AU763835B2 - Heteroaryl succinamides and their use as metalloproteinase inhibitors - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD -PATENT Applicant(s): AGOURON PHARMACEUTICALS, INC SYNTEX INC.

Invention Title: HETEROARYL SUCCINAMIDES AND THEIR USE AS METALLOPROTEINASE INHIBITORS

S

S

The following statement is a full description of this invention, including the best method of performing it known to me/us: HETEROARYL SUCCINAMIDES AND THEIR USE AS METALLOPROTEINASE INHIBITORS Matrix metalloproteases ("MMPs") are a family ofproteases (enzymes) involved in the degradation and remodeling of connective tissues. Members of this family of endopeptidase enzymes are secreted as proenzymes from various cell types that reside in or are associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells, and invasive or metastatic tumor cells. MMP expression is stimulated by growth factors and cytokines in the local tissue environment, where these enzymes act to specifically degrade protein components of the extracellular matrix, such as collagen, proteoglycans (protein core), fibronectin and laminin.

These ubiquitous extracellular matrix components are present in the linings of joints, interstitial connective tissues, basement membranes and cartilage.

The MMPs share a number of properties, including zinc and calcium dependence, secretion as zymogens, and 40-50% amino acid sequence homology. Eleven metalloenzymes been well-characterized as MMP's in humans, including three collagenases, three stromelysins, two gelatinases, matrilysin, metalloelastase, and membrane-type MMP, as discussed in greater detail below.

Interstitial collagenases catalyze the initial and rate-limiting cleavage of native collagen types I, II and III. Collagen, the major structural protein of mammals, is an essential component of the matrix of many tissues, for example, cartilage, bone, tendon and skin. Interstitial *collagenases are very specific matrix metalloproteases which cleave these collagens to give two fragments which spontaneously denature at physiological temperatures and therefore become susceptible to cleavage by less specific enzymes. Cleavage by the collagenases results in the loss of structural integrity of the target tissue, essentially an irreversible process. There are currently three known human collagenases, the first two of which are relatively well-characterized (FASEB la 5, 2145-54 (1991)). Human fibroblast-type collagenase (HFC, MMP-I, or collagenase-1) is produced by a wide variety of cells including fibroblasts and macrophages. Human neutrophiltype collagenase (HNC, MMP-8, or collagenase-2) has so far only been demonstrated to be produced by neutrophils. The most recently discovered member of this group of MMPs is human collagenase-3 (MMP-13), which was originally found in breast carcinomas Biol. Chem., 269, 16,766-16,773) (1994)), but has since shown to be produced by chondrocytes Clin. Invest., 97, 761-768, 1996).

The gelatinases include two distinct, but highly related, enzymes: a 72-kD enzyme (gelatinase A, HFG, MMP-2) secreted by fibroblasts and a wide variety of other cell types, and a 92-kD enzyme (gelatinase B, HNG, MMP-9) released by mononuclear phagocytes, neutrophils, corneal epithelial cells, tumor cells, cytotrophoblasts and keratinocytes. These gelatinases have been shown to degrade gelatins (denatured collagens), collagen types IV (basement membrane) and V, fibronectin and insoluble elastin.

Stromelysins 1 and 2 have been shown to cleave a broad range of matrix substrates, including laminin, fibronectin, proteoglycans, and collagen types IV and IX in their non-helical I domains.

Matrilysin (MMP-7, PUMP-1) has been shown to degrade a wide range of matrix substrates including proteoglycans, gelatins, fibronectin, elastin and laminin. Its expression has been documented in mononuclear phagocytes, rate uterine explants and sporadically in tumors.

Other less characterized MMPs include macrophage metalloelastase (MME, MMP-12), membrane type MMP (MMP-14), and stromelysin-3 (MMP-11).

Excessive degradation of extracellular matrix by MMPs is implicated in the pathogenesis of many diseases of both chronic and acute nature. For example, numerous studies, as reviewed in Exp. Opin. Invest. Drugs, 5, 323-335, (1996), have established that expression and activation of MMPs are critical events in tumor growth, invasion and metastasis. In addition, MMP activity has been found to be required for angiogenesis, which is necessary for tumor growth as well for other pathological conditions such as macular degeneration.

MMPs, especially stromelysin-1, collagenases-1, and collagenase-3, have been strongly implicated in the destruction of articular cartilage that is the hallmark of rheumatoid arthritis and osteoarthritis. See, for example, J. Clin. Invest., 97,761-768 (1996). In addition, the tissue destruction associated with gingivitis and periodontal disease is believed to be mediated by overexpression of MMPs in response to proinflamrnatory cytokines. See Molecular Pathogenesis of Periodontal Disease, Ch. 17, 191-202(1994). Other diseases in which critical roles for MMPs have been identified include multiple sclerosis Neuroimmunol., 41, 29-34 (1992)), corneal ulceration (Invest. Opthalmol and Visual Sci.. 32, 1569-1575 (1989)), stroke (Brain Research, 703, 151-155 (1995) and J. Cereb. Blood Flow Metab., 16, 360-366 (1996)), sun-induced skin ageing (Nature, 379, 335-339 (1996)), chronic obstructive pulmonary disease, such as emphysema (Am. J. Respir. Cell. Mol. Biol. 7,5160-5165 (1994)), chronic ulceration (J.

Clin. Invest., 94, 79-88 (1994)), cardiac arrhythmia, and endometriosis. Finally, roles for MMPmediated degradation of basement membranes have been proposed in the rupture of atherosclerotic plaques (Basic Res. Cardiol., 89(SUPPL. 59-70, (1994)) and in the development of glomerular disease Clin. Invest., 97, 1094-1101 (1996)).

Inhibitors of MMPs are expected to provide useful treatments for the diseases described above in which degradation of the extracellular matrix by MMPs contributes to the pathogenesis of the disease. In general, selective MMP inhibitors of particular subsets of MMPs may offer therapeutic advantages, as it has been typically observed that a limited number of members of the MMP family are involved in any one of the disease states listed above. For example, the involvement of individual collagenases in the degradation of tissue collagens probably depends markedly on the tissue. The tissue distribution of human collagenases suggests that collagenase- 3 is the major participant in the degradation of the collagen matrix of cartilage, while collagenase-I is more likely to be involved in tissue remodeling of skin and other soft tissues. In addition, stromelysin-1 appears to be largely responsible for excessive loss of proteoglycan from cartilage. Thus, the inventive compounds disclosed herein that are selective inhibitors for collagenase-3 and stromelysin over collagenase-1 are preferred for treatment of diseases associated with cartilage erosion, such as rheumatoid and osteoarthritis. Similarly, among the MMPs, metalloelastase has been specifically implicated in the pathology of pulmonary emphysema. SeeJ. Biol. Chem. 270, 14568-14575 (1995).

*The design and uses of MMP inhibitors are reviewed, for example, in J Enzyme Inhibition, 2, 1-22 (1987); Progress in Medicinal Chemistry 29, 271-334 (1992); Current Medicinal Chemistry, 2, 743-762 (1995); Exp. Opin. Ther. Patents, 5, 1287-1296 (1995); and Drug Discovery Today, 1, 16-26 (1996). MMP inhibitors are also the subject of numerous ,patents and patent applications. In the majority of these publications, the preferred inventive compounds are hydroxamic acids, as it has been well-established that the hydroxamate function is the optimal zinc-coordinating functionality for binding to the active site of MMPs. For 5 example, the hydroxamate inhibitors described in the literature are generally 100 to 1000-fold more potent than the corresponding inhibitors wherein the hydroxamic acid functionality is replaced by a carboxylic acid functionality. Nevertheless, hydroxamic acids tend to exhibit relatively poor bioavailability. The preferred compounds disclosed herein are carboxylic acid inhibitors that possess inhibitory potency against certain of the MMPs that is comparable to the potency of the hydroxamic acid inhibitors that have been reported in the literature. The following patents and patent applications disclose carboxylic acid inhibitors that are, as are the inventive carboxylic acid inhibitors disclosed herein, monoamine derivative of substituted siccinic acids: Celltech Ltd.: EP-A-0489577 (WO 92/099565), EP-A-0489579, (WO 93/24475), WO 93/244449; British Biotech Pharameuticals Ltd.: WO 95/32944, WO 95/19961; Sterling Winthrop, Inc.: US 5,256,657; Sanofi Winthrop, Inc.: WO/9522966; and Syntex Inc. WO 94/04735, WO 95/12603, and WO 96/16027.

20 Throughout the description and claims of this *specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", means "including but not limited to", and is not intended to exclude other additives, components, integers or steps".

All references, including any patents or patent applications, cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.

6 SUMMARY OF THE INVENTION The present invention provides a compound of formula I:

H

Ny Y R3

R

4 0 R2

S

9*

S.

wherein: X is a single bond or a straight or branched, saturated or unsaturated chain containing 1 to 6 carbon atoms, wherein one or more of the carbon atoms are optionally independently replaced with 0 or S, and wherein one or more of the hydrogen atoms are optionally replaced with F; Y is -CH(OH)- RI is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group;

R

2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group or C(O)Rio wherein R 10 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NR 11

R

12 wherein R 11 is H, an alkyl group, an O-alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and wherein R 12 is H, an alkyl group, an aryl group, a 7 heteroaryl group, a cycloalkyl group or a heterocycloalkyl group, or wherein R 11 and R12 form together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group, and R 3 is H or an alkyl group, or R 2 and R 3 together with the atoms to which they are attached form a cycloalkyl. R 4 is H or any suitable organic moiety; Rs is C(O)NHOH, C(0)OR 1 3 SH, N(OH)CHO, SC(O)Ri 4 P(O) (OH) Ris, or P(O) (OH) OR 13

R

13 is H, an alkyl group or an aryl group,

R

14 is an alkyl group or an aryl group, and

R

15 is an alkyl group; and wherein .o 0 .0 is a heteroaryl group having five ring atoms, containing one 0 atom only as the heteroatom; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound of the formula The present invention is further directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound of the formula The present invention is even further directed to methods of using the compounds of formula and pharmaceutically acceptable salts and solvates thereof, and \\perthOl\home$\yasminp\keep\Retype\ 7 8 2 53-Ol.1.doc 8 pharmaceutically acceptable prodrugs thereof, said prodrug being different from a compound of the formula The entire disclosure in the complete specification of our Australian Patent Application No. 48060/97 is..by this cross-reference incorporated into the present specification.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to compounds of the formula 1:

,R

X

H

Rt N YR(I)

R

4 0

R

2 wherein X is a single bond or a straight or branched, saturated or unsaturated chain containing 1 to 6 carbon atoms, wherein one or more of the carbon atoms are optionally independently replaced with O or S, and wherein one or more of the hydrogen atoms are optionally :replaced with F; Y is a single bond, or R, is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group;

R

2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C(O)R,, wherein Rio is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NR, ,R 2 wherein is H, an alkyl group, an O-alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and 9 wherein R 1 2 is H, an alkyl group, an arYI group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or wherein and form, together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group; and R3 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, NR, R 1 or wherein R, and R 1 2 are as defined above, or R, and R 3 together with the atom(s) to which they are attached, form a cycloalkyl group or a heterocycloalkyl group; R, -is H or any suitable organic moiety; is C(O)NHOH, C(O)0R 1 1 SH, N(OH)CHO, P(O)(OH)R,3, or P(O)(OH)0R 1 3 wherein R,3 is H, an alkyl group, or an aryl group; is an alkyl group or an aryl group; and is an alkyl group; and is a heteroaxyl group having five ring atoms, including 1, 2 or 3 heteroatorns selected from 0, S, and N; and pharmaceutically acceptable salts and solvates thereof, and pharmaceutically acceptable prodrugs thereof, said prodrugs being different frm compounds of the formula with the proviso that if the compound of formula is:

AA

CN-(CH)

R

4 H 11 R4 0 0 wherein R 1 R, and R5 are as defined above, W is H, OH, a halo group, an alkyl group, or an 0alkyl group, and further wherein when mis 2, 3,or4, nis 1, 2,3, or 4,and Ais CH 2 NH, or N-alk-YI;or when m is 4, 5, or 6, n is 0, and A is wherein J is carboxy, alkoxycarbonyl, or carbamoyl; 0: or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different fromr a compound of the formula said prodrug being different from a compound of the formula UI); then is pyrrolyl.

o.&J More preferably the compounds of the present invention are selected from compounds of the formula I wherein X is a single bond; Y is a single bond, -CH(OH)- or R, is an aryl group or a heteroaryl group; R, is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C(O)RIO, wherein Rio is as defined above; R3 is H, an alkyl group, a heteroaryl group, NRlIR 12 or OR, 1 wherein and R 1 1 are as defined above or R, and R 3 together with the atoms to which they are attached, form a cycioalkyl group or heterocycloalkyl group;

R,

1 is H, an alkyl group, OH, an 0-alkyl group, NH 2 NH-alkyl, or a cycloalkyl group; R, is C(O)NHOH, C(O)OR13, SH, or SC(O)R 1 wherein R 1 3 is H, an alkyl group, or an aryl group, and R 1 is an alkyl group or an aryl group; and is pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or triazolyl; or a pharmaceutically acceptable salt or solvate thereof; or a phannaceutically acceptable prodrug thereof, said prodrug being different from a compound of the formula In the compounds of the present invention, and the pharmaceutically acceptable salts and solvates thereof, and pharmaceutically acceptable prodrugs thereof preferably X is a single bond.

In particularly preferred embodiments, when Y is preferably R 3 is H or an alkyl group or together with R 2 and the atom(s) to which R, and R, are attached forms a cycloalkyl group or heterocycloalkyl group, and more preferably R 3 is H. When Y is preferably R 3 is an alkyl group, NR, R 12 or wherein and R 1 are as defined above, or together with R 2 and the atoms to which R, and R, are attached, forms a cycloalkyl group or heterocycloalkyl group. When Y is a single bond, preferably R 3 is a heteroaryl group, more preferably the heteroaryl group:

R

2 1 N R,

H

wherein R 2 and R,2 are independently any suitable organic moiety or together with the carbon atoms to which they are attached form an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group. Preferably R 21 and R 2 2 are selected from hydrogen, an alkyl group, an aryl group, a heteroaryl group, a halo group, a C(O)O-alkyl group, a carbamoyl group, a cycloalkyl group, or a heterocycloalkyl group.

Preferably R, is an aryl group or a heteroaryl group. More preferably R, is an aryl group of the formula: wherein Z is H, halogen, an alkyl group, an 0-alkyl group, a cyano group, a hydroxy group, an aryl group, a heteroa-yl group, or a heterocycloalicyl group.

Preferably P, is H, an alkyl group, or OH. More preferably R, is H or an alkyl group selected from CHRI 6 0H and CH(NHR 7

)RI

6 wherein R, 6 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and is C(Q)Rjg, SO,Rlg, H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or R 1 6 and together with the atoms to'which they are attached, form a heterocycloalkyl group; wherein R, 8 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an 0-aryl group, an 0-alkyl grup, or NR 1 9R2,; wherein Rig and R 20 independently are H, an alkyl group, an aryl group, a beteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or Rig and R 20 together with the nitrogen atom to which they are attached, formn a heterocycloalkyl group.

Preferably is pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or triazolyl, more preferably is pyrrolyl, fay[ or thienyl, and most preferably is pyrrolyl.

Preferably R5 is C(O)NI-IOH or C(O)0R 3 wherein R 13 is hydrogen.

Particularly preferred compounds according to the invention include: N-[2,2-Dimethyl-1 (S)-(methylcarbamoyl)propyl]-3(R)-(3-phenylolIH-pyrrol- 1yl)succinarnic Acid; N-(8-Oxo-4-oxa-1I,7-diazatricyclo(9.6. 1.0 2 7 )octadeca- 11(18),! 2,14,1 6-tetraen-9(S)-yl) -3(R)-(3-phenyl- 1H-pyrrol- 1-yI)succinamic Acid; N.[2,2-Dimethyl- I(S)-(methylcarbanioyI)propyl]-3(R)[3.(pyrd4-yi) I H-pyrroI. l.

yIlsuccinamic Acid; 3 (R)-[3-(Biphenyl-4-yl)- IH-pyrrol- i-yl]-N-[2,2-diniethyl- I(S)- (methylcarbanioyl)propyl~succinarnic Acid; iphenyl-yI).1 H-pyrrol-1I-yI]-N- [2-hydroxy- IH-imidazol-4yl)methyllethyl]succiriamic Acid; N-[2,2-Dimethyl-1 (S)-(methylcarbanioyl)propyI]-3(R)-[3-(4-pro pylpheny)- 1 H-pyrrol- I -ylJ succinamic Acid; 3(R)-[3-(4-Cyanophenyl)- IH-pyrrol-1I-yI]-N-[2,2-dimethyl- 1(S)- *~.(methy~carbamnoyl)propyl] succinamic Acid; N-(2,2-Dimethyl- 1(S)-(hydroxymethyl)propylJ-3 (R)-[3-[4-(pyridin-4-yI)phenyll- 11pyrrol- I -yI]succinamic Acid; N-(2-Hydroxy- 1 (S)-phenylethyI)-3(R)-[3-[(4-(pyridin4.y)pheny] 1 H-pyrrol- I1yI]succinaxnic Acid; 3(R)-(3-(4'-Cyanobiphenyl-4-y 1)-i H-pyrrol- i-yi]-N-(2,2-dimethyl- I(S)- (methylcarbamoyl)propyljsuccinamic Acid; ~3(R)-[3-(4'-Cyanobiphenyl-4-yI)- 1H-pyrrol- I -yI]-N-[2,2-dimethyl- I(S)-(pyridin-4ylcarbamoyL)-propyl]succinamic Acid; 3(R)-[3-(4'-Carbarmoylbiphenyl-4-yI)- 1H-pyrrol- 1-yl-N-[2,2-dimethyl- 1(S)- (methylcarbamoyl)propyl]succinamic Acid; 3 (R)-(3-(4'-Carbamoylbiphenyl-4-yI). 1 H-pyrrol- 1 -yl] ditnethyl- 1 (S)-(pyridin-4-yIcarbaznoyl)propyi)succinamic Acid; 3(R)-(3-(4-Cyanobiphenyl-4-yI)- I H-pyrrol- I -yl]-N-[,-iehl (hydroxyrnethyl)pTOPYl] succinaniic Acid; N-(2(R)-Hydroxyindan- 1 (R)-[3-(4-(pyridin-4-yl)phenyl)- I H-pyrroL- I -yl] succinarnic Acid; N-(2,2-Dimethyl- I(S)-(methylcarbamoyl)propyl)-3 (R)-fI3-(4-pyridin-4-yI)phenyI)- I Hpyrrol- 1 -yllsuccinarnic Acid; N-(4,4-Dimethyl-2-oxo-tetrahydrofuran-3(S)-yI)-3 (R)-[3-[4-(pyridin-4-yI)phenyl]- I Hpyrrol- I -yIlsuccinaniic Acid;F N-(g-Oxo-4-oxa- 1 ,7-diazatricyclo[9.6. 1.0 7 ]octadeca- 11(1 12,14,1 6-tetraen-9(S)-yi)-I 3 (R)-[3-(4-(pyridin-4-yl)phenyl]-1 H-pyrrol-1I-yI] succinaniic Acid; N.{2,2-Dimethyl- I(S)-(pyridin-4-ylcarbamoyl)propyl]-3(R)-[3-[4-(pyridin-4-yI)phenyl IH-pyrrol-l-yl]succinamic Acid; 1(S)-(IH-ImidazoL-2-yI)-3-methylbutyl]-3(R)-[3-[4-(pyridin-4-y)phenyl]- 1H-pyrrol- 1yl] succinamic Acid; N'-(2,2-Dimcthyl-1 (S)-(hydroxymethyl)propyl]-N'-hydroxy-2(R)-[3-[4-(Pyridin-4yl)phenylj- IH-pyrrol-l -yl] succinamide; ~N-[2,2-DiniethyL- I(S)-(methylcarbamoyl)propyl]-3(S)-[ I-(4-fluorophenyl)- IH-pyrrol-3yIlsuccinamic Acid; I -(4'-Cyanobiphenyl-4-yI)-l H-pyrrol-3.yI)-N-[2,2-dimethyl- I (methylcarbamoyl)propyl]succinaxnic Acid; -(4'-Cyanobiphenyl-4-yl). I H-pyrrol-3-yl]-N-[ I 1 H-irnidazol-2-yl)-3rnethylbutyllsuccinamic Acid; -(4'-Cyanobiphenyl-4-yl)- IH-pyrrol-3-yI]-N-(4,4-dimethyl.2-oxo-tetrahydrofuran- 3 (S)-yI)succinarnic Acid; [3-(4'-Cyanobiphenyl-4-yI)- IH-pyrro I IH-imi-dazol-2-yI)-3 methylbutyl]succinaxnic Acid; 3(R)-[3-(4-Cyanophenyl)- 1 H-pyrrol- I I H-imidazol-2-yl).3methylbutyljsuccinamic Acid; [2,2-Dimethyl- 1(S)-(hydroxymethyl)propyl]-3 I -[4-(pyridtin-4-yl)phenyl]- IHpyrrol-3-yi] succinarnic Acid; {3-[2-(4-Cyanophenyl)ethynyl]- 1H-pyrrol- 1-yi) -N-[2,2-dimethyl- I (S)(methylcarbamoyl)-propyl] succinamic Acid; (3-[2-(4-Cyanophenyl)ethyl]- IH-pyrrol- i-yI (2,2-dimethyl- I (S)(methylcarbanioyl)-propyl] succinaznic Acid; N' -Hydroxy-N'-methyl-3(R)-[3-(4-(pyridin4-yl)phenyl)- 1 H-pyrrol- 1 -yl]succinamide; 3(R)-[3-(4-Cyanobiphenyl-4-y}- I H-pyrrol- I -yI]-2(S)-cyclopropyl-N-(2,2-dimethyl- I (S)(methylcarbamoyl)propyl)succinamic Acid; -Cyanobiphenyl-4-y)furanA-yl]-N-[2,2-dinethyl- 1 (S)-(methylcarbaxnoyl) propyljsuccinamic Acid; 3(5)41 -(4'-CyanobiphenyI--y1)- IH-pyrrol-3-yI]-N-(2,2-diznethyl- I(S)- (methylcarbamoyl)propyl)-2(R)-(hydroxymethyl)succinamic Acid; 1 -(4'-Cyanobiphenyl-4-yl)- 1 H-pyrrol-3 -yl]-N-(2,2-dimethyl. I (methylcarbamoyl)propyl)-2(S)-(hydroxy)succinamnic Acid; 4 '-Cyanobiphenyl-4-yl)- I H-pyrrol- I -yI]-N-(2,2-dimethyl- 1(S)- (methylcarbamoyl)propyl)2(S)(hydroxy)succinmic Acid; and the pharmaceutically acceptable salts and solvates thereof, and the pharmace utically acceptable prodrugs thereof.

As used in the present application, the following definitions apply: An "alkyl group" is intended to mean a straight or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, pentenyl, buteriyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like, which may be unsubstituted containing only carbon and hydrogen) or substituted by one or more suitable substituents as defined below.

An "0-alkyl group" is intended to mean an oxygen bonded to an alkyl group, wherein the alkyl group is as defined above.

A "cycloalkyl group" is intended to mean a non-aromatic, monovalent monocyclic, *bicyclic, or tricyclic radical containing 3, 4,5, 6,7, 8, 9,10, 11, 12, 13, or 14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituets as defined below, and to which may be fused one or more heterocycloalcyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of cycloalcyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentYl, cyclopentenyl, cyclohexcyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo(2.2. 1. .heptyI, 18

I-

bicyclo[2.2. 1 .]hept-2-en-5.yl, bicyclo[2.2.2]oct, bicycLof3.2. I .Jnonyl, bicyclo[4.3 .Q]nonyl, bicyclo(4.4.0]decyl, indan-lI-yl, indan-2-yl, tetralin- I-yl, tetralin-2-yI, adamantyl, and the like.

A 'heterocycloalkyl group" is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6,7, 8, 9, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, and which includes 1, 2. 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the radical is unsubstituted or substituted byone or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H- 1 ,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1 ,3 -dioxolanyl, 1 ,3-dioxanyl, I ,4-dioxanyl, 1 ,3-oxathiolanyl, I ,3-oxathianyl, I ,3-dithianyl, azabicylo[3 .2.1 ]octyl, azabicylo(3.3. 1 ]nonyl, azabicylo[4.3.Ojnonyl, oxabicylo[2.2. 1 ]heptyl, so I ,S,9-triazacyclododecyl, and the like.

An "aryl group" is intended to mean an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heteracycloalkyl -groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluoren-2-yl, indan-5-yl, and the like.

A "heteroaryl group" is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heteroaryl groups include, but are not limited to, pyrrolyl, irnidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridyl, pyrinidyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, benzofuryl, isobenzofunyl, benzothienyl, quinolyl, isoquinolyl, phthalazinyl, carbazolyl, purinyl, pteridinyl, acridinyl, phenanthrolinyl, phenoxazinyl, phenothiazinyl, and the like.

An "acyl group" is intended to mean a radical, wherein R is any suitable substituent as defined below.

A "sulfonyl group" is intended to mean a -S(OXO)-R- radical, wherein R is any suitable :substituent as defined below.

The term "suitable substituent"' is intended to mean any of the substituents recognizable to those skilled in the art as not adversely affecting the inhibitory activity of the inventive *.compounds. Illustrative examples of suitable substituents include, but are not limited to, oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, itro groups, cycloalkyl groups, heterocycloallcyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups, groups of formula (A) 0 o (A) Ra wherein R. is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (B) 0 C1 Ra (B) -N0" a wherein R 1 is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (C) 11* (C) wherein RFt and R, are independently hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (D) Rd Ii(D) wherein Rd is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, anl alikYlaflufo group, a dialkylamino group, or an acylamino group; and R, is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an amino group, an alkylamino group, or a dialkylamino group, groups of formula (E) 0

II

S-R, (E)

II

O

wherein R, is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (F) 0

(F)

0 *h wherein R, and R, are independently hydrogen, an alkyl group, a cycloalkyl group, a "heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (G)

(G)

wherein R, is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula formula formula formula or formula «j groups of formula (H) N (H) Rj wherein R is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, or a group of formula formula formula or formula and wherein Rk is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula formula formula formula formula or formula groups of formula (J) s^

(J)

wherein R is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula and groups of formula (K) :i o 9 0 II (K)

-P-R,

wherein R, and R, are independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, an alkylamino group, or a dialkylamino group.

The term "suitable organic moiety" is intended to mean any organic moiety recognizable to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable organic moieties include, but are not limited to oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups, and groups of formulas and as defined above.

A "hydroxy group" is intended to mean the radical -OH.

An "oxo group" is intended to mean the divalent radical =0.

A "halo group" is intended to mean any of the radicals -Cl, -Br, or -I.

A "cyano group" is intended to mean the radical -C=N.

A "nitro group" is intended to mean the radical -NO A "trialkylsilyl group" is intended to mean the radical -SiR where R, and R, are S* each independently an alkyl group.

A "carboxy group" is intended to mean a group of formula wherein R, is hydrogen.

A "alkoxycarbonyl group" is intended to mean a group of formula wherein R, is an alkyl group as defined above.

A "carbamoyl group" is intended to mean a group of formula wherein R, and R, are both hydrogen.

An "amino group" is intended to mean the radical -NH 2 An "alkylamino group" is intended to mean the radical -NHR, wherein R, is an alkyl group as defined above.

A "dialkylamino group" is intended to mean the radical -NRR,, wherein R, and R,, which are the same or different, are each an alkyl group as defined above.

A "pharmaceutically acceptable prodrug" is intended to mean a compound that may converted under physiological conditions or by solvolysis to a compound of the formula I.

A "pharmaceutically acceptable solvate" is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of compounds of formula I.

Examples of pharmaceutically acceptable solvates include, but are not limited to, compounds of formula I in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

In the case of solid formulations, it is understood that the inventive compounds may exist in different forms, such as stable and metastable crystalline forms and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.

-A "pharmaceutically acceptable salt" is intended to mean those salts that retain the biological effectiveness and properties of the free acids and bases and that are not biologically or otherwise undesirable.

Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxyenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene- -sulfonates, naphthalene-2-sulfonates, and mandelates.

If the inventive compound is a base, the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such a p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, V such as an amine (primary, secondary or tertiary), an alkali metal or alkaline earth metal hydroxide or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The inventive compounds may exist as single stereoisomers, racemates and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Preferably, the compounds of the present invention are used in a form that contains at least 90% of a single isomer enantiomeric or diastereomeric excess), more preferably at least 95% (90% e.e. or even more preferably at least 97.5% (95% e.e. or and most preferably at least 99% (98% e.e. or Compounds identified herein as single stereoisomers are meant to describe compounds used in a form that contains at least 90% of a single isomer.

The present invention is further directed to methods of inhibiting matrix metalloproteinase activity that comprise contacting the protease with an effective amount of a compound of formula I or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt or solvate thereof. For example, one can inhibit matrix metalloproteinase activity in mammalian tissue by administering a compound of formula I or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt or solvate thereof.

The activity of the inventive compounds as inhibitors of matrix metalloproteinase activity Smay be measured by any of the methods available to those skilled in the art, including in vive and in vitr assays. Examples of suitable assays for activity measurements include the fluorometric determination of the hydrolysis rate of a fluorescently-labelled peptide substrate, which is described herein.

Administration of the compounds of the formula I, or their pharmaceutically acceptable S prodrugs or pharmaceutically acceptable salts or solvates, may be performed according to any of the accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include, but are not limited to, oral, nasal, intraocular, parenteral, topical, transdermal and rectal.

The inventive compounds of formula I, and their pharmaceutically acceptable prodrugs and pharmaceutically acceptable salts and solvates, may be administered as a pharmaceutical composition in any suitable pharmaceutical form recognizable to the skilled artisan. Suitable pharmaceutical forms include, but are not limited to, solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions and aerosols. The pharmaceutical composition may also include suitable excipients, diluents, vehicles and carriers, as well as other pharmaceutically active agents, depending upon the intended use.

Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions are known to those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating and compressing when necessary for tablet forms, or mixing, filling and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraural and/or rectal administration.

Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles or excipients may be employed in the pharmaceutical compositions. Illustrative solid carriers include starch, lactose, calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid. Illustrative liquid carriers may include syrup, peanut oil, olive oil, saline solution, and water. The carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid solution), or a nonaqueous or aqueous liquid suspension.

28 A dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound a compound of formula I or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt or solvate thereof) and preferably is made up of one or more pharmaceutical dosage units. The selected dose may be administered to a mammal, for example, a human patient, in need of treatment mediated by inhibition of matrix metalloproteinase activity, by any known method of administering the dose including topical, for example, as an ointment or cream; orally, rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural or intraocular infusion.

A "therapeutically effective amount" is intended to mean that amount of a compound of formula I or II that, when administered to a mammal in need thereof, is sufficient to effect treatment for disease conditions alleviated by the inhibition of the activity of one or more matrix metalloproteinases, such as tumor growth, invasion or metastasis, osteoarthritis, rheumatoid arthritis, osteoporosis, periodontitis, gingivitis, chronic dermal wounds, corneal ulcerations, degenerative skin disorders, multiple sclerosis, stroke, diabetic retinopathy, macular T'*i degeneration, angiofibromas, hemangiomas, chronic obstructive pulmonary disease, such as emphysema, atherosclerosis, glomerular disease, cardiac arrhythmia, endometriosis or disease conditions characterized by unwanted angiogenesis. The amount of a given compound of formula I that will correspond to a "therapeutically effective amount" will vary depending upon factors such as the particular compound, the disease condition and the severity thereof, and the identity of the mammal in need thereof, but can nevertheless be readily determined by one of skill in the art.

"Treating" or "treatment" is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is alleviated by the inhibition of the activity of one or more matrix metalloproteinase, such as tumor growth, invasion or metastasis, osteoarthrities, rhematoid arthritis, osteoporosis, periodontis, gingivitis, chronic dermal wounds, corneal ulcerations, degenerative skin disorders, multiple sclerosis, stroke, diabetic retinophathy, macular degeneration, angiofibromas, hemangiomas, or disease conditions characterized by unwanted angiogenesis, and includes: prophalactic treatment in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but not yet diagnosed as having it; inhibiting the disease condition; and/or alleviating, in whole or in part, the disease condition.

The inventive compounds, and their salts, solvates and prodrugs, may be prepared by Semploying the techniques available in the art using starting materials that are readily available.

Certain novel and exemplary methods of preparing the inventive compounds are described below.

METHODS FOR PREPARING CARBOXYLATE MATRIX NIETALLOPROTEASE

INHIBITORS

XRi

HE

Y-R3

X.R,

H

N,_Y-R

3 p 42 Y-R, R--YR vzz X"Rl

IH

42

IV

IH

R5 NN, Y--R3 j V4 42 V

VI

PREPARATION OF COMPOUNDS OF FORMA I The methods of preparing compounds of Formula 1, where R 5 is carboxyl, culminate in the deprotection of esters to the corresponding carboxylates as illustrated in Reaction Scheme I below. Appropriate types of esters and the cleavage of R1 5 are described, for example, in Greene, T; Wuts, P.G.M. "Protective Groups in Organic Synthesis," Wiley: 1991 and Kocienski, P.J. "Protecting Groups," Thieme: 1994, which are incorporated herein by reference. Some examples and conditions encountered herein are given below.

REACTION SCHEME I X-R,

X-R,

O H

H

R

6 N Y-R 3 HO N Y-R 3 HO 3 0 0 4 R4 R2 R4 R2 (1) As an example of a typical ester cleavage, an ester of Formula where R( is benzyl is placed in a suspension with solvent, for example, ethyl acetate also containing metal catalyst, preferably palladium(0) in a hydrogen source such as hydrogen gas at one atmosphere or above, at ambient temperature for 30 minutes to three days, preferably four hours. The carboxylates of Formula I, where RI is -COOH, are amenable to customary isolation and purification.

For esters of Formula where R is t-butyl, the ester is deprotected in a solution of solvent, preferably chloroform or dichloromethane, with excess trifluoroacetic acid, at ambient temperature for 15 minutes to 12 hours to obtain a carboxylate of Formula I.

For esters of Formula where R1 is allyl, the ester undergoes cleavage in an inert solvent, preferably acetonitrile, with a catalytic amount of palladium catalyst, such as tetrakis(triphenylphosphine)-palladium(0), with an excess of secondary amine, such as morpholine, for 15 minutes to 12 hours at ambient temperature.

*oo Where the above conditions are incompatible with functional groups contained in either R, or RP, other protective strategies may be used. For example, simultaneous protection where

R

4 is olefinic and R s is carboxylate may occur through their connection as in a halolactone of Formula where X is halogen, as displayed in Reaction Scheme II below. The halolactone (2) undergoes reductive opening to compounds of Formula I, where R 4 is allyl and Rs is carboxylate.

REACTION SCHEME II X--Ri H

O

S H -R0

H

O N Y-R 3 HO3 N Y-R 3 0 o O. H \x

IO

(2)

X

I

Preparation of Compounds of Formula I. where R is Allyl and PR is Carboxvlate A solution of halolactone is exposed to a reductive environment, preferably excess zinc powder in acetic acid. The resulting carboxylate of Formula I where R 4 is allyl is isolated and purified via conventional methods.

Compounds of Formula I where RI is hydroxamic acid (-C(O)NHOH) may be obtained from compounds of Formula I where R s is carboxyl. Any of the numerous commercially available coupling reagents can be used for conversion either to a protected version of a compound of Formula where R 7 is alkyl or directly to hydroxarnate as outlined by the Reaction Scheme III below: REACTION SCHEMIE 1ll 0 H 0 H step 2 0 H HO'0 -R 3 RI-O0, llt NO~ .Y -R, H N 4 Step 1 Preparation of Compounds of Formula or Carboxylic acids of Formula and hydroxylarnine or its 0-alkyl derivatives in inert **solvent, preferably dimethylformamnide (DMF), are coupled with any of the numerous available coupling reagents, preferably benizotriazol-lI-yloxytris(dimethyLamino)-phosphonium hexafluorophosphate (BOP), at ambient temperature for one to 24 hours to provide either hydroxamates or 0-alkyl hydroxamates respectively. The products are amenable to routine handling and purification.

Step 2 Preparation of Compounds of ormula from Compounds of FokrMula (4) Protected hydroxamates of Formula are deprotected as determined by the nature of the protecting group R 7 Where R 7 is a trialkylsilyl, mild acid hydrolysis or fluoride cleavage in protic or aprotic. solvent at ambient temperature or below for one to 12 hours is sufficient. Where

R-

7 is benzyl, selective deprotection without N-0 bond cleavage proceeds in the presence of palladium on carbon, with a hydrogen source, such as hydrogen gas at atmospheric pressure, in a suitable solvent, such as dirnethylformami.de or methanol.

!REP'ARATIjoN OF CO[MPOUTNDS OF FORMdULA

II

Pyrrole compounds of Formula 11 can be prepared from cyclocondensation of arnines of Formula with tetrahydrofurans of Formula as shown below in Reaction Scheme

IV:

REAC'TION SCHEME

TV

NH

3 -X N ,R I- R 6 N, _Y-R 3 e

*R

4 0 R 2 RAI 0 R 2 (7) T Preparation fPO Copuds of Formula 11 Condensation of amine salts of Formula and 2 ,S-dimethoxytetrahydrofurans of Formula may be carried out in acetic acid for a period of one to 24 hours at temperatures from 40.9.C Another effective set of conditions includes heating a solution of compounds and in inert organic solvent, for example I 2 -dichloroethane, with or without acid, such as trifluoroacetic acid, and with or without stoichionietric amounts of water, for a period of one to 48 hours at 40*-90'C. The product of Formula 11 is isolated and purified by conventional means.

ALTERNATE PREPARATION OF COMPOUNDS OF FORMULA 11 Another method for preparation of pyrrole compounds of Formula 11 involves earlier ring formation. Cyclocondensation of D-amino acids of Formula with tetrahydrofurans of Formula and subsequent coupling is shown below in Reaction Scheme V: RLEACTION SCHEME V

NH

2

R

5

OH

k 4 0 a a.

a a a.

a *aa.

(8)

R

2 MeC- OMe 'f-R 3 step 2 step IN

RS

5

OH

(9)

H

R6 NNS Y-Rll ft 4 0 k 11 Step 1 Preparation of Compounds of Formula (9) Amino acids of Formula and 2 ,5-dimethoxytetrahydrofurans of Formula are dissolved or suspended in solution in an inert organic solvent, for example 1,2-dichloroethane, with chlorotrimethylsilane, with or without acid, such as trifluoroacetic acid, and with or without a base, such as pyridine, for a period of one to 48 hours at ambient temperature to 80 C, preferably the latter. The product is isolated and purified by conventional means.

Step 2 Prenaration of Compounds of Formula II from Compounds of Formulas and Carboxylates of Formula and amines of Formula (10) are coupled under typical coupling conditions. Acids of Formula may first be converted to a corresponding activated ester acid fluoride) or used with a reagent, for example BOP, along with the amine (10) in an inert solvent such as chloroform, and with or without a base such as N-methylmorpholine 4 (NMM), for a period of one to 48 hours at 0°C to ambient temperature, preferably the latter. The product II is isolated and purified by conventional means.

PREPARATION OF STARTING MATERIALS "Preparation of Amines of Formula (6) Amines of Formula where R 4 is hydrogen and R 5 is an ester (-COOR 6 are available after two steps as shown in Reaction Scheme VI: coupling of commercially available D-aspartate derivatives (11) and various amines (10) of commercial or synthetic origin.

**Subsequent deprotection of protected amines furnish aine salts Subsequent deprotection of protected amines (12) furnish amine salts REACTION-SCHEMIE VT 0 H )IYI H2N_.,-R 3tp IKNstep 2 0 NHS .X

R

4 -0 HR...r

R,-O

(11~I~z0

A

1 Step I Preparation of Compjounds of Formula (12) Carboxylates of Formula (11) and amines (10) are condensed as described above for the preparation of a compounds of formula II according to Reaction Scheme V. Typical coupling reagents, for example BOP, are used in an inert solvent suzh as chloroform, and with or without a base such as N-methylmorpholine, at 0 0 C to ambient temperature, preferably the latter, for a period of one to 48 hours to furnish the product of Formnula which is isolated and purified by conventional means.

Step 2 Preparation of Aines of Formula (6) t-Butoxycarbonylamines of Formula (12) are deprotected traditionally, for example, in an inert solvent, preferably dichlorornethane or chloroform, with an excess of trifluoroacetic acid, at 0QeC -to ambient temperature, preferably the former, for 3 0 minutes to 18 hours to obtain amine salts which can be immediately used without furzther purification but are amenable to customary handling and purification.

Preparation of Compounds of Formula (18 Aspartates of Formula where R 4 is hydrogen are available for purchase, or from synthesis according to methods understood by those skilled in the art, such as those described in the literature. However, aspanates of Formula where R 4 is alkyl must be synthesized. An example of this synthesis is shown in Reaction Scheme VII below. D-Aspartate (13) is converted via diallyl ester (14) to aspartate which undergoes Ireland-Claisen rearrangement of the p-ester to allyl compound Appropriate processing provides carboxylates of Formula (18) where R 4 is allyl, which are suitable for later conversion to lower alkyls, for example, reduction to where R4 is propyl.

REACTION SCHEME VII 0* 0 0 5q

S

I 55 S. SO II' oo o a t op 3 *I *pi al ep 2 o 0

IS)

S

*O0 4 4 0 0 0° o 0 111 (r 1 0 u fly) steps o 0XO )2 (in( Sten 1- Prenaration of Comnounds of Formula (14) D-Aspartate dual esters can be produced in any of a variety of ways. For example, D-aspartate (13) is esterified with an excess of allyl alcohol, preferably in inert solvent such as benzene with stoichiometric amounts of acid, such as p-toluenesulfonic acid, for one to 12 hours, at reflux under conditions to azeotropically remove water. The salt (14) precipitates or is otherwise isolated and purified by conventional means.

Step 2 Preparation of Comnounds of Formula Protection of an amine is well documented and understood by those skilled in the art. For example, amine salt (14) is treated with excess di-t-butyl-dicarbonate in appropriate solvent, preferably dichloromethane, in the presence of base, preferably triethylamine for one to 24 hours at ambient temperature. The product (15) is isolated and purified by conventional means.

Step 3 Preparation of Compounds of Formula (16 Esters of Formula (15) are treated with a specified stoichiometric amount of hindered lithium amide base, preferably two equivalents of lithium hexamethyldisilazide, in an inert aprotic solvent, preferably tetrahydrofuran, at -78 0 C for 15 to 45 minutes, whereupon preferably two equivalents or more of trialkylsilyl chloride, preferably chlorotrimethylsilane, are added and the reaction solution is subsequently warmed at 50 to 70°C or reflux for 30 minutes to 4 hours, then allowed to cool, and quenched with methanol. Subsequent routine aqueous workup leads to isolation of allyl compound which is purified by conventional means.

Step 4 Preparation of Comnounds of Formula (17 i Acids of formula (16) are esterified to distinguish carboxyl termini. This esterification can be carried out by any of a number of means understood by those skilled in the art, preferably S* with an appropriate isourea to prevent racemization, for example with O-benzyl- N,N'-diisopropylurea, in inert solvent such as chloroform, at reflux for 3 to 6 hours. The diester (17) is isolated and purified by conventional means.

Step 5 Preparation of Compounds of Formula (18) Selective mono-deprotection of diesters of Formula (17) is effected preferentially by means of routine allyl ester cleavage conditions, as discussed above for Reaction Scheme I. A solution of the diester (17) is placed in polar aprotic solvent, preferably acetonitrile, with palladium catalyst, for example with palladium tetrakis-(triphenylphosphine) and excess secondary amine base, preferably morpholine at ambient temperature for 15 minutes to four hours, preferably 30 minutes. The product acid of Formula (18) is isolated and purified in routine manner.

Preparation of Compounds of Formula (2) For the simultaneous protection ofR 4 and R 5 functionality for certain compounds of Formula I, for example where R 4 is allyl and R is carboxyl, the halolactone-amide of Formula is prepared. The synthesis of these compounds of Formula uses methods described for Formula II in Reaction Scheme V, as shown in Reaction Schemes VIII and IX below.

In Reaction Scheme VIII, the monoacid (19) undergoes conventional coupling (as described for Reaction Scheme V) with amine of Formula (10) to give amide of Formula which is deprotected to amine of Formula The pyrrole ring is formed (as in the preparation of pyrroles in Reaction Scheme V) on amine (21) with dimethoxy-furan to obtain products of Formula REACTION SCH-EME Vill 0 oHN 0O1 0 (19 Y-3step 1 0 N Q 0 NH3W X

H

2 ~Y R3 ste 2YH x 0 R 1 2N (20) (21) (21) (7) 2 0 Step 1 Preparation of Compounds of Formula (201 The coupling of acid (19) and amnine (10) is accomplished with the routine peptide amide forming conditions as described above in Reaction Scheme V, Step 2.

Step 2 Preparation of Compounds of Formula (211 The deprotection of amine (20) to amine salt (21) is accomplished as described above for the preparation of arnines of Formula in Reaction Scheme VI, Step 2.

Step 3 Preplaration of Compounds of Formula (2) The formation of pyrroles, of Formula from (21) and can be accomplished as described above in Reaction Scheme V, Step 1.

An alternate route to compounds of Formula proceeds via formation of pyrrole (23) prior to a coupling, as illustrated by Reaction Scheme IX below: REACTION SCHEME I'X step 1 0 x(19) O NH 3

-X

0

OH

x 0 (22) (22) x /R1

S

H

3 CO- 0 OCH 3 (7)

H

2

Y-R

3 step 3 R2 x (23) tep 2_ 23) 1+ 0' x 41%.Y-R 3 (2) Step I Preparation of Compounds of Formula (22) The deprotection of monoacid (19) to amine salt (22) is as described above for the preparation of amnines of Formula in Reaction Scheme VI, Step 2.

Step 2 Preparaton of Compounds of Formula (23)I The condensation and cyclization of compounds (22) and provides pyrroles of Formula (23) in the same manner as discussed above for Reaction Scheme V, Step 1.

Step 3 Alternate Preparation of Compounds-of Formula (2Z) The coupling of acid (23) and amnine (10) is accomplished with the routine peptide amnide formation conditions described above for Reaction Scheme V, Step 2.

For the preparation of late stage intermediates of Formula aspartate derivatives of Formula (19) are needed. As shown in Reaction Scheme X below, intermediate (16) is alternatively cyclized to afford halolactones which simultaneously protect the ultimate carboxylate and olefin of R 4 at an early stage.

REACTION-SCHEME

X

0 HN x stop 1 lb steP 2 0 H~o 0 0

X

S. (19) 1: Preparation of Compounds of Formulaim' Carboxy-olefins of Formula (16) in a suspension of inert solvent; for example *..tetrahydroflnan or acetonitrile, and excess aqueous alkali, preferably sodium bicarbonate, are exposed to excess-halogen, preferably iodine, initially at -10 to 0 0 T, then allowed to warm and equilibrate at ambient temperature over a period of 2 to 24 hours. The product halolactone is isolated and purified according to routine methods.

Step 2: Preparation of Compounds of Formula (19) Compound (19) is prepared from compound of Formula (25) in a manner identical to that described above for the preparation of compounds of Formula (18) in Reaction Scheme VII, Step Preparation of Tetrahydrofurans of Formula (7T The tetrahydrofuran of Formula where R, is hydrogen and X is a single bond is commercially available. More often 3-substituted furans (26) are treated with bromine in methanol to provide 2,5-dimethoxy-dihydrofurans which are in turn hydrogenated to produce tetrahydrofurans The overall approach is illustrated in Reaction Scheme XI below: REACTION SCHEME XI .RI X-/Ri X/RI

X

ste p MeO O step 2 Me 0 Me 0 OMe (26) (27) (7) Step 1 Preparation of Compounds of Formula (27) Furans of Formula (26) are treated with. stoichiometric amounts of bromine in methanol as solvent or in mixtures with less polar solvents, at temperatures of-20 C to ambient temperature, preferably -10°C, for 10 minutes to 8 hours, preferably for 90 minutes. The products (27) are isolated and purified by conventional means.

SteD 2 Preparation of Compounds of Formula (7) Olefins of Formula (27) are reduced in a suitable protic or aprotic solvent under hydrogen at one atmosphere or above in the presence of metal catalyst, preferably rhodium on alumina or palladium on carbon, in the temperature range from about 0°C to 40*C, for about 1-8 hours, preferably 3 hours. Compounds are isolated and purified by conventional means.

The tetrahydrofuran (7a) of Formula where X is a single bond and R, is formyl (-CHO) is commercially available. Construction of various X and R t combinations are possible through elaboration upon the carboxaldehyde. One possible scenario is displayed in Reaction Scheme XII below.

REACTION SCHEME XII SnBu step I Me O step 2 SMeO MeO 0 OMe OMe O OMe (28) (29) (7a) step 3 (29) s- MeO RI (7b> S* Step 1 Preparation of the Compound of Formula (28) As an example, the aldehyde of Formula (7a) is added to a mixture with at least two equivalents of the reagent formed from carbon tetrabromide, triphenylphosphine, and zinc 46 powder in dichlormethane over 24 hours at ambient temperature. After 60 minutes at ambient temperature, the desired intermediate 1,1-dibromoolefin can be isolated and purified in conventional manner. The alkyne product of Formula (28) is produced from treatment of 1,1-dibromoolefin with alkyllithium, preferably n-butyllithium, in inert, aprotic solvent, preferably tetrahydrofuran, at low temperature, -78 °C to 0 C after 60 minutes, and subsequent capping with trialkylstannyl halide, such as chlorotributyl-tin The product (28) can be handled and purified with routine methods.

Step 2 Preparation of the Comnounds of Formula (29) The alkyne (28) is elaborated through an alkylation with the corresponding anion for compounds of Formula where X is and RI is alkyl, or the alkyne (28) is coupled in a Stille-type reaction to a compound of Formula where X is a and R 1 is aryl. For the former compounds of Formula (29) where R is alkyl, a solution of the alkyne (28) in inert solvent at low temperature, ambient or below, undergoes metal exchange with a suitable alkyllithium, and is subsequently alkylated with a suitable alkylating reagent, for example primary alkyl halides. For compounds of Formula (29) where R, is vinyl or aryl, the alkyne (28) and vinyl or aryl halide couple in the presence of palladium catalyst, such as tetrakis- (triphenylphosphine)palladium(0), with aprotic solvent at below or above ambient temperature.

The products of Formula (29) are isolable and can be purified by conventional techniques.

Step 3 Preparation of the Compounds of Formula (7b) The alkyne (29) can be hydrogenated in suitable solvent, with a hydrogen source, such as hydrogen gas at atmospheric pressure, in the presence of a catalyst, such as palladium on carbon, to furnish, for example, compounds (7b) of Formula where X is -CH 2

CH

2 The products of Formula (7b) can be subjected to routine handling and purification.

Other tetrahydrofurans of Formula where X is a single bond and R 1 is vinyl or aryl are available from the corresponding furans. The appropriately functionalized furans arise from substituent elaboration via coupling of appropriate vinyl or aryl partners: carefully choreographed sequential Suzuki, Heck, or Stille-style couplings with olefins, haloaryls, arylboronic acids, aryltriflates and/or aryltinalkyls can be used to prepare arylfurans as exemplified in Reaction Schemes XIII, XIV, XV, and XVI below.

An example of a Suzuki-style coupling to develop Rt is shown below in Reaction Scheme XIII.

REACTION SCHEME XIII Br HO BR 8 R

OH

(31) (32) Preparation of Compounds of Formula (32) 3-Bromofuran (30) and boronic acids of Formula (31) where R 8 is aryl or vinyl, in a mixture of inert solvent, for example benzene, and aqueous alkali, preferably sodium carbonate, in the presence of a suitable metal catalyst, are heated at 30° to reflux temperature for one to 24 hours. Suitable metal catalysts include palladium(O) tetrakis(mrphenylphosphine) or palladiurn(Il) acetate as examples. The product (32) is isolable and can be processed in routine fashion.

Alternatively, the roles of the reaction partners can be reversed, for example as shown in Scheme )UV below wherein ftiran-3-yl-boronic acid (33) and unsaturated halides of Formula where X is bromide, iodide, or triflate and R 8 is vinyl or aryl, couple to result in compounds (32).

REACTION SCHEME XIV

B(OH)

2 X-Rq Re 0 (34) (32) Preparation of ComgLounds of Formula (32) Furan-3-ylboronic acid (33) and vinyl or aryl halides of Formula (34) are reacted under conditions similar to those described above for Reaction Scheme )ILI The Heck coupling represents additional useful methodology to introduce and elaborate substituets on unsaturated systems as displayed in Reaction Scheme XV as follows: REACIONLS.ClENiE X Br +R

H-R

9 (35) (32) Alternate Preparation of Compounds of Formula (32) 3-Bromofuran (30) and olefinic compounds of Formula (35) where R s is aryl or vinyl, are placed in a suspension of inert solvent, in the presence of metal catalyst, preferably palladium(0) tetrakis(triphenylphosphine) or palladium(II) acetate with catalytic tertiary phosphine, preferably tri(o-tolyl)phosphine or tri(o-tolyl)arsine, at ambient to reflux temperature for one to 24 hours.

The product (32) is isolable and can be processed in routine fashion.

For larger R I groups, further elaboration of smaller R, groups can be obtained from different coupling conditions, complimentary to those reactions depicted in Reaction Schemes XIII, XIV, and XV above. For example, once the above methods are used to prepare a furan of Formula it can in turn be manipulated to join an additional vinyl or aryl group as shown in Reaction Scheme XVI below: REACTION SCHEME XVI Sstep 1 I0

O-S-CF

3 X(36) 1 (37) Me 3 Sn-R x Me sn step2 (37)or or Bu3Sn--Re (37a) (32b) (38) Step 1: Preparation of Compounds of Formula (37) Phenol of Formula (36) in a solution of inert solvent, for example chloroform, in the presence of amine base, preferably 2,6-lutidine, at a temperature of-10C or above, preferably 0°C, is treated with a stoichiometric amount of trifluoromethanesulfonic anhydride. The product triflate (37) is potentially reactive; it may be isolated and purified under anhydrous conditions in inert atmosphere, and should be used quickly.

Step 2: Alternate Preparation of Compounds of Formula (32b) Either triflate of Formula (37) or vinyl halide of Formula (37a) is coupled with trialkylvinyl or aryl tin(IV) of Formula (38) in a solution of inert solvent, such as benzene,in the presence of metal catalyst, such as palladium(II) acetate, with a stoichiometric amount of lithium chloride at ambient temperature or above. The coupled product (32b) is amenable to conventional isolation and purification.

The furan building components in Reaction Schemes XIII, XIV, XV, and XVI are readily available. 3-Bromofuran (30) can be purchased from Aldrich. Furan-3-yl-boronic acid can be prepared, for example, as described in Thompson, W. Gaudino, G. J. Org. Chem 1984, 49, 5237-5243. Furans of Formula (36) can be synthesized using the methodology outlined above for Reaction Schemes XIII, XIV, XV, and.XVI. Boronic acids of Formula (31) are known in the literature or can be synthesized. Organotin(IV) compounds of Formula (38) are also known in the literature or can be synthesized.

PREPARATION OF COMIPOUJNDS OF FORMUILAS IHI. V. V. VI. VH. AN1D laII All compounds of Formulas 111, IV, V, VI, VII, and VIII where R.

5 is carboxyl can be produced from the corresponding esters as described, above for Formula I in Reaction Scheme 1.

Compounds of Formulas 111, TV, V, VI, VII, and VIII where R15 is N-hydroxycarbamoyl C(O)NHOH) can be produced by the method described above for Reaction Scheme HI.

The heterocyclic acetic acid derivatives of Formula (40) where R 9 is alkoxy, alkylamino, or oxazolidin-3-yl, are alkylated with c-haloesters of Formula (39) where X is chloride, bromide, iodide, or triflate to target esters of Formula (4 1) as shown below in Reaction Scheme XVII. The R 9 group of compounds of Formula (40) can serve as a chiral auxiliary to help establish the absolute stereochemistry of compounds of Formula (41).

REACTION SCHEME XVII

R,

0. k4 0 0 (39) (41 Souton of copond of Foml 4)in ovnprfrbyttayrh r ade to souton wihsocimti ado eie rout fasial bsfreape soiu .*aeh~iiaaeo ihu ispoplmdi nr ovnpeeal terhyrfua, tlw epeaurpefrbl 78t .5T frfiemiue t nehu0 r R52 suitable to effect formation of the corresponding anion. Then a-haloesters of Formula (39) are added alone or in a solution of inert solvent. The cold reaction mixture is allowed to stir for minutes to 24 hours, preferably one hour, to form target esters which are isolated and purified by routine methods.

For an example of the alkylation process outlined by Reaction Scheme XVII where R 9 is a chiral auxiliary, see Reaction Scheme XVIII below. According to this scheme, amides of Formula (40) where R 9 are chiral oxazolidines (see Formula (42) below) can undergo stereoselective alkylation to provide products of Formula which in turn can furnish hydroxyethylamides of Formula (44) (Formula I where R1 is an ester, Y is REACTION SCHEME XVIII R*

R

*O

*x RI x RI R.,X 1, I step 1 W

SR

3

R

6 N R 3 O R 2

R

4 0 R 2 (39) (42) (43)

R,

4 3 0 F CH RRz R, O R, (44) 53 Sten 1 Prenaration of Comnounds of Formula (43' Compounds of Formula (43) are prepared from compounds of Formula (40) where R, is a chiral oxazolidine under conditions identical to those described above for the preparation of compounds of Formula (41) from compounds of Formulas (39) and (40) in Reaction Scheme XVII, except with compounds of Formula (42) substituted for compounds of Formula The product of Formula (43) is amenable to conventional isolation and purification.

Step 2 Preparation of Compounds of Formula (44) Compounds of Formula (43) in solvent, such as tetrahydrofuran, is treated with excess acid, preferably dilute, 0.5 molar aqueous hydrochloric acid, at ambient to reflux temperature, preferably the former. The product of Formula (44) is isolated and purified via routine methods.

The disubstituted heterocycles of Formula (41) may also be assembled in a variation in the order of execution shown above in Reaction Scheme XVIII. The alkylations in the above Schemes XVII and XVIII can precede the installation or elaboration of the portion that contains X and R 1 Late stages use appropriate sequences of coupling methods discussed in Reaction Schemes XIII, XIV, XV, and XVI. For example, in Reaction Scheme XIX below, monosubstituted heterocycle of Formula (46) might be halogenated to an appropriately disubstituted heterocycle of Formula which in turn is a coupling partner for methodology outlined in Reaction Schemes XIII, XIV, XV, and XVI. In this example, a Suzuki coupling with boronic acid of Formula (31) is used to give a compound of Formula (48).

REACTION SCHEME XIX 0 x R y X s t p 10s t e p 4 0 i lRq t AR (41 0 4 (39) (46) (46)Re 4( (47) HO, a-e so PREPARATION OF STARTING MATERIALS cc-Haloesters of Formula (39) where R 4 is hydrogen are commercially available. When

R

4 is alkyl, many compounds of Formula (39) can be prepared by syntheses described in literature. For example, many amino acids can be converted to optically active compounds of Formula (39) where R 4 is alkyl as described in Coppola, G. Schuster, H. F. Asymmetric Synthesis: Construction of chiral molecules using amino acids; J. Wiley Sons: New York, 1987.

***Certain heterocyclic actic acid derivatives of Formula (40) are commercially available in *..:certain cases (for example, 2- or 3-thiophene acetic acid), but usually must be synthesized in various ways, as described below.

Direct alkylation on the nitrogen of an appropriate heterocycle of Formula where T, U, and V are each independently carbon or nitrogen, by the a-haloacetic acid derivatives of Formula where X is halogen or triflate, produces the desired intermediates of Formula (51), as shown in Reaction Scheme XX below: REACTION SCHERME XX H I X

R

T V R 9 -N ,V H 0 rR 9 0 (49) (50) (51) Ste I..rprto fCmnud fFrua(1 Nirgncnann heeocce ofFrua(9.freape yaoe r lcdi apoi sovn uha*,-ieh~ommdadifwratd ertntdwt aesc .2 Ste atP ro epeatr Coraoved for ua on (o24hs. h rdcso Frua(1r am nietroen-containige hftr oletiof Fuan (49)ifictorxml.pr le r lcdi ~:An analogous straightforward substitution of the heterocyclic ring involves the alkylation of an organomnetallic derivative of Formula (53) where M is, for example, lithium, magnesium, or copper, with an a-haloacetic acid derivative of Formula as shown in Reaction Scheme XXI below: REACTION SCHEME. XXI Xz-Rl

"R

step 1 W

M

(52) (3 53) X 9 step2 H o

R

9 0 0(50) Ste I 4rprtono*opuds2~r a( aShte rcceaaof Fofl 5) Co Prunciad ehdsncuedpoo fprn of Formula (52) where W is hydrogen, or from halogen-metal exchange of the corresponding haloheterocycle of Formula (52) where W is halogen. These reactions are typically carried out in inert, aprotic solvent such as tetrahydrofiuran, at ambient temperature or below, in 15 minutes to 000 024 hours. The organometallics of Formula (53) are typically unstable to atmo'sphere and moisture. They are routinely formed in situ and used immediately without isolation.

Steil 2 Alternate Prepaation01 Of Compounds of Formula The organometallics of Formula (53) are alkylated by stoichiometric or excess amounts of acetate or acetamide of Formula (50) in inert solvent, preferably tetrahydroftuan, at low temperatures of -78 to 0 0 C, in ten to 90 minutes. The product of Formiula (40) is isolated and purified with routine methods.

As another alternative, an acylation can be carried out with oxalates or oxarnates of Formula (54) where RIO is, for example, halogen, alkoxy, or imidazol-l-yl, to ketoesters or ketoaniides of Formula which are subsequently deoxygenated in several steps to ester or amnides of Formula as shown in Reaction Scheme XXMI below.

fees.

REACTION SCHEME XXII a; K step 1 rR step 2E M 0 0 T9R 0t

HO

(S3) (54) (55) (S6 step 3 step 4 Q?

I

O 0 (57) Step I Preparation of Compounds of Formula H-eterocyclic organometallic derivatives of Formula (53) where M is lithium can be prepared as shown in Reaction Scheme XXI above and acylated by an oxalate or oxamate of :Formula (54) where RIO is typically halogen, alkoxy, or irnidazol- I -yl in inert solvent, preferably tetrahydrofliran, at low temperatures of -78 to 0*C, in ten to 90 minutes. The product of Formula is isolated and purified with routine methods.

Step 2 Preparation of Compounds of Formula (6 The ketoester or amnide of Formula (55) in solvent, preferably ethanol, at temperatures of to 0 is treated with hydride reducing agent, preferably sodium borohydride, for five minutes to four hours to provide products of Formula which are isolable and purified with conventional techniques.

Step 3 Preparation of Compounds of Formula (57 Alcohols of Formula (56) can be processed for deoxygenation by conversion to various moieties designated Q, preferably where Q is an ester or halide. Typically they are acylated in aprotic solution, for example chloroform, with excess acylating agent, for example acetic anhydride or acetyl chloride in the presence of excess amine base, preferably pyridine, with or without catalytic amounts of (4-dimethylamino)pyridine to give acetates of Formula (57) where Q is acetoxy, which are handled and purified in usual fashion.

Step 4 Preparation of Comnounds of Formula a-Halides or acetates of Formula (57) where Q is halogen or acetoxy, respectively, are reduced to products of Formula (40) with a metal catalyst, preferably palladium on carbon, and a source of hydrogen, preferably ammonium formate. The products (40) are handled and purified in customary manner.

The disubstituted heterocycles of Formula (40) can also be constructed in a differently ordered sequence: late formation of the portion that contains X and R, utilizing appropriate sequences of coupling methods discussed in Reaction Schemes XIII, XIV, XV, and XVI.

Many of the monosubstituted heterocycles that are commercially available bear only one carbon in the substituent, and additional processing is necessary to prepare disubstituted heterocycles of Formula as shown in Reaction Scheme XXIII below. Commercially available mono-substituted heterocycles of Formula (58) where R 11 is hydrogen, hydroxy, or alkoxy (for example, 3-furan carboxaldehyde or 3-furfural, where R 11 is hydrogen) can be homologated through any of numerous suitable methods known to those skilled in the art, for example, that described in Martin, S. F. Synthesis 1979, 633-665, to furnish 2-heterocyclic acetic acid derivatives which can be further substituted, for example as a halide of Formula Alternatively, the heterocycles Formula (58) are substituted as halides of Formula then homologated to derivatives of Formula Subsequent linkage of a compound of Formula with an appropriate coupling partner such as a compound of Formula (31) gives esters or amides of Formula As recognized by those skilled in the art, the versatility of the methods in Reaction Scheme XXIII allows interchangability of the steps. For example, the substitution of halides of Formula (61) with boronic acids of Formula (31) may precede a homologation to desired intermediates of Formula (62) (not shown).

REACTION SCHEME XXIII 9 step step 2 X HO59) :R 9 (3) 1 1 58) step2 6step (61) HO step- (60) HO/-B R9 (31) (62) Step 1 Preparations of Compounds of Formulas (59) and The heterocycles of Formulas (58) and (61) are homologated to compounds of Formulas (59) and respectively, depending upon the nature of R 11 and R9. See, for example, Martin, S. F. Synthesis 1979, 633-665. As an example, for compounds (58) and (61) when R 11 is hydrogen, the anion of 2-trimethylsilyl-1,3-dithiane is used in inert aprotic solvent, preferably tetrahydrofuran at low temperature, 0* to -78*C for 30 minutes to several hours, to obtain the corresponding dithiane adduct, which is subsequently converted through any of a variety of methods to derivatives of Formula An example of dithiane removal uses mercuric chloride in water and alcohol to afford an ester of Formula (59) where R 9 is alkoxy. The products of Formula (59) are amenable to conventional handling and purification.

Step 2 Preparations of Compounds of Formulas (601 and (61) As an example of the introduction of the second heteroaromatic substituents, compounds of Formulas (59) and (58) in an inert solvent are halogenated, for example, with a bromine source, such as bromine or N-bromosuccinimide, at ambient temperature or below, for an hour to a day. The resultant hetereoaryl halides of Formulas (60) and respectively, are subject to routine purification and manipulation.

Step 3- Preparations of Compounds of Formula (62) The coupling of heteroaryls of Formula (60) are carried out analogous to that described for Reaction Schemes XIII, XV, or XVI to obtain compounds of Formula (62).

Amides with the generic Formula (40) where R 9 is alkylamino are often available from the corresponding carboxylic acid or activated esters of Formula (40) where R9 is alkoxy or hydroxy, as exemplified in Reaction Scheme XXIV below: 62 REACTION SCHFME X~XTV HN. Y -R 3 Fk2 (63) (64) The formation of amides (64) Formula (40) where R 9 is alkylamine) results from acids of Formula (63) coupling with amines of Formula (10) under the same conditions as described above for Reaction Scheme V, Step 2. The products of Formula (64) are isolated and purified by conventional methods.

Oxazolidines of Formula (42) can be made from the acetamides of Formula (65) where Y in terms of formula I is as shown in Reaction Scheme XXV below: REACTION SCH4EME XXV I

OH

+0

N

O A2 (42) The hydroxyamides of Formula (65) are placed in solution containing acetone or its equivalent, preferably 2 -methoxypropene, with a catalytic amount of acid, such as p-toluenesulfonic acid, under dehydrating conditions, such as trapping of water with a Dean- Stark apparatus, at ambient temperature to reflux, for a suitable amount of time to convert starting material The product (42) is amenable to routine processing for isolation and purification.

A preferable avenue to oxazolidines of Formula (42) involves coupling of oxazolidines of Formula (67) to acetic acids of Formula as shown in Reaction Scheme XXVI below. The oxazolidines (67) in turn originate from amino-alcohols of Formula (66) of commercial and synthetic origin.

REACTION SCHEME XXVI

.OH

z step 1 0 SA -3 -R HN

R

2 (66) R2 (67) (67) step 2 OH

-R

0 O R, (63) (42) Step I Preparation of Compounds of Formula (67I Compounds of Formula (67) are prepared from compounds of Formula (66) using a method similar to that described above for the preparation of compounds of Formula (42) Reaction Scheme XXV, except lower temperatures are preferred. The products of Formula (67) can be somewhat unstable and are routinely used in situ or immediately in the next reaction without purification.

Step 2 Alternative Preparation of Compounds of-Formula (42) Conditions for the formation of amnides with typical coupling reagents as discussed above for Reaction Scheme V, Step 2, apply to the preparation of compounds of Formula (42).

For mono-substituted heterocycles that are not available commercially, the rings may be constructed. For example, for the compounds of Formula 111, as shown below in Reaction Scheme XXVII, tetrahydrofurans of Formula (68) where R 12 is hydrogen or alkyl are condensed with amines of Formula (69) to provide pyrroles of Formula Depending on the nature of X and RI, R 12 of pyrrole (70) may be converted from hydrogen to a halogen and subsequently an alkyl. (as in Reaction Scheme X=I, for example).

REACTION SCHIEMIEXXVII

H

2 N

C

OMe

R

12 (69) Preparation of Compounds of Formula Compounds of Formula (70) can be prepared from compounds of Formulas (68) and (69) using the conditions identical to those described for the preparation of pyrroles of Formula II in Reaction Scheme IV.

EXAMPLES

The following examples are merely illustrative of the invention and should not be construed as limiting the invention. The examples include preferred embodiments of the inventive compounds. One skilled in the art can make, without undue experimentation, various substitutions and variations.

4 Example N-(1 (S)-Benzyl.

2 -bydroxyethyly..3(R).[3..(biphenyI..4..y).lH.pyrroI 1 yllsuccinamic Acid 0N HOK)>. NH OH A suspension of 10% Pd/C (wet DeGussa type, 15 mrg) and I (S)-benzyl.2.

hydroxyethyl)-3 (R)-[3-(biphenyI.4-yl)- I H-pyrrol- I -yljsuccinamic acid benzyl ester (68 -mg, 0. 12 mrnol) in EtOAc (5 niL) was stirred under H 2 for 20 hours. The catalyst was filtered onto Celite and rinsed with MeOH. The filtrate was concentrated under reduced pressure to give a yellow oil, which was purified via flash column chromatography with a 1% HOAc/2-5% MeOH/CH 2

CI

2 stepwise gradient elution to provide 47 mg of 1 (S)-benzyl-2-hydroxyethyl)-3(R)-(3- (bipheny--y)IH-proI-1.yI]succinmic acid as a white solid. 'H NMR (CDCI 3 87.66-7.48 (in, 3H), 7.42 (t,2H4, J 7.2 Hz), 7.34-7.28 (mn, IH), 7 2 1 -7.12(m, 2H), 7.04-6.96 (nm, lH), 6.94 (bs, 6.68 (dd, lH, J 2.5 Hz), 6.55 (dd, 1H,JI= 1.6, 1.6 Hz), 5.78 (bd, lH, J =7.5 Hz), 4.90 IH, J 7.2 liz), 4.36-4.02 (mn, lH), 3.68 (dd, IH, J 3.4, 1-1.2 Hz), 3.50 (dd, 1H, J 5.3, 9. 0 Hz), 3.31 (dd, J 7.4 Hz), 3.12 (dd, I H, J 7.2, 17. 1 Hz), 2.74 (ddd, I H, J 6.2, 14.3, 14.3 Hz), 2.68 (ddd,JI= 8.7, 14.0, 14.3 Hz). IR(film): 3387,'3028, 2931, 1715, 1660, 1532, 1494, 1204, 702, 698 cmn'1. HRFABMS: Calculated for C 2 qH 2

SN

2 0 4 CS (M 643.1209.

Fou nd: 643.1185. Anal. calculated for C 29

H

28 N0 4 *0.1 CHCI 3 0.35 H 2 0: C, 71.80; H, 5.96; N, 5.75. Found: C, 71.92; H, 5.87; N, 5.77.

The starting material, 1(S)-benzyl-2-hydroxyethyl)-3(R).{3-(biphenyIA4-yl) I H-pyrrol- l-yl] succiiarnic acid benzyl ester, was prepared as follows: N-Cl (S)-Berizvl-2-hydroxyethvfl)3 (R)-(t-butoxycaxbonylarninosuccinmic Acid Benzyl Ester 0 H N H C To a solution of N-t-butoxycarbonyl-D-aspartic acid P-benzyI ester (2.00 g, 6.20 mmol) in CHCl 3 (80 ml) at 0 0 C was added in succession l-(3-dimethyiaxninopropyl)-3 -ethyl-; carbodiimide hydrochloride (EDC, 1.30 g, 6.82 rrimol) and N-hydroxybenzotriazole hydrate (HOBt e H 2 0, 1.04 g, 6.82 mznol). After 10 min at 0 2S-ainino-3-phenyl-lI-propanol (93 6 mg, 6.20 nol) was added and the resultant mixture was allowed to warm to ambient :temperature overnight. After 20 hours, the mixture was stirred with 10% aqueous HCI (5 m.L) and saturated aqueous NII 4 CI (25 mL). The separated aqueous layer was extracted with more CHC1 3 (2 x 10 The combined organic extracts were washed with saturated aqueous NaHCO 3

:H

2 0 (25:25 mL) two times, dried over Na 2

SO

4 and concentrated in vacuo to a yellow foam, 2.84 g, which was recrystallized from EtOAc/hex in successive crops to afford 2.34 g b(83%) of I(S)-benzyl- 2 hydroxyethyl)-3(R)-(t-butoxycarbonylanino)succinanic acid benzyl ester as white microneedles, mp 94-95*C. 1H NNM (CDC1 3 8 7.40-7.10 (mn, 1OH), 6.81 IH, 0J= 10.8 Hz), 5.55 lH,J =7.2 Hz), 5.11 (ddd, 2H, J= 1.2,6.9,7.4 Hz), 4.50-4.32 (bn, IH), 4.21-4.04 I 3.6 8 (dd, I H, J 11.2 Hz), 3.52 (dd, I H, J 5.3, 11.5 Hz), 3.03 (dd, I H, J 4.7, 17.1 Hz), 2.86 (dd, I H, J 13.7 Hz), 2.83 (dd, I H, J 7.2, 13.7 Hz), 2.64 (dd, I H, I 17.1 Hz), 1.43 IR (KBr): 3442, 3381, 3307, 1729, 1676, 1656, 1554, 1522, 1300, 1164, 1041, 701 cm'. Anal. Calculated for C 25

H

32

N

2 0 6 C, 65.77; H, 7.07; N, 6.14. Found: C, 65.74; H, 7. 10; N, 6.20.

4-Biphenyiboronic acid HOB 1 6H 4-Biphenylboronic acid was prepared differently than described in the literature (see Yabroff, D. Branch, G. Bettman, B. Am. Chem. Soc. 1934, 56, 1850-1857). To a solution of 4-bromobiphenyl (2.00 g, 8.58 mmol) in TI-F (20 mL) at -78*C was added nbutyilithium (4.0 mL of 2.5 M in hexanes) in a slow stream via syringe. After IS minutes, triisopropylborate (3.0 mL, 13 minol) was added in a slow streamn via syringe. After 10 minutes, the resultant homogeneous solution was allowed to warm to ambient temperature over minutes and partitioned between EtOAc (50 mL) and 10% aqueous HCI (50 mnL). The aqueous layer was separated and extracted with more EtOAc. The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated to give a crude product which was triturated with hexanes to yield 1.53 g of 4-biphenylboronic acid as a white solid. I H NNM (DMSO-d 6 6 8.05 2H), 7.83 2H, J1 8.5 Hz), 7.65 2H, J 7.0 Hz), 7.60 2H, J 8.1V Hz), 7.43 2H, J 7.4 Hz), 7.3 3 I1H, J 7.2 Hz). Anal. C 12 H I IB0 2 C, 72.7 8; H, 5.60.

Found: C, 72.5 1; H, 5.62.

3 4 Biphenyl.4-vl)furan 0' A biphasic mixture of 3-bromofuran (2.90 rnL, 32.1 mmol), benzene (70 rnL), and 2N aqueous Na 2

CO

3 (50 mL) was degassed and purged with argon. Tetrakis(triphenylphosphine) palladium(0) (3.7 g, 3.2 mmol) and a solution of 4-biphenylboronic acid (6.36 g, 32.1 rninol) in EtOH (50 mL) were added sequentially. The mixture was heated at 80*C for 18 hours, allowed to cool, and partitioned between CH 2

CL

2 and H 2 0. The aqueous layer was separated and extracted with CH 2

CI

2 two times. The combined organic layers were washed with brine, dried over Na-)SO 4 and concentrated to a crude product, which was dissolved in a minimal amount of CH,C1 2 and applied to a flash chromatography column packed with hexanes. Elution with

CH

2 C1 2 /hex led to some mixed fractions, which were rechromatographed. A total of 5.37 g of 3-(biphenyl-4-yl)furan was obtained as a pale yellow oil. 'H NMR: 6 8.28 I1-H), 7.64-7.55 (in, 6H), 7.50 I 7.45 2H1, J 7.35 Hz), 7.40 I H, J =7.3 5 Hz), 6.75 I H).

Anal. calculated for C 16

H,

2 0: C, 87.25; H, 5.49. Found: C, 87.15; H, 5.52.

3 ipheny l-4-vl)-2J -dihydro-2 0"

OH

To a slurry of 3-(biphenyl-4-yI)ftiran (100 mg, 0.450 mniol) and Na 2

CO

3 (48 mg, 0.45 mrnol) in benzene (1 m.L) and MeOH (I rnL) at -1I0 0 C was added bromine (22 g.L, 0.43 minol) dropwise via syringe. After 30 minutes at -l0*C, the mixture was diluted with EtOAc and filtered twice. The filtrate was concentrated to give a crude solid which was purified via flash column chromatography with a 0- 1% EtOAc/CH 2

CI

2 gradient eluant to Provide 90 mg of a diasteromeric mixture of 3-(biphenyl-4-yl)-2,5-dihydro-2,S-dimethoxyfuran as a colorless oil.

'H NMR (CDCl 3 6 7.70-7.28 (in, 9H), 6.35 (dd, 0.75H, major isomer, J 0.9, 0.9 Hz), 6.30 (d, 0.25H, minor isomer, J 6.0 Hz), 6.04-6.03 I H, major+-minor isomer), 5.71 0.15H, major isomer, J 0.9Hz), 3.60-3.40(in, 6H). Anal. Calculated for C 18

H

1 8 0 3 C, 76.57; H, 6.43.

Found: C, 76.52; H, 6.38.

3-(Biphenyl-4-vfl-2.5-dimethoxvetrahydrofuran

H

3

CO"

0 OC4 3 A mixture of 3-biphenyl-4-yl-2,5-dihydro-2,5-dimethoxyfuran (1 .00 g, 3.55 inmol) and Pd/C (300 mg) in EtOH:EtOAc was stirred under H 2 atmosphere for 1.75 hours. The catalyst was filtered onto Celite. The filtrate was concentrated to provide 0.97 g of a diastereoineric mixture of 3-biphenyl-4-yl-2,5-dimethoxy-terahydro-furan as a colorless oil which was typically used without purification. H NMR: 8 7.60-7.53 4H), 7.45-7.28 (m, 71 5.26 IH, J 5.5 Hz), 5.02 IH, J 4.4 Hz), 3.54 3H), 3.36 3 2.63-2.53 (m, IH), 2.41-2.30 1R). Anal. calculated for C 1 8

H

20 0 3 C, 76.03; H, 7.09. Found: C, 75.74; H, 6.92.

N-(I(S)-Ben=l-2.hvdroxvethvl)-3(R)-13-(bipienyI-4-v'- IH-pvrrol- i-vilsuccinanic Acid Bel Ester

N

113 o 0

.U,

To a solution of N-(1 (S)-benzyl-2-hydroxyethyl)-3(R)-(-butoxycarbonylanino) succinamic acid benzyl ester (389 mg, 0.851 imol) in CH 2

CI

2 (5 mL) was added trifluoroacetic acid (1 nL). After 2.5h at ambient temperature, the solvent was removed in vacuo to give 3(R)amino-N-( (S)-benzyl-2-hydroxyethyl)succinamic acid benzyl ester trifluoroacetate salt as a yellow foam that was placed with 3-(biphenyl-4-yi-)2,5-dimethoxytetrahydrofuran (182 mg, *.i 0.641 nmol) in HOAc (1 mL) and heated to 50*C. After 2 hours, the mixture was allowed to cool, carefully stirred with saturated aqueous NaHC03 (25 mL), and extracted into CHC1 3 (3 x mL). The combined organic layers were dried over Na 2

SO

4 and evaporated to give a brown oil, 685 mg. Flash column chromatography with 10%.MeOH/CH 2

CI

2 as eluant provided 276 mg of N-(1 (S)-benzyl-2-hydroxyethyl)-3(R)-(3-(biphenyl4-y)- I H-pyrrol- 1 -yl)succinamic acid benzyl ester as a yellow solid. 'H NMR (CDCI 3 6 7.70-7.48 10H), 7.44 (dd, 2H, J 7.2, 7.8 Hz), 7.38-7.12 7.08-6.98 21), 6.89 (bi, 1H), 6.63 (dd, IH, J 2.5, 2.5 Hz), 6.54 (dd, IlH, J 1.2, 1.2 Hz), 5.76 IH, J 7.5 Hz), 5.10(dd, 2H, J 12.1, 15.9 Hz), 4.95 (dd, I1H, J 8.7 Hz), 4.34-4.00 (bin, I 3.-66 (dd, I H, J 3.7, 11.2 Hz), 3.49 (dd, I1H, J 5.3, 11.2 Hz), 3.37 (dd, I H, J 5.0, 16.8 Hz), 3. 18 (dd, I H, J 8.7, 16.8 Hz), 2.74 (ddd, 2H-, J 13.7, 15.9 Hz). IR (KBr): 3314, 3029, 2925, 1731, 1658, 1548, 1495, 1355, 1196, 1165, 761, 698 cm- Anal. calculated for C 36

H

34

N

2 0 4 S 0.5 H 2 0: C, 76.17; H, 6.22; N, 4.94. Found: C, 76.24; H, 6.18; N, 4.97.

The following were prepared in a similar manner: Example N-[12,2-Di methy I- 1 (S)-(methy learba moy I)propyIJ1-3(R)(3-pheny I- H-pyrrolI- 1-yI)succinamic acid According to the procedure described in Example. N-[2,2-dimethyl- I(S)- (methylcarbamoyl)propyt].3(R)-(3-phenyl 1 8-pyrrol-i1-yl)succinamic acid benzyl ester (371 mg, 0.781 mrnol) in MeOH (15 m.L) was hydrogenolyzed to provide 301 mg (100%) of N-[2,2.

dimethyl- 1 (S)-(methylcarbamoyl)propyll.3(R)-(3-phenyl. I H-pyrrol- I -yI)succinamic acid as a yellow foam. 'H NMR (CDC 3 8 7.50-7.20 (mn, 4H), 7.15 (ftt I1H, J= 1.2, 7.3 Hz), 7.06 (dd, I H1, J 2.0, 2.0 Hz), 6.78 (dd, I H, J 2.5, 2.5 Hz), 6.48 (dd, I H, J 2.8 Hz), 5.20 I1H, J= 6.9 Hz), 4.20 I1H, J 9.3 Hz), 3.34 (dd, I H, J 6.9, 17.4 3.06 (dd, I1H, J 7.2, 17.4 Hz), 2.69 3 H, J= 4.7 Hz), 0.93 9H); IR (KBr): 3 318, 2966, 1718, 1654, 155 9, 1542, 1202, 745 cml HRFABMS: Calcd for C 2

H

27

N

3

O

4 CS (M 5 18.1056. Found: 518.1037. Anal.

Calculated for C 2 1

H

27

N

3 0 4 0.3 CHC1 3 C, 60.73; H, 6.53; N, 9.97. Found: C, 60.70; H, 6.58; N, 9.84.

The starting material, N-(2,2-dimethyl- I(S)-(methylcarbaxnoyl)propyl]-3(R)-(3.phenyl.

I H-pyrrol-1-yl)succinamic acid benzyl ester, was furnished as follows: 3(R)-t-Butoxycarbonylaxnino-N-(2.2-dimethvl- I(S)-(methvlcarbanoflpropyll-succinarnic Acid C)NH 0 0 1 >NHA- NHCH 3 To a solution of N-t-butoxycarbonyl-D-aspartic acid J-benzyl ester (2.19 g, 6.77 mmol) in DMF (40 mL) was added in succession 4-methylmorpholine (NMM, 13.5 mmol, 1.49 mL), 2- (I K-benzotriazole- I -yl)-N,N,N',N'-tetramethyluronjurn tetrafluoroborate (TBTLJ; 2.17 g, 6.77 mzniol) and a solution of L-t-leucine N-methylamide (see Malon, Pancoska, Budesinsky, NM.; Hiavacek, Pospisek, Blaha, K. Coil. Czech. Chem. Commun 1983, 48, 2 844-2 86 1; 8 86 mg, 6.15 mrnol) in DMF (10 miL). After 3 hours at ambient temperature, the mixture was stirred with 10% aqueous K.HS0 4 (25 rnL) and water (100 mL) and extracted with CHC1 3 (100 mL) three times. The CHC1 3 extracts were washed with 10% aqueous KHSO 4

:H

2 0 (10:250 mL.), saturated aqueous NaHCO 3

:H

2 0 (100:200. and water (200 mL).three times, dried over Na 2

SO

4 and evaporated to give 2.49 g of 3(R,)-t-butoxycarbonylamino.-N-(2,2-diniethyl- I (S)-(methylcarbamoyl)propyl)succinaxuic acid benzyi ester as a yellow foam, typically used without fur-ther purification. Flash column chromatagraphy with 3% MeOH/CHCl 3 as eluant afforded analytically pure amorphous solid. 1 H NMR: 8 7.40-7.30 (mn, 5M), 7.03 1H, J Hz), 5.90 (bd, IlH, J 4.7 Hz), 5.5 6 (bd, I H, J 8.5 Hz), S. 13 (dd, 2H, J 2.5, 17.4 Hz), 4.5 6 (bd, I1H, J =7.5 Hz), 4.11 I1H, J=9.0 Hz), 3.00 (dd, 2H, J=4.0, 16.2 Hz), 2.85 3H,J=14.7 Hz), 1.00 9H). Anal-Calculated for C-, 3 H3 5 N3O 6 C, 61 .45; H, 7.85; N, 9.35. Found: C, 61.56; H, 7.83; N, 9.27.

2 Sdmtox'.hnvt)a H 3 C X'-P 0 0CH 3 According to thie procedure described in Example 1(a) for the preparation of 3-biphenyl- 4-yl-2,5-dihydro-2,5-dimethoxyfuran, 3-phenylfuran (see Pridgen, L. Jones, S. S. J Org.

Chem. 1982, 4 7, 1590-1592 and Yang, Wong, H. N. C. Tetrahedron 1994, 32, 9583-9608; 848 mg, 5.89 inmol) provided 1.00 g of 2,S-dihydro-2,5-dimethoxy-3-phenylfuran as a yellow oil, which was an approximately 80:20 mixture of diastereomers by 1'H NMR and used without further purification. I'H NMR (CDCI 3 6 7.64-7.52 (in, 2M-I, 7.44-7.30 (mn, 3M), 6.36- 6.30 (in, 0.9H, major minor isomer), 6.28 (dd, 0.IH, minor isomer, J 1.2, 3.7 Hz), 6.04-6.00 (in, 0.9H, major minor isomer), 5.70 0.8H, major isomer, J 1.2 Hz), 3.52 2.2H, major isomer), 3.46 0.60H-, minor isomer), 3.43 2.2H, major isomer), 3.40 0.60H, minor isomer); Anal. Calculated for C 12

HI

4 0 3 0.04 Br 2 C, 67.78; H, 6.64. Found: C, 67.79; H, 6.45.

2 -5-Dimethox.3-pe vletahdrofran

H

3 C

OCH

3 A mixture of 2 ,5-dihydro-2,5-dimethoxy-3-phenylfuran (590 mg, 2.86 inrol) and Rh/A1 2 0 3 (1 10 mg) in EtOAc (10 mnL) was stirred under H 2 atmosphere for 24 hours. The catalyst was filtered onto Celite and rinsed with EtOAc. The filtrate was concentrated in vacua to afford 583 mg of 215-dimethoxy-3-phenyl-tetrahydrofuran as a colorless oil which was typically used without firther purification. IH NM: 8 7.40-7.18 (mn, 5H), 5.30-4.80 (in, 2H), 3.70-3.40 (mn, 6H), 2.78-2.43 (mn, 1.2H), 2.34 (ddd, 0.75H-1,3= 5.6,12.7, 18.3Hz), 2.17 (dd, 0. 1H, J 8.4, 12.8 Hz). Anal. Calcd for C 12

HI

6 0 3 0.2 H 2 0: C, 68.03; H, 7.80. Found: C, 68.11; H, 7.60.

3(R)-Amino-N-(2-2-dimethy- 1 (S)-(methvlcarbamovl~propvI'~succinamic Acid Benzv Ester :Trifluoroacetate Salt

:NH

3 -0 2

CCF

3 I

NH,

NHCHI

To a solution of 3(R)-butoxycarbonyl-amino-N-(2,2-dimethyl. I (methylcarbamoyl)propyl)succinarnic acid benzyl ester (2.05 g, 4.57 mmoi) in CHC1 3 (15 m.L) was added trifluoroacetic acid (3 mL). After 2.5 hours at ambient temperature, more trifluoroacetic acid was added (3 mL), and after 90 minutes, the solvent was removed in vacua to give crude 3 (R)-ainino-N-[ 2 2 -dimethyl- I(S> (methylcarbamoyl)propyl]succianic acid benzyl ester trifluoroacetate salt as a yellow oil that was used without further purification. NMR: a 7.50-7.20(in,5MH, 5.14 (dd, 2H, J= 12.1, 15.6 Hz),4.57 IlH,J3= 6.2 Hz), 4.33 IlH, J 8.7.

Hz), 3.13 114,J 6.2 Hz), 2.74 3H, J -4.7 Hz), 0.93 9H4).

N-[2.2-Dimethyl- 1(S)-(methylcarbamoflpropv11-3a(Rl(3-phenvl.I H-nvi-rol- I-vb)-succinanic 0y

C

KIIV

0

ZS~NH>I-NH.

A solution of crude 3(R)-amino-N-[2,2-dimethyl- I(S)-(rnethylcarbamnoyl)propyl]succinamic acid benzyl ester trifluoroacetate salt 3 rnmo1), 2,5-dimethoxy-3-phenyltetrahydrofuran (583 mng, 2.80 mxnol), trifluoroacetic acid (216 j±L, 2.80 mmnol), and water p.L, 2.8 rnmol) in 1,2-dichloroethane (I xnL) was heated at 70*C. After 20 hours, the mixture was allowed to cool and concentrated in vacuo to give a brown oil, which was purified via flash column chromatography with 0.5% HOAc/35% EtOAc/hex as eluant to affor d 407 mng of age' N-(2,2-dimethyl- I (S)-(methylcarbamnoyl)propyl)-3(R)-(3-phenyl- I H-pyrrol- I -yl)succinaznic acid benzyl ester as a yellow foam. 1 H NMR: a 7.52-7.44 (mn, 2M), 7.3 8-7.15 (in, 3 7.04 (dd, I H, J OS. 1.8 Hz), 6.78 1H, 3=2.5 Hz), 6.56 (dd, 1H, J 1.6,2.5 Hz), 6.42 18, 9.0 hz), 5.95 (bd, J 4.0 Hz), 5.18-5.04 (in, 381), 4.30 1H, J 9.0 Hz), 3.38 (dd, 1H, J 5.9, 16.8 Hz), 0.3. 10 (dd, IN, J 8.4, 16.8 hz), 2.72 3H, J 5.0 Hz), 0.93 9H). IR: 3301, 2960, 1736, *1645, 1542, 1166, 752, 695 cm' HRFABMS: Calculated for C 2

SH

33

N

3

O

4 CS (M S) 608.1525. Found: 608.1549. Anal. Calculated for C 28

SH

33

N

3 0 4 0.2 H20: C, 70.18; 8, 7.03; N, 8.77. Found: C, 70.45; H, 6.99; N, 8.84.

Example N-(8-Oxo-4-oxa-i ,7-diazatricyclol9.6. 1.0 12 17 joctadeca-1 1(18), 12,14,16tetraen-9(S)-yl)-3(R)-(3-pheny-1 H-pyrrol-i-yl)succinawic Acid 0ON 0 Ho-'X. NH) -NH-0 According to the procedure described in Example I1(a), N-(8-oxo-4-oxa- I ,7-diazatricyclo[9.6. 1.0 12, 17 ]octadeca- 11(1 12,14,1 6-tetraen-9S-yl)-3(R)-(3.phenyl- I H-pyrrol- 1yl)succinaznic acid benzyl ester was hydrogenolyzed to give in 94% yield N-(8-oxo-4-oxa-1,7diaza-tricyclo(9.6. 1.0 12 17 ]octadeca- 11(1 12,14,1 6-tetraen-9(S>-yl)-3(R)-(3-phenyl- I H-pyrrol- I-yl~succinanic acid as an amorphous solid. I H NMR (CD 3 CN): 6 7.65 18, J =7.4 Hz), 7.48 2H, J 7.7 Hz), 7.39 18H, J 8.1I Hz), 7.33 2H, I 7.7 Hz), 7.23-7.13 (in, 3H),

L..

~~7.11 18), 6.97 18), 6.78-6.71 (in,28), 6.43 lH, J=2.0 Hz), 5.46-5.43 (bi, 18), 5.11 lH, J =7.2 Hz), 4.42-4.34 (in, IH), 4.28-4.10 28), 3.45-3.24 (in, 3.07-2.76 Anal. Calcd for C 29

H

30

N

4 0 5 *0.35 820 0.1 MTBE: C, 66.89; H, 6.07; N, 10.58. Found: C, 66.99; H, 6.06; N, 10.33.

The starting material, N-(8-oxo-4-oxa- I ,7-diaza-tricyc lo[9.6. 1.0 12.17 7 octadeca- 11(18), 12,14,1 6-tetraen-9S-yl)-3(R)-(3-phenyl.l1H-pyrrol-1I-yl)succinamic acid benzyl ester, was available as follows: 3(R)-t-Butoxycarbonylaxnino-N-(8-Oxo-4-oxa-.7-iz-t ylo(9,6 21 loctadeca- 11(1 8V 12.14.1 6-tetraen-9S-vl')succinamic Acid Benzyl Ester 0 0OHN 0 0 y. NH2--NH- 0 According to the procedure described in Example 1(b) for the preparation of 3(R)-amino- N-(2,2-dirnethyl- I (S)-(mcthylcarbamoyl)propyl)succinamic acid benzyl ester trifluoroacetate ::salt, 9S-t-butoxycarbonylamino4-oxa- I ,7.diaza-tricyclo-(9.6. 1.0 1 -octadeca- I 1(I8),12,14,16-tetraen-8-one (see Castelhano, A. Liak, T. Home, Yuan, Krantz, A.

Int. Patent Appi. W095/04735-Al, 16 February 1995) was deprotected with trifluoroacetic, acid.

According to the procedure described in Example 1(b) for the preparation of N-(2,2-dimethyl- I (S)-(methylcarbarnoyl)propyl)-3(R)-t-butoxycarbonylaminosuccinamic acid benzyl ester, the crude amine salt and N-t-butoxycarbonyl-D-;aspartatic acid f3-benzyl ester was coupled with TBTU to afford in 70% yield 3(R)-t-butoxycarbonylarniino-N-(8-oxo4-oxa-1 ,7-diaza-tricyclo- 1.01 2 ,1 7 ].otadeca- 11(1 12,14,1 6-tetraen-9S-yl)succinamic acid benzyl ester. Trituration with MTBE gave an off-white amorphous solid that was suitable for further use without additional purification. I'H NMP. (DMSO-d 6 8 7.76 1 H, J 8.1 Hz), 7.49-7.28 (in, 8H), 7.14 I H, J 8.1 Hz), 7.08 I1H), 7.04 I1H, J 7.7 Hz), 6.98 I H, J1 7.0 H2), 5.07 (s, 4.38-4.15 (mn, 4H), 3.47-3.38 (mn, 2H), 2.96-2.75 (in, 5H), 2.65-2.53 (mn, 214), 1.34 9H-).

Anal. Calculated for C 3

IH

3

SN

4 0 7 C, 64.34; H, 6.62; N, 9.68. Found: C, 64.24; H, 6.65; N, 9.61.

N-(8-Oxo-4-oxa- I .7-diaza-tricyclor9.6. 1. 12,'17 joctadeca- 1 (1 8).12.14.1 6-tere-Svl3R.

phenxl- I H-prrol- I -xI)succiriamic Acid Benzyl Ester Oo 0 According to the procedure described in Example 1(b) for the preparation of 3(R)-amino- N-(2,2-dimethyl- I (S)-(nlethylcarbamnoyl)propyl)succinamic acid benzyl ester trifluoroacetate s alt, 3(R)-t-butoxycaxbonylainino-N-(g.oxo.4-oxa. I,7-diaza-tricyclo-[9.6. 1.0 12 17 ]-octadecalI(I8),12,14,16-tetraen-9S-yI)succinamic acid berizyl ester (157 mng, 0.27 rnmol) was deprotected with trifluoroacetic acid. A solution of dried crude amine salt and 2,5-diniethoxy-3phenyl-tetrahydrofuran (67 mg, 0.32 inmol, from Example in anhydrous 1,2-dichioroethane (2 mL) was heated at 75 *C for 17 hours, allowed to cool, and partitioned between EtOAc/ pH7 **.phosphate buffer. The combined organic layers were dried over Na 2

SO

4 and concentrated to give a residue which was purified via flash column chromatography with'0-25% EtOAc/CH 2

CI

2 gradient eluant and triturated with NME to provide 70 mg of N-(8-oxo-4-oxa- 1,7-diazatricyclo-[9.6. 1.0 12,17 ]-octadeca- 11(18), 12,14,1 6-tetraen-9S-yl)-3(R)-(3-phenyl- IH-pyrrol-l yl)succinamic acid benzyl ester as an off white solid, mp 163-6C. I'H NUR (CDC13): 6 7.68 (d, I H, J 6.6 Hz), 7.3 7-7.13 (in, 12H-1), 6.95 I 6-.64 I1H), 6.45 INH, j 2.2 Hz), 6.3 2 (s, I1H), 6.17 I1H, J 7.7 Hz), 5. 14 2H), 4.96 I H, J 7.2 Hz), 4.62-4.56 (mn, I M, 4.44-4.40 (in, I 4.12 2H, J =4.4 Hz), 3.49-3.40(in, 3H), 3.35-3.26 (mn, 1H), 3.09-2.96 (Mn, 3H), 2.92.

2.85 (in, 2H), 2.77-2.69 (mn, 1H). Anal.Calculated for C 36

H

36

N

4 0 5 e 0.4 H 2 0: C, 70.66; H, 6.06; N, 9.16. Found: C, 70.69; H, 6.11; N, 8.99.

Example N-([2,2-Dim ethyl-1I(S)-(methy Ica rba moy )propy I 3(R) [3.(py rid in4yI)-. 1 Hpyrrol-1-yijsuccinamic acid rON HOKs,'-rNH

"NHCH,

According to the procedure described in Example I1(a), N- (2,2-dimnethyl- I (inethylcarbamoyl)propyl]-3(R)-[3-(pyridin-4-y)- IH-pyrrol- 1-yl]succinamic acid benzyl ester was hydrogenolyzed in MeOH to give 60 mg; of N-[2,2-dimethyl- I(S)- (methylcarbanioyl)propyl]-3 (R)-(3-(pyridin-4-yl. 1 H-pyrrol-1I yl)]succinarnic acid as a yellow powder, mnp 145-V 0 C: H NMR (CD 3 OD): a 8.48 2H,J3= 6.2 Hz), 7.62 2H,JI= 6.2 Hz), 7.5 8 I1H), 6.94 I H, J 2.5 Hz), 6.64 I1H, J 2.2 Hz), 5.3 0 I1H, J1 7.3 Hz), 2.98 (dd, I H, I 7.2, 16.5 Hz), 2.64 3H, J 3.7 Hz), 1.00 9H). IR (KBr): 3315, 2959, 1710, 1654, 1545, 1400, 1206 cm. HRFABMS: Calculated for C 20

H

26

N

4

O

4 CS (M CS)V: 519.1008. Found: 519.1026. Anal. Calcd for C 20

H

26

N

4 0 4 0 0.1 EtOAc 0 0.2 CHC1 3 C, 59.03; H, 6.49; N, 13.37.

Found: C, 5 9.24; H, 6.75; N, 13. The starting materials were furnished as follows: 4-Furan- ylI-pvridine

-N

According to the procedure described in Example 1(a) for the preparation of 3..biphenyl- 4-yi-furan, 4-bromopyridine hydrochloride (500 mg, 2.57 mmol) was coupled to fresh 3furanboronic acid (see Thompson, W. Gaudino, G. Org. Chem. 1984, 49, 5237-5243) to furnish 373 mg (100%) of crude 4 -furan-3-yi-pyridine as an unstable solid that was used immediately. NMR and IR matched that of literature (see Ribereau, P.;.Queguiner, G. Can. J Chem. 1983, 61, 334-342 and Ishikura, Ohta, Terashima, M. Chem. Pharn. BuIL. 1985, 33, 4755-4763).

4-(2.5-Dimethoxv-2. 5-dihydro-fiia-3-l)pvridine H3C

OCH

3 According to the procedure describe in Example 1(a) for the preparation of 3-biphenyl-4yl-2,5-dihydro-2,5-dimnethoxyfuran, crude 4-furan-3-yl-;pyfidine (2.57 mmol) was treated with bromine in McOH at -15VC in the presence of Na 2

CO

3 to provide 450 mg of a mixture of diastereomers of 4-(2,5-dimethoxy-2,5-dihydro-furun-3-yl)pyridine as a yellow oil, which was used without fur-ther purification: IH NMvR (CDC13): 868.62 (di, 2H, J 5 .0 Hz), 7.44-7.3 8 (in, 2H), 6.52 I H, J 0.9 Hz), 6.02 (dci, 0.5H, J 0.9, 3.7 Hz), 6.00 (dci, 0.5H, J 3.7 Hz), 5.98 5.71 0.5H, J 1.2 Hz), 3.48-3.40 6H). IR: 2933, 1597, 1547, 1438, 1369, 1193, 1118, 1039, 974, 918, 889, 821 cm'. HRFABMS: Calculated for CI IH 1 4

N

3 (M 208.0974. Found: 208.0968.

4 2 .5-Diethox -tetrahvdro l 3 d

H

3

C

0 CH3 According to the procedure described in Example 1(a) for the preparation of 3-biphnyl- 4 -yl-2,5-dimethoxy-tetrahydro-furan, a mixture of 4 2 ,5-dimethoxy-2,5-dihydro-furan-3yl)pyridine (500 mg, 2.41 mmol) was hydrogenated in MeOH (2 mL) and EtOAc (8 nL) for 2h to give 5 0 0 mg (100%) of a mixture of diastereomers by NMR of 4-(2,5-dimethoxy-tetrahydrofuran-3-yl)pyridine as a yellow oil. I NMR (CDCI3): 8 8.52-8.48 2H), 5.34-4.98 2H), 3.60-3.20 6H), 2.76-1.94 38). IR (KBr): 2920, 1601, 1120, 988, 860 cm".

:HRFABMS: Calculated for C 11 H1 6 N0 3 (M 210.1130. Found: 210.1137.

N-(2.2-Dimethvl-I (S)-methvlcarbamovlpropvl)-3(R.-(3-2ridin-4-vi- I H-prrol- -vlsuccinamic 0 N. o 0 A r N NHCH 2 A solution of crude 3(R)-arnino-N-(2,2-dinethyl- 1(S)methylcarbanoylpropyl)succinamic acid benzyl ester trifluoroacetate salt (0.44 mmol), 4-(2,5dimethoxy-tetrahydro-furan-3-yl)pyridine (101 mg, 0.482 mmol), pyridine (156 pL, 1.92 mmol), and chlorotrimethylsilane (366 gL, 2.88 mmol) in 1,2-dichloroethane (5 mL) was heated at After 3 days, the mixture was allowed to cool and concentrated in vacuo to give a brown oil which was purified via flash column chromatography with 0.5% HOAc/10% MeOH/CH 2

CI

2 as eluant to afford 90 mg of N-( 2 2 -dirnethyl.1(S)-methylcarbamoylpropy)3(R)-(3.

pyridin-4-yl-IH-pyrrol-1-yl)succinamic acid benzyl ester as a pale yellow powder, mp 130-3*C.

IH NMR (CD3OD): a 8.36 (bs, 2H), 7.98 2H, J =4.4 Hz), 7.51 2H, J 5.0 Hz), 7.48 (t, I H, J= 1.8 Hz), 6.93 IH, J =2.5 Hz), 6.61 (dd, IH,i1=1.7, 3.0OHz), 5.34 IH, J= 7.6 Hz), 10 (dd, 2H, J= 2.5, 14.3 Hz), 4.16 I 3.14 (dd, I H,J 7.8 Hz, 16.5 Hz), 2.60 3 H, J 3.4 Hz), 0.92 9H). IR (KBr): 3314, 2965, 1734, 1648, 1604, 1543, 1400, 1167 cm' t HRFABMS: Calcd for C 27

H

32

N

4

O

4 CS (M 609.1478. Found: 609.1499. Anal: Calculated for C 27

H

32

N

4 0 4 0.1 CH 2

CI

2 0 MeOH: C, 65.27; H, 7.06; N, 10.83. Found: C, 65.52; H, 6.89; N, 10.52.

~Example 3(R)-[3-(Biphenyl-4-yl)-IH-pyrrl.1yl.N.[2,2.dimethyl1(S).

:(methylcarbamoyl)propyljsuccinamic Acid 0 N 0

ANHM.

0 According to the procedure described in Example 3(R [3-(bipheny-4-y1)-1Hpyrrol- I -yl]-N-[2,2-dimethyl- I (S)-(methylcarbamoyl)propyl]succinainic-acid benzyl ester was *hydrogenolyzed to give 3 10 mg of 33(R)-[3-(biphenyl.4.yl).1IH-pyrrol-1I-yl)-N-(2,2dimethyl- 1 (S)-(methylcarbamoyl)propyl]succinamic acid as an amorphous solid. IHNMR (CDCl 3 a 7.56 2H, J =7.4 Hz), 7.51 4M), 7.40 2H1-, J 7.4 Hz), 7.32-7.26 (in, 2H), 7.11 I 6.81 1iH), 6.51 I 5.96-5.93 (bin, I 5.23 INH, J 6.8 Hz), 4.17 ILH, J 9.6 Hz), 3.34 (dd, I1H, J 6.4, 17.1 Hz), 3.09 (dd, I H, J 17.5 Hz), 2.71 3H, J 4. 8 Hz), 0.90 9H); Anal Calculated for C 27

H

3 IN30 4 0.3 MTBE 0.1 H 2 0: C, 69.89; H, 7.16; N, 8.58. Found: C, 70.02; H, 7.33; N, 8.25.

The starting material was prepared as follows: 3(R)-r3-(Biphenvl-4-fl)- I H-pyrrol. -vt (2.2-dimethyl. I(S)- (methvlcarbamovfln2ropvflsuccinami c Ac id Benzyl Ester O N 0 0 O~ 2 NH-i. NHCH, According to the procedure described in Example 1(c) for the preparation of N-(8-oxo-4oxa- I ,7-diaza-tricyclo-[9.6. 1.0I2 1 7 -octa-deca- 11(18), 12,14,1 6-tetraen-9S-yl)-3(R)-(3-phenyt- I H-pyrrol- I -yl)succinamic acid benzyl ester, 3(R)-amino-N-(2,2-dimethyl- I (methylcarbamoyl)propyl)succinarnic acid benzyi ester (prepared as described in Example 1(b))was condensed with 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example in 1,2-dichioroethane with trifluoroacetic acid to provide in 35% yield (biphenyl-4-y I H-pyrrol- I -yI]-N-[2,2-dixnethyl- I (S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester as an amorphous solid. H NMR (CDCl3): a 7.63-7.57 (in, 6H), 7.44 Ct, 2H, J 7.6 Hz), 7.3 5-7.25 (in, 6M1, 7.09 1IH), 6.890 IlH, J 2.4 Hz), 6.61 1IH, J3 2.0 Hz), 6.28 (d, I H, J 8.8 Hz), 5.99-5.71 (bra, 111), 5.17-5.08 (in, 3H),-4.02 11H, J 8.0 Hiz), 3.40 (dd, LH, J 16.7 Hz), 3.12 (dd, IH, J 8.5, 16.9 Hz), 2.76 3H, J 4.8 Hz), 0.87 9H). Anal.

Calculated for C 34

H

37

N

3 0 4 C, 74.02; H, 6.76; N, 7.62. Found: C, 73.87; H, 6.93; N, 7.39.

Example N-(1 (S}-Benzyl-2-methoxyethyl)-3(R)- (3-(biphenyl-4-yI)-1 H-pyrrol- 1yllsuccinamic Acid

NY

0

UNO

According to the procedure described in Example N-(l(S)-benzyl-2-methoxyethyl)- 3 (R)-[3-(biphenyl-4-yI)- I H-pyrrol- i-yl~succinarnic acid benzyl ester was hydrogenolyzed in yield to I(S)-benzyl-2-methoxy-ethyl)-3(R}4[3-(biphenyl-4-yl)- 1H-pyrrol. 1yl~succinamic acid as an amorphous solid, nip 247 0 C. IH NMR (CDCI3): a 7.64-7.5 3 (in, 6H), 7.44 2H, J 7.5 Hz), 7.34 I H, J 7.4 Hz), 7.25-7.19 (mn, 3H) 7.10 2H, 3 8.1 Hz), 6.98 I1H), 6.70 I 6.59 18H), 5.83 18H, J 7.7 Hz), 4.97 18H, J 7.0 Hz), 4.22-4.15 18H), 3.43 (dd, IH, J 6.6, 16.5 Hz), 3.29-3.16 (mn, 5 3.00 (dd, I H, J 7.4, 16.9 Hz), 2.78 J =7.0 Hz). Anal. Calculated for C 0

H

3 N0 .0.25 H 2 0 ,7.7 ,63;N .5 3020 20 ,739;H 631 N Found: C, 73.99; H, 6.59; N, 5.45.

The starting materials were furnished as follows: N-(l (S')-Be=1v-2-inethoxyethvI')-3(R)-(t-butoxycarbonXIamino~succinamic Acid Renzyl Ester a H N r -JVHa

.K,

A mixture of N-t-butoxycarbonyl-D-aspartic acid 1-benzyl ester (480 mng, 1.50 minol), 2S-amino-1I-methoxy-3 -phenylIpropane hydrochloride (300 mg, 1.50 mmol), benizotriazole- Iyloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP; 663 mg, 1.50 minol) and triethylarnine (0.5 mnL, 3.6 mmol) in DMF (5 rnL) was stirred at ambient temperature for 4 hours.

The mixture was poured into H 2 0 (75 m.L) and extracted with EtOAc:hex 1; 2 x 50 mL). The combined organic extracts were washed with IN aqueous NaHSO 4 (2 x 25 rnL), saturated aqueous NaHCO 3 (25 m.L) two times, and brine (25 inL), dried over NaSO 4 and evaporated to give upon hexane trituration 545 mng of I (S)-benzyl-2-methoxyethyl)-3(R)-(tbutoxycarbonylamnino)succinamic acid benzyl ester as a solid, mp 60-3 'H NMR (CDC13): a 7.37-7.16 (mn, 101-), 6.74 (bs, 1H), 5.64 (bd, IH, J 6.6 Hz), 5.12 (dd, 2H, J 12.1, 17.7 Hz), 4.48-4.46 (in, IH), 4.25-4.20 (mn, IH), 3.34 3H), 3.31-3.23 (mn, 2HM, 2.98 (dd, IH, J 4.4, 16.9 Hz), 2.82 2H, J 7.4 Hz), 2.62-2.57 (in, I 1.44 9H). Anal. Calculated for C 26 H3 3

N

2

O

6 0.25 1-20: C, 65.87; H, 7.12; N, 5.91. Found: C, 65.73; H, 7.29;N, 5.89.

N-(0 (S)-Benzvl-2-methoxyethfl)-3(R)-r3 -(biphenyvI4-yl)- I H-pRroi- I -yljsuccinamic Acid

N.

NI

According to the proecdure described in Example 1(a) for the preparation of N-C 1(S)benzyl-2-hydroxyethyl)-3(R)-[3-(biphenyl-4-y)- 1 H-pyrrol- I -yljsuccinamic acid berizyl ester, N- (1 (S)-benzyl-2-inethoxy-ethyl)-3 (R)-(t-butoxycarbonylaniino)succinamic acid benzyl ester was deprotected and the crude salt condensed in HOAc with 3-(biphenyl-4-yl)-2,5dimethoxytetrahydrofiuran (prepared as described in Example to provi de in 54% yield N- (1 (S)-benzyl-2-methoxyethyl)-3(R)-[3-(biphenyl-4-yl)- I H-pyrrol- I -yl]succinamic acid benzvl ester as an oil, which was used without further purification. I'H NMR (CDCI3): 8 7.65-7.62 (in, 6H), 7.57 2H, J 7.4 Hz), 7.48-7.16 (in, 9H), 7.10 (di, 2H, J =7.7 Hz), 6.98 I1H), 6.69 (s, INH), 6.57 I 5.78 (ci, I1H, J 8.5 Hz), 5. 10 2H), 5.01 (dci, I H, J 9.2 Hz), 4.20-4.16 (mn, I 3.43 (dci, I H, J 5.3, 16.7 Hz), 3.28-3.15 (mn, 5H), 3.02 (dci, I H, I 9.2, 16.6 Hz), 2.76.

2H, J 7.4 Hz); IR: 3315, 3063, 3030, 2930, 2891, 1738, 1682, 1526, 1495, 1204, 1167, 764, 737, 698 cm 1 HRFABMS: Calculated for C 37

H

36

N

2 0 4 (M 572.2675. Found: 572.2674.

Example (3-(Biphenyl-4-yl)-1 H-pyrrol- 1-ylJ-N-12-hydroxy-1(S)-[((H-imidazol-4yl)methylletbyllsuccinamic Acid Trifluoroacetate Salt HOI%#LNHoH 0 'NH According to the provedure described in Example 3(R)-[3-(biphenyl-4-yl)-1H- ~pyrrol-I -yl]-N-[2-hydroxy- 1(5)4(1H-imidazol-4yl)methyl]ethyl]succinamic acid benzyl ester was hydrogenolyzed and, after purification via reversed-phase HPLC, of (biphenyl-4-yl)-1 H-pyrrol- 1-yl]-N-[2-hydroxy- 1H-imidazol-4-yI)methyl~ethyIlsuccinamic acid trifluoroacetate salt was obtained as a rust-colored amorphous solid. IH NMVR (CD3OD): 6 8.74 1iH), 7.61-7.51 (mn, 7.41 2H, J =7.5 Hz), 7.34-7.27 (mn, 2M), 7.19 INH), 6.81 (t, INH, J1 2.2 Hz), 6.48 INH), 5.00 (dci, 1iH, J 8.8 Hz), 4.17-4.12 (mn, I 3.58-3.46 (in, 2H), 3.30-3.21 (in, IM), 3.06 (dd, 1H, J 4.8, 15.1 Hz), 2.95-2.87 (in, 2H). Anal. Calculated for

C

26

H,-

6

N

4 0 4 1.0 TFA 0 1.4 H 2 0 0.15 C 6

H

1 4 C, 56.84; H, 5.27; N, 9.17. Found: C, 57.04; H, 5.00; N, 8.94.

The starting material was furnished as follows: 3(R)-(t-Butoxycarbonylamino)-N-[2-hvroxy- I IH-iniidazOl-4-vl)methvfetvlc ginamic Acid Benzl Ester 0 According to the procedure described in Example I1(b) for the preparation of 3 butoxycarbonylarnino-N-(2,2-dimethyl- 1 (S)-(rnethylcarbanoyl)propyl)succinamic acid benzyl ester, N-t-butoxycarbonyl-D-aspartic acid P-benzyl ester and L-histidinol dihydrochloride were coupled with TBTU to furnish 4 10 mg of 3 (-uoyarbnanio-[2hdoy I (S)-(1lH-imidazol-4-y1)methyl~ethyl]succinamic acid benzyl ester as a solid which was used without further purification.

0:3R-r3-cBiphenvl-4-vyv IH-pvrol- 1 -yl]-N-[2-hvdroxv- I I H-imidazol -4.

yflmethXI~ethMllsuccinamnic Acid Benzl Ester 0 I C V 0

OH

According to the procedure described in Example 1(c) for the preparation of N-(8-oxo-4oxa- 1 ,7-diaza-tricyclo-[9.6. 1 .012 17 -octadeca-I 11(18), 12,14,1 6-tetraen-9S-yl)-3(R)-(3-phenyl- I H-pyrrol- 1-yl)succinaxnic acid benzyt ester, 3 (R)-(t-butoxycarbonylamino)-N- (2 -hydroxy- I ((I1H-imidazol-4-yl)methyl)ethyl]succinarnic acid benzyl ester was deprotected, and the resultant crude amnine salt was condensed with 3 -(biphenyl-4-yl)-2,5-dirnethoxy-retrahydroft.-a (produced as described in Example in I ,2-dichloroethane in the presence of trifluoroacetic acid to give in 37% yield 3 (R)-f3-(bipheny-4-yI)- HpyrroII-y]N[2hydroxy imidazol-4.yl)methyllethyl)succinarnic acid benzyl ester as a yellow solid. I NMR (CDCI3): 8 7.65-7.59 (in, 4H), 7.53 2H, J 8.5 Hz), 7.45 2H-, J 7.4 Hz), 7.37-7.26 (in, 7M-1, 6.95 (s, IH), 6.70 INH, J 2.2 Hz), 6.65 I 6.52 I 6.45 (bs, I1-H), 5. 10 2H), 5.06-5.02 (in, I 4.13-4.11 (mn, IlH), 3.69 (dd, I1H,J 11.6 Hz), 3.56 (dd, I H,J 11.8 Hz), 3.42 (dd, I1H, J 5.5, 16.9 Hz), 3.06 (dd, I H, J 8.8, 16.9 Hz), 2.84 2H, J 4.8 Hz). Anal. Calculated for C 33

H

3 2

N

4 0 4 0.8 H 2 0 0 0. 15 MTBE: C, 70.34; H, 6.19; N, 9.72. Found: C, 70.5 1; H, :6.05; N, 10. :.Example 3 1R-3(ihn 4y)lHpro-- 2()hdrxccohx yI)succinamic Acid 0 N OH HOA&,-nNHO According to the procedure described in Example 3(R)-[3-(biphenyl-4-yl)- IHpyrrol- I -yl]-N-(2(R)-hydroxycyclohex- 1 (R)-yI)succinamic acid benzyl ester was hydrogenolyzed to obtain in 81% yield 3(R)-[3-(biphenyl-4-yl)-IH-pyrrol-1-yl]-N-(2(R)hydroxycyclohex- I(R)-yl)succinaniic acid as an amorphous solid. I H NMR (CD 3 OD): 6 8.00 1 H, J 8.9 Hz), 7.61 2H, J 7.4 Hz), 7.56 4H), 7.40 2H, J =7.5 Hz), 7.2 8 1 H, J 7.5 Hz), 7.2 3 I 6.8 6 I H, J 2.6 Hz), 6.48 I H, J =2.2 Hz), 5.07 11-f, J1 7.4 Hz), 3.59-3.53 (in, I1-M, 2.98 (dd, ILH, J 7.7, 16.9 Hz), 2.01-1.95 (in, IlH), 1.83-1.78 (in, INH), 1.72- 1.61 (in, 2H4), 1.3 4 -1.1 1(m, 4H). Anal. Calculated for C,- 6

H

28

N

2 0 4 o.0.5 H 2 0: C, 70.73; H, 6.62;N, 6.35. Found: C, 70.79; H, 6.61; N, 6.26.

The starting material was prepared as follows: 3 (R')-tButoxvcarbonvlamino-N-(2 (R)-hvdrxvcyclo hex-. I R-yl~succinmcAi e~v se 0OHN O cr o2NHO According to the procedure described in Example 1 (0 for the preparation of N-(I benzyl-2-methoxyethyl)-3(R)-t-butoxycarbonylamino.s uccinamic acid benzyl ester, N-tbutoxycarbonyl-D-aspartic acid P-benzyl ester and racernic rras-2-aminocyclohexanol were coupled with BOP to give a crude solid which was triturated with MTBE/hex, and then successively recrystallized from MTBElisooctane and MTBE/cyclohexanes/isooctane to provide 260 mng of the single diastereomer 3(R)-t-butoxycarbonylaniino-N-(2(R)-hydroxycyclohex-IR-yl)succinamic acid benzyl ester as an off-white solid, mp 124-5*C. 1 H NIR (DMSO-d 6 8 7.52 1H, J 7.0 Hz), 7.36-7.31 (mn, 511), 7.09 1H, J 9.2 Hz), 5.08, 5.05 (AB quartet, 2K, J 12.1 Hz), 4.48 I H, J 5.2 Hz), 4.34-4.27 (in, INH), 3.26-3. 18 INH), 2.7 *d,1,J44 62H) .6(d .015 m 2M1, 1.36 911), 1.20-1.08 (in, 4H1). Anal. Calculated for C 22

H

32

N

2 0 6 C, 62.84; H, 7.67; N, 6.66. Found: C, 63. 10; H, 7.69; N, 6.60.

3(R)-r3-(BiphenvI-4-vI)- 1H-pyrrol- I XI -N-(2(R')-hydroxyclo hex- I -v bsuccinam ic Acid 0 N OH 0 o~YNHb As described in Example 1(a) for the preparation of N.(1(S)-benzyl-2-hydroxyethyl).

-(biphenyl-4-yI)- 1H-pyrrol- I-yl)succinamic acid benzyl ester, 3(R)-tbutoxycarbonylamino-N-(2(R)-hydroxycyclohex-l(R)-yI )succinamic acid benzyl ester and 3biphenyl-4-yl-2,5-diniethoxy-tetahydrofliran (prepared as described in Example were condensed in acetic acid to furnish in 41% yield 3(R)-[3-(biphenyl-4-yI)-IH-pyrrol-l-yl]-N- (2(R)-hydroxycyclohex- I (R)-yl)succinamnic acid benzyl ester as an amorphous off-white solid.

H NMR (CDCI3): 8 7.63-7.54 6H), 7.45 2H, J =7.5 Hz), 7.36-7.26 (mn, 6H4), 7.06 (s, .2 IH), 6.76 IH, J =2.4 Hz), 6.58 IH), 5.46 IH, J 7.0 Hz), 5.15-5.10 (mn, 3H), 3.61- 3.55 (in, 1H), 3.49 (dd, 1H, J 16.6 Hz), 3.27-3.21 (mn, IH), 3.06 (dd, IH, J 16.7 Hz), 2.04-1.98 (mn, 111), 1.85-1.78 11-1), 1.71-1.51 (mn, 2H), 1.32-1.02 (mn, 4H). Anal. Calculated for C 33

H

34

N

2 0 4

H

2 0: C, 73.3 1; H, 6.7 1; N, 5.18. Found: C, 72.93; H, 6.72; N, 4.93.

Example 3(R)-[3-{Biphenyl-4-yI)-1 H-pyrrol-1-yl]-N-f2.hydroxy-l(S)-(bydrorymethyI)- 2-methylpropyllsuccinawic Acid 0 N 0 HOK~'\ NHOH According to the procedure described in Example a mixture of 3(R)-[3-(biphenyl-4yl)- I1--pyrrol-lI -yfl-N-[2-hydroxy- I (S)-(hydroxymethyl)-2-methylpropyl]succinamic acid benzyl ester (137 mg, 0.26 rnrnol) in EtCH (2.5 rnL) and EtOAc (2.5 m.L) was hydrogenolyzed after minutes to give a white solid, which was trituraed with CH 2

CI

2 Ihex to provide 85 mg of .3(R)-[3-(biphenyl-4-yl)- I H-pyrrol- I -yi]-N-(2-hydroxy- I (S)-(hydroxyniethyl)-2- *methylpropyl]succinamic acid as a white solid, rnp 150-2 H NMR (acetone-d 6 6 7.67- ~~7.61 (in, 6H), 7.46-7.39 (in,3H), 7.33 IH, J =7.4 Hz), 7.09 (bd, IH,JI= 8.5 Hz), 6.97 IH, I 2.4 Hz), 6.53 1H, J =2.2 Hz), 5.28 1 H, J =7.2Hz), 3.81-3.67 (in, 31), 3.35 (dd, I H,J 7.4, 16.9 Hz), 3.02 (dd, lH, J 7.4, 16.9 Hz), 1.24 3M1', 1.12 3H). Anal. Calculated for too**: 5 C 25

H

2

SN

2 0 5 C, 68.79; H, 6.47; N, 6.42. Found: C, 68.54; H, 6.50; N, 6.39.

The starting material was fum-ished as follows: 3-Ben=doxycarbonyl-2.2-dimethvL..4R-4 I -hydroxy- I -methylethyl~oxazolidine *V so: 0 0 AN To a solution of methyl 2 3 -benzyloxycarbony1-2,2.dimethyloxazolidin-4R-yl)acetate (see Delacotte, Galons, Schott, Morgat, Labelled Comp. RadiaPharm 1991, 29, 1141-1146; 500 mg, 1.70 mmol) in dry THF (10 mL) at -78"C was added dropwise via syringe a solution of methylmagnesium bromide (1.5 mL of 3M in ether). After 15 minutes, the reaction vessel was placed in a 0*C ice bath. After 2 hours, the mixture was cooled to -78 0 C and more methylmagnesium bromide (0.5 mL of 3M in ether) was added. The mixture was allowed to warm to 0*C over 2 hours, then quenched with acetone (I mL) and partitioned between EtOAc (50 mL) and IM pH7 phosphate buffer (50 mL). The separated organic layer was washed with 1IM pH7 phosphate buffer (50 mL) and brine (25 mL), dried over Na 2

SO

4 and concentrated to a residue which was purified via flash column chromatography with 0-12% EtOAc/CH 2

C

2 gradient eluant to furnish 280 mg of 3-benzyloxycarbonyl-2,2-dimethyl-4R-( I -hydroxy- 1methyl-ethyl)-oxazolidine as a colorless oil. H NMR (CD 3 CN): 8 7.52-7.45 5H), 5.35-5.2 (bm, 2H), 4.68 (bs, IH), 4.15-3.95 (bm, 3H), 1.67 3H), 1.57 3H), 1.21 6H). Anal.

Calculated for C 16

H

23

NO

4 0.3 H 2 0: C, 64.32; H, 7.96; N, 4.69. Found: C, 64.48; H, 7.87; N, 4.67.

4" 3(R)-t-Butoxvcarbonvamino-N-f2-hydroxy-1(S-(hydroxvmethyl-2-methylpropyllsuccinamic Acid Benzl Ester 0.

O NH O NH OH 0H 3-Benzyloxycarbonyl-2,2-dimethyl-4R-( I-hydroxy-1-methyl-ethyl)-oxazolidine was hydrogenolyzed in the presence of HCI according to conditions described in Example 1(a) to provide crude 2(R)-amino-3-methyl-butane-1,3-diol hydrochloride. According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butoxycarbonylamido-N-(2,2-dimethyl- Il(S)-(methylcarbamoyl)propyl)succinamnic acid benzyl ester, the crude amnine salt was coupled to N-t-butoxycarbonyl-D-aspartic acid P-benzyl ester with TBTU. Purification via column chromatography with EtOAc/CH 2 Cl 2 1) to 10%/ MeOIVCH 2

CI

2 gradient elution led to isolation in 52% yield of 3(R)-t-butoxycarbonylarnino-N-[2.hydroxy- I(S)-(hydroxymethyl)-2methylpropyl]succinamic acid benzyL ester, which was used without further purification. H NMR (CD 3 CN): 6 7.51 5H), 6.99 (bs, lH), 5.99 (bs, 5.25 2H), 4.57-4.50 (in, 1H), 3.83-3.76 (in, 3H), 3.00 (dd, I H, J 5.7, 16.4 Hz), 2.87 (dd, I1H, J 7.2, 16.6 Hz), 1.55 9H), 1.34 3 1.22 3H). Anal. Calculated for C 21

H

32

N

2 0 7 0 0.5 H 2 0 0. 1 O=C[N(CH 3 2 2 C, 58.02; H, 7.74; N, 6.92. Found: C, 58.29; H, 7.75; N, 6.82.

3-(Binhenyl-4-fl)- IH-nvrrol- 1 -vl-N-r2-hydroxy- I(S)-(hydroxvrnethfl)-2methylpropyl Thuccinarnic Acid Benzl Ester 0ON- C) A,,Xkr NH. -OH 00 According to the procedure described in Example 1(c) for N-(8-oxo-4-oxa- 1 ,7-diazatricyclo-[9.6. 1.0 1' 1 7 )-octa-deca- 1(1 12,14,1 6-tetraen-9S-yl)-3(R)-(3-phenyl- 1 H-pyrrol- 1 yl)succinaxnic acid bcnzyl ester, 3(R)-t-butoxycarbonylamino-N-(2-hydroxy- I hydroxymethyl-2-methyl-propyl)succinamic acid benzyl ester was deprotected with trifluoroacetic acid. The crude amine salt and 3-biphenyl-4-yL-2,5-dimethoxy-teuahYdrofuran (prepared as described in Example were condensed in anhydrous I1.2-dichloroethane with trifluoroacetic acid to give in 11% yield 3(R)-(3-(biphenyl-4-y1).1H-pyrrol-1-yl]-N-[2hydroxy- 1(S)-(hydroxymethyl)-2-methylpropylsucciflamic acid benzyl ester as an amorphous solid.H NM (acetone-d 6 8 7.67-7.61 (mn, 6H), 7.48 2H, J77H)7.39tHJ18z)7.- 7.2 7 (in, 6M-i, 7.09 (bd, I1H, J =9.2 Hz), 6.96 I H, J =2.6 Hz), 6.5 3 (dd, I H, J 7, 2.8 Hz), 5.35 IIH, J 7.4 Hz), 5.11 3.81-3.62 (in, 3H), 3.39 (dd, 1H, J 6.8, 16.4 Hz), 3.12 (dd, I H, J 16.6 Hz), 1.24 3H), 1.21 314). Anal. Calculated for C 32

H

34

N

2 0 5

C,

72.98; H, 6.5 1; N, 5.32. Found: C, 72.83; H, 6.60; N, 5.24.

Example 1 N-[2,2-Dimethyl-(S)-(methycarbamoyl)propylI.3(R)-f3-(4propylpbenyI).- 1H-pyrrol-1-yljsuccinamic Acid

HOI,,%,NHI,.NH-

0 -t According to the procedure described in Example I1(a), N-[2,2-dimethyl-lI(S)- (methylcarbamoyl)propyl]-3(R)-[3-(4-propylphenyI1H-pyrrol-1I-yl]succinamic acid benzyl ester in MeOH and EtOAc was hydrogcnolyzed to provide 30 mg (9 of N-[2,2-dirnethyl- I (S)-(inethylcarbamoyl)propyl]-3(R}.{3-(4-propylphenyl)- 1 -pyrrol-1I-yI]succinamic acid as a yellow powder, mp 104-6*C. H NMR (CD 3 OD): 87.95 (bs, 1H), 7.60 (bs,1I), 7.48 2H, 3 Hz), 7.16 (bs, 18H), 7.08 2H, J 7.5 Hz), 6.86 (bs, I1H), 6.42 (bs, I 5.34 18H, 3I 4.15 (bd, 18H, J 5.9 Hz), 2.83 (dci, I1H, J 6.2, 16.0 Hz), 2.62 3H), 2.60-2.50 (in, 2H), 1.7-1.58 (mn, 28), 0.95 9H). IR (KBr): 3300, 2960, 1642,1560,1195, 775 cm 4 HR.FABMS: Calculated for C 24

H

33

N

3

O

4 CS (M 560.1525. Found: 56.1509. Anal.

Calculated for'C 24

H

33

N

3 0 4 0 0.3 EtOAc: C, 66.67; H, 7.86; N, 9.26. Found: C, 66.93; H, 7.78; N, 8.89.

The starting materials were made as follows: Propy lpheny 11~furan As described in Example 1(d) for the preparation of 4-furan-3-yl-pyridine, I-iodo-4propylbeazene (500 mg, 2.03 mmol) was coupled to 3-furanboronic acid to furnish in high yield 3)-(4-propylphenyl)-furan as a light brown oil that was unstable and used immediately without further purification. IH NMR (CDCI3): 8 7.69 1LH, J 0.9 Hz), 7.46 I H, J 1.7 Hz), 7.40 2H, J 8.1 Hz), 7.18 2H, J 7.8 Hz), 6.68 I1-H, J 0.9 Hz), 2.59 2H, J 7.5 Hz), 1.66-1.60 (in, 2H), 0.95 3H, J =7.5 Hz).

2.5-Dimethoxy-3-(4-propvylphenvfl-2.5-dihydro-fura

.H

3 o-.

)OCH

3 As described in Example 1(a) for the preparation of 3-biphenyl-4-yl-2,S-dihydro-2,5dimethoxy-tetrahydrofuran, crude 3-(4-propylphenyl)-fuma was converted to 490 mg (98% from I -iodo-4-propylbenzene) of 2,5-dimethoxy-3-(4-propylphenyl)-2,5-dihydro-flirn as a light brown oil that was unstable and used immuediately without further purification. 1 H NMIR (CDCl3): a 7.47 (dd, 2H, J3=1.4, 8.1 Hz), 7.17 2H, J 8.1I Hz), 6.25, (dd, 111J3= 0.6, 1.2 Hz), 6.00 1H, J =0.6 Hz), 5.69 IN, 3 1.6 Hz), 3.49 2H), 3.43 IN), 3.40 2H), *3.38 IH), 2159 2H, J 7.5 Hz), 1.64 2H, J 7.5 Hz), 0.94 3H, J =7.5 Hz). IR: *2930, 1514, 1464, 1192, 1105 cm- 2 5 -Dir nethoxv.3-(4-proplpheny l)tetrahydrofuran

H

3

CO

0OC

H

3 As described in Example I1(b) for the preparation of 2,5-dimethoxy-3-phenyltetrahydrofuran, 2,5-dihydro-2,5-dimethoxy3(4-propyphenyl)-firan (320 mng, 1.29 mmol) was hydrogenated to give 322 mg (100%) of a diastereomeric mixture of 2,5-dirnethoxy-3-(4propylphenyl)-tetrahydrofuran as a viscous colorless oil that was unstable and used immediately without further purification. I HNMR (CDC13): 8 7.24 2H, J 8.1 Hz), 7.12 2H, J 8.1 Hz), 5.24 IlH, J 5.9 Hz), 3.60-3.30 (mn, 6H), 2.59 I1H, J 7.5 Hz), 2.52 I1-H, J =8.1 Hz), 2.32 (bs, 3H), 1.62 2H, J 7.5 Hz), 0.92 3H-, J 7.5 Hz).

N-r2.2-Dimethvl-I1 S)-methv Icarbamovflpropvll-3(R-(4-2roi~vl-3-phenvl-- IIH-pv-rl-1yl'lsuccinarnic Acid B3enzl Ester Or~ oQNH..tAN As described in Example 1 for the preparation of N-(2,2-dimethyl- I(S)xn~ethylcarbaznoyipropyl)-3(R)-(3-pyridin-4-yl- 1H-pyrrol- 1-yl)succinamic acid benz)'1 ester, 3(R)-aznno-N-[2,2-dimethyl- 1(S)-(methylcarbaxnoyl)propyllsuccinamic acid benzyl ester trifluoroacetate salt (prepared as described in Example 522 mng, 1. 16 mmzol) was condensed with crude 2,5-dimethoxy-3-(4-propylphenyl)-tetrahydrofuran (1.29 mmol) in 1 ,2-dichloroethane with chlorotrixnethylsilane at 90*C over 3 days. The crude dark oil was purified via flash column chromatography with 1% HOAc/10% MeOH/CH 2

CI

2 as eluant to provide 40 mg of N- [2,2-dimethyl- 1 (S)-(methylearbamoyl)propyll-3 (R)-[3-(4-propylphenyl)- I1H-pyrrol-lI yl)succinaxnic acid benzyl ester as a solid, mnp 63-5 I'H NMR (CDC13): a 7.40 2H, J 8.1 Hz), 7.34 -7.20 (in, 5H), 7.14 2H, J =8.1 Hz), 7.00 1H, J 1.9 Hz), 6.78 I H, J Hz), 6.56 1 H, J =1.9 Hz), 6.24 1H, J =8.7 Hz), 5.70 1 H, J =4.7 Hz), 5.16-4.96 (mn, 3H), 4.00 I H, J =9.0 Hz), 3.38 (dd, I1H, J 5.6, 16.8 Hz), 3. 10 (dd, I1H, J 8.7, 16.8 Hz), 2.76 3H K1 5.0 Hz), 2.59 I1-H, J 7.2 Hz), 2.56 I H, J 7.8 Hz), 1.65 2H, J Hz), 0.96 3H, J 7.5 Hz), 0.86 9H1). IR 3314, 2959, 1736, 1648, 1560, 1165, 697 cm .HRFABMS: Calculated for C 3

IH

39

N

3

O

4 CS (M +Cs 4 650.1995. Found: 650.1977.

Anal: Calculated for C 3 1

H

39

N

3 0 4 o 0.3 C 6

H

14 C, 72.33; H, 7.62; N, 7.71. Found: C, 72.36; H, 7.77; N, 7.38.

Example 4-f2S-[2(R)-13-(Biphenyl-4-yl)-1H-py rrol-1I-ylj-3-carboxy-propionylamino]- 4-methyl-pentanoylaminoJ beuzoic Acid Methyl Ester 0 :According to the procedure described in Example 4-{2S-[2(R)-(3-biphenyl-4-yIH- 2 ~pyrrol-1I-yl)-3-carbobenzyloxy-propionyl-amino]4-methyl-pentanoylamino)}-benzoic acid methyl ester was hydrogenolyzed in quantitative yield to furnish 4-{2S-(2(R)-(3-biphenyl-4-yl- 1 H-pyrrol- 1 -yl)-3-carbobenzyloxy-propionyl-amino]-4-nmethy-pentanoylanino -benzoic acid methylI ester as.a solid, mp 209-11 C. I H NMR (CD 3 OD): 8 7.81 2H, J =8.8 Hz), 7.60-7.50 (in, 8H1), 7.40 2H, J 7.4 Hz), 7.28 IH, J 7.4 Hz), 7.20 1H), 6.88 111), 6.48 111), 5.16 I H, J 7.2 Hz), 4.54 I H, J 7.2 Hz), 3.77 3H), 2.98 (dd, I1H, J 6.4, 17.1 Hz) 1.75-1.64 (in, 311), 0.95 611,3J 5.9 Hz). Anal. Calculated for C 34

H

35

N

3 0 6 0 0.6 H 2 0: C, 68.92; H, 6.16; N, 7.09. Found: C, 68.98; H, 6.20; N, 6.98.

The starting material was available as follows: 4 -t 2

S-(

3 -Benvloxcabonl2(R)tbuovcabonyaI opo ilamino)-4-methyI-.pentanolaininol-benzoic Acid Methyl Ester 0>o As described in Example I(f) for the preparation of N-(1 (S)-benzyl-2-methoxyethyl)- 3(R)-(t-butoxycarbonylamino)succinamic acid benzyl ester, N-t-butoxycarbonyl-D-aspartate benzyl ester and 4 2 S-amino-4-methyl-pentanoylamirio)benzoic acid methyl ester (Castelhano, A. Yuan, Home, Liak, T. J. W095/1260.Al1, May 11, 1995) were coupled with B OP to furnish in 9 1 %yield 4 2 S-(3-benzyloxycarbonyl-2(R-t-butoxycarbonylaxninopropionylamino)-4-methyl-pentanoy-amnino].benzoic acid methyl ester, which was used crude, without any purification. I HNMR (CDC13): 6 8.62 IlH), 7.98 2H, J 8.8 Hz), 7.73 (d, 2H, J 8.8 Hz), 7.3 8-7.26 (in, 5H), 6.68 (bd, I H, I 8.5 Hz), 5.45 (bin, I 5.09 (dd, 2H, J 12.1,29 Hz), 4.60-4.51 (in,2H), 3.89 3H), 3.34-3.26 lH), 2.82 (dd, lH, J 18.0 Hz), 2.01-1.95 (in, IH), 1.70-1.53 2H), 1.45 9H), 0.98-0.93.(m, 6H); Anal. Calculated for

C

30

H

39

N

3 0 3 0 0.4 H 2 0: C, 62.46; H, 6.95; N, 7.28. Found: C, 62.47; H, 6.98; N, 7.36.

4-1t2S-r3-Benzvloxycarbonvl-2(RO-(3-biphenvl.4v1-I H-ovrol- I vl')-propionylarninol4- methv Dentanoyiaminl -benzpic Acid Methyl Ester

N

2

YXHCOCI

As described in Example 1(b) for the preparation of 3(R)-amino-N-(2,2-dimethyl-ISmethyicarbanoyl-propyl) succinaxnic acid benzyl ester, 4-(2S-(3 -benzyloxycarbornyl-2(R)-tbutoxycarbonylamino-propionylamino).4-methylpentanoylamino] benzoic acid methyl ester was deprotected with trifluoroacetic acid.

As described in Example I1(b) for the preparation of N-(2,2-diznethyl-lI(S).

methylcarbarnoylpropyl)-3(R)-(3-phenyl-1 H-pyrrol-l-yl)succinamic acid benzyl ester, crude 4- 2 S-(2(R)-amino-3-benzyloxycarbonyl-propionylanino)-.ethy-pentanoyl-amino]-benzoic acid methyl ester trifluoroacetate salt and 3 -biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example were condensed in I ,2-dichloroethane with .2 trifluoroacetic acid and water to give in 27% yield 4-{2S-[3-benzyloxycarbonyl-2(R)-(3biphenyl-4-yl I H-pyrrol- 1-yI)-propionylamino]-4-methyl-pentanoyamino)-benzoic acid methyl ester as a solid, mnp 186-8 I'H NMR (CDCl3): 8 8.49 I1H), 7.95 2H, J 8. 8 Hz), 7.69- 7.26 (in, 16H4), 6.78 1H), 6.61 IH), 5.80 IH), 5.25-5.05 (mn, 3H), 4.54-.50 (in, IH), 3.88 3H), 3.38-3.35 (mn,2H), 1.89-1.80 (mn, 1H), 1.54-1.40 (mn,2H),O0.89 6H, J =6.3 Hz).

Anal. Calculated for C 41

H

41

N

3 0 6 C, 73.30; H, 6.15; N, 6.26. Found: C, 73.21; H, 6.16; N, 6.25.

Example 3(R)-(3-Biphenyl-4-yl I H-pyrro methoxy-Nmetbylcarbaznoyl)-3-metbylbutyllsuccinamic Acid 0 N 0

N'

0

CH

3 According to the procedure described in Example 3(R)-[3-(biphenyl-4-yl)- 1 Hpyrrol- 1(S)-(N-methoxy-N-methylcarbarnoyl).3methy 1-butyljsuccinamic acid benzy I ester was hydrogenolyzed to give in 97% yield 3(R)-(3-biphenyl-4-yIIH-pyrrol-yl)N[1(S)- (N-methoxy-N-methylcarbamoyl).3-inethyl-butyl]succinamic acid as an amorphous solid. 'H NM (CDCI3): 8 7.59-7.53 (mn, 6H), 7.40 2H, J 7.2 Hz), 7.3 3-7.26 (in. 1 7. 10 1 H), 6.88 (bd, 1H, J =9.2 Hz), 6.80 1H), 6.54 IH), 5.13 1H, J =6.8 Hz), 5.03-5.00 (in, H), 3.76 3.39 (dd, 1H, J 6.4, 17.5 Hz), 3.16 3H), 3.00 (dd, 1H, J 7.2, 1.7.1 Hz), 1.60- 1.42 (mn, 3H), 0.92 3H, J =6.6 Hz), 0.89 3H, J 6.6 Hz). Anal. Calculated for

C

23

H

33

N

3 0 5 e 0.25 H 2 0 o00.20 C 6

H

1 4 C, 68.32; H, 7.13; N, 8.19. Found: C, 68.28; H, 7.08; N, 7.93.

The starting material was available as follows: 3(R)-t-Butoxycarbonvlamino-N-rlI(SV--N-methoxy-N.methlcarbamylk3-methvl..

blljsuccinarnic Acid BenzvI Ester 0

>CH

3 As described in Example I1(b) for the preparation of N-(2,2-dimethyl- I(S)methylcarbamnoylpropyl)-3(R)-(3)-phenyl- 1H-pyrrol-1I-yl)succiriaric acid berizyl ester, 2Sbutoxycarbony lamino-N-methoxy-4- methyl-pentanoy lam ide was deprotected with trifluorolacetic acid. The resultant amine salt and N-t-butoxycarbonyl.D-aspartic acid P-benzyl ester were coupled with TBTU to provide in 89% yield 3(R)-t-butoxycarbonyamno-N-[ I (S)-(N-methoxy- N-methylcarbamoyl)-3-methyl-butyl~succinamic acid benzyl ester as an oil, which was used without further purification. IH NMR (CDCI13): 8 7.34 5H), 6.90 I H, J 8.5 Hz), 5.61 (d, I H, J 7.4 Hz), 5.13, 5.11 (AB quartet, 2H, J 12.3 Hz), 5.04-4.98 (in, I 4.61-4.54 (in, I H), 3.76 3 3.19 3 3.02 (dd, I H, J 4.4, 16.6 Hz), 2.74 (dd, I H, J 5.2, 16.6 Hz), 0. 93 3H, J 6.4 Hz), 0.90 3H, J 6.4 Hz). Anal. Calculated for C,- 4

H

37

N

3 0 7 e 0.3 H 2 0: C, 59.44; H, 7.82; N, 8.66. Found: C, 59.4 1; H, 7.69; N, 8.63.

butyl]succinamirc Acid Renzyl Ester 0I Nof- N H r C H As described in Example 1(c) for the preparation of N-(8-oxo-4-oxa- 1 ,7-diaza-tricyclo- 1.012I17 ]-octadeca-1 11(18), 12,14,1 6-tetraen-9-yl)-3-(3-phenyl- 1H-pyrrol- 1 -yl)succinamic acid benzyl ester, 3(R)-amino-N-( I(S)-(N-inethoxy-N-methylcarbamoyl)-3-methylbutyl)succinamic acid benzyl ester was deprotected. The crude amnine salt and 3-biphenyl-4-yl- (prepared as described in Example were condensed in anhydrous I ,2-dichloroethane with trifluoroacetic acid to provide in 48% yield 3(R)-(3-biphenyl- 4-yl-IH-pyrrol-1 l(S)-(N-methoxy-N-methylcarbamoyl)-3methyl-butylisuccinamic acid benzyl ester as an amorphous solid. 'H NMR (CDCI3): 6 7.62 2H, I 7.4 Hz), 7.58 3H), 7.44 2H, J 7.7 Hz), 7.35-7.21 7H), 7.10 I 6.80 IH, J 2.2 Hz), 6.60 (bs, IH), 5.17-1.13 IH), 5.10 4.97-4.92 1H), 3.77 3H), 3.44 (dd, I H, J 5.7, 17.1 Hz), 3.17 3H), 3.03 (dd, IH, J 8.8, 16.5 Hz), 1.67-1.36 3H), 0.92 3H, J 6.25 Hz), 0.87 3H, J 6.3 Hz). Anal. Calculated for C 3 5

H

3 9

N

3 0 5 C, 72.27; H, 6.76; N, 7.22. Found: C, 72.19; H, 6.78; N, 7.16.

Example 3(R)-[3-(4-Cyanophenyl)-H-pyrrol-1-ylJ-N-[2,2-dimetbyl-1(S)- (methylcarbamoyl)propyljsuccinamic Acid

CN

HO.ANH.)NH

0 :0 According to the procedure described in Example 3(R)-[3-(4-cyanophenyl)- IH- 1 pyrrol 1 -yI]-N-[2,2-dimethyl- 1 (S)-(methylcarbamoyl)propyl]succnamic acid benzyl ester in MeOH and EtOAc was hydrogenolyzed to provide 1.2 g of 3(R)-[3-(4-cyanophenyl)- I Hpyrrol- l-yl J-N-[2,2-dimethyl-I (S)-(methylcarbaxnoyl)propyl]succinarnic acid as a yellow powder, mp 138-40*C. IH NMR (CD 3 OD): 6 7.98 (bs, 1H), 7.82 (bd, IH, J 8.4 Hz), 7.68 (d, 2H, J 8.7 Hz), 7.50 2H, J 8.4 Hz), 7.38 J= 1.6 Hz), 6.92 1H, J. =2.5 Hz), 6.55 IH, J 2.2 Hz), 5.28 1H, J 7.5 Hz), 4.19 IH, J 9.0 Hz), 2.98 (dd, IH, J 6.9, 16.5 Hz), 2.64 3H, J 4.7 Hz), 0.98 9H). IR (KBr): 3317, 2963, 2225, 1648, 1550, 1410, 1180 cm HRFABMS: Calculated for C 22

H

26

N

4 0 4 Cs (M 543.1008. Found 543.1021. Anal.

Calculated for C2H 26

N

4

O

4 0 0.4 EtOAc: C, 63.60; H, 6.60; N, 12.57. Found: C, 63.80; H, 104 6.77; N, 12.57.

Starting materials were available as follows: 3 -i4-Cyanophenv b-fitranl

CN

0 As described in Example I(d) for the preparation of 3-(pyridin-4-yl)fura, 4brornobenzonitrile (4.00 g, 22.0 mmol) was coupled to 3-furanboronic acid to fturnish in high yield crude 3-(4-cyanophenyl)-furan as-a brown solid, mnp 55-7TC, which was used immediately without further purification. IH NMR (CDCl3): 6 7.82 (bs, 1 M-1, 7.67 2H, J 8.4 Hz), 7.59 2H-, J 8.4 Hz), 7.52 1H, J 1.9 Hz), 6.72 (bs, 1H). IR (KBr): 2214, 1608, 1160, 796 cmn* Anal. Calculated for C I H 7 NO 0. 1 CAH: C, 78.72; H, 4.33; N, 7.9 1.

Found: C, 78.32; H, 4.60; N, 7.65.

3-(4-Cyanophenfl)-2 S-dihvdro-2. As described in Example 1(a) for the preparation of 3-biphenyl-2,5-dihydro-2,5dimethoxy-tetrahydrofuran, crude .3-(4-cyanophenyl)fuxan was converted. Flash column .Chromatography with EtOAc:hex (30:70) as eluant furnished 3.8 g (73% from 4bromobeni-onitile) of 3-(4-cyanophenyl)-2,5-dihydro-2,5-dimethoxyfurnm as a yellow solid, mp 71-2 0 C. 1 HNNM(CDC13): 6_7.62 4W), 6.46 H, J=0.9 Hz), 6.22 (dd, 0.5H,5 0.9, 3.7 Hz), 6.00 (dd, 0.5H, J 0.9, 3.7 Hz), 5.97 0.5H, J =0.6 Hz), 5.71 0.511, J 1.3 Hz), 3.48-3.40 (in, 6H). 1k: 2933, 2832, 2227, 1607, 1505, 1369 cmf'. Anal. Calculated for

C

13

HI

3 N0 3 C, 67.52; H, 5.67; N, 6.06. Found: C, 67.39; H, 5.71; N, 6.14.

3-(4-Cyanophenvfl-2. 5 -dimethoxy-tetrahvdro firm

CN

WO

As described in Example 1(a) for the preparation of 3-(biphenyl-4-yl)-2,5-dimethoxytetrahydrofuran, 3 4 -cyano-phenyI)-2,5-dihydroXY-2,5-dimethoxyfuran (3.8 g, 16.43 rmro 1) was reduced to give 3.70 g of a diastereomeric mixture of 3-(4-cyanophenyl)-2, dimethoxy-tetrahydrofuran as an oily white solid, which was used without fther purification. I HNMR (CDCI3): 6 7.60 2H J1 7.8 Hz), 7.42 2H, J 8.1 Hz), 5.30- 4.94 (in, 2H), 3.60-3.20 (mn, 6H), 2.78-1.92 (in, 3H). IR: 2912,2833, 2227, 1607, 1511 cm-.

3(R')-f-3-(4-Cyanopzhenvl. I H-pvrrl- 1-vll-N-[2. 2-dimethyl- I (methylcarbainovflpropvllsuccimiamic Acid Benzl Ester

CN

0 (N 0 c',r o-J)NH-,"NHCH 3 According to the procedure described in Example 1 for the preparation of N-(1 ,7diaza-4-oxa-8-oxo-7trcyclo-E9.6. 1 .0 1 -octadeca- 11(1 12,14,1 6-tetraen-9S-Yl)-3 phenyl- 1 H-pyrrol- I -yl)-succinnamic acid benzyl ester, crude 3(R)-amino-N-(2, 2-dimethyl- I (S)-methylcarbantoylpropyl)succinanic acid benzyl ester trifluroacetate salt (prepared as described in Example and 3-(4-cyanophenyl)-2,5-dimethoxy-tetrahydrofuran were condensed. Drying the crude product via azeotrope with benzene gave 1.70 g of 3(R)t- 3 -(4-cyanopheriyl)- 1H-pyrrol- 2-dinethyl. 1(S)-(methylcarbamnoyl)propyl] succinnamnic acid beazyl ester as a Yellow solid, mp 1 02-4 0 C. 'H NMR (CDC13): 6 7.60- 7.55 4H), 7.30-7.25 (in, 5H), 7.12 I H, J 2.2 Hz), 6.80 1IH, J= 2.5 Hz), 6.56 (t, I H, J =2.8 Hz), 6.32 1H, J =8.7 Hz), 5.60 IH, J= 5.0 Hz), 5.18-5.05 (in, 3H), 4.05 (d, IH, J =9.0 Hz), 3.38 (dd, IH, J 5.9, 17.0 Hz), 3.08 (dd, I1H, J 8.7, 16.8 Hz), 2.76 3 H, J =5.0 Hz), 0.92 9H). IR: 3310, 2958, 2227, 1736, 1648, 1547 HR.FABMS: Calculated for C 29

H-

32

N

4

O

4 CS (MH4-Cs+): 63 3.1478. Found: 633 1452. Anal. Calculated for

C

29

H

32

N

4 0 4 0 0.4 CAH: C, 70.91; H, 6.52; N, 10.53. Found: C, 70.97; H, 6.15; N, 10.26.

Example 4 2 S-(3-Ca rboxy-2(R)- IHpyrro..I l-yl-p, ro pionylamid o).4-m ethylpentanoylaminolbenzoic Acid Ethyl Ester n 0 O N 0 :)4OHC, 0> According to the procedure described in Example I1(a), 4-(2S-(3-carbobenzyloxy- 2(R)-I H-pyrrol- 1 .y-propionylamido)-4-methypenaoylamino] benzoic acid ethyl ester in **:EtOH and THF was hydrogenolyzed. The crude product was successively purified via flash column chromatography with a 20-40% EtOAc/hex-S% MeOHICH 2

CI

2 stepwise gradient and preparative RPHPLC (C 18) with 50% CH 3 CN/I M aqueous NH 4 OAc to provide 45 mg of 4-[2S-(3-carboxy-2(R)- 1 H-pyrrol- I -yl-propionyl-amido)-4-methyl-pentanoylamino]benzoic acid ethyl ester as fluffy crystals, mp 11 14 FABMS: 444.1 (C 23

H

30

N

3 0 6

M

The starting mterials wer avial as follows: pentanoyl-aminol.benzoic Acid-Fthyl Ester 00 0 HN 0 "UHC3 O)_N"H2-NHOr~H~H According to the procedure described in Example I1(a) for the preparation of N.(I bezl2hdoyty)3R--utxcroyann-ucLai acid benzyl ester, N-tbutoxycarbonyl-D-aspartate P-benzyl ester and 4-(2S-amino-4-methylpentanoyiaznino)benzojc acid ethyl ester (Casteihano, A. Yuan, Home, Liak, T. J.

W095/12603-A1, May 11, 1995) were coupled with EDC to finrnish 2.4 g of bezlxcroy.()tbtxcroyunn-rpoyaio--ehlpnaot amino)-benzoic acid ethyl ester as a glassy solid, which was used without firther purification.

f2 Amino- 3-benzvloxvcarbonl1roinvIiamno)-4-methvl-pentanovlI-arninol :benzoic Acid Ethyl Ester 0 As described in Example 1(b) for the preparation of 3(R)-amino-N-(2,2-dimethyl- I (S)-(methylcarbamoyl)propyl)succinanic acid benzyl ester trifluoroacetate salt, 4-[2S-(3beiyoyabnl2R--uoyabnln-icpoinlmn)-ehipnaol **amnino]-berizoic acid ethyl ester was deprotected with tnifluroacetic acid, except that a solution of the resultant salt was neutralized by washing a CH- 2

CI

2 solution with IN aqueous 05.;08 2003 14:59 FAX 61 8 9221 4196 GRIFFITH BACK PERTH 003 WaOH. Removal of the solvent under reduced prssre afforded 2.00 g of 4-(2S- (2(R)am-3- yloxy oy-poyl-amn)Amtyl- na amino]-bezic acid ethyl ester as a viscous yelow oil, which was used without further purification.

4-(2S-(3.Carbobnzvloxy-2(-l H4-vrrol-l -y-ropionylaidoY.4iethvl-peflntafOliflif bcrizoic Acid Ethyl Ester C3 0

NH

A mixture of 4-[2S-(2(R)-amino3 .benzyloxycarbonyl-propianyl-amino)--methylpentanoyl-amino]-benzoic acid ethyl ester (150 mg, 0.310 mmol), tetrahydrofuran (43 mg, 0.33 mmol), sodium acetate (153 tug, 1.86 mmiol), and glacial HOAc (3 nL) was heated at reflux for 30 minutes. The mixture was allowed to cool, poured onto ice, diluted with H-20 (30 mL), and extracted with EtOAc (2 x 50 mL). The combined extacts were washed with brine, dried over MgSO 4 and concentrated in vacuo. Flash column chromatography with 15-20-25-30% EtOAc/bex stepwise gradient furnished 107 mg of 4-[2S-(3Ibrbobenzyloxy-2(R)-H-pyrrol-l-yl-propionylaimdo)4-methyL.

pcntanoylanino]-bnzoic acid ethyl ester.

Example 1(o) N-(9-Orol,diaz-tricyc o I.6. 1.0 1nonadeca-12(19),13 15,17tetrae-1OS-yl)-3(R)-1H.pyrrol1l4 cciflmiC Acid oN 0 HDAwkNH2N T) N7 According to the procedure described in Example N-(9-oxo-i,Sdian- 9.t 109 COMS ID No: SMBI-00283854 Received by IF Australia: Time 17:02 Date 2003-06-05 tricyclo[ 10.6. 1.0 13' 18 ]nonadeca-lI 2(19), 13,15,1 7 -tetraen- I OS-yl)-3(R)- I H-pyrrol- l-ylsuccinamic acid benzyl ester was hydrogenolyzed in EtOH and THF. Crystallization from

CH

2 C1 2 provided 120 mg of N-(9-oxo- 1 ,8-diaza-tricyclo[ 10.6.l1.0'~ 13, 8 ]nonadeca- 12(19), 13,15,1 7-terraen- IOS-yl)-3(R)- 1H-pyrrol-1I-yl-succinaxnic acid as fluffy colorless crystals, rnp 13 9-44 FABMS: 451 (C 25

H

3

IN

4 01; M Example 3(R)-13-I(4-Cyanophenyl)acetyll I H-pyrrol-1-yIJ-N-[2,2-dimetbyl- 1(S)- .(metbylcarbamoyl)propyljsuccinamic Acid

C

0ON 0

NHA.NHCH,

0 Routine ally[ ester cleavage conditions were previously described by Friedrich- Bochnitschek, Waldrnann, Kunz, H. J. Org. Chem. 1989, 54, 75 1-756. To a solution of 3)(R)-[3-[(4-cyanophenyl)acetyl]-lIH-pyrrol-l -yl.-N-[2,2-dirnethyl- 1(S)- (methylcarbamoyl)propyllsuccinarnic acid allyl ester (247 mg, 0.501 mmol) in acetonitrile (2 maL) was added in succession Pd(PPh 3 4 (29 mg, 0.026 mrnol) and morpholine (226 2.60 mrnol). The resultant mixture was carefully purged with argon. After 30 min, the resultant green mixture was stirred with 10% aqueous KHSO 4 .(20 rnL) and extracted with CHC1 3 (3 rnL). The organic layer was washed with 10% aqueous KH1S0 4 (20 mnL), dried over Na 2

SO

4 and concentrated. Flash column chromatography with 1% HOAc/3% MeOH/CHCl 3 and drying via azeotrope with n-heptane gave 243 mg of 3(R)-f 3-((4-cyanophenyl)acetyll- 1H-pyrrol-l-yl]-N-[2,2-dimethyl.1(S)-(methylcarbamoyl)propyl]succiiaic acid as a yellow solid. 'H NMR (CD 3 OD): 8 8.09 1H, J 8.7 Hz), 8.05 (dd, 1H, J 2.8, 6.9 Hz), 7.78 (Idd, I1H, J 1. 9, 1.9 Hz), 7.66 2H, J =8.4 Hz), 7.46 2H, J =8.4 Hz), 6.90 (dd, IH.i J= 2.,2.2 Hz), 6.59 (dd, J 1.9, 3.1 Hz), 5.33 I H, J 7.5 Hz), 4.22-4.15 (in, 3H), 3.24 (t, I1H, J =8.7 Hz), 2.98 (dd, I H, J 5.3, 17.4 Hz), 2.66 3H, J 4.7 Hz), 0.99 9H). IR (KJBr): 3332, 2696, 2230, 1719, 1654, 1532, 1412, 1177 cm HRFABMS: Calculated for

C

24

H

29

N

4 0 5 (M 453.2125. Found: 453.2125. Anal. Calculated for C 24

H

28

N

4 0 5 HOAc 0 0.3 CHCI 3 C, 58.62; H, 5.89; N, 10.81. Found: C, 58.41; H, 5.72; N, 10.50.

The starting materials were available as follows: 3 (R')-(t-Butoxycarbonvlamino)-N-(2 .2-dimethyl- 1 (S)-(methvlcarbamoyl)propvbsuccinamic AcidAIXL-Rste O HN 0 According to Example I1(b) for 3(R)-t-butyloxycarbonylamino-N-(2,2-dimethyl. I (rnethylcarbamoyl)propyl)succinamic acid benzyl ester, P-allyi-N-t-butoxycarbonyl-Daspartate (Beishaw, Mzengeza, Lajoie, G. Syn Commun 1990, 20, 3157-3160; 2.00 g, 7.32 mmcl) and L-t-leucine N-methylamide (Malon, Pancoska, Budesinsky, M.; Hlavacek, Pospisek, Blaha, K. Coll. Czech. Chemn Commun. 1983, 48, 2844-286 1; 1.05 g, 7.32 mmol) were coupled with TBTU The resultant yellow oil was routinely used without ::::*further purification. Flash column chromatography with 2% MeOICH 2 Cl 2 provided 2.44 g of 3(R.)-(t-butoxycarbonylamino)-N-(2,2-dimethyl. I (methylcarbamoyl)propyl)succinamic acid allyl ester as a pale yellow oil. 1

HNMR

(CDCl3): 8 7.05 1H, J =9.0 Hz), 5.98 IH, J 4.4 Hz), 5.77 (ddt, 1H, J 5.6, 10.3, Hz), 5.29 (ddd, I1H, J1 1.5, 2.8, 15.6 Hz), 5.23 (dd, 1H, J 1.3, 10.5 Hz), 4.57 (dddd, 2H, J 1.6, 3.1, 5.6, 12.1 Hz), 4.11 I H, J 9.4 Hz), 2.77 3H, J 5.0 Hz), 1.46 9H), 0.99 9H).

3(R)-Amino-N-(2.2-dimethvl. I(S)-(methvlcarbamovflpropDylsuccinamic Acid Allyl Ester Trifluoroacetate Salt

NH

3

*O

2

CCF

3 H)NH C 0* As described in Example 1(b) for the preparation of 3(R)-amino-N-(2,2-dinethyl- I (S)-(methylcarbaroyl)propyl)succinamic acid benzyl ester trifluoroacetate salt, crude 3(R)- (t-butoxycarbonylamino)-N-(2,2-dimethy 11(S)-(Nethylcarbamoyl)propy )succinmic acid allyl ester was deprotected after 2 hours. Flash column chromatography with 0.5% TFA/7% MeOH/CHC1 3 gave 2.46 g of 3 (R)-amino-N-(2,2-dimethyl- 1(S)- (methylcarbanoyl)propyl)succinanic acid allyl ester trifluoroacetate salt as a colorless foam.

IHNMR(CD

3 OD): 8 5.96 (ddt, IH, J= 5.6, 10.6,17.1 Hz), 5.35 (ddd, 1H, J 1.6, 3.1, 17.1 Hz), 5.25 (ddd, 1H, J 1.2, 2.5, 10.3 Hz), 4.66 (ddd, 2H, J 1.2, 1.3, 5.9 Hz), 4.34 (dd, 1H, J 5.6, 7.8 Hz), 4.21 IH), 3.03 (dd, IH, J 5.6, 17.4 Hz), 2.94 (dd, 1H, I 7.5, 17.4 Hz), 2.71 3H, J 5.0 Hz), 1.46 9H), 0.99 9H). IR (KBr): 3413, 2966, 1672, 1656, 1207, 1143 cm'. HRFABMS: Calculated for C 14

H

2 5

N

3 04Na (M +Na4): 322.1743. Found: 322.1747. Anal. Calculated for C 1 4 H2 5

N

3

O

4 2.5 F 3 COOH 0.5 CHC1 3 C, 36.36; H, 4.38; N, 6.52. Found: C, 36.34; H, 4.25; N, 6.51.

3-(2.2-Dibromoethen l'-2.5 -dimethoxy-tetrahydrofuran Br *3O AS Br A rnixcrure of Zn powder (1.65 g, 25.0 mmol), triphenylphosphine (6.54 g, 25.0 mrnol), and CBr 4 (8.30 g, 25.0 minol) in dry Cl-f 2 C1 2 (40 mL) was stirred at ambient temperature. After 24 hours, 2,5-dimethoxy-tetrahydrofuran-3-carboxaldehyde (2.00 g, 12.5 mxnol) was added and an exothermic reaction ensued. After 30 minutes, pet ether (100 rnL) was added and the resultant upper layer separated. The lower layer was twice diluted with CH-,C1 2 (50 mL) and pet ether (50 mL), and the upper layer reserved. The combined upper layers were combined, passed through a pad of Si0 2 and concentrated under reduced pressure at 30 0 OC or below to give 2.18 g of 3-(2,2-dibromoethenyl)-2,5-dimethoxytetrahydrofuran as a volatile colorless oil, which was a mixture of diastreomers by I NMR and used immediately without further purification.

imethoxy-3-(2-tributylstannvlethvnvl )-tetrahydroftira Sn(C 4

H

9 3 3C 0 O CH 3 To solution of crude 3-(2,2-dibromoethenyl)-2,5-dimethoxy-tetrahydrofurfan (1 .78g, 5.64 mnmol) in ether (30 m.L) at -78*C was added n-butyllithium (9.02 m.L of 1.25 M in hex).

After I hour at -78*C, tributyltin chloride (1.68 m.L, 6.20 minol) was added, and the mixture was allowed to warm to ambient temperature. After 16 hours, ether (35 niL) and saturated a queous N"H 4 CI (30 m.L) were added. The organic layer was separated, washed with saturated aqueous NH 4 CI (30 1-120 (25 mL), and saturated aqueous NaH-C0 3 (25 mL), dried over K 2 CO3, and evaporated to give an orange oil, which was purified via flash column chromatography with 2% MTBE/hex to furnish 1.92 g of 2,5-diniethoxy- 3 2 tributylstannylethynyl)-tetrahydrofuran as a colorless oil. A mixture of diastereomers was evident in the H NMR spectnrm, which was used immediately without further purification.

IR: 2923, 1456, 1374, 1215, 1105, 1017, 967 cm Anal. Calculated for C 70

H

38

O

3 Sn: C, 53.96; H, 8.60. Found: C, 54.2 1; H, 8.66.

3-12-(4-Cyanophenfl)-ethvnvll.5-dimethoxy-tetrahydrofuran

CN

H

3 C -110 OCH 3 A mixture of 2 ,5-dimethoxy- 3 -(2-tributylstannylethynyl)-tetrahydrofran (1.86 g, 4.18 rnmol), 4-iodobenzonitrile 15 g, 5.02 mmol), and tetrakis(triphenylphosphine) palladiurn(0) (145 mg, 0.125 mmrol) in tolucne(25 rnL) was heated at 100*C. After hours, the resultant red solution was allowed to cool, and the solvent was removed under reduced pressure. Flash column chromatography twice with 10% EtOAc/hex provided 1. 10 g (100%) of 3 -t 2 4 -cyanophenyl)-ethynyl]-2,5-dimethoxytetrahydrofuran as an orange oil. A mixture of diastereomers was observed by IH NMR, which was used without fuirther purification. I NMR (CDC13): 3.12 (ddd, I 2.8, 6.6, 9.0 Hz), 2.57 (ddd, J 5.6, 9.3, 13.4 Hz), 2.08 (dd, J 2.5, 4.7 Hz), 2.04 (dd, J 3.1,4.3 Hz). IR: 2227, 1603, 1216, 1102, 1012, 841 cm"n 1 Anal. Calculated for C 15 H 15 N0 3 0 0.1 EtOAc: C, 69.5 1; H, 5.98; N, 5.26.

Found: C, 69.52; H, 5.76; N, 5.32.

3 r 3 yaophenvfl )acetybl I H-nvrrol- I -vil-N-f2.2-dimethyl- If (methvlcarbamovlbproovfluccinamic Acid Allivi Ester

CN

0 As described in Example 1(c) for the preparation of N-(8-oxo-4-oxa- I ,7-diazatricyclo[9.6. 1 .0I 1 7 octadeca- 11I(1 12,14,1 6 -tetraen-9-yi)-3-(3-phenyl-lI H-pyrrol- I yl)succinamic acid berizyl ester, 3(R)-amino-N-(2,2-dimnethyl. I (methylcarbamoyl)propyl)succinarnic acid allyl ester trifluoroacetate salt and were heated with trifluoroacetic acid (I equiv) at 70'C for 4 hours. Flash column chromatography twice with 0.5% HOAc/ EtOAc/CH 2

CI

2 as eluant and azeotrope with n-heptane afforded 800 mg 43% based on recovered ffiran) of 3(R)-[3-[(4-cyanophenyl)acetyl]- I H-pyrrol- I -yl]-N-[2,2-diniethyl- I (methylcarbamoyl)propyl]succinarnic acid allyl ester as a brown oil. H NMR (CDC13): 6 7.58 (di, 2H, J 8.1 Hz), 7.47 (dci, I H, J 1.9, 1.9 Hz), 7.36 2H, J 8.1 Hz), 6.84 (di, IlH, 9.0 Hz), 6.74 (dci, 1H, J 2.8, 2.8 Hz), 6.63 (dci, IH, 1.6, 2.8 Hz), 6.08 (dcl, J 2.8, 6.8 Hz), 5.82 (ddt, IH, J 5.9, 10.3, 17.1 Hz), 5.26 (ddd, 1H, J 1.2, 2.8, 17.1 Hz), 5.19 (q, I H, J 7.2 Hz), 4.56 (cicicd, 2H, J 1.6, 2.8,4.4, 15.9 Hz), 4.18 (di, I H, J 9.0 Hz), 4.05 (s, 2H), 3.34 (dd, lH, J 16.8 Hz), 2.99 (dd, IH, J 7.2, 16.8 Hz), 2.72 (ci, 3H, J 5.0 Hz), 0.90 9H). 13C NMR (CDCI3): 8 191.2, 170.2, 169.4,168.0, 140.6, 132.2, 131.3, 130.3, 125.7, 125.7, 122.0, 119.0, 118.9, 110.5, 110.4, 66.0, 61.0,59.4,46.1, 37.5, 34.8, 31.9, 29.0, 26.5, 26.0. IR (KBr): 3320, 2965, 229, 1736, 1648, 1531, 1173 cm' 1

HRFABMS:

115 Calculated for C 27

H

33

N

4 0 5 (M +H 4 493.2451. Found 493.2462. Anal. Calculated for

C

27

H-

32

N

4 0 5 a 0.2 H 2 0 0 0.2 CH 2

CI

2 C, 63.66; H, 6.44; N, 10.92. Found: C, 63.86; H, 6.56; N, 10.58.

Example 2. 1(S)-Acetyl-3-rnethylbutyl)- 3(R)-[3-(bipenyi4yi)IH-pyrro 1 yl)succinamic Acid O N 0 .HOK ~N H _,U 0 To a solution of 3(R)-(3-biphenyl-4-yl- 1H-pyrrol-1I-yl)-N-[ I(S)-(N-methoxy-Nmethylcarbanioy 1)-3-methyl-butyl ]succinarric acid (prepared as described in Example 1(l); 209 mg, 0.425 mmol) in TEIF (5m.L) at -78*C was added methylmagnesiumr bromide (3 M in ether, 0.7mL) dropwise via syringe. After 15 minutes at -70 *C and 2 hours at 0 the mixture was quenched with acetone (50 and then added to EtOAc/lN NaHSO 4 The aqueousueous phase was extracted with EtOAc. The combined organic layers were dried over Na 2

SO

4 and concentrated. After 3 days at ambient temperature, the dark residue began to crystallize, and trituration with MTBE/hexanes provided 90 trig of pure N.(l acetyl-3-methylbutyl)-3(R)-[3-(biphenyl-4-y)-H-pyrrol- I -yl)succinamic acid as an offwhite solid. IH NIM (CDCl3): 6 7.62-7.5 5 (in, 6H), 7.44 2H, J 7.5 Hz), 7.3 3 I H, J Hz), 7.11 IlH), 6.81 I H, J 2.4 Hz), 6.62 (dd, 1 H, J 1.3, 2.4 Hz), 6.07 I H, J Hz), 5.12 I1H, J =6.8 Hz), 4.61-4.54 (in, I 3.46 (dd, I H, I 6.4, 16.7 Hz), 3.01 I H, J 16.9 Hz), 2.16 3H), 1.58-1.51 (in, 2H), 1.33 I1H, J 7.4 Hz), 0.92 (d, got* 3H, J 6.3 Hz), 0.87 3H, J =6.3 Hz). Anal. Calculated for C 27

H

30

N

2 0 4 0.5 H 2 0: C, 71.18; H, 6.86; N, 6.15. Found: C, 71.01; H, 6.78; N, 6.40.

ExampleI3 3(R)-13-(Biphenyl-4-yl)-1H-pyrrol. 1-ylJ-N-f (RS)-bydrory-etbyl)-3.

methylbutyljsuccinainic Acid 0 N OH HO-2Y NH,.X, To a solution of I(S)-acetyl-3-nethylbutyl)3(R)-(bipheny[4-y- I H-pyrrol- I yl)succinarnic acid (prepared as described in Example 2; 45 mng, 0. 10 innol) in TI-F (2 ml-) and EtOH (1 m.L) at -780C was added a solution of NaBH 4 (19 Mg, 0.50 rnumol) in EtOH (I rn.L). After 2 hours at -78 0 C, the reaction was quenched with acetone (0.5 m.L) and concentrated in vacuo to afford a residue which was partitioned with EtOAc and pH citrate buffer. The aqueous phase was further extracted with EtOAc. The combined organic layers were dried over Na 2

SO

4 and evaporated to give a solid that was dissolved in MTBE and precipitated with hexanes to give 30 mng of 3(R)-[3-(biphenyl-4-yl)-IH-pyrrol-l- I 1 RS-hydroxy-ethyl)-3-methylbutyljsuccinamic acid as an amorphous solid. IH NUR (CDCI3): 8 7.60-7.56 (mn, 7.44 2H, J 7.4 Hz), 7.33 I1H, J 6.8 Hz), 7.11 11-1), 6.82 IN), 6.61 I1H), 5.70 (mn, I H. minor isomer), 5.49 I H, J 8.1 Hz, maj or isomer), 5.05 I H, J 6.3 Hz), 4.04-4.01 (in, I H, major isomer), 3.86-3.82 (mn, I1-H), 3.76-3.74 (in, I1H, minor isomer), 3.41 (dd, I H, J1=5.9, 16.9 Hz), 3.16 (dd, 1 H, J 6.6, 10.7 Hz), 1.75-1.42 (in, IH), 1.28-1.13 (mn, 2H), 1.08 3H, J 6.3 Hz, minor isomer), 1.01 (d, 3H, J 6.3 Hz, major isomer), 0.87 6H, J =6.6 Hz). Anal. Calculated for C 27

H

32

N

2 0 4 0 0.8 H 2 0: C, 70.04; H, 7.32; N, 6.05. Found: C, 69.89; H, 7.33; N, 5.97:' Examaple N-(1(S)-Benzyl-2.hydroryethyl)-3(R)-f3-(4'cyanobiphenyk-4-yl) 1Hpyrrol-1-yllsuccinamic Acid

ON

0 N HOl,-rNH,.sOH According to the procedure described in Example N-(l(S)-benzyl-2hydroxyethyl)-3 (R)-[3-(4'-cyanobiphenyl-4-y)- IH-pyrrol-1I-yI~succinamic acid benzyl ester mg, 0.070 mrnol) hydrogenolyzed in NMeOH:EtOAc (2:3 m.L) after 2 hours to give a yellow powder, which was washed with CHC1 3 and hexane to furnish 3 5 mg (100%) of N- (I (S)-benzyl-2-hydroxyethyl)-3(R)-[3(4-cyaobipheny-4-y)- IH-pyrrol- I-yIjsuccinaznic acid as a yellow powder, mp 189-92 I H NMR (DMSO-d 6 6 8.82-8.78 (bin, I 7.90 7.72 2H, J 8.1 Hz), 7.50 2H, J =8.1 Hz), 7.20 (in, 6H), 6.82 I 6.45 (s, IH), 4.95 IH, J 7.2 Hz), 3.88-3.78 (mn, Ili), 2.84 IH, J =5.9 Hz), 2.75-2.60 (in, 3H).

4.

4%.IR (KBr): 3396, 3029, 2925, 2229, 1654, 1602, 1560, 1495 cm' HRFABMS: Calculated for C 30

H

27

N

3

O

4 Na (MH+ Na 516.1899. Found: 516.1912. Anal. Calculated for

C

30

H

27

N

3 0 4 0 0.81 CHCI 3 C, 62.69; H, 4.75; N, 7.12. Found: C, 62.64; H, 4.89; N, 7.23.

Ott The starting material was made as follows: Rromo-biphenv 1-4-carbonitrile

CN

Br As described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, 4bromobenzonitrile (9.42 g, 51.8 mmol) and 4-brornophenylboric acid (5.20 g, 25.9 mmol) were coupled in EtOH to afford 4.50 g of 4'-bromo-biphenyl-4-carbonitrile as a grey powder, nip 147-8 *C (lit 153-5 McNanmara, Gleason, W.B. J. Org. Chemn. 1976, 41, 107 The material had an NMR spectrum that matched literature (see Amatore, Juland, Negri, S. J. Organome. Chem. 1990, 390, 3 89-398) and was typically used without fuirther purification.

4'-(Furan-3-yl)-biphenyl-4-carbonitrile

CC

0- As described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, crude 4'bromo-biphenyl-4-carbonitrile (200 mg, 0.775 mmnol) and 3-furanborortic acid (see Thompson, W. Gaudino, Gi. J Org. Chem. 1984, 49, 5237-5243; 105 Mg, 0.937 mmol) in MeOH (2 mL) were coupled to give a-yellow solid, which was purified via preparative TLC- Elution with EtOAc:benzene (1:99) provided 100 mg of 4'-fua-3-yi-biphenyl-4carbonitrile as a grey powder, mp 199-203*C. I H NMR (CDCI3): 8 7.81 (bs, lH), 7.72 (d, 4H, J 1.9 Hz), 7.61 4H), 7.51 (bs, 1H), 6.75 IR (KBr): 2225, 1604, 1503, 1396, 1162, 1102, 1058 crm t Anal. Calculated for C 17 H, 1 NO e 0.3 EtOAc 0.2 C 6

H

6

C,

119 80.78; H, 5.05; N, 5.01. Found: C, 80.96: H, 4.88; N, 5.00.

4 '-2.5-Dimethoxv-2- 5-dihydro- furatn-3-vl)-biphenvl-4-carbonitrile

SCN

H

3 CO

IK

0

CCH

3 According to the procedure for the preparation of 3-biphenyl-4-yl-furan described in Example 1 4 '-furan-3-yI-biphenyl-4-carbonitrile (1.29g, 5.26 mrnol) was converted into 4 -dim ethoxy-2,5 -d ihydro- furan-3 -y I)-bipheny-4-carbontrle. The crude product was recrystallized from EtOAc/hex to furnish 1.03 g of a mixture of diastereomers by NMR as a pale white powder, rnp 1 36-7*C. I H NM (CDC13): 8 7.80-7.58 (mn, 8M), 6.40 11), 6.30 0.5H, J 3.7 Hz), 6.06 0.5H), 6.01 0.514, J 3.7 Hz), 5.72 0.5H, J 1.6 Hz), 3.55 1.5 3.48 L.5H), 3.44 1.5H), 3.02 1.5H). IR 2933, 2831, 2229, 1654, 1604, 1560, 1498 cm t HRFABMS: Calculated for C I 9 H 1 N0 3

(M

308.1287. Found: 308.1275. Anal. Calculated for C 19

H

17 N0 3 C, 74.25; H, 5.58; Vd. N, 4.56. Found: C, 74.11; H, 5.63; N, 4.49.

4'-(2.5-Dimethoxy-tetrahydrofira- 3-fl-biplheny 14-carboniti le

CN

OCH

3 As described in Example 1(a) for the preparation of 3-biphenyl-4-yI-2,5-dimethoxytetrahydrofuran, 4'-(2,5-dimethoxy.2,5-dihydro-furan3-yy-bipheiyl-4-carbonitrile (260 mng, 0.846 inmol) was reduced in 2 hours to give 260 mng of 4'-(2,5-dimethoxYbe tetrahydrofuan-3-yl)-biphenyl-4-carbonitrile as a white solid, mp 149-50 0 C, which was used without further purification. I'H NMR (CDCI3): 6 7.78-7.26 (in, 8H), 5.30-5.00 (in, 2H-), 3.52-3.22 (in, 6H), 2.78-2.00 IR (KBr): 2910, 2220. 1606, 1498, 1448, 1380, 1224, 1190 cm 1 Anal. Calculated for C I 9 H 1 9 N0 3 0.3 H,O: ,7.8 ,62;N Found: C, 72.28; H, 6.19; N, 4.11.

N-C! (S)-BenzvI-2-hvdroxvethvb)-3 (R)-r3-(4'-cyanobiphlenyl-4-v)- I H-pyrrol-lI-vilsuccina-mi c Acid Benzvl Ester

ONN

As described in Example 1(b) for the preparation of 3(R)-amino-N-(2,2-dimethyl- I (S)-(methylcarbamoyl)propyl)succinarnic acid benzyl ester trifluroacetate salt, crude 3(R)- J.aznino-N-( 1 (S)-benzyl-2-hydroxyethyl)succinarnic acid benzyl ester trifluoroacetate salt 00* (prepared as described in Example 0.876 rnxnol) was condensed with 4'-(2,5-diinethoxytetrahydrofuran-3-yl)-biphenyl-4-carbonitrile (326 mng, 1.05 mznol) in 1 ,2-dichloroethane niL). The solution was heated at 85-90*C for 5 hours, allowed to cool, and evaporated to give a brown oil which was purified via flash column chromatography with 1% EtOAc/hex as eluant. HOAc was removed via azeotrope with n-heptane layers to provide 200 mg of 1(S)-benzyl-2-hydroxyethyl)-3 (R).[3-(4'-cyanobiphenyl-4-yl)- IHpyrrol-l-yl]succinamic acid benzyl ester as a pale yellow powder, mp 149-50*C. 'H NMR Goo: (CDCl3): a 7.74 4H), 7.59 4H, J 4.1 Hz), 7.3 2-7.18 (mn, I 7.05 (bin, 2H), 6.94 (t, IH, J 2.2 Hz), 6.64 IlH, 2.5 Hz), 6.5 8 (brn, 11-1), 5.48 I H, J =7.89 HZ), 5. 10 d, 2H, J 3.1 Hz), 5.00 (dd, IH, J 5.0, 9.3 Hz), 4.46-4.32(in, 2H), 4.22-4.12 (in, lH), 3.41 dd, I1H, J 5.3, 17.1 Hz), 3.04 (dd, I H, J 9.1, 17.1 Hz), 2.70-2.63 (in, 2H). IR: 3389, 3030, 2948, 2225, 1735, 1665, 1603, 1528, 1495 cm" HRFABMS: Calculated for

C

37

H

33

N

3

O

4 CS (ME+ 716.1525. Found: 716.1503. Anal. Calculated for C 37

H-

33

N

3 0 4 0.4 CH 2

CI

2 C, 72.73; H, 5.52; N, 6.80. Found: C, 72.67, H, 5.53; N, 6.8 1.

The following compounds were made in a similar manner: Example N-(1-Benzyl-2-hydroryethyl)-3(R)[3-(4'-carbamoylbipbeny14-yi) 1Hpyrrol-1-yllsuccinamic acid 0 HOA--' NH_

NHO

41 According to the procedure described in Example N-(1(S)-benzyl-2hydroxyethyl)-3(R)-[3-(4'-carbamnoylbiphenyl.-l -yrl ylsciai cdbny ester was hydrogenolyzed to I (S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4'carbamoylbiphenyl-4-yi)- IH-pyrrol- 1.yljsuccinamic acid in 95% yield, mp 218-20*C. 1

H

NMR (DMSO.4): a 8. 12 I1H, J =8.5 Hz), 7.97 I 7.88 2H, J 8.5 Hz), 7.72 (d, 2H, J 8.5 Hz), 7.57 2H, J 8.1 Hz), 7.33 (bs, 7.24 1W), 7.22-7.11 (mn, 6H), 6.80 (bs, 1H), 6.42 (bs, lH), 4.984.90 (bin, 11W), 4.804.72 (in, 1W), 3.82-3.76 (mn, 1W), 2.82-2.70 (mn, 2H), 2.62-2.50 (mn, 1W). IR (KBr): 3402,2925,1658, 1601, 1400, 1202, 825, 782, 702, 633 cm-. HR.FA13MS: Calculated for C 30

H

2 qN 3 0 5 CS (M 644.1162. Found: 644.1147. Anal. Calculated for C 30

H

2 qN 3 0 5 0.3 CHCI 3 C, 66.49;- H, 5.40; N, 7.68.

122 Found: C, 66.30; H, 5.50; N, 7.50.

The starting materials were fu~rnished as follows: 3-(4'-Carboxamidobiphenvl-4-vi-2.5 .d irethoxvtetrahvdroftiran 0

NP,

OCH

2 To a solution of 4'-(2,5-dimethoxy-tetrahydrofuran-3-yl)-biphenyl-4-carbonitri le (100 mg, 0.32 mmol) in 95% EtOH (1.5 rnL) was added 30% hydrogen peroxide (114 P.L, 1. .12 inmol) and 6N aqueous NaOl- (13 iL, 0.08 mrnol). The resultant mixture was heated a! for 5 hours, allowed to cool, neutralized to pH7 by pH paper with 5% H 2 S0 4 diluted with water (10 mL), and extracted with CHCI 3 (2 x 30 mL). The organic layers were dried over MgSO 4 and evaporated under reduced pressure to give a solid, which was precipitated from EtOAc/hex to give 1.04g (100%) of 3-(4'-carboxarnidobiphenyl-4-yl)-2,5- ~dimethoxytetrahydrofuran as a white powder, mp 184-6'C. 1 H NMR (CDC3): 6 7.87 (d, 2H, J1=8.1 Hz), 7.66 2H, J 8.1 Hz), 7.56 2H, J =8.1 Hz), 7.42 2H, J =8.1 Hz), 5.26-5.00 (mn, 2H), 3.54-3.29 (in, 6H), 2.78-2.00 (in, IR (KBr): 3383, 3191, 2908, 1654, 1612, 1400, 1116, 983, 857, 779 cm HRFABMS: Calculated for C 1 9

H

22

N

3 0 4 (M 328.1549. Found: 328.1560. Anal. Calculated for C 1 9

H

2 1 N0 4 0, 69.69; H, 6.47; N, 4.28.

Found: C, 69.68, H, 6.43; N, 4.19.

1-Benzvl-2-hydroxyethfl)-3-f 3-(4'-carbamovlbiphenv-4-vl)- IH-pvrol- I-vilsuccinami 0

NH

2 0 C OA-'4rN"--OH As described in Example 4(a) for the preparation of N-(l (S)-benzyl-2-hydroxyethyl..

3(R)-[3-(4'-cyano-biphenyl-4-y)- I H-pyrrol- I -yljsuccinamic acid benzyl ester, N-(l benzyl-2-hydroxyethyl)-3(R)-butoxycarbony[.amino-succinamic acid benzyl ester (0.320 mmol) was deprotected. A solution of the resultant crude N-(1(S)-benzyl-2-hydroxyethyl)- 3(R)-amino-succinamic acid benzyl ester tnifluoroacetate salt and crude carboxamidobiphenyl-4-yl)-2,5.dimethoxytetrahydrofua (110 mg, 0.330 mmol) in 1,2dichioroethane condensed in 18 hours to give a brown solid, which was purified via flash column chromatography with 5% MeOH/CH 2

CI

2 as eluant to provide 60 mg (3 of 1benzyl-2-hydroxyethyl)-3.[3-(4'-carbamoylbiphenyk4-yl)- IH-pyrrol- 1-yljsuccinarnic acid benzyl ester as a pale yellow solid, trp I 92-4*C. 'H NMR (DMSO-d 6 8 8.18 (di, 1 H, J Hz), 8.00 IRH), 7.94 2H, J 8.1 Hz), 7.76 2H, J 8.5 Hz), 7.68 (di, 2H, J Hz), 7.58 (di, 2H, J =8.5 Hz), 7.36 -7.14 (brn, 6.84 I1H, J 2.2 Hz), 6.47 I H), 5.10-4.95 (in, 3H), 4.81 I H, I 5.1 Hz), 3.88-3.75 (mn, 1H), 3.00 2H, J =7.4 Hz), 2.80 (cid, 1H, J= 5.5, 13.2 Hz), 2.67 -2.60 I1H). IR (KBr): 3330, 2962, 1729, 1655, 1606, 1560, 1498, 1261, 1092 FA.BMS: 602 (M Anal. Calculated for C 37

H

35

N

3 0 5 0 0.4 CH 2

CL

2 C, 70.67; H, 5.68; N, 6.61. Found: C, 70.78; H, 5.86; N, 6.98.

Example 3 (R)-13-(4'-Carbanoybiphenyl..4-yl)-1 -pyrrol-l-ylJ-N-(I bydroxymethyl-2,2-dimethyl-propyl)succinamic Acid 0 NtM 2 0 00 HO-kr

NH..OH

0 According to the procedures described in Example caibamoylbiphenyl-4-yl)- I H-pyrrol-l-yli-N-( (S)-hydroxy-nethyl-2,2-dimethylpropyl)succinamic acid benzyl ester in MeOH and EtOAc was -hydrogenolyzed to afford in 88% yield 3(R)-[3-(4'-carbamoylbipheny l- 4 IH-pyrrol-1 -yIj-N-(I (S)-hydroxymethyl-2,2dimethyl-propyl)succinamic acid as a white powder, mp 192-40C. 'H NMR (CD 3 OD): 6 7.95 2H, J 8.4 Hz), 7.72 2H, J 8.1 Hz), 7.60 4H), 7.32 1-H, J 1.6 Hz), 6.92 1H, J 2.5 Hz), 6.51 1H), 5.20 ILH, J 7.5 Hz), 3.85-3.75 2H), 3.02 (dd, 1H, J 1P7.2, 17.0 Hz), 0.92 9H). IR (KBr): 3360,2961,1710, 1658, 1404, 1201, 770 cm 4 HRFABMS: Calculated for C 2 7

H

3 2

N

3 0 5 (M 478.2342. Found: 478.2360. Anal.

Calculated for C 2 7

H

1

IN

3 0 5 0.25 CH 2

CI

2 C, 65.62; H, 6.37; N, 8.42. Found: C, 65.86, H, 6.69; N, 8.30.

The starting materials were available as follows: 3 (RV(t-Butoxvcarbonviamino)-N-(I (S)-hdroxvmethl-2-2-dimethl-propvlsuccinamic Acid Benzy] Ester 0 H0~0 0NH -'OH As described in Example 1(0) for the preparat Ion of benzyl-2-methoxyethyi)- 3(R)-(t-butoxycarbonylamino)succinam ic acid benzy I ester, N-t-butoxycarbonyl.D..aspartic acid P-benzy1 ester (1.00 g, 3. 10 rnmol) and L-t-ieucinol (400 mg, 3.40 mmrol) were coupled with BOP to afford 1.20 g of 3 (R)-(t-butoxycarbonylamino)-N.(l(S)..hydroxymethyl- 2 2 -dimethyl-propyl)succinamic acid benzyl ester as a white powder, mp 186-7-C. 'Hi NMR (CDCI3): 567.22 5H), 6.52 I H, J =9.3 Hz), 5.62-5.52 (in, I1H), 5.25 (dd, 2H, IJ 12. L, 18.7 Hz), 4.58-4.48 (in, I 3.90-3.78 2H), 3.58-3.50 (in, I 3.22-3. 10 (in, I 2.78 (dd, I H, J 17.7 Hz), 2.52-2.45 (in, 1.22 9H), 0.98 9H). IR: 3322, 2960, 1730, 1664 1528, 1367, 1249, 1165, 1050 cm- Anal. Calculated for C 22

H

34

N

2 0 6

C,

62.52; H, 8.12; N, 6.63. Found: C, 62.20; H, 8.13; N, 6.62.

3(R)-[3-(4'-Carbanovibipheny1-4-vh...I H-pyrrol- I-vll-N-( 1(S)-hvdroxvmethvl-2.2-dimethvlm propylbsuccinamic Acid Benzyl Ester Ge HN 0 0E" NH OH As described for Example 4(a) for the preparation of N-(1 (S)-benzyl-2hydroxyethyl)-3(R)- (3-(4'-cyano-biphenyl-4-yl)- I H-pyrrol- I -yi]succinanmic acid benzyl ester, crude 3-(4'-carboxanhidobiphenyl)-2,5-dinethoxy.tetrllydrofwian and 3(R)wamnino-N-( Ihydroxymethyl-2,2-dimethyl-propyl)succinamic acid benzyl ester trifluoroacetate salt were condensed in 1 ,2-dichloroethane to furnish 10 mg (4 of 3(R)-(3-(4-carbamoylbiphenyl- 4-yl)-I H-pyrrol- 1-ylI-N-( 1(S)-hydroxyrnethy 1-2,2-diinethy I-propyl)succinamic acid benzy I ester as a solid, rnp 201-3 T. 1H NMR (CDC13): 6 7.88 2H, J 8.1 Hz), 7.69 2H, J =8.4 Hz), 7.61 2H, J 8.4Hz), 7.5 6 2H, J 8.7 Hz), 7.36-7.26 (in, 5H), 7. 10 IlH, J 126 =1.9 Hz), 6.81 I H, J =2.5 Hz), 6.61 I H, J 1.6 Hz), 5.60-5.56 (in, 1I-H), 5.10-5.02 (mn, 3H), 3.80.3.70 (in, 2H4), 3.50-3.38 (in, 3H), 3.24 (dd, I H, J 17.0 Hz), 0.80 9H). IR (KBr): 3356, 2961, 1735, 1655, 1606, 1560, 1542, 1406, 1200 cmn Anal. Calculated for

C

34

H

37

N

3 0 5 0.25 CH 2

CI

2 C, 69.85; H, 6.42; N, 7.14. Found: C, 69.82, H, 6.67; N, 7.12.

Example N-12,2- D imethyl[-I (S)-(byd roxy methylI)p ropyl I 13-f 4-(py rid io-4yl)phenyl- 1H-pyrrol- 1-yllsuccinaniic Acid HO0 N NH. O A mixture of I -benzyloxycarbonyloxy-3,3-dimethylbut-2(R)-yl)-3 (pyridin-4-yI)phenyl]- IH-pyrrol-1I-yl]succinamic acid benzyl ester (140 mg, 0.2 12 mmol) and Pd(QH) 2 (60 mng of 20% Pd by content) in MeOH (1 mL) and EtOAc (9 mL) was stirred under H 2 atmosphere for 3 hours. The catalyst was filtered onto Celite and rinsed with MeOH.CHCI 3 (75 niL). The filtrate was concentrated in vacua to provide a yellow solid,

J.

which was precipitated from hot CHC1 3 solution with hexane to furnish 68 mg of N- (2,2-dimethyl- I(S)-(hydroxymethy)propyl]-3(R)-[3- [4-(pyridin-4-yl)phenyl]- 1H-pyrrol-I1 U.yl]succinamic acid as a yellow solid, nip 192-4*C. IH NMR (CD 3 OD): 8 8.56 I H, J= 5.9 Hz), 7.78-7.60 (in, 711, 7.37 I1H, J 1.9 Hz), 6.96 I1H, J 2.5 Hz), 6.54 I1H, J= 1.6 Hz), 5.22 (dd, IH, J =2.5 Hz), 3.83-3.70 (mn, 214), 3.45-3.40 (in, lIH), 3.22 IH, J Hz), 3.02 (dd, 1H, J3 7.2, 16.8 Hz), 0.90 91-I). IR (KBr): 3405, 2960, 1718, 1656, 1602, 1560, 1408, 1364, 1203, 922, 818, 783 cm- HRFABMS: Calculated for C 25

H

29

N

3

O

4

CS

(M 568.1212. Found: 568.1189. Anal. Calculated for C 25

H

2 9N 3 0A *0.10 CHC1 3 C, 67.38; H, 6.55; N, 9.39. Found: C, 67.69, H, 6.90; N, 9.65.

The starting material was made as follows: 444- Bromno-phenvl')-pvri dine Br According to the procedure described in Example I1(a) for the preparation of 3 biphenyl-4-yl-furan, 4-bromopyridine (700 ing, 3.00 minol) underwent coupling to 4bromophenylboronic acid to give 2.3 8 g (100%) of 4-(4-bromo-phenyl)-pyridine as a yellow solid, which had an NM that matched literature (Boy, Combellas, Thiebault, A.; Arnatore, Jutand, A. Tetrahedron Lett. 1992, 33, 491-494) and was used without further purification. IR 1593, 1474, 1412, 1075, 1006, 807, 756, 693, 498 cm'.

3-(4'-Pyrdvdyjhenyl-4-vflfur

N

01 P According to the procedure described in Example 1(a) for the preparation of 3biphenyl-4-yl-furan, 4-(4-bromophenyl)pyridine (700 mng, 3.00 minol) underwent coupling to 3-furanboronic acid (see Thompson, W. Gaudino, G. J. Org. Chem. 1984, 49, 5237-5243).

Purification via flash column chromatography with 2% MeOICH 2

CI

2 as eluant led to obtention of 640 mng of 3-(4'-pyridylphenyl-4-yl)furan as a yellow solid, which was used in the next reaction. H NMR (CDCI3): 6 8.68 2H, J 5.9 Hz), 7.82 (dd, I H, J 1.6 Hz), 7.76-7.43 (mn, 6.76 (dd, 1IH, J 0.9, 1.8 Hz). Anal. Calculated for

C

15 H, NO: C, 81.43; H, 5.01; N, 6.33. Found: C, 81.32, H, 5.08; N, 6.28.

2 .5-Dihvdrn-2.5-dimethox-(.344vridin4v)henpfur

N~N

0OCH 3 According to the procedure described in Example 1(a) for the preparation of 3.

biphenyl-4-yl-2,5-dihydro-2,5-dimethoxyfijzan, 3-(4'-pyridylphenyl-4-yl)furan (470 mg, 2.12 mmol) was converted and purified via flash column chromatography with 2% MeOF{ICH 2

CI

2 as eluant to afford 600 mg (100%) of 2,S-dihydro-2,5-dimethoxy-3-{4- (pyridin-4-yl)phenyl)furan as a tan solid. I HNMR (CDCI3): 8 8.68 2H. I 4.0 Hz), .7.68 4H), 7.52 2H, J 5.9 Hz), 6.40 1H), 6.30 0.5H, J 3.7 Hz), 6.05 6.02 0.5H, J 3.7 Hz), 5.72 0.5H), 3.52 1.5M), 3.48 1.5H), 3.45 1.5H), 3.43 13SH). HRFABMS: Calculated for C 17

H

18 N0 3 (M 284.1287. Found: 284.1294.

Anal. Calculated for C 17 H 17 N0 3 C,72.07; H, 6.05 N, 4.94. Found: C, 71.97, H, 6.05; N, 4.95.

2.Dimethoxv-3-(4-(pvridin-vlphenyl'netrahydrofuran ct-o

OCH

3 According to the procedure described in Example 1(a) for the preparation of 3biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran, 2,S-dihydro-2,5-dimethoxy-3-(4-(pyridin-4yl)phenyl)furan (300 mg, 1.06 mmcl) was hydrogenated in MeOH after 6 hours to furnish ,%ooV300 mg (100%) of 2,5-dimethoxy-3-(4-{pyridin-4-y)phenyl)tetahydrofiaran as a yellow oil, 129 which was a mixture of diastereorners by NMR, and which was used without further purification. IH NNM (CDCI3): 6 8.68 (bs, 2H), 7.76-7.36(m, 6H), 5.344.94 (in, 2H), 3.72- 3.20 (in, 7H), 2.75 (ddd, 0. 15H, minor isomer, J 10.0, 13.7 Hz), 2.3 5 (ddd, 0.74H, major isomer, J 12.8, 12.8 Hz), 2.20 (dd, 0.0. 19H, minor isomer, J 12.0 Hz), 2.12 (ddd, 0.16H, minor isomer, J 3.7, 5.9, 13.7 Hz); Anal. Calculated for C 17 H 19 N0 3 0 0.2 H 2 0: C, 70.66; H, 6.77; N, 4.85. Found: C, 70.49; H, 6.74; N, 4.76.

I (S)-Benzvloxycarbonyloxvmethvl-2.dinethylpropy)-3 butoxycarbonylani no'~succinamic Acid Benzy Ester To a solution of 3 (R)-(t-butoxycarbonylamnino)-N-(2,2-dimethyl- 1(S)-hydroxymethylpropyl)succinaxnic acid benzyl ester (1.27 g, 3.01 inio; prepared as described in Example and DMAP (920 mg, 7.51 mrnol) in CHC1 3 (5 mL) was added benzyl chioroformate

-P

(1.07 mL, 7.51 imol). After 2 hours, 10% aqueous KHS0 4 (15 inL) was added. The P a,, aqueousueous layer was extracted with more CHC1 3 (15 m.L) two time. The combined CHC1 3 layers were washed with 10% aqueous KHS0 4 (10 mL), saturated aqueous NaHCO 3 mnL), and H20 (10 mL), dried over Na 2

SO

4 and evaporated to give a crude solid, which was purified via flash column chromatography to afford 1.42 g of benzyloxycarbonyl-oxyinethyl-2,2-dirnethyl-propyl)-3(R)-(tbutoxycarbonylamino)succinamic acid benzyl ester as a white solid, mp 69-71 OC. I H NMR 1:(CDC13): 6 7.37-7.27 (bin, 1011), 6.63 I H,J =9.3 Hz), 5.61 I H, J =7.5 Hz), 5.16 (s, 2H1), 5.15 I1H, J 12.3 Hz), 4.97 I H, J =12.3 Hz), 4.51 11H, J 5.6 Hz), 4.29 (dd, 130 I H, J 11.2 Hz), 4.15 (dd, I H, 7.8, 11.2 Hz), 4.05 (ddd, IlH, J 3.7, 7.8, 9.6 Hz), 3. 01 (dd, IlH, J 17.1 Hz), 2.72 (dd, 11-1, J 6.5, 17.1 Hz), 1.44 9H), 0.93 9H). IR: 3340, 2951, 1753, 1707, 1671, 1533, 1507, 1456, 1364, 1272, 1175, 790, 734 cm- 1 HRLSIMS: Calculated for C 30

H

4 0

N

2

O

8 Cs (M 689.1839. Found: 689.1826. Anal.

Calculated for C 30

H

40

N

2 0 8 C, 64.72; H, 7.24; N, 5.03. Found: C, 64.82; H, 7.25; N, 4.98.

I-Benzvoxycarbonyloxy.3 .3-dimethvlbut-2(R)-vfl.3(R).F3-4.(pndin.4-vI~henI..I

H-

pvXrrol-l-xllsuccinainic Acid Benzl Ester

N

0 N 0 According to the procedure described in Example 1(b) for the preparation of 3(R)-tbutoxycarbonylamino-N.(2,2.dimethyl- 1 (S)-methylcarbamoylpropyl)succinarnic acid benzyl ester, IR-benzyloxy-carbonyloxymethyl-2,2-dinethy-propyl)-3(R).(t- 0 butoxycarbonylamino)succinamic acid benzyl ester was deprotected. The corresponding .0 00 amine salt and 2,5-dimethoxy-3-(4'-pyridylphenyl-yl)-tetrahydTO-flxan was condensed in wet I ,2-dichloroethane at go-go 0 C after 18 hours to furnish a crude product, which was purified via flash column chromatography with 1% HOAcI 5% MeOH /CH 2

CI

2 as eluant to furnish 160 mg (541%) of 1-benzyloxycarbonyloxy-3 ,3-dimethylbut-2(R)-yi)-3(R)-[3-(4- (pyridin-4-yl)phenyl].1IH-pyrrol- I-yljsuccinamic acid benzyl ester as a yellow solid, mp 74boss.

6*C. IH NNM (CDCI3): 6 8.65 2H, J1 5.9 Hz), 7.58 5H, J 2.2 Hz), 7.55-7.43 (mn, 4H), 7.34-7.22 (mn, 7H), 7.08 1H, J 1.9 Hz), 6.74 1H, J 2.5 Hz), 6.54 (dd, lH, J 1.9, 2.8 Hz), 5.46 I, 9.3 Hz), 5.18-5.05 (in, 4H), 5.03 2H), 4.30 (dd, li4{,J= 2.5, 12.0 Hz), 4.00 (in, 2H), 3.46 (dd, I1H, J 5.3, 15.0 Hz), 3.00 (dd, I H, J 9.3, 15 .0 Hz), 0. 83 (s, 9H). IR (KBr): 2961, 1748, 1666, 1600, 1560, 1263, 1118, 815, 783, 73 7, 695, 541 cmI HRFABM4S: Calculated for C 4 0

H

4 jN 3 0 6 CS (M 792.2050. Found: 792.2034. Anal.

Calculated for C 40

H

4 jN 3 0 6 0.2 CHCL 3 0.3 C 6

H

14 C, 71.10; H, 6.45; N, 5.92. Found: C, 71.01, H, 6.36; N, 5.59.

The following compounds were made in a similar manner: Example N-(2-Hydroxy- 1(S)-phenylethyl)-3(R)-13-[4-(pyridin.4-yl)phenyl.. 1Hpyrrol-i-yljsuccinamic Acid

-N

0 N.

.HOK>- NH ~OH According to the procedure described in Example N-(2-benzyloxycarbonyloxy- C 1 (S)-phenylethyl)-3(R)-(3-[4-(pyridin.4yl)phenyl]-I H-pyrrol- I -yl]succinamic acid benzyl ester was hydrogenolyzed to afford 60 mg of N-(2-hydroxy-1I(S)-phenylethyl)-3(R)- 3(R)-[3-[4-(.pyridin-4-yl)phenyl]- 1H-pyrrol-1I-yllsuccinamic acid. I H NM4R (CD 3 OD): 8 8.56 2H, J 5.9 Hz), 7.78-7.60 (mn, 7H), 7.38 I1H, J 1.9 Hz), 6.95 IlH, J 2.5 Hz), 5 (dd, I1H, J 1.6, 2. 8 Hz), 5.22 (dd, I1H, J 7.2, 7.4 Hz), 3.76-3.64 (bin, 3.02 (dd, lH,J=7.2, 16.8Hz). IR(KBr): 3315, 1718, 1670, 1654, 1602,1560,1491,1406, 1202 cm' .HRFABMS: Calculated for C 27 H 5 3

O

4 CS (M +CS5: 588.0899. Found: 588.0914.

SO S Anal. Calculated for C 2 7

H

25

N

3 0 4 S 0.2 CHC1 3 C, 68.15; H, 5.30; N, 8.77. Found: C, beg.s* :605:68.19, H, 5.63; N, 8.38.

The starting materials were made as follows: 3 (R)-(t-Butoxycarbonvlamino)-N-(2-hydroxv- I(S)-phenvl-ethvflsuccinamic Acid Benzl

F-=

0 0 (2f' 0 NH_ OH 0 According to the procedure described in Example 1(f) for the preparation of I1(S)benzyl-2-methoxy-ethyl)-3 (R)-t-butoxycarbonyl-amino-succinamic acid benzyl ester, N-tbutoxycarbonyl.D-aspartic acid P-benzyl ester and 2S-phenylglycinol were coupled with BOP to provide 290 mng (8 of 3(R)-(t-butoxycarbonylamino)-N.(2-hydroxy- I (S)-phenylethyl)succinarnic acid benzyl ester, rnp 1 17-8*C. I'H NMR (CDCl3): 8 7.40-7.22 (in, I OH), 7. 10 (bd, I1H, J 9.3 Hz), 5.66 (bd, IlH, J 9.3 Hz), 5.14 (dd, 2H, J 12.1, 18.4 Hz), 5.08- 5.02(m, lH),4.58-4.50(m, 3.94-3.80(m,2H), 3.12 (dd, lH,J=4.4, 17.1 Hz), 2.75 (dd, I H, J 5.9, 17.4 Hz), 2.42-2.36 (mn, 118), 1.20 9H). IR: 3322, 2965, 1730, 1660, 1367, 1166 cm Anal. Calculated for C 24

H

30

N

2 0 6 0 0.25 H 2 0: C, 64.49; H, 6.88; N, 6.27.

Found: C, 64.34; H, 6.73; N, 6.29.

N-(2.Reniloxycarbonvloxv- I (S'i:phenlethvl)-3(JU1-t.(butoxycarbonvlaminolSgccinarnic 0 r0 0OHN 0 <0 A.N 0 0Tr According to the procedure described in Example 5(a) for the preparation of I Rbenzyloxycarbonyloxymethyl-2,2-dimethyl.propyl).

3 (R)-(-butoxycarbonylamnino)succinamic acid benzyl ester, N-(2-hydroxy- 1(S)-phenyl-ethyl)-3(R).(tbutoxycarbonylanhino)succinamic acid benzyl ester was acylated to provide crude product, which was purified via flash column chromatography with 30% EtOAc/hex as eluant to give 33mg of N-(2-benzyloxycarbonyloxy I (S)-phenyl-ethyl (R)-(t-butoxycarbonylamino)succinamic acid benz>'1 ester as a white solid, mp 105-6TC. H NMR (CDCI3): 8 7.40-7. 18 (mn, 15H), 5.63 (bs, 1 5.24 1 H, I 6.6 Hz), 5.12 2H), 5.06 2H, J= 10.3 Hz), 4.50 (bs, I 4.55 (ddd, 2H, J 5.0, 6.8, 11.2 Hz), 2.99 (dd, I H, J 4.4, 17.0 Hz), 2.66 (dd, I H, J 6.2, 17.0 Hz), 2.42-2.36 (mn, IH), 1.40 9H). IR: 3320, 2981, 1742, 1692, 1657, 1518, 1458, 1394, 1313. 1277, 1171 cm' 1 Anal. Calculated for C 32

H

36

N

2 0 8 C, 66.65; H, 6.29; N, 4.86. Found: C, 66.57; H, 6.3 1; N, 4.88.

~N-(2-Benzvloxycarbony loxy- I (S)-phenv iethvl)-3 r4-('pvnidin-4-flphenyll- I H-pvrrols. I -vllsuccirianic Acid Benzl Ester

ON

0 According to the procedure described in Example 1(b) for, the preparation of N-(2,2diinethyl- 1(S)-inethylcarbamnoylpropyl)-3(R).(3-phenyl- IH-pyrrol- 1-yl)succinamic acid benzyl ester, N-(2-benzyloxycarbonyioxy- I (S)-phenyl..ethyl)-3(R)-(t- .99 butoxycarboriylamino)succinarnic acid benzyl ester and 2,5-dimethoxy-3-(4-pyridin-4-ylphenyl)-tetahydrofuran (prepared as described in Example were condensed in wet 1,2dichioroethane at 80-90 0 C after 18 hours. Flash column chroinatagraphy with 4% MeOI/CH 2

CI

2 as eluant gave 140 mg of N-(2.berlzyloxycarbonyloxy

I(S)-

phenylethyl)-3 3 -[44jpyridin-4yI)phenyl]- I H-pyrrol- I -yl~succinamic acid benzyl ester as a yellow solid, mnp l38-40*C. I H NMR (CDCI3): 6 8.66 (bs, 2H), 7.60 5H), 7.50 (d, 3H, J =5.3 Hz), 7.34-7.22 (mn, I OH), 7.19 1FH, J =2.2 Hz), 7.17 lH, J =1.9 Hz), 7.09 I H, J 1.9 Hiz), 6.77 (dd, I1H, J 2.5, 2.8 Hz), 6.57 (bt, I H, J 1.9, 2.5 Hz), 6.24 1H, J 7.8 Hz), 5.2 6 (in, I-M, 4.25 (dd, I H, J 11.5 Hz), 3.44 (dd, I[H, J 7.2, 16.8 Hz), 3.00 (dd, I1H, 8.7, 16.8 Hz). IR (KBr): 2985, 1738, 1657, 1598, 1560, 1495, 1202, 815, 697 cm".

HRFABMS: Calculated for C 42

H

37

N

3

O

6 Cs (M 812.1737. Found: 812.1712. Anal.

Calculated for C 42

H

37

N

3 0 6 0.25 CHCI 3 C, 71.51; H, 5.29. Found: C, 71.72; H, 5.60.

Example 3(R)-13-(4'-Cyanobiphenyl-4-yI1H-pyrrol- 1-ylI-N-f2,2-dimethyl-1(S)- (methylcarbauzoyl)propyljsuccinamic Acid

CN

0 ON 0

.HOI>

7

NH,-NHCH,

According to the procedure described in Example 3(R)-[3-(4'-cyanobiphenyl-4yI)- IH-pyrrol- 1-yl]-N-(2,2-dixnethyl. 1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester (58 mng, 0. 101 mmol) was hydrogenolyzed to afford 31 mg of cyanobiphenyl4-yl). I H-pyrrol- 1 [2,2-dimethyl- I *.:(meithylcarbamoyl)propyl]succirlazmc acid as a solid, mp 142-4*C. 1 H NMR (CDC13): 6 7.61 (dd, 4Hf, J 8.4, 15.2 Hz), 7.45 (dd, 4H-, J 8.2, 16.6 Hz), 7.12 1Ff), 6.77 I1H), *6.44 1Ff), 6.31 (bs, 1H), 5.26 1H, J =6.8 Hz), 4.29 1H,J =9.3 Hz), 4.03 (bs, 1Ff), 3.32 (dd, I H, J 17.1 Hz), 3.07 (dd, 1FH, J 7.6, 17.3 Hz), 2.66 3H, J =4.05 Hz), 0.92 9H). IR 3354, 2955, 2367, 1737, 1719, 1655, 1561 cm' HRFABMS: Calculated for C 2

SH

31

N

4 0 4 (M 487-2345. Found: 487.2356. Anal. Calculated for

C

28

H

30

N

4 0 4 0 1.2 EtOAc: C, 66.5 1; H, 6.74; N, 9.46. Found: C, 66.57, H, 6.54; N, 9.28.

The starting material was available as follows: 3 (R)-f3 -(4'-Cvanobiphenvl-4-vli -I-pyrrol- I -YlL-.N-f22-dimethXL I Sj)- (rnethvlcarbazrovl)propvllsuccinamic Acid Benzyl Ester

CN

0 N 1 0 0 N H..NHCH, According to the procedure as described in Example I1(c) for N-(l,7-diaza-4-oxa-8oxo-tricyclo- 1 .0 12, 17 ]-octadeca- 11(1 8),l 2,14,1 6-tetraen-9S-yl)-3(R)-(3-phenyl-

IH-

pyrrol- I -yl)-sucinnamic acid benzyl ester, crude 3(R)-amino-N-(2,2-dirnethyl- I :methylcarbarnoylpropyl)succinamic acid benzyl ester trifluoroacetate salt (prepared as described inExample I1(b)) and 4'-(2,5-dimethoxy-tetrahydrofuran-3-yI)-biphenyl4carbonitrile (prepared as described in Example were condensed to give 84. mg of 3(R)-(3-(4-cyanobiphenyl-4yI)- I H-pyrrol-lI-yI]-N-[2,2-dimethyl-

I(S).

(inethylcarbaznoyl)propyl~succinamic acid benzyl- ester- as a yellow solid, mp l2OaC. I'H NMR (CDCI3): 8 7.72 4H), 7.59 4H), 732-7.28 (mn, 2H), 7.26 3H), 7.12 I1H, J= 2.1 Hz), 6.82 IH, J 2.7 Hz), 6.61 (dd, J1 1.8, 3.0 Hz), 6.27 IH, J 9.0 Hz), 5.58 (in, I1H), 5. 13 2H), 5. 12 (in, 4.01 2H, 8.7 Hz), 3.41I (dd, I H, J 5.8, 16.7 Hz), 3.11 (dd, I1H, 8.7, 16.8 Hz), 2.78 3H, 1 5.0 Hz), 0.87 9H). IR (KBr): 2960, 222 1, 1736, 1685, 1654, 1562, 1542 cm- H-RFABMS: Calculated for C 35

H

37

N

4 0 4 (M +H) 577.2815. Found: 577.2832. Anal. Calculated for C 35

H

36

N

4 0 4 o 0.2 DMF 0.5 HO: C, 71.23; H, 6.45; N, 9.80. Found: C, 71.14, H, 6.23; N, 10. 19.

Example 3(R)-[3-(4'-Cyanobiphenyl-4-yI)-1H-pyrrol-lyII-N-[2,2-dimetbyl-1(S)- (pyridin-4-ylcarbamoy)propyljsuccinamic Acid Formate Salt

N

0ON 0 rl':N .HOK NH>INH"z' 0 A mixture of palladium on carbon and 3(R)-[3-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-lyl]-N-[2,2-dimethyl-I (S)-(pyridin-4-ylcarbamoyl)propyl]succinaznic acid berzyl ester (72 mg, 0. 112 mmal) in MeOH with formic acid afforded 30 mg of cyanobiphenyl-4-yl)- 1 H-pyrrol-l yl]-N.42,2-dimethyl- 1(S)-(pyridin-4ylcarbamoyl)propyl]succinamic acid formate salt as a solid, mp 134-6*C. 'H NMR (DMSO- 6 8.39-8.35 31), 7.81 2H, J 5.9 Hz), 7.63 2H), 7.34-7.23 4H), 7.28 (d, 2H, J 10.3 Hz), 7.24 1H), 6.96-6.92 1H), 6.52 (dddd, IH, I 1.8, 2.9, 4.8, 7.4 Hz), 5.35-5.29 1H), 3.39-3.18 (bm, 1H), 3.09-2.91 (bin, IH), 1.06 9H). IR (KBr): 2966, 2225, 1719, 1654, 1594, 1560,1507, 1396, 1196 cm'. HRFABMS: Calculated for

C

28

H

31

N

4 0 4 (M 550.2454. Found: 550.2450. Anal. Calculated for C 32

H

3 1 NS04 0 HC0 2 H 0 2.5 CH 3 OH: C, 63.10; H, 6.41; N, 10.36. Found: C, 63.03, H, 6.75; N, 10.38.

The starting material was available as follows: 2S-t-Butoxycarbonvlamino-3 .3-dimethvl-N-pvridin-4-vl-butanaide OYNH )NH 0 To a mixture of N-t-butoxycarbonyl.L-t-leucine (made according to Shiosaki, K.; Tasker, A. Opgenorth, T. J. WO 92/13545, November 8, 1991 and matched with data from Pospisek, Blaha, K. CoIl Czech. Chem. Commun. 1977, 42, 1069-1076; 200 mg, 0.860 mmol) and 4-arninopyridine (356 mg, 1 .72 rnmol) in anhydrous DMF was added morpholine (284 11L, 2.58 mmn.oi). After cooling to 0 0 C, tetrafluoroforrnamidinium hexafluorophosphate (TFFH; see Carpino, L. EI-Faham, A. J Am. Chem. Soc. 1995, 117, 5401-5402; 340 mg, 1.29 inmol) was added. The mixture was allowed to warm to ambient temperature and stirred overnight. The resultant mixture was diluted with CH 2

CI

2 (50 mL), washed with saturated aqueous NH 4 C1 (25 mL), saturated aqueous NaHCO 3 (25 mL) and brine (25 rnL), dried over MgSO 4 and concentrated at reduced pressure to provide a yellow solid, which was purified via flash column chromatography to give 167 mg of 2S-t- A.butoxycarbonylamino-3,3-dimethyl-N-pyridin4-y-butananide as a white solid. H NMR: 8.60 (bs, 1 8.42 (bs, 2H), 7.34 (bs, 2H), 5.34 (bd, I H, J 8. 7 Hz), 4.08 (bs, I1H, J 8.7 Hz), 1.42 9H), 1.02 9H). IR (KBr): 3286, 2971, 1682, 1594, 1518, 1367, 1169 cm.

HR.FABMS: Calculated for C 1 6

H

26

N

3 0 3 (M 308.1974. Found: 308.1967. Anal.

Calculated for C1 6

H

25

N

3 0 3 0.37 H 2 0: C, 61.19; H, 8.26; N, 13.38. Found: C, 61.52; H, 8.18; N. 12.99.

2S-Amnino-3-3-dimethvl-N-4-pvridinl-butanamidc H2N NH'zOJ To a solution of 2S-t-butoxycarbonylamino-3,3-dimethyl-N-pyridin-4-yl-butanamide (3.00 g, 9.75 rmnol) in CH 2

CI

2 (10 mL) was added trifluoroacetic acid (3 After 3 hours at ambient temperature, the solvent was remnoved in v acuo and azeotropicaiy dried with hexane twice to fuirnish a colorless foam, which was dissolved in MeOH (50 rnL) and neutralized upon stirring with IRA-400 anion exchange resin (-HCO 3 form; 3 g) over 3 hours.

The resin was filtered off and the solution concentrated in vacua to furnish a white solid, which recrystallized from hexanes to give 1. 18 g of 2S-amino-3,3-dirnethyl-N-4pyridinyl-butanamide as a white powder (cited in Chapman, K. Hagmann, W. Durette, P. Esser, C. Kopka, 1. Caldwell, C. G. WO 9412169, November 18, 1995). 'H NMR: 6 9.40 (bs, lH), 8.50 IH, J 4.7 Hz), 7.50 2H, J 4.7 Hz), 3.15 3H), 1.02 9H). IR (KBr): 3250, 2962, 1686, 1592, 1517, 1418 cmrf t Anal. Calculated for C, 1

H

17

N

3 0: C, 63.74; H, 8.27; N, 20.27. Found: C, 63.79; H, 8.23; N, 20.35.

3(R)-t-Butoxycarbonylarnino-N-[2.2-dimethvl- I (S)-(N-pvridin-4vlcarbamoyvhpropijsuccinarnic Acid Benzl Ester *0 NH 0 N C OX-\NH~NC To a solution of 2S-amnino-3,3-dimethyl-N-4-pyridinyl-butanamide (100 mg, 0.482 mmol) and N-t-butoxycarbonyl-L-aspartate P-benzyl ester (156 mg, 0.482 rnxol) in dry DMF (3 mL) at 0 0 C was added sequentially diethylcyanophosphonate (81 ;IL, 0.482 mmol) and triethylarnine (200 ILL, 1.46 mmol). After 30 minutes at 0 0 C, the mixture was allowed to warm to ambient temperature. After 4, the resultant orange mixture was stirred with saturated aqueous NaHCO 3 and extracted with EtOAc three times. The combined organic layers were washed with 5% aqueous citric acid, H-20, and brine, dried over Na 2

SO

4 and evaporated to give a viscous yellow oil, which was purified via flash column chromatography with EtOAc as eluant to afford 150 mg of 3(R)-t-butoxycarbonylamino-N-[2,2dinethyl-1(S)-(N-pyridin-4-y-carbanoyl)-propyljsuccinamic acid benzyl ester as a yellow oil. 'H NMR: 6 9.11 (bs, IH), 8.37 2H, J 5.0 Hz), 7.43 2H, 4.7 Hz), 7.28 5.90 (bs, IH), 5.09 1H, J 12.1 Hz), 5.01 1H, I 12.1 Hz), 4.60 (dd, IH, J 5.5, 12.6 Hz), 4.35 IH, 8.1 Hz), 3.03 (ddd, IH, J 4.6, 4.6, 17.1 Hz), 2.83 (dd, IH, 5.6, 17.1 Hz), 1.47 9H), 1.05 9H). IR (KBr): 3319, 2966, 1737, 1719, 1701, 1666, 1596, 1525, 1420, 1367, 1290 cm- HRFABMS: Calculated for C 27

H

37

N

4 0 6 (M 513.2713. Found: 513.2726. Anal. Calculated for C 27

H

3 6

N

4 0 6 C, 63.26; H, 7.09; N, 10.92. Found: C, 63.11; H, 7.12; N, 10.89.

3(R)-3-(4'-Canobiphenyl-4-y- I 1H-vrrol- I vl]-N42.2 -dimethyl- (S')-(pvridin-4- XlcarbaniovIpropvl succiramic Acid Benzvl Ester

CN

.i0 N 0 0yo NH)NH 0 According to the procedure described in Example 1(c) for the preparation N-(1,7- *diaza-4-oxa-8-oxo-tricyclo-[96. 1.0 12' 7 -octadeca- 1(18),12,14,16-tetraen-9S-y)-3(R)-(3 phenyl- 1I-pyrrol-I-yl)sucinnamic acid benzyl ester, crude 3(R)-amino-N-[2,2-dimethyl- I (S)-(pyridin-4-ylcarbamoyl)popyl]succinamic acid benzyl ester influoroacetate salt and 4'- .(2,5-dimethoxy-tetrahydrofuran-3-yI)-biphenyl4-carbonitrile were condensed to give 75 mg 3: of 3(R)-(3-(4'-cyanobiphenyl-4-yi). 1 1-pyrrol-I yl]-N-[2,2dimethyl- 1(S)-(pyridin-4ylcarbanoyl)propyl]succinamic acid benzyl ester as an off-white powder, mp 115-6*C. 1

H

NMR: 6 8.42 2H, J 5.6 Hz), 7.72 2H), 7.58 21), 7.50 2H, .0 .5.0 Hz), 7.31 (s, 2H), 7.26 7H), 7.12 IH), 6.85 (dd, 1H, J 2.5, 2.5 Hz), 6.64 (dd, IH, J 1.6, 2.8 Hz), 6.25 5.20-5.10 3H), 4.15 1H, J= 8.1 Hz), 3.39(dd, IH, J= 5.5, 17.3 Hz), 3.25 (dd, IH, J 7.9, 17.3 Hz), 0.94 9H). IR (KBr): 3331, 2959, 2225, 1735, 1687, 1655, 1602, 1559, 1511, 1288, 1203, 825 cm' 1 HRFABMS: Calculated for C 35

H

37

N

4 0 4

(M

640.2924. Found: 640.2908. Anal. Calculated for C 39

H

37 NS0 4 .0 1.1 EtOAc: C, 70.76; H, 6.27; N, 9.51. Found: C, 70.73; H, 6.19; N, 9.16.

Example 3(R)-13-(4'-Carbamoylbiphenyl-4-y)-1H-pyrrol-1-yII-N-(2,2.dimethyl- 1(S)-(methylcarbamoyl)propyl)succinamic Acid 0

NH

2 O N 0 CH 3 HO4-\,ANH2N.

0 -I)NHNH According to the procedure described in Example carbamoylbiphenyl-4-yl)- 1 H-pyrrol- 1-yl]-N-(2,2-dimethyl- I(S)- (methylcarbamoyl)propyl)succinamic acid benzyl ester was hydrogenolyzed to provide mg of 3(R)-[3-(4'-carbanoylbiphenyl-4-y )-IH-pyrrol-1 -yl]-N-(2,2-dimethyl- I(S)- (methylcarbamoyl)propyl)sucinamic acid as a yellow solid. IH NMR (CD 3 OD): 6 7.98 (d, 2H, J 8.1 Hz), 7.78 2H, J 8.1 Hz), 7.62(s, 4H), 7.30 (bs, IR), 6.92 (bs, 1H), 6.54 (bs, IH), 5.98 (IH, J 2.8 Hz), 5.39 1H, J 6.5.Hz), 4.19 IH, J 9.3 Hz), 3.02 (dd, IH, J 7.2, 16.5 Hz), 2.60 3H), 0.98 9H). IR(KBr): 3332, 2915, 1658, 1547, 1408 cm' Anal. Calculated for C 2

SH

32

N

4 0 5 e 0.7 120: C, 65.03; H, 6.51; N, 10.83. Found: C, 65. H, 6.74; N, 10.43.

The starting material was made as follows: 414'-CarbamovlbiphenyL-4-vla. IH-pvrrol. I1 .vl-N(2-2-dimethvl. I (methylcarbamovhnropvlhsuccinamic Acid Benzyl Ester 0

NH

2 0 N 0H~ According to the procedure described in Example 1(b) for the preparation of N-(2,2dimethyl- I (S)-rnethylcarbamoylpropyl)-3(R)-(3-phenyl- 1H-pyrrol- I-yl)succinamic acid benzyl ester, 3(R)-t-butoxycarbonylamino-N-(2,2-dirnethyl- I methylcarbamoylpropyl)succinamic acid benzyl ester was deprotected. The crude amine salt and crude 3-(4'-carboxamidobiphenyl-4-yI)-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example were condensed in wet 1,2-dichioroethane at 90- 100*C to yield 180 mg (5 of 3(R)-f 3-(4'-carbamoylbiphenyl-4-yl)- I H-pyrrol- 1 -yl]-N-(2,2-dimethyl- I (S)-(methylcarbaznoyl)propyl)succinamic acid benzyl ester. IH NMR: 6 7.90 2H, J 8.4 Hz), 7.70 2H, J 8.7 Hiz), 7.60 (dd, 3H, J 8.7, 11.5 Hz), 7.38-7.22 (in, 8H), 7. 10 (t, I H, J 2.2 Hz), 6.82 I H, J 2.5 Hz), 6.62 I H, J 3.0 Hz), 6.32 I H, J 9.0 Hz), 5.63 (di, IH, J 4.70 Hz), S. 14 3H, J 3.7 Hz), 4.00 I H, J 8.7 Hz), 3.48 (dd, I H, J= 7.2, 13.1 Hz), 3.39 (di, FLi J 5.9 Hz), 3.14 (dd, 1IH, J3 8.7, 16.8- Hz), 2.78 3H, J 4.7 Hz), 0.92 9H). IR (KBr): 33 56, 2929, 1735, 1657, 1402 cm. Anal. Calculated for

**C

35

H

39

N

4 0 5 0.5 H 2 0: C, 69.63; H, 6.5 1; N, 9.28. Found: C, 69.85, H, 6.46; N, 9.14.

Example 3 (R)-r3-(4'-Carbamoylbiphenyl-4-yl) IH-pyrrol-I-ylJ-N- [2,2-dimethyl- 1(S)-(N-(pyridin-4-yl)carbamoyl)propylIsuccinamic Acid 0 HO'

NHNHCJ

0 According to the procedure described in Example carbamoylbiphenyl-4-yl)- H-pyrrol-I-yl]-N-[2,2-direthyl- 1(S)-(N-(pyridin-4yl)carbazoyl)propyl]succinamic acid benzyl ester was hydrogenolyzed in MeOR/EtOAc to provide 35 mg of 3 (R)-(3-(4-carbaoylbiphenyl-4-yl)- I H-pyrrol- I -ylj-N-[2,2dinethyl- I(S)-(N-(pyridin-4-yl)carbamoyl)propyllsuccinamic acid as a yellow solid, mp 194- 6 0 C. IH NMR (CD 3 OD): 6 8.35 2H, J 6.5 Hz), 7.95 2H, J 8.4 Hz), 7.75 3H, J 8.4 Hz), 7.70-7.52 6H), 7.28 1H, J 2.0 Hz), 6.90 1H, J 2.8 Hz), 6.52 (dd, IH, J 6.9, 16.8 Hz), 1.20(s, 9H). IR(KBr): 3400,2962, 1665, 1606, 1511, 1402 cm 1 HRFABMS: Calculated for C 32

H

34

N

5 0 5 (M 568.2560. Found: 568.2575. Anal.

Calculated for C 32

H

33

N

5 0 5 0 0.7 HOAc 0 0.5 CHC1 3 C, 60.83; H, 5.47; N, 10.46. Found: C, 60.93, H, 5.88; N, 10.19.

The starting materials were made as follows: 3 -(-CarbamobiW* 'l4- y iH-ivrrol- l-vy-N-r.2-dimethvl- I (S)-N-(pridin-4- *l)carbamoyl'lproyllsuccinamic Acid Benzvl Ester 0

,~N~NH

0 Or rO N cr 04%ArNHNHO C~oC~~N~0H According to the procedure described in Example 1(b) for the preparation of N-(2,2dimethyl- I(S)-methylcarbarnoylpropyl)-3(R)-(3-phenyl-.I H-pyrrol-1-I-y)succinamic acid benzyl ester, 3 (R)-t-butoxycarbonylarnino-N-[2,2-dimethyl.. 1(S)-(pyridin.4yl)carbamoylpropyljsuccinamic acid benzyl ester was deprotected. The crude amine salt and crude 3 4 '-carboxamidobiphenyl-4-yl)-2,5.dimethoxytetrahydrofran (prepared as described in Example were condensed in wet I,2-dichloroethane at 90-1 00*C to yield 130 mg of 3(R)-f3-(4'-carbamoylbiphenyl4-yl)- IH-pyrrol-1I-yl]-N-[2,2-dimethyll(S)-(N-(pyridin-4-yl)carbamoyl)propyl]succinamic acid benzyl ester. I'H NMR (CD 3

OD):

6 8.3 5 (bs, 2H), 7.95 2H, J 8.4 Hz), 7.72 2H, J 8.7 Hz), 7.60 (dd, 6H), J 8.7, 13.4 Hz), 7.28 5H), 6.90 I H, ZJ =2.8 Hz), 6.52 (dd, I H, 1.6, 2.8 Hz), 5.38 ILH, J Hz), 5.12 2H, J= 1.9 Hz), 4.40 I1H), 1I.00 9H). IR (KBr): 2725, 173 5, 1664, 15 cm .Anal. Calculated for C 39

H

39

N

5 0 5 o 1.0 HOAc: C, 68.38; H, 6.05; N, 9.76. Found: C, 683,H, 6.05; N, 9.38.

Example 13-(4'-Cyanobiphenyl-4-yl)-1 H-pyrrol-1-yJ-N- [2,2-dimethyl- 1(S)- (hydroxymethyl)propylj succinamic Acid Triethylamnionium Salt (HsC3NH *O-ASyNH..-OH 0 According to the procedure described in Example 1 a mixture of N-(2benzyloxycarboxymetiiyl- I(S)-dimethyipropyl).3(R)-(3-(4'-cyanobiphenyl-4-yl)- IH-pyrrol- 1 -yl]succinarnic acid benzyl ester and N-(2-benzyloxycarboxymethyl-1(S)-dirnethylpropyl)- 3 (R)-(3-(4-cyanophenyl)- I H-pyrrol- 1 -yllsuccinamic acid benzyl ester washlydrogenolyzed to give a mixture which was separated via preparative RPHPLC (C 18) with HOAcIEt 3 N/MeOH/CH 2

CI

2 as eluant to give 50 mg of 3(R)-[3-(4'-cyanobiphenyl-4-yl)- I Hpyrrol-1-yl]-N-[2,2-dimethyl- I(S)-(hydroxymethyl)propylsuccinamic acid as a solid, mp 110-2*C: H NMR (CD30D): 6 7.82 2H, J 8.3 Hz), 7.77 2H, J= 8.3 Hz), 7.65- 7.60 (bm, 4H), 7.34 1H), 6.93 IH), 6.50 1H), 5.19 (dd, IH, J 3.6, 3.6 Hz), 3.45 (dd, 1H, J 8.2, 12.1 Hz), 3.16 6H, J= 7.4 Hz), 1.28 9H J 7.4 Hz), 0.91 9H). IR (KBr): 3389, 2955, 2226, 1655, 1601, 1561, 1396, 1367, 1202, 920, 826, 779 cm' HRFABMS: Calculated for C 27

H

29 N30 4 Cs (MH+ Cs): 592.1212. Found: 592.1230.

Anal. Calculated for C 2 7

H

29

N

3 0 4 Et 3 N 2.5 H 2 0: C, 65.42; H, 7.87; N, 9.11. Found: C, 65.43; H, 8.15; N, 9.25.

Example (3-(4-Cyanophenyl)- 1H-pyrrol-1-yl]-N-(2,2-dimethyl- 1(S)- (hydroxymethyl)propyl)succinamic Acid Triethylammonium Salt

(H

5 C.)NH' V -NH-OH S..0 Separation via preparative HPLC of the mixture obtained as described in Example afforded 50 mg of 3(R)-[3-(4-cyanophenyl)- I H-pyrrol- 1 -yl]-N-[2,2-dimethyl- IL(S)- (hydroxymethyl)propyl]succinamic acid: IH NMR: 6 7.66 2H, J =8.1 Hz), 7.60 2H, J= 8.1 Hz), 7.42 1H), 6.94 1H), 6.51 1H), 5.18 (bs, 1H), 3.45 (dd, 1H, J 9.2, 12.1 Hz), 3.16 6H, J= 7.4 Hz), 1.96 (bs, 1H), 1.28 9H, J 7.4 Hz), 0.91 9H). IR (KBr): 3378, 2955, 2214, 1655, 1602, 1561, 1489, 1396, 1172, 1094, 920, 838, 785 cm FABMS: 516. Anal. Calculated for C 21

H

25

N

3 0 4 Et 3 N HOAc 1.7 H 2 0: C, 60.70; H, 8.05; N, 9.51. Found: C, 60.54; H, 8.30; N, 9.74.

Example N-(2(R)-Hydroxyindan- l(R)-yI)-3(R)-[3-f4-(pyridin-4-yl)pbenyl J-1Hpyrrol-1-yljsuccinamic Acid

N

0 According to the procedure described in Example I1(a), N-(2(R)-hydroxyindan- I1(R)y l)-3 [3 -[4-(pyridin-4-yl)phenyl] I H-pyrrol-1I-yl]succinarnic acid benzy I ester was hydrogenolyzed to obtain in 61% yield N-(2(R)-hydroxyindan-lI(R-)-yl)-3(R)-[3-[4-(pyridin- 4.yl)phenyl]. I H-pyrrol- I -yl~succinamic acid as a yellow amorphous solid. I'H NMR (DM4SO-d 6 6_12.52 (bs, 1H), 8.59 2H, J 5.9 Hz), 8.24 1H, J 8.5 Hz), 7.77 2H, J 8.5 Hz), 7.71 (d 2H, J 6.3 Hz), 7.64 2H, J 8.5 Hz), 7.45 1H), 7.30-7.15 (mn, 4H), *6.97 IlH, J =2.4 Hz), 6.51 I 5.34 I H, J 7.5 Hz), 5.17 (dd, IlH, J 5.0, 8.7 Hz), X :5.11 I H, J =3.7 Hz), 4.3 5 IlH, J 3.3 Hz), 3.27-2.94 (mn, 2H), 2.76 I H, J 16.0 Hz). Anal. Calculated for C 28

H

25

N

3 0 4 0.2 EtOAc: C, 71.30; H, 5.53; N, 8.66. Found: C, 71.24; H, 5.59; N, 8.52.

The starting material was available as follows: 2CR-3-4-Eddin-4vl')hny]-1H-pvyrrol- I -XIlsuccinic Acid 4-Benzl Ester Hydrochlord

N

HCI

N*

0 According to the procedure as described in Example 1(d) for the preparation of N..

(2,2-dimethyl- I (S)-methylcaxbamoylpropyl).3(R)-(3 -pyridin-4-yl- I H-pyrrol- I -yl)succInamic acid benzyl ester, to a solution of D-aspartate 1-benzyl ester (223 mng, 1 .00 rnol) and dimethoxy..3 4 -(pyridin4..yl)phenyl)tetrahydrof-ura (350 mng, 1.20 mmnol; prepared as described in Example in I ,2-dichloroethane was added sequentially pyridine 16 rnL, mmol), trifluoroacetic acid (0.08 mnL, I mmol), and chlorotrimethylsilane (0.38 mnL, mnmol). After 17 hours at 800 C, the mixture was allowed to cool to ambient temperature.

Filtration led to isolation of 408 mg of 2(R)-f 3-[4-(pyridin-4.yl)phenyl]. I H-pyrrol- I yljsuccinic acid 4-benzyl ester hydrochloride as a yellow solid, mp 203.5 0 C IHNMR (jDMSO-d 6 8 8.86 2H, J 6.3 Hz), 8.38 2H, J 6.6 Hz), 8.02 2H, I 8.5 Hz), 7.74 2H, J 8.5 Hz), 7.58 1H), 7.31-7.24 (mn, 5M), 6.96 1H, J 2.4 Hz), 6.58 (s, I lH), 5.23 I H, I1= 7.4 Hz), 5. 10 2H), 3.36 (dd, IlH, J 16.6 Hz), 3.21 (dd, I H, J= 16.9 Hz). Anal. Calculated for C 26

H

22

N

2 0 4 HCI 00.3 H 2 0: C, 66.68; 5.08; N, 5.98; Cl, 7.57. Found: C, 66.56; H, 5.01; N, 5.98; Cl, 7.80.

N-(2(R')-Hydroxvindan. 1 (R)-vli)-3(R Vf 3 -4-(pvridin-4.vlphenvl. I H-1vrro-1I-vllsuccinarnic

-N

0 N' OH According to the procedure as described in Example I(f) for 3(R)-tbutoxycarbonylaxnino-N-( 1(S)-benzyl-2-methoxy-ethyl)succinamic acid benzyl ester, 2(R).

3 -(4'-pridin-yl-phenyl)- IH-pyrrole- I yljsuccinic acid 4-benzyl ester hydrochloride and I (S)-amuno-2(R)-hydroxy-indane were coupled with BOP to afford in 60% yield hydroxyindan- 1(R)-yl)-3(R)-(3-[4-(pyridin.4.yl)pheny] I H-pyrrol- 1-yllsuccinamjic acid benzyl ester as an off-white solid, mp l99-202 0 C I'H NMR (DMSO-d 6 8_8.66 2H, J 5.9 Hz), 8.34 IlH, J 8.8 Hz), 7.84 2H, J =8.5 Hz), 7.79 2H, J 6.3 Hz), 7.73 2H, J 6.3 Hz), 7.69 1H), 7.36 5H), 7.29-7.21 (in, 4H), 7.04 IH, J 2.2 Hz), 6.58 IH), 5.49 lH, 7.2 Hz), 5.25-5.12 (in, 4H), 4.43-4.39 (in, IH), 3.48 (dd, lH, J 7.5, 16.5 Hz), 3.26 (dd, I1H, J 7.7, 16.5 Hz), 3.09 (dd, IlH, J 4.6, 15.6 Hz), 2.83 IlH, J =16.2 Hz). Anal. Calculated for C 35

H

3

IN

3 0 4 0 0.6 H 2 0: C, 73.95; H, 5.7 1; N, 7.3 9.

Found: C, 73.70; H, 5.6 1; N, 7.26.

The following were made in a simnilar manner: Example N-(2,2-Dimethyl- 1(S)-(methylcarbamoyl)propyl)-3(R)-[3-(4-(pyridin-4yl)phenyl)-1 H-pyrrol-1-yllsuccinamjc Acid ON 0 According to the procedure described in Example I1(a), N-(2,2-dimethyl- I (methylcarbamoyl)propyl)-3(R)-[3-(4-(pyridin4.yl)phenyl)- 1 H-pyrrol- 1-yllsuccinamic acid benzyl ester was hydrogenolyzed in MeQH after 20.hours. Purification via flash colunn chromatography with I% HOAc/ 10% MeOH/CHCl 3 as eluant and azeotrope with n-heptane **fuirnished 24 mug of N-(2,2-dimethyl- 1 (S)-(methylcarbamoyl)propyl)-3(R)-(3-(4- (pyridin-4-yl)phenyl)-IH-pyrrol-l-yl]succinamic acid as yellow crystals. IH NMR

(CD

3 OD): 6 8.54 2H, J 5.6 Hz), 7.99 (bd, 1H, J3 4.4 Hz), 7.80-7.59 6H), 7.34 (t, l H, J= 1.9 Hz), 6.92 I H, J 2.5 Hz), 6.55 (dci, 1H, J 1.9, 2.8 Hz), 5.28 I H, J 7.2 Hz), 4.17 IH), 3.23 (dd, I H, J 7.5, 16.7 Hz), 3.01 (dd, ILH. J 7.2, 16.7 Hz), 2.66 (di, 3H, 1=3.5Hz), 0.95 9H). IR(KBr): 3422,1654, 1598, 1562, 1535 cm- 1

HRFA.BMS:

Calculated for C 26

H

3 jN 4 0 4 (M 463.2345. Found: 463.2356. Anal. Calculated for

C

26

H

30

N

4 0 4 0 1.15 H 2 0 .0.01 CHCI 3 C, 63.30; H, 6.59; N, 11.31. Found: C, 63.28; H, N, 11 .08.

The starting material was available in the following manner: N-(2-2-Dimethvl- I(S)-(methylcarbamoflprOofl)-3 3-(4-(pvridin-4-vflphenfl)- I Hpvrro-1 -vl]succinamic Acid Benzl Ester

-N

0 N' S 0 According to teprocedure described in Example 1(b) for the preparation of N-(2,2dimethyl- I (S)-(mcthylcarbamoyl)propyl)-3(R)-t-butoxycarbonylamino-succinaniic acid benzyl ester, 2

(R)-E

3 -(4'-pyridin4-yl-phenyl)-1H-pyroie-1-yl]succinic acid 4-benzyl ester hydrochloride and L-t-leucine-N-methylamide trifluoroacetate salt (prepared as described in Example were coupled with TBTU to provide in 86% yield N-(2,2-dimethyl-1I(S)- (rnethylcarbamoyl)propyl)-3(R)-f3-(4-(pyridin.4-yl)phenyl)-1 H-pyrro1- 1-yljsuccinamnic acid lbenzyl ester. H NMR: 6 8.80-8.57 (bs, 7.76-7.50 (in, 6H), 7.36-7.22 (mn, 5H), 7.12 (d, lIH, J 1.6 Hz), 6.82 IH, J 1.9 Hz), 6.60 (dd, 1H, J 1.2, 1.2 Hz), 5.20-5. 15 (in, 3H), 4.09 (dd, IlH, J 2.8, 9.-0 Hz), 3.41 (dci, I H, J 5.3, 16.5 Hz), 3. 10 (dd, I H. J 8.4, 16.5 Hz), 2.76 (dd, 3H, J 2.5,4.4 Hz), 0.90 9M-1. IR 3314, 2959, 1736, 1652, 1598, 1560, 1550, 1409, 1166 cm'f 1 LSIMS: 553 (MH5'. Anal. Calculated for C 33

H

36

N

4 0 4 C, 70.56; H, 6.64; N, 9.98. Found: C, 70.70; H, 6.62; N, 9.78.

Example N-( 4 4 -D imethyl.2 -oxo- tetrahyd rofu ran-3 ridinA..

yI)pbenyll-1 H-pyrrol- 1-yljsuccinamic Acid

N

O N 0 According to the procedure described in Example N-(4,4-dimethyl-2-oxotetrahydrofuran-3(S)-yl)-3(R)-[3-4(pyridin4.yl)phenyl]- I H-pyrrol. I .yl]succinainic acid benzyl ester was hydrogenolyzed to obtain in 70%yield N-(4,4-diznethyl-2-oxotetrahydrofuran-3(Sy-yl).3 (R)-[3-(4.(pyridin.4-y)phenyll- I H-pyrrol. 1 -yl]succinaxnic acid as an amnorphous solid. I NMR (DMSO-d 6 6 12.60 (bs, I 8.82 I H, J 8. 8 Hz), 8.59 2H, J 5.9 Hz), 7.77 2H, J S.1I Hz), 7.71 2H, J 5.9 Hz), 7.64 2H, J 7.41 18), 6.92 18), 6.52 18), 5.16-5.11 (in, 1H), 4.75 18, J 8.8 Hz), 4.08, 4.00 (AB quartet, 28, J 8.3 Hz), 3.22 (dd, I H, J 9.2, 16.6 Hz), 2.93 (dd, IlH, J =5.9, 16.9 Hz), 1.05 3H), 0.96 3H). Anal. Calculated for C25H 25

N

3

O

5 0.2 VITBE 0 0.2 C, 66.62; H, 5.98; N, 8.97. Found: C, 66.55; H, 5.90; N, 8.98.

The starting material was available as follows: N-44Dmly--~ottavrfrn3S- -(-3f-nvii--l1hnlH-pvrrol- I -yilsuccinami cdBnv se

N

0ON 0

NH_>(

0-i- According to the procedure described in Example 1(1) for the preparation of 3(R)-t.

butoxycarbonylamino..N-( I(S)-benzyl-2-methoxy-ethyl)succinamic acid benzyl ester, 2(R)- [3-(4'-pyridin-4-yl). I H-pyi-role- I -ylsuccinic acid 2-benzyl ester hydrochloride and 3(R)amino- 4 ,4-dimethyl-2-oxo-tea-ahydrofuran (see Freskos, J. N. Syn. Commun. t994, 24, 557- 563) were coupled using BOP reagent to provide in 55% yield N-(4,4-dimethyl-2-oxo- :~jtetrahydrofuran-3(S)-yly..3(R)-[3.[ 4 -(pyridin-4-yl)phenyl]- I H-pyrrol- I -yl]succinamic acid benzyl ester as a white solid, mp I 75-7*C. 'HNMR: 68.64 2H, J =6.3 Hz), 7.64 2H, J 8.5 Hz), 7.59 2H, J 8.8 Hz), 7.53 2H, J =6.3 Hz), 7.32-7.26 (in, 5H), 7.13 (s, 1H), 6.83 IH,JI= 2.4 Hz), 6.61 (dd, 1H, J= 1.7,2.8Hz), 5.23 (dd, IH,JI= 5.9, 8.5 Hz), 5.13 2H), 4.59 I Hi J 8. 1 Hz), 4.01 2M), 3.50 (dd, I H, J 5.9, 16.9 Hz), 3.09 (dd, 11-~I,J1= 8.5, 16.9 Hz), 1.20 3H), 0.86 3H). Anal. Calculated for C 32 H 1 3 5

:C

71.49; H, 5.81; N, 7.82. Found: C, 71.57; H, 5.84; N, 7.77.

se..

Example N-( 8 -Oxo-4-oxa-1,7-diazatricyclo 19.6.1.0 J"octadeca-I 1(1 8),12, 14,16tetrae n- 9 3 rid in4-y )ph eny 11Hpyrlrol- y IIS UCCin m ic Acid

N

0 0 To a solution of N-(8-oxo-4-oxa- I ,7-diazatricyclo[9.6. 1. 1, 7 ]octadeca- 11 (1 12,14,1 6-tetraen-9(S)-y)-3(R)-[3-(4(pyridin.4.yl)phenyl3- I H--pyrrol- I -yllsuccinamic acid be~nzyl ester 185 mg, 0.280 mmol) in EtOAc/ EtOHfTHF was added in succession palladium on carbon (50 mg) and 88% formic acid 1 niL). After 1. 5 hours, HOAc (1 niL) 0was added. After 16 hours, more 10% palladium on carbon (25 mg), 8 8% formic acid 1 nL), and HOAc (1 mL) was added. At 24 hours, more 10% palladium on carbon (25 mg) was added. After 25 hours total elapsed time, the catalyst was filtered off. The filtrate was concentrated to a crude solid. The product dissolved in a minimal amount of MeOl-/EtOAc, and inorganic particulates were filtered away. The filtrate was concentrated to a solid that was tritmrmed with CH 2

CI

2 /hex to give 76 mg of N-(8-oxo-4-oxa- 1,7eta.

adiazatricyclo(9.6. 1.012. 17 ]octadeca- 11(18), 12,14,1 6-tetraen-9(S)-yl)-3(R)-[3-[4-(pyridin-4yl)phenyll-IH-pyrrol-1.yl]succinamic acid as a yellow solid, mp >172*C 1H NMR 5(CD 3 COOD): 6 8.91 2H-, J 6.6 Hz), 8.23 2H, J 6.6 Hz), 7.93 2H, J =8.5 Hz), 7.75 21H, J =8.5 Hz), 7.62 I H, J1 7.4 Hz), 7.40-7.33 (in, 2H), 7.17 I H, J 7.5 Hz), 7. 10 1H4, J 7.4 Hz), 7.04 I 6.93 I1H, J 2.6 Hz), 6.79 (bin. IH, partially exchanged), 6.5 8 I 5.3 4 IlH, J 7.5 Hz), 4.72 (dd, I H. J 4.6, 11.2 Hz), 4.3 5-4.3 0 (in, 1LH), 4.23-4.15 (mn, I 3.74-3.65 (mn, 2H), 3.56-3.42 (in, 2H), 3.31-3.00 (mn, 4H), 2.91 2.85 (rn, I 2.74-2.67 1H). Anal. Calculated for C 34

H

33 NS0 .0.4 H 2 0: C, 68.19; H, 5.69; N, 11. 70. Found: C, 6 8.13; H, 5. 77; N, 11. 81.

The starting material was available as follows: N-(8-Oxo-4-oxa- 1 .7-dia~ztricyclof 9.6. 1.0 12, 17 loctadeca- II(1I 8M. 2.14.1 6-tetraen-9(S)-yl).

3rR~r3-44pidi..4.yIphevl].Hpyrrol- -1l1succinamic cd B=I st ON N 0 y7>. NH~ N H 0 0. Z

N.

Acorin o hepocduedecrbd n xmpe N)o -2-dmty I() (mtycrany*rpl-()(tbtxcroyaiosciai aci .ezletr j3[*prdn--lpey] I.-yrl y~ucncaid4bn se yrclrd Accopredin toaepscdr described in Example S--uoyb fmior -(,-dieth- I(S-atricyclo-(9.6.l1.01' 17 J]-ocadeca- I 12,14,16&tetraen.8-one (see Castelbano, A. Liak, T. Home, Yuan, Krantz, A. Int. Patent AppI. W095/04735-A I, Feb. 16 1995) were coupled with TBTU to provide in 77% yield, after purification via column chromatography with 5% MeOH/EtOAc and trituation. with MTBE/hex, N-(8-oxo-4-oxa-1,7diazatricyclo[9.6. 1.0 12,1 'loctadeca- 11(1 12,14,1 6-tetraen-9(S)-yl)-3(R)-[3-(4-(pyridin-4yl)phenyl]-lH-pyrrol-1.yllsuccinamic benzyl ester as a pale yellow amorphous solid. 'H NMR: 6 8.91 2H, J 6.6 Hz), 8.23 2H, J 6.6 Hz), 7.93 2H, J 8.5 Hz), 7.74 (d, 2H, J 8.5 Hz), 7.59 IH, J 7.4 Hz), 7.37-7.25 (in, 7H), 7.17 I H, J =7.4 Hz), 7. 10 (t, I H, J =7.4 Hz), 7.03 I 6.90 I H, J 2.2 Hz), 7.79 (bd, I H, partially exchanged), 6.57 1H), 5.37 I H, J 7.5 Hz), 5.18 2H), 4.70 (dd, I H, J 5.0, 11.2 Hz), 4.35-4.30 (in, I1H), 4.23-4.15 (mn, I 3.70-3.65 (in, 2H), 3.56-3.43 (in, 2H), 3.31-3.15 (in, 3H), 3.02 (t, I H, J =12.7 Hz), 2.91-2.84 (mn, I 2.72-2.67 (in, IlH). Anal. Calculated for C 41

H

38 NS0 0. 5 H 2 0: C, 71.3 9; H, 5.70; N, 10. 15. Found: C, 71.47; H, 5.82; N, 10.26.

The following were available in a similar manner: Example N-[2,2-Dimethyl. 1(S)-(pyridin4-ylcarbamoy)propylJ-3()3 1 4- (pyridin-4-yl)pbcnylj-1 H-pyrrol-1-yl~succinamic Acid

N

HOK'k NH "NHJ) 0 According to the procedure described in Example N-[2,2-diinethyl-1I(S)- (pyridin-ylcarbamnoyl)propyl]-3(R)(3.(4..(pyridin4-yl)phenyJ 1 H-pyrrol- 1-yi]succinamic acid benzyl ester (185 mg, 0.280 inmol) was hydrogenolyzed in EtOH (10 mL) and HOAc (1 m.L) and funfished a solid that was triturated with EtOAc to give 60 mg (4 of N-[2,2dirnethyl- I (S)-prdn4ycraolpoy]3R-3(-prdn-lpeyl I H-pyrrol- I1 yl~succinamnic acid as a yellow solid. 'HNM(CD 3 OD): 68.54 2H. J =6.6 Hz), 8.33 (d, 2H, J =6.6 Hz), 7.73-7.68 41-),7.64-7.59(in, 7.32 6.91 (t,-14 J =2.4 Hz), 6.52 (dd, I1H, J 1.8, 2.9 Hz), 5.31 I H, J =7.5 Hz), 4.41 I 2.99 (dd, I H. J 6.8, 16.7 Hz), 1.03 9M). Anal. Calculated for C 30

H

3

IN

5 0 4 0.6 H 2 0 0 0.2 EtOAc: C, 66.77; H, 6.15; N, 12.64. Found: C, 66.72; H, 5.99; N, 12.62.

The starting material was available as follows: N4-22-Dimnethyl- I (S'1-(pvridin- 4 -vlcarbamovlprovl-3(RPF13f4( -di.4-v.pel ITHpvrrol- I-vllsuccinamic Acid Benzvl Ester

N

0 HNHL zI According to the procedure described in Example 1(b) for the preparation of N.(2,2dirnethyl- I (S)-(methylcarbamoyl)propyl)3(R)-tbuoxycarbonylminosuccinrnc acid benzyl ester, 2S-t-butoxycarbonylamino-3 ,3-dimethyl-N-(pyridin-4-yl)-butanamide (prepared as described in Example was deprotected with trifluoroacetic acid. The crude amnine salt and 2(R)-13-[4-(pyridin-4-yl)phenyl]- I H-pyrrol- I .yl)succinic acid 4-benzyl ester o hydrochloride (prepared as described in Example were coupled with TBTU to provide after purification via column chromatography with 5% MeOHICH 2 Cl 2 and trituration with MTBE/hex, in 76% yield N-[2,2-dirnethyl- I (S)-(pyridin-4-ylcarbamoyl)propyfl-3(R)-[3-[4- (pyridin-4-yl)phenyl]- IH-pyffol- I-yl]succinznic acid benzyl ester as a pale yellow amorphous solid, which was used without further purification. H NMR: 6 8.65 2H, J= 5.9 Hz), 8.4 3 2H, J 6.3 Hz), 8.26 I1-H), 7.64 2H, J 8.5 Hz), 7.5 8 2H, J Hz), 7.53 2H, J 6.3 Hz), 7.40 2H, J1 6.3 Hz), 7.32-7.24 (ni, 5H), 7.12 l11), 6.85 I1H, J=2.4 Hz), 6.64 (dd, I H, J 2.9 Hz), 6.23 1 H, J= 8.1-Hz), 5.19-5.08 (in, 3H-), 4.19 IH, J 8.1 Hz), 3.39 (dd, I H, J 5.2, 16.9 Hz), 3.23 (dd, I H, J 8.1, 17.3 Hz), 0.93 Anal. Calculated for C 37

H

37

N

5 0 4 e 0.9 H 2 0: C, 70.32; H, 6.19; N, 11.08. Found: C, 70.37; H, 6.11; N, 10.94.

Example N-[I ll-Imidazol-2.yi)-3-methy lbutyl 1-3(R)-[314(py rd n-4 yl)phenyl]-lH-pyrrol-1ylsuccinamic Acid Formate Salt

N

0 'NN 0 HO NHI"NH HO;sH 0 According to the procedure described in Example N-[1(S)-(IH-imidazol-2-yl)-3inethylbutyl]-3(R)-[3-4-(pyridin.4.yl)phenyl]- I H-pyrrol.. I -yI]succinamic acid beflzyl ester was hydrogenolyzed in EtOH:THF to yield in 81% yield N-[1(S)-(IH-iinidazol-2-yl)-3methylbutyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]- I H-pyrrol- I -yl]succinaniic acid formate salt as a yellow amorphous solid. I H NMR (DMSO-d 6 8 12.30 (bs, IH), 8.65 I1H, J 8.1 Hz), 8.59 (di, 2H, J1 4.4 Hz), 8.13 IH), 7.75 2H, J 8.5 Hz), 7.71 2H, J 4.4 Hz), 7.60 2H, J 8.5 Hz), 7.34 I1H), 6.91-6.83 (mn, 3 6.44 I1H), 5.08 IlH, J 7. Hz), 4.97 (dd, IlH, J 8.1, 16.2 Hz), 3. 10 (dci, I H, J 8.1, 16.6 Hz), 2.90 (cid, I H, J =7.2, 16.7 Hz), 1.68 2H, J 7.2 Hz), 1.52-1.45 (in, 1H), 0.86 3H, J1 7.0 Hz), 0.83 (di, 3H, J =6.6 Hz). Anal. Calculated for C 27

H

29

N

5 O3 0 HCO 2 H 0 0.5 EtOAc: C, 64.15; H, 6.28; N, 12.4 7. Found: C, 64.2 1, H, 6.40; N, 12.60.

The starting materials were made as follows: I 1 H-Imidazol-2.vlv-3-methvlbutl..3(R)-_3 -[4-(p~vridin-4-vflphenyll- I H-pvrrol. I yllsuccinamic Acid Reazl Ester

N

0 According to the procedure described in Example 1(b) for the preparation. of 3(R)-tbutyloxycarbonylamino-N-(2,2-dimethyl. I (S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2 -(l(S)-amino-3-rnethyl-butyl)-imidazole (See Chen, Zhang, Y.; Hammond, Dewdney, Ho, Browner, Casteihano, submitted for publication; and Abel-Meguid, Metcalf Caw, DeMarsh, Des Jarlais, Fisher, Green, et al. Biochemistry, 1994, 33, 11671-11677) and 2(R)-13-[4- (pyridin-4-yl)phenylj- I H-pyrrol- I -yl~succinic acid 4-benzyl ester hydrochloride (prepared as described in Example were coupled with TBTU. Flash column chromatography with 0- MeOIVH/C 2 C1 2 gradient eluant and recrystallizationfrom EtOAc gave in 41% yield N- I1 1 H-imidazol.2-yl)-3-mcthylbutyq.-3 R)-[3-(4-(pyridin-4-yl)phenyl]- 1 H-pyrrol- I1yl]succinaiuic acid bcnzyl ester as white crystals, mp 179-81 *C H NMR (DMSO-d 6 8 11.84 (bs, I1H), 8.68 1H, J 8.5 Hz), 8.59 2H, J 4.4 Hz), 7.76 2H, J =8.5 Hz), 7.71 2H, J1 6.3 Hz), 7.60 2H, J 8.5 Hz), 7.36 IH), 7.30 5N), 6.94-6.80 (in, 3H), 6.46 IN), 5.17 I H, J 7.5 Hz), 5.11, 5.05 (AB quartet, 2H, J 12.7 Hz), 4.97 (dd, I1H, J= 7.7, 15.4 Hz), 3.24 (dd, I H, J= 7.4, 12.9 Hz), 3.11 (dd, IlH,J 16.6 Hz), 1. 67 2H, J 7.7 Hz), 1.48-1.40 (in, INH), 0.85 3H, J 6.6 Hz), 0.8 1 3H1,J 6.6 Hz).

157 Anal. Calculated for C 34

H

35

N

5 0 3 C, 72.70; H, 6.28; N, 12.47. Foutnd: C, 72.43, H, 6.33; N, 12.34.

Example N-Methyl.3(R)-13-(4-(pyridin-yI)pheny]-lH..pyrrol..lyllsuccinamic Acid

N

0 According to the procedure described in Example N-methyl-3(R)-f3-[4-(pyridin- 4 -yl)phenyi]l- I -pyrrol- I-yllsuccinamic acid benzyl ester was hydrogenolyzed in acetic acid .to yield in 90% yield N-methyl-3(R)-[3-(4-(pyridin-4-yl)phenyl]- 1.H-pyrrol- 1 -yllsuccinamic acid as a yellow amorphous solid. HNMR (DMSO-d 6 8 8.58 2H, J=5.9 Hz), 7.75 (d, 2H-, J=8.1 Hz), 7.71 2H, J=6.2 Hz), 7.61 2H, J=8.4 Hz), 7.29 I 6.77 I H, J=2.2 Hz), 6.42 IHJ.=2.2 Hz), 4.80 IH, 1=10.7 Hz), 3.16 (dd, IH, 1= 15.8, 11.0 Hz), 2.36 (s, 3H). Anal. Calculated for.C 2 0 HjqN 3 0 3 1.0 H 2 0*0.33 AcOH: C, 64.08; H, 5.81; N, 10.85.

Found: C, 64.23, 64.16; H, 5.66, 5.67; N, 10. 83, 10.78.

The starting mater ials were made as follows: N-Methvl- 3 (lO-3-(344vridin..4-vbphenyl. I H-pvi-rol-.i -vi isuccinamic Acid 5enzvl1 Ester According to the procedure described in Example I1(b) for the preparation of 3(R)-tbutyloxycarbonylamnino-N-(2,2-dimethyl. 1(S)-(rnethylcarbarnoyl)propyl)succinarnic acid benzyL ester, 2(R)-13-[4-(.pyridin-4-yI)phenyl]- 1 H-pyrrol- I -yilsuccinic 4-benzyl ester hydrochloride (prepared as described in Example and excess 40% aqueousucous methylamine were coupled with TBTU. The solid that precipitated from the reaction mixture *was washed with water and, after drying, with ethyl acetate to give 5 1% of N-methyl-3' [3-(4-(pyridin-4-yl)phenyl]- 1 H-pyrrol- 1 -yI]succinamnic acid benzyl ester as a yellow solid: 1 HNMR (DMSO-d 6 88.5 8 2H, J=4.4 Hiz), 7.84 (hr s, IlH), 7.76-7.70 (in, 4H), 7.60 (d, 2H, J=8.5 Hz), 7.29-7.25 (in, 6H), 6.76 IH), 6.40 1W), 5.03 2H), 4.67 I H, J=6.2 3.20 (dcl, I H, J=l15.8, 6.2 Hz), 2.86 (dd, I H, J= 16.0, 8.6 Hz), 2.32 3 Anal.

Calculated for C 27

H

25

N

3

O

3 0 1.3 H 2 0: C, 70.05; H, 6.01; N, 9.08. Found: C, 69.98, 69.97; H, 5.98, 6.00; N, 9.01, 9.00.

Example N 1 -(l(S)Benzy-2.hydroryetbyl)-3(R)..(3-(biphenyl.4yl)1 H-pyrrol- 1yI)-N -_hydroxysuccinamide 0

N

HON NH ,OH To a solution of 1 (S)-beazyl-2-hydroxyethyl)-3 (R)-(3-(bipheny l 4 1 H-pyrroll-yl)succinamic acid (prepared as described in Example 61 mg, 0.130 mmol) in CHC1 3 (2 mnL) was added in succession NMM (44 p±L, 0.39 nunol), benzotriazole-l-yloxy-tris- IHpyrrolidino-phosphonium hexafluorophosphate (PyBOP, 203 mg, 0.390 rnmol), and hydroxylamine hydrochloride (27 mg, 0.390 mmol). After 20 hours at ambient temperature, :10% aqueous HCl (2 mL) and saturated aqueous NH 4 CI (10 mL) were added, and the resultant mixture extracted with CHC1 3 (15 mL) three times. The combined organic layers were washed with saturated aqueous NH 4 Cl (10 mL), dried over Na 2

SO

4 and evaporated to provide a yellow solid, which was purified via flash column chromatography with 1% MeOH/CHC1 3 as eluant. Subsequent radial chromatography with a 1% 2 01 2 stepwise gradient eluant and azeotropic removal of HOAc with n- *heptane gave 9 mg of N I-(I1(S)-benzyl-2-hydroxyethyl)-3(R)-(3-biphenyl-4-yl- IHpyrrol-1-yl)-N 4 -hydroxysuccinamide as a yellow solid. 'H NMR (CD 3 O) d69-6.79 (in, I1H), 6.5 8-6.76 (in, I 5.18-5.02 (mn, I 4.19-4.01 (in, IlH), 3.00-2.84 (in, I1H), 2.84-2.7 0 (mn, 3H). IR (CHC1 3 3244, 3018, 1659,1208, 1201 cm.

1 HRFABMS: -Calculated for 160

C

29 1- 3 0 N30 4 (M 483.2158. Found: 483.2139. Anal. Calculated for C 29

H

30

N

3 0 4 N~HOH 0 0.2 CHC1 3 0 0.25 1120: C, 64.35; H, 6.05; N, 10.28. Found: C, 64. 13; H, 5.69; N, 10.56.

The following was mnade in a similar manner.

E xample N (S)-Benzyl-2-methoxyetbyl)-3(R)- 13-(biphmnyl-4-yi)-l H-pyrrol-1 yl)-N 4 -hydroxysucciflamlde

HH

0 According to the procedure described in Example 8 N-(1(S)-benzyl-2methoxyethyl).3(R)-(3-biphaflyl- 4 Yvl 1 H-pyrrol.1 -yl)succinamic acid (prepared as described in Example and hydroxyLamine hydrochloride were coupled with BOP and triturated wich MTBE/CH 2

CI

2 /bex to give in 62% yield N'-(l(S)-Bezyl-2-methoxyethyl)3(R)[ 3 (biphenl14-yi)- IH-pyrol y1)WhydoxysIccnamide as a solid, mp 180-2 *C I H NMR (DMSO-d 6 a 8.80 lI M, 8.26 IH, J1 8.5 Hz), 7.65 -7.49 (mn, 6H1), 7.41 2H, J -7.4 lHz), 7. 31-7.12 (mn, 71-H), 6.73 (N 6.40 I ED. 5.06- 5.01 (mn, IH), 4.00-3.95 (in, I 3.19 2H, J 5.2 Hz), 3.14 2H1), 2.81-2.29 4H). Anal. Calculated for

C

30 11 3 1N 3 0 4 C, 72.41; H, 6.28; N, 8.44;'Found: C, 72.24; H. 6.29; N, 8.39.

Example N 4 _Hydroxy-N I-(9-oxo-1,8-diazatrcyco[O.6.1.0 13.18 Inonadeca.

0ON 0 HO 0- N HK- NH -INH 0 A mixture of N 1-benzyloxy-N 4 .(9-oxo-,8-diaza-ricyclo(1.6.O 31Inonadeca- 12(19), 13,15,1 7-tetraen-I1OS-yI)-3(R)- 1H-pyrrol-l -yl-succindianiide (180 mg, 0.324 mmol) and 10% Pci/C (40 mg) in TH-F (250 mL) with a minirnal amount of EtOH was stirred under

H

2 atmosphere. After 3.5 hours, the catalyst was filtered off and rinsed with THF and EtOH.

The filtrate was concentrated to about 40 mnL, whereupon product precipitated. Filtration provided N 4 -hydroxy-N 1 ,8-diaza-tricyclo[ 10.6.l1.013, 18 ]nonadeca- 12(19), 13,15,17-

V,*

tetaen-IOS-yl)-3(R)-1H-(pyrrol-1..yl)succinamide as a solid, rnp 158-65*C. FABMS: 466. 1

*(C

25

H

32

N

5 0 4 M H) Example 9. N 1 -[2,2-Daznethyl- 1(S)-(ydroxymethyl)propyl]-N 4 -hydroxy-2(R)-[3-(4- (pyridin-4-yI)phenyljlH-pyrrol-1-yljsuccinamide

NN

HONMJ

NH,SOH

0 To a solution of N 4 -t-butydiphenylsiloxy-N 1 -[2,2-Dimethyl-1I(S)- (hydroxymethyl)propyl]-2(R)-(3-[4-(pyridin-4yl)phenyl]- 1H-pyrrol- 1-yljsuccinamide (112 mg, 0. 160 mnmol) in THF (5 rnL) was added a solution of tetra- n-buty larnmoniuzn fluoride (0.20 rnL of I M in TI-F). After 1.25 hours at ambient temperature, the mixture was added dropwise to I M pH7 phosphate buffer (40 mL). The resultant precipitate was collected by filtration and washed with H 2 0. A solution in CH 2

CI

2 i'MeOH was passed through a 0.45 p syringe filter, and the filtrate was concentrated to give a solid which was triturated with EtOH to yield 30 mng of N -(2,2-Dimethyl- I(S)-(hydroxymethyl)propyl].N 4 _hydroxy-2(R)- [3)-[4-(pyridin-4-yl)phenyl]-IH-pyrrol-1-yl]succinamnide as an amorphous solid, which decomposed >200*C. 'H NMR (CD 3 COOD): 6 8.91 2H, J 6.6 Hz), 8.23 2H, J Hz), 7.93 2H, J =8.8 Hz), 7.76 2H, J 8.5 Hz), 7.42 I1-H), 6.95 I 6.60 (s, I 5.44 IlH, J 7.4 Hz), 3.92-3.88 (in, 2H), 3.63-3.55 (in, I1K), 3.21 (dd, I H, J 6.4, 14.5 Hz), 3.03 (dd, INH, J 8.1, 15.1 Hz), 0.93 9H). Anal: Calculated for C 2

SH

30

N

4 0 4 0.4 H 2 0: C, 66.08; H, 6.96; N, 11.95. Found: C, 65.92; H, 6.79; N, 11. 86.

*fee e *g.

The starting material was available as follows:

N

4 -t-butyldiphenvlsiloxuYN I- 2.2-Dimethvl- I (S)-(hydroxymethvIpropvll-2(R)-(3.[4- (ovridin-4-l'hheny11-I H-pvrrol- I -vl Isuccinanide

NN

Si-O.NH

>NH,-OH

0~ According to the procedure described in Example 1(b) for the preparation of 3(R)-tbutyloxycarbonylamino-N.(2,2-dimethyl- 1 (S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, N-(2,2-dimethyl-l (S)-hydroxymethyl-propyl)-3(R)-f3-[4-(pyridin-4-yl)phenyl]- S1H-pyrrol- I -yllsuccinamic acid (prepared as described in Example and tbutyldiphenylsiloxyamine were coupled with TBTU. Flash column chromatography with 0- MeOlLCH 2

CI

2 gradient eluant ftirnished in 43% yield 4 -t-butyldiphenylsiloxy-N Dimethyl-1(S)-(hydroxymethyl)propyl]-2(R)-[3-(4-(pyridin-4-yl)phenyl]-IH-pyrrol- yl]succinamide as an amorphous solid. 'H NMR (DMSO-d 6 8 10.73 1 8.59 2H, J 6.3 Hz), 7.85-7.70 (in, 5H), 7.65-7.56 6H), 7.45-7.34 6H), 7.29 1H), 6.79 (s, IH), 6.43 IH), 5.20-5.14 lH), 4.38-4.36 1H), 3.54-3.50 2H), 2.82-2.70 (m, 11), 0.99 9H), 0.84 9H). Anal: Calculated for C 4 1

H

48

N

4

O

4 S 0.4 120: C, 70.74; H, 7.07; N, 8.05. Found: C, 70.83; H, 7.04; N, 8.33.

Example 10(a). 2S-f IR-(1 (S)-Benzyl-2-hydroxyethycarbamoyl)-(3..bipheny,.-ylI 1Hpyrrol-l-Yl)-methyll-pentanoic Acid 0 N' HOKA O According to the procedure described in Example 2S-(IR-(1(S)-benzyl-2 hydroxyethylcarbamoyl)-(3-biphenyl4-yl.I H-pyrrol- 1-yl)-methyl]-pent-4.enoic acid benzyl ester (50 mg, 0.08 minol) was hydrogenolyzed in EtOAc: (1 mnL) and MeOH (I mL). Radial chromatographic purification with 1% HOAc/ 1-2% MeOHY CH2,C1 2 gradient eluant provided 24 mg of 2S-[ IR-( I(S)-benzyl-2-hydroxyethylcarbamoyl).(3 -biphenyl-4-yl- iH-pyrrol- *,Pool-yl)-methyl]-pentanoic acid as a slightly pink powder, mp 179-81 -C NMR: a 7.64- 7 .54s 5H) 7.47-7.42 (mn, 2H), 7.670 m, 6 b, ff, .5 I H) 4.5 IH, J 8.4 Hz), 4.27-4.10 (bin, lH), 3.74-3.61 (bin, IH), 3.50-3.39 (bin, 2H), 2.83 (dd, IH, J 6.2, 13.4 Hz), 2.70 (dd, IlH, J 8.7, 13.4 Hz), 1.69-1.52 (bin, 1H), 0.87 3H, J 7.1 Hz).

HR.LSIMS: Calculated. for C 33

H

34

N

2

O

4 CS (M +CS 643.1573. Found: 643.1594. Anal.

Calc'd for C 32

H

34

N

2 0 4 0.5H 2 0:C, 73.96; H, 6.79; N, 5.39. Found: C, 74.02; H, 6.79; N, 5.41.

The starting materials were made as follows: Diallyl D-Aprtate p-Toluenesulfonate Salt o NH* -OTs 0 A mixture of D-aspartic acid (4.00g, 30.1 mniol), allyl alcohol (12.4 mL, 181 mmol), p-toluenesufonic acid hydrate (7.15g, 3 7.6 mniol) and benzene (3 5 mL) was refluxed with removal of water via Dean-Stark trap. After 4 hours, the resultant yellow solution was allowed to cool and then concentrated in vacua to a yellow solid, which was dissolved in a minimal amount of hot MeQH 15 rnL). The solution was diluted with Et 2 O (200mL), and upon gradual addition of hexanes (-100 mL), pale yellow crystals were obtained. Filtration gave 10.00 g (86% yield) of diallyl D-aspartate p-toluenesulfonate salt as analytically pure crystals, mp 60-61 I'H NMR: a 8.40-8.10 (bin, 3H), 7.72 2H, J 8.1 Hz), 7.12 (d, 2H, J 8. 1 Hz), 5.76 (dddd, 2H-, J 2.5, 2.5, 8.7, 13.1 Hz), 5.23 (ddd, 2H, J 2.8, 8.7, 13.1 Hz), 5. 18 (dd, 2H1, J 2.8, 13.1 Hz), 4.58 (ddd, lI-H, J 13.1, 13.1 Hz), 4.49 (dd, 211, J= vo a* 1.6, 4.4 Hz), 3. 15 (ddd, 2H, J 5.0, 18.1, 18.1 Hz), 3.09 (ddd, 2H, J 5.2, 18.1, 18.1 Hz), Le ~2.17 (s,311). IR (KBr): 3436, 2923, 1734, 1215,1126, 1035, 1011, 685, 569 cm- Anal.

Calculated for C 17 H23NO 7 S 0.5 H 2 0: C, 51.76; H, 6.13; N, 3.55; S, 8.13. Found: C, 1.6 1; H, 6.06; N, 3 60; S, 8.04.

DialivI N-t-Butoxycarbonyl-D-Asqartae 0 0 To a solution of diallyl D-aspartate p-toluenesulfonate salt (5.00 g, 13.0 inmol) in

CH

2

CI

2 (50 rnL) was added mrethylamine (1.99 mL, 14.3 inmol) and di-t-butyl dicarbonate (3.12 g, 14.3 mniol). After 20 hours at amnbient temperature, the resultant-Mixture was stirred with 10% aqueous HCI (5 rnL) and H 2 0 (25 mL). The organic layer was separated, washed with saturated aqueous N&HCO 3 :H4 2 0 (2 x 25:25 mL), dried over Na 2

SO

4 and evaporated to give a yellow oil, which was fractionally distilled under vacuum to remove t-BuOH as a forefraction and gave 3.33g of diallyl D-N-t-butoxycarbonyl-aspartate as a colorless oil, bp 160-170'C (I nun Hg). H1- NMR: 8 5.90 (dddd, 2H, J 4.7, 10.5, 10.6, 17.1 Hz), 5.51 (bd, I H, J 8.7 Hz), 5. 31 (dddd, 2H, J 1.6, 5.9, 17.1 Hz), 5.24, (dd, 2H, J 1.3, 10.3 Hz), 4.68-4.5 5 (in, 5 3.05 (dd, IlH, J 17.1 Hz), 2.87 (dd, I1H, J 4.7, 17. 1 Hz), 1.45 9H). IR: 1736, 1719,1501. 1368, 1166 cm'. Anal. Calculated for C I H 23 N0 6

C,

57.50; H, 7.40; N, 4.47. Found: C, 57.35; H, 7.39; N, 4.44.

a-Allyl 3 (R)t-A Ill-N-t-butoxycarbonyl-D-aspartate 0 4. 0 060 in TH)dows i*diin unloe 0mnts Atr3 iue t.8 trmtyslyc*rd unloe teprtore a solution fdas Ntenhetedatbny5-5a*C.rAfte (15.00r, 47. miour inaTs (300we mLt colad8eH 5CL was added, awouinofltihexaetho yllawzsuden.0iof resulte the slant gold seoluieaprtion was aloeowredce slwlroerssur to ambient yellow solid, which was stirred with 10% aqueous KH1-S0 4 (100 H 2 0 (100 mIL), and extracted with CHCI 3 (100 ml,) three times. The combined organic layers were washed with saturated aqueous NH 4

CI:H

2 0 (100: 100 dried over Na 2

SO

4 and evaporated to give 16.2 g of brown oil, which was purified via flash column chromatography with silica gel.

Elution with I1% HOAc/3%N MeOH/CH 2 C1 2 provided 14.94 g (100%) of an (80:20) mixture of epirners by NMR of a-allyl 3(R)-allyl-N-t-butoxycarbonyl-D-aspartate as a light brown oil. This material was routinely used without further purification. I NMR: a 9.00-8.24 (bs, 111), 5.99-5.72 (mn, 2H), 5.53-5.08 (in, 4H), 4.71-4.55 (in, 2H), 3.25 (ddd, 0.2H, minor isomer, J 3.4, 6.2, 7.5 Hz), 2.97 (ddd, 0.8H, major isomer, J 4.7, 7.2, 11.8 Hz), 2.68-2.51 (in, if1), 2.47-2.30 (in, 1.42 9H). IR: 3330, 3082, 2980, 1737, 1715, 1369, 1251, 1163 cm' 1 Anal. Calculated for C, 5

H

2 3NO 6 0.15 H 2 0: C, 57.00; H, 7.43; N, 4.43.

~Found: C, 56.94; H, 7.45; N, 4.3 1.

a-Allyl. D-Renzl 3(R)-Allyl-t-butoxycarbonvl-D-aspartate w 0* To a solution of a-ally[ 3(R)-a~lyl-N-t-butoxycarbonyl-D-aspartate (213 mng, 0.681 rmnol) in CC 3 (2 mL) was added O-bcnzyl-NN'-diisopropyiisourea (see Mathias, L.J.

Synthesis 1979, 561-576, 165 IiL, 1.02 inmol). The resultant solution was heated at reflux .see.

for 5.5 hours, allowed to cool, filtered to remove urea byproduct, and evaporated to funish a suspension, which was purified by passage through a pad of silica gel withe'O% EtOAc/hex as eluant to provide 270 mg (100%) of a-allyl, P-benzyl 3(R)-allyl-t-butoxycarbonyl-Daspartate as a colorless oil. I NMR: a37.3 6 (bs, 5 5.86 (ddt, I H, J 5.9, 10.6, 16.2 Hz), 5.76 (ddt, I H, 6.9, 10.0, 17.1 Hz), 5.30 (ddd, I H, J 2.8, 17.1 Hz), 5.3 1 (bs, I 5.24 (ddd, IlH, J 0.9, 1.2, 10.4 Hz), 5.11 2H), 5.07 (quintet, I H, J 1.6 Hz), 5.04 (bs, I H), 4.66 (dd, I1H, J 4.9, 8.9 Hz), 4.5 7 2H, J 5.6 Hz), 3.00 (bq, I1H, J 7.5 Hz), 2.59 (ddd, I H, J 7.5, 8.1, 14.6 Hz), 2.37 (ddd, I1H, J 6.9, 13.7, 14.0 Hz), 1.43 9H). IR: 3374, 2979, 1730, 1504, 1368, 1163, 989 cm'. Anal. Calculated for C 22

H

29 N0 6 C, 65.49; H, 7.24; N, 3.47. Found: C, 65.46; H, 7.25; N, 3.45.

fl-Benzvl 3(R)-All-N-t-butoxycarbonylD-aspartte 0 X MN0< a a As in Example a-allyl, P-benzyl 3(R)-allyl-t-butoxycarbonyl-D-.aspartate (216 mg, 0.535 mmol) was deprotected. Flash column chromatography with 1% EtOAc/hex as eluant provided 154 mg of j3-benzyl 3(R}-ally-N-t-butoxycarbonyl-Daspartate as a yellow oil. 'H NIM (CDC1 3 8 7.40-7.20 (in, 5H), 6.75 (bs, I 5.68 (dddd, IH, J=7.2, 10.0, 10.0, 16.5 Hz), 5.98 I1H, J=9.7 Hz), 5.18-4.95 (mn, 211), 4.47 (dd, I1H, J 3.4, 10.0 Hz), 3.15 (ddd, I H, J 3.4, 5.9, 8.4 Hz) 2.45 (ddd, I1H, J 6.3, 7.1, 13.5 Hz), 2.26 (ddd, I H, J 7.8, 8.7, 13.5 Hz), 1.3 8 914). IR: 3425, 2978, 1722, 1499, 1164 cmV'; Anal.

Calcd for C 1 9

H

25

NO

6 0. 15 C 6 C, 63.5 1; H, 7.26; N, 3.72. Found: C, 63.50; H, 693; N, 3.44.

2S- I 1 (SY-Benzvl-2-hvdroxvethvlcarbamov I -(t-butoxvcarbonylamino)methll-pent-4enoic Acid BenzYl Ester 0

HNXOI<

0 T>H--OH According to the procedure described in Example 1(a) for the preparation of N-(1 (Sibenzyl-2-hydroxyethyl)-3(R)-t-butoxycarbonyl-amino-succinanic acid benzyl ester, P-benzyl 3(R)-allyl-N-t-butoxycarbonyl-D-aspartate was coupled with EDC to 2S-amino-3-pheny-l1propanol to give 2.30 g of 2S-[IR-(1(S)-benzyl-2-hydroxyethylcarbamoyl)-1-(tbutoxycarbonylamino)methyl]-pent-4-enoic acid benzyl ester as white solid. I NMR: a a 7.31 (in, 5H), 7.20 6.59 1H, J 8. 1 Hz), 5.78 1H, J 9.0 Hz), 5.71 (ddd, IH, J 6.9, 9.7, 16.5 Hz), 5.09 4H), 4.31 (dd, 1 H, J 4.2, 9.0 Hz), 4. 10 IH), 3.63 IH, J 11.8 Hz), 3.48 lH, J 11.8 Hz), 3.28 (dd, lH, J 7.8, 10.9 Hz), 2.83 (ddd, 2H, J 7.3, 13.9, 21.6 Hz), 2.46 IH), 2.39 (ddd, 1H, J 6.5, 6.9, 13.7 Hz), 2.20 (ddd, IH, J 7.8, 8.1, 15.0 Hz), 1.44 9H). IR (KBr): 3319, 1735, 1686, 1654, 1560, 1542, 1522, 1297 cm'.

HRLSIMS: Calculated for C 2 8H 36

N

2

O

6 Cs (M +Cs ):.629.1628. Found: 629.1603. Anal.

Calculated for C 28

H

3 fN 2 0 6 C, 67.71; H, 7.32; N, 5.64. Found: C, 67.68; H, 7.37; N, 5.64.

2S-r I R-(I (S')-Ben vl.

2 Lydroxvethylcarbamovh..(3bhipheny4vl I H-pyr-rol- I -Xfl-methvllp2ent-4-enoic-Acid Benzyl Ester 0D 0 k

OH

K

0 According to the procedure described in Example I1(a) for the preparation of 1(Sybenzyl-2-hydroxyethyl)-3 (R)-(3-biphenyl-4-yl- IH-pyrrol- I -yl)succinamic acid benzyl ester, 2S-[ I1 I (S)-benzyl-2-hydroxyethylcarbamoyl) 1 -(t-butoxycarbonylarnino)methyl]-pent-4enoic acid benzyl ester was deprotected and the crude amine salt condensed with 3-biphenyl- 4 -yl-2,5.-dimethoxy-tetrahydrofiuran in HOAc. Radial chromatography with 1% ~MeOH/CH 2 C1 2 as eluant provided 77 mg of 2S-[ IR-(1 (S)-benzyl.2hydroxyethylcarbamoyl)-(3-biphenyl-4-ylIIH-pyrrol- I-yl)-methyl]-pent-4-enoic acid benzy I 00 "Ow'Oester, mp 166-7"C. IH NMR: a 7.68-6.97 (in, 20H), 6.69 (dd, IH, J 2.5, 2.8 Hz), 6.53 (dd, I H, I 1.6, 2.8 Hz), 5.79 I H, J 7.5 Hz), 5.69 (dddd, 1IH, J 6.5, 8.2, 10.0, 16.9 Hz), 0 ~5.15-4.94 (in, 4H), 4.57 1H, J 7.2 Hz), 4.28-4.19 (bin, 3.73-3.63 (bin, 2H), 3.50 (ddd, 1H, J 5.3, 11.5 Hz), 2.81 (dd, 1H, J 6.2, 13.8 Hz), 2.68 (dd, 1H, J 8.2, 13.8 Hz), 2.59-2.44 (mn, 2H), 2. 10 (ddd, I H, J 7.1, 7.1, 14.3 Hz). HRLSIMS: Calculated for

*C

39

H

38

N

2

O

4 CS (M ±Cs+ 731.1886. Found: 731.1853. Anal. Calculated for C 39 140N 2 0 4 C, 78.29; H, 6.42; N, 4.68. Found: C, 78.17, H, 6.43; N, 4.63.

The following compounds were made in a similar manner: Example 10(b). 2(RS)-(1 R-f 1(S)-Benzyl-2-hy droxyethylcarbamoyl-( 3 4 'cyaflobipbenyl-4-yI)-1 H-pyrrol-l .yi1-Iethy)-pelt1oic Acid

CN

ON

According to the procedure described in Example I1(a), 2(RS)-{f1IR-[ I(S)-benzyl-2hydTOXyethYlcabamoylV{[3 -(4'-cyano-biphenyl-4-yl)- 1 H-pyrrol- I -yl]-methyl I -pent.4-enoic acid benzyl ester was hydrogenated in EtOAc and MeGH-. Flash column chrmatography with IO/ HOAc/ 1%1 MeOI-tCH 2

CI-

2 as eluant gave 29 mg of 2(RS)

I-

2-hydroxythylcarbaloyl]-3-(4'-cyalo-biphenlyl-4-yI)- 1H-pyrrol- I -y1-methyl -pentanoic acid as a yellow powder. 1 H NM.IR: 8 7.72 4H). 7.60 7.21-6.99 (bin, 6H), 6.70 (s, 111), 6.58 I 4.70 0.67H{, major isomer, J3 10.3 Hz); 4.62 0.33H, minor isomer, J Hz), 4.19 (bs, 0.33H, minor isomer), 4.02 (bs, 0.67H, major isomer), 3.25-3.14 (bin, IH),2.78(d,2H,J=7.OHz). IR(K~r):3334,2226, 1652, 1604, 1558, 1496.1200,824cm' .HRFABMS: Calculated for C 33

H-

34

N

3 0 4 (M 536.2549. found: 536.2555; Anial.

Calculated for C 3 3

H

3 3

N

3 0 4 a 0.8 FIQAc: C, 71-20, H, 6.25; N 7.20. Found: C, 71.21; H.

6.49; N, 7.25.

The starting material was available as follows: 2(RS)-r I I 3ezI2(yrxetv~abmyl 1 3 -(4-cyanobiphenvL...VI). 1 H- D V I r o l- I v l e t h l e n 4 e o i A cdAn v s e

CN

0 N According to the procedure described in Example 1(c) for the preparation of N-(8oxo-4-oxa- 1,7-diaza-tricyclo[9.6. 1 .0 12.17 ]octadeca- 11(18), 12,14,1 6-tetraen-9S-yl)-3(R)-(3phenyl-lI-1-pyrrol-lI-yi)succinamic acid benzyl ester, P-benzyl 3(R)-allyl-N-tbutoxycarbonyt-D-aspartate was deprotected. The corresponding amine salt and **wo dimethoxy-tetrahydrofuran-3-yi)-biphenyI-4-cabontfjle were condensed in 1,2dichloroethane with trifluoroacetic acid under anhydrous conditions and purified via radial chromatography with 0-20-30-40% EtOAc/hex stepwise gradient to give 168 mg (5 of 1(R)-fl (S)-Benzyl-2-(hydroxyethyl)carbamoy)- I -(3-(4'-cyanobiphenyl-4-yl)-

IH-

pyrrol-1I-yljinethyl]pent-4-enoic acid benzyl ester as a gold powder, nip 84 0 C, which was used without further purification. I'H NMR: 6 7.72 2H, J 3.1 Hz), 7.64-7.50 (mn, 3H), 7.4 1-6.96 (mn, 4H), 6.72 0.33H, minor. isomer, J 2.5 Hz), 6.68 0.67H, major isomer, J 2.5 Hz), 6.57 (dd, 0.67H, major isomer, J 1.8, 2.8 Hz), 6.52 (dd, 0.33H, minor isomer,J 1.6, 2.8 Hz), 5.83 18H, J 7.8 Hz), 5.62 (dddd, I1H, J 7.8, 10.3, 16.8 Hz), 5.18 (d, 28, J 1.2 Hz), 4.73 0-67H, major isomer, J 10.6 Hz), 4.57 0.33H, minor isomer, J =7.8 Hz), 4.15 (bin, lH), 3.99 (dddd, I H, J 5.0, 7.5, 7.5, 10.9 Hz), 3.75-3.48 (in, 28), 3.38 (dddd, IlH, J 5.3, 5.3, 5.3, 7.8 Hz), 2.93-2.64 2H). IR: 3406, 2226, 1731, 1660, 1605 cm" HRFABMS: Calculated for C 40

H

37

N

3 01 (M -H 4 624.2862. Found: 624.2875.

Anal. Calculated for C 40

H

37

N

3 0 4 a 0.25 EtOAc 0 0.5 H-20: C, 75.2 1; H, 6.16-; N, 6.42.

Found: C, 75.29; H, 5.97; N, 6.42.

Example 10(c). 2S-( lR-( 3 4 '-Cyanobiphenyl4y)-Hpyrro.1yi).1.(2,2dimethyl.

Il(S)-(hyd roxy methyl)p ropy lcarba moy I).met hylj-penta no ic Acid

CN

MNN

04- NH H0K.

2

NHOH

According to the procedure described in Example 2S-(lR.(3-(4'-cyanobiphenyl-4-yi)- IH-pyn-ol-1I-yl)-N-(2,2-dimethyl. 1(S)-hydroxymethylpropyl-carbaxnoyl)- ZZ methyl)]-pentanoic acid benzyi ester was debenzylated in MeOH: EtOAc after 1 8h to provide 30 mg of 2S-[ IR-(3-(4'-cyanobiphenyl-4-yl)- 1H-pyrrol- l-yl)-l -(2,2-dimethyl- 1 (S)-(hydroxymethyl)propylcarbanioyl)methyl)]-pernanoic acid as a white solid, mp 130- 2 1 H NMR: a 7.70 (mn, 7.60 (mn, 4H), 7. 15 I1H), 6.85 IlH), 6.75 I 5 .72 I1H, J 8. 7 Hz), 4.86 I H, .J =9.7 Hz), 3.90-3.82 (in, 21-H), 3.45-3.3 8 (mn, 1iH), 3.3 0-3.20 (mn, INH), 1.45- 1. 10 4H), 0.95 3H), 0.90 9M). IR (KBr): 3406, 2962, 2227, 1719, 1664, 1604, 1560, 1497, 13 67, 1200 cm'. FABMS: 502 (M Anal. Calculated for

C

3 0 H 5 3 0 4 0. 15 CHCI 3 C, 69.70; H, 6.82; N, 8.09. Found: C, 69.7 1;H,68;N8.1 The starting material was rnmished as follows: 2S-r I R-(t-Butoxycarbonvlarnino-(2.2..dimethvl.. I (bv~droxymethvflpropvlcarharmovflmethyl J-pent-4-enoic Acid Benzvl Es-ter HNX 0

NH~O

Following the procedure described in Example I(f) for the preparation of N-(l benzyl-2-methoxyethyl).3 (R)-t-butoxycarbony lamino-succinamic acid benzyl ester, 1-benzyl .3(R)-allyl-N-t-butoxycarbonyl-D-aspartate(154 mg, 0.424 mmnol) was coupled wih BOP to L-t-leucinol (55 mg, 0.466 mmol). Flash column chromatography with 5% MeOEVLCH 2

CI

2 as eluant provided 176 mg (90% yield) of 2S-f IR-(t-butoxycarbonylamino.-(2,2-dimethyl.

I (S)-(hydroxymethyl)propylcarbamoyl)-methyl]..pent.4.enoic acid benzyl ester as waxy plates, mp 75-7*C. 'H NMR: 8 7.43.7.20(bs, 5H), 6.38 11-, J =9.7 Hz), 5.73 (dddd, IH, J 7.2, 10.0, 10.3, 16.8 Hz), 5.60 (bin, I 5.20-4.95 (in, 4H), 4.40 (dd, I1H, J 7.2, 8.4 Hz), 3.78 (ddd, 2H, I 3 9.3, 9.3 Hz), 3.50 (ddd, I H, J 0.9, 8.7, 11.2 Hz), 2.98 INH, J Hz), 2.55 (ddd, 2H, J 7.2, 14.6, 14.6 Hz), 2.48 (ddd, 2H, J 7.2, 14.6, 14.6 Hz), 2.18 (bs, INH), 1.42 9H), 0.95 9H); IR (KBr): 3363, 2996, 1734, 1708, 1654, 1508, 1367, I .8.N .6 1253, 1173, 105 5 cm' 1 Anal. Calculated for C 25

H

3

SN

2 0 6 C, 64.9 1; ,88N60.

Found: C, 65.02; H, 8.33; N, 6.11.

2S-t(1R-[3-(4. Cvanobiphenyl,4-vfl- I H-pyrrol- I _yll-(2.2-dlimethyl- 1 (hydroxymethvl')propvl-carbainofl)-methv I l-rpnt-4-enoic Acid Ben=zv Ester

CN

0 N

ONH

N0~.O According to the procedure described in Example 4(a) for the preparation of N-(l benzyl-2-hydroxyethyl)-3 (R)-[3-(4'cyano-biphenyi-4-yl)- IH-pyrrol- 1-yI]succinamic acid benzyl ester, 2S-[ I R-(t-butoxycarbonylamino-(2,2-dimethyl- I (S)-hydroxymethylpropylcarbamoyl)-rnethyl].pent-4-enoic acid benzyl ester was deprotected. The corresponding crude amnine salt and 4'-(2,S-dimethoxy-tetrahydro-furan-3-yl)biphenyl-4carbonitrile were condensed in 1 ,2-dichloroethane. Flash column chromatography with 1% HOAc/ 20% EtOAc/ hex as eluant afforded 160 mg of 2S.{ I R-[3-(4'-cyanobiphenyl- 4 -yl)-1I H-pyrroi- 1 -yl]-(2,2-dimethyl- I (S)-(hydroxymethyl)propyl-carbamoyl)-methyl -pent- 4-enoic acid benzyl ester as a yellow foamn, rnp 74-6 I H NMR: 6 7.70 4H), 7.50 (s, 4H), 7.20 5H1), 7.05 11H), 6.80 I1H), 6.60 1I1), 5.60 1 H, J 8. 1 Hz), 5.20 (d.

2H, J 4.0 Hz), 5.05-4.82 (in, 3H), 3.86-3.68 (mn, 211), 3.30-3. 10 (mn, 211), 2.30-2.20 I H), 1.70-1.50 (in, 211, 0.90 9H1). IR (KBr): 3358, 3067, 2962,"2226, 1732, 1682, 1604, 1557, 1496, 1360 cm'K Anal. Calculated for C 37 11 39

N

3 0 4 0.35 CHC1 3 C, 70.69; H, 6.25; N, 6.62. Found: C, 70.8 1; H, 6.20; N, 6.70.

Example 11. 2S-( lR-(3-(Bipbenyl.4-yl)- lH-pyrrol-1-yI)-I-(1(S)-hydroxymethyl2,2.

dimethyI-propylcarbamoyl)-methylI1.Shydroxypentanoic acid 0 N' H04O---NHOH

HO~

A suspension of palladium (11) hydroxide (20% Pd content on carbon, 30 mg) and 2S- [1 R-(3 .(biphenyl-4-yl)- 1 H-pyrrol- 1-yl)- 1 (S)-hydroxymethyl.2,2-dimethylacid benzyl ester (120 mg, 0. 141 mmol) in MeOH (20 niL) was stirred in an H 2 atmosphere for 2 hours. The catalyst was filtered onto P Ov Celite and rinsed with MeOH (20 mnL). The filtrate was concentrated to afford 70 mg (100%) of 2S-[ 1R-(3-(biphenyl-4-yl)- IH-pyrrol- 1 yl)- 1-(1 (S)-hydroxymethyl-2,2-dimethyl- I V..

acid as white crystals. IH NMR (CD 3

OD):

a 7.70-7.55 (in, 6H), 7.43 2H, J 7.4 Hz), 7.38-7.27 (in, 2H), 6.93 (dd, 1H, J 2.2, 2.2 Hz), 6.5 3 (bin, IlH), 3.80-3.77 (in, 3H), 2.7 5-1.23 (in, 4H), 0.97 9H). IR (KBr): 3406, 2958, 1719, 1656, 1200, 763 cm. FABMS: 493 (MI 515 (MH Anal.

Calculated for C 29

H

36

N

2 0 5 a 0.2 CHCI 3 C, 67.90; H, 7.06; N, 5.42. Found: C, 67.85; H, 7.11; N, 5.41.

The starting materials were made as follows: 2 S-[I R-t.ButOxvcarbony lam inp..(2 -2 -di methvl II ('-hvd vechvI-nrnpvlcrbamv1 methyll-5-hvydrox-pen-4-enoic Acid Benivi Ester 0

HOA

To a solution of BH 3 *THF (6.93 mL of 1 M in THF) at 0 0 C was added cyclohexene (1 .40 niL, 13.9 mmol) dropwise via syringe. After 5 minutes, the white suspension was diluted with dry THE (5 After 15 minutes at 0 0 C, the dicyclohexylborane suspension was cautiously added via cannula to a solution of 2S-[ I R-t-butoxycarbonylamino.(2,2.

*dirnethyl- l)-hydroxymethyl-propyl-carbamoyi)-methyJ.pent-4-enoicacdbnyesr (1 .07 g, 2.31 mmol) in dry TI-F (10 mL) at 0 0 *C and vigorous gas evolution was observed.

After 10 minutes at 0 0 C, the resultant suspension was allowed to warm to ambient temperature. After 90 minutes, the mixture was treated in succession with p1-7 phosphate buffer (50 mL), EtOH (20 mL), and 30% aqueous H-202 (10 mL), and then allowed to stir overnight. After 20 hours at ambient temperature,- the mnixtur-e was cooled to 0 0 C and stirred with fresh I100/ aqueous Na 2

S

2

O

3 (100 rnL). The mixture was allowed to warm to ambient temperature and extracted with CHC1 3 (75 mL) three time. The combined organic layers were stire with p-TsH* H0 0 0 Mg for 15minutes, te ahdwt auae aqueous NaHC0 3

H

2 0 (100: 100 mL), dried over Na 2 SO0 4 and evaporated to give 1. 96 g o f yellow oil, which was purified via flash column chromatography with 5% MeOI-1CHCI 3 as eluant to afford 500 mg of 2 S IlR-t-butoxycarbonylamino>(2,-dimethyl

I(S)-

178 hydroxymethyl-propylcarbanoyl)methyl]..Shydroxypent.4enoic acid benzyl ester as a white foam. 1H NMR: a 7.45-7.20 (bs, 5H), 6.56(d, IH, J 9.7 Hz), 5.87(d, IH, J 7.8 Hz), 5.23-5.05 2H), 4.56 (dd, IH, J 5.9, 8.4 Hz), 3.82 (ddd, 2H, J 3.4, 9.3, 11.8 Hz), 3.70-3.39 4H), 3.06 (ddd, IH, J 5.9, 10.3, 10.3 Hz), 1.90-1.38 4H), 0.98 9H), 0.95 9H). IR: 3342, 2955, 1718, 1696, 1682, 1661, 1522,1367, 1249, 1166 cmn. Anal.

Calculated for C 25

H

40 N,0 7 9 0.4 CHCI 3 C, 57.74; H, 7.71; N, 5.30. Found: C, 57.74; H, 7.85; N, 5.42.

5-Benzloxvcarboxy-2S-[ I R-t-butoxvcarbonviami no-(2 1-dimethyl- I (S)-hvdroxvmethvlpropvl-carbaovl)-methvll-pentanic Acid Benzvl Ester HNZ 0 s o 00 N H OH W* U0 According to the procedure described in Example 5(a) for the preparation of carbonic acid 1 (S)-benzyloxycarbonyloxymethyl-2,2-dimethyl-propyl)..3(R)-(tbutoxycarbonylamino)succinamic acid benzyl ester, 2S4 IR-t-butoxycarbonylamino-(2,2dimethyl- 1 (S)-(hydroxymethyl)propylcarbamoyl)methyl]S.hydroxy-pent4.enoic acid benzyl ester was initially acylated with benzyl chioroformate to give a yellow oil, which was purified via flash column chromatography with 4% MeOl/CHCI 3 as eluant to furnish 172 mg of 5-benzyloxycarboxy-2S-1 R-t-butoxycarbonylamino-(2,2-dimethyl-

I(S)-

(hydroxymthyl)propylcarbamoyl )methyl]pentanoic acid benzyl ester as a colorless oil and 67 mg of S-benzyloxycarboxy-2S-f( (S)-benzyloxycarboxymethyl.2,2-dimethyl- 179 propylcarbanoyl)-tbutoxycarbonyl-amino-methy1]-pentoic acid benzyl ester. 'H NMR: 7.45-7.20 10H), 6.38 IH, J 9.7 Hz), 5.48-5.32 (bi, IH), 5.23-5.05 4H), 4.45- 4.30 IIH), 4.20-3.95 2H), 3.80-3.72 2H), 3.5 5-3.40 1H), 3.00-2.89 I H), 2.08-1.55 4H), 1.42 9H), 0.95 914). IR (KBr): 3322, 2964, 1741, 1664, 1264, 1169 cm FABMS: (M 747.

5-Benzloxvcarboxv-2S-(( I (S')-benzvioxvcarboxvmethv -2.2 -dimethvyl DrovIcarbmov)-tbutoxvcarbonvlamino-methvll-pentanoic Acid Benzvl Ester 0

HNO

0 NH--OAO 0 J. 0 To a solution of 5-benzyoxycarboxy-2S-[ R--butoxycarbonylarino-(2,2-dimethyl- I (S)-hydroxymethyl-propylcarbamoyi)methyltni acid benyl ester (170 mg, 0.277 mmol) in CHC13 (3 mL) was added DMAY (68 mg, 0.692 mmol) and benzyloxychlofonate (100 pL, 0.692 nunol). After 2.5 hours, the mixture was stirred with 10% KHS04 (15 mL) and extracted with CHC13 0 0 mL two times). The CHC13 layers were washed with 10% aqueous KHS04 (10 md,) and saturated aqueous NaHC0:H20 (10: 10 mL), dried over Na2S04, and evaporated to provide a yellow oil, which was purified via flash column chromatography with 10-20-30% EtOAc/hex stepwise gradient. In this fashion, 135 mg of 5-benzyloxycarboxy-2S-[( 1(S)benzyloxycarboymethyl-2,2dimethyl-propylcarbamoy)-t-butoxycarbonylmn-ehl-etni acid benzyl ester was 180 isolated as radial plates. I H NMR: a87.3 5-7.25 (in, I SH), 6.40 (bd, I H, J 8.4 Hz), 5.22- 5.04 (in, 6H), 4.48 (dd, IRH, 3J= 6.9, 8.7 Hz), 4.33 I H, J 7.3) Hz), 4.16-3.95 (mn, 4H), 3.67 (bin, ILH), 3.51 (dd, ILH, J 4.4,.5.3 Hz), 2.91 (ddd, Ilh, J3 3.7, 7.2, 10.3 Hz), 1.80-1.50 (in, 4H), 1.41 9H4), 0.93 9H). IR: 3330, 2964,1743, 1263, 1170 cm* HR.FABMS: Calculated for C 41

H

52 N4 2

O

11 CS (M 881.2625. Found: 881.2631.

2S- I I R- r(3-Bi-phenvl-4.vh.- I H-12yrrol- I I (S)-hvdroxvmethv1-2.2-dimethvlpropvlcarbarnofl)-methvll 1 -5-hvdroxypentanoic Acid Benzv Ester d''I To a solution of 5-benzyloxycarboxy-2S-f( I(S)-benzyioxycarboxymethyl.2,2dimethyl-propylcarbanoyl)t-butoxycarbonylanino-methyl]-pentanoic acid benzyl ester (13 mg, 0. 180 inmol) in CHC1 3 (2 m.L) was added trifluoroacetic acid (0.5 mL). After 4 hours at ambient temperature, the solvent was removed in vacua to give a yellow oil that was placed with 3-biphenyl-4-y-2,5-dinethoxytetrhydrofuran (66 mg, 0.23 mmol), trifluoroacetic acid pL), and H 2 0 (20 4iL) in ClCI- 2

CH

2 CI (1 rnL). The mixture was heated to 70*C for minutes, allowed to cool, and evaporated to give a brown oil. Flash column chromatography with I %HOAcI20% EtOAc/hex as eluant and removal of HOAc via n-heptane azeotrope a provided 126 mg of 2S-( IR-f(3-bi-phenyl-4-yI)-I H-pyrrol. l-yl-(l (S)-hydroxymethyl- 2,2-dimethyl-propylcarbanoyl)-methyl] }-5-hydroxypentanoic acid benzyl ester as a yellow solid. 11 NMR: a 7.59-7.50 9H), 7.44 2H, J 7.4 Hz), 7.38-7.20 13H), 7.04 (brn, 1H), 6.70 (dd, 1H, J 2.5, 2.5 Hz), 6.49 (bi, 1H), 5.57 1H, J 9.6 Hz), 5.22 IH, J 12.1 Hz), 5.14(d, 1H,J= 12.1 Hz), 5.05 2H), 4.97 (dd, 2H,J= 12.1, 15.5 Hz), 4.84 (d, IH, J 10.3 Hz), 4.26 (dd, 1H, J 2.9, 11.0 Hz), 4.10-3.88 4H), 3.32-3.20 I 1.70- 1.15 4H), 0.87 9H). IR (KBr): 2961, 1743, 1687, 1453, 1398, 1263, 1167, 763, 697 cm'. HRFABMS: Calculated for C 5 2H 54

N

2 0 9 CS (M +Cs 4 983.2884. Found: 983.2861.

Anal. Calculated for C 52

H

54

N

2 0 9 0. 15 CHCI 3 C, 72.02; H, 6.28; N, 3.22. Found: C, 72.03; H, 6.43; N, 3.26.

e. *e 4.= Example 12. 2S, 2(1S)-[[3-(Biphenyl4-y)-1H-pyrrol-R-ylj-12,2-dimethyl-1(S)- S (hydroxymethyl)propylcarbamoyljmetbylj pent-4-enoic Acid *r

HONH.,-O

To a solution of 2R-[2(R)-(3-biphenylA4-yl- I H-pyrrol- I -yl)-2-(5R-iodomethyl-2-oxotea-ahydrofuma-3(S)-Yl)aetylamino]-3,3-ehiuy 2,22-tricoroethyl carbonate (100 mg, 0.129 mmol) in HOAc (2 m) was added zinc powder (86 mg, 1.3 mmol). After 24 hours at ambient temperature, the resultant mixture was partitioned with H20 (25 mL) and CHC13 (IS mL). The aqueousueous layer was adjusted to pH 5 with saturated aqueous NaHC03 and extracted with CHCI 3 (1 0mL) two times. The CHCI 3 layers were dried over NaSO 4 and evaporated to give a white solid, which was purified via radial chromatography with a 0.5% HOAc/5-10% MeOHICHCI 3 stepwise gradient to furnish 32 mg of 2S, 2(1 S)-[[3-(iphenyl-4-yl)- 1 H-pyrrol- R-yl]-[2,2-dimethyl-

I(S)-

(hydroxymethyl)propylcarbamoyl]methylpent-4-enoic acid as a pale yellow solid. 'HNMR (DMSO-d 6 a 7.89 IH, J 9.3 Hz), 7.80-7.50 6H), 7.44 2H, J 7.8 Hz), 7.36-7.23 2H), 6.88 (bm, 1H), 6.49 (bm, IH), 5.68 (ddd, 1H, J= 7.5, 9.3, 16.8 Hz), 5.03-4.78 (m, 2H), 2.09-1.85 2H), 0.83 9H).IR(KBr): 3384, 3240,2960, 2916, 1743, 1717, 1651, 1562, 1456, 1362 1240, 1196, 758 cm 1 HRFABMS: Calculated for C 29

H

33

N

2 04CS (M Cs 607.1573. Found: 607.1555. Anal. Calculated for C 29

H

34

N

2 0 4 0.17 CHClJ: C, 70.80; H, 6.96; N, 5.66. Found: C, 70.76; H, 7.03; N, 5.55.

The starting material was furnished as follows: 2(R)-t-Butoxarbonviamin-25R-ioomethl-2-oxo-ttrahdro-furan-3(S-lacetic Acid Allyl Ester 0 HN 0

OO

To a solution of 2 S-allyl- 3 (R)-t-butoxycarbonylamino-succinic acid 4-allyl ester (230 mg, 0.734 mmol) in THF (10 mL) was added saturated aqueous NaHCO 3 (10 mL). After minutes, the mixture was cooled to O'C, and iodine (742 mg, 2.94 mmol) was added. The resultant mixture was allowed to slowly warm to ambient temperature overnight. After hours, fresh 10% aqueous Na 2 S203 (20 mL) was added, and the mixture was extracted with EtOAc (15 mL) three times. The combined organic layers were washed with 10% aqueous Na 2

S

2 03 (25 mL), dried over MgSO 4 and evaporated to give 322 mg (100%) of 2(R)-tbutoxycarbonylamino-2-(5R-iodomethyl-2-oxo-tetrahydro-furan-3(S)-yl)acetic acid allyl ester as a yellow oil, which was used without further purification. 'H NMR: 8 5.80 (dddd, 1H, J= 6.3, 6.8, 11.1, 12.0 Hz), 5.58 (bs, IH), 5.27-5.15 2H), 4.64-4.47 3H), 4.40 (dddd, 1H, J 5.0, 6.1, 8.6, 10.8 Hz), 3.41-3.04 3H), 2.65-2.47 1H), 2.02-1.45 (m, 2H), 1.32 9H). IR: 3374, 2976, 1774, 1714, 1507, 1367, 1161 cm 1 Anal. Calculated for C 1 5H 22

NOI

6 1 0.25 EtOAc: C, 41.66; H, 5.24; N, 3.04; 1, 27.51. Found: C, 41.93; H, 5.00; N, 3.04.

2(R)-t-ButoxAarbondamino-2- 5R-iodomethyl-2-oxo-tetrahydrofiran-3(S)-vlaceticAcid HN0 0

OH

.0 According to the procedure described in Example 10(a) for the preparation of 3(R)allyl-N-t-butoxycarbonyl-D-aspartate P-benzyl ester, 2(R)-t-butoxycarbonylamino-2-(5Riodomethyl-2-oxo-tetrahydrofuran-3(S)-yl)acetic acid allyl ester (322 mg, 0.734 mmol) was deprotected to give 293 mg (100%) of 2(R)-t-butoxycarbonylamino-2-(5R-iodomethyl-2oxo-tetrahydrofuran-3(S)-yl)acetic acid as a yellow oil, which was used without further purification. Analytical sample furnished upon flash column chromatography with 1% MeOH/YCH 2

CI

2 gradient eluant and azeotrope with n-heptane. 'H NMR: a9.30 (bs, I 5.40 I1H, J 8.7 Hz), 4.84-4.36 (in, 3H), 3.64 (bt, I H, J 9.5 Hz), 3.56-3.15 (mn, 4H), 2.67 (ddd, IlH, J 4.1, 9.0, 13.1 Hz), 1.25 9H). IR: 33095, 2978, 1772, 1708, 1511, 1366, 1251, 1160 cm- 1 FABMS: 5 32 (M Anal. Calculated for C 12 H 1 8 N0 6 1 0 0.12

C

7 1-1 6 C, 37.50, H, 4.88, N, 3.41; 1, 30.86. Found: C, 37.51; H, 4.78; N, 3.52; 1, 30.94.

2(R)-t-Butoxycarbonylamino-N-(3 .3 -dimethyl. I-hydroxv-but-2(R).vI R-iodo-methyl -2oxo-tetrahvdrofuran-3(S)-vlacetamide Hw-oH According to the procedure described in Example 1 (0 for the preparation of N-(1 benzyl-2-methoxy-ethyi)-3(R)-t-butoxycarbonylamino-succinamic acid benzyl ester, 2(R)-tbutoxycarbonylamino-2-(SR-iodomethyl-2-oxo-tetrahydro-furan-3(S)-yl)acetic acid (293 mg, 0.734 inmol) was coupled to L-t-leucinol (55 mg, 0.466 rnmol) with BOP. After colurm chromatography with silica gel and 1 0 /fHOAc/5% MeOHICHC13 as eluant, azeotropic removal of HOAc with n-heptane, and crystallization from EtOAc/hex, 184 mg (50% yield) of 2(R)-t-butoxycarbonylamino-N-(3,3-dimethyl- 1-hydroxy-but-2(R)-yl)-2-(5R-iodo-methyl- 2-oxo-tetrahydrofuran-3(S)-yl)acetainide was obtained as a white powder, mp 142-3 H NMR: a 6.78 (bd, I H, I 8.2 Hz), 6.23 (bd, I1H, J 8.2 Hz), 3.88-3.68 (in, 2M), 3.60-3.40 (mn, 2H), 3.40-3.25 (in, 2H), 3.15-2.99 (bin, INM, 2.63 (ddd, I H, J 7.1, 10.5, 13.4 HZ), 2.37 (bs, 2H), 2.00 INH, J =I11.0 Hz), 1.44 9H), 0. 94 9H). IR: 3 319, 2965, 1774, 1665, 185 1530, 1367, 1153, 755 Anal. Calculated for C 18

H

3

IN

2 0 6 1: C;43.38, H, 6.27; N, 5.62; 1, 25.46. Found: C, 43.13; H, 6.34; N, 5.54; 1, 25.31.

2(R')-f2(R'-t-But oxv-carbonlamino-2 -(5R-iodomethv-2-oxo-tetrahvdroftran-.3(S)yl)acetvlainol-3 -3-dimethvlburvl 22-2-Trichloroethyl Carbonate 0 0HN-40 0

CI

To a solution of 2(R)-t-butoxycarbonylaznino-N-(3 ,3-dimethyl. 1 -hydroxy-but-2(R)yl)-2-(5R-iodomethyl-2-oxo-tetrahydrofuran-3(Sy)acetamide (155 mg, 0.311 mmol) in CHCl 3 (5 mL) was added DMAP (84 mg, 0.68 mmol) and 22,2-trichloroethylchlorofornate (86 gL, 0.62 mxnol). After 2 hours at ambient temperature, the resultant mixture was stiffed with 10% aqueous HCI (10 The organic layer was separated, washed with aqueous -CI (10 rnL) and saturated aqueous NaHCO 3

:H

2 0 (10: 10 mL), dried over Na 2

SO

4 and evaporated to provide a yellow oil, which was purified via flash column chromatography with 25% EtOAc/hex as eluant to afford 138 mg of 2(R>-[2(R)-t-butoxycarbonylamino-2-(5R-iodomethy-2-oxo .etrahydrofuran-3(S)-yl)acetylamino]-3,3dimethylbutyl 2,2,2-trichloroethyl carbonate as a yellow oil. 'H NMR: a 6.82 (bd, 1H, J Hz), 6.17 (bd, IH, J 7.8 Hz), 4.77 2H), 4.60 (quintet, 1H), 4.49 (dd, IH, J 4.7, 8.7 Hz), 4.42 (dd, 1H, J 3.1, 10.9 Hz), 4.20-4.00 2H), 3.48 (dd, lH, J 5.3, 10.0 Hz), 3.33 IH, J 9.3 Hz), 3.04-2.90 (bi, 1 2.64 (ddd, IH, J 10.0, 12.8 Hz). 1.99 ILH, J 12.2 Hz), 1.82-1.72 (bra, 1H), 1.46 9H), 0.97 9H). IR (KBr): 3386, 2966, 1764, 186 1703, 1683, 1676, 1521, 1369, 1244, 1165 cm- Anal. Calculated for C 21

H

32

N

2 0 8

C

3 1 0.25 C 6 H 14 C. 38.87; H, 5. 15; N, 4.03; Cl, 15.30; 1, 18.25. Found: C, 39.04; H, 5.13; N, 4.12; Cl, 15.64; 1, 18.65.

2(R'i- 2(R)-(3-Biphenyl-4-X1- I H-pvrro- 1-vl)- 2 -(5R-iodomethyl-2.oxo-tetrahydrofiiran-3 vflacerl,-aminol-3.3-dimethylbutyI 2-2-2-Trichloroethyl Carbonate 0~J NHA

C

According to the procedure described in Example 1(b) for the preparation of N-(2,2dimethyl- I (S)-methylcarbamoylpropyl)-3(R)-(3-phenyl- 1 H-pyrrol- 1 -yI)succinamic acid benzyl ester, 2(R)-[2(R)-t-butoxycarbonylamnino-2-(5R-iodomethyl-2-oxo-tetrahydrofuran- 3(S)-yI)acetylaxnino]-3,3-dimethylbutyl 2,2,2-trichioroethyl carbonate (105 mg, 0. 156 mol) was deprotected with trifluoroacetic acid and then condensed with 3-biphenyl-4-yi-2,5dimethoxytetrahydrofuran (prepared as described in Example in 1,2-dichloroethane with H 2 0 and trifluoroacetic acid. Flash column chromatography with 0.5% HOAcI2O% EtOAc/hex as eluant furnished 120 mg of 2(R)-[2(R)-(3-biphelyL-4-yl-1IH-.pyrrol4 yl).2-(5R-iodoznethy1-2-oxo-tetrahydrofuran-3(S)-yl)ac-y1.arino]-3,3-dimethylbutyl 2,2,2trichloroethyl carbonate as a yellow solid, which was used in the next reaction. 'H NMR: a 7.74-7.54 (in, 5H), 7.48-7.19 7.16 (dd, 11-1, J 1.9, 1.9 Hz), 6.86 (dd, I H, J Hz), 6.59 (dd, IH, J3 1.9, 2.5 Hz), 5.80 1H, 3 10.0 Hz), 5.20 1141, 3 3.4 Hz), 4.63 (dd, 2H, J 12.1, 18.0 Hz), 4.53-4.35 2H), 4.21 (ddd, IH, J=3.4, 9.0, 9.0 Hz), 4.05 Hz), 3.02 (dd, 18,1J 7.5, 9.3 Hz), 2.70 (ddd, 1H, I 6.2, 9.3, 12.8 Hz), 1.74 (ddd, IH, J= 9.7, 12.1, 12.8 Hz), 0.97 9H). IR (KBr): 1763, 1686, 1242, 1166,819, 764 cm 1 Example 13. N-(1 (S)-Beazyl-2-hydroxyethyl)-3(S)-I 3-ibiphenyI4-yI)-lH-pyrro-3.

yljsucciuamic Acid To a solution of N-(4(S)-benzyl-2,2-dimehyl-oxazolidifl-3-Yl)-3(S)-1 3 -(biphenyl-4yl)-IH-pyro.3-y]su.Cciflamic acid t-butyl ester (80 0.14 mmol) in THF (5 rnL) was added 2M aqueous LiOH (5 mnL). EtCH (few drops) and H 2 0 were added until a homogeneous solution was obtained. The resultat solution was heated at 50*C. After 12 hours, the mixture was acidified with 6N HCI to pHl. After another 5.5 hours at 50CC, the mixtrue was partitioned between EtOAc and 11M pH 7 phosphate buffer. The aqueousuevus phase was separated and extracted with EtOAc two timnes. The combined organiic layers were washed with brine, dried over Na 2

SO

4 and concentrated to a residue which, upon triruration with CH 2 C1 2 /hex, provided 32 mg of pure N-(I (S)-bezyl.2-hydroxycthy)-3(S)-[ 3 (biphenyl-4-yl)- IH-pyrrl-3-ylsuccinamic acid as a white solid, mnp 151-4*C. I H NMR: (DMSO-4,): 8 7.83 lH, I 8.5 Hz), 7.74 2H1. I 8.8 Hz), 7.69 2H, I1 7.4 Hz), 7.59 2H, I 8.8 Hz), 7.46 2H1, 7.4 Hz), 7.38-7.31 (mn, 2H), 7.28-7.13 (mn, 6H), 6.22 1H), 4.81-4.70 (mn, IH), 3.89-3.78 (mn, 2H), 2.85-2.69 2H). Anal. Calculated for

C

2 7 9

H

28

N

2 0 4 00.4 H 2 0: C, 73.21; H, 6.10; N, 5.89. Found: C, 73.39; H, 6.09; N, 5.93.

The starting material was furnished as follows: N-BiphenXW-4-vlI-nv1rrole To a solution of 4-amninobiphenyl (1 .0g, 5.9 rnnol) in 1,2-dichloroethane (20 m.L) was added TFA (0.46 ml, 5.9 mmol). To the resultant suspension of the TFA salt was added (0.92 mL, 7.1 rnol). The suspension was heated at 75*C for 17 hours. The mixture was allowed to cool, partitioned between EtOAc and I M pH 7 phosphate buffer, and the aqueousueous layer was extracted again with EtOAc. The combined organic layers were dried over Na 2

SO

4 and concentrated to a crude residue, which wa-s purified via flash column chromatography with 10-25% CH 2

CI

2 /hex gradient eluent.

The purified material was triturated with MTBE/hex to give 800 mg of N-biphenyl-4ylIH-pyrroie as an off-white solid, mpl9O-2*C. I H NMR: 6 .7.65 2H,J 8.5 Hz), 7.61 2H,1J7.0 Hz), 7.48-7.43 (in, 411, 7.36 I H, J =7.0 Hz), 7.14 2H, J 2.0 Hz), 6.37 2H, J 2.0 Hz). Anal. Calculated for Cj 6

H

13 N: C, 87.63; H, 5.98; N, 6.39. Found: C, 87.48; H, 6.01; N, 6.30.

N-(Biphenyl-4-vfl-3-bromno- I H-pyrrole_ -Br To a mixture of N-biphenyl-4-yl I H-pyrrole (500 mg, 2.28 mmol), dimethylsulfide (0.25 niL, 3.4 mmol), CH 2

CI

2 (30 mL), and acetonitrile (10 mL) at -10 0 C! was added dropwise a solution of bromine in CH 2

CI

2 (5 mL) over 15 minutes. The mixture was allowed to warm to I10 0 C over 2 hours. -The resultant mixture was -washed with 1 MpH 7 phosphate buffer (50 mL) and extracted with CH 2

CI

2 (25 mL). The combined organic layers were dried over Na 2

SO

4 and concentrated to a crude residue which was purified via flash column chromatography with 0- 10%/ CH 2 Cl 2 fhex gradient eluant to furnish 240 mng of N-(biphenyl-4-yi)-3-bromo-lH-pyrrole as a white solid, mp 141-3*C. 1 H NMR:687.65 (d, 2H, J 8.5 Hz), 7.59 2H, J 8.1 Hz), 7.49-7.34 (in, 5H), 7.12 I1-H), 7.02 I H, J =2.6 Hz), 6.36 (dd, 1H, J 1.7 Hz). Anal. Calculated for C 1 6

H

12 NBr: C, 64.45; H, 4.06; N, 4.70; Br, 26.80. Found: C, 64.37; H, 4.10; N,4.64; Br, 26.69.

N-(4(S)i-Benzvl-2-2-dimethyl-oxazolidin-3-vfl-oxamic Acid Ethyl Ester M9SO 4 (4 g) was added to a solution of 2S-amino-3-phenyl-lI-propanol (2.0 g, 3.12 mmcl) in CH 2

CI

2 (30 mL) and acetone (15 niL). After 17 hours at ambient temperature, triethylamine (2 mL, 14.3 mmol) was added and the mixture cooled to -75 IC. Ethyl oxalyl chloride (1 .5 mL) was added dropwise via syringe and the mixture was allowed to warmi to ambient temperature over 4 hours. The mixture was filtered and the filtrate washed with 1 M pH 7 phsophate buffer (50 mnL). The aqueousueous layer was extracted with CH 2

CI

2 mL). The combined CH 2

CI

2 layers were washed with brine, dried over Na 2

SO

4 and concentrated to a minimal volume, which was diluted with MTBE and filtered. The filtrate was concentrated to an oily residue, which was dissolved in MTBE/ hex/ iso-octane and resulted in a gummy residue that was removed by decanting. The supernatant was concentrated to an oil which was passed through a short column of silica gel with 0-25% EtOAc/ hex gradient eluant to provide 3.l1g (83 of N-(4(S)-benzyl-2,2-dimethyloxazolidin-3-yl)-oxamnic acid ethyl ester as a colorless oil. IH NMR: 8 7.35-7.22 (mn, 3H), 7.19 2H, J 7.4 Hz), 4.53-4.47 (in, IRH), 4.3 7-4.25 (in, 2H), 3.89 (mn, 2H), 3.00 (dd, IlH, J 13.2 Hz), 2.82 (dd, lH, J 10.5, 13.1 Hz), 1.76 3H), 1.59 (s 3H), 1.38 3H, J= Hz). Anal. Calculated for C 16

H

21 N0 4 C, 65.96; H, 7.26; N, 4.81. Found: C, 65.96; H, 7.26; N, 4.84.

I -(4(S)-Be=1v-2-2-dimethvl-oxazolidin-3-fl)-2-4 I -(biphenvl-4-vI)- I -12=rro-3-ylkethaiie- 1-2din 0 Q To a solution of N-biphenyl-4-yl-3)-bromo- IH-pyrrole (0.45g, 1.5 rnmol) in dry TI-F rnL) at -78*C was added dropwise via syringe n-butyllithium (0.7 ruL of 2.5M in hexanes). After 15 minutes at -78*C, the resultant mixture was transferred via cannula to a solution of N-( 4 (S)-benzyl-2,2-dimethyl-oxazolidin3.yl)-oxarnic acid ethyl ester (714 mig, 2.4 mmrol) in dry THFf at -90*C. The mixture warmed to -59*C over 15 minutes and then was cooled at -78 *C for 45 minutes before quenching with saturated aqueous NH 4 CI (25 mL) and allowed to stir at ambient temperature. After 16 hours, the aqucousucous layer was separated and extracted with EtOAc (15 The combined organic layers were washed with brine, dried over Na 2

SO

4 and evaporated to give a residue which was purified via flash column chromatography with 0- 1% EtOAc/CH 2

CI

2 gradient eluant. The purified product was triturated from MTBE/hex to obtain 300 mg of l-(4(S)-benzyl-2,2-dimethyloxazolidin-3-yl).2-[ 1-(biphenyl-4-yl)- IH-pyrrol-3-yl)ethane-1I,2-dione as an off-white solid, nip 150-2'C. I H NMR: 8 7.86 I1-H), 7.70 2H, J 8.8 Hz), 7.61 2H, J =7.0 Hz), 7.51-7.45 (in, 4H), 7.39 I H, J 7.4 Hz), 7.32-7.23 (in, 7.17-7.13 (mn, 3H), 7.10 (dd, 1H, J 2.2, 2.9 Hz), 6.91 (dd, 11-,1I 1.7, 3.1 Hz), 4.53-4.48 (mn, IH), 3.87 2H), 3.00 (dd, I H, J 12.7 Hz), 2.76 (dd, I H, J= 10.7, 13.2 Hz), 1. 85 3H), 1.67 3H). Anal.

Calculated for C 30

H

28

N

2 0 3 C, 77.56; H, 6.07; N, 6.03. Found: C, 77.6 1; H, 6.11; N, 6.05.

I -4(S'-DenzyI.2 2-dimethI-oxazoidin-3-vi)-2.r I -(binhenvl-4-vfl I H-pvrrQl-3-vIJ-2.

hydroxy-ethanone 0 To a solution of I -(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2.[I-(biphenyl-4-yl)lH-pyrrol-3 -yI)ethane-l,2-dione (250 mg, 0.54 mrnol) in EtOAc (6 mL) and MeOH (2mL) at 0 0 C was added NaBH 4 (20 mg, 0.54 mnuol). After 2.75 hours at OeC, more NaBH 4 (20 mg, 0.54 mrnol) was added. After 1.25 hours at aeC, the reaction was quenched with HOAc (few drops) and H 2 0 (2mL). The pH was adjusted to 5 (by pH paper) with HOAc and partitioned between H20 (25 nL) and EtOAc (25 mL). The organic layers were dried over Na 2

SO

4 and concentrated to provide 0.25 g of I -(4(S)-benzyl-2,2-dimethyloxazolidin-3-yl)-2-[ I -(biphenyl-4-yI) 1 H-pyrrol-3-yl]-2-hydroxy-ethanone as a crisp foam.

H NMR: 6 7.65 2H, J 8.5 Hz), 7.59 2H, J 7.4 Hz), 7.48-7.19 10), 7.14 (t, 1H, J 2.0 Hz), 7.06 IH, J 2.6 Hz), 6.31 1H, J 2.4 Hz), 5.11 IH, J 7.4 Hz), 4.29 1H, J 6.6 Hz), 3.99-3.95 1 3.76 1H, J 9.2 Hz), 3.60 (dd, 11, J 8.6 Hz), 3.08-3.02 11), 2.90 (dd, 1H, J 10.5, 13.4 Hz), 1.82 3H), 1.60 3H). Anal.

Calculated for C 30

H

30

N

2 0 3 0 0.4 H20: C, 76.05; H, 6.55; N, 5.91. Found: C, 76.17; H, 6.66; N, 5.74.

2-Acetoxy- I -(4(S)-benzvl-2.2-dimethyl-oxazolidin-3-vl-2-f I -(bichenvl-4-vfl- 1H-pyrrol-3yl-ehanone

N

cP To a solution of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(1 -(biphenyl-4yl) I H-pyrrol-3-yl]-2-hydroxy-ethanone (867 mg, 1.86 mmol) in dry pyridine (5 mL) was added acetic anhydride (0.42 mL, 4.5 mmol). After 4.5 hours at ambient temperature, the mixture was partitioned between IN aqueous NaHSO 4 (25 mL) and EtOAc (25 mL). The EtOAc layer was washed with IN pH7 phosphate buffer (25 mL) two times, H 2 0 (25 mL), and brine (25 mL), dried over Na 2

SO

4 and evaporated to give 0.91 g (100%) of 2-acetoxy-l- (4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[I-(biphenyl-4-yI)-IH-pyrrol-3-yI]-ethanone as an amorphous solid that was used without further purification. An analytical sample was obtained upon flash column chromatography with 0-2% EtOAc/CH 2

CI

2 gradient eluent. I H NMR: 6 7.65 2H, J 8.5 Hz), 7.62 2H, J= 7.0 Hz), 7.48-7.24 1H), 7.10 1H, J 2.6 Hz), 6.46 (dd, 1H, J= 1.7,2.8 Hz), 6.25 11), 3.98-3.93.(m, 1H), 3.81 1H, J 9.2 Hz), 3.64-3.60 (mn, 3.42 1H, J 13.6 Hz), 2.96 (dd, 1H, J= 11.6, 13.8 Hz), 2.22 (s 3H), 1.78 3H), 1.55 3H). Anal. Calculated for C 32

H

32

N

2 0 4 C, 75.57; H, 6.34; N, 5.51. Found: C, 75.47; H, 6.37; N, 5.45.

1 -(4(S)-benzX-72-dimethyl-oxazolidin-3.vi).24 I -(bighenvl-4.vl)- LH-nvrrok.vl1ethanone To a mixture of crude 2-acetoxy- 1 -(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-24 1- (biphenyl-4-yl)- IH-pyrrol-3-ylJ-ethanorie (1.82 mniol) and 10% palladium on carbon (120 mg) in.EtOAc (4.5 miL) and EtQH (4.5 m.L) was added ammnonium formnate (0.58 g, 9.2 mmol). After 40 hours at ambient temperature, the resultant mixture was filtered and the filtrate concentrated to a residue which was dissolved in EtOAc, washed with 1 M pH7 phosphate buffer, dried over Na 2

SO

4 and evaporated under reduced pressure to give a crude product. Flash column chromatography with EtOAc/CH 2

CI

2 gradient eluant yielded 220 mg of I -(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-( I -(biphenyl-4-yl)- I Hpyrroi-3-yl]-ethanone as a pale yellow amorphous solid. I NMR: 8 7.62 4H, J 9.4 Hz), 7.47 2H, J 7.4 Hz), 7.42 2H, J3 8.5 Hz), 7.35 2H, J 6.6 Hz), 7.30-7.2 1 (in, 4H), 7.08 I H, J 2.6 Hz), 7.05 IlH), 6.28 IlH, J 2.21 Hz), 4.16-4. 10 (in, 11H), 3.82 (in, 2H), 3.62, 3.54 (AB quartet, 2H, J 15.5 Hz), 3.07 (dd, lH, J 3.9, 13.8 Hz), 2.91 (dd, lH, J 9.9, 13.6 Hz), 1.78 3H1), 1.59 314. Anal. Calculated for C 30

H-

30

N

2 0 2 0 0.25

H

2 0: C, 79.18; H, 6.76; N, 6.16. Found: C, 79.24; H, 6.79; N, 6.12.

N-(4(S)-Benzvl.2 2-dimethyl-oxazolidin-3-vyl-2(SL-(biphenvl4-vl- I H-pvrrol-3.vl)succinamic Acid t-Butvl Ester

OP

0 To a solution of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl- I H.

pyrrol-3-yl)-ethanone (226 mg, 0.500 mmol) in dry THF (5 mL) at -78*C was added dropwise via syringe a solution of sodium hexamnethyldisilazide (0.60 mL of IM in THF).

After 15 minutes at -78*C, to the resultant dark red mixture was added t-butyl bromoacetate (100 pL, 0.68 mmol). The mixture warmed to -50*C over 1 hour, then was quenched with IM pH7 phosphate buffer, and allowed to warm to ambient temperature. The aqueousueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated to give a residue which was purified via flash column chromatography with 0-25% EtOAc/hex gradient eluant to afford 108 mg of N-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2(R)-(biphenyl-4-yl- 1 H-pyrrol-3- 1 yl)succinamic acid t-butyl ester as a colorless amorphous solid. H NMR: 6 7.60 4H, J 8.3 Hz), 7.46 2H, I 7.4 Hz), 7.41 2H, J 4.8 Hz), 7.36 2H, J 8.1 Hz), 7.31 (d, 2H, J 7.4 Hz), 7.21 2H, J 8.1 Hz), 7.11 1H, J 2.0 Hz), 7.03 1H, J 2.6 Hz), 6.35 (dd, 1H, J= 1.7,2.8 Hz), 4.56-4.50 1IH),4.33 (dd, 1I, J= 4.0, 10.3 Hz), 3.93-3.88 1H), 3.82 1H, J=9.2 Hz), 3.18 (dd, 1H, J 10.5, 16.7 Hz), 2.96 (bd.1H, J 12.5 Hz), 2.73-2.63 2H), 1.71 1.57 3H-1), 1.44 9H). Anal. Calculated for

C

36

H

40

N

2 0 4 C, 76.57; H, 7.14; N, 4.96. Found: C, 76.31; H, 7.16; N, 4.93.

Example 14(a). N-[2,2.Dimethyl-(S)-(methylcarbamoyi)propylj-3(S)( I-(4 fluoropheyl)-1H-pyrrol-3-ylsuccinamic Acid

F

0 As described in Example N-[2,2-dinethyl-I (S)-(methylcarbamoy)propyl]-3(S)- 4 -fluorophenyl)-IH-pyrrol.3-yllsuccinamic acid benzyl ester was hydrogenolyzed in EtOH afier 1.5 hours. Trituration with MTBE/hex gave in quantitative yield N-(2,2dimethyl-I (S)-(methylcarbamoyl)propyl]-3(S){ 1 -(4-fluorophenyl). 1 H-pyrrol-3yl]succinamic acid as a colorless amorphous solid. IH NMR: 8 7.27-7.23 2H), 7.07 (t, 2H, J 8.6 Hz), 6.90-6.89 2H), 6.21 1H, J 2.2 Hz), 6.13-6.10 IH), 4.24 IH, J 9.6 Hz), 4.03 (dd, IN, J 5.2, 8.5 Hz), 3.14 (dd, IH, J 8.5, 16.6 Hz), 2.80 (dd, IH, J 5.7, 16.7 Hz), 2.72 3H, J 4.8 Hz), 0.94 9H). Anal. Calculated for C 2 jH 26

N

3 0 4 F: C, 63.17; H, 6.80; N, 10.09. Found: C, 62.89; H, 6.93; N, 9.81.

The starting material was prepared in the following fashion:- 2 2 -5S-Dimethoxy-tetrahydrofiiran.-3-vi-methylidene). I .3-dian HC0 According to a procedure described in Boger, Brotherton, G.E. J Org. Chem.

1984, 49, 4050-4055, to a solution of 2-trimethylsilyl- 1,3-dithiane (1.2 mL, 6.3 mmnol) in dry TI-F (40 mL) at 0 0 C was added n-butyllithium (4 mL of 1.6 M in hexanes). After minutes at 0 0 C and 20 minutes at 4 m.L of 1.6 M ambient temperature, a solution of dimethoxytetahydrofuran3.caboxaldehyde (1.00 g, 6.00 mmol) in dry TKF (10 m.L) was added dropwise. After 17 hours at ambient temperature, the resultant mixture was treated with saturated aqueous NH 4 CI (10 mL) and partitioned between EtOAc and H 2 0. The layers were separated and the aqueousueous phase extracted with EtOAc:hex 1) two times. The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated to afford a residue which was purified via flash column chromatograpy with 10% EtOAc/hex as eluant to yield 1 .06g of a mixture of diastereomeric 2-(2,5-!dimethoxy-tetrahydrofuran- 3-yl-methylidene)-1,3-dithiane as a yellow oil, which was used without any further purification. I NMR: 8 6.00 (di, I H, J1 9.6 Hz), 5.93 I H, J 9.6 Hz), 5.77 IRH, J= 9.6 Hz). Anal. Calculated for C, 1

H

18 0 3

S

2 C, 50.35; H, 6.92; S, 24.44. Found: C, 50.07; H, 7.00; S, 24.33.

Methyl 2 -(2.5-Dimethoxy-tetrahvdrfurann-3-VI'nacetate M Co 0 Also according to a procedure from Boger, Brotherton, G.E. J Org. Chem.

1984, 49, 4050-4055, to a solution of 2-( 2 ,5-dimethoxy-tetrahydrofura-3-ylirnethylidene)- 1,3-dithiane (200 mg, 0.76 mmol) in a mixture of MeOH:THF:H 2 0 1: 1; 10 mL) was added mercuric chloride (450 mg, 1.66 mrnol). Upon heating at 80TC, a white precipitate formed, and after 5 hours at 80 0 C, the mixture was filtered through Celite. The collected solid was washed with EtOAc followed by aqueous. NH 4 CI. The filtrates were combined, and the biphasic mixture separated. The aqueousueous layer was extracted twice with EtOAc.

The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated to yield 120 mg of methyl 2-(2,5-dimethoxy-tetrahydrofuran-3-yl)-acetate as an oil, which was a mixture of diastereomers as evident by NMR, and which was used without further purification. An analytical sample was obtained by flash column chromatography with 0-20% EtOAc/hex as gradient eluant. H NMR: 6 3.68 3H), 3.67 3H). Anal.

Calculated for C 9 Hi 16 0 5 C, 53.27; H, 7.90. Found: C, 5 3.11; H, 7.96.

24r1 4-jFluorophenvlh~ I H-pVrol-3-yll-acetic Acid Methyl Ester

F

~OCH

3 0 According to the procedure described in Example 1(c) for the preparation of N-(8oxo-4-oxa-1,7-diaza-tricyclo[9.6. 1 .0 12 17 ]octadeca- 11I(1 8),12,14,1I6-tetraen-9-yI)-3.-(3phenyl-IH-pyrrol-1-yl)succinaxnic acid benzyl ester, to a mixture of crude methyl 2-(2,5dimethoxy-tetrahydrofuran-3-yl)-acetate (120 mng, -0.58 rnxol) and 4-fluoroaniline (50 jiL, 0.53 mmol) in 1,2-dichloroethane (10 mL) was added trifluoroacetic acid (0.2 mL, 0.26 mmol). After 16 hours at 80 0 C, the resultant mixture was partitioned between EtOAc and IM pH 7 phosphate buffer. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated to a crude oil, which was purified via flash column chromatography with 0- 15% EtOAc/hex gradient eluant to yield 100 mg of 2-(l.(4-fluorophenyl)- IH-pyfrol-3-yll-acetic acid methyl ester as an oil. 'HNM: 8 7.34-7.30 2H), 7.10 2H, J =8.6 Hz), 6.96-6.94 (n, 6.28 (t,lH, J =2.2 Hz), 3.72 3H), 3.56 2H). Anal. Calculated for C 13

H

12 N0 2

)F

*0.6 H-20: C, 63.98; H, 5.45; N, 5.74. Found: C, 64.01; H, 5.04; N, 5.65.

24r1 -(4-Fluorophenfl)- I H-pyrro-3-yIJ-acetic Acid

F

N

0 To a solution of 2-(1-(4-fluorophenyl)-IH-pyrrol-3-y]-acetic acid methyl ester (100 mg, 0.43 inmol) in THF (I m.L) at 0 0 C was added dropwise 2N aqueous LiOH (0.5 niL).

After warming to ambient temperature over 4 hours, the mixture was added-dropwisC to aqueous HCI (10 mL). The resultant light brown solid was collected by filtration, washed with H 2 0, and dried in vacuo over P 2 0 5 to yield 700 mg of analytically pure 241 fluorophenyl)- IH-pyrrol-3 -yi]-acetic acid as a solid, mp 100-2 H NMR: 8 7.34-7.30 (in, 2H), 7. 10 2H, J 8.6 Hz), 6.97-6.95 (in, 2H1), 6.29 I H, J 2.2 Hz), 3 .60 2H).

Anal. Calculated forC 1 2 H I N0 2 F 0 0. 15 H,O: C, 64.95; H, 4.68; N, 6.3 1. Found: C, 65.03; H, 4.71; N, 6.25.

I .(4(S)-Renzv-oxazolidiri.2-on-3-.vlV2-r I -(4-fluorophenyb)- I H-pyrrol-3-vil-ethanone

F

N

0 To a solution of (S)-(-)-4-benzyl-2-oxazolidinone (710 mg, 4 rnmol) in dry THF 0 00 mL) at -78 *C was added n-butyllithium (2.5 mL of 1.6 M in hexanes). In a separate reaction 0 vessel, to a solution of 2-[l-(4-fluorophenyl)- IH-pyrrol-3-y]-acetic acid (920 mg, 4.2 mmol) 0..:and triethylamine (0.7 aL., 5 mmxol) in dry THF (20 mL.) at -78 *C was added dropwise *o 0000pivaloyl chloride (0.5 nL., 4 mmrol). After stirring at -780 to 0 0 C over I hour, then recoolig o 00 00to -78 the above solution was added via cannula. The resultant mixture was allowed to warm to ambient temperature over 17 hours, then partitioned with EtOAc and aqueous

N

4 The separated aqueousueous phase was extracted with EtOAc. Te combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrate~d to an oil, which was purified via flash column chromatography with 15-20% EtOAc/hex gradient eluant. The oily product crystallized from benzene to give 1.04 g of l-(4(S)-benzy1-oxazolidjn-2on-3-yl)-2-[ 1-(4-fluorophenyl)- I H-pyrrol-3 -yl]-ethanone as a solid, mp 106-8 0 C. I'H NMR: 8 7.3 6-7.25 (in, 5H), 7.17-7.07 (in, 4H), 7.04 1H), 6.98 1H, J 2.6 Hz), 6.35 (dd, I1H, J 1. 8, 2.6 Hz), 4.72-4.67 (mn, I 4.28-4.14 (in, 4H), 3.2 8 (dd, I H, J 3.3, 3.6 Hz), 2.79 (dd, I H, J 9.4, 13.4 Hz). Anal. Calculated for C 22 H 19

N

2 0 3 F: C, 69.83; H, 5.06; N, 7.40.

Found: C, 69.80; H, 5.07; N, 7.30.

I -(4(S)-Benzv-oxazoiidin-2-on-3-vh.-3(S)-f 1 -(4-fluoro~henvl)- 1 H-pvroi-3-yIlsuccinamic Aci Bnzvl t

F

N~j According to the procedure described in Example 13 for the preparation of benzyl-2,2-dimethyl-oxazolidin-3-yl)-3(S)-(1 -biphenyl-4-yl- 1H-pyrrol-3-yl)succinarnic tbutyl ester, 1 -(4(S)-benzyl-oxazolidin-2-on-3-yl)-2-( I-(4-fluoro-phenyl)- IH-pyrrol-3-Yl]ethanone was alkylated with benzyl bromoacetate to give 550 mg of 1-(4(S)-benzyloxazolidin-2-on-3-yI)-3 I-(4-fluorophenyl)- lH-pyrrol-3.yI]succinamnic acid benzyl ester as an amorphous solid. 'H NMvR: 8 7.35-7.20 (in, 12H), 7.09 2H, J 8.6 Hz), 7.02 1IH, J 2.0 Hz), 6.91 I H, J 2.6 Hz), 6.3 0 (dd, I H, J 2.9 Hz), 5.54 (dd, I H, J 4.0, 11.4 5.13 2H), 4.59-4.53 (in, I1H), 4.06 2H, J 4.8 Hz), 3.49 (dd, 11H, J 11.4, 17.3 Hz), 3.25 (dd, I1H, J 13.1 Hz), 2.79 (dd, LH,J 17.3 Hz),2.51 (ddi, IH, J 10.1, 202 13.4 Hz). Anal. Calculated for C~ 1

H

27 N,0 5 F: C, 70.71; H, 5.17; N, 5.32. Found: C, 70.83; H, 5.27; N, 5.30.

2(S)-f I -(4-Fhiorophenvl)- I H-pyrrol-3-vl-succinic Acid 4-Benzl Pster

F

0

N

0 To solution of I -(4(S)-benzyl-oxazolidin-2.on-3-yl)-3(S)( I -(4-fluorophenyl)- 114pyrrol-3-yIjsuccinamic acid benzyl ester (900 mg, 1.7 mmnol) in THF (15 m.L) at 0Oec was added 30%b aqueous H 2 0 2 8 m.L, 6.8 rnmol), followed by dropwise addition of 2N aqueous LiOH (1.7 mL). After stirring at 0 0 C for I hour, more 30%/ aqueous H 2 0 2 (0.O4mL) and 2N aqueous LiQH (0.08 mL) were added. After 45 minutes at 0 0 C, the mixture was treated with a mixture of saturated aqueous NaHCO 3 (10 znL) and 2N aqueous Na 2 SO3 (5 niL). After minutes at 0 0 C, the mixture was partitioned with EtOAc and IM pH? phosphate buffer. The aqueousucous phase was separated and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na 2

SO

4 and. concentrated to an oil which was purified via flash column chromatography with a 0-5% MeOHICH 2

CI

2 gradient eluant to yield 320 mig of 2(S)-[1-(4-fluorophenyl)-1H-pyrrol.3-yl~succinic acid 4-benzyl ester as an oil. IH NMR: 8 7.36-7.26 (in, 7H), 7.10 2H-, J 8.6 Hz), 6.93-6.92 (in, 2H), 6.27 (t, I H, J 2.4 Hz), 5.14 2H), 4.14 (dd, I H, J 9.4 Hz), 3.19 (dd, I1H, J 9.6, 16.9 Hz), 2.81 (dd, IH, J 5.9, 16.9 Hz). Anal. Calculated for C 2 1 1 8 N0 4 F 0 0.5 C, 67.01; H, 5.09; N, 3.72. Found: C, 66.96; H, 4.95; N, 3.63.

N-[2.2-Dimethvl- I(S)-(methvlcarbamoflpropvl3(S).. r-(4-flujorophenif- IH-pvrrol-3yIlsuccinamic Acid Be=Iv Ester

F

0S

NHCH

3 According to the procedure described in Example 1(b) for the preparation of 3(R)-tbutoxycarbonylarnino-N.(2,2.dimethyl. 1 (S)-(methylcarbaznoyl)propyl)succinamic acid benzyl ester, 2 (S)-[(I-(4-fluorophenyl).1IH-pyrrol.3-yl]psuccinic acid 4-benzyl ester and L-tleucine N-methylamide (see Malon, Pancoska, Budesinsky, Hlavacek, J.; Pospisek, Blaha, K. Coil. Czech. Chem Commun. 1983, 48, 2844-2861) were coupled with TBTU. Flash column chromatography with 0-5% MeOH/CHCI as gradient eluant provided ~in 82% yield N-(2,2-dimethyl- I(S)-(methylcarbamoyl)propyl)-3(S)- I -(4-fluorophenyl)- IHpyrrol-3-yl]succinamnic acid benzyl ester as a crisp foam. I'H NMR: 6 7.34-7.26 (mn, 7H), 7. 10 2H, J 8.6 Hz), 6.95 I H, J 2.4 Hz), 6.89 I H, J 2.0 Hz), 6.49 I1H, J 8.-8 Hz), 6.23 (dd, IH, J 1.8, 3.0 Hz), 5.76-5.74 (mn, I 5.11l(s, 2H), 4.12 IH, J 9.2 Hz), 00(t, I H,J 7.2 Hz), 3.20 (dd, I H, J 16.5 Hz), 2.84 (dd, I1H, J 16.6 Hz), 2.7 3H, J 4.8 Hz), 0.95 9H). Anal. Calculated for C 2 8H 32

N

3 0 4 F: C, 67.89; H, 6.55; N, 8.48. Found: C, 67.78; H, 6.52; N, 8.50.

The following compound was made in similar fashion: Example 14(b). 3(S)-I1-(4'-Cyanobiphnyl-4-yi)- H-pyrrol-3-yll-N-2,2-dimethyl.I (metbylcarbamoyl)propyllsuccinamic Acid

CN

2, NH NHCH3 0 According to the procedure described in Example 3(S)-f I-(4'-cyanobiphenyl-4yI)-I H-pyrrol-3-yl]-N-[2,2-dimethyl. I (S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester was hydrogenolyzed in EtOHEtOAc after 6 hours to give in 87% yield cyanobiphenyl-4-yl)- I H-pyrrol-3-yl]-N.[2,2-dinethyl-

I(S)-

(methylcarbanoyl)propyl]succinamic acid as a colorless amorphous solid. INM: 8 7.74 2H, 8.5 Hz), 7.68 2H, 8.5 Hz), 7.63 2H, J 8.5 Hz), 7.45 2H, J 8.5 Hz), 7.08 IH, J 2.4 Hz), 6.89-6.83 IH), 6.29(t, IH,J 1.8 Hz), 5.77-5.71 1H), 4.17 (d, IH, J 9.2 Hz), 4.06-4.01 IH), 3.19 (dd, IH, J 8.6, 16.4 Hz), 2.85 (dd, 1H, J 4.6, 16.4 Hz), 2.78 3H, J 4.8 Hz), 0.96 9H). Anal. Calculated for C 28

H

3 0

N

4 0 4 0 0.25 EtOAc 0.2 C 6

H

14 C, 68.98; H, 6.67; N, 10.66. Found: C, 68.91; H, 6.79; N, 10.64.

The starling material was furnished in the following fashion: 2-r f -(4'-CyanobiphenX 1-4-y H-2yrrol- 3-y QJ-acetic Acid M~ethyl Este

CN

~OCH

3 0 According to the procedure described in Example 14(a) for the preparation of 2-[1I-(4fluorophenyl)- I H-pyrrol1-3-yl] -acetic acid methyl ester, 4-arnino-4-cyano-biphenyl (commercially available from TCI) and methyl 2-(2,5-dimethoxy-terahydrofuran-3yl)acetate were condensed in 6 hours at 80*C to give a crude product. Successive flash column chromatography with EtOAc/CH 2

CI

2 /hcx gave in 60% yield 2.{l-(4'-cyanobiphenyl- 4-yl)-1IH-pyrrol-3-yl]-acetic acid methyl ester as an amorphous solid. I'H NMR: 6 7.75 (d, 2H, J 8.8 Hz), 7.69 2H, J 8.8 Hz), 7.64 2H, J 8.5 Hz), 7.48 2H, J 8.8 Hz), 7.10-7.09 (in, 2H), 6.33 I H, J 2.2 Hz), 3.73 3H), 3.58 2H). Anal. Calculated for

C

20 Hl 6

N

2 0 2 C, 75.93; H, 5.10; N, 8.86. Found: C, 75.86;H, 5.14; N, 8.90.

~24( 1 -&4-Cyanobiphenyl-4-1l)- I H--pvrol-3.vll-acetic Acid .00.

CN

N4)

~OH

0 According to the procedure described in Example 14(a) for the preparation of fluorophenyl)- I H-pyrrol-3-yl]-acetic acid, I-(4'-cyanobiphenyl-4-yl)-1 H..pynfo3-yll 206 acetic acid methyl ester was hydrolyzed in 86% yield to 2-[l-(4'-cyanobiphenyl.4.yl)- I Hpyrrol-3-yII-acetic acid as a solid, rnp 201-4 0 C I'H NMR (DMSO-d 6 6 12.20 (bs, Il-H), 7.92 4H), 7.84 2H, J 8.8 Hz), 7.68 2H-,JI 8.5 Hz), 7.40 I1H), 7.35 I H), 6.22 IH), 3.41 Anal. Calculated for C 19

H

14

N

2 0 2 C, 74.81; H, 4.73; N, 9.18.

Found: C, 74.90; H, 4.92; N, 9.12.

1 44(S)-Benzvl-oxazolidin-2-on-3.vfl.24 1 -(4'-canbiphenl4-viY.. I H-pyrrol-3-vIJ-ethanone

CN

~0/

N

0 0 As in Example 14(s) for I -(4(S)-benzyl-oxazolidin-2-on-3)-yl)-2-fl1-(4-fluorophenyl)- 1 H-pyrrol-3-yl]-ethanone, 241 -(4'-cyanobiphenyl-yI)- I H-pyrrol-3 -yl ]-acetic acid and 4(S)benzyl-2-oxazolidinone were coupled. Flash column chromatography with 10-25% EtOAc/hex to CH 2

CI

2 stepwise gradient eluant and subsequent trituration with EtOAcIMTBE/hex provided in 59% yield 1-(4(S)-benizyl-oxazolidin-2-on-3-yl)-2-[1-(4'cyanobiphenyl4yl)-IH-pyrrol-3-yl]-ethanone as a pale yellow amorphous solid. H NMR: 000. 87.75 (di, 2H, J 8.8 Hz), 7.70 (di, 2H, J 8.5 Hz), 7.65 2H, J 8.8 Hz), 7.49. 2H, J 8.8 Hz), 7.32-7 .25 (in, 3H), 7.17-7.15 (in, 3 7.12 IlH, J =2.8 Hz), 6.40 (cid, I H. J 1.7, 2.8 Hz), 4.74-4.68 (in, 1 4.31-4.16 (in, 41-1), 3.29 (dd, I H, J 13.6 Hz), 2.80 (cid, I H J 207 9.4, 13.4 Hz). Anal. Calculated for C 29

H,

3

N

3 0 3 C, 75.47; H, 5.02; N, 9.11. Found: C, 75.36; H, 5.08; N, 9.15.

1-(4(S)-BenyI-oxazolidin-2-on-3 r -(4'-cvanobiohenvl-4-vyl. I H-pvrro 1-3vilsuccinaric Acid Benzyl Ester

CN

N

0

~OS~NO

0: According to the procedure described in Example 14(a) for the preparation of benzyl-oxazolidin-2-on-3-yl)-3(S)-[ I-(4-fluorophenyl)- 1 H-pyrrol-3-ylsuccinanic acid benzyl ester, 1 -(4(S)-benzyl-oxazolidin-2-on-3-yl)-2-[ I -(4'-cyanobiphenyl-4-yl)- 1 H-pyrrol-3yl]-ethanone was alkylated with benzyl broroacetate. Flash column chromatography with EtOAc/hex and CH 2

CI

2 as stepwise gradient eluant gave in 60% yield 1-(4(S)-benzyloxazolidin-2-on-3-yI)-3(S)-[ I -(4'-cyanobiphenyl4-yl)- IH-pyrrol-3-yl]succinamic acid benzyl ester as an amorphous solid. 'H NMR: 8 7.74 2H, J 8.5 Hz), 7.68 2H, J 8.8 Hz), 7.63 2H, J 8.8 Hz), 7.45 2H, J 8.5 Hz), 7.35-7.21 IOH), 7.16 IH, J 2.2 Hz), 7.05 1H, J 2.8 Hz), 6.35 (dd, 1H, J 1.8, 2.9 Hz), 5.57 (dd, 1H, J 4.2, 11.2 Hz), 5.14 2H), 4.61-4.56 IH), 4.07 2H, J 5.2 Hz), 3.51 (dd, IH, J 11.4, 17.3 Hz), 3.26 (dd, 11, i 2.9, 13.6 Hz), 2.81 (dd, IH, J 4.2, 17.1 Hz), 2.53 (dd, 1H, J 10.1, 13.4 Hz). Anal. Calculated for C 38

H

31

N

3 0 5 0.4 H 2 0: C, 73.98; H,5.20; N, 6.8 1. Found: C, 73.87; H, 5.53; N, 6.63.

2(S)-f I 4 '-Cyanobiphenyl-4-vn- I ryrrol-3-yilssuccinic Acid 4-Benzvl E-ster

CN

kS$%OH According to the procedure described in Example 14(a) for the preparation of (4-fluorophenyl)- IH-pyrrol-3-yl~succinic acid 4-benzyl ester, 1 -(4(S)-benzyl-oxazolidin-2- I -(4'-cyanobiphenyl-4-yi)- I H-pyrrol-3-yl~succinanic acid benzy I ester was hydrolyzed and purified via flash column chromatography with a 25-75% EtOAc/hex to MeOHC- 2 C1 2 gradient eluant to yield in 55% I -(4'-cyanobiphenyl-4-yl)- 1 H-pyrrol-3 eo .o :oo.*yl]succinic acid 4-benzyl ester as an oil, which had some residual 4(S)-benzyl-2oxazolidinone by NMvR, and which was used withouturather purification. Analyses were 0 ~performed on pure chromatography fractions. H NNM: 8 7.74 2H, J 8.5 Hz), 7.68 (d, 2H, J Hz), 7.63 2H, J 8.5 Hz), 7.43 2H, J 8.8 Hz), 7.32 5H), 7.07 IN), *.7.06 1H), 6.33 1H, J 2.4 Hz), 5.14 4.16 (dd, IN, J 9.4 HZ), 3.21 (dd, I1H, J 9.6, 16.9 Hz), 2.83 (dd, 1lH, J 5.9, 16.9 Hz). Anal. Calculated for C 2 8H2 2 N2O 4

S

0.4 H 2 0: C, 73.48; H, 5.02; N, 6.12. Found: C, 73.38; H, 5.17; N, 6.00.

I- (4Cvanobip~henl-4-Xvh- IH-pvrrol-3 vlI-N-(2 2-dimethvl.IdhS- (methvlcarbamovlWpropyl~succin~-ic Acid Benzvl Ester

CN

or O 0S, y.

According to the procedure described in Example 1(b) for the preparation of 3(R)-tbutoxycarbonylaniino-N-(2,2.dimethyl. I (S)-(methylcarbamoyl)propyi)succinamnic acid benzyl ester, 2 l-(4-cyanobipheny..4-yI)- I H-pyrrol-3-yljsuccinic acid 4-benzyl ester and L-t-leucine N-methylamide (see Malon, Pancoska, Budesinsky, Hiavacek, J.; Pospisek, Blaha, K. Coil. Czech. Chem Commun. 1983, 48, 2844-2861) were coupled with TBTU. Successive flash column chromatography with 0-30% EtOAc/CH 2

CI

2 and MeOH/CH 2 Cl 2 gradient eluants, respectively, and radial chromatography with 0-40% EtOAc/hex gradient eluant furnished in 66% yield -(4'-cyanobiphenyl-4-yl)- IHpyrrol-3-yl]-N-(2,2-dimethyl- 1(S)-(methylcarnoyl)propyl)succinamic acid benzyl ester as *a crisp foam. I H NMR: 867.75 2H, J 8.5 Hz), 7.69 2H, J =8 .5 Hz), 7.64 2H, J= *8.8 Hz), 7.44 2H, J 8.5 Hz), 7.31 5H), 7.09 I1H, J 2.6 Hz), 7.04 I H, J 1. 8 6.50 (bd, I H, J 9.6 Hz), 6.28 (dcl, I1H, J 2.8 Hz), 5.70-5.67 (in, lIH), 5.12 2H), 4.13 I H, J 9.2 Hz), 4.02 I1H, J 7.4 Hz), 3.23 (dd, I1H, J 7.5, 16.7 Hz), 2. 85 (dd, I1H, J 6.8, 16.7 Hz), 2.76 3H, J 4.8 Hz), 0.96 9H). Anal. Calculated for

C

35

H

36

N

4 0 4 0.5 H 2 0: C, 71.77; H, 6.37; N, 9.57. Found: C, 71.73; H, 6.35; N, 9.54.

210 Example 14(c). 3(S)-[1-(4'-Cyanobiphenyl-4-yl)- 1H-pyrrol-3-yi H-imidazol- 2-yl)-3-methylbutylj succinamic Acid

CN

HO/

0>= According to the procedure described in Example 3(S)-[1-(4'-cyanobiphenyl-4yl)- IH-pyrrol-3 1H-imidazol-2-yi).3-methylbutyl]succinaznic acid benzyl ester was hydrogenolyzed in EtOHITHF for 3h to give a 54%/ yield of 3(S)-[1-(4'-cyanobiphenyl- 4-yl)- 1H-pyrrol-3-ylI-N- I 1H-imidazol-2-yl)-3-methylbutyl]succinaxnic acid: rnp 206- ~210 0 C (dcc); H-NMR(DMSO-d 6 812.0 (bs, 18, 8.31 18, .8.45 Hz), 7.93 48), 7.86 2H, J=8.5 Hz), 7.63 2H, .1=8.8 Hz), 7.33-7.30 (in, 2H). 6.81 6.18 18H), 5.02 (dd, 18H, J1=15.8, 8.8 Hz), 3.86 (dd, 18H, J=9.6, 4.8 Hz), 2.87 (dd, I1H, J1=16.9, 10.3 Hz), 2.60 (dd, I H, J= 16.5, 4.8 Hz), 1.7-1..5 (in, 3M), 0.87 38H, J=6.6 Hz), 0. 84 3H, J=5.9 Hz); HRFABMS Calculated for C 29

H

29

NSO

3 Cs 628.1325 Found: 628.1335 The starting material was furnished in the following fashion: 3(S)-1 I-( 4 -Cvanobip2henyl-4-vfl- IH-ovrrol-3-vfl-N-[ 1(SY-( IH-imidazol-2 v m~ethylbutllsuccinainic Acid Bemzl Fster-

CN

H

0 0 According to the procedure described in Example 1(b) for the preparation of 3(R)-tbutoxycarbonylainino-N-(2,2-dimethyl- I (S)-(methylcarbaxnoyl)propyl)succinaxnic acid benzyl ester, I -(4'-cyanobiphenyl-4-yl)- I H-pyrrol-J-yllsuccinic acid 4-benzyl ester (prepared as described in Example 14(b)) and 2-(lI (S)-amino-3-methyl-butyl)-imidazole (see Chen, Zhang, Hammond, Dewdney, Ho, Browner, Casteihano, A.L., submitted for publication; and Abel-Meguid, Metcalf B.W; Caw, DeMarsh, P.; Des Jarlais, Fisher, Green, D. et al. Biochemistry, 1994, 33, 11671-11677) were coupled with TBTU to provide a 49% yield of 3(S)-[l-(4'-cyanobiphenyl-4-yI)-1IH-pyrrol-3- 1 1 H-imidazol-2-yl)-3-methylbutyl~succinamic acid benzyl ester: znp 186-188 *C (dec); IHNMR (DMSO-d 6 8 11.79 INH), 8.40 I H, J=8.5 Hz), 7.92 4H), 7.85 (d, J=8.5 Hz), 7.62 (di, 2H, J=8.8 Hz), 7.34 5 6.97 I 6.84 IiH), 6.20 1IH), S. 513-5.00 (mn, 3H), 3.96 (dd, I H, J=9.9, 5.5 Hz), 2.99 (dd, I1H, J1l6.4, 10.8 Hz), 2.78 (dd, IH, J=16.4, 5.0 Hz,1.67-1.60 (mn, 2H), 1.55-1.45 (mn, IN), 0.85 3H, J=6-6 Hz), 0.81 (d, 3H, J=6.3 Hz); Anal. Calculated for C 36

H

3 5

N

5 0 3

OH

2 0: C, 71.62; H, 6.18; N, 11.60.

Found: C, 71.50,71.45; H, 5.97, 6.01; N, 11.51,11.48.

Example 14(d). 3(S)-f 1-(4'-Cyanobipbenyl-4-yI)- IH-pyrrol-3-ylj-N-(4,4-dimethyl-2oxo.

tetra hydrofurau-3(S)-yI)succinam ic Acid

CN

0 HO& INH>.O 0J According to the procedure described in Example 3 (S)-[1-(4'-cyanobiphenyl-4.

yl)- I H-pyrrol-3 -ylI-N-( 4 ,4-dimethyl-2-oxo-tetrahydrofuran.3(S).yl)succinamic acid benzyl ester was hydrogenolyzed in EtOH/EtOAc for 3h to give a 81% yield of cyanobiphenyl-4-yi)- I H-pyrrol-3-yI]-N-(4,4-dimethyl.2.oxo-tetrahydrofuan-3(S).

yl)succinrnic acid: 1HNMR (DMSO-d 6 8 12.2 (bs, IE), 8.48 (d,iH, J=8.8 Hz), 7.92 (s, 7.86 2H, J=8.5 Hz), 7.67 2H, J8.5 Hz), 7.40 lH), 7.37 IH), 6.33 Cs, IH), *4.75 IlH, J=8.8 Hz), 4.08, 4.00 (AB quartet, 2H, J=8.6 Hz), 3.97-3 .92 (mn, IlH), 3.01-2.92 I 2.64 (dd, I H, J= 16.54, 4.0 Hz), 1.05 3 0. 97 3 Anal. Calculated for

C

27

H

2 5

N

3 0 5 0CSH 12 0 (MTBE): C, 68.67; H, 6.66; N, 7.51. Found: 69.00, 68.91; H, 6.37, 6.42; N, 7.60, 7.52.

The starting material was furnished in the following fashion: 3(S)-Fl -(4'-CvaobpenlA..vl) I W-pvrroi oottavrfrn 3(S)-ybsuccinarnjc Acid Benzl Ester

CN

0 njZr According to the procedure described in Example 1(b) for the preparation 3(R)-tbutoxycarbonylanmino-N-(2,2-dimethy- 1 (S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2 (S)-[lI-(4'-cyanobiphenyl.4-yl)- IH-pyrrol-3-ylsuccinic acid 4-benzyl ester V. (prepared as described in Example 14(b)) and 3(R)-amino--4,4-dimethyl-2-oxo- :tetrahydrofuiran (see Freskos, J. N. Syn Commun. 1994, 24, 557-563) were coupled using TBTU with N-methyimorpholine as the base to provide a mixture of diastereomers which were separated using chromatography on silica gel column with 0 to 5% MeOH gradient in

CH

2

CI

2 Mixed fraction was repurified on a chroinatotron asing 0-2.5% MeOH/CH 2

CI

2 then 0- 1.25% MeOH/CH 2

CI

2 .as cluent to obtain I-(4'-cyanobiphenyl-4-yl)- IH-pyrrol- 3 4 4 -diznethyl-2-oxo-tetahydrofuran-3(S).yl)succnarnic acid benzyl ester in 29% *yield as an amorphous solid: IH NMR (CDCI 3 7.75 2H, 8.1 Hz), 7.69 2H, Hz), 7.64 2H, J=8.5 Hz), 7.46 2H, 1=8.5 Hz), 7.32 7.13 I 7.09 (t 7 I H, J=2.2 Hz), 6.32 6.06 IH, J=7.7 Hz), 5.13 21H), 4.67 1H, J=7.7 Hz), 4.08- 4.01 (in, 3H), 3.31 (dd, I*H, J=16.9, 8.5 Hz), 2.82 (dd, If!, J-16.7, 6.1 Hz), 1.23 3H), 0.98 3H); Anal. Calculated for C 34 H4 3 1

N

3

O

5 00.2 H 2 0: C, 72.25; H,-560; N, 7.43. Found: 72.32, 72.26; H, 5.8 8, 5.9 1; N, 7.07, 7.02.

Example 15(a). N-(1 (S)-Benzyl-2-hyd roxyetby l)-3(S)-(2-(bipbenyl-4-yl)furan.5 yl)succinamic Acid N H .HO I< OH 0 To a solution of N-4S-ezl22dmty-xzlii--i-()(-ihnl-i furan-5-yl)succinamic acid t-butyl ester (240 mng, 0.42 inmol) in CH 2

CI

2 (6 m.L) was added trifluoroacetic acid (3 mL). After 30 minuntes at ambient temperature, the inixure was .9,...partitioned between CH 2

CI

2 /pH7 phosphate buffer. The organic layer was washed with pH7 phosphate buffer and brine, dried over Na 2

SO

4 and evaporated to give a residue which was purified via flash columin chromatography with 0-1%HOAcIIO%MeOICH 2 Cl 2 gradient eiuant. The purified product was triturated with CH 2

CI

2 /hex to obtain 40 mg of N- (I (S)-benzyl-2-hydroxyethyl).3(S)-(2-Qiphenyl.4..yl)furan-5-yl)succinanijc acid as a pale yellow solid. 'H NMR (DMSO-d 6 6 8.12 (bin,IH), 7.74-7.68 (in,6H), 7.46 2H, J 7.35 1H, J 7.4 Hz), 7.25-7.12 (in, 5H), 6.86 I H,J =3.3 Hz), 6.26 (ci, IH, J Hz), 4.04 1H, J 7.5 Hz), 3.89-3.84 (mn, 1H), 2.83 (dd, 1H, J 5.7, 13.8 Hz), 2.71-2.59 (in, 3H). Anal. Calculated for C 29

H

27 N0 5

H

2 0: C, 71.44; H, 6.00; N, 2..87. Found: C, 71.5 1; H, 5.78; N, 2.92.

The starting material was fturnished in the following fashion:- 2-Birphenyl-4-vi-fliran To a mixture of 4-bromobiphenyl (1.00 g, 4.80 rnunol) and bis(triphenylphosphine) palladium(II) chloride (0.3 g, 0.4 rnmol) in TI-F (10 rnL) was added 2-tributylstannylfuran (1.6 mL, 5.0 mmol). After heating at reflux for l1h, the resultant mixture was concentrated to a residue which was dissolved in minimal CH 2

CI

2 and applied .to a flash chromatography colun. Elution with 10% CH,C1 2 fhex led to isolation of a mixture, which upon successive triturations with hexanes or pentane gave pure product. The mother liquor was partitioned with acetonitrile and hexanes. The separated acetonitrile layer was evaporated to obtain more pure product. A total of 0.55 g of pure 2-biphenyl-4-yi-furan as pale yellow solid, mp 4155-7*C was made. IH NMR: 8 7.75 2H-, J 8.1 Hz), 7.63 4H, J 8.5 Hz), *7.49-7.43 (in, 3H), 7.35 I H, J 7.0 Hz), 6.69 I1H, J 3.3 Hz), 6.50 (dd, I H, J1 3.3 Hz). Anal. Calculated for C 16

HI

2 0: C, 87.25; H, 5.49. Found: C,.87.16; H, 5.49.

216 I l2.2imethvl-oxaolidin-3.vfl2.(2-biphenvl-4-vIffti S- veha- 1 2 dionr= 0 0 e N0 According to the procedure described in Example 13 for the preparation of berzyl-2,2-direthyl-oxazolidin-3-yl)-2-(biphenyl-4-yl- I H-pyrrol-3-yl)ethane- 1,2-diane, 2biphenyl-4-yl-furan was deprotonated and alkylated with N-(4(S)-benzyl-2,2-dimethyloxazolidin-3-yl)-oxamic acid ethyl ester to give in 57% yield 1-(4(S)-benzyl-2,2-dimethyl.

i: oxazolidin-3-y)-2-(2-biphenyl-4-yl-fiuran-5yl)ethane- 1,2-diane as a pale yellow amorphous 1 solid. H NMR: 6 7.91 2H, J 8.1 Hz), 7.69 2H, J 8. 1 Hz), 7.64 2H, J 8.1 Hz), 7.49-7.36 4H), 7.25-7. 10 5H), 6.85 1H, J 4.0 Hz), 4.62-4.57 1H), 3.91 2H), 3.00 (dd, 1H, J 5.0, 13.0 Hz), 3.82 (dd, IH, J 10.1, 13.2 Hz), 1.86 3H), 1.68 3H). Anal. Calculated for C 30

H

2 7 N0 4 C, 77.40; H, 5.85; N, 3.01. Found: C, 77.43; H, 5.88; N, 3.06.

I -(4(S)-Benzv-2.2-dimeffiv-oxazoidin-3-vfl.2-(2-biphenvI-4-vl-fiira-5-yfl.2.hvdroxv- 0,I 0 According to the procdure described in Example 13 for the preparation of benzyl-2,2-dixnethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl- I H-pyrrol-3-yI)-2-hydroxy-ethanone, I -(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yI)-2-(2-bipheny-4-yI-furan-5-yl)ethane- 1,2-diane was reduced with NaBH 4 to give in quantitative yield l-(4(S}-benzyl-2,2-dimnethyloxazolidin-3-yI)-2.(2-biphenyl-4-y-furan-5-yl)-2-hydroxy-ethanone. I NMR: 8 7.70 (d, 2H, J 7.7 Hz), 7.61 4H, J 8.5 Hz), 7.45 2H, J 7.4 Hz), 7.38-7.19 (zm, 6H), 6.64 (d, J =2.9 Hz), 6.43 IH, J= 3.3 Hz), 5.08 1H, J =6.6 Hz), 4.45 IH, J =7.0 Hz), 3.88.-3.85 1H), 3.78 IH,J3= 8.8 Hz), 3.63 (dd, IH,J=5.2, 8.8 Hz), 3.03 (dd, 18,3 4.2, 13.1 Hz), 2.89 (dd, 1H, J 9.8, 13.4 Hz), 1.83 3H), 1.58 3H). Anal. Calculated *..for C 30

H

29 N0 4 0 0.5 H, 2 0: C, 75.61; H. 6.34; N, 2.94. Found: C, 75.62; H, 6.32; N, 2.88.

')-Acetoxy- I -(4(SI-benvl-2.2-dimethvI-oxazolidin-3-yi)-2-(2-binhenv-4vi-fiiran-5-yI /0 0 N 0 06 According to the procedure described in Example 13 for the preparation of 2-acetoxy- I -(4(S)-benzyl-2,2-dimethyl-oxazalidin-3-yl)-2-(biphenyl4-yl- 1H-pyrrol-3-yl)-ethanone, 1- (4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yI)-2-(2-biphenyl4-yl-furan-5-yi)-2-hydroxyethanone was acylated to furnish in quantitative yield 2-acetoxy-l-(4(S)-benzy1-2,2dimethyl-oxazolidin-3-yi)-2.(2-biphenyl-4-yl- firan-5-yl)-ethanone as an off white solid, nip 120-8*C, which was used without furher purification. 1 HNMR: 67.75 (d,2H, J=8.5 Hz), 7.66-7.62 (in, 4H), 7.46 2H, J 7.4 Hz), 7.39-7.22 (in, 6H), 6.70 18H, J =3.7 Hz), 6.62 18H, J 3.3 Hz), 6.3 9 I 3.86- 3.79 (in, 2H), 3.64-3.60 (in, 18H), 3.3 9 I H, J =14. 0 Hz), 2.96 (dd, 1H, J 11.4, 14.0 Hz), 2.25 3H1), 1.78 3H). Anal. Calculated for

C

32

H-

3 IN0 5 C, 75.42; H, 6.13; N, 2.75. Found: C, 75.27; H, 6.22; N, 2.65.

219 I -((S~BenvI- 2-imethvl -oxazo lidin-3 -ylh-2 -(2-bj phenX 1-4-vl-Jrn5v'.ehnn According to the procedure described in Example 13 for the preparation of 1 benzyl-2,2-dimethyl-oxazolidin3-yi)-2(biphenyl4-yl I H-pyrrol-3-yl)-ethanone, 2-acetoxy- I 4 (S)-benzyl- 2 ,2-dimethyI-oxazolidin-3-yl). 2-(2-biphenyl-4-yi-fuan-5-yl)-ethanorie was hydrogenolyzed to provide in 42% yield 1 -(4(S)-benzyl-2,2-dimethyl-oxazolidin.3-yl)-2-(2.

as an amorphous solid. IH NMR: 8 7.68 2H, J B.1I Hz), 7.62-7.58 (in, 4H), 7.44 2H, J 7.5 Hz), 7.37-7.25 (in, 6H), 6.64 I1H, J 3.3 Hz), 6.32 I H, J 2.9 Hz), 4.17-4.14 (mn, I 3.87 (mn, 2H), 3.77, 3.65 (AB quartet, 2H, J 15.8 Hz), 3.09 (dd, IH, J 13.6 Hz), 2.94 (dd, I1H, J 9.6, 13.6 Hz), 1.78 3H), 1.59 3H). Anal. Calculated for C 30

H

29 N0 3 C, 79.80; H, 6.47; N, 3. 10. Found: C, 79.72; H, 6.49; N, 3.03.

220 N-(4(-Ben~yl-2 -dimethvi-oxazolidin-.i-(R-2bpenl4y-frn vvscia A-c-W-t-Butl Ester 0 According to the procdure described in Example 13 for the preparation of benzyl-2,2-diethy-oxazolidin-3-yl)-3(R)-(I -biphenyl-4-yl-I H-pyrrol-3-yl)succinarnic acid t-butyl ester, 1 -(4(S)-benzy.2,2-direthyl-oxazolidir-3-y)-2-(2-biphenyl.4ylfu..syi) ethanone was deprotonated with sodium hexarethyldisilazide and alkylated to furnish in 74% yield N-(4(S)-benzyI-2,2-dimethyl-oxazolidin-3-i)-3(R)(2biphenyl.ylur..4 yl)succinamic acid t-butyl ester. IH NMR: 8 7.65 2H, J 8.5 Hz), 7.57 4H, J 8.3 Hz), 7.43 2H, J 7.4 Hz), 7.35-7.22 (in, 6H), 6.63 I H, J 3.3 Hz), 6.36 1H, J 3.3 Hz), 4.88-4.52 2H), 3.96-3.87 2H), 3.24 (dd, 1H, J 10.9, 17.1 Hz), 3.04 1H, J 11.4 Hz), 2.88-2.81 2H), 1.72 3H), 1.44 31). Anal. Calculated for C 3 6

H

39 N0 5 e 0.25 H 2 0: C, 75.83; H, 6.98; N, 2.46. Found: C, 75.83; H, 6.97; N, 2.46.

Example 15(b). N-[2,2-Dimethy I- I(S)-(metby Ica rba moy)pro py11 '4(2-(bip heny 4.yi) Acid 0 0 0 HO NH2NIlH 0 According to the procedure described in Example 15(a) for the preparation of N- (1 (S)-benzyl-2-hydroxyethyl)-3 (S)-(2-biphenyl-4-yl-furan-5.yl)succinamic acid, N-(2,2diznethyl- 1 (S)-(niethylcarbamoyl)propyl]-3-(2-(biphenyl-4-yl)-furan-5-yl)succinamic acid tbutyl ester was deprotected with trifluoroaceuic acid in CH 2

CI

2 after 1 hour. Trituration of crude with MTBE/hex provided in 48% yield N-[2,2-diznethyl-1I(S)- (methylcarbamoyl)propyl]-3-(2-(biphenyl-4-yl)-firnw-5-y)succinamic acid as a rust-colored amorphous solid. H NMR (CD 3 CN): 6 7.75 2H, J =8.5 Hz), 7.69-7.66 (in, 4H), 7.47 (t, 2 H, J 7.2 Hz), 7.3 7 I H, J 7.2 Hz), 6.91 I H, J =7.7 Hz), 6.77 I H, J -3.3 Hz), 6.56 (bs, 1H), 6.39 (d,iH, J =3.3 Hz), 4.24-4.19 IH), 4.12 iN, 1=9.2 Hz), 3.17-3.08 2.82 (dd, III, J 5.0, 17.1 Hz), 2.67 3H, I 4.8. Hz), 0.86 9H). HRFABMS: Calculated for C 2

,H

31

N

2 0 5 (M 463.2233. Found: 463.2236.

lot.

The starting material was furnished in the following fashion: 2 2 -Rip~henvi-4-yl-furan-S5-vt)-2-oxoacetic Acid Ethyl Ester According to the procedure described in.Example 13 for the preparation of 1 benzyl-2,2-dimethyl-oxazolidjn-3-yl)-2 -(biphenyl-4-yl- I H-pyrrol-3.yl)ethane- 1,2-dione, 2biphenyl-4-yl-furan was deprotonated and alkylated with diethyl oxalate to give in 74% yield 2 -(2-biphenyl-4-yI-furan-5-yl)-2-oxoacetic acid ethyl ester as a yellow solid, rnp 91-94 *C.

'H NMR: 8 7.94 2H, J 8.5 Hz), 7.83 I H, J 4.1 Hz), 7.69 2H, J 8.1 Hz), 7.64 2 H, J 7.7 Hz), 7.4 7 2H, J 7.4 Hz), 7.3 9 I H, J 7.2 Hz), 6.90 I H, J 4.2 Hz), **4.44 2H, J 7.0 Hz), 1.45 3H, J 7.2 Hz). Anal. Calculated for C 20

HI

6 0 4 C, 74.99; H, 5.03. Found: C, 75.11; H, 5.07.

2-(2-Biphenvl-4-vI-furan-5-fl)-2-hydraxv-acetic Acid Ethyl Ester 0 0 0 0 According to the procedure described in Example 13 for the preparation of benzyl.2,2-dimethyl-oxazoidin3.yl)-2(biphenyl..yl. I H-pyrrol.3-yl)-2-hydroxy.ethanone, 2 2 -biphenyl-4-yl-furan-5-yl)-2-oxoacetic acid ethyl ester was reduced with NaBH 4 to give in quantitative yield 2 2 -biphenyl-4yl-fran-5-yl)-2-hyroxy-acetic acid ethyl ester as a yellow solid, mp 75-80*C which was used crude without purification. H NMR: 8 7.73 2H, J 8.5 Hz), 7.62 4H, J 8.1 Hz), 7.45 2H, J 7.4 Hz), 7.35 IH, J 7.4 Hz), 6.66 1H, J 3.3 Hz), 6.48 lH, J 3.3 Hz), 5.24 IH, J 5.9 Hz), 4.36-4.28 2H), 3.42 IH, J 6.3 Hz), 1.30 3H, J 7.2 Hz).

2 -Acetox-2(2.biphenvl-4-vl-f 'an-aceic Acid Ethyl Ester 0 0 0 0 0 According to the procedure described in Example 13 for the preparation of 2-acetoxyl-( 4 (S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl4yl I H-pyrrol-3-yl)-ethanone, 2.

2 -biphenyl-4-yI-fuan5-yl)-2-hydroxy-acetic acid ethyl ester was acylated to furnish in 83% yield 2 -acetoxy-2-(2-biphenyl4-yl-furan-5-yl)-acetic acid ethyl ester which was used without purification. Flash column chromatography with 0-20% EtOAc/hex as eluant gave an analytically pure pink solid, mp 136-140*C. 1 H NMR: 6 7.74 2H, J 8.5 Hz), 7.63 (d, 4H, J 8.5 Hz), 7.46 2H, 7.4 Hz), 7.36 I H, J 7.2 Hz), 6.68 li, J 3.7 Hz), 6.58 IH, J 3.3 Hz), 6.57 IH), 4.29 2H, J 7.0 Hz), 2.21 3H), 1.29 3H, J 7.2 Hz). Anal. Calculated for C22H2005: C, 72.5 1. H, 5.53. Found: C, 72.6 1; H, 5.63.

2-(2-Bihenl-4YI- furan-5-y -acetic Acid Ethyl Ester According to the procdure described in Example 13 for the preparation of benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(nl--l H-pyrrol-3-yl)-ethanone, 2-acetoxy- 2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid ethyl ester was hydrogenolyzed to provide in 61% i yield 2-(2-biphenyl-4-yl-uran-5-y)-acetic acid ethyl eter a a white solid mp 77-78C. I H NMR: 8 7.71 2H1, J 8.5 Hz), 7.63-7.59 4H), 7.45 2H, J 7.4 Hz), 7.35 I H, J 7.4 Hz), 6.64 I H, J 2.9 Hz), 6.34 I H, J 3.3 Hz), 4.22 2H, J 7.2 Hz), 3.76 (s, 1.30 3 H1, J 7.2 Hz). Anal. Calculated for C20H 1803: C, 78.4 1; H, 5.92. Found: C, 78.16; H, 5.92.

2-(2-Bihenyl4-4yi-fuan- 5-y I)-aetic Acid

HO

To a solution of 2-(2-biphenyl-4-yl-furan-S-yly-acetic acid ethyl ester (0.465 g, 1.44 mmrol) in TI-F (10 rnL) at 0 0 C was added 21M aqueous LiOH (2 The mixture was allowed to warm over 4 hours to ambient temperature and then poured into 0.5M aqueous HCI (50 niL). The resultant pale orange precipitate was filtered off, rinsed with water, and dried under vacuum over P 2 0 5 to provide 400 mg (100%) of 2-(2-biphenyl-4-yl-furan.5-yl)acetic acid as a light orange solid, nip 196-210'C, used without further purification. IH NMR (acetone-d 6 8 7.78 2H, J1 8.1 Hz), 7.72-7.67 (mn, 4H), 7.46 2H-, J 7.4 Hz), 7.35 I H, J 7.4 Hz), 6.84 1H, J 3.3 Hz), 6.41 1H, J 3.3 Hz), 3.81 2H). Anal.

Calculated for CISH 14 0 3 C, 77.68; H, 5.07. Found: C, 77.44; H, 5.16.

N-r2-2-Dimethyl- I S-Nmty-abmvi-2o~l-.2bphnl4y-l=5y aceamide 00 Acodn to th rcdr4ecie nEape10frtepeaaino bezl2mtoyehl*()tbtxcr ny o -aiosciai cd ezletr -2 aci wa opeSoLtlecn -ehlm trfuoocei acdsl ihBP4ls ouncrmtgah ih05 eIC2I grdin 4latpoie n58 il -22dmthl S-Nmty-abmy)po~l 2-2bpey4y*ua--l-ctmd as 0n ornefomHhchdcmpsd>5 n Acue wtongto uther prourctin decibe in~ Eametn 1( for2 the prpaion of 1. Hz)-.6 226 4H, J =7.7 Hz), 7.45 2H, J 7.5 Hz), 7.35 I1-H, J 7.4 Hz), 6.65 I H, J 3.3 Hz), 6 I1H, J 9.2 Hz), 6.3 6 I1H, J 3.3 Hz), 5.93 (bs, 4.22 I1-H, J 9.2 Hz), 3.71 2H4), 2.79 3H, J 4.5 Hz), 0.94 9H). Anal. Calculated for C 25

H

28

N

2 0 3 0 0.6 H-fO 0. 1 MTBE: C, 72.2 1; H, 7.23; N, 6.61. Found: C, 72. 10; H, 6.97; N, 6.39.

N-[2-2-Dimethyl- I (S-mtycraoipoyl3(-2ihni-l-ua--lsciai 0 According to the procedure described in Example 13 for the preparation of benzyl-2,2-dimethyl-oxazoiidin-3-yI)-2(R)-(biphenyl-4.yl- 1H-pyrrol-3-yl)succinamic acid tbutyl ester, but N-(2,2-dimethyl- 1 (S)-(N-inethylcarbamoyl)-propyl)-2-(2-biphenyl-4-ylwas instead deprotonated with n-butyllithiumn (3.1 equiv) and alkylated to furnish 17 mng of N-[2,2-diinethyl- 1 (S)-(methylcarbamoyl)propyl]-3-(2-(biphenyl-4yl)-furan-S-yl)succinamic acid t-butyl ester as an amorphous solid. 'H NMR: 6 7.70 (di, 2H, J 8.1 Hz), 7.62-7.5 9 (in, 7.45 2H, J 7.5 Hiz), 7.3 5 IH, J 7.4 Hz), 6.63 (di, I H, 3.3 Hz), 6.50 I H, J 9.6 Hz), 6.33 I1H, J 3.3 Hz), 5.09 (bin, IMH), 4.19-4. 10 (mn, 2H), 3.15 (dd, I H, J 8.5, 16.6 Hz), 2.86-2.73 (in, 4H), 1.41 9H), 0.89 9H). ER.MS: Calculated for C 31 H3 9

N

2

O

5 (M 519.2859. Found: 519.2865.

Example 16. 1(S)-Benzyl-2-hydroxyethy l)-3(R)-[4-(bipherlyl-4-yI)-.pyrazol-. 1 yllsuccinamic Acid N7 O N .H OAZ>NH OH According to the procedure described in Example 1 N.(I (S)-benzyl-2hydroxyethyl).3(R)-[4-(biphenyl-4.yl)pyrazol.I -yljsuccinamnic acid benzyl ester was hydrogenolyzed to obtain in 74% yield 1 (S)-benzyl-2-hydroxyethyl)-3(R)-[4.{biphenyl-4yi)pyrazol- I ylsuccinaznic acid as a white solid, mp 154-9 0 C. IH NMR (D 3 COOD): 6 8.17 I1H), 8.06 I1H), 7.64-7.67 (in, 6H), 7.49 2H, J 7.5 Hz), 7.3 8 I H, J 7.0 Hz), 7.29-7.16 (in, 5H), 5.60 I H, J 7.2 Hz), 4.32-4.28 (in, 1H), 3.79-3.65 (in, 2H), 3.35 (d, 2H, J 6.6 Hz), 2.96-2.83 (in, 2H). Anal. Calculated for C 2 gH 27

N

3 0 4 *0.25 H 2 0 *0.25

C

6

H

14 C, 71.49; H, 6.3 1; N, 8.48. Found: C, 71.54; H, 6.30; N, 8.40.

The starting material was furnished in the following fashion: 2-Bromo-N-( I (S~-hvdroxvmethvI-2-phenylethl~acetaniide

-NH--O

0 To a solution of 2 -arnino-3-phenyl- I-propanol (1.00 g, 6.61 mmxol) and triethylarnine (I niL, 7.17 mmol) in TH-F (70 inL) at -780C was added dropwise bromnoacetyl bromide (0.60 mL, 6.9 mmol). After 1.25 hours at -78 0 C, the resultant mixture was partitioned between I M pH7 phosphate buffer 100 mL) and hexanes (100 The aqueous layer was extracted with EtOAc: hex 50 mL). The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated to give 1.59 g of 2bromo-N-( 1 (S)-hydroxymethyl-2-phenylethyl)acetamide as a solid, mp 83-5 'H NMR (DMSO-d 6 6 8.15 I1H, J 8.1 Hz), 7.32 11 (in, 5H), 4.82 I H, J 5.3 Hz), 3.83- 3.74 (in, 3H), 2.80 (dd, I1H, J 5.9, 13.6 Hz), 2.59 (dd, IlH, J 8.9, 13.6 Hz). Anal.

Calculated for C 11

H

14

NO

2 Br: C, 48.55; H, 5.19;N, 5.15; Br,29.36. Found: C, 48.69; H, 5.13; N, 5.13; Br, 29.30.

3-(2-Bromoacetyfl-2-2-dimethylI-4(S')-phenylmethv1-oxazolidine Br N 0 To a mixture of 2-bromo-N-( 1 (S)-hydroxymethyl-2-phenylethyl)acetaznide (1.5 5 g, 5.45 mmol) and p-toluenesulfonic acid monohydrate.(100.mg) in CH 2 Cl 2 (50 rnL) was added 2-rnethoxypropene (1.50 mL, 15.7 inmol) dropwise -via syringe. After 15 minutes at ambient temperature, the resultant mixture was washed vwith 1 M pH7 phosphate buffer (25 mnL) and brine (25 dried over Na 2

SO

4 and concentrated to give a dark solid, which was triturated with MTBE/hex to provide 1.46 g of 3-(2-bromoacetyl)-2,2-dimnethyl-4(S)phenylmethyl-oxazolidine as a pale yellow solid. IHNM(DMSO-d 6 '-7..33-7.17 (i, 4.21-4.15 (M,1IH), 4.04, 3.86 (AB quartet, 2H, J =12.1 Hz), 3.79 (dd, I H, I 4.8, 9.2 Hz), 3.71 I H, J =9.2 Hz), 2.99 (dd, IlH, J 5.0, 13.4 Hz), 2.70 (dd, I H, J 13.2 Hz), 1.55 3Hf), 1.38 3H). Anal. Calculated for C 14 Hj 8

NO

2 Br: C, 53.86; H, 5.81; N, 4.49; Br, 25.39. Found: C, 53.91; H, 5.82; N, 4.47; Br, 25.58.

1 -(4(S)-Benzyl-2.2-dimethvl-oxazol idinfl)-2-f4-iodopvrazol. 1-v l'-ethanone KN 0 0 To a suspension of hexane-washed sodium hydride (from 15 mg of 60% dispersion in oil, 0.38 rnrol) in THF (2mL) at 0 0 C was added a solution of pyrazole (62 mg, 0.32 mmol) in THF (1 mL) dropwise via cannula. After 15 minutes at O'C, a solution of 3-(2- Y bromoacetyl)-2,2-diniethyl-4(S)-phenylmethyl-oxazolidine (100 mg, 0.320 mmol) in THF (1 mL) was added via cannula. After 5 minutes at 0 0 C, the mixture was allowed to stir at ambient temperature for 30 minutes. The resultant mnixture was partitioned between EtOAc and pH7 phosphate buffer. The aqueousueous layer was extracted -with more EtOAc. The combined organic layers were dried over Na 2

SO

4 and concentrated to an oily residue, which spontaneously crystallized. The crystals were triturated with MTBE/hex to obtain a white solid. The filtrate yielded another crop and in total 100 mg of 1-(4(S)-beiizyl-2,2dimethyl-oxazolidinyl)-2-(4-iodopyrazol- I-yl)-ethanone as white crystals, mnp 1 17.200 C, were obtained. '11NMvR (DMSO-d 6 87.76 IH), 7.51 IH), 7.37-7,2,4(ni,5H), 5.25, 4.87 (A.B quartet, 2H, J =16.6 Hz), 4.35-4.30 (in, 1H), 3.86-3.81 (in, IH), 3.76 I1-H, J= 8.8 Hz), 3.06 (dd, I H, J 13.6 Hz), 2.80 (dd, IN, J 9.9, 13.6 Hz), 1.55 1.41 (s, 3H.Aa.CluaedfrC 7 2 N0l C, 48.01; H, 4.74; N, 9.88. Found: C, 48.28; H, 4.78; N, 9.79.

1 4 (S)-Benzyl-2.2-diinethyl-oxazolidinvl)-2-4-biphenvl..4-vl..pvraol. I-vlb-ethanone

N

NYO

V .According to the procedure described in Example 1(a) for the preparation of 3biphenyl-4-yi-furan, I 4 (S)-benzyl-2,2-dimethyl-oxazoidinyl)-2-(4-iodopyazol- l-yl)ethanone was coupled to 4-biphenylboronic acid to provide in 39% yield 1-(4(S)-benzyl-2,2dimethy-oxazolidinyl)-2-(4-biphenyl..4-yi-pyrazol.. I -yl)-ethanone as a white solid, mp 150lo 0 c. I'H NMR: 8 7.83 IM1, 7.68 IH), 7.62-7.52 (in, 6H), 7.47-7.28 8H), 4.83, 4.38 (AB quartet, 2K J, 15.6 Hz), 4.22,4.18 I1-H), 3.94 (mn, 2H), 3.09 (dd, 1H, J 6.4, 13 .0 Hz), 2.97 (dci, IN, J 8.5, 13.2 Hz), 1.79 3H), 1.55 3H). Anal. Calculated for

C

29

H

29

N

3 0 2 C, 77.14; H, 6.47; N, 9.3 1. Found: C, 77.04; H, 6.52; N, 9.37.

4-(4(S)-Benzv-22-dimethvl-oxazolidin-3-vlb-3(R)-(4-biphenvl..4-vi-pvrazoI- 1-vfl)suciaj Acid BenZyl Ester

N

To a solution of diisopropylamine 10 mrL, 0.76 mmol) in THF (2 ml) at 0 0 C was added n-butyllithium (0.4 rnL of 2.5M in hexanes). After 30 minutes at 0 0 C, the solution was added dropwise to a solution of l-(4(S)-benzyl-2,2-dimethyl-oxazolidinyl)-2-(4- ~biphenyl-4-yI-pyrazol-l-yl)-ethanone (325 mug, 0.720 rrunol) in TI-F (8 mnL) at -78 0 C. After :15 minutes at -78*C, the bright yellow solution was cooled to -100*C and benzyl 2.

brornoacetate (freshly passed through A1 2 0 3 0. 16 mL, 1.0 mrnol) was added. After 1 hour at -100 to -70 C, the mixture was partitioned between EtOAc and water and the aqueousueous layer was extracted with more EtOAc. The combined organic layers were dried over Na 2

SO

4 and concentrated to furnish a crude oil which was purified via flash column chromatography with 0-5% EtOAc/CH 2

CI

2 gradient eluant to give 150 mg of 4-(4(S)-benzyl-2,2diinethyl-oxazolidin-3-yl)-3(R)(4-biphenyl4-yl-pyrazol. I yl)succinamic acid benzyl ester as an oil, which was used without further purification. An analytical samnple was obtained after trituration with MTBE/hex and drying to an amorphous solid. H NMR: 8 8 .01 I1H), 7.82 1H), 7.62-7.53 (in, 7M), 7.44 2H, J 7.7 Hz), 7.36-7.30 (in, 1OH), 5.83 (dd, IlH, J 10.5 Hz), 5.14 211), 4.44-4.39 (mn, IH), 3.85 IH, J 9.2 Hz), 3.79-3.74 (mn, IH), 232 3.57 (dd, I1H, J =10.3, 16.9 Hz), 3.08 (dd, I H, I 3.1, 15.6 Hz), 2.79-2.64 (in, 2Ff), 1.67 (s, 1.50 3M). Anal. Calculated for C 3 SH3 7

N

3 0 4 0.2 H 2 0: C, 75.65; H, 6.25; N, 6.97.

Found: C, 75.74; H, 6.56; N, 6.90.

I(S)-Benzy-2-hydroxvethv 3(R)-(4-biphenyl-4-vl-pyrazol- I-vhsuccinamjc Acid

N'

ry-kI~NH

OH

.0 To a solution of 4-(4(S)-berizyl-2,2-dimethyl-oxazolidin-3-yl)-3(R)-(4-biphenyl.4-ylpyrazol- I -yl)succinaznic acid benzyl ester (174 mg, 0.290 mxnoL) in THF (3 mL) was added aqueous HCI (I mL). After 1 hour at ambient temperature with no apparent reaction, 6N HCI (4 drops) was added and the mixture was warmed to 45 After 17 hours, the mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 and the aqueousueous layer was extracted with CH 2

CI

2 The combined organic layers were washed with water, dried over Na 2

SO

4 and concentrated to-provide 70. mg of N-(1(S)-benzyl- 2-hydroxyethyl)-3(R)-[4-(biphenyl-4-yl)pyrazol- 1 -yI]succinamnic-acid benzyl ester as :colorless crystals, mp 1 16-7 I'H NMR: 6 7.88 IH), 7.65 Sf1, J 8.1 Hz), 7.53 (d, 2H, J 8. 1 Hz), 7.47 2H, J 7.5 Hz), 7.37 I H, J 7.5 Hz), 7.34-7.23 (in, S5H), 7.19- 7.13 (in, 3H), 7.01 211, J 7.7 Hz), 6.54 IH, J 6.6 Hz), 5.22 1H, J 6.8 Hz), 5.11, 5.06 (AB quartet, 2H, J 12.1 Hz), 4.20-4. 10 (mn, I 3.72 (dd, I1H, J 3.7, 11.0 Hz), 3.5 6 (dd, I H, J 11.4 Hz), 3.34-3.31 (in, 2H), 2.82 (dd, I1-H, J 6.6, 13.6 Hz), 2.70 (dd, I H, J 13.8 Hz). Anal. Calculated for C 35

H

33

N

3 0 4 o 0.3 H 2 0: C, 74.39; H, 5.99; N, 7.44.

Found: C, 74.49; H, 6.02; N, 7.44.

Example 17(a). 4- I 2 2 (R)-Carboxyinethy.2-(tbien-2.yl)acetylamino 14-methylv aleroylJ -amino benzo ic Acid Methyl Ester

HO.K

5

NH)NCG<

00 According to the procedure described in Exanmplc 15(a). butoxycarbonylmethy-2-tien2-ylacetlamino)-4methylvaleroylI..uninobenzoic acid methyl ester was hydrolyzed with trifluoroacetic acid, except in CH 2

CI

2 :anisole 1) as solvent, to give in 88% yield 4 2 S-(2(R)-carboxymethyl-2-thien2yacetylanino)4-methyl- 9 .0.

0 valeroyl]-aminobenzoic acid methyl ester as a white solid, mp 1 97-200'C. IH NMR (DMSO-d 6 8 12.25 1H), 10.32 1H), 8.52 IlH, J 7.7 Hz), 7.88 2H, J 8.7 Hz), 7.68 2H, J 8.7 Hz), 7.33 111, J 5.0 Hz), 6.96-6.90 (mn, 2H), 4.49-4.45 (mn, 1H), 4.31 (dd, 1 H, I 5.4, 9.8 Hz), 3. 80 311), 2.92 (dd, I H, J 9.8, 16.5 Hz), 2.61 (dd, I11, J 16.6 Hz), 1.74-1.46 (mn 3H), 0.90 311, J 6.6 Hz), 0.86 3H, J 6.5 Hz). Anal.

Calculated for C22H 26

N

2

O

6 S: C, 59.18; H, 5.87; N, 6.27; S, 7.18. Found: C, 59.28; H, 5.92; N, 6.29; S, 7.27.

The starting materials were available as follows: 00 N IL0 To a solution of (S).(-)-4-benzyl-2-oxazolidinone (350 mg, 2.00 mmol) in dry THF mL) at -30*C was added dropwise n-butyllithium (2.59 M in hexanes, 0.8 mL). The mixture was cooled to -78-C and treated with 2-thiopheneaceryl chloride (0.25 rnL, 2 mmnol).

After stirring at -78 0 C for 45 minutes, the mixture was allowed to warm to ambient temperature and stir for I hour. The mixture was diluted with hexanes (10 mL), quenched 0 0.

with 1 M pH7 phosphate buffer, and stined for 45 minutes. The layers of the resultant biphasic mixture were separated and the aqueousueous phase extracted with EtOAc. The combined organic layers were washed with 0.5N aqueous HCI two times, saturated aqueous NaH-C0 3 two times, and brine, dried over Na 2

SO

4 and concentrated to provide a crude residue which was purified via flash column chromatography with 20% EtOAcfhex as eluant to yield 319 mg of 4(S)-benzyl-3-(2-thien.2-yi..acetyl).2.oxazolidinone as a tan solid, rnMp 56-9 0 C. 1 HNMR: 8 7.34-7.26 (in, 5H), 7.17-7.14 (in, 2H), 7.02-6.98 (mn, IH), 4.72- 4.67 (in, I 4.57, 4.48 (AB quartet, 2H, J 16. 8 Hz), 4.26-4.17 (mn, 2H4), 3.29 (dd, I1H, J= 3.2, 13.4 Hz), 2.79 (dd, I H, J~ 9.5, 1.4. Anal. Calculated for C 16 H 15 N0 3 S: C, 63.77; H, 5.02; N, 4.65; S, 10.64. Found: C, 63.87; Hi, 5.04; N, 4.71; S, 10.74.

4-(4(S)-Benvyloxazolidin2-on3vl-3(Rthien2-vlsuccinamir Acid t:EuvL Ester According to the procedure described in Example 13 for the preparation of benzyl.2,2-dimethyl-oxazolidin-3-yl)-3(R).(biphenyl.4-yl. I H-pyrrol-3-Yl)succinainic acid tbutyl ester, the corresponding anion of 4 (S)-benzyl-3-(2-thieri.2.yl-acetyl)-2-oxazolidinone was alkylated with t-butyl 2-bromoacetate. Flash column chromatography with EtOAc/hex as eluant provided in 65% yield 4-(4(S)-benzyloxazolidin-2-on-3-yI)-3 (R)-thien- 2-yI-succinamic acid t-butyl ester as a white solid, rnp 109-l11aC. I HNMR: 6 7.36-7.26 (mn, 5H), 7.22 I H, J 5.0 Hz), 7.06 I H, J 3.5 Hz), 6.93 (dd, I H, J 3.9, 5.2 Hz), 5.85 (dd, I H, I 4.2, 11.4 Hz), 4.62-4.57 (in, 11-1), 4.14-4.09 (mn, 2H4), 3.42-3.33 (in, 2H), 2.82- 2.70 (in, 2H), 1.43 9H). Anal. Calculated for C 22

H

25 N0 5 S: C, 63.60; H, 6.06; N, 3.37; S, 7.72. Found: C, 63.3 7; H, 6.07; N, 331; S, 7.69.

2CR)'-Thien-2-yl-suceinic Acid 4-t-Butvl Ester

>LOASO

0 To a solution of 4-(4(S)-benzyloxazolidin-2-on-3-yi)-3(R)-thien-2-yi-succinamic acid t-butyl ester (630 mg, 1.52 inmol) in THF (15 rnL) at 0 0 C was added 2N aqueous LiOR (1.14 mL). H 2 0 was added periodically to maintain homogeneity. After 5.75 hours at 0 0

C,

saturated aqueous NaHCO 3 (5 mnL) was added. THF was removed under r~duced pressure, 236 and the mixture extracted with CH 2 C1 2 (5 mnl) three times. The combined organic layers were extracted with saturated aqueous NaHCO 3 The combined aqueouslayers were acidified to -pH2 using 2N aqueous HCI and extracted with CH 2 C1 2 (5 rnL) three times. These extracts were dried over Na 2

SO

4 and concentrated to yield 350 mg of 2(R)-thien-2-ylsuccinic acid 4-t-butyl ester as an oil, which was pure and used without further purification.

IH NMR: 6 7.22 I1H, J 5.1 Hz), 6.99 (in, 2H), 4.33 (dd, I1H, J 5.4, 9.9 Hz), 3.11 (dd, I H, J 9.9, 16.7 Hz), 2.74 (dd, ILH, J 5.4, 16.7 Hz), 1.41 9H). IR: 2980, 2934, 1732, 1715, 1370, 1285, 1256, 1152, 843, 702 cm 1 Anal.. Calculated for C I 2 H I 6 N0 4 S: C, 56.23; H, 6.29; S, 12.5 1. Found: C, 56.24; H, 6.35; S, 12.45.

4-f 2S-2(R)-t-Butoxycarbonylmethvl-2-thien-2-vlacetvlamino)-4-methvlvaleryLj- *:arninobenzoic Acid Methyl Ester .3 *LZ 0 According to the procedure described in Example 1(0) for the preparation of N-(1 4....benzyl-2-methoxy-ethyl)-3(R)-t-butoxycarbonyl-amino-succinami c acid -benzyl ester, 2(R)thien-2-yL-succinamic acid 4-t-butyl ester and 4-(2S-amino-4-methyl- :pentanoylamino)benzoic acid methyl ester (see Castelhano, Yuan, Home, Liak, T.J. W095/12603-AI, May 11, 1995) were coupled with BOP to give a mixture of diastereomers; which were separated via flash column chromatography with a 10-25% EtOAc/hex gradient eluant. Mixed fractions were purified via radial chro maiography with 237

MTBE/CH,C

2 /hex as eluant. I this manner a total yield of 51% of butoxycabonylmethyl-2-tie2ylactyllio)4mehylvaleroyllIuniobcflzoic acid methyl ester as a white solid, mnp 8 0-1 'C was obtained. I H NMR: 6 8.72 lH), 7.95 (di, 2H, J 8.6 Hz), 7.61 (di, 2H, J 8.6 Hz), 6.99-6.96 (mn, 2H), 6.02 1Ki J 8.0 Hz), 4.64- 4.56 (in, I 4.20 Ili, J -6.2 Hz), 3.89 3H1), 3.04 211,1 =6.2 Hz), 1.89-1.83 (in, I 1. 44 9H1), 0.9 1(t, 6H, I1 6.2 Hiz). Anal. Calculated for C 26

H

34

N

2 0 6 S: C, 62.13; H, 6.82; N, 5.57; S, 6.38. Found: C, 62.13; H, 6.83; N, 5.54; S, 6.46.

Example 17(b). 4-.()1()Croyehl2(lin3yaey~ia--ehl valeroyll-azniuobenzoic Acid Methyl Ester S 0 o0 OC~H ga H of HOk N N codi: to the procedure described in Exanple 17(a), butoxycarbonyimethyl-2-tbicfl- 3 -ylacetylamiino)-4--methyl-valeroyI-znilObelzoic acid 620 methyl ester was hydrolyzed with trifluoroacetic acid in CH{ 2 C1 2 :anisolc to give in 8% 0 yield 4-[2S-(2(R)-carboxymethyl-2-thien-2-ylacetylw mo)-4-methyl-valeroyl] -aminobenzoic acid methyl esteras awhite solid mp 199-201T. 1H NW D SO 8 12.15 1M 10.31 1H) 8.43 (di, 11H, J1 7.5 Hz), 7.89 2H, 8.6 Hz), 7.68 21-, J S. 7 Hiz), .7.44-7.41 (rIH), 7.25 1H, I1 2.5 Hz), 7.09 Ii. J1 4.1 Hz), 4.48-4.45 (Mn liH), 4.08 (dd, IH, J 10.2 Hz), 3.80 2.89 (dd, 1i, I 10.3, 16.5 Hz), 2.61 (ddi, 1H, J 16.6 Hz), 1.75-1.44 (Ta, 3H), 0.90 3H, J 6.6 Hz), 0.86 (di, 3H. J 6.5 Hz). Anal.

Calculated for C 22

H

26

N

2 0 6 S: C, 59.18; H, 5.87; N, 6.27; S, 7.18. Found: C, 59.2 1; H, 5.92; N, 6.21; S, 7.25.

The starting materials were available as follows: S3 0 0 According to the procedure described in Example 17(a). for the preparation of 4(S)benzyl.

3 -(2-thien-2.yl-acetyl)-2.oxazolidinone 3-thiopheneacetyl chloride and benzyl-2-oxazolidinone furnished in 68% yield 4(S)-benzyl-3-(2-thien-3-yi-acetyl)-2oxazolidinone as a solid, mp 80-1 'H NMR: 5 7.33- 7.24 (in, 5H), 7.15-7.09 (in, 3H), 4.72-4.65 (in, 1H), 4.39, 4.28 (AB quartet, 2H, J= 15.9 Hz), 4.22-4.15 (in,2H), 3.26 (dd, 1H, J 13.4 Hz), 2.77 (dd, I H, J 9.4, 13.4 Hz). Anal. Calculated for C 16

H

1 SN0 3 S: C, 63.77; H, 5.02; N, 4.65; S, 10.64. Found: C, 63.80; H, 5.04; N, 4.69; S, 10.70.

4 4 (S')-RenZvloxazolidin-2-on-3-vfl.3(R)-.thien-3-.vl.succinamic Acid t-Butyl Ester 9- AS 0~ 0 0o According to the procedure described in Example 13 for the preparation of benzyl-2,2-dirnethyl-oxazolidin-3-yl)-3 (R)-(biphenyl-4-yl- I H--pyrrol-3)-yl)succinamic acid tbutyl ester, the corresponding anion of 4(S)-benzyl-3-(2-thien-3-yl-acetyl)-2-oxazolidinone was alkylated with t-butyl 2..bromoacetate. Flash column chromatography with EtOAc/hex as eluant afforded in 77% yield 4-(4(S)-benzyloxazolidin-2-on-3-yl)-3(R)-thien- 2-yl-succinamnic acid t-butyl ester as a white solid, mp 103-4'C. I NMR: 6 7.36-7.25 (in, 7H1), 7. 10 I1H, J 3.2 Hz), 5. 64 (dd, I H, J 4.4, 11.2 Hz), 4.62 -4.5 7 (mn, I1H), 4.14-4.04 (in, 2H1), 3.39-3.27 (mn, 2H), 2.78 (dd, I H, J 10.0, 13.4 Hz), 2.63 (dd, I H, J 4.4, 17.1 Hz), 1.43 9H1). Anal. Calculated for C 22

H

24 N0 5 S: C, 63.60; H1, 6.06; N, 3.37; S, 7.72.

Found: C, 63.44; H, 6.09; N, 3.33; S, 7.78.

M: 2(R)-Thien-3-yl-succinic Acid 4-t-Butyl Ester 0 *.:According to the procedure described in Example 17(a) for the preparation of 2(R)thien-2-yl-succinic acid 4-t-butyl ester, 4-(4(S)-benzyloxazolidin-2-on-3-yI)-3(R)-thien-3-y Isuccinamic acid t-butyl ester was hydrolyzed in 70%.yield to 2(R)-thien-3-yl-succiniic acid 4- *t-butyl ester as an oil, which was used without furthev~purification. H NMR: 8 7.29 (dd, 11, J 4.9 HZ), 7.17 IH, J=2.7 Hz), 7.05 1H,J= 5.0 Hz), 4.18 (dd, IH, 9.8 Hz), 3.06 (dd, I H, J 9.9, 16.7 Hz), 2.66 (dd, I H, J 5.6, 16.7 Hz), 1.40 (S 911). IR: 3104, 2978, 2934, 1728, 1715, 1370, 1258, 1154, 855, 774 cm- 1 Anal. Calculated for C 12 H 16 N0 4 S: C, 56.23; H,6.29; S, 12.5 1. Found: C, 56.29; H, 6.35; S, 42-42.

4- r2S-(2(R)-t-Butoxycarbonvlmethyj.2-thien-3 -vlacetvlarnino)-4-methvlvalerovllazninobenzoic Acid Methyl Ester 0>0 According to the procedure described in Example 1(0) for the preparation of benzyl-2-methoxy-ethyl)-3(R)-t-butoxycarbonylanino-succinamic acid benzyl ester, 2(R)thien-3-yI-succinamic acid 4-t-butyl ester-and 4-(2S-amino-4-methylpentanoylarnino)benzoic acid methyl ester (see Castellano, Yuan, Z; Home, Liak, T.J. W095112603-A1, May 11, 1995) were coupled with BOP. Precipitation with H 2 0 and recrystallization from toluene gave in 55% yield 4-[2S-(2(R)-t-butoxy-carbonylmethyl-2- :thien-3-ylacetylamnino)-4-rnethylvaleToyl]-aminobenzoic acid methyl ester as a white solid, mp 168-70 0 C. t H NMR: 8 8.62 I 7.96 2H, J 8.6 Hz), 7.56 2H, J 8.8 Hz), 7.3 3 (dd, I1H, J 3.0, 4.8 Hz), 7.19 I1-H), 7.02 IlH, J 5.1 Hz), 5.86 (bd, 1 H, J 6.7 Hz), 4.57-4.51 (in, 1H), 4.04 I H, J 6.6 Hz), 3.89 3.04 (dd, I1H, J 7.4, 16.9 Hz), 2.88 (dd, lH, J 5.6, 16.9 Hz), 1.88-1.81 (mn, IH), 1.42 0.92 6H, J 6.5 Hz).

Anal. Calculated for C 26

H

34

N

2 0 6 S: C, 62.13; H, 6.82; N, 5.57; S, 6.38. Found: C, 62.08; H, 6.79; N, 5.64; S, 6.46.

Example 17(c). N-12,2-Dimethyl-1 (S)-(pyridin-4-ylcarbamoyl)-propylI-3(R)-thien.3-y[succinamic Acid 14O 0: According to the procedure described in Examp le 17(a), N- [2,2 -dimethylI- I(S)- (pyridin-4-ylcarbamnoyl)-propyl J-3 (RS)-thien-3-yl-succinamic acid t-butyl ester was deprotected. Flash column chromatography with 1% HOAc/5% MeOl{ICH-,C1 2 as eluant led to isolation of the major isomer; 15 mg (21 of N-[2,2-dimethyl-lI(S)-(pyridin4ylcarbamoyl)-propyl]-3(R)-thien-3-yl-succinanic acid as a white solid, mp 205*C IH NMR (DMSO-d 6 8 8.30 2H, J 6.0 Hz), 7.45 (dd, 2H, J 1 6.0 Hz), 7.26 (dd, I H, J =3 3.0, 5.0 Hz), 7.21-7.18 (in, I1H), 7.04 (dd, I H,J 5.0 Hz), 4:38 I1-1). 4.26 (dd, I H, J 5.0, 10.0 Hz), 3.04 (dd, I H, J 10.0, 16.5 Hz), 2.65 (dd, IlH, J 16.5 Hz), 1.0 1 (s, 9H). Anal. Calculated for C 19 H 23 3 0 4 S 0.6 HOAc: C, 57.02; H, 6.02; N, 9.88; S, 7.54.

Found: C, 56.99; H, 6.06; N, 9.88; S, 7.55.

The starting material was made as follows: N-12.2-Dimethyl. Il(S)-(pyidin4-vlcarbanovy propvyl.3(RS--.thien-3.vl..succinamic Acid t- BuM Ester 0g N H,_1NHC According to the procedure described in Example I1(f) for the preparation of N-(l benzyl.2-methoxyethyl)3(R)-tbutoxycarbony lamino-succinamic acid benzy I ester, 2(R)thien-3-yl-succanamic acid 4-t-butyl ester (prepared as described in Example 17(b)) and 2Saniino-3 ,3 -dimethyl..N-4-pyridinyl-butanamide (prepared as -described in- Example were coupled with BOP in 48h at ambient temeprature. Flash column chromatography with MeOH in CH 2

CI

2 gave 718mg of N.[2,2-dimethyl I (S)-{pyridin-4ylcarbamoyl)- **:propyll- 3 (RS)-thien-3.ylksuccinanic acid t-butyl ester as a white solid, mp 205*C which was an inseparable mixture of isomers by NMR 87:13, respectively) and used without further purification. IH NMR (DMSO-d 6 8 8.48 1.74H, J =5.5 Hz, major iso mer), 8.38 0.87H, J 9.0 Hz, major isomer), 7.65 1.74H, J =5.5 Hz, major isomer), 7.59 0.26H, J 5.0 Hz, minor isomer), 7.49 (dd, 0.87H, J 3.0, 4.0 Hz, major isomer), 7.43 (in, 0.87H, major isomer), 7.30 (in, 0. 13H,. minor isomer), 7.23 0.87H, J 5.0 Hz, major isomer), 7.12 0.13H1, J 5.0 Hz, minor isomer), 4.52 0.87H, J 9.0 Hz, major isomer), 4.37 dd, 0.87H, J 5.0, 10.0 Hz, major isomer), 4.08 dd, 0. 13H, J 15.5 Hz, minor isomer), 3.00 (dd, 0.87H1, J 10.0, 16.0 Hz, major isomer), 1.40 1. 17H1, minor isomer), 1.29 7.83H1, major isomer), 1.03 0.13H, minor isomer), 0.84 7.83H, major isomer).

Example 18(a). 3(RS)-(3-Biphenyl-4-yl-l H-imidazol- 1-yl)-N-(hexahydroazepin-2-on- Acid 0N 0 0N According to the procedure described in Example a suspension of 3(RS)-(3biphenyl-4-yl- IH-imidazol-1I-yl)-N-(hexahydroazepin-2-on-3(S)-yl)succinamic acid benzyl ester in EtOH was hydrogenolyzed after 90 minutes to provide 779 mg of 3(RS)-(3biphenyl-4-yi- I H-imidazol- I -yI)-N-(hexahydroazepin-2-on-3 (S)-yl)succinamic acid as a solid. FABMS: 447 (C 25

H

27

N

4 0 4 1; M The starting materials were prepared as follows: 2[RS)-(3-Bip~henvI-4-yl- I H-imidazol- I -yi)-succinic Acid Dibenzyl Ester N I o) N A mixture of dibenzyl flhmarate.(5.30 g, 18.0 mxrnol) and 4-biphenyl-4-yi-I11imidazole (see Ellis, et al. J Pharm. PharmacoL 1964, 400-3; 3.94 g, 18.0 mamol) was heated at 11I0-5 After 4 hours, the mixture was allowed to cool, diluted with ether, washed with 0.05% aqueous HCl, 0.0 iN aqueous NaOH, and brine, dried over Na 2

SO

4 and concentrated under reduced pressure to give 5.75 g of 2(RS)-(3I-biphenyIA4-yl- IH-IridzolI -ly).

succinic acid dibenzyl ester. FABNS: 517.3 (C 33

H

29

N

2 -0 4 M +H 2(RS).(3..Binhenyl-4-vi- I H-imidazol- i-vi )-succinic Acid 4 -RenZyl eter

N

0

N

Qo&4,

OH

A suspension of 2(RS)-(3-bipheny

I-

4 -ylIH-imidazol-1l-yI).succinic acid dibenzyl ester (551 mg, 1.07 mmol) in H 2 0 (0.5 mL) was refluxed overnight. Once allowed to cool to ambient temperature, the resultant precipitate was collected and dried in vacuo to provide 436 mg of 2(RS)-(3-biphenyl..4-yI- 1 H-iniidazol- I -yi)-succinic acid 4-benzyl ester.

FA.BMS: 427 (C 26

H

23

N

2 0 4 M 3(RS')-(3-Binhenyl-4-vI- IH..imidazoI- i-yfl-N-(hexahvdrozepin-2-on3(S)..vhsuccinamic

N

0 N0 According to the procedure described in Example 2(RS)-(3-biphenyl-4-yl- I Himidazol-lI-yi)-succinic acid 4-benzyl ester 1.20 g, 2.82 mmxol) and L-ax-amino-ccaprolactam (469 mg, 3.67 mmol) was coupled in DMF with pyBOP to furnish 1.02 g (67%) of 3(RS)-(3-biphenyl-4-yl- IH-imidazol- I-y l)-N-(hexahydroazepin-2-on-3 (S)-yI)succjnamjc acid benzyl ester. FABMS: 537.5 (C 32

H

33

N

4 0 4 M The following were made in a similar manner: Example 18(b). 3(RS)-(3-Bipbenyl-4.yl. 1H-imidazol-1-yl)-N.(2,2.dimethyll bydroxymethylpropyl)succinamic Acid rN

J

.HN OH According to the procedure described in Example a suspension of 3(RS)-(3biphenyl-4-yI. I H-imidazol- 1 -yl)-N-(2,2-dirnethyI- I (S)-hydroxymethylpropyl)succinarnic acid berizyl ester in EtOH- was hydrogenated to provide 3(RS)-(3-biphenyl-4-yl-IH-imidazol- I -yI)-N-(2,2-dimethyl- I(S)-hydroxyxnethylpropyl)succinamic acid as a solid, mp 145.500 C.

FABMS: 436.1 (C 25

H,

0

N

3 0 4 M Example 18(c). 3(RS)-(3-Biphenyl-4-y[IH-imidazol-1-yl)-N-(2,2-dimethyl-1 methylcarbamoylpropyl)succinamic Acid N

NHN

HOKA, -HINH.CH According to the procedure described in in Example 1 a suspension of 3(RS)-(3biphenyl-4-yI- 1 H-imidazol- 1 -yl)-N-(2,2-dirnethyl- 1 (S)-methylcarbamoyipropyl)succinamic acid benzyl ester in EtOH was hydrogenated tD provide 3(RS)-(3-biphenyl-4-yl-lIH-imridazol- 1-yI)-N-(2,2-dimethyl-l(S)-methylcarbamoylpropy)succinanic acid as a solid, mp 187.0.

8.2*C. FABMS: 463.2 (C 26

H-

3 1

N

4 0 4 M Example 19(a). 3(RS)-(3-Bipbenyl-4-yl-1 H-imidazol-1-yI)-N -_(2,2-dimethyl- 1(S)bydroxymethylpropyl)-N 1-bydroxy-succindiamide

NJ

HO-NH HkAIrN~H A suspension of crude N -benzyloxy-3(RS)-(3-biphenyl-4-yl- I H-imidazol- 1 y)-4 (hexahydroazepin-2-on-3(S)-yl)-succindianide (800 mg, 1.45 mmol) and 10% Pd/C (800 mig) in EtOH (100 rnL) was stirred under H~2 atmosphere. After 6 hours, more catalyst (300 mg) was added. After 2 hours, the catalyst was filtered onto Celite and rinsed. The filtrate w as concentrated to provide 301 mg of 3 (RS)-(3-biphenyl-4-yl- I H-imidazol- I -yl)-N- (hexahydroazepin-2-on-3(S)-yl)-N 1-hydroxy-succindiamide as a solid, which effervesced at .180.5aC. FABMS: 462.2 (C25H 28

N

5

O

4 M S The starting materials were frnmished as follows: 247 N 1-&enzvloxy-3(RS').(3.biphenl.4vI. I H-inidazol-l1-yI)-N 4 _(hexahdozpn.o3(~ yi)-succindiamide N N 0 N According to the procedures described in Example 3(RS)-(3-biphenyl..4-yl- I Himidazol- I -yl)-N-(hexahydroazepin-2on3 (S)..y)succinmic acid (prepared as described in Example 18(a); 779 mg, 1.74 mmol) and benzyloxyamnine hydrochloride (334 mg, 2.09 mxnol) were coupled with pyBOP to afford 800 mg of N 1-benzyloxy-3 biphenyl.4-yl- 1 H-imidazol- Il-yi)-N 4 -(hexahydroazepin.2..orl.3(S).yl).succjndiamide.

FABMS: 552.2 (C 32

H

34

N

5 0 4 M The following were made in a similar manner: Example 19(b). 3(RS)- (3-Biphenyl4-ylI.H-imidazol-1-yI)-N 4 -(2,2-dimethyl- 1(S)hydroxymetbylpropyl)-N hydroxy-suceindiamide

N

HO-NH1 ,,NHIOH 0*0** According to the procedure described in Examnple 19(a), N -benzyloxy-3(RS)-(3biphenyl-4-yI- 1 H-imidazol- 1 -yl)-N 4 -(2,2-dirnethyl- I (S)-hydroxymethylpropyl)succindiaxnjde was selectively hydrogenated to provide 3(RS)-(3-biphenyl-4-yl- IH-imidazol- I -yl)-N 4 -(2,2-dimethyl. I(S)-hydroxymethylpropy)-Nl*hydroxy-succindiamide.

FA.BMS-

451.3 (C 25

H

3 1

N

4 0 4 M Example 19(c). ipbenyl-4-yl-1 H-imidazol-1-yl)-N 4 -(2,2-dimethyl.I(S).

bydroxymethylprpy).N hydroysuccindiamide

NI

0 N 1 HO- NH4N-I NH O 0- The diastereomeric mixture N I-benzyloxy-3(RS).(3-biphenyk-4yl. 1 H-fmidazol- I yl)-N 4 .(2,2-dimethyl- I (S)-hydroxymethylpropyl).succindiamicje (Example 19(b)) was purified via preparative RPHPLC (C 18) to provide 3(R)-(3-biphenyl-4.yl- I H-imidazol- Il-yl)- N-(2,2-dimethyl- 1(S)-hydroxymethylpropyl)-N -hydroxy-succindiamide as a solid, mp I57.-60 0 C. FABMS: 451.2 (C 25

H

3 N0;MH) Example 19(d). 3(SN-3-Biphny-4-yl-H-imidazol--y)-N 4 -(2,2-dimethyl. bydroxymethylpropyl)-N 1 hydroxy..succzadiamide

N

HO.NH >NH. OH The separation of Example 19(b) described in Example 19(c) also furnished biphenyl-4-yl- 11--imidazol- 1-yl)-N-(2,2-dirnethyl- 1 (S)-hydroxymethylpropyl)-N I-hydroxysuccindiamide as a solid, rnp 134.5-6.5*C. FABMS: 451.1 (C 25

H

31

N

4 0 4 M Example 19(e). 3(RS)-(3-BiphenyI-4-yl-1 H-imidazol-1-y)-N .(2,2!!dim ethyl. t(S)methylcarbamoylpropyl)-N -hydroxy succindiamide

N

HO NHk' NH,--"NHCH 0- According to the procedure described in Example 19(a), N 1 -benzyloxy-3(RS)-(3biphenyl-4-yl- 1 H-imidazol- I -yl)-N 4 _(2,2-dimethyl- I (S)-inethylcarbamoylpropyl)succindiarnide was selectively hydrogenated to provide 3(RS)-(3-biphenyl-4-yl- I H-imidazol- 1 -yl)-N 4 -(2,2-dimethyl- I(S)-methylcarbamoylpropyl)-N I-hydroxy-succindiamide as a solid, which effervesced at 169*C. FABMS: 478.2 (C 26

H

32 N,0 4 M The results obtained during biological testing of some preferred embodiments of the inventive compounds are described below.

RIOLOGICAL DATA Isolation of MIMP's- for Asmay catalytic domain of human collagcnase- I was expressed as a fusion protein with ubiquitin in E. coli (see Gehring, JBiol. Chem., 1995,270,22507). After purification of the fusion protein, the fibroblast collagenase-I catalytic domain (HFC) was released either by treatment with purified, active sfromelysin- 1 50 w/w ratio), which generated nearly 100% N-terminal Phel, or by autoprocessing the concentrated collagenase-1 fusion and then incubating at 37 OC for 1 hour. Final purification was completed using zinc chelate chromatography.

The propeptide and catalytic domain of human collagenase-3 (Coll3) was expressed in E. coli as an N-terminal fusion protein with ubiquitin. After purification of the fusion from inclusion bodies, the catalytic domain was liberated by treatment with 2mM APMA at room temperature overnight. Final purification was completed using copper chelate chromatography.

The catalytic domain of human stromelysin (Hsin) was obtained by expression and purification of a C-terminally truncated prostromelysin-l from E. coli host BL21 (see Marcy et al. Biochem., 1991, 30, 6476). The subsequent activation of the mature form (Hsln) was completed with 2mM APMA for 1 hour at 37 followed by separation using a sizing column.

Human matrilysin (Matr) was expressed in E. coli as a fusion protein with ubiquitin.

After purification of the matrilysin/ubiquitin fusion from inclusion bodies, the catalytic domain was liberated by treatment with 2mM APMA at 37 *C for 2 hours. Final purification was complete using copper chelate chromatography.

The catalytic and fibronectin-like portion of human progelatinase A (GelA) was expressed as a fusion protein with ubiquitin in E. Coli. Assays were carried out on autocatalytically activated material.

Compounds of Formula I exhibited the ability to inhibit MMPs when tested in the following assay.

In Vitro Assay Procedure Assays were performed in assay buffer (50 mM Tricine pH 7.5, 200 mM sodium chloride, 10 mM calcium chloride, 0.5 mM zinc acetate containing 2% dimethyl sulfoxide (DMSO)) once the substrate and inhibitor were diluted into it. Stock solutions of inhibitors were prepared in 100% DMSO. Stock solutions of the substrate were prepared in 100% DMSO at a concentration of 6 mM.

The assay method was based on the hydrolysis of MCA-Pro-Leu-Gly-Leu-DPA-Ala- Arg-NH 2 (American Peptide Co.) at 37 *C (see Knight, C.G. et al., FEBS, 1992, 296, 263- 266). The fluorescence changes were monitored with a Perkin-Elmer LS-50B fluorimeter using an excitation wavelength of 328 nm and an emission wavelength of 393 nm. The substrate concentration used in the assays was 10 gM. The inhibitor was diluted into the assays from a solution in 100% DMSO, and controls substituted an equal volume of DMSO so that the final DMSO concentration from inhibitor and substrate dilution in all assays was The concentration of enzyme in the assay ranged from 60 pM for gelatinase A to 1.5 nM for stromelysin and is a function of the: enzymes respective kcat/Km for the MCA peptide substrate. Proper determination of steady-state rates of substrate cleavage required assay lengths of 60 minutes to allow for complete equilibration of the enzyme-inhibitor complex.

The for the MCA peptide substrate with the matrix metalloproteinases is quite high and exceeds its solubility under assay conditions. Consequently, the apparent K, was determined to describe the strength of inhibition. However, in this case, would be essentially equal to K, since For the determination of the concentration of the inhibitor was varied at a constant and low concentration of substrate and the steady-state rates of fluorescence change determined. In most cases absorptive quench due to the presence of ligand was not observed. For slow-binding inhibitors, onset of inhibition curves were collected for at least 45 minutes so that equilibrium was established. Steady-state rates of fluorescence change were obtained by fitting a curve to an equation for a single exponential decay containing a linear phase. The fitted value of the linear phase was taken as the steadystate rate. The steady-state rates were fitted to the Michaelis equation describing competitive inhibition by non-linear methods. Data resulting from tight-binding inhibition was analyzed, and determined by fitting the data to the tight-binding equation of Morrison (Biochem.

Biophys. Acta, vol. 185, pp. 269-286 (1969)) by non-linear methods.

ooo* The results of the above-described tests are presented below in Table 1.

TABLE 1 a Example Hsln Matr

K

FC GelA Col3 LogP (K,app) (Ki,app) (Kiapp) (K,app) (K,app) l(a) 65.0 1000 5.40 30.0 l(b) 2000 5.91 18.3 -0.83 I(c) 486 16900 2.00 0868 -0.97 Hsin Matr HFC GelA ColU LogP Example (Ki,app) (Ki,app) (Ki,app) (Ki,app) (Kiapp) I(d) 1220 4500 3.90 24.0 l(e) 3.10 500 0.108 0.900 1.19 1(f) 331 1000 93.0 542 1(g) 58.0 8.50 58.5 1(h) 822 58.0 3000 1(i) 113 8.00 89.6 1(j) 133 1.43 9.43 1(k) 0.150 11.0 1.90 1(1) 317 54 227 1(m) 50 997 0.410 1.00 S(n) 2000 >10000 1900 8500 1(o) >10000 15000 51500 1(p) 55000 1230 2 89 400 6.20 123 3 150 1250 58 180 4(a) 30 5200 1.30 2.70 4(b) 23 1520 1.11 2.13 4(c) 64 2530 7.20 84 1.60 1.80 0.11 30 5200 >12000 .1.04 9.10 1.50 305 1500 0.041 0.049 3.41 S(d) 1.60 4.50 >2000 0.028 0.23 1.70 182 530 0.109 0.076 1.71 5(f) 0.460 2.10 818 0.023 0.012 2.56 5(g) 57 2.20 14.5 650 17.4 43.0 6(a) 15.0 1500 8860 6.62 15.6 oo Ioeo ,oeo 2900 0.066 0.210.

SI 1 A Example Hsln Matr HFC GelA Coll3 LogP (Ki,app) (Ki,app) (Ki,app) (Ki.app) (Ki,app) 6(c) 54 5000 0.806 7.60 7(a) 2.00 640 333 0.015 0.013 7(b) 0.290 5.00 453 0.0070 0.010 7(c) 26 5326 0.055 1.30 7(d) 1580 121 284 8(a) 0.690 36 0.027 8(b) 0.390 71 0.330 0.450 9 0.200 0.011 0.018 1.50 617 3.30 16 510 9.60 23.5 40 2185 22 11 62 60 >750 12 >500 >500 13 35 16900 72000 1.70 21 14(a) 558 4.30 7.20 14(b) 1.30 0.012 0.028 14(c) 17.7 0.044 14(d) 19 0.900 92 72 300 122 91 1025 16 1500 63000 81 17(a) 965 454 32000 17(b) 720 309 20000 17(c) 935 156 157 18(b) 3000 >100000 490 18(c) 180 24000 31 19(a) 31 57000 43 19(b) 17 66000 9.7' I 255 Example Hsln Matr HFC GeIA Coll3 LogP (Kiapp) (Kiapp) (Ki,app) (Ki,app) (Kiapp) 19(c) 17 45000 19(d) 120 >100000 43 19(e) 2.3 310 0.13 Determination of Inhibitor Concentration in Plasma after Oral Dosing The dosing solution consisted of the inhibitor dissolved in either a molar equivalent of HCI in water (vehicle in 60% aq. propylene glycol (vehicle or in 2.8 mg/mL sodium bicarbonate in 60% aqueous propylene glycol (vehicle yielding a final concentration that ranged from 10-15 mg/ml. Sprague Dawley rats (Hilltop Lab Animals, Scottsdale, PA) were dosed as a function of drug weight per body weight, usually 50 mg per kg. Blood was taken from the rats and centrifuged, and the plasma was stored in the freezer.

Drug was extracted from a 50 pi plasma aliquot by adding 1 ml of acetonitrile, shaking for 2 minutes, centrifuging for 15 minutes at 4000 rpm, collecting the supematant, and then evaporating it to dryness under a stream of nitrogen. The samples were reconstituted with 130 pl of mobile phase, shook for 2 minutes, and centrifuged for 15 minutes at 4000 rpm.

The supernatant was collected and the samples were analyzed by injecting 100 l1 of supernatant onto HPLC.

Quantitation of drug levels was accomplished by generating a standard curve of known drug amounts that were extracted from added plasma. Drug levels were plotted as a function of time and analyzed to provide area under the curve (AUC) and maximum concentration (Cmax) values. The results are shown in Table 2.

IABLa-2 AUG Cmax Example dose (mg/kg) Vehicle (glminmL) (gg/ml-) 7(b) 50 B 24 0.21 50 B 73 0.41 B 37 0.30 1 50 B 58 0.59 6(c) 25 A 56 0.45 6c*50 A 265 1.14 50 A 211 1.6 14(a) 50 B 94 .0.82 14(d) 25 C 349 1.37 p. *dosed as the benzyl ester prodrug 257

Claims (28)

1. A compound according to formula I: /R 1 X H N YR 3 R4 0 R2 wherein X is a single bond or a straight or branched, saturated or unsaturated chain containing 1 15 to 6 carbon atoms, wherein one or more of the carbon atoms are optionally independently replaced with O or S, and wherein one or more of the hydrogen atoms are optionally replaced with F; 20 Y is a single bond, or C(O); RI is an aryl group or a heteroaryl group; R 2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C(O)Rio, wherein R 10 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NR 11 R 12 wherein R 11 is H, an alkyl group, an 0- alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and wherein R 12 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or wherein R 11 and R 12 form, together with the 259 nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group, and R3 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, NR 11 R 12 or OR 11 wherein R 11 and R 12 are as defined above, or R 2 and R 3 together with the atom(s) to which they are attached, form a cycloalkyl group or a heterocycloalkyl group; R4 is H or any suitable organic moiety; R 5 is C(O)NHOH, C(O)OR 13 SH, N(OH)CHO, SC(O)R 14 P(O) (OH)R 15 or P(O) (OH)OR 1 3 wherein R 13 is H, an alkyl group, or an 15 aryl group, S. R 14 is an alkyl group or an aryl group, and R 15 is an alkyl group; and is a heteroaryl group having five ring atoms, containing one 0 heteroatom only; with the proviso that the compound according to formula is not: w RI H A N -N-(CH2)n H R 4 0 O wherein RI, R 4 and R 5 are as defined above, W is H, OH, 260 a halo group, an alkyl group, or an O-alkyl group, and further wherein when m is 2, 3, or 4, n is 1, 2, 3, or 4, and A is CH 2 O, NH, or N-alkyl; or when m is 4, 5, or 6, n is 0, and A is CHJ--, wherein J is carboxy, alkoxycarbonyl, or carbamoyl; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula

2. A compound according to claim 1, wherein X is a single bond; or a pharmaceutically acceptable salt or solvate 15 thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula

3. A compound according to claim 1, wherein Y is CH(OH)- 20 or or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound *according to the formula

4. A compound according to claim 3, wherein Y is CH(OH)- and R 3 is H or an alkyl group or together with R 2 and the atom(s) to which R 2 and R 3 are attached forms a cycloalkyl group or heterocycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula A compound according to claim 4, wherein Y is CH(OH)- and R 3 is H; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula (I) 261

6. A compound according to claim 3, wherein Y is and R 3 is an alkyl group, NR 11 R 12 or OR 11 wherein R 11 is H, an alkyl group, an O-alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and wherein R 12 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or wherein R 11 and R 12 form, together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group; or wherein Y is and R 2 and R 3 together with the atoms to which they are attached, form a cycloalkyl group or a heterocycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically 15 acceptable prodrug thereof, said prodrug being different from a compound according to the formula 9

7. A compound according to claim 1, wherein RI is an aryl group of the formula: .wherein Z is H, halogen, an alkyl group, an O-alkyl group, a cyano group, a hydroxy group, an aryl group, a heteroaryl group, or a heterocycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula

8. A compound according to claim 1, wherein R 2 is an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula (I) 262

9. A compound according to claim 1, wherein R 4 is H, an alkyl group, OH, O-alkyl, NH 2 NH-alkyl, or a cycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula A compound according to claim 9, wherein R 4 is an alkyl group selected from CHR 16 OH and CH(NHR17)Ri 6 wherein R 16 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and R 17 is C(0)R 1 8 SO 2 R 18 H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a 15 heterocycloalkyl group, or R 16 and R 17 together with the atoms to which they are attached, form a heterocycloalkyl group; wherein R 18 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NR 19 R 20 20 wherein R 19 and R 20 independently are H, an alkyl group, an e aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or R 19 and R 20 together with the nitrogen atom to which they are attached, form a heterocycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula

11. A compound according to claim 1, where R 5 is C(O)NHOH or C(O)OR 13 wherein R 13 is hydrogen; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula

12. A compound according to claim 1, wherein Y is a single bond and R 3 is a heteroaryl group. 263

13. A compound according to claim 12, wherein R 3 is the heteroaryl group: R21 R 22 H wherein R 21 and R 22 are independently any suitable organic moiety or together with the carbon atoms to which they are attached form an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group; or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula 15

14. A compound according to claim 13, wherein R 2 1 and R 2 2 are independently selected from hydrogen, an alkyl group, an aryl group, a heteroaryl group, a halo group, a C(O)O- alkyl group, a carbamoyl group, a cycloalkyl group, or a heterocycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula (I) A pharmaceutical composition comprising: a therapeutically effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula and a pharmaceutically acceptable carrier, diluent, vehicle, or excipient.

16. A method of treating a mammalian disease condition mediated by metalloproteinase activity that comprises 264 administering to a mammal in need thereof a therapeutically effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula

17. A method according to claim 16 wherein the mammalian disease condition is tumor growth, invasion or metastasis.

18. A method of inhibiting the activity of a metalloproteinase that comprises contacting the metalloproteinase with an effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable 15 salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound according to the formula

19. A compound according to formula I: H R 4 R 3 R4 0 R2 265 wherein: X is a single bond or a straight or branched, saturated or unsaturated chain containing 1 to 6 carbon atoms, wherein one or more of the carbon atoms are optionally independently replaced with O or S, and wherein one or more of the hydrogen atoms are optionally replaced with F; Y is CH(OH)--; RI is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group; R2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a 15 heterocycloalkyl group, or C(O)Ro 0 wherein R 10 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an O-aryl group, an O-alkyl group, or NR11 R 12 wherein R 11 is H, an alkyl group, an O- alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, and wherein R 12 is H, an alkyl group, an 25 aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or wherein R 11 and R 1 2 form together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group; and R3 is H or an alkyl group; or R 2 and R 3 together with the atoms to which they are attached, form a cycloalkyl group or a heterocycloalkyl group; R4 is H or any suitable organic moiety; is C(0)NHOH, C(0)OR 13 SH, N(OH)CHO, 266 SC (0)R 14 wherein P(O) (OH)R 15 or P(0) (OH)OR 13 R 13 is H, an alkyl group, or an aryl group, R 14 is an alkyl group or an aryl group, and R 15 is an alkyl group; and is a heteroaryl group having five ring atoms consisting of four carbon atoms and one oxygen heteroatom; with the proviso that the compound according to formula is not: W R SN-(CH 2 )m H A wherein R 1 R 4 and R 5 are as defined above, W is H, OH, a halo group, an alkyl group, or an O-alkyl group, and further wherein when m is 2, 3, or 4, n is 1, 2, 3,.or 4, and A is CH 2 O, NH, or N-alkyl, or when m is 4, 5, or 6, n is 0, and A is CHJ--, wherein J is carboxy, alkoxycarbonyl, or carbamoyl; or a pharmaceutically acceptable salt or solvate of the compound according to formula I, or a pharmaceutically 267 acceptable prodrug of the compound according to formula I. A compound according to formula I: R, /R l x H R5 Y N YR 3 R 4 0 R2 wherein: X is a single bond or a straight or branched, saturated or unsaturated chain containing 1 to 6 carbon atoms, wherein one or more of the carbon atoms are optionally independently replaced with 0 or S, and wherein one or more of the hydrogen atoms are optionally replaced with F; Y is a single bond; RI is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group; 25 R2 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, or C(O)Ro 0 wherein R 0 o is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalky group, an O-aryl group, an O-alkyl group, or NR 11 P 1 2, wherein R 11 is H, an alkyl group, an O- alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a 268 heterocycloalkyl group, and wherein R 12 is H, an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group, or wherein R 11 and R 12 form, together with the nitrogen to which they are attached, a heteroaryl group or a heterocycloalkyl group; R3 is a heteroaryl group; R4 is H or any suitable organic moiety; and is C(O)NHOH, C(0)OR 13 SH, N(OH)CHO, SC(0)R 14 P(O) (OH)R 15 or P(O) (OH)ORi 3 wherein R 13 is H, an alkyl group, or an 15 aryl group, R 14 is an alkyl group or an aryl group, and R 15 is an alkyl group; and is a heteroaryl group having five ring atoms, containing one 0 hetero-atom only; 25 with the proviso that the compound according to formula is not: R, N-(CH2)To H A R 5 N "C- N -(CH 2 n I II H R 4 0 0 wherein R 1 R 4 and R 5 are as defined above, W is H, OH, a 269 halo group, an alkyl group, or an O-alkyl group, and further wherein when m is 2, 3, or 4, n is 1, 2, 3, or 4, and A is CH 2 O, NH, or N-alkyl, or when m is 4, 5, or 6, n is 0, and A is CHJ--, wherein J is carboxy, alkoxycarbonyl, or carbamoyl; or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof.

21. A compound selected from the group consisting of: N-(1(S)-benzyl-2-hydroxyethyl)-3(S)-(2-(biphenyl- succinamic acid; 15 N-[2,2-dimethyl-l(S)-(methylcarbamoyl)propyl]-3- (2-(biphenyl-4-yl)-furan-5-yl) succinamic acid; and the pharmaceutically acceptable salts or solvates thereof, and the pharmaceutically acceptable prodrugs thereof.

22. A compound selected from the group consisting of: 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2- (2-(biphenyl-4-yl)furan-5-yl)ethane-1,2-dione; 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2- 25 (2-(biphenyl-4-yl)furan-5-yl)-2-hydroxy-ethanone; 2-acetoxy-l-(4(S)-benzyl-2,2-dimethyl-oxazolidin- 3-yl)-2-(2-(biphenyl-4-yl) 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2- (2-(biphenyl-4-yl)furan-5-yl)ethanone; N-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-3R- (2-(biphenyl-4-yl)furan-5-yl)succiramic acid t- butyl ester; and the pharmaceutically acceptable salts or solvates thereof, and the pharmaceutically acceptable prodrugs thereof.

23. A method of treating a mammalian disease condition mediated by metalloproteinase activity that 270 comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound of the formula

24. A method according to claim 23, wherein the mammalian disease condition is tumour growth, invasion or metastasis. A method according to claim 23, wherein the mammalian disease condition is osteoarthritis, rheumatoid arthritis, osteoporosis, periodontitis, or gingivitis.

26. A method according to claim 23, wherein the mammalian disease condition is chronic dermal wounds, corneal ulceration, or degenerative skin disorders.

27. A method according to claim 23, wherein the mammalian disease condition is multiple sclerosis or stroke.

28. A method according to claim 23, wherein the 25 mammalian disease condition is atherosclerosis, glomerular disease, or Alzheimer's disease.

29. A method according to claim 23, wherein the mammalian disease condition is characterized by unwanted angiogenesis. A method according to claim 23, wherein the mammalian disease condition is diabetic retinopathy, macular degeneration, angiofibromas, or hemangiomas.

31. A method of inhibiting the activity of a metalloproteinase that comprises contacting the 271 metalloproteinase with an effective amount of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt of solvate thereof, or a pharmaceutically acceptable prodrug thereof, said prodrug being different from a compound of the formula

32. Use of a compound according to any one of claims 1 to 22 in the manufacture of a medicament used for the treatment of a mammalian disease condition mediated by metalloproteinase activity.

33. Use according to claim 32, wherein the disease is selected from the group consisting of osteoarthritis, rheumatoid arthritis, osteoporosis, periodontitis, S. 15 gingivitis, chronic dermal wounds, corneal ulceration, degenerative skin disorders, multiple sclerosis, stroke, atherosclerosis, glomerular disease, or Alzheimer's disease, diabetic retinopathy, macular degeneration, angiofibromas, or hemangiomas.

34. A compound according to claim 1 substantially as hereinbefore described with reference to any one of the O S examples. 25 Dated this 5th day of October 2001 AGOURON PHARMACEUTICALS INC and SYNTEX (USA) INC By their Patent Attorneys GRIFFITH HACK Fellows Institute of Patent and Trade Mark Attorneys of Australia