WO2005092304A2 - Antifungal agents - Google Patents

Abstract

Compounds of formula (I), and pharmaceutically acceptable salts thereof, may be used in therapy, for example as antifungal agents, wherein: R1, R2 and R3 are as defined herein. Certain compounds of formula (I) are also provided. Compounds of formula (I), and agriculturally acceptable salts thereof, may also be used as agricultural fungicides.

Description

ANTIFUNGAL AGENTS

Field of the invention This invention relates to 2,3-dihydro-l,3,4-thiadiazole compounds and their therapeutic use in prevention or freatment of fungal diseases. It also relates to the use of the compounds as agricultural fungicides.

Background of the invention Chem. Pharm. Bull. 1998,46(2), 329-31 discloses 3-ρhenyl-2,3-dihydro-l,3,4- thiadiazoles for the treatment of wheat powdery mildew. These differ from the compounds of the present invention which are unsubstituted in the 3-position of the 2,3- dihydro-l,3,4-thiadiazole ring. EP-A- 1004241 discloses certain 2-aryl-Δ²-l,3,4-(oxa and thia)diazoline compounds as insecticidal and acaricidal agents. The thiadiazoline compounds differ in structure from the compounds of the present invention since they contain a carbamate group at N3. However, some compounds which may be used in the present invention are described as intermediates to carbamate end products. US 4,699,913 discloses certain compounds which may be used in the present invention as insecticides. However, US 4,699,913 does not disclose antifungal activity for these compounds. WO 03/062392 discloses the use of Spiro 5'-p-tolyl-2',3'-dihydro- [r,3',4']thiadiazol-2',3-l,3-dihydro-5-methyl-indol-2-one in a method of modulating an Edg-2 receptor mediated biological activity. The following compounds which may be used in the present invention are commercially available and are sold without mention of use:

Spiro 5'-p-tolyl-2',3'-dihydro-[r,3',4']thiadiazol-2',3-l,3-dihydro-5-methyl-indol-2-one, 5-(2-Hydroxyphenyl)-2-(5'-methylfuran-2'-yl)-2-methyl-2,3-dihydro-[l,3,4]thiadiazole, 5-Phenyl-2-(4'-cyclohexylphenyl)-2-methyl-2,3-dihydro-[l,3,4]thiadiazole, Spiro 5^,-p-tolyl-2',3'-dihydro-[l^,,3^,,4']thiadiazol-2',3-l,3-dihydro-5-bromo-indol-2-one, Spiro 5'-(2"-hydroxy-phenyl)-2',3^,-dihydro-[l',3',4^,]thiadiazol-2',3-l,3-dihydro-5-ethyl- indol-2-one, Spiro 5'-(2"-naphthyl)-2^,,3'-dihydro-[r,3',4^,]thiadiazol-2^,,3-l,3-dihydro-l-methyl-indol-

2-one,

Spiro 5 '-(phenylmethyl)-2',3 '-dihydro-[ 1 ',3 ',4']thiadiazol-2', 1 -cyclooctane,

5-(p-Tolyl)-2-(2^,-hydroxy-5'-methoxyρhenyl)-2,3-dihydro-[l,3,4]thiadiazole, 5-Phenylmethyl-2-(2'-hydroxy-5'-methoxyphenyl)-2,3-dihydro-[ 1 ,3,4]thiadiazole,

Spiro 5'-(phenyl-methyl)-2',3'-dihydro-[r,3',4']thiadiazol-2',l-cyclododecane,

5-Phenyl-2-(4'-hydroxyphenyl)-2,3-dihydro-[l,3,4]thiadiazole,

Spiro 5^,-phenyl-2^,,3^,-dihydro-[r,3^,,4^,]thiadiazol-2',3-l,3-dihydro-l-(2",6"- dichlorobenzyl)-indol-2-one, Spiro 5'-ρhenyl-2^,,3'-dihydro-[r,3^,,4']thiadiazol-2',3-l,3-dihydro-5-bromo-l-methyl- indol-2-one,

Spiro 5^,-(2"-hydroxyphenyl)-2^,,3'-dihydro-[r,3',4']thiadiazol-2^,,3-l,3-dihydro-indol-2- one,

Spiro 5'-phenyl-2',3 '-dihydro-[ 1 ',3 ',4']thiadiazol-2',3- 1 ,3 -dihydro-5-methyl-indol-2-one, Spiro 5'-phenyl-2',3 '-dihydro-[ 1 ',3 ',4']thiadiazol-2', 1 -cyclododecane,

Spiro 5'-phenyl-2^,,3'-dihydro-[r,3',4']thiadiazol-2',3-l,3-dihydro-5-bromo-indol-2-one,

5-Phenylmethyl-2-(4'-N-phthalimidophenyl)-2-methyl-2,3-dihydro-[l,3,4]thiadiazole,

5-Phenyl-2-(4'-N-acetamidophenyl)-2,3-dihydro-[l,3,4]thiadiazole,

Spiro S'-phenylmethyW^'-dihydro-Cl'^'^'jthiadiazol^'^-l^-dihydro-S-ethyl-indol^- one,

Spiro 5'-(p-tolyl)-2',3'-dihydro-[r,3',4']thiadiazol-2',l-3,3-dimethyl-4-oxa-cyclohexane,

5-(2'-naphthyl)-2-phenyl-2,3-dihydro-[l,3,4]thiadiazole,

Spiro 5'-phenyh-nethyl-2',3'-dihydro-[r,3',4']thiadiazol-2',3-l,3-dihydro-5-bromo-l- methyl-indol-2-one, 5-Phenyl-2-(2'-methoxy-5'-nitroρhenyl)-2,3-dihydro-[l,3,4]thiadiazole,

5-Phenyl-2-methoxycarbonyl-2-(2'-oxo-3',3'-dimethylbutyl)-2,3-dihydro-

[l,3,4]thiadiazole,

5-Phenyl-2-methoxycarbonylmethyl-2-methyl-2,3-dihydro-[l,3,4]thiadiazole,

5-(p-Tolyl)-2-methoxycarbonylmethyl-2-methyl-2,3-dihydro-[l,3,4]thiadiazole, 5-Phenylmethyl-2-(2^,,4'-dihydroxyphenyl)-2,3-dihydro-[ 1 ,3,4]thiadiazole,

5-Phenyl-2-ethoxycarbonylmethyl-2-methyl-2,3-dihydro-[l,3,4]thiadiazole,

5-Phenyl-2-(2'-hydroxyphenyl)-2,3-dihydro-[ 1 ,3,4]thiadiazole, 5-Phenylmethyl-2-methoxycarbonylmethyl-2-methyl-2,3-dihydro-[l,3,4]thiadiazole,

2-[2,3-Dihydro-5-(phenylmethyl)-l,3,4-thiadiazol-2-yl]-4-methoxy-phenol,

3-(Phenylmethyl)- 4-thia-l,2-diazaspiro[4.7]dodec-2-ene,

2-[4,5-dihydro-5-methyl-5-(5-methyl-2-furanyl)-l,3,4-thiadiazol-2-yl]-phenol, 5-Ethyl-5^,-(2-hydroxyphenyl)- spiro[3H-indole-3,2'(3'H)-[l,3,4]thiadiazol]-2(lH)-one, l-Methyl-5'-(l-naphthalenyl)- spiro[3H-indole-3,2^,(3Η)-[l,3,4]thiadiazol]-2(lH)-one,

4-(2,3-Dihydro-5-phenyl-l,3,4-thiadiazol-2-yl)-phenol, l-[(2,6-Dichlorophenyl)methyl]-5'-phenyl- spiro[3H-indole-3,2'(3'H)-[l,3,4]thiadiazol]-

2(lH)-one, 5'-(2-Hydroxyphenyl)- spiro[3H-indole-3,2^,(3Η)-[l,3,4]thiadiazol]-2(lH)-one,

2-[2,3-Dihydro-5-(4-tolyl)-l,3,4-thiadiazol-2-yl]-(4-methoxy)-phenol,

2-(4-Cyclohexylphenyl)-2,3-dihydro-2-methyl-5-phenyl-l,3,4-thiadiazole,

3-(Phenylmethyl)-4-thia-l,2-diazaspiro[4.11]hexadec-2-ene,

Spiro 5'-(2-hydroxyphenyl)-2^,,3^,-dihydro-[l^,,3^,,4^,]thiadiazol-2',3-l,3-dihydro-5-ethyl- indol-2-one,

7,7-Dimethyl-3-phenyl-8-oxa-4-thia-l,2-diaza-spiro[4.5]dec-2-ene,

2-(4-hydroxyphenyl)-5-(benzyl)-2,3-dihydro-[l,3,4]thiadiazole,

Spiro S'- heny^^'^'-dihydro-tr^'^^thiadiazol^'^-l^-dihydro-S-methyl-indol^- one, Spiro S'- heny - ^S'-dihydro-fr^'^' thiadiazol^'^-l^-dihydro-S-bromo-l-methyl- indol-2-one,

Spiro 5'-(phenyl)-2',3 '-dihydro-[ 1 ',3 ',4']thiadiazol-2',3 - 1 ,3 -dihydro-5-bromo-indol-2-one and

Spiro S'-^enzy ^'^'-dihydro-tr^'^^thiadiazol^'^-l^-dihydro-S-ethyl-indoW-one.

Summary of the invention The present inventors have surprisingly found that certain 2,3-dihydro-l,3,4- thiadiazole compounds are antifungal. In particular, the compounds inhibit the growth of human pathogenic fungi such as Candida and AspergiUus and therefore may be used to treat fungal infection and disease. Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for treatment of the human or animal body by therapy:

wherein: RI is aryl, heterocyclyl, -CR8R9-X-aryl, -CR8R9-X-heterocyclyl, -CR8R9-X- (C1-C4 alkylene)-aryl, -CR8R9-X-(C1-C4 alkylene)-heterocyclyl, -(C2-C4 alkenylene)- aryl or -(C2-C4 alkenylene)-heterocyclyl; R8 and R9 independently represent hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-

C4 alkynyl, halogen or hydroxy; X is a bond, -O-, -S-, -SO-, -SO₂- or -? R'-; R2 and R3 independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2- C8 alkynyl, aryl, heterocyclyl, -CO₂R\ -CONR'R", -COR', -CN, -CF₃ or -Y-Z; or R2 represents hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heterocyclyl, -CO₂R'₅ -CONR'R", -COR', -CN, -CF₃ or -Y-Z and R3 is an aryl or heterocyclyl group which is substituted with a group (lb)

wherein Λ™" represents the position of attachment to R3, RI' is aryl, heterocyclyl, -CR8R9-X-aryl, -CR8R9-X-heterocyclyl, -CR8R9-X-(C1-C4 alkylene)- aryl, -CR8R9-X-(C1-C4 alkylene)-heterocyclyl, -(C2-C4 alkenylene)-aryl or -(C2-C4 alkenylene)-heterocyclyl, wherein R8, R9 and X are, independently, as defined above, and -R2' represents hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heterocyclyl, -CO₂R', -CONR'R", -COR', -CN, -CF₃ or -Y-Z; or R2 and R3, together with the carbon atom to which they are attached, form a non-aromatic monocyclic 5- to 16-membered carbocyclyl or heterocyclyl group, which is optionally fused to one or two aryl or heterocyclyl groups; Y is C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene; Z is halogen, aryl, heterocyclyl, cycloalkyl, -OR', -SR', -SOR', -SO₂R', - SO₂?NR'R", -SO₃H, -NR'R", -NR'COR", -NO₂, -CO₂R', -CONR'R", -COR', -OCOR', -CN or -CF₃; and R' and R" independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-

C6 alkynyl, aryl, heterocyclyl, -(C1-C6 alkylene)-aryl, -(C1-C6 alkylene)-heterocyclyl, -(C2-C6 alkenylene)-aryl, -(C2-C6 alkenylene)-heterocyclyl, -(C2-C6 alkynylene)-aryl or -(C2-C6 alkynylene)-heterocyclyl.

The compounds of formula (I) are typically those wherein: RI is aryl, heterocyclyl, -CR8R9-X-aryl, -CR8R9-X-heterocyclyl, -CR8R9-X- (C1-C4 alkylene)-aryl, -CR8R9-X-(C1-C4 alkylene)-heterocyclyl, -(C2-C4 alkenylene)- aryl or -(C2-C4 alkenylene)-heterocyclyl; R8 and R9 independently represent hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, halogen or hydroxy; X is a bond, -O-, -S-, -SO-, -SO₂- or --NR'-; either R2 and R3 independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heterocyclyl, -CO₂R\ -CONR'R", -COR', -CN, -CF₃ or - Y-Z; or R2 and R3, together with the carbon atom to which they are attached, form a non-aromatic monocyclic 5- to 12-membered carbocyclyl or heterocyclyl group, which is optionally fused to one or two aryl or heterocyclyl groups; Y is C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene; Z is halogen, aryl, heterocyclyl, -OR', -SR', -SOR', -SO₂R', -SO₂NR'R", - SO₃H, -NR'R", -NR'COR", -NO₂, -CO₂R', -CONR'R", -COR', -CN or -CF₃; and R' and R" independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, aryl, heterocyclyl, -(C1-C6 alkylene)-aryl, -(C1-C6 alkylene)-heterocyclyl, -(C2-C6 alkenylene)-aryl, -(C2-C6 alkenylene)-heterocyclyl, -(C2-C6 alkynylene)-aryl or -(C2-C6 alkynylene)-heterocyclyl.

Detailed description of the invention As used herein, a C1-C8 alkyl group or moiety can be linear, branched or cyclic but is preferably linear. It is preferably a C1-C6 alkyl group, more preferably a C1-C4 alkyl group, most preferably a C1-C3 alkyl group. Suitable such alkyl groups and moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and tert-butyl, as well as pentyl, hexyl, heptyl and octyl and isomers thereof. As used herein, a C2-C8 alkenyl group or moiety can be linear, branched or cyclic but is preferably linear. It contains one or more carbon-carbon double bonds. It is preferably a C2-C6 alkenyl group, more preferably a C2-C4 alkenyl group, most preferably a C2-C3 alkyl group. Suitable such alkenyl groups and moieties include vinyl, allyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl and isomers thereof. As used herein, a C2-C8 alkynyl group or moiety can be linear, branched or cyclic but is preferably linear. It contains one or more carbon-carbon triple bonds. It is preferably a C2-C6 alkynyl group, more preferably a C2-C4 alkynyl group, most preferably a C2-C3 alkynyl group. Suitable such alkynyl groups and moieties include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl and octynyl and isomers thereof. An alkyl, alkenyl or alkynyl group or moiety can be substituted or unsubstituted. Typically, it carries up to three substituents, e.g. one or two substituents. Suitable substituents include halogen such as fluorine, hydroxy, amino, (C1-C4 alkyl)amino, di(Cl-C4 alkyl)amino, and C1-C4 alkoxy such as methoxy or ethoxy. The substituents are typically themselves unsubstituted. As used herein, a C1-C6 alkylene group or moiety can be linear or branched, but is preferably linear. It is preferably a C1-C4 alkylene group, more preferably a C1-C3 alkylene group. Suitable such alkylene groups or moieties include methylene, ethylene, propylene, butylene, pentylene and hexylene and isomers thereof. As used herein, a C2-C6 alkenylene group or moiety can be linear or branched, but is preferably linear. It is preferably a C2-C4 alkenylene group, more preferably a C2 or C3 alkenylene group. Suitable such alkenylene groups include ethenylene, propenylene, butenylene, pentenylene and hexenylene and isomers thereof. As used herein, a C2-C6 alkynylene group or moiety can be linear or branched, but is preferably linear. It is preferably a C2-C6 alkynylene group, more preferably a C2 or C3 alkynylene group. Suitable such alkynylene groups include ethynylene, propynylene, butynylene, pentynylene and hexynylene and isomers thereof. As used herein, a cycloalkyl group is typically a C3-C6 cycloalkyl group, preferably a C5 or C6 cycloalkyl group. Typically a cycloalkyl group is unsubstituted or substituted with up to three substituents, e.g. one or two substituents. Suitable substituents include C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined. Typically, a cycloalkyl group is unsubstituted. When Rl is -R8R9-X-(C1-C4 alkylene)-aryl or -R8R9-X-(C1-C4 alkylene)- heterocyclyl, the C1-C4 alkylene moiety is preferably methylene. When RI is -(C2-C4 alkenylene)-aryl or -(C2-C4 alkenylene)-heterocyclyl, the C2-C4 alkenylene moiety is preferably ethenylene. R8 and R9 preferably independently represent hydrogen, C1-C4 alkyl, halogen or hydroxy. When R8 or R9 is halogen, it is preferably fluorine. Typically, R8 is hydrogen. Typically, R9 is hydrogen. When R2 or R3 is C1-C8 alkyl, it is preferably C1-C4 alkyl, more preferably methyl, ethyl or propyl, e.g. methyl. When R2 or R3 is C2-C8 alkenyl, it is preferably C2-C4 alkenyl, more preferably ethenyl. When R2 or R3 is C2-C8 alkynyl, it is preferably C2-C4 alkynyl, more preferably ethynyl. In one embodiment of the invention when RI is optionally substituted phenyl and one of R2 and R3 is hydrogen or C1-C4 alkyl, the other of R2 and R3 is not unsubstituted pyridyl. In this embodiment, for example, R2 and R3 are not unsubstituted pyridyl, or, R2 and R3 are not pyridyl. When Y is C1-C6 alkylene, it is preferably C1-C4 alkylene, more preferably methylene or ethylene. When Y is C2-C6 alkenylene, it is preferably C2-C4 alkenylene, more preferably ethenylene. When Y is C2-C6 alkynylene, it is preferably C2-C4 alkynylene, more preferably ethynylene. When R' or R" is C1-C6 alkyl, it is preferably C1-C4 alkyl, more preferably methyl or ethyl. When R' or R" is C2-C6 alkenyl, it is preferably C2-C4 alkenyl, more preferably ethenyl. When R' or R" is C2-C6 alkynyl, it is preferably C2-C4 alkynyl, more preferably ethynyl. As used herein, an aryl group or moiety is typically a C6-C10 aryl group or moiety. Suitable such aryl groups and moieties include phenyl and naphthyl. An aryl group or moiety may be substituted or unsubstituted. Each ring atom may be substituted or unsubstituted. Typically, an aryl group or moiety carries up to three substituents, e.g. one or two substituents. Suitable substituents include C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined. Typically, where an aryl group or moiety is substituted with a substituent containing a further aryl or a heterocyclyl group, the aryl or heterocyclyl group of the substituent is itself unsubstituted or substituted with one, two or three halogen atoms. As used herein, a heterocyclyl group or moiety can be saturated or unsaturated. It is typically a 5- to 12-membered ring system in which the ring contains at least one heteroatom. Typically, the ring contains up to three divalent heteroatom groups, e.g. one or two divalent heteroatom groups. Suitable divalent heteroatom groups include - O-, -S-, -SO-, -SO₂-, -NR'- and -NCOR'-, wherein R' is as hereinbefore defined. Suitable such heterocyclyl groups and moieties include, for example, monocyclic saturated 5- to 8-membered rings such as tetrahydrofixranyl, piperidinyl, morpholinyl, piperazinyl and tetrahydropyranyl, e.g tefrahydrofuranyl, piperidinyl, morpholinyl and piperazinyl; monocyclic unsaturated 5- to 8-membered rings such as furanyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and di- and tefrahydropyridinyl, e.g. furanyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl and pyrazinyl; bicyclic ring systems such as indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, purinyl and cyclopentapyridines which may optionally be partially unsaturated, e.g. indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, quinazolinyl, cinnolinyl and purinyl; and tricyclic ring sytems such as acridinyl, pteridinyl and benzathiazinyl. A heterocyclyl group or moiety may be substituted or unsubstituted. Each ring atom may be unsubstituted or may carry one or two substituents. Typically, a heterocyclyl group or moiety carries up to three substituents, e.g. one or two substituents. Suitable substituents include C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined. The heterocycle may be connected to the remainder of the molecule by a bond to any of its available ring positions. Typically, where a heterocyclyl group or moiety is substituted with a substituent containing an aryl or a further heterocyclyl group, the aryl or heterocyclyl group of the substituent is itself unsubstituted or substituted with one, two or three halogen atoms. As used herein, a halogen is typically chlorine, fluorine, bromine or iodine, and is preferably chlorine, fluorine or bromine. In one embodiment of the invention, Z is halogen, aryl, heterocyclyl, -OR', - SR', -SOR', -SO₂R\ -SO₂NR'R", -SO₃H, -NR'R", -NR'COR", -NO₂, -CO₂R\ - CONR'R", -COR', -CN or -CF₃. In a preferred aspect of the invention, RI is aryl, heterocyclyl or CR8R9-X-aryl wherein X is typically a bond and R8 and R9 are typically hydrogen. For example, RI may be aryl or heterocyclyl. hi another preferred aspect of the invention, R2 represents hydrogen, C1-C4 alkyl, -C0₂R\ -CONR'R", -COR', -CN, -CF₃, -Y-Z or heterocyclyl; R3 is aryl or heterocyclyl; Y is C1-C3 alkylene; Z is fluorine, -OR', -SR', -SOR', -SO₂R', -?NR'R", - -NR'COR", -CO₂R', -CO-NR'R", -OCOR', -CN or -CF₃; and R' and R" independently represent hydrogen, C1-C6 alkyl, aryl or heterocyclyl. Where R2 is heterocyclyl it is typically pyridyl. For example, in this embodiment, R2 represents hydrogen, C1-C4 alkyl, - CO₂R', -CONR'R", -COR', -CN, -CF₃ or -Y-Z ; R3 is aryl or heterocyclyl; Y is C1-C3 alkylene; Z is fluorine, -OR', -SR', -SOR', -SO₂R', -NR'R", -NR'COR", -CO₂R', - CONR'R", -CN or -CF₃; and R' and R" independently represent hydrogen, C1-C6 alkyl, aryl or heterocyclyl. In another preferred aspect of the invention, ?R2 is methyl and R3 is aryl or heterocyclyl. Where R3 is aryl it is typically phenyl which is unsubstituted or substituted with one or two substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined. Typically, where an aryl group is substituted with a substituent containing a further aryl or a heterocyclyl group, the aryl or heterocyclyl group of the substituent is itself unsubstituted or substituted with one, two or three halogen atoms. Where R3 is heterocyclyl, it is typically a 5- to 12-membered heterocyclic group having one or two divalent heteroatom groups selected from -O-, -S-, -SO-, -SO₂-, - NR'- and -NCOR'-, wherein R' is as hereinbefore defined. The heterocyclyl group may be unsubstituted or substituted with one or two substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined. Typically, where a heterocyclyl group is substituted with a substituent containing an aryl or a further heterocyclyl group, the aryl or heterocyclyl group of the substituent is itself unsubstituted or substituted with one, two or three halogen atoms. In another preferred embodiment of the invention, RI and R2 are as defined above and R3 is an aryl or heterocyclyl group which is substituted with a group of formula (lb). In the group of formula lb, RI ' is typically a group RI as defined above. Typically RI is identical to RI '. R2' is typically a group R2 as defined above. Preferably, R2 and R2' are independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2- C8 alkynyl, -C0₂R', -CO-NR'R", -COR', -CN, -CF₃ or -Y-Z, more preferably C1-C4 alkyl or hydrogen, most preferably hydrogen. Typically R2 is identical to R2' . Preferably ? 2 and R2' are hydrogen. R3 is typically a phenyl or pyridyl group, for example a pyridyl group, which is substituted with a group of formula (lb) and optionally with one or more, e.g. none, one or two further substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined. Typically, R3 is substituted with a single substituent of formula (lb). In another preferred aspect of the invention, R2 and R3, together with the carbon atom to which they are attached, form a non-aromatic monocyclic 5- to 16-membered, e.g. 5- to 12-membered, carbocyclyl or heterocyclyl group, which is optionally fused to one or two aryl or heterocyclyl groups. When R2 and R3 together form a non-aromatic heterocyclyl group, both of the ring atoms attached to the spiro carbon are preferably carbon atoms. The non-aromatic monocyclic 5- to 16, e.g. 5- to 12-membered carbocyclyl group can be saturated or partially unsaturated. It is preferably a 5- to 8-membered ring. Typically, it is a saturated hydrocarbon ring, i.e. a cycloalkyl group. Suitable such carbocyclyl groups include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and cyclohexadecyl, e.g. cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. I?n the non-aromatic monocyclic 5- to 16-membered carbocyclyl group, each ring atom may be unsubstituted or may carry one or two substituents or may be fused to an aryl or heterocyclyl group. Suitable substituents include oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined. The non-aromatic monocyclic 5- to 16-, e.g. 5- to 12-membered heterocyclyl group can be saturated or unsaturated. It is preferably a 5- to 8-membered ring. Typically, the ring contains up to three divalent heteroatom groups, e.g. one or two divalent heteroatom groups. Suitable divalent heteroatom groups include -O-, -S-, -SO-, -SO -, -?NR'- and -N(-COR')-, wherein R' is as hereinbefore defined. Suitable non- aromatic monocyclic 5- to 12-membered heterocyclyl groups include 3-oxacyclopentyl, 4-azacyclohexyl, 3-thiacycloheptyl and 3-oxa,5-azacyclononyl. Further examples of suitable non-aromatic monocyclic 5- to 12-membered heterocyclyl groups are given in the general list of heterocyclyl groups and moieties above. In the non-aromatic monocyclic 5- to 16-membered heterocyclyl group, each ring atom maybe unsubstituted or may carry one or two substituents or may be fused to an aryl or heterocyclyl group. Suitable substituents include oxo, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, Z and -Y-Z wherein Y and Z are as hereinbefore defined. h an especially preferred aspect of the invention, RI is a substituted or unsubstituted phenyl ring, a substituted or unsubstituted thiophene ring, a substituted or unsubstituted pyridine ring, a substituted or unsubstituted benzyl group or a substituted or unsubstituted naphthylene group. For example, RI may be a substituted or unsubstituted phenyl ring, a substituted or unsubstituted thiophene ring or a substituted or unsubstituted pyridine ring, e.g. a substituted or unsubstituted phenyl ring or a substituted or unsubstituted thiophene ring. Preferred substituents on RI include halogen, e.g. chlorine, C1-C4 alkyl, e.g. methyl, and hydroxyl. Preferably, a pyridine, t-hiophene, benzyl or naphthalene group at RI is unsubstituted. In another especially preferred aspect of the invention, ?R2 represents hydrogen, methyl, ethyl, propyl, -CF₃, -CH₂O-(Cl-C4 alkyl), -CO₂R', -CONR'R", CH₂OCO-(Cl- C4-alkyl), -CN or pyridinyl; R3 is aryl or heterocyclyl; and R' and R" independently represent hydrogen, C1-C3 alkyl, aryl, heterocyclyl or optionally substituted benzyl. In this embodiment, for example, ?R2 represents methyl, ethyl, -CF₃, -CH O-(Cl-C4 alkyl), -CO₂R', -CONR'R" or -CN; R3 is aryl or heterocyclyl; and R' and R" independently represent hydrogen, C1-C3 alkyl, aryl, heterocyclyl or optionally substituted benzyl. Preferably in this embodiment, ?R2 represents methyl, ethyl, propyl, -CF₃, - CH₂O-(Cl-C4 alkyl), -CO₂R', -CONR'R", CH₂OCO-(Cl-C4-alkyl) or -CN wherein R' and R' ' are as defined above. hi another especially preferred aspect of the invention, the compound of formula (I) is a compound of formula (la):

wherein: RI is as hereinbefore defined; R4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or -Y-Z as hereinbefore defined; and R5, R6 and R7 independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or Z as hereinbefore defined. In the compounds of formula (la), RI is preferably aryl, heterocyclyl, -CH₂-aryl, -CH₂CH -aryl, -CH₂-heterocyclyl or -CH₂CH₂-heterocyclyl. More preferably, RI is substituted or unsubstituted phenyl, substituted or unsubstituted naphthalenyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted -CH₂-phenyl, or substituted or unsubstituted -CH₂CH₂-phenyl, e.g. RI is substituted or unsubstituted phenyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted -CH₂-phenyl, or substituted or unsubstituted -CH₂CH₂-phenyl. For example, RI may be chlorophenyl such as 4-chloroρhenyl, hydroxyphenyl such as 3-hydroxyphenyl, tolyl, naphthalenyl, pyrazin-2-yl, methylphenyl such as 4-methylphenyl, or phenethyl, e.g RI may be chlorophenyl such as 4-chlorophenyl, hydroxyphenyl such as 3-hydroxyphenyl, pyrazin-2-yl, methylphenyl such as 4-methylphenyl, or phenethyl. In the compounds of formula (la), R4 is preferably hydrogen, C1-C4 alkyl or substituted benzyl. More preferably, R4 is hydrogen or methyl. In the compounds of formula (la), R5, R6 and R7 preferably independently represent hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, aryl, heterocyclyl, hydroxy, C1-C4 alkoxy, -CN, -CO₂H, -CO₂-(Cl-C4 alkyl), -COR', - CO-NR'R", (Cl-4 alkyl)thio, -SO₃H, -SO₂-(Cl-C4 alkyl), -SO₂NR'R", -NR'R", - NR'COR" or -NO₂. In the compounds of formula (la), R5 is preferably hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, --NR'R", -NR'COR", -OR', -CN or -SO₂NR'R". More preferably, R5 is hydrogen, methyl, -CN or -SO₂?NHCH₃. In the compounds of formula (la), R6 is preferably hydrogen. hi the compounds of formula (la), R7 is preferably hydrogen. In the compounds of formula (la), R' and R" preferably independently represent hydrogen, C1-C4 alkyl, aryl or heterocyclyl. In another especially preferred aspect of the invention, R2 is methyl; R3 is - CO?NR'R"; and R' and R" independently represent hydrogen, C1-C4 alkyl, aryl or heterocyclyl, -(C1-C4 alkylene)-aryl or -(C1-C4 alkylene)-heterocyclyl. The most preferred embodiments of the invention are those in which: RI is unsubstituted phenyl or phenyl substituted with one or two substituents selected from halogen, e.g. chlorine, C1-C4 alkyl, e.g. methyl, and hydroxyl, an xmsubstituted thiophene ring, an unsubstituted pyridine ring, an xmsubstituted benzyl group or an unsubstituted naphthylene group; and R2 represents hydrogen, methyl, ethyl, propyl, -CF₃, -CH₂O-(Cl-C4 alkyl), - CO₂R', -CONR'R", CH₂OCO-(Cl-C4-alkyl), -CN or pyridinyl; R3 is phenyl which is xmsubstituted or substituted with one or two substituents selected from C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z, or R3 is a 5- to 12-membered heterocyclic group having one or two divalent heteroatom groups selected from -O-, -S-, -SO-, -SO₂- , -NR'- and -NCOR'-, the heterocyclic group being unsubstituted or substituted with one or two substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Z and -Y-Z, wherein Y and Z are as hereinbefore defined; and R' and R" independently represent hydrogen, C1-C3 alkyl, aryl, heterocyclyl or optionally substituted benzyl; or R2 represents hydrogen and R3 represents phenyl or pyridyl which is substituted with a single substituent of formula (lb) wherein RI' is as defined for RI above and R2' is hydrogen; or R2 and R3, together with the carbon atom to which they are attached, form a non-aromatic monocyclic 5- to 16-membered carbocyclyl or heterocyclyl group, which is optionally fused to one or two aryl or heterocyclyl groups. In the most preferred embodiments of the invention, for example, R2 and R3, together with the carbon atom to which they are attached, form a substituted or unsubstituted indol-2-on-3-yl ring; or R2 is methyl and R3 is a substituted or unsubstituted furanyl or thiophenyl ring, such as a substituted or unsubstituted furan-2-yl or thiophen-2-yl ring. Alternatively, R2 is methyl and R3 is a 5- to 12-membered heterocyclyl group containing at least one nitrogen atom, e.g. pyridyl, pyrazinyl, 5-phenyl-pyridin-2-yl or quinoxaline. The invention specifically provides the following compoxxnds of formula (I): 4-(2-Methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine, Spiro 5'-(2-pyrazinyl)-2^,,3^,-dihydro-[ 1 ',3',4']thiadiazol-2',3- 1 ,3-dihydro-indol-2-one, Spiro S'- henethy^^'^'-dihydro-tl'^'^^thiadiazol^'^-l^-dihydro-indol^-one, Spiro 5^,-(4-hydroxy)-2^,,3'-dihydro-[r,3^,,4']thiadiazol-2',3-l,3-dihydro-indol-2-one, 2-(4-Chlorophenyl)-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-(4-Methoxyphenyl)-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-(5 ' -Methylfuran-2-yl)-2-methyl-5-(p-tolyl)-2,3 -dihydro-[ 1 ,3 ,4]thiadiazole, 2-(5'-Methylfuran-2-yl)-2-methyl-5-(4"-chloroρhenyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-Furan-2-yl-2-methyl-5-(ρ-tolyl)-2,3-dihydro-[l,3,4]thiadiazole₅ 2-Furan-2-yl-2-methyl-5-phenethyl-2,3-dihydro-[l,3,4]thiadiazole, 2-Furan-2-yl-2-methyl-5-chlorophenyl-2,3-dihydro-[ 1 ,3 ,4]thiadiazole, 2-Furan-2-yl-2-methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazole, 2-Pyrrol-2-yl-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-Methyl-2,5-di-ρ-tolyl-2,3 -dihydro-[ 1 ,3 ,4]thiadiazole, 2-Methyl-2-phenyl-5-(p-tolyl)-2,3-dihydro-[ 1 ,3,4]thiadiazole, 2-Methyl-2-thiophen-2-yl-5-(4-chloroρhenyl)-2,3-dihydro-[l,3,4]thiadiazole,

2-Methyl-2-(5-bromothiophen-2-yl)-5-(4-chlorophenyl)-2,3-dihydro-[l,3,4]thiadiazole, 4-[4-(2-Methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-phenyl]-morpholine, Spiro 5'-(3"-hydroxyphenyl)-2',3^,-dihydro-[r,3^,,4']thiadiazol-2^,,3-l,3-dihydro-indol-2- one, Spiro 5^,-(4"-chloroρhenyl)-2',3'-dihydro-[l',3',4^,]thiadiazol-2^,,3-l,3-dihydro-indol-2- one,

Spiro S'-^-toly ^'^'-dihydro-tr^'^'JthiadiazoW^-l^-dihydro-indol^-one, Spiro S'-phenethyW^'-dihydro-fl'^'^^thiadiazol^'^-l^-dihydro-indol^-one, Spiro 5'-p-tolyl-2',3'-dihydro-[l'₅3',4']thiadiazol-2',3-l,3-dihydro-l-methyl-indol-2-one, Spiro S'-p-tolyl^'^'-dihydro-fr^'^^thiadiazol^'^-l^-dihydro^-oxo-lH-indole-S- sulfonic acid,

Spiro S'- -toly ^'^'-dihydro-tl'^'^'Jthiadiazol^'^-chroman, 2-Benzoflιran-2-yl-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-Biphenyl-4-yl-2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole, 2-(4-Chlorophenyl)-2-ethyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole, 2-(4-Chlorophenyl)-2-propyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole, 4-Methyl-2-(2-methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridine, 2,6-Bis-(5-phenyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyτidine, 5-Chloro-2-(2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridine, 2-(2-Methyl-5-p-tolyl-2,3-dihydro-[ 1 ,3,4]thiadiazol-2-yl)-5-phenylpyridine,

2-Methoxy-6'-(2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-[3,3']bipyridinyl, 3-Chloro-6-(2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridazine, 2-(2,4-Dichlorophenyl)-2-methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazole, 2-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyrazine, 2-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)quinoxaline, 2-[4-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-phenyl]-pyridine, 4-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)benzonitrile, 2-(2-Methyl-5-ρ-tolyl-2,3-dihydro[l,3,4]thiadiazol-2-yl)pyridine, 3-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridine, 2-(2,4-Dichlorophenyl)-2-methyl-5-p-tolyl-2,3-dihydro[l,3,4]thiadiazole, 2-(2-Methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridine, 3-(p-Tolyl)-4-thia-l,2-diaza-spiro[4.4]non-2-ene,

2-(4-Nitro-phenyl)-5-p-tolyl-2,3-dihydro-[l ,3,4]thiadiazole-2-carboxylic acid ethyl ester,

2-(3,4-Dichlorophenyl)-2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole, 2-Phenyl-5-p-tolyl-2-trifluoromethyl-2,3-dihydro-[l,3,4]thiadiazole, Acetic acid 2-phenyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl-methyl ester, l-[6-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-pyridin-2-yl]-ethanol, 2-(2-Methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)quinoline, 2-(4-Chlorophenyl)-2-methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazole, 2-Biphenyl-4-yl-2-methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazole, 2-(2-Methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyrazine,

Spiro 5'-p-tolyl-2',3'-dihydro-[l',3',4']thiadiazole-2',l-5-chloro-indan,

2-(5-Phenyl-2-pyridin-2-yl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-py idine,

2-(2-Methyl-5-pyridin-2-yl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine,

Spiro 5'-(p-hydroxyphenyl)-2',3'-dihydro-[ ,3',4']thiadiazole-2',3-l,3-dihydro-indol- 2-one,

Spiro 5'-(p-tolyl)-2',3'-dihydro-[l',3',4']thiadiazol-2',9-9H-l,8-diazafluorene,

Spiro 5'-(p-tolyl)-2',3'-dihydro-[l',3',4']thiadiazol-2',4-chroman,

Spiro 5'-(m-tolyl)-2',3'-dihydro-[l',3',4']thiadiazol-2',3-l,3-dihydro-indol-2-one. The present invention includes pharmaceutically acceptable salts of the compounds of formula (I). Suitable salts include salts with pharmaceutically acceptable acids, both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Salts may also be formed with pharmaceutically acceptable bases such as alkali metal (e.g. sodium or potassium) and alkaline earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines. A preferred salt is the hydrochloride salt. Some of the compounds of the invention include one or more chiral centre. The present invention includes enantiomers and diastereoisomers of such compounds. An example of this is at C2 of the thiadiazole ring which becomes a chiral cenfre when its ring substituents are different from one another. The 2,3-dihydro-l,3,4-thiadiazole compounds of the invention can be synthesised by one of three main methods: 1) The conversion of one 2,3-dihydro-l,3,4-thiadiazole compound to another by chemical manipulation of one or more of its substituent groups. 2) The reaction of an acylhydrazone with a chlorinating agent to give a 1 -chloro 2,3-diazabuta-l,3-diene analogue and its subsequent reaction with hydrogen sulphide to give a 2,3-dihydro-l,3,4-thiadiazole. 3) The reaction of a thioacyl hydrazide with a ketone or aldehyde. These methods are shown in Scheme A.

Scheme A. Methods for synthesising 2,3-dihydro-1,3,4-thiadiazoles Method 1

N-N ^W N-N ^z H H Intermediate 1

Method 2

Intermediate 2 Method 3

Intermediate 3 Intermediate 4

Groups U,V, W, X, Y represent different substituents. the first method a 2,3-dihydro-l,3,4-thiadiazole (intermediate 1) with substituents U, V and W is converted to another 2,3-dihydro-l,3,4-thiadiazole with substituents X, Y and Z wherein one or more substituents U, V and W is different from X, Y and Z. An example is where groups U, V or W may contain a protected form of a chemical group, such as an ester, ether, amide or carbamate which can be selectively deprotected using methods known in the art to different groups X, Y or Z containing carboxylic acids, alcohols or amines. Similarly it is anticipated that certain chemical groups contained within U, V or W can be converted by chemical reaction to other types of group. Thus alcohols may be selectively converted to ethers or esters; amines to other amines, amides, ureas or carbamates; carboxylic acids to esters, amides or cyano groups. It is also anticipated that aliphatic halides, epoxides or O-sulfate esters can be converted to ethers or amines by reaction with alcohols or amines; and aromatic or heterocyclic halides may be converted to carbon-based substituents by the action of a Suzuki, Stille, Sonigashira or Heck reaction, or into substituted amines using a Buchwald reaction. These synthetic methods are well known in the art. Intermediates of type 1 may be synthesised by methods 2 or 3 described below. In the second method, an acyl hydrazide (intermediate 2) is converted to a 1- chloro-2,3-diazabuta-l,3-diene using a chlorinating agent and then into a 2,3-dihydro- 1,3,4-thiadiazole using hydrogen sulphide or an alkali metal sulphide. The acyl hydrazone is converted into the 1-chloro 2,3-diazabuta-l,3-diene intermediate by the action of a chlorinating agent such as thionyl chloride, phosphorus oxychloride or phosphorus pentachloride in a suitable inert solvent such as dichloromethane, chloroform or toluene at between 0°C and 100°C. The intermediate 1-chloro 1,3- diazabutene is reacted with hydrogen sulphide or an alkali metal sulphide according to the method of US 4,699,913 to give a 2,3 -dihydro- 1,3,4-thiadiazole. In the third method, a thioacyl hydrazide (intermediate 3) is reacted with an aldehyde or ketone (intermediate 4) to give a 2,3-dihydro-l,3,4-thiadiazole in a manner -known per se (D. M. Evans et al., J. Chem. Soc. Chem. Commun. 1982, pg 188., K.N. Zelenin et al., -Khim. Geterotsikl. Soedin, 1982,7, pg 904). Suitable solvents for this reaction are aromatic hydrocarbons, tetrahydrofuran, dioxane, diethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, aliphatic alcohols such as methanol, ethanol or propanol, esters of aliphatic acids such as ethyl acetate, aliphatic amides such as dimethyl formamide and dimethyl acetamide, dimethyl sulfoxide or other solvents that do not impair the reaction, hi some instances the reaction maybe performed without solvent in the presence of one or more equivalents of the ketone or aldehyde reactant (for example acetone or cyclohexanone) which can itself act as the solvent. The reaction temperature may be varied over a wide range from -10 °C to +100 °C. The reaction may also be performed in the presence of an acidic catalyst such as an aliphatic carboxylic acid catalyst, preferably formic or acetic acid. Acyl hydrazones (intermediate 2) can be prepared from a ketone or aldehyde (intermediate 4) and an acyl hydrazide (intermediate 5) according to method 4 (Scheme B). Scheme B. Synthetic route to acyl hydrazones Method 4

intermediate 5 intermediate 4 intermediate 2 X, Y and Z represent different substituents

This can be accomplished by analogy with -known methods (for example, Palla G et al, Tetrahedron, (1986), 42, 3649-3654; Bekhazi, M. et -al, Can. J. Chem. (1991), 69, 1507-1510; and Pei-Lin-Wu, Synthesis, (1995), 435-438. Suitable solvents for this reaction are aromatic hydrocarbons, tetrahydrofuran, dioxane, diethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, alcohols such as methanol, ethanol or propanol, esters of aliphatic acids such as ethyl acetate, aliphatic amides such as dimethyl formamide and dimethyl a.cetamide, dimethyl sulfoxide or other solvents that do not impair the reaction. In some instances the reaction may be performed without solvent in the presence o-f an excess of the ketone or aldehyde reactant (for example acetone or cyclohexanone). The reaction temperature may be varied over a wide range from -10 °C to +100 °C. Th_e reaction may also be performed in the presence of an aliphatic carboxylic acid catalyst such as formic or acetic acid. Acyl hydrazides (intermediate 5) can be obtained commercially or prepared by reaction of known carboxylic acid chlorides with hydraziπe, or from -known carboxylic acids, hydrazine and a coupling agent. Examples of reactions of this type include those described in Synthesis, 549,1974 and references therein; benzotriazole-1- yl-oxy-tris-(dimethylamino)-phospho-tιiumhexafluorophospha.te (BOP) as coupling reagent: B. Casfro, et al. (1975) Tetrahedron Lett. (1975) 16 1219; carbonyl diimidazole as coupling reagent: T. Kamijo, et al. (1984) Chem. Pharm. Bull 2*2 5044; and 2-(lH- benzotriazole-l-yl)-l,l,3,3-teframethyluronium hexafluorop-tiosphate (HBTU) as coupling reagent: R. Knorr, et al. (1989) Tetrahedron Lett. 3C 1927. The coupling agent used may be dicyclohexylcarbodimide (with or without 1-hy roxybenzotriazole or HATU), 2-ethoxy-l-ethoxycarbonyl-l,2-dihydro-quinoline (IEEDQ), 2-(lH-7aza- benzotriazole-l-yl)-l,l,3,3-tetramethylxxronivim hexafluoroptiosphate (?HATU), 2-(lH- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU) in a suitable inert solvent such as dimethylformamide, dichloromethane, ethyl acetate, tetrahydrofuran or dioxane. Thiahydrazides (intermediate 3) may be prepared by one of three methods shown in Scheme C. These are: 1) By conversion of thioamide products of the Willgerodt reaction with hydrazine to give thiohydrazides (Method 6). 2) By reaction of a Grignard reagent with carbon disulfide followed by conversion of the dithio carboxylic acid intermediate to the thiohydrazide either directly or via an alkyl dithioester intermediate (Method 7). 3) By dilithiation of carboxylic acids containing at least one alpi a C-H bond, followed by condensation with carbon disulfide, alkylation an_d decarboxylation to give a dithio ester and its subsequent conversion to a thiohy/drazide with hydrazine (Method 8). Aldehydes and ketones can be converted to thioamides using the Willgerodt reaction (Brown, Synthesis 1975, pg 358-375; Jerry March, Advanced Organic Chemistry, Wiley-friterscience 3^rd edition, pgl 119-1120; and references therein). A mixture of the carbonyl compound, sulfur and an amine is heated at b>etween 50°C and 150°C, either neat or with an inert solvent present. Preferred solvents include higher boiling solvents such as dimethylformamide, toluene and dioxane. A_ particularly preferred method is the -known -Kindler modification (Saus & Triem, -Angew. Chem. Int. Ed. Engl. 1964, 3, 19-28) wherein the carbonyl component is heated in piperidine or morpholine at about 100°C. In a second step the thioamide is treated with hydrazine either neat or in a suitable solvent such as methanol, ethanol, tetrahyclrofuran or dioxane at a temperature between 0°C and 90 °C to give a thiohydrazide. Thiohydrazides (intermediate 3) may be obtained from Grignard reagents by other -known procedures (Method 7) (see, for example, WO 94/0787L , pgl2). Thus aryl magnesium halides prepared from the corresponding aryl bromides, chlorides and iodides are added to carbon disulfide in anhydrous tetrahydrofuran and dioxane at between 0°C and 20°C to form an aryldithiocarboxyhc acid. After neutralisation, the crude aryldithiocarboxyhc acid can be reacted with neat hydrazine or with hydrazine in a suitable solvent such as methanol or ethanol at between 0°C and 50^"°C to give a thiahydrazide (intermediate 3). Alternatively, the crude aryldithiocarboxyhc acid can be converted to the corresponding alkyl aryldit-hiocarboxylic ester with a base such as an alkali metal carbonate or hydroxide and an alkylation agent, such as methyl iodide or other lower alkyl halide. This can be isolated and separately treated with hydrazine neat or in solvent as described for the analogous aryldithiocarboxylic acid.

Scheme C. Methods for synthesising thioacyl hydrazides Method 6

Intermediate 3 Method 7 S H₂N-NH₂ Mc S ,Hal X' X SH X^ΛM-^{N H}* S=S H Intermediate 3 M ethod 8

Me — I Intermediate 3 X represents a substituent and R represents oxygen or nitrogen

Thiohydrazides (intermediate 3) may be obtained by a two-step -known procedure involving intermediate alkyl dithiocarboxyhc esters (method 8) (see, for example, Wei Yean et al, J. Org. Chem., 1989, 54, 906-910). Carboxylic acids containing at least one alpha hydrogen are dilithiated using a strong hindered base such as lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (Li-EIMDS) in the presence of hexamethylphosphoramide (HMPA) in an inert anhydrous solvent such as tetrahydrofuran or dioxane at between -78°C and 0°C, and then condensed with carbon disulfide at between -50°C and 0°C. Subsequent alkylation using a lower alkyl halide such as methyl iodide furnishes an alkyl dithioester. This can be treated with hydrazine either neat or in an alcoholic solvent to give the thiohydrazide (intermediate 3). Ketones and aldehydes (intermediate 4) are either commercially available or can be readily synthesised using methods known in the art from other starting materials (see, for example, R. C. Larock, Comprehensive Organic Transformations, NCR 1989, pg 583-817). A group of compounds that are not all commercially available are the isatins. Scheme D indicates -known routes to these compounds. Thus substituted anilines can be reacted in a one or two pot procedure with oxalyl chloride and a Lewis acid to give isatins. The substitution pattern of the products depends upon the relative orientation of the substituents in the aniline. Thus para-substituted anilines will give 5- substituted isatins, ortho substituted anilines give 7-substituted isatins and meta substituted anilines give a mixture of 4-substituted isatins and 6-substituted isatins. By extension, the reaction can be applied to multiply substituted anilines having at least one hydrogen ortho to the amino group to furnish multiply substituted isatins.

Scheme D: Methods of synthesising regiospecifically substituted isatins Method 9

Lewis acid

c cι Lewis acid

Bicyclic ketones related to isatins in which the phenyl ring is replaced by a 5- or 6-membered heterocycle such as thiophene or pyridine can be prepared in an analoguous manner to method 8. The starting materials for these ring systems are amino-substituted heterocycles with one or more unsubstituted positions ortho to the amino group. Scheme E: Methods for synthesising ketones

Method 12 Dess-Martin MeMgBr periodane

Scheme E illustrates synthetic routes to other examples of ketones that are not commercially available. These are: 1) Reacting the appropriate aryl bromide with a strong base, typically sec-BuLi or n-BuLi, and N,N-dimethylacetamide (Method 10). 2) Biaryl ketones may be obtained by reacting the appropriate aniline with bromine, hydrobromic acid and sodium nitrite, followed by Suzuki coupling, and finally displacement of the bromine, using base and N,N-dimethylacetamide (Method 11). 3) By reaction of a Grignard reagent with the appropriate aldehyde to give the corresponding secondary alcohol, which is then oxidised using Dess-Martin periodane to give the desired ketone (Method 12). 4) By reaction of quinoxaline, with pyruvic acid, AgNO₃, (NH₄)₂S₂O₈, and trifluoroacetic acid to give the desired ketone (Method 13). The compounds of the invention have antifungal activity. Accordingly, they may be used in a method of treating a subject suffering from or susceptible to a fungal disease. Examples of fungal diseases which can be prevented or treated using the compounds of the invention include both systemic and superficial infections. The fungal diseases include invasive fungal diseases caused by AspergiUus and Candida species such as aspergillosis or candidiasis, but also local forms of these infections. The compounds of the invention are particularly useful against diseases caused by

AspergiUus species, for which a fungicidal drug is required which has lower toxicity than amphotericin. The invention also provides for the treatment of dermatological infections. The diseases caused by AspergiUus species include diseases caused by A. fumigatus, A. flavus, A. terreus and A. niger. The diseases cause by Candida species include diseases caused by C. albicans, C. glabrata, C. -krusei, C. tropicalis and C. parapsillosis. The relative importance of the human fungal pathogens by prevalence is approximately, for AspergiUus species: A. fumigatus 85% A. flavus 8% A. terreus 5% A. niger 2% and for Candida species: C. albicans 80% C. glabrata 9% C. parapsillosis 5% C. tropicalis 4% C. -krusei 2% Examples of systemic infections which can be prevented or treated using the compounds of the invention include: systemic candidiasis; pulmonary aspergillosis, e.g. in immunosuppressed patients such as bone marrow recipients or AIDS patients; systemic aspergillosis; cryptococcal meningitis; rhinocerebral mucomycosis; blastomycosis; histoplasmosis; coccidiomycosis; paracoccidiomycosis; and disseminated sporotrichosis. Examples of superficial infections which can be prevented or treated using the compounds of the invention include: ring worm; athlete's foot; tinea unguium (nail infection); candidiasis of s-kin, mouth or vagina; and chronic mucocutaneous candidiasis. The present invention includes a pharmaceutical composition comprising a compound according to the invention and a pharmaceutically acceptable carrier or diluent. The compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. The compounds of the invention may also be administered parenterally, either subcutaneously, intravenously, intramuscularly, intrasternally, fransdermally or by infusion techniques. The compounds may also be administered as suppositories. A compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film coating processes. Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol. Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginte, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride. Solutions for intravenous or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions. A therapeutically effective amount of a compound of the invention is administered to a patient. A typical daily dose is up to 50 mg per kg of body weight, for example from 0.001 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration. Preferably, daily dosage levels are from 0.05 mg to 2 g, preferably from 0.1 mg to 10 mg. The present invention also provides a method of controlling a fungal disease of plants, which comprises applying to the locus of the plants a compound of formula (I) or an agriculturally acceptable salt thereof. The compounds of the invention may, for example, be applied to the seeds of the plants, to the medium (e.g. soil or water) in which the plants are grown, or to the foliage of the plants. Examples of fungal diseases of plants which can be controlled using the compounds of the invention include fungal diseases caused by the following plant pathogens: Blumeria graminis; Colletotrichium trifolii; Fusarium graminarium; Fusarium solani; Fusarium sporotrichoides,' Leptosphaeria nodorum; Magnaporthe grisea; Mycosphaerella graminicola; Neurospora crassa; Phytophthora capsici; Phytophthora infestans; Plasmopara viticola; Puccinia coronata; Puccinia graminis; Pyricularia oryzae; Pythium ultimum; Rhizoctonia solani; Trichophyton rubrum; and Ustilago maydis. The present invention includes a composition comprising a compound of formula (T), or an agriculturally acceptable salt thereof, and an agriculturally acceptable carrier or diluent. Suitable agriculturally acceptable salts include salts with agriculturally acceptable acids, both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Salts may also be formed with agriculturally acceptable bases such as alkali metal (e.g. sodium or potassium) and alkaline earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines. A preferred agriculturally acceptable salt is the hydrochloride salt. The compounds of the invention may be applied in combination with inert carriers or diluents, as in aqueous sprays, granules and dust formulations in accordance with established practice in the art. An aqueous spray is usually prepared by mixing a wettable powder or emulsifiable concentrate formulation of a compound of the invention with a relatively large amount of water to form a dispersion. Wettable powders may comprise an intimate, finely divided mixture of a compound of the invention, an inert solid carrier and a surface-active agent. The inert solid carrier is usually chosen from among the attapulgite clays, the kaolin clays, the montmorillonite clays, the diatomaceous earths, finely divided silica and purified silicates. Effective surfactants, which have wetting, penetrating and dispersing ability are usually present in a wettable powder formulation in proportions of from 0.5 to 10 percent by weight. Among the surface active agents commonly used for this purpose are the sulfonated lignins, naphthalenesulfonates and condensed naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates and non-ionic surfactants such as products of condensation of ethylene oxide with alkylphenols. Emulsifiable concentrates may comprise a solution of a compound of the invention in a liquid carrier which is a mixture of a water-immiscible solvent and a surfactant, including an emulsifier. Useful solvents include aromatic hydrocarbon solvents such as the xylenes, alkylnaphthalenes, petroleum distillates, terpene solvents, ether-alcohols and organic ester solvents. Suitable emulsifiers, dispersing and wetting agents may be selected from the same classes of products which are employed in formulating wettable powders. The fungicide formulations desirably contain from 0.1 percent to 95 percent by weight of the compound of the invention and from 0.1 to 75 percent of an inert carrier or surfactant. The direct application to plant seeds prior to planting may be accomplished in some instances by mixing either a powdered solid compound of the invention or a dust formulation with seed to obtain a substantially uniform coating which is very thin and represents only one or two percent by weight or less, based on the weight of the seed. In some instances, however, a non-phytotoxic solvent such as methanol is conveniently employed as a carrier to facilitate the uniform distribution of the compound of the invention on the surface of the seed. When a compound of the invention is to be applied to the soil, as for pre- emergence protection, granular formulations or dusts are sometimes more convenient than sprays. A typical granular formulation comprises a compound of the invention dispersed on an inert carrier such as coarsely ground clay, or clay which has been converted to granules by treatment of a rolling bed of the powdered material with a small amount of liquid in a granulating drum. In the usual process for preparing granular formulations, a solution of the active compound is sprayed on the granules while they are being agitated in a suitable mixing apparatus, after which the granules are dried with a current of air during continued agitation. Dust formulations customarily employ essentially the same inert diluents as wettable powders and granules, but are well-mixed in powder form and do not usually contain emulsifiers. Dusts may contain some surface active agents to facilitate uniform distribution of the active ingredient in the formulation and to improve the uniformity and adhesion of the dust coating on seeds and plants. The colloidal dispersion of dust formulations in the air is usually prevented by incorporation of a minor amount of an oily or waxy material in the formulation to cause agglomeration of colloidal size particles. In this way the dust may be applied to seeds or plants without generation of an air-polluting aerosol. The following Examples illusfrate the invention. Examples

Example 1.

4-MethyI-thiobenzoic acid hydrazide To a solution of carbon disulfide (11.4mL, 0.19mol) in anhydrous tetrahydrofuran

(50m?L) was added dropwise p-tolylmagnesium bromide (200mL, IM solution in diethyl ether). The reaction temperature was kept below 45°C so as to maintain a gentle reflux of CS . The resulting deep red mixture was stirred for 1 hour, poured onto ice, acidified with 2N HCL to pH 0.5 and extracted with dichloromethane and toluene until the water layer became colourless. The combined organic phase was the stirred with a solution of hydrazine hydrate (50mL) in water (50mL). The hydrazine layer was taken out and the procedure repeated. Hydrazine layers were combined, neutralised with glacial acetic acid at 0°C until pH 5 and then extracted with toluene. The organic phase was dried over MgSO₄ overnight then evaporated in vacuo. The solid residue was recrystallised from cyclohexane-methanol to give 4-methyl-thiobenzoic acid hydrazide (5g, 18%) as yellow plates.

Example 2.

Spiro S' p-tolyl^'^'-dihydro-ll'^'^'lthi diazol^ S-l^-dihydro-indoI-l-one A mixture of isatin (264mg, 1.8m-M?) and 4-toluic thiohydrazide (166mg, l.OmM) was refluxed in ethanol (7ml) containing 5 drops acetic acid for 20 hours. After cooling to room temperature, the precipitate was filtered and dried to give the titled compound (151mg, 51% yield) as orange crystals.

Example 3.

Spiro 5^,-(p-toIyl)-2',3^,-dihydro-[l',3',4']thiadiazol-2',3-l,3-dihydro-5-methyI-indol- 2-one

Prepared from 5-methyl isatin (291mg, 1.8mMol) and 4-toluic thiohydrazide (166mg, l.O Mol) using the same procedure as example 2. Off-white crystals of the titled compound (15 lmg, 49% yield) were obtained.

Example 4. Spiro S'-φ-tol ^^ S'-dihydro-tl'jS'^'lthiadiazol^'-S-ljS-dihydro-S-b omo-indol- 2-one

A mixture of 5-bromo isatin (813mg, 3.6mMol) and 4-toluic thiohydrazide (338mg, 2.0mMol) was refluxed in ethanol (14mL) with 10 drops acetic acid, for 20 hours. After cooling to room temperature the precipitate was filtered and dried. Brown crystals of the titled compound (467mg, 70.2% yield) were obtained.

Example 5.

Spiro S'^p-toly ^'^'-dihydro-Il'^'^'lthiadiazol-l S-l^-dihydro-l-methyl-indol- 2-one

A mixture of 1 -methyl isatin (291mg, 1.8mMol) and 4-toluic thiohydrazide (166mg, l.OmMol) was refluxed in ethanol (7mL) with 5 drops acetic acid, for 20 hours. After cooling to room temperature the precipitate was filtered and dried. Red crystals of the titled compound (175mg, 57% ? ield) were obtained.

Example 6.

Spiro S'-p-tolyl-l'^'-dihydro-ϊl'jS'^'lthiadiazol^ S-ljS-dihydro-Z-oxo-lH-indole-

5-suIfonic acid

A mixture of 5 -isatin sulfonic acid (450mg, 1.8mMol) and 4-toluic thiohydrazide (166mg, 1.OmMol) was refluxed in ethanol (7mL) with 5 drops acetic acid, for 20 hours. After cooling to room temperature the precipitate was filtered and dried. Orange crystals of the titled compound (174mg, 47% yield) were obtained.

Example 7. 2-Methyl-2-phenyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole

A mixture of acetophenone (217mg, 1.8mMol) and 4-toluic thiohydrazide (166mg, 1. OmMol) was heated under reflxxx in ethanol (7mL) with 5 drops acetic acid for 20 hours. The reaction mixture was evaporated in vacuo and the residual oil was triturated from petroleum ether. The suspension was left overnight at 4°C and the resulting crystalline mass was filtered off and dried. The titled compound (30mg, 11% yield) was obtained as orange crystals. Example 8. 2-Furan-2-yl-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole

A mixture of 2-acetyl furan (199mg, l.δmMol) and 4-toluic thiohydrazide (166mg, 1. OmMol) was heated under reflux in ethanol (7mL) with 5 drops acetic acid, for 20 hours. The reaction mixture was evaporated in vacuo and the resultant crude oil was chromatographed on silica, eluant EtO Ac/Petroleum ether (2:8). The crude product was recrystallised from petroleum ether-methanol to give the titled compound (30mg, 12% yield) as orange crystals.

Example 9.

2-(4-Methoxy-phenyl)-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole

A mixture of 4-methoxy acetophenone (271mg, 1.8mMol) and 4-toluic thiohydrazide (166mg, 1. OmMol) was refluxed in ethanol (7mL) with 5 drops acetic acid, for 20 hours. After cooling to room temperature the precipitate was filtered and dried. Yellow crystals of the titled compound (200mg, 67% yield) were obtained.

Example 10. 2-(4-Chloro-phenyl)-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole

A mixture of 4-chloro acetophenone (279mg, 1.8mMol) and 4-toluic thiohydrazide (166mg, l.OmMol) was refluxed in ethanol (7mL) with 5 drops acetic acid for 20 hours. After cooling to room temperature, the precipitate was filtered and dried to give the titled compound (38mg, 12% yield) as orange plates.

Example 11. 4-[4-(2-Methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-phenyl]-morpholine

A mixture of 4-morpholino acetophenone (371mg, l.δmMol) and 4-toluic thiohydrazide (166mg, 1. OmMol) was heated under reflux in ethanol (7mL) with 5 drops acetic acid for 20 hours. After cooling to room temperature the precipitate was filtered and dried to give the titled compound (143mg, 40% yield) as orange crystals.

Example 12. 4-(2-Methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine Procedure is the same as with example 8, using 3-acetyl pyridine (218mg, 1.8mMol). Off-white crystals of the titled compound (292mg, 60.2% yield) were obtained.

Example 13. (4-Chloro-phenyl)-piperidin-l-yl-methanethione

A mixture of sulphur (859mg, 27 mMol) and 4-chlorobenzaldehyde (3.77g, 26.8mM?ol) was heated under reflux in piperidine (2.28g, 26.8mMol) for 2 hours to give a heterogenous solid mass. Recrystallisation from methanol gave the titled compound (5.03g, 78% yield) as yellow crystals.

Example 14.

4-Chloro-thiobenzoic acid hydrazide

(4-Chloro-phenyl)-piperidin-l -yl-methanethione (5g, 20mMol) and hydrazine monohydrate (5mL, 5 molar excess) were stirred in methanol (15mL) for 5 days at room temperature. The reaction mixture was neutralised with acetic acid and the crude product precipitated. The solid was filtered and washed with water to remove excess hydrazine. The titled compound (1.8g, 46% yield) was obtained as beige crystals after drying under vacuum.

Example 15.

Spiro 5'-(4"-chlorophenyl)-2 ',3'-dihydro-[l '^'Ithiadiazol^-l^-dihydro-indol- 2-one

A mixture of isatin (220mg, 1.5mMol) and 4-chloro-thiobenzoic acid hydrazide (280mg, 1.5mMol) was heated under reflux in ethanol (7mL) with 5 drops acetic acid for 20 hours. Upon cooling, the precipitate was filtered, recrystalhsed from acetonitrile and dried to give the titled compound (189mg, 40% yield) as orange crystals.

Example 16. 5-(4-Chloro-phenyl)-2-fura-α-2'-yl-2-methyl-2,3-dihydro-[l,3,4]thiadiazole A mixture of 2-acetylfuran (165 mg, 1.5 mMol), 4-chlorobenzoic thiohydrazide (280 mg, 1.5 mMol) and 0.5 mL of glacial acetic acid in 7 mL of ethanol was refluxed for 24 hrs. After the mixture was cooled, orange solid precipitated and was collected by filtration and dried to give 110 mg of product. Yield 27%.

Example 17. (3-Hydroxy-phenyl)-piperidin-l-yl-methanethione

A mixture of sulfur (953mg, 39.8 mMol) and 3-hydroxybenzaldehyde (3.63g, 30 mMol) was heated under reflux in piperidine (3.79g, 45mMol) for 2 hours. Upon cooling, the dark green oily mixture was dissolved in ethyl acetate and passed through a pad of silica. The yellow filtrate was concentrated in vacuo to give an oil which crystallised on standing at 4 C. Yellow/green crystals of the titled compound (3.83g, 58% yield) were retrieved.

Example 18.

3-Hydroxy-thiobenzoic acid hydrazide A mixture of (3-hydroxyphenyl)-piperidin-l-yl-methanethione (1.5g, 68mMol) and hydrazine monohydrate (5.25g) was stirred under nitrogen at 50°C. After 2 hours, the reaction mixture was diluted with water (30mL) and the solution carefully adjusted to pH6 with acetic acid (30mL). The desired product was extracted with ethyl acetate (lOOmL), washed with water (2x30mL) and used directly in subsequent reactions. Note: this compound readily dimerises to a symmetrical thiadiazole upon concentration and isolation.

Example 19.

Spiro S'^S'^hydroxy heny ^ S'-dihydro-Il'^'^'lthiadi zol-Z'^-l^-dihydro- indol-2-one

Isatin (1.47g, lOmMol) was added to a solution of crude 3-hydroxy-thiobenzoic acid hydrazide (prepared as in Example 19) and the reaction mixture was heated under reflux for 4 hours, and left to cool overnight. Evaporation in vacuo gave an oil which was chromatographed on silica, (ethyl acetate/petroleum ether eluent) to give orange crystals of the titled compound (189mg, 10%).

Example 20. 3-Methyl-thiobenzoic acid hydrazide a) Preparation of m-tolylmagnesixxm bromide. m-Bromotoluene (14.1 g, 82 mMol) was added dropwise to a mixture of (2.2 g, 92 mMol) of magnesium turnings and 1,2-dibromoethane (0.2 mL) in anhydrous tetrahydrofuran (100 mL) under the nitrogen atmosphere. After the addition was complete, 0.2 mL of 1,2-dibromoethane was added to the vigorously stirred mixture which was cooled using an ice bath. The most of the magnesium dissolved within 1 hr. b) Preparation of m-toluic thiohydrazide.

The tetrahydrofuran solution of m-tolylmagnesixxm bromide was transferred into an oven-dried addition fixnnel under nitrogen and was then added dropwise to an ice-bath cooled mixture of carbon disulfide (5.5 mL) in anhydrous tetrahydrofuran (50 mL). The resulting deep red solution was stirred at room temperature for l?hr, poured onto ice, acidified with 2N HCl(aq) to pH 0.5 and extracted with dichloromethane until the water layer became colourless. The dichloromethane phase was then stirred with 50 mL of hydrazine monohydrate dissolved in 50 mL of water. The hydrazine layer was then taken out and neutralised with glacial acetic acid until pH 5.0. The hydrazine phase was then extracted with toluene and dried over MgSO₄ overnight. The solvent was then evaporated to give 5g of product. Yield 37 %.

Example 21.

Piperidin-l-yl-pyridin-4-yl-methanethione

Piperidine (17.9g, 200 mMol) was slowly added to a stirred mixture of ρyridine-4- carboxaldehyde (15g, 140 mMol) and sulphur (6.7g, 200 mMol), the exothermic reaction occurred causing the mixture to boil. The mixture was stirred and heated at 100°C for 2 ?hrs and then cooled to room temperature. The dark brown oil was poured into cold water (500mL) and stirred for 30 mins until crystallisation commenced. The obtained solid was collected by filtration and recrystalhsed from cyclohexane to give the desired product 29.4 g as yellow crystals.

Example 22.

Thioisonicotinic acid hydrazide Hydrazine hydrate (3.3 mL) was added to a solution of piperidin-l-yl-pyridin-4-yl- methanethione (3g,14 mMol) in methanol (50mL) and the reaction mixture was stirred for 1.5 -hrs. Water (lOOmL) was then added and the mixture was neufralised with glacial acetic acid and extracted with 100 mL of ethyl acetate. The presence of the thiohydrazide was detected by LC/MS and the crude product solution was used immediately in the further reactions.

Example 23.

3-Phenyl-dithiopropionic acid methyl ester To a stirred solution of lithium diisopropylamide (35 m?L, 70 mMol, 2M solution in tetrahydrofuran) in anhydrous tetrahydrofuran (100 mL) were added hydrocinnamic acid (5g, 30 mMol) and ?H?1VIPA (5.75 mL) at -50°C under nitrogen. The reaction mixture was warmed to 35°C over 45 min to complete dianion formation. The solution was recooled to -30°C and carbon disulfide (2.2 mL, 40 mMol) was added. After 20 min., the solution was cooled to -50°C and methyl iodide (2.1 mL, 30mMol) was added. The temperature of the reaction mixture was maintained at -50°C for 45min. The mixture was acidified with diluted 2M HCl(aq) with rapid increase in temperature. The water layer was separated and extracted with petroleum ether (3 x 70 mL). The combined organic layers were washed with dilute HCl(aq), then water, dried over Na₂SO₄ and concenfrated in vacuo. The concentrate was kept at 50°C for lhour and the residual solvent was then evaporated. Column chromatography of the crude yellow oil (silica gel, petroleum ether) gave the title compound (5.3g 85%) as a light yellow oil.

Example 24. 3-Phenyl-thiopropionic acid hydrazide

3-Phenyl-dithiopropionic acid methyl ester (2g,10 mMol) was dissolved in 40 mL of methanol and 4 mL of hydrazine monohydrate were added to the solution. The mixture was stirred at room temperature for 1.5hrs. Water (50m?L) was added to the mixture which was then neutralised with glacial acetic acid and extracted with 100 mL of ethyl acetate. The organic solution of 3-phenyl-thioρropionic acid hydrazide was used immediately in the -further reactions. Example 25.

Spiro 5'-phenethyl-2',3'-dihydro-[l ',3',4']thiadiazol-2',3-l ,3-dihydro-indol-2-one

Isatin (0.7g, 5 mMol) was added to the 3-phenyl-thiopropionic acid hydrazide solution (50mL) obtained previously (example 28) followed by 1 mL of glacial acetic acid. The mixture was stirred at reflux overnight. The solvent was evaporated and the residual solid was purified by column chromatography to give 600mg of bright yellow crystals.

Example 26. 2-Benzofuran-2'-yl-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole 2-Acetyl[b]benzofuran (320 mg, 2mMol) was added to a solution of 4-methyl- thiobenzoic acid hydrazide (352 mg, 2 mMol) in methanol (5 mL) and heated under reflux for 24?hrs. Upon cooling, bright red crystals precipitated and were collected by filtration and dried in vacuo to give 450mg of product.

Example 27.

2-(5'-methylfuran-2'-yl)-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole

2-Acetyl-5-methylfuran (160 mg, 1.2 mMol) was added to a mixture of 4-methyl- thiobenzoic acid hydrazide (200 mg, 1.2 mMol), methanol (5 L) and glacial acetic acid (1.5 mL). The mixture was stirred at reflux for 24 hrs. After cooling, the precipitated solid was collected by filtration, washed with methanol and dried in vacuo to give 150 mg of product.

Example 28.

2-(5'-methylfuran-2'-yl)-2-methyl-5-(4-chlorophenyl)-2,3-dihydro- [l,3,4]thiadiazole

2-Acetyl-5-methylfuran (160 mg, 1.2 mMol) was added to a mixture of of 4- chlorobenzoic thiohydrazide (200 mg, 1.0 mMol), methanol (5mL) and glacial acetic acid (1.5 mL). The mixture was stirred at reflux for 24 hrs. After cooling, the precipitated solid was collected by filtration, washed with methanol and dried in vacuo to give 170 mg of product. Example 29.

Py r azine-2-carb aldehyde

A round bottom flask was charged with pyrazine carboxylic acid (17.7 g, 140 mMol), methanol (200 mL) and cone, sulphuric acid (2 mL) and the mixture was stirred at reflux for 4 hrs then left to stand overnight. The next day the mixture was refluxed for 2 more hours. The solvent was then evaporated in vacuo, the residue was diluted with dichloromethane and neufralised with 20% sodium bicarbonate solution. The dichloromethane phase was dried over MgSO₄ and evaporated to give the crude product as an off-white solid. Purification by column chromatography (silica gel, dichloromethane) gave pyrazinecarboxylic acid methyl ester 13.5 g as a white solid. LiAlH₄ (4g, 100 mMol) was slowly added to a solution of pyrazinecarboxylic acid methyl ester (12.8g, 100 mMol) in tetrahydrofuran (400 mL) at -70° C. The mixture was stirred at this temperature for 40 min, followed by neutralisation with 20 mL of glacial acetic acid. The solvent was evaporated in vacuo and the residue was partitioned between 30 mL of 2N HCL and dichloromethane. A large amount of brown solid precipitated which was filtered off. The dichloromethane layer was passed through a pad of silica, the solvent was evaporated to give the pyrazine 2-carboxaldehyde (1.4g) as a yellow oil.

Example 30.

Spiro 5'-(pyrazin-2"-yl)-2',3'-dihydro-[l',3',4^,]thiadiazol-2^,,3-l,3-dihydro-indol-2- one

A mixture of pyrazine-2-carboxaldehyde (1.1 g, 10 mMol), sulphur powder (0.6 g, 18 mMol), and piperidine (3 mL) was stirred at 110° C for 2 ?hrs. The resultant dark brown mixture was left to stand overnight and then was poured into cold water. The solid was collected by filtration and purified by column chromatography (silica gel, dichloromethane) to give 400 mg of crude thio piperidyl amide as a yellow solid. This was dissolved in methanol (5 mL) and hydrazine hydrate (0.1 mL) was added to the solution. The mixture was stirred at room temperature for 1 hr. More hydrazine hydrate (0.5 mL) was added and the mixture was stirred for 1 ?hr more. After neutralisation with glacial acetic acid the mixture was extracted with ethyl acetate and dried over MgSO₄. Isatin (300 mg) and glacial acetic acid (1 mL) were added to the solution and the reaction mixture was heated under reflux overnight. The solvent was evaporated in vacuo and the residue was recrystalhsed from acetonitrile to give the desired product (130 mg) as a beige solid.

Example 31.

2-Biphenyl-4-yl-2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole

4-Methylthiobenzoic acid hydrazide (0.3g, l.δmmol) and l-biphenyl-4-yl-ethanone

(0.35g, l.δmmol) were dissolved in a 4:1 mixture of MeOH/AcOH (7.5ml) and refluxed for 24 ?hrs. Yellow solid precipitated which was collected by filtration and dried in vacuo to give 2-biphenyl-4-yl-2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole (0.41g, )

Examples 32 to 65.

Examples 32 to 65 set out below were prepared in the same way as in Example 31, using appropriate starting materials. Some examples required purification by silica gel column chromatography.

Example Name 32 2-(4-Chlorophenyl)-2-ethyl-5-p-tolyl-2,3-dihydro-[1 ,3,4]thiadiazole 33 2-(4-Chlorophenyl)-2-propyl-5-p-tolyl-2,3-dihydro-[1,3,4]thiadiazole 34 4-Methyl-2-(?2-methyl-5-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl)pyridine 35 2,6-Bis-(5-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl)pyridine 36 5-Chloro-2-(2-methyl-5-p-tolyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl)pyridine 37 2-(2-Methyl-5-p-tolyi-2,3-dihydro-[1,3,4]thiadiazol-2-yl)-5-phenylpyridine 38 2-Methoxy-6^,-(2-methyI-5-p-tolyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl)-[3,3']bipyridinyl 39 3-Chloro-6-(2-methyl-5-p-tolyl-2,3-dihydro-I1,3,4]thiadiazol-2-yl)pyridazine 40 2-(2,4-Dichlorophenyl)-2-methyl-5-phenyl-2,3-dihydro-[1,3,4]thiadiazole 41 2-(2-Methyl-5-p-tolyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl)pyrazine 42 2-(2-Methyl-5-p-tolyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl)quinoxaline 43 2-[4-(2-Methyl-5-p-tolyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl)-phenyl]-pyridine 44 Spiro S'-p-tolyl-^.S'-dihydro-tr.S'^'lthiadiazol- .I-δ-chloro-indan 45 2-(5-Phenyl-2-pyridin-2-yl-2'3-dihydro-[1 ,3,4]thiadiazol-2-yl)-pyridine 46 2-(2-Methyl-5-pyridin-2-yI-2,3-dihydro-[1,3,4]thiadiazol-2-yl)-pyridine 47 4-(2-Methyl-5-p-tolyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl)benzonitrile 48 Spiro 5^,-(p-hydroxyphenyl)-2',3'-dihydro-[1',3',4^,]thiadiazol-2',3-1,3-dihydro-indol-2-one 49 2-(2-Methyl-5-p-tolyl-2,3-dihydro[1,3,4]thiadiazol-2-yl)pyridine 50 3-(2-Methyl-5-p-tolyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl)pyridine 51 2-(2,4-Dichlorophenyl)-2-methyl-5-p-tolyl-2,3-dihydro[1,3,4]trιiadiazole 52 2-(2-Methyl-5-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl)pyridine 53 3-(p-Tolyl)-4-thia-1,2-diaza-spiro[4.4]non-2-ene 54 2-(4-Nitro-phenyl)-5-p-tolyl-2,3-dihydro[1,3,4]thiadiazole-2-carboxylic acid ethyl ester 55 2-(3,4-Dichlorophenyl)-2-methyl-5-p-tolyl-2,3-dihydro-[1,3,4]thiadiazole 56 2-Phenyl-5-p-tolyl-2-trifluoromethyl-2,3-dihydro-[1,3,4]thiadiazole 57 Acetic acid 2-phenyl-5-p-tolyl-2,3-dihydro-[1 ,3,4]thiadiazol-2-yl-methyl ester 58 1-[6-(2-Methyl-5-p-tolyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl)-pyridin-2-yl]-ethanol 59 2-(2-Methyl-5-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl)quinoline 60 Spiro ^-(p-tolyl^'.S'-dihydro-tr.S'^'lthiadiazol-Z.Θ-ΘH-l.δ-diazafluorene 61 2-(4-Chlorophenyl)-2-methyl-5-phenyl-2,3-dihydro-[1,3,4]thiadiazole 62 2-Biphenyl-4-yl-2-methyl-5-phenyl-2,3-dihydro-[1,3,4]thiadiazole 63 2-(2-Methyl-5-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl)pyrazine 64 Spiro δ'-tp-tolylJ-Σ'.S'-dihydro-tr.S'^'lthiadiazol-Z^-chroman 65 Spiro ^-(m-toly -Z.S'-dihydro-II'.S'^'lthiadiazol-^.S-I.S-dihydro-indol^-one

Example 66. l-(5-Phenyl-pyridin-2-yl)-ethanone

2-Bromo-5-phenyl-pyridine (2.2g, 9mmol) was added to dry diethyl ether (250ml). The mixture was cooled to -60°C and a solution of n-BuLi (2.5M in hexane, 4mL) was added dropwise and the mixture was stirred for 2hrs. N,N-dimethylacetamide (lmL) in diethyl ether (15ml) was then added slowly dropwise and the solution was left to stir for 3?hrs. The system was brought to room temperature, hydrolysed with 2N HC1 and exfracted with DCM. The organic phase was washed with water, dried over MgSO4 and evaporated to give l-(5-phenyl-pyridin-2-yl)-ethanone (l.Og, 54%). Examples 67 to 69.

Examples 67 to 69 set out below were prepared in the same way as in Example 66, using appropriate starting materials. Example Name 67 1-(2'Methoxy-[3,3']bipyridinyl-6-yl)-ethsnone 68 1-(4-Pyridin-2-yl-phenyl)-ethanone 69 1-(6-Chloro-pyridazin-3-yl)-ethanone

Example 70. 2-Bromo-5-phenyl-pyridine

2-Bromo-5-iodopyridine (4.4g, 16mmol) was dissolved in toluene (70ml). To this solution benzene boronic acid (2.6g, 20mmol) was added-, followed by aqueous K2CO3 (8.5M, 70ml) and Pd(Ph₃P) (23mg, 0.02mmol). The mi xtxxre was vigorously stirred at 120°C for 4 days. The solvent was evaporated in vacuo and the residue was purified by column chromatography to give 2-bromo-5-phenyl-pyridi:ne (3.5g, 93%).

Examples 71 to 72. Examples 71 to 72 set out below were prepared in the same way as in Example 70, using appropriate starting materials. Example Name 71 6'-Bromo-2-methoxy-[3,3']bipyridinyl 72 3-Bromo-6-chloro-pyridazine

Example 73. 2-Bromo-5-iodo-pyridine

Bromine (3ml) was added dropwise to a solution of 2-amino-5-iodo-pyridine (5g, 20mmol) in 48% hydrobromic acid in water (10ml). An. ice bath was used to cool the system. Sodium nitrite (3.4 g in 5ml of water) was then added dropwise so that the temperature does not go above 15°C. After the addition was complete, sodium hydroxide (16g) in water (40ml) was added. Brown solid precipitated and was exfracted with DCM (50ml). The DCM extract was washed with water, brine, dried over MgSO₄ and evaporated in vacuo to give 2-bromo-5-iodo-pyridine (4.4g, 78%). Example 74. l-(5-Chloro-pyridin-2-yl)-ethanone

2-Bromo-5-chloropyridine (5.8g, 30mtnol) was added to dry diethyl ether (100ml). The mixture was cooled to -60°C and a solution of sec-BuLi (1.4M solution in hexanes, 22mL) was added dropwise and the mixture was stirred for 2?hrs. A solution of N,N- dimethylacetamide (3.1ml, 33mmol) in diethyl ether (20ml) was added slowly dropwise and the solution left to stir for 3hrs. The reaction was brought to room temperature, hydrolysed with 2N HC1 and extracted with DCM. The organic phase was washed with water, dried over MgSO4 and evaporated to give l-(5-Chloro-pyridin-2-yl)-ethanone (4.0g, 85%).

Example 75. l-Quinolin-3-yl-ethanone l-Quinolin-3-yl-ethanol (0.92g, 5.3mmol) and Dess-Martin periodane (2.48g, 5.8 mmol) in DCM (12ml) were stirred at room temperature for 3 hrs. The reaction mixture was diluted with ether and neutralised with NaOH (IM). The mixture was extracted with ether, washed with brine and dried over MgSO₄. Recrystallisation from ether gave pure l-quinolin-3-yl-ethanone (0.8 lg, 89%).

Example 76. l-Quinolin-3-yl-ethanol

2-Quinolinecarbaldehyde (3g, 19mmol) was dissolved in anhydrous diethyl ether under nitrogen. Methylmagnesium bromide (3M, 7ml, 21 mmol) was added dropwise and the reaction mixture was refluxed for 3 ?hrs. It was cooled to room temperature and stirred for 2 days. The reaction mixture was quenched with saturated ammonium chloride. The mixture was exfracted with ether and dried over Na SO₄. The solvent was evaporated in vacuo to give brown solid. Further recrystallisation from hot ether gave l-quinolin-3-yl- ethanol (0.92g, 28%).

Example 77. l-Quinoxalm-2-yl-ethanone Quinoxaline (0.65g, 5 mmol), pyruvic acid (1.32g, 15 mmol), AgN0₃ (0.068g, 0.4 mmol), (NH₄)₂S₂O₈ (1.71g, 7.5 mmol), CF₃CO₂H (1.7g, 15 mmol) were dissolved in a 1:1 mixture of DCM/H₂O (50ml). The reaction mixture was stirred at 40° C. After cooling to room temperature the mixture was exfracted with DCM, wa-shed with brine and dried over Mg SO₄, then evaporated to give l-quinoxalin-2-yl-ethanone (0.89g, 100%).

Example 78. Analytical data for compounds representative of Examples 1 to 77.

Examples 79 to 96 are available commercially and have also been shown to have anti- fungal activity in accordance with the present invention. Example 79. 2-[2,3-Dihydro-5-(phenylmethyl)-l,3,4-thiadiazol-2-yl]-4-methoxy-phenol

Example 80. 3-(Phenylmethyl)- 4-thia-l,2-diazaspiro[4.7]dodec-2-ene

Example 81. 2-[4,5-dihydro-5-methyl-5-(5-methyl-2-furanyl)-l,3,4-thiadiazol-2-yl]-phenol

Example 82.

5-Ethyl-5'-(2-hydroxyphenyl)- spiro[3H-mdole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)- one

Example 83. l-Methyl-5'-(l-naphthalenyl)- spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)- one

Example 84.

4-(2,3-Dihydro-5-phenyl-l,3,4-thiadiazol-2-yl)-phenol

Example 85. l-[(2,6-Dichlorophenyl)methyl]-5'-phenyl- spiro[3H-indole-3,2'(3Η)-

[l,3,4]thiadiazol]-2(lH)-one

Example 86.

5^,-(2-Hydroxyphenyl)- spiro[3H-indole-3,2'(3'H)-[l,3,4]thiadiazol]-2(lH)-one

Example 87.

2-[2,3-Dihydro-5-(4-tolyl)-l,3,4-thiadiazol-2-yl]-(4-methoxy)-phenol

Example 88. 2-(4-Cyclohexylphenyl)-2,3-dihydro-2-methyl-5-phenyl-l,3,4-thiadiazole Example 89. 3-(Phenylmethyl)-4-thia-l,2-diazaspiro[4.11]hexadec-2-ene

Example 90.

Spiro 5^,-(2-hydroxyphenyl)-2',3^,-dihydro-[l',3^,,4^,]thiadiazol-2^, ₅3-l,3-dihydro-5- ethyl-indol-2-one,

Example 91. 7,7-Dimethyl-3-phenyl-8-oxa-4-thia-l,2-diaza-spiro[4.5]dec-2-ene

Example 92. 2-(4-hydroxyphenyl)-5-(benzyl)-2,3-dihydro-[l,3,4]thiadiazole

Example 93.

Spiro S'-φhenyl '^'-dihydro-tl'jS'^'lthiadiazol^'^-l^-dihydro-S-methyl-indol- 2-one

Example 94. Spiro S'- phenyl^'^'-dihydro-Il S'^'Jthiadiazol^'^-l^-dihydro-S-bromo-l- methyl-indol-2-one

Example 95.

Spiro S' phenyl^'^'-dihydro-tl S'^'lthiadiazol^ S-l^-dihydro-S-bromo-indol- 2-one

Example 96.

Spiro S'- enzyl^'^'-dihydro-Il'^'^'lthiadiazol-∑ S-l^-dihydro-S-ethyl-indol^- one

It is envisaged that the following compounds can be synthesised according to the general reaction conditions described in Example 8, using appropriate starting materials: Example 97. 2-Methyl-2-thiophen-2-yl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole,

Example 98.

3-(5-Furan-2-yl-5-methyl-4,5-dihydro-[l,3,4]thiadiazol-2-yl)-phenol,

Example 99.

2-Furan-2-yl-2-methyl-5-(m-tolyl)-2,3-dihydro-[l,3,4]thiadiazole,

Example 100. 4-(5-Furan-2-yl-5-methyl-4,5-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine,

Example 101. 4-[5-(4-Chloro-phenyl)-2,3-dihydro-[l,3,4]thiadiazol-2-yI]-phenol,

Example 102. 2-(5-Bromothiophen-2-yl)-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole.

Example 103.

Measurement of minimum inhibitory concentrations (MICs) Between 1 and 5mgs of compound were accurately weighed out into a sterile Eppendorf tube. The compound was dissolved in DMSO to give a solution containing 5mg/ml. Tubes were stored at -20°C until required. On the day of testing thawed solutions were vortex mixed to ensure homogeneity. 30μl of solution was removed and added to 570μl of sterile water in a separate sterile Eppendorf. The thoroughly mixed solution was used to prepare a series of doubling dilutions in water, in a deep well plate. Eleven replicate plates were prepared using a Minifrak by aspirating 20μl from each well into eleven clear polystyrene 96 well plates. Spores of AspergiUus spp were harvested from cultures grown on Sabaurads agar, and resuspended in PBS/Tween 80 to approx lxlO⁷ cfix/ml. Harvested cultures of yeasts from sabaraud agar were resuspended in PBS/Tween 80 to approx lxlO⁶ cfu/ml. Each organism suspension was diluted in ?RPMI medium, containing 2% glucose and 0.135M MOPS buffer (pH7.0) to 2xl0⁴ cfu/ml for AspergiUus spp and 2x 10³ cfix/ml for yeast. 80μL of an organism suspension was added to each well of the plate containing drug dilutions. This produced MIC plates with a drug range 50-0.05 mg/L and organism inocula of l-2xl0⁴ cfu/ml for AspergiUus spp and 1-2 xlO³ cfix/ml for yeasts. AU plates were incubated for 44-48hrs at 35°C. Growth was assessed by monitoring the optical density at 485nm for each well. The MIC of a compound is the lowest drug concentration that inhibits growth of an organism by >80% compared with a drug free confrol. MICs are recorded as mg/L. The following organisms were tested: AspergiUus fumigatus AF293, AspergiUus niger, AspergiUus terreus, AspergiUus flavus, Candida albicans, Candida -krusei, Candida tropicalis, Candida glabrata, Candida parapsilosis. Table 1 shows the antifungal MICs of selected compounds of the invention against AspergiUus and Candida species. Table 1: MICs in μg/mL against AspergiUus and Candida spp

Table 1 continued

Table 2: MICs of commercial compounds in μg/mL against AspergiUus and Candida spp

10

Claims

1. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or freatment of a fungal disease:

wherein: RI is aryl, heterocyclyl, -CR8R9-X-aryl, -CR8R9-X-heterocyclyl, -CR8R9-X- (C 1 -C4 alkylene)-aryl, -CR8R9-X-(C 1 -C4 alkylene)-heterocyclyl, -(C2-C4 alkenylene)- aryl or -(C2-C4 alkenylene)-heterocyclyl; R8 and R9 independently represent hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, halogen or hydroxy; X is a bond, -O-, -S-, -SO-, -SO₂- or -NR'-; R2 and R3 independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-

C8 alkynyl, aryl, heterocyclyl, -CO₂R', -CONR'R", -COR', -CN, -CF₃ or -Y-Z; or R2 represents hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heterocyclyl, -CO₂R\ -CO? R'R", -COR', -CN, -CF₃ or -Y-Z and R3 is an aryl or heterocyclyl group which is substituted with a group (lb)

wherein M * represents the position of attachment to R3, RI ' is aryl, heterocyclyl, -CR8R9-X-aryl, -CR8R9-X-heterocyclyl, -CR8R9-X-(C1-C4 alkylene)- aryl, -CR8R9-X-(C 1 -C4 alkylene)-heterocyclyl, -(C2-C4 alkenylene)-aryl or -(C2-C4 alkenylene)-heterocyclyl, wherein R8, R9 and X are, independently, as defined above, and R2' represents hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heterocyclyl, -CO₂R', -CONR'R", -COR', -CN, -CF₃ or -Y-Z; or R2 and R3, together with the carbon atom to which they are attached, form a non-aromatic monocyclic 5- to 16-membered carbocyclyl or heterocyclyl group, which is optionally fused to one or two aryl or heterocyclyl groups; Y is C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene; Z is halogen, aryl, heterocyclyl, cycloalkyl, -OR', -SR', -SOR', -SO₂R', - SO₂?NR'R", -SO₃H, -NR'R", -NR'COR", -NO₂, -CO₂R', -CONR'R", -COR', -OCOR', -CN or -CF₃; and R' and R" independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-

C6 alkynyl, aryl, heterocyclyl, -(C1-C6 alkylene)-aryl, -(C1-C6 alkylene)-heterocyclyl, -(C2-C6 alkenylene)-aryl, -(C2-C6 alkenylene)-heterocyclyl, -(C2-C6 alkynylene)-aryl or -(C2-C6 alkynylene)-heterocyclyl.

2. Use according to claim 1, wherein RI is aryl, heterocyclyl or -CH₂-aryl.

3. Use according to claim 2, wherein RI is substituted or unsubstituted phenyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted benzyl or substituted or unsubstituted naphthylenyl.

4. Use according to any one of claims 1 to 3, wherein R2 represents hydrogen, C1-C4 alkyl, -CO₂R', -CONR'R", -COR', -CN, -CF_3> -Y-Z or heterocyclyl; R3 is aryl or heterocyclyl; Y is C1-C3 alkylene; Z is fluorine, -OR', -SR', -SOR', - SO₂R', -NR'R", -NR'COR", -CO₂R', -CONR'R", -OCOR', -CN or -CF₃; and R' and R" independently represent hydrogen, C1-C6 alkyl, aryl or heterocyclyl.

5. Use according to any one of claims 1 to 3, wherein R2 represents methyl, ethyl, propyl, -CF₃, -CH₂O-(Cl-C4 alkyl), -CO₂R', -CO?NR'R", -CH₂OCO-(Cl-C4 alkyl) or -CN; R3 is aryl, heterocyclyl, -CO₂R', -CONR'R" or -CN; and R' and R" independently represent hydrogen, C1-C3 alkyl, aryl, heterocyclyl or optionally substituted benzyl.

6. Use according to any one of claims 1 to 3, wherein R2 is hydrogen and R3 is phenyl or pyridyl which is substituted with a single substituent of formula (lb) wherein RI ' is identical to RI and R2' is hydrogen.

7. Use according to any one of claims 1 to 3, wherein ?R2 and R3, together with the carbon atom to which they are attached, form a 5- to 8-membered carbocycle or heterocycle optionally fused to an aryl or heterocyclyl ring.

8. Use according to claim 1 of a compound of formula (la) or a pharmaceutically acceptable salt thereof:

wherein: RI is as defined in claim 1 ; R4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or -Y-Z as defined in claim 1; and R5, R6 and R7 independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or Z as defined in claim 1.

9. Use according to any one of claims 1 to 3, wherein R2 is methyl; R3 is - CO?NR'R"; and R' and R" independently represent hydrogen, C1-C4 alkyl, aryl or heterocyclyl.

10. Use according to any one of claims 1 to 3, wherein R2 is methyl and R3 is a substituted or unsubstituted furanyl or thiophenyl ring.

11. Use according to claim 1 of: 2-(4-Chloroρhenyl)-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-(4-Cyclohexylphenyl)-2-methyl-5-(phenyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-(4-Methoxyphenyl)-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-(5-Methylfixran-2-yl)-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-(5-Methylfuran-2-yl)-2-methyl-5-(2-hydroxyphenyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-(5-Methylfuran-2-yl)-2-methyl-5-(4"-chlorophenyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-Fxιran-2-yl-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-Furan-2-yl-2-methyl-5-phenethyl-2,3-dihydro-[l,3,4]thiadiazole, 2-Furan-2-yl-2-methyl-5-(4-chlorophenyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-Furan-2-yl-2--methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazole, 2-Pyrrol-2-yl-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-Methyl-2,5-di-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole, 2-Methyl-2-ρhenyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-Methyl-2-thiophen-2-yl-5-(4-chlorophenyl)-2,3 -dihydro-[ 1 ,3 ,4]thiadiazole, 2-Methyl-2-thiophen-2-yl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-Methyl-2-(5-bromothiophen-2-yl)-5-(ρ-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-Methyl-2-(5-bromothiophen-2-yl)-5-(4-chloroρhenyl)-2,3-dihydro-[l,3,4]thiadiazole, 3-(5-Furan-2-yl-5-methyl-4,5-dihydro-[l,3,4]thiadiazol-2-yl)-phenol, Spiro 5'-(benzyl)-2^3'-dihydro-[1^3^4']thiadiazol-2 -cyclododecane, 4-(5-Furan-2-yl-5-methyl-4,5-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine, 4-[4-(2-Methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-phenyl]-morpholine, Spiro 5^,-(3-hydroxyphenyl)-2',3^,-dihydro-[l^,,3^,,4^,]thiadiazol-2^,,3-l,3-dihydro-indol-2- one, Spiro S'-Oenzy^^'^'-dihydro-tl'^'^^thiadiazoWJ-cyclooctane,

Spiro 5'-(4-chlorophenyl)-2',3'-dihydro-[r,3',4']thiadiazol-2',3-l,3-dihydro-indol-2-one, Spiro 5^,-(4-ρyridyl)-2^,,3^,-dihydro-[r,3',4']thiadiazol-2^,,3-l,3-dihydro-indol-2-one, Spiro 5'-(m-tolyl)-2',3 '-dihydro-[ 1 ',3 ',4']thiadiazol-2',3- 1 ,3 -dihydro-indol-2-one, Spiro S'-phenethyl^'^'-dihydro-tl'^'^^thiadiazoW^-l^-dihydro-indol^-one, Spiro 5'-ρhenyl-2',3'-dihydro-[l',3',4']thiadiazol-2',3-l,3-dihydro-indol-2-one,

Spiro S'-p-tolyl^'^'-dihydro-Cl'^'^'lthiadiazol^'^-l^-dihydro-l-methyl-indol^-one, Spiro S'-p-tolyl^'^'-dihydro-tr^'^'jthiadiazoW^-l^-dihydro-indol^-one, Spiro S'- -toly^^'^'-dihydro-fr^'^^thiadiazol^'^-chroman, Spiro 5'-(p-tolyl)-2',3'-dihydro-[1',3',4']thiadiazol-2',3-1,3-dihydro-5-methyl-indol-2- one,

Spiro 5'-(2-hydroxyphenyl)-2',3'-dihydro-[l^,,3^,,4']thiadiazol-2',3-l,3-dihydro-5-ethyl- indol-2-one,

Spiro S'- -toly^^'^'-dihydro-fr^'^^thiadiazol^'^-S-bromo-l^-dihydro-indol^- one, 7,7-Dimethyl-3-phenyl-8-oxa-4-thia-l,2-diaza-spiro[4.5]dec-2-ene,

2-Benzofuran-2-yl-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-(2-hydroxy-5-methoxyphenyl)-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-(2-hydroxy-5-methoxyphenyl)-5-(benzyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-(4-hydroxyphenyl)-5-(benzyl)-2,3-dihydro-[l,3,4]thiadiazole, Spiro 5^,-(phenyl)-2^,,3'-dihydro-[r,3',4']thiadiazol-2^,,3-l,3-dihydro-l-(2,6- dichlorobenzyl)-indol-2-one, Spiro 5^,-(2-hydroxyphenyl)-2',3'-dihydro-[r,3',4']thiadiazol-2',3-l,3-dihydro-indol-2- one,

Spiro 5^,-(phenyl)-2',3^,-dihydro-[l^,,3^,,4']thiadiazol-2^,,3-l,3-dihydro-5-methyl-indol-2- one, Spiro 5'-(phenyl)-2',3^,-dihydro-[ 1 ^,,3',4']thiadiazol-2',3-l ,3-dihydro-5-bromo- 1 -methyl- indol-2-one,

Spiro S'- heny ^'^'-dihydro-Cr^'^^thiadiazoW^-l^-dihydro-S-bromo-indol^- one,

Spiro S'- enzy^^'^'-dihydro-fl'^'^^thiadiazoW^-l^-dihydro-S-ethyl-indol^-one,

2-Biphenyl-4-yl-2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole, 2-(4-Chlorop enyl)-2-ethyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole, 2-(4-Chlorophenyl)-2-propyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole, 4-Methyl-2-(2-methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridine, 2,6-Bis-(5-phenyl-2,3-dihydro-[ 1 ,3,4]thiadiazol-2-yl)pyridine, 5-Chloro-2-(2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridine, 2-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-5-phenylpyridine,

2-Methoxy-6'-(2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-[3,3^,]bipyridinyl, 3-Chloro-6-(2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)ρyridazine, 2-(2,4-Dichlorophenyl)-2-methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazole, 2-(2-Methyl-5-ρ-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyrazine, 2-(2-Methyl-5 -p-tolyl-2,3-dihydro-[ 1 ,3,4]thiadiazol-2-yl)quinoxaline,

2-[4-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-phenyl]-pyridine, Spiro S'-p-tolyW^'-dihydro-fr^'^^thiadiazol^ -S-chloro-indan, 2-(5-Phenyl-2-pyridin-2-yl-2'3-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine, 2-(2-Methyl-5 -pyridin-2-yl-2,3-dihydro-[ 1 ,3,4]thiadiazol-2-yl)-pyridine, 4-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)benzonitrile,

Spiro S'- -hydroxypheny ^'^'-dihydro-tl'^'^^thiadiazoW^-LS-dihydro-indol^- one, 2-(2-Methyl-5-p-tolyl-2,3-dihydro[l,3,4]thiadiazol-2-yl)pyridine, 3-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridine, 2-(2,4-Dichlorophenyl)-2-methyl-5-p-tolyl-2,3-dihydro[l,3,4]thiadiazole, 2-(2-Methyl-5-phenyl-2₅3-dihydro-[l,3,4]thiadiazol-2-yl)pyridine, 3-(p-Tolyl)-4-thia-l,2-diaza-spiro[4.4]non-2-ene,

2-(4-Nifro-phenyl)-5-p-tolyl-2,3-dihydro[l,3,4]thiadiazole-2-carboxylic acid ethyl ester,

2-(3,4-Dichlorophenyl)-2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole,

2-Phenyl-5-p-tolyl-2-trifluoromethyl-2,3-dihydro-[l,3,4]thiadiazole,

Acetic acid 2-phenyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl-methyl ester, l-[6-(2-Methyl-5-ρ-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-pyridin-2-yl]-ethanol, 2-(2-Methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)quinoline, Spiro S'- -toly ^'^'-dihydro-Cr^'^'lthiadiazol^'^-ΘH-l^-diazafluorene, 2-(4-Chlorophenyl)-2-methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazole, 2-Biphenyl-4-yl-2-met yl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazole, 2-(2-Methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyrazine,

5-Ethyl-5'-(2-hydroxyphenyl)- spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, l-Methyl-5'-(l-naphthalenyl)- spiro[3H-indole-3,2'(3Η)-[l₅3,4]thiadiazol]-2(lH)-one, 4-(2,3 -Dihydro-5-phenyl- 1 ,3 ,4-thiadiazol-2-yl)-phenol, 2-(4-Cyclohexylphenyl)-2,3-dihydro-2-methyl-5-phenyl-l,3,4-thiadiazole, Spiro S'-p-tolyW^'-dihydro-tl'^'^'jthiadiazoW^-l^-dihydro^-oxo-lH-indole-S- sulfonic acid,

4-(2-Methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine, Spiro 5'-(pyrazin-2"-yl) -2',3 '-dihydro-[ 1 ',3 ',4']thiadiazol-2',3 - 1 ,3 -dihydro-indol-2-one, 2-[2,3-Dihydro-5-(phenylmethyl)-l,3,4-thiadiazol-2-yl]-4-methoxy-phenol 3-(Phenylmethyl)- 4-thia-l,2-diazaspiro[4.7]dodec-2-ene

2-[4,5-dihydro-5-methyl-5-(5-methyl-2-furanyl)-l,3,4-thiadiazol-2-yl]-phenol, l-[(2,6-Dichlorophenyl)methyl]-5'-phenyl- spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]- 2(lH)-one, 5'-(2-Hydroxyphenyl)- spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 2-[2,3-Dihydro-5-(4-tolyl)- 1 ,3,4-thiadiazol-2-yl]-(4-methoxy)-phenol, 3 -(Phenylmethyl)-4-thia- 1 ,2-diazaspiro[4.11 ]hexadec-2-ene, or a pharmaceutically acceptable salt thereof.

12. Use according to any one of claims 1 to 11, wherein the disease is caused by Candida or AspergiUus species.

13. Use according to any one of claims 1 to 11, wherein the disease is caused by a fungal dermatophyte.

14. Use according to any one of claims 1 to 11, wherein the disease is Allergic Bronchopulmonary Aspergillosis (ABPA).

15. Use according to any one of claims 1 to 11, wherein the disease is asthma.

16. An agent for the treatment of a fungal disease comprising a compound of formula (I) as defined in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

17. A method of treating a subject suffering from or susceptible to a fungal disease, which method comprises administering to said subject an effective amount of a compound of formula (I) as defined in any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof.

18. A compound of formula (I) as defined in any one of claims 1 to 11, excluding Spiro 5'-p-tolyl-2',3^,-dihydro-[ ,3',4^,]thiadiazol-2',3-l,3-dihydro-5-methyl- indol-2-one, or a pharmaceutically acceptable salt thereof, for use in a method for treatment of the human or animal body by therapy.

19. A compound of formula (I) as defined in any one of claims 1 to 11, excluding:

(a) compounds of formula (I) in which: RI is unsubstituted phenyl or phenyl substituted by one to five groups selected from C1-C4 alkyl, halogen, nitro, cyano, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 haloalkyl containing 1 to 9 halogen atoms, C1-C4 haloalkoxy containing 1 to 9 halogen atoms, C1-C4 haloalkylthio containing 1 to 9 halogen atoms, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, pyridyloxy and substituted pyridyloxy; and one of the groups ?R2 and R3 is hydrogen or C1-C4 alkyl, and the other of the groups R2 and R3 is pyridyl;

(b) compounds of formula (I) in which: RI is xmsubstituted phenyl or phenyl substituted by one to three groups A; A is halogen, C1-C6 alkyl, C1-C6 haloalkyl, OA₆, S(O)_qA₇, nitro, cyano, NA₈A₉, CO₂Aι₀, C(O)An or phenyl optionally substituted with any combination of from one to three halogen, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, C 1 -C6 alkylthio or C1-C6 haloalkylthio groups, or two adjacent A groups may be taken together to form a ring wherein AA is represented by: -OCH₂O-, -OCF₂O- or -CH=CH-CH=CH-; A₆ and A₇ are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or phenyl optionally substituted with any combination of from one to three halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C4 haloalkoxy, C1-C6 alkylthio or C1-C6 haloalkylthio groups; A₈, A₉, Aι₃ and A₁₄ are each independently hydrogen, C1-C6 alkyl, C1-C6 alkylcarbonyl or phenyl optionally substituted with any combination of from one to three halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio or C1-C6 haloalkylthio groups; Aio and An are each independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; R2 and R3 are each independently hydrogen, C3-C7 cycloalkyl, C1-C6 haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 haloalkynyl, C2- C6 alkoxyalkyl, (CH₂)_vC(O)Aι₂, C1-C6 alkyl optionally substituted with one phenoxy or phenyl group wherein the phenyl ring of each group is independently, optionally substituted with from one to three halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio or C1-C6 haloalkylthio groups, phenyl optionally substituted with from one to three halogen, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio or C1-C6 haloalkylthio groups, or a 5- or 6-membered heteroaromatic ring optionally substituted with any combination of from one to three halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, Cl -C6 haloalkoxy, C1-C6 alkylthio or C1-C6 haloalkylthio groups, and when R2 and R3 are taken together with the atom to which they are attached they may form a C3-C6 cycloalkyl ring wherein R2R3 is represented by: -(CH )_t- where t is 2, 3, 4 or 5; q and v are each independently 0, 1 or 2; and Aw is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio or NAι₃A₁ ; and (c) the following compounds:

2,3-dihydro-5-(4-methoxyphenyl)-2-rrιethyl- 1 ,3,4-Thiadiazole-2-butanoic acid, (2,3-dihydro-2,5-diphenyl-l,3,4-thiadiazol-2-yl)phenyl-Methanone, 2,3-dihydro-2-(4-methoxyphenyl)-2-rrιethyl-5-(4-methylphenyl)-l,3,4-Thiadiazole, 2,3-dihydro-2-(4-methoxyphenyl)-2-n-ιethyl-5-phenyl-l,3,4-Thiadiazole, 2,3-dihydro-2-(4-methoxyphenyl)-5-(4-methylphenyl)-l,3,4-Thiadiazole-2-acetic acid ethyl ester, 2,3-dihydro-2-(methoxycarbonyl)-5-(4-methoxyphenyl)-l,3,4-Thiadiazole-2-acetic acid, methyl ester,

2,3-dihydro-2-(methoxycarbonyl)-5-phenyl-l,3,4-Thiadiazole-2-acetic acid, methyl ester,

2,3-dihydro-2,2,5-triphenyl-l,3,4-Thiadiazole,

2,3-dihydro-2,2-dimethyl-5-(4-methylρhenyl)-l,3,4-Thiadiazole, 2,3-dihydro-2,2-dimethyl-5-(phenylmethyl)-l ,3,4-Thiadiazole,

2,3-dihydro-2,2-dimethyl-5-phenyl-monohydratel,3,4-Thiadiazole,

2,3 -dihydro-2,2-dimethyl-5-phenyl-monohydrochloride 1 ,3 ,4-Thiadiazole,

2,3-dihydro-2,2-dimethyl-5-phenyl-l,3,4-Thiadiazole,

2,3-dihydro-2,5-dimethyl-2-[(5-methyl-l,3,4-thiadiazol-2-yl)methyl]-l,3,4-Thiadiazole, 2,3-dihydro-2,5-diphenyl-l,3,4-Thiadiazole-2-carboxylic acid, ethyl ester,

2,3-dihydro-2-methyl-2-(2-methylpropyl)-5-(phenylmethyl)-l,3,4-Thiadiazole, 2,3-dihydro-2-methyl-2-(2-methylpropyl)-5-phenyl-l,3,4-Thiadiazole, 2,3-dihydro-2-methyl-2-(4-nitrophenyl)-5-(phenylmethyl)-l,3,4-Thiadiazole, 2,3-dihydro-2-methyl-2-(4-nitrophenyl)-5-phenyl-l,3,4-Thiadiazole, 2,3-dihydro-2-methyl-2-(5-methyl-2-furanyl)-5-(4-methylphenyl)-l,3,4-Thiadiazole, 2,3-dihydro-2-methyl-2-(5-methyl-2-furanyl)-5-phenyl-l,3,4-Thiadiazole, 2,3-dihydro-2-methyl-2,5-diphenyl-monohydrochloridel,3,4-Thiadiazole, 2,3-dihydro-2-methyl-2,5-diphenyl-l,3,4-Thiadiazole, 2,3-dihydro-2-methyl-2-phenyl-5-(phenyhnethyl)-l,3,4-Thiadiazole, 2,3-dihydro-2-methyl-5-( 1 -naphthalenyl)-N-(phenylmethyl)- 1 ,3 ,4-Thiadiazole-2- acetamide, 2,3-dihydro-2-methyl-5-(l-naphthalenyl)-N-phenyl-l,3,4-Thiadiazole-2-acetamide, 2,3-dihydro-2-methyl-5-(4-methylphenyl)-l ,3,4-Thiadiazole-2-propanoic acid, ethyl ester,

2,3-dihydro-2-methyl-5-(4-methylphenyl)-l,3,4-Thiadiazole-2-acetic acid, ethyl ester, 2,3-dihydro-2-methyl-5-(4-methylphenyl)-l,3,4-Thiadiazole-2-acetic acid, methyl ester, 2,3-dihydro-2-methyl-5-(4-methylρhenyl)-2-(2-naphthalenyl)-l,3,4-Thiadiazole, 2,3-dihydro-2-methyl-5-(4-methylphenyl)-2-(4-nitrophenyl)-l,3,4-Thiadiazole, 2,3-dihydro-2-methyl-5-(4-methylρhenyl)-2-(5,6,7,8-tefrahydro-2-naphthalenyl)-l,3,4- Thiadiazole, 2,3-dihydro-2-methyl-5-(4-methylphenyl)-N-(phenylmethyl)-l,3,4-Thiadiazole-2- acetamide,

2,3-dihydro-2-methyl-5-(4-methylphenyl)-N-phenyl-l,3,4-Thiadiazole-2-acetamide, 2,3-dihydro-2-methyl-5-phenyl-l,3,4-Thiadiazole-2-acetic acid, methyl ester, 2,3-dihydro-2-methyl-5-phenyl-l,3,4-Thiadiazole-2-acetic acid, ethyl ester, 2,3-dihydro-2-methyl-5-phenyl-l,3,4-Thiadiazole-2-carboxylic acid, ethyl ester, 2,3-dihydro-2-methyl-5-phenyl-2-(5,6,7,8-tefrahydro-2-naρhthalenyl)-l,3,4- Thiadiazole,

2,3-dihydro-2-methyl-5-ρhenyl-2-[(5-ρhenyl-l,3,4-thiadiazol-2-yl)methyl]-l,3,4- Thiadiazole, 2,3-dihydro-2-methyl-5-phenyl-2-propyl- 1 ,3,4-Thiadiazole, 2,3-dihydro-2-methyl-5-phenyl-N-(phenyhnethyl)-l,3,4-Thiadiazole-2-acetamide, 2,3-dihydro-2-methyl-N,5-diphenyl-l,3,4-Thiadiazole-2-acetamide, 2,3-dihydro-5-(l -naphthalenyl)-2-phenyl- 1 ,3,4-Thiadiazole-2-carboxylic acid, ethyl ester, 2,3-dihydro-5-(4-methoxyphenyl)-2,2-dimethyl- 1 ,3,4-Thiadiazole, 2,3-dihydro-5-(4-methoxyphenyl)-2-methyl-l ,3,4-Thiadiazole-2-propanoic acid, 2,3-dihydro-5-(4-methoxyphenyl)-2-methyl-2-phenyl-l,3,4-Thiadiazole, 2,3-dihydro-5-(4-methylphenyl)-2,2-bis phenylmethyl)-l,3,4-Thiadiazole, 2,3-dihydro-a,2-dimethyl-5-phenyl-l,3,4-Thiadiazole-2-acetic acid, methyl ester,

2,3-dihydro-N-hydroxy-2-methyl-5-(4-methylphenyl)-N-(phenylmethyl)-l,3,4-

Thiadiazole-2-acetamide,

2,3-dihydro-N-hydroxy-2-methyl-5-(4-methylphenyl)-N-phenyl-l,3,4-Thiadiazole-2- acetamide,

2,3-dihydro-N-hydroxy-2-methyl-5-phenyl-N-(phenylmethyl)-l,3,4-Thiadiazole-2- acetamide,

2,3-dihydro-N-hydroxy-2-methyl-N,5-diphenyl-l,3,4-Thiadiazole-2-acetamide,

[2,3-dihydro-2-phenyl-5-(phenylmethyl)-l,3,4-thiadiazol-2-yl]phenyl-Methanone, [2,3-dihydro-5-(4-methylphenyl)-2-phenyl-l,3,4-thiadiazol-2-yl]phenyl-Methanone, l-(2,3-dihydro-2-methyl-5-phenyl-l,3,4-thiadiazol-2-yl)-oxime2-Propanone, l-(2,3-dihydro-2-methyl-5-phenyl-l,3,4-thiadiazol-2-yl)-2-Propanone, l-(2,3-dihydro-2-methyl-5-phenyl-l,3,4-thiadiazol-2-yl)-3-methyl-2-Pentanone, l-(2,3-dihydro-2-methyl-5-phenyl-l,3,4-thiadiazol-2-yl)-4-methyl-2-Pentanone, 1 -(2,3-dihydro-2-methyl-5-phenyl- 1 ,3,4-t?hiadiazol-2-yl)-Ethanone, l-(l-naphthalenylmethyl)-5'-phenyl-Spiro[3H-indole-3,2^,(3Η)-[l,3,4]thiadiazol]-2(lH)- one, l-(l-oxobutyl)-5'-phenyl-Spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, l-(4-bromophenyl)-2-(2,3-dihydro-2-methyl-5-p?henyl-l,3,4-thiadiazol-2-yl)-Ethanone, l-(4-chlorophenyl)-2-[2,3-dihydro-5-(4-methylp-tienyl)-2-(trifluoromethyl)-l,3,4- thiadiazol-2-yl] -Ethanone, l-(4-chlorophenyl)-2-[2,3-dihydro-5-phenyl-2-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]-

Ethanone, l-(5,5-dimethyl-4-ρhenyl-D2-l,3,4-thiadiazolin-2-yl)-D-galacto-l,2,3,4,5- Pentanepentol,

1 ,3-diphenyl-4-Thia- 1 ,2-diazaspiro[4.5]dec-2-ene, l-[(2,6-dichlorophenyl)methyl]-5'-phenyl-Spiro[3H-indole-3,2'(3Η)-[l₃3,4]thiadiazol]-

2(lH)-one, l-[(2-chlorophenyl)methyl]-5*-phenyl-Sρiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]- 2(lH)-one, l-[(2-fluorophenyl)methyl]-5'-phenyl-Spiro[3H-indole-3,2'(3'H)-[l,3,4]thiadiazol]-

2(lH)-one, 1 -[2,3-dihydro-2-(hydroxymethyl)-5-phenyl-l ,3,4-thiadiazol-2-yl]- 1 ,2,3,4-Butanetetrol, 1 - [2,3 -dihydro-2-(hydroxymethyl)-5 -phenyl- 1 ,3 ,4-thiadiazol-2-yl] -1,2,3 ,4-Butanetetrol, l-[2,3-dihydro-2-methyl-5-(phenylmethyl)-l,3,4-thiadiazol-2-yl]-Ethanone, 1 -[2,3-dihydro-5-(2-hydroxyphenyl)-2-methyl- 1 ,3,4-thiadiazol-2-yl]-3,3-dimethyl-2- Butanone, l-[2,3-dihydro-5-(4-methoxyphenyl)-2-methyl-l,3,4-thiadiazol-2-yl]-2-Propanone, l-[2,3-dihydro-5-phenyl-2-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]-3,3-dimethyl-2- Butanone, l-[3'-(4-bromophenyl)spiro[4H-l-benzopyran-4,2'(3Η)-[l,3,4]thiadiazol]-5'-yl]- Ethanone, l-acetyl-5"-(4-methoxyphenyl)-Spiro[3H-indole-3,2^,(3Η)-[l,3,4]thiadiazol]-2(lH)-one, l-acetyl-5'-phenyl-Spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 1 -cyclohexyl-3 -(4-nitrophenyl)-4-Thia- 1 ,2-diazaspiro [4.5] dec-2-ene, l-ethyl-5'-phenyl-Sρiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, l-methyl-3-(l-methyl-l,2,4-triazaspiro[4.5]dec-2-en-3-yl)-4-Thia-l,2- diazaspiro[4.5]dec-2-ene, l-methyl-5^,-(l-naphthalenyl)-Spiro[3H-indole-3,2'(3'H)-[l,3,4]thiadiazol]-2(lH)-one, l-methyl-5'-(4-methylphenyl)-Sρiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, l-methyl-5'-(phenylmethyl)-Spiro[3H-indole-3,2^,(3'H)-[l,3,4]thiadiazol]-2(lH)-one, l-methyl-5'-ρhenyl-Spiro[3H-indole-3,2'(3Η)-[l,3,4]t?hiadiazol]-2(lH)-one, 2-(2,3-dihydro-2-methyl-5-phenyl-l,3,4-thiadiazol-2-yl)-l-(4-methoxyphenyl)- Ethanone,

2-(2,3 -dihydro-2-methyl-5-phenyl- 1 ,3 ,4-t?hiadiazol-2-yl)- 1 -(4-methylphenyl)-Ethanone, 2-(2,3-dihydro-2-methyl-5-phenyl-l,3,4-thiadiazol-2-yl)-l-(4-nifrophenyl)-Ethanone, 2-(2,3-dihydro-2-methyl-5-phenyl-l,3,4-thiadiazol-2-yl)-l-[4-(dimethylamino)phenyl]- Ethanone,

2-(2,3-dihydro-2-methyl-5-phenyl-l,3,4-thiadiazol-2-yl)-l-phenyl-Ethanone, 2-(l,l-dimethylethyl)-2,3-dihydro-2-methyl-5-(phenylmethyl)-l,3,4-Thiadiazole, 2-(l,l-dimethylethyl)-2,3-dihydro-2-methyl-5-phenyl-monohydrochloridel,3,4- Thiadiazole,

2-(l,l-dimethylethyl)-2,3-dihydro-2-methyl-5-phenyl-l,3,4-Thiadiazole, 2-(3 ,3-dimethyl-2-oxobutyl)-2,3-dihydro-5-phenyl- 1 , 3 ,4-Thiadiazole-2-carboxylic acid, ethyl ester,

2-(3,3-dimethyl-2-oxobutyl)-2,3-dihydro-5-phenyl-l,3,4-Thiadiazole-2-carboxylic acid, methyl ester, 2-(4,5-dihydro-5,5-dimethyl-l,3,4-thiadiazol-2-yl)-Phenol,

2-(4-bromophenyl)-2,3-dihydro-2-methyl-5-(4-methylphenyl)-l,3,4-Thiadiazole,

2-(4-bromophenyl)-2,3-dihydro-2-methyl-5-(phenylnιethyl)-l,3,4-Thiadiazole,

2-(4-bromophenyl)-2,3-dihydro-2-methyl-5-phenyl-l ,3,4-Thiadiazole,

2-(4-cyclohexylphenyl)-2,3-dihydro-2-methyl-5-(4-mxethylphenyl)-l,3,4-Thiadiazole, 2-(4-cyclohexylphenyl)-2,3-dihydro-2-methyl-5-pherιyl- 1 ,3,4-Thiadiazole,

2-(4-t?hia-l,2-diazaspiro[4.11]hexadec-2-en-3-yl)-Phenol,

2-(4-thia-l,2-diazaspiro[4.7]dodec-2-en-3-yl)-Phenol,

2-(7,7-dimethyl-8-oxa-4-thia-l,2-diazaspiro[4.5]dec-2-en-3-yl)-Phenol,

2,2'-(l,2-ethanediyl)bis[2,3-dihydro-2-methyl-5-phenyl-l,3,4-Thiadiazole, 2,2-bis(l,l-dimethylethyl)-5-[2,2-dimethyl-l-(l-methylethyl)propylidene]-2,5-dihydro-

1,3,4-Thiadiazole,

2,3^,,5'-triphenyl-Spiro[lH-indene-l,2'(3'H)-[l,3,4]thiadiazol]-3(2H)-one,

2,5-dihydro-2,2,5-triphenyl- 1 ,3,4-Thiadiazole,

2,5-dihydro-5-methyl-2,2-diphenyl-l,3,4-Thiadiazole, 2,5-dihydro-5-phenyl-2,2-bis(trifluoromethyl)-l-oxidel,3,4-Thiadiazole,

2-[(2,3-dihydro-2,3,5-triphenyl-l,3,4-thiadiazol-2-yl)methyl]-Benzothiazole,

2-[(4-methoxyphenyl)methylene]hydrazide4-Thia-l,2-diazaspiro[4.5]dec-2-ene-3- carboximidic acid,

2-[2,3-dihydro-2-methyl-5-(4-methylphenyl)-l,3,4-thiadiazol-2-yl]-Phenol, 2-[2,3-dihydro-5-(4-methylphenyl)-2-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]-l-phenyl-

Ethanone,

2-[2,3-dihydro-5-phenyl-2-(trifluoromethyl)-l,3,4-thiadiazol-2-yl]-l-phenyl-Ethanone,

2-[4-(2,3 -dihydro-2-methyl-5-phenyl- 1 ,3 ,4-thiadiazol-2-yl)phenyl]hexahydro- 1 H-

Isoindole- 1 ,3 (2H)-dione, 2-[4,5-dihydro-5-methyl-5-(5-methyl-2-furanyl)-l,3,4-thiadiazol-2-yl]-Phenol,

2-[4-[2,3-dihydro-2-methyl-5-(phenylmethyl)-l,3,4-thiadiazol-2-yl]phenyl]hexahydro-

1 H-Isoindole- 1 ,3 (2H)-dione, 2-[5-(4-chlorophenyl)-2,3-dihydro-2-methyl-l,3,4-thiadiazol-2-yl]-Pyridine,

2-cyclopropyl-2,3-dihydro-2-methyl-5-phenyl-l,3,4-Thiadiazole,

2-ethyl-2,3-dihydro-2-methyl-5-phenyl-l,3,4-Thiadiazole,

3-(2,3-dihydro-2-methyl-5-ρhenyl-l,3,4-thiadiazol-2-yl)-2-Butanone, 3-(2,3-dihydro-2-methyl-5-ρhenyl-l,3,4-thiadiazol-2-yl)-Pyridine,

3-(l-naphthalenyl)-4-Thia-l,2-diazaspiro[4.11]hexadec-2-ene,

3 -( 1 -naphthalenyl)-4-Thia- 1 ,2-diazaspiro [4.5] dec-2-ene,

3-(l-naphthalenyl)-4-Thia-l,2-diazaspiro[4.7]dodec-2-ene,

3-(4-methoxyphenyl)-4-Thia-l,2-diazaspiro[4.5]dec-2-ene, 3-(4-methoxyphenyl)-8-methyl-4-Thia-l ,2,8-triazaspiro[4.5]dec-2-ene,

3-(4-methylphenyl)-4-Thia-l,2-diazaspiro[4.1 1]hexadec-2-ene,

3 -(4-methylphenyl)-4-Thia- 1 ,2-diazaspiro [4.5] dec-2-ene,

3-(4-methylphenyl)-4-Thia-l,2-diazaspiro[4.7]dodec-2-ene,

3-(phenylmethyl)-4-Thia-l,2-diazaspiro[4.11]hexadec-2-ene, 3-(phenylmethyl)-4-Thia-l,2-diazaspiro[4.7]dodec-2-ene,

3,3,5'-friphenyl-Spiro[lH-indene-l,2^,(3Η)-[l,3,4]thiadiazol]-2(3H)-one,

3,5-diphenyl-Spiro[l,3,4-thiadiazole-2(3H),2'-tricyclo[3.3.1.13,7]decane],

3-[5-(4-chlorophenyl)-2,3-dihydro-2-methyl-l,3,4-thiadiazol-2-yl]-Pyridine,

3-phenyl-4-Thia-l,2-diazaspiro[4.11]hexadec-2-ene, 3-phenyl-4-Thia-l,2-diazaspiro[4.4]non-2-ene-6-carboxylic acid, methyl ester,

3-phenyl-4-Thia-l,2-diazaspiro[4.5]dec-2-ene,

3-phenyl-4-Thia-l,2-diazaspiro[4.5]dec-2-ene-6-carboxylic acid, methyl ester,

3-phenyl-4-Thia- 1 ,2-diazaspiro[4.7]dodec-2-ene,

4,5-dihydro-5,5-dimethyl-(l-methylethylidene)hydrazide l,3,4-Thiadiazole-2- carboximidic acid,

4-[[(2,3-dihydro-2-methyl-5-phenyl-l,3,4-thiadiazol-2-yl)acetyl]hydroxyamino]-

Benzoic acid, methyl ester,

4-[[[2,3-dihydro-2-methyl-5-(4-methylphenyl)-l,3,4-thiadiazol-2- yl]acetyl]hydroxyamino]-Benzoic acid, methyl ester, 4-[5-(4-chlorophenyl)-2,3-dihydro-2-methyl- 1 ,3, 4-thiadiazol-2-yl] -Pyridine,

4-chloro-7-methyl-5'-phenyl-Spiro[3H-indole-3,2*(3Η)-[l,3,4]thiadiazol]-2(lH)-one,

5-(l,l-dimethylethyl)-2,3-dihydro-2,2-dimethyl-l,3,4-Thiadiazole, 5-(l-methylethyl)-5'-phenyl-Spiro[3H-indole-3,2^,(3Η)-[l,3,4]thiadiazol]-2(lH)-one,

5-(2,2-dimethylpropylidene)-2,2-diphenyl-l,3,4-Thiadiazolidine,

5-(2-benzot-hiazolylmethyl)-4,5-dihydro-4-(4-methylphenyl)-5-phenyl-l,3,4-

T?hiadiazole-2-carboxylic acid, ethyl ester, 5-(2-hydroxy-4,4-dimethyl-6-oxo-l -cyclohexen- 1 -yl)-N,2,2-frimethyl- 1,3,4-

Thiadiazole-3(2H)-carboxamide,

5'-(2-hydroxyphenyl)-l-methyl-Spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one,

5'-(2-hydroxyphenyl)-5-methyl-Sρiro[3H-indole-3,2^,(3'H)-[l,3,4]thiadiazol]-2(lH)-one,

5'-(2-hydroxyphenyl)-Spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 5-(4,4-dimethyl-2,6-dioxocyclohexylidene)-N,2,2-trimethyl-l,3,4-Thiadiazolidine-3- carboxamide,

5-(4-chlorophenyl)-2,3 -dihydro-2-(methoxycarbonyl)- 1 ,3 ,4-Thiadiazole-2-acetic acid, methyl ester,

5-(4-chlorophenyl)-2,3 -dihydro-2,2-dimethyl- 1 ,3 ,4-Thiadiazole, 5-(4-chlorophenyl)-2,2-dimethyl-N-[4-(trifluoromethoxy)phenyl] -1,1 -dioxide 1 ,3 ,4-

T?hiadiazole-3 (2H)-carboxamide,

5-(4-chlorophenyl)-2,2-dimethyl-N-[4-(trifluoromethoxy)phenyl]-l,3,4-Thiadiazole-

3 (2H)-carboxamide,

5-(4-chlorophenyl)-3-phenyl-Sρiro[l,3,4-thiadiazole-2(3H),2'- tricyclo[3.3.1.13,7]decane],

5'-(4-methoxyphenyl)-l-(l-oxobutyl)-Spiro[3H-indole-3,2^,(3Η)-[l,3,4]thiadiazol]-

2(lH)-one,

5-(4-methoxyphenyl)-3-phenyl-Spiro[ 1 ,3,4-thiadiazole-2(3H),2'- tricyclo[3.3.1.13,7]decane], 5-(4-methylphenyl)-3-phenyl-Sρiro[l,3,4-thiadiazole-2(3H),2'- tricyclo [3.3.1.13,7] decane] ,

5-(4-methylphenyl)-Spiro[l,3,4-thiadiazole-2(3H),2'-tricyclo[3.3.1.13,7]decane],

5^,-(4-methylphenyl)-Spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one,

5-[l-(l,l-dimethylethyl)-2-methylpropylidene]-2,5-dihydro-2,2-dimethyl-l,3,4- Thiadiazole,

5-[ 1 -(1 , 1 -dimethylethyl)-3-butenylidene]-2,5-dihydro-2,2-dimethyl-l ,3,4-Thiadiazole,

5-[dicyano(phenylamino)methyl]-l,3,4-Thiadiazole-2,2(5H)-dicarbonitrile, 5-[dicyano[(phenylmethyl)amino]methyl]-l,3,4-Thiadiazole-2,2(5H)-dicarbonitrile, 5-bromo-l-methyl-5'-(phenylmethyl)-Spiro[3H-indole-3,2'(3'H)-[l,3,4]thiadiazol]- 2(lH)-one,

5-bromo-l-methyl-5'-phenyl-Sρiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 5-bromo-5'-(l-naphthalenyl)-Spiro[3H-indole-3,2^,(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 5-bromo-5^,-(2-hydroxyphenyl)-Spiro[3H-indole-3,2"(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 5-bromo-5^,-(4-methylphenyl)-Spiro[3H-indole-3,2'(3'H)-[l,3,4]thiadiazol]-2(lH)-one, 5-bromo-5'-(phenylmethyl)-Spiro[3H-indole-3,2^,(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 5-bromo-5'-phenyl-l-(2-phenylethyl)-Sρiro[3H-indole-3,2^,(3Η)-[l,3,4]thiadiazol]- 2(lH)-one,

5-bromo-5'-ρhenyl-Sρiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 5-ethyl-5^,-(l-naphthalenyl)-Spiro[3H-indole-3,2'(3'H)-[l,3,4]thiadiazol]-2(lH)-one, 5-ethyl-5'-(2-hydroxyphenyl)-Spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 5-ethyl-5'-(4-methylphenyl)-Spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 5-ethyl-5'-(ρhenylmethyl)-Spiro[3H-indole-3,2'(3'H)-[l,3,4]thiadiazol]-2(lH)-one, 5-ethyl-5'-phenyl-Spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 5-hexyl-2,5-dihydro-2-methyl-2-(4-methyl-3-pentenyl)-l,3,4-Thiadiazole, 5-methyl-5'-(l-naphthalenyl)-Sρiro[3H-indole-3,2*(3Η)-[l,3,4]thiadiazol]-l(2H)-one, 5-methyl-5'-(4-methylphenyl)-Spiro[3H-indole-3,2^,(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 5-methyl-5'-phenyl-Spiro[3H-indole-3,2^,(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 5-methyl-Spiro[l,3,4-thiadiazole-2(5H),2'-tricyclo[3.3.1.13,7]decane], 5-nitro-5'-phenyl-Spiro[3H-indole-3,2'(3'H)-[l,3,4]thiadiazol]-2(lH)-one, 5'-phenyl-Spiro[phenanthrene-9(l OH),2'(3'H)-[ 1 ,3,4]thiadiazol]- 10-one, 5-phenyl-Sρiro[l,3,4-thiadiazole-2(3H),2'-tricyclo[3.3.1.13,7]decane], 5-ρhenyl-Spiro[l,3,4-thiadiazole-2(5H),2'-tricyclo[3.3.1.13,7]decane], 5^,-phenyl-Spiro[3H-indole-3,2*(3^,H)-[l,3,4]thiadiazol]-2(lH)-one, 6,7-dimethyl-5'-phenyl-Spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 6-bromo-5-methyl-5^,-phenyl-Spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, 6-methyl-3-(4-methylphenyl)-4-Thda-l,2-diazaspiro[4.5]dec-2-ene, 7,7,9-trimethyl-3-(4-methylphenyl)-4-Thia-l,2-diazaspiro[4.5]dec-2-ene,

7,7a-dihydro-2-(4-methoxyphenyl)-7a-methyl-Pyrrolo[2,l-b]-l,3,4-thiadiazol-5(6H)- one, 8-(l , 1 -dimethylethyl)-3-(4-methylphenyl)-4-Thia- 1 ,2-diazaspiro[4.5]dec-2-ene,

8-(l,l-dimethylethyl)-3-phenyl-4-Thia-l,2-diazaspiro[4.5]dec-2-ene,

8-(ethoxycarbonyl)-2,3-dihydro-2,2-dimethyl-5-(methylthio)-7-phenyl-l,3,4-

Tlιiadiazolo[3,2-a]pyridin-4-ium, iodide, 8-ethyl-3-(4-methylphenyl)-4-Thia- 1 ,2-diazaspiro[4.5]dec-2-ene,

8-ethyl-3-phenyl-4-Thia-l,2-diazaspiro[4.5]dec-2-ene,

8-methyl-3-(phenylmethyl)-4-Thia-l,2,8-triazaspiro[4.5]dec-2-ene, cyclohexylidenehydrazide4-Thia-l,2-diazaspiro[4.5]dec-2-ene-3-carboximidic acid,

N-(2,4-dimethoxyphenyl)-2,3-dihydro-2-methyl-5-(l-naphthalenyl)-l,3,4-Thiadiazole- 2-acetamide,

N-(2,4-dimethoxyphenyl)-2,3-dihydro-2-methyl-5-phenyl-l,3,4-Thiadiazole-2- acetamide,

N-(2,4-dimethylphenyl)-2,3-dihydro-2-methyl-5-(l-naphthalenyl)-l,3,4-Thiadiazole-2- acetamide, N-(4-chlorophenyl)-5-(2-hydroxy-4,4-dimethyl-6-oxo-l-cyclohexen-l-yl)-2,2-dimethyl-

1 ,3 ,4-Thiadiazole-3 (2H)-carboxamide,

N-(4-chlorophenyl)-5-(4,4-dimethyl-2,6-dioxocyclohexylidene)-2,2-dimethyl-l,3,4-

Thiadiazolidine-3-carboxamide,

N- [4-(2,3 -dihydro-2-methyl-5 -phenyl- 1 ,3 ,4-thiadiazol-2-yl)phenyl] - Acetamide, N-[4-[2,3-dihydro-2-methyl-5-(l-naphthalenyl)-l,3,4-thiadiazol-2-yl]phenyl]-

Acetamide, tetrahydro-2-(4-methoxyphenyl)-8a-methyl-5H-l,3,4-Thiadiazolo[3,2-a]pyridin-5-one,

2-[2,3-Dihydro-5-(phenylmethyl)-l,3,4-thiadiazol-2-yl]-4-methoxy-phenol,

3-(Phenylmethyl)- 4-thia- 1 ,2-diazaspiro[4.7]dodec-2-ene, 5-Ethyl-5^,-(2-hydroxyphenyl)- spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one, l-Methyl-5'-(l-naphthalenyl)- spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-2(lH)-one,

4-(2,3-Dihydro-5-phenyl-l,3,4-thiadiazol-2-yl)-phenol, l-[(2,6-Dichlorophenyl)methyl]-5'-phenyl- spiro[3H-indole-3,2'(3Η)-[l,3,4]thiadiazol]-

2(lH)-one, 5'-(2-Hydroxyphenyl)- spiro[3H-indole-3,2'(3'H)-[l,3,4]thiadiazol]-2(lH)-one,

2-[2,3-Dihydro-5-(4-tolyl)-l,3,4-thiadiazol-2-yl]-(4-methoxy)-phenol, Spiro 5'-(2-hydroxyphenyl)-2',3^,-dihydro-[r,3^,,4^,]thiadiazol-2^,,3-l,3-dihydro-5-ethyl- indol-2-one,

7,7-Dimethyl-3-phenyl-8-oxa-4-thia-l,2-diaza-spiro[4.5]dec-2-ene,

2-(4-hydroxyphenyl)-5-(benzyl)-2,3-dihydro-[l,3,4]thiadiazole, Spiro S'-^heny ^'^'-dihydro-tl'^'^'JthiadiazoW^-l^-diliydro-S-methyl-indol^- one,

Spiro S'- heny^^'^'-dihydro-tr^'^'JthiadiazoW^-l^-dihydro-S-bromo-l-methyl- indol-2-one,

Spiro 5^,-(phenyl)-2^,,3^,-dihydro-[l',3^,,4']thiadiazol-2^,,3-l,3-dihydro-5-bromo-indol-2- one,

Spiro S'-^enzy^^'^'-dihydro-tl'^'^'jthiadiazol^'^-l^-dihydro-S-ethyl-indol^-one; or a pharmaceutically or agriculturally acceptable salt thereof.

20. A compound of formula (I) as defined in claim I, which is:

4-(2-Methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine, Spiro 5'-(2-pyrazinyl)-2^,,3^,-dihydro-[r,3',4']thiadiazol-2^,,3-l,3-dihydro-indol-2-one,

Spiro 5^,-(phenethyl)-2',3^,-dihydro-[r,3^,,4']thiadiazol-2',3-l,3-dihydro-indol-2-one,

Spiro 5'-(4-hydroxy)-2',3^,-dihydro-[r,3^,,4']thiadiazol-2^,,3-l ,3-dihydro-indol-2-one,

2-(4-Chlorophenyl)-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole,

2-(4-Methoxyphenyl)-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-(5'-Methylfuran-2-yl)-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole,

2-(5'-Methylfuran-2-yl)-2-methyl-5-(4"-chlorophenyl)-2,3-dihydro-[l,3,4]thiadiazole,

2-Furan-2-yl-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole,

2-Furan-2-yl-2-methyl-5-phenethyl-2,3-dihydro-[l,3,4]thiadiazole,

2-Fxxran-2-yl-2-methyl-5-chlorophenyl-2,3-dihydro-[l,3,4]thiadiazole, 2-Furan-2-yl-2-methyl-5-phenyl-2,3-dihydro-[ 1 ,3,4]thiadiazole,

2-Pyrrol-2-yl-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole,

2-Methyl-2,5-di-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole,

2-Methyl-2-phenyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole,

2-Methyl-2-thiophen-2-yl-5-(4-chlorophenyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-Methyl-2-thiophen-2-yl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole,

2-Methyl-2-(5-bromothiophen-2-yl)-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole,

2-Methyl-2-(5-bromothiophen-2-yl)-5-(4-chlorophenyl)-2,3-dihydro-[l,3,4]thiadiazole, 3-(5-Furan-2-yl-5-methyl-4,5-dihydro-[l,3,4]thiadiazol-2-yl)-phenol, 4-(5-Fxxran-2-yl-5-methyl-4,5-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine, 4-[4-(2-Methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-phenyl]-morpholine, Spiro 5'-(3"-hydroxyphenyl)-2^,,3'-dihydro-[r,3',4"]thiadiazol-2^,,3-l,3-dihydro-indol-2- one,

Spiro 5'-(4"-chlorophenyl)-2',3^,-dihydro-[l^,,3^,,4^,]thiadiazol-2',3-l,3-dihydro-indol-2- one,

Spiro 5'-(m-tolyl)-2',3'-dihydro-[r,3',4']thiadiazol-2',3-l,3-dihydro-indol-2-one,

Spiro S'-phenethyl^^'-dihydro-tr^'^^thiadiazol^'^-l^-dihydro-indol^-one, Spiro 5'-ρ-tolyl-2',3^,-dihydro-[l^,,3',4']thiadiazol-2',3-l,3-dihydro-l-methyl-indol-2-one, Spiro 5^,-ρ-tolyl-2^,,3'-dihydro-[l',3',4']thiadiazol-2^,,3-l,3-dihydro-2-oxo-lH-indole-5- sulfonic acid,

Spiro S'- -toly ^'^'-dihydro-tl'^'^^thiadiazoW^-chroman, 2-Benzofxxran-2-yl-2-methyl-5-(p-tolyl)-2,3-dihydro-[l,3,4]thiadiazole, 2-Biphenyl-4-yl-2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole, 2-(4-Chloroρhenyl)-2-ethyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole, 2-(4-Chlorophenyl)-2-propyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole, 4-Methyl-2-(2-methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridine, 2,6-Bis-(5-phenyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridine, 5-Chloro-2-(2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridine, 2-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-5-phenylpyridine, 2-Methoxy-6'-(2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-[3,3']bipyridinyl, 3-Chloro-6-(2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridazine, 2-(2,4-Dichlorophenyl)-2-methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazole, 2-(2-Methyl-5-ρ-tolyl-2,3 -dihydro-[ 1 ,3 ,4]thiadiazol-2-yl)pyrazine, 2-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)quinoxaline, 2-[4-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-phenyl]-pyridine, 4-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)benzonitrile, 2-(2-Methyl-5-ρ-tolyl-2,3-dihydro[l,3,4]thiadiazol-2-yl)pyridine, 3-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridine,

2-(2,4-Dichlorophenyl)-2-methyl-5-p-tolyl-2,3-dihydro[l,3,4]thiadiazole, 2-(2-Methyl-5-ρhenyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyridine, 3-(p-Tolyl)-4-thia-l,2-diaza-spiro[4.4]non-2-ene,

2-(4-Nifro-phenyl)-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole-2-carboxylic acid ethyl ester,

2-(3,4-Dichlorophenyl)-2-methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazole, 2-Phenyl-5-p-tolyl-2-trifluoromethyl-2,3-dihydro-[l,3,4]thiadiazole,

Acetic acid 2-phenyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl-methyl ester, l-[6-(2-Methyl-5-p-tolyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-pyridin-2-yl]-ethanol, 2-(2-Methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)quinoline, 2-(4-Chlorophenyl)-2-methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazole, 2-Biphenyl-4-yl-2-methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazole, 2-(2-Methyl-5-phenyl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)pyrazine, Spiro 5'-p-tolyl-2',3'-dihydro-[l',3',4']thiadiazole-2',l-5-chloro-indan, 2-(5-Phenyl-2-pyridin-2-yl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine, 2-(2-Methyl-5-pyridin-2-yl-2,3-dihydro-[l,3,4]thiadiazol-2-yl)-pyridine, Spiro 5'-(p-hydroxyphenyl)-2',3'-dihydro-[l ',3',4']thiadiazole-2',3-l,3-dihydro-indol- 2-one,

Spiro 5'-(p-tolyl)-2',3'-dihydro-[l',3',4']thiadiazol-2',9-9H-l,8-diazafluorene, Spiro 5'-(p-tolyl)-2',3'-dihydro-[l ',3',4']thiadiazol-2',4-chroman, Spiro 5'-(m-tolyl)-2',3'-dihydro-[l',3',4']thiadiazol-2',3-l,3-dihydro-indol-2-one, or a pharmaceutically or agriculturally acceptable salt thereof.

21. A pharmaceutical composition comprising a compound of formula (I) according to claim 19 or 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

22. A method of controlling a fungal disease of plants which comprises applying to the locus of the plants a compound of formula (I) as defined in any one of claims 1 to 11 or an agriculturally acceptable salt thereof.

23. Use of a compound of formula (I) as defined in any one of claims 1 to 11 , or an agriculturally acceptable salt thereof, as an agricultural fungicide.

24. A composition comprising a compound of formula (I) according to claim 19 or 20, or an agriculturally acceptable salt thereof, and an agriculturally acceptable carrier or diluent.