AU2006257638A1 - Substituted arylpyrazoles - Google Patents

Description

WO 2006/134459 PCT/IB2006/001566 SUBSTITUTED ARYLPYRAZOLES This invention relates to pyrazole derivatives. The compounds of interest are C4 substituted aryl pyrazoles including, among others, those 1-arylpyrazoles in which the 4-position is substituted with 5 an acyclic, cycloalkyl or heterocyclic ring structure and which compounds are optionally further substituted at the position ax to the pyrazole ring. Such compounds are useful for having parasiticidal properties. International Patent Application Publication No. (WO) 98/24767, European Patent Application 10 Publication No. (EP) 933363, European Patent Application Publication No. (EP) 959071 and International Patent Application Publication No. (WO) 2005/060749 all describe arylpyrazoles having parasiticidal activity for the control of arthropods. However, the prior art compounds do not always demonstrate good activity or a long duration of 15 action against parasites. Similarly, some parasiticidal agents are useful only for a narrow spectrum of parasites. In some cases this may be attributed to the low bioavailability of the compounds in the treated animal and this can also lead to poor activity. It is an aim of the present invention to overcome various disadvantages of, or improve on, the properties of the prior art compounds. Thus it is an aim of the invention to provide an arylpyrazole which has the same or improved activity 20 relative to prior art compounds against parasites. It is a further aim of the present invention to provide arylpyrazole compounds with improved bioavailability whilst maintaining or improving their activity. The compounds of the present invention have especially good ability to control a broad spectrum of arthropods as shown by the results of tests demonstrating their potency and efficacy. In particular, the compounds of the present invention are significantly more active against fleas than 25 similar prior art compounds. It is a further aim to provide compounds with a long duration of action. Surprisingly it has been found that improving the bioavailability of the compounds does not negatively impact their duration of action. The extended duration of action is generally attributed to an extended half life of the 30 compound in vivo in the host mammal. It is also desirable that the compounds of the present invention should have an improved pharmacokinetic profile, improved safety, improved persistence and improved solubility. 35 Thus, according to the present invention, there is provided a compound of formula (1): WO 2006/134459 PCT/IB2006/001566 R4

R

8

R

3 R2 N N R9 R7 Ri wherein: X is selected from CR 1 0 or N; 5

R

1 is selected from halo, cyano, hydroxy, C1.6 alkyl, C1.6 alkoxy, C1.6 alkanoyl, C1.6 haloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, amino, C1.6 alkyl amino, di C1.6 alkyl amino, het, phenyl, SF 5 and S(O)nR'1; 10 R 2 is selected from cyano, C(O)OH, S(0)nR", C(O)NRaRb, and C(S)NRaRb; or R 2 is selected from C(0)OC1.6 alkyl, amino, C1.6 alkyl amino, and di C1.6 alkyl amino each of which may be optionally and independently further substituted by one or more substitutents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRcRd, NR*C(0)Rd, C1.6 15 alkyl, C2.6 alkenyl, C2-6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, C3.8 cycloalkyC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)OC1.6 haloalkyl, amino, NRCRd, het, phenyl and S(0)nR"; Ra and Rb are independently selected from hydrogen, het, phenyl and S(0)nR"; 20 or either one or both of Ra and Rb are independently selected from C1.6 alkyl, C2-6 alkenyl, C3. cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, C1.6 alkanoyl, and C(0)0C1.6 alkyl, each of which Ra and Rb may be optionally and independently further substituted by one or more substituents selected from, where chemcially possible, cyano, nitro, halo, oxo, hydroxy, C(0)OH, C(O)NRcRd, NR*C(0)Rd, C1.6 alkyl, 25 02.6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, C3.8 cycloalkylC1.6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)OC1.6 haloalkyl, amino, NRcRd, het, phenyl and S(0)nR; or Ra and R together with the N atom to which they are attached may form a three to seven 30 membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring which may optionally contain one or more further N, 0 or S atoms and which may be optionally further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, 2 WO 2006/134459 PCT/IB2006/001566 oxo, hydroxy, C(O)OH, C(O)NRCRd, NR"C(O)Rd, C1-6 alkyl, C.6 alkenyl, C2.6 alkynyl, C3- cycloalkyl, C3.8 cycloalkylC.6 alkyl, C3.8 cycloalkylI 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)OC1.6 alkyl, C1.6 haloalkyl, C3.6 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)OC1.6 haloalkyl, amino, NRCRd, het, phenyl and S(0)nR'; 5 or R 2 and R* together with the N atom to which R* is attached may form a six to seven - membered saturated, partially saturated, or unsaturated heterocyclic ring which may optionally contain one or more further N, 0 or S atoms and which may be optionally further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, 10 C(O)NRcRd, NRcC(0)Rd, C1.6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C.8 cycloalkylC1.6 alkyl, C3.8 cycloalkylC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C-8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, NRCRd, het, phenyl and S(O),R"; 15 R 3 and R 4 are independently selected from hydrogen, het, phenyl, S(O)nR 11 , and NRxRY; or either one or more of R 3 and R 4 are independently selected from C1.6 alkyl, C2.6 alkenyl, C4.8 cycloalkyl, C1.6 alkoxy, and benzyl, which R 3 and R 4 may be optionally and independently further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, 20 oxo, hydroxy, C(O)OH, C(O)NRRd, NRcC(O)Rd, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, C3.8 cycloalkylC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)OC1.6 haloalkyl, amino, NR R , het, phenyl and S(O)nRH; 25 or R 3 and R 4 together with the carbon to which they are attached may form a four to seven membered saturated, partially saturated, unsaturated or aromatic ring which may optionally contain one or more N, 0 or S atoms and which may be optionally further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(0)OH, C(O)NRcRd, NR*C(O)Rd, C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, 30 C3.8 cycloalkylC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)OC1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, NRCRd, het, phenyl and S(O)nR"; with the proviso that R 3 and R 4 are not both hydrogen; 35 Rx and Ry are independently selected from hydrogen, het, phenyl, benzyl and S(0),R; 11 or either one or more of RX and Ry are independently selected from C1.6 alkyl, C2.6 alkenyl, C.8 cycloalkyl, C3.8 cycloalkylC 1

.

8 alkyl, C1.6 alkanoyl, C(0)OC1.8 alkyl, each of which RX and Ry may be 3 WO 2006/134459 PCT/IB2006/001566 optionally and independently further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(0)NRRd, NRcC(0)Rd, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC1.6 alkyl, C3.8 cycloalkylC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 5 haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, NRCRd, het, phenyl and S(O)n

R"

; or RX and RY together with the N atom to which they are attached may form a three to seven membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring which may optionally contain one or more further N, 0 or S atoms and which may be optionally further 10 substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(0)NRRd, NRcC(O)Rd, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, C3.8 cycloalkylC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 Cd haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, NR R het, phenyl and S(O)nR"; 15

R

7 is selected from halo, C1.6 alkyl and C1.6 alkoxy where, when R 7 is C1.6 alkyl or C1.6 alkoxy, R 7 may be optionally substituted with one or more halo substituents;

R

8 is selected from hydrogen, cyano, hydroxy, C(O)OH, nitro, halo, het, phenyl, and -S(O),R; 20 or R 8 is selected from C1.6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, C1.6 alkoxy, C1.6 alkanoyl, and C(0)0C1.6 alkyl, which R 8 may be optionally and independently further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRRd, NR*C(0)Rd, C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.8 cycloalkyl, 25 C3.8 cycloalkylC 1

.

6 alkyl, C3.8 cycloalkylC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, NRcRd, het, phenyl and S(0)nR; or R 8 is amino, which R 8 may be optionally and independently further substituted by one or more 30 substituents selected from, where chemically possible, C(O)OH, C(O)NRRd, NRcC(0)Rd, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3-8 cycloalkyl, 03-8 cycloalkylC 1

.

6 alkyl, C-8 cycloalkyC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C1.6 haloalkyl, het, phenyl and S(O)nR' 1 ; 35 R 9 is selected from hydrogen, cyano, halo, hydroxy, C(O)OH, nitro, het, phenyl and S(O),R 1 and NR*Rf; or R 9 is selected from C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC1.6 alkyl, C1.6 alkoxy, C3.8 cycloalkylC 1

.

6 alkoxy, C1.6 alkanoyl, C(0)0C1.6 alkyl, which R 9 may be optionally and 4 WO 2006/134459 PCT/IB2006/001566 independently further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRCRd, NRCC(O)Rd, C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C3.8 cycloalkyl, C-8 cycloalkylC 1

.

6 alkyl, C3.8 cycloalkylC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0d 1

.

6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, 5 C(0)0C1.6 haloalkyl, amino, NRcRd, het, phenyl and S(O)nR; Re and Rf are independently selected from hydrogen, het, phenyl and S(O),R 1

;

or either one or both of R* and Rf are independently selected from C1.6 alkyl, C2.6 alkenyl, C3.8 10 cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, C1.6 alkanoyl, C(0)0C1.6 alkyl, -C(0)0C1.6 alkylC 3

.

8 cycloalkyl, C(O)OC3. cycloalkyl, each of which Re or Rf may be optionally and independently further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, Cdd hydroxy, C(0)OH, C(O)NR*R, NRcC(O)Rd, C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, C3.8 cycloalkylC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 od 15 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, NROR , het, phenyl and S(O)nR 1 ; or R* or Rf together with the N atom to which they are attached may form a three to seven membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring which may 20 optionally contain one or more further N, 0 or S atoms and which may be'optionally further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(0)OH, C(O)NRRd, NR C(O)Rd, C1.6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C-3 cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, C3.8 cycloalkylC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)OC1.6 haloalkyl, amino, NRcRd, 25 het, phenyl and S(O),R " ; or Re and R2 together with the atoms to which they are attached may form a six to seven membered heterocyclic ring as previously described; 30 R 1 0 is selected from halo, C1.6 alkyl and C1.6 alkoxy and where when R1 0 is C1.6 alkyl or C1.6 alkoxy it may optionally be substituted with one or more halo substituents; each RC and Rd are independently selected from hydrogen, C1.6 alkyl, C2-6 alkenyl, C3.8 cycloalkyl, C3.8 cycloalkyC 1

.

6 alkyl, C1.6 haloalkyl, C3.8 cycloalkylC 1

.

6 haloalkyl, C1.6 alkanoyl, 01.6 haloalkanoyl, 35 C(0)001.6 alkyl, het, phenyl and S(O)nR"; or Rc and Rd together with the N atom to at least one of them is attached may form a three to seven - membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring which may optionally contain one or more further N, 0 or S atoms; 5 WO 2006/134459 PCT/IB2006/001566 each n is independently 0, 1 or 2; each R" is independently selected from hydrogen, hydroxy, C1.6 alkyl, C1.6 haloalkyl, amino, C1.6 5 alkyl amino and di C1.6 alkyl amino; each phenyl may be optionally substituted by one or more further substitutents selected from the group consisting of halo, cyano, nitro, hydroxy, C1.6 alkyl, C1.6 haloalkyl, C1.6 alkoxy, C1.6 haloalkoxy, amino, C1.6 alkyl amino, di C1.6 alkyl amino, -NHS(O),R, and S(O),R 11 ; 10 and each het independently represents a four to seven membered heterocyclic group, which is aromatic or non-aromatic, unsaturated, partially saturated or satureated and which contains one or more heteroatoms selected from nitrogen, N-oxide, oxygen, sulphur and wherein said heterocyclic ring is optionally substituted, where the valence allows, with one or more substituents selected from 15 halo, cyano, nitro, C1.6 alkyl, C1.6 haloalkyl, C1.6 alkoxy, OC(0) C1.6 alkyl, C1.6 alkanoyl, C(0)0 C1.6 alkyl and NR9Rh, where R9 and R are independently selected from hydrogen, C1..6 alkyl and C2.6 alkenyl, and where each of the above groups may include one or more optional substituents where chemically possible independently selected from cyano, nitro, halo, oxo, hydroxy, C(0)OH, C(O)NRcRd, NR*C(O)Rd, C1.6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, 20 C3.8 cycloalkylC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)OC1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)OC1.6 haloalkyl, amino, C1.6 alkyl amino, di C1.6 alkyl amino, phenyl and S(O),R; or a pharmaceutically acceptable salt or a prodrug thereof. 25 Preferably, R 1 is selected from: C1.6 haloalkyl, for example, trifluoromethyl; C1.6 haloalkoxy, for example, difluoromethoxy or trifluoromethoxy; SF 6 ; and S(O),R where, for example, R 1 is C1.6 haloalkyl to form, for example, trifluoromethylthio, (trifluoromethyl)sulphinyl or (trifluoromethyl)sulphonyl. More preferably R 1 is selected from: C1.6 haloalkyl for example 30 trifluoromethyl; C1.6 haloalkoxy for example difluoromethoxy or trifluoromethoxy; and SF 6 . Even more preferably R 1 is selected from CF 3 , OCF 3 , or SF 6 . Most preferably R 1 is SF 6 . Suitably, R 2 is selected from: cyano and C(O)OH. 35 Equally suitably R 2 is C(0)NRaR or C(S)NRaR , preferably C(O)NRaR, where Ra and R are independently selected from: hydrogen; C1.6 alkyl, eg methyl, ethyl, isopropyl or isobutyl to form, for example, (methylamino)carbonyl, (dimethylamino)carbonyl or (isopropylamino)carbonyl, which C1.6 alkyl may in turn be substituted with one or more groups selected from fluoro to form, for example, (trifluromethylamino)carbonyl, or C3.8 cycloalkyl, eg cyclopropyl to form, for example, 6 WO 2006/134459 PCT/IB2006/001566 [(cyclopropymethyl)amino]carbonyl; C3.8 cycloalkyl eg cyclopropyl to form (cyclopropylamino)carbonyl; het, eg pyridinyl to form for example (pyridinylamino)carbonyl; and

S(O),R

1 where, for example, R" is C1.6 alkyl, eg methyl to form, for example, [(methylsulphonyl)amino]carbonyl. Where optionally Ra and Rb together with the N atom to which 5 they are attached form a three to seven - membered heterocyclic ring optionally'containing one or more further N, 0 or S atoms, the ring is suitably a pyrrolidinyl ring. Where R2 and Re together with the N atom to which R* is attached form a six to seven - membered saturated, partially saturated, or unsaturated heterocyclic ring which may optionally contain one or 10 more further N, 0 or S atoms it is preferred that R 2 is selected from C(O)NRaR, C(S)NRaRb wherein it is then Ra and Re together with the N atoms to which they are attached form a six to seven membered saturated, partially saturated, or unsaturated heterocyclic ring which may optionally contain one or more further N, 0 or S atoms. Suitably the ring is a partially unsaturated 1, 3 diazepanyl which may be further substituted by C1.6 alkyl, eg methyl to form, for example, a 7 15 methyl-5'-oxo-5',6',7',8'-tetrahydro-pyrazolo[3,4-d][1,3]diazepine. Equally suitable compounds include those where R 2 is amino or C1.6 alkyl amino, eg methylamino, ethylamino or isopropylamino, which C1.6 alkyl amino is optionally further substituted with S(O)nR 1 where, for example, R" is methyl to form, for example, (methyl)(methylsulphonyl)amino. 20 Still further equally suitable compounds include those where R 2 is S(O)nR" and R" is selected from: C1.6 alkyl, eg methyl, ethyl or isopropyl to form, for example, methylthio, methylsulphinyl, methylsulphonyl or 2-isopropylthio; amino to form, for example, aminosuiphonyl; and di C1.6 alkyl amino, eg dimethylamino to form, for example, (dimethylamino)sulphonyl. 25 Preferably, R 2 is selected from: cyano; C(O)NRaRb, where Ra and Rb are independently selected from hydrogen, C1.6 alkyl and C3.8 cycloalkyl wherein each of the above Ra and Rb groups may in turn be substituted with one or more groups selected from fluoro; amino; C1.6 alkyl amino, which C1.6 alkyl amino may optionally be substituted with S(O)nR 11 where, for example, R" is C1.6 alkyl; and S(O)nR 30 where R" is C1.6 alkyl. More preferably, R 2 is C(O)NRaRb where Ra is hydrogen and Rb is selected from hydrogen, C1.6 alkyl, and C3.8 cycloalkyl wherein each of the above Ra and Rb groups may in turn be substituted with one or more groups selected from fluoro. Most preferably, R 2 is C(O)NRaRb where both Ra and Rb are hydrogen. 35 Suitable compounds include those where R 4 is hydrogen and R 3 is C1.6 alkyl, eg methyl, ethyl, n propyl, or isopropyl which C1.6 alkyl may optionally be substituted with one or more substituents independently selected from: hydroxy; halo, eg fluoro or chloro to form, for example, trifluoromethyl; C1.6 alkyl, eg methyl, ethyl, n-propyl, or isopropyl; C1.6 haloalkyl, eg trifluoromethyl or trifluoroethyl; C3.8 cycloalkyl, eg cyclopropyl; C3.8 cycloalkylC 1

.

6 alkyl, eg cyclopropylmethyl or cyclopropylethyl 7 WO 2006/134459 PCT/IB2006/001566 which C3-8 cycloalkylC1.6 alkyl may be optionally substituted with one or more groups selected from halo eg fluoro or chloro, to form, for example, (1-fluorocyclopropyl)methyl, C1.4 alkyl, eg methyl or ethyl to form, for example, (1-methylcyclopropy)methyl or (1-ethylcyclopropyl)methyl, or C1.4 haloalkyl to form, for example, [(1-trifluoromethyl)cyclopropyl]methyl; C1-6 alkoxy, eg methoxy or 5 ethoxy; C1.6 haloalkoxy, eg trifluoromethoxy or trifluoroethoxy; C1.6 alkanoyl, eg acetyl or propanoyl; het, eg pyrazinyl, pyridinyl, pyrimidinyl, imidazolyl, 1-oxa-3, 4-diazolyl, 1, 3, 4-triazolyl; phenyl or benzyl which phenyl or benzyl may in turn be optionally substituted by one or more substituents selected from halo, eg chloro or fluoro to form, for example, 4-fluorophenyl, 3, 4-difluorophenyl, C1.4 alkyl optionally substituted by one or more halo groups, eg chloro or fluoro to form, for example, 4 10 (trifluoromethyl)phenyl; amino; C1.6 alkyl amino, eg methylamino; and S(O),R 11 , eg where R 11 is methyl. Suitable compounds also include those where both R 3 and R 4 are independently selected C1.6 alkyl, eg methyl, ethyl, n-propyl, or isopropyl which C1.6 alkyl may optionally be substituted with one or 15 more substituents independently selected from: hydroxy; halo, eg fluoro or chloro to form, for example, trifluoromethyl; C1.6 alkyl, eg methyl, ethyl, n-propyl, or isopropyl; C1.6 haloalkyl, eg trifluoromethyl or trifluoroethyl; C.8 cycloalkyl, eg cyclopropyl; C3.8 cycloalkylC 1

.

6 alkyl, eg cyclopropylmethyl or cyclopropylethyl which C3.8 cycloalkylC 1

.

6 alkyl may be optionally substituted with one or more groups selected from halo eg fluoro or chloro, to form, for example, (1 20 fluorocyclopropyl)methyl, C1.4 alkyl, eg methyl or ethyl to form, for example, (1-methylcyclopropyl) methyl or (1-ethylcyclopropyl)methyl, or C1.4 haloalkyl to form, for example, [(1 trifluoromethyl)cyclopropyl]methyl; C1.6 alkoxy, eg methoxy or ethoxy; C1.6 haloalkoxy, eg trifluoromethoxy or trifluoroethoxy; C1.6 alkanoyl, eg acetyl or propanoyl; het, eg pyrazinyl, pyridinyl, pyrimidinyl, imidazolyl, 1 -oxa-3, 4-diazolyl, 1, 3, 4-triazolyl; phenyl or benzyl which phenyl or benzyl 25 may in turn be optionally substituted by one or more substituents selected from halo, eg chloro or fluoro to form, for example, 4-fluorophenyl, 3, 4-difluorophenyl, C1.4 alkyl optionally substituted by one or more halo groups, eg chloro or fluoro to form, for example, 4-(trifluoromethyl)phenyl; amino; C1.6 alkyl amino, eg methylamino; and S(O),R 11 , eg where R 1 1 is methyl. 30 Equally suitable compounds include those where R 4 is hydrogen and R 3 is C1.6 alkoxy, eg methoxy or ethoxy which C1.6 alkoxy may optionally be substituted with one or more substituents independently selected from: hydroxy; halo, eg fluoro or chloro; C1.6 alkyl, eg methyl, ethyl, n-propyl, or isopropyl; C1.6 haloalkyl, eg trifluoromethyl or trifluoroethyl; C3.8 cycloalkyl, eg cyclopropyl; C3.8 cycloalkylC 1

.

6 alkyl, eg cyclopropylmethyl or cyclopropylethyl which C3.8 cycloalkylC 1

.

6 alkyl may be optionally 35 substituted with one or more groups selected from halo eg fluoro or chloro, to form, for example, (1 fluorocyclopropyl)methyl, C1.4 alkyl, eg methyl or ethyl to form, for example, (1-methylcyclopropyl) methyl or (1-ethylcyclopropyl)methyl, or C1.4 haloalkyl to form, for example, [(1 trifluoromethyl)cyclopropyl]methyl; C1.6 alkoxy, eg methoxy or ethoxy; C1.6 haloalkoxy, eg trifluoromethoxy or trifluoroethoxy; C1.6 alkanoyl, eg acetyl or propanoyl; het, eg pyrazinyl, pyridinyl, 8 WO 2006/134459 PCT/IB2006/001566 pyrimidinyl, imidazolyl, 1-oxa-3, 4-diazolyl, 1, 3, 4-triazolyl; phenyl or benzyl which phenyl or benzyl may in turn be optionally substituted by one or more substituents selected from halo, eg chloro or fluoro to form, for example, 4-fluorophenyl, 3, 4-difluorophenyl, C1-4 alkyl optionally substituted by one or more halo groups, eg chloro or fluoro to form, for example, 4-(trifluoromethyl)pheny; amino; 5 C1-6 alkyl amino, eg methylamino; and S(O),R 1 , eg where R 1 1 is methyl. Equally suitable compounds also include those where R 4 is hydrogen and R 3 is C3-8 cycloalkylC1.

6 alkyl eg cyclopropylmethyl or cyclopropylethyl which C3-8 cycloalkylC 1

.

6 alkyl may optionally be substituted with one or more substituents independently selected from: halo eg fluoro or chloro, to 10 form, for example, (1-fluorocyclopropyl)methyl; C1.4 alkyl eg methyl or ethyl to form, for example, (1 methylcyclopropyl)methyl or (1 -ethylcyclopropyl)methyl; and C1.4 haloalkyl to form, for example, [(1 trifluoromethyl)cyclopropyl]methyl. Further suitable compounds include those where the C38 cycloalkyl of the C3.8 cycloalkylC 1

.

6 alkyl is optionally substituted with one or more substituents independently selected from: halo, eg chloro or fluoro; and C1-4 alkyl, eg methyl which C4 alkyl may 15 be optionally further substituted by 1 to 5 halo groups independently selected from chloro or fluoro to form, for example, trifluoromethyl. Optionally a single carbon of the C-8 cycloalkyl of the C3.8 cycloalkylC 1

.

6 alkyl is di-substituted with the same substitutent selected from fluoro, chloro or methyl while the other carbon of the C3.8 cycloalkyl of the C3.8 cycloalkylC 1

-

6 alkyl remains di-substituted with hydrogen. 20 Further suitable compounds also include those where R 4 is hydrogen and R 3 is S(O),R" eg where

R

1 1 is C1.6 alkyl, eg methyl, or C1.6 haloalkyl, eg trifluoromethyl. Equally further suitable compounds also include those where R 4 is hydrogen and R 3 is NRXR where 25 each of Rx or RY is independently selected from: hydrogen; C6 alkyl, eg methyl, ethyl, isopropyl or t butyl, which C6 alkyl may in turn be substituted with one or more substituents independently selected from halo, eg fluoro or chloro to form, for example, trifluoromethyl or trifluoroethyl, C1.6 alkyl, eg t-b tyl to form, for example, t-butylmethyl, C3.8 cycloalkyl, eg cyclopropyl, het, eg pyrazinyl, imidazolyl, 1, 3, 4-triazolyl, or pyridinyl, phenyl to form, for example, benzyl which phenyl may in turn 30 be optionally substituted by one or more substituents selected from halo, eg chloro or fluoro to form, for example, 4-fluorobenzyl or 3, 4-difluorobenzyl, C.4 alkyl optionally substituted by one or more halo groups, eg chloro or fluoro to form, for example, (trifluoromethyl)benzyl, or S(O)nR 1 , eg where

R

11 is methyl to form, for example, (4-methylsulphonyl)benzyl; C1.6 haloalkyl, eg trifluoromethyl, or trifluoroethyl; C3-8 cycloalkyl, eg cyclopropyl; C3.8 cycloalkylCO 6 alkyl eg cyclopropylmethyl or 35 cyclopropylethyl which C3.8 cycloalkylCe.6 alkyl may be optionally substituted with one or more groups selected from halo eg fluoro or chloro, to form, for example, (1-fluorocyclopropyl)methyl, C.4 alkyl eg methyl or ethyl to form, for example, (1 -methylcyclopropyl)methyl or (1-ethylcyclopropyl)methyl, or C1.4 haloalkyl to form, for example, [(1-trifluoromethyl)cyclopropyl]methyl; C6 alkanoyl, eg acetyl or propanoyl; C(0)C6 alkyl, eg ethoxycarbonyl; and S(O),R 1 , eg where R 1 1 is methyl. Where RX and 9 WO 2006/134459 PCT/IB2006/001566 Ry together with the N atom to which they are attached form a three to seven - membered heterocyclic ring optionally containing one or more further N, 0 or S atoms, the ring is suitably a pyrrolidinyl ring. 5 Yet more equally suitable compounds also include those where R 4 is hydrogen and R 3 is het eg tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, pyrrolyl, furanyl, imidazolyl, oxazolyl, 1,3,4-triazolyl, 1-oxa-3,4-diazolyl, pyridinyl, pyrimidinyl or pyrazinyl, which het may optionally be substituted with one or more substituents independently selected from: hydroxy; halo, eg fluoro or chloro; C1.6 alkyl, eg methyl, ethyl, n-propyl, 10 or isopropyl; C1.6 haloalkyl, eg trifluoromethyl or trifluoroethyl; C3.8 cycloalkyl, eg cyclopropyl; C3.6 cycloalkylC 1

.

6 alkyl, eg cyclopropylmethyl or cyclopropylethyl which C3.8 cycloalkylC 1

.

6 alkyl may be optionally substituted with one or more groups selected from halo eg fluoro or chloro, to form, for example, (1-fluorocyclopropyl)methyl,

C

1

.

4 alkyl, eg methyl or ethyl to form, for example, (1 methylcyclopropyl) methyl or (1-ethylcyclopropyl)methyl, or C1.4 haloalkyl to form, for example, [(1 15 trifluoromethyl)cyclopropyl]methyl; C1.6 alkoxy, eg methoxy or ethoxy; C1.6 haloalkoxy, eg trifluoromethoxy or trifluoroethoxy; C1.6 alkanoyl, eg acetyl or propanoyl; phenyl or benzyl which phenyl or benzyl may in turn be optionally substituted by one or more substituents selected from halo, eg chloro or fluoro to form, for example, 4-fluorophenyl, 3, 4-difluorophenyl, C1.4 alkyl optionally substituted by one or more halo groups, eg chloro or fluoro to form, for example, 4 20 (trifluoromethyl)pheny; amino; C1.6 alkyl amino, eg methylamino; and S(O),R, eg where R" is methyl. Yet more equally suitable compounds also include those where R 4 is hydrogen and R 3 is phenyl which phenyl may optionally be substituted with one or more substituents independently selected 25 from: hydroxy; halo, eg fluoro or chloro; C1.6 alkyl, eg methyl, ethyl, n-propyl, or isopropyl; C1.6 haloalkyl, eg trifluoromethyl, or trifluoroethyl; C1.6 alkoxy, eg methoxy or ethoxy; C1.6 haloalkoxy, eg trifluoromethoxy or trifluoroethoxy; C1.6 alkanoyl, eg acetyl or propanoyl; and S(0)nR, eg where R" is methyl. 30 Even further equally suitable compounds include those where where R 4 is hydrogen and R 3 is C4.8 cycloalkyl which C4. cycloalkyl may be optionally substituted with one or more substitutents independently selected from: hydroxy; halo, eg fluoro or chloro to form, for example, trifluoromethyl; C1.6 alkyl, eg methyl, ethyl, n-propyl, or isopropyl; C1.6 haloalkyl, eg trifluoromethyl or trifluoroethyl; C3.8 cycloalkyl, eg cyclopropyl; C3.8 cycloalkylC1.6 alkyl, eg cyclopropylmethyl or cyclopropylethyl 35 which C3.8 cycloalkylC 1

.

6 alkyl may be optionally substituted with one or more groups selected from halo eg fluoro or chloro, to form, for example, (1-fluorocyclopropyl)methyl, C1.4 alkyl, eg methyl or ethyl to form, for example, (1-methylcyclopropyl) methyl or (1-ethylcyclopropyl)methyl, or C1.4 haloalkyl to form, for example, [(1-trifluoromethyl)cyclopropyl]methyl; C1.6 alkoxy, eg methoxy or ethoxy; C1.6 haloalkoxy, eg trifluoromethoxy or trifluoroethoxy; C1.6 alkanoyl, eg acetyl or propanoyl; 10 WO 2006/134459 PCT/IB2006/001566 het, eg pyrazinyl, pyridinyl, pyrimidinyl, imidazolyl, 1-oxa-3, 4-diazolyl, 1, 3, 4-triazolyl; phenyl or benzyl which phenyl or benzyl may in turn be optionally substituted by one or more substituents selected from halo, eg chloro or fluoro to form, for example, 4-fluorophenyl, 3, 4-difluorophenyl, C1-4 alkyl optionally substituted by one or more halo groups, eg chloro or fluoro to form, for example, 4 5 (trifluoromethyl)phenyl; amino; C1.6 alkyl amino, eg methylamino; and S(O),R", eg where R" is methyl. Preferably the C4.8 cycloalkyl is substituted with one or more substituents selected from halo, eg chloro or fluoro or C1.4 alkyl, eg methyl which C1.4 alkyl is optionally substituted by 1 to 5 halo groups independently selected from chloro or fluoro to form, for example, trifluoromethyl. More preferably, a single carbon of the C4.8 cycloalkyl is di-substituted with the same substitutent selected 10 from fluoro, chloro or methyl while the other carbons of the C4.8 cycloalkyl remain di-substituted with hydrogen. Even further equally suitable compounds also include those where R 4 and R 3 together with the carbon to which they are attached form a four to seven - membered ring optionally containing one or 15 more N, 0 or S heteroatoms to form, for example, a carbocyclic ring eg cyclobutyl, cyclopentyl, cyclohexyl, or het eg tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl or piperidinyl, which four to seven -membered ring may optionally be substituted with one or more substituents selected from: hydroxy; oxo; halo, eg fluoro or chloro; C1.6 alkyl, eg methyl, ethyl, n-propyl, or isopropyl; C1.6 haloalkyl, eg trifluoromethyl or trifluoroethyl; C3_8 20 cycloalkyl, eg cyclopropyl; C3.8 cycloalkylC 1

.

6 alkyl, eg cyclopropylmethyl or cyclopropylethyl which C3.8 cycloalkylC 1 .e alkyl may be optionally substituted with one or more groups selected from halo eg fluoro or chloro, to form, for example, (1-fluorocyclopropyl)methyl, C1.4 alkyl, eg methyl or ethyl to form, for example, (1-methylcyclopropyl) methyl or (1-ethylcyclopropyl)methyl, or C1.4 haloalkyl to form, for example, [(1-trifluoromethyl)cyclopropyl]methyl; C1.6 alkoxy, eg methoxy or ethoxy; C1.6 25 haloalkoxy, eg trifluoromethoxy or trifluoroethoxy; C1.6 alkanoyl, eg acetyl or propanoyl; phenyl or benzyl which phenyl or benzyl may in turn be optionally substituted by one or more substituents selected from halo, eg chloro or fluoro to form, for example, 4-fluorophenyl, 3, 4-difluorophenyl, C1.4 alkyl optionally substituted by one or more halo groups, eg chloro or fluoro to form, for example, 4 (trifluoromethyl)pheny; amino; C1.6 alkyl amino, eg methylamino; and S(0),R, eg where R" is 30 methyl. Preferably the four to seven membered ring is a carbocyclic ring, which carbocyclic ring is optionally substituted with one or more substituents selected from halo, eg chloro or fluoro or C1.4 alkyl, eg methyl which C1.4 alkyl is optionally substituted by 1 to 5 halo groups independently selected from chloro or fluoro to form, for example, trifluoromethyl. More preferably, a single carbon of the carbocyclic ring is optionally di-substituted with the same substitutent selected from fluoro, 35 chloro and methyl while the other carbon of the carbocyclic ring remains di-substituted with hydrogen. Preferably R 4 is hydrogen and R 3 is independently selected from: C1.6 alkyl, eg methyl, ethyl, n propyl, or isopropyl which C1.6 alkyl may optionally be substituted with one or more substituents 11 WO 2006/134459 PCT/IB2006/001566 selected from halo, eg fluoro or chloro to form, for example, trifluoromethyl, C1.6 haloalkyl, eg trifluoromethyl or trifluoroethyl to form, for example, (trifluoromethyl)methyl or (trifluoroethyl)methyl, C3.8 cycloalkyl, eg cyclopropyl to form, for example, cyclopropylmethyl, phenyl to form, for example, benzyl, which phenyl may in turn be optionally substituted by one or more substituents selected from 5 halo, eg chloro or fluoro to form, for example, 4-fluorobenzyl, and S(O)nR", eg where R" is methyl to form, for example, (methylsulphonyl)methyl; C1.6 alkoxy, eg methoxy, ethoxy, which C1.6 alkoxy may optionally be substituted with one or more substituents selected from halo, eg fluoro or chloro, C1.6 haloalkyl, eg trifluoromethyl, or trifluoroethyl, C3.8 cycloalkyl, eg cyclopropyl, and S(O),R, eg where R" is methyl; NRxRY where each of RX or RY is independently selected from hydrogen, C1.6 10 alkyl, eg methyl, which C1.6 alkyl is optionally substituted with one or more halo atoms, C1.6 alkanoyl eg acetyl, and S(O)nR", eg where R" is methyl; het eg tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, which het may be optionally substituted with one or more substituents selected from C1.6 alkyl or C1.6 haloalkyl; and phenyl which phenyl may optionally be substituted with one or more substituents selected from halo eg chloro or 15 fluoro, C1.6 alkyl eg methyl, C1.6 haloalkyl eg trifluoromethyl, and S(O)nR", eg where R 1 is methyl. Further preferred compounds also include those where both R 3 and R 4 are independently selected from C1.6 alkyl, eg methyl, ethyl, n-propyl, or isopropyl which C1.6 alkyl may optionally be substituted with one or more substituents selected from halo, eg fluoro or chloro to form, for example, trifluoromethyl, C1.6 haloalkyl, eg trifluoromethyl, or trifluoroethyl, C3.6 cycloalkyl, eg cyclopropyl, and 20 S(O),R 11 , eg where R" is methyl. Even further preferred compounds include those where R 3 and R 4 together with the carbon to which they are attached form a four to seven - membered carbocyclic ring which is optionally further substituted with one or more substituents selected from halo eg chloro or fluoro, C1.6 alkyl eg methyl, C1.6 haloalkyl eg trifluoromethyl, and S(O)nR 1 , eg where R 1 1 is methyl. 25 More preferably R 4 is hydrogen and R 3 is C1.6 alkyl, eg methyl, ethyl, n-propyl, or isopropyl which C1.6 alkyl may optionally be substituted with halo, eg fluoro or chloro to form, for example, trifluoromethyl, or phenyl to form, for example, benzyl, which phenyl may in turn be optionally substituted by one or more substituents selected from halo, eg chloro or fluoro to form, for example, 4-fluorobenzyl, or R 3 and R 4 are both independently selected from 01.6 alkyl, eg methyl, ethyl, n-propyl, or isopropyl which 30 may optionally be substituted with halo, eg fluoro or chloro to form, for example, trifluoromethyl; or R3 and R 4 together with the carbon to which they are attached form a four to seven - membered carbocyclic ring eg cyclobutyl. Even more preferably R 4 is hydrogen and R 3 is C1.6 alkyl, eg methyl or ethyl; or C1.6 alkyl which C1.6 35 alkyl is substituted with halo to form trifluoromethyl; or C1.6 alkyl which C1.6 alkyl is substituted with phenyl to form benzyl and which phenyl is in turn substituted by fluoro to form 4-fluorobenzyl; or R 3 and R 4 are both C1.6 alkyl, eg methyl or ethyl; or R 3 and R 4 are both C1.6 alkyl which C1.6 alkyl is substituted with halo to form trifluoromethyl; or R 3 and R 4 together with the carbon to which they are attached form a 4-membered carbocyclic ring. 12 WO 2006/134459 PCT/IB2006/001566 Most preferably R 4 is hydrogen and R 3 methyl; or R 4 is hydrogen and R 3 ethyl; or R 4 is hydrogen and

R

3 is trifluoromethyl; or R 4 is hydrogen and R 3 is 4-fluorobenzyl; or R 3 and R 4 are both methyl; or R 3 and R 4 are both trifluoromethyl. 5 Most preferably R 3 and R 4 together with the carbon to which they are attached form a cyclobutyl ring. Suitable compounds include those where, when R 7 is halo, preferred halo substituents are fluoro, chloro or bromo. Further suitable compounds include those where, when R 7 is selected from C1.6 10 alkyl or C1.6 alkoxy where the C1.6 alkyl or C1.6 alkoxy are optionally substituted with one or more halo substituents, preferred halo substituents are fluoro, chloro or bromo. Preferably R 7 is selected from chloro, or fluoro. Most preferably R 7 is chloro. Suitably, R 8 is selected from: cyano; halo, eg chloro or fluoro; C1.6 alkyl, eg methyl or ethyl which C1.6 15 alkyl may optionally be substituted with one or more fluoro groups to form, for example, trifluoromethyl; and C1.6 alkanoyl, eg acetyl or propanoyl which C1.6 alkanoyl may optionally be substituted by one or more groups independently selected from -S(O)nR" eg where R 1 is methyl, to form, for example, (methylthio)acetyl, halo eg chloro or fluoro, to form, for example, trifluoroacety or C1.4 alkoxy to form, for example, 2-ethoxy-2-oxoethyl. Preferably, R8 is cyano, trifluoromethyl or 20 methylthioacetyl. Most preferably, R8 is cyano. Suitably R 9 is selected from: hydrogen; cyano; hydroxy; and halo, eg chloro or fluoro. Equally suitably R 9 is C1.6 alkyl, eg methyl, ethyl, isopropyl, or t-butyl which C1.6 alkyl may in turn 25 optionally be substituted by one or more substituents selected from: halo, eg fluoro or chloro to form, for example, difluoromethyl, trifluoromethyl or trifluoroethyl; C1.6 alkyl, eg t-butyl to form, for example, t-butylmethyl; C.8 cycloalkyl, eg cyclopropyl, cyclopentyl or cyclohexyl to form, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or cyclopropylethyl; C1.6 alkoxy, eg methoxy or ethoxy to form, for example, methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethy; het, eg 30 pyrazinyl to form, for example, pyrazinylmethyl or pyrazinylethyl, imidazolyl to form, for example, (1 H-imidazolyl)methyl or (1H-imidazolyl)ethyl, 1, 3, 4-triazolyl to form, for example, (1, 3, 4 triazolyl)methyl or (1, 3, 4-triazolyl)ethyl, or pyridinyl to form, for example, (pyridin-2-yl)methyl, (pyridin-2-yl)ethyl, (pyridin-4-yl)methyl or (pyridine-2-yl)ethyl, where suitably the pyridinyl may be further substituted with, eg oxy to form, for example, (1 -hydroxy-pyridinyl)methyl or (1-hydroxy 35 pyridinyl)ethyl; phenyl to form, for example, benzyl or phenylethyl which phenyl may in turn be optionally substituted by one or more substituents selected from halo, eg chloro or fluoro to form, for example, 4-fluorobenzyl, (4-fluorophenyl)ethyl, 3, 4-difluorobenzyl or (3, 4-difluorophenyl)ethyl, C1.4 alkyl optionally further substituted by one or more halo groups, eg chloro or fluoro to form, for example, (trifluoromethyl)benzyl or [(trifluoromethyl)phenyl]ethyl, or S(O)nR, eg where R" is methyl 13 WO 2006/134459 PCT/IB2006/001566 to form, for example, (4-methylsulphonyl)benzyl or [(4-methylsulphonyl)phenyl]ethyl; -C(0)0C1.6 alkyl eg ethoxycarbonyl to form, for example, 2-ethoxy-2-oxoethyl; amino to form, for example, aminomethyl or aminoethyl; C1.6 alkyl amino, eg methylamino to form, for example, (methylamino)methyl, (methylamino)ethyl, (ethylamino)methyl or (ethylamino)ethyl; and S(O),R, eg 5 where R" is methyl to form, for example, (methylthio)methyl, (methylthio)ethyl, (methylsulphinyl)methyl, (methylsulphinyl)ethyl, (methylsulphonyl)methyl, or (methylsulphonyl)ethyl. Equally suitably R 9 is C3.8 cycloalkyl, eg cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl which 03.8 cycloalkyl may be optionally substituted with one or more groups selected from halo, eg fluoro or 10 chloro to form, for example, 1-fluorocyclopropyl, cyano to form, for example, 1-cyanocyclopropyl, and hydroxy to form, for example, 1 -hydroxycyclopropyl. Equally suitably R 9 is C 3

.

6 cycloalkylCl.6 alkyl eg cyclopropylmethyl or cyclopropylethyl which C3.8 cycloalkylC 1

.

6 alkyl may be optionally substituted with one or more groups selected from: halo eg 15 fluoro or chloro, to form, for example, (1-fluorocyclopropyl)methy; C1.4 alkyl eg methyl or ethyl to form, for example, (1-methylcyclopropyl)methyl or (1-ethylcyclopropyl)methy; and C1-4 haloalkyl eg trifluoromethyl to form, for example, [(1 -trifluoromethyl)cyclopropyl]methyl. Further equally suitable compounds include those where R 9 is C1.6 alkoxy, eg methoxy, ethoxy, 20 isopropoxy or t-butoxy which C1-6 alkoxy may in turn optionally be substituted by one or more substituents selected from: halo, eg fluoro or chloro to form, for example, trifluoromethoxy or trifluoroethoxy; C1.6 alkyl, eg t-butyl to form, for example, t-butylmethoxy; C3.8 cycloalkyl, eg cyclopropyl, cyclopentyl or cyclohexyl to form, for example, cyclopropylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy or cyclopropylethoxy; het, eg pyrazinyl to form, for example, pyrazinylmethoxy, 25 imidazolyl to form, for example, (1 H-imidazolyl)methoxy, 1, 3, 4-triazolyl to form, for example, (1, 3, 4-triazolyl)methoxy or (1, 3, 4-triazolyl)ethoxy, or pyridinyl to form, for example, pyridin-2-ylmethoxy or pyridin-4-ylmethoxy, where suitably the pyridinyl may be further substituted with, eg oxy to form, for example, (1 -hydroxypyridinyl)methoxy; phenyl to form, for example, benzyloxy which phenyl may in turn be optionally substituted by one or more substituents selected from halo, eg chloro or fluoro to 30 form, for example, (4-fluorobenzyl)oxy or (3, 4-difluorobenzyl)oxy, C1.4 alkyl optionally further substituted by one or more halo groups, eg chloro or fluoro to form, for example, [(trifluoromethyl)benzyl]oxy, or S(O),R, eg where Rl is methyl to form, for example, [(4 methylsulphonyl)benzy]oxy; and C(0)0C1.6 alkyl, eg ethoxycarbonyl to form, for example, 2-ethoxy 2-oxoethoxy. 35 Further equally suitable compounds include those where R 9 is C3.8 cycloalkyliC1.

6 alkoxy eg cyclopropylmethoxy or cyclopropylethoxy which C3.6 cycloalkylC 1

.

6 alkoxy may be optionally substituted with one or more groups selected from: halo eg fluoro or chloro, to form, for example, (1 fluorocyclopropyl)methoxy; C1.4 alkyl eg methyl or ethyl to form, for example, (1 14 WO 2006/134459 PCT/IB2006/001566 methylcyclopropyl)methoxy or (1-ethylcyclopropyl)methoxy; and C1.4 haloalkyl to form, for example, [(1 -trifluoromethyl)cyclopropyl]methoxy. Still further equally suitable compounds include those where R 9 is C2-6 alkenyl, eg ethenyl which C2-6 5 alkenyl may be substituted with one or more substituents selected from: het eg pyrazinyl, 1, 3, 4 triazolyl, imidazolyl, or pyridinyl; and phenyl, which phenyl may be further substituted by for example halo, eg chloro or fluoro to form, for example, 4-fluorophenyl or 3, 4-difluorophenyl, C14 alkyl optionally substituted by one or more halo groups, eg chloro or fluoro to form, for example, (trifluoromethyl)phenyl, or S(O)nR, eg where R" is methyl to form, for example, (4 10 methylsulphonyl)phenyl. Still further equally suitable compounds include those where R 9 is het, eg pyrazinyl, imidazolyl, or pyridinyl to form, for example, pyridin-2-yl or pyridin-4-yl, where suitably the pyridinyl may be further substituted with oxy to form, for example, 1 -hydroxypyridinyl. 15 Yet further equally suitable compounds also include those where R 9 is phenyl which phenyl may in turn be optionally substituted by one or more substituents selected from: halo, eg chloro or fluoro to form, for example, 4-fluorophenyl or 3, 4-difluorophenyl; and S(O)nR", eg where R" is methyl to form, for example, (4-methylsulphonyl)phenyl. 20 Yet further equally suitable compounds also include those where R 9 is S(O)nR", eg where R" is methyl to form, for example, methylsulphonyl. Even further equally suitable compounds include those where R 9 is NReRI where each of Re or R! is 25 independently selected from: hydrogen; C1.6 alkyl, eg methyl, ethyl, isopropyl or t-butyl to form, for example, methylamino, isopropylamino or isobutylamino, which C1.6 alkyl may in turn be substituted with one or more substituents selected from halo, eg fluoro or chloro to form, for example, trifluoromethylamino or trifluoroethylaminO, C1.6 alkyl, eg t-butyl to form, for example, (t butylmethyl)amino, C-8 cycloalkyl, eg cyclopropyl, cyclopentyl or cyclohexyl to form, for example, 30 (cyclopropylmethyl)amino, (cyclopentylmethyl)amino, (cyclohexylmethyl)amino or (cyclopropylethyl)amino, het, eg pyrazinyl to form, for example, (pyrazinylmethyl)amino, imidazolyl to form, for example, [(1H-imidazolyl)methyl]amino, 1, 3, 4-triazolyl to form, for example, [(1, 3, 4 triazolyl)methyl]amino or [(1, 3, 4-triazolyl)ethyl]amino, or pyridinyl to form, for example, (pyridin-2 ylmethyl)amino or (pyridin-4-ylmethyl)amino, where suitably the pyridinyl may be further substituted 35 with oxy to form, for example, [(1-hydroxy-pyridin-4-yl)methyl]amino, phenyl to form, for example, benzylamino which phenyl may in turn be optionally substituted by one or more substituents selected from halo, eg chloro or fluoro to form, for example, (4-fluorobenzyl)amino or (3, 4 difluorobenzyl)amino, C1.4 alkyl optionally substituted by one or more halo groups, eg chloro or fluoro to form, for example, [(trifluoromethyl)benzyl]amino, or S(O)nR", eg where R 1 1 is methyl to form, for 15 WO 2006/134459 PCT/IB2006/001566 example, [(4-methylsulphonyl)benzyl]amino. R* or Rf may also be independently selected from: C3-s cycloalkyl, eg cyclopropyl to form, for example, cyclopropylamino; C3.8 cycloalkylC1.6 alkyl eg cyclopropylm6thyl or cyclopropylethyl to form for example (cyclopropylmethyl)amino or (cyclopropylethyl)amino, which C3.8 cycloalkylC1.

6 alkyl may be optionally substituted with one or 5 more groups selected from halo eg fluoro or chloro, to form, for example, [(1 fluorocyclopropyl)methyl]amino, C1.4 alkyl eg methyl or ethyl to form, for example, [(1 methylcyclopropyl)methy]amino or [(1-ethylcyclopropyl)methyl]amino, or C1.4 haloalkyl to form, for example, {[1-(trifluoromethyl)cyclopropyl]methyl~amino; and -C(0)OC1.6 alkyl, eg ethoxycarbonyl to form, for example, ethoxycarbonylamino. 10 Preferably, R 9 is selected from: hydrogen; hydroxy; halo, eg chloro or fluoro; C 1

.

6 alkyl eg methyl, which C1.

6 alkyl may optionally be substituted by halo eg fluoro, to form, for example, difluoromethyl,

C

3

.

8 cycloalkyl eg cyclopropyl to form, for example, cyclopropylmethyl, or -C(0)0C1.6 alkyl eg ethoxycarbonyl to form, for example, 2-ethoxy-2-oxoethyl; C 3

.

8 cycloalkylC 1 .ealkyl eg 15 cyclopropylmethyl, which C3.8 cycloalkyl 1

.

6 alkyl may optionally be substituted by C 1

.

4 alkyl eg methyl to form, for example, (1-methylcyclopropyl)methyl;

C

1

.

6 alkoxy, eg methoxy which methoxy may optionally be substituted by halo eg fluoro, to form, for example, trifluoromethoxy, or -C(0)O0C1. alkyl eg ethoxycarbonyl to form, for example, 2-ethoxy-2-oxoethoxy;

C

3

-

8 cycloalkylC1.

6 alkoxy, eg cyclopropylmethoxy which C 38 cycloalkylC 1

.

6 alkoxy may optionally be substituted by C1.6 alkyl eg 20 methyl to form, for example, (1-methylcyclopropyl)methoxy; and NR*Rf where each of R* or Rf is independently selected from: hydrogen to form, for example, amino; C1.6 alkyl eg methyl to form, for example, methylamino, ethyl to form, for example, ethylamino or isopropyl to form, for example isopropylamino, which C1.6 alkyl may in turn be optionally further substituted by halo eg fluoro to form, for example, (trifluoromethyl)amino or (trifluoroethyl)amino,

C

3 .scycloalkyl eg cyclopropyl, to 25 form, for example, (cyclopropylmethyl)amino, het eg 1, 3, 4-triazolyl to form, for example, [(1, 3, 4 triazolyl)methyl]amino or pyridinyl to form for example (pyridin-4-ylmethyl)amino; -C(0)OC1.6 alkyl eg ethoxycarbonyl to form, for example, ethoxycarbonylamino; and C3.8 cycloalkylC 1

.

6 alkyl, eg cyclopropylmethyl to form (cyclopropylmethyl)amino which cyclopropylmethyl may optionally be further substituted with C1.6 alkyl eg methyl to form, for example, [(1 -methylcyclopropyl)methyl]amino. 30 More preferably, R 9 is selected from: hydrogen; halo eg chloro; C1.6 haloalkyl eg difluoromethyl; C3.8 cycloalkylC1.

6 alkoxy eg cyclopropylmethoxy; and NReRf where R' is hydrogen and Rf is independently selected from hydrogen, C1.6 alkyl for example methyl to form methylamino which methyl may in turn be optionally substituted by C3.8 cycloalkyl eg cyclopropyl to form, for example, 35 cyclopropylmethyl)amino, or het eg pyridinyl to form, for example, (pyridin-4-ylmethyl)amino. Even more preferably, R9 is selected from hydrogen; halo eg chloro; C3.8 cycloalkylC1.6 alkoxy eg cyclopropylmethoxy; and NReRf where R" is hydrogen and Rf is independently selected from hydrogen to from amino, methyl to form methyl amino, or pyridin-4-ylmethyl to form (pyridin-4 16 WO 2006/134459 PCT/IB2006/001566 ylmethyl)amino. Most preferably R9 is amino. 5 Preferably X is CR 10 . More preferably R 1 0 is chloro. Other preferred compounds are those in which

R

7 and R 10 are the same. More preferably, both R 7 and R 1 0 are Cl. A further group of suitable compounds of the present invention are those of formula (1) where: R1 - R 2 , R 7 - R 9 , X, RC, Rd, n, R 1 and het are all as defined for formula (1) above; R 4 is hydrogen and 10 R 3 is C4.8 cycloalkyl, eg cyclobutyl or cyclopentyl, which C4.8 cycloalkyl may optionally be substituted with one or more substitutents selected from cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRCRd, NRcC(O)Rd, C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C38 cycloalkyl, C3-8 cycloalkylC 1

.

6 alkyl, C3.8 cycloalkylC 1

.

6 haloalkyl, C16 alkoxy, C 1

.

6 alkanoyl, -C(O)OC1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, NRcRd, het, phenyl 15 and S(O)nR"; or a pharmaceutically acceptable salt or a prodrug thereof. Preferably, in these compounds of formula (1): R 1 is CF 3 , OCF 3 or SFq, more preferably SF 5 ; R 2 is CN or C(O)NRaRb, where Ra is hydrogen and Rb is selected from hydrogen, C1.6 alkyl and C38 cycloalkyl, wherein each of the above groups may include one or more optional fluoro substituents, more 20 preferably where both Ra and Rb are hydrogen; R 8 is cyano, trifluoromethyl or methylthiocarbonyl, more preferably cyano; R 9 is selected from hydrogen, chloro, methyl, difluoromethyl, cyclopropylmethoxy or NR*Rf where R* is hydrogen and Rf is independently selected from hydrogen, methyl, cyclopropylmethyl, (1-methylcyclopropyl)methyl, or pyridin-4-ylmethyl, more preferably R 9 is amino; X is CR 10 and both R 7 and R 1 0 are Cl. 25 A further group of suitable compounds of the present invention are those of formula (1) where: R' - R 2, R 7 - R 9 , X, Rc, R , n, R 1 are all as defined for formula (1) above; R 4 is hydrogen and R 3 is het eg tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, pyrrolyl, furanyl, imidazolyl, oxazolyl, 1, 3,4-triazolyl, 1-oxa-3, 4-diazolyl, pyridinyl, 30 pyrimidinyl or pyrazinyl which het may optionally be substituted, where chemically possible, with one or more substitutents selected from cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRCRd, NRCC(O)Rd, C1.6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C3.8 cycloalkyl, C-8 cycloalkylC 1

.

6 alkyl, C3.8 cycloalkylC1.6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(O)OC1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, NRcRd, het, phenyl 35 and S(O)nR 1 ; or a pharmaceutically acceptable salt or a prodrug thereof. Preferably, in these compounds of formula (1): R 1 is CF 3 , OCF 3 or SF 5 , more preferably SF5; R 2 is CN or C(O)NRaRb, where Ra is hydrogen and Rb is selected from hydrogen, C1.6 alkyl and C3.8 cycloalkyl, wherein each of the above groups may include one or more optional fluoro substituents, more 17 WO 2006/134459 PCT/IB2006/001566 preferably where both Ra and Rb are hydrogen; R 8 is cyano, trifluoromethyl or methylthiocarbonyl, more preferably cyano; R 9 is selected from hydrogen, chloro, methyl, difluoromethyl, cyclopropylmethoxy or NReRf where Re is hydrogen and Rf is independently selected from hydrogen, methyl, cyclopropylmethyl, (1-methylcyclopropyl)methyl, or pyridin-4-ylmethyl, more preferably R 9 is 5 amino; X is CR 1 0 and both R 7 and R' 0 are Cl. A further group of suitable compounds of the present invention are those of formula (1) where: R1 - R 2 , R 7 - R 9 , X, Rc, Rd, n, R" and het are all as defined for formula (I) above; R 4 is hydrogen and

R

3 is phenyl which phenyl may be optionally substituted by one or more further substitutents selected 10 from the group consisting of halo, cyano, nitro, hydroxy, C1.6 alkyl, C1.6 haloalkyl, C1.6 alkoxy, C1.6 haloalkoxy, amino, C1.6 alkyl amino, di C1.6 alkyl amino, -NHS(O)nR", and S(O)nR"; or a pharmaceutically acceptable salt or a prodrug thereof. Preferably, in these compounds of formula (1): R1 is CF 3 , OCF 3 or SF 5 , more preferably SF 6 ; R 2 is CN or C(O)NRaRb, where Ra is hydrogen and Rb is selected from hydrogen, C1.6 alkyl and C3.. cycloalkyl, 15 wherein each of the above groups may include one or more optional fluoro substituents, more preferably where both Ra and Rb are hydrogen; R 8 is cyano, trifluoromethyl or methylthiocarbonyl, more preferably cyano; R 9 is selected from hydrogen, chloro, methyl, difluoromethyl, cyclopropylmethoxy or NR*Rf where Re is hydrogen and Rf is independently selected from hydrogen, methyl, cyclopropylmethyl, (1-methylcyclopropyl)methyl, or pyridin-4-ylmethyl, more preferably R 9 is 20 amino; X is CR' 0 and both R 7 and R 0 are Cl. A further group of suitable compounds of the present invention are those of formula (I) where: R1 - R 2 , R 7 - R 9 , X, RC, Rd, n, R" and het are all as defined for formula (1) above; and R 4 and R 3 together with the carbon to which they are attached may form a four to seven - membered saturated, 25 partially saturated, unsaturated or aromatic ring which may optionally contain one or more further N, o or S atoms and which may be optionally further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(0)OH, C(O)NRcRd, NRCO(O)Rd, C1.6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC1.

6 alkyl, C3.8 cycloalkylC 1

.

6 haloalkyl, C1.6 alkoxy, C16. alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 30 haloalkoxy, C1.6 haloalkanoyl, -C(0)0OC1. haloalkyl, amino, NRcRd, het, phenyl and S(O)nR; or a pharmaceutically acceptable salt or a prodrug thereof. Preferably, in these compounds of formula (1): R1 is CF 3 , OCF 3 or SF 5 , more preferably SF 5 ; R 2 is CN or C(O)NRaRb, where Ra is hydrogen and Rb is selected from hydrogen, C1.6 alkyl and C3. cycloalkyl, wherein each of the above groups may include one or more optional fluoro substituents, more 35 preferably where both Ra and Rb are hydrogen; R 8 is cyano, trifluoromethyl or methylthiocarbonyl, more preferably cyano; R 9 is selected from hydrogen, chloro, methyl, difluoromethyl, cyclopropylmethoxy or NR*Rf where Re is hydrogen and Rf is independently selected from hydrogen, methyl, cyclopropylmethyl, (1-methylcyclopropyl)methyl, or pyridin-4-ylmethyl, more preferably R 9 is amino; X is CR'4 and both R 7 and R1 0 are Cl. 18 WO 2006/134459 PCT/IB2006/001566 A further group of suitable compounds of the present invention are those of formula (1) where:

R

1 - R 2 , R 7 - R 9 , X, R", Rd, n, R" and het are all as defined for formula (I) above; and both R 3 and R 4 are independently selected C1.6 alkyl, eg methyl, ethyl, or isopropyl, which C1.6 alkyl may optionally 5 be substituted with one, or more substitutents selected from cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRCRd, NR"C(O)Rd, C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, C3.3 cycloalkylC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 Cd haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.e haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, NR"R het, phenyl and S(O),R"; 10 or a pharmaceutically -acceptable salt or a prodrug thereof. Preferably, in these compounds of formula (1): R 1 is CF 3 , OCF 3 or SF5, more preferably SFq; R 2 is CN or C(O)NRaRb, where Ra is hydrogen and Rb is selected from hydrogen, C1.6 alkyl and C3.8 cycloalkyl, wherein each of the above groups may include one or more optional fluoro substituents, more preferably where both Ra and Rb are hydrogen; RE is cyano, trifluoromethyl or methylthiocarbonyl, 15 more preferably cyano; R 9 is selected from hydrogen, chloro, methyl, difluoromethyl, cyclopropylmethoxy or NR"Rf where R" is hydrogen and Rf is independently selected from hydrogen, methyl, cyclopropylmethyl, (1-methylcyclopropyl)methyl, or pyridin-4-ylmethyl, more preferably R 9 is amino; X is CR 10 and both R 7 and R 10 are C. 20 A further group of suitable compounds of the present invention are those of formula (I) where: R', R 3 - R', X, R 0 , Rd, n, R" and het are all as defined for formula (I) above; and R 2 is selected from cyano, C(O)OH, S(O)nR", C(O)NRa R , and C(S)NRaRb; or R 2 is selected from amino and C1.6 alkyl amino which amino or C1.6 alkyl amino may be optionally and independently further substituted by one or more substitutents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, 25 C(O)OH, C(O)NRcRd, NR"C(0)Rd, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, C3.8 cycloalkylC 1

.

6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 Cd haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)OC1.6 haloalkyl, amino, NR"R het, phenyl and S(O)nR"; where Ra and Rb are independently selected from hydrogen, het, phenyl and S(0),R", or either one or both of Ra and Rb are independently selected from C1.6 alkyl, C2 30 alkenyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1

.

6 alkyl, C1.6 alkanoyl, and C(0)OC1.6 alkyl, each of which Ra and Rb may be optionally and independently further substituted by one or more substituents selected from, where chemcially possible, cyano, nitro, halo, oxo, hydroxy, C(0)OH, C(0)NRRd, NR"C(O)Rd, C1.6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 03-8 cycloalkyC1.

6 alkyl, 03.8 cycloalkylC 1 -6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 35 haloalkoxy, C1.6 haloalkanoyl, -C(0)OCI.6 haloalkyl, amino, NRcRd, het, phenyl and S(O)R 11 , or Ra and Rb together with the N atom to which they are attached may form a three to seven - membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring which may optionally contain one or more further N, 0 or S atoms and which may be optionally further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, 19 WO 2006/134459 PCT/IB2006/001566 C(O)NRcRd, NR"C(O)Rd, C1.6 alkyl, C2-6 alkenyl, C2. alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylCI.6 alkyl, C0.8 cycloalkylCl.6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(O)0C 1

.

6 alkyl, C1.6 haloalkyl, C3-8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(O)OC1.6 haloalkyl, amino, NRcRd, het, phenyl and S(O),R; 5 or a pharmaceutically acceptable salt or a prodrug thereof. Preferably, in these compounds of formula (I): R' is CF 3 , OCF 3 or SFe, more preferably SFe; R4 is hydrogen and R 3 is C1.6 alkyl, eg methyl, ethyl, n-propyl, or isopropyl which C1.6 alkyl may optionally be substituted with halo, eg fluoro or chloro to form, for example, trifluoromethyl, or phenyl to form, for example, benzyl, which phenyl may in turn be optionally substituted by one or more substituents 10 selected from halo, eg chloro or fluoro to form, for example, 4-fluorobenzyl, or R 3 and R 4 are both independently selected from C1.6 alkyl, eg methyl, ethyl, n-propyl, or isopropyl which may optionally be substituted with halo, eg fluoro or chloro to form, for example, trifluoromethyl; or R 3 and R 4 together with the carbon to which they are attached form a four to seven - membered carbocyclic ring eg cyclobutyl; R8 is cyano, trifluoromethyl or methylthiocarbonyl, more preferably cyano; R9 is 15 selected from hydrogen, chloro, methyl, difluoromethyl, cyclopropylmethoxy or NR"Rf where Re is hydrogen and Rf is independently selected from hydrogen, methyl, cyclopropylmethyl, (1 methylcyclopropyl)methyl, or pyridin-4-ylmethyl, more preferably R 9 is amino; X is CR 10 and both R 7 and R 10 are Cl. 20 Preferred individual compounds of the invention are selected from: 1 -{5-amino-3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}cyclobutane carboxamide; 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}propanamide; 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}-2-methylpropanamide; 25 1 -{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethoxy)phenyl]-1 H-pyrazol-4 yl}cyclobutanecarboxamide; 1-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4 yl}cyclobutanecarboxamide; 1-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-(methylamino)-1H-pyrazol-4 30 yl}cyclobutanecarboxamide; 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazol-4-yl}propanamide; 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazol-4-yl}-3-( 4 fluorophenyl)propanamide; 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazol-4-yl}butanamide; 35 N-(1 -{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazol-4-yl}-2, 2

,

2 trifluoroethyl)-N-methylmethanesulfonamide; 5-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-[1 -(methylsulfonyl)ethyl]-1 H-pyrazole-3 carbonitrile; 1-[2,6-dichloro-4-pentafluorothiophenyl]-4-[1 -(methylsulfonyl)ethyl]-1 H-pyrazole-3-carbonitrile; 20 WO 2006/134459 PCT/IB2006/001566 2-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}propanamide; 2-{5-chloro-3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}propanamide; 2-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-[(pyridin-4-ylmethyl)amino]-1H-pyrazol-4 yl}propanamide; 5 5-amino-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[2,2,2-trifluoro-1 -(methylamino)-1 (trifluoromethyl)ethyl]-1 H-pyrazole-3-carbonitrile; 5-amino-4-[1 -amino-2,2,2-trifluoro-1 -(trifluoromethyl)ethyl]-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl] 1 H-pyrazole-3-carbonitrile; 5-amino-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[2,2,2-trif luoro-1 -(isopropylthio)-1 10 (trifluoromethyl)ethyl]-1 H-pyrazole-3-carbonitrile; 5-amino-4-[l -cyano-2,2,2-trifluoro-1 -(trifluoromethyl)ethyl]-1 -[2,6-dichloro-4-pentafluorothiophenyl] 1 H-pyrazole-3-carbonitrile; 2-{3-cyano-5-(cyclopropylmethoxy)-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4 yl}propanamide; 15 or a pharmaceutically acceptable salt or prodrug thereof. In the compounds according to formula (1) the term 'halo' means a group selected from fluoro, chloro, bromo or iodo. Preferably the term "halo" means a group selected from fluoro, chloro or bromo.. 20 Alkyl, alkenyl, alkynyl and alkoxy groups, containing the requisite number of carbon atoms, can be unbranched or branched. The term lower alkyl shall be taken to mean C1.6 alkyl. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of alkenyl include methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 25 1,3-propylene and 2,2-propylene. The term cycloalkyl shall be taken to mean C-8 cycloalkyl. Examples of include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In the compounds according to formula (1) the term phenyl shall be taken to mean a six membered aromatic carbon ring, which phenyl can be substituted as described for compounds of formula (1). 30 In the compounds according to formula (I) the term "het" shall be taken to mean those substituents which fall into the definition as set out in Claim 1. Preferably the term "het" shall be taken to mean those substituents which represent a five to six membered heterocyclic group, which is aromatic or non-aromatic, unsaturated, partially saturated or saturated and which contains one or more 35 heteroatoms selected from nitrogen, N-oxide, oxygen, and sulphur and wherein said heterocyclic ring is optionally substituted where the valence allows with one or more substituents selected from halo, C1.6 alkyl, C1.6 haloalkyl, NR9R , where R 9 and Rh are independently selected from hydrogen, and C1. 6 alkyl. More preferably the term "het" shall be taken to mean those substituents which represent a five to six membered heterocyclic ring, which is aromatic or non-aromatic, unsaturated, partially 21 WO 2006/134459 PCT/IB2006/001566 saturated or saturated and which contains at least one nitrogen or oxygen atom and optionally up to two further heterocyclic atoms selected from nitrogen, oxygen and sulphur and wherein said heterocyclic ring is optionally substituted where the valence allows with one or more substituents selected from halo, C6 alkyl, C1.6 haloalkyl, NRR, where R9 and Rh are independently selected 5 from hydrogen, and C1.6 alkyl. In the case of substituents R 2 , Ra, or Rb and further optional substituents thereof of compounds of formula (1), the term "het" shall most preferably be taken to mean those substituents which represent a five to six membered heterocyclic ring, which is aromatic, unsaturated, or partially saturated and 10 which contains at least one nitrogen atom and optionally up to two further heteroatoms selected from nitrogen, oxygen or sulphur and wherein said heterocyclic ring is optionally substituted where the valence allows with one or more substituents selected from halo, and C1.6 alkyl. Suitable preferred examples of such rings include 1-oxa-3, 4-diazolyl, 5-methyl-1-3,4-oxadiazol-2-yl, pyridinyl, 1, 2, 4 triazolyl, or thiazolyl. 15 In the case of substituents R 9 , Re, or Rf and further optional substituents thereof of compounds of formula (1), the term "het" shall most preferably be taken to mean those substituents which represent a five to six membered heterocyclic ring, which is aromatic, unsaturated, partially saturated, or saturated and which contains at least one nitrogen atom or one oxygen atom and optionally up to 20 two further heterocyclic atoms selected from nitrogen, oxygen or sulphur and wherein said heterocyclic ring is optionally substituted where the valence allows with one or more substituents selected from halo, and C1.6 alkyl. Suitable preferred examples of such rings include pyrazinyl, imidazolyl, pyridinyl, 1-hydroxy-pyridinyl, 1,2,4-triazolyl, 1,3,4-triazolyl, isoxaolyl, thiazolyl, 2-chloro 1,3-thiazol-4-yl, pyrazolyl, 1-methyl-1 H-pyrazol-4-yl, 1 -methyl-3-methyl-5-chloro-1 H-pyrazol-4-yl, and 25 tretrahydropyranyl. Most preferably in the case of substituents R 9 , R", or R' and further optional substituents thereof of compounds of formula (1) het is pyridinyl. In the compounds according to formula (1) each phenyl group may be optionally and independently substituted as set out in Claim 1. More preferably each phenyl group may be optionally and 30 independently substitueted with one or more further substitutents selected from the group consisting of halo, C1.6 alkyl, C1.6 haloalkyl, C1.6 alkoxy, C1.6 haloalkoxy, -NHS(O)nR", and S(O)nR". More preferably each phenyl group may be optionally substituted in the 4-position with a substituent selected from the group consisting of halo, C1.6 haloalkyl, -NHS(O)nR, and S(O)"R 11 . 35 In the case of substituents R 9 , R", or Rf and further optional substituents thereof of compounds of formula (1) it is preferred that each phenyl group may be optionally substituted in the 4-position a substituent selected from the group consisting of halo, C1.6 haloalkyl, -NHS(O)nR", and S(O)nR". Suitable examples of such phenyl groups include 4-fluorophenyl, 4-trifluoromethylphenyl, (4 methylsulphonyl)phenyl, 4-[(methylsulphonyl)amino]phenyl, and 4-[(methylamino)sulphonyl]phenyl. 22 WO 2006/134459 PCT/IB2006/001566 It will be understood that compounds of formula (1) may exist as one or more geometric isomers. Thus included within the scope of the present invention are all such possible geometric isomer forms of the compounds of the present invention. Geometric isomers may be separated by conventional 5 techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation. It will be understood that compounds of formula (1) may exist as one or more tautomeric isomers. Thus included within the scope of the present invention are all such possible tautomeric isomer 10 forms of compounds of the present invention. It is to be understood that compounds of formula (1) may contain one or more asymmetric carbon atoms, thus compounds of the invention can exist as two or more stereoisomers. Included within the scope of the present invention are all stereoisomers such as enantiomers and diasteromers. Also 15 included are acid addition or base salts wherein the counterion is optically active, for example, D lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a 20 salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (1) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting 25 diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may. be obtained in 30 enantiomerically-enriched form using chromatography, typically HPLC, using conditions such as on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. 35 Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994). Also included within the scope of the present invention are compounds exhibiting more than one type 23 WO 2006/134459 PCT/IB2006/001566 of isomerism, and mixtures of one or more thereof. For the avoidance of doubt, it will be understood that throughout the application all references to pharmaceutically acceptable compounds includes references to veterinarily acceptable compounds 5 or agriculturally acceptable compounds. Furthermore it will be understood that throughout the application all references to pharmaceutical activity includes references to veterinary activity or agricultural activity. Pharmaceutically acceptable salts of the compounds of formula (1) include the acid addition and base 10 salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, 15 mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen, phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, 20 tromethamine and zinc salts. The pharmaceutically, veterinarily and agriculturally acceptable acid addition salts of certain of the compounds of formula (1) may also be prepared in a conventional manner. For example, a solution of a free base may be treated with the appropriate acid, either .neat or in a suitable solvent, and the 25 resulting salt isolated either by filtration or by evaporation under reduced pressure of the reaction solvent. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Hereinafter, and throughout the application, all references to compounds of formula (1) include 30 references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof. The invention includes all polymorphs of the compounds of formula (1) as hereinbefore defined. The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' 35 is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g.

D

2 0, d 6 -acetone, d 6 -DMSO. 24 WO 2006/134459 PCT/IB2006/001566 Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing 5 two or more organic and/or inorganic components which may be in stoichiometric or non stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non-ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975). The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of 10 formula (1) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of 15 hydrogen, such as 2H and 3 H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18 F, iodine, such as 1231 and 1251 nitrogen, such as 13 N and 1 5 N, oxygen, such as 0, 0170 and 18, phosphorus, such as 3 2 P, and sulphur, such as 35S. Within the scope of the invention are so-called 'prodrugs' of the compounds of formula (1). Thus 20 certain derivatives of compounds of formula (1) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (1) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible 25 Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association). Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (1) with certain moieties known to those skilled in 30 the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985). Some examples of prodrugs in accordance with the invention include: 35 (i) where the compound of formula (1) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (C-C)alkyl; (ii) where the compound of formula (1) contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (C-C 6 )alkanoyloxymethyl; and 25 WO 2006/134459 PCT/IB2006/001566 (iii) where the compound of formula (1) contains a primary or secondary amino functionality (-NH 2 or NHR where R 6 H), an amide thereof, for example, replacement of one or both hydrogens with (C

C

1 0 )alkanoyl. 5 Prodrugs in accordance with the invention can, for example, be produced by replacing the 5-amino substituent on the pyrazole ring in the compounds of formula (1) with certain moieties known to those skilled in the art as 'pro-drug moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985); "Design and application of prodrugs," Textbook of Drug Design and 10 Discovery, ( 3 rd Edition), 2002, 410-458, (Taylor and Francis Ltd., London); and references therein. Suitable prodrugs may have an N-containing group at the 5-position of the pyrazole ring of formula (1) and are bound to the ring through N. The 5-N group can be substituted once or twice. Examples of substituents include: alkyl amines, aryl amines, amides, ureas, carbamates, cyclic carbamates, 15 imines, enamines, imides, cyclic imides, sulfenamides, and sulfonamides. The hydrocarbon portion of these groups contain C1.6 alkyl, phenyl, heteroaryl such as pyridinyl, C2.6 alkenyl, and C3.8 cycloalkyl; wherein each of the above groups may include one or more optional substituents where chemically possible independently selected from: halo; hydroxy; C1.6 alkyl and C1.6 alkoxy. 20 Further examples of replacement groups in accordance with the foregoing example and examples of other prodrug types may be found in the aforementioned references. A prodrug according to the invention can be readily identified by administering it to a host animal and sampling a body fluid for a compound of formula (1). Finally, certain compounds of formula (1) may 25 themselves act as prodrugs of other compounds of formula (1). Prodrugs may be cleaved to active drug by metabolism by the host or by the parasite targeting the host. In a further aspect, the present invention provides processes for the preparation of a compound of formula (I), or a pharmaceutically, veterinarily or agriculturally acceptable salt thereof, or a 30 pharmaceutically, veterinarily or agriculturally acceptable solvate (including hydrate) of either entity, as illustrated below. It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by 35 conventional methods, for example as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein. The following processes are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention. 26 WO 2006/134459 PCT/IB2006/001566 When one or more of R', R 2 , R 3 , R 4 , R 7 , R8, R9, R10 and R" contain reactive functional groups then additional protection may be provided according to standard procedures during the synthesis of compounds of formula (1). In the processes described below, for all synthetic precursors used in the 5 synthesis of compounds of formula (1), the definitions of R', R 2 , R 3 , R 4 , I, R , R 9 , R 1 0 and R", wherein R1, R 2 , R , R 4 , R , R , R 9 , R1 0 and R" are as defined for formula (1), are intended to optionally include suitably protected variants, Pl, P2, p3, p 7 , P, , 9 , P1 0 and P'. Such suitable protecting groups for these functionalities are described in the references listed below and the use of these protecting groups where needed is specifically intended to fall within the scope of the 10 processes described in the present invention for producing compounds of formula (1) and its precursors. When suitable protecting groups are used, then these will need to be removed to yield compounds of formula (1). Deprotection can be effected according to standard procedures including those described in the references listed below. For example, when R 9 in formula (1) is an unsubstituted amino group, certain precursors may require protection of the amino group in order to 15 perform the necessary transformations, for example, by an imidoformamide group such as a compound of formula (1), where R'-R 8 and R1 0 are as described for formula (1) and R 9 represents N=C(H)-NRcRd, where Rc and Rd independently represent C1.

6 alkyl, e.g. to form a N,N-dimethyl group. Such imidoformamides may be prepared by standard methods, typically by refluxing the unprotected amine in N, N-dimethylformamide dimethyl acetal for 2 - 16 hours, usually around 5 20 hours followed by stirring at room temperature for 5 - 24 hours, usually overnight. The imidoformamide protecting group may be removed using standard conditions, such as at elevated temperature, with a suitable acid such as hydrochloric acid or para-toluenesulfonic acid in a solvent such as methanol or dioxane. R 2 RR N 7 X R1 25 A compound of formula (11), wherein R1, R 2 , R 7 , and R 8 are as defined for formula (1) is a key intermediate for the synthesis of compounds of formula (I) in which R 9 = NH 2 . Compounds of formula (II) may be prepared by the Japp-Klingemann reaction. This reaction is described in Org. React., 1959, 10, 143-178. 3,4,5-Trisubstituted 1-arylpyrazoles may be produced directly in a reaction which involves coupling of an aryldiazonium species with an appropriately substituted precursor bearing a 30 desired substituent. The desired substituent is introduced concomitantly at the C-4 position in a process, which does not involve any rearrangement. Furthermore, a very wide variety of 4 substituents may be introduced conveniently and directly. Thus, a compound of formula (11) can be prepared by reacting a compound of formula (111) 27 WO 2006/134459 PCT/IB2006/001566 N R L CN with a compound of formula (IV) R N=N*Z~ (IV) R1 optionally in the presence of an acid, wherein: R' to R 1 0 are as defined above in relation to the 5 compounds of formula (1); L is an activating group; and Z is a compatible counter ion, followed by removal of group L. The counter ion Z~ may be any suitable counter ion normally found in diazonium reactions. Preferably, Z~ is halogen, HSO 4 ~, or tetrafluoroborate and most preferably is tetrafluoroborate. 10 The group L is an electron withdrawing group which stabilises the anion intermediate in the process. Thus, preferably, L is a group which is capable of stabilising a negative charge on an adjacent carbon atom. The group L must also be removable. L can be removed under basic conditions, for example by base hydrolysis or can be removed by reduction and/or elimination. The group L is important as it serves to direct the reaction of the diazonium species with the compound of formula 15 (IX) but then is removed in the subsequent stages of the reaction. Preferably L is an ester group or a group COR 5 . More preferably, L is a group selected from: - S(O),R 16 where p is 1 or 2, (R' 6 0) 2 PO, COOR' and -COR 5 , wherein R 1 5 is selected from: hydrogen, C1-8 alkyl, di-C1.

8 alkylamino, C1.8 alkylthio, C3.8 cycloalkyl, (CH 2 )nPh and (CH 2 )n heteroaryl wherein n = 0, 1 or 2, each of which groups may be optionally substituted on any carbon atom by one or more groups selected independently from: 20 halogen, hydroxy, cyano, nitro, C1.4 alkoxy, C1.4 haloalkoxy, C1.4 alkanoyl, C1.4 haloalkanoyl, C1.4 alkylsulphinyl, C1.4 haloalkylsulphinyl, C1.4 alkylsulphonyl, C1.4 haloalkylsulphonyl, C3.8 cycloalkyl and C3.8 halocycloalkyl; and wherein R' is selected from: C1.8 alkyl, C3.8 cycloalkyl, (CH 2 )nPh and (CH 2 )n heteroaryl wherein n = 0, 1 or 2, each of which groups may be optionally substituted on any carbon atom by one or more groups selected independently from: halogen, hydroxy, cyano, nitro, C1.4 alkoxy, 25 C1.4 haloalkoxy, C1.4 alkanoyl, C1.4 haloalkanoyl, C1.4 alkylsulphinyl, C1.4 haloalkylsulphinyl, C1.4 alkylsulphonyl, C1.4 haloalkylsulphonyl, C3.8 cycloalkyl and C3.8 halocycloalkyl. Preferably L is a selected from COR 5 and COOR". Most preferably L is -COOMe or -COOEt. In certain cases, the nature of the leaving group L means that the resulting intermediate is in the 30 wrong oxidation state. Thus, where necessary, one or more reaction steps may be added to ensure the correct oxidation state is reached prior to cyclising to form the aryl pyrazole. Ideally, for the coupling reaction to form the compound of formula (II), the solvent should be a polar solvent which does not react with either the diazonium salt or cation, or with the compound of 35 formula (111). The reaction may optionally be carried out under mildly acidic conditions. 28 WO 2006/134459 PCT/IB2006/001566 The diazonium salt of formula (IV) can be produced by conventional means and may be prepared in situ for further reaction or can be isolated and used in a subsequent reaction step. For example, by the dropwise addition of a solution of the corresponding aminobenzenes in glacial acetic acid to a 5 solution of sodium nitrite in concentrated sulphuric/glacial acetic acid mixtures at reduced temperature, typically 100C, followed by heating at 500C for several hours, typically 1 hour and allowing to cool to room temperature. This solution of the diazonium salt is then added dropwise to a solution of a compound of formula (111) in a suitable solvent, such as acetic acid followed by stirring at room temperature for up to 1 hour. The reaction mixture is poured into water and extracted with a 10 water immiscible organic solvent such as dichloromethane. Aqueous ammonium hydroxide is added to the organic extract and stirred overnight to give compounds of formula (11).

R

3 R 4

R

8 2 N 7 Compounds of formula (11) may be used to prepare compounds of formula (V), wherein R', R 3 , R 4 ,

R

7 , R 8

R

9 and X are as defined for formula (1), provided R2 is an electron withdrawing group capable 15 of stabilising an a-anion, by alkylation with R 3 Y and R 4 Y, wherein Y is any suitable leaving group such as Cl, I, Br, OTos, OMes, in a suitable solvent, such as tetrahydrofuran, in the presence of base, such as potassium bis(trimethylsilyl)amide. Those skilled in the art will recognise that using appropriate reagents and reaction conditions either monoalkylation or bisalkylation may be achieved. By reaction with a bidentate electrophile, compounds of formula (11) may be converted to compounds 20 of formula (V), wherein R 3 and R 4 , together with the carbon atom to which they are both attached, are joined to form an optionally substituted carbocyclic or heterocyclic ring as defined in formula (1). Alternatively, compounds of formula (V) may be prepared, using the Jappe-Klingemann reaction as described above, from intermediates of formula (VI) wherein R 2 , R 3 and R 4 are as defined for 25 compounds formula (1), L is a leaving group as defined for compounds of formula (Ill) and R 9 = NH 2 CN L

R

3 NC

R

2 (VI) Compounds of formula (VI) can be obtained from compounds of formula (VII) wherein R , R 4 and L are as defined for formula (VI), for example, by treating a compound of formula (VII) with a source of cyanide ions. 29 WO 2006/134459 PCT/IB2006/001566 ON L R R R R 2 (Vil) Compounds of formula (VII) can be obtained by reducing and then dehydrating a compound of formula (Vill). ON L R 3

R

4 o R 2 (Vill) 5 Compounds of formula (Vill) can, for example, be made by condensation of an alkyl cyanoalkanoate e.g. methyl cyanoacetate with an acid chloride in an aprotic solvent such as dichloromethane in the presence of a Lewis acid, such as magnesium chloride and a mild base, such as triethylamine, at reduced temperature. 10 Alternatively, compounds of formula (VII) can be accessed by Knoevenagel condensation of a suitable aldehyde or ketone with an alkyl alkanoate such as methyl cyanoacetate. The above reactions are particularly successful where in compounds of formula (11), (111), (IV), (V), (VI), (VII) and (VillI) R 2 is C(0)0C1-6 alkyl. 15 In addition, variations to the Japp-Klingemann reaction, utilising standard conditions well-known to those skilled in the art, for producing compounds of formula (1) and its precursors, are also intended to fall within the scope described in the present invention. For example, coupling of an aryldiazonium species with precursors of formula (IX): 0 alkylO Oalkyl CN 0 20 (IX) in the presence of a suitable base, may be useful in accessing compounds in which R 9 is OH. These compounds may then undergo standard alkylation, acylation, carbamoylation, sulphonation and other standard well known procedures to produce, for example, the corresponding alkoxy derivatives. 25 Alternatively, arylpyrazoles may be prepared by the reaction of optionally substituted phenylhydrazine derivatives with compounds of formula (X) or (XI): 30 WO 2006/134459 PCT/IB2006/001566 0 0 alkylKO R alkylKO- R7 0 0 0 (X) (XI) in which R 1 7 is C 1

.

4 alkyl or C 3

.

8 cycloalkyl. A compound of formula (11) may be converted to the diazonium salt of formula (XII): N2 2 R

CH

3 N R R X (XII) 5 R wherein R', R , R 8 , R 9 and X are as previously defined for formula (1), by reaction with an aryl sulphonylazide, in the presence of a suitable base, for example DBU. Diazonium salts of formula (XII) are versatile intermediates. 10 Compounds of formula (XII) may react with a wide range of nucleophiles, in a suitable solvent, typically dichloromethane, in the presence of-a suitable metal catalyst, such as rhodium tetraacetate, to give compounds of formula (V) wherein R 3 is for example,, without limitation, -Salkyl, -Oalkyl, Ocycloalkyl, -Oaryl, -Oheteroaryl wherein these substituents are as defined in compounds of formula (1) and, furthermore, may be optionally substituted as defined in compounds of formula (1). 15 Compounds of formula (XII) will undergo carbenoid addition reactions using standard literature procedures well known to those skilled in the art, for example C-H insertion reactions and cyclopropanation procedures. Compounds of formula (1i) may undergo a-bromination by reaction with typical brominating agents 20 e.g. N-bromosuccinimide in the presence of light or a catalytic quantity of a radical initiator to give compounds of formula (V) wherein R 3 = Br. These bromo compounds of formula (V) undergo standard nucleophilic substitution reactions as described in organic textbooks or literature precedent. 25 Alternatively, compounds of formula (11) may be a-hydroxylated by a variety of standard literature procedures. For example, reaction with TMS chloride in the presence of a suitable base, to give the enolate salt followed by reaction with a peracid, such as m-chloroperbenzoic acid, and subsequent removal of TMS can be used to prepare compounds of formula (V) wherein R 3 is OH. These hydroxy compounds of formula (V) wherein R 3 is OH may be alkylated, acylated and suiphonylated using 30 literature procedures well known to those skilled in the art. Similarly, compounds of formula (V) 31 WO 2006/134459 PCT/IB2006/001566 wherein R 3 is -Oacetyl may be prepared from compounds of formula (II) using manganese triacetate in a suitable solvent, typically acetic acid, optionally with an added inorganic salt, such as lithium chloride. 5 Compounds of formula (V), wherein R 3 is Cl may be prepared from compounds of formula (V) wherein R 3 is -OH by reaction with thionyl chloride. These chloro compounds undergo nucleophilic substitution reactions as described in organic textbooks or literature precedent; such nucleophiles include, without limitation, substituted thiols, mono and di-substituted amines, cyanide, and cyclic amines such as pyrrolidine, 10 Compounds of formula (V), wherein R 3 is -OH, may be prepared by the reduction of compounds of formula (XIII) using standard literature reduction procedures, typically sodium borohydride in a suitable solvent. 0 R R .N R RR7 R (XIII) 15 Compounds of formula (XIII) undergo organometallic additions using standard literature procedures. For example, a compound of formula (XIII), wherein R 2 = CF 3 is stirred with trimethylamine N-oxide and molecular sieves in tetrahydrofuran under nitrogen for 30 minutes. (Trifluoromethyl)trimethylsilane can be added dropwise over an hour followed by stirring at room temperature for several days, typically 3 days yielding compounds of formula (1) wherein R 2 = CF 3 , 20 R 3 = CF 3 and R 4 = OH. The a-hydroxyester products may be deoxygenated using literature procedures to give compounds of formula (V) wherein R 3 can be alkyl, cycloalkyl, aryl and heteroaryl as defined for formula (1). The a-hydroxyester products may also be alkylated to give compounds of formula (V) wherein R 3 can be alkyl, cycloalkyl, aryl and heteroaryl as defined for formula (1) and R 4 is an O-linked substituent as defined in formula (1). 25 Compounds of formula (XIII) may be prepared from compounds of formula (XIV) by sequential reaction with osmium tetroxide and sodium periodate in a suitable solvent, typically acetone. R' R 2 N R R (XIV) R3 32 WO 2006/134459 PCT/IB2006/001566 Compounds of formula (XIV) undergo a wide range of reactions described in organic textbooks or literature precedent. Nucleophilic addition to the a, p-unsaturated ester may be achieved using organometallic reagents such as organocuprates and Grignard reagents, cyanide ions, mono- and disubstituted amines, substituted thiolate anions, substituted alcoholate anions and heterocyclic 5 anions. Literature Heck coupling procedures lead to the expected products which can be reduced or cyclopropanated using procedures well known to those skilled in the art. Epoxidation of the a, p unsaturated ester may be achieved using a range of oxidising agents, typically a peracid such as m chloroperbenzoic acid. These epoxides undergo standard literature nucleophilic epoxide ring opening reactions. Reduction of the alkene to give compounds of formula (1), wherein R 3 = CH 3 can 10 be achieved using standard literature reagents, such as sodium borohydride in a suitable solvent, such as ethanol. Furthermore, compounds of formula (XIV) may be carbonylated using standard techniques to give compounds of formula (V) wherein R 3 is -CH 2 COOH and R 4 is -H; this acid functionality may be 15 converted to -CN, substituted amides or heterocycles using reactions described in organic textbooks or literature precedent. Reduction, for example with sodium borohydride, gives compounds of formula (V) wherein R 3 is -CH 2

CH

2 OH which may be tosylated and then reacted with a wide range of nucleophiles to give compounds of formula (1) 20 An alternative product of the carbonylation of compounds of formula (XIV) is a compound of formula (V), wherein R 3 is -CHO and R 4 is -CH 3 . This aldehyde may be reacted with diethylamino sulphur tetrafluoride to give a compound of formula (V) wherein R 3 is -CHF 2 and R 4 is -CH 3 . This aldehyde also undergoes functional group interconversions as described in organic textbooks or literature precedent. 25 Compounds of formula (XIV) can be synthesized using an organozinc reagent of formula (XV):

R

8 Zn-halo jR9 N R X (XV) R wherein R1, R 7 , R 8 , R 9 and X are as previously defined for formula (1). The organozinc reagent formula (XV) may be obtained by treatment of (XVI), wherein halo is preferably bromo or iodo, with 30 activated zinc (Rieke zinc) in an aprotic solvent such as tetrahydrofuran, for several hours. The organozincate can then be cross coupled to a haloalkene in the presence of a palladium (i) species such as dichlorobis(triphenylphosphine) palladium (11) and a reducing agent such as diisobutylaluminium hydride in an aprotic solvent such as tetrahydrofuran, at elevated temperatures, 33 WO 2006/134459 PCT/IB2006/001566 normally at ref lux. R halo NsN R9 R 7 (XVI) R 1 Alternatively, a compound of formula (XIV) may be obtained directly by the reaction of a compound of formula (XVI) with an organostannane in the presence of a metal catalyst such as 5 tetrakis(triphenylphosphine)palladium(0) at an elevated temperature for several hours. Alternatively, compounds of formula (XIV) may be prepared by dehydration of compounds of formula (I), wherein R 3 = OH and R 4 = CH 3 by converting the hydroxyl into a leaving group, for example by reaction with methane sulphonyl chloride, followed by by base catalysed elimination. A typical base 10 being triethylamine in a suitable solvent such as dichloromethane. A compound of formula (XVI) may be obtained from a compound of formula (XVIIA):

R

8 N 9 N R R 7 (XVIIA) R1 wherein R1, R , RE and R 9 are as previously defined for formula (1), by conventional bromination or 15 iodination procedures. For example, when halo is iodo, (XVIIA) is treated with N-iodosuccinimide in a suitable solvent such as adetonitrile at from about room temperature to about 85 C. Alternatively, a compound of formula (XVI) may be prepared as shown in Scheme 1 below: Scheme 1 R O R R R NH 2

R

8 R N 9 N$ N 9 "ci " R N N N R R 7-f-R -+N R 7R7 I |I |N RI RI R Ri 20 (XVII) (XVIII) (XIX) (XVI) wherein R', R , R 8 and X are as previously defined for formula (I) and R 9 is SRr, NRrRs or ORr 34 WO 2006/134459 PCT/IB2006/001566 wherein Rr and Rs are each independently H, alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl in accordance with the definition of R 9 informula (1), wherein each alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl may be optionally substituted. Compounds of formula (XVIII) can be prepared from compounds of formula (XVII) via standard 5 nucleophilic substitution procedures. The amine (XIX) may then be obtained by reduction using a suitable reducing agent, optionally in the presence of a catalyst, typically SnC 2 /HCI or Fe/CaCl 2 . Compounds of formula (XVI) may be prepared from (XIX) by conventional Sandmeyer procedures. Alternatively, a compound of formula (XX), wherein R', R 3 , R 7 , R 8 , R 9 and X are as previously 10 defined for formula (I), may be obtained by the reaction of a compound of formula (XVI) with a suitable Grignard reagent, such as isopropylmagnesium chloride, followed by the addition of a substituted pyruvate ester in a suitable solvent such as tetrahydrofuran.

O-CH

3 R O OH

R

3 R Compounds of formula (XX) may be deoxygenated to give compounds of formula (V), wherein R 2 = _ 15 COOCH 3 and R 4 = H, using a range of literature procedures well known to those skilled in the art. Compounds of formula (1), wherein R 2 = C(0)OC 6 alkyl and both R 3 and R 4 = H can be prepared by de-trifluoromethylation of a compound of formula (1) in which R 2 = C(0)OC 1

.

6 alkyl, R 3 = H, R 4 = CF 3 by stirring with potassium carbonate in acetonitrile with a few added drops of water for several hours, 20 typically overnight. The compound of formula (1) in which R 2 = C(O)OC 1

.

6 alkyl R 3 = H, R 4 = CF 3 can be prepared by the reduction of a compound of formula (1) in which R 2 C(O)0C 1

.

6 alkyl, R = Cl, R 4 =

CF

3 . A particularly useful reducing agent is zinc in an aprotic solvent such as diethyl ether. In another aspect, the invention provides processes for the preparation of compounds of formula (1) 25 from alternative compounds of formula (1) through functional group interconversion. For example, saponification of a compound of (I) in which R 2 is a methyl ester to give the acid, may be achieved using standard ester hydrolysis conditions, such as adding tetrahydrofuran, water and lithium hydroxide and stirring at room temperature for from 1 to 60 h or by the addition of pyridine and lithium iodide and heating at elevated temperatures for an extended period of time. This acid can be 30 further reacted with secondary, tertiary or cyclic amine compounds or ammonia or ammonium hydroxide in the presence of a suitable base such as triethylamine and an activating agent, such as ethyl chloroformate, in a suitable solvent such as tetrahydrofuran to give the amide derivative. For example, to a compound of formula (1) in which R 2 is CO 2 H in tetrahydrofuran and triethylamine, 35 WO 2006/134459 PCT/IB2006/001566 cooled to 00C can be added ethyl chloroformate, cyclopropylmethylamine and in tetrahydrofuran and allowed to warm to room temperature to give a compound of formula (I) in which R2 is cyclopropanecarboxamide. 5 Compounds of formula (I), in which R 2 is a carboxylic acid, can be reduced by standard literature procedures, such as sodium borohydride, to give the corresponding alcohol. Furthermore, compounds of formula (I), in which R 2 is a carboxylic acid, can rearrange under standard Curtius conditions to carbamates which after deprotection gave compounds of formula (1) 10 wherein R 2 is NH 2 . Compounds of formula (I), wherein R 2 is NH 2 may also be prepared from compounds of formula (1) wherein R2 is halo. For example, ammonia is added to a solution of a compound of formula (1), wherein R 2 is chloro, in a suitable solvent, typically acetonitrile, followed by stirring at room temperature for several hours, typically 1 hour. Compounds of formula (1), in which

R

2 is NH 2 may be alkylated, acylated and sulphonylated using standard literature procedures. 15 Sulphonylation can be achieved by a room temperature reaction with a sulphonyl chloride in a suitable solvent, typically dichloromethane, in the presence of a suitable base, such as triethylamine. Both monosulphonamides and bis-sulphonamides may be obtained. Monosulphonamides may be further N-alkylated; for example by reaction with an alkyl halide, such as methyl iodide, in a suitable solvent, typically acetone, in the presence of a base, such as potassium carbonate. Generally, 20 reactants are mixed at OC followed by refluxing for several hours. Using standard reaction conditions, compounds of formula (1), wherein R 2 is an alkyl ester may be converted to amides, wherein R2 is CONH 2 . For example, trimethyl aluminium in hexane is added to ammonium chloride in a suitable solvent, typically toluene, at 00C, optionally under nitrogen. After 25 stirring for 1-2 hours at room temperature, a solution of a compound of formula (1), wherein R 2 is COalkyl, in a suitable solvent is added. Conversion to the amide is achieved by stirring at elevated temperature, typically 50 0 C for 15 - 80 hours. Similarly, transesterifications may be achieved by reaction with a substituted alcohol and hydroxylamides (R 2 is CONHOH) prepared by reaction with hydroxylamine. Acylhydrazones and bis-acylhydrazones 'may be similarly prepared using literature 30 conditions. These bis-acylhydrazones may be converted to 1,2,4-oxadiazoles by reaction with phosphorus oxychloride in a suitable solvent. Compounds of formula (1) in which R 2 is an amide may undergo standard alkylation reactions with compounds of formula Ra-Y and Rb-Y, in which Y is a suitable leaving group and Ra and Rb are as 35 defined for formula (1), to give the substituted amide. Persons skilled in the art will recognise that by choosing the appropriate reagents and conditions either monosubstituted or disubstituted amides may be formed. Compounds of formula (1) in which R 2 is an amide may undergo a functional group interconversion by refluxing with Lawesson's reagent for several hours in a suitable solvent, typically tetrahydrofuran, to produce the thioamide or be dehydrated by reaction with trifluoroacetic anhydride 36 WO 2006/134459 PCT/IB2006/001566 and 1,4-dioxane in pyridine at 00C for several hours to give the nitrile, wherein R 2 is CN. Compounds of formula (1) in which R 2 is aminomethyl may be obtained via formation of the thioalkylated intermediate formed by treatment of (1) in which R 2 is a thioamide, with an alkylating 5 agent such as triethyloxonium tetrafluoroborate, in a suitable solvent, typically dichloromethane, at 00C and then by stirring at room temperature for an extended period of time, followed by reduction with sodium borohydride at 00C. Compounds of formula (1) in which R 2 is thioamide may be reacted with haloketones or 10 haloaldehydes to give (1) in which R 2 is substituted thiazole. Similarly, reaction with acylhydrazides to give compounds of formula (1) in which R 2 is substituted triazole. Compounds of formula (I) in which R2 is aminomethyl can be further treated with an acid anhydride, in a suitable solvent, typically dichloromethane and a mild base such as triethylamine and stirring at 15 room temperature for an extended period of time, typically 60 hours, to give the corresponding amide. Furthermore compounds of formula (1) in which R is aminomethyl can be monosulphonated or disulphonated with alkyl or aryl sulphonyl halides under standard conditions well-known to those 20 skilled in the art. Compounds of formula (1), wherein R2 is Cl may be prepared from compounds of formula (I) wherein

R

2 is -OH by reaction with thionyl chloride in a suitable solvent, such as dichloroethane. Reagent is added dropwise at room temperature, followed by heating at elevated temperature, typically 600C, 25 for 5 - 25 hours, typically overnight. These chloro compounds undergo nucleophilic substitution reactions as described in organic textbooks or literature precedent; such nucleophiles include, without limitation, substituted thiols, mono and di-substituted amines, cyanide,. and cyclic amines such as pyrrolidine, 30 Compounds of formula (1), wherein R 2 is OH may be prepared by the reduction of ketones of formula (1), in which R 2 and R 3 are oxo using standard reducing agents, such as sodium borohydride, or those described in "Handbook of Reagents for Organic Synthesis -Oxidising and Reducing Agents" edited by S.D.Burke and R.L.Danheiser 35 Compounds of formula (1) in which R 2 is halo can undergo standard nucleophilic substitution reactions by refluxing with a suitable acid catalyst such as p-toluenesulphonic acid and an alkylthiol or alcohol for an extended period of time, typically from 18 hours to several days, to produce the corresponding ether or thioether respectively. Compounds of formula (1) in which R 2 is halo can also undergo base catalysed standard nucleophilic substitution reactions with nucleophiles such as 37 WO 2006/134459 PCT/IB2006/001566 cyanide ion, alkylthiols and primary or secondary amines in a suitable solvent, such as acetonitrile. Reactions are stirred at room temperature for 2 - 24 hours and a typical base is potassium carbonate. Compounds of formula (1) in which R 2 is -Salkyl can be oxidised to the corresponding sulphines or sulphones using standard oxidizing agents, such as m-chloroperoxybenzoic acid or 5 those described in "Handbook of Reagents for Organic Synthesis -Oxidising and Reducing Agents" edited by S.D.Burke and R.L.Danheiser Compounds of formula (1) in which R 2 contains a secondary alcohol can be oxidized, for example by stirring with Dess Martin Periodinane at room temperature for 30 minutes in a suitable solvent, 10 typically dichloromethane, to produce the corresponding ketone Compounds of formula (1) in which R 9 is NH 2 may be used to synthesis imines by reacting the amino functionality of formula (I) with aldehydes and an appropriate acid catalyst, typically p toluenesulphonic acid at room temperature, for an extended period of time, typically 16 hours or with 15 aldehydes in the presence of a mild reducing agent such as sodium triacetoxyborohydride and a mild base to form secondary amines. For example, a compound of formula (I) in which R 9 is NH 2 undergoes reaction with isonicotinaldehyde and a mild base to give the corresponding imine functionality which can be further reduced by reaction with a suitable reducing agent such as sodium hydride to give the secondary amine. This can be further oxidized using standard procedures to give 20 the N-oxide. Similarly, compounds of formula (1) in which R 9 is NH 2 may be reacted with optionally substituted ketones. Compounds of formula (1) in which R 9 is NH 2 , can undergo reaction with triethyl orthoformate in acidic conditions, by heating at elevated temperatures, typically 60 0 C, for several, typically from 2 to 25 4 hours, to give (1) in which R9 is -N=CHOC 2

H

5 . This can, in turn, be further reduced by a suitable reducing agent, such as sodium borohydride, to give a compound of formula (I) in which R 5 is NHCH 3 . Compounds of formula (1) in which R 9 is NH 2 may be functionalised in a similar manner A compound of formula (I) in which R 9 is H, may be prepared by the diazotisation of a compound of 30 formula (I) in which R 9 is NH 2 by a variety of standard diazotisation procedures. For example, the reaction of a compound of formula (I), wherein R 9 is NH 2 , with isoamyl nitrite in a suitable aprotic solvent, such as acetonitrile, at room temperature for 5 - 30 hours, typically 18 hours. In a similar manner, compounds of formula (I) in which R 9 is -Salkyl, may be formed by coupling the 35 diazonium species formed from a compound of formula (I) in which R 9 is NH 2 and an appropriate nucleophile such as (alkylS) 2 . Furthermore, compounds of formula (1) in which R 9 is S-alkyl may be oxidised, using standard oxidising agents, such as hydrogen peroxide, to give the corresponding sulphines and sulphones. 38 WO 2006/134459 PCT/IB2006/001566 Compounds of formula (1) in which R 9 is NH 2 , can be converted to give a compound of formula (1) wherein R 9 is halo, utilising standard Sandmeyer reaction conditions. For example, the reaction of a compound of formula (I), wherein R 9 is NHa, with isoamyl nitrite in a suitable aprotic solvent, such as acetonitrile, in the presence of cuprous chloride yields compounds of formula (1), wherein R 9 is Cl. 5 These halo compounds may be used in standard organometalic coupling procedures, for example in the preparation of a compound of formula (I) in which R 9 = -CF 3 . Compounds of formula (I), wherein R 9 = OH can be alkylated using standard literature procedures. For example by reaction with an alkyl halide in a suitable solvent, such as acetonitrile, in the 10 presence of a suitable base, typically potassium carbonate at elevated temperatures, 45 - 600C, for several hours, typically 3 hours. Compounds of formula (I) in which R 9 is CH 2 Y, in which Y is a suitable leaving group such as halo, may, in the presence of a suitable base, undergo a wide range of nucleophilic substitution reactions 15 well known to those skilled in the art. Furthermore, compounds of formula (I) in which R 9 is -NH 2 or aminoalkyl can be monosulphonated or disulphonated with alkyl or aryl sulphonyl halides under standard conditions well-known to those skilled in the art, to give the corresponding sulphonamides. 20 Compounds of formula (I) in which R9 is -NH 2 , may also be converted to compounds of formula (1) in which R 9 is -CH 3 or -CHF 2 as shown in Scheme 2 below. Firstly, compounds (XXI) may be converted to (XXII) by the radical arylation of methyl acrylate with the corresponding diazonium salts. Compounds of formula (XXII) can be dehydrobrominated using standard conditions by stirring with 25 base, such as DBU, for several hours, to give enones, (XXIII). Conversion of (XXIII) to (XXIV) can be achieved via diol formation, utilising Os0 4 , followed by oxidative cleavage, using an oxidising agent such as sodium periodate, to generate the aldehyde. Aldehydes of formula (XXIV) may be reduced to give alcohols of formula (XXV) by stirring with a reducing agent, typically sodium borohydride or reacted further with a halogenating reagent such as diethylaminosulfur trifluoride to obtain a 30 compound of formula (I) in which R 9 is difluoromethyl. Reaction of (XXV) with thiony chloride and heating at reflux for several hours gives the intermediate chloro derivative from compounds of formula (XXVI) may then be obtained by reduction, for example using Rieke zinc. Scheme 2 39 WO 2006/134459 PCT/IB2006/001566 4

R

3

R

4 SR R R R 3 R4 R 2

R

8 9 R 6 2 HR 2 Br TH N 0 NN NH 2 : N N N R0 O R X R 7 O X 0 (XXI) (XXII) R (XXIII) R R

R

3

R

4

R

3

R

4

R

3

R

4 R 2 R R R R R 2 N'NN OH N R R N ~ NX (XXVI) (XXV) (XXIV) R R R Compounds of formula (XXIV) and (XXV) may be used to prepare compounds of formula (1) in which R9 encompasses a wide variety of carbon linked substituents. For eXample, (XXV) may be alkylated and acylated using standard literature procedures. Also, in (XXV), activation of the hydroxyl, such as 5 by mesylation or tosylation, gives an intermediate that undergoes a wide range of nucleophilic substitution reactions. The aldehyde, (XXIV) may be readily converted to the acid, nitrile, esters, amides and thioamides under standard conditions well-known to those skilled in the art. Standard Wittig olefination of the aldehyde (XXIV) may be followed by routine cyclopropanation procedures to give compounds in which R 9 is substituted cyclopropyl. For example, methylenation may be 10 achieved using the Wittig reaction, using a Peterson reagent, using a Tebbe reagent or using the Lombardt procedure. Organometallic addition to the aldehyde, (XXIV), followed by oxidation of the secondary alcohol, then Wittig olefination and cyclopropanation may be used to prepare compounds of formula (XXVII), for example wherein R 1 = -CF 3 . 15 Such cyclopropanation methods may include treatment with a reactive species such as trimethylsily difluoro(fluorosulfonyl)acetate (TFDA) at reflux in the presence of sodium fluoride, as described by Dolbier et al., in J. Fluor Chem., 2004, 125, 459. Other methods for in situ carbenoid generation include treatment of chloroform or bromoform with base, preferably under phase transfer catalysis conditions, thermolysis of a suitable organometallic precursor such as an aryl trifluoromethyl, 20 trichloromethyl, tribromomethyl or phenyl(trifluoromethyl) mercury derivative or treatment with a diazoalkane in the presence of a transition metal catalyst and treatment with a diazoalkane in the absence of a transition metal catalyst followed by thermolysis of the intermediate pyrazoline, or generation from a sulphur ylid. 40 WO 2006/134459 PCT/IB2006/001566

R

3

R

4 RS N/ R22 N. N Ry R12 (XXVII) RI Alternatively, organometallic addition to the aldehyde, (XXIV), followed by elimination of the hydroxyl group using standard procedures such as reaction with SOC1 2 in the presence of a zinc catalyst, may be a. means to generate compounds of formula,(I) in which R 9 is optionally substituted alkyl, 5 optionally substituted aryl or arylalkyl and optionally substituted heteroaryl or heteroarylalkyl in accordanced with the definition of R 9 for formula (1). Compounds of formula (XXIV) may also undergo standard Knovenagel type reactions, followed by reduction and partial hydrolysis and heating at elevated temperature to give the corresponding ester derivative which may be further derivatised. Alternatively, methylenation of compounds of formula (XXIV) may be readily achieved 10 utilising standard known reactions such as the Wittig or the Horner-Wadsworth-Emmons reaction. The resulting compounds of formula (I) in which R 9 is vinyl, may be hydroxylated using standard conditions such as by reaction with hydrogen peroxide and a suitable base to give compounds in which R 9 is -CH 2

CH

2 OH. These compounds can, in turn, be further oxidised to give the corresponding aldehydes and acids, i.e. where R 9 is -CH 2 CHO or -CH 2 COOH. These aldehydes 15 undergo reactions well known to those skilled in the art, such as Wittig olefination reductive amination. The acids undergo the Curtius rearrangement o give compounds of formula (1), in which

R

9 is -CH 2

NH

2 , which may be alkylated, acylated, sulphonylated and other electrophiles. Furthermore, compounds in which R 9 is -CH 2

CH

2 OH may be activated for example by the addition of SOC12 or TsCI and further reacted with a wide range of nucleophiles such as ~CN, ~SR or 'OR to 20 achieve the corresponding alkylated derivative. Alternatively, standard known catalysed cross coupling reactions, such as the Heck reaction, may be employed to generate compounds of formula (I) in which R 9 is substituted vinyl from the vinyl derivative. 25 Oxidation of compounds of formula (XXIV) using standard reaction conditions followed by further derivatisation of the acid formed may be a means of accessing compounds of formula (1) in whch R 9 is a heterocyclic moiety. For example, the oxidised product may undergo reaction with substituted acyl hydrazides to give oxadiazoles. Those skilled in the art will recognise that a wide variety of 30 optionally substituted heterocycles may be synthesised from the aldehydes (XXIV) or the corresponding acids. These acids may also be derivatised using standard literature procedures. A compound of formula (1) in which R" is -C(O)SCH 3 may be prepared from (1) RB = -CN by the acid catalysed addition of methanethiol by heating under pressure at elevated temperatures, typically 41 WO 2006/134459 PCT/IB2006/001566 800C for several hours, typically 16 hours. Compounds of formula (1) in which R 8 is -CN may undergo reactions of nitriles as recorded in organic chemistry textbooks and literature precedent. It will also be appreciated by persons skilled in the art that, within certain of the processes described, 5 the order of the synthetic steps employed may be varied and will depend inter afla on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates, and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent for use in the said synthetic steps. 10 The skilled person will appreciate that the compounds of the invention could be made by methods other than those herein described, by adaptation of the methods herein described and/or adaptation of methods known in the art, for example the art described herein, or using standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later editions). 15 It is to be understood that the synthetic transformation methods mentioned herein are exemplary only and they may be carried out in various different sequences in order that the desired compounds can be efficiently assembled. The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound. 20 The present invention also relates to intermediates of formula (XXX) below: 4 4R2 N N=\ RG

R

7 \ Rd R1 (xxx) where: R1 - R 8 , X, R*, Rd, n, R 1 1 and het are all as defined for formula (I) above; or a pharmaceutical salt or 25 a prodrug thereof. With reference to formula XXX), suitably Rc = Rd = methyl. The present invention also relates to further intermediates of formula (XXXI) below: 42 WO 2006/134459 PCT/IB2006/001566 R4 N RR 3 R7 0 -3 Ri (XXXI) where: R' - R", X, n, R" and het are all as defined for formula (1) above; where R 5 4 is independently selected from hydrogen, C1.6 alkyl, C3.8 cycloalkyl, C.8 cycloalkylC 1

.

6 alkyl, C 2 - alkenyl, C1.6 alkanoyl, 5 C(O)OC1.6 alkyl, het, phenyl and S(O)nR 1 1 ; or a pharmaceutical salt or a prodrug thereof. With reference to formula (XXXI), suitably R5 0 is methyl. It will be understood that throughout the application all references to formula (1) apply equally to compounds of the formulas (XXX) and (XXXI). Furthermore, it will be understood that all the suitable 10 groups and preferences applied to R' - R 8 , X, Rc, Rd, n, R 1 1 and het above for formula (I) apply equally to compounds of the formulas (XXX) and (XXXI). This invention also relates to a pharmaceutical composition comprising a compound of formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, 15 together with a pharmaceutically acceptable diluent or carrier, which may be adapted for oral, parenteral or topical administration. Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions 20 and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995). The compounds may be administered alone or in a formulation appropriate to the specific use envisaged, the particular species of host mammal being treated and the parasite involved or as 25 appropriate for the agricultural pest being treated and the crop designated for treatment. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the 30 nature of the dosage form. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, for example, spray-dried dispersions or as produced by melt-extrusion or nano 43 WO 2006/134459 PCT/IB2006/001566 milling. They may be obtained, for example, as solid plugs, powders, or films (for example, rapid dissolving or mucoadhesive films) by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. 5 The methods by which the compounds may be administered include oral administration by capsule, bolus, tablet, powders, lozenges, chews, multi and nanoparticulates, gels, solid solution, films, sprays, or liquid formulation. Liquid forms include suspensions, solutions, syrups, drenches and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise 10 a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. Oral drenches are commonly prepared by dissolving or suspending the active ingredient in a suitable medium. 15 Thus compositions useful for oral administration may be prepared by mixing the active ingredient with a suitable finely divided diluent and/or disintegrating agent and/or binder, and/or lubricant etc. Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents. 20 For oral dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. Examples of suitable disintegrants for use herein include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium 25 alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Examples of suitable binders for use herein include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural 30 and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Examples of diluents include lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. 35 Oral formulations may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 wt% to 5 wt% of the tablet, and glidants may comprise from 0.2 wt% to 1 wt% of the tablet. 44 WO 2006/134459 PCT/IB2006/001566 Lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. 5 Exemplary tablets contain up to about 80% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant. The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. 10 Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X). The compounds may be administered topically to the skin, that is dermally or transdermally. The compounds may also be administered via the mucosa or mucous membranes. Typical formulations for this purpose include pour-on, spot-on, dip, spray, mousse, shampoo, powder formulation, gels, 15 hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Pour-on or spot-on 20 formulations may be prepared by dissolving the active ingredient in an acceptable liquid carrier vehicle such as butyl digol, liquid paraffin or a non-volatile ester, optionally with the addition of a volatile component such as propan-2-ol. Alternatively, pour-on, spot-on or spray formulations can be prepared by encapsulation, to leave a residue of active agent on the surface of the animal. 25 Injectable formulations may be prepared in the form of a sterile solution which may contain other substances, for example enough salts or glucose to make the solution isotonic with blood. Acceptable liquid carriers include vegetable oils such as sesame oil, glycerides such as triacetin, esters such as benzyl benzoate, isopropyl myristate and fatty acid derivatives of propylene glycol, as well as organic solvents such as pyrrolidin-2-one and glycerol formal. The formulations are prepared 30 by dissolving or suspending the active ingredient in the liquid carrier such that the final formulation contains from 0.01 to 10% by weight of the active ingredient. These formulations may be self preserving, self-sterilising or may be non-sterile to which preservatives may be optionally added. Equally suitably the compounds can be administered parenterally, or by injection directly into the 35 blood stream, muscle or into an internal organ. Suitable routes for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, 45 WO 2006/134459 PCT/IB2006/001566 carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as powdered a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by Iyophilisation, may readily be 5 accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility enhancing agents. 10 Such formulations are prepared in a conventional manner in accordance with standard medicinal or veterinary practice. These formulations will vary with regard to the weight of active compound contained therein, depending on the species of host animal to be treated, the severity and type of infection and the 15 body weight of the host. For parenteral, topical and oral administration, typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is 0.1 to 10mg per kg. Formulations may be immediate or be designed to have a controlled or modified release profile. 20 Modified release formulations include those formulations which have a delayed-, sustained-, pulsed-, targeted, or programmed release. Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve 25 controlled release is described in WO 00/35298. Alternatively, compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug coated stents and PGLA microspheres. 30 As an alternative the compounds may be administered to a non-human animal with the feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed. All aqueous dispersions, emulsions or spraying mixtures of the present invention can be applied, for 35 example, to crops by any suitable means, chiefly by spraying, at rates which are generally of the order of about 100 to about 1,200 liters of spraying mixture per hectare, but may be higher or lower (eg. low or ultra-low volume) depending upon the need or application technique. The compounds or compositions according to the invention are conveniently applied to vegetation and in particular to roots or leaves having pests to be eliminated. Another method of application of the compounds or 46 WO 2006/134459 PCT/IB2006/001566 compositions according to the invention is by chemigation, that is to say, the addition of a formulation containing the active ingredient to irrigation water. This irrigation may be sprinkler irrigation for foliar pesticides or it can be ground irrigation or underground irrigation for soil or for systemic pesticides. 5 Concentrated suspensions, which can be applied by spraying, are prepared so as to produce a stable fluid product which does not settle (fine grinding) and usually contain from about 10 to about 75% by weight of active ingredient, from about 0.5 to about 30% of surface-active agents, from about 0.1 to about 10% of thixotropic agents, from about 0 to about 30% of suitable additives, such as anti foaming agents, corrosion inhibitors, stabilizers, penetrating agents, adhesives and, as the carrier, 10 water or an organic liquid in which the active ingredient is poorly soluble or insoluble Some organic solids or inorganic salts may be dissolved in the carrier to help prevent settling or as antifreezes for water. Wettable powers (or powder for spraying) are usually prepared so that they contain from about 10 to 15 about 80% by weight of active ingredient, from about 20 to about 90% of a solid carrier, from about 0 to about 5% of a wetting agent, from about 3 to about 10% of a dispersing agent and, when necessary, from about 0 to about 80% of one or more stabilizers and/or other additives, such as penetrating agents, adhesives, anti-caking agents, colorants, or the like. To obtain these wettable powders, the active ingredient(s) is (are) thoroughly mixed in a suitable blender with additional 20 substances which may be impregnated on the porous filler and is(are) ground using a mill or other suitable grinder. This produces wettable powders, the wettability and the suspendability of which are advantageous. They may be suspended in water to give any desired concentration and this suspension can be employed very advantageously in particular for application to plant foliage. 25 "Water dispersible granules (WG)" (granules which are readily dispersible in water) have compositions which are substantially close to that of the wettable powders. They may be prepared by granulation of formulations described for the wettable powders, either by a wet route (contacting finely divided active ingredient with the inert filler and a little water, e.g. 1 to 20% by weight, or with an aqueous solution of a dispersing agent or birider, followed by drying and screening), or by a dry 30 route (compacting followed by grinding and screening). The rates and concentrations of the formulated compositions may vary according to the method of application or the nature of the compositions or use thereof. Generally speaking, the compositions for application to control arthropod, plant nematode, helminth or protozoan pests usually contain 35 from about 0.00001 % to about 95%, more particularly from about 0.0005% to about 50% by weight of one or more compounds of formula (I), or pesticidally acceptable salts thereof, or of total active ingredients (that is to say the compound of formula (1), or a pesticidally acceptable salt thereof, together with: other substances toxic to arthropods or plant nematodes, anthelmintics, anticoccidials, synergists, trace elements or stabilizers). The actual compositions employed and their rate of 47 WO 2006/134459 PCT/IB2006/001566 application will be selected to achieve the desired effect(s) by the farmer, livestock producer, medical or veterinary practitioner, pest control operator or other person skilled in the art. The compounds of the invention may be combined with soluble macromolecular entities, such as 5 cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms 10 and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148. 15 Compounds of the present invention may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). For example, compounds of the invention can also be mixed with one or more biologically active compounds or agents including insecticides, acaricides, anthelmintics, fungicides, 20 nematocides, antiprotozoals, bactericides, growth regulators, vaccines (including live, attenuated or killed vaccines), entomopathogenic bacteria, viruses or fungi to form a multi-component pesticide giving an even broader spectrum of pharmaceutical, veterinary or agricultural utility. Thus, the present invention also pertains to a composition comprising a biologically effective amount of compounds of the invention and an effective amount of at least one additional biologically active 25 compound or agent and can further comprise one or more of surfactant, a solid diluent or a liquid diluent. Specific further active compounds include those described in International Patent Application No WO 2005/090313, at pages 39 to 44. Inasmuch as it may desirable to administer a combination of active compounds, for example, for the 30 purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. 35 Thus this invention also relates to a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (1) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. 48 WO 2006/134459 PCT/IB2006/001566 The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically 5 comprises directions for administration and may be provided with a so-called memory aid. The compounds of the invention, i.e. those of formula (1), possess parasiticidal activity in humans, animals, insects and plants. They are particularly useful in the treatment of ectoparasites. 10 This invention also relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a pharmaceutical composition containing any of the foregoing, for use as a medicament. A further aspect of this invention relates to the use of a compound of formula (1), or a 15 pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, for the manufacture of a medicament for the treatment of a parasitic infestation. As used herein the term "long duration of action" shall be taken to mean compounds which have a duration of action of 14 days or greater, more preferably of 21 days or greater and most preferably of 20 28 days or greater. In one embodiment this invention is useful for the manufacture of a medicament for the treatment of a parasitic infestation in humans. 25 In one embodiment this invention is useful for the manufacture of a medicament for the treatment of a parasitic infestation in animals. An even further aspect of this invention relates to a method of treating a parasitic infestation in a which comprises treating said animal with an effective amount of a compound of formula (1), or a 30 pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a pharmaceutical composition containing any of the foregoing. A yet further aspect of this invention relates to a method of preventing a parasitic infestation in a animal which comprises treating said animal with an effective amount of a compound of formula (1), 35 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a pharmaceutical composition containing any of the foregoing. In a still further embodiment this invention also relates to a method of controlling disease transmission in an animal which comprises treating said animal with an effective amount of a 49 WO 2006/134459 PCT/IB2006/001566 compound of formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a pharmaceutical composition containing any of the foregoing. In one embodiment this invention is useful for the manufacture of a medicament for the treatment of 5 a parasitic infestation in plants. According to another aspect of the present invention, there is provided a method for the control of arthropod, plant nematode or helminth pests at a locus which comprises the treatment of the locus (e.g. by application or administration) with an effective amount of a compound of general formula (1), 10 or a pesticidally acceptable salt thereof. According to a yet further aspect of the present invention, there is provided a method for the control or eradication of a parasitic infestation from the environment, for example the living or accommodation areas of an animal, particularly a companion animal, which comprises treating said 15 animal with an effective amount of a compound of formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a pharmaceutical composition containing any of the foregoing. For the avoidance of doubt, references herein to "treatment" as used herein includes references to 20 curative, palliative and prophylactic treatment, references to "control" (of parasites and / or pests etc.) include kill, repel, expel, incapacitate, deter, eliminate, alleviate, minimise, eradicate. The compounds of the invention have utility in the control of arthropod pests. They may have activity against resistant strains where control is not achievable by known parasiticides or combinations 25 thereof. They may, in particular, be used in the fields of veterinary medicine, livestock husbandry and the maintenance of public health: against arthropods which are parasitic internally or externally upon humans and animals, including mammals, poultry and fish. Examples of mammals include domestic animals such as dogs, cats, cattle, sheep, goats, equines, swine. Examples of arthropods include Acarina, including ticks (e.g. Ixodes spp., Boophilus spp. e.g. Boophilus microplus, 30 Amblyomma spp., Hyalomma spp., Rhipicephalus spp. e.g. Rhipicephalus appendiculatus, Haemaphysalis spp., Dermacentor spp., Ornithodorus spp. (e.g. Omithodorus moubata), mites (e.g. Damalinia spp., Dermanyssus gallinae, Sarcoptes spp. e.g. Sarcoptes scabiei, Psoroptes spp., Chorioptes spp., Demodex spp., Eutrombicula spp.); Diptera (e.g. Aedes spp., Anopheles spp., Muscidae spp. e.g. Stomoxys calcitrans and Haematobia irritans, Hypoderma spp., Gastrophilus 35 spp., Simulium spp.); Hemiptera (e.g. Triatoma spp.); Phthiraptera (e.g. Damalinia spp., Linognathus spp.); Siphonaptera (e.g. Ctenocephalides spp.); Dictyoptera (e.g. Periplaneta spp., Blatella spp.) and Hymenoptera (e.g. Monomorium pharaonis). The compounds of the present invention also have utility in the field of control of plant pests, soil inhabiting pests and other environmental pests. Specific further arthropod pests include those described in International Patent Application No WO 50 WO 2006/134459 PCT/IB2006/001566 The present invention is particularly useful in the control of arthropod pests in humans and animals, particularly mammals. Preferably this invention is useful in the control of arthropod pests in animals 5 which includes livestock such as cattle, sheep, goats, equines, swine and companion animals such as dogs and cats. The compounds of the invention are of particular value in the control of arthropods which are injurious to, or spread or act as vectors of diseases in, man and domestic animals, for example those 10 hereinbefore mentioned, and more especially in the control of ticks, mites, lice, fleas, midges and biting, nuisance and myiasis flies. They are particularly useful in controlling arthropods which are present inside domestic host animals or which feed in or on the skin or suck the blood of the animal, for which purpose they may be administered orally, parenterally, percutaneously or topically. 15 The compounds of the invention are of value for the treatment and control of the various lifecycle stages of parasites including egg, nymph, larvae, juvenile and adult stages. According to another aspect of the present invention, there is provided a method for the control of arthropod pests of insects which comprises treatment of the insect with an effective amount of a 20 compound of general formula (1), or a pesticidally acceptable salt thereof. Compounds of the present invention may also be used for the treatment of infections caused by mites, and in particular varoaa mites. In particular compounds of the present invention may also be used for the treatment of varoaa mite infection in bees. 25 According to another aspect of the present invention, there is provided a method for the control of arthropod pests of plants which comprises treatment of the plant with an effective amount of a compound of general formula (1), or a pesticidally acceptable salt thereof. The compounds of the invention also have utility in the control of arthropod pests of plants. The active compound is generally applied to the locus at which the arthropod infestation is to be controlled at a rate of about 30 0.005 kg to about 25 kg of active compound per hectare (ha) of locus treated, preferably 0.02 to 2 kg/ha. Under ideal conditions, depending on the pest to be controlled, the lower rate may offer adequate protection. On the other hand, adverse weather conditions and other factors may require that the active ingredient be used in higher proportions. For foliar application, a rate of 0.01 to 1 kg/ha may be used. Preferably, the locus is the plant surface, or the soil around the plant to be 35 treated. According to another aspect of the present invention, there is provided a method for the protection of timber which comprises treatment of the timber with an effective amount of a compound of general formula (I), or a pesticidally acceptable salt thereof. Compounds of the present invention are also 51 WO 2006/134459 PCT/IB2006/001566 valuable in the protection of timber (standing, felled, converted, stored or structural) from attack by sawflies or beetles or termites. They have applications in the protection of stored products such as grains, fruits, nuts, spices and tobacco, whether whole, milled or compounded into products, from moth, beetle and mite attack. Also protected are stored animal products such as skins, hair, wool 5 and feathers in natural or converted form (e.g. as carpets or textiles) from moth and beetle attack; also stored meat and fish from beetle, mite and fly attack. Solid or liquid compositions for application topically to timber, stored products or household goods usually contain from about 0.00005% to about 90%, more particularly from about 0.001 % to about 10%, by weight of one or more compounds of formula (I) or pesticidally acceptable salts thereof. 10 The liquid compositions of this invention may, in addition to normal agricultural use applications be used for example to treat substrates or sites infested or liable to infestation by arthropods (or other pests controlled by compounds of this invention) including premises, outdoor or indoor storage or processing areas, containers or equipment or standing or running water. 15 The present invention also relates to a method of cleaning animals in good health comprising the application to the animal of compound of formula (1) or a veterinarily acceptable salt. The purpose of such cleaning is to reduce or eliminate the infestation of humans with parasites carried by the animal and to improve the environment in which humans inhabit. 20 The flea membrane feed test is used to measure the biological activities of the compounds claimed. The assay involves in vitro testing against Ctenocephalides felis conducted according to the following general procedure. 25 Fleas are cultured in vitro using dog blood. 25-30 adult Ctenocephalides felis (cat flea) were collected and placed in a test chamber (50ml polystyrene tube with fine nylon mesh sealing the end). Citrated dog blood was prepared by adding aqueous sodium citrate solution (10 ml, 20% w/v, 20g sodium citrate in 100 ml water) to dog blood (250 ml). Test compounds were dissolved in dimethylsulfoxide to give a working stock solution of 4 mg/ml. The stock solution (12.5 pl) was 30 added to citrated dog blood (5 ml) to give an initial test concentration of 10 pg/ml. For testing at 30pg/ml, working stock solutions of 12mg/ml were prepared. Citrated dog blood containing the test compound (5 ml, 1 OOg/ml) was placed into a plastic Petri dish lid, which was kept at 370C on a heated pad. Parafilm was stretched over the open top to form a 35 tight membrane for the fleas to feed through. The test chamber containing the fleas was placed carefully onto the parafilm membrane and the fleas commenced feeding. The fleas were allowed to feed for 2 hours and the test chambers were then removed and stored overnight at room temperature. 52 WO 2006/134459 PCT/IB2006/001566 The fleas were observed and the percentage of fleas killed recorded. Compounds were initially tested at 10pg/ml, wherefrom relevant dose responses (100, 30, 10, 3, 1, 0.3, 0.1pg/ml) were conducted and repeated n=5. Data was plotted to generate ED80, ED90 & ED95 values. 5 The compounds of the present invention have significantly better activity than the prior art compounds. All the Examples of the present invention have flea ED80 values of less than 1OOpg/ml. Results for some of the compounds are presented below. Example Flea feed ED80 results pg/ml 1 1 2 1 4 1 9 1 11 <1 15 1 10 EXAMPLES The following Examples illustrate the preparation of compounds of the formula (1). In the following experimental details, nuclear magnetic resonance spectral data were obtained using 15 Varian Inova 300, Varian Inova 400, Varian Mercury 400, Varian Unityplus 400, Bruker AC 300MHz, Bruker AM 250MHz or Varian T60 MHz spectrometers, the observed chemical shifts being consistent with the proposed structures. Mass spectral data were obtained on a Finnigan Masslab Navigator, a Fisons Instrument Trio 1000, or a Hewlett Packard GCMS System Model 5971 spectrometer. The calculated and observed ions quoted refer to the isotopic composition of lowest 20 mass. HPLC means high performance liquid chromatography. Room temperature means 20 to 25 0 C. Example 1 1-{5-amino-3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4 25 yl}cyclobutanecarboxamide 53 WO 2006/134459 PCT/IB2006/001566

NH

2 0 N' NH2 Cl CI

SF

5 To a solution of Preparation 23 (500 mg, 1.05 mmol) in tetrahydrofuran (12.5 ml), under nitrogen, was added triethylamine (0.29 ml, 2.10 mmol), followed by ethyl chloroformate (0.11 ml, 1.12 mmol) in tetrahydrofuran (0.5 ml), added dropwise. After stirring for 10 min, aqueous ammonium hydroxide 5 solution (29.7 wt%, 0.62 g, 5.25 mmol) was added and the reaction mixture was stirred under nitrogen for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (25 ml) and ethyl acetate (35 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (35 ml). The combined organic phases were washed with brine (25 ml), dried (MgSO 4 ) and concentrated in vacuo. The residue was dissolved in 10 acetonitrile/dimethyl sulphoxide (2.5 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm x 50 mm Sunfire LUNA C18 10pm column) using an acetonitrile : water [50:50 to 98:2] gradient. The appropriate fractions were combined and concentrated to give the titled compound (153 mg). Experimental MH* 475.9; expected 476.0 15 1 H-NMR (d 6 -DMSO): 1.80 - 1.93 (2H), 2.41 - 2.48 (2H), 2.62 - 2.70 (2H), 5.74 - 5.79 (2H), 7.13 - 7.19 (1 H), 7.27 - 7.33 (1 H), 8.41 - 8.44 (2H) Example 2 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}propanamide N

H

3 C

NH

2 0 N NH 2 C 1 CI 20 SFS To a mixture of Preparation 18 (1.91 g, 4.24 mmol) and triethylamine (0.65 ml, 4.66 mmol) in tetrahydrofuran (20 ml), at -100C, was added ethyl chloroformate (0.45 ml, 4.66 mmol). After stirring for 1 h at 00C, aqueous ammonium hydroxide solution (35%, 0.35 pl, 6.36 mmol) in tetrahydrofuran (3 ml) was added and the reaction mixture was stirred at room temperature for 18 h. To the reaction 25 mixture was added saturated brine solution (60 ml) and the mixture was extracted with ethyl acetate (3 x 25 ml). The combined extracts were dried (MgSO 4 ) and concentrated in vacuo. The residue was dissolved in acetonitrile/water (4 ml) and purified by automated preparative liquid 54 WO 2006/134459 PCT/IB2006/001566 chromatography (Gilson system, 150 mm x 30 mm LUNA C18(2) 10pm column) using an acetonitrile : water gradient [45:55 to 98:2]. The appropriate fractions were concentrated in vacuo to give the titled compound 1.87g. Experimental MH* 449.9; expected 450.0 5 1 H-NMR (d 6 -DMSO): 1.25 - 1.30 (3H), 3.50 - 3.56 (1H), 6.00 - 6.07 (2H), 7.00 - 7.03 (1H), 7.40 7.44 (1 H), 8.40 - 8.42 (2H) Example 3 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}-2-methylpropanamide N__ H-1C CH " NH2 N, O N NH 2 Cl Cl 10

SF

5 To a solution of Preparation 20 (280 mg, 0.60 mmol) in tetrahydrofuran (10 ml), at -100C and under nitrogen, was added triethylamine (167 pl, 1.20 mmol), followed by ethyl chloroformate (115 pl, 1.20 mmol). After stirring for 3 h at 00C, aqueous ammonium hydroxide solution (702 pl, 1.20 mmol) was added and the reaction mixture was stirred for a further 3 h at room temperature. To the reaction 15 mixture was added brine (10 ml) and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined extracts were dried (MgSO 4 ) and concentrated in vacuo. The residue was dissolved in acetonitrile (3 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm Phenomenex LUNA C18 10pm column) using an acetonitrile : water [45:55 to 95:5] gradient. The appropriate fractions were combined and concentrated to give the titled compound (84 20 mg). Experimental MH* 463.9; expected 464.0 1 H-NMR (CDC13): 1.73 - 1.78 (6H), 4.44 - 4.57 (2H), 5.36 - 5.44 (1H), 5.79 - 5.89 (1H), 7.88 - 7.91 (2H) 25 Similarly prepared were:

NH

2 0 R3 R4 N R9 CI Cl R1 Example R1 R3 R4 R9 From 55 WO 2006/134459 PCT/IB2006/001566 Example 4 CF 3 0 cyclobutyl NH 2 Preparation 24 Example 5 CF 3 cyclobutyl NH 2 Preparation 25 Example 6 SF 5 cyclobutyl NHCH 3 Preparation 26 Example 7 CF 3

CH

3 H NH 2 Preparation 19 Example 8 CF 3 4-fluorobenzyl H NH 2 Preparation 21 Example 9 CF 3

C

2

H

5 H NH 2 Preparation 22 Example 4 1 -{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethoxy)phenyl]-1 H-pyrazol-4 yl}cyclobutanecarboxamide 5 Experimental MH* 434.0; expected 434.0 'H-NMR (d 6 -DMSO): 1.79 - 1.92 (2H), 2.41 - 2.48 (2H), 2.61 - 2.70 (2H), 5.65 - 5.72 (2H), 7.12 - 7.19 (1 H), 7.26 - 7.33 (1 H), 7.90 - 7.93 (2H) Example 5 1-{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazol-4 10 yl}cyclobutanecarboxamide Experimental MH* 418.1; expected 418.0 1 H-NMR (d 6 -DMSO): 1.80 - 1.92 (2H), 2.41 - 2.48 (2H), 2.62 - 2.71 (2H), 5.68 - 5.75 (2H), 7.13 - 7.20 (1 H), 7.28 - 7.35 (1 H), 8.21 - 8.24 (2H) Example 6 15 1-{3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-5-(methylamino)-1 H-pyrazol-4 yl}cyclobutanecarboxamide Experimental MH* 490.0; expected 490.0 1 H-NMR (CDC13): 2.00 - 2.20 (2H), 2.45 - 2.50 (3H), 2.65 - 2.80 (4H), 5.40 - 5.50 (1 H), 5.80 - 5.90 (1 H), 7.90 - 7.95 (2H) 20 Example 7 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazol-4-yllpropanamide Experimental MH* 392.0; expected 392.0 'H-NMR (CDC13): 1.50 - 1.54 (3H), 3.61 - 3.64 (1 H), 5.38 - 5.42 (1 H), 5.80 - 5.90 (1 H), 7.70 - 7.74 (2H) 25 Example 8 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazol-4-yl}-3-(4 fluorophenyl)propanamide Experimental MH* 486.0; expected 486.1 1 H-NMR (d 6 -DMSO): 2.90 - 3.00 (1H), 3.10 - 3.20 (1H), 3.65 - 3.70 (1H), 6.05 - 6.15 (2H), 7.00 30 7.10 (4H), 7.19 - 7.21 (1 H), 7.70 - 7.80 (1 H), 8.18 - 8.24 (2H) Example 9 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazol-4-yl}butanamide Experimental MH* 406.0; expected 406.0 56 WO 2006/134459 PCT/IB2006/001566 'H-NMR (CDC1 3 ): 0.94 - 1.01 (3H), 1.84 - 1.95 (1H), 1.98 - 2.10 (3H), 3.37 - 3.43 (1H), 5.40 - 5.51 (1 H), 5.84 - 5.94 (1 H), 7.74 - 7.79 (2H) Example 10 5 N-(1 -{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazol-4-yl}-2,2,2 trifluoroethyl)-N-methylmethanesulfonamide

CF

3 S02CH, N N N

CH

3 WN

'NH

2 Cl CI

CF

3 To a solution of Preparation 1 (70 mg, 0.14 mmol) in acetone (2 ml), at 00C, was added potassium carbonate (20 mg, 0.14 mmol), followed by methyl iodide (9 pl, 0.17 mmol). The reaction mixture 10 was heated at reflux for 2 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the two layers were separated. The aqueous layer was extracted with ethyl acetate (x 2) and the combined organic phases were dried (MgSO 4 ) and concentrated in vacuo. The residue was dissolved in methanol (1 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm LUNA C18(2) 10pim column) using an acetonitrile 15 : water gradient [45:55 to .95:5]. The appropriate fractions were concentrated in vacuo to give the titled compound (17 mg). Experimental MH* 509.9; expected 510.0 'H-NMR (CDC1 3 ): 2.90 - 2.95 (3H), 2.95 - 2.98 (3H), 4.35 - 4.45 (3H), 5.50 - 5.60 (1 H), 7.77 - 7.81 (2H) 20 Example 11 5-amino-1 -[2,6-dichloro-4-pentafluorothiophenyl]-4-[1 -(methylsulfonyl)ethyl]-1 H-pyrazole-3 carbonitrile

H

3 C CH3 /\0 N, NH2 CI- CI

SF

5 25 A mixture of Preparation 9 (363 mg, 0.67 mmol), methanol (1 ml), dioxane (8 ml) and hydrochloric acid (1 N, 1 ml) was heated at 800C for 5 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in methanol (2 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm x 4.6 mm LUNA C18(2) 5pm column) using an acetonitrile 57 WO 2006/134459 PCT/IB2006/001566 water gradient [50:50 to 98:2]. The appropriate fractions were concentrated in vacuo to give the titled compound (77 mg). Experimental MH* 485.0; expected 485.0 'H-NMR (CDCI): 1.80 - 1.84 (3H), 2.85 - 2.88 (3H), 4.21 - 4.25 (1 H), 4.40 - 4.50 (2H),.7.90 - 7.92 5 (2H) Example 12 2-{3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}propanamide

H

3 C NH 2 N Cl Cl

SF

5 10 To a solution of Example 2 (100 mg, 0.22 mmol) and copper (II) chloride (45 mg, 0.33 mmol) in acetonitrile (3 ml) was added tert-butylnitrite (30 si, 0.27 mmol) in acetonitrile. The reaction mixture was stirred at room temperature for 18 h and then partitioned between ethyl acetate and water., The organic phase was separated, dried (MgSO 4 ) and concentrated in vacuo. The residue was dissolved in acetonitrile : water (1:1, 0.75 ml) and purified by automated preparative liquid chromatography 15 (Gilson system, 150 mm x 30 mm LUNA C18(2) 10pim column) using an acetonitrile : water gradient [50:20 to 98:2]. The appropriate fractions were concentrated in vacuo to give the titled compound (21 mg) together with the 5-chloro derivative. Experimental MH* (acetonitrile adduct) 476.1; expected 476.0 'H-NMR (d 6 -DMSO): 1.38 - 1.42 (3H), 3.70 - 3.80 (1H), 7.00 - 7.05 (1H), 7.58 - 7.61 (1H), 8.25 20 8.30 (1 H), 8.45 - 8.50 (2H) Similarly prepared was: Example 13 1-[2,6-dichloro-4-pentafluorothiopheny]-4-[1 -(methylsulfonyl)ethyl]-1 H-pyrazole-3-carbonitrile from 25 Example 11 H - 3 C 0 S=O NH 3 N Cl CI

SF

5 Experimental MH* 470.0; expected 470.0 1 H-NMR (CDC13): 1.79 - 1.82 (3H), 2.80 - 2.82 (3H), 4.30 - 4.39 (1H), 7.81 - 7.83 (1H), 7.88 - 6.92 58 WO 2006/134459 PCT/IB2006/001566 (2H) Example 14 2-{5-chloro-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}propanamide

H

3 C

NH

2

N

0 N,N C1 Cl Cl 5

SF

5 To a solution of Example 2 (100 mg, 0.22 mmol) and copper (II) chloride (45 mg, 0.33 mmol) in acetonitrile (3 ml) was added tert-butylnitrite (30 tl, 0.27 mmol) in acetonitrile. The reaction mixture was stirred at room temperature for 18 h and then partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO 4 ) and concentrated in vacuo. The residue was dissolved 10 in acetonitrile : water (1:1, 0.75 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm LUNA C18(2) 1 Ogm column) using an acetonitrile : water gradient [50:50 to 98:2]. The appropriate fractions were concentrated in vacuo to give the titled compound (35 mg) together with the 5-hydrido derivative. Experimental MH* (acetonitrile adduct) 510.1; expected 510.0 15 1 H-NMR (d 6 -DMSO): 1.45 - 1.55 (3H), 3.70 - 3.80 (1H), 7.10 - 7.20 (1H), 7.60 - 7.70 (1H), 8.60 8.65 (2H) Example 15 2-{3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-5-[(pyridin-4-ylmethyl)amino]-1 H-pyrazol-4 20 yl}propanamide

H

3 C

NH

2 NO N CI N CI/ SFS To a solution of Preparation 41 (240 mg, 0.44 mmol) in methanol (10 ml), at 00C, was added sodium borohydride (40 mg, 1.06 mmol). The reaction mixture was stirred at room temperature for 18 h and then quenched with water. The mixture was adjusted to pH 2 by addition of hydrochloric acid (4N) 25 and the two layers were separated. The aqueous layer was extracted with ethyl acetate (x 3) and the combined organic phases were washed with brine and aqueous sodium hydrogen carbonate solution, dried (MgSO 4 ) and concentrated in vacuo. The residue was dissolved in acetonitrile (2 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm x 21.4 mm 59 WO 2006/134459 PCT/IB2006/001566 LUNA C18(2) 5pm column) using an acetonitrile : 0.1% trifluoroacetic acid gradient [45:55 to 95:5]. The appropriate fractions were concentrated in vacuo to give the titled compound (6 mg). Experimental MH* 541.0; expected 541.0 1 H-NMR (CDCI 3 ): 1.60 - 1.70 (3H), 3.70 - 3.80 (1 H), 4.10 - 4.20 (1 H), 4.35 - 4.45 (1 H), 5.80 - 5.90 5 (1 H), 6.20 - 6.30 (2H), 7.50 - 7.70 (4H, 8.60 - 8.70 (2H) Example 16 5-amino-4-[1 -amino-2,2,2-trifluoro-1 -(trifluoromethyl)ethyl]-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl] 1 H-pyrazole-3-carbonitrile

H

2 N

CF

3 N

CF

3 N NH2 Cl Cl 10 CF 3 To a slurry of potassium carbonate (100 mg, 0.70 mmol) in acetonitrile (0.5 ml) was added ammonia (35% in water, 50 pl, 1.00 mmol), followed by Preparation 29 (50 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 18 h and then partitioned between dichloromethane and water. The mixture was filtered through a hydrophobic frit and the filtrate was concentrated under a 15 stream of nitrogen. The residue was dissolved in acetonitrile/water/dimethyl sulphoxide (1 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm LUNA C18(2) 10pim column) using an acetonitrile : water gradient [60:40 to 95:5]. The appropriate fractions were concentrated in vacuo to give the titled compound (18 mg). Experimental MH* 485.9; expected 486.0 20 'H-NMR (d 6 -DMSO): 3.60 - 3.70 (2H), 6.30 - 6.45 (2H), 8.21 - 8.27 (2H) Similarly prepared, using the appropriate nucleophile, were: R2

CF

3

CF

3 N, NH N N-2 Cl Cl R1 Example R1 R2 From Example 17 CF 3

NHCH

3 Preparation 29 Example 18 CF 3 i-Prs Preparation 29 Example 19 SF 5 CN Preparation 6 60 WO 2006/134459 PCT/IB2006/001566 Example 17 5-amino-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[2,2,2-trifluoro-1 -(methylamino)-1 (trifluoromethyl)ethyl]-1 H-pyrazole-3-carbonitrile 5 Experimental MH* 500.0; expected 500.0 'H-NMR (CD30D): 2.40 - 2.45 (3H), 8.00 - 8.05 (2H) Example 18 5-amino-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[2,2,2-trifluoro-1 -(isopropylthio)-1 (trifluoromethyl)ethyl]-1 H-pyrazole-3-carbonitrile 10 Experimental MH* 544.8; expected 545.0 H-NMR (CD3OD): 1.35 - 1.40 (6H), 3.10 - 3.20 (1 H), 8.05 - 8.08 (2H) Example 19 5-amino-4-[1 -cyano-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-1-[2,6-dichloro-4-pentafluorothiophenyl] 1 H-pyrazole-3-carbonitrile 15 1 H-NMR (CDCI3): 6.35 - 6.40 (2H), 7.95 - 8.00 (2H) Example 20 2-{3-cyano-5-(cyclopropylmethoxy)-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4 yl}propanamide HC NH2 0 N0 O NN O- -' Cl Cl 20 SF 5 To Preparation 46 (65 mg, 0.13 mmol) in tetrahydrofuran : water (4:1, 3 ml) was added lithium hydroxide monohydrate (55 mg, 1.30 mmol) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was acidified with hydrochloric acid (1M) and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO 4 ) and concentrated 25 in vacuo. To a solution of the residue in tetrahydrofuran (3 ml), at 00C, was added triethylamine (46 pi, 0.33 mmol) and ethyl chloroformate (15 pl, 0.16 mmol). After stirring for 30 min, aqueous ammonium hydroxide solution (0.5 ml) was added and the reaction mixture was warmed to room temperature. The reaction mixture was adjusted to pH 1 by addition of hydrochloric acid (1 M) and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO 4 ) and 30 concentrated in vacuo. The residue was dissolved in acetonitrile (0.6 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm LUNA C18(2) 10ptm column) using an acetonitrile : water gradient [20:80 to 98:2]. The appropriate fractions were concentrated in vacuo to give the titled compound (10 mg). 61 WO 2006/134459 PCT/IB2006/001566 Experimental MH* 505.0; expected 505.0 'H-NMR (CD 3 OD): 0.10 - 0.20 (2H), 0.45 - 0.50 (2H), 0.95 - 1.05 (1H), 1.61 - 1.66 (3H), 3.80 - 3.89 (3H), 8.22 - 8.27 (2H) 5 The following Preparations illustrate the synthesis of certain intermediates used in the preparation of the preceding Examples. Preparation 1 N-(1-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)pheny]-1H-pyrazol-4-yl}-2,2,2 10 trifluoroethyl)-methanesulfonamide To a solution of Preparation 2 (100 mg, 0.24 mmol) in dichloromethane (2 ml), at 00C, was added triethylamine (53 pl, 0.38 mmol) and methanesulphonyl chloride (28 pl, 0.36 mmol). The reaction mixture was stirred at room temperature for 1 h, before addition of ethyl acetate. The mixture was washed with water and brine, dried (MgSO 4 ) and concentrated in vacuo to give the titled compound 15 (70mg). Experimental MH* 495.9; expected 496.0 Preparation 2 5-amino-4-(1 -amino-2,2,2-trifluoroethyl)-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazole-3 20 carbonitrile To a solution of Preparation 3 (100 mg, 0.23 mmol) in acetonitrile (1.5 ml) was added ammonia (35% in water, 80 pl) and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The two layers were separated and the organic layer was washed with saturated brine solution (x 2), dried 25 (MgSO 4 ) and concentrated in vacuo to give the titled compound (100 mg). The compound was used directly in the synthesis of Preparation 1. Preparation 3 5-amino-4-(1 -chloro-2,2,2-trifluoroethyl)-1-[2,6-dichloro-4-(trifluoromethy)phenyl]-1 H-pyrazole-3 30 carbonitrile ' To a solution of Preparation 8 (1.0 g, 2.39 mmol) in dichloroethane (10 ml) was added dropwise thionyl chloride (261 pl, 3.59 mmol). The reaction mixture was then stirred at 600C overnight. The reaction mixture was concentrated in vacuo and to the residue was added dichloromethane. This solution was washed with water, dried (MgSO 4 ) and concentrated in vacuo to give the titled 35 compound (900 mg) as a white solid. 1H-NMR (CDCI 3 ): 4.10 - 4.30 (2H), 5.21 - 5.24 (1H), 7.76 - 7.80 (2H) Similarly prepared were: 62 WO 2006/134459 PCT/IB2006/001566 R4 R3 R2 N N R9 CI CI R1 Preparation R1 R2 R3 R4 R9 From Preparation 4 CF 3

COOCH

3

CF

3 Cl -N=CH-N(CH 3

)

2 Preparation 38 Preparation 5 CF 3

CF

3

CF

3 Cl -N=CH-N(CH 3

)

2 Preparation 47 Preparation 6 SF 5

CF

3

CF

3 Cl NH 2 Preparation 32 Preparation 7 SF 5

COOCH

3

CH

3 Cl cyclopropylmethoxy Preparation 39 Preparation 4 methyl 2-chloro-2-(3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[ 5 (dimethylamino)methylene]amino}-1 H-pyrazol-4-yl)-3,3,3-trifluoropropanoate Experimental MH* 550.1; expected 550.0 Preparation 5 N'-{4-[1 -chloro-2,2,2-trifluoro-1 -(trifluoromethyl)ethyl]-3-cyano-1 -[2,6-dichloro-4 (trifluoromethyl)phenyl]-1 H-pyrazol-5-yl}-N,N-dimethylimidoformamide 10 Experimental MH* 560.0; expected 560.0 Preparation 6 5-amino-4-[1 -chloro-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-1-[2,6-dichloro-4-pentafluorothiophenyl] 1 H-pyrazole-3-carbonitrile Experimental MH* 562.8; expected 562.9 15 Preparation 7 methyl 2-chloro-2-{3-cyano-5-(cyclopropylmethoxy)-1 -[2,6-dichloro-4 pentafluorothiophenyl]-1 H pyrazol-4-yl}propanoate Experimental MH* 554.0; expected 554.0 20 Preparation 8 5-amino-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(2,2,2-trifluoro-1 -hydroxyethyl)-1 H-pyrazole-3 carbonitrile To a stirred solution of Preparation 61 (214 mg, 0.51 mmol) in ethanol (4 ml) was added sodium borohydride (20 mg, 0.51 mmol). The reaction mixture was then stirred at room temperature for 20 25 min. To the reaction mixture was added acetic acid (0.5 ml) and the mixture was concentrated in vacuo. To the residue was added dichloromethane and the solution was washed with water, followed by saturated aqueous sodium bicarbonate solution and brine. The organic phase was then dried (MgSO 4 ) and concentrated in vacuo to give the titled compound (178 mg, 83%) as a white 63 WO 2006/134459 PCT/IB2006/001566 solid. Experimental MH* 419.3; expected 419.0 Preparation 9 5 N'-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-[1-(methylsulfonyl)ethyl]-1 H-pyrazol-5-yl}-N,N dimethylimidoformamide To a suspension of Preparation 12 (520 mg, 0.96 mmol) in ethanol (30 ml) was added sodium borohydride (160 mg, 4.20 mmol) and the reaction mixture was stirred at room temperature for 18 h. To the reaction mixture was added hydrochloric acid (1 N, 7 ml) and the solution was concentrated in 10 vacuo. The residue was partitioned between dichloromethane (25 ml) and water (25 ml) and the two layers were separated. The aqueous layer was extracted with dichloromethane (2 x 25 ml) and the combined organic phases were dried (MgSO 4 ) and concentrated in vacuo to give the titled compound (430 mg). Experimental MH* 539.9; expected 540.0 15 Similarly prepared were: Preparation 10 methyl 2-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[-(dimethylamino)methylene]amino} 1 H-pyrazol-4-yl)propanoate from Preparation 34. 20 Experimental MH* 462.0; expected 462.1 Preparation 11 methyl 2-(3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-5-{[-(dimethylamino)methylene]amino 1 H-pyrazol-4-yl)propanoate from Preparation 35. Experimental MH* 520.1; expected 520.0 25 Preparation 12 N'-{3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-4-[1 -(methylsulfonyl)vinyl]-1 H-pyrazol-5-yl}-N,N dimethylimidoformamide N H 2 C 0 S=0

CH

3 NN N "N-CHS C CI OH 3 F, .F F F F 30 To a solution of Preparation 70 (5.50 g, 29.70 mmol) in tetrahydrofuran (75 ml) was added Rieke@ Zinc (0.76M in tetrahydrofuran, 100 ml, 76.00 mmol) and the mixture was stirred at room temperature for 4 h. To a solution of tetrakis(triphenylphosphine)palladium(0) (560 mg) and Preparation 13 (5.55 g, 9.90 mmol) in tetrahydrofuran (75 ml) was added a solution of the zinc 64 WO 2006/134459 PCT/IB2006/001566 reagent in tetrahydrofuran (approximately 14.90 mmol), via syringe. The reaction mixture was then heated at reflux for 24 h. The reaction mixture was passed through a silica plug, eluting with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica) eluting with ethyl acetate/cyclohexane [35:65]. The appropriate fractions 5 were combined and concentrated to give the titled compound (1.40 g). Experimental MH* 538.0; expected 538.0 Preparation 13 N'-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-iodo-1 H-pyrazol-5-yl}-N,N 10 dimethylimidoformamide A solution of Preparation 16 (52.00 g, 103.00 mmol) in N,N-dimethylformamide dimethyl acetal (300 ml) was heated at reflux for 5 h, cooled to room temperature and stirred for 18 h. The reaction mixture was purified by column chromatography (silica, 1 kg) with gradient elution, hexane : ethyl acetate [6:1 to 4:1]. The appropriate fractions were combined and concentrated to 15 give the titled compound (45.00 g). The reaction mixture was purified by column chromatography (silica, 1 kg) with gradient elution, hexane : ethyl acetate [6 : 1 to 4 : 1]. The appropriate fractions were combined and concentrated to give the titled compound (45 g) as a light brown solid. 'H-NMR (CDCl3): 2.77 - 2.81 (3H), 3.02 - 3.05 (3H), 7.78 - 7.81 (2H), 8.21 - 8.24 (1 H) 20 Similarly prepared were Preparation 14 N'-{3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-iodo-1 H-pyrazol-5-yl}-N,N dimethylimidoformamide from Preparation 63. 25 Experimental MH* 502.1; expected 502.9 Preparation 15 N'-{3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoroacetyl)-1 H-pyrazol-5-yl}-N,N dimethylimidoformamide from Preparation 61. Experimental MH* 472.0; expected 472.0 30 Preparation 16 5-amino-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-iodo-1H-pyrazole-3-carbonitrile To a solution of Preparation 62 (40.00 g, 106.00 mmol) in acetonitrile (400 ml) was added N iodosuccinimide (26.40 g, 117.00 mmol) and the reaction mixture was stirred at room temperature for 35 18 h. The reaction mixture was diluted with ethyl acetate (1 I) and washed with aqueous sodium thiosulphate solution (10%, 3 x 500 ml) and brine (500 ml). The organic phase was dried (MgSO4) and concentrated in vacuo to give the titled compound (53.00 g). H-NMR (CDCI3): 3.87 - 3.94 (2H), 7.88 - 7.90 (2H) 65 WO 2006/134459 PCT/IB2006/001566 Preparation 17 5-(cyclopropylmethoxy)-l -[2,6-dichloro-4-pentafluorothiophenyl]-4-iodo-1 H-pyrazole-3-carbonitrile To a solution of Preparation 59 (2.97 g, 6.84 mmol) in ethanol (68 ml) was added silver sulphate (4.30 g, 13.70 mmol), followed by iodine (3.50 g, 13.70 mmol). After stirring for 3 h, the solution was 5 filtered and the precipitate partitioned between aqueous sodium hydroxide solution (1M) and dichloromethane. The two layers were separated and the organic layer was washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The residue was filtered through silica, washing through with ethyl acetate, and the filtrate was concentrated in vacuo to give the titled compound (3.53 g). Experimental MH+ (acetonitrile adduct) 600.8; expected 600.9 10 Preparation 18 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}propanoic acid A mixture of Preparation 30 (2.00 g, 3.84 mmol) and lithium hydroxide monohydrate (323 mg, 7.69 mmol) in tetrahydrofuran (20 ml) and water (4 ml) was stirred at room temperature for 60 h. The 15 reaction mixture was acidified and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the organic phase was separated, dried (MgSO 4 ) and concentrated in vacuo to give the titled compound (1.91 g). Experimental MH* 451.0; expected 451.0 20 Similarly prepared were: R4 R3 N COOH NN R9 Ckl C1 R1 Experimental Expected From Preparation R1 R3 R4 R9 MH* MHF Preparation 19 C17 CH3 H NH2 392.9 393.0 Preparation 28 Preparation 20 SF5 CH3 CH3 NH2 465.0 465.0 Preparation 27 Preparation 21 CF 3 4-fluorobenzyl H NH 2 486.9 487.0 Preparation 31 Preparation 22 CF3 ethyl H NH2 407.0 407.0 Preparation 33 66 WO 2006/134459 PCT/IB2006/001566 Preparation 23 SF6 cyclobutyl NH2 476.9 477.0 Preparation 50 Preparation 24 CF 3 0 cyclobutyl NH 2 435.0 435.0 Preparation 51

CF

3 cyclobutyl NH 2 419.0 419.0 Preparation 25 Preparation 52 Preparation 26 SF6 cyclobutyl NHCH 3 491.0 491.0 Preparation 57 Preparation 27 methyl 2-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}-2 methylpropanoate 5 A mixture of Preparation 42 (540 mg, 1.00 mmol) and hydrochloric acid (5M, 0.5 ml) in methanol (4 ml) and 1,4-dioxane (4 ml) was heated at 900C, under nitrogen, for 5 h. The reaction mixture was concentrated in vacuo and to the residue was added water (5 ml). The mixture was extracted with ethyl acetate (3 x 5 ml) and the combined extracts were dried (MgSO 4 ) and concentrated in vacuo to give the titled compound (581 mg). 10 Experimental MH* 479.0; expected 479.0 Similarly prepared were: R4 R3 N~ R2 N"N NH 2 C1 CI R1 Experimental Expected Preparation R1 R2 R3 R4 MH* MH* From Preparation 28 CF3 COOCH3 CH3 H 407.0 407.0 Preparation 10 Preparation 29 CF3 OH CF3 CF3 505.0 504.9 Preparation 5 Preparation 30 SF5 COOCH3 CH3 H 465.0 465.0 Preparation 11 Preparation 31 CF 3

COOCH

3 4-fluorobenzyl H 500.9 501.1 Preparation 43

SF

5 OH CF 3

CF

3 545.0 544.9 67 WO 2006/134459 PCT/IB2006/001566 Preparation 32 Preparation 48

CF

3

COOCH

3 ethyl H 420.9 421.0 Preparation 33 Preparation 49 Preparation 34 methyl 2-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[-(dimethylamino)methylene]amino} 1 H-pyrazol-4-yl)acrylate 5 To a solution of Preparation 36 (7.2 g, 15.1 mmol) in dichloromethane (600 ml), at 00C, was added triethylamine (5.3 ml, 37.8 mmol), followed by methanesulphonyl chloride (1.5 ml, 19.6 mmol). The reaction mixture was then allowed to warm to room temperature over 2 h. The reaction mixture was poured into ice/hydrochloric acid (0.5M) and the mixture was extracted with dichloromethane (3 x 150 ml). The combined extracts were washed with brine, dried (MgSO 4 ) and 10 concentrated in vacuo. The residue was purified by column chromatography (silica) with gradient elution, hexane : ethyl acetate [2 : 1 to 1 : 1]. The appropriate fractions were combined and concentrated to give the titled compound (6.2 g). Experimental MH* 460.07; expected 461.3 15 Similarly prepared was Preparation 35 methyl 2-(3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(dimethylamino)methylene]amino}-1

H

pyrazol-4-yl)acrylate from Preparation 37. 20 Experimental MH* 518.0; expected 518.0 Preparation 36 methyl 2-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[-(dimethylamino)methylene]amino} 1 H-pyrazol-4-yl)-2-hydroxypropanoate

O-CH

3 NO0 OH CH N N-\ CI Cl N-CH, ci ci r-c 3

CH

3 F F 25 F To a solution of Preparation 14 (6.3 g, 12.5 mmol) in tetrahydrofuran (50 ml), at -780C, was added isopropylmagnesium chloride (2M in tetrahydrofuran, 6.9 ml, 13.8 mmol), using a syringe. After stirring at -780C for 30 min, the solution was warmed to -300C and methyl pyruvate (1.73 ml, 18.9 mmol) in tetrahydrofuran (30 ml) was added via syringe. The reaction mixture was then allowed to 30 warm to room temperature over 2 h. The reaction mixture was added to an ice/hydrochloric acid (2M) 68 WO 2006/134459 PCT/IB2006/001566 mixture (300 ml) and extracted with ethyl acetate (3 x 150 ml). The combined extracts were dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by column chromatography (silica) with gradient elution, hexane :'ethyl acetate [1 : 1 to 1 : 2]. The appropriate fractions were combined and concentrated to give the titled 5 compound (8.7 g). Experimental MH* 480.0; expected 479.3 Similarly prepared were: Preparation 37 10 methyl 2-(3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-5-{[-(dimethylamino)methylene]amino} 1 H-pyrazol-4-yl)-2-hydroxypropanoate from Preparation 64. Experimental MH* 536.0; expected 536.0 Preparation 38 methyl 2-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[-(dimethylamino)methylene]amino} 15 1 H-pyrazol-4-yl)-3,3,3-trifluoro-2-hydroxypropanoate from Preparation 14. Experimental MH* 532.2; expected 532.0 Preparation 39 methyl 2-{3-cyano-5-(cyclopropylmethoxy)-1-[2,6-dichloro-4-pentafluorothiophenyl]-1H-pyrazol-4-yl} 2-hydroxypropanoate from Preparation 17. 20 Experimental MH* 536.1; expected 536.0 Preparation 40 N'-{3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-4-(trifluoroacetyl)-1H-pyrazol-5-yl}-N,N dimethylimidoformamide from Preparation 64. Experimental MH* 530.0; expected 530.0 25 Preparation 41 2-(3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-5-{[1 -pyridin-4-ylmethylene]amino}-1 H-pyrazol-4 yl)propanamide To a solution of Example 2 (200 mg, 0.44 mmol) in toluene (4 ml) was added 4A molecular sieves 30 (175 mg), 4-pyridinecarboxaldehyde (0.13 ml, 1.33 mmol) and p-toluenesulphonic acid (8 mg). The reaction mixture was heated at 1150C, under nitrogen, for 18 h and then cooled to room temperature. The reaction mixture was concentrated in vacuo to give the titled compound (240 mg). Experimental MH* 539.0; expected 539.0 35 Preparation 42 methyl 2-(3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-5-{[-(dimethylamino)methylene]amino} 1 H-pyrazol-4-yl)-2-methylpropanoate To a solution of Preparation 11 (1.10 g, 2.10 mmol) in tetrahydrofuran (20 ml), at -780C and under nitrogen, was added potassium bis(trimethylsilyl)amide (0.5M in toluene, 5.08 ml, 2.50 mmol). After 69 WO 2006/134459 PCT/IB2006/001566 stirring at -780C for 20 min, methyl iodide (0.26 ml, 4.20 mmol) was added and the reaction mixture was allowed to warm to room temperature over 3 h. To the reaction mixture was added saturated aqueous ammonium chloride solution (15 ml) and the mixture was extracted with ethyl acetate (3 x 15 ml). The combined extracts were dried (MgSO 4 ) 5 and concentrated in vacuo to give the titled compound (540 mg). Experimental MH* 534.1; expected 534.1 Similarly prepared was: Preparation 43 10 methyl 2-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[-(dimethylamino)methylene]amino} 1 H-pyrazol-4-yl)-3-(4-fluorophenyl)propanoate from Preparation 44. Experimental MH* 556.1; expected 556.1 Preparation 44 15 methyl (3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[-(dimethylamino)methylene]amino}-lH pyrazol-4-yl)acetate To a solution of Preparation 45 (201 mg, 0.39 mmol) in acetonitrile (10 ml) was added potassium carbonate (539 mg, 3.90 mmol), followed by water (few drops). The reaction mixture was stirred at room temperature for 18 h and then quenched with hydrochloric acid (2N). The mixture was 20 concentrated in vacuo and the residue was partitioned between water (15 ml) and ethyl acetate (15 ml). The two layers were separated and the organic layer was washed with brine (15 ml), dried (MgSO 4 ) and concentrated in vacuo to give the titled compound (100 mg). Experimental MH* 448.1; expected 448.1 25 Preparation 45 methyl 2-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[-(dimethylamino)methylene]amino} 1 H-pyrazol-4-yl)-3,3,3-trifluoropropanoate To- a solution of Preparation 4 (112 mg, 0.20 mmol) in acetic acid (5 ml) and diethyl ether (5 ml) was added zinc powder (78 mg, 1.20 mmol). The reaction mixture was stirred at room temperature for 18 30 h and then quenched with saturated ammonium chloride solution (10 ml). The mixture was extracted with diethyl ether (2 x 10 ml) and the combined extracts were dried (MgSO 4 ) and concentrated in vacuo to give the titled compound (200 mg). Experimental MH* 516.1; expected 516.0 35 Similarly prepared was: Preparation 46 methyl 2-{3-cyano-5-(cyclopropylmethoxy)- 1 -[2,6-dichloro-4-(pentafluoro-lambda-6sulfanyl)phenyl]-1 H-pyrazol-4-yl}propanoate from Preparation 7 Experimental MH* 490.8; expected 491.0 70 WO 2006/134459 PCT/IB2006/001566 Preparation 47 N'-{3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[2,2,2-trifluoro-1 -hydroxy-1 (trifluoromethyl)ethyl]-1 H-pyrazol-5-yl}-N,N-dimethylimidoformamide 5 A mixture of Preparation 15 (5.42 g, 11.50 mmol), trimethylamine N-oxide (860 mg, 11.40 mmol) and molecular sieves in tetrahydrofuran (50 ml) was stirred under nitrogen for 30 min. To the solution was added (trifluoromethyl)trimethylsilane (9.4 ml, 63.20 mmol), via syringe over 1 h, and the reaction mixture was stirred at room temperature for 3 days. To the mixture was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 10 ml), with cooling, and the mixture was stirred 10 for 30 min. Water (100 ml) was added and the two layers were separated. The aqueous layer was extracted with diethyl ether (2 x 100 ml) and the combined organic phases were washed with brine, dried (Na 2

SO

4 ) and concentrated in vacuo. The residue was dissolved in dichloromethane and filtered through silica, washing through with dichloromethane. The filtrate was concentrated in vacuo to give the titled compound (4.38 g). 15 Experimental MH* 542.1; expected 542.0 Similarly prepared was: Preparation 48 N'-{3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-4-[2,2,2-trifluoro-1 -hydroxy-1 20 (trifluoromethyl)ethyl]-1 H-pyrazol-5-yl}-N,N-dimethylimidoformamide from Preparation 40. Experimental MH* 600.0; expected 600.0 Preparation 49 methyl 2-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[-(dimethylamino)methylene]amino} 25 1 H-pyrazol-4-yl)butanoate To a solution of Preparation 44 (200 mg, 0.44 mmol) in tetrahydrofuran (6 ml), at -78 0 C and under nitrogen, was added potassium hexamethyldisilazide (0.5M, 0.94 ml, 0.46 mmol), followed by iodoethane (0.14 ml, 1.76 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h. To the reaction mixture was added ammonium chloride solution (10 ml) and the 30 mixture was extracted with ethyl acetate (3 x 10 ml). The combined extracts were dried (MgSO 4 ) and concentrated in vacuo to give the titled compound (221 mg). Experimental MH* 475.9; expected 476.1 Preparation 50 35 methyl 1-{5-amino-3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4 yllcyclobutanecarboxylate To a solution of Preparation 71 (534 mg, 1.85 mmol) in ethanol (15 ml), at -20C and under nitrogen, was added aqueous tetrafluoroboric acid solution (48 wt%, 0.48 ml, 3.70 mmol). The reaction mixture was cooled to -40C and isoamyl nitrite (239 mg, 2.04 mmol) was added. After stirring at -2OC 71 WO 2006/134459 PCT/IB2006/001566 for 1 h, Preparation 53 (511 mg, 2.04 mmol) was added and the reaction mixture was stirred at -20C for 1 h and then at room temperature for 24 h. To the reaction mixture was added dropwise aqueous ammonium hydroxide solution (29.7 wt%, 0.65 g, 5.55 mmol) and the solution was stirred for 80 min. The reaction mixture was partitioned between water (100 ml) and diethyl ether (100 ml) and the two 5 layers were separated. The aqueous layer was extracted with diethyl ether (50 ml) and the combined organic phases were washed with brine (50 ml), dried (Na 2

SO

4 ) and concentrated in vacuo to give the titled compound (660 mg). Experimental MH* 490.8; expected 491.0 10 Similarly prepared were: Preparation 51 methyl 1-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethoxy)phenyl]-1 H-pyrazol-4 yl}cyclobutanecarboxylate from Preparation 68. Experimental MH* 449.0; expected 449.0 15 Preparation 52 methyl 1-{5-amino-3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazol-4 yl}cyclobutanecarboxylate from Preparation 69. Experimental MH* 433.0; expected 433.0 20 Preparation 53 methyl 1-(1,2-dicyano-3-methoxy-3-oxopropyl)cyclobutanecarboxylate To a solution of Preparation 54 (730 mg, 2.70 mmol) in methanol (15 ml), at 00C and under nitrogen, was added potassium cyanide (210 mg, 3.20 mmol). The reaction mixture was stirred in an ice bath for 18 h, before addition of silica (10 g) and glacial acetic acid (324 mg, 5.40 mmol). The mixture 25 was concentrated in vacuo and the residue was purified by column chromatography (silica), eluting with diethyl ether/pentane [55:45]. The appropriate fractions were combined and concentrated to give the titled compound (676 mg). Experimental MH* 251.2; expected 251.1 30 Preparation 54 methyl 1-[-2-cyano-3-methoxy-3-oxoprop-1-en-1-yl]cyclobutanecarboxylate A mixture of Preparation 55 (390 mg, 2.70 mmol), methyl cyanoacetate (0.24 ml, 2.70 mmol) and piperidine (54 jil, 0.54 mmol) in glacial acetic acid (2 ml) was heated at 650C, under nitrogen, for 18 h. The reaction mixture was poured into water (65 ml) and extracted with dichloromethane (2 x 20 35 ml). The combined extracts were washed with saturated aqueous sodium hydrogencarbonate solution (35 ml) and brine (35 ml), dried (Na 2

SO

4 ) and concentrated in vacuo to give the titled compound (1.02 g). 'H-NMR (CDC13): 1.94 - 2.06 (2H), 2.47 - 2.58 (4H), 3.78 - 3.79 (3H), 3.88 - 3.89 (3H), 7.78 - 7.80 (1 H) 72 WO 2006/134459 PCT/IB2006/001566 Preparation 55 methyl 1-formylcyclobutanecarboxylate To a solution of oxalyl chloride (0.61 ml, 7.00 mmol) in dichloromethane (35 ml), at -780C and under 5 nitrogen, was added dropwise dimethyl sulphoxide (1.01 ml, 14.20 mmol), followed by a solution of Preparation 56 (0.84 g, 5.80 mmol) in dichloromethane (17.5 ml) and triethylamine (4.04 ml, 29.00 mmol). The reaction mixture was stirred at -780C for 45 min and then at room temperature for 20 h. The reaction mixture was partitioned between hydrochloric acid (1M, 50 ml) and dichloromethane (100 ml) and the two layers were separated. The organic phase was washed with hydrochloric acid 10 (1M, 50 ml), water (50 ml), saturated aqueous sodium hydrogencarbonate solution (50 ml) and brine (50 ml), dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by column chromatography (silica), eluting with diethyl ether/pentane [5:95]. The appropriate fractions were combined and concentrated to give the titled compound (390 mg). 'H-NMR (CDCI): 1.90 - 2.06 (2H), 2.45 - 2.51 (4H), 3.78 - 3.80 (3H), 9.77 - 9.79 (1 H) 15 Preparation 56 methyl 1-(hydroxymethyl)cyclobutanecarboxylate To a solution of dimethyl 1,1-cyclobutanedicarboxylate Preparation 65 (4.29 g, 24.90 mmol) in dry tetrahydrofuran (140 ml), under nitrogen, was added lithium tri-tert-butoxyaluminohydride (1M in 20 tetrahydrofuran, 54.8 ml, 54.80 mmol). The reaction mixture was heated at reflux, under nitrogen, for 18 h, and then stirred at room temperature for a further 18 h. The reaction mixture was poured into a mixture of aqueous ammonium chloride solution (10 wt%, 450 ml) and brine (100 ml) and extracted with ethyl acetate (250 ml). The combined extracts were washed with brine (200 ml), dried (MgSO 4 ) and concentrated in vacuo to give the titled compound 25 (6.50 g). 'H-NMR (CDC13): 1.93 - 2.00 (4H), 2.38 - 2.47 (2H), 3.74 - 3.75 (3H), 3.82 - 3.83 (2H) Preparation 57 methyl 1-{3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-5-(methylamino)-1 H-pyrazol-4 30 yl}cyclobutanecarboxylate To a solution of Preparation 58 (578 mg, 1.06 mmol) in acetic acid (11 ml), under nitrogen, was added sodium cyanoborohydride (133 mg, 2.12 mmol). After stirring for 1.5 h, the reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (50 ml), water (50 ml) and brine (5 ml). The organic phase was separated, dried (MgSO 4 ) and concentrated in vacuo to 35 give the titled compound (768 mg). Experimental MH* 505.0; expected 505.0 Preparation 58 - methyl 1-(3-cyano-1-[2,6-dichloro-4-pentafluorothiophenyl]-5-{[(1E)-ethoxymethylene]amino}-1H 73 WO 2006/134459 PCT/IB2006/001566 pyrazol-4-yl)cyclobutanecarboxylate To a suspension of Preparation 50 (1.02 g, 2.10 mmol) in triethyl orthoformate (50 ml) was added concentrated hydrochloric acid (4 drops). The reaction mixture was then stirred at 500C, under nitrogen, for 1.5 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in 5 toluene (50 ml) and re-concentrated (x 3). The residue was then dissolved in ethyl acetate (50 ml), washed with saturated aqueous sodium hydrogen carbonate solution (50 ml), dried (Na 2

SO

4 ) and concentrated in vacuo to give the titled compound (1.09 g). Experimental MH* 547.0; expected 547.0 10 Preparation 59 5-(cyclopropylmethoxy)-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazole-3-carbonitrile To a mixture of Preparation 60 (6.37 g, 16.80 mmol) and potassium carbonate (7.00 g, 50.40 mmol) in acetonitrile (75 ml) was added (bromomethyl)cyclopropane (6.5 ml, 67.20 mmol). The reaction mixture was stirred at room temperature for 1 h and then heated at 500C for 3 h. The reaction 15 mixture was concentrated in vacuo and the residue was partitioned between hydrochloric acid (1 M) and ethyl acetate. The two layers were separated and the organic layer. was washed with water, dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by column chromatography with gradient elution, ethyl acetate : cyclohexane [2:98 to 20:80]. The appropriate fractions were combined and concentrated to give the titled compound (2.97 g). 20 Experimental MH* 433.9; expected 434.0 Preparation 60 1-[2,6-dichloro-4-pentafluorothiophenyl]-5-hydroxy-1 H-pyrazole-3-carbonitrile Sodium nitrite (1.32 g, 19.1 mmol) was added carefully to sulphuric acid (concentrated, 6.8 ml), 25 whilst cooling the solution to 0*C. The solution was heated to 600C for 30 min, allowed to cool and then diluted with acetic acid (12 ml). To the solution was added Preparation 67 (5.0 mg, 17.4 mmol) in acetic acid (11 ml) and the reaction mixture was heated at 550C for 1 h. To a solution of Preparation 66 (3.09 g, 18.1 mmol) in acetic acid (24 ml) and water (36 ml) was added dropwise the solution of the diazonium salt, followed by sodium acetate (24.2 g) in water (42 30 ml). The reaction mixture was then stirred at room temperature for 30 min. The reaction mixture was poured into ice/water (200 ml) and the mixture was extracted with dichloromethane (4 x 60 ml). The combined extracts were then washed with ammonium hydroxide (48 ml), dried and concentrated in vacuo. To a solution of sodium methoxide (25 wt.%, 11.5 ml, 50.1 mmol) in methanol (450 ml) was added 35 dropwise a solution of the residue in methanol (100 ml). The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and to the residue was added water. This solution was adjusted to pH 1 by addition of hydrochloric acid (4N) and the mixture was extracted with dichloromethane (3 x 100 ml). The combined extracts were dried (MgSO 4 ) and concentrated in 74 WO 2006/134459 PCT/IB2006/001566 vacuo. The residue was purified by column chromatography, eluting with hexane/ethyl acetate [3 : 1]. The appropriate fractions were combined and concentrated to give the titled compound (4.5 g). Experimental MH* 380.0; expected 380.0 5 Preparation 61 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoroacetyl)-1 H-pyrazole-3-carbonitrile Reference: WO 98/04530 Al, EP 918756 Al, JP 08311036 A2 10 Preparation 62 5-amino-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazole-3-carbonitrile Reference: WO 93/06089 Al, EP 605469 Al Preparation 63 15 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-iodo-1 H-pyrazole-3-carbonitrile Reference: US 6069157 A, EP 933363 Al, WO 98/28278 Al Preparation 64 N'-{3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-4-iodo-1 H-pyrazol-5-yl}-N,N 20 dimethylimidoformamide Reference: WO 2005/060749 Preparation 65 dimethyl cyclobutane-1,1 -dicarboxylate 25 Commercially available from Lancaster Synthesis Ltd. Newgate, White Lund Morecambe Lancashire LA3 3BN UK Preparation 66 dimethyl 2-cyanosuccinate 30 Reference: EP 28430 Al, JP 56075584 A2, Hall, H. K., Jr.; Ykman, P., J. Am. Chem. Soc. (1975), 97(4), 800-807, US 4028201 A Preparation 67 2,6-dichloro-4-pentafluorothioaniline 35 Reference: WO 94/21606 Al, WO 93/06089 Al Preparation 68 2,6-dichloro-4-(trifluoromethoxy)benzenediazonium tetrafluoroborate To a solution of 2,6-dichloro-4-(trifluoromethoxy)aniline (1.00 g, 4.10 mmol) in ethanol (1.2 ml), at 75 WO 2006/134459 PCT/IB2006/001566 50C and under nitrogen, was added dropwise tetrafluoroboric acid (48 wt%, 0.54 ml, 8.50 mmol), followed by isoamyl nitrite (0.60 ml, 4.50 mmol). The reaction mixture was stirred at room temperature for 1 h and the resulting precipitate was collected by filtration, washed with ethanol and diethyl ether and dried under nitrogen to give the titled compound (126 mg) which was used directly. 5 Preparation 69 2,6-dichloro-4-(trifluoromethyl)benzenediazonium tetrafluoroborate Reference: WO 2005/023773 Al 10 Preparation 70 1 -bromo-1 -(methylsulfonyl)ethylene Reference: JACS (1972), 94 (3), 1012-13 Preparation 71 15 2,6-dichloro-4-pentafluorothioaniline Reference: W094/21606A1 76

Claims (20)

1. A compound of formula (1): R4 RR 3 / 2 N N N R Ri (I) 5 wherein: X is selected from CR 1 0 or N; R 1 is selected from halo, cyano, hydroxy, C1.6 alkyl, C1.6 alkoxy, C1.6 alkanoyl, C1.6 haloalkyl, 01.6 10 haloalkoxy, C1.6 haloalkanoyl, amino, C1.6 alkyl amino, di C1.6 alkyl amino, het, phenyl, SF5 and S(O)nR11 R 2 is selected from cyano, C(0)OH, S(O),R 1 1 , C(0)NRaRb, and C(S)NRaRb; 15 or R2 is selected from C(0)0C1.6 alkyl, amino, C1.6 alkyl amino, and di C1.6 alkyl amino each of which may be optionally and independently further substituted by one or more substitutents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRcRd, NRCO(O)Rd, C1.6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3. cycloalkylC 1 . 6 alkyl, C3.8 cycloalkylC 1 . 6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 20 haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, NR R d, het, phenyl and S(O)nR 11 ; Ra and Rb are independently selected from hydrogen, het, phenyl and S(O),R 11 ; or either one or both of Ra and Rb are independently selected from C1.6 alkyl, C2.6 alkenyl, C3-8 25 cycloalkyl, C3.8 cycloalkylC 1 . 6 alkyl, C1.6 alkanoyl, and C(0)0C1.6 alkyl, each of which Ra and Rb may be optionally and independently further substituted by one or more substituents selected from, where chemcially possible, cyano, nitro, halo, oxo, hydroxy, C(0)OH, C(O)NRcRd, NR"C(O)Rd, C1.6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1 . 6 alkyl, C3. cycloalkylI 1 . 6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(O)OC1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 30 haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, NRCRd, het, phenyl and S(O)nR 1 ; or Ra and Rb together with the N atom to which they are attached may form a three to seven 77 WO 2006/134459 PCT/IB2006/001566 membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring which may optionally contain one or more further N, 0 or S atoms and which may be optionally further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRRd, NR"C(O)Rd, C1.6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C- cycloalkyl, 5 C3.8 cycloalkylCle 6 alkyl, C3. cycloalkylC 1 . 6 haloalkyl, C1.6 alkoxy, C16 alkanoyl, -C(0)0C16 alkyl, C1.6 haloalkyl, C3. halocycloalkyl, CO6 haloalkoxy, C1.6 haloalkanoyl, -C(O)OC16 haloalkyl, amino, NRcRd, het, phenyl and S(0)nR 11 ; or R 2 and R* together with the N atom to which Re is attached may form a six to seven - membered 10 saturated, partially saturated, or unsaturated heterocyclic ring which may optionally contain one or more further N, 0 or S atoms and which may be optionally further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRcRd, NR*C(0)Rd, C1.6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylCe 6 alkyl, C3.8 cycloalkylC1. 6 haloalkyl, C6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C3.8 15 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, NRcRd, het, phenyl and S(0)nR' 1 ; R 3 and R 4 are independently selected from hydrogen, het, phenyl, S(0),R 11 , and NRRY; 20 or either one or more of R 3 and R 4 are independently selected from C6 alkyl, C2.6 alkenyl, C4.8 cycloalkyl, C1.6 alkoxy, and benzyl, which R 3 and R 4 may be optionally and independently further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRRd, NRcC(O)Rd, C1.6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C-8 cycloalkyl, C- cycloalkylC 1 . 6 alkyl, C3.8 cycloalkylC 1 . 6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)OC1.6 alkyl, C1.6 25 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C16 haloalkyl, amino, NRcRd, het, phenyl and S(0),R 1 ; or R 3 and R 4 together with the carbon to which they are attached may form a four to seven membered saturated, partially saturated, unsaturated or aromatic ring which may optionally contain 30 one or more N, 0 or S atoms and which may be optionally further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(0)OH, C(O)NRRd, NR*C(0)Rd, C16 alkyl, C2.6 alkenyl, C2.6 alkynyl, C-8 cycloalkyl, C3.8 cycloalkylCe 6 alkyl, C3. cycloalkylo 1 e 6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(O)OC1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C16 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C16 haloalkyl, amino, NR*Rd, het, phenyl 35 and S(O)nR; with the proviso that R 3 and R 4 are not both hydrogen; Rx and RY are independently selected from hydrogen, het, phenyl, benzyl and S(0)nR 1 ; 78 WO 2006/134459 PCT/IB2006/001566 or either one or more of Rx and RY are independently selected from C1.6 alkyl, C2.6 alkenyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1 . 6 alkyl, C1.6 alkanoyl, C(O)0C 1 . 6 alkyl, each of which RX and RY may be optionally and independently further substituted by one or more substituents selected from, where 5 chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRRd, NRCC(O)Rd, C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1 . 6 alkyl, 03.8 cycloalkyC 1 . 6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(O)OC1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)OC1.6 haloalkyl, amino, NRcRd, het, phenyl and S(O),R; 10 or Rx and RY together with the N atom to which they are attached may form a three to seven membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring which may optionally contain one or more further N, 0 or S atoms and which may be optionally further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRRd, NROC(O)Rd, C1-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C3-8 cycloalkyl, 15 C3- cycloalkylC 1 . 6 alkyl, C3.8 cycloalkylC 1 . 6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)OC1.6 alkyl, C1.6 Cd haloalkyl, C-8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, NR R, het, phenyl and S(0)nR"; R 7 is selected from halo, C1.6 alkyl and C1.6 alkoxy where, when R 7 is C1.6 alkyl or C1.6 alkoxy, R 7 may 20 be optionally substituted with one or more halo substituents; R 8 is selected from hydrogen, cyano, hydroxy, C(0)OH, nitro, halo, het, phenyl, and -S(O),R"; or R8 is selected from C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1 . 6 alkyl, C1.6 25 alkoxy, C1.6 alkanoyl, and C(0)0C1.6 alkyl, which R 8 may be optionally and independently further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRCRd, NRcC(O)Rd, C1.6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1 . 6 alkyl, C3.8 cycloalkylC 1 . 6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 cd haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)OC1.6 haloalkyl, amino, NR R 30 het, phenyl and S(O)nR; or R3 is amino, which R 8 may be optionally and independently further substituted by one or more substituents selected from, where chemically possible, C(O)OH, C(O)NRcRd, NRcC(O)Rd, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1 . 6 alkyl, C3.8 cycloalkyI 1 . 6 haloalkyl, C1.6 35 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C1.6 haloalkyl, het, phenyl and S(O)nR; R 9 is selected from hydrogen, cyano, halo, hydroxy, C(0)OH, nitro, het, phenyl and S(O)nR" and NReR'; 79 WO 2006/134459 PCT/IB2006/001566 or R 9 is selected from C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C-8 cycloalkyl, C3.8 cycloalkylC 1 . 6 alkyl, C1.6 alkoxy, C3.8 cycloalkylC 1 . 6 alkoxy, C1.6 alkanoyl, C(0)0C1.6 alkyl, which R9 may be optionally and independently further substituted by one or more substituents selected from, where chemically 5 possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(O)NRcRd, NRCC(0)Rd, C1.6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1 . 6 alkyl, C3. cycloalkyI 1 . 6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(O)OC1.6 alkyl, C1.6 haloalkyl, C3.8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, C(O)OC1.6 haloalkyl, amino, NRcRd, het, phenyl and S(O)nR 1 ; 10 R* and Rf are independently selected from hydrogen, het, phenyl and S(O),R 1 ; or either one or both of Re and Rf are independently selected from C1.6 alkyl, C2.6 alkenyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1 . 6 alkyl, C1.6 alkanoyl, C(0)0C1.6 alkyl, -C(0)0C1.6 alkyC 3 . 8 cycloalkyl, C(O)C-8 cycloalkyl, each of which Re or Rf may be optionally and independently further substituted 15 by one or more substituents selected from, where chemically possible, cyano, nitro, halo, oxo, hydroxy, C(O)OH, C(0)NRRd, NR"C(O)jd, C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.8 cycloalkyl, C-8 cycloalkyI 1 . 6 alkyl, C3.8 cycloalkylC 1 . 6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 Cd haloalkyl, C-8 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(O)OC1.6 haloalkyl, amino, NR"R het, phenyl and S(O)n R" ; 20 or Re or Rf together with the N atom to which they are attached may form a three to seven membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring which may optionally contain one or more further N, 0 or S atoms and which may be optionally further substituted by one or more substituents selected from, where chemically possible, cyano, nitro, halo, 25 oxo, hydroxy, C(0)OH, C(0)NRRd, NRcC(0)Rd, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1 . 6 alkyl, C3.8 cycloalkylC 1 . 6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 Cd haloalkyl, C-8 halocycloalkyl, C 1 . 6 haloalkoxy, C1.6 haloalkanoyl, -C(0)OC1.6 haloalkyl, amino, NR R het, phenyl and S(O)nR 1 ; 30 or Re and R 2 together with the atoms to which they are attached may form a six to seven membered heterocyclic ring as previously described; R' 0 is selected from halo, C1.6 alkyl and C1.6 alkoxy and where when R 1 0 is C1.6 alkyl or C1.6 alkoxy it may optionally be substituted with one or more halo substituents; 35 each Rc and Rd are independently selected from hydrogen, C1.6 alkyl, C2.6 alkenyl, C3.8 cycloalkyl, C3.8 cycloalkylC 1 . 6 alkyl, C1.6 haloalkyl, C3.8 cycloalkylC 1 . 6 haloalkyl, C1.6 alkanoyl, C1.6 haloalkanoyl, C(O)OC1.6 alkyl, het, phenyl and S(0),R"; 80 WO 2006/134459 PCT/IB2006/001566 or Rc and Rd together with the N atom to at least one of them is attached may form a three to seven - membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring which may optionally contain one or more further N, 0 or S atoms; 5 each n is independently 0, 1 or 2; each R" is independently selected from hydrogen, hydroxy, C1.6 alkyl, C1.6 haloalkyl, amino, C1.6 alkyl amino and di C1.6 alkyl amino; 10 each phenyl may be optionally substituted by one or more further substitutents selected from the group consisting of halo, cyano, nitro, hydroxy, C1.6 alkyl, C1.6 haloalkyl, C1.6 alkoxy, C1.6 haloalkoxy, amino, C1.6 alkyl amino, di C1.6 alkyl amino, -NHS(O)nR 1 , and S(O)nR; and each het independently represents a four to seven membered heterocyclic group, which is 15 aromatic or non-aromatic, unsaturated, partially saturated or satureated and which contains one or more heteroatoms selected from nitrogen, N-oxide, oxygen, sulphur and wherein said heterocyclic ring is optionally substituted, where the valence allows, with one or more substituents selected from halo, cyano, nitro, C1.6 alkyl, C1.6 haloalkyl, C1.6 alkoxy, OC(O) C1.6 alkyl, C1.6 alkanoyl, C(0)0 C1.6 alkyl and NR9R , where R9 and R are independently selected from hydrogen, C1.6 alkyl and C2-6 20 alkenyl, and where each of the above groups may include one or more optional substituents where chemically possible independently selected from cyano, nitro, halo, oxo, hydroxy, C(0)OH, C(O)NRRd, NRcC(O)Rd, C1.6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C3.8 cycloalkyl, C3-8 cycloalkylC 1 . 6 alkyl, C3.6 cycloalkylC 1 . 6 haloalkyl, C1.6 alkoxy, C1.6 alkanoyl, -C(0)0C1.6 alkyl, C1.6 haloalkyl, C3.6 halocycloalkyl, C1.6 haloalkoxy, C1.6 haloalkanoyl, -C(0)0C1.6 haloalkyl, amino, C1.6 alkyl amino, di 25 01.6 alkyl amino, phenyl and S(O),R 1 "; or a pharmaceutically acceptable salt or a prodrug thereof.

2. A compound as claimed in Claim 1 wherein R 1 is CF 3 , OCF 3 , or SF5. 30

3. A compound as claimed in Claim 1 or Claim 2 wherein R 2 is cyano; C(O)NRaR, where Ra and Rb are independently selected from hydrogen, C1.6 alkyl and C3.8 cycloalkyl; amino; C1.6 alkyl amino, which C1.6 alkyl amino is optionally substituted with S(0),R 1 ; or S(O),R". 35

4. A compound as claimed in Claim 3 wherein R 2 is C(0)NRaRb and where both of Ra and Rb are hydrogen.

5. A compound as claimed in any of Claims 1 to 4 wherein R 4 is hydrogen and R 3 is C1.6 alkyl, which C1.6 alkyl may optionally be substituted with halo or phenyl which phenyl may in turn be 81 WO 2006/134459 PCT/IB2006/001566 optionally substituted with halo.

6. A compound as claimed in Claim 5 wherein R 4 is hydrogen and R 3 is methyl, ethyl, trifluoromethyl or 4-fluorobenzyl. 5

7. A compound as claimed in any of Claims 1 to 4 wherein R 3 and R 4 are both independently selected from C 1 . 6 alkyl which may optionally be substituted with halo.

8. A compound as claimed in Claim 7 wherein R 3 and R 4 are both independently selected from 10 methyl or trifluoromethyl.

9. A compound as claimed in any one of Claims 1 to 4 wherein R 3 and R 4 together with the carbon to which they are attached form a four to seven - membered carbocyclic ring. 15

10. A compound as claimed in Claim 9 wherein R 3 and R 4 together with the carbon to which they are attached form a cyclobutyl ring.

11. A compound as claimed in any of Claims 1 to 10 wherein R 8 is cyano. 20

12. A compound as claimed in any of Claims 1 to 11 wherein R 9 is selected from the group consisting of hydrogen; halo; C 3 . 8 cycloalkylC 1 . 6 alkoxy; and NReRf where Re is hydrogen and Rf is independently selected from hydrogen, methyl or 4-pyridinyl methyl.

13. A compound as claimed in Claim 12 wherein R 9 is amino. 25

14. A compound as claimed in any of Claims 1 to 13 wherein X is CR 1 0 and R 1 0 is chloro.

15. A compound as claimed in Claim 14 wherein both R 7 and R 10 are Cl. 30

16. A compound selected from: 1 -{5-amino-3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4 yl}cyclobutanecarboxamide; 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}propanamide; 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}-2-methylpropanamide; 35 1 -{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethoxy)phenyl]-1 H-pyrazol-4 yl}cyclobutanecarboxamide; 1 -{5.amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazol-4 yl}cyclobutanecarboxamide; 1 -{3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-5-(methylamino)-1 H-pyrazol-4 82 WO 2006/134459 PCT/IB2006/001566 yl}cyclobutanecarboxamide; 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-i H-pyrazol-4-yl}propanamide; 2-{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazol-4-yl}-3-(4 fluorophenyl)propanamide; 5 2-{5-amino-3-cyano-i -[2,6-dichloro-4-(trifluoromethyl)phenyl]-I H-pyrazol-4-yl}butanamide; N-(1 -{5-amino-3-cyano-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazol-4-yl}-2,2,2 trifluoroethyl)-N-methylmethanesulfonamide; 5-amino-1 -[2,6-dichloro-4-pentafluorothiophenyl]-4-[1 -(methylsulfonyl)ethyl]-1 H-pyrazole-3 carbonitrile; 10 1-[2,6-dichloro-4-pentafluorothiophenyl]-4-[1 -(methylsulfonyl)ethyl]-1 H-pyrazole-3-carbonitrile; 2-{3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}propanamide; 2-{5-chloro-3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4-yl}propanamide; 2-{3-cyano-1 -[2,6-dichloro-4-pentafluorothiophenyl]-5-[(pyridin-4-ylmethyl)amino]-1 H-pyrazol-4 yl}propanamide; 15 5-amino-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[2,2,2-trifluoro-1 -(methylamino)-1 (trifluoromethyl)ethyl]-1 H-pyrazole-3-carbonitrile; 5-amino-4-[1 -amino-2,2,2-trifluoro-1 -(trifluoromethyl)ethyl]-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl] 1 H-pyrazole-3-carbonitrile; 5-amino-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[2,2,2-trifluoro-1 -(isopropylthio)-1 20 (trifluoromethyl)ethyl]-1 H-pyrazole-3-carbonitrile; 5-amino-4-[1 -cyano-2,2,2-trifluoro-1 -(trifluoromethyl)ethyl]-1 -[2,6-dichloro-4-pentafluorothiophenyl] 1 H-pyrazole-3-carbonitrile; 2-{3-cyano-5-(cyclopropylmethoxy)-1 -[2,6-dichloro-4-pentafluorothiophenyl]-1 H-pyrazol-4 yl}propanamide; 25 or a pharmaceutically acceptable salt or prodrug thereof.

17. A pharmaceutical composition comprising a compound as claimed in any of Claims 1 to 16 and a pharmaceutically acceptable carrier. 30

18. A compound as claimed in any of Claims 1 to 16 for use as a medicament.

19. The use of a compound as claimed in any of Claims 1 to 16 for the manufacture of a medicament for the treatment of a parasitic infection. 35

20. A method of treating a parasitic infection comprising treating an animal with an effective amount of a compound according to Claims 1 to 16. 83