AU768182B2 - Process for the solid phase synthesis of aldehyde, ketone, oxime, amine, hydroxamic acid and alpha,beta-unsaturated carboxylic acid and aldehyde compounds - Google Patents

Description

WO 99/67192 PCT/US99/14251 PROCESS FOR THE SOLID PHASE SYNTHESIS OF ALDEHYDE, KETONE, OXIME, AMINE, HYDROXAMIC ACID AND a,P3-UNSATURATED CARBOXYLIC ACID AND ALDEHYDE COMPOUNDS CROSS REFERENCE TO RELATED APPLICATIONS This invention is a continuation-in-part of International Patent Application No.

PCT/US97/23920, filed Dec. 17, 1997, which claims benefit of U.S. Patent Application Ser. No.

60/032,453, filed Dec. 19, 1996, and U.S. Patent Application Ser. No. 60/033,881, filed Dec. 24, 1996: and a continuation in part of U.S. Patent Application Ser. No. 08/928,943, filed Feb. 23, 1998, which in turn is a continuation of International Patent Application No.PCT/US97/00264, filed Jan. 2, 1997.

FIELD OF THE INVENTION This invention is directed to processes for the solid-phase synthesis of aldehyde, ketone, oxime, amine, and hydroxamic acid and t,j3-unsaturated carboxylic acid and aldehyde compounds and to polymeric hydroxylamine resin compounds useful therefor.

BACKGROUND OF THE INVENTION Solid-phase synthetic techniques, in which a reagent is immobilized on a polymeric material which is inert to the reagents and reaction conditions employed, as well as being insoluble in the media used, are important synthetic tools for preparing amides, peptides and hydroxamic acids. For solid phase peptide synthesis, a summary of the many techniques may be found in J.M. Stewart and J.D. Young, Solid Phase Peptide Synthesis, 2nd. Ed., Pierce Chemical Co. (Chicago, IL, 1984); J. Meienhofer, Hormonal Proteins and Peptides, vol. 2, p. 46, Academic Press (New York), 1973; and E. Atherton and R.C. Sheppard, Solid Phase Peptide Synthesis: A Practical Approach, IRL Press at Oxford University Press (Oxford, 1989). For the use of solid phase methodology in the preparation of non-peptide molecules see Leznoff, Acc. Chem. Res., 1, 327-333 (1978).

A number of polymeric reagents have found synthetic use in simple functional group transformations. See A. Akelah and D.C. Sherrington, Application of Functionalized Polymers in Organic Synthesis, Chem Rev., 81., 557-587 (1981) and W. T. Ford and E. C. Blossey, Polymer Supported Reagents. Polymer supported Catalysts, and Polymer Supported Coupling Reactions, in Preparative Chemistry using Supported Reagents, Pierre Laszlo, ed., Academic Press, Inc., 193-212 (1987). For the use of polymeric reagents in oxidation reactions see J. M. J. Frechet et al., J. Org.

Chem., 43, 2618 (1978) and G. Cainelli et al., J. Am. Chem. Soc., 98, 6737 (1976). For the use of polymeric reagents in halogenation reactions see J. M. J. Frechet et al., J. Macromol. Sci. Chem., A-11 507 (1977) and D. C. Sherrington et al., Eur. Polym. 13. 73, (1977). For the use of polymeric reagents in epoxidation reactions see J. M. J. Frechet et al., Macromolecules, 8, 130 (1975) and C. R. Harrison et al., J. Chem. Soc. Chem. Commun., 1009 (1974). For the use of polymeric reagents in acylation reactions see M. B. Shambhu et al.. Tet. Lett., 1627 (1973) and M. B. Shambhu et al., J. Chem. Soc. Chem.

Commun.. 619 (1974). For the use of polymeric reagents in Wittig reactions see S. V. McKinley et al., Chem. Soc. Chem. Commun.. 134 (1972).

Polymeric reagents also have found widespread use in combinatorial synthesis and for preparing combinatorial libraries. See F. Balkenhohl et al.. Angew. Chem. 1n. Ed. Engl. 2288-2337 (1996) and L.A. Thompson et al.. Chem Rev., 96, 555-600 (1996).

A polymeric reagent has the advantage of ease of separation from low molecular weight reactants or products by filtration or selective precipitation. The polymeric reagent also can be used in excess to effect fast and quantitative reactions, such as in the case of acylations. or a large excess of reactants may be used to drive the equilibrium of the reaction towards product formation to provide essentially quantitative conversion to product, as in solid phase peptide synthesis. A further advantage of supported reagents and catalysts is the fact that they are recyclable and that they lend easily to automated processes. In addition. supported analogs of toxic and odorous reagents are safer to use.

PCT application publication no. W096/26223 discloses the synthesis of hydroxamic acid compounds using a solid phase hydroxylamine substrate.

Prasad et al. disclose a O-methylhydroxylamine-polysiyrene resin compound in J. Steroid Biochem., 18. 257-261 (1983).

Resin-bound Weinreb-like amides are disclosed by Fehrentz et al., Tet. Lett., 1995. 36, 7871- 7874 and Dinh et al., Tet. Lett., 1996, 37, 1161-1164.

Polymeric Horner-Wadsworth-Emmons reagents are disclosed by Wipf et al., J. Org. Chem., 1997. 62, 1586 and Johnson et al., Tetrahedron Lett.. 1995, 36. 9253.

eoe *e e SUMMARY OF THE INVENTION The invention is directed to a polymeric N-protected hydroxylamine resin compound of fon-mula

H

wherein is a solid support; P is an amine protecting group, provided that P is other fthn 4-methoxybenzy] or 2,4dimethoxybenzyl; and L is a group of formula wherein R' and R2 are independently H or F and R" and R' are independently ring system substituents provided that R',R 2 and A' are not simultaneously F; and one of R3 and X! is H and the other is H or 2,4-dimethoxyphenyl.

2b In another aspect the invention is directed to a polymeric fluorophenyl hydroxylamine resin compound of formula

RR

2

ONHP'

wherein is a solid support; A is absent or a group of formula wherein X1 is -CHR- or -CHR-Y-CO-(CH 2 wherein R is H, alkyl, phenyl, or phenyl substituted with alkyl, alkoxy. halogen, nitrile or -NO 2

R'

9 and R'O are ring system substitt provided that 11 2 ei, and R' 0 are not simultaneously F; or R 2 and RP' taken together with the carbon atoms through which they are linked form a 6 mnembered aryl or a 5 tO 6 membered heteroaryl, Y is or -NH-, n is an integer from 1 to 6, and Z is or -NH-; R' and R 4 are independently alk, phenyl, or phenyl substituted with one or more substituents selected from alkyl, alkoxy, halogen nitrile and -NO 2 and P' is H or an amine protecting group.

2c This specification discloses a process for the preparation of a ketone compound of formula Rc) Ra wherein R, and R, are independently aliphatic or aromatic. comprising reacting an N-alkylated polymeric'hydroxamic acid resin compound of formula 100 O -L-0-NRb

R

wherein is a solid support. L is absent or a linking group and Rt is aliphatic or ar-yi 0 0 3 with an organometallic reagent of formula R.M wherein Ri is an aliphatic or aryl anion and M is a metal cation; and liberating the ketone compound from the resin.

In another aspect, this specification discloses a process for the preparation of an aldehyde compound of formula R 3 CHO wherein Ra is defined above, comprising reacting an N-alkylated polymeric hydroxamic acid resin compound of formula 0 L-O-N Ra Rb wherein L and R, and Rb are defined above; with a reducing agent: and liberating the aldehyde compound from the resin.

In another aspect. this invention is directed to a process for the preparation of a N-alkylated polymeric hydroxamic acid resin compound of formula

S*A

L-O-N. Ra Rb wherein L and R, and R, are defined above, comprising coupling a carboxylic acid compound of formula RCO,H with a polymeric hydroxylamine resin compound of formula :oo

H

L-O-N

H

to form a polymeric hydroxamic acid resin compound of formula 0

O

LL--O-N Ra

H

:and reacting the polymeric hydroxamic acid resin compound with an alkylating agent of formula RbLG wherein LG is a leaving group.

In another aspect, this specification discloses a process for the preparation of a Nalkylated polymer yic hydroxaic acid resin compound of formula 0 Ra wherein L and R, and Rb are defined above, comprising *Loo reacting a N-protected polymeric hydroxamic acid resin compound of formula p L -N oo H wherein P is an amine protecting group, with an alkylating agent of formula RhLG wherein LG is defined above, to form a polymeric N-protected N-alkylated hydroxylamine resin compound of formula

O-L--N

*:*Rb oO oo removing the amine protecting group to form a polymeric N-alkylated hydroxylamifle resin compound of formula

~H

O -L-0-NRb;. and coupling the polymeric N-alkylated hydroxylamine resin compound with a carboxylic acid compound of formula RC,COH.

In another aspect, this specification discloses a process for preparing a hydroxamic acid compound of formula n R 1 R 9 R 12 R11 0 wherein

A

2 is a direct bond, alkylene, or NR 1 3 R 1 3 is hydrogen or alkyl;

R

9 is -L I-R 14 or L I is a direct bond or alkylene;

R

14 is hydrogen, aryl, carboxy, cyano, cycloalkyl, cycloalkenyl, cyclocarbamoyl, cycloim idylalkyl. heterocyclyl, heteroaryl, -NH-C(=O)-NH2, (N-carbamoyl)cyclic amine, t Iy 2 -NY ISO 2 aryl, -NHR 13 -SR 13 or -OR 1 3

L

2 is alkenylene or alkynylene; RI 5 is hydrogen, aryl, carboxy,.cyano, cycloalkyl, cycloalkenyl, heterocyclylalkyl or heteroaryl; RI 0 and R 12 are independently hydrogen or alkyl; or RIO and R 12 together form a bond, or R 10 and R 9 taken tog-ether with the carbon atom through which R 10 and R 9 are attached form spirocycloalkyl: R' IIis a group -0~-0 6 or R I Iand R 9 taken together with the carbon atoms through which R I and R 9 are attached form cycloalkylene; or R I and R 12 taken together with the *carbon atom through which RI and R 12 are attached form spirocycloalkyk- P- is a direct bond. alkylene. alkenylene or alkvnviene, PCTIUS99/14251 6 R 1 6 is hydrogen, cycloalkyl. cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, fused arylcycloalkyl. fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyLI fused aryiheterocyclyl, fused heteroaryiheterocyclyl. fused arylheterocyclenyl. fused heteroarylheterocycleflyl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl. fused heterocyclenylaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl. fused heterocyclenyiheteroaryl, fused heterocyclylheteroaryl, -NH-C(=O)-NH -C(=0)-NYy 2 -NY'SO,aryl, -NR'3, -SR"3, or -OR'1 3 Y I and Y2 are independently hydrogen, alkyl. aralkyl, and aryl, or Y I and y 2 taken together with the n itrogen atom to which Y I and y 2 are attached form azaheterocyclyl; Ar is selected from the group of formulae R 1 7 Zl Q1Ri7z

R

18 A 3 z 2 and R. 19A3 E -B; R 1 7 is alkyl, or when Z 3 is a direct bond then R 17 is hydrogen, alkyl, alkenyl or alkynyl; Rl 8 is cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, fused arylcyc loalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkeflyl, fused aryiheterocyclyl. fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyL. fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl. fused cycloalkyiheteroaryl, fused cycloalkenyiheteroaryl, fused heterocyclenylheteroaryl or fused heterocyclylheteroaryl; R 19 is R 20

-OR

20

-SR

20 -S0R 2 0

,-SO,R

2 Q. -S02)NR 20

R

2 1

NR

2 0 S0 2

R

2 1

-NR

2 0

R

2 1

-O(C=O)NR

20

R

2 1

-NR

2 0 C(0O)R 2 1 -N(OH)C=O0)R 2 0 or -C(0)N(OH)R 2 1

R

20 and R 2 1 are independently hydrogen, alkyl. alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, fused arylcycloalkyl, fused heteroarylcycloalkyI, 2 5 fused arylcycloalkenyl fused heteroarylcycloalkenyl, fused aryiheterocyclyl, fused heteroarylheterocyclyl., fused aryiheterocyclenyl, fused heteroarylbeterocyclenyl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, fused cycloalkylheteroaryl. fused cycloalkenylheteroaryl, fused heterocyclenyiheteroaryl, fused heterocyclylheteroaryl. aralkyl or heteroaralkyl; or R 2 0 and R 2 1 taken together with the nitrogen atom to which R 20 and R 21 are attached form azaheterocyclyl;, AM is a direct bond. alkylene, alkenylene or alkynylene; Z I and Z 3 are independently a direct bond. oxygen. sulfur or NH;

Z

2 is a direct bond. oxyg-en or sulfur: B, C, D. and E are independently are CH or heteroatom selected from O, S, N, NOR 22 or

NR

2 2 or three of B, C. D or E are independently CH or heteroatom selected from 0. S. N or

NR

2 2 and the other of B, C, D or E is a direct bond; and two of B, C. D and E that are in adjacent positions are other than O or S;

R

22 is hydrogen alkyl, aryl, lower aralkyl, heteroaryl or lower heteroaralkyl;

Q

1

Q

2 and Q 3 independently are CH, CX 1 orN;

X

1 is halogen: and n is 0, 1 or 2; or a prodrug thereof. acid isostere thereof, pharmaceutically acceptable salt thereof, or solvate thereof, comprising treating a polymeric hydroxamic acid resin compound of formula (0)n R 10

R

9

H

ArA-S -X

N'O-L-

R1 2 R 0O with acid.

In another aspect, this specification discloses a process for the preparation of a polymeric oxime ether resin compound of formula V Rd L-O- N= R o* wherein and L are as defined herein is and and R, are independently H. aliphatic or aromatic.

comprising reacting a polymeric hydroxylamine resin compound of formula

H

L-O-NH

H

with a carbonvl compound of formula S S

O

Rd Re In another aspect, this specification discloses a process for the preparation of an a-amine compound of formula

NH

2

H

Rd Re wherein R, and RF are independently H, aliphatic or aryl, provided that R, and R, are not both H, comprising reductively cleaving a polymeric oxime ether resin compound of formula L N Rd

O-L-O-N==

Re wherein and L are as defined herein.

In another aspect, this specification discloses a process for the preparation of a substituted a-amine compound of formula

NH

2 Rf '-Re Rd 20 wherein Rd and RP are independently H, aliphatic or aromatic, provided that Rd and R, are not both H. and Rf is aliphatic or aromatic. comprising reacting a polymeric oxime ether compound of formula Rd S. A N== Re *~t wherein and L are as defined herein, with an organometallic reagent of formula RrM wherein Rf is an aliphatic or aromatic anion and M is a metal cation, to form a polymeric a-substituted hydroxylamine resin compound of formula Rd

R

and reductively cleaving the a-substituted hydroxylamine resin compound.

In another aspect, this specification discloses a process for the preparation of a lactone compound of formula Rh Rg' SPh g On R.

O0 O

R,

wherein R Rh and R, are aliphatic or aromatic and Ph is phenyl, comprising treating an a.3-unsaturated polymeric hydroxamic acid ester resin compound of formula *a wherein and L are as defined herein, with thiophenol and a radical initiator to form a polymeric oximyl lactone compound of formula Rh R, SPh 0 R L-O-N and ;and treating the polymeric oximyl lactone compound with aqueous acid.

In another aspect, this specification discloses a process for the preparation of an a,3unsaturated polymeric hydroxamic acid ester resin compound of formula Rh R 9 Ri

L-O-N

wherein L and R, and Rh and R, are as defined herein, comprising reacting a polymeric hydroxylamine resin compound of formula

H

O-L-0-N 15 with an cLa,-unsaturated carboxylic acid ester compound of formula Rh R 9 0 0 Ri .l In another aspect, this specification discloses a process for the preparation of an a-cyclic 20 hydroxylamine compound of formula *o *ooo 11

H

2

C

R

HOHN

-R

wherein Rj and R, are aliphatic or aromatic and Q is or -CH2-. comprising treating a polymeric acetophenone oxime compound of formula Rk H2 Br L- O- N Q C Rj wherein O and L are as defined herein, with trialkyltin hydride and a radical initiator to form a polymeric ot-cyclic hydroxylamine resin compound of formula

H

2

C

R R L-O-N. 1 R ;.and treating the polymeric oa-cyclic hydroxylamine resin compound with aqueous acid.

In another aspect, this specification discloses a process for the preparation of a a-cyclic amino compound of formula

H

2

C

R

O

H

2 2 wherein R: and Rk are aliphatic or aromatic and Q is or comprisimg reductively cleaving a polymeric ax-cyclic hydroxylamime resin compound of formula

H

2

C

RX: 'Q wherein 0 and L are as defined herein.

In another aspect, this specification discloses a process for the preparation of a aL-cyclic hydroxylamine compound of formula

HOHN

wvher ein Rj, R, and R, are aliphatic or aromatic and Q is or comprising treating a polymeric acetophenone oxime compound of formula S. S S

S

*5

S

*.SS *5

S

*5SS

S

wherein 0 and L are as defined herein, with trialkyltin hydride and a radical initiator to form a polymneric aL-cyclic hydroxylamifle resin compound of formula and treating the polymeric a-cyclic hydroxylamine resin compound with aqueous acid.

In another aspect, this specification discloses a process for the preparation of a a-cyclic amino compound of formula

R,

Rk

H

2

N

o *o *o wherein Rj, R, and R, are aliphatic or aromatic and Q is or comprising reductively cleaving a polymeric a-cyclic hydroxylamine resin compound of formula

OL-O-N,

r r 0 wherein and L are as defined herein.

In another aspect, this specification discloses a N-protected hydroxylamine resin compound of formula

O-L-O-N

wherein and L are as defined herein and P is an amine protecting group, provided that P is other than 4-methoxybenzyi or 2.4-dimethoxybenzyl.

In another aspect, this specification discloses a polymeric fluorophenyl hydroxylamine resin compound of formula

ONHP'

R

30

F

wherein A. R' and R 4 are as defined herein, P' is an amine protecting group, and R 2 and R'n are ring system substituents. or R 2 s and R 9 taken together with the carbon atoms through which they are linked form a 6 membered aryl or a 5 tO 6 membered heteroaryl.

In another aspect, this specification discloses a process for preparing a a,p-unsaturated alkenoate resin compound of formula 0 Rm .r *'9 wherein comprising and L are as defined herein: R, is H or aliphatic; and is aliphatic or aromatic, treating a mixture in a reaction vessel of a first solvent and a polymeric phosphonoacetoxy resin compound of formula LP\-OR 20 L-O

OR

21 Rm wherein RZ and are alkyl. with excess base: draining the solvent from the reaction vessel: and adding a solution of an aldehyde of formula R,,CHO in a less polar second solvent.

In another aspect, this specification discloses the N-alkylated polymeric hydroxamic acid resin compound of formula

O

L-O-N, Ra Rb wherein is a solid support containing one or more fluorine atoms.

In another aspect, this specification discloses the use of the N-alkylated polymeric hydroxamic acid resin compound of formula 0 OL-O-N, Ra Rb

R

wherein is a solid support containing one or more fluorine atoms, for the solid-phase synthesis of aldehyde. ketone, oxime. amine. and hydroxamic acid and a,p-unsaturated carboxylic acid and aldehyde compounds, wherein the solid support containing one or more fluorine atoms facilitates monitoring and quantifying the solid-phase reactions b' 1 F NMR. A detailed discussion of the method of quantifying solid-phase reactions by F NMR. and the synthesis of fluorinated resins is described in 25 PCT/US98/26512 filed December 14, 1998. the contents of which is incorporated heein by reference DETAILED DESCRIPTION OF THE

INVENTION

DETAILED DESCRIPTION OF THE INVENTION ooo o WO 99/67192 PCT/US99/14251 16 Definitions of Terms As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings.

"Solid support" means a substrate which is inert to the reagents and reaction conditions described herein, as well as being substantially insoluble in the media used. Representative solid supports include inorganic substrates such as kieselguhr, silica gel, and controlled pore glass; organic polymers including polystyrene, including 1-2% copolystyrene divinyl benzene (gel form) and 20-40% copolystyrene divinyl benzene (macro porous form), polypropylene, polyethylene glycol, polyacrylamide. cellulose, and the like; and composite inorganic/polymeric compositions such as polyacrylamide supported within a matrix of kieselguhr particles. See J.M. Stewart and J.D. Young, Solid Phase Peptide Synthesis. 2nd. Ed., Pierce Chemical Co. (Chicago, IL, 1984). Solid support is designated generally as throughout the description.

In addition, "solid support" includes a solid support as described above which is affixed to a second inert support such as the pins described in Technical Manual, MultipinTM SPOC, Chiron Technologies (1995) and references therein which comprise a detachable polyethylene- or polyproylenebased head grafted with an amino functionalized methacrylate copolymer and an inert stem.

In addition, "solid support" includes polymeric supports such as the polyethylene glycol supports described by Janda et al.. Proc. Natl. Acad. Sci. USA, 92, 6419-6423 (1995) and S. Brenner, WO 95/16918, which are soluble in many solvents but can be precipitated by the addition of a precipitating solvent.

In addition "solid support" includes polymeric supports as described above, containing one or more fluorine atoms. Polymeric supports containing one or more fluorine atoms are prepared by polymerization using methods known in the art so as to incorporate one or more fluorine-containing monomers into the solid support. Representative suitable fluorine-containing monomers include 4fluorostyrene, 4-trifluoromethylstyrene, 2-fluoro-4-vinylbenzyl chloride and the like. Polymeric supports containing one or more fluorine atoms are readily prepared, for example by copolymerizing mixtures of 4-fluorostyrene, styrene, 1,4-divinylbenzene and 4-vinylbenzyl chloride. A detailed discussion of the method of synthesizing fluorinated resins is described in PCT/US98/26512 filed December 14. 1998. the contents of which is incorporated herein by reference. Solid supports containing one or more fluorine

F

atoms, may be designated as or throughout the description.

"Polymeric hydroxylamine resin compound" means a solid support as defined above which is chemically modified as is known in the art to incorporate a plurality of hydroxylamine or protected hydroxylamine (-ONHP) groups. The hydroxylamine or protected hydroxylamine groups are covalently bound directly to the solid support or attached to the solid support by covalent bonds through a linking group. The polymeric hydroxylamine resin compounds according to the process aspect of this PCT/US99/14251 n9/6'7192 H P we* 7 invention are designated herein as or wherein is a solid support as defined herein, L is absent or a linking group and P is an amine protecting group.

"Linking group" and "linker" mean a group through which the amino or aminomethyl functionality may be covalently linked to the solid support. The linking group is generally inert to the reagents and reaction conditions described herein.

"Amine protecting group" means an easily removable group which is known in the art to protect an amino group against undesirable reaction during synthetic procedures and to be selectively removable.

The use of N-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known. CF, for example.

T.H. Greene and P.G.M. Wuts. Protective Groups in Organic Synthesis, 2nd edition, John Wiley Sons, New York (1991). incorporated herein by reference. Preferred N-protecting groups are acyl. including formyl. acet 1. chloroacetyl. trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl. trifluoroacetyl.

acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl. acylisothiocyanate. aminocaproyl.

benzoyl and the like. and acyloxy including methoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2.2,2trifluoroethoxycarbonyl, 2-trimethylsilylethxoycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, tbutyloxycarbonyl (BOC), I,1-dimethylpropynyloxycarbonyl, benzyloxycarbonyl (CBZ), pnitrophenylsulfinyl, p-nitrobenzyloxycarbony, 2,4-dichlorobenzyloxycarbonyl, allyloxycarbonyl (Alloc), and the like.

"Carboxylic acid protecting group" and "acid protecting group" mean an easily removable group which is known in the art to protect a carboxylic acid group against undesirable reaction during synthetic procedures and to be selectively removable. The use of carboxylic acid protecting groups is well known in the art and many such protecting groups are known. CF, for example. T.H. Greene and P.G.M. Wuts. Protective Groups in Organic Synthesis. 2nd edition, John Wiley Sons. New York (1991). incorporated herein by reference. Examples of carboxylic acid protecting groups include esters such as methoxvmethyl, methylthiomethyl, tetrahydropyranyl. benzyloxymethyl. substituted and unsubstituted phenacyl. 2,2.2-trichloroethyl, iert-butvl. cinnamyl. substituted and unsubstituted benzyl, trimethylsilyl. allyl. and the like. and amides and hydrazides including N,N-dimethyl, 7-nitroindolyl.

hydrazide. N-phenylhydrazide, and the like. Especially preferred carboxylic acid protecting groups are tert-butyl and benzyl.

"Hydroxy protecting group" means an easily removable group which is known in the art to protect a hydroxy group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy protecting groups is well known in the art and many such protecting groups are known. cf.. for example. T.H. Greene and P.G.M. Wuts. Protective Groups in Organic Synthesis. 2nd edition. John Wiley Sons. New York (1991), incorporated herein by reference.

Examples of hydroxy protecting groups include ethers such as methyl; substituted methyl ethers such as methoxymethyl (MOM). methylthiomethyl (MTM). 2-methoxyethoxymethyl

(MEM),

bis(2-chloroethoxy)methyl, tetrahydropyranyl (THP). tetrahydrothiopyranyl, 4-methoxvtetrahydropyranyl. 4-methoxytetrahydrothiopyranyl. tetrahydrofuranyl. tetrahydrothiofuranyl.

and the like: substituted ethyl ethers such as I-ethoxyeth~ 1-methyl- I-methoxyethyl.

WO 99/67192 PCTIUS99/14251 18 2-(phenvlselenyl )ethyl. t-butvl. allyL. benzvl, o-nitrobenzyl, triphenylmethvl. a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, 9-(9-phenyl-0-oxo)anthranyl (tritvione), and the like: silyl ethers such as trimethylsilyl (TMS). isopropvldimethylsilyl. t-butvldimethvlsiiI (TBDMS) t-butyldiphenylsilyl. tribenzvlsilyl. tri--xvylylsilyl. triisopropylsilyl. and the like: esters such as formate.

acetate, trichloroacetate. phenoxyacetate, isobutyrate, pivaloate. adamantoate. benzoate, 2,4,6trimethvlbenzoate. and the like; and carbonates such as methyl. 2,2.2-trichloroethyl. allyl, p-nitrophenyl.

benzyl,p-nitrobenzyl. S-benzyl thiocarbonate. and the like.

"Amino acid" means an amino acid selected from the group consisting of natural and unnatural amino acids as defined herein.

"Natural amino acid" means an a-amino acid selected from the group consisting of alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan. methionine, glycine. serine, threonine.

cysteine, tvrosine. asparagine, glutamine, lysine. arginine. histidine, aspartic acid and glutamic acid.

"Unnatural amino acid" means an amino acid for which there is no nucleic acid codon.

Examples of unnatural amino acids include. for example, the D-isomers of the natural a-amino acids as indicated above; aminobutyric acid (Aib), 3-aminoisobutyric acid (bAib), norvaline (Nva), -Ala, 2-aminoadipic acid (Aad), 3-aminoadipic acid (bAad), 2-aminobutyric acid (Abu), y-aminobutyric acid (Gaba), 6-aminocaproic acid (Acp), 2,4-diaminobutryic acid (Dbu), a-aminopimelic acid, trimethylsilyl-Ala (TMSA), allo-isoleucine (alle), norleucine (Nile), terl-Leu, citrulline (Cit), ornithine (Orn), 2,2'-diaminopimelic acid) (Dpm), 2,3-diaminopropionic acid (Dpr), a- or -Nal, cyclohexyl-Ala (Cha), hydroxyproline, sarcosine (Sar), and the like; cyclic amino acids; N 0 -alkylated amino acids such as N 0 -methylglycine (MeGly), N"-ethylglycine (EtGly) and N"-ethylasparagine (EtAsn); and amino acids in which the a-carbon bears two side-chain substituents.

"Equivalent amino acid" means an amino acid which may be substituted for another amino acid in the peptides according to the invention without any appreciable loss of function. In making such changes, substitutions of like amino acids is made on the basis of relative similarity of side chain substituents. for example regarding size. charge, hvdrophilicity, hydropathicity and hydrophobicity as described herein.

"Peptide"' and "polypeptide" mean a polymer in which the monomers are natural or unnatural amino acid residues joined together through amide bonds. The term "peptide backbone" means the series of amide bonds through which the amino acid residues are joined. The term "amino acid residue" means the individual amino acid units incorporated into the peptides or polypeptides.

"Aliphatic" means a radical derived from a non aromatic C-H bond by removal of the hydrogen atom. The aliphatic radical may be further substituted by additional aliphatic or aromatic radicals as defined herein. Representative aliphatic groups include alkyl. alkenyl, alkynyl, cycloalkyl., cycloalkenyl.

heterocyclyl. heterocyclenyl, aralkenvl. aralkvloxyalkyl, aralkyloxycarbonylalkyl. aralkyl. aralkvnyl.

aralkyloxyalkenyl. heteroaralkenyl. heteroaralkyl. heteroaralkyloxyalkenyl, heteroaralkyloxyalkyl.

heteroaralkynyl. fused arylcvcloalkyl. fused heteroarvlcycloalkyl. fused arylcycloalkenyl, fused heteroarlcycloalkenyl. fused arylheterocyclyl. fused heteroarylheterocyclyl. fused arylheterocyclenyl, fused heteroarvlheterocyclenvl. and the like. "Aliphatic". as used herein. also encompasses the residual.

non-carboxyl portion of natural and unnatural amino acids as defined herein.

WO 00/7101) PCT/US99/14251 19 "Aromatic'" means a radical derived from an aromatic C-H bond by removal of the hydrogen atom. Aromatic includes both anl and heteroaryl rings as defined herein. The aryl or heteroaryl ring may be further substituted by additional aliphatic or aromatic radicals as defined herein. Representative aromatic groups include aryl, fused cycloalkenylaryl. fused cycloalkylaryl, fused heterocyclylaryl, fused S heterocyclenvlaryl. heteroaryl. fused cycloalkylheteroaryl, fused cvcloalkenvlheteroaryl. fused heterocyclenylheteroaryl, fused heterocyclylheteroaryl. and the like.

"Acid bioisostere" means a group which has chemical and physical similarities producing broadly similar biological properties (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,2 l,p283 "Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993,33,p576- 5 7 9 "Application Of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 1995,p34-3 8 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham, Theochem, 1995,343,p105-109 "Theoretical Studies Applied To Drug Design: ab initio Electronic Distributions In Bioisosteres").

Examples of suitable acid bioisosteres include: -C(=O)-CH20H, -C(=O)-CH 2

SH,

sulpho, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl. 3-hydroxy-3-cyclobutene- 1,2-dione, 1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy- I -methylpyrazolyl.

"Acvl" means an H-CO- or alkyl-CO- group wherein the alkyl group is as herein described.

Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2methylpropanoyl. butanoyl and palmitoyl.

"Acylamino" is an acyl-NH- group wherein acyl is as defined herein.

"Alkenoyl" means ani alkenyl-CO- group wherein alkenyl is as defined herein.

"Alkenyl" means a straight or branched aliphatic hydrocarbon group of 2 to about 15 carbon atoms which contains at least one carbon-carbon double bond. Preferred alkenyl groups have 2 to about 12 carbon atoms: more preferred alkenyl groups have 2 to about 4 carbon atoms. The alkenyl group is optionally substituted with one or more alkyl group substituents as defined herein. Representative alkenyl groups include ethenyl propenyl, n-butenyl, i-butenyl. 3-methylbut-2-enyl, n-pentenyl. heptenyl.

octenyl, cyclohexylbutenyl and decenyl.

"Alkenvloxy" means an alkenyl-O- group wherein the alkenyl group is as herein described.

Representative alkenvioxy groups include allyloxy or 3-butenyloxy.

"Alkoxv" means an alkyl-O- group wherein the alkyl group is as defined herein. Representative alkoxy groups include methoxy. ethoxy. n-propoxy, i-propoxy. n-butoxy, heptoxy, and the like.

"Alkoxvalkvl" means an alkyl-O-alkylene- group wherein alkyl and alkylene are as defined herein. Representative alkoxvalkyl groups include methoxyethyl, ethoxymethyl. n-butoxymethyl and cvclopentylmethyloxyethyl.

"Alkoxvalkoxv" means an alkyl-O-alkylenyl-O- group. Representative alkoxyalkoxy include methoxymethoxy. methoxvethoxy, ethoxyethoxy. and the like.

"Alkoxvcarbonvl" means an ester group; i.e. an alkyl-O-CO- group wherein alkyl is as defined herein. Representative alkoxycarbonyl groups include methoxvcarbonyl, ethoxycarbonyl. Ibutyloxvcarbonyl. and the like.

WO 0/67192 PCT/US99/14251 "Alkoxvcarbonvyalkyl" means an alkyl-O-CO-alkylene- group wherein alkyl and alkylene are as defined herein. Representative alkoxycarbonylalkyl include methoxycarbonylmethyl, and ethoxycarbonylmethyl, methoxycarbonyl ethyl. and the like.

"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have I to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alk:l chain. "Lower alkyl" means about 1 to about 4 carbon atoms in the chain which may be straight or branched. The alkyl is optionally substituted with one or more "alkyl group substituents" which may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy. amino, carbamoyl.

acylamino, aroylamino. carboxy, alkoxycarbonyl, aralkyloxycarbonyl, or heteroaralkyloxycarbonyl.

Representative alkyl groups include methyl, trifluoromethyl. cyclopropylmethyl. cyclopentylmethyl, ethyl. n-propyl, i-propyl. n-butyl, t-butyl, n-pentyl, 3-pentyl. methoxyethyl. carboxymethyl.

methoxvcarbonvlethyl. benzvloxycarbonylmethyl, and pyridylmethyloxycarbonylmethyl.

"Alkvlene" means a straight or branched bivalent hydrocarbon chain of 1 to about 6 carbon atoms. The alkylene is optionally substituted with one or more "alkylene group substituents" which may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy, carbamoyl, carboxy, cyano, aryl, heteroaryl or oxo. The alkylene is optionally interrupted by, a carbon thereof is substituted for, (where m is phenylene or (where R' is lower alkyl). Preferred alkylene groups are the lower alkylene groups having 1 to about 4 carbon atoms. Representative alkylene groups include methylene. ethylene. and the like.

"Alkenylene" means a straight or branched bivalent hydrocarbon chain containing at least one carbon-carbon double bond. The alkenylene is optionally substituted with one or more "alkylene group substituents" as defined herein. The alkenylene is optionally interrupted by, a carbon thereof is substituted for, -S(0)m (where m is phenylene or (where R' is lower alkyl).

Representative alkenylene include -CH=CH-, -CH2CH=CH-, -C(CH 3

-CH

2

CH=CHCH

2 and the like.

"Alkynvlene" means a straight or branched bivalent hydrocarbon chain containing at least one carbon-carbon triple bond. The alkynylene is optionally substituted with one or more "alkylene group substituents" as defined herein. The alkynylene is optionally interrupted by, a carbon thereof is substituted for. (where m is phenylene or (where R' is lower alkyl).

Representative alkynylene include CHECH- CH CH- CH- CH CH- CH(CH 3 and the like.

"Alkylsulfinyl" means an alkyl-SO- group wherein the alkyl group is as defined above.

Preferred alkylsulfinyl groups are those wherein the alkyl group is lower alkyl.

"Alkylsulfonyl" means an alkyl-SO,-group wherein the alkyl group is as defined herein.

Preferred alkylsulfonyl groups are those wherein the alkyl group is lower alkyl.

"Alkylsulfonylcarbamoyl" means an alkvl-SO2-NH-CO- group wherein alkyl group is defined herein. Preferred alkvlsulfonylcarbamoyl groups are those wherein the alkyl group is lower alkyl.

WO 99/67192 PCT/US99/14251 21 "Alkvlthio" means an alkyl-S- group wherein the alkyl group is as defined herein. Preferred alkylthio groups are those wherein the alkyl group is lower alkyl. Representative alkylthio groups include methylthio. ethylthio, i-propylthio, heptylthio, and the like.

"Alkvnvl" means a straight or branched aliphatic hydrocarbon group of 2 to about 15 carbon atoms which contains at least one carbon-carbon triple bond. Preferred alkynyl groups have 2 to about 12 carbon atoms. More preferred alkynyl groups contain 2 to about 4 carbon atoms. "Lower alkynyl' means alkynyl of 2 to about 4 carbon atoms. The alkynyl group may be substituted by one or more alkyl group substituents as defined herein. Representative alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl. 3-methylbutynyl, n-pentynyl, heptynyl, octynyl, decynyl. and the like.

"Alkynyloxy" means an alkynyl-O- group wherein the alkynyl group is defined herein.

Representative alkynyloxy groups include propynyloxy. 3-butynyloxy, and the like.

"Alkynvloxyalkyl'" means alkynyl-O-alkylene- group wherein alkynyl and alkylene are defined herein.

NR

2 11 26 "Amidino" or -amidine" means a group of formula -C-NR wherein R" is hydrogen;

R

7 0 2 C- wherein R" is hydrogen. alkyl, aralkyl or heteroaralkyl;

R

27

R

27 cyano; alkyl: nitro: or amino, and R 6 is selected from hydrogen; alkyl: aralkyl; and heteroaralkyl.

"Amino" means a group of formula YyI 2 N- wherein Y 1 and Y 2 are independently hydrogen: acyl or alkyl, or Y 1 and Y2 taken together with the N through which YI and Y2 are linked form a 4 to 7 membered azaheterocyclyl. Representative amino groups include amino methylamino, dimethylamino. diethvlamino and the like.

"Aminoalkyl" means an amino-alkylene- group wherein amino and alkylene are defined herein.

Representative aminoalkyl groups include aminomethyl, aminoethyl, dimethylaminomethyl, and the like.

"Aralkenvl" means a aryl-alkenylene- group wherein aryl and alkenylene are define herein.

Preferred aralkenyls contain a lower alkenylene moiety. A representative aralkenyl group is 2-phenethenyl.

"Aralkyloxy" means an aralkyl-O- group wherein aralkyl is defined herein. Representative aralkoxy groups include benzyloxy, naphth-1-ylmethoxy, naphth-2-ylmethoxy, and the like.

"Aralkyloxyalkyl" means an aralkyl-O-alkylene- group wherein aralkyl and alkylene are defined herein. A representative aralkyloxyalkyl group is benzyloxyethyl.

"Aralkyloxvcarbonyl" means an aralkyl-O-CO- group wherein aralkyl is defined herein. A representative aralkoxycarbonyl group is benzyloxycarbonyl.

"Aralkyloxycarbonylalkyl" means an aralkoxycarbonyl-alkylene- wherein aralkyloxycarbonyl and alkvlene are defined herein. Representative aralkoxycarbonylalkyls include benzvloxvcarbonvlmethyl. benzyloxycarbonylethyl.

"AralkxlF means an aryl-alkylenyl- Preferred alkylsulfonylcarbamoyl groups are those wherein the alkyl group is lower alkyl group. Preferred aralkyls contain a lower alkyl moiety. Representative aralkyl groups include benzyl, 2-phenethyl, naphthlenemethyl, and the like.

"AralkvloxvalkenyI" means an aralkyl-O-alkenvlene- group wherein aralkyl and alkenylene are defined herein. A representative aralkyloxyalkenyl group is 3-benzyloxyallyl.

PCT/US99/14251 WO~ 99/67192 WOn 09/67192PTIS9/45 22 "Aralkylsulfonyl" means an aralkyl-SO,- group wherein aralkyl is defined herein.

"Aralkylvsulfinyl" means an aralkyl-SO- group wherein aralkyl is defined herein.

"Aralkvlthio" means an aralkyl-S- group wherein aralkyl is defined herein. A representative aralkylthio group is benzylthio.

"Arovi" means an aryl-CO- group wherein arvl is defined herein. Representative aroyl include benzoyl. naphth- l-oyl and naphth-2-oyl.

"Cvcloalkvl" means a non-aromatic mono- or multicyclic ring system of about 3 to about carbon atoms, preferably of about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about to about 6 ring atoms. The cycloalkyl is optionally substituted with one or more "ring system substituents" which ma' be the same or different, and are as defined herein, or where R 18 is a substituted cycloalkyl. the cycloalkyl is substituted by one or more 1,2 or 3) substituents chosen from OR 2 '3,

SR

2 4

SOR

2 4 S02R 2 4

NH

2

NR

2 2R2 4

=NOR

2 4 =NOH, =NNHR 2 4

=NOCONHR

2 4

=NCO'R

2 4

SOR

2 4

NHCOR

2 4 NHSO2R 2 4 S0 2

NR

2 2

R

2 4

R

2 3, CONHR 2 4 CONHCH2,CO2R 2 2

CONR

2 4

R

2 2

N

3 or azaheterocyclyl: wherein R 2 3 is as defined herein; R 2 3 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and R 2 4 is alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl. arylalkyl, heteroaryl or heteroarylalkyl. Representative monocyclic cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Representative multicyclic cycloalkyl include I -decalin, norbornyl, adamantyl, and the like. The prefix spiro before cycloalkyl means that geminal substituents on a carbon atom are replaced to form 1,1-cycloalkyl. "Cycloalkylene" means a bivalent cycloalkyl having about 4 to about 8 carbon atoms. Preferred cycloalkylenyl groups include or 1,4- cis or transcyclohexylene.

"Cycloalkenyl" means a non-aromatic mono- or multicyclic ring system of about 3 to about carbon atoms, preferably of about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkylene rings contain about 5 to about 6 ring atoms. The cycloalkenyl is optionally substituted with one or more "ring systemn substituents" which may be the same or different.

and are as defined herein. Representative monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. A representative multicyclic cycloalkenyl is norbornylenyl.

"Cvclocarbamoylalkyl" means a compound of formula 0 HN 0k HN 0 -alkvlene- or alkylene- 30 or in which the cvclocarbamoyl group consists of the oxooxazaheterocyclyl ring moiety, and the alkylene group is as defined herein. The alkylene moiety may be attached to the carbamoyl through either a carbon atom or the nitrogen atom of the carbamoyl moiety. An exemplary cyclocarbamoylalkyl group is N-oxazolidinylpropyl.

"Cvcloimidvialkyl' means a compound of formula /4t f 710/ PCT/US99/14251 VVJ 771 23 0 o A 0 H HN NH HN HN NH alkylene- HN NH alkylene- alkylene- or in which the imide group consists of the oxodiazaheterocyclyl ring moiety, and alkylene is as defined herein. The alkylene moiety may be attached to the carbamoyl through either a carbon atom or nitrogen atom of the carbamoyl moiety. An exemplary cycloimidylalkyl group is N-phthalimidepropyl.

"Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system of about 3 to about ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen or sulphur atom of the heterocyclenyl is optionally oxidized to the corresponding N-oxide. S-oxide or S,S-dioxide. Representative monocyclic azaheterocyclenyl groups include 1,2,3,4- tetrahydropyridine, 1,2-dihydropyridyl, 1.4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2pyrazolinyl, and the like. Representative oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran.

dihydrofuranyl, fluorodihydrofuranyl, and the like. A representative multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Representative monocyclic thiaheterocyclenyl rings include dihydrothiophenyl. dihydrothiopyranyl, and the like "Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl is optionally substituted by one or more "ring system substituents" which may be the same or different. and are as defined herein, or wherein R 18 is a substituted heterocyclyl, the heterocyclyl is substituted the ring carbon atoms by one or more 1. 2 or 3) substituents chosen from oxo, cyano, CO2R 2 2

CONHCH

2 CO2R 2 2 aryl. arylalkyl. alkyl or hydroxyalkyl, or is substituted on a ring nitrogen atom by a substituent chosen from R 2 2

(CH

2 )nCO2H. (CH 2 )nCO 2

R

24

(CH

2 )nCONR 22

R

24

(CH

2 )nCOR 2 4 CONH2. CONHR 24

COR

24 SO2R 24 or OR 2 4 wherein R 2 2 and R 24 are as defined herein. The nitrogen or sulphur atom of the heterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S.S-dioxide. Representative monocyclic heterocyclyl rings include piperidyl.

pyrrolidinyl. piperazinyl. morpholinyl. thiomorpholinyl. thiazolidinyl. 1,3-dioxolanyl, 1.4-dioxanyl.

tetrahvdrofuranvl. tetrahydrothiophenyl. tetrahydrothiopyranyl. and the like.

WO 99/67192 PCT/US99/14251 24 "Aryl" means an aromatic monocyclic or multicyclic ring system of 6 to about 14 carbon atoms, preferably of about 6 to about 10 carbon atoms. The aryl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Representative aryl groups include phenyl and naphthyl.

"Heteroaryl" means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" is optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide.

Representative heteroaryls include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl.

isothiazolyl. oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1.2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1.2-a]pyridine. imidazo[2,1-b]thiazolyl.

benzofurazanyl. indolyl, azaindolyl. benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl.

quinazolinyl. thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl. benzothiazolyl and the like.

"Fused arylcycloalkenyl" means a radical derived from a fused aryl and cycloalkenyl as defined herein by removal of hydrogen atom from the cycloalkenyl portion. Preferred fused arylcycloalkenyls are those wherein aryl is phenyl and the cycloalkenyl consists of about 5 to about 6 ring atoms. The fused arylcycloalkenyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. Representative fused arylcycloalkenyl include 1,2dihydronaphthylene. indene, and the like, in which the bond to the parent moiety is through a nonaromatic carbon atom.

"Fused cycloalkenylaryl" means a radical derived from a fused arylcycloalkenyl as defined herein by removal of hydrogen atom from the aryl portion. Representative fused cycloalkenylaryl are as described herein for a fused arylcycloalkenyl. except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused arylcycloalkyl" means a radical derived from a fused aryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred fused arylcycloalkyls are those wherein aryl is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. The fused arylcycloalkyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. Representative fused arylcycloalkyl includes 1.2,3,4tetrahydronaphthyl, and the like. in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused cycloalkylaryl" means a radical derived from a fused arylcycloalkyl as defined herein by removal of a hydrogen atom from the aryl portion. Representative fused cycloalkylaryl are as described herein for a fused arylcycloalkyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused arylheterocyclenyl" means a radical derived from a fused aryl and heterocyclenyl as defined herein by removal of a hydrogen atom from the heterocyclenyl portion. Preferred fused WO 99/67192 PCT/US99/14251 arylheterocyclenyls are those wherein aryl is phenyl and the heterocyclenyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl portion of the fused arylheterocyclenyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused arylheterocyclenyl is optionally substituted by one or more ring system substituents, wherein "ring S system substituent" is as defined herein. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused arvlheterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.

Representative fused arvlheterocyclenyl include 3H-indolinyl, 1 H-2-oxoquinolyl, 2H- I-oxoisoquinolyl.

1.2-dihydroquinolinyl, 3.4-dihydroquinolinyl. 1,2-dihydroisoquinolinyl. 3,4-dihydroisoquinolinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused heterocyclenylaryl" means a radical derived from a fused arylheterocyclenyl as defined herein by removal of a hydrogen atom from the aryl portion. Representative fused heterocyclenylaryl are as defined herein for a fused arylheterocyclenyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused arvlheterocyclyl" means a radical derived from a fused aryl and heterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Preferred fused arylheterocyclyls are those wherein aryl is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused arylheterocyclyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen or sulphur atom of the heterocyclyl portion of the fused arylheterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative preferred fused arylheterocyclyl ring systems include phthalimide, 1,4-benzodioxane. indolinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 1H-2,3-dihydroisoindolyl, 2.3-dihydrobenz[f]isoindolyl, 1,2,3.4-tetrahydrobenz[g]isoquinolinyl. and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused heterocyclylaryl" means a radical derived from a fused aryheterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Representative preferred fused heterocyclylaryl ring systems are as described for fused arylheterocyclyl. except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused heteroarylcycloalkenyl" means a radical derived from a fused heteroaryl and cycloalkenyl as defined herein by removal of a hydrogen atom from the cycloalkenyl portion. Preferred fused heteroarlvcycloalkenyls are those wherein the heteroaryl and the cycloalkenyl each contain about to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen.

oxygen or sulfur atom respectively is present as a ring atom. The fused heteroarylcycloalkenyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkenyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkenyl include 5,6-dihydroquinolyl. 5,6-dihydroisoquinolyl. 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, H-benzimidazolyl. 4.5-dihydrobenzoxazolyl. and the like. in which the bond to the parent moiety is through a non-aromatic carbon atom.

WO 99/67192 PCT/US99/14251 26 "Fused cvcloalkenvlheteroaryl" means a radical derived from a fused heteroarylcycloalkenyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkenylheteroaryl are as described herein for fused heteroarylcycloalkenyl. except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused heteroarvlcycloalkyl'' means a radical derived from a fused heteroaryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred fused heteroarylcycloalkyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylcycloalkyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkyl include 5,6,7.8-tetrahydroquinolinyl, 5,6,7.8-tetrahydroisoquinolyl, 5,6.7,8-tetrahydroquinoxalinyl, 5,6.7,8-tetrahydroquinazolyl, 4,5,6.7-tetrahydro-1H-benzimidazolyl.

4,5.6,7-tetrahydrobenzoxazolyl, 1 H-4-oxa- 1,5-diazanaphthalen-2-onyl, 1,3-dihydroimidizole-[4,5]-pyridin-2-onyl. and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused cycloalkylheteroaryl" means a radical derived from a fused heteroarylcycloalkyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkylheteroaryl are as described herein for fused heteroarylcycloalkyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused heteroarvlheterocyclenyl" means a radical derived from a fused heteroaryl and heterocyclenyl as defined herein by the removal of a hydrogen atom from the heterocyclenyl portion.

Preferred fused heteroarylheterocyclenyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclenyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroar'l or heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylheterocyclenyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylheterocyclenyl is optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused heteroarylheterocyclenyl is optionally oxidized to the corresponding N-oxide. S-oxide or S,S-dioxide.

Representative fused hereroarylheterocyclenyl include 7,8-dihydro[l,7]naphthyridinyl, 1.2-dihydro[2.7]naphthyTidinyl, 6,7-dihydro-3H-imidazo[4.5-c]pyridyl, 1,2-dihydro-1,5-naphthyridinyl.

1.2-dihydro-1.6-naphthyridinyl, 1,2-dihydro-1.7-naphthyridinyl, 1.2-dihydro-1,8-naphthyridinyl, 1,2-dihydro-2,6-naphthyridinyl. and the like, in which the bond to the parent moiety is through a non aromatic carbon atom.

"Fused heterocyclenylheteroaryl" means a radical derived from a fused heteroarylheterocyclenyl as defined herein by the removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclenylheteroaryl are as described herein for fused heteroarylheterocyclenyl. except that the bond to the parent moiety is through an aromatic carbon atom.

WO 99/67192 PCT/US99/14251 27 "Fused heteroarx'lheterocyclyl" means a radical derived from a fused heteroaryl and heterocyclyl as defined herein, by removal of a hydrogen atom from the heterocyclyl portion. Preferred fused heteroarylheterocyclYls are those wherein the heteroaryl thereof consists of about 5 to about 6.ring atoms and the heterocyclyl consists of about 5 to about 6 ring atoms. The prefix aza. oxa or thia before the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused heteroaryiheterocyclyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylheterocyclyl is optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur atom of the heterocyclyl portion of the fused heteroaryiheterocyclyl is optionally oxidized to the corresponding N-oxide. S-oxide or S,S-dioxide. Representative fused heteroarviheterocyclyl include 2.3-dihydro-lIH pyrrol[3 .4-b]quinolin-2-yl, 1 ,2.3,4-tetrahyvdrobelz [1 ,7]naphthyridin-2-y 1 I .2,3.4-tetrahydrobeflz [b][1I.6Thaphthyridin-2-vl. I ,2.3.,4-tetrahiydro-9H-PYrido[ 3 A4-b1 indol-2y1.

1 .2.3.4-tetrahvdro-9H-pyrido[4.3'-blindol- 2 yl, 2.3,-dihydro- I 1-pyrrololi3,4-b] indol-2-yl.

I H-2,3.4,5-tetrahyvdroazepiflo[i 3 b] indol-2-yl, I H-2,3,4.5-tetrahydroazepino[4,3-blindol- 3 -yl.

I H-2,3 ,4,5-tetrahydroazepino[ 4 indol-2 yl, 5 ,6.7,8-tetrahydro[ I.7]napthyridinyl,.

1,2,3 .4-tetrhydro[2,7]naphthYridyl, 2,3-dihydro[1I,4]dioxino[2.

3 -blpyridyl, 2,3)-dihydro[l1 .4]dioxinol2,3-blpryidyl. 3,4-dihydro-2H- I -oxa[4,6]diazanaphthalelyl..

4,5,6,7-tetrahvdro-3 H-imidazo[4,5-clpyridyl, 6.7-dihydro[5,8]dazanaphthalenyI, 1 ,2,3,4-tetrahydroi1 napthyridinyl, 1 ,2,3.4-tetrahydrol I,6]napthyridinyl, I ,2,3,4-tetrahvdro[I1.7]napthyridinyl, 1,2,3 ,4-tetrahydro[ I.8]napthyridinyl, I ,2,3,4-tetrahydro[2.6]napthy'ridiny'l. and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused heterocyclyiheteroarYl" means a radical derived from a fused heteroarylheterocyclyl as 2 5 defined herein, by removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclyiheteroaryl are as described herein for fused heteroaryiheterocyclyi. except that the bond to the parent moiety is through an aromatic carbon atom.

"AralkynyF" means an aryl-alkynylene- group wherein aryl and alkynylene are defined herein.

Representative aralkynyl groups include phenylacetylenyl and 3-phenylbut-2-yflyl.

"Arvldiazo" means an aryl-N=N- group wherein aryl is defined herein. Representative arldiazo groups include phenyldiazo and naphthyldiazo.

"Arylcarbamnoyl" means an aryl-NHCO- group, wherein aryl is defined herein.

"Benz,%T' means a pheny-CH,- group. Substituted benzyl means a benzyl group in wvhich the phenyl ring is substituted with one or more ring system substituents. Representative benzyl include 4bromobenzyl, 4-methoxybenzvl. 2,4-dimethoxybenzyli. and the like.

"CarbamoNTF means a group of formula Y I Y )NCO- wherein YIand Y are defined herein.

Rersentative carbamoyl groups include carbamyl (H2NCO-), dimethylaminocarbamoyl (Me-)NCO-).

and the like.

"Carboxv" and "carboxyl" mean a HO(O)C- group a carboxylic acid).

"Carboxyalkyl-" means a HO(O)C-alkylene- group wherein alkylene is defined herein.

Representative carbox-valkyls include carboxym ethyli and carboxyethyl.

WO 99/61192 WO 9967192PCTIUS99/1 4251 "Cvcloalkyloxy" means a cycloalkyl-O- group wvherein cycloalkyl is defined herein.

Representative cvcloalkyloxy groups include cyclopentyloxy, cyclohexyloxy. and the like.

"Diazo" means a bivalent radical.

"Ethvlenl" means a -CI-=CH- group.

"Halo" or Thalogen" meani fluoro, chioro. bromno. or iodo.

*'Heteroaralkenyl" means a heteroaryl-alkenylene- group wherein heteroaryl and alkenylene are defined herein. Preferred heteroaralkenyls contain a lower alkenylene moiety. Representative heteroaralkenyl roups include 4-pyridyl]vinyl, thienylethenyl, pyridylethenyl, im idazolylethenyl.

pyrazinylethenyl. and the like.

"Heteroaralkyl" means a heteroaryl-alkylene- group wherein heteroaryl and alkylene are defined herein. Preferred heteroaralkyls contain a lower alkylene group. Representative heteroaralkyl groups include thienylmethyl. pyridyimethyl, imidazolylmethyl, pyrazinylmethyl, and thle like.

"Heteroaralkyloxv" means an heteroaralkyl-O- group wherein heteroaralkyl is defined herein. A representative heteroaralky lox)' group is 4-pyridylmnethyloxy.

1 5 "Heteroaralkyloxyalkenyl" means a hieteroaralkyl-O-alkenyleiie- group wherein heteroaralky I and alkenylene are defined herein. A representative heteroaralkyloxyalkenyl group is 4-pyridylmethyloxyallyl.

"Heteroaralkyloxyalkyl" means a heteroaralkyl-O-alkylefle- group wherein heteroaralkyl and alkylene are defined herein. A representative heteroaralkyloxy group is 4-pyridylmethyloxyethyl.

"Heteroaralkynyl" means an heteroaryl-alkynylene- group wherein heteroaryl and alkynylene are defined herein. Preferred heteroaralkynyls contain a lower alkynylene moiety. Representative heteroaralkynyl groups include pyrid-3 -ylacetylenyl, quinoilii-3-ylacetylenyl, 4-pyridylethynyl. and the like.

,,Heteroaroyl" means an means a heteroaryl-CO- group wherein heteroaryl is defined herein.

2 5 Representative heteroaroyl groups include thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl, pyridinoyl, and the like.

",Heteroaryldiazo" means an heteroaryl-N=N- group wherein heteroaryl is as defined herein.

"Heteroarlsulphonylcarbanloyl" means a heteroaryl-SO-)-NH-CO- group wherein heteroaryl is defined herein.

"Heterocyclylalkyl" means a heterocyclyl-alkylene- group wherein heterocyclyl and alkylene are defined herein. Preferred heterocycly'lalkyls contain a lower alkylene moiety. A representative heteroaralkyl group is tetrahydropyranylmethyl.

"Heteroc\vclvlalkyloxyalkyF' means a heterocyclylalkyl-O-alkylene group wherein heterocyclylalkyl and alkylene are defined herein. A representative heterocyclylalkvloxvalkyl group is tetrahvdropyranylmethyloxymethyl.

"Heterocyclyloxy" means a heterocyclyl-O- group wherein heterocyclyl is defined herein.

Representative heterocyclyloxy groups include qu inuclidyloxy, pentamethylenestilfideoxy, tetrahydropyrany loxy, tetrahydroth iopheny loxy, pyrrolidinyloxy, tetrahydrofuraflyloxy, 7-oxabicyclo[2.2. I }eptanyloxy,. hvdroxy-tetrahydropyranyloxy.

hydroxy-7-oxabicyclo[ 2 2 1 ]heptanvloxy. and the like.

WO 99/67192 PCT/US99/14251 29 "Hvdroxvalkyl means an alkyl group as defined herein substituted with one or more hydroxy groups. Preferred hydroxyalkyls contain lower alkyl. Representative hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

0O "N-oxide" means a N group.

"Oxo" means a group of formula >C=O a carbonyl group).

"Phenoxy" means a phenyl-O- group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.

"Phenvlene" means a -phenyl- group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.

"Phenylthio" means a phenyl-S- group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.

"Pvridyloxy" means a pyridyl-O- group wherein the pyridyl ring is optionally substituted with one or more ring system substituents as defined herein.

"Ring system substituents" mean substituents attached to aromatic or non-aromatic ring systems inclusive of hydrogen, alkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl. halo, nitro, cyano, carboxy. alkoxycarbonyl, aryloxycarbonyl. aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl. alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, nitrile, NO, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryldiazo. heteroaryldiazo, amidino, YIY 2 Y y 2 N-alkyl-, Y Y2NCO- or y 1 y 2 NSO2-, wherein Y and Y 2 are independently hydrogen, alkyl, aryl, and aralkyl. or where the substituent is l Y 2 N- or yl 2N-alkvl- then one ofY 1 and Y2 is acyl or aroyl and the other ofY 1 and Y 2 is hydrogen. alkyl, arvl, and aralkyl. When a ring system is saturated or partially saturated, the "ring system substituent" further comprises methylene oxo and thioxo Preferred ring system substituents are hydrogen, CF 3 fluoro. alkyl, alkoxy, nitrile or NOz.

"Sulfamovl" means a group of formula Y Y 2 NSO2- wherein

Y

1 and Y 2 are defined herein.

Representative sulfamoyl groups are sulfamoyl (H2NSO2-) and dimethylsulfamoyl (Me2NSO2-).

Preferred Embodiments A process for the preparation of aldehydes and ketones according to this invention is outlined in Scheme 1 wherein R, and Rb independently represent any aliphatic or aromatic group amenable to the solvents and reagents utilized in the processes described herein. The groups R, and Rb may be further substituted and may contain functional groups suitable for further chemical transformations while attached to the hydroxvlamine resin. Such functional groups may be suitable protected to prevent interference with the reactions described below. For a comprehensive treatise on the protection and deprotection of common functional groups see T.H. Greene and P.G.M. Wuts, Protective Groups in WO 99/67192 WO 9967192PCT/US99/1 4251 Organic Synthesis, 2nd edition, John Wiley Sons, New York (199 incorporated herein by reference.

R, represents any aliphatic or aromatic group suitable for use as an organometallic reagent.

Scheme I L- H RaCO 2 H L O NARa

RL

wH

H

1 2 a)R~M0 W L-O-N R b) H 3 Rc 0- Ra 3 4 a) [Hr] b) H 3 0+ RaCHO According to the foregoing Scheme 1, a polymeric hydroxylamine resin compound I is coupled with a carboxylic acid derivative of formula R.,COH to form the polymeric hydroxamic acid resin compound 2. The coupling reaction is accomplished in the presence of an activating agent as is known in the art of peptide synthesis. Representative activating agents include isopropyl chioroformate.

diisopropylcarbodiimide (DIG). I- .(3dimethy lam inopropyl)-3 -ethylcarbodi im ide (EDC).

I -hydroxybenzotriazole (H-OBT), bis(2-oxo-3'-oxazol idinyl)-phosphonic chloride (BOP-CI).

benzotriazole- I -vloxv .tris((dimethy lam ino)phosphoniuim)hexafluorophosphate

(BOP),

benzotriazole- I -vlox-,-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBROP), bromo-tris-pyrTrolidino-phosphonium hexafluorophosphate (PyBOP), 2-(1I H-benzotriazole- I 1. 1.3 .3 -tetramethyluronium tetrafluoroborate

(TBTU),

2-(1I H-benzotriazole- I 1. .1.3 .3-tetramethyluronium hexafluoroborate

(HBTU),

2-[2-oxo- I 2H)-pyridylll- 1, 1.3 .3-bispentamethvleneuroloium tetrafluoroborate (TOPPipU).

NXN-dicvclohexvlcarbodiimide (DCC). and the like. Suitable solvents for the coupling reaction include dichlIorom ethane. DMF. DMSO, THEIF and the like. Coupling times range from about 2 to about 24 hours. depending upon the resin and carboxylic acid derivative to be coupled, activating agent. solvent and temperature. The coupling is accomplished at from about -10 'C to about 50 0 C, preferably at about ambient temperature.

The coupling reaction is preferably accomplished at ambient temperature in DMF using 1I(3 dimethylam inoprop I\-3-ethylcarbodiimide hydrochloride over about 12 hours.

wn o/67I9 PCT/US99/14251 31 The polymeric hydroxamic acid resin compound 2 is then alkylated with an alkylating agent of formula RLG. where LG is a leaving group, in the presence of a non-nucleophilic base such as 1,8diazabicvclo[5.4.0]undec-7-ene (DBU) in an inert organic solvent such as toluene to form the Nalkylated polymeric hvdroxamic acid resin compound 3. The alkylating agent Ri,LG may be added in an equimolar amount to an excess of to about 25 molar equivalents. About 15 molar equivalents is preferred. The non-nucleophilic base may be added in an equimolar amount to an excess of to about molar equivalents. About 5 molar equivalents is preferred. The leaving group LG is any group amenable to nucleophilic displacement by the nitrogen atom of the polymeric hydroxamic acid resin compound 2 under the reaction conditions described above. A preferred leaving group is halogen. A sample of the N-alkylated polymeric hydroxamic acid resin compound 3 may be subjected to acidolysis to cleave the substituted hydroxamic acid to confirm that the reaction proceeded satisfactorily.

Reaction of the polymeric N-alkylated hydroxamic acid resin compound i with an organometallic reagent of formula RM. wherein R, is an aliphatic or aromatic anion and M is a metal cation. followed by acid hydrolysis provides the ketone 4. Preferred organometallic reagents are organolithium reagents of formula RLi and Grignard reagents of formula RMgX wherein X is halogen.

In a preferred preparation of ketones according to this aspect of the invention, the polymeric N-alkylated hydroxamic acid resin compound 3 is treated with ReMgX in diethyl ether at ambient temperature over about 18 hours. and the reaction mixture is then quenched by addition of aqueous HCI or aqueous KHSO, to liberate the ketone 4.

Aldehydes are prepared by treatment of the polymeric N-alkylated hydroxamic acid resin compound 3 with a hydride reducing agent, followed by acid hydrolysis as shown in Scheme I above.

Representative hydride reducing agents include LiAlH 4 (iso-Bu),AIH, LiAH(O-t-Bu) 3 LiAIH,-EtOH, LiAIH,-MeOH, and the like. Preferred reducing agents are LiAIH, and LiAIH 4 -MeOH. The acid hydrolysis is preferably accomplished aqueous KHSO, As shown in Scheme 1. the N-alkylated polymeric hydroxamic acid resin compound 3 is a Weinreb-like amide useful for the synthesis of aldehydes and ketones Nahm and S. Weinreb, Tet Lett.

1981, 22. 3815-3818). This N-alkylated polymeric hydroxamic acid resin compound has advantages over the previous examples of resin bound Weinreb-like amides (See Fehrentz et al.. Tet. Lett.. 1995. 36.

7871-7874 and Dinh et al.. Tet. Lett.. 1996, 37, 1161-1164) in that it can be N-alkylated with bulky lipophilic groups such as benzyl, substituted benzyl, naphthyl or any alkyl group necessary to optimize the reaction on the solid phase. The N-benzyl-O-methylpolystyrenyl moiety, for example, is well suited to form a stable metal chelated intermediate. The lipophilic benzyl group is believed to help shield the chelate adding to its stability.

A preferred process for the preparation of aldehydes and ketones is outlined in Scheme 2. In Scheme 2. designates an amine protecting group as defined herein.

Scheme 2 WO 99/67192 PCT/US99/14251 32 H H RbL L-O-N H

L-O-N

H

P

1 6 Rb ,Rb RaCO 2

H

L-O-N L-O-N. H IP

H

7 8 0a)M 0 L-O-NA Ra P Rc Ra Rb b) H304 3 4 a) [H] b) H 3 0+ RaCHO As shown in Scheme 2 above, the polymeric hydroxylamine resin compound is protected with an amine protecting group to form the N-protected polymeric hydroxylamine resin compound 6. The Nprotected polymeric hydroxylamine resin compound 6 is then alkylated as described in Scheme I above to form the N-alkylated N-protected polymeric hydroxylamine resin compound 7. Removal of the amine protecting group provides the mono N-alkylated polymeric hydroxylamine resin compound 8. Coupling of 8 with a carboxylic acid compound of formula R.COH as described above provides the polymeric Nalkylated hydroxamic acid resin compound 2, which is converted to ketone 4 or aldehyde 5 as described in Scheme 1 above.

Preferred amine protecting groups include allyloxycarbonyl (Aloc). benzyloxycarbonyl (Cbz). p-methoxybenzyloxycarbonyl (Moz). p-nitrobenzyloxycarbonyl trimethylsilylethoxvcarbonyl (Teoc). 2,4-dimethoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, o-nitrobenzylsulfonyl (o-Nbs), p-nitrobenzylsulfonyl (p-Nbs), and 2-nitro-4-trifluoromethIylbenzenesulfonyl.

The most preferred amine protecting group is allyloxycarbonyl.

In a preferred aspect of the processes described in Schemes I and 2 above, R. represents the residual, non-carboxyl portion of a natural or unnatural amino acid or peptide. Accordingly, the foregoing processes present a facile route to the heretofore difficult to obtain amino acid or peptide aldehyde compounds.

ILUd'% 001r.'710') PCTIUS9Q/1 4251 V~t~ PCTUUS99/14251 in a process for preparing amino acid aldehyde or peptide amino acids according to this invention, the N-terminal nitrogen atom of the amino acid or peptide starting material is preferably protected with a suitable amine protecting group, designated herein as Furthermore, any functional groups contained in the amino acid or peptide side chain(s) may be suitably protected to prevent interference with the reactions described herein.

In a preferred aspect of the preparation of amino acid or peptide aldehydes described above, Rb is benzyl or substituted benzyl.

In a more preferred aspect of the preparation of amino acid or peptide aldehydes described above, Rb is benzyl or benzyl substituted with halogen, haloalkyl or alkoxy and P" is t-butyloxycarbonyl

(BOC).

In addition, the N-alkylated hydroxamic acid resin compound 3 in which R, is the residual noncarboxyl portion of a natural amino acid or peptide are amino acid or peptide aldehyde equivalents which may be stored and used to generate the corresponding amino acid or peptide aldehyde as needed by treatment with a hydride reducing agent and acid hydrolysis as described above.

Preferred polymeric N-protected hydroxylamnine resin compounds include N-allyloxycarbonyl-4-(O-methylhydroxylamife)phenoxymethyIvcopoly(styrene- I% divinylbenzene) resin, N-lyoyabni4[-Omtvhdoyaie-3)-eloyhnx]-N4mehlbnhdy) butyramide-copoly(styrene- l%-divinylbenzene)-resin, N-allyloxycarbonyl-4-(2 -dimethoxyphenyl-O-methylhydroxylam ine)-phenoxymethylcopoly(styrene- 1% divinvlbenzene) resin.

N-allyloxycarbonyl-4-[4-(I ioyty)--elo butyramide-copoly(styrene- 1% divinylbenzene) resin.

2 5 N-allyloxycarbonyl-O-hydroxy lam ine-2 '-chlorotrityl-copolystyrene- I %-divinylbenzene-resifl, N-lyoyabni0hdoylmn-rtlcplsyee 1 %-divinylbenzene-resin, -3 ,5-dimethoxyphenoxy)-valeric acid-copolystyrene- 1%-divinyl benzene resin.

mtoxpinx-ooytrn-%-divinyl benzene resin.

N-allyloxycarbonyl-4-(O-methylhydroxylam ine)-2-- .5.6-tetrafluorophenoxymethyl-copoly(styrene I1% divinylbenzene) resin, N-al lyloxycarbony .4-dimethoxyphenyl-O-methyllydroxy lam ine)-2,3 .5,6tetrafluorophenoxymeth\yl-copoly(styrene- 1% divinylbenzene) resin and 3 5 N-lyoyabnl'-vrx-xnhdoaiecplsree1 %-diviniylbenzene resin.

The most preferred polymeric N-protected hydroxylamine resin compound is N-lyovabni4(-etvhdoyaiepeo lehlcpl~trn-% d ivinylbenzene) resin.

WO 99/67192 PCT/US99/14251 34 A process for the preparation of amines according to this invention is outlined in Scheme 3. In Scheme 3, Rd and R, independently represent H or any aliphatic or aromatic group amenable to the solvents and reagents utilized in the processes described herein, provided that Rd and R, are not both H.

The groups Rb and R, may be further substituted and may contain functional groups suitable for S further chemical transformations while attached to the hydroxylamine resin. It is understood that when these functional groups possess reactivity such that they could potentially interfere with the reactions described below, such functional groups should be suitably protected. For a comprehensive treatise on the protection and deprotection of common functional groups see T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley Sons, New York (1991), incorporated herein by reference. Rf represents any aliphatic or aromatic group which is amenable for use as an organometallic reagent.

Scheme 3 L-O-N H LO N R H Rd Re 10 Re NaCNBH 3 or BH 3 THF,/ RfM then LiAIH4

NH

2 L N Rd R

L

Re Rd Re 11 12 LiAIH 4 or BH 3

THF

NH

2 Rf- Re Rd 13 According to the foregoing Scheme 3, reaction of the polymeric hydroxylamine resin compound 1 with an aldehyde or ketone 9 provides the polymeric oxime ether resin compound 10. Oxime formation is preferably accomplished at about ambient temperature by swelling the polymeric hydroxylamine resin compound I in a suitable inert organic solvent such as dichloromethane, followed by addition of an excess of aldehyde or ketone. Reductive cleavage of the resin, for example by reaction with NaCNBH., or BH THF, followed by LiAlH 4 provides the amine 11. Reaction of the polymeric oxime ether resin compound 10 with an organometallic reagent of formula RfM, wherein Rf is an aliphatic or aromatic anion and M is a metal cation as defined herein, provides the polymeric asubstituted hvdroxvlamine resin compound 12. Cleavage of the ao-amine 13 from the resin, is accomplished, for example. using BH THF or LiAIH,. See Y. Ukaji et al., Chem. Lett., 173, (1991) and R. P. Dieter et al.. Can. J. Chem. 71. 814 (1993). Preferred metal cations are Li and MgX wherein X is WO 99/67192 PCTIUS99/1 4251 halogen. With the aid of a chiral auxiliary such as a chiral benzyl hydroxyl amine linker, chiral asubstituted amines will result.

A process for the preparation of lactones via radical cyclization is shown in Scheme 4. In Scheme 4, RI, Rh and R, are aliphatic or aryl as defined herein.

Scheme 4

-L-O-N

R

R9 L- O- N PhSH, AIBN Rh Rg s'SPh L-0-N O Ri 10% HCI 'SPh 0. As shown in the foregoing Scheme 4, the polymeric hydroxylamine resin compound I is reacted with the a,p unsaturated carboxylic acid ester compound 14 to form the polymeric oximyl resin compound 15. Radical cyclization of 15, for example by heating in the presence of 2,2'azobisisobutyronitrile (AIBN) and thiophenol in an inert organic solvent such as benzene results in formation of the polymeric g-lactone resin compound 16. Acid hydrolysis of 16, using, for example aqueous HCI, provides the lactone 17. See O. Miyata et al., Tet. Lett., 37, 229-232, (1996).

A process for the preparation of carbocyclic or heterocylic compounds by radical cyclization is shown in Scheme 5. In Scheme 5, Rj, R, and R, are aliphatic or aryl as defined herein. The methodology described in Scheme 1 is applicable to the preparation of 6- or 7-membered rings. Carbocycles result when the phenolic oxygen atom is replaced with a carbon atom.

Scheme WO 99/67192 L-0-N, H

+R

1 PCTLJS99/14251 Rk H2C ~Br BrCH 2 C(Br)=CH 2 0-L-0-N 19 Bu 3 SnH, AIBN L- 0-N,

H

2 C 0

R

HOHN

R

21 LiAIH 4 Scheme 5, cont.

L-O-N=

23 Rk\ OL-0-N' 24 RiBu 3 SnH,_AIBN_ [Hf] Rk

HOHN

PCT/US99/14251 WO 99/67192 37 According to the foregoing Scheme 5, the polymeric hydroxylamine resin compound I is reacted with the acetophenone compound 18 and a bromoalkene compound or o-bromobenzyl compound to form the polymeric acetophenone oxime compounds 19 or 23. Radical cyclization of 19 or 23, for example by heating in the presence of AIBN and tri-n-butyltin hydride in an inert organic solvent such as benzene results in formation of the polymeric N-cyclyl hydroxylamine resin compounds 20 or 24. Treatment of or 24 with acid, preferably trifluoroacetic acid, results in formation of the cyclic hydroxamic acid compounds 21 or 25. Reductive cleavage of 20 or 24, for example using LiAIH 4 as described in Scheme 3 above, results in formation of the cyclic amine compounds 22 or 26. See S.E. Booth et al., J. Chem.

Soc. Commun., 1248-1249, (1991).

Hydroxamic acid compounds of formula 29, wherein Ar, A 2

R

9 Ro 1

R

1 2 and n are defined herein, are disclosed in WO 97/24117, incorporated herein by reference. Compounds of formula 29 inhibit the production or physiological effects of tumor necrosis factor (TNF) and are useful in treating a patient suffering from a pathological condition such as inflammation or autoimmune disease characterized by a physiologically detrimental excess of TNF.

A process for the preparation of a hydroxamic acid compound of formula 29, wherein Ar, R",

R'

0

R

1 and n are as defined above, according to this invention is shown in Scheme 6.

Scheme 6

L-O-NH

H

ArA 2,

H

o-L

"CO

2

H

ii NA/ OH

R

1 R" O 29 i) 3-(4-methyoxyphenylsulfonyl) propionic acid (5 equiv.); 1-(3-dimethylaminopropyl)- 3 -ethyl carbodiimide nydrochionde (EDCI 5 equiv.): DMF: 250C: 12 hours.

WO 99/67192 PCTIUS99/1 4251 38 ii) 50% TFA in CHCI, (100 equiv.); 30 minutes.

According to the foregoing Scheme 6. the carboxylic acid compound 27 is coupled to the polymeric hvdroxylamine resin compound I as described in Scheme 1 above to form the polymeric S hvdroxamic acid resin compound 28. The polymeric hydroxamic acid resin compound 28 is then be treated with an acid such as trifluoroacetic acid (TFA) in an inert solvent such as dichloromethane to liberate the hydroxamic acid compound 29. A higher percentage of TFA (trifluoroacetic acid) and longer reaction times are needed to cleave the hvdroxamic acid from the Wang version compared to the Rink version of the resin. During the evaporation of the TFA in the work-up to isolate the hydroxamic acid. it is found that heating the sample during concentration would generate a significant amount of the N,Odiacvlated dimer of the parent hydroxamic acid as a side-product. To minimize this side reaction the reaction mixture is concentrated at or below room temperature with toluene used as an azeotrope.

A process for the preparation of a polymeric a,3-unsaturated alkenoate resin compound 54 according to this invention is outlined in Scheme 7. In Scheme 7, R, is H or aliphatic, R, is aliphatic or aromatic, and R, 2 and are alkyl. R, and R, may contain additional functional groups. It is understood that these functional groups may be suitably protected to prevent interference with the reactions described below.

Scheme 7 0 0 L-OH base, PL-- OR 2 0 RnCHO O O Rm 0 311 R31 2 1 HO RO 2 0 Rm (51) 0 0 -L-O -Rn HO Rn 32 Rm 54 Rm According to the foregoing Scheme 7, coupling of the polymeric hydroxy resin 30 with the phosphono acetic acid compound 51 provides the polymeric phosphonoacetoxy resin compound 1. The coupling is preferably accomplished using a preformed symmetric anhydride (method i below), or using the 2.6-dichlorobenzoic acid anhydride described by Sieber, Tetrahedron Lett., 1987, 28, 6147-6150 (method ii below).

i) 51 (6 equiv.): diisopropylcarbodiimide (3 equiv.); dichloromethane; 0 OC 30 minutes, then 8. 4dimethylaminopyridine (0.2 equiv.); 12 hours.

ii) 51 (3 equiv.): 2.6-dichlorobenzoyl chloride (3 equiv.); pyridine (6 equiv.): DMF: 12 hours.

WO 99/7f192 PCT/US99/14251 39 The Horer-Emmons condensation of the polymeric phosphonoacetoxy resin compound 31 with the aldehyde RCHO is then accomplished by treating 1 with an excess of a base such as potassium tertbutoxide, potassium bis(trimethylsilyl)amide or lithium bis(trimethylsilyl)amide in an organic solvent such as THF or toluene at about 0 OC to about 25 oC. The mixture is stirred or shaken for a sufficient amount of time to quantitatively generate the resin-bound anion, generally from about 15 minutes to about 2 hours. The aldehyde RCHO is then added and the mixture is stirred for up to three days to generate the polymeric alkenoate resin compound 32.

In an especially preferred preparation of the polymeric alkenoate resin compound 32, the polymeric phosphonoacetoxy resin compound 31 is treated with an excess of a base such as potassium tert-butoxide or lithium bis(trimethylsilyl)amide in an organic solvent such as THF at about 0 °C to about 25 OC. The mixture is stirred or shaken for a sufficient amount of time to quantitatively generate the resin-bound anion, generally from about 15 minutes to about 2 hours. The solvent and excess base are then removed from the reaction vessel and a solution of the aldehyde in a less polar solvent mixture, comprising the solvent used in the generation of the resin-bound anion and a second, less polar solvent, is added at ambient temperature and the mixture is stirred for up to three days to generate the polymeric alkeneoate resin compound 32.

Preferred less polar solvents are alkanes such as pentane, hexane or heptane, or cycloalkanes such as cyclohexane, cyclopentane or cycloheptane. An especially preferred less polar solvent mixture is cyclohexane-THF.

Use of the less polar solvent mixture in the Horner-Emmons condensation as described above presents a number of advantages over generation of the anion and condensation with the aldehyde using strong base in a polar solvent. A strong base is required to quantitatively generate the resin-bound anion.

However, under the reaction conditions of strong base and a relatively polar solvent, the resin linkage was hydrolyzed resulting in a low yield of the polymeric alkeneoate resin compound 32. However.

draining the solvent and excess base following essentially quantitative generation of the resin-bound anion and adding a solution of the aldehyde RnCHO in a less polar solvent mixture appears to stabilize the resin linkage toward hydrolysis and thereby results in unexpectedly high yields of the polymeric alkeneoate resin compound 32.

The polymeric alkeneoate resin compound 32 may be used for further transformations as described in Scheme 8, or the a,f3-unsaturated acid compound 54 may be cleaved from the resin using methods commonly known in the art, for example by treating a mixture of the polymeric alkeneoate resin compound 53 in a suitable organic solvent such as dichloromethane, dichloroethane or dioxane, with acid. Cleavage is preferably accomplished at about ambient temperature using a trifluoroacetic acid (TFA)-dichloromethane solvent mixture over about 1 hour.

A process for the solid phase synthesis of the carboxylic acid compound 27, an intermediate useful for preparing the hydroxamic acid compound 2 in which Ar. A 2 n and R" are as defined herein and R 9

R'

0 and R are H. is shown in Scheme 8.

Scheme 8 PCT/US99/14251 wn 0/67192

SA

0 O ROL ArA 0

R

32a 33 0 ArI OH ArA A i 0 A A 20 34 27 The polymeric diethylphosphonoacetoxy-resin compound 3l is treated with a base such as potassium bis (trimethylsilyl) amide in an inert solvent such as toluene, at a temperature of about o0C, followed by an aldehyde of formula R"CHO wherein R" is as defined above, at about ambient temperature to give the polymeric alkenoate resin compound 32.

According to the foregoing Scheme 8, reaction of the polymeric alkenoate resin compound 32a.

prepared as described in Scheme 7, with a thiol of formula Ar-A 2 -SH, wherein Ar and A 2 are as defined above, provides the polymeric alkanoate resin compound 33. The addition may be conveniently carried out under mild basic conditions, for example in the presence of lithium hydroxide at about ambient temperature.

The polymeric alkanoate resin compound 33 may then be hydrolyitically cleaved by treatment with acid as described in Scheme 7. above, to prepare the carboxylic acid compound 27 wherein n is 0.

Alternatively. the polymeric alkanoate resin compound 33 may be treated with an oxidizing agent such as m-chloro-perbenzoic acid in an inert solvent such as dioxane at about ambient temperature to give the polymeric sulfoxide (n 1) or sulfone (n 2) resin compound 34. Acid hydrolysis of 34 as described in Scheme 7.above, provides the carboxylic acid compound The preparation of the polymeric hydroxylamine resin compound 1 is outlined in Scheme 9a.

Scheme 9a

O

L-OH *-L-0-N 36 o

H

L-0- NH

H

WO 99/67192 PCT/US99/14251 41 According to the foregoing Scheme 9a, a polymeric hydroxy resin compound 30 is converted to the polymeric N-hvdroxylphthalimido resin compound 36 by coupling with N-hydroxyphthalimide under Mitsunobu conditions (Mitsunobu. Svnthesis 1981, by conversion of the hydroxy group to a leaving group such as the mesylate followed by nucleophilic displacement, or by reaction of the polymeric hydroxy resin compound with N-hydroxyphthalimide in the presence of an acid such as benzenesulfonic acid. Removal of the phthalimido group provides the polymeric hydroxylamine resin compound 1.

For example, when 30 is 4 -(hydroxymethyl)phenoxymethyl-copoly(styrene-l %-divinylbenzene)resin (Wang resin), N-hydroxyphthalimide is coupled to the resin in the presence of diisopropylazodicarboxylate and triphenylphosphine in DMF. The phthalimido protection is removed by methvlaminolysis in THF at 40 The reaction is complete in about 2 hours. The use of the methvlamine to cleave the phthalimide protection offers a significant advantage over the commonly used hydrazinolysis procedure (Wolf et al., Can. J. Chem., 1970, 48, 3572.

When 4-(2',4-dimethoxyphenyl-0-methylhydroxylamine)-phenoxymethyl-copoly(styrene- divinylbenzene)-resin (Rink resin) is utilized, I is preferably prepared by reaction of the polymeric hydroxy resin compound with N-Hydroxy phthalimide in DMF in the presence of catalytic benzene sulfonic acid to form the polymeric N-hydroxyphthalimido resin compound 36. The phthalimido protecting group is then removed by reaction with hydrazine hydrate in tert-butanol at about 60'C to give the corresponding polymeric hydroxylamine resin compound.

An alternative route to the polymeric N-protected hydroxylamine resin 6 is outlined in Scheme 9b.

Scheme 9b

P

HO. ,P L-O- N L-OH P' 37 38

P

L-0- NN

H

6 According to the foregoing Scheme 9, a polymeric hydroxy resin compound 30 is coupled with a NN-diprotected hydroxylamine compound 27, wherein P and P' are amine protecting groups as described in Scheme 8 above to form the polymeric N.N-diprotected hydroxylamine resin compound 38.

The amine protecting group P' is then selectively removed to form the polymeric N-protected hydroxylamine resin compound 6.

WO 99/67192 PCT/US99/14251 42 In a preferred embodiment of the synthesis described in Scheme 9. P is benzyl and P' is allyloxycarbonyl. Selective removal of the allyloxycarbonyl protecting group is effected by treatment with tetrakis(triphenylphosphine)Palladium(0).

The N.N-diprotected hydroxylamine compound 3 is prepared by sequential introduction of the protecting groups P and P' to an O-protected hydroxylamine compound of formula H,NOP 2 wherein P 2 is a hydroxy protecting group. A preferred hydroxy protecting group is alkyl. The amine protecting groups P and P' are then introduced using reagents and reaction conditions well known in the art of organic synthesis. For Example, reaction of O-tert-butylhydroxylamine with allyloxychloroformate results in formation of N-allyloxycarbonyl-O-tert-butylhydroxylamine, which is then reacted with benzyl bromide to form N-benzyl-N-allyloxycarbonyl-O-tert-butyydroxylamine. Treatment of N-benzyl-Nallyloxycarbonyl-O-tert-butylhydroxylamine with trifluoroacetic acid gives N-benzyl-Nallyloxycarbonylhvdroxylamine.

The preparation of a polymeric 4-(methyl-O-methylhydroxylamine)-2-fluorophenoxmethyl resin compound is shown in Scheme Scheme HO 0 F 39 0 F F OH F 0-N 0 41 42

F

_O -0-NH 2 43 According to the foregoing Scheme 10, a polymeric chloromethyl resin compound such as chloromethyl polystrene (39, Merrifield resin) is reacted with 4-hydroxy-2-flUOroacetophenone in the presence of base to form the 4-(1-hydroxylethyl)-2-fluorophenoxymethyl resin compound Reduction of the ketone group, for example using lithium borohydride in THF provides the 4-(1hydroxyethyl-2-fluorophenoxymethyl resin compound 41. Conversion of 41 to the hydroxyphthalimido resin compound 42, followed by removal of the phthalimido group as described in Scheme 8 above provides the 4-(methyl-O-methylhydroxylamine)-2fluorophenoxymethyl -copoly(styrene-1% divinylbenzene) resin compound 43.

The preparation of a polymeric 4-(O-methylhydroxylamine)-fluorophenoxymethyI resin compound is shown in Scheme 11.

PCT/US99/14251 WO 9/67 192PC/S/145 43 Scheme 11I F F HO F0-/ C0 2 H F F O2 39 F F 44 F F OH F F 0 -O -F F F H 46 F F 47 F F According to the foregoing Scheme 11, a polymeric chioromethyl resin compound such as chloromethyl polystyrene (39, Merrifield resin) is reacted with 4-hydroxy-2,3,5,6-belzoic acid in the presence of base to form the 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl resin compound 44. Reduction of the carboxylic acid group, for example using LiAIH4, diisobutylaluminumn hydride, or BH 3

-THF

provides the 4-hydroxymethy-2,3,5,6tetrafluoropheloxymethyI resin compound 45. Conversion of to the hvdroxyphthalimido resin compound 46. followed by removal of the phthalimido group as described in Scheme 8 above provides the 4-(O-methylhydroxylamine)- 2 3 ,5, 6 tetrafluorophenoxymethl-copoly(styrene- 1% divinylbenzene) resin compound 47.

The preparation of a polymeric 4-(2 -iehxpeyl0mtyhdoylmn)2356 tetrafluorophenoxymethyl resin compound is shown in Scheme 12.

PCTIUS99/14251 WO 99/67192TIS9/125 44 Scheme 12

OCH

3 OCH 3 F F/F F HO OCH 3 3 W~%j~ci+HO0 0 -OCH 3

POCH

39 F F F84

OHOCH

3 F

O

OCH

3 OCH 3 CHU"

OCH

3

NNH

52 F2 0 According to the foregoing Scheme 12, a polymeric chioromethyl resin compound is reacted with 4-phenoxy-2.3-5.6-tetrafluorophenyl 2,4-dimethoxyphenyl ketone 48 in the presence of base as described in Scheme I11 above to form the 4-(2'A4'-dimethoxyphenylarboflyl) 2 3 6 tetrafluorophenoxymethyl-resin compound 49. Reduction of the carbonyl, for example using LiBH4, provides the 4-(hydroxymethyl-2 '-dimethoxyphenyl)- 2 3 ,S,6-tetrafluoropheloxymlethyl resin compound 50. Conversion of 50 to the hydroxyphthalimido resin compound 51, followed by removal of the phthalimido group as described in Scheme 8 above provides the 4-(2',4'-dimethoxypheflyl-Omethylhydroxylamnine)-2,3 ,5.6-tetrafluorophenoxym ethyl- resin compound 5-2.

Preferred polymeric hydroxylamine resin compounds have formnula I wherein L is a linking group.

Preferred linking groups L have the formula PCT/US99/14251 WO 99/67192 R 2 R 2a wherein A is absent or a group of formula wherein X' is -CHR- or -CHR-Y-CO-(CH),- wherein R is H, alkyl, phenyl, or phenyl substituted with alkvl. alkoxy. halogen, nitrile or -NO,, Y is or -NH-.

n is an integer from 1 to 6, and Z is or -NH-: R and R 2 are independently ring system substituents; and

R

3 and R 4 are independently alkyl, phenyl, or phenyl substituted with one or more substituents selected from alkyl. alkoxy. halogen nitrile and -NO 2 or one of R' and R taken together with one of R 3 and R and the carbon atoms to which they are attached define a linking group of formula wherein R' is alkvl. alkoxv. halogen, nitrile or and

R

6 R and RE are independently selected from alkyl. alkoxy. halogen, nitrile or -NO More preferred linking groups have formula WO 99/67192 WO 9967192PCTIUS99/1 4251 wherein R' and R 2 are independently H or F;and R 2 are independently ring system substituents; and one of R' and R' is H and the other is H or 2.4-dimethoxypheflyl.

Representative preferred polymeric hydroxylamine resin compounds include 4-(O-methylhydroxy lam ine)phenoxymethyl copoly(styrene- I% divinylbenzene) resin, designated herein as 0 -0

ONH

2 copoly(styrene- 1 %-divinvlbenzene)-resin, designated herein as OCH 3 0 ONI-1 2

CH

3 4-(2 l,4 dimethoxyphenvliO0rfethyhdroxylam ine)-piienoxymethyI-copoly(styreflI% divinylberizene) resin. designated herein as OCH 3

PONH

2 4- 1-amin ehl--ehx--irphnxl(--ehlezvrl)btrmd-ooysyee 1% divinvlbenzefle) resin, designated herein as PCT/US99/14251 WO 99/67192 PTU9/45 N0 2 O-hvdroxvlam1ne- 2 -ch orotrity -copo Iystyrefe- I %-di1v in NlIbenzene- resin. desigonated herein as O-hydroxylamine-trityl-copolystyreine-l1%-divinylbenzene-res in. designated herein as 5-(4-O-methylhydroxylaniine -3 .5-dimethoxyphenoxy)-v.aleric acid-copolystyrefle- I %-divitiyl benzene resin, designated herein as OCH 3 0

ONH

2 OCH 3 4-O-methyl hvdroxy lam ine-3 -methoxyphenoxy-copoIlyst~rene 1 %-divinvl benzene resin, designated herein as PCTIUS99/14251 WOA 99/67192PC/S/145 48 3 -hydroxy-xailthydroxy.lainie-copolystryene- I %-div invlbenzene resin, designated herein as 4-(O-methylhydroxylam ine)-2.3.5.6-tetrafluoropheloxylethyl-cOooy(styreiie-I divinylbenizene) resin, designated herein as F F

ONH

2 F F 1-methyl-I -one)-3-fluioropeloxyfliethy1-copoly(styrene-I divinylbenzene) resin, designated herein as

F

0 1-methylI-I -hvdroxyi- am ine)-' fl Uorophenoxym ethyl coIy(styrene- I% divinylbenzefle) resin.

designated herein as.

F

0-NH 2 1methy-I -hdrox 3fiuorophenoxvmethvl-copo1y(tyrene- I% divinylbenzene) resin. designated herein as

F

OH

4-(carboxyv)3 )-fl uorophenoxvm et h vI cOooy(styrene- I% ditvinyl benzene) resin, designated herein as WO 99/67192 PCTIUS99/14251 49

F

OH

4-(carboxvaldehyde )-3)-fluorophenoxvniethyl-copoiy(styrele- 1% divi'nylbenzene) resin, designated herein as

F

H

0 methylalcohol)-3-fluorophenoxymetl-copoly(styrene- 1% divinylbenzene) resin, designated herein as

F

OH

and I0 4-(2 i methoxyphenyl-O-m ethyl hydroxyl am ine)-23 ,5 ,6-tetrafl uorophenoxymethyl-copoly(styrele- 1% divinylbenzene) resin, designated herein as The most preferred polymeric hydroxylamine resin compounds are 4-(O-methylhvdroxylamine)-2.3 ,5 ,6-tetrafluorophenoxymethy I-copoly(styrene- I div inylbenzene) resin, 4-(2 -dimethoxy-phenyl-O-methy~lhvdroxylam ine)-2.3 .5.6-tetrafluorophenoxymethyl-copoly(styrene- 1% divinylbenzene) resin, 4-(O-methylhv~drox-vllamine)phenoxymethyl-copoly(styrene- I divinylbenzene) resin, 4-(1 -methyl- I- one-.)-3-fluorophenioxymethyl-copo]l(styrene- 1 divinvlbenzene) resin, 4-(1 -methyl- I -hydroxy lam ine)-2-fiu orophenoxymethylI-copo ly(styrene- 1 divinylbenzene) resin.

4-(1I -methvl- I hvdroxN--)-' -fiuorophenoxvmethyl-copoly(styrenie- I1% d ivinylbenzene) resin, 4-(carboxv)-3 -fluorophenoxymethyl-copoly( styrene- 1% d ivinylbenzene) resin, 4-(O-miethvlhvdroxvlamine)phenoxymethyl-copoIy,(styrene- I divinylbenzene) resin..

carboxvaldehvde)')--fluorophenoxvmethyI-copolv(st-yrenie- I d ivinylbenzene) resin,and4-(2' dii-nethoxvphienvI]-O-methivlhvdrox.Iiamine)-plhenoxvnmethvl-copoly(styrene- I% divinvlbenzene) resinl.

Wn 99/67192 PCT/US99/14251 The Rink handle Rink, Tel. Let., 28. 3787-3790, 1987) has the advantage of being cleaved under mild acidolysis for short periods of time 10% TFA in DCM for 10-15 minutes.). However, due to the cost of the resin it is desirable to synthesize the corresponding functional resin on the Wang solid support S. S. Wang, J. Am. Chem. Soc.. 1973, 95, 1328. b) Lu et al.. J. Org. Chem.. 1981. 46, 3433).

The polymeric hydroxylamine resin compounds in which R, and Rb are F are especially useful as it lends itself to ready quantification of resin loading and monitoring of reactions conducted on the resin using fluorine NMR.

The methods described herein are also useful for the preparation of peptide aldehydes, ketones and hydroxamic acids. In general, this method involves coupling the carboxyl group of a suitably Nprotected first amino acid to the resin to form the polymeric N-protected amino acid hydroxamic acid resin compound. The amino acid N-protecting group is then removed and the unprotected polymeric amino acid hydroxamic acid resin compound is coupled with a second suitably N-protected amino acid.

This process is then repeated until the desired amino acid residues have been incorporated in the peptide.

Alternatively, peptides comprising multiple amino acids are prepared by coupling a suitably Nprotected peptide subunit comprising two or more amino acids to form the polymeric N-protected peptide hydroxamic acid resin compound. The amino acid N-protecting group is then removed and the unprotected polymeric peptide hydroxamic acid resin compound is coupled with a second suitably Nprotected amino acid or peptide. Thus, in addition to the sequential addition of individual amino acid subunits described above, a polypeptide may be prepared by coupling of peptide subunits.

Once the desired amino acids have been incorporated into the peptide, the polymeric peptide hydroxamic acid compound is reacted with an organometallic reagent followed by acid hydrolysis to form the peptide ketone compound; reductively cleaved to form the peptide aldehyde compound; or cleaved with acid to form the peptide hydroxamic acid compound. Any remaining protecting groups may be removed prior to or subsequently to cleavage of the peptide from the resin.

N-protecting groups suitable for use in peptide synthesis as described herein should have the properties of being stable to the conditions of coupling to the polymeric hydroxylamine resin compound while being readily removable without destruction of the growing peptide chain or racemization of any of the chiral centers contained therein. Suitable protecting groups are 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), biphenylisopropyloxycarbonyl, tamyloxycarbonyl. isobomyloxycarbonyl, (a,a)dimethyl-3.5-dimethoxybenzyloxycarbonyl, onitrophenylsulfenyl. 2-cyano-t-butyloxycarbonyl, and the like.

Additionally. this resin is useful for constructing arrays of aldehyde, ketone or amine combinatorial libraries or arrays of aldehydes and ketones as reagents in combinatorial library synthesis.

for example reagents for the Ugi 4-component condensation (Ivar Ugi, in Isonitrile Chemistry, 1971. p.

145. Academic Press). The hydroxylamine bound resin may be used not only for single functional group transformations, but also multiple step solid phase synthesis to generate combinatorial libraries.

VUO 9n6al PCT/US99/14251 V V, 51 The functionalized resin of this invention is also useful for the parallel synthesis of a multiplicity of different aldehyde, ketone or amine end products as outlined for ketone compounds in Schemes 12a and 12b. In Schemes 12a and 12b, Rb and R, are as defined above. n is an integer which represents the total number of different aldehyde, ketone or amine products which are to be prepared. Rai-Rn represent.

independently, an aliphatic or aromatic group as defined herein.

Scheme 13a

H

L-O8 Rb 8 0 0 0 0 RO-N RO-N Rb -NRb Ral RC Ra 2 Rc Ra 3 Rc Ra R an c The parallel synthesis of a multiplicity of ketone compounds using a multiplicity of carboxylic acid compound R,COH-R.COH and a single organometallic compounds RIMgX is shown in Scheme 13a. According to Scheme 13a, the N-alkylated hydroxylamine resin compound 8, prepared as described in Scheme 2, is divided into n portions. Each portion of resin is then coupled with a different carboxylic acid compound to give n portions of polymeric N-alkylated hydroxamic acid resin compound. Each portion of polymeric N-alkylated hydroxamic acid resin compound is then reacted with a Grignard reagent of formula RX and subjected to acid hydrolysis to give n portions of ketone derived from a single organometallic reagent.

PCT/US99/14251 WO 99/67192 Scheme 13b

H

L-O-N. Rb 8

O

(pyO-NRa 0 R, "R 0 R Rc 2 0 R Rc3 0 O0-N &Ra 0 Ra Rc The parallel synthesis of n different ketone compounds derived from a single carboxylic acid S compound RCO,H and n different organometallic compounds R,,MgBr to RMgBr is outlined in Scheme 13b above. According to Scheme 13b. the polymeric N-alkylated hydroxylamine resin compound is coupled with a carboxylic acid of formula RCOH. The resulting polymeric N-alkylated hydroxamic acid resin compound is then divided into n portions, and each portion of polymeric

N-

alkylated hydroxamic acid resin compound is then reacted with a different Grignard reagent RI-RnMgBr and subjected to acid hydrolysis to give n different ketone compounds derived from a single carboxylic acid compound.

The functionalized resins of this invention are also useful for constructing a combinatorial library of ketones or amines as illustrated for the ketone library derived from 4 carboxylic acid compounds and 4 Grignard reagents as outlined in Scheme 14.

WO 99/67192PCIS/145 PCT/US99/14251 Scheme 14

L-O-N,.R

8

X/~

'RbRai Q~-0-NRb 0 Ra 3 O--0-N Ra4 combine (YO-N fRa -N ARa4 K> Rb 'Rb divide WO 99/67192 PCT/US99/14251 Scheme 14, cont.

O

O-N. Ra1 Rb 0 (PVO-N

R

Rb Rai Re, Ra3 Rcl Ra2 Rci Ra Rel 0 0 Ra 3 P0-N R4 Rb Rb 0 0 P-0-N. Rba3 Y-0N. Rb 0 0 O-N Ra3 o-N R2 0 0 R-N 3 -0-N.Rb o 0b -O-N.Rb

R

Ra R2 Ra2 R,2 0 0 Rk R2 'd J Z c 0 0 Rai R, R2 RC 3 Ra3 a4R~R 0RK c R 0~ 0 0 O-N Ra3

R,

0

R,

Ra 3

R,

0 R,4 R,4 According to the foregoing Scheme 14, the polymeric N-alkylated hydroxylamine resin compound 8 is divided in 4-portions, and each portion is coupled with a different carboxylic acid compound to prepare 4 different polymeric N-alkylated hydroxamic acid resin compounds. The 4 portions of polymeric N-alkylated hydroxamic acid resin compounds are then mixed together to form a single portion which is then divided into 4 portions of polymeric N-alkylated hydroxamic acid resin compounds, in which each portion contains approximately equal amounts of each individual polymeric N-alkylated hydroxamic acid resin compound. Each of the 4 portions is then reacted with a different Grignard reagent R,-R, 4 MgBr and subjected to acid hydrolysis to give 4 portions of ketone compound.

each of which contains 4 compounds representing the products of reaction of each of the 4 different polymeric N-alkylated hydroxamic acid resin compounds with a single Grignard reagent. In this manner a combinatorial library containing a multiplicity of ketone compounds may be quickly constructed.

In a similar manner, a combinatorial library of peptides may be assembled by repeating the dividing-recombining sequence for each amino acid or peptide building block.

PCT/US99/14251 7i11 2'/It VVJ 77/1U 17 The foregoing may be better understood by reference to the following Examples, which are presented for illustration and not intended to limit the scope of the invention.

Example 1 4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-phenoxyinethyl-copoly(styrene-1% divinylbenzene) resin.

OCH 3

H

3 CO

ONH

2 Rink acid resin (1 g; 0.63 mmol) is swelled in DMF (10 mL) for 15 minutes at ambient temperature. N-Hydroxyphthalimide (514 mg; 3.15 mmol) is added to the resin suspension followed by benzene sulfonic acid (19 mg; 0.13 mmol). The mixture is stirred by means of a mechanical stirrer and heated to 50 oC for five hours. The mixture is then cooled to ambient temperature and stirred for an additional 12 hours. after which the resin is filtered and washed extensively with DMF (5 x 25 mL); DMF:HO (70:30; 5 x 25 mL); THF (10 x 25 mL); and diethyl ether (10 x 25 mL). The resin is then dried overnight under high vacuum at 40 oC. The IR spectrum shows a carbonyl absorbance at 1733 cm' corresponding to the phthalimido carbonyl stretch. Elemental analysis: calcd.:0.28% N. Found: 0.26%N. Loading 0.18 mmol/g.

The resin is swelled in 20 mL of tert-butanol for ten minutes. Hydrazine hydrate (10 mL) is added to the mixture and the reaction is warmed to 60 oC with mechanical stirring for 12 hours. After which the reaction is cooled to ambient temperature. The resin is filtered and washed extensively with DMF (10 x 25 mL). THF (10 x 25 mL), and diethyl ether (10 x 25 mL). then dried under high vacuum at °C overnight. The IR spectrum of resin III showed the loss of the carbonyl stretch at 1733 cm which is present in the starting material. Elemental Analysis: %N found 0.43; 0.42 (corresponding to a loading level of 0.3 mmol/g).

PCT/US99/14251 WO 99/6719~2PCUS9145 56 Example 2 N-[3-((4-methoxylphenyl I)sulfonyl )prop- I -vlcarbonylil4-(2 'A '-dimethoxyphenyl-Omethy IllydroxylIam i ne)-phenoxyrnethy-copo Iy( styrene- 1% divinylbenizene) resinl.

OCH 3

H

3 00 Os 0

OCH

3

NN

divinylbenzene) resin (20 mg) is swelled in DMF (3 mL). To this suspension is added 3(4 methoxyplhenylsulfon'l)propioflic acid (610 mg; 2.5 mmol) and l-(3-dimethylaminopropy1)- 3 -ethyl carbodiimide hydrochloride (EDGI; 477 mg; 2.5 mmol) at ambient temperature. The reaction mixture is shaken at ambient temperature using a vortex shaker for 12 h1, after which the resin is filtered and washed extensively with DMF:H,0 (80:20; 5 x 5 mL), DMF (5 x 5 mnL), THF (5 x 5 mL), and diethyl ether (5 x mL). Thle resin IV is dried under high vacuum at 40 'C for 12 hours. The IR spectrum shows a carbonyl absorbance at 1675 cm-' corresponding to the bound hydroxamate.

Example 3 N-hydroxy-3 (4-methoxyphenYlsulfonyl)propioflamide.

Dry N-[3)-((4-methioxyphenyl)sulfoflvl)prop- 1-ylcarbonyl]4-( 2 .4'-dimethoxyphenyl-Omethylhvdroxy lam ine)-phenoxymethyl-copo lY(styrene- I% divinylbenzene) resin (200 mg), prepared as in Example 2. is swelled in 3 mL of methylene chloride for 10 minutes. Trifluoroacetic acid (TFA; 0.3 mL) is added to the mixture dropwise at ambient temperature and the resulting mixture is vortexed for minutes. The resin turned a dark blue upon addition of the TFA. The mixture is then filtered and washed with two 5 mL portions of methylene chloride The filtrate is evaporated by rotary evaporation to yield 20 mg of crude product. An LC/MS trace of the crude reaction mixture showed it to contain better than 75 area of the desired product. 3-(4-methoxyphenysulfonyl)propionic acid is present in 6 area 'H NMR (MeOH-d 4 5 2.45 3.45 3.90 7.15 2H); 7.85 2H).

wnO/ Q/671Q92 PCT/US99/14251 57 Example 4 ine)phenoxymethyl-copoly(styrene- 1%-divinylbenzene)-resin (100-200 mesh).

ONH

2 A 1-L jacketed reactor with a bottom valve and overhead stirrer (Ace catalog #8090) is charged with Wang resin (18.35 g. 20 meq) and anhydrous tetrahydrofuran (THF, 450 mL). This mixture is stirred gently for about 15 minutes, then as much solvent as possible is removed through a tube fitted with a porous glass frit via vacuum aspiration. Fresh THF is added, followed by triphenylphosphine (15.74 g, 60 mmol) and N-Hydroxyphthalimide (16.31 g, 100 mmol). The resulting mixture is stirred and cooled to -5-0 OC. Diisopropyl azodicarboxylate (11.8 mL. 60 mmol) is added slowly so as to maintain the temperature at <5 When the addition is complete, the stirred mixture is allowed to warm slowly to room temperature and stirred overnight. As much of the reaction liquors as possible is removed by aspiration through the dip tube as above. The resin is washed by charging N,N-dimethylformamide (DMF, 200 mL), stirring the mixture for 3-5 minutes, and then removing by aspiration as much of the wash solution as possible. Similarly, the resin is washed sequentially with an additional portion of DMF and portions of methanol (twice), THF (twice), and methanol (once). A portion of the resin may be removed for analysis: IR 1734 cm-1 To the resin remaining in the reactor is added THF (400 mL) and 200 mL of a 40% aqueous solution of methylamine (2.31 mol). This reaction mixture is stirred gently at 40 °C for 2 hours. then cooled to room temperature (the mixture may be held overnight at this temperature). As much of the reaction liquor as possible is removed by aspiration, and the resin is washed with the solvent array as above. Following the final methanol wash, additional methanol is used to flush the resin out of the bottom of the reactor and isolate it by filtration. The filtered resin is dried at 40 oC under vacuum. Yield 18-18.5 g resin: amine load 1.02 meq/g (based on potentiometric titration of a THF suspension with p-toluenesulfonic acid); IR (microscopy) 3316 cm' Analysis found C, 87.07%; H, 7.77%: N.

1.58%, which corresponds to 1.13 nitrogen atoms/g resin.

Assay: preparation of 4-nitrophenylethanehydroxamic acid.

A 200 mg sample of the dried resin (ca. 0.2 mmol) is charged to a 5- or 10-mL resin reactor (a polypropylene svringe barrel fitted with a polypropylene frit). The resin is swelled for about 15 minutes in dry DMF. and then 115 mg l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI. 0.6 mmol) is added. To this mixture is then added 4-nitrophenylacetic acid (115 mg, 0.6 mmol). The reactor is capped and the mixture is agitated slowly overnight (a rocker bed apparatus is used). The reaction liquors are removed by vacuum filtration (the resin reactor is inserted through a small rubber vacuum flask adapter). and the resin is washed by several small (2-3 mL) portions of the following solvents: wn oo/67192 PCT/US99/14251 58 DMF (4-5 portions). MeOH or 50% aq. DMF (3-4 portions), THF (3-4 portions), and MeOH (2-3 portions). The resin (still in the syringe reactor) is dried for at least 4 hours under vacuum at 40 °C.

To this dried resin is added 2 mL dichloromethane followed by 2 mL trifluoroacetic acid (TFA).

Additionally, 20 mL water is added (believed to reduce "anhydride" formation from hydroxamic acid S product). The mixture is allowed to react for about 1 hr. and the reaction liquors are drained into a tared collector. The resin is washed with 1-2 1-mL portions of dichloromethane followed by 1-2 1-mL portions of toluene. The combined filtrates are concentrated to about 2 mL at 30 OC, 2 mL additional toluene is added, and the resulting solution is concentrated to dryness under vacuum (rotary evaporator followed by vacuum oven at 30 oC; note that heating in the presence of TFA promotes formation of the "anhydride" impurity). The residue is weighed and analyzed for weight purity (HPLC, using the carboxylic acid as a response factor standard). Typical results for 4-nitrophenylethanehydroxamic acid: 29-30 mg solids at 60-70 wt% purity, 90-97 A% purity (261 nm); 'H NMR (CDsOD) 8 8.13 2H), 7.25 2H). 4.85 (bs, OH, NH), 3.55 2H); "C NMR 5 169.4, 144.3. 131.3, 124.6. 40.2. This reflects a load/clip chemical yield of 50-55% from resin at 1 meq/g.

Example N-4-phenylbut-1 -oyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene- I %-divinylbenzene)resin.

Dry 4-0-Methylhydroxylamine)phenoxymethyl-copoly(styrene- 1%-divinylbenzene)-resin (2 g.

mmol), prepared as in Example 4. is allowed to swell in DMF (8 mL) for 10 minutes and then is treated with 4-phenyl butyric acid and EDC (0.86 g, 4.5 mmol). The mixture is shaken for 24 hours and filtered. The resin is washed with DMF. DMF/H,O, DMF, THF and Et,O and dried under vacuum at 0 C to give N-4-phenylbut- 1-oyl- 4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene- 1%divinylbenzene)-resin (2.2 IR: C=O 1670 Elemental analysis: calcd; N, 1.05%. Found: N.

1.07%.

WO 99/67192 PCTIUS99/14251 59 Example 6

N-(

4 -brom o-3- methy Ibelzov1)40-m ethy lhydroxy lam ine )phenoxymethyl-COPO ly(styrefle- I% divinylbenizene)-resifl.

0 -N CH C- 3

H

Br Dry- 4-O.Methylhvdroxylam ine)phenoxymethyl-copoI y(styrenie- I %-divinylbeflzefle)-resifl (4 a, 3 mmol). prepared as in Example 4. is allowed to swell in DMVF (32 mL) for 10 minute s, then is treated with 4-bromo-3-methlvbelzoic acid and EDC (1 .725g. 9 mmol). The mixture is shaken for 24 hours and filtered. The resin is washed with DMF, DMF/HO, DMF. THY and Et,O and dried under vacuum at to give N (-rmo3mehlbnol--- ty hydroxylam i ne)phenoxym ethy l-copoly(styrene- 1%-divinylbenzene)-resin (4.5 IR: C=O 1677.5cm-'. Elemental analysis: calcd: Br, N. 1.05%.

Found: Br, N, 0.9 1%.

Example 7 N-Hydroxy-4-bromo-3)-methyl benzamide.

N-(4-bromo--3)methybenzov)4O0methylhydroxylam ine)phenoxymethyl-copoly(styrene-l divinvibenizene)-resin, prepared as in Example 6. is suspended in 50% TFAICH 2 C1 2 for 2 hours. The resin is filtered and wvashed three times with CH,C1 2 to give N-ydroxy-4-bromo-3-methyl benzamide.

LC MS: mlz 230,!232 (Br)[M+H]F Area 78%: 'H NMR (300 MHz. CDC1 3 5: 2.42 3H), 7.4 (bd J 7.89. 1 H) 7.5 8 (bd J =7.89 1 7.62 (bs. I H).

Example 8 N-4-bromobenzy l-N-4- phenylbut- I -ylcarbonyl- 4-O-methiyIhydroxylam ine)phenoxymethy[copoly(styrene- I %-divinylbenzene)-reSin.

00 i /0 0- N Br N-4-phenylbut- I -oy l-4-O-methlhydroxylamn ine)phenioxymethvl-copoly(stvrene-I divinvlbenzene -resin (1 .46 g. 1 .095 mmol). prepared as in Example 5. is suspended in toluene (26 ml) \11"1 O/671o) PCT/US99/14251 for 10 minutes. DBU (0.83 mL; 5.5 mmol) is added and the mixture is agitated for 2 hours on a wrist shaker. Bromobenzyl bromide (4.1 g. 16.425 mmol) is added and the reaction mixture is vigorously agitated for 4 days. The resin is filtered and washed with DMF, DMF/HO. DMF, THF and EtO and dried under vacuum at 40 0 C to give N-4-bromobenzyl-N-4-phenylbut- -ylcarbonyl- methylhydroxylamine)phenoxymethyl-copoly(styrene-l%-divinylbenzene)-resin (1.4 IR C=O 1668 Elemental Analysis: calcd: Br. N,0.94%. Found: Br, N, 0.85%.

Example 9 4-Phenyl butyraldehyde.

N-4-bromobenzyl-N-4-phenylbut- -oyl-4-O-methylhydroxylamine)phenoxymethylcopoly(styrene-l%-divinylbenzene)-resin (0.2 g, 0.6 mmol/g 0.12 mmol) is suspended in diethyl ether for 10 minutes and then cooled to 5 OC in an orbital shaker. The suspension is treated with LiAIH,OMe (0.46 M in diethyl ether. 0.22 mL. 0.1 mmol) and agitated for 30 minutes at this temperature. The reaction mixture is quenched by the addition of 2 M HCI (aq) and vortexed for 30 minutes. Sodium potassium tartrate is added and the mixture vortexed for a further 10 minutes. Sodium sulfate is added and the mixture is filtered through a plug of silica gel, washing thoroughly with dichloromethane. The filtrate is concentrated to give 4-phenyl butyraldehyde. GC: Area 91%; 'H NMR (CDCI 3 8 9.75 7.05-7.30 2,58-2.68 2.41-2.50 1,91-2.02 MS m/z 149 Example 6-Phenylhexan-3-one.

N-4-bromobenzyl-N-4-phenylbut- 1 copoly(styrene-l%-divinylbenzene)-resin (0.15 g, approx. 0.75 mmol/g 0.11 mmol) is suspended in diethyl ether (1 mL) and treated with 1 M solution of ethyl magnesium bromide in tetrahydrofuran (0.34 mL. 0.34 mmol). The reaction mixture is agitated for 18 hours, and then quenched by the addition of 2 M HCI (aq) (approx. pH 3 is obtained). The mixture is agitated for 30 minutes. Sodium sulfate is added and the mixture is filtered through a plug of silica gel. washed thoroughly with dichloromethane and concentrated to give of 6-phenylhexan-3-one. GC MS (El) Area 97.1%, m/z 176.2 MS (El- LRP) m/z 176 NMR (300 MHz, CDCI,) 1.02 3H), 1.9 2H). 2.4 4H) 2.6 2H). 7.2- 7.3 IWI GO/f.1101 PCT/US99/1 4251 ZY~~'A7M61 Example I1I N-4-ch lorobenzyl-N-(4-bromo-3-methylbenzoyl )-4-O-methylhiydroxylamne)phenoxymethylcopoly(styrene- I %-divinylbenzene)-resin.

0 0-N NCH3 Br Cl N-(4-bromo-3-methylbenzoyl )-4-O-methylhydroxylam ine)phenoxymethyl-copoly(styrene- I1%divinylbenzene)-resin (2.8 g. 2.1 mmol), prepared as in Example 6, is suspended in toluene (27 ml) and the mixture is stirred for 10 minutes. DBU (1.6 g,10.5 mmol) is added and the mixture is agitated for 2 hours on a wrist shaker. Chlorobenzyl bromide (6.47 g, 31.5 mmol) is added and the reaction mixture is vigorously agitated for' 3 days. The resin is filtered and washed with DMF, DMF/H 2 0, DMF, THF and Et 2 O, and dried under vacuum at 40'C to give N-4-chlorobenzyl-N-(4-bromo-3-methylbenzoyl)- 4

-O-

methyihydroxylam ine)phenoxymethyl-copoly(styreine- I %-divinylbenzene)-resin (3 IR C=O 1644 cm'1; Elemental Analysis: calcd: Br,. Cl, N, Found: Br, CL. N, 0.9%.

Example 12 N-(4-Chlorobenzyl)-N-hydroxy-3-methyl-4-bromobenzamide.

N--hooezlN(-rm- copoly(styrene-1%-divinylbenzene)-resin,. prepared as in Example 11, is suspended in 50% TFA/CH 2

CII

for 2 hours. The resin is filtered and washed three times with CH 2

CI

2 to give N-(4-Chlorobenzyl)-Nhydroxy-3-methyl-4-bromobenzamide. LC MIS (H-ISP) mlz 3 54/356 (Cl/Br) Area 64%; 'H NMR (300 MHz, CDCI 3 8 2.3 (bs, 4.65 (bs, 2H), 7.2-7.6 (in, 7H-).

Example 13 4-Bromo-3-methyl benzaldehyde.

copoly(styrene- I%-divinylbeflzene)-resin (0.2 g& 0.5 mmol/g 0. 1 mmol). prepared as in Example 11, is suspended in diethyl ether for 10.minutes and then cooled to 5 'C in an orbital shaker. The suspension is treated with LiAlHOMe (0.46 M in diethyl ether, 0.2 mL, 0.092 inmol) and agitated for 30 minutes at this temperature. The reaction mixture is quenched by the addition of aqueous 2 M HCI and vortexed for minutes. Sodium potassium tartrate is added and the mixture is vortexed for a further 10 minutes.

Sodium sulfate is added and the mixture is filtered through a plug of silica gel. washing thoroughly with dichloromethane. The filtrate is concentrated to give 4-bromo-3-methyl benzaldehyde. GC MS: El Area 111n 00/4,7100) P9-TII QOOIA')r1 m/z 179/199 (Br)[MI: 'H NMR (CDC 3 6 9.94 (1 7.70 7.52 (I 2.45 (3H,s)Tz MIS r-n/z= 199 Example 14 1 -(4-Bromo-3-mnethyl phenyl) propan- I -one.

N -4-ch Iorobenzyl-N-(4-bromo-3 -methyl benzoyl)-4-O-m ethyl hydroxy lam i ne)phenoxymethylcopoly(stvr-ene- 1%-divinylbenzene)-resin (0.23 g, 0.5 mmol/g 0.11 5 mmol), prepared as in Example I L.

is suspended in diethyl ether (I mL) and treated with ethyl magnesium bromide (1.0 M in THF, 0.23 mL, 0.23 mmol). The reaction mixture is agitated for 18 hours, and then quenched by the addition of aqueous 2 M HCI (approx. pH 3 is obtained). The mixture is agitated for 30 minutes. Sodium sulfate is added and the mixture is filtered through a plug of silica gel, wvashing thoroughly with dichioromethane. The residue is concentrated to give l-(4-Bromo-3-methyl phenyl) propan-1-one. GC Area 78.7%; MS (El) mlz 226 Br NMR (300 MHz. CDC1 3 5 1.22 7.89, 2.96 (qJl= 7.89, 2H). 7.6 (bs, 2H), 7.8 I1H).

Example N-3-bromobenzaldehyde oxime-4-O-Methylhydroxylamine)phenoxyniethyl-copoly(styrele- I1%divinylbenzene)-resun.

7 Br 4-O-Methylhydrox\vlamine)phenoxymethyl-copoiy(styrene-1I%-divinyibenzenie)-resin (105 mg-, 0.08 mmol) is swelled in dichloromethane mL) for 1 0 minutes. Trim-ethylorthoformate (I mL) and 3-bromo-benzaldehyde (500 mg; 2.7 mmol; 34 equiv.) is added to the resin and the mixture is shaken overnight. The slurry is then filtered, rinsed with dichloromethane (5 mL), DMF (5 rnL x H 2 0 mL x THF (5 mL x 10. and Et.,O (5 mL x 10). The resin is dried in vacuo at 40 IC for 12 hours.

IR oxime stretch 1602 Elemental Analysis: calcd: Br, 5.52%: N, 1.04%. Found: Br, N, 1.08%.

WOA 00/67192 PCTIUS99/1 4251 63 Example 16 N-3 -(4-mnethoxphenyl)propan- I -oyl-4-O-methylhydroxy am ie)phenoxvmethvl-copoIy(styr-ene-

I%

divinylbenzene)-resin.

0-H

OCH,

hydroxy lam ine)phenoxyrnethyl-copo ly(styrefle- I ivinylbenzene)-resin (1 g, 0.73 mmol) is allowed to swell in DMF for 10 minutes and then is treated with 3-(4-methoxyphenyl)propionic acid (0.658 g. 3.65 rnrol) and DIG (0.46 g, 3 .65 mmol). The mixture is shaken for 24 hours, then filtered and the residue is washed with DMF. DMF/H,O. DMF, TI-F and ET,O. and dried under vacuum at 40 'C to give N-3-(4-methoxphienyl)propani- I-oyl-4-O-methylhvdr-oxylam ine)phenoxymethylcopoly(styrene- I %-divinylbenzene)-resin. IR: C=O 1 698 Elemental Analysis: caled: N, 1.02%.

Found: N, 1.21%.

Example 17 N-hydroxy-3-(4-imethoxyphienyl)propionam ide.

N-hydroxy-3-(4-methoxyphenlyl)propionamlide is prepared by reaction of N-3-(4niethoxphenyl)propan- I -ov 1-4-0-methylhydroxylainine.)phenoxymietlv-copoly(styrefle-

I%-

divinylbenzene)-resin with TFA using the procedure of Example 7. 'H NMR 300MHz CD.,OD) 6 2.25 2H), 2.78 2H). 3.68 3 6.72 2H). 7.04 2H).

Example 18 N-2-(4-brom ophenyl)ethan- I -oyl-4-O-rnethylhydroxy lam iie)phenoxymethyl-copoly(styrene-

I%

div iny lbenzene)- resin.

Br 0N

H

The title resin is prepared usinga the method of Example 1 6, except substituting 4bromophenylacetic acid for 3-(4-methoxyphenyl)propionic acid. IJR C=0 1713.9 Elemental analysis: calcd: Br, N. 1.02%. Found: Br, 8.29%, 8.1 N, 0.97%,.0.96%.

WO 99/67192 WO 99/67192PCTIUS99Q/1425~1 64 EDS: Net X-ray Counts K line L line M line 0: 969 1024 C: 2662 Br: 12855 10436 Example 19 N-4-bromocinnanol-4-0-methylhydroxylainne)pheoxvinethyl-copol(styrene- 1 %-div inyl benzene)resin.

0 0-N 1! Br The title resin is prepared using the method of Example 16, except substituting 4-bromocinnamic acid for 3-(4-methoxyphenyl)propionic acid. IR:C0O 1671.7 cm-' (broad). Elemental analysis: Calcd: Br, N, 1 Found: Br, 4.45%, 4.54%.

EDS: Net X-ray Count K line L line M line 0: 818 1365 C: 4549 5059 Br: 6384 5271 Example N-hydroxy-4-bromocinnamam ide.

N-hydroxy-4-bromocininamam ide is prepared by treating N-4-bromocinnaimoyl-4-Omethylhydroxylamine)phenoxymethyl-copoly(styrene- 1 iv inyl benzene)- resin with TFA using thle procedure of Example 7. LC MS (H-ISP) m/z 24 1/243 Br Area 'H NMR (3 00 MHz, CDCIVjCD 3 OD) 8: 3.23 I 6.3 J 15.8), 7.3 J= 7.4 J= 7.6 15.8).

WO 99/67192 PCTJIUS99/1 4251 65 Example 21 N-(4-ch lorobenzoyl)-4-O-miethylhydroxylam ine)phenoxymethy I-copoly(styreie- I iv inyl Ibenzene)resin.

0 a -O-N N

C

The title resin is prepared using the method of Example 16. except substituting 4-chlorobenzoic acid for 3-(4-methoxyphenyl)propionic acid. IR: C=O 1678 cm-I. Elemental Analysis: calcd: Cl, 2.66%; N. 1.05%. Found: Cl, 2.39%, N. 1 .02%.

Example 22 N-Hydroxy-4-chlorobenzam ide.

N-Hydroxy-4-chlorobenzam ide is prepared by treating N-(4-chlorobenzoyl)-4-O- 1 5 methylhvdroxylamine)phierioxymnethyl-copoly(styrene- I %-divinylbenzene)-resin with TFA using the procedure of Example 7. LC MS (Fl-ISP) mlz 172.174 (Cl) [M+H] 0 Area 96%; NMR (300 MHz, DMSO-d 6 6 7.48 (dJ. 9.42. 2H 7.69 (d J =9.42, 2H 8.9-9.2 (broad,. 11 .28 I H).

Example 23 N-methyl-N-(4-ch lorobenzoy I)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrele- I d ivinylbenzene)-resin.

0 C13l N-(4-ch lorobenzoyl)-4-O-miethylhydroxylaine)phenoxymetlv-copoly(styrene-

I%

divinylbenzene)-resin 1 g. 0.075 mmol, 0.75 mmol/g) is suspended in toluene (2 mnL) and cooled to The mixture is treated with methyl iodide (1.5 mmol, 0.21 g, 93il) followed by DBU (0.22 mL, 0.228 g, 1.5 mmol The reaction mixture is placed in a vortexer and allowed to warm to ambient temperature. Within a few minutes a copious white precipitate forms and the mixture is diluted further with toluene (2 mL). Agitation of the reaction mixture is continued for 18 hours. The N-methyl-N-(4clorobenzoyl)-4-O-methvlhydroxylam ine)phienoxym-ethyl-copoly(styrene- 1%-div inylbenzene)-resin is filtered and washed with DMF. DMF/H 2 0. DMF, THF, Et,O and dried in vacuc at WO 99/67192 PCTIIJS99/1 4251 66 Example 24 I -(4-chlorophenyl)propan- 1 -one.

N-rn ethylI-N -(4-ch lorobenzoyl1)-4-0-mrethylhydroxy lam i ne)phenoxymethylI-copo ly(styrene- I1%divinylbenzene)-resin is suspended in diethyl ether (0.7 mL) and treated with ethyl magnesium bromide M in THF. 0.225 mL, 0.225 mmol). The reaction mixture is agitated for 18 hours on a wrist shaker and then quenched by the addition of 5% HCI in ethanol. Agitation is maintained for a further minutes and the mixture is then filtered through a small plug of silica to remove the inorganic material.

The filtrate is concentrated to afford 1-(4-chlorophenyl)propan- I-one. MS (EI-LRP) mn/z 168/170 Cl 169/171 Cl 1-1 NMR (300Mhz, CDCI 3 6 1.22 311), 2.98 2H), 7.42 2H), 7.9 (d.

2H1).

Example N-[3-((4-methioxyphenyl)su Ifonyl )propan- I -oylcarbonil- 4-0-mnethylhydroxylarn ine)phenoxymethylcopoly(styrene- I %-divinylbenizene)-resin.

0 OCH 3 H 0 N- [3-((4-methioxyphenvl)sulfonyl )propan- 1-oylcarbonyl]- methylhydroxylam ine)phienoxymethyl-copoly(styrene-l1%-divinylbenzene)-resin is prepared using the method of Example 16. except substituting added 3 ethoxyphenyl sulfonyl)prop ion ic acid for 3-(4methoxyphenyl)propionic acid. I R C=O 1691.6 cm-' (broad). Elemental Analysis: calcd: N, 1.02%; S, 2.34%. Found: N. 1.03%; S. Example 26 N-hydroxy-3-(4-methoxyphenylsu lfonyl.)propioniamide.

N-hydroxy-3-(4-methoxyphenylsu lfoniyl)propionamide is prepared by treating methoxyphenyl)sulfonyl)propan- I -oylcarbonyl]- 4-0-mnethyihydroxylam ine)phenoxymethylcopoly(styrene- I%-divinylbenzene)-resin with TFA using the procedure of Example 7. 'H NMR (300Mhz. DMSO-d 6 8 2.25 2H). 3.42 2H) 3.85 3H), 7.13 211), 7.79 211); LC MS (Ion Spray) ml/z 259 Area =44% PCT/US99/14251 WO 99/67192PCIS9145 67 Example 27 N-allyoxycarbonyl-4-(O-methylhydroxylam ine)phenoxymethyl-copoly(styrenie- 1% divinylbenzene) resin.

H

0 N 0 4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene- 1% divinylbenzene) resin (2 g, 2 mmol) is suspended in 15 ml of dichioromethane and shaken on a wrist shaker for 10 minutes and 284 mg (383 [tL, 2.2 mmol) of diisopropylethyl amine is added. The mixture is shaken for 30 minutes. Allyl chloroformate (265 mg, 233u1, 2.2 mmol) is added and the mixture is shaken overnight. The Nal lyoxycarbony-4-(O-methylhydroxylamine)phenoxymethyI-copoIy(styrene-l% divinylbenzene) resin is washed with 15 ml of dichioromethane, THF (3x) and dichlorornethane (3x) and dried in vacuo Example 28 N-4-bromobenzyl-N-allyoxycarbofl-4-(O-methylhydroxylam ine)phenoxymethyl-copoIy(styrene 1% divinylbenzene) resin.

Br \0 0 The N-allyoxycarbonyl-4-(O-methylhydroxylam ine)phenoxymethyl-copoIy(styrefle 1% divinylbenzene) resin prepared in Example 27 is suspended in 15 mL of toluene. DBU (1,522 g,1.5 ml, mmol) and 4-bromobenzyl bromide (2.5 g, 10 mmol) are added and the mixture is shaken for hours. The N--rmbny--lyxcroy--Omtyhdoyaiepeoyehl copoly(styrene- I% divinylbenzene) resin is washed with 15 mL of DMF (3 TI-IF (3x) and dichloromethane (3x) and dried in vacuo PCT/US99/14251 WO 99/6i7192PCUS/145 68 Example 29 N--rmbny--Omtyhdoyamn~hnxmty-ooysy e I% div inylbenzene) resin.

r~a Br N-4-bromobenzyl, N-allyoxycarbonyl-4-(O-methylhydroxylamifle)Phenoxymethylcopoly(styrene-1% divinylbenzene) resin, prepared as in Example 28, is swelled in 6 mL of THE, 6 mL of DMSO, 3 mL of 0.5 n HCI. Pd(Ph 3

P)

4 (347 mg, 15 weight is added and the mixture is shaken for minutes. Morpholine (4.3 mL) is added and the mixture is shaken overnight. The reagents are drained off and the N--rmbny--Omtyhdoyamn~hnxmty-ooysy e I% divinylbenzene) resin is washed with DMF THEF dichloromethane 0.5 diisopropylethyl amine in dichioromethane 0.5 sodium diethyldithiocarbamate in DMF DMF THF (3x) and dichioromethane (3x) and dried in vacuo overnight.

Example N-idl2ycroy)N4bombny -Omtyhdoyaine)phenoxymethyl-copoly(styrene- 1% divinylbenzene) resin.

?a Br O) N

H

N--rmbny--Omthlyrxlmn hnxyehlcpl~trn-% divinylbenzene) resin (1 .17 g, I mmole), prepared as in Example 29, is suspended in 15 ml of DMF.

Indole-2-carboxylic acid (483 mg, 3 mmol) and 575.1 mg (3 mmol) of 1(3-dimethylaminopropylY 3 diethylcarbodiimide hydrochloride are added and the mixture is shaken for 16 hours. The N-(indol-2ylabnl---rmbny--Omtyhdrxlmn~hnxmty-ooysyee divinylbenzene) resin is drained and washed with 15 ml of DMF THF/20% H,0 THIF (3x), and dichloromethane (3x) and dried in vacuo wo 99/67192 PCT/US99/14251 69 Example 31 Indole-2-carboxaldehyde.

Dry N-(indol-2-ylcarbonyl)-N-4-bromobenzyl-4-(O-methylhydroxylamine)phenoxymethylcopoly(styrene-l% divinylbenzene) resin is swelled in 12 mL of THF, shaken and cooled at 0 OC for minutes. LiAIH 4 (0.62 ml, 3 eq) is added and the mixture is shaken at O °C for 30 minutes. Saturated KHSO4 solution (0.5 mL) and 0.3 mL of potassium, sodium tartrate solution are added and the mixture is shaken for 30 minutes while warming to room temperature. Excess HzO is dried by adding dry Na 2

SO

4 and shaking for 15 minutes more. The mixture is filtered under low nitrogen pressure and washed 3 more times with 8 mL of dichloromethane followed by filtration. The filtrate is dried with Na 2

SO

4 and filtered twice through a short bed (1 inch) of silica gel 60 for column chromatography (particle size 0.040-0.063 mm) and the solvent is removed in vacuo to give indole-2-carboxaldehyde. 'H NMR (CDCI) 5 9.84 9.22 (1H,brs), 7.75 7.14-7.48 MS m/z 146 Example 32 N-(3,4-dimethoxycinnamoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-l%divinylbenzene)-resin.

O-N

OCH

3 4-O-Methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin resin (1g, Immole) is washed with DMF (15 mL), then suspended in 15 mL of DMF and 624.6 mg (3 mmole, 3 x excess) of3,4-dimethoxy cinnamic acid and 575.1 mg (3 mmol, 3 x excess) of 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added and the mixture is shaken for 16 hours. The resin is drained and washed with 15 mL of DMF THF/20% H 2 0 THF (3x), dichloromethane (3x) and dried under vacuum overnight.

WO 99/67192 PCT/US99/14251 Example 33 N-4-bromobenzyl-N-(3,4-dimethoxycinnamoyl)-4-O-methylhydroxylamine)phenoxymethylcopoly(styrene-1 %-divinylbenzene)-resin.

0 -O0 O-N N OCH 3

OCH

3 Br Dry N-(3,4-dimethoxycinnamoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene- 1%-divinylbenzene)-resin is shaken in 15 mL of toluene for 10 minutes, then 0.9 mL (6 mmol, 6 x excess) of DBU is added and the mixture is shaken for 2 hours. p-Bromo benzyl bromide (1.5 g, 6 mmol, 6 x excess) is added and the mixture is shaken for 3 days. The resin is dried overnight in vacuo.

Example 34 3-4-dimethoxycinnamaldehyde.

Dry N-4-bromobenzyl-N-(3,4-dimethoxycinnamoyl)-4-Omethylhydroxylamine)phenoxymethyl-copoly(styrene-l%-divinylbenzene)-resin is swelled in 12 mL of dry THF, shaken and cooled to o0C for 30 minutes. LiAIH, in THF (0.5 mL, 2 equivalents) is added and the mixture is shaken at 0 oC for 30 minutes. Saturated aqueous KHSO 4 solution (0.5 mL) and potassium, sodium tartrate solution (0.3 mL) are added and the mixture is shaken for 30 minutes while warming to ambient temperature. Excess HO is dried by adding dry NaSO 4 and shaking for 15 minutes. The mixture is filtered under low nitrogen pressure, washed 3 times with 8 mL of dichloromethane and filtered. The filtrate is further dried with Na 2

SO

4 and filtered through a short (1 inch) bed of silica gel for column chromatography (particle size 0.040-0.063 mm) and the solvent is removed in vacuo to give 3,4-dimethoxycinnamaldehyde. 'H NMR (CDCI 3 8 9.65 7.40 7.12 7.06 (1H,s), 6.87 6.60 (1H,dd), 3.90 MS m/z 193 Examples 35-42 The compounds of Examples 35-42 are prepared from the desired carboxylic acid starting material using the procedures of Examples 32-34.

Example anthranilic aldehyde.

'H NMR (CDCI 3 8 9.88 7,52-7.58 7.11-7.38 6.81 MS m/z 198 WO 99/6i7192 PCTIIJS99/1 4251 71 Example 36 2-bibenzylic aldehyde.

'H NMR (CDCI 3 8 10.18 7.83 (1 7. 14-7.52 3.30 2.87 MIS m/z 211 Example 37 4-methoxy-2-quinoline aldehyde.

'H NMR (CDCI 3 6 10.17 8.27 (1 8.18 7.78 7.62 (1 7.38 (IH,s), 4.12 MS m/z 188 Example 38 3-acetamido benzaldlehyde.

'H NMR (CDCI 3 6 9.98 7.97 7.86 7.62 7.48 2.21 (3H,s).

MS m/z 164 Example 39 4-(4-N-propylphenyl) benzaldehyde.

'H NMR (CDC1 3 6 10.02 (1 7,92 7.72 7.53 7.26 2.65 (2H,t), 1.68 (2H, dt), 0.95 MS m/z 225 Example 3-quinoline aldlehyde.

'H NMR (CDCI1 3 6 10.26 (1 9.3 8 (1 8.64 (1 8.20 (1IH,d), 7.98 (1 7.89 (1 H,t), 7.65 MIS mlz 158 [M+H+I.

Example 41 3-(3,4-methylenedioxy) propionaldehyde.

'I-INMR (CDCI 3 6 9.80 7.60-7.74 5.92 2.88 2,74 MS (El): m/z 179 [M+H+j.

Example 42 2-phenyl-4-quinoline aldehyde.

WO 99/67192 PCT/US99/14251 72 'H NMR (CDCI 3 8 10.58 9.00 (1H,d) 8.19-8.30 7.82 7.70 7.47- 7.59 MS m/z 234 Example 43 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene- 1% divinylbenzene) resin.

\OCO 2

H

F F Merrifield resin (2 mmol/g, 600 mg, 1.2 mmol) is swelled in anhydrous DMF (20 mL). 2,3,5,6tetrafluoro-4-hydroxy benzoic acid hydrate (2.28 g, 10 mmol) and cesium carbonate (3.26 g, 10 mmol) are added and the reaction mixture is heated at 85 °C for 12 hours with gentle agitation. The reaction mixture is filtered and the 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin is washed with DMF 20% aqueous DMF THF (5x) and dichloromethane and dried overnight in vacuo. IR (microscope, cm-1): 1640 9 F NMR (nanoprobe) -144.4 ppm, -160.2 ppm.

Example 44 N-4-benzyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1% divinylbenzene) resin.

2 00/ 0' H 4-(O-Methylhydroxylamine)phenoxymethyl-copoly(styrene-1 %-divinylbenzene)-resin (2g; 2 mmol), prepared as in Example 4, is swelled in DCM (15 ml), DIEA (0.383 ml; 2.2 mmol) is added and the mixture is shaken for 1 hour. Allyl chloroformate (0.234 ml; 2.2 mmol) is added and the mixture is shaken overnight. The resin is drained and washed three times each with DCM, THF and DCM and dried in vacuum. The dry resin is swelled in anhydrous toluene (18 ml), DBU (1.5 ml; 10 mmol) added and the mixture is shaken for 1 hour. Benzyl bromide (1.19 ml; 10 mmol) is added and the mixture is shaken for 3 days. The resin is drained and washed three times each with DCM, DMF, THF and DCM and dried overnight in vacuum. To the resin is added THF (6 ml), DMSO (6 ml), 0.5 N HCI (2.5 ml), tetrakis(triphenylphosphine)palladium(0) (347 mg; 15 mol and morpholine (4.3 ml) and the mixture is shaken overnight. The resin is then drained and washed in three times each with DMF, THF, DCM, in DCM, 0.5% sodium diethyldithiocarbamate in DMF, DMF, THF and DCM and then dried in vacuum. A resin sample is cleaved with excess 1:1 TFA/DCM for 1 hour at ambient temperature, then WO 99/67192 PCT/US99/14251 73 washed three times with I ml of the cleavage mixture, evaporated and dried in vacuo. 'H NMR

(CD

3 OD): 8 7.44 (in, 5H), 4.36 2H); MS m/z 124 Example Preparation of I ethanone)-2-(fluorophenoxyinethV1)-copolv (st-yrene- 1% divinvibenzene) resin F 0 HO0 CI CS 2

CO

3 DMF 0 0 To a suspension of chloromethyl polystyrene (Merrifield resin) (5.0 g, 8.9 mmol, resin loading 1.78 mmol/g) and cesium carbonate (29.0 g, 90 inmol, 10 eq.) in dry DMF (100 ml) was added 4-hydroxy-2fluoroacetophenone (6.9 g, 45 mmol, 5 eq.) in dry DMF (20 mrl). The mixture was mechanically stirred at 80 'C for 24 hours. The solution was cooled, washed with THF: IN HCI soln. 1, x3), THF:H,0 1, x3), TI-IF (x3) and DCM The 4-(1 -ethanone)-2-fluorophenoxymethyl)-copoly (styrene-1% divinylbenzene) resin was dried in vacuo at 40 'C overnight. IR 1682 d' 9 F (CDCI 3 -108 ppm. Theoretical loading 1.47 mmol/g. Analysis found C, 80.04; H, 6.47; F, 2.92, which corresponds to 1.53 fluorine atoms/g; 1.47 calculated for 100% loadinga.

Example 46, Preparation of 4-(hvdroxvlethyl)-2-(fluorophenoxyinethVylcopolV(stvrene- I% divinylbenzene) resin 0

OH

To a suspension of the 4-1-taoe--loohnxmty)cpl~trn-I divinylbenzene) resin (0.25 g, 0.37 inmol) in dry THIF was added lithium borohydride (0.93 ml of a 2.0 M soln. in THF, 1.85 minol, 5 The mixture was shaken at room temperature for 4 hours. The resin was filtered, washed with THF THF:H,O 1, x3), THIF (x3) and DCM The 4-(hydroxylethyl)- 2 fluorophenoxymethyl)-copoly(styrene- I% divinylbenzene) resin was dried in vacuo at 40 0 C overnight.

IR disappears. d'"F (CDCI 3 -121 ppm. Theoretical loading 1.47 mmol/g. Analysis found C, 78.02; H, 6.79; F, 2.76. which corresponds to 1.45 fluorine atoms/g; 1.47 calculated for 100% loading.

WO 99/67192 PCT/US99/14251 74 Example 47, Preparation of 4-(m ethy 1-0-m ethy lhydroxv lam ine)-2-fluorophenoxymeth yl-copo ly(styrene- I divinylbenzene) resin.

0

N-OH

0 F N0 F IDIAD, PPh,THF H1- 0 MeNH 2

THF

00NH To a suspension of 4-(hydroxylethyl)-2-fluorophenoxymethyl)-copoly(styrene- 1% divinylbenzene) resin g, 2.9 mmol), triphenylphosphine (2.3 g, 8.7 mmol, 3 eq.) and N-hydroxyphthalimide (2.4 g, 14.5 mmol, 5 eq.) in THIF (30 ml) at 0 'C was added diisopropylazodicarboxylate (1.7 ml, 8.7 mmol, 3 eq.).

The solution was allowed to warm to room temperature over ca. 30 minutes. The mixture was shaken for 24 hours. The resin was filtered, washed with DMF MeOH THIF DCM The hydroxyphthalimido resin was dried in vacuc at 40 'C overnight. IR 1737 9 F (CDCI 3 -119 ppm. Theoretical loading 1. 19 mmol/g.

The hydroxyphthalimido resin was re-suspended in THIF (40 ml) and methylamine (20 ml of a 40% wti.

soin. in water) was added. The reaction mixture was heated at 40 'C for 2 hours. The resin was filtered, washed with DMF MeOH TI-IF DCM The resin was dried in vacuo at 40 'C overnight to give the 4-mty--ehlyrxlmn)2floohnxmty-ooysy e I% divinylbenzene) resin. IR disappears, 3380 cm' broad. Analysis found C, 82.62; H, 7.21; N, 0.60; F, 3.13. d' 9 F (CDCI 3 -120 ppm. Theoretical loading 1.41 mmol/g.

Example 48, Preparation of N-benzvl-4-(methyl-0-methvlhvdroxylamifle)-2-fl uorophenoxymethl-coPoly(syrele- I %-divinylbenzene) resin WO 99/67192 PCT[US99/14251 0 0 0 1 ,N 00 0 To a suspension of the 4-mty--ehlyrxlmn)2f oohnxmty-ooysyee1% divinylbenzene) resin (2.78 g, 3.92 mmol) in CH 2 CI, (30 ml) was added ally! chloroformnate (1.25 ml, 11.8 mmol, 3 eq.) and diisopropylethylamine (2.05 ml, 11.8 ml, 3 The mixture was shaken for 24 hours. The resin was filtered, washed with CH 2 CI, THIF THF:H 2 0 1, x3), THIF DCM The I -poyeeabnl--mty--ehlyrxlmn)2furpeoyehl copoly(styrene- I %-divinylbenzene) resin was dried in vacuc at 40 'C overnight. IR 1757 cm-'.

9 F (CDCI 3 -120 ppm. Theoretical loading 1.26 mmol/g.

The N-(I poyeeabnl--mty--ehlyrx la n)2furpenxmehlcpl (styrene-1%/-divinylbenzene) resin was re-suspended in dry toluene (30 ml) and DBU (2.93 ml, 19.6 mmol, 5 eq.) was added. The reaction mixture was shaken for 1 hour. Benzyl bromide (2.33 ml, 19.6 mmol, 5 eq.) was then added. The resin was shaken overnight. The resin was filtered, washed with THIF THF;H,O 1, x3), THF DCM The N-benzyl-N-(1 -propylenecarboflyl)-4-(methylmethylhydroxylam ine)-2-fluorophenoxymethyl-copoly(styrefle- 1 %-divinylbenzene) resin was dried in vacuo at 40 'C overnight. IR 1761 V'F (CDCI 3 -120 ppm. Theoretical loading 1. 13 mmol/g.

The resin was suspended in DMVSO (10 ml) and THIF (10 nil). 0.5 N HICI soln (2.5 ml) was added followed by tetrakis(triphenylphosphine)palladium (0.23 g, 0. 196 mmol, 5 mol%) and morpholine ml). The mixture was shaken overnight. The resin was filtered, washed with DMF THIF (x3), MeOH DCM 0.5 conc. HCI in DMF 5 wt% diethyldithiocarbamate in DMF (x3), DMF THIF MeOH DCM (x3) and dried in vacuo at 40 'C overnight to afford the the Nbenzyl-4-(methyl-O-methylhydroxylam ine)-2-fluorophenoxymethyl-copoly(styrene- 1 %-divinylbenzene) resin. IR disappears. d'F (CDCl 3 -120 ppm. Theoretical loading 1.25 mmol/g.

Example 49, Preparation of O-(N-9-fluorenylmethoxvcarbonyl glycine)-4-(hydroxyethvl)-2-fluorophenoxym ethyl)covoly(styrene- 1% divinxlbenzene) resin.

WO 99/67192 PCT/US99/14251 76 C1. 0 0 H OH e OH Pyridine, DMF To a suspension of the 4-(hydroxyethyl)-2-fluorophenoxymethyl)-copoly(styrene- 1% div inylbenzene) resin (1.0 g, 1.47 mmol) in dry DMF (20 ml) was added Fmoc-Gly-OH (1.31 g, 4.41 mmol, 3 eq.), pyridine (0.71 ml, 8.82 mmol. 6 eq.) and 2,6-dichlorobenzoyl chloride (0.63 ml, 4.41 mmol, 3 The mixture was shaken overnight. The mixture was filtered and washed with THIF THF:l-1 2 1, x3), THIF MeOH (x3) and CH,CI., The O-(N-9-fluorenylmethoxycarbonyl glycine)-4- (hydroxyethyl)-2-fluorophenoxymethyl)-copoly(styrene- 1% divinylbenzene) resin was dried in vacuo at 'C overnight. IR 1726 9 17 -118 ppm. Theoretical loading 1.04 mmol/g.

Example Preparation of O-(N-diphenylmethylene alyci ne)-4-(hydroxyethyl)- 2-fl uorophenoxym ethyl)cop~olv(styrene- 1% divinylbenzene) resin 0 F O'I 00 Ph 0 lNFmoc ON<

P

O H 0 The resin (0.75 g, 0.78 mmol) was suspended in 20% piperidine solution in DMF (10 ml). The mixture was shaken for 2 hours. The solution was filtered and washed with DMF and NMP The resin was re-suspended in NMP (8 ml) and benzophenone imine (1.3 ml, 7.8 mmol, 10 eq.) and acetic acid (0.40 ml, 7.0 mmol, 9 eq.) was added. The mixture was shaken overnight. The solution was filtered and washed with NMP CH2CI2 THF THF:H,O 1, x3), THIF CH,Cl 2 The O-(N-diphenylmethylene glycine)-4-(hydroxyethyl)-2-fluorophenoxymethyl)-copoly(styrene- I% divinylbenzene) resin was dried in vacuo at 40 'C overnight. IR 1742 1627 cm-'.

Theoretical loading 1.11 mmol/g.

Example 5 1, Preparation of N- r I-(4-methvlvhenyl)-ethanoic acid] -2-naphthalenecarboxam ide WO 99/67192 PCTIUIS99/14251 77 00 Ph 0N

OH

N Ph H 0 0 The O-(N-diphenylmethylene glycine)-4-(hydroxyethyl)-2-fluorophenoxymethyl)-copoly(styrele- 1% divinylbenzene) resin (0.045 g, 50 mmol) was suspended in dry NMP (I ml) and 4-methylbenzyl bromide (0.0 19 g, 100 mmol, 2 eq.) was added followed by 2-tert-butylimino-2-diethylamino- 1,3dimethyl-perhydro-1,3,2-diaza-phosphorine (0.03 ml, 100 mmol, 2 The mixture was shaken overnight. The resin was filtered and washed with NMP DCM THIF THF:H,0 1, x3), THF (x3).

A mixture of THF: IN HCI soln. 1.5 ml) was added to the resin and the mixture shaken for 4 hours.

The resin was filtered and washed with NMP DIEA:NMP 10, x3), NMP DCM NMP (x3).

The resin was re-suspended in NMP (I ml) and 2-naphthoic acid (0.086 g, 500 mmol, 10 HOBt (0.068 g, 500 mmol, 10 eq.) and DIC (0.078 ml, 500 mmol, 10 eq.) was added. The mixture was shaken overnight. The resin was filtered and washed with NMP DCM DCM:MeOH 1, x3), MeOH (x3) and DCM (x3).

Trifluoroacetic acid (1 ml) and DCM (I ml) were added and the mixture was shaken for I hour. The solution was filtered into a tared vial, the resin was washed with DCM The solvent was removed in vacuo to yield I-(4-methylphenyl)-ethanoic acid]-2-naphthalenecarboxam ide (0.0167 g, 100%).

LCMS gives 333 100%].

Example 52, Preparation of 0-dehlhshnact)4( 1xehl)2furpeoyehy)cpl~trn-% divinylbenzene) resin O 0 alc

HO'L-*

0 CI 0 E% O f C P(O OH OH 00 Pyridine, DMF To a suspension of the 4-(hydroxyethyl)-2-fluorophenoxymethyl)-copoly(styrene- 1% divinylbenzene) resin (1.0 g, 1.47 mmol) in dry DMF (8 ml) was added diethylphosphonoacetic acid (0.71 ml, 4.41 mmol, 3 pyridine (0.71 ml, 8.82 mmol, 6 eq.) and 2,6-dichlorobenzoyl chloride (0.63 ml, 4.41 mmol, 3 The reaction mixture was shaken overnight. The resin was filtered, washed with DMF WO 99/67192 PCTIUS99/14251 78 THIF DCM MeOH (x3) and THIF The O-(diethylphosphonoacetoY- 4 (hydroxyethyi)-2-fluorophenoxymethyI)-copoIy(styrene- I% d ivinylbenzene) resin was dried in vacuo at 'C overnight. IR 1737 (P0O) 1260 d' 9 F (CDCI 3 -119 ppm. Theoretical loading 1. 17 mmol/g.

Example 53, Preparation of 4-methvlcinnamic acid 0 0 0 F 1. LiHMDS, THF N OH 2. p-Tolualdehyde, ID O~ (O0 cyclohexane 0 0 To a suspension of the O-(diethylphosphonoaceto)-4-(hydroxyethyl)-2fluorophenoxymethyl)copoly(styrene- 1 divinylbenzene) resin 1 g, 0. 117 mmol) in dry THIF (3 ml) at 0 'C was added LiHMDS soln (0.29 ml of a 1.0 M soln. in THF, 0.29 mmol, 2.5 The solution was allowed to warm to room temperature over 30 minutes. The solution was filtered under an inert atmosphere and ptolualdehyde (0.033 ml, 0.28 mmol, 2.4 eq.) in dry cyclohexane (1.5 ml) was added. The reaction mixture was shaken overnight. The resin was filtered, washed with DMF THF:H 2 0 1, x3), DCM TI-IF (x3) and DCM The resin was dried in vacuo at 40 'C overnight. IR disappears, (P0O) disappears.

Trifluoroacetic acid (I ml) and DCM (I ml) were added and the mixture was shaken for I hour. The solution was filtered into a tared vial, the resin was washed with DCM The solvent was removed in vacua to yield 4-methylcinnamic acid (0.0201 g, quant). LCMS gives 144 >90%1.

Example 54, Preparation of Nhydroxv-phenvi-acetaimide 1.

OH

N. 0 I EDCI, DMF 0 F 2. TFA, 0CM

N'O

,C 0

NH

2

H

To a suspension of the 4-mty--ehlyrxlmn)2floohnxmty-ooysy e I% divinylbenzene) resin (0.10 g, 0.14 mmol) in dry DMF (2 mrl) is added 1-[3-(dimethylamino)propyI- 3 ethylcarbodiimide hydrochloride (0.08 g, 0.42 mmol, 3 To the mixture is then added phenylacetic WO 99/67192 PCT/ISOQ/14 l 79 acid (0.06 g, 0.42 mmol, 3 The mixture was shaken overnight. The resin was filtered and washed with DMF THF:H,O x5), THF MeOH (x3) and DCM (x3).

To the resin is added TFA (I ml) and DCM (1 mi) and the mixture shaken for 1 hour. The mixture is filtered into a tared vial and the resin washed with DCM (x2) and toluene The combined filtrates are evaporated in vacuo to yield N-hydroxy-phenyl-acetamide (0.0084 g, LCMS gives 151 Example The 4-(1-ethanone)-2-(fluorophenoxymethyl)-copoly (styrene-l% divinylbenzene) resin depicted below could easily be oxidized by known methods, such as sodium hydroxide in the presence of iodine, to afford the carboxylic acid resin derivative (as in Hing et al. J. Am. Soc., 66, 894, 1944).

00o 010

OH

Example 56 The carboxylic acid resin derivative depicted below could easily be reduced using diborane, or other reducing agents to give the benzylic alcohol resin derivative.

0 OH OH Example 57 The mono-fluoro-benzyl alcohol resin derivative depicted below could easily be converted to the hydroxyl amine resin under analogous conditions for the synthesis of 4-(methyl-Omethylhydroxylamine)-2-fluorophenoxymethyl-copoly(styrene- 1% divinylbenzene) resin in Example 47 above.

WO 99/67192 WO 9967192PCT/US99/1 4251 0 F S OH .01NH 2 Example 58, Preparation of I ethanone)-2-fluoropheioxymethy)-copoly(styrele 1% divinylbenzene-5% 4fluorostyrene) resin F 0 F

F

I HObN

F

C1

CS

2

CO

3 DMF 01 0 To a suspension of fluorinated chioromethyl polystyrene (fluoro-Merrifield resin) (5.0 g, 8.0 mmol, resin loading 1.60 mmol/g, 5 wt% Fluorostyrene) and cesium carbonate (26.1 g, 80 mmol, 10 eq.) in dry DMF ml]) was added 4-hydroxy-2-fluoroacetophenone (6.17 g,40 mmol, 5 eq.) in dry DMF (20 ml). The mixture was mechanically stirred at 80 'C for 24 hours. The solution was cooled, washed with THF: IN HCI soln. 1, x3), TI-IF:H 1 0 1, x3), THF (x3) and DCM The 4-(1 -ethanone)-2fluorophenoxymethyl)-copoly(styrene- 1% divinylbenzene-5% 4-fluorostyrene) resin was dried in vacuo at 40 'C overnight. IR 1682 d' 9 F (DMF) 109, -122 ppm. Theoretical loading 1.3 5 mmol/g.

Analysis found C, 84.25; H, 6.80; F, 3.86, Example 59, Preparation of I-hvdroxylethyl)-2-fluorophenoxymethvl )-copoly(stvrene- 1% divinvbenzene-5% 4fluorostyrene) resin WO 99/67192 PCTIUS99/1 4251 81 F

F

THE

0

OH

To a suspension of the I-ethanone)-2-fluorophenoxymethyl )-copoly(styrenie- 1% 4-fluorostyrene) resin (3.0 g, 4.05 mmol) in dry THIF (50 Ml) was added lithium borohydride (10. 1 ml of a 2.OM soin. in THF, 20.2 mmol, 5 The mixture was shaken at room temperature for 2 hours. The resin was filtered, washed with THIF THF:H 2 0 1, x3), THF (x3) and DCM The 4-(1hydroxylethyl)-2-fluorophenoxymethyl)-copoly(styrefle- I% div inylbenzene-5% 4-fluorostyrene) resin was dried in vacuo at 40 'C ovemnight. IR disappears. d' 9 F (DMF) 121, -122 ppm. Theoretical loading 1.3 5 mmol/g. Analysis found C, 84.00; H, 7. 10; F, 3.77.

Example Preparation of 0-dehlhshnaeae--hdoyty)2fur~eoyehl-ooysyee 1% divinvlbenzene-5% 4-fluorostyrene) resin F

F

N0 0 0F H O 'J "1 1P(~ 0 F% C1 0 OH N. OH 0 0 Pyridine, DMF To a suspension of the 4-(1I -hydroxylethyl)-2-fluorophenoxymethyl)-copoly(styrene- 1% divinylbenzene- 4-fluorostyrene) resin (1.5 g, 2.03 mmol) in dry DMF (20 ml) was added diethylphosphonoacetic acid (0.98 ml, 6.1 mmol, 3 pyridine (0.99 ml, 12.2 mnmol, 6 eq.) and 2,6-dichlorobenzoyl chloride (0.87 ml, 6.1 mmol, 3 The reaction mixture was shaken overnight. The resin was filtered, washed with DMF THF DCM MeOH (x3) and TI-F The O-(diethylphosphonoacetate)-4- (hydroxyethyl)-2-fluorophenoxymethyl)-copoly(styrene- 1% divinylbenzene-5% 4-fluorostyrene) resin was dried in vacuo at 40 'C overnight. IR 1742 cm', 1265 9 F (DMF) 120, -121 ppm. Theoretical loading 1. 17 mmol/g.

Example 6 1, Preparation of 4-methylcinnamic acid WO 99/67192 82

F

0 I. 0 F 1.LiHMDS, THF NOH 2. p-Tolualdehyde, To a suspension of the O-(diethylphosphonoacetate)-4-(hydroxyethyl)-2-fluorophenoxymethyl)copoly(styrene-1I% divinylbenzene-5% 4-fluorostyrene) resin 1 g, 0. 11 mmol) in dry THIF (3 ml) at 0 'C was added LiHMDS soln (0.55 ml of a 1.0 M soin. in THF, 0.55 mmol, 5 The solution was allowed to warm to room temperature over 30 minutes. The solution was filtered under an inert atmosphere and p-tolualdehyde (0.08 ml, 0.66 mmol, 6 eq.) in dry cyclohexane (1.5 ml) was added. The reaction mixture was shaken overnight. The resin was filtered, washed with DMF THF:H,O x3), DCM THF (x3) and DCM The resin was dried in vacuo at 40 'C overnight. IR (C=O) disappears, disappears. 9 F (DMF) 119, -121 ppm.

Trifluoroacetic acid (1 mi) and DCM (1 ml) were added to the resin and the mixture was shaken for I hour. The solution was filtered into a tared vial, the resin was washed with DCM The solvent was removed in vacuc to yield 4-methylcinnamic acid (17.6 mg, 'H NMR (MeOH) 2.35 (3H, 6.40 (I1H, d, J= 16 Hz), 7.21 d, J= 8 Hz), 7.46 (2H, d, J 8 Hz), 7.63 (1IH, d, J= 16 Hz). LCMS gives 162 1006/6].

Example 62, Preparation of O-(N-9-fluorenylmethoxvcarbonyl phenvlalanine)-4-(hydroxethyl)-2fluorOphenoxymethyl)-copoly(styrene- 1% divinylbenzene-5% 4-fluorostyrene) resin

F

F

F Fmoc-Phe-OH Ph CI 1 0 NFmoc OH Nc OH0

H

Pyridine, DMF To a suspension of the resin (0.25 g, 0.34 mmol) in dry DMF (4 ml) was added Fmoc-Phe-OH (0.40 g, 1.02 mmol, 3 pyridine 16 ml, 2.04 mmol, 6 eq.) and 2,6-dichlorobenzoyl chloride 15 ml, 1.02 mmol, 3 The mixture was shaken overnight. The mixture was filtered and washed with THF (03), THF:H,O 1, x3), T14F MeOH (x3) and CH 2

CI

2 The O-(N-9-fluorenylmethoxycarbonyl phenylalanine)-4-(hydroxyethyl)-2-fluorophenoxymethyl)-copoy(styrele- 1% divinylbenzene-5% 4fluorostyrene) resin was dried in vacuo at 40 'C overnight. IR 1732 Theoretical loading 0.89 mmoL/g.

WO 99/671i q PCT/IIS99/14251 83 Example 63, Preparation of Fmoc-Glv-Phe-OH

F

0 F ph H 0 O NFmoc- FmocN

OH

O NFmoc

I

SH O O H To a suspension of the O-(N-9-fluorenylmethoxycarbonyl phenylalanine)-4-(hydroxyethyl)- 2 fluorophenoxymethyl)-copoly(styrene-l% divinylbenzene-5% 4-fluorostyrene) resin (0.04 g, 0.036 mmol) was added piperidine in DMF (10% soln., 1 ml). The mixture was shaken for 1 hour. The mixture was filtered and washed with DMF (x5) and NMP IR 1737 cm''.

The resin was re-suspended in NMP (1.5 ml) and Fmoc-Gly-OH (0.069 g, 225 mmol, 5 HOBt (0.034 g, 225 mmol, 5 eq.) and DIC (0.035 ml, 225 mmol, 5 eq.) was added. The mixture was shaken overnight. The mixture was filtered and washed with NMP DCM DCM:MeOH x3), MeOH (x3) and DCM IR 1668, 1732 Trifluoroacetic acid (1 ml) and DCM (1 ml) were added to the resin and the mixture was shaken for 1 hour. The solution was filtered into a tared vial, the resin was washed with CH 2

CI

2 The solvent was removed in vacuo to yield Fmoc-Gly-Phe- OH (12.2 mg, LCMS gives 444 100%].

Example 64 N-at-(tert-Butoxycarbonyl)-L-alaninal.

N-4-benzyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene- 1% divinylbenzene) resin (1.08g; Immole), prepared as in Example 44, is washed with DMF (15 ml), suspended in 15 ml of DMF and Boc-Ala-OH (568 mg; 3 mmol) and EDCI (575.1 mg; 3 mmol) are added and the mixture is shaken for 16 hours. The resin is drained and washed with 15 ml of DMF THF/20% H,O THF DCM (3x) and dried in vacuo overnight. The dry resin is swelled in 12 ml of anhydrous THF under nitrogen, shaken for 10 minutes and cooled to 0 oC for 30 min. LAH in THF (0.75 ml; 3 mmol) is added and the mixture is shaken at 0 OC for 30 minutes. Saturated KHSO 4 (0.5 ml) and K,Na tartrate (0.3 ml) solutions are added and the reaction mixture is shaken for 20 minutes while warming to ambient temperature. Excess water is dried by addition of dry NaSO0 4 and shaking for 15 minutes. The mixture is filtered under low nitrogen pressure, washed three times with 8 ml of DCM and filtered. The filtrate is further dried with Na,SO 4 and filtered with DCM through a short (1 inch) bed of silica gel 60 for column chromatography (particle size 0.040-0.063 mm). Solvent removal and drying in vacuo afford 44 mg of the title compound. 'H NMR: 8 9.56 1H), 5.10 (brs, 1H), 4.22 1H), 1.45 9H), 1.34 3H); MS m/z 173 Purity estimated 90% by 'H NMR.

Examples 65-69 WOl 99/67192 PCTIUS99/1 4251 84 The following compound as prepared from the appropriate amino acid starting material using the method of Example Example N-ct-(tert-Butoxycarbonyl)-L-valinal.

'H NMR: 6 9.61 I 5.09 (brs, I 4.27 (in, 1 1.80 (bin, I 1.48 (in, 911), 1.03 (d, 3H), 0.95 3H); MIS m/z 201 Purity estimated 90% by 'H NMR.

Example 66 N-(x-(tert-Butoxycarbonyl)-L-phenylaflninal.

'H NMR: 869.62 I1H), 7.12-7.34 (in, 5H), 5.04 (brs, I 4.42 I 3.09 2H), 1.39 (s, 9H); MIS mlz =250 [M+H]Y LC Area 0 9 1%.

Example 67 N-(x-(tert-Butoxycarbonyl)-3-(t-butyl)-L-apartal.

'H NMR: 6 9.63 1H), 5.60 (brs, I 2.82 (in, 2H), 2.02 (in, I 1.42 (in, 1 8H); MS in/z 274 LC Area (UV, 2 WO 99/67192 PCT/US99/14251 Example 68 N-a-(tert-Butoxycarbonyl)-N-E-(tert-butoxycarbonyl)-L-lysinal-OH.

'H NMR: 5 9.53 1H), 5.21 (brs, 1H), 3.12 2H), 1.88 2H), 1.18-1.66 22H); MS (IS): m/z 331 LC Area (UV 220 67%.

Example 69 Indole-2-carboxaldehyde.

'H NMR: 6 9.82 1H), 7.14-7.75 6H); MS m/z 145 LC Area (UV 254 Examples 70-120 Parallel Synthesis of Arrays of Anthranilic Acid Compounds 0 0 0 0 Rm OEt i 17 m Rn

HOR

1736 cm 1710 cm i) Lithium bis(trimethylsilyl)amide (4 equiv., 1.0 M in THF); THF, 1 hour, 25 *C.

ii) Remove solvent; add RnCHO (5 equiv., 0.5 M in 60% cyclohexaneTHF); 2-3 days; 25 °C.

iii) 30% trifluoroacetic acid/dichloromethane; 1 hour; 25 °C.

The Parallel syntheses are accomplished using a Tecan Combitec organic synthesis robot. Forty eight reaction vessels are placed in the robot's reaction block and a slurry of ethyl phosphonate resin compound in THF is transferred by pipette into each of the reaction vessels. For this synthesis it is found to be more convenient to load the phosphonates to the resin on a large scale, then split the resin into the reaction block. The robot dispenses anhydrous THF to the reaction vessels, followed by the solution of base (1.0 molar in THF) as they sit on the deck of the robot in an ice bath. The sixteen aldehydes (see Table 1) are prepared as 0.5 molar solutions in 60% cyclohexane in THF. The reaction block is then manually moved to an orbital shaker and agitated for one hour at ambient temperature. The reaction block is then placed back on the instrument. The vessels are then drained, and solutions of the aldehydes are dispensed to their respective reaction vessel. The reaction block is then moved to an orbital shaker and agitated for 2-3 days at ambient temperature. Work-up of the reaction on the robot consists of draining the vessels and washing the resin with THF, 20% aqueous DMF, DMF, THF, and then dichloromethane. A total of 21 washes are needed to remove all the impurities in the resin matrix. The resin is then sampled for single bead FT IR analysis. The diagnostic carbonyl shift is a qualitative means of determining whether the reaction has gone to completion.

The anthranilic acid products are then cleaved from the resin using 30% trifluoroacetic acid (TFA) in dichloromethane. The TFA solutions are transferred to pre-tared test tubes contained in a Benchmate II 6 compatible 5 x 10 position rack, which had been defined on the deck of the robot. This WO 99/67192 PCT/US99/14251 86 format effectively couples sample concentration and weighing. Sample concentration is achieved using the Zymark Turbovap concentrator, in which the Benchmate II compatible rack fits, for efficient nitrogen blow-down of the samples. The Benchmate 11 compatible rack containing the desired samples is then placed in a Zymark Turbovap concentrator to remove the solvent (the Turbovap had been modified slightly by coating the manifolds with Teflon to prevent corrosion of the gas nozzles). The forty eight samples each containing approximately 3 mL of 30% TFA in dichloromethane are concentrated in about thirty minutes. The samples are usually chased with a one milliliter portion of methanol, then reevaporated, to ensure complete removal of the TFA solution. The reaction set is then analyzed by 'H NMR and LC-MS (See Table 1).

Table I Example km JR Resin RI Anthramlic C=O Acid Purity Stretch UV 2 2 0 TTOEt T1733 71l Ph(CH23 173 72 H1/37 73 Et FO A T78 74 i t 104 B 92 t 1711 U _76 Et 1 1699 D 77 Et 1F"03 E 78 Et 1 1708 1 79 Et 11706 G 1Et 11709 H I9U T81i 1t 17 96 82 Et 17 5 1 19-/ 83 Et 1 1704 K 77 84 E 1706 L 75 1 Et T7 T i X86 Et T 1705 1 N 93 87 t 1703 0 1 81 88 Et T703 P 89 Ph(CH,)3- 11707 A h(H)-1705 n Ph(CH 2 3 i7 3 IW 8 X 91 Ph(CH,3- 1711 C 89 92 Ph(CH2)3- 169 87 93 Ph(CH2l3- 1 703 E 18 94 Ph(CH217 82 Ph(CH2- 1 T7O 1 96 Ph(CWH)3- 1708 H 86 97 Ph(CH 2 3 1708 1 97- 98 Fh(CH2)37 I I A4 I 9 99 Ph(CH2 3 17/04 i 76 100 Ph(CHI)3- 170 IL U-93 101 Ph(H2)3- 1_/U6 M 73 i102 1Ph(CH2)3 3-0 1N 8 1103 Ph(CH2)3- 102 104 Ph(CH2)3- 1-/02 1P 83 105 H 1712 1K 76 '106 H 11711 KB 87 :107 H Y7 1T T C 93 WO 99/67192 PCT/US99/14251 1108 H 11706 i Tf 48 T109 i H i1708 110 -H 1711 ~F 1-m1 H 1 08 1 G 112 H 1712 H i 8 f13 H I 1714 I i 70 i 114 H 1 171 1 J 81 115 H 1708 K -116 IH 1711 L S117 H 1711 M 74 S118 H- 1711 IN 76 i 119 H 171 1 0 I120 H 1711 P 89 A- E-= I ICLo O O I= ~7 j

CH,

N

I A- i

CH,

O-CH,

Example 121 3-(3,4-dimethoxybenzenesulfonyl)-5-methylhexanoic acid hydroxyamide.

Step A: Wang resin (20 g, 15 mmol) is swelled in 300 mL of anhydrous DMF for 15 minutes.

Then a solution ofdiethyl phosphonoacetic acid (8.83 g, 45 mmol) in 50 mL of DMF is added followed by pyridine (7.12 g, 90 mmol) and 2,6-dichlorobenzoyl chloride (9.4 g, 45 mmol). The mixture is agitated for 20 hours at room temperature. The resin is filtered and washed successively with DMF (3x), HO DMF THF (1Ox) and EtO (1Ox) followed by drying in vacuo at 40 OC for 20 hours. IR (micro) u c=o 1738 cm"' Step B: The loaded resin from Step A (1 g, 0.75 mmol) is swelled in anhydrous THF (10 mL) for minute followed by the addition of a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (4 mL) at 0 oC. The mixture is allowed to warm up to room temperature and is shaken for 30 minutes.

The solvent is then drained to the top of the resin followed by the addition of anhydrous cyclohexane mL) and isovaleraldehyde (0.17 g, 2 mmol). The mixture is shaken for approximately 72 hours and worked up as described in Step A. IR (micro) u c=o 1718 cm'' WO 99/67192 PCT/US99/14251 88 Step C: To a solution of 3,4-dimethoxybenzenethiol (11.9 g, 70 mmol) in anhydrous THF (54.4 mL) at 0 °C is added a 2.5 M solution of n-butyllithium (5.6 mL, 14 mmol) and the solution is stirred at room temperature for 15 minutes.

The resin from Step B (0.25 g, 0.19 mmol) is swelled in anhydrous THF (2.5 mL) for 15 minutes and 4 mL of the above prepared 1 N thiol/thiolate stock solution is added. The mixture is shaken for approximately 100 hours and worked up as described in Step A. IR (micro) u c=o 1732 cm'' Step D: The resin from step 3 (0.25 g, 0.19 mmol) is swelled in 1,4-dioxane (5 mL) for minutes and a solution of m-chloroperoxybenzoic acid (0.44 g, 2.5 mmol) in 2 mL of 1,4-dioxane is added. The mixture is shaken for 16 hours and worked up as described in Step A.

Step E: The resin from Step D (0.25 g, 0.19 mmol) is treated with 1:1 dichloro-methane/ trifluoroacetic acid (3 mL) for 1-2 hours. The resin is filtered and washed with dichloromethane (2x1 mL). The combined filtrates are concentrated in vacuo to provide 3-(3,4-dimethoxybenzenesulfonyl)-5methylhexanoic acid (9.8 mg). 'H NMR (300 MHz, CDC 3 8 0.85 3H), 0.92 3H), 1.4 1H), 1.6-1.8 2H), 2.55 (dd, 1H), 2.9 (dd, 1H), 3.65 1H), 3.92 3H), 3.95 3H), 7.0 IH), 7.32 (s, 1H), 7.5 1H). MS (APCI; Loop) m/z 348 (M+NH 4 331 (M+H) Step F: The hydroxylamine bound Wang resin (50 mg, 0.037 mmol) is swelled in anhydrous DMF (1 mL) for 15 minutes followed by the addition of 1-(3-dimethyl-aminopropyl)-3ethylcarbodiimide hydrochloride (30 mg, 0.16 mmol) and a solution of the carboxylic acid from Step E in 1 mL of anhydrous DMF. The mixture is shaken for 20 hours and worked up as described in Step A.

Step G: The resin from Step F is treated with 1:1 dichloromethane/trifluoroacetic acid (2 mL) for 1.5 hours. The resin is filtered and washed with dichloro-methane (2x1 mL). The combined filtrates are concentrated in vacuo to provide 3-(3,4-dimethoxybenzenesulfonyl)-5-methylhexanoic acid hydroxyamide (9.8 mg). MS (H-isp; LCMS) m/z 363 (M+NH 4 346 Examples 122-147 The following hydroxamic compounds are synthesized using appropriate starting materials and following the steps of this example: Example 122 5-(4-Butoxyphenyl)-3-(3,4-dimethoxybenzenesulfonyl)-pentanoic acid hydroxyamide.

MS (APCI; LCMS) m/z 466 (M+H) Example 123 3-(3,4-Dimethoxybenzenesulfonyl)hexanoic acid hydroxyamide.

MS (H-isp; LCMS) m/z 332 Example 124 11 n-I VCTIfI TQOQh1 A1) 3-(3 ,4-Dimethoxybenzenesulfonyl)-4-metlylpentanoic acid hydroxyamide.

MIS (H-isp; LCMS) mlz 332 (M+H)y Example 125 3-(3 ,4-Dimethoxybenzenesulfonyl)-5 -methyihexanoic acid hydroxyamide.

MIS (H-isp; LCMS) mlz 346 Example 126 3-(3-Benzyloxyphenyl)-3-(3 ,4-dimethoxybenzenesulfony)-N-hydroxypropoflam ide.

MIS (H-isp; LCMS) m/z 472 Example 127 3-(2-Benzvloxyphenyl)-3-(3 ,4-dimetlhoxybenzenesulfonyl )-N-hydroxypropionamide.

MIS (APCI;- LCMS) m/z 472 Example 128 3-(3-Benzyloxy-4-methoxyphenyl)-3-(3 ,4-dimethoxybenzenesulfonyl)-N-hydroxypropioflamide.

MIS (APCI; LCMS) mlz 502 Example 129 3-(3 ,4-Dimethoxybenzenesulfonyl)-N-hydroxy-3-(3-pheoxypheyl)propioflaide.

MIS (APCI; LCMS) m/z 458 Example 130 3-(3-(4-Ch lorophenoxy)phenyl)-3-(3,4-dimethoxybenzenesufofl)-N-hydroxypropiolam ide.

MIS (H-isp; LCMS) mlz 492 Example 131 3-(3,4Dmtoyeznsloy)--yrx--3(-ehx-peoypey~rpoaie MS (H-isp; LCMS) m/z 488 Example 132 2-[Biphenyl-4-yl-(3 ,4-dimethoxybenzenesulfonyl)methyl-4-methylpeltaloic acid hydroxyamide via 2- [Biphenyl-4-yl-(3 ,4-dimethoxybenzenesulfonyl)-methyl]-4-methylpentanoic acid.

'H NMR (300 MHz, CDC1 3 8 0.9-1.1 (2xd, 6H), 1.6 (in, IH), 1.9 2.35 (in, I 3.55 (s, 3H), 3.7 (in. 1H), 3.9 3H), 4.3 IH), 6.6-7.5 (series m, 12H). MIS (APCI; LCMS) m/z 500 483 (M+H)Y yields 2-[Biphenyl-4-yl-(3 ,4-dimethoxybenzenesulfonyl)methyl]- 4 methylpentanoic acid hydroxyamide (4.9 mng). MIS (APCI; LCMS) mlz 515 (M+NH 4 498 Example 133 WO 99/6i7192 PCT/US99Q/1 d251 90 24[(3 ,4-Dimethoxybenzenesulfony)-(4-phenoxypheny)methyIII-N-hydroxy- 4 2 methoxyethoxy)butyramide.

MS (APCI; LCMS) mlz 560 Example 134 2-[(3,4-Dimethoxybenzenesulfonyl)-(4-phenoxyphenyl)methyl-N-hydroxy-butyramlide.

MS (APCI; LCMS) mlz 486(M+H)'.

Example 135 4-Benzenesulfonyl-2- [biphenyI-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl-N-hydroxybutyramide.

MS (isp; Loop) mlz 610 Example 136 2-Bpey--l(,-iehxbneeufnlmty]Nhdoy4pey-uyaie MS (APCI; LCMS) mlz 546 Example 137 2-Bpey--l(,-iehxbneeufny~ehl--yrx--2mtoyehx) butyram ide.

MS (isp; Loop) m/z 544 Example 138 2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-N-hydroxybutyram ide.

MS (APCI; LCMS) mlz 470 Example 139 2-[Biphenyl-4-yl-(3 ,4-dimethoxybenzenesulfonyl)methyl]-4-methylpeltaloic acid hydroxyam ide.

MS (APCI; LCMS) mlz 498 (M+H) t Example 140 2-[Biphenyl-4-yl-(3 ,4-dimethoxybenzenesulfonyl)methyl]-N-hydroxy-3-methyl-butyram ide.

MS (APCI; LCMS) m/z 484 Example 141 2-[Biphenyl-4-yl-(3 ,4-dimethoxybenzenesulfonyl)methyl]-7-phenylheptaloic acid hydroxyam ide.

MS (APCI; LCMS) m/z 588 Example 142 2-[Biphenyl-4-yl-(3 ,4-dimethoxybenzenesulfonyl)methyl]-5-phenylpentanoic acid hydroxyamide.

MS (APCI; LCMS) m/z 560 WO 09/67192 PCTIUS99/14251 91 Example 143 2- 3 4 -Dimethoxybenzenesulfony1)-(4-phefloxypeflyl)methy]Nhydroxy-3methyl-butyram ide.

MS (APCI:, LCMS) m/z 500 (M+H)Y.

Example 144 2- t(3,4-Dimethoxybenzenesufoflyl)-(4-pheloxypheflY)methyl 7 -phenylheptanoic acid hydroxyamide.

MS (APCI; LCMS) m/z 604 Example 145 3 -(3,4-Dimethoxybenzenesufoflyl)-2-ethylhexalic acid hydroxyam ide.

Modified procedure for Step C: Reaction temperature 60 Reaction time 2x20 hours.

MS (APCI; LCMS) mlz 360 (M+H) t Example 146 3-(3 ,4-Dimethoxybenzenesufonyl)-2-(3-phenyl-propyl)hexaloic acid hydroxyamnide.

Modified procedure for Step C. Reaction temperature 60 Reaction time Wx2 hours.

MS (APCI; LCMS) m/z 450 Example 147 2 -[(3-Benzyloxyphenyl)-(3,4-dimlethoxybelzeflesulfoflyl)methyl-5phenylpentanoic acid hydroxyam ide.

Modified procedure for Step C. Reaction temperature 60 Reaction time 2x20 hours.

MS (APCI; Loop) m/z 590 Examples 148-161 Step A: The hydroxylamine bound Rink resin (0.1 g, 0.031 mmol) is swelled in anhydrous DMF (1 mL) for 15 minutes followed by the addition of l-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg-, 0. 16 mmol) and a solution of the appropriate carboxylic acid prepared as in Example 73, Steps A-E in I mL of anhydrous DMF. The mixture is shaken for 20 hours and worked up as described in Example 73 Step A.

Step B: The resin from Step A 1 g, 0.031 mmol) is treated with 9:1 dichloromethane/trifluoroacetic acid (2 mL) for I hour. The resin is filtered and washed with dichloromethane (2x1 mL). The combined filtrates are concentrated in vacuo to provide the following hydroxamic, acids: Example 148 ,4-Dimethoxybeflzenesulfonyl)-3-hydroxycarbamoy[-propyl]-N methyl-benzamide.

MS (APCI; Loop) m/z 437 WO 99/67192 PCTIUS99/14251 92 Example 149 ,4-Dimethoxybenzenesulfoflyl)-3-hydroxycarbamoylbutyIF-N methyl-benzam ide.

MIS (APCI; Loop) m/z 451 Example 150 Methyl-phenyl-carbam ic acid 3-(3,4-dimethoxybenzenesulfofl)A4hydroxycarbamoyl-butyI ester.

MS (APCI; Loop) mlz 452 Example 151 4 -Dimethoxybenzenesulfofl)4hydroxycarbamoylbuty]methyl-carbam ic acid benzyl ester.

MS (APCI; Loop) m/z 481 Example 152 3-(3 ,4-Dimethoxybenzenesulfolyl)hexalediic acid- I -hydroxyamide-6-(methyl-phel-almide).

MS (APCI; Loop) m/z 451 Example 153 3-(3 ,4-Dimethoxybenzenesulfofly)heptaledioic acid- I -hydroxyamn ide-7-(methyl-pheflyl-amide).

MS (APCI; Loop) m/z 465 Example 154 3-(3,4-DimethoxybelzeleSUlfoflyl)- 6 ,3-dioxo-1,3-dihydro-isoifldo-2-y1)hexanoic acid hydroxyamide. MS (APCI; Loop) m/z 477 (M+-IY Example 155 7-(3,4-Dihydro-2H-quinolifl- Il-yl)-3-( 3 ,4-dimethoxybenzenesulfofl)-7-oxoheptanoic acid hydroxyamide.

MS (APCI; Loop) mlz 491 Example 156 7-(3,4-Dihydro-2H-quilifl- ,4-dimethoxybenzenesulfoflyl)--oxo-hexanoic acid hydroxyamide.

MS (APCI; Loop) mlz 477 Example 157 7-Benzo(1I,3)dioxol-5-yl-3-(3 ,4-dimethoxybenzenesulfonyl)heptaloic acid hydroxyamide.

MS (APCI; Loop) mlz 466 Example 158 3 3 4 -Dimethoxybeflzefesufonyl)3(thien3-y)N-hydroxypropionamide.

MS (APCI; Loop) mfz 372 WO 99/67192 PCT/US99/14251 93 Example 159 3-(3,4-Dimethoxybenzenesulfonyl)-5-phenylpentanoic acid hydroxyamide.

MS (APCI; Loop) m/z 394 Example 160 3-(3,4-Dimethoxybenzenesulfonyl)-5-(3-phenoxyphenyl)pentanoic acid hydroxyamide.

MS (APCI; Loop) m/z 486 (M+H) 4 Example 161 5-(4-Benzyloxyphenyl)-3-(3,4-dimethoxybenzenesulfonyl)pentanoic acid hydroxyamide.

MS (APCI; Loop) m/z 500 Example 162 2- {(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy-phenyl]methyl}-4-methylpentanoic acid hydroxyamide.

Step A: Wang resin (2 g, 1.5 mmol) is swelled in 20 mL of anhydrous DMF for 15 minutes.

Then a solution of the phosphonoacetic acid in DMF (1.13 g, 4.5 mmol) is added followed by pyridine (0.71 g, 9 mmol) and 2,6-dichloro-benzoyl chloride (0.94 g, 4.5 mmol). The mixture is agitated for hours at room temperature. The resin is filtered and washed successively with DMF H 2 0 (3x), DMF THF (1Ox) and Et20 (1Ox) followed by drying in vacuo at 40 oC for 20 hours. IR (micro) u c=o 1730cm' Step B: The loaded resin from Step A (0.5 g, 0.375 mmol) is swelled in anhydrous THF (5 mL) for minute followed by the addition of a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (2 mL) at 0°C. The mixture is allowed to warm up to room temperature and is shaken for 30 minutes. The solvent is drained to the top of the resin followed by the addition of anhydrous cyclohexane(10 mL) and the aldehyde (0.25 g, 1 mmol). The mixture is shaken for approximately 72 hours and worked up as described in Step A. IR (micro) u c=o 1704 cm-' StepC: To a solution of 3,4 dimethoxybenzenethiol( 1.9 g, 70 mmol) in anhydrous THF (54.4 mL) at 0°C is added a 2.5 M solution ofn-butyllithium (5.6 mL, 14 mmol) and the solution is stirred at room temperature for 15 minutes.

The resin from step 2 (0.2 g, 0.15 mmol) is swelled in anhydrous THF (2.5 mL) for 15 minutes and 4 mL of the above prepared 1 N thiol/thiolate stock solution is added. The mixture is shaken for approximately 100 hours and worked up as described in step 1. The thiol addition did not go to completion as evidenced by IR spectra (u c=o 1703 The reaction is driven to completion by repeating the above procedure twice. IR (micro) u c=o 1731 cm-' WO 99/67192 WO 9967192PCT/US99/14251 94 Step D: The resin from Step C (0.2 g, 0. 15 mmol) is swelled in dioxane (5 mL) for 15 minutes and a solution of m-chloroperoxybenzoic acid (0.44 g, 2.5 mmol) in 2 mL of dioxane is added. The mixture is shaken for 16 hours and worked up as described in step 1.

Step E: The resin from Step D (0.2 g, 0. 15 mmol) is treated with 1: 1 dichloro-methane/ trifluoroacetic acid (3 mL) for 1-2 hours. The resin is filtered and washed with dichloromethane (2x] mL). The combined filtrates are concentrated in vacuo to provide 2-{(3,4-dimethoxybenzenesulfonyl)- [4-(4-fluorobenzyloxyphenyl]methyl}-4-methylpentanoic acid (40 mg). 'H NMR (300 MHz, CDCI 3 0.7-1.1 (2xd, 6H), 1.55 (in, I 1.85 (in, I 2.35 (in, I 3.65 3H), 3.85 3H), 4.18 I1H), 4.9 2H), 6.6-7.4 (series of mn, 1 IH). MIS (H-isp; Loop) m/z 548 531 Step F: The hydroxylamine bound Rink resin 1 g, 0.031 minol) is swelled in anhydrous DMF (I inL) for 15 minutes followed by the addition of 1-(3-diinethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mng, 0. 1 inmol) and a solution of the carboxylic acid from step 5 in I mL of anhydrous DMF. The mixture is shaken for 20 hours and worked up as described in step A.

Step G: The resin from Step F 1 g, 0.031 mmol) is treated with 9:1 dichloro-methane! trifluoroacetic acid (2 mL) for 1 hour. The resin is filtered and washed with dichloromethane (2xI mL).

The combined filtrates are concentrated in vacuo to provide 2-{(3,4-dimethoxybenzenesulfonyl)-[4-( 4 fluorobenzyloxy-phenyljmethyl)}-4-methylpentanoic acid hydroxyam ide (2.3 mg). MIS (H-isp; LCMS) m/z 546 (M+H) t Examples 163-183 The following hydroxamic compounds are synthesized using appropriate starting materials and following the steps of this example: Example 163 3-(3 ,4-dimethoxybenzenesulfonyl)-7-phenyl-2-(4-phenylbutyl)heptanoic acid hydroxyainide.

MS (APCI; LCMS) m/z 554 Example 164 2- [1-(3-(3,4-dimethoxybenzenesulfonyl)-5-phenylpentyl]-N I -hydroxy-N 4-methyl-N 4phenylsuccinamide.

MS (APCI; LCMS) m/z 568 Example 165 3-(3,4-dimetboxybenzenesulfonyl)-7-phenyl-2-(3-phenylpropyl)heptanoic acid hydroxyamide.

MIS (APCI; LCMS) m/z 540 Example 166 3-(3,4-diinethoxybenzenesulfonyl)-2-isopropyl-7-phenylheptanoic acid hydroxyainide.

PCTIUS99/14251 WO 99/67192 PTU 9I4S 95 MIS (APCI; LCMS) m/z 464 Example 167 3-(3,4-dimethoxybenzenesulfonyl)-2-isobutyl-7-phelheptaloic acid hydroxyamide.

MS (APCI; LCMS) m/z 478 Example 168 3-(3 ,4-dimethoxybenzenesulfofl)-7-phelyl-2-propylheptaloic acid hydroxyam ide.

MS (APCI; LCMS) mlz 464 Example 169 3-(3 ,4-dimethoxybenzenesulfonyl)-7-phelyl-2-(4-phel-butyl)heptaloic acid hydroxyam ide.

MS (APCI; LCMS) m/z 450 Example 170 3-(3 ,4-dimethoxybenzenesu lfonyl)-2-[2-(2-methoxyethoxy)ethyl]-7-phelheptaloic acid hydroxyamide.

MIS (APCI; LCMS) m/z 524 Example 171 3-(3 ,4-dimethoxybenzenesulfonyl)2benzenesufoflylethyl-7-phelheptaloic acid hydroxyam ide.

MS (APCI; LCMS) m/z 590 Example 172 3..(3,4-dimethoxybenzenesulfonyl)-7-phelyl-2-(5-phelpeltyl)heptaloic acid hydroxyamide.

MS (APCI; LCMS) m/z 568 Example 173 4-Benzenesulfonyl-2- .4-dimethoxybenzenesulfonyl)- [4-(4-fluorobenzyloxy)phenylflmethyl)}-Nhydroxy-butyramide.

MS (APCI; LCMS) m/z 658 Example 174 2- {(3,4-dimethoxybenzenesulfonyl)- [4-(4-fluorobenzyloxy)phenyllmethyl)}-N-hydroxy-4-pheflylbutyramide.

MS (APCI; LCMS) m/z 594 Example 175 2- {(3,4-dimethoxybenzenesulfony)-[4-(4-fluorobel~oxy)phellmethyl} -N-hydroxy-4-(2methoxyethoxy)butyraniide.

MS (APCI; LCMS) m/z 592 (M+H)Y.

WO 99/67192 PCTIUS99/14251 96 Example 176 2- (3,4-d imethoxybenzenesufony )[4(4fluorobezyioxy)phefl inethyl)4 -N-hydroxy-butyram ide.

MS (APCI; LCMS) mlz 518 Example 177 2- (3 ,4-dimethoxybenzenesulfonyl) [4(4-fluorobelzyylX)Phefll iethyl)4 -pentano ic acid hydroxyam ide.

MS (APCI; LCMS) m/z 532 Example 178 2- ,4-dimethoxybenzenesulfonyl)- [4-(4-fl uorobezyloxy)phell mnethyl)} -4-methy lpentanoi c acid hydroxyam ide.

MIS (APCI; LCMS) mlz 546 Example 179 2- ,4-dimethoxybenzenesulfonyl)-[4(4-fluorobenzyoxy)phelmlethyl 4-N-hydroxy-3methylbutyramide.

MS (APCI;- LCMS) mlz 532 (M+H) 4 Example 180 ,4-dimethoxybenzenesulfonyl)-[4-(4-fuorobelzyoxy)phellmethyl)4-7-phenylheptanoic acid hydroxyamide.

MS (APCI; LCMS) mlz 636 Example 181 2- ,4-dimethoxybenzenesufonyl)- [4-(4-fluorobeloxy)phefl inethyl 5-phenyl pentanoic acid hydroxyamide.

MS (APCI; LCMS) m/z 608 Example 182 2- {(3,4-dimethoxybenzenesulfony)[4(4fuorobezyloxy)Pheljmethyl 4-N I -hydroxy-N 4-methyl-N 4-phenyl-succinim ide.

MIS (APCI; LCMS) mlz 63 7 Example 183 2- {(3,4-dimethoxybenzenesulfonyl)-I4(4-fluorobelzyloxy)phefllm~ethyl)}-6-phenylhexanoic acid hydroxyamide.

MIS (APCI; LCMS) mlz 622 Example 184 WO 99/67192 PCT/US99/14251 97 3-(4-methoxybenzenesulfonyl)-3-(4-ethoxyphenyl)propionic acid hydroxyamide.

Step A: Wang resin (20 g, 15 mmol) is swelled in 300 mL of anhydrous DMF for 15 minutes.

Then a solution of diethyl phosphonoacetic acid (8.83 g, 45 mmol) in 50 mL of DMF is added followed by pyridine (7.12 g, 90 mmol) and 2,6-dichlorobenzoyl chloride (9.4 g, 45 mmol). The mixture is agitated for 20 hours at room temperature. The resin is filtered and washed successively with DMF (3x), H,O DMF THF (10x) and EtzO (1Ox) followed by drying in vacuo at 40 oC for 20 hours. IR (micro) u c=o 1738 cm-' Step B: The loaded resin from Step A (1 g; 0.63 mmol) is swelled in anhydrous THF (10 mL) for minute followed by the addition of a 1 M solution of lithium bis(trimethylsilyl)amide in THF (1.6 mL; 1.57 equiv.) at 0 oC. The mixture is allowed to warm up to room temperature and is shaken for minutes. The solvent is then drained to the top of the resin followed by the addition of anhydrous cyclohexane (10 mL) and 4-ethoxy-benzaldehyde (0.5 g; 3.3 mmol). The mixture is shaken for approximately 72 hours. The resin is then filtered and washed successively with DMF HO (3x), DMF THF (10x) and EtO (10x) followed by drying in vacuo at 40 °C for 20 hours. IR (micro) u c=o 1709 cm'' Step C: To a solution of 4-methoxybenzene thiol (0.6 mL; 5 mmol) in anhydrous THF (1 mL) at 0 °C is added n-butyllithium (2.5 M in hexanes; 0.02 mL; 0.05 mmol) and the solution is stirred at room temperature for 15 minutes. The resin from step 2 (1 g; 0.63 mmol) contained in a polypropylene peptide synthesis cartridge is swelled in anhydrous THF (10 mL) for 15 minutes. The above prepared 1 N thiol/thiolate stock solution is added. The mixture is shaken for approximately 100 hours. The resin is then filtered and washed successively with DMF H,O DMF THF (lOx) and Et,O followed by drying in vacuo at 40 oC for 20 hours. IR (micro) u c=o 1734 cm-' Step D: The resin from Step C (1 g, 0.63 mmol) is swelled in 1,4-dioxane (5 mL) for 15 minutes and a solution of m-chloroperoxybenzoic acid (0.863 g; 5 mmol) in 2 mL of 1,4-dioxane is added. The mixture is shaken for 16 hours, the resin is then filtered and washed successively with DMF HO DMF THF (1Ox) and Et,O (1Ox) followed by drying in vacuo at 40 "C for 20 hours.

Step E: The resin from Step D (1 g, 0.63 mmol) is treated with 1:1 dichloromethane/trifluoroacetic acid (8 mL) for 1-2 hours. The resin is filtered and washed with dichloromethane (2 x 1 mL). The combined filtrates are concentrated in vacuo to provide 3-(4methoxybenzenesulfonyl)-3-(ethoxy-phenyl)propionic acid 84 mg; 'H NMR (300 MHz, CDCI 3 d3) 5 1.42 J 9.0 Hz, 3H); 3.08 (dd, J 10.8 Hz, 1H); 3.44 (dd, J 7.2 Hz, 1H); 3.86 3H 4.02 (q, J 9.0 Hz, 2H); 4.54 (dd, J 7.1 Hz, 1H); 6.72 J 12.6 Hz, 2H); 6.82 J 12.3 Hz, 2H); 6.98 J 12.4 Hz, 2H); 7.42 J 12.3 Hz, 2H); 7.52 (bs, 1H). MS (H-isp; LCMS); m/z 387 382 365 WO 99/67192 PCT/US99/14251 98 Step F: The hydroxylamine bound Rink resin (200 mg, 0.04 mmol) is swelled in anhydrous DMF (1 mL) for 15 minutes followed by the addition of 1-(3-dimethyl-aminopropyl)- 3 ethylcarbodiimide hydrochloride (38 mg, 0.2 mmol) and a solution of the carboxylic acid from step 5 (84 mg; 0.2 mmol) in 1 mL of anhydrous DMF. The mixture is shaken for 20 hours. The resin is then filtered and washed successively with DMF HO DMF THF (1Ox) and Et20 (lOx) followed by drying in vacuo at 40 oC for 20 hours.

Step G: The resin from Step F (200 mg; 0.04 mmol) is treated with 1:1 dichloromethane/trifluoroacetic acid (3 mL) for 30 minutes. The resin is filtered and washed with dichloromethane (2 x 1 mL). The combined filtrates are concentrated in vacuo to provide 3-(4methoxybenzenesulfonyl)-3-(4-ethoxyphenyl)propionic acid hydroxyamide (9.6 mg). MS (H-isp; LCMS); m/z 402 [M+Na] 380 Examples 185-189 The following hydroxamic compounds are synthesized using appropriate starting materials and following the steps of Example 184.

Example 185 3-(4-methoxybenzenesulfonyl)-3-(4-biphenyl)propionic acid hydroxy amide) MS (H-isp; LCMS); m/z 412 [M+H] t A% 89% 220 nm Example 186 3-(4-methoxybenzenesulfonyl)-3-(4-phenoxyphenyl)propionic acid hydroxy amide MS (H-isp; LCMS); m/z 428 A% 75% 220 nm Example 187 3-(4-methoxybenzenesulfonyl)-3-(4-benzyloxyphenyl)-propionic acid hydroxy amide MS (H-isp; LCMS); m/z 442 A% 60% 220 nm Example 188 3-(4-methoxybenzenesulfonyl)-3-(4-fluorobenzyloxyphenyl)-propionic acid hydroxy amide MS (H-isp; LCMS); m/z 460 A% 68% 220 nm Example 189 3-(4-methoxybenzenesulfonyl)-3-(4-(3-trifluoromethylphenoxy)-phenyl-propionic acid hydroxy amide MS (H-isp; LCMS); m/z 496 A% 74% 220 nm

EDS

The energy dispersive x-ray measurements are made with an Electroscan Scanning Electron Microscope with an attached PGT digital detector. The beads are mounted on aluminum stubs and tested 99 without a conductive coating. The net x-ray counts are reported after correction for the background. No corrections are made for atomic number, fluorescence or absorption.

Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

e*

S

Claims (11)

1. A polymeric N-protected hydroxylamine resin compound of formula W YP H wherein is a solid support; P is ana amine Protecting group, provided that P is other than 4-methoxyberyl or 2,4- dirnethoxybenzyl; and L is a group of formula wherein R' and R 2 are independently H or F and R" and R 2 are independently ring system substituents provided that R' ,R 2 ,RO and W"2 are not simultaneously F; and one of R' and R' is H and the other is H or 2,4-dimethoxyphenyt. S S S. S S *S.S S S S 101

2. A polymeric N-protected hydroxylamine resin compound according to claim 1 where P is allyloxycarboyl, benzyloxycarbonly, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, trim ethyl silyl ethoxyca rbonYl, 2,4- dimethoxybenzyloxyca rbonyl, o-nitrobenzyloxycarboflYl, o-nitrobenzylsulfonyl, p- nitrobenzylsulfonyl, and 2-n itro-4-trifl uo rom ethyl belze n e su fonyl.

3. A polymeric N-protected hydroxylamine resin compound according to claim 2 wherein P is allyloxycarbonyl.I

4. A polymeric fluorophynyl hydroxylamine resin compound of formula Ftle fe A ONMP' R" F R wherein is a solid support; A is absent or a group of formula wherein X1 is -CHR- or wherein R is H, alkyl, phenyl, or phenyl substituted with -,alkyl, alkoxy. halogen, nitrIle or -NO 2 RW, WO, and R'O are ring system substituents provided that R 2 8, e 2 and are not simultaneously 1F; or R 8 and 03 taken together with the carbon atoms through which they are linked form a 6 nmembered aryl or a 5 tO 6 memnbered heteroaxyl, Y is or -NH-, n is an integer from I to 6, and Z is or -NH-; R' and R 4 are independently alkyl, phenyl, or phenyl substituted with one or more substituents selected from alkyl, alkoxy, halogen nitrile and -NO 2 and P' is H or an amine protecting group. 102 A polymeric fluorophenyl hydroxylamine resin compound according to claim 4 wherein A is and R 2 1, R 29 and R 30 are fluoro groups.

6. A polymeric fluorophenyl hydroxylamine resin compound according to claim 5 wherein one of R 3 *and R 4 is H and the other is H or 2,4- dimethyoxyphenyl.

7. A polymeric fluorophenyl hydroxylamine resin compound according to claim 6 wherein P 1 is H.

8. A polymeric fluorophenyl hydroxylamine resin compound according to claim 7 wherein P 1 is allyloxycarbonyl.

9. A polymeric fluorophenyl hydroxylamine resin compound according to claim 7 which is 4-(0-methylhyd roxylamine)-2 ,3,5,6-tetrafluorophenoxymlethyl- copoly(styrene-1 divinyl benzene) resin or ,-dimethoxyphenyl-0- methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethylcopoly(styrene-1 divinylbenzene) resin. 103 A process for preparing a a,p-unsaturated alkenoate resin compound of formula 0 L-O Rn Rm wherein is a solid support; L is absent or a linking group; is H or aliphatic; and R, is aliphatic or aromatic. comprising treating a mixture contained in a reaction vessel of a first solvent and a polymeric phosphonoacetoxy resin compound of formula 0 0 O-L-o- 20 OR 21 wherein R20 and R21 are alkyl; with excess base; draining the solvent from the reaction vessel; and adding a solution of an aldehyde of formula R,,CHO in a less polar second solvent. S 104

11. The process of claim 10 wherein L is a linking group.

12. The process of claim 11 wherein L is a linking group of formula R 2 a wherein A is absent or a grroup of formula wherein XV is -CI-R- or -CHR-Y-CO-(CH 2 wherein R is H, alkyl, phenyl, or phenyl substituted with alkyl, alkoxy, halogen, nitrile or -NO, Y is or -NH-. n is an integer from 1 to 6, and Z is or -NH-; RiaB, R 2 .and R 2 are independently ring system substittuents; and R' and R' are independently alkyl, phenyl, or phenyl substituted with one or more substituents selected from alkyl, alkoxy, halogen nitrile and -NO 2 or one of R' and R 2 taken together with One of R 3 and R' and the carbon atoms to which they are attached define a linking gyroup of formula 9O 0 0e 0 *000 000* *000 *0 0 0 *00* 0000 0* *0 0 *000 *000 0 *0*0 0 *00000 wherein R" is alkyl, alkoxy. halogen, nitrile or and R' and R' are independently selected from 411, alkyl, alkoxy. halogen, nitrile or -NO,.

29- 9-03:15:25 :WATERMARK PATENT:6 398 600# 4 6 1 3 9 8 1 9 6 a 1 0 4/ 105 13. The process of claim 12 wherein L is a group of formula RI R 1 0 R 3 -CHi- 0 +R/ R 2 R 23 wherein R' and R 2 are independently H or F; and R2' are independently ring system substituents; and one of W 3 and R" is H and the other is H or 2,4-dimethoxyphenyl. 14. The process of claim 13 wherein the second sblvent comprises the first solvent and an alkane or cycloalkane. The process of claim 14 wherein the first solvent is tetrahydrofuran and the second solvent is cyclohexane. 16. The process of claim 15 wherein the second solvent is 60% cyclohexane- tetrahydrofuran. DATED this 29th day of September 2003 AVENTIS PHARMACEUTICALS INC WATERMARK PATENT TRADE MARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 312'2 AUSTRALIA KJSIKMHIMEH P1 8652AUOO COMS ID No: SMBI-00434851 Received by IP Australia: Time 15:38 Date 2003-09-29