ZA200200435B - Fungicidal heterocyclic aromatic amides and their compositions, methods of use and preparation. - Google Patents

Description

FUNGICIDAL HETEROCYCLIC AROMATIC AMIDES AND THEIR COMPOSITIONS,

METHODS OF USE AND PREPARATION

Priority Claim

This application claims a priority based on provisional applications 60/149,977 and 60/150,248 which were filed in the U.S.

Patent and Trademark Office on August 20, 1999 and August 23, 1999 respectively, the entire disclosures of which are hereby incorporated by reference. Provisional applications 60/149, 977 and 60/150,248 both claim a priority from provisional application 60/144,646 which was filed on July 20, 1999, the entire disclosure of which is hereby incorporated by reference.

This application claims a priority from non-provisional application 09/620,662 which was filed on July 20, 2000, the entire disclosure of which is hereby incorporated by reference. :

BACKGROUND OF THE INVENTION Field of the Invention:

The present invention relates to the field of fungicidal compositions and methods. More particularly, the present invention concerns novel fungicidal heterocyclic aromatic amides and methods involving application of fungicidally effective amounts of such compounds to the locus of a plant pathogen. The present invention also concerns methods useful in the preparation of heterocyclic aromatic amides and their fungicidal compositions.

Description of the Prior Art:

A variety of antifungal compositions and methods are well known in the art. Antimycin, for example, has been identified as a naturally occurring substance produced by Streptomyces spp. with ot ~ WO 01/14339 PCT/US00/21523 antibiotic properties (Barrow, C. J.; et al., Journal of

Antibiotics, 1997, 50(9), 729). These substances have also been found to be effective fungicides (The Merck Index, Twelfth Edition,

S. Budavari, Ed., Merck and Co., Whitehouse Station, N.J., 1996, p. 120). WO 97/08135 describes acylaminosalicylic acid amides which are useful as pesticides. EP-A-0-661269 discloses substituted heterocyclic carboxylic acid amides useful as medical drugs. Jp-A- 7-233165 discloses antifungal dilactones having 3- hydroxypyridinecarboxyl groups with antimycotic action. The iso- butyryl, tigloyl, iso-valeryl and 2-methylbutyryl derivatives of these latter compounds are further described in the following references: Tetrahedron 1998, 54, 12745-12774; J. Antibiot. 1997, 50(7), 551; J. Antibiot. 1996, 49(7), 639; J. Antibiot. 1996, 49(12), 1226; and Tetrahedron Lett. 1998, 39, 4363-4366.

However, there has remained a need for new fungicides. The present invention provides fungicides which have a high residual activity, greater activity at lower application rates, curative activity, and a broader spectrum of efficacy.

SUMMARY OF THE INVENTION

Briefly describing one aspect of the present invention, there are provided compounds comprising heterocyclic aromatic amides (HAA) of the Formula I:

OM

H - / N—A i

ZO .

XX, Z

Formula I wherein X;-X,, M, Z, and A are hereafter defined. The invention also encompasses hydrates, salts and complexes thereof.

The present invention also provides fungicidal compositions comprising the HAA in combination with phytologically acceptable carriers and/or diluents. Methods for the use of the heterocyclic aromatic amide compounds and compositions are also disclosed.

It is an object of the present invention to Provide HAA and compositions thereof which are effective as antifungal agents.

Another object of the present invention is to provide methods for the control and/or prevention of fungal infestations, which methods include the application of HAA and compositions containing same.

Further objects and advantages of the present invention will be apparent from the description which follows.

General Scope of the Invention

The present invention relates to various HAA compounds which are active as antifungal agents. Also included are formulations including the HAA compounds, and methods of using the HAA compounds and formulations. The methods of preparing the HAA compounds are also encompassed by the present invention and their method of preparation and use as fungicides.

HAA Compounds

The novel antifungal HAA compounds of the present invention are described by the following Formula I: i

OM

H

/ N—A “eo

X3—X, Z

Formula I

- + WO 01/14339 PCT/US00/21523 wherein: “eo

XX a. represents a 5- or 6-membered heterocyclic aromatic ring in which (i) each of X,-X, is independently 0, S, NR’, N,

CR” or a bond; (ii) no more than one of X,-X, is 0, S or NR’; (iii) no more than one of X,-X, is a bond; (iv) when any one of X,-X, is S, O or NR’, one of the adjacent X,-X, must represent a bond; and (v) at least one of X,-X, must be O, S, NR’ or N; wherein

R’ is H, C,-C, alkyl, C,-C, alkenyl, C,-C, alkynyl, hydroxy, acyloxy, C,-C, alkoxymethyl, CHF,, cyclopropyl or C,-C, alkoxy; and R” is independently H, halogen, cyano, hydroxy, C,-C, alkyl, C,-C; haloalkyl, cyclopropyl, C,-C, alkoxy,

C,-C; haloalkoxy, C,-C, alkylthio, aryl, ¢,-c,

NHC (0) alkyl, NHC(O)H, C,-C, halecalkylthio, C,-C, = alkenyl, C,-C, haloalkenyl, C,-C, alkynyl, C,-C, ) haloalkynyl or nitro wherein adjacent R” : substituents may form a ring or adjacent R‘’ and

R” substituents may form a ring; b) Z is O, S or NOR, in which R, is H or C,-C, alkyl; and c) A represents (i) C,-C,, alkyl, C,-C,, alkenyl, or C,-C,, alkynyl, all of which may be branched or unbranched, unsubstituted or substituted with halogen, hydroxy, nitro, aroyl, aryloxy, C,-C, acyloxy, C,-C, alkylthio, arylthio, aryl, heteroaryl, heteroarylthio, heteroaryloxy, C,-C¢ acyl,

C,-C¢ haloalkyl, C,-C, alkoxy or C,-C, haloalkoxy, (ii) C,-C,, cycloalkyl, containing 0-3 heteroatoms and 0-2 unsaturations, which may be unsubstituted or substituted with halogen, hydroxy, C,-Cs alkyl, C,-c, haloalkyl, cyano, nitro, aroyl, aryloxy, heteroaryloxy,

C,-C¢ alkylthio, arylthio, heteroarylthio, C,-C¢ alkoxy,

C,-C¢ haloalkoxy, C,-C, acyloxy, aryl, heteroaryl, C,-cC, acyl, carboaryloxy, carboheteroaryloxy, C,-C¢ carboalkoxy or amido unsubstituted or substituted with one or two C,-C; alkyl groups, (iii) C4-C,, bi- or tricyclic ring system, containing O- 3 heteroatoms and 0-2 unsaturations, which may be unsubstituted or substituted with halogen, hydroxy, C,-

Ce alkyl, C,-C; haloalkyl, cyano, nitro, aroyl, aryloxy, heteroaryloxy, C,-C, alkylthio, arylthio, : heteroarylthio, C,-C, alkoxy, C,-C, halocalkoxy, C,-Cq acyloxy, aryl, heteroaryl, C,-C; acyl, carboaryloxy, carboheteroaryloxy, C,-C, carboalkoxy or amido - unsubstituted or substituted with one or two C,-C; alkyl : groups, (iv) aryl or heteroaryl, which may be unsubstituted or substituted with nitro, C,-C, alkyl, C,-C, haloalkyl, C,-

C¢ cycloalkyl, C,-C, alkenyl, C,-C, alkynyl, aryl, heteroaryl, halogen, hydroxy, C,-C, alkoxy, C,-Cq haloalkoxy, carboaryloxy, carboheteroaryloxy, C,-C

- ~ WO 01/14339 PCT/US00/21523 carboalkoxy or amido unsubstituted or substituted with one or two C,-C¢ alkyl groups, C,-C¢ alkylthio, C,-Cs alkylsulfonyl, C,-C alkylsulfinyl, C,-C, OC (0) alkyl, oc (0)aryl, C,-C, OC (0) cycloalkyl, C,-C, NHC (0) alkyl, C,-C;

NHC (0) cycloalkyl, NHC (0O)aryl, NHC (O) heteroaryl, C,-C, cycloalkylthio, C,-C, cycloalkylsulfonyl, C,-C, cycloalkylsulfinyl, aryloxy, heteroaryloxy, hetercarylthio, hetercarylsulfinyl, heteroarylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, C(O)R,, C (NOR) Ry, in which any alkyl or cycloalkyl containing substituent may be substituted with one or more halogens and in which any aryl or heteroaryl containing substituent may also be unsubstituted or substituted with halogen,

Cyano, nitro, aroyl, aryloxy, aryl, heteroaryl, c,-c, . acyl, C,-C¢ haloalkyl, C,-C, alkoxy, C,-C¢ haloalkoxy, c,-

C¢ carboalkoxy or amido unsubstituted or substituted with one or two C,-C4 alkyl groups, where R, and R, are independently H, C,-C, alkyl, C;-C, alkenyl, C,-C, cycloalkyl, aryl or heteroaryl, and (v)

H i we or o "Rg iy 0 AVR where * = point of attachment - H H = R, .

R, Q, 5 ® in which N

Qi. Q, are O or S;

W is O, CH,, CHR,, or a bond;

R, is C,-C, alkyl, C,-C, alkenyl, C.-C, alkynyl, C,-

Cy cycloalkyl, aryl or heteroaryl;

R, is H, C,-C, alkyl, C,-C; alkenyl or C,-C, alkynyl;

R, is H, R,, OR,, OC(O)R,, OC(O)OR, or OC(O)NR,R,;

R, and R; are independently H, C,-C, alkyl, or C,-C, alkenyl, provided that the sum of carbons for

R, plus Ry is six or less, and further provided that R, and R, may be joined into a C,-C; ring;

R, and R, are independently H, C1-Cé alkyl, C3-Ce6 cycloalkyl, C2-C5 alkenyl or C2-CS5 alkynyl provided that at least one of R, and R, is H; with the proviso that when

OM

H

/ N—A “oe

X5—X, Z is " 0

R H H CH, — A YR

HN wo © CHC, \_,7 Het APY

[0] H u H 3 oc— R bo : wherein :

R" is H or OCH,, then

R, is not isobutyryl, tigloyl, isovaleryl, or 2-methylbutanoyl;

: © WO 01/14339 PCT/US00/21523 d) M represents

H, Si(t-Bu)Me,, Si(Ph)Me,, SiEt,, SiMe,, C(Z)R,, SO,R, where R, is H, C,-C,; alkyl, C;-Cs alkenyl, C,-C; alkynyl,

C,~C¢ cycloalkyl, alkoxyalkyl, haloalkyl, alkoxyalkenyl, haloalkenyl, alkoxyalkynyl, haloalkynyl, substituted and unsubstituted arylalkyl, substituted and unsubstituted arylalkenyl, substituted and unsubstituted arylalkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, C,-C; alkoxy, C,-C¢ cycloalkoxy, C,-C, haloalkoxy, C,-C¢ alkenyloxy, C,-C haloalkenyloxy, C,-C alkynyloxy, C,-Cs haloalkynyloxy, C,-C, thioalkoxy, substituted and unsubstituted arylalkoxy, substituted and unsubstituted arylalkenyloxy, substituted and unsubstituted arylalkynyloxy, substituted and unsubstituted aryloxy, substituted and unsubstituted heteroaryloxy, amino unsubstitued or substituted with one or two C,-C, alkyl groups, and R, is C.-C alkyl, C,-

Cs alkenyl, C,-C, alkynyl, C,-C, cycloalkyl, aryl, or heteroaryl.

The terms alkyl, alkenyl, alkynyl and the like, as used herein, include within their scope both straight and branched groups; the terms alkenyl, alkenylene and the like are intended to include groups containing one or more double bonds; and the terms alkynyl, alkynylene and the like are intended to include groups i containing one or more triple bonds. Cycloalkyl, as used herein, : refers to C,-C,, cycloalkyl groups containing 0-3 heteroatoms and 0- ) 2 unsaturations. Bi- or tricyclic ring systems refers to Cs-C,4 aliphatic ring systems containing 0-3 heteroatoms and 0-2 unsaturations. The foregoing terms further contemplate either substituted or unsubstituted forms. Unless specifically defined otherwise, a substituted form refers to substitution with one or more groups selected from halogen, hydroxy, cyano, nitro, aroyl,

aryloxy, aryl, arylthio, heteroaryl, heteroaryloxy, heteroarylthio,

C.-C, acyl, C,-C, haloalkyl, C,-C¢ alkoxy, C,-C; haloalkoxy, C,-C, alkylthio, C,-C, haloalkylthio, carboaryloxy, carboheteroaryloxy,

C.-C; carboalkoxy or amido unsubstituted or substituted with one or two C,-C¢ alkyl groups. All of the above terms and definitions assume that the rules of chemical bonding and strain energy are satisfied.

The term aryl as used herein refers to a substituted phenyl or naphthyl group. The term heteroaryl refers to any 5 or 6 membered aromatic ring containing one or more heteroatoms; these heteroaromatic rings may also be fused to other aromatic systems.

The foregoing terms further contemplate either substituted or unsubstituted forms. A substituted form refers to substitution with one or more groups selected from nitro, C,-C, alkyl, C,-Cs haloalkyl, C,-Cs cycloalkyl, C,-C, alkenyl, C,-C; alkynyl, aryl, heteroaryl, halogen, hydroxy, C,-C, alkoxy, C,-C; haloalkoxy, C,-C, . alkylthio, C,-C¢ alkylsulfonyl, C,-C, alkylsulfinyl, C,-C; OC(0O)alkyl,

OC(O)aryl, C,-Cg OC(0O)cycloalkyl, C,-C, NHC(O)alkyl, C,-C

NHC (0) cycloalkyl, NHC(O)aryl, NHC(O)heteroaryl, C,-C, cycloalkylthio, C;-C, cycloalkylsulfonyl, C;-C, cycloalkylsulfinyl, aryloxy, heteroaryloxy, heteroarylthio, heterocarylsulfinyl, heteroarylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, C(O)R,,

C(NOR,)Ry where Ry, and R, are independently H, C,-C, alkyl, C,-C, alkenyl, C,-Cs cycloalkyl, aryl or heteroaryl in which any alkyl or cycloalkyl containing substituent may be substituted with one or more halogens and provided that the rules of chemical bonding and i strain energy are satisfied. N

The terms halogen and halo as used herein include chlorine, bromine, fluorine and iodine. The terms haloalkyl and the like refer to groups substituted with one or more halogen atoms.

The term Me as used herein refers to a methyl group. The term Et refers to an ethyl group. The term Pr refers to a propyl

. © WO 01/14339 PCT/US00/21523 group. The term Bu refers to a butyl group. The term Ph refers to a phenyl group. The term EtOAc refers to ethyl acetate.

The term alkoxy as used herein refers to a straight or branched chain alkoxy group. The term haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms.

The term heteroatom as used herein refer to O, S and N.

The preferred 5- or 6-membered heterocyclic aromatic rings of the formula

Vo . “e)

XX include the appropriate isomers of pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, pyrazole, imidazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, and thiadiazole. The most preferred heterocyclic aromatic rings are pyridine, pyrimidine, pyrazine, pyridazine, thiazole, isothiazole, thiadiazole, and oxazole. Particularly preferred compounds of

Formula I are based upon 2-amido-3-hydroxypyridine, 2-amido-3- hydroxy-4-methoxypyridine, 2-amido-3-hydroxypyrazine, and 4-amido- 5-hydroxypyrimidine.

It will be appreciated that certain combinations of - substituent groups for compounds which fall within the definitions R given herein will be impossible to prepare for steric and/or chemical reasons. Such compounds are not included within the scope of the invention.

Various hydrates, salts and complexes of compounds of Formula

I can be made in the conventional ways. For example, salts may be formed by replacing the hydroxyl hydrogen atom (M = H) with a cation, for example NH,*, ‘N(Bu),, K', Na’, ca®, Li", Mg*, Fe®, cu®, etc. These derivatives are also useful in accordance with the present invention.

Throughout this document, all temperatures are given in degrees Celsius (°C) and all percentages are weight percentages, unless otherwise stated. The term ppm refers to parts per million.

The term psi refers to pounds per square inch. The term m.p. refers to melting point. The term b.p. refers to boiling point.

Preparation of Compounds

The compounds of this invention are made using well known chemical procedures. The required starting materials are commercially available or readily synthesized utilizing standard procedures.

GENERAL PREPARATION OF PYRIDINE-2 «CARBOXAMIDES.

The desired HAAs (2) are prepared by reacting the appropriate ortho-hydroxyheterocaromatic carboxylic acid (1) with an amine in the presence of a coupling reagent (phosgene or 1-[3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI)) plus l1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) and an acid scavenger, e.g. N-methylmorpholine (NMM), triethylamine, 4- (dimethylamino) pyridine (DMAP), or diisopropylethylamine) (Scheme 1). In some cases acid chlorides with protected hydroxy groups such as (3) could be reacted with the - appropriate amine to give the intermediate amides (4). Removal of J the protecting groups via hydrogenation in the presence of a - palladium (Pd) catalyst gives the desired product (2X). Capping the hydroxyl group of the heterocycle in compound 2 with an acyl, sulfonyl, or silyl group (M) can be readily accomplished by reacting the appropriate 2 with a carboxylic acid chloride, sulfonyl chloride, or silyl chloride (MCl) in a suitable solvent such as pyridine, using an acylation catalyst such as DMAP, to

: © WO 01/14339 PCT/US00/21523 provide the corresponding O-acyl, O-sulfonyl, or O-silyl derivative

Q iPNEt ANH, N—A vol mE, AM

X . COxH Ci Cl THF Et,N \

Xg—X 0

XZ EDCl, HOBt __—" "21 + ANH,

NMM 2 1

MCI

Base

OM

: H

N-—A §

XJ X14 0 2Y

OMe OMe

OMe

OCHoPh Pd/C/H

OCH,Ph EtN =~ ki 2 ZN OH 1] LN TG wm

X NHA X, A > of N

Br” °N Br™ °N I fo) 0) 3 4 2X

Scheme 1

PREPARATION OF THE ORTHO-HYDROXYHETEROAROMATIC CARBOXYLIC ACIDS 1. -

Preparation of carboxylic acids 1 (X, = N, X,= X= CH, X, = . independently C-Me, C-SMe, C-Cl) is shown in Scheme 2. Reaction of ) 3-hydroxy-2-bromopyridine (5) with 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl) using potassium tert-butoxide as the base in a 1:1 mixture of dimethylformamide (DMF) - tetrahydrofuran (THF) gave the desired ether 6. Deprotonation of 6 with lithium diisopropylamide (LDA) followed by condensation with the appropriate electrophile (iodomethane, dimethyldisulfide, or hexachloroethane) gave the 4-substituted pyridine 7.

Bromine/lithium exchange between 7 and n-butyllithium (n-BuLi) followed by carboxylation with carbon dioxide (CO,) and acid hydrolysis gave the necessary 4-substituted-3-hydroxypicolinic acid 1x. 10 .

Zz OH ~ OCH,OCH,CH,SiMe, +4 CICH,OCH,CH SiMe, BUOK _

SN Br DMF/THF >

N Br 5 6

X

OCH,OCH,CH,SiMe, g (NLDA “ (2) Electrophile x

N Br 7

X

. OH ; (1) n-BuLi oY (2) CO, >

N COH

(3) H+ 2 1X

Scheme 2

Alternatively, 3-hydroxypyridine (8) could be condensed with

SEM-Cl to give 9 (Scheme 3). Deprotonation of 9 with tert- butyllithium (t-Buli) followed by condensation with N- ) fluorobenzensulfonimide gave the 4-fluoro derivative 10. -

Condensation of 10 with sodium ethoxide gave the diether 11. :

Deprotonation of 11 with t-BuLi followed by carboxylation and acid hydrolysis gave the desired 4-ethoxypyridine 1X (X = OEt) .

= OH 0 OCH,OCH,CH,SiMe, + semi — \N NY

N N

9 8

F

OCH, OCH.CH_SiMe a 2 22> 2 3 : 9 + tBuli (PhSO,),NF - x

N 10

OEt

OCH,OCH,CH,SiMe, 10 + NaOEt ————— x

N

1"

OEt

OH

. 1 = 11 + t-Buli Mmeco, (2) H* x

N CO,H 1X

Scheme 3

The preparation of acid chloride 3 is outlined in Scheme 4.

Thus, 3-hydroxypicolinic acid (12) was converted to the methyl ester 13 in refluxing methanol using boron trifluoride as catalyst. 13 was then brominated using bromine in aqueous base to give the - dibromide 14. The benzyl ether 15 was then prepared by N condensation of 14 with benzyl chloride in the presence of sodium : hydride. Careful methanolysis of 15 in methanol /potassium carbonate gave the 4-methoxypicolinic acid derivative 16.

Conversion of 16 to the acid chloride 3 was accomplished with oxalyl chloride using benzene as a solvent and a catalytic amount of DMF.

Br

YZ OH YZ OH _ OH — — x x ~

N CO,H N CO,CH, Br N CO,CH, 12 13 14

Br OMe _\_-OCH,Ph A OCHPh 1“ —- | — [1 — a

Br” "N” “CO,CH, Br 'N” "COM 15 16

Scheme 4

PREPARATION OP 4-ETHOXY-3-HYDROXYPICOLINIC ACID (1, X, =N, X, = X, = CH, X, = COEt) (SEE SCHEMES 1 AND 3).

OFEt yZ OH >

N COH a. PREPARATION OF 3-(2- (TRIMETHYLSILYL)ETHOXYMETHOXY) -PYRIDINE (9).

To a stirred mixture of DMF (100 mL) and THF (100 mL), was added solid potassium tert-butoxide (17.96 g, 0.16 mol). After all of the solid had dissolved, the solution was cooled to <5 °C and 3- hydroxypyridine (14.25 g, 0.15 mol) was added all at once. After ] stirring for 10 minutes, the mixture was cooled to -10 °C and SEM- -

Cl, 25 g, 0.15 mol) was added dropwise at such a rate that the : internal temperature remained at ¢<-5 °C. After the addition was complete, the mixture was stirred at 0 °C for 1 hour, then at room temperature for 2 hours. The mixture was poured into water (600 : mL), then extracted with ether (3 x 150 mL). The ether extracts were combined, washed sequentially with 2N NaOH (100 mL), water (50 mL), and saturated NaCl solution (100 mL), dried (MgSO,) and

© WO 01/14339 PCT/US00/21523 concentrated to give a brown liquid. Distillation gave the desired ether 9 as a colorless liquid (20.8 g), b.p. 95-99 °C @ 0.03 mm Hg. b. PREPARATION OF 4-FLUORO-3-(2- (TRIMRTHYLSILYL)ETHOXYMETHOXY) PYRIDINE (10).

To a stirred solution of 9 (12.39 g, 0.055 mol) in ether (200 mL) cooled to <-70 °C under an atmosphere of argon was slowly added t-BuLi (40 mL, 1.5 M pentane solution). During the addition, the reaction temperature was maintained at <-68 °C. After the addition was complete the mixture was stirred an additional 60 minutes at < -70 °C, then transferred via cannula to a stirred solution of N- fluorobenzenesulfonimide (18.92 g) in dry THF (200 mL) which was also cooled to <-70 °C under argon. After the addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature. Water (100 mL) was added and the organic phase was separated, dried (MgSO,) and concentrated to give a brown oil. Chromatography (silica gel, hexane-acetone, 9:1) gave the desired product 10 as an orange oil (7.5 g) which contained about 15% starting material. This crude mixture was used directly in the next reaction. c. PREPARATION OF 4-BTHOXY-3-(2- (TRIMETHYLSILYL) RTHOXYMRTHOXY) PYRIDINE (11).

To a stirred solution of sodium ethoxide (0.9 g, 13 mmol) in ethanel (10 mL) was added all at once 10 (1.07g, 4.4 mmol). The resulting mixture was stirred at room temperature for 48 hours, } then poured into water (100 mL). The resulting mixture was p extracted with ether (3x50 mL). The ether extracts were combined, : dried (MgSO,) and concentrated. The resulting amber oil was chromatographed (silica gel, hexane-acetone, 4:1) to give 11 as a yellow oil (0.6 gq). d. 4-BTHOXY-3-HYDROXYPYRIDINE-2-CARBOXYLIC ACID (1, X, = N, X, = X, = CH, X, = COEt).

A stirred solution of 11 (2.9 g) in THF (50 mL) under an argon atmosphere was cooled to <-70 °C. To this was slowly added t-

BuLi (8 mL, 1.5M pentane solution) while keeping the reaction temperature at <-66 °C. After the addition was complete, the mixture was stirred at <-70 °C for 45 minutes and then poured into a slurry of crushed dry ice in ether. The resulting mixture was stirred until it reached room temperature, then the solvents were evaporated. THF (25 mL) and 4N HCl (15 mL) were added to the residue and the resulting mixture was stirred at room temperature for two hours. At the end of this period, the insoluble material was filtered, washed with a small volume of THF and air dried to give the title compound as a white solid (1.05 g).

PREPARATION OF 6-BROMO-3-BENZYLOXY-4-METHOXYPYRIDINE-2-CARBOXYLIC

ACID (16) AND ITS ACID CHLORIDE (3) (SEE SCHEME 4).

OMe OMe

Po Joos x | SS | Cl

Br N CO,H Br N 16 3 0 a. PREPARATION OF METHYL 4,6-DIBROMO-3-~HYDROXYPYRIDINE-2-

CARBOXYLATE (14).

To a 2 L, 3-necked flask equipped with a dropping funnel and a mechanical stirrer, was added water (800 mL) and methyl 3- hydroxypyridine-2-carboxylate (15.3 g). To this stirred solution - was slowly added bromine (32 g). As the reaction progressed, a a solid separated from solution and the reaction mixture became - difficult to stir. After the addition was complete, the mixture was vigorously stirred until the bromine color disappeared. ‘H-NMR (CDC1,) of a small sample of the crude product showed that it was about a 3:1 mixture of mono to dibrominated product. Sodium carbonate (31.8 g) was carefully added to the reaction mixture and then additional bromine (12 g) was added dropwise. After the bromine color had disappeared, the reaction mixture was adjusted to approximately pH 5 with conc. HCl, and the resulting mixture was extracted with CH,Cl, (3x150 mL). The organic extracts were combined, dried (MgSO,) and concentrated to give an orange solid (14 9g). This material could be recrystallized from methylcyclohexane (after charcoal treatment) to give 14 as a white solid, m.p. 181- 183 °C. b. PREPARATION OF METHYL 4,6-DIBROMO-3-BENZYLOXYPYRIDINE-2-

CARBOXYLATE (15).

Is To a stirred mixture of sodium hydride (0.6 g) in DMF (50 mL) was slowly added 14 (7.1 g). After the addition was complete, the mixture was stirred at room temperature for 15 minutes, then benzyl chloride (3.05 g) was added all at once. The mixture was then heated at 90 °C for six hours, cooled, poured into water (S00 mL) and extracted with ether (2x200 mL). The ether extracts were - combined, washed with 2N NaOH (50 mL), dried (Mgso,) and the solvent was evaporated to give 15 as a light yellow solid (8.3 qg).

Recrystallization from a small volume of methanol gave an analytical sample, m.p. 75-76 °C. ©. 6-BROMO-3-BEN2YLOXY-4-METHOXYPYRIDINE-2 -CARBOXYLIC ACID (16).

A vigorously stirred mixture of 15 (25.5 g), potassium carbonate (75 g) and methanol (300 mL) was heated at reflux for 30 hours. The mixture was cooled, poured into water (800 mL), and the

PH adjusted to 2 by the addition of conc. HCl. The resulting - mixture was extracted with CH,C1l, (3x150 mL). The organic extracts N were combined, dried (MgSO,) and the solvent was evaporated to give . a nearly colorless oil (20.5 g) which slowly solidified upon standing. This was recrystallized from methanol (125 mL) /water (40 mL) to give the desired acid 16 (11.6 g), m.p. 134-135 °C.

d. PREPARATION OF 6-BROMO-3-BENZYLOXY-4-METHOXYPYRIDINE-2 -CARBONYL

CHLORIDE (3).

To a stirred mixture of 16 (2.54 g., 7.5 mmol) in benzene (30 mL) containing DMF (3 drops) was added oxalyl chloride (1.90 g, 1S mmol) in one portion. After gas evolution had ceased (about 45 min.), the now homogeneous solution was stirred an additional 15 min., then the solvent was evaporated. 1,2-Dichlorocethane (30 mL) was added and again the solvent was evaporated to give a quantitative yield of 3 as a nearly colorless oil. This material was dissolved in CH,Cl, (10 mL) or THF (10 mL) and used directly in subsequent coupling reactions. 6 -BROMO-3 -HYDROXYPICOLINIC ACID (17).

Br” SN” “CO,H 17

To a mechanically stirred solution of methyl 3- hydroxypicolinate (30.6 g) in water {800 mL) was slowly added bromine (32 g) over a 30 minute period. After the addition was complete, stirring was continued for an additional hour. Ether (300mL) was added and stirring continued until all the solids had dissolved. The organic layer was separated and the aqueous phase extracted with ether (200mL). The organic phases were combined, dried (MgsO,) and the solvent evaporated to give 32.8 g of methyl 6- bromo-3-hydroxypicolinate as an off-white solid. Recrystallization ) from methanol/water gave an analytical sample, m.p. 115-117 °C. ©

To a stirred solution of this ester (2.32 g) in THF (15 mL) : was added all at once a solution of LiOH.H,0 (1 g) in water (7 mL).

The resulting mixture was stirred for 2 hours at room temperature then poured into water (100 mL). The pH was adjusted to approximately 3 with 1N HCl, then the mixture was extracted with

CH,Cl, (3 x 100 mL). The organic extract was dried (MgSoO,),

- WO001/14339 PCT/US00/21523 filtered and concentrated to give 2.0 g of a white solid, whose :H-

NMR and MS were consistent with the desired title acid 17. 3 ~-BENZYLOXY - 6 -METHOXYPICOLINIC ACID (18). oe

MeO” N” “CO H 18

A solution of methyl 3-benzyloxypicolinate (4.86 g) and 3- chloroperoxybenzoic acid (5.75 g, 60% peracid) in CH,C1, (100 mL) was stirred at room temperature for 40 hours. The reaction mixture was then extracted with 5% sodium bisulfite solution {100 mL) then with 0.5N NaOH solution (150 mL). After drying (MgSO,), the solvent was evaporated to give 4.9 g of methyl 3-benzyloxypicolinate-1- oxide as a white solid. Recrystallization from methylcyclohexane/toluene gave a crystalline solid, m.p. 104-106 °C.

A solution of this compound (16.1 g) in acetic anhydride (80 mL) was stirred and heated in an oil bath at 125 °C for 3 hours.

The excess acetic anhydride was removed on a rotary evaporator and the residue taken up in methanol (200 mL). Conc. sulfuric acid (1 mL) was added and the resulting mixture heated at reflux for 90 minutes. The solvent was evaporated then saturated sodium bicarbonate added to the residue. The resulting mixture was extracted with CH,C1l, (3 x 100 mL). The organic fractions were combined, dried (MgSO,) and the solvent evaporated to give 15.5 g of = methyl 3-benzyloxy-6-hydroxypicolinate as a yellow solid. .

Recrystallization from toluene gave a pale yellow solid, m.p. 91-92 ) °C.

To a stirred solution of this compound (10.25 g) in toluene (125 mL), warmed in an oil bath at 60 °C, was added silver carbonate (16.6 g), then methyl iodide (8.52 g). The resulting mixture was stirred and heated for 3 hours at 60 °C. After cooling, the mixture wag filtered through Celite® and the solvent evaporated to give a yellow oil. Silica gel chromatography (4:1 hexane/acetone) gave a nearly colorless oil, whose 'H-NMR and MS data were consistent with methyl 3-benzyloxy-6-methoxypicolinate. Hydrolysis of this ester to the title acid 18 was accomplished with LiOH.H,0 as described above for related esters. 4-HYDROXYPYRIMIDINE-5- CARBOXYLIC ACID (19).

NS CO,H 19

Ethyl 4-hydroxypyrimidine-S-carboxylate can be prepared following the procedure of M. Pesson et al., Eur. J. Med. Chem. -

Chim. Ther. 1974, 9, 585. A solution of this ester (500 mg, 3 mmol) in THF (10 mL) and MeOH (5mL) was treated with LiOH.H,0 (373 mg, 8.9 mmol) and stirred overnight. The mixture was quenched with conc. HCl (1 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extract was dried (Mgso,) and concentrated to give 260 mg of the title compound 19 as an orange solid, m.p. 220 °¢ (dec) . 4 -HYDROXY-2-METHYLPYRIMIDINE-S - CARBOXYLIC ACID (20).

Tr

NS CO,H 20 -

Ethyl 4-hydroxy-2-methylpyrimidine-5-carboxylate was prepared . following the procedure of Geissman et al., J. Org. Chem., 1946, : 11, 741. A solution of this ester (750 mg, 4.11 mmol) in THF (10 mL) and MeOH (SmL) was treated with LiOH.H,0 (431 mg, 10.3 mmol) and stirred overnight. The mixture was quenched with conc. HCl (1 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extract was dried (MgSO,) and concentrated to give 155 mg of the title compound 20 as a white solid, m.p. 180 °C (dec).

: ~ WO 01/14339 PCT/US00/21523 5,6 -DICHLORO- 3 -HYDROXYPYRAZINE-2 - CARBOXYLIC ACID (21).

BYE cI” SN" CoH 21

Methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (5.0 g, 23 mmol) was stirred in conc. sulfuric acid (140 mL) and cooled to 0 °C. Sodium nitrite was added slowly, maintaining the temperature close to 0 °C. After an additional 30 minutes at 0 °C, the mixture was allowed to warm to ambient temperature and stirred for 3 hours.

The mixture was poured into 500 g of ice, resulting in bubbling and foaming. After 30 minutes, the mixture was extracted 3 times with

EtOAc. The combined organic extract was dried (MgSO,), filtered and : concentrated. The yellow solid which was left was washed with water and air-dried, to leave 5.0 g of a yellow solid, m.p. 114-116 °C, whose C-NMR spectrum was consistent with the methyl ester of the title compound.

This solid (5.0 g) was treated with 1N NaOH (20 mL) and the mixture heated at 90 °C for 1.5 hours. After allowing to cool, the mixture was acidified with conc. HCl, then extracted 3 times with

EtOAc. Drying (MgsoO,), filtration and concentration afforded 0.48 g of a dark yellow solid, whose H-NMR and MS spectra were consistent with the title acid 21. 6 - CHLORO- 3 - HYDROXY - 5 -METHOXYPYRAZINE - 2 - CARBOXYLIC ACID (22). - ed : cI” SN" CoH 22

A stirred mixture of methyl 3-amino-$, 6-dichloropyrazine-2- carboxylate (5.0 g, 23 mmol) and sodium methoxide (3.6 g, 67.5 mmol) in absolute MeOH (50 mL) was heated at reflux for 2 hours, then allowed to cool and acidified with conc. HCl. The precipitate bh was collected by filtration, washed with water and air-dried to afford 3.6 g of a brown solid. Recrystallization from hexane-EtOAc (1:1) afforded 2.6 g of a pale yellow solid whose spectra were consistent with methyl 3-amino-6-chloro-S-methoxypyrazine-2- carboxylate.

This compound (1 g, 4.6 mmol) was taken up in conc. sulfuric acid, cooled to 0 °C, and treated slowly with sodium nitrite (0.5 g, 6.9 mmol). After 30 minutes at 0 °C, the mixture was poured into 300 g of ice/water, resulting in foaming. Stirring was continued for 30 minutes, then the solid was collected by filtration and washed with water. The wet solid was taken up in

EtOAc, dried (MgsO,), filtered and concentrated. This gave 0.95 g of an off-white solid, m.p. 180-182 °C, whose NMR spectra were consistent with methyl 6-chloro-3-hydroxy-5-methoxypyrazine-2- carboxylate.

This solid (0.9 g, 4.1 mmol) was treated with 1N NaOH (60 mL), and the mixture was stirred for 1 hour, then acidified with conc. HCl. The precipitate was collected by filtration and washed with water, then was dissolved in EtOAc, dried (Mgso,), filtered and concentrated. This afforded 0.62 g of a pale yellow solid, m.p. 170-173 °C, whose spectra were consistent with the desired title acid 22. 4 -HYDROXYISOTHIAZOLBE-3-CARBOXYLIC ACID (23).

This acid was obtained following the procedure shown in

Scheme 5. A

: © WO 01/14339 PCT/US00/21523

Oo CH,COSH 0] 2 Br HO CO,Et [oreo Ny SAN co 2Bn I

NHAC KOH, EtOH oO NHAC CHCl, Ss’

HO COH THF-H,0 2) HCI, HO 23

Scheme 5

Thus, to a stirred solution of solid KOH (88%, 6.98 g, 0.11 mol) in 75 mL of EtOH in a flask flushed with nitrogen was added thiolacetic acid (8.36 g, 0.11 mol) washed in with 25 mL of EtOH. y 10 The mixture was stirred under nitrogen for 5 minutes in the stoppered flask. To this was added 0.1 mol of the crude bromo compound (freshly prepared according to M. Hatanaka and T.

Ishimaru, J. Med. Chem., 1973, 16, 798). The flask was flushed with nitrogen and stoppered. The mixture was stirred in an ambient water bath for 3 hours, then was poured into 300 mL CH,Cl, and 1000 mL water. The aqueous layer was extracted four times with 200 mL of CH,Cl,. The combined organic extracts were washed with 100 mL of cold water and saturated salt solution and dried. The crude mixture was filtered and concentrated. The resulting oil was chromatographed on silica gel, using diethyl ether as eluent, to give 13 g of a light yellow oil which solidified on standing to a gummy solid. Spectral data were consistent with ethyl 2- i acetylamino-4-acetylthio-3-oxobutanoate. N

To a rapidly stirred solution of this compound (12.95 g) in 450 mL of chloroform, cooled in an ice bath to below 5 °C, bromine (15.8 g, 2 equivalents) in 50 mL of chloroform was added dropwise over 45 minutes. Stirring was continued in the ice bath for an additional 45 minutes, and then at ambient temperature for 30 hours. Then the mixture was washed with 200 mL of water, followed by another 100 mL of water. The combined aqueous washes were re- extracted with 100 mL of chloroform. The combined chloroform solutions were washed with saturated salt solution and dried over

MgSO,. The solution was filtered and concentrated to a crude oil.

This was chromatographed on silica gel using a serial gradient from petroleum ether-CH,Cl, (3:1) to CH,Cl,, to give first 0.79 g of ethyl

S5-bromo-4-hydroxyisothiazole-3-carboxylate, and then 3.40 g of ethyl 4-hydroxyisothiazole-3-carboxylate as colorless crystals, m.p. 44-7 °C, consistent by MS and ‘H-NMR.

To 710 mg of the latter ester in 30 mL of THF was added 370 mg of LiOH'H,0 (2.2 equivalents) in 10 mL of water. The mixture was stirred for 3 hours at ambient temperature, then cooled in the refrigerator. The precipitated solid was collected by filtration to give 710 mg of the dilithium salt of the carboxylic acid. This salt was taken up in 7 mL of water, cooled in an ice bath, and taken to pH 1 by addition of 2N HCl. The resulting solution was extracted three times with 50 mL of EtOAc. The combined extracts were washed with 5 mL of brine and dried (Na,SO,), filtered, and the filtrate placed in the refrigerator. The chilled solution was re- filtered and the filtrate concentrated to give 230 mg of a colorless solid, m.p. 185-89 °C, whose ‘H-NMR and **C-NMR spectra were consistent with the title compound 23. 3 -BENZYLOXY~1-METHYLPYRAZOLE-4 -CARBOXYLIC ACID (24) AND 5-

BENZYLOXY-1-METHYLPYRAZOLR-4-CARBOXYLIC ACID (25).

N._-O-_-Ph \ O._Ph

PS p +L N

CO,H CO,H 24 25

A mixture of ethyl 3-hydroxy-1l-methylpyrazole-4-carboxylate and ethyl S5-hydroxy-1-methylpyrazole-4-carboxylate (obtained by the procedure of Y. Wang, et al., Zhejiang Gongxueyuan Xuebao, 1994, 2, 67), was benzylated according to the procedure of S. Yamamoto, et

: © WO 01/14339 PCT/US00/21523 al., Japanese Patent JP 62148482, 1987, and the mixture was separated by column chromatography, using 3:1 hexanes:EtOAc as the eluent, to provide ethyl 3-benzyloxy-1-methylpyrazole-4-carboxylate and ethyl 5-benzyloxy-1-methylpyrazole-4-carboxylate, which were pure by H-NMR.

Ethyl 3-benzyloxy-1-methylpyrazole-4-carboxylate (283 mg, 1.08 mmol) in THF (10 mL), MeOH (2 mL}, and water (5 mL) was treated with LiOH.H,0 (91 mg, 2.17 mmol) and stirred overnight. The mixture was quenched with conc. HCl (1 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Mgso,) and concentrated to give a white solid (227 mg), m.p. 169-172 °C, whose spectra were consistent with 3-benzyloxy-1-methylpyrazole-4- carboxylic acid (24).

Ethyl 5-benzyloxy-1-methylpyrazole-4-carboxylate (755 mg, 2.9 mmol) was likewise hydrolyzed using LiOH.H,0 (243 mg, 5.8 mmol) in . 20 THF (20 mL), MeOH (4 mL), and water (10 mL), to afford 608 mg of S- benzyloxy-1-methyl-4-carboxylic acid (25) as a white solid, m.p. 117-122 °C.

PREPARATION OF OTHER HETEROAROMATIC CARBOXYLIC ACIDS. 4-Hydroxynicotinic acid was prepared by the procedure of M.

Mittelbach et al., Arch. Pharm. (Weinheim, Germany) 1985, 318, 481- 486. 2-Hydroxy-6-methylnicotinic acid can be prepared following the method of A. Dornow, Chem. Ber. 1940, 73, 153. 4,6-Dimethyl-2- hydroxynicotinic acid can be prepared following the method of R.

Mariella and E. Belcher, J. Am. Chem. Soc., 1951, 73, 2616. §&- -

Chloro-2-hydroxy-6-methylnicotinic acid can be prepared by the . procedure of A. Cale et. al., J. Med. Chem., 1989, 32, 2178. 2,5- )

Dihydroxynicotinic acid can be prepared by the method of P. Nantka-

Namirski and A Rykowski, Chem. Abstr., 1972, 77, 114205. 3-

Hydroxyisonicotinic acid was prepared according to the method of J.

D. Crum and C. H. Fuchsman, J. Heterocycl. Chem. 1966, 3, 252-256. 3-Hydroxypyrazine-2-carboxylic acid can be prepared according to the method of A. P. Krapcho et al., J. Heterocycl. Chem. 1997, 34,

Claims (15)

1. A compound of Formula R" OM H —N Z Formuia wherein:

(@) R" is H, halogen, cyano, hydroxy, C4-Cs alkyl, C4-C3 haloalkyl, cyclopropyl, C1- Cs alkoxy, C4-Cs haloalkoxy, C4-C3 alkylthio, substituted or unsubstituted aryl, C4-C3 NHC(O)alkyl, NHC(O)H, C;-Cs haloalkylthio, C»-C4 alkenyl, C;-C4 haloalkenyl, C,-C4 alkynyl, C,-C4 haloalkynyl or nitro;

(b) Zis O, S or NORz in which Rz is H or C4-C3 alkyl: and (c) A represents (i) C3-Cq4 cycloalkyl, containing 0-3 heteroatoms and 0-2 unsaturations, which may be unsubstituted or substituted with halogen, hydroxy, C4-Cs alkyl, C;- Ce haloalkyl, cyano, nitro, aroyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, C4-Cs alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, C;-Cg alkoxy, C4-Cg haloalkoxy, C4-Cg acyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C4-Cs acyl, substituted or unsubstituted carboaryloxy, substituted - or unsubstituted carboheteroaryloxy, Ci-Cg carboalkoxy or amido unsubstituted or substituted with one or two C4-Cg alky! groups,

(i) Ce-C14 bi- or tricyclic ring system, containing 0-3 heteroatoms and 0-2 unsaturations, which may be unsubstituted or substituted with halogen, hydroxy, C4-Ce alkyl, C1-Ce¢ haloalkyl, cyano, nitro, aroyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, C;-Cg alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, C4-Cs alkoxy, C4-Ce haloalkoxy, C1-Cs acyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C;-Cqg acyl, substituted or unsubstituted carboaryloxy, substituted or unsubstituted

~186- Amended Sheet 24.03.2003 carboheteroaryloxy, C;-Cg¢ carboalkoxy or amido unsubstituted or substituted with one or two C¢-Cg alkyl groups, and

(iii) H Q, R, » ("Rs ood where * = point of attachment Rg z NH R; Q, Reh 3 in which Q, Qo are O or S, Wis O, CH, CHR, or a bond, R1 is C4-Cg alkyl, C2-Cs alkenyl, C,-Cg alkynyl, C3-Cg cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, Rz is H, C4-Cj alkyl, C2-Cs alkenyl or C,-Cs alkynyl, Rs is H, Ry, ORy, OC(O)R(where this Ry is C3-Cg cycloalkyl, substituted or unsubstituted ary! or substituted or unsubstituted heteroaryl), OC(O)OR; or OC(O)NR1Rs, Rs and Rs are independently H, C1-Cg alkyl, or C,-Cg alkenyl, provided that the sum of carbons for Rs plus Rs is six or less, and further provided that R4 and Rs may be joined into a C3-Cg ring, Re and Ry are independently H, C4-Cg alkyl, C3-Cg cycloalkyl, C,-Cs alkenyl or C,-Cs alkynyl provided that at least one of Rg and Ry; is H; and (d) M represents Si(t-Bu)Me;, Si(Ph)Me;, SiEts, SiMes;, C(Z)Rs, SO2Rg where Rg is H, C,-Cg alkenyl, C2>-Cs alkynyl, C3-Cs cycloalkyl, alkoxyalkyl, haloalkyl, alkoxyalkenyl, haloalkenyl, alkoxyalkynyl, haloalkynyl, substituted and unsubstituted arylalkyl, substituted and unsubstituted arylalkenyl, substituted and unsubstituted arylalkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, C1-Cs alkoxy, Cs3-Ce cycloalkoxy, Ci-Cs haloalkoxy, C,-Cq alkenyloxy, C2-Cs haloalkenyloxy, C»-Ce alkynyloxy, C2-Ce haloalkynyloxy, C;- Ce thioalkoxy, substituted and unsubstituted arylalkoxy, substituted and -187- Amended Sheet 24.03.2003 unsubstituted arylalkenyloxy, substituted and unsubstituted arylalkynyloxy, substituted and unsubstituted aryloxy, substituted and unsubstituted heteroaryloxy, amino unsubstituted or substituted with one or two C,-Cg alkyl groups, and Rg is C,-Ce alkenyl, C3-Cg alkynyl, C3-Cg cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

2. A compound according to claim 1 wherein R” is H, halogen, cyano, hydroxy, Cs-Cs alkyl, C4-Cz haloalkyl, C4-Cs alkoxy, C4-Cs haloalkoxy, C;-Cs alkylthio, C4-C3 haloalkylthio, or nitro.

3. A compound according to Claim 1 in which R” is H, OMe, Me, Cl, OEt, or SMe.

4. A compound according to Claim 1 in which Z is O.

5. A compound according to Claim 1 in which A is a C3-Cq4 cycloalkyl, containing 0-3 heteroatoms and 0-2 unsaturations, which may be unsubstituted or substituted with halogen, hydroxy, C-Cs alkyl, C1-Cg haloalkyl, cyano, nitro, aroyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, C;-Cs alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, C,- Cs alkoxy, C4-Ce¢ haloalkoxy, C1-Cg acyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C4-Cg acyl, substituted or unsubstituted carboaryloxy, substituted or unsubstituted carboheteroaryloxy, C+-C¢ carboalkoxy or amido unsubstituted or substituted with one or two C4-Cg alkyl groups.

~ 6. A compound according to Claim 1 in which A is a Cg-C14 bi- or tricyclic ring system, containing 0-3 heteroatoms and 0-2 unsaturations, which may be unsubstituted or substituted with halogen, hydroxy, C;-Cg alkyl, C1-Cg haloalkyl, cyano, nitro, aroyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, C,- Ce alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, C4-Cs alkoxy, C;-Cgs haloalkoxy, Ci-Cg acyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C4-C¢ acyl, substituted or -188- Amended Sheet 24.03.2003 unsubstituted carboaryloxy, substituted or unsubstituted carboheteroaryloxy, C1-Ce carboalkoxy or amido unsubstituted or substituted with one or two C;-Cs alkyl groups.

7. A compound according to Claim 1 in which A is H Q, R, ) "Rs ood where * = point of attachment Re £ N_=H R; Q, k= 3 in which Qq, QrareOorsS, W is O, CH,, CHRs, or a bond, Ry is C4-Cg alkyl, C,-Cg alkenyl, C,-Cg alkynyl, C3-Cg cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, R2 is H, C4-Cs alkyl, C,-Cs alkenyl or C,-Cs alkynyl, Rs is H, Ry, OR, OC(O)Rs(where this R; is C3-Cg cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl), OC(O)OR; or OC(O)NR1Rs, Rs and Rs are independently H, C4-Cg alkyl, or C,-Cg alkenyl, provided that the sum of carbons for Ra plus Rs is six or less, and further provided that R, and Rs may be joined into a C3-Cs ring, Re and Ry; are independently H, C4-Cg alkyl, C3-Cg cycloalkyl, C-Cs alkenyl or C»-Cs alkynyl provided that at least one of Rg and Ry; is H.

8. A compound of Claim 1 in which R” is H, OMe, Me, CI, OEt, or SMe, Z is O and A is a C;-Cq4 cycloalkyl, containing 0-3 heteroatoms and 0-2 unsaturations, which may be unsubstituted or substituted with halogen, hydroxy, C1-Cs alkyl, C1-Cs haloalkyl, cyano, nitro, aroyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, C;-Cs alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, C4-C¢ alkoxy, C1-Ce¢ haloalkoxy, C;-Cg acyloxy, -189- Amended Sheet 24.03.2003 substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C;-Cs acyl, substituted or unsubstituted carboaryloxy, substituted or unsubstituted carboheteroaryloxy, C;-Cg carboalkoxy or amido unsubstituted or substituted with one or two C4-Cg alkyl groups.

9. A compound of Claim 1 in which R” is H, OMe, Me, Ci, OEt, or SMe, Z is O and A is a Cg-Cq4 bi- or tricyclic ring system, containing 0-3 heteroatoms and 0-2 unsaturations, which may be unsubstituted or substituted with halogen, hydroxy, Ci- Ce alkyl, C4-Cs haloalkyl, cyano, nitro, aroyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, C;-Cg alkylthio, substituted or unsubstituted aryithio, substituted or unsubstituted heteroarylthio, C4-Cg alkoxy, Ci- Ce haloalkoxy, Ci-Cg acyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C4-C¢ acyl, substituted or unsubstituted carboaryloxy, substituted or unsubstituted carboheteroaryloxy, C;-Cs carboalkoxy or amido unsubstituted or substituted with one or two C1-Cg alkyl groups.

10. A compound according to Claim 1 in which R” is H, OMe, Me, CI, OEt, or SMe, Z is OandAis H Q, R, R— ooh where * = point of attachment R; Q, Reg, in which Qq, QrareOorS, Wis O, CHz, CHRe, or a bond, Ry is C4-Cg alkyl, C2-Cg alkenyl, C,-Cs alkynyl, C3-Cg cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, Ris H, C4-C3 alkyl, C2-Cs alkenyl or C,-Cs alkynyl, Rs is H, Ry, OR4, OC(O)Ri(where this Ry is C3-Cg cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl), OC(O)OR, or -190- Amended Sheet 24.03.2003

OC(O)NR4Rs, Rs and Rs are independently H, C4-Cg alkyl, or C,-Cg alkenyl, provided that the sum of carbons for Ry plus Rs is six or less, and further provided that R4; and Rs may be joined into a C3-Cg ring, Res and Ry; are independently H, C4-Cs alkyl, C3-Cs cycloalkyl, C,-Cs alkenyl or C2-Cs alkynyl provided that at least one of Rg and R7 is H.

11. A compound according to Claims 1 through 10 in which M is C(O)CH;CH,OCH:s.

12. A composition comprising a hydrate, salt or complex of a compound according to Claims 1 through 11.

13. A fungicidal composition comprising a compound according to Claims 1 through 11, and a phytologically acceptable carrier.

14. The composition according to Claim 13 which further includes at least one other compound selected from the group consisting of insecticides, fungicides, herbicides, nematocides, miticides, arthropodocides, bactericides, and combinations thereof.

15. A method for the control or prevention of fungal infestation, which method comprises applying to the locus of the fungus or the locus in which the infestation is to be controlled or prevented, a fungicidally effective amount of a compound according to Claims 1 through 11. -191- Amended Sheet 24.03.2003