), 3.65 J=8Hz, 1H), 3.79 (s, WO 99/06397 PCTIUS98/15479 2 -155- 5.95 2H), 6.72 J=8Hz, 1 6.82 J=8Hz, 1 6.87 J=8Hz, 2H), 7.01 1H), 7.32 J=8Hz, 2H1). MS (DCI/NH 3 m/e 561 trans, trans-i1 N-Di(n-butyflaminocarboflylmethyl)-2-( 4 O methoxymethoxypheflyfl-4-(l .3-benzodioxol-5-yl)D2vrrolidifl.3-carboxylic acid 0 4- Hyd roxya cetophefnonle was treated with chloromethyl methyl o) ether and triethylamifle in THIF at room temperature to give ethyl 4met ho xymethoxybelzoyl acetate which was treated by the procedures described in Example 1 to afford the title compotind as a white solid.

m.p. 48-49 0 C. 1 NMR (CDCI 3 300 MHz) 8 0.81 J=7Hz, 3H), 0.88 (t, J=7Hz, 3H), 1.06 (sextet, J=7Hz, 2H), 1.20-1.35 (in, 4H), 1.44 (quintet, J=7Hz, 2H), 2.75 (d J=l2Hz, 1H), 2.94-3. 10 (in, 4H), 3.25-3.35 (in, 1H), 3.40 (di, J=l2Hz, 1H), 3.43-3.52 (in, 2H), 3.47 3H), 3.55-3.62 (in, 1H), 3.77 J=9Hz, 1H), 5.15 2H), 5.94 (in, 2H), 6.73 J=8Hz, 1H), 6.86 (dd, J=lHz, 8Hz, 1H), 7.0 J=8Hz, 2H), 7.04 J=lHz, 1H), 7.32 (d, J=8Hz, 2H). MS (DCI/NH3) in/e 541 Examgle 118 trans, trans-i1 N- Di (n-butillam inocarbonym ethyl)-2(4-hydroxylhenfl)l 4 (1.3benzodixol-5vl)1yrrolidile-3-carboxlic acid hydrochloiesl The compound resulting from Example 11.6 was treated with concentrated HCI in 1:1 THE-isopropanol to give the title compound as a white solid. m.p. 211-212 OC. 1 H NMR (CD 3 O D, 300 MHz) 8 0.90 (t, J=8Hz, 6H), 1.12-1.27 (in, 6H), 1.36-1.45 (in, 2H), 3.04 (bs, 1H), 3.14- 3.35 J=9Hz, 1H), 3.90 (bs, 3H1), 4.17 J=l5Hz, 111), 5.96 2H), 6.82-6.93 (in, 4H), 7.03 J=lHz, 1H1), 7.42 (bs, 2H). MS (DCI/NH3) m/e 497 Example 119 trans. trans-i sobutyl-N-12ro1ylsulf onylamnino)ethyr)-2-(4-methoxylhenyfl- 4 (1 .3-benzodioxol-5-ylDyrrolidife3carboxylic- acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 73-74 0 C. I H NMR (CDC1 3 300 MHz) 8 0.80 J=6Hz, 6H), 0.98 J=8Hz, 3H), 1.62 (sextet, J=6Hz, 1H), 1.74 (sextet, J=8Hz, 2H), 2.23-2:34 (in, 1H), 2.68-2.98 (in, 3.08-3.18 (in, WO 99/06397 PCT/US98/15479 Ct -156- 1 3.26-3.42 (in, 2H), 3.52-3.58 (in, I1H), 3.65 J=9Hz, 1 3.80 (s, 3H1), 5.90 2H), 6.74 J=8Hz, 1H), 6.82 J=8Hz, 1H), 6.86 J=8Hz, D 2H), 6.98 J=lHz, 1H), 7.33 J=8Hz, 2H). MS (DCI/NH3) mle 547 "A Examgle 120 D trans, trans-i1 (NBneeufnlNpoyaioehl--4mtoyhnIL4 DK (1.

3 benzodioxolI5-yl)2yrrolidie3-carbgxyLic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 89-91 00. 1 H-NMR (CDCI3, 300 MHz) 8 0.74 J=6Hz, 3H), 1.33 (sextet, J=6Hz, 2H), 2.20-2.30 (in, 1H), 2.62- 2.72 (in, 1H), 2.85-3.05 (in, 4H), 3.12-3.22 (in, 1H), 3.38 (dd, J=3Hz, 9Hz, 1H), 3.49-3.57 (in, 1H), 3.62 J=9Hz, 1H), 3.82 3H1), 5.96 2H), 6.73 J=8H-z, 1H), 6.84 (dd, J=1 Hz, 8H1z, 1H), 6.85 J=9Hz, 2H), 7.02 J=lHz, 1H), 7.28 J=9Hz, 2H), 7.39-7.54 (in, 3H), 7.70 J=7Hz, 2H). MS (DCI/NH3) m/e 567 Example 121 trans. trans-i4- 4-MethoxvbeflzefleS~dfnl)-NDo~a i thyl)-2-(4methoxyghelyl- 4 (1 .3-benzod ioxol-5-vflyrrolidile-3-carboXylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 96-97 00. 1 H NMR (CDC13, 300 MHz) 8 0.73 J=7Hz, 3H1), 1.34 (sextet, J=7Hz, 2H), 2.20-2.30 (in, 1H), 2.62- 2.71. (in, 1 2.82-3.03 (mn, 4H), 3.08-3.18 (mn, 2H), 3.38 (dd, J=3Hz, 9Hz, IH), 3.48-3.56 (in, 1H), 3.62 J=9Hz, 1H), 3.81 3H), 3.86 3H), 5.95 2H), 6.73 J=8Hz, 1H), 6.81-6.89 (mn, 5H), 7.01 J=lHz, 1H), 7.28 J=8Hz, 2H), 7.62 J=8Hz, 2H). MS (DCl/NH3) mWe 597 Examgle 122 trans, trans!! 1(N N-i n-bu nm inoronvlehf.(int&~toY methoxyphelyl')- 4 4-(l 3 .enodOXl-- -I Drrldnecro/ic ad was treated with sodium hydride and broinoethyl methyl ether in THE at 70 00 to provide ethyl 2m ethoxyethoxy-4flmethoxybenzoyl acetate which was treated by the procedures described in Example 1 to provide the title compound as a white solid. in.p. 63-65 00. 1 H NMR (CDC13, 300 MHz) 8 0.84 J=7Hz, WO 99/06397 PCTIUS98/1 5479 -157- 3H), 0.89 J=7Hz, 3H), 1.16 (sextet, J=7Hz, 2H), 1.28 (sextet, J=7Hz, 2H), 1.45-1.52 (in, 4H), 2.87-2.94 (in, 2H), 3.00-3.16 (in, 3H), 3.26-3.36 (in, 2H), 3.43 3H), 3.47-3.54 (in, 3H), 3.66-3.72 (in, 2H), 3.78 3H), 3.76-3.84 (in, 1H), 4.02-4.10 (in, 2H), 4.25 J=9Hz, 1H), 5.92 2H), 6.40 J=2Hz, 1H), 6.52 (dd, J=2Hz, 9Hz, 1H), 6.70 J=8Hz, 1H), 6.83 'A (dd, J=1lHz, 8Hz, 1 5.98 J=2Hz, 1 7.53 J=9Hz, 1 MS

(DCI/NH

3 mle 585 Example 123 trpns. trans- 1 2(-rplN(.-i tytnzns fnla n~ty)2LL methoxypheflvl)-4-(l-.3-benzodioxol-5-yl)Dyrrolidife3-arboXyl-c aid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-90 0 C. 1 H NMR (CDC13, 300 MHz) 8 0.69 J=7H-z, 3H), 1.32 (sextet, J=7Hz, 2H), 2.12-2.20 (in, 1H), 2.32 3H), 2.47 3H), 2.62-2.69 (in, 1H), 2.78 J=9Hz, 1H), 2.89 (dd, J=BHz, 1H), 3.02 (sextet, J=9Hz, 2H), 3.15-3.32 (in, 3H), 3.46-3.55 (in, 1H), 3.60 J=9Hz, 1H), 3.82 3H), 5.96 2H), 6.72 J=7Hz, 1H), 6.80 (dd, J=lHz, 9Hz, 6.86 J=9Hz, 2H), 6.97 J=lHz, 1H), 7.03 (bs, 2H), 7.29 J=9Hz, 1H). MS (DCI/NH3) m/e 595 Exain~le 124 trans, trans- 1 2(-rplW-hlrpoyluI nla n~ty)2 4 methoxyhenfl)- 4 1.3-benzodioxol-5-yflDnrrolidinfle3-caroxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 75-76 OC. I H NMR (CDC13, 300 MHz) 8 0.80 J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.15-2.31 (mn, 3H), 2.70- 2.80 (in, 1H), 2.85-3.10 (in, 6H), 3.23-3.31 (in, 2H), 3.43 (bd, J=9Hz, 1H), 3.55-3.66 (mn, 4H), 3.81 3H), 5.94 2H), 6.73 J=BHz, 1H), 6.82 (d, J=BHz, 1H), 6.86 J=8Hz, 2H), 7.00 1H), 7.33 J=8Hz, 2H). MS (DCI/NH3) m/e 567 Example 12 trans. trans-i 1 2 -(N.Pr Iy.N =fehnxyvthvjSu-J-Ifr~aiinehyl- 2 4 4 m-ethoxyghe yl')- 4 3 -benzodioxol-5ylDyrrlidine3-carboxylic ai Using the procedures described in Example 66, trans, tranls- 1 (N-Propyl-N(viylsulfoflyl)anino)ethyl)-2(4methoxyphenyl)4(,3- WO 99/06397 PCT/US98/15479 -158benzodioxol-5-yl)pyrrolidife3carbox lic acid was prepared. Ester hydrolysis using aqueous sodium hydroxide in methanol afforded the D title compound as a white solid. m.p. 62-64 OC. 1 H NMR (CDCI3. 300 MHz) 8 0.78 J47Hz, 3H), 1.42 (sextet, J=7Hz, 2H), 2.23-2.32 (in, 1H), 2.72-2.79 (in, 1H), 2.86-3.05 (in, 4H), 3.10-3.27 (in, 4H), 3.32 3H), 3.43 (dd, J=3Hz, 9Hz, 1H), 3.53-3.58 (in, 1H), 3.65 J=9Hz, 1H), 3.69 (t, D J=6Hz, 2H), 3.80 3H), 5.94 2H), 6.73 J=8Hz, 1H), 6.82 (dd, D J=lHz, 8Hz, 1H), 6.87 J=8Hz, 2H), 7.02 J=lHz, 1H), 7.33 J=8Hz, 2H). MS (DCI/NH3) m/e 549 trans. trans:- 2 -(N-PropylN(2ethogyehylsulfonY1'lgmino~etl) 2 4 mthox 1efyl 4 aci Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 58-60 OC. 1' NMR (CDCI3, 300 MHz) 5"0.78 J=7Hz, 3H), 1.18 J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.24- 2.33 (in, 2.70-2.80 (in, 1H), 2.87-3.05 (in, 4H), 3.13-3.20 (mn, 2H), 3.22-3.32 (in, 2H), 3.42 (dd, J=2Hz, 9Hz, 1H), 3.46 J=7Nz, 2H), 3.52- 3.58 (in, 1 3.65 (d J=9Hz, 1 3.72 J=6Hz, 2H), 3.80 3H), 5.95 2H), 6.73 J=7Hz, 1H), 6.83 (dd, J=lHz, 7Hz, 1H), 6.87 J=8Hz, 2H). 7.00 J=lHz, 1H), 7.32 J=8Hz, 2H). MS (DCI/NH3) m/e 563 Example- 127 trans, trans- 1 -(2.(N-Propyl N.5-imtyan 1 naghthyls Ifff n I mO'eh

I~-

(4-methoXygheflyl'I- 4 (i.

3 -benzodiox I- -Yfl0rrolidine3-arboxli acid Using the procedures described in Example 66, the title compound was prepared as a yellow solid. in.p. 102-104 00. 1 H NMR (00013. 300 MHz) 8 0.62 J=7Hz, 3H), 1.28 (sextet, J=7Hz, 2H), 2.12-2.20 (in, 1H), 2.78 J=9Hz, 1H), 2.88 6H), 2.72-2.89 (mn, 1H), 3.05-3.12 (mn, 2H), 3.26-3.45 (in, 3H), 3.45-3.52 (in, 1H), 3.58 J=9Hz, 1H), 6.97 J=1HZ, 1H), 7.13 J=7Hz, 1H), 7.26 J=8Hz, 1H), 7.42-7.50 (in, 2H), 8.08 (dd, J=lHz, 7Hz, 1H), 8.20 (d,J8Hz, 1H), 8.48 J=8Hz, 1H), MS (O01/NH 3 mle 660 WO 99/06397 PCTIUS98/1 5479 -159- Exam~le-12 trans, trans-1 2 -(N.Propyl-N-(ethysulfoflyI mino)ethyl2-(4-methoxIphenyl')- 4 (1 .3-benzodioxoli5 -f1)yrr i -r.carboxyjic ac-id Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 70-72 0 C. 1 H NMR (CDCI3, 300 MHz) 0.79 J=BHz, 3H), 1.28 J=7Hz, 3H), 1.43 J=8Hz, 2H), 2.22-2.30 1H), 2.71-2.80 (in, 11K), 2.82-3.10 (in, 3.18-3.32 (in, 2H), 3.43 0 (dd, J=3Hz, 9Hz, 1H), 3.53-3.60 (in, 1H), 3.65 J=9Hz, 1H), 3.80 3H), 5.96 2H), 6.73 J=7Hz, 1H), 6.82 (dd, J=lHz, 7Hz, 1H), 6.88 (d, J=BHz, 2H), 7.00 J=lHz, 1H), 7.32 J=8Hz, 2H1). MS (DCI/NH3) ine 519 Examlole 129 trans. trans- 1 (-NPo~lN(-ehleneeufoy~mn)ty)2 methoxyphenl)f-4-( 1.

3 -benzodioxol-5VflDpyrroliine3.carboM±licai Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 78-79 00. I H NMR (CDCI3, 300 MHz) 8 0.73 J=7Hz, 3H), 1.33 (sextet, J=7Hz, 211), 2.20-2.30 (in, 1H), 2.40 3H), 2.61-2.72 (in, 1H), 2.83-3.05 (in, 4H), 3.08-3.19 (in, 2H), 3.48 (dd, J=3Hz, 9Hz, 1H), 3.49-3.57 (in, 1K), 3.62 J=9Hz, 1H), 3.81 3H), 5.95 2H), 6.73 J=B~z, 1KH), 6.82 J=8Kz, 1KH), 6.87 J=8Kz, 2H), 7.00 1H), 7.21 J=8Hz, 2H), 7.29 J=8Hz, 2H), 7.57 J=8Kz, 2H).

MS (DCI/NH3) Wne 581 Examp~le 130 trans. trns-i .N-DI(n-butlamifocarbonyliethyl-2(3Dpyridyl.- 4 ben zodixol- 5-VI) gyrrolI id ine-3-carbpxyl ic acid Methyl nicotinoyl acetate was prepared by the method of Wenkert, et al., J. Org. Chem. 48: 5006 (1983) and treated by the procedures described in Example 1 to provide the title compound as a white solid..

m.p. 167-168 00. 1 K NMR (CDCI3, 300 MHz) 8 0.82 J-7Hz, 3H), 0.89 J=7Kz, 3H), 1.14 (sextet, J=7Kz, 2K), 1.23-1.48,(in, 6H), 2.86-3.20 (mn, 6H), 3.34-3.43 (in, 2K), 3.57 (dd, J=3H1z, 9Hz, 1H), 3.75-3.83 (in, 1K), 4.08 J=9Kz, 1H), 5.93 2H), 6.73 J=8Hz, 1H), 6.90 (dd, J=2Kz, 8Hz, 1K), 7.03 J=2Kz, 1H), 7.38 (dd, J=4Hz, 8Hz, 1H), 8.04 J=8Kz, 1H), 8.48 (dd, J=2Kz, 4Hz, 2K). MS (DCI/NH3) Wne 482 WO 99/06397 PCTIUS98/1 5479 -160- Examl~le 1 0 trans.-trans-i 2(-po~i--nbuys fnlaino)ethy I 4mthXhnl 4 (1 .3-benzdioxol-5-vl~yrrolidife3carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 65-66 00. I H NMVR (CDCI3, 300 MHz) 8 0.78 J=7Hz, 3H), 0.92 J=7Hz, 3H), 1.31-1.46 (in, 4H), 1.68 Ni (quintet, J=7Hz, 2.21-2.32 (in, 1H), 2.70-3.08 (in, 7H), 3.12-3.23 (mn, 2H), 3.42 (dd, J=2Hz, 9Hz, 1H), 3.52-3.58 (mn, 1H), 3.64 J=9Hz,

IH),

3.80 3H), 5.96 2H), 6.72 J=7H-z, 1H), 6.83-(dd, J=lHz, 7Hz, 1H), 6.86 J=BHz, 2H), 7.00 J=lHz, 1H1), 7.32 J=8Hz, 2H). MS (DCI/NH3) m/e 547 Example 132 Is trans. trans- 1l-( 2 -(N-PropyI.N-(4-chIrobenzenesulfonyl)aimnoethyII 2 4 methopheflyfl-4 4 l .3-benzodioxgl-5aylD~rpldin cr olic aid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 105-106 QC. 1 H NMR (CDC13, 300 MHz) 8 0.72 J-4'Hz, 3H1), 1.34 (sextet, J=7Hzm 2H), 2.56-2.62 (in, 1H), 2.78-2.86 (in, 2.96-3.03 (mn, 51H), 3.13-3.26 (in, 3H1), 3.51 (dd, 9Hz, 1H), 3.62-3.68 (in, 1H), 3.80 3H), 3.94 J=9Hz, 1H), 5.92 (s, 2H), 6.75 J=8Hz, 1H), 6.84 (dd, J=2Hz, 81-z, 1H), 6.94 J=8Hz, 2H), 6.98 J=2Hz, 1H), 7.36 J=8Hz, 1H1), 7.49 J=8Hz, 1H), 7.68 (d, J=BHz, 1H). MS (DCI/NH3) m/e 601 Example 133 tans, trans-i 1 (2-(N-ProgyI-N-(belzylsu IfonyIlamino)ethyI)-2-(4- ft xvohefl (1 3 -benz dioxol5Vl)pyrrolidine carbox lic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-89 00. 1 HNMR (CDCI3, 300 MHz) 8 0.72 J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.06-2.16 (in, 1H), 2.56- 2.67 (mn, 1 2.75-3.10 (in, 6H), 3.30 (dd, J=2Hz, 9Hz, 1H), 5.95 2H), 6.73 J=7Hz, 1H), 6.80 (dd, J=1 Hz, 7Hz, 111), 6.86 J=8Hz, 2H), 6.97 J=lHz, 1H), 7.27-7.35 (mn, 71-1). MS (DCI/NH3) in/e 581 WO 99/06397 PCT/US98/15479 -161- ExampJ&-U4 trans. trans- 1l.( 2 -(N-Propyl.N.(4iluoro enzenesulfonylamino)thyl- 2 methoxypheflyl)- 4 (1.

3 benzodiool5-yl)DYrrolidif3carboxylacd Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 91-93 OC. I H NMR (CDCI3, 300 MHz) S 0.73 J=7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 2.18-2.27 (in, 1 2.56- 2.67 (in, 1 2.78-2.87 (in, 2H), 2.97 (septet, J=BHz, 2H), 3.11-3.1 6 (in, 2H), 3.33 (dd, J=2Hz, 9Hz, IH), 3.43-3.50 (mn, 1H1), 3.57 J=9Hz, 1H), 3.78 3H), 7.08 J=8H-z, 2H), 7.24 J=8Hz, 2H), 7.69 (dd, 8Hz, MVS (DCI/NH3) mle 585 Example 135 trn. rn-i~N.ehI~~OylamiiocaronlmethyI)-2-4inethoxvphe-nl benzofuraflyl')D)yrrolidine3carboxylic aid Exam oe 1 35A Benzofurafl.4-car'boxald~hy-de To a suspension of 60% sodium hydride in mineral oil (4.00 g, 104 mmol, 1.25'eq) in DMF (60 mL) at 0 OC was added a solution of 3broinophenol (13.8 g, 80 mmol) in DMF (5 mL). After 10 minutes, bromoacetaldehyde diethyl acetal (14.9 ML, 96.6 mmol, 1.24 eq) Was added, and the resultant mixture then heated at 120 0 C for 2.5 hours.

The mixture was cooled to room temperature and was poured into water, and extracted once with ether. The organic solution was dried over MgSO4, filtered, evaporated and vacuum distilled to yield a 0 colorless liquid (17.1 g, b.p. 160-163 -Q at 0.4 mmI Mg.

To warm polyphosphoric acid (15.3 g) was added a solution of the above compound (17.1 g, 59.3 inmol) in benzene (50 inL. The resultant mixture was heated under reflux with vigorous stirring for 4 hours, after which time the benzene layer was carefully decanted off, and the lower layer washed once with hexanes. The combined organic solutions were concentrated in vacuo, and then vacuum distilled to yield a colorless liquid (8.13 g, b.p. 62-72 0 C at 0.6 mm Hg.

Ad~ I gatIar To a solution of the above compounds (8.1 1 g, 4 1 (80 mL) at -78 0 C was added 1.7 M t-butyllithium~ (48.8 eq) such that the temperature did not exceed -70 OC.

Qi~ie rnlijtion of DMF (6.5 inL, 83 ininl, 2 eq) inL, 83 iniol, 2 After stirring for in ether (20 mL) WO 99/06397 PCT/US98/15479 -162was added, and the mixture allowed to warm to room temperau~re over 2 hours. The mixture was poured into water and the phases separated.

D The organic solution was dried over MgSO4 and concentated in vacuo.

S The residue was purified by flash chromatography on silica gel eluting with 10% ether in hexanes to yield benzofuran-6-carboxaldehyde (1.22 D g) and benzofuran-4-CarboxaldehYde (1.86 both as colorless oils.

trans. trans-i (N-Methyl-N-groD~ylam inocarbonylmnethyfl)-2(4-methoXYphenl)l 4 4 benz.ofuranfl~yrrolid ine-3-carboxyLic acid The title compound was prepared using the procedures described in Examples 1 and 49 substituting the compound resulting from Example 1 35A in Example 49A for piperonal. 1H NMR (300 MHz, CDCI3) (minor rotamer) 8 7.59 (1H, t, J=3Hz), 7.4-7.2 (6H, mn), 6.8 (2H, d, J=BHz), 4.03 (1 H, mn), 3.94 (1 H, dd, J=8Hz, 3Hz), 3.77 (3H, 3.61 (1 H, dd, J=8Hz, 7 3Hz), 3.42 (1H, dd, J=llHz, 5Hz), 3.40-2.90 (5H, mn), 2.82 (2.81) (3H, s), 1.50 (2H, septet, J=7Hz), 0.82 (0.75) (3H, t, J=7Hz). MS (DCI/NH3) in/e 451 (M+H) 4 Anal.calc. for C 26

H

3

ON

2 Os AcOH: 0, 65.87; H, 6.71; N ,5.49.

Found: C, 66.04; H, 6.42; N, 5.60. s Example 136 trans. trans-i 1 (N-Methyl-N-12rogylinfO rb I pmthYl)2(4methox hn 1 4 benzofurafnl)OrrOidifle3-carboxYvic acid The title compound was prepared using the procedures described in Examples 1 and 49 substituting be o a--abxleye prepared as described in Example 135A, in Example 49A for piperonal.

1 H NMR (300 MHz, CDCI3) (minor rotainer) 8 7.65 (1H, bd), 7.60 (1H, d, J=2Hz), 7.55 (1H, d, J=BHz), 7.35 (3H, mn), 6.85 (2H, dd, J=8Hz, 3Hz), 6.75 O1H, dd, J=3Hz, 2Hz), 3.83 (2H, mn), 3.79 (3H, 3.60-3.0 (7H, in), 2.91 (2.83) 3H), 1.51 (2H, septet, J=7Hz), 0.83 (0.78) (3H, t, J=7Hz).

MS

(DC I/NH 3 m/e 451 Anal~calc. for C 26

H

3 oN205 0.5 H20: C, 67.96; H, 6.80; N, 6.10. Found: C, 67.90; H, 6.71; N, 6.07.

WO 99/06397 WO 9906397PCT/US98/1 5479 Ct;__4-163tran~s. trans-i 1 (-ehlN1rplmncroymt oben zo-2.3-dihyd rof uranyl) pyrro idile-3-ca rboxyl ic acid The title compound was prepared by catalytic hydrogenation (4 atmospheres of H 2 in AcOH, followed by preparative hplc) of the cN compound resulting from Example 136 1 H NMR (300 MHz, CDCI3) (minor o rotamer) 8 7.49 (7.47) (2H, d, J=8Hz), 7.19 (1H, d, J=8Hz), 7.00 (1H, in), 7.82 (3H, in), 5.40 (1H, dd, J=llHz, 7Hz), 4.58 (2H, t, J=BHz), 4.18 (OH, mn), 4.10 (1H, mn), 3.88 (1H, mn), 3.79 (3H, 3.60 (1H, in), 3.35 (1H, in), 3.19 t, J=BHz), 3.00 (4H, in), 2.91 (2.78) 3H), 1.53 (1.40) (2H, septet, J=7Hz), 0.88 (0.78) (3H, t, J=7Hz). MS (DCI/NH3) Wne 453 Anal.calc. for C 26

H

32 N205 1.25 TFA: C, 57.53; 5.63; N, 4.71. Found: C, 57.68; H, 5.68; N, 4.70.

15Exml13 trans. trans-i1 .N-DI(n-butylI~amiflocar ~ln mhl I) -4-meh~xoell) 4 benzofuranyflo12rrolidife3carbo~lic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-4-carboxaldehyde in Example 49A for piperonal and substituting N,N-dibutyl bromoacetamide for N-inethyl-N-propyl bromoacetamide. 1 H NMR. (300 MHz, CDCI3) 7.62 011H, d, J=3Hz), 7.39 (1 H, dt, J=8Hz, 2Hz), 7.34 (3H, in), 7.26 (1 H, d, J=2Hz), 7.23 (1 H, d, J=8Hz), 6.84 (2H, d, J=8Hz), 4.02 (1 H, ddd, J=8, 6Hz,4Hz), 3.89 (1H, d, J~gHz) 3.79 (3H, 3.67 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, mn), 3.35-3.15 (3H, in), 3.00 (2H, in), 2.84 (1H, d, J=l4Hz), 1.43 (3H, in), 1.23 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) Wne 507 Anal.calc. for C 30

H

38 N2OS: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.86; H, 7.45; N, 5.24.

trans. trans-i .N4Di(nbutyl)minfocabonylmth l2(meho henyl)- 4 4 benzofura Iy Prr iife3carbmfyin add The title compound was prepared by the procedures described in Examples 1 and 49 substituting bezf a--abxleye prepared by the procedures described in Example 1 35A substituted 4bromophenol for 3-broinophenol, in Example 49A for piperonal and subsi-ciibu1'; brcrmacetam'nrip for N-methl- N-Oropvl D WO 99/06397 PCTIUS98/15479 Ct -164bromoacetamide. 1 H NMR (300 MHz, CDC13) 8 7.64 (1KH, bd), 7.59 (1H, d, J=2Hz), 7.43 (2H, in), 7.33 (2H, d, J=8Hz), 6.85 (2H, d, J=BHz), 6.73 (1 H, D~ dd, J=3Hz, 1 Hz), 3.82 (1 H, d, J=1lIHz), 3.89 (1KH, d, J=9Hz) 3.79 (3H, s), 3.53 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, in), 3.30 (1K, mn), 3.20-2.95 (5H, mn), DKl 2.82 (1H, d, J=l4Kz), 1.43 (3H, mn), 1.23 mn), 1.08 (2H, mn), 0.87 (3H, r) t, J=7Hz), 0.82'(3H, t, J=7Hz). MS (DCI/NH3) mWe 507 Anal.calc.

D for C 3

OH

3 8N205: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N, S 5.29.

EampJle 14 trns tan-I-(. ~i(n-butyI')amiflocarbonylm ethj)2 4r nto yfl)l4- (6 The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-6-carb0xaldehyde in Example 49A for piperonal and substituting N,N-dibutYl bromoacetamide for N-methyl-N-proPYl bromoacetamide. 1H NMR (300 MHz, CDCI3) 8 7.63 (1K, bd), 7.59 (1H, d, J=2Hz), 7.53 (1H, d, J=8Kz), 7.36 (3H, Mn), 6.85 (2H, d, J=8Hz), 6.73 (1K, dd, J=3Hz, 1Hz), 3.82 (1H, d, J=llHz), 3.89 (1K, d, J=9Hz) 3.79 (3H, 3.53 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, in), 3.30 (1H, in), 3.20-2.95 (5H, in), 2.80 (1H, d, J=l4Hz), 1.43 (3H, in), 1.23 (3H, mn), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz).

MS

(DCI/NH3) mWe 507 Anal.calc. for C 30

H

3 8N205 0.75 H 2 0: C, 69.28; K, 7.65; N, 5.39. Found: C, 69.11; H, 7.33; N, 5.32.

Exampinle 141 trans. trans-i1 n.Dim tbutD-1min)44-bnylmethvl~24metho)(1f benzo- 2 3 -dihyd )fura vroiin~aboxylc -acid The title compound was prepared by catalytic hydrogenation of the compound resulting from Example 140 (4 atmospheres of H 2 in AcOK, followed by preparative hp!c). 1K NMR (300 MHz, CDCI3) 8 7.40 (2H, d, J=8Hz), 7.16 (1K, d, J=8Hz), 6.97 (1K, dd, J=8Kz, 2Hz), 6.89 (3K, in), 5.90 (1H, bs) 4.57 (2H, t, J=9Hz), 4.93 (2K, in), 3.80 (3K, 3.70-3.58 (2K, in), 3.40 (1KH, in), 3.30-2.90 (BK, in), 1.40 (2K, in), 1.29 (3K, in), 1.08 (2H, in), 0.92 (3H, t, J=7Hz), 0.82 (3K. t, J=7Hz). MS (DCI/NK3) n/e 509 Anal.calc. for C 3 oH 4 oN205 0.85 TEA: C, 62.88;

K,

6.80; N, 4.63. Found: C, 63.04; H, 6.66; N, 4.60.

WO 99106397 WO 9906397PCT[US98/15479 Ct -165- Examgle 142 Strans.trans- l 4 (NMethyI.N-Dronyamiflocarbofy m ethyl 2(4meth oxvphenyl.

4 IND indanyl~prrolidifle-3-carbxvl-c acid Example 142A was prepared by formylation of indane under the conditions described for 2,3-di hyd robenlzof uraf in Example 52A. The resultant mixture of and 5-carboxaldehydeS was purified as follows: to a 6:1 mixture of indane-4-carboxaldehYde and carboxaldehyde (3.46 g, 23 mmol) was added aniline (2.20 g, 23 mmol, 1 eq). The resultant solution slowly solidfied to a mixture of imines which was recrystallized from hot acetonitrile to yield the as a white solid. The aldimine (2.65 g) was suspended in water (6 mL), and treated with 4 N hydrochloric dioxane (10 mL). The mixture was boiled for 1 hour, cooled to room temperature, and poured into ether.

The organic solution was dried over MgSO4, filtered, and concentated in vacuo. Vacuum distillation of the residue afforded carboxaldehyde (1.54 g, 88%) as a colorless liquid. b.p. 88-90 00 at 0.9 mm Hg.

toans, trans-i -(-ehlN1rlya ioatymty)2(4methoxyghenyl)- 44 indaflyDrrolidine3-carbox~lic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting indane-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) (minor rotamer) 6 7.25-7.1 in), 6.78 d, J=BHz), 3.89 (1H, d, J=B1-z), 3.75 (3H, 3.50- 2.90 (6H, in), 2.88 (6H, t, J=6Hz), 2.82 (2.80) (3H, 2.04 (2H, t, J=8Hz), 1.48 (2H, septet, J=7Hz), 0.83 (0.73) (311, t, J=7Hz). MS (DCI/NH3) m/e 451 473 (M+Na) 4 Anal.calc. for C 27

H

34 N204 2.5 H 2 0: C, 65.44; H, 7.93; N, 5.65. Found: C, 65.36; 7.45; N, 5.53.

WO 99/06397 PCTIUS98/15479 -166- Exampl 14 tras. ran- .(NMetylN-roOylmifl nlehl(4eh~Pe~)( O The. title compound was prepared by the procedures described in Examples 1 and 49 substituting indole-6-carboxaldehyde, prepared by the method of Rapoport, J. Org. Chem. 51: 5106 (1986), for piperonal in Cl Example 49A. IH NMR (300 MHz, CDCI3) (minor rotamer) 8 8.43 brs), 0 7.57 (1 H, d, J=8Hz), 7.43 (1H, 7.31 (2H1, dd, J=6Hz, 3Hz), 7.22 (1 H, d, N J=8Hz), 7.1 (1H, t, J=3Hz), 6.78 (2H,dd, J=6H-z, 3Hz), 6.45 (1H1, in), 3.93 (1H1, dd, J=6Hz, 3Hz), 3.80 (11H, in), 3.73 (3H, 3.60-2.90 in), 2.86 (2.82) (3H1, 1.47 septet, J=7Hz), 0.83 (0.73L. (3H, t, J=7Hz).

MS

(DCI/NH3) m/e 450 Anal.calc. for C 26 H31 N304 0.75 H20:

C,

67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91.

Examgle 144 trans. trans-i 1 ty--inr-rn Arah~n

J

(34diloracey~prgidin lt n The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobeflzaidehyde for piperonal in Example 49A. IIH NMVR (300 MHz, CDC13) (minor rotainer) 8 7.60-7.3 (4H1, 7.13 (1 H, q, J=9H-z), 6.90 d, J=8H-z), 3.90 (1 H, in), 3.79 (3H, 3.60-2.95 (6H, mn), 2.92 (2.78) 1.55 (2H, septet, J=7H-z), 0.88 (0.73) (3H, t, J=7Hz). MS (DCI/NH:3) m/e 447 Anal~calc. for

C

24

H

28 F2N204 -1.80

H

2 0: C, 60.19; H, 6.65; N, 5.85. Found: C, 60.13;

H,

6.34; N, 5.84.

Example 145 tr n. rn-1 hlN1rpl m h x h nl, (phenl~pyrro' inil3ar i ci d The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) (minor rotamer) 8 7.53 d, J=6H1z), 7.40-7.20 (3H, in), 6.88 (2H, d, J=8Hz), 3.90 (1H, in), 3.79 (3H, -3.70- 2.95 (8H, in), 2.90 (2.79) 1.50 (211, sept, J=7Hz), 0.87 (0.72) (311, t, J=7Hz). MS (OCI/NH3) mle 411 Anal.calc. for C 24

H-

3 oN2O4 2.00 H 2 0: C, 64.55;, H, 7.67; N, 6.27. Found: C, 64.37; H, 7.43; N, 6.29.

17JAR.2005 16:52 17. AR. 005 6:52SPRUSON FERGUSON 61 2 92615486 O 06 P NO. 1096 P. I WO 99/06397 PCFIUS98fIS 479 -167r-xmp~ja 146 trans. trans. 1 -(N-Methyl.N-propmingcarbalymethy-2-4methoX~henYl).

4 4 S The title compound was prepared by the procedures descibed in.

IND Examples 1 and 49 substituting 4-hydroxybeflzaldehYde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3-CD3OD) (minor rotamer) 7.35 (2H, d, J=81-z), 7.28 dd, J=7Hz, 3H-z), 6.90 (21-1 dd, J=7Hz, 3Hz), 6.89.

d, J=8Hz), 3.81 3.65 (11-1. d, J=8Hz), 3.70-3.00 mn), 2.92 i O (2.83) (31-1 1.50 septet, J=7Hz), 0.87 (0.177).(3H, t, J=7Hz). MVS

(D)CIIH

3 W/e 427 Anal.calc. for C 24 H30N2O5 -1.00 1- 2 0; C, 64.85; H, 7.26; N, 6.30. Found: C, 64.82; H, 7.39; N, 6.46.

E;SamnDt 14 trans. trans-I -(N-MdethvI.N-proDvlam inocarbonvirneth vl)-2-(4-M ethoxvytbefly)- 4 (2.4-diMethoXy helpv rrolidinle-3-caroxlc.ca The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-dimethoxybelzaldehyde for piperonal In Example 49A. 1H NMR (300 MHz, CDCls-OD3OD) (minor rotamer) 8 7.61 d, J=8Hz), 7.30 (21-1 d, JB8Hz), 6.82 d, J=8Hz), 6.55 d, J=8H-z), 6.45 O1H, d, J=3Hz), 3.90 (IH, in), 3.81 3.79 3.77 3.70-2.90 (SH, in), 2.85 (3H.1 1.50 sept, J=7Hz), 0.87 (0.77) t, J=7Hz). MS (DCIINH3) We 471 (M+H)4.

AnaI.calc. for C 26 3420 .0.75 H 2 0: C, 64.51; H, 7.39; N, 5.79. Found: C, 64.65; H, 7.07: N, 5.75.

Exanple 148 benzo-2.3-dihdrofu ranyl~pvrrolidifle-3-caboxlic acid The title compound was prepared by the procedures described: in Examples 1 and 49 substituting 2,3-dihydrobeflzofuraf.5carboxaldehyde forpiperoflal in Example 49A. 1 H NMR (300 MHz, CDCI3) 8 7.31 d, J=B1-z), 7.27 d, J=2H-z), 7.18 dd, J=7H-z, 3H-1), 6.86 d, J=8Hz), 6.72 (11H, d, J=8Hz), 4.56 (214, t, J=7Hz), 3.78 (3H, s); 3.62 (1H, in), 3.50-3.25 (411. in), 3.17 t, J~m7Hz), 3.15-2.90 mn), 2.79 (1H, d, J=14Hz), 1.43 in), 1.26 mn), 1.08 (21-1 in), 0.87 (3H-, WO 99/06397 PCT/US98/15479 -168t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 509 Anal.calc.

for C 30

H

40 N205 -0.25 H20: C, 70.22; H, 7.95; N, 5.46. Found: C, 70.2.1; H, 0) 7.92; N, 5.36.

-trns. trans-i N-Dl(n-butyflam inocarboflylm ethyfl 2-(4-m ethoxyphelyl)- 4 4 O) methoxyo~henyflopyrrolidile-3-carboxylic ai 0 The title compound was prepared by the procedures described in Examples 1 and 49- substituting 4-methoxybenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz,. CDCI 3 8 7.38 (2fl, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.87 (4H, dd, J=7Hz, 3Hz), 3.78 (3H, 3.76 (3H, 3.63 (1H, in), 3.50-3.20 (4H, mn), 3.15-2.90 (5H, rn), 2.78 (1H, d, J=l4Hz), 1.43 (3H, mn), 1.27 (3H, mn), 1.09 (2H, mn), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 497 Anal.calc. for C 29

H

4 0N2O5:

C,

.70.13; H, 8.12; N, 5.64. Found: C, 69.78; H, 8.10; N, 5.54.

trans. trans-i1 N-Di(n-butylpinfoc r ~ln th W24-ethoxgyphmnyl.

4 dif Iuoroh en ylpyrro lid ifle- 3-crboxyl ig acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobeflzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, ODC1 3 8 7.35 (iH, in), 7.30 (2H, d, J=BHz), 7.20-7.00 (2H, mn), 6.87 (2H, d, J=8Hz), 3.78 (3H, 3.79 (1H, in), 3.62 (iN, mn), 3.50-3.30 (3H, in), 3.23 (iH, in), 3.15-2.90 (4H, in), 2.78 (1H, d, J=l4Hz), 1.43 (2H, in), 1.27 (4H, mn), 1.08 (2H, in), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH3) in/e 503 Anal.calc.

for C 28

H

36

F

2 N204" 1 H20: C, 64.60; H, 7.36; N, 5.38. Found: C, 64.59; H, 7.20; N, 5.35.

Example 151 trans. trans-i1 N-Di(n-butyflamn inocarbonylmethyF)-2-(4-methoxYi2 enyl) 4 2 .4dimethoxvphenylI)Prroli ine3carbx fir. acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting' 2,4-dimethoxybenzaidehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 8 7.37 (2H, d, J=8Hz), 7.20 (1H, d, J=8Hz), 6.92 (2H, d, J=8Hz), 6.60 (1H, d, J=3Hz), WO 99/06397 PCT/US98/15479 -169- 6.49 01H, dd, J=6Hz, 2Hz), 5.35 (1 H, d, J=8Hz), 4.20 (3H, in), 4.10 (3H, s), 3.83 (3H, 3.81 (3H, 3.75 (3H, in), 3.17 (2H, hep, J=7Hz), 3.05 (2H, t, J=7Hz), 1.30 (4H, mn), 1.07 (4H, mn), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, 0 J=7Hz). MS (DCI/NH 3 mle 527 Anal.oalc. for C 30

H

42

N

2 0 6 1.30 TFA: C, 58.02; H, 6.47; N, 4.15. Found: C, 57.92; H, 6.43; N, 4.07.

Example 152 trans. trans-i N-Di(n-butyl)am ingcarbonylmethyl'i-2-phenfl-l 44 yflyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B.

1 H NMR (300 MHz, CDC13) 8 7.50-7.25 (5H, in), 7.04 (1 H, d, J=3Hz), 6.87 (1H, dd, J=7Hz, 3Hz), 6.74 (1H, d, J=8Hz), 5.94 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.85 O1H, d, J=8Hz), 3.64 (1H, in), 3.42 (3H, in), 3.27 (2H, in), 3.20-2.90 5H, in), 2.81 (1H, d, J=l4Hz), 1.43 (2H, mn), 1.27 (4H, in), 1.05 (2H, in), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH 3 m/e 481 Anal.calc. for C 28 H36N205: C, 69.98; H, 7.55; N, 5.83.

Found: C, 69.69; H, 7.63; N, 5.71.

Exmgle 153 trans. trans-i1 .N-Di (n-butyl)aminocarbonlmethyl)-2-1henfl-4-(Sbenzo- 2 3 dihydrofuranyl)Dyrrolidile-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCl3) 8 7.53 (2H, in), 7.40 (4H, in), 7.13 (1H, dd, J=7Hz, 3Hz), 6.72 (1H, d, J=8Hz), 5.40 (1H, d, J=lOHz), 4.56 (2H, t, J=BHz), 4.18 (1H, d, J=l4Hz), 4.07 (2H, in), 3.79 (2H, in), 3.48 (1H, d, J=l4Hz), 3.35 (1H, in), 3.28 (3H, in), 2.95 (2H, in), 1.47 (2H, in), 1.28 30(4H, in), 1.10 (2H, in), 0.93 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). MS

(DCI/NH

3 m/e 479 Anal.calc. for C 29

H

38

N

2 04 1.10 TFA: C, 62.04; H, 6.52; N, 4.64. Found: C, 61.89; H, 6.44; N, 4.57.

WO 99/06397 PCT/US98/15479 -170- Famgle 154 trans. trans-i1 N-Di (n-buylaioS ~llehYL2.(4tbutylpheny) 4 (benzo- 2 3 -dihydrofuraflyl)pyrroliiifle3-carboxylic acid O The title compound was prepared by the procedures described in Examples 1 and 49 substituting t-butyl benzoylacetate, prepared by the method of Krapcho et al.,.Org. Syn. 47:20 (1967) starting from 4-t- S butylacetophenone, in Example 49B and 2,3-dihydrobeflzofurafl5- S carboxaldehyde for piperoflal in Example 49A. IH NMR (300 MHz, CDC13) 8 7.60-7.30 (6H, in), 6.90 (1 H, mn), 4.50 (2H, in), 3.95 (1 H, mn), 3.85-2.95 (11H, mn), 2.90 (11H, d, J=l4Hz), 1..58 (2H, in), 1,50 (7H, in), 1.41 (6H, 1.10 (2H, mn), 1.00 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). MS (DCI/NH3) Wne 535 Anal.calc. for C 33 H46N204 -0.25 H 2 0: C, 73.50; H, 8.69; N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14.

trans. trans-2-(N N-1i(-uy)a!ncromehl -rn -ethoxyph?,n (4fluoroohe~nyflpyrrolidie3-carbo(ylic ai The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-fluorobeflzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) 6 7.50 (1H, in), 7.42 (111, dd, J=7Hz, 3Hz), 7.36 (2H, d, J=8Hz), 7.01 (3H, t, J=8Hz), 6.87 (1H, d, J=8Hz), 3.83 (1 H, in), 3.8 (3H1, 3.67 (1 H, in), 3.47 in), 3.30-2.90 (5H, in), 2.82 (1H, d, J=l4Hz), 1.43 (2H1, mn), 1.28 (4H, in), 1.08 (2H1, in), 0.90 (31-, t, J=7HZ), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) m/e 485 (M+H) 4 Anal.calc.

for C 28

H

3 7FN204: C, 69.40; H, 7.70; N, 5.78. Found: C, 69.03; H, 8.00; N, 5.74.

trans, trans-i1 N-Di(n-butyl)amiflocpra f let -2(3ur 4 1 -bnzodioxol- 54vflyrrolidifle-3-garboxylic aid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 1 3-oxo3-turanpropionate in Example 49B. 1 H NMR (300 MHz, CDC13) 8 7.41 (2H1, in), 6.97 (1 H, d, J=3Hz), 6.85 (1 H, dd, J=7Hz, 3Hz), 6.72 (1 H, d, J=8H-z), 6.42 (1 H, 5.94 (11-H, d, J=4Hz), 5.92 (1WH, d, J=4Hz), 3.90 (1 H, in), 3.70-3.25 (5H, in), 3.20-2.90 (4H, in), 2.85 d, J=l4Hz), 1.43 (2H1, in), 1.40-1.05 (6H1, in), 0.90 (6H, WO 99/06397 PCT/US98/15479 -171r- n).MS (DCI/NH3) mWe 471 Anal.calc. for C 26

H

34

N

2 06: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.09; H, 7.24; N, 5.87.

trans. trans-i .N-Di(n-butyflam inocalrbonylmethyl)-2-(isOuroDYl) 4 (l .3- O b-enzodioxl-5-yfl Dyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in o) Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 498.

S 1 H NMR (300 MHz, CDCI3) 8 6.85 (1 H, d, J=2Hz), 6.76 (1H, dd, J=6Hz, 2Hz), 6.71 (1H, d, J=BHz), 5.92 (2H, 3.75 (1H, d, J=141-z), 3.66 (1H, q, J=7Hz), 3.42 (3H, mn), 3.25 (3H, in), 3.11 (2H,in), 2.83 (1H, t, J=7Hz), 1.88 (1H, in), 1.55 (4H, in), 1.32 (4H, mn), 0.92 (12H, mn). MS (DCI/NH3) W/e 447 Analcalc. for C 25

H

38 N2015 -0.50 H 2 0: C, 65.91; H, 8.63; N, 6.15. Found: C, 66.07; H, 8.10; N, 6.03.

Example 158 trans, trans-i1 N-Di(n-butyr)am inocarbonylmethyl)-2-(4-t-butylphenyl_ 4 (L .3 ten zodioxo 1-5-l) pyrro Iidinpe.3-carbgxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 4-t-butylbeflzoylacetate, prepared by the method of Krapcho et al., Org. Syn. 47: 20 (1967) starting with 4t-butylacetophenOne), in Example 496. IH NMR (300 MHz, ODC1 3 5 7.32 (4H, d, J=3Hz), 7.04 (1H, d, J=2Hz), 6.87 (1H, dd, J=8Hz, 3Hz), 6.74 d, J=9Hz), 5.94 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.77 (1H, d, J=l4Hz), 3.65-3.25 (5H, mn), 3.15-2.85 (4H, in), 2.73 (1H, d, J=14Hz), 1.45 (2H, in), 1.29 (13H, 1.00 (2H, in), 0.86 (3H, t, J=7Hz), 0.76 (3H, t, J=7Hz).

MS

(DCIINH3) m/e 537 Anal.calc. for C 32

H

4 4N205: C, 71.61; H, 8.26; N, 5.22. 'Found: C, 71.43; H, 8.09; N, 5.11.

Example- 159 trans. trans-i N-Di(nbutlaminocarboflylmethyl)2(4tbutylphenyl- 4 2. 3-dihyd rofuranyl'12yrrolidine3carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) 8 7.30 (1 H, 7.13 (1 H, dd, J=7Hz, 2Hz), WO 99/06397 PCT/US98/15479 -172- 6.82 (1 H, d, J=8Hz), 4.68 (2H, t, J=8Hz), 4.48 (1H, 3.19 (3H, in), 3.80 (3H, in), 3.48 (2H, in), 3.3 (5H, in), 2.41 (1 H, in), 1.65 (4H, in), 1.44 (4H, inm), 1.21 (3H, d, J=5Hz), 1.17 (3H, d, J=5Hz), 1.05 (6H, in). MS (DCI/NH3) O mle 445 Anal.calc. for C 26 H40N204 -1.2 TFA: C, 58.67; H, 7.14; N, 4.8.2 Found: C, 58.54; H, 7.25; N, 4.74.

trans, trans-i1 N-Din-butyl~a incrbI-ety)2-anti-4-ethox cyclohexyl)- 1.3-benodioxoI.5-ylPyrrlidife3carboxcylic acid syn and anti Ethyl 4methoXVyclhexaflOyla=ta Syn, anti-4-Methoxycyclohexane carboxylic acid (5.00 g, 31.6 mmol) and carbonydlmidazole (6.15 g, 37.9 mmol, 1.2 eq) were stirred in anhydrous tetrahydrofuran (50 mL) for 6 hours at room temperature.

At the same time, magnesium chloride (3.01 g, 31.6 mmol) and ethyl malonate potassium salt (7.52 g, 44.2 inmol, 1.4 equivalents) were stirred in anhydrous tetrahydrofuran (75 mL) for 6 hours at 50 OC. The mixture was cooled to room temperature, and the imidazole-acid mixture added to it. The reaction stirred overnight at room temerature.

The solvents were removed under reduced pressure, and the residue was taken up in chloroform/water. The organic phase washed with potassium bisulfate, water, and brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 175 g silica gel, eluting with ethyl acetate in hexanes. Pure fractions of the syn and anti methoxycyclohexyl J-keto esters were obtained. The solvents were removed under reduced pressure to yield the trans4-methoxyclohexyl 1-keto ester (914 mg) as a colorless oil and the cis 4methoxycyclohexyl 13 keto ester (1.07 g) as a colorless oil.

Example 160B trans. trans-i N-Di(n-butyl)am in )ca rbonylIrmethyl)-2- (an ti-4-m etho ycvlo he Mal 4- (1 3 -benzodioxol..Y'- r-idn crbxlic acid The title compound was prepared by the procedures described in Fxanles 1 and 49 substituting the anti-compound resulting from WO 99/06397 PCT/US98/15479 -173- Example 160A in Example 49B. 1 H NMR (300 MHz, CDCI 3 8 6.84 (1 H, d, J=2H-z), 6.76 (1 H, dd, J=7Hz, 2Hz), 6.61 (1 H, d, J=BHz), 5.92 (2H, 3.69 (2H, in), 3.50-3.27 (5H, mn), 3.26 (3H1, 3.25-3.00 (3H, in), 2.88 (1 H, in), 0 1.95 (2H, in), 1.62 (7H, in), 1.33 (9H, in), 0.97 (3H, t, J=7Hz), 0.92 (3H, t, J=7Hz). MVS (DCI/NH3) Wne 517 Anal.calc. for C 29 H44N206 -0.50 H20: C, 66.26; H, 8.63; N, 5.33. Found: C, 66.27; H, 8.50; N, 5.13.

C trns. trans- 1 N -inbtlaioabnl jy)2(y-- tovylha) 4-(1 3bnoixl5-l1yrldne3cryai acid The title compound was prepared by the procedures described in Examples I and 49 substituting the syn-compound resulting from Example 160A in Example 49B. 1 H NMR (300 MHz, CDCI3) 8 6.84 (1 H, d, J=2Hz), 6.77 (1H, dd, J=6Hz, 21-z), 6.61 (1H, d, M=Hz), 5.92 (2H, 3.65 (2H1, in), 3.42 (2H, in), 3.32 (3H, 3.30-3.00 (6H, in), 2.82 (1 H, in), 2.10 (2H1, 1.83 (2H1, in), 1.52 in), 1.33 (4H, mn), 1.20-1.00 (4H, in), 0.96 (3H, t, J=7Hz), 0.91 (3H, t, J=7Hz). MS (DCIINH 3 Wne 517 Anal.calc. for C 29

H

44 N206 -0.30 H 2 0: C, 66.72; H, 8.61; N, 5.37. Found: C, 66.76; H, 8.65; N, 5.28.

Example 162 trans, trans-i1 N-Di(n butyl')ainocarbonlmlethyl- 2 .4-di(5-benzo-2.adihydrofu ran I orrglidine-3-carbgXylic acid Example 162A 5-Acetyl-2 3dihyd roben zoturanl To a 0 OC solution of acetyl chloride (1.64. mL, 23.0 minol, 1.3 equivalents) in mnethylene chloride (30 mL) was added stannic chloride (2.49 inL, 21.3 minol, 1.2 equivalents), maintaining the temperature below 5 OC. The solution was stirred 15 minutes at 0 CC, and then a solution of 2,3-dihydrofuran (2.00 rnL, 17.7 iniol) in inethylene chloride mL) was added dropwise while maintaining the temperature below 8 The dark red solution was stirred 1 hour at 2 0 C and then poured into 50 inL of ice water. The reaction was stirred an additional minutes, and the layers were separated. The organic layer was washed with water and aqueous sodium bicarbonate, dried over magnesium WO 99/06397 PCT/US98/15479 -174sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 150 g silica gel, eluting with D 18% ethylI acetate in hexanes. The solvents were removed under reduced O pressure to yield the title compound (2.68 g, 93%) as a yellow solid.

trans. trans-il N-Diffi-butyl) am ingcarbonylm ethyl) 2 (5-benzo-2 .3- D ~dihydrofuranyflDprrolidine3-arboxvlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 162A in Example 49B and 2 ,3-di hyd robenzof uran 5-carboxald ehYde for piperonal in Example 49A. 1H NMR (300 MHz, CDC13) 8 7.43 (1H, 7.38 (1 H, 7.06 (2H, in), 6.75 (1 H, d, J=6Hz), 6.70 (1 H, d, J=6Hz), 5.40 (1 H, d, J=9H-z), 4.58 (4H, q, J=7Hz), 4.16 (1H, d, J=l4Hz), 4.09 (2H, mn), 3.82 is (2H, in), 3.57 (1H, d, J=14H-z), 3.38 (1H, in), 3.30-3.05 (6H, in), 2.95 (2H, q, J=6Hz), 1.50 (2H, mn), 1.30 (4H, in), 1.15 (2H, in), 0.94 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCI/NH3) mle 521 Anal.calc. for

C

31

H

40 N205 -1.25 TFA: C, 60.67; H. 6.27; N, 4.22. Found: C, 60.49;

H,

6.18; N, 4.13.

Example 163 trans. trans-i I Di(n-butyflam inocarbonylmethyl)-2-(3-f 1-l4-5-beflZ2. 3dihydofu ranylIyrrlidifle3-Carbogylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl I3-oxo-3-uranpropionate in Example 49B and 2 3 -dihydrobenzofuran5carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI 3 8 7.42 (1 H, in), 7.38 (1 H, in), 7.13 (1IH, 7.16 (1H, dd, J=7Hz, 3Hz), 6.70 (1H, d, J=8Hz), 6.41 (1H, in), 4.57 (2H, t, J=7Hz), 3.95 (1H, d, J=8Hz), 3.63 (1H, in), 3.55 (1H, d, J=14), 3.50-3.25 (4H, in), 3.18 (2H, t, J=6Hz), 3.15-2.95 (3H, in), 2.87 (1H, d, J=l4Hz), 1.45 (4H, in), 1.35-1.10 (4H, in), 0.85 (6H, in). MS (DCI/NH3) in/e 469 Anal.calc. for C 27

H

36 N205 -0.25 H20: C, 68.55; H, 7.78; N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82.

WO 99/06397 PCT/US98/15479 c-I -175- FampikJL trans. trans-i N-Di (n-butyl~aminoca 0f~mt~~(~mtoYhnl 4 3 fluorophenyfl Dyrrplidin3cabylcci The title compound was prepared by the procedures described in SExamples 1 and 49 substituting 3-fluorobeflzefecarboxaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDCI3) 5 7.30 (211I, d, cIJ=8Hz), 7.22 in), 6.91 (1H1, in), 6.86 (2H1, d, J=B1-z), 3.79 (1H1, m), S3.78 (3H1, 3.68 (1H, mn), 3.55-3.37 (3H1, in), 3.29 (1H1, in), 3.15-2.90 cI(5H1, in), 2.78 (1 H, d, J=1l4Hz), 1.43 (2H1, in), 1.25 (4H, mn), 1.07 (2H, mn), 0.87 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MIS (DCILNH3) m/e 485 Anal.calc. for C2mH37FN2O4 -0.25 H 2 0: C, 68.76; H, 7.73; N, 5.73. Found: C, 68.87; H, 7.69; N, 5.67.

Example 165 Lmtrns. trans-i1 N-Di (n-butyflanl inocarbonylm ethyfl-2-4-metho(ylhenyl)- 4 pyridyl)o2yrrolidifle-3 -ar~ o cid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-pyridinecarboxaldehyde for piperorial in Example 49A. The nitro styrene was prepared by the method of Bourguignon ,et al., Can. J. Chem. 63: 2354 (1985). 1 11 NMR (300 MHz, CDCI3) 8 8.82 (1H, bs), 8.73 (1H, bd, J=9Hz), 8.62 (1 H, bd, J=7Hz), 7.78 (111I, bdd, J=9Hz, 3Hz), 7.38 (2H1, d, J=1QHz), 6.90 (2H1, d, JlO01-z), 4.39 d, J=l2Hz), 3.95 (114, in), 3.80 (31-1, 3.79 (1H1, in), 3.68 (1H1, d, J=l8Hz), 3.50-3.30 (3H, in), 3.25-2.90 (6H, in), 1.47 (2H, mn), 1.31 (4H, in), 1.20 (2H, mn), 0.92 (3H, t, J=7Hz), 0.83 (3H, t, J=7Hz). MIS (DCI/NH3) m/e 468 Anal.calc. for C 27 H37N3O4 1.65 TFA: C, 55.50; H, 5.94; N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27.

Example 16 trans. tranls- Il-(N. 4Di( ibutyl)pfniflocarbonylmeIh-l)-2(fluo ohnY 3 henzoixl5YlDrOiin3.axlic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 2-f luorobenZOYl acetate in Example 49B. 1 H NMR (300 MHz, CDC13) 8 7.52 (1H1, dt, J=7H-z, 3Hz), 7.25 (1 H, in), .7.13 (1 H, dt, J=7Hz, 3Hz), 7.02 (2H1, in), 6.88 (1H1, dd, J=7Hz, 3Hz), 6.73 (111, d, J=8Hz), 5.93 (1H, d, J=4Hz), 5.92 (1H1, d, J=4Hz), 4.25 (1H, d, J=9H1z), 3.68 (1H1, in), 3.42 (3H, in), 3.39 (1H, in), 3.20-2.95 (4H1, WO 99/06397 PCTIUS98/I 5479 -176- Z in),2.91 (1H, d, J=l4Hz), 1.45 (3H, in), 1.26 (3H, in), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCIINH3) mWe 499 S AnaI.calC. for C 28

H

35 FN205 -0.25 H 2 0: C, 66.85; H, 7.11; N, 5.57. Found: S C, 66.51; 6.67; N, 5.18.

Exgmpile167 _trns. trans-i -N-Di(n butyl)amino rhll etyl2 (-loooell-(13 le-nzodioxol-5-yl)pyrrolidie3-caroxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 3-f luorobe11zoyl acetate in Example 49B. 1 H NMR (300 MHz, CDCI3) 8 7.38 (1H, in), 7.18 (1H, d, J=7Hz), 7.15 (IH, mn), 7.00 (1H, d, J=2Hz), 6.95 (1H, in), 6.86 (1H, dd, J=7Hz, 2Hz), 6.75 (1H, d, J=8Hz), 5.93 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.94 (IH, d, J=14H-z), 3.63 (1H, in), 3.42 (3H, in), 3.35-2.95 (5H, in), 2.87 is(1H, d, J=l4Hz), 1.44 (3H, mn), 1.27 (3H, in), 1.10 (2H, in), 0.88 (3H, t, J=7Hz), 0.81 (3H, t, J=7.Hz). MVS (DCI/NH3) m/e 499 Anal.calc.

for C 28

H

35 FN205: 0, 67.45; H, 7.08; N, 5.62. Found: C, 67.32; H, 7.05; N, 5.40.

Example 168 -trans. trans- 1 4(4-N. N-D (nbtla 4mtoyhnl- .3ben zodioxol-5-VflDiyrrol id ie3-carboxylic acid 4-Nitro-1 -fluorobeflzene, ethyl trans, trans-2 methoxyphenyl)- 4 3 -benzodioxol5y )pyrroli di e3carboxylate (the compound resulting from Example 6A), and diisopropylethylainine are heated in dioxane to give ethyl trans, trans-2-(4-inethoxyphenyl)- 4 (1 ,3-benzodioxol-5-yl)-l 4 -nitrophel)-pyrrolidine-3-carboxylate- The nitro compound is hydrogenated to give the corresponding aminophenyl compound. The aminopheflyl compound is reacted with butyraldehyde and sodium cyanoborohydride according to the method of Borch, J. Am Chein. Soc. 93: 2897 (1971) to give the corresponding

N,N-

dibutylaminophenyl compound. Hydrolysis with sodium hydroxide using the method of Example 1 D affords the title compound.

WO 99/06397 PCT/US98/15479 -177trans trans-i1- (-N.NDibulylaminopyr'mdf.Y)(mtoc~hnl-( 3 enodioxol-5-yl~PYrrolidife3caboxlic acid 2 2-(Dibutylamiflo)-4chlo ropyri mi dine is prepared from 2,4- 'o dichloropyrimidine according to the method of Gershon, J. Heterocyclic 0Chem. 24: 205 (1987) and reacted with ethyl trans, trans-2-( 4 Cl methoxyphenyl) 4 (l 3 -benzodi oxol5yl)pyrro Iidi ne3carboxyl ate o (the compound resulting from Example 6A) and diisoproplyethylamine in O dioxafle with heating to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the methodl of Example 1 D to the title compound.

Using the procedures described in Examples 1, 4, 5, 7, 8 and 9 and Scheme X, the following compounds can be prepared.

Ex. No. Name 170 trntas2(-etoyhnl--13 (j 5 Qpropylaminocarbonylmethyl)pyrrolidine- 3 carboxylic acid, 171 trns trn--4Mtoyhnl-13- -(ethylanhinocarbornylmethyl)pyrrolidine-3carboxylic acid; 172 trans, trans-2(4Methoxyphenyl) 4 methyl pro pyl amino carbon yl methyl)- py rrol idine- 3carboxylic acid; 173 trns tas2(-ehxpny)41,3- -(phenylamiflocarbonylmethyl)pyrrolidine-3-carboxylic acid; 174 trans, trans2(4Methoxyphenyl) 4 -(l13- I -(pipe ridinyl carbonylm ethyl)pyrrolidine-3-carboxylic acid; WO 99/06397 PCTIUS98/1 54'79 -178- 175 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 (pro pyl am inoca rb ony ethyl). p yrrol idin e-3 carboxylic acid; 176 trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yl)-l1-(a- (propylaminocarbonyl)benzyl)-pyrrolidifle-3carboxylic acid; 177 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 -(bis- (p ropyl ami nocarbonyl) met hyl)- pyrrot idi ne-3carboxylic acid; 178 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 (propylaminocarbonyl)ethyl)-pyrrolidifle-3carboxylic acid; 179 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 ropyl am inosulIfonyl methyl)pyrrolidine-3-carboxylic acid; 180 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-l1-(2-phenethyl)-pyrrolidifle-3carboxylic acid; 181 trans, trans-2-(4-Methoxypheflyl)-4-(1 ,3benzodioxol-5-yI)-1 -(pentanoylm ethyl)pyrrolidine-3-carboxylic acid; 182 trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3benzodioxol-5-yl)-1 -(benzoylmethyl)-pyrrolidifle- 3-carboxylic acid; 183 trans, trans-2-(4-M ethoxypheflyl)- 4 ,3benzodioxol-5-yl)-1 -(hexyl)-pyrrolidine-3carboxylic acid; 184 trans, trans-2-(4-Methoxypheflyl)-4-(1 13benzodioxol-5-yI)-1 -(2-hexynyl)-pyrrolidine-3carboxylic acid; 185 trans, trans-2-(4-Methoxypheflyl) 4 1 -(pro poxymethylcarbonylpyrroliciine-3-carboxylic acid; WO 99/06397 PCTIUS98/15479 -179- 186 trans, trans-2-(4-M ethoxypheflYl) 4 (l,3- 1 (phenylacetyI)-pyrrolidifle-3 carboxylic acid; 1 87 trans, trans-2-(4-Methoxyphefl) 4 -(l13benzodioxol-5-yi)-1 -(anilinylcarboflyl)pyrrolidine-3-carboxylic acid; 188 trans, trans-2-(4-MethoxypheflY> 4 -(l13- 1 -(2-acetylamifloethyl)pyrrolidine-3-carboxylic acid; 189 trans, trans2-(4-MethoxyphenYl)- 4 -(l1,3benzodioxol-5-yI)-1 -(2-phenoxyethyI)-pyrrolidile- 3-carboxylic acid; 190 trans, trans-2-(4-MethoxyphelY) 4 -(l13ben zo dioxot-5-yI) 1 be nzod ioxalyfl ethyI)pyrrolidine-3-carboxylic acid: 191 trans, trans-2-(4-MethoxyphelY) 4 -(l13- -(2-tetrahydrofuranlmethyt)pyrrolidine-3-carboxylic acid; 192 trans, trans-2-(4-MethoxyphelY) 4 -(l13- 1-(2- (propylamiflocarboflamiflo)ethenyl)-pyrroidine- 3 carboxylic acid; 193 trans, trans-2-(4-Methoxyphenfl)- 4 (propylaminocarboflylamiflo)ethyl)pyrrolidine- 3 carboxylic acid; 1 94 trans, trans-2-(4-Methoxyphenyl) 4 (l ,3- 1 -(3-oxohex- 1-enyt)pyrroli dine- 3-carboxylic acid; 195 trans, trans-2-(2,4-Di methoxypheny) 4 benzodioxol-5-yl)-l1-(propylamilocarboflmethYl)pyrrolidine-3-carboxyliC acid; 196 trans, trans-2-(2-Carboxy-4methoxyphenyl)- 4 (1 ,3-benzodioxo-5-y)l1 (propylamiflocarbofl m ethyl pyrrol idi ne- 3 carboxylic acid; WO 99106397PCUS/I57 PCT/US98/15479 -180- 197 trans, trans-2-(2-Am in oca rbonyl-4methoxyph~enyl)-4-( 1,3- be nzodioxol-5-yI)-1 (p ropylami nocarbonyl m ethyl) -pyrrol idi ne-3carboxylic acid; 198 trans, trans-2- (2 -Meth anesulf on amido-4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1- (propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 1 99 trans, trans-2-(2-Aminocarbonylmethoxy-4methoxyphenyl)-4-(1 ,3-benzodioxoI--yI)-l- (propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 200 trans, trans-2-(2-Methoxyethoxy-4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 (propylaminocarbonyl methyl) -pyrrol idine-3carboxylic acid; 201 trans, trans-2-(2-Carboxym ethoxy-4methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1 (pro pylamin ocarbonyl methyl) -pyrrol idin e-3carboxylic acid; 202 trans, trans-2-(4-Methoxy-2tetrazolylmethoxyphenyl)-4-( 1,3-benzodioxol-5yI)-1 -(propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 203 trans, trans-2- (2 -All ylo xy-4-methoxyphenyl) -4- (1 ,3-benzodioxol-5-yI)-1 (propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 204 trans, trans 2,4 -Bis (4 -m eth oxyp h enyl) -1 (p ropyla m in o carbo n y Imet hyl1) -py rroIi d ine -3 carboxylic acid; 205 trans, trans 2,4-Bis(1 ,3-benzodioxol-5-yI)-1 (propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; WO 99/06397 PCT/US98/15479 206 trans, trans -2-(4-Methoxypheflyl)- 4 3 I -(N-methyl-Npropylaminocarbonylmethyl)-pyrrolidifle- 3 carboxylic acid; 207 trans, trans-2-(4-MethoxyPhelYl) 4 1,3benzodioxole-5-yl)-1 -(N-methyl-Nbutylaminocarbonyl)pyrrolidile-3-carboxylic acid; 208 trans, trans-2-(4-Methoxyphel)- 4 1,3benzodioxol-5-yl)-1 -(N-methyl-N-(4methoxyphenyl)amilocarboflyl)-3-pyrrolidifle- 3 carboxylic acid; 209 trans, trans ethoxyp heflYl)- 4 benzodioxol-5-yl)-1I -m ethyl- Nphenylaminocarboflyl)-pyrrolidile-3-carboxylic acid; 210 trans, trans-2-(4-Methoxypheflyl)-4-(l13benzodioxol-5-yt)-1 -(N-methyl-Nallylaminocarbonylmethyl)-pyrrolidifle- 3 carboxylic acid; 211 trans, trans-2-(4-MethoxyphelYl) 4 ethyl- N-(nbutyl)aminocarboflylmethyl)-pyrrolidifle- 3 carboxylic acid; 212 trans, trans-2-(4-Methoxypheflyl)- 4 -(l13benzodioxol-5-yl)-l1-(N -methyl-Niso butyl amino ca rbonflImethyl)- py rro lid in e-3carboxylic acid; 213 trans, trans-2-(4-Methoxyphefl)- 4 -(l13- 1 -(N-rn ethyl- Ncyclopentylaminocarboflylmethyl)pyrrolidine- 3 carboxylic acid; 214 trans, trans-2-(4-Methoxypheyl) 4 (1, 3 1 -(N-methyl-N-(2methoxyethyl)amiflocarbofyl)pyrrolidine- 3 carboxylic acid; WO 99/06397 WO 9906397PCTIUS98/15479 -182- 215 trans, trans.2-(4-Methoxyphenyl)-4-( 1,3- 1 -(N-methyl-Nbutoxyethylaminocarbonyl)-pyrrolidifle- 3 carboxylic acid; 216 trans, trans-2-(1 Ben zod ioxol-5-yl)-4-(4methoxyphenyl)- 1 -m ethyl- Npropylaminocarbonyl methyl)-pyrrolidine-3carboxylic acid; 217 trans, trans-2-(4-Methoxyphefyl) 4 (l.

4 benzodioxan-6-y)-1 -(N-methyl-Npropylaminocarbonymethyl)-pyrrolidifle- 3 carboxylic acid; 218 trans, trans-2-(4-Methoxypheflyl)- 4 benzodioxol 1 ethyl- Nisopropylaminocarbonylmethyl)-pyrrolidile- 3 carboxylic acid; 219 trans, trans MethoxypheflYl)- 4 (1,3benzodioxol-5-yl)-1 -(N-methyl-Nethylaminocarbonylmethyl)-pyrrolidifle- 3 carboxylic acid; 220 trans, trans-2-(4-MethoxypheflYl)- 4 3 benzodioxot-5-yl)-1 -(N-methyl-N-( 1methylpropyl)aminocarboflmethyl)-pyrrolidile- 3 carboxylic acid; 221 trans, trans MethoxyphelYl)- 4 1,3benzodioxol-5-yl)-1 -(N-methyl-NphenylaminocarbOflylm ethyl)-pyrrolidifle-3carboxylic acid; 222 trans, trans-2-(4-Methoxypheflyl)-4-(l ,3- 1 -(N-methyl-Npropylaminocarbonyl)ethyl)-pyrrolidifle- 3 carboxylic acid; 223 trans, trans-2-(4-Methoxypheflyl)- 4 3 benzodioxol-5-yl)-1 -(a-(N-methyl-Npro pylaminocarbonyl)belzyl)-pyrrolidifle-3carboxylic acid; WO 99/06397 WO 9906397PCT/US98/1 5479 -183- 224 trans, trans -2-(4-Methoxypheflyl)- 4 1 -(N-ethyl-Npropylaminocarbonylmethyl)-pyrrolidile-3carboxylic acid; 225 trans, trans-2-(4-MethoxyPheflYl)- 4 ,3benzodioxole-5-yi)-1 N-ethyl-Nbutylaminocarboflyl)-pyrrolidile-3-carboxylic acid; 226 trans, trans-2-(4-MethoxyphelYl) 4 benzodioxol-5-yl)-1 N-ethyl-N-(4methoxyphenyl) aminocarbonyl)-3-pyrrolidifle-3carboxylic acid; 227 trans, trans-2(4-MethoxypheflYl)- 4 benzodioxol-5-yl)-1 -(N-ethyl-Nphenylaminocarboflyl)-pyrrolidile-3-carboxylic acid; 228 trans, trans-2-(4-Methoxyphel)- 4 ,3benzodioxol-5-yl)-1 -(N-ethyl- Nal lylami noca rbolylrflethyl) pyrroI i dine-3carboxylic acid; 229 trans, trans-2-(4-Methoxypheflyl) 4 -(l3benzodioxol-5-yI)-1 -(N-ethyl-NisobutylaminocarboflYlmethyl)-PYrrOlidi ne-3carboxylic acid; 230 trans, trans-2-(4-Methoxyphelyl) 4 (l13benzodioxol-5-yi)-1 -(N-ethyl-Ncyclopentylaminocarbonylmethyl)-pyrrolidine- 3 carboxylic acid; 231 trans, trans-2-(4- Metho xypheflYl)- 4 3 1 -(N-ethyl-Nmethoxyethylamiflocarboflyl)-pyrrolidie 3 carboxylic acid; 232 trans, trans-2-(4-Methoxypheflyl)-4-(l,3- -(N-ethyl-Nbutoxyethylamilocarboflyl)-pyrrolidifle- 3 carboxylic acid; WO 99/06397 PCTIUS98/15479 -184- 233 trans, trans-2-(1 Ben zodi oxolI-5-yI)-4-(4methoxyphenyl)- 1 -(N-ethyl-Npro pyl am inocarbo nyl met hyl) -pyrrol idifle-3carboxylic acid; 234 trans, trans Met hoxypheflyl)-4- (l,4benzodioxan-6-yI)- 1 -(N-ethyl-Npropylaminocarbonylmethyl)-pyrrolidifle- 3 carboxylic acid; 235 trans, trans-2-(4-M ethoxypheflyl)-4-( 1,3benzodioxol-5-yl)-1 -(N-ethyl-Nisopropylaminocarbonylmethyl)-pyrrolidifle- 3 carboxylic acid; 236 trans, trans-2-(4-Methoxypheflyl)- 4 1,3benzodioxol-5-yI)-1 diethylaminocarbonylmethyl)-pyrrolidifle-3 carboxylic acid; 237 trans, trans-2-(4-Methoxypheflyl)-4-(l ,3benzodi oxol-5-yl)- 1 -ethyl- 1methylpropyl)aminocarbolylmfethyl)-pyrrolidifle- 3 carboxylic acid; 238 trans, trans -2-(4-Methoxypheflyl)-4(l, 3 benzodioxol-5-yl)-1 -(N-ethyl-Nphenylaminocarboflyl m ethyl) -pyrrolid ifle- 3 carboxylic acid; 239 trans, trans Metho xypheflyl)- 4 (1,3benzodioxol-5-yl)-1 -(N-ethyl-Npropylaminocarbonyl)ethyl)-pyrrolidifle- 3 carboxylic acid; 240 trans, trans-2-(4-M ethoxyphefl)l 4 (l, 3 benzodioxol-5-yl)-l1-(ct-(N-ethyl-Npro pylamin ocarbony) b ezyl)-pyrro lid inle- 3 carboxylic acid; 241 trans, trans Met ho xypheyl)-4- (1,3 b enzodioxol 1 -m ethyl- Ni sobutyl amino carbo nyl m ethyl)- pyrrolidifle- 3 carboxylic acid; WO 99/06397 WO 9906397PCTIUS98/15479 -185- 242 trans, trans -2-(4-MethoxyPhelY) 4 1 3 1 -(N-methyl-Ncyclohexyl ami nocarbofnl lmethyl)-pyrrolidi ne- 3 carboxylic acid; 243 trans, trans Metho xyphefnl)- 4 (l13benzodioxol-5-y1)-l dipropylaminocarboflylmethyl)hpyrrolidine- 3 carboxylic acid; 244 trans, trans-2-(4-MethoxyphelY) 4 3 1 -(isobutyloxyethyl4pyrrolidine-3-carboxylic acid; 245 trans, trans-2-(4-MethoxypheflY)- 4 (1, 3 -I utylsulf onyl)- pyrro i dinle-3carboxylic acid; 246 trans, trans-2-(4-Methoxyphefl)- 4 -(l1,3- 1- (isopropylsulfolamiloethyl)-pyrrolidine- 3 carboxylic acid; 247 trans, trans-2 (4-Met ho xyphenlY) 4 ,3- 1- (ethoxymethylcarbolylmethyl)-pyrrolidine- 3 carboxylic acid; 248 trans, trans-2 -M ethoxy phefnl)- 4 ('13- 1-(2-ethylbutyrylmethyl)pyrrolidine-3-carboxylic acid; 249 trans, trans Met ho xyphenyI) 4 ('13- -(N-methyl-N-(3, 4 di methoxybelzyl)amilocarbonylmethYl)pyrrolidine-3-carboxylic acid-, 250 trans, trans-2-(4-MethoxypheylY) 4 R)-1 -(N-methyl-Nprop .ylaminocarboflyl)butylWpyrroidine- 3 carboxylic acid; 251 trans, trans2-(4-Methoxypheny) 4 3 S)-1 -(N-methyl-Npropylaminocarboflyl)butyl]Vpyrroidine-a carboxylic acid-, WO 99/06397 WO 9906397PCTIUS98/15479 252 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- 1 -(3-isopropoxypropyl)pyrrolidine-3-carboxylic acid; 253 'trans, trans-2-(4-Methoxyphenyl)-4-(1,3ben zodioxol 1 (5-m ethyl hexyl) -pyrroli di ne- 3-carboxylic acid; 254 trans, trans Met ho xyp he nyl)-4- (1,3benzodi oxol 1 ethyl -2 -hexe nyl)pyrrotidine-3-carboxylic acid; 255 trans, trans-2-(4-Methoxyphelyl)-4-(1 3benzodioxol 1 methyl -4-h exeflyl)pyrrolidine-3-carboxylic acid; 256 trans, trans-2-(4-Methoxypheflyl)- 4 3 benzodioxot-5-yI)-1 ,5-dimethyl-2-hexenyl)pyrrolidine-3-carboxylic acid; 257 trans, trans Met ho xyp heflyl) (1,3benzodioxol-5-yl)-1 -(2-(N-methyl-Niso butyryl ami no)eth yl)-pyrroti dine-3-ca rboxyl ic acid; 258 trans, trans-2-(4-Methoxyphefl)- 4 1 3 benzodioxol-5-yI)-1 -(N-methyl-N-(2 ,2di methyl propyl) amiloca rb ofnl m ethyl) pyrroli difle- 3-carboxylic acid; 259 trans, trans-2-(4-Methoxyphel)-4-(1 ,3benzodioxot-5-yl)-1 -(N-ethyl-Nbutylaminocarbonylmethyl)-pyrrolidifle-3carboxylic acid; 260 trans, trans-2-(4- Met ho xyp heflyl)-4-(l ,3benzodioxol-5-yl)-l1-(N-rnethyl-Nbenzylaminocarbolylmethyl)-pyrrolidifle- 3 carboxylic acid; 262 trans, trans-2-(4-Methoxypheflyl)4(5-ifdaflyl)l (N-methyl-N-propylamilocarboflylmethyl)pyrrolidine-3-carboxylic acid; WO 99/06397 WO 9906397PCTIUS98/15479 -187- 262 trans, trans-2-(4-Methoxyp he nyl) 4 2 3 dihydrobelzof urafl-5-yi)-1 -(N-methyl-Npropyl ami nocarbonyl methyl)pyrrol idi ne- 3 carboxylic acid; 263 trans, trans-2-(4-Methoxypheflyl) 4 (l methylindol-5-yl)-l1-( N-methyl-Npropylaminocarbonylmethyl)-pyrrolidifle- 3 carboxylic acid; 264 trans, trans2-(4-Methoxyphelyl)4(2-naphthyl)- 1 -(N-methyl-N-propylamilocarboflylmthyl)pyrrolidine-3-carboxylic acid;, 265 trans, trans-2-(4-MethoxyphelYl) 4 ,2dimethoxy-4-phenYl)-l1-(N-methyl-Npropylam inocarbol rlethyl) pyrro i di necarboxylic acid; 266 trans, trans Meth oxyphel)l- 4 (1 -m eth oxy-3phenyl)-l1-(N-methyl-Npropylami nocarbol m lethyl) -pyrrolidi ne- 3 carboxylic acid; Examples 267-288 Following the procedures described in Example 1 and Scheme 11, the following compounds can be prepared.

267 trans, trans-3-(4-Methoxyphenyl)SO(13- .(propyl ami nocarbofylm ethyl) piperidine-4-carboxylic acid; 268 trans, trans-3-(4-M ethoxypheflYl) 5 (l,3- 1 .(ami nocarboflyl methyl)piperidine-4-carboxylic acid; 269 trans, trans-3-(4-Methoxyphelyl) (l13- -(4-fluorobeflzyl)-piperidine- 4-carboxylic acid; 270 trans, trans-3-(4-Methoxypheflyl)5(l3benzodioxolSYl)-l -(2-ethoxyethy)-piperidine- 4 carboxylic acid; WO 99/06397 WO 9906397PCTLTS98/I 5479 -188- 271 trans, trans -3-(4-Methoxyphenyl)-5-(1 ,3- 1 -(2-propoxyethyl)-piperidifle- 4-carboxylic acid; 272 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3benzodioxol-5-yi)-1 -[2-(2-methoxyethoxy) ethyl]-.

pipe rid ine-4-carboxylic acid; 273 trans, trans-3-(4-Methoxyphenyt)-5-(1 ,3benzodioxol-5-yi)-1 -pyridyl) ethyl]piperidine-4-carboxylic acid; 274 trans, trans-3-(4-Methoxypheflyl)-5-( 1 p3benzodioxol-5-yi)-1 -(morpholin-4-ylcarbonyl)piperidine-4-carboxylic acid; 275 trans, trans-3-(4-Methoxyphenyl)-5-(1 13benzodioxole-5-yi)-l1-(butylaminocarbonyl)piperidine-4-carboxylic acid; 276 trans, trans-3-(4-Methoxypheflyl)-5-( 1,3benzodioxol-5-yI)-1 methoxyphenylaminocarbolyl)-3-Pi peridine-4carboxylic acid; 277 trans, trans-3-(4-M ethoxyphenyl)-5-(l,3ben zodioxoi-5-yi) 1 acetyl pipe ridine-3-carboxylic acid; 278 trans, trans-3-(4-M ethoxypheflyl)-5-(1,3benzodioxol-5-yI)-l1-(2-furoyl)-piperidine-3carboxylic acid; 279 trans, trans-3-(4-Methoxypheflyl)-5-(l,3- 1 -(phenylaminocarboflyl)piperidine-4-carboxylic acid; 280 trans, trans-3-(4-Methoxyphenyl)-5-(1 ,3benzodioxol-5-yi)-1 -(allylaminocarbonylmethyl)piperidine-4-carboxylic acid; 281 trans, trans-3-(4-Methoxypheflyl)-5-(l,3benzodioxol-5-yI)-1 butylaminocarboflylmlethy)-piperidile-4-carboxylic acid; WO 99/06397 PCT[US98/15479 'A -189- 282 trans, trans-3-(4-Methoxyphefl)l>5-l ,3benzodioxol-5-yl)-1 -(N-n-butyl-Nmnethyl ami nocarbaflyl methyl)pipe ridi ne- 4 carboxylic acid; D 283 trans, trans (4-M et hoxyphefyl)- 5- (l13benzodioxol-5.yI)-1-(pyrrolidifl-l- KI ylcarbonylmethyl).piperidile-4-CarboxYlic acid; 284 trans, trans-3-(4-Methoxypheflyl)-5-(l 3benzodioxol-5-yi)-1- (isobutylaminocarboflylmethyl)piperidIne-4, carboxylic acid; 285 trans, trans-3(4-Methoxypheflyl)-5-(l 3..

(cyclopentylanfocarboflylmethyl)piperidine- 4 carboxylic acid; 286 trans, trans.3-(4-Methoxypheflyl)-5S(l,3..

benzodioxol-5-yl)-l1-(morpholin-4ylaminacarbonylmethyl)-piperidine-4carboxylic acid; 287 trans, trans-3-(4-Meth0xypheflY)5(1, 3 1 phen oxyethyl)-piperi dine- 4-carboxylic acid; 288 trans, trans ethoxypheflyl)5(l, 3 benzodioxol-5-yl)-1 (methoxyethylailocarbolYl)pipe ridin e-4-carboxylic acid.

Example 289 trans. trans-- 2-(4-Methoxypheflyl)-4-(l .3-benzodioxol-5-yI)-l 4dibutylaminophelyl)-pyrrolidifle3-carboxylic acid 4-Nitro-fluorobeflzefe, ethyl trans, trans-2-(4-methoxypheflyl)- 4 (1 ,3.benzodioxol.5yI)..pyrrolidifle-3-carboxylate (example 6A) -and diisopropyl ethylamine are heated in dioxane to give ethyl trans,trans-2- (4-methoxyphenyl)-4-(l ,3..benzodioxol5y)-1-(4nitrophenyl)pyrroli dine-3-carboxyl ate. The nitro compound is hydrogenated to the corresponding aminophenyl compound. This is reacted with butyraldehyde and sodium cyanoborohyd rde according to the method of Borch Am Chem. Soc., 93, 2897, 1971) to: give the corresponding

N,N-

WO 99/06397 WO 9906397PCTIUS98/1 5479 -190dibutylaminopheflyl compound, which is hydrolyzed with sodium hydroxide using the method of example 10 to give the- title compound.

trans. trans-2- (4-Megthoxyh eflyl)- 4 l .3 -ben zod ioxol--y)1 dibutylamino-1Dyrimidine-4yfl)Dyrrolidinle-3-carboxylic acid \1 ~2-(Di butyl amino) 4-chloropyrimidine is prepared from 2-4dichioropyrimidirle according to the method of Gershon Heterocyclic \1 Chem. 24, 205, 1987). This compound, ethyl trans, trans-2-(4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-pyrroljdifle-3-carboxylate (example 6A), and di-isopropyl ethylamine are heated in dioxane to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the method of example 1D to give the title compound.

Example 291 trans. trans-2-(4-Methoxyphenyl)- 4 1.3-benzodioxol-5-y')- 1 -(N-butyl-N- ~h enylam inocarboflyl methyl) -oyrrol idin e-3ca rbo(l ic acid The title compound was prepared according to the general procedure of Example 1. 1H NMR (CD 3 00) 8 0.87 1.2-1.35 1.35-1.5 2.78 (in, 211); 3.10 (t,1H, 3.26 (d,1H,J=15); 3.44 (dd,1H,J=5,10);, 3.5-3.7 3.77 3.78 5.93 6.7-6.9 7.0-7.2 7.4 MS (DCI/NH 3 m/e 531 Anal calcd for C 31

H-

34

N

2 0 6 C, 70.17; H, 6.46; N, 5.28.

Found: 0,70.36; H, 6.52; N, 4.99.

Examole 292 Sodium trans. trans-2-(4-Methoxy~helyl)- 4 1.3-benzodioxol-5-yfl-1 N-dihn butvl~aminocarboflylmeth vI)-pyrrolidine-3-carboxylate Examgle 292A Ethyl 34methoxy~henvYl-3 -o xo rOpiofate Simultaneous reactions were run in both a 65-L reactor and a L reactor that share the same reflux system. A nitrogen atmosphere was maintained in both. 4.0 kg (100 moles) of 60% sodium hydride in mineral oil and 32 L toluene were charged into the ambient temperature reactors. The mixture was agitated for 5 minutes and .qllowed to settle. 20 L of the toluene solution was aspirated. 28 L of WO 99/06397 PCT/US98/15479 -191- Z toluene was added, agitated for 5 minutes, allowed to settle and 28 L of the toluene solution was aspirated. 68 L of toluene and 8.4 L (69.7 moles) diethyl carbonate were added. The agitation was begun and the flow of Syltherm (Note 4) in reactor jackets was initiated. A solution of 5.0 kg (33.3 moles) 4-methoxyacetophenone in 12 L toluene was added over 20 minutes. When additions were complete, the jacket S temperaturewas reduced to 100 C and stirring continued for 16 hours.

S A solution of 6.7 L (117 moles) glacial acetic acid in 23 L deionized water was fed at the same rate that was previously used for the acetophenone solution. When addition was complete, agitation was stopped and the layers separated. The aqueous layer was washed once with 13 L toluene. The combined organic layers were washed twice with 6.7 L portions of 7% aqueous sodium bicarbonate. The toluene solution was washed once with 6.7 L of 23% aqueous 1i sodium chloride The organic solution was dried over 10 kg sodium sulfate, filtered, and the solvent removed on the rotary evaporator to provide the desired product.

Example 292B 3.4-Methvlenedioxv- 1-(2-nitroethenyl)-benzene In a 45-L cryogenic reactor with a contoured, anchor stirrer was dissolved 5.537 kg (36.9 moles) piperonal in 9 L methanol and 2.252 kg (36.9 moles) nitromethane at 150-200 C. The jacket temperature was set to -50 C and the reaction solution cooled to a temperature of +3.50 C. A 210 C solution of 3.10 kg (38.8 moles) 50% aquous sodium hydroxide diluted with 3.7 L water was pumped in. The reaction temperature was maintained between 100-150 C. When addition was complete, the jacket temperature was reset to 10 C and stirring continued for 30 minutes. A mixture of 7 kg ice in 19 L water was added to dissolve most of the solid. The reaction mixture was filtered through canvas and then a 27R10SV Honeycomb filter. The filtered solution was metered into a 210 C mixture of 7.4 L concentrated hydrochloric acid in 11.1 L deionized water. The final reaction temperature was 260 C. The resulting product was centrifuged and washed until the wash pH rose to at least 6 (by pH indicating paper).

The crude product was dissolved in 92 L dichloromethane and the layers separated. The aqueous layer was washed once with 8 L WO 99/06397 PCT/US98/15479 1-192dichloromethane. The combined organics were dried over 1.32 kg S magnesium sulfate and filtered through Whatman #1 paper. The volume was reduced to 20% and the solution cooled to 40 C. Filtration through Whatman #1 paper, followed by ambient temperature drying in vacuo with an air leak afforded 1.584 kg of a first crop Concentration of the MLS to 25% followed by similar cooling, filtration, and drying afforded 0.262 kg of a second crop. The yellow product darkened on standing in light and air.

Example 292C Ethyl 2-(4-methoxvbenzoyl)-3-(1.3-benzodioxol-5-yl)-4-nitrobutanoate Into a 45-L stirred reactor at ambient temperature were charged 5.819 kg (30.1 moles) 3,4-methylenedioxy-1-(2-nitroethenyl)-benzene and 24 L ethyl acetate A solution of 5.355 kg (24.1 moles) ethyl 3-(4methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1,8-diaza-bicyclo[5.4.0]undec-7-ene in four equal portions was added over a 2.5 hour period. The reaction mixture was filtered through dicalite and the resulting filtered solution was used in the next step without any further purification.

Example 292D Ethyl 2-(4-methoxyphenvl)-4-(1.3-benzodioxol-5-vyl-4.5-dihydro-3H- Dvrrol-3-carboxylate The product of Example 292C (1316 ml solution consisting of 300 g Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxyphenyl)-4 nitrobutanoate in ethyl acetate) was added to a glass reactor containing RaNi 28 (300 The reaction mixture was shaken under a hydrogen environment of 4 atm at room temperature for 18 hoursand filtered through a nylon 0.20 micron 47 mm millipore.

The filtrate was concentrated to 1.4 kg of dark solution and purified by normal phase silica gel chromatography eluting with 85:15, hexanes: ethyl acetate. The pure fractions were combined and concentrated (as above) until crystals formed. The solution was cooled to 00 C and filtered. The solid was washed with 2 L of 85:15, hexane: ethyl acetate (00 The solids were dried in vacuo at 50° C to a constant weight of 193.4 g (21% yield, melting point 80-81° C) of the

I

WO 99/06397 PCT/US98/15479 -193title compound. A further 200 g (23% yield) of product was obtained from the mother liquors.

Example 292E Ethyl 2-(4-methoxyDhenyl)-4-(1.3-benzodioxol-5-yl)-pyrrolidine 3- O carboxvlate (N Into a 12-L flask equipped with magnetic stirring, addition funnel, O temperature probe, and nitrogen inlet was charged 0.460 kg ethyl 2-(4- N, methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-4,5-dihydro-3H pyrrole-3-carboxylate (1.25 mol). The reaction vessel was degassed with nitrogen. Absolute 3.7 L ethanol and 1.12 L of THF were added. 31 mg bromocresol green and 94.26g sodium cyanoborohydride (1.5 mol) were added. A solution containing 400 mL absolute ethanol and 200 mL of 12 M HCI was then added. The reaction mixture was stirred for minutes after addition was complete. After the starting material was consumed, 0.5 L of 7% aq. NaHCO3 was added. The reaction mixture was concentrated and diluted with 5 L ethyl acetate. The organic layer was washed twice with 2 L of 7% aq. NaHCO3 and once with 2.5 L of 23% aq.

NaCI, the dried over 190g MgSO4, filtered, and concentrated to give 447 g of the title compound as a thick yellow oil.

Example 292F Ethyl 2-(4-methoxypheny)-4-(1.3-benzodioxol-5-vl)-1-(N.N-di(nbutyl)aminocarbonylmethyl) pyrrolidine 3-carboxvlate Into a 22-L flask equipped with overhead stirring, nitrogen inlet, and condenser was charged ethyl 2-(4-methoxyphenyl)-4-(3, 4 methylenedioxyphenyl)-pyrrolidine-3-carboxylate (2.223 kg,6.02 mol).

The reaction vessel was degassed with nitrogen. 13.2 L ofacetonitrile, 3.66 L diisopropylethylamine (2.71 kg, 20.9 mol), and 1.567 kg dibutylamidomethyl bromide (6.26 mol) were added. The mixture was refluxed at 78° C for 17 hrs. After the disappearance of starting material the mixture was concentrated until crystals formed. The solid was filtered and washed with 4 L ethyl acetate (00 C).

Concentrating of the filtrate was continued as above until all volatiles were removed. The residue was diluted with 40 L ethyl acetate and washed with 20 L deionized water. The organic layer was washed with 8 L of 23% aq. NaCI nad dried over 0.399 kg MgSO4 and filtered.

WO 99/06397 PCT/US98/15479 t- 194- Concentration as above provided 3.112 kg (96 yield) of the title compound as a dark oil.

SExample 292G trans, trans-2-(4-MethoxyDhenyl-4-( 1.3-benzodioxol-5-yl)-Dvrrolidine 3-carboxylate and preoaration of trans.trans 2-(4-methoxvDhenyl)-4- (3.4-dioxvDhenvl-Dvyrrolidine-3-carboxvlic acid ethyl ester Into a 35-L reactor equipped with overhead stirring, nitrogen inlet, and condenser was charged 3.112 kg ethyl 2-(4-methoxyphenyl)- 4-(3,4-methylenedioxyphenyl)-pyrrolidine 3-carboxylate (5.78 mol).

16.4 L of absolute ethanol was added and the reaction vessel was degassed with nitrogen. 0.115 kg of sodium ethoxide (1.69 mol) was added and the mixture was refluxed at 790 C for 1 hr. The mixture was cooled to 150 C and 5 L of 7.6 M NaOH solution (38.1 mol) was added. The mixture was stirred at 150 C for 18 hrs. The solvent was evaporated and the residue dissolved in 15.8 L of deionized water and extracted with 28 L of ether. The ether solution was washed with 9.5 L deionized water. The aqueous wash was extracted with 3 L ether. 0.340 L of 12 M HCI was added to the aqueous layer. The aqueous layer was extracted with 24 L of ethyl acetate. The organic layer was washed with 9 L of 23% aq. NaCI, dried with 0.298 kg MgSO4 filtered, and concentrated to give 2.132 kg of a dark oil. The oil was triturated with 18 L ether. The undesired solids were filtered and saved for later use. The mother liquors were concentrated to obtain 1.102 kg of light foam. The foam was dissolved in 5.5 L ethyl acetate with heating to 650 C. 14 L hexane was added slowly enough to keep the solution refluxing. The reaction mixture was cooled to 100 C and filtered. The crystals were washed with 2 L ether (00 C) and dried to constant weight in vacuo at 500 C to give 0.846 kg (43% yield, melting point 119-120) of crude product, which was further purified by normal phase silica gel chromatography.

Example 292H Sodium trans trans-2-(4-methoxyDhenvl-4-( 1.3-benzodioxol-5-yl)- 1- (N.N-di(n-butvl)aminocarbonylmethyll pyrrolidine 3-carboxylate Into a 20-L flask was charged trans,trans 2-(4-methoxyphenyl)- 4-(3,4-methyledioxyphenyl)-1 -(N,N-dibutylamino- carbonyl methyl) pyrrolidine 3-cartoxylic acia (0.927 ky, 1.G19 ni. A soution WO 99/06397 PCT/US98/15479 .195- Z0.0720 kg NaOH (1.80 mol) dissolved in 4.65 L methanol was added. The reaction mixture was concentrated to an oil. Pentane (4 L) was added and the solution concentrated again. Pentane (4 L) was added again and concentration of this solution gave a light tan foam. The foam was dried 0 in vacuo at 500 C to a constant weight of 0.937 kg (97% yield) of the title compound.

Example 293 trans-trans-2-(4-MethoxyphenlW4-(l .3-benzodioxol-5-yl)-1 rdecahydroisoguinolin-2- carbonylmethyll-Dyrr-idine-3-carboxylic The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) shows a mixture of isomers. MS (DCI/NH3) mlz 521. Anal calcd for C 30

H

36 N20 6 1.3 TFA: C, 58.54; H, 6.62; N, 4.19 Found: C, 58.34; H, 5.58; N, 4.00 Example 294 trpns-trans-2-(4-Methoxyphenyfl- 4 .3-benzodioxol-5-yi)-1 -r3,3dimethylpiperidinyl- garbonylmethyll-pyrrolidine-3-carbgxylic acid.

The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) indicates presence of rotamers. 8 0.84 3H), 0.86 3H), 1.35-1.6 (in, 4H), 3.83 3H), 5.96 2H), 6.81 I1H, 6.90 (dd, I1H, 7.01 2H, 7.03 1H), 7.47 2H-, MS (DCI/NH 3 m/z 495. Anal calcd for C 28 H34N206 1.4 TEA: C, 56.55; H, 5.45; N, 4.28 Found: C, 56.52; H, 5.83; N, 4.26 Example 295 trans- trans-2-(4--Meth oxyphenyl 4 1.3-benzodi oxol.5..yl) 1 prOlyl.N-iso-butoxycarbonylamliflo)ethll1yrrolidine3carboxYlic acid The title compound was prepared by the methods detailed in Example 61, but substituting propylamnine for methylamine in Example 61B and isobutyl chloroformate for isobutyryl chloride in Example 610.

The crude product was purified by trituration with 1:1 diethyl ether/ hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (C~DC 3 300 MHz) 8 0.80 3H, 0.92 (in, 3H), 1.43 2H, J=7Hz), 1.7-1.9 (in, 1H), 2.72 (in, 1H), 2.90 (mn, 2H), 3.10 (in, 2H), 3.25 (in, 2H), 3.40 (mn, 1H), WO 99/06397 WO 9906397PCTIUS98/15479 '4.-196- 3.55 (in, 1H), 3.62 (in, 1H), 3.7-3.9 (in, 2H) 3.78 3H), 5.95 2H), 6.72 1H-, J= 8Hz), 6.82 (in, 3H), 7.00 1H), 7.30 2H, J=8Hz). MS (DCI/NH3) mie 527 Anal calcd for C 29

H

3 8N206 -0.5 H 2 0: C, 65.03; H, 7.34; N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95.

t-ransa-tran&2-(4-Mdethoxylhenyl- 4 -(l.3-benzodioxol-5-yfl-1 41i.2.3.4letrahvdrgoiguiflolin- 2 carbonvlmethYIl12PYrrotidne-3-carboxylic The title compound was prepared using the.procedures described in example 1. NMR (CD 3 OD, 300 MHz) indicates presence of rotamers. 2.97 (mn, 2H), 4.68 3H), 5.97 2H), 6.83 1 H, 6.9-7.0 (in, 3H), 7.03 1H,- 7.1-7.3 (in, 4H), 7.4-7.5 (in, 2H). MS (DCI/NH3) mlz 515.

trans-trans-2-(4-Mehoxyphenyl- 4 -(l.3-benzodioxol-5-fl-l -r2-(N- 12ropyl -N-di methyl ai nocarboflyl ami no)ethyll1- yrro lid ine3ca rbo xyli V The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for inethylanline in Example 61B and dimethylcarbamyl chloride for isobutyryl chloride in Example 61C. The crude product was purified by preparative 1-PLC (Vydac iC1 8) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1 H NMR (CDC13, 300 MHz) 8 0.70 3H, J=7),.1.28 (mn, 2H), 2.75 3H), 2.82 (in, 2H), 3.1-3.45 (in, 4H), 3.70 (in, 1 3.80 3H), 3.90 (in, 3H), 4.72 (in, 1KH), 5.95 2H), 6.75 I1H, J= 8Hz), 6.87 (in, 3H), 7.05 1 7.40 (d, 2H, J=8Hz). MS (DCI/NH3) m/e 498 (M+H) 4 Anal calcd for C 27 Has5N 3 O6~ 1.25 TEA: C, 55.35; H, 5.71; N, 6.56. Found: C, 55.41; H, 5.71; N, 6.41.

Example 298 trans. trans-2-(4-Methoxyphenl)l 4 .3-benzodioxol-5-YIV- 1 pr y N-(-ntobneeufony)ain)ehl-yroid e3 carboxylic acid Using the procedures described in Eample 66, the title compound r~ reared qq nyellow solid. mjo. 85-87'C. 1H NMVR (CDCI3, 300 MHz) WO 99/06397 WO 9906397PCT/US98/15479 -197- 60.77 J=7.5Hz, 3H), 1.38 (sextet, J=7.5Hz, 2H), 2.20-2.29 (in, 11H), 2.57-2.66 (in, 2.82-3.15 (in, 4H), 3.22 J=7.5Hz, 2H) 3.38 (dd,.

J=3Hz,J=9Hz, I1H), 3.49-3.57 (in, 1 3.59 J=9Hz, 1 3.83 3H), D 5.96 2H), 6.73 J=8Hz, 1H), 6.82 (dd, J=lHz,J=8Hz, 1H), 6.87 (d, J=9Hz, 2H), 6.98 J=lHz, 1H), 7.27 J=9Hz, 2H), 7.82 J=9Hz, 2H), D 8.23 J=9Hz,2H). MS (DCI/NH3) m/e 612 D Example 299 trans, trans-2-(4-Methoxypheflyfl- 4 .3-benzodioxol-5-yfl-1 12gy1Nnpnaeuinlmn~ehl-yrlcie3croyi acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 59-610C 1H NMR (CDC1 3 300MHz) 6 0.79 J=7.5Hz, 3H), 0.90 J=6Hz, 3H), 1.26-1.32 (in, 4H), 1.43 (sextet, J=7.5Hz, 2H), 1.67-1.76 (mn, 2H), 2.23-2.32 (in, 1H), 2.70-3.08 (mn, 7H), 3.15-3.32 3.42 (dd, J=3Hz,J=9Hz, 1H), 3.52-3.57 (in, 3.63 J=9Hz, 3.80 3H), 5.95 2H), 6.73 J=7.5Hz, 1H), 6.83 (dd, J=lHz,J=7.5Hz, 1H), 6.87(d, J=8Hz, 2H), 7.00 J=lHz, 1H), 7.32 J=BHz, 2H). MS (DCI/NH3) Wne 561 Example 300 trans, trans-2-(4-Methoxyhenyl) 4 -(l.3-benzodioxol-5-yfl- 1 -(2(N prplN(-rflooehxbneeufnlaioehu pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p.122-124 0 C. 1 H NMR (CD3OD, 300MHz) 80.75 J=7.5Hz, 3H), 1.26-1.45 (in, 2H), 2.96-3.08 (in, 2H), 3.23 (bs, 2H), 3.35-3.45 (in, 2H), 3.52 J=lOHz, 1H), 3.81 J=9Hz, 2H), 3.86 (s, 3H), 3.92 J=9Hz, 1H), 4.63 J=lOHz, 1H), 5.97 2H), 6.82 (d, J=9Hz, 1H), 6.93 (dd, J=3Hz,J=9Hz, 1H), 7.06-7.08 (in, 3H), 7.46 (d, J=9Hz, 2H), 7.56 J=9Hz, 2H), 7.89 J=9Hz, 2H). MS (DCI/NH3), in/e 651 WO 99/06397 PCT/US98/15479 DK -198- Example 301 trans. trans-2-(4-Methoxyghenl)l- 4 (l.3-benzodioxol-5-yfl-I Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 69-71 0 1 H NMR (CDCI3, 300MHz) 8 "A 0.79 J=7.5Hz, 3H), 1.93 (sextet, J+7.5Hz, 2H), 1.92 3H), 2.25-2.35 11H), 2.68-2.77 (in, 1H), 2.85-3.28 (in, 7H), 3.40 J=9Hz, 1H), 3.52- DK 3.68 (mn, 2H), 3.66 J=9Hz, I1H), 3.80 3H), 4.92 1 5.07 1 H), 5.97 21H), 6.74 J=7Hz, 1H), 6.82-6.89 7.01 7.33 (d, J=9Hz, 21H). MVS (DCI/NH3), mWe 545 Example 302 trans-trans-2-(4-MthoxvgheflYi) 4 .3-benzodioxol-5-yb)-1 412ethyl pi oerid! nyl-carbonfl miethYll1 pyrro i din e 3 carboxylic acid.

The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) shows a mixture of isomers. 8 0.75 3H, 1.4-1.7 (in, 8H), 3.84 3H), 5.96 2H), 6.83 1 H, 6.91 1 H, 7.0-7.1 (in, 3H), 7.52 2H, MS (DCI/NH3) in/z 495. Anal calcd for C 2 8

H

3 4N206 1.6 TEA: C, 55.35; H, 5.30; N, 4.14.

Found: C, 55.26; H, 5.37; N, 4.01 Examlnle Q3 trans, trpns-2-(4-Methoxypheflyl)- 4 .3-benzodioxol-5-yl)-1 propyl-N-(2-methylgrogaflesulfonfl~laiino~ethyl)pyrroidine- 3 carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 72-73 0 C. 1H NMR (CDCI3, 300 MHz) 8 0.82 J=7.5Hz, 3H),1.04 J=6Hz, 6H), 1.44(q, J=7.5Hz, 2H), 2.15-2.33 (m,21H), 2.57-2.75 (in, 2H), 2.84-3.08'(in, 3H), 3.12-3.21 (mn, 1H), 3.23- 3.45 (mn, 1H), 3.43 J=llHz, 1H), 3.55-3.62 (in, 1H), 3.66 J=9Hz, 1H), 3.80 3H), 5.95 2H), 6.75 J=9Hz, 1H), 6.83 (dd, J=lHz,J=9Hz, 1H), 6.87(d, J=9Hz, 2H), 7.02 J=lHz, 1H), 7.33 J=9Hz, 2H). MS (DCI/NH3) m/e 547 M+iH)+.

WO 99/06397 WO 9906397PCT/US98/15479 '4 -199- Exam ple 30Q4 -l trans. trans-2-_(4-Methoxypghefl)fl 4 3-benzodioxol--l)1

(-N

p2rooyl-N-heptplesUlfoflylamiflo~ethyI)-pyrrolidine 3 carboxyli aid D Using the procedures described in Example 66, the title compound was prepared as a white solid. m-p.58-59 0 C. 1 H NMR (CDCI3, 300MHz) 8 D0.80(t, J=7.5Hz, 3H), 0.'88 J=7Hz, 3H), 1.23-1.36 (in, 8H), 1.94 (qt r) J=7.5Hz, 2H), 1.71(quintet, J=7Hz, 2H), 2.23-2.32 (in, 1H), 2.70-3.09(m, D 7H), 3.13-3.32 3.43(dd, J=3Hz,J=9Hz, 1H), 3.52-3.58(m,1H), 3.65(d, J=9Hz, 1H), 3.80 3H), 5.96(s, 2H), 6.73 J=7Hz, 1H), 6.83 (dd, 1=1Hz, J=7Hz, 1H), 6.87(d, J=9Hz, 2H), 7.01(d; J=lHz, 1H), 7.32(d, J=9Hz, 2H). MS (DCI/NH3) mWe 589 Example -305 trans-trans-2-(4-MethoXyphenYl)- 4 .3-benzodioxol-5-yl')-l -f2-(Nethyl-N-ethoxycarbonl apfmin oethyl-pyrroi d ine 3 ca rboxyl ic acid Prepared by the methods detailed in Example 61, but substituting ethylamine for methylamine in Example 61 B and ethyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac jiCl8) eluting with a 10-70% gradient of CH 3

CN

in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. IH NMR (CDCI3, 300 MHz) 8 0.90 3H, 1.22 (in, 3H), 3.0-3.2 (in, 4H), 3.42 (in, 3.78 3H), 3.82 (in, 4H), 4.10 2H, J=7Hz), 3.5 (br s, 1H), 5.97 (dd, 2H, J=1,7Hz), 6.72 1H, J= 8Hz), 6.84 (mn, 3H), 7.00 1H), 7.42 2H, J=8Hz). MS (DCI/NH3) mWe 485 Anal calcd for C 2 r 6

H

32 N2O7 1.2 TFA: C, 54.90; H, 5.39; N, 4.51. Found: C, 55.01; H, 5.36; N, 4.56.

trans. trans-2-(4-Methoxyphenyl) 4 -l .3-benzodigol-5-l1-(2-(NprplNhxnsloyaioehl-yrldn--abxlc acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.59-60 0 C. 1 HNMR (CDC13, 300MHz) 8 0-80(t, J=7.5Hz,3H), 0.89(t, J=7Hz, 3H), 1.25-1.36(mn, 6H), 1.53(sextet, 2H), I .72(quintet, J=7Hz, 2H), 2.23-2.32(mn, 1 2.72-3.08(m, 7H), 3.15-3.32(in, 2H), 3.43(d, J=9Hz, 1H), 3.55-3-62(m, 1H), 3.65 (d, J=lOHz, 1H), 3.80(s, 3H), 5.96(s, 2H), 6.74(d, J=7.5Hz,1H), 6.82(d, WO 99/06397 WO 9906397PCTfUS98/1 5479 -200- J=7.5Hz,1H), 6.87(d, J=9Hz, 2H), 7.O1(s,1H), 7.32(d, J=9Hz,2H). MS (DCI/NH3), mle 575 Example -307 trans -trans--2-(4- Ethyl phel)-4-(1 ben zodi oxol 1 -rN.N-di(n- D butyl)aminocarbolylmethyll-pyrrolidile-3-carboxylic acid.

'A

The title compound was prepared using the procedures described D in examples 1 and 49, substituting ethyl 4-ethyl ben zoylacetate (prepared by the method of Krapcho et al., Org. Syn. AL, 20 (1967) starting with 4'-ethylacetophenone) in procedure 49B. NMR (C~DC 3 300 MHz) 8 7.31 (2H, d, J=BHz), 7.16 (2H, d, J=8Hz), 7.03 (1H, d, J=3Hz), 6.86 (111, dd, J=8&3Hz), 6.73 (1H, d, J=9H-z), 5.94 (1H, d, J=4Hz), 5.92 (1H, d, J=4Hz), 3.77 (1H, d, J=9Hz), 3.60 (1H, in), 3.53-3.23 (5H, mn), 3.13-2.90 (4H, in), 2.73 (1H, d, J=l4Hz), 2.62 (2H, q, J=9Hz), 1.45 (2H, in), 1.40- Is 1.10 (6H, in), 1.02 in), 0.87 t, J=7H-z), 0.78 (3H, t, J=7Hz). m/e (DCl, NH 3 509'(MH+) Anal.calc. for C 30

H

40

N

2 Os C 70.84, H 7.93, N 5.51.

Found C 70.80, H 7.85, N 5.25.

Examlle 308 trans- trans-2 ethoxyphe nyl)-4 1.3-ben zodi oxol- 5-yl) 14-2-N prplN(-hootoycronlmn~tylproiie3 carboxylic acid Prepared by the methods detailed in Example 61, but substituting propylamine for inethylamine in Example 61B and 2-chioroethyl chloroforinate for isobutyryl chloride in Example 610. The crude product was purified by trituration with 1:1 diethyl ether/ hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (COCl 3 300 MHz) 6 0.80 3H, J=7), 1.22 (mn, 3H), 2.15 (in, 1 2.75 (in, 1 2.85 (in, 1 3.1 (mn, 2H), 3.25 (in, 3.5 (in, 311), 3.65 (mn, 2H), 3.80 3H), 4.18 (in, 1 4.30 (in, I1H), 5.98 6.72 (mn, 1 6.82 (mn, 3H), 7.00 (mn, 1 7.30(mn, 2H).

MS (DCI/NH 3 Wne 533 Anal calcd for C 27

H

33

N

2 07C1: C, 60.84; H, 6.24; N, 5.26. Found: C, 60.48; H, 6.04; N, 5.10.

WO 99/06397 WO 9906397PCTIUS98/15479 -201trans-trans-2-(2-Methoxyethvi)- 4 -(l.3-benzodioxol-5-yfl-l1-lN.N-di(nbutyflaminocarboflylmethyll12yrrolidine3carboxylic acid.

O The title compound was prepared using the procedures described in example 1, substituting ethyl 5-methoxy-3-oxoPefltafoate for ethyl 4o methoxybenzoyl acetate in Example IA. The title compound is a yellow foam. 1H c-~NMR (CDCI3, 300 MHz) 8 0.91 J=7Hz) and 0.95 J=7Hz, 6H total), 1.28-1.41 (br O m, 4H), 1.45-1.63 (br m, 4H), 2.00-2.20 (br m, 2H), 3.06 (br t. J=9Hz, 1 3.30 (s) c~and 3.20-3.68 (br m, 11 H total), 3,72-4.10 (br m, 4H), 5.92 2H), 6.72 1 6.82 (dd, J= 1.5, 8.5Hz, 1 6.91 J=1.5Hz, 1 MS (FAB) m/e 463 Anal calcd for C 2 5H 3 8N 2 05-H2O: C, 62.48; H, 8.39; N, 5.83. Found: C, 62.13; H, 8.15; N, 5.69.

Example 310 trans. transt 2-(4-Methoxyphenl)l4-(l.3-be nzodi oxol 1 ethyl-N -n-pentanesulfgn yl amin) ethyl)pyrroli di neacarbo xylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.57-58 0 C. 1 H NMR (CDC13, 300MHz) 6 0.89(t, J=7Hz, 3H1), 1.06(t, J=7.5Hz, 1.26-1.37(m, 4H), 1.72(quintet, J=7.5Hz, 2.22-2.32(m, 1H), 2.71 -2.96(m,5H), 3.08-3.30(m,4H), 3.95(d, J=9Hz, 1H), 3.53-3.60(m, 1H), 3.67(d, J=9Hz,1H), 3.80(s, 1-H), 5.97(s, 2H), 6.73(d, J=9Hz, 1H),.6.82(d, J=9Hz,1H), 6.88(d, J=9H-z, 7.33(d, J=9Hz, 2H). MS (CDI/NH3) m/e 547 Example 311 trans-tran-2-(4-MethoxyPhelYl) 4 -(l.3-benzodioxgl-5-yl)-1 -lEN.Ndicyclohexylamino carbonylmethyll-pyrrolidifle-3-carboxYlic acid The title compound was prepared using the procedures described in example 1. -NMR (CD 3 OD, 300 MHz) 6 1.0-2.0 (in, 20H), 3.0-3.1 (in, 2H-), 3.80 3H), 5.95 2H), 6.75 1 H, 6.86 (dd, 1 H, 6.95 (d, 21-, 7.04 (d 1 H, 7.38 2H, MS (DCI/NH3) m/z 563.

Anal calod for C 33

H-

42 N206 0.5 H 2 0: C, 69.33; H, 7.58; N, 4.90 Found: C, 69.42; H, 7.29;, N, 4.78.

WO 99/06397 WO 9906397PCTIUS98/15479 -202trains-trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)-1 -r2-(N- 0 p ropyl -N-te rt- butoxya ro yl am io) ethyl I-pyrrolid i ne-3ca rboxy ic The title compound was prepared using the procedures described S in example 61, -substituting propylamine for aqueous methylamine in 'l Example 61 B and di-tert-butyldicarbonate for isobutyryl chloride in C) Example 61C. NMR (CD 3 OD, 300 MHz) suggests presence of rotamers 8 0.81 3H, 1.2-1.5 (in, 11H), 3.78 3H), 5.92 (dd, 2H, J=1,2), 6.74 1H, 6.84 (dd, 1H, 6.92 2H-IJ=9), 6.99 (bd s, 1H), 7.35 2H. MS (DCI/NH3) m/z 527. Anal calcd for C 29 H38N207: C, 66.14; H, 7.27; N, 5.32 Found: C, 66.,05; H, 7.36; N, 5.15.

trans- trans-2-(4-Mthoxy-3-f uo rophenl)-4-(1 .3-ben 1 -[N.N-di(n-butyl)aminocarbonylmethyl-yrrolidile-3-carboxylic-- acid, The title compound was prepared using the methods described in examples 1 and 43, using 4-methoxy-3-fluoro acetophenone in place of 4-methoxy acetophenone. m.p. 142-143 NMR (CDC1 3 300 MHz) 8 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.03-1.50 (in, 8H), 2.82 J=l3Hz, 1H), 2.90-3.13 (in, 4H),.3.20-3.50 (in, 3H), 3.39 J=13H, 1H), 3.55-3.65 (in, 1H), 3.82 J=lOHz, 1K), 3.87 3H), 5.91 (dd, J=2Hz, 4Hz, 2H), 6.72 J=8Hz, 1H), 6.83-6.91 (in, 2H), 6.99 J=2H-z, 1H), 7.06 (in, 2H).

Anal calcd for C 2 9

H

37

N

2 06F: C, 65.89; H, 7.06; N, 5.30 Found: C, 65.82; H, 7.13; N, 5.29.

Examole 314 trans, trans-2-(Progyl)-4-( 1.3-benzodioxol-5-yl)- 1 -(2-(N-orooyl- 12entanesu lfonvlamino~ethyl)1yrrolidine-3-carboaylic acid Examole-314A Prolyl pentpnesulfonamide Pentane sulfonyl chloride (687 mg, 4.03 mmol) was dissolved in 5 mL

CH

2 01 2 and added to an ice-cooled solution of n-propylamine (0.40 mL, 4.82 inmol) and ethyldilsopropylamine (0.85 mL, 4.88 mmol) in 5 mL CH 2

CI

2 under a nitrogen atmosphere. The reaction was stirred at 0 00 for 30 min, then at 25 00 for 4 h. The Soiuiiunl wkl ont~re betec 2) mL A! 10 M Nq, I- 4 ~n 25 mL WO 99/06397 WO 9906397PCTIUS98/I 5479 -203-

CH

2 CI2. The organic phase was washed sequentially with 25 mL H 2 0 and 25 mL brine, then dried (Na2SQ4), filtered, and concentrated in vacuo to provide 739 mg (3.83 mmol, 95%) of the title compound as a white solid. TLC (25% EtOAc-hexane) Rf 0.23; 1 H NMR (CDCI3, 300 MHz) 8 0.92 J=7Hz, 3H), 0.97 J=7Hz, 3H), 1.28- 1.50 (br m, 4H), 1.52-1.68 (in, 2H), 1.75-1.90 (br m, 2H), 2.98-3.06 (in, 2H), 3.08 (q, J=6Hz, 2H), 4.10-4.23 (br m, 1H); MS (DCI/NH 3 m/e 211 (M+NH 4 Examp~e 149B~ Ethyl trans. trans--4-( 1.3-benzodioxol-5-yl)-1 -(2-broinoethyl-2-roDlYrrolidine- 3 cab.xy.late The title compound was prepared according the procedure of Example 61 A, substituting the compound of Example 94B for the pyrrolidine mixture.

Examgle 314C Ethyl trans. trans-2-(Prol~vI)-4-( 1.3-benz!odioxol-5-yl)- 1 (2-(N-Qrogylpentanesulfonylamino)ethyflDyrrolidine3carboxylate A solution of the compound of Example 314A (6.6 mng, 34 pmol) in 0.1 mL DMF was treated with sodium hydride (2 mg, 60% oil dispersion, 1.2 mg NaH, laimol). The resulting mixture was stirred at room temperature for 15 min, then a solution of the compound of Example 189B (9.0 mng, 22 jun01) in 0.1 mL DMF was added, followed b y 0.5 mg of tetra-n-butylammonitim iodide. The reaction was sealed under argon and stirred at 60 00 overnight. The reaction was concentrated under high vacuum, and the residue was partitioned between 2 mL of saturated aqueous NaHCO3, 1 mL water and 5 mL EtOAc. The organic phase was washed with 1 ml brine, dried by passing through a plug of Na 2 SO4, and the filtrate concentrated in vacuo to an oil. The crude product was purified by preparative TLC (silica gel, 8 x 20 cm, 0.25 mm thickness, eluting with 20% EtOAc-hexane, providing 8.4 mng of the title compound as a wax.

Examn~le 314D trans, trans-4-(1 .3benzodioxol-5-Yfl-2-(Propyl)-1 -(2-(N-lorooyIp2entanesufonvlamino'~ethyl)D2Yrrolidine 3 carboxYlic acid The title compound was prepared according to the procedure of Example 710C. 1 H NMR (00013, 300 MHz) 8 0.88-1 .00 (mn, 9H), 1.20-1.55 (br m, 6H), 1.55-1.68 (in, 3H), 1.70-1.85 .(br in, 2H), 1.90-2.16 (br in, 2H), 2.84-3.26 (br in, 6H), 3.26-3.90 (br in, 6H), 5.95 2H), 6.76 J=BHz, WO 99/06397 WO 9906397PCT/US98/1 5479 '4 -204- 1 6.79 (in, 1 6.93 (br s, 1 HRMS (FAB) calcd for C251-4 1

N

2 0 6

S

497.2685, found 497.2679.

D Example 315 trans. trans.2-(4-MethoxyPhelYl)-4-(1 .3-benzodioxol-5-yl)-1 D proovl-N-dimethylsulfamoylamilo'ethyflLpyrrglidifle-3carboxyic acid r) Using the procedures described in Example 66, the title compound D was preapred as a white solid. m.p.59-61 0 C. 1 H NMR (CDCI3, 300MHz) 8 0-.79 J=7.5Hz, 3H), 1.45(sextet, J=.5Hz, 2H), 2.22-2.31(m,11-), 2.65(s, 6H), 2.70-2.79(m, IH), 2.85-3.04(m, 4H), 3.09-3.32(m, 2H), 3.40(d, J=9Hz, 1H),3.55 J=9Hz,1H), 3.65(d, J=9Hz,1H), 3.81(s, 3H), 5.96(s,2H), 6.75(d, J=9Hz, 1H), 6.83(d, J=9Hz, 1H), 6.88(d, J=9Hz, 2H), 7.02(s, 1H-), 7.34(d, J=9Hz, 2H). MS (DCIINH3) m/e534 aml31 trans -trans-2-(4-Methgxphenyl)- 4 .3-ben zodioxol-5-yl) -1 r2-(Nprolyl-N-[4-methoxyphenyllsulfoflylamino~proDyl1pyrrolidine- 3 carboxylic acid xmle36 Ethyl trans-trans and cis-trans 2-(4-Methoxylphenyfl-4-( 1.3-benzodiox- -14-3-bromogropyfl pyrrolidine-3-carboxylate A 2:1 mixture of trans-trans and cis-trans ethyl 2-(4methoxyphenyl)-4-( 1,3-benzodiox-5-Vl) -pyrrolidi ne-3-carboxyl ate (4.00 g; prepared according to example 10), 32 ml dibromopropane, and 200 mng sodium iodide, were heated at 1000, for 1.25 hrs. The excess dibromopropane was removed in vacuo and the residue was dissolved in toluene. After shaking with potassium bicarbonate, the solution was dried (Na2SO4) and the solution concentrated. The residue was chromatographed on silica gel eluting with 5:1 hexane:EtOAc. yielding 5.22 of the title compound.

WO 99/06397 PCTIUS98/15479 -205- Examole 316B Ethyl trans-trans and cis- trans -2-(4-Methoxyo~heflyl)-4-( 1.3-benzodiox- 1.(3-propylaminopropyl) gyrrolidine-3-carboxylatpe The compound described in Example 316A (5.22 g) was heated at 800 for 2 hrs.with 35 ml. ethanol, 2.5 g. propylamine and 35 mg. sodium iodide. The solvents were removed in vacuo. The residue was dissolved Sin toluene, shaken with potassium bicarbonate solution and dried 0 (Na2SO4). The soilution was concentated in vacuum to give 4.96 g of the N- title compound as an orange oil. This was used in the next step without pu ri f ication.

Example 3160 trans -trans-2-(4-M ethoxghenyl)- 4 enzod ioxol-5-yfl- 1 -f2-(Npropyl-N-[4-methoxyphenyl~sulfonylamino~propyllbDyrrolidine- 3 croylcai Using the method described in example 66, the compound prepared in Example 316B was reacted with 4-methoxybenzelesulfolYl chloride in acetonitrile containing diisopropylethylamine. The resulting product was chromatographed on silica gel (30% EtOAc in hexane), and hydrolyzed to the title compound by the method of example 1D. NMR

(C~DC

3 300 MHz) 8 0.83 J=7Hz, 3H), 1.40-1.52 (in, 2H), 1.56-1.70 (in, 2H), 2.00-2.11 (in, 1H), 2.40-2.51 (mn, 1H), 2.69-2.78 (in, 1H), 2.84-3.03 (in, 4H), 3.19-3.34 (in, 2H), 3.48-3.59 (in, 2H), 3.80 3H), 3.86 3H), 5.95 2H), 6.74 J=8Hz, 1H), 6.85 J=8Hz, 3H), 6.93 J=81-z, 2H), 7.02 J=2Hz, 1H), 7.29 J=8Hz, 2H), 7.69 J=8H-z, 2H). Anal calcd for C 32

H

3 8N2QBS: C, 62.93; H, 6.27; N, 4.59. Found: C, 62.97; H, 6.39; N, 4.45.

Example 317 trans-trans-2-(4-Methoxphenyl- 4 -(l.3-benzodioxol-5-yfl-l propyl-N -1ropylsulf ofyl mino propyllpyrrol idine 3 carboxyli c acid Using the method described in example 66, the propylamino compound prepared in Example 31 6B was reacted with propanesulfonyl chloride in acetonitrile containing diisopropyl ethyl aminle. The resuling product Was chromatographed on silica gel.(30% EtOAc in hexane) and hydrolyzed to the title compound by the method of example 10. NMIR (CDC13, 300 MHz) 8 0.85 J=7Hz, 3H), 1.02 J=7Hz, 3H), 1.47-1.60 WO 99/06397 WO 9906397PCT/US98/15479 -206- (in, 2H), 1.65-1.85 (in, 4H), 2.04-2.16 (in, I1H), 2.42-2.57 (in, I1H), 2.72- 3.11 (in, 5H), 3.25-3.41 (in, 3.50-3.62 (in, 2H), 3.80 5.85 2H), 6.72.(d, J=81-z, 11H), 6.80-6.90 (in, 3H), 7.02 J=2Hz, 7.30 (d, 0J=9Hz, Anal calcd for C 28

H

38 N207S: C, 61.52; H, 7.01; N, 5.12 Found: C, 61.32; H, 7.01; N, 5.01.

Example 318 trans. tr-ans--2-(3-Fluoro-4-methoxylhenlI 4 1.3-benzodioxol-5yl) I 2-(-pr y tanesUI onla )ehl yr 3 carboxylic acid Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.66-68 0 C. 1 H NMR (CDCI3, 300MHz) 8 0.81(t,J=7.5Hz, 3H), 0.89(t, J=7Hz, 3H), 1.26-1.35(m, 4H), 1.45(sextet, J=7.5Hz, 2H), 1.68-1.76(m, 2H), 2.25-2.33(m, 1H), 2.72-2.92(m, 2.97-3.1 2(m, 2H), 3.1 6-3.33(m,2H), 3.43(dd, J=3Hz,J=9Hz,1H), 3.53-3.60(m, 1H), 3.66(d, J=lOHz, 3.88(s, 3H), 5.95(s, 2H1), 6.74(d, J=8Hz, 1H), 6.82(dd, J=lHz,J=8Hz,1 6.92(t, J=8Hz,1H), 6.97(d, J=lHz, 111), 7.12(d, J=8Hz, 1H), 7.18(dd, J=lHz,J=l2Hz, 11H). MS (DCI/NH3) mle 579 Example 319 trans-trans-2-(4-Pyridiflyl)- 4 1.3-benzodioxol-5-yf)l-rN.N-di(nbutyl)aminocarbonylmethyll-pyrrolidine-3-carboxylic acid.

The title compound was prepared using the methods described in examples 1 and 43, using methyl 3-oxo-3-(4-pyridyl)propafloate Am.

Chem. Soc. 1993, 115, 11705) in place of ethyl (4methoxybenzoyl)acetate. m.p. 131-132 IC. NMR (CDCI3, 300 MHz) 8 0.82 J+7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.50 (in, 8H), 2.90 (dd, J= 7Hz, 9H1z, 1H), 2.974(d, J=l3Hz, 3.00-3.25 (mn, 4H), 3.32 (in, 1H), 3.39 (d, J=l3Hz, 1H), 3.45-3.52 (in, 1H), 3.67-3.78 (in, 1H), 4.10 J=9Hz, 1H), 5.92 (dd, J=2Hz, 4 Hz, 2H), 6.75 J=9Hz, 1H), 6.90 (dd, J=9Hz, 2Hz, 1H-), 7.02 J=2Hz, 7.45 J=8Hz, 2H), 8.50 J=8Hz, 2H). Anal calcd for C 2 7H35N305: C, 67.34; H, 7.33; N, 8.73 Found: C, 67.39; H, 7.45; N, 8.61.

WO 99/06397 WO 9906397PCT/US 98/15479 Nj .207- Example 320 trans- trans-2(4-M ethoxyph enl)- 4 "(l.3-benzodioxg I-5-yl) -1 -f 2-(Nprogyl.Ndiethylmincarbonylpmino)ethyllpyrrolidine 3 carboxylic The title compound was prepared using the procedures described D in example 61, substituting propylamine for aqueous methylamine in A Example 61 B and diethylcarbamyl chloride for' isobutyryl chloride in D Example 61C. NMR (CD 3 OD, 300 MHz) 8 0.74 3H, 1.09 6H, "A 1.33 (in, 2H), 3.17 4H, 3.78 3H), 4.04 (in, 1 5.93 (s, 2H), 6.86 1H, 7.06 (dd, 1H, 6.94 2H, 7.04 1H, 7.40 2H, MS (DCI/NH3) m/z 526. Anal calcd for

C

29

H

39

N

3 06 0.1 TFA: C, 65.31; H, 7.34; N, 7.82 Found: C, 65.33; H, 7.43; N, 8.14.

xml32 trans-trans-2-(4-MethoxyphenYfl 4 .3-benzodioxol-5-yi)- 1 dimethylgiperidinyl- carbonylmethyll.pyrrolidine-3-carboxylic acid.

The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) shows mixture of isomers. 8 0.88 3H, 0.93 3H, 3.82 3H), 5.95 2H), 6.82 1 H, 6.89 (dd, 1H, 7.00 d, 2H, 7.03 (in, 1H), 7.47 2H, MS (DCI/NH3) m/z 495.

Example 322 trans-trans-2(4-Methoxyphenyl)Y 4 .3-benzodioxol-5-yil-I

-N.N-

di(s-butyl)aminocarbonylmfethyll-pyrrolidine3carboxylic acid.

The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) suggests a mixture of isomers. 8 0.83 6H, 1.27 6H, 1.6 (in, 2H), 3.79 3H), 5.93 2H), 6.75 1 H, 6.86 I1H, 6.94 2H, 7.03 1 H, J=2), 7.35 2H, MS (DCI/NH3) mlz 511.

WO 99/06397 WO 9906397PCTIUS98/15479 -208- Example 323 trans-trans-2-(4-MethoxyohenYfl-44 1 .3-benzodioxol-5-yfl)-1-rN-(2- D Methylphenyl)I-N-butylamifl0 carbonylmet hyll-gyrrolidine-3-carboxylic The title compound was prepared using the procedures described DK in example 1. MS (DCI/NH3) mlz 545. Anal calcd for C 32

H

36

N

2 0 6 0.9 r) H 2 0: C, 68.53; H, 6.79; N, 4.99 Found: 0, 68.56; H, 6.62; N, 4.71.

Example 34 trans-trans-2-(4-MethoxyphelYl)-4-( 1.3-benz-odioxol-5-yl)-1 Methylphenyfl-N-butylamino carbonylmethyll-pyrrolidine-3-carbo~yi The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) d 0.88 3H, 1.2-1.5 (in, 4H), 2.31 3H), 2.8 (in, 2H), 3.14 1 H, J=1O0), 3.3 (in, 1 3.44 (dd, 1 H, J=5,10), 3.53 (in, 1 3.60 2H, 3.79 3H), 3.82 (in, I1H), 5.93 2H), 6.74 I1H, 6.8-6.9 (in, 5H), 7.06 1H, 7.09 2H, 7.18 1H, 7.27 I1H, MS (DCI/NH 3 m/z 545. Anal calcd for C 32

H

3 6N 2 06 0.8 H 2 0: C, 68.75; H, 6.78; N, 5.01 Found: C, 68.70; H, 6.67; N, 4.85.

Example 325 trans, trans-4-( 1.3-Benzodioxol-5-yl-2-(benzylxymthl)-1

N-

dibutvlaminocarboflylmthyfl)12rrolidine-3-carboxylic acid Exam Die 325A Ethyl trans. trans-4- (1 Ben zodioxol-5-fl (bezyoxyflethI) 1 N-d i(nbutyflam inocarbonymethyliyrrolidile-3-carboxylate, The procedures of Example 1 A-1iD were followed, substituting ethyl 4benzyloxy-3-oxobutyrate for 4-methoxybenzoylacetate in Example 1 A, to afford the title compound as a colorless oil. TLC (30% EtOAc-hexane) Rf 0.18; 1H NMR (CDC13, 300 MHz) 5 0.88 J=7Hz, 6H), 1.17 J=7Hz, 3H), 1.20-1.34 (br mn, 4H), 1.40-1.56 (br m, 2.85 J=8Hz, 1H), 2.98-3.30 (mn, 5H), 3.39-3.60 (in, 3.64- 3.75 (in, 3.92 J-l14Hz, 1 4.10 (two overlapping q, J=6.5Hz, 2H), 4.53 (s, 21-1), 5.91 (in, 2H), 6.69 J=9Hz, 11H), 6.77 (dd, J=1.5, 9Hz, 1H), 6.91 1 MS (D01/NH 3 Wne 553 WO 99/06397 WO 9906397PCT/US98/1 5479 -209trans. trans-4- (1 Benzodi oxol5-yl)2- (ben7Zyloxymethyl). 1 N-di(nbutyl)aminocarboflylmethyl~PYrrolidife3-carbo~lic acid D The title compound was prepared according to the procedure of Example 71 C, as a colorless glass. TLC MeOH-CH2CI2) Rf 0. 13; 1 H NMR (CDCI3, 300 D MHz) 8 0.86 J=7Hz), and 0.90 J=7Hz, 6H total), 1. 15-1.52 (br m, 8H), 2.96-3.35 "A (br m, 5H), 3.50-3.75 (br m, 2H), 3.80 (dd, J=3, 13Hz, 1 3.88- 4.40 (br m, 6H), 4.45 D (AB, 2H), 5.90 2H), 6.70 J=8Hz, 1 6.84 (dd, J=1,8Hz, I1H), 6.93 J=1 Hz, A1 7.28-7.39 (in, 5H); MS (DCI/NH 3 m/e 524 ExampJl 26 trans, trans-4-(1 Ben zodioxol-5-yl)-2- (hyd roxym ethyl)-I1 N -di (nbutyflaminocarbonylmlethylD1yrrolidine3-carboxylig acid Example 320 Ethyl trans. trans-4- 1.3- Benzod io xol-5-yl) (hyd roXym ethyl) 1 N-d i(n butyflam inogarbonyln'ethylpyrro lid ine-3-carboxylat The resultant product from Example 325A (128 mg, 0.232 minol) and 25 mg of 20% Pd(OH) 2 on charcoal in 7 mL EtOH was stirred under 1 atm hydrogen for 48 h. The mixture was filtered through a plug of celite, and the catalyst was washed with 2 x 10 mL EtOH, then the combined filtrate and washes were concentrated under reduced pressure to afford the crude product. Purification by flash chromatography (40%EtOAc-hexane) provided the title compound.

25Exml32 trans. trans-4-( 1. 3-Benz-odioxol-5-yl)- 2 (hydroxyvmethyl)-

N-

di(butyI)aminocarbonylmlethyflprrolidine3carboxlic acid The title compound was prepared according to the procedure of Example 71 C.

Example 327 trans. trans-4- (1.3Bno ioo--l--N-mehlrl nai-3y) .N-di(nbuyl)aminocarbonylinethyl')Oyrrolidine-3carboxyic acid WO 99/06397 WO 9906397PCT/US98/15479 -210- Example 327A Ethyl trans. trans--4-( 1.3-Benzodioxol-5-yl)-2-(formyl)-1 N-di(nbutyl~am inocarbonylmethyl)pyrrolidine-3-carboxylate T he title compound is made by selective oxidation using the Swamn oxidation with DMSO, oxalyl chloride, ethyldiisopropylamine or using the Dess- Martin periodinane) of the compound of Example 326A.

Example 27B Ethyl trans, trans--4-( 1.3-Benzodioxol-5-yl)-2-(O-tert-butyllropenoat-3-yl)-1 Ndi(n-butyflaminocarbonylmethyl)pyrrolidine-3-carboxylt The title compound is produced by condensing the compound of Example 327A with tert-butyl triphenylphosphoranylidine acetate in 0H 2 C1 2 Solution.

Example 3270 Ethyl trans, trans--4-( 1.3-Benzodioxol-5-yl)-2-(Drpni acid-3-yi)-l N-di(n- Ib utyl~am i nocarbonylmepth yl) pyrro lid ine -3-ca rboxylate The title compound is produced by reacting the compound of Example 327B with trifluoacetic acid in CH 2 01 2 Eapea7 Ethyl trans. trans--4- (1 Ben zodioxol- 5-yl)-2-(N -m ethylp ropen am id-3-Yl) 1 N di(n-butyl)am inocarbonylmethyl)pyrrolidine-3-carboxylate The title compound is produced by condensing the compound of Example 3270 with methylamine hydrochloride in the presence of a carbodiimide Nethyl-N-(3-dimethylam ino)propylcarbodiimide, DCC).

Example 327E trans. trans--4- 1.3-Benzodioxol-5 -yfl-2- (N-m et hylpropen am i d-3-y1) 1 N- di(n butyflaminocarbonylmethyflo1yrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 327D with lithium hydroxide according to the procedure of Example 71C.

Example328 trans, trans--4-(1 .3-Benzodioxol-5-yl)-2-( 1 -hydroxy-2-propen-3-yl)-l 1-(N .N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid WO 99/06397 PCT/US98/15479 -211- Example 328A Ethyl trans, trans- 4- 1.3-Benzod ioxo, (1 -h yd rox-2-Dropen- 3-yl)- 1 N-di(nbutyl)am inocarbonylmethyl)pyrrolidine-3-carbOxylate The title compound is produced by reacting the compound of Example 3270 with borane methyl sulfide complex.

trans. trans--4.(1 .3-Benzodioxol-5-yl)-2-( 1 -hydrox-2-propen-3-yl)-j N-di(nbutyflam inocarbonylm ethyl pyrrol id ine- 3-ca rboU ic acid The title compound is produced by condensing the compound of Example 328A with lithium hydroxide according to the procedure of Example 71 C.

trans, trans--4-(1 Benzod ioxo 1-5-yi)-2- (N -benzyla minollethyl)- 1 N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid Example 29A Ethyl trans. trans-4- (1.3-Benzodioxol-5-yl)I-2- (N-ben7zylam in om ethyl) 1 N-d i(n butyl) am inocarbonylm eth yl)yrro id i ne-3-carbo xylate The title compound is produced by condensing the compound of Example 327A with benzylamine in the presence of sodium cyanoborohyd ride in ethanol.

Example 329B trans, trans--4-(1 .3-Benzodioxol-5-yl)-2-(N-benzylam inomthyl)-1 N-di(nbutyflam inocarbonlm ethyl) yrrolidine-3-ca rboyl ic acid The title compound is produced by reacting the compound of Example 329A with lithium hydroxide according to the procedure of Example 71 C.

trans. trans--4-(1 .3-Benzodioxol-5-yfl-2-( N-acetyl-N-benzylam inomethyl 1 Ndi (n-butyl'am inocarbonyl methyl) pyrrol idine-3-ca rboxyl ic acid Ethyl trans, trans--4- (1 .3-Ben zod ioxol- 5-yl) (N -acetyl- N-benzyla rin o rethyl)- 1- (N.N-di(n-butyl)am inocarbonylmethyl)oyrrolidine-3-carboxylate The title compound is produced by reacting the compound of Example 3294A with acetic anhydride in the presence of pyridine or triethylamine.

WO 99/06397 WO 9906397PCTIUS98/15479 ci -212trans. trans--4-( 1.3-Benzodioxol-5-yl)-2-(N-acetyl- N-benzylam 'nom ethyl)- 1 Ndi(n-butyflam inocarbonylmethyl)pyrrolidine-3-carboxylic acid _C 5 The title compound is produced by reacting the compound of Example 330A with lithium hydroxide according to the procedure of Example 710.

Example 331, trans. trans--4-( 1.3-Benzodioxol-5-yl)-2-(ethynyl)-1 N-di(nbutyl)aminlocarbonylmethyl)pyrrolidine-3-carboxylic acid Example 331 A Ethyl trans. trans--4-(1 Ben zod ioxol-5-yl)-2- (et hynyl) 1 N-di1(n butyl)am inocarbonyl meth yl)pyrro lid ine-3-carboxylate The title compound is made by employing the procedure of Corey and Fuchs (Tetrahedron Lett. 1972, 3769-72), using the compound of Example 327A.

Example, 331 B trans. trans--4-( 1.3-Benzodioxol-5-yl)-2-(ethynyl)-1 -(N.N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 331 A with lithium hydroxide according to the procedure of Example 710.

Example 33 trans. trans--4-( 1.3-Benzodioxol-5-yfl-2-( 1 -pentynyl)- 1 N-di(nbutvl)aminocarbonylmethyl)pyrrolidine-a-carboxylic acid Exampl 32A Ethyl trans, trans--4-( 1.3-Benzodioxol-5-yl)-2-(pentynyl)-1 -(N.N-di(nb utyl) am inocarbonyl meth yl)pyrro Iid ine-3-carboxyl ate The title compound is made by pal ladi u m-catalyzed coupling of the compound of Example 206A and propyl iodide, employing the procedure of Taylor, et. al. Org. Chem. 1989, 54(15), 3618-24).

WO 99/06397 PCT/US98/15479 -213- Example 332B trans, trans--4-( 1 .3-Benzodioxol-5-yl)-2-(1 -pentynyl)-l -(N.N-di(nbutyl'aminocarbonvlmethyl)pyrrolidine-3-carboxvlic acid The title compound is produced by reacting the compound of i Example 332A with lithium hydroxide according to the procedure of Example 71C.

Example 333 trans-trans-2-(4-Methoxphenvyl-4-(1.3-benzodioxol-5-yl)-1-12-(2.6dioxopiperidinyl) ethyll-pyrrolidine-3-carboxylic acid- The compound of example 61A is added to a solution of the sodium salt of glutarimide in dimethylformamide. After stirring 24 hours, water is added and the mixture is extracted with ether. The resultant glutarimide is hydrolyzed to the title compound by the method of example 1D.

Example 334 trans-trans-2-(4-Methoxvyphenvyl)-4-(1 .3-benzodioxol-5-yl)-1 -N.NdiDhenylaminocarbonyvImethyll-Dvrrolidine-3-carboxylic acid.

The title compound was prepared according to the procedures described in Example 1. 1 H NMR (300 MHz, CD30D) 8 2.83 (dd, 1, J 8.1, 2.99 1, J 15.4), 3.19 1, J 3.49 1, J 15.3), 3.51 (dd, 1, J 4.6, 3.57 3.79 3.85 1, J 5.90 (s, 6.71 1, J 6.84 7.04 1, J 7.14-7.16 6), 7.19-7.34 MS (DCI/NH 3 m/z 551; Anal Calcd for

C

33

H

3 0

N

2 06*0.65H 2 0.0.35C2H5OCOCH3: C, 69.77, H, 5.77, N, 4.76. Found: C, 69.75, H, 5.55, N, 4.64.

Example 335 trans-trans-2-(4-Methoxvyphenyl-4-(1.3-benzodioxol-5-yl)-l-IN.Ndiisopropylaminocarbonylmethyll-Dvrrolidine-3-carboxylic acid.

The title compound was prepared according to the procedures described in Example 1. 1 H NMR (300 MHz, CD30D) 8 0.95 3, J 1.24 3, J 1.30 6, J 2.85 1, J 12.5), 3.04 (dd, 1, J 8.1, 3.14 1, J 3.32-3.55 3.63 5.92 (s, 6.75 1, J 6.85 (dd, 1, J 1.7, 6.93 7.02 1, WO 99/06397 WO 9906397PCTIUS98/15479 -214- J 7.35 (in, MS (DCt/NH 3 mlz 483. Anal Calcd for C27H- 34

N

2 06 .0.65 EtOAc: C, 65.86, H, 7.32, N, 5.19. Found: C, 5.74, H, 7.26, N, 5.52.

Example 336 trans, trans-2-(3- Fl uo r-4- meth oxyphe nyl) 1.3- ben zod 1 -N-p ro pyl- N-butanes uIf onylam ino)ethyfl-pyrro lid ine- 3-carboxyl ic acid Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.65-66 0 C. 1 H NMR (CDCI3, 300MHz) 8 0.82(t, J=7.5Hz, 3H), 0.92(t, J=7.5Hz, 3H), 1.34- 1 .52(m, 4H), 1 .72(quintet, J=7.5Hz,2H), 2.25-2.35(m, 1H), 2.72-2.94(m, 2.97-3.12(m, 2H), 3.19-3.46(m, 2H), 3.44(d, J=9Hz,1H), 3.53- 3.60(m, 3.67(d, J=9Hz, 3.89(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 1H), 6.82(d, J=8Hz, 1H), 6.92(t, J=9Hz, 1H), 6.97(s, 1H), 7.12(d, J=9Hz, 1H), 7.18(d, J=l2Hz, MS (DCI/NH3) m/e 565 Eg~ampe 3 Using methods described in the above examples, the compounds disclosed in Table 1 can be prepared.

FI

3

C

R- CJOOH Table 1 R R R o 2N H NN:: WO 99/06397 PCTIUS98/1 5479 -215- Table 1 cont.

R

6.

1- 0 0 7.

-Th c?0 0,$1 13.

0 16.

c0 H300-F2'%,: o 0 YX 0 0 00

H

3

CO

14.

17.

0 0 .0 18.

020 0 0 4 WO 99/06397 WO 9906397PCT/US98/15479 0 0 22.

H3CO%, 0 0 1^1 F3, 0 0 28.

FH2C

F

2 0 0 31.

F

2 0 0 34.

0 0 -2 16- Table 1 cont.

R

0 0 23.

H

3 C0:.4 o0 26.

FH

2

C~~

0 0 29.

FH

2 C. g

F

2 0 0 32.

F

2 P 0 35.

0 0 24.

0 0 27.

o0 N-Ih

F

2 HC..oNp;

F

2 0 0 33.

F

3

F

2 0 '0 36.

0 0 WO 99/06397 WO 9906397PCT/US98/15479 -2 17- Table 1 cont.

d' 0 FC0~a,, 0 41. 42.

43.

Oo 44.

0 52.

Or 0 48.

54.

57.

PN -r 56.

0 59.

0 WO 99/06397 PCT[S9815479 0 61.

64.

0 67.

QOyN7 -218- Table 1 cont.

R

62.

65.

68.

71.

r"" 63.

oc 0 66.

69.

72.

0 78.

73.

0 76.

0 74.

0 77.

WO 99/06397 PCTIUS98/1 5479 -219- Table 1 cont.

100,*1q

C~O~QN~

H

3 0 88.

0 91.

86. 87.

C~LAKN

92. 93.

I

WO 99/06397 PCTIUS98/1 5479 0 97.

K

1.00.

0 103.

NyN 0 106.

CH

3 109.

0 112.

115.

-220- Table 1 cont.

R

0 98.

(N

101.

0 104.

H

107.

CH

3 110.

0 113.

YH

3 rN

N

0 0o 99.

WK"

102.

0 105.

H

108.

111.

114.

qH3 (N II"6 d'o 116.

117.

I I PCT/US98/15479 WO 99/06397 118.

I aN 121.

124.

127.

130.

133.

-221- Table 1 cont.

R

119.

122.

00 120.

123.

126.

129.

129.

125.

C'

0 128.

OCH

3 131.

132.

134.

135.

WO 99/06397 PCT/US98/15479 -222- Table 1 cont.

R

&KO0 137.

138.

138.

136.

o 139.

d0 142.

cro 145.

148.

00 140.

0 o 143.

0 146.

1H34 149.

141.

144.

147.

150.

1 1 151.

N 0 152.

153.

I I WO 99/06397 PCT/US98/15479 -223- Table 1 cont.

R

154.

157.0 157.

0 155.

160.

0 gN 0 158.

161.

164.

FF 6'O 0 156.

o 159.

162.

163.

165.

166.

166.

d168.

168.

167.

WO 99/06397 PTU9/57 PCTIUS98/15479 169.

0 0 172.

y~ 175.

Y

00 178.

F 3 C0- N% 0 0 181.

H

3 Cc?>, 0 0 184.

-224- Table 1 cant.

R

Y

0 0 170.

173.

Y

F F 0~ 176.

179.

0 0 182.

H

3 C0>' o~ 185.

Y

0 0 171.

0 174.

y 177.

F

3 F F 6 0 180.

0 0 183.

0 0 186.

H

3

CO"

F F 0 *o

H

3 =10*> Xe~w" 0 H3aO'> 0 0,o 187.

87.188. 189.

WO 99/06397PCIS8I47 PCT/US98/15479 -225- Table 1 cont.

R

H

3 c*> F3N do S

HCO')

roq- 190. 191.

193.

00 196.

F3W 199.

00 205.

do 194.

197.

0 0 200.

192.

0 0 195.

00 198.

00 201.

203.

y 206.

204.

y 207.

I

WO 99/06397 PCTIUS98/15479 -226- Table 1 cont.

R

210.

208.

209.

y 211.

V

NcrA 214.

217.

V

V

212.

215.

218.

CF3 O-"N-r 213.

216.

219.

;F

3 OV,.r 220.

221. 222.

I

WO 99/06397 PCT/US9815479 -227-

R

Ff 223.

226.

229.

V

232.

235.

Table 1 cont.

R

9F 3

Y

224.

)y 227.

y 230.

233.

y )y236 236.

R

F

3 225.

Nor 7 0 228.

y 231.

cl 234.

237.

I

WO 99/06397 PCT/US98/15479 -228-

R

NI~-

238.

y 241.

Table 1 cont.

R

239.

242.

R

240.

y 243.

FrO 246.

249.

252.

244. 245.

247.

V

250.

248.

NCQ

251.

WO 99/06397 PCT/tS98/15479 -229-

R

NC.,,V~r ""0~0 253.

V

256.

Table 1 cont.

R

y 254.

257.

255.

258.

K

261.

#NO

264.

267 267.

259.

260.

263.

262.

266.

265.

I

IN

CA

\O

WO 99/06397 PCT/US98/15479 -230- 268.

C'crNr 271.

274.

274.

Table 1 cont.

R

HN

269.

No 272.

275.

275.

R

9F 3

N

OcrY4 270.

Nr

Y

273.

27N.

276.

277.

278. 279.

280.

282.

281.

PCTIUS98/15479 WO 99/06397 -231- Table 1 cont.

R

283.

284.

285.

286.

289.

292.

y 295.

287.

Vy~ N 0 290.

293.

296.

291.

y 294.

297.

288.

WO 99/06397 PCTIUS98/15479 -232- Table 1 cont.

NJ

,,,AON 0 N 0a 298.

299. 300.

N-1

%-,AV

KIr y SN. ra 301. 302.

303.

N-

tNY0

N

304.

305.

306.

O~Tr N 0* N 0 307. 308. 309.

NK0 y ar Ny0 310.

311.

312.

WO 99/06397 PCTfUS98/15479 -233- Table 1 cont.

I

N 0" VyN)r, oa N 315.

313.

314.

C1,16'r "I-rA N 0

NIA

t-~s~ 316.

317. 318.

Nyr SOYA0 319.

320. 321.

322.

323.

324.

~"a~hkrc 325. 326.

327.

I

I

WO 99/06397 PCTIUS98/1 5479 328.

331.

.234- Table 1 cont.

R

329.

V

332.

335.

338.

N

oi 334.

337.

340.

330.

333.

v 336.

339.

)y 341.

342.

WO 99/06397 PTU9/57 PCT/US98/15479 -235- Table 1 cont.

R

y 343.

346.

N<

349.

y 345.

344.

347.

350.

353.

348.

351.

V

354.

y 357.

352.

355.

356.

WO 99/06397 PTU9/57 PCT/US98/15479 -236- Table 1 cont.

358.

359.

V

360.

V

361.

362.

363.

364.

'y NyK 365.

V

368.

366.

367.

i.N 368.

Kr 370. 31 371. 372.

I I WO 99/06397 PCT/US98/15479 -237- Table 1 cont.

R

y3 373.

374.

376.

377.

375.

378.

381.

379.

382.

380.

383.

I>"

384.

387.

385. 386.

I

WO 99/06397 PCT[US98/1 5479 y 388.

391.

394.

397.

400.

-238- Table 1 cont.

R

y 389.

V

392.

395.

390.

393.

396.

399.

402.

398.

401.

WO 99/06397 PCT/US98/15479 -239- Table 1 cont.

R

404.

407.

403.

406.

405.

408.

N

411.

4 Ny14 414.

409.

412.

415.

415.

410.

413.

416.

417.- 417.

I

WO 99/06397 PCT/US98/1 5479 -240- Table 1 cont.

R

'COOER

418.

419.

420.

NO

2 423.

'COOEt 421. 422.

C NO2 424.

427.

430.

Ny N0 2 425.

428 428.~-

V

426.

429.

431.

432.

I

I

WO 99/06397 PCT/S98/1 5479 -241- Table 1 cont.

R

433.

0 436.

439.

442.

434.

437.

440.

0 435.

0 438.

441.

Nr, 4o 443.

444.

445 445.

0 446.

447.

I

WO 99/06397 PCTIUS98/15479 F~rA 448.

451.

0 454.

Meox.4<N4 0 457.

-242- Table 1 cont.

R

449.

y 0 F F 0 450.

453. 452.

Meo MoO 0 456.

455.

458. 459.

0 mqo):oIV 0 462. 460.

461.

WO 99/06397 PJU9157 PCr/US98/15479 -243- Table 1 cont.

R

463. 464.

465.

466. 467.

468.

MO 0 470.

469.

471.

474.

372. 473.

475. 46 476.

477.

WO 99/06397 PCT/US98/5479 0 478.

1.

cix k,*Ir -244- Table 1 cont.

R

479. 0 cc 482.

485.

0 488.

a~o), 'c 0 480.

cl y" T 0 483.

IVn 0 486.

484.

F Nr 0 487.

0 490.

489.

491. 492.

I

WO 99/06397 PCT/US98/1 5479 493.

-245- Table 1 cont.

R

0 494.

0 497.

0 500.

0 496.

499.

0 502.

0 505.

0 495.

0 498.

oi4NC 501.

0 504.

Moojq uy-' 0Me 0 507.

503.

A I 506.

WO 99/06397 PCTIUS98/1 5479 OM. 0 508.

-246- Table 1 cont.

R

OMO 0 509.

OMe 0 512.

OMO 0 515.

Oo OMe 0 510.

MO

513.

OMe 0 516.

511.

OMO 0 514.

OM. 0 517.

M o 0MS 0 518. 519.

mO~0II OMO 0 520.

521.

522.

WO 99/06397 PCTIUS98/15479 -247- Table 1 cont.

M100, 523.

0 526.

00 0 524.

527.

y Brcr~~d Me

H

0 525.

BrNy-/ 528.

L-K

Br/ 529.

530.

531.

Br 0 532.

A -ro,'

I,

533.

V

Brd 534.

F 0 537.

0 535.

536.

WO 99/06397 PTU9/57 PCT[US98/15479 y 538.

0 540.

544.

>0 550.

-248- Table 1 cont.

R

539.

542.

545.

0 548.

551.

0 540.

543.

y B )r-vr 546.

01 549.

552.

WO 99/06397 PTU9/57 PCT/LJS98/15479 -249- Table 1 cont.

553.

556.

Br $0O 559.

y 562.

565.

y 554.

557.

560.

Br 0 N~yg

F

K

555.

V

558.

561.

564. 563.

566.

567.

I

WO 99/06397 PCT/US98/15479 -250- Table 1 cont.

R

R

Fc 0d 568.

y 571.

V

574.

oo* NrA 0 .577.

0 580.

583.0 583.

R

FY

570.

569.

F>

cix"yJ4 572.

0 575.

Y

0 578.

0 581.

584.0 584.

573.

0 576.

0 579.

0 582.

585.

585.

I

CA

tf)

\O

WO 99/06397 PCT/US98/15479 -251-

R

o 586.

589.

y 592.

595.

Table 1 cont.

R

ca 0 587.

590.

593.

V

596.

599.

602.

R

0 588.

591.

594.

597.

y 600.

603.

598.

601.

I

WO99/06397 PCT/US98/15479 -252- Table 1 cont.

R

605.

H

604.

H

0 606.

6H 607.

610.

H

613.

H

S0 616.

619.

608.

611.

614.

609.

612.

615.

H

0 617.

620.

618.

621.

WO 99/06397 PCTIUS98/15479 -253- Table 1 cont.

R

622.

0

H~

624.

623.

625. 626.

628.

631.

629.

0 H 632.

635.

Ky >rYB

H

627.

H

N-J

630.

633.

636.

639.

i)- 634.

y aNNIrA 0J i 638.

637.

WO 99/06397 PCT/US98/15479 -254- Table 1 cont.

>xyIL 640.

641.

0 643.

o 0 644.

0 642.

0 645.

0 648.

-646. 647.

649.

650.

651.

652.

0 653.

654.

WO 99/06397 PTU9/57 PCT/US98115479 -255- Table 1 cont.

R

R

655. 656.

657.

658. 659.

662.

660.

661.

663.

664.

667.

665.

666.

668. 69 669.

WO 99/06397 WO 9906397PCTIUS98/15479 -256- Table 1 cont.

R*

Ay.

670.

673.

672.

671.

674.

675.

677.

676.

678.

680.

679.

681.

682. 63 683.

684.

WO 99/06397 PCTIUS98/15479 -257- Table 1 cont.

y 685.

11 688.

691.

686. 687.

689.

690.

692.

693.

694.

695.

696.

698.

H

607.

699.

I

WO 99/06397 PCT/U~S98/1 5479 -258- Table 1 cant.

R

701.

,a0 700.

0 703.

0 702.

704.

706.

707.

0 709.

712.

F

3 C~/~:Nr 00 715.

0 710.

713.

705.

:4 0 708.

00 711.

0i 0 714.

I

WO 99/06397 -259- CjI/uS9/ss7/y Example 338 Using methods described in the above examples, compounds comprising a parent structure selected from those disclosed in Table 2A and an R substituent selected from those disclosed in Table 2B can be prepared.

Table 2A CH3

,COOH

R-

WO 99/06397PCIS8157 PCTIUS98/15479 -260- Table 2A cont, mom F

COOH

\IF

O.COOH

0cH

OCH

3 14.

'OCH

3

F

Pr

COOH

OCH

3 mom 16.'7 Pr-N

_COOH

19. 0O830

CH

3

,COOH

OCH

3 H43

,COOH

fk-N 20. 0 WO 99/06397 WO 9906397PCT/US98/15479 -261- Table 2A cont.

CH

3

R-S

23. 0

MO

R-

COOH

22. 0

F

IcooH R

I

24. o

OCH

3

,,COOH

26.

CH

3

,PCOOH

29.

CH

3

VPCOOH

fl-N WO 99/06397 WO 9906397PCTIUS98/1 5479

MOM

%34.

-262- Table 2A cont.

IOCOOH

R-

CH

3 R-N7 ~.OH 0 38. OCH 3

RCH

3

OCH

3 41.

F

A- .COOH 39.

OCH

3

F

COOH

IFlN 0

OCH

3 42.

mom IOC0OH f%-N0

CH

3

OMOM

OCH

3

OCH

3 .4C00H WO 99/06397 WO 9906397PCT/US98/I 5479 mom

.OCOOH

46. F

PCOOH

49.

F

-283- Table 2A cont.

CH3 R-j

COOH

47.

4,COOH IeCO

F

R

COOH

48.

pr

OOOO

5.

.COOH

56.

F

0OCH 3 WO 99/06397 PCT/US98/15479 -264- Table 2A cont.

I,

0 59.

A1- .#0OOH 64. F

.#COOH

j\OCH 3 65.

OCH,

~.COOH

68. WO 99/06397PCIS/I57 PCTIUS98/15479 -265- Table 2A cont.

R-

#OOH

CH

3 0

OOH

R-

COOH

73. 0

CH

3 A -OOH 76.

OH3 72. om OCI43

COOH

75. 0

OCH

3

.COOH

77.

H

3

~OH

Bi..

WO 99/06397 PCT/US98/I 5479 -266- Table 2A cont.

CH

3

H

OH

3

O

H3 O 3 0 OH

OH

dO oICOOH

,COOH

eCOOH

-R

8.83. a84.

H

3

OCH

3

OHCH

3

O

eH e-OH

O

0 f.0OOH 4COOH COOOH R- I -8W 8.

H

3

OH

3

OH

3 OH .llOCH 3

OCH

0 C.CO0H

O.COOH

FF %COO R- I Ft

NOCH

3 88.

OCH

3 89. OH C3 O 001 3

OCH

3

OCH

3

OH/

/01 O~ COOH COOH eCOOH

P

-92. 93.

WO 99/06397 PTU9/57 PCTIUS98/15479 -267- Table 2A cont.

CH3 H 3 H 3

OH

0 R- OHR- F

CH

3 94. F 95. 0CM 3 0CH 3

.COOH

104.

105.

103.

WO 99/06397 WO 996397PTIUS98/15479 -268- Table 2A cont.

H

3

CO

,%,COON

110.

F

H

3 00

F

O.COON

j\OCH 3

C~OCH

3 109.

112.

113.

~.COOH

115.

R

,COON

fl- ,,.COON 116.

COOH

120.

118. 19 119.

PCT/US98/15479 Wo 99/06397 -269- Table 2A cont.

,COOH

0CH3 124. 0

OCH

3 00 126.

125.

OICOOH

128. 0 19*COOH 1 0 0 130.

132.

131.

WO 99/06397 PCTIUS98/15479 -270- Table 2A cont.

SCH3 133.

H

3 IOCO0H 138.

137.

H

3

OCOOH

139.

F

OCH

3

.OCOOH

R-N

NA

140. 0) CH 3

COOH

R-

143.

OCH

3

R-ZCOOH

H

3

CO\

144.

PCTIUS98/1 5479 WO 99/06397 -271- Table 2A cont.

CH3

,.COOH

R-

H

3

CO

145.

146. lNr

H

CH

3

F

,#ICOOH

H

3 CO

OCH

150.

148.

149.

I OCH 3

F

152.

F

OMOM

H

3 CO 0013 156.

154. 155.

WO 99/06397PCUS/157 PCTIUS98/15479 -272- Table 2A cont.

M-OMCW

157. OCH 3

MOM

flJ-N

#CO

158.

F

OCH

3 0 "-OCH 3 159. o H3H R-

COOH

I

3 H

-IOCH

3 161.

162.

CH

3

OH

R-

.COOH

163. OCH 3 164.

F

H

fl-N -N 167. 0

MOMO

/r

N

168. 0 166.

WO 99/06397 PTU9157 PCTIUS98/15479 -273- Table 2A cont.

F

H

169. 0

F

0 173.

H

176.

F

H

171.

MOMO

H

17.F 175.

MOMO

178.

MO

OCH

3 180.

'OCH

3 179.

PCT/US98/15479 WO 99/06397

F

H

181.

H

3 R- H 184. 0 -274- Table 2A cont.

MOMO

H

R-N

182.

D

H

3

H

183. 0

MOMO

N' CH3

HZI

188. 0

F

)N-S-CH,

189. 0

MOMO

R- H 192.

N2'Y S. CH3 WO 99/06397 PTU9/57 PCTIUS98/15479 -275- Table 2A cont.

X'CH

3

H

195.

193.

194.

N:t CH 3

H

'OCH

3 197.

F

H

MOMO

ks.ECH 3 fl- H 200. 0~?

H

3 go CH 2

CF

3 R- H .203. 0 1w N(CH 3 2

H

204.

202.

PCT[US98I1 5479 WO 99/06397 -276- Table 2A cont.

207.

206.

205.

?H

3 N.

CH

208.

209. 210.

H3

JCOOH

211.

OH

H

3

OCH

3

,-HO

0' 0 214.

OCH,

,.OOH

212. OCH 3

H

3

,.COOH

/00 213. OCR 3 215. OCH 3 216.

OCH,

WO 99/06397PCIS/ 47 PCT/US98/15479

.COOH

'0

OCH

3 217.

-277- Table 2A cont.

Et to COOH 218B.

EtO F eCOOH 221.

EtO F

,COOH

OCH

3 224.

.,COOH

'0 0 227.

EIO F

*COOH

219.

EDO F

,COOH

-RRI

222.

220.

EIO

OCOOH

223.

0 226.

225.

228.

PCTIUS98/I 5479 WO 99/06397 -278- Table 2A cont.

RSO

229.

H43 00H3 0 0H 232.

1430C14 3

.COOH

235.

1430 OCH3 ~,CO0H 238. 00143 0 0 0 0H 231. OCH 3 230.

H

3

OCH

3 f0 233.

,COON

236.

H

3 C 0CH

OCOOH

23.

0 4PCOOH '0 240.

239.

PCTIUS98/15479 WO 99/06397 -279- Table 2A cont.

243.

242.

241.

244. 245.

246.

H

3

F

COOH

0 247.

H

3

-F

,ODOH

250.

H

3

F

.0COOH 0 0 248.

H

3 F

A

0) 251.

249.

252.

WO 99/06397 PCTIUS98/1 5479 -280- Table 2A cont.

F F

O.OOH

254.

255.

253.

Fk

,COOH

256.

Fq

?OH

257.

258.

j 1

,COOH

261.

260.

262.

,COOH

265.

4 eOOOH RW N 263.

~COOH

266. 0CH 3 264.

7F 267.

WO 99/06397 PCTIUJS98/15479 -281- Table 2A cont.

1 COOH 0 270.

268.

269.

0 271.

0COOH 272.

eCOOH 275.

,COOH

278.

273.

276.

274.

,COOH

277.

279.

WO 99/06397 PTU9/57 PCTIUS98/15479 ~00 280. OC)4 3 283.

286.

-282- Table 2A cont.

281.

J,COOH

284.

~00 287. OCH 3 C00H /0 290.

.COOH

,OOH

_0 282.

285.

288.

291.

289.

293. 24 294.

292.

I

WO 99/06397 PCT/US98/1 5479 -283- Table 2A cont.

4

COOH

/0 296.

4

OOOH

R- 0) 295.

.COOH

Rw-' 297.

=C0H R- c 0) 300.

.,CO0H '0 303.

298.

299.

COOIH

301. OCH 3 304.

302.

306.

305.

WO 99/06397 PTU9/57 PCT/US98/15479 -284- Table 2A cont.

OOQH tOOOH

-R

It 0' 307. 38.OCHH COH COH CO 7t=COHS CH ,PW COOH *.COOH R- R- "it 319. 31. 32 321.

319.

320.

WO 99/06397 PCTIUS98/I 5479 -285- Table 2A cont.

323.

325. 326.

328.

*COOH

329.

OH

.COOH

332.

00 COOH 335.

I

,COOH

/0 324.

',I

327.

,,COOH

0 330. OCH3 333.

336.

331.

0OOH 334.

PCT/US98/15479 WO 99/06397 -286-

A

0

,OOH

Table 2A cont.

0(

.,COOH

337.

338.

339.

beCOOH 342. OCH 3 340.

341.

C O O

H

343.

.OCOOH

R-0 345.

344.

0'0 348. 347.

346.

349. 350.

351.

PCT/US98/1547 9 WO 99/06397 -287- Table 2A cont.

353.

352.

0 0 /0 355. 0C14 3

H

2 C F d~y:NH W.N 0 356.

HAC

0C4 359.

EtO0 0 "CH3 004 EtO

NH

_/0 357.

E0 0 /0 360.

358.

0 0 \C _/0 361. 0CH3 363.

362.

PCTIUS98/1 5479 WO 99/06397

H

3 00

H

8 36.

H

3

H

3 FrF 1-288- Table 2A cont.

H

3

H

'0 365.

H

3

C

h y!,WNH 368.

366.

369.

371.

H

3

C

R\ 0) 372.

0 t

CH

3 H0 375.

373. 34 374.

WO 99/06397 PCTIUS98/15479 -2 89- Table 2A cont.

377.

378.

376.

O 0 S-CH 3 )iF 380.

.NH

381.

379.

\/o 382.

NH

/0 385.

383. 384.

~~NH

S0) 386.

NR ,NH

F

387.

WO 99/06397 W09916397PCTIUS98/1 5479 388.

-290- Table 2A cont.

389.

F

3

,,COOH

~0 392.

F

3

.*OOOH

395.

390.

W*NH

391.

F

3

.COOH

'0 394.

F

3 R/0 393.

396.

399, 397. 38 398.

WO 99/06397 WO 9906397PCT/US98/15479 -291- Table 2A cont.

kF 2

CF

3

',COOH

'~0 400.

F

2

CF

3

,,COOH

403.

kF 2

CF

3 1

OH

OCH

3 406.

9

#COOH

409.

kF 2

CF

3

,,COOH

/0 401.

1F 2

CF

3

#.COOH

Ft' 402.

.404.

405.

,COOH

407.

408.

411.

410.

OCOOH

413.

414.

412.

WO 99/06397PC/S/157 PCT/US98/15479 -292- Table 2A cont.

416.

'Irl 417.' 415.

418.

419.

420.

"cC& 421.

,COOH

R-N 0 424.

,.COOH

FrN 422.

.,COOH

R.N

423.

425.

.COOH.

RN

426.

,,POOH

WN 0 429.

427. 48 428.

WO 99/06397 WO 9906397PCTIUS98/I 5479 -293- Table 2A cont.

j .COOH 0CO 430.

432.

431.

,COOH

R- 0>.

434.

P'0 435.

433.

438.

436. 437.

439.

"p.COOH 441.

440.

444.

442. 43 443.

WO 99/06397PCISII57 PCT/US98/15479

.COOH

445.

448.

451.

-294- Table 2A cont.

.COOH

~COOH

0 449.

447.

450.

453.

452.

454.

454. 455. 46 456.

WO 99/06397PCUS8147 PCTIUS98/15479 -295- Table 2A cont.

.,CDOH

457.

COOH

459. 458.

462.

461.

460.

o 0COWH 0 '0 463.

.Co m Fr 0 '/0M 465.

464.

WO 99/06397PCUS/157 PCTIUS98/15479

R

4.

0 7.

0 0 13.

0 16.

-296- Table 2B

R

2.

5.

B.

R

0T 3.

6.

9.

0 14.

0 0 0 12.

0 H3CO~Q 0 0 0 6 0 WO 99/06397PCUS/I47 PCT/US98/15479 22.

F

3

S,

28.

FH r~lo 31.

F2H(:.

34.

0' 37.

-297- Table 2B cont.

R

H

3

CQ~

6' 0 23.

26.

FH

2

,,SN%

29.

F

2 0 Q 32.

H

3

CO*

24.

27.

-Th 0

F

2

HC..

F2O6 0 33.

F

3 rCe-

F

2 0 36.

39.

F

2 6' '35.

38.

0 0 .0 00O

I

PCT/US98/1 5479 WO 99/06397 00 43.

F

3 cck,(..

0 0 46.

-298- Table 28 cont.

R

0 44.

00 47.

F3 OW (r 0 0

H

3 SQ9v 48.

48.

49.

52.

58.

53.

53.

00 54.

57.

ct.Ys.

CI

WO 99/06397 PCT/US98/15479 -299- Table 2B cont.

R

61.

OCH

3 ecr"lC H3C 64.

FH

3 00 o 00 73.

o6.

76.

&KV

68.

71.

do 74.

o0 69.

72.

00 0 WO 99/06397PCIS/I47 PCTIUS98/15479 c0 79.

82.

F3~T 0 0 88.

0 91.

94.

0 0 -300- Table 2B cont.

R

0 0 80.

F3di 0~ 81.

F3" 0 0- 83. 84.

86.

89.

Y

F Fo 0 92.

o o

Y

0 0 87.

Y

6 bo 93.

F F ci o F .F F~c~00

H

3 C0>* 0 0 WO 99/06397 PTU9/57 PCTIUS98/15479 -301- Table 2B cont.

R

H

3 Cao'Th H3ca,,* 0 0 100 H3C 00 0 0 112.

F A

A-

F F 0 *0 0 0 102.

FF00 104. 105.

0 *0 107.

110.

0 0 113.

F F HIC0> 108.

0 0 F4 114.

0 116.

115.

117.

WO 99106397 PCT/US98/15479 .302-

R

118.

121.

124.

y 127.

130.

Table 2B cont.

R

119.

y 122.

R

120.

"y 123.

126.

129.

125.

128.

OH

KOA

131.

132.

WO 99/06397 PCT/US98/1 5479 133.

136.

0 O NrA 142.

-303- Table 2B cont.

R

134.

9F3~ 135.

137. 138.

140.

141.

144.

143.

145.

y Q, rf4,rA 0 147.

146.

I

WO 99/06397 PCT[US98/15479 304- Table 2B cont.

R

148.

r

FO

151.

154.

y 157.

v

P

t h..aur/ 4 149.

150.

y

FV

152.

PvYrA 155.

V

158.

FV

153.

156.

K

159.

162.

160.

161.

I

WO 99/06397 PCTfUS98/15479 -305- Table 2B cont.

R

y ~cV 164.

163.

166.

165.

167.

168.

169.

y N C.V C 170.

173 y 0 171.

Kr 172. 174.

KN~A

K

176.

177.

175.

I

WO 99/06397 PCT/US98/15479 -306- Table 2B cont.

R

179.

178.

182.

180.

183.

186.

0~~ 181.

184.

185.

N c 0 187.

190.

188. 189.

N0 191.

N

192.

WO 99/06397 PCT/US98/15479 -307- Table 2B cont.

R R

R

KY

N N~ 193. 194. 195.

NyN V 196. 198.

196 197.

199. 200. 201.

2y 2N.

N

202. 203. 204.

205. 206.

207.

WO 99/06397 PCTIUS98/1 5479 N 0 208.

y 211.

V

214.

217.

NyK)Or -308- Table 2B cont.

R

N 0 209.

Ny0 212.

215.

218.

UA

220. 222.

210.

JN 0 213.

216.

y 219.

vc ejlNKa o 220.

222.

I

PCTIUS98/1 5479 WO 99/06397 -309- Table 2B cont.

223.

226.

229.

232.

KN0 224.

y 227.

230.

0 225.

r 228.

231.

0, 233. 234.

N- *y YIrl ej 0 I\t ;N3, II~rl 235. 237.

236.

PCT/US98/15479 WO 99/06397 -310- Table 2B cont.

238.

239.

240.

243.

243.

241.

244.

2 247y 247.

242.

245.

V

248.

oY 246.

249.

250. 252.

252.

PCTIUS98/1 5479 WO 99/06397 -311- Table 2B cont.

254.

255.

253.

257.

256.

259.

CLN

262.

FV~

265.

258.

y 261.

264.

260.

263.

267.

266.

PCTIUS98/1 5479 Wo 99/06397 3 12- Table 2B cont.

R

V

270.

268.

269.

271.

272.

273.

274.

275.

276.

NN

278.

277.

K-I.

281. 22 282.

280.

PCT/US98/15479 WO 99/06397 -313- Table 2B cont.

283.

286.

y jy~A 289.

v 292.

295.

284.

"GN

287.

290.

293.

296.

285.

288.

291.

294.

y 297.

WO 99/06397 PCT/US98/1 5479 -314- Table 2B cont.

R

299.

302.

298.

301.

304.

V

300.

"YN

303.

>j#N 306.

309.

Ky1A 312.

305.

307. 308.

310.

311.

WO 99/06397PCUS/I47 PCT/US98/15479 -315- Table 2B cont.

R

313.

314.

315.

316.

317.

318.

319.

320.

321.

322.

323.

326.

324.

325.

327.

WOD 99/06397 PCT/US98/1 5479 -316- Table 2B cont.

R

328.

331.

334.

329.

332.

330.

333.

335. 336.

COOEt N02 33. 339.

'COOEt 337.

ko% N02

V

NO

2 342.

340.

340. 341.

I

PCT/US98/I 5479 Wo 99/06397 -317- Table 2B cont.

343.

346.

349.

0 352.

355.

344.

02,> 347.

is 02J/> 350.

0.

353.

N56 356.

C N 345.

02/r 348.

0 351.

V

0 354.

074 357.

WO 99/06397 PCTIUS98/1 5479 -318- Table 2B cont.

R

359 359.

y 0 360.

358.

361.

364.

F3a 0 367.

V

362.

0> 365.

y 368.

363.

366.

K

369.

M

moo.

372.

0 371.

370.

WO 99/06397 PCT/US98/1 5479 -319- Table 2B cont.

R

R

MOO

0 373.

0 376.

0 379.

0 382.

374. 375.

377.

moo 0 380.

1o 0 383.

0 386.

Moo moo 0 378.

meo;R 0 381.

0 384.

0 387.

385.

390.

388.

389.

WO 99/06397 PCT/S98/1 5479 -320- Table 2B cont.

R

0 392.

0 391.

0 394.

0 393.

395.

396.

397.

398.

400.

C',

0 401.

399.

0 402.

403.

404.

405.

F 4)r 0 407.

408.

406.

WO 99/06397 PCT/US98/15479 -321- Table 2B cont.

R

o 410.

410. 409.

0 412.

0 415.

411.

413.

414.

417.

417.

416.

0 419. 418.

0 ~o 421.

MeO OM4 0 424.

420.

OM. 0 423.

OMo O 426.

425.

PCT/US98/1 5479 WO 99/06397 -322- Table 2B cont.

0Me 0 427.

Oo 0 430.

OMO 0 433.

42B.

moo rS OMO 0 429.

Mo OMe 0 432.

MO%~

OMe 0 431.

OMO 0 434.

OMO 0 435.

437.

436.

MoO1 439.

?Me 442.

440.

443.

OMe 0 438.

~N{

441.

444.

WO 99/06397 PCT/US9/I/ 5479 445.

448.

451.

y 454.

*323- Table 2B cont.

R

y 446.

449.

452.

455.

V

"anK~rx

K

447.

V

450.

453.

456.

459.

457.

458.

PCT/US98/I 5479 Wo 99/06397 -324- Table 2B cont.

462.

460.

461.

463.

B~

2 a 0

A

464.

467.

465.

A 1 466.

'a A 469.

468.

471.

474.

470.

473.

472.

I

PCTIUS98/1 5479 WO 99/06397 -325- Table 2B cont.

S

0

A

475.

478.

476.

479.

Br yx 477.

480.

483.

F Y cl N- Kd* 0 481.

484.

0

V

482.

F ~S~ 4)/ 485. 486.

0 489..

487.

488.

I

WO 99/06397 PCT/US98/15479

C

O\

\o -326- 490.

0 o 493.

0 496.

Co 0 499.

0 502.

505.

Table 2B cont.

R

o 0 491.

0 494.

CYY,

0 497.

500 500.

R

492.

0 495.

0 498.

0 501.

0 504.

507 0 507.

503.

S506.

506.

WO 99/06397 PCT[US98/15479 -327- Table 2B cont.

y 02Y

K

NX

508.

509.

510.

r0 511.

512.

513.

y 0 0

NW

516.

515, 514.

K-1 NcxY*

V

NWa 519.

517.

518.

K-~

520. 521.

522.

WO 99/06397PCUS8/57 PCTIUS98/15479 -328- Table 2B cont.

H

0 0 525.

524.

523.

f- 526. 527.

528.

160C 530.

531.

529.

533.

534.

532.

H

537.

535.

536.

I

PCT/US98/15479 WO 99/06397 -329- Table 2B cont.

r H538.

538.

0

H

K8-o 539.

H

(/y 542.

545.

540.

540.

541.

543.

546.

544.

547.

550.

548.

551.

551.

549.

552.

PCT/US98/1 5479 WO 99/06397 -330- Table 2B cont.

y aNrl_ 553.

K

554.

v 0c 555.

~J~

558.

556. 557.

559. 560.

561.

564.

oa 562.

563.

o 565.

566.

567.

WO 99/06397PCIS8157 PCTIUS98/15479 -331- Table 2B cont.

R

568.

569. 570.

571.

572. 573.

576.

574.

575.

578.

579.

577.

581.

581. 582.

580.

PCTIUS98/1 5479 WO 99/06397 -332- Table 2B cont.

0~ 583.

586.

V

YS4 0 584. 585.

587.

588.

589.

590.

591.

593. 594.

592.

596. 597.

595.

WO 99/06397 PCTIUS98/I 5479 -333- Table 2B cont.

R

598.

y 601.

F*N

604.

607.

610.

599.

602.

600.

603.

605.

606.

0 609. 608.

611. 62 612.

I

WO 99/06397 PCT/US98/1 5479

R

613.

616.

0 619.

622.

0 -334- Table 2B cont.

R

614.

617.

620.

R

615.

0 618.

621.

624.

623.

0 00 627.

626.

625.

WO 99/06397 PCT/US98/15479 -335- Table 2B cont.

R

H

628.

631.

0.0 630.

629.

00 632.

Example 339 Using methods described in the above examples, compounds comprising a parent structure selected from those disclosed in Table 3A and an R substituent selected from those disclosed in Table 3B can be prepared.

WO 99/06397PCIS8I57 PCTIUS98/15479 -336- Table 3A

F

R- ,COOH

H

3

,OOH

4.

F

3. 0 4#COOH

I'.

OCH

3 oe0I OH3

R-N

I%0 9. 0 WO 99/06397 -337- Table 3A cont.

N

H

3

C

R- O00H

.*COOH

13. 14. 0o

CH

3

H

3

C

H

COOH

~OCH

3 0 16. 17.

eCOOH

ICOOH

OCOOH

A

00 19. PCT/US98/1 5479 0 0

CH

3

H

I

WO 99/06397 PCTIUS98/1 5479 -338- Table 3B 0 1.

0 4.

'o 0 7.

0 0 13.

0 2.

5.

8.

11.

0 3.

0 6.

9.

00 12.

0 14.

0 -Th 0 0 18.

0O0 0 WO 99/06397PCIS8157 PCT/US98/15479 22.

28.

FH

2 CO.

F

2 06 0 31.

F

2

HC,

F2O 0 34.

0' 37.

-339- Table 3B cont.

R

0 0 23.

H

3 C0N,.$ 26.

29.

F

2 6 0 32.

35.

38.

0 .0 41.

24.

27.

-1h

FH

2 6' 0

F

2 6 o 33.

F

3

Q.CNI~

F

2 i0' 36.

39.

d0 42.

I

PCT[US98/15479 WO 99/06397 -340- Table 3B cont.

43.

0 0 46.

44.

H3 47.

47.

F3 0al 0 0 0 0 48.

49.

52.

58.

50.

53.

F

56.

59.

00 51.

~qT0 54.

57.

I

WO 99/06397 PCTIUS98/1 5479 -341- Table 3B cont.

R

61.

R

0CH 3 62.

R

63.

64.

9H 3

W'O

73.

dO 76.

68.

YH

3 71.

74.

00 L)0 69.

72.

0 'o

I

WO 99/06397 PCTIUS98/15479 79.

d o 82.

00

Y

88.

00 91.

Y

F3-. al- q d o0 94.

00 -342- Table 3B cont.

R

0 0 80.

F F 0 -0 81.

81.

F36 *b 83. 84.

86.

0 0 89.

Y

F

3 C F F 0ro '92.

F3y'&% y 00 95.

F

98.

Y

87.

y'' y 93.

-Th- F F 0 -oF 96.

HACO">

0 0 WO 99/06397 PCTIUS98/I 5479 -343- Table 3B cont.

H

3

CO**

100.

00 H3CO>" 101.

0 0 102.

F3~~ 103. 104.

105.

H3CO>

H

3 Cl(> 0 0 3c F3X 0 108.

106.

107.

0A 0A 0 0 109.

0 0 110.

ill.

So 0 0 112:' 113.

114.

A-k

A

F

3 C0-I 00 115. 17 116.

117.

WO 99/06397 PCTIUS98/1 5479 -344- Table 3B cont.

118.

119.

y 0 120.

r CNyNr 121.

)Iloe' 122.

123.

124.

125.

C1'a Icr 4-10 126.

y Icr 127.

129.

128.

OH

a A 130. 131. 132.

I I WO 99/06397 PCT/US98/1 5479 -345-

R

moo o 133.

H

0 136.

CF, 3 139.

.F

3 142.

145.

Table 3B cont.

R

y 134.

9F, )-I 137.

9F 3

Y

O-N"

140.

143.

y 146.

R

135.

qF 3 138.

9F 3 141.

~0 144.

147.

I

WO 99/06397 PCTIUS98/1 5479

CA

-346-

R

148.

151.

154.

y 157.

160.

Table 3B cont.

R

)y 149.

y 152.

155.

V

158.

R

150.

r 153.

156.

K

159.

~rv 162.

161.

WO 99/06397 WO 9906397PCTIUS98/15479 .347- Table 3B cont.

R

165.

163.

164.

166.

167.

168.

169.

y NC~QN0 170.

171.

174.

Ka 172.

173.

175.17.1.

176.

177.

WO 99/06397 PCTIUS9811 5479 -348- Table 3B cant.

R

178.

179.

R

180.

183.ll 183.

182.

181.

184.

187.

190.

0 185.

188.

N0 191.

186.

189.

N 0 192.

WO 99/06397 PTU9/57 PCT/US98/15479 -349- Table 3B cont.

R R

R

193. 194. 195.

v 196. 198.

197.

N Ny 199. 200. 201.

N

N

202. 203. 204.

205.

205. 206. 27 207.

I I WO 99/06397 PCTIUS98/1 5479 208.

y 211.

V

214.

N RI~r 217.

220.

-350- Table 3B cont.

R

209.

212.

215.

218.

221.

210.

jN 0 213.

NK0 216.

y 219.

V

222.

I

WO 99/06397 PCTfUS98/15479 223.

y -351- Table 3B cont.

R

N,,

224.

y

N

226.

227.

225.

228.

231.

234.

229.

232.

V

230.

233.

235.

236.

237.

I

PCT/US98/15479 WO 99/06397 -352- Table 3B cont.

238.

239.

240.

241.

244.

247.

242.

245.

248.

248.

243.

246.

249.

249.

250.

252.

252.

WO 99/06397 PCTIUS98/15479 -353- Table 3B cont.

253.

254.

255.

256.

257. 258.

y 260. 261.

259.

262.

264.

263.

265.

266.

267.

WO 99/06397 TIS/147 PCTIUS98/15479 -354- Table 3B cont.

y 268.

Kr v 270.

269.

271.

272. 273.

274.

275. 276.

277.

278.

280.

281.

279.

NyA 282.

I

PCTIUS98/154 7 9 WO 99/06397 -355- Table 38 cont.

283.

286.

y 289.

V

292.

295.

284.

287.

290.

293.

296.

285.

288.

291.

294.

y 297.

I I WO 99/06397 PCT/US98/15479 -356- Table 3B cont.

R

298.

301.

304.

V299. 300.

299. 300.

302.

y 305.

303.

306.

309.

312.

312.

307. 308.

c~"

N

310.

311.

WO 99/06397 PCTIUS98/1 5479 -357- Table 3B cont.

R

313.

314. 315.

316.

317.

318.

319.

320.

321.

322.

323.

326.

324.

325.

327.

WO 99/06397 PCT/US98/15479 -358- Table 3B cont.

R

328.

331.

V

334.

329.

332.

V

330.

333.

336.

335.

COOEt 337.

NOz 340.

338.

341.

341.

NO

2 339.

V

342.

PCT/US98/15479 WO 99/06397 -359- Table 3B cont.

R

343.

346.

02N, 349.

0 352.

355.

344.

347.

350.

0 353.

356.

R

CN

345.

O2- 348.

O

351.

0 354.

357.

I

WO 99/06397 PCTIUS98/1 5479 -360- Table 3B cont.

R

358.

361.

364.

367.

V

370.

359.

V

362.

365.

y 368.

moot~T~ 0 371.

360.

363.

366.

369.

moo.

0 372.

I

PCT/US98/15479 WO 99/06397 -361- Table 3B cont.

R

373.

374. 375.

377. 378.

376.

0 379.

0 382.

o 380.

o 383.

0 386.

o 0 381.

MoOo 0 384.

0 387.

385.

390.

388.

389.

I

WO 99/06397 PCT/US98/15479 -362- Table 3B cont.

R

0 o 392.

0 391.

0 393.

395.

394.

396.

397. 398.

399.

2CI o 402.

400. 401.

403. 404.

405.

408.

407.

406.

I

PCTIUS98/15479 WO 99/06397 -363- Table 3B cont.

0 410. 409. 411.

0 412.

0 415.

413.

.414.

0 417.

416.

0 419. 418.

420.

0 421.

OMO 0 424.

I/

OMe 0 423.

0Ms 0 OMO 0 425.

426.

I

I

WO 99/06397 PCTIUS98/15479 -364- Table 3B cont.

R

oi 427.

OM. 0 430.

428.

Mee OM. 0 431.

Mee Oo 0 434.

OM. 0 OM. 0 429.

OMO 0 432.

Mo y OMO 0 435.

0Me 0 433.

436.

437.

438.

moo 1( 439.

440.

B~OAV

441.

444.

442.

443.

WO 99/06397 PCTIUS98/I1479 445.

448.

Ny 451.

y 454.

S457.

457.

-365- Table 3B cont.

R

y 446.

449.

452.

455.

V

K

447.

v 450.

r 453.

456.

459.

458.

PCTIUS98/115479 WO 99/06397 366- Table 3B cont.

462.

460.

461.

463.

0

A

464.

467.

465.

466.

469.

472.

F cl 468.

470.

1 0 473.

471.

F

CI

474.

I

I

WO 99/06397 PCTIUS9811 5479

B

475.

478.

-367- Table 3B cont.

R

476.

479.

4 482.

477.

480.

481.

484.

487.

487.

F

F 0 483.

y 486.

c8rA 489.

485.

488.

I I PCT/US98/1 5479 WO 99/06397 -368-

R

F

490.

0 493.

0 o 496.

o 0 499.

24 502.

505.

505.

Table 3B cont.

R

0 491.

0 494.

0 497.

500.

R

0 492.

o 495.

V

0 498.

0 501.

0 504.

07 507.

503.

506.

I

WO 99/06397 PCT/US98/15479 -369-

R

y 508.

511.

514.

'^r 517.

520.

520.

Table 3B cont.

R

r 509.

512.

515, 518.

521.

521.

R

510.

513.

y 516.

vrcv 519.

522.

PCT/US98/15479 WO 99/06397 -370- Table 3B cont.

A

0 523.

-0 524.

-K fY^' 527.

530.

H

525.

526.

528.

H

0 531.

529.

H

532.

535.

535.

H

533.

H

0 536.

534.

Yr 537.

I

WO 99/06397 PCT/US98/15479

R

0

H

538.

-371- Table 3B cont.

R

0

H.

539.

R

H

N

540.

543.

541. 542.

545.

544.

~&H

546.

549.

552.

552.

547.

y550.

550.

548.

551.

I

PCT/US98/15479 WO 99/06397 -372- Table 38 cont.

y 553.

556.

I,<

554.

557.V 557.

555.

555.

558.

561.

559. 560.

562.

0 565.

564.

563.

566. 567.

Wo 99/06397 PCT/US98/1 5479 -373- Table 38 cont.

568.

569. 570.

571.

572. 573.

Icr 0Vie 574.

575.

576.

578. 579.

577.

rYS4 0 581. 52 582.

580.

WO 99/06397 PCTIUS98/I 5479 -374- Table 3B cont.

R

583.

584. 585.

586.

Ny 589.

587.

588.

590.

591.

593. 594.

592.

596. 596. 597.

595.

PCT/US98/15479 WO 99/06397 -375- Table 3B cont.

R

599.

600.

598.

601.

604.

607.

610.

602.

603.

605.

608.

606.

609.

611.

612.

I

WO 99/06397 PCTIUS98/1 5479

R

613.4 .613.

-376- Table 3B cont.

R

61-4.

617.

620.

H

616.

MoO A 0 619.

0 622.

*N

YA

R

0 615.

0 618.

621.

623. 624.

00 627.

625.

626.

WO 99/06397 PCTIUS98/1 5479 .377- Table 3B cont.

R

H

-0 628.

631.

0 0 630.

629.

0 0 632.

Examgle 340 trans, trans-4-( 1.3Benzodixol5yV2(4-methoxylhenvl 1 1 -(3-methvlbut- 1 N-phenyl aminocarbon imethyI -pyrrolidine-3-carbo ylic acid Using .the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD 3 oD) a 0.85 J=6 Hz, 6H), 1.25 (q, J=7 Hz, 2H), 1.42-1.56 (in, 1H), 3.43-3.85 (in, 9H), 3.88s 5.95 (S, 2H), 6.80 J=7 Hz, 1 6.86 (dd, J=9 Hz, I1H), 6.89-7.00 (mn, 2H), 6.97 J=1 Hz, 1IH), 7.04 J=9 Hz, 2H), 7.37 J=9 Hz, 2H), 7.40-7.47 (in, 3H). MS mle C (53.12, 53.11), H (4.63, 4.80), N (3.33, 3.28).

WO 99/06397 PCT/US98/1 5479 -378- Example 341 tran. trn -4 I.enzodioxol5yl-2-4mLethoxyphenyl>)l butyl-N-(4 -metylheYaminocaBonLt2tMethyl)-Dyrroidigt-- Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.47 (in, 4H), 2.37 3H), 2.83 J=7 Hz, 2H), 3.06-3.25 (in, 2H), 3.40- 3.50 (in, I 3.51-3.63 (in, 3H), 3.80 3H), 3.87 J=9 Hz, 1IH), 5.92 2H), 6.74 J=8 Hz, I1H), 6.80-6.86 (in, 3H), 6.89 J=8 Hz, 2H), 7.04 J=2 Hz, 1H), 7.12 J=8 Hz, 2H), 7.19 4=8 Hz, 2H). MS (DCI) mle 545 Analysis calcd for C32H36N206: C, 70.57; H, 6.66;

N,

5.14. Found: C, 70.20; H, 6.81; N, 5.03.

Example 342 ras. tran-- 3 Benzodioxol-5l2(4-Dro,,oxv~phent

-N

dI(n-butylmIno~cprbnylmeth l)y roli--ge 3 oyli acid Using the procedures described in Example 1, the title compound was prepared. I H (300MHz, CDC13 8 7.30 (2H1, d, 7.03 (1 H, d, 6.83 mn), 6.72 (1 H, d, 5.95 (1H, d, 5.93 (1 H, d, J=2), 3.88 t, 3.73 (1H1, d, J=12), 3.58 (1H, in), 3.53-3.20 (4H1, in), 3.10-2.90 in), 2.72 (1H, d, J=15), 1.79 (211, q, 1.50-1.05 (8H, in), 1.02 (3H, 1, 0.87 (3H, t, 0.80 (3H1, t, MVS (DCI/NH3) m/e 539 Anal calcd for C 3 11-42N206 0.51-12: C, 67.98;

H

J7.91; N, 5.11. Found: 0,68.24; H, 7.70; N, 5.03.

Example 343 tra s~trafls- 4 3 Befzodioxo-5l2 4roPVlhen Fl-1(N.Ldin butyLainfocarbon Imeth I Drrolidine 3 carbxli cid Using the procedures described inl Example 1, the title compound was prepared. 1i-i (300MHZ, CDC13 8 7.31(2H, d, 7.13 (2H, d, J=9), 7.03 (1 H, d, 6.84 (1 H, dd, J=6, 6.73 (1 H, d, 5.95 (18, d, 5.93 (1H, d, 3.76 d, J=10), 3.60 in), 3.55-3.20 (41-, in), 3.13-2.88 (4H, in), 2.75 (1H, d, J=15), 2.55 (2H, t, J=8),1.62 (2H, q, J=8)1 1.50-1.00 (88, in), 0.92 (3H, t, 0.85 t, 0.78 t, MVS (DCIINH3) m/e 523 Anal calcd for C31H42N205-0.

2 C. 70.63; 8, 8.13; N, 5.31. Found: C, 70.55; H, 8.08; N, 5.18.

WO 99/06397 PCT/US98/1 5479 -379- Example 344 trans trans2-(4-MethoxyghenIVl)- 4 (l.3-benzodi~oxol-5-Yl)- -r3-(Nl~ov-- pet ai DoIr iip3creyi aci Using the procedures described in Example 316, the title compound was prepared. 1 H NMIR (300MHZ, CDCI3) 8 0.85 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.3-1.4 (in, 4H), 1.5-1.6 (sextet, J=7, 2H), 1.65-1.8 (in, 4H), 2.05-2.15 (in, 1H), 2.43-2.56 (in, 1H), 2.72-3.1 (mn, 7H), 3.27- 3.4 (in, 2H), 3.5-3.6 (in, 2H), 3.80 3H), 5.95 2H), 6.73 J=8Hz, 1 6.8-6.9 (in, I1H), 6. 85 J= 9Hz, 2H), 7.02 (df, J=2Hz, 1 7.80 (d, J=9Hz, 2H).

Exampe 345 trans-trpfs- 4 2 Dih drobezffura-5Yl)2(4- I lhenl) 1 n~utfamin oca rbonylm ethyl) -yrldn croyir aid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 7.40 (3H, mn), 7.22 (2H, d, J=8), 7.13 (1H, dd, J=8, 6.72 (1H, d, 5.28 (1H, d, J=12), 4.55 (2H, t, 4.15 (OH, d, J=18), 4.03 (2H, in), 3.75 (2H, in), 3.40 (2H, mn), 3.20 (2H, t, 3.15 (1H1, in), 3.10-2.90 (2H1, in), 2.63 (2H1, q, 1.47 (2H-, in), 1.31 (4H, in), 1.12 (3H, t, 1.10 0.92 (3H, t, 0.80 (3H, t, MS (DCI/NH3) Wne 507 Anal caicci for 031 H42N204 TFA: C ,63.86 H, 6.98; N, 4.51. Found: C, 63.95; H, 7.12; N, 4.43.

Example 346 trans, trans-4-(l 3 e zodioLol5yl)2.(4methoxyphenyI petl-- nlaiocr nl ty)yr]idne3croy acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.93 J=7.3 Hz, 3H), 0.94 J=7.3 Hz, 3H), 1.33 (mn, 4H), 2.72 J=15.2 Hz, IN), 2.81 (nm, 1K), 3.1-1-3.23 (mn, 2H), 3.45-3.57 (mn, 2H), 3.79 3.83 J=9.8 Hz, 1H), 4.54 (in, 1H), 5.92 2H), 6.73 (ci,.J=7.8 Hz, 1H), 6.83 (in, 3H), 6.98 (bs, 2H), 7.04 (di, J=1.7 Hz, 1 7.07 7.37 (mn, 3H). MS (DCI) m/e 545 Anal calcd for C 3 2H-33N206 .0.35H20: C, 69.76; H, 6.71;

N,

5.08. Found: C, 69.72; H, 6.66; N, 4.94.

WO 99/06397 WO 9906397PCT/U59815479 -380- Example- 347 trans, trans-4-(l-3Bnoixl5y)2 4-ehklhnl- b tyII-N-(- fIuor thy 1 -)amino ar l m et hyl) py rroIi d ifne 3-carboxylic aci Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 0.87 J=6.6 Hz, 3H), 1.17- 1.45 (in, 4H), 2.65 J=16.5 Hz, 1H), 2.72 (in, 11H), 3.10 J=9.5 Hz, 1H), 3.21-3.27 (mn, 1H), 3.40 (dd, J=4.1, 9.9 Hz, 1H), 3.54 (in, 1H), 3.61- 3.74 (in, 3H), 3.77 3H), 5.93 2H), 6.73-6.85 (in, 4H), 7.02 (in, 3H), 7.33 J=7.5 Hz, 1H), 7.40 1H), 7.58 J=7ZiHz, 1H), 7.69 Hz, 1H). MS (DCI) Wle 599 Anal calcd for C32H133F3N206:

C,

64.21; H, 5.56; N, 4.68. Found: C, 64.09; H, 5.63; N, 4.57.

Example 348 trans. trans-!4-( 1.

3 Bnzodioxgl5Y)2(4-methoxyphenyl) propyl-N (~nr h invlcarboQ-ny)aininocarbn lin thvI)P1y nine3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 6 0.78 J=7 Hz, 1.43 (q, J=7 Hz, 2H), 2.07-3.01 (in, 1H), 2.76 (dd, J=7, 9 Hz, 2H), 2.77-3.00 (in, 5H1), 3.05 (3.70, J=m Hz, 11 3.76 3H), 5.88 2H), 6.67 J=8 Hz, 1H), 6.80 (dd, J=7 Hz, 1H), 6.83-6.90 (mn, 2H), 6.98 J=2 Hz, 1H), 7.32- 7.39 (in, 2H). MS Wne calc'd for C29H39N307: 540.2710,.

Found 540.2713.

Examole 349 trans, tran 3 Benzodioxo5yl)2(4met ioxyphenI)-1 -(cis- 2 .6-dimethylliperidin-fll Icarbofylmfeth flDrroidine3-carboxYic Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 5 0.94 J=7 Hz, 3H), 1.15d 3H), 1.10-1.70 (in, 6H), 1.70-1.90 (mn, 1H), 2.9. J=13 Hz, 11-), 3.00-3.20 (mn, 2H), 3.50 (3.70, J=m Hz, 2H), 3.79 3H), 3.80-4.00 (in.

1H), 4.10-4.65 (in, 2H), 5.95 2H), 6.70 (7.10, J=m Hz, 5H), 7.35 (in, 2H). MS Wne calc'd for 0 2 8 H35N206: 495.2495. Found 495.2493.

WO 99/06397 PCT/US98115479 Cl -381- Exam-nple 35-0 trans, trans-2-(4-Methoxymethoxyphenyl- 4 1-2(-rly--)pnaeufoyaioehlproiie3 carboxyliC a-cid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 57-59 00. 1H NMR (CDCI3, 300 MHz) 8 0.78 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.28-1.36 (in, 4H), 1.93 (sextet, J=7Hz, 1.72 J=7Hz, 2H), 2.20-2.32 (in, 1H), 0 2.72-3.10 (in, 7H), 3.18-3.41 (in, 2H), 3.43 (dd, J=-3Hz, J=9Hz, 1H), 3.48 3H), 3.52-3.59 (in, 1H), 3.68 J=9Hz, 1H), 5.15 2H), 5.94 (s,2H), 6.73 J=8Hz, 1H), 6.82 (dd, J=lHz, J=8Hz, 1H), 6.98-7.02 (mn, 3H), 7.32 J=9Hz, 2H). MS (DCI/NH3) Wne 591 trans, trans-4-(l 3 Benzodioxol5yl2-44iethoxylhenyl)-1 buy)N1hnlmn~abn~~ety)2roiie3croyi acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 0.79-0.89 (in, 6H), 1. 14-1.21 (in, 1H), 1.25-1.40 (mn, 1H), 2.64 (dd, J=4.6, 15.4 Hz, 1H), 2.76 Hz, 1H), 3.05-3.13 (in, 2H), 3.37-3.49 (in, 2H), 3.70 3H), 3.80 J=9.8 Hz, 1H), 4.53 (in, 1H), 5.83 (mn, 2H), 6.65 J=8.1 Hz, 1H), 6.72 6.76, J=m Hz, 3H), 6.87 (in, 2H), 6.95 J=1.7 Hz, 1 7.03 (mn, 2H), 7.29 (in, MS (DCI) Wne 531 Anal calcd for C31 H34N206 0.4H20: C, 69.23; H, 6.52; N, 5.21. Found: C, 69.19; H, 6.52; N, 5.03.

Example 352 trans, trans74-(l 3 Benzodioxo -5y)2(4.ineth!2xyjhenyll

-WN-(

12oy)Npeyaiocroy~mty~y-oiie3cro i acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3QD) 8 0.99 J=6.8 Hz, 6H), 2.71 J=15.6 Hz, 2.84 (in, 1H), 3.13-3.18 (in, 2H), 3.45-3.58 (in, 2H), 3.79 3H), 3.88 J=9.8 Hz, 1 4.80 (mn, 1 5.92 2H), 6.74 (d, J=8.1 Hz, 1H), 6.83 (mn, 6.96 (br s, 2H), 7.04 J=1.7 Hz, 1H), 7.13 (mn, 2H), 7.38 (mn, 3H). MS (DCI) m/e 517 Anal calcd for WO 99/06397 WO 9906397PCT/U598/1 5479 -382-

C

3 0H32N206 6 0.4H20 -0.08CH3C02C2H5: C, 68.65; H. 6.28; N. 5.28.

Found: C, 68.64; H, 6.35; N, 5.14.

Examn2,35 trans, trans-4-(4-PropoxyghelyL 2-(4-methgxynhenl'-1 b-utyflaminocarboflYlmethYlP1Yrrolidine-acarboxYlic aci-d Using the procedures described in Example 1, the title compound was prepared. I H (300MHz, CDC13 8 7.42 d, J=l OHZ), 7.38 (2H, d, J=lOHz), 6.92 d, J=lO1-z), 6.88 d, J=lOHz), 5.13 bd, J=l2Hz), 4.02 in), 3.90 (2H, t, J=8Hz), 3.80 3.71 (3H, in), 3.40 (2H1, in), 3.19 (1H, in), 3.10-2.90 (2H, mn), 1.80 (2H, in), 1.48 (2H, in), 1.29 (4H, mn), 1.13 (2H, in), 1.03 (3H, t, J=8Hz), 0.92 (3H, t, J=9Hz), 0.82 t, J=9Hz). MS (DCI/NH3) m/e 525 Anal calcd for C31H44N2O5- 1 TFA: C, 62.06 H 7.10; N, 4.39 Found: C, 62.43; H, 7.28; N, 4.39.

Example 354 -tra-ns. trans-4-(1 .3Benzodioxol5vY2(4methoxyohenYl)-l .2.3.4-tetrahydrogpiflolifl-l yl)carbonyflmethYfl)P-Yrrrrolidine- 3 carboxyl aci Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 5 1.88 (quintet, J=6.5 Hz, 2H), 2.67 J=6.4 Hz, 2.87 J=8.6 Hz, 1 3.14 (in, 2H), 3.42 (dd, J=4.6, 9.7 Hz, 1 3.53-3.70 (in, 3H), 3.72-3.78 (in, 1 3.77 3H), 3.86 J=9.6 Hz, I1H), 5.91 2H), 6.73 J=8.1 Hz, 1 6.83 (in, 31-), 6.98 J=1.1 Hz, 1H), 7.02-7.23 (in, 6H). MS (DCI)'m/e 515 Anal calcd for C30H3ON206 0.3H20 0.15 CH 3 002C2H5: C, 68.93; H, 6.01; N, 5.25. Found: C, 68.91; H, 5.86; N, 5.19.

Example 355 trpnsgt rans2(3.4Diiethoxyphenyl- 4 (N .N-di~n-butylaminfocarbonylmpinthyl)pyrrolidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 64-65 0 C. 1 H NMIR (CDCI3, 300MHz) 5 0.79 J=7Hz, 3H), 0.88 J=7Hz, 3H),1.07 (sextet, 1=7H7:' 2H). 1.20-1.35 (in, 4H), 1.43 (sextet, J=7Hz, 2H), 2.83 (d, WO 99/06397 PCT/US98/15479 -383- J=13.MHz, 1 2.94-3.17 (in, 4H), 3.22-3.42 (in, -1 3.40-3.48 (in, 3H), 3.58-3.65 (in, I 3.82 3H), 3.85 4H),5.92 2H), 6.73 J=BHz, I1H), 6.81 J=8Hz, 1 6.86-6.96 (in, 3H), 7.07 J=3Hz, 1 MS (DCI/NH3) Wne 541 trans. trans-2-(3.4-Diinethoxylhenl)- 4 -(l.3-benz-odioxol -5-yi)-l -2- 0 Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 75-86 0 C. 1 HNMR (CD3OD, 300 MHz) 5 0.75 J=7Hz, 0.82 J=7Hz, 3H), 1.32-1.43 (in, 6H), 1.65-1.77 (in, 2H), 3.0-3.09 (in, 4H), 3.23-3.27 (in, 2H), 3.44 (t, J=6Hz, 1H), 3.47-3.56 (in, 2H), 3.78 J=9Hz, 1H), 3.83-3.93 (in, 2H), 3.87 3H), 3.92 3H), 4.63 J=1l3Hz, 1 5.97 2H), 6.82 (d, J=7Hz, 1H), 6.93 J=7Hz, 1H), 7.06 J=7Hz, 1H), 7.08 J=3Hz, 1H), 7.16 (dd, J=3Hz, J=7Hz, 1H), 7.27 J=3Hz, 1H). MS (DCI/NH3) m/e 591 Example 357 trans, trans-2-(3.4-Diinethoxyphgnyl- 4 -(l.3-beflzodioxol5y'l l-1-2- (N -1ro yl -N he xa n e ul fon yI amin thyl1p r rll dine -3-arbo y Using the procedures described In Example 1, the title compound was prepared and isolated as a white solid. in.p. 65-66 0 G. I H NMR (CDCI3, 300 MHz) 8 0.80 J=7Hz, 3H), 0.89 J=7Hz, 3H), 1.23-1.48 (mn, 6H), 1.43 (sextet, J=7Hz, 2H), 1.72 (sextet,J=7Hz, 2H), 2.25-2.35 (in, 1 2.73-3.10 (mn, 3.19-3.32 (in, 2H), 3.45 (dd, J=3Hz,- J=9Hz, 1 H), 3.53-3.59 (mn, 111), 3.68 J=9Hz, 1H),3.87 6H), 5.95 2H), 6.74 (d, J=8Hz, 1H), 6.79-6.86 (in, 2H), 6.92-6.97 (mn, 2H), 7.02

MS

(DCIINH3) in/e 605 WO 99/06397 PCTIUS98/I 5479 -384- Examgle 358 trans. tra s-2-(4-MethoxvphenYl- 4 ('.3-benzodioxoI-5-yl) I (phthalimidO th I rr lidin-3-carkroxulic ci The compound of Example 10 (250 mg), N-bromoethylphthalimide 6 (206 mg), and diisopropylethylamifle (175 mg) were dissolved in 1 mL of acetonitrile and heated for 2.5 hours at 95 OC. Toluenle was added, and the mixture was washed with KHCQ3 solution. The solution was dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel eluting with 3:1 EtOAc-hexane to give 216 mg of an intermediate ethyl ester which was hydrolyzed by the method of Example 1 D to give 130 mg of the title compound as a white powder.

I H NMR (300 MHz, CDCI3) 8 3.12-3.26 (in, 2H), 3.60-3.75 (in, 2H), 3.70 3H), 3.98-4.12 (mn, 2H), 4.45-4.55 (in, lIH), 4.69 J=9Hz, 1H), 4.76- 4.88 (in, 1H), 5.96 2H), 6.55 J=8Hz, IH), 6.60-6.70 (in, 3H), 6.79 J=8Hz, 7.05-7.45 (in, 5H), 7.75 J=7Hz, 1H).

Examl tS. t as--(lzdoo-5v)2( -met(N-( p Using the procedures described Iin Example 1, the title compound was prepar ed. 1 H NMR (300 MHz, CD3OD) 8 0.86-0.98 (in, 1.17-1.22 (in, 1H), 1.23-1.41 (in, 3H), 2.70 (dd, J=11.2, 15.3 Hz, 1H), 2.83 (in, 1H), 3.10-3.21 (in, 2H), 3.45-3.60 (in, 2H), 3.79 3H), 3.86 (in, 1H), 4.74 (in, 1H), 5.91 (in, 2H), 6.73 (dd, J=1.1, 7.7 Hz, 3H), 6.82 (in, 2H), 7.04- 7.14 (in, 3H), 7.36 (in, 3H). MS (DCI) m/e 545 Anal calcd for C32H-36N206 0.25 CH3002C2H5: 0, 69.95; H, 6.76; N, 4.94. Found:

C,

70.03; H, 6.54; N, 4.78.

Example 360 trans trafls- 4 3 enzdiX5Y 2(ethoxYhen I~ -1(Nbutyl-N-(2-nar~hth~l iaminocarbonylieth l~rlii crboxjjLc Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz,

CD

3 OD) 5 0.83 J=7 Hz, 3H), 1.23- 1.39 (mn, 4H), 1.40-1.55 (mn, 3H), 2.60-2.72 (in, 2H), 3.00-3.80 (in, 3.66 3H), 5.87 2H), 6.39 J=9 Hz, 2H), 6.74-6.85 (in, 3H), 7.17 WO 99/06397 PCTIUS98/15479 -385- J=2 Hz, I 7.40 (dd, J=8 Hz, 1 7.52-7.62 (in, 3H), 7.80-7.90 (in, 1H), 7.90-8.00 (in, 2H). MIS (DCI) m/e 581 Analysis calcd for

C

35 H36N206 0.3 H20: C, 71.73; H, 6.29; N, 4.78. Found: C, 71.74;

H,

6.26; N, 4.72.

Exampil 31 t-rans-trails!! 2 4-P roo~oxypheflyl)- 4(l.3-endOXlSYl

E--

prpy- N-n-entanleUfoflylamino)ethyll1pyrolidine3carboxylic agcid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 53-54 OC. 1 H NMR (CDCI3, 300MHz) 6 0.79 J=7Hz, 3H), 0.89 J4-Hz, 3H), 1.03 (t, J=7Hz, 3H), 1.24-1.34 (mn, 4H), 1.43 (sextet, J=7Hz, 2H), 1.67-1.75 (in, 2H), 1.80 (sextet, 2H), 2.23-2.33 (mn, 1H1), 2.72-2.93 (mn, 5H), 3.05 (septet, J=7Hz, 2H), 3.15-3.35 (in, 2H), 3.42 J=9Hz, 1H), 3.54-3.62 (in, 1 3.67 J=9Hz, I1H), 4.90 J=7Hz, 2H), 5.95 2H), 6.73 (d, J=BHz, 1H), 6.85 J=8Hz, 2H), 7.02 1H), 7.32 J=BHz, 2H). MIS (DCI/NH3) mWe 589 (M+H) 4 trans. trpfls- 4 3 enzodioxol5Yl2(ihx-eyl) 1 methylindolinl1 -yflcarbonyl)ineh I Pr ~i ine3-carb-w~ic aci Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 mixture of indole C2 diastereoinerS, 0.95 (in, 1.5 (CH3 1.05 6.3H, 1.5 2.62 (in, 1 3.01 (mn, 211), 3.14-3.25 (in, 1 3.37-3.52 (in, 1.5H), 3.56-3.80 (in, 2H), 3.65 1.5 (CH3O)), 3.76 1.5 (CH3O)), 3.93 (in, 0.5H), 4.05-4.13 (mn, 4.42 (mn, 0.5H), 4.65-4.74 (mn, 1 5.91 (in, 2H), 6.72 J=8-1 Hz, 0.5H), 6.75 (in, 0.5H), 6.85 (in, 2H), 6.92 J=8.5 Hz, I1H), 7.00-7.06 (in, 2H), 7.14 J=7.7 Hz, 1 7.21 J=6.6 Hz, 1 7.38 (mn, 2H), 7.99 (in, I1H). MIS (DCI) Wne 515 Anal calcd for C30H30N2O6 0.35H20 0.3 CH3CO2C2H5: C, 68.47; H, 6.10; N, 5.12. Found: C, 68.46; H, 5.97; N, 5.07.

WO 99/06397 PCTIUS98/1 5479 -386- Example 363 trans, trans-4-(1 .3.Benzodioxol.5.Vl2-(4-methokyghenyIl)1 hyd roxy-3-12ropyl hex -flpvrroli dine-3-carbxyl ic aci-d Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 1.06 (in, 6H), 1.26-1.60 (in, 9H), 3.16 (dd, J=10.9, 12.6 Hz, 1H), 3.18 J=11 Hz, 1H), 3.44 Hz, I1H), 3.61 J=1 1 Hz, I1H), 3.73 J=1 1.0 Hz, I1H), 3.85 (mn, I1H), 3.96-4.17 (mn, 2H), 4.02 1.5 (CH3O diastereorner)), 4.03 1.5 (CH3O ci diastereoiner)), 6.15 2H), 7.01 J=8.1 Hz, 0.5H), 7.00 J=8.1 Hz, 0 0.5H1), 7.10 (in, 1H), 7.23 (in, 3H), 7.77 (in, 2H). WvS (DCI.) m/e 484 Anal catcd for C28H37N06 -0.33 H3P04: C, 65.34; H, 7.44; N, 2.72. Found: C, 65.30; H, 7.40; N, 2.60.

trans, trans-4-(l -ezdool5v)2(-etoyhnl- he~gtvl)-N-(3 4 -dimethgxybenlZ~flmilo')garbonyl~~methyl)Pvrroidine- 3 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR ('300 MHz; CD3OD) 81:1 mixture of rotainers, 0.61 J=7.1 Hz, 1.5H), 0.72 1.511), 0.76 J=7.1, 1.5, 0.83, t' 7.3 Hz, 1.05-1.60 (in, 8H), 2.84-3.10 (mn, J=2.5, 3.18, t, 9.7 Hz, 3.41-3.52 (in, 2H), 3.47-3.69 (mn, 2H), 3.66 1.5H), 3.73 1.5H), 3.77 1.5H), 3.78 1.5H), 3.79 1.5H), 3.86 J=9.8 Hz, 0.5H1), 4.19 (d, J=17.7 Hz, 0.5H1), 4.29 J=15.2 Hz, 0.5H1), 4.40-4.49 (in, 0.5H), 4.47 (d, J=15.3 Hz, 0.5H), 4.60 J=17.6 Hz, 5.93 (in, 2H), 6.46 (dd, J=1.7, 8.2 Hz, 0.5H), 6.52 J=2.0 Hz, 0.5H1), 6.74 (in, 2.5H), 6.80 1H), 6.83- 6.88 (in, 1H), 6.92 (en, 1.5H), 7.03 (dd, J=1.7, 6.8 Hz, 1H), 7.19 (in, 111), 7.36 (in, 1H). MS (DCI) m/e 647 Anal calcd for C37H46N208:

C,

68.71; H, 7.17; N, 4.33. Found: C, 68.41; H, 7.26; N, 4.11.

Example 365 trans. trans- 4 1.

3 Bnzodioxol-5l)2(4-melhoxyphen

I)

1 ((indolifl-1 yl)carbonyl)inehylIPrr lidncabxl cd Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 82.97 (dd, J=8.1, 9.5 Hz, 1 H), 3.10 J=8.1 Hz, 2H), 3.16-3.22 (mn, 2H), 3.51-3.68 (mn, 3H), 3.73 (in, WO 99/06397 WO 9906397PCT/US98/15479 -387- 3H), 3.83-4.05 (in, 3H), 5.90.(in, 2H1), 6.73 J=8.1 Hz, 1H), 6.86 (in, 3H), 6.99 (dt, J=1.1, 7.4 Hz, 1H), 7.08 J=0.7 Hz, 1H1), 7.11 (in, 1H), 7.18 J=7.1 Hz, 1 7.38 J=8.5 Hz, 2H), 8.02 1, 1 MS (C.l1.) m/e 501 Anal calcd for C29H28N2O6 0.5 H20 0.15 ~CH3002C2H5: C, 68.01; H, 5.82; N, 5.36. Found: C, 68.03; H, 5.65; N, 5.25.

ExampJle 6 trans, trans-4-(1 .3-BenZodioxol-5-yl)-2-(4-inethoxylhenfl)l-l-(N- Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 50.89 (dt, J=7 Hz, 3H), 1.23- 1.51 (in, 4H), 2.52-4.00 (mn, 8H), 3.78 J=6 Hz, 3H), 5.92 J=6 Hz, 2H), 6.70-6.87 (mn, 4H), 7.02-7.21 (in, 4H), 7.27-7.52 (in, 3H). MS (DCI) m/e 565 Analysis calcd for C31 H32N206Cl 0.6H20: C, 64.66; H, 5.99; N, 4.86. Found: C, 64.59; H, 6.00; N, 4.64.

Example 367 transtrans-2-(4-Methoxiheny) 4 -(l.3-benzodioxol-5-yV-1 -acid The compound resulting from Example 1IC (0.25 g) was reacted with 0.169 g of 3,4,5-trimethoxybelzyl chloride and 0.175 g of diisopropylethylamine in 1 mL of acetonitrile for 2 hours at room temperature. The resulting ester was isolated and then hydrolyzed by the method of Example 1 D to give 0.193 g of the title compound. m.p.

108-110 11C. 1 H NMR (300 MHz, CDCI3) 82.75 J=9Hz, I1H), 2.95-3.05 (mn, 211), 3.20 J=11 Hz, 1H), 3.45-3.55 (mn, 1H), 3.7-3.8 (in, 3.84 3H), 5.95 (dd, J=2Hz, 6Hz, 2H1), 6.55 6.70 J=8Hz, 1 H), 6.30-6.35 (in, 1IH), 6.90 J=9Hz, 2H), 7.13 J=2Hz, I1H), 7.43 J=9Hz, 211).

WO 99/06397 WO 996397PI'/US98/I 5479 -388- Example 368 trans, trans-4-( 1 Bnoigo--l-2(-ehxyhnl- butyl- N-(3-ch loroph enlyam n gcarboflylm ethyl -yrrolidi ne- 3 carboxylic aci 6 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.89 J=7 Hz,. 3H), 1.20- 1.42 (in, 4H), 3.42-3.87 (in, 9H1), 3.9 5.96 2H), 6.75 (7.10, J=m Hz, 7H), 7.33-7.50 (in, 4H). MS mle 565(M+H). Analysis calcd for

C

3 1lH 33 N2O6CIO1.OCF3C00H: C, 58.37; H, 5.05; N, 4.13. Found:. C, 58.41; H, 4.99; N, 4.08.

Eam 6 trans..trans-2-(4-Methoxghenl)- 4 -(l.3-benzodioxol-5- yl)-1 butyl amino) pyrinidil-4-vilDyrrlidi e 3 carboxyuic- acid The compound resulting from Example 10 (0.25 g) was reacted with 0.11 g of 2,4-dichloropyrimlidine and 0.175 g of diisopropylethylamine in 1 mL of acetonitrile for 2 hours at room temperature to give 0.218 g of ethyl 2-(4-inethoxphenYl)-4*(l ,3- 1 -(2-chloro-4-pyrimidyl)Pyrrolidine- 3 carboxylate. This compound was reacted with 1 mL of dibutylamifle in 2 mL of toluene at 125 00 for 17 hours. The resulting ethyl este r was hydrolyzed by the method of Example 1D to give 0.142 g of the title comopund as a white powder. 1 HNMR (300 MHz, CDCI3) 50.75-0.90 (broad, 6H), 1.1-1.3 (br, 1.35-1.55 (br, 4H), 3.05 (mn, 1H), 3.3-3.5 (br, 2H), 3.55-3.67 (in, 2H), 3.75 3H), 4.6 (br, 1H), 5.2 (br, 1H), 5.45 (br, 1H), 5.87 2H), 6.3 (br, 1H), 6.67 J=8Hz, 1H), 6.7-6.85 (in, 4H), 7.10 J=9Hz, 2H).

Example 370Q trans. tran-4 (1 .3Ben zod i oxol 5yi)-2(4meth oxylhe nYl)- m -hl t2y) -hnlmn~abnlmehl yrl ie3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.90 J=7.5 Hz, 1.12 3H), 1. 14 3H), 2.06 J=7.5 Hz, 2H), 2.73 J= 15.3 Hz, I1H), 2.91 J=9.5 Hz, 1H), 3.11 J=15.6 Hz, 1H), 3.21 J=8.8 Hz, 1H), 3.50- PCTIUS98/I 5479 WO W99/06397 PTU9/57 -389- 3.61 (in, 2H), 3.80 3H), 4.00 J=10.2 Hz,. 1H), 5.91 2H), 6.74 (d, J=7.8 Hz, 1H), 6.85 (in, 6.93 (in, 1H), 6.98 (in, 1H), 7.03 J=1.7 Hz, 1H), 7.17 (in, 2H), 7.36 (in, MS (DCI) mle 545 Anal calcd for C32H36N206: 0, 70.57; H, 6.66; N, 5.14. Found: C, 70.17; H, 6.53; N, 'O s 4.97.

c-i Example 371 trans. trans-2 Ethyl pheyl)f4(5-i ndanyl)l .N-di(ncibutyl)aminocarbonlalethy-IlD1yrrolidine 3 carbgxylic acid- 0 Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDCI3) 8 7.25 (3H, in), 7.21 (1KH, d, 3Hz), 7.17 (311, in), 3.80 (1H, d, 10Hz), 3.65 (1H, ddd, 6, 5, 3Hz), 3.4 (4H, mn), 3.10 (2H, in), 2.98 (2H, mn), 2.88 in), 2.79 (1H, d, 16Hz), 2.62 (2H, q, 7Hz), 2.05 (2H, in), 1.42 (2H1, in), 1.32 (1KH, in), 1.21 (3H, t, 7Hz), is 1.05 (2H, sext, 7Hz), 0.87 (3H, t, 7Hz), 0.79 (3H, t, 7Hz). MS (DCI, NH3) Wne 505 Anal calcd for C32H44N203: C, 76.15; H, 8.79; N 5.55.

Found: C, 75.96; H, 8.75; N, 5.36.

Examle 32 trans. rans2(3.4Difluorohenyl)l- 4 -(l3blzgdoxol-5y)l-(N

.N-

di(n-butyI)aminocarbonflmlethyl-PYrrolidine 3 carboxylic cid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. in.p. 62-63 11C. 1 H NMR (CDCI3, 300 MHz), 8 0.83 J=7Hz, 3H), 0.88 J=7Hz, 3K), 1.13 (sextet, J=7Hz, 2H),1 .20-1.32 1.36-1.49 (in,3H), 2.85-2.93 (in,2H), 2.98-3.23 (mn, 4H), 3.36-3.45 (in, 3K), 3.58-3.66 (m 1H), 3.94 (d, J=8Kz, 1H), 5.93 2H), 6.72 J=7.5Kz, 1K), 6.84 (dd, J=lHz, 1H), 6.98 J=7.5Hz, 1H), 7.08-7.15 (in, 2K), 7.22-7.28 (mn, 1H). MS (CDI/NH3) m/e517 Examgle 37 trans, trans-2-(3.4-Dif lUoroph enyl) 4 -(l3befzodioxol-5I)- .1 gropyl-N-n-pentanesulfoflylainino~ethy11DYrrolidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid.' m.p. 71-72 OC. 1 H NMR (CDC13, 300 MHz) 8 0.82 J=7Hz, 3H), 0.90 J=7Hz, 1.25-1.38 WO 99/06397 WO 9906397PCT/US98/1 5479 '4 -390- (in, 4H), 1.46 (sextet, J=7Hz, 2H), 1.74 (quintett, J=7Hz, 2H1), 2.26-2.36 (in, 1H), 2.72-2.95 (mn, 5H), 2.98-3.12 (in, 2H), 3.15-3.34 (in, 2H), 3.45 (dd, J=3Hz, J=9Hz, 1H), 3.53-3.60 (in, 1H), 3.71 J=9Hz, 1H), 5.96 (s, 2H), 6.75 J=9Hz, IH), 3.82 J=2Hz, J=9Hz, IH), 5.96 Kd J=2Hz, 1H), 7.09-7.18 (mn, 2H), 7.23-7.34 (in, 1H). MS (CDI/NH3) m/e567 EXample 374 trans. trans-4- Benzodioxol-5-yfl.2-(eth oxymethyl)- N-di (nbutyflamnocarbonylethyfl)pyrrolidifle-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2CI2) Rf 0.53. 1 H NMR (CDCI3, 300 MHz, rotameric forms) 8 0.70 J=7Hz), 0.80 J=7Hz) and 0.96-1.04 (in, 6H total), 1.04-1.75 (mn, 11H), 1.34-1.53 (br in, 4H), 2.65 (AB) and 2.80-3.08 (in, 2H total), 3.10-3.82 (br m, 12H), 4.03 (in) and 4.22-4.45 (br mn, 2H total), 5.90 and 5.91 2H total), 6.65-6.84 (in) and 6.93 (in) and 6.99 (mn, 3H total). MS (FAB) m/e 463 Anal calcd for C25H38N206 -1.5 H20: C. 61.33; H, 8.44; N, 5.72. Found: C, 61.28; H, 7.78; N, 5.62.

Examl~le 37 -trans, trans-!4-(1 .3.Benzodioxol-5-yl)-2-(t--butYl)-1 di(n-butyflaminocarbonlyimethyI-PYrrolidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a colorless wax. TLC (10% MeOH-CH2CI2) Rf 0.37. 1H NMR (CDCI3, 300 MHz, rotaineric forms) 8 0.71 J=7Hz) and 0.77-1.05 (mn, 9H t otal), 1.05-1.20 (mn, 2H), 1.20-1.72 (br m, 13H), 2.48-2.52 (mi, 1H), 2.87-3.00 (mn, 1H), 3.05-3.60 (mn, 5H), 3.60-3.80 (br in, 2H), 3.88-4.05 (br in, 1H), 4.28 (br d, J=l5Hz, 1H total), 5.90 and 5.92 2H total), 6.67-6.82 (mn, 3H total). MS (FAB) m/e 461 Anal calcd for C26H40N205 1.75 H20: C, 63.45; H, 8.90; N, 5.69.

Found: C, 63.18; H, 8.22; N, 5.60..

WO 99/06397 PCTJUS98/1 5479 KI -391- Examole 376 trans. trans-4-(l .3-Benzodioxol5yl2-(2-methYlbutyl)-1 -(N.N-dI(flbutyflamiflocarboflYlmethyl-Pyrrolidine 3 carboxyuic acid Using the procedures described in Example 1, the title compound D was prepared and isolated as a colorless glass. TLC (10% MeOH- CH2CI2) Rf 0.49. 1H NMR (CDCI3, 300 MHz, rotameric forms and 'A mixture of diastereorners) 6 0.69 (br t, J=7Hz) and 0.75-2.15 (several br m, approx. 26H total), 2.48-2.65 (br m, 1H), 2.87-3.01 (br m, 1H), 3.06- 'A 3.82 (br m, 711), 3.90-4.40 (br m, 2H), 5.90 and 5.92 2H total), 6.67-6.90 (in, 3H total). MS (FAB) m/e 475 -trans. trans-4-(l .3Benzodioxol-5Y)2(3methylbutyIl)- -(N.N-di(flb -u-t -yflaminocarbonlmlethyl-pyrrlidine-3-arboxylic acid Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2012) Rf 0.41. 1 H NMR (CDCI3, 300 MHz, rotameric forms) 8 0.73 J=7Hz) and 0.77-1.05 (mn, 12H total), 1.07-1.75 (mn, approx. 14H plus H20), 2.48-2.63 (in, 1H), 2.87-3.05 (in, 1H), 3.05-3.60 (several br mn, 5H), 3.62-4.02 (br m, 2H1), 4.29 (br d, J=l5Hz, 1H), 5.89 and 5.93 2H total), 6.65-6.90 (in, 3H total). MS (FAB) m/e 475 ExamlRle 37 trans. trans-2-(4-bMethoxylhenyl)- 4 ('.3-bnzodioxol5Yll prly--(-ehlNpo~lmnQ~~fnlgioehlproiie I3-carboxylic--cid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 58-59 IOC. IH NMR (CDC13, 300MHz) 8 0.78 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.27 (sextet, J=7Hz, 2H), 1.48 (mn, 4H), 2.22-2.30 (in, 1H), 2.62 3H), 2.68-2.78 (in, 1H), 2.84-3.03 (in, 5H), 3.08-3.31 (in, 3H),3.39 (dd, J=3Hz, J=9Hz,1H), 3.50-3.58 (in, 1H), 3.63 J=9Hz, 1H),3.79 311), 5.95 2H1), 3.73 (d, J=8Hz, 1H), 6.83 (dd, J=2Hz, J=8Hz, 1H), 3.87 J=9Hz, 2H), 7.01 (d, J=2Hz, 1H1), 7.33 J=9Hz, 2H). MS (DCI/NH3) Wne 576 NO.395 P.1 17.MRR.2005 17:05 SPRUSON FERGUSON 61 2 92615486 pCT iS98/15479 WO099106397 -392.

Usaing the procedures described In -Example 1. the i prepared. 1 H NMR (300MHz, CDC3 8 7.35 mn), 7.

4.87 (IH, d, J=12)9 4.00-3.60 (5H, in), 3.60-3.10 (3H. iM), in), 1.45 (2H. mn), 1.29 (4H, in), 1.15 (2H, Mn), 0.91 (3H, t, J% t, MS (DCI/NH3) mle 509 Anal calad for C271 0.75 TFA: C, 57.62; Ho 5.56; N, 4.72. Found: C, 57.72; H. V.

tralS. trnS 4.DID3.lethy v)-?-4m~oxP1_ biltylamiloCarboncyl Ieth-f H n r 4lidfle a b ox using the procedures described in Example I, the ti was prepared. I HNMR (300 MHz_, CDC13 8 7.43 (2H, d, Ja bs), 7.18 (1H, dd. J=8, 7.11 (IN, d, J=9)1 6.90 d, J! d, J=12), 4.26 (IH. d, J=18), 4.16 (2H, in), 3.83 (2H, rn), 3.

3.56 (1H, bd, J=18)1 3.37 rn), 3.20 (iH, in). 2.96 (2H, 2.22 (3H, 1.47 (2H, mn), 1.27 (4H. iVn), 1.10 (2H, in), 0.81 (3H, tv MS (OCIINH3) m/e 495

J

030H-42N204-1.25 TFA: C, 61.28; H. 6.84; N. 4.40. Found., 7.05; N, 4.38.

trAns. trans--2.-Di (3-f IUoro.4-m efloxvp-helYl LI hutyfl minocarbonv0iinethItb- ro-ilarbox! Using the procedures described in Example 1, the was prepared. I1 NMR (300MHz. CDCI3) 8 7.20 (2H. in), 6.93 (2H, mn). 5.48 (1H, mn), 4.26 (1H, mn), 4.16 in), 3.

(6H, 3.56 (lIH, in). 3.37 (1H, mn), 3.20 (1H. mn), 2.96 (21 in), 1.27 (4H, in), 1.10 (2H, in), 0.93 (3H-1 t, 0.81 (31- (DCI/NH3) nile 533 Anal catcd for C 29

H

3 8F2N2C 63.78; H, 7.29; N, 5.13. Found: C, 63.77: H. 7.08; N, 4.99, magjd 9 compound 8 (4H, in), .10-2.90 (21-lo 0.83 (3H.

132F4N203- 7; N, 4.66.

ie compound 7.25 (11-, dIo), 5.48 (iH.

31 s), 2.24 (3H, ).93 (3H, tt nat calcd for C, 61.16; H.

itle compound 7.17 (2HO in), 3(211, in), 3.87 m) in) 1.47 (2H.

t.

MS

510.75 H20; C, WO 99/06397 PCTfUS98/15479 -393- Example-382K trans. trans-4-(l .ezdool5y)2(-etoyhnl- p2entyl) N ethyl ghenyl)amino)carbonl) mgthyl)Pvrrglid i ne-3carboxylic, acd Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.90 (in, 3H), 0.95 J=7.3 Hz, 3H), 1.13-1.37 (in, 4H), 2.30 3H), 2.34 (s,(CH3 rotainer)), 2.73- 2.91 (in, 2H), 3.17-3.26 (in, 2H), 3.32-3.62 (in, 2H), 3.77-4.08 (in, 1H), 3.80.(s, 3H), 4.71 (in, 1H), 5.92 (in, 2H), 6.61-6.84 (in, 6H), 7.04-7.16 0 (mn, 3H), 7.23-7.29 (in, 2H). MS (DCI) Wne 559 Anal calcd for C33H38N206 -0.35 H20 -0.05 CH3CO2C2H5: C, 70.03; H, 6.92; N, 4.92.

Found: C, 70.08; H, 6.82; N, 4.95.

trans. -trans-!4-(1-3Bnoixl5v)2(-phxrhnl 1-(Nbutyl-N-(- 1 naphthyflaminocarbonlmlethylOyrrolidineacarbx-yLic Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.40 (in, 2H), 1.40-1.60 (in, 2H), 2.42-2.80 (in, 2H), 2.85-4.00 (in, 6H), 3.77 J=1.5 Hz, 3H), 4.05-4.20 (in, 1H), 5.94 J=2 Hz, 2H), 6.6 (dd, J=9, 10 Hz, 1H), 6.70-6.85 4H), 6.95-7.02 (in, 2H), 7.17 (dd, 8K, 7.25 (dd, 8H, 7.38-7.60 (in, 411), 7.87-8.00 (in, 2H). MS ine 581. Analysis calcd for C35H36N206 -1.4 H20: C, 69.38; H, 6.45; N, 4.62. Found: C, 69.36; H, 6.07; N, 4.41.

Examplpa 34 trans, trans-2-(4-MethoxyheflYI) 4 -(i.3-benzodioxol5ylk phenyI-N-r?-hexanesulfgflyl min ~ehvl1Pyrrlidine-3crboYic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a tan solid. m.p. 67-68 0 OC. 1 H NMR (CD3OD, 300 MHz) 8 0.88 J=7Hz, 1.25-1.40 (mn, 6H), 1.73 (quintet, J=7Kz, 2K), 2.13-2.23 (in, 1K), .2.64-2.88 (in, 3H), 3.02 (sextet, J=8Hz, 2K), 3.44-3.53 (in, 2H), 3.58 J=9Hz, 1H), 3.56-3.75 (in, 1K), 3.78 3K), 3.88-3.98 (in, 1KH), 5.93 2H), 6.72 J=9Hz, 1 5.78- WO 99/06397 PCTIUS98/1 5479 I94 5.84 (in, 3H), 6.96 J=2Hz, 1 7.20 J=9HZ, 2H), 7.27-7.36 (in, 51-).

MS (DCIINH3) mWe 609 -tragns. trns-4-(l 3 eflzOdi~x~l-yl(mto-pey~1-2 D methyl-i *234tetrhdroginoin1yl ~ylabonlehfDroii aroxylic cd D Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 1.03 (in, 3H), 1.10-1.45 (in, 1H), 2.10-2.85 (in, 4H), 2.90-4.00 (in, 3.76 1.5H), 3.77 1.5H1, isomer), 5.90 (in, 2H), 6.70-7.40 (in, 1 I1H). MS (DCI) We 529 Analysis calcd for C31 H32N206 -0.3 H20: C, 69.73; H, 6.15; N, 5.25.

Found: C, 69.74; H, 6.10; 5.01.

386 tr.rans7S 4 3 Benzodioxol5vyl -2(methoxyp. enyIj-(-L buty-he t-2-en-lV yfrrolidineacarbox icacid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 0.86 J=7.0 Hz, 3H), 0.90 J=7.0 Hz, 3H), 1.20-1.41 (in, 8H), 1.95-2.06 (in, 4H), 3.24 J=11.0 Hz, 1H), 3.51-3.59 (in, 3.60-3.71 (in, 3.77-3.84 (in, 1H), 3.81 4.45 J=1 1.0 Hz, 1iH), 5.52 J=7.4 Hz, 1 5.93 2H), 6.77 J=8.1 Hz, 1H), 6.87 (dd, J=1.8, 8.1 Hz, 1H), 6.99 (mn, 3H), 7.46 (in, 2H).

MS (DCI) m/e 494 Anal calcd for C30H39N05: C, 72.99; H, 7.96; N, 2.84. Found: C, 72.73; H, 7.89; N, 2.64.

Examl 87 trans, trans2M-37FUoro4mpttoxy~henyI- 4 3-bnZodioxjI- 5 -yI.L: cabxlic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 63-65 11C. 1 H NMR (CDCI3, 300MHZ) 5 0.82 J=7Hz, 0.88 J=6Hz, 1.23-1.47 (in, 1 .44 (sextet, J=7Hz, 2H), 1.71 (quintet, J=6Hz, 2H), 2.24-2.34 (in, 1H), 2.70-2.93 (in, 2.96-3V2 (in, 2H), 3.15-3.35 (mn, 2H), 3.43 (dd, IrrlH 7. -1=9Hz. 1H1). 3.52-3.59 (in, 1H), 3.66 J=9H1z, 1H), 3.87 3H), WO 99/06397 PCT/US98/15479 -395- 5.95 2H), 6.74 J=8Hz, 1H), 6.82 J=8Hz, 1H), 6.42 J=BHz, 1H), 6.96 1H), 7.12 J=9Hz, 1H), 7.17 J=l2Hz, 1H). MS (DCI/NH3) mWe 593 Example 388 trans, trans-4-(l 3 -Benzodioxol-5.yfl.2-(4-methgxyphenvIl)1 pyridyflmethvfl12yrrolidifle3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 2.87 (in, 2H), 3.04 (dd, J=3.2, 0 9.7 Hz, 1H), 3.21 J=13.7 Hz, 1H), 3.51 (in, IH) ,3.76-3.85 (in, 2H), 3.79 3H), 5.90 (mn, 2H), 6.71 (in, I1H), 6.79 (dd, J=1.7 Hz, 7.BH), 6.94 (in, 3H), 7.36-7.45 (in, 3H), 7.81 (in, 1H), 8.39 (in, 1H), 8.46 (dd, J=1.4 Hz, 1H). Anal calcd for C25H24N205 -0.70 H20 -0.05 0H3C02C2H5:

C,

67.34; H, 5.79; N, 6.23. Found: C, 67.31; H, 5.63; N, 5.90.

Exampe 3 ,trans.trans-2-(fl-Hexyl 4 -(l.3belzodioxol-5yil1(N.N-di(nb utyflamino carbonl methyl-pyrrolidine3carb xlC_ aId Using the procedures describ ed in Example 1, the title compound was prepared. I H NMR (CDCI3, 300 MHz) 8 0.82-1.00 (in, 9H), 1.20-1.40 (in, 12H), 1.45-1.60 (in, 4H), 1.70-1.90 (br m, 2H), 3.10-3.46 (in, 6H), 3.65 J=10.8 Hz, 1H), 3.76 J=11.0 Hz, 1H), 3.92-4.06 (in, 2H), 4.14- 4.34 (in, 2H), 5.94 2H), 6.73 J=8.1 Hz, 1H), 6.79 (dd, J=8.1, 1.8 Hz, 1H), 6.87 J=1.8 Hz, IH). MS(DCI/NH3) m/e 489 Anal calcd for C28H44N205 -0.9 TFA: 0, 60.53; H, 7.65; N, 4.74. Found: C, 60.62; H, 7.69; N, 4.6 1.

Examale 39 trans. trans-4-(l Benzoioxol.5.yf-2(4-m ehoxYhenyl)l p2ent yl (4-f lu oro -3methylphenyIlaino)carbonyl)methyl Dyrrolidine3carboxylic -acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 0.92 (in, 3H), 0.97 J=7.1 Hz, 3H), -1.13-1.40 (in, 4H), 2.22 (in, 3H), 2.58-2.74 (mn, 1H), 2.78-2.87 (in, 1H), 3.09-3.25 (mn, 2H), 3.39-3.60 (mn, 2H), 3.70-3.90 (mn, 1H), 3.80 3H), 4.70 (mn, 1H), 5.93 (in, 2H), 6.70-6.76 (in, 1H), 6.75 (dd, J=1.49 WO 99/06397 PCT/US98/15479 -'396- 8.1 Hz, IH), 6.80-6.94 (in, 4H), 6.96-7.13 (in, 4H). MS (DCI.) mWe 577 Anal calcd for C 33 H37FN206 -0.25 H20: C, 68.20; H, 6.50; N, 4.82. Found: C, 68.21; H, 6.46; N, 4.74.

trns tan-4-(1 3 Ben -OO5Yl(4- noy~henl) 1 pidyflineth.flPr iltdne 3 caruox1lc aci Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 2.97 (dd, J=7.9, 9.7 Hz, 1 H), 3.04 J=9.6 Hz, IH), 3.18 (dd, J=4.4 Hz, 9.9H), 3.47 J=14.0 Hz, IH), 3.59 (in, 1H), 3.78 3H), 3.96 J=9-9 Hz, 1H), 3.97 J=13.6 Hz, 1H), 5.90 (in, 2H), 6.73 J=8.1 Hz, 1H), 6.83 (dd, J=1-7, 7.9 Hz, 1H), 6.92 (in, 2H), 6.96 J=1.8 Hz, 1H), 7.28 (in, 1H), 7.44 (in, 2H), 7.53 J=8.1 Hz, IH), 7.80 (dt, J=1.8, 7.7 Hz, 1H), 8.42 (mn, 1H). MS (DCI) mle 433 Anal calcd for C25H24N205 0.35 H20: C, 68.43; H, 5.67; N, 6.38.

Found: C, 68.44; H, 5.61; N, 6.24.

Example 392 trans, trans23 'helylpropyl- 4 (l.3ben di(n- utvI aminfoc r onvimeth I rrolidin 3 -croyl_ acid Using the procedures described inl Example 1, the title compound was prepared. IH NMR (CDC13, 300 MHz) 8 0.89-0.97 (in, 6H), 1.22-1.36 (mn, 4H), 1.41-1.55 (in, 4H), 1.63-1.95 (in, 4H), 2.62 (dt, J=7.2, 2.1 Hz, 2H), 3.05-3.44 (in, 7H), 3.53-3.60 (in, 2H), 3.65-3.76 (in, 1H), 3.82-3.90 (in, 1H), 3.96-4.10 (in, 1H), 5.92 2H), 6.71 J=8.1 Hz, 1H), 6.77 (dd, J=8.1, 1.5 Hz, 1H), 6.86(d, J=1.2 Hz, 1H), 7.10-7.28 (in, MS(DCI/NH3) Wne 523 Anal calcd for C31H42N205 -0.6 TFA:

C,

65.43; H, 7.26; N, 4.74. Found: C, 65.28; H, 7.29; N, 4.50.

Examnple-39 trans- trans- 2 4 -Methoxy- -lUg ~hn 1 7inthoxv-

'I-

benz~iXIS~ (N-di(n-butylam'inorarbonvlingjhylL pyrrolidine-a-QarboxYl'c_ acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 115-117 0 C. 1 H NMR (300 MHz, CDC13) 5 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.5 (in, WO W99/06397 PCT/US98/1 5479 -397 8H), 2.85 J=l3Hz, 1H), 2.90-3.17 (in, 5H), 3.20-3.35 (in, 1KH), 3.35- 3.50 (in, 3H), 3.55-3.65 (in, 1K), 3.84 J=lOHz, 1H), 3.87 3H), 3.92 3H), 5.94 (dd, J=4Hz, 2Hz, 2H), 6.62 1H), 6.70 1H), 6.90 (t, J=8Hz, 1H), 7.05-7.20 (in, 2H).

Examgle 394 Lrp ns-trafls-24(1,4 .Ben zod i xan-6l4(7inethoxY-1.3-benz~diOx~l- 5-yl)-l1-(N. N-di(n-butyl~aminocarbony iethyl)-pyrrolidine- 3 0 Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 107-110 OC. 1H NMR (300 MHz, CDC13) 8 0.82 J=7Hz, 3H). 0.88 J=7Hz, 3H), 1.05-1.50 (in, 8H), 2.75 J=l3Hz, 1K), 2.90-3.12 (in, 4H), 3.32-3.60 (in, 5H), 3.69 J= 8Hz, 1KH), 3.90 3H), 4.23 4H), 5.95 (dd, J=4Hz, 2Hz, 2H), 6.62 is I1H), 6.70 I1H), 6.78-6.93 (m ,3H).

Example 395 trans, trafls- 4 3 Benzodi oxol5l2(4methoxyphenyl)- 1 butyl-2.luor-het2en- vyloyrrolidine-3-carbo xylic acid Using the procedures described in Example 1, the title compound was prepared. IKH NMR (300 MHz, CD3OD) 5 0.84 J=7.0 Hz, 3H), 0.88 J=7.0 Hz, 3H), 1.16-1.37 (in, 8H), 1.83 J=8.5 Hz, 2H), 2.03-2.08 (in, 2H), 2.76-2.92 (in, 2H), 3.02 J=9.3 Hz, 1H), 3.32-3.42 (in, 2H), 3.50 (in, 1 3.71 J=9.2 Hz, 1 3.78 3H), 5.91 (in, 2H), 6.72 J=7.8 Hz, 1K), 6.83 (dd, J=1.7, 8.1 Hz, 1H), 6.90 (in, 2H), 7.02 J=1.7 Hz, 1H), 7.34 (in, 2H). MS (DCI) mle 512 Anal calcd for C 3 0H38FN05:

C,

70.43; H, 7.49;, N, 2.74. Found: C, 70.58; H, 7.54; N, 2.66.

Example 396 trans. trpls-2(3-Flugro-4ethoxyphenyl) 4 -(l.3-bnzodigxcl- 5-Yl N-12rgpyl-N-rfltpntnesulfnylpiino)ehylDyrrolidin 3 cargyI Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid.. m.p. 65-66 00. I H NMR (CDCI3, 300 MHz) 8 0.82 J=7Hz, 3K), 0.90 J=7Kz, 3H), 1.26-1.36 (mn, 4H1), 1.41-1.52 (in, 5H), 1.73 (quintet, J=7Hz, 2H), 2.23-2.33 (mn, 1K), WO 99106397 PCT/US98/15479 -398- 2.69-2.96 (in, 5H), 2.97-3.12 (in, 2H), 3.16-3.37 (in, 2H), 3.43 J=9Hz, IH), 3.52-3.59 (in, 1H), 3.66 J=9HZI 1H), 4.08 J=7Hz, 2H), 5.95 (s, D 2H), 6.74 J=BHz, 1H), 6.82 J=8Hz, 1H), 6.92 J=8Hz, 1H), 6.97 (s, 0 7.07 J=8Hz, 1H), 7.15 J=l2Hz, 1H). MS (DCI/NH3) m/e 593 D FExamnple397 tra s.trans2-(4-Methxy-afluorophenyl)-4-7-m th xl -13ben todioxol-5- I N-buty4-Nvropylamino~caronlmethyll yrrolidine- r x fir acid Using the procedures described inl Example 1, the title compound was prepared and isolated as a white solid. m.p. 118-120 O0. I H NMR (300 MHz, CDCI3) 8 0.70-0.90 (4 triplets, J=7Hz), 1.05-1.55 (in, 8H), 2.80-3.50 (in, 9H), 3.55-3.65 (in, 1H), 3.82 J= 10Hz, 1H), 3.85 3H), 3.92 3H), 5.96 2H), 6.62 1H), 6.70 1H), 6.90 J=BHz, 11H), 7.08-7.22 (in, 2H).

Examnple 98 tra n-4-1,-b zo io)15 nethoxV henYIl butyl.N-(4- hloro hen I~ aminocarboflnetvIPrrldi carboxylica~cid Using the procedures described in Example 1, the title compound was prepared. I1 NMR (300 MHz, CD300) 8 0.87 J=7 Hz, 1.20- 1.50 (in, 4H), 2.66-4.00 (in, 9H), 3.81 3H), 5.95 2H), 6.77 J=7 Hz, 1H), 6.85 J=8 Hz, 3H1), 7.05 (in, 5H), 7.33-7.42 (mn, 2H). MS (0.1, in/e 565 Analysis calcd for C 3 1H33N2O6CI 0.25 H3P04:

C,

63.16;, H, 5.77; N, 4.75. Found: C, 63.14; H, 5.59; N, 4.53.

taS. trn-4-( 1 3 Benzodiioxol-5il2(4inethoxyDnI llm ethyl-i1 .2.3.4tetrgh rOOinlinl Iylhcarb-fllineth -"-vrr li -n 3 carbgoxyiC acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 5 1.27 J=7 Hz, 1.5H), 1.28 (di, 7H1, 1.5-diastereoiner), 1.39-1.55 (in. 1H), 2.02-2.15 (in, 1H), 2.60- 3.25 (mn, 5H), 3.33-4.00 (in, 5H), 3.78 jks, 3Jri), D5.9. ku, J= ru., 2;1) 57 WO 99/06397 PCT/US98/15479 .399.

(dd, J=8 Hz, 1 6.75-6.90 (in, 3H), 6.91-7.35 (in, 7H). MS (DCI) m/e 529 Analysis calcd for C31H32N206.: C, 70.44; H, 6.10; N, 5.30.

Found: C, 70.16; H, 6.04; N, 5.04.

trans, tralns-2-(3.Fluoro-4-methoxvghenyl- 4 1 r2-(N-propl.N-(2-(pilpridin- 1 yflethanesulfolylaino~thyl1~Yrrolidine3carboxylic acid Using the procedures described-in Example 66, the title compound was prepared and isolated as a white solid. m.p. T5-96 11C. 1 HNMR (CDCI3, 300MHz) 8 0.82 J=7Hz, 3H), 1.43-1.55 (in, 4H), 1.63-1.72 (in, 4H), 2.29-2.38 (in, 1H), 2.64-2.78 (in, 5H), 2.87 J=8Hz, 1H), 2.95-3.04 (in, 5H), 3.20-3.30 (in, 1H), 3.32-3.43 (in, 4H), 3.54-3.63 (in, 1H), 3.78 J=8Hz, 1 3.87 3H), 5.92 2H), 6.72 J=8Hz, 1 6.78 (dd, is J=2Hz, J=8Hz, 1H), 6.88 J=8Hz, 1H), 6.94 J=2Hz, 1H), 7.08-7.20 (in, 2H). MS (DCI/NH3) m/e 620 Example 401 -trans. tran- 2 (r-Heptyl 4 .3-benzodioxol-5-Yfl-i -(N.N-di nbutyflasinocarbonYlinethylpyrrolidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (CDCI3,. 300 MHz) 8 0.83-0.98 9H), 1.18-1.40 (in, 14H), 1.44-1.60 (in, 4H), 1.72-1.96 (br in, 2H), 3.12-3.45 (in, 6H), 3.65 J 10.5 Hz, 1H), 3.76 J =11.2 1H), 3.90-4.06 (in, 2H), 4.13- 4.33 (mn, 2H), 5.93 2H), 6.73 J =7.8 Hz, 1 6.79 (dd, J 7.8, 1.7 Hz, 1H), 6.87 J 1.7 Hz, 1H). MS(DCI/NH3) m/e 503 Anal calcd for C29H46N205. 0.75 TEA: 0, 62.28; H, 8.01; N, 4.76. Found:

C,

62.20; H, 7.99; N, 4.50.

Example 42 trans.trans-4-(1l 3 Bn oi 1-[5Y1v) 2 -mth xyoeyll-3 methyl-i 1 3.4tetrahiydroquiflolin- 1 ylcrbn IiethyI~orrnidjne.

3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 5 0.99 1 1.03 J=6 Hz, 1.5H, second diastereoiner), 2.60-4.00mn 3.78 1.5H), 3.79 (s, WO 99/06397 PCTIUS98/1 5479 KI -400second diastereomer), 5.92 11H), 5.93 1H, diastereomer), 6.65-7.40 (in, 11 MS (DCI) mle 529 Analysis calcd for C311-H32N206 0.8 H20: C, 68.57; H, 6.24; N, 5.16. Found: C, 70.44;

H,

6.10; N, 5.30.

D~

trans. rans-- 3 Benzodioxgl5yIj-9(4- ethoxvphnI

I-N

butyl-N-( 4 -luorophgnyl)aminocarbonylmethylpyroine3 carboxylic acid Using the procedures described inl Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 6 0.87 J=7 Hz, 1.2-1.47 (in, 4H), 2.7 J=12 Hz, 2.80 J=9 Hz, 1H), 3.09 J=9 Hz, 1H-), 3.25 J=15 Hz, 3.40-3.47 (in, 3.49-3.65 (in, 3H), 3.75 (d, J=12 Hz, 1H), 3.80 3H), 5.94 6.72-6.86 (in, 4H), 7.00-7.15 (in, MIS (DCI) mle 549 Analysis calcd for C 3 1H33N206F 0.4 C, 66.99; H, 6.13; N, 5.04. Found: C, 66.99; H, 5.94; N, 4.99.

Exa a~le 404 trans. trans-1- N-hnIaioaboymty)- 4 -methoxy nyl4-(5-benzof urany'- rrolidi 3croyc acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300MHz, CDCI3) S 7.66 (1 H, bs), 7.60 (1 H, d, J=3Hz), 7.45 (2H, 7.15 (4H, in), 6.75 (5H, in), 3.96 (1 H, d, J=1lOHz), 3.78 3.74 (1 H, in), 3.59 (3H, in), 3.21 (1 H, t, J=9Hz), 3.19 (1 H, d, J=1l6Hz), 2.92 (1 H, t, J=9Hz), 2.70 (1 H, d, J=1l6Hz), 2.29 (3H, s), 1.41 (2H, mn), 1.24 (2H, mn), 0.85 (3H, t, J=7Hz). MS (DCI, NH3) mle 541 Anal. calcd for C 3 3H34N20 -1 H20: C, 71.21; H, 6.52; N 5.03.

Found: C, 71.31; H, 6.30; N, 4.98.

Example tn. trn-1 N-ItIN y) 4 -fluoro n 1 -4 nzofurainrrli-DvrrolinY gy~-acid Using the procedures described in Example 1, the title compound was prepared.

I

1 H NMR (300 MHz. CDC13) 5 7.67 (1H, bs), 7.60 (111, d, J=3Hz), 7.45 (2H, in), 7.18 (3H, in), 7.12 (1K, d, J=7Hz), 6.93 (2H, in), WO 99/06397 PTU9/57 -401in,3.29 (1 H, in), 3.19 (1H. in), 2.94 (1 H, mn), 2.71 (1 H, in), 2.30 (31-, 1.45 mn), 1.26 (2H, sexi, J=7Hz), 0.84 (3H, t, J=7Hz). MS (DCI, NH3) Wne 529 Anal. calcd for C33H34N205 0.2 HOAc:

C,

71.98; H, 6.30; N 5.18. Found C, 71.68; H, 5.89; N, 5.25.

E-gampip,406 trans-trpflS- 4 1.

3 BenodioxoI-5yf-2(4.inethoxyphenvIl 1 (d ty hnl mi )c Doy~ht groiig2croyr Using the procedures described in Example'l1,the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 5 2.27 6H), 2.81 (dd, J=8. 1, Hz, 1H), 2.98 J=15.3 Hz, 1H), 3.20 J=16.6 Hz, 111), 3.47-3.60 (in, 3H), 3.80 3H), 3.85 J=9.5 Hz, 1 5.91 2H), 6.73 J=7.8 Hz, 1H), 6.85 (in, 3H), 6.95 (in, 4H), 7.05 J=1.7 Hz, 1H), 7.06-7.24 (mn, is 6H). MS (DCI) Wne 579 Anal calcd for C35H34N206 -0.15 0.20 CH3C02C2H5: C, 71.79; H, 6.04; N, 4.68. Found: C, 71.81; H, 5.79; N, 4.5 1.

Exainle 407 trans, trafls- 4 2 Dihyd robelzof ur 1-5F)2(4-mhox henyIl)carboxylic -aci Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 7.73 (2H, in), 7.40-7.10 in), 6.92 (2H, mn),.6.72 d, 6.63 in), 5.40 (1 H, in), 4.55 (2H4, t, 4.30-4.10 (3H, in), 3.84 (3H, 3.82 (1 H, in), 3.65 (1 H, in), 3.39 (1 H, in), 3.21 (2H, t, 3.10-2.90 (2H, in), 2.26 (3H, 1.55 (2H, in), 1.45 (2H, in), 0.92 (3H. t, MS (DCI/NH3) mWe 543 Anal calcd for C33H38N205 0.65 H20: C, 71.50; H, 7.15; N, 5.05 Found:

C,

71.47; H, 6.96; N, 4.83.

WO 99/06397 WO 9906397PCTIUS98/1 5479 -402trans ran -2L"-FlUoro-4methoxyvrhenYtIA 4 (l 1 -j2-(NA2LrODYl1-N-r2-(NNdimeth I minO ethansufonmnlamh-i oe-hyl, rb xydt Using the procedures described inl Example 66, the title compound was prepared and isolated as a white solid. m.p. 81-82 00. 1 H NMR (CDCI3, 300 MHz) 8 0.80 J=7Hz, 3H), 1.43 (sextet, J=7H-z, 2H), 2.15- 2.24 (in, 1H), 2.36 2.66-2.76 111), 2.83-3.04 (in, 61-1), 3.18- 3.41 (mn, 5H), 3.55-3.63 (mn, 1H), 3.72 J=8Hz, 11-1), 3.85 3H), 5.90 J=6Hz, 2H), 6.67 J=8Hz, 1H), 6.78 (dd, J=21-z, J=BHz, 1H), 6.84 (t, J=BHz, 7.94 J=2Hz, 1H), 7.09 J=8Hz, 1H), 7.20 (dd, J=2Hz, J=l2Hz, MS (DCI/NH3) m/e 580 -trans. tran- (N-NDibutylminocrbonymethy)2(4fluro hn 4 -(5-benzoifurany I rr l in rboxyliQ acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) &87.88 (1 H, bs), 7.80 (2H, in), 7.61 (111, d, J=3Hz), 7.55 (1H, bd, J=BHz), 7.46 (1H, d, J=8H1z), 7.07 (2H, t, J=8Hz), 6.76 (1KH, d, J=3Hz), 5.53 (1 H, bd, J=i1 1Hz), 4.18 (21-1, in), 3.9 1 (3H, in), 3.55 (1K, d, J=l6Hz), 3.30 (3H, in), 3.12 (111, dd, J=10&9Hz), 2.95 (111, in), 1.51 in), 1.31 (4H, in), 1.12 (211, in), 0.92 (3H, in), 0.83 (3H1, t, J=7Hz). MS We (DCI, NH3) 595 Example 410 trans trans- 4 2 DihdrobeflZofuran5yl')2 4eth I henyl)-.LN b utyi- N -(3mty Dhn yI a mi no c a rbony h)methiyl) oyr ro lid in e-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.35 (211, in), 7.20-7.00 (7H, in). 6.70 (2H, d, 5.38 (1KH, in), 4.55 (2H, t, 4.05 (1KH, in), 3.64 (2H, mn), 3.45 (1KH, in), 3.21 (2H, t, 2.95 (1 H, in), 2.75 (1KH, in), 2.63 (211, q, 2.38 (2K, in), 2.27 (3H, 1.43 in), 1.30 (2H, in), 1.22 (3H, t, 0.89 (3H, t, MS (DCI/NH3) m/e 541 Anal WO 99106397 WO 9906397PCT/US98/I 5479 403calcd for C34H40N204 -1.6 AcOH: C, 70.17; H, 7.34; N, 4.40. Found: C, 70.11; H, 7.06; N, 4.80.

Eample Al1 trans, trans-4-(l .2-Dihydrobenzof uran-5-yfl-2-(4-f luo rophenyl)- 1 (N.N-di(n-butyl)aminocarbonylmethyl)-yrrolidie-3-cabox lic acid Using the procedures described in Example 1, the title compound I) was prepared. 1 H NMR (300 MHz, CDC13 8 7.40 (2H, in), 7.28 (1 H, bs), D 7.18 (1H1, dd, J=8, 7.00 (2H, t, 6.72 (1H, d, 4.53 (2H, t, 3.92 (1 H, mn), 3.65 (1 H, in), 3.42 (3H, in), 3.19 (2H, t, 3.15- 2.90 (6H, mn), 1.43 (3H, in), 1.25 (3H, in), 1.10 (2H, in), 0.90 (3H, t, J=8), 0.83 (3H, t, MIS (DCI/NH3) m/e 497 Anal calcd for C29H37FN204 0.25 H20: 0, 69.51; H, 7.54; N, 5.59. Found: C, 69.45; H, 7.60; N, 5.44.

Exam e 41 trans, trans-4-(1 .2-Dihydrobenzofuran-5-yl)-2-(4-fluorophenyI)-1 -but yl-N- -(3-methyl p2hen yl )amin o)carbon yl) m ethyl) 1Dy rro lid in e-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 6 7.28 (1 H, bs), 7.25-7.00 in), 6.91 (2H, in), 6.72 (3H, d, 4.54 (2H, t, 4.00 (1 H, in), 3.60 (3H, in), 3.45 (1 H, in), 3.19 (2H1, t, 3.11 (2H, mn), 2.84 in), 2.67 (1H, bd, J=18), 2.26 1.42 (2H, in), 1.25 (2H1, in), 0.88 (3H, t, J=8).

MIS (DCI/NH3) m/e 531 Anal calcd for C32H35FN204 0.25 0, 71.82; H, 6.69; N, 5.23. Found: C, 71.66; H, 6.55; N. 5.03.

Examp~le 413 trans. trans-4-(l ndan-5-yi-2-(4-methoxylhenyl- 1 N-di(nbutyflaininocarbonylmethyl)-yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 5 7.32 (3H, in), 7.18 (2H, mn), 6.85 (2H, d, 3.83 (IH, in), 3.79 (3H, 3.67 (1H, in), 3.50-3.20 (4H, in), 3.20-2'.92 (4H, in), 2.87 (5H1, in), 2.79 bd, J=15), 2.06 (2H, mn), 1.43 (2H, in), 1.27 (4H, in), 1.08 (2H, in), 0.88 (3H, t, 0.82 (3H, to WO 99/06397 WO 9906397PCTIUS98/I 5479 -404- MVS (DCI/NH3) We 507 Anal calcd for C31H42N204:

C,

73.49; H, 8.36; N, 5.53. Found: C, 73.18; H, 8.29; N, 5.17.

Examnle 14 trans. tr ns7_2(4-Metho .xylhefll4(3.4-dtfluorophenyl) 1 -t(N-butyl- I N-( 3 methylheyl~famiaO rron beh 9D-xtdeyiIr Using the procedures described in Example 1, the title compound was prepared. I H NMR (300MHz, CDCI3) 8 0.86 J=7Hz, 3H), 1.10-1.35 (in, 2H), 1.35-1.52 (in, 2H), 2.29 3H), 2.63 J=l3Hz, 1H), 2.76 (t, J=7Hz, 1H), 3.06-3.20 (in, 2H), 3.42-3.53 (in, 1H), 3.50-3.64 (in, 3H), 3.80 3H), 3.86,(d, J=9Hz, 1H), 6.66-6.82 (mn, 4H), 7.02-7.22 (in, 6H), 7.30-7.40 (in, 1H).

~Exampl 1 trans. tran-1- XN(-hlrnov),m-- 4 -fluoro~heyl4(5-benzofuranY1~Pyrr li in rkoIl aci Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, 00013) 8 7.64 (1 H, d, J=2Hz), 7.61 (1H, d, J=3Hz), 7.47 (1H, d, J=BHz), 7.41 dd, J=8&3Hz), 7.30 (iH, dt, J=8&2Hz), 7.21 (1H, d, J=8Hz), 7.19 (2H, in), 7.00 (1H, bs), 6.94 (2H, t, J=8Hz), 6.83 (1H, bd, J=8Hz), 6.74 (1H, dd, J=2&lHz), 3.96 d, J=lOHz), 3.75 (1H, ddd, 6, 5&3Hz), 3.59 (3H, in), 3.23 (1H, t, J=1OHz), 3.18 (1H, d, J=l6Hz), 2.92 (1H, dd, J=10&9Hz), 2.69 (iH, d, J=l6Hz), 1.41 (2H, in), 1.23 (2H, in), 0.87 (3H, t, J=7Hz). MS (DCl, NH3) 549, 551 Anal. calcd for C 3 1lH30CIFN20: C, 67.82; H, 5.51; N, 5A.10 Found: C, 67.43; H, 5.33; N, 4.78.

Example 416 trans, trans 4 (l 3 Bn jdiOOl5YVl% 2(4methOXYphpnyl)i-(((Ncabxylic acid *Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD013 8 (rotainer) 7.40-7.20 (5H, in), 7.13 (2H, in), 6.98 (2H, in), 6.93-6.60 (7H, in), 5.93 (1H, d, 5.88 (5.85) (1Hi, o, '.90 (45' i. 105).

WO 99/06397 WO 9906397PCTIUS98/1 5479 -405- 3.77 (3.73) (3H, 3.72 (1H, in), 3.60 (1K, in), 3.53-3.20 (3H1, in), 3.15- 2.75 (4H, in), 1.60-1.20 (2H, in), 0.83 (0.64) (3H, t, MS (DCI/NH3) m/e 623 Anal calcd for C 3 7H38N207 .0.25 H20: C, 70.85; H, 6.19; N, 4.4 7. Found: C, 70.68; H, 6.10; N, 4.42.

Exgle 4~17 trans. trans-4-(1 .2-Dihydrgbenzof ural-5yl -2-(4-ethyloheflyfl-l (2-pentyfl-N-(4-fluoro-3m ethyloh e nyl)aino) crbo nl) m ethvl)1Dyrrol d i ne3ca rb oxyag- acid Using the procedures described in Example l, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.30 (1 H, bs), 7.20-7.00 in), 6.87 (1KH, in), 6.73 (2H, d, 6.57 (1KH, in), 4.81 (1KH, mn), 4.55 (2H, t, 3.92 (1 H, bd, J=1 3.60 (1KH, in), 3.43 (1 H, mn), 3.18 (2H, t, J=9), 3.17 (1H, in), 3.06 (IH, dd, J=15, 2.88 (1H, dd, J=11, 2.61 (2H, q, 2.59 (1H, in), 2.18 (3H, mn), 1.40-1.10 (4H 1.22 (3H, t, J=9), 1.00-0.80 (6H, in). MVS (DCI/NH3) m/e 573 Anal calcd for C35H41FN204 .0.75 H20: C, 71.71; H, 7.31; N, 4.78. Found: C, 71.56;

H,

7.33; N, 4.56.

Example 418 trans. trans-2-(4-Methoxnhenfl)- 4 .3benzodioxol-5-YJLYU- 2-(Npropyl-N-r2yrimidinylamino)ethyIlpyrrolidine 3 carboxyli acid Ethyl 2-(4-methoxyphenYl)4(l,3-benzodioxol-5-yl)-l propylamino)propyllpyrrolidine-3-carboxylate, prepared by the procedures of Example 61B (300 mg), 138 mng of 2-broinopyrimnidine, and 150 mng of diisopropylethylainine were heated at 95 0 IC for 15 hours in 2 mL of acetonitrile. The resulting intermediate trans-trans ethyl ester was isolated by chromatography onl silica gel eluting with 5-10% ETOAc in CH2CI2 and hydrolyzed with NaOH in ethanol/water to give mng of the title compound. 1 H NMR (300 MHz, CDCI3) 8 0.82 J=7Hz, 3H), 1.50 (sextet, J=7Hz, 2H), 2.15-2.30 (mn, 1H), 2.75-2.97 (in, 3H), 3.40-3.55 (m 3.60-3.70 (in, 3H), 3.75 3H), 5.95 2K), 6.34 (t, J=4Hz, 1H), 6.65 J=8Hz, 1H), 6.75-6.82 (mn, 1H), 6.78 J=9Hz, 2H), 6.96 J=2Hz, 1H), 7.27 J=9Hz, 2H), 8.20 J=4Hz, 2H).

WO 99/06397 WO 9906397PCT/US98/I 5479 '4 -406- Example 412 trans, trans-4-(1 3Bnoixl5y)2-4mtoyhnl- butyl-2-chloro-helt-2-enfl-.yflyrrlidine-3-Carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD300) 8 0.84 J=6.8 Hz, 3H), 0.88 J=6.7 Hz, 3H), 1.19-1.39 (in, 8H), 2.05-2.09 (in, 2H), 2.17-2.23 (in, 2H), 2.78 (dd, J=6.6. 9.2 Hz, 1H), 2.95 J=9.2 Hz, 1H), 3.32-3.37 (in, 2H), 3.49 (in, 1H), 3.70 J=9.2 Hz, 3.77 3H), 5.91 (in, 2H), 6.72 J=8.1 Hz, 1H),,6.85 (dd, J=1.9. 8.1 Hz, 1H), 6.89 (in, 2H), 7.08 (d.

Hz, 1H), 7.36 (in, 2H). MS (DCI) Wne 528 Anal calcd for C30H38C1N05 -0.25 H20: C, 67.66; H, 7.29; N, 2.63. Found: C, 67.62; H, 7.18; N, 2.40.

Examnle 2Q trans. trans-4-(l.-iyrbno urn5y)2(-mtgyh~D (((N-(2-pentyI)-N-(4-fluoro 3 methyinheflyflpino~carbonllmethyI)Dyrrolidne3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 7.28 (1 H, bs), 7.15 (3H, in),- 6.90 (1 H, in), 6.77 (2H, dd, J=9, 6.71 (2H, d, 6.56 (1 H, in), 4.80 (I1H, in), 4.53 (2H, t, 3.92 (1 H, in), 3.79 (3H, 3.60 (1IH, in), 3.45 (1H, in), 3.19 t, 3.18 (1H, in), 3.03 dd, J=15, 2.85 (1H, in), 2.55 (1H, in), 2.18 (3H1, in), 1.40-1.05 (4H, in), 1.00-0.80 in). MS (DCl/NH3) rn/e 575 Anal catcd for C 34 H39FN205 0.35 H20: C, '70.29; H, 6.89; N, 4.82. Found: 0, 70.37; H, 6.92; N, 4.30.

ExmuiA 4 trans. rans-4 1.

2 D ihydroben zof ura-5yl-2 (4-methoxyphe nyl) -1 (0btlN0cl)ohnlaigcabnlmty~vrlAingcarboxyLic-acid- Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.29 (1 H, d, 7.25-7.05 in), 6.98 (1 H, bs), 6.80 (2H, in), 6.72 (2H, d, 4.53 (2H, t, J=9), 3.85 (1H, d, J=10), 3.79 (3H, 3.58 (3H, in), 3.42 (1H, dd, J=10, 3.18 (4H, in), 2.87 (1H, mn), 2.66 (1H, in), VAO (2H, mn), 1.25 (2H, in), 0.86 (3H, WO 99/06397 WO 9906397PCT/US98/I 5479 -407t, MS (DCI/NH3) mle 563 Anal calcd for C32H35CIN205 0.25 H20: C, 67.72; H, 6.30; N, 4.94. Found: C, 67.72; H, 6.21; N, 4.55.

Example 422 trans. trans-4-(1 .3-Benzodioxo1-5yl2(5ethylfuran-2-Yl)- di(n-butyflaminocarbonylmethyl)-12Yrrolidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDC13 8 7.77 (1H, bs), 7.11 (1H, d, 7.02 (1 H, dd, J=9, 6.82 (1 H, d, 6.52 H, d, 6.08 (1 H, 0 d, 5.98 (2H, 5.80 (1H, d, 4.70 (1H, bd, J=15), 4.37 (2H, in), 3.70 (2H, mn), 3.39 (2H, in), 3.20 (1 H, mn), 3.10-2.82 (2H, in), 2.76 (2H, q, 1.45 (2H, mn), 1.32 (3H, t, 1.30-1.10 (6H, in), 0.87 (3H, t, 0.85 (3H, t, MS (DCI/NH3) m/e 499 Anal calcd for 028H38N206 -1.75 HCI: C, 59.80; H, 7.12; N, 4.98. Found: C, 59.51; H, is 6.96; N, 4.88.

trans. trpns-4-(1 2hdoezfrn5y)2(-urpLryLinethylphenylaino)carbonyl~~mgthyl~pyrrolidine3-carboxylic ai Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CDC13 8 7.30-7.10.(4H, in), 6.92 (3H, in), 6.73 (2H, d, 6.59 (1H, in), 4.80 (1H, in), 4.53 (2H, t, 4.00 (1H, bd, J=10), 3.62 (1H, in), 3.45 (1H, in), 3.22 (1H, in), 3.21 (2H, t, 3.02. (1 H, dd, J=1 5, 3.85 (1 H, t, J=1 2.58 (1 H, bd, J=1 2.20 (3H, bs), 1.40-1.30 (3H, in), 1.15 (1H, in), 1.00-0.80 (6H, in). MS (DCI/NH3) Wne 563 Anal calcd for C 3 3 H36F2N204: C, 70.44; H, 6.45; N, 4.98. Found: C, 70.06; H, 6.47; N, 4.71.

Example 424 trans. trpns-4-(1 .2Dihydrobenzofuran-5-yl 2(4-fluoroph.enYl N(-ciorjhnl m ocroy)mty)1yrldie3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CDC13 8 7.30 (2H, in), 7.25-7.10 (4H, WO 99/06397 PTU9/57 -408in,6.95 (3H, in), 6.82 (1 H, bd, 6.73 (1KH, d, 4.55 (2H, t, J=9).

3.92 (1 H. bd, J=1 3.60 (3H, mn), 3.43 (1 H. dd, J=9, 3.21 (2H, t, J=9), 3.16 (2H, mn), 2.87 (1K, mn), 2.69 (1H, in), 1.42 (2H, in), 1.26 in), 0.87 (3H, t, MS (DCI/NH3) m/e 55-1 Anal calcd for C31 H32C1FN204 0.25 H20: C, 67.02; H, 5.90; N, 5.04. Found: C, 66.98; H, 5.71; N, 4.76.

irans. 3 butyl-N-( 3 -chlorophenyl)am n n~abnI)iethl)pyr U sing the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.30 (1 H, mn), 7.21 (1KH, d, 7.15 (2H, mn), 7.09 (4H, bs), 6.96 (1K, bs), 6.80 (1H, bd, 6.73 is(1 H, d, 4.54 (2K, t, 3.89 (1 H, bd, J=1 3.60 (3H, in), 3.43 (1KH, in), 3.22 (2H, t, 3.18 (2H, mn), 2.92 in), 2.72 (1KH, mn), 2.62 (2H, q, 1.41 (2H, in), 1.26 (2H, in), 1.23 (3H, t, 0.87 (3H, t, MIS (DCI/NH3) m/e 561 Anal calcd for C 33 H37CIN204 0.25 H20: C, 70.08; H, 6.68; N, 4.95. Found: C, 70.13; H, 6.59; N, 4.65.

Example 426i trans. trans -1 v~ab-nioelv--2-L mthoxy heYi)4(5be nnf irn -1 v yrr i i a royi-aid Using the procedures described in Example 1, the title compound was prepared. 'K NMR (300 MHz, CDCI3) 87.67 (1K,bs), 7.60 (1K,d, J=3Kz), 7.48 (1K, d,J=8Hz), 7.42 (1K,dd, J=8&3Kz), 7.29 (1K,dt, J=8&3Hz), 7.21 (1H, d, J=8Hz), 7.14 (2K, in), 6.99 (1K, bs), 6.76 (4H, in), 3.88 (1H, d, j=lO~z), 3.75 ddd, J=6, 5&3Kz), 3.59 (2K. in), 3.53 (1K, dd, J=10&3Kz), 3.22 (1K, t, J=9Hz), 3.19 (1K, mn), 2.96( 1H, in,2.70 (1K, d, J=l6Hz), 1.42 mn), 1.26 (2H, mn), 0.87 (3K, t, J=7Hz). MS (DCI, NH3) m/e 563, 561 Anal. calcd for

C

3 2H-33C1N205 0.5 H20: C. 67.42; K, 6.01; N, 4.91. Found: C, 67.45;

H,

5.82; N, 4.68.

WO 99/06397 pCT/US98/I 5479 -409- Example 427

-(N

transtaS( 3 BZdiXlY2(mtoyhnl cyciohexyl1Nutyl min ~arbgnylimethyl)yrrdn--aboK"- ICO 5 Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, 00013) (rotamer) 8 0.78 (0.86) 3H, ci J=7Hz), 0.90-1.90 (envelope, 14H), 2.69 (2.80) (,1,JlH) (envelope, IGH), 3.78 (3.80) 3H), 5.92 2H), 6.72 IH, J=9Hz) 0N 6.86 (in, 3H) 7.03 1H-, J=6Hz), 7.34 (mn, 2H). MS (DCI/NH3) in/e 537 0 Anal. calc'd for 0 31 H4-14206 1 H20: C, 67.13; H, 7.63; N, 5.05.

Found: C, 67.09; H, 7.34; N, 4.92.

trnstrn- 4 (i 3 Qpnzodlox 0-5yl2(4eQth fphenyl) meh hn -N-butl-ainncarbnl'ImetYI) acid Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, 00013) 8 0.86 3H, 3=7Hz), 1.22 (t, 3H, J=71-z), 1.25 (in, 2H), 1.43 (in, 2H), 2.26 3H), 2.6 2H, 3=7Hz), 2.68 1H, 3=12Hz), 2.86 1H, J=BHz), 3.19 2H, 3=7Hz), 3.44 (dd, 1H, J= 3Hz,1OHz), 3.59 (in, 3H), 3.94 1H, 9Hz), 5.92 2H), 6.75 (in, 3H), 6.86 (dd, 1H, J= 2Hz, 8Hz), 7.08 (in, 6H), 7.17 1H, J= 8Hz).

MS

(DCI/NH3) m/e 543 Anal. calc'd for C 33 H-38N205 0.60 H20:

C,

71.61;.H, 7.14; N, 5.06. Found: C, 71.57; H, 6.80; N, 4.87.

trans. trans- 4 -(Bef frp5l24 ehlhe 1( (N(3 inethyphefly)Nbut~amivo carnI Inth nvPrrnfidine3carbox l Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, 00013) 8 0.90 3H, 3=7Hz), 1.30 (t, 3H, J=7Hz), 1.31 (in, 2H), 1.43 (in, 2H), 2.27 3H), 2.73 2H, 3=7Hz), 3.15 2H, J=17Hz), 3.61 2H, J= 8Hz), 3.82 (mn, 2H), 4.00 1 H, 12Hz), 4.26 (in, 2H), 5.53 (br d, 1H), 6.54 (br s, 2H), 6.76 I1H, J= 2Hz), 7.14 (in, 3H), 7.28 1 7 .40 (in, 3H), 7.48 1 H, J= 8Hz), 7.63 I1H, WO 99/06397 WO 9906397PCT/US9815479 -4 J=2Hz), 7.73 1H1). HRMS. calc'd for 0 3 4H39N204 539.2910.

Found: 539.2891 trans. trans-!4-( 1.4Benzodioxaf6yvl2-(4-ethylohenYIl- methyl 1helyl I-N-butyl ami no) crbonyl)m ethyj) yrroli dine3-carboxy i c Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 0.87 3H, J=7Hz), 1.22 (t, 3H1, J=7Hz), 1.24 (in, 2H), 1.42 (in, 211), 2.30 3H1), 2.61 2H1, J=7H-z), 2.67 IH, J=l4Hz), 2.86 1H, J= 8Hz), 3.18 2H, J=7Hz), 3.41 (dd, 1 H, J=4,1OHz), 3.59 (mn, 3H1), 3.93 1H, J=lO1-z), 4.25 (mn, 411), 6.74 (br s, 2H1), 6.80 111, J=8Hz), 6.93 (dd, IIH, J=2Hz,8Hz), 6.99 1H, J=2Hz), 7.07 (in, 5H), 7.17 1H, J=8Hz). MS (DCI/NH3) W/e 557 Anal.

calc'd for C34H40N2O5~ 0.40 H20: C, 72.42; H, 7.29; N, 4.97. Found:

C,

72.49;, H, 7.16; N, 4.62.

Examnl~l 4 transa. rans-2-(3-Fluoro-4methoxYiphenyl- 4 -(l.3beflzgdioxgl-SYl)- Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. in.p. 80-82 0 C. I NMR (CDCI3, 300 MHz) 8 0.69 J=7Hz, 311), 1.37 (sextet, J=7Hz, 2H1), 2.09- 2.17 (mn, 1H1), 2.24 3H), 2.53 6H), 2.54-2.64 (in, 2.73-2.86 (mn, 2H), 3.02 (sextet, J=7Hz, 2H), 3.13-3.28 (in, 3.44-3.53 (in, 1H), 3.57 J=9Hz, 1H), 3.89 5.94 21-1), 6.74 J=BHz, 6.78 (dd, J=2Hz, J=8H-z, 1H1), 6.85 2H), 6.92 J=8Hz, 11H), 9.94 J=2Hz, 7.06 J=8Hz, 1H1), 7.13 (dd, J=2Hz, J=l2Hz, 1H). MS (DCI/NH3) We 627 Exampie 432 trans. trang-2 44.Met h0xylhe-nyl).4(3.4difluorophef 1~ u N-by[

N-(

3 -chlor e-fpiil~b nmthyl- yrrolide 3 ca acL- id Using the procedures described in Example 1, the title compound IKA .IO flQ M-4 C'lnl) 8 0.86 J=7Hz. 3H), 1.18-1.32 WO 99/06397 PCTIUS98/15479 1.35-1.48 (in, 2H), 2.64 J=13Hz, 1H), 2.71 J= 7Hz, 1H), 3.08-3.18 (in, 2H), 3.42-3.48 (in, 1 3.53-3.64 (in, 3H), 3.77 3H), 3.80 J=9Hz, 1H), 6.73-6.85 (in, 3H), 6.94 1H), 7.04-7.40 (in, 7H).

Examnpe 43 -trans, tr n~~3Fl r4-mathogynhanyh- 4 z(1x .beldI carboxylic acd ci Using the procedures described inl Example 1, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 0.80(t, 3H, 1.47 (bd hex, 2H, 2.15 (pen, 2H, J 2.32 (in, 1H), 2.7-3.2 (mn, 9H), 3.46 (dd, I1-H, J=4, 10), 3.57 (in, I1H), 3.64 2H, 3.67 I1-H, 3.86 3H), 5.92 6.74 11-H, 6.84 (dd, 1iH, J=2, 6.96 I1H, 7.06 iNH, 7.18 (in, 2H). MS (DCI/NH3) Wne 585

(M+H;

35CI)+; 587 3 7 Anal calcd for C 27

H

34 N20701FS: C, 55.43;

H,

5.86; N, 4.79. Found: C, 55.65; H, 5.81; N, 4.70.

Exampl 43 tras.tra .Q-(Fluorontoyhnl 4 l .3bfZd~o.~' 1-( 2 j Io -YN- 3h oron ron eY I i roii Using the procedures described in Example 66, the title compound was prepared. I H NMR (CD3OD, 300 MHz) 8 0.79 3H, 0.84 3H, J=7),1.68 (hept, 1H, 2.18 (pen, 2H, 2.8-3.4 (mn, ION), 3.'5-3.8 (in, 3H), 3.65 2H, 3.90 3H), 5.94 6.77 IH, J=8), 6.87 (dd, 1H, J=2, 6.99 1lH, 7.13 1H-, 7.27 (in, 2H).

MS (DCIINH3) mWe 599 Anal calcd for C 2 8

H

3 6N2O7C1FS 0.3 TFA: C, 54.24; H, 5.78; N, 4.42. Found: C, 54.19; H, 5.71; N, 4.01.

FExamnple 435 trans. trans vPOPXmeh I- 1.3benz Jiox inbutyflaiiO ronlm F1Prrolidin acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (CDCl3, 300 MHz) 8 0.87-0.98 (in, 9H), 1.21-1.39 (in, 1.43-1.57 (in, 4H), 1.58-1.70 (mn, 2H), 3.13-3.29 (in, 4H), 3.34- 3.43 3H), 3.45-3.55 (mn, 3H), 3.69 (dd, J 10.2, 4.5 Hz, 11-H), 3.80- WO 99/06397 PCTIUS9815479 -412- 4.20 (in, 4H), 5.93 2H), 6.73 J =7.8 Hz, 1 6.84 (dd, J 1.7 Hz, 1 6.93 J 1.7 Hz, 1 MS(DCI/NH3) W/e 477 Anal calcd f or C26H-40N2O6-0.5O TFA: C, 60.77; H, 7.65; N, 5.25. Found:

C,

60.73; H, 7.74; N, 5.22.

Eamnle 436 V)trans trn~~3Fluoro4methoxylhenvI) 4 L1 Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 65-67 0 G. 1 H NMR (CDCI3, 300MHz) 8 0.82'(t, J=7Hz, 3H), 0.88 J=5Hz, 6H), 1.46 (sextet, J=7Hz, 2H), 1.56-1.64 (mn, 3H), 2.24-2.33 (in, 111), 2.68-2.93 (in, 2.98-3.12 (in, 2H), 3.15-3.35 (in, 2H), 3.43 (dd, J=3Hz, J=9Hz, 11H), 3.52- 3.58 3.65 J=l2Hz, 1H), 3.87 3H), 5.95 2H), 6.73 (d, J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 J=BHz, 6.97 (d, J=2Hz, 1 7.10 J=9Hz, 1 Hz) 7.16 (dd, J=2Hz, J= 12Hz, I1H). MS (DCI/NH3) mWe 579 Examn~Le_43-7 frans~trans-2(4Mto y-3-luorop ienyl)-4- mthoxy 1.3benzodioxol- -yl)-l-r2- N-gropylN(? pentaineslfolfai io~ptiyl1pyrroiinecrbox lic acid Using the procedures described in Example 66, the title compound was prepared. I1 NMR (300MHz, CDC13) 0.81 J=7Hz, 3H), 0.90 (t, J=9Hz, 3H), 1.25-1.35 (in, 4H), 1.44 (sextet, J=7HZ, 2H), 1.67-1.78 (mn, 2H), 2.22-2.34 (mn, 1H), 2.30-2.95 (mn, 5H), 2.95.-3.10 (mn, 2H), 3.15-3.33 (in, 2H1), 3.45 (dd, J=3Hz, 9Hz, 1H1), 3.47-3.56 (mn, 1H), 3.65 J=9Hz, 11H), 3.88 3H), 3.94 3H), 5.95 211), 6.55 1 6.65 1 H), 6.92 J=7H, 1H), 7.11 J=9Hz,1H), 7.17 J=l2Hz, 11-1).

WO 99/06397 WO 9906397PCTIUS98/1 5479 -413- Examle 438 trans.trans-2-3-Fluoro-4-nth xyphenyl- 4 1 -r2-(N-2rolyl-N-(2.2,3.

3 3 1pntafluoroprgDoxyethanesulfonl)amiflo~ethyllP~yrrolidne- 3 7 carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 63-64 OC. 1 HNMR (CDCI3, 300MHz) 8 0.82 J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.24- 2.33 (in, 1H), 2.70-2.82 (in, 1H), 2.85-3.09 (mn, 5H), 3.14-3.28 (in, 4H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52-3.58 (in, 1H), 3.t5 J=9Hz, 3.87 3H), 3.92-3.98 (in, 3H), 5.94 2H), 6.74 J=8Hz, 1 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 J=8Hz, 1H), 6.97 J=2Hz, 1H), 7.10 (d, J=9Hz, 1H), 7.17 (dd, J=2Hz, J=l2Hz, 1H). MS (DCI/NH3) W/e 685 15Exampe439 trans.trans-2-( 1.4enzodioxafl-6-yl)-4-(7-mnethgxyl1 .3-bgnzodioxol- 1 -f-Npoy1N(,--naeufoy~mn~ty]2r~iiecarboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CDCI3) 8 0.81 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.23-1.36 (in, 4H), 1.45 (sextet, J=7Hz, 2H), 1.65-1.78 (in, 2K), 2.20- 2.30 (in, 1H), 2.30-2.95 (mn, 5H), 2.95-3.10 (in, 2H), 3.15-3.35 (in, 2H), 3.42 (dd, J=3Hz, 9Hz, 1H), 3.46-3.56 3.59 J=9Hz, 1H), 3.91 3H), 4.24 4H), 5.95 2H), 6.57 1KH), 6.68 1KH), 6.82 (d, J=8Hz, 1H), 6.88 (dd, J=2Hz, 8Hz, 1H), 6.95 J=2Hz, 1H).

Exmple 440 trans, trans-4-(1 .3 Ben zodi oxol-5-y1 )2(4-m ethoxyph en tl)- buy--4mtovgzlaiocroy~ehlproiiea cabxlcai Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 (rotainer) 7.32 (1H, d, 7.22 (1H, in), 7.10 (1H, d, 7.03 (6.98) (1H, d, 6.90-6.80 (4H, in), 6.79 (2H, d, 6.77 (1H, t, 5.8.5 (2H, 4.92 (4.10) (1H, d, J=15), 4.42 (4.22) (1H, d, J=15), 3.81 (1K, in), 3.79 (3.78) (3H, 3.76 (3H, 3.62 (1K in 3.43 (2H, in), 3.30-2.70 (5H, in), 1.42 (1KH, in), 1.23 WO 99/06397 WO 9906397PCT/US98/1 5479 -414- (2H1, in), 1.01 (1H, in), 0.83 (0.75) (3H1, f, MS (DCI/NH3) m/e -575 Anal calcd for C33H138N207 .0.5 H20: C, 67.91; H, 6.73; N, 4.80.

Found: C, 67.78; H. 6.44; N, 4.55.

Example 41 trans, trans-2-(3-Fluoro-4-methoxyghenyl)-4-(1 1 -(2-(N-isobutyl-N-(pentanesulfonylamingletyflpyrrofidine-3- Using the procedures described in Example 66, the title compound was prepared. 1H NMR (CD3OD, 300 MHz) 8 0.76 3H1, 0.84 3H, 0.92 3H1, 1.36 (in, 4H),1.70 (mn, 3H1), 2.90 (in, 2H1), 3.02 (mn, 2H), 3.1-3.8 (in, 7H1), 3.84 2H, 3.91 3H), 5.96 2H1), 6.80 (d, 11-H, 6.88 (dd, I1H, J=2, 7.00 1 H, 7.19 1 H. 7.35 (in, 2H). MS (DCIINH3) Wle 593 Anal calcd for C30H141 N207F 0.5 TFA: C, 57.31; H, 6.44; N, 4.31. Found: C, 57.08; H, 6.15; N, 3.95.

Example 442 trans. trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxyp-hefyl)-1 butyl-N-(3-f luo ro~h enil amino~ca rbonylm ethyfl) yrrolidi ne-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 6 0.87 J=7 Hz, 3H), 1.10- 1.30 (in, 4H), 2.70-2.90 (in, 2H1), 3.13 J=8 Hz, 11H), 3.40-3.90 (in, 6H-), 3.79 3H), 5.93 2H), 6.75 J=8 Hz, 1H), 6.80-7.20 (in, 911), 7.40 (in, 1 MS (DCI) Wne 549 Anal calcd for C 3 1 H33N206F 0.8 C, 66.13; H, 6.19; N, 4.98. Found: C, 66.21; H, 5.83; N, 4.84.

Example 443 trans. trans-4-( 1.3.Benzodioxol-5-yl)-2-(4-f luoropheflyl)-l utyl- N- (3-chlo roph enylaino) carbo nylm ethyfl) yrrol idi n e-3-ca rboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (in, 4H1), 2.65-2.85 (in, 3.05-3.85 (in, 7H1), 5.93 211), 6.75 (d, J=8 Hz, 1H), 6.85 (dd, J=8 Hz, 1H), 6.90-7.10 (in, 4H), 7.10-7.25 (in, 3H), 7.33-7.45 (in, 2H). MS (DCI) Wne 553 Anal calcd for WO 99/06397 WO 9906397PCT1US9811 5479 -415- C30H30N205FCl: C, 65.16; H, 5.47; N, 5.07. Found: C, 65.37; H, 5.41; N, 4.98.

Example44 s trans. trans-4-(1 Ben zodioxol-5-yl)-2-(4-m ethoxyphenyl)- 1 butyl-N-(3.4-dimethoxybenzylamino~carbonylmethyl)Dyrrolidine- 3 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 (rotamer) 7.33 (1 H, d, J=1 0), 7.23 (1H. in), 7.03 (6.97) (1 H, 6.90-6.60 (6H, in), 6.47 (1 H, in), 5.93 (2H, mn), 4.83 (4.09) (1K, d, J=15), 4.45 (4.22) (1K, d, J=15), 3.83 (3.86) (3H, 3.79 (1 H, mn), 3.77 (3.76) (3H, 3.75 (3.65) (3H, 3.60 (I1H, in), 3.43 (2H, in), 3.28 (1 H, in), 3.20-2.70 (4H, in), 1.43 H. 1.23 (2H, in), 1.02 in), 0.84 (0.77) (311, t, MVS (DCI/NH3) W/e 605 Anal calcd for C34H40N208: C, 67.53; H, 6.67; N, 4.63. Found: C, 67.28; H, 6.63; N, 4.38.

Example, 445 trans, trans-4-(1 .3-Benzodioxo l-5-yfl-2-(4-methoxyphenyl)-1 butyl -meth oxyb enzyD amnino) carbonl)m ethl)pyrrol id! ne--3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 (rotamer) 7.33 (1 H, d, 7.11 in), 7.03 (1 H, dd, J=8, 6.90-6.60 in), 5.93 in), 4.83 (4.15) (1H, d, J=15), 4.47 (4.30) (1H, d, J=15), 3.81 (1H, in), 3.78 (3.73) 3.72 3.59 (1KH, in), 3.43 in), 3.30 (1KH, in), 3.20-2.70 (4H, in), 1.42 (1H, in), 1.23 (2H, in), 1.01 (1H, in), 0.83 (0.77) (3H, t, J=8).

MVS (DCI/NH3) Wne 575 (M+H Anal calcd for C33H38N207: C, 68.97; H, 6.66; N, 4.87. Found: C. 68.70; H. 6.56; N, 4.61.

WO 99/06397 WO 9906397PCTIUS98/15479 -4 16- Example 446 trans. trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxypheniyl)-1 bUtyt-N-(3-methoxybenzyl)aminglcarbonyl)m-ethyflpyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR '(300 MHz, CDC13 8 (rotamer) 7.31 (1 H, d, J=1 0), 7.13 (1 H. d, 7.16 (1 H, dt, J=8, 7.03 (1 H, dd, J=1 0, 6.90-6.60.

(6H, in), 6.50 (1 H, in), 5.94 (2H, in), 4.82 (4.19) (1 H. d, J=1 4.50 (4.23) (111, d, J=15), 3.78 (3.76) 3.77 (1H, in), 3.75 (3.67) (311, 3.59 (11H, in), 3.57-3.35 (2H, mn), 3.25 (11H, in), 3.20-2.70 mn), 1.43 (1111 in), 1.23 (2H, mn), 1.02 (1H, mn), 0.84 (0.77) (3H, t, MS (DCI/NH3) Wne 575 Anal calcd for C33H38N207: 0, 68.97; 6.66; N, 4.87.

Found: C, 68.72; H, 6.55; N, 4.60.

Ex5mple447 trans. trans-2-(3-Fluoro-4-methoxypheoyl-4-(1 1 -(2-(N-(2-methoxyethyl)-N-(3chloropropanesufonyflamino~ethyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 2.15 (pen, 2H, 2.33 (mn, 1 2.81 (in, 2H); 2.93 1 H, 3.1-3.6 (in, I1OH), 3.24 3H); 3.65 2H, 3.70 1 H, 3.87 3H), 5.92 2H), 6.74 1 H.

6.84 (dd, 1H, J=2, 6.97 1H, 7.07 1H, 7.17 (in, 2H). MS (DCI/NH3) mWe 601 Anal calcd for C27H34N208CIFS: C, 53.95; H, 5.70; N, 4.66. Found: C, 53.65; H, 5.49; N, 4.26.

Example trans. trans-2 Flu gro-4-m eth oxyphenyl) (1 .3-ben zoi X 1 -(2-(N-(2-methoxyethyl)-N-(pentanesulfonyl)amino)ethyl)pyrrolidine= 3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 0.93 (in, 3H), 1.34 (mn, 4H), 1.69 2H), 2.33 (mn, 1H), 2.75-3.1 (mn, 7H), 3.23 3H), 3.3-3.6 (in, 6H), 3.70 1H, 3.86 3H), 5.92 2H), 6.74 1H, 6.84 (dd. 1 H, J=2, 6.97 I1H, 7.07 I1H, 7.18 (in, 2H). MS WO 99/06397 WO 9906397PCT/UJS98/I 5479 -4 17- (DCI/NH3) m/e 595 Anal calcd for C29H39N208FS: C, 58.57; H, 6.61; N, 4.71. Found: C, 58.21; H, 6.29; N, 4.29.

trans. trans-4-(1 Ben zodi oxo I-5-yfl)-2-(4 -metho xyph efyl) 1 he ptyl -N -(4-flu pro -3methylphetnylamino~carbonylmethyl)pyrrolidile-3-carboxylc acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.89 (in, 6H), 1.18-1.36 (mn, 8H), 2.15 (bs, 1.5 (CH3 rotamer)), 2.28 (bs, 1.5 (CH3 rotainer)), 2.64 (t, J=14.9 Hz, 1H), 2.82 (in, 1H), 3.07-3.29 (in, 2H), 3.32-3.41 (in, 1H).

3.53-3.60 (in, 1H), 3.70-3.79 (in, 1H), 3.79 3H), 4.68 (in, 1H), 5.92 (in, 2H), 6.69-6.90 (in, 6H), 6.93-7.07 (in, 4H). MS (DCI) Wne 605 Anal calcd for C35H41 FN206: C, 69.52; Hs 6.83; N, 4.63. Found: C, 1569.31; H, 6.78; N, 4.35.

Example 450 trcans.trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxyphelyfl)-I-(((N-(5nonyl)-N-(4-fluoro-amnethyl phenyl~a min o~carbonyfl) ethylpyrrolidine-3-ca rboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 6 0.81-0.90 (in, 6H), 1.30 (mn, 12H), 2.14 1.5 (CH3 rotamer)), 2.30 1.5 (CH3 rotainer)), 2.60 (t, J=14.8 Hz, 1H),-2.80 (in, 1H), 3.09-3.24 (in, 2H), 3.33-3.42 (in, 1H), 3.50-3.55 (in, 1H), 3.65-3.77 (in, 1H), 3.79 3H). 4.64 (mn, 1H), 5.93 (in, 2H), 6.70-6.84 (in, 5H), 6.91-7.13 (in, 5H). MS (DCI.) Wne 633 Anal calcd for C37H45FN206: C, 70.23; H, 7.17; N, 4.43. Found: C, 70.14; H, 7.13; N, 4.19.

Examole- 451 trans, trans-4-(1 .3-Benzodjioxol-5-yl)-2-(4-methoxypheflyl)- 1 nonylamino~carbonyflm nethyl) pyrrolidin e-3-ca rboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.80 J=7.0 Hz, 3H), 0.84 J=7.1 Hz, 3H), 1.15-1.55 (in, 12H), 2.88 J=15.9 Hz, 1H), 3.07 2H), 3.26 J=1 6.3 Hz, I 3.36 (dd, J=4.4, 9.8 Hz, I1H), 3.64 (mn, IH), WO 99/06397 WO 9906397PCT/US98/I 5479 -4 18- 3.76 (in, 1 3.79 3H), 3.98 J=9. '5 Hz, I1H), 5.93 (in, 2H), 6.77 (d, J=7.8 Hz, 1 6.85 (dd, J=1.7, 8.1 Hz, 1 6.93 (in, 2H), 6.99 J=1.7 Hz, 1H), 7.39 (in, 2H). MS (DCI) mWe 525 Anal calcd for C30H46N206 -0.35 H20: C, 67.86; H, 7.73; N, 5.28. Found: C, 67.87; H, 7.63; N, 5.11.

trans. trans-4-(l Ben zodi oxol-5-y)-2 1ehoxyph eyl) -I butyl-N-(2-fluorophenyl)aMino)carbonylmethylDyrrglidifle- 3 m Using the procedures described in Example 1, the title compound was prepared. IH NMR (300 MHz, CD3OD) 8-0.87 (dt, J=7 Hz, 3H), 1.15- 1.32 (in, 4H), 3.77 J=2 Hz, 3H), 2.65-5.92 (in, 9H), 5.93 J=4 Hz, 2H), 6.70-6.90 (mn, 4H), 7.00-7.45 (in, 7H). MS (DCI) W/e 549 is Anal calcd for C31H33N206 .0.4 H20: C, 66.99; H, 6.13; N, 5.04. Found: C, 67.01; H, 6.23; N, 4.68.

Example 453 trans, trans-2-(4-Methoxphenyl)-4-(1 .3-benzodioxol-5-yl)-I p ropyl-N-(2 -ben zothipzolyl) amin o~ethyllpyrrol idine-3-ca rboxylic acid The title compound was prepared by the method of Example 418, substituting 2-chlorobenzothiazole for 2-broinopyrimidine. 1H NMR (300 MHz, CDCI3) 8 0.88 J=7Hz, 3H), 1.59 (sextet, J=7Hz, 2H), 2.25- 2.37 (in, 1H), 2.85-2.97 (in, 3H), 3.28-3.36 (in, 2H), 3.50-3.58 (in, 3H), 3.60-3.65 (in, 1 3.67 J=9Hz, I1H),3.71 3H), 5.87 J=2Hz, 1 H), 5.91 J=2Hz, 1H), 6.57 J=8Hz, 1H), 6.73 (dd, J=2Hz, 9,Hz, IH), 6.76 J=8 Hz, 2H), 6.91 J=2Hz, 1H), 7.01 J=8Hz, 1H), 7.22 J=8Hz, 1H), 7.29 J=8Hz, 2H), 7.40 J=7Hz, 1H), 7.55 J=7Hz, 1H).

Example 454 trans. trans-2-(2- Et hoxyeth yl)-4 -(13 -bnz ix l-l-( butyl~aininocarbonylnethyl-yrrolidile-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (CDCI3, 300 MHz) 5 0.91 J 7.4 Hz, 3H), 0.94 J 7.4 Hz, 3H), 1.19 J -7.0 Hz, 3H), 1.24-1.38 (in, 5H), 1.46-1.60 (in, 4H), 2.03-2.12 (in, 2H), 3.07 J 8.0 Hz, 1H), 3.07-3.34 (mn, 6H),

I

WO 99/06397 WO 9906397PCTIUS98/15479 -419- 3.43-3.52 (in, 3H), 3.59-3.74 (in, 311), 3.80-4.01 (in, 2H), 5.93 2H), 6.72 J 8.1 Hz, 1 6.79 (dd, J 8.2 Hz, 1.7 Hz, I 6.87 J 1.7 Hz, I1H). MS(DCI/NH3) m/e 477 Anal calcd for 0 2 6H40N206 0.4 TFA: C, 61.64; H, 7.80; N, 5.36. Found: C, 61.63; H, 7.84; N, 5.29.

Example 455 trnstansI!2-(4-MethoxY-3fluoohnl 4 ylethyflsulfonylamin&)eh I Drrliine3-carl--ditc ci Ethyl 2 4 -methoxy3fluorphelyl)4(13benzodioxolS5yl)- Eth(-pyl-N[-iys~ nl mn)ehlproidncarboxylic acid, prepared. by the procedures of Example 125, was reacted with excess morpholine for 4 hours at room temperature.

Chromatography on silica gel eluting with EtOAc gave a 65% Yield of an intermediate ethyl ester which was hydrolyzed to the title compound with NaOH in ethanol/water. 1 NMR (300 MHz, CDCI3) 8 0.81 J=7Hz, 311), 1.46 (sextet, J=7Hz, 2H), 2.43-2.52 (in, 4H). 2.70-2.92 (in, 511), 2.97-3.33 (in, 6H), 3.60 (dd, J=3Hz, 9Hz, 111), 3.51-3.59 (in, 1H), 3.62- 3.70 (in, 511), 3.88 3H), 5.95 211), 6.72 J=8Hz, 1H), 6.70 (dd, J=2Hz, 8Hz, 1H), 6.90 J=9Hz, 1H), 6.96 J=2Hz, 1H), 7.10 J=8Hz, 1H), 7.18 (dd, J=2Hz, 12Hz, 1H).

Example 456 trns, tras 2-3Fur-- eh yen)- (.3-benzodi oxol-SYI)- 1 -l2-(Npropyl-N-((2.2.

2 trif lu orogth gxyeth ane*su f onyl) amnino) ethyll pyrrol idi n- carjboQxl Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. in.p. 95-96 00. 111 NMR (CD3OD, 300MHz) 8 0.80 J=7Hz, 3H), 1.35-1.48 (mi, 2H),3.07 (sextet, J=7Hz, 2H), 3.23-3.55 (in, 811), 3.80-3.87 (in, 211), 3.93 311), 3.94- 4.02 (in, 411), 4.66 J=l2Hz, 111), 5.96 2H), 6.83 J=8Hz, 1H), 6.94 J=8Hz, 1H),7.06 J=211z, 1H), 7.23 J=9Hz, 111), 7.43 J=9Hz, 1H1). 7.49 (dd, J=2Hz,J=l2Hz, 1H). MS (DCI/NH3) We 635 WO 99/06397 WO 9906397PCT/US98/15479 -420- Example 457 trans, trans--4-(1 .3-Benzodioxo1-5-y)-2-(4-f lugrophenl)ll -(N-butyl- N-(3-methylohbenyl)amilocarboflylnethyl)pyrrolidife 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (in, 4H1), 2.31 3H), 2.65-2.80 (in, 2H), 3.19 J=7 Hz, 1 3.25 J=10 Hz, 3.35-3.65 (in, 4H), 3.79 J=10 Hz, IH), 5.93 2H), 6.74 J=7 Hz, 1H), 6.80-6.90 (in, 3H), 6.91-7.09 (in, 3H), 7.10-7.35 (in, 4H1). MS (DCI) m/e 533 Anal calcd for C31 H33N205F: C, 69.91; H, 6.25; N, 5.26. Found: C, 69.56; H, 6.26; N, 5.23.

ExampJe--458 trans. trans--2 -(3-171u oro-4-m ethO2xyph enyl 4 (l 3-benzodi oxol -5 yfl 1 (-N(-ehxghl)N(uaeufnlmioehlproiie 3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1H NMR (CD3OD, 300 MHz) 8 0.94 (in, 3H), 1.23 (hex, 2H, 1.69 (in, 2H), 3.08 3.20 3.3-3.5 (in, 101-), 3.77 (in, 2H), 3.92 3H), 4.60 (in, I 5.96 6.81 1 H, 6.88 (dd, 11-, J=2, 6.99 1H, 7.22 1H, 7.38 (in, 2H1). MS (APCI) m/e 581 Anal calcd for C28H37N208FS -1.1 TFA: C, 51.37; H, 5.44; N, 3.97. Found: C, 51.27; H, 5.35; N, 4.11.

Exml trans. trans2(3-Fluoro-4-inethoxyphenyl)- 4 3-carboxylic aid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 77-78 0 C. IH* NMR (CDCI3, 300MHz) 8 0.83 J=7H1z, 3H),1.06 J=6Hz, 6H),1.45 J=7Hz.

2H), 2.20 (septet, J=6Hz, 2.26-2.36 (in, iH), 2.62-2.78 (in, 3H).

2.85-2.95 (in, 2.97-3.10 (in, 2H), 3.15-3.35 (mn, 3.43 (dd, J=3Hz, J=9Hz, iH), 3.53-3.62 (mn, 11H), 3.66 J=9Hz, 11H), 3.88 31-), 5.95 6.74 J=8Hz, 1H), 6.82 (dd. J=2Hz, J=8Hz, 1H), 6.92 (t.

J=8Hz, 1H), 6.97 J=2Hz, 1H), 7.12. J=9Hz, 1H), 7.18 (dd, J=2Hz, .l=12Hz. MS (DCI/NH3) m/~e 565 WO 99/06397 WO 9906397PCTIUS98/I 5479 -42 1- Examgle 460 trans, trans!4-(1 .3-Benzodioxol-5-yl)-2-(4-mehoxylhenyl)-1 b utyl it robenzyl) aming) ca rbonyl)methyl) pyrroli din e-3carboxylic acid Using the procedures described in Example 1, the title compound was prepar ed. I1 NMR (300 MHz, CDC13 8 (rotamer) 8.11 (2H, m),7.32 (3H, dd, J=9. 7.16 (7.07) (1H1, bd, J=10), 6.98 (6.94) (1H, d, 6.85 (2H, 6.83-6.70 (2H, in), 5.99 (5.97) (2H, d, 5.02 (4.18) (1H, d, J=15), 4.63 (4.38) (1H, d, J=15), 3.79 (3.77) (3K 3.72 (1H, d, 3.61 (1H, mn), 3.48 (1H, bd, J=15), 3.43-3.20 (2H, mn), 3.06 (2H, mn), 2.90 (iN, mn), 3.79 (1H, bd, J=14), 1.43 (1H, in), 1.23 (2H, in), 1.02 (1H, in), 0.84 (0.78) (3H, t, MS (DCI/NH3). Wne 590 Anal calcd for C32H35N308: C, 65.18; H, 5.98; N, 7.13. Found: C, 65.89; H, 5.85; N, 6.85.

Example 461 trans. trans-2-(4- Ethylp1h enyfl-4-(3 .4-dif Iuorop henyfl- 1 N-difn butyl) am inoca rbonyl methyl)-D2yrro lid! ne-3-ca rboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (CD300, 300 MHz) 6 0.78 3H, 0.87 3H, 1.02 (hex, 2H, 1.22 3H, 1.27 (in, 2H), 1.45 (in. 2H, 2.63 2H, 2.77 1H, J=14), 2.94 (dd, 1H, J=7, 3.05 (in, 3H), 3.3-3.5 m, 3H), 3.44 1H, J=14), 3.66 (in, 1H), 3.75 1H, 7.20 (td, 2H, 7.22 (in, 2H), 7.32 (td, 2H, 7.43 (ddd, 1IH, J=2.8,12). MS (DCIINH3) W/e 501 Anal calcd for C29H38N203F2 0.6 H20: C, 68.11; H, 7.73; N, 5.48. Found: C, 68.03; H, 7.53; N, 5.37.

Example 462 trans. trpns!4-(1 3-Bpnzodioxol-5-yl)-2-(4-methoxyphenyfl-1 but yl N- -(4-flIu pro ~-methylp D en yl amnino carbon yl met hyl ~p yr rolid i n e 3-carboxylic aicid.

Using the procedures described in Example 1, the title compound 3S was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (in, 4H), 2.21 J=2 Hz, 3H), 2.64 J=14 Hz, 1H), 2.75 (dd, WO 99/06397 WO 9906397PCT/US98/15479 -422- Hz, 1H), 3.05 J=7 Hz, 1H), 3.25 J=15 Hz, 1H), 3.35-3.70 (in, 3.77 3H), 5.92 2H), 6.70-6.92 (in, 6H), 6.96-7.10 (in, 4H). MS (DCI) mle 563 Anal calcd for C 32

H

3 5N206F -0.5 H20: 0, 67.24; H, 6.35; N, 4.90. Found: C, 67.16; H, 6.06; N, 4.81.

6 trans, trans-4-(1 .3-Benzodioxgl-5y)2-(4-methoxynhenYl)- butyl-N-((3-isop~ropyl)phenl)amiflo)carbonylmethyl-pyrrolidine 3

;I

Using the procedures described in Example'1, the title compound was prepared. I H NMR (300 MHz; CD3OD) 8 0.87 3H), 1.17 J=7 Hz, 6H), 1.20-1.50 (in, 4H), 2.63 J=15 Hz, 1H), 2.75 J=7 Hz, 1H), 2.85 (in, 1H), 3.00 J=7 Hz, 1H), 3.25 J=15 Hz, 1H), 3.40-3.70 (in, 5H1), 3.75 3H), 5.90 2H), 6.65-6.80 (in, 3H), 6.71 (dt, J=7 Hz, 3H), 7.07 (in, 3H), 7.20-7.35 (in, 2H). MS (DCI) mWe 573 Anal calcd for C34H40N206 -0.15 H3P04: C, 69.52; H, 6.94; N, 4.77. Found: C, 63.31; H, 6.72; N, 4.43.

Exampe 4_64 trans, trans-4-( 1.3-enzodioxol5y)2(4methoxyphenyIl)1 butyl-N-(3-ethylphenylainocarbonlmethy)pyrrolidife 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 (mn, J=7 Hz, 3H), 1.16 (t, J=7 Hz, 3H), 1.20-1.47 (in, 4H), 2.50 J=7 Hz, 2H), 2.70-2.85 (in, 2H), 3.13 J=7 Hz, IH), 3.20-4.5 (in, 6H), 3.78 3H), 3.83 J=8 Hz, 1H), 5.92 2H), 6.72 J=8 Hz, 1H), 6.80-6.90 (in, 5H), 7.02-7.13 (in, 3H), 7.15-7.25 (mn, 2H). MVS (DCI) m/e 559 Anal calcd for C33H38N206 0.3 H20: C, 70.27; H, 6.90; N, 4.97. Found: C, 70.31;, H, 6.63; N, 4.60.

WO 99/06397 WO 9906397PCTIUS98/15479 -423- Example 465 tran2. trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-ethylphenyl)- chl oroh enyfl-N-b utyl amino) carbonyl)m ethyflpyrrol idin e-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CDCI3) 8 0.87 311, J=7H1z), 1.23 (t, 3H1, J=7H1z), 1.28 (in, 2H1), 1.41 (in, 2H1), 2.63 2H1, J=7Hz), 2.67 (in, 1 H), 2.92 (in, 111), 3.20 (in, 2H1), 3.42 (in, 1 3.60 2H, J=7Hz), 3.93 (in, 1H), 5.92 2H), 6.75 1H, J=8H1z), 6.84 (in, 3H1), 6.95 (br s, 11H), 7.02 1H), 7.10 (br s, 3H1), 7.25 (in, 2H1). MS (APOI) ni~e 563 Anal.

calc'd for C32H-35N205C1.- 0.80 H3P04: C, 59.92; H, 5.88; N, .4.37.

Found: C, 59.90; H, 5.83; N, 4.07.

1s trans. trans-4-(l Ben zod io xan-6-y)- 2-(4 -ethyl 1h en yl)- 1 chlorophenyfl-N-butylamino'carbonylmethyl)D2yrrolidine-3-carboxylic Using the procedures described in Example 1, the title compound was prepared. I 1 H NMR (300 MHz, CDCI3) 8 0.86 3H1, J=7Hz), 1.23 (t, 3H, J=7H1z), 1.25 (in, 211), 1.40 (in, 2H), 2.64 2H, J=7H1z), 2.70 (in, 1 H), 2.95 (in, 1H), 3.20 (in, 2H), 3.40 (in, 1 3.57 (mn, 3H), 3.90 (in, 1H), 4.25 4H), 6.80 1H, J=8Hz), 6.95 1H, J=2Hz), 6.95 (mn, 2H), 7.07 (br 7.22 (in, 3H1). MS (APOI) mWe 577. Anal. calc'd for C33H37N205C1 0.85 H20: C, 66.90; H, 6.58; N, 4.73. Found: C, 66.92; H, 6.25; N, 4.36.

trans. trans-4-(Benzofuran-5-yl)-2-(4-ethylphenyfl)- rchl orgph nyl)-N-butyl amino) parbo nyl) methyl) py rrol idine-3-ca rbo xYli c Using the procedures described in Example 1, the title compound was prepared. I1 NMR (300 MHz, CDC13) 8 0.85 3H, J=7Hz), 1.26 (t, 3H1, J=7Hz), 1.30 (mn, 2H1), 1.40 (in, 2H), 2.60 2H, J=7Hz), 2.72 IIH), 2.93 (in, 1H), 3.22 (in, 2H), 3.50 (in, 1H), 3.55 (in, 2H1), 3.75 (nm, 1H1), 3.90 (br d, 111), 6.75 I1H, J=1 Hz), 6.80 (br d, 1 6.95 (br s, 1 7.08 (in, 41-1). 7.20 1H1, J=8H-z), 7.28 1H, J=8Hz), 7.42 (in, 2H), 7.58 I1H, WO 99/06397 WO 9906397PCT/US98/15479 -424- J=11Hz), 7.63 1H). MIS (APCI) mWe 559 Anal. calc'd for C33H35N204C1'- 0.45 H20: C, 69.88; H. 6.38; N, 4.94. Found: C. 69.83; H, 6.04; N, 4.87.

trans. trans--2-(4-Mthoxy3flugrphelyl)4(methoxy-1 -3- -uylNI nlmioehllvroiie3 Ethyl 2-(4-methoxy-3.fluorophenyl)-4-(7-methoxy-1,3benzodioxol-5-yl)-1 romoethyl]-pyrrolidine-3-carboxyl ate, prepared using the procedures of Example 61A (300 mg), was reacted with N-butyl aniline (190 mg) in 1 mL of dioxane containing 130 mg of diisopropylethylamine to give the ethyl ester. The ester was hydroyzed with sodium hydroxide to give 148 mg of the title compound as a white powder. 1 H NMR (300 MHz, CDCI3) 8 0.90 J=9Hz, 3H1), 1.28 (sextet, J=7Hz, 211), 1.46 (quintet, J=7Hz, 2H), 2.20-2.32 (in, 11H), 2.68-2.77 (mn, 1H1), 2.82-2.95 (in, 2H1), 3.12-3.22 (mn, 2H1), 3.30-3.44 (mn, 3H1), 3.45-3.55 (in, 111), 3.62 J=9Hz, 1H), 3.83 3H),.3.90 5.95 2H), 6.51 J=7H1z, 2H1), 6.55-6.62 2H), 6.69 J=2Hz, 6.84 J=8Hz, 1H), 7.02-7.15 (in, 3H1), 7.19 (dd, J=2H1z, 1211z, 1H1).

Example 469 trans. trans-4 .4.Be nzo di ox an-6-yi 24-ethyl phenyl)- 1 Ndi (n-butyflamin carbonyl m ethylp roldi carboxylc ai Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13) 8 0.78 3H, J=7HZ), 0.88 (t, 3H, J=7H-z), 1.05 2H, J=7Hz), 1.23 3H1, J=7H-z), 1.28 (in, 2H), 1.45 (in, 2H), 2.64 2H, J=7H1z), 2.78 (in, 1K), 2.9-3.2 (envelope, 3.30 (mn, 1 3.40 (in, 3H), 3.60 (in, I1H), 3.80 (mn, 1 4.25 4H), 6.80 (d, 1KH, J=8H-z), 6.90 (in, 1KI 6.98 1 H, J=2Hz), 7.17 211, J=8H-z), 7.30 (in, 2H). MS (APOI) m/e 523 (M+H) 4 Anal. calc'd for C31 H42N205 1 .1 HOAc: C, 67.73; H, 7.94;, N, 4.76. Found: C, 67.81; H, 7.55; 4.48..

WO 99/06397 WO 9906397PCT/US98/1 5479 -425- Example 470 trans, tra ns74-(1 Ben zodi oxan-6-yI) (4-methoxyg hen l)l buy--3mtypgyaiocroy~ehlpr~iie3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD300) 8 0.87 J=7.1 Hz, 3H), 1.30 (in, 2H), 1.44 (in, 2H), 2.30 3H), 2.80 J=15.2 Hz, 1H), 2.85 J=9.3 Hz, 3.19 J=9.3 Hz, 1H), 3.33 J=10.2 Hz, 1H), 3.42-3.61 (in, 3H), 3.79 3.91 J=9.8 Hz, 1H), 4.22 6.75-6.86 (in, 6H), 6.95 J=2.0 Hz, 1 7.09 J=8.8 Hz, 2H), 7.22 J=1 0.2 Hz, I1H), 7.26 J=7.6 Hz, I1H). MS (DCI1) mWe 559 Anal calcd for C33H38N206 0.4 CH3CO2C2H5: C, 69.97; 6.99; N, 4.72. Found: C, 0.06; H, 6.66; N, 4.48.

15Exml47 trans. trans.4-(1-4Bn.doa--l--4mtoy~ey) 1 buy--3clrpeyaiocrov~ghjproiie3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7.0 Hz, 1.25 (in, 2H), 1.40 (in, 2H), 2.78 J=14.6 Hz, 1H), 2 .86 J=9.0 Hz, 1 H), 3.16 J=9.5 Hz, I1H), 3.34-3.43 (mn, 3.48-3.62 (in, 3H), 3.79 (s, 3H), 3.85 J=9-5 Hz, 1 4.22 4H), 6.78 J=8.5 Hz, I1H), 6.81 6.86 (in, 3H), 6.93-7.09 (mn, 5H), 7.33-7.38 (in, 2H). MS (DCI) m/e 579 Anal calcd for C32H-35CIN206 1.1 CH 3 002C2H5 -0.15 H3P04: C, 63.30; H, 6.46; N, 4.06. Found: C, 63.54; H, 6.09; N, 3.98.

Example- 472 trans2.trans!4-(1,-ezdoo5-l2-4mthxpnv- 1 pyridylmethyl)pyrrolidine-3-carboxyli-c acid Using the procedures described in Example the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 5 2.84 J=9.6 Hz, 1H), 2.88 (dd, J=9.6, 7.3 Hz, 3.09 (dd, J=3.3. 9.6 Hz, 1H), 3.21 J=14.3 Hz, 1H), 3.53 (in, 1H), 3.78 3H), 3.81 (mn, 2H), 5.92 (in, 2H), 6.73 J=8.1 Hz, 1H), 6.82 (dd, J=1.8. 8.1 Hz, 1H), 6.93 (in, 2H), 6.95 J=1.5 Hz, 1H), 7.43 (in. 8.44 J=5.2 Hz, 2H). MS (DCI) Wne 433 Anal WO 99/06397 WO 9906397PCTIUJS98/1 5479 -426calcd for C25H24N205 0.3 CH3CO2C2H5: C, 68.57; H, 5.80; N, 6.10.

Found: C, 68.68; H, 5.60; N, 5.81.

Example 473 trans. trans-4-(l .3-Benzodioxol-5-yi)-2-(4-methoxyphenyl)-I butyl- 3-te rt-butylohenylamino~carbonyflmethyflp1yrrolidi ne-3- Scarboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.88 J=7.2 Hz, 3H), 1.23 9H), 1.26-1.45 (in, 4H), 2.74 (dd, J=15.1 Hz, 1H), 2.84 (in, 1H), 3.13 J=9.0 Hz, 1H), 3.29 J=15.1 Hz, 1H), 3.50-3.66 (in, 4H), 3.77 3H), 3.84 J=9.6 Hz, IH),.5.92 2H), 6.74 J=7.7 Hz, 1H), 6.79-6.85 (in, 4H), 6.86-6.90 (in, 1H), 6.99 J=1.8 Hz, 1H), 7.06 J=1.8 Hz, 1H), 7.13 (in, 2H), 7.33 J=7.7 Hz, 1H), 7.42 (in, 1H). MS (DCI) Wne 587 Anal calcd for C35H42N206: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.56; H, 7.33; N, 4.69.

Example 474 trans, trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxyphenyl)-I butyl-N-(3-n-butyl phenyl imi no)ca rbonyfl)methyfloyr-roli din e-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. IH NMR (300 MHz, CD3OD) 8 0.88 J=7.3 Hz, 3H), 0.92 J=7.3 Hz, 3H), 1.23-1.59 (in, 8H), 2.58 J=7.6 Hz, 2H), 2.75 (d, J=15.3 Hz, 1H), 2.80 (dd, J=8.5, 9.5 Hz, 1H), 3.12 J=9.3 Hz, 1H), 3.29 J=1.5.6 Hz, I1H), 3.46 (dd, J=4.9, 9.7 Hz, I1H), 3.52-3.64 (in, 3.78 3H), 3.83 J=9.8 Hz, 1H), 5.92 2H), 6.74 J=8-1 Hz, 1H), 6.79- 6.87 (in, 4H), 7.05 J="1.7 Hz, 1H), 7.10 J=8.8 Hz, 2H), 7.20 (d.

7.8H), 7.29 J=7.6 Hz, 1H). MS (DCI) in/e 587 Anal calcd for C35H42N206: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.33; H, 7.28; N.

4.74.

WO 99/06397 WO 9906397PCT/US98/15479 -427- Example 475-b t trans, trans:4-(3.4-Difluoroghenyl2(4-ethylphenyl)l -(N-(nbuy- N-(3-rmethylphenyflpmiflocarboflvlmethyl)pyrrolidine 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 11H NMR (CD3OD, 300 MHz) 8 0.87,(t, 3H. 1.19 3H, 1.28 (in, 2H), 1.43 (mn, 2H1), 2.28 3H), 2.60 2H, 2.66 (in, 2H), 3.06 (in, 1H), 3.21 IIH, J=15), 3.42 (dd, 11H, 3.58 (mn, 3H1), 3.71 1H, 6.80 2H), 7.06 4H), 7.18 (mn, 4H), 7.45 (in, 1H).

MS (APCI) Wne 535 Anal calcd for C32H36N203F2 -1.3 HOAc: C, 67.83; H, 6.78; N, 4.57. Found: C, 67.83; H, 6.46; N, 4.70.

Example-476 trnE.t s2( Ehlhny)4(.4dfurohn (N-(n-butyfl- N-(3-ghlorophenyflpaminocarbonlmlethyl)PYrrolidine 3 carboxylic -acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (CD3OD, 300 MHz) 8 0.82 3H. 1.16 3H, 1.23 (mn, 2H),"1.35 (in, 2H1), 2.55 2H1, 2.66 (in, 2H), 3.01 (t, 1H, 3.16 1H, J=15), 3.32 (dd, 1H, 3.56 (mn, 3H), 3.67 (d, 11-H, 6.94 1 H, 7.02 (in, 5H), 7.14 (in, 211), 7.32 (in, 3H). MS (APCI) m/e 555 Anal calcd for C 3 1 H33N203C1F2 -0.6 TEA: C, 61.88; H, 5.42; N, 4.48. Found: C, 61.9.0; H, 5.62; N, 3.98.

Example 47 trans, trans-4-(1.4Snoixn6y)2(- lu rohnl-(N-butyl- N-(3-chlorophenyl)aiinocarb~flylinethyl)pyrrolidine3carboxylic Acid Using the--procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3O1D) 8 0.87 J=7 Hz, 3H1), 1.10- 1.30 (in, 4H), 2.60-2.75 (in, 2H), 3.03 J=7 Hz, 1H), 3.15-3.75 (mn, 6H), 4.02 (in; 4H), 6.75 J=6 Hz, 1H1), 6.85 (dd, J=7 Hz, 1H), 6.90 (7.19, Jrn Hz, 6H), 7.32-7.43 (in, 3H). MS (DCI) m/e 567 Anal calcd for C31H32N2O5FCl 1.6 H20: C, 62.49; H, 5.95; N, 4.70. Found: C, 62.20; H, 5.54; N, 4.42.

WO 99/06397PCUS8I59 PCT/US98/15479 -428- Examlle 478 trans, trans-4-(Benzof uran-5-yl )-2-(4-ethyl Dhenyl)- I N-di (nbutyl~aminocarbonyl methyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 NMR (300 MHz, CDCI3) 8 0.78 3H, J=7Hz), 0.84 (t, 3H, J=7Hz), 1.05 2H, J=7Hz), 1.21 3H, J=7Hz), 1.25 (in, 2H), 1.45 (in, 2H), 2.62 2H, J=7Hz), 1 H, J=1l3Hz), 3.0 (in, 2H1), 3.15 (in, 2H), 3.35 (in, 1H), 3.43 (in, 2H1), 3.52 (in, 1H), 4.40 (mn, 2H), 6.73"(d, 1H.

J=lHz), 7.14 2H, J=8Hz), 7.26 1H), 7.31 2H1, J=8Hz), 7.44 (s.

2H), 7.60 I1H, J=I Hz), 7.65 1IH). MS (APCI) Mi/e 505 Anal.

calc'd for C31H40N204: C, 73.78; H, 7.99; N, 5.55. Found: C, 73.69; H, 7.97; N, 5.2 1.

Example 479 trans.trans-2-(4-Methoxy-3-fluorophenyl)-4-(7-nethoxy-1 .3benzodioxol-5-yfl-l1-f2-(N-proo~yl-N-(pyrrolidine- 1carbonylmethyl)amino)ethyllpyrrolidine-3-carboxylic acid Ethyl 2-(4-methoxy-3-fluorophenyl)-4-(7-inethoxy-1 ,3benzodioxol-5-yl)-1 -[2-(N-propyl-aminoethyl]-pyrrolidine-3carboxylate, prepared according to the procedures of Example 61 B (300 mg), N-broinoacetyl pyrrrolidine (132 mng) and dilsopropylethylamnine (154 mng) were heated for 1 hour at 50 OC in 1 mL of acetonitrile to give the intermediate ethyl ester. The ester was hydrolyzed to the title compound by the method of Example I D. 1 H NMR (300 MHz, CDC13) 8 0.88 J=7Hz, 3H), 1.30-1.45 (in, 2H), 1.75-1.92*(in, 4H1), 2.30-2.40 (mn, 1H), 2.47-2.58.(in, 2H), 2.70-3.00 (mn, 5H), 3.24-3.45 (in, 6H), 3.50-3.70 (in, 2H), 3.83 3H), 3.86 J=9Hz, 1 3.88 3H), 5.93 2H), 6.58 (d, J=2Hz, 1 6.70 J=2Hz, 1 6.87 J=8Hz, I1H), 7.10 J=9Hz, 1 H)! 7.21 (dd, J=2Hz, 12Hz, 1H1).

Examnlle 480 trans, trans-2-(4-Methoxyphenyfl-4-( 1.3-benzo-dioxol-5-yfl-1 N- (perhydroazepinylcarbo2nyl)-(D)-leucyl)aming)ethyl)oyrrolidine-3carboxylic acid

I

WO 99/06397 PCT/US98/15479 -429- Example 480A D-Leucine O-benzyl ester Tosylate salt To benzyl alcohol (8.2 g) dissolved in benzene (30 mL) was added D-leucine (5.0 g) and p-toluenesulfonic acid monohydrate (8.0 The reaction was warmed to reflux with removal of water overnight. Once TLC indicated consumption of starting material, the reaction was cooled, and the resulting solid was filtered and washed with EtOAc to give the title compound as a white powder (14.26 g, 99%).

Example 480B N-PerhydroazeDinylcarbonyl-D-Leucine O-Benzyl ester To the compound resulting from Example 480A (1.0 g) dissolved in chloroform (20 mL) was added triethylamine (0.4 mL). The solution was cooled to 0 and carbonyldiimidazole was added. After hours, TLC indicated complete consumption of starting material, so hexamethylene imine (0.327 mL) was added. After 1 hour, an additional amount of hexamethylene imine (0.330 mL) was added, and the reaction was stirred at ambient temperature overnight. The solution was washed with sodium bicarbonate (2 x 20 mL), 1 N H3P04 (2 x 20 mL), and brine (20 mL), dried over Na2SO4, decanted and evaporated. The residue was purified by flash chromatography on silica gel eluting with 50% EtOAc in hexanes to give the title compound as a crystalline solid (0.835 g, 89%).

Example 480C N-Perhydroazepinylcarbonyl-D-Leucine To the compound resulting from Example 480B (200 mg) dissolved in dry ethanol (1.0 mL) was added 10% palladium on carbon (10 mg).

After flushing the flask with nitrogen, the reaction was stirred vigorously under an atmosphere of hydrogen for 1 hour. The reaction was filtered through infusorial earth and evaporated to give the title compound (140 mg).

WO 99/06397 PCT/US98/15479 -430- Example 480D trans, trans-2-(4-MethoxvDhenyl-4-( 1.3-benzodioxol-5-yl- 1- (cyanomethyl)-Dvrrolidine-3-carboxvlic acid ethyl ester To the compound resulting from Example 1C (510 mg of a 50 wt.

solution in toluene) dissolved in acetonitrile (2.0 mL) was added diisopropylethylamine (0.24 mL), followed by bromoacetonitrile (0.072 mL). After 2 hours, TLC indicated complete comsumption of starting material. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel eluting with 20 40% EtOAc in hexanes to give the title compound as a colorless"oil (0.28 g, 99%).

Example 480E trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-1-(2aminoethyl)-pyrrolidine-3-carboxylic acid ethyl ester is To the compound resulting from Example 480D (275 mg) dissolved in 10 mL each of triethylamine and ethanol was added Raney nickel catalyst (0.2 and the reaction was placed under a hydrogen atmosphere (4 atmospheres) for 3 days. The reaction was filtered and evaporated. The residue was dissolved in methylene chloride (10 mL) and extracted with 1 M HCI (5 x 1 mL). The combined aqueous extracts were basified and then extracted with methylene chloride (5 x 2 mL).

The combined organic extracts were dried with MgSO4, filtered and evaporated to give the title compound as an unstable oil (0.14 g).

Example 480F trans, trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-y)-1 (perhydroazepinylcarbonyl)leucyl)amino)ethyl)-pyrrolidine-3carboxylic acid, ethyl ester The compound resulting from Example 480E (0.10 g) was dissolved in methylene chloride (3.0 mL), and the compound resulting from Example 480C (0.07 g) was added. The solution was cooled to 0 and EDCI (0.052 g) was added. After 4 hours, the reaction was evaporated and partitioned between water (1 mL), and EtOAc (10 mL).

The orgainc solution was washed with water (1 mL) and brine (1 mL), dried over MgS04, filtered and evaporated. The residue was purified by WO 99/06397 WO 9906397PCT/US98/I 5479 -431flash chromatography on silica gel eluting with 50 60% EtOAc in hexanes to give the title compound as a colorless oil (0.075 g, 48%).

Examole 480G trans~trans-2-(4-Methoxypheflyl)- 4 -(l.3-benzodioxgl-5-yl)-1 (D2erhyd ro azepi nyl ca rbo nyfl)le ucyl) aminlo)et hyl)PYrrolid ine3carboxyl ic Acid The compound resulting from Example 480F (0.75 g) was dissolved in ethanol (1.0 ml-) and 5 M NaOH (0.050 mL) was added. After 2 hours, additional 5 M NaOH (0.090 mL) was added. After an additional hours, the reaction was evaporated. The residue was dissolved in water (5 ml-) and washed with diethyl ether (2 x 2 mL). The aqueous solution was acidified with 1 N1 H3P04 to pH 3. The solid which precipitated dissolved when the mixture was extracted with chloroform (3 x 3 mL). The chloroform extracts were washed with brine (2 mL), dried with MgSO4, filtered and evaporated to give the title compound as a tan solid (0.053 Purification by HPLC (Vydac mCl8) eluting with a 10 70% gradient of CH3CN in 0.1%/TFA provided suitable material (0.049 g) after lyophilization of the desired 2o fractions. IH NMVR (CDCI3, 300 MHz) 8'0.82 (dd, 6.4, 4.4 Hz, 6H), 0.87 (dd, J 5.7, 5.7 Hz, 6H), 1.04-1.28 (in, 1.34-1.65 (in, 19H), 2.95 (br m. 3.15-3.40 (in, 14H). 3.40-3.55 (in. 4H), 3.58-3.68 (in, 3.70- 3.76 (br in, 3.80 3H1), 3.81 4.15 (br in, 2H), 5.10 (br in, 5.93 3H), 5.95 6.70-6.97 (in, 13H), 7.43-7.56 (br mn, 3H), 8.2 (br s, 8.5 (br s, 1 MS(DCI/NH3) in/e 623 Anal calcd for C34H46N407 2.00 TFA: C, 53.65; H, 5.69; N, 6.58. Found: C, 53.66; H, 5.66; N, 6.54.

Example 481 trans. trans-4-(1 3Bnoixl--l--4mthxpey. di (r-hexyl)aininocarbonylmiethyl)pyrrolidine-3-carboxylic -acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CID3O1D) 5 0.80-0.95 (in, 6H), 1.0 (in, 1.07 (1.55, J=in Hz, 14H), 2.70 J=13 Hz, 2.85-3.15 (in, 4H), 3.20-3.60 (in, 911), 3.64 J=1 0 Hz, 1 3.79 5.90 (in, 6.70 1, 6.80-6.93 (in, 3H1), 7.05 1H1). 7.35 J=10 Hz, 2H1). Anal WO 99/06397 WO 9906397PCT/U598/115479 -432calcd for C 3 3H46N206 -1.7 H20: C, 66.35; H, 8.34; N, 4.69. Found: C, 66.32; H, 8.04; N, 4.52.

E-amplAa48 -trans. trans-4-(1.4Bnoiga--i-2(-loo hnl--(N-butyl-

N-(

3 -methylph el) amilocarbonl lm ethyl) 12yrroidine3-carboxlic acidI Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD300) 6 0.87 J=7 Hz, 3H), 1.20- 1.35 (in, 2H), 1.35-1.40 (mn, 2H), 2.32 3H),'2.55-2.70 (in, 2H), 2.97 (t, J=7 Hz, IH), 3.22 J=14 Hz, 1H), 3.25-3.70 (in, 5H), 4.20 (mn, 4H), 6.97 J=2 Hz, 1 7.09 (in, 2H), 7.15-7.35 (in, 2H). MS (DCI) m/e 547 Anal calcd for C 3 2 H35N2O5F -1.2 H20: C, 67.64; H, 6.63; N, 4.93. Found: C, 67.73; H, 6.37; N, 4.70.

Examgle- 483 trans.trans-.4-(1.-ezdool y)2(-etoyhnl- carboxylic aid Using the procedures described in Example 1, the, title compound 2o was prepared. I H NMR (300 MHz, CDC13 8 (rotamer) 8.14 (2H, mn), 8.05 (7.83) (1H, in), 7.60-7.30 (3H, in), 7.13 in), 7.10-6.70 (5H, in), 5.94 (2H, in), 5.43 (5.33) (1H, d, J=12), 4.75 (1H, bd, J=15), 4.60-4.20 (2H, in), 4.10 (2H, mn), 3.80 (3.76) (3H, 3.75-3.40 (3H, in), 3.20-2.80 (2H, in), 1.50 (1H, mn), 1.30 (1H, in), 1.20-1.00 (2H, in), 0.91 (0.78) (3H, t, MS (DCI/NH3) m/e 590 Anal calcd for C32H35N308 -2.1 TEA: C, 52.44; H, 4.51; N, 5.07. Found: C, 52.25; H, 4.83; N, 5.71.

Example 484 trans, trans-4(1 .2 Di hydrobe nzof uran-5 .yl2 (4ethyl hen 1~ carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 (rotainer) 7.40 (2H, in), 7.30-7.10 (4H, in), 6.90-6.70 (311, in), 6.48 (1 H, in), 5.45 (1 H, in), 4.65 (1 H, d, J=15), 4.57 (2H, dt, J=9, 4.40-4.00 (5H, in), 3.87 (3.85) (3H1, 3.84 in), '3.03 (3.79) (3 3. 5 2 0 (2H. t. J =10) 2. 90 (I1H, WO 99/06397 WO 9906397PCTIUS98/1 5479 -433in), 2.64 (2H, q, 1.52 (1 H, mn), 1.31 (2H, in), 1.22 (3H, dt, J=9, 2), 1.07 (1H, in), 0.92 (0.78) (3H, t, MS (DCI/NH3) mWe 601 Anal calcd-for C36K44N206 -1.35 TFA: C, 61.59; H, 6.06; N, 3.71.

Found: C, 61.69; H, 6.04; N, 3.63.

trans. trans-4-(l .3.Benzodioxol-5-y)-2-(4-methoxylheflyl)-1 -(N butyl-N-(4-hegtyflamino)carbonylmethyl~yrrolidine-3-carboxylC Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.71-1.04 (in, 11H), 1.07- 1.35 (in, 6H), 1.73-1.53 (mn, 4H), 2.79-3.25 (in, 5H), 3.35-3.44 (in, 1 H), 3.51-3.68 (in, 3H), 3.78-3.89 (mn, 1K), 3.79 3H), 5.92 (in, 2H), 6.74 (dd, J=1.7, 8.1 Hz, 1 6.85 (td, J=1.7, 8.1 Hz, 1KH), 6.93 (in, 2H), 7.02 J=1.7, 9.5 Hz, 1KH), 7.36 (in, 2H). MS m/e 553 Anal calcd for C32K44N206:. C, 69.54; H, 8.02; N, 5.07. Found: C, 69.31; H, 7.89; N, 5.06.

Example 486 trans. trans-2-(4-Methylcyclohexyfl-4-(1 .3-benzodioxol-5-Vi)- 1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. IH NMR (CD%*CI'3, 300 MHz) 6 0.88 d, J 7Hz), 0.92 (3H, t, J 7Hz), 0.96 (3H, t, J 7Hz), 1.05 (1K, in), 1.22-1.40 (7K, mn), 1.45-1.65 (6K, in), 1.67-1.84 (4H, in), 3.17-3.45 (6H, in), 3.70 -(1KH, bin), 3.82 (1KH, dd, J 9Hz, 15Hz), 3.86 (1KH, d, J 15Hz), 5.93 (2K, 6.73 (1H, d, J 8Hz), 6.78 (1H, dd, J 2Hz, 8Hz), 6.88 (1H, d, J 2Hz). MS (DCI/NH3) We 501 Anal calcd for C29K44N205 0.25 CF3002K C, 66.96; K, 8.43;, N, 5.29. Found: C, 66.79; H, 8.60; N, 4.87.

WO 99/06397 WO 9906397PCT/US98/1 5479 -434- Examgle 487 trans, trans2-(2-ProDylgentyl)-4-( 1.3-benzgdioxol-5-yl)- 1 N-di (nb utyfl)ami n carbon yl methyl-Rrroi die-3-ca rbo xy ic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDC13, 300 MHz) 8 0.85 (6H, in), 0.92 (3H, t, J 7Hz), 0.97 (3H, t, J 7Hz), 1.12- 1.40 (13H, in), 1.42-1.68 (6H, in), 2.90 (1H, in), 3.14-3.30 (2H, mn), 3.33 (4H, in), 3.72 (1 H, brm), 3.90 (1 H, brm), 5.93 (2H, dd, J 2Hz, 4Hz), 6.73 01H, d, J 8Hz), 6.78 (1H, dd, J 2Hz, 8Hz), 6.88 (1 H, d, J 2Hz). MS (DCI/NH3) Wne 517 Anal calcd for C30H48N205 0 CF3002H: C, 66.24; H, 8.76; N, 5.03. Found: C, 66.26; H, 8.82; N, 4.98.

Example 488 trans, trans-4-(l .4-Benzodioxan-6-yfl-2-(4-f luorophenyfl)- N-di(nbutyflaininocarbonylmethyl)-pyrrolidine-3-carboxylic- acid Using the procedures described in Example 1, the title compound was'prepared. 1H NMR (300 MHz, CD3OD) 8 0.83 J=7 Hz, 3H), 0.89 (t, J=7 Hz, 3H), 0.90-1.17 (in, 4H), 1.20-1.65 (mn, 5H), 2.77d (13, 1H), 2.87 (dd, J=8, 2 Hz, 1H), 2.95-3.60 (mn, 7H), 3.71 J=9 Hz, 1H), 4.21 4H), 6.72 1 6.91 (dd, J=8 Hz. 1 6.97 J=2 Hz, 1 7.05 J=7 Hz, 2H), 7.40-7.50 (in, 2H). MIS (DCI) in/e 513 Anal calcd for C29H37N205F -1.2C F3COOH: C, 58.07; H, 5.93;, N, 4.31. Found: C, 57.94;. H, 5.81; N, 4.56.

trana. trans-2- (3-M ethyl pentyl)-4-(l-.3-benzodioxol-5-yl))1 -(N.N-di(nbutyl)amino2carbonylnethyl)-pyrrolidine-3-CarboxyliC -acild Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDC13, 300 MHz) 8 0.83 (3H, t, J 7Hz), 0.85 (3H, d, J= 7Hz), 0.91 (3H, t, J 7Hz), 0.97 (3H, t, J 7Hz), 1.05-1.22 (2H, in), 1.22-1.41 (7H, in), 1.43-1.68 mn), 1.89 (1 H, in), 2.94 (1 H, t, J 6Hz), 3.15-3.27 (3H, in), 3.29-3.60 in), 3.72 (1 H, brd, J 6Hz), 3.92 (1 H, brd, J 13.5Hz), 5.93 (2H, dd, J 2Hz, 4Hz), 6.73 (1H, d, J 8Hz), 6.78 (1 H, dd, J 2H1z, 8Hz), 6.88 (1 H, d, J 2Hz). MS (DCI/NH3) in/e 489 Anal calcd for C 2 8H44N205

I

WO 99/06397 WO 9906397PCT/IJS98/15479 -435- .0.30 CF3CO2H: C, 65.70; H, 8.54; N, 5.36. Found: C, 65.93; H, 8.81; N, 4.84.

trans. trans-2-(2-Ethylbutyfl-4-(1 .3-benzodioxol-5-yfl-1 N-di(nlbutyflaminocarbnylmethyl-pyrrolidie3-carboxyic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.85 (6H, in), 0.92 (3H, t, J 7Hz), 0.97 (3H1, t, J 7Hz), 1.13- 1.41 (13H, in), 1.43-1.72 in), 2.96 (1H, bin), 3.12-3.52 (6H, in), 3.55-3.70 (1H1, mn), 3.70-3.86 (21H, in), 3.99 (111, brm), 5.93 dd, J- 2Hz, 4Hz), 6.73 (1H, d, J 8Hz), 6.78 (1H1, dd, J 2Hz, 8Hz), 6.88 (1 H, d, J 2Hz). MS (DCI/NH3) Wne 489 Anal calcd for C28H44N205 0.45 CF3002H-: C, 64.28; H, 8.30; N, 5.19. Found: C, 64.16; H, 8.38; N, is 5.08.

Exainple 491 trans, trans-2-(3-Fluoro-4-methOXyphenyl) 4 1 -(2-(N-isobutyl-N-(butanesulf onylainn0Yethyl 1yrroldi ne- 3 carboxylic -acid Using the procedures described in Example 66, the title compound was prepared. I H NMR (CD3OD, 300 MHz) 8 0.74 3H, 0.83 3H, 0.94 311, 1.44 (hex, 211), 1.67 411), 2.91 2H, J=8).

3.04 (dd, 211, J=8,10), 3.1-3.6 (in, 5H), 3.78 (mn, 2H), 3.92 311), 4.60 (in, 111), 5.97 211), 6.82 111, 6.89 (dd, 111, J=2, 7.01 111, 7.22 1 H, 7.9(in, 211). MS (ESI) Wne 579 Example 492 trans, trans-2-(4-Methoxy-3-f luorophepnyl)- 4 1[2(-rp-Nr-typrmdn2yamnetylyo liie carboxylic -acid 1-Diinethylainino-1-pentene-3-one, prepared by the method described in Syn. Comm. 12 35 (1982), was converted to 2-amino- 4-ethylpyriinidine with guanidine by the method of Chem. Ber. 97, 3397 (1964). This material was converted to 2-b roino-4-ethyl-pyrihi dine with NaNO2 and HBr, using the method of HeIv. Chim. Acta 75, 1629 WO 99106397 WO 9906397PCT[US98/15479 -436- (1992). This bromopyrimidine was reacted with ethyl 2-(4methoxphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 -[2-(N-propylamino)propyl]pyrrolidine-3-carboxylate, prepared using the -procedures of Example 6113, using the procedure for Example 418, to give the title compound as a white powder. 1 HNM R (300 MHz, CDCI3) 8 0.83 J=7Hz, 3H), 1. 11 (t, J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H1), 2.18-2.27 (in, 1H), 2.45 J=7Hz, 2H), 2.80-2.97 (in, 3H), 3.40-3.75 (mn, 7H), 3.83 3K), 5.95 2H), 6.25 J=4Hz, 1H), 6.68 J=8Hz, IH), 6.79 (dd, J=2Hz, 8Hz, 1H1), 6.82 J=9Hz, 1K), 6.92 J=2Hz, 1K), 7.05 J=9Hz- IH), 7.15 (dd, J=2Hz, 12Hz, 1H), 8.10 J=4Hz, 1H).

Examlle 493 trans. trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-methoxyphenyl)-1 butyl- N-(3 .4-dim ethyl phenyfl)aminocarbonvi) m ethyl)P2yrro ldine- 3 carboxylic acid Using -the procedures described in Example 1, the title compound was prepared. I H NMVR (300 MHz, CD3OD) 8 0.87 J=7.3 Hz, 3H), 1.23- 1.36 (in, 2H), 1.38-1.43 (in, 2H), .2.22 3K), 2.29 3H), 2.79 (d, J=14.9 Hz, 1H), 2.84 (dd, J=8.6, 9.7 Hz, 1H), 3.16 J=9.5 Hz, 1H), 3.32 J=15.3 Hz, 1H), 3.43-3.61 (in, 4H), 3.79 3K), 3.88 J=9.8 Hz, 1H), 5.93 2H), 6.74 (in, 3H), 6.83 (in, 3H), 7.04 J=1.7 Hz, 1H), 7.11 (in, 3H). MS Wne 559(MH+). Anal calcd for C33H38N206-0.3H20:

C,

70.27; H, 6.90; N, 4.97. Found: C, 70.24; H, 6.62; N, 4.58.

Example- 494 trans. trans-2-(3-M ethyl pent-3-e n-l1 -yfl-4-(l A N-Nd i(n-b utyllaiinoca rbo nyl methyl)-pyrrolidin e-3-ca rbo xy i crid Using the procedure described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1 H NMR (C 0013, 300 MHz) 8 0.92 (3H, t, J 7H-z), 0.97 (3H, t, J 7H-z), 1.22-1.40 in), 1.44-1.61 (8H, in), 1.82 (11K, brm), 2.02 (211, in), 3.05-3.30 (4H, in), 3.3.8 (1K, in), 3.55 (1K, bin), 3.85 (2H. in), 4.12 (11H1 bind, J 15Hz), 5.11 (111, dd, J 6Hz, 12Hz), 5.93 6.73 (1KH, d, J 8Hz), 6.78 (1KH, dd, J= 2Hz, 8Hz), 6.88 (1H, d, J 2Hz). MS (DCI/NH3) Wne 487 Anal calcd for C 2 8H42N205 0.7 CF3002H 62.34; H, 7.60; N, 4.95.

Found: C. 62.49; H, 7.43; N, 4.1~3.

WO 99/06397 WO 9906397PCT/US98/15479 -437- Examlle 495 1-(N-PhenyIaminlOcarboflvmth l2(mehoY9enl)(l.3 benzodigoxl-5-yl)pyrr~lidifle'3-carboxyLp _aci-d Example 495A N-Phenylbromoacetamide To a stirred solution of aniline (7.40 mmol) in methylene chloride mL) at -50 OC was added successively N,N-diisopropylethylamifle (1.58 mL, 8.14 mmol, 1.1 eq) -and bromoacetyl bro'fide (0.72 mL, 7.40 mmol, 1 eq) such that the temperature did not exceed -40 00. On completion of. the addition, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether (70 niL) and poured into 1 N sodium bisulfate solution. The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2SO4) and the solvent evaporated to half volume, at which point the product crystallized. The crystals were removed by vacuum filtration to afford the title compound.

Example 495B transg. trans-i1 -(N-Ph enylamin ocarbonylm ethyfl)-2-( 4 -ml eth oxyphe nyfl- 1 .3-benzodioxgl-5-ylyrrolidie3-carboxylic-acid Using the procedures described in Example 1 and the compound resulting from Exampe 495A, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 8.8 (bs, 1H) 7.49 (2H, d, J=8Hz), 7.38 (4H, in), 7.11 (1H, tt, J=8&2Hz), 6.99 (1H, d, J=2Hz), 6.91 (2H1, d, J=8Hz), 6.86 (1H, d, J=2H1z), 6.81 (1H1, d, J=8Hz), 5.99 (1H, d, J=2Hz), 5.98 (1H1, d, J=2Hz), 3.94 (1H1, d, J=l'OHz), 3.78 (3H, 3.70 (1H, ddd, J=6, 5&3Hz),-3.42 (1H, dd, J=10&3Hz), 3.41 (1H1, d, J=l6Hz), .3.18 (1H, dd, J=11&9Hz), 3.01 (OH, t, J=lOHz), 2.93 (1H, d, J=l6Hz). MS (DCl, NH3) m/e 475 Anal. Caic for C27H26N206 -1 H20: C, 65.85, H, 5.73, N 5.69. Found: C. 65.95, H, 5.52, N, 5.38.

WO 99/06397 WO 9906397PCT1US98/15479 -438- Examlle 496 trans, trans-i .3-Dimethylphenyl) aminocarboflylmlethyl)-2-(4methoxyphenyl)-4-(1 .3-b-enzodioxol-5-yl~pyrrolidifle-3- carboxylic -acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CDC13) 8 8.68 (1 H, bs), 7.64 J=8Hz), 7.38, (2H, d, J=8Hz), 7.09 (1H, t, J=8Hz), 6.97, (1H, d, J=8Hz), 6.90 (1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, J=8&3Hz), 6.76 (1H, d.

J=8Hz), 5.97 (1H, d, J=2Hz), 5.96 (11H, d, J=2Hz), 3.95 (1H, d, J=lOHz), 3.80 (3H, 3.70 (1H, ddd, J=6, 5&3Hz), 3.48 (1H, dd, J=10&3Hz), 3.44 (1H, d, J=l6Hz), 3.18 (1H, dd,. J=11&9Hz), 3.06 (IH, t, J=lOHz), 2.96 (1H, d, J=l6Hz), 2.31 (3H, 2.16 (3H, MS (DCl, NH3) m/e 503 Anal. Caic for C29H30N206 0.5 H20: C, 68.09, H, 6.11, N, 5.48. Found: C, 68.13, H, 5.91, N, 5.29.

Example 497 trans. trans-i1 .4-Di methylph enyflam inoca rb onylm ethyfl)-2- (4methoxyphenyl)-4-(1 .3-benzodioxol5-yl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 8.60 (1H, bs), 7.78 (d, J=8Hz), 7.38, (2H, d, J=8Hz), 6.99 (1H, in), 6.95, (1H, d, J=8Hz), 6.94 (1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, J=8&3Hz), 6.77 (1H, d, J=8Hz), 5.97 (1 H, d, J=2Hz), 5.96 (1H, d, J=2Hz), 3.92 (1H, d, J=lOHz), 3.79 (3H, 3.68 (1H, ddd,.J=6, 5&3Hz), 3.43 (1H, dd, J=1 0&3Hz), 3.42 (1 H, d, J=l 6Hz), 3.18 (1 H, dd, J=1 1&9Hz). 3.04 (1 H, t, J=lOHz), 2.95 (1H, d, J=l6Hz), 2.29 (3H, 2.24 (3H, MS (DCI, NH3) mWe 503 Anal. Calc for .C2qH30N206 -0.75 H20: C, 67.50, H, 6.15, N 5.43. Found: C, 67.42; H, 5.95; N, 5.13.

Example 498 trans. transw1 -(N-(2.5-Dim ethyl phenyl)aminocarbgnyl thl- 4 methoxyphenyl)-4-( 1.3-benzodi xol-5-yflpyrroli dine -3-carbxylig, acId .Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 8.62 (1 H, bs), 7.79 (1 H, bs), 7.38, (2H,d, J=8Hz), 7.03 (1H, d, J=8Hz), 6.95, (11H, d, J=8Hz), 6.94 (1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, J=8&3Hz), 6.77 (1H, q) 1.92.fl.H. d. .1=10Hz), 3.78 (3H1, 3.70 (1H, WO 99/06397 WO 9906397PCT/L1S98/1 5479 -439ddd, J=6, 5&3Hz), 3.48 (1 H, dd, J=I01-13z), 3.42 (1 H, d, J=l 6Hz), 3.18- (1H, dd, J=11&9Hz), 3.04 (1H, t, J=lO1-z), 2.95 (1H. d, J=l6Hz), 2.29 (3H, 2.24 MS (DCI, NH3) mWe 503 Anal. Caic for C29H30N206 0.5 H20: C, 68.09; H, 6.11; N, 5.48. Found: C, 67.72; H, 5.89; N, 5.25.

Eample 49 tranis. trans- I (3 .4Di methylh enyl) amino carb ofyl met yl)- 2 4 methoxyo~henyfl)--( 1.3-be~nzodioxol-5-yl~yrroliinle-3-carboxyliC acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 8.73 (1H, bs), 7.38 (2H, bd, J=8Hz). 7.30, (1H, d, J=3Hz), 7.20 (1 H, bs), 7.08, (1 H, d, J=8Hz), 7.01 (1H, bs), 6.90 (2H, d, J=8Hz), 6.85 (1 H, bs), 6.80 (1IH, d, J=8Hz). 5.99 (1H, d, J=3Hz), 5.98 (1H, d, J=3Hz), 3.92 (1H, d, J=lOHz), 3.78 (3H, s), 3.70 (I1H, ddd, 5&3Hz), 3.48 (1 H. dd, J=1 0&3Hz), 3.42 (1 H, d, J=l6Hz), 3.18. (1H, dd, J=11&9Hz), 3.04 (1H, t. J=lOHz), 2.95 (1H, d, J=1l6Hz), 2.25 (3H, 2.21 (3H, MS (DCI, NH3) mWe 503 Anal. Calc for C29H30N206 0.75 H20: C, 67.50: H, 6.15; N 5.43. Found: C, 67.24; H, 5.94; N, 5.20.

Example 500 trans. trans- .5-Dimethylphenyflaminocarbonylmethyl) 2 4 methoxyphenyl)-4-( 1.3bn ix]S-l1yrldne3croy acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3)868.75 (1H, bs), 7.35, (2H, d, J=8Hz), 7.10 (2H, 7.02 (1K, d, J=3Hz), 6.90 (2H, d, J=8Hz), 6.84 (1 H.

d, J=2Hz), 6.80, (1H, d, J=BHz), 6.76 (1H, bs), 5.99 (1H, d, J=3Hz), 5.98 OIH, d, J=3Hz), 3.92 (1H, d, J=lOHz), 3.79 (3H, 3.68 (1H, ddd, J=6, 5&3Hz), 3.40 (2H, in), 3.18 (1H, dd, J=11&9Hz), 2.98 (1H, t, J=lOHz), 2.88 (1H, d, J=l6Hz), 2.3 (6H, MS (DCl, NH3) mWe 503 Anal.

Calc for C29H30N206 0.5 H20: C, 68.09; H, 6.11; N 5.48. Found: C, 67.93; H. 6.01: N, 5.19.

WO 99/06397 PCT/US98/15479 -440- Example 501 Alternate Preparation of (+)-trans. trans-1 -(N.N-Di(n-butyl)aminocarbonvlmethvl)-2-(4methoxyphenyl)-4-(1 3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acid Hydrochloride Salt Example 501A N. N-Dibutyl bromoacetamide To a solution of bromoacetyl bromide (72.3 mL, 830 mmol) in toluene (500 mL) cooled to 0 °C was added a soTution of dibutylamine (280.0 mL, 1.66 mol) in toluene (220 mL) via an addition funnel maintaining the reaction temperature below 10 Upon completion of the addition, the reaction mixture was stirred at 0 °C for 15 minutes.

A solution of 2.5% aqueous H3P04 (500 mL) was slowly introduced, and the reaction mixture was allowed to warm to room temperature with vigorous stirring. The solution is 2.5% phosphoric acid by weight. The layers were separated and the organic phase washed with water (500 mL) and concentrated to provide the bromoacetamide as a solution in toluene.

Example 501B 5-(2-Nitrovinyl)-1.3-benzodioxole To piperonal (15.55 kg, 103.5 mol) under mechanical stirring and under nitrogen was added ammonium acetate (13.4 kg, 173.8 mol), acetic acid (45.2 kg), and nitromethane (18.4 kg, 301.4 mol) sequentially. The mixture was warmed to 70 OC. After about minutes, the yellow product began to crystallize. The reaction temperature was raised to 80 °C and stirred for about 10 hours until minimal piperonal remains. The somewhat thick reaction mixture was cooled to 10 °C and filtered. The precipitate was washed with acetic acid (2 x 8 kg) and then water (2 x 90 kg). The product was dried under a nitrogen purge and then in a vacuum oven at 50 OC for 2 days to afford 15.94 kg of the title compound as a bright yellow solid.

WO 99/06397 PCT/US98/15479 -441- Example 501C 4-Methoxybenzoyl acetate To potassium t-amylate (25 wt 50.8 kg, 99.26 mol) in toluene (15.2 kg) cooled to 5 °C under mechanical stirring and under nitrogen was added a mixture of 4-methoxyacetophenone (6.755 kg, 44.98 mol) and diethyl carbonate (6.40 kg, 54.18 mol) in toluene over 1 hour maintaining the temperature below 10 The reaction mixture was heated to 60 °C for 8 hours until no 4-methoxyacetophenone was detected by HPLC. The mixture was cooled to 20 °C and quenched by adding to a mixture of acetic acid (8 kg) and water (90 kg) over minutes while maintaining the temperature at <20 The layers were separated, and the organic layer was washed with 5% sodium bicarbonate solution (41 kg) and concentrated to 14.65 kg. The temperature is maintained below 50 °C during the distillation. The yellow product concentrate was assayed by HPLC against an external standard and the yield was found to be 9.40 kg Example 501D Ethyl 2-(4-methoxybenzoyl)-4-nitromethvl-3-.3-benzodioxol-5-yl) butyrate To the compound resulting from Example 501B (7.5 kg, 37.9 mol) suspended in THF (56 kg) with mechanical stirring under nitrogen was added the compound resulting from Example C (8.4 kg, 37.9 mol). The mixture was cooled to 17 sodium ethoxide (6.4 g, 0.095 mol) was added, and the reaction was stirred for 30 minutes. After about minutes, the nitrostyrene was completely dissolved. Sodium ethoxide (6.4 g, 0.095 mol) was added, and the mixture was stirred at 25 °C until HPLC shows less than 1 area ketoester remaining. The reaction was concentrated to 32.2 kg which was determined by HPLC assay to be -14.9 kg Example 501E Ethyl cis, cis-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl) pyrrolidine-3-carboxylate Raney nickel (20.0 from which the water had been decanted, was charged to a stirred hydrogenator equipped with a thermocouple.

WO 99/06397 PCT/US98/15479 -442- THF (20 mL), the crude compound resulting from Example 501D (40.82 g, S 0.0482 mol), and acetic acid (2.75 mL, 0.0482 mol) were added sequentially. The mixture was put under a hydrogen atmosphere at S psi until the hydrogen uptake slowed dramatically. TFA was added, and the mixture was hydrogenated at 200 psi until HPLC shows no residual imine and <2 area nitrone. The catalyst was filtered away and washed with 100 mL of methanol. The filtrate was assayed by HPLC and found to contain 13.3 g (75% yield) of the cis, cis-pyrrolidine C compound. The filtrate was concentrated and chased with additional THF (200 mL) to give a final volume of 100 mL. The mixture was neutralized with 2 N NaOH solution (50 mL), diluted with water (200 mL), and extracted with ethyl acetate (2 x 100 mL). The combined nearly colorless ethyl acetate layers were assayed against an external standard by HPLC to be13.0 g of the title compound.

Example 501 F Ethyl trans, trans-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl) pyrrolidine-3-carboxylate The solution of the compound resulting from Example 501E (38.1 g, 0.103 mol) was chased with ethanol (200 mL) to a final volume of 100 mL and sodium ethoxide (3.40 g, 0.050 mol) was added. The mixture was heated to 75 When HPLC shows of the cis,cis isomer remaining, the mixture was cooled to room temperature. The product was assayed by HPLC against an external standard and found to contain 34.4 g (90% yield) of the title compound. The crude compound solution was concentrated and the residue taken up in isopropyl acetate (400 mL). The organic layer was washed with water (2 x 150 mL) and then extracted with 0.25 M phosphoric acid solution (2 x 400 mL). The combined phosphate layers were stirred with ethyl acetate (200 mL) and neutralized to pH 7 with solid sodium bicarbonate (21 The organic layer was separated and found to contain 32.9 g of the title compound.

I

WO 99/06397 PCT/US98/15479 -443- Example 501G Ethyl (2R.3R. 4S)-(+)-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl) pyrrolidine-3-carboxylate. mandelate salt SThe solution resulting from Example 501F was chased with s acetonitrile (100 mL) to give a final volume of 50 mL. (S)-(+)-Mandelic acid (2.06 g, 0.0136 mmol) was added and allowed to dissolve. The mixture was seeded with the product and allowed to stir at room temperature for 16 hours. The reaction mixture was cooled to 0 °C and stirred for 5 hours. The product was filtered and dried in a vacuum o oven with a nitrogen purge for 1 day at 50 °C to give 5.65 g of the title compound. The purity of the product can be determined by chiral HPLC using Chiralpak AS, isocratic elution with 95:5:0.05 hexaneethanol-diethylamine; flow 1 mL/min.; UV detection at 227 nm.

Retention times: (+)-enantiomer: 15.5 min.; (-)-enantiomer: 21.0 min.

Example 501H (2R.3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-vly-1-(N.Ndi(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid The compound resulting from Example 501G (20.0 g, 0.0383 mol) was suspended in ethyl acetate (150 mL) and 5% sodium bicarbonate solution (150 mL). The mixture was stirred at room temperature until the salt dissolved and carbon dioxide evolution had ceased. The organic layer was separated and concentrated. The residue was chased with acetonitrile (200 mL) to a final volune of 100 mL and cooled to 10 °C.

Diisopropylethylamine (11.8 mL, 0.0574 mol) and the compound resulting from Example A (10.5 g, 0.0421 mol) were added, and the mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated and chased with ethanol (200 mL) to a final volume of 100 mL. Sodium hydroxide solution 20 mL, 0.200 mol) was added, and the mixture was heated at 60 °C for 4 hours until HPLC showed no starting material remaining. The reaction mixture was poured into water (400 mL) and washed with hexanes (2 x 50 mL). The aqueous layer was washed with hexane (2 x 20 mL). A stirred mixture of the aqueous layer and ethyl acetate (400 mL) was neutralized to pH 5 with concentrated HCI (12 mL). The organic layer was separated and found to contain 18.3 g (94% yield) of the title compound.

WO 99/06397 PCT/US98/15479 -444- Example 5011 (2R.3R.4S)-(+)-2-(4-methoxyphenyl-4-(1.3-benzodioxol-5-yl)-1-(N.Ndi(n-butyl)aminocarbonylmethyll- pyrrolidine-3-carboxylic acid hydrochloride salt To a solution of the compound of Example 501H in ethyl acetate at room temperature in a mechanically stirred vessel equipped with a thermocouple, was added 39.4 mL of 1 N HCI in ethanol (0.0394 mol) The resultant solution was filtered to remove foreign matter, to concentrated in vacuo, and chased with ethyl acetate (400 mL). The solution was seeded repeatedly, as the solvent was removed, until crystallization was initiated. The mixture was concentrated to a volume of 100 mL, and the product was filtered and washed with ethyl acetate (25 mL). The resultant white solid was dried in a vacuum oven under a nitrogen purge at 50 °C to afford 17.6 g of the title compound.

Example 502 trans, trans-2-(2-Methylpentyl)-4-(1.3-benzodioxol-5-yl)-1-(N.Ndi(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Example 502A (±)-Ethyl 3-methylhexanoate To a slurry of 60% sodium hydride (2.26g, 57 mmol) in 10mL of hexanes and 100mL of diethyl ether was added triethylphosphonoacetate (10.3mL, 52mmol). Once gas evolution ceased, 2-pentanone (6.0mL, 64mmol) was added. After 3 hours at room temperature, the reaction was quenched with water, and partitioned into ether. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in of ethanol and 10% palladium on carbon (6.0g) was added. The vessel was pressurized to 4 atmosphere of hydrogen, and was shaken at room temperature for 3 hours. The reaction was filtered and the solvent was removed under reduced pressure to give 3.0g of the title Cnmnnilind.

C i WO 99/06397 PCT/US98/15479 -445- Example 502B (±)-Ethyl 5-methyl-3-oxooctanoate s To a solution of ethyl 3-methylhexanoate in 150mL of ethanol was added sodium hydroxide (2.3g, 57.6mmol). After 48 hours at room temperature, solvent was removed under reduced pressure, and the residue was dissolved in 150mL of water. The solution was washed with ether, then acidified with concentrated hydrochloric acid and washed with methylene chloride. The organic layer was dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 2.7g of the corresponding acid from which 3.9g of the title compound was prepared by the method of Bram and Vilkas, Bul. Chem. Soc. Fr., 945 (1964).

Example 502C trans. trans-2-(2-Methylpentyl)-4-(1.3-benzodioxol-5-yl)-1-(N.Ndi(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1 and substituting ethyl 5-methyl-3-oxooctanoate for ethyl (4-methoxybenzoyl)acetate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. Note that the multiplicity of the signals in the aryl region of the NMR spectrum reflects a 1:1 mixture of diastereomers on the alkyl chain. 1H NMR (CDCI3, 300 MHz) 8 0.8-1.0 12H), 1.2-1.4 7H), 1.45-1.6 6H), 1.6-1.74 1H), 1.8-2.0 1H), 3.1-3.4 5H), 3.67-3.78 1H), 3.8-3.91 1H), 4.0-4.2 2H), 4.3-4.5 2H), 5.93 J=1.5 Hz, 2H), 6.73 (dd, J=8.1, 1.2 Hz, 1H), 6.79 (ddd, J=7.8, 1.8, 1.8 Hz, 1H), 6.86 (dd, J=3.9, 1.5 Hz, 1H). MS (DCI/NH3) m/e 489 (M+H) Anal calcd for C 2 8H44N205*1.0 TFA* C, 58.91; H, 7.58; N, 4.58. Found: C, 58.91; H, 7.58; N, 4.45.

WO 99/06397 WO 9906397PCT/US98/1 5479 -446- Example 503 trans.- trans-2-(2.2-Dimethylpentyl)-4-(1 .3-benzodioxol-5-yl)-1 di(n-butyl)aminocarbonylmethy)-pyrrolidile-3-carboxylic Acid Ethyl 3,3-dimethyihexanoate was prepared using the general procedure of Cahiez et al., Tetrahedron Lett., 3 1, 7425 (1990). Using the procedures described in Example 502 and substituting ethyl 3,3dimethylhexanoate for ethyl 3-methylhexanoate afforded the title co .mpound, which was isolated by lyophilization from dilute aqueous TFAICH3CN. 'H NMR (CDCI3,.300 MHz) 8 0.80-0.99 (in, 15H), 1.10-1.37 (in, 8H), 1.43-1.58 (mn, 4H), 1.77-1.97 (in, 2H), 3.48-3.12 (in, 5H), 3.60- 3.69 (in, 1H), 3.75-3.86 (mn, 1H), 3.95-4.16 (in, 4.28-4.4 (in, 2H), 5.94 2H), 6.74 J=7.8 Hz, 1H), 6.8 (dd, J=8.1, 1.5 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H). MS (DCI/NH3) m/e 503 Anal calcd for C29H46N20501.05 TFA: C, 60.01; H, 7.62; N, 4.50. Found: C, 60.21; H, 7.37; N, 4.33.

Example 504 trans. trans72 (1 .3-Digoxo-2 -yl) ethyfl)-4- (1 ben zod ioxol-5-Yfl- 1 (N.N-di(n-butyl~aminocarbonylmethyl-pyrrolidine-3-carboxylic acid Examlole 504A Ethyl 5-(1 .3-dioxolyh)-3-oxopentanoate The title compound was synthesized from ethyl aceto acetate and 2-bromomethyl-1 ,3-dioxane, according to the procedure of Huckin and Weiler, Tetrahedron Lett. 3927, (1971).

Sodium hydride 4.97 g (0.124 mol), as a 60%/ mineral oil dispersion, was weighed into a 250 mL flask, into which 80 ml of tetrahydrofuran was directly added. The flask was capped with septum cap, flushed with nitrogen, and cooled in an ice bath. To above stirred slurry was added dropwise 15.0 mL (0.118 inol) ethyl acetoacetate.

After the addition was complete, the resulting mixture was stirred at 0 00 for additional 10 min. To above mixture was then added 48.4 mL (0.121 mol) n-butyl lithium, a 2.50 M solution in hexane, in a dropwise m~qnnpr- The resultina orange color solution was stirred for 10 min WO 99/06397 PCT/US98/15479 -447before 13.5 mL (0.130 mol) bromomethyl-1,3-dioxane was added in one portion. The reaction mixture was then allowed to warm to room temperature and stirred for additional 120 min before it was then quenched by slow addition of 9.8 ml (ca. 0.12 mol) concentrated hydrochloric acid. The biphasic mixture was poured to 50 ml of water and extracted with 150 ml of ethyl ether. The aqueous layer was extracted thoroughly with additional ethyl ether. The ethereal extracts were combined, washed with 2x50 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give an brown oily residue. The crude product was purified using silica gel flash chromatography eluting with 20% ether/hexane to give 5.40 g of b-keto ester as a light yellow oil.

Example 504C trans. trans-2-(2-(1.3-Dioxo-2-vylethyl)-4-( 1.3-ben zodioxol-5-yl)-1 (N.N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502 and substituting ethyl 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate afforded the title compound. 1 H NMR (CDCI3, 300 MHz) 8 0.93 J 7.2 Hz, 3H), 0.95 J 7.2 Hz, 3H), 1.23-1.38 4H), 1.52 (sextet, J 7.9 Hz, 4H), 1.85-1.95 2H), 2.02-2.17 2H), 3.18 (dd, J 6.0 Hz, Hz, 2H), 3.30 (dd, J 9.0 Hz, 18.0 Hz, 2H), 3.35 1H), 3.79 (dd, J 3.6 Hz, 6.9 Hz, 1H), 3.83-3.88 3H), 3.97 (dd, J 4.8 Hz, 6.0 Hz, 1H), 4.05 J 9.6 Hz, 2H), 4.30-4.40 1H), 4.37 2H), 4.87 J 3.6 Hz, 1H), 5.94 2H), 6.73 J 8.1 Hz, 1H), 6.79 (dd, J 1.8 Hz, 8.1 Hz, 1H), 6.87 J 1.8 Hz, 1H). MS (APCI) at m/e 505. Anal calcd for C27H40N207-1.2 TFA: C, 55.05; H, 6.47; N, 4.37. Found: C, 55.12; H, 6.44; N, 4.27.

Example 505 trans. trans-2-(2-(2-Tetrahydro-2H/pyran)ethyl)-4-(1.3-benzodioxol- 5-yll-1-(N.N-di(n-butyl)aminocarbonylmethyl-pyrrolidine-3carboxylic acid WO 99/06397 WO 996397CTIUS98/15479 -448- Example- 505A Ethyl 5-(2-tetrahydro-2Hi-pyran)-3-oxopentanopte Usin g the procedure of Huckin and Weiler, Tetrahedron. Lett. 3927, 6 (1971), the title compound was prepared from ethyl acetoacetate and 2-(bromomethyl)tetrahydro-2H-pyran as a light yellow. oil.

Example- 505B trans. trans.!2-(2-(2-Tetrahydro-2-Ipyranethyl)-4-( 1.3-benzodioxol- 5-yf)l-(N.N-di(n-butyflaminocarbonylmetfiyl)-oyrrolidine-3carboxylic acid Using the procedures described in Example 502 and substituting ethyl 5-(2-tetrahydro-2H-pyran)-2-oxopentanoate for ethyl 3methylhexanoate afforded the title compound as an amorphous solid.

1H NMR (CDCI3, 300 MHz) as a mixture of two diastereolsomers: 8 0.89 J =8.1 Hz, 3H), 0.89 J 8.1 Hz, 3H), 0.91 J 8.1 Hz, 3H), 0.91 J =8.1 Hz, 3H), 1.20-1.40 (in, 10H), 1.42-1.66 (in, 18H), 1.71 (brm, 2H), 1.85 (brm, 2H), 1.96-2.23 (brm, 4H),'3.10-3.29 (in. 8H), 3.29-3.52 (in, 6H), 3.54-3.81 (in, 6H), 4.01 J 9 Hz, 2H), 4.12-4.25 (mn, 4H), 4.43 J 9 Hz, 2H), 4.50 J 2.7 Hz, 2H), 5.94 2H), 5.95 2H), 6.76 2H), 6.76 2H), 6.81 1H), 6.81 1H). MS (APOI) at m/e 517. Anal calcd for C29H44N206-1.4 TEA: C, 56.48; H, 6.77; N, 4.14. Found: C, 56.46;, H, 6.99; N, 3.83.

Example 506 trans. trans-2-(2.2.4-Trim ethyl -3 -pentenyl)-4-( 1 .3-be yl)-1I N-di (n-b utyl) ami nocarbonyl methyl) -pyrrol id ine-3-c a rboxyli-C Example 506A Methyl 3.3.5-trimethyl-4-hexenoat-e To a slurry of isopropyltripenylphosphoniuin iodide (20.5g, 47mmol) in 200mL- of tetrahydrofuran was added n-butyllithium (27mL of a 1.6M solution in hexane, 43mmol), and the solution was briefly WO 99/06397PCJS9/47 PCTIUS98/15479 -449warmed to 0 0 C. After recooling, a solution of methyl 3,3-dimethyl-4oxobutenoate (5.7g, 4Ommol), prepared according to the procedure of Hudlicky et al, Synth. Commun., 16 169 (1986) in IlOmL of tetrahydrofuran was added, and the reaction was warmed to OOC for 30mn.' The reaction was quenched with dilute hydrochloric acid, and partitioned with ethyl acetate. The organic layer was washed with water, and brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate in hexanes to give 2.1 g of the title-compound.

Example 506B trans. trans-2-(2.2.4-Trirnethyl-3-pentenyfl-4-(1 yl)-l1-(N. N-di(n-butyl) aminocarbonylmethyfl)-nyrrolidine-3-carboxylic acid Using the procedures described in Example 502 and substituting methyl 3,3,5-trimethyl-4-hexenoate for ethyl 3-m ethyl hexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1 NMR (CDCI3, 300 MHz) 8 0.92 J=7.2 Hz, 3H), 0.94 J=7.2 Hz, 3H), 1.11 3H), 1.13 3H), 1.24-1.37 (in, 4H), 1.46-1.59 (in, 4H), 1.61 J=1.2 Hz, 3H), 1.69 J=1.2 Hz, 3H), 2.04-2.11 (mn, 2H), 3.10-3.20 (in, 2H), 3.30-3.39 (in, 3H), 3.67-3.82 (in, 2H), 3.95-4.08 (in, 1H),'4.32 (in, 2H), 4.37-4.47 (mn, 1H), 4.99 1H), 5.95 2H), 6.73 J=7.8 Hz, I1H), 6.78 (dd, J=8.4, 1.2 Hz, 1 6.84 (d, J=1.2 Hz, 1H). MS (DCI/NH3) W/e 515 Anal calcd for C30H46N205.11.05 TFA: C, 60.77; H, 7.48; N, 4.42. Found: C, 60.83; H, 7.20; N, 4.43.

Example 507 trans. trans-2-(2 .2.-Dimethyl-2-(1 .3-dioxolan-2-yl)ethyl)-4-(1 .3benzodioxol-5-yfl)-1 -(N.N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid WO 99/06397 WO 9906397PCT/US98/15479 -450- Example- 507A Methyl 3.3 dim ethyl 1, 3-di oxolIan-2 -yI)p-ropano-ate Methyl 3,3-dimethyl-4-oxobuta noate (10g, 7Ommol), prepared according to the procedure of Hudlicky et aL., Synth. Commun., 169 (1986), was dissolved in 4OmL- of benzene, followed by addition of ethylene glycol (2OmL-), and p-toluenesulfonic acid monohydrate (1 .3g).

The reaction was ref luxed with azeotropic removal of water for 1 hour.

The reaction was poured into 200ml- of ether, washed with saturated sodium bicarbonate, water and brine, dried with 'anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 12.4g of the title compound.

Example 507B trans, trans-2-(2.2.-Dimethyl-2-(1 .3-dioxolan-2-ylbethyl)-4-( 3benzodioxol-5-yl)-1 N-d i(n-butyl ~aminocarbonylmethyl)-' pyrrolidine-3-carboxylic acid Using the procedures described in Example 502 and substituting methyl 3,3-dimethyl-3-( 1,3-dioxolan-2-yl)propanoate for ethyl 3methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFAICH3CN. 1H NMR (CDCI3, 300 MHz) 8 0.82-1.00 (in, 12H), 1.24-1.40 (in, 4H), 1.43-1.64 (in, 5H), 1.76- 1.84 (in, IH), 2.93-3.00 (mn, 1H), 3.15-3.47 (in, 6H), 3.60-3.70 (in, 3H), 3.74-3.95 (in, 5H), 4.48 1H), 5.94 (mn, 2H), 6.72 J=8.0 Hz, 1H), 6.83 (dd, J=8.0, 1.2 Hz, 1H), 6.94 J=1.2 Hz, 1H). MS (DCI/NH3) Wne 533 Anal calcd for C29H44N207 -1.1 TFA*0.2 H20: C, 56.63; H, 6.93; N, 4.23. Found: C, 56.60; H, 6.96; N, 4.25.

Example 508 trans, trans (1 .3 -D ioxo-2 -yl) ethyb)-4- (1 .3-ben zodi oxol -5-Y)-l1 rr(44-he ptyl-N-.(2-methyl-3-fluorophenyl)I amino carbonylinethy Dvrrolidine-3-carboxvlimc acid

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WO 99/06397 PCT/US98/15479 -451-

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t Example 508A 4-HeDtanol O To an ice cooled solution of 1.14g (10.0 mmol) of 4-heptanone in mL of diethyl ether was added 370 mg (10.0 mmol) of LiAIH4, in S portions to keep ether reflux at a minimum. After 45 minutes, the cl reaction was quenched by sequential dropwise addition of 0.4 mL 0 0.4 mL 15% NaOH(aq), and 1.2 mL H20. After stirring another c minutes, MgSO4 was added until the salts were free flowing, then the reaction was filtered. The salts were washed with diethyl ether (3 x mL), then the filtrate and washings were concentrated to a colorless oil. Yield 1.16g (100%).

Example 508B 4-Methanesulfonyloxyheptane To an ice cooled solution of 834 mg (7.19 mmol) of 4-heptanol in mL of CH2CI2 was added 1.5 mL of triethylamine. Next, 0.7 mL (9 mmol) of methanesulfonyl chloride was added, dropwise, over 1 minute.

The mixture was stirred at 0 °C for 30 minutes, then extracted with (1 x 15 mL), 5% NH40H (2 x 15 mL), 1M HCI (2 x 15 mL), and brine (1 x 15 mL), dried over MgSO4, filtered, and concentrated to an oil. Yield 1.31g 1 H NMR (300 MHz, CDCI3) d 0.96 6, J 1.43 4), 1.64 3.00 4.73 (quintet, 1 J Example 508C 4-Fluoro-3-methylaniline To a solution of 20g (129 mmol) of 2-fluoro-5-nitrotoluene in 400 mL of ethanol was added 2g of 10% Pd-C. The mixture. was shaken under 45 P.S.I. H2 until hydrogen uptake ceased. The catalyst was filtered away and washed with ethanol, then the combined filtrate and washings were concentrated to 15.2 g of a colorless oil.

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WO 99/06397 PCT/US98/15479 -452- Example 508D N-Heptyl-4-fluoro-3-methylaniline O To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline Ss in 30 mL of acetonitrile was added 7.64 g (3.93 mmol) of 4- S methanesulfonyloxyheptane, and 3.4 g (4.1 mmol) of NaHCO3(s). The mixture was stirred at reflux for 24 hours, then poured into 150 mL of O H20 and extracted with diethyl ether (2 x 30 mL). The combined ether cK, layers were back extracted with brine (1 x 30 mL), dried over MgSO4, o filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 97.5: 2.5 hexanes: ethyl acetate, to give 2.56g of a pale yellow oil.

Example 508E NN.(4-Heptyl)-(4-fluoro-3-methyl)phenylbromoacetamide To an ice cooled solution of 4.88g (21.9 mmol) of N-(4-heptyl)-4fluoro-3-methylaniline and 4.9 mL (61 mmol) of pyridine in 100 mL of toluene was added a solution of 4.90 mL (56.2 mmol) of bromoacetyl bromide in 7 mL of toluene. The solution was stirred for 24 hours, gradually warming to 25 then extracted with 1M HCI (1 x 100 mL).

The aqueous layer was back extracted with diethyl ether (1 x 50 mL), then the combined organic layers were washed with H20 (2 x 50 mL), saturated NaHCO3(aq) (2 x 50 mL), and brine (1 x 50 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. This was purified via silica gel chromatography, eluting with 90:10 hexanes: ethyl acetate to give 7.48g of a light yellow oil. 1 H NMR (300 MHz, CDCI3) d 0.94 6, J 1.33 1.43 2.30 2.31 (s, 3.54 4.72 (quintet, 1, J 6.96-7.04 7.07(d, 1, J= 7).

WO 99/06397 WO 9906397PCT/US98/I 5479 c-I -453- Examuie 508F trans, trans-2-(2-( 1.3-Dioxol-2-yflethyl)-4-(1 .3-benzodioxol-5-yfl-1 rrN4 -he Dtyl-N(2-methyl-3-fluorolhelylU amino carbonylmethyll- -yrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl Cl 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methyihexanoate and N,N-(4-heptyl)-(4-fluoro-3-methyl)phenyl-bromoacetamide for N,N- 0 dibutyibromoacetamide afforded the title compound as an amorphous solid. IH NMR (CDCI3, 300 MHz) 8 0.93 (brt, 6H)-,1.23-1.47 (in, 8H), 1.67-2.10 (in, 4H), 2.32 3H1), 3.16 J 9.0 Hz, 1 3.52-3.67 (brm, 3.73 J 9.0 Hz, 3.81-4.02 (in, 6H), 4.13 (brm, 111), 4.72 (quintet, J 6.9 Hz, 1IH), 4.86 J 4.0 Hz, 1 5.93 2H), 6.72 J 8.1 Hz, 6.780(d, J 1.8 Hz, 8.1 Hz, 1H1), 6.85 J 1.8 Hz, 1H-), 6.96 (in, 2H), 7.08 J 9.0 Hz, 1 MS (DC IINH3) at W/e 599.

Anal Calcd for C33H43N207F-0.8 TFA: C, 60.24; H, 6.40; N. 4.06. Found: C, 60.21; H, 6.14; N, 3.86.

Example 509 transa.trans-2-(2-(1 .3-Dioxol-2-yflethyl)-4-(1 (N.N-di(n-butyflaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl (1 ,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate and 6methoxypiperonal for piperonal afforded the title compound as an amorphous solid. I1 NMR (CDC13, 300 MHz) 8 0.93 J 7.8 Hz, 3H), 0.95 J 7.8 Hz, 3H), 1.31 (in, 4H), 1.53 (mn, 4H), 1.90 (in, 2H), 2.09 (in, 2H), 3.19 (dd, J 8.4 Hz, 8.4 Hz, 2H), 3.30 J 9.6 Hz, 2H), 3.25-3.42 (mn, 1H), 3.73 J 10.5 Hz, 1H), 3.78-3.94 (in, 4H), 3.88 3H), 3.96 (dd, J 5.1 Hz, 6.0 Hz, 1H), 4.03 (dd, J 3.0 Hz, 6.3 Hz, 2H), 4.33 (in, 4.87 J 3.6 Hz, 11H), 5.94 2H), 6.53 J 1.8 Hz, 1H), 6.63 (d J 1.8 Hz, I MS (DCI/NH3) at m/e 535. Anal calcd for C28H42N208-1.05 TFA: C, 55.25; H, 6.63; N, 4.28. Found: C, 55.39; H, 6.66; N, -4.26.

WO 99/06397 WO 9906397PCT/US98/15479 -454- Example 510Q trans, trans- 2-((2-Methoxyphenoxy)-methyfl-4-(1 1 .N-di(n-butyflaminocarbonylmethyl)-pyrrolidine-3-carboxylic' acid 2; Using the procedures described in Example 502, substituting amethoxyphenoxyacetic acid for 3-methylhexanoic acid, the above compound was prepared as an amorphous solid. I1 NMR. (CDCI3, 300 D MHz) 8 0.85 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.15-1.35 (in, 4H), 1.40- 1.55 (in, 4H), 3.05-3.25 (in, 4H), 3.28-3.55 (mn, 4H), 3.58-3.68 (in, 1H), 3.75-3.80 (in, 1H), 3.82 3H), 3.91 J=l4Hz, TH), 4.05-4.15 (mn, 1H), 4.23-4.33 (in, 1 H),5.91 2H), 6.70 J=8Hz, 1 6.82-6.95 (in, 7.03 I1H). MS (DCI/NH3) at Wne 541. Anal calcd for C30H40N207: C, 66.65; H, 7.46; N, 5.18. Found: C, 66.37; H, 7.61; N, 5.09.

(22.jR,4S)-2-(2,2- Dim ethyl pentyl)-4 .3-be nzod ioxol -5-Yf 1 h ePt yl N -(4-flIug ro -methyl phen yl) g mino ca rbon yl methyl)'~pyrrolidine-3-carboxylic acid Example 511A trans. trans- N -t ert-Buto xycarbonyl -2 -(2.2-di methyl pentyl) 4- (1.3benzodioxol-5-yl)-pyrrolidine-3-carboxylic acid Ethyl trans, trans-2-(2,2-diinethylpentyl)-4-(1 yl)-pyrrolidine-3-carboxylate (2.5g, 6.9minol), prepared according to Example 503, was dissolved in 50mL of methylene chloride and di-tertbutyldi carbonate (1 .5g) was added. After stirring overnight at room temperature, the solvent-was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexanes to give the ethyl ester of the title compound (2.8g) as a colorless oil. The ester was dissolved in 5OmL of ethanol followed by addition of sodium hydroxide 1lOinL of a SM aqueous solution). After stirring for 20 hours at room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in 1 5OiL of water, and acidified with concentrated phosphoric acid. The

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WO 99/06397 PCT/US98/15479 S-455- Smixture was extracted with chloroform (3X50mL), and the organic layers were washed wiith brine, dried over.anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give the title compound (2.4g) as a white foam.

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Example 511B Methyl trans, trans-2-(2.2-dimethvlpentvl)-4-(1.3-benzodioxol-5-vl)- 1-(N-4-heptyl-N-(4-fluoro-3-methylDhenylaminocarbonylmethyl)- O pyrrolidine-3-carboxylate: As a single enantiomer The product from Example 510A (1.97g, 4.5 mmol) was dissolved in 20mL of THF and cooled to 0 0 C, followed by addition of DMF (0.017mL, and oxalyl chloride (0.437mL, 5.00mmol). After 1 hour, solvent was removed at OC under a stream of nitrogen. The residue was dissolved in 5mL of benzene and evaporated.- In a separate flask, (S)-4-benzyl-2-oxazolidinone (1.2g, 6.8mmol) was dissolved in of THF followed by addition of n-butyllithium (4.0mL of a 1.6M solution in hexanes) at 0°C, and the slurry was stirred for 15min. The acid chloride was dissolved in 20mL of THF and cooled to 0°C, followed by dropwise addition of the lithium oxazolide suspension via cannula.

After 30min, the reaction was partitioned between ether and saturated bicarbonate. The organic phase was washed with water then brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate/hexanes to give the undesired diastereomer (1.17g, then elution with ethyl acetate/hexanes gave the desired diastereomer (1.04g, 38%).

The desired diastereomer of the N-acyloxazolidinone (0.84g, 1.42mmol) was dissolved in 2.5mL of dichloromethane, and 2.5mL of trifluoroacetic acid was added. After 30min, the volatiles were removed under a stream of nitrogen, and the residue was twice dissolved in 5mL of toluene and evaporated under reduced pressure.

The TFA salt was stirred with 4mL of acetonitrile followed by addition of diisopropylethyl amine (1.0mL, 5.7mmol), and N-4-heptyl- N-(4-fluoro-3-methylphenyl)bromoacetamide (589mg, 1.7mmol) as a solution in 2mL of acetonitrile. After 21 hours, the reaction was

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WO 99/06397 PCT/US98/15479 S-456- -4 warmed to 50°C for 3.5 hours. The reaction was cooled, the solvent removed under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with 20-30% ethyl acetate/hexanes to give 0.939g of amide as a colorless oil.

The above amide (200mg, 0.26mmol) was dissolved in 2.0mL of I THF and 0.7mL of water. Solid lithium hydroxide monohydrate (22mg, 0.53mmol) was added at 0°C, followed by 30% hydrogen peroxide (0.050mL, 0.55mmol). After 1 hour, the reaction was warmed to room temperature. After an additional hour, the reaction was partitioned between 1:1 ethyl acetate:hexanes and water, 0.15g of sodium thiosulfate was added and the mixture was mixed thoroughly. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The crude residue was dissolved in 2mL of ether, and 1mL of methanol. A solution of (trimethylsilyl)diazomethane in hexanes was added dropwise until the yellow color remained. The reaction was quenched by addition of 2 drops of glacial acetic acid, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on 10g of silica gel eluting with 20% ethyl acetate/hexanes to give 70mg of the title compound as a crystalline solid (mp137.5 0

C).

Example 511C (2S.3R.4S)- trans. trans-2-(2.2-Dimethylpentvl-4-( 1 yl)- -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylate The product from Example 510B (65mg, 0.10mmol) was dissolved in 1.0mL of methanol and sodium hydroxide (0.1mL of a 5M aqueous solution) was added. After 2 hours, the reaction was warmed to reflux.

After 6 hours, the reaction was cooled, and the solvent was removed under reduced pressure. The residue was dissolved in water and acidified with concentrated phosphoric acid. The aqueous solution was washed with chloroform (3X5mL), which was then washed with brine, dried with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The title compound was isolated by lyophilization WO 99/06397 WO 9906397PCT/US98/1 5479 C-I .457- S from dilute aqueous TFN/CH3CN. 1 NMR (CDC13, 300 MHz) d 0.78-0.95 (in, 15H), 1.04-1.46 (in, 12H), 1.76-2.95 (in, 2H), 2.31 3H), 3.23-3.33 (in, 1H), 3.47-3.58 (in, 1H), 3.6-3.75 (in, 2H), 3.80-3.95 (in, 2H), 4.05o 4.15 (in, 1H), 4.73 (in, lH), 5.94 2H), 6.70-6.80 (in, 2H), 6.82-6.93 (in, 2H), 6.96-7.14 (in, 2H). MIS (DCI/NH3) mWe 597 Anal calcd for C35H49N2F05 -0.05H20 -0.8TFA-: C, 63.81; H, 7.30; N, 4.07. Found: c I21 46 (c 2 7 C C 3 C, 63.84; H, 7.18; N, 3.94. [a]D +6(c2gIC I3 Exampe 52 trans. trans Oxopyrrdl idi n -1 -yflethyfl-4-(1 .3-ben zgdi oxol- yfl)-1-(N. N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic is 2-Oxopyrrolidin-1-ylpropionic acid To a stirred solution of 5.0 mL (40.5 mmol) 2-oxopyrrolidin-1ylpropionitrile -in 15 mL of dioxane was added 8.1 mL of hydrochloric acid, a 6.0 M aqueous solution. The resulting mixture was then refluxed at 110 0 IC over night. The reaction mixture was then allowed to cool to room temperature, extracted with inethylene chloride three times. The extracts were combined and washed with saturated brine solution once, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.60 g of acid as a brown oil.

Exain~le 512B Ethyl 5-(2-oxopyrrolidin-1 -yfl-3-oxopentanoate The title compound was prepared from the above acid by adapting the method of Brain and Vilkas, Bul. Chem. Soc. Fr., 945 (1964).

WO 99/06397 WO 9906397PCT/US98/1 5479 -458- Example 5 12C trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(1 .3-ben yl)-l -(N.N-di(n-butyflamlnocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl 5-(2-oxopyrrolidin-1-yl)-3-oxopentanoate .for ethy[' 3methyihexanoate afforded the title compound as an amorphous solid.

1 HNMR (CDCI3, 300 MHz) 8 0.91 J 7.5. Hz, 3H), 0.94 J 7.5 Hz, 3H), 1.23-1.38 (in, 4H), 1.44-1.60 (m 2.05 J 6.9 Hz, 2H), 2.12- 2.25 (in, I1H), 2.38 (td, J 4.2 Hz, 8.4 Hz, 2H), 2.47-2.61 (in, 1 3.17 (dd, J 6.0 Hz, 8.7 Hz, 2H), 3.24 J 9 Hz, 1 3.32 J 7.8 Hz, 2H), 3.38-3.48 (in, 3H), 3.52 J 9 Hz, 1 3.66 J 6.9 Hz, 1 3.96 (mn, 2H), 4.14 (mn, 1H), 4.38 (brs, 2H), 5.93 2H), 6.74 J 8.1 Hz, 6.89 (dd, J 1.8 Hz, 8.1 Hz, 1 6.87 J 1.8 Hz, 1 MS (DCI/NH3) at W/e 516. Anal calcd for C28H41 N306-1.4 TEA: C, 54.78; H, 6.33; N, 6.22. Found: C, 54.69; H, 6.33; N, 6.14.

Example 513 trans.trans--2-(2-(1 .3-Dioxol-2-yflethyl)-4-(7-methoxy-1 .3benzodioxol-5-yl)-l1-(N-4-heptyl-N-(4-fluoro-3methylo~henyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl 1,3-dioxolyl)-2-oxopentanoate for ethyl 3-m ethyl hexanoate, N -4heptyl-N-(4-fluoro-3-methylphenyl) brOmoacetainide for N ,N-dibutyl bromoacetamide and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 0.93 (br t, 6H), 1.23-1.47 (in, 8H), 1.67-2.10 (in, 4H), 2.32 3H), 3.16 J 9 Hz, 1H), 3.60-4.03 (mn, 8H), 3.88 3H), 4.21 (brs, 1H), 4.72 (quintet, J 6.6 Hz, 1 4.86 J 3.6 Hz, I1H), 5.93 2H), 6.49 1 6.61 1H), 6.96 (in, 2H), 7.08 J 9 Hz, 1H). MS (DCI/NH3) at m/e 629. Anal calcd for C34H45N208F.1.0 TEA: C, 58.21; H, 6.24; N, 3.77.

Found: C, 58.11; H, 6.11; N, 3.58.

WO 99/06397 WO 9906397pCTIUJS98/15479 -459- Example 514 trans.trans-2-(2.2-Dimethylpentyfl.4(7methoxy1.3benzodioxo..syl)- N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine..3-carboxylic INDi Using the procedures described in Example 502, substituting ethyl hyl-3-oxooctano ate for ethyl 3-methyihexanoate and 6methoxypiperonal for piperonal afforded the title compound as an ciamorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 0.81 3H1), 0.84 3H1), 0.86 J 6.9 Hz, 3H), 0.93 J 6.9 Hz, 3H), 01-6 J 6.9 Hz, 3H-), 1.09-1.38 (in, 1.45-1.59 (mn, 4H1), 1.84-2.00 (in, 21-1), 3.15 (dd, J 6.9 Hz, 10.0 Hz, 3.30-3.42.(mn, 311), 3.72 J 10.5 Hz, 1H1), 3.86 (t, J 10.5 Hz, 11H), 3.88 3H1), 4.02 J 10.0 Hz, 111), 4.12 J 16.8 Hz, 1 4.29 J 16.8 Hz, 1 4.41 (brm, 1 5.94 1 6.52 J =1.8 Hz, 1H1), 6.67 J 1.8 Hz, 1H1). MS (DCI/NH3) at W/e 533.

Anal calcd for C30H148N206.0.9 TFA: C, 60.12; H1, 7.76; N, 4.41. Found: C, 60.18; H, 7.62; N, 4.33.

Example 515 trans. trans- 2 -(2.2-dimethylpentyl-42.3-dihydrobenzofuran-5-y)- N-di (n-butyfl)ami noca rbonylm ethyl)- pyrrolidine.3.carboxylic acid Using the procedures described, in Example 502, substituting ethyl 3.3-dimethylhexanoate for ethyl 3-m ethylihexanoate and 2,3-dihydrobenzofuran-5-carbaldehyde for piperonal afforded the title compound as an amorphous solid by lyophylization with CH3CNITFAIH2O. 11-1 NMR (300 MHz, CDC13) 8 0.83 311), 0.85 311), 0.86 J=7.2 Hz, 311), 0.92 J=7.2 Hz, 3H1), 0.95 J=7.2 Hz, 3H1), 1.09-1.39 (in, 8H), 1.44-1.59 (in, 411), 1.88 (dd. J=15.0, 7.2 Hz, 2.00 J=15.0 Hz, 11-1), 3.09 (mn, 21-1), 3.18 J=9.0 Hz, 211), 3.27-3.38 (in, 311), 3.65-3.95 (in, 211), 4.05 (q, J=10.0 Hz, 4.1.8 J=16.8 Hz, 111), 4.30-4.45 (in, 211), 4.55 Hz, 211), 6.70 J=8.4 Hz, 111), 7.04 (dd, J=8.4, 2.1 Hz, 111), 7.23 (brs, 111). MS (DCVNH3) at Wne 501 Anal calc'd for C30H-48N204.1.05 TFA: C, 62.14; H, 7.97; N, 4.51. Found: C, -62.19; H, 8.00; N. 4.43.

WO 99/06397 WO 9906397PCT1UJS98/15479 -460- Example 516 trans.trans-2-(2.2*-Dimethyl-2-(1 .3-dioxolan-2 .yl)ethyl)-4-(l1 methoxy-1 .3-benzodioxol-5-yi)-l -(N.N-di(nbutyflaminocarbonylmethyl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting methyl 3,3-di m ethyl 1,3-d ioxolan-2-yI)propanoate for ethyl 3methyihexanoate and 6-methoxypiperonal for piperonal afforded the 'A title compound as an amorphous solid by lyophylization with CH3CN/TFAIH2O. 1 H NMR (CDCI3, 300 MHz) 8 0.93 J=7.2 Hz, 3H1), 0.94 J=7.2 Hz, 3H), 0.95 3H), 0.96 3H), 1.31 .(sextet, J=7.2 Hz, 4H), 1.45 (in, 4H), 1.93 J=15.9, 6.0 Hz, 1H), 2.13 J=15.9 Hz, I1H), 3.20 (dd, J=7.7, 7.7 Hz, I1H), 3.26-3.40 (in, 3.60 (in, 1 3.75-3.86 (in, 3H), 3.88 3H), 3.93-4.01 (mn, 3H), 4.00-4.11 (in, IH), 4.23 J=15.9 Hz, 1 4.37-4.48 (in, 211), 4.49 I1H), 5.94 2H1), 6.51 J=2.1 Hz, 1H1), 6.64 J=2.1 Hz, 1H). MS (DCI/NH3) at mWe 563 Anal calcd for C30H46N208-0.9 TEA: C, 57.41; H, 7.11; N, 4.21; found: C, 57.35; H.

6.86; N, 4.05.

Example 517 trans, trpns-2-(2-(2-Methoxyphenyfl-ethyfl- 4 1-(N.N-di(n-butyl~aminocarbonylmnethyl)-pyrrolidine-3-arboxylic acid Using the procedures described in Example 502, substituting omethoxyphenylproponi.c acid for 3-m ethyl hexanoi c acid, the above compound was prepared as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 5 0.85 J=7Hz, 3H), 0.91 J=7Hz, 3H1), 1.10-1.27 (mn, 4H), 1.42- 1.60 (in, 4H), 1.72-1.89 (in, 1H1), 1.91-2.02 (mn, 1H1), 2.55-2.77 (mn, 2H1), 2.94 J=GHz, 1H), 3.05-330 (in, 6H), 3.59-3.82 (mn, 3H), 3.73 (d, J=l4Hz, 1H), 3.77 3H), 5.91 2H), 6.70 J=8Hz, 1H), 6.78-6.88 (in, 3H),6.92 J=2Hz, 1H), 7.08-7.19 (in, 2H). MS (DCIINH3) at Wle 539. Anal calcd for C31 H42N206: C, 69.12; H, 7.86; N, 5.20. Found: C, 68.89; H, 7.70; N, 4.99.

WO 99/06397PC/S8159 PCT/US98/15479 -461- Examole 518 trans, trans- 2-(2.2-D im ethyl-3 -(Q)-pentenyfl-4- (1 -m ethoxy- 1 .3benzodioxol 1 N-d i(n- butyl) aminoca rbo nyl methyl)pyrrolidine-3-carboxylic acid Example-518A 4-Methyl-3-penten-2-ol ci To a stirred solution of 3-methyl-2-butenal (8.7g, lO3mmol) in I OOmL *of tetrahydrofuran under N2 at 0 OC was added methylmagnesium bromide (38mL of a 3.OM solution in ethyl ether, 1 l4mmol) dropwise. The resulting mixture was allowed to warm to room temperature slowly and stirred at room temperature for 1 hour before it was quenched with 25mL of saturated NH4CI. The resulting biphasic mixture was partitioned between ethyl ether and water. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 8.4g (81 of alcohol as a colorless oil.

Example 518B trans-Ethyl 3.3-dimethyl-4-12entenoate A mixture of 4-methyl-3-penten-2-ol (7.4g, 74mmol), triethyl orthoacetate (13.6mL, 74mmol) and propionic acid (0.28mL, 3.7mmol) was heated at 150 OC for 7 hours. The product was then distilled under normal pressure (200-220 OC) to give 5.Og of crude ester as a colorless oil.

Examole 518C trans. trans-2-(2 .2-Dimethyl-3-(E)-oentenyfl-4-(1 -methoxy-1 .3benzodioxol-5-yl)-l1-(N. N-di( n-butylaminocarbonylmethyl)p2yrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting trans-ethyl 3,3-dimethyl-4-p enteno ate for ethyl 3-methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound. as an

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WO 99/06397 PCT/US98/15479 -462amorphous solid by lyophilization from dilute aqueous TFA/CH3CN. 1H NMR (CDCI3, 300 MHz) 8 0.92 J=7.2 Hz, 3H), 0.95 J=7.2 Hz, 3H), 0.97 3H), 0.99 3H), 1.31 (sextet, J=7.2 Hz, 4H), 1.52 (quintet, D J=7.2 Hz, 4H), 1.58 J=5.4 Hz, 3H), 1.92 (dd, J=15.0, 6.6 Hz, 1H), 2.04 J=15.0 Hz, 1H), 3.15 (dd, J=7.8, 7.8 Hz, 1H), 3.30-3.40 3H), 3.75 2H), 3.87 3H), 3.99 J=9 Hz, 2H), 4.11-4.30 3H), 5.29 (d, J=15.6 Hz, 1H), 5.38 (dd, J=15.6, 6 Hz, 1H), 5.94 2H), 6.50 J=1.8 Hz, 1H), 6.63 J=1.8 Hz, 1H). MS (DCI/NH3) at m/e 531 Analysis calc'd for C30H46N206-0.95 TFA: C, 59.95; H, 7.41; N, 4.38; S found: C, 60.00; H, 7.33; N, 4.35.

Example 519 trans, trans-2-(3-(2-pyridyl)ethyl)-4-(1.3-benzodioxol-5-yl-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid Example 519A 3-(2-Pyridyl)-propionic Acid In a 50 mL round-bottomed flask equipped with a stirring bar was placed 3-(2-pyridyl)-propanol (1 g, 7.6 mmol), water (13 mL) and concentrated sulfuric acid (0.5 g, 5.1 mmol). To this stirred solution was added over a period of 30 min potassium permanganate (1.8 g, 11.3 mmol) while the reaction temperature was maintained at 50 After the addition was completed, the mixture was held at 50 °C until the color of the reaction mixture turned brown, then heated at 80 °C for 1 hour and filtered. The filtrate was evaporated to dryness to yield quantitatively the desired acid (1.14 g) suitable for next step without further purification. To prepare a pure acid, the residue thus obtained was boiled in ethanol (10 mL) in the presence of charcoal (0.1 g) for min, filtered and cooled to give crystalline 3- (2-pyridyl)-propionic acid (0.88 g, 78%).

WO 99/06397 WO 9906397PCT[US98/15479 -463- Example 51 9B __trans. trans-2- (3-(2-pyri d yflethyfl)-4-( 1.3-benzodioxol- 5-yfl- 1 -IN. Ndi(n-butyflaminocarbnylmethy)-yrrolidine-3-cprbocylic acid Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFA/CH3CN as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 8.65 J=6.0 Hz, 1H), 8.06 J=6.91 Hz, 1 7.70 J=9.0 Hz, 1 7.51 J=6.91 Hz, I1H), 6.82- Nl 6.66 (in, 3H), 5.91 2H), 4.45 2H), 4.29-4.18 (mn, 1H),'4.04 (dd, J=20.1, 10.5 Hz, 1 3.84 J=12.6 Hz, 1 3.62 (dd, J=13.8, 9.6 Hz, 1H), 3.46-3.13 (mn, 7H), 2.51 (broad s, 2H), 1.60-1.43 (in, 4H), 1.37-1.22 (in, 4H), 0.91 J=8.4 Hz, 6H). MS (DCI/NH3) Wne 510 Anal calcd for C29H39N305*1.75 TFA: C, 55.04; H, 5.79; N, 5.92. Found:. C.

55.08; H, 5.64; N, 5.8 1.

Example 520 3R. 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1 yl)-1 -(N.N-di(n-butyflaminocarbonylmethyl).Dyrrolidine-3.carboxylic Exainple-520A L2S. 3R. 40)-Ethyl-2-(2- (2-oxo pyrroli din- 1 -yl) ethyl) (1 .3ben zodioxol-5-yfl pyrro Ii din e-3-ca rboxyl ate-sC.M andelate The raceinic amino ester from Example 512 (3.45g, 8.98inmol) in 1 OiL of ethyl acetate was treated with (S)-(+)-inandelic acid (0.75g, 4.93inmol). Upon the formation of the clear solution, hexane was dropped in slowly with stirring till the solution became light cloudy.

The solution was left stirred at room temperature over night. The crystals was then collected by filtration, recrystalized from ethyl acetate/hexane twice to give a yield of 800 mg of pure salt.

WO 99/06397 WO 9906397PCT/US98/15479 -464- Example 520B 3R. 4S)-Ethyl-2-(2-(2-oxopyrrol1idin-1 -yl)ethyl)-4-(1 .3benzgdioxol-5-yl)-1 N-di(n-butyl)aminocarbonylrmethy) pyrrolidine-3-carboxyla-te To a stirred solution of pure mandelate (150 mg, 0.28 mmol) -in CH3CN was added NN-dibutylbromoacetamide(84 mg, 0.34 mmol) and dilsopropylethylamine (98uL, O.56mmol). The resulting mixture was stirred at room temperature over night. Solvent was then removed under reduced pressure and the .crude product was purified by silica gel flash chromatography to give 140 mg (90% yield) of the title compound.

Examgle 5200 (2.3R. 4S)-2 xopyrroli d in- 1-yi) ethyl) -4 1.3-ben zodio is yl)-1 N-di(n -butyl) am inocarb onyl methyl)- pyrrolidin e- 3-carbo xylic Using the procedures described in Example 502, the title compound was prepared as an amorphous solid by lyophylization with CH3CNITFA/H20. 1 H NMR (CDCI3, 300 MHz) 8 0.91 J 7.5 Hz, 3H), 0.94 J 7.5 Hz, 3H), 1.23-1.38 (in, 4H), 1.44-1.60 (in 2.05 J 6.9 Hz, 2H), 2.12-2.25 (in, 1 2.38 (td, J 4.2 Hz, 8.4 Hz, 2H), 2.47- 2.61 (in, 1H), 3.17 (dd, J 6.0 Hz, 8.7 Hz, 2H), 3.24 J 9 Hz, 1H), 3.32 J 7.8 Hz, 2H), 3.38-3.48 (in, 3H), 3.52 J 9 Hz, I1H), 3.66 J= 6.9 Hz, 1H), 3.96 (in, 2H), 4.14 (in, 1H), 4.38 (brs, 2H), 5.93 2H), 6.74 J 8.1 Hz, 1 6.89 (dd, J 1.8 Hz, 8.1 Hz, 1 6.87 J 1.8 Hz, I1H). MS (DCI/NH3) at m/e 516. Anal calcd for C28H-41N306*0.85 TFA: C, 58.23;, H, 6.89; N, 6.86. Found: C, 58.37; H, 6.90; N, 6.84.

WO 99/06397 WO 9906397PCT/US98/15479 CI -465- Example--521 (2S. 3R. 4S)-2-(2-(2-oxopyrrolidin-1 -yflethyl)-4-(1 .3benzodioxol-5-yl)-l1-(N-4-heptyl-N-(4-fluoro-3-, m ethyl phenyfl))am inoca rb onylmethyl)-pyrrolidi ne-3-carboxylic acid Using the procedures described in Example 520, substituting N,Nci (4-heptyl)-(4-fl uoro-3-methyl)phenyl-bromoacetamide for N,N- V dibutyibromoacetamide afforded the title compound as an amorphous 0 solid by lyophylization with CH3CN/TFN/H2O. 1H NMR (CDCI3, 300 MHz) 8 0.85-0.98 (in, 6H), 1.22-1.55 (in, 8H), 2.04 (quitiet, J=7.9 Hz, 4H), 2.32 3H), 2.36 J=7.9 Hz, 2H), 2.61 (mn, 1H), 3.14 (in, 1H), 3.25-3.61 (in, 5H), 3.66-3.77 (in, 1H), 3.79-3.90 (in, 2H), 3.92-4.03 (in, 1H), 4.69 (quintet, J=6.8 Hz, 1H), 5.95 2H), 6.71 2H), 6.78 1H), 6.93-7.13 (in, 3H); MS (DCI/NH3) at ine 610 Anal calc'd for 15C34H44N306FI-1.45 TFA: C, 57.18; H, 5.91; N, 5.42. Found: C, 57.20; H, 5.62; N, 5.52.

Example-522 trans. -trans-2-(2-( 1-pyrazolyl)ethyl)-4-(1 (N.N-din-butyl~aminocarbonylmethyl)-pyrrolidine-3-carboxylic -acid Examp~l 22A.

Pyrazol1yfl)-propDion ic Acid 2S In a 10 mL round-bottomed flask equipped with a condenser and a stirring bar was placed pyrazole (0.50 g, 7.3 inmol), acrylic acid (0.50 inL, 7.3 minol) and triethylamine (3 mL). The reaction mixture was refluxed for 6 hours. After removing triethylamine, the viscous oil was dried on high vacuo during 12 hours to yield quantitatively the desired acid (1.0 g) suitable for the next step without further purification.

WO 99/06397 WO 996397PTI US98/1 5479 -466- Example 522B trans. transe!2 -pyra zo lyl) ethyl) .3 -ben zodioxol-5-yl)-l N-di(n-butyl)aminocarbonylmethyfl)-pyrrolidine-3-carboxylic acid 'CO 5 Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFA/CH3CN as an amorphous solid 1HNMR (CDCI3, 300 MHz) 8 7.56 J=3.0 Hz, 1 7.50 J=3 Hz, 1IH), 6.83-6.66 (in, 6.28 J=3 Hz, 1 5.91 2H), c-i 4.55-3.98 (in, 6H), 3.83-3.72 J=10.5 Hz, 1H), 3.61-3.40 J=10.5 Hz, D 1 3.36-3.12 (in, 5H), 2.69-2.43 (in, 2H), 1.59-1.42 (in, 4H), 1.38-1.21 (in, 4H), 0.91 J=7.5 Hz, 6H). MVS (DCI/NH3) at mWe 499 Anal calcd for C27H38N405-0.75 TFA: C, 58.60; H, 6.69; N, 9.59. Found: C, 58.53; H, 6.45; N, 9.67.

Example 523 trans. trans-2 Met hoxyphenyl)-4-(1I.3-b enzod ioxol- 5-yi 1 -r(N butyl-N-(3-hydroxygrolyl)amino~carbonylmethyl1Dyrrolidine-3-, carboxylic acid Examlle-523A N-Butyl-N-(3-hyd roxygropyfl-amine To a solution of 15.9g (100 minol) of methyl 3-N-(nbutyl)aminopropionate-in 150 mL of diethyl ether at 0 'C was added mL (0.35 inmol) of 1 .OM LiAIH4 in diethyl ether, keeping reflux at a minimum. The mixture was stirred at 0 .0 for 2.25 hours, the quenched by sequential dropwise addition of 1.9 mL H20, 1.9 mL NaOH(aq), and 5.7 mL H20. After stirring for 30 min, the salts were filtered and washed with diethyl ether, then the filtrate was concentrated to 11.3 g of a light yellow oil.

Example 523B N- Butyl-N-(3-hydroxypropyl)-chlo roacetamide To an ice cooled solution of 1.31g (10.0 inmol) of N-butyl,N-(3hydroxypropyl)amnine in -20 mL of ethyl acetate was added a solution of WO 99/06397 WO 9906397PCT/US98/15479 -467- 1.71g (10.0 mmol) of chloroacetic anhydride in lOmL of ethyl acetate.

The mixture was stirred, and gradually warmed to room terrnperature over 18 hours. The reaction was extracted with H20 (11 x 50 mL), saturated- NaHCO3 (aq) (2 x 50 mL), and brine (1 x 50 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was purified via silica gel chromatography, eluting with 80:20 hexanes:ethyl acetate to give 723 mg of a light yellow oil.

Example -523C p trans, trans-2-(4-Methoxyphenyl)z-. -1 3-beniodioxolI-5-yl)-1 buty.N- 3 .hyrox~royl)aminolcarbonylmethyll .yrrolidine-3 carboxylic acid Using the procedures described in Example ID, substituting

N-

butyl-N-(3-hydroxypropyl).chloroacetarnjde for N-propyl bromoacetamide and adding DM50S as cosolvent, afforded the title compound, which was isolated by l1yophilization from dilute aqueous TFAICH3CN. 1 H NMR (CD3OD, 300 MHz) 8 0.78-0.95 (in, 3H), 1.00-1.80 (in, 4H), 2.80-3.65 (in, 15H), 3.80 J=1.5 Hz, 2H), 5.93 2H), 6.72- 7.05 (in, 5H), 7.33-7.40 (in, 2H1). MS (DCI/NH3) at W/e 513 Anal calc'd for C261H30207-1.6 H20: C, 62.12; H, 7.30; N, 5.17. Found: C, 62.04; H, 7.21; N, 4.88.

Example 524 trans. trns2-(4-Methoxyphenyl)-4(1 .3-benzodioxol-5-yl)-l1-((N- 1Propyl-Nprooxyamino)carbonylmpethyl-12yrrolidine3-crboxylic acid Example 524A N-Boc-O-allyl hydroxylIamine 0-Allylhydroxylamine hydrochloride hydrate (5.0g) was dissolved in THF (15 mL). The solution was cooled to 0OC in an ice bath.

Diisopropylethylamine (8mL) and di1-t-butyldi carbonate (10.0g) were added. The mixture was stirred at 000 for 1 hour at which point the bath was removed and the reaction allowed to warm to room

I

WO 99/06397 PCT/US98/15479 -468temperature and stirred overnight. The THF was removed in vacuo and the residue taken up in EtOAc (25 mL), and washed with water (1 x mL), saturated sodium bicarbonate solution (3 x 50 mL), 1N phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil which was used without any further purification.

SExample 5248 N-Boc-N-propyl-O-allylhydroxvlamine N-Boc-O-allylhydroxylamine (6.5g) from the above procedure wasdissolved in dry THF (25 mL) and the solution cooled to 0°C in an ice bath. Sodium hydride (1.5g, 60% dispersion in oil) was added portionwise over 5 min. The resulting mixture was stirred for 30 min at 0°C. 1-lodopropane (3.8mL) was added dropwise to the mixture. The reaction was stirred at 0°C for 1 hour, then stirred overnight at room temperature. The THF was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 50 mL), saturated sodium bicarbonate solution (3 x 50 mL), 1N phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil, which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil Example 524C N-Boc-N-propyl-N- propoxyamine N-Boc-N-propyl-O-allylhydroxylamine (6.0g) was dissolved in EtOAc (100 mL). 10% Palladium-on-carbon (0.5g) was added, and the mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at room temperature for 6 hours. The catalyst was removed by filtration through a pad of Celite and the solvents were removed in vacuo to give a yellow oil which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil (5.8g).

WO 99/06397PCIS8 47 PCr[US98/1'5479 CIA -469- Examlle 524D N-Propyl-N-propoxyamine hydrochloride N-Boc-N-propyl-N-propoxyamine (5.8g) was dissolved in 4N IND HCI/dioxane (l0mL-) and stirred at room temperature for 7 hours. The S solvent was removed in vacuo and the residue triturated with diethyl S ether. The resulting yellow solid (2.1g) was collected by filtration and washed with diethyl ether.

Example 524E N-D ropyl-N-propoxy-bromoacetamide N-Propyl-N-propoxyamine hydrochloride (0.30 g) was dissolved in acetonitrile and cooled to -20 0 C. Pyridine (0.2 ml-) was added.

is Bromoacetyl bromide (0.15g) was added dropwise over 5 min. The solution was stirred at -200C for 30 min. The bath was removed and the solution was stirred for 6 h ours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 ml-) and washed with water (1 x 25 mL), 1N phosphoric acid (3 x 25 mL), and brine (1 x 25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oil (0.35g). The product is a mixture of chloroand bromoacetamides in a ratio of -3:1.

Example 524F trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)-l1-[(Nbutyl- N- (3-hyd roxyp ropyfl)amino) carbonyl methyl1oyrrol id ine-3carboxylic acid Prepared according to the procedure of Example 523C, employing N-propyl-N-propoxy-bromoacetamide and ethyl 2-(4-methoxyphenyl)- 4-(1 3- be nzodioxol- 5- yl)-pyrrol idine-3-carboxyl ate. The crude product was purified by preparative HPLC (Vydac mCi 8) eluiting with a 10-70% gradient of CH3CN in 0.1% TFA. The appropriate fraction was lyophilized. to. give the product as a white solid. 1 H NMR (CDCI3, 300 IAHz) 8 0.87 (in, 6H, J=8Hz), 1.49 (in, 2H, J=8Hz), 1..61 (in, 2H, J=8Hz), 3.55 (in, 6H), 3.80 (in, 2H), 3.81 3H)1, 4.00 (in, 2H), 4.13 2H, WO 99/06397 PCT/US98/15479 -470- J=17Hz), 5.96 2H), 6.77 1H, J=9Hz), 6.90 3H), 7.05 1H, J=1Hz), 7.44 2H, J=9Hz). MS (DCI/NH3) m/e 499 Anal catcd for C27H34N207 1.20 TFA: C, 55.57; H, 5.58; N, 4.41. Found: C, 55.59; H, O 5.58; N, 4.55.

Example 525 Strans. trans-2-(4-Methoxyphenyl)-4-(1,.3-benzodioxol-5-vl)-1-[(N- Sbutyl-N-propoxyamino)carbonylmethyll-Dyrrolidine-3-carboxylic acid Example 525A N-butyl-N-(2-hydroxyethyl)-amine In a thick walled glass tube 5 ml (100 mmol) of ethylene oxide was condensed at -78'C. To this12.5 ml (120 mmol) of butylamine was added and the tube was sealed. The resultant solution was allowed to heat in an oil bath at 50'C for 18 hours. Unreacted reagents were removed by evaporation to give the title compound.

Example 525B N-Butyl-N-(2-azidoethyl)-chloroacetamide To 500 mg of N-butyl,N-2-hydroxyethylamine was added 2 mL of thinoyl chloride, dropwise. After the initial reaction had ceased, the reaction was stirred for 10 min, then concentrated to an oil. Diethyl ether was added and evaporated to aid in removal of the thionyl chloride. The residue was taken up in 10 mL of DMF, and 1.0g (16 mmol) of sodium azide was added. The reaction was stirred at 75 'C for 2 hours, then poured into 50 mL of 0.6M NaHCO3(aq.) and extracted with diethyl ether (3 x 15 mL). The combined ether layers were back extracted with brine (1 x 15 mL), dried over MgSO4, and, filtered. To the ether solution was added 850 mg (4.97 mmol) of chloroacetic anhydride. The reaction was stirred for 10 min, then concentrated to an oil. This was taken up in 10 mL of saturated NaHCO3(aq.) and extracted with diethyl ether (3 x 5 mL). The combined ether layers were back extracted with brine (1 x 5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel WO 99/06397 PCT/US98/15479 S-471- Schromatography, eluting with 30% ethyl acetate: hexanes, to give 161 mg of an oil.

D Example 525C 0 5 trans. trans-2-(4-Methoxyphenyl-4-(1.3-benzodioxol-5-vl)-l-r(Nbutyl-N-(2-aminoethyl)amino)carbonylmethyll-pyrrolidine-3- Scarboxylic acid

D

According to the procedure of Example 523C, N-butyl-N-(2- S azidoethyl)-chloroacetamide was coupled with 6thyl 2-(4- Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate.

The crude product was chromatographed on silica, using 40% EtOAc in hexanes to elute. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and water added.

The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3P04 and extracted with EtOAc. The latter organic extract was washed with brine and dried over Na2SO4. To 100 mg (0.10 mmol) of the azide was added lmL of 1M HCI(aq.), 0.5 mL of dioxane, and 5 mg of 10% Pd-C. The suspension was stirred under 1 atm. of H2 for 5 hours, then filtered and concentrated to a white solid. The product was purified via HPLC, eluting with a 0 to 70 CH3CN in 0.1% aqueous TFA gradient to give the title compound as its TFA salt. 1H NMR (CD30D, 300 MHz) 5 0.92 J=7.0 Hz, 3H), 0.96 rotamer), 1.23 2H), 1.41 2H), 3.06 4H), 3.39 2H), 3.69 2H), 3.84 (s, 3H), 3.94 3H), 4.18 2H), 5.05 (bd, J=10.7 Hz, 1H), 5.98 2H), 6.84 J=7.7 Hz, 1H), 6.93 (dd, J=1.8, 8.1 Hz, 1H), 7.05 3H), 7.56 (m, 2H). MS (DCI/NH3) at m/e 498 (M+H) Anal calcd for C27H35N306*3.15 TFA: C, 46.68. H, 4.49. N, 4.90. Found: C, 46.61; H, 4.73; N, 4.79.

WO 99/06397 PCT/US98/15479 -472- Example 526 trans, trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl-1 -r(Nbutyl-N-(3-aminopropyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid To and ice-cold solution of the compound of Example 523C (100 S mg, 0.19 mmol) in 1 mL of dichloromethane was added 17mL of methanesulfonyl chloride, and 39 mL of triethylamine. The mixture was stirred for 20 min, then diluted with 1.5 mL of dichloromethane S and extracted once with 5mL of water to which had been added 1 drop of 85% H3P04, then 5% ammonium hydroxide (1 x 2.5 mL), and brine (1 x mL), dried over MgSO4, filtered, and concentrated to an oil. To a solution of 81 mg (0.13 mmol) of the mesylate in 1mL of DMF was added mg (10 mmol) of sodium azide. The mixture was stirred for 1 hour at 50 then poured into 10 mL of water and extracted with diethyl ether (3 x 5 mL). The combined ether layers were back extracted with brine (1 x 5 mL), dried over MgSO4, filtered, and concentrated to an oil.

This was purified via silica gel chromatography, eluting with 60:40 hexanes: ethyl acetate to give 57 mg of a colorless oil. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3PO4 and extracted with EtOAc. The latter organic extract was washed with brine and dried over Na2SO4. To this azide was added imL of 1M HCI(aq.), 0.5 mL of dioxane, and 5 mg of 10% Pd-C. The suspension was stirred under 1 atm. of H2 for 5 hours, then filtered and concentrated to a white solid. The product was purified via HPLC, eluting with a 0 to CH3CN in 0.1% aqueous TFA gradient to give the title compound as its TFA salt. 1 H NMR (D6-DMSO, 300 MHz) 5 0.85 (apparent q, J=6.8 Hz, 3H), 1.17 2H), 1.30 2H), 1.67 2H), 2.71 2H), 3.04 1H), 3.21 3H), 3.45 1H), 3.75 3H), 3.97 3H), 3.85-4.80 (broad m, 3H), 6.03 2H), 6.87 (dd, J=1.4, 8.1 Hz, 1H), 6.92 J=7.8 Hz, 1H), 7.01 2H), 7.16 1H), 7.55 2H), 7.72 2H), 7.85 1H); MS (DCI/NH3) at m/e 512. Anal calcd for C28H37N306-3.0 TFA: C, 47.84. H. 4.72. N, 4.92. Found: C, 47.86; H, 4.75; N, 4.97.

WO 99/06397 WO 9906397PCTIUS98/15479 CIA -473- Example 527 trans. trans-2-(4-Methoxyphenyfl-4-( 1.3-be nzodioxol-5-yfl- 1-FLNbutyl-N-(3-dim ethyl aminop ro pyl)amino)-carbonylmethyl..pyrroI idine..3.

carboxylic acid Example 527A N-butyl-N -(3-.rom o propyl) brom oaceta mid e 0 To 1 .50g (11.4 mmol) of N-butyl-N-(3-hydr-bxy)propylamine was added 3 mL of 48% HBr(aq.), and 1.5 mL of conc. H2S04. The reaction was stirred at reflux for 3 hours, then cooled to room temperature and stirred for 22 hours. The mixture was poured over 50 mL of ice, and the solution was treated with 50 mL of 2M NaOH(aq.). The basic is solution was extracted with ethyl acetate (3 x 25 mL), then the combined ethyl acetate layers were back extracted with brine (1 x mL), dried, and filtered. To the ice cooled ethyl acetate solution was added 3mL of triethylamine, then 1.5 mL of bromoacetyl bromide as a solution in 3.5 mL of ethyl acetate. The reaction was stirred at 0 'C for 30 min, then extracted with 1 M HCI(aq.) (2 x 25 mL) saturated NaHCO3(aq.) (1 x 25 mL) and brine (1 x 25 mL). The organic layer was dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 30% ethyl acetate in hexanes to give 1 .47g of a coloriess oil.

Example 527B Ethyl trans, trans-2-(4-Methoxyphenyl)-4.(1 .3-benzodioxol-5-y)-1 L(N-butyl-N-(3-brom opropyl) amino) carbonylmethyll-pyrrolidin e-3c arb oxyl ate According to the procedure of Example 523C, N-butyl-N-(3bromopropyl-bromoacetamide was coupled with ethyl 2-(4- Methoxyphe nyl)-4- (1 ,3-ben zo d i ool yl) -p yrrolidi ne-3-carboxyl ate.

The crude product was chromatographed on silica, using 40% EtOAc in hexanes to elute.

WO 99/06397 WO 9906397PCTIUS98/1 5479 -474- Example--5270 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-be nzodio-xol-5-yl)-1 butyl-N-,(3-dim ethylaminopropyfl amino)carbognylmethyll-Pyrrolidifle-3carboxylic acid To 400 mg (0.663 mmol) of the compound of Example 527B in 4 mL of absolute EtOH was added 1.2 mL of 2.0 M Me2NH in THF. The reaction was heated at 50 .0 for 3h, then stirred at room temperature for 18 hours. The mixture was concentrated, then reconcentrated from CH3CN to remove most of the trimethylamine. The product was purified via silica gel chromatography, eluting with 9:1 CH2CI2: MeOH over about mL of silica gel to give the ethyl ester. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 3 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3P04, and the product was p urified by preparative HPLC. 1 H NMR (CD3OD, 300 MHz) 8 0.92 (t, Hz, 3H), 1.22 (in, 2H), 1.39 (in, 2H), 1.90 (in, 2H), 2.87 6H), 3.07 (in, 4H), 3.24 (in, I1H), 3.43 (in, 1 3.62 (in, 1 3.84 3H), 3.88 (mn, 3H), 4.07 (in, I1H), 4.17 (in, 1 4.97 (in, 1 5.97 2H), 6.83 J=8-1 Hz, 1 6.93 (dd, J= 1.7, 8.1 Hz, 1 7.05 (in, 3H), 7.53 (in, 2H). MS (DC l/NH3) at m/e 540 Anal calcd for C30H41 N306-2.95 TFA: C, 49.22. 5.06. N, 4.80. Found: C, 49.16; H, 5.11; N, 4.62.

Examlie 528 trans. -trans-2-(4-Methoxyphenyl)-4-(1I.3-benzodioxol-5-yl)-l -f(Nbutyl-N-(3-t rim ethyl ammo ni opropyl) aino) ca rb nyl methyl pyrrolidine-3-carboxyli-c acid Prepared according to the procedures of Example 5270, substituting aqueous Me3N for Me2NH. 1 NMR (CD3OD, 300 MHz) 8 0.91 (in, 3H), 1.24 (in, 2H), 1.40 (in, 2H), 1.99 (in, 2H), 3.13 9H), 3.18 (s, rotainer), 3.20 (in, 3H1), 3.39 (mn, 3.72 (in, IH), 3.84 3H), 4.03 (in.

4.35 (in, 1 5.19 (in, I1H), 5.97 2H), 6.84 J=8-1 Hz, 1 6.96 (dd, J=1.7, 7.9 Hz, 1 7.10 (in, 3H), 7.62 (in, 2H). MS (DCI/NH3) at Wne WO 99/06397 PCT/US98/15479 S-475- S554 Anal calcd for C31H44N306*0.1 H20-1.65 TFA: C, 47.25.

i H, 4.96. N, 4.32. Found: C, 47.25; H, 4.74; N, 4.75.

D Example 529 0.

trans. trans-2-(4-Methoxyphenyl)-4-(1.3-benzodioxol-5-yl)1-[(NbutyI-N-(4-aminobutyl)amino)carbonylmethyll-pyrrolidine-3- Scarboxylic acid Example 529A N-butyl-N-(4-hydroxybutyl)-amine A solution of 8.1 g (110 mmol) of n-butylamine and 8.6 g of butyrolactone in 50 ml toluene was allowed to reflux under nitrogen atmosphere for 50 hours. Volatile solvents were removed in vacuo. To a solution of 3.18 gm (20 mmol) of the resultant N-butyl -4hydroxybutyramide in 50 ml of toluene were added 120 ml (120 mmol) The solution was heated with stirring at 70 'C for 18 hours. After cooling to O'C, the reaction was quenched with methanol (1/3 amount of DIBAL solution was used) followed by addition of saturated solution of Rochelle's salt. The mixture was extracted twice with EtOAc; the organic extracts were washed with brine and dried over Na2SO4.

Example 5298 N-butyl-N-(4-hydroxybutyl)-chloroacetamide Pyridine (2 ml) was added to an ice cold solution of 0.58 gm (4 mmol) of N-butyl-N-(4-hydroxybutyl)-amine in 10 ml of EtOAc. To this solution 0.769 gm (4.5 mmol) chloroacetic anhydride was added in small portions. The reaction mixture was allowed to stir for 5 hours at O'C, and then was allowed to warm to room temperature.

Bicarbonate was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. The crude material was purified by column chromatography.

WO 99/06397 WO 9906397PCT1UJS98/15479 -476- Example--529C Ethyl-trans, trans-!2-(4-Methoxyo~henyfl-4-(1 .3-benzodioxol-5-y)-1 [(N-butyl-N-(4-hydroxybutyl~amino~caroylmethyll-pyrrolidifle-3carboxylate According to the procedure of Example 523C. N-butyl-N-(4hydroxybutyl-chloroacetamide was coupled with ethyl 2-(4- M ethoxyphenyl)-4- (1 be nzod ioxol-5-yl)-pyrrol idinle-3-carboxyl ate.

ci The crude product was chromatographed on silica gel.

Examgle 529 Ethyl trans, trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yfl)-1r( N-butyl- N (4-bro m o btylam i no~arbonl mnethyl I-pyrrolidi ne-3carboxylate To the solution of 0.180 gm (0.33 mmol) of the compound of Example 5290 in 2 ml DMF 0.086 gm (1 mmol) of lithium bromide and 0.120 ml (0.66 mmol) of PBr3 was added. The reaction mixture was allowed to stir at 0.0 for 2 hours and was slowly,-warmed to room temperature. Bicarbonate was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine. The crude material was purified by column chromatography.

Example 529E trans, trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxoI -5-yi)-l butyl.N-(4-aminobutyl)amino)carbonylmethy1-pyrrolidine- 3 carboxylic acid To a solution of 0.135 gm (0.21 mmol) of the compound of Example 5290 in 2 ml DMF was added 0.1 gm of sodium azide. Reaction was allowed to stir at room temperature for 18 hours under nitrogen atmosphere. After addition of water, the product was extracted into EtOAc. The crude product (117 mg) was dissolved in 10 ml ethanol under nitrogen atmosphere. To -this 45 mgs of 10% Pd/C catalyst was added, the nitrogen from the reaction flask was evacuated and was flushed with hydrogen by placing a balloon filled with hydrogen.

WO 99106397 WO 9906397PCT/US98/I 5479 -477- The reaction was allowed to stir for 4 hours under hydrogen atmosphere, and was worked up by filtering through a Celite pad. The product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 8 hours at room' temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with IN H3P04, and CI the product was purified by preparative HPLC. I NMR (CD3OD, 300 0 MHz) 8 0.90 J=7 Hz, 3H), 1.10-1.65 (in, 6H), 2.85-2.95 (in, 2H1), 3.00ci 4.10 (in, 14H), 5.50 J=3 Hz, 2H), 5.97 2H), 6.82 J=8 Hz, 1 H), 6.91 (dd, J=7 Hz, I1H), 7.00-7.06 (mn, 3H), 7.45-7.55 2H). MS (DCI/NH3) at We 526 Anal calc'd for C29H39N30 6 .2.2 TFA: C, 51.75; H, 5.35; N, 5.41. Found: 0, 51.75; H, 5.31; N, 5.30.

Examn~le 530 trans. trans-2-(4-Methoxyphenyn)-4-(1 .3-benzodioxol-5-yl)-1 -r(Nbutyl-N-(4-dim ethyl aininobutyl) am ino2)ca rbonylmethyll-pyrrolidi ne-3carboxylic acid The title compound was prepared from the compound of Example 529D, employing the procedures of Example 527C. 1 H NMR (CD300, 300 MHz) 8 0.90 (dt, J=7Hz, 3H), 1.1-1.75 (mn, 8H), 2.75 J=7 Hz, 6H), 4.25 (mn, 16H), 5.97 2H), 6.83 J=8 Hz, 111), 6.93 (dd, J=8 Hz, I1H), 7.02-7.08 (in, 3H1), 7.49-7.56 (in, 2H). MS (DCI/NH3) at in/e 554 Anal calc'd for C31 H43N3OG-2.1 TFA: C, 53.31; H, 5.73; N, 5.30. Found: C, 53.50; H, 5.38; N, 5.34.

Example 531 trans. trans-2-(4-Methoxyphenyl)-4.(1 .3-benzodioxol-5-yl)-1 bUtyl-N -(3-pyridyl) amino)carbonylmethyll-pyrrolidine-3-carb oxylic d Exmpl 531A N- but yl yrid yl am iner To a solution of 941 mg (10 inmol) of 3-aininopyridine and 0.9 mL of butyraldehyde in 30 mL of CH30H was added 10 mL of glacial acetic WO 99/06397 WO 9906397PCT/US98/1 5479 -478acid. The mixture was stirred at room temperature for 1 hour, then the reaction was cooled with an ice bath, and 650 mg (10.3 mmol) of sodium cyanoborohydride was added. The ice bath was removed, and the reaction was stirred for 4.5 hours at room temperature. The mixture was poured into 300 mL of 0.67M NaOH(aq.), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were back extracted with brine (1 k 50 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was isolated via silica gel chromatography, eluting, with 3:1 ethyl acetate: hexanes to give 1 .18g of a colorless solid.

to Examlole 531 B trans, trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yfl)-1-r(Nbutyl.N-(3-pyridyflamino)carbonylmethyll-pyrrolidine-3-carboxyLic acid The compound of Example 531A was reacted according to the procedures of Example 523, to give the title compound. I H NMR (D6- DMS0, 300 MHz) 8 0.80 J=-6.4 Hz, 3H1), 1.15-1.99 (in, 4H1), 2.59 (in, 1H), 3.05 (in, 2H), 3.26 (in, 2H), 3.49 (mn, 2H), 3.56 J=7.1 Hz, 2H), 3.73 (s, 3H), 6.00 2H), 6.80 (in, 3H1), 6.85 J=8.1 Hz, I1H), 6.98 (in, 2H), 7.04 (mn, 1 7.41 (dd, J=1, 4.7 Hz, S. 1H), 7.58 (in, 1 8.36 (bs, 1 8.54 (bs, 1H), 12.24 (bs, I1H). MS (DCI/NH3) at mWe 532 Anal calcd for C30H33N306-0-1 H3P04: 0, 66.55. H, 6.20. N, 7.76. Found: C, 66.59; H, 6.06; N, 7.60.

Example 532 trans, trans-2- Met hoxyphe nyfl-4-(1 .3-be nzodi oxol1-5 -Yfl- 1 -r (Nbutyl-N-(3-aminoinethylphenyflamino)carbonylmfethyll-pyrrolidine- 3 carboxylic acid Example 532A N-butyl-N-(3-hydroxymethyl phenyl)-amine To a solution of 3.69 g (30 minol) of 3-amino benzyl alcohol in ml DMSO was added 3.78 g (45 minol) solid NaHCO3 and 2.91 ml (27 inmol) 1-bromobutane. The reaction was allowed to stir at 50 *C for WO 99/06397 PCT/US98/15479 -479- S18 hours (overnight). Reaction was worked up by adding 250 ml water and product was extracted in ethyl acetate. Water was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine.

OD

Example 532B N N-butyl-N-(3-hydroxymethylDhenyl)-bromoacetamide O To a solution of 3.42 g (19.2 mmol) of the compound of Example 532A in 20 ml toluene, was added 2.42 ml (30 mmol) pyridine. The mixture was cooled to O'C; 4.025 gm (20.0 mmol) of bromoacetyl bromide (diluted with 5 ml toluene) was added in a dropwise fashion.

The reaction mixture was allowed to stir for 5 hours at O'C and then was allowed to warm to room temperature. Saturated potassium carbonate solution was added, and the mixture was stirred vigorously for 2 hours. The mixture was extracted with EtOAc; the organic layer was washed with 1N H3P04, water, and brine.

Example 532C Ethyl trans, trans-2-(4-Methoxyvhenyl)-4-(1.3-benzodioxol-5-yl)-1- [(N-butvl-N-(3-chloromethylph enyl)amino)carbonylmethyll-pyrrolidine- 3-carboxylate According to the procedure of Example 523C, N-butyl-N-(3hydroxymethylphenyl)-bromoacetamide was coupled with ethyl 2-(4- Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate.

The crude product (129 mg) was dissolved in 0.5 ml of DMF and cooled to 0°C; 19 mg of LiCI was added, followed by 85 gil of thionyl chloride.

The mixture was allowed to stir for 30 min; water was added, and the mixture was extracted with EtOAc. The organic extracts were washed with water and brine, and dried over Na2SO4.

I

WO 99/06397 PCT/US98/15479 S-480- Example 532D S trans. trans-2-(4-Methoxyphenvl)- 4 -(1.3-benzodioxol-5-lv- l-r(Nbutyl-N-(3-aminomethylphenylamino)carbonylmethyl-Dvrrolidine-3carboxylic acid 0 The compound of Example 532C (182 mg) was dissolved in 1 mL of DMF. Two drops of water were added, followed by 126 mg (2.0 mmol, 3 6.5 eq) of sodium azide. The resultant solution was heated at 115 °C D for 3 hours. Water was added, and the mixture was extracted with EtOAc. The organic extracts were washed with water and brine, and dried over Na2SO4.

Example 532E trans, trans-2-(4-Methoxyphenyl)-4-(1 3-benzodioxol-5-yl)-1-[(Ns1 butyl-N-(3-aminomethylphenyl)amino)carbonylmethyl-pyrrolidine- 3 carboxylic acid In a 50 ml round bottom flask 0.090 gm Tin (II) chloride was suspended in 1 ml acetonitrile. Triethylamine (0.2 mL) was added, followed by 0.19 ml of thiophenol the reaction mixture turned yellow.

Reaction flask was cooled to O'C in ice bath; a solution of 0.185 gm of the compound of Example 532D in 2 ml acetonitrile was added. The mixture was allowed to stir for 30 min. Ether (10 ml) was added, followed by addition of 10 ml 2N HCI The aqueous extract was basified with 4N NaOH and extracted with dichloromethane. The organic layer was washed with water and brine. The crude product was dissolved in a solution of ethanol and aqueous 2.5 N sodium hydroxide and stirred for 8 hours at room temperature. The solution was concentrated in vacuo and water added. The mixture was extracted with ether; the aqueous layer was acidified to pH 4 with 1N H3P04, and the product was purified by preparative HPLC. 1H NMR (CD30D, 300 MHz) 8 0.88 J=7 Hz, 3H), 1.15-1.45 4H), 3.40-4.20 14H), 5.97 2H), 6.82 J=8 Hz, 1H), 6.88 (dd, J=8 Hz, 1H), 6.97-7.20 7.40 J=9 Hz, 2H), 7.56 J=5 Hz, 2H). MS (DCI/NH3) at m/e 560 (M+H) Anal calcd for C32H37N306*4.2 TFA: C, 46.72; H, 4.00; N, 4.05.

Found: C, 46.66; H, 4.06; N, 4.00.

WO 99/06397 WO 9906397PCT/US98II 5479 c-I -481- Examlle 533 trans, trans-2-(4-Methoxy henyl).4-( 1 3-bendoxl5y-I butyl-N-( 3 -tri mgth ylamm on i oethyl Dhenyl~a m!no) arbo ny m eth yl..

0 5 p2yrrolidine-3-carboxylic acid To a stirred solution of 0.128 gm of the compound of Example 532C in 0.5 ml methanol, 0.25 ml of an aqueous sol ution of tnimethylamine was added. The mixture was allowed to stir at room c0 temperature under nitrogen atmosphere for 4 hours. 1 N HCI was added; the aqueous was washed with'ether to extract organic impurities. The aqueous layer was dried azeotropically with toluene, and the. residue was dried under high vacuum. Yield 0. 115 gin. 1H NMR (300 MHz, D6- 8 0.83 J=7 Hz, 3H), 1.15-1.40 (in, 4H), 2.62 2H), 3.35 (s, 9H), 3.40-3.80 (in, 1OH), 4.47 2H), 6.00 J=3 Hz, 2H), 6.75-6.90 (in, 3H), 7.25-7.37 (in, 2H), 7.45-7.60 (in, 3H). MS (DCIINH3) at W/e 602 Example 534 2

R.

3 R.4S2)-2-(3-Fluoro-4-methoxylhenyl.4.( 1 .3--benzodioxol-5-yl) 1- L-(N-oropyl- N-pentanes ulf onyl amino) ethvi)-pyrrol idine.3.carbpxyllc acid Example' 534A Ethyl (34f luogro-4-m ethoxy)benzoyl acetate Sodium hydride (17g of a 60% suspension in mineral oil) is washed three times with toluene. The powder is suspended in 138 mL of toluene, and 35 mL of diethyl carbonate is added. The mixture is heated to 90 IOC, and a solution of 25 g o f 3-fluoro-4methoxyacetophenone and 50 ml of diethyl carbonate in 50 ml of toluene was added portionwise. Heating is continued for 30 min, then the reaction is cooled to room temperature. A solution of 50. ml of concentrated HCI in 75 ml of ice water is added slowly, and the mixture is stirred. The mixture is extracted with* toluene; the combined organic extracts are washed with brine and bicarbonate solutions. The product

I

WO 99/06397 PCT/US98/15479 -482is dried over Na2SO4 and decolorized with charcoal to give 34.5 g (97%) S of the title compound.

D Example 534B Ethyl 2-(3-Fluoro-4-methoxyphenvyl-4-(1.3-benzodioxol-5-vl)pyrrolidine-3-carboxylate SThe compound of Example 534A (12.5 g) and 5-(nitrovinyl)-1,3benzodioxole (13.1 g, 20% excess) were suspended in a mixture of 75 ml of THF and 13 ml of iPrOH. DBU (0.25 g) was added, and the mixture was stirred at room temperature for 30 min. An additional 0.1 g of DBU was added, and the solution was stirred for 1 hour. The solvents were removed in vacuo; toluene was added, along with brine containing 3 ml of concentrated HCI. The mixture was extracted twice with toluene; s1 the organics were dried over MgSO4. The residue was flashed on silica, using CH2CI2 to elute. Yield 75%. This material (17.4 g) is combined with 35 g of Raney Nickel (washed) in 250 mL of EtOAc.. The mixture is shaken under 4 atm of hydrogen for 18 hours. The solution is concentrated in vacuo; the residue is chromatographed on silica, eluting with 4% EtOAc in CH2CI2. Yield 10.13 g 66%. The product is combined with 26 ml of THF and 50 ml of EtOH; 2.18 g of NaBH3CN are added, along with a trace of bromcresol green as indicator. A solution of 1:2 concentrated HCI/EtOH is added dropwise to maintain pH at greenyellow; after color persists, the reaction mixture is stirred for an additional 20 min. The solvents are removed in vacuo; the residue is stirred with mixture of toluene and KHCO3 solution. The organic phase is washed with water and brine, and dried over MgSO4. The crude product is purified by flash chromatography on silica, eluting with 2:1 EtOAc/hexanes. Yield 5.92 g of a 2:1 mixture of trans-trans and cis-trans isomers.

WO 99/06397 PCT/US98/15479 N -483- SExample 534C Ethyl (2R.3R.4S-2-(3-Fluoro-4-methoxyphenyl)-4-(.3-benzodioxol- 5-yl)-Dyrrolidine-3-carboxylate To the racemic amino ester above (15.0 g, 38.8 mmol), dissolved in 75 ml methylene chloride and cooled in an ice bath, was added Boc anhydride (9.30 g, 42.7 mmol). After stirring 2 hours at room temperature, the solution was concentrated in vacuo the residue was dissolved in 50 ml ethanol and treated with a solution of 3.75 g sodium S hyroxide in 19 ml water. The solution was warmed until all was soluble. After stirring for 2 hours at room temperature, the solution was concentrated and redissolved in 200 ml of water. This was extracted with 75 ml of diethyl ether. The ether layer was extracted with 40 ml of water. The combined aqueous phases were acidified with 7.5 g acetic acid; the mixture was stirred until a solid formed. The solid was filtered, washed with water and dissolved in methylene chloride. After drying with sodium sulfate, the solution was concentrated and the residue crystallized from 1:1 ether:hexane to get 15.99 g of product, m.p. 200-203 (90% yield). The crude acid was suspended in 80 ml ethyl acetate and treated with 4.00 g (33.1 mmol) of (S)-(-)-a-methylbenzylamine. After heating to dissolve the acid, ml of ether was added. Scratching with a glass rod caused the product to crystallize. The solids were filtered and washed with ether-ethyl acetate solution to give 8.22 g (81% yield based on 50% maximum recovery) of salt, m.p. 165-1680C. After one recrystallization, chiral HPLC analysis, using a Regis Whelk-O column, indicated >99.5 e.e.

The salt was dissolved in 500 ml of 36% HCI in ethanol; a white solid forms. The resultant suspension was heated for 16 hours at 520C.

After concentrating in vacuo, the residue was combined with toluene and stirred with potassium bicarbonate in water for 30 minutes. The toluene was separated, dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel, eluting with 33% hexane-67% ethyl acetate to get 6.9 g of the resolved amino ester.

I

WO 99/06397 PCT/US98/15479 S-484- Example 534D Ethyl (2R.3R4S)-2-(3-Fluoro-4-methoxyphenvl)- 4 -(1.3-benzodioxol- 5-yl)1-(2-(N-Dropylamino)ethyl)-pyrrolidine-3-carboxylate The compound of Example 534C was dissolved in 1,2dibromoethane 10 mL per 1. g of starting material diisopropylethylamine (1 mL per 1 g of starting material and Nal 100 mg per 1 g of starting material) were added, and the mixture was stirred at 100°C for 1 hour. Toluene was added, and the mixture was washed with bicarbonate. The solvents were concentrated, and the resultant black residue was chromatographed on silica gel, eluting with 4:1 hexane-EtOAc to give the N-(2-bromoethyl)pyrrolidine (85-92%).

This compound was combined with n-propylamine (3.5 eq.) and Nal by weight of bromide) in ethanol 5 mL per 1 g of bromide), and was heated at 800C for 2 hours. Toluene was added, and the mixture was washed with bicarbonate, dried (Na2SO4), and concentrated. More toluene was added, and removed in vacuo, to get rid of the primary amine. The residue was dissolved in heptane and filtered to remove a small amount of insoluble material. Evaporation of the solvent gave the desired product (86-93% yield), which was used for the next step without further purification.

Example 534E 1-Pentanesulfonyl chloride 1-Pentanesulfonic acid, sodium salt (10 g, 57.5 mmol) was charged into a 250 ml round bottom flask (allow headroom). Thionyl chloride (20 mL) is added; gas evolves, and a while solid forms. The mixture is heated at 60 °C for 3 hours. The solvents are removed in vacuo; toluene is added and removed in vacuo to remove residue of SOC12. The residue is partitioned between CH2CI2 and ice water; the organic layer is dried over Na2SO4 The crude product is purified by distillation (bp 54-56 OC 0.5 mm Hg) to give a clear oil, 61% yield.

I

WO 99/06397 PCT/US98/15479 1 -485- SExample 534F (2R.3R.4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl 1- (2-(N-Dropyl-N-Dentanesulfonylamino)ethyl)-pyrrolidine-3-carboxyli acid The compound of Example 534D (200 mg, 0.43 mmol) was dissolved in 5 mL of CH3CN; 110 mg (2 eq) of N,N- S diisopropylethylamine and 72.8 mg (1.2 eq) of 1-pentanesulfonyl S chloride were added sequentially, the resultant solution was allowed to stir at room temperature for 30 min. The solvint was evaporated under reduced pressure and the residue was dissolved in EtOAc. The solution was washed with saturated NaHCO3 solution, 1N H3P04, and brine, dried over Na2SO4 and evaporated to give a yellowish oil which was purified by flash chromatography on silica gel eluting with EtOAc/hexane to give 220 mg of product This ester was dissolved in 5 mL of EtOH, to which was added NaOH (46 mg, 3 eq) solution in 2 mL of H20. This mixture was stirred for 3 hours at room temperature. The solution was-concentrated in vacuo using low (<400C) heat. Water (10 mL) and ether (50 mL) were added; the ether layer was extracted with 5 mL of water. The combined aqueous mixture was back-extracted with ether and then neutralized with acetic acid. This solution was extracted twice with ether. The ether was dried (Na2SO4) and concentrated in vacuo. EtOAc (1 mL) and ether (1 mL) were added to dissolve the product, and hexane was added dropwise to produce a white solid. The solid was collected and dried in vacuo to give 125 mg of the title compound.

Example 534H (2R.3R.4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl) (2-(N-propyl-N-pentanesulfonylamino)ethylv-pyrrolidine-3-carboxylic acid, hydrochloride salt The free amine is dissolved in iPrOH; a slight excess of HCI in iPrOH is. added, and the solution is concentrated in vacuo. More IPA is added, and the solution is reconcentrated. The resultant sticky WO 99/06397 PCT/US98/15479 -486material is stirred with ether overnight to give a white powder, which is collected by filtration and dried overnight in vacuo at 60 Yield Example 535 The compounds in Table 3C may be prepared using methods presented in the above Examples.

Table 3C.

1 2 HO NCOOH O N eCOOH 0

O

WO 99/06397 WO 9906397PCT/US98/15479 487 6 -COOH N 11C 7 NW N. Th N'q 9~

MZC

I

Wo 99/06397 WO 9906397PCT/JS98II 5479 488 13 14 -"COOH$0 16 WO 99/06397 WO 9906397PCT/US98115479 489

H

2 trN WO 99/06397 WO 9906397PCTIUS98/15479 -490 26

CH

28 32

H

2 NeN.

WO 99/06397 wo 9906397PCT1UJS98/15479 -491- 34 Hie 39 WO 99/06397 WO 9906397PCTIUS98/1 5479 492 *42 44 0 WO 99/06397 WO 9906397PCT/US98/15479 493.

-I

H2N

N,

WO 99/06397 WO 9906397PCT/US98/15479 -494- H2Nfl$N loCOOH 00 0 C0

CH

3 64 0

II"COOH

0 WO 99/06397 WO 9906397PCT/US98/15479 495

N'

N~N.

Wo 99/06397 WO 9906397PCT/US98/15479 496

H

2

N~~N.

I H2 ~~0 WO 99/06397 PCT/US98/15479 -497- 82 83 IN 40ICOOH N 84 uOOH HNN~.

86 87 0..O 0~ WO 99/06397 WO 9906397pCT/U5S98/15479 498 'N1Th ".oN 96 WO 99/06397 PCTIUS98/15479 499.

98 99 100 101 -eCOO

*ICOOH

0 0

CH

3 0 102 103 HO .l 10410 105 PCT/US98J11 4 7 9 WO 99/06397 500 106 109 108 N )rN

,COOH

0

CH

3 i 110 I 0 ci 112 r4 PCT/US98/I 5479 WO 99/06397 -501 114 115 HNN.,~COOH *rN.COOH

CH

3 CH 116 117 Q .sCOOH

*.CO

0 118 119 120 WO 99/06397 PTU9/57 PCT/US98/15479 502 122 123 124 125 126 128 129 PCTIUS9811 5479 WO 99/06397 503 130 131 N ICOH s 132 133 HO.CNr 0

J.

134 135 ,"COOH 2

N

136 137 WO 99/06397PCUS8I57 PCT/US98/15479 504 138 139 H24I-COOHI 140 141 iCOOHI e 142 143 N 2 144 145 PCT[US98115479 wo 99/06397 505 146 149 148 150 152 153 0 I PCTIUS98/1 5479 WO 99/06397 506 154 155 157 156 159 157 160 WO 99/06397 PCT/US98/1 5479 507- 162 163 164 165 166 167 16816 169 WO 99/06397 PCT/U598/15479 508 170 171 uGOOH 172 173 N H 2

N

N *ssCOOH 174 175

NN

*.COOH

176 177 N iCOOHH 2

N.-

0 WO 99/06397 PCT/US98/I 5479 509 178 179 181 180 182 183 185 18418 WO 99/06397PCUS8147 PCT/US98/15479 -510- 186 187 .uCOOH 00

CH

3

M

190 191 19219 193 PCT/US98/15479 WO 99/06397 -511- 194 195 196* 197 198 200 199 201 PCTIUS98/1 5479 WO 99/06397 -512- 202 203 N "ICOOH 0 206 207 00

I..'COOH

208 209 PCTJUS98II 5479 WO 99/06397 -513- 210 211 I

'COOH

0 214 213 216 217 PCTIUS98/1 5479 Wo 99/06397 -514- 218 219 221 220 223 222 224 225 PCTIUS98/1 5479 WO 99/ 06397 -515- 226 227 228 229 230 231 23223 233 PCT/US98/15479 WO 99/06397 -516- 234 235 c:OOH 0 CH CI 236 237 22 I COH 0 0 0 CH

-C

240 241 N, *.sC0 WO 99/06397 PCTIUS98/1 5479 -517.

242 243 244 245 246 247 24824 249 PCT/U598/1 5479 WO 99/06397 -518- 250 251 252 253 254 255

-%I

25625 257 PCTIUS98/1 5479 WO 99/06397 -519- 258 259 0 u6COOH 260 261 *"iCOOH 262 263

.ICOOH

264 265 ,N.Th N-woo

,OW'

PCTIUS98/15479 WO 99/06397 520 266 267 268 269 270 271 27227 27 PCT/US98/1547 9 wo 99/06397 -521- 275 274 276 277 278 279 280 281 PCT/US98/154 7 9 WO 99/06397 522 282 283 284 285 286 287 H2N.I-V, ~N4~NI 289 288

N

PCT[Us98/1 5479 Wo 99/06397 523 291 290 0 293 292 295 294 296 297 N PCT/US98/1 5479 WO 99/06397 524 298 299 300 301 .eCOOH HN0* 302 303 30430

CH:

pCTIUS98/I 5479 Wo 99/06397 525 307 306 309 308 311 310 313 312 N

N.

0 ~1 pCTIUS98/15 4 7 9 WO 99/06397 526 315 314 317 316 318 319

H:

HC

321 320 PCT/US98/I 5479 WO 99/06397 527 323 322 0

CH

0 324 325

CH

3 H2N-- Y-'N COOH 327 326 328 329

I

.N

I

PCT/US98115 479 wo 99/06397 528 330 331 CH3 H2 .4COOH CHf 3 33233

H

3 ~yN *.iCOOH F 334 335 337 336 WO 99/06397 PCTIUS981 15479 529 338 339 340 341 0 *.sCOOH 342 343 34434 345 PCT/U598/1 5479 WO 99/06397 -530- 347 346 348 aCOOH 350

OCH

3 H2N -r N ,ICOOM 352

QOCH

3 ~N .400H 349

QOCH

3 0 *.nCOOH 351 353 PCT/US98/15479 WO 99/06397 -531- 355 354 357 356 4e 358 359 P-10CH3 360 H3 Of -r N

ICO(OH

0 .,i 361 *4iOOOH

CH

3 PCT/US98/I 5479 WO 99/06397 532 362 363 364 365 366 367

*"ICOOH

0 CH- 3 368 )jo' N

-"COOH

0

CH

3 1 369 PCTIUS98/1 5479 WO 99/06397 -533 371 370 372 373 374 375 9 bCH3 >rdNfN~rN

.I'COOH

C H4 3 377 376 PCTIUS98/15479 WO 99/06397 534 378 379 380 381

H

2

N..N

382 383

.ICOOH

385 384

I

PCTIUS98/1 5479 WO 99/06397 -535- 386 387 0

H

NN

4 0~a00H L~ 388 389 N ICOOH 39039 39039 393 392 pCTIUS98/I 5479 WO 99/06397 -536 395 394 397 396 399 398

H

2

N-

401 400 pCTIUS98/154 7 9 WO 99/06397 -537 402 403 0

"COOHH

N(3 H2N--aa 0

OO

01 cl-I 3 0 PCT/US98/15479 WO 99/06397 538- 411 410 412 CH 3 0 413 0

CH

3 -i 414 415 N N 0

H

2 N DI O I 417 416 WO 99/06397PCIS/I57 PCTIUS98/15479 539- 418 419 420 421 422 423 42442 425 WO 99/06397PC/S8157 PCT/US98/15479 540 427 426 428 429 HW__

N

430 431 432 433

N

+Nf PCTIUS98/1 5479 WO 99/06397 541- 434 435 437 436 438 439 441 440 PCT/US98/I 5479 Wo 99/06397 542 442 *.nCOO)H 443 444 445 446 447

.COOH

449 448 WO 99/06397 PTU9/57 PCTIUS98/15479 450 543 451 -N *"'COOH CH 3

M

453 452 454 455 0 457 456 t wo 99/06397 PCT/US98/15479 544 460

QO

I 0

CH

3 459

NO

H

2 Noo *"aiCOO IH 0 CH 3 0 463 462 464 465 -N 0

CH

3 a o'- PCT/US98/I 5479 WO 99/06397 545 467 466 N-A {N *sCOOH 468 469 470 471 472 473 'N~ N~I PCTIUS98/15479 Wo 99/06397 546 474 475 477 476 N+1 479 478 481 480 PCTIUS98/15 479 Wo 99/06397 547 482 483 HoN.,,% 1 485 484 487 486 488 489 H2N PCT/US98/I 5479 WO 99/06397 548 490 491 *'dCOOH 492 493 No N .1'nCOOH COO OO 496 497 WO 99/06397 PCTIUJS98/I 5479 549 498 499 Ho N, 500 501 502 503 504 505

CH

3

-O

WO 99/06397 PCTIUS98/15479 550 506 507 508 509 510 511 512

F

513 N~N-h .uCOOIH 0O PcTIUS98/I 5479 Wo 99/06397 -551- 515 514 517 516 518 519 521 520 PCT/US98/15479 WO 99/06397 552- 523 522 524 H2C COOH 525 527 526 528 529 Th N PCT[US98/15479 WO 99/06397 530 553 531 532 533 534 535 53653 537 PCT/US98/1 5479 Wo 99/06397 554- 538 539

H

2 541 540 Ni 543 542 545 544 PCT/US98/15479 WO 99/06397 555 547 546 548 549

IN

551 550 552 553 PCTIUS98/1 5479 Wo 99/06397 556 54 555 01Q 0

-COOH

CH

556 557

O.COOH$C

558 559 560 PCTIUS98/1 5479 WO 99/06397 557 562 563 564 565 567 566 iGsOOH

,CO

NC),oN I 569 568 PCTIUS98/I 5479 WO 99/06397 558 571 570 Y%%C~N~rN iCOOH 573 572 575 574 577 576 0

.COOH

WO 99/06397 PCT/US98/15479 559 578 -uCOOH 579 580 581 582 583 584 585 PCTIUS98/1 5479 WO 99/06397 560 586 587 589 588

.COOH

CH

3 591 590 593 592

NT

CH

3 U 0w- PCTJUS98/I 5479 Wo 99/06397 561 595 594 597 596 599 598 H2N~ 601 600 lICOOH 7QHM, -j PCT/US98/I 5479 WO 99/06397 562 602 603 604 605 -11h 606 607 H N, 609 608 WO 99/06397 PCT/US98/1 5479 -563- 610 611 612 613 o N

*..COOH

0 614 615

N~N

00

ICMI

614 615 #9~,W PCT/US98/1 5479 WO 99/06397 564 618

H

2

.'COOH

620 .4'COOH 619 621 622 623 624 625 *mcQO WO 99/06397 WO 9906397PCT/US98/I 5479 565 626 627

HIICOOH

628 629 <CO0 00 630 631 N 0

-COOH

CH3.

632 633 CLO

*N

WO 99/06397 PCT/US98/15479 634 566- 635 636

CH

3 638 410 640 637 @0 00

CH

3 j 639 0 0.1~ N *"COOH CCH0 641 @0o Nk PCTIUS98/1547 9 Wo 99/06397 567 643 642 645 644 646 647 649 648 WO 99/06397 PCTIUS98/15479 -568- 650 651 0 652 653 654 655 Q0 0 657 656 PCT/US98/ 54'79 Wo 99/06397 658 569 659

.*COOH

0 ~T0 661 660 $JII~N g0

H"N.

663 662 664 665 ~~.1'ICOOH 00 PCTIUS98/15479 WO 99/06397 .570- 666 668 667 H2-Th 669 671 67.0 672 673

"'ICOOH

0 0 PCTIUS98/15479 WO 99/06397 -571- 674 675 676 0u00

CH

3 *Co 678 CHI3 680 *suCOOI-

CH

3 j 677

OICOOH

0

CH

3

C

679 681 pCTIUS98/1 5479 Wo 99/06397 572 682 683 685 684 r *461COOH I N

CH

3 686 I ,C(OOH C H 3 r Nt 687 688 689

*.'COOIH

0 PCT/US98/1547 9 wo 99/06397 573- 690 691 692 693 694 695 69669 697 PCT/US98/15479 WO 99/06397 574 698 I .eiaCO0 699 701 700 702 703 705 704

COOH

0 0-- 17.MAR.2005 17:09 wo 99106397 SPRUSON FERGUSON 61 2 92615486 .575-.

707 706 HOfl.

708 710 712 PCTIUS98/15479 WO 99/06397 576 714 715.

716 717 719 718 721 720 F loo

N

PCTJUS98/1547 9 WO 99/06397 722 577 723 724 725 H9~-~N 726 727 PCTfUS98/1547 9 WO 99/06397 -578- 728 729

-I

731 730 733 732 H2N.

735 734 0 PCT/LJS98/I 5479 WO 99/06397 579 737 736 738 H2N-I

'COOIH

740 739 741 742 .1

'OO

743 PCTIUS98/15 479 wo 99/06397 744 746 580 745 747 749 748 750 751 PCT/US98/154 7 9 WO 99/06397 581 752 753

H

2 755 754 756 757 759 758 PCTIUS98/15479 WO 99/06397 582 761 760 762 763

.,N

765 764 767 766

I

WO 99/06397 PTU9/57 PCT/US98/15479 583 768 0 770 769 0

CH

3 771 0

CH

3 772 773 774 775 (N 00 0

"COOH

CH3O 0 WO 99/06397 PCTfUS98/15479 584 776 777 H H2.COOH

CH

3

-H

7780 781 COH HO N ."iCOH 783 782 PCT/US98/15479 WO 99/06397 585 785 784 786 788 790 787 Hie 789 791 PCT/US98/15479 WO 99/06397 -586 792 N 0O 794 793 795

F~X~

796 797 798 799 H2N pCT/US98/15479 WO 99/06397 587 800 9 N 0 802 801 803 804 805 806 807 TH2N-, WO 99/06397 PTU9/57 PCTIUS98/15479 588 808 809 810 812 814 811 .'iCOOH 0

CH

813 0 H2N~~ 1

.COOH

00

CH

3 815 (0/ 00 00

OH

3 WO 99/06397 PTU9/57 PCT/US98/15479 589 816 817 *"4COH

H

2

NN

818 CH819 I 6 .nCOOH 820 CH 3 82 8220H 821 OH3 WO 99/06397 PTU9/57 PCTIUS98/15479 590 824 826 825 827 829 828 83083 831 PCTIUS98/1 5479 WO 99/06397 591 832 833 H2N--- 834 835 836 837 H2 IIII-V 838 N o

*'UCOOH

00 839 WO 99/06397 PCT/US98/15479 -592- 840 841- 0 842 843 .aCOOH H2N-- 844 845 84684 847 WO 99/06397 PTU9/57 PCT/US98/15479 848 593 849 851 850 852 853 85485 855 WO 99/06397 PCTIUS98/1 5479 -594- 856 857 858 859

H~N~N

860 861 86286 863 WO 99/06397PCIS8157 PCTIUS98/15479 595 864 865 866 867 868 869 870 871

FVO

HO,.

PCT/US98/1 5479 WO 99/06397 -596- 872 873 874 875 877 876 I..I 878 879 N IN' -:~hzi~IICOOHr WO 99/06397 PCT/US98/15479 597 880 881 882 883 88485 (1 N

NCO

88687 WO 99/06397PCIS8157 PCTIUS98/15479 598 888 889 890 891 892 893

N"'

894 895

N,

PCT/US98/1 5479 WO 99/06397 599 896 897 898 899 900 0 0

CH

3 902 901 903 WO 99/06397 PCT/US9SII 5479 600 904 905 906 908 907 0' CH, 4 909 91091 911 PcTIUS98/I 5479 WO 99/06397 601 912 913 914 915 916 917 91891 919 PCTIUS98/I 5479 Wo 99/06397 602 920 922 921 923 924 925 92692 927 PCT/US98/1 5479 Wo 99/06397 603 928 929 *u-COOH 0 930 931 932 0 0 .0glCOOH 933 H2N-I l 934 935 00 PCTIUS98/I 5479 WO 99/06397 604 936 uo 937 938 939 940 941 943 942 PCTIUS98/I 5479 WO 99/06397 605 944 945 946 947 948 949 950 1""COOH

CH

3 951 WO 99/06397 WO 9906397PCTUS98/ 5479 606 95295 0 "0

CH,

954 955 ""1COOH

N

CH

95695

"A

0 aC0OH

HN"

CH

3 95895 "0

CH

3 WO 99/06397PC I S8I57 PCTIUS98/15479 607 961 960 962 963

H

2

N~-

964 965 "'1COOH 967

<A

0 H2 -*viCOOH 966

I

PCTIUS98/1 5479 WO 99/06397 -608- 968 969 I ~eICOOH 970 971 .0"gCOOH+ 972 973 974 975 PCTIUS98/1 5479 Wo 99/06397 .609 976 978 HX'-

.'COOH

980 977 979

H

2 I .9SICOOH 981 982 983

*-N

0

'COOH

0 PCTIUS98II 5479 WO 99/06397 610 984 985 986 987 988 989 990

.COOH

0

OH

3 991

*.'COOH

OH

3 PCT/US98/1 5479 WO 99/06397 -611- 99293

*"COOH

CH

3 C3 996,99 998 998 999 WO 99/06397 -612- 1000 1001 N~yoN uCOOH+ 1002 1003 00

CH

3 04 1005 N~Vto 0

"COOH

1006 1007 PCTIUS98/1 5479 PCT/US98/I 5479 WO 99/06397 -613- 1008 1009 1010 1011

I

1012 1013 1014 11 1015 PCTIUS98/1 5479 WO 99/06397 -614- 1016 1017 1018 1019 1020 1021 -Th-

"-ICOOH

0 0 0- 1022 12 1023 PCTIUS98/1 5479 WO 99/06397 615- 1024 1025

COOH

1026 1027

H

2 NN A N sccH ll 0 1028 1029 1030 13 1031 PCTIUS98/I 5479 Wo 99/06397 -616- 1032 1033

-I

CH

3 1034 1035 1036 1037 H2 N )rN

.COOH

0

I

0

CH

3 0 1038 1039 0 PCTIUS98/1 5479 WO 99/06397 -617- 1040 k~tloo% N

'COOH

0

CH

3 1042 1041

H

2 N N "<NN .0s'OH 0 CH3 1043 1044 1045 1046 1047 PCTIUS98/1 5479 WO 99/06397 618- 1049 1048 1051 1050 0 1053 1052 1055 1054 PCTJUS98/1 5479 WO 99/06397 -619- 1056' 1057 1059 1058 1061 1060 1063 1062 PCTIUS98/1 5479 WO 99/ 06397 620 1064 1065 1066 1067 1069 1068 1071 1070 PCT/U598/1 5479 WO 99/06397 621 1072 1073 1074 1076 1075 1077 1078 1079 .mCOOH

CH

WO 99/06397 PCTIUS98/1 5479 622 1080 1081 00 3 CH3 1082 18 H2N 2 fl"N .COOH IICO 0 0 0 C H CH 3 1084 18 1 A7- N

NN

IJ

.,NN

.COOH

."'COOH N

.I

PCTIUS98/1 5479 WO 99/06397 623 1088 1089

N

N, )ro" N "ICOOH 0I 01%

CH

3 1090 1091 1-k N N, *"'COOH 2 CH3 1092 1093

N

C

3 1094 1095 Wo 99/06397 PCT/US98/1 5479 624 1097 1096 0 1098 1099 0 1101 1100 I 1102 1103 WO 99/06397PCIS/157 PCT/US98/15479 625 1104 1105 NI "'k 1106 1107 1108 1109 1110 11 lill WO 99/06397 PCTIUS98/1 5479 626 1112 1113 1114 1115 1116 1117 H N ~N, 1118 11 1119 Nr PCTIUS98/15479 WO 99/06397 627 1120 1121 1122 1123 1124 1125 1126 12 1127 PCTIUS98/1 5479 Wo 99/06397 628 1128 1129 1131 1130

-N

I'tCOOH 0 0

CH

3 1132

N

CH

H2N.,,

N,

1133

-N

'J'N

*"'COOH

0

CH

3 1135 1134 WO 99/06397PCIS8I47 PCTIUS98/15479 629 1136 1137 1138 1139 1140 1141 1142 14 1143 PCTLJS98/1 5479 WO 99/06397 630 1144 1145 0 1147 1146 1148 1149 1150 1151 PCTIUS98/1 5479 WO 99/06397 631 1152 1153 1154 1155 HO,,h 1156 1157 1158 1159 r 0 WO 99/06397PCUS/157 PCT/US98/15479 632- 1160 00 1161 1162 1163 1164 1165 1166 1167

-N

.COOH

PCTIUS98/15479 WO 99/06397 633 1168 1170 1169 1171 1172 1173 1174 17 1175 PCTIUS98/1 5479 WO 99/06397 .634 1176 1177 1178 1179

N~T

1181 1180 1183 1182 PCTUS98/15479 WO 99/06397 635 1184 -1185

-N

.SCOOH

1188 1189 1190 19 1191 PCTIUS98/1 5479 Wo 99/06397 636 1192 1193 1194 1195 1196 1197 1198 1199

-N

iiCOOH 0 PCTIUS98/15 479 WO 99/06397 .637 1200 1201 HO,, A 1202 1203 1204 1205 1206 1207 H2

N.

Wo 99/06397 PCT/US98/15479 638 1208 1209

N

12100 121 1212 1213

N

0 1214 1215

-N

FACJ

COOH

0H PCTIUS98/1 5479 WO 99/06397 639 1216 1217 1218 1219 1220 1221 1222 0

CH

1223 0 PCTIUS98/1 5479 WO 99/06397 -640- 1224 1225 1226 1227 1228 1229 1230 1231 0 PCT/US98/15479 WO 99/06397 641 1232 1233 1234 1235 1236 1237

"N

I

1238 13 1239 WO 99/06397 PCT/US98/15479 642 1240 1241 1242 1243 1244 1245 1246 1247

I

WO 99/06397 PCT/US98/1 5479 643 1248 1249 1250 1251 1252 1253 1254 1255 Nt PCT/US598115479 WO 99/06397 644- 1256 1257 1258

-N

CH-

3 1259

OH

.1260 1261 1262 16 1263 PCTIUS98/1547 9 Wo 99/06397 645 1264 1265 1266 1267

-N

I

1268 1269

N

1270 17 1271 PCT/US98/15479 WO 99/06397 .646- 1272 1273 >rIQ- %j(N .uCOOH N~A~

CH

1274 1275 'mCOOH H .N 1276 1277 0 0 1278 1279 H.N N N, N PCTIUS98/1 5479 WO 99/06397 647 1280 1281 1282 1283 Ne 1284 1285

N

1286 18 1287 PCT/US98/1 5479 WO 99/06397 .M4- 1288 1289 1290 ~rr~N *s'COOH 0 1292 H~N~jOO 1291 1293 1294 19 1295 PCTIUS98/1 5479 Wo 99/06397 649 1296 1297

H

2 N# .IICOOH I01c

-CO

1298 1299 .uCOOH N .uCOOH 1300 1301 00 1302 1303 0 WO 99/06397 PCT/US98/1 5479 -650- 1304 1305 -$1 1306 1307 H2N 1308 1309 1310 1311 NTh H2N--- PCT/US98/1 5479 Wo 99/06397 -651- 1312 1313 1314 1315 1316 1317 1318 11 1319 WO 99/06397PCUS/I57 PCT[US98/15479 652 1320 0 -s o 1322

H

2 N 1324 N% loco( 1326 1321 1323 1325 1327 WO 99/06397PC/S8I57 PCT[US98/15479 653 1329 1328 1330 1331 H2NOOO'-V' 1332 1333 1334 13 1335 Wo 99/06397 PCTIUS98/15479 654- 1337 1336 ~Th 1338 1340 1339 1341 1343 1342 WO 99/06397 PTU9/57 PCT/US98/15479 655 1344. 1345

."C

0 1346 1347

N

NN

C 0 CH3 1350 1351 -Th NcTh

H

2 N~N.f(%N o WO 99/06397 PCTJLJS98/15479 656 1352 1353 N .COOH 0

CHC

1355 H 2N,, N foo .sI're 1354 1356 1357 1358 1359 WO 99/06397PC/S8147 PCT/US98/15479 1360 657 1361 1363 1362 1364 1365 1367 1366 WO 99/06397 PTU9/57 PCTIUS98/15479 -658- 1368 1369 N sCOOH 1370 1371 H N% N N *'nICOOH

N

1372 1373 0 *"COOH Ir 1374 17 1375 WO 99/06397PCUS8I47 PCT/US98/15479 659 1376 1377 1378 1379 1380 1381 1382 1383

.N

WO 99/06397 PT1S8I57 PCT/US98115479 .660- 1384 1385 1386 1387 1388 1389 1390 1391

O.COOH'

PCTIUS98/1 5479 WO 99/06397 661 1392 1393

N

CH

3 1394 1395 0 8"COOH

CH

3 3 1396 1397 1398 1399 WO 99/06397 PTU9/57 PCTIUS98/15479 662 1400 1401 1402 1403 1404 1405 1406 1407 PCTIUS98/15479 WO 99/06397 663 1408 1409 'r N aOOOH 1410 1411

NQI

1412 1413

.,COQH

1414 1415

OON

WO 99/06397pC/S8I57 PcTIUS98/15479 664 1416 1417

N+,

1418 1419 1420 1421 1422 12 1423 PCTIUS98/15479 WO 99/06397 665 1424 1425 1426 1427

,ICOOH

00 1429 1428

,N

1430 13 1431 WO 99/06397 PCT/US98/15479 666 1432 1433

N

N, ICO N COOH 0 .COH0

CH

0 0 1434 1435 N

N

N

N

.COOH H2NN .iCO 0

O

1436 143 1438 13 1439 WO 99/06397PC/S/I57 PCT/US98/15479 667 1440 1441N N-111* r N, r N .#IC OH 2N -90 N .,iCOOH 0"CO 0 0

CH

3 CH 3 1442 1443N 0 0 CHj l CH 1444 1445 1446 14 1447 WO 99/06397 PTU9/57 PCTIVS98/15479 668 1448 1449 1450 1451 1452

\N

0 .1CO 1453 F

.COOH

1455

N

-Th N *.0OI 1454 PCTIUS98/1 5479 WO 99/06397 669 1456 1457 1458 1459

N

.%COOH

0 1461 *'asCOOH 0 1460 1462 1463 PCTIUS98/1 5479 WO 99/06397 670 1464 1465 1466N N 'rN *,ujCOOH 1467 1468 1470 1469 1471 PCT/US98/I 5479 WO 99/06397 -671- 1473 1472 1474 1475 1477 1476 1478 17 1479

N

.N

WO 99/06397 PCTIUS98/1 5479 672- 1480 1481 1482 1483 1484 1485 1486 18 1487 PCT/US98/15 479 Wo 99/06397-63 .673- 1488 1489 0

.,C=OH

00

CH

3 j 1490 Q1491 62., Ir

CH

3 1492 1493 1495 1494 PCTIUS98/1 5479 wo 99/06397 674 1496 1497 1498 1599 1500 1501 0 1502 1503 I PCTIUS98/1 5479 Wo 99/06397 675 1504 1505 1506 1507 1508 1509

>N

1510 1511 WO 99/06397 PCT/US98/15479 676 1512 1513 1514 1515 0 1516 1517 1518

,N

1519 PCT/US98/1 5479 Wo 99/06397 677 1520

H

2

N'

1522 1521 1523 1524 1525 1526 1527 WO 99/06397 PTU9/57 PCT/US98/15479 *-678- 1528 1529 CH

CH

"U1COOH 0

CH

3

CH

3 1530 1531

CH

3

CH

3

CH;

3

CH

3 cH 3 H3 1534 13 1534 pCTIUS98/1 5479 Wo 99/06397 679 1536 1537 1538 1539

N

I a: 1540 1541 1542 14 1543 WO 99/06397 PCTIUS98/15479 -680- 1544 1545

CH

1645 1647

CH

3 N *suoCOOH 02, e,, 1548 14

CH

-s.COOH 0 1550

CH

WO 99/06397 -681- 1552 1553

CH

3 tieCOOH 1554 1555

CH

3 1556 1557

CH

3 I 'r 1 L.J.

ICOOH

PCT/US98/1 5479 1558 1559 WO 99/06397 CIS/157 PCTIUS98/15479 -682- 1560 15610 *'CCOH iCMOOH 00 1562 1563 0cr 0 HN- Nr N .OOH

N'.'COOH

1564 1565 1566 16 1567 WO 99/06397 WO 9906397PCTIUS98/15479 683 1568 1569 I r N N -COO HN 1570 1571 0 H2N r .,crO 0 1572 1573 0~

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3 1574 1575 au N "COOH

N~~

0 cr 0 WO 99/06397PCUS8147 PCTIUS98/15479 684 1576 1577

(X

H

2 NOO4 1

N

1 r o"iGOOH 2N.e 00

CH

3 1578 1579 0N 0 0

CH

3 1580 1581 1582 18 1583 WO 99/06397PCUS/147 PCT/US98/15479 -685- 1584 1585 1586 1587 1588 1589 1590 19 1591 WO 99/06397PC/S8147 PCT[US98/15479 686 1592 a0 N *"'COOH 1594 1595 a0 1596 1597 1598 1599 >ONr 0r WO 99/06397 CUS/157 PCT/US98/15479 -687- 1600 1601 a 0 c~r 0 1602 1603 1604 1605 1606 1607 WO 99/06397 PTU9/57 PCT/US98/15479 1608 688 1609

~COOH

1611 1610 1612 1613 1614 1615

H

2 N r~N b-' WO 99/06397PC/S/157 PCT/US98/15479 689 1616 1617 CH3 *l-.COOH 0 1618 1619

CH

3 N

',ICOOH

CH

3 1620 1621

CH

3 0 'Nr^ "COOH H~ 0 C H 3 1622 1623

CH

3 dI

I

WO 99/06397 PCT/US98/15479 1624 -690- 1625 HN 1627 1626 1628 1629 'IyrN

CH

3 1631

-%>CI

1630 WO 99/06397PC/S/I57 PCTIUS98/15479 -691- 1632 1633 1634 1635 1636 1637 1638 13 1639 WO 99/06397 PCTIUS98/15479 692 1640 4N

"OOH

1641 1642 1643 1644 1645

CH,

H

2 N

~N{

1646 1647

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3 0

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I-

WO 99/06397PCUS/I57 PCT/US98/15479 693 1648 1649 1650 1651 1652 1653 1654 1655 PCTIUS9815479 WO 99/06397 694 1656 1657 0

.ICOOH

1658 1659 00 1660 1661

CH

3 0 miCOOH 1662 1663 WO 99/06397PCUS/I57 PCT/US98/15479 695 1664

CI-

1666 1665 1667 1668

CH

.,NA -Nr 0 1669 1670 CH2 iC00H

CO.

1671 WO 99/06397PCUS8I47 PCTIUS98/15479 696 1672 1673 ~Th UM 1674 1675 1676 1677 1678 17 1679 PCTIUS98/1 5479 WO 99/06397 -697- 1680 1681 -Th 1683 1682

N.'>UM

r 1684 1685 H2N- 1686 18 1687 PCTIUS98/15479 WO 99/06397 698 1688 1689

COOH

1690 1691 1692 1693 1695 1694 WO 99/06397 PCTIUS98/1 5479 699 1696 1697 N

COOH'

1698 1699 ,N COOH 0 1700 1701H 1703 1702 PCTIUS98/1 5479 WO 99/06397 700- 1705 1704 1706 1707 NI **"COOH 0

CCH

1709 1708 1711 1710 0 CH3 WO 99/06397 PCTIUS98/1 5479 -701 1712 1713

I

I'Z'

1714 1715

H

2

N""

1717 1716 1719 1718 PCTIUS98/1 5479 WO 99/06397 -702- 1720 1721 H2N oiCOOH CH /1 1722 1723

N-N

*"'COOH

1724 1725 0

N

2

N

WO 99/06397 PCT/US9815479 703 1728 1729 04 N N 4COOH 1730 1731 z coO> 1732 1733 1734 13 1735 WO 99/06397PCUS8157 PCT/US98/15479 704 1736 ~Tz l*.uCOO 1737

H

00 )-3 1738 1739 1740 1741 1742 1743

HN,

.0COOH 0 0 WO 99/06397PCUS8157 PCTIUS98/15479 705 1744 1746 H 0

-COOH

0 1748 1745 H 1 0

COOH

00 1747 1749 1750 1751 WO 99/06397 WO 9906397PCTIUS98/1 5479 706- 1752 H

CH

1753 HNAF 0 0

CH

3 -3 1754 1755 1756 1757 1758 1759 WO 99/06397 WO 9906397PCT/US98/15479 707 1760 1761 H2N~ 1762 1763

CH,

1765 H2NY 1764 1766 1767

HNS,%=

N

COOH

0

O

I

WO 99/06397 WO 9906397PCTIUS98/1 5479 708 1768 1769 1770 1771 1772 1774 1773 1775 WO 99106397 CUS/I57 PCT/US98/15479 709 1776 1777 1778.

1779 1780 18 1781 WO 99/06397 PCT/US98/15479 -710- N Example 536 12S.3R.4S-2-(2.2-DimethylDentyll-4-(7-methoxy-1.3-benzodioxol-5yl)-l-(N.N-di(n-butyl)aminocarbonylmethyll-nyrrolidine-3-carboxylic acid Example 536A SEthyl 5.5-dimethyl-3-oxooctanoate Ethyl 3,3-dimethylhexanoate was prepared using the general procedure of Cahiez et al., Tetrahedron Lett., 31, 7425 (1990). To a S solution of 63.8 g (370 mmol) of this compound in 400 mL of ethanol, cooled to O°C, was added a solution of 30 g of NaOH in 150 mL of water.

The resultant solution was warmed to ambient temperature and stirred overnight. Solvents were removed in vacuo; the residue was taken up in 700 mL of water, and extracted twice with 1:1 ether/hexanes. The aqueous layer was acidified to pH3 with 1N HCI and extracted twice with hexanes. The combined hexane extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. A 20.2 g (150 mmol) sample of the crude product is dissolved in 150 mL of THF; 27.3 g of 1,1'-carbonyldiimidazole is added portionwise, to control gas evolution. In meantime, 33.4 g of potassium ethylmalonate and 13.4 g of magnesium chloride are combined in 350 mL of THF (overhead mechanical stirring) and warmed to 50 0 C for 3 hrs. This mixture is cooled to ambient temperature, and the above acid imidazolide solution is added. The resultant slurry is stirred overnight. Ether (600 mL), hexanes (600 mL) and aqueous 1N phosphoric acid (500 mL) are added, and the mixture is sitrred for 30 min. The aqueous layer is separated; the organics are washed sequentially with bicarb water and brine.

The organics are dried over sodium sulfate, filtered and concentrated to give 30.2 g (95% yield) of a colorless liquid.

Example 536B 4-Methoxy-6-(2-nitrovinyl)-1.3-benzodioxole 3-Methoxypiperonal (50.0 g) is combined with 71.9 mL of nitromethane in 250 mL of acetic acid; 36 g of ammonium acetate is WO 99/06397 PCT/US98/15479 C -711r- added, and the mixture is heated to 500C for 4 hrs. Solvents are removed in vacuo; the residue is taken up in water and stirred for min. The solution is filtered; the filtrate is washed with water, then ,O ether, to give'51.8 g of a yellow solid.

SExample 536C 0 Ethyl trans, trans-2-( 2 2 .Dimethyoentyl-4-(7-methoxy'-1.3- O benzodio 5-lY)-liyrroldine3-Crt ate The compound of Example 536A (6.42 g, 30 mmol) was combined with 5.79 g of the compound of Example 536B in 40 mL of THF. DBU mL) was added, and the mixture was stirred at ambient temperature for 6 hrs, during which time it turns reddish brown, and homogeneous. The solvents were removed in vacuo; the residue was taken up in EtOAc and washed sequentially with aqueous 1N phosphoric acid and brine. The organic phase was dried over sodium sulfate, filtered and concentrated.

The residue was dissolved in 50 mL of THF; 12 g of Raney Nickel catalyst (washed sequentially with water and ethanol) was added, followed by 10 mL of acetic acid. The resultant mixture was hydrogenated under 4 atmospheres of hydrogen until hydrogen uptake ceased 3 hrs). The catalyst was removed by filtration; solvents were removed in vacuo. The residue was dissolved in 90 mL of 2:1 ethanol/THF; 30 mg of bromcresol green indicator was added, followed by 30 mL of 1N sodium cyanoborohydride in THF. Concentrated HCI was.

added dropwise to maintain pH at the indicator point,. over 1 hr. The resultant solution was stirred overnight at ambient temperature.

Bicarb was added, and the solvents were removed in vacuo; the residue was partitioned between water and EtOAc. The organic material was washed with water (2X) and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in 100 mL of acetonitrile; 10 mL of HOnig's base was added, and the solution was warmed to 4000C overnight. Removal of solvents in vacuo provided 5.0 g of a yellowish oil.

WO99/06397 PCT/US98/15479 -712- Example 536D Ethyl r2S.3R.4S-2-(2.2-Dimethvylepntyl)4-(7-methox -1.3benzodioxol-5-yl)-ovrrolidine-3-carboxylate The crude compound of Example 536C (2.0 g) was combined with 4 mL of triethylamine in 40 mL of THF; 2.0 g of di-tert-butyldicarbonate was added, and the mixture was stirred at ambient temperature for hrs. Solvents were removed in vacuo, and the residue was taken up in mL of ethanol. Aqueous sodium hydroxide (10 mL of 2.5 N solution) was added, and the resultant solution was stirred overnight. Solvents were removed in vacuo; the residue was taken up in water and extracted with ether. The aqueous phase was acidified with aqueous 1N phosphoric acid and extracted with EtOAc. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 1.0 g of a colorless oil. A sample of this material (0.734 g, 1.58 mmol) was combined with 0.35 g of pentafluorophenol and 0.364 g of EDAC in 5 mL of DMF. The resultant solution was stirred at ambient temperature for 1 hr, then was poured onto 50 mL of 0.6M sodium bicarbonate solution and extracted (3 X 15 mL) with ether. The combined ether extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a foam, which was dissolved in 5 mL of THF and cooled to o°C. Simultaneously, 0.418 g (2.37 mmol) of R-4benzyl-2-oxazolidinone was combined with -0.1 mg of pyreneacetic acid in 5 mL of THF and cooled to 0°C. N-butyllithium (1.6M in hexanes) was added to a red endpoint (persists -10 sec), and the solution was stirred for 10 min. The solution was transferred into the solution of the pentafluorophenyl ester, and the resultant solution was stirred at 00C for 40 min. Solvents were removed in vacuo; the residue was taken up in bicarb and extracted with ether (3 X 10 mL). The combined ether extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture of diasteromeric products was separated by flash chromatography on silica gel, eluting with a gradient from hexanes/EtOAc, giving 423 mg of the faster-moving and 389 mg of the slower-moving diastereomer, respectively. The faster-moving diastereomer was dissolved in 2 mL of a 2.OM solution of sodium methoxide in methanol (freshly prepared,

I

WO 99/06397 PCT/US98/15479 S-713containing 5% methyl formate by volume) and stirred at ambient temperature for 16 hrs. Solvents were removed in vacuo, and the residue was partitioned between ether and aqueous 1N sodium hydroxide.

The ether laypr was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 4:1 hexanes/EtOAC. The resultant material was dissolved in 5 mL of TFA and stirred at ambient temperature for 1 hr. Solvents were removed in vacuo; the residue was suspended in bicarb and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 98 mg of product.

Example 536E The compound of Example 536D (48 mg) was combined with 35 mg of the compound of Example 501A in 3 mL of acetonitrile; 0.5 mL of H nig's base was added, and the solution was allowed to stir overnight at ambient temperature. Solvents were removed in vacuo; the residue was partitioned between EtOAc and aqueous 1N phosphoric acid. The organic layer was washed with bicarb and brine, then dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 2:1 hexanes/EtOAc. sThe product was dissolved in 4 mL of ethanol; 1 mL of 2.5N aqueous sodium hydroxide was added, and the resultant solution was stirred overnight at ambient temperature. Solvents were removed in vacuo; the residue was taken up in water and extracted with ether. The aqueous phase was acidified to pH 3 with aqueous 1N phosphoric acid and extracted with EtOAc. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give a colorless oil. Lyophilization from acetonitrile/0.1% aqueous TFA gave 56 mg of a white solid.

IH NMR (CDCI3, 300 MHz) d 0.81 3H), 0.84 3H), 0.86 J 6.9 Hz, 3H), 0.93 J 6.9 Hz, 3H), 0.96 J 6.9 Hz, 3H), 1.09-1.38 8H), 1.45-1.59 4H), 1.84-2.00 2H), 3.15 (dd, J 6.9 Hz, 10.0 Hz, 2H), WO 99/06397 WO 9906397PCTIUS98/1 5479 -714- 3.30-3.42 (in, 3H), 3.72 J 10.5 Hz, 1H), 3.86 J 10.5 Hz, 1H), 3.88 3H), 4.02 J 10.0 Hz, 1H), 4.12 J 16.8 Hz, 1H), 4.29

J

16.8 Hz, I 4.41 (bin, I1H), 5.94 1 6.52 J 1.8 Hz, 1 6.67 (d, J 1.8 Hz, I1H). MS (ESI) at mle 533. Anal calcd for

C

30

H

48

N

2 06-0.7 TFA: C, 61.57; H, 8.01; N, 4.57. Found: C, 61.59; H, 8.20; N, 4.63.

rZ.R4--22Dieh nv)4(.3 benzodioXol-5-YIi ,d-i(n-butyl)amino~abfYiehl~~rldn~abxlc ai

D

Ethyl trans, trans2-(2.2Qiiethylentl-

I-

4 l pyrrolidine-3-carOx-ylate Prepared according to the procedures of Example 536C above, substituting the compound of Example 501B (5-(2-nitrovinYl)-l ,3benxodioxole) for 4-methoxy-6-(2-nitrovinyl)l ,3-.benzodioxole.

Examp.e537B Ethyl l 2 S3R4S-2(22Dimthy lentyl)- 1 t3bflriOXl- 5 -YlV prroli in -3-carboxviate The compound of Example 537A (6.8 g) was dissolved in 100 mL of ether; a solution of 1.6 g of (S)-(+)-mandelic acid in 60 mL of ether was added, the total volume was made up to -200 mL, and the solution was seeded. The mixtu re was stirred slowly overnight. The resultant crystals were collected by filtration and recrystallized from ether/EtOAc to give 1.8 g of a white solid. Thsi material was partitioned between bicarb and ether; the ether layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the enantiomerically pure product WO099/06397 PCTIUS98/1 5479 1 -715r2S.3R4S1-2(2.2-Dim ethYlIpentYl) 4 .3-be nzodio xol- 5-yI) -1 di(n-butvl)aminocarboflylmethyl).pyrroldife3carboxylic acid Prepared from the compound of Example 537B according to the procedures of Example 536E. 1 H NMR (CDCI3, 300 MHz) d 0.80-0.99 (in, 1.10-1.37 (in, 8H), 1.43-1.58 (in, 4H), 1.77-1.97 (in, 2H), 3.48-3.12 (mn, 5H), 3.60-3.69 (in, 1H), 3.75-3.86 (in, 1H), 3.95-4.16 (in, 2H), 4.28- 4.4 (in, 2H), 5.94 6.74 J=7.8 Hz, I1H), 6.8 (dd, J=8.1, 1.5 Hz, 1H), 6.87 J=1.8 Hz, 1H). MS (APCI+) m/e 503 Example 538 f2S.3R.42-2-(2.2- Dim ethylpentyl- 4 -(1.3b enzo dio x p2roooxy. N(n-butyl)lainflcarboylmiethyl)pyrrolidine3carboxylic 99i d N-Boc-N-butyl-0-allylhydroxylamine O.Allylhydroxylamifle hydrochloride hydrate (5.0g) was dissolved in THE (15 inL. The solution was cooled to 000 in an ice bath.

Diisopropylethylainine (8mL) and di-t-butyldicarbonate (1 0.0g) were added. The mixture was stirred at 000 for one hour at which point the bath was removed and the reaction allowed to warm to room temperature and stirred overnight. The THE was removed in vacuo and the residue taken up in EtOAc (25 mL), and washed with water (1 x inL), saturated sodium bicarbonate solution (3 x 50 inL), 1 N phosphoric acid (3 x 50 mL), and brine (1 x 50 inL. The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil This crude product was dissolved in dry THF (25 inL and the solution cooled to 000 in an ice bath. Sodium hydride (1 .5g, 60% dispersion in oil) was added portionwise over five minutes. The resulting mixture was stirred for 30 minutes at 000. 1-lodobutane (4.1 mQL was added dropwise to the mixture. The reaction was stirred at 000C for one hour, then stirred overnight at room temperature. The THF was removed in vacuo and the residue taken up in EtOAC (50 mL) and washed with water (1 x 50 mL), WO 99/06397 PCT/US98/15479 -716saturated sodium bicarbonate solution (3 x 50 mL), 1N phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil, which was purified by flash chromatography on silica gel eluting with S EtOAc/hexanes to give the title compound as a colorless oil (6.0 g).

Example 538B i N-butvl-N-propoxvamine trifluoroacetate The compound of Example 538A (6.0 g) was dissolved in EtOAc (100 mL). 10% Palladium-on-carbon (0.5 g) was added, and the mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at room temperature for 6 hours. The catalyst was removed by filtration through a pad of Celite and the solvents were removed in vacuo to give a yellow oil which was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give a colorless oil (5.8 A sample of the resultant material (1.15 g) was dissolved in CH 2

CI

2 (5 mL) and cooled in an ice bath. Trifluoroacetic acid (3mL) was added and the solution stirred cold for two hours. The solvent was removed in vacuo care being taken not to allow the solution to warm above room temperature. The residue contained considerable TFA and was used without further purification.

Example 538C N-butyl-N-proOoxy-bromoacetamide The salt of Example 538B (0.60 g) was dissolved in acetonitrile mL) and cooled to -20 0 C. Hunig's base (5.5 mL) was added slowly.

Bromoacetyl bromide (0.5 mL) was added dropwise over five minutes.

The solution was stirred at -200C for 30 minutes. The bath was removed and the solution was stirred for six hours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1 x 25 mL), 1N phosphoric acid (3 x 25 mL), and brine (1 x 25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oil (0.65 g) which was used without further ourification.

WO 99/06397 PTU9/57 CI -717f2S.3R.4S1-2-(2.2- Dim ethylpefltyfl-4-(l .3-ben-od ioxoI- 5-yi) -1 p2ropoxy. N-nbutyl)aminocarbonflymethyl-Dyrrlidife3carboxylic The compound of Example 537B was reacted with the compound of SExample 538C according to the procedures of Example 536E.

r2S.3R.4SI-2-(2.2-Di methyl pentYl)- 4 3-ben 7od ioxo 1 p2ropoxy. N(n12ropyl))amilocarboflylmethyl)pyrroldine3car-bozyic Eape59 N-p2ropyl-N-propoxy bromoacetamide Prepared according to the procedures of Example 538A-C, substituting lodopropane for iodobutane in Example 538A.

r2S.3R.4S1-2-(22-DimethylPentlY)- 4 -(l.3-benz.odioxQ- 5 yl)l prpr.- N(nroyl)gmiflocarboylmetYl-pyrroidine3carboxvtIc The compound of Example 537B was reacted with the compound of Example 539A according to the procedures of Example 536E.

WO 99/06397 WO 9906397PCTIUS98/I 5479 '4 -718- Exgml r2S.3R.4S]-2-(2.2-DimethylpegntyI)-4-(7-methoxy-l yl)-1-((N-propoxy, N(nbutyl))aminocarbonylmlethYl)-pyrrolidifle- 3 cabxic agi IThe compound of Example 536D was reacted with the compound of Example 538C according to the procedures of Example 536E.

(2S.3R.4SI-2(22DimethylpenW)4(7-methoxy-1 yl)-1-((N-prgpoxy. N(npropy))amiflocarbonYlmethy)Pyrro1idine- 3 The compound of Example 536D was reacted with the compound of Example 539A according to the procedures of Example 536E.

Examgle 42 (2S-3R.4S1-2(2.2Dimethylpent-3-nYl) 4 (l benzodioxol- 5 ((N-propoxy, N(nutyl))aminocarbonylmthyl)pyrr idine- 3 carboxylic aid Example 542A -tra ns-Ethyl 33dimethyl-4-hexenat A mixture of 4-methyl-3-penten-2-ol (7.4 g, 74 mmol), triethyl orthoacetate (13.6 mL, 74mmol) and propionic acid (0.28 mL, 3.7 mmol) was heated At 15000 for 7 hr. The product was then distilled under normal pressure (200-220 OC) to give 5.0 g of crude ester as a colorless oil.

Example 542B Ethyl- trans. trans2(2.2Dimehylpet3enYl) 4 -(l.3-benzodiOxgL- 5 yl)-1pyrrolidine-3-carboxylate The title compound is prepared according to the procedures of Examples 536A and 5360, substituting the compound of Example 542A WO 99/06397 WO 9906397PCT/US98/15479 -719for ethyl 3,3-dimethylhexarioate in Example 536A and the compound of Example 501 B (5-(2-nitrovinyl)-1 ,3-benxodioxole) for 4-methoxy-6-(2nitrovinyl)-1 ,3-benzodioxole in Example 536C.

Ethyl r2S.3R.4S-2-(2.2- D imethyl ppnt-3-e nyl)-4-(1 .3-ben zod io xo yfl-pyrrolidi ne-3-carboxyl ate The compound of Example 542B was resolved according to the procedure described in Example 537B.

Example 42D r2S.3R.4S1-2(2.2Dimethylpent-3-enyfl-4-(1 .3-be nzodioxol-5-yl)-1 ((N-propoxy. -N-(n-butyl))aminocarbonylmlethyl)-pyrrolidine- 3 carboxylic acid The compound of Example 542C was reacted with the compound of Example 538C according to the procedures of Example 536E.

Example 543 [2S.3R.4S-2-(2.2-Dimethylpent-3-enyfl-4-(1 .3-benzodigxol1-5-yl)-1 ((N-propoxy, -N(n-propyl))gminocarbonylmethyl)-pyrrolidine- 3 carboxylic acid The compound of Example 542C was reacted with the compound of~ Example 539A according to the procedures of Example 536E.

benzodioxol-5-yl)-1 -((N-propoxy. N-(n-butyl))aminocarboflylmethY)pyrrolidine-3-carboxylic acid WO 99/06397 WO 9906397PCTJUS98/I 5479 N -720- Examl 44A Ethyl trans. trans-2-(2.2 -Dim ethylle ntw3-eflyl)4-( 7 -methoxy- 1 .3bpenzodiogxol5-y1) pyrrolidi ne-3-carboxyl ate The title compound is prepared according to the procedures of Examples 536A and 536C, substituting the compound of Example 542A for ethyl 3,3-dimethylhexanoate in Example 536A.

Example 44B Ethyl- r2,R4j--2 vipt3 y)4(-ehx .3ne-3-caUrboxyl=t The compound of Example 544A was resolved according to the procedure described in Example 536D.

Exmple- 544C r 2 iS.

3 R.4S1-2(2.22Qim ethyl penta-enyl)4(7methoxy3-- -((N-propoxy. N (nbutyl)) am inocarb ofylm ethyl)pyrrolidine-acarbox li acd The compound of Example 544B was reacted with the compound of Example 538C according to the procedures of Example 536E.

Example545 r 2

S.

3 R.4a -2 (2.2 Dim ehy pent3 enyl)4(Z thX 3-n -((N-propoxy. N(npropyl))amingcarb Illmeh h) pyrrolidine-3-carboxylic aid The compound of Example 544B was reacted with the compound 01 Example 539A according to the procedures of Example 536E.

Example 546 rS3.E2(-2pyiy ty)4(.3-benzodioxol-5yl 1N heapty I (2-m ethyl-3f luorophenyll aino crbonylmethylll p2yrrolidine-3-carboxyligC acid WO 99/06397 PCT/US98/15479 -721- SExample 546A Ethyl trans.trans-2-(2-(2-pyridyl)ethyl)- 4 -(1.3-benzodioxol-5-yl)pyrrolidine-3-carboxylate

D

The title compound is prepared according to the procedures of 3 Examples 536A and 536C, substituting the compound of Example 519A r for 3,3-dimethylhexanoic acid in Example 536A.

Example 546B Ethyl f2S.3R.4S-2-(2-(2-pyridyl)ethyl-4-(1 pyrrolidine-3-carboxylate The compound of Example 546A (1.5 g) was dissolved in CH2CI2 mL). Di-t-butyldicarbonate (0.9 g) was added and the solution stirred overnight at room temperature. The solvent was evaporated in vacuo and the residue taken up in EtOAc (50 mL), washed with water (1x50 mL), saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL). The organic layer was dried with sodium sulfate and evaporated in vacuo to give an oil with was purified by flash chromatography on silica gel eluting with 1/10/10 EtOH/EtOAc/hexanes to give a colorless oil (1.5 The oil was dissolved in EtOH (10 mL) and NaOH solution (0.5 mL) and water (5 mL) were added. The mixture was stirred overnight at room temperature. The solvents were evaporated in vacuo and the residue taken up in EtOAc (25 mL) and acidified with 1 N H3P04 (10 mL). The layers were separated and the organic layer dried with sodium sulfate and evaporated to give a white semi-solid (1.3 A sample of the resultant Boc-protected amino acid (0.9 g) was dissolved in DMF (5 mL). (S)-Phenylalaninol (0.32 HOOBt (0.33 and EDCI (0.40 g) were added and the solution sitrred ovemight at room temperature. Water (50 mL) was added and the mixture extracted with EtOAc (3x25 mL). The organic layers were combined, washed with water (2x50 mL), saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL), and evaporated to give a yellow oil; tic indicated the presence of two diastereomeric products. The diastereomeric amides were separated by flash chromatography on silica gel eluting with 1/12/12 EtOH/EtOAc/hexanes to give faster-

I

WO 99/06397 PCT/US98/15479 S-722- (450 mg) and slower-moving isomers (400 mg). The faster-moving S diastereomer (400 mg) was taken up in 6N HCI and heated at reflux overnight. The solvent was evaporated and the residue was taken up in toluene (75 mL) and evaporated. This was repeated two additional times S to give a brown solid, which was dissolved in EtOH (50mL). 4N SHCI/dioxane (10 mL) was added and the solution heated at reflux S overnight. The EtOH was evaporated and the residue taken up in EtOAc which was treated with saturated sodium bicarbonate solution (3x50 mL), and brine (1x50 mL), and evaporated to give a brown solid. Flash chromatography on silica gel eluting with 30% EtOH/EtOAc gave a mixture of products (130mg) which was approximately 70% desired material. This product was carried forward without additional purification.

Example 546C [2S.3R.4S.-2-(2-(2-pyridyl)ethyl)-4-( .3-benzodioxol-5-vyl-1 -IN. 4 heDtyl-N.(2-methyl-3-fluorophenvyl) amino carbonylmethyllpyrrolidine-3-carboxylic acid The compound of Example 546B was reacted with the compound of Example 508E according to the procedures of Example 536E.

Example 547 [2S.3R.4SI-2-(4-MethoxvDhenvl)- 4 1.3-benzodioxol-5-yl)- -(N-butyl-

N-(

4 -dimethylaminobutyl)amino)carbonylmethvyl-PYrrolidine-3carboxvlic acid Example 547A N-butyl-4-hydroxvbutvramide To 30 mL (390 mmol) of g-butyrolactone was added 45 ml (455 mmol) of n-butylamine. The solution was heated at 85°C for 1.5 hr, then the excess n-butylamine was removed in vacuo. The product crystallized on standing to give about 62 g of a colorless, low melting solid.

I

WO 99/06397 PCT/US98/15479 o -723- S Example 547B N-butyl-4-hydroxvbutyl chloroacetamide To an ice cooled solution of 3.40 g (91.9 mmol) of LIAIH4 in 90 mL of THF was added 2.4 mL of 98% H2S04, dropwise, with stirring. After bubbling had ceased, a solution of 4.7 g of the compound of Example 547A in 10mL of THF was added. The mixture was stirred at reflux for O 24 hr, then cooled with an ice bath and quenched by sequential dropwise o addition of 1.7 mL H20, and 17 mL of 25% w/v aqueous NaOH. The white precipitate was filtered, and washed with about 50 mL of THF. The combined filtrate and washings were concentrated to 3.85 g of an oil.

To an ice cooled solution of this material in 35 mL of ethyl acetate was added a solution of 5.0 g (29.2 mmol) of chloroacetic anhydride in 10 mL of ethyl acetate. The solution was stirred at 0°C for 30 min, then extracted with saturated aqueous NaHCO3 solution (1 x 25 mL), 2M NaOH (1 x 25 mL), 5% NH40H (1 x 25 mL), 1M HCI (1 x 25 mL), and brine (1 x mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with 98:2 diethyl ether: methanol, to give 1.52 g of a colorless oil.

Example 547C Ethyl .3R.4S-2-(4-Methoxvyphenyl)- 4 (1.3-benzodioxol-5-yl)-1

(N-

butyl-N-(4-hydroxybutvl)amino)carbonlethy-pyrrnlidine- 3 carboxylate To 1.52 g (6.85 mmol) of the compound of Example 547B was added 2.75 g (7.44 mmol) of the ethyl [2S,3R,4S]-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yl)-pyrrolidine-3-carboxylate (prepared by neutralization of the compound of Example 501G), 10 mL of DMSO, and 2 mL of N,N-diisopropylethylamine. The solution was stirred at ambient temperature for 22 h, then poured into 100 mL of water and extracted with diethyl ether (3 x 25 mL). The combined ether layers were washed with water (1 x 25 mL), 4% H3PO4 (1 x 25 mL), saturated aqueous NaHCO3 solution (1 x 25 mL), and brine (1 x 25 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel WO 99/06397 PCT/US98/15479 -724- Schromatography, eluting with 98:2 diethyl ether: methanol to give of a colorless oil.

Example 547D Ethyl 2S.3R.4S 2(4.MethOXyDhenyl)- 4 -(.3-benzodioxol-5-Yll -f(N butvyl-N(4bromobutvl)aminocarbonvlmethvl1-pvrrolidine-3" rcarboxvlate To an ice cooled solution of 2.80 g (5.05 mmol) of the compound of Example 547C in 27 mL of diethyl ether was added 1.4 mL (10 mmol) of triethylamine, then 0.58 mL of methanesulfonyl chloride. A white precipitate formed, and the suspension was stirred at 0 °C for 20 min.

The reaction was diluted with 75 mL of diethyl ether, then extracted with saturated aqueous NaHCO3 solution (2 x 25 mL), 5% NH4OH (2 x mL), and brine (1 x 25 mL), dried over MgSO4, filtered, and concentrated to 3.0 g of a colorless oil. To this material in 45 mL of DMF was added g (69 mmol) of LiBr. The reaction warmed to about 50 then gradually cooled. The solution was stirred at ambient temperature for 4h, then poured into 450 mL of water, and extracted with diethyl ether (3 x 100 mL). The combined ether layers were back extracted with water (1 x 100 mL), and brine (1 x 100 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with 3:1 diethyl ether: petroleum ether, to give 2.65 g of a colorless oil.

Example 547E 2 S.3R.4SI-2-(4-MethoxYphenvyl)-4-( 3-benzodiool-5-vYl-1-(N-butv- N-(4-dimethvaminobu t v l)amino) c a r b o n v lm e t h v l p y r ro l i d in e 3 carboxylic acid To a solution of the compound of Example 547D (0.825 g, 1.34 mmol) in 3 mL of ethanol was added 5 mL of 4.07M dimethylamine in ethanol; the resultant solution was heated at reflux for 75 min.

Solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 9:1 dichloromethane/methanol. Ihe resultant maieriia w iken up WO 9906397PCT/US98/I 5479 -725- Sof 1.4N NaOH in 5:1 ethanol/water and stirred at ambient temperature for 14 hrs. Solvents were removed in vacuo; the residue was taken up in water, then adjusted to pH 6-7 with 1 M HOI mL required). The 0 mixture was extracted with EtOAc the aqueous layer was concentrated in vacuo. The residue was washed 3X with acetonitrile; combined washes were filtered through Celite and concentrated to Sgive 596 mg of a white foam.

W2.3R,4sq-2- Di methyl pentyl) (1 ben zod ioxoI- 5-Yl)- 1 -r (N butyl- dimethyl am inobuty) am ino) carbonyl methyllpyrroli din e- 3 carboxylic acid Prepared according to the procedures of Example 547, substituting the compound of Example 537B (ethyl [2S,3R,4S]-2-(2,2- D imethyl pe ntyl)-4-( 1,3-benzodi oxol-5-yi)-pyrrol idi ne3-carboxyl ate) in Example 547C.

US-3R.46 imethyl pentyl)-4-(7- rneth~xy-l 1.3- be nzo di oxol yl)-l-(-uy--4dmty obtlaiocroymtyl pyrrolidine-3-carboxylic acid Prepared according to the procedures of Example 547, substituting the compound of Example 536D (ethyl [2S,3R,4S]-2-(212- Dimethylpentyl)-4-(7-methoxy- 1,3-benzodioxol-5-yl)-pyrrolidine- 3 carboxylate) in Example 547C.

(2S.3f.4SJ-2-(2.2-Dimethylent3eny) 4 -(l.3-benzodioxol-,5-y1)- r(N-butyl. N-(4-dimethylamin obutyl) amino) ca rb onylm thyllpyrrol idine- 3-carboxylic acid Prepared according to the procedures of Example 547, substituting the compound of Example 542C (ethyl [2S,3R,4S]-2-(2,2- WO 99/06397 PCTIUS98/1 5479 -726- D im ethylpeflt-3 -eflyl) 4 ,3-benzod ioxol- 5-y) pyrro lid inle- 3 carboxylate) in Example 547C.

Example 551 r2S.3.i4S-2-(2 .2-Dimethylpeft3-enyl)f4(7-methoxy-..3- N-butyl-N-(4 dimethylamiflgbUtyl)amiflo~carbonvlmethy1PYrrolidte3carboxylc K=i Prepared according to the procedures of Example 547, substitu ting the compound of Example 544A (ethyl [2S,3R,4S]-2-(2,2- Dim ethylpet 3efyl)4(7methoxy- 1,3-ben zodi pyrrolidine-3-carboxylate) in Example 5470.

Example552 T2.R4q2 (9bnodo~-5Y~ D ehlpn-3ey)f(N .N-di(nbujyl)amIno)carbofl IethI -nrrolidnea--ArboxYI- acid Prepared according to the procedures of Example 1, substituting the compound of Example 5410 (ethyl[2S, 3R,4S-2(2,2-Dim ethylpe nt- 3 enyl)-4-(l 3 -benzodioxol5y)pyrrolidine3carboxylate).

Example 553 [PS-3R.4S1-2-(2 Dim ethylpet3en yl)4 (7-eth xl 3benzodioxgl-5-yl)-1 -r(N N-di(n-butyl)amino)carbgnylmethyl]pyrrolidine-a-carbogylic aid Prepared according to the procesureS of. Example 1, substituting the compound of Example 544B (ethyl [2S, 3H,4S]-2-(2,2-Dimethylpent- 3 enyl) (7-m ethoxyl 1, 3 be nzodi oxol-5yl) PYrrol di n e3carbo xyl ate) As an indication that the compounds described herein act through binding to endothelin receptors, the compounds have been evaluated for their ability to displace endothelin from its receptor.

WO 99/06397 PCT/US98/15479 0 -727- As an indication that the compounds described herein act through binding to endothelin receptors, the compounds have been evaluated for S their ability to displace endothelin from its receptor.

0Binding Assay N ETA Receptor S Preparation of membranes from MMQ cells: CI MMQ [MacLeod/MacQueen/Login cell line (prolactin secreting rat' 0 pituitary cells)] cells from 150 mL culture flasks were collected by c centrifugation (1000xg for 10 min) and then homogenized in 25 mL of mM Hepes (pH 7.4) containing 0.25 M sucrose and protease inhibitors [3 mM EDTA 0.1 mM PMSF, and 5 ig/mL Pepstatin A] by a micro ultrasonic cell disruptor (Kontes). The mixture was centrifuged at 1000xg for 10 min. The supernatant was collected and centrifuged at is 60,000xg for 60 min. The precipitate was resuspended in 20 mM Tris, pH 7.4 containing the above protease inhibitors and centrifuged again.

The final pellet was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitors and stored at -80 0 C until used. Protein content was determined by the Bio-Rad dye-binding protein assay.

[1251]ET-1 binding to membranes: Binding assays were performed in 96-well microtiter plates pretreated with 0.1% BSA. Membranes prepared from cells were diluted -100 fold in Buffer B (20 mM Tris, 100 mM NaCI, 10 mMMgCI2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 gg/mL Pepstatin A, 0.025% bacitracin, and 3 mM EDTA) to a final concentration of 0.2 mg/mL of protein. In competition studies, membranes (0.02 mg) were incubated with 0.1 nJM of 1 2 5 1]ET-1 in Buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of unlabeled ET-1 or a test compound for 4 hours at 25 After incubation, unbound ligands were separated from so bound ligands by a vacuum filtration method using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., MA), followed by washing the filter strips with saline (1 mL) for three times.

Nonspecific binding was determined in the presence of 1 I1M ET-1. The data are shown in Table 4. The per cent inhibition at a concentration of 1 mM is shown. The data show that the compounds of the invention bind to the endothelin receptor.

WO 99/06397 WO 9906397PCTIUS98II 5479 -72 8- Table 4 Binding Data Example Inhibition Example Inhibition of ETA at I of ETA atl1 gimJI ID 96.4 34 95.5 2 58.4 35 91.8 3 42.2 36 94.5 4 78.2 37 47.9 95.1 38 100.0 6B 34.9 39 83.6 7 63.4 40 94.8 8 53.7 41 89.9 9 69.2 42 95.2 66.1 43 99.2 14 86.6 44 91.3 84.8 45 85.4 16 96.0 46 90.4 17 73.9 47 95.1 18 97.3 48 96.3 19 90.3 52 84.0 80.9 54 64.6 21 56.3 55 50.5 22 86.3 56 34.3 23 85.9* 57 93.2 26 83.0 58 81.9 27 61.2 59 70.8 28 63.8 60 42.8 29 85.3 61iC 90.6 80.0 62 94.1 31 B 93.6 63 92.0 WO 99/06397 WO 9906397PCT/US9815479 -729- Example Inhibition ETA at 1 Example Inhibition ETA at 1 64 66 67 68 6913 71 720 730 74 76 79 82 83 84 86 87 88 89 910c 920 93C 96 9-7 95.0 82.8 87.7 96.3 84.6 37.4 62.7 81.4 80.7 96.3 95.6 95.3 93.1 100.4 89.4 90.3 85.0 52.6 62.4 84.3 84.6 91.6 107.4 59.2 82.1 86.1 89.0 98 99 100 101 102 103 104 105 106 107 109 110 i11 112 113 114 115 116 117 118 119 120 121 122 125 126 127 128 86.8 92.1 76.8 89.2 75.2 69.0 98.0 98.6 90.0 97.2 96.8 94.4 101.8 94.9 94.3 86.2 88.4 79.3 95.2 93.2 86.6 99.5 98.6 95.3 97.2 91.7 91.4 95.4 WO 99/06397 WO 9906397PCT/US98/I 5479 -730- Example Inhibition Example Inhibition of ETA atlI of ETA atlI 123 89.7 156 92.6 124 91.0 157 83.8 129 100.1 158 91.8 130 91.0 159 36.2 131 89.5 160B 80.3 132 90.0 161 93.6 133 88.6 162B 91.5 134 92.2 163 90.6 135B 77.7 164 98.6 136 79.4 165 54.1 138 83.0 166 91.6 139 98.6 167 94.4 140 106.3 291 100.0 141 92.8 293 89.8 142B 78.7 294 77.7 143 20.6 295 93.0 144 78.2 296 87.1 145 32.4 297 84.4 146 25.0 298 93.3 147 73.0 299 90.4 148 94.7 300 96.1 149 84.6 301 96.7 150 93.6 302 86.6 151 80.5 303 87.2 152 86.9 304 89.7 153 97.1 305 87.4 154 80.2 306 93.3 155 92.7 307 92.2 WO 99/06397 C/S8157 PCTIUS98/15479 -73 1- Example 3 08 309 310 311 312 313 314 315 31.6 317 318 319 320 322 323 324 334 335 340 341 342 343 344 345 346 348 349 350 Inhibition of ETA at 1 93.0 80.7 87.1 92.3 88.2 96.3 86.0 82.7 74.0 68.5 79.0 79.0 82.2 95.6 91.3 95.0 88.0 84.1 94.0 87.4 89.9 98.7 95.6 86.6 88.9 91.3.

73.0 92.1 Example 351 352 353~ 354 355 356 357 358 359 360 361 362 363 365 366 367 368 370 371 372 373 374 375 376 377 378 379 380 Inhibition of ETA at 1 AiM 99.0 96.2 73.7 79.3 100 93.5 96.3 62.7 94.7 93.7 92.8 94.1 82.3 59.2 91.5 71.0 94.6 84.3 97.2 91.6 92.9 91.4 97.8 90.2 85.6 91.1 90.7 99.0 WO 99/06397 WO 9906397PCT/U598/I 5479 -73 2- Example 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 Inhibition of ETA at 1 tiM 95.7 96.8 91.4 79.4 86.2 47.8 98.7 69.2 100 98.2 45.6 93.7 100 97.8 79.8 98.7 100 90.0 59.9 93.0 96.5 80.5 96.1 95.4 86.4 94.5 100 Example Inhibition ETA at 1 408 409 410 411 412 413 414 415 416 417 418 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 100 89.4 91.4 93.5 86.4 99.5 91.4 87.3 86.4 98.7 100 100 100 96.6 89.1 85.8 90.8 97.2 100 100 100 94.1 99.1 95.5 99.6 100 97.8 WO 99/06397 WO 9906397PCT/US98/15479 -73 3- Example Inhibition ETA at 1 Example Inhibition ETA at 1 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 100 100 94.3 94.3 100 98.3 100 100 100 98.1 97.8 96.9 97.4 100.0 99.7 100 100 94.4 96.8 99.1 95.3 88.9 93.4 459 460 461 462 463 464 465 466 467 468 469 470 471 475 476 477 479 495 496 497 498 499 500 97.4 91.6 99.6 98.3 96.1 97.1 95.1 94.2 93.6 88.7 98.7 100 100 91.6 82.3 80.1 96.5 95.9 92.7 83.7 81.6 68.5 55.7 WO 99/06397 WO 9906397PCT/US98/I 5479 -734- Example.

502 503 504 505 506 507- 508 509 510 511 512 513 514 515 516 517 518 519 5.20 521 523 524 525 526 527 528 529 531 532 533 536 537 Inhibition ETA at 1 AiM 95.7 97.0 97.1 95.8 99.7 99.3 97.6 100 100 99.2 98.9 98.0 100 99.1 99.7 94.1 96.3 99.1 97.4 100 99.0 99.2 1010 100 96.6 98.3 98.1 99.8 100 97.9 100 97.2 WO 99/06397 PCT/US98/15479 -735- Ct As further demonstration of the efficacy of the described compounds as functional antagonists of endothelin, the ability of the Sdescribed compounds to inhibit ET-1-induced phosphatidylinositol ND hydrolysis was measured.

S Determination of Phosphatidvlinositol (PI) Hydrolysis 0 MMQ cells (0.4 x 106 cells/mL) were labeled with 10 iCi/mL of 3 H]myo-inositol in RPMI for 16 hours. The cells were washed with PBS, then incubated with Buffer A containing protease inhibitors and mM LiCI for 60 minutes. The cells were then incubated with test compounds for 5 minutes, and then challenged with 1 nM ET-1. ET-1 challenge was terminated by the addition of 1.5 mL of 1:2 (v/v) chloroform-methanol. Total inositol phosphates were extracted after adding chloroform and water to give final proportions of 1:1:0.9 (v/v/v) chloroform-methanol-water as described by Berridge (Biochem. J. 206 587-595 (1982)). The upper aqueous phase (1 mL) was retained and a small portion (100 gL) was counted. The rest of the aqueous sample was analyzed by batch chromatography using anion-exchange resin AG1- X8 (Bio-Rad). The IC50 is the concentration of test compound required to inhibit the ET-induced increase in PI turnover by 50%. The results of the above study clearly indicate that the compounds act as functional ET antagonists.

I

WO 99/06397 PCT/US98/15479 -736- Table Phosphatidylinositol Hydrolysis Example IC50 RM 1D 0.025 14 0.017 0.010 16 0.009 18 0.009 19 0.024 0.001 31B 0.002 43 0.0001 46 0.002 47 0.0005 48 0.0004 291 0.0098 300 0.0012 534 0.05 553 0.0004 s Table 6 ETA/ETB Selectivity MMQ cells, porcine cerebellar tissues (known to contain ETB receptors) and chinese hamster ovary cells (CHO) permanently transfected with the human ETA or ETB receptor were homogenized in ml of 10 mM Hepes (pH 7.4) containing 0.25 M sucrose and a protease inhibitor [50 mM EDTA 0.1 mM PMSF, 5 jIg/ml Pepstatin A, and 0.025% Bacitracin] using a micro ultrasonic cell disruptor. The mixture was centrifuged at 1000xg for 10 min. The supernatant was collected and 1i centrifuged at 60,000xg for 60 min. The precipitate was resuspended in mM Tris, pH 7.4 containing protease inhibitor and centrifuged again.

The final membrane pellet was resuspended in 20 mM Tris, pH 7.4 WO 99/06397 PCT/US98/15479 '1 -737-* containing protease inhibitors and stored at -80 °C until used. Protein content was determined by the Bio-Rad dye-binding protein assay.

Binding assays were performed in 96-well microtiter plates S pretreated with 0.1% BSA. Membranes prepared from cells were diluted -100 fold in Buffer B (20 mM Tris, 100 mMNaCI, 10 mM MgCI2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 ttg/mL Pepstatin A, 0.025% bacitracin, and 50 mM EDTA) to a final concentration of 0.2 mg/mL of protein. In S competition binding studies, membranes (0.02 mg) were incubated with N 0.1 nM of [1251]ET-1 (for ETA assay in MMQ or CHO cells transfected with human ETA receptor) or [1251]ET-3 (for ETB assay in porcine cerebellum or CHO cells transfected with human ETB receptor) in Buffer B (final volume: 0.2 mL) in the presence of increasing concentrations of the test compound for 3 hours at 25 After incubation, unbound ligands were separated from bound ligands by a vacuum filtration method using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., MA), washing the filter strips three times with saline (1 mL). Nonspecific binding was determined in the presence of 1 jIM ET-1. IC50 values are calculated using an average of at least two separate determinations. The data shows the selectivity of the compounds of the invention in binding to the endothelin receptors.

Table 6 EXAMPLE rET-A rET-A pET-B Selectivity hET-A hET-B Selectivity NO. IO IC50 IC50 (rA/pB IC50 IC50 (hA/hB 1itM) (nM) (nM) ratio) (nM) (nM) ratio) 502 95.7 3.0 71,000 23,000 503 97.0 1.4 50,000 35,000 0.92 52,000 56,000 504 97.1 3.1 >100,000 >32,000 4.6 >100,000 >21,000 505 95.8 2.0 60,000 30,000 5.7 68,000 12,000 506 99.7 3.2 >100,000 >31,000 3.0 61.000 20,000 WO 99/06397 WO 9906397PCT/US98/I 5479 -73 8- 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 523 524 525 99.3 3.0 100,000 97.6 100 100 99.2 98.9 98.0 1 00 99.1 99.7 94.1 96.3 99.1 97.4 100 99.0 99.2 100 1.9 0.56 0.50 0.81 0.42 0.30 1.0 1.6 0.71 1.0 1.3 0.38 0.20 0.67 0.42 0.79 8.2 45,000 30,000 35,000

N.D.

>80,000 8,800 26,000 >62,000 29,000 30,000 85,000 14,000 28,000 37,000 360 1,700 560 >33,000 23,000 53,000 68,000 1.63 100,000 >190,000 29,000 26,.000 >37,000 40,000 30.000 63.000 36,000 130,000 54,000 880 2,100 2.1 0.51 1 .0 0.60 0.58 0.36 0.36 6.7 1.8 0.43 0.31 0.23 0.33 0.82 51,000 23,000 11,000 15,000 60,000 14,000 9,800 100,000 37,000 12,000 38,000 19,000 290 890 >60,000 24,000 45,000 11,000 25,000 >102,000 37,000 29,000 >15,000 21,000 29,000 124,000 83,00 880 1,100

I

WO 99/06397 PCT/US98/15479 -739- 526 527 528 529 531 532 100 96.6 98.3 98.1 99.8 100 97.9 10,000 43,000 6,300 1,300 3.800 1,700 17 0.71 7,400 1.2 5.1 3,200 76 7,900 1,200 100 97.2 97.3 100 0.12 0.52 0.96 0.36 17,000 5,900 100 3.0 33,000 6,200 0.08 0.92 0.23 1.0 0.29 0.28 52,000 1,900 40 22,000 560 56,000 8,200 0.78 7100,000 7125,000 >96,000 >96,000 0.26 42,400 160,000 39,500 136,000 Determination of Plasma Protein Binding A stock solution of the test compound in 50% ethanol (2 mg/mL) was diluted 10X into PBS. A 0.4 mL sample of this secondary stock solution was added to 3.6 mL of fresh plasma, and incubated at room temperature for 1 hour. A 1 mL sample of this incubation mixture was transferred to a Centrifree ultrafiltration tube. The sample was centrifuged in a fixed-bucket rotor for approximately 2 min and the filtrate was discarded. The sample was centrifuged for another 15-30 min. A 100 pL sample of the ultrafiltrate was transfered to a micro HPLC sample vial containing 150 ML of HPLC mobile phase and mixed thoroughly. A 50 pL sample was injected and the concentration of drug in the ultrafiltrate was determined by HPLC analysis compared against a standard sample prepared identically in the absence of plasma.

Ultrafiltrate concentrations are calculated from a calibration curve. Protein binding is calculated according to the equation: 739 WO 99/06397 PCT/US98/15479 -740- %PB 100% where Cu is the ultrafiltrate concentration and Ci is the initial O plasma concentration. The percent of bound compound is listed in Table 7.

c- Table 7.

0 Example #43 99.5 bound Example #530 78% bound Example #531 92% bound Example #532 96.8% bound Example #533 82.6% bound It has been demonstrated in the literature (Wu-Wong, et al., Life Sci. 1996, 58, 1839-1847, and references contained therein) that compounds which are highly protein bound show decreased potency in vitro in the presence of plasma proteins. A decrease in in vitro potency may correspondingly result in reduced in vivo potency. An endothelin antagonist which has reduced protein binding might be expected to be less susceptible to this effect, and thus be more potent as an in vivo agent.

The ability of "reduced protein binding" endothelin antagonists to exhibit enhance activity in the presence of serum albumin has been demonstrated through the following study: A series of binding curves is recorded for a given antagonist, each experiment performed in the presence of increasing concentrations of serum albumin.

Protocol for Albumin-induced binding shift studies: Binding assays were performed in 96-well microtiter plates precoated with 0.1 BSA unless otherwise indicated. Membranes were diluted in Buffer B (20mM Tris 100mM NaCI, 10mM MgCI2, pH 7.4, 0.1 mM PMSF, 5mg/mL Pepstatin A, 0.025% bacitracin and 3 mM EDTA) to a final concentration of 0.05 mg/ml of protein.

Varying concentrations of human serum albumin (HSA) were added as indicated.

In competition studies, membranes were incubated with 0.1 nM of [1 25 1]ET in WO 99/06397 PCT/US98/1 5479 -741- Buffer B (final volume: 0.2 ml) in the presence of increasing concentrations of unlabeled test ligands for 4 hours at 25 0 C. After incubation, unbound ligands were separated from bound ligands by vacuum filtration using glass-fiber filter strips in PHD cell harvesters (Cambridge Technology, Inc., Watertown, MA), followed by washing the filter strips with saline (1 ml) for three times.

Nonspecific binding was determined in the presence of 1 pM ET-1.

Figure 1A.

i 10" 1C [Example 43], M >98% Protein Bound Figure 1B. Figure 1C.

10" 10 1 1 10 10 10 10-" 10"- .Example 531], M [Example 530], M 2% protein bound 78% Protein Bound Figure 1 Inhibition of 1 25 ]ET-1 binding to human ETA receptor by ETA antagonists. Each curve was determined in the presence of either or 5% HSA, and WO 99/06397 PCT/US98/15479 742 assays were performed as described above. The results are expressed as of control binding, with [1 25 1]ET-1 binding in the absence of antagonist defining 100%. Each point represents the mean of three determinations.

IN As observed in Figure 1A, a compound which is highly protein bound (Example 4 >98% bound) shows a rightward shift of the binding curve (toward decreasing potency C in the presence of increasing albumin levels. The compound of Example 531 (Figure 1 B 0 in which protein binding is reduced to 92%, shows a substantial diminution of this c rightward shift; the shift is completely eliminated with the compound of Example 530 (Figure 1C), in which protein binding is reduced to 78%. This experiment demonstrates that a reduction in protein binding translates into increased potency in the presence of plasma proteins, and suggests that such compounds may exhibit enhanced in vivo activity.

The observed reduction in protein binding, in compounds which retain high affinit for endothelin receptors, appears linked to the placement of "basic" functionality (group which carry a positive charge at physiological pH).

Such compounds also exhibit improved solubility in aqueous solutions, as demonstrated below (Table 1) in an experiment in which maximum solubility was measured in aqueous media at varying pH at about 25 0 C. These results indicate that compounds that contain charged groups on the amide sidechain exhibit increased solubility over a significant range of pH. Such increased aqueous solubility, coupled wit the enhanced potency resulting from decreased protein binding, might make such compounds preferred for development as parenteral agents. Table 8 presents the pH- Solubility profiles for representative compounds of the present invention.

Table 8.

pH (Example 43] (mg/m [Example 531] (mg/ 5.1 0.08 >3.3 0.51 >3.4 7.1 0.99 3.54 7.6 1.14 3.55 742

I

WO 99/06397 PCT/US98/15479 -743- The present invention provides less protein bound compounds having improved in vitro and in vivo activity as pharmaceutical agents. The present invention Salso provides compounds that show that the affinity of hydrophobic acids for plasma protein may be reduced by attaching a counterbalanced charge at a biologically acceptab c site. For example, protein binding is reduced by attaching a "basic" functionality (group 0 which carry a positive charge at physiological pH) on the amide sidechain (see Formula 0 N wherein R 3 has an amide sidechain).

The present invention covers compounds having the formula XII: R2 Z R3

(CH

2 )n

R

RI

XII

wherein Z is -C(R 1 8

)(R

1 9 or wherein R18 and R 1 9 are independently selected from hydrogen and loweralkyl; 2 n is 0 or 1; R is -(CH2)m-W wherein m is an integer from 0 to 6 and W is

-C(O)

2 -G wherein G is hydrogen or a carbdxy protecting group, -P0 3

H

2 -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl,

-CN,

-C(O)NHR

1 7 wherein R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(0) 2

R

16 wherein R 1 6 is loweralkyl, haloalkyl, aryl or dialkylamino, WO 99/06397 PCT/US98/1,5479 744 (in) -S(O)2NHC(O)Rl6 wherein R 16 is-defi ned as above,

HO

0 HO 0 00

H

N

0

NNH

0

NN

Ho

N

Rl and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, al kynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyal koxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl,' cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl) aminoal kyl, alkylsulonylamidoalkyl, WO 99/06397 PCT/US98/15479 745 heterocyclic, (heterocyclic) alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl. and RC is alkylene, with the proviso that one or both of R, and R 2 is other than hydrogen;

R

3 is (a)R 4 -C(0)-R 5 R4-C(O)-R 5

N(R

6 wherein R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20

)-R

8 or -RaNR0-8 wherein RS and R 8 a are independently selected from the group consisting of alkylene and alkenylene and R 2 0 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl or cycloalkylalkyl or -0-R3 9 or -Rga-0-R 9 wherein R 9 and R 9 a are independently selected from alkylene;

R

4 and R 6 are (11 11 1 1 2 wherein Rl 1 and R1 2 are independently selected from hydrogen,.

loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, (11) heterocyclic, (12) arylalkyl, (1 3) (heterocyclic) alIkyl, (14) hydroxyalkyl, alkoxy, (16) aminoalkyl, (17) trial kylaminoal kyl, (18) alkylaminoalkyl, (19) dialkylaminoalkyl, carboxyalkyl, (21) (cycloalkyl)aminoalkyl, (22) (cycloalkyl)alkylaminoalkyl, (23) (heterocyclic) aminoal kyl, and (24) (heterocyclic)aminoalkyl, with the proviso that at least one of R~ 1 and R, 2 is selected from heterocyclic, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, trial kylarninoalkyl, alkylaminoalkyl, dial kylaminoal kyl, carboxyalkyl, (cycloalkyl)aminoalkyl, (cycloalkyl) al kylaminoalkyl, (heterocyclic) aminoalIkyl, and (heterocyclic) alkylaminoalkyl; or a pharmaceutically acceptable salt thereof.

745 WO 99/06397 PCT/US98/15479 746 Preferred compounds having reduced protein binding are shown in Table 9A wherein R may be selected from the substituents shown in Table 98.

Table 9A.

OCH

3 OCH3OH R. NR. CO R *N R. OON COOH

OH..CH

0 0 1 0~ 2 0 3 o

OCH

3 R .NR

R.N

CON coo H- C OOH ci -C

C

4 ci 5 cH 3 o 0 J 6 0-1 R.N R. N oR.H -COOH COOH

COOH

0. ci 7 0 8 o-/9 ci R N R N Co o N 0 H 0 -0 3 11 0 12 0 746 WO 99/06397 PCTIUS98II 5479 747 COCOO *NW R N R. NN

OO

0 ci 0 13 14 cI 15 0HO R.N R.N R. N COOH- -COOH COlH 0 0 0 16 0 17 *018 ml0o -NN R. N R.N R.N -COH "COOH "COOH 0 -0C0 22 0l 23 CH0 24 OC R.N R. RN _'COOH COOH .,-COOH 0 25. 0 26 0J 27

I

IN

CA

WO 99/06397 PCT/US9S1 5479 -748- Table 9B.

HCNH N.< 0 H '4 0 7 0 10 0 13 0

H

16 0 748

HCNH_N.<V

2 0

H

5 0 8 0 11 0 14 0 17 0

H

3 CN 3 0

H

6 0 9 H

H

12 0 15 0 18 0

I

WO 99/06397 PCTIUS98/15479 -749- 19 H 0 22 0 0 28 0 31 0 0 34 37 0 43 0 46 0,, HN 0

ONL~

49 0 2 20> 0 23 H 0 26 0 29 0 (H3C)2N,,- N rl 32 0 0 35 0 0 41 0 ON 0 47 0 50HN,,J

CH

3 0 53 21 H 0 24 0 27 0 (HaC)NN~h/ 30 0 0 33 0 36 39 0 420 0 0o

ONO

480~) 51 54CH3N~ 749 WO 99/07 PCT/US98/15479 -750-

CH

3 N 0 0 H 0 .56 CH3 ZN 57 o0 HN 0 58 59 s 60 H H 0 Hl 0 61 o 62 H O0

H

64 For the purposes of this disclosure, the term "(cycloalkyl)aminoalkyl" as used herein refers a cycloalkyl moiety attached to the parent compound through an aminoalkyl. Examples of (cycloalkyl)aminoalkyl include (cyclohexane)aminopropyl, (cyclohexane)aminoethyl, and the like.

The term "(heterocyclic)aminoalkyl" as used herein refers to a heterocyclic moiety attached to the parent compound through an aminoalkyl. Examples of (heterocyclic)aminoalkyl include (pyridine)aminopropyl, (benzofuran)aminopropyl, (tetrahydopyran)aminoethyl, and the like.

The term "(cycloalkyl)alkylaminoalkyl" refers to a cycloalkyl moiety attached to the parent compound through an alkylaminoalkyl. Examples of (cycloalkyl)alkylaminoalkyl include (cyclohexane)ethylaminomethyl, (cyclopentane)methylaminoisopropyl, and the like.

The term "(heterocyclic)alkylaminoalkyl" as used herein refers to a heterocyclic moiety attached to the parent compound through an alkylaminoalkyl.

Examples of (heterocyclic)alkylaminoalkyl include (pyridine)ethylaminopropyl, (benzofuran)methylaminoisobutyl, (tetrahydopyran)methylaminoethyl, and the like.

The ability of the compounds of the invention to lower blood pressure can be demonstrated according to the methods described in Matsumura, et al., Eur. J.

Pharmacol. 185 103 (1990) and Takata, et al., Clin. Exp. Pharmacol. Physiol. 10 131 (1983).

The ability of the compounds of the invention to treat congestive heart failure can be demonstrated according to the method described in Margulies, et al., Circulation 82 2226 (1990).

750 WO 99/06397 PCT/US98/15479 751- The ability of the compounds of the invention to treat myocardial ischemia can be demonstrated according to the method described in Watanabe, et al., Nature 344 114(1990).

The ability of the compounds of the invention to treat coronary angina can be demonstrated according to the method described in Heistad, et al., Circ. Res. 54 711 (1984).

3The ability of the compounds of the invention to treat cerebral vasospasm can be demonstrated according to the methods described in Nakagomi, et al., J.

Neurosurg. 66 915 (1987) or Matsumura, et al., Life Sci. 49 841-848 (1991).

I 0 The ability of the compounds of the invention to treat cerebral ischemia can be demonstrated according to the method described in Hara et al., European. J.

Pharmacol. 197: 75-82, (1991).

The ability of the compounds of the invention to treat acute renal failure can be demonstrated according to the method described in Kon, et al., J. Clin. Invest. 83 1762 (1989).

The ability of the compounds of the invention to treat chronic renal failure can be demonstrated according to the method described in Benigni, et al., Kidney Int. 44 440-444 (1993).

The ability of the compounds of the invention to treat gastric ulceration can be demonstrated according to the method described in Wallace, et al., Am. J. Physiol.

256 G661 (1989).

The ability of the compounds of the invention to treat cyclosporin-induced nephrotoxicity can be demonstrated according to the method described in Kon, et al., Kidney Int. 37 1487 (1990).

The ability of the compounds of the invention to treat endotoxin-induced toxicity (shock) can be demonstrated according to the method described in Takahashi, et al., Clinical Sci. 79 619 (1990).

The ability of the compounds of the invention to treat asthma can be demonstrated according to the method described in Potvin and Varma, Can. J.

Physiol. and Pharmacol. 67 1213 1989).

The ability of the compounds of the invention to treat transplant-induced atherosclerosis can be demonstrated according to the method described in Foegh, et al., Atherosclerosis 78 229-236 (1989).

The ability of the compounds of the invention to treat atherosclerosis can be demonstrated according to the methods described in Bobik, et al., Am. J. Physiol.

258 C408 (1990) and Chobanian, et al., Hypertension 15 327 (1990).

WO 99/06397 PCT/IJS98/15479 -752- The ability of the compounds of the invention to treat LPL-related lipoprotein disorders can be demonstrated according to the method described in Ishida, et al., Biochem. Pharmacol. 44 1431-1436 (1992).

The ability of the compounds of the invention to treat proliferative diseases can be demonstrated according to the methods described in Bunchman ET and CA Brookshire, Transplantation Proceed. 23 967-968 (1991); Yamagishi, et al., Biochem. Biophys. Res. Comm. 191 840-846 (1993); and Shichiri, et al., J. Clin.

Invest. 87 1867-1871 (1991). Proliferative diseases include smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels.

The ability of the compounds of the invention to treat acute or chronic pulmonary hypertension can be demonstrated according to the method described in Bonvallet et al., Am. J. Physiol. 266 H1327 (1994). Pulmonary hypertension can be associated with congestive heart failure, mitral valve stenosis, emphysema, lung fibrosis, chronic obstructive pulmonary disease (COPD), acute repiratory distress, syndrome (ARDS), altitude sickness, chemical exposure, or may be idiopathic.

The ability of the compounds of the invention to treat plaletet aggregation, and thrombosis, can be demonstrated according to the method described in McMurdo et al. Eu. J. Pharmacol. 259 51 (1994).

The ability of the compounds of the invention to treat cancers can be demonstrated according to the method described in Shichiri, et al., J. Clin. Invest. 87 1867 (1991).

The ability of the compounds of the invention to treat IL-2 (and other cytokine) mediated cardiotoxicity and vascular permeability disorders can be demonstrated according to the method described in Klemm et al., Proc. Nat. Acad. Sci. 92 2691 (1995).

The ability of the compounds of the invention to treat nociception can be demonstrated according to the method described in Yamamoto et al., J. Pharmacol.

Exp. Therap. 271 156 (1994).

The ability of the compounds of the invention to treat colitis can be demonstrated according to the method described in Hogaboam et al (EUR. J.

Pharmacol. 1996, 309, 261-269).

WO 99/06397 PCT/US98/15479 -753- The ability of the compounds of the invention to treat ischemia-repurfusion injury in kidney transplantation can be demonstrated according to the method described in Aktan et al (Transplant Int 1996, 9, 201-207).

The ability of the compounds of the invention to treat angina, pulmonary hypertension, raynaud's disease, and migraine can be demonstrated according to the method described in Ferro and Webb (Drugs 1996, 51,12-27).

The compounds of the present invention can be used in the form of salts K derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, q 10 benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogencontaining groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula or separately by reacting the carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Such pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quatemary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other i V WO 99/06397 PCT/US98/15479 0 754representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

The compounds of the invention are useful for antagonizing endothelin in a O 5 human or other mammal. In addition, the compounds of the present invention are S useful (in a human or other mammal) for the treatment of hypertension, acute or S chronic pulmonary hypertension, Raynaud's disease, congestive heart failure, C myocardial ischemia, reperfusion injury, coronary angina, cerebral ischemia, cerebral vasospasm, chronic or acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin-induced toxicity, asthma, fibrotic or proliferative diseases, including smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels, LPL-related lipoprotein disorders, transplantation-induced atherosclerosis or atherosclerosis in general, platelet aggregation, thrombosis, cancers, prostate cancer, IL-2 and other cytokine mediated cardiotoxicity and permeability disorders, and nociception, especially treatment of bone pain associated with bone cancer.

Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more usually 0.1 to 100 mg/kg for oral administration or 0.01 to 10 mg/kg for parenteral administration. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.

The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use 754 WO 99/06397 PCT/US98/15479 o -755- C of transdermal administration such as transdermal patches or iontophoresis devices.

The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous or oleagenous 0 5 suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may Salso be a sterile injectable solution or suspension in a nontoxic parenterally i' acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among 0 the acceptable vehicles and solvents that may be employed are water, Ringer's N 0 solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any nontoxic, physiologically aceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the 755 WO 99/06397 PCT/US9815479 S-756 C like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), Sboth natural and synthetic.

Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

A representative solid dosage form, for example, a tablet or a capsule, 0 comprises: Compound of the invention: 35% w/w SStarch, Pregelatinized, NF 50% w/w

C

N Microcrystalline Cellulose, NF 10% w/w Talc, Powder, USP 5% w/w While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more cardiovascular agents independently selected from diuretics, adrenergic blocking agents, vasodilators, calcium channel blockers, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, potassium channel activators and other cardiovascular agents.

Representative diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamterene, chlorthalidone and the-like or a pharmaceutically acceptable salt thereof.

Representative adrenergic blocking agents include phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol and the like or a pharmaceutically acceptable salt thereof.

Representative vasodilators include hydralazine, minoxidil, diazoxide, nitroprusside and the like or a pharmaceutically acceptable salt thereof.

Representative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene, verapamil, gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof.

Representative renin inhibitors include enalkiren, zankiren, RO 42-5892, PD-134672 and the like or a pharmaceutically acceptable salt thereof.

Representative angiotensin II antagonists include DUP 753, A-81988 and the like.

Representative ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.

756 WO 99/06397 PCT/US98/15479 3 -757- 3 Representative potassium channel activators include pinacidil and the like or a pharmaceutically acceptable salt thereof.

Other representative cardiovascular agents include sympatholytic agents such as methyldopa, clonidine, guanabenz, reserpine and the like or a pharmaceutically acceptable salt thereof.

0 The compounds of the invention and the cardiovascular agent can be S administered at the recommended maximum clinical dosage or at lower doses.

Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of S administration, severity of the disease and the response of the patient. The combination can be administered as separate compositions or as a single dosage form containing both agents.

When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds, processes, compositions and methods.

Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

757

Claims (6)

1. [2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy- z di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or [2S,3R,4S]-2-(4- methoxyphenyl)-4-(1 ,3 -benzodioxol-5-yl)- I -[(N-butyl-N-(4-dimethylaminobutyl)amino) carbonylmethyl]-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt of either one thereof. NO 2. A pharmaceutical composition comprising [2S,3R,4S]-2-(2,2-dimethylpentyl)-4- (7-methoxy-1 (Ni 3-carboxylic acid or [2S,3R,4S]-2-(4-methoxyphenyl)-4-(1 ,3 -benzodioxol-5-yl)- butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3 -carboxylic acid or ri a pharmaceutically acceptable salt of either one thereof together with a pharmaceutically acceptable carrier.

3. A process of making a compound as defined in claim 1 which process is substantially as herein described with reference to Example 536 or Example 547. Is 4. A method of treating bone pain due to bone cancer in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 2. The method of claim 4 wherein the mammal is a human.

6. Use of [2S,3R,4S]-2-(2,2-dimethylpentyl)-4-(7-methoxy- l-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or [2S,3R,4S]-2- (4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1- [(N-butyl-N-(4- dimethylaminobutyl)amino)carbonylmethyl] -pyrrolidine-3 -carboxylic acid or a pharmaceutically acceptable salt of either one thereof in the preparation of a medicament for treating bone pain due to bone cancer in a mammal.

7. [2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy- di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid or [2S,3R,4S]-2-(4- methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- 1 -[(N-butyl-N-(4-dimethylaminobutyl)amino) carbonylmethyl]-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt of either one thereof when used in a therapeutically effective amount to treat bone pain due to bone cancer in a mammal.

8. [2S,3 R,4S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy- I di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 -carboxylic acid or [2S,3 R,4S] methoxyphenyl)-4-( 1,3-benzodioxol-5-yl)-1 -[(N-butyl-N-(4-dimethylaminobutyl)amino) carbonylmethyl]-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt of either one thereof when used according to claim 7 wherein the mammal is a human. (1010754 I):KZA

9. [2S,3R,4S]-2-(2,2-Dimethylpentyl)-4-(7-methoxy- I di(n-butyl)aminocarbonylmethyl)-pyrrol idine-3 -carboxyl ic acid or [2S,3 R,4S] z methoxyphenyl)-4-( 1,3 -benzodioxol-5-yl)- I-[(N-butyl-N-(4-dimethylaminobutyl)amino) carbonylmethyl]-pyrrolidine-3-carboxylic acid or a pharmaceutically acceptable salt of either one thereof for use in treating bone pain due to bone cancer in a mammal. IND Dated 7 November, 2007 Abbott Laboratories Patent Attorneys for the ApplicantlNominated Person 10SPRUSON FERGUSON (1010754 I):K-ZA