WO2004074287A1

WO2004074287A1 - Novel compounds

Info

Publication number: WO2004074287A1
Application number: PCT/SE2004/000215
Authority: WO
Inventors: Andrew Baxter; Sarah King; Austen Pimm; James Reuberson
Original assignee: Astrazeneca Ab
Priority date: 2003-02-19
Filing date: 2004-02-18
Publication date: 2004-09-02
Also published as: SE0300457D0

Abstract

The invention relates to pyridine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

Description

NOVEL COMPOUNDS

The present invention relates to pyridine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The invention also relates to their use in the modulation of autoimmune disease.

T-cells play an important role in the immune response, however in auto-immune disease T-cells are inappropriately activated against particular tissues and proliferate, eg causing the inflammation associated with rheumatoid arthritis. Inhibition of the proliferation of T-cells is beneficial in the modulation of autoimmune disease. The present invention relates to compounds which are beneficial in the modulation of autoimmune disease.

In accordance with the present invention, there is provided a compound of formula (I):

(I) wherein:

A is a 4-, 5- or 6-membered saturated ring;

R¹ is hydrogen, C_1-6 alkyl, halogen, NR⁴R⁵ or X-Cι_-6 alkyl where X is O, S or NR⁴;

R² is hydrogen or C_1-6 alkyl;

R³ is phenyl, a 5- or 6-membered aromatic ring with 1 or more nitrogen atoms, or R³ is an aromatic or partially saturated bicyclic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, each R³ group being optionally substituted by one or more groups selected from saturated monocyclic rings containing one or more heteroatoms and carbonyl groups and optionally substituted by carboxamide groups; 5- or 6-membered aromatic rings containing one or more heteroatoms; halogen; C_1-6 alkyl; Cj,₆ alkoxy; SC_1-6 alkyl; NO₂; NR⁴R⁵; NR⁴(CH₂)_pCONR⁴R⁵; CONR⁴R⁵; CO₂R⁴; CF₃ and SO₂Me; where p is 1 to 3; and

R⁴ and R⁵ are independently hydrogen or C_1-4 alkyl (optionally substituted by hydroxy);

and pharmaceutically acceptable salts and solvates thereof.

As used herein, the term "heteroatoms" includes oxygen, nitrogen and sulphur. Where necessary to satisfy valency requirements, nitrogen atoms may carry hydrogen or a permitted substituted. Sulphur atoms may be oxidised to SO or SO₂. The term "halogen" includes fluoro, chloro, bromo and iodo. The term "Me" refers to methyl.

For the avoidance of doubt, the expression "containing one or more carbonyl groups" used in relation to a ring, means that a C=O group is part of the ring structure. Specifically, the carbon atom of the C=O group is a ring atom, and the oxo group is therefore a substitutent on the ring.

The ring A contains 4, 5 or 6 ring atoms including the nitrogen atom shown. Thus the rings comprise 3, 4 or 5 carbon atoms in the form of CH₂ groups in addition to the nitrogen atom shown in formula (I). Thus, examples of 4-, 5- or 6-membered saturated rings for A include azetidinyl, pyrrolidine and piperidinyl.

Preferably A is an azetidine or pyrrolidine ring, and most preferably A is a pyrrolidine ring.

Particular examples of R¹ include hydrogen, C_1-6 alkyl such as methyl or ethyl, or halogen such as fluoro, chloro or bromo.

Preferred examples of R¹ are hydrogen and halogen. A particularly preferred halogen group for R¹ is chloro.

Most preferably R¹ is hydrogen, methyl or chloro.

Where R¹ is other than hydrogen, it is suitably arranged at the 3- position on the pyridyl ring. Thus particular compounds of formula (I) are compounds of formula (IA)

Preferably R² is hydrogen or methyl.

When R is an aromatic ring system with 1 or more nitrogen atoms, examples include pyridyl, pyrimidyl, triazinyl, thieno[3,2-cTjpyrimidine and 7H-purinyl rings.

W ' hen R 3 is a partially saturated bicyclic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, examples of suitable ring systems include thiazolo[4,5- ]pyrimidine.

Each R³ group is suitably optionally substituted by one or more groups suitably selected from saturated monocyclic rings containing one or more heteroatoms and carbonyl groups and optionally substituted by carboxamide groups; 5- or 6-membered aromatic rings containing one or more heteroatoms; halogen; C_1-6 alkyl; C_1-6 alkoxy; SC]_-6 alkyl; NO₂; NR⁴R⁵; NR⁴(CH₂)_P CONR R⁵; CONR⁴R⁵; CO₂R⁴ and SO₂Me, where R⁴ and R⁵ are as described above.

Particular examples of R⁴ and R⁵ include hydrogen, methyl and hydroxyethyl.

Particular examples of saturated monocyclic rings which may be substituted onto R³ are saturated nitrogen containing rings such as piperidinyl and piperazinyl. These suitably comprise at least one substituent selected from oxo and carboxamide. In addition, they are suitably linked to the group R by way of a nitrogen atom.

Particular examples of 5- or 6-membered aromatic rings containing one or more heteroatoms which may be substituted onto R³ include pyridyl and thienyl.

Preferred substituents for R³ are selected from methyl, NH₂, NO_2> CO₂Me, N(Me)CH₂CH₂OH, NHCH₂CH₂OH, 3-oxo-l -piperazinyl, NHCH₂CH₂CONH₂, 3- piperidinecarboxamide, pyridyl, methoxy, thienyl. More than one substituent can be present on the R³ group. In one embodiment, R is phenyl, optionally substituted as described above.

In an alternative embodiment, R is a 5- or 6-membered aromatic ring with 1 or more nitrogen atoms, such as pyridyl (in particular 2-pyridyl), pyridimidinyl (in particular 2- pyrimidinyl) or triazinyl, any of which are optionally substituted as described above.

Particular substitutents for such R groups include saturated monocyclic rings containing one or more heteroatoms and carbonyl groups and optionally substituted by carboxamide groups; 5- or 6-membered aromatic rings containing one or more heteroatoms; NO₂; C_1-6 alkoxy such as methoxy; NR⁴(CH₂)_pCONR⁴R⁵; NR⁴R⁵; and CO₂R⁴, where R⁴ and R⁵ are as defined above.

In yet another embodiment, R is an aromatic bicyclic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, which may be optionally substituted as described above. In this case, R³ suitably comprises a 6-membered ring, fused to a five membered ring. For instance, R³ may comprise a group of subformula (i)

(i)

1 9 wherein Y and Y are selected from CH and N; one of Y³ or Y⁴is selected from O, S and N, and the other is selected from CR⁹ or NR⁹, and

R and R are independently seletected from hydrogen or from saturated monocyclic rings containing one or more heteroatoms and carbonyl groups and optionally substituted by carboxamide groups; 5- or 6-membered aromatic rings containing one or more heteroatoms; halogen; C_}-6 alkyl; C].₆ alkoxy; SC_1-6 alkyl; NO₂; NR⁴R⁵; NR⁴(CH₂)_pCONR⁴R⁵; GONR⁴R⁵; CO₂R⁴; CF₃ and SO₂Me, R⁴, R⁵ and p are as defined above.

In particular Y¹ and Y² are nitrogen. Suitably where Y³ or Y⁴ is N, the other is a group NR⁹. Where one of Y³ or Y⁴ is O or S, the other is suitably CR⁹.

Preferably, Y³ is selected from O, S and N and Y⁴ is selected from CR⁹ or NR⁹. Particular groups R⁸ and R⁹ include hydrogen, C_1-6 alkyl such as methyl, NR⁴R⁵ such as amino,

Preferred compounds of formula (I) include:

1 -[[6-[4-(9H-Purinr6-yl)- 1 -piperazinyl]-3-pyridinyl]carbonyl]pyrrolidine ditrifmoroacetate

1 -[[5-Chloro-6-[4-(9H-purin-6-yl)- 1 -piperazinyl]-3-pyridinyl]carbonyl]pyrrolidine l-[[5-Chloro-6-[4-(7-methyl-7H-purin-6-yl)-l-piperazinyl]-3- pyridinyl]carbonyl]pyrrolidine.

1 -[[5-Chloro-6-[4-(9-methyl-9H-purin-6-yl)-l -piperazinyl]-3- pyridinyl] carbonyl]pyrrolidine.

1 -[[6-[4-(2-Amino-9H-purin-6-yl)-l -piperazinyl]-5-chloro-3- pyridinyl]carbonyl]pyrrolidine. l-[[5-Clιloro-6-[4-(3-ru^ro-2-pyridinyl)-l-piperazinyl]-3-pyridinyl]carbonyl]pyrrolidine.

2-[4-[3-Chloro-5-(l-pyrrolidinylcarbonyl)-2-pyridinyl]-l-piperazinyl]-3- pyridinecarboxylic acid, methyl ester l-[[5-CUoro-6-[4-[4-[(2-hydroxyethyl)methylamino]-2-pyrimidinyl]-l-piperazinyl]-3- pyridinyl]carbonyl]pyrrolidine. 1 -[[5-Chloro-6-[4-[4-[(2-hydroxyethyl)amino]-2-pyrimidinyl]- 1 -piperazinyl]-3- pyridinyl] carbonyljpyrrolidine l-[[5-Chloro-6-[4-[4-(3-oxo-l-piperazinyl)-2-pyrimidinyl]-l-piperazinyl]-3- pyridinyl] carbonyljpyrrolidine

3-[[2-[4-[3-Chloro-5-(l-pyrrolidinylcarbonyl)-2-pyridinyl]-l-ρiperazinyl]-4- pyrimidinyl]amino]propanamide l-[2-[4-[3-Chloro-5-(l-pyrrolidinylcarbonyl)-2-pyridinyl]-l-piperazinyl]-4- pyrimidinyl]-3-piperidinecarboxamide l-[[5-Chloro-6-[4-[4-(3-pyridinyl)-2-pyrimidinyl]-l-piperazinyl]-3- pyridinyl]carbonyl]pyrrolidine 1 -[[5-Chloro-6-[4-(7-memylthieno[3,2-rf]pyrimidin-4-yl)- 1 -piρerazinyl]-3- pyridinyl]carbonyl]pyrrolidine trifluoroacetate l-[[5-Chloro-6-[4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-l-piperazinyl]-3- pyridinyl] carbonyljpyrrolidine

1 -[[6-[4-(4- Amino- 1 ,3 ,5-triazin-2-yl)- 1 -piperazinyl]-5-chloro-3- pyridinyl]carbonyl]pyrrolidine l-[[6-[4-(2-Amino-9H-purin-6-yl)-2-methyl-l-piperazinyl]-5-chloro-3- pyridinyl]carbonyl]pyrrolidine 1 -[[5-Chloro-6-[3-methyl-4-(9H-purin-6-yl)-l -piperazinyl]-3- pyridinyl] carbonyl]pyrrolidine

1 - [[6- [4-(2- Amino-9H-purin-6-y l)-2-methyl- 1 -piperazinyl] -3 - pyridinyl]carbonyl]pyrrolidine 1 -[[6-[(25}-4-(2-Amino-9H-purin-6-yl)-2-methyl- 1 -ρiperazinyl]-5-chloro-3 - pyridinyl]carbonyl]pyrrolidine l-[[6-[(2i?)-4-(2-Amino-9H-purin-6-yl)-2-methyl-l-ρiperazinyl]-5-chloro-3- pyridinyl]carbonyl]pyrrolidine l-[[5-Chloro-6-[4-(7-methylthieno[3,2-c }pyrimidin-4-yl)-l-piperazinyl]-3- pyridinyl]carbonyl]azetidine

1 -[[5-Chloro-6-[4-[4-(2-thienyl)-2-pyrimidinyl]- 1 -piperazinyl]-3- pyridinyl] carbonyl] azetidine and pharmaceutically acceptable salts and solvates thereof.

Alkyl groups, whether alone or as part of another group, can be straight chained or branched.

It will be understood that a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the drawings within this specification represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. These also form an aspect of the present invention.

Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I) and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of the compounds of formula I as hereinbefore defined which are sufficiently basic to form such salts. Such acid addition salts include for example salts with inorganic or organic acids affording pharmaceutically acceptable anions such as with hydrogen halides (especially hydrochloric or hydrobromic acid of which hydrochloric acid is particularly preferred) or with sulphuric or phosphoric acid, or with trifiuoroacetic, citric or maleic acid. Suitable salts include hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates and tartrates. In addition where the compounds of formula (I) are sufficiently acidic, pharmaceutically acceptable salts may be formed with an inorganic or organic base which affords a pharmaceutically acceptable cation. Such salts with inorganic or organic bases include for example an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Preferred salts include an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p- toluenesulfonate, or an alkali metal salt such as a sodium or potassium salt.

In a further aspect the invention provides a process for the preparation of a compound of formula (I) which comprises:

(a) reacting a compound of formula (II):

(II)

in which A, R and R are as defined in formula (I) or are protected derivatives thereof, with a compound of formula (III):

R³ -L

(III)

in which R³ is as defined in formula (I) or is a protected derivatives thereof, or (b) reacting a compound of formula (IV):

(IV)

in which A and R¹ are as defined in formula (I) with a compound of formula (V):

(V)

9 in which R and R are as defined in formula (I) and optionally thereafter (a) or (b) in any order:

• removing any protecting groups

• forming a pharmaceutically acceptable salt

In compounds of formula (III) leaving groups L include halogen, in particular chloro. Compounds of formula (II) and (III) or (IV) and (V) are typically reacted in an inert solvent such as NMP or IPA in the presence of a base such as a tertiary amine, for example diisopropylethylamine, at a temperature of about 50°C to about 150°C, optionally in a microwave.

Compounds of formula (II) can be prepared from compounds of formula (IV) as defined above by reacting with a compound of formula (VI):

(VI) in which R² is a defined in formula (I) and P¹ is hydrogen or a protecting group, followed by deprotection of the P group. Preferred leaving groups L¹ are halogen, in particular chloro. The reaction is carried out under similar conditions to that of compounds (II) and (III). Suitable protecting groups P¹ include t-butoxycarbonyl which can be removed using acidic conditions such as TFA in a solvent such as dicloromethane, between 10°C and 100°C, optionally in a microwave.

Compounds of formula (IV) are prepared by reacting a compound of formula (VII):

(VII)

in which R¹ and L¹ are as defined above, with an amine of formula (VIII):

(VIII)

in which A is as defined above. The reaction is carried out in the presence of a coupling reagent such as carbonyl diimidazole or thionyl chloride in a solvent such as dichloromethane, NMP or dioxane, preferably between 0°C and 50°C.

Compounds of formula (V) are prepared by reacting a compound of formula (VI) as defined above with a compound of formula (III), as defined above, using conditions similar to those for reaction of compounds (II) and (III) with appropriate deprotection of P¹.

Compounds of formula (III) are available commercially or can be prepared using appropriate chemistry. For example, a compound of formula (III) having an amine derived substituent can be prepared from a compound of formula (IX):

L²-D-L³ (IX) In which D is a 5- or 6-membered aromatic ring with 1 or more nitrogen atoms, or R³ is a partially saturated bicyclic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, and L² and L³ are leaving groups with a suitable amine nucleophile in the presence of a base such as triethylamine in a neutral solvent such as ethanol, to selectively displace one of the leaving groups. Examples are described herein in examples 8a,10a,l la and 12a.

Further compounds of formula (III) can be prepared having a thioalkyl leaving groups as shown below and exemplified in example 16a:

The thiol is alkylated preferably using methyliodide in a neutral solvent such as acetone to give the thioalkyl which is a leaving group

N ^N N ^N

HS N NH,

(III)

Starting materials as defined above are available commercially or can be prepared using routine chemistry known in the art.

The compounds of the invention are useful because they possess pharmacological activity in human and non-human animals. They are indicated as pharmaceuticals for use in the (prophylactic) treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).

Examples of these conditions are:

(1) (the respiratory tract) airways diseases including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including crbupous, fibrinous and pseudo embranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia; (2) (bone and joints) rheumatoid arthritis, seronegative spondyloarthropathies

(including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome and systemic sclerosis;

(3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis;

(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema;

(5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura;

(6) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease; and (7) cancer.

Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

The invention further provides a method of effecting immunosuppression (e.g. in the treatment of allograft rejection) which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.

The invention still further provides a method of treating, or reducing the risk of, an airways disease (e.g. asthma or COPD) in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (1) or a pharmaceutically-acceptable salt thereof as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. However, in general, for effecting immunosuppression, the daily dosage of the compound of formula (I) will be in the range from 0.1 mg/kg, preferably from 0.3 mg/kg, more preferably from 0.5 mg/kg and still more preferably from lmg/kg up to and including 30 mg kg. For the treatment of airways diseases, the daily dosage of the compound of formula (I) will typically be in the range from 0.001 mg/kg to 30 mg/kg.

The compounds of formula (I) and pharmaceutically-acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically-acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably less than 80 %w, e.g. from 0.10 to 70 %w, and even more preferably less than 50 %w, of active ingredient, all percentages by weight being based on total composition.

Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier. The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.

The ability of compounds which can inhibit PMA ionomycin-stimulated peripheral blood mononuclear cell proliferation can be assessed, for example using the procedure set out below.

The invention will now be illustrated in the following Examples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration;

(iϊ) operations were carried out at ambient temperature, that is in the range 18-25°C and under an atmosphere of an inert gas such as argon or nitrogen where appropriate;

(iii) yields are given for illustration only and are not necessarily the maximum attainable;

(iv) the structures of the end-products of the formula I were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques; proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, quartet, quin, quintet; (v) intermediates were not generally fully characterised and purity was assessed by thin layer chromatography (TLC), high-performance liquid chromatography (HPLC), mass spectrometry (MS), infra-red (IR) or NMR analysis;

Abbreviations

Tetrahydrofuran THF

Isopropanol IPA

N-Methylpyrrolidinone NMP

Dichloromethane DCM

The following examples illustrate the invention.

Example 1 l-[[6-[4-(9H-Purin-6-yl)-l-piperazinyl]-3-pyridinyl]carbonyl]pyrrolidine ditrifluoroacetate

a) 1 - [(6-Chloro-3 -pyridinyl)carbonyl]pyrrolidine

Carbonyl diimidazole (5.0g) was added to 6-chloro-3-pyridinecarboxylic acid (5.0g) and pyrrolidine (2.8ml) in DCM (20ml). The mixture was stirred for 2h, concentrated in vacuo and purified by column chromatography (ethyl acetate:isohexane 1:1) to give the sub-title compound as a solid (5.0g). 1H NMR δ₍c_DC ) 8.57 (d,lH), 7.84 (dd,lH), 7.38 (d,lH), 3.65 (t,2H), 3.45 (t,2H), 1.89- 2.05 (m,4H)

b) 4-[5-(l -Pyrrolidinylcarbonyl)-2-pyridinyl]- 1 -piperazinecarboxylic acid, 1,1- dimethylethyl ester

The product of example 1 step a) (0.20g), 1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (0.19g) and Hunigs base (0.2ml) were irradiated in a CEM Discover microwave, 100W/140°C for lOmin. The mixture was cooled and concentrated in vacuo to give the sub-title compound as a yellow gum (0.25g). MS (APCI+) 361 [M+H]⁺

c) 1 -[[6-(l -Piperazinyl)-3-pyridinyl]carbonyl]pyrrolidine trifluoroacetate

The product from example 1 step b) (0.25g) in trifluoroacetic acid (0.6ml) and dichloromethane (2ml) was irradiated in a CEM Discover microwave 20W/50°C for lOmin. Concentration in vacuo gave the sub-title compound (0.25g). MS (APCI+) 261 [M+H]⁺

d) l-[[6-[4-(9H-Purin-6-yl)-l-ρiperazinyl]-3-pyridinyl]carbonyl]ρyrrolidine ditrifluoroacetate

The product from example 1 step c) (0.25g), 6-chloro-7H-purine (0.15g) and Hunigs base (2ml) in isopropanol (2ml) was irradiated in a CEM Discover microwave 1 OOW/150°C for 1 Omin. The precipitate was filtered off and the filtrate was purified by reverse phase HPLC (gradient 95-50% aqueous, trifluoroacetic acid (0.2% aq.) in acetonitrile) to give the title compound as a green solid (40mg). MS (APCI+) 379 [M+H]⁺

1H NMR 5₍DM_SO) 8.38 (s,lH), 8.37 (s,lH), 8.30 (s,lH), 7.82-7.84 (d,lH), 6.98-7.00

(d,2H), 4.27-4.47 (m,4H), 3.77-3.87 (m,4H), 3.40-3.55 (m,4H), 1.77-1.90 (m,4H)

Example 2 l-[[5-Chloro-6-[4-(9H-purin-6-yl)-l-piperazinyl]-3-pyridinyl]carbonyl]pyrrolidine

a) 1 -[(5,6-Dichloro-3 -pyridinyl)carbonyl]pyrrolidine

The sub-title compound was prepared as a solid by the method of example 1 step a) using 5,6-dichloro-3-pyridinecarboxylic acid. MS (APCI+) 245 [M+H]⁺ 1H NMR 5_(CDCI3) 8.46 (s,lH), 7.98 (s,lH), 3.65 (t,2H), 3.47 (t,2H), 1.90-2.00 (m,4H)

b) 4-[3-Chloro-5-(l -pyrrolidinylcarbonyl)-2-pyridinyl]-l-piperazinecarboxylic acid,

1 , 1 -dimethylethyl ester

The product of example 2 step a) (2.0g), 1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (1.5g) and Hunigs base (2ml) in isopropanol (15ml) was heated at 85°C for 48h. The mixture was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and brine, the organic phase was separated, dried (MgSO ) and concentrated in vacuo. Purification by column chromatography (ethyl acetate:isohexane 1 :1) gave the sub-title compound as a solid (2.75g). MS (APCI+) 339/341 [M+H-tBuf

c) l-[[5-Chloro-6-(l-piperazinyl)-3-pyridinyl]carbonyl]pyrrolidine trifluoroacetate

The product from example 2 step b) (2.75g) in trifluoroacetic acid (4ml) and dichloromethane (12ml) was stirred at room temperature for 24h. Concentration in vacuo gave the sub-title compound as the trifluoroacetate salt (2.9g). MS (APCI+) 295/297 [M+H]⁺

d) 1 -[[5-Chloro-6-[4-(9H-purin-6-yl)- 1 -piperazinyl]-3 -pyridinyl]carbonyl]pyrrolidine

The product from example 2 step c) (0.20g), 6-chloro-7H-purine (0.08g) and Hunigs base (0.2ml) in isopropanol (2ml) and NMP (2ml) was heated at 100°C for 18h. The mixture was poured into ethyl acetate and washed with brine, the organic phase was separated, dried (MgSO ) and concentrated in vacuo to give a pale yellow solid. Trituration with ether gave the title compound as a white solid (72mg). MS (APCI+) 413/415 [M+H]⁺

1H NMR 5_(DM_SO) 13.08 (s,lH), 8.42 (s,lH), 8.25 (s,lH), 8.16 (s,lH), 7.97 (s,lH), 4.39 (m,4H), 3.44-3.52 (m,8H), 1.84-1.99 (m,4H)

Example 3 1 -[[5-Chloro-6-[4-(7-methyl-7H-ρurin-6-yl)-l -piperazinyl]-3- pyridinyl] carbonyl]pyrrolidine.

The product from example 2 step c) (0.20g), 6-chloro-7-methyl-7H-ρurine (80mg) and

Hunigs base (0.2ml) in isopropanol (2ml) and NMP (2ml) was heated at 100°C for 18h.

The mixture was poured into ethyl acetate and washed with brine. The organic phase was separated, dried (MgSO ) and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 75-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give the title compound as a white solid (44mg) .

MS (APCI+) 427/429 [M+H]⁺

1H NMR δ_(DMso) 8.50 (s,lH), 8.44 (s,lH), 8.43 (s,lH), 7.97 (s,lH), 4.04 (s,3H), 3.49 (m,8H), 3.43-3.51 (m,4H), 1.81-1.89 (m,4H)

Example 4

1 -[[5-Chloro-6-[4-(9-methyl-9H-purin-6-yl)- 1 -piperazinyl] -3- pyridinyl]carbonyl]pyπOlidine.

The title compound was prepared by the method of example 3 using the product from example 2 step c) and 6-chloro-9-methyl-9H-purine. MS (APCI+) 427/429 [M+H]⁺ 1H NMR δ_(DMso) 8.42 (s,lH), 8.30 (s,lH), 8.18 (s,lH), 7.97 (s,lH), 4.33-4.43 (m,4H), 3.75 (s,3H), 3.44-3.52 (m,8H), 1.81-1.88 (m,4H)

Example 5 l-[[6-[4-(2-Amino-9H-purin-6-yl)-l-piperazinyl]-5-chloro-3- pyridinyl]carbonyl]pyrrolidine.

The product from example 2 step c) (0.20g), 2-amino-6-chloro-7H-purine (80mg) and Hunigs base (0.2ml) in isopropanol (2ml) and NMP (0.5ml) was heated at 95°C for 72h. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (gradient 75-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give the title compound as an off white solid (25mg). MS (APCI+) 428/430 [M+H]⁺

1H NMR δ(D_MSo₎ 12.21 (s,lH), 8.42 (s,lH), 7.96 (s,lH), 7.71 (s,lH), 5.77 (s,2H), 4.19- 4.39 (m,4H), 3.40-3.56 (m,8H), 1.77-1.89 (m,4H)

Example 6 l-[[5-Chloro-6-[4-(3-m^o-2-pyridmyl)-l-piperazinyl]-3-pyridinyl]carbonyl]ρyrrolidine.

The title compound was prepared by the method of example 5 using 2-chloro-3- nitropyridine. MS (APCI+) 417/419 [M+H]⁺

1H MR δ(_DMso₎ 8.43-8.54 (m,lH), 8.41 (s,lH), 8.27,8.30 (d,lH), 7.96 (s,lH), 6.92-6.96 (m,lH), 3.39-3.59 (m,12H), 1.80-1.89 (m,4H)

Example 7 2-[4-[3-Chloro-5-(l-pyrrolidinylcarbonyl)-2-ρyridinyl]-l-piperazinyl]-3- pyridinecarboxylic acid, methyl ester

The title compound was prepared by the method of example 5 using methyl 2-chloro-3- pyridinecarboxyl ate.

MS (APCI+) 430/432 [M+H]⁺

1H NMR δ_(DMso) 8.41 (s,lH), 8.30-8.32 (m,lH), 7.96-7.98 (m,2H), 6.85-6.89 (m,lH),

3.84 (s,3H), 3.44-3.52 (m,12H), 1.79-1.88 (m,4H)

Example 8 l-[[5-CWoro-6-[4-[4-[(2-hydroxye yl)methylamino]-2-pyrimidinyl]-l-piperazinyl]-3- pyridinyl] carbonyl]pyrrolidine.

a) 2-[(2-Chloro-4-pyrimidinyl)methylamino]ethanol

2-(Methylamino)ethanol (0.5g), 2,4-dichloropyrimidine (lg) and triethylamine (1.4ml) in THF (15ml) was stirred for 20h, water was added and the mixture extracted with ethyl acetate. The ethyl acetate phase was concentrated in vacuo and purified by column chromatography (ethyl acetate:isohexane 3:1) to give the sub-title compound (2.8g). 1H NMR δ₍cDCi3) 8.04 (d,lH), 6.37 (d,lH), 3.88 (t,2H), 3.77 (t,2H), 3.13 (s,3H), OH exchanged

b) l-[[5-Chloro-6-[4-[4-[(2-hydroxyethyl)methylamino]-2-pyrimidmyl]-l-piperazinyl]- 3-pyridinyl]carbonyl]pyrrolidine.

The title compound was prepared by the method of example 5 using the product from example 8 step a). MS (APCI+) 446/448 [M+H]⁺

1H NMR δ_(DMSθ) 8.42 (s,lH), 7.99 (s,lH), 7.80-7.89 (m,lH), 6.45-6.53 (m,lH), 3.38- 3.97 (m,20H), 1.74-1.89 (m,4H)

Example 9 l-[[5-Chloro-6-[4-[4-[(2-hydroxyethyl)amino]-2-pyrimidinyl]-l-ρiperazinyl]-3- pyridinyl] carbonyl]pyrrolidine

The title compound was prepared by the method of example 5 using 2-[(2-chloro-4- pyrimidinyl)amino] ethanol. MS (APCI+) 432/434 [M+H]⁺

1H NMR δ_(CDCi₃) 8.37 (s,lH), 7.91 (s,lH), 7.85 (s,lH), 7.55,7.57 (d,lH), 6.05,6.07 (d,lH), 3.91-3.98 (m,4H), 3.83-3.88 (m,2H), 3.61-3.66 (m,4H), 3.50-3.58 (m,6H), 1.88- 2.05 (m,4H), OH exchanged. Example 10 l-[[5-Chloro-6-[4-[4-(3-oxo-l-piperazinyl)-2-pyrimidinyl]-l-piperazinyl]-3- pyridinyl]carbonyl]ρyrrolidine

a) 2-Chloro-4-(4-methyl- 1 -piperazinyl)pyrimidine

2,4-Dichloropyrimidine (1.Og), piperazone (0.8g) and Hunigs base (2ml) in ethanol (2ml) were stirred for 18h. The insoluble solid product was filtered and recrystallised from ethanol (1.05g). MS (APCI+) 213/215 [M+H]⁺

b) l-[[5-Chloro-6-[4-[4-(3-oxo-l-piperazinyl)-2-pyrimidinyl]-l-piperazinyl]-3- pyridinyl] carbonyl]pyrrolidine

The title compound was prepared by the method of example 5 using the product from example 10 step a).

MS (APCI+) 471/473 [M+H]⁺

1H NMR δ_(CDCi₃₎8.38 (s,lH), 8.02,8.04 (d,lH), 7.85 (s,lH), 6.49 (s,lH), 5.86,5.88 (d,lH), 4.23 (s,2H), 3.91-3.95 (m,4H), 3.84-3.87 (m,2H), 3.60-3.66 (m,2H), 3.47-3.56 (m,8H), 1.92-2.02 (m,4H)

Example 11 3-[[2-[4-[3-Chloro-5-(l-pyrrolidinylcarbonyl)-2-pyridinyl]-l-piperazinyl]-4- pyrimidinyl]amino]propanamide

a) 3-[(2-Chloro-4-pyrimidinyl)amino]propanamide

2,4-Dichloropyrimidine (l.Og), 3-aminopropanamide (0.7g) and Hunigs base (2ml) in ethanol (2ml) were stirred for 18h. The mixture was concentrated in vacuo and purified by column chromatography (ethyl acetate) to give the sub-title compound. MS (APCI+) 201/203 [M+H]⁺

b) 3-[[2-[4-[3-Chloro-5-(l-pyrrolidinylcarbonyl)-2-pyridinyl]-l-piperazinyl]-4- pyrimidinyl] amino]propanamide

The title compound was prepared by the method of example 5 using the product from example 11 step a).

MS (APCI+) 459/461 [M+H]⁺

1H NMR δ_(CDci3) 8.37 (s,lH), 7.82-7.91 (d,lH), 7.84 (s,lH), 5.62-5.82 (s,2H), 5.42-5.55 (s,lH), 5.20-5.33 (s,lH), 3.80-4.00 (m,4H), 3.39-3.76 (m,10H), 2.46-2.58 (m,2H), 1.80- 2.07 (m,4H)

Example 12 l-[2-[4-[3-Chloro-5-(l-pyrrolidinylcarbonyl)-2-pyridinyl]-l-piperazinyl]-4- pyrimidinyl]-3-piperidinecarboxamide

a) 1 -(2-Chloro-4-pyrimidinyl)-3-piperidinecarboxamide

The sub-title compound was prepared by the method of example 11 step a) using 3- piperidinecarboxamide. MS (APCI+) 241/243 [M+H]⁺

b) l-[2-[4-[3-Chloro-5-(l-pyrrolidinylcarbonyl)-2-pyridinyl]-l-piperazinyl]-4- pyrimidinyl]-3-piperidinecarboxamide

The title compound was prepared by the method of example 5 using the product of example 12 step a). MS (APCI+) 499/501 [M+H]⁺

1H NMR δ₍cDCi3) 8.37 (s,lH), 7.96,7.98 (d,lH), 7.85 (s,lH), 6.27 (s,lH), 5.92,5.94 (d,lH), 5.41 (s,lH), 3.49-4.05 (m,15H), 3.21-3.29 (m,lH), 2.44-2.51 (m,lH), 1.89-2.07 (m,6H), 1.55-1.64 (m,2H)

Example 13 l-[[5-Chloro-6-[4-[4-(3-pyridinyl)-2-pyrimidinyl]-l-piperazinyl]-3- pyridinyl]carbonyl]pyrrolidine

The title compound was prepared by the method of example 5 using 2-chloro-4-(3- pyridinyl)pyrimidine.

MS (APCI+) 450/452 [M+H]⁺

1H NMR δ₍c_DCi₃₎9.26 (s,lH), 8.69-8.72 (m,lH), 8.45 (d,lH), 8.39 (s,lH), 8.33-8.37

(m,lH), 7.86 (d,lH), 7.40-7.44 (m,lH), 7.00 (d,lH), 4.08-4.11 (m,4H), 3.54-3.67

(m,8H), 1.90-2.01 (m,4H)

Example 14 l-[[5-CWoro-6-[4-(7-methylthieno[3,2-cTjpyrimidin-4-yl)-l-piperazinyl]-3- pyridinyl]carbonyl]pyrrolidine trifluoroacetate

The title compound was prepared by the method of example 3 using 4-chloro-7-methyl- thieno[3,2- ]pyrimidine.

MS (APCI+) 444/6 [M+H]⁺

1H NMR δ(_DMSθ) 8.71 (s,lH), 8.42 (d,lH), 8.08 (s,lH), 7.98 (d,lH), 4.21 (t,4H), 3.64 (t,4H), 3.47 (dt,4H), 2.39 (d,3H), 1.84 (quintet,4H)

Example 15 l-[[5-Chloro-6-[4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-l-piperazinyl]-3- pyridinyl]carbonyl]pyrrolidine

The title compound was prepared by the method of example 5 using 2-chloro-4,6- dimethoxy-1 ,3,5-triazine.

MS (APCI+) 434/436 [M+H]⁺

1H NMR δpMSO) 8.41 (s,lH), 7.97 (s,lH), 3.89-3.98 (m,4H), 3.87 (s,6H), 3.39-3.54

(m,8H), 1.76-1.92 (m,4H)

Example 16 l-[[6-[4-(4-Amino-l,3,5-triazin-2-yl)-l-piperazinyl]-5-chloro-3- pyridinyl] carbonyl]pyrrolidine

a) 4-(Methylthio)-l,3,5-triazin-2-amine

4-amino-2-thio-l,3,5-triazine (lg), methyliodide (0.49ml) and cesium carbonate (2.55g) was stirred in acetone (50ml) at room temperature for 18h. The precipiate was filtered off to give the sub-title compound as a white solid (lg). MS (APCI+) 143 [M+H 1H NMR δp so) 8.23 (s,lH), 7.53 (s,2H), 2.42 (s,3H)

b) l-[[6-[4-(4-Amino-l,3,5-triazin-2-yl)-l-piperazinyl]-5-chloro-3- pyridinyl] carbonyljpyrrolidine

The product from example 2 step c) (0.4g), 4-(methylthio)-l,3,5-triazin-2-amine (0.14g) and Hunigs base (0.5ml) were irradiated in a CEM Discover microwave, 1 OOW/150°C for lOmin. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (gradient 75-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give the title compound as a white solid (60mg). MS (APCI+) 389/391 [M+H]⁺

1H NMR 6_(DM_SO) 8.41 (s,lH), 8.07 (s,lH), 7.95 (s,lH), 6.90 (s,2H), 3.82-3.89 (m,4H), 3.42-3.51 (m,4H), 3.36-3.41 (m,4H), 1.79-1.89 (m,4H)

Example 17

1 - [[6- [4-(2- Amino-9H-purin-6-yl)-2-methyl- 1 -piperazinyl]-5-chloro-3 - pyridinyl]carbonyl]pyrrolidine

a) 1 -[[5-Chloro-6-(2-methyl-l -piperazinyl)-3-pyridinyl]carbonyl]pyrrolidine trifluoroacetate

The product from example 2 step a) (0.3g), 3 -methyl- 1-piperazinecarboxylic acid, 1,1- dimethylethyl ester (0.26g) and Hunigs base (0.4ml) in isopropanol (2ml) were irradiated in a CEM Discover microwave, 100W/140°C for 5h. The mixture was cooled and concentrated in vacuo. The residue was taken up in dichloromethane (2ml) and trifluoroacetic acid (0.5ml) and irradiated in a CEM Discover microwave, 50W/50°C for 5min. The reaction mixture was filtered and the filtrate was concentrated in vacuo, then azeotroped with toluene to give the sub-title compound as a white solid. MS (APCI+) 309/311 [M+H]⁺

b) l-[[6-[4-(2-Amino-9H-purin-6-yl)-2-methyl-l-piperazinyl]-5-chloro-3- pyridinyl] carbonyljpyrrolidine

The title compound was prepared by the method of example 5 using the crude product from example 17 step a) and 2-amino-6-chloro-7H-purine at 140°C.

MS (APCI+) 442/444 [M+H]⁺

Η NMR δ_(BMS₀₎ 12.12 (s,lH), 8.42 (s,lH), 7.96 (s,lH), 7.70 (s,lH), 5.75 (s,2H), 3.85-

3.94 (m,lH), 3.42-3.52 (m,5H), 3.25-3.35 (m,3H), 3.06-3.14 (m,lH), 2.93-3.03 (m,lH), 1.78-1.89 (m,4H). 1.33,1.34 & 1.09,1.10 (d,3H) (Me, racemate)

Example 18 l-[[5-Chloro-6-[3-methyl-4-(9H-purin-6-yl)-l-piperazinyl]-3- pyridinyl]carbonyl]pyrrolidine

a) 6-(2-Methyl-l-piperazinyl)-9H-ρurine ditrifluoroacetate

6-Chloro-9H-ρurine (0.38g) and 3-methyl-l-piperazinecarboxylic acid, 1,1- dimethylethyl ester (0.5g) and Hunigs base (0.5ml) in isopropanol (3ml) was heated at 90°C for 12h. The mixture was cooled and concentrated in vacuo. The residue was taken up in dichloromethane (15ml) and trifluoroacetic acid (4ml) and stirred at room temperature for 24h. The reaction mixture was concentrated in vacuo, azeofroping with toluene to give the sub-title compound as a yellow gum. MS (APCI+) 219 [M+Hf

b) l-[[5-Chloro-6-[3-methyl-4-(9H-purin-6-yl)-l-piperazinyl]-3- pyridinyl]carbonyl]pyrrolidine

The title compound was prepared by the method of example 5 using the product from example 18 step a) and the product from example 2 step a) at 130°C. MS (APCI+) 427/429 [M+H]⁺

1H NMR δ_(DMso₎ 8.43 (s,lH), 8.25 (s,lH), 8.14 (s,lH), 7.97 (s,lH), 3.92-3.97 (m,2H), 3.43-3.52 (m,4H), 3.28-3.34 (m,3H), 3.13-3.19 (m,lH), 2.99-3.07 (m,lH), 1.80-1.88 (m,4H). 1.37,1.38 (d, 3H), NH exchanged.

Example 19 l-[[6-[4-(2-Amino-9H-purin-6-yl)-2-methyl-l-piperazinyl]-3- pyridinyl] carbonyljpyrrolidine

a) 6-(3-Methyl-l -piperazinyl)-7H-purin-2-amine

2-Methylpiperazine (0.5g), 2-amino-6-chloro-7H-purine (0.85g) and Hunigs base (1ml) in isopropanol (3ml) and NMP (3ml) was heated at 50°C for 18h. The precipitate was filtered off to give the sub-title compound as a white solid ( 1.1 g). MS (APCI+) 234 [M+H]⁺

b) l-[[6-[4-(2-Amino-9H-purin-6-yl)-2-methyl-l-piperazinyl]-3- pyridinyl] carbonyl]pyrrolidine

The product from example 19 step a) (0.25g), the product of example 1 step a) (0.2g) and Hunigs base (0.5ml) in NMP (1ml) were irradiated in a CEM Discover microwave lOOW/l 50°C for 5h. The mixture was acidified with acetic acid and purified by reverse phase HPLC (gradient 75-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give after recrystallation from methanol the title compound as a white solid (25mg). MS (APCI+) 408 [M+H]⁺ 1H NMR δ(_DMSθ) 12.20 (s,lH), 8.37 (s,lH), 7.75 (d,lH), 7.70 (s,lH), 6.83 (d,lH), 5.76 (s,2H), 4.20-4.26 (m,lH), 3.39-3.55 (m,4H), 3.25-3.36 (m,4H), 3.13-3.24 (m,2H), 1.78- 1.88 (m,4H). 1.07 (d,3H)

Example 20 1 -[[6-[(2₁S)-4-(2-Amino-9H-ρurin-6-yl)-2-methyl- 1 -piperazinyl]-5-chloro-3- pyridinyl] carbonyl]pyrrolidine

a) 6-[(35)-Methyl-l-piperazinyl]-7H-purin-2-amine

(25)-2-Methylpiperazine (0.5g), 2-aιmno-6-chloro-7H-purine (0.85g) and Hunigs base (lml) in and NMP (5ml) was heated at 50°C for 5h. The precipitate was filtered off to give the sub-title compound as a white solid (lg). MS (APCI+) 234 [M+H]⁺

b) l-[[6-[(2-S -4-(2-Amino-9H-purin-6-yl)-2-methyl-l-ρiperazinyl]-5-chloro-3- pyridinyl] carbonyl]pyrrolidine

The product from example 20 step a) (0.23g), the product from example 2 step a) (0.2g) and Hunigs base (0.4ml) in NMP (1ml) was heated at 140°C for 48h. Pyrrolidine (0.2ml) was added and the mixture was irradiated in a CEM Discover microwave 1 OOW/120°C for 5 min. (Pyrrolidine reacts with a co-running impurity). The mixture was acidified with acetic acid and purified by reverse phase HPLC (Symmetry, gradient 75-5% ' aqueous, ammonium acetate (0.2% aq.) in acetonitrile) followed by further purification by reverse phase HPLC (Xterra, gradient 80-50% aqueous, trifluoroacetic acid (0.2% aq.) in acetonitrile). The product was partitioned between ethyl acetate and sat.aq. sodium hydrogen carbonate, the organic phase was separated, dried (MgSO₄) and concentrated in vacuo to give the title product as a white solid (19mg). MS (APCI+) 442/444 [M+H]⁺

1H NMR δ(_D so) 12.19 (s,lH), 8.42 (s,lH), 7.95 (s,lH), 7.70 (s,lH), 5.76 (s,2H), 4.22- 4.33 (m,lH), 3.65-3.75 (m,lH), 3.39-3.66 (m,8H), 3.26-3.36 (m,lH), 1.77-1.89 (m,4H), 1.08,1.10 (d,3H)

Example 21 l-[[6-[(2Λ)-4-(2-Amino-9H-ρurin-6-yl)-2-methyl-l-piperazinyl]-5-chloro-3- pyridinyl] carbonyl]pyrrolidine

The title compound was prepared as a white solid by the method of example 20 step a) followed by example 20 step b) using (2i?)-2-methylpiperazine. MS (APCI+) 442/444 [M+H]⁺ 1H NMR δ_(DMso₎ 12.19 (s,lH), 8.42 (s,lH), 7.95 (s,lH), 7.70 (s,lH), 5.76 (s,2H), 4.22- 4.32 (m,lH), 3.63-3.75 (m,lH), 3.36-3.58 (m,8H), 3.22-3.34 (m,lH), 1.77-1.91 (m,4H), 1.08,1.10 (d 3H)

Example 22 l-[[5-CMoro-6-[4-(7-methylthieno[3,2-(i]pyrimidin-4-yl)-l-piperazinyl]-3- pyridinyl]carbonyl]azetidine

. a) 1 -[(5,6-Dichloro-3-pyridinyl)carbonyl]azetidine

Oxalyl chloride (1.6ml) was added to 5,6-dichloro-3-pyridinecarboxylic acid (3.0g) and dimethylformamide (3 drops) in DCM (25ml). The mixture was stirred for lh, concenfrated in vacuo and dissolved in DCM (20ml). Triethylamine (4.35ml) and azetidine hydrochloride (1.46g) were added and stirred for lh. The mixture was concentrated in vacuo and purified by column chromatography (ethyl acetate:DCM 1 :4) to give the sub-title compound as a solid (1.4g). Η NMR δ_(CDci₃₎ 8.60 (s,lH), 8.27 (s,lH), 4.36 (t,2H), 4.06 (t,2H), 2.27 (pent,2H) b) 1 -[[5-Chloro-6-(l -piperazinyl)-3-pyridinyl]carbonyl]azetidine trifluoroacetate

The product of example 22 step a) (lg), 1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (0.8g) and Hunigs base (0.95ml) in NMP (5ml) was heated at 100°C for 24h. The mixture was cooled and concentrated in vacuo. The residue was partitioned between diethyl ether and sat.aq. sodium hydrogen carbonate, the organic phase was separated, dried (MgSO ) and concentrated in vacuo to give an oil, which was dissolved in trifluoroacetic acid (5ml) and dichloromethane (20ml) and stirred at room temperature for 4h. Concentration in vacuo followed by trituration (methanohdiethyl ether 1:50) gave the sub-title compound as the trifluoroacetate salt (1.1 g). MS (APCI+) 281/283 [M+H]⁺

1H NMR δ_(DMso) 8.87 (bs,lH), 8.47 (d,lH), 7.99 (d,lH), 4.37 (t,2H), 4.04 (t,2H), 3.58 (t,4H), 3.25 (t,4H), 2.27 (quin,2H)

c) 1 -[[5-Chloro-6-[4-(7-methylthieno[3,2- ]pyrimidin-4-yl)-l -piperazinyl]-3- pyridinyl]carbonyl]azetidine

The product from example 22 step b) (0.39g), 4-chloro-7-methyl-thieno[3,2- φyrimidine (0.19g) and Hunigs base (0.55ml) and NMP (5ml) was heated at 120°C for 6h. The mixture was poured into ethyl acetate and washed with brine, the organic phase was separated, dried (MgSO ) and concentrated in vacuo to give a pale yellow solid. Trituration with etheπmethanol gave the title compound as a white solid (0.22g). MS (APCI+) 429/431 [M+H]⁺ 1H NMR δ(DMS0) 8.56 (s,lH), 8.46 (d,lH), 7.97 (d,lH), 7.88 (d,lH), 4.37 (d,2H), 4.10 (t,4H), 4.04 (t,2H), 3.61 (t,4H),-2.36 (s,3H), 2.26 (quin,2H)

Example 23 l-[[5-Chloro-6-[4-[4-(2-thienyl)-2-pyrimidinyl]-l-ρiperazinyl]-3- pyridinyl] carbonyl] azetidine

The title compound was prepared by the method of example 22 step c) using 2-chloro-4- (2-thienyl)pyrimidine with secondary purification by reverse phase HPLC (Symmetry, gradient 75-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile).

MS (APCI+) [M+H]⁺

1H NMR δ_(DMSo) 8.47 (d,lH), 8.41 (d,lH), 7.97 (d,lH), 7.95 (d,lH), 7.77 (d,lH), 7.21

(t,lH), 7.17 (d,lH), 4.39 (s,2H), 4.04 (bs,2H), 3.94 (bs,4H), 3.52 (bs,4H), 2.26 ( quin,2H).

Pharmacological Data

Inhibition of PMA ionomycin-stimulated peripheral blood mononuclear cell proliferation

The assay for PMA/ionomycin-stimulated PBMC proliferation was performed in 96- well flat-bottomed microtitre plates. Compounds were prepared as 1 OmM stock solutions in dimethyl sulfoxide. A 50-fold dilution of this was prepared in RPMI and serial dilutions were prepared from this solution. 1 Oμl of the 50-fold diluted stock, or dilutions of it, were added to the well to give concentrations in the assay starting at 9.5μM and going down. Into each well was placed 1 x 10⁵ PBMC, prepared from human peripheral blood from a single donor, in RPMI1640 medium supplemented with 10% human serum, 2mM glutamine and penicillin/streptomycin. Phorbol myristate acetate (PMA) (0.5ng/ml final concentration) and ionomycin (500ng/ml final concentration) were added to these cells in supplemented RPMI 1640 medium (as above) so that the final volume of the assay was 0.2ml. The cells were incubated at 37°G in a humidified atmosphere at 5% carbon dioxide for 72 hours. ³H-Thymidine (0.5μCi) was added for the final 6 hours of the incubation. The level of radioactivity incorporated by the cells was then determined and this is a measure of proliferation.

The compounds of the Examples were found to exhibit an IA₅o value of less than 1 x 10^"5 M in the above test. The compounds of examples 3, 12 and 13 have IA₅0 values of 1780, 490 and 36 nM respectively.

Claims

1. A compound of formula (I):

(I) wherein:

A is a 4-, 5- or 6-membered saturated ring;

R¹ is hydrogen, C_1-6 alkyl, halogen, NR⁴R⁵ or X-C_1-6 alkyl where X is O, S or NR⁴;

R² is hydrogen or C_1-6 alkyl;

R is phenyl, a 5- or 6-membered aromatic ring with 1 or more nitrogen atoms, or R is an aromatic or partially saturated bicyclic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, each R³ group being optionally substituted by one or more groups selected from saturated monocyclic rings containing one or more heteroatoms and carbonyl groups and optionally substituted by carboxamide groups; 5- or 6-membered aromatic rings containing one or more heteroatoms; halogen; Ci.₆ alkyl; C_1-6 alkoxy; SC_1-6 alkyl; NO₂; NR R⁵; NR⁴(CH₂)_pCONR⁴R⁵; CONR⁴R⁵; CO₂R⁴; CF₃ andSO₂Me; where p is 1 to 3; and R⁴ and R⁵ are independently hydrogen or C_1-4 alkyl (optionally substituted by hydroxy);

and pharmaceutically acceptable salts and solvates thereof.

2. A compound according to claim 1 in which A is a pyrrolidine ring.

3. A compound according to claim 1 or 2 in which R¹ is hydrogen, C]_-6 alkyl or halogen.

4. A compound according to any one of claims 1 to 3 in which R² is hydrogen or methyl.

5. A compound according to any one of claims 1 to 4 in which R³ is a, pyrimidyl, triazinyl, 7H-purinyl, thieno[3,2-<i]pyrimidine, or thiazolo[4,5-< |pyrimidine ring system, each R group being optionally substituted by one or more groups selected from methyl, NH₂, NO₂, CO₂Me, N(Me)CH₂CH₂OH, NHCH₂CH₂OH, 3 -oxo-1 -piperazinyl, NHCH₂CH₂CONH₂, 3 -piperidinecarboxamide, pyridyl, methoxy, thienyl.

6. A compound according to claim 1 selected from: l-[[6-[4-(9H-Purin-6-yl)-l-piperazinyl]-3-ρyridinyl]carbony]]pyrrolidine ditrifluoroacetate l-[[5-Chloro-6-[4-(9H-purin-6-yl)-l-piperazinyl]-3-pyridmyl]carbonyl]pyrrolidine

1 -[[5-Chloro-6-[4-(7-methyl-7H-purin-6-yl)-l -piperazinyl] -3- pyridinyl]carbonyl]pyrrolidine. l-[[5-Chloro-6-[4-(9-methyl-9H-purin-6-yl)-l-piperazinyl]-3- pyridinyl] carbonyl]pyrrolidine.

1 -[[6-[4-(2-Amino-9H-purin-6-yl)-l -piperazinyl]-5-chloro-3- pyridinyl] carbonyl]pyrrolidine. l-[[5-Chloro-6-[4-(3-nifro-2-pyridinyl)-l-piperazinyl]-3-pyridinyl]carbonyl]pyrrolidine.

2-[4-[3 -Chloro-5-(l -pyrrolidinylcarbonyl)-2-pyridinyl]- 1 -piperazinyl]-3 - pyridinecarboxylic acid, methyl ester l-[[5-CUoro-6-[4-[4-[(2-hydroxyethyl)methylamino]-2-pyrimidinyl]-l-piperazinyl]-3- pyridinyl]carbonyl]pyrrolidine. 1 -[[5-Chloro-6-[4-[4-[(2-hydroxyethyl)amino]-2-pyrimidinyl]-l -piperazinyl]-3- pyridinyl] carbonyl]pyrrolidine l-[[5-Chloro-6-[4-[4-(3-oxo-l-piperazinyl)-2-pyrimidinyl]-l-piperazinyl]-3- pyridinyl] carbonyl]pyrrolidine

3-[[2-[4-[3-Chloro-5-(l-pyrrolidinylcarbonyl)-2-pyridinyl]-l-piperazinyl]-4- pyrimidinyl]amino]propanamide l-[2-[4-[3-Chloro-5-(l-pyrrolidinylcarbonyl)-2-pyridinyl]-l-piρerazinyl]-4- pyrimidinyl]-3-piperidinecarboxamide l-[[5-Chloro-6-[4-[4-(3-pyridinyl)-2-pyrimidinyl]-l-piperazinyl]-3- pyridinyl] carbonyl]pyrrolidine l-[[5-Chloro-6-[4-(7-methylthieno[3,2-rf]pyrimidin-4-yl)-l-ρiperazinyl]-3- pyridinyl]carbonyl]pyrrolidine trifluoroacetate 1 -[[5-Chloro-6-[4-(4,6-dimethoxy-l ,3,5-triazin-2-yl)-l -piρerazinyl]-3- pyridinyl] carbonyl]pyrrolidine

1 -[[6-[4-(4-Amino-l ,3 ,5-triazin-2-yl)-l -piperazinyl]-5-chloro-3- pyridinyl] carbonyl]pyrrolidine 1 -[[6-[4-(2-Amino-9H-purin-6-yl)-2-methyl-l -piperazinyl]-5-chloro-3- pyridinyl] carbonyl]pyrrolidine l-[[5-Chloro-6-[3-methyl-4-(9H-purin-6-yl)-l-piperazinyl]-3- pyridinyl] carbonyl]pyrrolidine

1 -[[6-[4-(2-Amino-9H-purin-6-yl)-2-methyl-l -piperazinyl] -3- pyridinyl]carbonyl]pyrrolidine l-[[6-[(25)-4-(2-Amino-9H-ρurin-6-yl)-2-methyl-l-piperazinyl]-5-chloro-3- pyridinyl]carbonyl]pyrrolidine

1 -[[6-[(2_JR)-4-(2-Amino-9H-purin-6-yl)-2-methyl- 1 -piperazinyl]-5-chloro-3- pyridinyl]carbonyl]pyrrolidine 1 -[[5-Chloro-6-[4-(7-methylthieno[3 ,2- ]pyrimidin-4-yl)-l -piperazinyl]-3- pyridinyl]carbonyl]azetidine

1 -[[5-Chloro-6-[4-[4-(2-thienyl)-2-pyrimidinyl]- 1 -piperazinyl]-3- pyridinyl] carbonyl] azetidine and pharmaceutically acceptable salts thereof.

A compound according to any one of claims 1 to 6 for use in therapy.

8. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 6 in association with a pharmaceutical carrier.

9. A method of effecting immunosuppression (e.g. in the treatment of allograft rejection) which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 6.

10. A method of treating, or reducing the risk of, an airways disease (e.g. asthma or COPD) in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (1 ) or a pharmaceutically-acceptable salt thereof as defined in any one of claims 1 to 6.