WO2005028452A1 - Substituted triazole derivatives as oxytocin antagonists - Google Patents

Abstract

The present invention relates to a class of substituted 1,2,4-triazoles of formula (I) with activity as oxytocin antagonists, uses thereof, processes for the preparation thereof and compositions containing, said, inhibitors. These inhibitors have utility in a variety of therapeutic areas including sexual dysfunction, particularly premature ejaculation (P.E.).

Description

Substituted Tnazole Derivatives as Oxytocin Antagonists

^" The present invention relates to a class of substituted 1 ,2,4-triazoles with -activity as oxytocin antagonists, uses thereof, processes for the preparation thereof and^"

5 compositions containing said inhibitors These inhibitors have utility in a^" variety of therapeutic areas including sexuaj dysfunction, particularly premature ejaculation (P E )

Eur J ^" Med Chem 1985, 20(3), pp257-266, refers to derivatives of-0- 1 ,2,4-triazoles having analgesic and antnnflammatory properties - - WO 03/053437 refers to 1 ,2,4-triazoles having activity as oxytocin antagonists, EP ^"1 ,293,503 refers to derivatives of-1 , ,4-tπazoles having glycine transporter inhibiting properties . - 5 - The first aspect Of the present invention provides for compounds of formula (I) —

wherein^" 0 V,^"W, X and Y, which may be the same or different, represent C-R⁶ or N,

^" Z ιs^'C-H or N

R¹ is selected from-

25

(i) a phenyl ring substituted with Two or more substituents which may be the same or different each independently selected from halo (Cι-Cβ)alkyl, (C C₆)alkoxy, cyano, C(0 NR^"R^S NR R^{8 "} NR^"C(0)R¹⁰ and N[C(O)R¹⁰]₂, and ^~\\\) a five to seven membered aromatic heterocyclic ring .containing 1-3 hetero atoms selected from N, O and S and N-o.xides thereof; said ring being optionally substituted with two or more substituents, which may be the same or different,. -selected from halo, (Ci-C-₆)aIkyl, (Cι-C₆)alkoxy, cyano, C(O)NR⁷R^δ, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂;

R² is selected from:

10 (ⁱ) H, OH, OR⁹, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]2i. - -- . -

(ii) a 5-7 memberecl =N-linked heterocycle containing _1 -3 heteroatoms selected from N,O and S ^"said ring-being optionally substituted with one or more groups selected from -(Cι-C₆)a!kyl, (Cι-Cβ)alkoxy and C(O)NR⁷R⁸,

15 ^" and . ^"- _ .

(iii) (Cι-Cβ)alkyl optionally substituted -with an N-linked 5-7 membered ^{' • "} heterocycle containing 1 -3 heteroatoms selected from N,.Q and S;_

20^{" " "} R^"3 is selected from- H and (C G₆)alkyl,

R⁴ is selected from-H, (C C₆)alkyl and OR⁹;

R⁵ is selected ^"from haloχ(Cι-C₆)alkyl, (CrC₆)alkoxy, NR⁷R⁸, NR⁷C(O)R¹⁰ and ^"25 N[C(O)R¹⁰]i;

R-^ - selected from H, halo, (C C₆)alkyl, (Cj-C₆)alkoxy, cyano, NR⁷R⁸, NR⁷C^'(O)R¹ , N[C(O)R¹⁰]₂ and C(O)NR⁷R⁸;

30 R' and R^δ, Λ hich may -be the same or different, are selected from H and - (C C₆)alkylf ^' . . _- _ _. . - R⁹ is (CrCβ)alkyl, which is optionally substituted with with one or more groups eachϊndepende^'ntly selected from (C₁-C₆)alkoxy and an N-linked 5-7 membered - heterocycle containing 1-3 heteroatoms-selected from N, O and S; and - -_-_

5 R¹⁰ is setected^'from (C C₆)alkyl and (Cι-C₆)alkoxy;

a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound. or tautomer; 0 with the proviso that the compound of formula (I) is nσt^~

^~ 3-ethyr-5-(4-imidazol-1-y phrenyl)-4-(4-methoxyphenyl)-4H-:[1 ,2,4]triazole, . - - ^• 3-(3',5"-dichlorobiphenyl-4-yl)-4-(2-methoxyphenyl)-5-methyl-4H-[1 ,2,4]triazole, 3-(3^r,5^,-bis-trifluoromethylbiphenyl-4-yi)-4-(2-fluorophenyl)-5-methyl-4H- [1 ,2^~4]triazole, or. 5 3-(3^,,5'-bis-trifluoromethylbiphenyl-4-yl)-5-methyl-4-(3-trifluoromethylphenyl)-4H- " ^{* "}-- [ ,2,4]triazole - - - -

-^~~ - Unless otherwise indicated, allkyl and alkoxy groups may be_.straight or branched and contain 1 to 6 carbon .a tom^ahd preferably 1 to 4 carbon atoms. Examples 0 " ΌT alkyl include methyl,

isopropyl, n-butyl₇. isobutyl, sec-butyl, pentyl and hexyl. Examples of- alkoxy -include methoxy, -ethoxy, isopropoxy and n-butoxy. - - . -

Halo means fluoro, chloro, bromo of iodo and is preferably fluoro. 5

^{" "} - A^" heterocycle may be saturated, partially_, saturated or aromatic. Examples- of - heterocyclic groups are thiolanyl, pyrrotidinyl, pyrrolinyl, - tr dazolidinyl, imidazolinyl, sulfolanyl, dioxolanyl, dihydropyranyl, tetrahydropyranyl, p peridmyl, pyrazolinyl, pypaz lidinyl dioxanyi ~ moφholinyl, dithianyl, thiomorpholinyl, 30 piperazinyl, azepinyl, oxazepinyl, thiazepinyl, thiazolinyl and diazapanyl. Examples of aromatic heterocyclic .groups are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyi, imidazolyl, pyrazolyl,- isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, -pyrirnidinyl, pyrazinyl, pyridazinyl, triazinyl. Unless otherwise indicated, the term substituted means substituted by one or- more defined groups In the case- where groups may be selected from a number of alternative groups, the selected groups may be the same or different - _ -

Preferred aspects of the invention are defined below

In a preferred aspect, the present invention comprises compounds of formula (I) wherein - ^" . -

1 or 2 of the groups V, W, X and Y represent N when the.remamder represent

C-R^te

Z is C-H or N

R¹ is selected from

(i) a phenyl ring substituted with two or more substituents, which may be the slSϊpe or different, each independently selected from halo, (CrGf atkyl, (Cι-C_β)alkoxy, cyano, C(Q)NR⁷R⁸, NR⁷R^δ _l-NR⁷C(O)R¹⁰ and

N[C(O R¹⁰]₂, and

- ^~(iι) a -five to seven membered- aromatic heterocyclic ring containing -1-3 hetero atoms selected from N , O and S and N-oxides thereof, said ring being optionally substituted with two or more substituents, which may be the same ΌΓ different, selected from halo, (CrC₆)alkyl, (Cι-C₆)alkoxy,_ ^{" "} cyano, C(O)NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂,

^"Preferably-, R² ιs^~seϊeeted from

(i) H, (C C₆)alkoxy (CrC₆)al oxy-(C₁-C₆)alkoxy, NR⁷R⁸, NR⁷C(O)R¹⁰ and

N[C(O)R 1^ι0^υι]₂, and (li) a 5-7 membered N-linked heterocycle containing 1-3 heteroatoms selected from N.O -and S, said ring optionally substituted wittTone or more - groups selected from (Cι-Cβ)alkyl, (CrC₆)alkoxy and C(O)NR⁷R⁸;

R³ is selected from H and (C C₆)alkyl,

R⁴ is selected from H, (C C₆)alkyl and OR⁹,

R⁵ is (C C₃)alkyl, (d-G^alkoxy or NR⁷R⁸; - . - ~ ^" -

R⁶ is H, halo, (C C₆)alkyl, (Cι-C₆)alkoxy_J cyano or NR⁷R⁸,

R' and R , which may be the same or different, are selected from H -and (CrCβ)alkyl, - _ . = ~ ^"

R⁹ is (CrCβ)alkyl optionally substituted with (Cι-C₆)alkoxy, and

R¹⁰ is selected from (C C₆)alkyl and (C C₆)alkoxy,

^"-- a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph_. of said compound or tautomer. - _

In^" another preferred aspect, the present invention comprises compounds of formula (1) wherein - - - " - - : .

^"1 or 2 of the groups- V, W and Y represent N when the remainder represent C-R⁶

ZT'is C-H or N, . ^' ; - - ^"

R¹ is selected from (i) a phenyl ring substituted with two substituents, which may be the same or different, each independently selected from halo,_ (Cι-C₃)alkyl, (CrC₃)alkoxy, and cyano; and

> (ii) a pyridyl ring or N-oxide thereof each substituted with two substituents,

' which may be the same or different, each independently selected from - - halo, (CrC₃)alkyl, (C C₃)alkoxy, and-cyano; .

R² is selected from' -^~

10

^' - (^j) H, (C C₃)alkoxy, (C₁-C₃)alkoxy-(Cι-C₃)alkoxy and N((C C₃)alkyl)₂;_and

(ii) a 5 membered N-linked heterocycle containing 1-3 nitrogen atoms, said ring optionally substituted with C(O)NR⁷R⁸;

^"15

R³ is ^"selected from H ah^'d (Ci-C₆)alkyl; - - -

R⁴ is selected from H,-(C C₆)alk l and OR⁹; .-

20 R⁵ is (CrC₃)alkyl, (C C₃)aJkoxy or NR⁷R⁸

R° is H, (Cr€₆)alkyl, (Gι-C₆)alko> y or NR 7_DR8.

R'^" and R⁸,^" which may be the same or different, are selected from. H _.and- 25^" - (Cι-C_β)alkyl; and

R⁹ is (C -C₆)alkyl optionally substituted with methoxy,

^{~ "}--a-tautomer thereof or-a pharmaceutically acceptable. salt, solvate or polymorph 30 of said compound^" or tautomer. _ __

In another preferred aspect, the -present invention comprises compounds of formula (I) wherein W and Ϋ are each independently CH or N and X and V are each CH;

ZisN; - .:- - - . ^■- ^■ :^■ _

5

R¹ is a phenyl ring substituted with two substituents, which may be the same or - - different, each independently selected from fluoro, chloroy-methyl, methoxy, and. cyano;

TO ^''" ~R²- is ^"selected from -H, methoxy, ethoxy, -2-methoxyethoxy, .dimethylamino, - ^'"'"' 1,2,^"3-triazbl2-yl and pyrollidinyl, the latter- being -ropti.onally- ^"substituted by CONH₂; ^■■■--.^■ : -^•-^'-

R³ is selected from.Hand (-Cι-C₆)alkyl;-

15

R >4^4' is H; and

R⁵ is methoxy;

20 a tautomer thereof °r a pharmaceutically acceptable salt, solvate or polymorph of said compound or faϋtomer. ^' -.- : ^■-■^■_,.

^"Preferred embodiments of the compounds of formula (l)-according. to the above aspects are those that incorporate two or. moτe of the following preferences-

25 , -.r ::• - - .^' - - ^• - .- _ -^■ _:-.-

Preferably, 1 or 2 of the groups V, Λ/V, X and Y represent N when the remainder

^{■' " "} represent C-R⁶.- - ^"-^■' • ^' _.. ^•' " ^■- ^{■ "} -■■^■ - ^■■ ^■":•^' . ^■. ^{;. ,}x-_x ^. x ^{. "L':} n apVeferred_.emodiment, Xis CH. ■ ^■■- .-- .- - .-. . -.

"In a preferred emodiment, 1-or 2 of the groups V, W and-Y represent-N-wheή the

30 ^"remainder represent C-R⁶ and. X is GH; Preferably,^'Y is N or CR⁶.

More preferably, V; and Y are eaόh independently CH,^" C-OCH₃ or N. -Most preferably, W and Y are each independently CH or N. In the most preferred embodiment, W and Y are each independently CH or N and X ancrV are each CH

In a preferred emodiment, Z is h . - 5 ^" In another preferred emodiment, Z is CH

^"Preferably, R is selected from _ - _- _

- (i) a phenyl ring substituted with two or more substituents, which may be 10^{" z} the same or different, each independently selected; from halo,

(CrCβ)alky , (C₁-C_β)alkoxy, .-cyano.- C(O)NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰ -and - N[C(O)R¹⁰]₂ and

(n) a five to seven membered aromatic heterocyclic ring containing 1-3

15 hetero atoms selected from N, O and-S and N-oxides thereof, said ring

_ being optionally substituted -with ^"two or more substituents, which may be the same or different, selected- from halo, (Cι-C₆)alkyl, (C-ι-Ce)alkoxy,

_ cyan C(O)NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂₎ -

-20^"-^"" More preferably, R¹ is selected from

(i) a phenyl ring -substituted ΛΛ ιth.-two-sub&tιtuents, which may be he same or different, eaGh independently selected from halo, (Cι-Ce)alkyl, Cι-C₆)alkoxy, cyano, C( )NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂,

25 and - ^" ,= 1 - _ -

(ii) a pyπdyl πng or N-oxide thereof each substituted with two substituents,

- which may be the same or different, each independently selected from - - halo, (C C₆)aLkylχ(Cι-C₆)alkoxy_τ cyano, C(O)NR⁷R^δ, NR⁷R⁸, NR⁷G(O)R¹⁰

30 - and N[C(O)R¹⁰]₂ - - -

Yet mocepreferably, R¹ is selected from _ _ . (I) a phenyl nrrg substituted with two substituents, which may be the same or different, ^" each independently selected from halo, (C C₃)alkyl, (CrC₃)alkoxy and cyano, and _ - -

(ii) a pyndyl ring or N-oxide thereof each substituted with two substituents, which may be the ^"same or different, each independently selected from halo, (Cι-C₃)alkyl^~ (Cϊ-C₃)alkoxy and cyano

In a preferred embodiment, R¹ is a phenyl ring substituted with two substituents,- which may^" be the same or different, each independently selected from fluoro, chloro, methyl, methoxy and cyano ^"- ^~ .

In another preferred embodiment, R¹ is pyπdine-N-oxide substituted with two methyl groups _ _

Preferably, R² rs selected from

(i) H, (Cι-C₆)alkoxy, (C₁-C₆)alkoxy-(C₁-C₆)alkoxy, NR^7"R⁸, NR⁷C(O)R¹⁰ and

_

.(II) a 5-7^" membered N-lmked heterocycle containing 1-3 heteroatoms - selected from N,Q and S said ring optionally substituted with one or more groups selected from (C C₆)alkyl, (C₁-C₆)alkoxy and C(O)NR⁷R⁸

More preferably, R² is selectedjrom

(f) H, (C Cf)alkoxy, (CrC₃)alkoxy-(Cι-C₃)alkoxy and N((C C₃)alkyl)₂, nd

. (ii) a 5 mem ered-N-linked heterocycle containing 1-3 nitrogen atoms, said ring^" optionally substituted with C(O)NR⁷R^δ Yet-more preferably, R² is selected from , methoxy, ethoxy, 2-methoxyethoxy, dimethylamino, 1 ,2,3-triazol-2-yl and pyroHidinyl, .the latter being optionally -substituted by CONH₂. _.

Most preferably, R² is selected from H and methoxy* x - _ -

5. - - Preferably, R³ is H or (Cι-C₃)alkyl. - . , _

Most preferably, R³ is H. - - - .

Preferably, R⁴is H^C C^alkyl or OR⁹. .^{" "} 0 - More preferably, R⁴ is H, (C_rC₃)alkyl or (C C₃)alkoxy._ Most preferably, R⁴ is H,-methyLor methoxy: - ^~ -In a preferred embodiment, R⁴ is H. - - _.-_ _

Preferably, R⁵ is (Ci-C₃)alkyl, (C C₃)alkoxy or NR⁷R^δ: 5 - More-preferabJy, ^"R⁵ is (C C₃)alkoxy or NR⁷R^δ - - - _-

^" Most preferably, R⁵ is methoxy or NHCH₃ - . - -

In a preferred embodiment, R⁵ is methoxy.

- Preferably, R⁶ is H, halo, (Cι-C₆)alkyl, (C C₆)alkoxy, cyano or N_R⁷R⁸ 0 - More preferably, R⁶ is H, (C C₆)alkyl, (Cι-C₆)alkoxy or NR⁷R⁸.

- Yet more preferably,.^⁶ is H, (Cι-C₃)alkyl or (Cι-C₃)alkoxy,_

- Most preferably, R-⁶ s JH, methyl or methoxy.- - _. - _ - - -^{" _} In-a preferred embodiment, R⁶ is H or methyL

In a most preferred embodiment, R⁶ is H 5

- Preferably, R⁷ is H or (C C₃)alkyl - ._{. .}_-. . -

Most preferably, R⁷ isΗ or methyl . . ^■

Preferably. R⁸ is H or (C C₃)alkyl 0 - Most preferably, R⁸ is H or. methyl -- - _. - .

Preferably, R⁹ is ^Cι-C₆)alkyl optionally substituted -with (Cg_-C₆)alkoxy. More preferably, R⁹ is (C_1rC₆)alkyl optionally substituted with methoxy. Most preferably, R^θ is methyl: - - -^" - ^{"" "}_---

Preferred compounds of formula (I) are: . - - . - ^"

2-(4-fluoro-2-methylphenyl)-5-(5-methoxymethyl-4-(6-methoxypyridin^"-3-yl)-4H- - [1,2,4]triazol-3-yl)-pyridihe; ^{" '} - - - ^{* "}

2-(2,3-dimethylphenyl)-^_5-(5-meth^"oxymethyl-4-(6-methoxypyridin-3-yl)-4H- [T,2,4}ffiazol-3-yl)-pyridine; ^" -. - - _^:-

5-(4-fluoro-2-methylphenyl)-2-(5-methoxymethyl-4-(6τmethqxypyridin-3-yl)-4H- tTT2,4]triazol-3-yl)-py?idine, - . -_- ^" :_.- - 5-(2,3-dimethylphenyl)-2-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H- [1,2,4)^"friazol-3-yl)-pyridinef- ^"" - ^"- - -

1 -[5-[5-(2,3-dimethylphehyl)-pyridin-2-yl]-4-(6-methoxypyridin-3-yl)-4H- . [1,2,4]triazol-3-ylmethyl]-pyrrolidine-(2S)-2-carboxy1ιcacid amide; 5-(2,3-dimethylphenyl)-2-(5-pyrrolϊdin-1-ylmethyl-4-(6-τnethoxypyridin-3-yl)-4H- [Y,2,4]triazol-3-yl)-pyfidine; ^{' "} . _.. ^"-^"" - - --^"-

2-(4-fTuo^~ro-2-methyrphenyr)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H- [f,2,4]triazol-3-yl]-pyrazihe; - ^" . ^~ - . - x- -

2-(2,3-dimethylphenyl)-5[5-rhethoxymethyl-4-(6-methoxypyridin-3-yl)-4_.H-- [1,2,4]triazol-3-yi]-pyrazine; ; - - ^' -^{~ " "} - .- ^" 2-(4-fluoro2-met^"hylphenyl)-5^"^4-(6-rnethoxyρyridin-3-yl)-5-methyl-4H-- [1^2,4]friazol-3-yl]-pyrazine; ^{" "} - -- ^" -^" _ -- .-.-_

^" 2-(2,3-dιmethylp^"henyl)-5-[4-^"(6-methoxypyπdin-3-yl)-5-methyl-_4H-[1,2,4ltriazol-3- yf]-pyrazinef ^{" "} — - - ^"

2-(4-cyano-2-methylphenyl)-ι5-[4-^"(6-methoxypyridin-3-yl)-5-methyl-4H- ^{" ~}-[1,^"2,-4]triazbl-3-^"yl]-pyrazine; ^{" " * " '}_^" ,^" - ^{' "} -: - ^'-' ' i 2-(5-fluoro-2-methόxyphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H- ^" [1,2,4]triazol-3-yl]-pyrazine; - . - . _^". -;-^" 2-(4-cyano-2-methylphenyl)-5-[5-methόxyn-ιethyl-4-(6-meth^"oxypyridin-3-yl)-4H- [1,2;4]triazoϊ-3-yl]-ργrazine, - - ^~~ - . ' - ~ . 5-(4-cyano-2-methylphenyl)-2^;(5-methoxyrnethyl-4-(6-methoxypyridin-3-yl)-4H- [1 ,2,4]triazol-3-^"yϊ]-pyridine; -- ^{" "}' - - -

2-(5-fluoro^;2-methoxyphenyl)-5^[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-_.4H- [1 ,2,4]triazol-3-yl]-pyπdine; -^■..^"" 2-(2-fluoro-5--methoxyphenyl)-5-[4-(6-rηethoxypyridin.-3-yl)-5,-methyl-4H-- ^' [1,2,4]triazol-3-yl]-pyrazine; ._. . , - -

2-(2-fluoro-5-methylphenyl)-5_:[4-(6-methoxypyridin-3-yl)-5-methyl-4H- .-. [1,2,4]triazol-3-yl]-pyrazine; .. _. _ .

^'■■■■^■5 ^"--^.(2,5-diflϋbrop

^{■■. ;.}- ,2,4]triazol_-3-

yl]-pyraziner -__. ■-_...

^■■-^;•■ - 2-(2-,5-dimethVlphenyl)-5-[4-(6-methoxypyridib-3-yl.)r5-methyl-4Η ,_.2 ]triazol-3-- 10 yl]-pyrazine; _.. .. .. _. ..

_. -^•2-(2,5-dichiorophenyl)-5-[4-(6-methoxypyridin-3-yl)^5--methyl-4H-[1,2,4]triazo 3-_ yl]-pyrazine; ^{~ '} .... . - ; -. _: ^■■■^■■-■■^■. ^_.- --■^■-■^■ ■ -

^! _τ .2^(2-fluoo5-me.thoxyphenyl)-5-[4-(6-metho>cypyridin-3-yl)-5-methyl-4 - - ^; . ._. H-[1,2,4]triazol-3-yl]-pyrazine; . ._ _ -_χ _. . . .^..

:15 ^" 2-(3,5ⁱdifluoro-phenyl)-5-[4-(6methoxypyridin-3-yl)-5-methyl-4H-[1,2,4.]triazo 3-^^ - yl]-pyrazine; -_. ;; - ^■■:,. - . ^•- . - -_.- ^■---_.

:^"-^■■■ 2-2,3-dimethylphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6._τmethoxypyrid ., 4H-1,2,4^"-triazol-3-yl]pyridine; _■ - x - .... .-.._•

^■• ^{• ■}:^■-^' 2-(5-^;chloro-2-methoxyp_henyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6- ;xχ .-' x. ^; 20 methoxypyridin-3-yl)-4H-.1,2,4.rtriazol-3-yl]pyridine; ._-__.. .. - ; 2 4-fluoro-2-methpxyphenyl)-5_:I5-[(2-methoxyethoxy)methyl]-4;-(6--- .XiL-r . ■

2-(2,5-dιmethoxyphenyl)-5-[5-[(2-methoxyeth9xy)methyl]-4 (6-methoxypyridin-3-_ yl)-4H-1 ,2,4-triazol-3ryl]ρyrιdine; ^" . - -

- 2-(3-chloro-4-fluorophenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxyρyridin-

3-yl)-4rV-1 ;2,4-triazoμ3-y1]pyπdine and 5 2-(3-fluoro-2-methoxyp enyl)-5-[5-met oxyTOet yll-4-(S-jrιethoxypyr5din-3- . _ yl)-4H-[1 ,2,4]triazo1-3-yl]-pyrazine; - -(3-fluoro-2-methoxy henyl)-5-[4-(6-methoxy-pyrid!n-3-yl)-5- ethyl-:4-H- [1,2,4]triazol-3-yl]-pyrazfne; - - _ . . and tautomers thereof and pharmaceutically acceptable -salts, solvates. and 10 polymorphs of said compound-or tautomer

Most preferred compounds of formula (l)-are: .- _ ^-_.

2-(4-?iuoro-2-methylphenyl)-5-(5-methoxγmethyl-4-(6-methoxypyridin-3-yl)-4H- -

[1 ,2,4]triazol-3-yl)-pyπdιne; - - — -- 1^"5 2-(2,3-dιmethylphenyl)-5-(5-methoxymethyl-4-(6-methoxypy_.ridin-3-yl)-4H-

[1 ,2,4]tπazol-3-yT)-pyridihe; ^{* "} -

5-(4-fluoro-2-methylphenyl)-2-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-

[1 ,2,4Jtriazol-3-yl)-pyridine; - . - - - . - ^" - - . _.- _..

5-(273-dimethylphenyl)-2-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H- 20 [1 ,2,4]triaz l-3-yl)-pyridιne; ^" -^"-- , - . - , -

^* ^-[5-[5^"-(2,3-dimethylphenyl)-pyrιdin-2^yl]-4-(6-methoxypyridin-3-yl)-4H- _. ..

[1 ,2, 4]triazol-3-ylmethyl]-ρyrrolιdιne-(2S)-2-carboxylic acid amide;.

5-(2,3-dιmeth^"ylphenyl)-2-(5-pyrrolιdιn-1 -ylmethyl-4-(6-me_thoxypyrιdin-3-yl)-4H- ~ [1 ,2,4)trιazol-3-yl)-pyrιdine, ^{" ~} . - _„ - ~ -X

25 ^~"""2-(4-flubro-2-methylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-y -4H-

[1 ,2,4]tπazol-3-yl]-pyrazine; -. - - r* . _. I

2-(2,3-dimethylphenyl)^"-5-[5-methoxyrrιethyJ-4-(6-methoxypyridin-3-yl)-4H- " [1 ,2,4]tπazol-3-yl]-pyrazιne, - - - -- .- . ._._ - - ..

2-(4-fluoro-2-methylphenyl)-5-[4- 6-methoxypyrιdin-3-yl)-5-methyl_r4H- 30^" [1 ,2,4]trιazol-3-yl]-pyrazιne, - -- - - . . . ._^ -

^" - ^" 2-^"(2,3-dimethylphenyl)-5-[4-(6-methoxypyridιn-3-yl)-5-methyl-4H-[-1 ,2,4]triazol-3- yl]-pyrazιne, _, - ~ . - .- . ,._ -, 2-(4-cyano-2-^"me^"thylphenyl)-5-[4-(6-metboxypyridin-3-yl)-5-methyl-4H-- ^" [1 ,2 4]triazol-3^yl]-pyrazine; . . _. . . --

2-(5-fluoro-2τmethoxyphenyl)-5-[4-(6-meth xypyridin-3-yl)-5-methyl-4H- [1 ,2,4]triazol-3-yl]-pyrazine; . • .^" . .-. - . „ ^■.. ^•'- - -

5^{'"" '}2-(4-cyano^2--rnethylphenyl)-5-[5-methoxymethyl-4-(6^meth^"oxypyridin-3-yl)-4H- =.-; [1 ,2,4^']triazol-3-yl]-pyraztne; -_- - -. ... - - - ^' -

^"" 5^~(4-cyano-2-methylphenyl)-2-[5-methoxymethyl-4-(6-methoxypyrLdin-3-yl)-4H- [i ,2,^"4]triazdl-3-y-l]-p^"yridine; - . . _-.. X -.--_ ;_ -

2-(5-fluoro-2-methoxyphenyl)-5-[5=methoxymethyl-4-(6-methffi<ypyridin-3-yl)-4H- -

10 [1 ,2,4]triazol-3-yl]-pyridine; and

^"15 ^• and" tautomers thereo an p armaceut ca y -acceptable salts, solvates and : poiymbrphέ^"θf said compound or tautomer. -- . - - - . --• ^■,-

^'- ^" Pharmaceutically acceptable salts of the compounds of formula (I) comprise the acid^' addition salts thereof; ^' - . . -. . ^{"■ ■} -^•-^• ...

20 Suitable acid addition salts are formed from^" acids which form^" ήon-toxic salts.

Examples iriGlude^""— the acetate, aspartate, benzoatex .besyfate

^"' bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate,^' esylate, formate, fumarate, gluceptate, - gluconate, ^'■■ glucuronate, nexafluorophosphate^", hibenzate, hydrochloride/chloride, hydroteromide bromide,

25 ^~-hydroiodide/Jodide,, isethionate lactate; malate, maleate, malonate, mesylate,

^"methylsulphate, naphthylate^', 2-napsylate, nicotinate, nitrate, orotate,-- oxalate, " palnfilate, - pamoate, -phosphate/hydrogen phosphate/dihydrogen-¹ phosphate,

^" saccharate, stearate.-sυccinate, tartrate, tosylate-and trifluoroacetate salts. ^{"" """■}■

30 ^Hemisalts of acids may also be.formed, for example, hemisulphate "salts^". ^"■ -

For a review on suitable salts, see Handbook of Pharmaceutical Salts:^" Properties, Selection and Use by Stahl and Wermuth (Wiley* VGH, Weinheim, Germany; 2002). - . ^: - . Pharmaceutically acceptable salts of. compounds of formula (I) may be prepared_^ -^~r bybne or more⁵ of three methods: , _ - - - ,. . _ , - _..

- (i) ^by ^"reacting the compound of formula (I) with the desired acid; 5 (ii) by removing an acid-labile protecting, group from, a suitable precursor of ' ^{■ ■ ■} ^he compound of formula (l)-usingjhe_. desired acid;, or

^" - v(iii)^: by converting -one salt of thexcompound of- formula (I) to ..another, by reaction witrr-an appropriate acid or by means cf a suitable ion exchange

-10^'- ..-_. column: ^" . x . . ..

All three reactions- are typically carried out jn .sojution, The jesulting salt may precipitate out and be collected by filtration or may be recovered.by evaporation of -the solvent. The. degree of ionisation in the resulting salt , may -vary from 15 ^" - completely -ionised to almost . non-ionised.., ^■-^•.. -^••...-^■•, ,^■■. . . . _, .._/. χ .

^"-^{• '•■■■■'■■■"'■}•The compounds of- the invention may exist in , oth, unsolvated and.solvated. . ^. ,^, ό_rm^ ^"The^: term 'solvatey is used herein to. describe a molecular complex ^ comprising, the, compound of the - invention .and^a stoichiometric or- non-_ 20 F-stoichiometric amount of one or more pharmaceutically acceptable solvent

^" be in stoichiometric or non-stoichiometric amounts. The resulting complexes

^{' :} -may- be ionised,--. partially . ionised,, or _n_on-ioηised. For a -review of such

30 - cornpϊexes^:; see-J Pharm Sci, 64 (8), .1269-1288, .by HaJeblian.(ALigust_.1975).- ._.. Hereinafter all references to compounds of formula (I) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereot X : . - ; - - . - _. . -_._~ -

The compounds of_. the - invention include compounds of formula (I) as hereinbefore defined^ - including all polymorphs and crystal habits- .thereof,

- prodrugs- and isomer.s thereof (including, .optical, geometric and taυtomeric

^". isόrhers) as hereinafter defined and isotopically-labeled compounds of formula

10

- As indicated,- so-called - 'pro-drugs' of- the compounds of formula (I.) -are.-also- within the scope of-the. inventL0Jϊχ:Thus certain derivatives of compounds of formula, (I) which may _.have little, or. no pharmacological activity themselves can,

- ^{r "} when -administered .into.- or onto :the body, be . converted- into compounds^" of

15 formula (I) having the desired activity, for-example,χb hydrolytic cleavage. Such

^'-" derivatives : are . referred- to as -^:,'prodrugs'÷ Further information- on . the use .of

- prodrugs- may .be founeUn Pro-drugs as Novel Delivery Systems, Vol. 14, ACS

^' -^τ -Symposium Series (T._. Higuchi and . -.Stella.) --and Bioreversible Carriers in Drug -

:■ ■ Design,. Pergamon Press, .1967 - ted. E, B. Roche, . American Pharmaceutical 20 Association). _ - ^' . x,

Prodrugs-

invention ^"can,- for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain_. moieties known to those skilled in the art as ' pro-moieties' :as described, 25 ifόr example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985). ^■.--•:

^' - -Some examples of prodrugs in accordance with, the invention include - ;..-^•; ^"

(i) where the compound of formula (I) contains an alcohol functionality (-OH),

- 30 -^• - ^": "^': an ether thereof, fo example;, a. compound, wherein the hydroge .of the^". alcohol functionality. of the compound ,. of- formula (I) is replaced . by

- : ^■■■- ^•. (C.ι-C₆)alkanoyloxymethyl; and. _. - _.. ,. • . -= (ii)^" where -the -compound- of formula (I) contains a primary or secondary amino functionality- (-NH₂ or -NHR where R ≠ H), an- amide thereof, for

. ^{" =}- _ -example, a compound wherein, as the case may be,, one _.or both hydrogens of the amino functionality of the compound of formula- (I) is/are

- 5 ~^~- - -replaced by -(Gi-Cιo)alkanoyl.- . - _. - " ._.

- Further -examples of replaeertent groups -in accordance with the foregoing examples and examples of other - prqdrug types may be Jound . in the

^" aforementioned references. - . - - - _ -_-- --_. ---- - - 0 ;-, - - .:- . - - - - . _. -_ . _ ...

- Moreover, certain compounds of formula .(I) may themselves act as prodrugs of other compoundsjβ formula (J). - ---,-..

^"- Also included within the scope ot- he invention are metabolites of compounds of 15 ^" formula (I), that is, compounds filme _, in vivo upoα administration of the drug -^" -Some^" examples of metabolites in ^"accordance with -the invention .include -... .

(i) .- here the compound of formula ^"(I) contains a methyl, group, an

- -- hydroxymethyl derivative thereof (-CH₃ -> -CH₂OH):

20 - . -. _.

- -^"(ii) ^" -where the compound of-formula (I) containa_^a alkoxy .group,- an hydroxy. z ^lχ- "derivative thereof (-OR--> -OH),_.... -. - ___. - . ___ _

(iii) ^" where the compound of formula (I) contains a tertiary amino group, a 25 - - -^" - secondary amincderivative thereof (-NR¹R? -> -NHR¹ or --NHR²); . ,_:

^* (iv) where-the compound of formula_. (I) contains a secondary amino group, a

- - - primary derivative-thereof-(-NHR¹ -> -NH₂);- . -

-30 - (v)-^' where, the compound _of formula (I) contains a phenyl moiety, a phenol - ^"derivative thereof.(-Ph - -PhOH), and - _- - .. _ ^" (vi) - where the compound of formula (I) contains an- amide group, a carboxylic " ^" - - - acid derivative thereof (-CONH₂ -> CΘOH) - . .

Compounds of formula (I) containing one or more asymmetric carbon atoms can 5 -exist as two or more stereoisomers Where a compound of formula (I) contains a alkenyl or alkenylene group,--ljeometrιc cis/trans (or Z/E) isomers -are possible Where structural isomers are interconvertible via a low energy barrier, tautomeπc isomerism ('iautomeπsm') can occur This can take the form of proton - ^"lautomerism in compounds of formula (I) containingr for example, an imino, keto, TO or oxime-group, or so-calle -valence tautomerism in compounds which contain, an aromatic moiety It follows that a single^'compound may-exhibit rriorerthan one - "type of isomerism —- - - - - - - - - _Σ..

^" Included within the -scope of the present invention are all stereorsomers, 15 geometric^" isomers and tautomeric forms of the compounds of- formula (I), "includinc/compounds exhibiting more than one type-of isomerism, and mixtures - "^" of one- or more thereof Also- included are acid addition salts, wherein- the cou rteriori is optically active, for example, cf-lactate, or racemic, for example, dl- tartrate^"" - ^"- ■: - -^{" '} _ - -

20 - - -- ^'

^{'■' "} Cisltrans Isomers ^"may be separated by conventional-techniques well known to - those skilled in the art, for example, chromatography. and^" -fractional crystallisation - - ^" - r _ -

25 Conventional techniques for the preparation/isolation of individual eαantiomers- include chiral synthesis-from a suitable optically pure precursor or resolution^" of the racemate (or the racemate of a salt or derivative) using, for example.-cbiral

- ^"" - high pressure liquid chromatography (HPLG) .- - - _ - - - -

30^{" "}

the racemate (or a racemic precursor) may be reacted with _a suitable optically active compound, for example, an alcohol, or,, in t e ^'case where the compound of formula f) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamιne or tartaπc acid The resulting diastereomeπc " 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 - . - -

5 Chiral compounds of the invention (and chiral precursors thereof) may be

- ^" obtained in enantiomerically-enπched form using chromatography, typically

- 4- HPLC, on an -asymmetric resin with a mobile phase consisting of a hydrocarbotv- fypically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, -typically0 ^"0 1%-dιethylamιne Concentration of the_^eluate affords the enriched mixture _- -

Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by f..L ^~Elrel and S H Wilen (Wiley, New- York, 1994). ^"— -5

The present invention includes^" all pharmaceutically acceptable -isotopically- labelled compounds of formula^" (I) 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 which predominates in mature - 0 - - ^'^~ ^" - ^■ - - - --. -_ - - .

Examples^" of isotopes suitable for inclusion in the compounds'-of -the invention include isotopes of hydrogen, such as ²H and ³H, carbon, suclras ¹¹C, ¹³C and C, chlorine, such as ³⁶CI, fluorine,- such as ^1δF, iodine_τ ^such as ¹²³ ind ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen,^" such as ¹⁵O, ¹⁷O and ^1δO, phosphorus, 5 - ^"such as ^P, and sulphur, such as ³⁵S - % .

Certalπ Tsotσpically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope,- are useful in drug and/or -substrate tissue- - ^'distribution

t e ■ 30 ' ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection - Substitutiόn with heavier isotopes such as deuterium; i.e.²H, may afford certain " ■ therapeutic ^'advantages resulting from greater metabolic^rstability, for example,, - increased^" v^'n V/Vb • half-life or reduced dosage requirements, and-hence may-be. " ^{' "}preferred^" in some circumstances. - ^r_ - - - _.^■ -^■■ -- . - -. - -

Substitutiorrwith^' positron-emitting isotopes, such as -¹¹.C, ¹⁸F, ¹⁵O and ¹³N, can be -^{' ""} useful in Positron Emission Topography (PET) studies^" for-examining. substrate - - receόtor occupancy. --- ^{~ ~} —^{' •} - - ^■--- . -

10 Tsόtopically-labeled ■ compounds of formula^" (I) can generally be prepared._. by '^''■^■'' cbnveritϊorfal technique known tδ^"those skilled - in the art ^"or by processes;¹ analogous to those described in the accompanying Examplesand Preparations using a appropriate ϊsotOpiCally-labeled reagent in place of the npn-labeled-

-^{: ~} Teageήt previoϋslyemplόyedx - .-- .-- ^•:^■ . -^: - -. --_~χ .;.^,..^■ xx: .^; - -- -, .

15 '^; - - --^{■ ■}^;- ^•"- -.-^■.- ^■. -^:-^-- ^{. ■ .}. ,- ^■ _^•:^■. . _ ^■_.^. -^".. .... .„. . -..._.._-

"Pharmaceutically acceptable solvates in accordance with the invention include- thσse ^"wherein ^"the solvent ^"of crystallisation maybe isotopically. substituted, e.g: ^■-^?- ^"•'bϊb d^'έ-acetoneV d₆-DMSO. ^{" '}-^' - ^{'■ ■}_-.-^■■ -^{■ ■}:^■■: ^{■ '■}.. -^• . x - ^■ -- ^ -^" „;^" -

20 -^{f ■■'}-- Alsb ^"within the^" scope -of the invention are intermediate.

"^"hereinafter defined, all- salts^", solvates and complexes thereof and all solvates and complexes of salts thereof as: defined hereinbefore -for compounds of formula (\y. The invehtion hclύdes all polymorphs of the-aforementioned species and crystal habits thereof. . .. . _ - ^' -^"

in accordance- with the invention, rHs ~^"operi to a^r person skilled In the art to όutihely -select the form of intermediate^ which provides the- best c^'όmbinato όf features for this purpose; Such features include the melting^" point, solubilϊtyrprocessability and-yield of the intermediate

30 ^" form ancTthe resulting ease with which the product may be purified on isolation.,, ~

v ^" -bruαr Product ^"" '"^''-^{' ■} -^■■;..>^■-^•'■■- - . .- :-..-^•.^,:^■■ --.,-r: --_^ -^,=-, . ^.. _:. Cσmpounds of ^"the invention intended for pharmaceutical use may be

^""" administered ^"as crystalline or amorphous products They may be obtained, for example, as^" solid plugs, powders, or fιlms-by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying Microwave or

5 radio frequency ^"drying may be used for this purpose

- They 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) Generally, they will be ,adnmr»istered_ as a -

10 formulation in association . with one or more pharmaceutically acceptable excipients The term 'exαpienf 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 nature of the dosage

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 and methods foe their preparation ^"20 may be found, for example, in Remington's Pharmaceutical Sciences. t9th "Edition (Mack Publishing Company, 1995) X ._ -

Ora Administration

" 25 The compounds of the invention may be administered orally- Oral administration may involve swallowing, so that the compound enters the gastrointestinal tractr or buccal or sublingual administration may be employed by which -the compound enters the blood stream directly from the mouth- - -

30 Formulations suitable for oral administration include solid formulations- such as- tablets, capsules containing particulates, liquids, or powders, lozenges (including liquιd-fιlled),^""chews, multi- and nano-partιculates--gels, solid solutιon_r Irposome,- films, ovules, sprays and liquid formulations - ^" Liquid formulations include suspensions, - solutions, syrups - and- elixirs. Such formulations may be employed- as fillers in soft or hard capsules and typically

- comprise a carrier, for example, water., ethanol, polyethylene glycol, propylene . ^": 5^" glycol, methylce!lulo^"se,-or a suitable oil, and one or more- emulsifying agents-

^{~ ""}and/or ^"suspending -agents. Liquid formulations may -also be- prepared by the - - - recohstitutiori of a solid, for example, -from a sachet. .- - -„ -- - _ _

- The compounds ^" of the "invention may also be used- in fast-dissolving, fast- _ 10 disintegrating ^"dosage forms such as ^"those described in Expert Opinion in

^" Therapeutic Patents, 11 (6), 981-986- by-Liang and Chen (2001 ). - . _ X - ^"

For⁼ tablet dosage forms, depending on dose, the drug may make up from 1 ^{" "} - - weight % to- 80 weight % of the dosage form, more typically fronrδ weight % to - 1

a disiήtegranϊx Examples- of disintegrants -include sodium - starch- glycolater- sodium - carboxymethyl - cellulose, . calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, -poly vinylpyrrolidone, ^" methyl cellulose, microcrystalline cellulose, lower alkyi-substituted hydroxypropyl cellulose, starch, ^• 20^" pregelatinised starch ^"and sodium alginate.^ Generally, the disintegrant will -

^^"comprise from 1 weight %^" to 25 weight %, preferably from 5 weight^" % to 20 ~ ~^" weight % of the dosage form. - - - - -- - .. .- ^'" - -

- ^~ Binders are generally used to impart cohesive qualities to a tablet formulation.

25 ^{" "}Suitable- binders include microcrystalline cellulose, gelatin, sugars_r polyethylene ^ glycorxnatural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, - hydroxypropyl^" cellulose and hydroxypropyl methylcellulose. Tablets miay also

- contain diluents, ^"such as lactose (monohydrate, .spray-dried - monohydrate, ^"-- — anhydrous and the like), mannitol, xylitol, dextrose, sucrose_r. -sorbito ^{" "}30 ^" mfc^'rocry stall) ne cellulose, starch and dibasic calcium phosphate dihydrate. ..-. -

^'■ -^"' '-^""-Tabtets 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 weight % to_.5 weight % of the tablet, and glidants may comprise from 0 2 weight % to 1 weight % of the tablet

Tablets also generally contain lubricants such as magnesium stearate, calcium -stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate Lubricants generally comprise from 0 25^~ weight % to 10 weight % preferably from 0,5 weight % to 3 weight % of the tablet - - _ _ "

Other possible ingredients include anti-oxidants, colourants, flavouring agents, 'preservatives and laste-masking-agents

Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder. frcm about 0 weight % to about 85_ weight % diluent, -from about 2 weight % to about 10 weight % disintegrant, and from about 0 25 weight % to about 10_weιght % lubricant

-Tablet blends may be compressed directly or by roller. to form tablets Tablet blends or portions of blendsjnay alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting The final formulation may comprise one or more layers and may be coated or uncoated, i jnay even be encapsulated - _

-The- formulation of tablets is discussed in Pharmaceutical Dosage Forms Tablets, Vol 1 , by H Lieberman and L Lachman (Marcel Dekker, New York, 1980) - - , - -

Consumable oral films for human or veterinary use. are typically pliable water- soTuble or water-swellable thin-film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound, of formula (I), a~fιlm-~ "^" forming polyrner, a^"-bιnder a solvent, a humectant, a-plasticiser,- a stabiliser or- emulsifier, a viscosity-modifying agent and a solvent, Some, components of the formulation may perform more than one function

Trie-compound offormula (I) may be water-soluble or insoluble.- A water-soluble compound typically comprises from 1 weight % to 80 weight %, morextypically

^"from 20 weight %^" to 50 weight %, of the solutes Less soluble compounds may comprise a ^"greater proportion of the composition, typically up- to 88 weight % of the solutes. Alternatively, -the compound of. formula (I) may be in the- form- of

^" mϋltiparticulate beads, — - -_ -. - ^" -

10

^"

proteins, or synthetic hydfocolloids and is typically present in the range 0.01 to 99 weight %, more typically^" in the range 30 to 80 weight % -

^"15 Other possible ingredients include^" anti-oxidants, colorants, flavourings- and flavour enhancersT preservatives; salivary stimulating agents, cooling agents, co_: solvents (including oils), - emo1lients_r bulking agents, anti-ioammg -agents, surfactants and taste-ma^"sking agents.

20 Films in aecordance with the invention .are typically prepared by evaporative " drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, -or by freeze-drying or vacuuming. ^" . _ _-_ _ _ .

^"25 -Solid formulations, for oral administration may be.formulated to bejmmediate anoVor modified release. Modified release formulations include delayed-, sustained-7 pulsed-, controlled-, targeted and programmed release.,

- - ^"Suitable modified release formulations for the purposes of the invention are 30^{" "} described iri 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 Pharrhaceutical Technology Θn-lιne_r.25.(2), 1-14, by Verm a et. al (2001) The use of chewing gum to achieve controlled release is described in " WO 00/35298 . ^{" "}

Parenteral Administration- - - ^'

The compounds ofthe invention may also be administered directly ^"into the blood stream, into^" muscle, or into an internal organ -Suitable means^" for parenteral administration include intravenous, intraarterial, intraperitoneal , intrathecal, infraveritπcufar, intraurethral, - -mtrasternal,-- intracranial, - intramuscular and subcutaneous Suitable deviGes- for parenteral administration include^"" needle

microneedte) injectors, needle-free injectors and -infusio -techniques

Parenteral formulations are typically .aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH -of from 3-to 9), but, for somefapplications, they may be more suitably formulated as a^" sterile non-aqueous solution or as 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, -0 by lyophilisation, may readily be accomplished using standard pharmaceutfeal 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 ^creased by the use of appropriate formulation techniques,5 such as the mcorporat on-of solubility-enhancing agents -_ ^~_

- ^"*•""- Formulations for- parenteral administration may be formulated to^"" be^"ιmmedιate~ and/or modified release Modified release formulations include delayed-, sustained-,^" pulsed-,- controlled-, targeted and programmed release^" Thus0 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 poly(o7-lactιc-coglycolιc)acιd (PGLA) microspheres - opical^" Administration -

-The compounds of the invention may also be administered topically to. the skin or mύcosa, that is, dermally or transdermally. Typical formulations for his purpose include gels, hydrogels, lotions, solutions, creams, ointments, dgsting 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 maybe ϊncorporate^'d - see, forexample. Pharm Sci, 88 (10),-955-958, by Finnm and Morgan -(October 1999).. - __

Other means ot topical administration - include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or need]e-free πe.αxPowderject^τ-^M, Bioject™, etc.) injection. _. __. -

- Formulations^" for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, - sustained-; pulsed-, controlled-, targeted and programmed release ^

InhaJed/lntranasal Administration

The compounds of the invention, can also be administered intranasally or by inhalation, typically in the form of a- dry powder (either alone, as a mixture,- for example,- in . a dry blend with lactose, or as a mixed component particle,- for

- example, mixed with phospholipids,- such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container,, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebulιser,-wιth or without the use of a suitable propellant, such as - -^" 1^",1 ,t,2-tetcafluoroethane_._ or 1,1 ,1 , 2,3, 3,3-heptafluoroρropane For intranas_.al_. - use, the^" powder may- comprise a bioadhesive agent, for example, chitosan of cyclodextπn. - _^ The pressurised container, pump, spray, atomizer, or nebuliser contains- a solution or suspension cf the compound(s) of the invention comprising, for example^", ethanol, - aqueous^" ethanol, or a suitable -alternative agent for dispersing, solubilisirig, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. - -.. -^; - . -. - -

^" Prior to use^" in a dry powder or suspension formulation, the drug product, is , micronised to a size suitable for delivery by inhalation .(typically less, thian ^"_5 microns). This may be ^"achieved by any appropriate comminuting method, such- as spiral jet milling, fluid bed jet-milling, supercritical, fluid processing- to form nanoparticles, high pressure homogenisation, or spray drying.

^"- Capsules (made, for -example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use-in an inhaler or insufflator may be formulated to.

^" contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such^" as /-leucine, mannitol. or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter Other suitable_excipients include dextran; glucose, ma_.ftose_r sorbitol, xylitol, fructose, sucrose and trehalose.

^"A^" suitable solution formulation for use in. an atomiser - musing electrohydrodynamics to produce a fine mist may contain from Iμg .to 2Omg of ^{" "} the compound of the ιnventιon_per actuation and the actuation volume-may vary . from 1 μl to 100μl^" A typical formulation may comprise a compound ofjormula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative -soJvents- which may be used instead of propylene glycol include glycerol and polyethylene glycol ^' - - ■_ _ .- ^"

Suitable flavours, such as menthol and levomenthoj, or sweeteners, -such as-. saccharin¹ orsacchaπri sodium, may be added to those formulations^', of the invention" intended forinhaled/intranasal administration - - : ^" Formulations for inhaled/intranasal ,administration may be formulated to be. immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained^, pulsed_.-, controlled-, targeted _; and 5 programmed release. .. .... - - -- _.- _. -- _ . ^■

In the case ^"of dry powder inhalers and aerosols, the -dosage unit_, is determined

- x - by means of a valve which .delivers a metere amount Units in accordance with

- the ^"invention are typically arranged-, to administer, a metered dose or "puff 10 ^"containing from 2 to 30mg of the compound of formula (I). The overall daily_. ■- ^• dose-will typically be in the range 50 to 100mg which may be administered, in a single dose or,- more usualb .,,as^"divided.doses throughout the day. - . ...

'^■-^' Re^'ctai/lntravaginai Administration - . ..... . _■ -,, . -_, : - :_.: i _.. -

15

The- compounds of the invention .may be administered rectally or vaginally, for " example, in the form of. a.suppository,. pessary, or enema;. Cocoa. butter. is a traditional suppository base, but various alternatives may be^" used as appropriate, - x

20

Formulations for rectal/vaginal —administration; may- be- formulated .^'to- be imi iediate and/or modified release„.Modified release, formulations; _.iricrude ^•

The compounds of the invention may also be administered directly to_.the eye or ear, , typically in the - form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline, Other formulations -suitable for ocular and

30 ^; aural administration .include ointments, , biodegradable (e,g_: absorbabl_.e gel

^'- -^τ' sponges?^" collagen)- and - non-biodegradable {e.g. silicone) implants, wafers,

^{■ ;,;'}- ^■"'■• lenses and- particulate or vesicular systems, such, as-niqsdmes or liposo es, -

^: pbfyme^'r such as crossed-linked polyacrylic acid,, pόlyvinylalcohol,. hyaluronic acid, a^" celϊulosic -_-. polymer, for example, -hydroxypropylmethylcellulose, hydroxyethylcellulosex or. methyl cellulose, or a heteropolysaccharide polymer, for ^" -^: - ^{' " •"■} . ^" ..^" -.. ... . - _... -__

- ^''"''- exarripleTgelah gum, may be incorporated together- with, a preservative; such- as_; 5 benzalkonium chloride. Such formulations - may .also be- delivered by "^"" iontophoresis. - - - ^{" ■ ■} .■. :.. ,--:^■

Formulations for ocular^'/aural administration may be formulated to be immediate and/or modified releases Modified, release^" formulations include delayed-,

10^" sustained-, pulsed-, controlled-, targeted, or-programmed-release. ■ .

^" Other Technologies-— ^■-- -. ^■:^■.--~x -. ,v - - ._ _. ;^■-■-^•-_._

The compounds of the invention may be combined .with soluble macromo|ecular 15 entities, such as cyclodextriri: and- suitable derivatives thereof or- olyethylene; glycol-containin^'g 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, ^" ..

20.^'. Drϋgf-cyclodextrin complexesx^for example, are found, to be generally useful for most dosage forms^" and administration .routes. Both inclusion, and non_:inclusio complexes may be used. As an alternative to direct compϊexation with the drug, .

_. ^'" ,xthe cyclodextriri may be used as an auxiliary additive, i.e. as a carrier, diluent or

- solubiliser. Most commonly used Tor these, purposes- are- alpha-, beta- and-

25 gamma-cyclodextrins,._. examples of which may. be found in International Patent

^■-^*- Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

^"'" "Xit-bfrPartS^{" '}-^'••'-- :,_ ^"■: .^{'" ■' " " ■}: ^■..^'■.^'. ^■■ ?-,^'"-- Xy^{' :}..-.-- -^{■ '}■-,_.:^"

3.0 .: Inasmuch as t may desirable to administer a combination of active compounds, for example,¹ for the.purpose of treating .a particular disease ©recondition^", it ^"is within the, scope of.-the present ihNeritiαn- 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 coadrniriistration ofthe compositions. - - -

^"Thus the kit ofthe invention ^"comprises two_or more separate_, pharmaceutical - 5" conopositions, at least one of which contains a compound of formula (I) in accordance with -the invention, and means -for, separately retaining said compositions such ^"as a container, divided bottle, or divided foil packet An exarriple of such a kit is the farηiliar blister, pack used for the_. packaging, of - ' tablets ^capsules and^'the lke. ._^■-. , ^• ιo ^{"■ ■ ■ '} -,^{τ ": '}r;- - XX . ₌-. ^■ . -. ^'- .... . __...

⁼ 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 -

15 Comprises ^"direction^'s for administration;. and may -be provided with a so-called

^'" _. memory aid; ^:- ^{^} - ,_:- ■[-^■-.. , . - .

Dosage ^{'■' ""~ '■};.^■' - ^{'"' "} _. ■, - . ^■ -

20 -_. For administration to hufnan patients, the total daily dose of the compounds of "^{" "} the^" invention is typfcally ^"in the range 50mg to, 100mg depending,_. of course, on. the mode of administration arid efficacy. Fo example oral administration may ;._:-. require .a. total daily dose of from 50mg to 100mg- The total daily dose may be ,.. ad.rnήistered.in single or divided ^"doses and may, at the physician's discretion,-_. 25 ^"fall outside Of the typical range given herein. _. ^"1 _• ^'.^' -^{' "}

r. x. These dosages" are based on an average human subject having a -weight of_. ^" _; . ^'■:-. abbut.60kg to 70kg: The physician will readily^" e able ^"to determine .doses for = . subjects. whose-weight- alls outside this range, such as infants and trie elderly. .

30_..-_.v_r:v.-.,._. :■ .,. _- ^' - - _.. ^' - -.- ^"" .

. For the avojdance ^"of doubt^", references herein to "freatmeritinclude references ,,,^", to curative, ^"palliative and prophylactic treatment. ^" - - ^{' ~~' "}-^{' '"'""' '} ...

conditions comprise heating 1 equivalent of aryl ester (II) and 1.2-3 equivalents - of hydrazine monohyrate in methanol at reflux for 18-48 hours.

^{" "}Compounds of formula (IV) may be prepared from compounds of formula (lll).by- 5 process step (ii), whicl comprises reaction with N,N-dimethylacetamide dimethyl ^■'"' ^' acetal (available - from _. Aldrich). - in a suitable -solvent: -such as N,N-dimeth^"ylformarriide, N-methyl pyrroiidine or toluene followed by the ^"addition of a suitable acid catalyst such as trifluoroacetic-acid, para-toluenesulfonic acid, ~- ^""camphor sulfonic acid, or hydrochloric acid. -Typical conditions comprise heating 10 equivalent of ^"aryl hydrazϊde (III) and 1.3 equivalents of N,N-dimethylacetamide dimethyl acetal in N,N-dimethylformamide to 60°C for 2 hours, followed by concentration in vacuo, addition of toluene and- 0 025 equivalents_^ of para- toluenesulfonic acid, which is then-heated to reflux for 2 hours.

15 ^" - Compounds- of formura-(V) may be prepared from compounds of formula- (IV) by process step XiijJ;-- which comprises reaction with a suitable aniline- or

3-amihopyridine in the presence^" of a suitable acid, such as trifluoroacetic acid,

" para-toluenesulfonic acid, camphor sulfonic acid, or hydrochloric -acid in a suitable solvent, such as xylene, heated at 150°C. Typical conditions comprise

20 heating 1 equivalent of 1 ,2,4-oxadiazole (IV), 2-3 equivalents of aniline or aminopyridine and ύ.04-0.1 equivalents of para-toluenesulfonic acid in xylene at

^" 150 for 18-23-hours. - ^" -

Compounds^"bf formula (I) may be prepared from compounds of formula (V) by 25 process step (iv), which comprises a Suzuki coupling reaction with a suitable bόronic acid such as 2,3-dimethylphenyl boronic acid (commercially available), in - a suitable solvent, in the presence of a base and a palladium catalyst, such as - [2- (Dimethylamino-κN)methyl]phenyl-κC](tricyclohexylphosphine)- ^" - (trifluoroacetato-κO-(SP-4-3)-palladium, prepared as described in"^' 30- . Organometallics, 2003, 22 (5), 987-999. ^"

. - The Suzuki coupling ^"reaction can be carried out. as describ^'ed lri^" the literature:^' Suzuki, A. Pure & Appl. Chem. 1985, 57, 1749 and reference contained^" within,^" Angew. Chem. Int. Ed: 2002, 41, 4176-4211 and references contained within. Typical conditions corripTise heating 1- equivalent, of- aryl bromide (V), .2.5 equivalents of boronic acid, 3 equivalents cesium carbonate ._0.06 equivalents -of palladium catalyst from preparation 3 in 1 ,4-dioxane at.12.0°C for 4 hours. .,- ..

Compounds of general formula (I) where. -R³ is H and and where_{^ .}R¹, R², R⁴, R⁵, R⁶, X,-V, W, Y and Z are as described herein,- except R² ≠ H.- may be prepared according to reaction scheme 2. _...^• ■ ^{■ ■ :}

1.3 equivalents of acid chloride, 1.2-2.0 equivalents of N-methyl morpholine in dichloromethane at 0-25°C for 3-18 hours. Compounds of formula^"(VII) can be prepared from compound (VI) by process step (vi), which comprises reaction with a suitable dehydrating agent such as phosphofous ^"oxychlόtide, tπfluoromethanesulfonic anhydride, or phosphorous pentachloride between a temperature of 25°C and 110°C. Typical conditions^{^} comprise heating 1.0 equivalents of (VI) in phosphorous oxychloride at 110°C for 4 hours - -

Compounds of formula (VIII) may be prepared from compounds of formula (VII) by process step (in), which comprises reaction - with a suitable aniline .or

3-am riδpyridine in the -presence of a suitable acid, such .as trifluoroacetic acid, para-toluenesulfonic acid, camphor- sulfonic acrd, or hydrochloric acid, in a^" - suitable solvent such as xylene, which is heated at 150°C. Typical conditions comprise heating 1 equivalent of 1 ,2,4-oxadiazole (VII), 3 equivalents of aniline/aminopyridfne and 0 04-0 1 equivalents of para-toluenesulfonic acid in xylene at 150°C for 18-22 hours

Compounds of formula (I) may be prepared from compounds of formula (VIII) by pjrocess step (iv), which comprises a Suzuki coupling reaction as -described in .scheme 1. - . _ ^{" "} _^ .

Compounds of general formula (I) where R² ιs NR⁷R^δ or a.5-7 rnembered ^_.N-linked hete^"rocycle as ^"described herein, R³ is H and where -R¹, R⁴, R⁵, R⁶, R⁷, R^δ, X, V, W^", Y and Z are as described herein may be prepared according to reaction scheme 3.

halo = Cl or Br (III) (IX) (X)

Scheme 3

Compounds of formula (IX) can be prepared from aryl hydrazides of formula (III) by process step (v)_L which comprises reaction with a suitable acid chloride, such as chloreacetyl chloride, in the presence of a base, such as tπethyiamine, ^" N-methyl morpholine, sodium carbonate or potassium hydroxide Typical conditions comprise reacting 1 0 equivalents of aryl hydrazide (III), 1 0-1.3 equivalents of chloroacetyl chloride, 1 2-2 0 equivalents of N-methyl morpholine in dichloromethane at 25°C.

- Compounds of -formula (X) can be prepared from compounds of formula (IX) by process step (vi), which comprises reaction with a suitable dehydrating agent such as phosphorous oxychloπde, tnfluoromethanesulfonic anhydride, or phosphorous pentachloride between a temperature of 25°C and^" 110°C Typical conditions comprise heating 1 0 equivalent of compound (IX) in phosphorous oxychloπde at 1 10°C for 4 hours Compounds of formula (XI) can be prepared from alkyl chlorides ofJormula (X) ^by process step (vii), which comprises reaction with a suitable primary or secondary a^"mine_(HNR^zR⁸) or a 5-7 membered N-linked heterocycle, optionally in the presence of a base such as potassium carbonate, sodium carbonate or cesium carbonate, in . a suitable solvent such as acetonitrile or - N,N-dimethylformamJde, by heating at 25-50°C for 2-18 hours. Typical conditions comprise reacting -1 equivalent of.-alkyl chloride (X), 1.5 equivalent ^"of amine (HNR⁷R⁸) or 5-7 membered N-linked heterocycle and 2 equivalents of potassium carbonate in. acetonitrile for 18 hours at 25°C. _ - ^"

10

Compounds of- formula (XII) may be preparedfrom compounds of formula (XI) by proeess- step (iii)_f- -which comprises reaction with a suitable._aniline or 3-a_.miriopyridine, in the presence of a suitable acid, such as trifluoroacetic acid, - para-toluenesulfonic acid, camphor -sulfonic acid, .or hydrochloric .acid, in a 15 ^" -suitable solvent such as xylene^ heated at 150°C. Typical conditions comprise , heating 1 equivalent o ^ϊt 2,4-oxadiazole (XI), 3- . equivalent of aniline/aminopyridfne- and 0 04-0..1 equivalents of para-toluenesulfonic add in xylene.at 15 )°C for 18-24 hours

20 ^" Compounds of formula (I) -may be_. prepared from compounds of formula (Xll).by process step (iv), which comprisies reaction with a suitable boronic acid such as .2,3-dimethylphenyl boronic acid (commercially available), in a suitable solvent, in -.- the, -presence of a -suitable base and palladium catalyst as described in. - scheme T. 25 _. ;

^" -^" Compounds of-generaϊ formula (I) where R¹, R², R³,-R⁴, R⁵,^" R⁶, X, V, W, Y and Z - ^"" are as described herein may alternatively be prepared according to reaction scheme-4. . - - - . . .. ..

(XIV)

(ii) (XIII)

Scheme 4

Compounds of formula (II) are prepared as described in scheme 1.

_.Compounds of general formula (XIII) can be prepared from compounds of general^" formula^" (II) by process step (iv) as describedϊn scheme 1^".

Compounds Wgeneral formula (XIV) can be prepared ^"from compounds of 10_. general formula (XIII) by process step^"(i) as described in ^"scheme 1

When R²=H, co^~rnpδunds of ^"general fo^"rmula (XV) can ^" be prepared from compounds of general formula (XIV) by process ^"step ^_< iπ), using a method analogous to process step (ii), as described in scheme 1.

15

When R²≠FT, compounds of general formula (XV) can be prepared from compounds of general formula (XIV) by process^" step^" (viii), ^"using methods analogous to steps (v) and (vi), as described in scheme 2 or steps (v), (vi) arid^" (yii)^" as described in scheme 3

20

^"Compounds of general formula (I) can be prepared from compounds of general formula (XV) by process step (iii), as described in scheme 1

Compounds of general formula (I) where X is C-R⁶, R is H and where R , R , 25 R⁴, R⁵. R⁶, V, W, Y arid Z are as described herein may ^"alternatively be prepared according to^" reaction scheme 5 ^" -

Scheme 5 -

- Compounds of formula (lll)-are prepared as described in scheme 1 5 ^'

- When T ²=H,~ compounds of general formula (IV) can be prepared from

- compounds of general- formula (III) by process step (vni),- using a. method - - analogousto rocess step (n), as described in scheme 1.

10 ^L When- R²≠H, compounds of general formula (IV) can be prepared from corήpQunds^~--ϋf general - formula (III) by process- step (vni), using methods analogous tσsteps (v)- and (vi), as described in scheme 2 and steps v),-(vι)_and ~{viι) as described in Scheme 3 -

15 Compounds- of general formula (XV) may be prepared from compounds (cf general formula (IV) by process step (iv) as described in scheme 1.

- ^* Compounds of general formula (I) may be prepared from compounds of general

^""formula^" (XV) by process^" step (HI) as described in scheme 1 -20

-Compounds of general formula (I) and (VIII) where R¹, R², R⁴, R⁵, V, W, X, and Y are described -herein and R³ = H may be prepared according to reaction scheme 6

Scheme

Compounds of formula (I) and (VIIJ) may be prepared from compounds of 5 formula ^"(XIV) and-(lll) respectively by process step (ix),- which comprises. sequential ^"reaction with a dimethylacetamide dimethylacetal in-a suitable solvent "^"'such a^"s tetrahydofurancr acetic ^"acid heated at 55-60°C followed by reaction with a suitable aniline or aminopyridme in the presence of a suitable acid-such as ^"acetic acid heated at 90-100°C -Typical conditions comprise heating 1 0 10 ^" equivalent of acyl - hydrazide, - 1.5- equivalents of dimethylacetamide - dimethylacetal (Aldrich) in THF at 55°C for 2 hours followed by.the addition of. ^{"" '" ~}1.5^" equivalents of 2-methoxy-5^'-aminopyridine (Aldrich) and heating in acetic-acid - at 90°C for 5 hours..

15 All of the above reactions and the preparations of novel starting materials ' ^rdιscf sed irfthe ^"preceding methods are conventional and appropriate reagents

" arid^" reaction^" conditions for^" their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled

" - ϊrrfJ e^"' art^" with^" reference to literature precedents and. the. Examples and^" 20 ^{" ~} Preparations hereto .- Utilitv-

The compounds of the invention are useful because they have pharmacological activity in mammals; including humans. More particularly, they are useful in the 5 ^"" treatment or prevention of ^"a disorder- in which modulation of the levels .of oxytocin ^'could provide^" a beneficial-- effect. Disease -states that may be mentioned include ^' sexual dysfunction, particularly - premature - ejaculation, preterrh labour,^" complications in labour, appetite and feeding disorders, benign prostatic hyperplasia, premature birth, dysmenorrhoea, congestive heart failure,^" 1O arterial hypertension, - liver- -cirrhosis, ^"nephrofic hypertension, occular hypertension, obsessive compulsive disorder and neuropsychiatric disorders^- -

Sexual dysfunction (SD) is a significant clinical problem which can affect both males and females. The causes of SD may be both organic as well as

15 ^" psychological ^*" ^"Organic aspects of SD are- typically caused by- ϋnderlying- vascullr diseases, such as those,- associated with hypertension or diabetes mellitus, by prescription^" medication^" and/or by psychiatric disease^" such as depression; ^" Physiological factors include ^"fear, performance anxiety and

-interpersonal conflict. SD-impairs sexual performance, diminishes- self-esteem

^"20 and disrupts personal relationships thereby inducing personal distress. - In-the ' clinic, SD disorders have been divided into female sexual dysfunction (FSD) disorders and male sexual dysfunction (MSD) disorders (Melman et al, J. Urology, 1999. 161. ^"5-11).

^"25 -FSD can be defined as the difficulty or inability^" of a woman to find satisfaction in sexual expression. FSD is a collective^'term for several diverse female sexual disorders (Leiblum, S R-, (1998) Definition and classification of female sexual disorders. Int J Impotence Res , T0-, S104-S106; Berman, J R., -Herman, l T &- Go Tstein I. (1999) Female ^"sexual dysfunction: Incidence,- pathophysiolόgy,

30 evaluations and ^"treatment options. Urology, 54, 385-391). The woman may have lack of desire, difficulty with arousal or orgasm, pain with intercourse^" or a "combination of these problems Several types of disease, medications, injuries or psychological problems can cause FSD Treatments in development are^{" "} targeted to treat specific subtypes of FSD, predominantly desire and arousal disorders.

- The categories of FSD are best defined by contrasting them to the phases of normal female sexual response' desire, arousal and orgasm Leiblum, S.R.

^" (1998) Definition and classification of female sexual disorders, Int. J. Impotence Res., 10, S104-S106). Desire or- libido is the drive for sexual expression. Its- manifestations often include sexual thoughts either when in the company of an"

^~ riferested^~~"partner or when exposed to_ other erotic stimuli. Arousal is the_. Vascular response to sexual stimulation, an important component of which is^" genital engorgement and includes -increased vaginal lubrication,- elongation of the vagina and increased genital sensation/sensitivity. Orgasm is the release of sexual tension that has culminated during arousal. -

Hence, FSD occurs when a woman- has an. -inadequate or- unsatisfactory response^" in any^"" of these phases, - usually desire, arousal or orgasm. FSD categories include hypoaGtive -sexual desire disorder, sexual arousal disorder, orgasmic^" disorders and sexual pain disorders. Although the compounds of the invention will improve the genital response to sexual stimulation- (as in female "sexual arousal disorder)-; in -doing so .it may_a!so improve the associated pain,_, distress and discomfort associated . with-ϊntercourse and- so treat other- female sexual disorders.

Thus, in accordance with a further aspect of the invention, there is provided the ^" use of a compound of the invention in the preparation of a medicament for the - -treatment or ^"prophylaxis of hypoactive sexual desire disorder-;, sexual arousal^" disorder^", orgasmic disorder and sexual -pain disorder, more- referably fof the treatment or prophylaxis of sexual arousal disorder, orgasmic disorder,- arid sexual pain disorder_τ-and^~most preferably in the -treatment orxprophylaxis of sexual arousal disorder

Hypoactive sexual desire disorder ι_s present if a woman -has no or-ljttle-desire to - be sexual, arid has no or few sexual thoughts or fantasies. This type of FSD can be caused by low testosterone levels, due either to natural menopause or to "surgical menopause. - Other causes include illness, medications, atigue, depression and anxiety.

Female sexual arousal disorder (FSAD) is characterised by inadequate genital response to sexual stimulation. The genitalia do not undergo the engorgement that characterises^" normal sexual arousal. The - vaginaL walls are poorly_^ lubricated, so that intercourse is painful, Orgasms may be impeded. Arousal, disorder canrbe caused by reduced oestrogen at menopause or after childbirth_^ ^{" "}and -during lactation, as well as ^"by illnesses, with vascular components such as diabetes and atherosclerosis. .Other causes result from treatment with diuretics, antihistamines, antidepressants eg SSRIs or antihypertensive agents.

Sexual pain -disorders ^"(includes dyspareunia and vaginismus) is characterised by pain resulting from penetration and may be caused by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.

The prevalence of. FSD is difficult to gauge because the. term covers several fypes of problem^ some of which ^"are difficult to measure, and because the "interest ^"in treating FSD-is relatively recent, .Many-women's sexual problems are . associated either directly with the -female ageing process, or with chronic illness^"es^"such as diabetes and hypertension-,

Because FSO consists of several subtypes that express symptoms in separate phases of the sexual^" response cycle, there- is not a single therapy, Current treatment of FSD- ocuses principally on psychological or relationship.; issues. Treatment of FSD. is--gradually evolving- as more clinical and basic science , studies ^"-are dedicated - to the investigation of this- medjcal_. problem. Femaje sexual complaints are not all psychological in pathophysiology, especially for those individuals who ^"may have a component of vasculogenic dysfunction (eg

FSAD) contributing -to the overall female sexual complaint There are at present

^" no drugs licensed for the treatment of FSD_. Empirical drug therapy includes oestrogen administration- ^"(topically or . as . hormone -replacement therapy), aridrogens. or mood-altering drugs such as buspifone or trazodone. These treatment options are often unsatisfactory due to low efficacy .or unacceptable side effects,

- ^• The Diagnostic and Statistical^" Manual .(DSM) IV of- the American Psychiatric Association defines Female Sexual Arousal-Disorder (FSAD) asbeing:.-_.- ~ "a persistent or - recurrent inability to. attain or to maintain .until completion- of the -^' sexual activity adequate - lubrication-swelling : response of sexual excitement. The. disturbance -must- cause marked distress or interpersonal difficulty."

"The arousal response . consists -of- vasocongestien . in the. pelvisx vaginal - lubrication and expansion and swelling of the external genitalia. The disturbance - ^"causes marked distress and/or- interpersonal difficulty;

FSAD is a highly prevalent sexual 7 disorder affecting pre-,, peri-, and post menόpausal (±HRT) women. - It is associated with concomitant disorders such as depression, cardiovascular diseases, diabetes- andJJG disorders_*.

The primary consequences .of FSAD are.lack_.of engorgement/s.welling, lack of --lubrication -and lack of pleasurable genital sensation. - The sepondary consequences of FSAD are reduced sexual desire, pain during . intercouτse--and difficulty- in achieving ah orgasήr -

Male sexual - dysfunction (MSD) is. generally^, associated- with -either erectile dysfunction, also known as male erectile dysfunction (MED). and/or ejaculatory

- disorders such as prerriature ejaculation, anorgasmia -(unable to achieve

' orgasm) or desire disorders such as hypoactive .sexual desire disorder (lack of interest in sex), PE is a relatively common sexual dysfunction in men. - It has been defined in several different- ays but the most widely accepted is the Diagnostic and Statistical Manual ofMental Disorders IV one-which states:

,^JPE is a lifelong -persistent or recurrent ejaculation with minimal sexual ^"stimulation before,- upon or shortly after penetration and. before the patientwishes it. -The clinician must take into account "- factors that^" affect duration of the excitement phase, such as age; novelty o the sexual partner- or- stimulation, arid .frequency . of sexual activity. The^" disturbance causes marked distress of interpersonal difficulty."

The International Classification of Diseases 10 definition states:-

"There is an . inability to delay ejaculation sufficiently to enjoy ^" lovemakfng, ^"manifesfXas either of the following: (1) θGcurrence^~of ejaculation before or very sόon.after the beginning of intercourse (if - a time limit is required: before or within 15 seconds- of the beginning of intercourse); (2) ejaculation occurs in the absence of - sufficient-erection to make ntercourse possible. The problem is not the result of prolonged abst^'mence from sexual activity-

Other definitions ^"which have been used include classification on the following criteria: -- "^""• Related to partner's orgasm

• Duration between penetration and ejaculation

# Number of thrust and capacity for voluntary control

^" Psychological factors may be involved in PE, with relationship problems,- anxiety, depression, prior sexual failure all playing a role.

^{" '} Ejaculation is^" dependent on the ^" sympathetic and parasympa hetic nervous systems. - Efferent impulses via the sympathetic nervous system to the vas deferens and the epididymis produce smooth muscle contraction, moving sperm^", into the pόsteriorurethra. ^" Similar contractions ^"of the seminal vesicles, prostatic gland and the bulbouretheral glands- increase, the volume and fluid content of - semen.- Expulsion of ^"semen is mediated by efferent impulses-originating- from a . population of lumber spinothalamic cells in the1umbosacral .spinatcord_(Coolen & Truitt, Sc/er>cer2002, 297, 1-566) which pass-via the.parasympathetic nervous- system and cause rhythmic contractions of the biribocavernous, ischiocavernous "and pelvic floor muscles. Cortical control of ejaculation is still under _.debate, in -humans. In the rat the medial pre-optic area and the paraventricular nucleus of_ - the hypothalamus seem to be involved in ejaculation.

^~- Ejaculation ^"comprises two sepajgite components - emission and- ejaculation.

Emission is the deposition of seminal fluid and- sperm from the distal epididymis, . vas deferens^", seminal vesicles and prostrate into the prostatic urethra. --Subsequent- to this^~deposition- is the forcible expulsion of the s_.eminal .contents from- he urethra! meatus. Εjaculation is distinct from orgasm, which is purely a

^" cerebral event. Often the two processes are coincidental.

A pulse of oxytocin in peripheral serum accompanies ejaculation in mammals. In- nan oxytOGiir but not vasopressin plasma concentrations are significantly raised

.^"at or around ejaculation, Oxytocin does .not induce ejaculation itself; this process is 100% under nervous control via α1-adrenoceptor/sympathetic nerves originating from the lumbar region of the spinal cord. The systemic pulse of

^"oxytocin may have a role in the peripheral ejaculatory response. It coαld serve -15 modυlate he contraction of ducts and glandular lobules throughout the male

-genitaf tract, thus ^"influencing the fluid volume of different ejaculate components for- example. Oxytocir eleased centrally into the brain could influence -sexual

- behaviour, subjective appreciation of arousal (orgasm) and latency to

- subsequentejaculation

Accordingly,.one aspect of the invention provides for the use of a compound of formula (1), without the proviso, in the preparation of a medicament for the prevention or treatment of sexual dysfunction, preferably male sexual "dysfunction, most preferably premature ejaculation.

It has been demonstrated in the scientific literature that the number of oxytocin

5- - receptors in the .uterus increases during pregnancy, most markedly before the

-onset of labour (Gimpl &- FahrenhoJz, 2001 , Physiological Reviews, 8 (2),- 629-

683,). Without being bound by anytheory- it is known that the inhibition of

- oxytocin can assist in preventing preterm labour and in resolving complications in labour

10

Accordingly, another aspect of the invention provides, for the use of a compound ot formula (J),- without the proviso, in .the-.pceparation of . a- medicament ior the -prevention or-treatment of preterm labour and complications in labour.

15 -^' Oxytocin -has a role in feeding , it reduces_^ the desire to eat (Arletti ef -a/,, Peptides^ 989, 10,-89). By inhibiting oxytocin it is possible to increase.the desire to eat. Accordingly oxytocin inhibitors-are -useful in treating appetite and feeding disorders. -

- 20 - Accordingly,- a further aspect of the invention provides for the use of a compound

- of formula (l)τ without the proviso, in_:Jhe preparation of a medicament^" for the.^, prevention or treatment of appetite .and feeding disorders.

Oxytocin is implicated as one- of the causes of benign, prostatic .hyperplasia 25- ^"-- (BPH)r Analysis of prostate tissue have show that -patients wjth BPH have. ncreased levels- of -oxytocin (Nicholson & Jen kin, -Adv.- Exp. Med. & Biol, 1995, 395, 529). Oxytocin antagonists can help treat this condition.

-Accordingly, another aspect of the invention provides for.the.use of -a compound

- 30 - - of-formula _.(l), wihout the proviso, in the preparation of a medicament for the preventionpr treatment of benign prostatic hyperplasia.- Oxytocin has a role -in the causes of dysmenorrhdea .due to its activity, as a uterine vasoconstrictor (Akerlurid, Ann. NY ^"Acad. Sci., 1994, 734,-^7). Oxytocin - antagonists can have a therapeutic effect on this condition.

5 Accordingly, a further aspect of the invention provides for the use of a compound of formula (I), without ;the ^" proviso, in the preparation of a medicament- for the prevention of treatment of dysfriehorrhoea.

-|f is to ^"be -appreciated that all ^"references herein to treatment include curative, 10 palliauve^'an prophylactic treatment

The compounds -of the^" present invention may be coadministered with one .or,: more ^'agents selected from:

15 ^"t) One of more selective serotonin^"" reuptake inhibitors (SSRIs) -such_τ^as

^" dapoxeti e, - ^"'- parόxetine, ^" 3-[(^"dimethylamino)niethyl]-4-[4- irrietHyis^"ulfariyl)jDherioxy]benzeriesulfonami_.de -- (Example x .28, _.. WO

0172687), ^{' ":} " . -3-[(dimethy!aminb)methyl]-4-[3-nrιethyl-4-

(ihethylsulfariyl^pheriόxyiberizehesulfόnamide (Example 12,.- WO

^"20 -^""- - ^" 0218333),^" ;. ^:: - "W-methyl-Λ/-({3-i3-methyl-4^methylsulfanyl)ph.enox l-4.-

- ^{: :} pyridiriyl}tfιethyl)amine^" (Example- - ,38,- . -PCT . Application no

- * PCT/IB02/01032).

2) ^" One mdr local aήaesthetics;-

-3) one or more α-adfenergie receptor antagonists (also known as

25 ^" α-adrenόceptof blockers,^" α-receptor- blockers or ά-blockers); suitable .-04- _

^÷- ^"adrenefgic receptor antagonists include: phentolamirie, -prazosin, phentolamine mesylate, ^" trazodone, alfuzosiri, indoramin; naftopidil, tamsulosiri, pheriόxybenzamirie,^" raϋwolfa alkaloids, Recordaff 15/2739,

^" SNAP 1069 ^' SNAP 5089, ^"RS17053,-.SL 89:0591 , doxazosin,:Example 19

30 ^"of WO9830560, terazbsin and abanoqύil; suitable α₂- adrenergic receptor antagonists ^" include dibenamine, ^" tolazoline, trimazosin,^" efaroxan,7 yohimbine,^" idazoxan όlonidiri and ^'dibenarnirie; suitable non-selective α-

^" adrenergic receptor antagonists include dapiprazole; further α- adrenergic receptor antagonists are .described in PCT application WO99/30697

- published on 14th June 1998 and US patents: 4,188,390; 4,026,894;

3,5 1 ,836;- -4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063;

3,381-,009;.4,252,721 and 2,599,000 each of which is incorporated herein

5 - by reference; - . - - _. _

4) ; one or more ^"cholesterol lowering agents such as statins (e.g.

- atorvastatin/Lipitor- trade mark) and fibrates;

5)^" - onexor more of a serotonin, receptor agonist,, antagonist or modulator, more-particularly agonists, antagonists or modulators for example 5HT1A,

10 5HT2Ar 5HT2O, 5HT3, 5HT6. and/or 5HT7 receptors, including those

- ^"- -described in WO-09902159, WO-00002550. and/or WO-000289 3;

6) ^■ one ormore NEP nhibitors, preferably wherein-said NEP.is EC 3.4.24.11 . and more preferably wherein said NEP inhibitor is a selective inhibitor for

- - EC 3.4.24.11 , more . referably a selective NEP inhibitor is a selective 15 - _. ^" inhibitor -for EC 3.4.24.11 , -which .has an JC₅₀ of-less than 100nM (e.g. ompatrilat, sampatπlat) suitable NEP inhibitor compounds -are described

- i EP-A-1097719; IC50 values against NEP.and ACE may be determined - - -_- - using methods described in published patent application EP1097719-A1 ,

-paragraphs [0368] to [0376]; _ . - _ . _.

20 7>- one or ^"more of-an antagonist. or modulator for vasopressin receptors, ■- - ^" - such^" -as _.relcσvaptan (SR 49059), conivaptan, atosiban, VPA-985,- CL- .^" -385004, Nasotocin. . - . . .

- - 8) ^: Aporhbrphine - teachings on the use of apomorphine as a pharmaceutical r may be found in US-A-5945117; 25 ^ 9)^~ Dopamine agonists (in particular selective D2₂ selective D3, selective D4

- and selective D2-lιke agents) such as Pramipexole (Pharmacia Upjohn compound number PNU95666), ropinirole, apomorphine, surmaniroje,

- quinelorane, PNU-142774, bromocriptine, carbergoline, Lisuride;.

- -10)- - Melanocortin^". receptor -agonists, (e.g. Melanotan II and _ PJ141 ) and 30 selective MC3 and MC4 agonists (e.g.THIQ);

11 ) Mono, amine transport inhibitors, particularly Noradrenaline Re-uptake Inhibitors (NRIs) ^"(e g Reboxetme), other Serotonin Re-uptake, Inhibitors (SRls) (e-g. paroxetine, dapoxetine) or Dopamine Re-uptake Inhibitors (DRIs); - - 12) -5-HT-i_A antagonists (e.g. robalzotan); and ~^" . -13) PDE- inhibitors such as PDE2 (e.g, erythro-9-(2-hydroxyl-3-npnyl)-- -5 - adenine) and Example 100 of EP 0771799-incorporated- herein - b . reference) and in particular a PDE5 inhibitor such as the pyrazolo [4,3 -

- d]pyrirnidin-7 oήes -disclosed in EP-A-0463756; the pyrazolo [4,3- d]pyrimidin-7-ones disclosed in ER.-A-0526004; the pyrazolo - [4,3- d]pyrimidin-7-ones disclosed in published international patent application -

10 " WO 3/Q6104; the isomeric pyrazolo [3 ,4-d]pyrimidin-4-ones-disclosedjn published international patent application WO- 93/07149; the quinazolin-4-

- ones disclosed in published international patent, application -WO 93/12095; the- pyrido [3,2-d]pyrimidin-4-ones disclosed in published - international patent application WO 94/05661 ; the purin-6-ones disclosed

15 - in published international patent application WO 94/00453; the pyrazolo

[4,3-d]pyrimidin-7-ones disclosed in published international patent application WO 98/49166; the pyrazolo _[4,3-d]pyrimidin-7-ones disclosed. "in published international patent application WO 99/54333; the pyrazolo

- [4,3-d]pyrimidin-4-ones disclosed in. EP-A-0995751 X the pyrazolo [4,3_r 20 ^{" "} djpyrimidin-7-ories disclosed in published international patent application

WO 00/24745; the pyrazolo [4,3-d]pyrimidin-4-ones disclosed in EP-A- 0995750; the compounds disclosed, in published international application - WO95719978;^" the compounds disclosed in published international, application WO 99/24433 and the compounds disclosed in . published

25 ^" -" ^" international application WO 93/07124; the pyrazolo [4,3-d]pyrimidin=7- ones disclosed in published . international application WO.01/27112; the- pyrazolo [4,3 d]pyrimidin-7-ones disclosed in published international application WO 01/27113; the compounds disclosed in~EP-A--109271θ and the compounds disclosed in E-P-A-1092719,.

30 Preferred PDE5 inhibitors for use with the invention:

5-[2-ethoxy-5-(4-methy!-1 -piperazinylsulphonyl)phenyl]-1 -methyl-3-n- propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil) also known as 1 -[[3-(6,7-dihydro-1 -methyl-7-oxo-3-propyl-1 H-pyrazolo[4,3- d]pyrimidin-5-yl)-4-ethoxyphenyl]s_.ulphonyl]-4-metbylpiperazine_-(see EP-

A-0463756);

5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro - 7H-pyrazolo[4,3-d]pyrimidin-7-one (see EP-A-0526004); 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2- x fpyridin^y methyl^^-dihydro^H-pyrazolo^.S-dlpyrimidin^-one . -(see -

WO98/49166);

3^ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-nαethoxyethoxy)pyάdin- -. 3-yl]- -(pyridiri-2-yl)methyl-2,6-dιhydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO99/54333); (+)-3-ethyl-5-[5-(4-ethylpιperazin-1 -ylsulphonyl)-2-(2-methoxy-1 (R)- methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3- d]pyrimidιn-7-one, - ^' also known -as - 3-ethyl-5-{5-[4-ethylpiperazin-1- ylsulphonyl]-2-([(1R)-2-methoxy-1-methylethyl]oxy)pyridin-3-yl}-2-methyl- 2,6-dιhydro=?H-pyrazolo[4,3-d] pyrimidin-7-one (see WO99/54333); 5-[2-ethoxy-.5-(4-ethylpiperazin-1-ylsulph.onyl)pyridin-3-yl]-3-ethyl-2=[2~ . . methoxyethyl]-2,6-dιhydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, also- nown as - ^' 1-{6^"-ethoxy-5-[3-ethyJ-6,7-clihydro-2r(2-methoxyeth l)-7-oxo-2H- pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulphonyl}-4-ethylpiperazine (see WO 03/27113, Example 8); - . - - - ^"" -. ^"- 5-[2-/so-Butoxy-5-(4-ethylpiperazin-1.-ylsulphonyl)pyridin-3-yl]-3-ethyl-2- -

C1-meth^"ylpiρeridin-4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one- - (see WO 01 2J1 13, Example 15); -

_5-[2-Ethoxy-5-(4-ethylpiperazin- 1 -ylsulphQnyl)pyr_din-3-ylJ-3-ethyJ.-2- - - pheny -2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see-WO. i/27113, Example 66); _ . . - — -

5-(5-Acetyl-2-propoxy-3-pyrιdιnyl)-3-ethyl-2-(1 -isopropyl-3-azetidinyl)-2,6- dihydro-7H-pyr-azolo[4,3-d]pyrimιdin-7-one (see WO 01/27 12,- Example 124); 5-(5-Acetyl-2-butoxy-3-pyridjnyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6^ dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-.one (see WO 01/27112, Example

132);

(6R, 12aR)-2, 3,6,7,12, 12a-hexahydro-2-methyl-6-(3,4- methylenedioxyphenyl) - -pyrazino[2',1 ':6,1]pyrido[3,4-bjindole-1 ,4-dione

(IC-351 ), i.e. the compound of examples -78 and 95 of published international application WO95/19973, as well as the compound of examples 1 , 3,- 7 and 8; . - .

2-[2-ethoxy^"-5-(4-ethyl-piperazιn-1-yl-1-sulphonyl)-phenyl]-5-methyl-7- propyV3H-inϊidazo[5,1-f][1 ,2,4]triazin-4-one (vardenafil) also known as 1--

[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazin-2-yl)-4- ethoxyphenyl]sulphσnyl]-4-ethylpiperazin^"e, i.e. ihecompound of examples.

20, 19, 337 and 336 of published international application WO99/24433; and the - compound of example 11 of published international - application

WO93/07124 (EISAI); and compounds 3 and_14-from Rotella D P, J. Med,. Chem., 2000, 43, .1257.

Still further PDE5 inhibitors for use with the invention include' 4-br^'όmo-5-(pyridylmethylaminσ)-6-[3-(4-chlorophenyl)-propoxyl-

3(2H)pyridazinone -[4-{(1 ,3-benzodioxol-5- ylmethyl)amiono]-6-ch!oro-2- quinozolinyl]-4-piperidine-carboxylic acid, monosodium ._.salt; (+.)-cis- 5,6a,7,9,9,9a-hexahydro-2-[4-(trιfluoromethyl)-phenylmethyl-5-methyl- cyclopent-4,5]imιdazo[2,1-b]purin-4(3H)one; furazlocillin; cis-2-hexyl-5- methyl-3,4,5,6a,7,8,9,9a- octahydrocyclopent[4,5]-imidazo[2,1-b]purin-4- orie; 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6- carboxylate; 3-acetyl-1-. (2-chlorobenzyl)-2_rpropylindole-6-carboxylate; 4-bromo-5-(3- pyridylmethylamino)-6-(3-(4-chlorophenyl) propoxy).-3- (2H)pyridaz^none; l-methyl-5(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1₁6-dihydro- . 7H-pyrazqlo(4,3-d)pyrimidιn-7-one; 1-[4-[(1 ,3-benzodibxol-5- ylmethyl)arnιno]-6-chloro-2- quinazolinyl]-4-piperidinecarboxylic acid, moriosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharrriaprojeets No. 5051 (Bayer); Pharmaprojects -No.- 5064 (Kyowa Hakko; see WO 96/26940); Pharmaprojects No. 5069 (Schering Plough); GF-196960 (Glaxo Wellcome); E-δOΪ and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer)xand Sch,5.1866,

The contents of the published patent applications and journal articles and in particular the general formulae of the therapeutically active compounds of the claims and exemplified^" compounds therein .are incorporated herein in their entirety by reference thereto. .

More preferred PDE5 inhibitors for use with the invention are. selected from the group:

5-[2-ethoxy-5-^4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n- prόpyl-1 ,6-dihydr^"o-7H-pyrazolo[4-,3-d]pyrimidin-7--one (sildenafil); . (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4- - methylenediόxyphenyl) ^" -pyrazino[2',1':6,1]pyrido[3,4-b]indole-1 ,4-dione

(IC-351);

2r[2 ethoxy-5-(4-ethyt-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7- propyl-3H-imidazo[5,1-f][1 ;2,4]triaz.in-4-one (vardenafil); and 5-{2-ethoxy-5-(4-ethy!piperazin-1.-ylsulphonyl)pyridin-3-yl]-3-^"ethyl-2-[2- methoxyethylI-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-qne or 5r(5-

Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one and pharmaceutically acceptable salts thereof^"

A particularly^" preferred PDE5 , inhibitor is 5-[2-ethpxy-5-(4-methyj,-1- "-piperazinylsulph^"onyJ)phenyl]-1-methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazoloJ4,3- d]pyrimidin-7-one (sildenafil) (also known as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3- propyl-1H-pyrazolo[4^",3 d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4- methylpiperazine)- and~^"pharrnaceutical_.ly acceptable salts thereof. SUdenafil- _. citrate is a preferred ^'salt ÷ -

Preferred agents for^' coadministration with the compounds of the present invention are -PDE5^" inhibitors^",-- selective serotonin reuptake inhibitors (SSRIs), vasopressin V_1A antagonists, α-adrenergic receptor antagonists, NEP inhibitors, dopamine agonists and melariocortin receptor agonists as described above. Particularly preferred agents for coadministration are PDE5 inhibitors, SSRIs, andΛ i_A antagonists as described herein.

Assay

A suitable assay for determining the oxytocin antagonist activity of a compound is detailed herein^'below -

Oxytocϊn Receptor Beta-lactamase Assay

Materials:

Cell culture/Reagents

A: cell culture

Nutrient Mixture

F12 Ham's

Foetal Bovine Serum (FBS) Geneticin

Zeocin

Trypsin/EDTA-

PBS.(phosphate buffered saline)

HEPES ..

B: reagents

Oxytocin .

Q-T receptor-specific antagonist -

Molecular grade Dimethyl Sulphoxide (DMSO)- Trypan Blue Solution 0.4%

CCF4-AM (Solution A) ^"

Pluronic F127s (Solution B) 24%PEG, 18%TR40 (Solution C)

Probenecid (Dissolved at 200mM in 200mM NaOH, Solution D)

Methods

Cell Culture

Cells - used are CHO-OTR/NFAT-β-Lactamase. The NFAI-β-lactamase expression construct was transfected into the CHO-OTR cell line ^"and clonal ^"populations were isolated, via fluorescence activated cell sorting (FACS). An appropriate clone.was selected to develop the assay.

Growth Medium -

90%^'F12 Nutrient -Mix, 15mM HEPES 10% FBS 400μg/ml Geneticin 200 μg/ml Zeocin 2mM L-Glutamine-

Assay media 99.5% F12 Nutrient Mix, 15mM HEPES 0:5%^' FBS

Recovery of cells- A vial of frozen cells isjhawed rapidly in 37°C water bath and the cell suspension transferred- into a T225 flask with 50ml of fresh- growth medium and then incubated at 37°C, 5% CO₂ in an incubator until the cells adhered to the flask Replace media with 50ml of fresh growuV_media the following day.

Culturing cells-^"- CHO-OTR-NFAT-βLactamase cells were , grown ^"in— growth medium, CeJIs were harvested when they reached 80-90% confluence removing the medium and washing with pre-warmed PBS PBS was then removed and Trypsin/EDTA added (3mls c^r T225cm² flask) before incubating for 5 min i 37°C/5%CO^" ₂ incubator. When cells were detached, pre-warmed growth media was added (7mls for T225cm² flask) and the cells re-suspended and mixed gently by pipetting to achieve single cell suspension The cells were split into T225 flask at T10 (for 3days growth) and 1 30 (for 5 days growth) ratio in 35ml growth medium.^"

β-Lactamase assay Method

DAY 1

Cell plate preparation

^" Cells grown at 80-90% confluence were harvested and counted. Suspensions of - cells at 2x105 cells/ml in growth medium were prepared and 30μl of cells suspension added^" in 384-well, black clear-bottom plates, A blank plate containing diluents from each reagent was used for background^'subtraction.

Plates were incubated at 37°C, 5% CO₂ overnight

DAY 2

Cells stimulation

• 10μl antagonist/compound (diluted in assay media containing 1.25% DMSO ^" -- = antagonist diluent) was added to appropriate wells and incubated for 15 minutes at 37°C, 5% CO₂

• 10μl oxytocin, made up in assay media, was added to all wells and incubated for 4 hours at 37°Cr5% CO₂.

_• A separate 384-well cell plate was used to generate an oxytocin dose response curve. (10 μl antagonist diluent was added to every well. Oμl of - oxytocin was then added The cells are then treated as per

^" antagonist/compound cell plates) ^Preparation of 1ml of 6x Loading Buffer with Enhanced Loading Protocol (this equires scale-up according to number of plates to be screened) _

» 12μl of solution A (1mM C.CF4-AM. ιn Dry^"DMSO) was-- added to 60μ_l_.pf solution B (100mg/ml Pluronic-F127 in DMSO + 0Λ% Acetic Acid) and vortexed. ^"

• The resulting solution was -added to 925μl of solution C (24% w/w PEG400, 18% TR40 v/v in water),

• 75μl of solution D was added (200mM probenecid in 200mM NaOH). _ • 10μl of 6x Loading Buffer was added to ^"all welfs and incubated Tor 1.5hrs - 2hrs at room temperature Tn the dark.

• The plates were read using an LJL Analyst, ^citation 405nm, Emission 450nm and 530nm,- gam optimal, lagtime 0.40μs integration, 4 flashes, bottom reading.

Using the assay described above, the compounds of the present invention all exhibit oxytocin antagonist activity, expressed as a Ki value, of less than 500nM, Preferred examples have Ki values of less than 200nM and particularly preferred examples have Ki values of less than 50nM.

The compound of example 8 has a Ki value of 3nM.

The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are usedx

Arbocel ,© Filtration agent, from J. Rettenmaier & Sohne, Germany

APCI+ Atmospheric Pressure Chemical lonisation (positive scan)

CDCI₃ Chloroform-d1 d Doublet dd Doublet of doublets

DMSO Dimethylsulfoxide " ES+ , Electrospray ionisation positive scan. ' q - ^{" "} Equivalent -χι . _-

¹H NMR Proton Nuclear Magnetic ResonanceSpectroscopy

MS (Low Resolution) Mass Spectroscopy m^" Multiplet- ^"rn z ^"Mass spectrum peak q Quartet s Singlet t - ^{■" "} - Triplet δ - - Chemical shift

Preparation 1 bis[2-l(Dimethylamino- N)methvnphenyl-κC1bislu-(trifluoroacetato_^κO: κO')T- palladium

To a suspension of palladium chloride (3.43g, 19.4mmol) in methanol (200mL) under nitrogen at room temperature was added Λ/.Λ/-dimethylbenzylamine (5.82mL, 38.7mmo!) via syringe. The resulting red/brown suspension was stirred at -rόbm temperature for 24 hours. The now green/brown suspension was concentrated in vacuo to remove methanol, re-dissolved in dichloromethane (150mL) and passed through a pad of silica gel washing through with dichloromethane. The resulting bright yellow- filtrate was concentrated in vacuo and recrystallised from dichloromethane:ether to give the desired product, 4.66g, 1HNMR(CDCI₃; 300MHz) δ' 2.86(s, 6H), 2.89(s, 6H), 3.95(s, 4H), 6.84-7.24(m, 8H)

Preparation 2

"- bisf2-[(Dimethylamino-κN)methvnphenyl-κC]bislμ-(trifluoroacetato- O ^• KO'VI-

- palladium

To a solution of silver trifluoroacetate (4.48g, 20.3mmol) in acetone (30mL) under nitrogen at room temperature.. was. added, a solution ofthe complex of preparation 1 (5.60g, 10.15mmo!) in dichloromethane (100mL). A thick white precipitate appeared during addition The suspension was stirred for 15 minutes, and was then filtered. through a pad of silica gel, washing with dichloromethane. ^{" "}Concentration in vacuo gave a bright yellow powder that was recrystallised frpm dichloromefhane.^'ether to give the desired product, 7.06g.

¹HNMR(CDCl_3r 300MHz) δ 2.05(s, 6H), 2 88(s, 6H), 3 18(d, 2H), 3.63(d, 2H),_ '6^~89-6.θ7(m, 6H), 7.00-7.10(m, 2H) Preparatton 3

[2-l(Dimethylamino-κN')methvπphenyl- κCl(tricvclohexylphosphine)(trifluoroacetato-κO-(SP-4-3Vpalladium

- To a solution of the, product of preparation 2 (6.43g, 9.10mmol) in dichlorometharie (50mL) under nitrogen at room, temperature was added a solution of tricyclohexylphosphine (6.89g, 24.5mmol) in dichloromethane (20mL). After stirring for 1 hour, the solution was passed ^"through a plug of silica gel (7cm ~x 2cm) washing with dichloromethane ^~(400mL)_t and the pale yellow filtrate concentrated^' in vacuo. Recrystallisation from dichloromethaneether gave the desired complex, 10.53g.

¹HNMR(CDCI₃, 300MHz) δ: 1.05-2.30(m, 33H), 2.57(s, 3H), 2.58(s, 3H), 3.93(s, 2H), 6.86-5.98(m, 3H), 7,10-7.12(m, 1H)

Preparation 4 _;

2-(4-Bromo-phenyl)-5-methyl-f1 ,3.41oxadiazole

4-Bromo-benzoic acid hydrazide (12.90g, 60mmol) and N,N-dimethylacetarhide

, dimethyl acetal 12mL, 82.0mmol) were dissolved in N,N-dimethylformamide

(100mL) and the ^"solution heated to 60°C for 2 hours. The solution was concentrated in vacuo and the residue taken up in toluene (80mL) and treated with para-toluenesulfonic acid monohydrate (200mg, 1.50mmol). The mixture was heated to reflux for 2 hours, allowed to cool,- and the product crystallised from the solution and was collected by filtration. The crude product was washed with ether and dried in vacuo to yield a white" solid. The filtrate was concentrated in vacuo and the residue combined with the white solid, dissolved in toluene

- 5 <50mL) and treated ^" with para-toluenesulfonic acid monohydrate (100mg,

0.75mmol). The mixture was heated to reflux for 3 hours, allowed to cool and concentrated in vacuo. The residue was purified by column chromatography on

^" silica gel eluting with pentaneethyl acetate 80:20 to 40:60 to yield the title product, 12. OOg ^" - -

10- ¹HNMR(CDCI₃, 400MHz) δ: 2.61(s, 3H)/7.62(d, -2H), 7.88(d, 2H). tvl^'S ES+- m/z- 239 [MH]⁺ - - - - _s __- -

^" - Preparation^'s

3-(4-Bromo-phenvD-4-(4-methoχy-phenyr>-5-methyl_:4H-l1 ,2.41triazole 15

The product of preparation 4 (5. OOg, 20.9mmol) was added to a solution of , para-toluenesulfonic acid , monohydrate (100mg, 0.75mmol) and

20 4-methpxypheηylamine (7 70g, 62.5mmol) in xylene (150mL) and the reaction mixture heated to 150°C. for 22 hours. The reaction mixture was concentrated in vacuo, and the residue taken up in dichloromethane and purified by column chromatography on silica gel . eluting with dichloromethane:methanol:0.88 ammonia 100 0.0_. to 97:3:0.3 to yield the title product, 7.05g.

25 ¹HNMR(DMSO-D₆, 400MHz) δ: 2.20(s, 3H), 3.81 (s, 3H), 7.07(m, 2H), 7.28(m, 2H), 7 34(m, 2H), 7.56(m, 2H). MS APCI+ m/z 344 [MHf Preoaration 6

5-^:Bromo-pyridine-2-carboχylic acid hydrazide

_,.5-Brprno-pyridine-2-carboxylic acid methyl ester (J. Org. Chem., 2001, 66(2),

._.6Q5-6QS, compoun 4) (18.10g, 83ηϊmol) and hydrazϊne monohydrate (12.5mL,

250mmoi) were dissolved in methanol (400mL)^"arid t e reaction mixture heated to reflux for 48 hours. The reaction mixture was then filtered and the precipitate

10 collected dried ϊn vacuo to yield ^"the title product, 15.40g. ^' "

,_.., HNMR(pMSO-D6, 400MHz)-δ: ^:4.57(d;2H), 7.91(m, 1H)^",^" 8.22(m, 1H), 8.72(m,

1H), 9,98(m, 1H). MSΕS+.m/z217 [MHf ;^'.^' v^: -^■----^■- ^•-^.•

Preparation 7

15 . 5^""-Chloro-pyrazine-2-carboxylic acid hydrazide ^"

The title compound was prepared by. the method of preparation 6 using 5-chloro-

20: -pyrazine-2^carbo.xyJic acid methyl ester, 5.01 g, 50% yield of th desired_^product

- was produced. _r- ._.. ,_.:^■"-...- ,-.,.^•. ... _

. ¹HNMR(CDCI₃₎.400MHz) δ: 4.09(d, 2H), 8.52(s, 1H), 8.66(bs, 1H), 9.14(s, 1H).

^•-•■^" Micfόanaϊysis: CgHsCI^O requires: C 34.80; H 2.92; N 32.47; found 034,89; H

2.91, N 32.32. MS APCI+ m/z .173 [MH]⁺ . _{. ..} -_.

25 ^" - . . ■: ■ Preparation 8

5-Bromo-pyridine-2 -carboxylic acid N'-(2-methoxy-acetyl)-hvdrazide

- ^" The product of preparation 6 (2.0g, 9.3mmol)- and N-methylmorpholine (1.3mL,

12.0rnmol) were dissolved in dichloromethane (60mL) and the solution treated with methoxyacetyl chloride (868μL, 9.50mmol). The reaction mixture was stirred

- at room temperatufe for 5 hours and then washed with water and concentrated

10 in vacuo to .afford 2.41g, 90% yield of the title product.

¹HNMR(CDCI₃, 400MHz) δ: 3.46(s, 3H), 4.07(s, 2H), 7.98(dd,.1 H), 8.02(dd, 1 H), . 8.61 (d, 1 H), 8 89(d, 1 H), 9 95(d, 1 H). MS ES+ m/z 289 [MHf

Preparation 9

15 ^■ 6-Chloro-nicotinic acid N'-(2-methoxy-acetylVhvdrazide

The title product was prepared by the method of preparation 8 using 20 6-chloronicόtinic acid hydrazide. 19.0g, 90% yield of the ^"desired product was produced, ^" - -.

¹HNMR(CDCI₃, 400MHz) δ: 3.36(s, 3H), 3,97(s, 2H), 7.68(d, 1H), 8.26(dd, ΪH), 8.84(s, 1 H), 9.99(s, 1H), 10.61(s, -H). MS ES+ m/z 246 [MHf

25 Preparation 10 .

5-Chloro-pyrazirie-2-carboxylic acid N'-(2-methoxy-acetyl^'>-hydra^'zide

5

The title product was prepared by the method of preparation.- 8 using the^" hydrazide of preparation 7. 3.90g 70% yield , of the desired product was produced. ^{■ '}-

... MS APCI+ m/z 245 [MHf - 0 _.

Preparation 11

5-Chloro-pyrazine-2-carboxylic acid N'-acetyl-hvdrazide

15 The title product -was prepared by the method of preparation 8 using the '_{. ..} hydrazide of preparatiori- 7. and acetyl chloride. 4.0g, 64% of the desired product , was produced. ^" - -

MS APCI+ m/z 215 [MHf .

20 " Preparation 12

5-Bromo-Pyridin^"e-2-carboxylic acid N'-(2-chloro-acetyl)-hv^"d^"ra^"zide

The tftle product was prepared by the method of preparation 8 using the hydrazide of preparation 6 and chloroacetyl chloride: 4.30g, 59%. yield of the desired product was produced,

¹HNMR(CDCI₃, 400MHz) δ:^" 4.20(s, 2H), 8.00(d, 1 H), &30(d, 1 H), 8.80(s, 1H), iθ^".40(s, 1 H),-^"10,70(s, H). MS APCI+ m/z 293 [MHf

Preparation 13

- -5-Broroo-2-(5-methoxymethyl-f1 ,3,4loxadiazol-2-yl)-pyridine

The product of preparation 8 (2.41g, 8.4mmol)^~ and phosphorous oxychloride (7mL) were combined and heated to ^"110°C for 4 hours.- The reaction mixture ' was concentrated irf-vacuo and the^" residue taken up in ethyl acetate and- water. The rhixture as neutralised'by the addition of 10% sodium carbonate solution.- and the phases separated. The aqueous phase was extracted with ethyl acetate and the combined organics^" dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to yield the title product, 1.01 g, 45% yield: ^{" ~} -

¹HNMR(CDCI₃, 400MHz) δ: 3.48(s, 3H), 4.73(s, 2H)^', 8.01 (dd, j H)^", 8.12(dd, 1H), . 8.81 (dd, 1 H). MS APCI+ m/z 272 [MH]⁺

Preparation 14

2-Chloro-5-(5-methoxymethyl-M ,3,41oxadiazol-2-yl)-ρyridine

The title compound was prepared by the method of preparation 13 using the product of preparation 9 provide 7 93g, 40% yield of title compound as a rust brown solid

¹HNMR(CDCI₃, 400MHz) δ 3 52(s, 3H), 4 74(s, 2H), 7 50(d, 1 H), 8 32(dd, 1 H), 9 06(d, 1 H) Microanalysis C₉H_δCIN₃O requires C 47 91 , H 3 57, N 18 62, found C 47 75, H 3 50 N 18 46 MS APCI-r- m/z 226 [MHf

Preparation 15

2-Chloro-5-(5-methoxymethyl-f1 ,3,4loxadιazol-2-yl)-pyrazιne

The title compound was prepared by the method of preparation 13 using the product of preparation 10 1 38g, 38% yield of the desired product was produced as a light brown solid

¹HNMR(CDCI₃, 400MHz) δ 3 52(s, 3H), 4 78(s, 2H), 8 75(s, 1 H), 9 25(s, 1 H) MS APCI+ m/z 227 [MH]⁺

Preparation 16

2-Chloro-5-(5-methyl-f1 ,3,41oxadιazol-2-v -Pyrazιne

The title compound was prepared by- the method of preparation 13 using the product of preparation 11 30g, 35% of the desired product was produced as a brown solid

¹HNMR(CDCI₃ 400MHz) δ 2 68(s, 3H), 8 71(s, 1 H), 9 22(s, 1 H) MS APCI+ m/z 197 [MHf Preparation 17

5-Bromo-2-(5-chloromethyl-f1 ,3,4loxadiazol-2-yl)-pyridine

The title compound was prepared by Jhe method of preparation 13 using. the product of preparation 12. 2.3g 57% yield of desired product, was obtained as an off white solid. 1HNMR(DMSO-D₆, 400MHZ) δ: 4.80(s, 2H), 8.05(d, 1 H), 8.15(d, 1H), 8.85{s, 1H). ^" MS APCI+_ m/z 276 [MH]⁺ -

Preparation 18

5-Bromo-2-f5-(methoxymethyl)-4-(6-methoxypyridin-3-yl)-4H-1-2.4-triazol-3- yllpyridine

The product of preparation 13 (1.01g, 3.74mmol), 5-amind-2-methόxypyridine^" (ϊ .40g, 11.3mmol) and ^" para-toluenesulfonic acid monohydrate (50mg, 0.37mmol) were ^"dissolved in xylene (25mL) and the reaction mixture heated to 150°C for 23 hours. The reaction mixture ^"was concentrated in vacuo and the -residue purified by column chromatography on silica gel eluting with dichloromethane.methanol 100.0 to 90:10 to yield the ^"title product, 1.0g, 72% - yield as a. purple gum. ¹HNMR(CDCI₃,^""400MHz),δ: 3.32(s, 3H), 3.99(s, 3H), 4.46(s, 2H)_P 6.82(d, 1H), 7.54(dd, 1 H), 7.90(dd,-1H>, 8 05(d, 1 H), 8.13(d, 1 H), 8.37(d, 1 H). MS ES+ m/z 398 [MHf - - • - -

Preparation 19

2-(4-Fluoro-2-methyl-phenyl)-5-(5-methoxymethyl-f1 ,3,4loxadiazol-2-yl)-pyridine

10 _The chloro compound of preparation 14 (500mg, 2.22^"mmol), 4-fluoro-2-

- methylphenyl boronic acid (361 mg, 2 65mmol), the palladium complex of- preparation 3^" (10mg, cat.) and caesium carbonate (2 16g, 6.66mmol) were

. dissolved in 1 ,4-dioxan (10mL) and .the reaction mixture heated to reflux for 2 hours. Additional palladium complex (10mg) was added and the reaction mixture

15 refluxed for_^a further 1 hour. The reaction mixture was concentrated in vacuo- and the residue taken up in ethyl acetate and water. The phases were separated and the ethyl acetate phase washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield the title product, 690mg^"in quantitative yield.

^{* " '■} MS-APCI÷-m/z 300 [MHf - ^" - ._ _. - ^"-

20

Preparation 20

2-(-2,3-Dimethyl-phenyl)-5-(5-methoxymethyl-[1 ,3,4]oxadiazol-2-yl)-pyridine

25

The title product was prepared by the method of preparation 19 using 2,3-dimethylphenyl boronic acid (399mg, 1 2eq) and the product of preparation 14 (500mg, -2 22mmol). 712mg, quantitative yield, of the desired product was produced -^{" "} - MS APC l+ /z 296 [MHf

Preparation 21

2-(2,3-Dimethyl-phenyl)-5-(5-methoxymethyl-[1 ,3,41oxadiazol-2-vh-pyrazine

The title product was prepared by the method of - preparation iy using -2,3-dimethylphenyl boronic acid and the chloro compound of preparation 15.

466mg, quantitative yield, of the de_sired product yyas produced.

¹HNMR(CDCI₃, 400MHz) δ: 2.29(s, 3H), 2.39(s, 3H), _3.52(s,- 3H), 4.78(s-, 2H)^",

7.23-7.37(m, 3H), 8 84(s, 1 H), 9.54(s, 1 H) MS APCI+ m z 297[MHf

Preparation 22

2-(4-Fluoro-2-methyl-phenyl)-5-(5-methoxymethyl-f1 _>.3,4]oxa^"diazol-2-yl)-pyrazrne

The title product was prepared by the method of preparation 19 using-4-fluoro-2- methyl-phenyl boronic acid and the chloro compound of preparation .15. 450mg, 97% of the desired p^"roduct was produced. MS APCI+ m/z 301 [MHf Preparation 23. _

.2-(2,3τDimethyl-phenyl-5-(5-methyl-l1,3,4loxadiazol-2-yl)-pyrazine

Preparation 25

^"20 ^{'" ' : ' ■'} ■J-f5-(5-Brόmo-pyridin-2-vh-T1-,3,41oxadiazol-2-ylmethyrl-pyrroridine-(2S-2- t

^■- ■--^' - ^■•' carboxylic acid amide ^'-^'• -^■•^''<

The chloro compound of preparation 17 (500mg, 1 82mmol) and (S)-prolinamide

(312mg, 2 73rrimol) were -dissolved^" in acetonitrile (10mL) and the mixture treated with potassium carbonate (503mg, 3.64mmol) The reaction mixture was stirred at room temperature for-18 hours and then at 50°C for 2 hours. The reaction

5 mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The precipitate formed was filtered off and the organic layer of the filtrate washed with water, 1M sodium hydroxide solution and brine. The organic layer was then concentrated in vacuo to yield the title product, 540mg,

84% yield.

10 ¹HNMR(^"DMSO-D₆, 400MHZ) δ: 170(m, 3H), 2 00(m, 1 H), 2 60(m, 1 H), 3.10(m,

1H), 3.20(m, 1 H), 4.00(d, 1 H), 4.20(d, 1H), 7.00-7 20(d, 2H), 8.10(d, 1H), 8.30(d,

1 H), 8.90(s, 1H).

- Preparation 26

j-5 . - - 5-Bromo-2-(5-pyrrolidin-1-ylmethyl-[1 ,3,4]oxadiazdl-2-vπ-pyridine

_. Pyrrolidine (324mg, 0.38mL,- 4 56mmol) was added to a stirred solution of the

20 chloro compound of preparation 17 (500mg, 1 82mmol) in aceoriitrile (15mL) at room temperature. After stirring for 18 hours the reaction mixture was concentrated in vacuo and the residue taken u -in ethyl acetate (50mL) and washed with 2M aqueous sodium hydroxide, followed by water followed by brine.

- The^""Organκf phase was dried over sodium sulfate, filtered .and. concentrated in

25 vacuo to _.afford 407 mg, 72% yield of the title compound. HNMR(CDCI₃, 400MHz) δ' 1.90(m, 4H), 2 70(m, 4H), 4.00(s, 2H),^"8.00(d, 1 H), 8.20(d, 1 H), 8 80(s, 1H)

30 Prβparation 27

Preparation 28

: 5-Brόmo-2- (5-pyrrolidιh-1-ylmethyl)-4-(6-methόxypyridin-3-yl))-4Η

3-yl)-pyridine

412 mg, 77% yield, of the title compoun was prepared by the method ot preparation 27 using the product of preparation 26.

MS ES+ m/z -417 [MHf - _. - - - - - . Preparation 29 ...

3-Methyl-4-(4.4,5.5-tetramethyl-f1 ,3,21dioxaborolan-2-yl)-benzonitrile^"

Palladium (II) acetate (224mg, 5 mol%),- potassium acetate (3.68gr 61.2 mmol) and bis(pinacolato)diboron (5.4g, 21.4 mmol) were added to a sόlufion^of

1-bromo-4-cyano-2-methylbenzene (4.0g, 20.4 mmol) in,N,N-dimethylformamide

^{" "} (40 rtiL-J and heated at 80°C for 18 hours. After such time the mixture was cooled and filtered through a pad~of Celite^®, washing with ethyl acetate and water. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo to-afford a brown solid. The solid was purified by- trituration iri pentane, filtration and drying to afford the title compound as a beige solid .(2.68g, ^"54%

_. yield): _. -- ^{' "} _ ^" . -

^{" 1}HNMR(CDCI₃, 400MHz) δ: 1.35(s, 12H), 2.55(s, 3H), 7.^"41-7.45(m, 2H), 7.82(d, .H). MS APCI+ m/z^"261 [MNH₄f ^"

Preparation 30

2-Chloro-5-f4-(^β-methoxy-pyridin-3-yl)-5-methyl-4H-M .2.41triazol-3-yl|- pyrazine

The title product was prepared by the method of preparation _. 18 using the oxadiazole compound of preparation 16 and 5-amιno-2-methoxypyridine. 4-3g, . 44% yield of the desired product was produced as a beige solid. - - - lHNMR(CDCI₃, 400MHz) δ: 2.36(s, 3H), 3 99(s, 3H), 6.86(d, 1 H), 7.45(dd, 1H), 8 02(d, 1 H), 8 27(d, 1H), 9 23(d, 1 H).

Preparation 31

2-Chloro-5-f5-methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-[1 ,2,4ltriazo1-3-vn- pyrazine

10

- The title product was prepared by the method of preparation 18 using the oxadiazole^"compdund of preparation 15 and 5-amino=2-methoxypyridine. 10_L5g, -15- 59% yield of the^~desired product was produced as a beige solid. - - ¹HNMR(CDCI₃, 400MHz),δ: 3.33(s, 3H), 3 99(s, 3H), 4.47(s, 2H)^", 6.83(d, _1 H), -- 7.53(dd, H), 8.06(d, 1 H), a 30(d, 1 H), 9 25(d, iii). . -

MS APCI+ m/z 333 [MHf - -

20 . . . Preparation 32 _. .

2-(5-Fluoro-2-methoxy-phenyl)-5-(5-methoxy^"methyl- 1 ,3,41oxadiazol-2-yl)- pyndine ^" - ^{~ "}

The title product was prepared by the method of preparation 19 using 5-fluoro-2- -" methoxy-phenyl boronic acid (5.65mg, 3.33mol) and the chloro compound from_, preparation 14 (Sθϋmg, 2.22rrimol).669mg, 96% yield. of- the desired product 5 was produced. - ^' _. ^' _.-■-•^• -

¹HNMR(CDCI₃, 400MHz) δ: 3.51(s, 3H), 3.88(s,-3H), 4.75(s, 2H);, 6.97(d, 1H), - .-^"'7.11(m, 1H), 7.70(dd, 1H), 8.11(d, 1H),8.37(dd, 1H), 9.34 (d, 1H). . - MS APCI* m/z 316 [MHf _......

The title product was prepared- from the product of preparation 7 and chloroacetylchlorϊde, -Using the method of preparation 33, as a solid in 37% yield. "MS APCI+mVz 249/251 -[MHf - =- . _. .-

^• _' ^■.--^'■"-' ^" - . Preparation 35 ■ ^■- 6-Chloro-nicotinic acid N'-acetyl-hydrazide

then stirred in diethyl ether for 2 hours, filtered and dried to afford the title compound as a pale yellow solid in 51% yield, 1.7g. tHNMR(CDCI₃, 400MHz) δ:3.46(s, 3H), 3.62(m, 2H), 3.78(m, 2H), 4.21(s, 2H), 7 42(d, 1H)^", 8.07(ddχ1 H), 8.82(d, 1 H) 9.28(brs, 1 H), 9.83(brs, 1 H). -MS APCL+ m/z 288 [MHf - - : ^' .- - - .

Preparation 37

6-Chloro-nicotinιc acid N'-(2-ethoxy-acetyl)-hvdrazide

(2-Ethoxy)-acetyl chloride [(1.72g, 13 99mmol), Tett. Lett., 35, (39), 7269; 1994)] "was added to an ice-cold solution of 6-chloronicotϊhic acid hydrazide (2g„ 11 66mmol)^~ and N-methylmorpholme (1.92mL, 17 49mrhof) ^"in dichloromethane (60mL) and the mixture was stirred at room temperature for 18 hours. The ..mixture was then washed with citric acid, sodium hydrogen- carbonate solution and^" brine and the solvent was evaporated under reduced pressure to yield some title product as a white solid, 880mg. The combined aqueous washings were - extracted^" with ethyl acetate- (x2) and the combined organic solutions were dried over sodium sulfate- and concentrated in vacuo to afford a further crop of title^{" "}compound as a pale yellow solid, 1 6g (total yield of 83%). ^" - -

^" _ HNMR(CpCI₃,- 400MH^"z)_. δ 1^~ 21(t, 3H), 3.55(q, 2H), 4.06^~(s, 2H), 7.38(d, 1H)/ 8O0(dd,^"" l H), 8.77 d, ^"l H) 8.99(brs, 1H), 9.15(brs, 1 H). MS APCI+ m/z 258/260 ^" [MHf Preparations 38 to 42.

The following compounds, of .the general formula shown below, were prepared by the^'.method of preparation 13 using the appropriate hydrazide (preparations 33-37) and phosphorus oxychloride.

Preoaration 42 was purified by column chromatography on silica gel, eluting with pentaneethyl acetate, 100:0 to 90.10.

Preparation 43

- - 2-Chloro-5-(5-f1 ,2,31triazol-2-ylmethyl-π ,3,41oxadiazol-2-vn-pyridine

1H-1,2,3-Triazole (264mg, 3.85mmol) was added to a suspension of the chloro compound of preparation 38 (800mg, 3 5mmol), and potassium carbonate (1.4g, 7mmol) in N,N-dimethylformamide (15mL) and the mixture stirred- at room temperature for 18 hours. The reaction -mixture was then partitioned between ethyl acetate and water and the organic layer was separated, washed with brine, dried_.over sodium sulfate and concentrated in vacuo to afford the title compound as a yellow solid in 71% yield, 650mg. HNMR(CDCI₃, 400MHz) δ: 6.08(s, 2H), ?66(d, 1H), 7 80(s, 2H), 8.38(dd, 1H), 8.99(d, 1H). MS APCI+ m/z 263 [MHf ^:-

Preparations 44 to 45

Jhe following compounds, of the general formula shown below, were prepared from the product ^"of preparations 38 and 39 using the method of preparation 43.

45 H₃C CH ¹HNMR(CDCI₃, 400MHz) δ^~ 2 34(s_> 82%

N-

H₃C 6H), 3 78(s, 2H), 7 43(d, 1H), 8 28(dd, 1 H), 9 01 (d, 1 H) MS APCI+ m/z 239/241 [MHf -_ _

Preparations 46 to 52

The -following compounds, of the general formula shown below, were prepared by the method of preparation 18 using the appropriate oxadiazole (preparations 14 and 40-45) and 5-amιno-2-methoxypyrιdιne

Preparation 48 was purified by column chromatography on silica gel, eluting with dιchloromethane methanol.0 88 ammonia, 99 1 0 1 to 97'3:0.1 , followed by trituration with diethyl ether

Preparation 49 was purified by column c romatography on silica gel, eluting with ethyl acetate pentane, 10 90 to 100 0, followed by trituration with diethyl ether. Preparation 50 was purified by re-crystallisation from ethyl acetate. Preparation 51 was purified by column chromatography on silica gel, eluting with dichforomethane:methanol:0.88 ammonia, 100:0:0 to 99:1 :0.1.

Preparation 53

> 4-Bromo-2,3-dimethyl-pyricHne 1 -oxide

A mixture of 2,3-dιmethyl-4-nitropyridine N-oxide (5g, 29.7mmol) and hydrogen 10-.. bromide (30% wt in acetic acid, 100mL) was heated for 48 hours at 100°C. The mixture was then filtered, washing through with 2M sodium hydroxide and the filtrate was extracted with dichloromethane (x3). The combined organic solutions were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography ^"on silica gel, eluting with^" 15 ethyl acetate:^"pentane, 50:50, to afford the title product as a pale yellow solid. 1HNMR(CDCI₃, 400MHZ) δ: 2.44(s, 3H),^~2.58(s, 3H), 7,30(d, 1 H), 8.01(d, 1H) ^" - ^"MS APCΪ+ m/z 202/204 [MHf

Preparation 54 - .

20 4^~-(2,3-Dimethyl--1-oxy-pyridin-4-yl)-benzoic acid methyl-ester

A mixture of the product of preparation 53 (765mg, 3.78mmol),

4-methoxycarbonylphenylboronic acid (750mg, 4.16mmol), caesium carbonate

(3.7g, 1 34mrήol) and the product of preparation 3 (50mg, cat.) in 1 , 4-dioxan

(20mL) was heated at 11Θ°C for 3 hours. The mixture was then partitioned- between ethyl acetate and water and the aqueous layer was separated and extracted by dichloromethane (x3). The combined organic solutions were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a dark yellow_solid. This solid was triturated with diethyl ether to afford the title

- compound as a pale brown solid in 87^"%_yield. __. . _ - " ¹HNMR(CDCi₃₎ 400MHz) δ: 2.24(s, 3H), 2.60(s, 3H), 3.95(s, 3H), 7.02(d, 1 H),

7.35(m, 2H), 8 2(m, 2H), 8.22(d, 1 H). MS APCI_.+ m/z 258 [MHf

Preparation 55

4-(2.3-Dimethyl-1-oxy-pyridin-4-vh-benzoic acid hydrazide -

A mixture of the product of preparation 54 (850mg, 3.3mmol) and hydrazine monohydrate <482μi, 9.9mmol) in methanol (15rhL) was heated under reflux for 3 hours. A further amount of hydrazine monohydrate (482μL, 9.9mmol) was then added-to the reaction mixture and heating continued for 18 hours. The ^"mixture was then filtered through Gelite^®, washing through with rriethanol and the filtrate was concentrated in vacuo to give a white solid. The solid was slurried in ethyl acetate, filtered- off, washed with diethyl ether (x2) and vacuum dried to afford the title compound as a white solid in 94% yield, 800mg. - .- _-

¹HNMR(CDCJ₃, 400MHz) δ: 2 18{s, 3H), 2.41 (s, 3H), 4.58(m, 2H), 7.14(d, 1 H), " 7.42(d, 2H), 7.96(d,-2H), 6.-18(d, TH), 9-85(s, 1 H): MS ARCI+ m/z 258 [MHf Preparation 56

1 rl ,1 ,2-Tetramethoxy-ethane

Methoxyacetonitnle (50 Og, 704mmol) was dissolved in a mixture of methanol (34mL) and diethyf ether (21OmL) and the mixture cooled to 0°C^" Hydrogen chloride gas was bubbled through the solution for 20 minutes and the reaction mixture was stirred at room temperature for 2 hours Hydrogen chlonde gas was then bubbled through, the mixture for a second time and it was allowed to stand at room temperature for 18 hours The mixture was filtered and the resulting white solid was washed with diethyl ether, dissolved in methanol (340mL) and stirred for 90 minutes The solution was then diluted with ether (370mL), heated under reflux for 6 hours and left to stand at room temperature for 18 hours Additional ether (200mL) was added and the mixture was filtered off The filtrate was washed with 10% sodium carbonate solution, dried over magnesium sulfate and concentrated in vacuo to yieldihe title product, 34 5g

^THNMR^~(CDCI₃, 400MHz) δ 3 29(s, 9H) 3 39(s, -3H), 3 50(s, 2H) ^'

^"Preparation 57

4-f4-(5-Methoxymethyl-f1 ,3,4loxadιazol-2-yl⁾-^phenvn-2,3-dιmethyl-pyrιdιne 1- oxide

para-Toluenesulfonic acid (20mg, cat ) was added to a_. mixture of the products of preparations 55 (400mg, 1 56mmol) and 56 (470mg, .3.12mmol in methanol (8mL) and the mixture was heated under reflux for 10 hours. The mixture was then treated with sodium hydrogen carbonate solution and the aqueous mixture was extracted with, ethyl acetate (x3) The combined organic solutions were washed with brine, dried .over sodium sulfate and concentrated in vacuo to afford the title product as a-yellow oil in 25% yield, 122mg.

¹HNMR(CDCf₃ ^", 400MHz) δ' 2 25(s, 3H), 2.62(s, 3H), 3 52(s, 3H), 4.70(s, 2H), 7.04(d, 1 H), 7.41(d, 2H),.8.16(d, 2H), 8.25(d, 1H). MS APCI+ m/z 312 [MHf

Preparation 58

6-Chloro-pyridazine-3-carboxylic acid methyl ester

Oxaly] chloride (1.14mL,..13.09mmol), was added dropwise to an ice-cold suspension of 6-chloro-pyridazine-3-carboxylic acid [(1.9g, 11.9mmol), J. Her. Chem. 29(6), 1583-92; .1992] in a mixture of dichloromethane (50mL) ^"and N,N-dimethylform^"amide (1 drop) and the mixture was stirred for 1 hour at room temperature The reaction mixture was then evaporated under reduced pressure and the residue was diluted with dichloromethane (30mL) and cooled to 0°C. Methanol (485μL, 11.9mmol) was added and the mixture was stirred at 0°C for 1 hour. ^"Sodium hydrogen carbonate solution was then added to the reaction mixture and the aqueous layer was separated and extracted with dichloromethane (x2). The combined organic solutions -were washed with brine, -dried ovefsodium sulfate and concentrated in vacuo to afford the title compound ~"--as a

65% yield, 1 33g - - - . -_ . ^" ~ ^.-__ _^"- ¹HNMR(eDei₃, 400MHz) δ 4 09 (s_L 3H), 7 67(d; -1 H), 8 16(d; 1H) MS APCI+ - m/z 173 [MHf - - - - ^" - Preparation 59

6-(4-Fluoro-2-methyl-phenyl)-pyridazine-3-carboxylic acid methyl ester

The title compound was prepared from the product of preparation 58 and

4-fluoro-2-methylphenyl boronic acid, using the method of preparation 54.

^{" "} Purification of the crude product by column chromatography on silica gel, eluting ^{" '} with pentane:ethyl acetate methanol 75:25:1 to 50:50:1 afforded the desired product as a beige solid jn^"1 % yield

¹HNMR(CDCΪ₃, 400MHz) δ: 2 44(s, 3H),- 4 11(s, H), 7.06(m, 2H), 7.47(dd, 1H), 7.71(d, 1 H), 8.26(d,-1H). MS APCI+ m/z 247 [MHf

Preparation 60

6-(4-Fluoro-2-methyl-phenyl)-pyridazine-3-carboχylicacid hydrazide

Hydrazine monohydrate (69μL, 1.42mmol) was added to a suspension of the ".product of preparation ^"59 (290mg, 1.1 δmmol) in methanol (5mL) and the mixture, was stirnέd for 18 hours at room temperature The resulting precipitate. was_ filtered off and dried to afford the title compound as .a peach solid, in 83%„yjeld, -240mg. - ¹HNMR(CDCI₃, 400MHz) δ: 2.42(s, 3H), 4.18(brs, 2H), ,7.06(m, 2H), -7.46(dd, 1H), 7.75(d,^" H)/8,33(d, 1H), 9.18(brs, 1H). MS APCI+ m/z 247 [MHf

Preparation 81

^" 6τ(4-Fiuoro-2-rnethyl-phenyl)-pyridazine-3-carboxylic acid N'-(2-methox y-acetyl)-hydrazide- ^■ . .-- , .

The title compound was prepared. from the product of preparation 60- and methoxyacetyl chloride, using the method of preparatiori 8, as a beige foam_.in r95% yield. ^X^{1 "''■}::,^■.- -.v— X ^..X .. ^. ., - ...../,. ^•.^■■•-__.._ ■ .. HNMR(^'CDCl₃, 400MHz) δ: 2.43(s, 3H), 3.52(s;3H), 4.14(s, 2H), 7.06(m, 2H), 7.46^'(m, 1^'H)-,-^'7 J6(d;- 1H) 8.33(d,.1-H), 8.80(brs, IH), 1O.06(brs, 1H)~ MS APCI+; m7z319[MHf- ^{^} -^""- .- : ... . _ . , ^" .^•,.;-_ ,.-χ^' --.

^'-^"" Preparation^" 62 - ^{■ •} • .^■_..■■ ^^~....

3-(4-Fluoro-2-rriethyl-phehyh-6-(5-methoxyrriethyl-[1 ,3,41oxadiazol-2-ylV- x- 1 pyridazine ;

^" The title compound was^" prepared from "the product of .preparation 61 and' phosphorous oxychloride, using the¹ method of preparation 13. The crude ^" product was purified by column chromatography- on silica gel, elutirig with dichlόromethane:methanol„ 99:1 to 98:2, to afford the desired compound as a - beige solid in 15%.yield. xχ - .. x ... . •^• -_. ^{; "} : _. .._.

¹HNMR(CDCI₃, 400MH*) δ: 2.43(s, 3H); 3;53(s, 3H), 4.80(s, 2H), 7,06(m, 2H), 7.46(m, 1 H), 7.74(d, 1H) 3:43(d_τ 1H). MS APCI+ m/z 301 [MHf - .

5

Preparation 63

- 5-Bromo-pyrimidine-2-carbonitrile ^" - ^■"-^'-

1.0 ^{'" ' " ' '} .

A solution of 5-bromo-2-chloropyrimidine (10g, 51.δmmol)_. in dimethylsulfoxide • (26rhL) was added to a mixture, of sodium^" cyanide (2.59g, 51 ,8mmol) and -^'. ; ^{■■ "}. friethylenediamine (1.2g, 10.^""4mmol) in^" dimethylsulfoxide^" (14mL) and water - (28mL). The resulting mixture was stirred for 1δ hours at room temperature. The; 15 mixture was -then diluted with wate (130mL) and extracted with- diethyl ether " (3x150mL), The combined organic solutions were dried ever sodium sulfate and X _ ^"concentrated in vacuo to give, a pale yellow solid. Re-crystallisation of ^"the solid. .^r: ^: from hot dichlorornethane afforded -the title product in 99% yield, 9.4g. ^:" -x^~x χ ■ ¹H^"NMR CDCi₃, 400MHz) δ: 8.84 (s, 2H). ^ , ^{" ■}::.^'•_.. . - : -

20

Preparation 64 . x -^"---• 5--Bromo-pyrimidine-2-carboxylic acid

25

XA-mjxture of sodium_, hydroxide (4.8δg 120mmol) and the product of preparation, 6.3 (7.5g,,_.40.δmmo!)-_; in water (122mL) was heated at 60°C for 1 hour._τ The mixture was then acidified withΛM hydrochloric acid, extracted with ethyl acetate and dichloromethane and concentrated in vacuo to afford some title compound as a white solid, 300mg. . The aqueous, solution was also_, evaporated under ^" reduced pressure and the residue was extracted into dιchloromethane:methanol,

90' 10. The precipitate was filtered off and the filtrate was concentrated in va_Guo - to^'afford.further titleiompound as a white solid, 5.5g.

¹HNMR(DMSO-T ₆, 400MHZ) δ: 9.10(s, 2H),^~ 13 δfbrs, 1 H). MS APCI+- m/z 203

[MHf

Preparation 65 ^~

5-Bromo-pyrimidine-2-carboxylic acid methyl ester

Fuming hydrochloric acid was passed through an ice-cooled solution of the product of preparation 64 (5.5g, 27mmol) in methanol (50mL)- until saturated The reaction mixture was warmed to room temperature and was stirred for 18 hours. The solvent was then evaporated under reduced pressure and the residue was dissolved in dichloromethane, washed with water and sodium

- hydrogen carbonate solution, dried-over magnesium sulfate and concentrated in

Vacuo to afford the^"title compound as yellow solid in 57% yield, 3.5g. 1HNMR(CDCI₃, 400MHz) δ: 4 05(s, 3H), 9 00(s, 2H). MS APCI+ m/z 218 [MHf_

- - - Preparation 66 - - _

5-Brbmo-pyrimidine-2-carboxylic acid hydrazide

The title compound was prepared from the product of preparation 65 and hydrazine monohydrate, using the^" method of preparation 6, as a yellow solid in quantitative yield^". 1HNMR(CDCI₃, 400MHz) δ: 4 20(s, 2H), 8 90(m, 3H) MS APCI+ m/z 217 [MHf ^"•'"■•^■ _ Preparation 67

5-Brόmo-pyrimidine-2-carboxylJcacid.N'-(2-methoχy-acetvh-hydrazide .-.

The, title compound, was prepared from the product of preparation 66 and methoxyacetyl chloride^ using. the method of preparation 8, as a white solid in -45% yield, -= .. ._ _..... ^: _.._.. ._...

¹HNMR(DMSO-D₆, 400MHz) δ: 3.32(s, 3H), 3.98(s, 2H), 9.20(s, 2H), 10.02(s, H);_;10,66. (s, 1H). MjS,APCI+ m/z 290 [MHf . __{.. .}.. __: _ , . ,

A solution of sodium carbonate (295mg, 2.7δmmol) in water (3mL) was added to a^b solution of the product of preparation 6δ (376mg, 1 39mmol), 4-fluoro-2-- methylphenyl Doronic acid <32 mg, 2 Oδmmol) and palladium triphenylphosphine 5 <48mg, cat) in 1 ,2-dιmethoxyethane (3mL) and the -mixture was heated under reflux for 2 hours The reaction mixture was then evaporated under reduced pressure ^"and the residue was partitioned between water and ethyl acetate The resulting precipitate was filtered off, washing through with water, ethyl acetate and diethyl ether, and dried to afford the title compound as a beige solid in 59% 10 yield, 332mg -

¹HNMR(CDCI₃, 400MHz) δ 2 33(s, 3H), 3 53(s, 3H), 4 81 (s, 2H), 7.09(m, 2H) 7 25(m, 1 H),- 8 90(s,-2H) MS APCI+ m/z 301 [MHf

I - - Preparation 70

15 5-Bromo-2-(5-methyl-[1 ,3,4]oxadιazol-2-vh-pyrιdιne

The title compound was prepared from the product of preparation 6 and N,N-dιmethylacetamιde dimethyl acetal, using the method of preparation 4, as a 20 white solid in 47% yield ^~ ,

- - - ^~1HNMR(CDC1₃, 400MHz) δ 2 65(s. 3H), 8 01(m, 1 H), 8 12(m, 1 H), δ.δ0(m, 1H MS APG1+ fn/z 240/242 [MHf

Preparation 71

• 25 3T3-(5-Bromo-Pyrιdin-2-vπ-5-methyl-f1 _r2,4ltrιazol-4-yl1-2.6-dιmethoxy-pyrιd e

3-Amino-2,6-dιmethoxypyrιdιne monohydrochloπde ^g, 13mmol) was partitioned between sodium carbonate solution and ethyl acetate The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the free base The base was then dissolved in xylene (30mJ-) and the product of preparation 70-(1 δg, 7 5mmol) and para-toluenesulfonic acid (50mg,^""cat) were added The resulting mixture was heated under reflux for 1δ hours The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane methanol 100 0 to 98 2, to afford thelitle product as a purple solid in 23% yield, 628mg 1HNMR(CDCI₃, 400MHz) δ 2 49(s, 3H), 3 80(s, 3H), 3 9δ(s, 3H), 6 41(d, 1H), 7 45(d, 1H), 7 92(dd, 1H), δ 11 (d, 1 H), δ 37(d, TH) MS APCI+ m/z 377 -[MHf

- - -- - Preparation 72 5-(4-Fluoro-2-methyl-phenyl)-2-(5-methyl-f1 ,3,41oxadιazol-2-yl)-Pyrιdιne,

A mixture of the product of preparation 40 (545mg, 2 79mmol), 4-fluoro-2- methylphenyl boronic acid (643mg, 4 Iδmmol), caesium carbonate (2.7g,„ 8 29mraol) -and the product of preparation 3 (10mg, cat ) in 1 ,4-dιoxan (25mL) was heated under reflux for 4 hours The reaction mixture was then cooled to room temperature, filtered through Celιte~ and concentrated in vacuo to afford - the title compound -as a pale yellow solid in quantitative yield 1HNMR(CDCI₃, 400MHz) δ 2 40(s,.3H), 2 66(s, 3H), 7 00(m, 2H), 7 43(dd, 1H), 7 _53(d, 1 H), 8 37(d, TH) 9 29(d, 1 H) MS APCI+ m/z 270 [MHf . Preparations 73 to 81

The following compounds^'" of the general formula shown below were prepared in quantitative yield, by the method of preparation 72, using the appropriate oxadiazole (preparations 14-16) and boronic acid

^" The progress of the reactions was monitored by tic analysis and the mixtures were heated under reflux until all of the starting materials had been consumed.

Preparation 82

Methyl-(5-nιtro-pyridin-2-yl)-amιne -

5 Methylamine gas was bubbled through a stirred solution of 2-chloro-5- " nitropyπdirie (4g, 25 2mmol) in dichloromethane (60mL),^~ at room temperature, until saturation had occurred The resulting yellow- precipitate was then filtered off, washed with dichloromethane and dried under vacuum to afford ^"the title compound as a_yellow solid in 80% yield, 3.07g. "0 ^N R CDCI_S, 400MHz) δ' 3 05(d, 3H), 5 41 (bs, 1 H), 6 37(d, 1 H),^""8 21 (d, 1 H), 9 03(d, 1 H) MS APCI+ m/z 154 [MHf

Preparation 83 5 _ . N*2*-Methyl-pyridιne-2,5-dιamine

. The product of preparation 62 (3 0g, 19 5mmol) and 10% Pd/C (300mg, cat ) were stirred in ethanol (150mL) under 60psι of hydrogen gas for 16 hours-. The 0 reaction mixture was then filtered through Celite^® and the filtrate was concentrated in vacuo to afford the title product in 17% yield, _400m^"g. 1HNMR(CDCI₃, 400MHZ) δ 2 85(s, 3H), 3 19(s, 2H), -4 1 1 (s, 1 H), 6 31 (d, 1 H), 6.97(dd, 1 H), 7 69(d, 1 H) MS APCI+ m/z 269 [MNaf Preparation 84

- 4,6-Dichloro-nicotinic acid methyl ester .-

3-Pyridinecarboxylic acid [(27g, 160mmol), J.Het Chem, 20, 1363; 1983] was added portidnwise to phosphorus oxychloride (180mL) and the mixture was . he^"ated under^" reflux- for 7 -hours an -stirred at room temperature for 18. hours.

The mixture was then concentrated in -vacuo to a low volume and the residue - was quenched with water The aqueous mixture was neutralised with sodiut hydrogen carbonate solution and extracted with ^"chloroform (3x150mL). The -^"- combined organic-solutions were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a red oil in 63% yield,

27.2g. ^{: '} _ ^{" " 1}HNMR(CPCI₃, 400MHz) δ: 3,96(s, 3H), 7.47(s, 1H), 8.85(s, 1H). MS APCI+ m/z

206 [MHf

Preparations 85 and 86

Sodium methoxide (Q.δM.-in methanol, 4δ.6mL, 24.3mmol) was added dropwise

-to an .ice-cold solution of the product of preparation 64 (5.0g, 24.3mmol) in methanol (20mL). The mixture was allowed to warm to room temperature and was stirred for 2 hours. The solvent was then evaporated under reduced

_ pressure and the residue was partitioned between water^" (50mL) and chloroform (50mL), The layers were separated and^" the aqueous layer was extracted with chloroform (2 x 75mL). The combined organic solutions were then dried over

^"- sodium sulphate and concentrated in vacuo to give an orange oil. The oil was purified by .column chromatography on silica gel, eluting with dichloromethane

(100%) to afford the product of preparation 65 as a white solid in 7.6% yield, 370mg. Further elution with dichloromethane then isolated the product of preparation 86 as a white solid in 27% yield, 1 32g.

Preparation 85

4-Chloro-β-methoxy-nicotιmc acid methyl ester

¹HNMR(CDCI₃, 400MHz) δ 3 90(s, 3H), 3 96(s, 3H), 6.81 (s, 1H)_T 8,71(s, 1 H) MS APCI+ m/z-202 [MHf

Preparation 86

6-Chloro-4-methoxy-nιcotιnic acid methyl ester -

¹HNMR(CDCI₃, 400MHz) δ, 3.37(s, 3H), 3.94(s, 3H), 6.90(s, 1H), δ.68(s, 1H), MS APCI+ m/z 202^" [MHf

Preparation 87

6-Chloro-4-methoxy-nιcotinιc acid hydrazide

Hydrazine monohydrate (690μL, 14 2mmol) was added to a suspension of the product of preparation δ6 (2.7g, 13 4mmol) in methanol (35mL), cooled to -5°C, and the mixture was stirred for 3 hours. The mixture was then warmed to room temperature and was stirred for 18 hours. The resulting precipitate was filtered 5 off and dried to afford some title compound as a white solid, 990mg. Tic analysis of the filtrate showed that not all of the starting material had been consumed and so further hydrazine monohydrate (267μL, 5.51mmol) was added and the reaction mixture was stirred for 24 hours. The resulting precipitate was collected by filtration and dried to afford a further crop of title compound as a yellow solid, 10 832mg.

^{" 1}HNMR(CDCI₃, 400MHz) δ: 3.92(s, 3H), 4.55(bd, 2H), 7.29(s, 1H), 8.37(s, 1 H), -.9.38(m, 1 H), MS APCI+ m/z 247 [MHf - .

Preparation 88

15 6-Chloro-4-methoxy-nicotinic acid N'-(2-methoxy-ac^"etvD-hvdrazide - .-

Methoxyacetyl chloride (733μL, 8.02mmol) was added to an ice-cold suspension 20 of the product of preparation 87 (1.16g, 5 73mmol) in dichloromethane (20mL) and triethylamine (1.2mL, 8 61 mmol) and the mixture was stirred for 18 hours at room temperature_^ The reaction mixture was then washed with water and brine, - dried over sodium sulphate and concentrated in vacuo to give a pale yellow gum.

The gum was purified by column chromatography on silica gel, eluting with 25 - dich!oromethane:_.methanol_, .100 0 0 to 95:5, to afford the title compound as a

_ clear-glass in 31 % yield, 480mg. - , ¹HN_MR(CDCI_3l 400j iHz) δ: 3.48(s, 3H), ^~4.08(s, 3H), 4.10(s, 2H), 6.96(s, 1 H),

9.03(s, 1 H), 9.25 d, 1 H , _.9 99(d, 1 H) MS APCI+ m/z 274/276 [MHf Preparation 89

^-Chloro^-methoxy^^δ-methoxymethyl- l.S^lόxadiazol^-vD-pyridine-

The title .compound was prepared form the product of preparation δδ and phpsphorus oxychloride, using the method of preparation 13, as a yellow oil in quantitative yield.- .^"' . ^" [^':^'" .:

¹HNMR(^"CDCI₃-,-.400MHzf δ: 3;49(s, 3H), 4.04(s, 3H), 4.73(s, 2H), 7.01(s, 1H), δ.83(s, 1 H). MS ^"APCJ+ m/z 256 [MHf

Preparation 90

2-Chloro-4-methoxy-^"5-[5-methoχymethyl-4-(6-methoxy-pyridin-3-vπ-4H-f1

,2,41triazol-3-yn-pyridine

The title compound was. prepared from the product of preparation 89 :and 5 arriinb-2-ihethoxypyridine, using the method of preparation 18, -as a pale yellow.^" foarri i 29% yield; •- - - - --- . .

¹HNMR(CDCI₃, 400MHz) δ: 3.37(s, 3H)_; 3.61(s, 3H), 3.93(s, 3H)₅ ^" 4.49(s, 2H), 6J6(m, 2H), 7.43(dd> H), 7.98(d, 1 H),-8.42(s, 1H). MS APCI+ m/z 362 [MHf . Preparation 91

5-,4-Fluoro-2-methyl-phenyl)-pyrazine-2-carboxy!ic acid methyl ester -

5 4-Fluoro-2-methylphenyl boronic acid (17.36g, 112,7mmol), caesium carbonate

^" (70.8g, 216 δmmol) and the product of preparation 3 (1.5mg, 8.67mmol.) were added to a solution of 5.-chloropyrazine-2-methylcarboxylate (15g, 86,7mmol) in

1 ,4-dioxan (2L) and the mixture was heated under reflux for 2 hours. The

- reaction mixture was then filtered and concentrated in vacuo to afford the title

10 compound in 99% yield, 21.33g.

_. ^" _. ¹HNMR(CDCI₃, 400MHz) δ: 2,40(s, 3H), 4.05(s, 3H), 7 05(m, 2H), 7,45(m,^"1^"H), 8.80(1, 1H), 9.35(s, 1 H), MS APCI+ m/z 247 [MHf

Preparation 92 ^' -

15. 5-(4-Fluor^"o-2-methyl-phenyl)-ρyrazine-2 -carboxylic acid hydrazide

A mixture of the product of preparation 91 (42.5g,- 172. δmmol) and hydrazine "monohydrate ^"(9.46mL, 207.3mmol) in methanol (600mL) was heated under 20 reflux for 30 hours. The reaction mixture was then cooled to room temperature and the precipitate was filtered off and dried in vacuo to afford the title - compound in 75% yield, 7.1 Og - ^"

¹HNMR(DMSO, 400MHZ) δ: 2.35(s, 3H), 4.60(s, 2H), 7.20(m, 2H)^',- 7.60(m, 1H), δ 80(s, 1H), 9.15(s, 1H), 10.2(s-, 1H) Examples 1 - 4

The bromo compound of preparation 5 (100mg, 0 29mmol), the palladium complex of preparation 3 (10mg, cat ), caesium carbonate (440mg, 1.35mmo!) and the appropriate boronic acid (0.73mmol) were suspended in 1,4-dioxan (5rηL) and^" the reaction mixture heated to 120°C for 90 minutes. Additional 1 ,4-dioxari (4fhL) was added and the reaction mixture heated to f θ°C for a further 4 hours. The reaction mixture was filtered under vacuum, washing through with dichloromethane The filtrate was concentrated in vacuo and the-residue purified - by column chromatography on silica gel eluting with dichloromethane:methanol:0 68 ammonia 95:5:0:5 to yield the desired product.

7 27 m, 2H), 7 34(d, 2H), 7 41(d, 2H), .

7.57(d, 2H)

MS APCI+ m/z 390 [MHf

Example 5

2-(4-Fluσro-2-methylphenyl)-5-(5-methoχymethyl-4-⁽6-methoxypyrιdιn-3-vh -4H- -^"" - [1.2,41trιazol-3-yl)-pyrιdιne

The title product was prepared by the method of preparation 18 using the product of preparation 19 and 5-amιno-2-methoxypyπdιne 140rrig, 15% yield of the desired product was produced

¹HNMR(CDCI₃, 400MHz) δ 2 36(s, 3H), 3 3δ(s, 3H), 4 01 (s, 3H), 4 51(s, 2H), 6 88(d, 1H), 6 93-7 00(m, 2H), 7 36(dd, 1 H), 7 40(d, 1 H), 7 56(dd, 1H), 8 00(dd, 1 H); 8 15(d, 1 H), 864(d, H) Microanalysis C₂2H₂oFN₅O₂ requires; C 65.18, H 4 97, N 1727, found C 65 01 , H 496 N 17 27 MS APC1+ ra/z 06 [MHf -

Example 6

2-⁽2.3-Dιmethylphenyl)-5-(5-methoxymethyl-4-(6-methoxypyrιdin-3-v -4}-l-

[1 ,2,4]tnazol-3-yl)-pyπdιne

The title product was prepared by the method -of preparation 18 using the . . product of preparation 20 and 5-amino_:2-methoxypyridine. 325mg,_.36% of the desired product_. was produced. - -

^{" 1}HNMR(CDCI₃, 400MHz) δ: 2^".21(s, 3H), 2.34(s, 3H), 3.38(s, 3H), 4.00(s, 3H), 4.52(s, 2H), 6.88(d, 1H), 7.13-7 22(m, 3H), 7.40(d, 1 H), 7.55(d, 1H), 7.99(dd,

1 H), 6.16(d, 1 H), 8.64(d, 1 H). Microanalysis: C₂₃H2₃N₅O₂.O.I H₂0 requires; C

68.50, H 5.80, N 1.7:37; found C 68.24, H 5.90, N 17.05. MS APCI+ m/z 402

[MHf - -

- -. - - Exampl 7

5-(4-FluorQ-2-methyrphenyl)-2-(((5-methoxymethyl-4-(6-methoxyr>yridin-3-yl))- . - _. - 4H 1 ,2_t4]triazoi-3-vh-pyridine - _ -

5 ^" -

^' The bromo compound of preparation 16 (250mg^", 0.66mmol), 2-jhethyl-4-fluoro- phenylboronic acid (235mg, 1.53mmol), the palladjum complex of preparation^ (10mg, cat.) and caesium carbonate (1.00g, 3.07mmol) were added , to 1 ,4-dioxan (15mL) and the reaction mixture heated to 110°C for 4 hours. The0 -reaction mixture was filtered through Arbocel^®, washed through with dichloromethane and the filtrate concentrated in vacuo. The residue was purified by column chrorhatography on silica gel eluting with dichloromethane:methariol 100:0 to 95:5 to yield the title product, 128mg, 48% yield as a pale pink solid. 1HNMR(DMSO-D₆, 400MHz) δ: 2.21(s, 3H), 3.18(s, 3H), 3.89(s, 3H), 4.44(s, 2H),5 6.94(m, 1 H);.7.09(m, ^"1 H), 7.19(m, 1 H), 7.2δ(m, 1 H), 7.δ1 (m, 1H), 7.94(m, W), ; _; 8 32(m, 1 H).. . " - _. .

. Example 8 . _-. . ._

5-(2.3-Dimethylphenyl)-2-f5-(methoxymethyl-4-(6-methoxypyridin-3-yl)4H-1,2,4-

^'XXX^'''-- ^' ' ■-.-^{" ■} -.. ^' triazol-3-vπpyridine

The title product was prepared by the method of example 7 ^" using 2,3-dimethylphenylborbnic acid. 132mg, 49% yield of the ^"desired product was prepared as a pale pink solid. 1HNMR(DMSO-D₆, 400MHz) δ: 2.07(s-, 3H), 2.3δ(s^~, 3H), 3,17(s, 3H), 3.δ9(s, 3H), 4.44(s, 2H), 6,94(m, 1H), 7.04(m, 1H), 7,15(m, 1H), 7 2(m, 1H), 7.82(m, 1H), 7.90(m, 1H), 8,15(m, ΪH),B.^'24^'(m, 1H), 6^":28(m, 1H). ^"MS APCI+⁷ rri/z 402 [MHf

• ._..- _. . Example 9

1-l5-r5-(2;3-bimethylph^"envh-pyridiιi-2-yll-4-(6-methoxypyridin-3-yl>-4H- f1,2,4ltriazol-3-ylmethyn-pyr^"rolidiήe-(2S)-2-carboxylicacid amide

The bro o compoun of preparaton mg, . mmo , 2,3^:diriιethylphenyl- boronic acid (61 mg, 0.41 mmol) and the palladium complex of preparation 3 (10mg) were dissolved in 1 ,2-dimethoxyethane (4mL) and the solution was treated with sodium carbonate (5δmg, 0 55mmol). The reaction mixture was heated -to reflux for. 1 hour and then concentrated in vacuo. The resjdue was taken-up in ethyl acetate (25mL) and washed with water (25mL), 2M sodium hydroxide solution (25mL) and brine (25mL). The solution was dried over- 5 magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on _. silica gel eluting with dichloromethane:methanol:0.δδ ammonia 100.0.0 to 97:3:0.3 to yield the title -product, 95mg, 72% yield. .- ¹HNMR(CDCI₃, 400MHz) δ: 1 30(m, 2H), 2.00(m, 1 H), 2.10(s, 3H), 2.20(m_r 1 H),_. 10 2.40(s, 3H), 2.60(m, 1 H), 3 20(m, 2H), 3.δO(m, -2H), 4.00(s, -3H), 5.00(s, 1 H), 6.30(s, 1 H), 6.90(d, 1H), 700(d, -1 H), -7.10(d, 1 H), 7.20(d, 1 H), 7.60(d, 1H), -7.70(d,- 1H),-S.80(s, 1 H), 8.20(m, 2H). MS ES+ m/z 4δ4 [MHf ^

i 5 - ^" Example 10

" 5-(2,3-Dimethylphenyl)-2-(5-pyrrolidιn-1-ylmethyl-4-(6-methoxypyridin-3-yl)-4H- f 1 ,2,41triazol-3-yl)-pyridine . - -~

20 _ , . - - δbmg, 36% yield of the title product was prepared by the method of example 9 using the bromo compound of preparation 2δ.

¹HNMR(CDCI₃, 400MHz) δ: 1.80(s, 4H), 2.10(s, 3H), 2.40(s, 3H), 2.50(s,^" 4H), 3.70(s_, 2H), 4.00(s, 3H), 6 δ0(d, 1 H), 7.00(d, 1 H), 7.20(m, 2H)-, 7.70(t, 2H),

25 8.10(d, 1H), δ.20(d, 1H), 6 30(s, 1H) MS ES+ m/z 441 [MHf Exampl 11.

2-(4-Fluoro-2-methylphenyl)-5-[5-methoxymethyl-4-(6-methoχypyridinr3-yl)-4H- ' - l1,2,41triazol-3-yll-pyrazine

The product of preparation^' 22 (450mg, T.SOmmol), para-toluenesulfonic acid monohydrate (30mg) and 5-amino-2-methoxypyridine (205mg, 1 ,65mmol) were added to xylene (8mL) and the reaction mixture heated to 145°C for 18 hours.

10 The reaction mixture was concentrated in vacuo and- the residue purified by colur n chromatography on -. silica gel. eluting with dichl6rofhethane:metha ol:0.δδ ammonia :.100:0.0 to 99,5:0.5:0,05. to 99:1:0; to

^.-:: ^Xyt ld the title^"product, 300mg, 49% yield.as a-green solid -

¹HNMR(CDCI₃, 400MHz) δ: 2:3δ(s, 3H), 3.34(s, 3H), 3.99(s, 3H), 4.50(s, 2H),

15. - 6.85(d, iH)χ:β:95- 03.(rh,^" 2H), 7.36r7,42(m, 1H),.7.6Q(dd, .1H), 8,12(d, H), "^'"' ^^(s; TH);"9:48(s, THf S APCI+ m/z407[MHf -: . .,.

Example 12 -^.. -^.- ^.

2-(2,3-Dimethylphenyl)-5-f5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-

20 - • -- - ^" .f1,2,41triazol-3-yl]-pyrazine X. x ~ _.

42mg, 7% yield of the title product was prepared by the method of example 11, using the product of preparation 21. ■ ^{"" 1}flNMR(CDCI₃, 400MHz) δ: 2.23(s, 3H), 2;34(s,^"3H),-3.36(s, 3H), ^'.4.00(8, 3H),_ ' 4.50(m, 2H), 6.86(d,-1FI), 7,19(d, 1H), 7,20(s, 1H), 7.24(m, 1H), 7.62(dd, 1H), 5 δ.14(dχ1H),8.41(d, 1H), 9.49(d,^'1H). MS APG1+ m/z 403 [MHf

Example 13

^{'"'"' ":}2-(2,3-Dlmethylphenyl-5-l4-(6-methoxypyridin-3-yl)-5-methyl-4H-f1,2.4]triazol-3-

-.- ^'.^'- ^{"" ■ '} yll-pyrazine - - - -X:..

The chloro^" compound of. - preparation 30 (δOOmg, 2.60mmol), 4,-fluoro-2- methylphenyl boronic acid (470mg7 3.12mmol), the palladium complex of preparation 3 (5mg) and caesium carbonate (2.50g, 7.90mmol) were added to 1 ,4-dioxan (80mL) arid the reaction mixture heated to reflux for 2 hours. The mixture was filtered-through a filter tube and then filtered through a pad_. of silica

^"eluting with dichloromethane:methanol 96:4. The filtrate was concentrated- in vacuo- and purified by column chromatography on silica gel, eluting with dichloromethane:methanol 100:0 to 95:5 to afford the title product as a white solid in 66% yield, 646mg. - _ .. - _

¹HNMR(CDCI₃, 400MHz) δ: 2.39(s, 3H), 2.41 (s, 3H), 4.01(s, 3H), 6.89(d, 1 H),

. 6.95-7.63(m, 2H), 7.33(dd, 1 H)„ 7.54(dd, 1 H), δ.09(d, -1H), δ.3δ(d, .1 H), 9.49(d,

1 H). MS APCΪ+ m/z 3.77 [MHf

-Alternative method - ^~ - _{. .}

Dimethylacetamide dimethylacetal (2δmL, _. 192.1 mmol) was added to a suspension of the product of preparation 92 (31.5g, 127_;9mmol) in glacial acetic acid (315mL) and the mixture was heated at 6G°C for 5 hours. 5-Amino-2- ^" methoxy pyridine (23.9g, 192mmol) was added and the mixture was heated_, at 100^qC for a further 6 hours. The mixture was then cooled to room, temperature and evaporated under reduced pressure. The residue was taken up in dichloromethane (750mL) and washed with saturated sodium hydrogen carbonate solution (1 L). The organic solution was dried over magnesium sulfate "^' and concentrated in vacuo. Re-crystallisation of the residue from hpt acetone 'then afforded the title compound as a white solid in 31 % yield, 14.81g. ^'" Exa ple 15

- ^" - 2-(4-Cyano-2-methylphenyl)-5-l4-(6-methoxypyridin-3-yl)-5-methyl-4H- -

- ^{" "} - -.. 1 [1 ,2,41triazol-3-yl1-pyrazine- -

The title product was prepared by the method of. example 14 using the chloro compound of preparation 30 (200mg, 0.66mmol) and the product of-preparation x 29 (240mg, 0.99mmol). 68m^"g,- 27% yield of the title product was prepared as a white solid. . - - - - HNMR(CDCI₃, 400MHz) δ: 2.40(s, 3H), 2.43(s, 3H), 4.01(s, 3H), 6.90(d, 1H), 7.50-7.55(m, 2H), 7.57(s, 1H), 7.60(s, 1.H), 8.0δ(d, 1 H), 8.41(d, 1HJ, 9.55(d, 1H).

- Microanalysis: C₂ιHι₇N₇O0.1 H₂O requires; C.65.79, H 4.47; N 25.57; ^"found C

- 65.23, H 4.48, N 25.09_:. MS APCI+ m/z 34-[MHf . ^{. "} - ^. . -

Example 16 2-(5-Fluoτo--2-methoxyphenyl)-5-f4-(6-methoxypyridin-3-yl)-5-methyl-4H- ^" - f 1 ,2,4]triazol-3-yn-oyrazine ^" - -

The title product was prepared by the method of example 14 using -the chloro compound of preparation _.30 .(2_.00mg, 0.66mmol) and 5-fluoro-2-methpxyphenyl boronic acid (168mg, 0.99mmol). 150mg, 58% yield of the title product was prepared as a cream solid. ¹HNMR(CDCf₃, 400MHz) δ: 2.37(s, 3H), 3,85(s, 3H), .4.00(s,3H), 6,δδ(d, 1H), 6.92(dd, 1H), 7.09(m^", 1H),.7.50(dd, 1H), 7.66(dd, 1H),- 8.07(d, 1H), 8.9_.3(d, 1H), "9.46(d, 1^"H); ^' - _. .^•: -.-.^■ -.-

Example 17 : ^"".

2-(4-Cvano-2-methylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl^-4H- 1 ,2,41triazol-3-yll-pyrazine _...; ^• -

The title product was prepared by the method of example 7 using the product of preparation 29_(100mg, 0 41 mmol) and the bromo compound of preparation 18 ^" (155mg, 0 41 mmol) 67mg 39% yield of the desired product was prepared as a white solid

¹HNMR(CDCI₃, 400MHz) δ 2 28(s, 3H), 3 35(s, 3H), 3 99(s, 3H), 4 50(s, 2H), 6 35(d, 1 H), 7 2δ(d, 1 H), 7 52-7 58(m, 2H), 7 62(dd, 1 H), 7 74(dd, 1 H), 8 11(d, 1 H), 8 28(dd, 1 H), δ 33(1 H, d) Microanalysis C23H20N6O₂DO 5H₂O requires, C 66 55, H 5 02, N 19 94, found C 66 02, H 4 -90, N 19 83 MS APCI+ m/z 413 [MHf

Example 19

2-(5-Fluoro-2-methoxyphenyQ-5-f5-methoxymethyl-4-(6-methoxypyrιdιn-3-vπ-4H- f 1 ,2,41trιazol-3-vn-pyrιdιne

The title compound was prepared using the method of example 11 , using the oxadiazole compound of preparation 32 and 5-ammo-2-methoxy pyridine, as a pale green solid (325mg, 30%>)

¹HNMR(CDCI₃, 400MHz) δ -3 36(s, 3H), 3 84(s, 3H), 3 98(s, 3H), 4 49(s, 2H), 6 δ7(d, 1H), 6 92(dd, 1H), 7 06(m, 1 H), 7 54(dd, 1 H), 7 58(dd, 1 H), 7 96-δ 00(m,

^" 2H), 8 14(d, 1 H), 8 60(d, 1 H) MS APCI+ m/z 422 [MHf

Examples 20-22

The following compounds, of the general formula shown below, were -prepared by the method of examples 1-4 using the products of preparations 46 or 47 and the appropriate boronic acid The crude compounds were purified firstly by column chromatography on silica gel, eluting with ethyl acetate m_.ethanol 0.88 ammonia, 100 0.0 to 99:1 0.1 to 95.5 0 5, followed by purification by HPLC using a Phenomenex Luna C18 system, eluting with water/acetonitrile/tπfluoroacetic acid (5 95.0.1) acetonιtπle, 95'5 to 5.95

Example 23

4-r^"5-f5-(Mefhoxymethyl)-4-(6-methoxypyridin-3-yl)-4/-/-1 ,2,4-triazol-3-vnpyridin-2- - ^{" ""} ylV3-methylbenzonitrile

The chloro compound of preparation 49 (170mg, 0 87mmol), the palladium corήplex of preparation 3 (5m^"g, cat ), caesiu carbonate (847mg, 2.61mmol) and the product of preparation 29 (317mg, 1.31mmol) were suspended in

10 1 ,4-dioxan (5mL) and the reaction^' mixture heated to 110°C for 2 hours. The

^{" ~} - reaction mixture was diluted with ethyl acetate and water, and filtered througrr

. Celite^®. The Jayers of the filtrate were separated and the aqueous solution was re-extracted with, ethyl acetate (x2). The combined organic solutions were then washed with brine, dried over sodium sulfate and concentrated in vacuo. The

-15 residue was purified by column chromatography on silica gel eluting. with dichloromethane:methanol O 88 ammonia 100:0 0 to 97.5:2.5.0.25 to afford the -title compound as a white foam in 45% yield, 160mg.

-¹HNMR(CDCI₃, 400MHz) δ: 2.38(s, 3H), 3 38(s, 3H_), 4.00(s, 3H), 4.51(s, 2H), 6.90(d, 1 H), 7.45(d, 1H), 7 4δ(d, 1 H), 7.55-7.60(m, 3H), 8.03(dd, 1 H), 8.15(d,

20 1 H), 8.70(dd, 1H). MS APCI+ m/z 413 [MHf

Examples 24 to 28

The following compounds, of the general formula shown below, were prepared 25 by the fnethod _.of -example 23, using the appropriate triazole compounds (preparations 31 and 50-51) and boronic acids.

Example 29

[5-[6-(4-Fluoro-2-methyl-phenyl)-pyridin-3-yπ-4-(6-methoxy-pyridin-3- yl)-4H-fl,2,41triazol-3-ylmethyll-dιmethyl-amine

The title compound ^"was prepared from the product of preparation 46 and 4-fluoro-2-rnethylphenylboronic acid, using the method- of examples 1-4, as a white foam in 70% yield. 1HNMR(CDCI₃, 400MHz) δ. 2 25(s, 6H)_r 2 34(s, 3H), ^"3.47(s, 2H), 3.99(s, 3H), "6.36(d, 1H), 6 93-7 00(m, 2H), 7 38(m, 2H), 7.64^~(dd, Ϊ H), 8 00(dd, 1 H), 8.16(d, 1H), 8 63(d, 1 H). Microanalysis: C₂3H2₃FN₆O 0 25 H₂O requires; C 65.31 , H - 5.60, N 19.87 found C 65.19, H 5 63, N 19.58 MS APCI+ m/z 419 [MHf

. . . .. Example 30

- 5-f3-(Ethoxymethyl)-5-[6-(4-fluoro-2-methylphenyl)pyridin-3-yll-4H-1 ,2,4-triazol-4- yl -2-methoxypyridιne

The> chloro compound of preparation 52 (230mg, 0.67mmol), the palladium complex of preparation 3 (10mg, cat ), caesium carbonate (64δmg, 2.01 mmol) and 4-ffuoro-2-methylphenylboronιc acid (143mg, 0 94mmol) were suspended in 1 ,4-dιoxan (4mL) and the reaction mixture heated to 1 10°C for 2 hours. A further amount of the product of preparation 3 (5mg) was added and heating continued for 3 5 hours The mixture was then partitioned between ethyl acetate and water, and the organic layer was separated, dried over sodium sulfate and concentrated in vacuo The residue was purified HPLC using a Phenomenex 5 Luna C18 system, eluting with water/acetonitnle/trifluoroacetic acid (5 95 0 1) acetonitrile, 95 5 to 5 95 to afford the title compound as a white powder in 16% yield, 44mg

¹HNMR(CDCI₃, 400MHz) δ 1 16(t 3H), 2 35(s, 3H), 3 54(q, 2H), 3 99(s, 3H), 4 55(s, 2H), 6 88(d, 1 H), 6 93-7 00(m, 2H), 7 34-7 42(m, 2H), 7 56(dd, 1H), 10 6 00(dd, 1 H), 8 16(d, 1 H), 8 65(d, 1H) Microanalysis C₂₃H₂₂FN₅O₂ 0 5 H₂O^" requires, C 64 48, H 5 41 , N 16 35 found C 64 46, H 5 27, N 16 40. MS APCI+ m/z 420 [MHf

Example 31

Ϊ5 4-(5-l5-(Ethoxymethvh-4-(6-methoxypyrιdιn-3-yl)-4H-1 ,2,4-trιazol-3-yllPyridιn-2- ylV3-methylbenzonιtrιle

20 The title compound was prepared from the product of preparation 52 and the product of preparation 29, using the method of example 30, as a beige solid in 15% yield

¹HNMR(CDCI₃, 400MHz) δ 1 16(t, 3H), 2 38(s, 3H), 3 52(q, 2H), 4 00(s, 3H), 4 55(s, 2H), 6 89(d 1 H) 7 43(d, 1 H), 7 49(d, 1 H), 7 58(m, 3H), 8 02(dd, 1H),

^"25 ^" 8 17(d, 1 H), 8 70(d, 1 H)- Microanalysis C24Η22N5O2 0 5 H₂O requires, C 66 19, H 5 32, N-19 30 found C 66 57 H 5 17 N 19 53 MS ES+ m/z 427 [MHf Example 32

2-(3,4-Dimethyl-phenyl)-5-f5-methoxymethyl-4-(6-methoxy-pyridιn-3-vh- - - 4H-f1 ,41triazol-3-vπ-pyrazine

The title compound was prepared from the product of preparation 31 and 3,4-dimethylbenzene boronic acid, using the method of example 30. The crude compound was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.38 amfnonia, 96:4.0.4 followed by 100% ethyl acetate to afford the desired compound as a beige solid in 68%> yield. 1HNMR(CDCI₃, 400MHz) δ' 2 31(s, 3H), 2.33(s, 3H), 3.35(s, 3H), 4.00(s, 3H), 4.50(s, 2H), 6 85(d, 1H), 7 23(s, 1H), 7.58(dd, _1 H), 7 71 (dd, 1 H), 7.8Q(s, 1H), 8.11(d, 1 H), 8.71(d, 1H), 9.42(d, 1H). MS APCI+ m/z 403 [MHf

Example 33 4-(4-f5-Methoxymethyl-4-(6-methoxy-pyridin-3-yl)-4H-l1 ,2.4 riazol-3-v π-phenyll-2,3-dimethyl-pyridine 1 -oxide

A mixture -of the product of preparation 57 (230mg, 0.74mmol), 5-amino-2- methoxy pyridine (100mg, 0 81 mmol) and para-toluenesulfonic acid (30mg, cat) in xylene (4mL) was heated under reflux for 13 hours. The mixture was then acidified with 1 M hydrochloric acid and washed with ethyl acetate and the organic layer was discarded. The aqueous solution was basified with 1M sodium "hydroxide solution and extracted with ethyl acetate (x2). The combined organic extracts were washed with brine, dried over sodium sulfate and. concentrated in vacuo to give a brown oil. Purification of the oil by column chromatography on silica gel. eluting with dichloromethane:methanol:0.8δ ammonia, 100:0:0 . to 98:2:0.1, afforded the title compound as a beige foam in 24% yield, 74^'mg. HNMR(CDCI₃, 400MHz) δ: 2.16(s, 3H), 2.53(s, 3H), ^'3.31(8, 3H), 3.94(s, 3H), 4.43(s, 2H), 6.81 (d, 1 H), 6.94(d, 1 H), 7.19(m, 2H), 7.49(m, 3H), 8.08(d, 1 H), 8.16^"(d, TH). MS APCI+ m/z 4T8 [MHf_. . ^{" "} - , -

Example 34-

2-(4-Fluoro-2-methylphenyl)-5-f4-(6-methoxypyridin-3-yl)-5-methvf4H-1 ,2,4-- triazol-3-ynpyridine

The title compound was prepared from the product of preparation. 72 and 5-amino-2-methoxy pyridine, using the method of exarnple 33, as. a brown solid, in 54% yield. ^{" " '} ... .._.._. •

¹HNMR(CDCΪ₃, 400MHz) δ: 2.34(s, 3H), 2.39(s, 3H), 3.99(s, 3H), 6.87-7.01(m, 3H), 7;35(dd; TH), 7:^'39(dd, 1 H), 7.45(dd, 1 H)χ7.97(dd₍ 1 H); 8.11(d, 1 H), 8.59(d,- 1 H). MS APCH- m/z 376^" [MHf ^'.. -

Examples 35 to 45

^": ; The following compounds, of the general formula shown below, were prepared by the. method of example^" 34 using the appropriate oxadiazole (preparations 7.3^ ^' 81) and aminopyridine.- ^• - -- ^{■ ■ ■ •} The progress of the_. reactions was monitored by tic analysis -and the mixtures were heated under reflux until all of the starting materials had been consumed,

-121

-120-

gel, ^"eluting with ethyl acetate:methanol, 98:2. ^". ^{" '} -

Examples 35,^" 37, 38, 41 , 43, 44 and 45: crude products were purified by trituration with diethyl ether.

Example 46

5-(3-[5-(4 Fluorό-2-methyl-phenyl)-pyrazin-2-vn-5-methv1-[1 ,2,41tria " ^{"" ' "}"^" zol-4-yl)-pyridin-2-yl)-methyl-amine

A mixture of the product of preparations 74 (437mg, 1.62mrhol) and 83 (434mg, 3.52mmol) and para-toluenesulfonic acid in xylene (10mL) was heated _. under reflux for 100 hours. The mixture was then filtered through Celite^®, washing - through with dichloromethane and the filtrate was concentrated in vacuo. Purification by column chromatography on silica gel, eluting with dichloromethane:methanol:0.8δ ammonia, 98:2:0.2, followed by ethyl acetate:methanol, 98:2, afforded the title compound as a beige solid in 9% yield, 57mg. .

¹HNMR(CDCI₃, 400MHz) δ: 2.38(m, 6H), 2.98(d, 3H), 4.89(m, 1H), 6.47(d, 1H),

10 6.94-7.02(m, 2H), 7.36(m, 2H), 7.97(d, 1 H) 8.43(s, 1 H), 9.41 (d, 1 H). MS APCI+ m/z 376 [MHf

Example 47

3-(4-Fluoro-2-methyl-phenyl)-6-f5-methoxymethyl-4-(6-methoxy-pyridin-3

15 -ylV-4H-π ,2,4ltria2θl-3-yH-pyτidazine

^{" " ' "} The ^"product of preparation 62 (40mg, 0.13mmol), 5-amino-2-meth^"oxypyridine

20 (16mg, 0.13m^"mol) ^"and:para-toluenesulfonic acid monohydrate (5mg, cat) were

- dissolved in xylene (2mL) arid the reaction mixture was heated under reflux Tor3 hours. The reaction mixture was then partitioned between dichloromethane and sodium hydrogen carbonate solution and the organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was

25 purified by ^"HPLC using a Phenomenex Luna C18 system, eluting with water/acetonitrile/trifluoroacetic acid (5:95:0.1):acetonitrile, 95:5 to 5:95 to afford the title compound as a yellow oil in 8% yield, 4mg. ¹HNMR(CDCI₃, 400MHz)- δ: 2 33(s, 3H), 3 36(s, 3H), 3 94(s, 3H), 4.52(s, 2H), 6.83(d, 1 H), 7.02(m, 2H), 7.39(d, 1 H), 7.70(m, 2H) 8.11 (s, 1 H), 8.46(d, 1 H).

Example 48 : .

5-(4-Fluoro-2-methyl-phenv -2-f5-methoxymethyl-4-(6-methoxy-pyridin-3 -yl)-4H-f1 ,2,4]trιazol-3-vn-pyrimidine

The product of preparation^" 69 (80mg, 0 27mmol), 5-amino-2-methoxyp^"yridine (50mg, 0.39mmol) and para-toluenesulfonic acid monohydrate (10mg, cat) were dissolved in xylene (3mL) and the reaction mixture was heated under reflux for 18 hours. Additional para-toluenesulfonic acid monohydrate (10mg; cat) was added and^'heating continued for a further 18 hours. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in ethyl acetate, washed with 1M hydrochloric acid, sodium hydrogen carbonate solution and brine, dried ^"over magnesium^" sulfate and concentrated in vacua. Purification of the residue ^"by column chromatography on ^" silica gel,^" eluting with- dichloromethane methanol, 97 3, afforded the title compound in 46% yield, 49.3mg. HNMR(CDCI₃, 400MHz) δ. 2 23(s, 3H), 3 32(s, 3H), 3.99(s, 3H), 4.51 (s, 2H), 6.82(d, 1 H), 6 9δ(m, 2H), 7 17(d, 1 H), 7.60(d, 1 H), δ.11 (s, 1 H), 8.67(s, 2H). MS APCH- m/z 407 [MHf Examples 49 to 52

The following compounds; of the general formula shown below, were prepared by the method of example 46, using the product of preparation 71 and the appropriate boronic acid

Example 53

3-f5-[4-(6-Methoxy-pyridin-3-yl)-5-rhethyl-4H-M ,2,4]triazol-3-vn-pyra zin-2-yl)-4-methyl-benzonitrile x

A mixture of 3-chloro-4-methylbenzόnitrile (1g, 6.6mmol), bis(pinacolato)diborόn

10 (1.8g, 7.0mmol), caesium carbonate (6.4g, 19.8mmoi) and the product of

_. , preparation 3 (5mg, cat) in 1 ,4-dioxan (50mL) was heated under reflux for 4 hours. The reaction mixture was then cooled to ^"room temperature, filtered through Celite^® and concentrated in vacuo.

15 A portion of the residue (145mg, 0.6mmol), the product of preparation 30 (90mg, 0.3mmol), caesium carbonate (293mg, 0.9mmol) and the product of preparation 3 (2mg, cat) were then dissolved in 1 ,4-dioxan and the mixture was heated under reflux for 16 hours. The mixture was then cooled to room temperature, filtered through Celite^® and concentrated in vacuo. Purification of the residue by

20 .column chromatography on silica gel, eluting with dichloromethane.methanol, 100:0 to 97:3, afforded the title compound as a white solid in 3% yield, 3mg. 1HNMR(CDCI₃, 400MHz) δ: 2.41 (s, 3H), 2.46(s, 3H), 4.02(s, 3H), 6.90(d, 1 H),^" 7.43(d, 1 H), 7.53(dd, 1 H), 7.63(dd, 1 H), 7.70(d, 1 H), 8.09(d, 1 H), δ.41 (d, 1 H), 9.55(d, 1 H). MS APCI+ m/z 363 [MHf Example 54 .- ^■ -. 2-(4^"-Fluoro-2-methyl-phenyl)-4-methoxy-5-[5-methoxymethyl-4-(6-methoxy- pyridin-3-yl)-4H-f1 ,2,4ltriazol-3-vn-pyridine

A mixture Of the product of preparations 90 (60mg, 0.17mmol) and 3 (10mg, cat), 4-fluoro-2-me^"thylbenzene boronic acid (33mg, 0.21 mmol) and caesium carbonate (110mg; 0.34mmol) in dioxan-(4mL) was heated under reflux for -16 hours. Catalytic amounts of 4-fluoro-2--methylbenzene boronic acid and the product of preparation 3 were then added to -the reaction mixture and heating continued for a further 3 hours. The mixture was diluted with dichloromethane and was purified directly by column chromatography on -silica gel, eluting with ^"dichloromethane:methanol, 10.0:0 to.96 4, to. obtain the title compound as .a white foam in 54% yield, 39mg. - - - ; -._.

¹HNMR(CDCI₃, 400MHz) δ 2.34(s, 3H), 3 39(s, 3H), 3 62(s, 3H), 3.94(s, 3H), 4.51(s, 2H), 6.77(m, 2H), 6.96(m, 2H), 7.33(dd,- 1 H), 7.50(dd, 1 H), 8.05(d, 1 H), 8.70(d, 1 H). MS APCH- m/z 436 [MHf

Example 55

2-(5-Fluoro-2-methoxy-phenyl)-4-methoxy-5-[5-methoxymethyl-4-(6-methoxy- pyridιn-3-yπ-4H-M .2,41triazol-3-vn-pyridine

The title compound was prepared from the product of preparation 90 and 5-fluoro-2-methoxybenzene benzoic acid, using the method of example 54, as a yellow foam in 53% yield 1HNMR(CDCI₃, 400MHz) δ 3 39(s, 3H), 3 63(s, 3H), 3.83(s, 3H), 3 93(s, 3H), 4.51(s, 2H), 6 76(d, 1 H), 6 93(dd, 1 H), 7 07(m, 1 H), 7 41(s, 1 H), 7 49(dd, 1 H), 7 63(dd, 1 H), δ 04(d, 1 H), 8 70(s, 1 H) MS APCI+ m/z 452 [MHf

Example 56 2-(3-Fluoro-2-metho^χy-phenyl)-5-f4-(6-methoxy-pyridin-3-vπ-5-methyl-4-H- f 1 ,2,41triazol-3-vπ-pyrazine

The title product was prepared by the method of example 14 using the chloro compound of preparation 30 (108mg, 0.32mmol) and 2-methoxy-3- fluoro-benzene boronic acid (72mg, 0.48mmol). 107mg, 79% yield of the title product was prepared as a white solid. ¹HNMR(CDCI₃, 400MHz) δ: 3.35(s, 3H), 3.85(s, 3H), 4.00(s, 3H), 4.5(s, 2H), 6.85(d, 1H), 7.20(m, 2H), 7.60(m, 2H), 8.15(s, 1H), 8.85(s, 1H), 9.50(s, 1H). Microanalysis: C₂₁H₁₉FN₆P₃0.2H₂O requires; C 59.21, H 4.59, N 19.73; found C 59.27, H 4.69, N 19.33. MS APCI+ m/z 423 [MHf

Claims

Claims

1 , A compound of formula (I)

wherein

V, W, X and Y, which may be the same or different, represent C-R^e or N;

Z is C-H or N^

R¹ is selected from

(i) a phenyl ring substituted with two or more substituents, which may be the same or different, each independently selected from halo,

(C C₆)alkyl, (C C₆)alkoxy, cyano, C(O)NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰ and NLC(O)R¹⁰]₂; and

(ii) a five to seven membered aromatic heterocyclic ring containing 1-3 hetero atoms selected from N, O and S and N-oxides thereof; said ring being optionally substituted with two or more substituents, which may be the same or different, selected from halo, (CrCe)alkyl, (CrC₆)alkoxy, cyano, C(O)NR⁷R^δ, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R ⁰]₂;

R² is selected from'

(i) H, OH, OR⁹, NR-R⁸, NR^{^}C(0)R¹⁰ and N[C(O)R ⁰]₂; (ii) a 5-7 membered N-linked heterocycle containing 1-3 heteroatoms selected from N,O and S; said.ring being optionally substituted with one or - more groups selected from (Cι-C₆)alkyl, (C₁-C₆)alkoxy and- C(O)NR⁷R⁸; and

(iii) (CrCe)alkyl optionally substituted with an N-linked 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, O and S;

R³ is selected from H and (CrC₆)alkyl; 0

R is¹ selected from H, (C C₆)alkyl and OR⁹;

R⁵ is selected from halo, . (CrC₆)alkyl, (C Cβ)alkoxy, NR⁷R⁸, NR⁷C(O)R¹⁰ and

N[C(O)R¹⁰]₂; 5

- ^" R⁶ is ^{^} selected from H, halo, (C C₆)alkyl, {Cι-C₆)alkoxy,_. cyano,_. MR⁷R⁸,- - NR⁷C(O)R¹⁰, N[C(O)R¹⁰]₂ and C(O)NR⁷R⁸; . . . . . . . .

R⁷ and R⁸, which- may be the same or -different, are selected from H and 0 (d-CβJalkyl;

R⁹ is (Cι-C₆)alkyl, which is optionally substituted with with one or more groups each independently selected from (C C₆)alkoxy and an N-linked 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, O and S; and 5

R ,10 -is selected from (C C₆)alkyl and (C C₆)alkoxy;

a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer; 30 . with the proviso that the compound of formula (I) is not ' -^" 3-ethyl-5-(4-imidazol-1-ylphenyl)-4-(4-methoxyphenyl)-4.H-[1 ,2_r4]triazole₁-. _.. .

3-(3^,,5'-dichlorobiphenyl-4-yl)-4-(2-methoxyphenyl)-5-methyl-4H-[1 ,2,4]triazole, - 3-(3',5'-bis-trifluoromethylbiphenyl-4-yl)-4-(2-fluorophenyl)-5-methyl-4H- - [1 ,2,4]triazole, or -

S^S'.S'-bis-trifluoromethylbiphenyM-y -δ-methy ^S-trifluoromethylpheny ^H- [1 ,2,4]triazole. 5^{~ "} -

2. A compound according to claim 1 wherein X is CH.

3. A compound according to either claim 1 or claim 2 wherein V, W and Y are each independently CH, C-OCH3 or N. -

10 -^{: " " "} - . - -

4. A compound according to^"any one of claims -1 to 3 wherein W and Y are each independently CH or N and X and V are each CH.

5. ^" A compound according to any one of claims^" 1 to 4-wherein Z is N.

-15

6. A compound according to any one of claims 1 to 4. wherein Z is CH.

7. A compound according to any one of claims 1 to 6 wherein R is selected from:

20

(i) a phenyl ring substituted with two substituents, which may be the same

- or different; each independently selected from - halo, (Cι-C₆)alkyl,

- (Cι-Cβ)alkoxyτ ^"cyano, C(O)NR⁷R⁸,^" NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂; and

25

(ii) a pyridyl ring or N-oxide thereof each substituted with two substituents, which may be the same or different, each independently selected from halo, (Cι-C₆)artkyl, (C C₆)alkoxy, cyano, C(O)NR⁷R⁸, NR⁷R⁸, NR⁷C(O)R¹⁰ and N[C(O)R¹⁰]₂. -

30

8^'. A compound according to claim 7 wherein R¹ is a phenyl ring substituted with two substituents, which may be the same or different, each independently selected from fluoro, chloro, methyl, methoxy and cyano.

9. A compound according to claim 7 wherein R¹ is pyridine-N-oxide substituted with two methyl groups - 10. A compound according to any one of claims 1 to 9 wherein R² is selected from:

(i) H, (CrC₃)alkoxy, (C₁-C₃)alkoxy-(C C₃)alkoxy and N((Cι-C₃)alkyl)₂; and

(II) a 5 membered N-linked heterocycle containing 1-3 nitrogen atoms,

^{" "} - - said ring optionally substituted with C(O)NR⁷R⁸.

-11. - A^" compound according to claim 10 wherein -R² -is selected from H, methoxy, ethoxy, 2-methoxyethoxy, -_ dimethylamino, 1 ,2,3-tπazol-2-yl and pyroHidinyl, the latter being optionally substituted by_CONH₂.

12. A compound according to claim 11 wherein R is selected from H and methoxy.

13. A compound according to any one of claims 1 to 12 wherein R³ is H.

14. A compound according to any one of claims 1 to 13 wherein R⁴ is H, methyl or methoxy.

4 15. - A compound according to claim 14 wherein R_ is H

- 16. -A compound according to any one of claims 1 to 15 wherein R⁵ is methoxy or NHCH₃

17. A compound according to claim 16 wherein R⁵ is methoxy

18. A compound according to claim f which is selected from 2-(4-fluoro-2-methylphenyl)-5-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H- [1 ,2,4]triazol-3-yl)-pyridine;

2-(2,3-dimethylphenyl)-5-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H- - . [1 ,2,4]triazol-3-yl)-pyridine;

5 5-(4-fluoro-2-methylphenyl)-2-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H- [1 ,2,4]triazol-3-yl)-pyridine;

^{■" ' •}-- 5-(2,3-dimethylphenyl)-2-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-. . [1 ,2,4]triazol-3-yl)-pyridine;

^{•* "}- ^'. 1-[5-[5-^"(2,3-dimethylphenyl)-pyridin-2-yl]-4-(6-methoxypyridin-3-yl)-4H- - . 10 [1 ,2_i4]triazol-3-ylmethyl]-pyrrolidine-(2S)-2-carboxylic acid amide;

5-(2,3-dimethylphenyl)-2-(5-pyrrolidin-1-ylmethyl-4-(6-methoxypyridin-3-yl)-4H- - [1 ,2,4]triazol-3-yl)-pyridine; - . ..

2-(4-fluOro-2-methylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H- - [1 ,2,4]triazol.-3-yl]-pyrazine;

15 - ^" 2-(2,3-dimethylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4Η- — -. [1 ,2,4]triazol-3-yl]-pyrazineχ

- 2-(4-fluoro-2-methylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methy H . [1 ,2,4]triazol-3-yl]-pyrazine;

- 2-(2,3-dimethylpheny!)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1 ,2,4]triazol-3- 20 ylfpyrazine;

2-(4-cyano-2-methylphenyl)-5-[4-(6-methoxypyridin=-3_ryl)-5-methy H- .. . [-1 ,2-,4]triazol-3-yl]-pyrazine; .-.

^'-^' -^' 2-(5-fluoro-2-methoxyphenyl)-5-[4-(6-methoxypyridin-3.-yl)-5-methyl-4H- . [1 ,2,4]triazol-3-yl]-pyrazine; .

25 2-(4-cyano-2-methylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H- [1 ,2,4]triazol-3-yl]-pyrazine;

- 5-(4-cyano-2-methylρhenyl)-2-[5-methoxymethyl-4-(6-methoxypyridin-3 yl)-4H- - • [1 ,2,4]triazol-3-yl]-pyridine;

- - 2-(5-fluoro-2-methoxyphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-y.l)-4H- 30 [1 ,2,4]triazoU3-yl].-pyridine;.

2-(2-fluoro-5-methoxyphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H- [1 ,2,4]triazol-3-yl]-pyrazine; - - 2-(2-fruoro-5-methylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-

[1 ,2,4]triazol-3-yl]-pyrazine, -

2-(2,5-difluorophenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1 ,2,4]triazol-3- ylfpyrazine; - 2-(3_J5-dimethylphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1 ,2,4]triazol-3- ylfpyrazine; - 2--(2,5-dimethylphenyl)-5--[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1 ,4]triazol-3- ylfpyrazine;

2-(2,5-dichlorophenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1 ,2,4]triazol-3- - ylfpyrazine; - -

2-(2-fluoro-5-methoxyphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4

H-[1 ,2,4]triazol-3-yl]-pyrazine; -

2-(3,5-difluoro-phenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H-[1 ,2,4]triazol-3- yl]-pyrazine; . - 2-(2,3-dimethylphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin-3-yl)-

4H-1 ,2,4-triazol-3-yl]pyridine; . .

2-(5-chloro-2-methoxyphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6- methoxypyridin-3-yl)-4H-1 ,2,4-triazol-3-yl]pyridine; - - .

2-(4-fluoro-2-methoxyphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6- methoxypyridin-3-yl)-4H-1 ,2,4-triazol-3-yl]pyridine;

- 2-(5-fluoro-2-methoxyphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6- - -methoxypyridin-3-yl)-4H-1 ,2,4-triazol-3-yl]pyridine;

2-(5-fluoro-2-methylphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin-

3-yl)-4H-1 ,2,4-tπazol-3-yl]pyridine; 2-methoxy-5-{3-[(2-methoxyethoxy)methyl]-5-[6-(2-methoxy-5- methy!phenyl)pyridιn-3-yl]-4H-1 ,2,4-triazol-4-yl}pyridine;

2-(2-fluoro-3-methoxyphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6- methoxypyridin-3-yl)-4H-1 ,2,4-trιazol-3-yl]pyrιdine;

2-(3,5-dιfluorophenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin-3-yl)- - ^" 4/-/-1 ;2,4-triazol-3-yl]pyridine,

2-(2,5-dimethoxyphenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin-3- yl)-4H-1 ,2,4-trιazol-3-yl]pyπdine, 2-(3-chloro-4-fluorophenyl)-5-[5-[(2-methoxyethoxy)methyl]-4-(6-methoxypyridin- 3-yl)-4H-1 ,2,4-triazol-3-yl]pyridine; and

2-(3-fluoro-2-methoxyphenyl)-5-[5-methoxymethyl-4-(6-methoxypyrid!n-3- yl)-4H-[1,2,4]triazol-3-yl]-pyrazine; 2-(3-fluoro-2-methoxy-phenyl)-5-[4-(6-methoxy-pyrSdin-3-yl)-5-methyl-4-H- [1,2,4Jtriazol-3-yl]-pyrazine; and tautomers thereof and pharmaceutically acceptable salts, solvates and polymorphs of said compound or tautomer.

19. A compound according to^~claim 18, which is selected from:

2-(4-fluoro-2-methylphenyl)-5-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-

[1 ,2,4]triazol-3-yl)-pyridine;

2-(2,3-dimethylphenyl)-5-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H- [1 ,2,4]triazol-3^"-yl)-pyridine;

5-(4-fluoro-2-methylphenyl)-2-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-

[1 ,2,4]triazol-3-yl)-pyridιne,

5-(2,3-dιmethylphenyl)-2-(5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-

[1 ,2,4]triazol-3-yl)-pyridine; 1-[5-[5-(2,3-dimethylphenyl)-pyridin-2-yl]-4-(6-methoxypyridin-3-yl)-4H-

[1 ,2,4]triazol-3-ylmethyl]-pyrrolidine-(2S)-2-carboxylic acid amide;

5-(2,3-dimethylphenyl)-2-(5-ρyrrolidin-1-ylmethyl-4-(6-methoxypyridin-3-yl)-4H-

[1 ,2,4]triazol-3-yl)-pyridιne;

2-(4-fluoro-2-methylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H- [1 ,2,4]triazol-3-yl]-pyrazine,

2-(2,3-dimethylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H-

[1 ,2,4]trfazol-3-yl]-pyrazine, "2-(4-fluoro-2-methylphenyl)-5-[4-(6-methoxypyrιdin-3-yl)-5-methyl-4H-

[1 ,2,4]triazol-3-yl]-pyrazine; 2-(2,3-dimethylphenyl)-5-[4-(6-methoxypyrιdin-3-yl)-5-methyl-4H-[1 ,2,4]triazol-3- ylfpyrazine;

2-(4-cyano-2-methylphenyl)-5-[4-(6-methoxypyrιdιn-3-yl)-5-methyl-4H- [1 ,2,4]triazol-3-yl]-pyrazιne, 2-(5-fluoro-2-methoxyphenyl)-5-[4-(6-methoxypyridin-3-yl)-5-methyl-4H- [1 ,2,4]triazol-3-yl]-pyrazine;

2-(4-cyano-2-methylphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H- [1 ,2,4]triazol-3-yl]-pyrazine; 5-(4-cyano-2-methylphenyl)-2-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H- - [1 ,2,4]triazol-3-yl]-pyridine;

2-(5-flύoro-2-methoxyphenyl)-5-[5-methoxymethyl-4-(6-methoxypyridin-3-yl)-4H- [1 ,2,4}triazol-3-yl]-pyridine; and

2-(3-fluoro-2-methoxyphenyl)-5-[5-methoxymethyl-4-(6-methoxypyrβdin-3- yl)-4H-[1 ,2,4]triazol-3-yl]-pyrazine;

2-(3-fluoro-2-methoxy-phenyl)-5-[4-(6-methoxy-pyridin-3-yl)-5-methyl-4-H- [1 ,2,4]triazol-3-yl]-pyrazine;

and tautomers thereof and pharmaceutically acceptable salts, solvates and "polymorphs of said compound or tautomer.

20. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 19, or pharmaceutically acceptable salts, solvates or polymorphs thereof, and a pharmaceutically acceptable diluent or carrier.

21. A compound of formula (I) as claimed in any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or polymorph thereof, for use as a medicament.

22. A method of treatment of a disorder or condition where inhibition of

- oxytocin is known, or can be shown, to produce a beneficial effect, in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) as claimed in any one of claims 1 to 19, without the proviso, or a pharmaceutically acceptable salt, solvate or polymorph thereof.

23. Use of a compound of formula (I) as claimed in any one of claims 1 to 19, without the proviso, or a pharmaceutically acceptable salt, solvate or polymorph thereof, in the preparation of a medicament for the treatment of a disorder or condition where inhibition of oxytocin is known, or can be shown, to produce a beneficial effect

24. A method according to claim 22 or use according to claim 23, wherein the disorder or condition is selected from sexual dysfunction, male sexual dysfunction,- female sexual dysfunction, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, sexual pain disorder, premature ejaculation, preterm labour, complications in labour, appetite and feeding disorders, benign prostatic hyperplasia, premature birth, dysmenorrhoea, congestive heart failure, arterial hypertension, liver cirrhosis, nephrotic hypertension, ocular hypertension, obsessive compulsive disorderand neuropsychiatric disorders.

25. A method or use according to claim 24 wherein the disorder or condition is selected from sexual arousal disorder, orgasmic disorder, sexual pain disorder and premature ejaculation.