WO2004074278A1 - Novel compounds - Google Patents

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Publication number
WO2004074278A1
WO2004074278A1 PCT/SE2004/000216 SE2004000216W WO2004074278A1 WO 2004074278 A1 WO2004074278 A1 WO 2004074278A1 SE 2004000216 W SE2004000216 W SE 2004000216W WO 2004074278 A1 WO2004074278 A1 WO 2004074278A1
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WIPO (PCT)
Prior art keywords
pyridinyl
carbonyljpyrrolidine
piperidinyl
chloro
piperidinylj
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PCT/SE2004/000216
Other languages
French (fr)
Inventor
Andrew Baxter
Christine Eyssade
Simon Guile
Sarah King
Austen Pimm
James Reuberson
Philip Thorne
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Astrazeneca Ab
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Publication of WO2004074278A1 publication Critical patent/WO2004074278A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to pyridines, 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.
  • A is a 4-, 5- or 6-membered saturated ring
  • p 1 or 2;
  • R 1 is hydrogen, C ⁇ -6 alkyl, halogen, NR 4 R 5 or X-C 1-6 alkyl where X is O, S or NR 4 ;
  • B is a bond, CH 2 , O, S, SO, SO 2 or NH group
  • R is phenyl, an aromatic ⁇ ng system with 1 or more nitrogen atoms, or R is a saturated or partially saturated bicyclic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulphur each R 2 group being optionally substituted by one or more groups selected from halogen, C 1-6 alkyl, oxo, SC 1-6 alkyl, NO 2 , NR 6 R 7 , CONR 6 R 7 , SO 2 Me, or a 6-membered saturated ring containing one or more heteroatoms and optionally substituted by one or more groups selected from C 1-6 alkyl and carbonyl;
  • R 4 and R 5 are independently hydrogen or C 1- alkyl;
  • R 6 and R 7 are independently hydrogen or C 1-4 alkyl;
  • heteroatoms includes oxygen, nitrogen and sulphur. Where necessary to satisfy valency requirements, nitrogen atoms may carry hydrogen or a permitted substitutent. Sulphur atoms may be oxidised to SO or SO 2 .
  • halogen includes fluoro, chloro, bromo and iodo.
  • Me refers to methyl.
  • the ring A contains 4, 5 or 6 ring atoms including the nitrogen atom shown.
  • the rings comprise 3, 4 or 5 carbon atoms in the form of CH 2 groups in addition to the nitrogen atom shown in formula (I).
  • 4-, 5- or 6-membered saturated rings for A include azetidinyl, pyrrolidine and piperidinyl.
  • A is an azetidine or pyrrolidine ring, and most preferably A is a pyrrolidine ring.
  • R 1 is selected from hydrogen, C 1-6 alkyl such as methyl or ethyl, NR 4 R 5 where RR 44 iiss hhyyddrrooggeenn oorr mmeetthhyyll,, aanndd RR 55 iiss CC 11-- aa]lkyl, or O-C 1-6 alkyl such as methoxy, or halogen such as fluoro, chloro or bromo.
  • C 1-6 alkyl such as methyl or ethyl
  • NR 4 R 5 where RR 44 iiss hhyyddrrooggeenn oorr mmeetthhyyll, aanndd RR 55 iiss CC 11-- aa]lkyl, or O-C 1-6 alkyl such as methoxy, or halogen such as fluoro, chloro or bromo.
  • R 1 include hydrogen, C 1-6 alkyl such as methyl or ethyl, or halogen such as fluoro, chloro or bromo.
  • R 1 are hydrogen and halogen.
  • a particularly preferred halogen group for R 1 is chloro.
  • R 1 is hydrogen, methyl or chloro.
  • R 1 is other than hydrogen, it is suitably arranged at the 3- position on the pyridyl ring.
  • R 1 is other than hydrogen, it is suitably arranged at the 3- position on the pyridyl ring.
  • compounds of formula (I) are compounds of formula (IA)
  • p is 2.
  • B is a bond, O, NH, or SO 2 group.
  • Suitable substituents for R 2 include halogen and in particular fluorine or chlorine, (C 1-6 alkyl such as methyl), oxo, SC 1-6 alkyl (such as thiomethyl or thioethyl), NR R (such as amino, methylamino or dimethylamino,) CONR R (such as carboxamide), SO 2 Me 3 or a, piperazinyl ring, optionally substituted by C 1-6 alkyl such as methyl or carbonyl ; where
  • R and R are as defined above.
  • R is substituted by a piperazinyl ring, it is suitably linked to the group R by way of a nitrogen atom.
  • R is phenyl
  • R is an aromatic ring system with 1 or more nitrogen atoms.
  • Such ring systems may be mono or bicyclic and may be optionally substituted by any of the groups listed above.
  • Examples of monocyclic rings including one or more nitrogen atoms for R 2 are pyridyl (such as 2-pyridyl), pyrimidinyl (such as 2-pyrimidinyl), pyridazinyl, and triazinyl.
  • Particular substitutents for monocyclic aromatic nitrogen containing rings R 2 are fluorine, chlorine methyl, thiomethyl , thioethyl, amino, methylamino or dimethylamino, carboxamide, SO 2 Me, or a, piperazinyl ring, optionally substituted by methyl or carbonyl.
  • bicyclic aromatic rings R 2 include fused 5 and 6 membered aromatic rings, where at least one nitrogen atom is present in one or both rings.
  • the bicyclic rings suitably contain up to 4 nitrogen atoms.
  • Examples include lH-benzimidazole, IH- 1,2,3- benzotriazole, 3H-imidazo[4,5-b]pyridine and 7 ⁇ -purine rings. These may be substituted as described above on either ring.
  • a particular subsitutent in this case however is a group NR 6 R 7 such as amino, or C 1-6 alkyl such as methyl.
  • R 2 is an aromatic ring system with 1 or more nitrogen atoms
  • examples include pyridyl, pyrimidyl, pyridazine, triazine, lH-benzimidazole, 1H-1,2,3- benzotriazole, 3H-imidazo[4,5-b]pyridine and 7 ⁇ - ⁇ urine rings.
  • a fused 5- and 6-membered ring structure can form the basis of R 2 groups which are partially saturated.
  • one ring is aromatic and one ring is saturated.
  • the non-saturated ring is suitably the five membered ring, which in a particular embodiment, is substituted with an oxo group.
  • the bicyclic ring system contains at least one nitrogen atom, suitably from 1 to 4 nitrogen atoms.
  • the ring further contains a sulphur atom which is optionally oxidised to SO or preferably SO 2 .
  • a particular substitutent for such groups is SO 2 Me, which is suitably present on the aromatic ring.
  • R is a partially saturated bicyclic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulphur
  • suitable ring systems include 2,3-dihydro-lH-benzimidazole, 2,3-dihydro-lH-imidazo[4,5-b]pyridine, 2,3-dihydro-lH-imidazo[4,5-c]pyridine, 8,9-dihydro-7H-purine and 1,3-dihydro- [1 ,2,5]thiadiazolo[3,4-b]pyridine.
  • R 2 is phenyl, pyridyl, pyrimidyl, pyridazine, triazine and 7 ⁇ -purine when B is O, N or SO2, and R 2 is lH-benzimidazole, lH-l,2,3-benzotriazole, 2,3-dihydro-lH- benzimidazole, 2,3-dihydro-lH-imidazo[4,5-b]pyridine, 2,3-dihydro-lH-imidazo[4,5- c]pyridine, 8,9-dihydro-7H-purine, 3H-imidazo[4,5-b]pyridine and 1,3-dihydro- [l,2,5]thiadiazolo[3,4-b]pyridine when B is a bond.
  • Preferred compounds of formula (I) include: l-[[6-[4-(2-Pyrimidinyloxy)-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine l-[[5-CUoro-6-[4-[[2-(dimemylamino)-4-pyrimidinyl]oxy]-l-piperidinyl]-3- pyridinyl]carbonyl]pyrrolidine l-[[5-Chloro-6-[4-[[4-(dimethylamino)-2-pyrimidinyl]oxy]-l-pi ⁇ eridinyl]-3- pyridinyl]carbonyl]pyrrolidine l-[[6-[4-[[4-(Dimethylamino)-2- ⁇ yrimidinyl]oxy]-l-piperidinyl]-3- pyridinyl]carbonyl]pyrrolidine l-[[5-Chloro-6-[4
  • Alkyl groups whether alone or as part of another group, can be straight chained or branched.
  • 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 trifluoroacetic, citric or maleic acid.
  • Suitable salts include hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates and tartrates.
  • 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.
  • 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, aleate, tartrate, citrate, oxalate, methanesulfonate o ⁇ p- toluenesulfonate, or an alkali metal salt such as a sodium or potassium salt.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, aleate, tartrate, citrate, oxalate, methanesulfonate o ⁇ p- toluenesulfonate, or an alkali metal salt such as a sodium or potassium salt.
  • the invention provides a process for the preparation of a compound of formula (I) which comprises:
  • A, p and R 1 are as defined in formula (I) or are protected derivatives thereof, optionally activated with a base, with a compound of formula (III):
  • 2 . is as defined in formula (I) or is a protected derivatives thereof, L is a leaving group or a nasent leaving group on Mitsunobu activation, and L 3 is hydrogen or a further leaving group, and, where L is a leaving group, reacting the resulting compound with a further nucleophile; or
  • Suitable protecting groups P 1 include t- butoxycarbonyl which can be removed using standard acidic conditions.
  • R is as defined in formula (I) or is a protected derivatives thereof
  • L is a leaving group, preferably a halogen, followed by reduction of the nitro group and optional cyclisation, or.
  • R3 is an amine, an alcohol or a carbonyl or is a protected derivatives thereof
  • L 2 is halogen, more preferably chloro, which can be reacted with an oxygen or nitrogen based nucleophile in the presence of a base such as a tertiary amine, for example triethylamine, in an inert solvent such as NMP or dioxane at a temperature of between 10°C to 100°C, preferably 25°C to 75°C.
  • a base such as a tertiary amine, for example triethylamine
  • Compunds of formula (I) are also prepared by reacting compounds of formula (XI) with a compounds of formula (V) followed by reaction with compounds of formula (XII).
  • a compound of formula (III) is available commercially or can be prepared using appropriate chemistry.
  • L 3 is hydrogen
  • having an amine derived substituent can be prepared from a compound of formula (III)
  • L 2 and L 3 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.
  • 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).
  • AIDS Acquired Immunodeficiency Syndrome
  • COPD chronic obstructive
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy.
  • 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.
  • 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 (I) or a pharmaceutically-acceptable salt thereof as hereinbefore defined.
  • an airways disease e.g. asthma or COPD
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • 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 1 mg/kg up to and including 30 mg/kg.
  • 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.
  • 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.
  • the present invention also provides a pharmaceutical composition
  • 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 title compound was prepared by the method of example 2 step c) and 2-chloro-4- dimethylaminopyrimidine.
  • the title compound was prepared by the method of example 2 step c) and 2-chloro-4- dimethylaminopyrimidine.
  • the title compound was prepared by the method of example 1 step c) and 2-chloro-4- (propylthio)pyrimidine. Purification by reverse phase HPLC (Symmetry®, gradient 90- 50% aqueous, TFA (0.2% aq.) in acetonitrile).
  • step b) The product of example 8 step b) (25mg) and ammonia aq. (2ml) were combined in dioxane (2ml) and heated in a sealed tube at 100°C for 24h. Purification by reverse phase HPLC (Xterra®, gradient 75-5% aqueous, ammonia (0.2% aq.) in acetonitrile) gave the title compound as a solid (6mg). MS (APCI+) 403/405 [M+H] +
  • the title compound was prepared by the method of example 1 step c) and 4-chloro-2- (methylthio)pyrimidine. Purified by column chromatography (ethyl acetate).
  • step a The product of example 9 step a) (l.Og) and oxone® (15.0g) were combined in DCM (40ml). After 48h, solids were removed by filtration and the supernatant concentrated.
  • step b) (0.15g) and aq. ammonia (1ml) were combined in dioxane (3ml) and irradiated in a CEM Discover microwave, 50W/100°C/10min. Purification by reverse phase HPLC (Xterra®, gradient 85-50% aqueous, ammonia (0.2% aq.) in acetonitrile), gave the title compound as a solid (60mg).
  • Example 18 1 -[[6-[4-[(2-Amino-6-methyl-4-pyrimidinyl)oxy]-l -piperidinyl]-3- pyridinyl J carbonyljpyrrolidine ditrifluoroacetate
  • the title compound was prepared as a solid by the method of example 2 step c) and 2- fluoropyridine.
  • step a) The product of example 28 step a) (140mg) was dissolved in ethanol (20ml) and acetic acid (1ml). Palladium on charcoal (10%, 70mg) was added as a slurry in ethanol and the resultant mixture hydrogenated at 4 bar for 20h. The reaction mixture was filtered and the filtrate concentrated. Purification by reverse phase HPLC (Xterra®, gradient 80-
  • the title compound was prepared as a white foam (O.lg) by the method of example 1 step c) and 6-chloro-7H-purine followed by purification by reverse phase HPLC (Symmetry®, gradient 95-60% aqueous, TFA (0.2% aq.) in acetonitrile).
  • Example 32 1 -[[6-[4-[(2-Amino-9H-purin-6-yl)oxy]-l -piperidinylJ-3-pyridinylJcarbonylJpyrrolidine ditrifluoroacetate
  • Trimethylsilylchloride (4.05ml) was added to a solution of 2-amino-5-bromo-3- methylpyridine (1.5g) in chloroform (30ml) and heated at reflux for 30min. The solution was cooled, isobutylamylnitrite (9.5ml) was added and heated again at reflux for 21h. The solution was cooled, filtered through a pad of silica and concentrated to an oil.
  • step b) To the product from example 44 step b) (1 OOmg) in DCM (10ml) was added carbonyl diimidazole (0.13g) and stirred for 3 days. The resulting mixture was concentrated and purified by reverse phase HPLC (Symmetry, gradient 95-50% aqueous, ammonium acetate (0.2 % aq.) in acetonitrile) to give the title compound as a white solid (30mg).
  • the sub-title compound was prepared as a solid by the method of example 1 step a) using 2,6-dichloro-3-pyridinecarboxylic acid.
  • the title compound was prepared by the method of example 60 and 4-chloro-N,N- dimethyl-2-pyrimidinamine.
  • the assay for PMA/ionomycin-stimulated PBMC proliferation was performed in 96- well flat-bottomed microtitre plates. Compounds were prepared as lOmM stock solutions in dimethyl sulfoxide. A 50-fold dilution of this was prepared in RPMI and serial dilutions were prepared from this solution. 1 O ⁇ l of the 50-fold diluted stock, or dilutions of it, were added to the well to give concentrations in the assay starting at 9.5 ⁇ M and going down. Into each well was placed 1 x 10 5 PBMC, prepared from human peripheral blood from a single donor, in RPMI 1640 medium supplemented with 10% human serum, 2mM glutamine and penicillin/streptomycin.
  • Phorbol myristate acetate (PMA) 0.5ng/ml final concentration
  • ionomycin 500ng/ml final concentration
  • the cells were incubated at 37°C in a humidified atmosphere at 5% carbon dioxide for 72 hours.
  • 3 H-Thymidine 0.5 ⁇ Ci 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 examples 29, 37 and 48 have IA 5 o values of 220, 20 and 1050 nM respectively.

Abstract

The invention relates to pyridine derivatives of formula (I) where the variables are defined in the specification.Processes for the preparation of these compounds together with pharmaceutical compositions containing them and their use in therapy in particular in the modulation of autoimmune disease is also described.

Description

NOVEL COMPOUNDS
The present invention relates to pyridines, 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):
Figure imgf000002_0001
wherein:
A is a 4-, 5- or 6-membered saturated ring;
p is 1 or 2;
R1 is hydrogen, Cι-6 alkyl, halogen, NR4R5 or X-C1-6 alkyl where X is O, S or NR4;
B is a bond, CH2, O, S, SO, SO2 or NH group;
R is phenyl, an aromatic πng system with 1 or more nitrogen atoms, or R is a saturated or partially saturated bicyclic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulphur each R2 group being optionally substituted by one or more groups selected from halogen, C1-6 alkyl, oxo, SC1-6 alkyl, NO2, NR6R7, CONR6R7, SO2Me, or a 6-membered saturated ring containing one or more heteroatoms and optionally substituted by one or more groups selected from C1-6 alkyl and carbonyl;
R4 and R5 are independently hydrogen or C1- alkyl; R6 and R7 are independently hydrogen or C1-4 alkyl;
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 substitutent. Sulphur atoms may be oxidised to SO or SO2. The term "halogen" includes fluoro, chloro, bromo and iodo. The term "Me" refers to methyl.
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.
Suitably R1 is selected from hydrogen, C1-6 alkyl such as methyl or ethyl, NR4R5 where RR44 iiss hhyyddrrooggeenn oorr mmeetthhyyll,, aanndd RR55 iiss CC11-- aa]lkyl, or O-C1-6 alkyl such as methoxy, or halogen such as fluoro, chloro or bromo.
Particular examples of R1 include hydrogen, C1-6 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)
Figure imgf000004_0001
(IA)
Preferably p is 2.
Preferably B is a bond, O, NH, or SO2 group.
Suitable substituents for R2 include halogen and in particular fluorine or chlorine, (C1-6 alkyl such as methyl), oxo, SC1-6 alkyl (such as thiomethyl or thioethyl), NR R (such as amino, methylamino or dimethylamino,) CONR R (such as carboxamide), SO2Me3 or a, piperazinyl ring, optionally substituted by C1-6 alkyl such as methyl or carbonyl ; where
R and R are as defined above.
When R is substituted by a piperazinyl ring, it is suitably linked to the group R by way of a nitrogen atom.
In particular
Figure imgf000004_0002
are hydrogen, methyl or ethyl.
In one embodiment, R is phenyl.
In another embodiment of the invention, R is an aromatic ring system with 1 or more nitrogen atoms. Such ring systems may be mono or bicyclic and may be optionally substituted by any of the groups listed above.
Examples of monocyclic rings including one or more nitrogen atoms for R2 are pyridyl (such as 2-pyridyl), pyrimidinyl (such as 2-pyrimidinyl), pyridazinyl, and triazinyl. Particular substitutents for monocyclic aromatic nitrogen containing rings R2 are fluorine, chlorine methyl, thiomethyl , thioethyl, amino, methylamino or dimethylamino, carboxamide, SO2Me, or a, piperazinyl ring, optionally substituted by methyl or carbonyl.
Examples of bicyclic aromatic rings R2 include fused 5 and 6 membered aromatic rings, where at least one nitrogen atom is present in one or both rings. The bicyclic rings suitably contain up to 4 nitrogen atoms. Examples include lH-benzimidazole, IH- 1,2,3- benzotriazole, 3H-imidazo[4,5-b]pyridine and 7Η-purine rings. These may be substituted as described above on either ring. A particular subsitutent in this case however is a group NR6R7 such as amino, or C1-6alkyl such as methyl.
Thus when R2 is an aromatic ring system with 1 or more nitrogen atoms examples include pyridyl, pyrimidyl, pyridazine, triazine, lH-benzimidazole, 1H-1,2,3- benzotriazole, 3H-imidazo[4,5-b]pyridine and 7Η-ρurine rings.
Similarly a fused 5- and 6-membered ring structure can form the basis of R2 groups which are partially saturated. In particular in such cases, one ring is aromatic and one ring is saturated. The non-saturated ring is suitably the five membered ring, which in a particular embodiment, is substituted with an oxo group. Preferably the bicyclic ring system contains at least one nitrogen atom, suitably from 1 to 4 nitrogen atoms. In a particular embodiment, the ring further contains a sulphur atom which is optionally oxidised to SO or preferably SO2. A particular substitutent for such groups is SO2Me, which is suitably present on the aromatic ring.
When R is a partially saturated bicyclic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulphur examples of suitable ring systems include 2,3-dihydro-lH-benzimidazole, 2,3-dihydro-lH-imidazo[4,5-b]pyridine, 2,3-dihydro-lH-imidazo[4,5-c]pyridine, 8,9-dihydro-7H-purine and 1,3-dihydro- [1 ,2,5]thiadiazolo[3,4-b]pyridine.
Preferably R2 is phenyl, pyridyl, pyrimidyl, pyridazine, triazine and 7Η-purine when B is O, N or SO2, and R2 is lH-benzimidazole, lH-l,2,3-benzotriazole, 2,3-dihydro-lH- benzimidazole, 2,3-dihydro-lH-imidazo[4,5-b]pyridine, 2,3-dihydro-lH-imidazo[4,5- c]pyridine, 8,9-dihydro-7H-purine, 3H-imidazo[4,5-b]pyridine and 1,3-dihydro- [l,2,5]thiadiazolo[3,4-b]pyridine when B is a bond.
Preferred compounds of formula (I) include: l-[[6-[4-(2-Pyrimidinyloxy)-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine l-[[5-CUoro-6-[4-[[2-(dimemylamino)-4-pyrimidinyl]oxy]-l-piperidinyl]-3- pyridinyl]carbonyl]pyrrolidine l-[[5-Chloro-6-[4-[[4-(dimethylamino)-2-pyrimidinyl]oxy]-l-piρeridinyl]-3- pyridinyl]carbonyl]pyrrolidine l-[[6-[4-[[4-(Dimethylamino)-2-ρyrimidinyl]oxy]-l-piperidinyl]-3- pyridinyl]carbonyl]pyrrolidine l-[[5-Chloro-6-[4-(2-pyrimidinyloxy)-l-piperidinyl]-3-ρyridinyl]carbonyl]pyrrolidine l-[[6-[4-[[4-(Propylthio)-2-pyrimidinyl]oxy]-l-piρeridinyl]-3- pyridinyl]carbonyl]pyrrolidine l-[[5-Chloro-6-[4-[[4-(propylthio)-2-pyrimidinyl]oxy]-l-piperidinyl]-3- pyridinyl] carbonyl]pyrrolidine
1 -[[6-[4-[(2-Atnino-4-pyrimidinyl)oxy]-l -piperidinyl]-5-chloro-3- pyridinyl] carbonyl]pyrrolidine 1 -[[6-[4-[(2-Amino-4-pyrimidinyl)oxy]-l -piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine l-[[6-[4-[(2-Amino-5-ethyl-6-methyl-4-pyrimidinyl)oxy]-l-piperidinyl]-3- ρyridinyl]carbonyl]pyrrolidine acetate
1 -[[6-[4-[[4-(4-Methyl-l -piperazinyl)-2-pyrimidinyl]oxy]-l -piperidinyl]-3- pyridinyl] carbonyl]pyrrolidine l-[[6-[4-[[2-(Methylamino)-4-pyrimidinyl]oxy]-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine l-[[6-[4-[[4-(3-Oxo-l-piperazinyl)-2-pyrimidinyl]oxy]-l-piperidinyl]-3- pyridinyl] carbonyl]pyrrolidine l-[[6-[4-[[5-Methyl-2-(methylamino)-4-pyrimidinyl]oxy]-l-piperidinyl]-3- pyridinyl] carbonyl]pyrrolidine l-[[6-[4-[4-Pyrimidinyl)oxy]-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine l-[[6-[4-(3-Pyridazinyloxy)-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine acetate l-[[6-[4-[(2-Amino-6-methyl-4-pyrimidinyl)oxy]-l-piperidinyl]-3- pyridinyl] carbonyl]pyrrolidine l-[[6-[4-[[2-(Dimethylamino)-6-methyl-4-pyrimidinyl]oxy]-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine
1 -[[6- [4-[(4-Amino-5-methyl-2-pyrimidinyl)oxy]- 1 -piperidinyl]-3- pyridinyl] carbonyl]pyrrolidine
1 -[[6-[4-[(2-amino-5-methyl-4-pyrimidinyl)oxy]-l -piperidinyl]-3- pyridinyl] carbonyljpyrrolidine
1 -[[6-[4-[([4-(Methylamino)-2-pyrimidinyl]oxy]-l -piperidinyl]-3- pyridinyl] carbonyljpyrrolidine
1 -[ [5 -Chloro-6- [4- [(6-fluoro-2-pyridinyl)oxy] - 1 -piperidinyl]-3 - pyridinyl] carbonyljpyrrolidine 1 -[[5-Chloro-6-[4-(2-pyridinyloxy)- 1 -piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine
1 -[[6-[4-[(6-Amino-2-pyridinyl)oxy]- 1 -piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine
5-Chloro-6-[[l-[5-(l-pyrrolidinylcarbonyl)-2-pyridinyl]-4-piperidinyl]oxy]-3- pyridinecarboxamide l-[[6-[4-[(5-Amino-2-pyridinyl)oxy]-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine l-[[6-[4-[(5-Amino-3-methyl-2-pyridinyl)oxy]-l-piperidinyl]-3- pyridinyl]carbonyl]pyrrolidine l-[[6-[4-[(6-Amino-3-pyridazinyl)oxy]-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine acetate
1 -[[6-[4-[(4-Amino-l ,3,5-triazin-2-yl)oxy]-l -piperidinyl]-3- pyridinyl]carbonyl]pyrrolidine 1 - [[6- [4-(9H-Purin-6-yloxy)- 1 -piperidinylj -3 -pyridinyl] carbonyljpyrrolidine
1 -[[6-[4-[(2-Amino-9H-ρurin-6-yl)oxyJ- 1 -piρeridinyl]-3-pyridinylJcarbonyl]pyrrolidine
1 -[[6-(4-Phenoxy- 1 -piperidinyl)-3 -pyridinyl J carbonyljpyrrolidine l-[[5-Chloro-6-(4-phenoxy-l-piperidinyl)-3-pyridinylJcarbonylJpyrrolidine l-[[5-(Dimethylamino)-6-(4-phenoxy-l-ρiperidinyl)-3-ρyridinyl]carbonylJpyrrolidine l-[[6-[4-(Phenylsulfonyl)-l-piperidinylJ-3-pyridinylJcarbonyl]pyrrolidine l-[[5-Chloro-6-[4-(lH-indol-3-yl)-l-piperidinylJ-3-pyridinyl]carbonyl]pyrrolidine
1 - [[6- [4-( 1 H-Indol-3 -yl)- 1 -piperidinyl J-3 -pyridinyl J carbonyljpyrrolidine l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-ρiperidinylJ-3- pyridinyl] carbonyljpyrrolidine
1 -[[5-Chloro-6-[4-(2,3-dihydro-2-oxo-l H-benzimidazol-1 -yl)- 1 -piperidinylJ-3- pyridinyl J carbonyljpyrrolidine l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinylJ-5-methyl-3- pyridinyl J carbonyljpyrrolidine 1 -[[5-Chloro-6-[4-(7,8-dihydro-8-oxo-9Η-purin-9-yl)-l -piperidinyl]-3- pyridinyljcarbonyljpyrrolidine l-[[5-Chloro-6-[4-(l,2-dihydro-2-oxo-3H-imidazo[4,5-bJpyridin-3-yl)-l-piperidinylJ-3- pyridinyljcarbonyljpyrrolidine l-[[5-Chloro-6-[4-(2-methyl-3H-imidazo[4,5-b]ρyridin-3-yl)-l-piρeridinyl]-3- pyridinyl J carbonyljpyrrolidine l-[[5-CMoro-6-[4-(2,2-dioxido[l,2,5Jthiadiazoϊo[354-b]pyridin-3(lH)-yl)-l-piperidinylJ-
.3 -pyridinylj carbonyljpyrrolidine l-[[5-Chloro-6-[4-(2,3-dihydro-2-oxo-lH-imidazo[4,5-cJpyridin-l-yl)-l-piperidinyl]-3- pyridinylj carbonyljpyrrolidine l-[[5-Chloro-6-[4-[2,3-dihydro-5-(methylsulfonyl)-2-oxo-lH-benzimidazol-l-ylJ-l- piperidinylJ-3-pyridinylJcarbonylJpyrrolidine l-[[6-[4-[2,3-Dihydro-5-(methylsulfonyl)-2-oxo-lH-benzimidazol-l-ylJ-l-piperidinylJ-
3 -pyridinylj carbonyl Jpyrrolidine l-[[6-[4-(Phenylamino)-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine 1 -[[5-Chloro-6-[4-[[4-(dimethylamino)-2-pyrimidinylJaminoJ-l -piperidinyl]-3- pyridinyl J carbonyljpyrrolidine l-[[6-[4-[[4-(Dimethylamino)-2-pyrimidinyl]amino]-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine l-[[6-[4-(2-Pyrimidinylamino)-l-piperidinylJ-3-pyridinyl]carbonyl]pyrrolidine l-[[6-[4-(lH-l,2,3-Benzotriazol-l-yl)-l-piperidinyl]-5-chloro-3- pyridinyl] carbonyljpyrrolidine l-[[2-Chloro-6-[4-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piρeridinyl]-3- pyridinyl J carbonyljpyrrolidine
1 -[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l -yl)-l -piρeridinylJ-2-[(2- methylpropyl)amino]-3-pyridinyl]carbonylJpyrrolidine l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinylJ-2-(methylamino)-3- pyridinyl] carbonyl]pyrrolidine l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinyl]-2-methoxy-3- pyridinylj carbonyljpyrrolidine 1 -[ [6- [4-(2,3 -Dihy dro-2-oxo- 1 H-benzimidazol- 1 -yl)- 1 -piperidinyl] -2-(dimethylamino)-
3 -pyridinylj carbonyljpyrrolidine l-[[6-[3-[[4-(Dimethylamino)-2-pyrimidinyl]oxy]-l-pyrrolidinyl]-3- pyridinyl] carbonyljpyrrolidine l-[[6-[3-[[2-(Dimethylamino)-4-pyrimidinyl]oxyJ-l-pyrrolidinylJ-3- pyridinyljcarbonyljpyrrolidine and pharmaceutically acceptable salts or 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 trifluoroacetic, 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, aleate, tartrate, citrate, oxalate, methanesulfonate oτp- 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) for compounds of formula (I) where B is O, reacting a compound of formula (II):
Figure imgf000009_0001
(II)
in which A, p and R1 are as defined in formula (I) or are protected derivatives thereof, optionally activated with a base, with a compound of formula (III):
L2-R2-L3
(III)
in which R |2 . is as defined in formula (I) or is a protected derivatives thereof, L is a leaving group or a nasent leaving group on Mitsunobu activation, and L3 is hydrogen or a further leaving group, and, where L is a leaving group, reacting the resulting compound with a further nucleophile; or
(b) for compounds of formula (I) where B is S, SO or SO2, converting the OH group of a compound of formula (II) as defined above to a leaving group such as a mesylate and displacing with an appropriate nucleophile such as thiophenol, followed by optional oxidation; or (c) reacting a compound of formula (IV):
Figure imgf000010_0001
(IV)
in which A and R1 are as defined in formula (I) or are protected derivatives thereof, with a compound of formula (V):
Figure imgf000010_0002
(V)
in which B, p and R2 are as defined in formula (I) or are protected derivatives thereof,
(d) for compounds of formula (I) in which B is NH, reacting a compound of formula
(VI):
Figure imgf000010_0003
(VI)
in which A, p and R1 are as defined in formula (I) or are protected derivatives thereof, with a compound of formula (VII):
R -NH2 (VII)
in which R2 is as defined in formula (I) or is a protected derivatives thereof, followed by reduction, (e) for compounds of formula (I) in which B is a NH, reacting a compound of formula (VIII):
Figure imgf000011_0001
(VIII)
in which in which A, p and R1 are as defined in formula (I) or are protected derivatives thereof and P1 is hydrogen or a protecting group, followed by deprotection of the P1 group, with a compound of formula (III). Suitable protecting groups P1 include t- butoxycarbonyl which can be removed using standard acidic conditions.
(f) for compounds of formula (I) in which B is a bond, reacting a compound of formula (VIII) with a compound of formula (IX)
L2-R2-NO2
(IX)
in which R is as defined in formula (I) or is a protected derivatives thereof, and L is a leaving group, preferably a halogen, followed by reduction of the nitro group and optional cyclisation, or.
(g) for compounds of formula (I) in which R1 is NR4 or NR R5, reacting a compound of formula (I), R1 is H, in the presence of bromine followed by convertion of the bromide to NR4 or NR4R5 by metal-catalysed amination, and
and optionally thereafter any of the above processes,
• removing any protecting groups
• forming a pharmaceutically acceptable salt. Compounds of formula (II), (VI) and (VIII) are prepared by reacting a compound of formula (IV) with a compound of formula (X)
Figure imgf000012_0001
(X)
in which R3, and optionally the carbon to which it is attached, is an amine, an alcohol or a carbonyl or is a protected derivatives thereof
Compounds of formula (IV) are prepared by reacting a compound of formula (XI):
Figure imgf000012_0002
(XI)
in which R > ι a „—nd^ L are as defined above, with an amine of formula (XII):
Figure imgf000012_0003
(XII)
in which A is as defined above. The reaction is carried out in the presence of a coupling reagent such as carbonyl diimidazole in a solvent such as dichloromethane, preferably between 0°C and 50°C. Compounds of formula (IV) are also prepared from a compound of formula (XIII):
Figure imgf000013_0001
(XIII)
in which R1 is defined above, by diazotisation of the amine to a leaving group, preferably chloro, followed by metal-catalysed carbonylation of the bromo in the presence of a compound of formula (XII).
Compounds of formula (IV) can also be prepared from compounds of formula (XIII):
Figure imgf000013_0002
(XIII)
1 in which A and L are as defined above and L is a leaving group, by reaction with a nucleophile containing an R1 group. Preferably L2 is halogen, more preferably chloro, which can be reacted with an oxygen or nitrogen based nucleophile in the presence of a base such as a tertiary amine, for example triethylamine, in an inert solvent such as NMP or dioxane at a temperature of between 10°C to 100°C, preferably 25°C to 75°C.
Compunds of formula (I) are also prepared by reacting compounds of formula (XI) with a compounds of formula (V) followed by reaction with compounds of formula (XII).
Compounds of formula (III) are available commercially or can be prepared using appropriate chemistry. For example, a compound of formula (III), L3 is hydrogen, having an amine derived substituent can be prepared from a compound of formula (III), 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. 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 croupous, fibrinous and pseudomembranous 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 (I) 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 1 mg/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; (ii) 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-pressure liquid chromatography (HPLC), mass spectrometry (MS), infra-red (IR) or NMR analysis;
Abbreviations
Dichloromethane DCM
Tetrahydrofuran THF N-methylpyrrolidinone NMP
Trifluoroacetic acid TFA
O-Benzotriazol-l-yl-N,N,N',N'-tetramethyluronium TBTU Tetrafluoroborate
The following examples illustrate the invention.
Example 1 l-[[6-[4-(2-Pyrimidinyloxy)-l-piρeridinylJ-3-pyridinylJcarbonylJpyrrolidine
Figure imgf000018_0001
a) l-[(6-Chloro-3-pyridinyl)carbonyl]pyrrolidine
Figure imgf000018_0002
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(CDci3) 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) l-[[6-(4-Hydroxy-l-piperidinyl)-3-pyridinyl]carbonyl]pyrrolidine
Figure imgf000018_0003
The product from example 1 step a) (5.0g) and 4-hydroxypiperidine (2.4g) in Hunigs base (10ml) were heated at 110°C for 16h. The mixture was cooled, concentrated in vacuo and purified by column chromatography (ethyl acetate) to give the sub-title compound as a solid (2.1g). MS (APCI+) 276 [M+H]+
1H NMR 5(CDCI3) 8.41 (d,lH), 7.72 (dd,lH), 6.64 (d,lH), 4.08-4.14 (m,2H), 3.93-3.98 (m,lH), 3.61 (d,4H), 3.25 (dt,2H), 1.90-2.00 (m,6H), 1.53-1.69 (m,3H)
c) l-[[6-[4-(2-Pyrimidinyloxy)-l-piperidinyl]-3-pyridinyl]carbonylJpyrrolidine
Figure imgf000018_0004
Potassium t-butoxide (122mg) was added to the product of example 1 step b) (0.2g) and 2-chloropyrimidine (0.12g) in THF (2ml) and the mixture was stirred at room temperature for 20h. The resulting mixture was cooled, diluted with methanol (3ml), filtered and the filtrate was purified by reverse phase HPLC (gradient 75-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give the title compound as a solid (0.18g).
MS (APCI+) 354 [M+H]+
1H NMR δ(CDci3) 8.61 (d,2H), 8.35 (d,lH), 7.72 (dd,lH), 7.13 (t,lH), 6.88 (d,lH), 5.26- 5.20 (m,lH), 4.08 (ddd,2H), 3.36-3.55 (m,6H), 2.11-2.02 (m,2H), 1.88-1.79 (m,4H), 1.63-1.73 (m, 2H)
Example 2 l-[[5-Chloro-6-[4-[[2-(dimethylamino)-4-pyrimidinylJoxy]-l-piperidmyl]-3- pyridinyl] carbonyljpyrrolidine dihydrochloride
Figure imgf000019_0001
a) 1 -[(5,6-Dichloro-3-pyridinyl)carbonyl]pyrrolidine
Figure imgf000019_0002
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+) 245/7/9 [M+HJ+ 1H NMR δ(CDCi3) 8.46 (s,lH), 7.98 (s,lH), 3.65 (t,2H), 3.47 (t,2H), 1.9-2.0 (m,4H)
b) l-[[5~Chloro-6-(4-hydroxy-l-piperidinyl)-3-pyridinyl]carbonyl]pyrrolidine
The sub-title compound was prepared as a solid by the method of example 1 step b) using the product of example 2 step a). MS (APCI+) 241/3 [M+HJ+ 'H NMR ^CDCB) 8.35 (d,lH), 7.81 (d,lH), 3.92 (ddt,lH), 3.81 (dt,2H), 3.62 (t,2H), 3.50(t,2H), 3.12 (dt,2H), 1.85-2.1 (m,6H), 1.7 (ddt,2H), OH exchanged
c) l-[[5-Chloro-6-[4-[[2-(dimethylamino)-4-pyrimidinyl]oxyJ-l-piperidinyl]-3- pyridinylj carbonyljpyrrolidine dihydrochloride
Figure imgf000020_0001
Sodium hydride (60% in oil, 17mg) was added to the product of example 1 step b) (0.13g) and 4-chloro-N,N-dimethyl-2-pyrimidinamine (66mg) in NMP (2ml) and the mixture was heated at 80°C for 20h. The resulting mixture was cooled, diluted with ethanol (3ml), filtered and the filtrate was purified by reverse phase HPLC (gradient 75- 5% aqueous, ammonium acetate (0.2% aq ) in acetonitrile) to give an oil, which on treatment with ethereal HCl in ether gave the title compound as a solid (28mg). MS (APCI+) 431/433 [M+HJ+ 1H NMR δ(DMso) 8.39 (d,lH), 8.13 (d,lH), 7.93 (s,lH), 6.38 (d,lH), 5.39 (s,lH), 3.6- 3.75 (m,2H), 3.4-3.55 (m,4H), 3.25-3.4 (m,2H), 3.22 (s,6H), 2.08-2.22 (m,2H), 1.8-2.0 (m,6H)
Example 3 l-[[5-Chloro-6-[4-[[4-(dimemylamino)-2-pyrimidinyl]oxy]-l-piperidinyl]-3- pyridinyljcarbonyljpyrrolidine
Figure imgf000020_0002
The title compound was prepared by the method of example 2 step c) and 2-chloro-4- dimethylaminopyrimidine.
MS (APCI+) 431/433 [M+H]+
1H MR δ(D so) 8.39 (d,lH), 7.97 (d,lH), 7.92 (d,lH), 6.30 (d,lH), 5.14-5.08 (m,lH),
3.72 (dt,2H), 3.53-3.43 (m,4H), 3.24-3.18 (m,2H), 3.03 (s,6H), 2.11-2.09 (m,2H), 1.87-
1.74 (m,6H) Example 4 l-[[6-[4-[[4-(Dimethylamino)-2-pyrimidinylJoxyJ-l-piperidinyl]-3- pyridinyljcarbonyljpyrrolidine
Figure imgf000021_0001
The title compound was prepared by the method of example 2 step c) and 2-chloro-4- dimethylaminopyrimidine.
MS (APCI+) 397 [M+H]+
1H NMR δ(DMso) 8.33 (d,lH), 7.97 (d,lH), 7.71 (dd,lH), 6.87 (d,lH), 6.30 (d,lH), 5.13 (heptet,lH), 4.05 (dt,2H), 3.60-3.20 (m,6H), 3.02 (s,6H), 2.10-2.00 (m,2H), 1.83 (s,4H),
1.69-1.57 (m,2H)
Example 5 l-[[5-Chloro-6-[4-(2-pyrimidinyloxy)-l-ρiperidinyl]-3-pyridinyl]carbonyl]pyrrolidine
Figure imgf000021_0002
The title compound was prepared by the method of example 1 step c) and 2- chloropyrimidine. MS (APCI+) 388/390 [M+HJ+ 1H NMR δ(CDCB) 8.52 (d,2H), 8.36 (d,lH), 7.83 (d,lH), 6.93 (t,lH), 5.31-5.22 (m,lH), 3.90-3.86 (m,2H), 3.60 (dt,4H), 3.34 (td,2H), 2.26-2.16 (m,2H), 2.09-1.80 (m,6H) Mp 167-169°C Example 6
1 -[[6-[4-[[4-(Propylthio)-2-pyrimidinyl]oxy]-l -piperidinyl]-3- pyridinyl] carbonyljpyrrolidine trifluoroacetate salt
Figure imgf000022_0001
a) 2-Chloro-4-(propylthio)pyrimidine
Figure imgf000022_0002
Propanethiol (3.1ml) was added to 2,4-dichloropyrimidine (5g) in triethylamine (5.5ml) in THF (60ml). After stirring for 2h, sodium hydride (60%, 1.6g) was added and the mixture was stirred for 2h. Water was added and extracted with ethyl acetate. The organic phase was washed with sodium hydroxide (IM) and then hydrochloric acid (IM), dried (MgSO ) and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetateasohexane 1 :20) to give the sub-title compound as an oil (4.57g). MS (APCI+) 189 [M+H]+
1H NMR δ(CDci3) 8.18 (d,lH), 7.06 (d,lH), 3.18 (t,2H), 1.70-1.82 (m,2H), 1.06 (t,3H)
b) 1 -[[6-[4-[[4-(Propylthio)-2-pyrimidinyl]oxyJ-l -piperidinylJ-3- pyridinylj carbonyljpyrrolidine trifluoroacetate salt
Figure imgf000022_0003
The title compound was prepared by the method of example 1 step c) and 2-chloro-4- (propylthio)pyrimidine. Purification by reverse phase HPLC (Symmetry®, gradient 90- 50% aqueous, TFA (0.2% aq.) in acetonitrile). MS (APCI+) 428 [M+HJ+ 1H NMR δ(CDci3) 8.61 (d,lH), 8.16-8.12 (m,2H), 6.98 (d,lH), 6.85 (d,lH), 5.41 (quin,lH), 4.00-3.60 (m,8H), 3.14 (t,2H), 2.17 (q,4H), 1.97 (s,4H), 1.77 (sextet,2H), 1.05 (t,3H)
Example 7 l-[[5-Chloro-6-[4-[[4-(propylthio)-2-pyrimidinylJoxy]-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000023_0001
The title compound was prepared by the method of example 1 step c) and 2-chloro-4- (proρylthio)pyrimidine. Purified by column chromatography (ethyl acetate). MS (APCI+) 462/464 [M+H]+
'H NMR β^DCis) 8.36 (d,lH), 8.12 (d,lH), 7.83 (d,lH), 6.77 (d,lH), 5.30-5.20 (m,lH), 3.90-3.80 (m,2H), 3.64 (t,2H), 3.55 (t,2H), 3.36 (td,2H), 3.14 (t,2H), 2.25-2.17 (m,2H), 2.10-1.92 (m,6H), 1.77 (sextet,2H), 1.05 (t,3H)
Example 8
1 -[[6-[4-[(2-Amino-4-pyrimidinyl)oxy]-l -piperidinyl]-5-chloro-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000023_0002
a) l-[[6-[4-[[2-(Methylthio)-4-pyrimidinyl]oxy]-l-piperidinyl]-5-chloro-3- pyridinyl]carbonyl]pyrrolidine
Figure imgf000023_0003
The title compound was prepared by the method of example 1 step c) and 4-chloro-2-
(methylthio)pyrimidine . Purified by column chromatography (ethyl acetate).
MS (APCI+) 434/436 [M+H]+
1H NMR δ(CDci3) 8.37 (d,lH), 8.24 (d,lH), 7.83 (d,lH), 6.38 (d,lH), 5.42-5.37 (m,lH),
3.77-3.69 (m,2H), 3.64 (t,2H), 3.53 (t,2H), 3.36 (td,2H), 2.54 (s,3H), 2.21-2.14 (m,2H),
2.04-1.90 (m,6H)
b) l-[[6-[4-[[2-(Methylsulfonyl)-4-pyrimidinyl]oxyJ-l-piperidinyl]-5-chloro-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000024_0001
The product of example 8 step a) (30mg) and oxone® (l.Og) were combined in DCM
(5ml). After 48h solids were removed by filtration and the supernatant concentrated, to give the title compound as an oil (30mg).
MS (APCI+) 466/468 [M+H]+ 1H NMR δ(cDCi3) 8.55 (d,lH), 8.37 (d,lH), 7.84 (d,lH), 6.90 (d,lH), 5.55-5.50 (m,lH),
3.80-3.70 (m,2H), 3.66 (t,2H), 3.55 (t,2H), 3.42-3.34 (m,2H), 3.33 (s,3H), 2.25-2.15
(m,2H), 2.10-1.90 (m,6H)
c) l-[[6-[4-[(2-Amino-4-pyrimidinyl)oxy]-l-piperidinyl]-5-chloro-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000024_0002
The product of example 8 step b) (25mg) and ammonia aq. (2ml) were combined in dioxane (2ml) and heated in a sealed tube at 100°C for 24h. Purification by reverse phase HPLC (Xterra®, gradient 75-5% aqueous, ammonia (0.2% aq.) in acetonitrile) gave the title compound as a solid (6mg). MS (APCI+) 403/405 [M+H]+
1H NMR 6 DMSO) 8.39 (d,lH), 7.95 (d,lH), 7.91 (d,lH), 6.50 (s,2H), 5.99 (d,lH), 5.30- 5.20 (m,lH), 3.75-3.65 (m,2H), 3.55-3.40 (m,4H), 3.30-3.15 (m,2H), 2.10-2.00 (m,2H), 1.90-1.70 (m,6H) Example 9 l-[[6-[4-[(2-Amino-4-pyrimidmyl)oxy]-l-piperidinylJ-3-pyridinylJcarbonyl]ρyrrolidine
Figure imgf000025_0001
a) l-[[6-[4-[[2-(Methylthio)-4-ρyrimidinyl]oxy]-l -piperidinyl]-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000025_0002
The title compound was prepared by the method of example 1 step c) and 4-chloro-2- (methylthio)pyrimidine. Purified by column chromatography (ethyl acetate).
Figure imgf000025_0003
1H NMR δ(CDci3) 8.43 (d,lH), 8.23 (d,lH), 7.76 (dd,lH), 6.67 (d,lH), 6.38 (d,lH), 5.46- 5.38 (m,lH), 4.02-3.94 (m,2H), 3.58-3.49 (m,6H), 2.54 (s,3H), 2.14-2.05 (m,2H), 2.00- 1.80 (m,6H).
b) 1 -[[6-[4-[[2-(Methylsulfonyl)-4-pyrimidinyl]oxyJ-l -piperidinylJ-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000025_0004
The product of example 9 step a) (l.Og) and oxone® (15.0g) were combined in DCM (40ml). After 48h, solids were removed by filtration and the supernatant concentrated.
Purification by column chromatography (5-20% methanol in DCM) gave the title compound as an oil (0.16g).
MS (APCI+) 432 [M+HJ+
1H MR δ(cDCi3) 8.55 (d,lH), 8.43 (d,lH), 7.76 (dd,lH), 6.89 (d,lH), 6.67 (d,lH), 5.59- 5.50 (m,lH), 4.05-3.95 (m,2H), 3.64-3.50 (m,6H), 3.34 (s,3H), 2.18-2.10 (m,2H), 1.95-
1.83 (m,6H) c) 1 -[[6-[4-[(2-Amino-4-pyrimidinyl)oxyJ-l -piperidinyl]-3- pyridinylj carbonyljpyrrolidine
Figure imgf000026_0001
The product of example 9 step b) (0.15g) and aq. ammonia (1ml) were combined in dioxane (3ml) and irradiated in a CEM Discover microwave, 50W/100°C/10min. Purification by reverse phase HPLC (Xterra®, gradient 85-50% aqueous, ammonia (0.2% aq.) in acetonitrile), gave the title compound as a solid (60mg). MS (APCI+) 369 [M+H]+ 1H NMR δ(DMso) 8.34 (d,lH), 7.95 (d,lH), 7.71 (dd,lH), 6.87 (d,lH), 6.51 (s,2H), 5.97 (d,lH), 5.24 (heptet,lH), 4.04 (dt,2H), 3.60-3.30 (m,6H), 2.10-1.90 (m,2H), 1.83 (s,4H), 1.73-1.56 (m,2H)
Example 10 l-[[6-[4-[(2-Amino-5-ethyl-6-methyl-4-pyrimidinyl)oxy]-l-piperidinylJ-3- pyridinylj carbonyljpyrrolidine acetate
Figure imgf000026_0002
The title compound was prepared by the method of example 2 step c) and 4-chloro-5- ethyl-6-methyl-2-pyrimidinamine.
MS (APCI+) 411 [M+H]+
1H NMR δ(DMS0) 11-95 (s,lH), 8.34 (d,lH), 7.72 (dd,lH), 6.87 (d,lH), 6.13 (s,2H), 5.28
(heptet,lH), 3.90-3.80 (m,2H), 3.65-3.55 (m,2H), 3.50 (s,4H), 2.40 (q,2H), 2.17 (s,3H),
2.05-1.90 (m,5H), 1.83 (s,4H), 1.75-1.60 (m,2H), 0.99 (t,3H) Example 11
1 -[[6-[4-[[4-(4-Methyl-l -piperazinyl)-2-pyrimidinylJoxy]-l -piρeridinyl]-3- pyridinyl] carbonyljpyrrolidine tetrahydrochloride
Figure imgf000027_0001
a) 2-Chloro-4-(4-methyl- 1 -piperazinyl)pyrimidine
Figure imgf000027_0002
2,4-Dichloropyrimidine (l.Og), N-methylpiperazine (0.8g) and Hunigs base (2ml) in ethanol (2ml) were stirred for 18h. The insoluble solid product was filtered and recrystallised from ethanol (0.4g). MS (APCI+) 213/215 [M+H]+
b) l-[[6-[4-[[4-(4-Methyl-l-piperazinyl)-2-pyrimidinyl]oxy]-l-ρiperidinyl]-3- pyridinyl] carbonyl]pyrrolidine tetrahydrochloride
Figure imgf000027_0003
The title compound was prepared as the tetrahydrochloride by the method of example 2 step c) and the product from example 11 step a). MS (APCI+) 452 [M+H]+ 1H NMR δ(DMso) 11.90 (s,lH), 8.27 (d,lH), 8.24 (d,lH), 7.90 (dd,lH), 7.13 (d,lH), 6.91 (d,lH), 5.46 (heptet,lH), 4.65 (s,2H), 4.05-3.98 (m,2H), 3.75-3.60 (m,4H), 3.60-3.40 (m,9H), 3.20-3.10 (m,2H), 2.80 (s,3H), 2.15-2.08 (m,2H), 1.90-1.75 (m,6H) Example 12
1 -[[6-[4-[[2-(Methylamino)-4-pyrimidinyl]oxyJ-l -ρiρeridinyl]-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000028_0001
The title compound was prepared as a solid by the method of example 8 step c).
MS (APCI+) 383 [M+HJ+
1H NMR δ(DMSθ) 8.33 (d,lH), 8.01 (d,lH), 7.71 (dd,lH), 6.94 (s,lH), 6.87 (d,lH), 5.98
(d,lH), 5.26 (s,lH), 4.04 (dt,2H), 3.60-3.35 (m,6H), 2.77 (d,3H), 2.10-2.00 (m,2H), 1.83 (s,4H), 1.64 (qt,2H)
Example 13
1 -[[6-[4-[[2-(Methylamino)-4-pyrimidinyl]oxyJ-l -piperidinylJ-3- pyridinyljcarbonyljpyrrolidine
Figure imgf000028_0002
The title compound was prepared as a solid by the method of example 8 step c). MS (APCI+) 397 [M+H]+
1H NMR δ(DMso) 8.33 (d,lH), 8.06 (d,lH), 7.71 (dd,lH), 6.87 (d,lH), 5.98 (d,lH), 5.27 (heptet,lH), 4.04 (dt,2H), 3.55-3.37 (m,6H), 3.09 (s,6H), 2.10-2.00 (m,2H), 1.83 (s,4H), 1.65 (qt,2H)
Example 14 l-[[6-[4-[[4-(3-Oxo-l-piperazinyl)-2-pyrimidinylJoxyJ-l-ρiperidinyl]-3- pyridinyljcarbonyljpyrrolidine dihydrochloride
Figure imgf000029_0001
a) 2-Chloro-4-(4-methyl-l -piperazinyl)pyrimidine
Figure imgf000029_0002
2,4-Dichloropyrimidine (l.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-[[6-[4-[[4-(3-Oxo-l-piperazinyl)-2-pyrimidinyl]oxyJ-l-piperidinyl]-3- pyridinylj carbonyljpyrrolidine dihydrochloride
Figure imgf000029_0003
The title compound was prepared as the dihydrochloride by the method of example 2 step c) and the product from example 14 step a). MS (APCI+) 452 [M+H]+ 1H NMR δ(DMso) 8.39 (s,lH), 8.30 (s,lH), 8.19 (d,lH), 7.86 (d,lH), 7.08 (d,lH), 6.86 (d,lH), 5.51-5.42 (m,lH), 4.35-4.29 (m,2H), 4.00-3.94 (m,4H), 3.72- 3.62 (m,2H), 3.53- 3.41 (m,4H), 3.37-3.33 (m,2H), 2.16-2.08 (m,2H), 1.89-1.77 (m,6H) Example 15 l-[[6-[4-[[5-Methyl-2-(methylamino)-4-pyrimidinylJoxy]-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000030_0001
Potassium t-butoxide (0.23 g) was added to the product of example 1 step b) (0.5g) in THF (10 ml) and the mixture was stirred at 0°C for 20 minutes. Meanwhile a solution of 2,4-dichloro-5-methylpyrimidine (290mg) in THF (10ml) was cooled to 0°C. The preformed potassium salt of example 1 step b) was then added dropwise and the resulting mixture stirred at 0°C for 30min. After this time the mixture was concentrated in vacuo, redissolved in dioxane (4 ml) with aqueous methylamine (1ml, 40 % by weight) and irradiated in a CEM Discover microwave, 100W/90°C(using internal cooling) for 1 Omin. After concentration in vacuo, the resultant gum was purified by reverse phase HPLC (Symmetry, gradient 75% to 5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give the title compound as a white solid (25mg). MS (APCI+) 397 [M+H]+
1H MR δ(DMso) 8.34 (d,lH), 7.85 (s,lH), 7.72 (dd,lH), 6.88 (d,lH), 6.67 (d,lH), 5.32 (t,lH), 3.87-3.97 (m,2H), 3.42-3.59 (m,6H), 2.75 (d,3H), 1.96-2.07 (m,2H), 1.90 (s,3H), 1.80-1.87 (m,4H), 1.62-1.76 (m,2H)
Example 16 l-[[6-[4-[4-Pyrimidinyl)oxy]-l-piperidinyl]-3-pyridmylJcarbonylJpyrrolidine
Figure imgf000030_0002
a) 1 -[[6-[4-[(Methylsulfonyl)oxy]-l -piperidinyl]-3-pyridinyl]carbonylJpyrrolidine
Figure imgf000030_0003
The product from example 1 step b) (0.3 g), methanesulfonyl chloride (0.2ml) and
Hunigs base (0.2ml) were combined in DCM (15ml). After lh the reaction mixture was diluted with DCM and extracted with water. The organic phase was dried (Na2SO_ι) and concentrated to give the sub-title product as a solid (0.5g).
MS (APCI+) 354 [M+H]+
1H NMR δ(CDCi3) 8.43 (d,lH), 7.78 (dd,lH), 6.66 (d,lH), 4.99 (heptet,lH), 4.00-3.90
(m,2H), 3.75-3.50 (m,6H), 3.06 (s,3H), 2.13-2.05 (m,2H), 2.00-1.85 (m,6H)
b) 1 -[[6-[4-[4-Pyrimidinyl)oxy]-l -piperidinyl] -3 -pyridinyl] carbonyljpyrrolidine
Figure imgf000031_0001
Sodium hydride [60% in oilj (35mg) was added to 4(3H)-pyrimidinone (62mg) in NMP
(6ml). After lOmin the product from example 16 step a) (160mg) was added and the reaction mixture heated to 100°C for 5h. The reaction was cooled, acidified with acetic acid, diluted with methanol (2ml) and purified by reverse phase ΗPLC (Symmetry® gradient 90-20% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give the title compound as a solid (30mg).
MS (APCI+) 354 [M+ΗJ+
1H NMR δ(DMso) 8.79 (s,lH), 8.52 (d,lH), 8.34 (d,lH), 7.72 (dd,lH), 6.94 (dd,lH), 6.88 (d,lH), 5.41-5.33 (m,lH), 4.11-4.04 (m,2H), 3.55-3.37 (m,6H), 2.12-2.01 (m,2H), 1.83
(s,4H), 1.75-1.60 (m,2H)
Example 17
1 -[[6-[4-(3-Pyridazinyloxy)-l -piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine acetate
Figure imgf000031_0002
The title compound was prepared as a solid by the method of example 16 step b). MS (APCI+) 354 [M+H]+
1H NMR δ(D S0) 8.34 (d,lH), 7.92 (dd,lH), 7.72 (dd,lH), 7.38 (dd,lH), 6.94 (dd,lH), 6.89 (d,lH), 5.12 (quin,lH), 4.53 (d,2H), 3.48 (s,4H), 3.06 (quin,2H), 1.90-1.75 (m,l IH)
Example 18 1 -[[6-[4-[(2-Amino-6-methyl-4-pyrimidinyl)oxy]-l -piperidinyl]-3- pyridinyl J carbonyljpyrrolidine ditrifluoroacetate
Figure imgf000032_0001
Potassium t-butoxide (82mg) was added to the product of example 1 step b) (0.2g) and 4-chloro-6-methyl-2-pyrimidinamine (0.1 lg) in THF (5ml) and NMP (2ml). The mixture was stirred at 60°C for 20h. The resulting mixture was cooled, acidified with trifluoroacetic acid (1ml) and purified by reverse phase HPLC (Symmetry® gradient 95- 60% aqueous, trifluoroacetic acid (0.2% aq.) in acetonitrile) to give the title compound as a solid (0.25g).
MS (APCI+) 383 [M+HJ+
1H NMR δ(DMS0) 8.72-8.10 (m,2H), 8.34 (d,lH), 7.75 (dd,lH), 6.92 (d,lH), 6.35 (d,lH), 5.35 (heptetJH), 4.10-3.94 (m,2H), 3.58-3.36 (m,6H), 2.33 (s, 3H), 2.12-2.00 (m,2H), 1.88-1.80 (m, 4H), 1.78-1.64 ( , 2H)
Example 19 l-[[6-[4-[[2-(Dimethylamino)-6-methyl-4-pyrimidmylJoxy]-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine ditrifluoroacetate
Figure imgf000032_0002
The title compound was prepared as a solid by the method of example 18.
MS (APCI+) 411 [M+HJ+
1H NMR δ(DMso) 8.33 (d,lH), 7.77 (dd,lH), 6.95 (d,lH), 6.24 (s,lH), 5.37 (heptet,lH),
4.07-3.94 (m,2H), 3.56-3.40 (m,6H), 3.20 (s,6H), 2.34 (s,3H), 2.13-2.01 (m,2H), 1.88- 1.79 (m,4H), 1.78-1.65 (m,2H)
Example 20 & 21 l-[[6-[4-[(4-Amino-5-memyl-2-pyrimidinyl)oxyJ-l-piperidinylJ-3- pyridinyljcarbonyljpyrrolidine & 1 -[[6-[4-[(2-amino-5-methyl-4-pyrimidinyl)oxy]-l - piperidinyl] -3 -pyridinyl] carbonyljpyrrolidine
Figure imgf000033_0001
a) 2-Chloro-5-methyl-4-pyrimidinamine & 4-chloro-5-methyl-2-pyrimidinamine
Figure imgf000033_0002
2,4-dichloro-5-methylpyrimidine (2.6g), Hunigs base (2.8ml) and aqueous ammonia (4ml) in dioxane (4ml) were irradiated in a CEM discover microwave at 100°C/1 OOW for 15min. The resultant mixture was shaken between isohexane and sataq. sodium hydrogen carbonate. The insoluble white solid was filtered off and dried in vacuo to give a mixture of the sub-title compounds (2g).
2-chloro-5-methyl-4-pyrimidinamine: Major(85%) 1H NMR 6(DMSO) 7.82 (s,lH), 7.21 (s,2H), 1.94 (s,3H)
4-chloro-5-methyl-2-pyrimidinamine: Minor(l 5%)
1H NMR δ(DMso) 8.13 (s,lH), 6.83 (s,2H), 2.07 (s,3H)
b) l-[[6-[4-[(4-Amino-5-memyl-2-pyrimidinyl)oxy]-l-ρiperidinyl]-3- pyridinyl] carbonyljpyrrolidine & l-[[6-[4-[(2-amino-5-methyl-4-pyrimidinyl)oxy]-l- piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine
Figure imgf000033_0003
Potassium t-butoxide (0.41 g) was added to the product of example 1 step b) (0.5g) and the mixture of products of example 20 & 21 step a) (0.26g) in NMP (5ml). The mixture was stirred at 70°C for 20h. The resulting mixture was cooled, acidified with acetic acid (2ml) and purified by reverse phase HPLC (Symmetry® gradient 90-50% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give the title compounds as a solids (15mg each). 1 -[[6-[4-[(4-amino-5-me yl-2-pyrimidinyl)oxy]-l -piperidinyl]-3- pyridinylj carbonyljpyrrolidine. MS (APCI+) 383 [M+H]+
1H NMR δ(DMso) 8.34 (d,lH), 7.71 (dd,lH), 7.70 (s,lH), 6.86 (d,lH), 6.64 (s,2H), 5.08 (heptet,lH), 4.03-3.97 (m,2H), 3.55-3.35 (m,6H), 2.03-1.93 (m,2H), 1.90 (s,3H), 1.83 (s,4H), 1.65-1.55 (m,2H) l-[[6-[4-[(2-amino-5-methyl-4-pyrimidinyl)oxy]-l-piperidinylJ-3- pyridinyl J carbonyljpyrrolidine MS (APCI+) 383 [M+HJ+
1H NMR 6(DMSO) 8.34 (d,lH), 7.80 (dd,lH), 7.72 (s,lH), 6.88 (d,lH), 6.23 (s,2H), 5.31 (heptet,lH), 3.97-3.87 (m,2H), 3.58-3.40 (m,6H), 2.03-1.94 (m,2H), 1.89 (d,3H), 1.83 (s,4H), 1.72-1.62 (m,2H)
Example 22 l-[[6-[4-[([4-(Methylamino)-2-pyrimidinylJoxy]-l-piρeridinylJ-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000034_0001
Potassium t-butoxide (165mg) was added to the product of example 1 step b) (0.2g) and
2-chloro-N-methyl-4-pyrimidinamine (105mg) in NMP (3ml). The mixture was stirred at 60°C for 20h. The resulting mixture was cooled, acidified with acetic acid (1ml) arid purified by reverse phase HPLC (Symmetry® gradient 90-50% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give the title compound as a solid (40mg).
MS (APCI+) 383 [M+HJ+
1H NMR δ(DMso@90°c) 8.32 (d,lH), 7.82 (d,lH), 7.68 (dd,lH), 6.97 (s,lH), 6.81 (d,lH), 6.08 (d,lH), 5.15 (heptet,lH), 4.05-3.97 (m,2H), 3.51-3.44 (m,4H), 3.43-3.36 (m,2H),
2.78 (d,3H), 2.07-2.00 (m,2H), 1.87-1.82 (m,4H), 1.73-1.63 (m,2H)
Example 23 l-[[5-Chloro-6-[4-[(6-fluoro-2-pyridinyl)oxyJ-l-piperidinylJ-3- pyridinylj carbonyljpyrrolidine dihydrochloride
Figure imgf000034_0002
The title compound was prepared as a solid by the method of example 2 step c) and 2,6- difluoropyridine. MS (APCI+) 405/7 [M+H]+ 1H NMR δ(DMso) 8.39 (s,lH), 7.92 (s,lH), 7.85 (dd,lH), 6.76 (d,lH), 6.69 (dd,lH), 5.13 (dt,lH), 3.62-3.76 (m,2H), 3.4-3.55 (m,4H), 3.27 (t,2H), 2.05-2.20 (m,2H), 1.70-1.90 (m,6H)
Example 24 l-[[5-Chloro-6-[4-(2-pyridinyloxy)-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine hydrochloride
Figure imgf000035_0001
The title compound was prepared as a solid by the method of example 2 step c) and 2- fluoropyridine.
MS (APCI+) 387/9 [M+H]+
1H NMR 6(DMSO) 8.39 (d,lH), 8.17 (dd,lH), 7.92 (d,lH), 7.72 (dd,lH), 6.98 (dd,lH),
6.84 (d,lH), 5.26 (tt,lH), 3.70-3.80 (m,2H), 3.40-3.55 (m,4H), 3.20-3.55 (m,2H), 2.08- 2.20 (m,2H), 1.70-1.92 (m,6H)
Example 25 l-[[6-[4-[(6-Amino-2-pyridinyl)oxy]-l-piperidmyl]-3-pyridinylJcarbonyl]pyrrolidine
Figure imgf000035_0002
The title compound was prepared from the product of example 1 step b) by the method of example 2 step c) and 2,6-difluoropyridine followed by the method of example 9 step c) (140°C, 6h).
MS (APCI+) 368 [M+H]+ 1H NMR δ(DMso) 8.34 (s,lH), 7.73 (dd,lH), 7.27 (dd,lH), 6.88 (d,lH), 5.99 (d,lH), 5.86
(d,lH), 5.82 (s,2H), 5.19-5.11 (m,lH), 4.08-4.00 (m,2H), 3.53-3.29 (m,6H), 2.04-1.95
(m,2H), 1.88-1.79 (m,4H), 1.66-1.55 (m,2H)
Example 26 5-Chloro-6-[[l-[5-(l-pyrrolidinylcarbonyl)-2-pyridinyl]-4-piperidmyl]oxy]-3- pyridinecarboxamide
Figure imgf000036_0001
The title compound was prepared by the method of example 2 step c) and 5,6-dichloro- 3 -pyridinecarboxamide. MS (APCI+) 431/433 [M+H]+ 1H NMR δ(DMso) 8.62 (d,lH), 8.35 (d,lH), 8.30 (d,lH), 8.06 (s,lH), 7.73 (dd,lH), 7.55 (s,lH), 6.89 (d,lH), 5.47-5.42 (m,lH), 4.03-3.93 (m,2H), 3.64-3.40 (m,6H), 2.15-2.00 (m,2H), 1.90-1.64 (m,6H)
Example 27 1 - [ [6- [4-[(5 - Amino-2-pyridinyl)oxyJ- 1 -piperidinyl] -3 -pyridinyl] carbonyljpyrrolidine
Figure imgf000036_0002
Sodium hydride [60% in oil] (90mg) was added to the product of example 1 step b) (0.3g) and 2-chloro-5-nitropyridine (250mg) in NMP (3ml). The mixture was stirred at 60°C for 20h. The resulting mixture was cooled, diluted with ethyl acetate and extracted once with water, sat.aq. sodium hydrogen carbonate and with brine. The organic phase was dried (Na2SO_ι) filtered and evaporated. The resultant residue was dissolved in ethanol (15ml) and acetic acid (1ml). 10% Palladium on charcoal (20mg) was added as a slurry in ethanol and the resultant mixture hydrogenated at 4 bar for 20h. The reaction mixture was filtered over celite and the filtrate concentrated. Purification by reverse phase HPLC (Symmetry® gradient 75-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give the title compound as a solid (7mg). MS (APCI+) 368 [M+H]+ 1H NMR δpMso) 8.33 (d,lH), 7.70 (dd,lH), 7.50 (d,lH), 6.99 (dd,lH), 6.86 (d,lH), 6.52 (d,lH), 5.07-5.01 (m,lH), 4.74 (s,2H), 4.10-4.00 (m,2H), 3.60-3.20 (m,6H), 2.10-1.90 (m,2H), 1.83 (s,4H), 1.70-1.50 (m,2H)
Example 28
1 -[[6-[4-[(5-Amino-3-methyl-2-pyridinyl)oxy]-l -piperidinyl]-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000037_0001
a) l-[[6-[4-[(3-Methyl-5-nitro-2-pyridmyl)oxyJ-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000037_0002
Sodium hydride [60% in oilj (lOOmg) was added to the product of example 1 step b) (230mg) and 2-chloro-3-methyl-5-nitropyridine (300mg) in NMP (5ml). The mixture was stirred at 60°C for 20h. On cooling the reaction was acidified with acetic acid and purified by reverse phase HPLC (Symmetry® gradient 75-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give the sub-title compound as a solid (0.14g). MS (APCI+) 412 [M+HJ+
1H NMR 6(DMSO) 8.94 (d,lH), 8.41 (d,lH), 8.35 (d,lH), 7.73 (dd,lH), 6.91 (d,lH), 5.47 (heptet,lH), 4.00-3.90 (m,2H), 3.65-3.40 (m,6H), 2.25 (s,3H), 2.10-2.00 (m,2H), 1.90- 1.70 (m,6H)
b) 1 -[[6-[4-[(5-Amino-3 -methyl-2-pyridinyl)oxyJ- 1 -piperidinyl]-3 - pyridinyljcarbonyljpyrrolidine
Figure imgf000037_0003
The product of example 28 step a) (140mg) was dissolved in ethanol (20ml) and acetic acid (1ml). Palladium on charcoal (10%, 70mg) was added as a slurry in ethanol and the resultant mixture hydrogenated at 4 bar for 20h. The reaction mixture was filtered and the filtrate concentrated. Purification by reverse phase HPLC (Xterra®, gradient 80-
20% aqueous, ammonia (0.2% aq.) in acetonitrile) to give the title compound as a solid
(40mg).
MS (APCI+) 382 [M+H]+ 1H NMR δ(DMso) 8.33 (d,lH), 7.70 (dd,lH), 7.33 (d,lH), 6.90-6.80 (m,2H), 5.11
(heptet,lH), 4.63 (s,2H), 3.96-3.88 (m,2H), 3.55-3.45 (m,6H), 2.04 (s,3H), 1.99-1.90
(m,2H), 1.83 (s,4H), 1.67-1.56 (m,2H) Example 29 l-[[6-[4-[(6-Amino-3-pyridazinyl)oxy]-l-piperidinyl]-3-pyridinyl]carbonylJpyrrolidine acetate
Figure imgf000038_0001
The title compound was prepared by the method of example 2 step c) and 3,4- dichloropyridazine followed by the method of example 13 step c) (170°C, 8h). MS (APCI+) 369 [M+H]+
1H NMR 6(DMSO) 8.34 (s,lH), 7.71 (d,lH), 7.14 (d,lH), 6.87 (d,lH), 6.85 (d,lH), 4.91 (quintet,lH), 4.09-3.98 (m,2H), 3.52-3.34 (m,8H), 2.09-1.98 (m,2H), 1.90-1.78 (m,4H), 1.70-1.58 (m,2H)
Example 30 l-[[6-[4-[(4-Amino-l,3,5-triazin-2-yl)oxy]-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000038_0002
a) 4-(Methylthio)-l ,3,5-triazin-2-amine
Figure imgf000038_0003
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 (AP.CI+) 143 [M+H]+
1H NMR δφMso) 8.23 (s,lH), 7.53 (s,2H), 2.42 (s,3H)
b) 4-(Methylsulfinyl)-l,3,5-triazin-2-amine
Figure imgf000038_0004
The product from example 30 step a) (0.5g) was stirred as a suspension in DCM at 0°C. wz-chloroperbenzoic acid (77%) (0.89g) was added and the reaction mixture stirred at 0°C for lh, followed by room temperature for lh. A pink precipitate formed and dilution of the reaction mixture with DCM, followed by stirring at room temperature for 72h gave a white preciptate. This was collected by filtration and washed with DCM to give the sub-title compound (0.35g). 1H NMR δpMso) 8.57 (s,lH), 8.23 (s,lH), 8.14 (s,lH), 2.83 (s,3H)
c) l-[[6-[4-[(4-Amino-l,3,5-triazin-2-yl)oxy]-l-piperidinylJ-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000039_0001
Potassium t-butoxide (0.33g) was stirred with the product from example 1 step b) (0.2g) in NMP (3ml). The product from example 30 step b) (0.35g) was added and the reaction mixture heated to 60°C for 48h. The reaction mixture was allowed to cool, filtered and the solid washed with methanol. The filtrate was concentrated in vacuo, the residue dissolved in acetic acid (1ml) and purified using reverse phase HPLC (gradient 90-50% aqueous, ammonium acetate (0.4% aq.) in acetonitrile) . The residue obtained was triturated in diethyl ether to give the title compound as a white solid (13mg). MS (APCI+) 370 [M+H]+
JH NMR δ(DMso) 8.34 (d,lH), 8.28 (s,lH), 7.72 (ddd,lH), 7.46 (d,2H), 6.88 (d,lH), 5.24- 5.16 (m,lH), 4.07-3.98 (m,2H), 3.54-3.38 (m,6H), 2.06-1.97 (m,2H), 1.89-1.79 (m,4H), 1.70-1.59 (m,2H)
Example 31
1 - [ [6- [4-(9H-Purin-6-yloxy)- 1 -piperidinyl] -3 -pyridinylj carbonyljpyrrolidine ditrifluoroacetate
Figure imgf000039_0002
The title compound was prepared as a white foam (O.lg) by the method of example 1 step c) and 6-chloro-7H-purine followed by purification by reverse phase HPLC (Symmetry®, gradient 95-60% aqueous, TFA (0.2% aq.) in acetonitrile). MS (APCI+) 393 [M+H]+ 1H NMR 6(DMSO) 8.53 (s,lH), 8.45 (s,lH), 8.33 (d,lH), 7.83 (dd,lH), 7.05 (d,lH), 5.64 (dquin,lH), 4.12 (td,2H), 3.43-3.57 (m,6H), 2.12-2.23 (m,2H), 1.76-1.91 (m,6H), NH exchanged
Example 32 1 -[[6-[4-[(2-Amino-9H-purin-6-yl)oxy]-l -piperidinylJ-3-pyridinylJcarbonylJpyrrolidine ditrifluoroacetate
Figure imgf000040_0001
The title compound was prepared as a white foam (0.2 lg) by the method of example 1 step c) and 6-chloro-7H-purin-2-amine followed by purification by reverse phase HPLC
(Symmetry®, gradient 95-65% aqueous, TFA (0.2% aq.) in acetonitrile).
MS (APCI+) 408 [M+H]+
1H NMR δ(DMso) 8.61 (s,lH), 8.35 (d,lH), 7.78 (dd,lH), 6.98 (d,lH), 5.56 (dquin,lH),
3.98-4.06 (m,2H), 3.59 (dd,2H), 3.48 (d,4H), 2.07-2.15 (m,2H), 1.76-1.89 (m,6H), NH exchanged
Example 33 l-[[6-(4-Phenoxy-l-piperidinyl)-3-pyridinyl]carbonyl]pyrrolidine
Figure imgf000040_0002
The product of example 1 step b) (O.llg), 4-phenoxypiperidine (O.lg) and Hunigs base (0.2ml) in NMP (5ml) ) were heated at 140°C for 16h. The resulting mixture was concentrated in vacuo and purified by reverse phase HPLC (Symmetry®, gradient 75- 5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give the title compound as a solid (70mg).
MS (APCI+) 352 [M+H]+ 1H NMR δ(cDCB) 8.42 (d,lH), 7.75 (dd,lH), 7.30 (t,2H), 7.00-6.91 (m,3H), 6.66 (d,lH), 4.62-4.58 (m,lH), 4.00-3.90 (m,2H), 3.70-3.50 (d,6H), 2.10-1.80 (m,8H)
Example 34 1 -[[5-Chloro-6-(4-phenoxy-l -piperidinyl)-3 -pyridinyl] carbonyljpyrrolidine hydrochloride
Figure imgf000041_0001
The product from example 2 step a) (0.24g) and 4-phenoxypiperidine (0.18g) in NMP (5ml) and Hunigs base (0.5ml) were heated at 100°C for 6h. The mixture was cooled and partitioned between ether and water. The phases were separated and the ether phase was dried (Na2SO ) and concentrated in vacuo. The resultant gum was purified by reverse phase HPLC (Symmetry, 75-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to yield a gum, which on treatment with ethereal HCl gave the title compound as a pale yellow solid (0.15g).
MS (APCI+) 386 [M+H]+
1H NMR 5(DMSO) 8.39 (d,lH), 7.92 (d,lH), 7.29 (ddt,2H), 7.00 (dd,2H), 6.93 (dt,lH), 4.64 (dquintetlH), 3.69 (dd,2H), 3.47 (dd,4H), 3.26 (ddd,2H), 2.12-2.03 (m,2H), 1.91- 1.70 (m,6H)
Example 35 l-[[5-(Dimethylamino)-6-(4-phenoxy-l-piperidinyl)-3-ρyridinyl]carbonyl]pyrrolidine hydrochloride
Figure imgf000041_0002
a) 1 -[[5-Bromo-6-(4-phenpxy-l -piperidinyl)-3-pyridmylJcarbonyl]pyrrolidine
Figure imgf000041_0003
Bromine (0.14ml) was added to the product from example 33 (0.93g) in DCM (10ml) at 0°C. The mixture was stirred for 3h, water (2ml) was added and the phases were separated. The aqueous was extracted with DCM (2x2ml) and the combined DCM phases were concentrated and purified by reverse phase HPLC (Symmetry, gradient 75- 5% aqueous, trifluoroacetic acid (0.1% aq.) in acetonitrile) to give the sub-title compound as an oil. MS (APCI+) 432/434 [M+HJ+
b) 1 -[[5-(Dimethylamino)-6-(4-phenoxy-l -piperidinyl)-3 -pyridinyl] carbonyljpyrrolidine hydrochloride
Figure imgf000042_0001
The product from example 35 step a) (lOOmg), methylamine hydrochloride (21mg), potassium t-butoxide (65mg), tris(dibenzylideneacetone)dipalladium(0) (4.4mg) and 1,3- bis(2,4,6-trimethylphenyl)imidazol-2-ylidene hydrochloride (4.0mg) in dioxane (3ml) were heated at 100°C for 20h. The mixture was cooled, filtered through a silica plug and purified by reverse phase HPLC (Symmetry, gradient 75-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give after treatment with ethereal HCl (1ml) the title compound as a solid (7mg).
MS (APCI+) 395 [M+H]+
1H NMR 6(DMSO) 12.94 (s,lH), 7.69 (s,lH), 7.32 (dd,2H), 7.00 (d,2H), 6.94 (dd,lH), 6.02 (s,lH), 4.70 (dt,lH), 3.80-3.90 (m,2H), 3.38-3.60 (m,4H), 3.28 (t,2H), 3.04 (s,6H), 2.00-
2.12 (m,2H), 1.80-1.95 (m,4H), 1.65-1.80 (m,2H)
Example 36 l-[[6-[4-(Phenylsulfonyl)-l-piρeridinylJ-3-pyridinylJcarbonyl]pyrrolidine
Figure imgf000042_0002
a) l-[[6-[4-(Phenylthio)-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine
Figure imgf000042_0003
The product from example 16 step a) (0.5g), potassium carbonate (0.6g) and benzenethiol (0.4ml) in acetonitrile (20ml) were heated to reflux for 24h. On cooling the reaction mixture was diluted with ethyl acetate and extracted with water, then brine. The organic phase was concentrated and purified by column chromatography (ethyl acetate) to give the sub-title compound (0.4g). MS (APCI+) 368 [M+H]+
1H NMR δ(CDC ) 8.40 (d,lH), 7.74 (dd,lH), 7.45 (d,2H), 7.35-7.23 (m,3H), 6.61 (d,lH), 4.23 (dt,2H), 3.59 (s,4H), 3.34 (ttlH), 3.13 (td,2H), 2.05 (dd,2H), 1.92 (s,4H), 1.65 (qd,2H)
b) l-[[6-[4-(Phenylsulfonyl)-l-piperidinylJ-3-pyridinylJcarbonylJpyrrolidine
Figure imgf000043_0001
The product from example 36 step a) (0.39g) and oxone® (8g) were stirred in DCM (30ml). After 24h the solids were removed by filtration and the filtrate purified by column chromatography (0-5% methanol in DCM) and reverse phase HPLC
(Symmetry®, gradient 75-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile), to give the title compound as a foam (50mg).
MS (APCI+) 400 [M+H]+ 1H NMR δpMSO) 8.31 (d,lH), 7.85 (d,2H), 7.79 (t,lH), 7.72-7.65 (m,3H), 6.83 (d,lH),
4.47 (d,2H), 3.63 (tt,lH), 3.45 (s,4H), 2.87 (t,2H), 1.90-1.75 (m,6H), 1.46 (qd,2H)
Example 37 l-[[5-Chloro-6-[4-(lH-indol-3-yl)-l-piperidinylJ-3-pyridinylJcarbonyl]pyrrolidine
Figure imgf000043_0002
The title compound was prepared as a white solid by the method of example 1 step b) using the product from example 2 step a) and 3-(4-piperidinyl)-lH-indole. MS (APCI+) 409/11 [M+Η]+ 1H NMR δ(DMS0) 10.80 (s,lH), 8.41 (s,lH), 7.91 (s,lH), 7.58-7.60 (d,lH), 7.32-7.34 (d,lH), 7.14 (s,lH), 7.04-7.08 (t,lH), 6.94-6.98 (t,lH), 3.99-4.03 (d,2H), 3.44-3.52 (m,4H), 3.01-3.07 (t,3H), 2.06-2.09 (m,2H), 1.78-1.87 (m,6H)
Example 38 l-[[6-[4-(lH-Indol-3-yl)-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine
Figure imgf000044_0001
The title compound was prepared by the method of example 1 step b) using the product from example 1 step a) and 3-(4-piperidinyl)-lH-indole. MS (APCI+) 375 [M+Η]+
1H NMR 6(DMSO) 10.78 (s,lH), 8.35 (s,lH), 7.71 (d,lH), 7.57 (d,lH), 7.32 (d,lH), 7.00- 7.71 (m,2H), 6.95 (d,lH), 6.86 (d,lH), 4.52 (d,2H), 3.38-3.48 (m,4H), 3.01-3.13 (m,3H), 1.98-2.06 (m,2H), 1.83 (s,4H), 1.57-1.70 (m,2H)
Example 39 l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piρeridinyl]-3- pyridinylj carbonyljpyrrolidine
Figure imgf000044_0002
The title compound was prepared as a solid by the method of example 1 step b) using the product from example 1 step a) and l,3-dihydro-l-(4-piperidinyl)-2H-benzimidazol-2- one.
MS (APCI+) 392 [M+Η]+ 1H NMR δ(DMso) 10.83 (s,lH), 8.36 (s,lH), 7.74 (d,lH), 7.12-7.14 (m,lH), 6.90-6.97 (m,4H), 4.58 (d,2H), 4.44-4.48 (m,lH), 3.45-3.52 (m,4H), 3.03 (t,2H), 2.24-2.33 (m,2H), 1.75-1.84 (m,6H) Example 40
1 -[[5-Chloro-6-[4-(2,3 -dihydro-2-oxo- 1 H-benzimidazol- 1 -yl)- 1 -piperidinyl]-3 - pyridinylj carbonyljpyrrolidine
Figure imgf000045_0001
The title compound was prepared by the method of example 1 step b) using the product from example 2 step a) and l,3-dihydro-l-(4-piperidinyl)-2H-benzimidazol-2-one. MS (APCI+) 426/8 [M+ΗJ+
1H NMR δ(CDCi3) 10.81 (s,lH), 8.40 (s,lH), 8.27 (s,lH), 7.86 (s,lH), 7.00 (s,3H), 4.54- 4.56 (m,lH), 4.17 (d,2H), 3.55-3.65 (m,4H), 2.89 (t,2H), 2.54-2.68 (m,2H), 1.94-2.00 (m,6H)
Example 41 l-[[5-Chloro-6-[4-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinylJ-3- pyridinylj carbonyljpiperidine
Figure imgf000045_0002
a) 5-Chloro-6-[4-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinyl]-3- pyridinecarboxylic acid
Figure imgf000045_0003
5,6-dichloro-3-pyridinecarboxylic acid (2g), l,3-dihydro-l-(4-piperidinyl)-2H- benzimidazol-2-one (2.3g) and Hunigs base (5.5ml) in NMP (10ml) were heated together at 100°C for 24h. The reaction mixture was allowed to cool, diluted with water and acidified with 2M HCl. The brown precipitate was collected by filtration and washed with water, 2M HCl, isohexane and diethyl ether to give the sub-title compound as a solid (3.35g).
1H NMR δ(DMSo) 10.87 (s,lH), 8.69 (d,lH), 8.10 (d,lH), 7.20-7.16 (m,lH), 7.00-6.96 (m,3H), 4.51-4.40 (m,lH), 4.21 (d,2H), 3.09 (t,2H), 2.48-2.43 (m,2H), 1.85-1.77 (m,2H), OH exchanged
b) 1 -[[5-Chloro-6-[4-(2,3-dihydro-2-oxo-lH-benzimidazol-l -yl)-l -ρiperidinyl]-3- pyridinyl] carbonyljpiperidine
Figure imgf000046_0001
The product from example 41 step a) (0.2g), piperidine (0.16ml), Hunigs base (0.56ml) and TBTU (0.189g) were stirred in DCM at room temperature for 24h. Concentration in vacuo gave a residue that was purified by column chromatography (DCM / methanol 98:2-95:5) to give the title compound as a solid (0.13g). MS (APCI+) 440/2 [M+HJ+
1H NMR 6 (DMSO) 10.87 (s,lH), 8.26 (d,lH), 7.83 (d,lH), 7.22-7.17 (m,lH), 7.00-6.97 (m,3H), 4.47-4.37 (m,lH), 4.03 (d,2H), 3.60-3.41 (m,4H), 3.29-3.23 (m,2H), 3.02 (t,2H), 1.84-1.77 (m,2H), 1.66-1.58 (m,2H), 1.57-1.49 (s,4H)
Example 42
1 -[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l -yl)-l -piperidinylJ-5-methyl-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000046_0002
Trimethylsilylchloride (4.05ml) was added to a solution of 2-amino-5-bromo-3- methylpyridine (1.5g) in chloroform (30ml) and heated at reflux for 30min. The solution was cooled, isobutylamylnitrite (9.5ml) was added and heated again at reflux for 21h. The solution was cooled, filtered through a pad of silica and concentrated to an oil. The oil was added to a solution of dichloro[l,l 'bis(diphenylphosphino)ferroceneJpalladium (II) dichloromethane adduct (30mg) and pyrrolidine (0.6ml) in dioxane (5ml) and heated at 100°C under 7bar of CO for 2h. The mixture was cooled and partially purifed by reverse phase HPLC (gradient 75-5% aqueous, trifluoroacetic acid (0.1% aq.) in acetonitrile) to give an oil (1:1 mixture of l-[(6-chloro-5-methyl-3- pyridinyl)carbonyl]pyrrolidine (MS (APCI+) 225/227 [M+H]+) and l-[[5-methyl-6-(l- pyrrolidinyl)-3-pyridinyl]carbonyl]pyrrolidine). The oil (0.3g), l,3-dihydro-l-(4- piperidinyl)-2H-benzimidazol-2-one (0.2g) and Hunigs base (1ml) in NMP (2ml) were heated at 130°C for 22h, cooled and purified by reverse phase HPLC (Symmetry, gradient 75-5% aqueous, trifluoroacetic acid (0.1% aq.) in acetonitrile) to give the title compound as a solid (28mg).
MS (APCI+) 406 [M+HJ+
1H NMR δ(DMS0) 10.90 (s,lH), 8.31 (s,lH), 7.68 (s,lH), 7.25 (d,lH), 6.99 (s,3H), 4.40 (t,lH), 3.71 (d,2H), 3.52-3.42 (m,4H), 2.96 (t,2H), 2.32 (s,3H), 1.91-1.74 (m,8H)
Example 43 l-[[5-Chloro-6-[4-(7,8-dihydro-8-oxo-9H-ρurin-9-yl)-l-ρiρeridinyl]-3- pyridinyl] carbonyljpyrrolidine trifluoroacetate
Figure imgf000047_0001
a) l-[[6-(4-Amino-l-piperidinyl)-5-chloro-3-pyridinyl]carbonylJpyrrolidine ditrifluoroacetate
Figure imgf000047_0002
The product from example 2 step a) (2.4g) and 4-piperidinyl carbamic acid, 1,1- dimethylethyl ester (2g) by the method of example 1 step b) followed by treatment of the resulting solid with TFA (5ml) in DCM (5ml) for 8h gave after concentration in vacuo the sub-title compound as a solid (2.9g). 1H NMR δ(DMS0) 8.39 (d,lH), 8.00 (s,2H), 7.93 (d,2H), 3.91 (d,2H), 3.46 (q,4H), 2.92 (t,2H), 1.99 (d,2H), 1.73-1.91 (m,4H), 1.65 (dq,2H) b) 1 -[[5-Chloro-6-[4-(7,8-dihydro-8-oxo-9H-purin-9-yl)-l -piperidinylJ-3- pyridinylj carbonyljpyrrolidine trifluoroacetate
Figure imgf000048_0001
The product from example 43 step a) (0.84g) was added to a stirred solution of 4,6- dichloro-5-nitroρyrimidine (0.39g) and triethylamine (0.87ml) in THF (10ml) at 0°C. After lh, the mixture was filtered and the filtrate was washed with sat.aq. sodium hydrogen carbonate, dried (MgSO4) and concentrated. The resulting oil (0.95g) was dissolved in ethanol (50ml) and acetic acid (0.05ml) and palladium on carbon (5%, 0.2g) was added. Hydrogenation of the mixture at 4 bar for 18h followed by filtration over celite gave a brown foam (0.65g). To the brown foam (0.6g) in DCM (50ml) was added carbonyl diimidazole (0.82g) and stirred for 20h. The resulting mixture was concentrated and purified by reverse phase HPLC (Symmetry, gradient 80-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile then gradient 75-5% aqueous, trifluoroacetic acid (0.1% aq.)in acetonitrile) to give the title compound as a solid (0.18g). MS (APCI+) 428/430 [M+HJ+
1H NMR δ(DMso) 11.54 (s,lH), 8.63 (s,lH), 8.41 (d,lH), 8.29 (s,lH), 7.95 (d,lH), 4.53- 4.44 (m,lH), 4.05 (d,2H), 3.42-3.54 (m,4H), 3.00 (t,2H), 2.59-2.73 (m,2H), 1.76-1.94 (m,6H)
Example 44
1 -[[5-Chloro-6-[4-(l ,2-dihydro-2-oxo-3H-imidazo[4,5-b]pyridin-3-yl)-l -piperidinyl]-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000048_0002
a) 1 -[[5-Chloro-6-[4-[(3-nitro-2-pyridinyl)aminoJ- 1 -piperidinylJ-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000049_0001
The product from example 43 step a) (0.84g) was added to a stirred solution of 2-chloro- 3-nitropyridine (0.3 lg) and triethylamine (1.1ml) in acetonitrile (50ml) and heated at reflux for 24h. The mixture was allowed to cool and partitioned between ethyl acetate and water. The phases were separated and the aqueous extracted with ethyl acetate. The combined ethyl acetate layers were dried (Na SO ) and concentrated in vacuo to give a yellow gum. Trituration with ether yielded the sub-title compound as a yellow crystalline solid (0.68g). MS (APCI+) 431/3 [M+H]+ 1H NMR δ(DMso) 8.53 (dd,lH), 8.45 (dd,lH), 8.40 (d,lH), 8.20 (d,lH), 7.93 (d,lH), 6.81 (dd,lH), 4.51-4.37 (m,lH), 3.89 (d,2H), 3.48 (dt,4H), 3.07 (t,2H), 2.08 (d,2H), 1.91-1.71 (m,6H)
b) 1 -[[6-[4-[(3-amino-2-pyridinyl)aminoJ-l -piperidinyl]-5-chloro-3- pyridinyljcarbonyljpyrrolidine
Figure imgf000049_0002
The product from example 44 step a) (0.68g) was dissolved in ethanol (50ml) and acetic acid (0.5ml) and palladium on carbon (5%, 0.2g) was added. Hydrogenation of the mixture at 4 bar for 18h followed by filtration over celite gave, after concentration, a glassy solid, that upon trituration with ether yielded the sub-title compound as a grey crystalline solid (0.58g). MS (APCI+) 401/3 [M+HJ+
1H NMR δ(DMso) 8.40 (d,lH), 7.92 (d,lH), 7.34 (dd,lH), 6.76 (d,lH), 6.44 (t,lH), 4.08 (dd,lH), 3.92 (d,2H), 3.55-3.40 (m,4H), 3.01 (t,2H), 2.06 (d,2H), 1.89-1.79 (m,4H), 1.69-1.57 (m,2H), NH exchanged c) 1 -[[5-Chloro-6-[4-(l ,2-dihydro-2-oxo-3H-imidazo[4,5-b]pyridin-3-yl)-l -piperidinylj- 3 -pyridinyl] carbonyljpyrrolidine
Figure imgf000050_0001
To the product from example 44 step b) (1 OOmg) in DCM (10ml) was added carbonyl diimidazole (0.13g) and stirred for 3 days. The resulting mixture was concentrated and purified by reverse phase HPLC (Symmetry, gradient 95-50% aqueous, ammonium acetate (0.2 % aq.) in acetonitrile) to give the title compound as a white solid (30mg). MS (APCI+) 427/9 [M+H]+ 1H NMR 6(DMSO) 8.42 (d,lH), 7.96-7.94 (m,2H), 7.30 (dd,lH), 7.00 (dd,lH), 4.50 (tt,lH), 4.05 (d,2H), 3.49 (dt,4H), 2.99 (t,2H), 2.80-2.68 (m,2H), 1.89-1.76 (m,7H)
Example 45 l-[[5-Chloro-6-[4-(2-methyl-3H-imidazo[4,5-bJpyridin-3-yl)-l-piperidinylJ-3- pyridinyljcarbonyljpyrrolidine
Figure imgf000050_0002
The product from example 44 step b) (lOOmg) and acetic anhydride (0.2ml) were heated at 160°C for 2h. The resulting mixture was diluted with methanol (5ml) and purified by reverse phase HPLC (Symmetry, gradient 95-50% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to yield a gum, which on treatment with ethereal HCl gave the title compound as a pale yellow solid (30mg).
MS (APCI+) 425/7 [M+HJ+
1H NMR δ(DMS0) 8.61 (d,lH), 8.44 (d,lH), 8.28 (d,lH), 7.97 (d,lH), 7.59 (dd,lH), 4.83 (d,lH), 4.10 (d,2H), 3.54-3.44 (m,4H), 3.10 (t,2H), 2.96 (s,3H), 2.93-2.85 (m,2H), 2.12
(d,2H), 1.86 (s,4H) Example 46 l-[[5-Chloro-6-[4-(2,2-dioxido[l,2,5Jthiadiazolo[3,4-bJpyridin-3(lH)-yl)-l-ρiρeridinylJ- 3 -pyridinylj carbonyljpyrrolidine
Figure imgf000051_0001
The product from example 44 step b) (lOOmg) and sulfamide (48mg) in glycol (2ml) was heated to 160°C for 6h. The black mixture was allowed to cool, diluted with methanol (5ml), filtered and the filtrate purified by reverse phase HPLC (Symmetry, gradient 95-50% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give the title compound as a grey solid (30mg). MS (APCI+) 463/5 [M+HJ+
1HNMR δ(DMS0) 8.40 (d,lH), 7.91 (d,lH), 7.10 (dd,lH), 6.43-6.34 (m,2H), 4.17-4.08 (m,lH), 4.02 (d,2H), 3.55-3.40 (m,4H), 2.98-2.85 (m,2H), 1.97-1.79 (m,8H), NH exchanged
Example 47
1 -[[5-Chloro-6-[4-(2,3 -dihydro-2-oxo- 1 H-imidazo[4,5-c]pyridin- 1 -yl)- 1 -piperidinylJ-3 - pyridinyljcarbonyljpyrrolidine
Figure imgf000051_0002
a) l-[[5-Chloro-6-[4-[(3-mtro-4-pyridinyl)amino]-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000051_0003
The product from example 43 step a) (0.9g) was added to a stirred solution of 4- methoxy-3-nitropyridine (0.32g) and Hunigs base (1ml) in NMP (3ml) and heated at 120°C for 3h. The mixture was allowed to cool and partitioned between ethyl acetate and water. The phases were separated and the aqueous extracted with ethyl acetate. The combined organic phases were dried (Na2SO ) and concentrated in vacuo to give a yellow gum which was purified by column chromatography (ethyl acetate:isohexane (1:1), then dichloromethane:methanol (10:1)) to give the sub-title compound as a yellow solid (0.28g). MS (APCI+) 431/3 [M+H]+ 1H MR δ(DMso) 9.05 (s,lH), 8.40 (d,lH), 8.30 (d,lH), 8.10 (d,lH), 7.93 (d,lH), 7.19 (d,lH), 4.00 (d,lH), 3.88 (d,2H), 3.54-3.43 (m,4H), 3.11 (t,2H), 2.07 (d,2H), 1.90-1.69 (m,6H)
b) 1 -[[6-[4-[(3-Amino-4-pyridinyl)aminoJ-l -piperidinylJ-5-chloro-3- pyridinyl] carbonyljpyrrolidine trifluoroacetate
Figure imgf000052_0001
The product from example 47 step a) (0.29mg) was dissolved in ethanol (50ml) and acetic acid (0.5ml) and palladium on carbon (5%, O.lg) was added. Hydrogenation of the mixture at 4 bar for 2h followed by filtration over celite gave a foam that was purified by reverse phase HPLC (Symmetry, gradient 95-50% aqueous, trifluoroacetic acid (0.4% aq.) in acetonitrile) to yield the title compound as a buff solid (75mg).
MS (APCI+) 401/3 [M+H]+
1H NMR δ(DMS0) 8.40 (d,lH), 7.94 (s,lH), 7.85 (d,lH), 7.61 (s,lH), 6.96 (d,lH), 6.90 (d,lH), 5.60 (s,2H), 3.94 (d,4H), 3.47 (t,4H), 3.07 (t,lH), 2.05 (d,2H), 1.85 (s,4H), 1.75-
1.64 (m,2H) c) l-[[5-Chloro-6-[4-(2,3-dihydro-2-oxo-lH-irmdazo[4,5-cJpyridin-l-yl)-l-piperidinylJ- 3 -pyridinyljcarbonyljpyrrolidine
Figure imgf000053_0001
The title compound was prepared as a white solid by the method of example 44 step c). MS (APCI+) 427 [M+H]+
1H NMR δ(DMS0) 10.80 (s,lH), 8.43 (d,lH), 8.20 (s,lH), 8.17 (d,lH), 7.95 (d,lH), 7.26 (d,lH), 4.44 (t,lH), 4.06 (d,2H), 3.49 (dt,2H), 3.37 (s,2H), 3.03 (t,2H), 1.92-1.76 (m,8H)
Example 48 l-[[5-CWoro-6-[4-[2,3-dihydro-5-(methylsulfonyl)-2-oxo-lH-benzimidazol-l-ylJ-l- piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine
Figure imgf000053_0002
2-Fluoro-5-methylsulphonylnitrobenzene (2.0g) and tert-butyl 4-aminopiperidine-l- carboxylate (1.82g) in acetonitrile (50ml) were stirred at 50°C for lhr. The mixture was allowed to cool, and concentrated in vacuo. The residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was dried (Na2SO ) and concentrated in vacuo to yield a solid that was taken up in ethanol (50 ml) and acetic acid (50 ml). To this solution was added activated iron powder (0.5g) and the mixture stirred for 3h. The brown solution was filtered through a celite plug, and the filtrate concentrated in vacuo. The resulting brown gum was partitioned between DCM and sataq. sodium hydrogen carbonate and the organics dried (Na2SO ). Carbonyl diimidazole (0.44g) was added and stirred for 2h. After this time sat.aq. sodium hydrogen carbonate solution was added and the organics separated, and dried (Na2SO ). TFA (5ml) was added and stirred for 24h. After this time the reaction was concentrated in vacuo. The crude gum and the product from example 2 step a) (0.12g) in NMP (2ml) and Hunigs base (1ml) were heated at 120°C for 6h. The mixture was allowed to cool and concentrated in vacuo. The residue was diluted with methanol (3ml) and acidified with acetic acid (3 drops), filtered, and the filtrate purified by by reverse phase HPLC (Symmetry, gradient 85- 40% aqueous, trifluoroacetic acid (0.2% aq.) in acetonitrile) to yield a gum, which was triturated with ether :methanol (10:1) to yield the title compound as a buff solid (30mg). MS (APCI+) 504/6 [M+H]+
1H NMR δ(DMSθ) 11.39 (s,lH), 8.43 (d,lH), 7.95 (d,lH), 7.60 (dd,lH), 7.47 (s,lH), 7.45 (s,lH), 4.50 (s,lH), 4.07 (d,2H), 3.49 (d,4H), 3.17 (s,3H), 3.04 (t,2H), 1.86 (s,8H)
Example 49 l-[[6-[4-[2,3-Dihydro-5-(methylsulfonyl)-2-oxo-lH-benzimidazol-l-ylJ-l-piperidinylJ- 3 -pyridinylj carbonyljpyrrolidine
Figure imgf000054_0001
The title compound was prepared as a solid (35mg) by the method of example 48 and the product of example 1 step a). MS (APCI+) 470 [M+H]+
1H NMR δ(DMso) 11.37 (s,lH), 8.36 (d,lH), 7.75 (dd,lH), 7.56 (dd,lH), 7.45 (s,lH), 7.43 (s,lH), 6.93 (d,lH), 4.63-4.50 (m,3H), 3.49 (d,2H), 3.16 (s,3H), 3.04 (t,2H), 2.31 (dd,4H), 1.89-1.78 (m,6H)
Example 50 l-[[6-[4-(Phenylamino)-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine
Jdec-8-yl)-3-pyridinyl]carbonylJpyrrolidine
Figure imgf000054_0002
The product from example 1 step a) (l.lg), l,4-dioxa-8-azaspiro[4.5]decane (1.5g) and Hunigs base (2ml) were heated in NMP (15ml) at 130°C for 16h. The reaction mixture was cooled, diluted with ethyl acetate and washed with sat.aq. sodium hydrogen carbonate and once with brine. The organic phase was dried (Na2SO_ι), concentrated and purified by column chromatography (ethyl acetate/methanol 9:1) to give the sub-title compound as an oil (1.8g). MS (APCI+) 318 [M+HJ+
1H NMR δ(CDci3) 8.41 (d,lH), 7.73 (dd,lH), 6.65 (d,lH), 4.00 (s,4H), 3.76 (t,4H), 3.70- 3.50 (m,4H), 2.00-1.83 (m,4H), 1.76 (t,4H)
b) 1 -[[6-(4-Oxo-l -piperidinyl)-3 -pyridinylj carbonyljpyrrolidine trifluoroacetate
Figure imgf000055_0001
The product from example 50 step a) (1.8g) and TFA (6ml) in DCM were heated at 50°C (5ml) for lOh. The reaction mixture was cooled and concentrated to give the sub- title compound as an oil (3.0g). MS (APCI+) 274 [M+HJ+
1H NMR δ(cDCi3) 8.52 (d,lH), 8.44 (s,lH), 8.22 (dd,lH), 7.05 (d,lH), 4.07 (t,4H), 3.64 (d,4H), 2.78 (t,4H), 2.00 (s,4H)
c) l-[[6-[4-(Phenylamino)-l-piperidinyl]-3-pyridinyl]carbonylJpyrrolidine
Figure imgf000055_0002
The product from example 50 step b) (0.4g), benzenamine (0.15ml) and sodium triacetoxyborohydride (0.62g) were combined in DCM (10ml). After 3h the reaction mixture was diluted with ethyl acetate and washed with sat.aq. sodium hydrogen carbonate and once with brine. The organic phase was dried (Na2SO_t) concentrated and purified by reverse phase HPLC (Symmetry®, gradient 75-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile), to give the title compound (70mg). MS (APCI+) 351 [M+H]+ 1H NMR δ(CDci3) 8.33 (d,lH), 7.70 (dd,lH), 7.06 (t,2H), 6.85 (d,lH), 6.60 (d,2H), 6.50 (t,lH), 5.45 (d,lH), 4.29 (d,2H), 3.60-3.40 (m,5H), 3.10 (t,2H), 1.96 (dd,2H), 1.83 (s,4H), 1.40-1.24 (m,2H) Example 51 l-[[5-Chloro-6-[4-[[4-(dimethylamino)-2-pyrimidinyl]amino]-l-piperidinyl]-3- pyridinyljcarbonyljpyrrolidine
Figure imgf000056_0001
The product from example 43 step a) (0.2g) and 2-chloro-N,N-dimethylpyrimidin-4- amine (74mg) in NMP (3ml) and Hunigs base (0.26ml) were heated at 140°C for 48h.
The mixture was cooled and partitioned between ether and water. The phases were separated and the ether phase was dried (Na2SO4), concentrated in vacuo and the gum obtained purified by reverse phase HPLC (Symmetry, gradient 95-50% aqueous, ammonium acetate (0.4% aq.) in acetonitrile) to yield the title compound as a buff solid
(15mg).
Figure imgf000056_0002
1H NMR δ(DMS0) 8.38 (d,lH), 7.90 (d,lH), 7.77 (d,lH), 6.42 (d,lH), 5.88 (d,lH), 3.97-
3.74 (m,3H), 3.52-3.42 (m,4H), 2.98 (s,6H), 1.96 (d,2H), 1.84 (s,4H), 1.70-1.54 (m,4H)
Example 52 l-[[6-[4-[[4-(Dimethylammo)-2-pyrimidinyl]amino]-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000056_0003
a) l-[[6-(4-Amino-l-piperidinyl)-3-pyridinyl]carbonyl]pyrrolidine ditrifluoroacetate
Figure imgf000056_0004
The product from example 1 step a) (2.1g), 4-piperidinyl carbamic acid, 1,1- dimethylethyl ester (2g) and Hunigs base (5ml) in NMP (2ml) were heated at 140°C for 6h. The resulting mixture was cooled and partitioned between ether and sat. aq. sodium hydrogen carbonate. The phases were separated and the aqueous was extracted with ether. The combined ether phases were concentrated and triturated with ether:methanol (50:1) to give a solid (3.8g), which was treated with TFA (5ml) in DCM (5ml) for 18h to give after concentration in vacuo the sub-title compound as a solid (2.1g). 1H NMR δ(DMso) 8.34 (d,lH), 7.96 (s,4H), 7.77 (dd,lH), 6.94 (d,lH), 4.40 (d,2H), 3.40- 3.57 (m,4H), 3.20-3.40 (m,lH), 2.99 (t,2H), 1.96 (d,2H), 1.84 (s,4H), 1.45 (ddt,2H)
b) l-[[6-[4-[[4-(Dimethylamino)-2-ρyrimidinyl]amino]-l-piperidinyl]-3- pyridinyljcarbonyljpyrrolidine
Figure imgf000057_0001
The product from example 52 step a) (0.4g) and 2-cMoro-N,N-dimethylpyrirnidin-4- amine (0.16g) in NMP (2ml) and Hunigs base (1ml) were heated at 140°C for 12h. The resulting mixture was cooled, diluted with methanol (3ml), filtered and the filtrate purified by reverse phase HPLC (XTerra, gradient 95-50% aqueous, ammonia (0.2% aq.) in acetonitrile) to yield the title compound as a buff solid (0.43g). MS (APCI+) 396 [M+HJ+
1H NMR δ(DMso) 8.33 (d,lH), 7.77 (d,lH), 7.69 (dd,lH), 6.83 (d,lH), 6.36 (s,lH), 5.88 (d,lH), 4.33 (d,2H), 3.97 (s,lH), 3.48 (s,4H), 3.03 (d,2H), 2.97 (s,6H), 1.91 (d,2H), 1.83 (s,4H), 1.49-1.35 (m,2H)
Example 53
1 -[[6-[4-(2-Pyrimidinylamino)- 1 -piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine
Figure imgf000057_0002
The product from example 52 step a) (0.4g) and 2-chloropyrimidine (0.1 lg) in NMP
(2ml) and Hunigs base (1ml) were heated at 140°C for 6h. The resulting mixture was cooled, diluted with methanol (3ml), filtered and the filtrate purified by reverse phase
HPLC (XTerra, gradient 95-50% aqueous, ammonia (0.2% aq.) in acetonitrile) to yield the title compound as a buff solid (1 Omg).
MS (APCI+) 353 [M+HJ+ 1H NMR 6(DMSO) 8.33 (d,lH), 8.27 (d,2H), 7.70 (dd,lH), 7.12 (d,lH), 6.85 (d,lH), 6.55 (t,lH), 4.35 (d,2H), 4.01 (t,lH), 3.47 (d,4H), 3.03 (t,2H), 1.92 (d,2H), 1.83 (s,4H), 1.44 ( q,2H)
Example 54 l-[[6-[4-(lH-l,2,3-Benzotriazol-l-yl)-l-piperidinyl]-5-chloro-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000058_0001
The product from example 2 step a) (0.25g), l-piperidin-4-yl-lH-l,2,3-benzotriazole hydrochloride (0.24g) in NMP (5ml) and Hunigs base (0.5ml) were heated at 100°C for 6h. The mixture was cooled and partitioned between ether and water. The phases were separated and the ether phase was dried (Na2SO4) and concentrated in vacuo. The resultant gum was purified by reverse phase HPLC (Symmetry, gradient 75-5% aqueous, ammonium acetate (0.2 % aq) in acetonitrile) to yield the title compound as a white solid (120mg).
MS (APCI+) 386/8 [M+HJ+
1H NMR δ(DMS0) 8.42 (dd,lH), 8.06 (d,lH), 7.98-7.95 (m,2H), 7.58 (ddd,lH), 7.42 (ddd,lH), 5.21 (tt,lH), 4.09 (d,2H), 3.54-3.44 (m,4H), 3.25-3.17 (m,2H), 2.38 (qd,2H), 2.29-2.21 (m,2H), 1.91-1.80 (m,4H)
Example 55
1 -[[2-Chloro-6-[4-(2,3 -dihydro-2-oxo- lH-benzimidazol- 1 -yl)- 1 -piperidinylJ-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000058_0002
a) 1 -[(2,6-Dichloro-3-pyridinyl)carbonylJpyrrolidine
Figure imgf000058_0003
The sub-title compound was prepared as a solid by the method of example 1 step a) using 2,6-dichloro-3-pyridinecarboxylic acid.
MS (APCI+) 244/6/8 [M+HJ+
1H NMR δ(CDCi3) 7.65 (d,lH), 7.34 (d,lH), 3.66 (t,2H), 3.25 (t,2H), 1.9-2.1 (m,4H)
b) 1 -[[2-Chloro-6-[4-(2,3-dihydro-2-oxo-lH-benzimidazol-l -yl)-l -ρiρeridinylJ-3- pyridinyl J carbonyljpyrrolidine
Figure imgf000059_0001
The product of example 55 step a) (0.2g), l,3-dihydro-l-(4-piperidinyl)-2H- benzimidazol-2-one (0.2g) and Hunigs base (0.3ml) in NMP (2ml) were heated at 100°C for 16h. The mixture was cooled and purified by column chromatography (isohexane: ethyl acetate:ethanol 1:1 :0 to 0:100:3) to give the sub-title compound as a solid (9mg). MS (APCI+) 426/8 [M+H]+
1H NMR δφMso) 10.85 (s,lH), 7.56 (d,lH), 7.17 (dd,lH), 6.9-7.0 (m,3H), 6.91 (d,lH), 4.4-4.53 (m,3H), 3.42 (t,2H), 3.21 (d,2H), 3.03 (t,2H), 2.30 (ddt,2H), 1.73-1.95 (m,6H)
Example 56 l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinyl]-2-[(2- methylpropyl)aminoJ-3-pyridmyl]carbonyl]pyrrolidine
Figure imgf000059_0002
a) l-[[6-Chloro-2-[(2-methylpropyl)amino]-3-pyridinyl]carbonyl]pyrrolidine
Figure imgf000059_0003
The product of example 55 step a) (0.2g), isobutylamine (0.8ml) and triethylamine (0.23ml) in NMP (5ml) were heated at 50°C for 5 days. The reaction mixture was cooled, concentrated in vacuo and purified by column chromatography (isohexane:ethyl acetate 5:1) to give the sub-title compound as an oil (0.15g). MS (APCI+) 281/3 [M+HJ+
1H NMR δ(CDCi3) 7.38 (d,lH), 7.05 (t,lH), 6.45 (d,lH), 3.55 (s,4H), 3.25 (dd,2H), 1.8-2.0 (m,5H), 0.97 (d,6H)
b) l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-ρiρeridinylJ-2-[(2- methylpropyl)amino] -3 -pyridinyl] carbonyljpyrrolidine
Figure imgf000060_0001
The product of example 56 step a) (75mg), l,3-dihydro-l-(4-piperidinyl)-2H- benzimidazol-2-one (58mg) and Hunigs base (0.1ml) in NMP (5ml) were heated at 120°C for 24h. The mixture was cooled and purified by reverse phase HPLC
(Symmetry, gradient 95-50% aqueous, ammonium acetate (0.4% aq.) in acetonitrile) to yield the title compound as a solid (16mg).
MS (APCI+) 463 [M+HJ+
1H NMR δ(DMso) 10.40 (s,lH), 7.63 (d,lH), 7.49 (d,lH), 7.11 (dd,lH), 7.0-6.9 (m,3H), 6.02 (d,lH), 4.53 (d,2H), 4.42 (tt,lH), 3.45 (t,4H), 3.15 (t,2H), 2.95 (t,2H), 2.20-2.35
(m,2H), 1.80 (sept,lH), 1.81 (s,4H), 1.74 (d,2H), 0.89 (d,6H)
Example 57 l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinylJ-2-(methylamino)-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000060_0002
a) 1 -[[6-Chloro-2-(methylamino)-3-pyridinylJcarbonyl]pyrrolidine
Figure imgf000061_0001
The sub-title compound was prepared as a solid by the method of example 56 step a) using methylamine. MS (APCI+) 239/241 [M+H]+ 1H NMR δ(cDci3) 7.38 (d,lH), 6.84 (s,lH), 6.49 (d,lH), 3.4-3.7 (s,4H), 2.96 (d,3H), 1.92 (s,4H)
b) 1 -[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l -yl)-l -piperidinylJ-2-(methylamino)- 3 -pyridinyl] carbonyl]pyrrolidine
Figure imgf000061_0002
The title compound was prepared as a solid by the method of example 57 step b). MS (APCI+) 421[M+Η]+
1H NMR δ(DMS0) 10.40 (s,lH), 7.46 (d,lH), 7.23 (dd,lH), 7.14 (dd,lH), 7.0-6.9 (m,3H), 6.02 (d,lH), 4.56 (d,2H), 4.43 (tt,lH), 3.2-3.5 (m,4H), 2.95 (t,2H), 2.82 (d,3H), 2.28 (ddt,2H), 1.7-1.9 (m,6H)
Example 58
1 -[[6- [4-(2,3 -Dihydro-2-oxo- lH-benzimidazol- 1 -yl)- 1 -piperidinyl]-2-methoxy-3- pyridinylj carbonyljpyrrolidine
Figure imgf000061_0003
The title compound was prepared as a solid by the method of example 56 step a) using sodium methoxide and step b). MS (APCI+) 422 [M+Η]+ 1H NMR δ(DMso) 10.85 (s,lH), 7.46 (d,lH), 7.10-7.14 (m,lH), 7.00-6.90 (m,3H), 6.23 (d,lH), 4.38 (tt,lH), 4.01 (d,2H), 3.84 (s,3H), 3.43 (t,2H), 3.00 (t,2H), 2.38 (ddt,2H), 1.89 (t,4H), 1.75 (d,2H)
Example 59 l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinyl]-2-(dimethylamino)- 3 -pyridinyl] carbonyljpyrrolidine ditrifluoroacetate
Figure imgf000062_0001
The title compound was prepared as a solid by the method of example 56 step a) using dimethylamine and step b).
MS (APCI+) 435[M+Η]+
1H NMR δ(DMso) 10.45 (s,lH), 7.29 (d,lH), 7.20 (d,lH), 7.00-6.90 (m,3H), 6.19 (d,lH),
4.40-4.50 (m,3H), 3.40 (t,2H), 3.21 (t,2H), 2.93 (t,2H), 2.89 (s,6H), 2.25-2.35 (m,2H), 1.70-1.90 (m,6H)
Example 60
1 -[[6-[3-[[4-(Dimethylamino)-2-pyrimidinyl]oxy]-l -pyrrolidinyl]-3- pyridinylj carbonyljpyrrolidine
Figure imgf000062_0002
The product from example 1 step a) (0.3g) and 3-hydroxypyrrolidine (0.12g) in Hunigs base (0.75ml) were irradiated in a CEM Discover microwave, 100W/150°C for lOmin. The mixture was cooled and concentrated in vacuo. The residue was taken up in THF (2.5ml) and NMP (1ml) and potassium t-butoxide (0.4g) then 2-chloro-4- dimethylaminopyrimidine were added. The mixture was stirred at room temperature for 20h then at 70°C for 5h. The resulting mixture was cooled, concentrated and purified by column chromatography (DCM:methanol 95:5) then by reverse phase HPLC (gradient 75-5% aqueous, ammonium acetate (0.2% aq.) in acetonitrile) to give the title compound as a solid (76mg).
MS (APCI+) 383 [M+H]+ 1H NMR δ(CDci3) 8.32 (d,lH), 8.08 (d,lH), 7.70 (dd,lH), 6.49 (d,lH), 6.01 (d,lH), 5.67 (quin,lH), 3.91-3.51 (m,8H), 3.10 (s,6H), 2.42-2.30 (m,2H), 1.90-1.76 (m,4H)
Example 61 l-[[6-[3-[[2-(Dimethylamino)-4-pyrimidinylJoxy]-l-pyrrolidinylJ-3- pyridinyl] carbonyljpyrrolidine
Figure imgf000063_0001
The title compound was prepared by the method of example 60 and 4-chloro-N,N- dimethyl-2-pyrimidinamine.
MS (APCI+) 383 [M+H]+
1H NMR 6(DMSO) 8.32 (d,lH), 8.07 (d,lH), 7.70 (dd,lH), 6.49 (d,lH), 6.01 (d,lH), 5.67
(quin,lH), 3.80 (dd,lH), 3.70-3.59 (m,2H), 3.56-3.39 (m,5H), 3.12 (s,6H), 2.42-2.30
(m,lH), 2.29-2.19 (m,lH), 1.90-1.76 (m,4H)
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 lOmM 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 9.5 μM and going down. Into each well was placed 1 x 105 PBMC, prepared from human peripheral blood from a single donor, in RPMI 1640 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°C 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 examples 29, 37 and 48 have IA5o values of 220, 20 and 1050 nM respectively.

Claims

Claims
1. A compound of formula (I) :
Figure imgf000065_0001
(I)
wherein:
A is a 4-, 5- or 6-membered saturated ring;
p is 1 or 2;
R1 is hydrogen, C1-6 alkyl, halogen, NR4R5 or X-C1-6 alkyl where X is O, S or NR4;
B is a bond, CH2, O, S, SO, SO2 or NH group;
R2 is phenyl, an aromatic ring system with 1 or more nitrogen atoms, or R2 is a saturated or partially saturated bicyclic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulphur each R group being optionally substituted by one or more groups selected from halogen, C1-6 alkyl, oxo, SC1-6 alkyl, NO2, NR6R7, CONR6R7, SO2Me, or a 6-membered saturated ring containing one or more heteroatoms and optionally substituted by one or more groups selected from C1-6 alkyl and carbonyl;
R4 and R5 are independently hydrogen or C1- alkyl;
Figure imgf000065_0002
are independently hydrogen or C1-4 alkyl;
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, C1-6 alkyl or halogen.
4. A compound according to any one of claims 1 to 3 in which p is 2.
5. A compound according to any one of claims 1 to 4 in which B is a bond, O, NH, or SO2 group.
6. A compound according to any one of claims 1 to 5 in which R2 is pyridyl, pyrimidyl, pyridazine, triazine, 7H-purine, lH-benzimidazole, lH-l,2,3-benzotriazole, 2,3-dihydro-lH-benzimidazole, 2,3-dihydro-lH-imidazo[4,5-b]pyridine, 2,3-dihydro- lH-imidazo[4,5-cJpyridine, 8,9-dihydro-7H-purine, 3H-imidazo[4,5-&]pyridine or 1,3- dihydro-[l,2,5]thiadiazolo[3,4-bJpyridine.
7. A compound according to claim 1 selected from:
1 -[ [6- [4-(2-Pyrimidinyloxy)- 1 -piperidinylj -3 -pyridinyl] carbonyl]pyrrolidine l-[[5-Chloro-6-[4-[[2-(dimethylamino)-4-pyrimidinyl]oxyJ-l-piperidinyl]-3- pyridinyl J carbonyljpyrrolidine l-[[5-Chloro-6-[4-[[4-(dimethylamino)-2-pyrimidinyl]oxy]-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine
1 - [[6- [4- [ [4-(Dimethylamino)-2-pyrimidinyl] oxyj- 1 -piperidinylJ-3 - pyridinyl] carbonyljpyrrolidine l-[[5-Chloro-6-[4-(2-pyrimidinyloxy)-l-piperidinyl]-3-pyridinyl]carbonylJpyrrolidine l-[[6-[4-[[4-(Propylthio)-2-pyrimidinylJoxy]-l-piperidinyl]-3- pyridinyljcarbonyljpyrrolidine l-[[5-Chloro-6-[4-[[4-(propylthio)-2-pyrimidinylJoxyJ-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine l-[[6-[4-[(2-Amino-4-pyrimidinyl)oxyJ-l-piperidinyl]-5-chloro-3- pyridinyl J carbonyljpyrrolidine l-[[6-[4-[(2-Amino-4-pyrimidmyl)oxyJ-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine l-[[6-[4-[(2-Amino-5-ethyl-6-methyl-4-pyrimidinyl)oxyJ-l-piperidinyl]-3- pyridinylj carbonyljpyrrolidine acetate l-[[6-[4-[[4-(4-Methyl-l-piperazinyl)-2-pyrimidinylJoxy]-l-piperidinyl]-3- pyridinylj carbonyljpyrrolidine
1 - [ [6- [4- [ [2 -(Methy lamino)-4-pyrimidinyl] oxyj - 1 -piperidinyl J -3 - pyridinylj carbonyljpyrrolidine l-[[6-[4-[[4-(3-Oxo-l-piperazinyl)-2-pyrimidinylJoxy]-l-piperidinyl]-3- pyridinyl J carbonyljpyrrolidine
1 -[ [6- [4- [[5 -Methyl-2-(methylamino)-4-pyrimidinyl] oxyj- 1 -piperidinylj -3 - pyridinylj carbonyljpyrrolidine
1 - [[6- [4- [4-Pyrimidinyl)oxy] - 1 -piperidinylj -3 -pyridinylj carbonyljpyrrolidine l-[[6-[4-(3-Pyridazinyloxy)-l-piperidinyl]-3-pyridinylJcarbonyl]pyrrolidine acetate l-[[6-[4-[(2-Amino-6-methyl-4-pyrimidinyl)oxyJ-l-piperidinylJ-3- pyridinyl] carbonyljpyrrolidine l-[[6-[4-[[2-(Dimethylamino)-6-methyl-4-pyrimidinylJoxy]-l-piperidinylJ-3- pyridinyl J carbonyljpyrrolidine l-[[6-[4-[(4-Amino-5-methyl-2-pyrimidinyl)oxyJ-l-ρiperidinyl]-3- pyridinylj carbonyljpyrrolidine
1 -[[6-[4-[(2-amino-5-methyl-4-pyrimidinyl)oxyJ-l -piperidinylj -3- pyridinyl] carbonyljpyrrolidine
1 -[[6-[4-[([4-(Methylamino)-2-pyrimidinylJoxy]-l -piperidinylj -3- pyridinyl] carbonyljpyrrolidine l-[[5-Chloro-6-[4-[(6-fluoro-2-pyridinyl)oxy]-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine l-[[5-Chloro-6-[4-(2-pyridinyloxy)-l-piperidinylJ-3-pyridinyl]carbonylJpyrrolidine
1 - [[6- [4- [(6- Amino-2-pyridinyl)oxy] - 1 -piperidinylj -3 -pyridinyl] carbonyljpyrrolidine 5-Chloro-6-[[l-[5-(l-pyrrolidinylcarbonyl)-2-pyridinyl]-4-piperidinylJoxy]-3- pyridinecarboxamide l-[[6-[4-[(5-Amino-2-pyridinyl)oxyJ-l-piperidinyl]-3-pyridinyl]carbonylJpyrrolidine l-[[6-[4-[(5-Amino-3-methyl-2-pyridinyl)oxy]-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine 1 -[[6-[4-[(6-Amino-3-pyridazinyl)oxyJ-l -piperidinyl]-3-pyridinyl]carbonylJpyrrolidine acetate
1 -[[6-[4-[(4-Amino-l ,3,5-triazin-2-yl)oxyJ-l -piperidinylJ-3- pyridinyl J carbonyljpyrrolidine l-[[6-[4-(9H-Purin-6-yloxy)-l-piperidinylJ-3-pyridinyl]carbonyl]pyrrolidine l-[[6-[4-[(2-Amino-9H-purin-6-yl)oxyJ-l-piperidinylJ-3-pyridinyl]carbonylJpyrrolidine
1 -[[6-(4-Phenoxy-l -piperidinyl)-3 -pyridinyl] carbonyljpyrrolidine l-[[5-Chloro-6-(4-phenoxy-l-piperidinyl)-3-pyridinylJcarbonylJpyrrolidine l-[[5-(Dimethylamino)-6-(4-phenoxy-l-piperidinyl)-3-pyridinyl]carbonylJpyrrolidine
1 - [[6- [4-(Phenylsulfonyl)- 1 -piperidinylj -3 -pyridinylj carbonyljpyrrolidine l-[[5-Chloro-6-[4-(lH-indol-3-yl)-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine l-[[6-[4-(lH-Indol-3-yl)-l-piperidinyl]-3-pyridinyl]carbonyl]ρyrrolidine l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piρeridinylJ-3- pyridinyl J carbonyljpyrrolidine
1 -[[5-Chloro-6-[4-(2,3 -dihydro-2-oxo- 1 H-benzimidazol- 1 -yl)- 1 -piperidinyl]-3- pyridinylj carbonyljpyrrolidine l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinylJ-5-methyl-3- pyridinyl] carbonyljpyrrolidine l-[[5-Chloro-6-[4-(7,8-dihydro-8-oxo-9Η-ρurin-9-yl)-l-piperidinylJ-3- pyridinyl J carbonyljpyrrolidine l-[[5-Chloro-6-[4-(l,2-dihydro-2-oxo-3H-imidazo[4,5-bJpyridin-3-yl)-l-ρiperidinylJ-3- pyridinyl] carbonyljpyrrolidine l-[[5-Chloro-6-[4-(2-methyl-3H-imidazo[4,5-bJpyridin-3-yl)-l-ρiρeridinyl]-3- pyridinyl J carbonyljpyrrolidine 1 -[[5-Chloro-6-[4-(2,2-dioxido[l ,2,5Jthiadiazolo[3,4-b]ρyridin-3(lH)-yl)-l -piperidinylj-
3 -pyridinyl] carbonyljpyrrolidine l-[[5-Chloro-6-[4-(2,3-dihydro-2-oxo-lH-imidazo[4,5-c]pyridin-l-yl)-l-piperidinyl]-3- pyridinylj carbonyljpyrrolidine l-[[5-Chloro-6-[4-[2,3-dihydro-5-(methylsulfonyl)-2-oxo-lH-benzimidazol-l-yl]-l- piperidinylj -3 -pyridinylj carbonyljpyrrolidine l-[[6-[4-[2,3-Dihydro-5-(methylsulfonyl)-2-oxo-lH-benzimidazol-l-yl]-l-ρiperidinylJ-
3 -pyridinyl] carbonyljpyrrolidine l-[[6-[4-(Phenylamino)-l-piperidinyl]-3-pyridinyl]carbonyl]pyrrolidine l-[[5-Chloro-6-[4-[[4-(dimethylamino)-2-pyrimidinyl]aminoJ-l-piperidinyl]-3- pyridinyl] carbonyljpyrrolidine l-[[6-[4-[[4-(Dimethylamino)-2-pyrimidinylJamino]-l-piperidinyl]-3- pyridinyl J carbonyljpyrrolidine l-[[6-[4-(2-Pyrimidinylamino)-l-piperidinyl]-3-pyridinylJcarbonylJpyrrolidine l-[[6-[4-(lH-l,2,3-Benzotriazol-l-yl)-l-piperidinylJ-5-chloro-3- pyridinyl] carbonyljpyrrolidine l-[[2-Chloro-6-[4-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinylJ-3- pyridinylj carbonyljpyrrolidine l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piρeridinyl]-2-[(2- methylpropyl)amino]-3-pyridinyl]carbonyl]ρyrrolidine l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinyl]-2-(methylamino)-3- pyridinyl] carbonyljpyrrolidine l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidazol-l-yl)-l-piperidinylJ-2-methoxy-3- pyridinyl] carbonyl Jpyrrolidine l-[[6-[4-(2,3-Dihydro-2-oxo-lH-benzimidaz;ol-l-yl)-l-piperidinylJ-2-(dimethylamino)- 3 -pyridinyl] carbonyljpyrrolidine
1 -[ [6- [3 - [[4-(Dimethylamino)-2-pyrimidinyl]oxyJ- 1 -pyrrolidinyl] -3 - pyridinyljcarbonyljpyrrolidine
1 -[[6-[3-[[2-(Dimethylamino)-4-pyrimidinyl]oxy]-l -pyrrolidinyl]-3- pyridinyljcarbonyljpyrrolidine
8. A compound according to any one of claims 1 to 7 for use in therapy.
9. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 7 in association with a pharmaceutical carrier.
10. 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 7.
11. 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 (I) or a pharmaceutically-acceptable salt thereof as defined in any one of claims 1 to 7.
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