AU5200800A - Antiviral agents - Google Patents

Description

WO 00/78746 PCT/AU00/00680 -1 ANTIVIRAL AGENTS This invention relates to antiviral agents, in particular to compounds useful in the treatment of infections caused by Picomrnaviridae, such as human rhinovirus (HRV) and methods for 5 their preparation. The invention also relates to the use of these compounds in the treatment of picomavirus infections and to intermediates useful in the preparation of these compounds. The compounds of the invention are especially suitable for use in the treatment of HRV and accordingly it will be convenient to describe the invention in connection with these viruses. However it is to be understood that the invention is also 10 applicable to other viruses of the Picomavirus family. Human rhinovirus are a member of the genus Rhinovirus of the picomrnavirus family and are believed to be responsible for between 40 and 50% of common cold infections. Human rhinoviruses comprise a group of over 100 serotypically distinct viruses and accordingly 15 antiviral activity for multiple serotypes and potency are considered to be equally important factors in drug design. Two cellular receptors have been identified to which almost all typed HRVs bind. The major group, which comprises 91 of the more than 100 typed serotypes, binds to the 20 intracellular adhesion molecule-1 (ICAM-1) while the minor group, which comprises the rest of typed serotypes with the exception of HRV87, binds to the low density lipoprotein receptor family of proteins. Another genus of the Picornaviridae family is represented by the Enteroviruses. This genus 25 includes polioviruses 1-3, coxsackieviruses A (23 serotypes) and B(6 serotypes), echoviruses (31 serotypes) and numbered enteroviruses 68-71. The clinical syndromes caused by enteroviruses include poliomyelitis, meningitis, encephalitis, pleurodynia, herpangina, hand foot and mouth disease, conjunctivitis, myocarditis and neonatal diseases such as respiratory illnesses and febrile illnesses. 30 WO 00/78746 PCT/AU00/00680 -2 Viruses of the Picornavirus family are characterised by a single stranded (+) RNA genome encapsidated by a protein shell (or capsid) having pseudo icosahedral symmetry. The surface of the capsid contains "canyons" which surround each of the icosahedral fivefold axes and it is believed that the cellular receptors bind to residues on the canyon floor. 5 A hydrophobic pocket lies underneath the canyon within which a number of antiviral compounds are capable of binding, sometimes with consequential conformational changes. Some of these compounds have been shown to inhibit the uncoating of HRVs and, for some of the major receptor group viruses, inhibition of cell receptor binding has also been 10 demonstrated. It has also been shown that when a compound is bound within the hydrophobic capsid pocket, HRVs are more stable to denaturation by heat or acids. Examples of antipicornoviral compounds believed to act by binding within the hydrophobic pockets of the picornavirus capsid are described in US Patents 4,992,433, 15 5,100,893, 5,070,090 and Australian Patent No. 628172. One compound which has been the subject of recent human clinical trials is ethyl 4-[2-[1-(6-methyl-3-pyridazinyl)-4 piperidinyl]-ethoxy]benzoate, otherwise known as "Pirodavir". ("Intranasal Pirodavir (R77,975) Treatment of Rhinovirus Colds" F.G. Hayden, et al., Antimicrobial Agents and Chemotherapy, 39, 290-294, 1995). 20 A novel class of antiviral compounds has now been discovered which has been found to exhibit particularly favourable antipicornaviral properties. Accordingly the present invention provides a compound of formula I 25 Het-A-Alk-W-Ar-C(X 2 )=NO-X I its salts, and pharmaceutically acceptable derivatives thereof where 30 Het is an optionally substituted 5- or 6-membered monocyclic heterocyclic radical or an optionally substituted 9- or 10-membered bicyclic heterocyclic radical; WO 00/78746 PCT/AU00/00680 -3 A is O, S, NH, N(CI- 6 alkyl), CH 2 0, a bond or a bivalent heterocyclic radical of the formula

(CH

2 )m -N

Z

(CH2)n (b- 1)

(CH

2 )m N C

(CH

2

)

n - C

R

4 (b-2), 5

(CH

2 )m SN Z (CH21- CHR (b-3), or

(CH

2 )1- Z N Z (CH2)n (b-4) 10 where one or more of the carbon atoms within the radicals (b-1) to (b-4) may be optionally substituted with CI- 6 alkyl or two carbon atoms in the radicals (b-1) to (b-4) may be bridged with a C 2 -4alkylene radical, m and n are each WO 00/78746 PCT/AU00/00680 -4 independently integers of 1 to 4 inclusive with the proviso that the sum of m and n in radicals (b-1) to (b-4) is 3, 4 or 5; Z is N or CR 6 where R 6 is hydrogen, hydroxy, Cl- 6 alkyl, Cl- 6 alkoxy or amino; 5 Z' is O, S, CHR 7 or NR 8 where R 7 is hydrogen, hydroxy, CI- 6 alkyl, Cl- 6 alkoxy or amino and R 8 is hydrogen or C 1

-

6 alkyl;

R

4 is hydrogen or Cl- 6 alkyl; and 10

R

5 is hydrogen, hydroxy, Cl- 6 alkyl or Cl- 6 alkoxy; Alk is CI-7alkylene or a direct bond; 15 W is O, S, OCH 2 , a direct bond or NR 9 where R 9 is hydrogen or CI.- 6 alkyl; Ar is an optionally substituted 5- or 6-membered monocyclic aryl radical or an optionally substituted 9- or 10-membered bicyclic aryl radical; 20 X' is Cl- 6 alkyl, C 3

-

6 alkenyl, C 3

-

6 haloalkenyl, C 3

-

6 alkynyl, C 3

-

6 haloalkynyl or CI- 6 alkyl substituted by halo, cyano, nitro, hydroxy, aryl, Cl 1 4 alkoxy, C 2

-

6 alkoxyalkoxy, acyl or Cl- 4 alkylthio; and

X

2 is hydrogen, cyano, F, Cl, CI- 4 alkyl, C 1

-

4 haloalkyl or a bivalent radical of formula 25 -(CH 2

)

2 -, -(CH 2

)

3 -, -CH 2 0- or -(CH 2

)

2 0- which forms a 5- or 6-membered ring with a neighbouring carbon atom of Ar. The oxime ether compounds of the present invention may be in cis or trans form, or a mixture of these forms. 30 WO 00/78746 PCT/AU00/00680 -5 As used herein the term "aryl" refers to aromatic rings or ring systems. The aromatic rings may be carbocyclic, heterocyclic or pseudo aromatic, and may be mono- or bi-cyclic ring systems. The aromatic rings or ring systems are generally composed of 5 to 10 carbon atoms and, in the case of heteroaromatic rings, may contain one or more heteroatoms 5 selected from N, S and O. Examples of suitable aryl groups include but are not limited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, pyridinyl, thiophenyl, benzothiophenyl, furyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indolizinyl, isoindolyl, purinyl, oxazolyl, thiazolyl, isothiazolyl, isooxazolyl, triazinyl, triazolyl, tetrazolyl and the like, each of which may be optionally substituted with 10 C l- 6 alkyl, C l- 6 alkoxy, C 3

-

6 alkynyl, C 3

-

6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(CI- 6 alkyl) amino. The term "pseudoaromatic" refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings. Examples of pseudoaromatic rings include but are not limited to furan, thiophene, pyrrole and the like. 15 Preferred aryl groups include phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, 1,2,4 triazinyl, furyl, thiophenyl thiazolyl, isothiazolyl, isoxazolyl, 1,2,4-triazolyl, oxazolyl, imidazolyl, pyrazolyl, 1,4-benzothiazinyl, indolyl and benzofuranyl. Particular examples of bivalent monocyclic and bicyclic aryl radicals are radicals of formula (c-1) to (c-6) 20 below:' Rio Rll (c-1) Y (c-2) 25 WO 00/78746 PCT/AU00/00680 -6 Rio Y (c-3) (c-4) R10 Y N 5 (c-5) (c-6) where Y is as defined above; and 10 Rio and R" 11 are each independently hydrogen, CI.

6 alkyl, hydroxy CI.- 6 alkyl, halo, amino, cyano, nitro, CI- 6 alkoxy, hydroxy, C 1

-

6 alkylthio, or trifluoromethyl. Examples of Ar groups in combination with 5- or 6-membered rings formed by X 2 with the neighbouring carbon atom of Ar include indanones, tetralones, benzofuranones and 15 benzopyranones. The term "heterocyclic radical" as used herein refers to mono or bicyclic rings or ring systems which include one or more heteroatoms selected from N, S and O. The rings or ring systems generally include 1 to 14 carbon atoms in addition to the heteroatom(s) and 20 may be saturated, unsaturated, aromatic or pseudoaromatic. Examples of 5-membered monocyclic heterocycles include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, WO 00/78746 PCT/AU00/00680 -7 oxadiazolyl, thiadiazolyl and examples of 6-membered monocyclic heterocycles include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. Examples of 9 and 10 membered bicyclic heterocycles include indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, isoquinolinyl, 5 quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl and the like. Examples of preferred heterocyclic ring systems include (optionally substituted) isoxazoles, isothiazoles, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-oxadiazoles, 1,2,4 thiadiazoles, oxazoles, thiazoles, pyridines, pyridazines, pyrimidines, pyrazines, 1,3,5 triazines, benzoxazoles, benzothiazoles, benzisoxazoles, benzisothiazoles, quinolines and 10 quinoxalines. Particular examples of the group Het are radicals of formula (a-1) to (a-14) below: N-N R R 2 R3 (a-1) 1 .Y 15 N- N (a-2)

NY'

N Ri (a-3) R )-LN 2 R (a-4) 20 R_(a-N a5 IN Ri 1 I _ I(a-5) WO 00/78746 PCT/AU00/00680 -8 y Y R

R

2 I NI (a-6) R N (a-7) N 5 Y (a-8) N RlK N (a-9) N R1 N (a-10) 10 R N N (a-11) N R N N2 R (a-12) N=N R 15 2 (a-13) WO 00/78746 PCT/AU00/00680 -9 R N-N (a-14) wherein R' is hydrogen, C1- 6 alkyl, halo, hydroxy, mercapto, haloCl- 6 alkyl, 5 amino, mono or di(Cl- 6 alkyl)amino, cyano, formyl, CI- 6 alkoxy, hydroxyC1 4 alkyl, Cl- 4 alkoxyCl-4 alkyl, Cl- 6 haloalkoxy, aryloxy, C 1

-

6 alkylthio, arylthio, Cl- 6 alkylsulphinyl, C 1

-

6 alkylsulphonyl, arylsulphinyl, arylsulphonyl, CH=NO-Cl4alkyl, Cl- 6 alkyloxycarbonyl, Cl- 6 alkylcarbonyl or aryl; 10 R 2 and R 3 are each independently selected from hydrogen, Cl.

6 alkyl,

C

1

.-

6 alkoxy, halo or, in radicals (a-1), (a-4), (a-7) and (a-13), R' and R 2 , or R 2 and R 3 combined may represent a bivalent radical of formula -CH=CH CH=CH- or (CH 2 )p where p is an integer from 2 to 4; 15 Y is O or S; and Y' is O, S, SO or SO 2 . In some preferred embodiments of the invention one or more of the following definitions 20 apply: Het is a radical of formula (a-1), (a-2) or (a-8); R' is hydrogen, methyl, ethyl, chloro, methoxy or trifluoromethyl; 25

R

2 and R 3 are each independently hydrogen, chloro or methyl; Y isO or S; 30 A is O, NH, NMe, a bond, or a radical of formula (b-1); WO 00/78746 PCT/AU00/00680 -10 Z is CH or N; Alk is Cl- 6 alkylene or a direct bond; 5 W is O; Ar is a radical of formula (c-1), (c-2) or (c-4); 10 R 1 0 and R 1 are each independently H, methyl, chloro, hydroxy, methoxy, cyano or nitro; X' is Cl- 4 alkyl, C 2 4alkoxyalkyl, C 3

-

4 alkenyl, C 3

-

4 alkynyl, Cl 4 haloalkyl, C 3

-

4 haloalkenyl,

C

3

-

4 haloalkynyl or cyanomethyl; 15 X 2 is H, methyl or a bivalent radical of formula (CH 2

)

2 or (CH 2

)

3 which forms a 5- or 6 membered ring with the Ar group. As used herein the term "Cl- 6 alkyl" as used alone or as part of a group such as "di(Cl- 6 alkyl)amino" refers to straight chain, branched or cyclic alkyl groups having from 1 20 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopentyl and cyclohexyl. Similarly Cl-4 alkyl refers to such groups having from 1 to 4 carbon atoms. As used herein the term "halo" as used alone or as part of a group such as "C 3

-

6 halo 25 alkenyl" refers to fluoro, chloro, bromo and iodo groups. As used herein the terms "Cl- 6 alkoxy" and "Cl- 6 alkyloxy" refer to straight chain or branched alkoxy groups having from 1 to 6 carbon atoms. Examples of CI- 6 alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, and the different butoxy isomers. 30 WO 00/78746 PCT/AU00/00680 -11 As used herein the term "C 3

-

6 alkenyl" refers to groups formed from C 3

-

6 straight chain, branched or cyclic alkenes. Examples of C 3

-

6 alkenyl include allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1 hexenyl, 3-hexenyl, cyclohexenyl, 1,3-butadienyl, 1-4,pentadienyl, 1,3-cyclopentadienyl, 5 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl and 1,4-cyclohexadienyl. As used herein the term "C 3

-

6 alkynyl" refers to groups formed from C 3

-

6 straight chain or branched groups as previously defined which contain a triple bond. Examples of

C

3

-

6 alkynyl include 2,3-propynyl and 2,3- or 3,4-butynyl. 10 The term "optionally substituted" as used herein means that a group may include one or more substituents which do not interfere with the binding activity of the compound of formula I. In some instances the substituent may be selected to improve binding. Examples of optional substituents include halo, Cl-4alkyl, C 2 4 alkenyl, C24alkynyl, 15 Cl4alkoxy, haloCl4alkyl, hydroxyCl 4 alkyl, Cl 1 4 alkoxy, Cl- 4 alkyl, hydroxy, aryl, amino, cyano, mercapto, Cl 1 4 alkylamino, Cl- 4 dialkylamino, aryloxy, formyl, Cl4alkylcarbonyl and C l- 4 alkoxycarbonyl. A particular group of compounds of the invention has the formula II: 20 II X2 R N Z-Alk-O N-N R11 wherein: WO 00/78746 PCT/AU00/00680 -12 R' is hydrogen, C 1

-

4 alkyl, halo, hydroxy, mercapto, trifluoromethyl, amino, mono or di(Cl- 4 alkyl)amino, cyano, formyl, -CH=NO-C,_4 alkyl, Cl4alkoxy, Cl-4haloalkoxy, aryloxy, Cl-4alkylthio, or aryl; 5 Z is CH or N; Alk is C 1

.

6 alkylene; R"o and R" are each independently hydrogen, C 14 alkyl, Cl 14 alkoxy, halo, hydroxy; 10

X

1 is Cl- 6 alkyl, C 3

-

6 alkenyl, C 3

-

6 haloalkenyl, C 3

-

6 alkynyl, C 3

-

6 haloalkynyl or Cl- 6 alkyl optionally substituted by halo, cyano, nitro, hydroxy, aryl, C 1 4alkoxy or Cl_ 4 alkylthio; and 15 X 2 is hydrogen, cyano, C 14 alkyl, Cl-4haloalkyl or X 2 is -CH 2

CH

2 - or -CH 2

CH

2

CH

2 forming a 5- or 6-membered ring with a carbon atom on the phenyl ring. Another particular set of compounds of the invention have the formula III:

RR

1 N x 1 R C X2X NA AIk-Alk-O 20 R 11 III wherein: R' is hydrogen, Cl- 4 alkyl, halo, hydroxy, mercapto, trifluoromethyl, amino, mono or di(C 1

-

4 alkyl)amino, cyano, formyl, -CH=NO-C_4alkyl, C 1 4alkoxy, C 1 4haloalkoxy, 25 aryloxy, C 1 4 alkylthio, or aryl; A is a bond or CH 2 0; WO 00/78746 PCT/AU00/00680 - 13 Alk is C,.7alkylene; R'o and R" are each independently hydrogen, C 4 alkyl, C 1

-

4 alkoxy, halo, hydroxy; 5 X 1 is Cl- 6 alkyl, C 3

-

6 alkenyl, C 3

-

6 haloalkenyl, C 3

-

6 alkynyl, C 3

-

6 haloalkynyl or Cl- 6 alkyl optionally substituted by halo, cyano, nitro, hydroxy, aryl, Cl- 4 alkoxy or Cl-4alkylthio; and

X

2 is hydrogen, cyano, C 1 4alkyl, C 1 4haloalkyl or X 2 is -CH 2

CH

2 - or -CH 2

CH

2

CH

2 10 forming a 5- or 6-membered ring with a carbon atom on the phenyl ring. A particular group of compounds of the invention has the formula IV R i x , //

XK

2 /Alk-O RN R N= N IV 15 wherein: R' is hydrogen, C14 alkyl, halo, hydroxy, mercapto, trifluoromethyl, amino, mono or di(C,- 4 alkyl)amino, cyano, formyl, -CH=NO-Cl- 4 alkyl, C 1 4alkoxy, C 1 4haloalkoxy, aryloxy, C 1 4alky1thio, or aryl; 20 Z is CH or N; Alk is C_ 6 alkylene; 25 R1 0 and R" are each independently hydrogen, C 14 alkyl, C 4alkoxy, halo, hydroxy; WO 00/78746 PCT/AU00/00680 -14

X

1 is C 1

-

6 alkyl, C 3

-

6 alkenyl, C 3

-

6 haloalkenyl, C 3

-

6 alkynyl, C 3

-

6 haloalkynyl or Cl 6 alkyl optionally substituted by halo, cyano, nitro, hydroxy, aryl, Cl_ 4 alkoxy or Cl- 4 alkylthio; and

X

2 is hydrogen, cyano, Cl- 4 alkyl, Cl 4 haloalkyl or X 2 is -CH 2

CH

2 - or -CH 2

CHCH

2 5 forming a 5- or 6-membered ring with a carbon atom on the phenyl ring. A particular group of compounds of the invention has the formula V

R

lo N.-O- Xl C //2 C~x Het-N Z-AIk-O

R

11 V 10 wherein: Het is pyridyl, pyrazinyl, thiadiazolyl, benzoxazolyl, 1,3,5-triazinyl, pyrimidinyl or quinoxalinyl, each of which may be optionally substituted with 1 to 3 substituents selected from halo, trifluoromethyl, Cl4alkyl, Cl- 4 alkoxy or hydroxy; 15 Z is CH or N; Alk is Cl- 6 alkylene;

R'

i o and R" are each independently hydrogen, C 1 4alkyl, C 14 alkoxy, halo, hydroxy; 20 XI is Cl- 6 alkyl, C 3

-

6 alkenyl, C 3

-

6 haloalkenyl, C 3

-

6 alkynyl, C 3

-

6 haloalkynyl or C_ 6 alkyl optionally substituted by halo, cyano, nitro, hydroxy, aryl, Cl 4 alkoxy or C.l- 4 alkylthio; and 25 X 2 is hydrogen, cyano, Cl 4 alkyl, C 1 4haloalkyl or X 2 is -CH 2

CH

2 - or -CH 2

CH

2

CH

2 forming a 5- or 6-membered ring with a carbon atom on the phenyl ring.

WO 00/78746 PCT/AU00/00680 - 15 Another group of compounds of the invention has the formula VI Rio N-O-X R0 5 wherein: Het is pyridyl, pyrazinyl, thiadiazolyl, benzoxazolyl, 1,3,5-triazinyl, pyrimidinyl or quinoxalinyl, each of which may be optionally substituted with 1 to 3 substituents selected from halo, trifluoromethyl, Cl- 4 alkyl, C 1 4alkoxy or hydroxy; 10 A is a direct bond, O, NH or NMe; Alk is C 1

-

6 alkylene; R'o and R 1 " are each independently hydrogen, C 1 4alkyl, Cl- 4 alkoxy, halo, hydroxy; 15 X' is Cl 6 alkyl, C 3

-

6 alkenyl, C 3

-

6 haloalkenyl, C 3

-

6 alkynyl, C 3

-

6 haloalkynyl or Cl- 6 alkyl optionally substituted by halo, cyano, nitro, hydroxy, aryl, Cl 14 alkoxy or C 1 4alkylthio; and 20 X 2 is hydrogen, cyano, Cl-4alkyl, Cl-4haloalkyl or X 2 is -CH 2

CH

2 - or -CH 2

CH

2

CH

2 forming a 5- or 6-membered ring with a carbon atom on the phenyl ring. Examples of specific compounds within the scope of the present invention are shown in Tables 1 to 8 below. 25 WO 00/78746 PCT/AU00/00680 -16 Table 1 Ri o 2 3 R rN (CH 2 )n-O / C NX----O X 6 5 R 5 Compd R n Rio , R1 X 1 X Number 1 Cl 2 H CH 2

CH

3 H 2 Me 2 H CH 2

CH

3 H 3 Cl 2 H CH 2

CH

3

CH

3 4 Me 2 H CH 2

CH

3

CH

3 5 Cl 2 2-(OMe) CH 2

CH

3 H 6 Cl 2 2,6-(OMe) 2

CH

2

CH

3

CH

3 7 Me 2 H CH 3 H 8 Cl 2 H CH 3 H 9 Me 2 H CH 3 CH3 10 Cl 2 H CH 3

CH

2

CH

3 11 Cl 2 H CH 2

CH

2

CH

3 H 12 Cl 2 H CH(CH 3

)

2 H 13 Cl 2 H CH 2

CH=CH

2 H 14 Cl 2 H CH 2 CN H 15 Cl 2 H CH 2

C

6

H

5 H 18 Cl 2 2,6-(Me) 2

CH

3 H 19 Cl 2 2-(OMe) CH 3

CH

3 20 Cl 2 H (CH 2

CH

2 0)2CH 2

CH

3 H 21 CF 3

CH

2 0 2 H CH 2

CH

3 H 26 CH 3 0 2 H CH 2

CH

3 H 29 Cl 1 H CH 2 Phenyl H 30 Cl 1 H CH 2

CH=CH

2 H 31 Cl 1 H CH 2

CH

3 H 32 Cl 3 H CH 2

CH

3 H 33 Cl 2 2-(OMe) CH 3 H 34 Cl 2 H CH 2

CH

3

CH

2

CH

3 35 Cl 2 H CH 2

CH=CH

2

CH

2

CH

3 36 Cl 2 2-NO 2

CH

2

CH

3 H 37 Cl 2 3-OH CH 2

CH

3 H 42 Cl 2 2-Me CH 2

CH

3 H 43 Cl 2 2-Me CH 2

CH=CH

2

H

WO 00/78746 PCT/AU00/00680 -17 44 Cl 2 2-Me CH 3 H 45 Cl 2 2,6-(Me) 2

CH

2

CH

3 H 49 H 2 H CH 2

CH

3 H 50 Cl 2 3-OMe CH 2

CH

3 H 51 Me 2 2-Me CH 2

CH

3 H 52 Me 2 2-Me CH 3 H 53 Me 2 2-Me CH 2

CH=CH

2 H 54 Me 2 2-Me CH 2

CH

2

CH

3 H 55 Cl 0 H CH 2

CH

3 H 56 Phenyl 2 H CH 2

CH

3 H 57 Cl 2 H CH 2

CH

3 (cis isomer) H 58 CF 3 2 H CH 2

CH

3 H 59 Me 2 H CH 2

CF

3 H 63 MeO 2 H CH 2

CH=CH

2 H 85 Me 2 H CH 2

CH

2

CH

3 H 86 Me 2 H CH 2

CH

2

OCH

3 H 87 Me 2 H CH 2

CH=CH

2 H 88 Me 2 H CH 2 C=-CH H 89 Cl 3 H CH 3 H 90 Cl 3 H CH 2

CH=CH

2 H 94 Me 3 H CH 3 H 95 Me 3 H CH 2

CH

3 H 96 Me 3 H CH 2

CH=CH

2 H 100 CF 3 3 H CH 3 H 102 H 3 H CH 3 H 103 H 3 H CH 2

CH

3 H 104 H 3 H CH 2

CH=CH

2 H 128 O=CH 2 H CH 2

CH

3 H 129 HOCH 2 2 H CH 2

CH

3 H 143 Me 2 H CH 2

CH

2 F H 144 Me (Pyridazine 2 H CH 2

CH

3 H N-oxide) 145 Me 2 H CH 2

CH

3 H 146 Me 2 2-OH CH 2

CH

3 H 185 Me 2 3,5-(Me)2 CH 2

CH

3 H 186 Me 2 3,5-(Me) 2

CH

3 H 187 Me 2 3-OMe CH 2

CH

3 H 188 Me 2 3-Me CH 2

CH

3 H 189 Me 2 3-Me CH 3 H 190 Me 2 2,5-(Me) 2

CH

2

CH

3 H 191 Me 2 2,5-(Me) 2

CH

3 H 192 ME 2 2,3-(Me) 2

CH

2

CH

3 H 193 Me 2 2,3-(Me) 2

CH

3 H 208 MeON=CH- 2 H CH 2

CH

3

H

WO 00/78746 PCT/AU00/00680 - 18 Table 2 R 10 N/ N 'O x 1 2 " X 2 RN (CH 2 )n-O 1 4 N-N NN 6 5 5 Compound R n R X X number 16 Cl1 2 H CH 3 H 17 Cl1 2 6-OMe CH 3 H 38 Cl1 2 5-OH CH 3 H 39 Cl 2 5-OH CH 2

CH

3 H 40 Cl 2 5-OH CH 2

CH=CH

2 H 41 Cl 2 H CH 2

CH

3 H 46 Me 2 H CH 2

CH

3 H 47 Me 2 H CH 2

CH=CH

2 H 48 Me 2 H CH 3 H 60 Cl 1 H CH 3 H 61 Cl 1 H CH 2

CH

3 H 62 C 1 H CH 2

CH=CH

2 H 91 Cl1 3 H CH 3 H 92 Cl 3 H CH 2

CH

3 H 93 Cl 3 H CH 2

CH=CH

2 H 97 Me 3 H CH 3 H 98 Me 3 H CH 2

CH

3 H 99 Me 3 H CH 2

CH=CH

2 H 101 CF 3 3 H CH 3 H 105 H 3 H CH 3 H 106 H 3 H CH 2

CH

3 H 107 H 3 H CH 2

CH=CH

2 H 213 Me 2 H CH 2

CH

3

-CH

2

-CH

2 (2-position) 10 WO 00/78746 PCT/AU00/00680 -19 Table 3 Ri ~Ri 2\3 (CH 2 )n-O / C N O "0 X2 6 5 R Compd R 1 n Ri 0, R" XI X 2 number 22 Me 3 2,6-(Me) 2

CH

3 H 23 Me 3 2,6-(Me) 2

CH

2

CH=CH

2 H 24 Me 3 2,6-(Me) 2

CH

2

CH

3 H 25 Me 3 2,6-(Me) 2

CH

2

C

6

H

5 H 108 Me 3 H CH 2

CH

3 H 109 Me 3 2,6-(Me) 2

CH

3 Me 110 Me 3 2,6-(Me) 2

CH

2

CH=CH

2 Me 111 Me 3 2,6-(Me) 2

CH

2

CH=CH

2 Me (cis-isomer) 112 Me 3 2,6-(Me) 2

CH

2

CH

2

CH

3 H 113 Me 3 2,6-(Me) 2

CH

3 Et 114 Me 3 2,6-(Me) 2

CH

2

CH

3 Et 115 Me 3 2,6-(Me) 2

CH

2

CH=CH

2 Et 116 Me 3 2,6-(Me) 2

CH

2

CH

3 Me 117 Me 3 2,6-(Me) 2

CH(CH

3

)

2 H 118 Me 3 2,6-(Me) 2

CH

2 CN H 119 Me 3 2,6-(Me) 2

CH

2 C CH H 120 Me 6 2,6-(Me) 2

CH

2

CH

3 H 121 Me 7 2,6-(Me) 2

CH

2

CH

3 H 122 Me 5 2,6-(Me) 2

CH

2

CH

3 H 123 Me 4 2,6-(Me) 2

CH

2

CH

3 H 124 Me 3 2,6-(Me) 2

CH

2

CF

3 H 125 Me 3 2,6-(Me) 2

CH

2

CH

2

OCH

2

CH

3 H 126 Me 3 2,6-(Me) 2

CH

2

COCH

3 H 127 Phenyl 3 2,6-(Me) 2

CH

2

CH

3 H 130 Et 3 2,6-(Me) 2

CH

2

CH

3 H 131 n-Pr 3 2,6-(Me) 2

CH

2

CH

3 H 132 Et 2 2,6-(Me) 2

CH

2

CH

3 H 133 n-Pr 2 2,6-(Me) 2

CH

2

CH

3 H 134 Me 3 2,6-(Me) 2

CH

2

CH

2 F H 137 Cyclopropyl 3 2,6-(Me) 2

CH

2

CH

3 H 138 Et 4 2,6-(Me) 2

CH

2

CH

3 H 139 nPr 4 2,6-(Me) 2

CH

2

CH

3

H

WO 00/78746 PCT/AU00/00680 - 20 Table 4 2 3 CN-

O-X

1 N-""' SN=N - N-(CH 2

)

2 -"-\/ 4 X 6 5 5 Compd R' Position of Oxime X X No. ether on phenyl ring 27 Cl 4 CH 2

CH

3 H 64 H 4 CH 2

CH

3 H 65 H 3 CH 2

CH

3 H 66 H 4 CH 2

CH=CH

2 H 67 Me 4 CH 3 H 68 Me 4 CH 2

CH

3 H 69 Me 4 CH 2

CH=CH

2 H 70 Me 3 CH 3 H 71 Me 3 CH 2

CH

3 H 72 Me 3 CH 2

CH=CH

2 H 73 Cl 4 CH 3 H 74 C1 4 CH 2

CH=CH

2 H 75 Cl 3 CH 3 H 76 Cl 3 CH 2

CH

3 H 77 Cl 3 CH 2

CH=CH

2 H 78 CF 3 4 CH 3 H 79 CF 3 4 CH 2

CH

3 H 80 CF 3 4 CH 2

CH=CH

2 H 81 CF 3 3 CHI 3 H 82 CF 3 3 CH 2

CH

3 H 83 CF 3 3 CH 2

CH=CH

2 H 135 Me 4 CH 2

CH

2

CH

3 H 136 Me 3 CH 2

CH

2

CH

3 H 148 C1 4 CH 2

CH

2

CH

3 H 149 Cl 3 CH 2

CH

2

CH

3 H 10 15 WO 00/78746 PCT/AU00/00680 -21 Table 5

SN-O-X

1 CH

(CH

2 )nO H R N N-N 5 Compd R 1 n Position of Oxime X1 No ether on Phenyl ring 28 Cl 1 4 CH 2

CH

3 140 Cl 2 4 CH 3 141 Cl 2 4 Allyl 142 Cl 2 4 Ethyl 150 Cl 3 4 Ethyl 151 Cl 3 4 Allyl 164 CF 3 3 4 Methyl 165 CF 3 3 4 Ethyl 166 CF 3 3 4 Allyl 167 CF 3 3 3 Methyl 168 CF 3 3 3 Ethyl 169 CF 3 3 3 Allyl 170 Me 3 4 Allyl 171 Me 3 3 Methyl 172 Me 3 3 Ethyl 173 Me 3 3 Allyl 174 Cl 1 4 Methyl 175 Cl 1 4 Allyl 176 Cl 1 3 Methyl 177 Cl 1 3 Ethyl 178 Cl 1 3 Allyl 179 CF 3 1 4 Methyl 180 CF 3 1 4 Ethyl 181 CF 3 1 4 Allyl 182 CF 3 1 3 Methyl 183 CF 3 1 3 Ethyl 184 CF 3 1 3 Allyl 10 WO 00/78746 PCT/AU00/00680 - 22 Table 6

SN-O-X

1 ~/7 Het-N /Z-(CH 2

)

2 -O / C H H 5 Compound Het Z X1 No 84 5-CF 3 -2-Pyridyl CH Ethyl 152 5-Chloro-2-Pyrazinyl N Ethyl 153 5-CF 3 -1,3,4-thiadiazol-2-yl CH Methyl 154 5-CF 3 -1,3,4-thiadiazol-2-yl CH Ethyl 157 5-Methyl-1,3,4-thiadiazol-2-yl CH Methyl 158 5-Methyl-1,3,4-thiadiazol-2-yl CH Ethyl 159 5-Chloro-2-Pyrazinyl CH Methyl 160 5-Chloro-2-Pyrazinyl CH Ethyl 196 6-Methyl-2-Pyridyl CH Ethyl 197 4-EtO 2 C-Thiazol-2-yl CH Methyl 198 4-Ethoxycarbonyl-2-Thiazolyl CH Ethyl 199 6-Chloro-2-Pyrazinyl CH Methyl 200 Benzoxazol-2-yl CH Methyl 201 Benzoxazol-2-yl CH Ethyl 202 4,6-Dimethoxy-1,3,5-Triazin-2-yl CH Methyl 203 4,6-Dimethoxy-1,3,5-Triazin-2-yl CH Ethyl 204 5-Ethyl-2-Pyrimidin-2-yl CH Methyl 205 5-Ethyl-2-Pyrimidin-2-yl CH Ethyl 206 Benzothiazol-2-yl CH Methyl 207 Benzothiazol-2-yl CH Ethyl 210 6-Chloro-2-quinoxalinyl CH Ethyl 212 6-Chloro-5-Methyl-3-Pyridazinyl CH Ethyl 10 15 WO 00/78746 PCT/AU00/00680 - 23 Table 7

-

N-O-X Het-A-(CH 2 )n-O_/ Compd Het A n X1 No 147 6-C1-3-Pyridazinyl NH 5 Ethyl 161 6-C1-3-Pyridazinyl NMe 5 Ethyl 162 6-Cl-3-Pyridazinyl NH 6 Ethyl 163 6-Cl-3-Pyridazinyl NH 4 Ethyl 194 6-Cl-3-Pyridazinyl NMe 6 Methyl 195 6-Cl-3-Pyridazinyl NMe 4 Ethyl 209 6-Cl-3-Pyridazinyl O 5 Ethyl 211 6-Cl-2-Quinoxalinyl Direct bond 0 Ethyl 5 Table 8 N RN

(CH

2 )n-O N H N-N S 10 Compound No R' n X1 155 Me 2 Ethyl 156 Me 2 Methyl The compounds of the present invention may be prepared using methods analogous to 15 those described in the prior art. For example, compounds in which the Het radical is of formula (a-1) may be prepared using methodology analogous to the processes described in US Patents 4,992,433, 5,112,825 and 5,100,893. Similarly, compounds in which Het is (a 2), (a-3), (a-4), (a-5) or (a-6) may be prepared using methodology similar to that described in US Patent 5,070,090 and Australian patent No. 629172, and compounds in which Het is 20 (a-7) or (a-8) may be prepared in accordance with methodology similar to that described in US Patent 5,364,865.

WO 00/78746 PCT/AU00/00680 - 24 In one method the compounds of the present invention are prepared via an intermediate of formula VII: N - O-X 3 H-A- Alk -W -Ar-C

X

2 vii 5 where A, Alk, W, Ar and X 2 are as described above, and X 3 is X 1 or an oxime protecting group. This intermediate may be prepared using methodology similar to that described in US 10 Patent 5,231,184. In one example intermediates of formula VII, when W is O, are prepared by the reaction of compounds of the formula P-A-Alk-OH or P-A-Alk-L with hydroxy aromatic compounds of formula VIII. HO-Ar-C(X2)=NO-X 3 VIII 15 where Ar, X', X 2 and X are as defined above, P is H or a protecting group, and L is a leaving group. Removal of the protecting group P in the reaction product affords the reactive intermediates of formula VII. 20 Examples of suitable protecting groups P in compounds of formula P-A-Alk-OH or P-A-Alk-L include benzyl or acyl moieties which can be introduced and removed by standard methods (see "Protective Groups in Organic Synthesis" Theodora Green, Wiley Interscience, 1981). 25 The intermediate of formula VII may be reacted with a compound of formula Het-L, where Het is as defined above and L is a suitable leaving group, optionally followed by deprotection and/or conversion of X 3 to X 1 , to afford a compound of formula I. This N alkylation reaction can be conducted using procedures known to the art, such as under the conditions described in US Patent 5,231,184 for performing analogous N-alkylations.

WO 00/78746 PCT/AU00/00680 - 25 The intermediates of formula VII are novel and represent a further aspect of the present invention. Examples of suitable leaving groups include halogen, such as fluoro, chloro, bromo and 5 iodo, and halogen-like groups such as p-toluenesulphonyloxy and methanesulphonyloxy. Another method for the preparation of the compounds of formula I involves the addition of an alkoxyamine H 2

NOX

1 to an aldehyde or ketone of formula IX 10 Het-A-Alk-W-Ar-C(= O)X 2 IX where Het, A, Alk, W, Ar X' and X 2 are as defined for formula I above. This reaction is carried out using standard conditions, such as in an aqueous or alcoholic solvent at ambient temperature or with warming. 15 A further method of forming the compounds of the invention involves reaction of a carbonyl compound of formula IX with hydroxylamine to give of an oxime of formula X, Het-A-Alk-W-Ar-C(= NOH)X 2 X 20 which is then O-alkylated with a compound L-X', where L is a leaving group and X' is as defined for formula I. An additional method of preparing certain compounds of the invention of formula Ia 25 (Compounds for formula I where W = O) involves condensing an oxime ether of formula XI with a suitable precursor of formula (XII) HO-Ar-C(X 2 ) =NO-X 1 + Het-A-Alk-OH -4 Het-A-Alk-O-Ar-C(X 2 ) =N-O-X' (XI) (XII) (Ia) 30 WO 00/78746 PCT/AU00/00680 - 26 using Mitsunobu Reaction conditions (see Chemical Syntheses, Vol. 42, p 335, 1992) and where Het, A, Alk, Ar, X' and X 2 are as defined for formula I. Methods for the preparation of intermediate carbonyl compounds of formulae IX have 5 been described in the chemical literature (US Patents 4,992,433, 4,451,476). Compounds of formula XI are well known in the chemical literature (eg German Patent DE 3,601,564). Several references, including US Patents 5,112,825 and 5,242,924 describe methods for the preparation of various compounds of formula XII. 10 The compounds of the present invention are useful in the prevention or treatment of picornoviral infections in mammals, particularly humans. Accordingly in a further aspect the invention provides a method for the treatment or prophylaxis of a picornaviral infection in a mammal including the step of administering 15 an effective amount of a compound of formula I. The picornavirus infection may be caused by any virus of the family Picornaviridae. Representative family members include human rhinoviruses, polioviruses, enteroviruses including coxsackieviruses and echoviruses, hepatovirus, cardioviruses, apthovirus, 20 hepatitis A and other picornaviruses not yet assigned to a particular genus, including one or more of the serotypes of these viruses. Preferably the invention is used in the prevention or treatment of infection caused by one or more serotypes of rhinovirus. Without wishing to be limited by theory it is believed that the oxime ether moiety of the 25 compound of formula I may be involved in hydrogen bonding with an asparagine residue generally present near the opening of the hydrophobic pocket and that this interaction enhances the binding of the compounds in the capsid pocket, relative to the prior art compounds. It is further believed that the oxime ether bond may be more resistant to hydrolysis and esterase activity than the ester bond of pirodavir, and that this may allow 30 more flexibility in the methods of administration of the compound to the site of activity, than available for readily hydrolysable pirodavir. In particular it may allow oral WO 00/78746 PCT/AU00/00680 - 27 administration of the compounds or reduce metabolism in the nasal mucosa following topical administration. The salts of the compound of formula I are preferably pharmaceutically acceptable, but it 5 will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts. The pharmaceutically acceptable salts may include conventional non-toxic salts or quartenary ammonium salts of these compounds, which may be formed, e.g. from organic or inorganic acids or bases. Examples of such acid 10 addition salts include, but are not limited to, those formed with pharmaceutically acceptable acids such as acetic, propionic, citric, lactic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicyclic, ascorbic, hydrochloric, orthophosphoric, sulphuric and hydrobromic acids. Base salts includes, but is not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium 15 magnesium, ammonium and alkylammonium. Also, basic nitrogen-containing groups may be quaternised with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others. 20 The compounds of the invention may be in crystalline form or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art. Pharmaceutically acceptable derivatives may include any pharmaceutically acceptable salt, 25 hydrate or any other compound or prodrug which, upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an antivirally active metabolite or residue thereof. Any compound that is a prodrug of a compound of formula I is within the scope and spirit 30 of the invention. The term "pro-drug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives WO 00/78746 PCT/AU00/00680 -28 would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group is converted into an ester derivative or a ring nitrogen atom is converted to an N-oxide. Examples of ester derivatives include alkyl esters, phosphate esters and those formed from amino acids, preferably valine. 5 It will be appreciated that some derivatives of the compound of formula I may have an asymmetric centre, and therefore are capable of existing in more than one stereoisomeric form. The invention extends to each of these forms individually and to mixtures thereof, including racemates. The isomers may be separated conventionally by chromatographic 10 methods or using a resolving agent. Alternatively the individual isomers may be prepared by asymmetric synthesis using chiral intermediates. The invention also provides the use of a compound of formula I in the manufacture of a medicament for the treatment or prophylaxis of picornavirus infection. 15 While it is possible that, for use in therapy, a compound of the invention may be administered as the neat chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. 20 In view of the general lipophilic nature of the compounds they are particularly suitable to oral forms of administration, however other forms of administration are also envisaged. The invention thus further provides pharmaceutical formulations comprising a compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with 25 one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. 30 The compounds of this invention may also be useful in combination with known anti-viral or anti-retroviral agents or other pharmaceuticals used in the treatment of viral infections.

WO 00/78746 PCT/AU00/00680 - 29 Representative examples of these additional pharmaceuticals include immunomodulators, immunostimulants, antibiotics and anti-inflammatory agents. Exemplary anti-viral agents include zanamivir, rimantidine, amantidine, ribavirin, AZT, 3TC, (-) FTC, acyclovir, famciclovir, penciclovir, ddl, ddC, ganciclovir, saquanivir, loviride, other non-nucleotide 5 reverse transcriptase (RT) inhibitors and protease inhibitors, antiviral and antireceptor antibodies and receptor analogues, such as ICAM-1. Exemplary immunomodulators and immunostimulants include various interleukins, cytokines and antibody preparations. Exemplary antibiotics includes antifungal agents and antibacterial agents. Exemplary anti inflammatory agents include glucocorticoids and non-steroidal anti-inflammatory 10 compounds. Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or 15 insufflation. The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in 20 the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. 25 Formulations containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to two hundred (200) milligrams, per tablet, are accordingly suitable representative unit dosage forms. The compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a 30 compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.

WO 00/78746 PCT/AU00/00680 -30 For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. 5 A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely 10 divided active component. In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. 15 The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term preparation" is intended to include the formulation of the active compound with 20 encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration. 25 For preparing suppositories, a low melting wax, such as admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

WO 00/78746 PCT/AU00/00680 -31 Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. 5 Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. The compounds according to the present invention may thus be formulated for parenteral 10 administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, 15 the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. Aqueous solutions suitable for oral use can be prepared by dissolving the active component 20 in water and adding suitable colorants, flavours, stabilizing and thickening agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, 25 methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the 30 active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

WO 00/78746 PCT/AU00/00680 -32 For topical administration to the epidermis the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of 5 suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Formulations suitable for topical administration in the mouth include lozenges comprising 10 active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. Solutions or suspensions are applied directly to the nasal cavity by conventional means, for 15 example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump. To improve nasal delivery and retention the compounds according to the 20 invention may be encapsulated with cyclodextrins, or formulated with their agents expected to enhance delivery and retention in the nasal mucosa. Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable 25 propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

WO 00/78746 PCT/AU00/00680 -33 Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). 5 Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler. 10 In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 1 to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. 15 When desired, formulations adapted to give sustained release of the active ingredient may be employed. The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active 20 component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. 25 Liquids or powders for intranasal administration, tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions. The invention will now be described with reference to the following examples which illustrate some preferred aspects of the present invention. However it is to be understood 30 that the particularity of the following description of the invention is not to supersede the generality of the preceding description of the invention.

WO 00/78746 PCT/AU00/00680 - 34 EXAMPLES Example 1 Preparation of 4-{2-[1-(6-Chloro-3-pyridazinyl)-4-piperidinyl]ethoxy}benzaldehyde O-ethyloxime (Compound 1) 5 \ / /Et Cl N CHy-CH 2 -O C N O N=N 4- { 2-[1-(6-Chloro-3-pyridazinyl)-4-piperidinyl]ethoxy}benzaldehyde (Intermediate IIa) was prepared from 4-hydroxybenzaldehyde and 2-[1-(6-Chloro-3-pyridazinyl)-4 10 piperidinyl]ethanol using a Mitsunobu Reaction and following the general methods described in US Patent 4,992,433. The aldehyde (60mg, 0.17mmol) was dissolved in ethanol (5 ml) with stirring at room temperature and a solution of ethoxyamine in water (0.5 ml, 50% EtONH 2 ) was added. The reaction was stirred at room temperature for 2 days and then concentrated on a rotary evaporator and the residue was purified by 15 chromatography (silica gel 18g) using chloroform as eluent. The first compound to elute was the O-ethyloxime (1) which was obtained as a pale cream solid (30mg, 44%). 1H nmr spectrum (CDCl 3 ) 8 (ppm): 1.20-1.40 (min, 5H); 1.65-1.95 (min, 5H); 2.95 (bt, 2H); 4.05 (t, 2H); 4.18 (q, 2H); 4.35 (bd, 2H); 6.87 (d, 2H); 6.90 (d, 1H); 7.16 (d, 1H); 7.52 (d, 2H); 8.02 (s, 1H). 20 Mass Spectrum (ESI) 389 (M+1) + Example 2 Preparation of 4- {2-[1-(6-Methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}benzaldehyde O-ethyloxime (Compound 2) 25 N -- O Et

CH

3 -/ \ N CH2-CH 2 -O / C N=N

H

WO 00/78746 PCT/AU00/00680 -35 (a) A solution of 4-hydroxybenzaldehyde (100mg, 0.88mmol) and 50% O ethylhydroxylamine aqueous solution (0.6ml, 4.9mmol) in dioxane (2 ml) was stirred under an atmosphere of argon at room temperature for 16 hours and then heated at 90-1000 for 3 hours when thin layer chromatography (silica, dichloromethane) indicated the 5 reaction was complete. The solution was evaporated to dryness and the residue partitioned between ethyl acetate (20 ml) and water (5 ml). The organic layer was washed with water, dried (Na 2

SO

4 ) and evaporated to afford 4-hydroxybenzaldehyde O-ethyloxime (125mg, 92.5%). 10 (b) To a solution of 4-hydroxybenzaldehyde O-ethyloxime (49mg, 0.4mmol), 2-[1-(6 methyl-3-pyridazinyl)-4-piperidinyl]ethanol (88mg, 0.4mmol) and triphenylphosphine (115mg, 0.44mmol) in dry tetrahydrofuran (THF) (5 ml) under argon at room temperature was added dropwise diisopropylazodicarboxylate (89mg, 0.44mmol) in dry THF. The resulting solution was stirred at 200 for 24 hours and the solvent was then removed on a 15 rotary evaporator. The residue was chromatographed on silica gel, using firstly ethyl acetate/hexane (1:1) as eluent to give the product (Compound 2) as a white solid (103mg, 70%). 'H nmr spectrum (CDC1 3 ) 8 (ppm): 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.53 (s, 3H); 2.95 (bt, 2H); 4.05 (t, 2H); 4.18 (q, 2H); 4.35 (bd, 2H); 6.88 (d, 2H); 6.90 (d, 1H); 7.05 (d, 20 1H); 7.52 (d, 2H); 8.02 (s, 1H). Mass Spectrum (ESI) 369 (M+1) + Example 3 25 The Compound No's 5, 8, 11, 12, 13, 14, 15, 20, 21 and 22-25 from Tables 1 and 3 of the invention were prepared following essentially the same method as described in Example 1 for Compound 1, using the appropriate carbonyl compound (Het-A-Alkylene-O-Aryl C(X2 )=O and alkoxyamine (H 2 NO-X'). The compounds were purified by chromatography on silica gel and characterised by their nuclear magnetic resonance (nmr) spectra and Mass 30 Spectral (MS) data. For convenience the nmr and MS data are recorded in Table 9 below.

WO 00/78746 PCT/AU00/00680 -36 Table 9 Compd MS data NMR data: Proton Chemical Shift, Number (ESI) 6 in ppm (CDC1 3 ) 5 419 (M+1) 1.20-1.40(m, 5H); 1.65-1.95(m, 5H); 3.0(bt, 2H); 3.89(s, 3H); 4.08(t, 2H); 4.21(q, 2H); 4.35(bd, 2H); 6.85(d, 1H); 6.92(d, 1H); 7.0(dd, 1H); 7.15(d, 2H); 7.24(d, 1H); 8.02(s, 1H) 8 375 (M+1) 1.30(m, 2H); 1.65-1.95(m, 5H); 2.95(t, 2H); 3.93(s, 3H); 4.05(t, 2H); 4.40(d, 2H); 6.88(d, 2H); 7.0(d, 1H); 7.24(d, 1H); 7.51(d, 2H); 8.02(s, 1H) 11 403 (M+1) 0.95(t, 3H); 1.30(m, 2H); 1.65-1.95(m, 5H); 1.77(t, 2H); 2.95(t, 2H); 3.92-4.20(m, 4H); 4.35(d, 2H); 6.85(d, 2H); 6.90(d, 1H); 7.20(d, 1H); 7.50(d, 2H); 8.07(s, 1H) 12 403 (M+1) 1.25(d, 6H); 1.30(m, 2H); 1.65-1.95(m, 5H); 2.95(t, 2H); 4.05(t, 2H); 4.35(d, 2H); 4.42(m, 1H); 6.85(d, 2H); 6.90(d, 1H); 7.20(d, 1H); 7.51(d, 2H); 8.05(s, 1H1). 13 401 (M+1) 1.30(m, 2H); 1.65-1.95(m, 5H); 2.95(t, 2H); 4.05(t, 2H11); 4.35(d, 2H); 4.66(d, 2H); 5.25(dd, 1H); 5.38(dd, 1H); 6.08(m, 1H); 6.85(d, 2H); 6.90(d, 1H); 7.20(d, 1H); 7.50(d, 2H11); 8.13(s, 1H) 14 400 (M+1) 1.30(m, 2H); 1.65-1.95(m, 5H); 2.95(t, 2H); 4.05(t, 2H); 4.35(d, 2H); 4.75(s, 2H); 6.85(d, 2H); 6.90(d, 1H); 7.20(d, 1H); 7.50(d, 2H); 8.07(s, 1H) 15 451 (M+1) 1.30(m, 2H); 1.65-1.95(m, 5H); 2.95(t, 2H11); 4.05(t, 2H11); 4.35(d, 2H11); 5.20(s, 2H11); 6.85(d, 2H); 6.88(d, 1H); 7.20(d, 1H1); 7.41(s, 5H1); 7.50(d, 2H); 8.08(s, 1H) 20 Not 1.15-1.45(m, 5H); 1.65-1.95(m, 5H); 2.95(bt, 2H); 3.50(q, recorded 2H); 3.55-3.80(m, 6H); 4.05(t, 2H); 4.3(t, 4H11); 4.36(d, 2H); 6.85(d, 2H); 6.90(d, 2H); 7.2(d, 1H1); 7.45(d, 2H); 8.05(s, 1H) 21 Not 1.15-1.45(m, 5H); 1.65-1.95(m, 5H); 3.0(bt, 2H11); 4.05(t, 2H); recorded 4.22(q, 2H11); 4.30(bd, 2H); 4.83(q, 2H); 6.90(d, 2H); 7.04(d, WO 00/78746 PCT/AU00/00680 -37 1H); 7.20(d, 1H); 7.53(d, 2H); 8.05(s, 1H) 22 303 (M+1) 2.2(m, 2H); 2.26(2xs, 9H); 2.99(t, 2H); 3.81(t, 2H); 3.94(s, 3H); 5.87(s, 1H); 7.23(s, 2H); 7.95(s, 1H) 23 329 (M+1) 2.2(m, 2H); 2.26(2xs, 9H); 2.99(t, 2H); 3.81(t, 2H); 4.65(m, 2H); 5.2-5.4(m, 2H); 6.0-6.15(m, 1H); 5.87(s, 1H); 7.23(s, 2H); 8.01(s, 1H) 24 Not 1.3(t, 3H); 2.2(m, 2H); 2.27(2xs, 9H); 2.99(t, 2H); 3.81(t, 2H); recorded 4.18(q, 2H); 5.87(s, 1H); 7.23(s, 2H); 7.96(s, 1H) 25 401 2.2(m, 2H); 2.26(2xs, 9H); 2.99(t, 2H); 3.81(t, 2H); 5.19(s, (M+23) 2H); 5.87(s, 1H); 7.23(s, 2H); 7.3-7.45(m, 5H); 8.04(s, 1H) Example 4 The Compound No's 3, 4, 6, 7, 9, 10, 16, 17, 18, 19 from Tables 1 and 2 of the invention 5 were prepared using essentially the same method as described in Example 2 for Compound 2 and were obtained in yields of 61-73%. The compounds were purified by column chromatography on silica gel and characterised by their nuclear magnetic resonance (nmr) spectra and Mass Spectral (MS) data. For convenience the nmr and MS data are recorded in Table 10 below. 10 Table 10 Compound MS data NMR data: Proton Chemical Shift, Number (ESI) 8 in ppm (CDCl 3 ) 3 403 (M+I) 1.20-1.40(m, 5H); 1.65-1.95(m, 5H); 2.15(s, 3H); 2.95(t, 2H); 4.05(t, 2H); 4.23(q, 2H); 4.35(d, 2H); 6.85(d, 2H); 6.94(d, 1H); 7.18(d, 1H); 7.60(d, 2H) 4 383 (M+1) 1.20-1.40(m, 5H); 1.65-1.95(m, 5H); 2.15(s, 3H); 2.53(s, 3H); 2.95(t, 2H); 4.05(t, 2H11); 4.18(q, 2H); 4.35(d, 2H); 6.89 6.90(2xd, 3H); 7.12(d, 1H); 7.61(d, 2H) 6 463 (M+1) 1.20-1.40(m, 5H); 1.65-1.95(m, 5H); 2.15(s, 3H); 2.95(t, 2H); WO 00/78746 PCT/AU00/00680 -38 3.90(s, 6H); 4.05(t, 2H); 4.22(q, 2H); 4.35(d, 2H); 6.85(s, 2H); 6.90(d, 1H); 7.14(d, 1H) 7 355 (M+1) 1.30(m, 2H); 1.65-1.95(m, 5H); 2.53(s, 3H); 2.95(t, 2H); 3.93(s, 3H); 4.05(t, 2H); 4.35(d, 2H); 6.88(d, 2H); 6.90(d, 1H); 7.05(d, 1H); 7.51(d, 2H); 8.05(s, 1H) 9 369 (M+1) 1.32(m, 2H); 1.65-1.95(m, 5H); 2.15(s, 3H); 2.49(s, 3H); 2.95(t, 2H); 3.93(s, 3H); 4.06(t, 2H); 4.35(d, 2H); 6.88(d, 2H); 7.15(d, 1H); 7.25(d, 1H); 7.55(d, 2H) 10 403 (M+1) 1.02-1.40(m, 5H); 1.65-1.95(m, 5H); 2.70(q, 2H); 2.95(t, 2H); 3.91(s, 3H); 4.05(t, 2H); 4.35(d, 2H); 6.82(d, 2H); 6.88(d, 1H); 7.15(d, 1H); 7.55(d, 2H) 16 375 (M+1) 1.30(m, 2H); 1.65-1.95(m, 5H); 2.95(t, 2H); 3.93(s, 3H); 4.03(t, 2H); 4.35(d, 2H); 6.85(d, 2H); 7.03(d, 1H); 7.12(d, 1H); 7.18(d, 1H); 7.28(d, 1H); 8.03(s, 1H) 17 405 (M+1) 1.30(m, 2H); 1.65-1.95(m, 5H); 2.95(t, 2H); 3.85(s, 3H); 3.93(s, 3H); 4.15(t, 2H); 4.35(d, 2H); 6.85(d, 1H); 6.90(d, 1H); 6.98(dd, 1H); 7.16(d, 1H); 7.23(d, 1H); 8.0(s, 1H) 18 403 (M+1) 1.30(m, 2H); 1.65-1.95(m, 5H); 2.25(s, 6H); 3.0(t, 2H); 3.85(t, 2H); 3.91(s, 3H); 4.35(d, 2H); 6.92(d, 1H); 7.10(d, 1H); 7.26(s, 2H); 8.0(s, 1H) 19 419 (M+1) 1.30(m, 2H); 1.65-1.95(m, 5H); 2.15(s, 3H); 2.95(t, 2H); 3.90(s, 3H); 3.95(s, 3H); 4.07(t, 2H); 4.35(d, 2H); 6.82(d, 1H); 6.90(d, 1H); 6.99(dd, 1H); 7.14(d, 1H); 7.26(d, 1H) 5 WO 00/78746 PCT/AU00/00680 -39 Example 5 Preparation of 3,5-Dimethyl-[4-{3-(3-Phenyl- 5-isoxazolyl)propoxy}]benzaldehyde O ethyloxime (Compound 127) 5 - N-OEt // NO O 10 (a) Condensation of 4-pentyn-1-ol and 4-hydroxy-3,5-dimethylbenzaldehyde O-ethyloxime using Mitsunobu Reaction conditions (see for example J. Med. Chem., 36, 3240, 1993 and references cited therein) gave 3,5-dimethyl-4-(4-pentyn- 1 -yloxy)benzaldehyde O-ethyl oxime in good yield. (b) Isoxazole ring formation (also see J. Med. Chem., 38, 1355, 1995) 15 A solution of benzaldehyde oxime (45 mg, 0.372 mmol) in DMF (0.5 ml) was added dropwise to a solution of N-chlorosuccinimide (50mg, 0.374mmol) and pyridine (1 drop) in DMF (0.5 ml), keeping the temperature between 25-30oC. The resulting solution was allowed to stir at room temperature for 90 minutes. To this was added a solution of 3,5 dimethyl-4-(4-pentyn-1-yloxy)benzaldehyde O-ethyl oxime (49mg, 0.189mmol) in DMF 20 (0.5mL, the resulting solution was then heated at 85-90oC for 10 minutes. To this was added, dropwise over 10 minutes, a solution of triethylamine (541, 0.386mmol) in DMF (0.5 ml), the resulting solution was then heated at 85-90 0 C for 1 hour. The reaction was cooled and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (15 ml). The organic phase was washed with brine (15mL), dried 25 (MgSO 4 ), filtered and concentrated in vacuo. Purification by flash chromatography (Ethyl acetate/Hexane 5%) gave the product (Compound 127) as a clear oil (23mg, 32 %). The structure was confirmed by the 'H nmr spectrum which is given in Table 11 below.

WO 00/78746 PCT/AU00/00680 - 40 Example 6 The Compound No's 130, 131, 132, 133, 137, 138, and 139 from Table 3 of the invention were prepared using the appropriate oxime and essentially the same method as described in Example 5 for Compound 127. The compounds were purified by column chromatography 5 on silica gel and characterised by their nuclear magnetic resonance (nmr) spectra and Mass Spectral (MS) data which are summarised in Table 11 below. Example 7 Preparation of 2-(1-(6-methyl-3-pyridazinyl)-4-piperidinylethoxy)-thiazole-4 10 carboxaldehyde O-ethyl oxime (Compound No. 155) e N N-OEI N-N s 15 (a) Sodium borohydride (690mg, 18mmol) was added as a single portion to a solution of ethyl 2-chloro-4-thiazolecarboxylate (1.6g, 9mmol) in ethanol (70ml) at 0 0 C, then the mix was allowed to warm to room temperature with stirring overnight. The reaction was acidified to pH 5 with IN HCI and concentrated under vacuum, then the white residue was partitioned between water (125ml) and ethyl acetate (3x300ml). The organic phase was 20 washed with brine and dried (Na 2

SO

4 ), then the solvents were removed. Chromatography of the residue on silica gel (15g, eluent 15%-30% hexane/ethyl acetate) gave 2-chloro-4 hydroxymethylthiazole (850mg, 5.5mmol) in 63% yield as a clear oil, 'H nmr; 4.72 (s, 2H), 7.11 (s, 1H). 25 (b) Tert-butyldimethylsilylchloride (1.07g, 7. 1 mmol) was added as a single portion to a solution of the hydroxymethylthiazole (840mg, 5.6mmol) and imidazole (500mg, 7.34mmol) in anhydrous DMF (20ml). The solution was stirred overnight under an argon atmosphere. Solvents were removed under vacuum and the residue was partitioned between water (100ml) and ethyl acetate (500ml). The organic layer was washed with 30 brine, dried (MgSO 4 ) and concentrated under reduced pressure. The residue was chromatographed on silica gel (200g; eluent 5%-50%DCM/hexane) to give 2-chloro-4-t- WO 00/78746 PCT/AU00/00680 -41 butyldimethylsilyloxymethylthiazole (1.29g, 4.9mmol) in 87% yield, 1H nmr 0.11 (s, 6H), 0.94 (s, 9H11), 4.78 (s, 2H), 7.08 (s, 1H1). (c) A suspension of sodium hydride (60%, 135mg, 3.4mmol) and 1-(6-methyl-3 5 pyridazinyl)-4-(2-hydroxyethyl)-piperidine (250mg, 1.1 mmol) in dimethoxyethane (DME; 4ml) was stirred at room temperature for 2hr. A solution of 2-chloro-4-t butyldimethylsilyloxymethylthiazole (385mg, 1.46mmol) in DME (Iml) was added and the mixture stirred at reflux under argon for 5hr then at room temperature overnight. The mixture was diluted with ether, filtered and then concentrated. The residue was 10 chromatographed on silica gel (25g; eluent 30%-50% ethyl acetate/hexane) to give 2-(1-(6 methyl-3-pyridazinyl)-4-piperidinylethyl- 1 -oxy)-4-t-butyldimethylsilyloxymethylthiazole (274mg, 54%), 'H nmr; 0.11 (s, 6H), 0.94 (s, 9H), 1.3-1.87 (m, 7H), 2.58 (s, 3H), 2.93 (t, 2H), 4.31-4.35 (m, 2H), 4.48 (t, 2H), 4,64 (s, 2H), 6.51 (s, 1H), 6.93 (d, 1H), 7.11 (d, 1H). 15 (d) A solution oftetrabutylammonium fluoride (IM in THF, 0.6ml, 0.6mmol) was added dropwise to a solution of 2-(1-(6-methyl-3-pyridazinyl)-4-piperidinylethyl-1-oxy)-4-t butyldimethylsilyloxymethylthiazole (274mg, 0.6mmol) in THF (10ml) and the reaction was stirred under argon overnight. The mixture was partitioned between water (10 Oml) and ethyl acetate (40ml) then the organic layer was washed with brine, dried (MgSO 4 ) and 20 concentrated. The residue was chromatographed on silica gel (25g; eluent 0%-10% isopropanol/ethyl acetate) to give 2-(1-(6-methyl-3-pyridazinyl)-4-piperidinylethoxy)-4 hydroxymethylthiazole (157mg, 0.47mmol) in 76% yield, 'H nmr; 1.78-1.9 (m, 5H), 2.51 (s, 3H), 2.96 (t, 2H), 4.31-4.37 (m, 4H), 4.58 (s, 2H), 6.02 (s, 1H), 7.22 (d, 1H), 7.30 (d, 1H). 25 (e) A solution of anhydrous DMSO (8091, 1.13mmol) in DCM (lml) was added to a solution of oxalyl chloride (459l, 0.5mmol) in DCM (lml) at -60 0 C. After 15min a solution of 2-(1 -(3-methyl-6-pyridazinyl)-4-piperidinylethyl- 1 -oxy)-4 hydroxymethylthiazole (157mg, 0.5mmol) in DCM (2ml) was added. The reaction was 30 stirred at -50 0 C for 10min then triethylamine (325gd, 2.33mmol) was added and the reaction allowed to warm to room temperature. The mixture was partitioned between DCM WO 00/78746 PCT/AU00/00680 - 42 (1 50ml) and dilute sodium bicarbonate solution (75ml) then washed with brine, dried (MgSO 4 ) and concentrated. The residue was adsorbed onto silica gel and chromatographed on silica gel (15g; eluent 65% ethyl acetate/hexane) to give 2-(1-(6 methyl-3-pyridazinyl)-4-piperidinylethoxy)thiazole-4-carboxaldehyde (103mg, 66%), 'H 5 nmr; 1.3-1.9 (m, 7H), 2.63 (s, 3H), 2.94 (m, 2H), 4.34-4.38 (m, 2H), 4.59 (t, 2H), 7.04 (d, 1H), 7.20 (d, 1H), 7.61 (s, 1H), 9.74 (s, 1H). (f) The O-ethyl oxime ether (Compound 155) of the aldehyde in part (e) was prepared from by reaction with ethoxyamine following similar conditions to those described in Example 1 10 and the spectra for Compound 155 are given in Table 11 below. Example 8 Preparation of 4-{N-(6-Chloro-3-pyridazinyl)-N-methyl-5-aminopentan-1 oxy}benzaldehyde O-ethyloxime (Compound No. 161) 15 - Me - N-OEI C l \

N-(CH

2

)

5

-

0 N-N \C / (a) A mixture of 5-amino- -pentanol (433mg, 4.2mmol), dichloropyridazine (1.25g, 20 8.39mmol) and sodium carbonate (890mg, 8.39mmol) was stirred in 1,4-dioxane (40 ml) and heated at 70-800 for 3 days under an atmosphere of argon. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (300 ml) and water (38 ml). The organic layer was separated, dried and concentrated to give an orange solid which was chromatographed on silica, using hexane/ethyl acetate (1:1). The 25 product, 5-(6-chloro-3-pyridazinyl)amino-1-pentanol was isolated as a pale yellow solid (202 mg, 22%). (b) 5-(6-Chloro-3-pyridazinyl)amino-1-pentanol was coupled to 4-hydroxybenzaldehyde using the Mitsunobu Reaction and following essentially the same method as described in 30 Example 2, part (b). The product, 4-{N-(6-Chloro-3-pyridazinyl)-5-aminopentan-1 oxy}benzaldehyde, was isolated by chromatography and characterised by its nmr spectrum WO 00/78746 PCT/AU00/00680 -43 in CDCl 3 ; 1.65 (min, 2H); 1.76 (min, 2H); 1.90 (min, 2H); 3.45 (t, 2H); 4.15 (t, 2H); 6.92 (d, 1H); 7.10 (d, 2H); 7.30 (d, 1H); 7.89 (d, 2H); 9.86 (s, 1H). (c) Sodium hydride (10mg, 0.24mmol) was added to a solution of 4-{N-(6-Chloro-3 5 pyridazinyl)-5-aminopentan-1-oxy}benzaldehyde (51 mg, 0.16mmol) in THF (3.5 ml) and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (50l, 0.8mmol) was added to the reaction mixture and the suspension was stirred at room temperature for 48 hours. The reaction mixture was poured into water (1.5ml) and concentrated under reduced pressure. The residue was partitioned between water (2 ml) 10 and ethyl acetate (40 ml), shaken thoroughly and the organic layer was separated, dried and evaporated to give a yellow solid. Purification by chromatography on silica gel (6g, 30% ethyl acetate/hexane) gave 4- {N-(6-Chloro-3-pyridazinyl)-N-methyl-5-aminopentan-1 oxy}benzaldehyde (16mg, 30%) as a pale yellow oil. 15 (d) Reaction of 4- {N-(6-Chloro-3-pyridazinyl)-N-methyl-5-aminopentan- 1 oxy}benzaldehyde with ethoxyamine following similar conditions to those in Example 1 gave 4-{N-(6-Chloro-3-pyridazinyl)-N-methyl-5-aminopentan-l1-oxy} benzaldehyde O ethyloxime (Compound 161) as a colourless oil. The nmr and mass spectral data are given below in Table 11. 20 Example 9 Preparation of 4- {2-[1-{5-Methyl-2-(1,3,4-thiadiazinyl)}-4 piperidinyl]ethoxy}benzaldehyde O-ethyloxime (Compound 158) Me.S - N-OEI 25 / N oZ N-O N- N (a) A suspension containing 2-bromo-5-methyl-1,3,4-thiadiazole (Modarai, B., et al. J. Heterocyclic Chem. (1974) 11, 343-5) (100mg, 0.56mmol), 4-piperidine ethanol (87mg, 30 0.67mmol) and potassium carbonate (77mg, 0.56mmol) was heated overnight at 120 0 C. The reaction was cooled and the mixture partitioned between water (10 Oml) and ethyl WO 00/78746 PCT/AU00/00680 -44 acetate (30ml), then the organic layer was washed with brine, dried (Na 2

SO

4 ) and concentrated. Chromatography of the residue on silica gel (8g; eluent 2.5% methanol/DCM) gave 1-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(2-hydroxyethyl)piperidine (41mg, 32%), 'H nmr; 1.33 (min, 2H), 1.54 (q, 2H), 1.7 (min, 1H), 1.79 (min, 2H), 2.54 (s, 3H), 5 3.08 (min, 2H), 3.71 (t, 2H), 3.88 (min, 2H). (b) 1-(5-methyl-2-[1,3,4-thiadiazolyl])-4-piperidineethanol from part (a) was converted into the oxime ether Compound No. 158 by reaction with 4-hydroxybenzaldehyde and ethoxyamine following a similar method to that described in Example 1. The spectral data 10 are recorded below in Table 11. Example 10 The Compound No's 84, 152-154, 157, 159-160, 196-207, 210 and 212 from Table 6 above were prepared using the appropriate heterocycle and essentially the same method as 15 described in Example 9 for Compound 158. The compounds were purified by column chromatography on silica gel and characterised by their nuclear magnetic resonance (nmr) spectra and Mass Spectral (MS) data which are summarised in Table 11 below. Example 11 20 Most of the compounds in Tables 1-8 were prepared from the appropriate heterocyclic alcohol derivative (Het-A-Alk-OH) by reaction with the appropriate hydroxyaromatic carbonyl compound (HO-Ar-C(X2)=0) or hydroxy aromatic oxime ether (HO-Ar C(X2)=NO-X') following similar conditions to those described in Examples 1 and 2. An alternative method which was used for some compounds is the reaction of the heterocyclic 25 alkyl halide (Het-A-Alk-C1) with the appropriate hydroxyaromatic carbonyl compound (HO-Ar-C(X2)=0) or hydroxy aromatic oxime ether (HO-Ar-C(X 2 )=NO-X'). The compounds were generally purified by column chromatography on silica gel and characterised by their nuclear magnetic resonance (nmr) spectra and Mass Spectral (MS) data. For convenience the nmr data are recorded in Table 11 below. 30 WO 00/78746 PCT/AU00/00680 - 45 Table 11 Compd MS data NMR data: Proton Chemical Shift, Number (ESI) 8 in ppm (CDCl 3 unless otherwise noted) 26 - 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.95 (bt, 2H); 4.0 (s, 3H); 4.05 (t, 2H); 4.17 (q, 2H); 4.27 (bd, 2H); 6.85-6.95 (2xd, 3H); 7.10 (d, 1H); 7.52 (d, 2H); 8.03 (s, 1H) 27 - 1.31 (t, 3H); 2.78 (m, 4H); 3.72 (m, 4H); 4.22 (m, 6H); 6.91 (m, 4H); 7.52 (d, 2H); 8.02 (s, 1H) 28 - 1.31 (t, 3H); 1.86 (m, 5H); 3.19 (m, 2H); 3.92 (m, 2H); 4.20 (m, 4H); 6.89 (m, 3H); 7.01 (d, 1H11); 7.50 (d, 2H); 8.01 (s, 1H) 31 397 1.32 (t, 3H); 1.35-1.51 (m, 2H); 1.95-2.17 (m, 3H); 3.01 (t, 2H); (M+Na) 3.86 (d, 2H); 4.22 (q, 2H); 4.38-4.45 (m, 2H); 6.91 (m,3H); 7.17 (d, 1H1); 7.48 (d, 2H); 8.02 (s, 1H) 32 425 1.25-1.35 (m, 7H); 1.45-1.50 (m, 2H); 1.65-1.87 (m, 5H); 3.01 (M+Na) (m, 2H); 4.00 (bt, 2H); 4.21 (q, 2H); 4.37-4.40 (m, 2H); 6.89 (d, 3H); 7.21 (d, 1H); 7.53 (d, 2H); 8.04 (s, 1H) 33 405.1693 1.30 (m, 2H); 1.75-1.95 (m, 5H); 2.97 (t, 2H); 3.87 (s, 3H); 3.99 (M+1) (s, 3H); 4.10 (t, 2H); 4.35 (d, 2H); 6.85 (d, 1H), 6.90 (d, 1H1); 7.00 (dd, 1H); 7.15 (d, 1H); 7.25 (d, 1H); 8.00 (s, 1H) 36 434 (M+1) 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.98 (bt, 2H); 4.21 (t, 2H); 4.28 (q, 2H11); 4.33 (bd, 2H); 6.87 (d, 1H1); 7.06 (d, 1H1); 7.16 (d, 1H); 7.73 (dd, 1H); 8.02 (s, 1H); 8.05 (d, 1H) 37 405 (M+1) 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.95 (bt, 2H); 4.05 (t, 2H); 4.22 (q, 2H); 4.30 (bd, 2H); 6.40-6.55 (m, 3H); 6.93 (dd, 1H1); 7.01 (d, 1H11); 8.02 (s, 1H1); 10.05 (bs, 1H) 40 417 (M+1) 1.20-1.40 (m, 2H); 1.65-1.95 (m, 5H); 2.95 (bt, 2H); 4.0 (t, 2H); 4.25 (bd, 2H); 4.65 (m, 2H); 5.10 (d, 1H); 5.22 (d, 1H); 5.35 (bs, 1H1); 5.98 (m, 1H1); 6.30 (d, 1H); 6.55 (m, 2H); 6.79 (d, 1H11); 7.02 (d, 1H); 7.95 (s, 1H) WO 00/78746 PCT/AU00/00680 - 46 41 389 (M+1) 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.95 (bt, 2H); 4.05 (t, 2H); 4.18 (q, 2H); 4.38 (bd, 2H); 6.90 (bd, 2H); 7.05-7.30 (m, 4H); 8.02 (s, 1H) 42 403 (M+1) 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.15 (s, 3H); 2.95 (bt, 2H); 3.95 (t, 2H); 4.18 (q, 2H); 4.32 (bd, 2H); 6.77 (d, 1H); 6.86 (d, 1H); 7.13 (d, 1H); 7.29 (d, 1H); 7.41 (s, 1H); 8.01 (s, 1H) 43 415 (M+1) 1.30 (m, 2H); 1.65-1.95 (m, 5H); 2.20 (s, 3H); 2.95 (t, 2H); 4.08 (t, 2H); 4.35 (d, 2H); 4.65 (d, 2H); 5.17 (dd, 1H); 5.33 (dd, 1H); 6.05 (m, 1H); 6.75 (d, 1H); 6.87 (d, 1H); 7.13 (d, 1H); 7.27 (d, 1H); 7.41 (s, 1H); 8.07 (s, 1H) 44 389 (M+1) 1.30 (m, 2H); 1.65-1.90 (m, 5H); 2.18 (s, 3H); 2.95 (t, 2H); 3.88 (s, 3H); 3.95 (t, 2H); 4.29 (d, 2H); 6.75 (d, 1H); 6.85 (d, 1H); 7.08 (d, 1H); 7.28 (d, 1H); 7.34 (s, 1H); 7.90 (s 1H) 45 417 (M+1) 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.28 (s, 6H); 2.95 (bt, 2H); 3.82 (t, 2H); 4.18 (q, 2H); 4.32 (bd, 2H); 6.87 (d, 1H); 7.13 (d, 1H); 7.24 (s, 2H); 7.98 (s, 1H) 46 369 (M+1) 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.53 (s, 3H); 2.95 (bt, 2H); 4.05 (t, 2H); 4.21 (q, 2H); 4.35 (bd, 2H); 6.82-6.95 (m, 2H); 7.05 7.30 (m, 4H); 8.01 (s, 1H) 48 355 (M+1) 1.30 (m, 2H); 1.65-1.95 (m, 5H); 2.50 (s, 3H); 2.92 (t, 2H); 3.98 (s, 3H); 4.05 (t, 2H); 4.32 (d, 2H); 6.86-6.89 (m, 2H); 7.05 (d, 1H); 7.10 (d, 1H); 7.16 (d, 1H); 7.28 (dd, 1H); 8.02 (s, 1H) 49 355 (M+1) 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.91 (bt, 2H); 4.05 (t, 2H); 4.18 (q, 2H); 4.38 (bd, 2H); 6.85-6.95 (m, 3H); 7.12 (dd, 1H); 7.49 (d, 2H); 8.01 (s, 1H); 8.50 (d, 1H) 50 419 (M+I) 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.95 (bt, 2H); 3.78 (s, 3H); 3.95 (t, 2H); 4.18 (q, 2H); 4.32 (bd, 2H); 6.42 (dd, 1H); 6.48 (dd, 1H); 6.88 (d, 1H); 7.15 (d, 1H); 7.18 (dd, 1H); 8.35 (s, 1H) 51 383 (M+I) 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.25 (s, 3H); 2.57 (s, 3H); 2.95 (bt, 2H); 4.08 (t, 2H); 4.23 (q, 2H); 4.35 (bd, 2H); 6.83 (d, 2H); 6.87 (d, 1H); 7.09 (d, 1H); 7.33 (d, 1H); 7.44 (bs, 1H); 8.01 WO 00/78746 PCT/AU00/00680 -47 (s, 1H) 52 369 (M+I) 1.20-1.45 (m, 2H); 1.70-1.90 (m, 5H); 2.20 (s, 3H); 2.53 (s, 3H); 2.90 (t, 2H); 3.90 (s, 3H); 4.08 (t, 2H); 4.31 (d, 2H); 6.75 (d, 1H); 6.85 (d, 1H); 7.04 (d, 1H); 7.30 (dd, 1H); 7.42 (d, 1H); 7.95 (s, 1H) 54 397 (M+1) 0.97 (t, 3H); 1.30 (m, 2H); 1.60-1.95 (m, 7H); 2.18 (s, 3H); 2.55 (s, 3H); 2.92 (t, 2H); 4.00-4.22 (m, 4H); 4.33 (d, 2H); 6.78 (d, 1H); 6.87 (d, 1H); 7.08 (d, 1H); 7.32 (dd, 1H); 7.45 (d, 1H); 8.02 (s, 1H) 55 - 1.31 (t, 3H); 1.8-2.2 (m, 4H); 3.55-3.7 (m, 2H); 3.80-3.98 (m, 2H); 4.22 (q, 2H); 4.61 (m, 1H); 6.85-6.98 (dd, 3H); 7.21 (d, 1H); 7.50 (d, 2H); 8.01 (s, 1H) 56 - 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.95 (bt, 2H); 4.05 (t, 2H); 4.18 (q, 2H); 4.46 (bd, 2H); 6.89 (d, 2H); 6.92 (d, 1H); 7.4-7.6 (m, 5H); 7.65 (d, 1H); 7.96-8.05 (m, 3H) 57 389 (M+1) 1.20-1.40 (m, SH); 1.65-1.95 (m, 5H); 2.95 (bt, 2H); 4.05 (t, 2H); 4.22 (q, 2H); 4.33 (bd, 2H); 6.87 (bd, 3H); 7.16 (d, 1H); 7.21 (s, 1H); 7.88 (d, 2H) 58 423 (M+1) 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 3.05 (bt, 2H); 4.05 (t, 2H); 4.20 (q, 1.7H, trans); 4.26 (q, 0.3H, cis); 4.55 (m, 2H); 6.87 (d, 2H); 6.93 (d, 1H); 7.21 (d, 0.3H, cis); 7.44 (d, 1H); 7.51 (d, 1.70H, trans); 7.87 (s, 0.15H, cis); 8.02 (s, 0.85H, trans) 59 - (d 6 -DMSO) 1.20-1.40 (m, 2H); 1.65-1.95 (m, 5H); 2.49 (s, 3H); 2.91 (bt, 2H); 4.15 (t, 2H); 4.37 (bd, 2H); 4.78 (q, 2H); 7.08 (d, 1H); 7.25 (d, 2H); 7.29 (d, 1H); 7.64 (d, 2H); 8.41 (s, 1H) 61 375 (M+1) Not recorded 67 356 (M+1) Not recorded 68 370 (M+1) Not recorded 70 356 (M+1) Not recorded 71 370 (M+1) Not recorded 73 376 (M+1) Not recorded WO 00/78746 PCT/AU00/00680 -48 75 376 (M+1) Not recorded 76 390 (M+I) Not recorded 77 402 (M+1) 84 422 (M+1) 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.89 (bt, 2H); 4.03 (t, 2H); 4.17 (q, 2H); 4.39 (bd, 2H); 6.65 (d, 1H); 6.87 (d, 2H); 7.45 (d, 2H); 7.58 (dd, 1H); 8.02 (s, 1H); 8.38 (bs, 1H) 85 383 (M+1) 0.97 (t, 3H); 1.32-1.34 (m, 1H); 1.69-1.88 (m, 8H); 2.52 (s, 3H); 2.88-2.95 (m, 2H); 4.02-4.10 (m, 2H); 4.31-4.34 (m, 4H); 6.84 6.88 (m, 3H); 7.03 (d, 1H); 7.49 (d, 2H); 8.02 (s, 1H) 86 399 (M+1) 1.25-1.34 (m, 1H); 1.74-1.90 (m, 6H); 2.65 (s, 3H); 3.05 (m, 2H); 3.41 (s, 3H); 3.69 (t, 2H); 4.05 (t, 2H); 4.29 (t, 2H); 4.32-4.40 (m, 2H); 6.87 (m, 3H); 7.10 (d, 1H); 7.52 (d, 2H); 8.08 (s, 1H) 88 379 (M+1) 1.29-1.38 (m, 2H); 1.73-1.86 (m, 6H); 2.52 (s, 3H); 2.88-2.94 (m, 2H); 4.06 (t, 2H); 4.31-4.34 (m, 2H); 4.74 (s, 2H); 6.85-6.91 (m, 3H); 7.06 (d, 1H); 7.51 (d, 2H); 8.06 (s, 1H) 89 389 (M+1) Not recorded 91 389 (M+1) Not recorded 92 403 (M+1) Not recorded 94 369 (M+1) Not recorded 95 383 (M+1) Not recorded 97 369 (M+1) Not recorded 98 383 (M+1) Not recorded 106 369 (M+I) Not recorded 108 311 1.52 (t, 3H); 2.16 (m, 2H); 2.20 (s, 3H); 2.82 (t, 2H); 4.01 (t, 2H); (M+Na) 4.20 (q, 2H); 5.84 (s, 1H); 6.85 (d, 2H); 7.51 (d, 2H); 8.01 (s, 1H) 109 - 2.16-2.21 (m, 4H); 2.22 (s, 9H); 2.99 (t, 2H); 3.81 (t, 2H); 3.97 (s, 3H); 5.87 (s, 1H); 7.28 (s, 2H) 112 331 (M+1) 0.97 (t, 3H); 1.70-1.76 (m, 2H); 2.16-2.20 (m, 2H); 2.20-2.27 (m, 9H); 2.99 (t, 2H); 3.82 (t, 2H); 4.10 (t, 2H); 5.87 (s, 1H); 7.23 (s, 2H); 7.97 (s, 1H) WO 00/78746 PCT/AU00/00680 - 49 118 328 (M+1) 2.17-2.23 (m, 2H); 2.27 (s, 9H); 2.99 (t, 2H); 3.83 (t, 2H); 4.77 (s, 2H); 5.87 (s, 1H); 7.27 (s, 2H); 8.03 (s, 1H) 119 349 2.17-2.20 (m, 2H); 2.27 (s, 9H); 2.48 (t, 1H); 2.99 (t, 2H); 3.82 (t, (M+Na) 2H); 4.75 (d, 2H); 5.87 (s, 1H); 7.26 (s, 2H); 8.02 (s, 1H) 120 381 0.92-1.3 (m, 7H); 1.71-1.82 (m, 4H); 2.26 (s, 9H); 2.72 (t, 2H); (M+Na) 3.75 (t, 2H); 4.20 (q, 2H); 5.81 (s, 1H); 7.24 (s, 2H); 7.91 (s, 1H) 121 395 1.26-1.33 (m, 5H); 1.39-1.43 (m, 4H); 1.67-1.81 (m, 4H); 2.25 (s, (M+Na) 3H); 2.26 (s, 6H); 2.70 (t, 2H); 3.75 (t, 2H); 4.20 (q, 2H); 5.79 (s, 1H); 7.23 (s, 2H); 7.97 (s, 1H) 122 367 1.31 (t, 3H); 1.53-1.60 (m, 2H); 1.81 (m, 4H); 2.26 (s, 9H); 2.75 (M+Na) (t, 2H); 3.76 (t, 2H); 4.21 (q, 2H); 7.23 (s, 2H); 7.97 (s, 1H) 123 353 1.29 (t, 3H); 1.86-1.95 (m, 4H); 2.27 (s, 9H); 2.82 (t, 2H); 3.78 (t, (M+Na) 2H); 4.19 (q, 2H); 5.85 (s, 1H); 7.23 (s, 2H); 7.98 (s, 1H) 124 393 2.19 (m, 2H); 2.27 (s, 9H); 2.99 (t, 2H); 3.83 (t, 2H); 4.49 (q, (M+Na) 2H); 5.87 (s, 1H); 7.24 (s, 2H); 8.03 (s, 1H) 125 383 1.24 (t, 3H); 2.17 (m, 2H); 2.26-2.27 (m, 9H); 2.98 (t, 2H); 3.56 (M+Na) (q, 2H); 3.71-3.73 (m, 2H); 3.80 (t, 2H); 4.29 (t, 2H); 5.86 (s, 1H); 7.19 (s, 2H); 8.02 (s, 1H) 126 367 2.16-2.29 (m, 14H); 2.99 (t, 2H); 3.81 (t, 2H); 4.62 (s, 2H); 5.87 (M+Na) (s, 1H); 7.23 (s, 2H); 8.10 (s, 1H) 127 - 1.31 (t, 3H); 2.24-2.28(m, 8H); 3.12 (t, 2H); 3.86 (t, 2H); 4.20 (q, 2H); 6.36 (s, 1H); 7.41-7.43 (m, 3H); 7.78-7.81 (m, 2H); 7.97 (s, 1H) 128 383 (M+1) 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 3.05 (bt, 2H); 4.05 (t, 2H); 4.18 (q, 2H); 4.35 (bd, 2H); 6.88 (d, 2H); 6.90 (d, 1H); 7.52 (d, 2H); 7.72 (d, 1H); 8.02 (s, 1H); 10.11 (s, 1H) 129 385 (M+I) 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.95 (bt, 2H); 4.05 (t, 2H); 4.18 (q, 2H); 4.35 (bd, 2H); 4.80 (s, 2H); 6.87 (d, 2H); 6.95 (d, 1H); 7.05 (d, 1H); 7.52 (d, 2H); 8.02 (s, 1H) 130 331 (M+1) 1.25-1.34 (m, 6H); 2.21 (m, 2H); 2.25 (s, 6H); 2.70 (q, 2H); 2.99 (t, 2H); 3.83 (t, 2H); 4.21 (q, 2H); 5.89 (s, 1H); 7.23 (s, 2H); 7.96 WO 00/78746 PCT/AU00/00680 -50 (s, 1H) 131 345 (M+1) 0.96 (t, 3H); 1.31 (t, 3H); 1.72 (m, 2H); 2.18 (m, 2H); 2.27 (s, 6H); 2.64 (t, 2H); 2.99 (t, 2H); 3.81 (t, 2H); 4.20 (q, 2H); 5.88 (s, 1H); 7.23 (s, 2H); 7.96 (s, 1H) 132 317 (M+I) 1.24-1.33 (m, 6H); 2.22 (s, 6H); 2.69 (q, 2H); 3.22 (t, 2H); 4.06 (t, 2H); 4.20 (q, 2H); 6.04 (s, 1H); 7.26 (s, 2H); 7.96 (s, 1H) 134 335 (M+1) 2.20 (m, 2H); 2.27 (s, 6H); 2.99 (t, 2H); 3.82 (t, 2H); 4.31-4.34 (m, 1H); 4.41-4.43 (m, 1H); 4.59-4.62 (m, 1H); 4.75-4.78 (m, 1H); 5.87 (s, 1H); 7.23 (s, 2H); 8.03 (s, 1H) 135 384 (M+1) Not recorded 136 384 (M+1) Not recorded 138 1.22-1.33 (m, 6H); 1.86-1.97 (m, 4H); 2.27 (s, 6H); 2.67 (q, 2H); 2.81 (t, 2H); 3.79 (t, 2H); 4.20 (q, 2H); 5.78 (s, 1H); 7.24 (s, 2H); 7.97 (s, 1H) 139 359 (M+1) 0.98 (t, 3H); 1.32 (t, 3H); 1.65 (m, 2H); 1.85-1.98 (m, 4H); 2.27 (s, 6H); 2.62 (t, 2H); 2.82 (t, 2H); 3.79 (t, 2H); 4.22 (q, 2H); 5.85 (s, 1H); 7.24 (s, 2H); 7.98 (s, 1H) 145 385.2229 1.20-1.40 (m, 5H); 1.65-1.95 (m, 5H); 2.52 (s, 3H); 2.90 (t, 2H); (M+1) 4.03 (t, 2H); 4.19 (q, 2H); 4.32 (d, 2H); 6.40-6.50 (m, 2H); 6.85 (d, 1H); 7.03 (d, 1H); 7.05 (d, 1H); 8.05 (s, 1H); 10.12 (s, 1H) 146 385.2246 1.20-1.40 (m, 5H); 1.70-1.90 (m, 5H); 2.53 (s, 3H); 2.91 (t, 2H); (M+1) 4.12 (t, 2H); 4.20 (q, 2H); 4.30 (d, 2H); 5.75 (br s, 1H); 6.82 (d, 1H); 6.86 (d, 1H); 7.02 (dd, 1H); 7.06 (d, 1H); 7.28 (d, 1H); 7.96 (s, 1 H) 147 363 (M+1) (CD 3 OD) 1.32 (t, 3H); 1.64 (m, 2H); 1.75 (m, 2H); 1.88 (m, 2H); 3.44 (t, 2H); 4.06 (t, 2H); 4.20 (q, 2H); 6.94 (m, 3H); 7.30 (d, 1H); 7.54 (m, 2H); 8.05 (s, 1H) 149 404 (M+1) Not recorded 150 403 (M+1) Not recorded 152 Not 1.31 (t, 3H); 2.81-2.97 (m, 6H); 3.68 (m, 4H); 4.21 (q, 2H); 4.21 recorded 4.26 (m, 2H); 6.90 (d, 2H); 7.51 (d, 2H); 7.86 (s, 1H); 8.02 (s, WO 00/78746 PCT/AU00/00680 -51 1H); 8.07 (s, 1H) 153 415 (M+1) 1.38-1.45 (m, 2H); 1.88-1.92 (m, 3H); 1.79 (t, 2H); 3.17-3.27 (m, 2H); 3.93 (s, 3H); 3.97-4.05 (m, 2H); 4.05 (t, 2H); 6.86 (d, 2H); 7.51 (d, 2H); 7.99 (s, 1H). F19 -60.05ppm 154 429 (M+1) 1.31 (t, 3H); 1.4-1.5 (m, 2H); 1.78 (t, 2H); 1.89-1.93 (m, 3H); 3.19-3.27 (m, 2H); 3.99-4.05 (m, 2H); 4.07 (t, 2H); 4.21 (q, 2H); 6.87 (d, 2H); 7.52 (d, 2H); 8.01 (s, 1H) 155 376 (M+1) 1.24-1.37 (m, 5H); 1.73-1.85 (m, 5H); 2.52 (s, 3H); 2.89 (t, 2H); 4.20 (q, 2H); 4.33-4.40 (m, 2H); 4.52 (t, 2H); 6.87-6.90 (m, 2H); 7.05 (d, 1H); 7.95 (s, 1H) 156 362 (M+1) 1.23-1.37 (m, 2H); 1.73-1.85 (m, 5H); 2.52 (s, 3H); 2.88 (t, 2H); 3.95 (s, 3H); 4.28-4.33 (m, 2H); 4.52 (t, 2H); 6.87-6.89 (m, 2H); 7.05 (d, 1H); 7.93 (s, 1H) 157 361 (M+1) 1.39-1.43 (m, 2H); 1.77-2.04 (m, 5H); 2.57 (s, 3H); 3.12 (t, 2H); 3.92-3.95 (m, 2H); 3.95 (s, 3H); 4.04 (t, 2H); 6.88 (d, 2H); 7.50 (d, 2H); 8.01 (s, 1H) 158 375 (M+1) 1.31 (t, 3H); 1.39-1.43 (m, 2H); 1.76-2.03 (m, 5H); 2.56 (s, 3H); 3.11 (t, 2H); 3.91-3.94 (m, 2H); 4.04 (t, 2H); 4.20 (q, 2H); 6.88 (d, 2H); 7.52 (d, 2H); 8.02 (s, 1H) 159 Not 1.25-1.33 (m, 2H); 1.75-1.88 (m, 5H); 2.88-2.94 (m, 2H); 3.95 (s, recorded 3H); 4.05 (t, 2H); 4.23-4.27 (m, 2H); 6.89 (d, 2H); 7.49 (d, 2H); 7.86 (s, 1H); 8.01 (s, 1H); 8.04 (s, 1H) 160 Not 1.29-1.36 (m, 5H); 1.74-1.88 (m, 5H); 2.88-2.95 (m, 2H); 4.05 (t, recorded 2H); 4.17-4.24 (m, 4H); 6.88 (d, 2H); 7.52 (d, 2H); 7.86 (s, 1H); 8.02 (s, 1H); 8.04 (s, 1H) 161 377 (M+1) (CD 3 OD) 1.32 (t, 3H); 1.57 (m, 2H); 1.74 (m, 2H); 1.87 (m, 2H); 3.15 (s, 3H); 3.65 (t, 2H); 4.05 (t, 2H); 4.18 (q, 2H); 6.94 (m, 2H); 7.15 (d, 1H); 7.38 (d, 1H); 7.54 (m, 2H); 8.05 (s, 1H) 162 377 (M+1) 1.32 (t, 3H); 1.51 (m, 4H); 1.72 (m, 2H); 1.81 (m, 2H); 3.40 (m, 2H); 3.98 (t, 2H); 4.20 (q, 2H); 5.94 (bs, 1H); 6.80 (bd, 1H); 6.88 (m, 2H); 7.22 (m, 1H); 7.50 (m, 2H); 8.02 (s, 1H) WO 00/78746 PCT/AU00/00680 - 52 163 349 (M+1) 1.32 (t, 3H); 1.90 (m, 4H); 3.50 (m, 2H); 4.04 (m, 2H); 4.20 (q, 2H); 5.93 (bs, 1H); 6.80 (m, 1H); 6.88 (m, 2H); 7.22 (d, 1H); 7.51 (m, 2H); 8.02 (s, 1H) 167 423 (M+I) Not recorded 168 437 (M+1) Not recorded 171 369 (M+1) Not recorded 172 383 (M+I) Not recorded 177 375 (M+1) Not recorded 180 409 (M+1) Not recorded 182 395 (M+1) Not recorded 183 409 (M+1) Not recorded 185 397.2584 1.25-1.45 (m, 5H); 1.70-1.90 (m, 5H); 2.35 (s, 6H); 2.50 (s, 3H); (M+I) 2.90 (t, 2H); 4.02 (t, 2H); 4.19 (q, 2H); 4.30 (d, 2H); 6.60 (s, 2H); 6.85 (d, 1H); 7.03 (d, 1H); 8.36 (s, 1H) 186 383.2448 1.30 (m, 2H); 1.70-1.90 (m, 5H); 2.40 (s, 6H); 2.52 (s, 3H); 2.90 (M+1) (t, 2H); 3.94 (s, 1H); 4.02 (t, 2H); 4.32 (d, 2H); 6.60 (s, 2H); 6.88 (d, 1H); 7.02 (d, 1H); 8.32 (s, 1H) 187 399.4 1.20-1.40 (m, 5H); 1.70-1.95 (m, 5H); 2.52 (s, 3H); 2.92 (t, 2H); (M+1) 3.85 (s, 3H); 4.03 (t, 2H); 4.15 (q, 2H); 4.31 (d, 2H); 6.42 (d, 1H); 6.47 (dd, 1H); 6.86 (d, 1H); 7.05 (d, 1H); 7.71 (d, 1H); 8.39 (s, 1 H) 188 383.2435 1.20-1.45 (m, 5H); 1.70-1.90 (m, 5H); 2.38 (s, 3H); 2.51 (s 3H); (M+1) 2.90 (t, 2H); 4.05 (t, 2H); 4.22 (q, 2H); 4.32 (d, 2H); 6.69 (d, 1H); 6.72 (dd, 1H); 6.83 (d, 1H); 7.06 (d, 1H); 7.65 (dd, 1H); 8.28 (s, 1H) 189 369.2272 1.30 (m, 2H); 1.70-1.90 (m, 5H); 2.38 (s, 3H); 2.51 (s 3H); 2.90 (M+1) (t, 2H); 3.98 (s, 3H); 4.05 (t, 2H); 4.31 (d, 2H); 6.71 (d, 1H); 6.72 (dd, 1H); 6.82 (d, 1H); 7.05 (d, 1H); 7.63 (dd, 1H); 8.26 (s, 1H) 190 397.2602 1.20-1.45 (m, 5H); 1.70-1.90 (m, 5H); 2.16 (s, 3H); 2.32 (s, 3H); (M+1) 2.52 (s, 3H); 2.90 (t, 2H); 4.09 (t, 2H); 4.21 (q, 2H); 4.32 (d, 2H); 6.59 (s, 1H); 6.85 (d, 1H); 7.03 (d, 1H); 7.51 (s, 1H); 8.23 (s, 1H) WO 00/78746 PCT/AU00/00680 -53 191 383.2436 1.32 (m, 2H); 1.72-1.90 (m, 5H); 2.18 (s, 3H); 2.38 (s, 3H); 2.54 (M+1) (s, 3H); 2.89 (t, 2H); 3.98 (s, 3H); 4.05 (t, 2H); 4.32 (d, 2H); 6.59 (s, 1H); 6.87 (d, 1H); 7.05 (d, 1H); 7.52 (s, 1H); 8.28 (s, 1H) 192 397.2583 1.20-1.45 (m, 5H); 1.70-1.90 (m, 5H); 2.15 (s, 3H); 2.30 (s, 3H); (M+1) 2.53 (s, 3H); 2.92 (t, 2H); 4.06 (t, 2H); 4.22 (q, 2H); 4.32 (d, 2H); 6.78 (d, 1H); 6.84 (d, 1H); 7.08 (d, 1H); 7.52 (d, 1H); 8.38 (s, 1H) 193 383.4 1.30 (m, 2H); 1.72-1.90 (m, 5H); 2.15 (s, 3H); 2.30 (s, 3H); 2.52 (M+1) (s, 3H); 2.90 (t, 2H); 3.95 (s, 3H); 4.03 (t, 2H); 4.33 (d, 2H); 6.71 (d, 1H); 6.85 (d, 1H); 7.04 (d, 1H); 7.53 (d, 1H); 8.35 (s, 1H) 194 377 (M+1) 1.42-1.85 (m, 8H); 3.14 (s, 3H); 3.63 (t, 2H); 3.93 (s, 3H); 4.02 (m, 3H); 6.94 (m, 2H); 7.14 (d, 1H); 7.38 (d, 1H); 7.54 (m, 2H); 8.05 (s, 1H) 195 363 (M+I) (CD30D) 1.32 (t, 3H); 1.85 (m, 4H); 3.16 (s, 3H); 3.70 (m, 2H); 4.09 (m, 2H); 4.18 (q, 2H); 6.95 (m, 2H); 7.16 (d, 1H); 7.39 (d, 1H); 7.54 (m, 2H); 8.05 (s, 1H) 196 368.2343 1.20-1.40 (m, 5H); 1.70-1.90 (m, 5H); 2.39 (s, 3H); 2.80 (t, 2H); (M+1) 4.05 (t, 2H); 4.21 (q, 2H); 4.32 (d, 2H); 6.45 (d, 2H); 6.88 (d, 2H); 7.35 (d, 1H); 7.51 (d, 1H); 8.03 (s, 1H) 197 418 (M+1) 1.30-1.34 (m, 5H); 1.70-1.95 (m, 5H); 3.0-3.15 (m, 2H); 3.94 (s, 3H); 4.05 (m, 4H); 4.33 (q, 2H); 6.87 (s, 2H); 7.41 (s, 1H); 7.50 (d, 2H); 8.01 (s, 1H) 198 432 (M+1) 1.29-1.39 (m, 8H); 1.76-1.88 (m, 5H); 3.00-3.09 (m, 2H); 4.06 4.07 (m, 4H); 4.20 (q, 2H); 4.33 (q, 2H); 6.87 (d, 2H); 7.41 (s, 1H); 7.50 (d, 2H); 8.02 (s, 1H) 199 375 (M+1) Not recorded 200 380 (M+I) Not recorded 202 402 (M+1) Not recorded 204 369 (M+1) Not recorded 206 396 (M+1) Not recorded 207 410 (M+1) Not recorded WO 00/78746 PCT/AU00/00680 -54 208 Not 1.31 (t, 3H); 1.2-1.5 (min, 2H11); 1.7-2.0 (min, 5H); 3.05 (t, 2H); 3.9 recorded 4.1 (min, 5H); 4.20 (q, 2H); 4.55 (bd, 2H); 6.87 (d, 2H); 7.03 (d, 1H); 7.52 (d, 2H); 7.82 (d, 1H); 8.02 (s, 1H); 8.32 (s, 1H) 209 364 (M+1) 1.31 (t, 3H); 1.5-1.85 (min, 6H); 3.98 (t, 2H); 4.19 (q, 2H); 6.88 (min, 3H); 7.16 (d, 1H1); 7.50 (d, 2H); 8.02 (s, 11H) 210 Not 1.2-1.45 (min, 5H); 1.7-1.95 (min, 5H); 3.02 (t, 2H); 4.03 (t, 2H); recorded 4.16 (q, 2H); 4.55 (bd, 2H); 6.89 (d, 2H); 7.45-7.65 (min, 4H); 7.80 (d, 1H); 8.02 (s, 1H); 8.58 (s, 1H) 211 Not 1.30 (t, 3H); 4.24 (q, 2H11); 7.30 (d, 2H); 7.55-7.75 (min, 4H); 8.09 recorded (d, 1H); 8.14 (s, 1H); 8.58 (s, 1H) 212 Not 1.25-1.40 (m, 5H); 1.70-1.95 (min, 5H); 2.30 (s, 3H); 2.45 (t, 2H); recorded 4.08 (t, 2H); 4.20 (q, 2H); 4.36 (bd, 2H); 6.80 (s, 1H11); 6.88 (d, 2H); 7.51 (d, 2H11); 8.06 (s, 1H) 213 Not 1.25-1.45 (min, 5H); 1.75-1.95 (m, 5H); 2.65 (s, 3H); 2.75-3.05 (inm, recorded 6H); 4.07 (t, 2H); 4.20 (q, 2H); 4.36 (d, 2H); 6.78 (d, 1H1); 7.07 (d, 1H1); 7.17-7.25 (min, 2H); 7.29 (d, 1H) Example 12 Preparation of 4- {2-[1-(6-Formyl-3-pyridazinyl)-4-piperidinyl]ethoxy}benzaldehyde 5 O-ethyloxime (Compound 128) A solution of 4- {2-[1-(6-Methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}benzaldehyde O ethyloxime (200mg, 0.54mmol, Compound 2) and selenium dioxide (70mg, 0.63mmol) in 1,4-dioxane (5 ml) was stirred and heated at 70-800 for 60 hr. The reaction mixture was filtered to remove most of the black selenium powder and then the filtrate was 10 concentrated and applied to a column of silica gel (20g). Elution with chloroform gave the aldehyde product (55mg, 26%, Compound 128) as the fastest running component (see Table 11 for the nmr and mass spectral data). Compounds No. 129 and 208 were prepared from Compound No. 128 by standard reactions with sodium borohydride and methoxyamine. 15 WO 00/78746 PCT/AU00/00680 -55 Example 13 Anti-HRV activity in mammalian cell culture assays Inhibition of viral cytopathic effect (CPE) and measurement of cytotoxicity The ability of compounds to suppress virus replication and thereby protect cells from 5 HRV-induced CPE was measured using human embryo lung (MRC-5) and human epidermoid carcinoma of the mouth (KB) cells infected with HRV type lA and HRV type 2, respectively. Cells grown in 96 well tissue culture plates using conventional mammalian tissue culture medium (such as minimum essential medium) supplemented with fetal calf serum were used in an assay essentially similar to that described by Sidwell 10 and Huffman (Applied Microbiology, 22, 797-801 (1971)). Test compounds were dissolved in 100% anhydrous dimethyl sulfoxide and serially diluted in tissue culture medium. The antiviral potency of the test compounds was assessed by exposing replicate tissue culture wells to a selected dilution series of between 6 and 7 compound concentrations in the presence of sufficient test virus to invoke significant CPE over the 15 course of the assay. Control cells were also exposed to identical concentrations of compounds in the absence of virus or were infected with virus under the same conditions but in the absence of compounds. Compounds of established anti-HRV efficacy (enviroxime, ribavirin and pirodavir) were assayed by identical procedures in parallel to the test compounds. Tissue culture media were identically supplemented to maintain cell 20 viability and support viral growth while suppressing bacterial growth over the period of the assay (supplements: 2% fetal calf serum, 0.01% sodium bicarbonate, 50 pg/ml gentamicin, 5 [tM magnesium chloride, 10 mM of zinc chloride). The assays were incubated at 37 0 C in a 5% CO 2 atmosphere until significant CPE was observed by microscopic examination of the untreated, HRV infected control cells (generally between 5 25 and 8 days). At this time all infected cultures were examined by eye using a light microscope and CPE scored on a scale of 0 (no CPE) to 4 (maximum CPE). Uninfected treated cultures were similarly scored for cytotoxic effects (eg. cell enlargement, granularity, rounding, detachment). These scores were used to generate EC 50 (concentration of compound yielding 50% antiviral efficacy) and CC 50 (concentration of 30 compound yielding 50% cytotoxicity) values by line regression analysis from plots of compound concentration versus % CPE or % cytotoxicity, respectively. As an alternative WO 00/78746 PCT/AU00/00680 - 56 to a CC50 value, cytoxicity in some cases was expressed as the Minimum Toxic Concentration (MTC). The MTC corresponds to the lowest compound concentration at which cytotoxic effects were observed. In some cases the visual scoring system described above was validated by vital dye 5 staining to measure cell viability. The vital dye technique used was a modification of the method described by McManus (Appl. Environment. Microbiol., 31, 35-38, 1976). After the assay had been scored by eye with the aid of a microscope, 100 pl of neutral red (NR) solution (0.34% NR in phosphate buffered saline (PBS)) was added to each well and mixed gently. The assays were returned to the 37 0 C incubator for 2 hours to facilitate uptake of 10 the NR by viable cells. The medium/NR mixture was then aspirated from the surface of the cells, which were washed twice with PBS. 0.25 ml of absolute ethanol containing Sorensen's citrate buffer I, was added with gentle mixing and the assays incubated at room temperature in the dark for 30 minutes to dissolve the NR. NR staining of viable cells was then quantified spectrophotometrically by measuring the colour density of the NR solution 15 using a BioTek EL-309 microplate reader at dual wavelengths of 540 and 405 nm. The differences in the two readings were automatically determined to eliminate background errors. EC 5 0 and CC 50 values were determined by regression analysis matching compound concentration to NR staining. 20 The results are shown in the Table 12 below. Selectivity indices (SI) are the CC 50 or MTC divided by the ECs 5 0

.

WO 00/78746 PCT/AU00/00680 - 57 Table 12 Compound Activity on Rhinovirus Type 2a Activity on Rhinovirus Type 1 A No. EC 5 0 (ig/ml) CC 5 0 SI ECs 50 ([tg/ml) MTC SI 1 < 0.001 > 1 > 1000 0.0002 > 10.0 >37317 1 0.003 >1 >312 2 0.0002 10 50,000 <0.000156 >50 > 320000 3 0.01 > 1 > 100 0.005 > 10.0 1841 4 0.5 > 1 > 2 0.39 10.00 25.55 5 0.009 >1 >111 <0.0032 >1 >312 6 0.1 > 50 > 500 0.06 > 10.00 > 167.09 7 0.15 >1 >7 <0.0032 >1 >312 8 0.03 >1 >33 <0.0032 >1 >312 9 0.08 >1 >13 <0.0032 >1 >312 10 0.4 >1 >3 0.0142 >1 >70.54 11 0.004 >1 >250 <0.0032 >1 >312 12 0.02 1 50 0.00355 >1 >273.7 13 0.006 0.5 83 <0.0032 >1 >312 14 0.046 0.6 13 <0.0032 >1 >312 15 0.9 0.6 <1 >1.0 >1.0 NA 16 <0.001 1 >1000 <0.0032 >1 >312 17 >1 >1 NA 0.00612 >1 >163.2 18 0.09 >1 >11 0.0063 >1 >158.6 19 0.019 >1 >53 <0.0032 >1 >312 20 3 2 1 3.28 > 50.00 > 15.24 21 0.3 >1 >3 >1 >1 NA 22 <0.05 20 >400 <0.16 36.0 >320 23 <0.05 17 >340 <0.16 >50 >320 24 <0.05 25 >500 <0.16 >50 >320 25 0.5 17 34 0.36 >50 >139.4 WO 00/78746 PCT/AU00/00680 -58 26 0.16 >1 >6 0.077 >1 >13.0 27 0.1 >1 >10 0.017 >1 >59.6 28 0.06 >1 >17 0.180 >1 >5.5 30 0.036 >1 >28 31 0.003 >1 >333 0.017 >1 >59.6 32 0.014 >1 >70 0.222 >1 >4.5 33 0.04 >1 >25 0.014 >1 >72.4 34 0.7 >1 >1 0.627 >1 >1.59 36 0.03 >1 >33 0.009 0.89 99.4 37 0.048 >1 >21 0.010 >1 >96.0 38 0.69 >1 >1.45 40 0.4 >1 >3 0.583 >1 >1.72 41 <0.001 >1 >1000 0.016 >1 >63.5 42 0.006 >1 >167 0.006 >1 >177.8 43 0.01 >1 >100 0.006 >1 >170 44 0.026 >1 >38 <0.003 >1 >312 45 0.03 >1 >32 0.029 >1 >34.0 46 NT 0.062 >1 >16.0 47 NT 0.066 >1 >15 48 NT 0.016 >1 >62 49 NT 0.056 >1 >17.8 50 NT 0.008 >1 >121.7 51 NT <0.003 0.663 >207.3 52 NT <0.003 >1 >312 53 NT <0.003 0.667 >208 54 NT 0.007 0.663 91 55 NT 2.68 >10 >3 56 NT 2.31 >10 >3 57 0.00025 >0.1 >400 0.001 >0.1 >56.3 58 NT 0.498 >1 >2 WO 00/78746 PCT/AU00/00680 -59 59 NT 0.162 0.56 3.4 60 NT 0.183 >1 >17 61 NT 0.058 >1 >14 62 NT 0.067 >1 >14 63 NT 0.06 >1 >15 64 NT 0.05 >1 >17 65 NT 0.21 >1 >4.5 66 NT 0.05 >1 >18 67 NT 0.04 >1 >20 68 NT 0.04 >1 >25 69 NT 0.18 >1 >5 70 NT 0.05 >1 >16 71 NT 0.05 >1 >18 72 NT 0.16 >1 >6 73 NT 0.003 >1 >312 74 NT 0.02 >1 >46 75 NT 0.01 >1 >98 76 NT 0.01 >1 >98 77 NT 0.003 >1 >279 84 NT 0.05 >1 >19.6 85 NT 0.08 >1 >12 87 NT 0.01 >1 >51 88 NT 0.005 >1 >172 89 NT 0.005 >1 >174 91 NT 0.02 >1 >46 92 NT 0.20 >1 >5 94 NT 0.024 >1 >41 95 NT 0.30 >1 >3 98 NT 0.255 >1 >3 99 NT 0.205 >1 >4 WO 00/78746 PCT/AU00/00680 - 60 102 NT 0.059 >1 >17 103 NT 0.266 >1 >3 105 NT 0.126 >1 >8 107 NT 0.062 >1 >16 108 0.6 >1 >1 >1 >1 NA 109 NT 0.053 >1 >18.8 119 NT 0.046 >1 >21.4 120 NT 0.04 >1 >20 121 NT 0.05 >1 >16 122 NT 0.181 >1 >5 123 NT 0.060 >1 >16 124 NT 0.719 >1 >1 125 NT 126 NT NT 127 NT 0.329 >1 >3 128 NT 0.063 >1 >15 129 NT 0.048 >1 >20 136 NT 0.598 >1 >1 137 NT 0.054 >1 >18 138 NT 0.07 >1 >15 139 NT 0.19 >1 >5 140 NT 0.016 >1 >61 141 NT 0.166 >1 >6 142 NT 0.055 >1 >18 143 NT 0.020 >1 >50 144 NT <0.0032 >1 >312 145 NT <0.0032 >1 >312 146 NT 0.051 >1 >19 147 NT 0.194 >1 >5 210 NT 3.96 >10 >2.5 WO 00/78746 PCT/AU00/00680 -61 211 NT 0.07 >10 >151 Comparative compound: Compound 2 30 15 12.06 > 50.00 > 4.14 No. 110 of US Patent 4,992,433a Controls: Pirodavir 0.003 > 1 > 300 0.02 > 10.00 555.74 Ribavirin NT 1.93 98.3 51.03 Enviroxime NT 0.006 0.49 75.91 aThe comparative compound is the aldehyde intermediate IIa in Example 1 of this invention. Example 14 5 Activity against Enteroviruses in Mammalian cell culture assays Compounds No 1 and 2 of the invention were tested against other picornaviruses using similar cell based assays to those described in Example 5 above and results are shown in Table 13 below. 10 Table 13 Compound Activity on Enterovirus 70 Activity on Coxsackie A21 Number ECs 5 0 (g/ CC 5 0 SI EC 50 so(g/ml) CC 5 0 SI ml) 1 0.03 >50 > 158 <0.000156 >50 >320000 2 2 0.00698 4.48 6409 <0.000156 3.43 > 21927 Controls: Ribavirin > 100 > 100 - > 100 > 100 Enviroxime 0.21 4.11 19.35 0.39 9.55 24.25 WO 00/78746 PCT/AU00/00680 - 62 Example 15 Following a similar method to that described in Example 13 above, the anti-HRV-14 activity in mammalian cell culture assay was determined for the compounds of the 5 invention listed in Table 14 below. 10 Table 14 Compound Activity on Rhinovirus Type 14 No. EC 50 so (ptg/ml) CC 50 SI 2 0.0018/0.0009 >0.1 >55 5 0.0077 >0.1 >13 7 0.0068 >0.1 >14 8 0.0072 >0.1 >13 11 0.0077 >0.1 >13 13 0.0078 >0.1 >12 33 0.0138 >0.1 >7 42 0.0111 >0.1 >9 44 0.0194 >0.1 >5 51 0.0093 >0.1 >10 52 0.0054 >0.1 >18 145 0.0072 >0.1 >13 146 0.0084 >0.1 >11 154 0.0514 >0.5 >9 155 0.0138 >0.5 >36 158 0.00095 >0.5 >526 160 0.0502 >0.5 >9 WO 00/78746 PCT/AU00/00680 - 63 161 0.0348 >0.5 >14 185 0.0697 >1 >14 186 0.0349 >1 >28 187 0.0103 >1 >97 188 0.0032 >1 >311 189 0.0011 >1 >872 190 0.0593 >1 >16 191 0.0256 >1 >39 192 0.0258 >1 >38 193 0.0308 >1 >32 195 0.038 >0.5 >13 196 0.0424 >1 >23 198 0.125 >0.5 >4 199 0.0402 >0.1 >2.5 200 0.021 >0.1 >4.8 201 0.0261 >0.1 >3.8 202 0.0593 >0.1 >1.7 203 0.060 >0.1 >1.7 204 0.0554 >0.1 >1.8 205 0.0638 >0.1 >1.6 206 0.0233 >0.1 >4.3 209 0.0157 >0.5 >31 212 0.0107 >0.5 >46 Comparative 0.0608 >0.1 >1.6 compound: Pleconaril WO 00/78746 PCT/AU00/00680 - 64 Example 16 The Inhibitory Concentrations of several compounds of the present invention against Human Rhinovirus strains 1B, 3, 4, 5, 6, 8, 9, 11, 12, 13, 16, 17, 21, 25, 30, 32, 33, 38, 39, 40, 42, 43, 45, 48, 52, 54, 56, 57, 59, 60, 63, 67, 68, 69, 72, 73, 85, 86, 89, 91, 92 and 100 5 were determined by a standard CPE reduction assay similar to that described in Example 13. From these assays it was found that compounds 1 and 2 of the invention showed superior activity to Pirodavir on nearly all HRV strains tested and compound 24 of the invention showed superior activity to Pleconaril. 10 Example 17 The Inhibitory Concentrations of several compounds of the present invention against the Enterovirus strains Poliovirus 2, Echoviruses 2, 3, 9, 21 and 30 and Coxsackie B3 were determined by a standard CPE reduction assay similar to that described in Example 13. From these assays it was found that compounds 1 and 2 of the invention showed superior 15 activity to Pirodavir on all strains tested. Example 18 Comparison of Compound 2 of the invention with Pirodavir in a time of addition study using HRV-2 20 The CPE inhibition assay used in this study was performed as described by Sidwell and Huffman (Appl. Microbiol., 22, 7979, 1971) with slight modifications. For most time of addition experiments virus at a multiplicity of infection (MOI) = 0.001 was added to the monolayers (1 x 105 cells/well) in each plate and incubated at 37 0 C. At the appropriate 25 time after virus exposure (0, 1, 2, 4, 6, 8, 24 hr post-virus exposure) Compound 2 or Pirodavir was added to the cells at varying concentrations without removal of the virus and without significantly altering the volume in the wells. The plates were incubated for 5 days at 37 0 C. 30 When a pre-treatment was done (-1 hr) compound was added to the wells and incubated for 1 hr at 37 0 C. Following the 1 hr incubation of the compound, virus was added to each well WO 00/78746 PCT/AU00/00680 - 65 in a volume that did not significantly alter the concentration of the drug and the plate was incubated for 5 days. For all other treatment times the two compounds were also added within 5 minutes of virus exposure (0 time) and incubated for 5 days. 5 The assay was stopped at the end of the fifth day when the virus CPE in the virus infected, untreated, control cells was seen in all cells. Both compounds were assayed for virus inhibition in quadruplicate cups in a 96-well microplate; duplicate wells were used for cytotoxicity controls at each compound dosage. For each compound, two wells were set aside as uninfected, untreated cell controls per test and four wells per test received virus 10 only and represented controls for virus replication. Changes due to CPE were graded on a scale of 1-4, grade 4 representing a scenario in which the entire (100%) monolayer in a well showed viral CPE. For all CPE-based assays the 50% effective concentration (EC50so) was calculated by regression analysis using the means of the CPE ratings at each concentration of compound. 15 Results: Neither compound was cytotoxic at the doses used in the study (up to 0.1 Ig/ml). The EC 5 0 values for the two compounds at the various time points are shown in the Table below. Table 19 Effects of the time of addition of Compound 2 and Pirodavir to infected KB cells 20 on the inhibition of HRV-2 replication Time of addition of EC 5 0 (pg/ml) for EC 5 0 (Jtg/ml) for Pirodavir Compound (hr) Compound 2 (visual assay) (visual assay) -1 0.002 0.023 0 0.002 0.004 1 0.008 0.1 2 0.02 >0.1 4 0.02 >0.1 6 0.02 >0.1 8 0.02 >0.1 24 0.1 >0.1 WO 00/78746 PCT/AU00/00680 - 66 The results confirm that Compound 2 is more active than Pirodavir when added at the same time as virus (0 hr). More significantly the results show that Compound 2 has a much stronger effect than Pirodavir when added prior to virus (-1 hr) and that Compound 2 5 has much more activity than Pirodavir when added several hours after cells have been exposed to virus. The data indicate that Compound 2 may have a different mode of action to Pirodavir and the data is also consistent with Compound 2 being more stable and therefore having a longer lasting activity against HRV. 10 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. 15 Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or 20 more of said steps or features.

Claims (31)

1. A compound of formula I 5 Het-A-Alk-W-Ar-C(X 2 )=NO-X 1 I its salts, and pharmaceutically acceptable derivatives thereof where Het is an optionally substituted 5- or 6-membered monocyclic heterocyclic radical or an 10 optionally substituted 9- or 10-membered bicyclic heterocyclic radical; A is O, S, NH, N(C 1 - 6 alkyl), CH 2 0, a bond or a bivalent heterocyclic radical of the formula (CH 2 )m N (CH 2 )n (b-1) 15 (CH 2 )m N C ~/7 (CH 2 )n C R 4 (b-2), (CH 2 )m N Z 5 (CH2)n-1 - CHR (b-3), or WO 00/78746 PCT/AU00/00680 - 68 (CH 2 )m-1-Z N Z (CH2)n (b-4) where one or more of the carbon atoms within the radicals (b-1) to (b-4) may 5 be optionally substituted with C 1 - 6 alkyl or two carbon atoms in the radicals (b-1) to (b-4) may be bridged with a C 2 - 4 alkylene radical, m and n are each independently integers of 1 to 4 inclusive with the proviso that the sum of m and n in radicals (b-1) to (b-4) is 3, 4 or 5; 10 Z is N or CR 6 where R 6 is hydrogen, hydroxy, C 1 - 6 alkyl, C 1 - 6 alkoxy or amino; Z' is O, S, CHR or NR where R 7 is hydrogen, hydroxy, C 1 - 6 alkyl, Cl-6 alkoxy or amino and R is hydrogen or C 1 - 6 alkyl; 15 R 4 is hydrogen or CI- 6 alkyl; and R 5 is hydrogen, hydroxy, Cl- 6 alkyl or C 1 - 6 alkoxy; 20 Alk is C 1 .- 7 alkylene or a direct bond; W is O, S, OCH 2 , a direct bond or NR 9 where R 9 is hydrogen or C.-6 alkyl; Ar is an optionally substituted 5- or 6-membered monocyclic aryl radical or an optionally 25 substituted 9- or 10-membered bicyclic aryl radical; WO 00/78746 PCT/AU00/00680 - 69 X 1 is Cl- 6 alkyl, C 3 - 6 alkenyl, C 3 - 6 haloalkenyl, C 3 - 6 alkynyl, C 3 - 6 haloalkynyl or C1- 6 alkyl substituted by halo, cyano, nitro, hydroxy, aryl, C 1 -4 alkoxy, C 2 - 6 alkoxyalkoxy, acyl or C 1 -4 alkylthio; and 5 X 2 is hydrogen, cyano, F, Cl, C-4 alkyl, C 1 4 haloalkyl or a bivalent radical of formula -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH 2 0- or -(CH 2 ) 2 0- which forms a 5- or 6-membered ring with a neighbouring carbon atom of Ar.

2. A compound according to claim 1 wherein Het is a radical selected from: 10 N-N Ri R2 R3 R 2 R 3(a-i) 1 N- N (a-2) N 15 R (a-3) R2 R (a-4) N R (a-5) 20 WO 00/78746 PCT/AU00/00680 - 70 Y (a-6) R R 2 R (a-7) N 5 Y (a-8) N R N: (a-9) N R N (a-10) 10 R N (a-11) N R N R2 (a-12) N=N / RN 15 R2 (a-13) WO 00/78746 PCT/AU00/00680 -71 N / N=N (a-14) wherein R' is hydrogen, CI- 6 alkyl, halo, hydroxy, mercapto, haloCI-4alkyl, 5 amino, mono or di(CI- 6 alkyl)amino, cyano, formyl, CI- 6 alkoxy, hydroxyCI-4 alkyl, C1-4alkoxyCl-4 alkyl, C 1 - 6 haloalkoxy, aryloxy, CI- 6 alkylthio, arylthio, Ci- 6 alkylsulphinyl, C 1 - 6 alkylsulphonyl, arylsulphinyl, arylsulphonyl, -CH=NO-CI- 4 alkyl, CI- 6 alkoxycarbonyl, CI- 6 alkylcarbonyl or aryl; 10 R 2 and R 3 are each independently selected from hydrogen, CI- 6 alkyl, CI- 6 alkoxy, halo or, in radicals (a-1), (a-4), (a-7) and (a-13), R' and R 2 , or R2 and R 3 combined may represent a bivalent radical of formula -CH=CH CH=CH- or (CH 2 )p where p is an integer from 2 to 4; 15 Y is O or S; and Y' is O, S, SO or SO 2 .

3. A compound according to claim 1 wherein Ar is a radical selected from 20 R l o R (c-1) (c-2) (c-2) WO 00/78746 PCT/AU00/00680 - 72 R o 10 Y (c-3) <Y (c-4) R 10 5 (c-5) (c-6) where Y is as defined above; and 10 R 1 0 and R" 1 are each independently hydrogen, CI- 6 alkyl, hydroxy Cl- 6 alkyl, halo, amino, cyano, nitro, C l- 6 alkoxy, hydroxy, Cl- 6 alkylthio, or trifluoromethyl.

4. A compound according to claim 2 wherein Het is a radical of formula (a-1), (a-2) or (a-8). 15

5. A compound according to claim 2 wherein R' is selected from hydrogen, methyl, ethyl, chloro, methoxy and trifluoromethyl.

6. A compound according to claim 2 wherein R 2 and R 3 are independently hydrogen, 20 chloro or methyl.

7. A compound according to claim 2 wherein Y is O or S. WO 00/78746 PCT/AU00/00680 - 73

8. A compound according to claim 1 wherein A is O, NH, NMe, a bond or a radical of formula (b-1).

9. A compound according to claim 1 wherein Z is CH or N. 5

10. A compound according to claim 1 wherein Alk is Cl- 6 alkylene or a direct bond.

11. A compound according to claim 1 wherein W is O. 10

12. A compound according to claim 3 wherein Ar is a radical of formula (c-1), (c-2) or (c-4).

13. A compound according to claim 3 wherein R1 0 and R" are each independently H, methyl, chloro, hydroxy, methoxy, cyano or nitro. 15

14. A compound according to claim 3 wherein Y is O or S.

15. A compound according to claim 1 wherein X' is selected from CI- 4 alkyl, C 2 4 alkoxyalkyl, C3-4alkenyl, C 34 alkynyl, Cl-4haloalkyl, C 3 - 4 haloalkenyl, C3-4haloalkynyl 20 or cyanomethyl.

16. A compound according to claim 1 wherein X 2 is selected from H, methyl or a bivalent radical of formula (CH 2 ) 2 or (CH 2 ) 3 which forms a 5- or 6-membered ring with the Ar group. 25

17. A compound of formula II: WO 00/78746 PCT/AU00/00680 - 74 Rio N-O .X1 _\ X2 R N Z-Alk-O N-N 1 R II wherein: R' is hydrogen, C14 alkyl, halo, hydroxy, mercapto, trifluoromethyl, amino, mono or 5 di(Cl4alkyl)amino, cyano, formyl, -CH=NO-C 1 4 alkyl, C 1 - 4 alkoxy, C 1 - 4 haloalkoxy, aryloxy, C 1 4alkylthio, or aryl; Z is CH or N; 10 Alk is Cl- 6 alkylene; R'o and R" are each independently hydrogen, C , 4 alkyl, C 1 4alkoxy, halo, hydroxy; X' is C 1 6 alkyl, C 3 - 6 alkenyl, C 3 - 6 haloalkenyl, C 3 - 6 alkynyl, C 3 . 6 haloalkynyl or C 1 6 alkyl 15 optionally substituted by halo, cyano, nitro, hydroxy, aryl, Cl- 4 alkoxy or C-4alkylthio; and X 2 is hydrogen, cyano, C 14 alkyl, C 14 haloalkyl or X 2 is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 forming a 5- or 6-membered ring with a carbon atom on the phenyl ring. 20

18. A compound of formula III: R N-O R A-Alk-O C2/ R WO 00/78746 PCT/AU00/00680 - 75 wherein: R' is hydrogen, C 1 4 alkyl, halo, hydroxy, mercapto, trifluoromethyl, amino, mono or di(Cl- 4 alkyl)amino, cyano, formyl, -CH=NO-C,4alkyl, Cl 14 alkoxy, Cl4haloalkoxy, 5 aryloxy, Cl4alkylthio, or aryl; A is a bond or CH 2 0; Alk is C 1 7 alkylene; 10 Ro and R" are each independently hydrogen, C 14 alkyl, C 1 - 4 alkoxy, halo, hydroxy; X 1 is C 6 alkyl, C 3 - 6 alkenyl, C 3 - 6 haloalkenyl, C 3 - 6 alkynyl, C 3 - 6 haloalkynyl or C 1 6 alkyl optionally substituted by halo, cyano, nitro, hydroxy, aryl, C-4alkoxy or C-4alkylthio; 15 and X 2 is hydrogen, cyano, C 4 alkyl, C 1 - 4 haloalkyl or X 2 is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 forming a 5- or 6-membered ring with a carbon atom on the phenyl ring. 20

19. A compound of formula IV Rio N'- Xl Cx RAlk-O R N RIV N--N IVwherein: wherein: WO 00/78746 PCT/AU00/00680 - 76 R' is hydrogen, C-4 alkyl, halo, hydroxy, mercapto, trifluoromethyl, amino, mono or di(C- 4 alkyl)amino, cyano, formyl, -CH= NO-C 4 alkyl, C 1 4 alkoxy, C 1 4 haloalkoxy, aryloxy, C- 4 alkylthio, or aryl; 5 Z is CH or N; Alk is Cl- 6 alkylene; R" and R" are each independently hydrogen, C 1 - 4 alkyl, C 1 4 alkoxy, halo, hydroxy; 10 X' is C- 6 alkyl, C 3 - 6 alkenyl, C 3 - 6 haloalkenyl, C 3 - 6 alkynyl, C 3 - 6 haloalkynyl or C_ 6 alkyl optionally substituted by halo, cyano, nitro, hydroxy, aryl, C- 4 alkoxy or C 14 alkylthio; and X 2 is hydrogen, cyano, C 14 alkyl, C 14 haloalkyl or X 2 is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 15 forming a 5- or 6-membered ring with a carbon atom on the phenyl ring.

20. A compound of formula V Rio X C// X2 Het-N Z-Alk-O R V 20 wherein: Het is pyridyl, pyrazinyl, thiadiazolyl, benzoxazolyl, 1,3,5-triazinyl, pyrimidinyl or quinoxalinyl, each of which may be optionally substituted with 1 to 3 substituents selected from halo, trifluoromethyl, C_ 4 alkyl, C 1 4 alkoxy or hydroxy; 25 Z is CH or N; Alk is C- 6 alkylene; WO 00/78746 PCT/AU00/00680 - 77 R 1 o and R" are each independently hydrogen, C 1 - 4 alkyl, C 1- 4 alkoxy, halo, hydroxy; XI is C 1 - 6 alkyl, C 3 - 6 alkenyl, C 3 - 6 haloalkenyl, C 3 - 6 alkynyl, C 3 6 haloalkynyl or C 1 - 6 alkyl 5 optionally substituted by halo, cyano, nitro, hydroxy, aryl, C,4alkoxy or Cl- 4 alkylthio; and X 2 is hydrogen, cyano, Cl- 4 alkyl, C 1 4haloalkyl or X 2 is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 forming a 5- or 6-membered ring with a carbon atom on the phenyl ring. 10

21. A compound of formula VI Rio IN-O-X 1 Het-A-Alk- / 2 11 X2 Rl wherein: Het is pyridyl, pyrazinyl, thiadiazolyl, benzoxazolyl, 1,3,5-triazinyl, pyrimidinyl or 15 quinoxalinyl, each of which may be optionally substituted with 1 to 3 substituents selected from halo, trifluoromethyl, C 1 4alkyl, Cl4alkoxy or hydroxy; A is a direct bond, O, NH or NMe; 20 Alk is C 1 *- 6 alkylene; R"o and R" are each independently hydrogen, C1- 4 alkyl, Cl- 4 alkoxy, halo, hydroxy; XI is C_ 6 alkyl, C 3 - 6 alkenyl, C 3 6 haloalkenyl, C 3 - 6 alkynyl, C 3 - 6 haloalkynyl or C 1 - 6 alkyl 25 optionally substituted by halo, cyano, nitro, hydroxy, aryl, C 1 4alkoxy or C 1 - 4 alkylthio; and WO 00/78746 PCT/AU00/00680 - 78 X 2 is hydrogen, cyano, C_ 4 alkyl, C 1 4haloalkyl or X 2 is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 forming a 5- or 6-membered ring with a carbon atom on the phenyl ring.

22. A compound of formula I as described in any one of Tables 1 to 8. 5

23. A compound of formula VII: N -O-X 3 H-A- Alk -W -Ar-C X 2 VII 10 where A, Alk, W, Ar and X 2 are as defined in claim 1, and X 3 is X or an oxime protecting group.

24. A compound of formula IX 15 Het-A-Alk-W-Ar-C(= NOH)X 2 X where Het, A, Alk, W, Ar and X 2 are as defined in claim 1.

25. A composition comprising a compound of formula I according to claim 1 together 20 with a pharmaceutically acceptable carrier.

26. A composition according to claim 24 which is a pharmaceutical composition.

27. A composition according to claim 24 further including a known anti-viral or anti 25 retroviral agent or other pharmaceutical used in the treatment of viral infections.

28. A method for the treatment or prophylaxis of a picornavirus infection in a mammal including the step of administering an effective amount of a compound of formula I as claimed in claim 1. WO 00/78746 PCT/AU00/00680 - 79

29. A method of claim 27 wherein the picornaviral infection is caused by one or more serotypes of rhinovirus. 5

30. Use of a compound of formula I in the manufacture of a medicament for the treatment or prophylaxis of picornavirus infection in mammals.

31. Use according to claim 30 wherein the picornavirus infection is one caused by one or more of the serotypes of rhinovirus. 10