WO2009132000A1 - Quinoline or isoquinoline substituted p2x7 antagonists - Google Patents

Quinoline or isoquinoline substituted p2x7 antagonists Download PDF

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WO2009132000A1
WO2009132000A1 PCT/US2009/041249 US2009041249W WO2009132000A1 WO 2009132000 A1 WO2009132000 A1 WO 2009132000A1 US 2009041249 W US2009041249 W US 2009041249W WO 2009132000 A1 WO2009132000 A1 WO 2009132000A1
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Prior art keywords
alkyl
compound
hydroxy
alkyloxy
mol
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PCT/US2009/041249
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French (fr)
Inventor
Christopher John Love
Joseph Elisabeth Leenaerts
Ludwig Paul Cooymans
Alec Donald Lebsack
Bryan James Branstetter
Jason Christopher Rech
Elizabeth Ann Gleason
Jennifer Diane Venable
Danielle Wiener
Deborah Margaret Smith
James Guy Breitenbucher
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Janssen Pharmaceutica Nv
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Priority to US12/988,891 priority Critical patent/US8431704B2/en
Priority to EP09735472A priority patent/EP2285800B1/en
Priority to CA2722035A priority patent/CA2722035C/en
Priority to CN2009801246595A priority patent/CN102066360B/en
Priority to AT09735472T priority patent/ATE533762T1/en
Priority to AU2009239471A priority patent/AU2009239471B2/en
Priority to JP2011506394A priority patent/JP5369173B2/en
Priority to ES09735472T priority patent/ES2376092T3/en
Publication of WO2009132000A1 publication Critical patent/WO2009132000A1/en

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    • 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
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
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    • A61P27/06—Antiglaucoma agents or miotics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
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    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61P35/00—Antineoplastic agents
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    • A61P35/00—Antineoplastic agents
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • 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
    • C07D471/10—Spiro-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the present invention is related to novel compounds of formula (I) having P2X7 antagonistic properties, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds and their use in the treatment or prophylaxis of diseases associated with P2X7 receptor activity in animals, in particular humans.
  • the P2X7 receptor is a ligand-gated ion channel and is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B).
  • IL-I P interleukin-P
  • giant cell formation macrophages/ microglial cells
  • degranulation mass cells
  • L-selectin shedding lymphocytes
  • P2X7 receptors are also located on antigen-presenting cells (APQ, keratinocytes, salivary acinar cells (parotid cells), hepatocytes, erythrocytes, erythroleukaemic cells, monocytes, fibroblasts, bone marrow cells, neurones, and renal mesangial cells.
  • AQ antigen-presenting cells
  • the P2X7 receptor is also known to be a pain sensor in the nervous system.
  • Experiments using P2X7 deficient mice demonstrate the role of P2X7 in the development of pain as these mice were protected from the development of both adjuvant-induced inflammatory pain and partial nerve ligation induced neuropathic pain.
  • the present invention relates to a compound of formula (I)
  • R 3 is hydrogen, halo, C ⁇ alkyl or C ⁇ alkyloxy
  • X represents O, S, SO 2 , CR 4 R 5 or NR 6
  • R 4 and R 5 are each independently from another selected from hydrogen, halo, hydroxy, C ⁇ alkyl, C ⁇ alkyloxy, or aryl
  • R 6 is hydrogen, phenyl, -CO-R 7 , or -CO-O-R 7 , wherein R 7 is C ⁇ galkyl or amino;
  • R 1 is a heterocycle selected from pyridinyl or pyrimidinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, C ⁇ alkyl, C ⁇ galkyloxy, polyhaloC ⁇ alkyl, phenyl, C 3 . 6 cycloalkyl, C 3 . 6 cycloalkyloxy, C ⁇ gcycloalkylC ⁇ alkyloxy, Or NR 8 R 9 ; wherein R 8 and R 9 are independently from another selected from hydrogen, C ⁇ galkyl, hydroxyC ⁇ alkyl, C 3 .
  • R 8 and R 9 may be taken together with the nitrogen atom to which they are attached to form a azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from C ⁇ alkyl, C ⁇ alkyloxy, halo, hydroxy, or C ⁇ alkylcarbonyl;
  • R 2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, C ⁇ galkyl, C ⁇ alkyloxy, C 3 .
  • R 10 and R 11 are independently from another selected from hydrogen, C ⁇ galkyl, C 3 _gcycloalkyl, polyhaloC ⁇ alkyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, TV-(1 ,5-dioxa-9-aza-spiro[5.5]undec-9-yl), TV-(1 ,7-diaza-spiro[4.4]non-7-yl), TV-(2,6-diaza-spiro[4.5]dec-2-yl), and C ⁇ galkyl substituted with one or two substituents selected from hydroxy, halo, aryl 1 , C ⁇ alkyloxy, C 3 _gcycloalkyl, hydroxycarbonyl, C ⁇ alkylsulfonylamin
  • aryl 1 is phenyl or phenyl substituted with one substituent selected from halo, C ⁇ alkyl,
  • - halo is generic to fluoro, chloro, bromo and iodo
  • Ci- 4 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1 -methyl- ethyl, 2-methylpropyl and the like;
  • Ci- 6 alkyl is meant to include Ci ⁇ alkyl and the higher homologues thereof having
  • polyhaloCi_ 4 alkyl is defined as polyhalosubstituted C ⁇ alkyl, in particular C ⁇ alkyl (as hereinabove defined) substituted with 2 to 6 halogen atoms such as difluoro- methyl, trifluoromethyl, trifluoroethyl, and the like; - A -
  • polyhaloC ⁇ galkyl is defined as polyhalosubstituted C ⁇ alkyl, in particular C ⁇ galkyl (as hereinabove defined) substituted with 2 to 6 halogen atoms such as difluoro- methyl, trifluoromethyl, trifluoroethyl, and the like;
  • - C 3 - 6 cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • stereochemically isomeric forms as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
  • the pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are able to form.
  • These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxy acetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • butanedioic acid maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, /?-toluenesulfonic, cyclamic, salicylic, / ⁇ -aminosalicylic, pamoic and the like acids.
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds of formula (I) may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular association comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g. water or ethanol.
  • the term 'hydrate' is used when said solvent is water.
  • the present invention concerns compounds of formula (I) wherein n is an integer 1, 2 or 3; m is an integer 1, 2 or 3; p is an integer 1 or 2;
  • R 3 is hydrogen, halo, C ⁇ alkyl or C ⁇ alkyloxy
  • X represents O, S, SO 2 , CR 4 R 5 or NR 6
  • R 4 and R 5 are each independently from another selected from hydrogen, halo, hydroxy, C ⁇ alkyl, C ⁇ alkyloxy, or aryl
  • R 6 is hydrogen, phenyl, -CO-R 7 , or -CO-O-R 7 , wherein R 7 is C ⁇ galkyl or amino;
  • R 1 is a heterocycle selected from pyridinyl or pyrimidinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, C ⁇ alkyl, C ⁇ alkyloxy, polyhaloC ⁇ alkyl, phenyl, C 3 _ 6 cycloalkyl, C 3 _ 6 cycloalkyloxy, C 3 _ 6 cycloalkylC j _ 4 alkyloxy, Or NR 8 R 9 ; wherein R 8 and R 9 are independently from another selected from hydrogen, C ⁇ galkyl, C 3 _ 6 cycloalkyl, and wherein R 8 and R 9 may be taken together with the nitrogen atom to which they are attached to form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from C ⁇ alkyl, C ⁇ alkyloxy,
  • R 10 and R 11 may be taken together with the nitrogen atom to which they are attached to form a azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, JV-[l,4]-oxazepanyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from halo, hydroxy, C ⁇ alkyl,
  • aryl is phenyl or phenyl substituted with one substituent selected from halo, C 1 _ 4 alkyl, C j _ 4 alkyloxy or hydroxy.
  • R 1 is a heterocycle selected from pyridinyl or pyrimidinyl wherein said heterocycle is substituted with one substituent selected from hydrogen, halo, hydroxy, C ⁇ alkyl,
  • R 1 is a heterocycle selected from pyridin-3-yl or pyrimidin-5-yl wherein said heterocycle is substituted with one substituent selected from hydrogen, halo, hydroxy, C ⁇ alkyl, C ⁇ alkyloxy or polyhaloC ⁇ alkyl; or c) R 1 is a heterocycle selected from pyridin-3-yl or pyrimidin-5-yl wherein said heterocycle is substituted with one substituent selected from hydrogen, halo, hydroxy, methyl, methoxy or trifluoromethyl; or d) R 2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, C ⁇ alkyl or C ⁇ alkyloxy; or e) R 2 is a heterocycle selected from quinolin
  • R 4 and R 5 are each independently from another selected from hydrogen or halo; or j) R 3 is hydrogen, n is an integer 2, m is an integer 2, and X represents NR 6 wherein
  • R 6 is hydrogen, phenyl or -CO-O-R 7 wherein R 7 is C ⁇ galkyl; or k) R 1 is 2-triflouromethylpyridin-5-yl; or 1) R 1 is 2-triflouromethylpyrimidin-5-yl; or m)n is an integer 2, m is an integer 2, and X represents CR 4 R 5 wherein R 4 and R 5 are each fluoro; or n) n is an integer 1, m is an integer 3, and X represents CR 4 R 5 wherein R 4 and R 5 are each fluoro; or o) R 3 is hydrogen, n is an integer 2, m is an integer 3, and X represents O; or p) R 2 is quinoline-5-yl substituted or unsubstituted at the 6-position with Cl, F, OCH 3 ,
  • the present invention relates to a subset of compounds of formula (I) which are defined as compounds of formula (I-a)
  • R a is hydrogen, halo, hydroxy, Ci.galkyl, Ci_ 6 a lkyloxy, polyhaloC ⁇ alkyl, phenyl,
  • R 2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, C ⁇ galkyl, C ⁇ galkyloxy, C 3 _gcycloalkyl, C 3 . 6 cycloalkyloxy, polyhaloC 1-4 alkyl, and NR 10 R 11 ; wherein R 10 and R 11 are independently from another selected from hydrogen,
  • R 10 and R 11 may be taken together with the nitrogen atom to which they are attached to form a azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, JV-[l,4]-oxazepanyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from halo, hydroxy, C ⁇ alkyl, C ⁇ alkyloxy, C ⁇ alkyloxyC ⁇ alkyl, C 3 _ 6 cycloalkyl,
  • R 3 is hydrogen, halo, C ⁇ alkyl or C ⁇ alkyloxy
  • X represents O or CR 4 R 5 ; wherein R 4 and R 5 are each independently from another selected from hydrogen, halo, hydroxy, C ⁇ alkyl, C ⁇ alkyloxy, or aryl; aryl is phenyl or phenyl substituted with one substituent selected from halo, C ⁇ alkyl, C ⁇ alkyloxy or hydroxy; or a pharmaceutically acceptable acid addition salt thereof, or a solvate thereof.
  • Compounds of formula (I) can generally be prepared by reacting an intermediate of formula (II) with an intermediate of formula (III), in at least one reaction-inert solvent and optionally in the presence of at least one suitable coupling reagent and/or a suitable base, the said process further optionally comprising converting a compound of formula (I) into an addition salt thereof, and/or preparing stereochemically isomeric forms thereof.
  • reaction promoters include carbonyldiimidazole, ⁇ iV-dicyclohexyl-carbodiimide or l-(3- dimethylaminopropy l)-3 -ethylcarbodiimide, hydroxybenzotriazole, benzotriazolyl- oxytris (dimethylamino)-phosphonium hexafluorophosphate, tetrapyrrolidino- phosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate, or a functional derivative thereof, such as disclosed by D. Hudson, J.Org.Chem. (1988), 53:617.
  • Compounds of formula (I) can also be prepared by JV-acylation an intermediate of formula (II) with an intermediate of formula (IV), wherein W is an appropriate leaving group such as, for example, halo, e.g. fluoro, chloro, bromo, iodo, or in some instances W may also be a sulfonyloxy group, e.g. methanesulfonyloxy, trifluoromethane- sulfonyloxy, benzenesulfonyloxy and the like reactive leaving groups.
  • W is an appropriate leaving group such as, for example, halo, e.g. fluoro, chloro, bromo, iodo, or in some instances W may also be a sulfonyloxy group, e.g. methanesulfonyloxy, trifluoromethane- sulfonyloxy, benzenesulfonyloxy and the like reactive leaving groups.
  • the reaction can be performed in a reaction-inert solvent such as, for example, acetonitrile, dimethyl acetamide, JV-methyl-pyrrolidone or DMF, and optionally in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate or triethylamine. Stirring may enhance the rate of the reaction.
  • a reaction-inert solvent such as, for example, acetonitrile, dimethyl acetamide, JV-methyl-pyrrolidone or DMF
  • a suitable base such as, for example, sodium carbonate, potassium carbonate or triethylamine. Stirring may enhance the rate of the reaction.
  • the reaction may conveniently be carried out at a temperature ranging between room temperature and the reflux temperature of the reaction mixture.
  • the compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.
  • NR 10 R 11 substituent bearing a C ⁇ alkyloxycarbonyl group may be converted into their corresponding compounds of formula (I) wherein said C ⁇ alkyloxycarbonyl group is removed by hydrolysis under acid conditions.
  • the starting materials and some of the intermediates are known compounds and are commercially available or may be prepared according to conventional reaction procedures generally known in the art.
  • the compounds of formula (I) as prepared in the hereinabove described processes may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
  • Those compounds of formula (I) that are obtained in racemic form may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid.
  • Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali.
  • An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecif ⁇ cally.
  • said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the compounds of formula (I), the pharmaceutically acceptable salts and stereoisomeric forms thereof possess P2X7 receptor antagonizing properties as demonstrated in the Pharmacological Example D.I. Therefore the present compounds of formula (I) are useful as a medicine especially in the treatment of a condition or disease mediated by the P2X7 receptor, in particular P2X7 receptor antagonistic activity. Subsequently the present compounds may be used for the manufacture of a medicine for treatment of a condition or a disease mediated by P2X7 receptor activity, in particular P2X7 receptor antagonistic activity.
  • the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of conditions or diseases selected from P2X7 receptor mediated conditions or diseases.
  • the present invention provides a compound of formula (I) for use as a medicine or for use in the treatment of conditions or diseases selected from P2X7 receptor mediated conditions or diseases.
  • the present invention also provides a method of treatment of a condition mediated by P2X7 receptor activity, in a mammalian subject, which method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • P2X7 receptor mediated conditions or disorders are e.g. rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, hyperresponsiveness of the airway, chronic obstructive pulmonary disease (COPD), bronchitis, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, neurodegenerative disease, Alzheimer's disease, multiple sclerosis, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke, peripheral vascular disease, varicose veins, glaucoma, bipolar disorder, and neuropathic pain conditions such as diabetic neuropathy, post-herpatic neuralgia, low back pain, chemotherapy-induced neuropathic pain, fibromyalgia and spinal cord injury pain.
  • COPD chronic obstructive pulmonary
  • treating refers to curative, palliative and prophylactic treatment, including reversing, alleviating, inhibiting the progress of, or preventing the disease, disorder or condition to which such term applies, or one or more symptoms of such disease, disorder or condition.
  • compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I).
  • compositions of this invention an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with at least one pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for oral administration, rectal administration, percutaneous administration or parenteral injection.
  • any of the usual liquid pharmaceutical carriers may be employed, such as for instance water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid pharmaceutical carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • the pharmaceutical carrier will mainly comprise sterile water, although other ingredients may be included in order to improve solubility of the active ingredient.
  • Injectable solutions may be prepared for instance by using a pharmaceutical carrier comprising a saline solution, a glucose solution or a mixture of both. Injectable suspensions may also be prepared by using appropriate liquid carriers, suspending agents and the like.
  • the pharmaceutical carrier may optionally comprise a penetration enhancing agent and/or a suitable wetting agent, optionally combined with minor proportions of suitable additives which do not cause a significant deleterious effect to the skin. Said additives may be selected in order to facilitate administration of the active ingredient to the skin and/or be helpful for preparing the desired compositions.
  • These topical compositions may be administered in various ways, e.g., as a transdermal patch, a spot-on or an ointment. Addition salts of the compounds of formula (I), due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.
  • Dosage unit form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • the pharmaceutical compositions of the present invention may take the form of solid dose forms, for example, tablets (both swallowable and chewable forms), capsules or gelcaps, prepared by conventional means with pharmaceutically acceptable excipients and carriers such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like), fillers (e.g. lactose, microcrystalline cellulose, calcium phosphate and the like), lubricants (e.g. magnesium stearate, talc, silica and the like), disintegrating agents (e.g. potato starch, sodium starch glycollate and the like), wetting agents (e.g. sodium laurylsulphate) and the like.
  • Such tablets may also be coated by methods well known in the art.
  • Liquid preparations for oral administration may take the form of e.g. solutions, syrups or suspensions, or they may be formulated as a dry product for admixture with water and/or another suitable liquid carrier before use.
  • Such liquid preparations may be prepared by conventional means, optionally with other pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous carriers (e.g. almond oil, oily esters or ethyl alcohol), sweeteners, flavours, masking agents and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats
  • emulsifying agents e.g. lecithin or acacia
  • Pharmaceutically acceptable sweeteners useful in the pharmaceutical compositions of the invention comprise preferably at least one intense sweetener such as aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose (4,r,6'-trichloro-4,r,6'-trideoxygalactosucrose) or, preferably, saccharin, sodium or calcium saccharin, and optionally at least one bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.
  • intense sweetener such as aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose (4,r,6'-trichloro-4,r,6
  • Intense sweeteners are conveniently used in low concentrations.
  • concentration may range from about 0.04% to 0.1% (weight/volume) of the final formulation.
  • the bulk sweetener can effectively be used in larger concentrations ranging from about 10% to about 35%, preferably from about 10% to 15% (weight/volume) .
  • the pharmaceutically acceptable flavours which can mask the bitter tasting ingredients in the low-dosage formulations are preferably fruit flavours such as cherry, raspberry, black currant or strawberry flavour. A combination of two flavours may yield very good results.
  • stronger pharmaceutically acceptable flavours may be required such as Caramel Chocolate, Mint Cool, Fantasy and the like.
  • Each flavour may be present in the final composition in a concentration ranging from about 0.05% to 1% (weight/volume). Combinations of said strong flavours are advantageously used. Preferably a flavour is used that does not undergo any change or loss of taste and/or color under the circumstances of the formulation.
  • the compounds of formula (I) may be formulated for parenteral administration by injection, conveniently intravenous, intra-muscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in ampoules or multi-dose containers, including an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as isotonizing, suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be present in powder form for mixing with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter and/or other glycerides.
  • rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter and/or other glycerides.
  • a therapeutically effective dose will be from about 0.001 mg/kg to about 50 mg/kg of body weight, more preferably from about 0.01 mg/kg to about 10 mg/kg of body weight of the patient to be treated.
  • Said sub-doses may be formulated as unit dosage forms, for example each containing from about 0.1 mg to about 1000 mg, more particularly from about 1 to about 500 mg, of the active ingredient per unit dosage form.
  • a "therapeutically effective amount" of a compound is the quantity of a compound which, when administered to an individual or animal, results in a sufficiently high level of that compound in the individual or animal to cause a discernible P2X7 receptor antagonistic response.
  • the exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as the other medication, the patient may be taking, as is well known to those skilled in the art.
  • said "therapeutically effective amount” may be lowered or increased depending on the response of the treated patient and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • the effective daily amount ranges mentioned hereinabove are therefore only guidelines.
  • 'MeOH' means methanol
  • 'DCM' means dichloromethane
  • 'CH3CN' means acetonitrile
  • 'DIPE' means diisopropyl ether
  • 'DIPEA' means diisopropylethylamine
  • 'MgSO 4 ' means magnesium sulphate
  • 'Na 2 SO 4 ' means sulfuric acid disodium salt
  • 'Na 2 CO 3 ' means carbonic acid disodium salt
  • 'THF' means tetrahydrofuran
  • 'EtOH' means ethanol
  • 'DMF' means ⁇ /, ⁇ /-dimethylformamide
  • 'CF3COOH' means trifluoroacetic acid
  • 'H 2 SO 4 ' means sulfuric acid
  • 'KOAc' means potassium acetate
  • 'NH 3 ' means ammonia
  • 'NaBH 4 ' means sodium borohydride
  • Some compounds have been isolated by resolving a mixture of two enantiomers into its individual enantiomers using chiral column chromatography whereby one of the isolated individual enantiomers is indicated with R* (or S*) and its mirror image indicated with S* (or R*). These compounds indicated with R* or S* are single enantiomers of unknown absolute configuration.
  • 4,4-Difluoropiperidine hydrochloric acid salt (0.0286 mol) was dissolved in water (35 ml) and converted into its free base by treatment with a solution of NaHCO 3 (2.4 g, 0.0286 mol) in water (10 ml). The mixture was stirred for 30 minutes at room temperature. THF (23 ml) was added at room temperature. 6-(Trifluoromethyl)-3- pyridinecarboxaldehyde (0.0286 mol) and 4-methylbenzene-sulfonic acid (0.030 mol) were added and the mixture was stirred for 30 minutes. A solution of sodium cyanide (0.0286 mol) in water (15 ml) was added slowly and dropwise.
  • reaction mixture was heated to 70 0 C, then stirred overnight at 70 0 C.
  • the mixture was cooled to room temperature, then poured out into a 10% aqueous K 2 CO 3 solution (150 ml).
  • This mixture was extracted with DCM (2 x 100 ml).
  • the organic layers were combined, washed with a 10% aqueous NaHCO 3 solution (3 x 100 ml), dried (Na 2 SO 4 ), filtered and the solvent was evaporated, yielding 5.9 g of intermediate (1).
  • a mixture of intermediate (1) (0.045 mol) in NH 3 /CH 3 OH was hydrogenated at 14°C with Raney Nickel as a catalyst in the presence of a thiophene solution (1 ml; 4 % in DIPE). After uptake of hydrogen (two equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in DCM. The organic solution was washed with an aqueous 1 % Na 2 CO 3 solution. The organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was purified on a silica gel tube.
  • intermediate (19) was prepared starting from 6-(trifluoromethyl)-3-pyridinecarboxaldehyde and 4-phenyl- piperidine
  • intermediate (20) was prepared starting from 6-(trifluoromethyl)-3- pyridinecarboxaldehyde and 4-phenyl-piperazine
  • intermediate (22) was prepared starting from 1 -methyl- lH-imidazo Ie -2-carboxaldehyde and 4,4-difluoropiperidine hydrochloride.
  • intermediate (4) was prepared starting from 2-chloro-3-pyridinecarboxaldehyde
  • intermediate (5) was prepared from 3,3-difluoropyrrolidine hydrochloride and 6-(trifluoromethyl)-pyridine- 3-carboxaldehyde
  • intermediate (6) was prepared from 3,3-difluoroazetidine hydrochloride and 6-(trifluoromethyl)-pyridine-3-carboxaldehyde
  • intermediate (7) was prepared from l-(tert-butyloxycarbonyl)piperazine and 6-(trifiuoromethyl)-pyridine-3- carboxaldehyde
  • intermediate (8) was prepared starting from 3-pyridinecarboxaldehyde
  • intermediate (9) was prepared from ⁇ -chloro-S-pyridinecarboxaldehyde and 4,4-difluoropiperidine hydrochloride
  • intermediate (12) was prepared from 2-benzo- furancarboxaldehyde and 4,4
  • intermediate (13) was prepared starting from 3-thiophenecarboxaldehyde and 4,4-difluoro-piperidine hydrochloride
  • intermediate (14) was prepared starting from 5-methyl-2- furancarboxaldehyde and 4,4-difluoro-piperidine hydrochloride
  • intermediate (15) was prepared starting from 5-methyl-2-thiophene-carboxaldehyde and 4,4-difluoro- piperidine hydrochloride.
  • Trimethylsilanecarbonitrile (0.006 mol) was added slowly to a mixture of 4,4-difluoro- piperidine hydrochloride (0.006 mol) and 2-pyridinecarboxaldehyde (0.006 mol) in acetic acid (6 ml), while the reaction temperature was kept below 10 0 C.
  • the reaction mixture was stirred overnight and aqueous ammonia (3 M) was added until the pH turned 10.
  • the reaction mixture was extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 1.2 g of intermediate (16).
  • intermediate (18) was prepared starting from 6-(trifluoromethyl)-3-pyridinecarboxaldehyde and piperidine hydrochloride
  • intermediate (21) was prepared starting from 6-(trifluoromethyl)-3- pyridinecarboxaldehyde and 4-(4-chlorophenyl)-4-piperidinol
  • intermediate (23) was prepared starting from 6-(trifluoromethyl)-3-pyridinecarboxaldehyde and morpholine
  • intermediate (24) was prepared starting from 6-(trifluoromethyl)-3-pyridine-carbox- aldehyde and 1,1-dioxo-l-thio-morpholine
  • intermediate (25) was prepared starting from 2-(trifluoromethyl)-5-pyrimidinecarboxaldehyde and 4,4-difluoro-piperidine hydrochloride
  • intermediate (26) was prepared starting from 6-(trifluoromethyl)-3- pyridinecarboxaldehyde and 4-(amin
  • intermediate (202) was prepared starting from 6-methyl-2-chloroquinoline and intermediate (203) was prepared starting from 6-chloroquinoline.
  • intermediate (205-207) were prepared starting from either 2-trifluoromethyl-pyrimidine-5-carbaldehyde or 2- methylsulfanyl-pyrimidine-5-carbaldehyde and 4,4-difluoropiperidine hydrochloride or morpholine, or piperdine respecively.
  • intermediate (213) was prepared starting from 5-bromo-2-chloro-6-fluoro-quinoline and 3(R)-hydroxypyrrolidine
  • intermediate (214) was prepared starting from 5-bromo-2-chloro-6-fluoro-quinoline and ethanolamine
  • intermediate (215) was prepared starting from 5-bromo-2-chloro-6- fluoro-quinoline and N-methylpiperazine
  • intermediate (216) was prepared starting from 5-Bromo-l-chloro-isoquinoline and morpholine
  • intermediate (217) was prepared starting from 5-Bromo-l-chloro-isoquinoline and ethanolamine
  • intermediate (218) was prepared starting from 5-bromo-2-chloro-6-methoxy-quinoline and morpholine.
  • Oxalyl dichloride (0.002 mol) was added to a suspension of 5-quinolinecarboxylic acid (0.001 mol) in DCM (10 mL). DMF (small drop) was added, and the mixture stirred for 16 hours. The solvent was removed. The residue was dissolved in DCM (10 mL), and intermediate (9) (0.001 mol) and triethylamine added in rapid succession at 0 0 C. Stirring was continued for 4 hours, allowing the temperature to increase to 20 0 C. HCl (0.001 M, 10 mL) was added, and the phases separated. The organic layer was washed with Na 2 CO 3 (aq) (50% saturated), water and brine.
  • the vial was sealed and heated to 150 0 C in a microwave reactor.
  • the resulting mixture was diluted with DCM and washed with water.
  • the organic layer was dried with Na 2 SO 4 , filtered through celite and evaporated in vacuo and purified by high-performance liquid chromatography (eluent: CH 3 CN/H 2 O 10/95 to CH 3 CN/H 2 O 95/5 with 0.1% CF 3 COOH).
  • the product fractions were collected and the solvent was removed by lyophilization (0.05 mg, 25%) to give the title compound as the trifluoroacetate salt.
  • Tables F-I, F-2, F-3 and F-4 lists the compounds that were prepared according to one of the above Examples. Table F-I
  • melting points (m.p.) were determined with a DSC823e (Mettler-Toledo). Melting points were measured with a temperature gradient of 30°C/minute. The reported values are peak values.
  • melting points (m.p.) were determined with a WRS- 2A melting point apparatus that was purchased from Shanghai Precision and Scientific Instrument Co. Ltd. Melting points were measured with a linear heating up rate of 0.2- 5.0°C/minute The reported values are melt ranges. The maximum temperature was 300 0 C.
  • melting points were obtained with a Kofler hot bench, consisting of a heated plate with linear temperature gradient, a sliding pointer and a temperature scale in degrees Celsius.
  • the HPLC measurement was performed using an Alliance HT 2790 (Waters) system comprising a quaternary pump with degasser, an autosampler, a column oven (set at 4O 0 C, unless otherwise indicated), a diode-array detector (DAD) and a column as specified in the respective methods below.
  • Flow from the column was split to a MS spectrometer.
  • the MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 1 second using a dwell time of 0.1 second.
  • the capillary needle voltage was 3 kV and the source temperature was maintained at 140 0 C. Nitrogen was used as the nebulizer gas.
  • Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
  • LCMS General procedure B The LC measurement was performed using an Acquity UPLC (Waters) system comprising a binary pump, a sample organizer, a column heater (set at 55 0 C), a diode- array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.18 seconds using a dwell time of 0.02 seconds. The capillary needle voltage was 3.5 kV and the source temperature was maintained at 140 0 C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
  • the HPLC measurement was performed using an Agilent 1100 module comprising a pump, a diode-array detector (DAD) (wavelength used 220 nm), a column heater and a column as specified in the respective methods below.
  • Flow from the column was split to a Agilent MSD Series G1946C and G1956A.
  • MS detector was configured with API- ES (atmospheric pressure electrospray ionization). Mass spectra were acquired by scanning from 100 to 1000.
  • the capillary needle voltage was 2500 V for positive ionization mode and 3000 V for negative ionization mode. Fragmentation voltage was 50 V. Drying gas temperature was maintained at 350 0 C at a flow of 10 1/min.
  • Reversed phase HPLC was carried out on an Xterra MS Cl 8 column (3.5 ⁇ m, 4.6 x 100 mm) with a flow rate of 1.6 ml/min.
  • Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 1 % A, 49 % B and 50 % C in 6.5 minutes, to 1 % A and
  • Reversed phase HPLC was carried out on an Atlantis C18 column (3.5 ⁇ m, 4.6 x 100 mm) (3.5 ⁇ m, 4.6 x 100 mm) with a flow rate of 1.6 ml/min.
  • Two mobile phases (mobile phase A: 70 % methanol + 30 % H 2 O; mobile phase B: 0.1 % formic acid in H2 ⁇ /methanol 95/5) were employed to run a gradient condition from 100 % B to 5 % B + 95 % A in 12 minutes.
  • An injection volume of 10 ⁇ l was used.
  • Cone voltage was 10 V for positive ionization mode and
  • Reversed phase HPLC was carried out on a YMC- Pack ODS-AQ, 50x2.0 mm 5 ⁇ m column with a flow rate of 0.8 ml/min.
  • Two mobile phases (mobile phase A: water with 0.1 % TFA; mobile phase B: acetonitrile with 0.05 % TFA) were used.
  • 100 % A was hold for 1 minute.
  • a gradient was applied to 70 % A and 30 % B in 4.5 minutes and hold for 2 minutes. Typical injection volumes of 2 ⁇ l were used.
  • Oven temperature was 50 0 C. (MS polarity: positive).
  • Reversed phase HPLC was carried out on a YMC- Pack ODS-AQ, 50x2.0 mm 5 ⁇ m column with a flow rate of 0.8 ml/min.
  • Two mobile phases (mobile phase A: water with 0.1 % TFA; mobile phase B: acetonitrile with 0.05 % TFA) were used.
  • 100 % A was hold for 1 minute.
  • a gradient was applied to 40 % A and 60 % B in 4 minutes and hold for 2.5 minutes. Typical injection volumes of 2 ⁇ l were used.
  • Oven temperature was 50 0 C. (MS polarity: positive).
  • the optical rotation was measured using a Perkin Elmer 341 polarimeter.
  • [ ⁇ ]o 20 indicates the optical rotation measured with light at the wavelength of the D-line of sodium (589 nm) at a temperature of 20 0 C .
  • the cell pathlength is 10 cm. Behind the actual value the concentration and solvent of the solution which was used to measure the optical rotation are mentioned.
  • a ZQ mass spectrometer (Waters, Milford, MA, USA) with an orthogonal Z-electrospray interface is coupled with the SFC-system. Instrument control, data collection and processing were performed with an integrated platform consisting of the SFC ProNTo software and Masslynx software.
  • mobile phase A CO 2
  • mobile phase B one of the solvents mentioned above containing 0.2 % 2-propylamine
  • Extracellular binding of ATP to P2X7 that is expressed in the cell-membrane opens the ligand gated cation channel and allows Ca 2+ entry into the cell. This ligand-induced Ca 2+ flux was measured in 132 INl astrocytoma cells overexpressing hP2X7 for the compounds of the present invention.
  • the calcium assay kit used (Molecular Devices, R8090), provides a Ca 2+ sensitive dye together with a quenching dye. However, no specifications are given by the manufacturer.
  • the kit most likely consists of a membrane permeable acetoxymethyl (AM) ester of a fluorescent Ca 2+ indicator, such as fluo-4 or fluo-3. Upon cellular uptake, the AM esters get cleaved by esterases, liberating the Ca 2+ -sensitive dye which can then bind calcium.
  • the dyes have an absorption spectrum compatible with excitation at 488 nm by argon laser sources and a large fluorescence intensity increase in response to Ca 2+ binding without an accompanying spectral shift. Emission wavelength is in the range of 510-560 nm.
  • the human monocytic cell line THP-I was grown as a suspension culture in RPMI medium supplemented with 10% fetal bovine serum, penicillin/streptomycin (50 units/mL), 2 mM L-glutamine, and 20 ⁇ M 2-mercaptoethanol. Cells were maintained at a density below 0.5 million per mL. On the day of the assay, cells were washed twice with assay buffer, and then resuspended at 2 million per mL in assay buffer containing 2 ⁇ M Yo-Pro-1 (Invitrogen).
  • the assay buffer contained (in mM): 280 sucrose, 5 KCl, 10 glucose, 10 HEPES, 5 N-methyl-D-glucamine.
  • the cells were added at 200k/well into poly-D-lysine- coated black-walled 96-well plates (Biocoat, Becton-Dickinson). Test compounds were dissolved in DMSO, and then added at the test concentration to each well of the 96-well plate. Concentration dependence of block was determined by exposing each well of cells in duplicate rows of a 96-well plate to a serial dilution of test compound. The concentration series usually started at lO ⁇ M with a three-fold decrement in concentration. The final DMSO concentration seen by the cells was less than 0.5%. Cells were incubated with test compounds for 30 minutes at 37°C.
  • a background reading was taken using a Gemini SpectraMax with 490 nm excitation and 530 nm emission. Then, 50 ⁇ L/well of the dye/stimulation buffer containing 2 ⁇ M Yo-Pro-1 and 200 ⁇ M BzATP was added (final concentration seen by the cells was 2 ⁇ M Yo-Pro-1 and 50 ⁇ M BzATP). After incubation for 60 minutes at 37°C, an endpoint read was taken in the SpectraMax plate reader. The amount of block of the response was determined by comparing the fluorescence intensity in each well to the average of control wells on each plate. The control wells contained either a known antagonist of P2X7 (positive controls) or a concentration of DMSO equal to that in the test wells. Data were analyzed using a nonlinear regression program (Origin, OriginLab, MA). Results are reported as the -log of the IC50 (pICso).
  • Table F-IO mean pIC50 values for P2X7 antagonism

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Abstract

The present invention is related to novel compounds of formula (I) having P2X7 antagonistic properties, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds and their use in the treatment or prophylaxis of diseases associated with P2X7 receptor activity in animals, in particular humans. (I)

Description

QUINOLINE OR ISOQUINOLINE SUBSTITUTED P2X7 ANTAGONISTS
The present invention is related to novel compounds of formula (I) having P2X7 antagonistic properties, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds and their use in the treatment or prophylaxis of diseases associated with P2X7 receptor activity in animals, in particular humans.
The P2X7 receptor is a ligand-gated ion channel and is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X7 receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of interleukin-P (IL-I P) and giant cell formation (macrophages/ microglial cells), degranulation (mast cells) and L-selectin shedding (lymphocytes). P2X7 receptors are also located on antigen-presenting cells (APQ, keratinocytes, salivary acinar cells (parotid cells), hepatocytes, erythrocytes, erythroleukaemic cells, monocytes, fibroblasts, bone marrow cells, neurones, and renal mesangial cells.
The P2X7 receptor is also known to be a pain sensor in the nervous system. Experiments using P2X7 deficient mice demonstrate the role of P2X7 in the development of pain as these mice were protected from the development of both adjuvant-induced inflammatory pain and partial nerve ligation induced neuropathic pain.
In view of the clinical importance of P2X7, the identification of compounds that modulate P2X7 receptor function represents an attractive avenue into the development of new therapeutic agents. Such compounds are provided herein.
The present invention relates to a compound of formula (I)
Figure imgf000003_0001
including any stereochemical^ isomeric form thereof, wherein n is an integer 1 , 2 or 3; m is an integer 1, 2 or 3; p is an integer 1 or 2;
R3 is hydrogen, halo, C^alkyl or C^alkyloxy; X represents O, S, SO2, CR4R5 or NR6; wherein R4 and R5 are each independently from another selected from hydrogen, halo, hydroxy, C^alkyl, C^alkyloxy, or aryl; wherein R6 is hydrogen, phenyl, -CO-R7, or -CO-O-R7, wherein R7 is Cμgalkyl or amino;
R1 is a heterocycle selected from pyridinyl or pyrimidinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, C^alkyl, Cμgalkyloxy, polyhaloC^alkyl, phenyl, C3.6cycloalkyl, C3.6cycloalkyloxy, C^gcycloalkylC^alkyloxy, Or NR8R9; wherein R8 and R9 are independently from another selected from hydrogen, Cμgalkyl, hydroxyC^alkyl, C3.6cycloalkyl, and wherein R8 and R9 may be taken together with the nitrogen atom to which they are attached to form a azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from C^alkyl, C^alkyloxy, halo, hydroxy, or C^alkylcarbonyl; R2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, Cμgalkyl, C^alkyloxy, C3.6cycloalkyl, C3.6cycloalkyloxy, polyhaloC1-4alkyl, NR10R11, and OR12; wherein R10 and R11 are independently from another selected from hydrogen, Cμgalkyl, C3_gcycloalkyl, polyhaloC^alkyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, TV-(1 ,5-dioxa-9-aza-spiro[5.5]undec-9-yl), TV-(1 ,7-diaza-spiro[4.4]non-7-yl), TV-(2,6-diaza-spiro[4.5]dec-2-yl), and Cμgalkyl substituted with one or two substituents selected from hydroxy, halo, aryl1, C^alkyloxy, C3_gcycloalkyl, hydroxycarbonyl, C^alkylsulfonylamino, C^gcycloalkylsulfonylamino, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyridinyl, morpholinyl, amino, mono- or di(Ci_4alkyl)amino, amino substituted with C^alkyl substituted with hydroxy; and wherein R10 and R11 may be taken together with the nitrogen atom to which they are attached to form a azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, TV-[l,4]-oxazepanyl, morpholinyl, TV-(2,6-diaza-spiro[3.3]hept- 2-yl), 6-acetyl-2,6-diaza-bicyclo[2.2.2]octane-2-yl, 2-(tetrahydro-furo[3,4- c]pyrrol-5-yl), 2-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl), 1,1-dioxo- thiomorpholin-4-yl, 2-(2,6-diaza-bicyclo[2.2. l]hept-2-yl), l-(l-amino-3- aza-bicyclo[3.1.0]hex-3-yl), 7V-(3-acetylamino-8-aza-bicyclo[3.2.1]oct-8- yl), JV-[l,4]-diazepanyl, 2-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl), 2- (hexahydro-pyrrolo[3,4-b]pyrrol-l-yl), 2-(hexahydro-pyrrolo[3,4- b]pyrrol-5-yl), 2-(octahydro-pyrrolo[3,4-b]pyridin-6-yl), or 2-(3,6-diaza- bicyclo[3.2.0]hept-3-yl), l-amino-3-aza-bicyclo[3.1.0]hex-3-yl ring; which may be optionally substituted with one or two substituents each independently from another selected from halo, hydroxy, C^alkyl, C^alkyloxy, C^alkyloxyC^alkyl, C3.6cycloalkyl, C^alkylcarbonyl,
C^alkyloxycarbonyl, C^alkyloxycarbonylamino, Cμgalkyl substituted with hydroxy; trifluoromethyl, amino, mono- or di(C j_4alkyl)amino, amino, mono- or di(C^_4alkyl)amino, trifluoromethyl, N-(2-oxo- pyrrolidin- 1 -yl), 2,4-dihydro-[ 1 ,2,4]triazolone-5-yl, C\ _4alkylcarbonylamino, 2,4-dihydro-[ 1 ,2,4]triazolone-4-yl,
(C i _4alkylcarbonyl)(C i .4alkyl)amino, trifluoromethylcarbonylamino, hydroxycarbonyl, methylsulfonylamino, aminocarbonyl; wherein R12 is azetidinyl, pyrrolidinyl, piperidinyl, or Cμgalkyl substituted with amino, C3_gcycloalkyl, trifluoromethyl, trifluoroethyl, tetrahydrofuranyl, JV-(I -methylpyrrolidinyl), JV-(5-oxo-pyrrolidin-2-yl), or pyridinyl; aryl is phenyl or phenyl substituted with one substituent selected from halo, C^alkyl,
C^alkyloxy or hydroxy; aryl1 is phenyl or phenyl substituted with one substituent selected from halo, C^alkyl,
C^alkyloxy or hydroxy; or a pharmaceutically acceptable acid addition salt thereof, or a solvate thereof.
As used in the foregoing definitions :
- halo is generic to fluoro, chloro, bromo and iodo;
- Ci-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1 -methyl- ethyl, 2-methylpropyl and the like;
- Ci-6alkyl is meant to include Ci^alkyl and the higher homologues thereof having
5 or 6 carbon atoms, such as, for example, 2-methylbutyl, pentyl, hexyl and the like;
- polyhaloCi_4alkyl is defined as polyhalosubstituted C^alkyl, in particular C^alkyl (as hereinabove defined) substituted with 2 to 6 halogen atoms such as difluoro- methyl, trifluoromethyl, trifluoroethyl, and the like; - A -
- polyhaloCμgalkyl is defined as polyhalosubstituted C^alkyl, in particular Cμgalkyl (as hereinabove defined) substituted with 2 to 6 halogen atoms such as difluoro- methyl, trifluoromethyl, trifluoroethyl, and the like;
- C3-6cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
The absolute stereochemical configuration of the compounds of formula (I) and of the intermediates used in their preparation may easily be determined by those skilled in the art while using well-known methods such as, for example, X-ray diffraction.
Furthermore, some compounds of formula (I) and some of the intermediates used in their preparation may exhibit polymorphism. It is to be understood that the present invention encompasses any polymorphic forms possessing properties useful in the treatment of the conditions noted hereinabove.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are able to form. These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxy acetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, /?-toluenesulfonic, cyclamic, salicylic, /^-aminosalicylic, pamoic and the like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into the free base form. The compounds of formula (I) may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular association comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g. water or ethanol. The term 'hydrate' is used when said solvent is water.
In an embodiment, the present invention concerns compounds of formula (I) wherein n is an integer 1, 2 or 3; m is an integer 1, 2 or 3; p is an integer 1 or 2;
R3 is hydrogen, halo, C^alkyl or C^alkyloxy; X represents O, S, SO2, CR4R5 or NR6; wherein R4 and R5 are each independently from another selected from hydrogen, halo, hydroxy, C^alkyl, C^alkyloxy, or aryl; wherein R6 is hydrogen, phenyl, -CO-R7, or -CO-O-R7, wherein R7 is Cμgalkyl or amino;
R1 is a heterocycle selected from pyridinyl or pyrimidinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, C^alkyl, C^alkyloxy, polyhaloC^alkyl, phenyl, C3_6cycloalkyl, C3_6cycloalkyloxy, C3_6cycloalkylCj_4alkyloxy, Or NR8R9; wherein R8 and R9 are independently from another selected from hydrogen, Cμgalkyl, C3_6cycloalkyl, and wherein R8 and R9 may be taken together with the nitrogen atom to which they are attached to form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from C^alkyl, C^alkyloxy, halo, hydroxy, or C i _4alkylcarbonyl; R2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, Cμgalkyl, Cμgalkyloxy, C3_6cycloalkyl,
C3.6cycloalkyloxy, polyhaloC1-4alkyl, and NR10R11; wherein R10 and R11 are independently from another selected from hydrogen, Cμgalkyl, C3.6cycloalkyl, polyhaloC^alkyl, tetrahydrofuranyl, tetrahydropyranyl, or Cμgalkyl substituted with hydroxy, halo, phenyl, C^alkyloxy, C3.6cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl; and wherein R10 and R11 may be taken together with the nitrogen atom to which they are attached to form a azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, JV-[l,4]-oxazepanyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from halo, hydroxy, C^alkyl,
C^alkyloxy, C^alkyloxyC^alkyl, C3_6cycloalkyl, C i _4alkylcarbonyl, C i _4alkyloxycarbonyl,
C^alkyloxycarbonylamino or C^alkylsubstituted with hydroxy; aryl is phenyl or phenyl substituted with one substituent selected from halo, C1 _4alkyl, C j _4alkyloxy or hydroxy.
Interesting compounds of formula (I) are those compounds of formula (I) wherein one or more of the following restrictions apply : a) R1 is a heterocycle selected from pyridinyl or pyrimidinyl wherein said heterocycle is substituted with one substituent selected from hydrogen, halo, hydroxy, C^alkyl,
Ci_6 alkyloxy, polyhaloC^alkyl or phenyl; or b) R1 is a heterocycle selected from pyridin-3-yl or pyrimidin-5-yl wherein said heterocycle is substituted with one substituent selected from hydrogen, halo, hydroxy, C^alkyl, C^alkyloxy or polyhaloC^alkyl; or c) R1 is a heterocycle selected from pyridin-3-yl or pyrimidin-5-yl wherein said heterocycle is substituted with one substituent selected from hydrogen, halo, hydroxy, methyl, methoxy or trifluoromethyl; or d) R2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, C^alkyl or C^alkyloxy; or e) R2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with NR10R11 wherein R10 and R11 are independently from another selected from hydrogen, Ci_6 alkyl, C3_6cycloalkyl, polyhaloC^alkyl, tetrahydrofuranyl, tetrahydropyranyl, or Ci_6 alkyl substituted with hydroxy, halo, phenyl, C^alkyloxy, C3_6cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl; or f) R2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with NR10R11 wherein R10 and R11 are taken together with the nitrogen atom to which they are attached to form a azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, JV-[l,4]-oxazepanyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from halo, hydroxy, C^alkyl, C^alkyloxy, Cμ4 alkyloxyCμ4 alkyl, C3_6cycloalkyl, C^alkylcarbonyl, C^alkyloxycarbonyl,
C^alkyloxycarbonylamino or C^alkylsubstituted with hydroxy; or g) p is an integer 1 ; or h) R3 is hydrogen, n is an integer 2, m is an integer 2, and X represents O; or i) R3 is hydrogen, n is an integer 2, m is an integer 2, and X represents CR4R5 wherein
R4 and R5 are each independently from another selected from hydrogen or halo; or j) R3 is hydrogen, n is an integer 2, m is an integer 2, and X represents NR6 wherein
R6 is hydrogen, phenyl or -CO-O-R7 wherein R7 is Cμgalkyl; or k) R1 is 2-triflouromethylpyridin-5-yl; or 1) R1 is 2-triflouromethylpyrimidin-5-yl; or m)n is an integer 2, m is an integer 2, and X represents CR4R5 wherein R4 and R5 are each fluoro; or n) n is an integer 1, m is an integer 3, and X represents CR4R5 wherein R4 and R5 are each fluoro; or o) R3 is hydrogen, n is an integer 2, m is an integer 3, and X represents O; or p) R2 is quinoline-5-yl substituted or unsubstituted at the 6-position with Cl, F, OCH3,
CH3, CF3, with or without an additional substituent at the 2-position.
In an embodiment, the present invention relates to a subset of compounds of formula (I) which are defined as compounds of formula (I-a)
Figure imgf000009_0001
including any stereochemically isomeric form thereof, wherein Ra is hydrogen, halo, hydroxy, Ci.galkyl, Ci_6 alkyloxy, polyhaloC^alkyl, phenyl,
C3_6cycloalkyl, C3_6cycloalkyloxy, C3_6CycloalkylCi_4alkyloxy, Or NR8R9; wherein R8 and R9 are independently from another selected from hydrogen,
Ci.galkyl, C3_6cycloalkyl, and wherein R8 and R9 may be taken together with the nitrogen atom to which they are attached to form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from C^alkyl, C^alkyloxy, halo, hydroxy, or
C i _4alkylcarbonyl; R2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, Cμgalkyl, Cμgalkyloxy, C3_gcycloalkyl, C3.6cycloalkyloxy, polyhaloC1-4alkyl, and NR10R11; wherein R10 and R11 are independently from another selected from hydrogen,
Cμgalkyl, C3.6cycloalkyl, polyhaloC^alkyl, tetrahydrofuranyl, tetrahydropyranyl, or Cμgalkyl substituted with hydroxy, halo, phenyl, C^alkyloxy, C3.6cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl; and wherein R10 and R11 may be taken together with the nitrogen atom to which they are attached to form a azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, JV-[l,4]-oxazepanyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from halo, hydroxy, C^alkyl, C^alkyloxy, C^alkyloxyC^alkyl, C3_6cycloalkyl,
C i _4alkylcarbonyl, C i _4alkyloxycarbonyl,
C^alkyloxycarbonylamino or C^alkylsubstituted with hydroxy; R3 is hydrogen, halo, C^alkyl or C^alkyloxy; X represents O or CR4 R5; wherein R4 and R5 are each independently from another selected from hydrogen, halo, hydroxy, C^alkyl, C^alkyloxy, or aryl; aryl is phenyl or phenyl substituted with one substituent selected from halo, C^alkyl, C^alkyloxy or hydroxy; or a pharmaceutically acceptable acid addition salt thereof, or a solvate thereof.
Compounds of formula (I) can generally be prepared by reacting an intermediate of formula (II) with an intermediate of formula (III), in at least one reaction-inert solvent and optionally in the presence of at least one suitable coupling reagent and/or a suitable base, the said process further optionally comprising converting a compound of formula (I) into an addition salt thereof, and/or preparing stereochemically isomeric forms thereof.
Figure imgf000010_0001
(H) (HI) It may be convenient to activate the carboxylic acid of formula (III) by adding an effective amount of a reaction promoter. Non- limiting examples of such reaction promoters include carbonyldiimidazole, Λ^iV-dicyclohexyl-carbodiimide or l-(3- dimethylaminopropy l)-3 -ethylcarbodiimide, hydroxybenzotriazole, benzotriazolyl- oxytris (dimethylamino)-phosphonium hexafluorophosphate, tetrapyrrolidino- phosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate, or a functional derivative thereof, such as disclosed by D. Hudson, J.Org.Chem. (1988), 53:617.
Compounds of formula (I) can also be prepared by JV-acylation an intermediate of formula (II) with an intermediate of formula (IV), wherein W is an appropriate leaving group such as, for example, halo, e.g. fluoro, chloro, bromo, iodo, or in some instances W may also be a sulfonyloxy group, e.g. methanesulfonyloxy, trifluoromethane- sulfonyloxy, benzenesulfonyloxy and the like reactive leaving groups. The reaction can be performed in a reaction-inert solvent such as, for example, acetonitrile, dimethyl acetamide, JV-methyl-pyrrolidone or DMF, and optionally in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and the reflux temperature of the reaction mixture.
Figure imgf000011_0001
(H) (IV)
The compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.
For instance
• compounds of formula (I) wherein the heterocycle R2 is substituted with halo can be JV-alkylated with H-NR10R11 to obtain compounds of formula (I) wherein the heterocycle R2 is substituted with NR10R11 using art-known JV-alkylation procedures;
• compounds of formula (I) wherein the heterocycle R2 is substituted with halo can be converted into the corresponding compounds of formula (I) wherein said halo is replaced by Cμgalkyloxy or C3_gcycloalkyloxy by treatment with a strong base and an alcohol; • compounds of formula (I) wherein the heterocycle R2 is substituted with a
NR10R11 substituent bearing a C^alkyloxycarbonyl group may be converted into their corresponding compounds of formula (I) wherein said C^alkyloxycarbonyl group is removed by hydrolysis under acid conditions.
Other examples of art-known group transformation reactions to converted compounds of formula (I) into other compounds of formula (I) are hydrolysis of carboxylic esters to the corresponding carboxylic acid or alcohol; hydrolysis of amides to the corresponding carboxylic acids or amines; alcohols may be converted into esters and ethers; primary amines may be converted into secondary or tertiary amines; double bonds may be hydrogenated to the corresponding single bond.
The starting materials and some of the intermediates are known compounds and are commercially available or may be prepared according to conventional reaction procedures generally known in the art.
The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. Those compounds of formula (I) that are obtained in racemic form may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifϊcally. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The compounds of formula (I), the pharmaceutically acceptable salts and stereoisomeric forms thereof possess P2X7 receptor antagonizing properties as demonstrated in the Pharmacological Example D.I. Therefore the present compounds of formula (I) are useful as a medicine especially in the treatment of a condition or disease mediated by the P2X7 receptor, in particular P2X7 receptor antagonistic activity. Subsequently the present compounds may be used for the manufacture of a medicine for treatment of a condition or a disease mediated by P2X7 receptor activity, in particular P2X7 receptor antagonistic activity.
The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of conditions or diseases selected from P2X7 receptor mediated conditions or diseases.
In an embodiment, the present invention provides a compound of formula (I) for use as a medicine or for use in the treatment of conditions or diseases selected from P2X7 receptor mediated conditions or diseases.
Further, the present invention also provides a method of treatment of a condition mediated by P2X7 receptor activity, in a mammalian subject, which method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
P2X7 receptor mediated conditions or disorders are e.g. rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, hyperresponsiveness of the airway, chronic obstructive pulmonary disease (COPD), bronchitis, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, neurodegenerative disease, Alzheimer's disease, multiple sclerosis, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke, peripheral vascular disease, varicose veins, glaucoma, bipolar disorder, and neuropathic pain conditions such as diabetic neuropathy, post-herpatic neuralgia, low back pain, chemotherapy-induced neuropathic pain, fibromyalgia and spinal cord injury pain.
The term "treating" and "treatment", as used herein, refers to curative, palliative and prophylactic treatment, including reversing, alleviating, inhibiting the progress of, or preventing the disease, disorder or condition to which such term applies, or one or more symptoms of such disease, disorder or condition.
Additionally the present invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I).
In order to prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with at least one pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for oral administration, rectal administration, percutaneous administration or parenteral injection.
For example in preparing the compositions in oral dosage form, any of the usual liquid pharmaceutical carriers may be employed, such as for instance water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid pharmaceutical carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral injection compositions, the pharmaceutical carrier will mainly comprise sterile water, although other ingredients may be included in order to improve solubility of the active ingredient. Injectable solutions may be prepared for instance by using a pharmaceutical carrier comprising a saline solution, a glucose solution or a mixture of both. Injectable suspensions may also be prepared by using appropriate liquid carriers, suspending agents and the like. In compositions suitable for percutaneous administration, the pharmaceutical carrier may optionally comprise a penetration enhancing agent and/or a suitable wetting agent, optionally combined with minor proportions of suitable additives which do not cause a significant deleterious effect to the skin. Said additives may be selected in order to facilitate administration of the active ingredient to the skin and/or be helpful for preparing the desired compositions. These topical compositions may be administered in various ways, e.g., as a transdermal patch, a spot-on or an ointment. Addition salts of the compounds of formula (I), due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the pharmaceutical compositions of the invention in dosage unit form for ease of administration and uniformity of dosage. "Dosage unit form" as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
For oral administration, the pharmaceutical compositions of the present invention may take the form of solid dose forms, for example, tablets (both swallowable and chewable forms), capsules or gelcaps, prepared by conventional means with pharmaceutically acceptable excipients and carriers such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like), fillers (e.g. lactose, microcrystalline cellulose, calcium phosphate and the like), lubricants (e.g. magnesium stearate, talc, silica and the like), disintegrating agents (e.g. potato starch, sodium starch glycollate and the like), wetting agents (e.g. sodium laurylsulphate) and the like. Such tablets may also be coated by methods well known in the art.
Liquid preparations for oral administration may take the form of e.g. solutions, syrups or suspensions, or they may be formulated as a dry product for admixture with water and/or another suitable liquid carrier before use. Such liquid preparations may be prepared by conventional means, optionally with other pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous carriers (e.g. almond oil, oily esters or ethyl alcohol), sweeteners, flavours, masking agents and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
Pharmaceutically acceptable sweeteners useful in the pharmaceutical compositions of the invention comprise preferably at least one intense sweetener such as aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose (4,r,6'-trichloro-4,r,6'-trideoxygalactosucrose) or, preferably, saccharin, sodium or calcium saccharin, and optionally at least one bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey. Intense sweeteners are conveniently used in low concentrations. For example, in the case of sodium saccharin, the said concentration may range from about 0.04% to 0.1% (weight/volume) of the final formulation. The bulk sweetener can effectively be used in larger concentrations ranging from about 10% to about 35%, preferably from about 10% to 15% (weight/volume) . The pharmaceutically acceptable flavours which can mask the bitter tasting ingredients in the low-dosage formulations are preferably fruit flavours such as cherry, raspberry, black currant or strawberry flavour. A combination of two flavours may yield very good results. In the high-dosage formulations, stronger pharmaceutically acceptable flavours may be required such as Caramel Chocolate, Mint Cool, Fantasy and the like. Each flavour may be present in the final composition in a concentration ranging from about 0.05% to 1% (weight/volume). Combinations of said strong flavours are advantageously used. Preferably a flavour is used that does not undergo any change or loss of taste and/or color under the circumstances of the formulation.
The compounds of formula (I) may be formulated for parenteral administration by injection, conveniently intravenous, intra-muscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or multi-dose containers, including an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as isotonizing, suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be present in powder form for mixing with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
The compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter and/or other glycerides. Those of skill in the treatment of diseases linked to the mediation of the cannabinoid receptors will easily determine the therapeutically effective amount of a compound of formula (I) from the test results presented hereinafter. In general it is contemplated that a therapeutically effective dose will be from about 0.001 mg/kg to about 50 mg/kg of body weight, more preferably from about 0.01 mg/kg to about 10 mg/kg of body weight of the patient to be treated. It may be appropriate to administer the therapeutically effective dose in the form of two or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example each containing from about 0.1 mg to about 1000 mg, more particularly from about 1 to about 500 mg, of the active ingredient per unit dosage form.
As used herein, a "therapeutically effective amount" of a compound, is the quantity of a compound which, when administered to an individual or animal, results in a sufficiently high level of that compound in the individual or animal to cause a discernible P2X7 receptor antagonistic response. The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as the other medication, the patient may be taking, as is well known to those skilled in the art. Furthermore, said "therapeutically effective amount" may be lowered or increased depending on the response of the treated patient and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.
Experimental part
In the procedures described hereinafter the following abbreviations were used: 'MeOH' means methanol, 'DCM' means dichloromethane, 'CH3CN' means acetonitrile, 'DIPE' means diisopropyl ether, 'DIPEA' means diisopropylethylamine, 'MgSO4' means magnesium sulphate, 'Na2SO4' means sulfuric acid disodium salt, 'Na2CO3' means carbonic acid disodium salt, 'THF' means tetrahydrofuran, 'EtOH' means ethanol, 'DMF' means Λ/,Λ/-dimethylformamide, 'CF3COOH' means trifluoroacetic acid, 'H2SO4' means sulfuric acid, 'KOAc' means potassium acetate, 'NH3' means ammonia, 'NaBH4' means sodium borohydride, 'NH4Cl' means ammonium chloride, 'NaOH' means sodium hydroxide, and 'NaHCO3' means carbonic acid sodium salt (1 :1).
Some compounds have been isolated by resolving a mixture of two enantiomers into its individual enantiomers using chiral column chromatography whereby one of the isolated individual enantiomers is indicated with R* (or S*) and its mirror image indicated with S* (or R*). These compounds indicated with R* or S* are single enantiomers of unknown absolute configuration.
The absolute stereochemical configuration for some of the compounds was determined using vibrational circular dichroism (VCD). A description on the use of VCD for the determination of absolute configuration can be found in Dyatkin A.B. et. al, Chirality, 14:215-219 (2002). A. Synthesis of the intermediates Example A.1
a) Preparation of intermediate (1)
Figure imgf000018_0001
4,4-Difluoropiperidine hydrochloric acid salt (0.0286 mol) was dissolved in water (35 ml) and converted into its free base by treatment with a solution of NaHCO3 (2.4 g, 0.0286 mol) in water (10 ml). The mixture was stirred for 30 minutes at room temperature. THF (23 ml) was added at room temperature. 6-(Trifluoromethyl)-3- pyridinecarboxaldehyde (0.0286 mol) and 4-methylbenzene-sulfonic acid (0.030 mol) were added and the mixture was stirred for 30 minutes. A solution of sodium cyanide (0.0286 mol) in water (15 ml) was added slowly and dropwise. The reaction mixture was heated to 700C, then stirred overnight at 700C. The mixture was cooled to room temperature, then poured out into a 10% aqueous K2CO3 solution (150 ml). This mixture was extracted with DCM (2 x 100 ml). The organic layers were combined, washed with a 10% aqueous NaHCO3 solution (3 x 100 ml), dried (Na2SO4), filtered and the solvent was evaporated, yielding 5.9 g of intermediate (1).
b) Preparation of intermediate (2)
Figure imgf000018_0002
A mixture of intermediate (1) (0.045 mol) in NH3/CH3OH was hydrogenated at 14°C with Raney Nickel as a catalyst in the presence of a thiophene solution (1 ml; 4 % in DIPE). After uptake of hydrogen (two equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in DCM. The organic solution was washed with an aqueous 1 % Na2CO3 solution. The organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified on a silica gel tube. The impurities were eluted with DCM/MeOH (98/2) and the product was eluted with DCM/(MeOH/NH3) (90/10). The product fractions were collected and the solvent was evaporated, yielding 12.2 g of intermediate (2).
Using an analogous procedure as described in steps a) and b) intermediate (19) was prepared starting from 6-(trifluoromethyl)-3-pyridinecarboxaldehyde and 4-phenyl- piperidine, intermediate (20) was prepared starting from 6-(trifluoromethyl)-3- pyridinecarboxaldehyde and 4-phenyl-piperazine, and intermediate (22) was prepared starting from 1 -methyl- lH-imidazo Ie -2-carboxaldehyde and 4,4-difluoropiperidine hydrochloride.
Figure imgf000019_0003
Example A.2
a) Preparation of intermediate (3 a)
Figure imgf000019_0001
Water (10 ml) and hydrochloric acid (IN, 2 drops) were added to a mixture of 4,4- difluoropiperidine hydrochloride acid salt (0.025 mol) in ethanol (15 ml). 6-Bromo-3- pyridinecarboxaldehyde (0.025 mol) was added portionwise and the mixture was stirred for 30 minutes. Then, the mixture was cooled in an ice-bath. Sodium cyanide (0.025 mol) in water (5 ml) was added dropwise and the mixture was stirred for 1 hour at room temperature. The mixture was stirred overnight at 500C. The mixture was cooled in an ice-bath while it was stirred. The precipitate was filtered off and washed with water. The precipitate was purified by column chromatography (eluent: DCM/MeOH 99/1). The product fractions were collected and crystallized from DIPE. The precipitate was filtered off and dried, yielding 2.8 g of intermediate (3a).
b) Preparation of intermediate (3b)
Figure imgf000019_0002
A mixture of intermediate (3a) (0.009 mol) in a solution of ammonia in methanol (150 ml) was hydrogenated at 14°C with Raney nickel (1 g) as a catalyst in the presence of a thiophene solution (1 ml). After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in DCM and was washed with a 1% Na2CO3 solution. The organic layer was separated, dried and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/MeOH 80/20). The product fractions were collected and the solvent was evaporated, yielding 0.320 g of intermediate (3b).
Using an analogous procedure as described in steps a) and b) intermediate (4) was prepared starting from 2-chloro-3-pyridinecarboxaldehyde, intermediate (5) was prepared from 3,3-difluoropyrrolidine hydrochloride and 6-(trifluoromethyl)-pyridine- 3-carboxaldehyde, intermediate (6) was prepared from 3,3-difluoroazetidine hydrochloride and 6-(trifluoromethyl)-pyridine-3-carboxaldehyde, intermediate (7) was prepared from l-(tert-butyloxycarbonyl)piperazine and 6-(trifiuoromethyl)-pyridine-3- carboxaldehyde; intermediate (8) was prepared starting from 3-pyridinecarboxaldehyde, intermediate (9) was prepared from β-chloro-S-pyridinecarboxaldehyde and 4,4-difluoropiperidine hydrochloride, intermediate (12) was prepared from 2-benzo- furancarboxaldehyde and 4,4-difiuoropiperidine hydrochloride.
Figure imgf000020_0002
Example A.3
a) Preparation of intermediate (10)
Figure imgf000020_0001
NaHCO3 (0.006 mol) in water was added to a mixture of 4,4-difluoropiperidine hydrochloric acid salt (0.006 mol) in water (5 ml). The reaction mixture was stirred for 30 minutes. Then 3-furancarboxaldehyde (0.006 mol) and 4-methylbenzenesulfonic acid (0.006 mol) in THF (6 ml) were added and the reaction mixture was stirred for 30 minutes. Sodium cyanide (0.0072 mol) in water (3 ml) was added slowly and the reaction mixture was heated at 700C for 16 hours. The reaction mixture was cooled and poured into a 10% aqueous NaHCO3 solution. The reaction mixture was extracted with DCM. The organic layer was separated, washed with water, dried with MgSO4, filtered and the solvent was evaporated, yielding 1 g of intermediate (10).
b) Preparation of intermediate (11)
Figure imgf000021_0001
Lithium aluminum tetrahydride (0.012 mol) was added to a mixture of intermediate (10) (0.0044 mol) in THF (10 ml) at 00C. The reaction mixture was stirred below 5°C for 3 hours. Water was added to terminate the reaction. The precipitate was filtered off and the filtrate was extracted with DCM. The organic layer was separated, dried with Na2SO4, filtered and the solvent was evaporated, yielding 0.56 g of intermediate (11).
Using an analogous procedure as described in steps a) and b) intermediate (13) was prepared starting from 3-thiophenecarboxaldehyde and 4,4-difluoro-piperidine hydrochloride, intermediate (14) was prepared starting from 5-methyl-2- furancarboxaldehyde and 4,4-difluoro-piperidine hydrochloride, and intermediate (15) was prepared starting from 5-methyl-2-thiophene-carboxaldehyde and 4,4-difluoro- piperidine hydrochloride.
Figure imgf000021_0002
Example A.4
a) Preparation of intermediate (16)
Figure imgf000022_0001
Trimethylsilanecarbonitrile (0.006 mol) was added slowly to a mixture of 4,4-difluoro- piperidine hydrochloride (0.006 mol) and 2-pyridinecarboxaldehyde (0.006 mol) in acetic acid (6 ml), while the reaction temperature was kept below 100C. The reaction mixture was stirred overnight and aqueous ammonia (3 M) was added until the pH turned 10. The reaction mixture was extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 1.2 g of intermediate (16).
b) Preparation of intermediate (17)
Figure imgf000022_0002
A 4% thiophene solution in DIPE (0.06 ml) was added to a mixture of intermediate
(16) (0.00166 mol) in NHs/MeOH (12 ml), while the mixture was stirred in an ice bath. Raney Nickel (0.5 g) was added at 00C and the reaction mixture was stirred for 16 hours, under hydrogen flow. The catalyst was filtered off and the filtrate was evaporated to dryness, yielding 0.250 g of intermediate (17).
Using an analogous procedure as described in steps a) and b) intermediate (18) was prepared starting from 6-(trifluoromethyl)-3-pyridinecarboxaldehyde and piperidine hydrochloride, intermediate (21) was prepared starting from 6-(trifluoromethyl)-3- pyridinecarboxaldehyde and 4-(4-chlorophenyl)-4-piperidinol, intermediate (23) was prepared starting from 6-(trifluoromethyl)-3-pyridinecarboxaldehyde and morpholine, intermediate (24) was prepared starting from 6-(trifluoromethyl)-3-pyridine-carbox- aldehyde and 1,1-dioxo-l-thio-morpholine, intermediate (25) was prepared starting from 2-(trifluoromethyl)-5-pyrimidinecarboxaldehyde and 4,4-difluoro-piperidine hydrochloride, intermediate (26) was prepared starting from 6-(trifluoromethyl)-3- pyridinecarboxaldehyde and 4-(aminocarbonyl)piperidine, intermediate (27) was prepared starting from 2-(trifluoromethyl)-5-pyrimidinecarboxaldehyde and piperidine, intermediate (28) was prepared starting from 2-(trifluoromethyl)-5-pyrimidine- carboxaldehyde and morpholine, intermediate (31) was prepared starting from 2-(trifluoromethyl)-5-pyrimidinecarboxaldehyde and pyrrolidine, intermediate (32) was prepared starting from 2-(trifluoromethyl)-5-pyrimidinecarboxaldehyde and homopiperidine, intermediate (33) was prepared starting from 2-(trifluoromethyl)-5- pyrimidinecarboxaldehyde and 2-piperazinone, intermediate (34) was prepared starting from 2-(trifluoromethyl)-5-pyrimidinecarboxaldehyde and 3,3-difluoropiperidine hydrochloride, intermediate (35) was prepared starting from 2-(trifluoromethyl)-5- pyrimidinecarboxaldehyde and 3-fluoropiperidine hydrochloride, intermediate (36) was prepared starting from 2-(trifluoromethyl)-5-pyrimidinecarbox-aldehyde and 2- methylmorpholine, intermediate (37) was prepared starting from 2-(trifluoromethyl)-5- pyrimidinecarboxaldehyde and 2-methylpiperidine, intermediate (38) was prepared starting from 2-(trifluoromethyl)-5-pyrimidinecarboxaldehyde and 1 ,4-oxazepane hydrochloride, intermediate (39) was prepared starting from 2-methyl-5-pyrimidine- carboxaldehyde and 4,4-difluoropiperidine hydrochloride, intermediate (40) was prepared starting from 2-(trifluoromethyl)-5-pyrimidinecarboxaldehyde and 3-methoxypiperidine hydrochloride, intermediate (55) was prepared starting from 2-methyl-5-pyrimidinecarboxaldehyde and morpholine, intermediate (53) was prepared starting from 2-(trifluoromethyl)-5-pyrimidinecarboxaldehyde and 4-fluoropiperidine hydrochloride, and intermediate (54) was prepared starting from 2-methoxy-5- pyrimidine-carboxaldehyde and 4,4-difluoropiperidine hydrochloride.
Figure imgf000023_0001
Figure imgf000024_0003
Example A.5
a) Preparation of intermediate (29)
Figure imgf000024_0001
Phosphoryl chloride (10 ml) was added into a mixture of 2-oxy-quinoline-5-carboxylic acid methyl ester (0.03 mol) in 1 ,2-dichloro-ethane (10 ml). The reaction mixture was stirred at 800C overnight. The reaction mixture was quenched with water and extracted with DCM. The organic layer was separated, dried with Na2SO4, filtered and the solvent was evaporated, yielding 6 g of intermediate (29).
b) Preparation of intermediate (30)
Figure imgf000024_0002
Lithium hydroxide (100 ml) was added into a mixture of intermediate (29) (0.027 mol) in MeOH (50 ml). The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated under vacuum and aqueous HCl (2M) was added dropwise into the residue. The precipitate was filtered off and the residue was purified by preparative high-performance liquid chromatography. The product fractions were collected and the solvent was evaporated, yielding intermediate (30).
Example A.6 diate
diate
Figure imgf000025_0001
Intermediate (25) (2 g) was separated in its enantiomers with preparative SFC purification. SFC was carried out on a Chiralpak AD-H column (30 x 250 mm) (Daicel Chemical Industries Ltd): eluent CCVOnethanol containing 0.2 % 2-propylamine) 75/25 was hold for 10 minutes; flow rate 50 ml/min; column heater temperature 400C; nozzle pressure 100 bar; load: 55 mg / 1.5 ml. 2 Peaks were obtained and collected. The first peak was concentrated to dryness and was solidified by drying in the oven under vacuum, yield 0.8 g of intermediate (41). The second peak was concentrated to dryness and was solidified by drying in the oven under vacuum, yielding 0.8 g of intermediate (42).
Example A.7
a) Preparation of intermediate (43)
Figure imgf000025_0002
5-Bromo-2-chloro-quinoline (0.02 mol) and l-(tert-butyloxycarbonyl)piperazine (0.06 mol) in l-methyl-2-pyrrolidinone (10 ml) were stirred for 2 hours at 1000C. The reaction mixture was poured into 150 ml water, a solid was formed, filtered off, washed and dried. Then the solid was taken up in hot diisopropylether, cooled and filtered off, washed and dried, yielding 4.6 g of intermediate (43). b) Preparation of f- intermediate (43 a)
Figure imgf000026_0001
A mixture of intermediate (43) (0.0117 mol), Pd(OAc)2 (0.02 g), l,3-bis(diphenyl- phosphino)-propane (0.08 g), triethylamine (5 ml) and THF/MeOH (3:1) (80 ml) was reacted under 50 atmosphere CO gas pressure at 125°C for 16 hours in an autoclave. The reaction mixture was cooled and the solvent evaporated. The residue was taken up in DCM and washed with Brine. The organic layer was dried (MgSO4), filtered and evaporated. The residue was suspended in hot diisopropylether , filtered off, washed and dried, yielding 3.45g of intermediate (43a).
c) Preparation of intermediate (44)
Figure imgf000026_0002
Intermediate (43a) (0.0011 mol) was stirred in THF/MeOH (2:1) (3 ml) and water (2 ml). Lithium hydroxide (0.0022 mol) was added at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The organic solvents were removed by evaporation. Water (5 ml) was added and HCl IN was added dropwise until pH is 3 to 4. A precipitate was formed. The precipitate was filtered off, washed and dried to give a light brown solid, yielding 0.28 g of intermediate (44).
Example A.8 a) Preparation of intermediate (45)
Figure imgf000026_0003
5-Bromo-2-chloro-quinoline (0.0220 mol) and morpholine (0.1 mol) were shaken in a closed tube at 1000C for 2 hours. The reaction mixture was poured into water, a solid was formed, filtered off, washed and dried, yielding 5.9 g of intermediate (45).
b) Preparation of intermediate (45a)
Figure imgf000026_0004
A mixture of intermediate (45) (0.02 mol), Pd(OAc)2 (0.02 g), l,3-bis(diphenyl- phosphino)-propane (0.08 g), triethylamine (5 ml) and THF/MeOH (3:1) (80 ml) was reacted under 50 atmosphere CO gas pressure at 125°C for 16 hours in an autoclave. The reaction mixture was cooled and the solvent evaporated. The residue was taken up in DCM and washed with Brine. The organic layer was dried (MgSO4), filtered and evaporated. The residue was suspended in hot diisopropylether, filtered off, washed and dried, yielding 4.45 g of intermediate (45a).
c) Preparation of intermediate (46)
Figure imgf000027_0001
Intermediate (45a) (0.016 mol) was stirred in THF/MeOH (2:1) (100 ml) and water (50 ml). Lithium hydroxide (0.032 mol) was added at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The organic solvents were removed by evaporation. Water (50 ml) was added and the impurities were extracted with DCM. The water layer was acidified by adding HCl IN until pH is 3 to 4. A precipitate was formed. The precipitate was filtered off, washed and dried, yielding 3.12 g of intermediate (46) .
Example A.9
a) Preparation of intermediate (47)
Figure imgf000027_0002
5-Bromo-2-chloro-quinoline (0.02 mol) and 3-amino-l-propanol (20 ml) were stirred for 4 hours at 800C. The reaction mixture was diluted with water and extracted with DCM twice. The combined organic layers were once washed with water, then dried over MgSO4, filtered and evaporated. The residue was crystallised in isopropylether with 2% acetonitrile. The crystals were collected by filtration and dried in vacuum, yielding 2.97 g of intermediate (47).
b) Preparation of intermediate (48)
Figure imgf000027_0003
A mixture of intermediate (47) (2.9 g), Pd(OAc)2 (0.02 g), l,3-bis(diphenylphosphino)- propane (0.08 g), triethylamine (5 ml), THF (40 ml) and methanol (10 ml) was reacted under 50 atmosphere CO gas pressure at 125°C for 16 hours in an autoclave. After reaction, the solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate (3x). The combined organic layers were washed with water (twice), dried over MgSO4, filtered and the solvent was evaporated. The residue was crystallised in isopropylether. The precipitate was filtered and dried in vacuum, yielding 1.25 g of intermediate (48). c) Preparation of intermediate (49)
Figure imgf000028_0001
Intermediate (48) (0.002 mol) and dioxane (16 ml) were stirred at room temperature. Lithium hydroxide hydrate (0.0025 mol) and water (4 ml) were added dropwise. The reaction mixture was stirred at 500C for 4 hours and stirring was continued at room temperature overnight. The reaction mixture was evaporated, redissolved in water and neutralised with IN HCl. The precipitate was filtered and dried in vacuum, yielding 0.45 g of intermediate (49).
Example A.10
a) Preparation of intermediate (50)
Figure imgf000028_0002
5-Bromo-2-chloroquinoline and cyclopropanamine were stirred for 5 days in a closed vessel at 600C. The reaction mixture was evaporated and the residue was crystallised in CH3CN. The precipitate was filtered and dried in vacuum, yielding 9.3 g (88%) of intermediate (50).
b) Preparation of intermediate (51)
Figure imgf000028_0003
Intermediate (50) (36.5 mmol), methanol, palladium diacetate (0.2 mmol), 1,3-bis- (diphenylphosphino)propane (0.4 mmol), triethylamine (10 ml) in THF were stirred under 50 atm CO at 125°C for 16 hours. The reaction mixture was filtered over dicalite and the filtrate was evaporated. The residue was purified over silica gel (DCM/MeOH 100/0 to 98/2). The corresponding fractions were evaporated. The first residue was triturated in isopropylether, the precipitate filtered and dried in vacuum, yielding 1.95 g of intermediate (51).
c) Preparation of intermediate (52)
Figure imgf000028_0004
Intermediate (51) (8 mmol) and dioxane (40 ml) were stirred at room temperature while lithium hydroxide hydrate (16.1 mmol), dissolved in demineralised water (20 ml) was added dropwise. Stirring was continued overnight at room temperature. The reaction was evaporated and redissolved in 50 ml water. This solution was neutralised with IN HCl while stirring. After 4 hours stirring the precipitate was filtered and dried in vacuum, yielding 1580 mg of intermediate (52).
Example A.11
Preparation of intermediate (56)
Figure imgf000029_0001
Intermediate (30) (3.0 g, 0.013 mol) was suspended in DCM (100 ml; anhydrous). First ethanedioyl dichloride (9.0 g, 0.072 mol) and then DMF (3 drops) were added. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, yielding 3.1 g of intermediate (56).
Example A.12 a) Preparation of JL Ji J intermediate (57)
' O N
Reaction under nitrogen atmosphere. Sodium (0.00026 mol) was added to ethanol (300 ml) at O0C. The mixture was stirred at ambient temperature until the solid was dissolved completely. Intermediate (83) (0.0929 mol) was added with stirring until the temperature of the mixture was cooled down to ambient temperature. The trifluoro- methanesulfonate salt of isopropyl imidocarbamate (0.0872 mol) was added with stirring. The reaction mixture was stirred at ambient temperature overnight and the solvent was evaporated in vacuo. The residue was dispersed in water (300 ml). The mixture was extracted with DCM (2 x 200 ml). The organic layers were combined, washed with a saturated aqueous NaCl solution (200 ml). The separated organic fraction was dried over Na2 S 04, filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 10/1, v/v). The product fractions were collected and the solvent was evaporated. The residue was dried in vacuo, yielding 6.5 g of intermediate (57).
b) Preparation of intermediate (58)
Figure imgf000029_0002
A mixture of intermediate (57) (0.0120 mol), trimethylethynylsilane (0.0240 mol), morpholine (0.0144 mol) and sodium acetate (0.0180 mol) in acetic acid (30 ml) was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo. The solvent was evaporated in vacuo. Water (50 ml) was added. The mixture was alkalized with solid NaOH to pH 10. The resulting precipitate was collected by filtration and washed with water (3 x 50 ml). The precipitate was filtered off and dried in vacuo, yielding 2.5 g of intermediate (58).
c) Preparation of intermediate (59)
Figure imgf000030_0001
A mixture of crude intermediate (58) (0.0095 mol) dissolved in a mixture of methanol saturated with ammonia (7N, 20 ml) and THF (100 ml) was hydrogenated at ambient temperature under hydrogen atmosphere with Raney nickel (4 g) as a catalyst in the presence of hydrogen overnight. After uptake of hydrogen (2 equivalents), the catalyst was filtered off. The filtrate was evaporated, yielding 2.3 g of intermediate (59).
Example A.13
a) Preparation of intermediate (60)
Figure imgf000030_0002
A mixture of intermediate (57) (0.0120 mol), trimethylsilyl cyanide (0.0240 mol), 4,4-difluoropiperidine hydrochloride (0.0144 mol) and sodium acetate (0.0180 mol) in acetic acid (30 ml) was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo. The solvent was evaporated in vacuo. Water (50 ml) was added. The mixture was basified with solid NaOH to pH 10. The resulting precipitate was collected by filtration and washed with water (3 x 50 ml). The precipitate was collected and dried in vacuo, yielding 3.7 g of intermediate (60).
b) Preparation of intermediate (61)
Figure imgf000030_0003
A mixture of intermediate (60) (0.0125 mol) dissolved in a mixture of methanol saturated with ammonia (7N, 20 ml) and THF (100 ml) was hydrogenated at ambient temperature under hydrogen atmosphere with Raney nickel (6 g) as a catalyst in the presence of hydrogen overnight. After uptake of hydrogen (2 equivalents), the catalyst was filtered off. The filtrate was evaporated , yielding 3.5 g of intermediate (61). Example A.14
a) Preparation of intermediate (62)
Figure imgf000031_0001
A mixture of 2-ethyl-5-pyrimidinecarboxaldehyde (0.0235 mol), morpholine (0.0282 mol), trimethylsilyl cyanide (0.047 mol) and sodium acetate (0.0294 mol) in acetic acid (50 ml) was stirred at room temperature overnight. The reaction mixture was filtered and the solvent was evaporated. The residue was dissolved in water, alkalized with NaHCO3 until pH 8 and extracted twice with ethyl acetate. The organic layers were combined, dried, filtered and the filtrate's solvent was evaporated, yielding 4.8 g of intermediate (62).
b) Preparation of intermediate (63)
Figure imgf000031_0002
A mixture of intermediate (62) (0.0207 mol), Raney nickel (9.6 g) and methanol saturated with ammonia (7N, 10 ml) in methanol (60 ml) was hydrogenated at room temperature overnight. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The crude residue was purified by high- performance liquid chromatography over Cl 8 (eluent: CH3CN/water from 25/75 to 55/45 with 0.1% NH3). The pure fractions were collected and the solvent was evaporated, yielding 2.7 g of intermediate (63).
Example A.15
a) Preparation of intermediate (64)
Figure imgf000031_0003
A mixture of 2-(l-piperidinyl)-5-pyrimidinecarboxaldehyde (0.00314 mol), trimethylsilyl cyanide (0.00628 mol), 4,4-difluoropiperidine hydrochloride (0.00377 mol) and sodium acetate (0.00408 mol) in acetic acid (15 ml) was stirred at room temperature. The reaction mixture was evaporated under reduced pressure. The residue was stirred in water (20 ml). The aqueous phase was treated with NaHCO3 until pH 8. This mixture was extracted with DCM (3 x 30 ml). The separated organic layer was dried (Na2SO4), filtered and the solvent was evaporated, yielding 1.0 g of intermediate (64).
b) Preparation of intermediate (65)
Figure imgf000032_0001
A mixture of intermediate (64) (0.00311 mol), Raney nickel (2.0 g) as a catalyst and methanol saturated with ammonia (7N, 5 ml) in ethanol (30 ml) was hydrogenated at room temperature (atmospheric pressure). After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by preparative high-performance liquid chromatography over YMC (150 x 30 mm; C 18; eluent: CH3CN/water from 16/84 to 46/54 with 0.1% CF3COOH). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in MeOH and converted into the hydrochloric acid salt by using HCl/l,4-dioxane (40 ml). The precipitate was filtered off and dried by evaporation of remaining solvent, yielding 0.45 g of intermediate (65).
Example A.16
a) Preparation of intermediate (66)
Figure imgf000032_0002
A mixture of 2-ethoxy-5-pyrimidinecarboxaldehyde (0.01314 mol), trimethylsilyl cyanide (0.02628 mol), morpholine (0.01445 mol) and sodium acetate (0.01577 mol) in acetic acid (20 ml) was stirred at room temperature. The reaction mixture was evaporated under reduce pressure. Water (30 ml) was added to resulting residue. The aqueous phase was basified with NaHCO3 till pH was 8, extracted with DCM (40ml, 3 times). The separated organic layer was dried (Na2SO4), filtered, evaporated, yielding 3.5 g of intermediate (66).
b) Preparation of intermediate (67)
Figure imgf000032_0003
. 2HCl A mixture of intermediate (66) (0.01410 mol), Raney nickel (6 g) as a catalyst and methanol saturated with ammonia ( 7N, 10 ml) in THF (60 ml) was hydrogenated at room temperature (atmospheric pressure). After uptake hydrogen (2 equivalents), the catalyst was filtered off. The residue was evaporated to give 3.4 g crude product. The crude product was purified by preparative high-performance liquid chromatography over YMC (150*30 mm) (C18, eluent: CH3CN / water from 5/ 95 to 20/ 80 with 0.1% CF3COOH ). The desired fraction was collected and evaporated. The residue was dissolved in methanol and converted into the hydrochloric acid salt by using 1 ,A- dioxane HCl (40 ml). The residue was evaporated, yielding 2.0 g of intermediate (67).
Example A.17
a) Preparation of intermediate (68)
Figure imgf000033_0001
A mixture of 2-(l-methylethyl)-5-pyrimidinecarboxaldehyde (0.01332 mol), trimethylsilyl cyanide (0.02664 mol), morpholine (0.01465 mol) and sodium acetate (0.01598 mol) in acetic acid (20 ml) was stirred at room temperature. The reaction mixture was evaporated under reduce pressure. Water (30 ml) was added to the resulting residue. The aqueous phase was basified with NaHCO3 till pH was 8, extracted with DCM (40ml, 3 times). The separated organic layer was dried (Na2SO4), filtered, evaporated, yielding 3.3 g of intermediate (68).
b) Preparation of intermediate (69)
Figure imgf000033_0002
A mixture of intermediate (68) (0.01340 mol), Raney nickel (6 g) as a catalyst and methanol saturated with ammonia (7N) in THF (60 ml) was hydrogenated at room temperature (atmospheric pressure). After uptake of hydrogen (2 equivalents), the catalyst was filtered off. The residue was evaporated to give 3.3 g crude product. The crude product was purified by preparative high-performance liquid chromatography over YMC (150*30 mm) (C18, eluent: CH3CN / H2O from 15/ 85 to 30/ 70 with 0.1% CF3COOH ). The desired fraction was collected and evaporated. The residue was dissolved in methanol and converted into the hydrochloric acid salt by using dioxane HCl (40 ml). The residue was evaporated to give the final product, yielding 2.9 g of intermediate (69).
Example A.18
a) Preparation of intermediate (70)
Figure imgf000034_0001
Pyrrolidine (0.041237 mol)) was added to chloroquinoline (0.041237 mol)). A vigorous exotherm warmed the reaction solution to boiling point. A reflux condenser was attached, and the solution stirred for 16 hours at 200C. The bulk of the pyrrolidine was removed by rotary evaporation, and the residue taken up in Na2CO3 (50% aqueous) / DCM. The phases were separated, and the organic layer washed with NaCl (50% saturated). The organic layer was dried (Na2SO4) and the solvent removed. Azeotroped with phenylmethyl, yielding 12 g of intermediate (70).
b) Preparation of intermediate (71)
Figure imgf000034_0002
A 75 -ml stainless steal autoclave was charged under nitrogen atmosphere with intermediate (70) (0.043296 mol), palladium acetate (0.00433 mol, 1.3 bis(diphenyl- phosphino) propane (0.0866 mol) and potassium acetate (0.86593 mol) in MeOH/ THF 1/1 (40 ml). The autoclave was closed and pressurized to 50 bar CO and the reaction was carried out for 16 hours at a temperature of 1000C, yielding intermediate (71).
c) Preparation of intermediate (72)
Figure imgf000034_0003
Intermediate (71) was converted to intermediate (72) using the methodology of Example A.5.
Example A.19
a) Preparation of /^N IT N *0 intermediate (73)
2-(Methylthio)pyrimidine-5-carboxaldehyde (0.01193 mol) and pyrrolidine (0.02983 mol) were dissolved in ethanol. The mixture was reacted in a steal-tube at 9O0C overnight. The reaction mixture was evaporated under reduced pressure. The residue was purified by column (silica gel, eluent: petroleum ether/ethyl acetate =20:1). The pure fractions were collected and the solvent was evaporated, yielding 1.56 g of intermediate (73).
Preparation of intermediate (74)
Figure imgf000035_0001
A mixture of intermediate (73) (0.0088 mol), trimethylsilyl cyanide (0.1760 mol), 4,4-difluoropiperidine hydrochloride (0.1056 mol) and sodium acetate (0.1144 mol) in acetic acid (20 ml) was stirred at room temperature. The reaction mixture was evaporated under reduced pressure. The residue was added water (20ml). The aqueous phase was acidified to pH=8 with NaHCO3, extracted with DCM (30ml -3 times), the separated organic layer was dried (Na2SO4), filtered and evaporated, yielding 2.4 g of intermediate (74).
c) Preparation of intermediate (75)
Figure imgf000035_0002
A mixture of intermediate (74) (0.0078 mol) and Raney nickel (6 g) as a catalyst in methanol saturated with ammonia (7N, 17 ml) was hydrogenated at room temperature (atmospheric pressure). After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by preparative high-performance liquid chromatography over YMC (250*20 mm) (C 18, eluent: CH3CN / water from 2 / 98 to 32/ 68with 0.1% CF3COOH ). The desired fraction was collected and evaporated. The residue was acidified to pH=5 with HCl/dioxane. The residue was evaporated, yielding 2.4 g of intermediate (75).
Example A.20
a) Preparation of intermediate (76)
Figure imgf000035_0003
A mixture of carbamimidothioic acid, methyl ester, sulfate (2:1) (0.118 mol), 1-acetyl- piperazine (0.094 mol) and NaOH (6 g) in water (100 ml) was stirred at 8O0C for 5 hours. On cooling, enough ethanol (400 ml) was added. The precipitate was filtered off. The filtrate was collected and evaporated under reduced pressure, yielding 15 g of intermediate (76).
b) Preparation of intermediate (77)
Figure imgf000036_0001
Sodium (6 g) was dispersed in ethanol (200 ml). After sodium was completely dissolved, intermediate (76) and intermediate (83) were added. The mixture was stirred at ambient temperature overnight. Solid was filtered off. The filtrate was collected and evaporated under reduced pressure. Then reside was added to DCM (200 ml) and washed with water (200 ml, four times). The resulting organic layer was dried over Na2SO4 and evaporated. The residue was purified with column chromatography (silica gel, eluent: MeOH/DCM=l/30 v/v). The pure fraction was collected and the solvent was evaporated, yielding 2 g of intermediate (77).
c) Preparation of intermediate (78)
Figure imgf000036_0002
A mixture of intermediate (77) (0.0085 mol), 4,4-difluoropiperidine hydrochloride (0.01 mol), trimethylsilyl cyanide (0.017 mol) and sodium acetetate (0.011 mol) in acetic acid (20 ml) was stirred at ambient temperature overnight. Solvent was removed under reduced pressure. Water (50 ml) was added to above residue and basified with NaHCO3 till pH was 8. DCM was added and extracted (50 ml, three times). The organic lay was combined and evaporated under reduced pressure, yielding 3 g of intermediate (78) and was used directly in the next reaction.
d) Preparation of intermediate (79)
Figure imgf000036_0003
A mixture of intermediate (78) (0.0082 mol), Raney nickel (6 g) as a catalyst and methanol saturated with ammonia (7N, 15 ml) in THF (100 ml) was hydrogenated at ambient temperature (atmospheric pressure) overnight. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and filtrate was collected and evaporated under reduced pressure. The residue was purified with high performance liquid chromatography, (eluent: 0.5% CF3COOH in water/ CH3CN 45/55 v/v). The desired fraction was collected and evaporated under reduced pressure. The residue was dissolved in DCM (50 ml) and converted into the hydrochloric acid salt (1 :2) with HCl/dioxane. The solvent was removed under reduced pressure, yielding. 2 g of intermediate (79).
Example A.21 a) Preparation of intermediate (80)
Figure imgf000037_0001
Sodium (2.3 g) was dissolved in ethanol (150 ml). JV-cyclopropyl- guanidine, sulfate (2:1) (0.0337 mol) and intermediate (83) (0.0674 mol) were added. The reaction mixture was stirred at room temperature overnight. The mixture was evaporated under reduced pressure. The residue was dissolved in water (50 ml) and extracted with DCM (50 ml, three times). The organic layer was collected and evaporated under reduced pressure. The crude product was purified by column (silica gel, eluent: Petroleum ether/ethyl acetate 3/1). The pure fractions were collected and the solvent was evaporated, yielding 3.6 g of intermediate (80).
b) Preparation of intermediate (81)
Figure imgf000037_0002
A mixture of intermediate (80) (0.01599 mol), trimethylsilyl cyanide (0.03198 mol), 4,4-difluoropiperidine hydrochloride (0.01759 mol) and sodium acetate (0.01919 mol) in acetic acid (100 ml) was stirred at room temperature. The reaction mixture was evaporated under reduced pressure. Water (60ml) was added to resulting residue. The aqueous phase was basified with NaHCO3 till pH was 8, extracted with DCM (50ml*3), the separated organic layer was dried (Na2SO4), filtered, evaporated, yielding 4.4 g of intermediate (81). c) Preparation of intermediate (82)
Figure imgf000038_0001
A mixture of intermediate (81) (0.015 mol), Raney nickel (8g) as a catalyst and methanol saturated with ammonia (7N, 25 ml) in THF (150 ml) was hydrogenated at room temperature (atmospheric pressure). After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by preparative high-performance liquid chromatography over YMC (150*30 mm) (C 18, eluent: CH3CN /water from 16/ 84 to 46/ 54 with 0.1% CF3COOH ). The desired fraction was collected and evaporated. The residue was dissolved in MeOH and converted into the hydrochloric acid salt by using 1,4-dioxane HCl (40 ml). The residue was evaporated, yielding 2.O g (40%) of intermediate (82).
Example A.22
a) Preparation of intermediate (83)
Figure imgf000038_0002
Phosphoric trichloride (2.1 mol) was added slowly into DMF (850 ml) at O0C and maintaining the internal temperature between 5 and 1O0C. The mixture was stirred for 2 hours. 2-bromo- acetic acid (0.72 mol) was added and the mixture was heated to 9O0C overnight. The solution was cooled to room temperature. The slurry was poured into isopropanol (400 ml) at 0 0C with stirring. Water (30 ml) was added drop wise at O0C. The slurry was diluted with isopropanol (300 ml) and isopropanyl acetate (300 ml) was added dropwise with stirring. The precipitate was collected by filtration and washed with CH3CN (300 ml). The residue was dried under reduced pressure, yielding 170 g of intermediate (83).
b) Preparation of intermediate (84)
Figure imgf000038_0003
A mixture of intermediate (83) (0.1115 mol), carbonic acid, compd. with guanidine (1 :2) (0.0555 mol) and Na2CO3 (18 g) in ethanol (200 ml) was refluxed at 8O0C overnight. The reaction mixture was filtrated, dried (Na2SO4) and evaporated, yielding 12.2 g of crude intermediate (84). c) Preparation of intermediate (85)
Figure imgf000039_0001
A mixture of intermediate (84) (0.02437 mol), trimethylsilyl cyanide (0.04873 mol), 4,4-difluoropiperidine hydrochloride (0.02681 mol) and sodium acetate (0.02924 mol) in acetic acid (80 ml) was stirred at room temperature. The reaction mixture was evaporated under reduced pressure. Water (30 ml) was added to resulting residue. The aqueous phase was basifϊed with NaHCO3 till pH was 8, extracted with DCM (40ml, three times), the separated organic layer was dried (Na2SO4), filtered, evaporated, yielding 1.86 g of intermediate (85).
d) Preparation of intermediate (86)
Figure imgf000039_0002
A mixture of intermediate (85) (0.00395 mol), Raney nickel (2g) as a catalyst and methanol saturated with ammonia (7N, 5 ml) in ethanol (30 ml) was hydrogenated at room temperature (atmospheric pressure). After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by preparative high-performance liquid chromatography over YMC (250*20 mm) (C 18, eluent: CH3CN / water from 8/ 92 to 18/ 82with 0.1% CF3COOH ). The desired fraction was collected and evaporated. The residue was acidified to pH = 5 with HCl/dioxane. The residue was evaporated, yielding.0.9 g of intermediate (86).
Example A.23 a) Preparation of intermediate (87)
Figure imgf000039_0003
Sodium (2.8 g) was dissolved in ethanol (300 ml). 2-Methylpropionamidine hydrochloride (0.08157 mol) and intermediate (83) (0.08157 mol) were added. The reaction mixture was stirred at room temperature overnight. The mixture was evaporated under reduce pressure. The residue was dissolved in water (50 ml) and extracted with DCM (50 ml, three times). The organic layer was collected and evaporated under reduce pressure. The crude product was purified by column (silica gel, eluent: Petroleum ether/ethyl acetate 10/1 V /V). The pure fractions were collected and the solvent was evaporated, yielding 6.0 g of intermediate (87). b) Preparation of intermediate (88)
Figure imgf000040_0001
A mixture of intermediate (87) (0.01998 mol), trimethylsilyl cyanide (0.03996 mol), 4,4-difluoropiperidine hydrochloride (0.02198 mol) and sodium acetate (0.02398 mol) in acetic acid (30 ml) was stirred at room temperature overnight. The reaction mixture was evaporated under reduce pressure. Water (50 ml) was added to the resulting residue. The aqueous phase was basifϊed with NaHCO3 till pH was 8 and extracted with DCM (40ml, three times). The separated organic layer was dried (Na2SO4), filtered, evaporated, yielding 5.2 g of intermediae (88).
c) Preparation of intermediate (89)
Figure imgf000040_0002
A mixture of intermediate (88) (0.01855 mol), Raney nickel (10 g) as a catalyst and methanol saturated with ammonia (7N, 10 ml) in THF (60 ml) was hydrogenated at room temperature (atmospheric pressure). After uptake of hydrogen (2 equivalents), the catalyst was filtered off. The residue was evaporated to give the final product, yielding
4.9 g of intermediate (89).
Example A.24
a) Preparation of intermediate (90)
Figure imgf000040_0003
Sodium (5.8 g) was dissolved in ethanol (300 ml). Cyclopentanecarboximidamide monohydrochloride (0.16819 mol) and intermediate (83) (0.16819 mol) were added. The reaction mixture was stirred at room temperature overnight. The mixture was evaporated under reduce pressure. The residue was dissolved in water (50 ml) and extracted with DCM (50 ml, three times). The organic layer was collected and evaporated under reduce pressure. The crude product was purified by column (silica gel, eluent : petroleum ether/ethyl acetate 10/1 Y /V). The pure fraction was collected and evaporated under reduce pressure, yielding 6.0 g of intermediate (90). b) Preparation of intermediate (91)
Figure imgf000041_0001
A mixture of intermediate (90) (0.01702 mol), trimethylsilyl cyanide (0.03404 mol), 4,4-difluoropiperidine hydrochloride (0.01872 mol) and sodium acetate (0.02042 mol) in acetic acid (30 ml) was stirred at room temperature. The reaction mixture was evaporated under reduce pressure. Water (30 ml) was added to the resulting residue. The aqueous phase was basifϊed with NaHCO3 till pH was 8, extracted with DCM (40ml, three times), the separated organic layer was dried (Na2SO4), filtered, evaporated, yielding 3.86 g of intermediate (91).
c) Preparation of intermediate (92)
Figure imgf000041_0002
A mixture of intermediate (91) (0.0126 mol), Raney nickel (7 g) as a catalyst and methanol saturated with ammonia (7N, 6 ml) in THF (40 ml) was hydrogenated at room temperature (atmospheric pressure). After uptake of hydrogen (2 equivalents), the catalyst was filtered off. The solvent was evaporated, yielding 4.1 g of crude intermediate (92).
Example A.25
a) Preparation of intermediate (93)
Figure imgf000041_0003
A mixture of 2-(4-morpholinyl)-5-pyrimidinecarboxaldehyde (6.6 g), 4,4-difluoropiperidine hydrochloride (0.0213 mol), trimethylsilyl cyanide (0.0647 mol), and sodium acetate (2.6 g) in acetic acid (120 ml) was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuum. The residue was dissolved in water (100 ml). The aqueous solution was basified with NaHCO3 to pH = 10. The aqueous was extracted by DCM (200ml, three times). The separated organic layers was dried over Na2SO4 and filtered off. The filtrate was concentrated in vacuum, yielding 4.8 g of intermediate (93).
b) Preparation of intermediate (94)
Figure imgf000042_0001
A mixture of intermediate (93) (4.8 g) and methanol saturated with ammonia (7N, 40 ml) in ethanol (350 ml) was hydrogenated at ambient temperature under hydrogen atmosphere with Raney nickel (10 g) as a catalyst in the presence of H2 overnight. After uptake of hydrogen (2 equivalents), the catalyst was filtered off. The filtrate was evaporated in vacuum to afford the crude product. The crude product was purified by high-performance liquid chromatography (C 18, eluent: CH3CN /water from 10 / 90 to 40/ 60 with 0.1% CF3COOH). The fraction was concentrated in vacuum. The residue was dissolved in methanol and converted into the hydrochloric acid salt by HCl in using 1, 4-dioxane (150 ml), yielding 2.5 g of intermediate (94).
Example A.26
a) Preparation of intermediate (95)
Figure imgf000042_0002
A mixture of 2-(dimethylamino)-5-pyrimidinecarboxaldehyde (0.0331 mol), trimethylsilyl cyanide (0.0662 mol), 4,4-difluoropiperidine hydrochloride (0.0397 mol), and sodium acetate (0.0496 mol) in acetic acid (50 ml) was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuum. The residue was dissolved in water (300 ml). The aqueous solution was basified with NaHCO3 to pH = 10. The aqueous was extracted by DCM (300 ml, three times). The separated organic layers was dried over Na2SO4 and filtered off. The filtrate was concentrated in vacuum, yielding 7.5 g of intermediate (95).
b) Preparation of intermediate (96)
Figure imgf000042_0003
.2 HCl A mixture of intermediate (95) (7.5 g) and methanol saturated with ammonia (7N, 50 ml) in THF (300 ml) was hydrogenated at ambient temperature under hydrogen atmosphere with Raney nickel (10 g) as a catalyst in the presence of hydrogen overnight. After uptake of hydrogen (2 equivalents), the catalyst was filtered off. The filtrate was evaporated.in vacuum to afford the crude product. The crude product was purified by high-performance liquid chromatography (C 18, eluent: CH3CN / water from 10 / 90 to 40/ 60 with 0.1% CF3COOH). The fraction was concentrated in vacuum. The residue was dissolved in MeOH and converted into the hydrochloric acid salt by using 1,4-dioxane HCl (150 ml), yielding 3.5 g of intermediate (96).
Example A.27
a) Preparation of intermediate (97)
Figure imgf000043_0001
A mixture of 2-(l-pyrrolidinyl)-5-pyrimidinecarboxaldehyde (0.0169 mol), morpholine (0.0203 mol), trimethylsilyl cyanide (0.0508 mol) and sodium acetate (0.15 g) in acetic acid (45 ml) was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuum. The residue was dissolved in water (100 ml). The aqueous solution was basified with NaHCO3 to pH=10. The aqueous was extracted by DCM (200ml, three times). The separated organic layers was dried over Na2SO4 and filtered off. The filtrate was concentrated in vacuum, yielding 3.5 g of crude intermediate (97).
b) Preparation of intermediate (98)
Figure imgf000043_0002
A mixture of intermediate (97) (3.5 g) and methanol saturated with ammonia (50 ml) in THF (100 ml) and methanol (200 ml) was hydrogenated at ambient temperature under hydrogen atmosphere with Raney nickel (9 g) as a catalyst in the presence of hydrogen overnight. After uptake of hydrogen (2 equivalents), the catalyst was filtered off. The filtrate was evaporated in vacuum to afford the crude product. The crude product was purified by high-performance liquid chromatography (C 18, eluent: CH3CN / water from 10 / 90 to 40/ 60 with 0.1% CF3COOH). The fraction was concentrated in vacuum. The residue was dissolved in methanol and converted into the hydrochloric acid salt by using HCl in 1, 4-dioxane (150 ml), yielding 3 g of intermediate (98). Example A.28 a) Preparation of intermediate (99)
Figure imgf000044_0001
Sodium (8 g) was added to ethanol (300 ml) at O0C under nitrogen atmosphere. The mixture was stirred at ambient temperature until the solid was dissolved completely. Intermediate (83) (0.1432 mol) was added with stirring until the temperature of the mixture was cooled down to ambient temperature. Carbamimidic acid, cyclopropylmethyl ester 1,1,1-trifluoro-methanesulfonate (0.0946 mol) was added with stirring. The reaction mixture was stirred at ambient temperature overnight. The solvent was evaporated in vacuum. The residue was dispersed in water (300 ml). The mixture was extracted with DCM (300 ml*2). The combined organic fraction was washed with saturated brine aqueous (200 ml). The separated organic fraction was dried over Na2SO4 and the solvent was evaporated in vacuum. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate = 10 / 1, v / v). The pure fraction was collected and the solvent was evaporated in vacuum. The residue was dried in vacuum, yielding 15.O g of intermediate (99).
b) Preparation of intermediate (100)
Figure imgf000044_0002
A mixture of intermediate (99) (0.0112 mol), 4,4-difluoropiperidine hydrochloride (0.0135 mol), trimethylsilyl cyanide (0.0224 mol), and sodium acetate (0.0169 mol) in acetic acid (30 ml) was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuum. The solvent was evaporated in vacuum. Water (50 ml) was added. The mixture was basified with solid NaOH to pH=10. The resulting precipitate was collected by filtration and washed with water (50 ml, three times). The precipitate was collected and dried in vacuum, yielding.3.2 g of intermediate (100).
c) Preparation of intermediate (101)
Figure imgf000044_0003
A mixture of intermediate (100) (3.2 g) and methanol saturated with ammonia (7N, 20 ml) in THF (100 ml) was hydrogenated at ambient temperature under hydrogen atmosphere with Raney nickel (6 g) as a catalyst in the presence of hydrogen overnight. After uptake of hydrogen (2 equivalents), the catalyst was filtered off. The filtrate was evaporated in vacuum to afford the crude product, yielding 3.0 g of intermediate (101)
Example A.29
a) Preparation of intermediate (102)
Figure imgf000045_0001
A mixture of intermediate (87) (0.01323 mol), trimethylsilyl cyanide (0.02646 mol), morpholine (0.01455 mol) and sodium acetate (0.01588 mol) in acetic acid (20 ml) was stirred at room temperature. The reaction mixture was evaporated under reduce pressure. Water (30 ml) was added to resulting residue. The aqueous phase was basified with NaHCO3 till pH was 8, extracted with DCM (40 ml, three times). The separated organic layer was dried (Na2SO4), filtered, evaporated, yielding 3.3 g of intermediate (102).
b) Preparation of intermediate (103)
Figure imgf000045_0002
A mixture of intermediate (102) (0.01334 mol), Raney nickel (6 g) as a catalyst and methanol saturated with ammonia (7N, 10 ml)in THF (60 ml) was hydrogenated at room temperature (atmospheric pressure). After uptake of hydrogen (2 equivalents), the catalyst was filtered off. The residue was evaporated to give 3.0 g crude product. The crude product was purified by preparative high-performance liquid chromatography over YMC (150*30 mm) (C18, eluent: CH3CN /water from 15/ 85 to 25/ 75 with 0.1% CF3COOH ). The desired fraction was collected and evaporated. The residue was dissolved in MeOH and converted into the hydrochloric acid salt by using 1 ,4-dioxane HCl (40 ml). The residue was evaporated to give the final product, yielding 1.8 g of intermediate (103). Example A.30
a) Preparation of intermediate (104)
Figure imgf000046_0001
A mixture of 2-ethyl-5-pyrimidinecarboxaldehyde (0.0235 mol), 4,4-difluoropiperidine hydrochloride (0.0282 mol), trimethylsilyl cyanide (0.047 mol) and sodium acetate (0.0294 mol) in acetic acid (50 ml) was stirred at room temperature overnight. Then the mixture was filtered and the solvent was evaporated. The residue was dissolved in water, basified with NaHCO3 to pH = 8 and extracted by ethyl acetate twice. The combined organic phase was dried, filtered and concentrated to give the desired product, yielding 5.O g of intermediate (104).
b) Preparation of intermediate (105)
Figure imgf000046_0002
A mixture of intermediate (104) (0.0188 mol), Raney nickel (10 g) and methanol saturated with ammonia (7N, 10 ml) in methanol (60 ml) was hydrogenated at room temperature overnight. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated, yielding 4.4 g of intermediate (105).
Example A.31 a) Preparation of V^ OJL NJ intermediate (106)
Sodium (8.2 g) was added to ethanol (500 ml) at O0C under nitrogen atmosphere. The mixture was stirred at ambient temperature until the solid was dissolved completely. Intermediate (83) (0.2378 mol) was added with stirring until the temperature of the mixture was cooled down to ambient temperature. The trifluoro-methanesulfonate salt of cyclobutyl imidocarbamate (0.1189 mol) was added with stirring. The reaction mixture was stirred at ambient temperature overnight. The solvent was evaporated in vacuum. The residue was dispersed in water (500 ml). The mixture was extracted with DCM (200 ml, 3 times). The combined organic fraction was washed with saturated brine aqueous (200 ml). The separated organic fraction was dried over Na2SO4 and the solvent was evaporated in vacuum. The residue was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate = 10 / 1). The pure fraction was collected and the solvent was evaporated in vacuum. The product was dried in vacuum to yield the corresponding product as white solid, yielding 16.6 g of intermediate (106).
b) Preparation of intermediate (107)
Figure imgf000047_0001
A mixture of intermediate (106) (0.0112 mol), 4,4-difluoropiperidine hydrochloride (0.0127 mol), trimethylsilyl cyanide (0.0224 mol), and sodium acetate (0.0146 mol) in acetic acid (30 ml) was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuum. The solvent was evaporated in vacuum. Water (50 ml) was added. The mixture was basified with solid NaOH to pH = 10. The resulting precipitate was collected by filtration and washed with water (50 ml, three times). The precipitate was collected and dried in vacuum to afford the crude product, yielding 3.0 g of crude intermediate (107).
c) Preparation of intermediate (108)
Figure imgf000047_0002
A mixture of intermediate (107) (3 g crude) and methanol saturated with ammonia (7N, 20 ml) in THF (100 ml) was hydrogenated at ambient temperature under hydrogen atmosphere with Raney nickel (10 g) as a catalyst in the presence of hydrogen overnight. After uptake of hydrogen (2 equivalents), the catalyst was filtered off. The filtrate was evaporated in vacuum to afford the crude product, yielding 3.0 g of crude intermediate (108).
Example A.32
intermediate a) Preparation of
Figure imgf000047_0003
Bromine (5.2 mL, 101 mmol) was added dropwise over a period of 30 min. to 2,6-dichloroquinoline (20 g, 101 mmol) and aluminum chloride (40 g, 303 mmol) at 120 0C. The resulting mixture was stirred at 120 0C for 1 hour, cooled to rt and methanol/water (1 : 1 v:v, 150 mL) was slowly added. The methanol was removed under reduced pressure and the resulting slurry was extracted with DCM. The organic phases were combined, washed with saturated aqueous sodium bicarbonate, dried with Na2SO4, filtered, concentrated and purified by flash column chromatography (30-100% DCM in hexanes) to provide the desired product (23 g, 83%). 1H NMR (500 MHz, CDCl3) δ 8.51 (dd, J= 8.9, 0.7, IH), 7.92 (dd, J= 9.0, 0.7, IH), 7.76 (dd, J= 8.9, 4.2, IH), 7.49 (d, J= 8.6, IH). diate a) Preparation of
Figure imgf000048_0001
To a solution of intermediate (200) (20.0 g, 72.3 mmol) in THF (200 mL) at 0 0C was added dropwise 2 M isopropylmagnesium chloride in THF (36.5, 72.9 mmol). The reaction mixture was stirred for 30 min. and anhydrous CO2 was gently bubbled through the reaction mixture, which was kept at 0 0C, for 60 min. The reaction mixture was poured into water and extracted with EtOAc. The organic phases were combined, dried with Na2SO4, filtered and concentrated to provide the desired product (13 g, 74%). 1H NMR (500 MHz, DMSO) δ 14.40 (s, IH), 8.29 (dd, J= 8.9, 0.7, IH), 8.07 (dd, J= 9.0, 0.7, IH), 7.94 (d, J= 9.0, IH), 7.74 (d, J= 8.9, IH).
Using an analogous procedure as described in steps a) and b) intermediate (202) was prepared starting from 6-methyl-2-chloroquinoline and intermediate (203) was prepared starting from 6-chloroquinoline.
Figure imgf000048_0003
Intm. (202): 1H NMR (500 MHz, DMSO) δ 13.84 (s, IH), 8.59 (d, J= 8.9, OH), 8.33 (d, J= 8.9, IH), 7.96 (d, J= 8.7, IH), 7.75 (d, J= 8.7, IH), 7.64 (d, J= 8.9, IH). Intm. (203): 1H NMR (500 MHz, DMSO) δ 14.24 (s, IH), 9.01 (dd, J= 4.2, 1.5, IH), 8.24 (dd, J= 7.9, 0.7, IH), 8.13 (d, J= 9.0, IH), 7.87 (d, J= 9.0, IH), 7.69 (dd, J= 8.6, 4.2, IH).
Example A.33
a) Preparation of intermediate (204)
Figure imgf000048_0002
To a mixture of 2-trifluoromethyl-pyrimidine-5-carbaldehyde (8.8 g, 0.049 mol), 4,4- difluoropiperidine hydrochloric acid salt (8.3 g, 0.052 mol), and sodium acetate (6.1 g, 0.075 mol) in acetic acid (35 mL) was added trimethylsilylcyanide (13.6 mL, 0.099 mol). The resulting solution was allowed to stir for 12h at rt. The resulting mixture was concentrated, then neutralized with saturated aqueous sodium bicarbonate to pH 7- 8, partitioned between H2O (100 mL), and CH2Cl2 (75 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting orange solid was used without purification (6.9 g, 45%). MS (ESI): mass calcd. for Ci2HnF5N4, 306.1; m/z found, 305.1 [M-H]. 1H NMR (CDCl3) δ 9.09 (d, J= 7.5, 2H), 5.03 (s, IH), 2.86 - 2.63 (m, 4H), 2.21 - 1.97 (m, 4H).
Using an analogous procedure as described in steps a) intermediate (205-207) were prepared starting from either 2-trifluoromethyl-pyrimidine-5-carbaldehyde or 2- methylsulfanyl-pyrimidine-5-carbaldehyde and 4,4-difluoropiperidine hydrochloride or morpholine, or piperdine respecively.
Figure imgf000049_0002
Example A.34
a) Preparation of intermediate (208)
Figure imgf000049_0001
A mixture of (4,4-difluoro-piperidin- 1 -yl)-(2-trifluoromethyl-pyrimidin-5-yl)- acetonitrile (6.0 g, 0.019 mol) and 7N ammonia in MeOH (6 mL) in MeOH (60 mL) was hydrogenated with Raney Nickel as a catalyst at rt. After uptake of hydrogen (two equivalents), the catalyst was filtered off and the filtrate was evaporated. The resulting oil was used without purification (5.9 g, 98%). MS (ESI): mass calcd. for Ci2Hi5F5N4, 310.1; m/z found, 311.2 [M+H]+ . 1H NMR (CD3OD) δ 8.94 (d, J= 9.3, 2H), 3.78 (t, J = 6.7, IH), 3.22 (dd, J= 13.3, 7.2, IH), 2.99 (dd, J= 13.3, 6.3, IH), 2.67 - 2.48 (m, 4H), 2.07 - 1.94 (m, 4H).
Using an analogous procedure as described in steps a) intermediates (27) and (28) were prepared.
Figure imgf000050_0003
Example A.35
a) Preparation of intermediate (209)
Figure imgf000050_0001
To a solution of (4,4-difluoro-piperidin-l-yl)-(2-methylsulfanyl-pyrimidin-5-yl)- acetonitrile (2.6 g, 9.0 mmol) and CH2Cl2 (100 mL) at -60 0C was added diisobutylaluminum hydride (18 mL, 1 M in CH2Cl2) dropwise. After Ih, the resulting solution was warmed to 0 0C over 3 h and quenched with 30% aqueous Rochelle salt (50 mL). The resulting mixture was stirred vigorously at rt for 1 h. After which time, organic layer separated and the aqueous layer was extracted (CH2Cl2 x 50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel using CH2Cl2-MeOH (10% NH3 solution) to afford an orange oil (1.2g, 46%). MS (ESI): mass calcd. for Ci2Hi8F2N4S, 288.1; m/z found, 289.1 [M+H]+. 1H NMR (CD3OD) δ 8.50 (s, 2H), 3.66 (dd, J= 8.4, 6.0, IH), 3.24 (dd, J= 13.1, 8.4, IH), 2.93 - 2.84 (m, 2H), 2.64 - 2.53 (m, 5H), 2.49 - 2.38 (m, 2H), 2.05 - 1.84 (m, 5H).
Example A.36
Preparation of intermediate (210)
Figure imgf000050_0002
a) 5 -Bromo-6-fluoro- 1 -hydroxy-quinolinium. To a stirred solution of 5-bromo-6- fluoro-quinoline (1.1 g, 4.87 mmol) in DCM (25 niL) was added 3-chloroperoxy- benzoic acid (1.00 g, 5.839 mmol) in portions. The mixture was heated in a 45 0C oil bath for 16h. The reaction was cooled to r.t. and sodium thiosulfate was added (10 mL) followed by saturated sodium hydrogen carbonate (30 mL). The mixture was extracted with DCM (3 X 50 mL), the organic layers combined, dried with Na2SO4, filtered and evaporated in vacuo to afford a white solid (986 mg, 84%) which was used without further purification. MS (electrospray): mass calculated for CgH6BrFNO, 241.96; m/z found 243.2, [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.79 (dd, J= 9.6, 5.1, IH), 8.52 (d, J= 6.1, IH), 8.06 (dd, J= 8.8, 0.7, IH), 7.51 (ddd, J= 17.7, 9.7, 6.2, IH), 7.43 (dd, J= 8.8, 6.1, 1H).
Preparation of intermediate (211)
Figure imgf000051_0001
b) 5-Bromo-2-chloro-6-fluoro-quinoline. To a stirred solution of 5-bromo-6-fluoro-l- hydroxy-quinolinium (1.1 g, 4.53 mmol) in DCM (23 mL) was added phosphorous oxychloride (0.82 mL, 9.05 mmol). The mixture was heated in a 45°C oil bath for 4 h, cooled to r.t. and evaporated to dryness in vacuo. The residue was partitioned between DCM (100 mL) and saturated sodium hydrogen carbonate (100 mL). The organic layer was dried with Na2SO4, filtered, evaporated in vacuo and purified by silica gel chromatography (EtOAc/hexanes) to obtain a pale pink solid (815 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J= 8.9, IH), 8.01 (dd, J= 9.3, 5.0, IH), 7.60 - 7.45 (m, 2H).
Preparation of intermediate (212)
Figure imgf000051_0002
c. 5-Bromo-6-fluoro-2-morpholin-4-yl-quinoline. A solution of 5-bromo-2-chloro-6- fluoro-quinoline (0.20 g, 0.77 mmol) and morpholine (0.27 mg, 3.07 mmol) in NMP (0.8 mL) was heated in a heating block at 120 0C in a sealed microwave vial for 16h. The reaction was cooled to rt and partitioned between DCM (20 mL) and 10% aqueous NH4Cl (10 mL). The organic layer was dried with Na2SO4, filtered and evaporated to give the crude product as a yellow oil (200 mg, 83%) which was used without further purification. MS (electrospray): mass calculated for Ci3Hi2BrFN2O, 310.01, m/z found 313.0, [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J= 9.4, 0.6, IH), 7.70 - 7.51 (m, IH), 7.35 (dd, J= 9.1, 8.4, IH), 7.01 (dd, J= 23.8, 9.3, IH), 3.85 (dd, J= 6.0, 3.8, 4H), 3.77 - 3.67 (m, 4H). Using an analogous procedure as described in step c) intermediate (213) was prepared starting from 5-bromo-2-chloro-6-fluoro-quinoline and 3(R)-hydroxypyrrolidine, intermediate (214) was prepared starting from 5-bromo-2-chloro-6-fluoro-quinoline and ethanolamine, intermediate (215) was prepared starting from 5-bromo-2-chloro-6- fluoro-quinoline and N-methylpiperazine, intermediate (216) was prepared starting from 5-Bromo-l-chloro-isoquinoline and morpholine, intermediate (217) was prepared starting from 5-Bromo-l-chloro-isoquinoline and ethanolamine, and intermediate (218) was prepared starting from 5-bromo-2-chloro-6-methoxy-quinoline and morpholine.
Figure imgf000052_0001
B. Preparation of the final compounds Example B.I
Preparation of compound (1)
Figure imgf000052_0002
A mixture of intermediate (2) (0.0032 mol), 5-quinolinecarboxylic acid (0.0064 mol), jV-cyclohexylcarbodiimide, TV-methyl polystyrene (0.013 mol, supplier Novabiochem product number;01-64-0211) and 1 -hydroxybenzotriazole (HOBT) /l-methyl-2- pyrrolidinone (NMP) (0.0032 mol; 400 mg HOBT in 6 ml NMP) in DCM (60 ml) was stirred for 3 hours at room temperature. (Polystyrylmethyl)trimethylammonium bicarbonate (0.032 mol, supplier Novabiochem product number; 01-64-0419) and methylisocyanate polystyrene (0.0036 mol, supplier Novabiochem product number; 01- 64-0169) were added to the reaction mixture and then again stirred for 2 hours at room temperature. The reaction mixture was filtered. The filtrate's solvent was evaporated. The residue was recrystallized from H2O/CH3CN. The precipitate was filtered off and dried (vacuum), yielding 0.630 g of compound (1). Example B .2
Preparation of compound (2)
Figure imgf000053_0001
A mixture of intermediate (3b) (0.0003 mol), 5-quinolinecarbonyl chloride, hydrochloride (0.0005 mol) and DIPEA (1 ml) in ethyl acetate (5 ml) was stirred overnight at room temperature. This mixture was washed with a 1% Na2CO3 solution (10 ml). The organic layer was separated, dried and the solvent was evaporated. The residue was crystallized from CH3CN, filtered off and dried, yielding 0.100 g of compound (2).
Example B .3
Preparation of compound (8)
Figure imgf000053_0002
6N HCl in 2-propanol (0.4 ml) was added to a solution of compound (9) (0.0005 mol) in 2-propanol (9 ml) and stirred for 2 hours at 600C. 6N HCl in 2-propanol was added again and the reaction mixture was stirred for 3 hours at 600C. 6N HCl in 2-propanol was added again and the reaction mixture was stirred for 30 minutes at 700C. The solvent was evaporated. The residue was suspended in 2-propanone. The precipitate was filtered off and dried (vacuo), yielding 0.1717 g of compound (8).
Example B .4
Preparation of compound (10)
Figure imgf000053_0003
and compound (11)
Figure imgf000054_0001
Compound (1) (0.0004 mol) was separated in its enantiomers with preparative SFC purification. SFC was carried out on a Chiralpak AD-H column (Daicel Chemical Industries Ltd): eluent CO2Z(MeOH containing 0.2 % 2-propylamine) 50/50 (isocratic); flow rate 50 ml/min; column heater temperature 400C; nozzle pressure 100 bar. Two product fraction groups were collected and their solvent was evaporated. Each residue was suspended in water and the resulting precipitate was filtered off and dried, yielding 0.062 g of compound (10) (R or S) and 0.057 g of compound (11) (R or S).
Example B .5
Preparation of compound (12)
Figure imgf000054_0002
Intermediate (2) (0.0002 mol) was dissolved in DMF (3 ml). 1 -Hydroxy- IH- benzotriazole (0.022g) was added. A solution of 4-methoxy- 2-quinolinecarboxylic acid (0.0003 mol) in DMF (1 ml) was added. iV-cyclohexylcarbodiimide, TV-methyl polystyrene (0.00064 mol, supplier Novabiochem product number; 01-64-0211) was added. The resultant reaction mixture was shaken for 3 hours at room temperature. (Polystyrylmethy l)trimethylammonium bicarbonate (0.0016 mol, supplier
Novabiochem product number; 01-64-0419) and methylisocyanate polystyrene (0.0002 mol, supplier Novabiochem product number; 01-64-0169) were added. The resultant reaction mixture was stirred overnight at room temperature. The scavenger and resin were filtered off and the filtrate's solvent was evaporated. The residue was purified by reversed-phase high-performance liquid chromatography (Shandon Ηyperprep® Cl 8 BDS (Base Deactivated Silica) 8 μm, 250 g, LD. 5 cm). A gradient with a buffer solution and organic solvents was applied. The desired fractions were collected and worked-up, yielding compound (12).
Using an analogous procedure but replacing 4-methoxy-2-quinolinecarboxylic acid with 3-quinolinecarboxylic acid, 2-quinolinecarboxylic acid, 5-isoquinolinecarboxylic acid, 2-propyl-4-quinoline-carboxylic acid, 6-quinolinecarboxylic acid and 3-ethyl-2- methyl-6-quinoline-carboxylic acid respectively yielded compounds (13), (14), (16), (18), (19) and (24). Example B .6
Prepaparation of compound (7)
Figure imgf000055_0001
Oxalyl dichloride (0.002 mol) was added to a suspension of 5-quinolinecarboxylic acid (0.001 mol) in DCM (10 mL). DMF (small drop) was added, and the mixture stirred for 16 hours. The solvent was removed. The residue was dissolved in DCM (10 mL), and intermediate (9) (0.001 mol) and triethylamine added in rapid succession at 00C. Stirring was continued for 4 hours, allowing the temperature to increase to 200C. HCl (0.001 M, 10 mL) was added, and the phases separated. The organic layer was washed with Na2CO3 (aq) (50% saturated), water and brine. The solvent was removed, and the residue was purified by column chromatograpy over silica gel (DCM/CH3OH 100-97.5%). The pure fractions were collected and the solvent removed. The residue was triturated under DIPE, and then dried at 6O0C in a vacuum oven, yielding 0.26 g of compound (7).
Example B .7
Preparation of compound (15)
Figure imgf000055_0002
1 -Hydroxy- lH-benzotriazole (0.180 g) and Λ/'-(ethylcarbonimidoyl)-N,Λ/-dimethyl-l,3- propanediamine, monohydrochloride (0.120 g) were added to a mixture of intermediate (11) (0.00087 mol) and 5-quinolinecarboxylic acid (0.00087 mol) in DCM (5 ml). The reaction mixture was stirred overnight, was washed with a 10% aqueous NaOH solution and dried with Na2SO4. The solvent was evaporated, yielding 0.12O g of compound (15). Example B .8
Preparation of compound (46)
and compound (47)
Figure imgf000056_0001
Intermediate (25) (0.0075 mol), 5-quinolinecarboxylic acid (0.0075 mol), l-[bis- (dimethylamino)methylene]-lH-benzotriazoliumhexafluorophosphate(l-) 3-oxide (1 : 1) (0.008 mol), DIPEA (3.3 ml) and DMF (75ml) were stirred during 16 hours in a closed vessel. The reaction mixture was diluted with water (150 ml) and acetonitrile (10 ml) and stirred overnight at room temperature. The precipitate was filtered and dried in vacuum. A part (2.85 g) of the residue (3.383 g, 97%) was purified in its enantiomers by preparative SFC. SFC was carried out on a Chiralpak AD-Η column (30 x 250 mm) (Daicel Chemical Industries Ltd): eluent CO2Z(MeOH containing 0.2 % 2-propylamine) 60/40; flow rate 50 ml/min; column heater temperature 400C; nozzle pressure 100 bar; load: 76 mg / 4 ml. Two Peaks were obtained and collected. The first combined fractions were evaporated and the residue was crystallised from isopropylether/acetonitrile 10/1. The precipitate was filtered off and dried in vacuum, yielding 1.099 g of compound (46). The second combined fractions were evaporated and the residue was crystallised in isopropylether/acetonitrile 10/1. The precipitate was filtered and dried in vacuum, yielding 1.082 g of compound (47).
Example B .9
Preparation of compound (34)
Figure imgf000056_0002
IH- 1 ,2,3-triazolo[4,5-b]pyridinium, 1 -[bis(dimethylamino)methylene]- hexafluorophosphate(l-), 3-oxide (0.001422 mol) was added to a mixture of intermediate (26) (0.000948 mol) and 5-quinolinecarboxylic acid (0.001138 mol) and DIPEA (0.001422 mol) in DMF (10 ml), at 00C under nitrogen flow. The reaction mixture was stirred and gradually warmed to room temperature, overnight. The solvent was evaporated under vacuum. The residue was purified by preparative high- performance liquid chromatography. The product fractions were collected and the solvent was evaporated, yielding 0.18O g of compound (34).
Example B.10
Preparation of compound (35)
Figure imgf000057_0001
A mixture of intermediate (27) (0.0026 mol), 5-quinolinecarboxylic acid (0.0026 mol), Λ/"-(ethylcarbonimidoyl)-Λ/,Λ/-dimethyl- 1 ,3-propanediamine, monohydrochloride (0.0038 mol), pyridine (0.0077 mol) and DCM (50 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured out in water and K2CO3 (1 g). The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified on a Biotage flash silica column, eluent : DCM/MeOH, gradient 100/0 to 95/5 , the pure fractions were collected and evaporated. The residue was crystalized from DIPE, yielding 0.773 g of compound (35).
Example B.l l
Preparation of compound (39)
Figure imgf000057_0002
Compound (38) (0.0001 mol) and 2-amino-ethanol (1 ml) were stirred overnight at 8O0C. The reaction mixture was diluted with water and three times extracted with ethyl acetate. The combined organic layers were evaporated and purified over a normal phase disposable flash column with DCM/MeOH 95/5. The corresponding fractions were evaporated and the residue was dried in vacuum, yielding 0.026 g of compound (39). Example B.12
Preparation of compound (41)
Figure imgf000058_0001
Compound (38) (0.0002 mol) and MeOH (p. a., 2 ml) were stirred at room temperature and NaOCH3 30 % in MeOH (0.1 ml) was added. The reaction mixture was allowed to stir for 20 hours at 600C, followed by an evaporation. The residue was purified on a normal phase disposable flash column with DCM/MeOH 98/2 as eluent. The corresponding fractions were evaporated, yielding 0.08 Ig of compound (41).
Example B.13
Preparation of compound (77)
Figure imgf000058_0002
Compound (38) (0.0004 mol), HCl (IM, 1 ml) and acetic acid (1 ml) were stirred at 600C for 48 hours. The reaction mixture was diluted with water and acetonitrile. The precipitate was filtered and dried in vacuum, yielding 0.144 g of compound (77).
Example B.14
Preparation of compound (78)
Figure imgf000058_0003
Compound (74) (0.0006 mol) and DCM (6 ml) were stirred at room temperature. A mixture Of CF3COOH (2 ml) in DCM (2 ml) was added dropwise. The reaction mixture was allowed to stir for 16 hours. The reaction mixture was evaporated and the residue dissolved in water. This solution was alkalised with K2CO3 and two times extracted with DCM. The combined organic layer was dried with MgSO4, filtered and evaporated. The residue was purified over a normal phase disposable flash column with DCM/MeOH-ammonia 98/2 to 95/5. The corresponding fractions were evaporated and triturated in isopropylether. The precipitate was filtered and dried in vacuum, yielding 0.305 g of compound (78).
Example B.15
Preparation of compound (135)
Figure imgf000059_0001
Intermediate (39) (0.0053 mol), intermediate (30) (0.0053 mol), l-[bis(dimethyl- amino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate(l-) 3- oxide (1 :1) (ΗATU) (0.0053 mol), DIPEA (0.016 mol) and DMF 60 ml) were stirred during 20 hours in a closed vessel. The reaction mixture was evaporated, dissolved in DCM and washed with saturated sodium carbonate solution and with water. The organic layer was dried over MgSO4, filtered and evaporated. The residue was crystallised in DIPE with 20% acetonitrile. The filtrate was evaporated, yielding 1.5 g of compound (135).
Example B.16
Preparation of compound (102)
Figure imgf000059_0002
Compound (37) (0.001 mol) and piperazine (0.01 mol) in l-methyl-2-pyrrolidinone (3 ml) were stirred for 2 hours at 115°C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was suspended in diisopropylether and a little 2-propanol, the solid was filtered off, washed and dried in vacuum, yielding 0.12 g of compound (102).
Example B.17
Preparation of compound (117)
Figure imgf000059_0003
A mixture of sodium hydride (0.0146 mol) and 2-propanol (10 ml) was stirred for 15 minutes. Then a mixture of compound (156) (0.00146 mol) in 2-propanol (5 ml) was added and this mixture was stirred and refluxed at 1400C for 30 minutes, in a microwave oven. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by high-performance liquid chromatography (eluent: CH3CN/H2O 75/25 to CH3CN/H2O 55/45 with 0.1% CF3COOH). The product fractions were collected and the solvent was evaporated, yielding 0.17 g of compound (117).
Example B.18
Preparation of compound (156)
Figure imgf000060_0001
Intermediate (56) (0.014 mol) was suspended in DCM (q.s., anhydrous). A solution of intermediate (55) (0.011 mol) and triethylamine (0.023 mol) in DCM was added to the suspension, stirred at room temperature. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (eluent: CH3CN/H2O from 25/75 to 55/45 + 0.1% CF3COOH). The product fractions were collected and then dried by lyophilization, yielding 4.0 g (88%) of compound (156).
Example B.19
Preparation of compound (134)
Figure imgf000060_0002
Compound 164 (0.5 mmol), isopropylpiperazine (1 mmol) and dimethylsulfoxide (1 ml) were stirred at 1000C for 6 hours. The reaction mixture was diluted with 10 ml water and under reflux further dissolved with addition of methanol (about 5 ml). The solution was stirred overnight, the precipitate was filtered and dried in vacuum, yielding 218 mg of compound (134). Example B .20
Preparation of compound (168)
Figure imgf000061_0001
A mixture of compound 37 (0.644 mmol), tris(dibenzylideneacetone)dipalladium (0.022 mmol), 2,2'-bis(diphenylphosphino)-l,r-binaphthyl (0.033 mmol) and sodium tert-butoxidc (2.0812 mmol) in 2-propanamine (5 ml) was stirred at 8O0C overnight. The mixture was filtered and concentrated to give the crude product. The crude product was purified by high-performance liquid chromatography (C 18, eluent: CH3CN /water from 22 / 78 to 42 / 58 with 0.1% CF3COOH ). The pure fractions were collected and the organic solvent was evaporated. The product was obtained by lyophilization, yielding 0.08 g of compound (168).
Example B .21
Preparation of compound (140)
Figure imgf000061_0002
Compound 164 (0.5 mmol), cis-2,6-dimethylmorpholine (2 mmol) and 2-methoxy- ethanol (2 ml) were stirred at 8O0C for 16 hours. The reaction mixture was evaporated and 300 mg residue was purified by reversed-phase high-performance liquid chromatography (Shandon Hyperprep® Cl 8 BDS (Base Deactivated Silica) 8 μm, 250 g, LD. 5 cm). A gradient with 2 mobile phases was applied. Phase A: a 0.25 % NH4HCO3 solution in water; phase B: CH3CN). The corresponding fractions were collected and evaporated. The residue was crystallised in isopropylether with 5% CH3CN. The crystals were collected by filtration and dried in vacuum, yielding 120 mg of compound ( 140).
Example B .22
Preparation of compound (173)
Figure imgf000061_0003
A mixture of compound (37), 1-cyclopropyl-piperazine (0.0027 mol), tris(dibenzylidene- acetone)dipalladium (0.054 mmol), l,r-[l,r-binaphthalene]-2,2'-diylbis[l,l-diphenyl- phosphine (0.081 mmol) and 2-methyl-propanol, sodium salt (1 :1) (0.00162 mol) in THF (5 ml) was stirred at 8O0C for 40 minutes under microwave. The mixture was filtered and concentrated to give the crude product. The crude product was purified by high-performance liquid chromatography (C 18, eluent: CH3CN / water from 8 / 92 to 38 / 62 with 0.1% CF3COOH ). The pure fractions were collected and the organic solvent was evaporated. The aqueous mixture was basified with solid NaHCOs to pH = 8. The aqueous mixture was extracted with DCM (40 ml) twice. The combined organic layers was washed with de-ion water (20 ml). The separated organic fraction was dried over sodium sulfate, filtered off the solid and the solvent was evaporated. The product was obtained by lyophilization, yielding 0.04 g of compound (173).
Example B .23
Preparation of compound (273)
Figure imgf000062_0001
A mixture of compound (316) (0.19 mmol) and 4,4-dimethyl-piperidine (0.98 mmol) was stirred at 6O0C for 3 days. The reaction mixture was concentrated in vacuum. The residue was purified by high-performance liquid chromatography (reverse phase column, eluent: CH3CN / water from 10 / 90 to 40 / 60 with 0.1% CF3COOH). The pure fractions were collected and the product was obtained by lyophilization, 25.77 mg of compound (273).
Example B .24
Preparation of compound (316)
Figure imgf000062_0002
A mixture of compound (37) (0.0043 mol) and phosphoric tribromide (0.0209 mol) was stirred at 1000C for 5 hours. Ice-water was added into the reaction mixture with stirring. The aqueous solution was acidified by NaHCO3 to pH = 10. The aqueous solution was extracted by DCM (300 ml, three times). The combined organic layers were dried over Na2SO4 and filtered off. The solvent was concentrated in vacuum to afford the product, yielding 2 g of compound (316).
Example B.30
a) Preparation of Compound (400)
Figure imgf000063_0001
To intermediate (201) (2.4 g, 9.9 mmol) and (benzotriazol-l-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (4.4 g, 9.9 mmol) in DCM (15 mL), at 0 0C was added triethylamine (5.5 mL, 39 mmol) and the reaction mixture stirred for 20 min. Intermediate 25 (3.1 g, 9.9 mmol) was added and the reaction mixture was slowly warmed to rt and stirred for 12 hours. Water was added and the reaction mixture was extracted with DCM. The organic phases were combined, dried with Na2SO4, filtered, concentrated and purified by flash column chromatography (0-100 % EtOAc in hexane) to provide the desired product (4.5 g, 85%).
Using an analogous procedure as described in example B.30 compound (401) was prepared starting from intermediate (202) and compound (402) was prepared starting from intermediate 201 and intermediate (23). Additionally one skilled in the art will recognize that compounds analogous to compound 400 can be made by the coupling of any commercially available quinoline or isoquinoline carboxylate, with the appropriate amine intermediates listed above in examples A1-A43 to afford final products of formula (I).
Figure imgf000063_0002
Example B .31
a) Preparation of compound (403)
Figure imgf000064_0001
To compound (402) (75 mg, 0.14 mmol) and triethylamine (0.10 mL, 0.56 mmol) in acetonitrile (2 mL) was added morpholine (25 mg, 0.28 mmol). The reaction vessel was sealed and heated to 12O0C for 14 h. The reaction mixture was cooled to rt and purified by HPLC (C 18, eluent: CH3CN/water from 10/90 to 100/0 with 0.1% CF3COOH) to provide the desired product (70 mg, 71%). One skilled in the art will realize that certain examples wherein the amine nucleophile contains an additional nucleophilic functionality will require the use of a protecting group such as a Boc group. In these cases a deprotection step may be required to reveal the final compound.
Example B .32
a) Preparation of compound (582)
Figure imgf000064_0002
Compound 582, 6-chloro-quinoline-5-carboxylic acid [2-(4,4-difluoro-piperidin-l-yl)- 2-(2-methylsulfanyl-pyrimidin-5-yl)-ethyl]-amide was prepared analogous to Example B.30 by coupling 6-chloro-quinoline-5-carboxylic acid and 2-(4,4-difluoro-piperidin-l- yl)-2-(2-methylsulfanyl-pyrimidin-5 -yl)-ethylamine .
Example B.33
a) Preparation of compound (583)
Figure imgf000064_0003
To a solution of 6-chloro-quinoline-5-carboxylic acid [2-(4,4-difluoro-piperidin-l-yl)- 2-(2-methylsulfanyl-pyrimidin-5-yl)-ethyl] -amide (400 mg, 0.8 mmol) in CH2Cl2 (5 mL) and DMF (2 mL) was added 1 M solution of methansulfonic acid in CH2Cl2 (1.6 niL, 1.6 mmol) at rt. The resulting solution was cooled to -20 0C and 3- chloroperoxybenzoic acid (77% maximum in H2O) (192 mg, 1.1 mmol) was added in a single portion. After Ih, the solution was allowed to warm to rt over 3h. The reaction mixture was portioned between aqueous saturated sodium bicarbonate (10 mL). The aqueous layer was extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified directly by silica gel CH2Cl2-MeOH to afford a white solid (150 mg, 36%). MS (ESI): mass calcd. for C22H22ClF2N5O2S, 493.1; m/z found, 494.1 [M+H]+. 1H NMR (CD3OD) δ 9.08 (s, 2H), 9.01 (dd, J = 4.6, 1.6, IH), 8.42 - 8.31 (m, IH), 8.12 (dd, J = 9.1, 0.7, IH), 7.88 (d, J = 9.1, IH), 7.77 (dd, J = 8.6, 4.6, IH), 4.35 (t, J = 7.0, IH), 4.22 (dd, J = 13.8, 6.4, IH), 4.11 (dd, J = 13.6, 8.0, IH), 2.99 (s, J = 1.4, 3H), 2.94 - 2.78 (m, 4H), 2.09 (ddd, J = 20.9, 13.2, 6.7, 4H).
Example B .34
Preparation of compound (584)
Figure imgf000065_0001
To a solution of ό-chloro-quinoline-S-carboxylic acid [2-(4,4-difluoro-piperidin-l-yl)- 2-(2-methanesulfinyl-pyrimidin-5-yl)-ethyl] -amide (20 mg, 0.04 mmol) and CH3CN (1 mL) was added triethylamine (0.01 mL, 0.08mmol) followed by morpholine (7 mg, 0.08 mmol) in a sealed tube. The reaction vessel was heated to 90 0C. After 12 h, the resulting solution was cooled and purified by preparative reverse-phase HPLC to afford a white solid (17 mg, 66%). MS (ESI): mass calcd. for C25H27ClF2N6O2, 516.1; m/z found, 517.2 [M+H]+. 1H NMR (CD3OD) δ 8.97 (dd, J = 4.5, 1.6, IH), 8.57 (s, 2H), 8.13 - 8.07 (m, 2H), 7.83 (d, J = 9.1, IH), 7.65 (dd, J = 8.6, 4.5, IH), 4.70 (dd, J = 10.4, 5.4, IH), 4.36 - 4.26 (m, 2H), 3.89 - 3.84 (m, 4H), 3.76 - 3.72 (m, 4H), 3.56 - 3.40 (m, 4H), 2.44 - 2.34 (m, 4H).
Example B.35
Preparation of compound (593)
Figure imgf000065_0002
To a solution of 2,6-dichloro-quinoline-5-carboxylic acid [2-(4,4-difluoro-piperidin-l- yl)-2-(2-trifluoromethyl-pyrimidin-5-yl)-ethyl] -amide (100 mg, 0.2 mmol) and 4N HCl in dioxane (3 mL) was added water (7 μL). The resulting mixture was heated to 90 0C. After 12 h, the resulting mixture was concentrated and purified by preparative reverse- phase HPLC to afford the title compound as a colorless solid (56 mg, 58%). MS (ESI): mass calcd. for C22Hi9ClF5N5O2, 515.1; m/z found, 516.2 [M+H]+. 1H NMR ((CDs)2SO) δ 11.96 (s, IH), 9.13 (s, 2H), 8.79 (t, J = 5.8, IH), 7.55 (m, 2H), 7.31 (d, J = 8.9, IH), 6.53 (d, J = 9.8, IH), 4.25 - 4.22 (m, IH), 3.94 - 3.82 (m, 2H), 2.75 - 2.54 (m, 4H), 2.06 - 1.93 (m, 4H).
Example B.36
Preparation of compound (596)
Figure imgf000066_0001
A solution of 2,6-dichloro-quinoline-5-carboxylic acid [2-(4,4-difluoro-piperidin-l-yl)- 2-(2-trifluoromethyl-pyrimidin-5-yl)-ethyl] -amide (100 mg, 0.2 mmol) and 7N ammonia in MeOH was heated to 100 0C. After 60 h, the resulting mixture was cooled, concentrated, and purified directly by preparative reverse-phase HPLC to afford the title compound as a colorless solid (13 mg, 13%). MS (ESI): mass calcd. for C22H20ClF5N6O, 514.1; m/z found, 516.2 [M+H]+. 1H NMR (CDCl3) δ 8.90 (s, 2H), 7.95 (d, J = 9.3, IH), 7.89 (d, J = 9.2, IH), 7.68 (d, J = 9.0, IH), 6.82 (d, J = 9.5, IH), 6.55 - 6.47 (m, IH), 4.08 (d, J = 3.7, 3H), 2.70 (d, J = 23.7, 4H), 2.07 (d, J = 2.3, 4H).
Example B.37
Preparation of compound (598)
Figure imgf000066_0002
To a mixture of sodium hydride (0.88 mmol) and THF (0.8 mL) was added t-butyl 3- (hydroxymethyl)azetidine-l-carboxylate (0.8 mmol), and the reaction mixture was allowed to stir for 15 min. followed by the addition of compound 402 (0.8 mmol). The mixture was sealed and heated tol20 0C in a heating block for 12 hours. Upon complete consumption of starting material, the reaction mixture was poured over brine (100 mL) and extracted three times with DCM (75 mL). Combined organics were dried with Na2SO4, filtered, and evaporated in vacuo. The resulting residue was dissolved in formic acid (1 mL) and treated with 4 M HCl in dioxane (1 mL). This mixture was allowed to stir for 3 hours, until complete Boc removal was observed. The reaction mixture was then concentrated in vacuo and purified by HPLC (eluent: CH3CN/H2O 10/95 to CH3CN/H2O 95/5 with 0.1% CF3COOH). The product fractions were collected and the solvent was removed by lyophilization yielding 0.009 g of compound as the trifluoroacetate salt. In subsequent examples some alcohols will not have an amine functionality requiring Boc protection. In these cases the acidic Boc deprotection step is deleted.
Example B .38
Preparation of compound (609)
Figure imgf000067_0001
6-Fluoro-quinoline-5 -carboxylic acid r2-morpholin-4-yl-2-(2-trifluoromethyl- pyrimidin-5 -vD-ethyll -amide.
To a solution of intermediate (28) (0.17 g, 0.62 mmol) in THF (0.9 mL), in a 5 mL microwave vial containing a magnetic stirbar, was added sequentially 5-bromo-6- fluoro-quinoline (0.10 g, 0.44 mmol), l,8-diazabicyclo(5.4.0)undec-7-ene (0.05 g, 0.30 mmol), trα/?5-di-u-acetobis[2-(di-o-tolyl-phosphine)-benzyl]di-palladium (II) (0.005 g, 0.005 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.004 gg, 0.02 mmol) and molybdenum hexacarbonyl (0.12 mg, 0.44 mmol). The vial was sealed and heated to 150 0C in a microwave reactor. The resulting mixture was diluted with DCM and washed with water. The organic layer was dried with Na2SO4, filtered through celite and evaporated in vacuo and purified by high-performance liquid chromatography (eluent: CH3CN/H2O 10/95 to CH3CN/H2O 95/5 with 0.1% CF3COOH). The product fractions were collected and the solvent was removed by lyophilization (0.05 mg, 25%) to give the title compound as the trifluoroacetate salt.
Tables F-I, F-2, F-3 and F-4 lists the compounds that were prepared according to one of the above Examples. Table F-I
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Co.No.27; Ex. B.7 Co.No.llO;Ex. B.4
Figure imgf000072_0002
Co.No.28; Ex. B.7 Co.No.lll; Ex. B.4
Figure imgf000072_0003
Co.No.29; Ex. B.7 Co.No.ll2;Ex. B.9
Figure imgf000072_0004
Co.No.31; Ex. B.7 Co.No.ll3;Ex. B.9
Figure imgf000072_0005
Co.No.32; Ex. B.9 Co.No.ll4;Ex.B.4;(R)
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Table F-2
Figure imgf000083_0002
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
.C2HF3O2 : stands for the trifluoroacetate salt Table F-3 :
Figure imgf000098_0002
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
- Ill -
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Table F-4 :
Figure imgf000117_0002
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
C. Analytical Part Cl Melting Points
(a) For a number of compounds, melting points (m.p.) were determined with a DSC823e (Mettler-Toledo). Melting points were measured with a temperature gradient of 30°C/minute. The reported values are peak values.
(b) For a number of compounds, melting points (m.p.) were determined with a WRS- 2A melting point apparatus that was purchased from Shanghai Precision and Scientific Instrument Co. Ltd. Melting points were measured with a linear heating up rate of 0.2- 5.0°C/minute The reported values are melt ranges. The maximum temperature was 3000C.
(c) For a number of compounds, melting points were obtained with a Kofler hot bench, consisting of a heated plate with linear temperature gradient, a sliding pointer and a temperature scale in degrees Celsius.
Values were obtained with experimental uncertainties that are commonly associated with this analytical method.
Table F-5 : melting points
Figure imgf000126_0002
Figure imgf000126_0003
Figure imgf000126_0004
m.p. (0C) Co. No. m.p. (0C)
173 (c) 62 177.9 (a) 187.3 (a) 63 190.4 (a)
198 (c) 64 154.3 (a) 208.9 (a) 65 219.6 (a)
208.7 (a) 67 171.2 (a) 175.8-176.2 (b) 68 173.8 (a) 165.3-165.7 (b) 69 160.6 (a) 155.0-162.2 (b) 70 160.9 (a) 191.0-195.4 (b) 74 218.2 (a)
219.2 (a) 75 169.4 (a) 253.7-254.3 (b) 76 214.6 (a)
183.6 (a) 77 206.9 (a)
206.6 (a) 78 202.9 (a) 211.9 (a) 79 186.2 (a)
116.8 (a) 80 210.8 (a)
125.3 (a) 81 212.8 (a) 208.3 (a) 82 212.9 (a)
180.9 (a) 83 247.1 (a)
217.7 (a) 84 246.3 (a)
217.7 (a) 86 177.0 (a) 181.0 (a) 231.2 (a)
159.8 (a) 91 200.7 (a)
120.2 (a) 92 167.2 (a) 199.6 (a) 93 218.1 (a)
162.9 (a) 96 160.0 (a) 151.0 (a) 97 125.3 (a) 202.9 (a) 99 190.3 (a) 231.6 (a) 100 143.2 (a) 156.6 (a) 101 165.0 (a)
228.3 (a) 102 234.3 (a) 184.6 (a) 103 141.3 (a)
Figure imgf000127_0001
C.2 LCMS
LCMS General procedure A
The HPLC measurement was performed using an Alliance HT 2790 (Waters) system comprising a quaternary pump with degasser, an autosampler, a column oven (set at 4O0C, unless otherwise indicated), a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 1 second using a dwell time of 0.1 second. The capillary needle voltage was 3 kV and the source temperature was maintained at 1400C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
LCMS General procedure B The LC measurement was performed using an Acquity UPLC (Waters) system comprising a binary pump, a sample organizer, a column heater (set at 55 0C), a diode- array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.18 seconds using a dwell time of 0.02 seconds. The capillary needle voltage was 3.5 kV and the source temperature was maintained at 1400C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
LCMS General procedure C
The HPLC measurement was performed using an Agilent 1100 module comprising a pump, a diode-array detector (DAD) (wavelength used 220 nm), a column heater and a column as specified in the respective methods below. Flow from the column was split to a Agilent MSD Series G1946C and G1956A. MS detector was configured with API- ES (atmospheric pressure electrospray ionization). Mass spectra were acquired by scanning from 100 to 1000. The capillary needle voltage was 2500 V for positive ionization mode and 3000 V for negative ionization mode. Fragmentation voltage was 50 V. Drying gas temperature was maintained at 3500C at a flow of 10 1/min.
LCMS - Procedure 1
In addition to general procedure A: Reversed phase HPLC was carried out on an Xterra MS Cl 8 column (3.5 μm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 1 % A, 49 % B and 50 % C in 6.5 minutes, to 1 % A and
99 % B in 1 minute and hold these conditions for 1 minute and reequilibrate with
100 % A for 1.5 minutes. An injection volume of 10 μl was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
LCMS - Procedure 2
In addition to general procedure A: Reversed phase HPLC was carried out on an Atlantis C18 column (3.5 μm, 4.6 x 100 mm) (3.5 μm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Two mobile phases (mobile phase A: 70 % methanol + 30 % H2O; mobile phase B: 0.1 % formic acid in H2θ/methanol 95/5) were employed to run a gradient condition from 100 % B to 5 % B + 95 % A in 12 minutes. An injection volume of 10 μl was used. Cone voltage was 10 V for positive ionization mode and
20 V for negative ionization mode.
LCMS - Procedure 3
In addition to general procedure A: Column heater was set at 600C. Reversed phase HPLC was carried out on an Xterra MS Cl 8 column (3.5 μm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C : methanol) were employed to run a gradient condition from 100 % A to 50 % B and 50 % C in 6.5 minutes, to 100 % B in 0.5 minute and hold these conditions for 1 minute and reequilibrate with 100 % A for 1.5 minutes. An injection volume of 10 μl was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
LCMS - Procedure 4
In addition to general procedure C: Reversed phase HPLC was carried out on a YMC- Pack ODS-AQ, 50x2.0 mm 5μm column with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: water with 0.1 % TFA; mobile phase B: acetonitrile with
0.05 % TFA) were used. First, 90 % A and 10 % B was hold for 0.8 minutes. Then a gradient was applied to 20 % A and 80 % B in 3.7 minutes and hold for 3 minutes. Typical injection volumes of 2 μl were used. Oven temperature was 500C. (MS polarity: positive)
LCMS - Procedure 5
In addition to general procedure B: Reversed phase UPLC (Ultra Performance Liquid
Chromatography) was carried out on a bridged ethylsiloxane/silica hybrid (BEH) Cl 8 column (1.7 μm, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: 0.1 % formic acid in IHtO/methanol 95/5; mobile phase B: methanol) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 minutes and hold for 0.2 minutes. An injection volume of 0.5 μl was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
LCMS - Procedure 6
In addition to general procedure C: Reversed phase HPLC was carried out on a YMC- Pack ODS-AQ, 50x2.0 mm 5μm column with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: water with 0.1 % TFA; mobile phase B: acetonitrile with 0.05 % TFA) were used. First, 100 % A was hold for 1 minute. Then a gradient was applied to 70 % A and 30 % B in 4.5 minutes and hold for 2 minutes. Typical injection volumes of 2 μl were used. Oven temperature was 500C. (MS polarity: positive).
LCMS - Procedure 7
In addition to general procedure C: Reversed phase HPLC was carried out on a YMC- Pack ODS-AQ, 50x2.0 mm 5μm column with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: water with 0.1 % TFA; mobile phase B: acetonitrile with 0.05 % TFA) were used. First, 100 % A was hold for 1 minute. Then a gradient was applied to 40 % A and 60 % B in 4 minutes and hold for 2.5 minutes. Typical injection volumes of 2 μl were used. Oven temperature was 500C. (MS polarity: positive).
LCMS - Procedure 8 In addition to general procedure A: Reversed phase HPLC was carried out on an
Ultimate XB-C 18, 50x2.1 mm 5μm column with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase C: 10 mmol/L NH4HCO3; mobile phase D: acetonitrile) were used. First, 100 % C was hold for 1 minute. Then a gradient was applied to 40 % C and 60 % D in 4 minutes and hold for 2.5 minutes. Typical injection volumes of 2 μl were used. Oven temperature was 500C. (MS polarity: positive).
Table F-6 : Retention time (Rt) in minutes, [M+H]+ peak, LCMS procedure
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Table F-7: Retention time (Rt) in minutes, [M-H]" peak, LCMS procedure
Figure imgf000133_0002
C.3 Optical Rotation
The optical rotation was measured using a Perkin Elmer 341 polarimeter. [α]o20 indicates the optical rotation measured with light at the wavelength of the D-line of sodium (589 nm) at a temperature of 200C . The cell pathlength is 10 cm. Behind the actual value the concentration and solvent of the solution which was used to measure the optical rotation are mentioned.
* The optical rotation of compound (10) was measured at 23°C (measured without temperature regulator). T able F-8 : optical rotation
Figure imgf000134_0001
CA SFC-MS
For some compounds SFC-MS (Supercritical fluid chromatography-mass spectrometry) was measured with an analytical SFC system from Berger Instruments (Newark, DE, USA) comprising a dual pump control module (FCM- 1200) for delivery of carbon dioxide (CO2) and modifier, a thermal control module for column heating (TCM2100) with temperature control in the range of 1-1500C and column selection valves (Valco, VICI, Houston, TX, USA) for six different columns. The photodiode array detector (Agilent 1100, Waldbronn, Germany) is equipped with a high-pressure flow cell (up to 400 bar) and configured with a CTC LC Mini PAL auto sampler (Leap Technologies, Carrboro, NC, USA). A ZQ mass spectrometer (Waters, Milford, MA, USA) with an orthogonal Z-electrospray interface is coupled with the SFC-system. Instrument control, data collection and processing were performed with an integrated platform consisting of the SFC ProNTo software and Masslynx software.
For Co. No. (10) an enantiomeric excess of 100.0 % was detected when SFC-MS was carried out on a Chiralpak AD-H column (500 x 4.6 mm) (Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min. Two mobile phases (mobile phase A: CO2; mobile phase B: methanol containing 0.2 % 2-propylamine) were employed to run a gradient from 10 % B to 40 % B at a rate of 1.6 %/minute. Then a gradient was applied from 40 % B to 50 % B in 2 minutes and hold for 3.6 minutes. Column temperature was set at 500C. This measurement was compared against the racemic mixture.
For Co. No. (67) an enantiomeric excess of 100.0 % was detected when SFC-MS was carried out on a Chiralpak AD-H column (500 x 4.6 mm) (Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min. Two mobile phases (mobile phase A: CO2; mobile phase B: methanol containing 0.2 % 2-propylamine) were employed. First 30 % B (and 70 % A) was hold for 18.5 minutes. Then a gradient was applied from 30 % B to 50 % B in 2 minutes and hold for 4.1 minutes. Column temperature was set at 500C. This measurement was compared against the racemic mixture.
Identical SFC-MS conditions as for Co. No. ( 67), were used for the SFC-MS measurements of Co. No. (68), (69), (70).
For Co. No. (83) an enantiomeric excess of 100.0 % was detected when SFC-MS was carried out on a Chiralpak AD-H column (500 x 4.6 mm) (Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min. Two mobile phases (mobile phase A: CO2; mobile phase B: methanol containing 0.2 % 2-propylamine) were employed. First 40 % B (and 60 % A) was hold for 19.5 minutes. Then a gradient was applied from 40 % B to 50 % B in 2 minutes and hold for 4.1 minutes. Column temperature was set at 500C. This measurement was compared against the racemic mixture.
Identical SFC-MS conditions as for Co. No. (83), were used for the SFC-MS measurements of Co. No. (84).
For Co. No. (110) an enantiomeric excess of 100.0 % was detected when SFC-MS was carried out on a Chiralpak AD-H column (500 x 4.6 mm) (Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min. Two mobile phases (mobile phase A: CO2; mobile phase B: methanol containing 0.2 % 2-propylamine) were employed. First 35 % B (and 65 % A) was hold for 19.0 minutes. Then a gradient was applied from 35 % B to 50 % B in 1.5 minutes and hold for 4.1 minutes. Column temperature was set at 500C. This measurement was compared against the racemic mixture.
Identical SFC-MS conditions as for Co. No. (110), were used for the SFC-MS measurements of Co. No. (111). For Co. No. (114) an enantiomeric excess of 100.0 % was detected when SFC-MS was carried out on a Chiralpak AD-H column (500 x 4.6 mm) (Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min. Two mobile phases (mobile phase A: CO2; mobile phase B: ethanol containing 0.2 % 2-propylamine) were employed. First 25 % B (and 75 % A) was hold for 18.0 minutes. Then a gradient was applied from 25 % B to 50 % B in 2.5 minutes and hold for 4.1 minutes. Column temperature was set at 500C. This measurement was compared against the racemic mixture.
Identical SFC-MS conditions as for Co. No. (114), were used for the SFC-MS measurement of Co. No. (124).
For Co. No. (115) an enantiomeric excess of 100.0 % was detected when SFC-MS was carried out on a Chiralpak AD-H column (500 x 4.6 mm) (Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min. Two mobile phases (mobile phase A: CO2; mobile phase B: methanol containing 0.2 % 2-propylamine) were employed. First 40 % B (and 60 % A) was hold for 19.5 minutes. Then a gradient was applied from 40 % B to 50 % B in 1 minute and hold for 4.1 minutes. Column temperature was set at 500C. This measurement was compared against the racemic mixture.
For Co. No. (138) an enantiomeric excess was found of 100 % when a screening (no racemic mixture available to compare) was performed with 4 different columns (Chiralcel OJ-H, Chiralpak AD-H, Chiralcel OD-H, Chiralpak AS-H; 500 x 4.6 mm; Daicel Chemical Industries Ltd) and 3 different solvents (MeOH, EtOH, 2-propanol; the solvent is containing 0.2 % 2-propylamine). SFC-MS was carried out with one of the columns mentioned above with a flow rate of 3 ml/min. Two mobile phases (mobile phase A: CO2; mobile phase B: one of the solvents mentioned above containing 0.2 % 2-propylamine) were employed to run a condition from 10 % B to 40 % B in 18.75 minutes. Then a gradient was applied from 40 % B to 50 % B in 2 minutes and hold for
3.6 minutes. Column temperature was set at 500C.
C.5 NMR
For a number of compounds, 1H NMR spectra were recorded on a Bruker DPX-360, on a Bruker DPX-400 or on a Bruker Avance 500 spectrometer with standard pulse sequences, operating at 360 MHz, 400 MHz and 500 MHz respectively, using CHLOROFORM-J or DMSO-J6 as solvents. Chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as internal standard.
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
IH), 7.58 (d, J= 9.0, IH), 7.54 (d, J = 9.0, IH), 7.29 (d, J= 9.5, IH), 4.68 d, J= 12.7, IH), 4.29 - 4.22 (m, IH), 4.21 - 4.14 (m, IH), 4.08 - 3.86 m, 2H), 3.47 - 3.37 (m, IH), 3.35 - 3.25 (m, IH), 3.21 - 3.11 (m, IH), .87 (s, 6H), 2.74 - 2.57 (m, 4H), 2.15 - 2.07 (m, IH), 2.06 - 1.95 (m, H), 1.92 - 1.83 (m, IH), 1.83 - 1.74 (m, IH), 1.59 - 1.46 (m, IH). IH NMR (600 MHz, MeOD) δ 9.06 (s, 2H), 8.00 - 7.91 (m, IH), 7.84 - .74 (m, 2H), 7.17 (d, J= 8.5, IH), 4.20 - 4.11 (m, 2H), 4.10 - 4.02 (m, IH), 3.99 - 3.90 (m, IH), 3.75 (t, J= 4.7, 4H), 3.73 - 3.63 (m, 3H), 3.61 - .55 (m, IH), 3.37 - 3.34 (m, IH), 2.79 - 2.70 (m, 2H), 2.70 - 2.63 (m, H).
IH NMR (600 MHz, MeOD) δ 9.09 (s, 2H), 7.91 (d, J= 9.3, IH), 7.84 (d, /= 8.5, IH), 7.76 (d, J= 9.0, IH), 7.11 (d, J= 9.4, IH), 4.25 - 4.15 (m, H), 4.14 - 4.05 (m, IH), 3.77 (t, J= 4.6, 4H), 3.73 (t, J= 5.9, 2H), 3.67 t, J= 6.9, 2H), 2.87 - 2.76 (m, 2H), 2.76 - 2.69 (m, 2H), 2.02 - 1.91 (m, H).
IH NMR (600 MHz, MeOD) δ 9.06 (s, 2H), 7.95 (d, J= 7.5, IH), 7.83 (d, /= 7.5, IH), 7.78 (d, J= 8.9, IH), 7.16 (d, J= 7.5, IH), 4.24 - 4.09 (m, H), 4.09 - 4.01 (m, IH), 3.95 - 3.85 (m, 2H), 3.83 - 3.71 (m, 6H), 3.66 - .52 (m, IH), 2.79 - 2.58 (m, 4H), 2.22 - 2.09 (m, IH), 2.04 - 1.91 (m, H), 1.78 - 1.67 (m, IH).
IH NMR (600 MHz, MeOD) δ 9.16 (s, 2H), 8.01 (d, J = 9.8, IH), 7.92 (d, = 9.1, IH), 7.71 (d, J = 9.1, IH), 7.40 (d, J = 9.9, IH), 4.48 - 4.41 (m, IH), 4.31 - 4.16 (m, 2H), 3.94 - 3.87 (m, 2H), 3.82 (t, J = 4.7, 4H), 3.40 s, 3H), 3.14 - 3.08 (m, 2H), 3.06 - 2.99 (m, 2H), 2.94 - 2.86 (m, 2H), .71 (s, 3H), 2.18 - 2.08 (m, 2H).
IH NMR (400 MHz, MeOD) δ 9.01 (s, 2H), 7.58 (dd, J = 9.1, 3.7, 2H), .50 - 7.18 (m, 6H), 6.82 (d, J = 9.2, IH), 4.66 (s, 2H), 4.14 - 3.95 (m, H), 3.82 - 3.67 (m, 4H), 2.70 - 2.51 (m, 4H).
IH NMR (600 MHz, MeOD) δ 9.11 (s, 2H), 8.88 (s, IH), 8.73 (d, J = 5.1, IH), 8.49 (d, J = 8.1, IH), 7.92 (dd, J = 8.0, 5.5, IH), 7.87 (d, J = 9.3, IH), .74 (d, J = 9.1, IH), 7.65 (d, J = 9.0, IH), 7.10 (d, J = 8.7, IH), 4.95 (s, H), 4.32 - 4.26 (m, IH), 4.23 - 4.10 (m, 2H), 3.78 (t, J = 4.6, 4H), 2.93 - .84 (m, 2H), 2.82 - 2.74 (m, 2H).
IH NMR (600 MHz, MeOD) δ 9.12 (s, 2H), 7.85 (d, J = 9.5, IH), 7.69 (dt, = 5.8, 2.9, IH), 7.53 (d, J = 9.0, IH), 7.33 (d, J = 9.5, IH), 4.80 - 4.73 m, 2H), 4.39 - 4.31 (m, IH), 4.25 - 4.19 (m, IH), 4.19 - 4.11 (m, IH), .80 (t, J = 4.7, 4H), 3.49 - 3.40 (m, 2H), 3.04 - 2.91 (m, 4H), 2.87 - 2.78 m, 2H), 1.42 (d, J = 6.6, 6H). IH NMR (600 MHz, MeOD) δ 9.06 (s, 2H), 8.01 - 7.94 (m, IH), 7.91 - .85 (m, IH), 7.79 (d, J = 9.0, IH), 7.38 - 7.22 (m, 6H), 7.16 (d, J = 9.6,
Figure imgf000140_0001
IH), 4.74 (s, 2H), 4.20 - 4.11 (m, 2H), 4.10 - 4.03 (m, IH), 3.75 (t, J =
Figure imgf000141_0001
Figure imgf000141_0002
= 9.1, IH), 7.83 (s, IH), 7.74 (d, J = 9.0, IH), 7.55 (d, J = 10.0, IH), 4.64 d, J = 13.8, 2H), 4.35 - 4.25 (m, 2H), 4.25 - 4.19 (m, IH), 4.17 - 4.08 (m,
IH), 3.78 (t, J = 4.6, 4H), 3.49 (t, J = 12.3, 2H), 2.94 - 2.83 (m, 2H), 2.83
- 2.74 (m, 2H), 2.28 - 2.19 (m, 2H), 2.18 - 2.06 (m, 2H).
IH NMR (600 MHz, MeOD) δ 9.05 (s, 2H), 7.98 (d, J = 9.3, IH), 7.81 (d, = 9.0, IH), 7.75 (d, J = 9.0, IH), 7.15 (d, J = 9.6, IH), 7.10 - 7.04 (m, H), 6.99 - 6.93 (m, IH), 4.80 (s, 2H), 4.17 - 4.01 (m, 3H), 3.73 (t, J =
4.6, 4H), 2.72 - 2.66 (m, 2H), 2.66 - 2.59 (m, 2H).
IH NMR (400 MHz, MeOD) δ 9.28 (s, 2H), 7.94 - 7.81 (m, 2H), 7.72 (d, = 9.0, IH), 7.09 (d, J = 9.3, IH), 4.96 - 4.85 (m, IH), 4.58 - 4.31 (m, H), 3.42 - 3.21 (m, 4H), 3.18 (s, 3H), 1.97 - 1.83 (m, 4H), 1.63 (s, 2H).
IH NMR (400 MHz, MeOD) δ 9.30 (s, 2H), 7.99 (d, J = 10.0, IH), 7.92 d, J = 9.1, IH), 7.72 (d, J = 9.1, IH), 7.39 (d, J = 10.0, IH), 4.94 (dd, J =
10.3, 4.9, IH), 4.63 - 4.29 (m, 2H), 3.44 (s, 6H), 3.42 - 3.25 (m, 4H), 1.93 d, J = 5.0, 4H), 1.65 (s, 2H).
IH NMR (400 MHz, MeOD) δ 9.30 (s, 2H), 7.93 (d, J = 9.6, IH), 7.84 (d, = 9.1, IH), 7.66 (dd, J = 9.1, 1.1, IH), 7.17 (d, J = 9.6, IH), 4.95 (dd, J =
10.1, 5.0, IH), 4.55 - 4.35 (m, 2H), 4.16 - 3.83 (m, 5H), 3.56 - 3.30 (m, H), 2.83 (d, J = 1.1, 3H), 2.70 - 2.56 (m, IH), 2.48 - 2.33 (m, IH), 2.00 -
1.88 (m, 4H), 1.76 - 1.58 (m, 2H).
IH NMR (400 MHz, MeOD) δ 9.30 (s, 2H), 7.94 (dd, J = 9.6, 1.8, IH), .85 (d, J = 9.1, IH), 7.66 (d, J = 9.1, IH), 7.17 (d, J = 9.7, IH), 4.95 (dd, J
= 10.2, 5.2, IH), 4.60 - 4.35 (m, 2H), 4.21 - 3.82 (m, 6H), 3.59 - 3.30 (m, H), 2.83 (s, 3H), 2.72 - 2.57 (m, IH), 2.49 - 2.33 (m, IH), 1.99 - 1.84 m, 4H), 1.73 - 1.55 (m, 2H). .13 - 8.94 (m, 2H), 8.11 - 7.96 (m, IH), 7.91 - 7.80 (m, IH), 7.80 - 7.72 m, IH), 7.57 - 7.41 (m, IH), 4.21 - 3.97 (m, 6H), 3.85 - 3.68 (m, 6H), .70 (d, J = 25.6, 4H), 2.06 (s, 2H), 1.81 - 1.67 (m, 2H) .07 (s, 2H), 8.06 (d, J = 9.9, IH), 7.79 (dd, J = 52.8, 9.1, 2H), 7.49 (d, J = .9, IH), 4.40 - 4.22 (m, 2H), 4.21 - 4.13 (m, 2H), 4.12 - 4.02 (m, 2H), .81 - 3.68 (m, 6H), 3.46 - 3.35 (m, IH), 3.10 - 3.01 (m, IH), 2.84 - 2.60 m, 4H), 1.29 (d, J = 6.2, 3H) .04 (s, 2H), 8.04 (d, J= 10.0, IH), 7.81 (dd, J= 42.0, 9.1, 2H), 7.52 (d, J
= 10.0, IH), 4.18 - 3.87 (m, 7H), 3.84 - 3.69 (m, 5H), 2.74 - 2.57 (m, H), 2.05 (t, J= 15.4, 2H), 1.79 (d, J= 14.7, 2H)
8.98 (s, 2H), 7.74 (d, J = 9.5, IH), 7.59 (d, J = 9.0, IH), 7.44 (d, J = 9.0,
IH), 7.18 (d, J = 9.5, IH), 4.17 - 3.94 (m, 3H), 3.89 - 3.77 (m, 2H), 3.68 t, J = 4.5, 4H), 3.60 - 3.21 (m, 10H), 2.82 - 2.56 (m, 4H) .12 - 9.01 (m, 2H), 8.01 - 7.87 (m, IH), 7.86 - 7.73 (m, 2H), 7.21 - 7.07 m, IH), 4.32 - 4.20 (m, IH), 4.19 - 3.97 (m, 3H), 3.87 - 3.66 (m, 5H),
Figure imgf000142_0001
.66 - 3.55 (m, IH), 2.77 - 2.58 (m, 4H), 1.40 - 1.30 (m, 3H)
Figure imgf000143_0001
Figure imgf000143_0002
Figure imgf000144_0002
Figure imgf000146_0001
Figure imgf000147_0001
.40 (dd, J = 8.7, 7.6, 2H), 4.11 - 3.90 (m, 4H), 3.90 - 3.80 (m, 2H), 3.71 t, J = 4.6, 4H), 2.66 - 2.48 (m, 4H) .04 (s, 2H), 7.70 (dd, J = 12.5, 9.2, 2H), 7.57 (d, J = 9.0, IH), 6.89 (d, J = .3, IH), 4.26 - 4.12 (m, IH), 4.12 - 4.01 (m, 2H), 3.97 - 3.88 (m, 6H), .54 - 3.41 (m, 6H), 2.81 - 2.60 (m, 4H), 2.12 - 1.92 (m, 4H) .01 (s, 2H), 7.58 (dd, J = 15.6, 9.2, 2H), 7.55-7.42 (m, IH), 6.78 (d, J = .2, IH), 4.14 - 3.93 (m, 2H), 3.88 - 3.75 (m, IH), 3.76 - 3.58 (m, 8H), .00 - 2.87 (m, 2H), 2.82 (t, J = 5.5, 2H), 2.66 - 2.47 (m, 4H) .05 (s, 2H), 8.05 (d, J = 10.0, IH), 7.85 (d, J = 9.0, IH), 7.76 (d, J = 9.0, IH), 7.52 (d, J = 10.0, IH), 4.52 - 4.38 (m, 2H), 4.19 (dd, J = 7.7, 6.4, IH), 4.14 - 3.96 (m, 2H), 3.65 - 3.52 (m, 2H), 3.11 - 2.99 (m, IH), 2.81 - .54 (m, 4H), 2.31 - 2.14 .02 (s, 2H), 7.63 (d, J = 9.9, IH), 7.57 (dd, J = 9.1, 0.6, IH), 7.44 (d, J = .1, IH), 7.15 (d, J = 9.5, IH), 4.14 - 3.94 (m, 5H), 3.76 - 3.66 (m, 4H), .61 - 3.45 (m, 2H), 2.65 - 2.44 (m, 4H), 1.64 (dt, J = 13.7, 8.9, 4H), 1.26 s, 3H) .04 (s, 2H), 7.93 (d, J = 9.1, IH), 7.84 (d, J = 9.0, IH), 7.67 (d, J = 9.0, IH), 7.08 (d, J = 9.1, IH), 4.88 - 4.81 (m, 2H), 4.18 (d, J = 6.4, IH), 4.12
- 4.03 (m, 2H), 3.71 - 3.60 (m, 2H), 3.01 (s, 6H), 2.79 - 2.59 (m, 4H), .02 (t, J = 13.6, 4H). .05 (s, 2H), 8.03 (d, J = 9.6, IH), 7.87 - 7.78 (m, 2H), 7.73 (d, J = 9.1, IH), 7.50 (d, J = 10.0, IH), 4.69 - 4.60 (m, 2H), 4.36 - 4.23 (m, IH), 4.23
- 4.14 (m, IH), 4.14 - 4.00 (m, 2H), 3.51 - 3.42 (m, 2H), 2.80 - 2.61 (m, 4H), 2.27 - 2.16 (m, 2H), 2.16 - 1.95 (m, 6H) .02 (s, 2H), 7.74 - 7.55 (m, 2H), 7.44 (d, J = 9.1, IH), 6.86 (d, J = 9.4,
IH), 4.13 - 3.92 (m, 3H), 3.81 - 3.66 (m, 6H), 3.65 - 3.47 (m, 2H), 3.11 - .90 (m, 2H), 2.69 - 2.40 (m, 4H), 2.21 - 2.02 (m, 2H), 2.01 - 1.77 (m, H) .02 (s, 2H), 7.70 - 7.56 (m, 2H), 7.45 (d, J = 9.0, IH), 6.87 (d, J = 9.0,
IH), 4.11 - 3.90 (m, 3H), 3.80 - 3.50 (m, 8H), 2.96 - 2.69 (m, 2H), 2.67 - .44 (m, 4H), 2.18 - 1.94 (m, 2H), 1.80 - 1.41 (m, 6H) .38 (s, 2H), 8.14 - 7.96 (m, 3H), 7.72 (d, J = 9.1, IH), 7.58 (d, J = 10.0,
IH), 4.58 (d, J = 13.4, 2H), 4.50 - 4.36 (m, 2H), 4.01 - 3.87 (m, 4H), 3.56
- 3.35 (m, 4H), 3.25 - 3.08 (m, 2H), 2.99 - 2.89 (m, 2H), 2.28 - 1.99 (m, H), 1.67 - 1.45 (m, 2H) .00 (s, 2H), 7.69 - 7.57 (m, 2H), 7.48 (d, J = 9.0, IH), 6.70 (d, J = 9.0, IH), 4.40 - 4.28 (m, 2H), 4.09 - 3.95 (m, 3H), 3.95 - 3.86 (m, 2H), 3.75 - .64 (m, 5H), 2.65 - 2.47 (m, 4H), 2.38 (s, 3H)
8.90 (s, 2H), 7.40 - 7.32 (m, IH), 7.33 - 7.28 (m, IH), 7.08 - 6.99 (m, IH), 6.68 - 6.50 (m, IH), 4.10 - 3.81 (m, 3H), 3.78 - 3.55 (m, 7H), 3.25 -
Figure imgf000148_0001
.09 (m, 2H), 2.79 - 2.65 (m, 2H), 2.59 - 2.42 (m, 4H)
Figure imgf000149_0001
Figure imgf000149_0002
Figure imgf000150_0001
Figure imgf000150_0002
Figure imgf000151_0001
Figure imgf000151_0002
Figure imgf000152_0001
Figure imgf000152_0002
Figure imgf000153_0001
Figure imgf000153_0002
Figure imgf000154_0001
Figure imgf000154_0002
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000156_0002
.84 - 2.75 (m, 2H), 2.66 - 2.46 (m, 4H), 2.17 - 2.06 (m, 2H), 1.82 - 1.68 m, 2H). .02 (s, 2H), 8.87 (dd, J = 4.3, 1.5, IH), 8.22 (ddd, J = 8.7, 1.5, 0.8, IH), .13 (dd, J = 9.4, 5.2, IH), 7.66 - 7.49 (m, 2H), 4.18 - 4.08 (m, IH), 4.00
- 3.89 (m, 2H), 3.72 (t, J = 4.6, 4H), 2.69 - 2.45 (m, 4H) .00 (s, J = 11.8, 2H), 8.21 (d, J = 8.4, IH), 7.76 (d, J = 6.3, IH), 7.58 (dd, = 7.2, 1.2, IH), 7.50 (dd, J = 8.4, 7.2, IH), 6.87 (dd, J = 6.3, 0.8, IH), .10 - 3.98 (m, IH), 3.97 - 3.85 (m, 2H), 3.84 - 3.76 (m, 2H), 3.72 (t, J = .6, 4H), 3.69 - 3.61 (m, 2H), 2.65 - 2.48 (m, 4H) .03 (s, J = 4.2, 2H), 8.89 - 8.80 (m, IH), 8.24 (ddd, J = 8.7, 1.6, 0.8, IH), 8.13 (dd, J = 9.4, 5.2, IH), 7.62 (t, J = 9.2, IH), 7.57 (dd, J = 8.6, 4.3, IH), .20 - 4.06 (m, 2H), 4.03 - 3.92 (m, IH), 2.78 - 2.59 (m, 4H), 2.12 - 1.87 m, 4H) .04 (s, 2H), 8.29 (d, J = 8.4, IH), 8.05 (d, J = 6.1, IH), 7.68 (dd, J = 7.1, 1.2, IH), 7.59 (dd, J = 8.4, 7.2, IH), 7.39 (dd, J = 6.1, 0.7, IH), 4.16 - 4.03 m, 2H), 3.99 - 3.87 (m, 5H), 3.38 - 3.32 (m, 4H), 2.78 - 2.63 (m, 4H), .10 - 1.94 (m, 4H). .04 (s, 2H), 8.31 (d, J = 8.4, IH), 8.07 (d, J = 6.1, IH), 7.68 (dd, J = 7.1,
1.0 IH), 7.61 (dd, J = 8.4, 7.2, IH), 7.37 (dd, J = 6.1, 1.0, IH), 4.15 - 4.03 m, IH), 4.00 - 3.93 (m, 6H), 3.75 (t, J = 4.6, 4H), 3.42 - 3.35 (m, 4H), .71 - 2.52 (m, 4H) .03 (s, 2H), 8.20 (d, J = 8.4, IH), 7.77 (d, J = 6.3, IH), 7.59 (dd, J = 7.2,
1.2, IH), 7.50 (dd, J = 8.4, 7.2, IH), 6.90 (dd, J = 6.3, 1.2, IH), 4.17 - 4.00 m, 2H), 3.96 - 3.87 (m, IH), 3.81 (t, J = 5.5, 2H), 3.66 (t, J = 5.5, 2H), .77 - 2.59 (m, 4H), 2.11 - 1.93 (m, 4H) .01 (s, 2H), 7.85 (d, J = 9.4, IH), 7.70 (dd, J = 9.0, 5.4, IH), 7.34 (t, J = .3, IH), 7.16 (d, J = 9.5, IH), 4.15 - 4.00 (m, IH), 3.97 - 3.86 (m, 2H), .84 - 3.75 (m, 4H), 3.75 - 3.58 (m, 9H), 2.67 - 2.47 (m, 4H) .05 (s, 2H), 8.22 (d, J = 9.9, IH), 7.98 (dd, J = 9.3, 4.4, IH), 7.64 (t, J = .1, IH), 7.30 (d, J = 9.1, IH), 4.74 - 4.60 (m, IH), 4.22 - 4.13 (m, IH), .12 - 4.04 (m, IH), 4.04 - 3.81 (m, 4H), 3.75 (t, J = 4.6, 5H), 2.78 - 2.59 m, 4H), 2.36 - 2.14 (m, 2H). .04 (s, 2H), 8.24 (d, J = 9.9, IH), 7.99 (dd, J = 9.2, 4.3, IH), 7.65 (t, J = .1, IH), 7.39 - 7.16 (m, IH), 4.72 - 4.65 (m, IH), 4.23 - 4.07 (m, 2H), .06 - 3.64 (m, 5H), 2.82 - 2.63 (m, 4H), 2.37 - 2.13 (m, 2H), 2.12 - 1.90 m, 4H) .04 (s, 2H), 8.15 - 8.00 (m, IH), 7.96 - 7.80 (m, IH), 7.61 (t, J = 9.1, IH), 7.24 - 7.01 (m, IH), 4.19 - 4.10 (m, IH), 4.09 - 3.93 (m, 2H), 3.87 t, J = 5.0, 2H), 3.79 - 3.63 (m, 6H), 2.79 - 2.57 (m, 4H) .03 (s, 2H), 8.14 - 8.04 (m, IH), 7.93 - 7.81 (m, IH), 7.62 (t, J = 9.1,
Figure imgf000157_0001
IH), 7.22 - 7.08 (m, IH), 4.19 - 4.05 (m, 2H), 4.02 - 3.92 (m, IH), 3.87
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
D. Pharmacological examples D.I P2X7 antagonism
Extracellular binding of ATP to P2X7 that is expressed in the cell-membrane opens the ligand gated cation channel and allows Ca2+ entry into the cell. This ligand-induced Ca2+ flux was measured in 132 INl astrocytoma cells overexpressing hP2X7 for the compounds of the present invention.
The calcium assay kit used (Molecular Devices, R8090), provides a Ca2+ sensitive dye together with a quenching dye. However, no specifications are given by the manufacturer. The kit most likely consists of a membrane permeable acetoxymethyl (AM) ester of a fluorescent Ca2+ indicator, such as fluo-4 or fluo-3. Upon cellular uptake, the AM esters get cleaved by esterases, liberating the Ca2+-sensitive dye which can then bind calcium. The dyes have an absorption spectrum compatible with excitation at 488 nm by argon laser sources and a large fluorescence intensity increase in response to Ca2+ binding without an accompanying spectral shift. Emission wavelength is in the range of 510-560 nm.
The fluorescence, and thus the changes in intracellular [Ca 2+η ] in the 132 INl cells was monitored in time before and after addition of the agonist. The effect of the antagonist was measured as %control and as IC50. The pIC50 values (= -log(ICso) values) are listed in Table F-9.
Table F-9 : mean pIC50 values
Figure imgf000162_0001
Figure imgf000162_0002
Figure imgf000162_0003
Figure imgf000163_0001
Figure imgf000163_0002
Figure imgf000163_0003
Figure imgf000164_0001
Figure imgf000164_0002
Figure imgf000164_0003
D.2 THP-I YoPro Uptake assay
The human monocytic cell line THP-I was grown as a suspension culture in RPMI medium supplemented with 10% fetal bovine serum, penicillin/streptomycin (50 units/mL), 2 mM L-glutamine, and 20μM 2-mercaptoethanol. Cells were maintained at a density below 0.5 million per mL. On the day of the assay, cells were washed twice with assay buffer, and then resuspended at 2 million per mL in assay buffer containing 2 μM Yo-Pro-1 (Invitrogen). The assay buffer contained (in mM): 280 sucrose, 5 KCl, 10 glucose, 10 HEPES, 5 N-methyl-D-glucamine. The cells were added at 200k/well into poly-D-lysine- coated black-walled 96-well plates (Biocoat, Becton-Dickinson). Test compounds were dissolved in DMSO, and then added at the test concentration to each well of the 96-well plate. Concentration dependence of block was determined by exposing each well of cells in duplicate rows of a 96-well plate to a serial dilution of test compound. The concentration series usually started at lOμM with a three-fold decrement in concentration. The final DMSO concentration seen by the cells was less than 0.5%. Cells were incubated with test compounds for 30 minutes at 37°C. A background reading was taken using a Gemini SpectraMax with 490 nm excitation and 530 nm emission. Then, 50μL/well of the dye/stimulation buffer containing 2 μM Yo-Pro-1 and 200 μM BzATP was added (final concentration seen by the cells was 2 μM Yo-Pro-1 and 50 μM BzATP). After incubation for 60 minutes at 37°C, an endpoint read was taken in the SpectraMax plate reader. The amount of block of the response was determined by comparing the fluorescence intensity in each well to the average of control wells on each plate. The control wells contained either a known antagonist of P2X7 (positive controls) or a concentration of DMSO equal to that in the test wells. Data were analyzed using a nonlinear regression program (Origin, OriginLab, MA). Results are reported as the -log of the IC50 (pICso).
Table F-IO : mean pIC50 values for P2X7 antagonism
Figure imgf000165_0001
Figure imgf000165_0002
Figure imgf000165_0003
Figure imgf000166_0003
Figure imgf000166_0001
Figure imgf000166_0002

Claims

Claims
1. A compound of formula (I)
Figure imgf000167_0001
including any stereochemical^ isomeric form thereof, wherein n is an integer 1, 2 or 3; m is an integer 1, 2 or 3; p is an integer 1 or 2;
R3 is hydrogen, halo, C^alkyl or C^alkyloxy; X represents O, S, SO2, CR4R5 or NR6; wherein R4 and R5 are each independently from another selected from hydrogen, halo, hydroxy, C^alkyl, C^alkyloxy, or aryl; wherein R6 is hydrogen, phenyl, -CO-R7, or -CO-O-R7, wherein R7 is
Ci_6 alkyl or amino; R1 is a heterocycle selected from pyridinyl or pyrimidinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, C^alkyl, C^alkyloxy, polyhaloC^alkyl, phenyl, C3_6cycloalkyl, C3^CyC loalkyloxy,
Cs^cycloalkylC^alkyloxy, or NR8R9; wherein R8 and R9 are independently from another selected from hydrogen, Cμgalkyl, hydroxyC^alkyl, C3_6cycloalkyl, and wherein R8 and R9 may be taken together with the nitrogen atom to which they are attached to form a azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from C^alkyl, C^alkyloxy, halo, hydroxy, or C^alkylcarbonyl;
R2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, C^alkyl, C^alkyloxy, C3.6cycloalkyl, C3.6cycloalkyloxy, polyhaloC^alkyl, NR10R11, and OR12; wherein R10 and R11 are independently from another selected from hydrogen, Ci_6 alkyl, C3_6cycloalkyl, polyhaloC^alkyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, JV-(1, 5-dioxa-9-aza-spiro[5.5]undec-9- yl), N-(l,7-diaza-spiro[4.4]non-7-yl), N-(2,6-diaza-spiro[4.5]dec-2- yl), and Cμgalkyl substituted with one or two substituents selected from hydroxy, halo, aryl1, C^alkyloxy, C3.6cycloalkyl, hydroxycarbonyl, C^alkylsulfonylamino,
C3.gcycloalkylsulfonylamino, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyridinyl, morpholinyl, amino, mono- or di(Ci_4alkyl)amino, amino substituted with C^alkyl substituted with hydroxy; and wherein R10 and R1 * may be taken together with the nitrogen atom to which they are attached to form a azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, JV-[l,4]-oxazepanyl, morpholinyl, N-(2,6- diaza-spiro[3.3]hept-2-yl), 6-acetyl-2,6-diaza-bicyclo[2.2.2]octane-2- yl, 2-(tetrahydro-furo[3,4-c]pyrrol-5-yl), 2-(2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl), l,l-dioxo-thiomorpholin-4-yl, 2-(2,6-diaza- bicyclo[2.2. l]hept-2-yl), l-(l-amino-3-aza-bicyclo[3.1.0]hex-3-yl), Λ/-(3-acetylamino-8-aza-bicyclo[3.2.1]oct-8-yl), N-[l,4]-diazepanyl, 2-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl), 2-(hexahydro-pyrrolo[3,4- b]pyrrol-l-yl), 2-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl), 2- (octahydro-pyrrolo[3,4-b]pyridin-6-yl), or 2-(3,6-diaza- bicyclo[3.2.0]hept-3-yl), l-amino-3-aza-bicyclo[3.1.0]hex-3-yl ring; which may be optionally substituted with one or two substituents each independently from another selected from halo, hydroxy, C^alkyl, C^alkyloxy, C^alkyloxyC^alkyl, C3_6cycloalkyl, C^alkylcarbonyl, C^^alkyloxycarbonyl,
Ci_4alkyloxycarbonylamino, Cμgalkyl substituted with hydroxy; trifluoromethyl, amino, mono- or di(Cj_4alkyl)amino, amino, mono- or di(C^_4alkyl)amino, trifluoromethyl, JV-(2-oxo-pyrrolidin-l-yl), 2,4-dihydro-[ 1 ,2,4]triazolone-5-yl, C \ _4alkylcarbonylamino, 2,4- dihydro-[l,2,4]triazolone-4-yl, (Ci.4alkylcarbonyl)(C1.4alkyl)amino, trifluoromethylcarbonylamino, hydroxycarbonyl, methylsulfonylamino, aminocarbonyl; wherein R12 is azetidinyl, pyrrolidinyl, piperidinyl, or Cμgalkyl substituted with amino, C3_gcycloalkyl, trifluoromethyl, trifluoroethyl, tetrahydrofuranyl, N-(I -methylpyrrolidinyl), N-(5 -oxo-pyrrolidin-2- yl), or pyridinyl; aryl is phenyl or phenyl substituted with one substituent selected from halo,
C^alkyl, C^alkyloxy or hydroxy; aryl1 is phenyl or phenyl substituted with one substituent selected from halo,
C^alkyl, C^alkyloxy or hydroxy; or a pharmaceutically acceptable acid addition salt thereof, or a solvate thereof.
2. The compound as claimed in claim 1 wherein n is an integer 1, 2 or 3; m is an integer 1, 2 or 3; p is an integer 1 or 2;
R3 is hydrogen, halo, C 1.4 alky 1 or C^alkyloxy; X represents O, S, SO2, CR4R5 or NR6; wherein R4 and R5 are each independently from another selected from hydrogen, halo, hydroxy, C^alkyl, C^alkyloxy, or aryl; wherein R6 is hydrogen, phenyl, -CO-R7, or -CO-O-R7, wherein R7 is
Ci_6 alkyl or amino; R1 is a heterocycle selected from pyridinyl or pyrimidinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, C^alkyl, C^alkyloxy, polyhaloC^alkyl, phenyl, C3_6cycloalkyl, C3_6cycloalkyloxy,
C3_6cycloalkylCi_4alkyloxy, or NR8R9; wherein R8 and R9 are independently from another selected from hydrogen, Ci.galkyl, C3_6cycloalkyl, and wherein R8 and R9 may be taken together with the nitrogen atom to which they are attached to form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from C^alkyl, C^alkyloxy, halo, hydroxy, or C^alkylcarbonyl;
R2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, C^alkyl, C^alkyloxy, C3_6cycloalkyl, C3_6cycloalkyloxy, polyhaloC^alkyl, and NR10R1 *; wherein R10 and R11 are independently from another selected from hydrogen,
Ci.galkyl, C3_6cycloalkyl, polyhaloC^alkyl, tetrahydrofuranyl, tetrahydropyranyl, or C^alkyl substituted with hydroxy, halo, phenyl, C^alkyloxy, C3_6cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl; and wherein R10 and R11 may be taken together with the nitrogen atom to which they are attached to form a azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, JV-[l,4]-oxazepanyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from halo, hydroxy, C^alkyl,
C^alkyloxy, C^alkyloxyC^alkyl, C3_6cycloalkyl, C i _4alkylcarbonyl, C i _4alkyloxycarbonyl,
C^alkyloxycarbonylamino or C^alkylsubstituted with hydroxy; aryl is phenyl or phenyl substituted with one substituent selected from halo, C1 _4alkyl, C j _4alkyloxy or hydroxy; or a pharmaceutically acceptable acid addition salt thereof, or a solvate thereof.
3. The compound as claimed in claim 1 wherein R1 is a heterocycle selected from pyridinyl or pyrimidinyl wherein said heterocycle is substituted with one substituent selected from hydrogen, halo, hydroxy, C^alkyl, C^alkyloxy, polyhaloC^alkyl or phenyl.
4. The compound as claimed in claim 1 wherein R2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with one or two substituents each independently from another selected from hydrogen, halo, hydroxy, C^alkyl or C^alkyloxy.
5. The compound as claimed in claim 1 wherein R2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with NR10R11 wherein R10 and R11 are independently from another selected from hydrogen,
Cμgalkyl, C3_6cycloalkyl, polyhaloC^alkyl, tetrahydrofuranyl, tetrahydropyranyl, or Ci_6 alkyl substituted with hydroxy, halo, phenyl, C^alkyloxy, C3_6cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl.
6. The compound as claimed in claim 1 wherein R2 is a heterocycle selected from quinolinyl or isoquinolinyl, wherein said heterocycle is substituted with NR10R11 wherein R10 and R11 are taken together with the nitrogen atom to which they are attached to form a azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, JV-[l,4]-oxazepanyl or morpholinyl ring which may be optionally substituted with one or two substituents each independently from another selected from halo, hydroxy, C^alkyl, C^alkyloxy, C^alkyloxyC^alkyl, C3.6cycloalkyl, C^alkylcarbonyl, C^alkyloxycarbonyl, C^alkyloxycarbonylamino or Cμgalkylsubstituted with hydroxy.
7. The compound as claimed in claim 1 wherein R3 is hydrogen, n is an integer 2, m is an integer 3, and X represents O.
8. The compound as claimed in claim 1 wherein n is an integer 2, m is an integer 2, and X represents CR4R5 wherein R4 and R5 are each fluoro.
9. The compound as claimed in claim 1 wherein n is an integer 1, m is an integer 3, and X represents CR4R5 wherein R4 and R5 are each fluoro.
10. The compound as claimed in claim 8 or claim 9 wherein R1 is 2-triflouro- methylpyridin-5-yl or R1 is 2-triflouromethylpyrimidin-5-yl.
11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in any of claims 1 to
10.
12. A process for preparing a pharmaceutical composition as claimed in claim 11 wherein a therapeutically active amount of a compound as claimed in any of claims 1 to 10 is intimately mixed with a pharmaceutically acceptable carrier.
13. The compound as claimed in any of claims 1 to 10 for use as a medicine.
14. The compound as claimed in any of claims 1 to 10 for use in the treatment of conditions or diseases selected from P2X7 receptor mediated conditions or diseases.
15. A process for preparing a compound of formula (I) wherein a) an intermediate of formula (II) is reacted with an intermediate of formula (III), in at least one reaction-inert solvent and optionally in the presence of at least one suitable coupling reagent and/or a suitable base;
Figure imgf000171_0001
(II) (III) b) an intermediate of formula (II) is reacted with an intermediate of formula (IV), wherein W is an appropriate leaving grou,p in a reaction-inert solvent and optionally in the presence of a suitable base;
Figure imgf000172_0001
(H) (IV)
or c) compounds of formula (I) are converted into each other following art-known transformation reactions; or if desired; a compound of formula (I) is converted into a pharmaceutically acceptable acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof.
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