NL1027084C2 - Substituted triazole derivatives as oxytocin antagonists. - Google Patents

Description

ψ. ’· i ··

SUBSTITUTED TRIAZOL DERIVATIVES AS OXYTOCINE ANTAGONISTS

5

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

EUR. J. Med. Chem. 1985, 20. (3), pages 257-266, relates to derivatives of 1,2,4-triazoles with analgesic and anti-inflammatory properties. WO 03/053437 relates to 1,2,4-triazoles with activity as oxytocin antagonists. EP 1 293 503 relates to derivatives of 1,2,4-triazoles with glycine transporter-inhibiting properties.

The first aspect of the present invention provides compounds of formula (I) v R 5 wherein V, W, X and Y, which may be the same or different, represent C-Re or N; Z is C-H or N; R 1 is selected from: (i) a phenyl ring substituted with two or more substituents, which may be the same or different, each independently selected from halogen, (C 1 -C 6) alkyl, (C 1 -C 6) - 1027084-r * - 2 - alkoxy, cyano, C (O) NR 7 R 8, NR 7 R 8, NR 7 C (O) R 10 and N [C (O) R 10] 2; and (ii) a five to seven membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from N, O and S and N-oxides thereof / which ring is optionally substituted with two or more substituents, which may be the same or different are selected from halogen, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, cyano, C (O) NR 7 R 8, NR 7 R 8, NR 7 C (O) R 10 and N [C (O) R 10] 2; R 2 is selected from: 10 (i) H, OH, OR 9, NR 7 Re, NR 7 C (O) R 10 and N [C (O) R 10] 2; (ii) a 5-7 membered N-linked heterocycle containing 1-3 heteroatoms selected from N, 0 and S; which ring is optionally substituted with one or more groups selected from (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy and C (O) NR 7 R 8; and (iii) (C 1 -C 6) alkyl optionally substituted with an N-linked 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, 0 and S; R 3 is selected from H and (C 1 -C 8) alkyl; R 4 is selected from H, (C 1 -C 8) alkyl and OR 9; R 5 is selected from halogen, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, NR 7 Re, NR 7 C (O) R 10 and N [C (O) R 10] 2; R 6 is selected from H, halogen, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, cyano, NR 7 R 8, NR 7 C (O) R 10, N [C (O) R 10] 2 and C (O) NR 7 R 8; R 7 and R 8, which may be the same or different, are selected from H and (C 1 -C 6) alkyl; R 9 is (C 1 -C 6) alkyl optionally substituted with one or more groups each independently selected from (C 1 -C 6) alkoxy and an N-linked 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, 0 and S; and R 10 is selected from (C 1 -C 8) alkyl and (C 1 -C 8) alkoxy; a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or said tautomer; with the proviso that the compound of formula (I) is not: 3-ethyl-5- (4-imidazol-1-ylphenyl) -4- (4-methoxyphenyl) -4H- [1,2,4] triazole, 1027084- τ '* -3.-.

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-fluoro-phenyl) -5-methyl-4H- [1,2,4] triazole, or 5 3- (3 ', 5'-bis-trifluoromethyl-biphenyl-4-yl) ) -5-methyl-4- (3-trifluoromethylphenyl) -4H- [1,2,4] triazole.

Unless otherwise specified, alkyl and alkoxy groups may be straight or branched and contain 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl and hexyl. Examples of alkoxy include methoxy, ethoxy, isopropoxy and n-butoxy.

Halogen means fluorine, chlorine, bromine or iodine and is preferably fluorine.

A heterocycle can be saturated, partially saturated or aromatic. Examples of heterocyclic groups are thiolanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, sulfolanyl, dioxolanyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, pyrazolinyl, pyrazolidinyl, dioxanyl, morpholinyl, dithianol-nepropyl, azazorepyazepropyl, azazorphi-pyropyl, azazorepi-pyropyl, azazorphi-pyropyl, azazorphi-pyropyl, azazoropyl thiazolinyl and diazapanyl. Examples of aromatic heterocyclic groups are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxa-diazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl.

Unless otherwise specified, the term "substituted" means substituted with one or more defined groups. In the case where groups can be selected from a number of alternative groups, the selected groups can be the same or different.

Preferred aspects of the invention are described 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 balance represents C-R 6; 1027064-I - 4 - Ζ C-H Or Ν Ï S; R 1 is selected from: (i) a phenyl ring substituted with two or more substituents, which may be the same or different, each independently selected from halogen, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, cyano, C (0) NR 7 R 8, NR 7 R 8, NR 7 C (O) R 10 and N [C (O) R 10] 2; and (ii) a five to seven membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from N, 0 and S and N-oxides thereof; which ring is optionally substituted with two or more substituents, which may be the same or different, selected from halogen, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, cyano, C (O) NR 7 R 8, NR 7 R 8, NR 7 C (0) R10 and N [C (O) R10] 2;

Preferably, R 2 is selected from: (i) H, (C 1 -C 8) alkoxy, (C 1 -C 6) alkoxy- (C 1 -C 6) alkoxy, NR 7 R 8, NR 7 C (O) R 10 and N [C (O) R 10) 2; and (ii) a 5-7 membered N-linked heterocycle containing 1-3 heteroatoms selected from N, O and S; which ring is optionally substituted with one or more groups selected from (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy and C (O) NR 7 R 8; R 3 is selected from H and (C 1 -C 6) alkyl; R 4 is selected from H, (C 1 -C 8) alkyl and OR 9; R 5 is (C 1 -C 3) alkyl, (C 1 -C 5) alkoxy or NR 7 R 8; R 8 is H, halogen, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, cyano or NR 8 R 8; R 7 and R 8, which may be the same or different, are selected from H and (C 1 -C 8) alkyl; R 9 is (C 1 -C 8) alkyl, optionally substituted with (C 1 -C 8) alkoxy; and R 10 is selected from (C 1 -C 8) alkyl and (C 1 -C 8) alkoxy; a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or said tautomer.

In another preferred aspect, the present invention comprises compounds of formula (I) wherein 1 or 2 of the groups V, W and Y represent N when the balance represents C-R 6 and X is CH; 1027084- * * -5-Z C-H or N; R 1 is selected from: (i) a phenyl ring substituted with two substituents, which may be the same or different, each independently selected from halogen, (C 1 -C 6) alkyl, (C 1 -C 2) alkoxy and cyano; and (ii) a pyridyl ring or N-oxide thereof, each substituted with two substituents, which are the same or different. can be each independently selected from halogen, (C 1 -C 6) alkyl, (C 1 -C 3) alkoxy and cyano; R 2 is selected from: (i) H, (C 1 -C 3) alkoxy, (C 1 -C 3) alkoxy- (C 1 -C 3) alkoxy and N ((C 3 -C 3) alkyl) 2; and (ii) a 5-membered N-linked heterocycle containing 1-3 nitrogen atoms, which ring is optionally substituted with C (O) NR 7 R 8; R 3 is selected from H and (C 1 -C 8) alkyl; R 4 is selected from Η, (0χ-06) alkyl and ORs; R 5 is (C 1 -C 3) alkyl, (C 1 -C 4) alkoxy or NR 7 R 8; R 6 is H, (C 1 -C 12 alkyl, (C 1 -C 12 alkoxy or NR 7 R 8; R 7 and R 8, which may be the same or different, are selected from H and (C 1 -C 6) alkyl; and R 9 is (C 1 -C 6) alkyl optionally substituted with methoxy, a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or said tautomer.

In another preferred aspect, the present invention includes compounds of formula (I) wherein W and Y are each independently CH or N and X and V are both CH; Z is N; R 1 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; R 2 is selected from H, methoxy, ethoxy, 2-methoxyethoxy, (1027084-6-dimethylamino, 1,2,3-triazol-2-yl and pyrollidinyl, the latter optionally substituted with CONH 2; R 3 is selected from H and (C 1 -C 6) alkyl; R 4 is H; and R 5 is methoxy, a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or said tautomer.

Preferred embodiments of the compounds of formula (I) according to the above aspects are those comprising two or more of the following preferences.

Preferably 1 or 2 of the groups V, W, X and Y represent N when the radical represents C-R 6.

In a preferred embodiment, X is CH.

In a preferred embodiment, 1 or 2 of the groups V, W and Y represent N when the radical represents C-R 6 and X is CH.

Preferably Y is N or CR6.

More preferably, V, W and Y are each independently CH, C-OCH 3 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 and V are both CH.

In a preferred embodiment. Z N.

In another preferred embodiment, Z is CH.

Preferably, R 1 is selected from: (i) a phenyl ring substituted with two or more substituents, which may be the same or different, each independently selected from halogen, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, cyano, C (O) NR 7 R 8, NR 7 R 8, NR 7 C (O) R 10 and N [C (O) R 10] 2; and (ii) a five to seven membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from N, 0 and S and N-oxides thereof; which ring is optionally substituted with two or more substituents, which may be the same or different, selected from halogen, (C 1 -C 8) alkyl, (C 1 -C 12 alkoxy, C (O) NR 7 R 8, NR 7 R 8, NR C (O) R 10 and N [C (O) R 10] 2; 1027084 - J.

More preferably, R1 is selected from: (i) a phenyl ring substituted with two substituents, which may be the same or different, each independently selected from halogen, (Cx-C6) alkyl, (Cx-C6) alkoxy, cyano , C (O) NR 7 R 8, NR 7 R 8, NR 7 C (0) R 10 and N [C (0) R 10] 2; (ii) a pyridyl ring or N-oxide thereof each substituted with two substituents, which may be the same or different, each independently selected from halogen, (C 1 -C 6) alkyl, (C 3 -C 6) alkoxy, cyano, C (O) NR 7 R 8, NR 7 R 8, NR 7 C (O) R 10, and N [C (O) R 10] 2.

Even more preferably, R 1 is selected from: (i) a phenyl ring substituted with two substituents, which may be the same or different, each independently selected from halogen, (C 1 -C 2) alkyl, (C 3 -C 8) 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 halogen, (C 1 -C 8) alkyl, (C 3 -C 8) alkoxy and cyano.

In a preferred embodiment, R 1 is a phenyl ring substituted with two substituents, which may be the same or different, each independently selected from fluorine, chlorine, methyl, methoxy and cyano.

In another preferred embodiment, R 1 is pyridine-N-oxide substituted with two methyl groups.

Preferably, R 2 is selected from: (i) H, (C 1 -C 6) alkoxy, (C 8 -C 6) alkoxy- (C 8 -C 6) alkoxy, NR 7 R 8, NR 7 C (O) R 10 and N [C (O) R 10] 2 ; and (ii) a 5-7 membered N-linked heterocycle containing 1-3 heteroatoms selected from N, O and S; which ring is optionally substituted with one or more groups selected from (C 8 -C 6) alkyl, (C 8 -C 6) alkoxy and C (O) NR 7 R 8.

More preferably, R 2 is selected from: (i) H, (C 1 -C 3) alkoxy, (C 3 -C 3) alkoxy- (C 3 -C 3) alkoxy and N ((C 3 -C 3) alkyl) 2; and (ii) a 5-membered N-linked heterocycle containing 1-3 nitrogen atoms, which ring is optionally substituted 1027084 - * * - 8 - with C (O) NR 7 R 8.

Even more preferably, R2 is selected from H, methoxy, ethoxy, 2-methoxyethoxy, dimethylamino, 1,2,3-triazol-2-yl and pyrollidinyl, the latter optionally being substituted with CONH2.

Most preferably, R2 is selected from H and methoxy. Preferably, R 3 is H or (C 1 -C 3) alkyl.

Most preferably, R3 is H.

Preferably, R 4 is H, (C 1 -C 3) alkyl or OR 9.

More preferably, R * is H, (Cx-C3) alkyl or (Cx-C3) alkoxy.

Most preferably, R 4 is H, methyl or methoxy.

In a preferred embodiment, R 4 is H.

Preferably R5 is (Cx-C3) alkyl, (Cx-C3) alkoxy or NR7 R8. More preferably, R 5 is (C x -C 3) alkoxy or NR 7 R 8.

Most preferably, R 5 is methoxy or NHCH 3.

In a preferred embodiment, R 5 is methoxy.

Preferably, R 6 is H, halogen, (Cx-C6) alkyl, (Cx-C6) alkoxy, cyano or NRV.

More preferably, R 6 is H, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy or NR 7 R 8.

Even more preferably, R 6 is H, (C 1 -C 6) alkyl or (C 1 -C 6) alkoxy.

Most preferably, R 6 is H, methyl or methoxy.

In a preferred embodiment, R 6 is H or methyl.

In a most preferred embodiment, R6 is H.

Preferably, R7 is H or (Cx-Ca) alkyl.

Most preferably, R 7 is H or methyl.

Preferably, R8 is H or (Cx-C3) alkyl.

Most preferably, R8 is H or methyl.

Preferably, R 9 is (C 1 -C 6) alkyl optionally substituted with (C 1 -C 6) alkoxy.

More preferably, R 9 is (C 1 -C 6) alkyl optionally substituted with methoxy.

Most preferably, R 9 is methyl.

Preferred compounds of formula (I) are: 2- (4-fluoro-2-methylphenyl) -5- (5-methoxymethyl-4- (6-1027084-f *).

-9-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- (6-5 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-dimethyphenyl) -pyridin-2-yl] -4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazole-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- (6-15 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] triazol-3-yl] pyrazine; 2- (4-fluoro-2-methylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] pyrazine; 2- (2,3-dimethylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] pyrazine; 2- (4-cyano-2-methylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] pyrazine; 2- (5-fluoro-2-methoxyphenyl) -5- [4- (6-methoxypyridin-3-25 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-fluoro-2-methoxyphenyl) -5- [5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4 H- [1,2,4] triazol-3-yl] pyridine; 2- (2-fluoro-5-methoxyphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4 H- [1,2,4] triazol-3-yl] pyrazine; 2- (2-fluoro-5-methylphenyl) -5- [4- (6-methoxypyridin-3-35 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-yl] pyrazine; 1027084-. * * - 10 - 2- (3/5-dimethylphenyl) -5- [4- (6-methoxypyridin-3-yl) - 5-methyl-4H- [1,2,4] triazol-3-yl] - pyrazine; 2- (2,5-dimethylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] pyrazine; 2- (2,5-dichlorophenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4 H- [1,2,4] triazol-3-yl] -pyrazine; 2- (2-fluoro-5-methoxyphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] pyrazine; 2- (3,5-difluoro-phenyl) -5- [4- (6-methoxypyridin-3-yl) -10-5-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) -15 methyl] -4- (6-methoxypyridin-3-yl) -4H-1,2,4-triazole- 3-yl] pyridine; 2- (4-fluoro-2-methoxyphenyl) -5- [5 - [(2-methoxyethoxy) methyl] -4- (6-methoxypyridin-3-yl) -4 H -1,2,4-triazole-3 -yl] pyridine; 2- (5-fluoro-2-methoxyphenyl) -5- [5-t (2-methoxyethoxy) methyl] -4- (6-methoxypyridin-3-yl) -4 H -1 / 2,4-triazole- 3-ylpyridine; 2- (5-fluoro-2-methylphenyl) -5- [5 - [(2-methoxyethoxy) methyl] -4- (6-methoxypyridin-3-yl) -4H-1,2,4-triazole-3 -25 yl] pyridine; 2-methoxy-5- {3 - [(2-methoxyethoxy) methyl] -5- [6- (2-methoxy-5-methylphenyl) pyridin-3-yl] -4H-1,2,4-triazole-4 -yl} pyridine; 2- (2-fluoro-3-methoxyphenyl) -5-t5 - [(2-methoxyethoxy) -30 methyl] -4- (6-methoxypyridin-3-yl) -4H-1,2,4-triazole-3 -yl] pyridine; 2- (3,5-difluorophenyl) -5- [5 - [(2-methoxyethoxy) methyl] -4- (6-methoxypyridin-3-yl) -4 H -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-triazole-3- yl] pyridine; 1027084- -11- <> 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-4-5 (6-methoxypyridin-3-yl) -4H- [1,2,4] triazol-3-yl] pyrazi -ne; 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 said tautomer.

Most 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) 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) 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) -4 H-II, 2,4] 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-raethylphenyl) -5- [5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4 H-tl, 2,4] triazol-3-yl] pyrazine; 2- (2,3-dimethylphenyl) -5- [5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazol-3-yl] pyrazine; 2- (4-fluoro-2-methylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] pyrazine; 2- (2,3-dimethylphenyl) -5- [4- (6-methoxypyridin-3-yl) - 5-methyl-4H - [1,2,4] triazol-3-yl] pyrazine; 2- (4-cyano-2-methylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] pyrazine; 1027084- • * - 12 - 2- (5-fluoro-2-methoxyphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazole-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 5- (4-cyano-2-methylphenyl) -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-yl) -4H- [1,2,4] triazol-3-yl] pyridine; and 2- (3-fluoro-2-methoxyphenyl) -5- [5-methoxymethyl-4-10 (6-methoxypyridin-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-4H- [1,2,4] triazol-3-yl] pyrazine, and tautomers thereof and pharmaceutically acceptable salts, solvates and polymorphs of said compound or said tautomer.

Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition salts thereof.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, glucate, gluconate , glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

Acids hemi salts may also be formed, for example hemisulfate salts.

For an overview of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use, 35 by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds 1027084- - ------- - ... -__ • <. .

- of formula (I) can be prepared by one or more of three methods: (i) by reacting the compound of formula (I) with the desired acid; (Ii) by removing an acid-labile protecting group from a suitable precursor of the compound of formula (I) using the desired acid; or (iii) by converting a salt of the compound of formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

All three reactions are typically performed in solution. The resulting salt can precipitate and be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from fully ionized to almost non-ionized.

The compounds of the invention can exist in both unsolvated and solvated form. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, e.g., ethanol. The term "hydrate" is used when the said solvent is water.

Within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug which contain two or more organic and / or inorganic components, which may be present in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized or non-ionized. For an overview of such complexes, see. Haleblian, J. Pharm. Sci., 64 (8), 1269-1288 (Aug 1975).

(1027084-4).

- 14 -

Hereinafter, all references to compounds of formula (I) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

The compounds of the invention include compounds of formula (I) as defined above, comprising all polymorphs and crystal habitats thereof, pro-drugs and isomers thereof (including optical, geometric and tautomeric isomers) as described below and isotope-labeled compounds of formula (1).

As indicated, so-called "pro-drugs" (drug precursors) of the compounds of formula (I) are also within the scope of the invention. For example, certain derivatives of compounds of formula (I) which themselves may have little or no pharmacological activity, when administered in or on the body, can be converted into compounds of formula (I) with the desired activity, for example by hydrolytic cleavage. Such derivatives are referred to as "pro-drugs". Further information regarding the use of pro-drugs can be found in Pro-drugs as New Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E.B. Roche, American Pharmaceutical Association).

Prodrugs of the invention can be produced, for example, by replacing appropriate functionalities present in the compounds of formula (I) by certain groups known to those skilled in the art as "pro-groups" as described, for example, in Design of Prodrugs of H Bundgaard (Elsevier, 1985).

Some examples of prodrugs according to the invention include: (i) when the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example a compound wherein the hydrogen of the alcohol functionality of the compound of formula (I) is replaced by {C 1 -C 4) alkanoyloxymethyl; and (ii) when the compound of formula (I) contains a primary or secondary amino functionality (-NH 2 or -NHR wherein R * H), an amide thereof, for example a compound wherein, depending on of the case, one hydrogen or both hydrogen of the amino functionality of the compound of formula (I) has been replaced by (c 1 -C 12) alkanoyl.

Further examples of replacement groups according to the above examples and examples of other prodrug types can be found in the aforementioned literature sites.

Furthermore, certain compounds of formula (I) may themselves serve as pro-drugs of other compounds of formula (I). Also included within the scope of the invention are metabolites of compounds of formula (I), ie compounds formed in vivo after drug administration. Some examples of metabolites according to the invention include: (i) when the compound of formula (I) contains a methyl group, a hydroxymethyl derivative thereof (-CH 3 -> -CH 2 OH); (ii) when the compound of formula (I) contains an alkoxy group, a hydroxy derivative thereof (-OR -> -OH); (Iii) when the compound of formula (I) contains a teriary amino group, a secondary amino derivative thereof (-NR ^ R2 -> -NHR1 Or -NHR2); (iv) when the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHR1 -> · -NH2); (v) when the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and (vi) when the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CN NH 2 -> COOH).

Compounds of formula (I) that contain one or more asymmetric compounds. .

- 16 - carbon atoms may exist as two or more stereoisomers. When a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. When structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ("tautomerism") can occur. This can take the form of proton automerism in compounds of formula (I) containing, for example, an imino, keto or oxime group, or so-called valentietautomerism in compounds containing an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

All stereoisomers, geometric isomers and automeric forms of the compounds of formula (I) are included within the scope of the present invention, including compounds that exhibit more than one type of isomerism and mixtures of one or more thereof. Also included are acid addition salts wherein the counter ion is optically active, e.g., d-lactate, or racemic, e.g., dl-tar-20.

Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis of a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography ( HPLC).

Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example an alcohol, or, in the case where the compound of formula (I) contains an acid or a basic portion, a base or an acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or 1027084, fractional crystallization and one diastereoisomer or both diastereoisomers can be converted to the corresponding pure enantiomer (the corresponding pure enantiomers) by means well known to those skilled in the art.

Chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form by chromatography, typically HPLC, on an asymmetric mobile phase resin consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50 volume% isopropanol, typically 2% to 20%, and 0 to 5 volume% of an alkylamine, typically 0.1% diethylamine. Evaporation of the eluate provides the enriched mixture.

Stereo isomeric conglomerates can be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds from E.L. Eliel and S.H. Wilen (Wiley, New York, 1994).

The present invention encompasses all pharmaceutically acceptable isotope-labeled compounds of formula (I) wherein one or more atoms has been replaced by atoms with the same atomic number but with an atomic mass or mass number different from the atomic mass, or the mass number that dominates in nature.

Examples of isotopes suitable for incorporation into the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, 1.8.1, 23 chlorine, such as Cl, fluorine, such as F, iodine, such as I and 1.25 13 15 15 17 I, nitrogen, such as N and N, oxygen, such as 0, 0 and 180, phosphorus, such as 32 P, and sulfur, such as 35 S.

Certain isotope-labeled compounds of formula (I), for example those containing a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The triti-35 µm radioactive isotopes, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their easy incorporation and their easy detectability.

1027084-18-

Substitution with heavier isotopes such as deuterium, i.e., 2H, may provide certain therapeutic benefits resulting from greater metabolic stability, for example, increased half-life in vivo or reduced dosage requirements, and may therefore be preferred under some circumstances. Substitution with positron-emitting isotopes, such as 14C, 13F, 150 and 13N, may be useful in Positron Emission Topography (PET) studies for substrate receptor occupancy studies.

Isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying Examples and Preparations using an appropriate isotope-labeled reagent in place of the unlabelled reagent used to date.

Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent may be isotopically substituted, for example D20, d6-acetone, dg-DMSO. Also within the scope of the invention are intermediates as defined below, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined above for compounds of formula (I). The invention encompasses all polymorphs of the aforementioned species and crystal habitats thereof.

In the preparation of compounds of formula (I) according to the invention, a person skilled in the art is free to choose, on a routine basis, the form of intermediate compound which provides the best combination of aspects for this purpose. Such aspects include the melting point, the solubility, the processability and the yield of the intermediate compound form and the resulting ease with which the product can be purified after isolation.

35 Medicinal product

Compounds of the invention intended for pharmaceutical use can be administered as crystal 1027084;

"I

- 19 - line or amorphous products. They can be obtained, for example, as solid chunks, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying or evaporative drying. Microwave or radio 5 frequency drying can 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). In general, they will be administered as a composition in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe a component other than the compound or compounds of the invention. The choice of excipient will largely depend on factors such as the specific method of administration, the effect of the excipient on the solubility and stability and the nature of the dosage form.

Pharmaceutical compositions suitable for the release 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 for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

Oral administration

The compounds of the invention can be administered orally. Oral administration may consist of swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, whereby the compound enters the blood stream directly from the mouth.

Preparations suitable for oral administration include solid preparations such as tablets, capsules containing particulate material, liquids or powders, suction tablets (including liquid-filled tablets), chewable preparations, multi- and nano-particulate materials, 1027004a "

1 I

- 20 gels, solid solution, liposome, films, ovules, sprays and liquid preparations.

Liquid preparations include suspensions, solutions, syrups and elixirs. Such compositions can be used as a filling in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil and one or more emulsifiers and / or suspending agents. Liquid preparations can also be prepared by reconstitution of a solid, for example from a sachet.

The compounds of the invention can also be used in rapidly dissolving, rapidly disintegrating dosage forms such as those described in Expert Opinion in The Pharmaceutical Patents, 11 (6), 981-986, by Liang and Chen (2001).

For tablet dosage forms, depending on the dose, the drug may form 1 to 80% by weight of the dosage form, more typically 5 to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrating agents include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. In general, the disintegrant will make up 1 to 25% by weight, preferably 5 to 20% by weight of the dosage form.

Binders are generally used to provide cohesive qualities to a tablet preparation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pre-gelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate. dihydrate.

Tablets may optionally also include surfactants such as sodium lauryl sulfate and polysorbate 80 and lubricants such as silica and talc. When present, surfactants can form 0.2 to 5% by weight of the tablet and lubricants can form 0.2 to 1% by 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 sulfate. Lubricants generally form 0.25 to 10% by weight, preferably from 0.5 to 3% by weight of the tablet.

Other possible ingredients include antioxidants, colorants, flavorants, preservatives, and flavor masks.

Exemplary tablets contain up to about 80% drug, about 10 to about 90% binder, about 0 to about 85% diluent, about 2 to about 10% disintegrant and about 0.25 to about 10% lubricant .

Tablet mixtures can be pressed directly or with a roll to form tablets. Tablet blends or portions of blends may alternatively be granulated wet, dry or melt, solidified as melt, or extruded for tableting. The final preparation may comprise one or more layers and may be coated or uncoated, it may even be coated.

The composition of tablets is discussed in

Pharmaceutical Dosage Forms: Tablets, Vol. 1, from H. Lie-berman and L. Lachman (Marcel Dekker, New York, 1980).

Consumable oral films for human or veterinary use are typically foldable water-soluble or water-swellable thin film dosage forms that can be rapidly dissolving or mucoadhesive and typically a compound of formula (I), a film-forming polymer, a binder, 1027084 ; A solvent, a wetting agent, a plasticizer, a stabilizing or emulsifying agent, a viscosity modifier, and a solvent. Some components of the preparation can perform more than one function.

The compound of formula (I) can be water-soluble or insoluble. A water-soluble compound typically constitutes 1 to 80% by weight, more typically 20 to 50% by weight, of the dissolved materials. Less soluble compounds can form a larger part of the composition, typically up to 88% by weight of the dissolved materials. Alternatively, the compound of formula (I) may be in the form of multi-particle granules.

The film-forming polymer can be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is typically present in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight.

Other possible ingredients include antioxidants, colorants, flavorings and flavor enhancers, preservatives, saliva stimulants, coolants, co-solvents (including oils), emollients, volume-providing agents, anti-foaming agents, surfactants and taste-masking agents.

Films according to the invention are typically prepared by evaporative drying of thin aqueous films applied to a peelable support or paper. This can be done in a drying oven or tunnel, typically a combined coating / drying device, or by freeze drying or vacuum treatment.

Solid compositions for oral administration can be formulated to provide immediate release and / or modified release. Modified-release preparations include delayed, sustained, pulsed, controlled, targeted, and programmed release preparations.

"027084- A .1" - 23 -

Suitable modified-release compositions for the purposes of the invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high-energy dispersions and osmotic and coated particles can be found in Pharmaceutical Technology On-Line, 25 (2 ), 1-14, from Verma et al. (2001). The use of chewing gum for achieving controlled release is described in WO 00/35298.

Parenteral administration The compounds of the invention can also be administered directly into the blood stream, into a muscle or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intra-urethral, intrastemal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including micro needle) injectors, needle free injectors and infusion techniques.

Parenteral compositions are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffering agents (preferably up to a pH of 3 to 9), but for some applications, they may be formulated in a more appropriate manner in the form of a sterile non-aqueous solution or in the form of a dried form for use in combination with a suitable carrier such as sterile, pyrogen-free water.

The preparation of parenteral compositions under sterile conditions, for example by lyophilization, can be easily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Preparations for parenteral administration may be formulated to provide immediate release and / or modified release. Modified release preparations include delayed, sustained, pulsed, controlled, targeted and programmed release preparations. For example, compounds of the invention can be formulated in the form of a solid, a semi-solid or a thixotropic liquid for administration in the form of an implanted depot providing modified release of the active compound. Examples of such compositions include drug-coated stents and poly (dl-lactic acid-co-glycolic acid) - (PGLA) microspheres.

Topical administration

The compounds of the invention can also be administered topically to the skin or mucous membranes, i.e.

15 dermal or transdermal. Typical compositions for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusts, dressings, foams, films, patches, waffles, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used.

Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be included - see, for example, J. Pharm. Sci., 88 (10), 955-958, by Finnin and Morgan (October 1999).

Other means for topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and micro needle or needle free (e.g. Powderject ™, Bioject ™, etc.) injection.

Preparations for topical administration can be formulated to provide immediate release and / or modified release. Modified-release preparations include delayed, sustained, pulsed, controlled, targeted and programmed release preparations.

35 Inhaled / intranasal administration

The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone or in the form of a mixture, e.g. in a dry mixture with lactose, either in the form of a mixed component particle, for example mixed with phospholipids, such as phosphatidylcholine, from a dry powder inhaler or in the form of an aerosol spray from a pressurized container. upright container, pump, spray can, atomizer (preferably an atomizer using electrohydrodynamics to provide a fine mist) or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal application, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurized container, pump, spray can, ver-15. atomizer or nebulizer contains a solution or suspension of the compound (s) of the invention which, for example, ethanol, aqueous ethanol or a suitable alternative means for dispersing, solubilizing agents or extending the release of the active substance, one or more propellants as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligactic acid.

Prior to use in a dry powder or suspension preparation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 μαι). This can be accomplished by any appropriate crushing method, such as spiral-jet-mold and, fluid-bed-jet milling, supercritical-fluid processing to form nanoparticles, high-pressure homogenization, or spray drying.

Capsules (e.g. made from gelatin or hydroxypropyl methylcellulose), blisters and cartridges for use in an inhaler or insufflator can be formulated to form a powder mixture of the invention compound, a suitable powder base such as lactose or starch and a performance modifier such as 1-leucine, mannitol or magnesium stearate. The lactose can be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution preparation for use in a sprayer using electrohydrodynamics to provide a fine mist can contain 1 μg to 20 mg of the compound of the invention per actuation and the actuation volume can vary from 1 μΐ to 100 μΐ.

A typical preparation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavorings, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, can be added to those compositions of the invention intended for inhalation / intranasal administration.

Preparations for inhalation / intranasal administration may be formulated to provide immediate release and / or modified release using, for example, PGLA. Modified-release preparations include delayed, sustained, pulsed, controlled, targeted, and programmed release preparations.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered amount. Units of the invention are typically adjusted to administer a metered dose or "puff" containing 2 to 30 mg of the compound of formula (I). The total daily dose will typically be in the range of 50 to 100 mg, which dose can be administered in a single dose or more commonly as divided doses over the day.

Rectal / intravaginal administration

The compounds of the invention can be rectal or 1027084. - -. - are administered vaginally, for example in the form of a suppository, a pessary or an enema. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate.

Preparations for rectal / vaginal administration can be formulated to provide immediate release and / or modified release. Modified-release preparations include delayed, sustained, pulsed, controlled, targeted, and programmed release preparations.

Ocular / aural administration

The compounds of the invention can also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline solution. Other compositions suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, waffles, lenses, and particulate or vesicular systems such as niosomes or liposotes . A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example hydroxypropyl methylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer, for example gel gum, may be included together with a preservative such as benzalkonium chloride. Such compositions can also be delivered by iontophoresis.

Preparations for ocular / aural administration may be formulated to provide immediate release and / or modified release. Modified-release preparations include delayed, sustained, pulsed, controlled, targeted and programmed release preparations.

35 Other technologies

The compounds of the invention can be combined with soluble macromolecular entities, such as 1027084-J.

As cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, to improve solubility, dissolution rate, taste masking, bioavailability and / or stability thereof for use in one of the aforementioned methods of administration.

Drug-cyclodextrin complexes, for example, have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used in the form of an auxiliary additive, i.e. in the form of a carrier, diluent or solubilizing agent. Most commonly used for these purposes are α, β and γ-cyclodextrins, examples of which can be found in international patent applications WO 91/11172, WO 94/02518 and WO 98/55148.

Combination kit

Since it may be desirable to administer a combination of active compounds, for example, to treat a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which one compound of the invention can be suitably combined in the form of a kit suitable for combined administration of the compositions.

Therefore, the kit of the invention comprises two or more separate pharmaceutical preparations, at least one of which contains a compound of formula (I) according to the invention and means for separately containing said preparations, such as a container, shared bottle or shared foil package . An example of such a kit is the known blister pack used for packaging tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, for example oral and parenteral, for administering the individual compositions in different dosage ranges, or for titrating the dosage forms. individual preparations against each other. To support the ingestion behavior, the kit typically comprises a manual and may be provided with a so-called memory support.

5 Dosage

For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of 50 to 100 mg, of course depending on the mode of administration and efficacy. For example, oral administration may require a total daily dose of 50 to 100 mg. The total daily dose can be administered in a single dose or in divided doses and, at the physician's discretion, may fall outside the typical range given here.

These doses are based on an average person with a weight of approximately 60 to 70 kg. The doctor will certainly be able to determine doses for people whose weight falls outside this range, such as babies and the elderly.

For the avoidance of doubt: when "treatment" is involved, this includes curative, palliative and prophylactic treatment.

Methods

Compounds of the general formula (I) wherein R2 is H, R3 is H and wherein R1, R4, R *, R6, X, V, W, Y and Z are as described herein can be prepared according to reaction scheme 1.

rVLcH, -U ΓΥ ^ ν · νη ’-

halοΛν'-ν H hal ° W "V

(II) (ΊΙ).

halo = CL: or Br iii '

N-N

"-V, Vu V2 R5 (V)

R5

1027084-5 * t - 30 -

Compounds of formula (II) are commercially available or may be prepared by analogy with the methods described in J. Org. Chem., 66 (2), 605-608; 2001 and British Patent Application 2 219 793, December 20, 1989.

Alternatively, when V, W, X or Y = CR 6, compounds of formula (II) can be prepared from commercial compounds using standard chemical reactions and transformations of R 6.

When R 6 is alkoxy, preferably methoxy, R 6 is included by substitution of a functional group, preferably chlorine, as exemplified in Preparations 84-86.

Compounds of formula (III) can be prepared from compounds of formula (II) by process step (i) which comprises reaction with hydrazine monohydrate in a suitable solvent such as methanol or ethanol between -10 ° C and refluxing. Typical conditions include refluxing of 1 eq aryl ester (II) and 1.2-3 eq hydrazine monohydrate in methanol for 18-48 hours.

Compounds of formula (IV) can be prepared from compounds of formula (III) by process step (ii), which comprises: reaction with N, N-dimethylacetamide-dimethylacetal (available from Aldrich) in a suitable solvent such as Ν, Ν-dimethylformamide , N-methylpyrrolidine or toluene followed by addition of a suitable acid catalyst such as trifluoroacetic acid, p-toluenesulfonic acid, camphorsulfonic acid or hydrochloric acid. Typical conditions include heating 1 eq of aryl hydrazide (III) and 1.3 eq of N, N-dimethylacetamide-dimethylacetal in N, N-30-dimethylformamide to 60 ° C for 2 hours, followed by evaporation in vacuo, addition of toluene and 0.025 eq p-toluenesulfonic acid, and then reflux for 2 hours.

Compounds of formula (V) can be prepared from compounds of formula (IV) by process step (iii), which comprises: reaction with a suitable aniline or 3-amino-pyridine in the presence of a suitable acid, such as tri-1027084 ' Fluoracetic acid, p-toluenesulfonic acid, camphorsulfonic acid or hydrochloric acid, in a suitable solvent such as xylene, heated to 150 ° C. Typical conditions include: heating 1 eq 1,2,4-oxadiazole (IV), 2-3 eq aniline or amino-5-pyridine and 0.04-0.1 eq. p-toluene sulfonic acid in xylene at 0 ° C for 18-23 hours.

Compounds of formula (I) can be prepared from compounds of formula (V) by process step (iv), which comprises: a Suzuki coupling reaction with a suitable boronic acid such as 2,3-dimethylphenylboronic acid (commercially available), in a suitable solvent, in the presence of a base and a palladium catalyst such as [2 - [(dimethylamino-KN) methyl] phenyl-KC] (tricyclohexylphosphine) - (trifluoroacetato-κθ- (SP-4-3) -palladium, prepared as be-15 written in Organometalücs, 2003, 22 (5), 987-999.

The Suzuki coupling reaction can be performed as described in the literature: Suzuki, A. Pure & Appl. Chem. 1985, 57, 1749 and literature mentioned therein, · Angew. Chem. Int. Ed. 2002, 41, 4176-4211 and the literature mentioned therein. Typical conditions include heating 1 eq aryl bromide (V), 2.5 eq boronic acid, 3 eq cesium carbonate, 0.06 eq palladium catalyst from Preparation 3 in 1,4-dioxane at 120 ° C for 4 hours.

Compounds of the general formula (I) wherein R 3 is H and wherein R 1, R 2, R 4, R 5, R 6, X, V, W, Y and Z are as described herein, with the exception of R 2 * H, can be prepared according to Reaction Scheme 2 .

35, 1027084-4.

- 32 - jV \ -NH '- / VfyV' * halo ^ w-, V _H halc> w''V H 0

5 halo * -CL or Br 0 »W

I *

^ f ^ YR - * m- fV ^ o ^ R

10 T ^ Z halo ^ vv * ^ (VIII) £ · \ | v (vu) N-N o

15 R W'V

\ Y

Rs 0

Schedule 2 20

Compounds of formula (VI) can be prepared from aryl hydrazides of formula (III) by process step (v), which comprises: reaction with an acid chloride, such as methoxyacetyl chloride (for R2 = OCH3), in the presence of a base such as triethylamine, N-methyl morpholine, sodium carbonate or potassium hydroxide. Typical conditions include: heating 1.0 eq aryl hydrazide (III), 1.0-1.3 eq acid chloride, 1.2-2.0 eq N-methylmorpholine in dichloromethane at 0-25 ° C for 3-18 hour.

Compounds of formula (VII) can be prepared from compound (VI) by process step (vi), which comprises: reaction with a suitable dehydrating agent such as phosphorus oxychloride, trifluoromethanesulfonic anhydride or phosphorus pentachloride at a temperature between 25 ° C and 110 ° C . Typical conditions include: heating 1.0 eq (VI) in phosphorus oxychloride at 110 ° G for 4 hours.

Compounds of formula (VIII) can be prepared from compounds of formula (VII) by process step (iii), which comprises: reaction with a suitable aniline or 3-aminopyridine in the presence of a suitable acid, such as trifluoroacetic acid , p-toluenesulfonic acid, camphorsulfonic acid or hydrochloric acid, in a suitable solvent such as xylene, which is heated to 150 ° C. Typical conditions include heating 1 eq 1,2,4-oxadiazole (VII), 3 eq aniline / aminopyridine and 0.04-0.1 eq p-toluenesulfonic acid in xylene at 150 ° C for 18-22 hours.

Compounds of formula (I) can be prepared from compounds of formula (VIII) by process step (iv), which comprises: a Suzuki coupling reaction as described in Scheme 1.

Compounds of the general formula (I) wherein R 2 is NR 7 R 8 or a 5-7 membered N-linked heterocycle as described herein, R 3 is H and wherein R 1, R 4, R 5, R 6, R 7, R 8, X, V, W, Y and Z are as described herein can be prepared according to Reaction Scheme 3.

jVoH

Halo '^ - V H Hato ^ W', V H o Halo ^ w - V Cl

/ 1V \ W

halo = α or Br (III) w / 25 N-N 2

Halo vv'V Λ u Λ v ^ ° rj ^ 1 ° w-v (XII) r '\ 30 · N-N -

] VnM

J y R * L, z 35 R 5 0)

Schedule 3 t027084-

i I

- 34 -

Compounds of formula (IX) can be prepared from aryl hydrazides of formula (III) by process step (v), which comprises: reaction with a suitable acid chloride, such as chloroacetyl chloride, in the presence of a base such as triethylamine, N-methylmorpholine, sodium carbonate or potassium hydroxide. Typical conditions include: reacting 1.0 eq of aryl hydrazide (III), 1.0-1.3 eq of chloroacetyl chloride, 1.2-2.0 eq of N-methylmorpholine 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 phosphorus oxychloride, trifluoromethanesulfonic anhydride or phosphorus pentachloride at a temperature between 25 ° C and 110 ° C. Typical conditions include: heating 1.0 eq of compound (IX) in phosphorus oxychloride at 110 ° C for 4 hours.

Compounds of formula (XI) can be prepared from alkyl chlorides of formula (X) by process step 20 (vii), which comprises: reaction with a suitable primary or secondary amine (HNR7R8) 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-dimethylformamide, by heating at 25-50 ° C for 2-18 hours. Typical conditions include: reacting 1 eq of alkyl chloride (X), 1.5 eq of amine (HNR 7 R 8) or a 5-7 membered N-linked heterocycle and 2 eq of potassium carbonate in acetonitrile for 18 hours at 25 ° C.

Compounds of formula (XII) can be prepared from compounds of formula (XI) by process step (iii), which comprises: reaction with a suitable aniline or 3-aminopyridine, in the presence of a suitable acid, such as trifluoroacetic acid, p-toluenesulfonic acid, camphorsulphonic acid or hydrochloric acid, in a suitable solvent, such as xylene, heated to 150 ° C. Typical conditions include: heating 1 eq. 1, 2,4-oxadiazole (XI), 3 eq.

line / aminopyridine and 0.04-0.1 eq p-toluenesulfonic acid in xylene at 150 ° C for 18-24 hours.

Compounds of formula (I) can be prepared from compounds of formula (XII) by process step (iv), which comprises: reaction with a suitable boronic acid such as 2,3-dimethylphenylboronic acid (commercially available), in a suitable solvent, in presence of a suitable base and palladium catalyst as described in Scheme 1.

Compounds of the general formula (I) wherein R 1, R 2, R 3, R 4, R 5, R 6, X, V, w, Y and Z are as described herein can alternatively be prepared according to Reaction Scheme 4.

halo ^ WiV R * ^ weV R W'v 15 (ii) (XIII) {m

Viii

N-N, T

Γ N-N,

JfVoNT

Γ T rv ^ w = v rs 20 T egg m

Schedule 4

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

Compounds of the general formula (XIII) can be prepared from compounds of the general formula (II) by process step (iv) as described in Scheme 1.

Compounds of the general formula (XIV) can be prepared from compounds of the general formula (XIII) by process step (i) as described in Scheme 1.

When R2 = H, compounds of the general formula (XV) can be prepared from compounds of the general formula (XIV) by process step (viii), using a method analogous to process step (ii), as described in Scheme 1.

When R2 Φ H, compounds of the general formula (XV) can be prepared from compounds of the general formula (XIV) by process step (viii), using methods analogous to the steps ( v) and (vi), as described in Scheme 2, or steps (v), (vi) and (vii), as described in Scheme 3.

Compounds of the general formula (I) can be prepared from compounds of the general formula (XV) by process step (iii), as described in Scheme 1.

Compounds of the general formula (I) wherein X is C-R6, R3 is H and wherein R1, R2, R4, R5, R6, V, W, Y and Z are as described herein can alternatively be prepared according to Reaction Scheme 5.

i'VCNH "j'VCNt

15 ^ w-v (| V) R

h - N-N j FVV - ^ - R 3 N-N 2

piYl v V «« χ-Ύν Jt \ __. R

w "ArR" "0s

20 L Z H WsV

Y (XV) k -ro

Schedule 5

Compounds of formula (III) are prepared as described in Scheme 1.

When R2 = H, compounds of the general formula (IV) can be prepared from compounds of the general formula (III) by process step (viii), using a method analogous to process step (ii), as described in Scheme 1.

When R2 * H, compounds of the general formula (IV) can be prepared from compounds of the general formula (III) by process step (viii), using methods analogous to steps (v) and (vi), as described in Scheme 2, and steps (v), (vi) and (vii) as described in Scheme 3.

Compounds of the general formula (XV) can be obtained.

Prepared from compounds of the general formula (IV) by process step (iv) as described in Scheme 1.

Compounds of the general formula (I) can be prepared from compounds of the general formula (XV) by process step (iii) as described in Scheme 1.

Compounds of the general formula (I) and (VIII) wherein R1, R2, R4, R5, v, w, X and Y are as described herein and R3 = H can be prepared according to Reaction Scheme 6.

10 x x, J-W

X-YVJ? 1x, J

, J n'nh> -► R w'-v X, R4 «V H rj (XIV) (I) k" o riJTLS.

, NH, 1x J1 Y (.R

Y T ^ N * - halo-V-V Ia *

hato ^ Vv H riT

(III) (VIII) R5 Scheme 6

Compounds of formula (I) and (VIII) can be prepared from compounds of formula (XIV) and "(III), respectively, by process step (ix), which comprises: sequential reaction with a dimethylacetamide-dimethylacetal in a suitable solvent such as tetrahydofuran or acetic acid heated to 55-60 ° C followed by reaction with a suitable aniline or aminopyridine in the presence of a suitable acid such as acetic acid heated to 90-100 ° C. Typical conditions include: heating 1.0 eq acyl hydrazide, 1, 5 eq dimethylacetamide-dimethylacetal (Aldrich) in THF at 55 ° C for 2 hours followed by addition of 1.5 eq 2-methoxy-5-aminopyridine (Aldrich) and heating in acetic acid at 90 ° C for 5 hours.

35 All the above reactions and the preparations of! new starting materials described in the above methods are conventional and appropriate reagents and reagents.

'- 38.

action conditions for the implementation or preparation thereof, as well as procedures for isolating the desired products are well known to those skilled in the art on the basis of literature precedents and the accompanying Examples 5 and Preparations.

Applicability

The compounds of the invention are useful because they have pharmacological action in mammals, including humans. More particularly, they are useful in the treatment or prevention of a condition in which modulation of the levels of oxytocin could provide a beneficial effect. Disease states that may be mentioned include sexual dysfunction, in particular premature ejaculation, preterm contractions, contractions in contractions, appetite and eating disorders, benign prostatic hyperplasia, preterm delivery, dysmenorrhea, congestive heart failure, arterial hypertension, cirrhosis of the liver rot ische hypertension, ocular hypertension, obsessive compulsive disorder and neuropsychiatric disorders.

Sexual dysfunction (SD) is a significant clinical problem that can affect both men and women.

The causes of SD can be both organic and psychological. Organic aspects of SD are typically caused by underlying vascular diseases, such as those associated with hypertension or diabetes mellitus, by prescribed medication and / or by psychiatric illness such as depression. Physiological factors include anxiety, failure anxiety and interpersonal conflicts. SD reduces sexual performance, reduces self-esteem and disrupts personal relationships, causing personal stress. In the clinic, SD disorders are subdivided into female sexual dysfunction disorders (FSD) and male sexual dysfunction disorders (MSD) (Melman 35 et al., J. Urology, 1999, 161, 5-11).

FSD can be described as the difficulty or inability of a woman to find satisfaction in sexual 1027084 expression. FSD is a collective name for various sexual disorders in women {Leiblum, S.R. (1998). Definition and classification of female sexual disorders. Int. J. Impotence Res. 10, S104-S106; Berman, J.R. " Berman, L. & 5 Goldstein, I. (1999). Female sexual dysfunction: Incidence, pathophysiology, evaluations and treatment bptions. Urology, 54, 385-391). The woman may suffer from little sense, it may be difficult to get excited or orgasm, may have sexual intercourse or a combination of these problems. Various types of illness, medication, injuries or psychological problems can cause FSD. Treatments under development are aimed at treating specific subtypes of FSD, mainly disorders in sense and excitement.

15 The categories of FSD are best described by contrasting them with the phases of the woman's normal sexual response: sense, arousal and orgasm (Leiblum, SR (1998). Definition and classification of female sexual disorders, Int. J. Impotence Res. 10, S104-S106). Sentence 20 or libido is the engine for sexual expression. Its manifestations often include sexual thoughts either in the company of an interested partner or when exposed to other erotic stimuli. Excitement is the vascular response to sexual stimulation, an important component of which is genital congestion, and includes increased vaginal lubrication, vagina lengthening, and increased genital sensation / sensitivity. Orgasm is the release of the sexual tension that has accumulated during the excitement.

30 There is therefore FSD when a woman has an inadequate or insufficient response in one of these phases, usually sense, excitement or orgasm. FSD categories include hypoactive sense-in-sex disorder, sexual arousal disorder, orgasmic disorders, and sexual pain disorders. Although the compounds of the invention will improve the genital response to sexual stimulation (such as in female sexual arousal disorder), they may also reduce the associated pain, stress and discomfort associated with sexual intercourse and thus reduce other treat sexual disorders in women.

Thus, according to 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 sense-in-sex disorder, sexual arousal disorder, orgasmic disorder and sexual pain disorder, more preferably for the treatment or prophylaxis of sexual arousal disorder, orgasmic disorder and sexual pain disorder, and most preferably for the treatment or prophylaxis of sexual arousal disorder.

Hypoactive sense-in-sex disorder is present if a woman has little or no desire to have sex and has little or no sexual thoughts or fantasies. This type of FSD can be caused by low testosterone levels, due to either natural menopause or surgical menopause. Other causes include illness, medication, fatigue, depression, and anxiety. Female sexual arousal disorder (FSAD) is characterized by inadequate genital response to sexual stimulation. The genitals do not undergo congestion that characterizes normal sexual arousal. The vaginal walls are poorly lubricated, making sexual intercourse painful.

25 Orgasms can be inhibited. Arousal disorder can be caused by reduced estrogen during menopause or after delivery and during lactation, as well as by diseases, with vascular components such as diabetes and atherosclerosis. Other causes result from treatment with diuretics, antihistamines, antidepressants, for example SSRIs or antihypertensive agents.

Sexual pain disorder (includes dispareunia and vaginism) is characterized by pain resulting from penetration and may be caused by medications that reduce lubrication, endometriosis, pelvic inflammatory disease, bowel inflammatory disease, or urinary tract problems.

The prevalence of FSD is difficult to calibrate because the term 1027004 covers several problem types, some of which are difficult to measure and because the interest in treating PSD is relatively recent. Many women's sexual problems are associated either directly with the woman's aging process or with chronic diseases such as diabetes and hypertension.

Because FSD consists of various subtypes that give symptoms in separate phases of the sexual response cycle, there is not a single therapy. The current treatment of 10 FSD is mainly focused on psychological or relational aspects. The treatment of FSD develops gradually as more clinical and fundamental scientific studies are dedicated to investigating this medical problem. Sexual complaints in women are not all psychologically in pathophysiology, in particular for those persons who may have a component of vasculogeneic dysfunction (for example FSAD) that contributes to the woman's total sexual complaint. There are currently no medicines allowed for the treatment of FSD. Empirical drug therapy includes the administration of estrogen (topically or as hormone replacement therapy), androgens or mood-altering drugs such as buspiron or trazodone. These treatment options are often unsatisfactory due to low efficacy or unacceptable side effects. American Psychiatry Association's Diagnostic and Statistical Manual (DSM) IV defines sexual arousal disorder in women (FSAD) as: "a persistent or recurring inability to complete sexual activity lubrication / swelling response to sexual arousal to achieve or maintain. The disorder must cause clear personal or interpersonal problems. "

The excitement response consists of vasocongestion in the pelvis, vaginal lubrication and expansion and swelling of the external genitalia. The disorder causes clear personal and / or interpersonal problems.

1027084-4.

-42- /.

FSAD is a common sexual disorder that affects pre-, peri- and post-menopausal (± HRT) women. It is accompanied by accompanying disorders such as depression, cardiovascular diseases, diabetes and urogenital disorders.

The primary consequences of FSAD are lack of congestion / swelling, lack of lubrication and lack of pleasant genital sensation. The secondary consequences of FSAD are less sense of sex, pain during sexual intercourse 10 and difficulty in reaching an orgasm.

Male sexual dysfunction (MSD) is generally associated with erectile dysfunction, also known as male erectile dysfunction (MED) and / or ejaculation disorders such as premature ejaculation, anorgasmia (unable to orgasm) or sun disorders such as hypoactive sense-in-sex disorder (lack of interest in sex).

PE is a relatively common sexual dysfunction in men. It has been described in various different ways, 20 but the most generally accepted definition is that of the Diagnostic and Statistical Manual of Mental Disorders IV, which reads: "PE is a lifelong sustained or recurrent ejaculation with minimal sexual stimulation, before, during, or shortly after penetration and before the patient wants it.The practitioner must take into account factors that influence the duration of the excitement phase, such as age, novelty of the sexual partner or stimulation, and frequency of sexual activity.The disorder causes a clear personal or interpersonal problem. "

The definition of the International Classification of Diseases 10 is: "One is unable to postpone the ejaculation sufficiently to enjoy the act of love, as evidenced by one of the following points: (1) ejaculation occurs before or very soon after the commencement of sexual intercourse (if a time limit is required: before or within 15 sec. 1027084-.

after sexual intercourse); (2) ejaculation takes place in the absence of sufficient erection to allow sexual intercourse. The problem is not the result of long-term abstinence from sexual activity. "

Other definitions used include classification based on the following criteria: - related to partner's orgasm - time lapse between penetration and ejaculation 10 - number of shocks and ability to consciously control

Psychological factors can be involved in PE, in which relationship problems, anxiety, depression, and earlier sexual failure all play a role. :

Cum is dependent on the sympathetic and parasympathetic nervous system. Drain impulses through the sympathetic nervous system to the ductus deferens and the epididymis cause smooth muscle contraction, through which sperm is transported to the posterior urethra. Similar contractions of the seminal vesicles, the prostate glands and the bulbulal glands increase the volume and fluid content of the semen. Semen rejection is mediated by expulsion impulses from a population of lumbar spinothalamic cells in the lum-bosacral spinal cord (Coolen & Truitt, Science, 2002, 297, 25 '1566) that go through the parasympathetic nervous system and rhythmic contractions of the bulbocaverous nose, ischiocaver - cause nasal and pelvic floor muscles. Cortical control of ejaculation is still under discussion in humans. In the rat, the medial pre-optic region and the paraventricular core of the hypothalamus appear to be involved in ejaculation.

Ejaculation includes two separate components - emission and ejaculation. Emission is the introduction of seminal fluid and sperm from the distal epididymis, the ductus deferens, the seminal vesicles and the prostate into the prostate urethra. After this deposition, powerful ejection of the seminal content from the urethral meatus takes place.

ί027084- 4, - 44 -

Ejaculation can be distinguished from orgasm, which is purely a cerebral event. The two processes often coincide.

A pulse of oxytocin in peripheral serum is accompanied by ejaculation in mammals. In the male, the oxytocin but not the vasopressin plasma concentration is significantly increased at or around ejaculation. Oxytocin does not itself lead to ejaculation; this process is 100% under nerve control via alpha-adrenoceptor / sympathetic nerves that spring into the lumbar region of the spinal cord. The systemic oxytocin pulse may play a role in the peripheral ejaculation response. It could serve to modulate the contraction of channels and glandular lobes that are located everywhere in the male genital tract, and thus, for example, influence the fluid volume of various ejaculate components. Oxytocin released centrally in the brain could affect sexual behavior, subjective appreciation of arousal (orgasm), and latency for subsequent ejaculation.

Therefore, one aspect of the invention provides the use of a compound of formula (I), without the condition, in the preparation of a medicament for the prevention or treatment of sexual dysfunction, preferably male sexual dysfunction, with the most prefer premature ejaculation.

The scientific literature has shown that the number of oxytocin receptors in the uterus increases during pregnancy, most clearly before the onset of contractions (Gimpl & Fahrenholz, 2001, Physiological Reviews, 81 (2), 629-683). Without being bound by any theory: it is known that the inhibition of oxytocin pretention can help prevent contractions and help resolve complications in contractions.

Another aspect of the invention therefore provides the use of a compound of formula (I), without the condition, in the preparation of a medicament for the 1027084-J.

- 45 - prevention or treatment of preterm contractions and complications in contractions.

Oxytocin plays a role in food; it reduces appetite (Arletti et al., Peptides, 1989, 10, 89). By inhibiting oxytocin, it is possible to increase the appetite. Oxytocin inhibitors are therefore useful in the treatment of appetite and eating disorders.

A further aspect of the invention therefore provides the use of a compound of formula (I), without the condition, in the preparation of a medicament for the prevention or treatment of appetite and eating disorders.

Oxytocin has been mentioned as one of the causes of benign prostatic hyperplasia (BPH). Analysis of prostate tissue has shown that patients with BPH have elevated levels of oxytocin (Nicholson & Jenkin, Adv. Exp. Med. & Biol., 1995, 395, 529). Oxytocin antagonists can help treat this condition.

Another aspect of the invention therefore provides the use of a compound of formula (I), without the condition, in the preparation of a medicament for the prevention or treatment of benign prostatic hyperplasia.

Oxytocin plays a role in the causes of dysmal norrhoea by virtue of its activity as a uterine vaso constrictor (Akerlund, Ann. NY Acad. Sci., 1994, 734, 47). Oxytocin antagonists can have a therapeutic effect on this condition.

A further aspect of the invention thus provides the use of a compound of formula (I), without the condition, in the preparation of a medicament for the prevention or treatment of dysmenorrhea.

It is to be understood that all references herein to treatment include curative, palliative and prophylactic treatment.

The compounds of the present invention can be administered simultaneously with one or more agents 1027084-46 selected from: 1) one or more selective serotonin reuptake inhibitors (SSRIs) such as dapoxetine, paroxetine, 3 - [(dimethylamino)] methyl] -4- [4- (methylsulfanyl) phenoxy] benzene-5sulfonamide (Example 28, WO 0172687), 3 - [(dimethylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzene sulfonamide (Example 12, WO 0218333), N-methyl-N - ({3- [3-methyl-4- (methylsulfanyl) phenoxy] -4-pyridinyl} methyl) amine (Example 38, PCT- application PCT / IB 02/01032).

2) one or more local anesthetics; 3) one or more α-adrenergic receptor antagonists (also known as α-adrenoceptor blockers, α receptor blockers or α blockers); suitable al-adrenergic receptor antagonists include: phentolamine, prazosin, phentolamine ne mesylate, trazodone, alfuzosin, indoramine, naphthopidil, tamsulosin, phenoxybenzamine, rauwolfa alkaloids, Recordati 15/2739, SNAP 1069, SNAP5389, SNAP5389 , SL 89.0591, doxazosin, Example 19 of WO 9830560, terazosin and abanoquil; suitable α2-adrenergic receptor antagonists include dibenamine, tolazoline, trimazosin, epharoxane, yohimbine, idazoxan clonidine and dibenamine; suitable non-selective α-adrenergic receptor antagonists include dapiprazole; further α-adrenergic receptor antagonists are described in PCT application WO 99/30697, published June 14, 1998, and U.S. Patent Nos. 4,188,391; 4,026,894; 3,511,836; 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4 703 063; 3 381 009; 4,225,721 and 2,599,000, each of which is incorporated herein by reference; 4) one or more cholesterol-lowering agents such as statins (for example atorvastatin / lipitor (trade mark) and fibrates; 5) one or more of a serotonin receptor agonist, antagonist or modulator, more particularly agonis-35 antagonists or modulators, for example 5HT1A,

5HT2A, 5HT2C, 5HT3, 5HT6 and / or 5HT7 receptors, including those described in WO 09902159, WO 00002550 and / or WO

1027084 - 47 -.

00028993; 6) one or more NEP inhibitors, preferably wherein said NEP is EC 3.4.24.11 and more preferably wherein said NEP inhibitor is a selective inhibitor for EG 3.4.24.11, more preferably is a selective NEP inhibitor a selective inhibitor for EC 3.4.24.11, which has an IC50 of less than 100 nM (for example ompatrolat, sampatrilat). Suitable NEP inhibitor compounds are described in EP-A-1,097,719; IC50 values against NEP and ACE can be determined using methods described in the published patent application EP 1 097 719-A1, paragraphs [0368] to [0376]; 7) one or more antagonists or modulators for vasoppressin receptors, such as relcovaptan (SR 49059), conivaptan, atosiban, VPA-985, CL-385004, Vasotocin.

8) Apomorphine - a description of the use of apomorphine as a pharmaceutical can be found in US-A-5 945 117; 9) Dopamine agonists (in particular selective D2, selective D3, selective D4 and selective D2-like agents) such as Pramipexole (Pharmacia Upjohn compound number PNU-95666), ropiniole, apomorphine, surmaniroole, chinelorane, PNU-142774, bromcriptine , carbergoline, Lisuride; 10) Melanocortin receptor agonists (for example

Melanotan II and PT 141) and selective MC3 and MC4 agonists (for example THIQ) 11) Monoamine transport inhibitors, in particular noradrenaline reuptake inhibitors (NRIs) (for example Reboxetine), other serotonin reuptake inhibitors ( SRIs) (e.g., paroxetine, dapoxetine) or dopamine reuptake inhibitors (DRIs); 12) 5-HT 2a antagonists (e.g., robalzotan); and 13) PDE inhibitors such as PDE2 (for example ery-thro-9- (2-hydroxyl-3-nonyl) adenine) and Example 100 of EP 0 771 799 - incorporated herein by reference) and in particular a PDE5- inhibitor such as the pyrazolo [4,3-d] pyri-1027084-48-midin-7-ones described in EP-A-0 463 756; the pyrazolo [4,3-d] pyrimidine-7-ones described in EP-A-0 526 004; the pyrazolo [4,3-d] pyrimidine-7-ones described in the published international patent application WO 93/06104; the isomeric pyrazolo [3,4-d] pyrimidine-4-ones described in published international patent application WO 93/07149; the quinazoline-4-ones described in the published international patent application WO 93/12095; the pyrido [3,2-d] pyrimidin-4-ones described in the published international patent application WO 94/05661; the purine 6-oxides described in the published international patent application WO 94/00453; the pyrazolo [4,3-d] pyrimidin-7-ones described in published international patent application WO 98/49166; the pyrazolo [4,3-d] pyrimidin-7-ones described in the published international patent application WO 99/54333; the pyrazolo [4,3-d] pyrimidine-4-ones described in EP-A-0 995 751; the pyrazolo [4,3d] pyrimidine-7-ones described in the published international patent application. WO 00/24745; the pyrazolo [4,3-d] pyrimidine-4-ones described in EP-A 0 995 750; the compounds described in published international application WO 95/19978; the compounds described in the published international application WO 99/24433 and the compounds described in the published international application WO 93/07124; the py-razolo [4,3-d] pyrimidine-7-ones described in the published international application WO 01/27112; the pyrazolo [4,3-d] pyrimidine-7-ones described in published international application WO 01/27113; the compounds described in EP-A-1 092 718 and the compounds described in EP-A-1 092 719.

Preferred PDE5 inhibitors for use with the invention are: 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H -pyrazolo [4,3-d] pyrimi-35-dine-7-one (sildenafil), also known as 1 - [[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1H]) pyrazolo [4,3d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl] -4-methylpiperazine (see EP-A-0 1027084-49 - 463 756); 5- (2-ethoxy-5-morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7 H -pyrazolo [4,3-d] pyrimidin-7-one (see EP-A-0 526 004); 3-ethyl-5- [5- (4-ethylpiperazine-1-ylsulfonyl) -2-n-propoxyphenyl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7 H -pyrazolo [4, 3-d] pyrimidine-7-one (see WO 98/49166); 3-ethyl-5- [5- (4-ethylpiperazine-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl) -2- (pyridin-2-yl) methyl-2,6-10 dihydro 7 H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 99/54333); (+) - 3-ethyl-5w [5- (4-ethylpiperazine-1-ylsulfonyl) -2- (2-methoxy-1- (R) -methylethoxy) pyridin-3-yl] -2-methyl-2 6-dihydro-7 H -pyrazolo [4,3d] pyrimidin-7-one, also known as 3-ethyl-5- {5- [4-ethylpiperazine-1-ylsulfonyl] -2 - ([(IR) - 2-methoxy-1-methylethyl] oxy) pyridin-3-yl} -2-methyl-2,6-dihydro-7 H -pyrazolo [4,3-d] pyrimidin-7-one (see WO 99/54333); 5- [2-ethoxy-5- (4-ethyl-piperazine-1-ylsulphonyl) -pyridin-3-yl] -3-ethyl-2-t 2-methoxy-ethyl] -2,6-dihydro-7 H -pyrazolo [4,3-d) pyrimidin-7-one, also known as 1- {6-ethoxy-5- [3-ethyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-] pyrazolo [4,3-d] pyrimidin-5-yl) -3-pyridylsulfonyl} -4-ethyl-piperazine (see WO 01/27113, Example 8); 5- [2-iso-butoxy-5- (4-ethyl-piperazine-1-ylsulphonyl) -pyridin-3-yl] -3-ethyl-2- (1-methyl-piperidin-4-yl) -2,6-dihydro 7 H -pyrazolo [4,3-d] pyrimidin-7-one (see WO 01/27113, Example 15); 5- [2-Ethoxy-5- (4-ethyl-piperazine-1-ylsulphonyl) -pyridin-3-yl] -3-ethyl-2-phenyl-2,6-dihydro-7 H -pyrazolo [4,3- d] pyrimidine-7-one (see WO 01/27113, Example 66); 5- (5-Acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7 H -pyrazolo [4 (3-d] pyrimidine -7-one (see WO 01/27112, Example 124); 5- (5-Acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) - 2,6-dihydro-7 H -pyrazolo [4,3-d] pyrimidin-1-one (see WO 01/27112, Example 132); 1027084¾ -50->, (6R, 12aR) -2.3.6, 7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) pyrazino [2 ', 1': 6,11-pyrido [3,4-b] indole-1,4-dione ( IC-351), ie the compound of Examples 78 and 95 of the published international application WO 95/19978, as well as the compound of Examples 1, 3, 7 and 8; 2- [2-ethoxy-5 - (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3 H -imidazo [5,1-f] [1,2,4] triazine-4-one (vardenafil) also known as 1 - [[3- (3,4-dihydro-5-10 methyl-4-oxo-7-propylimidazo [5,1-f] ash-triazin-2-yl) -4- ethoxyphenyl] sulfonyl] -4-ethyl piperazine, ie the compound of Examples 20, 19, 337 and 336 of published international application WO 99/24 433; and the compound of Example 11 of the published international application WO 93/07124 (EISAI), * and the compounds 3 and 14 from Rotella D.P .., J. Med. Chem. 2000, 43, 1257.

Still further PDE5 inhibitors for use according to the invention include: 4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) propoxy] (2H) pyridazinone; 1- [4 - [(1,3-benzodioxol-5-ylmethyl) -amiono] -6-chloro-2-quinozolinyl] -4-piperidine-carboxylic acid monosodium salt, · (+) -cis-5, 6a, 7,9,9,9a-hexahydro-2- [4- (trifluoromethyl) -phenylmethyl-5-methylcyclopent- [4,5] -25 imidazo [2,1b] purine-4 (3 H) -one; furaziocillin; cis-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydrocyclopent [4,5] imidazo [2,1-b] purine-4-one; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 4-bromo-5- (3-pyridylmethyl-30 amino) -6- (3- (4-chlorophenyl) propoxy) -3- (2H) pyridazinone; 1-methyl-5- (5-morpholinoacetyl-2-n-propoxyphenyl) -3-n-propyl-1,6-dihydro-7 H -pyrazolo (4,3-d) pyrimidine-7-one; 1- [4 - [(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid monosodium salt; Pharmaprojeets 35 No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa Hakko; see WO 96/26940); 1027084-> * - 51 -

Pharmaprojects No. 5069 (Schering Plow); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer) and Sch-51866.

The contents of the published patent applications and journal articles and in particular the general formulas of the therapeutically active compounds of the claims and the compounds mentioned therein are incorporated 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-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1, 6-dihydro-7 H -pyrazolo [4,3-d] pyrimidine-7-one (sildenafil); 15 (6R, 12aR) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl-pyrazino [2 ', 1': 6.1] pyrido [3, 4- b] indole-1,4-dione (IC-351); 2- [2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl] -5-methyl-7 -propyl-3 H -imidazo [5,1f] [1,2,4] triazine-4-one (vardenafil), and 5- [2-ethoxy-5- (4-ethylpiperazine-1-ylsulfonyl) pyridine] -3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7 H -pyrazolo [4,3-d] pyrimidin-7-one or 5- (5-acetyl-2) -butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7 H -pyrazolo [4,3-d] pyrimidine-7-one and pharmaceutically acceptable salts thereof.

A particularly preferred PDE5 inhibitor is 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7 H -pyrazolo [4, 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] sulfonyl] -4-methylpiperazine) and pharmaceutically acceptable salts thereof. Sildenafil citrate is a preferred salt.

.35 Preferred agents for administration simultaneously with the compounds of the present invention are PDE5 inhibitors, selective serotonin reuptake inhibitors 10270843 - 52 - (SSRIs), vasopressin V1A antagonists, α-adrenergic receptor antagonists, NEP inhibitors, dopamine agonists and melanocortin receptor described above. Particularly preferred agents for co-administration are PDE5 inhibitors, SSRIs and V1A antagonists as described herein.

Assay

A suitable assay for determining the oxytocin antagonistic action of a compound is detailed below.

Oxytocin * · Receptor β-lactamase Assay Materials:

Cell culture / Reagents A: cell culture 15 Nutrient mixture F12 Ham

Fetal bovine serum (FBS)

Geneticin

Zeocin

Trypsin / EDTA

PBS (phosphate buffered saline)

HEPES

B: reagents Oxytocin OT receptor-specific antagonist

Dimethyl sulfoxide of molecular purity (DMSO) Trypan Blue Solution 0.4% CCF4-AM (Solution A)

Pluronic Fl27s (Solution B) 30 24% PEG, 18% TR40 (Solution C)

Probenecid (Dissolved in an amount of 200 mM in 200 mM NaOH, Solution D)

Methods

Cell culture The cells used are CHO-OTR / NFAT-E-Lactamase. The NFAT-B lactamase expression construct was transfected into the CHO-OTR cell line and clonal populations were isolated.

1027084-0% - 53 - learned via fluorescence-activated cell sorting (FACS).

An appropriate clone was chosen to develop the assay.

Growth medium

5 90% F12 Nutrient mixture, 15 mM HEPES

10% FBS

400 µg / ml Geneticin 200 µg / ml Zeocin 2 mM L-Glutamine 10 Assay medium

99.5% F12 nutrient mixture, 15 mM HEPES 0.5% FBS

Cell recovery - A frozen cell vial is rapidly thawed in a 37 ° C water bath and the cell suspension is transferred to a T225 flask with 50 ml of fresh culture medium and then incubated at 37 ° C, 5% CO 2 in an incubator until the cells adhered to the flask. Replace the medium the next day with 50 ml of fresh culture medium.

Culture cells - CHO-OTR-NFAT-Ê-Lactamase cells were grown in culture medium. Cells were harvested when they reached 80-90% confluence, removing the medium and washing with preheated PBS. PBS was then removed and Trypsin / EDTA was added (3 ml for a T225 cm * flask) before incubating for 5 minutes in an incubator at 37 ° C / 5% CO2. When the cells were detached, preheated culture medium was added (7 ml for a T225 cm * flask) and the cells were resuspended and gently mixed by pipetting to achieve a single cell suspension. The cells were split in a T225 flask in a ratio of 1:10 (for 3 days of culturing) and of 1:30 (for 5 days of culturing) in 35 ml of culture medium. β-Lactamase assay method 35 DAY 1

Cell plate preparation

Cells grown at 80-90% confluence were harvested WO02 7084 - ---- -: ---- -: -: _: _ - 54 - ψ% harvest and counted. Cell suspensions with 2 x 10 5 cells / ml in culture medium were prepared and 30 μΐ cell suspension was added to 384 well-cleared black plate plates. A blank plate containing diluent from each reagent was used for background subtraction.

Plates were incubated overnight at 37 ° C / 5% CO 2.

DAY 2

Stimulation of the cells - 10 μΐ antagonist / compound (diluted in assay medium 10 containing 1.25% DMSO = antagonist diluent) was added to appropriate wells and incubated for 15 min at 37 ° C, 5% CO 2.

10 μΐ oxytocin prepared in assay medium was added to all wells and incubated for 4 hours at 37 ° C, 5% CO 2.

- A separate 384 well cell plate was used to generate an oxytocin dose response curve.

(10 μΐ antagonist diluent was added to each well. 10 μΐ oxytocin was then added. The 20 cells are then treated in the same manner as the antagonist / compound cell plates).

Preparation of 1 ml 6 x loading buffer with improved loading protocol (this requires scaling up depending on the number of plates to be screened) 25 - 12 μΐ of solution A (1 mM CCF4-AM in dry DMSO) was added to 60 μΐ of solution B (100 mg / ml of Pluonic F127 in DMSO + 0.1% acetic acid) and vortexed.

- The resulting solution was added to 925 μΐ of solution C (24% by weight PEG 400, 18% by volume TR40 in water).

- 75 μΐ of solution D was added (200 mM pro-benecid in 200 mM NaOH).

10 μΐ 6 x loading buffer was added to all wells and incubated for 1.5-2 hours at room temperature in the dark.

- The plates were read using an LJL Analyst, Excitation 405 nm, Emission 450 nm and 530 nm, 1027084 - optimal gain, delay time 0.40 με integration, 4 flashes, bottom reading.

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

The compound of Example 8 has a Ki value of 10 3 nM.

The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used: Arbocel® Filtration Agent, from J. Rettenmaier & Sohne,

Germany APCI + Chemical ionization at atmospheric pressure (positive scan) CDC13 Chloroform-dl 20 d Doublet dd Doublet of doubles DMSO Dimethyl sulfoxide ES + Electrospray ionization positive scan.

eq. Equivalent 25-H NMR Kemspin resonance spectroscopy MS (Low resolution) mass spectroscopy m Multiplet m / z Mass spectrometry q Quartet 30 s Singlet t Triplet 8 Chemical shift

Preparation 1 35a [2 - [(Dimethylamino-KN) methyl] phenyl-KC] bis [μ- (trifluoroacetato-KO: KO ')] palladium 1027084- * * - 56 - O- ^ NMe,

/ yCI

Cl-PdV ^ 5 Me ^ N 1 /

To a suspension of palladium chloride (3.43 g, 19.4 mmol) in methanol (200 ml) under nitrogen at room temperature was added N, N-dimethylbenzylamine (5.82 ml, 38.7 mmol) via a syringe . The resulting red / brown suspension was stirred at room temperature for 24 hours. The now green / brown suspension was evaporated in vacuo to remove methanol, redissolved in dichloromethane (150 ml) and passed through a pad of silica gel with flushing with dichloromethane. The resulting clear yellow filtrate was evaporated in vacuo and recrystallized from dichloromethane / ether to provide the desired product, 4.66 g.

20 ΧΗ NMR (CDCl 3, 300 MHz) δ: 2.86 (s, 6H), 2.89 (s, 6H), 3.95 (S, 4H), 6.84-7.24 (m, 8H)

Preparation 2 bis (2 - [(Dimethylamino-KN) methyl] phenyl-KC] bis [11- (trifluoroacetato KO: KO ')] palladium

Co 30 “Öq 35 To a solution of silver trifluoroacetate (4.48 g, 20.3 mmol) in acetone (30 ml) under nitrogen at room temperature was added a solution of the complex of Preparation 1027084 - 57 - 1 (5, 60 g, 10.15 mmol) in dichloromethane (100 ml) added. A thick white precipitate appeared during the addition. The suspension was stirred for 15 minutes and then filtered through a silica gel pad, rinsing with dichloromethane. Evaporation in vacuo gave a clear yellow powder which was recrystallized from dichloromethane / ether to give the desired product, 7.06 g.

NMR (CDCl 3, 300 MHz) δ: 2.05 (s, 6H), 2.88 (s, 6H), 3.18 (d, 2H), 3.63 (d, 2H), 6.89- 6.97 (m, 6H), 7.00r7, 10 (m, 2H).

Preparation 3 [2 - [(Dimethylamino-KN) methyl] phenyl-KC] (tricyclohexyl-phosphine) (trifluoroacetato-κθ- (SP-4-3) -palladium 15 sNMe2 F3CCO / PCy3 20

To a solution of the product of Preparation 2 (6.43 g, 9.10 mmol) in dichloromethane (50 ml) under nitrogen at room temperature was added a solution of tricyclohexylphosphine (6.89 g, 24.5 mmol) in dichloromethane (20 ml) added. After stirring for 1 hour, the solution was passed through a plug of silica gel (7 cm x 2 cm) under rinsing with dichloromethane (400 ml) and the pale yellow filtrate was evaporated in vacuo. Recrystallization from dichloromethane / ether gave the desired complex, 10.53 g.

30 * H NMR (CDCl 3, 300 MHz) δ: 1.05-2.30 (m, 33H), 2.57 (S, 3H), 2.58 (s, 3H), 3.93 (s, 2H ), 6.86-6.98 (m, 3H), 7.10-7.12 (m, 1H).

Preparation 4 2- (4-Bromo-phenyl) -5-methyl- [1,3,4] oxadiazole 35 r-th TH

Br 4 O 4 CH 3 f027084-4-Bromo-benzoic acid hydrazide (12.90 g, 60 mmol) and N, N-dimethylacetamide-dimethylacetal (12 ml, 82.0 mmol) were dissolved in N, N-dimethylformamide (100 ml) and the solution was heated to 60 ° C for 2 hours. The solution was evaporated in vacuo and the residue was taken up in toluene (80 ml) and treated with p-toluenesulfonic acid monohydrate (200 mg, 1.50 mmol). The mixture was heated to reflux for 2 hours, allowed to cool, and the product was crystallized from the solution and collected by filtration. The crude product was washed with ether and dried under vacuum to provide a white solid. The filtrate was evaporated in vacuo and the residue was combined with the white solid, dissolved in toluene (50 ml) and treated with p-toluene sulfonic acid monohydrate (100 mg, 0.75 mmol). The mixture was refluxed for 3 hours, allowed to cool, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane / ethyl acetate 80:20 to 40:60 to provide the title product, 12.00 g.

1 H NMR (CDCl3, 400 MHz) δ: 2.61 (s, 3H), 7.62 (d, 2H), 7.88 (d, 2H). MS ES + m / z 239 [MH] +

Preparation 5 3- (4-Bromo-phenyl) -4- (4-methoxy-phenyl) -5-methyl-4 H -25 [1,2,4] triazole-1 V-CH,

(T ^ r "N

^ 6 30 \

0 "CHS

The product of Preparation 4 (5.00 g, 20.9 mmol) was added to a solution of p-toluenesulfonic acid monohydrate (100 mg, 0.75 mmol) and 4-methoxyphenylamine (7.70 35 g, 62 1.5 mmol) in xylene (150 ml) and the reaction mixture was heated to 150 ° C for 22 hours. The reaction mixture was evaporated in vacuo and the residue was taken up in 1027084. · * ·.

- 59 - 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 give the title product, 7.05 g.

5 * Η NMR (DMS0-D6, 400 MHz) 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 [MH] +

Preparation 6 5-Bromo-pyridine-2-carboxylic acid hydrazide 10. -CHO 4 = / N-NH-H 2 5-Bromo-pyridine-2-carboxylic acid methyl ester (J. Org.

Chem., 2001, 66 (2), 605-608, compound 4) (18.10 g, 83 mmol) and hydrazine monohydrate (12.5 ml, 250 mmol) were dissolved in methanol (400 ml) and the reaction mixture was heated under reflux for 48 hours. The reaction mixture was then filtered and the collected precipitate was dried under vacuum to provide the title product, 15.40 g.

ΧΗ NMR (DMSO-D6, 400 MHz) δ: 4.57 (d, 2H), 7.91 (m, 1H), 8.22 (m, 1H), 8.72 (m, 1H), 9, 98 (m, 1 H). MS ES + m / z 25 217 [MH] 4

Preparation 7 5-Chloro-pyrazine-2-carboxylic acid hydrazide

CmTU

30 'Ns / N-NH 3

H

The title compound was prepared by the method of Preparation 6 using 5-chloropyrazine-2-carboxylic acid methyl ester. 5.01 g, 50% yield of the desired product was produced.

1 H NMR (CDCl 3, 400 MHz) δ: 4.09 (d, 2H), 8.52 (s, 1H), 8.66 (bs, 1H), 9.14 (s, 1H). Microanalysis: C 5 H 5 ClN 4 O 11027084 - 60 requires: C, 34.80; H, 2.92; N, 32.47; found C, 34.89; H 2.91, N 32.32. MS APCI + m / z 173 [MH] *

Preparation 8 5- Bromo-pyridine-2-carboxylic acid N '- (2-methoxy-acetyl) -5 hydrazide rvVV'0' ™ 3

0 O

Br 10

The product of Preparation 6 (2.0 g, 9.3 mmol) and N-methyl morpholine (1.3 ral, 12.0 mmol) were dissolved in dichloromethane (60 mL) and the solution was treated with methoxyacetyl chloride (868 μΐ , 9.50 mmol). The reaction mixture was stirred at room temperature for 5 hours and then washed with water and evaporated in vacuo to give 2.41 g, 90% yield of the title product.

1 H NMR (CDCl 3, 400 MHz) δ: 3.46 (s, 3H), 4.07 (s, 2H), 7.98 (dd, 1H), 8.02 (dd, 1H), 8.61 (d, 1 H), 8.89 (d, 1 H), 9.95 (d, 1 H). MS ES + m / z 289 [MH] +

Preparation 9 6-Chloro-nicotinic acid N '- (2-methoxy-acetyl) -hydrazide 25 f / sVo'CH

As? O

cr n 30

The title product was prepared by the method of Preparation 8 using 6-chloronicotinic acid hydrazide. 19.0 g, 90% yield of the desired product was produced.

35 * 1 NMR (CDCl 3, 400 MHz) 5: 3.36 (s, 3H), 3.97 (s, 2H), 7.68 (d, 1H), 8.26 (dd, 1H), 8, 84 (s, 1H), 9.99 (s, 1H), 10.61 (S, 1H). MS ES + m / z 246 [MH] + 1027084 ·! * β - 61 -

Preparation 10 5-Chloro-pyrazine-2-carboxylic acid N '- (2-methoxy-acetyl) -hydrazide.

The title product was prepared by the method of Preparation 8 using the hydrazide of Preparation 7. 3.90 g, 70% yield of the desired product, was produced.

MS APCI + m / z 245 [MH] *

Preparation 11 5-Chloro-pyrazine-2-carboxylic acid N'-acetyl hydrazide

ff H

yV-n-Y "·

Xj h l cr n 20

The title product was prepared by the method of Preparation 8 using the hydrazide of Preparation 7 and acetyl chloride. 4.0 g, 64%, of the desired product was produced.

MS APCI + m / z 215 [MH] +

Preparation 12 S-bromo-pyridine-4-carboxylic acid N '- (2-chloroacetyl) hydrazide

N N — N Cl Η H

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

1027084- * - 62 - * Η NMR (CDCl 3, 400 MHz) δ: 4.20 (s, 2H), 8.00 (d, 1H), 8.30 (d, 1H), 8.80 (s, 1 H), 10.40 (s, 1 H), 10.70 (S, 1 H). MS APCI + m / z 293 [MH] *

Preparation 13 5 5-Bromo-2- (5-methoxymethyl- [1,3,4] oxadiazol-2-yl) -pyridine - (Ηύ CH 3 10

The product of Preparation 8 (2.41 g, 8.4 tnraol) and phosphorus oxychloride (7 ml) were combined and heated to 110 ° C for 4 hours. The reaction mixture was evaporated in vacuo and the residue was taken up in ethyl acetate and water. The mixture was neutralized by the addition of 10% sodium carbonate solution and the phases were separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to provide the title product, 1.01 g, 45% yield.

1 H NMR (CDCl3, 400 MHz) δ: 3.48 (s, 3H), 4.73 (s, 2H), 8.01 (dd, 1H), 8.12 (dd, 1H), 8.81 (dd, 1 H). MS APCI + m / z 272 [MH] +

Preparation 14 2-Chloro-5- (5-methoxymethyl- [1,3,4] oxadiazol-2-yl) -pyridine 30. n N = ch 3 The title compound was prepared by the method of

Preparation 13 using the product of Preparation 1027084 to provide 7.93 g, 40% yield, of the title compound in the form of a rust-brown solid.

1 H NMR (CDCl 3, 400 MHz) δ: 3.52 (s, 3H), 4.74 (s, 2H), 7.50 (d, 1H), 8.32 (dd, 1H), 9.06 ( d, 1 H). Microanalysis: C 9 H 8 ClN 3 O 2 requires: C 47.91; H, 3.57; N, 18.62; Found: C, 47.75; H 3.50, N 18.46. MS APCI + m / z 226 [MH] 4.

Preparation 15 2-Chloro-5- (5-methoxymethyl- [1,3,4] oxadiazol-2-yl) -pyrazine 10%

Cl— ("") -? (1 V = / o ^ .o.cHa

The title compound was prepared by the method of Preparation 13 using the product of Preparation 10. 1.38 g, 38% yield, of the desired product was produced in the form of a light brown solid.

1 H NMR (CDCl 3, 400 MHz) δ: 3.52 (s, 3H), 4.78 (s, 2H), 8.75 (s, 1H), 9.25 (s, 1H) MS APCI + m / z 227 [MH] +

Preparation 16

2-Chloro-5- (5-methyl- [1,3,4] oxadiazol-2-yl) -pyrazine 25 C, "<r> - </ X

N ° ^ ch3

The title compound was prepared by the method of Preparation 13 using the product of Preparation 11. 30 g, 35%, of the desired product was produced in the form of a brown solid.

1 H NMR (CDCl3, 400 MHz) 6: 2.68 (s, 3H), 8.71 (s, 1H), 9.22 (s, 1H) MS APCI + m / z 197 [MH] + 35 Preparation 17 5 - Bromo-2- (5-chloromethyl- [1,3,4] oxadiazol-2-yl) -pyridine 1027084-64 -

Br - ((yni \ = N 0'AN ^ C ') The title compound was prepared by the method of

Preparation 13 using the product of Preparation 12. 2.3 g, 57% yield, of the desired product was obtained in the form of an off-white solid.

10 X H NMR ≤ DMSO-D6, 400 MHz) δ: 4.80 (s, 2H), 8.05 (d, 1H), 8.15 (d, 1H), 8.85 (s, 1H). MS APCI + m / z 276 [MH] +

Preparation 18 5-Bromo-2- [5- (methoxymethyl) -4- 4- (6-methoxypyridin-3-yl) -4H-1,2,4-triazol-3-yl] pyridine 15 XV0 CH

(O

20 V

° -ch3

The product of Preparation 13 (1.01 g, 3.74 mmol), 5-25 amino-2-methoxypyridine (1.40 g, 11.3 mmol) and p-toluene sulfonic acid monohydrate (50 mg, 0, 37 mmol) were dissolved in xylene (25 ml) and the reaction mixture was heated to 150 ° C for 23 hours. The reaction mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane / methanol 100: 0 to 90:10 to give the title product, 1.0 g, 72% yield, in the shape of a purple gum.

1 H NMR (CDCl 3, 400 MHz) 5: 3.32 (s, 3H), 3.99 (s, 3H), 4.46 (S, 2H), 6.82 (d, 1H), 7.54 (dd, 1H), 7.90 (dd, 1H), 8.05 (d, 1H), 8.13 (d, 1H), 8.37 (d, 1H).

MS ES + m / z 398 [MH] + t027084-4 * 65

Preparation 19 2- (4-Fluoro-2-methyl-phenyl) -5- (5-methoxymethyl [1,3,4] oxadiazol-2-yl) -pyridine 5. CH3 7 = / N = / o- ^ o ^ 10 The chloro compound of Preparation 14 (500 rag, 2.22 mmol), 4-fluoro-2-methylphenylboronic acid (361 mg, 2.65 mmol), the palladium complex of Preparation 3 (10 mg, cat.) And cesium carbonate (2.16 g, 6.66 mmol) were dissolved in 1,4-dioxane (10 ml) and the reaction mixture was refluxed for 2 hours. Additional palladium complex (10 mg) was added and the reaction mixture was refluxed for 1 hour. The reaction mixture was evaporated in vacuo and the residue was taken up in ethyl acetate and water. The phases were separated and the ethyl acetate phase was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give the title product, 690 mg in quantitative yield.

MS APCI + m / z 300 [MH] *

Preparation 20 2- (2,3-Dimethyl-phenyl) -5- (5-methoxymethyl- [1,3,4] oxadiazol-2-yl) -pyridine h3c ^ ch3 w - 0 - (1 ', n 'Nv == / N = / 30 ch3

The title product was prepared by the method of Preparation 19 using 2,3-dimethylphenylboronic acid (399 mg, 1.2 eq) and the product of Preparation 14 (500 mg, 2/22 mmol). 712 mg, quantitative yield, of the desired product was produced.

MS APCI + m / z 296 [MH] * 1027084 *

J

i t I '· - 66 -

Preparation 21 2- (2,3-Dimethyl-phenyl) -5- (5-methoxymethyl- [1,3,4] oxadiazol-2-yl) -pyrazine

HgC CHj

5 O

- / N = / CH3

The title product was prepared by the method of Preparation 19 using 2,3-dimethylphenylboronic acid and the chlorine compound of Preparation 15. 466 mg, quantitative yield, of the desired product was produced.

TE NMR (CDCl 3, 400 MHz) 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, 1H), 9.54 (s, 1H) MS APCI + m / z 297 [MH] +

Preparation 22 2- (4-Fluoro-2-methyl-phenyl) -5- (5-methoxymethyl-20 [1,3,4] oxadiazol-2-yl) -pyrazine C (43

N = / 0 ^ S ^ 0V

CH3 25

The title product was prepared by the method of Preparation 19 using 4-fluoro-2-methyl-phenylboronic acid and the chlorine compound of Preparation 15. 450 mg, 97%, of the desired product was produced.

MS APCI + rn / z 301 [MH] +

Preparation 23 2- (2,3-Dimethyl-phenyl) -5- (5-methyl- [1,3,4] oxadiazol-2-yl) -pyrazirte Hsc. CH3 1027084-67 - t t

The title product was prepared by the method of Preparation 19 using 2,3-dimethylphenylboronic acid and the chlorine compound of Preparation 16. 404 mg, quantitative yield, of the desired product was produced.

MS APCI + m / z 267 [MH] +

Preparation 24 2- (4-Fluoro-2-methyl-phenyl) -5- (5-methyl- [1,3,4] oxadiazol-2-yl) -pyrazine 10 CH 3 - (3 - (ΓΐΛ N =) / Λη, 15 The title product was prepared by the method of

Preparation 19 using 4-fluoro-2-methyl-phenylboronic acid and the chlorine compound of Preparation 16. 377 mg, quantitative yield, of the desired product was produced.

MS APCI + m / z 271 [MH] +

Preparation 25 1- [5- (5-Bromo-pyridin-2-yl) - [1,3,4] oxadiazol-2-yl-methyl] -pyrrolidine- (2S) -2-carboxylic acid amide N 2 N

The chlorine compound of Preparation 17 (500 mg, 1.82 30 mmol) and (S) -prolinamide (312 mg, 2.73 mmol) were dissolved in acetonitrile (10 ml) and the mixture was treated with potassium carbonate (503). mg, 3.64 mmol). The reaction mixture was stirred at room temperature for 18 hours and then at 50 ° C for 2 hours. The reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The precipitate formed was filtered off and the organic layer of the filtrate was washed with water, sodium hydroxide solution and saline. The organic layer was then evaporated in vacuo to provide the title product, 540 mg, 84% yield.

1 H NMR (DMS0-D6, 400 MHz) δ: 1.70 (m, 3H), 2.00 (m, 5H), 2.60 (m, 1H), 3.10 (m, 1H), 3 , 20 (m, 1H), 4.00 (d, 1H), 4.20 (d, 1H), 7.00-7.20 (d, 2H), 8.10 (d, 1H), 8, 30 (d, 1H), 8.90 (s, 1H).

Preparation 26 5-Bromo-2- (5-pyrrolidin-1-ylmethyl- [1,3,4] oxadia-10-zol-2-yl) -pyridine

Br — 0 ^ oA ^ nO

Pyrrolidine (324 mg, 0.38 ml, 4.56 mmol) was added to a stirred solution of the chlorine compound of Preparation 17 (500 mg, 1.82 mmol) in acetonitrile (15 ml) at room temperature. After stirring for 18 hours, the reaction mixture was evaporated in vacuo and the residue was taken up in ethyl acetate (50 ml) and washed with 2M aqueous sodium hydroxide, followed by water, followed by saline. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to provide 407 mg, 72% yield, of the title compound.

αΗ NMR (CDCl 3, 400 MHz) δ: 1.90 (m, 4H), 2.70 (m, 4H), 4.00 (s, 2H), 8.00 (d, 1H), 8.20 (d, 1 H), 8.80 (s, 1 H).

Preparation 27 1- [5- (5-Bromo-pyridin-2-yl) -4- (6-methoxy-pyridin-3-30 yl) -4H- [1,2,4] triazol-3-ylmethyl] - pyrrolidine (2 S) -2-carboxylic acid amide NN f ^ S | / = 0 ° "CH, 9", 1027084- * * - 69 -

The product of Preparation 25 (500 mg, 1.20 mmol) and 5-amino-2-methoxypyridine (224 mg, 1.81 mmol) were dissolved in xylene (15 mL) and the solution was treated with catalytic p-toluenesulfonic acid monohydrate and refluxed for 18 hours. The reaction mixture was evaporated in vacuo and the residue was taken up in ethyl acetate and washed with water, 2M citric acid solution, 2M sodium hydroxide solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane / methanol 100: 0 to 95: 5 to give the title product, 252 mg, 46% yield.

X H NMR (CDCl 3, 400 MHz) δ: 1.80 (m, 2H), 2.20 (m, 1H), 2.60 (m, 1H), 3.10 (m, 1H), 3.20 ( m, 1H), 3.90 (m, 2H), 4.00 (s, 3H), 5.00 (S, 1H), 6.70 (s, 1H), 6.90 (d, 1H) > 7.90 (d, 1H), 8.05 (d, 1H), 8.20 (d, 1H), 8.40 (s, 1H).

MS ES + m / z 458 [MH] +

Preparation 28 5-Bromo-2 - (((5-pyrrolidin-1-ylmethyl) -4- (6-methoxy-pyridin-3-yl)) -4H- [1,2,4] triazol-3-yl pyridine 25 ° CH 3 412 mg, 77% yield of the title compound was prepared by the method of Preparation 27 using 30. the product of Preparation 26.

MS ES + m / z 417 [MH] +

Preparation 29 3-Methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile 35 1027084¾ -70. ° ch3 NC, ^ CH, 5

Palladium (II) acetate (224 mg, 5 mol%), potassium acetate (3.68 g, 61.2 mmol) and bis (pinacolato) dibor (5.4 g, 21.4 mmol) were added to a solution of 1 -bromo-4-cyano-2-methylbenzene (4.0 g, 20.4 mmol) in N, N-dimethylformamide (40 ml) and heated at 80 ° C for 18 hours. After this 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 evaporated in vacuo to give a brown solid. The solid was purified by trituration in pentane, filtering and drying to give the title compound as a beige solid (2.68 g, 54% yield).

X H NMR (CDCl 3, 400 MHz) 5: 1.35 (S, 12H), 2.55 (s, 3H), 7.41-7.45 (m, 2H), 7.82 (d, 1H) . MS APCI + m / z 261 [MNH] +

Preparation 2 2-Chloro-5- [4- (6-methoxy-pyridin-3-yl) -5-methyl-4 H- [1,2,4] triazopl-3-yl] pyrazine 25 / Τ ~ Ά Ns. ,

Cl— ^ ^

f ch3 O 30 HjC "0

The title product was prepared by the method of Preparation 18 using the oxadiazole compound of Preparation 16 and 5-amino-2-methoxypyridine. 4.3 g, 44% yield, of the desired product was produced in the form of a beige solid.

1 H NMR (CDCl 3, 400 MHz) 6: 2.36 (s, 3H), 3.99 (S, 3H), 1027084-1, 71-6.86 (d, 1H), 7.45 (dd, 1H), 8.02 (d, 1H), 8.27 (d, 1H), 9.23 (d, 1H).

Preparation 31 2-Chloro-5- [5-methoxymethyl-4- (6-methoxy-pyridin-3-5 yl) -4 H- [1,2,4] triazol-3-yl] pyrazine

Cl— \ H

\ = / A cHa 10)

VN

H3C "0

The title product was prepared by the method of Be-15 preparation 18 using the oxadiazole compound of Preparation 15 and 5-amino-2-methoxypyridine. 10.5 g, 59% yield, of the desired product was produced in the form of a beige solid.

1 H NMR (CDCl 3, 400 MHz) δ: 3.33 (s, 3H), 3.99 (s, 3H), 4.47 (s, 2H), 6.83 (d, 1H), 7.53 (dd, 1H), 8.06 (d, 1H), 8.30 (d, 1H), 9.25 (d, 1H). MS APCI + m / z 333 [MH] +

Preparation 32 2- (5-Fluoro-2-methoxy-phenyl) -5- (5-methoxymethyl- [1,3,4] oxadiazol-2-yl) pyridine 25

H, C

o / 3-0 - F CHa 30

The title product was prepared by the method of Preparation 19 using 5-fluoro-2 methoxy-phenylboronic acid (565 mg, 3.33 mol) and the chlorine compound of Preparation 14 (500 mg, 2.22 mmol). 669 mg, 96% yield of the desired product was produced.

X H NMR (CDCl 3, 400 MHz) 5: 3.51 (s, 3H), 3.88 (s, 3H), 4.75 (s, 2H), 6.97 (d, 1H), 7.11 ( m, 1 H), 7.70 (dd, 1 H), 1027084-

* I

- 72 - 8.11 (d, 1H), 8.37 (dd, 1H), 9.34 (d, 1H).

MS APCI + m / z 316 [MH] *

Preparation 33

6-Chloro-nicotinic acid N '- (2-chloro-acetyl) -hydrazide S

Chloroacetyl chloride (2.8 ml, 34.9 ramol) was added dropwise to an ice-cooled solution of 6-chloomicotinic acid hydrazide (5 g, 29.1 mmole) and 4-methyl-morpholine (4.8 ml, 43, 7 mmol) in dichloromethane (100 ml) and the reaction was stirred at room temperature for 3 hours; The resulting precipitate was then filtered off, suspended with dichloromethane, filtered again, washed with dichloromethane (x 3) and dried to give the title compound in the form of a beige solid in a yield of 57%, 4.1 g.

20 * Η NMR (DMS0-D6, 400 MHz) δ: 4.20 (S, 2H), 7.68 (d, 1H), 8.23 (d, 1H), 8.84 (m, 1H), 10.50 (s, 1H), 10.83 (s, 1H). MS APCI + m / z 248/250 [MH] +

Preparation 34 5- Chloro-pyrazine-2-carboxylic acid N '- (2-chloro-acetyl) - 25 hydrazide C1 - Vw 30

The title product was prepared from the product of Preparation 7 and chloroacetyl chloride, using the method of Preparation 33, in the form of a solid in a yield of 37%.

35 MS APCI + m / z 249/251 [MH] +

Preparation 35 6-Chloro-nicotinic acid-N'-acetyl-hydrazide 7027084 - 73 - c, - / VfVCN, N = / (Th 5 The title compound was prepared from 6-chloomicotinic acid hydrazide and acetyl chloride, using from the method of Preparation 33, in the form of a white solid in a yield of 64%.

X H NMR (DMSO-D 6 <400 MHz) δ: 1.91 (s, 3 H), 7.68 (d, 10 1 H), 8.24 (dd, 1 H), 8.82 (d, 1 H), 10 .00 (s, 1H), 10.58 (S,.

1H). MS APCI + m / z 214 [MH] +

Preparation 36 6-Chloro-nicotinic acid N '- [2- (2-methoxy-ethoxy) -acetyl] hydrazide 15%.

N Η H '—O

20 (2-Methoxy-ethoxy) -acetyl chloride (2.13 g, 13.99 in mol) was added to an ice-cold solution of 6-chloomicotinic acid hydrazide (2 g, 11.66 mmol) and N-methyl morpholine (1 (92 ml, 17.49 mmol) in dichloromethane (60 ml) and the mixture was stirred at room temperature for 18 hours. The mixture was then treated with sodium hydrogen carbonate solution and evaporated in vacuo.

The aqueous residue was extracted with dichloromethane (x 2) and the combined organic solutions were washed with brine and dried over sodium sulfate and evaporated in vacuo to give a pale yellow residue. The residue was then stirred in diethyl ether for 2 hours, filtered and dried to give the title compound as a pale yellow solid in a yield of 51%, 1.7 g.

35 1 H NMR (CDCl 3, 400 MHz) δ: 3.46 (s, 3H), 3.62 (m, 2H), 3.78 (m, 2H), 4.21 (s, 2H), 7.42 (d, 1 H), 8.07 (dd, 1 H), 8.82 (d, 1 H) 9.28 (br s, 1 H), 9.83 (br s, 1 H). MS APCI + 1027084-

·. J

- 74 - m / z 288 [ΜΗ] +

Preparation 37

6-Chloro-nicotinic acid N '- (2-ethoxy-acetyl) -hydrazide 5% O

N Η H CH 3 (2-Ethoxy) acetyl chloride [{1.72 g, 13.99 mmol), 10 Tetr. Lett., 35, (39), 7269; 1994)] was added to an ice-cold solution of 6-chloronicotinic acid hydrazide (2 g, 11.66 tnmol) and N-methylmorpholine (1.92 ml, 17.49 mmol) in dichloromethane (60 ml) and the mixture was left for 18 hours stirred at room temperature. The mixture was then washed with citric acid, sodium hydrogen carbonate solution and brine, and the solvent was evaporated under reduced pressure to provide some title product in the form of a white solid, 880 mg. The combined aqueous washings were extracted with ethyl acetate (x 2) and the combined organic solutions were dried over sodium sulfate and evaporated in vacuo to provide a further yield of title compound as a pale yellow solid, 1.6 g (total yield) 83%).

25 1 H NMR (CDCl 3, 400 MHz) δ: 1.21 (t, 3H), 3.55 (q, 2H), 4.06 (S, 2H), 7.38 (d, 1H), 8.00 (dd, 1H), 8.77 (d, 1H), 8.99 (br s, 1 H), 9.15 (br s, 1 H). MS APCI + m / z 258/260 [MH] +

Preparations 38 to 42 The following compounds, of the general formula below, were prepared by the method of Preparation 13 using the appropriate hydrazide (Preparations 33-37) and phosphorus oxychloride.

/ r \ /? '«35 α-Ο-Ot ^ R» N = i / Ό 1027084-

♦ I

- 75 - No. R2 _Y_Data ___Pub.

38 Cl CH 1 H NMR (CDCl 3, 400 MHz) 5: 4.80 55% (S, 2H), 7.52 (d, 1H), 8.35 (dd, 1H), 9.08 (d, 1H) ). MS APCI + m / z _____ 230/232 [MH] * ___ 39 Cl N ΧΗ NMR (CpCl3, 400 MHz) δ: 4.83 38% (s, 2H), 8.76 (s, 1H), 9.36 (s, ____1H). MS APCI + m / z 231/233 [MH] * 40 H CH 2 H NMR (CDCl 3, 400 MHz) δ: 2.66 77% (S, 3H), 7.51 (d, 1H), 8.31 ( d, 1 H), 9.02 (s, 1 H).

Microanalysis: C8 H6 ClN3 O0.25H2 O requires: C 48.32; H, 3.27; N, 21.00; found C, 47.89; H, 3.23; ________N, 20.95. 41 CH 1 H NMR (CDCl 3, 400 MHz) δ: 3.39, 68% Q - (S, 3H), 3.59-3.61 (m, 2H ), 3.78-3.80 (m, 2H), 4.86 (s, 2H), 7.52 (d, 1H), 8.33 (dd, 1H), 9.07 (d, 1H) . MS APCI + m / z 270/272 [MH] + * r · "1 .............. .......... - '" 1 "'» - » - 1 1 ... 1 42 CH 2 H NMR (CDCl 3, 400 MHz) δ: 1.28 75% (t, 3H), 3.69 (q, 2H), 4.77 (S, 2H), 7.49 (d, 1H), 8.34 (dd, 1H), 9.07 (d, 1H).

__J_ IMS ES + m / z 262 [MNa] * __ |

Preparation 42 was purified by column chromatography on silica gel, eluting with pentane / ethyl acetate, 100: 0 to 90:10.

Preparation 43 2-Chloro-5- (5- [1,2,3] triazol-2-ylmethyl- [1,3,4] oxadiazol-2-yl) -pyridine

/ r- \ N

1027084 - <t - 76 - 1 H -1,2,3-Triazole (264 mg, 3.85 mmol) was added to a suspension of the chlorine compound of Preparation 38 (800 mg, 3.5 mmol) and potassium carbonate (1 , 4 g, 7 mmol) in N, N-dimethylformamide (15 ml) and the mixture was 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 evaporated in vacuo to give the title compound as a yellow solid in a yield of 71%, 650 mg .

* Η NMR (CDCl 3, 400 MHz) δ: 6.08 (s, 2H), 7.66 (d, 1H), 7.80 (s, 2H), 8.38 (dd, 1H), 8.99 (d, 1 H). MS APCI + m / z 263 [MH) +

Preparations 44 to 45 The following compounds, of the general formula below, were prepared from the product of Preparations 38 and 39 using the method of Preparation 43. .

r — Y

20 nr R2_ ’Y Data_Or.

44 N MS APCI + m / z 264 [MH] + 40% / = 1 V ^ 45 CH X H NMR (CDCl 3> 400 MHz) δ: 2.34 82%

H C

3 (S, 6H), 3.78 (s, 2H), 7.43 (d, H, C 1 H), 8.28 (dd, 1 H), 9.01 (d, 1 H) | __J_I | MS APCI + m / z 239/241 [MH] * __

Preparations 46 to 52 The following compounds, of the formula below, were prepared by the method of Preparation 18 using the appropriate oxadiazole (Preparations 14 and 40-45) and 5-amino-2-methoxypyridine.

1027084-1. T - 77 - 5 C11 H, C11 ° R2 Y_Data ____Br.

46 CH X H NMR (CDCl 3, 400 MHz) δ: 3.97 (s, 25% / = ^ 3 H), 5.75 (S, 2 H), 6.78 (d, 1 H), 7.24 (d, 1 H), 7.34 (d, 1 H), 7.56 (S, 2 H), 7.90 (dd, 1 H), 7.94 (m, 1 H), 8.30 (d, 1 H) _____MS APCI + m / z 369 [MH] + 47 N MS APCI + m / z 370 [MH] + 29% / = "48 CH 1 H NMR (CDCl 3, 400 MHz) δ: 2.25 (s, 36% H 3 Cl x 6 H), 3.46 (S, 2H), 3.99 (s, 3H), H 6.85 (d, 1H), 7.34 (d, 1H), 7.60 (dd, 1H), 7.88 ( dd, 1H), 8.10 (d, 1H), 8.34 (d, 1H) ______MS APCI + m / z 345/347 [MH] * 49 OCH3 CH1 NMR (CDCl3, 400 MHz) δ: 3.35 (S, 50% 3 H), 3.99 (S, 3 H), 4.48 (s, 2 H), 6.88 (d, 1 H), 7.34 (d, 1 H), 7.50 (m, 1 H) , 7.88 (m, 1H), 8.10 (d, 1H), 8.35 (m, 1H) _____MS APCI + m / z 332 [MH] * 50 H CH 1 H NMR (CDCl 3, 400 MHz) δ : 2.38 33% (s, 3H), 4.00 (s, 3H), 6.90 (d, 1H), 7.35 (d, 1H), 7.40 (dd, 1H), 7.88 ( dd, 1H), 8.06 (d, 1H), 8.31 1 (d, 1H) MS APCI + m / z 302/304 [MH] * f027084-

<I

78 - 51 CH X H NMR (CDCl 3, 400 MHz) δ: 3.33 (s, 62% 3H), 3.48 (m, 2H), 3.64 (m, 2H), 3.99 (s. 3 H), 4.60 (s, 2 H), 6.86 V (d, 1 H), 7.35 (d, 1 H), 7.60 (dd, 1 H), 7.88 (dd, 1 H), 8 , 09 (d, 1H), 8.35 (d, 1H).

____MS APCI + m / z 376/378 [MH] * 52 CH 1 H NMR (CDCl 3, 400 MHz) δ: 1.14 (t, 3H), 3.50 (q, 2H), 4.00 (s, 3H 4.52 (S, 2H), 6.86 (d, 1H), 7.34 (d, 1H), 7.51 (dd, 1H), 7.90 (dd, 1H), 11 (d, 1H), 8.36 (d, 1H).

____MS APCI + m / z 346 [MH] * _; ___

Preparation 46 was purified by column chromatography on silica gel, eluting with ethyl acetate / pentane, 25:75 to 50:50 to 75:25.

Preparation 48 was purified by column chromatography on silica gel, eluting with dichloromethane / 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 chromatography on silica gel, eluting with ethyl acetate / pentane, 10:90 to 100: 0, followed by trituration with diethyl ether.

Preparation 50 was purified by recrystallization from ethyl acetate.

Preparation 51 was purified by column chromatography on silica gel, eluting with dichloromethane / methanol / 0.88 ammonia, 100: 0: 0 to 99: 1: 0.1.

Preparation 53 4-Bromo-2,3-dimethyl-pyridine-1-oxide

Br 20 flT ^ 3 f CH3 0 "1027084- <- 79 -

A mixture of 2,3-dimethyl-4-nitropyridine N-oxide (5 g, 29.7 mmol) and hydrogen bromide (30 wt% in acetic acid, 100 mL) was heated at 100 ° C for 48 hours. The mixture was then filtered, flushing with 2 M sodium hydroxide and the filtrate extracted with dichloromethane (x 3). The combined organic solutions were washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / penane, 50:50, to provide the title product as a pale yellow solid.

* Η NMR (CDCl3, 400 MHz) δ: 2.44 (s, 3H), 2.58 (s, 3H), 7.30 (d, 1H), 8.01 (d, 1H). MS APCI + m / z 202/204 [MH] + 15 Preparation 54 4- (2,3-Dimethyl-1-oxy-pyridin-4-yl) -benzoic acid methyl ester 20

-'N <s JL

° CH 3 A mixture of the product of Preparation 53 (765 mg, 3.78 mmol), 4-methoxycarbonylphenylboronic acid (750 mg, 4.16 mmol), cesium carbonate (3.7 g, 11.34 mmol) and the product of Preparation 3 (50 mg, cat.) In 1,4-dioxane (20 ml) was heated at 110 ° C for 3 hours. The mixture was then partitioned between ethyl acetate and water and the aqueous layer was separated and extracted by dichloromethane (x 3). The combined organic solutions were washed with brine, dried over sodium sulfate and evaporated in vacuo to give a dark yellow solid. This solid was triturated with diethyl ether to provide the title compound in the form of a pale brown solid in a yield of 87%.

10270843 4 - * - 80 - * * Η NMR (CDCl3 / 400 MHz) δ: 2.24 (S, 3H), 2.60 (S, 3H), 3.95 (s, 3H), 7.02 ( d, 1 H), 7.35 (m, 2 H), 8.12 (m, 2 H), 8.22 (d, 1 H). MS APCI + m / z 258 [MH] +

Preparation 55 5 4- (2,3-Dimethyl-1-oxy-pyridin-4-yl) -benzoic acid hydrazide

P

io ~ 4. J, CH, ch3

A mixture of the product of Preparation 54 (850 mg, 3.3 mmol) and hydrazine monohydrate (482 μΐ, 9.9 mmol) in methanol (15 mL) was heated under reflux for 3 hours. A further amount of hydrazine monohydrate (482 μΐ, 9.9 mmol) was then added to the reaction mixture and heating continued for 18 hours. The mixture was then filtered through Celite®, flushing with methanol and the filtrate evaporated in vacuo to provide a white solid. The solid was suspended in ethyl acetate, filtered, washed with diethyl ether (x 2) and dried in vacuo to give the title compound as a white solid in a 94% yield, 800 mg.

* H NMR (CDCl 3, 400 MHz) δ: 2.18 (s, 3H), 2.41 (s, 3H), 4.58 (m, 2H), 7.14 (d, 1H), 7.42 (d, 2H), 7.96 (d, 2H), 8.18 (d, 1H), 9.85 (s, 1H). MS APCI + m / z 258 [MH] + 30 Preparation 56 1,1,1,2-Tetramethoxyethane

H3C

P

H 3 C-O 2 ~ 30 3 ch 3 35 3 ch 3

Methoxyacetonitrile (50.0 g, 704 mmol) was dissolved in a mixture of methanol (34 ml) and diethyl ether (210 ml) and the mixture was 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. Water-5 chlorine gas was then bubbled through the mixture a second time and allowed to stand for 18 hours at room temperature. The mixture was filtered and the resulting white solid was washed with diethyl ether. dissolved in methanol (340 ml) and stirred for 90 minutes. The solution was then diluted with ether (370 ml), refluxed for 6 hours and then allowed to stand for 18 hours at room temperature. Additional ether (200 ml) was added and the mixture was filtered off. The filtrate was washed with 10% sodium carbonate solution, dried over magnesium sulfate and evaporated in vacuo to give the title product, 34.5 g.

1 H NMR (CDCl 3, 400 MHz) δ: 3.29 (s, 9H), 3.39 (s, 3H), 3.50 (s, 2H)

Preparation 57 20 4- [4- (5-Methoxymethyl- [1,3,4] oxadiazol-2-yl) -phenyl] -2,3-dimethylpyridine-1-oxide

N - N

25 p-Toluenesulfonic acid (20 mg, cat.) Was added to a mixture of the products of Preparations 55 (400 mg, 1.56 mmol) and 56 (470 mg, 3.12 mmol) in methanol (8 ml) and the mixture was refluxed for 10 hours. The mixture was then treated with sodium hydrogen carbonate solution and the aqueous mixture was extracted with ethyl acetate (x 3). The combined organic solutions were washed with brine, dried over sodium sulfate, and evaporated in vacuo to give the title product in the form of a yellow oil in a 25% yield, 122 mg.

1 H NMR (CDCl 3, 400 MHz) δ: 2.25 (S, 3H), 2.62 (s, 3H), 3.52 (s, 3H), 4.70 (s, 2H), 7.04 (d, 1H), 7.41 (d, 2H), 8.16 (d, 2H), 8.25 (d, 1H). MS APCI + m / z 312 [MH] +

Preparation 58 6-Chloro-pyridazine-3-carboxylic acid methyl ester ie .8.

λΧ, Oxalyl chloride (1.14 ml, 13.09 mmol), was added dropwise to an ice-cold suspension of 6-chloro-pyridazine-3-carboxylic acid [(1.9 g, 11.9 mmol), J. . Chem. 29 (6), 1583-92; 1992] in a mixture of dichloromethane (50 ml) and Ν, Ν-dimethylformamide (1 drop) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then evaporated under reduced pressure and the residue was diluted with dichloromethane (30 ml) and cooled to 0 ° C. Methanol (485 μΐ, 11.9 mmol) 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 (x 2). The combined organic solutions were washed with brine, dried over sodium sulfate and evaporated in vacuo to give the title compound as a white solid in a 65% yield, 1.33 g.

X H NMR (CDCl 3, 400 MHz) δ: 4.09 (s, 3H), 7.67 (d, 1H), 8.16 (d, 1H). MS APCI + m / z 173 [MH] + 35 Preparation 59 6- (4-Fluoro-2-methyl-phenyl) -pyridazine-3-carboxylic acid methyl ester 1027084- * * - 83 -

O

o F '^ V ^ SS'CH3

The title compound was prepared from the product of Preparation 58 and 4-fluoro-2-methylphenylboronic 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 provided the desired product in the form of a. beige solid in a yield of 16%. .

15 * 1 NMR (CDCl 3, 400 MHz) δ: 2.44 (s, 3H), 4.11 (s, 3H), 7.06 (m, 2H), 7.47 (dd, 1H), 7, 71 (d, 1H), 8.26 (d, 1H).

MS APCI + m / z 247 [MH] +

Preparation 60 6- (4-Fluoro-2-methyl-phenyl) -pyridazine-3-carboxylic acid-hydrazide or VNH "F> - <CH 3

Hydrazine monohydrate (69 μΐ, 1.42 mmol) was added to a suspension of the product of Preparation 59 (290 mg, 1.18 mmol) in methanol (5 mL) and the mixture was stirred at room temperature for 18 hours . The resulting precipitate was filtered off and dried to give the title compound in the form of a peach-colored solid in a yield of 83%, 240 mg.

1 H NMR (CDCl 3, 400 MHz) δ: 2.42 (s, 3H), 4.18 (br s, 2H), 7.06 (m, 2H), 7.46 (dd, 1H), 7.75 (d, 1H), 8.33 (d, f027084 - 84 - κ β 1Η), 9.18 (br S, 1Η). MS APCI + m / z 247 [ΜΗ] +

Preparation 61 6- (4-Fluoro-2-methyl-phenyl) -pyridazine-3-carboxylic acid N '- (2-methoxy-acetyl) -hydrazide 5

O

il N -CH,

10 JL

F CH3

The title compound was prepared from the product of Preparation 60 and methoxyacetyl chloride, using the method of Preparation 8, in the form of a beige foam in a yield of 95%.

ΧΗ NMR (CDCl3, 400 MHz) δ: 2.43 (S, 3H), 3.52 (s, 3H), 4.14 (s, 2H), 7.06 (m, 2H), 7.46 ( m, 1 H), 7.76 (d, 1 H), 8.33 (d, 1 H), 8.80 (br S, 1 H), 10.06 (br S, 1 H). MS APCI + 20 m / z 319 [MH] +

Preparation 62 3- (4-Fluoro-2-methyl-phenyl) -6- (5-methoxymethyl [1,3,4] oxadiazol-2-yl) pyridazine O-CH3 30 3

The title compound was prepared from the product of Preparation 61 and phosphorus oxychloride, using the method of Preparation 13. The crude product was purified by column chromatography on silica gel, eluting with dichloromethane / methanol, 99: 1 to 98: 2, ter provision of the desired compound in the form of a beige solid 1027084 - 85 - in a yield of 15%.

1 H NMR (CDCl 3, 400 MHz) 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, 1 H), 8.43 (d, 1 H). MS APCI + ta / z 301 [MH] + 5 Preparation 63 5-Bromo-pyrimidine-2-carbonitrile.

Jj

A solution of 5-bromo-2-chloropyrimidine (10 g, 51.8 mmol) in dimethyl sulfoxide (26 ml) was added to a mixture of sodium cyanide (2.59 g, 51.8 mmol) and triethylene diamine (1.2 g, 10.4 mmol) in dimethyl sulfoxide (14 ml) and water (28 ml). The resulting mixture was stirred at room temperature for 18 hours. The mixture was then diluted with water (130 ml) and extracted with diethyl ether (3 x 150 ml). The combined organic solutions were dried over sodium sulfate and evaporated in vacuo to give a pale yellow solid. Recrystallization of the solid from hot dichloromethane provided the title product in a yield of 99%, 9.4 g.

25 X H NMR (CDCl 3, 400 MHz) δ: 8.84 (s, 2H).

Preparation 64 5-Bromo-pyrimidine-2-carboxylic acid

Λ — N P

Br— \ ^^

30 '= n O-H

A mixture of sodium hydroxide (4.88 g, 120 mmol) and the product of Preparation 63 (7.5 g, 40.8 mmol) in water (122 ml) was heated at 60 ° C for 1 hour. The mixture was then acidified with 1 M hydrochloric acid, extracted with ethyl acetate and dichloromethane and evaporated in vacuo to give some title compound in the form of 1027084 - a white solid, 300 mg. The aqueous solution was also evaporated under reduced pressure and the residue was extracted in dichloromethane / methanol, 90:10. The precipitate was filtered off and the filtrate was evaporated in vacuo to provide further title compound as a white solid, 5.5 g.

* H NMR (DMSO-De, 400 MHz) δ: 9.10 (s, 2H), 13.8 (br s, 1H). MS APCI + m / z 203 [MH] +

Preparation 65 10 5-Bromo-pyrimidine-2-carboxylic acid methyl ester * -Cnm ° v = N 0 -CH 3

Fuming hydrochloric acid was passed through an ice-cooled solution of the product of Preparation 64 (5.5 g, 27 mmol) in methanol (50 mL) to saturation. The reaction mixture was warmed to room temperature and 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 evaporated in vacuo to give the title compound in the form of a yellow solid in a yield of 57% 3.5 g.

* Η NMR (CDCl3, 400 MHz) δ: 4.05 (s, 3H), 9.00 (s, 2H). MS APCI + m / z 218 [MH] +

Preparation 66 5-Bromo-pyrimidine-2-carboxylic acid hydrazide 30

r. — N P

Br— \ ^ —K

\ = N N-NH 2 35

The title compound was prepared from the product of Preparation 65 and hydrazine monohydrate, using 1027084 of the method of Preparation 6, in the form of a yellow solid in quantitative yield.

X H NMR (CDCl 3, 400 MHz) δ: 4.20 (s, 2H), 8.90 (m, 3H). MS APCI + m / z 217 [MH] + 5 Preparation 67 5-Bromo-pyrimidine-2-carboxylic acid N '- (2-methoxy-acetyl) -hydrazide

λ — N. O O

10 Η K

\ = N N-N O-CH, Η H 3

The title compound was prepared from the product of

Preparation 66 and methoxyacetyl chloride, using the method of Preparation 8, in the form of a white solid in a yield of 45%.

1 H NMR (DMS0-D6, 400 MHz) δ: 3.32 (s, 3Ή), 3.98 (s, 2H), 9.20 (s, 2H), 10.02 (s, 1H), 10.66 (s, 1 H). MS APCI + m / z 290 [MH] + Preparation 68 5-Bromo-2- (5-methoxymethyl- [1,3,4] oxadiazol-2-yl) -pyrimidine

N - N

J1 · 25; ° CHs

The title compound was prepared from the product of Preparation 67, using the method of Preparation 13. The crude product was purified by column chromatography on silica gel, eluting with dichloromethane / methanol, 99.5: 0.5 to 99: 1 to provide the desired compound in the form of a white solid. in a yield of 45%.

35 1 H NMR (CDCl 3, 400 MHz) δ: 3.52 (s, 3H), 4.78 (S, 2H),. 9.02 (s, 2H). MS APCI + m / z 271 [MH] + 01027084 =

* I

- 88 -

Preparation 69 5- (4-Fluoro-2-methyl-phenyl) -2- (5-methoxymethyl [1,3,4-oxadiazol-2-yl) pyrimidine

N - N

CH, ch3. A solution of sodium carbonate (295 mg, 2.78 mmol) in water (3 ml) was added to a solution of the product of Preparation 68 (376 mg, 1). 39 mmol), 4-fluoro-2-methylphenylboronic acid (320 mg, 2.08 mmol) and palladium triphenylphosphine (48 mg, cat.) In 1,2-dimethoxyethane (3 ml) and the mixture was refluxed for 2 hours far warmed up. 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, rinsed with water, ethyl acetate and diethyl ether and dried to give the title compound in the form of a beige solid in a yield of 59%, 332 mg.

1 H NMR (CDCl 3, 400 MHz) 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, 2 H). MS APCI + m / z 301 [MH] +

Preparation 70 5-Bromo-2- (5-methyl- [1,3,4] oxadiazol-2-yl) -pyridine, -0 (1 B \ = N 0 ^ CH 3)

The title compound was prepared from the product of Preparation 6 and N, N-dimethylacetamide-dimethylacetal, using the method of Preparation 4, in the form of a white solid in a 47% yield.

(H NMR (CDCl3, 400 MHz) δ: 2.65 (s, 3H), 8.01 (m, 1H), 1027084 - δ - 89 - 8.12 (m, 1H), 8.80 (m 1 H) MS APCI + m / z 240/242 [MH] +

Preparation 71 3- [3- (5-Bromo-pyridin-2-yl) -5-methyl- [1,2,4] triazol-4-yl] -2,6-dimethoxy-pyridine 5

Br __ / W 11, N == ^ X ^ CH 3

C x 16 CH 10 HSC 3 3-Amino-2,6-dimethoxypyridine monohydrochloride (2 g, 13 mmol) was partitioned between sodium carbonate solution and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated in vacuo to provide the free base. The base was then dissolved in xylene (30 mL) and the product of Preparation 70 (1.8 g, 7.5 mmol) and p-toluene sulfonic acid (50 mg, cat.) Were added. The resulting mixture was heated under reflux for 18 hours.

The reaction mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane / methanol 100: 0 to 98: 2 to give the title product in the form of a purple solid in a yield of 23%, 628 mg.

X H NMR (CDCl 3, 400 MHz) δ: 2.49 (s, 3H), 3.80 (s, 3H), 3.98 (S, 3H), 6.41 (d, 1H), 7.45 ( d, 1 H), 7.92 (dd, 1 H), 8.11 (d, 1 H), 8.37 (d, 1 H). MS APCI + m / z 377 [MH] +

Preparation 72 30 5- (4-Fluoro-2-methyl-phenyl) -2- (5-methyl- [1,3,4] oxadiazol-2-yl) -pyridine

N - N

jQjCr1 ^ ch3 1027084 - 90 -

A mixture of the product of Preparation 40 (545 mg, 2.79 mmol), 4-fluoro-2-methylphenylboronic acid (643 mg, 4.18 mmol), cesium carbonate (2.7 g, 8.29 mmol) and the product of Preparation 3 (10 mg, cat.) in 1,4-dioxah (25 ml) was heated under reflux for 4 hours. The reaction mixture was then cooled to room temperature, filtered through Celite® and evaporated in vacuo to provide the title compound as a pale yellow solid in quantitative yield.

10 X H NMR (CDCl 3 <400 MHz) 5: 2.40 (S, 3H), 2.66 (s, 3H), 7.00 (m, 2H), 7.43 (dd, 1H), 7.53 (d, 1 H), 8.37 (d, 1 H) 9.29 (d, 1 H). MS APCI + m / z 270 [MH] +

Preparations 73 to 81

The following compounds of the general formula 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 followed by dl analysis and the mixtures were heated under reflux until all starting materials were used up.

N = ^ 1027064-91 - No. R1_R2 Y_ Data ___ 73 Η N 1 H NMR (CDCl3, 400 MHz) δ: 2.29 (s, 3H), 2.37 (s, 3H), 2.70 (s, 11, 3 H), 7.217.34 (m, 3 H), 8.81 (d, CH, CH 1 H), 9.51 (d, 1 H). MS ES + m / z 289 [MNa] + 74 Η N X H NMR (CDCl3, 400 MHz) δ: 2.46 (S, 3H), 2.70 (S, 3H), 7.06 (m, il '2H ), 7.50 (m, 1 H), 8.82 (d, 1 H), 9.49 (d, 1 H). MS ε S + m / z 293 _____ .___ [MNa] * _ = _______ 75 OCH 3 CH 1 H NMR (CDCl 3, 400 MHz) δ: 2.41 f 1 ^ T ^ (S, 3H), 3.52 (S, 3H) , 4.75 (S, 2H), 6.947.04 (m, 2H), 7.44 (dd, 1H), 7.55 (dd, 1H), 8.42 (d, 1H), 9.35 ( dd, 1 H). MS APCI + m / z 300 _______________ [MH] *, __ 76 OCH 3 N X H NMR (CDCl 3, 400 MHz) δ: 2.46 fY * (S, 3H), 3.53 (s, 3H), 4.79 ( S, 2H), 7.06 (m, 2H), 7.51 (m, 1H), 8.84 (d, 1H), 9.51 (d, 1H). MS APCI + m / z 301 [MH] + 77 OCH 3 N x H NMR (CDCl 3, 400 MHz) δ: 2.40 ff (d, 3H), 3.52 (s, 3H), 4.51 (s, 2H) , 7.23-7.30 (m, 3H), 9.06 (S, CH3 1H), 9.40 (S, 1H) __________MS ES + m / z 433 [MCs] * __ 78 CHa F OCH3 N 1 H NMR (CDCl3, 400 MHz) δ: 3.78 (S, 3H), 4.09 (s, 3H), 4.80 (s, | j T 2H), 7.01-7.18 (m, 2H) , 7.54-7.72 (m, 1H), 9.26 (s, 1H), 9.57 (s, 1H) MS ES + m / z 449 [MCs] + 1027084-

*. I

92 - 79 - CH 3 OCH 3 N X H NMR (CDCl 3, 400 MHz) δ: 2.37? (s, 3H), 3.52 <s, 3H), 3.89 (S, 3H), 4.78 (s, 2H), 6.95 (d, 1H), 7.25 (τη, 1H) , 7.77 (m, 1H), 9.35 (d, 1H), 9.49 (d, 1H).

CH

3 ___ MS ES + m / z 445 [MCs] * ___ 80 o -0 "8 OCH 3 N a H NMR (CDCl 3, 400 MHz) δ: 3.52 (S, 3H), 3.91 (s, 3H), 4 , 78 (s, 2H), 6.99 (m, 1H), 7.17 (m, 1H), 7.77 (m, 1H), 9.41 (d, 1H), 9.50 yr (d 1 H) MS ES + m / z 461 [MCs] * 81 'CH OCH 3 N * 1 NMR (CDCl 3, 400 MHz) δ: 2.39 (s, 3H), 2.40 (S, 3H), 3, 53 (s, 3H), 4.79 (S, 2H), 7.03-7.41 (m, CH 2 H), 8.86 (S, 1 H), 9.52 (d, 1 H).

II 3 1 1 IMS ES + m / z 429 [MCs] * _

Preparation 82

Methyl (5-nitro-pyridin-2-yl) -amine

O-JOT

5 N

9

.NH

H.CT

10 3

Methylamine gas was bubbled through a stirred solution of 2-chloro-5-nitropyridine (4 g, 25.2 tmmol) in dichloromethane (60 ml), at room temperature, until saturation had occurred. The resulting yellow precipitate was then filtered off, washed with dichloromethane and dried under vacuum to provide the title compound in the form of a yellow solid in a yield of 80%, 3.07 g.

1 H NMR (CDCl 3, 400 MHz) δ: 3.05 (d, 3H), 5.41 (bs, 1H), 6.37 (d, 1H), 8.21 (d, 1H), 9, 03 (d, 1 H). MSAPCI + m / z 154 [MH] + 1027084- 93

Preparation 83 N * 2 * -Methylpyridine-2,5-diamine NH 2

5 rS

^ .NH.

HaC

10

The product of Preparation 82 (3.0 g, 19.5 ramol) and 10% Pd / C (300 mg, cat.) Were stirred in ethanol (150 ml) under 60 psi of hydrogen gas for 18 hours. The reaction mixture was then filtered through Celite® and the filtrate was evaporated in vacuo to provide the title product in a yield of 17%, 400 mg.

ΧΗ NMR (CDCl 3, 400 MHz) 6: 2.85 (S, 3H), 3.19 (s, 2H), 4.11 (S, 1H), 6.31 (d, 1H), 6.97 ( dd, 1H), 7.69 (d, 1H).

MS APCI + m / z 269 [MNa] + 20 Preparation 84 4,6-dichloro-nicotinic acid methyl ester

C10 XA0 -CH3

25 JL

cr n 3-Pyridinecarboxylic acid [{27 g, 160 mmol), J. Het. Chem, 20, 1363; 1983] was added portionwise to phosphorus oxychloride (180 ml) and the mixture was returned to 7 for 30 hours. heated and stirred for 18 hours at room temperature. The mixture was then evaporated in vacuo to a low volume and the residue was quenched with water. The aqueous mixture was neutralized with sodium hydrogen carbonate solution and extracted with chloroform (35 x 150 ml). The combined organic solutions were washed with brine, dried over sodium sulfate and evaporated in vacuo to give the title compound in the form of a red oil in a yield of 83%, 27.2 g.

X H NMR (CDCl3, 400 MHZ) 6: 3.96 (s, 3H), 7.47 (S, 1H), 8.85 (s, 1H). MS APCI + m / z 206 [MH] + 5 Preparations 85 and 86

Sodium methoxide (0.5 M in methanol, 48.6 ml, 24.3 mmol) was added dropwise to an ice-cold solution of the product of Preparation 84 (5.0 g, 24.3 mmol) in methanol (20 ml). The mixture was allowed to warm to room temperature and stirred for 2 hours. The solvent was then evaporated under reduced pressure and the residue was partitioned between water (50 ml) and chloroform (50 ml). The layers were separated and the aqueous layer was extracted with chloroform (2 x 75 ml). The combined organic solutions were then dried over sodium sulfate and evaporated in vacuo to give an orange oil. The oil was purified by column chromatography on silica gel, eluting with dichloromethane (100%) to give the product of Preparation 85 in the form of a white solid in a yield of 7.6%, 370 mg. Further eluting with dichloromethane then isolated the product of Preparation 86 in the form of a white solid in a yield of 27%, 1.32 g.

Preparation 85 4 - Chloro-6-methoxy-nicotinic acid methyl ester

Cl

J1, JL, CH, yT, O1 H NMR (CDCl3, 400 MHz) δ: 3.90 (s, 3H), 3.96 (s, 3H), 6.81 (S, 1H), 8.71 (S, 1H). MS APCI + m / z 202 [MH] + 35 Preparation 86 6-Chloro-4-methoxy-nicotinic acid methyl ester 1027084k - 95 -HSC ^ 0.10 λλr 4 tc 5 1 H NMR (CDCl 3/400 MHz) δ: 3, 87 (s, 3H), 3.94 (s, 3H),

6.90 (s, 1H), 8.68 (s, 1H). MS APCI + m / z 202 [ΜΗ] V

Preparation 87 6-Chloro-4-methoxy-nicotinic acid hydrazide 10

H3CV

o o / NH 2 ij N.

15

Hydrazine monohydrate (690 μΐ, 14.2 mmol) was added to a suspension of the product of Preparation 86 (2.7 g, 13.4 in mol) in methanol (35 ml), cooled to -5 ° C and the mixture was stirred for 3 hours. The mixture was then warmed to room temperature and stirred for 18 hours. The resulting precipitate was filtered off and dried to give some title compound in the form of a white solid, 990 mg. TLC analysis of the filtrate showed that not all of the starting material had been consumed, and thus additional hydrazine monohydrate (267 μΐ, 5.51 mmol) was added and the reaction mixture was stirred for 24 hours. The resulting precipitate was collected by filtration and dried to provide a further yield of title compound in the form of a yellow solid, 832 mg.

1 H NMR (CDCl 3, 400 MHz) δ: 3.92 (s, 3H), 4.55 (bd, 2H), 7.29 (S, 1H), 8.37 (s, 1H), 9.38 ( m, 1 H). MS APCI + m / z 247 [MH) +

Preparation 88 35 6-Chloro-4-methoxy-nicotinic acid N '- (2-methoxy-acetyl) -hydrazide 10270843 - 96 - HSC

O O

^ CH.

fYY Y ^ ° JL J o cr n 5

Methoxyacetyl chloride (733 μΐ, 8.02 mmol) was added to an ice cold suspension of the product of Preparation 87 (1.16 g, 5.73 mmol) in dichloromethane (20 ml) and triethylamine (1.2 ml, 8.61 mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then washed with water and brine, dried over sodium sulfate and evaporated in vacuo to give a pale yellow gum. The gum was purified by column chromatography on silica gel, eluting with dichloromethane / methanol, 100: 0: 0 to 95: 5, to provide the title compound as a clear glass in a 31% yield, 480 mg.

X H NMR (CDCl 3, 400 MHz) δ: 3.48 (s, 3H), 4.08 (s, 3H), 4.10 (s, 2H), 6.96 (s, 1H), 9.03 ( s, 1 H), 9.25 (d, 1 H), 9.99 (d, 1 H). MS APCI + m / z 274/276 [MH] +

Preparation 89 2-Chloro-4-methoxy-5- (5-methoxymethyl- [1,3,4] oxa-diazol-2-yl) -pyridine 25 * S> N-Nv

The title compound was prepared from the product of

Preparation 88 and phosphorus oxychloride, using the method of Preparation 13, in the form of a yellow oil, in quantitative yield.

X H NMR (CDCl3, 400 MHz) 5: 3.49 (s, 3H), 4.04 (s, 3H), 4.73 (s, 2H), 7.01 (s, 1H), 8.83 (s, 1 H). MS APCI + m / z 256 [MH] + 1027084-97

Preparation 90 2-Chloro-4-methoxy-5- [5-methoxymethyl-4- (6-methoxy-pyridin-3-yl) -4 H- [1,2,4] triazol-3-yl] pyridine

1 i'K

o-ch3 v

\ N

10 H3c

The title compound was prepared from the product of Preparation 89 and 5-amino-2-methoxypyridine, using the method of Preparation 18, in the form of a pale yellow foam, in a yield of 29%.

X H NMR (CDCl 3, 400 MHz) δ: 3.37 (s, 3H), 3.61 (s, 3H), 3.93 (S, 3H), 4.49 (s, 2H), 6.76 ( m, 2H), 7.43 (dd, 1H)., 7.98 (d, 1H), 8.42 (S, 1H). MS APCI + m / z 362 [MH] +

Preparation 91 5- (4-Fluoro-2-methyl-phenyl) -pyrazine-2-carboxylic acid methyl ester ^ CH3 25 ° F ^ ^ CH3 30 4-Fluoro-2-methylphenylboronic acid (17.36 g, 112.7 mmol) cesium carbonate (70.8 g, 216.8 mmol) and the product of Preparation 3 (1.5 mg, 8.67 mmol) were added to a solution of 5-chloropyrazine-2-methyl carboxylate (15 g, 86, 7 mmol) in 1,4-dioxane (2 L) and the mixture was refluxed for 2 hours. The reaction mixture was then filtered and evaporated in vacuo to give the title compound in 99% yield, 1027084-

"I

- 98 - 21.33 g.

* H NMR (CDCl 3, 400 MHz) δ: 2.40 (s, 3H), 4.05 (s, 3H), 7.05 (m, 2H), 7.45 (m, 1H), 8.80 (s, 1H), 9.35 (s, 1H).

MS APCI + m / z 247 [MH] + 5 Preparation 92 5- (4-Fluoro-2-methyl-phenyl) -pyrazine-2-carboxylic acid hydrazide. ".

fNy ^ ^

x ° H

A mixture of the product of Preparation 91 (42.5 g, 172.8 mmol) and hydrazine monohydrate (9.46 tll, 207.3 mmol) in methanol (600 ml) was heated under reflux for 30 hours. The reaction mixture was then cooled to room temperature, and the precipitate was filtered off and dried in vacuo to provide the title compound in a yield of 75%, 7.10 g.

1 H NMR (DMSO, 400 MHz) δ: 2.35 (s, 3H), 4.60 (s, 2H), 7.20 (m, 2H), 7.60 (m, 1H), 8.80 ( s, 1H), 9.15 (s, 1H), 10.2 (S, 1H).

Examples 1-4

N "N

a ó 30 O-CH,

The bromine compound of Preparation 5 (100 mg, 0.29 mmol), the palladium complex of Preparation 3 (10 mg, cat.), Cesium carbonate (440 mg, 1.35 mmol) and the appropriate boronic acid (0.73 mmol) ) were suspended in 1,4-dioxane (5 ml) and the reaction mixture was heated to 120 ° <3 for 90 minutes. Additional 1,4-dioxane (4 ml) was added and the reaction 1027084-99.

The mixture was heated to 100 ° C for a further 4 hours. The reaction mixture was filtered under vacuum, flushing with dichloromethane. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane / methanol / 0.88 ammonia 95: 5: 0.5 to provide the desired product.

nr R1_Data _ '_ Rem.

1 MS ES + m / z 390 [MH] + 9%

F

11 .chs 2 * 1 NMR (CDCl 3, 400 MHz) δ: 2.01 (s, 10% CH 3 3H), 2.22 (S, 3H), 2.26 (s, 3H), 3.75 <s (3H), 6.87 (d, 1H), 7.02 [IJ (m, 4H), 7.20 (m, 2H), 7.24 (m, 2H), 7.39 (m, 2H) ___ MS APCI + m / z 370 [MH] * __! 3 MS APCI + m / z 370 [MH] + 36%

CH

<x 4 1 H NMR (CDCl 3, 400 MHz) δ: 2.31 (S, 52% 3 H), 3.79 (s, 3 H), 3.83 (s, 3 H), H 3 C. A ^ J 7 ', O 2 (m, 3 H), 7.27 (m, 2 H), 7.34 (d, 2 H), 7.41 (d, 2 H), 7.57 (d, _ | 2 H) . MS APCI + m / z 390 [MH] * 10

Example 5 2- (4-Fluoro-2-methylphenyl) -5- (5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazol-3-yl) pyridine 1027084 - n - 100 - nN o-ch.

I ys *

rw ^ ssr ^ 'N

° -ch3

The title product was prepared by the method of Preparation 18 using the product of Preparation 10 19 and 5-amino-2-methoxypyridine. 140 mg, 15% yield of the desired product was produced.

ΧΗ NMR (CDCl 3, 400 MHz) 6: 2.36 (s, 3H), 3.38 (S, 3H), 4.01 (s, 3H), 4.51 (s, 2H), 6.88 ( d, 1H), 6.93-7.00 (m, 2H), 7.36 (dd, 1H), 7.40 (d, 1H), 7.56 (dd, 1H), 8.00 (dd , 1 H), 8.15 (d, 1 H), 8.64 (d, 1 H). Microanalysis: C 22 H 20 FN 5 O 2 requires: C 65.18, H 4.97, N 17.27, found C 65.01, H 4.96, N 17.27. MS APCI + m / z 406 [MH] +

Example 6 2- (2,3-Dimethylphenyl) -5- (5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazol-3-yl) - pyridine jN ^ O-ch,

? 3 T T L

25 h V

° '-ch3

The title product was prepared by the method of Preparation 18 using the product of Preparation 30 and 5-amino-2-methoxypyridine. 325 mg, 36% of the desired product was produced.

X H NMR (CDCl3, 400 MHz) 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, 1H), 7.55 (d, 1H), 7.99 (dd , 35 H), 8.16 (d, 1 H), 8.64 (d, 1 H). Microanalysis: C23H23N502.

0.1 H2 O required; C 68.50, H 5.80, N 17.37; found C 68.24, H 5.90, N 17.05. MS APCI + m / z 402 [MH] + 1027084- * * - 101 -

Example 7 5- {4-Fluoro-2-methylphenyl) -2 - (((5-methoxymethyl-4- (6-methoxypyridin-3-yl)) -4H- [1,2,4] triazol-3-yl pyridine 5; V 5 ch 3

CHS

10

The bromine compound of Preparation 18 (250 mg, 0.66 mmol), 2-methyl-4-fluorophenylboronic acid (235 mg, 1.53 mmol), the palladium complex of Preparation 3 (10 mg, cat.) And cesium carbonate (1, 00 g, 3.07 mmol) were added to 1,4-dioxane (15 ml) and the reaction mixture was heated to 110 ° C for 4 hours. The reaction mixture was filtered through Arbocel®, flushed with dichloromethane and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane / methanol 100: 0 to 95: 5 to give the title product, 128 mg, 48% yield, as a pale pink solid.

X H NMR (DMSO-D6, 400 MHz) 5: 2.21 (s, 3H), 3.18 (s, 3H), 3.89 (S, 3H), 4.44 (s, 2H), 6, 94 (m, 1H), 7.09 (m, 1H), 7.19 (m, 1H), 7.28 (m, 1H), 7.81 (m, 1H), 7.94 (m, 1 H), 8.15 (m, 1 H), 8.23 (m, 1 H), 8.32 (m, 1 H).

MS APCI + m / z 406 [MH] +

Example 8 5- (2,3-Dimethylphenyl) -2- [5- (methoxymethyl) -4- (6-30 methoxypyridin-3-yl) -4H-1,2,4-triazol-3-yl] pyridine w -No-ch, yy y Y 3? Hi (Ti 1 35 ^ ° ^ ch 3 1027084-

t A

- 102 -

The title product was prepared by the method of Example 7 using 2,3-dimethylphenylboronic acid. 132 mg, 49% yield, of the desired product was prepared in the form of a pale pink solid.

5 X H NMR (DMSO-D6, 400 MHz) δ: 2.07 (s, 3 H), 2.38 (S, 3 H), 3.17 (S, 3 H), 3.89 (s, 3 H), 4 44 (s, 2H), 6.94 (rn, 1H), 7.04 (m, 1H), 7.15 (m, 1H), 7.22 (m, 1H), 7.82 (m, 1 H), 7.90 (m, 1 H), 8.15 (ra-1 H), 8.24 (m, 1 H), 8.28 (m, 1 H). MS APCI + m / z 402 [MH] + 10 Example 9 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 H3C Phs m tpQ-jX "? 20 Ox CH3

The bromine compound of Preparation 27 (125 mg, 0.27 mmol), 2,3-dimethylphenylboronic acid (61 mg, 0.41 mmol) and the palladium complex of Preparation 3 (10 mg) were dissolved in 1,2-dimethoxyethane (4 ml) and the solution was treated with sodium carbonate (58 mg, 0.55 mmol). The reaction mixture was heated under reflux for 1 hour and then evaporated in vacuo. The residue was taken up in ethyl acetate (25 ml) and washed with water (25 ml), 2M sodium hydroxide solution (25 ml) and saline (25 ml). The solution was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane / methanol / 0.88 ammonia 100: 0: 0 to 97: 3: 0.3 to give the title product, 95 mg, yield 72%.

X H NMR (CDCl 3, 400 MHz) δ: 1.80 (m, 2H), 2.00 (m, 1H), 1027084- <. · 103 - 2.10 (s, 3H), 2.20 (m, 1H), 2.40 (s, 3H), 2.60 (τη, 1Η), 3.20 (τη, 2Η), 3.80 (τη , 2Η), 4.00 (s, 3Η), 5.00 (s, 1Η), 6.80 (s, 1Η), 6.90 (d, 1Η), 7.00 (d, 1Η), 7.10 (d, 1Η), 7.20 (d, 1Η), 7.60 (d, 1Η), 7.70 (d, 1Η). 8.80 (s 1H), 5.20 (τη, 2H). MS ES + m / z 484 [MH] +

Example 10 5- (2,3-Dimethylphenyl) -2- (5-Pyrrolidin-1-ylmethyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazol-3-yl) pyridine v

oV

CH 3 80 mg, 38% yield, of the title product was prepared by the method of Example 9 using the bromine compound of Preparation 28.

1 H NMR (CDCl 3, 400 MHz) 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), 6.80 (d, 1H), 7.00 (d, 1H), 7.20 (m, 2H), 7.70 (t, 2H), 8.10 (d, 1 H), 8.20 (d, 1 H), 8.30 (s, 1 H). MS ES + m / z 441 [MH] + Example 11 2- (4-Fluoro-2-methylphenyl) -5- [5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4H- [1,2 4] triazol-3-yl] -pyrazine CH3 r λ r ~ N Nw 30 f \ _ / - \ y-1 ^ = 7 ^ = 7 N - ^ \> Os / ch3 yj η30-ο

The product of Preparation 22 (450 mg, 1.50 mmol), p-toluenesulfonic acid monohydrate (30 mg) and 5-amino-2-methoxypyridine (205 mg, 1.65 mmol) were added to xylene (8 ml) and the reaction mixture was heated to 145 ° C for 18 hours. The reaction mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane / methanol / 0.88 ammonia 100: 0: 0 to 99.5: 0.5: 0.05 to 99: 1: 0 1 to provide the title product, 300 mg, 49% yield, in the form of a green solid.

* Η NMR (CDCl 3, 400 MHz) δ: 2.38 (s, 3H), 3.34 (s, 3H), 3.99 (S, 3H), 4.50 (s, 2H), 6, 85 (d, 1H), 6.95-7.03 (m, 2H), 7.36-7.42 (m, 1H), 7.60 (dd, 1H), 8.12 (d, 1H) , 8.40 (s, 1H), 9.48 (S, 1H). MS APCI + m / z 407 [MH] +

Example 12 2- (2,3-Dimethylphenyl) -5- (5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazol-3-yl] - pyrazine

HgC CH 3 ^ J 2 O 4 CH 2 3 3} h 3 C 42 ° 42 mg, 7% yield of the title product was prepared by the method of Example 11, using the product of Preparation 21.

X H NMR (CDCl3, 400 MHz) δ: 2.23 (s, 3H), 2.34 (s, 3H), 3.36 (s, 3H), 4.00 (s, 3H), 4.50 ( m, 2H), 6.86 (d, 1H), 7.19 (d, 1H), 7.20 (s, 1H), 7.24 (m, 1H), 7.62 (dd, 1H) , 8.14 (d, 1H), 8.41 (d, 1H), 9.49 (d, 1H). MS APCI + m / z 403 [MH] +

Example 13 2- (2,3-Dimethylphenyl) -5- [4- (6-methoxypyridin-3-yl) -35-5-methyl-4H- [1,2,4] triazol-3-yl] -pyrazine 1027084 - Λ. 3.05 h3c CH3.

Ö-Y'V / '. V'

"" ^ 1 == / N-'V

_f CH3 · 5 V ^

5 V-N

HjC'O

The title product was prepared by the method of Example 11 using the product of Preparation 23. 14 mg, 3%, of the desired product was produced in the form of a white solid.

ΧΗ NMR (CDCl 3, 400 MHz) δ: 2.22 (s, 3H), 2.34 (s, 3H), 2.39 (s, 3H), 4.01 (s, 3H), 6.88 ( d, 1H), 7.18-7.25 (m, 3H), 7.52 (dd, 1H), 8.0 g (d, 1H), 8.37 (s, 1H), 9.49 ( s, 15 1H). MS APCI + m / z 373 [MH] +

Example 14 2- (4-Fluoro-2-methylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4 H- [1,2,4] triazol-3-yl] pyrazine

, CHS

20 _ /

F-A / 1JS

y) H 3 C-O

The chlorine compound of Preparation 30 (800 mg, 2.60 mmol), 4-fluoro-2-methylphenylboronic acid (470 mg, 3.12 mmol), the palladium complex of Preparation 3 (5 mg) and cesium car-30. bonate (2.50 g, 7.90 mmol) was added to 1,4-dioxane (80 ml) and the reaction mixture was heated under 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 evaporated in vacuo and purified by column chromatography on silica gel, eluting with dichloromethane / methanol 100: 0 to 95: 5 to afford 1027084 - the title product in the form of a white solid in a yield from 66%, 646 mg.

X H NMR (CDCl 3, 400 MHz) 5: 2.39 (s, 3H), 2.41 (s, 3H), 4.01 (s, 3H), 6.89 (d, 1H), 6.95- 7.03 (m, 2H), 7.38 (dd, 1H), 7.54 (dd, 1H), 8.0 g (d, 1H), 8.38 (d, 1H), 9.49 (d, 1 H). MS APCI + m / z 377 [MH] +

Alternative method

Dimethylacetamide-dimethylacetal (28 ml, 192.1 mmol) was added to a suspension of the product of Preparation 92 (31.5 g, 127.9 mmol) in glacial acetic acid (315 ml) and the mixture was heated at 60 for 5 hours ° C. 5-Amino-2-methoxy-pyridine (23.9 g, 192 mmol) was added and the mixture was heated at 100 ° C for an additional 6 hours. The mixture was then cooled to room temperature and evaporated under reduced pressure. The residue was taken up in dichloromethane (750 ml) and washed with saturated sodium hydrogen carbonate solution (1 L). The organic solution was dried over magnesium sulfate and evaporated in vacuo. Recrystallization of the residue from hot acetone then afforded the title compound in the form of a white solid in a yield of 31%, 14.81 g.

Example 15 2- (4-Cyano-2-methylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] pyrazine 25

CH

nc-O ^ V ^% n N “J * ch3

30 y-N

H3C "°

The title product was prepared by the method of Example 14 using the chlorine compound of Preparation 30 (200 mg, 0.66 mmol) and the product of Preparation 29 (240 mg, 0.99 mmol). 68 mg, 27% yield, of the title product was prepared in the form of a white solid 1027084 "*) - 107 substance.

* Η NMR (CDCl 3, 400 MHz) 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, 1H), 8.08 (d, 1H), 8.41 (d, 1H), 9.55 5 (d, 1 H). Microanalysis: C21H17N70.0.1H2 O requires: C 65.79, H 4.47, N 25.57; found C 65.23, H 4.48, N 25.09.

MS APCI + m / z 384 [MH] +

Example 16 2- (5-Fluoro-2-methoxyphenyl) -5- [4- (6-methoxypyridin-3-10 yl) -5-methyl-4H- [1,2,4] triazol-3-yl] - pyrazine

F

N

N = / Λ

15 P

H3C O

7 ^ n Η, 0- °

The title product was prepared by the method of Example 14 using the chlorine compound of Preparation 30 (200 mg, 0.66 mmol) and 5-fluoro-2-methoxy-phenylboronic acid (168 mg, 0.99 mmol). 150 mg, 58% yield, of the title product was prepared in the form of a cream-colored solid.

25 X H NMR (CDCl 3, 400 MHz) δ: 2.37 (s, 3H), 3.85 (s, 3H), 4.00 (s, 3H), 6.88 (d, 1H), 6.92 (dd, 1H), 7.09 (m, 1H), 7.50 (dd, 1H), 7.68 (dd, 1H), 8.07 (d, 1H), 8.93 (d, 1H) , 9.46 (d, 1 H).

Example 17 2- (4-Cyano-2-methylphenyl) -5- (5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazol-3-yl] - pyrazine ch3 '-' N = / N n ^ -Os 0ch3 H3C "0 1027084 - <- 108 - t

The title product was prepared by the method of Example 14 using the chlorine compound of Preparation 31 (1.0 g, 3.0 in mol) and Preparation 29 (1.02 g, 4.2 in mol). 814 mg, 66% yield of the desired product was prepared in the form of a pale yellow solid.

1 H NMR (CDCl 3, 400 MHz) δ: 2.35 (s, 3H), 3.15 (s, 3H), 3.80 (s, 3H), 4.45 (s, 2H), 6.95 ( d, 1 H), 7.65-7.90 (m, 4 H). MS APCI + m / z 414 (MH) +

Example 18 5- (4-Cyano-2-methylphenyl) -2- [5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazol-3-yl] - pyridine CH3 / T-N N N-v K1 15 NcHQHCMi o 'ch3 h3C "0 20

The title product was prepared by the method of Example 7 using the product of Preparation 29 (100 mg, 0.41 mmol) and the bromine compound of Preparation 18 (155 mg, 0.41 mmol). 67 mg, 39% yield, of the desired product was prepared in the form of a white solid.

X E NMR (CDCl 3> 400 MHz) δ: 2.28 (s, 3H), 3.35 (s, 3H), 3.99 (s, 3H), 4.50 (s, 2H), 6.85 ( d, 1H), 7.28 (d, 1H), 7.52-7.58 (m, 2H), 7.62 (dd, 1H), 7.74 (dd, 1H), 8.11 (d (30 H), 8.28 (dd, 1 H), 8.33 (1 H, d). Microanalysis: C23H20N6O2.

0.5H20 required; C 66.55, H 5.02, N 19.94; found C 66.02, H 4.90, N 19.83. MS APCI + m / z 413 [MH] +

Example 19 2- (5-Fluoro-2-methoxyphenyl) -5- [5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazol-3-yl] - pyridine 1027084- *> - 109 -

HaC

O

N = /) * For F -5 / ch3 5 4)

V-N

H3C-0

The title compound was prepared using the method of Example 11, using the oxadiazole compound of Preparation 32 and 5-amino-2-methoxy-pyridine, in the form of a pale green solid (325 mg, 30%) - NMR (CDCl3, 400 MHz) δ: 3.36 (s, 3H), 3.84 (s, 3H), 3.98 (s, 3H), 4.49 (s, 2H), 6 87 (d, 1H), 6.92 (dd, 1H), 7.06 (m, 1H), 7.54 (dd, 1H), 7.58 (dd, 1H), 7.96-8, 00 (m, 2H), 8.14 (d, 1H), 8.60 (d, 1H). MS APCI + m / z 422 [MH] +

Examples 20-22

The following compounds, of the general formula 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 first purified by column chromatography on silica gel, eluting with ethyl acetate / methanol / 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 / trifluoroacetic acid (5: 95: 0.1) / acetonitrile, 95: 5 to 5:95.

yN

h3c, 35 I027084 - 110 - no. R1 - Y_Data_. - Yield 20 * "CH * H NMR (CDCl3, 400 MHz) δ: 2.37 21% (S, 3H), 3.97 (S, 3H), 5.77 (S,

J1 (2H), 6.80 (d, 1H), 7.31 (dd, NC CH3, 1H), 7.45 (m, 2H), 7.56 (m, 4H), 7.99 (d, 1H) ), 8.04 (dd, 1H), 8.66 (dd, 1H). MS APCI + m / z 450 _____ [MH] * _____ 21 N NMR (CDCl3, 400 MHz) δ: 2.40 15% (s, 3H), 3.97 (S, 3H), 5.77 (s, 2H) ), 6.75 (d, 1H), 7.35 (dd, NC vH * 1H), 7.50 (d, 1H), 7.54-7.67 (m, 4H), 7.95 (d 1 H), 8.41 (s, 1 H), 9.58 (S, 1 H). MS APCI + m / z 450 ___ [MH] * _________ 22 · CH * Η NMR (CDCl3, 400 MHz) δ: 2.34 43% (s, 3H), 3.97 (s, 3H), 5.77 (s, 2H), 6.78 (d, 1H), 6.95 (m, 2H), F CH, 7.30 (dd, 1H), 7.35 (dd, 1H), 7.42 (dd 1 H), 7.57 (s, 2 H), 8.00 (m, 2 H), 8.60 (d, 1 H).

| _J_ [MS APCI + m / z 443 [MH] * _

Example 23 4- {5- [5- (Methoxymethyl) -4- (6-methoxypyridin-3-yl) -4H-1,2,4-triazol-3-yl] pyridin-2-yl} -3 ^ methylbenzonitrile 5 r \ 10 H 3 C "0

The chlorine compound of Preparation 49 (170 mg, 0.87 mmol), the palladium complex of Preparation 3 (5 mg, cat.), Cesium carbonate (847 mg, 2.61 mmol) and the product of 1027084a * * * '. · · - 111 -

Preparation 29 (317 mg, 1.31 mmol) were suspended in 1,4-dioxane (5 ml) and the reaction mixture was heated to 110 ° C for 2 hours. The reaction mixture was diluted with ethyl acetate and water and filtered through Celite®. The layers of the filtrate were separated and the aqueous solution was re-extracted with ethyl acetate (x 2). The combined organic solutions were then washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane / methanol / 0.88 ammonia 100: 0: 0 to 97.5: 2.5: 0.25 to give the title compound in the form of a white foam in a yield of 45%, 160 mg.

ΧΗ NMR (CDCl 3, 400 MHz) δ: 2.38 (s, 3H), 3.38 (s, 3H), 4.00 (s, 3H), 4.51 (s, 2H), 6.90 (d, 1H), 7.45 (d, 1H), 7.48 (d, 1H), 7.55-7.60 (m, 3H), 8.03 (dd, 1H), 8.15 ( d, 1 H), 8.70 (dd, 1 H). MS APCI + m / z 413 [MH] +

Examples 24 to 28

The following compounds, of the general formula below, were prepared according to the method of Example 23, using the appropriate triazole compounds (Preparations 31 and 50-51) and boronic acids.

r. γ.

H3C "0 30 35 1027004 - 112 - no. R1 ___ Y__R ^ __ Rem.

24 CH H 37%

XX

nc '^ v // xch3

Data: X H NMR (CDCl 3, 400 MHz) δ: 2.38 (s, 3H), 2.41 (s, 3H), 4.00 (S, 3H), 6.92 (d, 1H), 7, 45 (m, 3H), 7.55 (S, 1H), 7.58 (S, 1H), 8.02 (dd, 1H), 8.12 (d, 1H), 8.66 (d, 1H) ). Microanalysis: C22 H18 N6 O required; C 69.10, H 4.74, N 21.98; found C 68.74, H 4.75, N 21.83. MS APCI + m / z 383 [MH] * ____ 25 CH H 83%

I T

1 ch3 I | _____ [_

Data: 1 H NMR (CDCl 3, 400 MHz) δ: 2.39 (s, 3H), 3.83 (s, 3H), 3.99 (s, 3H), 6.88-6.94 (m, 2H ), 7.05 (m, 1H), 7.45 (dd, 1H), 7.58 (S, 1H), 7.97 (m, 2H), 8.11 (d, 1H), 8.57 (d, 1 H). MS APCI + m / z 392 [MH] *.

26 N OCH 3 35% 2 CH 3 1 | __

Data: 1 H NMR (CDCl 3, 400 MHz) δ: 3.35 (s, 3H), 3.86 (s, 3H), 4.00 (S, 3H), 4.49 (s, 2H), 6, 71 (dd, 1H), 6.80 (m, 1H), 6.85 (d, 1H), 7.59 (dd, 1H), 7.91 (dd, 1H), 8.12 (d, 1H) ), 8.88 (d, 1H), 9.44 (d, 1H). MS APCI + m / z 423 [MH] * 27 ^ CH 31%

XX

Data: 1 H NMR (CDCl 3, 400 MHz) δ: 2.38 (s, 3H), 3.34 (s, 3H), 3.50 (ra, 2H), 3.66 (m, 2H), 3, 99 (s, 3H), 4.62 (s, 2H), 6.88 (d, 1H), 7.44 (d, 1H), 7.48 (d, 1H), 7.56 (d, 2H) ), 7.66 (dd, 1H), 8.02 (dd, 1H), 8.15 (d, 1H), 8.70 (d, 1H). Microanalysis: C 25 H 24 N 6 O 3 0.5H 2 O requires: C 64.50, H 5.41, N 18.05; found C 64.71, H 5.33, N 17.94. MS APCI + | ra / z 457 [MH] * 1027084 - 113 -> t 28 CH 90%

F ^ CHS

Data: 1 H NMR (CDCl 3, 400 MHz) 5: 2.35 (s, 3H), 3.34 (s, 3H), 3.50 (τη, 2H), 3.66 (m, 2H), 3, 98 (s, 3H), 4.62 (s, 2H), 6.87 (d, 1H), 6.93-7.00 (m, 2H), 7.36 (dd, 1H), 7.41 (d, 1H), 7.65 (dd, 1H), 7.97 (dd, 1H), 8.15 (d, 1H), 8.64 (d, 1H). MS APCI + m / z 450 [MH] * __

Example 29 [5- [6- (4-Fluoro-2-methyl-phenyl) -pyridin-3-yl] -4- (6-methoxy-pyridin-3-yl) -4H- [1,2,4 ] triazol-3-ylmethyl] -di-5 methylamine [7], CH-CH

V-N

"ο Y "H3C-0

The title compound was prepared from the product of Preparation 48 and 4-fluoro-2-methylphenylboronic acid, using the method of Examples 1-4, in the form of a white foam in a 70% yield.

X H NMR (CDCl3, 400 MHz) 5: 2.25 (s, 6H), 2.34 (s, 3H), 3.47 (s, 2H), 3.99 (s, 3H), 6.86 ( d, 1H), 6.93-7.00 (m, 2H), 7.38 (m, 2H), 7.64 (dd, 1H), 8.00 (dd, 1H), 8.16 ( d, 1 H), 8. 63 (d, 1 H). Microanalysis: C23H23FN60.0.25H2 O required; C 65.31, H 5.60, N 19.87; found C 65.19, H 5.63, N 19.58. MS APCI + m / z 419 [MH] +

Example 30 5- {3- (Ethoxymethyl) -5- [6- (4-fluoro-2-methylphenyl) pyridin-3-yl) -4H-1,2,4-triazol-4-yl] -2 -methoxypyridine 1027084- • »- 114 -

/ N ^ N

CH 3/5 H 3 C "°

The chlorine compound of Preparation 52 (230 mg, 0.67 inmol), the palladium complex of Preparation 3 (10 mg, cat.), Cesium carbonate (648 mg, 2.01 mmol) and 4-fluoro-2-methyl-10-phenylboronic acid ( 143 mg, 0.94 mmol) were suspended in 1,4-dioxane (4 mL) and the reaction mixture was heated to 110 ° C for 2 hours. A further amount of the product from Preparation 3 (5 mg) was added and heating was 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 evaporated in vacuo. The residue was 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 provide the title compound in the form of a white powder in a yield of 16%, 44 mg.

X H NMR (CDCl 3, 400 MHz) δ: 1.16 (t, 3H), 2.35 (s, 3H), 3.54 (q, 2H), 3.99 (s, 3H), 4.55 ( s, 2H), 6.88 (d, 1H), 6.93-7.00 (m, 2H), 7.34-7.42 (m, 2H), 7.56 (dd, 1H), 8.00 (dd, 1H), 8.16 (d, 1H), 8.65 (d, 1H). Microanalysis: C23H22FN5O2.0.5H2O 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 [MH] +

Example 31 4- {5- [5- (Ethoxymethyl) -4- (6-methoxypyridin-3-yl) -4H-1,2,4-triazol-3-yl] pyridin-2-yl} -3-methylbenzonitrile

M SOH

NC "\ === / CH, 35 L 11 H 3 Cl 2 1027084s - 115 -

The title compound was prepared from the product of Preparation 52 and the product of Preparation 29, using the method of Example 30, in the form of a beige solid in a yield of 15%.

5 X H NMR (CDCl 3, 400 MHz) δ: 1.16 (t, 3H), 2.38 (s, 3H), 3.52 (q, 2H), 4.00 (s, 3H), 4.55 (s, 2H), 6.89 (d, 1H), 7.43 (d, 1H), 7.49 (d, 1H), 7.58 (m, 3H), 8.02 (dd, 1H) , 8.17 (d, 1H), 8.70 (d, 1H). Microanalysis: C24H22NeO2.0.5H2 O 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 [MH] +

Example 32 2- (3,4-Dimethyl-phenyl) -5- [5-methoxymethyl-4- (6-methoxy-pyridin-3-yl) -4 H- [1,2,4) triazole-3- yl] pyrazine

15 yc-N

H3C Γ \.

Vn H3C "0 20 3

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 / 0.88 ammonia 96: 4: 0.4 followed by 100% ethyl acetate to provide the desired compound in the form of a beige solid in a yield of 68%.

30 ^ NMR (CDCl3, 400 MHz) 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, 1H), 7.71 (dd, 1H), 7.80 (s, 1H) , 8.11 (d, 1H), 8.71 (d, 1H), 9.42 (d, 1H). MS APCI + m / z 403 [MH] + 35 Example 33 4- {4- [5-Methoxymethyl-4- (6-methoxy-pyridin-3-yl) -4H- (1,2,4] triazole-3- yl] -phenyl} -2,3-dimethylpyridine-1-oxide 1027084- 116 -

0 VSh, W / N

) θ

HSC

A mixture of the product of Preparation 57 (230 mg, 0.74 mmol), 5-amino-2-methoxy pyridine (100 mg, 0.81 mmol) and p-toluenesulfonic acid (30 mg, cat.) In xylene ( 4 ml) was heated under reflux for 18 hours. The mixture was then acidified with 1 M hydrochloric acid and washed with ethyl acetate and the organic layer discarded. The aqueous solution was made basic with 1 M sodium hydroxide solution and extracted with ethyl acetate (x 2). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated in vacuo to give a brown oil. Purification of the oil by column chromatography on silica gel, eluting with dichloromethane / methanol / 0.88 ammonia, 100: 0: 0. to 98: 2: 0.1, afforded the title compound in the form of a beige foam in a yield of 24%, 74 mg.

ΧΗ NMR (CDCl 3, 400 MHz) δ: 2.16 (s, 3H), 2.53 (S, 3H), 3.31 (s, 3H), 3.94 (s, 3H), 4.43 (s, 2H), 6.81 (d, 1H), 6.94 (d, 1H), 7.19 (m, 2H), 7.49 (m, 3H), 8.08 (d, 1H) , 8.16 (d, 1 H). MS APCI + m / z 418 [MH] +

Example 34 2- (4-Fluoro-2-methylphenyl) -5- [4- (6-methoxypyridin-3-30 yl) -5-methyl-4H-1,2,4-triazol-3-yl] pyridine

JS V

/ ch, I n N 3

, Nλ N O

35 CH3 γ, Η3 ° / 0 1027084 - 117 -

The title compound was prepared from the product of Preparation 72 and 5-amino-2-methoxypyridine, using the method of Example 33, in the form of a brown solid in 54% yield.

5 X H NMR (CDCl 3, 400 MHz) δ: 2.34 (s, 3H), 2.39 (s, 3H), 3.99 (S, 3H), 6.87-7.01 (m, 3H) , 7.35 (dd, 1H), 7.39 (dd, 1H), 7.45 (dd, 1H), 7.97 (dd, 1H), 8.11 (d, 1H), 8.59 ( d, 1 H). MS APCI + m / z 376 [MH] +

Examples 35 to 45 The following compounds, of the general formula below, were prepared by the method of Example 34 using the appropriate oxadiazole (Preparations 73-81) and aminopyridine.

The progress of the reactions was followed by dlc analysis and the mixtures were heated under reflux until all starting materials were used up.

20 N ^

C4 H4 C3 O5 O3.

N-N

HjC''0 nr R1_ R2 Y Data_Ob.

1027084-4.

- 118 - 35 OCH 3 CH X H NMR (CDCl 3, 400 MHz) 25% δ: 2.07 (s, 3H), 2.34 (s, 3H), 3.32 (S, 3H), 3.97 (s (3 H), 4.38 (d, 1 H), 4.49 (d, 1 H), 6.74 (d, 1 H), 6.95 (ra, 2 H), 7.35 (dd, 1 H), 7.39 (d, 1H), 7.50 (d, 1H), 8.02 (d,

1 H), 8.65 (d, 1 H). MS

______ APCI + ra / z 420 [MH] * 36 OCH 3 N * Η NMR (CDCl 3, 400 MHz) 33% ifV '. δ: 2.12 (S, 3H), 2.38 (s, 3H), 3.32 (s, 3H), 3.99 (s, 3H), 4.39 (d, 1H), 4.49 (d (1 H), 6.66 (d, 1 H), 6.99 (m, 2 H), 7.37 (d, 1 H), 7.39 (d, 1 H), 8.39 (d, 1 H), 9 52 (d, 1H) __________ MS APCI + ra / z 421 [MH] * __ 37 Η N X H NMR (CDCl3, 400 MHz) 50% δ = 2.17 (s, 3H), 2.23 (s, 3H) , 2.44 (s, 3H), 4.00 (s, 3H), 6.64 (d, 1H), 7.01 (m, 2H), 7.37 (m, 2H), 8.37 ( s, 1H), 9.43 (s, 1H). MS APCI + m / z 390 ______ [MH] * _____ 38. Η N 2Η NMR (CDCl 3, 400 MHz) 36% fjT δ: 2.15 (s, 3H), 2.21 (s, | ^ CH> 3H), 2.31 (S, 3H), 2.33 CH , (S, 3H), 3.99 (S, 3H), 6.68 (d, 1H), 7.18 (m, 2H), 7.24 (m, 1H), 7.33 (d, 1H) ), 8.35 (d, 1 H), 9.50 (d, 1 H). MS APCI + m / z __ I 387 [MH] * __ 1027084 - 119 - • N-Ν, ff CHa HSC ° N ° R1_R2 Y_Data _ Rem.

39 Η N ΧΗ NMR (CDCl 3, 400 MHz) 69% fV "δ: 2.33 (s, 3H), 2.38 (s, 3H), 3.82 (s, 3H), 3.98 (s, 3 H), 6.41 (d, 1 H), 6.99 (m, 2 H), 7.38 (dd, 1 H), 7.43 (d, 1 H), 8.38 (d, 1 H), 9, 45 (d, 1H) -________ MS APCI + m / z 407 [MH] * 40 Η N * H NMR (CDCl 3, 400 MHz) δ: 49% (yy 2.21 (s, 3H), 2.33 ( m, (6H), 3.82 (s, 3H), 3.98

CH

(s, 3H), 6.41 (S, 1H), 7.21 (m, 3H), 7.44 (d, 1H), 8.37 (d, 1H), 9.44 (d, 1H) . MS APCI + m / z 403 _ 1 1 [MH] * ____

N-N

/ Vnm

R '- \ J V

'Φ V' ° 10270043 - 120 - no.

41 OCH 3 N X H NMR (CDCl 3, 400 MHz) 6: 33% 2.34 (d, 3H), 3.35 (s, 3H), 4.00 (s, 3H), 4.50 (S, 2H) 6.85 (d, 1H), 7.10 (dd, CH3 1H), 7.58 (dd, 1H), 7.79 (m, 1H), 7.87 (dd, 1H), 8.11 (d, 1 H), 8.69 (d, 1 H) 9.44 (d, 1 H) MS APCI + m / z 407 [MH] * ______ 42 OCH 3 N 1 NMR (CDCl 3, 400 MHz) 40% δ: 3.36 (s, 3H), 3.93 (s, 3H), 4.01 (s, 3H), 4.51 [IJ (S, 2H), 6.86 (d, 1H), 7 , 06 (dd, 1H), 7.21 (dd, 1H). 7.57 (m, 2H), 8.11 (d, 1H), 8.79 (d, 1H), 9.51 (d, 1H) MS APCI + m / z ______ 423 [MH] * ___ 43 CH OCH3 N X H NMR (COCl 3, 400 MHz) 31% 3.5: 2.34 (s, 3H), 3.83 (s, 3H), 3.35 (s, 3H), 4.00 I (S, 3H) , 6.85 (d, 1H), 4.50 (S, 2H), 6.89 (d, 1H)

Ch3 1 7.19-7.26 (m, 1H), 7.59 (dd, 1H), 7.68 (S, 1H), 8.12 (d, 1H), 8.91 (s, 1H), 9.44 ( d, 1 H) MS APCI + m / z ____419 [MH] * __, 44 ^ CH 3 OCH 3 N 1 NMR (CDCl 3, 400 MHz) 39% 7 δ: 3.35 (S, 3H), 3.85 (s, 3H) ), 4.00 (s, 3H), 4.50 IJ (s, 2H), 6.85 (d, 1H), 6.93 (d, 1H), 7.10 (m, 1H) F 7, 59 (dd, 1H), 7.69 (s,

1 H), 8.12 (d, 1 H), 8.96 (S, 1 H), 9.47 (d, 1 H). MS

1 _ 1 [aPCI + m / z 423 [MH] + _: 1027084 - * * - 121 - ..

45 OCH 3 N * 1 NMR (CDCl 3, 400 MHz) 5: 41% CH, 2.33 (s, 3H), 2.34 (s, 3H), 3.35 (S, 3H), 4.00 μT (S, 3H), 4.50 (S, 2H), 6.85 (d, 1H), 7.17 (dd, 2H), 7.24 (m, 1H), 7.60 (dd, 1H) , 8.13 (d, 1H), 8.43 (d, 1H), 9.48 (d, 1H). MS APCI + m / z 403 __ [MH] * __

Example 42: The crude product was purified again by column chromatography on silica gel, eluting with ethyl acetate / methanol, 98: 2.

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

Example 46 5- {3 - [5- (4-Fluoro-2-methyl-phenyl) -pyrazine-2-yl] -5-10 methyl- [1,2,4] triazol-4-yl] -pyridine- 2-yl) methylamine

Mch.N: J

15 O

u r — N 3 H

A mixture of the product from Preparations 74 (437 mg, 1.62 mmol) and 83 (434 mg, 3.52 mmol) and p-toluene sulfonic acid in xylene (10 ml) was heated under reflux for 100 hours . The mixture was then filtered through Celite®, rinsing with dichloromethane, and the filtrate was evaporated in vacuo. Purification by column chromatography on silica gel, eluting with dichloromethane / methanol / 0.88 ammonia, 98: 2: 0.2, followed by ethyl acetate / methanol, 98: 2, provided the title compound in 1027084- 122 in the form of a beige solid in a yield of 9%, 57 mg.

1 H NMR (CDCl 3, 400 MHz) δ: 2.38 (m, 6H), 2.98 (d, 3H), 4.89 (m, 1H), 6.47 (d, 1H), 6.94- 7.02 (m, 2H), 7.36 (m, 2H), 7.97 (d, 1H), 8.43 (s, 1H), 9.41 (d, 1H). MSAPCI + m / z 376 [MH) +

Example 47 3- (4-Fluoro-2-methyl-phenyl) -6- [5-methoxymethyl-4- (6-methoxy-pyridin-3-yl) -4 H- [1,2,4] triazole-3- yl] pyridazine

10 rX

^ JL. Va «.

N ° CHa

ΓΎΓΎ ^ 'fV

'H3c

The product of Preparation 62 (40 mg, 0.13 mmol), 5-amino-2-methoxypyridine (16 mg, 0.13 mmol) and p-toluene-sulfonic acid monohydrate (5 mg, cat) were dissolved in xylene (2 ml) and the reaction mixture was heated under reflux for 3 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 evaporated in vacuo. The residue was 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 provide the title A compound in the form of a yellow oil in a yield of 8%, 4 mg.

NMR (CDCl3, 400 MHz) 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, 2 H), 7.39 (d, 1 H), 7.70 (m, 2 H), 8.11 (s, 1 H), 8.46 (d, 1 H).

Example 48 5- (4-Fluoro-2-methyl-phenyl) -2- [5-methoxymethyl-4- (6-methoxy-pyridin-3-yl) -4 H- [1,2,4] triazole-3 -yl] -pyrimidine 027084- 123 - * 1, 10 ^ CH 5: cH, δ H, c ^ 30 '

The product of Preparation 69 (80 rag, 0.27 mmol), 5-10 amino-2-methoxypyridine (50 mg, 0.39 mmol) and p-toluene sulfonic acid monohydrate (10 mg, cat) were dissolved in xylene (3 ml) and the reaction mixture was heated under reflux for 18 hours. Additional p-toluenesulfonic acid monohydrate (10 mg, cat) was added and the heating was 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 evaporated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane / methanol, 97: 3, afforded the title compound in a 46% yield, 49.3 mg.

X H NMR (CDCl 3, 400 MHz) δ: 2.23 (s, 3H), 3.32 (s, 3H), 3.99 (s, 3H), 4.51 (s, 2H), 6.82 ( d, 1 H), 6.98 (m, 2 H),

25 7.17 (d, 1H), 7.60 (d, 1H), 8.11 (s, 1H), 8.67 (s, 2H). MS

APCI + m / z 407 [MH] +.

Examples 49 to 52

The following compounds, of the general formula below, were prepared by the method of Example 30, using the product of Preparation 71 and the appropriate boronic acid.

Λ-ο, L II ch3 35 H3C ° 10270843 - 124 -

Nr R1 _Data__ Rem.

49 * 1 NMR (CDCl 3> 400 MHz) 5: 2.20 50% (s, 3H), 2.30 (s, 3H), 3.79 (s, f 3H), 3.95 (s, 3H) ), 6.38 (d, 1 H),.

6.88-6.98 (m, 2H), 7.10 (dd, 1H), 7.42 (d, 1H), 7.65 (dd, 1H), 8.19 (d, 1H), 8 , 21 (d, 1 H). ________MS APCI + m / z 406 [MH] * 50 X H NMR (CDCl 3, 400 MHz) δ: 2.09 50% (S, 3H), 2.30 (S, 3H), 2.39 (s, 1J 3H ), 3.80 (S, 3H), 3.96 (S, 3H), 1 CH »6.39 (d, 1H), 6.98 (d, 1H), CH3 7.09-7.02 ( m, 2H), 7.46 (d, 1H), 7.68 (d, 1H), 8.19 (d, 1H), 8.24 (d, 1H), MS APCI + m / z 402 [MH ] 4__51 MS APCI + m / z 422 [MH] + 69% ch3 52 MS APCI + 406 tMH] + 46%

FJyJ

CH3

Example 53 3- {5- [4- (6-Methoxy-pyridin-3-yl) -5-methyl-4 H- [1,2,4] triazol-3-yl] -pyrazine-2-yl} -4 methyl benzonitrile 5

NC

<Q> _ fj.

CH 3 CH 3

10 J-U

H3 Cl0 1027084-125 - 3 t

A mixture of 3-chloro-4-methylbenzonitrile (1 g, 6.6 mmol), bis (pinacolato) dibor (1.8 g, 7.0 mmol), cesium carbonate (6.4 g, 19.8 mmol) ) and the product of Preparation 3 (5 mg, cat) in 1,4-dioxane (50 ml) was heated under reflux for 4 hours. The reaction mixture was then cooled to room temperature, filtered through Celite® and evaporated in vacuo. A portion of the residue (145 mg, 0.6 mmol), the product of Preparation 30 (90 mg, 0.3 mmol), cesium carbonate (293 mg, 0.9 mmol) and the product of Be-10 preparation 3 ( 2 mg, cat) were then dissolved in 1,4-dioxane and the mixture was heated under reflux for 18 hours. The mixture was then cooled to room temperature, filtered through Celite® and evaporated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane / methanol, 100: 0 to 97: 3, afforded the title compound in the form of a white solid in a 3% yield, 3 mg.

1 H NMR (CDCl 3, 400 MHz) δ: 2.41 (s, 3H), 2.46 (s, 3H), 4.02 (s, 3H), 6.90 (d, 1H), 7.43 (d, 1H), 7.53 (dd, 1H), 7.63 (dd, 1H), 7.70 (d, 1H), 8.09 (d, 1H), 8.41 (d, 1H) ), 9.55 (d, 1 H). MS APCI + m / z 383 [MH] +

Example 54 2- (4-Fluoro-2-methyl-phenyl) -4-methoxy-5-95-methoxy-methyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazole -3-25 yl] pyridine

H, C

O

'\ N = / CH 3 CH,

30 yJ

H3 Cl0

A mixture of the product of Preparations 90 (60 mg, 0.17 mmol) and 3 (10 mg, cat), 4-fluoro-2-methylbenzene boronic acid (33 mg, 0.21 mmol) and cesium carbonate (110 mg 0.34 mmol) in dioxane (4 ml) was heated under reflux for 16 hours. Catalytic amounts of 4-fluoro-2-methyl-1027084-1-126-benzene-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, 100: 0 to 96: 4, to give the title compound in the form of a white foam in a yield of 54%, 39 mg.

X H NMR (CDCl 3, 400 MHz) 6: 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, 1H), 7.50 (dd, 1H), 8.05 (d, 1H) , 8.70 (d, 1 H). MS APCI + m / z 436 [MH] +

Example 55 2- (5-Fluoro-2-methoxy-phenyl) -4-methoxy-5- [5-methoxy-15-methyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4 ] triazol-3-yl] pyridine

H, C

20 o 20 \ N = / νΛ ^ ο, β-J CH 3 H * c o Λ-Ν H 3 Cl 2 The title compound was prepared from the product of

Preparation 90 and 5-fluoro-2-methoxybenzene-benzoic acid, using the method of Example 54, in the form of a yellow foam in a yield of 53%.

X H NMR (CDCl3, 400 MHz) δ: 3.39 (s, 3H), 3.63 (s, 3H), 3.83 (s, 3H), 3.93 (s, 3H), 4.51 (s, 2H), 6.76 (d, 1H), 6.93 (dd, 1H), 7.07 (m, 1H), 7.41 (s, 1H), 7.49 (dd, 1H) , 7.63 (dd, 1H), 8.04 (d, 1H), 8.70 (s, 1H). MS APCI + m / z 452 [MH] +

Example 56 35- (3-Fluoro-2-methoxy-phenyl) -5- [4- (6-methoxy-pyridin-3-yl) -5-methyl-4-Η- [1,2,4] triazol-3-yl] pyrazine 1027084-1.

- 127 - "FC)" H * C "o

5 y-N

h3c- · 0

The title product was prepared by the method of Example 14 using the chlorine compound of Preparation 30 (108 mg, 0.32 mmol) and 2-methoxy-3-fluoro-benzene-boronic acid (72 mg, 0.48 mmol) . 107 mg, 79% yield, of the title product was prepared in the form of a white solid.

1 H NMR (CDCl 3, 400 MHz) 6: 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: C21 H19 FN6 O3.0.2H2 O required; C 59.21, H 4.59, N 19.73; found C 59.27, H 4.69, N 19.33. MS APCI + m / z 423 [MH] + 1027084-

Claims (25)

1. Compound of formula (I) 5 N-N yy- <(I) The compound of claim 1, wherein X is CH. A compound according to claim 1 or 2, wherein V, W and Y are each independently CH, C-OCH 3 or N. A compound according to any of claims 1 to 3, wherein W and Y are each independently CH or N and X and Y are both CH. A compound according to any of claims 1 to 4, wherein Z is N. R 7 and R 8, which may be the same or different, are selected from H and (C 1 -C 6) alkyl; R 9 is (C 1 -C 8) alkyl optionally substituted with one or more groups each independently selected from (C 1 -C 8) alkoxy and an N-linked 5-7 membered heterocycle containing 10 to 3 heteroatoms selected from N, 0 and S; and R 10 is selected from (C 1 -C 6) alkyl and (C 1 -C 6) alkoxy; a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or said tautomer; With the proviso that the compound of formula (I) is not: 3-ethyl-5- (4-imidazol-1-ylphenyl) -4- (4-methoxyphenyl) -4H- [1,2,4] triazole , 3- (3 ', 5'-dichlorobiphenyl-4-yl) -4- (2-methoxyphenyl) -5-methyl-4 H- [1,2,4] triazole, 3- (3', 5, - bis-trifluoromethyl-biphenyl-4-yl) -4- (2-fluoro-phenyl) -5-methyl-4H- [1,2,4] triazole, or 3- (3, 5, -bis-trifluoromethyl-biphenyl-4-) yl) -5-methyl-4- (3-trifluoromethylphenyl) -4H- [1,2,4] triazole. A compound according to any of claims 1 to 4, wherein Z is CH. A compound according to any of claims 1 to 6, wherein R 1 is selected from: (i) a phenyl ring substituted with two substituents, which may be the same or different, each independently selected from halogen, (C 1 -C 1 alkyl, (C 1 -C 6) alkoxy, cyano, C (O) NR 7 R% NR 7 R 8, NR 7 C (O) R 10 and N [C (O) R 10] 2, and (ii) a pyridyl ring or N-oxide thereof each supported -5 with two substituents, which may be the same or different, each independently selected from halogen, ((C 1 -C 6) alkyl, (C 1 -C 12 alkoxy, cyano, C (O) NR 7 R 8, NR 7 R 8, NR 7 C (O) R 10 and N [C (O) R10] 2. A compound according to claim 7, wherein R 1 represents a phenyl ring substituted with two substituents, which may be the same or different, each independently selected from fluorine, chlorine, methyl, methoxy and cyano. The compound of claim 7, wherein R 1 is pyridine-N-oxide substituted with two methyl groups. The compound of any one of claims 1 to 9, wherein R 2 is selected from: (i) H, (C 1 -C 3) alkoxy, {C 1 -C 2) alkoxy- (C 1 -C 3) alkoxy and N ((C 1 -C 3) C 1-6 alkyl) 2; and (ii) a 5-membered N-linked heterocycle containing 1-3 nitrogen atoms, which ring is optionally substituted with C (O) NR 7 R 8. R 5 where V, w, X and Y, which may be the same or different, represent C-R 6 or N; Z is C-H or N; 11. A compound according to claim 10, wherein R 2 is selected from H, methoxy, ethoxy, 2-methoxyethoxy, dimethylamino, 1,2,3-triazol-2-yl and pyrollidinyl, the latter being optionally substituted with CONH 2 . The compound of claim 11, wherein R 2 is selected from H and methoxy. The compound of any one of claims 1 to 12, wherein R 3 is H. A compound according to any one of claims 1 to 13, wherein R 4 is H, methyl or methoxy. The compound of claim 14, wherein R 4 is H. R 1 is selected from: (i) a phenyl ring substituted with two or more substituents, which may be the same or different, each independently selected from halogen, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, cyano, C (0) NR 7 R 8, NR 7 R 8, NR 7 C (O) R 10 and N [C (δ) R 10] 2; and (ii) a five to seven membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, and N-oxides thereof; which ring is optionally substituted with two or more substituents, which may be the same or different, selected from halogen, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, cyano, C (O) NR 7 R 8, NR 7 R 8, NR 7 C ( 0) R10 and N [C (O) R10] 2; R a is selected from: (i) H, OH, OR 9, NR 7 R 8, NR 7 C (O) R 10 and N [C (O) R 10] 2; (ii) a 5-7 membered N-compound heterocycle containing 1-3 heteroatoms selected from N, O and S; which ring is optionally substituted with one or more groups selected from (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy and C (O) NR 7 R 8; and (iii) (C 1 -C 6) alkyl optionally substituted with an N-linked 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, O and S; R 3 is selected from H and (C 1 -C 8) alkyl; R e is selected from H, (C 1 -C 8) alkyl and OR 9; 1027084- * t. R5 is selected from halogen, (C1 -C8) alkyl, (C1 -C8) alkoxy,. NrV, NR7C (O) R10 and NtC (O) R10] 2; R 6 is selected from H, halogen, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, cyano, NR 7 R 8, NR 7 C (O) R 10, N [C (O) R 10] 2: and C (O) NR 7 R 8 ; A compound according to any of claims 1 to 15, wherein R 5 is methoxy or NHCH 3. The compound of claim 16, wherein R 5 is methoxy. The compound of claim 1, which is selected 1027064. 131 - from: 2- (4-fluoro-2-methylphenyl) -5- (5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazole-3- yl) pyridine; 2- (2,3-dimethylphenyl) -5- (5-methoxymethyl-4- (6-meth-thoxypyridin-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) pyridine; 5- (2,3-dimethylphenyl) -2- (5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazol-3-yl) pyridine; 10 1- [5- [5- (2,3-dimethylphenyl) -pyridin-2-yl] -4- (6-methoxypyridin-3-yl) -4 H- [1,2,4] 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) pyridi -15 ne; 2- (4-Fluoro-2-methylphenyl) -5-t5-methoxymethyl-4- (6-Tnethoxypyridin-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] triazol-3-yl] pyrazine; 2- (4-fluoro-2-methyl-phenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] -pyrazine, 2 - (2,3-dimethylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] pyrazine; 2- (4-cyano-2-methylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] -pyrazine; 2- {5-fluoro-2-methoxyphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-raethyl-4H- [1,2,4] triazol-3-yl] pyrazine; 2- (4-cyano-2-methylphenyl) -5- [5-methoxymethyl-4- (6-methoxypyridin-3-yl) - 4 H- [1,2,4] triazol-3-yl] pyrazine; 5- (4-cyano-2-methylphenyl) -2- [5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4 H- [1,2,4] triazol-3-yl] pyridine; 2- (5-fluoro-2-methoxyphenyl) -5- [5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazol-3-yl] pyridine; 2- (2-fluoro-5-methoxyphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4 H- [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; 1027084 - 132 - 2- (2,5-difluorophenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl pyrazine; 2- (3,5-dimethylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H "[1,2,4] triazol-3-yl] pyrazine; 2- (2,5-dimethylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] pyrazine; 2- (2,5-dichlorophenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4 H- [1,2,4] triazol-3-yl] pyrazine; 2- (2-fluoro-5-methoxyphenyl) -5- [4- (6-methoxypyridin-3-10 yl) -5-methyl-4H- [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) -nethyl] -4- (6-methoxypyridin-3-yl) -4H-1,2,4-triazole-3 -yl] pyridine; 2- (4-fluoro-2-methoxyphenyl) -5- [5 - [(2-methoxyethoxy) -20 methyl] -4- (6-methoxypyridin-3-yl) -4H-1,2,4-triazole- 3-yl] pyridine; 2- (5-fluoro-2-methoxyphenyl) -5- [5 - [(2-methoxyethoxy) -methyl] -4- (6-methoxypyridin-3-yl) -4H-1,2,4-triazole -3-yl] pyridine; 2- (5-fluoro-2-methylphenyl) -5- [5 - [(2-methoxyethoxy) methyl] -4- (6-methoxypyridin-3-yl) -4H-1,2,4-triazole - 3-yl] pyridine; 2-methoxy-5- {3 - [(2-methoxyethoxy) methyl] -5- [6- (2-methoxy-5-methylphenyl) pyridin-3-yl] -4H-1,2,4-triazole-30 4-yl} pyridine; 2- (2-fluoro-3-methoxyphenyl) -5- [5 - [(2-methoxyethoxy) methyl] -4- (6-methoxypyridin-3-yl) -4H-1,2,4-triazole-3 -yl] pyridine; 2- (3,5-difluorophenyl) -5- [5 - [(2-methoxyethoxy) methyl] -35 4- (6-methoxypyridin-3-yl) -4H-1,2,4-triazol-3-yl ] pyridi. ne; 2- (2,5-dimethoxyphenyl) -5- [5 - [(2-methoxyethoxy) - 1027084-] - 133 - methyl] -4- (6-methoxypyridin-3-yl) -4H-1,2, 4-triazol-3-yl] pyridine; 2- (3-chloro-4-fluorophenyl) -5- [5 - [(2-methoxyethoxy) methyl] -4- (6-methoxypyridin-3-yl) -4 H -1,2,4-triazole-3 -5 yl] pyridine; and | 2- (3-fluoro-2-methoxyphenyl) -5- [5-methoxymethyl-4- (6-1 methoxypyridin-3-yl) -4 H- [1,2,4] triazol-3-yl] pyrazine; 2- (3-fluoro-2-methoxy-phenyl) -5- [4- (6-methoxy-pyridin-3-yl) -5-methyl-4H-tl / 2,4] triazol-3-yl] - pyrazine; And tautomers thereof and pharmaceutically acceptable salts, solvates and polymorphs of said compound or said 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- (6-20 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- [1,2,4] triazole-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) pyri -dine; 2- (4-fluoro-2-methylphenyl) -5- [5-methoxymethyl-4- (6-30 methoxypyridin-3-yl) -4H- [1,2,4) triazol-3-yl] pyrazine; 2- (2,3-dimethylphenyl) -5- [5-methoxymethyl-4- (6-methoxypyridihe-3-yl) -4H- [1,2,4] triazol-3-yl] pyrazine; 2- (4-fluoro-2-methylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] pyrazine; 2- (2,3-dimethylphenyl) -5- [4- (6-methoxy-pyridin-3-yl) -5-methyl-4 H- [1,2,4] triazol-3-yl] -pyrazine; 2- (4-cyano-2-methylphenyl) -5- [4- (6-methoxypyridine-1027084- - 134-3-yl) -5-methyl-4H- [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; 2- (4-cyano-2-methylphenyl) -5- [5-methoxymethyl-4- (6-5 methoxypyridin-3-yl) -4H-11/2/4] 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-fluoro-2-methoxyphenyl) -5- [5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4H- [1,2,4] triazol-3-yl] pyridine; 10 and 2- (3-fluoro-2-methoxyphenyl) -5- [5-methoxymethyl-4- (6-methoxypyridin-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. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 19, or pharmaceutically acceptable salts, solvates or polymorphs thereof, and a pharmaceutically acceptable diluent or carrier. A compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or polymorph thereof, for use as a medicament. 22. A method for treating a disorder or condition in which it is known, or can be demonstrated, that inhibition of oxytocin provides a beneficial effect, in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) according to any of claims 1 to 19, without the condition, or a pharmaceutically acceptable salt, solvate or polymorph thereof. Use of a compound of formula (I) according to any of claims 1 to 19, without the condition, or a pharmaceutically acceptable salt, solvate or polymorph thereof, in the preparation of a medicament for the treatment of a disorder or condition in which it is known, or can be demonstrated, that inhibition of oxytocin provides a beneficial effect. The method of claim 22 or the use of claim 23, wherein the disorder or condition is selected from sexual dysfunction, male sexual dysfunction, female sexual dysfunction, hypoactive sense-in-sex disorder, sexual arousal disorder, orgasmic disorder, 10 sexual pain disorder, premature ejaculation, contraction pretension, complications in contractions, appetite and eating disorders, benign prostatic hyperplasia, preterm delivery, dysmenorrhea, congestive heart failure, arterial hypertension, levercirrosis, nephrotic hypertension, ocular hypertension, obsessive compulsive disorder, 15 neuropsychiatric disorders. The method or use of claim 24 wherein the disorder or condition is selected from sexual arousal disorder, orgasmic disorder, sexual pain disorder, and premature ejaculation. 1027084-