WO2007072163A2 - Pyrimidine derivatives - Google Patents

Pyrimidine derivatives Download PDF

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Publication number
WO2007072163A2
WO2007072163A2 PCT/IB2006/003668 IB2006003668W WO2007072163A2 WO 2007072163 A2 WO2007072163 A2 WO 2007072163A2 IB 2006003668 W IB2006003668 W IB 2006003668W WO 2007072163 A2 WO2007072163 A2 WO 2007072163A2
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WO
WIPO (PCT)
Prior art keywords
diamine
pyrimidine
methylamino
azetidin
alkyl
Prior art date
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PCT/IB2006/003668
Other languages
French (fr)
Other versions
WO2007072163A3 (en
Inventor
Andrew Simon Bell
Charlotte Alice Louise Lane
Charles Eric Mowbray
Matthew Duncan Selby
Nigel Alan Swain
David Howard Williams
Original Assignee
Pfizer Limited
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Publication date
Priority to JP2008546672A priority Critical patent/JP5166280B2/en
Priority to CN2006800484357A priority patent/CN101341134B/en
Priority to MEP-2008-5A priority patent/ME00004B/en
Priority to EA200801381A priority patent/EA200801381A1/en
Priority to ES06831747.8T priority patent/ES2628482T3/en
Priority to AU2006327876A priority patent/AU2006327876B2/en
Priority to EP06831747.8A priority patent/EP1966162B1/en
Priority to CA2634018A priority patent/CA2634018C/en
Priority to BRPI0620201-2A priority patent/BRPI0620201A2/en
Priority to DK06831747.8T priority patent/DK1966162T3/en
Priority to RS20170607A priority patent/RS56102B1/en
Priority to AP2008004486A priority patent/AP2008004486A0/en
Application filed by Pfizer Limited filed Critical Pfizer Limited
Priority to LTEP06831747.8T priority patent/LT1966162T/en
Priority to KR1020087014871A priority patent/KR101152719B1/en
Priority to RSP-2008/0278A priority patent/RS20080278A/en
Priority to SI200632178A priority patent/SI1966162T1/en
Priority to AP2008004485A priority patent/AP2008004485A0/en
Publication of WO2007072163A2 publication Critical patent/WO2007072163A2/en
Publication of WO2007072163A3 publication Critical patent/WO2007072163A3/en
Priority to IL191432A priority patent/IL191432A/en
Priority to TNP2008000269A priority patent/TNSN08269A1/en
Priority to NO20082980A priority patent/NO341075B1/en
Priority to HK09101141.7A priority patent/HK1120269A1/en
Priority to HRP20170896TT priority patent/HRP20170896T1/en
Priority to CY20171100619T priority patent/CY1118987T1/en

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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D497/08—Bridged systems

Definitions

  • This invention relates to pyrimidine derivatives and to processes for the preparation of, compositions containing and the uses of, such derivatives.
  • the pyrimidine derivatives of the present invention are histamine H 4 receptor ligands and have therefore a number of therapeutic applications, particularly in the treatment of asthma, allergic rhinitis, chronic obstructive pulmonary disorder (COPD) and histamine-mediated inflammatory diseases.
  • COPD chronic obstructive pulmonary disorder
  • the histamine H 4 receptor is a 390 amino-acid, seven-transmembrane G protein coupled receptor with approximately 40 % homology to the histamine H 3 receptor. In contrast to the H 3 receptor, which is primarily located in the brain, the H 4 receptor is expressed at greater levels in eosinophils and mast cells, among other inflammatory cells. H 4 receptor ligands should thus be suitable for the treatment of various inflammatory disorders.
  • diseases where treatment with H 4 ligands are inflammatory bowel disease, Crohn's disease, colitis ulcerosa, dermatitis, psoriasis, conjunctivitis, rheumatoid arthritis, respiratory diseases such as adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion and allergic congestion.
  • respiratory diseases such as adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy-induced airway responses, allergic r
  • Histamine H 4 receptor ligands have been developed. An overview of the current advance in H 4 ligand research and patenting is given in Expert Opin. Ther. Patents (2003) 13(6). Examples of Histamine H 4 receptor ligands can be found in WO 02/072548, WO 04/022537 and in Terzioglu et al., J. Bioorg. Med. Chem. Lett. 14 (2004), 5251-5256.
  • H 4 ligands are known there is still a need to further provide new H 4 ligands that are good drug candidates.
  • preferred compounds should bind potently to the histamine H 4 receptor whilst showing little affinity for other receptors. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favourable pharmacokinetic properties. They should be non-toxic and demonstrate few side-effects.
  • the present invention thus relates to pyrimidine derivatives of formula (I):
  • R 1 is Ci. 8 alkyl, C ⁇ cycloalkyl-Co-ealkyl- optionally substituted with methyl, alkoxyalkyl containing 3 to 8 carbon atoms, het-C 0 - 6 alkyl-, CFrC ⁇ alkyl-, CF 3 OC 2 - 3 alkyl-, aryl-C 0 - 6 alkyl- or C ⁇ hydroxyalkyl;
  • R 2 is het, provided that the het group contains at least one nitrogen atom or is substituted by a group which contains at least one nitrogen atom; or R 2 is NH(CH 2 ) 2 NH 2 , NH(CHz) 2 NHCH 3 , or NH(CH 2 ) 2 NH(CH 3 ) 2 ,
  • R 3 is H, C 1- ⁇ alkyl, (CH ⁇ p C ⁇ cycloalkyl, alkoxyalkyl containing 3 to 8 carbon atoms, (CH 2 ) n CF 3 , (CH 2 ) X OCF 3 or Ci. ⁇ hydroxyalkyl; or R 3 and R 2 together with the nitrogen atom to which they are bound form a 4 to 8 membered non-aromatic heterocyclic group which optionally contains one or more further heteroatoms or groups inde pendently selected from N, O, S, S(O) and S(O) 2 , wherein the heterocyclic group is optionally a bridged bicyclic group, a spiro bicyclic group or is optionally fused to a 3-, 4-, 5- or 6- membered carbocyclic group or a A-, 5- or 6-membered heterocyclic group which contains at least one ring member independently selected from N, O, S , S(O) and S(O) 2 , and wherein the ring system as
  • R 5 is H or NR 11 R 12 ;
  • R 6 and R 7 are each independently selected from H, C ⁇ alkyl and (CH 2 ) j C 3 . 7 cycloalkyl; or R 6 and R 7 , together with the nitrogen atom to which they are bound, form a 4, 5 or 6 membered heterocyclic group;
  • R 8 is H or C 1-3 alkyl;
  • R 9 and R 10 are each independently selected from H, C ⁇ alkyl and (CH 2 ) k C 3 . 7 cycloalkyl; or R 9 and R 10 , together with the nitrogen atom to which they are bound, form a 4, 5 or 6 membered heterocyclic group;
  • R 11 and R 12 are each independently selected from H, C 1-6 alkyl and (CH 2 )
  • R 13 and R 14 are each independently selected from H, C 1-6 alkyl and (CH 2 ) m C 3-7 cycloalkyl; or R 13 and R 14 , together with the nitrogen atom to which they are bound, form a 4, 5 or 6 membered heterocyclic group;
  • aryl 1 is phenyl, naphthyl, anthracyl or phenanthryl; and het 1 is an aromatic or non-aromatic 4-, 5- or 6- membered heterocycle which contains at least one N, O or S heteroatom, optionally fused to a 4-, 5- or 6- membered carbocyclic group or a second 4-, 5- or 6- membered heterocycle which contains at least one N, O or S heteroatom.
  • aryl is phenyl.
  • each separate substituent may be the same or different to the other substituent(s) defined by the same term.
  • R 1 and R z both comprise a "het" group, then the two het groups may be the same or different.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, and R 8 is hydrogen. In a further embodiment, R 1 , R 2 , R 3 , R 5 and R 8 are as defined above, and R 4 is hydrogen.
  • R 2 , R 3 , R 5 and R 8 are as defined above, R 4 is hydrogen and R 1 is C 3 . 7 cycloalkyl-
  • R 2 , R 3 , R 5 and R 8 are as defined above, R 4 is hydrogen and R 1 is C 3 . 5 cycloalkyl-
  • R 2 , R 3 , R 5 and R B are as defined above, R 4 is hydrogen and R 1 is cyclopropyl , cyclopropyl-methyl or methyl-cyclopropyl.
  • R 2 , R 3 , R 5 and R 8 are as defined above, R 4 is hydrogen and R 1 is C 1 -C 8 alkyl.
  • R 2 , R 3 , R 5 and R 8 are as defined above, R 4 is hydrogen and R 1 is C 1 -C 6 alkyl.
  • R 2 , R 3 , R 5 and R 8 are as defined above, R 4 is hydrogen and R 1 is ethyl, propyl, butyl, 1-methyl-propyl, 2-methyl-propyI, 2,2-dimethyl-propyl, 2-methyl-butyl, ter-butyl, 1 -methyl-butyl, 3- methyl-butyl, 3,3-dimethyl-butyl, 1 ,2-dimethyl-propyl or isopropyl.
  • R 1 , R 4 , R 5 and R 8 are as defined above, and R 2 is net, provided that the het group contains at least one nitrogen atom or is substituted by a group which contains at least one nitrogen atom and R 3 is H, Ci.
  • R 1 , R 4 , R 5 and R 8 are as defined above, and R 2 and R 3 , together with the nitrogen atom to which they are bound, form a 4 to 8 membered non-aromatic heterocyclic group which optionally contains one or more further heteroatoms or groups independently selected from N, O, S, S(O) and S(O) 2 , wherein the heterocyclic group is optionally a bridged bicyclic group or is optionally fused to a 3-, A-, 5- or 6- membered carbocyclic group or a A-, 5- or 6-membered heterocyclic group which contains at least one ring member independently selected from N, O, S , S(O) and S(O) 2 , and wherein the ring system as a whole is optionally substituted by one or more substituents independently selected from C 1- 6 alkyl, NR 6 R 7 , (CH 2 ) a C 3 - 7 cycloalkyl, alkoxyalkyl containing 2 to
  • R 1 , R 4 , R 5 and R 8 are as defined above, and R 2 and R 3 , together with the nitrogen atom to which they are bound, form a 4 to 8 membered non-aromatic heterocyclic group which optionally contains one or more further nitrogen atoms, wherein the heterocyclic group is optionally a bridged bicyclic group or is optionally fused to a 3-, 4-, 5- or 6- membered carbocyclic group or a A-, 5- or 6-membered heterocyclic group which contains at least one nitrogen atom, and wherein the ring system as a whole is optionally substituted by one or more substituents independently selected from Ci -6 aikyl, NR 6 R 7 , (CH 2 ) a C 3-7 cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH 2 ) b het 1 , (CH 2 ) 0 CF 3 , (CH 2 ) y OCF 3 , (CH 2 )
  • R 1 , R 4 , R 5 and R 8 are as defined above, and R 2 is NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 2 NHCH 3 , NH(CH 2 ) 2 NH(CH 3 ) 2 and R 3 is H.
  • R 1 , R 4 , R 5 and R 8 are as defined above, and R 2 and R 3 , together with the nitrogen atom to which they are bound, form a 4 to 8 membered non-aromatic heterocyclic group selected from the following ring systems:
  • ring system as a whole may be substituted by one or more C 1-S alkyl or (CH 2 )aC 3 . 6 cycloalkyl groups.
  • R 1 , R 4 , R 5 and R 8 are as defined above, and R 2 and R 3 , together with the nitrogen atom to which they are bound, form a 4 to 8 membered non-aromatic heterocyclic group selected from the following ring systems: wherein R 6 and R 7 are independently selected from H or CH 3 .
  • R 1 , R 4 , R 5 and R 8 are as defined above, R 3 is H and R 2 is a pyrrolidinyl group, optionally substituted by one or more substituents independently selected from d. 6 alkyl, NR 6 R 7 , (CH 2 )aC 3 . 7 cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH 2 ) b het 1 , (CH 2 ) C CF 3 , (CH 2 ) y OCF 3 , (CH 2 ) d aryl and C ⁇ hydroxyalkyl.
  • R 1 , R 4 , R 5 and R 8 are as defined above, R 3 is H and R 2 is a pyrrolidinyl group, optionally substituted by one or more substituents independently selected from C 1-6 alkyl, NR 6 R 7 , (CH 2 ) a C 3 - 7 cycloalkyl and alkoxyalkyl containing 2 to 8 carbon atoms.
  • R 1 , R 2 , R 3 , R 4 and R 8 are as defined above, and R 5 is H or NH 2 .
  • halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo, in particular fluoro or chloro.
  • alkyl includes both straight-chain and branched chain groups. This also applies if they carry substituents such as a hydroxy substitutent or occur as substituents of other radicals, for example alkoxy groups.
  • C 1-4 alkyl includes methyl, ethyl, n-propyl, /so-propyl, /7-butyl, /so-butyl, sec- butyl and ferf-butyl moieties .
  • alkoxy moieties examples are methoxy, ethoxy, n- propyloxy, /so-propyloxy, /7-butyloxy, /so-butyloxy, sec-butyloxy and ferf-butyloxy.
  • suitable d ⁇ alkyl moieties substituted by an hydroxyl group examples are hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, etc.
  • C 3 -C 7 cycloalkyl includes bridged bicyclic cycloalky! such as bicyclo[1.1.1]pentyl.
  • Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[1.1.1]pentyl.
  • Preferred "4 to 8 membered heterocyclic group which optionally contains one or more further heteroatoms or groups independently selected from N, O, S, S(O) and S(O) 2 , wherein the heterocyclic group is a spiro bicyclic group" are 2,8-diaza-spiro[4.5]dec-2-yl and 2,7-diaza-spiro[4.4]non-2-yl.
  • Example compounds that fall within the above definition of the invention include:
  • An embodiment of the invention provides the following compounds: ⁇ / 4 -(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine, ⁇ / 4 -(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine tartrate, N 4 -lsobutyl-6-[(3R)-3-(methylamino)pyrrolidin-1 -yrjpyrimidine-2,4-diamine,
  • a further embodiment of the invention provides the following compounds: ⁇ / 4 -(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine, ⁇ / 4 -(Cydopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine tartrate, N 4 -(2,2-Dimethylpropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, and, N 4 -(2,2-Dimethyipropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine hydrochloride, or a pharmaceutically and/or veterinarily acceptable derivative thereof.
  • pharmaceutically and/or veterinarily acceptable derivative it is meant any pharmaceutically or veterinarily acceptable salt, solvate, ester or amide, or salt or solvate of such ester or amide, of the compounds of formula (I) or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
  • pharmaceutically and/or veterinarily acceptable derivative means any pharmaceutically or veterinarily acceptable salt or solvate of the compounds of formula (I)
  • Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluor
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • compositions of formula (I) may be prepared by one or more of three methods:
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non-ionised.
  • references to compounds of formula (I) include derivatives thereof and complexes of the compound or derivatives thereof.
  • the compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (I).
  • prodrugs and isomers thereof including optical, geometric and tautomeric isomers
  • isotopically-labeled compounds of formula (I) so-called so-called 'pro-drugs' of the compounds of formula (I) are also within the scope of the invention.
  • certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • prodrugs as Novel Delivery Systems. Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • prodrugs in accordance with the invention include:
  • metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug are also included within the scope of the invention.
  • Some examples of metabolites in accordance with the invention include:
  • Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic, or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic, or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically- enriched form using chromatography, typically HPLC, on an asymmetric resin.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. WiI en (Wiley, New York, 1994).
  • the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • Certain isotopically labelled compounds of formula (I) 1 for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically labelled reagent in place of the non-labelled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.
  • compounds of formula (I) may be prepared by the reaction of a compound of formula (II) with a suitable amine.
  • reaction is effected by using an excess of the amine or stoichiometric quantity of the amine in the presence of a base such as a tertiary amine base (e.g. triethylamine or N-ethyl-N-isopropylpropan-2-amine); optionally in the presence of a suitable solvent (e.g. dimethyl sulphoxide or 1-methylpyrrolidin-2-one); optionally in the presence of a catalyst (such as caesium fluoride); and at elevated temperature, such as 120°C to 150°C.
  • a base such as a tertiary amine base (e.g. triethylamine or N-ethyl-N-isopropylpropan-2-amine); optionally in the presence of a suitable solvent (e.g. dimethyl sulphoxide or 1-methylpyrrolidin
  • Compounds of formula (II) may be prepared by reaction of a compound of formula (III) with a suitable amine. Conveniently reaction is effected by using an excess of the amine or stoichiometric quantity of the amine in the presence of a base such as a tertiary amine base (e.g. triethylamine or N-ethyl-N- isopropylpropan-2-amine); in the presence of a suitable solvent (e.g. ethanol, 2-propanol or 1- methylpyrrolidin-2-one); and at ambient or elevated temperature, such as ambient temperature to 85°C.
  • a base such as a tertiary amine base (e.g. triethylamine or N-ethyl-N- isopropylpropan-2-amine)
  • a suitable solvent e.g. ethanol, 2-propanol or 1- methylpyrrolidin-2-one
  • ambient or elevated temperature such as ambient temperature to 85°C.
  • the groups X and Y represent a halogen atom (e.g. chlorine) or an alternative leaving group such as a sulphonate ester (e.g. 4-methylphenyl sulphonate) or a sulphonyl group (e.g. methane sulphonyl or phenyl sulphonyl) or a sulphinyl group (e.g. methane sulphinyl).
  • a halogen atom e.g. chlorine
  • an alternative leaving group such as a sulphonate ester (e.g. 4-methylphenyl sulphonate) or a sulphonyl group (e.g. methane sulphonyl or phenyl sulphonyl) or a sulphinyl group (e.g. methane sulphinyl).
  • transformations described may be carried out in a manner that does not require the isolation or purification of the intermediate compound of formula (II) but that requires sequential addition of suitable amines, with or without additional base (e.g. triethylamine or N-ethyl-N-isopropylpropan-2-amine) or solvent, to a compound or formula (III) in the presence of a suitable solvent (e.g. 1-methylpyrrolidin-2-one or dimethyl sulphoxide) with or without heating the reaction mixture between the addition of the two amines, and with or without the addition of a catalyst (such as caesium fluoride).
  • suitable solvent e.g. 1-methylpyrrolidin-2-one or dimethyl sulphoxide
  • the compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • excipients may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences. 19th Edition (Mack Publishing Company, 1995).
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano- particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, ⁇ (6), 981-986, by Liang and Chen (2001).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent.
  • Some components of the formulation may perform more than one function.
  • the compound of formula (I) may be water-soluble or insoluble.
  • a water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes.
  • the compound of formula (I) may be in the form of multiparticulate beads.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
  • ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.
  • Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line. 25(2), 1-14, by Verma ef a/ (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, ' intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug-coated stents and poly(d/-lactic-coglycolic)acid (PGLA) microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
  • Topical administration examples include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to ( form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to ( form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or hydroxypropyl-methylcellulose
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
  • a typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount or the drug product is packaged as discrete single dose units for use in the inhaler device.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from 1 ⁇ g to 4000 ⁇ g of the compound of formula (I).
  • the overall daily dose will typically be in the range 1 ⁇ g to 20 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethyl cellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene giycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene giycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma- cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
  • compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the total daily dose of the compounds of the invention is typically in the range 0.001 mg to 2000 mg depending, of course, on the mode of administration.
  • oral administration may require a total daily dose of from 0.1 mg to 2000 mg, while an intravenous dose may only require from 0.01 mg to 100 mg.
  • the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
  • These dosages are based on an average human subject having a weight of about 60 kg to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • the compounds of the invention can also be used as a combination with one or more additional therapeutic agents to be co-administered to a patient to obtain some particularly desired therapeutic end result.
  • the second and more additional therapeutic agents may also be a compound of the formula (I) or a pharmaceutically and/ or veterinarily acceptable derivative thereof, or one or more histamine H 4 receptor ligands known in the art. More typically, the second and more therapeutic agents will be selected from a different class of therapeutic agents.
  • co-administration co-administered” and “in combination with” referring to the compounds of the invention and one or more other therapeutic agents, is intended to mean, and does refer to and include the following:
  • Suitable examples of other therapeutic agents which may be used in combination with the compound(s) of the invention or compositions thereof, include, but are by no means limited to : • Histamine H 1 receptor antagonists, in particular loratidine, desloratidine, fexofenadine and cetirizine
  • Leukotriene antagonists including antagonists of LTB 4 , LTC 4 , LTD 4 , and LTE 4 ; for example Montelukast • Phosphodiesterase inhibitors, including PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDE7 inhibitors and inhibitors of two or more phosphodiesterases, such as dual PDE3/PDE4 inhibitors
  • neurotransmitter re-uptake inhibitors in particular fluoxetine, setraline, paroxetine, ziprasidone
  • OC 1 - and ⁇ 2 -adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use • Muscarinic M3 receptor antagonists or anticholinergic agents
  • Xanthines such as theophylline and aminophylline
  • Non-steroidal antiinflammatories such as sodium cromoglycate and nedocromil sodium • Ketotifen • COX-1 inhibitors (NSAIDs) and COX-2 selective inhibitors
  • Anti-tumor necrosis factor (anti-TNF- ⁇ ) agents • Adhesion molecule inhibitors including VLA-4 antagonists
  • MMPs matrix metalloproteases
  • Tachykinin NK 1 , NK 2 and NK 3 receptor antagonists • Elastase inhibitors
  • cytokine signaling pathways such as p38 MAP kinase inhibitors, syk tyrosine kinase inhibitors or JAK kinase inhibitors
  • Prostaglandin D2 receptor antagonists DP1 and CRTH2
  • Inhibitors of Prostaglandin D synthase PGDS
  • Histamine H 1 receptor antagonists in particular loratidine, desloratidine, fexofenadine and cetirizine,
  • Histamine H 2 receptor antagonists • Histamine H 2 receptor antagonists, • Leukotriene antagonists, including antagonists of LTB 4 , LTC 4 , LTD 4 , and LTE 4 , for example Montelukast, and/or,
  • Phosphodiesterase PDE4 inhibitors form a further embodiment of the invention.
  • the compounds of formula (I) have the ability to interact with the H 4 receptor and thereby have a wide range of therapeutic applications, as described further below, because of the essential role, which the H 4 receptor plays in the physiology of all mammals.
  • H 4 ligands are meant to include H 4 receptor antagonists, agonists and inverse agonists.
  • H 4 antagonists are believed to be most suitable.
  • a further aspect of the present invention relates to the compounds of formula (I) or pharmaceutically acceptable salts, derived forms or compositions thereof, for use as medicaments, more particularly in the treatment of diseases, disorders, and conditions in which the H 4 receptor is involved. More specifically, the present invention also concerns the compounds of the invention for use in the treatment of diseases, disorders, and conditions selected from the group consisting of:
  • respiratory diseases e.g. adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis
  • allergy allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion, allergic congestion;
  • the compounds of formula (I) according to the present invention are particularly suitable for the treatment of asthma, allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion and allergic congestion.
  • a still further aspect of the present invention also relates to the use of the compounds of the invention for the manufacture of a drug being a H 4 ligand.
  • the present inventions concerns the use of the compounds of formula (I), or pharmaceutically and/or veterinarily acceptable derivatives thereof, for the manufacture of a drug for the treatment of H 4 mediated diseases and/or conditions, in particular the diseases and/or conditions listed above.
  • the present invention provides a particularly interesting method to treat a mammal, including a human being, with an effective amount of a compound of formula (I), or a pharmaceutically and/or veterinarily acceptable derivative thereof. More precisely, the present invention provides a particularly interesting ' method for the treatment of a H 4 mediated diseases and/or conditions in a mammal, including a human being, in particular the diseases and/or conditions listed above, comprising administering to said mammal an effective amount of a compound of the invention.
  • the compounds of the invention may have the advantage that they are more potent, have a longer duration of action, have a broader range of activity, are more stable, are easier and/or safer to prepare, have fewer side effects or are more selective, or have other more useful properties than the compounds of the prior art.
  • Azetidin-3-yl-methyl-carbamic acid tert-butyl ester (1.97 g, 11 mmol) in IPA (5 mL) was added dropwise to a stirred solution of 4,6-dichloropyrimidine (1.49 g, 10 mmol) in IPA (20 mL) followed by dropwise addition of TEA (2.11 mL, 15.1 mmol) at ambient temperature under N 2 .
  • TEA 2.11 mL, 15.1 mmol
  • the resulting milky yellow solution was heated to 80 0 C and maintained at 80 0 C for 2 hours. The solution was allowed to cool and evaporated to dryness to give a yellow oil.
  • the crude material was partitioned between DCM (70 mL) and water (30 ml_).
  • the aqueous extract was re-extracted with DCM (70 mL).
  • the combined organic extract was washed with saturated aqueous sodium bicarbonate (30 mL), dried (MgSO 4 ), filtered and evaporated to give a golden coloured oil.
  • the crude oil was purified by flash column chromatography on silica gel eluting with DCM : MeOH (99 : 1 changing to 96 : 4 by volume) to yield the title compound as a solid (1.93 g, 64%).
  • the title compound was prepared by a method similar to that described for preparation 26, using the title compound of preparation 12 and cyclopropylmethylamine, in 48% yield.
  • the title compound was prepared by a method similar to that described for preparation 26, using the title compound of preparation 12 and 3,3-dimethylbutan-1 -amine, in 58% yield.
  • the title compound was prepared by a method similar to that described for preparation 26, using the title compound of preparation 12 and 3-fluorobenzylamine using 1 ,2-diethoxy-ethane as reaction solvent, in 53% yield.
  • the title compound was prepared by a method similar to that described for preparation 26, using the title compound of preparation 12 and 3-methoxy-benzylamine, in 17% yield.
  • 2-amino-4,6-dichloropyrimidine (508mg, 3.1mmol) was added to a suspension of 1- methylcyclopropylamine hydrochloride (1.0g, 9.3mmol) and sodium methoxide (502mg, 9.30mmol) in NMP (3ml). The resulting mixture was heated at 90°C for 16 hours and then cooled to room temperature. The reaction mixture was diluted with water (20ml) and the resulting precipitate filtered off, washed with further water (20ml) and dried in vacuo to give the title compound as a colourless solid (280mg, 15%).
  • the combined organic extracts were washed with saturated aqueous sodium chloride (100ml), dried (magnesium sulphate) and reduced in vacuo to give an orange oil.
  • the oil was re-dissolved in THF (85ml), cooled to 0 0 C and treated with potassium ferf-butoxide (3.0Og, 40.6mmol).
  • the reaction was left to stir for 30 minutes prior to the addition of methyl iodide (3.0ml, 41.7mmol) and then allowed to warm gradually to room temperature.
  • the reaction mixture was partitioned between ethyl acetate (200ml) and water (100ml). The aqueous phase was separated and extracted with further ethyl acetate (100ml).
  • the combined organic extracts were washed with saturated aqueous sodium chloride (100ml), dried (magnesium sulphate) and reduced in vacuo to give the title compound as an orange oil (15.3g, 100%).
  • the title compound was prepared by a similar method to that described for example 6, using the title compound of preparation 21 , in 70% yield.
  • a suspension of the compound of preparation 15 (1.8g, 5.5mmol) in cyclopropylmethanamine (5.4ml, 62.3mmol) and TEA (1.53ml, 11 mmol) was heated in a sealed pressure vessel at 120°C for 24 hours. The excess amine was removed in vacuo and the residue partitioned between water (100ml) and DCM (100ml). The aqueous phase was separated and extracted with further DCM (100ml). The combined organic extracts were washed with saturated aqueous sodium chloride (100ml) and the solvent removed in vacuo.
  • Example , 9a ⁇ -fCvclopropvlmethvD-S-rOffl-S-fmethvlaminotPvrrolidin-i-vnpyrimidine- ⁇ - diamine L -tartrate
  • the title compound of preparation 26 (22 mg, 0.07 mmol) was dissolved in trifluoroacetic acid (1 mL) and stirred at ambient temperature for 2 hours after which time the reaction mixture was concentrated in vacuo.
  • the residual gum was purified by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (98 : 2 : 0.2 changing to 90 : 10 : 1 , by volume) to yield the title compound as a gum (12mg, 73%).
  • the title compound was prepared by a method similar to that described for example 60, using the compound of preparation 25, in 91% yield.
  • Example 62 6-(3-Methylamino-azetidin-1-yl)-N 4 -(3,3,3-trifluoro-propyl)-pyrimidine-2.4-diamine
  • the title compound was prepared by a method similar to that described for example 60, using the compound of preparation 28, in 85% yield.
  • the title compound was prepared by a method similar to that described for example 60, using the compound of preparation 29, in 87% yield.
  • the title compound was prepared by a method similar to that described for example 60, using the compound of preparation 32, in 86% yield.
  • the title compound was prepared by a method similar to that described for example 60, using the compound of preparation 33, in 81% yield.
  • the title compound of preparation 18 (20 mg, 0.08 mmol) was treated with DMSO (150 ⁇ L) and N- methylpiperazine (88 ⁇ L, 0.79 mmol) and heated to 120 0 C in a sealed vessel for 16 hours.
  • the reaction mixture was cooled to ambient temperature, partitioned between water (2 mL) and ethyl acetate (2 ml_) and filtered through diatomaceous earth, washing with further ethyl acetate (15 mL).
  • Cell pellets from CHO cells expressing the histamine H 4 receptor were homogenised in ice-cold 5OmM Tris-HCI/0.5mM CaCI 2 buffer containing a protease inhibitor cocktail (Roche®, United Kingdom) using a ground glass homogeniser. Homogenates were centrifuged at 4800Og for 30min at 4°C. The membrane pellet was resuspended in fresh buffer and the centrifugation step was repeated as described above. The membrane pellet was resuspended in 5OmM Tris-HCI in the same volume as the original cell pellet.
  • the compounds of the Examples have been tested in the H 4 binding assay described above using either method 1 or method 2.
  • Preferred examples have a Ki value of less than 1 ⁇ M in the H 4 binding assay.
  • Most preferred examples have a Ki value of less than 500 nM in the H 4 binding assay (method 2).
  • the specific K; values for the Example compounds that have been tested in method 1 and method 2 are given in the table below:

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Abstract

A compound of Formula (I): or a pharmaceutically and/or veterinarily acceptable derivative thereof, wherein R1, R2, R3, R4, R5, and R8 are as defined above. The compounds are histamine H4 receptor ligands.

Description

PYRIMIDINE DERIVATIVES
This invention relates to pyrimidine derivatives and to processes for the preparation of, compositions containing and the uses of, such derivatives.
The pyrimidine derivatives of the present invention are histamine H4 receptor ligands and have therefore a number of therapeutic applications, particularly in the treatment of asthma, allergic rhinitis, chronic obstructive pulmonary disorder (COPD) and histamine-mediated inflammatory diseases.
The histamine H4 receptor is a 390 amino-acid, seven-transmembrane G protein coupled receptor with approximately 40 % homology to the histamine H3 receptor. In contrast to the H3 receptor, which is primarily located in the brain, the H4 receptor is expressed at greater levels in eosinophils and mast cells, among other inflammatory cells. H4 receptor ligands should thus be suitable for the treatment of various inflammatory disorders. Examples of diseases where treatment with H4 ligands is particularly appropriate are inflammatory bowel disease, Crohn's disease, colitis ulcerosa, dermatitis, psoriasis, conjunctivitis, rheumatoid arthritis, respiratory diseases such as adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion and allergic congestion.
Recently some histamine H4 receptor ligands have been developed. An overview of the current advance in H4 ligand research and patenting is given in Expert Opin. Ther. Patents (2003) 13(6). Examples of Histamine H4 receptor ligands can be found in WO 02/072548, WO 04/022537 and in Terzioglu et al., J. Bioorg. Med. Chem. Lett. 14 (2004), 5251-5256.
Although H4 ligands are known there is still a need to further provide new H4 ligands that are good drug candidates. In particular, preferred compounds should bind potently to the histamine H4 receptor whilst showing little affinity for other receptors. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favourable pharmacokinetic properties. They should be non-toxic and demonstrate few side-effects.
The present invention thus relates to pyrimidine derivatives of formula (I):
Figure imgf000002_0001
or a pharmaceutically and/or veteriπarily acceptable derivative thereof, wherein: R1 is Ci.8alkyl, C^cycloalkyl-Co-ealkyl- optionally substituted with methyl, alkoxyalkyl containing 3 to 8 carbon atoms, het-C0-6alkyl-, CFrC^alkyl-, CF3OC2-3alkyl-, aryl-C0-6alkyl- or C^hydroxyalkyl; R2 is het, provided that the het group contains at least one nitrogen atom or is substituted by a group which contains at least one nitrogen atom; or R2 is NH(CH2)2NH2, NH(CHz)2NHCH3, or NH(CH2)2NH(CH3)2,
R3 is H, C1-βalkyl, (CH^pC^cycloalkyl, alkoxyalkyl containing 3 to 8 carbon atoms, (CH2)nCF3, (CH2)XOCF3 or Ci.βhydroxyalkyl; or R3 and R2 together with the nitrogen atom to which they are bound form a 4 to 8 membered non-aromatic heterocyclic group which optionally contains one or more further heteroatoms or groups inde pendently selected from N, O, S, S(O) and S(O)2, wherein the heterocyclic group is optionally a bridged bicyclic group, a spiro bicyclic group or is optionally fused to a 3-, 4-, 5- or 6- membered carbocyclic group or a A-, 5- or 6-membered heterocyclic group which contains at least one ring member independently selected from N, O, S , S(O) and S(O)2, and wherein the ring system as a whole is optionally substituted by one or more substituents independently selected from C1-6alkyl, NR6R7, (CH2)aC3-7cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH2)bhet1, (CH2)CCF3, (CH2)yOCF3, (CH2)daryl and C^hydroxyalkyl, provided that the ring system as a whole contains at least two nitrogen atoms or contains one nitrogen atom and is substituted by a group which contains at least one nitrogen atom; R4 is H; or R1 and R4 together with the nitrogen atom to which they are bound form a 4 to 8 membered non-aromatic heterocyclic group which optionally contains one or more further heteroatoms or groups independently selected from N, O, S , S(O) and S(O)2, wherein the heterocyclic group is optionally a bridged bicyclic group or is optionally fused to a 3-, 4-, 5- or 6- membered carbocyclic group or a 4-, 5- or 6-membered heterocyclic group which contains at least one ring member independently selected from N, O, S, S(O) and S(O)2, and wherein the ring system as a whole is optionally substituted by one or more substituents independently selected from C^alkyl, fluoro, NR9R10, (CH2)eC3.7cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH2)fhet1, (CH2)gCF3, (CH2)ZOCF3, (CH2)haryl and d.6hydroxyalkyl; R5 is H or NR11R12;
R6 and R7 are each independently selected from H, C^alkyl and (CH2)jC3.7cycloalkyl; or R6 and R7, together with the nitrogen atom to which they are bound, form a 4, 5 or 6 membered heterocyclic group; R8 is H or C1-3alkyl;
R9 and R10 are each independently selected from H, C^alkyl and (CH2)kC3.7cycloalkyl; or R9 and R10, together with the nitrogen atom to which they are bound, form a 4, 5 or 6 membered heterocyclic group; R11 and R12 are each independently selected from H, C1-6alkyl and (CH2)|C3-7cycloalkyl; or R11 and R12, together with the nitrogen atom to which they are bound, form a 4, 5 or 6 membered heterocyclic group; R13 and R14 are each independently selected from H, C1-6alkyl and (CH2)mC3-7cycloalkyl; or R13 and R14, together with the nitrogen atom to which they are bound, form a 4, 5 or 6 membered heterocyclic group; a, b, c, d, e, f, g, h, j, k, I, m and p are each independently selected from O, 1 , 2 and 3; n is 1 , 2 or 3; x is 2 or 3, wherein if x is 3, then the (CH2)3 group may be replaced with a branched alkyl group containing 3 carbon atoms; y and z are each independently selected from 1 , 2 and 3 aryl is phenyl, naphthyl, anthracyl or phenanthryl, each optionally substituted by one or more groups independently selected from C1-8alkyl, C1-8alkoxy, OH, halo, CF3, CHF2, OCF3, OCHF2, SCF3, hydroxy-Ct. 6alkyl, CMalkoxy-C1-6alkyl, C1.4alkyl-S-C1.4a!kyl, aryl1, het1, Oaryl1, Ohet1, Saryl1, Shet1, CF2CF3, CH2CF3, CF2CH3, C(O)NR13R14, C3.8cycloalkyl, C^cycloalkyl-C^alkyl, Cs^cycloalkyl-C^alkoxy, C3.7cycloalkyl-O- C1-4alkyl, C3.7cycloalkyl-Ci-4alkoxy-Ci^alkyl, OC3.7cycloalkyl and SC3-7cycloalkyl, wherein the aryl1 and het1 grou'ps are optionally substituted by at least one group selected from C1-6alkyl, C3-7cycloalkyl, C1- 6alkoxy, OC3-7cycloalkyl, halo, CN, OH, CF3, CHF2, OCF3, OCHF2, hydroxyCi-6alkyl, C^alkoxy-C^alkyl, SC^alkyl and SCF3; het is 4 to 8 membered non-aromatic heterocyclic group which contains at least one heteroatom or group independently selected from N, O, S , S(O) and S(O)2, wherein the heterocyclic group is optionally a bridged bicyclic group or is optionally fused to a 3-, A-, 5- or 6- membered carbocyclic group or a A-, 5- or 6-membered heterocyclic group which contains at least one ring member independently selected from N, O, S, S(O) and S(O)2, and wherein the ring system as a whole is optionally substituted by one or more substituents independently selected from Ci-6alkyl, NR6R7, (CH2)aC3.7cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH2)bhet1, (CH2)CCF3, (CH2)yOCF3, (CH2)daryl and C^hydroxyalkyl; aryl1 is phenyl, naphthyl, anthracyl or phenanthryl; and het1 is an aromatic or non-aromatic 4-, 5- or 6- membered heterocycle which contains at least one N, O or S heteroatom, optionally fused to a 4-, 5- or 6- membered carbocyclic group or a second 4-, 5- or 6- membered heterocycle which contains at least one N, O or S heteroatom. Preferably aryl is phenyl.
For embodiments in which the groups "aryl", "aryl1", "het" and "het1" may be a substituent on more than one part of the compound, it is to be understood that each separate substituent may be the same or different to the other substituent(s) defined by the same term. For example, if R1 and Rz both comprise a "het" group, then the two het groups may be the same or different.
It has been found that the compounds defined above are ligands of the Histamine H4 receptor.
In an embodiment of the invention R1, R2, R3, R4 and R5 are as defined above, and R8 is hydrogen. In a further embodiment, R1, R2, R3, R5 and R8 are as defined above, and R4 is hydrogen.
In a further embodiment, R2, R3, R5 and R8 are as defined above, R4 is hydrogen and R1 is C3.7cycloalkyl-
Co-6alkyl- optionally substituted with methyl.
In a further embodiment, R2, R3, R5 and R8 are as defined above, R4 is hydrogen and R1 is C3.5cycloalkyl-
C0-ialkyl- optionally substituted with methyl. In a further embodiment, R2, R3, R5 and RB are as defined above, R4 is hydrogen and R1 is cyclopropyl , cyclopropyl-methyl or methyl-cyclopropyl.
In a further embodiment, R2, R3, R5 and R8 are as defined above, R4 is hydrogen and R1 is C1-C8 alkyl.
In a further embodiment, R2, R3, R5 and R8 are as defined above, R4 is hydrogen and R1 is C1-C6 alkyl.
In a further embodiment, R2, R3, R5 and R8 are as defined above, R4 is hydrogen and R1 is ethyl, propyl, butyl, 1-methyl-propyl, 2-methyl-propyI, 2,2-dimethyl-propyl, 2-methyl-butyl, ter-butyl, 1 -methyl-butyl, 3- methyl-butyl, 3,3-dimethyl-butyl, 1 ,2-dimethyl-propyl or isopropyl. In a further embodiment, R1, R4, R5 and R8 are as defined above, and R2 is net, provided that the het group contains at least one nitrogen atom or is substituted by a group which contains at least one nitrogen atom and R3 is H, Ci.8alkyl, (CH2)pC3.7cycloalkyl, alkoxyalkyl containing 3 to 8 carbon atoms, (CH2)nCF3, (CH2)XOCF3 or C^hydroxyalkyl; or R3 and R2 together with the nitrogen atom to which they are bound form a 4 to 8 membered non-aromatic heterocyclic group which optionally contains one or more further heteroatoms or groups independently selected from N, O, S, S(O) and S(O)2, wherein the heterocyclic group is optionally a bridged bicyclic group, a spiro bicyclic group or is optionally fused to a 3-, 4-, 5- or 6- membered carbocyclic group or a A-, 5- or 6-membered heterocyclic group which contains at least one ring member independently selected from N, O, S, S(O) and S(O)2, and wherein the ring system as a whole is optionally substituted by one or more substituents independently selected from Ci- 6alkyl, NR6R7, (CH 2)aC3-7cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH2)bhet1, (CH2)CCF3, (CH2)y0CF3, (CH2)daryl and C1-6hydroxyalkyl, provided that the ring system as a whole contains at least two nitrogen atoms or contains one nitrogen atom and is substituted by a group which contains at least one nitrogen atom;
In a still further embodiment, R1, R4, R5 and R8 are as defined above, and R2 and R3, together with the nitrogen atom to which they are bound, form a 4 to 8 membered non-aromatic heterocyclic group which optionally contains one or more further heteroatoms or groups independently selected from N, O, S, S(O) and S(O)2, wherein the heterocyclic group is optionally a bridged bicyclic group or is optionally fused to a 3-, A-, 5- or 6- membered carbocyclic group or a A-, 5- or 6-membered heterocyclic group which contains at least one ring member independently selected from N, O, S , S(O) and S(O)2, and wherein the ring system as a whole is optionally substituted by one or more substituents independently selected from C1- 6alkyl, NR6R7, (CH2)aC3-7cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH2)bhet\ (CH2)CCF3, (CH2)yOCF3, (CH2)daryl and Ci.-6hydroxyalkyl, provided that the ring system as a whole contains at least two nitrogen atoms or contains one nitrogen atom and is substituted by a group which contains at least one nitrogen atom.
In a further embodiment, R1, R4, R5 and R8 are as defined above, and R2 and R3, together with the nitrogen atom to which they are bound, form a 4 to 8 membered non-aromatic heterocyclic group which optionally contains one or more further nitrogen atoms, wherein the heterocyclic group is optionally a bridged bicyclic group or is optionally fused to a 3-, 4-, 5- or 6- membered carbocyclic group or a A-, 5- or 6-membered heterocyclic group which contains at least one nitrogen atom, and wherein the ring system as a whole is optionally substituted by one or more substituents independently selected from Ci-6aikyl, NR6R7, (CH2)aC3-7cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH2)bhet1, (CH2)0CF3, (CH2)yOCF3, (CH2)daryl and C1.6hydroxyalkyl, provided that the ring system as a whole contains at least two nitrogen atoms or contains one nitrogen atom and is substituted by a group which contains at least one nitrogen atom.
In a yet still further embodiment, R1, R4, R5 and R8 are as defined above, and R2 is NH(CH2)2NH2, NH(CH2)2NHCH3, NH(CH2)2NH(CH3)2 and R3 is H. In a yet still further embodiment, R1, R4, R5 and R8 are as defined above, and R2 and R3, together with the nitrogen atom to which they are bound, form a 4 to 8 membered non-aromatic heterocyclic group selected from the following ring systems:
Figure imgf000006_0001
wherein the ring system as a whole may be substituted by one or more C1-Salkyl or (CH2)aC3.6cycloalkyl groups.
In a yet still further embodiment, R1, R4, R5 and R8 are as defined above, and R2 and R3, together with the nitrogen atom to which they are bound, form a 4 to 8 membered non-aromatic heterocyclic group selected from the following ring systems:
Figure imgf000007_0001
wherein R6 and R7 are independently selected from H or CH3.
In a further embodiment, R1, R4, R5 and R8 are as defined above, R3 is H and R2 is a pyrrolidinyl group, optionally substituted by one or more substituents independently selected from d.6alkyl, NR6R7, (CH2)aC3.7cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH2)bhet1, (CH2)CCF3, (CH2)yOCF3, (CH2)daryl and C^hydroxyalkyl.
In a further embodiment, R1, R4, R5 and R8 are as defined above, R3 is H and R2 is a pyrrolidinyl group, optionally substituted by one or more substituents independently selected from C1-6alkyl, NR6R7, (CH2)aC3-7cycloalkyl and alkoxyalkyl containing 2 to 8 carbon atoms.
In a further embodiment, R1, R2, R3, R4 and R8 are as defined above, and R5 is H or NH2. In the here above formula "halo" denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo, in particular fluoro or chloro.
The term "alkyl" includes both straight-chain and branched chain groups. This also applies if they carry substituents such as a hydroxy substitutent or occur as substituents of other radicals, for example alkoxy groups. For example, the term C1-4alkyl includes methyl, ethyl, n-propyl, /so-propyl, /7-butyl, /so-butyl, sec- butyl and ferf-butyl moieties . Examples of the corresponding alkoxy moieties are methoxy, ethoxy, n- propyloxy, /so-propyloxy, /7-butyloxy, /so-butyloxy, sec-butyloxy and ferf-butyloxy. Furthermore, examples of suitable d^alkyl moieties substituted by an hydroxyl group are hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, etc.
The term C3-C7 cycloalkyl includes bridged bicyclic cycloalky! such as bicyclo[1.1.1]pentyl. Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[1.1.1]pentyl.
Preferred "4 to 8 membered heterocyclic group which optionally contains one or more further heteroatoms or groups independently selected from N, O, S, S(O) and S(O)2, wherein the heterocyclic group is a spiro bicyclic group" are 2,8-diaza-spiro[4.5]dec-2-yl and 2,7-diaza-spiro[4.4]non-2-yl.
The skilled person will of course appreciate that it is not possible to substitute some of the defined heterocyclic ring groups of Formula I in all positions with some of the optional substituents defined above. It is to be understood that such substitutions do not form part of the invention.
Example compounds that fall within the above definition of the invention include:
Λ/-(3,3-Dimethylbutyl)-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine,
6-[3-(Dimethylamino)pyrrolidin-1-yl]-Λ/-(3,3-dimethyIbutyl)pyrimidin-4-amine,
Λ/-(3,3-Dimethylbutyl)-6-[(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrimidin-4-amine,
6-[3-(Dimethylamino)azetidin-1-yl]-Λ/-(3,3-dimethylbutyl)pyrimidin-4-amine, Λ/-(3,3-DimethylbutyI)-6-[5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidin-4-amine,
/V-(3,3-Dimethylbutyl)-/V-[pyrrolidin-3-yl]pyrimidine-4,6-diamine,
/V-(3,3-Dimethylbutyl)-/V-[1-methylpyrrolidin-3-yl]pyrimidine-4,6-diamine,
Λ/4-(Cyclopropylmethyl)-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,
Λ/4-lsobutyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine, Λ/4-(2,2-DimethylpropyI)-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,
Λ/4-Ethyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,
Λ/-Ethyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine,
Λ/-lsobutyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine,
Λ/-(Cyclopropylmethyl)-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine, Λ/-(3,3-Dimethylbutyl)-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine,
6-[3-(Dimethylamino)pyrrolidin-1-yl]-Λ/-(3,3-dimethylbutyl)pyrimidin-4-amine,
Λ/-(Cyclopropylmethyl)-6-[3-(dimethylamino)pyrrolidin-1-yl]pyrimidin-4-amine,
6-[3-(Dimethylamino)pyrrolidin-1-yl]-Λ/-isobutylpyrimidin-4-amine,
6-[3-(Dimethylamino)pyrrolidin-1-yl]-Λ/-ethyIpyrimidin-4-amine, 6-[3-(Dimethylamino)pyrrolidin-1-yl]-Λ/-(2,2-dimethy]propyl)pyrimidin-4-amine, /^-(S.S-DimethylbutylJ-δ-foctahydro-eH-pyrrolofS^-bJpyridin-δ-ylJpyrimidiπe^^-diamine, Λ^-lsopropyl-δ-Ioctahydro-eH-pyrrolotS^-blpyridin-e-yOpyrimidine^^-diamine, Λ/4-Methyl-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, Λ^-Ethyl-δ-toctahydro-eH-pyrroloIS^-blpyridin-e-ylJpyrimidine^^-diamine, Λ^-lsobutyl-δ-toctahydro-δH-pyrroloIS^-bJpyridin-δ-yllpyrimidine^^-diamine, Λ/4-(Cyclopropylmethyl)-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, /^-(S-MethylbutyO-e-toctahydro-δH-pyrrololS^-blpyridin-δ-yllpyrimidine^^-diamine, Λ/4-(2,2-Dimethy!propyl)-6-[octahydro-6H-pyrrolot3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, Λ^-Cyclopropyl-δ-Ioctahydro-ΘH-pyrrolofS^-blpyridin-δ-ylJpyrinnidine^^-diannine, Λ/4-Cyclobutyl-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diannine, /^-(CyclopentylmethyO-δ-Ioctahydro-δH-pyrroloIS^-blpyridin-δ-yljpyrimidine^^-diamine, δ-fS-MethylhexahydropyrroloIS^-cJpyrrol^CI HJ-ylJ-Λ^-propylpyrimidine^^-diamine, Λ/4-Methyl-6-[5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrimidine-2,4-diamine, Λ/4-Ethyl-6-[5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl]pyrimidine-2,4-diamine, Λ/4-lsobutyl-6-[5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl]pyrimidine-2,4-diamine, /V4-(Cyclopropylmethyl)-6-[5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl]pyrimidine-2,4-diamine, Λ/4-(2,2-Dimethylpropyl)-6-[5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrimidine-2,4-diamine, Λ/4-(3,3-Dimethylbutyl)-6-[5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrimidine-2,4-diamine, Λ/4-(3-Methylbutyl)-6-[5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl]pyrimidine-2,4-diamine, Λ/4-Cyclopropyl-6-[5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrimidine-2,4-diamine, Λ/4-Cyclobutyl-6-[5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl]pyrimidine-2,4-diamine, Cyclopropylmethyl-[6-(3-methylamino-azetidin-1-yl)-pyrimidin-4-yl]-amine, (3-Fluoro-benzyl)-[6-(3-methylamino-azetidin-1-yl)-pyrimidin-4-yl]-amine, Λ/-lsopropyl-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-amine,
Λ/-(4-Fluorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-amine, Λ/-Ethyl-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-amine, Λ/-lsobutyl-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-amine, 2-({6-f3-(Methylamino)azetidin-1-yl]pyrimidin-4-yl}amino)ethanol, Λ/-Benzyl-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-amine,
Λ/-(2-Chlorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-amine, Λ/-Methyl-1-[6-(4-methylpiperidin-1-yl)pyrimidin-4-yl]azetidin-3-amine, Λ/-(2-Methoxyethyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-amine, 6-[3-(Methylamino)azetidin-1-yl]-Λ/-(3-methylbutyl)pyrimidin-4-amine, Λ/-Methyl-1-(6-piperidin-1-ylpyrimidin-4-yl)azetidin-3-amine,
Λ/-(2,2-Dimethylpropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-amine, Λ/-Methyl-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-amine, Λ/-(3,3-Dimethylbutyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-amine, Λ/4-lsopropyl-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine, Λ/4-(2,2-Dimethylpropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, 6-(3-Methylamino-azetidin-1-yl)-Λ/4-(3,3,3-trifluoro-propyl)-pyrimidine-2,4-diamine, Λ/4-Cyclopropylmethyl-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine, Λ/4-(3,3-Dimethyl-butyl)-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine, Λ/4-(3-Fluoro-ben2yl)-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine, /^-(S-Methoxy-benzyO-β^S-methylamino-azetidin-i-yO-pyrimidine^^-diamine, Λ^-Cyclobutylmethyl-e-CS-methylamino-azetidin-i-yO-pyrimidine^^-diamine, Λ/4-Cyclopentylmethyl-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine, Λ/4-Methyl-6-[3-(methylamino)a2etidin-1-yl]pyrimidine-2,4-diamine, Λ/4-Ethyl-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, Λ/4-lsobutyl-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, Λ/4-Cyclopropyl-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, 6-[3-(l\Λethylamino)azetidin-1-yl]-Λ/4-propylpyrimidine-2,4-diamiπe, 6-[3-(Methylamino)azetidin-1-yl]-Λ/4-(3-methylbutyl)pyrimidine-2,4-diamine, Λ/4-Cyclobutyl-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamiπe, 6-[3-(Methylamino)azetidin-1-yl]-Λ/4-[4-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine, 4-[({2-Arnino-6-[3-(rnethylarnino)azetidin-1-yl]pyrimidin-4-yl}amino)methyl]benzonitrile, Λ/4-(2-Fluorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, Λ^-Benzyl-e-tS^methylaminoJazetidin-i-ylJpyrimidine^^-diamine, 6-[3-(Methylamino)azetidin-1-yl]-Λ/4-[3-(trifluoromethyl)beπzyl]pyrimidine-2,4-diamine, /V4-(4-Chlorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, 6-[3-(Methylamino)azetidin-1-yl]-Λ/4-(2-methy!benzyl)pyrimidine-2,4-diamine, 6-[3-(Methylamino)azetidin-1-yl]-Λ/4-(3-methylbenzyl)pyrimidine-2,4-diamine, 6-[3-(Methylamino)azetidin-1-yl]-Λ/4-[2-(trifluoromethyl)benzyl]pyrimidine-2,4-diamine, 6-[3-(Methylamino)azetidin-1-yl]-Λ/4-[4-(trifluoromethyl)benzyl]pyrimidine-2,4-diamine, Λ/4-(3-Chlorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, Λ/4-(2-Methoxybenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, 6-t3-(MethyIamino)azetidin-1-yl]-Λ/4-(4-methyIbenzyl)pyrimidine-2,4-diamine, Λ/4-(2-Chlorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, Λ/4-(4-Fluorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, Λ/4-(3-Fluorobenzyl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine, Λ/4-(3-Fluorobenzyl)-6-[5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrimidine-2,4-diamine, /^-(S.S-DimethylbutylVe-tS-methylpiperazin-i-yllpyrimidine^^-diamine, Λ/4-(2,2-Dimethylpropyl)-6-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine, /\ΛEthyl-6-[3-methylpiperazin-1-yl]pyrimidine-2,4-diamine, Λ/-(2,2-Dimethylpropyl)-6-(4-methylpiperaziπ-1-yl)pyrimidin-4-amine, Λ/-(3-Methylbutyl)-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine,
/^-(S.S-DimethylbutylJ-N^tpyrrolidin-S-ylJpyrimidine^^.e-triamine, Λ/4-(3,3-Dimethylbutyl)-6-(4-nnethylpiperazin-1-yl)pyrimidine-2,4-diamine, Λ/-Ethyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine, Λ/-lsopropyI-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine, Λ/-lsobutyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine,
Λ/-(Cyclopropylmethyl)-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine, Λ/-(3-Methylbutyl)-N'-[pyrroIidin-3-yl]pyrimidine-4,6-diamine, /^-(S-MethylbutyO-e^^methylpiperazin-i-yOpyrimidine-Z^-diamine, Λ/-(2-Methoxyethyl)-6-(4-methylpipera2in-1-yl)pyrimidin-4-amine, Λ/-(3,3-Dimethylbutyl)-6-piperazin-1-ylpyrimidin-4-amine, 6-(4-Methylpipera2in-1-yl)-Λ/-[tetrahydrofuran-2-ylmethyl]pyrimidin-4-amine, 4-(4-Methylpiperazin-1-yl)-6-pyrrolidin-1-ylpyrimidine, 6-(4-Methylpiperazin-1-yl)-N-(3,3,3-trifluoropropyl)pyrimidin-4-amine, Λ/-lsobutyl-5-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine, Λ/-Ethyl-6-[5-methylhexahydropyrro!o[3,4-c]pyrrol-2(1H)-yl]pyrimidin-4-amine, 6-(3-Aminoazetidin-1 -yl)-Λ/-(3,3-dimethyibutyl)pyrimidin-4-amine, Λ/4-lsopropyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine, Λ/4-Ethyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine, Λ/4-lsobutyl-6-(4-methylpiperazin-1-yI)pyrimidine-2,4-diamiπe, Λ/4-(Cyclopropylmethyl)-6-(4-methyIpiperazin-1-yl)pyrimidine-2,4-diamine, Λ/-(Cyclopropylmethyl)-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-4-amine, Λ/4-(3,3-Dimethylbutyl)-6-[3,4-dimethylpiperazin-1-yI]pyrimidine-2,4-diamine, Λ/-lsobutyl-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-4-amine, 6-[ 6-Amino-3-azabicyclo[3.1.0]hex-3-yl]-Λ/4-(2,2-dimethyIpropyl)pyrimidine-2,4-diamine, Λ/-(2,2-Dimethylpropyl)-6-[QctahydrQ-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-4-amine, 6-[3-(Methylamino)azetidin-1-yl]-N4-(2-methylbutyl)pyrimidine-2,4-diamine,
N4-[(1 S)-1 ,2-Dimethylpropyl]-6-[3-(methylamino)azetidin-1 -yl]pyrimidine-2,4-diamine, N4-(2,5-Difluorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, N4-(2,3-Difluorobenzyl)-6-[3-(methy]amino)azetidin-1-yl]pyrimidine-2,4-diamiπe, N4-Butyl-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, 6-(1 ,4-Diazepan-1-yl)-N4-isobutylpyrimidine-2,4-diamine,
6-[.(3R)-3-(Methylamino)pyrrolidin-1-yl]-N4-(2-methylcycIopropyl)pyrimidine-2,4-diamine, N4-lsobutyl-6-(4-methyl-1 ,4-diazepan-1 -yl)pyrimidine-2,4-diamine, N4-(Cyclopropylmethyl)-6-(3-pyrrolidin-1-ylazetidin-1-yl)pyrimidine-2,4-diamine, N^lsopropyl-e-pa^.TaS^-octahydro-δH-pyrrolotS^-clpyridin-S-yOpyrimidine^^-diamine, N4-Bicyclo[1.1.1]pent-1-yl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine, 6-(4-Aminopiperidin-1-yl)-N4-ethylpyrimidine-2,4-diamine, 6-[3-Methyl-3-(methylamino)azetidin-1-yl]-N4-propylpyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-(hexahydropyrrolo[1 ,2-a]pyrazin-2(1H)-yl)pyrinnidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-(3-pyrrolidin-1-ylazetidin-1-yl)pyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-N6-[2-(methylamino)ethyl]pyrimidine-2,416-triamine, N4-[2-(Dimethylamino)ethyl]-N6-(2,2-dimethylpropyl)pyrimidine-2,4,6-triamine, N4-(2,2-Dimethylpropyl)-6-[3-(isopropylamino)azetidin-1-yl]pyrimidine-2,4-diamine, 6-[(3R)-3-(Methylamino)pyrroIidin-1-yl]-N-[(1 R)-1-methylpropyl]pyrimidin-4-amine, N-Butyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine, N4-(tert-Butyl)-6-[(3R)-3-(methyiamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,
6-[(3R)-3-(MethyIamino)pyrrolidin-1-yl]-N4-(1-methylcyclopropyl)pyrimidine-2,4-diamine, N4-(terf-Butyl)-6-[(4aS*,7aS*)-octahydro-6H-pyrrolo[3,4-b]pyridiπ-6-yl]pyrimidine-2,4-diamine, 6-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N4-[(1S)-1-methylpropyl]pyrimidine-2,4-diamine, 6-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N4-[(1 R)-1-methylpropyl]pyrimidine-2,4-diamine, and, N-(sec-Butyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-amine, or a pharmaceutically and/or veterinarily acceptable derivative thereof.
An embodiment of the invention provides the following compounds: Λ/4-(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine, Λ/4-(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine tartrate, N4-lsobutyl-6-[(3R)-3-(methylamino)pyrrolidin-1 -yrjpyrimidine-2,4-diamine,
N4-(2,2-Dimethylpropyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diaminN-lsobutyl-6-[(3R)-3- (methylamino)pyrrolidin-1-yl]pyrimidin-4-amine,
N-(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine, N4-(2,2-Dimethylprcipyl)-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[314-b]pyridin-6-yl]pyrimidine-2,4-diamine, N4-Cyclopropyl-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, N4-Cyclobutyl-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, 6-(3-Methylamino-azetidin-1-yl)-N4-(3,3,3-trifluoro-propyl)-pyrimidine-2,4-diamine, N4-Cyclopropylmethyl-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine, N4-(3,3-Dimethyl-butyl)-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine, N4-(3-Fluoro-benzyl)-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine, N4-Cyclopentylmethyl-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine, N4-lsobutyl-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, 6-[3-(Methylamino)azetidin-1-yl]-N4-propylpyrimidine-2,4-diamine, N4-(2-Methoxybenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine, N4-Ethyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine, N4-(Cyclopropylmethyl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine, 6-[3-(Methylamino)azetidin-1-yl]-N4-(2-methylbutyl)pyrimidine-2,4-diamine, N4-(2,5-Difluorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2l4-diamine, N4-(2,3-Difluorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, N4-Butyl-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, 6-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N4-(2-methylcyclopropyl)pyrimidine-2,4-diamine, N4-lsobutyl-6-(4-methyl-1 ,4-diazepan-1-yl)pyrimidine-2,4-diamine, ^-(CyclopropylmethyO-e-CS-pyrrolidin-i-ylazetidin-i-yOpyrimidine^^-diamine,
N4-Bicyclot1.1.1]pent-1-yl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine, 6-[3-Methyl-3-(methylamino)azetidin-1-yl]-N4-propylpyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-(hexahydropyrrolo[1 ,2-a]pyrazin-2(1H)-yl)pyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-(3-pyrrolidin-1-ylazetidin-1-yl)pyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-[3-(isopropylamino)azetidin-1-yl]pyrimidine-2,4-diamine, N4-(terf-Butyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine, 6-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N4-(1-methylcyclopropyl)pyrimidine-2,4-diamine, N4-(tert-Butyl)-6-[(4aS*,7aS*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamiπe, N4-(2,2-Dimethylpropyl)-6-piperazin-1-yipyrimidine-2,4-diamine,
N4-(2,2-Dimethylpropyl)-6-[3-(methylamino)a2etidin-1-yl]pyrimidine-2,4-diamine hydrochloride, N4-(2,2-Dimethylpropyl)-6-[(3aR*,7aS*)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-yI]pyrimidine-2,4-diamine, 6-Piperazin-1-yl-N4-propylpyrimidine-2,4-diamine,
N4-(Cyclopropylmethyl)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine1 N4-(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine, N4-lsopropyl-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, 4-[3-(Wlethylamino)azetidin-1-yl]-6-(4-methylpiperidin-1-yl)pyrimidin-2-amine, N4-(Cyclopentylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,> N4-Cyclobutyl-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, 6-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N4-propylpyrimidine-2,4-diamine, and, N4-Ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyrimidine-2,4-diamine, or a pharmaceutically and/or veterinarily acceptable derivative thereof.
A further embodiment of the invention provides the following compounds: Λ/4-(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine, Λ/4-(Cydopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine tartrate, N4-(2,2-Dimethylpropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, and, N4-(2,2-Dimethyipropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine hydrochloride, or a pharmaceutically and/or veterinarily acceptable derivative thereof.
By pharmaceutically and/or veterinarily acceptable derivative it is meant any pharmaceutically or veterinarily acceptable salt, solvate, ester or amide, or salt or solvate of such ester or amide, of the compounds of formula (I) or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof. Preferably, pharmaceutically and/or veterinarily acceptable derivative means any pharmaceutically or veterinarily acceptable salt or solvate of the compounds of formula (I)
Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Pharmaceutically acceptable salts of the compounds of formula (I) may be prepared by one or more of three methods:
(i) by reacting the compound of formula (I) with the desired acid or base;
(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or
(iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.
All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.
Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non-ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).
Hereinafter all references to compounds of formula (I) include derivatives thereof and complexes of the compound or derivatives thereof.
The compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (I). As indicated, so-called 'pro-drugs' of the compounds of formula (I) are also within the scope of the invention. Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Prodrugs as Novel Delivery Systems. Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
Some examples of prodrugs in accordance with the invention include:
(i) where the compound of formula (I) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (I) is replaced by (CrC8)alkyl; (ii) where the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula
(I) is replaced by (CrC6)alkanoyloxymethyl; and
(iii) where the compound of formula (I) contains a primary or secondary amino functionality (-NH2 or - NHR where R is not H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (I) is/are replaced by (CrC10)alkanoyl.
Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
Moreover, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).
Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include:
(i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative thereof (- CH3 -> -CH2OH):
(ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative thereof (-OR ■> -OH); (iii) where the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NRaRb -» -NHRa or -NHRb); (iv) where the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHRa -> -NH2);
(v) where the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof (-Ph -> - PhOH); and (vi) where the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof
(-CONRcRd -> COOH).
Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, d-lactate, /-tartrate or /-lysine, or racemic, for example, dl- tartrate or d/-arginine.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic, or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically- enriched form using chromatography, typically HPLC, on an asymmetric resin.
Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. WiI en (Wiley, New York, 1994).
The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S.
Certain isotopically labelled compounds of formula (I)1 for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as 11C, 18F1 15 O and 13N1 can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically labelled reagent in place of the non-labelled reagent previously employed.
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO.
Compounds of formula (I) may be prepared according to scheme 1 that follows.
Figure imgf000018_0001
Figure imgf000018_0002
Scheme 1 0) wherein R1, R2, R3, R4, R5 and R8 are as defined above, and X and Y are leaving groups.
According to scheme 1 , compounds of formula (I) may be prepared by the reaction of a compound of formula (II) with a suitable amine. Conveniently reaction is effected by using an excess of the amine or stoichiometric quantity of the amine in the presence of a base such as a tertiary amine base (e.g. triethylamine or N-ethyl-N-isopropylpropan-2-amine); optionally in the presence of a suitable solvent (e.g. dimethyl sulphoxide or 1-methylpyrrolidin-2-one); optionally in the presence of a catalyst (such as caesium fluoride); and at elevated temperature, such as 120°C to 150°C.
Compounds of formula (II) may be prepared by reaction of a compound of formula (III) with a suitable amine. Conveniently reaction is effected by using an excess of the amine or stoichiometric quantity of the amine in the presence of a base such as a tertiary amine base (e.g. triethylamine or N-ethyl-N- isopropylpropan-2-amine); in the presence of a suitable solvent (e.g. ethanol, 2-propanol or 1- methylpyrrolidin-2-one); and at ambient or elevated temperature, such as ambient temperature to 85°C.
According to scheme 1 , the groups X and Y represent a halogen atom (e.g. chlorine) or an alternative leaving group such as a sulphonate ester (e.g. 4-methylphenyl sulphonate) or a sulphonyl group (e.g. methane sulphonyl or phenyl sulphonyl) or a sulphinyl group (e.g. methane sulphinyl).
It will be appreciated by those skilled in the art that the transformations described may be carried out in a manner that does not require the isolation or purification of the intermediate compound of formula (II) but that requires sequential addition of suitable amines, with or without additional base (e.g. triethylamine or N-ethyl-N-isopropylpropan-2-amine) or solvent, to a compound or formula (III) in the presence of a suitable solvent (e.g. 1-methylpyrrolidin-2-one or dimethyl sulphoxide) with or without heating the reaction mixture between the addition of the two amines, and with or without the addition of a catalyst (such as caesium fluoride).
It will be further appreciated by those skilled in the art that it may be necessary or desirable to carry out the transformations described in the schemes in a different order from that described, or to modify one or more of the transformations, to provide the desired compound of formula (I).
It will be appreciated by those skilled in the art that, as illustrated in the schemes above, it may be necessary or desirable at any stage in the synthesis of compounds of formula (I) to protect one or more sensitive groups in the molecule so as to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect amino groups. The protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See, for example, those described in 'Protective Groups in Organic Synthesis' by Theodora W Green and Peter G M Wuts, third edition, (John Wiley and Sons, 1999), in particular chapter 7, pages 494-653 ("Protection for the Amino Group"), incorporated herein by reference, which also describes methods for the removal of such groups.
Compounds of formula (III) are known in the literature or easily prepared by methods well known to those skilled in the art.
The compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences. 19th Edition (Mack Publishing Company, 1995).
The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano- particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, ϋ (6), 981-986, by Liang and Chen (2001).
For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
Other possible ingredients include anti-oxidants, colorants, flavouring agents, preservatives and taste- masking agents. Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.
The compound of formula (I) may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, the compound of formula (I) may be in the form of multiparticulate beads.
The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.
Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line. 25(2), 1-14, by Verma ef a/ (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, ' intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents.
Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly(d/-lactic-coglycolic)acid (PGLA) microspheres.
The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to(form nanoparticles, high pressure homogenisation, or spray drying.
Capsules (made, for example, from gelatin or hydroxypropyl-methylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1μl to 100μl. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration. Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount or the drug product is packaged as discrete single dose units for use in the inhaler device. Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from 1 μg to 4000 μg of the compound of formula (I). The overall daily dose will typically be in the range 1 μg to 20 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethyl cellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene giycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma- cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.
For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 0.001 mg to 2000 mg depending, of course, on the mode of administration. For example, oral administration may require a total daily dose of from 0.1 mg to 2000 mg, while an intravenous dose may only require from 0.01 mg to 100 mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
These dosages are based on an average human subject having a weight of about 60 kg to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.
According to another embodiment of the present invention, the compounds of the invention can also be used as a combination with one or more additional therapeutic agents to be co-administered to a patient to obtain some particularly desired therapeutic end result. The second and more additional therapeutic agents may also be a compound of the formula (I) or a pharmaceutically and/ or veterinarily acceptable derivative thereof, or one or more histamine H4 receptor ligands known in the art. More typically, the second and more therapeutic agents will be selected from a different class of therapeutic agents. As used herein, the terms "co-administration", "co-administered" and "in combination with", referring to the compounds of the invention and one or more other therapeutic agents, is intended to mean, and does refer to and include the following:
• simultaneous administration of such combination of compound(s) of formula (I) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient,
• substantially simultaneous administration of such combination of compound(s) of formula (I) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said patient, whereupon said components are released at substantially the same time to said patient,
• sequential administration of such combination compound(s) of formula (I) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at consecutive times by said patient with a significant time interval between each administration, whereupon said components are released at substantially different times to said patient; and
• sequential administration of such combination of compound(s) of formula (I) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components in a controlled manner whereupon they are concurrently, consecutively, and/or overlapingly administered at the same and/or different times by said patient, where each part may be administered by either the same or different route.
Suitable examples of other therapeutic agents which may be used in combination with the compound(s) of the invention or compositions thereof, include, but are by no means limited to : • Histamine H1 receptor antagonists, in particular loratidine, desloratidine, fexofenadine and cetirizine
• Histamine H3 receptor antagonists
• Histamine H2 receptor antagonists
• Leukotriene antagonists, including antagonists of LTB4, LTC4, LTD4, and LTE4; for example Montelukast • Phosphodiesterase inhibitors, including PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDE7 inhibitors and inhibitors of two or more phosphodiesterases, such as dual PDE3/PDE4 inhibitors
• neurotransmitter re-uptake inhibitors, in particular fluoxetine, setraline, paroxetine, ziprasidone
• 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists
• OC1- and α2-adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use • Muscarinic M3 receptor antagonists or anticholinergic agents
• β2-adrenoceptor agonists
• Dual acting β2/M3 agents
• Xanthines, such as theophylline and aminophylline
• Non-steroidal antiinflammatories, such as sodium cromoglycate and nedocromil sodium • Ketotifen • COX-1 inhibitors (NSAIDs) and COX-2 selective inhibitors
• Oral or inhaled Glucocorticosteroids
• Monoclonal antibodies active against endogenous inflammatory entities
• Anti-tumor necrosis factor (anti-TNF-α) agents • Adhesion molecule inhibitors including VLA-4 antagonists
• KmJn-B1 - and B2 -receptor antagonists
• Immunosuppressive agents
• Inhibitors of matrix metalloproteases (MMPs)
• Tachykinin NK1, NK2 and NK3 receptor antagonists • Elastase inhibitors
• Adenosine A2a receptor agonists
• Inhibitors of urokinase
• Compounds that act on dopamine receptors, e.g. D2 agonists
• Modulators of the NFKb pathway, e.g. IKK inhibitors • Agents that can be classed as mucolytics or anti-tussive
• Antibiotics
• Modulators of cytokine signaling pathways, such as p38 MAP kinase inhibitors, syk tyrosine kinase inhibitors or JAK kinase inhibitors
• Modulators of the prostaglandin pathways, including inhibitors of H-PDGS and antagonists of DP-1 and CRTH2
• Antagonists of chemokine receptors CXCR1 and CXCR2
• Antagonists of chemokine receptors CCR3, CCR4 and CCR5
• Inhibitors of cytosolic and soluble phospholipase A2 (cPLA2 and SPLA2)
• Prostaglandin D2 receptor antagonists (DP1 and CRTH2) • Inhibitors of Prostaglandin D synthase (PGDS)
• Inhibitors of phosphoinositide-3-kinase,
• HDAC inhibitors,
• p38 inhibitors and/or
• CXCR2 antagonists.
According to the present invention, combination of the compounds of formula (I) with:
• Histamine H1 receptor antagonists, in particular loratidine, desloratidine, fexofenadine and cetirizine,
• Histamine H3 receptor antagonists,
• Histamine H2 receptor antagonists, • Leukotriene antagonists, including antagonists of LTB4, LTC4, LTD4, and LTE4, for example Montelukast, and/or,
• Phosphodiesterase PDE4 inhibitors form a further embodiment of the invention. The compounds of formula (I) have the ability to interact with the H4 receptor and thereby have a wide range of therapeutic applications, as described further below, because of the essential role, which the H4 receptor plays in the physiology of all mammals. According to this invention H4 ligands are meant to include H4 receptor antagonists, agonists and inverse agonists. For the preferred indications to be treated according to the invention, H4 antagonists are believed to be most suitable.
Therefore, a further aspect of the present invention relates to the compounds of formula (I) or pharmaceutically acceptable salts, derived forms or compositions thereof, for use as medicaments, more particularly in the treatment of diseases, disorders, and conditions in which the H4 receptor is involved. More specifically, the present invention also concerns the compounds of the invention for use in the treatment of diseases, disorders, and conditions selected from the group consisting of:
• inflammatory diseases;
• respiratory diseases (e.g. adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis), allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion, allergic congestion;
• female and male sexual dysfunction;
• skin diseases such as dermatitis and psoriasis; • cardiac dysfunctions such as myocardial ischaemia and arrythmia;
• diseases of the gastrointestinal tract such as inflammatory bowel disease, Crohn's disease and colitis ulcerosa;
• cancer;
• rheumatoid arthritis; • hypotension;
• inflammatory pain and
• overactive bladder conditions.
The compounds of formula (I) according to the present invention are particularly suitable for the treatment of asthma, allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion and allergic congestion.
A still further aspect of the present invention also relates to the use of the compounds of the invention for the manufacture of a drug being a H4 ligand. In particular, the present inventions concerns the use of the compounds of formula (I), or pharmaceutically and/or veterinarily acceptable derivatives thereof, for the manufacture of a drug for the treatment of H4 mediated diseases and/or conditions, in particular the diseases and/or conditions listed above.
As a consequence, the present invention provides a particularly interesting method to treat a mammal, including a human being, with an effective amount of a compound of formula (I), or a pharmaceutically and/or veterinarily acceptable derivative thereof. More precisely, the present invention provides a particularly interesting 'method for the treatment of a H4 mediated diseases and/or conditions in a mammal, including a human being, in particular the diseases and/or conditions listed above, comprising administering to said mammal an effective amount of a compound of the invention.
The compounds of the invention may have the advantage that they are more potent, have a longer duration of action, have a broader range of activity, are more stable, are easier and/or safer to prepare, have fewer side effects or are more selective, or have other more useful properties than the compounds of the prior art.
The following examples illustrate the preparation of compounds of formula (I) according to the present invention
1H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million (ppm) downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g. s (singlet), d (doublet), t (triplet), q (quartet) m (multiplet) and br (broad). The mass spectra (m/z) were recorded using either electrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI). Purfication by SCX indicates use of strong cation exchange resin.
In the examples section, the following abbreviations are used:
Figure imgf000029_0002
Examples
Preparation 1 : fetf-Butyl H-fβ-chloro-pyrimidin^-vD-azetidin-S-vπ-methyl-carbamate
Figure imgf000029_0001
Azetidin-3-yl-methyl-carbamic acid tert-butyl ester (1.97 g, 11 mmol) in IPA (5 mL) was added dropwise to a stirred solution of 4,6-dichloropyrimidine (1.49 g, 10 mmol) in IPA (20 mL) followed by dropwise addition of TEA (2.11 mL, 15.1 mmol) at ambient temperature under N2. The resulting milky yellow solution was heated to 80 0C and maintained at 80 0C for 2 hours. The solution was allowed to cool and evaporated to dryness to give a yellow oil. The crude material was partitioned between DCM (70 mL) and water (30 ml_). The aqueous extract was re-extracted with DCM (70 mL). The combined organic extract was washed with saturated aqueous sodium bicarbonate (30 mL), dried (MgSO4), filtered and evaporated to give a golden coloured oil. The crude oil was purified by flash column chromatography on silica gel eluting with DCM : MeOH (99 : 1 changing to 96 : 4 by volume) to yield the title compound as a solid (1.93 g, 64%).
1H NMR (400MHz, CD3OD): δ 8.25 (1H, d), 6.47 (1H, s), 4.9 (1H, br s), 4.31 (2H1 1), 4.21 (2H, m), 2.94 (3H, s), 1.45 (9H, s) ppm. MS (ESI) m/z 299 [M+H]+
Preparations 2 to 11
The following compounds of the general formula shown below were prepared by a method similar to that described for preparation 1 using the appropriate starting material and 4,6-dichloropyrimidine. The reactions were monitored by TLC analysis and were heated to reflux for 3 to 18 hours.
Figure imgf000030_0001
Figure imgf000030_0002
Figure imgf000031_0003
Preparation 12: ferf-Butyl ri-(2-amino-6-chloro-pyrimidin-4-yl)-azetidin-3-yl1-methyl-carbamate
Figure imgf000031_0001
2-Amino-4,6-dichloropyrimidine (26.2 g, 160 mmol) was added portionwise to a stirred solution of azetidin-3-yl-methyl-carbamic acid terf-butyl ester HCI salt (37.4 g, 168 mmol) in absolute EtOH (400 mL) followed by TEA (55.6 mL, 400 mmol) dropwise at ambient temperature. The resulting suspension was warmed to reflux (initially a clear solution was observed on warming) which resulted in the gradual formation of a precipitate. The mixture was refluxed for a total of 2 hours. The mixture was allowed to cool and diluted with water (200 mL) dropwise over 30 min and stirring continued for 45 min. The resulting solid was filtered, washed with water (150 mL) and dried under suction to yield the title compound as a white solid (42.74 g, 85%).
1H NMR (400MHz, CDCl3): δ 5.66 (1H, s), 5.02 (1H, br s), 4.86 (2H, br s), 4.20 (2H, t), 4.04 (2H, m), 2.91 (3H, s), 1.47 (9H, s) ppm. MS (APCI) m/z 314 [M+Hf
Preparation 13: 4-Chloro-6-r(3aR,6aS)-5-methvlhexahvdropvrrolor3,4-ciPvrrol-2(1H)-vπpvrimidin-2- amine
Figure imgf000031_0002
2-Atnino-4,6-dichloropyrimidine (1.64 g, 10 mmol) was added portionwise to a stirred solution (3aR,6aS)- 2-methyloctahydropyrrolo[3,4-c]pyrrole (1.6 g, 12.5 mmol) in absolute EtOH (10 mL) followed by TEA (1.8 ml_, 12.5 mmol) dropwise at ambient temperature. The resulting suspension was warmed to reflux (initially a clear solution was observed on warming) and resulted in the gradual formation of a tan coloured precipitate. The mixture was refluxed for a total of 3 hours. The mixture was allowed to cool, EtOH (30 mL) was added to the mixture and heated to give a solution and was left to cool to ambient temperature. The resulting solid was collected by filtration, washed with cold EtOH (50 mL) and dried under suction to yield the title compound as a solid (2.07 g, 82%).
1H NMR (400MHz, CD3OD): δ 5.88 (1H, s), 3.62 (2H1 m), 3.41(2H1 m), 3.0 (2H, m), 2.78 (2H, m), 2.47 (2H, dd), 2.33 (3H, s) ppm.
MS (APCI) m/z 254, 256 [M+H]+
Preparation 14: fert-Butyl (4aR*.7aR*)-6-f2-amino-6-chloropyrimidin-4-yl)octahvdro-1H-pyrrolor3,4- bipyridine-1-carboxylate
Figure imgf000032_0001
To a solution of racemic ferf-butyl (4aR*,7aR*)-octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (460 mg, 2.03 mmol) in EtOH (1 mL) containing DIPEA ( 590 μL, 3.39 mmol) was added a solution of 2- amino-4,6-dich!oropyrimidine (277 mg, 169 mmol) in EtOH (9 mL) with stirring and the solution was heated to reflux for 24 hours. The solution was cooled and diluted with water (10 mL) and the resulting solid was collected by filtration, washed with water (20 mL) and dried in vacuo at 60 0C to yield the title compound as a white solid (558 mg, 93%).
1H NMR (400MHz, CD3OD): δ 5.85 (1 H, s), 4.7 (1H, m), 3.98 (1H, m), 3.8 - 3.55 (1H, m), 3.47 (1H, m), 3.45 - 3.15 (1H1 m), 2.85 (1H, m), 2.25 (1H, m), 1.85 - 1.65 (2H, m), 1.5 - 1.15 (12H, m) MS (APCI) m/z 354, 356 [M+H]+ Preparations 15 to 19
The following compounds of the general formula shown below were prepared by a method similar to that described for preparation 1 using the appropriate amine and 2-amino-4,6-dichloropyrimidine. The reactions were monitored by TLC analysis and were heated to reflux for 3 to 18 hours.
Figure imgf000032_0002
Figure imgf000033_0002
Alternative method for preparation 15 fert-Butyl r(3RM-(2-amino-6-chloropyrimidin-4- yl)pyrrolidin-3-vπmethylcarbamate
NH2 yOs τyCh
A suspension of 2-amino-4,6-dichloropyrimidine (3.62g, 22.1mmol) and the amine of preparation 47 (5.4Og, 27.0mmo!) in ethanol (45ml) was treated with TEA (4.62ml, 33.1 mmol) and the resulting mixture heated at 80°C for 1 hour. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was separated and the aqueous extracted with further ethyl acteate. The combined organic extracts were dried (magnesium sulphate) and the solvent removed in vacuo to give an orange oil. Trituration with di-isopropy) ether gave a pale yellow solid which was filtered and dried in vacuo to give the title compound (7.Og, 87%).
1H NMR (400MHz, DMSOds): 65.77 (1H, s), 4.60 (1H, br m), 3.27 (4H, br m), 2.70 (3H, s), 2.02 (2H, br m), 1.39 (9H, s) ppm. MS (ESI) m/z 327 [M+H]+
Preparation 20: Λ/-r(3S)-1-Benzylpyrrolidin-3-vπ-Λr-(3.3-dimethylbutyl)pyrimidine-4.6-diamine
Figure imgf000033_0001
A solution of the title compound of preparation 9 (2.7 g, 9.4 mmol), 3,3-dimethylbutan-1-amine (6.3 mL, 46 mmol) and DIPEA (1.63 mL, 9.4 mmol) in NMP (100 mL) was heated to 150 0C in a sealed vessel for 24 hours. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with water (2 x 400 mL) followed by saturated aqueous sodium chloride (500 mL), dried (MgSO4) and concentrated in vacuo. The residue was triturated with diethyl ether and the resulting solid collected by filtration to yield the title compound as a white powder (2.15 g, 65%). MS (APCI) m/z 354 [M+H]+
Preparation 21 : Λ/-r(3R)-1-Benzylpyrrolidin-3-vn-Λr-(3,3-dimethylbutyl)pyrimidine-4,6-diamine
Figure imgf000034_0001
The title compound was prepared by a method similar to that described for preparation 20, using the title compound of preparation 8, in 48% yield. MS (APCI) m/z 354 [M+H]+
Preparation 22: fert-Butyl (1 -rs-fcvclopropylmethyl-aminol-Pyrimidin^-vπ-azetidin-S-ylVmethyl- carbamate
Figure imgf000034_0002
To a 5 mL reacti-vial™ containing the title compound of preparation 1 (100 mg, 0.33 mmol) and cyclopropylmethylamine (50 mg, 0.68 mmol) in DMSO (3 mL) was added TEA (94 μL, 0.68 mmol) and the solution was heated at 140 0C for 18 hours. The reaction was allowed to cool to ambient temperature, loaded onto a 5g SCX column, eluted with MeOH (100 mL) followed by 2M ammonia in MeOH (100 mL). Fractions containing product (as judged by TLC) were combined and evaporate to give a crude orange oil. The crude product was purified by flash column chromatography on silica gel eluting with DCM : MeOH (99 : 1 changing to 96 : 4 by volume) to yield the title compound as a colourless oil (75 mg, 67%). 1H NMR (400MHz, CDCI3): δ 8.13 (1H, s), 5.08 (1H, s), 4.79 (1H, br s), 4.20 (2H, t), 4.01 (2H, m), 3.04 (2H, t), 2.93 (3H, s), 1.46 (9H, s), 1.05 (1 H, m), 0.55 (2H, m), 0.24 (2H, m) ppm. MS (APCI) m/z 334 [M+H]+
Preparation 23: fert-Butyl ■f1-r6-(3-fluoro-benzylamino^-pyrimidin-4-vn-azetidin-3-ylVmethyl- carbamate
Figure imgf000034_0003
To a 5ml reacti-vial™ containing the title compound of preparation 1 (100 mg, 0.33 mmol) and 3- fluorobenzylamine (76 μL, 0.68 mmol) in DMSO (3 mL) was added TEA (9 μL, 0.68 mmol) and the solution was heated at 140 0C for 18 hours. The reaction was allowed to cool to ambient temperature and concentrated in vacuo to obtain crude product as a viscous orange oil. The crude product was purified by flash column chromatography on silica gel eluting with DCM : MeOH (99 : 1 changing to 97 : 3 by volume) to yield the title compound as a light beige coloured solid (49 mg, 38%). 1H NMR (400MHz, CDCI3): δ 8.18 (1H, s), 7.30 (1H, m), 7.09 (1H, m), 7.02 (1H, d), 6.97 (1H, m), 5.09 (1H, s), 5.0 (1H, br d), 4.46 (2H, d), 4.17 (2H, t), 3.98 (2H, m), 2.92 (3H, s), 1.47 (9H, s) ppm. MS (APCI) m/z 388 [M+H]+
Preparation 24: fert-Butyl (4aR*,7aR*)-6-(2-amino-6-r(3.3-dimethylbutvnaminoipyrimidin-4- yl)octahvdro-1H-pyrrolor3.4-bipyridine-1-carboxylate
Figure imgf000035_0001
To a solution of the title compound of preparation 14 (60 mg, 0.17 mmol) in DMSO (150 μL) was added 3,3-dimethylbutan-1-amine (229 μL, 1.7 mmol) and the reaction mixture was heated to 120 0C in a sealed vessel for 48 hours. The reaction mixture was diluted with water (4 mL) and extracted with ethyl acetate
(4 mL). The organic extract was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in
MeOH (0.5 ml) and purified using a phenomomnex HPLC C-18 column eluting with acetonitrile:water (5 :
95 changing to 95 : 5 by volume containing 0.1% TFA by volume) to yield the title compound as a gum (45 mg, 63%).
1H NMR (400MHz, CDCI3): δ 8.41 - 8.33 (1H, m), 7.6 - 7.3 (1H, m), 6.15 (1H, br s), 4.92 - 4.69 (1H, m), 4.65 (1 H, s), 4.05 (1H, d), 3.89 - 3.19 (5H, m), 3.17 - 3.09 (2H, m), 2.77 (1H, t), 2.39 - 2.19 (1H, m), 1.88 - 1.65 (2H, m), 1.62 - 1.51 (2H, m), 1.49 (9H, S), 1.44 - 1.17 (1H, m) 0.97 (9H, s) ppm. MS (ESI) m/z 419 [M+Hf
Preparation 25: .e/f-Butyl /1-f2-amino-6-r(2,2-dimethylpropyπamino1pyrimidin-4-ylTazetidin-3- vDmethyl-carbamate
Figure imgf000035_0002
To a solution of the title compound of preparation 12 (40 mg, 0.13 mmol) in DMSO (150 μL) was added isopropylamine (150 μL, 1.7 mmo!) and the resulting mixture was heated to 120 0C in a sealed vessel for 48 hours. The reaction mixture was concentrated in vacuo to give a brown gum. The residual gum was purified by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (990 : 10 : 1 changing to 190 : 10 : 1 by volume) to yield the title compound as a gum (20 mg, 42%). 1H NMR (400MHz, CD3OD): δ 4.83 (1H, s), 4.13 (2H, t), 3.97 (2H, dd), 3.01 (2H, s), 2.93 (3H, s), 1.46 (9H, s), 0.94 (9H1 s) ppm. MS (ESI) m/z 365 [M+H]+
Preparation 26: tert-Butyl ri-(2-amino-6-isopropylamino-pyrimidin-4-vO-azetidin-3-vπ-methyl- carbamatβ
Figure imgf000036_0001
To a solution of the title compound of preparation 12 (40 mg, 0.13 mmol) in DMSO (150 μL) was added isopropylamine (150 μL, 1.7 mmol) and the resulting mixture was heated to 120 °C in a sealed vessel for 48 hours. The reaction mixture was concentrated in vacuo to give a brown gum. The residual gum was purified by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (990 : 10 : 1 changing to 190 : 10 : 1 by volume) to yield the title compound as a gum (22 mg, 50%).
1H NMR (400MHz, CDCI3): δ 4.95 (1H, br s), 4.67 (1H, s), 4.48 (2H, br s), 4.33 (1H, br d), 4.16 (2H, br t), 3.95 (2H, dd), 3.72 (1H, m), 2.92 (3H, s), 1.46 (9H, s) 1.19 (6H, d) ppm. MS (APCI) m/z 337 [M+H]+
Preparation 27: fert-Butyl {1-r2-amino-6-(3,3,3-trifluoro-propylamino)-pyrimidin-4-vn-azetidin-3-yl>- methyl-carbamate
Figure imgf000036_0002
To a solution of the title compound of preparation 12 (30 mg, 0.1 mmol) in EtOH (200 μL) was added
3,3,3 trifluoropropylamine hydrochloride (48 mg, 0.3 mmol) followed by TEA ( 100 μL, 0.7 mmol) and the resulting mixture was heated under microwave irradiation to 130 0C in a sealed vessel for 90 min. The reaction mixture was concentrated in vacuo to give a brown gum. The residual gum was purified by flash column chromatography eluting with DCM : MeOH : 880 ammonia (99 : 1 : 0.1 changing to 95 : 5 : 0.5, by volume) to yield the title compound as a gum (15 mg, 38%).
1H NMR (400MHz, CD3COCD3): δ 5.71 (1H, br t), 5.13 (2H, br s), 4.87 (1H, br s), 4.84 (1H, s), 4.04 (2H, t), 3.88 (2H, dd), 3.54 (2H, q), 2.91 (3H, s), 2.52 (2H, m), 1.44 (9H, s) ppm.
MS (APCI) m/z 391 [M+H]+
Preparation 28: tert-Butyl fi^-amino-S-fcvclopropylmethyl-aminoVpyrimidin^-vπ-azetidin-S-yl'V- methyl-carbamate
Figure imgf000036_0003
The title compound was prepared by a method similar to that described for preparation 26, using the title compound of preparation 12 and cyclopropylmethylamine, in 48% yield.
1H NMR (400MHz, CD3COCD3): δ 5.51 (1H, m), 5.08 (2H, br s), 4.87 (1H, br s), 4.79 (1H1 s), 4.03 (2H, t), 3.87 (2H, dd), 3.08 (2H, t), 2.90 (3H, s), 1.43 (9H, s), 1.02 (1H, m), 0.42 (2H, m), 0.19 (2H, m) ppm. MS (APCI) m/z 349 [M+Hf
Preparation 29: fe/t-ButvK1-r2-amino-6-(3.3-dimethyl-butylamino)-pyrimidin-4-vn-azetidin-3-ylV methyl-carbamate
Figure imgf000037_0001
The title compound was prepared by a method similar to that described for preparation 26, using the title compound of preparation 12 and 3,3-dimethylbutan-1 -amine, in 58% yield.
1H NMR (400MHz, CDCl3): δ 5.0 (1H, br s), 4.67 (1H, s), 4.52 (2H, br s), 4.36 (1H br t), 4.16 (2H, t), 3.96 (2H, m), 3.13 (2H, m), 2.92 (3H, s), 1.50 - 1.45 (11 H, m), 0.95 (9H, s) ppm. MS (APCI) m/z 379 [M+H]+
Preparation 30: ferf-Butyl (1 -r2-amino-6-(3-fluoro-benzylamino)-pyrimidin-4-vn-azetidin-3-yl>- methyl-carbamate
Figure imgf000037_0002
The title compound was prepared by a method similar to that described for preparation 26, using the title compound of preparation 12 and 3-fluorobenzylamine using 1 ,2-diethoxy-ethane as reaction solvent, in 53% yield.
1H NMR (400MHz, CDCI3): δ 7.28 (1H, m), 7.08 (1H, d), 7.01(1 H, br d), 6.95 (1H, br t), 5.15 (1H, br t), 5.00 (1H, br s), 4.80 (2H, br s), 4.64 (1H, s), 4.41 (2H, br d), 4.13 (2H, t), 3.96 (2H, dd), 2.90 (3H, s), 1.45 (9H, s) ppm.
MS (ESI) m/z 403 [M+H]+
Preparation 31 : fert-Butyl f1 -F2-amino-6-(3-methoxy-benzylamino)-pyrimidin-4-vn-azetidin-3-yl'y- methyl-carbamate
Figure imgf000038_0001
The title compound was prepared by a method similar to that described for preparation 26, using the title compound of preparation 12 and 3-methoxy-benzylamine, in 17% yield.
1H NMR (400MHz, CD3COCD3): δ 7.20 (1H, t), 6.93 - 6.89 (2H, m), 6.78 (1H, dd), 5.96 (1H, br t), 5.12 (2H, br s), 5.00 - 4.70 (2H, m), 4.46 (2H, d), 4.01 (2H, t), 3.86 (2H, m), 3.76 (3H, s), 2.90 (3H, s), 1.44 (9H, s) ppm.
Preparation 32: .e/f-Butyl {1-r2-amino-6-(cvclobutylmethyl-amino)-pyrimidin-4-yll-azetidin-3-ylV methyl-carbamate
Figure imgf000038_0002
To a solution of the title compound of preparation 1 (30 mg, 0.10 mmol) in DMSO (150 μL) was added cyclobutylmethylamine hydrogen chloride (127 mg, 1 mmol) followed by DIPEA ( 300 μL, 1.76 mmol) and the resulting mixture was heated to 120 0C in a sealed vessel for 48 hours. The reaction mixture was concentrated in vacuo to give a gum. The residual gum was purified by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (990 : 10 : 1 changing to 190 : 10 : 1 by volume) to yield the title compound as a gum (12 mg, 33%). 1H NMR (400MHz, CD3COCD3): δ 5.52 (1H, m), 5.13 (2H1 br s), 4.87 (1H, br s), 4.79 (1H1 s), 4.05 (2H, t),
3.86 (2H, dd), 3.25 (2H, t), 2.91 (3H1 s), 2.56 (1H, m), 2.05 - 1.97 (H, m), 1.89 - 1.80 (2H, m), 1.77 - 1.69
(2H, m), 1.44 (9H, s) ppm.
MS (ESI) m/z 363 [M+Hf
Preparation 33: fe/f-Butyl {1-r2-amino-6-(cvclopentylmethyl-amino)-pyrimidin-4-vn-azetidin-3-yl>- methyl-carbamate
Figure imgf000038_0003
The title compound was prepared by a method similar to that described for preparation 26, using the title compound of preparation 12 and cyclopentylmethylamine hydrogen chloride, in 16% yield. 1H NMR (400MHz, CD3OD): δ 4.79 (1H1 s), 4.15 (2H1 1), 4.00 (2H, dd), 3.10 (2H, d), 2.93 (3H, s), 2.14 (1H, m), 1.83 - 1.75 (2H, m), 1.69 - 1.53 (4H, m), 1.46 (9H, s), 1.30 - 1.22 (2H, m) ppm. MS (APCI) m/z 377 [M+H]+
Preparations 34 to 42
The following compounds of the general formula shown below were prepared by a method similar to that described for preparation 1 using the appropriate amine and 2-amino~4,6-dichloropyrimidine. Reactions were monitored by TLC analysis.
Figure imgf000039_0001
Figure imgf000039_0002
Preparation 43: N4-(.ert-Butvπ-6-chloropyrimidine-2,4-diamine
Figure imgf000040_0001
A solution of 2-amino-4,6-dichloropyrimidine (400mg, 2.44mmol) and t-butylamine (2.6ml, 25.0mmol) in NMP (1ml) was heated in a microwave at 1500C for 60 minutes. The reaction mixture was partitioned between water (10ml) and ethyl acetate (10ml), the organic phase separated, dried and reduced in vacuo. Purification by flash column chromatography on silica gel eluting with ethyl acetate:pentane (30:70 changing to 80:20 by volume) to yield the title compound as a colourless solid (494mg, 100%). 1H NMR (400MHz, CDCI3): δ 5.80 (1H, s), 4.78 (2H, bs), 1.42 (9H, s) ppm. MS (ESI) m/z 201 [M+H]+
Preparation 44: 6-Chloro-N4-(1-methylcvclopropyπpyrimidine-2.4-diamine
Figure imgf000040_0002
2-amino-4,6-dichloropyrimidine (508mg, 3.1mmol) was added to a suspension of 1- methylcyclopropylamine hydrochloride (1.0g, 9.3mmol) and sodium methoxide (502mg, 9.30mmol) in NMP (3ml). The resulting mixture was heated at 90°C for 16 hours and then cooled to room temperature. The reaction mixture was diluted with water (20ml) and the resulting precipitate filtered off, washed with further water (20ml) and dried in vacuo to give the title compound as a colourless solid (280mg, 15%). 1H NMR (400MHz, CDCI3): δ 6.71 (1H, s), 1.37 (3H, s), 0.83-0.79 (2H, m), 0.72-0.65 (2H, m) ppm. MS (ESI) m/z 199 [M+Hf
Preparation 45 : Benzyl PRΪ-S-rfferf-butoxycarbonvDaminolpyrrolidine-i-carboxylate
Λo-rf /-
A solution of tert-Butyl (3S)-pyrrolidin-3-ylcarbamate (10.0g, 53.7mmol) in DCM (40ml) was treated with TEA (14.9ml, 107mmol) and cooled to 00C. Benzyl chloroformate (7.6ml, 53.7mmol) was added dropwise and the resulting suspension was allowed to warm gradually to room temperature over a period of 18 hours. The reaction mixture was diluted with water (100ml) and the organic phase separated. The aqueous phase was extracted with further DCM (2 x 50ml) and the combined organic extracts dried (sodium sulphate) and concentrated in vacuo to give a pale yellow solid (14.6g, 85%) 1H NMR (400MHz, CDCI3): 57.39-7.29 (5H, m), 5.13 (2H, s), 4.58 (1H, m), 4.19 (1 H, m), 3.66 (1 H, m), 3.49 (1H, m), 3.25 (1H, m), 2.14 (1H, m), 1.82 (1H, m), 1.44 (9H, s) ppm. MS (ESI) m/z 321 [M+H]+
Preparation 46 : Benzyl (SRVS-Kte/f-butoxycarbonylteminoipyrrolidine-i-carboxvlate
JU L L7 V \ ,
A solution of the carbamate of preparation 45 (14.6g, 45.6mmol) in THF (85ml) was cooled to O0C and treated with potassium ferf-butoxide (4.38g, 59.27mmol). The reaction was left to stir for 30 minutes prior to the addition of methyl iodide (4.26ml, 59.3mmol) and then allowed to warm gradually to room temperature. The reaction mixture was partitioned between ethyl acetate (200ml) and water (100ml). The aqueous phase was separated and extracted with further ethyl acetate (100ml). The combined organic extracts were washed with saturated aqueous sodium chloride (100ml), dried (magnesium sulphate) and reduced in vacuo to give an orange oil. The oil was re-dissolved in THF (85ml), cooled to 00C and treated with potassium ferf-butoxide (3.0Og, 40.6mmol). The reaction was left to stir for 30 minutes prior to the addition of methyl iodide (3.0ml, 41.7mmol) and then allowed to warm gradually to room temperature. The reaction mixture was partitioned between ethyl acetate (200ml) and water (100ml). The aqueous phase was separated and extracted with further ethyl acetate (100ml). The combined organic extracts were washed with saturated aqueous sodium chloride (100ml), dried (magnesium sulphate) and reduced in vacuo to give the title compound as an orange oil (15.3g, 100%).
1H NMR (400MHz, CDCI3): 5 7.35-7.26 (5H, m), 5.11 (2H, s), 4.70 (1H, m), 3.58 (2H, m), 3.34 (1H, m), 3.29 (1H, m), 2.74 (3H, s), 1.98 (2H, m), 1.43 (9H, s) ppm. MS (ESI) m/z 335 [M+H]+
Preparation 47 : fert-Butyl methyl[ϊ3R)-pyrrolidin-3-vπcarbamate
HO \>
A solution of the carbamate of preparation 46 (15.58g, 46.6mmol) in ethanol (150ml) was hydrogenated in the presence of 5%Pd/C (1g) at 50psi at room temperature for a period of 18 hours. Further Pd/C (500mg) was added and the resulting mixture hydrogenated under the same conditions for a further 26 hours. The catalyst was filtered off and the filtrate concentrated in vacuo. Purification by chromatography
(DCM:MeOH:0.880 ammonia (100:0:0 changing to 90:10:1 by volume) gave the title compounds as a pale yellow oil (5.85g, 62%).
1H NMR (400MHz, CDCI3): δ 4.56 (1H1 m), 3.06 (2H, m), 2.87 (1H, m), 2.79 (1H, m), 2.78 (3H, s), 2.54 (1H, s), 1.95 (1H, m), 1.73 (1H, m), 1.43 (9H1 s) ppm.
MS (ESI) m/z 201 [M+H]+
Example 1: A/-(3.3-Dimethylbutvπ-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine
Figure imgf000041_0001
A solution of the title compound (110 mg, 0.52 mmol) of preparation 6 in NMP (2 ml_) was treated with DlPEA (135 μL, 0.78 mmol) and 3,3-dimethylbutan-1 -amine (347 μL, 2.6 mmol) and heated to 150 0C for 18 hours in a sealed vessel. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate (20 mL) and water (20 mL). The organic fraction was washed with saturated aqueous sodium chloride (20 mL) dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (90 : 10 : 1 by volume) to yield the title compound as a gum (57mg, 40%). 1H NMR (400MHz, CD3OD): δ 7.95 (1H, s), 5.56 (1H, s), 3.51 (4H, m), 3.23 (2H, m), 2.47 (4H, m), 2.30 (3H1 s), 1.49 (2H, m), 0.95 (9H, s) ppm. MS (APCI) m/z 278 [M+H]+
Examples 2 to 5
The following compounds were prepared by a method similar to that described for example 1 using the appropriate starting material.
Figure imgf000042_0001
Figure imgf000042_0003
Example 6: ΛI'-(3.3-Dimethylbutyl)-Λr-r(3S)-pyrrolidin-3-vnpyrimidine-4,6-diamine
Figure imgf000042_0002
A solution of the compound of preparation 20 (2.15 g, 6.1 mmol) in EtOH (40 mL) and MeOH (20 mL) was cooled to 0 0C and treated with palladium hydroxide (20% on carbon 100 mg) followed by ammonium formate (5.8 g, 91 mmol) and heated to reflux for 2 hours. The reaction mixture was cooled to ambient temperature filtered and the filtrate concentrated in vacuo. The residue was purified directly by SCX resin, eluting non-basic compounds with MeOH and the basic compounds with 1N ammonia in MeOH. The basic washings were concentrated in vacuo and purified by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (1 : 0 : 0 changing to 80 : 20 : 1, by volume) to yield the title compound as a white powdery solid (1.2 g, 75%).
1H NMR (400MHz, CD3OD): δ 7.9 (1H, s), 5.4 (1H, s), 4.1 (1H, m), 3.2 (2H m), 3.1 (1H, m), 3.0 (1 H, m), 2.9 (1H, m), 2.7 (1H, m), 2.1 (1H, m), 1.7 (1 H, m), 1.5 (2H, m), 1.0 (9H, s) ppm. Accurate mass: found 264.2181, C14H26N5 requires 264.2183.
Example 7; N-(3.3-Dimethylbutyl)-N'-r(3RVpyrrolidin-3-vnpyrimidinβ-4.6-diamine
Figure imgf000043_0001
The title compound was prepared by a similar method to that described for example 6, using the title compound of preparation 21 , in 70% yield.
1H NMR (400MHz, CD3OD): δ 7.9 (1H, s), 5.4 (1H, s), 4.1 (1H, m), 3.2 (2H m), 3.1 (1H, m), 3.0 (1H, m),
2.9 (1H, m), 2.7 (1H, m), 2.1 (1H, m), 1.7 (1H, m), 1.5 (2H, m), 1.0 (9H, s) ppm.
MS (APCI) m/z 264 [M+H]+
Example 8: /V-(3.3-Dimethylbutyl)-Λr-rf3R)-1-methylpyrrolidin-3-vnpyrimidine-4.6-diamine
Figure imgf000043_0002
A suspension of the compound of example 7 (38 mg, 0.144 mmol) in THF (1.5 mL) containing aqueous formaldehyde (11 μL, 0.144 mmol, 37% in water) and acetic acid (8.3 μl_, 0.144 mmol) was treated with sodium triacetoxyborohydride (37 mg, 0.173 mmol) and stirred at ambient temperature for 10 min. The reaction mixture was applied directly to SCX resin, eluting non-basic compounds with MeOH and the basic compounds with 1N ammonia in MeOH. The basic washings were concentrated in vacuo and purified by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (1 : 0 : 0 changing to 40 : 10 : 1 , by volume) further purification on reverse phase silica eluting with water : acetonitrile (1 : 0 changing to 19 : 1 by volume) gave the title compound as a white solid (14 mg, 35%).
1H NMR (400MHz, CD3OD): δ 7.9 (IH, s), 5.4 1 H, s), 4.2 (1H, m), 3.2 (2H, m), 2.9 (1 H, m), 2.8 (1H, m), 2.5 (2H, m), 2.4 (4H, m), 1.7 (1H1 m), 1.5 (2H, m) 1.1 (9H, s) ppm. MS (APCI) m/z 278 [M+H]+, 276 [M-H]"
Example 9: Λ^-tCvclopropylmethvD-G-rOffl-S-^methylaminotpyrrolidin-i-vnpyrimidine-Σ^-diamine
Figure imgf000044_0001
A solution of the compound of preparation 15 (120 mg, 0.38 mmol) in NMP (2 mL) was treated with DIPEA (191 μL, 1.1 mmol) and 1 -cyclopropylmethylamine (99 μl_, 1.15 mmol) and heated to 150 0C in a sealed vessel for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (4 x 50 mL) and saturated aqueous sodium chloride (50 mL), dried (MgSO4) and concentrated in vacuo to give the crude intermediate terf-butyloxycarbonyl-protected compound. This crude material was dissolved in DCM (2 mL), treated with trifluoroacetic acid (2 mL) and stirred at ambient temperature for 3 h after which time the reaction mixture was concentrated in vacuo. The residue was purified directly by SCX resin, eluting non-basic compounds with MeOH and the basic compounds with 2 N ammonia in MeOH. The basic washings were concentrated in vacuo and purified by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (1 : 0 : 0 changing to 170 : 30 : 3, by volume) to yield the title compound as a white foam (16 mg, 17%).
1H NMR (400MHz, CD3OD): δ 4.89 (1H, s), 3.63 (1H, m), 3.55 (1H, m), 3.47 (1H, m), 3.39 (1H, m), 3.23 (1H, m), 3.05 (2H, d), 2.42 (3H, s), 2.21 (1H, m), 1.88 (1H, m), 1.06 (1H, m), 0.52 (2H, q), 0.23 (2H, q) ppm.
MS (APCI) m/z 248 [M+H]+
Alternative method for example 9: A/4-(Cvclopropylmethyl)-6-r(3R)-3-(methylamino)pyrrolidin-1- yllpyrimidine-2,4-diamine
Figure imgf000044_0002
A suspension of the compound of preparation 15 (1.8g, 5.5mmol) in cyclopropylmethanamine (5.4ml, 62.3mmol) and TEA (1.53ml, 11 mmol) was heated in a sealed pressure vessel at 120°C for 24 hours. The excess amine was removed in vacuo and the residue partitioned between water (100ml) and DCM (100ml). The aqueous phase was separated and extracted with further DCM (100ml). The combined organic extracts were washed with saturated aqueous sodium chloride (100ml) and the solvent removed in vacuo. Purification by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (98 : 2 : 0 changing to 95 : 5 : 0.2, by volume) gave the to give the intermediate tert- butyloxycarbonyl-protected compound (1.55g, 77%). 1H NMR (400MHz, CD3OD): δ 4.89 (1H, s), 4.71 (1H, m), 3.64 (2H, m), 3.32 (2H, m), 3.07 (2H, d), 2.80 (3H, s), 2.13 (2H, m), 1.46 (9H1 s), 1.05 (1 H, m), 0.52 (2H, m), 0.23 (2H, m) ppm. MS (APCI) m/z 363 [M+H]+
A solution of the intermediate terf-butyloxycarbonyl-protected compound (6.18g, 16.6mmol) in methanol (15ml) was treated with 4M HCI in 1 ,4-dioxan (42ml, 168mmol) and the resulting solution was left to stir at room temperature (exotherm observed on addition of the HCI) for 18 hours. The solvent was removed in vacuo and the residue partitioned between 0.880 ammonia (50ml) and DCM (400ml). The aqueous phase was separated and extracted with further DCM (200ml). The combined organic extracts were dried (sodium sulphate) and the solvent removed in vacuo to give a pale yellow oil (4.0Og, 92%).
Example , 9a : Λ^-fCvclopropvlmethvD-S-rOffl-S-fmethvlaminotPvrrolidin-i-vnpyrimidine-Σ^- diamine L -tartrate
Figure imgf000045_0001
A solution of the compound of example 9 (10.14g, 38.65mmol) in methanol (340ml) was treated with a solution of L(+) tartaric acid in (5.8g, 38.65mmol) in methanol (50ml). The resulting suspension was stirred at room temperature for 30 minutes and the resulting solid filtered off and dried in vacuo. The solid was dissolved in the minimum volume of boiling water (22ml) and then methanol was added until a permanent ppt was observed (102ml). The resulting suspension was allowed to cool gradually to room temperature and the solid filtered and dried in vacuo for 50°C for 3 days and then allowed to equilibrate at room temperature in air for a further 2 days to give the title compounds as a colourless solid (14.15g, 89%)
1H NMR (400MHz, CD3OD): δ 6.41 (1H, br s), 5.72 (2H, br s), 4.81 (1H, s), 3.92 (2H, s), 3.58 (2H, m), 3.40 (1H, m), 3.32 (2H, m), 3.03 (2H, m), 2.48 (3H, s), 2.18 (1 H, m), 1.95 (1H, m), 0.96 (1H, m), 0.39 (2H, m), 0.12 (2H, m) ppm. MS (APCI) m/z 263 [M+H]+
Examples 10 to 12
The following compounds were prepared by a method similar to that described for example 9 using the title compound of preparation 15 and the appropriate amine starting material.
Figure imgf000045_0002
Figure imgf000045_0003
Examples 13 to 15
The following compounds were prepared by a method similar to that described for example 9, using the compound of preparation 10 and the appropriate amine starting material.
Figure imgf000046_0001
Figure imgf000046_0004
Examples 16 to 17
The following compounds were prepared by a method similar to that described for example 9 using the compound of preparation 11 and the appropriate amine starting material.
Figure imgf000046_0002
Figure imgf000046_0005
Example 18: 6-r(3R)-3-(Dimethylamino)pyrrolidin-1-vn-N-(3,3-dimethylbutyl)pyrimidin-4-amine
Figure imgf000046_0003
A solution of the title compound of preparation 2 (120 mg, 0.53 mmol) in NMP (2 mL) was treated with DIPEA (276 μL 1.59 mmol) 3,3-dimethylbutan-1 -amine (213 μL, 1.59 mmol) and heated to 150 0C in a sealed vessel for 72 hours. The reaction mixture was cooled and purified directly by SCX resin, eluting non-basic compounds with MeOH and the basic compounds with 2 N ammonia in MeOH. The basic washings were concentrated in vacuo and purified by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (1 : 0 : 0 changing to 40 : 10 : 1 , by volume) to yield the title compound as a gum (72 mg, 47%).
1H NMR (400MHz, CD3OD): δ 7.92 (1H, s), 5.30 (1 H, s), 3.72 (1H, m), 3.61 (1H, m), 3.37 (1H, m), 3.24 (2H, m), 3.17 (1H1 m), 2.89 (1H, m), 2.32 (6H, s), 2.25 (1H, m), 1.87 (1H, m), 1.52 (2H, m), 0.98 (9H, s) ppm.
MS (APCI) m/z 292 [M+H]+
Examples 19 to 22
The following compounds were prepared by a method similar to that described for example 18 using the title compound of preparation 2.
Figure imgf000047_0001
Figure imgf000047_0003
Example 23: N4-(3.3-Dimethylbutvπ-6-r(4aR*,7aR*)-octahvdro-6H-pyrrolor3,4-b1pyridin-6- vπpyrimidinβ-2,4-diamine
Figure imgf000047_0002
The title compound of preparation 24 (45 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at ambient temperature for 1 hour after which time the reaction mixture was concentrated in vacuo.
The residue was purified directly by SCX resin, eluting non-basic compounds with MeOH and the basic compounds with 1 N ammonia in MeOH taking 4 mL fractions to yield the title compound as a solid (25 mg, 71%). 1H NMR (400MHz, CD3OD): δ 3.52 - 3.33 (5H, m), 3.22 - 3.14 (2H, m), 2.97 - 2.86 (1H, m), 2.66 - 2.57
(1H, m), 2.40 - 2.29 (1H, m), 1.80 - 1.72 (2H, m), 1.70 - 1.55 (1H, m), 1.53 - 1.43 (3H, m), 0.97 (9H, s) ppm.
MS (ESI) m/z 319 [M+Hf Example 24: N^lsoDropvl-B-rMaR^yaR^-octahvdro-ΘH-pvrrolors.Λ-biPvridin-B-vnpvrimidine-Σ^- diamine
Figure imgf000048_0001
The title compound was prepared by a method similar to that described for example 23 and preparation
24, by reaction of the compound of preparation 14 with isopropyl amine and subsequent deprotection, in
28% yield.
1H NMR (400MHz, CD3OD): δ 4.77 (1H, s), 3.86 - 3.74 (1H, m), 3.51 - 3.34 (5H1 m) 2.96 - 2.86 (1H, m),
2.66 - 2.56 (1H, m), 2.40 - 2.26 (1H, m), 1.81 - 1.72 (2H, m), 1.70 - 1.57 (1H, m), 1.54 - 1.41 (1H, m), 1.18
(6H, d) ppm
MS (ESI) m/z 277 [M+Hf
Examples 25 to33
The following compounds were prepared by a method similar to that described for example 23 and preparation 24 by reaction of the compound of preparation 14 with an appropriate amine and subsequent deprotection.
Figure imgf000048_0002
Figure imgf000048_0003
Figure imgf000049_0003
Example 34: 6-r(3aR*,6aS*)-5-IVlethylhexahvdropyrrolor3,4-c1pyrrol-2f1H)-vn-N4-DropylPyrimidine- 2,4-diamine
Figure imgf000049_0001
To a solution of the title compound of preparation 13 (20 mg, 0.08 mmol) in DMSO (75 μL) was added propylamine (75 μL, 1 mmol) and the mixture was heated to 120 0C in a sealed vessel for 48 hours. The reaction mixture was concentrated in vacuo to give a brown gum. The residual gum was purified by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (990 : 10 : 1 changing to 90 :10 : 1, by volume) to yield the title compound as a gum (10 mg; 45%). 1H NMR (400MHz, CD3COCD3): δ 5.28 (1H, br t), 4.97 (3H, m), 3.51 (2H, m), 3.20 (4H, m), 2.83 (H, m), 2.51 (2H, m), 2.41 (2H, m), 2.22 (3H, s) 1.56 (2H, m), 0.92 (3H, t) ppm MS (ESI) m/z 277 [M+H]+
Examples 35 to 43
The following compounds were prepared by a method similar to that described for example 34 using the compound of preparation 13 and the appropriate amine starting material.
Figure imgf000049_0002
Figure imgf000049_0004
Figure imgf000050_0003
Example 44: Cvclopropylmethyl-rθ-O-mβthylamino-azetidin-i-vD-pyrimidin^-vn-amine
Figure imgf000050_0001
A solution of the title compound of preparation 22 (70 mg, 0.21 mmol) in DCM (5 mL) was treated with trifluoroacetic acid (0.5 mL) and stirred at ambient temperature for 2 hours after which time the reaction mixture was concentrated in vacuo. The residue was purified directly by SCX resin, eluting non-basic compounds with MeOH and the basic compounds with 2 N ammonia in MeOH taking 20 mL fractions to yield the title compound (45 mg, 92%).
1H NMR (400MHz, CDCI3): δ 8.12 (1 H, s), 5.06 (1H, s), 4.89 (1H, br s), 4.20 (2H, m) 3.71 (3H, m), 3.03 (2H, m), 2.42 (3H, s), 1.05 (1H, m), 0.54 (2H, m), 0.24 (2H, m) ppm. Accurate mass: found 234.1709, Ci2H2oN5 requires 234.1719.
Example 45: (3-Fluoro-benzyl)-r6-(3-methylaιnino-azetidin-1-yl)-pyrimidin-4-vn-amine
Figure imgf000050_0002
A solution of the title compound of preparation 23 (42 mg, 0.11 mmol) in DCM (5 mL) was treated with trifluoroacetic acid (0.5 mL) and stirred at ambient temperature for 2 hours after which time the reaction mixture was concentrated in vacuo. The residual oil was purified by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (1 : 0 : 0 changing to 182 : 15 : 3, by volume) to yield the title compound as a solid (29 mg, 94%).
1H NMR (400MHz, CDCI3): δ 8.17 (1H, s), 7.29 (1H, m), 7.09 (1H, d), 7.02 (1H, d), 6.97 (1H, m), 5.07 (1H, d), 5.02 (1H, br s), 4.45 (2H, d), 4.16 (2H, m), 3.69 (3H, m), 2.42 (3H, s) ppm.
MS (APCI) m/z 288 [M+H]+ Examples 46 to 59
The following compounds were prepared by a method similar to that described for example 44 and preparation 22, by reaction of the compound of preparation 1 with an appropriate amine and subsequent deprotection.
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000052_0004
Example 60: N4-lsopropyl-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2.4-diamine
Figure imgf000052_0001
The title compound of preparation 26 (22 mg, 0.07 mmol) was dissolved in trifluoroacetic acid (1 mL) and stirred at ambient temperature for 2 hours after which time the reaction mixture was concentrated in vacuo. The residual gum was purified by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (98 : 2 : 0.2 changing to 90 : 10 : 1 , by volume) to yield the title compound as a gum (12mg, 73%).
1H NMR (400MHz, CD3OD): δ 4.74 (1 H1 s), 4.1 (2H, dd), 3.82 (1H, m), 3.67 (2H, m), 3.61 (1H, m), 2.33 (3H, s), 1.16 (6H, d) ppm. MS (APCI) m/z 237 [M+H]+
Example 61 : N4-(2.2-Dimethylpropyl)-6-r3-(methylamino)azetidin-1-vnpyrimidine-2,4-diamine
Figure imgf000052_0002
The title compound was prepared by a method similar to that described for example 60, using the compound of preparation 25, in 91% yield.
1H NMR (400MHz, CD3COCD3): δ 5.29 (1H, br t), 4.97 (2H, br s), 4.79 (1H, s), 3.97 (2H, t), 3.56 - 3.49 (3H, m), 3.08 (2H, br d), 2.32 (3H1 s), 0.93 (9H, s) ppm MS (ESI) m/z 265 [M+H]+
Example 62: 6-(3-Methylamino-azetidin-1-yl)-N4-(3,3,3-trifluoro-propyl)-pyrimidine-2.4-diamine
Figure imgf000052_0003
The title compound was prepared by a method similar to that described for example 60, using the compound of preparation 27, in 92% yield. 1H NMR (400MHz, CD3OD): δ 4.78 (1 H, s), 4.11 (2H, m), 3.68 (2H, dd), 3.62 (1H, m), 3.48 (2H, t), 2.42 (2H, m), 2.34 (3H, s) ppm MS (ESI) m/z 291 [M+H]+
Example 63: N -Cvclopropylmethyl-G-fS-methylamino-azetidin-i-vh-pyrimidine-Σ^-diamine
Figure imgf000053_0001
The title compound was prepared by a method similar to that described for example 60, using the compound of preparation 28, in 85% yield.
1H NMR (400MHz, CD3OD): δ 4.17 (2H, m), 3.76 (2H, m), 3.70 (1H, m), 3.06 (2H, d), 2.39 (3H, s), 1.01 (1 H, m), 0.52 (2H, m), 0.22 (2H, m) ppm. MS (APCI) m/z 249 [M+H]+
Example 64: N4-(3,3-Dimβthyl-butvil-6-(3-methylamino-azetidin-1-vπ-pyrimidine-2,4-diamine
Figure imgf000053_0002
The title compound was prepared by a method similar to that described for example 60, using the compound of preparation 29, in 87% yield.
1H NMR (400MHz, CD3OD): δ 4.73 (1H1 s) 4.11 (2H, m), 3.68 (2H, m), 3.62 (1H, m), 3.18 (2H, m), 2.33
(3H, s), 1.48 (2H, m), 0.96 (9H, s) ppm.
MS (APCI) m/z 279 [M+H]+
Example 65: N4-(3-Fluoro-benzvπ-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2.4-diamine
Figure imgf000053_0003
The title compound was prepared by a method similar to that described for example 60, using the compound of preparation 30, in 84% yield. 1H NMR (400MHz, CD3COCD3): δ 7.32 (1H, m), 7.16 (1H, d), 7.10 (1H, br d), 6.96 (1H, m), 6.01 (1H, m), 5.06 (2H, br s), 4.79 (1H, s), 4.51 (2H, d), 3.96 (2H, t), 3.57 - 3.48 (3H, m), 2.31 (3H, s) ppm. MS (APCI) m/z 303 [M+H]+
Example 66: N4-(3-Methoxy-benzyl)-6-(3-methylamino-azetidin-1-v»-pyrimidine-2.4-diamine
Figure imgf000053_0004
The title compound was prepared by a method similar to that described for example 60, using the compound of preparation 31, in 72% yield. 1H NMR (400MHz, CD3OD): δ 7.20 (1H, t), 6.89 - 6.85 (2H, m), 6.78 (1H, dd), 4.73 (1H, s), 4.37 (2H, s), 4.07 (2H, t), 3.76 (3H1 s), 3.65 - 3.55 (3H, m), 2.31 (3H, s) ppm. MS (APCI) m/z 315 [M+Hf
Example 67: N^Cvclobutylmethyl-β-O-methylamino-azetidin-i-vD-pyrimidine-Σ^-diamine
Figure imgf000054_0001
The title compound was prepared by a method similar to that described for example 60, using the compound of preparation 32, in 86% yield.
1H NMR (400MHz, CD3COCD3): δ 5.31 (1H, m), 4.99 (2H, br s), 4.73 (1H, s), 3.96 (2H, t), 3.58 - 3.50 (3H, m), 3.23 (2H, t), 2.55 (1 H, m), 2.32 (3H, s), 2.05 - 1.97(H, m), 1.90 - 1.82 (2H, m), 1.77 - 1.68 (2H, m) ppm. MS (APCI) m/z 263 [M+Hf
Example 68: N4-Cvclopentylmethyl-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2.4-diamine
Figure imgf000054_0002
The title compound was prepared by a method similar to that described for example 60, using the compound of preparation 33, in 81% yield.
1H NMR (400MHz, CD3OD): δ 4.75 (1H, s), 4.11 (2H, dd), 3.68 (2H, dd), 3.61 (1H, m), 3.09 (2H, d), 2.33 (3H, s), 2.13 (1H, m), 1.83 - 1.75 (2H, m), 1.70 —1.53 (4H, m), 1.29 - 1.21 (2H, m) ppm. MS (APCI) m/z 277 [M+H]+
Examples 69 to 90
The following compounds were prepared by a method similar to that described for example 60 and preparation 26 by reaction of the compound of preparation 12 with an appropriate amine and subsequent deprotection.
Figure imgf000054_0003
Figure imgf000054_0004
Figure imgf000055_0001
Figure imgf000056_0001
Example 91 : N4-(3-Fluorobenzvπ-6-(4-methylpiperazin-1-vπpyrimidine-2.4-diamine
Figure imgf000056_0002
The title compound of preparation 18 (20 mg, 0.08 mmol) was treated with DMSO (150 μL) and N- methylpiperazine (88 μL, 0.79 mmol) and heated to 1200C in a sealed vessel for 16 hours. The reaction mixture was cooled to ambient temperature, partitioned between water (2 mL) and ethyl acetate (2 ml_) and filtered through diatomaceous earth, washing with further ethyl acetate (15 mL). The organic fraction of the filtrate was concentrated in vacuo and purified by flash column chromatography on silica gel eluting with DCM : MeOH : 0.880 ammonia (90 : 10 : 1 changing to 90 : 10 : 1, by volume) to yield the title compound as a gum (20 mg, 79%).
1H NMR (400MHz, CD3OD): δ 7.34 - 7.27 (1H, m), 7.14 - 7.10 (1H, m), 7.08 - 7.01 (1H, m), 6.98 - 6.89 (1H, m), 5.11 (1H, s), 4.45 (2H, s), 3.51 - 3.42 (4H, m), 2.48 - 2.41 (4H, m), (2.30 (3H, s) ppm. MS (APCI) m/z 208 [M-C7H6F^H]+
Examples 92 to 98
The following compounds were prepared by a method similar to that described for example 91 using the appropriate pyrimidine starting material and the appropriate amine starting material.
Figure imgf000057_0001
Figure imgf000057_0002
Figure imgf000058_0001
Examples 99 to 127
The following compounds were prepared by similar method to those used to prepare the compounds above.
Figure imgf000058_0002
Figure imgf000059_0001
Figure imgf000060_0002
Examples 128 to 132
The following compounds were prepared by a method similar to that described for example 60 and preparation 26 by reaction of the compound of preparation 12 with an appropriate amine and subsequent deprotection. '
Figure imgf000060_0001
Figure imgf000060_0003
Figure imgf000061_0001
Examples 133 to 153
The following compounds were prepared by a method similar to that described for preparation 26 (solvent and temperature indicated in the table for a period between 10 and 72 hours) using the appropriate pyrimidine starting material and the appropriate amine. Deprotection (if necessary) was carried out using conditions described for example 60.
Figure imgf000061_0002
Figure imgf000062_0001
Figure imgf000063_0001
The following compounds were prepared by similar method to those used to prepare the compounds above, using the appropriate pyrimidine starting material and the appropriate amine:
Example Name
154 N4-(Cyclopropylmethyl)-6-piperazin-1-ylpyrimidine-2,4-diamine
155 N4-(4-Fluorobenzyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
156 N4-(2,2-Dimethylpropyl)-6-piperazin-1-ylpyrimidine-2,4-diamine
157 N4-(2,4-Difluorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine
158 6-[3-(Methylamino)azetidin-1-yl]-N4-(1-methylbutyl)pyrimidine-2,4-diamine
159 N4-(2,2-Dimethylpropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine hydrochloride
160 N4-[(1 R)-1 ,2-Dimethylpropyl]-6-t3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine
161 6-[3-(Methylamino)azetidin-1-yl]-N4-[(1S)-1-methylpropyl]pyrimidine-2,4-diamine
N4-(2,2-Dimethylpropyl)-6-[(3aR*,7aS*)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]pyrimidine-2,4- 162 diamine
163 6-Piperazin-1-yl-N4-propylpyrimidine-2,4-diamine
164 N4-Ethyl-6-[3-(methylamino)azetidin-1 -yl]pyrimidine-2,4-diamine N4-(Cyclopropylmethyl)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-
165 diamine
N4-(2,2-Dimethylpropyl)-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-
166 c diamine
167 N4-(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1 -yl]pyrimidine-2,4-diamine 168 N4-(ferf-Butyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine
169 N4-lsopropyl-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine
170 6-(3-Aminoazetidin-1-yl)-N4-ethylpyrimidine-2,4-diamine
171 6-(3-Aminoazetidin-1-y!)-N4-(cyclopropylmethyl)pyrimidine-2,4-diamine
172 N4-Cyclopropyl-6-[(3aR*,7aS*)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]pyrimidine-2,4-diamine
173 4-[3-(Methylamino)azetidin-1-yl]-6-(4-methylpiperidin-1-yl)pyrimidin-2-amine
174 N4-(Cyclopentylmethyl)-6-[(3R)-3-(methylamino)pyrroIidin-1-yl]pyrimidine-2,4-diamine
175 6-(1 ,4-Diazepan-1-yl)-N4-ethylpyrimidine-2,4-diamine
176 N4-(Cyclopropylmethyl)-N5-[2-(dimethylamino)ethyl]pyrimidine-2,4,6-triamine
177 N4-(2,2-Dimethylpropyl)-6-[(3S)-3-(methylamino)pyrroIidin-1-yl]pyrimidine-2,4-diamine
178 N4-Cyclobutyl-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine
179 N-Cyclobutyl-δ-tS-CmethylaminoJazetidin-i-ylJpyrimidin^-amine
180 6-[(3R)-3-(Methylamino)pyrrolidin-1 -yl]-N4-propylpyrimidine-2,4-diamine
181 N-Cyclobutyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-annine
182 N4-(2-Methoxyethyl)-6-[3-(methyIamino)azetidin-1-yl]pyrimidine-2,4-diamine
183 N-(2,2-Dimethylpropyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine
184 N4-(Cyclopropylmethyl)-6-[(3S)-3-methylpiperazin-1 -yl]pyrimidine-2,4-diamine
185 N4-Ethyl-6-(4-methyl-1 ,4-diazepan-1-yl)pyrimidine-2,4-diamine
186 N4-(2,2-Dimethylpropyl)-6-[3-methyl-3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine
187 N4-lsopropyl-6-piperazin-1-yIpyrimidine-2,4-diamine
N4-(Cyc!opropylmethyl)-6-[(3aR*,7aS*)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]pyrimidine-2,4- 188 diamine
189 N-Cyclopropyl-e-p-CmethylaminoJazetidin-i-ylJpyrinnidin^-amine
190 6-(3-Aminoazetidin-1-yl)-N4-(2,2-dimethylpropyl)pyrimidine-2,4-diamine
N4-(2,2-Dimethylpropyl)-6-[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-2,4- 191 diamine 192 N-(2,2-Dimethylpropyl)-6-(3-pyrrolidin-1-ylazetidin-1-yl)pyrimidin-4-annine
193 N4-Ethyl-6-[(3aR*,7aS*)-octahydro-5H-pyrro!o[3,2-c]pyridin-5-yl]pyrimidine-2,4-ciiamiπe
194 N-(Cyclopropylmethyl)-N1-[2-(dimethylamino)ethyl]pyrimidine-4,6-diamine
195 6-[(3R)-3-Aminopyrrolidin-1 -yl]-N4-(2-methylbuty!)pyrimidine-2,4-diamine
196 N4-(Cyclopropylmethyl)-6-t3-methyl-3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine
197 N4-Ethyl-6-(3-pyrrolidin-1-ylazetidin-1-yl)pyrimidine-2,4-diamine
198 N4-isoPropyl-6-(4-methyl-1 ,4-diazepan-1-yl)pyrimidine-2,4-diamine
199 N4-Cyclobutyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
200 N4-Methyl-6-[(3aR*,7aS*)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]pyrimidine-2,4-diamine
201 6-(4-Aminopiperidin-1-yl)-N4-(2,2-dimethylpropyl)pyrimidine-2,4-diamine
202 N-lsopropyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine
203 N-Cyclopropyl-6-[(3R)-3-(methyIamino)pyrrolidin-1-yl]pyrimidin-4-amine
204 N4-(Cyclopropylmethyl)-6-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamiπe
205 N4-Ethyl-6-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
206 6-[3-(MethyIamino)azetidin-1 -yl]-N-propylpyrimidin-4-amine
207 N4-(feAf-Butyl)-6-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
208 N4-Methyl-6-piperazin-1-ylpyrimidine-2,4-diamine
209 N4-(2,2-Dimethylpropyl)-6-{3-[(methylamino)methyl]azetidin-1-yl}pyrimidine-2,4-diamine
N4-(Cyclopropylmethyl)-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4- diamine
211 N4-(3,3-Dimethylbutyl)-6-[(3S)-3-(methylamino)pyrrolidin-1 -y!]pyrimidine-2,4-diamine
212 N4-(2-Aminoethyl)-N6-(cyclopropyImethyl)pyrimidine-2,4,6-triamine
213 N4-(2-Fluorobenzyl)-6-t(3S)-3-methyIpiperazin-1-yl]pyrimidine-2,4-diamine
214 N4-Ethyl-6-piperazin-1-ylpyrimidine-2,4-diamine
215 6-[(3R)-3-Aminopyrrolidin-1-yl]-N4-(cyclopropylmethyl)pyrimidine-2,4-diamine 216 6-[(3R)-3-Aminopyrrolidin-1-yl]-N4-isobutylpyrimidine-2,4-diamine
217 6-[(3aR*,6aS*)-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-N4-isobutylpyrimidiπe-2,4-diamine
218 6-[(3R)-3-Aminopyrrolidin-1 -yl]-N4-(cyclopentylmethyl)pyrimidine-2,4-diamine
219 6-[(3R)-3-Aminopyrrolidin-1 -yl]-N4-propylpyrimidine-2,4-diamine
220 N-(2-Aminoethyl)-N'-(cyclopropylmethyl)pyrimidine-4,6-diamine
221 N4-Methyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
N4-[(1R*,5S*,6s*)-3-Azabicyc!ot3.1.0]hex-6-yl]-N6-(2,2-dimethylpropyl)pyrimidine-2,4,6- triamine
223 N4-(tert-Butyl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine
224 N-Cyclopropyl-6-(4-methyl-1 ,4-diazepan-1-yl)pyrimidin-4-amine
225 6-[(3R)-3-Aminopyrrolidin-1-yl]-N4-(3,3-dimethylbutyl)pyrimidine-2,4-diamine
226 N-(2,2-Dimethylpropyl)-6-[3-(isopropylamino)azetidin-1-yl]pyrimidin-4-amine
227 N4-(Cyclopropylmethyl)-6-{3-[(methylamino)methyl]azetidin-1-yl}pyrimidine-2,4-diamine
228 N4-(3-Fluorobenzyl)-6-[(3S)-3-m ethylpiperazin-1 -yl]pyrimidine-2,4-diamine
229 6-(4-Aminopiperidin-1-yl)-N4-isobutylpyrimidine-2,4-diamine
230 N4-Cyclobutyl-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yi]pyrimidine-2,4-diamine
231 N4-lsopropyl-6-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)pyrimidine-2,4-diamine
232 6-(3-Aminoazetidin-1-yl)-N4-propylpyrimidine-2,4-diamine
233 N4-(3,4-Difluorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine
234 6-(4-Aminopiperidin-1-yl)-N4-isopropylpyrimidine-2,4-diamine
235 6-[(3R)-3-(Methylamino)pyrrolidin-1-y!]-N4-(3,3,3-trifluoropropyl)pyrimidine-2,4-diamine
236 4-(3,3-Difluoroazetidin-1-yl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2-amine
237 N4-(2-Fluorobenzyl)-6-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine
238 6-[(3aR*,6aS*)-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-N4-isopropylpyrimidine-2,4-diamine
239 N-(2,2-Dimethylpropyl)-6-(4-methyl-1 ,4-diazepan-1 -yI)pyrimidin-4-amine 240 N4-(4-Fluorobeπ2yl)-6-[(3S)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine
N4-lsopropyl-6-[(3aR*,6aS*)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrimidine-2,4- diamine
242 4-[3-(Methylamino)azetidin-1-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-amine
243 ^-(CyclobutylmethyO-e-KSRJrS^methylaminoJpyrrolidin-i-ylJpyrimidine^^-diamiπe
244 N-(3,3-Dimethylbutyl)-6-(3-pyrrolidin-1-ylazetidin-1-yl)pyrimidin-4-annine
245 N4-(2,5-Difluorobenzyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
246 6-(3-Amino-3-methylpyrrolidin-1-yl)-N4-(cyclopropylmethyl)pyrimidine-2,4-diamine
247 N4-(4-Fluorobenzyl)-6-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine
248 N4-Methyl-6-[3-methyl-3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine
249 N4-(3-Fluorobenzyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
250 N4-(2,2-Dimethylpropyl)-6-[3-(methylamino)piperidin-1-yl]pyrimidiπe-2,4-diamine
251 N4-Benzyl-6-[(3S)-3-methylpiperazin-1-yI]pyrimidine-2,4-diamine
252 N-Cyclopropyl-6-t(3S)-3-methylpiperazin-1-yl]pyrimidin-4-amine
253 N4-(2-Fluorobenzyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
254 N4-Benzyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
255 6-[(3R)-3-Aminopyrrolidin-1-yl]-N4-(2,3-difluorobenzyl)pyrimidine-2,4-diamine
256 N4-Cyclopropyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
257 N4-Ethyl-6-[3-methyl-3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine
258 6-[(3S)-3-Methylpiperazin-1-yl]-N-propylpyrimidin-4-amine
259 N4-Beπzyl-6-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine
260 6-(4-GyclohexyIpiperazin-1-yl)-N-(2,2-dimethylpropyl)pyrimidin-4-amine
261 N-lsopropyl-6-[3-methyl-3-(methylamino)azetidin-1-yI]pyrimidin-4-amine
262 N-Methyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine
263 4-[3-(Methylamino)azetidin-1-y!]-6-[(3R)-3-methylmorpholin-4-yl]pyrinnidin-2-amine 264 6-(3-Amino-3-methylpyrrolidin-1-yl)-N4-propylpyrimidine-2,4-diamine
265 6-(3-Amino-3-methylpyrrolidiπ-1-yl)-N4-ethylpyrimidine-2,4-diamine
266 6-(4-Aminopiperidin-1-yl)-N4-propylpyrimidine-2,4-diamine
267 N4-(3-Fluorobenzyl)-6-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine
268 4-t3-(Methylamino)azetidin-1-yl]-6-morpholin-4-ylpyrimidin-2-amine
269 6-(4-Aminopiperidin-1-yl)-N4-cyclopropylpyrimidine-2,4-diamine
270 N-(3,3-Dimethylbutyl)-6-(4-ethylpiperazin-1-yl)pyrimidin-4-amine
271 N4-(2,6-Difluorobenzyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
272 N4-(2,3-Difluorobenzyl)-6-[(3R)-3-(methylamino)pyrroiidin-1-yl]pyrimidine-2,4-diamine
273 N4-(3,5-Difluorobenzyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
(54[(3S)-3-({6-[(3,3-Dimethylbutyl)amino]pyrimidin-4-yl}amino)pyrrolidin-1-yl]methyl}-2- 274 furyl)methanol
275 4-(3,3-Difluoroazetidin-1-yl)-6-[(3R)-3-(methylamino)pyrroiidin-1-yl]pyrimidin-2-amine
276 N,N'-Bis(cyclopropylmethyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine
277 N4-(3,4-Difluorobenzyl)-6-[(3R)-3-(methylamino)pyrroiidin-1-yl]pyrimidine-2,4-diamine
278 N4-lsobutyl-6-[3-(methylamino)piperidin-1-yl]pyrimidine-2,4-diamine
279 N'-(3,3-Dimethylbutyl)-N-methyl-N-(1-methyIpiperidin-4-yl)pyrimidine-4,6-diamine
280 6-(1 ,4-Diazepan-1-yl)-N-(3,3-dimethylbutyl)pyrimidin-4-amine
281 N-Benzyl-N'-[(3S)-pyrrolidin-3-yl]pyrimidine-4,6-diamine
282 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-6-morpholin-4-ylpyrimidin-2-annine
283 6-(4-Aminopiperidin-1-yl)-N4-(cyclopropylmethyl)pyrimidine-2,4-diamine
284 6-(4-Aminopiperidin-1-yl)-N4-methylpyrimidine-2,4-diamine
285 N-(Cyclopropylmethyl)-6-piperazin-1-ylpyrimidin-4-amine
286 N4-]sopropyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
287 N4-(2,2-Dimethylpropyl)-6-(3-morpholin-4-ylazetidin-1-yl)pyrimidine-2,4-diamine 288 N-(3,3-Dimethylbutyl)-N'-(1-methylpiperidin-3-yl)pyrimidine-4,6-diamine
289 N-[(3S)-1-Benzylpyrrolidin-3-yl]-N'-(3,3-dimethylbutyl)pyrimidine-4,6-diamine
290 N-[(3S)-Pyrrolidin-3-yl]-N'-[(2S)-tetrahydrofuran-2-ylmethyl]pyrimidine-4,6-diamine
291 N-(Cyclopropylmethyl)-5-methyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine
292 6-(3-Aminopyrrolidin-1-yl)-N-(3,3-dimethylbutyl)pyrimidin-4-amine
293 4-[6-(4-Methylpiperazin-1 -yl)pyrimidin-4-yl]morpholine
294 N4-(Cyclopropylmethyl)-6-[3-(methylamino)piperidin-1-yl]pyrimidine-2,4-diamine
295 4-[3-(Methylamino)azetidin-1 -yl]-6-piperidin-1 -ylpyrimidin-2-amine
296 N-(3,3-Dimethylbutyl)-N'-[(3S)-1-methylpyrrolidin-3-yl]pyrimidine-4,6-diamine
297 (1 S,5R)-3-{6-[(2,2-Dimethylpropyl)amino]pyrimidin-4-yl}-3-azabicyclo[3.1.0]hexan-1 -amine
298 N4-(3,3-Dimethylbutyl)-6-[3-methyl-3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine
299 N-(3,3-Dimethy!butyl)-6-{4-[(1-methyl-1H-imidazol-2-yl)methyl]piperazin-1-yl}pyrimidiri-4-amine
(1R*,5S*,6s*)-3-{6-[(3,3-Dimethylbutyl)amino]pyrimidin-4-yl}-N,N-dimethyl-3- azabicyclo[3.1.0]hexan-6-amine
301 N-(3,3-Dimethylbutyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)pyrimidin-4-amine
302 6-[3-(Diethylamino)pyrrolidin-1-yl]-N-(2,2-dimethylpropyl)pyrimidiπ-4-amine
303 6-(4-Azetidin-3-ylpiperazin-1-yl)-N-(2,2-dimethylpropyl)pyrimidin-4-amine
304 (1S*,5R*)-3-{6-[(Cyclopropylmethyl)amino]pyrimidin-4-yl}-3-azabicyclo[3.1.0]hexan-1-amine
305 6-(4-Cyclohexylpiperazin-1-yl)-N-(cyclopropylmethyl)pyrimidin-4-amine
306 N'-(Cyclopropylmethyl)-N-[2-(diethylamino)ethyl]-N-methylpyrinriidine-4,6-diamine
307 2-(4-{6-[(3,3-Dimethylbutyl)amino]pyrimidin-4-yl}piperazin-1-yl)ethanol
308 6-(4-Azetidin-3-ylpiperazin-1-yl)-N-(cyclopropylmethyl)pyrimidin-4-amine
N4-(3,3-Dimethylbutyl)-6-[(1R,5S,6s)-6-(methylamino)-3-azabicyclo[3.1.0]hex-3-yl]pyrimidine- 2,4-diamine
310 N4-(Cyclopropylmethyl)-6-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine
311 6-[(3R)-3-Aminopyrrolidin-1 -yl]-N4-(2,5-difluorobenzyl)pyrimidiπe-2,4-diamine 312 N-(3,3-Dimethylbutyl)-6-(3-morpholin-4-ylazetidin-1-yl)pyrimidin-4-amine
313 6-[(3R)-3-Methylpiperazin-1-yl]-N-propylpyrimidin-4-amine
314 N-Cyclopropyl-6-(1 ,4-diazepan-1-yl)pyrimidin-4-amine
315 N-(2-Phenylethyl)-N'-[(3S)-pyrrolidin-3-y!]pyrimidine-4,6-diamine
316 N4-(3,5-Difluoroben2yl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine
317 N4-(2,6-Difluorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamiπe
N4-(2,2-Dimethylpropyl)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4- 318 diamine
319 N-[(3S)-Pyrrolidin-3-yl]-N'-[(2R)-tetrahydrofuran-2-ylmethyl]pyrimidine-4,6-diamiπe
320 6-(3-Amino-3-methylpyrrolidin-1-yl)-N4-methylpyrimidine-2,4-diamine
321 N4-Methyl-6-[3-(methylamino)piperidin-1-yl]pyrimidine-2,4-diamine
322 N4-(Cyclopropy!methyl)-6-(3-morphoIin-4-ylazetidin-1-yl)pyrimidine-2,4-diamine
323 6-[3-(Methylamino)piperidin-1-yl]-N4-propylpyrimidine-2,4-diamine
324 N4-Ethyl-6-[3-(methylamino)piperidin-1-yl]pyrimidine-2,4-diamine
325 N4-(2,4-Difluorobenzyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine
326 N-(2,2-Dimethylpropyl)-5-methyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine
327 6-[(3'S)-1 ,3'-Bipyrrolidin-1'-yl]-N4-(2,2-dimethylpropyl)pyrimidine-2,4-diamine
N-(3,3-Dimethylbuty))-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-4- 328 amine
329 N-(3-Methylbutyl)-N'-[(3R)-pyrrolidin-3-yl]pyrimidine-4,6-diamine
330 N4-(3,3-Dimethylbutyl)-N2,N2-dimethyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine
331 N-isoPropyl-5-methyl-6-(4-methyIpiperazin-1-yl)pyrimidin-4-amine
332 6-[(3'S)-1 ,3l-Bipyrrolidin-1'-yl]-N4-(3,3-dimethylbutyl)pyrimidine-2,4-diamine
6-[(1 R*,5S*,6s*)-6-Amino-3-azabicyclo[3.1.0]hex-3-yl]-N4-(3,3-dimethylbutyl)pyrimidine-2,4- diamine
334 . N-(Cyclopropylmethyl)-N-methyl-6-(4-methyipiperazin-1-yl)pyrimidin-4-amine
335 N-(2-Methoxyethyl)-N'-[(3R)-pyrrolidin-3-yl]pyrimidine-4,6-diamine 336 N-Methyl-1-(6-pyrrolidin-1-ylpyrimidin-4-yl)azetidin-3-amine
337 N-Ben2yl-N'-[(3R)-pyrroIidin-3-yl]pyrimidine-4,6-diamine
338 N4-[(3S)-1-Ben2ylpyrrolidin-3-yl]-Nδ-(3,3-dimethylbutyl)pyrinnidine-2,4,6-triamine
339 N4-(3,3-Dimethylbutyl)-N2-methyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine
340 6-(4-Aminopiperidin-1-yl)-N-(3,3-dimethylbutyl)pyrimidin-4-amine
341 N-[(3R)-Pyrrolidin-3-yl]-N'-[(2S)-tetrahydrofuran-2-ylmethyl]pyrimidine-4,6-diamiπe
342 6-[(3'S)-1 ,3'-Bipyrrolidin-1l-yl]-N-(3,3-dimethylbutyl)pyrimidin-4-amine
343 N-(3,3-Dimethylbutyl)-N'-(1 -methylpiperidin-4-yl)pyrimidine-4,6-diamine
344 N-(2-Methoxyethyl)-N1-[(3S)-pyrroIidin-3-yl]pyrimidine-4,6-diamine
345 N-[(3R)-Pyrrolidin-3-yl]-N'-[(2R)-tetrahydrofuran-2-ylmethyl]pyrimidine-4,6-diamine
346 N-(2-Phenylethyl)-N'-[(3R)-pyrrolidin-3-yl]pyrimidine-4,6-diamine
347 N-(Cyclopropylmethyl)-N'-[2-(methylamino)ethyl]pyrimidine-4,6-diamine
348 N-[(3R)-1-Benzylpyrrolidin-3-yl]-N'-(3,3-dimethylbutyl)pyrimidine-4,6-diamine
(5-{[(3R)-3-({6-[(3,3-Dimethylbutyl)amino]pyrimidin-4-yl}amino)pyrrolidin-1-yl]methyl}-2- «349 furyl)methanol
350 N-(2,3-Dihydro-1H-inden-2-yl)-N'-[(3R)-pyrrolidin-3-yl]pyrimidine-4,6-diamine
351 6-(3,4-Dihydroisoquinolin-2(1 H)-yl)-N-[(3R)-pyrrolidin-3-yl]pyrimidin-4-amine
352 N4-(3-Fluoroben2yl)-6-[3-(methylamino)a2etidin-1-yl]pyrimidine-2,4-diamine
N-(2,2-Dimethylpropyl)-6-[(1 R,5S)-1 ,2,4,5-tetrahydro-3H-1 ,5-epimino-3-benzazepin-3- yl]pyrimidin-4-amine
354 N4-Cyclobutyl-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine
N4-(Cyclopropylmethyl)-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4- 355 diamine
356 N4-(terf-Butyl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine
357 N4-(fert-Butyl)-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine
N4-(2,2-Dimethylpropyl)-6-[(1 R*,5S*,6s*)-6-(methylamino)-3-a2abicyclo[3.1.0]hex-3- 358 yl]pyrimidine-2,4-diamine
359 N4-Cyclopropy)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine 360 2-({2-Amino-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-yl}amino)ethanol
361 6-(1 ,4-Diazepan-1-yl)-N4-isopropylpyrimidine-2,4-diamine
362 6-[(1 R,4R)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-N4-(2,2-dimethylpropy!)pyrimidine-2,4-diamine
363 6-[(3R)-3-Aminopyrrolidin-1-yl]-N4-(2,2-dimethylpropyl)pyrimidine-2,4-diamine
364 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-6-(2-methyl-1H-imidazol-1-yl)pyrimidin-2-amine
365 6-[3-(Miethylamino)azetidin-1-yl]-N4-[(1 R)-1-methylpropyl]pyrimidine-2l4-diamine
366 6-[(3R)-3-Aminopyrrolidin-1-yl]-N4-ethylpyrimidine-2,4-diamine t
367 6-[(3R)-3-Aminopyrrolidin-1-yl]-N4-(3,3,3-trifluoropropyl)pyrimidine-2,4-diamine
368 6-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1S)-1-methylpropyl]pyrimidin-4-amine
369 6-[3-(Methylamino)azetidin-1-yl]-N-[(1 R)-1-methylpropyl]pyrimidin-4-amine
370 6-[(3R)-3-(Methylamino)pyrrolidin-1-yI]-N-propylpyrimidin-4-amine
371 6-(3-Aminoazetidin-1-yl)-N-(2,2-dimethylpropyl)pyrimidin-4-amine
372 N4-(Cyclopropylmethyl)-5-methyl-6-[(3R)-3-(methylamino)pyrro!idin-1-yl]pyrinnidine-2,4-diamine
373 N4-(Cyclopropylmethyl)-6-(2,8-diazaspiro[4.5]dec-2-yl)pyrimidine-2,4-diamine
374 6-(2,8-Diazaspiro[4.5]dec-2-yl)-N4-isobutylpyrimidiπe-2,4-diamine
375 N4-(Cyclopropylmethyl)-6-(2,7-diazaspiro[4.4]non-2-yl)pyrimidine-2,4-diamine
376 6-(2,7-Diazaspiro[4.4]non-2-yl)-N4-isobutylpyrimidine-2,4-diamine
Biology H* Binding
Cell pellets from CHO cells expressing the histamine H4 receptor were homogenised in ice-cold 5OmM Tris-HCI/0.5mM CaCI2 buffer containing a protease inhibitor cocktail (Roche®, United Kingdom) using a ground glass homogeniser. Homogenates were centrifuged at 4800Og for 30min at 4°C. The membrane pellet was resuspended in fresh buffer and the centrifugation step was repeated as described above. The membrane pellet was resuspended in 5OmM Tris-HCI in the same volume as the original cell pellet.
Aliquots of membrane preparations were stored at -8O0C and were used for [3H]-Histamine binding experiments. Method 1
Cell membranes (20-35μg/well) were incubated for 90 minutes shaking at room temperature with 3nM [2,5-3H]Histamine dihydrochloride (30-60Ci/mmol) in 5OmM Tris-HCI (pH 7.4), with or without competing H4 ligands. The reaction was terminated by rapid filtration through 0.5% polyethylenimine-soaked Unifilter GF/B plates (Packard) followed by three washes with 1ml ice-cold 5OmM Tris-HCI. Filters were dried for 45min at 45°C and bound radiolabel was determined using scintillation counting techniques. Non-specific binding was defined with 10μM JNJ7777120. For competition binding studies, Ki values were calculated from the IC50 value based on an experimentally determined ligand Kd of 5.2nl\Λ and a ligand concentration of 5nM according to the Cheng-Prussoff equation where; K, = (IC50)/(1+([L]/Kd)).
Method 2
Cell membranes (15μg/well) were pre-incubated for 120min shaking at 4°C with Ysi WGA beads (250μg/well) in 5OmM Tris-HCI (pH 7.4) followed by centrifugation at 1500rpm for 5minut.es and resuspension in 5OmM Tris-HCI (pH 7.4). The membrane/bead mixture (15μg membrane / 250μg beads well) was incubated for ΘOminutes shaking at room temperature with 6.5nM [2,5-3H] Histamine dihydrochloride (30-60Ci/mmol) in 5OmM Tris-HCI (pH 7.4), with or without competing H4 ligands. Nonspecific binding was defined with 10μM JNJ7777120. Bound radiolabel was determined using scintillation counting techniques after 90 minutes. For competition binding studies, Ki values were calculated from the IC50 value based on an experimentally determined ligand Kd of 5.2nM and a ligand concentration of 5nM according to the Cheng-Prussoff equation where; K( = (IC50)/(1+([L]/Kd)).
The compounds of the Examples have been tested in the H4 binding assay described above using either method 1 or method 2. Preferred examples have a Ki value of less than 1 μM in the H4 binding assay. Most preferred examples have a Ki value of less than 500 nM in the H4 binding assay (method 2). The specific K; values for the Example compounds that have been tested in method 1 and method 2 are given in the table below:
Figure imgf000073_0001
Figure imgf000073_0002
Figure imgf000074_0001
Figure imgf000074_0002
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000076_0001
Figure imgf000076_0002
Figure imgf000077_0002
Figure imgf000077_0001
NT: not tested

Claims

Claims :
1. A compound of Formula (I):
Figure imgf000078_0001
or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, wherein:
R1 is Ci.8alkyl, C3-7cycloalkyl-C0-6a!kyl- optionall y substituted with methyl, alkoxyalkyl containing 3 to 8 carbon atoms, het-CQ.Ba!kyl-, OFs-C^alky!-, CF3OC2-3alkyl-, aryl-Co-βalkyl- or C1-6hydroxyalkyl; R2 is het, provided that the het group contains at least one nitrogen atom or is substituted by a group which contains at least one nitrogen atom; or R2 is NH(CH2)2NH2, NH(CH2)2NHCH3, or NH(CH2)2NH(CH3)2;
R3 is H, Ci_8alkyl, (CH2)pC3-7cycloaIkyl, alkoxyalkyl containing 3 to 8 carbon atoms, (CH2)nCF3, (CH2)XOCF3 or Ci-6hydroxyalkyl; or R3 and R2 together with the nitrogen atom to which they are bound form a 4 to 8 membered .non-aromatic heterocyclic group which optionally contains one or more further heteroatoms or groups independently selected from N, O, S, S(O) and S(O)2, wherein the heterocyclic group is optionally a bridged bicyclic group, a spiro bicyclic group or is optionally fused to a 3-, A-, 5- or 6- membered carbocyclic group or a A-, 5- or 6-membered heterocyclic group which contains at least one ring member independently selected from N, O, S1 S(O) and S(O)2, and wherein the ring system as a whole is optionally substituted by one or more substituents independently selected from C1-6alkyl, NR6R7, (CH2)aC3.7cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH2)bhet1, (CH2)CCF3, (CH2)yOCF3l (CH2)daryl and Ci.6hydroxyalkyl, provided that the ring system as a whole contains at least two nitrogen atoms or contains one nitrogen atom and is substituted by a group which contains at least one nitrogen atom; R4 is H; or R1 and R4 together with the nitrogen atom to which they are bound form a 4 to 8 membered non-aromatic heterocyclic group which optionally contains one or more further heteroatoms or groups independently selected from N, O, S, S(O) and S(O)2, wherein the heterocyclic group is optionally a bridged bicyclic group or is optionally fused to a 3-, A-, 5- or 6- membered carbocyclic group or a A-, 5- or 6-membered heterocyclic group which contains at least one ring member independently selected from N, O, S, S(O) and S(O)2, and wherein the ring system as a whole is optionally substituted by one or more substituents independently selected from C^alkyl, fluoro, NR9R10, (CH2)eC3.7cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms,
Figure imgf000078_0002
(CH2)gCF3, (CH2)ZOCF3, (CH2)haryl and C1-6hydroxyalkyl; R5 is H or NR11R12; R6 and R7 are each independently selected from H, Ci_6alkyl and (CH2)jC3.7cycloalkyl; or R6 and R7, together with the nitrogen atom to which they are bound, form a 4, 5 or 6 membered heterocyclic group; R8 is H or C1-3alkyl;
R9 an d R10 are each independently selected from H, C1-6alkyl and (CH2)kC3.7cycloalkyl; or R9 and R10, together with the nitrogen atom to which they are bound, form a 4, 5 or 6 membered heterocyclic group; R11 and R12 are each independently selected from H, Ci.6alkyl and (CH2)iC3-7cycloalkyl; or R11 and R12, together with the nitrogen atom to which they are bound, form a 4, 5 or 6 membered heterocyclic group; R13 and R14 are each independently selected from H, C1-6alkyl and
Figure imgf000079_0001
or R13 and R14, together with the nitrogen atom to which they are bound, form a 4, 5 or 6 membered heterocyclic group; a, b, c, d, e, f, g, h, j, k, I1 m and p are each independently selected from 0, 1 , 2 and 3; n is 1 , 2 or 3; x is 2 or 3, wherein if x is 3, then the (CH2)3 group may be replaced with a branched alkyl group containing 3 carbon atoms; y and z are each independently selected from 1 , 2 and 3 aryl is phenyl, naphthyl, anthracyl or phenanthry), each optionally substituted by one or more groups independently selected from C^alkyl, Ci.8alkoxy, OH1 halo, CF3, CHF2, OCF3, OCHF2, SCF3, hydroxy-d. 6alkyl, Ci-4alkoxy-C1-6alkyl, C^alkyl-S-C^alkyl, aryl1, het1, Oaryl1, Ohet1, Saryl1, Shet1, CF2CF3, CH2CF3, CF2CH3, C(O)NR13R14, C3-βcycloalkyl, C^cycloalkyl-C^alkyl, C3.7cycloalkyl-Ci.4alkoxy, C3.7cycloalkyl-O- Ci-4alkyl, C3.7cycloa!kyl-Ci-4alkoxy-Ci-4alkyi, OC3.7cycloalkyl and SC^cycloalkyl, wherein the aryl1 and het1 groups are optionally substituted by at least one group selected from Chalky!, C3-7cycloalkyl, C1- 6alkoxy, OC^cycloalkyl, halo, CN, OH, CF3, CHF2, OCF3, OCHF2, hydroxyC1-6alkyl, Ci^alkoxy-C^alkyl, Sd-ealkyl and SCF3; het is 4 to 8 membered non-aromatic heterocyclic group which contains at least one heteroatom or group independently selected from N, O, S, S(O) and S(O)2, wherein the heterocyclic group is optionally a bridged bicyclic group or is optionally fused to a 3-, 4-, 5- or 6- membered carbocyclic group or a 4-, 5- or 6-membered heterocyclic group which contains at least one ring member independently selected from N, O, S1 S(O) and S(O)2, and wherein the ring system as a whole is optionally substituted by one or more substituents independently selected from Ci-6alkyl, NR6R7, (CH2)aC3-7cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH2)bhet1, (CH2)CCF3, (CH2)yOCF3, (CH2)daryl and C1-6hydroxyalkyl; aryl1 is phenyl, naphthyl, anthracyl or phenanthryl; and het1 is an aromatic or non-aromatic 4-, 5- or 6- membered heterocycle which contains at least one N, O or S heteroatom, optionally fused to a A-, 5- or 6- membered carbocyclic group or a second 4-, 5- or 6- membered heterocycle which contains at least one N, O or S heteroatom.
2. A compound according to Claim 1 , or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, wherein R8 is hydrogen.
3. A compound according to Claim 1 or Claim 2, or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, wherein R4 is hydrogen.
4. A compound according to any of claims 1 to 3, or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, wherein R1 is C3.7cycloalkyl-C0.6alkyl- optionally substituted with methyl.
5. A compound according to any of claims 1 to 3, or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, wherein R1 is C3.5cycloaIkyl-Co-i alkyl- optionally substituted with methyl.
6. A compound according to any of claims 1 to 3, or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, wherein R1 is cyclopropyl , cyclopropyl-methyl or methyl-cyclopropyl.
7. A compound according to any of claims 1 to 3, or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, wherein R1 is Ci-C6 alkyl.
8. A compound according to any of claims 1 to 3, or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, wherein R1 is ethyl, propyl, butyl, 1-methyl-propyl, 2-methyl-propyl, 2,2-dimethyl-propyl, 2-methyl-butyl, ter-butyl, 1 -methyl-butyl, 3-methyl-butyl, 3,3-dimethyl-butyl, 1 ,2-dimethyl-propyl or isopropyl.
9. A compound according to any of Claims 1 to 8, or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, wherein R2 and R3, together with the nitrogen atom to which they are bound, form a 4 to 8 membered non-aromatic heterocyclic group which optionally contains one or more further heteroatoms or groups independently selected from N, O, S, S(O) and S(O)2, wherein the heterocyclic group is optionally a bridged bicyclic group or is optionally fused to a 3-, 4-, 5- or 6- membered carbocyclic group or a A-, 5- or 6-membered heterocyclic group which contains at least one ring member independently selected from N, O, S, S(O) and S(O)2, and wherein the ring system as a whole is optionally substituted by one or more substituents independently selected from C1-6alkyl, NR6R7, (CH2)aC3-7cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH2)bhet\ (CH2)CCF3, (CH2)yOCF3, (CH2)daryl and C^hydroxyalkyl, provided that the ring system as a whole contains at least two nitrogen atoms or contains one nitrogen atom and is substituted by a group which contains at least one nitrogen atom.
10. A compound according to Claim 9, or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, wherein R2 and R3, together with the nitrogen atom to which they are bound, form a 4 to 8 membered non-aromatic heterocyclic group which optionally contains one or more further nitrogen atoms, wherein the heterocyclic group is optionally a bridged bicyclic group or is optionally fused to a 3-, A-, 5- or 6- membered carbocyclic group or a A-, 5- or 6-membered heterocyclic group which contains at least one nitrogen atom, and wherein the ring system as a whole is optionally substituted by one or more substituents independently selected from C1-6alkyl, NR6R7, (CHz)aC3.7cycloalkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH2)bhet1, (CH2)CCF3, (CH2)yOCF3, (CH2)daryl and Ci-Bhydroxyalkyl, provided that the ring system as a whole contains at least two nitrogen atoms or contains one nitrogen atom and is substituted by a group which contains at least one nitrogen atom.
11. A compound according to any of Claims 1 to 8, or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, wherein R2 is NH(CH2)2NH2, NH(CH2)2NHCH3, NH(CH2)2NH(CH3)2 and R3 is H.
12. A compound according to any of Claims 1 to 8, or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, wherein R2 and R3, together with the nitrogen atom to which they are bound, form a 4 to 8 membered heterocyclic group selected from the following ring systems:
Figure imgf000081_0001
wherein the ring system as a whole may be substituted by one or more Ci-6alkyl or (CH2)aC3.7cycloalkyl groups.
13. A compound according to Claim 12, or a pharmaceutically and/or veterinariiy acceptable salt or solvate thereof, wherein R6 and R7 are independently selected from H or CH3.
14. A compound according to any of Claims 1 to 3, or a pharmaceutically and/or veterinariiy acceptable salt or solvate thereof, wherein R3 is H and R2 is a pyrrolidinyl group, optionally substituted by one or more substituents independently selected from Ci-ealkyl, NR6R7, (CH2)aC3-7cycloaIkyl, alkoxyalkyl containing 2 to 8 carbon atoms, (CH2)bhet1, (CH2)CCF3, (CH2)yOCF3, (CH2)daryl and Ci-6hydroxyalkyl.
15. A compound according to any preceding claim, or a pharmaceutically and/or veterinariiy acceptable salt or solvate thereof, wherein R5 is H or NH2.
16. A compound according to claim 1 , or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, said compound being selected from
/^-(CyclopropylmethyO-β-KSRJ-S-CmethylaminoJpyrrolidin-i-yllpyrimidine^^-diamine, Λ/4-(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine tartrate, N4-lsobutyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,
N4-(2,2-Dimethylpropyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diaminN-lsobutyl-6-[(3R)-3- (methylamino)pyrrolidin-1-yl]pyrimidin-4-amine, N-(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine, N4-(2,2-Dimethylpropyl)-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, N4-Cyclopropyl-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, N4-Cyclobutyl-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, 6-(3-Methylamino-azetidin-1-yl)-N4-(3,3,3-trifluoro-propyl)-pyrimidine-2,4-diamine, N4-Cyclopropylmethyl-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine, N4-(3,3-Dimethyl-butyl)-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine, N4-(3-Fluoro-benzyI)-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine, N4-Cyclopentylmethyl-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine, N4-lsobutyl-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, 6-[3-(Methylamino)azetidin-1-yl]-N4-propyIpyrimidine-2,4-diamine,
N4-(2-Wlethoxybenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine, N4-Ethyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine, N4-(Cyclopropylmethyl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine, 6-[3-(Methylamino)azetidin-1-yl]-N4-(2-methylbutyl)pyrimidine-2,4-diamine,
N4-(2,5-Difluorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, N4-(2,3-Difluorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, N4-Butyl-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine, 6-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N4-(2-methylcyclopropyl)pyrimidine-2,4-diamine, N4-lsobutyl-6-(4-methyl-1 ,4-diazepan-1-yl)pyrimidine-2,4-diamine,
N4-(Cyclopropylmethyl)-6-(3-pyrrolidin-1-ylazetidin-1-yl)pyrimidine-2,4-diamine, N4-Bicyclo[1.1.1]pent-1-yl-6-[(3R)-3-(methylamino)pyrro!idin-1-yl]pyrimidine-2,4-diamine, 6-[3-Methyl-3-(methylamino)azetidin-1-yl]-N4-propylpyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-(hexahydropyrrolo[1 ,2-a]pyrazin-2(1H)-yl)pyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-(3-pyrrolidin-1-yIazetidin-1-yl)pyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-[3-(isopropylamino)azetidin-1-yl]pyrimidine-2,4-diamine, N4-(terf-Butyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine, 6-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N4-(1-methylcyclopropyl)pyrimidine-2,4-diamine, N4-(te/f-Butyl)-6-[(4aS*,7aS*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, N4-(2,2-Dimethylpropyl)-6-piperazin-1-ylpyrimidine-2,4-diamine,
N4-(2,2-Dimethylpropyl)-6-[3-(methyIamino)azetidin-1-yl]pyrimidine-2,4-diamine hydrochloride, N4-(2,2-Dimethylpropyl)-6-[(3aR*,7aS*)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-y!]pyrimidine-2,4-diamine, 6-Piperazin-1-yl-N4-propylpyrimidine-2,4-diamine,
N^^yclopropylmethyO-θ-^aR.yaRJ-octahydro-eH-pyrrolop^-bJpyridin-e-yllpyrimidine^^-diamine, N4-(2,2-Dimethylpropyl)-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, N4-(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine, N4-lsopropyl-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine, 4-[3-(Methylamino)azetidin-1-yl]-6-(4-methylpiperidin-1-yl)pyrimidin-2-amine, N4-(Cyclopentylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine, N4-Cyclobutyl-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridiπ-6-yl]pyrimidine-2,4-diamine, 6-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N4-propylpyrimidine-2,4-diamine, and, N4-Ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyrimidine-2,4-diamine.
17. A pharmaceutical composition including a compound according to any of claims 1 to 16, or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient.
18. A compound according to any of claims 1 to 16 or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, for use as a medicament.
19. The use of a compound according to any of claims 1 to 16 or a pharmaceutically and/or veterinarily acceptable salt or solvate thereof, for the manufacture of a medicament to treat a disease for which a H4 ligand is indicated.
20. The use according to claim 16, for the manufacture of a medicament to treat a disease selected from inflammatory diseases, respiratory diseases (e.g. adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis), allergy; allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion, allergic congestion, female and male sexual dysfunction, skin diseases such as dermatitis and psoriasis, cardiac dysfunctions such as myocardial ischaemia and arrythmia, diseases of the gastrointestinal tract such as inflammatory bowel disease, Crohn's disease and colitis ulcerosa, cancer, rheumatoid arthritis, hypotension, pain and overactive bladder conditions.
21. A method of treatment of a mammal, including a human being, suffering from a disease for which a H4 ligand is indicated, comprising administering to said mammal an effective amount of a compound according to any of claims 1 to 16.
22. A process for preparing a compound according to any of claims 1 to 16, comprising the steps of: (a) reacting a compound of Formula (111)
Figure imgf000084_0001
with an amine HN(R )(R ) to provide a compound of formula (II)
Figure imgf000084_0002
followed by reaction with an amine HN(R2)(R3) to provide a compound of formula (I); or (b) reacting a compound of formula (111)
Figure imgf000084_0003
with an amine HN(R )(R ) to provide a compound of formula (IV)
Figure imgf000084_0004
followed by reaction with an amine HN(R )(R ) to provide a compound of formula (I).
23. Combination of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, with other therapeutic agent(s) selected from:
• Histamine H1 receptor antagonists, in particular loratidine, desloratidine, fexofenadine and cetirizine
• Histamine H3 receptor antagonists • Histamine H2 receptor antagonists
• Leukotriene antagonists, including antagonists of LTB4, LTC4, LTD4, and LTE4; for example Montelukast
• Phosphodiesterase inhibitors, including PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDE7 inhibitors and inhibitors of two or more phosphodiesterases, such as dual PDE3/PDE4 inhibitors • neurotransmitter re-uptake inhibitors, in particular fluoxetine, setraline, paroxetine, ziprasidone
• 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists
■ • CX1- and α2-adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use
• Muscarinic M3 receptor antagonists or anticholinergic agents • β2-adrenoceptor agonists
• Dual acting β2/M3 agents
• Xanthines, such as theophylline and aminophylline
• Non-steroidal antiinflammatories, such as sodium cromoglycate and nedocromil sodium
• Ketotifen • COX-1 inhibitors (NSAIDs) and COX-2 selective inhibitors
• Oral or inhaled Glucocorticosteroids
• Monoclonal antibodies active against endogenous inflammatory entities
• Anti-tumor necrosis factor (anti-TNF-α) agents
• Adhesion molecule inhibitors including VLA-4 antagonists • Kinin-Bi - and B 2 -receptor antagonists
• Immunosuppressive agents
• Inhibitors of matrix metalloproteases (MMPs)
• Tachykinin NKt, NK2 and NK3 receptor antagonists
• Elastase inhibitors • Adenosine A2a receptor agonists
• Inhibitors of urokinase
• Compounds that act on dopamine receptors, e.g. D2 agonists
• Modulators of the NFKb pathway, e.g. IKK inhibitors
• Agents that can be classed as mucolytics or anti-tussive • Antibiotics
• Modulators of cytokine signaling pathways, such as p38 MAP kinase inhibitors, syk tyrosine kinase inhibitors or JAK kinase inhibitors
• Modulators of the prostaglandin pathways, including inhibitors of H-PDGS and antagonists of DP-1 and CRTH2 • Antagonists of chemokine receptors CXCR1 and CXCR2
• Antagonists of chemokine receptors CCR3, CCR4 and CCR5
• Inhibitors of cytosolic and soluble phospholipase A2 (cPLA2 and SPLA2)
• Prostaglandin D2 receptor antagonists (DP1 and CRTH2)
• Inhibitors of Prostaglandin D synthase (PGDS) • Inhibitors of phosphoinositide-3-kinase,
• HDAG inhibitors,
• p38 inhibitors and/or
• CXCR2 antagonists.
PCT/IB2006/003668 2005-12-20 2006-12-07 Pyrimidine derivatives WO2007072163A2 (en)

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DK06831747.8T DK1966162T3 (en) 2005-12-20 2006-12-07 pyrimidine
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AP2008004485A AP2008004485A0 (en) 2005-12-21 2006-12-11 Preparation of gamma-amino acids having affinity for the alpha-2-delta protein
IL191432A IL191432A (en) 2005-12-20 2008-05-14 Pyrimidine derivatives, pharmaceutical compositions comprising them, a process for their preparation and use thereof for the manufacture of medicaments
TNP2008000269A TNSN08269A1 (en) 2005-12-20 2008-06-18 Derives de pyrimidine
NO20082980A NO341075B1 (en) 2005-12-20 2008-07-01 Pyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing such derivatives and the use of such derivatives
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Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008060766A2 (en) * 2006-10-02 2008-05-22 Abbott Laboratories Histamine h4 receptor ligands for use in pain treatment
WO2009068512A1 (en) * 2007-11-30 2009-06-04 Palau Pharma, S. A. 2 -amino-pyrimidine derivatives as histamine h4 antagonists
WO2009077608A1 (en) * 2007-12-19 2009-06-25 Palau Pharma, S. A. 2 -aminopyrimidine derivatives as histamine h4 antagonists
WO2009114575A1 (en) * 2008-03-11 2009-09-17 Abbott Laboratories Tricyclic spiro pyrimidine derivatives as histamine h4 ligand
WO2010072829A1 (en) 2008-12-24 2010-07-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Selective histamine h4 receptor antagonists for the treatment of vestibular disorders.
US7750003B2 (en) 2006-08-24 2010-07-06 Astrazeneca Ab Compounds-943
WO2010084050A2 (en) 2009-01-13 2010-07-29 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
WO2010100215A1 (en) 2009-03-06 2010-09-10 F.I.S. Fabbrica Italiana Sintetici S.P.A. SYNTHESIS OF (4aS,7aS)-OCTAHYDRO-1H-PYRROLO[3,4-b]PYRIDINE
WO2010108059A1 (en) 2009-03-20 2010-09-23 Incyte Corporation Substituted pyrimidine derivatives as antagonists of the histamine h4 receptor
EP2315521A1 (en) * 2008-06-12 2011-05-04 Janssen Pharmaceutica NV Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine h 4 receptor
US7943628B2 (en) * 2005-12-20 2011-05-17 Pfizer Limited Pyrimidine derivatives
WO2011092293A2 (en) 2010-02-01 2011-08-04 Novartis Ag Cyclohexyl amide derivatives as crf receptor antagonists
WO2011092290A1 (en) 2010-02-01 2011-08-04 Novartis Ag Pyrazolo[5,1b]oxazole derivatives as crf-1 receptor antagonists
WO2011095450A1 (en) 2010-02-02 2011-08-11 Novartis Ag Cyclohexyl amide derivatives as crf receptor antagonists
US8138183B2 (en) 2007-07-09 2012-03-20 Astrazeneca Ab Morpholino pyrimidine derivatives used in diseases linked to mTOR kinase and/or PI3K
US8252802B2 (en) 2010-06-11 2012-08-28 Astrazeneca Ab Chemical compounds
JP2012526782A (en) * 2009-05-12 2012-11-01 サノフイ 5-membered heterocyclic compounds cyclopenta [c] pyrrolylalkylcarbamate derivatives, their preparation and their therapeutic use
US8501735B2 (en) 2009-10-29 2013-08-06 Palau Pharma, S.A. N-containing heteroaryl derivatives as JAK3 kinase inhibitors
WO2013152717A1 (en) 2012-04-10 2013-10-17 上海昀怡健康管理咨询有限公司 Fused pyrimidine compound, and preparation method, intermediate, composition， and uses thereof
WO2013175116A1 (en) * 2012-05-24 2013-11-28 Terrasse Gaetan Use of an h4 agonist molecule for treating cystic fibrosis
WO2013182711A1 (en) 2012-06-08 2013-12-12 Sensorion H4 receptor inhibitors for treating tinnitus
US8637528B2 (en) 2007-03-27 2014-01-28 Omeros Corporation Use of PDE7 inhibitors for the treatment of movement disorders
US8901146B2 (en) 2009-12-23 2014-12-02 Medicis Pharmaceutical Corporation Aminoalkylpyrimidine derivatives as histamine H4 receptor antagonists
WO2015043398A1 (en) 2013-09-30 2015-04-02 上海璎黎药业有限公司 Fused pyrimidine compound, intermediate, preparation method therefor, and composition and application thereof
WO2015055071A1 (en) 2013-10-16 2015-04-23 上海璎黎药业有限公司 Fused heterocyclic compound, preparation method therefor, pharmaceutical composition, and uses thereof
WO2016128140A1 (en) * 2015-02-13 2016-08-18 Merck Patent Gmbh Pyrimidine derivatives for use in the treatment of cancer
WO2017072131A1 (en) * 2015-10-26 2017-05-04 Ziarco Pharma Limited Pyrimidine compositions, ultra-pure compositions and salts thereof, methods of making the same, and methods of using the same for treating histamine h4 receptor (h4) mediated diseases and conditions
US10125144B2 (en) 2013-10-07 2018-11-13 Kadmon Corporation, Llc Rho kinase inhibitors
CN109906222A (en) * 2016-09-07 2019-06-18 加利福尼亚大学董事会 It reduces P-TAU and improves allosteric corticotropinreleasing factor receptor 1 (CRFR1) antagonist of cognition
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US10463675B2 (en) 2014-08-21 2019-11-05 Pfizer Inc. Aminopyrimidinyl compounds
WO2020079457A1 (en) * 2018-10-19 2020-04-23 Heptares Therapeutics Limited Pyrazole derivatives as h4 antagonist compounds
US10683293B2 (en) 2014-08-04 2020-06-16 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
WO2021214469A1 (en) * 2020-04-22 2021-10-28 Heptares Therapeutics Limited H4 antagonist compounds
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11447479B2 (en) 2019-12-20 2022-09-20 Nuevolution A/S Compounds active towards nuclear receptors
US11613532B2 (en) 2020-03-31 2023-03-28 Nuevolution A/S Compounds active towards nuclear receptors
US11780843B2 (en) 2020-03-31 2023-10-10 Nuevolution A/S Compounds active towards nuclear receptors

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0615880A2 (en) * 2005-09-13 2011-05-31 Palau Pharma Sa 2-aminopyrimidine-derived compounds as modulators of histamine h4 receptor activity, their use and pharmaceutical composition
US20090069343A1 (en) * 2006-04-10 2009-03-12 Dunford Paul J Combination Histamine H1R and H4R Antagonist Therapy for Treating Pruritus
TW200904437A (en) 2007-02-14 2009-02-01 Janssen Pharmaceutica Nv 2-aminopyrimidine modulators of the histamine H4 receptor
US20080217501A1 (en) * 2007-02-14 2008-09-11 Chad Jensen Power a-frame
US8138339B2 (en) 2008-04-16 2012-03-20 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
PT2323993E (en) 2008-04-16 2015-10-12 Portola Pharm Inc 2,6-diamino- pyrimidin- 5-yl-carboxamides as syk or jak kinases inhibitors
US8436008B2 (en) 2008-12-22 2013-05-07 Incyte Corporation Substituted heterocyclic compounds
JP5607241B2 (en) 2010-05-21 2014-10-15 ケミリア・エービー New pyrimidine derivatives
WO2012127032A1 (en) 2011-03-24 2012-09-27 Chemilia Ab Novel pyrimidine derivatives
AU2012340555B2 (en) 2011-11-23 2016-10-20 Portola Pharmaceuticals, Inc. Pyrazine kinase inhibitors
US10213421B2 (en) 2012-04-04 2019-02-26 Alkahest, Inc. Pharmaceutical formulations comprising CCR3 antagonists
WO2013172872A1 (en) * 2012-05-15 2013-11-21 Calasia Pharmaceuticals, Inc. Pyrimidine diamine derivatives as inhibitors of cytosolic hsp90
US9974759B2 (en) 2013-05-31 2018-05-22 Indiana University Research And Technology Corporation Beta 2 adrenoceptor antagonists for treating orthostatic hypotension
WO2015090224A1 (en) * 2013-12-20 2015-06-25 中国人民解放军军事医学科学院毒物药物研究所 Novel piperidine carboxamide compound, preparation method, and usage thereof
KR102566924B1 (en) * 2016-07-29 2023-08-11 랩트 테라퓨틱스, 인크. Chemokine receptor modulators and uses thereof
EP4153177A1 (en) * 2020-05-19 2023-03-29 Florida State University Research Foundation, Inc. Antifibrotic compounds and related methods
AU2021325431B2 (en) 2020-08-14 2024-01-18 Novartis Ag Heteroaryl substituted spiropiperidinyl derivatives and pharmaceutical uses thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991011172A1 (en) 1990-01-23 1991-08-08 The University Of Kansas Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
WO1994002518A1 (en) 1992-07-27 1994-02-03 The University Of Kansas Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
WO1998055148A1 (en) 1997-06-05 1998-12-10 Janssen Pharmaceutica N.V. Pharmaceutical compositions comprising cyclodextrins
WO2000035298A1 (en) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing gum containing medicament active agents
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2002072548A2 (en) 2001-03-09 2002-09-19 Ortho-Mcneil Pharmaceutical, Inc. Heterocyclic compounds and their use as histamine h4 ligands.
WO2004022537A2 (en) 2002-09-06 2004-03-18 Janssen Pharmaceutica, N.V. Thienopyrrolyl and furanopyrrolyl compounds and their use as histamine h4 receptor ligands

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60140435A (en) * 1983-12-28 1985-07-25 Hitachi Ltd Instruction processing unit
US5099019A (en) * 1985-09-12 1992-03-24 Upjohn Company Amines useful in producing pharmaceutically active CNS compounds
CA1338012C (en) * 1987-04-27 1996-01-30 John Michael Mccall Pharmaceutically active amines
JPH05501248A (en) * 1989-10-25 1993-03-11 ジ・アップジョン・カンパニー Pharmaceutically active amino-substituted heteroarylamines
HUT64323A (en) * 1992-06-09 1993-12-28 Richter Gedeon Vegyeszet Process for production new piperazinyl-bis(alkyl-amino)-pyrimidine derivatives
HU212308B (en) * 1992-06-09 1996-05-28 Richter Gedeon Vegyeszet Process for producing novel pregnane steroids and pharmaceutical compositions containing the same
JP2003519143A (en) 1999-12-28 2003-06-17 ファーマコピーア，インコーポレーティッド Pyrimidine and triazine kinase inhibitors
JP4469179B2 (en) * 2002-01-23 2010-05-26 バイエル ファーマセチカル コーポレーション Pyrimidine derivatives as Rho kinase inhibitors
DE10226943A1 (en) * 2002-06-17 2004-01-08 Bayer Ag Phenylaminopyrimidines and their use
ES2273047T3 (en) * 2002-10-28 2007-05-01 Bayer Healthcare Ag PHENYLAMINOPIRIMIDINES REPLACED WITH HETEROARILOXI AS INHIBITORS OF RHO-CINASA.
US7759336B2 (en) * 2002-12-10 2010-07-20 Ono Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic compounds and medicinal use thereof
US20050014753A1 (en) * 2003-04-04 2005-01-20 Irm Llc Novel compounds and compositions as protein kinase inhibitors
EP1505064A1 (en) * 2003-08-05 2005-02-09 Bayer HealthCare AG 2-Aminopyrimidine derivatives
US7223759B2 (en) * 2003-09-15 2007-05-29 Anadys Pharmaceuticals, Inc. Antibacterial 3,5-diaminopiperidine-substituted aromatic and heteroaromatic compounds
WO2005054239A1 (en) * 2003-12-05 2005-06-16 Bayer Healthcare Ag 2-aminopyrimidine derivatives
BRPI0615880A2 (en) * 2005-09-13 2011-05-31 Palau Pharma Sa 2-aminopyrimidine-derived compounds as modulators of histamine h4 receptor activity, their use and pharmaceutical composition
EP1767537A1 (en) 2005-09-21 2007-03-28 Cellzome (UK) Ltd. Pyrimidine compounds for the treatment of inflammatory disorders
NL2000323C2 (en) * 2005-12-20 2007-11-20 Pfizer Ltd Pyrimidine derivatives.

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991011172A1 (en) 1990-01-23 1991-08-08 The University Of Kansas Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
WO1994002518A1 (en) 1992-07-27 1994-02-03 The University Of Kansas Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2000035298A1 (en) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing gum containing medicament active agents
WO1998055148A1 (en) 1997-06-05 1998-12-10 Janssen Pharmaceutica N.V. Pharmaceutical compositions comprising cyclodextrins
WO2002072548A2 (en) 2001-03-09 2002-09-19 Ortho-Mcneil Pharmaceutical, Inc. Heterocyclic compounds and their use as histamine h4 ligands.
WO2004022537A2 (en) 2002-09-06 2004-03-18 Janssen Pharmaceutica, N.V. Thienopyrrolyl and furanopyrrolyl compounds and their use as histamine h4 receptor ligands

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, PERGAMON PRESS
"Remington's Pharmaceutical Sciences", 1995, MACK PUBLISHING COMPANY
E. L. ELIEL; S. H. WILEN: "Stereochemistry of Organic Compounds", 1994, WILEY
EXPERT OPIN. THER. PATENTS, vol. 13, no. 6, 2003
FINNIN; MORGAN, J PHARM SCI, vol. 88, no. 10, October 1999 (1999-10-01), pages 955 - 958
H. BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER
H. LIEBERMAN; L. LACHMAN: "Pharmaceutical Dosage Forms: Tablets", vol. 1, 1980, MARCEL DEKKER
HALEBLIAN, J PHARM SCI, vol. 64, no. 8, August 1975 (1975-08-01), pages 1269 - 1288
LIANG; CHEN, EXPERT OPINION IN THERAPEUTIC PATENTS, vol. 11, no. 6, 2001, pages 981 - 986
STAHL; WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
T. HIGUCHI; W. STELLA: "Pro- drugs as Novel Delivery Systems", ACS SYMPOSIUM SERIES, vol. 14
TERZIOGLU ET AL., J. BIOORG. MED. CHEM. LETT., vol. 14, 2004, pages 5251 - 5256
THEODORA W GREEN; PETER G M WUTS: "Protective Groups in Organic Synthesis", vol. 7, 1999, JOHN WILEY AND SONS, pages: 494 - 653
VERMA ET AL., PHARMACEUTICAL TECHNOLOGY ON-LINE, vol. 25, no. 2, 2001, pages 1 - 14

Cited By (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7943628B2 (en) * 2005-12-20 2011-05-17 Pfizer Limited Pyrimidine derivatives
US7750003B2 (en) 2006-08-24 2010-07-06 Astrazeneca Ab Compounds-943
WO2008060766A3 (en) * 2006-10-02 2009-02-19 Abbott Lab Histamine h4 receptor ligands for use in pain treatment
WO2008060766A2 (en) * 2006-10-02 2008-05-22 Abbott Laboratories Histamine h4 receptor ligands for use in pain treatment
US7985745B2 (en) 2006-10-02 2011-07-26 Abbott Laboratories Method for pain treatment
US9119822B2 (en) 2007-03-27 2015-09-01 Omeros Corporation Use of PDE7 inhibitors for the treatment of movement disorders
US8637528B2 (en) 2007-03-27 2014-01-28 Omeros Corporation Use of PDE7 inhibitors for the treatment of movement disorders
US8138183B2 (en) 2007-07-09 2012-03-20 Astrazeneca Ab Morpholino pyrimidine derivatives used in diseases linked to mTOR kinase and/or PI3K
WO2009068512A1 (en) * 2007-11-30 2009-06-04 Palau Pharma, S. A. 2 -amino-pyrimidine derivatives as histamine h4 antagonists
WO2009077608A1 (en) * 2007-12-19 2009-06-25 Palau Pharma, S. A. 2 -aminopyrimidine derivatives as histamine h4 antagonists
WO2009114575A1 (en) * 2008-03-11 2009-09-17 Abbott Laboratories Tricyclic spiro pyrimidine derivatives as histamine h4 ligand
US8278313B2 (en) 2008-03-11 2012-10-02 Abbott Laboratories Macrocyclic spiro pyrimidine derivatives
CN102118969A (en) * 2008-06-12 2011-07-06 詹森药业有限公司 Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine h4 receptor
EP2315521A1 (en) * 2008-06-12 2011-05-04 Janssen Pharmaceutica NV Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine h 4 receptor
US8841287B2 (en) 2008-06-12 2014-09-23 Janssen Pharmaceutica N.V. Diamino-pyridine, pyrimidine, and pyrazine modulators of the histamine H4 receptor
US9732087B2 (en) 2008-06-12 2017-08-15 Janssen Pharmaceutica N.V. Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine H4 receptor
JP2011524363A (en) * 2008-06-12 2011-09-01 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Diaminopyridine, pyrimidine, and pyridazine modulators of histamine H4 receptor
EP2315521A4 (en) * 2008-06-12 2012-04-25 Janssen Pharmaceutica Nv Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine h 4 receptor
WO2010072829A1 (en) 2008-12-24 2010-07-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Selective histamine h4 receptor antagonists for the treatment of vestibular disorders.
US9526725B2 (en) 2008-12-24 2016-12-27 Inserm (Institut National De La Sante Et De La Recherche Medicale) Selective histamine H4 receptor antagonists for the treatment of vestibular disorders
US10195195B2 (en) 2008-12-24 2019-02-05 Inserm (Institut National De La Sante Et De La Recherche Medicale) Selective histamine H4 receptor antagonists for the treatment of vestibular disorders
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WO2010100215A1 (en) 2009-03-06 2010-09-10 F.I.S. Fabbrica Italiana Sintetici S.P.A. SYNTHESIS OF (4aS,7aS)-OCTAHYDRO-1H-PYRROLO[3,4-b]PYRIDINE
US8481732B2 (en) 2009-03-20 2013-07-09 Incyte Corporation Substituted heterocyclic compounds
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US8999997B2 (en) 2010-06-11 2015-04-07 Astrazeneca Ab Chemical compounds
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US8552004B2 (en) 2010-06-11 2013-10-08 Astrazeneca Ab Chemical compounds
US9499561B2 (en) 2012-04-10 2016-11-22 Shanghai Yingli Pharmaceutical Co., Ltd. Fused pyrimidine compound, and preparation method, intermediate, composition, and uses thereof
WO2013152717A1 (en) 2012-04-10 2013-10-17 上海昀怡健康管理咨询有限公司 Fused pyrimidine compound, and preparation method, intermediate, composition， and uses thereof
FR2990859A1 (en) * 2012-05-24 2013-11-29 Gaetan Terrasse USE OF AN AGONIST H4 MOLECULE FOR THE TREATMENT OF MUCOVISCIDOSIS
WO2013175116A1 (en) * 2012-05-24 2013-11-28 Terrasse Gaetan Use of an h4 agonist molecule for treating cystic fibrosis
US9688989B2 (en) 2012-06-08 2017-06-27 Sensorion H4 receptor inhibitors for treating tinnitus
EP3378476A1 (en) 2012-06-08 2018-09-26 Sensorion H4 receptor inhibitors for treating tinnitus
WO2013182711A1 (en) 2012-06-08 2013-12-12 Sensorion H4 receptor inhibitors for treating tinnitus
US9745321B2 (en) 2013-09-30 2017-08-29 Shanghai Yingli Pharmaceutical Co., Ltd Fused pyrimidine compound, intermediate, preparation method therefor, and composition and application thereof
WO2015043398A1 (en) 2013-09-30 2015-04-02 上海璎黎药业有限公司 Fused pyrimidine compound, intermediate, preparation method therefor, and composition and application thereof
US10125144B2 (en) 2013-10-07 2018-11-13 Kadmon Corporation, Llc Rho kinase inhibitors
US9656996B2 (en) 2013-10-16 2017-05-23 Shanghai Yingli Pharmaceutical Co., Ltd. Fused heterocyclic compound, preparation method therefor, pharmaceutical composition, and uses thereof
WO2015055071A1 (en) 2013-10-16 2015-04-23 上海璎黎药业有限公司 Fused heterocyclic compound, preparation method therefor, pharmaceutical composition, and uses thereof
US10689383B2 (en) 2014-08-04 2020-06-23 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US10683293B2 (en) 2014-08-04 2020-06-16 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US11254681B2 (en) 2014-08-04 2022-02-22 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US10980815B2 (en) 2014-08-21 2021-04-20 Pfizer Inc. Aminopyrimidinyl compounds
US11197867B2 (en) 2014-08-21 2021-12-14 Pfizer Inc. Aminopyrimidinyl compounds
US10463675B2 (en) 2014-08-21 2019-11-05 Pfizer Inc. Aminopyrimidinyl compounds
WO2016128140A1 (en) * 2015-02-13 2016-08-18 Merck Patent Gmbh Pyrimidine derivatives for use in the treatment of cancer
AU2016344627B9 (en) * 2015-10-26 2019-11-28 Novartis Ag Pyrimidine compositions, ultra-pure compositions and salts thereof, methods of making the same, and methods of using the same for treating histamine H4 receptor (H4) mediated diseases and conditions
AU2016344627B2 (en) * 2015-10-26 2019-11-07 Novartis Ag Pyrimidine compositions, ultra-pure compositions and salts thereof, methods of making the same, and methods of using the same for treating histamine H4 receptor (H4) mediated diseases and conditions
US20170158671A1 (en) * 2015-10-26 2017-06-08 Ziarco Pharma Ltd. Pyrimidine compositions, ultra pure compositions and salts thereof, methods of making the same, and methods of using the same for treating histamine h4 receptor (h4) mediated diseases and conditions
WO2017072131A1 (en) * 2015-10-26 2017-05-04 Ziarco Pharma Limited Pyrimidine compositions, ultra-pure compositions and salts thereof, methods of making the same, and methods of using the same for treating histamine h4 receptor (h4) mediated diseases and conditions
US11077108B2 (en) 2016-09-07 2021-08-03 The Regents Of The University Of California Allosteric corticotropin-releasing factor receptor 1 (CRFR1) antagonists that decrease p-tau and improve cognition
EP3510029A4 (en) * 2016-09-07 2020-03-11 The Regents of The University of California Allosteric corticotropin-releasing factor receptor 1 (crfr1) antagonists that decrease p-tau and improve cognition
AU2017324942B2 (en) * 2016-09-07 2022-01-27 The Regents Of The University Of California Allosteric corticotropin-releasing factor receptor 1 (CRFR1) antagonists that decrease p-Tau and improve cognition
CN109906222A (en) * 2016-09-07 2019-06-18 加利福尼亚大学董事会 It reduces P-TAU and improves allosteric corticotropinreleasing factor receptor 1 (CRFR1) antagonist of cognition
US10537560B2 (en) 2017-10-05 2020-01-21 Fulcrum Therapeutics. Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11479770B2 (en) 2017-10-05 2022-10-25 Fulcrum Therapeutics, Inc. Use of p38 inhibitors to reduce expression of DUX4
WO2020079457A1 (en) * 2018-10-19 2020-04-23 Heptares Therapeutics Limited Pyrazole derivatives as h4 antagonist compounds
US11447479B2 (en) 2019-12-20 2022-09-20 Nuevolution A/S Compounds active towards nuclear receptors
US11613532B2 (en) 2020-03-31 2023-03-28 Nuevolution A/S Compounds active towards nuclear receptors
US11780843B2 (en) 2020-03-31 2023-10-10 Nuevolution A/S Compounds active towards nuclear receptors
WO2021214469A1 (en) * 2020-04-22 2021-10-28 Heptares Therapeutics Limited H4 antagonist compounds

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