WO2005011703A1

WO2005011703A1 - 2-cyano-1,3,5-triazine-4,6-diamine derivatives

Info

Publication number: WO2005011703A1
Application number: PCT/EP2004/051587
Authority: WO
Inventors: Zoran Rankovic; Jiaqiang Cai; Iain Cumming
Original assignee: Akzo Nobel NV
Current assignee: Akzo Nobel NV
Priority date: 2003-08-04
Filing date: 2004-07-23
Publication date: 2005-02-10
Anticipated expiration: 2006-02-04

Abstract

The invention relates to the use of a 2-cyano-1,3,5-triazine -4,6-diamine derivative having general formula (I), wherein R1 is (C1-6)alkyl, (C3-8)cycloalkyl, aryl, aryl(C1-4)alkyl, aryloxy(C1-4)alkyl, heteroaryl or heteroaryloxy(C1-4)alkyl; R2 is H or (C1-4)alkyl; or R1 and R2 together with the nitrogen to which they are bound form a 4-8 membered heterocyclic ring, optionally further comprising 1 or more heteroatoms selected from O, S or NR5, which ring may be substituted with (C1-4)alkyl, (C3-8)cycloalkyl, aryl, aryl(C1-4)alkyl or NR6R7,and which ring may be fused to a benzene ring; R3 is (C1-6)alkyl, (C3-8) cycloalkyl (optionally comprising 1 or more heteroatoms selected from O, S or NR8), aryl, aryl(C1-4)alkyl or heteroaryl; R4 is H or (C1-4)alkyl; or R3 and R4 together with the nitrogen to which they are bound form a 4-8 membered heterocyclic ring, optionally further comprising 1 or more heteroatoms selected from O, S or NR9; R5, R8 and R9 are independently H, (C1-4)alkyl, (C3-8) cycloalkyl, aryl or aryl(C1-4)alkyl; R6 and R7 are independently H or (C1-4)alkyl; or R6 and R7 form together with the nitrogen to which they are bound a 4-8 membered heterocyclic ring; or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of osteoporosis and atherosclerosis.

Description

2-CYANO-1 ,3,5-TRIAZINE-4,6-DIAMINE DERIVATIVES

The invention relates to the use of 2-cyano-1 ,3,5-triazine-4,6-diamine derivatives for the preparation of a medicament for the treatment of the cathepsin K related diseases osteoporosis and atherosclerosis, to certain 2-cyano-1 ,3,5-triazine-4,6- diamine derivatives per se and to pharmaceutical compositions containing the same.

Cysteine proteases represent a class of peptidases characterised by the presence of a cysteine residue in the catalytic site of the enzyme, and these proteases are associated with the normal degradation and processing of proteins. Many pathological disorders or diseases are the result of abnormal activity of cysteine proteases such as over expression or enhanced activation. The cysteine cathepsins, e.g. cathepsin B, K, L, SN, F, are a class of lysosomal enzymes which are implicated in various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors, coronary disease, atherosclerosis, autoimmune diseases and infectious diseases.

Cathepsin K has strong collagenolytic, elastase and gelatinase activities (Bromme et al., J. Biol, Chem, 271, 2126-2132, 1996) and is predominantly expressed in osteoclasts (Bromme and Okamoto, Biol. Chem. Hopp-Seyler, 376, 379-384, 1995). It cleaves key bone matrix proteins, including collagen type I and II (Kaffienah et al., Biochem. J. 331 , 727-732, 1998), gelatine, osteopontin and osteonectin, and as such is involved in extracellular matrix metabolism necessary for normal bone growth and remodelling (Bossard et al., J. Biol. Chem. 271, 12517-12524, 1996). Inhibition of cathepsin K should result in the diminuation of osteoclast mediated bone resorption. Cathepsin K inhibitors may therefore represent new therapeutic agents for the treatment of disease states in man such as osteoporosis.

Sukhova et al (J. Clin. Invest. 1Q2, 576-583, 1998) have thereafter demonstrated that cells (macrophages) that migrate into and accumulate within developing human atherosclerotic plaques also synthesize the potent elastases Cathepsin K and S. Matrix degradation, particularly in the fibrous cap of such plaques, is a crucial process in atherosclerotic lesion destabilization. Thus, the metabolism of the extracellular matrix components collagen and elastin, which confer structural integrity upon the lesion's fibrous cap, can critically influence the clinical manifestations of atherosclerosis, such as coronary artery thrombosis as a result of rupture of an atherosclerotic plaque. Inhibition of cathepsins K and/or S at sites of plaques prone to rupture may thus represent an effective way of preventing such events. Recently 2-cyano-4-amino-pyrimidine derivatives were disclosed as inhibitors of cathepsin K in the International Patent Application WO 03/020278 (Novartis Pharma GMBH). Structurally related pyrrolo-pyrimidines have likewise been disclosed as cathepsin K inhibitors in WO 03/020721 (Novartis Pharma GMBH).

2-Cyano-1 ,3,5-triazine-4,6-diamine derivatives having alkyl, alkyloxy and/or alkylthioalkyl substituents at the 4 and/or 6 amino groups have long been known as herbicidal compounds (BE 609808: J.R. Geigy A-G; DE 1 172684: Deutsche Gold und Silber; BE 724564, BE 725064, BE 744893 and BE 749309: Badische Anilin und Soad Fabrik, AG). 2-Cyano-1 ,3,5-triazine-4,6-diamine derivatives wherein the 4- and/or 6-amino group is part of a morpholino or a piperidino-group have likewise been described as compounds having herbicidal activity by Mikhailichenko et al (Khimiya I Khimicheskaya Tekhnologiya, 45, 136-141, 2002). 2-Morpholino-4- methylamino-6-cyano-1,3,5-triazine and 2-morpholino-4-diethylamino-6-cyano-1 ,3,5- triazine were disclosed in US Patent 3,549,757 (Shell Oil Company) as having analgesic and tranquillizing activity. A similar activity was disclosed for 2,4-bisanilino- 6-cyano-1,3,5-triazine (US 3,549,760: Shell Oil Company).

It has now been found that 2-cyano-1,3,5-triazine-4,6-diamine derivatives having the general formula I

Formula I wherein

Ri is (C-ι-₆)alkyl, (C₃-₈)cycloalkyl, aryl, ary^d-^alkyl, aryloxy(Cι- )alkyl, heteroaryl or heteroaryloxy(Cι- ₎al kyl;

R₂ is H or (Cι-₄)alkyl; or R-_t and R₂ together with the nitrogen to which they are bound form a 4-8 membered heterocyclic ring, optionally further comprising 1 or more heteroatoms selected from O, S or NR₅, which ring may be substituted with (d-^alkyl, (C₃.₈)- cycloalkyl, aryl, aryl(d- )alkyl or NR₆R_{7 ι}and which ring may be fused to a benzene ring; R₃ is (d-e^alkyl, (C₃-₈)cycloalkyl (optionally comprising 1 or more heteroatoms selected from O, S or NR₈), aryl,

or heteroaryl; R is H or (Cι-₄)alkyl; or

R₃ and R₄ together with the nitrogen to which they are bound form a 4-8 membered heterocyclic ring, optionally further comprising 1 or more heteroatoms selected from O, S or NR₉;

R₅ , R₈ and R₉ are independently H, (d-^alkyl, (C₃-8)cycloalkyl, aryl or aryl(d- )alkyl; R₆ and R₇ are independently H or (d-₄)alkyl; or

R₆ and R₇ form together with the nitrogen to which they are bound a 4-8 membered heterocyclic ring; or a pharmaceutically acceptable salt thereof, can be used for the preparation of a medicament for the treatment of osteoporosis and of atherosclerosis.

The term (Cι-₆)alkyl, as used in the definition of formula I, means a branched or unbranched alkyl group having 1-6 carbon atoms, like hexyl, pentyl, 3-methyl-butyl, butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.

The term (Cι- )alkyl likewise means a branched or unbranched alkyl group having

1-4 carbon atoms, like butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl. The term (C -₈)cycIoalkyl means a cycloalkyl group having 3-8 carbon atoms, such as cyclooctyl, cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.

The term aryl means an aromatic group having 6-12 carbon atoms like for example phenyl, naphthyl or biphenyl. These aromatic groups may be substituted with (Cι-₄)- alkyl, (Cι-₄)alkyloxy, benzoyl, halogen or cyano. The terms aryl(Cι- )alkyl and aryloxy(d-₄)alkyl, as used in the definition of Formula I, mean a (d- )alkyl group which is substituted with a (C₆.i₂)aryl group, like for example the benzyl group, or a (C₆-i₂)aryloxy group, respectively. The term heteroaryl means a 5 or 6-membered cyclic aromatic group having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are pyridyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl and the like. Preferred heteroaryl groups are 2-pyridyl and 3-pyridyl. In the definition of formula I Ri and R₂ can form together with the nitrogen to which they are bound a 4-8 membered heterocyclic ring, such as an azetidine, a pyr- rolidine, a piperidine, or a 1H-azepine ring. Such rings may contain 1 or more additional heteroatoms selected from O, S or NR₅ to form rings such as a morpho- line, a thiomorpholine, a hexahydro-1,4-oxazepine, a piperazine, a homopiperazine, an imidazolidine or a tetrahydrothiazole ring. Preferred is the piperazine ring. The term halogen means F, Cl, Br, or I. When halogen is a substituent at an alkyl group, F is preferred. A preferred halogen substituted alkyl group is trifluoromethyl.

Preferred in the invention are those compounds according to formula I wherein Ri and R₂ together with the nitrogen to which they are bound form a 4-8 membered heterocyclic ring, optionally further comprising 1 or more heteroatoms selected from O, S or NR₅, which ring may be substituted with (Cι.₄)alkyl, (C₃-₈)cycloalkyl, aryl or NR₆R and which ring may be fused to a benzene ring.

Even more preferred is the use in the invention of the compound of Formula I, wherein R R²N represents piperazin-1-yl or N-morpholinyl.

In another aspect the invention provides 2-cyano-1,3,5-triazine-4,6-diamine derivatives of general Formula I

wherein

R- and R₂ together with the nitrogen to which they are bound form a 4-8 membered heterocyclic ring, optionally further comprising NR_{5 t} which ring may be substituted with (Cι- )alkyl, (C₃-₈)cycloalkyl, aryl, aryl(Cι- )alkyl or NR₆R₇, and which ring may be fused to a benzene ring;

R₃ is (Cι-e)alkyl, (C₃.₈)cycloalkyl (optionally comprising 1 or more heteroatoms selected from O, S or NR₈), aryl, aryl(d- )alkyl or heteroaryl;

R₄ is H or (d- )alkyl; or R₃ and R₄ together with the nitrogen to which they are bound form a 4-8 membered heterocyclic ring, optionally further comprising 1 or more heteroatoms selected from

O, S or NR₉;

R , R₈ and R₉ are independently H, (Cι^)alkyl, (C₃.₈)cycloalkyl, aryl or aryl(Cι-₄)alkyl;

R₆ and R₇ are independently H or (Cι-₄)alkyl; or R₆ and R form together with the nitrogen to which they are bound a 4-8 membered heterocyclic ring; or a pharmaceutically acceptable salt thereof, with the exclusion of 4,6-di(piperidin-1-yl)-1 ,3,5-triazine-2-carbonitrile and 4-(morpolin-4-yl)-6-(piperidin-1- yl)-1 ,3,5-triazine-2-carbonitrile.

The 2-cyano-1 ,3,5-triazine-4,6-diamine derivatives for which no protection perse is sought relate to the disclosure by Mikhailichenko et al. (supra) wherein these compounds are described, without any pharmacological activity.

Within the priority year of the present application, the International Application

WO 2004/000819 (AstraZeneca AB) was published on 31 December 2003.

2-Cyano-1,3,5-triazine-4,6-diamine derivatives are disclosed therein as compounds useful in the manufacture of a medicament for use in the inhibition of cathepsin S in a mammal such as man, and are said to be useful in the treatment of inflammation and immune disorders such as asthma, rheumatroid arthritis, multiple sclerosis, Crohn's disease, Alzheimers disease and pain, in particular neuropathic pain.

The 2-cyano-1,3,5-triazine-4,6-diamine derivatives of the present invention, including the following compounds, specifically disclosed in WO 2004/000819 (example nr.),

4-morpholin-4-yl-6-(4-phenoxypiperidin-1-yl)-1 ,3,5-triazine-2-carbonitrile (example 2);

4-[(4-chlorophenyl)amino]-6-pyrrolidin-1-yl-1 ,3,5-triazine-2-carbonitrile (example 5);

4-[(4-chlorophenyl)amino]-6-piperidin-1 -yl-1 ,3,5-triazine-2-carbonitrile (example 6);

4-[(4-chlorophenyl)amino]-6-(4-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile (example 10);

4-morpholin-4-yl-6-(3-phenylpiperidin-1-yl)-1 ,3,5-triazine-2-carbonitrile (example 14);

4-(1 ,4'-bipiperidin-1'-yl)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile (example 15);

4-[4-(2-methoxyphenyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile

(example 21 ); 4-[(4-chlorophenyl)amino]-6-(4-methylpiperazin-1 -yl)-1 ,3,5-triazine-2-carbonitrile

(example 25); and

4-azetidin-1-yl-6-[(4-chlorophenyl)amino]-1 ,3,5-triazine-2-carbonitrile (example 26); have been identified as inhibitors of cathepsin K, and as such are useful in the manufacture of a medicament for the treatment of osteoporosis and of atherosclerosis.

Especially preferred compounds according to the present invention are:

- 4-cyclohexylamino-6-(piperdin-1-yI)-1 ,3,5-triazine-2-carbonitrile (4a);

- 4-(2-methoxypyridin-3-ylamino)-6-(piperidin-1-yl)-1 ,3,5-triazine-2-carbonitrile (4c); - 4-(morpholin-4-yl)-6-(tetrahydropyran-4-ylamino)-1 ,3,5-triazine-2-carbonitrile (5a);

- 4-cyclohexylamino-6-(2-methoxy-3-pyridinylamino)-1 ,3,5-triazine-2-carbonitrile (7a); - 6-cycIohexylamino-4-(piperazine-1 -yl)-1 ,3,5-triazine-2-carbonitrile (9a);

- 4-(3-diethylamino-pyrrolidin-1 -yl)-6-(2-methoxy-phenylamino)-1 ,3,5-triazine-2- carbonitrile (11u); and

- 4-(2-methoxyphenyl-amino)-6-(piperazine-1 -yl)-1 ,3,5-triazine-2-carbonitrile (12a).

The 2-cyano-1 ,3,5-triazine-4,6-diamine of general Formula I can be prepared, as depicted in the scheme below, by consecutive substitution of two of the 3 chlorines in cyanuric chloride with the amine derivatives RιR₂NH and R₃R NH, respectively, using a suitable base such as diisopropylethylamine or sodium hydroxide in solvents such as dichloromethane, tetrahydrofuran or water to give 2-chloro-4,6-disubstituted 1 ,3,5-triazine derivatives of formula II, which are then treated with potassium cyanide or another cyanide salt in a solvent such as dimethylsulfoxide or dimethylformamide under suitable heat.

olvent

Formula I Formula II

In the preparation of 2-cyano-1,3,5-triazine-4,6-diamine of general formula I in which one of the Ri or R₂ groups contain a basic amine nitrogen atom (either in the form of NR₅ or NR₆R₇), such a nitrogen is to be temporarily protected by a protecting group, such as for example the acid labile t-butyloxycarbonyl (Boc) group. Other suitable protecting groups for functional groups which are to be temporarily protected during syntheses, are known in the art, for example from Wuts, P.G.M. and Greene, T.W.: Protective Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999.

The compounds of the invention, which can be in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as, but not limited to, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonio acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.

Compounds of the invention may exist in solvated as well as in unsolvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Compounds of the present invention may exist as amorphous forms, but also multiple crystalline forms may be possible. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of this invention. The 2-cyano- ,3,5-triazine-4,6-diamine derivatives of general Formula I and their salts may contain a centre of chirality in one or more of the side chains R R , and may therefore be obtained as a pure enantiomer, or as a mixture of enantiomers, or as a mixture containing diastereomers. Methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g. synthesis with chiral induction or starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers or enantiomers using chromatography on chiral media. Such methods are for example described in Chirality in Industry (edited by A.N. Collins, G.N. Sheldrake and J. Crosby, 1992; John Wiley).

The compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0.001-100 mg per kg body weight, preferably 0.01-10 mg per kg body weight. Mixed with pharmaceutically suitable auxiliaries, e.g. as described in the standard reference, Gennaro et al., Remington's Pharmaceutical Sciences, (20th ed., Lippincott Williams & Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing) the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied in the form of a solution, suspension, emulsion, e.g. for use as an injection preparation, or as a spray, e.g. for use as a nasal spray. For making dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.

Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.

The invention is further illustrated by the following examples.

Methods

General Chemical Procedures. All reagents were either purchased from common commercial sources or synthesised according to literature procedures using commercial sources. Proton NMR (¹H NMR) were obtained on a Bruker DPX 400 spectrometer and are referenced to internal TMS. Mass spectra were recorded on a Shimadzu LC-8A (HPLC) PE Sciex API 150EX LCMS. Analytical reversed-phase LCMS analysis was carried out on LUNA C18 column (5μ; 30 x 4.6 mm) under gradient conditions (90% water / 0.1 % formic acid to 90% acetonitrile / 0.1 % formic acid) at a flow rate of 4 mL/min .

Abbreviations

Dimethylformamide (DMF), dichloromethane (DCM), dimethylsuphoxide (DMSO), tetrahydrofuran (THF), high pressure liquid chromatography (HPLC), diisopropylethylamine (DIPEA), triethylamine (TEA), broad (br), singlet (s), doublet (d), triplet (t), trifluoroacetic acid (TFA), tert-butyloxycarbonyl (Boc). EXAMPLE 1

1a: 4-Phenylamino-6-n-propylamino-1 ,3.5-triazine-2-carbonitrile.

A: To cyanuric chloride (10g) in DCM (200mL) at 0°C was added dropwise a solution of a mixture of aniline (5.02g) and DIPEA (10.40mL) in DCM (100mL). The mixture was stirred at room temperature for two hours then washed with HCI (200 ml, 2M) and water (100 ml), dried over sodium sulphate and evaporated at reduced pressure to afford 4,6-dichloro-2-phenylamino-1,3,5-triazine as an off white solid. ¹H NMR (CDCI₃)δ: 7.63 (s, 1 H), 7.55 (d, 2H), 7.40 (t, 2H), 7.23 (d, 1H). B: To 4,6-dichloro-2-phenylamino-1,3,5-triazine (482mg) in DCM (2mL) at 0°C was added dropwise a mixture of propylamine (2 mmol) and DIPEA (0.4ml). The compound was precipitated and filtered in a fritted tube using a Vacmaster multi- filtration apparatus to afford 2-chloro-4-phenylamino-6-propylamino-1 ,3,5-triazine (334mg). ¹H NMR (DMSO)δ: 9.7-9.85 (2bs, 1H), 7.85-8.05 (2bs, 1H), 7.56 (bs, 2H), 7.15 (bs, 2H), 6.88 (bs, 1H), 3.16 (m, 2H), 1.40 (m, 2H), 0.74 (m, 3H). MS m z: 264.0 (M+1), 94%.

C _, To 2-chloro-4-phenylamino-6-propylamino-1,3,5-triazine (334 mg) in DMSO (2ml) was added KCN (195mg). The mixture was heated to 120°C for 2 hours with stirring. To above mixture was then added ethyl acetate (20ml), 5% sodium carbonate (10ml) and saturated brine (5ml), the mixture was shaken briefly and the organic layer separated and washed again with a similar mixture. Solvent was removed under reduced pressure, the residue was triturated with ether giving 4- phenylamino-6-n-propylamino-1,3,5-triazine-2-carbonitrile, (115mg). ¹H NMR (CDCL₃)δ: 7.56 (bs, 1H), 7.50 (bs, 1H), 7.36 (bs, 2H), 7.14 (bs, 2H), 5.45- 5.65 (2bs, 1H), 3.41 (bs, 2H), 1.65 (m, 2H), 0.99 (m, 3H). MS mlz 255.3 (M+1), 94%.

The procedure described above was further applied, using the appropriate amine derivatives, to prepare the following compounds:

1b: 4-ethylamino-6-(N-ethyl-N-phenyI-amino)-1,3,5-triazine-2-carbonitrile,

MS mlz: 269.1 (M+1 ); c: 4-(2-methylpropylamino)-6-phenylamino-1 ,3,5-triazine-2-carbonitrile, MS mlz: 269.4 (M+1); Id: - 4-[2-(3-methylphenyl)ethylamino]- 6-phenylamino-1,3,5-triazine-2-carbonitrile, MS m z: 331.1 (M+1);

1e: - 4-[2-(4-morpholino)ethyl]amino-6-phenylamino-1 ,3,5-triazine-2-carbonitrile, MS mlz 326.1 (M+1);

If: 4-phenylamino-6-(4-phenyl)butylamino-1,3,5-triazine-2-carbonitrile, MS mlz 345.0 (M+1);

1g: 4-phenylamino-6-(4-methoxyphenyl)methylamino-1,3,5-triazine-2-carbonitrile, MS mlz: 333.0 (M+1);

1h: 4-[2-(4-fluorophenyl)ethyl]amino-6-phenylamino-1,3,5-triazine-2-carbonitrile, MS mlz: 335.1 (M+1); 1]: 4,6-diphenylamino-1,3,5-triazine-2-carbonitrile; MS mlz: 289.1 (M+1), 1j: 4-(3-methylbut-2-en)ylamino-6-phenylamino-1 ,3,5-triazine-2-carbonitrile, MS mlz: 281.0 (M+1);

Ik: - 4-(2-phenoxy)ethylamino-6-phenylamino-1 ,3,5-triazine-2-carbonitrile, MS m/z:333.0 (M+1);

EXAMPLE 2:

2a: 4-H ,4'1-Bipiperidinyl-1 '-yl-6-phenylamino-1 ,3,5-triazine-2-carbonitrile

Aj. To 2,4-dichloro-6-phenylamino-1 ,3,5-triazine (241 mg) in DCM (2ml) at 0°C was added dropwise a mixture of 4-piperidinopiperidine (168mg) and DIPEA (129mg). The mixture was stirred at room temperature for 2 hours, extracted with DCM (10mL), washed with saturated sodium bicarbonate (10mL x 2) then dried over sodium sulphate. Solvent was removed under reduced pressure to afford 2-chloro-4- [1,4']bipiperidinyl-1'-yl-6-phenylamino-1 ,3,5-triazine (370mg). ¹H NMR (DMSO)δ: 7.69 (d, 2H), 7.38 (t, 2H), 7.10 (t, 1H), 4.64 (m, 2H), 3.5 - 2.5 (m, 9H), 1.87 (m, 2H), 1.5 ( , 6H). MS mlz: 373.0 (M+1 ). f To 2-chloro-4-[1 ,4']bipiperidinyl-1 '-yl-6-phenylamino-1 ,3,5-triazine (350mg) in DMSO (2ml) was added KCN (195mg). The mixture was stirred and heated to 120°C for 2 hours then extracted with ethyl acetate (20mL) and washed with water (2 x 20ml). Solvent was removed under reduced pressure, the residue was re-dissolved in DMSO and purified by preparative HPLC to afford 4-[1,4']-bipiperidinyl-1'-yl-6- phenylamino-[1,3,5]triazine-2-carbonitrile (10mg).

¹H NMR (CDCL₃)δ: 7.45 (d, 2H), 7.37 (t, 2H), 7.18 (t, 1H), 4.95 (d, 1H), 4.84 (d, 1H), 4.55 (m, 3H), 3.55 (m, 3H), 2.93 (m, 2H), 2.00 (m, 10H). MS mlz: 364.3 (M+1)

The procedure described in Example 2a was further applied, using the appropriate amine derivatives, to prepare the following compounds:

2b: 6-phenylamiπo-4-[4-(1 -phenyl-ethyl)-piperazin-1 -yl]-1 ,3,5-triazine-2-carbonitrile, MS mlz: 386.3 (M+1);

2c: 4-(4-cycIoheptylpiperazin-1-yl)-6-phenylamino-1 ,3,5-triazine-2-carbonitrile,

MS mlz: 378.3 (M+1 );

2d:- 6-phenylamino-4-(4-pyrrolidin-1-yl-piperazin-1-yl)-1,3,5-triazine-2-carbonitrile,

MS mlz: 350.5 (M+1 ); 2e: 6-phenylamino-4-(piperidin-1-yl)-1 ,3,5-triazine-2-carbonitrile, MS mlz: 281.0 (M+1);

2f : 4-(4-benzyI-piperazin-1 -yl)-6-phenylamino-1 ,3,5-triazine-2-carbonitrile,

MS mlz: 372.0 (M+1 ).

EXAMPLE 3

3a: 4-(4-Benzoylphenylamino)-6-ethylamino-1,3,5-triazine-2-carbonitrile

To cyanuric chloride (369mg) and DIPEA (765μl) in DCM (1ml) at 0°C was added a solution of 4-aminobenzophenone in DCM (1ml). The mixture was allowed to warm to room temperature and was shaken for 2 hours. To the mixture was then added ethylamine (1 ml, 2M in MeOH). The mixture was shaken at room temperature for 2 hours, then the mixture was diluted with DCM (5ml) and washed with HCI (1N, 10ml) then water (10ml). Organic layer was dried over magnesium sulfate and solvent was evaporated under reduced pressure to afford a gummy oil. This oil was dissolved in DMSO (1ml) and KCN (260mg) was added. The mixture heated to 120°C for 6 hours. Mixture was cooled and diluted with ethyl acetate (10ml) then washed with water (10ml). Organic layer was dried over magnesium sulphate and solvent evaporated under reduced pressure. The residue was then dissolved in DMSO (2ml) and purified by prep-LCMS to afford 4-(4-benzoyl-phenylamino)-6-ethylamino-1,3,5-triazine-2- carbonitrile (1.6 mg)as a colourless oil.

¹H NMR (CDCI₃) δ: 7.90-7.75 (m, 4H), 7.69-7.34(m, 5H), 5.6(br, 1H), 3.52(m, 2H), 1.27(m, 3H). MS mlz 345.0 (M+1).

Similarly prepared, using the appropriate amine derivative, were: 3b: 4-(biphenyl-3-ylamino)-6-ethylamino-1,3,5-triazine-2-carbonitrile, MS mlz: 317.1 (M+1);

3c: 4-(phenethylamino)-6-ethylamino-1,3,5-triazine-2-carbonitrile, MS mlz: 269.3 (M+1);

3d: 4-Ethylamino-6-(2-methoxyphenyIamino)-1,3,5-triazine-2-carbonitrile, MS mlz: 271.4 (M+1);

3e: 4-(2,3-Dihydro-2H-quinolin-1 -yl)-6-ethylamino-1 ,3,5-triazine-2-carbonitrile, MS mlz: 281.0 (M+1);

EXAMPLE 4

4a: 4-Cyclohexylamino-6-(piperdin-1 -yl)-1 ,3,5-triazine-2-carbonitrile

A 6-(Piperidin-1 -yl)-2,4-dichloro-1 ,3,5-triazine Prepared as step A of example 1 using piperidine in place of aniline to give 6- (piperidin-1 -yl)-2,4-dichloro-1 ,3,5-triazine.

¹H NMR (CDCL3) δ: 3.82(m, 4H), 1.7-1.9(m, 6H). MS mlz: 282.3 (M+1). B: 2-chloro-4-cyclohexylamino-6-(piperdin-1-yl)-1 ,3,5-triazine Prepared as step B of example 1 using cyclohexylamine and 6-(piperidin-1-yl)-2,4- dichloro-1 ,3,5-triazine in place of propyl amine and 6-phenylamino-2,4-dichloro-1 ,3,5- triazine respectively to give 2-chloro-4-cyclohexylamino-6-(piperdin-1-yl)-1 ,3,5- triazine. MS mlz: 296.0 (M+1).

C^ Prepared as step C of example 1 using 2-chloro-4-cyclohexylamino-6-(piperdin-1- yl)-1 ,3,5-triazine in place of 2-chloro-4-phenylamino-6-n-propylamino-1,3,5-triazine to give 4-cyclohexylamino-6-(piperdin-1-yl)-1 ,3,5-triazine-2-carbonitrile (28 mg). ¹H NMR (CDCL3) δ: 6.2 and 5.2(2 x br, 1H), 3.7-4.0(m, 5H), 2.0(m, 2H), 1.5-1.85(m, 9H), 1.1-1.5(m, 5H). MS mlz: 287.0 (M+1 ).

Similarly prepared, using the appropriate amine derivative, were: 4b: 4-(piperdin-1-yl)-6-(pyrrolidin-1-yl)-1 ,3,5-triazine-2-carbonitrile,

MS mlz: 259.0 (M+1);

4c: 4-(2-methoxypyridin-3-ylamino)-6-(piperidin-1-yl)-1 ,3,5-triazine-2-carbonitrile, MS mlz: 312.1 (M+1);

4d: 4-(2-chlorophenylamino)-6-(piperidin-1-yl)-1,3,5-triazine-2-carbonitrile, MS mlz: 315.0 (M+1), 317.1 (M+1);

4e: 4-(2-methylphenylamino)-6-(piperidin-1-yl)-1 ,3,5-triazine-2-carbonitrile,

MS mlz: 295.5 (M+1 );

4f : 4-(3-cyanophenylamino)-6-(piperidin-1 -yl)-1 ,3,5-triazine-2-carbonitrile,

MS mlz: 306.3 (M+1 ); 4g: 4-cyclopropylamino-6-piperidin-1-yl-1 ,3,5-triazine-2-carbonitrile,

MS mlz 245.4 (M+1);

4h: 4-cyclobutylamino-6-(piperidin-1-yl)-1,3,5-triazine-2-carbonitrile,

MS mlz: 259.1 (M+1);

4i_: 4-cyclopentylamino-6-(piperidin-1-yl)-1,3,5-triazine-2-carbonitrile, MS mlz: 273.4 (M+1 );

4J: 4-cycloheptylamino-6-(piperidin-1 -yl)-1.S.δ-triazine^-carbonitrile,

MS mlz: 301.3 (M+1 );

4k: 4-lsobutylamino-6-(piperidin-1 -yl)-1 ,3,5-triazine-2-carbonitrile,

MS mlz: 261.1 (M+1); 41: 4-(3-methylbutylamino)-6-piperidine-1-yl-1.S.δ-triazine^-carbonitrile,

MS mlz: 275.1 (M+1);

4m: 4-(morpholine-4-yl)-6-(piperidine-1-yl)-1,3,5-triazine-2-carbonitrile,

MS mlz: 275.3 (M+1 );

4n: 4-[1,4]-oxazepan-4-yl-6-(piperidin-1-yl)-1,3,5-triazine-2-carbonitrile, MS mlz: 289.1 (M+1 );

4o: 4-(N-methyl-cyclohexylamino)-6-(piperidin-1-yl)-1,3,5-triazine-2-carbonitrile,

MS mlz: 292.3 (M+1 );

4p: 4-(cyclohexanemethylamino)-6-(piperidin-1 -yl)-1 ,3,5-triazine-2-carbonitrile,

MS mlz: 301.3 (M+1 ). EXAMPLE 5

5a: 4-(Morpholin-4-yl)-6-(tetrahvdropyran-4-ylamino)-1 ,3,5-triazine-2-carbonitrile

A: 2,4-Dichloro-6-(morpholin-4-yl)-1 ,3,5-triazine

Prepared as step A of example 1 using morpholine in place of aniline to give 2,4- dichloro-6-(morpholin-4-yl)-1 ,3,5-triazine. ¹H NMR (CDCL3) δ: 3.89(4, 4H), 3.75(m, 4H). MS m z; 235 (M+1).

B: Prepared as step B of example 1_, using tetrahydropyran-4-ylamine and 2,4- dichloro-6-(morpholin-4-yl)-1 ,3,5-triazine in place of n-propyl amine and 6- phenylamino-2,4-dichloro-1 ,3,5-triazine respectively to give 2-chloro-4-(morpholin-4- yl)-6-(tetrahydropyran^-ylamino)-1 ,3,5-triazine. MS mlz: 282.0 (M+1 ). C: Prepared as step C of example \ using 2-chloro-4-(morpholin-4-yl)-6- (tetrahydropyran-4-ylamino)-1 ,3,5-triazine in place of 2-chloro-4-n-propylamino-6- phenylamino-1 ,3,5-triazine to give 4~(morpholin-4-yl)-6-(tetrahydropyran~4-ylamino)- 1,3,5-triazine-2-carbonitrile (45mg). H NMR (CDCL3) δ: 5.3 and 5.1(2 x br, 1 H), 3.9- 4.2(m, 3H), 3.6-3.9(m, 8H), 3.5(m, 2H), 1.9(m, 2H), 1.5(m, 2H). MS mlz: 291.1 (M+1).

Similarly prepared, using the appropriate amine derivative, were:

5b: 4-(cyclohexylmethyl-amino)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,

5c: 4-(N-cyclohexyl-N-methylamino-6-(morpholin-4-yl)-1,3,5-triazine-2-carbonitrile,

MS m/z: 303 (M+1);

5d: 4-cyclopentylamino-6-(morpholin-4-yl)-1,3,5-triazine-2-carbonitrile,

MS z: 275(M+1); 5e: 4-cycloheptylamino-6-(morpholin-4-yl)-1 ,3,5-triazine-2-carbonitrile,

MS m/z:303 (M+1);

5f : 4-(2-methyl-cyclohexylam ino)-6-(morp hoi in-4-yl)- 1 , 3,5-triazine-2-carbonitrile,

MS m z: 303 (M+1);

5g: 4-cyclohexvlamino-6-(morpholin-4-vh-1 ,3,5-triazine-2-carbonitrile, MS m/z; 289 (M+1). EXAMPLE 6:

6a: 4-(2-Methoxypyridin-3-ylamino)-6-(morpholin-4-yl)-1,3.5-traizine-2-carbonitrile

A solution of 2-methoxypyridine-3-amine (62mg), 2,4-dichloro-6-(morpholin-4-yl)- 1 ,3,5-triazine (116mg) and DIPEA (90μl) in THF (1ml) was heated to reflux overnight. Mixture was cooled and diluted with DCM (10ml) and washed with HCI (1N, 10ml) then water (10ml). Organic layer was dried over magnesium sulphate, solvent was evaporated under reduced pressure. Resulting oil was dissolved in DMSO (1ml), KCN (62mg) was added and the mixture was heated to 180°C for 5 minutes in a SmithCreator microwave. Mixture was cooled, diluted with ethyl actetate (10ml) and washed with water (2 x 5ml). Organic layer was dried over magnesium sulphate then solvent was evaporated under reduced pressure. This residue was purified by prep- LCMS to afford 4-(2-methoxy-pyridin-3-ylamino)-6-(morpholin-4-yl)-1 ,3,5-traizine-2- carbonitrile (11.2mg) as a clear oil.

¹H NMR (CDCI₃)δ: 8.50 (m, 1H), 7.92 (d, 1H), 7.64 (br, 1H), 6.95 (t, 1H), 4.05 (s, 3H), 3.90 (m, 4H), 3.78 (m, 4H). MS mlz: 314.1 (M+1).

Similarly prepared was: 6b: 4-Morpholin-4-yl-6-(pyridin-4-ylamino)-[1 ,3,5]triazine-2-carbonitrile, MS mlz: 284.0 (M+1).

EXAMPLE 7

7a: 4-Cvclohexylamino-6-(2-methoxy-3-pyridinylamino)-1,3,5-triazine-2-carbonitrile

A: Prepared as step A of example using cyclohexylamine in place of aniline to give 2-cyclohexyIamino-4,6-dichloro-1,3,5-triazine. ¹H NMR (CDCI3) δ: 5.8(br-d, 1H), 3.92(m, 1 H), 2.0(m, 2H), 1.1-1.8(m, 8H). MS mlz: 247 A (M+1). fr To 2-cyclohexylamino-4,6-dichloro-1,3_]5-triazine (2.47 g) in THF (10 ml) was added DIPEA (2.6 ml) and 3-amino-2-methoxypyridine. The mixture was heated to 80°C for 20 hours, then diluted with DCM (100 ml), washed with water (2 x 150 ml), hydrochloric acid (1M, 100 ml). Organic layer was then dried, solvent removed under vacuum. The residue was column on silica gel using petroleum ether/ethyl acetate (2/1) as eluant to give 2-chloro-4-cyclohexylamino-6-(2-methoxy-3-pyridinylamino)- 1 ,3,5-triazine (2.3 g).

¹H NMR (DMSO) δ:8.6(m, 1H), 7.85(m, 1H), 7.65 and 7.6(2 x br, 1H), 6.9(m, 1H), 5.5 and 5.35(2 x br, 1 H), 4.02 and 4.00(2 x s, 3H), 3.95 and 3.84(m, 1 H), 2.05(m, 2H), 1.75(m, 2H), 1.66(m, 1 H), 1.15-1.55(m, 5H). MS mlz: 335.3 (M+1). fr 2-Chloro-4-cyclohexylamino-6-(2-methoxy-3-pyridinylamino)-1 ,3,5-triazine (0.669 g) and potassium cyanide (0.26 g) in DMSO (3 ml) was heated by microwave at 180°C for 10 minutes. The mixture was diluted with ethyl acetate (20 ml) and washed with water (2 x 20 ml), hydrochloric acid (1 M, 2 x 20 ml).Organic layer was dried over sodium sulphate, solvent was removed under vacuum, residue was columned on silica gel using petroleum ether/ethyl acetate (2/1) as eluant to give 4-cyclohexyl- amino-6-(2-methoxy-3-pyridinylamino)-1 ,3,5-triazine-2-carbonitrile (65 mg). ¹H NMR (CDCL3) δ: 9.9 and 10.3 (2xbr, 1H), 8.55(m, 1H), 7.86(m, 1 H), 7.7 and 7.55(2 x br, 1H), 6.9(m, 1H), 5.35 and 5.45(2 x br, 1H), 4.05 and 4.02(2 x s, 3H), 3.8- 4.0(m, 1H), 2.0(m, 2H), 1.75(m, 2H), 1.65(m, 1H), 1.1-1.5(m, 5H). MS mlz: 326.5 (M+1).

EXAMPLE 8:

8a: 4-(4-tert-Butoxycarbonylpiperazin-1-yl)-6-cvclohexylamino-1,3,5-triazine-2- carbonitrile

A To a solution of cyanuric chloride (500mg) in DCM (10mL) at -20°C was added dropwise a solution of cyclohexylamine (300μl) and DIPEA (520μl) in DCM (3ml).

The mixture was stirred at room temperature for 45 minutes then tert-butyl 1- piperazine carboxylate (502mg) and DIPEA (520μl) were added and the reaction stirred for a further 1 hour. The mixture was extracted with DCM (20mL), washed with HCI (1M, 20ml), dried over sodium sulphate and solvent removed under reduced pressure to afford 2-chloro-4-(4-tert-butoxycarbonylpiperazin-1-yl)-6-cyclohexyl- amino-1,3,5-triazine ¹H NMR (CDCI₃) δ: 5.20 (d, 1 H), 3.78 (m, 5H), 3.45 (m, 4H), 1.95 (m, 2H), 1.75 (m, 3H), 1.65 (m, 1H), 1.48 (s, 9H), 1.23 (m, 3H). MS mlz: 397.4 (M+1).

B _, The solution of 2-chloro-4-(4-tert-butoxycarbonylpiperazin-1-yl)-6- cyclohexylamino-1,3,5-triazine (998mg) in DMSO (4mL) with KCN (480mg) was stirred and heated to 120°C, under nitrogen, for 3 hours and 150°C for a further one hour. The mixture was extracted with ethyl acetate (20ml) and washed with water (2 x 15mL) then dried over sodium sulphate and solvent removed under reduced pressure. Crude product (50mg) was dissolved in ethyl acetate and purified using a silica column with petroleum ether / ethyl acetate (60:40) as eluant to afford 4-(4-tert- butoxycarbonylpiperazin-1-yl)-6-cyclohexylamino-1,3,5-triazine-2-carbonitrile (10mg) as solid. ¹H NMR (CDCI₃) δ: 5.29 (d, 1 H), 3.78 (m, 4H), 3.47 (m, 4H), 1.96 (m, 2H), 1.75 (m, 2H), 1.65 (m, 2H), 1.48 (s, 9H), 1.28 (m, 4H). MS mlz: 388.1 (M+1).

EXAMPLE 9:

9a: 6-cvclohexylamino-4-(piperazine-1-yl)-1 ,3,5-triazine-2-carbonitrile

4-(4-tert-Butoxycarbonylpiperazin-1-yl)-6-cyclohexylamino-1,3,5-triazine-2- carbonitrile (100mg) was stirred in TFA (0.5mL) and DCM (0.5mL) for 15 minutes. Solvent was removed under reduced pressure and the crude product purified by preparative LCMS to afford 6-cyclohexylamino-4-(piperazine-1-yl)-[1,3,5]-triazine-2- carbonitrile (15mg). ¹H NMR (CDCI₃) δ: 4.77 (m, 4H), 4.05 ( , 3H), 3.78 (1H), 3.31 (m, 5H), 1.92 (m, 1H), 1.78 (m, 1H), 1.65 (m, 1H), 1.31 (m, 3H). MS mlz: 288.0 (M+1).

EXAMPLE 10:

10a: 6-cyclohexylamino-4-(4-methyl-piperazin-1 -yl)-1 ,3,5-triazine-2-carbonitrile To a solution of 6-cyclohexylamino-4-(piperazine-1-yl)-1,3,5-triazine-2- carbonitrile (20mg) in DCM (1 l) was added formaldehyde (50μl). The mixture was stirred for 10 minutes then sodium triacetoxyborohydride (24mg) was added and the reaction stirred for 45 minutes. The mixture was extracted with DCM (4ml), washed with saturated sodium bicarbonate (4ml) and purified by preparative LCMS to afford 6-cyclohexylamino-4-(4-methyl-piperazin-1 -yl)-1 ,3,5-triazine-2-carbonitrile (5mg). ¹H NMR (CDCI₃) δ: 5.45 (d, 1H), 5.22 (d, 1H), 4.82 (m, 2H), 3.95 - 3.35 (m, 4H), 1.95 (m, 3H), 1.86 (m, 3H), 1.67 (m ,1H), 1.47 - 1.23 (m, 8H). MS mlz: 302.4 (M+1).

Similarly prepared, using acetaldehyde instead of formaldehyde, was:

10b: 6-cyclohexylamino-4-(4-ethyl-piperazin-1 -yl)-1 ,3,5-triazine-2-carbonitrile,

MS mlz: 316.1 (M+1).

EXAMPLE 11

11a: 4-(2-Methoxyphenylamino)-6-piperidin-1-yl-1 ,3,5-triazine-2-carbonitrile.

A 2-(2-Methoxyphenylamino)-4,6-dichloro-1 ,3,5-triazine was prepared as step A of example 1 using 2-methoxyaniline in place of aniline. ¹H NMR (CDCI₃) δ: 8.3 (d, 1 H), 8.17 (b, 1 H), 7.15 (t, 1 H), 7.05 (t, 1H), 6.95 (d, 1H), 3.91 (s, 3H). B: To 2-(2-methoxyphenylamino)-4,6-dichloro-1,3,5-triazine (271 mg) in DCM (1 ml) with DIPEA (191μl) at 5°C was added piperidine (98μl) dropwise with stirring. The mixture was stirred at room temperature for 2 hours, then diluted with DCM (10ml) and washed with HCI (1N, 10ml) then water (10ml). Organic layer was dried over magnesium sulphate, solvent evaporated under reduced pressure. The residue was dissolved in DMSO (1 l) and KCN (82mg) was added. The mixture was heated to 120°C for 2 hours. The mixture was then diluted with ethyl acetate (10ml) and washed with water (2 x 10ml), the organic layer was dried over magnesium sulphate, solvent evaporated under reduced pressure. The residue was dissolved in acetonitrile (2ml) and purified by prep-LCMS to afford 4-(2-methoxyphenylamino)-6- piperidin-1-yl-1 ,3,5-triazine-2-carbonitrile (22mg) as a yellow oil. ¹H NMR (CDCI₃)δ: 8.20 (d, 1 H), 8.07 (br, 1H), 7.12 (m, 1H), 6.97 (t, 1H), 6.91 (d, 1H), 3.89 (s, 3H), 3.77 (br, 4H), 1.76 - 1.58 (m, 6H). MS mlz: 311.0 (M+1).

Similarly prepared, using the appropriate amine derivative, were: 11b: 4-(2-methoxyphenylamino)-6-(2-methylpiperidin-1 -yl)-1 ,3,5-triazine-2- carbonitrile; MS mlz: 325.2 (M+1).

11c: 4-(2-methoxyphenylamino)-6-(3-methylpiperidin-1 -yl)-1 ,3,5-triazine-2- carbonitrile; MS mlz: 325.2 (M+1). lid: 4-(2-methoxyphenylamino)-6-(4-methylpiperidin-1 -yl)-1 ,3,5-triazine-2- carbonitrile; MS mlz: 325.2 (M+1).

11e: 4-(3,5-dimethylpiperidin-1-yl)-6-(2-methoxyphenylamino)-1,3,5-triazine-2- carbonitrile; MS mlz: 339.4 (M+1).

11f: 4-(2-methoxyphenylamino)-6-pyrrolidin-1 -yl-1 ,3,5-triazine-2-carboπitrile MS mlz: 297.0 (M+1).

11g: 4-(2-methoxyphenylamino)-6-morpholine-4-yl-1 ,3,5-triazine-2-carbonitrile;

MS mlz: 313.2 (M+1).

11h: 4-(azepan-1-yl)-6-(2-methoxyphenylamino)-1,3,5-triazine-2-carbonitrile;

MS mlz: 325.1 (M+1). 11]: 4-(azetidin-1-yl)-6-(2-methoxyphenylamino)-1 ,3,5-triazine-2-carbonitrile;

MS mlz: 283.1 (M+1).

11j: 4-(azepan-1-y)l-6-(2-methoxyphenylamino)-1 ,3,5-triazine-2-carbonitrile;

MS mlz: 339.0 (M+1).

11k: 4-(2-methoxyphenylamino)-6-(2-methyl-morpholin-4-yl)- 1 ,3,5-triazine-2- carbonitrile; MS mlz: 327 A (M+1).

111: 4-(2,6-dimethyl-morpholin-4-yl)-6-(2-methoxyphenylamino)-1,3,5-triazine-2- carbonitrile; MS mlz: 341.1 (M+1).

11m: 4-(2,2-dimethyl-morpholin-4-yl)-6-(2-methoxyphenylamino)- 1 ,3,5-triazine-2- carbonitrile; MS mlz: 341.1 (M+1). 11n: 4-(3,4-dihydro-2H-quinolin-1 -yl)-6-(2-methoxyphenylamino)-1 ,3,5-triazine-2- carbonitrile; MS mlz: 359.4 (M+1).

11o: 4-(3,4-dihydro-1r/-isoquinolin-2-yl)-6-(2-methoxyphenylamino)-1,3,5-triazine-2- carbonitrile; MS mlz: 359.4 (M+1).

11p: 1 -[4-cyano-6-(2-methoxyphenylamino)-1 ,3,5-triazin-2-yl]-piperidine-3-carboxylic acid diethylamide; MS mlz: 410.1(M+1).

11q: 4-(2-methoxyphenylamino)-6-(4-pyrrolidin-1-yl-piperidin-1-yl)-1,3,5-triazine-2- carbonitrile; MS mlz: 380.3 (M+1).

11n 4-[(2-methoxyphenyl)amino]-6-[4-(1-phenylethyl)piperazin-1-yl]-1,3,5-triazine-2- carbonitrile; MS mlz: 416.3 (M+1). 11s: 4-(2-methoxy-phenyl)amino-6-[4-(1-cycIoheptyl)-piperazin-1-yl]-1 ,3,5-triazine-2- carbonitrile; MS m/z:408.3 (M+1). 11t:: 4-[1,4']bipiperidinyl-1'-yl-6-(2-methoxy-phenyl)amino-1,3,5-triazine-2- carbonitrile; MS mlz: 394.1 (M+1).

11u: 4-(3-diethylamino-pyrrolidin-1-yl)-6-(2-methoxy-phenylamino)-1 ,3,5-triazine-2- carbonitrile; MS mlz: 368.1 (M+1).

EXAMPLE 12.

12a: 4-(2-methoxyphenyl-amino)-6-(piperazine-1-yl)-1 ,3,5-triazine-2-carbonitrile.

A To 2-(2-methoxyphenylamino)-4,6-dichIoro-1,3,5-triazine (see example 11, step A) (5g) in DCM (20ml) at -20°C was added dropwise a solution of tert-butyl 1 - piperazine carboxylate (3.35g), DIPEA (3.2ml) and DCM (20ml). The mixture was stirred at room temperature under nitrogen for two hours then extracted with DCM (50ml), washed with HCI (1M, 50mL) then dried over sodium sulphate and solvent removed under reduced pressure to afford 2-chloro-4-(4-tert-butoxycarbonyl- piperazin-1-yl)-6-(2-methoxyphenylamino)-1 ,3,5-triazine (7.5g). ¹H NMR (CDCI₃) δ: 8.28 (d, 1 H), 7.83 (m, 1 H), 7.05 (t, 1 H), 7.00 (t, 1 H), 3.89 (s, 3H), 3.85 (t, 3H), 3.50 (m, 4H), 1.61 (s, 1H), 1.50 (s, 9H). MS mlz: 421 A (M+1).

B: To 2-chloro-4-(4-tert-butoxycarbonylpiperazin-1-yI)-6-(2-methoxyphenylamino)- 1,3,5-triazine (7.5g) in DMSO (35ml) was added KCN (3.51 g). The mixture was stirred and heated to 120°C under nitrogen for 1 hour. The mixture was then extracted with ethyl acetate (200ml), washed with water (2 x 100ml), dried over sodium sulphate and solvent removed at reduced pressure. The crude product was columned on silica gel using petroleum ether / ethyl acetate (60:40) as eluant to afford 4-(4-tert-butoxycarbonylpiperazin-1 -yl)-6-(2-methoxyphenylamino)-1 ,3,5- triazine-2-carbonitrile (2g) as a yellow powder. ¹H NMR (CDCI₃) δ: 8.25 (d, 1H), 8.75 (m, 1H), 7.08 (t, 1H), 6.99 (t, 1H), 6.90 (d, 1H), 3.91 (s, 3H), 3.85 (m, 4H), 4.49 (m, 4H), 1.49 (s, 9H). MS mlz: 412.3 (M+1). C: 4-(4-tert-Butoxycarbonylpiperazin-1 -yl)-6-(2-methoxyphenylamino)-1 ,3,5-triazine- 2-carbonitrile (2g) was stirred for 15 minutes in TFA (5mL) and DCM (5mL) then solvent was removed under reduced pressure and the crude product purified using preparative LCMS to afford 4-(2-methoxyphenyl-amino)-6-piperazine-1 -yl-1 ,3,5- triazine-carbonitrile (100mg). ¹H NMR (MeOD) δ: 7.88 (m, 1H), 7.15 (m, 1H), 7.07 (m, 1 H), 6.98 (m, 1H), 4.77 (m, 1H), 4.08 (m, 4H), 3.89 (s, 3H). MS m/z: 312.0 (M+1).

12b: 4-(2-methoxy-phenyl-amino)-6-(4-methyl-piperazin-1 -yl)-1 ,3,5-triazine-2- carbonitrile

To a solution of 4-(2-methoxyphenylamino)-6-piperazine-1-yl-1,3,5-triazine-2- carbonitrile (15mg) in DCM (1 mL) was added formaldehyde( 50μl). The mixture was stirred for 10 minutes then sodium triacetoxyborohydride (17mg) added. The reaction was stirred for 45 minutes then extracted with DCM (5ml), washed with saturated sodium bicarbonate (2 x 5ml), dried over sodium sulphate and solvent removed under reduced pressure. The crude product was purified by preparative LCMS to afford 4-(2-methoxy-phenyl-amino)-6-(4-methyl-piperazin-1-yl)-1,3,5- triazine-2-carbonitrile (12mg). H NMR (MeOD) δ: 7.87 (d, 1H), 7.18 (t, 1 H), 7.05 (d, 1H), 6.99 (t, 1H), 3.89 (s, 3H), 3.80 - 2.80 (m, 8H), 2.95 (s, 3H). MS mlz: 326.4 (M+1 ).

EXAMPLE 13:

13a: 4-(4-tert-Butoxycarbonylpiperazin-1 -yl)-6-(2-methoxypyridin-3-ylamino)-1 ,3,5- triazine-2-carbonitrile.

A: To cyanuric chloride (2.0g) was added in DCM (50ml)at 0°C. was added dropwise a solution of N-Boc piperazine (2.02g) and DIPEA (1.40g) in DCM (10 ml). The reaction mixture was stirred at 0°C for 30minut.es, then washed with 1N HCI (20ml) and the organic layer was dried and solvent evaporated to give the desired product

2-(4-tert-Butoxycarbonylpiperazin-1-yl)-4,6-dichloro-1 ,3,5-triazine (3.41g) as a white solid. ¹H NMR (CDCI₃) δ: 3.85 (t, 4H), 3.50 (t, 4H), 1.5 (s, 9H). MS mlz: 334.4 (M+1). B^ To a solution of 2-(4-tert-butoxycarbonylpiperazin-1-yl)-4,6-dichloro-1 ,3,5-triazine (100mg) in acetonitrile (1ml) was added 2-methoxy-3-amino-pyridine (39mg) and DIPEA (52μl). The mixture was stirred and heated in a microwave to 150°C for 10 minutes. Solvent was removed under reduced pressure. The residue was dissolved in DMSO (2mL) and KCN (60mg) added. The mixture was stirred and heated to 120°C for 2 hours then extracted with ethyl acetate (20ml) and washed with water (20ml). Solvent was removed under reduced pressure and the crude product dissolved in DMSO and purified using preparative LCMS to afford 4-(4-tert- butoxycarbonylpiperazin-1-yl)-6-(2-methoxypyridin-3-ylamino)-1,3,5-triazine-2- carbonitrile (20mg). ¹H NMR (CDCI₃) δ: 8.48 (m, 1H), 7.87 (d, 1H), 7.65 (m, 1H), 6.95 (t, 1H), 4.05 (s, 3H), 3.87 (m, 2H), 3.52 (m, 2H), 1.96 (m, 4H), 1.49 (s, 9H). MS mlz: 413.1 (M+1).

13b: 4-(2-methoxy-pyridin-3-yl-amino)-6-piperazine-1-yl-1 ,3,5-triazine-2-carbonitrile.

4-(4-tert-butoxycarbonylpiperazin-1-yl)-6-(2-methoxypyridin-3-ylamino)-1,3,5-triazine- 2-carbonitrile (5mg) was stirred in TFA (0.5mL) and DCM (0.5mL) for 15 minutes then purified using preparative LCMS to afford 4-(2-methoxy-pyridin-3-yl-amino)-6- piperazine-1-yl-[1,3,5]-triazine-2-carbonitrile (LOmg). ¹H NMR (MeOD) δ: 8.25 (d, 1 H), 7.91 (d, 1H), 6.99 (t, 1H), 4.08 (m, 4H), 4.00 (s, 3H), 3.30 (m, 4H). MS mlz: 313.1 (M+1).

EXAMPLE 14:

14a: 4-(N-methylcvclohexylamino)-6-(piperazin-1-yl)-1,3,5-triazine-2-carbonitrile

A: To 2-(4-tert-butoxycarbonylpiperazin-1-yl)-4,6-dichloro-1 ,3,5-triazine (500mgs) in DCM (3ml) at -10°C. was added dropwise a solution of N-methylcyclohexylamine (169.5mg) and DIPEA (212mg) in DCM (5 ml). The reaction mixture was stirred at room temperature for 90 minutes. The reaction was quenched with water and washed with 2N HCI. The organic layer was evaporated down to give 2-chloro-4-(4- tert-butoxycarbonylpiperazin-1-yl)-6-(N-methylcyclohexylamino)-1 ,3,5-triazine (410mgs) as a white solid. ¹H NMR (CDCI₃) δ: 4.55, 4.45 (bt, 1 H), 3.80 (t, 4H), 3.45 (t, 4H), 3.05, 2.95 (d, 3H), 1.80 (m, 2H), 1.70 (m, 3H), 1.50 (s, 9H), 1.45 (m, 4H), 1.10 (m, 1H). MS mlz: 411(M+1).

B: 2-chloro-4-(4-tert-Butoxycarbonylpiperazin-1-yl)-6-(N-methyIcyclohexylamino)- 1 ,3,5-triazine (400mgs), KCN (127mg, 1.95mmol) in DMSO (6ml) were heated at 120°C for 6 hours. The reaction mixture was quenched with water (50ml) and extracted with ethyl acetate (2 x 20ml). The organic layer was dried over magnesium sulphate and the solvent evaporated down. Diethyl ether (10ml) was added and a pale yellow precipitate was removed by filteration and the mother liquor evaporated, the residue was columned on silica gel eluting with ethyl acetate/ petroleum ether (1/2) to give 4-(4-tert-butoxycarbonylpiperazin-1-yl)-6-(N-methylcyclohexylamino)- 1 ,3,5-triazine-2-carbonitrile.as a white solid (160mg).

¹H NMR (CDC ) δ: 4.55, 4.4 (bt, 1H), 3.80 (t, 4H), 3.50 (t, 4H), 3.00, 2.95 (bd, 3H), 1.85 ( , 2H), 1.70 (m, 3H), 1.48 (s, 9H), 1.20 (m, 1H). MS mlz: 402.5 (M+1 ). & 4-(4-tert-Butoxycarbonylpiperazin-1 -yl)-6-(N-methylcyclohexylamino)-1 ,3,5- triazine-2-carbonitrile (160mg) was dissolved in DCM (1ml) to which TFA (1ml) was added. The mixture was stirred at room temperature for 15 minutes. The solvent was evaporated to give 4-(N-methylcyclohexylamino)-6-piperazin-1-yl-[1,3,5] triazine-2- carbonitrile (117mgs) as a white solid. H NMR (MeOH) δ: 4.50 (m,1H), 4.05 (t, 4H), 3.30 (t, 4H), 3.0 (d, 3H), 1.85 (m, 2H), 1.70 (m, 3H), 1.60 (m, 2H), 1.45 (m, 2H), 1.20 (m, 1H). MS mlz: 302 (M+1).

Similarly prepared, using the appropriate amine derivative, were:

14b: 4-(N-ethylcyclohexylamino)-6-piperazin-1 -yl-1 ,3,5-triazine-2-carbonitrile;

MS m/z 316 (M+1). 14c: 4-(4-methyl-cyclohexylamino)-6-piperazin-1-yl-1 ,3,5-triazine-2-carbonitrile;

14d: 4-lsobutylamino-6-piperazin-1 -yl-1 ,3,5-triazine-2-carbonitrile;

MS m/z: 262(M+1).

14e: 4-(3-Methyl-butylamino)-6-piperazin-1 -yl-1 ,3,5-triazine-2-carbonitrile; MS m/z: 276 (M+1). EXAMPLE 15.

15a: 4.6-Bis-cvclohexylamino-1 ,3.5-triazine-2-carbonitrile.

To cyanuric chloride (100mg) in DCM (1ml) was added dropwise at 0°Ca mixture of cyclohexylamine (108mg) and DIPEA (140mg). The mixture was stirred at room temperature for 12 hours then diluted with DCM (20ml) and washed with hydrochloric acid (1 M, 10ml). The organic layer was dried and solvent evaporated. The residue was dissolved in DMSO to which was added KCN (25mg). The reaction was heated to 140°C for 6 hours. The reaction mixture was diluted with ethyl acetate (10ml) and washed with water (2 x 10ml). After removal of solvent, residue was purified using preparative LC-MS to afford 4,6-bis-cyclohexylamino-1,3,5-triazine-2-carbonitrile (1.2mg). ¹H NMR (CDCI₃) δ: 5.30 (bd, 2H), 3.80 (m, 2H), 1.98 (m, 4H), 1.72 (m, 5H), 1.39 (q, 4H), 1.20 (m, 7H). MS mlz: 301 (M+1).

EXAMPLE 16

16a: 4-Cvclohexylamino-6-(2-methyl-piperazin-1-yl)-1 ,3,5-triazine-2-carbonitrile.

A To a solution of 2-cyclohexylamino-4,6-dichloro-1 ,3,5-triazine (example 7, step A)

(706mg) in DCM (5mL) at 0°C was added 3-methyl-piperazine-1 -carboxylic acid tert- butyl ester (579mg) and DIPEA (502μl). The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was extracted with DCM (20mL) and washed with HCI (20ml, 1M), solvent was then removed under reduced pressure to yield 2-chloro-4-cyclohexylamino-6-(4-tert-butoxycarbonyl-2-methylpiperazin-1-yl)- 1 ,3,5-triazine (840mg) as a white powder. MS mlz 411.0 (M+1). B _, The mixture of 2-chloro-4-cyclohexylamino-6-(4-tert-butoxycarbonyl-2-methyl- piperazin-1-yl)-1 ,3,5-triazine (840mg) and KCN (386mg) in DMSO (2mL) was heated to 150°C for 5 hours. The mixture was extracted with DCM (50mL) and washed with water (40mL). Organic layer was dried over sodium sulphate and solvent removed under reduced pressure. Crude product was purified by preparative LCMS to give 4- cyclohexylamino-6-(4-tert-butoxycarbonyl-2-methylpiperazin-1-yl)-1,3,5-triazine-2- carbonitrile (10mg). MS mlz 402.5 (M+1). C _, 4-Cyclohexylamino-6-(4-tert-butoxycarbonyl-2-methylpiperazin-1 -yl)-1 ,3,5-triazine- 2-carbonitrile (10mg) was stirred in a mixture of TFA (1ml) and DCM (1ml) for 15 minutes. After removal of solvent and excess TFA, the residue was then purified by preparative LCMS to give 4-cyclohexylamino-6-(2-methyl-piperazin-1-yl)-1,3,5- triazine-2-carbonitrile (4.5mg) as a yellow gum. ¹H NMR (MeOD) δ: 5.18 (m, 1H), 3.80 (m, 1H), 3.40 (m, 3H), 3.28 (d, 1 H), 31.2 (m ,1H), 1.93 (m, 2H), 1.78 (m, 2H), 1.65 (m, 1H), 1.36 (m, 9H). MS mlz: 302.4 (M+1).

EXAMPLE 17

Cathepsin K Assay Procedure

The inhibitory activity of the compounds of the invention was demonstrated in vitro by measuring the inhibition of recombinant human Cathepsin K as follows: To a 384 well microtitre plate is added 5μl of a 100μM solution of test compound in assay buffer (100mM sodium acetate pH5.5, 5mM EDTA, 5mM dithiothreitol) with 10% dimethylsulfoxide (DMSO), plus 10μl of 100μM solution of the substratre Z-Phe- Arg-AMC (Bachem; 7-amido-coumarine derivative of the dipeptide N- benzyloxycarbonyl-Phe-Arg-OH) in assay buffer and 25μl of assay buffer. 10μl of a 1mg/l solution of activated recombinant human cathepsin K, in assay buffer, is then added to the well, yielding a final inhibitor concentration of 10μM. Enzyme activity is determined by measuring the fluorescence of the liberated aminomethylcoumarin at 440nM using 390nM excitation, at 10 minutes. Percentage enzyme activity is calculated by comparison of this activity to that of a solution containing no inhibitor. Compounds are subsequently subjected to a dose response curve analysis in order to determine IC50 values for active compounds (where IC₅₀ is the concentration of test compound causing 50 % inhibition of the enzymatic activity). Compounds of the invention typically have IC₅₀s for inhibition of human cathepsin K of less than about 500 nM, preferably less than 100nM such as for the compounds of Examples 2a, 2c, 4b, 4d, 4f, 4m, 5c, 5e, 8a, 11a, lid, 11f, 11m, 13b and 15a, and most preferably less than 20 nM, such as for the compounds of Examples 4a, 4c, 5a, 7a, 9a, 11u and 12a.

Claims

Claims.

1. Use of a 2-cyano-1 ,3,5-triazine -4,6-diamine derivative having general formula I

Formula I wherein Ri is (Cι-₆)alkyl, (C₃_₈)cycloalkyl, aryl, aryl(Cι-₄)alkyl, aryloxy(C₁-₄)alkyl, heteroaryl or

R₂ is H or (d-₄)alkyl; or Ri and R₂ together with the nitrogen to which they are bound form a 4-8 membered heterocyclic ring, optionally further comprising 1 or more heteroatoms selected from O, S or NR₅, which ring may be substituted with (Cι.₄)alkyl, (C₃.₈)- cycloalkyl, aryl, aryl(Cι- )alkyl or NR₆R7,and which ring may be fused to a benzene ring; R₃ is (Cι-₆)alkyl, (C₃-₈)cycloalkyl (optionally comprising 1 or more heteroatoms selected from O, S or NR₈), aryl, aryl(Cι-₄)alkyl or heteroaryl; R_A is H or (d- )alkyl; or R₃ and R together with the nitrogen to which they are bound form a 4-8 membered heterocyclic ring, optionally further comprising 1 or more heteroatoms selected from O, S or NR₉; R₅ , R₈ and Rg are independently H, (d-₄)alkyl, (C₃-₈)cycloalkyl, aryl or aryl(d-₄)alkyl; R₆ and R₇ are independently H or (Cι. )alkyl; or R₆ and R₇ form together with the nitrogen to which they are bound a 4-8 membered heterocyclic ring; or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of osteoporosis and atherosclerosis.

2. The use of a 2-cyano-1 ,3,5-triazine -4,6-diamine derivative according to claim 1 , wherein R and R₂ together with the nitrogen to which they are bound form a 4-8 membered heterocyclic ring, optionally further comprising 1 or more heteroatoms selected from O, S or NR₅, which ring may be substituted with (Cι.₄)alkyl, (C₃-₈)- cycloalkyl, aryl or NR₆R and which ring may be fused to a benzene ring.

3. The use of a 2-cyano-1 ,3,5-triazine -4,6-diamine derivative according to claim 2, wherein Ri and R₂ together with the nitrogen to which they are bound form a piperazin-1-yl or N-morpholinyl ring.

4. A 2-cyano-1,3,5-triazine -4,6-diamine derivative having general formula I

wherein Ri and R₂ together with the nitrogen to which they are bound form a 4-8 membered heterocyclic ring, optionally further comprising NR_{5 ι} which ring may be substituted with (d-₄)alkyl, (C₃.₈)cycloalkyl, aryl, aryl(d-₄)alkyl or NR₆R₇, and which ring may be fused to a benzene ring; R₃ is (Cι-₆)alkyl, (C₃.₈)cycloalkyl (optionally comprising 1 or more heteroatoms selected from O, S or NR₈), aryl, aryl(d- )alkyl or heteroaryl; R₄ is H or (d-₄)alkyl; or R₃ and R together with the nitrogen to which they are bound form a 4-8 membered heterocyclic ring, optionally further comprising 1 or more heteroatoms selected from O, S or NR₉; R₅, R₈ and R₉ are independently H, (Cι-₄)alkyl, (C3-₈)cycloalkyl, aryl or aryl(d-₄)alkyl; R₆ and R₇ are independently H or (C₁.₄)alkyi; or R₆ and R₇ form together with the nitrogen to which they are bound a 4-8 membered heterocyclic ring; or a pharmaceutically acceptable salt thereof, with the exclusion of 4,6-di(piperidin-1-yl)-1,3,5-triazine-2-carbonitrile and 4-(morpholin-4-yl)-6- (piperidin-1-yI)-1 ,3,5-triazine-2-carbonitrile.

5. The 2-cyano-1 ,3,5-triazine -4,6-diamine derivative which is selected from: - 4-cyclohexylamino-6-(piperdin-1-yl)-1,3,5-triazine-2-carbonitrile; - 4-(2-methoxypyridin-3-ylamino)-6-(piperidin-1-yl)-1 ,3,5-triazine-2-carbonitrile; - 4-(morpholin-4-yl)-6-(tetrahydropyran-4-ylamino)-1 ,3,5-triazine-2-carbonitrile; - 4-cyclohexylamino-6-(2-methoxy-3-pyridinylamino)-1,3,5-triazine-2-carbonitriIe; - 6-cyclohexylamino-4-(piperazine-1-yl)-1,3,5-triazine-2-carbonitrile; - 4-(3-diethylamino-pyrrolidin-1-yl)-6-(2-methoxy-phenylamino)-1,3,5-triazine-2- carbonitrile; and - 4-(2-methoxyphenyl-amino)-6-(piperazine-1-yl)-1 ,3,5-triazine-2-carbonitrile; or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a 2-cyano-1 ,3,5-triazine -4,6-diamine derivative according to general formula I as defined in claim 4, including 4,6- di(piperidin-1-yl)-1 ,3,5-triazine-2-carbonitrile and 4-(morpolin-4-yl)-6-(piperidin-1-yl)- 1 ,3,5-triazine-2-carbonitrile, together with a pharmaceutically acceptable carrier therefore.

7. A method of treatment of osteoporosis and atherosclerosis, which comprises administering to a mammal, including a human, an effective amount of a 2-cyano- 1,3,5-triazine -4,6-diamine derivative according to general Formula I as defined in claim 1.