WO2010067102A1 - Diazaspiro [5.5] undecane derivatives and related compounds as muscarinic-receptor antagonists and beta-adrenoreceptor agonists for the treatment of pulmonary disorders - Google Patents

Diazaspiro [5.5] undecane derivatives and related compounds as muscarinic-receptor antagonists and beta-adrenoreceptor agonists for the treatment of pulmonary disorders Download PDF

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WO2010067102A1
WO2010067102A1 PCT/GB2009/051657 GB2009051657W WO2010067102A1 WO 2010067102 A1 WO2010067102 A1 WO 2010067102A1 GB 2009051657 W GB2009051657 W GB 2009051657W WO 2010067102 A1 WO2010067102 A1 WO 2010067102A1
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optionally substituted
alkyl
ring
cycloalkyl
diazaspiro
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PCT/GB2009/051657
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French (fr)
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Lilian Alcaraz
Nicholas Kindon
Michael John Stocks
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Astrazeneca Ab
Argenta Discovery Limited
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Priority claimed from GB0822437A external-priority patent/GB0822437D0/en
Priority claimed from GB0913344A external-priority patent/GB0913344D0/en
Application filed by Astrazeneca Ab, Argenta Discovery Limited filed Critical Astrazeneca Ab
Publication of WO2010067102A1 publication Critical patent/WO2010067102A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators

Definitions

  • the present invention relates to spirocyclicmorpholine-substituted amides, a process for their preparation, pharmaceutical compositions containing them, a process for preparing pharmaceutical compositions, their use in therapy and intermediates of use in their preparation.
  • Muscarinic receptors are a G-protein coupled receptor (GPCR) family having five family members M 1 , M 2 , M 3 , M 4 and M5. Of the five muscarinic subtypes, three (M 1 , M 2 and M 3 ) are known to exert physiological effects on human lung tissue.
  • GPCR G-protein coupled receptor
  • Parasympathetic nerves are the main pathway for reflex bronchoconstriction in human airways and mediate airway tone by releasing acetylcholine onto muscarinic receptors.
  • Airway tone is increased in patients with respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD), and for this reason muscarinic receptor antagonists have been developed for use in treating airway diseases.
  • Muscarinic receptor antagonists often called anticholinergics in clinical practice, have gained widespread acceptance as a first-line therapy for individuals with COPD, and their use has been extensivley reviewed in the literature (e.g. Lee et al, Current Opinion in Pharmacology 2001,1, 223-229).
  • muscarinic receptor antagonists When used to treat respiratory disorders, muscarinic receptor antagonists are typically administered by inhalation. However, when administered by inhalation a significant proportion of the muscarinic receptor antagonist is often absorbed into the systemic circulation resulting in reported side effects such as dry mouth. Additionally, the majority of muscarinic antagonists have a relatively short duration of action requiring that they be administered several times a day. Such a multiple-daily dosing regime is not only inconvenient to the patient but also creates a significant risk of inadequate treatment due to patient non-compliance associated with the frequent repeat dosing schedule.
  • R 1 is selected from the following;
  • an optionally substituted 4-8 membered ring said ring being aromatic or fully or partially saturated and wherein up to four of the ring atoms may be replaced by heteroatoms independently selected from N, O and S.
  • examples of such rings include phenyl, thiazolyl, thienyl, isoxazolyl, furyl, cyclohex-3-enyl, cyclohexyl, cycloheptyl and the like.
  • Such rings include benzo[b]thienyl, benzofuranyl, benzo[d]imidazolyl, quinoxalinyl, pyrazolo [ 1 ,5 -ajpyrimidinyl, pyrazolo [ 1 ,5 -ajpyridinyl, dihydrobenzo [b] [ 1 ,4]dioxinyl, 4,5,6, 7-tetrahydro-2H-indazolyl, benzo[d][l,3]dioxolyl and the like.
  • Ci_ 6 alkyl group wherein one or two of the carbon atoms can be replaced by O, S or N and wherein said alkyl group may be substituted once or twice by a ring system independently selected from (i) and (ii) above, and wherein the Ci_6 alkyl chain may be substituted by up to five substituents selected from halogen, cyano, S(O) 0-2 R 10 , NR 8 R 9 , S(O) 2 NR 8 R 9 , C(O)NR 8 R 9 , C(O)OR 10 , NR 10 S(O) 2 R 11 , NR 10 C(O)R 10 , NR 10 C(O)OR 11 , NR 10 C(O)NR 8 R 9 , OR 10 , C 1-6 alkyl and C 3-6 cycloalkyl (wherein two C 1-3 alkyl chains may be joined to form a cycloalkyl ring of up to eight ring atoms), where
  • optionally substituted means optionally substituted by up to four substituents independently selected from halogen, cyano, nitro, SH, S(O) 0-2 R 10 , NR 8 R 9 , S(O) 2 NR 8 R 9 , C(O)NR 8 R 9 , C(O)OR 10 , NR 10 S(O) 2 R 11 , NR 10 C(O)R 10 , NR 10 C(O)OR 11 , NR 10 C(O)NR 8 R 9 , OR 10 , C 1-6 alkyl or C 3 .
  • alkyl or cycloalkyl may be optionally replaced by N, O or S
  • alkyl or cycloalkyl may be optionally substituted by up to five substituents selected from C 1-6 alkyl, halogen, cyano, SH, S(O) 0 - 2 R 10 , NR 8 R 9 , S(O) 2 NR 8 R 9 , C(O)NR 8 R 9 , C(O)OR 10 , NR 10 S(O) 2 R 11 , NR 10 C(O)R 10 , NR 10 C(O)OR 11 , NR 10 C(O)NR 8 R 9 , OR 10 ), phenyl or a 4-8 membered heterocyclic ring (containing up to 4 heteroatoms selected from N, O or S) and wherein the phenyl or 4-8 membered heterocyclic rings may be optionally substituted by up to 3 substituents independently selected from halogen, cyan
  • W represents CR 12 R 13 -CR 12 R 13 or CR 12 R 13 -CR 12 R 13 -CR 12 R 13 ;
  • V and Z independently represent a bond, CR 12 R 13 or CR 12 R 13 -CR 12 R 13 , provided that when X represents either O or S(O) 0-2 then m, V and Z are such that all the heteroatoms in the rings are separated by at least two carbon atoms;
  • Y represents C(O), C(O)NR 10 , SO 2 or SO 2 NR 10 ;
  • R 2 is a lone pair, or Ci_ 6 alkyl, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or R 3 is a group of formula (II)
  • L 1 and L 2 independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, wherein the Ci_6 alkyl and C 3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy; or
  • L 1 and/or L 2 may be linked to carbon atoms in the group L, or L 1 and L 2 may be linked to each other, to form aliphatic rings of up to 6 ring atoms, wherein each ring may comprise up to three heteroatoms independently selected from N, O and S; and wherein L represents a straight or branched hydrocarbyl chain of up to 15 carbon atoms; wherein up to three of the carbon atoms in the chain are optionally substituted once or twice by groups independently selected from halogen, cyano, S(0)o-2R 10 , NR 14 R 15 , S(O) 2 NR 8 R 9 , C(O)NR 8 R 9 , C(O)OR 10 , NR 10 S(O) 2 R 11 , NR 10 C(O)R 10 , NR 10 C(O)OR 11 , NR 10 C(O)NR 8 R 9 , OR 10 , C 1-6 alkyl and C 3 .
  • alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy; wherein up to three carbon atoms of the chain may be replaced by groups independently selected from O, NR 10 , S, S(O), S(O) 2 , C(O)O, OC(O), puzzle NR 10 C(O)NR 10 , NR 10 S(O) 2 NR 10 , OC(O)NR 10 , NR 10 C(O)O, provided that any such groups in the chain are separated by at least two chain carbon atoms; and wherein up to six carbon atoms of the chain may form part of an aryl, heteroaryl, fused bicyclic, alicyclic, or heteroaliphatic ring having up to four heteroatoms independently selected from N, O or S, said ring comprising up to 10 ring atoms, and wherein the ring is optionally substituted by up to three
  • R 8 and R 9 are independently hydrogen, Ci_6 alkyl or C 3 _6 cycloalkyl, or R 8 and R 9 may be joined together to form a heterocyclic ring comprising up to 9 ring atoms (optionally containing a further heteroatom selected from O, N or S) wherein the ring may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl, Ci_6 alkyl or C 3-6 cycloalkyl, and wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy;
  • R 10 represents hydrogen, Ci_6 alkyl or C 3-6 cycloalkyl, wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy;
  • R 11 represents Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, wherein the Ci_ 6 alkyl and C 3 _ 6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl or Ci_6 alkoxy;
  • R 12 and R 13 each independently represent hydrogen, fluorine, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl; or R 12 and R 13 when attached to the same carbon atom, together with the carbon atom to which they are both attached, may additionally form a 3 to 6 membered aliphatic ring;
  • R 14 represents hydrogen, Ci_6 alkyl or C 3 _6 cycloalkyl, and
  • R 15 represents (i) hydrogen or
  • R 1 may also conveniently represent an optionally substituted Ci_ 6 alkyl group wherein one or two of the carbon atoms can be replaced by O, S or N and wherein said alkyl group may be substituted by the ring systems described in (i) and (ii), and a convenient Ci_6 alkyl group is methylene or ethylene or propylene; wherein each ring in (i), (ii) and (iii) is optionally substituted by up to three substituents independently selected from halogen, cyano, OR 10 , Ci_6 alkyl, C3_8 cycloalkyl, or an optionally substituted phenyl ring.
  • R 1 is selected from thiophene or thiazole or benzofuran or pyrazolo[l,5-a]pyridine each optionally substituted by one or two substituents.
  • One of the optional substituents is conveniently selected from H, Cl, F and Ci_ 3 alkyl.
  • the other optional substituent is selected from methyl, ethyl, propyl, n-butyl, CF 3 , CH 2 CF 3 , CH(CH 3 ) 2 , CH(CH 2 CH 3 ) 2 , CH(CH 3 )CH 2 ,CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , cyclopropyl, cyclobutyl and cyclopentyl;
  • R 1 is selected from
  • R wherein the arrow marks the attachment point to the group Y and R is selected from methyl, ethyl, propyl, n-butyl, CF 3 , CH 2 CF 3 , CH(CH 3 ) 2 , CH(CH 2 CH 3 ) 2 , CH(CH 3 )CH 25 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , cyclopropyl, cyclobutyl and cyclopentyl;
  • the Group R 2 Conveniently R 2 represents a lone pair;
  • Y represents C(O), C(O)NR 10 , SO 2 or SO 2 NR 10 ; Conveniently Y represents C(O); Conveniently
  • W represents CR 12 R 13 CR 12 R 13 or CR 12 R 13 CR 12 R 13 CR 12 R 13 ;
  • V and Z independently represent a bond or CR 12 R 13
  • V and Z are such that all the heteroatoms in the rings are separated by at least two carbon atoms (e.g. When V is a bond then Z is CR 12 R 13 ).
  • the spirocycle is selected from (i), (ii) or (iii) above. Conveniently the spirocycle is (i)
  • group (II) is represented by a group selected from (i).
  • L 3 represents a bond or a Ci_io-alkylene, Ci_io-alkenylene group, or C 1-10 - alkynylene group, optionally containing an oxygen or sulfur atom in the chain, (conveniently the group has a chain of up to 8, up to 6 or up to 4 atoms) and;
  • D is an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring (such as an optionally substituted aryl or heteroaryl ring) , and;
  • L 4 represents a bond or a Ci_ 6 -alkylene group optionally containing an oxygen or sulfur atom in the chain (such as a chain of up to 4 atoms) , and R 14 and R 15 are as defined above; or
  • L 3 , L 4 and D are as defined in (i) above and G 1 is the group OR 10 or C(O)OR 10 ; or; (iii) A group of Formula (HIc)
  • L 3 and D are as defined in (i) above.
  • Convenient compounds are for example of formula (CH 2 ) m -(O) p -(CH 2 ) n -Ar (wherein Ar is as defined above and optionally substituted by halogen or Ci_ 6 alkyl, m is 1-3, p is 0 or 1, and n is 0-2 ), such as phenoxypropyl, 4-halobenzyloxyethyl (eg. 4-chlorobenzyloxyethyl) or 4-halophenethyl (eg. 4-fluorophenethyl); or; (iv) A group of formula (HId)
  • L 3 and D are as defined in (i) above, and; L 5 is a bond, Ci_6 alkylene group, or an oxygen or sulfur atom, and; Ring D' is is an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring; or: (v) A group of formula (HIe) wherein L 6 and L 7 are independently each a Ci_io-alkylene, Ci_io-alkenylene, or Ci_ l o-alkynylene group(conveniently the group has a chain of up to 8, up to 6 or up to 4 atoms) , and;
  • G 2 is a bond, or an oxygen or sulfur atom, and
  • group of Formula (Ilia) is a group of Formula (Illaa);
  • R 14 represents hydrogen or Ci_6 alkyl
  • R 15 represents independently
  • the compounds of formula (I) When the compounds of formula (I) is a quarternary ammonium salt, it comprises an anion "A" associated with the positive charge on the quaternary nitrogen atom.
  • the anion "A” may be any pharmaceutically acceptable anion of a mono or polyvalent (e.g. bivalent) acid.
  • "A” may be an anion of a mineral acid, for example chloride, bromide, iodide, sulfate, nitrate or phosphate; or an anion of a suitable organic acid, for example acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, methanesulphonate, p-toluenesulphonate, benzenesulphonate, napadisylate (naphthalene- 1, 5 -disulphonate) (e.g.
  • heminapadisylate 2,5-dichlorobenzenesulphonate, xinafoate (l-hydroxy-2-naphthoate) or l-hydroxynaphthalene-2-sulphonate.
  • the present invention encompasses the replacement of any quaternary carbon, more specifically the quaternary carbon present in the spirocyclic system, by a silicon atom for example as disclosed in "Silicon switches of Marketed Drugs: Mini-reviews in Med. Chem.”, 2006, 6, 1169-1177. Definitions
  • heteroaryl means an aromatic ring system of 5 to 7 atoms, conveniently from 5-6 atoms, having up to three heteroatoms selected from N, O and S.
  • heteroaryl rings include thiazolyl, thienyl, isoxazolyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, triazolyl and the like.
  • the heteroaryl group may be attached by any available carbon or nitrogen atom.
  • 'fused bicyclic ring' means a ring system of up to 12 atoms wherein 2 rings are fused together.
  • the system may optionally contain up to 4 heteroatoms selected from N, S and O.
  • the rings may independently be aromatic, partially saturated or fully saturated.
  • fused bicyclic ring systems include benzo[b]thienyl, benzofuranyl, benzo[d]imidazolyl, quinoxalinyl, pyrazolo[l,5-a]pyrimidinyl, pyrazolo[l,5- ajpyridinyl, dihydrobenzo[b][l,4]dioxinyl, 4,5,6,7-tetrahydro-2H-indazolyl, benzo[d][l,3]dioxolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthyl, 1,2,3,4-tetraydroquinolinyl, 5,6,7,8- tetrahydroquinolinyl and the like.
  • the ring system may be joined to the rest of the molecule by any coinvenient nitrogen
  • 'aryl' means an aromatic carbocyclic ring. Examples are phenyl, naphthyl and the like.
  • 'alicyclic' means a group having a carbocyclic ring structure which may be saturated or unsaturated, but may not be a benzenoid or other aromatic system.
  • 'aliphatic' means a non-aromatic group.
  • heteroaliphatic ring means a heterocyclic ring that is wholly or partially saturated, but not aromatic.
  • the ring has up to 10 atoms with up to 4 heteroatoms selected from N, O or S. Examples are piperidine, morpholine, tetrahydrofuran, pyrrolidine and the like.
  • the groups 'aryl', 'heteroaryl', 'fused bicyclic', 'alicyclic' and 'heteroaliphatic' ring may be substituted by one or more substituent groups selected from Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, halogen, cyano, nitro, SH, S(O) 0 - 2 R 10 , NR 8 R 9 , S(O) 2 NR 8 R 9 , C(O)NR 8 R 9 , C(O)OR 10 , NR 10 S(O) 2 R 11 , NR 10 C(O)R 10 , NR 10 C(O)OR 11 , NR 10 C(O)NR 8 N 9 , OR 10 .
  • alkyl groups and moieties may be straight or branched chain and include, for example, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl.
  • 'C 1-8 alkyl' means a straight or branched chain alkyl group having from one to eight carbon atoms; similarly 'C 1-6 alkyl' means a straight or branched alkyl chain having from one to six carbon atoms.
  • Cycloalkyl groups are monocyclic, for example cyclopentyl or cyclohexyl.
  • 'C 3-S cycloalkyl' means a cycloalkyl group having from three to eight carbon atoms.
  • Alkyl, alkylene and cycloalkyl groups may be optionally substituted by up to three groups selected from halogen, hydroxy, hydroxy-Ci_6alkyl or Ci_6 alkoxy.
  • 'Halogen' is for example, fluoride, chloride or bromide.
  • 'Alkoxy means an alkyl or cycloalkyl group attached to an oxygen atom. Examples are methoxy, ethoxy and cyclopropyloxy.
  • a group may be optionally substituted with up to three substituents, the group may be unsubstituted or substituted; when substituted the group will generally be substituted with one, two or three substituents.
  • a hydroxyl moiety will not be attached to a carbon atom which is adjacent to a nitrogen atom, another oxygen atom or a sulfur atom.
  • the invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises reacting a compound of formula (IV) with an Ci_ 6 alkyl halide eg. methyl iodide or ethyl iodide.
  • an Ci_ 6 alkyl halide eg. methyl iodide or ethyl iodide.
  • R 1 , m, n, V, W, X, Y and Z are as defined in formula (I) and L, L 1 and L 2 are as defined in formula (II) can be prepared by reacting a compound of formula (V) or a suitable salt thereof (e.g. hydrobromide, acetate or hydrochloride),
  • LG 1 represents a leaving group (e.g. chloride, bromide, iodide, methanesulfonate or/? ⁇ ra-toluenesulfonate) and L, L 1 and L 2 are as defined in formula (II) in the presence of a base (e.g. potassium carbonate, triethylamine or diisopropylethylamine) in an organic solvent, for example, JV,iV-dimethylformamide or dichloromethane, at a temperature, for example in the range from 0 to 6O 0 C.
  • a base e.g. potassium carbonate, triethylamine or diisopropylethylamine
  • organic solvent for example, JV,iV-dimethylformamide or dichloromethane
  • L and L 2 are as defined in formula (II) above in the presence of a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a palladium on carbon or palladium oxide catalyst) in an organic solvent, for example, JV-methyl-2-pyrrolidinone or ethanol, at a temperature, for example in the range from 0 to 6O 0 C.
  • a suitable reducing agent e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a palladium on carbon or palladium oxide catalyst
  • organic solvent for example, JV-methyl-2-pyrrolidinone or ethanol
  • L is as defined in formula (II) and P 1 is a suitable nitrogen protective group, with a reducing agent, for example, lithium aluminium hydride or borane tetrahydrofuran complex in an organic solvent, for example, tetrahydrofuran at a temperature, for example in the range from 0 to 6O 0 C, followed by removal of the protective group and reaction with a compound of formula (IX), or a suitable salt thereof,
  • a reducing agent for example, lithium aluminium hydride or borane tetrahydrofuran complex in an organic solvent, for example, tetrahydrofuran at a temperature, for example in the range from 0 to 6O 0 C, followed by removal of the protective group and reaction with a compound of formula (IX), or a suitable salt thereof,
  • the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole, 1-Propanephosphonic acid cyclic anhydride (T3P) or O-(7-azabenzotriazol-l-yl)-JV, ⁇ /,JV', ⁇ P- tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example, NJV- dimethylformamide or dichloromethane, optionally in a presence of a base (e.g. triethylamine), at a temperature, for example in the range from 0 to 60 0 C,
  • an activating reagent for example, carbonyldiimidazole, 1-Propanephosphonic acid cyclic anhydride (T3P) or O-(7-azabenzotriazol-l-yl)-JV, ⁇ /,JV', ⁇ P- tetramethyluroniumhexafluorophosphate (HATU)
  • reaction is conveniently carried out in the presence of a base, for example, triethylamine, diisopropylethylamine or pyridine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 25 0 C;
  • a base for example, triethylamine, diisopropylethylamine or pyridine
  • organic solvent for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 25 0 C;
  • P 2 is a suitable nitrogen protective group (e.g. tert-Butylcarbonate), with a compound of formula (IX), or a suitable salt thereof, wherein R 1 , Y and LG 2 are as defined in formula (IX),
  • the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole, 1-Propanephosphonic acid cyclic anhydride (T3P) or O-(7-azabenzotriazol-l-yl)-JV, ⁇ /,JV', ⁇ P- tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example, N,N- dimethylformamide or dichloromethane, optionally in a presence of a base (e.g. triethylamine), at a temperature, for example in the range from 0 to 60 0 C,
  • an activating reagent for example, carbonyldiimidazole, 1-Propanephosphonic acid cyclic anhydride (T3P) or O-(7-azabenzotriazol-l-yl)-JV, ⁇ /,JV', ⁇ P- tetramethyluroniumhexafluorophosphate (HATU
  • LG 2 represents a halide (e.g. chloride)
  • the reaction is conveniently carried out in the presence of a base, for example, triethylamine, diisopropylethylamine or pyridine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 25 0 C;
  • a base for example, triethylamine, diisopropylethylamine or pyridine
  • organic solvent for example, dichloromethane or tetrahydrofuran
  • the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole, 1-Propanephosphonic acid cyclic anhydride (T3P) or O-(7-azabenzotriazol-l-yl)-JV, ⁇ /,JV', ⁇ P- tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example, N,N- dimethylformamide or dichloromethane, optionally in a presence of a base (e.g. triethylamine), at a temperature, for example in the range from 0 to 60 0 C,
  • an activating reagent for example, carbonyldiimidazole, 1-Propanephosphonic acid cyclic anhydride (T3P) or O-(7-azabenzotriazol-l-yl)-JV, ⁇ /,JV', ⁇ P- tetramethyluroniumhexafluorophosphate (HATU
  • LG 3 represents a halide (e.g. chloride)
  • the reaction is conveniently carried out in the presence of a base, for example, triethylamine, diisopropylethylamine or pyridine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 25 0 C;
  • a base for example, triethylamine, diisopropylethylamine or pyridine
  • organic solvent for example, dichloromethane or tetrahydrofuran
  • P 2 , m and n are as defined in compound of formula (X), by treatment with a suitable reducing agent such as borane-THF complex in a suitable solvent such as tetrahydrofuran at 30-70 0 C with the resulting boron complex decomposed with a suitable amine such as ⁇ /Y, ⁇ /2-dimethyleneamine-l,2-diamine in methanol at 60-90 0 C
  • a suitable reducing agent such as borane-THF complex in a suitable solvent such as tetrahydrofuran at 30-70 0 C
  • a suitable amine such as ⁇ /Y, ⁇ /2-dimethyleneamine-l,2-diamine in methanol at 60-90 0 C
  • a compound of formula (XIII) can be prepared from a compound of formula (XIV)
  • LG 4 is a suitable leaving group such as halogen or tosylate and P 2 , m and n are as defined in compound of formula (XIII), by treatment with a suitable base such as potassium te/t-butoxide in a suitable solvent such as tetrahydrofuran at 50-90 0 C.
  • a suitable base such as potassium te/t-butoxide
  • a suitable solvent such as tetrahydrofuran at 50-90 0 C.
  • a compound of formula (XIV) can be prepared by reacting a compound of formula (XV) with a compound of formula (XVI)
  • LG 5 represents a hydroxyl or halogen group such as chloride and P 2 , m, n and LG 4 are as defined in compound of formula (XIV);
  • the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole, 1- Propanephosphonic acid cyclic anhydride (T3P) or O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example, N,N- dimethylformamide or dichloromethane, optionally in a presence of a base (e.g. triethylamine), at a temperature, for example in the range from 0 to 60 0 C;
  • an activating reagent for example, carbonyldiimidazole, 1- Propanephosphonic acid cyclic anhydride (T3P) or O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluroniumhexafluorophosphate (HATU)
  • organic solvent for
  • the reaction is conveniently carried out in the presence of a base, for example, triethylamine or diisopropylethylamine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 25 0 C;
  • a base for example, triethylamine or diisopropylethylamine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 25 0 C;
  • a compound of formula (XV) can be prepared by reacting a compound of formula (XVII)
  • P 2 , m and n are as defined in compound of formula (XV), with ammonia in a suitable solvent such as methanol at a temperature in the range from 20-60 0 C;
  • a compound of formula (XVII) can be prepared by reacting a compound of formula (XVIII) (XVIII) wherein P 2 , m and n are as defined in compound of formula (XVII), with trimethyl sulfoxonium iodide in the presence of a suitable base such as sodium hydride or potassium te/t-butoxide in a suitable solvent such as dimethylsufoxide at a temperature in the range from 0-20 0 C;
  • the compounds of the invention have activity as pharmaceuticals, in particular as anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonists, in particular M3 antagonists.
  • Diseases and conditions which may be treated with the compounds include:
  • respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature
  • osteoarthritides associated with or including osteoarthritis/osteoarthrosis both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal- induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connect
  • arthitides for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy
  • other joint disease such as intervertebral disc degeneration or temporomandibular joint degeneration
  • bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis
  • polychondritits such as osteoporosis, Paget's
  • skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber- Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma
  • eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;
  • gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema); 7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;
  • nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);
  • allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
  • CNS Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;
  • cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and, 15.
  • gastrointestinal tract Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food- related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema.
  • the present invention further provides a compound of formula (I), as hereinbefore defined for use in therapy.
  • the invention provides the use of a compound of formula (I), as hereinbefore defined, in the manufacture of a medicament for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • a further aspect of the invention provides a method of treating a disease state in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) as hereinbefore defined.
  • the present invention also provides a compound of formula (I) as hereinbefore defined, for treating chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention also provides a compound of formula (I) as hereinbefore defined, for treating asthma.
  • the present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the treatment of asthma.
  • the present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the manufacture of a medicament for use in the treatment of asthma.
  • the present invention further provides a method of treating chronic obstructive pulmonary disease (COPD) (such as irreversible COPD), in a warm-blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I) as hereinbefore defined.
  • COPD chronic obstructive pulmonary disease
  • the present invention further provides a method of treating asthma in a warmblooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I) as hereinbefore defined.
  • a compound of the invention for the therapeutic treatment of a warm-blooded animal, such as man, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition that comprises a compound of the invention as hereinbefore defined and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will, for example, comprise from 0.05 to 99%w (per cent by weight), such as from 0.05 to 80%w, for example from 0.10 to 70%w, such as from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
  • topical such as to the lung and/or airways or to the skin
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule, which contains between 0.1 mg and Ig of active ingredient.
  • a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of O.Olmgkg "1 to lOOmgkg "1 of the compound, for example in the range of O.lmgkg "1 to 20mgkg ⁇ 1 of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose, which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day
  • Another suitable pharmaceutical composition of this invention is one suitable for inhaled administration, inhalation being a particularly useful method for administering the compounds of the invention when treating respiratory diseases such as chronic obstructive pulmonary disease (COPD) or asthma.
  • COPD chronic obstructive pulmonary disease
  • the compounds of formula (I) may be used effectively at doses in the ⁇ g range, for example 0.1 to 500 ⁇ g, 0.1 to 50 ⁇ g, 0.1 to 40 ⁇ g, 0.1 to 30 ⁇ g, 0.1 to 20 ⁇ g, 0.1 to 10 ⁇ g, 5 to 10 ⁇ g, 5 to 50 ⁇ g, 5 to
  • a pharmaceutical composition comprising a compound of the invention as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, which is formulated for inhaled administration.
  • metered dose inhaler devices When administered by inhalation, metered dose inhaler devices may be used to administer the active ingredient, dispersed in a suitable propellant and with or without additional excipients such as ethanol, surfactants, lubricants or stabilising agents.
  • Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (e.g. heptafluoroalkane) propellants, or mixtures of any such propellants.
  • Preferred propellants are P134a and P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other excipients.
  • Nebulised aqueous suspensions or, preferably, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulations.
  • Dry powder inhalers may be used to administer the active ingredient, alone or in combination with a pharmaceutically acceptable carrier, in the later case either as a finely divided powder or as an ordered mixture.
  • the dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.
  • Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.
  • the invention further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
  • the compounds of the invention may be combined with agents listed below.
  • Non-steroidal anti-inflammatory agents including nonselective cyclo-oxygenase COX-I / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramus
  • the present invention still further relates to the combination of a compound of the invention together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin- like growth factor type I (IGF-I); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- ⁇ ) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular- weight agents such as pentoxyfylline.
  • a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signalling pathways such as modulators of the SOCS
  • the invention relates to a combination of a compound of the invention with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA- aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).
  • B-Lymphocytes such as CD20 (rituximab), MRA- aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15.
  • the present invention still further relates to the combination of a compound of the invention with a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C- X-C family) and CX 3 CRl for the C-X 3 -C family.
  • a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C- X-C family) and CX 3
  • the present invention further relates to the combination of a compound of the invention with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP- 1), collagenase-2 (MMP-8), collagenase-3 (MMP- 13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-11) and MMP-9 and MMP- 12, including agents such as doxycycline.
  • MMPs matrix metalloprotease
  • the present invention still further relates to the combination of a compound of the invention and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5- lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2- alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.
  • the present invention further relates to the combination of a compound of the invention and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
  • LT leukotrienes
  • the present invention still further relates to the combination of a compound of the invention and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
  • PDE phosphodiesterase
  • the present invention further relates to the combination of a compound of the invention and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
  • a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine
  • the present invention still further relates to the combination of a compound of the invention and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
  • a proton pump inhibitor such as omeprazole
  • a gastroprotective histamine type 2 receptor antagonist such as a gastroprotective histamine type 2 receptor antagonist.
  • the present invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
  • an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochlor
  • the present invention still further relates to the combination of a compound of the invention and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, or indacaterol or a chiral enantiomer thereof.
  • a beta-adrenoceptor agonist including beta receptor subtypes 1-4
  • the present invention further relates to the combination of a compound of the invention and a chromone, such as sodium cromoglycate or nedocromil sodium.
  • a chromone such as sodium cromoglycate or nedocromil sodium.
  • the present invention still further relates to the combination of a compound of the invention with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • the present invention further relates to the combination of a compound of the invention with an agent that modulates a nuclear hormone receptor such as PPARs.
  • the present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • Ig immunoglobulin
  • Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • anti-IgE for example omalizumab
  • the present invention further relates to the combination of a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • the present invention still further relates to the combination of a compound of the invention and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine
  • immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • the present invention further relates to the combination of a compound of the invention together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfmavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine
  • the present invention still further relates to the combination of a compound of the invention and a cardiovascular agent such as a calcium channel blocker, a beta- adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
  • a cardiovascular agent such as a calcium channel blocker, a beta- adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology such as pentoxyfylline
  • the present invention further relates to the combination of a compound of the invention and a CNS agent such as an antidepressant (such as sertraline), an antiparkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
  • a CNS agent such as an antidepressant (such as sertraline), an antiparkinsonian drug (such as deprenyl, L-dopa, ropinirole
  • the present invention still further relates to the combination of a compound of the invention and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent.
  • analgesic for example an opioid or derivative thereof
  • carbamazepine for example an opioid or derivative thereof
  • phenytoin for example an opioid or derivative thereof
  • sodium valproate for example an opioid or derivative thereof
  • amitryptiline or other anti-depressant agent-s for example an opioid or derivative thereof
  • paracetamol for example an opioid or derivative thereof
  • non-steroidal anti-inflammatory agent for example an opioid or derivative thereof
  • the present invention further relates to the combination of a compound of the invention together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a compound of the present invention can also be used in combination with an anti- osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • a hormonal agent such as raloxifene
  • a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a compound of the invention together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate de
  • -receptor antagonist for example colchicine
  • anti-gout agent for example colchicine
  • xanthine oxidase inhibitor for example allopurinol
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone
  • growth hormone secretagogue for example transforming growth factor (TGF ⁇ );
  • PDGF platelet-derived growth factor
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream for example tachykinin NKl or NK3 receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418;
  • elastase inhibitor such as UT-77 or ZD-0892
  • TNF-alpha-1 for example colchicine
  • xanthine oxidase inhibitor for example allopurinol
  • uricosuric agent for example
  • a compound of the invention can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include: (i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dact
  • a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5 ⁇ -reductase such as finasteride;
  • an antioestrogen for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene
  • an agent which inhibits cancer cell invasion for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function
  • an inhibitor of growth factor function for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7- bis
  • an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin ⁇ v ⁇ 3 function or an angiostatin);
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354
  • a compound that works by another mechanism for example linomide, an inhibitor of integrin ⁇ v ⁇ 3 function or an angiostatin
  • vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
  • an agent used in antisense therapy for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • an agent used in a gene therapy approach for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte -macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • GDEPT gene-directed enzyme pro-drug
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I) as hereinbefore described, and at least one further active ingredient selected from:-
  • the pharmaceutical product according to this embodiment may, for example, be a pharmaceutical composition comprising the first and further active ingredients in admixture.
  • the pharmaceutical product may, for example, comprise the first and further active ingredients in separate pharmaceutical preparations suitable for simultaneous, sequential or separate administration to a patient in need thereof.
  • the pharmaceutical product of this embodiment is of particular use in treating respiratory diseases such as asthma, COPD or rhinitis.
  • Examples of a phosphodiesterase inhibitor that may be used in the pharmaceutical product according to this embodiment include a PDE4 inhibitor such as an inhibitor of the isoform PDE4D, a PDE3 inhibitor and a PDE5 inhibitor.
  • PDE4 inhibitor such as an inhibitor of the isoform PDE4D
  • PDE3 inhibitor a PDE3 inhibitor
  • PDE5 inhibitor examples include the compounds (Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(2-indanyloxy-5-methoxy-2-pyridyl]propenenitrile, N-[9-amino-4-oxo-l-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,l -jk][l, 4]benzodiazepin-3(R)- yl]pyridine-3-carboxamide (CI- 1044)
  • Examples of a ⁇ 2 -adrenoceptor agonist that may be used in the pharmaceutical product according to this embodiment include metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol (e.g. as sulphate), formoterol (e.g. as fumarate), salmeterol (e.g. as xinafoate), terbutaline, orciprenaline, bitolterol (e.g. as mesylate), pirbuterol or indacaterol.
  • the ⁇ 2 -adrenoceptor agonist of this embodiment may be a long-acting ⁇ 2 -agonists, for example salmeterol (e.g.
  • Examples of a modulator of chemokine receptor function that may be used in the pharmaceutical product according to this embodiment include a CCRl receptor antagonist.
  • Examples of an inhibitor of kinase function that may be used in the pharmaceutical product according to this embodiment include a p38 kinase inhibitor and an IKK inhibitor.
  • protease inhibitor examples include an inhibitor of neutrophil elastase or an inhibitor of MMP12.
  • Examples of a steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include budesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. as furoate ester), beclomethasone (e.g. as 17- propionate or 17,21-dipropionate esters), ciclesonide, loteprednol (as e.g. etabonate), etiprednol (as e.g. dicloacetate), triamcinolone (e.g.
  • Examples of a modulator of a non-steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include those described in WO2006/046916.
  • the compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, for example an acid addition salt such as a hydrochloride (for example a mono- or di-hydrochloride), hydrobromide (for example a mono- or di- hydrobromide), trifluoroacetate (for example a mono-or di-trifluoroacetate), sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or /?-toluenesulphonate.
  • an acid addition salt such as a hydrochloride (for example a mono- or di-hydrochloride), hydrobromide (for example a mono- or di- hydrobromide), trifluoroacetate (for example a mono-or di-trifluoroacetate), sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate,
  • TLC Thin Layer Chromatography
  • silica particle size ⁇ 63 ⁇ m; porosity 60 A; surface area -500 m 2 /g
  • UV254 fluorescent indicator
  • the plates were visualized by either UV 254 irradiation, or development with a suitable indicator, such as iodine (pre- absorbed onto silica), an aqueous solution of potassium permanganate, or an aqueous solution of cerium (IV) ammonium nitrate.
  • suitable indicator such as iodine (pre- absorbed onto silica), an aqueous solution of potassium permanganate, or an aqueous solution of cerium (IV) ammonium nitrate. Examples of indicator preparations can be found in 'Experimental Organic Chemistry: Preparative and Microscale' 2 nd Ed. (Harwood, L., Moody, C. and Percy, J.), WileyBlackwell, 1998.
  • Analytical HPLC was carried out using either a Waters XBridgeTM C8 3.5 ⁇ m column eluting with a gradient of acetonitrile in either 0.1% aqueous trifluoroacetic acid, 0.1% aqueous formic acid, 0.1% aqueous ammonium acetate or 0.1% aqueous ammonia; a Waters XBridgeTM Cl 8 3.5 ⁇ m column with a gradient of acetonitrile in 0.1% aqueous ammonia; a Waters SymmetryTM C18 3.5 ⁇ m column with a gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid; a Waters Sunf ⁇ reTM C 8 3.5 ⁇ m column with a gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid; or a Phenomenex GeminiTM Cl 8 3 ⁇ m column with a gradient of acetonitrile in 0.1% aqueous trifluor
  • Preparative HPLC was carried out using a gradient of acetonitrile or methanol in 0.1% or 0.2% aqueous TFA, aqueous formic acid or aqueous ammonia solution, using a Phenomenex GeminiTM NX C18 (30 x 100 mm, 5 ⁇ m) column, a Waters SunfireTM Prep C8 (30 x 100 mm, 10 ⁇ m) column, a Waters SunfireTM Prep Cl 8 (30 x 100 mm, 5 ⁇ m) column or a Waters XBridgeTM C 8 (30 x 100 mm, 5 ⁇ m) column as stationary phase at a flow rate of 30 - 35 mL/min, as detailed. Fractions were collected following detection by UV spectroscopy at a wavelength such as 220 or 254 nm. Fraction purity was determined by either TLC or analytical HPLC.
  • Triton-B Benzyltrimethylammonium hydroxide tert-Butyl l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride salt was made using Preparation 1 described below. Naming package for title/subtitled compounds:
  • Chloroacetyl chloride (4.88 mL) was added dropwise to a vigorously stirred mixture at O 0 C of potassium carbonate (17.4 g) in water (78 mL) and tert-butyl 4-(aminomethyl)-4- hydroxypiperidine-1-carboxylate [Preparation 1, step a] (10.4 g) in ethyl acetate (92 mL). After 30 minutes at O 0 C, the mixture was extracted with ethyl acetate and the organic layer dried, filtered and the solvent evaporated under reduced pressure.
  • Trifluoroacetic acid (10 niL) was added to a solution of tert-butyi 4-(2-methylthiazole-4- carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate [Preparation 2, step a] (2.3 g) in DCM (50 mL) at O 0 C and the resulting mixture was stirred for 16 h. The solvent was evaporated in vacuo. Toluene (50 mL) was added and the mixture evaporated in vacuo. The residue was dissolved in methanol (20 mL) and applied to a SCX cartridge pre-wetted with methanol.
  • T3P (1.6M in THF, 51.3 mL) was added dropwise to a stirred suspension of tert-butyi 1- oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (18.1 g), 2-ethylthiazole-4-carboxylic acid [Preparation 7, step c] (12 g) and triethylamine (52 mL) in DMF (120 mL) under nitrogen, and the mixture stirred at ambient temperature for 20 hours. It was diluted with water and extracted into ethyl acetate (x 3).
  • Lithium hydroxide (2.07 g) was added to a solution of ethyl 2-(pentan-3-yl)thiazole-4- carboxylate [Preparation 9, step c] (2.8 g) in a mixture of THF (80 mL) and water (20 mL). The resulting mixture was stirred overnight. The reaction was acidified with concentrated hydrochloric acid ( ⁇ 6 mL) and the THF evaporated. The resulting aqueous mixture was saturated with sodium chloride and extracted with ethyl acetate (3 x 100 mL). The combined organics were dried over sodium sulphate, filtered and evaporated to give the titled compound as a white solid. Yield 2.3 g.
  • step a (0.136 g) was added to a stirred solution of (5-methylthiophen-2-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Preparation 6] (0.250 g) and triethylamine (0.278 mL) in MeCN (5 mL). After 1 h, the reaction mixture was concentrated and applied to a silica gel column eluting with ethyl acetate :triethylamine, 95:5 to give the titled compound. Yield 0.24 g.
  • step a (1.2 g) and triethylamine (2.3 mL) in acetonitrile (30 mL). The resulting mixture was stirred overnight at RT under nitrogen. The solvent was evaporated and the residue purified by silica gel chromatography, gradient elution 99: 1 :0.1 to 97:3 :0.3
  • Benzoyl peroxide (0.05 g) was added to a mixture of 2-(3-fluoro-5-methylphenyl)acetic acid (0.518 g) and N-bromosuccinimide (0.6 g) in DCM (10 mL). The reaction was heated at reflux for 1 h. DCM (10 mL) and water (20 mL) were added and the organic phase separated. The organic layer was washed with brine (20 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was triturated with toluene and the resulting white solid removed by filtration. The mother liquors were evaporated in vacuo to give the subtitled compound as a white solid which was used in the next step without further purification. Yield 0.38 g.
  • Methanesulphonyl chloride (1.3 mL) in DCM (20 mL) was added dropwise to a solution at 0 0 C of (5-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorophenyl)methanol [Example 6, step c] (4.66 g) and triethylamine (2.5 mL) in DCM (100 mL). The mixture was stirred at 0 0 C for 1 hour and then washed with water. The organic layer was dried, filtered and the solvent evaporated under reduced pressure.
  • HATU 1.1 g was added in one portion to a cooled solution of 2-(3-(l-oxa-4,9- diazaspiro[5.5]undecan-9-ylmethyl)-4-fluorophenyl)ethanol [Example 6, step fj (0.7 g) and 2-isopropylthiazole-4-carboxylic acid (0.39 g) and triethylamine (0.95 mL) in DMF (15 mL). The reaction mixture was stirred at 20 0 C for 1 hour and then partitioned between ethyl acetate and brine. The organic layer was washed with brine (x 2), dried, filtered and the solvent removed under reduced pressure.
  • Dibenzoyl peroxide (0.03 g) was added to a mixture of NBS (0.53 g) and 2-(2,6-difluoro- 3-methylphenyl)acetic acid (0.50 g) in DCM (10 mL). The reaction was heated at reflux for 4 h. DCM (10 mL) and water (20 mL) were added and the organic phase separated. The organic phase was washed with brine (20 mL), dried over sodium sulphate, filtered and evaporated. The residue was redissolved in THF (10 mL) and cooled in an ice bath. A solution of borane dimethyl sulfide complex (2M in THF, 4 mL) was added dropwise and the mixture stirred for 1 h.
  • step b] (4.07 g) was added to (2-isopropylthiazol-4-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4- yl)methanone trifluoroacetate [Preparation 4] (6.10 g) in a mixture of JV-methyl-2- pyrrolidinone (50 mL) and acetic acid (0.83 mL) and stirred for 30 min. Sodium triacetoxyborohydride (4.58 g) was then added and the mixture stirred overnight.
  • Benzoyl peroxide (1.33 g) was added to a suspension of 2-chloro-3-methylbenzoic acid (25 g) and ⁇ /-bromosuccinimide (28.7 g) in chlorobenzene (250 mL) and the resulting mixture was heated to 85°C for 4 h. The mixture was diluted with ethyl acetate (100 mL) and washed with 10% aqueous brine (3 x 100 mL). The organic layer was dried over magnesium sulphate, filtered and evaporated. The beige solid was recrystallised from ethyl acetate ( ⁇ 75 mL)/isohexane (-250 niL) to give the subtitled compound as a white solid. Yield 25.3 g.
  • the reaction mixture was partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate solution (50 mL). The mixture was shaken vigorously for 10 min and the layers were separated. The aqueous phase was extracted with ethyl acetate (100 mL). The combined organic solutions were washed with brine, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash silica chromatography using 95:5 ethyl acetate :triethylamine as solvent. The fractions containing the product were combined and evaporated to give the titled compound as a clear oil. Yield 3.4O g. m/z 464/466 (M+H) + (APCI).
  • the reaction was diluted with methanol (30 mL) and applied to a SCX cartridge pre-wetted with methanol.
  • the cartridge was washed with methanol (100 mL) and eluted with ammonia solution (3M in methanol, 100 mL).
  • the eluent was evaporated in vacuo and the residue purified by silica gel chromatography, eluting with 95:5 ethyl acetate :triethylamine to give the titled compound as a brown oil. Yield 0.74 g. m/z 446 (M+H) + (APCI).
  • the reaction mixture was quenched by the addition of saturated sodium bicarbonate solution:brine (1 :5) and extracted four times with ethyl acetate. The combined organic phases were dried (MgSO 4 ), filtered and concentrated in vacuo to afford an oil.
  • the oil was dissolved in THF (100 mL) and treated with TBAF (IM in THF, 18.0 mL). The resulting solution was stirred at room temperature for 50 minutes, then more TBAF (IM in THF, 18.0 mL) was added and the mixture was stirred for a further 100 minutes. The solution was then concentrated in vacuo to afford an oil.
  • HATU (0.35 g) was added to a colourless solution of 2-(3-(l-oxa-4,9- diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol [Example 15, step a] (0.364 g), 2-(pentan-3-yl)thiazole-4-carboxylic acid [Preparation 9] (0.141 g) and triethylamine (0.30 mL) in DMF (10 mL), pre-cooled in ice-water. The resulting yellow mixture was stirred in ice-water for 1 hour, then at room temperature for 1 hour. The solution was poured into a mixture of water and brine and extracted twice with ethyl acetate.
  • Butyllithium (36.1 niL) was added dropwise to stirred solution of ter£-butyldimethyl(2- (thiophen-3-yl)ethoxy)silane [J. Med. Chem. 2000, 43(8). 1508] (10.0 g) in THF (200 niL) cooled to -78°C. After the addition the reaction mixture was stirred in an ice bath for Ih and then cooled to -78°C. DMF (31.9 mL) was added dropwise over 5 min, and after a further 10 min the cooling bath was removed.
  • Triphenylphosphine (7.16 g) followed by carbon tetrabromide (8.62 g) were added in one portion to (4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)methanol [Example 17, Step b] (6.00 g) in DCM (50 mL) at 0 0 C under nitrogen. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was cooled to O 0 C and treated with tetraethylammonium cyanide (4.92 g), added in one portion. The mixture was diluted further with dichloromethane (20 mL) and stirred at room temperature for 40 minutes.
  • the resulting solution was stirred at 20 0 C for 1 hour.
  • the reaction mixture was diluted with THF (15 mL), cooled in ice-water, and treated with a solution of potassium carbonate (1.35 g) in water (15 mL). This mixture was stirred at O 0 C for 20 minutes.
  • the mixture was partitioned between ethyl acetate and aqueous brine, and the phases separated. The organic layer was washed twice with aqueous brine, dried, filtered and the solvent removed under reduced pressure.
  • the residue was dissolved in THF (40 mL), cooled in an ice bath and treated with borane tetrahydrofuran complex (IM in THF, 21 mL), added dropwise.
  • IM borane tetrahydrofuran complex
  • Example 9 (9-(3-(2-Hydroxyethyl)phenethyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone [Example 9] (2.4 g) was dissolved in acetonitrile (2 niL) and tert-butyi acrylate (1.7 niL) added, followed by benzyltrimethylammonium hydroxide (40% in water, 0.72 rnL). The mixture was stirred at ambient temperature for 3 hours.
  • Benzyltrimethylammonium hydroxide (40% in methanol, 0.031 mL) was added to a solution of (9-(4-(2-hydroxyethyl)phenethyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone [Example 8] (0.62 g) in toluene (20 mL). The solvent was removed under reduced pressure and the residue azeotroped with toluene. The resultant liquid, which was just mobile with traces of toluene, was treated dropwise with tert-butyi acrylate (0.225 g).
  • Trifluoroacetic acid (10 mL) was added to a solution o 3-( ⁇ 4-(2-(4-(2- isopropylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)ethyl)phenethoxy)propanoate [Example 19, step a] (0.55 g) in DCM (20 mL) and the resultant solution allowed to stand at 20 0 C for 1 hour. Toluene (30 mL) was added and the solvents were evaporated under reduced pressure. The residue was azeotroped with acetonitrile (x 2) to yield the titled compound. Yield 0.60 g. m/z 530 (M+H) + (APCI).
  • Example 20 Trifluoroacetic acid (10 mL) was added to a solution o 3-( ⁇ 4-(2-(4-(2- isopropylthiazole-4-carbonyl)-l-ox
  • step a (2.2 g) in place of tert-butyl 3-(4-(2-(4-(2-isopropylthiazole-4- carbonyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoate.
  • Triton-B (40% in water, 0.94 rnL) was added to a solution of (9-(2-chloro-3-(2- hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-ethylthiazol-4- yl)methanone [Example 11] (3.2 g) and tert-butyi acrylate (1.5 mL) in acetonitrile (1 rnL) and the resulting mixture stirred overnight at RT.
  • Example 12 4-yl)methanone [Example 12] (0.32 g) in DCM (20 niL) and the resulting black suspension was heated under reflux for 1 h. After cooling, the reaction mixture was passed through a pad of Celite. The pad was washed with DCM (2 x 30 mL) and the combined filtrate and washings evaporated in vacuo to give the subtitled compound as a gum. Yield 0.25 g. m/z 430 (M+H) + (APCI).
  • the reaction mixture was applied to a pre-washed bed of Tosic-65 resin and washed with methanol.
  • the product was eluted with methanolic ammonia solution and allowed to evaporate.
  • the residue was taken up in DMSO (0.4 mL) and purified by reverse phase HPLC using a gradient of acetonitrile in 0.1% aqueous TFA solution using a SunFireTM prep Cl 8 OBDTM 5 ⁇ m 19 x 50mm column (Waters Corporation) at a flow rate of 20 mL/min.
  • Trifluoroacetic acid (0.04 niL) was added to a solution of (9-(2-(4-(2- hydroxyethyl)phenoxy)ethyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4- yl)methanone [Example 13] (0.22 g) in DCM (3 niL) and the resulting mixture was stirred for 5 min. Dess-Martin periodinane (0.31 g) was then added and the resulting mixture stirred for 5 min.
  • reaction mixture was then treated with a solution of sodium triacetoxyborohydride (16 mg) in ethanol (0.2 mL) and allowed to stand overnight.
  • the reaction mixture was applied to a pre-washed bed of Tosic-65 resin and washed with methanol.
  • the product was eluted with methanolic ammonia solution and allowed to evaporate.
  • the residue was taken up in DMSO (0.4 mL) and purified by reverse phase HPLC using a gradient of acetonitrile in 0.1% aqueous TFA solution using a SunFireTM prep Cl 8 OBDTM 5 ⁇ m 19 x 50mm column (Waters Corporation) at a flow rate of 20 mL/min.
  • Trifluoroacetic acid (0.178 mL, 2.31 mmol) was added to a solution of (9-(4-fluoro-3-(2- hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4- yl)methanone (1.066 g, 2.31 mmol) in DCM (20 mL) at O 0 C and the resulting mixture stirred for 5min. Dess-MartinPeriodinane (1.470 g, 3.47 mmol) was then added and the mixture stirred at RT until consumption of the alcohol by LC-MS (45min).
  • Assay 1 Muscarinic 3 receptor calcium mobilisation assay, Spot Test (a), lOuM
  • the activity (% inhibition of fluorescence) of compounds on the M3 receptor is determined by hrM3 mediated intracellular calcium mobilisation in Fluo-4 loaded CHO (Chinese hamster ovary) cells expressing the human muscarinic acetylcholine M3 receptor (M 3 -ACh) using a FLIPR (fluorescence imaging plate reader).
  • CHO M 3 -ACh cells (Euroscreen ES-212-C) in Hams F 12 nutrient mixture containing glutamine (Sigma H6658) supplemented with 10% Foetal Calf Serum (PAA), 1% Nonessential Amino Acid Solution (Sigma), 0.5mg/ml geneticin (Invitrogen), are distributed into the wells of a 384 well plate at a density of 2.0 x 10 5 cells/ml. The cells are incubated at 37°C at 95%/5 % (v/v) air/CO 2 in 95% relative humidity for 18hrs.
  • the Molecular Devices Calcium assay kit (R8033-BLA4) is used to determine the calcium mobilisation response.
  • the culture medium is removed and the cells loaded with fluorescent dye for 60 minutes at 37°C, according to the manufacturers instructions.
  • Candidate compounds are then added to the cells at a final concentration of 10 ⁇ M in Dimethyl sulfoxide and incubated for 15 minutes at 37°C.
  • the cell plates are then transferred to the FLIPR; an EClOO of Acetyl- ⁇ -methylcholine bromide (Sigma A2126) is added to the cells and fluorescence measured.
  • the compound activity at 10 ⁇ M defined as % inhibition of fluorescent response, is determined.
  • Assay 2 Muscarinic 3 receptor binding assay, Spot Test (a), 1 and lOuM The activity (% inhibition specific binding) of compounds on the M 3 receptor is determined by competition binding of [ H]N-methyl scopolamine (NMS) to CHO-Kl (Chinese Hamster Ovary) cell membranes expressing the human muscarinic acetylcholine M 3 receptor (M 3 -ACh) in a scintillation proximity assay (SPA) format.
  • NMS N-methyl scopolamine
  • M 3 -ACh Choinese Hamster Ovary
  • SPA beads are precoated with membranes and then incubated at 2mg of beads per well with 1 or 10 ⁇ M compound of the invention, [ 3 H]NMS at 0.1 nM, quarter Kd (experimentally determined dissociation constant) and assay buffer (20 mM HEPES pH 7.4 containing 5 mM MgCl 2 and 0.1% (w/v) bovine serum albumin). The assay is conducted in a final volume of 200 ⁇ L, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO). Total binding of [ H]NMS is determined in the absence of competing compound and nonspecific binding of [ H]NMS is determined in the presence of 1 ⁇ M atropine.
  • DMSO dimethyl sulphoxide
  • the affinity (pIC 50 ) of compounds binding to the M 3 receptor is determined by competition binding of [ H]N-methyl scopolamine (NMS) to CHO-Kl (Chinese Hamster Ovary) cell membranes expressing the human muscarinic acetylcholine M 3 receptor (M 3 - ACh) in a scintillation proximity assay (SPA) format.
  • SPA beads are precoated with membranes and then incubated at 2mg of beads per well with serial dilutions of compounds of the invention, [ 3 H]NMS at O.lnM, quarter Kd (experimentally determined dissociation constant) and assay buffer (20 mM HEPES pH 7.4 containing 5 mM MgCl 2 and 0.1% (w/v) bovine serum albumin). The assay is conducted in a final volume of 200 ⁇ L, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO). Total binding of [ H]NMS is determined in the absence of competing compound and nonspecific binding of [ H]NMS is determined in the presence of 1 ⁇ M atropine.
  • DMSO dimethyl sulphoxide
  • Dunkin-Hartley guinea-pigs 300 - 60Og are supplied by a designated breeding establishment. Animals are dosed with test compound or vehicle either by inhalation in conscious guinea-pigs or by intratracheal instillation (0.5ml/kg) under recoverable gaseous anaesthesia (5% halothane). Animals are allowed to recover from the anaesthesia prior to the measurement of bronchoconstriction. Up to 48 hours post-dosing guinea-pigs are terminally anaesthetized with sodium pentobarbitone (60 mg/kg), the trachea cannulated for artificial ventilation and the jugular vein is cannulated for intravenous administration of methacholine.
  • the guinea-pigs are ventilated using a constant volume respiratory pump (Harvard Rodent Ventilator model 683) at a rate of 60 breath/min and a tidal volume of 5 ml/kg during surgical preparation.
  • Lung function (lung resistance and compliance) is measured in anaesthetised and ventilated guinea-pigs using a pulmonary measurement Flexivent system (SCIREQ, Montreal, Canada) connected to the tracheal cannulae.
  • SCIREQ pulmonary measurement Flexivent system
  • the animals are ventilated (quasi-sinusoidal ventilation pattern) at 60 breaths/min at a tidal volume of 5 ml/kg.
  • a positive end expiratory pressure of 2-3 CmH 2 O is applied.
  • Respiratory resistance is measured using the Flexivent "snapshot" facility (1 second duration, 1 Hz frequency). Lung resistance and compliance is measured before and after intravenous administration of methacholine (3, 10 and 30 ug/kg). The peak increase in resistance following methacholine challenge is calculated and the effect of the test compound on methacholine -induced lung function changes is calculated. Percentage inhibition of bronchoconstriction is calculated at each dose of methacholine as follows:
  • Guinea pigs (450-55Og) supplied by Harlan UK or David Hall, Staffs UK and acclimatised to the in-house facilities for a minimum of three days before use. Guinea pigs are randomly assigned into treatment groups and weighed. Each animal is lightly anaesthetised (4% Halothane) and administered compound or vehicle intranasally (0.5ml/kg) at up to 24 hours before challenge with pilocarpine. At the test time point, guinea pigs are terminally anaesthetised with urethane (25% solution in H20, 1.5g/kg).
  • Saliva production is calculated by subtracting the pre-weighed weight of the pad from each 5 minute period post weighed pad and these numbers added together to produce an accumulation of saliva over 15 minutes. Each 5 minute period may be analysed in addition to the whole 15 minute recording period. Baseline production of saliva is assumed to be constant and multiplied by three to produce a reading for baseline saliva production over 15 minutes.
  • Inhibition of saliva produced by the compound may be calculated by using the following equation: (l-(Test-baseline)/(Veh-baseline))* 100.

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Abstract

Spirocyclicmorpholine-substituted amides of formula (I): processes for their preparation, pharmaceutical compositions containing them, a process for preparing pharmaceutical compositions, their use in therapy and intermediates of use in their preparation.

Description

DIAZASPIRO [5.5] UNDECANE DERIVATIVES AND RELATED COMPOUNDS AS
MUSCARINIC-RECEPTOR ANTAGONISTS AND BETA-ADRENORECEPTOR
AGONISTS FOR THE TREATMENT OF PULMONARY DISORDERS
The present invention relates to spirocyclicmorpholine-substituted amides, a process for their preparation, pharmaceutical compositions containing them, a process for preparing pharmaceutical compositions, their use in therapy and intermediates of use in their preparation.
Muscarinic receptors are a G-protein coupled receptor (GPCR) family having five family members M1, M2, M3, M4 and M5. Of the five muscarinic subtypes, three (M1, M2 and M3) are known to exert physiological effects on human lung tissue.
Parasympathetic nerves are the main pathway for reflex bronchoconstriction in human airways and mediate airway tone by releasing acetylcholine onto muscarinic receptors. Airway tone is increased in patients with respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD), and for this reason muscarinic receptor antagonists have been developed for use in treating airway diseases. Muscarinic receptor antagonists, often called anticholinergics in clinical practice, have gained widespread acceptance as a first-line therapy for individuals with COPD, and their use has been extensivley reviewed in the literature (e.g. Lee et al, Current Opinion in Pharmacology 2001,1, 223-229).
When used to treat respiratory disorders, muscarinic receptor antagonists are typically administered by inhalation. However, when administered by inhalation a significant proportion of the muscarinic receptor antagonist is often absorbed into the systemic circulation resulting in reported side effects such as dry mouth. Additionally, the majority of muscarinic antagonists have a relatively short duration of action requiring that they be administered several times a day. Such a multiple-daily dosing regime is not only inconvenient to the patient but also creates a significant risk of inadequate treatment due to patient non-compliance associated with the frequent repeat dosing schedule.
There therefore remains a need for novel compounds that are capable of blocking muscarinic receptors. In particular, a need exists for new muscarinic antagonists that have high potency and reduced systemic side effects when administered by inhalation. Moreover, a need exists for new muscarinic antagonists that exhibit a long duration of action when dosed by inhalation, and which are amenable to either once or twice daily dosing.
In accordance with one aspect of the present invention there is provided a compound of formula (I): /
Figure imgf000003_0001
(I)
wherein R1 is selected from the following;
(i) an optionally substituted 4-8 membered ring, said ring being aromatic or fully or partially saturated and wherein up to four of the ring atoms may be replaced by heteroatoms independently selected from N, O and S. Examples of such rings include phenyl, thiazolyl, thienyl, isoxazolyl, furyl, cyclohex-3-enyl, cyclohexyl, cycloheptyl and the like.
(ii) an optionally substituted fused bicyclic ring system of up to 10 atoms, said rings being aromatic or fully or partially saturated, and wherein up to four of the ring atoms may be replaced by heteroatoms independently selected from N, O and S. Examples of such rings include benzo[b]thienyl, benzofuranyl, benzo[d]imidazolyl, quinoxalinyl, pyrazolo [ 1 ,5 -ajpyrimidinyl, pyrazolo [ 1 ,5 -ajpyridinyl, dihydrobenzo [b] [ 1 ,4]dioxinyl, 4,5,6, 7-tetrahydro-2H-indazolyl, benzo[d][l,3]dioxolyl and the like.
(iii) an optionally substituted Ci_6 alkyl group wherein one or two of the carbon atoms can be replaced by O, S or N and wherein said alkyl group may be substituted once or twice by a ring system independently selected from (i) and (ii) above, and wherein the Ci_6 alkyl chain may be substituted by up to five substituents selected from halogen, cyano, S(O)0-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8R9, OR10, C1-6 alkyl and C3-6 cycloalkyl (wherein two C1-3 alkyl chains may be joined to form a cycloalkyl ring of up to eight ring atoms), wherein any ring may be optionally substituted by up to three substituents independently selected from halogen, cyano, SH, S(O)0-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R11, NR10C(O)OR11, NR10C(O)NR8R9, OR10). and wherein for the ring systems in (i) and (ii) above "optionally substituted" means optionally substituted by up to four substituents independently selected from halogen, cyano, nitro, SH, S(O)0-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8R9, OR10, C1-6 alkyl or C3.6 cycloalkyl (wherein a carbon atom of alkyl or cycloalkyl may be optionally replaced by N, O or S) and alkyl or cycloalkyl may be optionally substituted by up to five substituents selected from C1-6 alkyl, halogen, cyano, SH, S(O)0-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8R9, OR10), phenyl or a 4-8 membered heterocyclic ring (containing up to 4 heteroatoms selected from N, O or S) and wherein the phenyl or 4-8 membered heterocyclic rings may be optionally substituted by up to 3 substituents independently selected from halogen, cyano, nitro, SH, S(0)o-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8R9, OR10, C1-6 alkyl or C3-6 cycloalkyl (wherein alkyl or cycloalkyl may be optionally substituted by up to 3 substituents selected from halogen or OR10 ); and wherein the saturated ring systems in (i) and (iii) may also be substituted by up to three Ci_6 alkyl groups that can be joined to form bridged ring structures, optionally substituted by halogen or OR10. Examples of these ring systems include adamantyl and bicyclo[2.2.1]heptyl;
X represents O, S(O)0-2 or CR12R13; m = O, 1, 2 or 3; n = 1, 2, 3 or 4; provided that m + n is greater than or equal to 2;
W represents CR12R13-CR12R13 or CR12R13-CR12R13-CR12R13;
V and Z independently represent a bond, CR12R13 or CR12R13-CR12R13 , provided that when X represents either O or S(O)0-2 then m, V and Z are such that all the heteroatoms in the rings are separated by at least two carbon atoms;
Y represents C(O), C(O)NR10, SO2 or SO2NR10;
R2 is a lone pair, or Ci_6 alkyl, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or R3 is a group of formula (II)
Figure imgf000004_0001
(H) wherein L1 and L2 independently represent hydrogen, Ci_6 alkyl or C3_6 cycloalkyl, wherein the Ci_6 alkyl and C3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy; or
L1 and/or L2 may be linked to carbon atoms in the group L, or L1 and L2 may be linked to each other, to form aliphatic rings of up to 6 ring atoms, wherein each ring may comprise up to three heteroatoms independently selected from N, O and S; and wherein L represents a straight or branched hydrocarbyl chain of up to 15 carbon atoms; wherein up to three of the carbon atoms in the chain are optionally substituted once or twice by groups independently selected from halogen, cyano, S(0)o-2R10, NR14R15, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8R9, OR10, C1-6 alkyl and C3.6 cycloalkyl, and wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy; wherein up to three carbon atoms of the chain may be replaced by groups independently selected from O, NR10, S, S(O), S(O)2, C(O)O, OC(O), „ NR10C(O)NR10, NR10S(O)2NR10, OC(O)NR10, NR10C(O)O, provided that any such groups in the chain are separated by at least two chain carbon atoms; and wherein up to six carbon atoms of the chain may form part of an aryl, heteroaryl, fused bicyclic, alicyclic, or heteroaliphatic ring having up to four heteroatoms independently selected from N, O or S, said ring comprising up to 10 ring atoms, and wherein the ring is optionally substituted by up to three substituents independently selected from halogen, cyano, S(O)0-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8R9, =0, OR10, C1-6 alkyl and C3_6 cycloalkyl, and wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy, with the proviso that L does not comprise an optionally substitued para- or meta-hydroxy phenyl- 1- hydroxy-ethylamino- group (or fused bicyclic derivative thereof) or an optionally substituted 4-hydroxy-2-pyridyl-l-hydroxy-ethylamino- group;
R8 and R9 are independently hydrogen, Ci_6 alkyl or C3_6 cycloalkyl, or R8 and R9 may be joined together to form a heterocyclic ring comprising up to 9 ring atoms (optionally containing a further heteroatom selected from O, N or S) wherein the ring may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl, Ci_6 alkyl or C3-6 cycloalkyl, and wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy;
R10 represents hydrogen, Ci_6 alkyl or C3-6 cycloalkyl, wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy;
R11 represents Ci_6 alkyl or C3_6 cycloalkyl, wherein the Ci_6 alkyl and C3_6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl or Ci_6 alkoxy;
R12 and R13 each independently represent hydrogen, fluorine, Ci_6 alkyl or C3_6 cycloalkyl; or R12 and R13 when attached to the same carbon atom, together with the carbon atom to which they are both attached, may additionally form a 3 to 6 membered aliphatic ring;
R14 represents hydrogen, Ci_6 alkyl or C3_6 cycloalkyl, and;
R15 represents (i) hydrogen or;
(ii) an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring, or;
(iii) a Ci_6 straight- or branched chain alkyl optionally containing an oxygen or sulfur atom in the chain and optionally substituted by up to 3 substituents selected from halogen, hydroxyl, OR10, -COOR10, C(=O)NR8R9, NR10C(=O)R10 (wherein R8' R9, and R10 are as defined above and each independently may additionally represent an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring), or an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring, or; (iv) a C3_8 cycloalkyl group optionally substituted by up to 3 substituents selected from halogen, hydroxyl, OR10, -COOR10, C(=O)NR8R9, NR10C(=O)R10 (wherein R8' R9, and R10 are as defined above and each independently may additionally represent an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring), or an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring; or R14 and R15 are joined together with the nitrogen atom to which they are attached to form a heterocyclic ring (optionally fused to an aryl or heteroaryl ring), optionally containing a further heteroatom selected from O, N, or S, and optionally substituted by Ci_ galkyl, =0, -C(=O)NR8R9, -NR10C(=O)R10, -C(=O)R10(wherein R8' R9, and R10 are as defined above and each independently may additionally represent an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring), or an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring; and pharmaceutically acceptable salts thereof. The Group R1 Conveniently R1 represents
(i) a phenyl ring or a 5- or 6-membered heteroaryl ring; (ii) a fused bicyclic ring ;
(iii) R1 may also conveniently represent an optionally substituted Ci_6 alkyl group wherein one or two of the carbon atoms can be replaced by O, S or N and wherein said alkyl group may be substituted by the ring systems described in (i) and (ii), and a convenient Ci_6 alkyl group is methylene or ethylene or propylene; wherein each ring in (i), (ii) and (iii) is optionally substituted by up to three substituents independently selected from halogen, cyano, OR10, Ci_6 alkyl, C3_8 cycloalkyl, or an optionally substituted phenyl ring.
Conveniently R1 is selected from thiophene or thiazole or benzofuran or pyrazolo[l,5-a]pyridine each optionally substituted by one or two substituents. One of the optional substituents is conveniently selected from H, Cl, F and Ci_3 alkyl. The other optional substituent is selected from methyl, ethyl, propyl, n-butyl, CF3, CH2CF3, CH(CH3)2, CH(CH2CH3)2, CH(CH3)CH2,CH3, CH2CH(CH3)2, C(CH3)3, cyclopropyl, cyclobutyl and cyclopentyl;
Conveniently R1 is selected from
* *
Figure imgf000007_0001
R wherein the arrow marks the attachment point to the group Y and R is selected from methyl, ethyl, propyl, n-butyl, CF3, CH2CF3, CH(CH3)2, CH(CH2CH3)2, CH(CH3)CH25CH3, CH2CH(CH3)2, C(CH3)3, cyclopropyl, cyclobutyl and cyclopentyl; The Group R2 Conveniently R2 represents a lone pair;
Figure imgf000008_0001
The group Y and the group
Y represents C(O), C(O)NR10, SO2 or SO2NR10; Conveniently Y represents C(O); Conveniently
X represents O or S. m = 1 or 2; n = 1 or 2;
W represents CR12R13CR12R13 or CR12R13CR12R13CR12R13;
V and Z independently represent a bond or CR12R13
V and Z are such that all the heteroatoms in the rings are separated by at least two carbon atoms (e.g. When V is a bond then Z is CR12R13).
Conveniently
(i) m and n = 2, V = bond, Z = CH2, X = O and W = CH2CH2 (ii) m and n = 2, V = bond, Z = CH2, X = O and W = CF2CH2 (iii) m and n = 1 , V = bond, Z = CH2, X = O and W = CH2CH2 (iv) m and n = 2, V = bond, Z = CH2CH2, X = O and W = CH2CH2
Conveniently the spirocycle is selected from (i), (ii) or (iii) above. Conveniently the spirocycle is (i)
The Group
Conveniently the group
Figure imgf000008_0002
(II) is represented by a group selected from (i). A group of formula (Ilia)
Figure imgf000009_0001
wherein L3 represents a bond or a Ci_io-alkylene, Ci_io-alkenylene group, or C1-10- alkynylene group, optionally containing an oxygen or sulfur atom in the chain, (conveniently the group has a chain of up to 8, up to 6 or up to 4 atoms) and;
D is an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring (such as an optionally substituted aryl or heteroaryl ring) , and;
L4 represents a bond or a Ci_6-alkylene group optionally containing an oxygen or sulfur atom in the chain (such as a chain of up to 4 atoms) , and R14 and R15 are as defined above; or
(ii) A group of Formula (HIb)
Figure imgf000009_0002
wherein L3, L4 and D, are as defined in (i) above and G1 is the group OR10 or C(O)OR10; or; (iii) A group of Formula (HIc)
Figure imgf000009_0003
wherein L3 and D are as defined in (i) above. Convenient compounds are for example of formula (CH2)m-(O)p-(CH2)n-Ar (wherein Ar is as defined above and optionally substituted by halogen or Ci_6alkyl, m is 1-3, p is 0 or 1, and n is 0-2 ), such as phenoxypropyl, 4-halobenzyloxyethyl (eg. 4-chlorobenzyloxyethyl) or 4-halophenethyl (eg. 4-fluorophenethyl); or; (iv) A group of formula (HId)
Figure imgf000010_0001
wherein L3 and D are as defined in (i) above, and; L5 is a bond, Ci_6 alkylene group, or an oxygen or sulfur atom, and; Ring D' is is an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring; or: (v) A group of formula (HIe)
Figure imgf000010_0002
wherein L6 and L7 are independently each a Ci_io-alkylene, Ci_io-alkenylene, or Ci_ lo-alkynylene group(conveniently the group has a chain of up to 8, up to 6 or up to 4 atoms) , and;
G2 is a bond, or an oxygen or sulfur atom, and;
G3 is a group -NR14R15, -C(=O)N 14R15Or OR10, and R10, R14 and R15 are as defined above.
Wherein in groups of formula (IIIa-d) rings D and D' are optionally substituted by up to three substituents independently selected from halogen, S(0)o-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8R9, =0, OR10, C1-6 alkyl and C3-6 cycloalkyl, and wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy;
Conveniently the group of Formula (Ilia) is a group of Formula (Illaa);
Figure imgf000010_0003
(Illaa)
wherein L3, D, and L4 are as defined in Formula (Ilia), and R8 and R9 are as defined above Conveniently the group of formula (HIe) is a group of formula (Illee);
Figure imgf000011_0001
(Illee) wherein L6, G2 and L7 are as defined in Formula (HIe) and G3 is a group -NR8R9, - C(=O)NR8R9 or OR10, and R8, R9 , and R10 are as defined above Conveniently
R14 represents hydrogen or Ci_6 alkyl R15 represents independently
(i) hydrogen or;
(ii) an optionally substituted aryl or heteroaryl ring, or;
(iii) a Ci-6 straight- or branched chain alkyl optionally containing an oxygen or sulfur atom in the chain and optionally substituted by up to 3 substituents selected from halogen, hydroxyl, OR10, -COOR10, C(=O)NR8R9, NR10C(=O)R10 (wherein R8' R9, and R10 are as defined above and each independently may additionally represent an optionally substituted aryl or heteroaryl ring), or an optionally substituted aryl or heteroaryl ring; or
(iv) a C3_8 cycloalkyl group optionally substituted by up to 3 substituents selected from halogen, hydroxyl, OR10, -COOR10, C(=O)NR8R9, NR10C(=O)R10 (wherein R8' R9, and R10 are as defined above and each independently may additionally represent an optionally substituted aryl or heteroaryl ring), or an optionally substituted aryl or heteroaryl ring; or
R14 and R15 are joined together with the nitrogen atom to which they are attached to form a heterocyclic ring (optionally fused to an aryl or heteroaryl ring), optionally containing a further heteroatom selected from O, N, or S, and optionally substituted by Ci_6alkyl, =0, - C(=O)NR8R9, -NR10C(=O)R10, -C(=O)R10 (wherein R8' R9, and R10 are as defined above and each independently may additionally represent an optionally substituted aryl or heteroaryl ring), or an optionally substituted aryl or heteroaryl ring;
When the compounds of formula (I) is a quarternary ammonium salt, it comprises an anion "A" associated with the positive charge on the quaternary nitrogen atom. The anion "A" may be any pharmaceutically acceptable anion of a mono or polyvalent (e.g. bivalent) acid. In an embodiment of the invention "A" may be an anion of a mineral acid, for example chloride, bromide, iodide, sulfate, nitrate or phosphate; or an anion of a suitable organic acid, for example acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, methanesulphonate, p-toluenesulphonate, benzenesulphonate, napadisylate (naphthalene- 1, 5 -disulphonate) (e.g. a heminapadisylate), 2,5-dichlorobenzenesulphonate, xinafoate (l-hydroxy-2-naphthoate) or l-hydroxynaphthalene-2-sulphonate.
It will be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
It is also to be understood that the present invention encompasses the replacement of any quaternary carbon, more specifically the quaternary carbon present in the spirocyclic system, by a silicon atom for example as disclosed in "Silicon switches of Marketed Drugs: Mini-reviews in Med. Chem.", 2006, 6, 1169-1177. Definitions
The term 'heteroaryl' means an aromatic ring system of 5 to 7 atoms, conveniently from 5-6 atoms, having up to three heteroatoms selected from N, O and S. Examples of such heteroaryl rings include thiazolyl, thienyl, isoxazolyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, triazolyl and the like. The heteroaryl group may be attached by any available carbon or nitrogen atom.
The term 'fused bicyclic ring' means a ring system of up to 12 atoms wherein 2 rings are fused together. The system may optionally contain up to 4 heteroatoms selected from N, S and O. The rings may independently be aromatic, partially saturated or fully saturated. Examples of such fused bicyclic ring systems include benzo[b]thienyl, benzofuranyl, benzo[d]imidazolyl, quinoxalinyl, pyrazolo[l,5-a]pyrimidinyl, pyrazolo[l,5- ajpyridinyl, dihydrobenzo[b][l,4]dioxinyl, 4,5,6,7-tetrahydro-2H-indazolyl, benzo[d][l,3]dioxolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthyl, 1,2,3,4-tetraydroquinolinyl, 5,6,7,8- tetrahydroquinolinyl and the like. The ring system may be joined to the rest of the molecule by any coinvenient nitrogen or carbon atom.
The term 'aryl' means an aromatic carbocyclic ring. Examples are phenyl, naphthyl and the like. The term 'alicyclic' means a group having a carbocyclic ring structure which may be saturated or unsaturated, but may not be a benzenoid or other aromatic system.
The term 'aliphatic' means a non-aromatic group.
The term 'heteroaliphatic ring' means a heterocyclic ring that is wholly or partially saturated, but not aromatic. The ring has up to 10 atoms with up to 4 heteroatoms selected from N, O or S. Examples are piperidine, morpholine, tetrahydrofuran, pyrrolidine and the like.
The groups 'aryl', 'heteroaryl', 'fused bicyclic', 'alicyclic' and 'heteroaliphatic' ring may be substituted by one or more substituent groups selected from Ci_6 alkyl, C3_6 cycloalkyl, halogen, cyano, nitro, SH, S(O)0-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8N9, OR10.
Unless otherwise stated, in the context of the present specification alkyl groups and moieties may be straight or branched chain and include, for example, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl. 'C1-8 alkyl' means a straight or branched chain alkyl group having from one to eight carbon atoms; similarly 'C1-6 alkyl' means a straight or branched alkyl chain having from one to six carbon atoms. Cycloalkyl groups are monocyclic, for example cyclopentyl or cyclohexyl. 'C3-S cycloalkyl' means a cycloalkyl group having from three to eight carbon atoms. Alkyl, alkylene and cycloalkyl groups may be optionally substituted by up to three groups selected from halogen, hydroxy, hydroxy-Ci_6alkyl or Ci_6 alkoxy.
'Halogen' is for example, fluoride, chloride or bromide.
'Alkoxy' means an alkyl or cycloalkyl group attached to an oxygen atom. Examples are methoxy, ethoxy and cyclopropyloxy.
In the context of the present specification, where it is stated that a group may be optionally substituted with up to three substituents, the group may be unsubstituted or substituted; when substituted the group will generally be substituted with one, two or three substituents. In general, a hydroxyl moiety will not be attached to a carbon atom which is adjacent to a nitrogen atom, another oxygen atom or a sulfur atom.
The invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises reacting a compound of formula (IV) with an Ci_6alkyl halide eg. methyl iodide or ethyl iodide. Compounds of formula (IV)
Figure imgf000014_0001
wherein R1, m, n, V, W, X, Y and Z are as defined in formula (I) and L, L1 and L2 are as defined in formula (II) can be prepared by reacting a compound of formula (V) or a suitable salt thereof (e.g. hydrobromide, acetate or hydrochloride),
Figure imgf000014_0002
wherein R1, m, n, V, W, X, Y and Z are as defined in formula (I) with a compound of formula (VI)
Figure imgf000014_0003
wherein LG1 represents a leaving group (e.g. chloride, bromide, iodide, methanesulfonate or/?αra-toluenesulfonate) and L, L1 and L2 are as defined in formula (II) in the presence of a base (e.g. potassium carbonate, triethylamine or diisopropylethylamine) in an organic solvent, for example, JV,iV-dimethylformamide or dichloromethane, at a temperature, for example in the range from 0 to 6O0C.
Compounds of the formula (IV), wherein L1 equals hydrogen and R1, m, n, V, W, X and Z are as defined in formula (I) and, L and L2 are as defined in formula (II), can be prepared by reacting a compound of formula (V) or a suitable salt thereof (e.g. hydrobromide, acetate or hydrochloride), with a compound of formula (VII) I/
0 (VII) wherein L and L2 are as defined in formula (II) above in the presence of a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a palladium on carbon or palladium oxide catalyst) in an organic solvent, for example, JV-methyl-2-pyrrolidinone or ethanol, at a temperature, for example in the range from 0 to 6O0C.
Compounds of formula (IV) in which both L1 and L2 equals hydrogen may be prepared by contacting a corresponding compound of formula (VIII).
Figure imgf000015_0001
wherein m, n, V, W, X, Y and Z are as defined in formula (I), L is as defined in formula (II) and P1 is a suitable nitrogen protective group, with a reducing agent, for example, lithium aluminium hydride or borane tetrahydrofuran complex in an organic solvent, for example, tetrahydrofuran at a temperature, for example in the range from 0 to 6O0C, followed by removal of the protective group and reaction with a compound of formula (IX), or a suitable salt thereof,
LG2- Y
H (IX) wherein R1 and Y are as defined in formula (I) and LG2 represents hydroxyl or a leaving group (e.g. halide, chloride), followed by removal of the protective groups (e.g. treatment with hydrochloric or trifluoroacetic acid);
When LG2 represents hydroxyl, the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole, 1-Propanephosphonic acid cyclic anhydride (T3P) or O-(7-azabenzotriazol-l-yl)-JV,Λ/,JV',ΛP- tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example, NJV- dimethylformamide or dichloromethane, optionally in a presence of a base (e.g. triethylamine), at a temperature, for example in the range from 0 to 60 0C, When LG2 represents a halide (e.g. chloride), the reaction is conveniently carried out in the presence of a base, for example, triethylamine, diisopropylethylamine or pyridine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 25 0C;
Compound of formula (V) wherein R1, V, X, W, and Z are as defmined in formula (I) can be prepared by contacting a compound of formula (X)
Figure imgf000016_0001
wherein P2 is a suitable nitrogen protective group (e.g. tert-Butylcarbonate), with a compound of formula (IX), or a suitable salt thereof, wherein R1, Y and LG2 are as defined in formula (IX),
When LG2 represents hydroxyl, the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole, 1-Propanephosphonic acid cyclic anhydride (T3P) or O-(7-azabenzotriazol-l-yl)-JV,Λ/,JV',ΛP- tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example, N,N- dimethylformamide or dichloromethane, optionally in a presence of a base (e.g. triethylamine), at a temperature, for example in the range from 0 to 60 0C,
When LG2 represents a halide (e.g. chloride), the reaction is conveniently carried out in the presence of a base, for example, triethylamine, diisopropylethylamine or pyridine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 25 0C;
Compound of formula (VIII) wherein m, n, V, W, X, Y and Z are as defined in formula (I), L is as defined in formula (II) and P1 is a suitable nitrogen protective group, can be prepared by contacting a compound of formula (XI)
Figure imgf000016_0002
with a compound of formula (XII), or a suitable salt thereof,
Figure imgf000017_0001
wherein LG3 is a suitable leaving group;
When LG3 represents hydroxyl, the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole, 1-Propanephosphonic acid cyclic anhydride (T3P) or O-(7-azabenzotriazol-l-yl)-JV,Λ/,JV',ΛP- tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example, N,N- dimethylformamide or dichloromethane, optionally in a presence of a base (e.g. triethylamine), at a temperature, for example in the range from 0 to 60 0C,
When LG3 represents a halide (e.g. chloride), the reaction is conveniently carried out in the presence of a base, for example, triethylamine, diisopropylethylamine or pyridine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 25 0C;
A compound of general formula (X), wherein V represents a bond, X represents O, W represents CR27R28CR29R30, Z represents CR37R38, R27, R28, R29, R30, R37, R38 each represent hydrogen, and P2 is as defined in formula (X), can be prepared from a compound of formula (XIII)
Figure imgf000017_0002
wherein P2, m and n are as defined in compound of formula (X), by treatment with a suitable reducing agent such as borane-THF complex in a suitable solvent such as tetrahydrofuran at 30-700C with the resulting boron complex decomposed with a suitable amine such as Λ/Y,Λ/2-dimethyleneamine-l,2-diamine in methanol at 60-900C
A compound of formula (XIII) can be prepared from a compound of formula (XIV)
LG4
Figure imgf000017_0003
(XIV) wherein LG4 is a suitable leaving group such as halogen or tosylate and P2, m and n are as defined in compound of formula (XIII), by treatment with a suitable base such as potassium te/t-butoxide in a suitable solvent such as tetrahydrofuran at 50-900C.
A compound of formula (XIV) can be prepared by reacting a compound of formula (XV) with a compound of formula (XVI)
LG4
Figure imgf000018_0001
wherein LG5 represents a hydroxyl or halogen group such as chloride and P2, m, n and LG4 are as defined in compound of formula (XIV);
For the case where LG5 represents hydroxyl, the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole, 1- Propanephosphonic acid cyclic anhydride (T3P) or O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example, N,N- dimethylformamide or dichloromethane, optionally in a presence of a base (e.g. triethylamine), at a temperature, for example in the range from 0 to 60 0C;
For the case where LG5 represents chloride, the reaction is conveniently carried out in the presence of a base, for example, triethylamine or diisopropylethylamine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 25 0C;
A compound of formula (XV) can be prepared by reacting a compound of formula (XVII)
Figure imgf000018_0002
wherein P2, m and n are as defined in compound of formula (XV), with ammonia in a suitable solvent such as methanol at a temperature in the range from 20-600C;
A compound of formula (XVII) can be prepared by reacting a compound of formula (XVIII)
Figure imgf000019_0001
(XVIII) wherein P2, m and n are as defined in compound of formula (XVII), with trimethyl sulfoxonium iodide in the presence of a suitable base such as sodium hydride or potassium te/t-butoxide in a suitable solvent such as dimethylsufoxide at a temperature in the range from 0-200C;
Also the process above refers to simple oxidation and reduction steps, these are performed under standard conditions well established in the literature (e.g. Dess-Martin, Swern, pyridinium chlorochromate, pyridinium sulfur trioxide complex oxidations). They can be conveniently performed in an organic solvent such as dichloromethane, in a range of temperature from -78 to 50 0C (Annual Reports on the Progress of Chemistry, Section B: Organic Chemistry, 2004, 100, 51-70).
Compounds of formula (VI), (VII), (IX), (XII), (XVI), and are either commercially available, known in the literature, or can be readily prepared by those skilled in the art using one of the process described above or using known techniques.
Other intermediate compounds are novel and represent independent aspects of the invention.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the reagents may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the addition or removal of one or more protecting groups.
The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3rd edition, T. W. Greene and P.G.M. Wuts, Wiley-Interscience (1999).
Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures.
The compounds of the invention have activity as pharmaceuticals, in particular as anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonists, in particular M3 antagonists. Diseases and conditions which may be treated with the compounds include:
1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;
2. bone and joints: arthritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal- induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle- Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies;
3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: arthitides (for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritits, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis);
4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber- Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;
5. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;
6. gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema); 7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;
8. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);
9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
10. CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;
11. other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome;
12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes;
13. cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;
14. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and, 15. gastrointestinal tract: Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food- related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema.
Accordingly, the present invention further provides a compound of formula (I), as hereinbefore defined for use in therapy.
In another aspect, the invention provides the use of a compound of formula (I), as hereinbefore defined, in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
A further aspect of the invention provides a method of treating a disease state in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) as hereinbefore defined.
The present invention also provides a compound of formula (I) as hereinbefore defined, for treating chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
The present invention also provides a compound of formula (I) as hereinbefore defined, for treating asthma.
The present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
The present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the treatment of asthma.
The present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD). The present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the manufacture of a medicament for use in the treatment of asthma.
The present invention further provides a method of treating chronic obstructive pulmonary disease (COPD) (such as irreversible COPD), in a warm-blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I) as hereinbefore defined.
The present invention further provides a method of treating asthma in a warmblooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I) as hereinbefore defined.
In order to use a compound of the invention for the therapeutic treatment of a warm-blooded animal, such as man, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition that comprises a compound of the invention as hereinbefore defined and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition, which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will, for example, comprise from 0.05 to 99%w (per cent by weight), such as from 0.05 to 80%w, for example from 0.10 to 70%w, such as from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions. A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule, which contains between 0.1 mg and Ig of active ingredient.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection. Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of O.Olmgkg"1 to lOOmgkg"1 of the compound, for example in the range of O.lmgkg"1 to 20mgkg~1 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose, which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day
Another suitable pharmaceutical composition of this invention is one suitable for inhaled administration, inhalation being a particularly useful method for administering the compounds of the invention when treating respiratory diseases such as chronic obstructive pulmonary disease (COPD) or asthma. When administered by inhalation the compounds of formula (I) may be used effectively at doses in the μg range, for example 0.1 to 500 μg, 0.1 to 50 μg, 0.1 to 40 μg, 0.1 to 30 μg, 0.1 to 20 μg, 0.1 to 10 μg, 5 to 10 μg, 5 to 50 μg, 5 to
40 μg, 5 to 30 μg, 5 to 20 μg, 5 to 10 μg, 10 to 50 μg, 10 to 40 μg 10 to 30 μg, or 10 to 20 μg of active ingredient.
In an embodiment of the invention, there is provided a pharmaceutical composition comprising a compound of the invention as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, which is formulated for inhaled administration.
When administered by inhalation, metered dose inhaler devices may be used to administer the active ingredient, dispersed in a suitable propellant and with or without additional excipients such as ethanol, surfactants, lubricants or stabilising agents. Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (e.g. heptafluoroalkane) propellants, or mixtures of any such propellants. Preferred propellants are P134a and P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other excipients. Nebulised aqueous suspensions or, preferably, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulations.
Dry powder inhalers may be used to administer the active ingredient, alone or in combination with a pharmaceutically acceptable carrier, in the later case either as a finely divided powder or as an ordered mixture. The dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.
Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.
The invention further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
In particular, for the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention may be combined with agents listed below.
Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including nonselective cyclo-oxygenase COX-I / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofm or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.
The present invention still further relates to the combination of a compound of the invention together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin- like growth factor type I (IGF-I); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular- weight agents such as pentoxyfylline.
In addition the invention relates to a combination of a compound of the invention with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA- aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).
The present invention still further relates to the combination of a compound of the invention with a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C- X-C family) and CX3CRl for the C-X3-C family.
The present invention further relates to the combination of a compound of the invention with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP- 1), collagenase-2 (MMP-8), collagenase-3 (MMP- 13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-11) and MMP-9 and MMP- 12, including agents such as doxycycline.
The present invention still further relates to the combination of a compound of the invention and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5- lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2- alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.
The present invention further relates to the combination of a compound of the invention and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
The present invention still further relates to the combination of a compound of the invention and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
The present invention further relates to the combination of a compound of the invention and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
The present invention still further relates to the combination of a compound of the invention and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
The present invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor.
The present invention still further relates to the combination of a compound of the invention and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
The present invention still further relates to the combination of a compound of the invention and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, or indacaterol or a chiral enantiomer thereof.
The present invention further relates to the combination of a compound of the invention and a chromone, such as sodium cromoglycate or nedocromil sodium.
The present invention still further relates to the combination of a compound of the invention with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
The present invention further relates to the combination of a compound of the invention with an agent that modulates a nuclear hormone receptor such as PPARs.
The present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
The present invention further relates to the combination of a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
The present invention still further relates to the combination of a compound of the invention and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
The present invention further relates to the combination of a compound of the invention together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfmavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.
The present invention still further relates to the combination of a compound of the invention and a cardiovascular agent such as a calcium channel blocker, a beta- adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
The present invention further relates to the combination of a compound of the invention and a CNS agent such as an antidepressant (such as sertraline), an antiparkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
The present invention still further relates to the combination of a compound of the invention and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent.
The present invention further relates to the combination of a compound of the invention together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
A compound of the present invention can also be used in combination with an anti- osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
The present invention still further relates to the combination of a compound of the invention together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-Bl. - or B2. -receptor antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogue; (xiv) transforming growth factor (TGFβ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NKl or NK3 receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; or (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS.
A compound of the invention can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include: (i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin);
(ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5α-reductase such as finasteride;
(iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function); (iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3- chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;
(v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin αvβ3 function or an angiostatin);
(vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213; (vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte -macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
In a further embodiment the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I) as hereinbefore described, and at least one further active ingredient selected from:-
• a phosphodiesterase inhibitor,
• a β2. adrenoceptor agonist,
• a modulator of chemokine receptor function,
• an inhibitor of kinase function,
• a protease inhibitor, • a steroidal glucocorticoid receptor agonist, and a
• a non-steroidal glucocorticoid receptor agonist.
The pharmaceutical product according to this embodiment may, for example, be a pharmaceutical composition comprising the first and further active ingredients in admixture. Alternatively, the pharmaceutical product may, for example, comprise the first and further active ingredients in separate pharmaceutical preparations suitable for simultaneous, sequential or separate administration to a patient in need thereof.
The pharmaceutical product of this embodiment is of particular use in treating respiratory diseases such as asthma, COPD or rhinitis.
Examples of a phosphodiesterase inhibitor that may be used in the pharmaceutical product according to this embodiment include a PDE4 inhibitor such as an inhibitor of the isoform PDE4D, a PDE3 inhibitor and a PDE5 inhibitor. Examples include the compounds (Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(2-indanyloxy-5-methoxy-2-pyridyl]propenenitrile, N-[9-amino-4-oxo-l-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,l -jk][l, 4]benzodiazepin-3(R)- yl]pyridine-3-carboxamide (CI- 1044)
3-(benzyloxy)-l-(4-fluorobenzyl)-N-[3-(methylsulphonyl)phenyl]-lH-indole-2- carboxamide,
(lS-exo)-5-[3-(bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]tetrahydro-2(lH)- pyrimidinone (Atizoram),
N-(3,5,dichloro-4-pyridinyl)-2-[l-(4-fluorobenzyl)-5-hydroxy-lH-indol-3-yl]-2- oxoacetamide (AWD- 12-281), β-[3-(cyclopentyloxy)-4-methoxyphenyl]- 1 ,3-dihydro- 1 ,3-dioxo-2H-isoindole-2- propanamide (CDC-801),
N-[9-methyl-4-oxo-l-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,l -jk][l, 4]benzodiazepin-3(R)- yl]pyridine-4-carboxamide (CI-1018), cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 -carboxylic acid (Cilomilast)
8-amino- 1 ,3-bis(cyclopropylmethyl)xanthine (Cipamfylline) N-(2,5-dichloro-3-pyridinyl)-8-methoxy-5-quinolinecarboxamide (D-4418), 5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-iminothiazolidin-4-one (Darbufelone), 2-methyl- 1 -[2-(I -methylethyl)pyrazolo[ 1 ,5-a]pyridin-3-yl]- 1 -propanone (Ibudilast), 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzofuran-6-yl methanesulphonate (Lirimilast), (-)-(R)-5-(4-methoxy-3-propoxyphenyl)-5-methyloxazolidin-2-one (Mesopram),
(-)-cis-9-ethoxy-8-methoxy-2-methyl-l,2,3,4,4a,10b-hexahydro-6-(4- diisopropylaminocarbonylphenyl)-benzo[c][l,6]naphthyridine (Pumafentrine),
3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide
(Roflumilast), the N-oxide of Roflumilast,
5,6-diethoxybenzo[b]thiophene-2-carboxylic acid (Tibenelast)
2,3,6,7-tetrahydro-2-(mesitylimino)-9,10-dimethoxy-3-methyl-4H-pyrimido[6,l- a]isoquinolin-4-one (trequinsin) and
3-[[3-(cyclopentyloxy)-4-methoxyphenyl]-methyl]-N-ethyl-8-(l-methylethyl)-3H-purine-
6-amine (V-11294A).
Examples of a β2-adrenoceptor agonist that may be used in the pharmaceutical product according to this embodiment include metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol (e.g. as sulphate), formoterol (e.g. as fumarate), salmeterol (e.g. as xinafoate), terbutaline, orciprenaline, bitolterol (e.g. as mesylate), pirbuterol or indacaterol. The β2-adrenoceptor agonist of this embodiment may be a long-acting β2-agonists, for example salmeterol (e.g. as xinafoate), formoterol (e.g. as fumarate), bambuterol (e.g. as hydrochloride), carmoterol (TA 2005, chemically identified as 2(1H)-Quinolone, 8- hydroxy-5-[l-hydroxy-2-[[2-(4-methoxy-phenyl)-l-methylethyl]-amino]ethyl]- monohydrochloride, [R-(R*, R*)] also identified by Chemical Abstract Service Registry Number 137888-11-0 and disclosed in U.S. Patent No 4,579,854), indacaterol (CAS no 312753-06-3; QAB- 149), formanilide derivatives e.g. 3-(4-{[6-({(2R)-2-[3-
(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}-butyl)- benzenesulfonamide as disclosed in WO 2002/76933, benzenesulfonamide derivatives e.g. 3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxy-methyl)phenyl]ethyl}amino)- hexyl]oxy}butyl)benzenesulfonamide as disclosed in WO 2002/88167, aryl aniline receptor agonists as disclosed in WO 2003/042164 and WO 2005/025555, indole derivatives as disclosed in WO 2004/032921 and US 2005/222144, and compounds GSK 159797, GSK 159802, GSK 597901, GSK 642444 and GSK 678007.
Examples of a modulator of chemokine receptor function that may be used in the pharmaceutical product according to this embodiment include a CCRl receptor antagonist. Examples of an inhibitor of kinase function that may be used in the pharmaceutical product according to this embodiment include a p38 kinase inhibitor and an IKK inhibitor.
Examples of a protease inhibitor that may be used in the pharmaceutical product according to this embodiment include an inhibitor of neutrophil elastase or an inhibitor of MMP12.
Examples of a steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include budesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. as furoate ester), beclomethasone (e.g. as 17- propionate or 17,21-dipropionate esters), ciclesonide, loteprednol (as e.g. etabonate), etiprednol (as e.g. dicloacetate), triamcinolone (e.g. as acetonide), flunisolide, zoticasone, flumoxonide, rofleponide, butixocort (e.g. as propionate ester), prednisolone, prednisone, tipredane, steroid esters e.g. 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-l lβ-hydroxy- 16α-methyl-3-oxo-androsta-l,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α,9α- difluoro- 11 β-hydroxy- 16α-methyl-3-oxo- 17α-propionyloxy-androsta- 1 ,4-diene- 17β- carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester and 6α,9α-difluoro-l lβ-hydroxy- 16α-methyl-l 7α-[(4-methyl- 1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta- 1 ,4-diene- 17β- carbothioic acid S-fluoromethyl ester, steroid esters according to DE 4129535, steroids according to WO 2002/00679, WO 2005/041980, or steroids GSK 870086, GSK 685698 and GSK 799943.
Examples of a modulator of a non-steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include those described in WO2006/046916.
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, for example an acid addition salt such as a hydrochloride (for example a mono- or di-hydrochloride), hydrobromide (for example a mono- or di- hydrobromide), trifluoroacetate (for example a mono-or di-trifluoroacetate), sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or /?-toluenesulphonate.
The present invention will now be illustrated with the following non-limiting Examples. General Methods
Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received. All operations were carried out at ambient temperature, i.e. in the range 17 to 280C and, where appropriate, under an atmosphere of an inert gas such as nitrogen. 'Microwave' heating refers to heating to constant temperature, using variable power microwave irradiation in a CEM Discover® microwave reactor. Hydrogenation reactions were carried out using a Bϋchi Peteric® system or a ThalesNano H-Cube® system, as detailed. Concentration of all solutions was carried out by evaporation under reduced pressure (in vacuo), e.g. using a Bϋchi Rotavapor® rotary evaporator.
Thin Layer Chromatography (TLC) was carried out using aluminium- or glass- backed plates coated with silica (particle size <63 μm; porosity 60 A; surface area -500 m2/g), with a fluorescent (UV254) indicator. Following elution, the plates were visualized by either UV254 irradiation, or development with a suitable indicator, such as iodine (pre- absorbed onto silica), an aqueous solution of potassium permanganate, or an aqueous solution of cerium (IV) ammonium nitrate. Examples of indicator preparations can be found in 'Experimental Organic Chemistry: Preparative and Microscale' 2nd Ed. (Harwood, L., Moody, C. and Percy, J.), WileyBlackwell, 1998.
Analytical HPLC was carried out using either a Waters XBridge™ C8 3.5 μm column eluting with a gradient of acetonitrile in either 0.1% aqueous trifluoroacetic acid, 0.1% aqueous formic acid, 0.1% aqueous ammonium acetate or 0.1% aqueous ammonia; a Waters XBridge™ Cl 8 3.5 μm column with a gradient of acetonitrile in 0.1% aqueous ammonia; a Waters Symmetry™ C18 3.5 μm column with a gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid; a Waters Sunfϊre™ C 8 3.5 μm column with a gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid; or a Phenomenex Gemini™ Cl 8 3 μm column with a gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid. UV spectra of the eluted peaks were measured using a diode array on an Agilant 1100® system, or equivalent.
Compounds in the tables below were characterised using the following analytical HPLC conditions: SunFire™ C18 2.5 μm 4.6 x 30 mm column (Waters Corporation), MeCN/0.1%aq TFA, gradient 5-95% MeCN).
Figure imgf000037_0001
Medium pressure liquid chromatography (MPLC) on silica (particle size <63 μm; porosity 60 A; surface area -500 m2/g) was carried out using pre-packed Biotage FLASH™ columns or equivalent, e.g. Thomson SINGLE StEP™, Biotage Isolute™, Teledyne Isco RediSep™, or Silicycle UltraPure silica columns at recommended solvent flow rates and sample loadings. Fraction purity was determined by either TLC or analytical HPLC.
Preparative HPLC was carried out using a gradient of acetonitrile or methanol in 0.1% or 0.2% aqueous TFA, aqueous formic acid or aqueous ammonia solution, using a Phenomenex Gemini™ NX C18 (30 x 100 mm, 5 μm) column, a Waters Sunfire™ Prep C8 (30 x 100 mm, 10 μm) column, a Waters Sunfire™ Prep Cl 8 (30 x 100 mm, 5 μm) column or a Waters XBridge™ C 8 (30 x 100 mm, 5 μm) column as stationary phase at a flow rate of 30 - 35 mL/min, as detailed. Fractions were collected following detection by UV spectroscopy at a wavelength such as 220 or 254 nm. Fraction purity was determined by either TLC or analytical HPLC.
1H NMR spectra were recorded on Bruker Avance 600 (600 MHz), a Bruker DRX 500 (500 MHz) or a Varian Unitylnova 500 MHz, 400 MHz or 300 MHz instrument. Either the central peaks of chloroform-J (CDCI3; 5H 7.27 ppm), dimethylsulfoxide-^ (d6- DMSO; 5H 2.50 ppm) or methanol-^ (CD3OD; 5H 3.31 ppm), or an internal standard of tetramethylsilane (TMS; 5H 0.00 ppm) were used as references. Mass spectra were recorded on an Agilent MSD (+ve and -ve APCI and/or electrospray (e.g. in multimode)) following analytical HPLC.
All other processes were carried out using standard laboratory techniques, e.g. as detailed in 'Experimental Organic Chemistry: Preparative and Microscale' 2nd Ed. (Harwood, L., Moody, C. and Percy, J.), WileyBlackwell, 1998.
The abbreviations or terms used in the examples have the following meanings: g grammes h hour(s) min minute(s) mL millilitres
AIBN azobisisobutyronitrile
CDI 1 , 1 ' -carbonyldiimidazole
DCM dichloromethane
DMF Λ/,Λ/-dimethylformamide
DMSO dimethylsulphoxide
HATU O-(7-azabenzotriazol- 1 -yl)-Λ/,Λ/,Λf yV'-tetramethyluronium hexafluorophosphate
HCl hydrogen chloride / hydrochloric acid
HPLC high performance liquid chromatography
Hunig's base Λ/,Λ/-diisopropylethylamine
IPA isopropanol
MeCN acetonitrile
MeOH methanol
MTBE methyl tert-butyl ether
NBS Λ/-bromosuccinimide
NCS JV-chlorosuccinimide
NMP 1 -methylpyrrolidin-2-one
RT room temperature
SCX strong cation exchange - silica based solid phase extraction with a sulfonic acid sorbent
T3P 2-propanephosphonic acid anhydride
TBAF tetrabutylammonium fluoride
TFA trifluoroacetic acid
THF tetrahydrofuran
Tosic-65 macroporous polymer bound ion exchange resin supplied by Biotage AB.
Triton-B Benzyltrimethylammonium hydroxide tert-Butyl l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride salt was made using Preparation 1 described below. Naming package for title/subtitled compounds:
Struct=Name 9.0.7 from CambridgeSoft Corporation Preparation of Synthetic Intermediates
Preparation 1
tert-Butyl l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate
Figure imgf000039_0001
a) tert-Butyl 4-(aminomethyl)-4-hydroxypiperidine-l-carboxylate
Figure imgf000039_0002
A solution of tert-butyi l-oxa-6-azaspiro[2.5]octane-6-carboxylate (9.6 g) in ammonia solution (7N in methanol, 220 mL) was stirred for 3 days at 200C. The solvent was evaporated under reduced pressure to yield the subtitled compound as a gum which crystallised on standing. Yield 10.4 g.
1H NMR (400 MHz, CD3OD) δ 3.81 - 3.73 (m, 2H), 3.22 - 3.09 (m, 2H), 2.56 (s, 2H), 1.58 - 1.36 (m, 4H), 1.43 (s, 9H). Three exchangeable protons not observed. b) tert-Butyl 3-oxo-l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate
Figure imgf000039_0003
Chloroacetyl chloride (4.88 mL) was added dropwise to a vigorously stirred mixture at O0C of potassium carbonate (17.4 g) in water (78 mL) and tert-butyl 4-(aminomethyl)-4- hydroxypiperidine-1-carboxylate [Preparation 1, step a] (10.4 g) in ethyl acetate (92 mL). After 30 minutes at O0C, the mixture was extracted with ethyl acetate and the organic layer dried, filtered and the solvent evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (200 mL) and added dropwise over 3 hours to a stirred solution under nitrogen and at reflux of potassium tert-butoxidc (IM in tert-butanol, 75 mL) and THF (250 rnL). The mixture was removed from reflux and allowed to stir for 18 hours at room temperature. Most of the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and brine, the aqueous layer was re-extracted with ethyl acetate and the combined organics were dried, filtered and the solvent removed under reduced pressure. The residue was purified by trituration with a mixture of ether (30 mL) and isohexane (20 mL) to give the subtitled compound as a white solid. Yield 8.2 g. 1H NMR (400 MHz, D6-DMSO) δ 7.95 (s, IH), 3.97 (s, 2H), 3.72 - 3.62 (m, 2H), 3.10 (d, J = 6.6 Hz, 2H), 3.05 - 2.93 (m, 2H), 1.77 - 1.69 (m, 2H), 1.53 - 1.43 (m, 2H), 1.40 (s, 9H). c) tert-Buty\ l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate
Figure imgf000040_0001
A solution of tert-butyl 3-oxo-l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate [Preparation 1, step b] (8.2 g) in tetrahydrofuran (100 mL) was treated dropwise with borane tetrahydrofuran complex (IM in THF, 91 mL) and the resultant mixture heated at 55°C for 2 hours. Borane dimethyl sulphide complex (2M in THF, 15.2 mL) was added and the resultant mixture heated at 55°C for 2 hours. The mixture was cooled to room temperature and quenched with methanol and the solvents were evaporated under reduced pressure. The residue was dissolved in methanol (250 mL) and the solution treated with Ni,Λ/2-dimethylethane-l,2-diamine (10 g), the resultant mixture was refluxed for 6 hours, further Ni,Λ/2-dimethylethane-l,2-diamine (3 g) was added and refluxing was continued for 6 hours. The mixture was cooled to room temperature and the solvents evaporated under reduced pressure. The residue was purified by flash silica chromatography, using 1% triethylamine and 5% methanol in dichloromethane as solvent. Fractions containing the product were evaporated to dryness to afford the titled compound as a white solid. Yield 7.4 g.
1H NMR (400 MHz, CDCl3) δ 3.72 (s, 2H), 3.68 - 3.64 (m, 2H), 3.14 (t, J = 20.0 Hz, 2H), 2.87 - 2.81 (m, 2H), 2.68 (s, 2H), 1.97 - 1.88 (m, 2H), 1.46 (s, 9H), 1.44 - 1.36 (m, 2H). One exchangeable proton not observed. Preparation 2
(2-Methylthiazol-4-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride
Figure imgf000041_0001
a) ter/-Butyl 4-(2-methylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate
Figure imgf000041_0002
l-Propanephosphonic acid cyclic anhydride (1.57M in THF, 4.18 rnL) was added to a solution of tert-butyi l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (1.92 g), 2-methylthiazole-4-carboxylic acid (0.94 g) and triethylamine (5.48 mL) in DMF (70 rnL) and the resulting mixture stirred for 16 h. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic solutions were washed with water (2 x 100 mL) and brine (100 mL), dried over magnesium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with ethyl acetate to give the subtitled compound as a clear oil. Yield 2.30 g.
1H NMR (400 MHz, D6-DMSO, 900C) δ 7.95 (s, IH), 3.80-3.45 (m, 8H), 3.18-2.96 (m, 2H), 2.67 (s, 3H), 1.77-1.62 (m, 2H), 1.43-1.31 (m, HH). b) (2-Methylthiazol-4-yl)(l-oxa-4,9-diazaspiro [5.5] undecan-4-yl)methanone hydrochloride
Figure imgf000042_0001
Trifluoroacetic acid (10 niL) was added to a solution of tert-butyi 4-(2-methylthiazole-4- carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate [Preparation 2, step a] (2.3 g) in DCM (50 mL) at O0C and the resulting mixture was stirred for 16 h. The solvent was evaporated in vacuo. Toluene (50 mL) was added and the mixture evaporated in vacuo. The residue was dissolved in methanol (20 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (250 mL) and eluted with ammonia solution (3M in methanol, 150 mL). The eluent was evaporated in vacuo, and the residue dissolved in MeCN (100 mL). HCl (IM in diethyl ether, 10 mL) was added and the solvent was evaporated in vacuo to give the titled compound as a yellow solid. Yield 1.9O g.
1H NMR (400 MHz, D6-DMSO, 900C) δ 9.16 (s, 2H), 7.92 (s, IH), 4.25 (s, 4H), 3.66-3.58 (m, 2H), 3.12-2.90 (m, 4H), 2.69 (s, 3H), 2.01-1.89 (m, 2H), 1.85-1.73 (m, 2H).
Preparation 3
(2-Methylthiazol-4-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate
Figure imgf000042_0002
1-Propanephosphonic acid cyclic anhydride (1.57M in THF, 2.49 mL) was added to a solution of tert-butyi l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (1.0 g), 2-methylthiazole-4-carboxylic acid (0.56 g) and triethylamine (3.26 mL) in DMF (30 mL) and the resulting mixture stirred for 16 hours at room temperature. The reaction was partitioned between water (500 mL) and ethyl acetate (200 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (2 x 150 mL). The combined organic solutions were washed with water (2 x 100 mL), and brine (100 mL), then dried over magnesium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with ethyl acetate. The resulting oil was dissolved in dichloromethane (30 mL) and trifluoroacetic acid (3 mL) was added dropwise. This was then stirred for 1 hour and concentrated in vacuo. The residue was azeotroped twice with toluene (20 mL). The resulting gum was triturated with ether to give the subtitled compound as a white solid. Yield 1.20 g. m/z 282 (M+H)+ (APCI).
1H NMR (300 MHz, D6-DMSO) δ 8.59-8.18 (m, 2H), 8.00 (s, IH), 3.86-3.49 (m, 6H), 3.22-2.86 (m, 4H), 2.69 (s, 3H), 2.00-1.90 (m, 2H), 1.74-1.58 (m, 2H).
Preparation 4
(2-Isopropylthiazol-4-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate
Figure imgf000043_0001
a) tert-Butyl 4-(2-isopropylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate
Figure imgf000043_0002
A solution of 2-isopropylthiazole-4-carboxylic acid (1 g) and tert-butyi l-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (1.71 g) in DMF (30 mL) was cooled in an ice bath and treated with triethylamine (2.44 mL) followed by HATU (2.89 g). The ice bath was removed and the mixture was stirred at 200C for 1 hour. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 70% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 2.0 g.
1H NMR (400 MHz, D6-DMSO, 9O0C) δ 7.93 (s, IH), 3.71 - 3.63 (m, 6H), 3.51 - 3.44 (m,
2H), 3.35 - 3.26 (m, IH), 3.18 - 3.10 (m, 2H), 1.74 - 1.67 (m, 2H), 1.49 - 1.41 (m, 2H),
1.39 (s, 9H), 1.34 (d, J = 7.6 Hz, 6H). b) (2-Isopropylthiazol-4-yl)(l-oxa-4,9-diazaspiro [5.5] undecan-4-yl)methanone trifluoroacetate
Figure imgf000044_0001
A solution of tert-butyl 4-(2-isopropylthiazole-4-carbonyl)-l-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate [Preparation 4, step a] (2.3 g) in a mixture of dichloromethane (40 mL) and trifluoroacetic acid (10 mL) was allowed to stand at 200C for 30 minutes. Toluene (50 mL) was added and the solvents were evaporated, then this process was repeated with more toluene (50 mL). The residue was triturated with ether. The gum was then dissolved in acetonitrile and the solvent evaporated to afford the titled compound. Yield 1.64 g. m/z 310 (M+H)+ (APCI).
Preparation 5 a) (2-Isopropylthiazol-4-yl)(l-oxa-4,9-diazaspiro [5.5] undecan-4-yl)methanone hydrochloride
Figure imgf000044_0002
A solution of 2-isopropylthiazole-4-carboxylic acid (12 g) and tert-butyl l-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate hydrochloride [WuXi PharmaTech] (20 g) in 2- methyltetrahydrofuran (140 mL) was cooled in ice-water and treated with triethylamine (47 mL), followed by T3P (1.6M in THF, 54 mL). The mixture was allowed to warm to RT and was stirred for 1 h. Water (140 mL) was added with stirring, then the phases were separated. The organic phase was washed with water (80 mL), and then concentrated to a volume of (-100 mL) under reduced pressure using a temperature of <30°C. IPA (75 mL) was added, and the mixture was concentrated to a volume of (-100 mL). More IPA (75 mL) was added, and the mixture was again concentrated to a volume of (-100 mL). A solution of hydrogen chloride in IPA (-6M, 81 mL) was added with cooling in ice-water, then the mixture was warmed to 400C and stirred for 3.5 h. The mixture was cooled to RT, diluted with MTBE (34 mL) and stirred for 30 min. The resulting precipitated solid was removed by filtration and dried in a vacuum oven at 55°C overnight to give the titled compound. Yield 20.5 g.
1H NMR (400 MHz, D6-DMSO) δ 8.88 (d, J = 41.0 Hz, 2H), 8.05 (s, 1 H), 3.86 - 3.46 (m, 6 H), 3.32 (quintet, J = 6.7 Hz, 1 H), 3.17 - 3.02 (m, 2 H), 3.01 - 2.85 (m, 2 H), 1.96 (d, J = 14.1 Hz, 2 H), 1.81 - 1.55 (m, 2 H), 1.35 (d, J = 6.9 Hz, 6 H).
Preparation 6
(5-Methylthiophen-2-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate
Figure imgf000045_0001
a) tert-Butyi 4-(5-methylthiophene-2-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate
Figure imgf000045_0002
1-Propanephosphonic acid cyclic anhydride (1.57M in THF, 0.64 mL) was added to a solution of tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride
(WuXi PharmaTech) (0.26 g), S-methylthiophene^-carboxylic acid (0.14 g) and triethylamine (0.84 rnL) in DMF (8 rnL) and the resulting mixture stirred for 16 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic solutions were washed with water (2 x 100 mL) and brine
(100 mL), then dried over magnesium sulphate, filtered and evaporated in vacuo.
Purification was by silica gel chromatography eluting with ethyl acetate :isohexane, 1 : 1 , to give the subtitled compound as a clear oil. Yield 0.32 g.
1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 3.6 Hz, IH), 6.72-6.69 (m, IH), 3.78 - 3.67 (m,
8H), 3.60 - 3.51 (m, 2H), 3.19 - 3.10 (m, 2H), 2.51 (s, 3H), 1.86 - 1.79 (m, 2H), 1.45 (s,
9H). b) (5-Methylthiophen-2-yl)(l-oxa-4,9-diazaspiro [5.5] undecan-4-yl)methanone trifluoroacetate
Figure imgf000046_0001
tert-Butyi 4-(5-methylthiophene-2-carbonyl)- 1 -oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate [Preparation 6, step a] (0.32 g) in DCM (3 mL) was treated with trifluoroacetic acid (1.0 g). After 2 h, the reaction mixture was evaporated in vacuo and azeotroped twice with toluene to yield the titled compound which was used directly. Yield 0.32 g. m/z 281 (M+H)+ (APCI).
Preparation 7
(2-Ethylthiazol-4-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate
Figure imgf000046_0002
a) Propanethioamide
Figure imgf000046_0003
Phosphorus pentasulfide (15.2 g) was added to a suspension of propionamide (20 g) in methyl t-butyl ether (900 rnL) and the mixture stirred for 18 hours. The mixture was filtered through Celite and concentrated in vacuo to afford the subtitled compound as a yellow oil. Yield 15.8 g.
1H NMR (300 MHz, CDCl3) δ 7.59 (s, IH), 6.88 (s, IH), 2.70 (q, J = 7.5 Hz, 2H), 1.32 (t, J = 7.5 Hz, 3H). b) Ethyl 2-ethylthiazole-4-carboxylate
Figure imgf000047_0001
Ethyl 3-bromo-2-oxopropanoate (24.7 mL) was added dropwise over 10 min to a solution of propanethioamide [Preparation 7, step a] (15.8 g) in ethanol (150 mL) at 0-100C under nitrogen. When the addition was complete the mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo, the residue diluted with water and extracted into ethyl acetate (x 3). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by flash silica chromatography, elution gradient 10, 15 and 20% ethyl acetate in isohexane. Fractions containing the product were evaporated to dryness to afford the subtitled compound as a pale green solid. Yield 16.0 g.
1H NMR (400 MHz, CDCl3) δ 8.06 (s, IH), 4.42 (q, J = 7.1 Hz, 2H), 3.10 (q, J = 7.5 Hz, 2H), 1.44 - 1.38 (m, 6H). c) l-Ethylthiazole^-carboxylic acid
Figure imgf000047_0002
Concentrated HCl (75 mL) was added to a suspension of ethyl 2-ethylthiazole-4- carboxylate [Preparation 7, step b] (16 g) in water (75 mL) and the mixture stirred at 1000C for 24 hours. The mixture was cooled and concentrated in vacuo. The residue was triturated with acetone, the solid collected by filtration and dried in vacuo to afford the subtitled compound as a grey solid. Yield 14.4 g. m/z 158 (M+H)+ / 156 (M-H)" (APCI).
1H NMR (400 MHz, D6-DMSO) δ 8.31 (s, IH), 3.01 (q, J = 7.5 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H). One exchangeable proton not observed. d) tert-Butyl 4-(2-ethylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate
Figure imgf000048_0001
T3P (1.6M in THF, 51.3 mL) was added dropwise to a stirred suspension of tert-butyi 1- oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (18.1 g), 2-ethylthiazole-4-carboxylic acid [Preparation 7, step c] (12 g) and triethylamine (52 mL) in DMF (120 mL) under nitrogen, and the mixture stirred at ambient temperature for 20 hours. It was diluted with water and extracted into ethyl acetate (x 3). The combined extracts were washed successively with 10% brine, 30% brine and saturated brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by flash silica chromatography, eluting with ethyl acetate. Fractions containing the product were evaporated to dryness to afford the subtitled compound as a yellow oil. Yield 24.0 g. m/z 340 (M-tBu+H)+ (APCI). e) (2-Ethylthiazol-4-yl)(l-oxa-4,9-diazaspiro [5.5] undecan-4-yl)methanone trifluoroacetate
Figure imgf000048_0002
Prepared by the method of Preparation 6, step b using tert-butyi 4-(2-ethylthiazole-4- carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate [Preparation 7, step d] (24.0 g) in place of tert-butyi 4-(5-methylthiophene-2-carbonyl)-l-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate. Trituration with ether afforded a white solid, which was collected by filtration and dried to give the titled compound. Yield 27.7 g. 1H NMR (400 MHz, D6-DMSO) δ 8.55 (s, IH), 8.39 (s, IH), 8.04 - 8.00 (m, IH), 3.81 - 3.51 (m, 6H), 3.18 - 2.91 (m, 6H), 2.00 - 1.90 (m, 2H), 1.72 - 1.56 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H). Preparation 8
2,2,2-Trifluoro-l-(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate
Figure imgf000049_0001
A solution of trifluoroacetic anhydride (9.6 rnL) in DCM (10 mL) was added dropwise, over a period of 15 minutes, to a stirred solution of triethylamine (15.2 mL) and tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride [WuXi PharmaTech] (9.95 g) in DCM (100 mL) at 00C under nitrogen. The resulting solution was stirred at 00C for 30 minutes. More triethylamine (2.5 mL) was added, followed by more trifluoroacetic anhydride (1.6 mL) in DCM (10 mL), and stirring at O0C was continued for 1 hour. Water (100 mL) was added and the mixture was vigorously stirred for 10 minutes. The organic layer was separated, dried, and the solvent evaporated under reduced pressure. The residue was dissolved in DCM (100 mL) and the solution treated with trifluoroacetic acid (25 mL). This mixture was allowed to stand at 2O0C for 10 minutes and then diluted with toluene (40 mL). The solvents were removed under reduced pressure and the residue azeotroped with more toluene (x 2) to yield the titled compound. Yield 14.0 g. m/z 253 (M+H)+ (APCI).
Preparation 9 2-(Pentan-3-yl)thiazole-4-carboxylic acid
Figure imgf000049_0002
a) 2-Ethylbutanamide
Figure imgf000049_0003
2-Ethylbutanoyl chloride (5 g) was cautiously added dropwise to ice cold 35% aqueous ammonia (50 mL) and the resulting suspension stirred for 1 h. The reaction mixture was extracted with DCM (3 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a white solid. Yield 3.4 g.
1H NMR (400 MHz, D6-DMSO) δ 7.23 (s, IH), 6.71 (s, IH), 1.98 - 1.88 (m, IH), 1.50 - 1.27 (m, 4H), 0.81 (t, J = 7.4 Hz, 6H). b) 2-Ethylbutanethioamide
Figure imgf000050_0001
Prepared by the method of Preparation 7, step a using 2-ethylbutanamide [Preparation 9, step a] (3.4 g) in place of propionamide. Yield 3.8 g. Used directly. c) Ethyl 2-(pentan-3-yl)thiazole-4-carboxylate
Figure imgf000050_0002
Prepared by the method of Preparation 7, step b using 2-ethylbutanethioamide [Preparation 9, step b] (3.8 g) in place of propanethioamide. Yield 2.8 g.
1H NMR (400 MHz, D6-DMSO) δ 8.42 (s, IH), 4.29 (q, J = 7.1 Hz, 2H), 2.99 - 2.89 (m, IH), 1.82 - 1.58 (m, 4H), 1.30 (t, J = 7.0 Hz, 3H), 0.81 (t, J = 7.4 Hz, 6H). d) 2-(Pentan-3-yl)thiazole-4-carboxylic acid
Figure imgf000050_0003
Lithium hydroxide (2.07 g) was added to a solution of ethyl 2-(pentan-3-yl)thiazole-4- carboxylate [Preparation 9, step c] (2.8 g) in a mixture of THF (80 mL) and water (20 mL). The resulting mixture was stirred overnight. The reaction was acidified with concentrated hydrochloric acid (~6 mL) and the THF evaporated. The resulting aqueous mixture was saturated with sodium chloride and extracted with ethyl acetate (3 x 100 mL). The combined organics were dried over sodium sulphate, filtered and evaporated to give the titled compound as a white solid. Yield 2.3 g.
1H NMR (300 MHz, D6-DMSO) δ 12.91 (s, IH), 8.34 (s, IH), 2.98 - 2.86 (m, IH), 1.84 - 1.56 (m, 4H), 0.81 (t, J = 7.3 Hz, 6H). Example 1
(9-(3-(2-Hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5- methylthiophen-2-yl)methanone
Figure imgf000051_0001
a) 2-(3-(Bromomethyl)phenyl)ethanol
Figure imgf000051_0002
Borane dimethyl sulphide complex (2M in THF, 5.78 mL) was added dropwise to a solution of 2-(3-(bromomethyl)phenyl)acetic acid (1.06 g) in THF (10 mL) at O0C and the resulting mixture stirred for 10 min. The reaction was then allowed to warm to room temperature and stirred overnight. Methanol (5 mL) was then added and the mixture concentrated in vacuo. Purification was by silica gel chromatography eluting with isohexane to diethyl ether gradient to give the subtitled compound as a white solid. Yield 1.0 g.
1H NMR (300 MHz, CDCl3) δ 7.34-7.24 (m, 3H), 7.22-7.12 (m, IH), 4.48 (s, 2H), 3.87 (t, J = 6.5 Hz, 2H), 2.87 (t, J = 6.5 Hz, 2H). One exchangeable proton not observed. b) (9-(3-(2-Hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5- methylthiophen-2-yl)methanone
Figure imgf000051_0003
2-(3-(Bromomethyl)phenyl)ethanol [Example 1, step a] (0.136 g) was added to a stirred solution of (5-methylthiophen-2-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Preparation 6] (0.250 g) and triethylamine (0.278 mL) in MeCN (5 mL). After 1 h, the reaction mixture was concentrated and applied to a silica gel column eluting with ethyl acetate :triethylamine, 95:5 to give the titled compound. Yield 0.24 g. m/z 415 (M+H)+ (APCI). 1H NMR (400 MHz, CDCl3) δ 7.28-7.24 (m, 2H), 7.18-7.15 (m, IH), 7.11-7.08 (m, 2H), 6.70-6.67 (m, IH), 3.86 (t, J = 6.6 Hz, 2H), 3.77-3.69 (m, 4H), 3.56 (s, 2H), 3.48 (s, 2H), 2.86 (t, J = 7.0 Hz, 2H), 2.55-2.48 (m, 5H), 2.40-2.32 (m, 2H), 1.89-1.82 (m, 2H), 1.70- 1.50 (2Hs under water peak). One exchangeable proton not observed. Example 2
9-(3-(2-Hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- methylthiazol-4-yl)methanone
Figure imgf000052_0001
(2-Methylthiazol-4-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate
[Preparation 3] (2.2 g) was added to a solution of 2-(3-(bromomethyl)phenyl)ethanol
[Example 1, step a] (1.2 g) and triethylamine (2.3 mL) in acetonitrile (30 mL). The resulting mixture was stirred overnight at RT under nitrogen. The solvent was evaporated and the residue purified by silica gel chromatography, gradient elution 99: 1 :0.1 to 97:3 :0.3
DCM:MeOH:'880' aqueous ammonia to give the titled compound as a clear foam. Yield
1.72 g. m/z 416 (M+H)+ (APCI).
1H NMR (400 MHz, D6-DMSO) δ 7.85 (s, IH), 7.18 (t, J = 7.4 Hz, IH), 7.12-7.04 (m, 3H),
4.24 (t, J = 5.1 Hz, IH), 3.71-3.54 (m, 8H), 3.42 (s, 2H), 2.71 (t, J = 6.9 Hz, 2H), 2.68 (s,
3H), 2.38-2.27 (m, 4H), 1.74-1.64 (m, 2H), 1.57-1.47 (m, 2H).
Example 3
(9-(9-Hydroxynonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4- yl)methanone
Figure imgf000052_0002
9-Bromononan-l-ol (0.29 g) was added to a suspension of (2-methylthiazol-4-yl)(l-oxa- 4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride [Preparation 2] (0.4 g) in a mixture of triethylamine (0.41 mL) and acetonitrile (10 mL). The resulting mixture was stirred for 16 h at 500C. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (30 mL) and saturated sodium bicarbonate solution (30 mL). The layers were separated and the aqueous extracted with ethyl acetate (2 x 30 mL). The combined organic solutions were washed with brine (30 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in methanol (10 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (10 mL) and eluted with ammonia solution (3M in methanol, 100 mL). The eluent was evaporated in vacuo to give the titled compound a yellow oil. Yield 0.32 g. m/z 424 (M+H)+ (APCI).
1H NMR (300 MHz, D6-DMSO) δ 7.95 (s, IH), 4.30 (t, J = 5.1Hz, IH), 3.78-3.44 (m, 8H), 3.42-3.33 (m, 2H), 2.69 (s, 3H), 2.35-2.14 (m, 8H), 1.71-1.57 (m, 2H), 1.55-1.19 (m, 12H).
Example 4
(9-(3-Fluoro-5-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- methylthiazol-4-yl)methanone
Figure imgf000053_0001
a) 2-(3-(Bromomethyl)-5-fluorophenyl)acetic acid
Figure imgf000053_0002
Benzoyl peroxide (0.05 g) was added to a mixture of 2-(3-fluoro-5-methylphenyl)acetic acid (0.518 g) and N-bromosuccinimide (0.6 g) in DCM (10 mL). The reaction was heated at reflux for 1 h. DCM (10 mL) and water (20 mL) were added and the organic phase separated. The organic layer was washed with brine (20 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was triturated with toluene and the resulting white solid removed by filtration. The mother liquors were evaporated in vacuo to give the subtitled compound as a white solid which was used in the next step without further purification. Yield 0.38 g.
1H NMR (400 MHz, D6-DMSO) δ 7.22 - 7.17 (m, 2H), 7.09 - 7.05 (m, IH), 4.68 (s, 2H), 3.61 (s, 2H). One exchangeable proton not observed. b) (9-(3-Fluoro-5-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- methylthiazol-4-yl)methanone
Figure imgf000054_0001
A solution of borane dimethyl sulfide complex (2M in THF, 3.85 mL) was added dropwise to a solution of 2-(3-(bromomethyl)-5-fluorophenyl)acetic acid [Example 4, step a] (0.38 g) in THF (10 mL) at O0C. The resulting mixture was allowed to warm to RT and stirred for 1 h. The reaction was cooled to O0C and methanol (1 mL) was added dropwise until bubbling ceased. The solvent was evaporated in vacuo and the residue redissolved in MeCN (10 mL). (2-Methylthiazol-4-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4- yl)methanone trifluoroacetate [Preparation 3] (0.61 g) was then added followed by triethylamine (0.54 mL) and the resulting mixture stirred for 70 h. The solvent was then evaporated in vacuo. Purification was by silica gel chromatography eluting with 99: 1 :0.1 to 94.5:5:0.5 DCM:methanol:'880' aqueous ammonia gradient. The fractions containing the product were combined and evaporated in vacuo to give the titled compound as a yellow foam. Yield 0.57 g. m/z 434 (M+H)+ (APCI).
1H NMR (400 MHz, D6-DMSO) δ 7.87 (s, IH), 7.30 - 6.75 (m, 3H), 4.47 - 4.20 (m, IH), 3.73 - 3.56 (m, 8H), 3.06 - 2.96 (m, 4H), 2.74 (t, J = 6.5 Hz, 2H), 2.68 (s, 3H), 2.50 - 2.27 (m, 2H), 1.93 - 1.47 (m, 4H). Example 5
(9-(4-Fluoro-3-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone
Figure imgf000054_0002
a) 2-(5-(Bromomethyl)-2-fluorophenyl)ethanol
Figure imgf000054_0003
Dibenzoyl peroxide (1 g) was added to a solution of NBS (10.6 g) and 2-(2-fluoro-5- methylphenyl)acetic acid (10 g) in DCM (250 rnL) and the resulting mixture was heated under reflux for 12 h. The solvent was evaporated and the white solid partitioned between ethyl acetate (250 mL) and 10% sodium chloride solution (500 mL). The layers were separated and the organic phase washed with 10% sodium chloride solution (500 mL), dried over magnesium sulphate, filtered and evaporated. The white solid obtained was redissolved in tetrahydrofuran (150 mL) and cooled in an ice bath. A solution of borane dimethyl sulfide complex (2M in THF, 89 mL) was added cautiously and the mixture was then allowed to warm to RT and stirred overnight. The reaction was cooled in an ice bath and cautiously quenched with methanol. Once bubbling had ceased the solvent was evaporated and the residue was triturated with a 4:1 mixture of isohexane: ether. Purification was by silica gel chromatography eluting with 9:1 to 4:1 ethyl acetate :isohexane gradient to give the subtitled compound as a clear oil. Yield 6.5 g. 1H NMR (300 MHz, CDCl3) δ 7.32 - 7.21 (m, 2H), 7.04 - 6.97 (m, IH), 4.46 (s, 2H), 3.87 (t, J = 6.5 Hz, 2H), 2.93 - 2.87 (m, 2H). One exchangeable proton not observed. b) (9-(4-Fluoro-3-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone
Figure imgf000055_0001
A solution of 2-(5-(bromomethyl)-2-fluorophenyl)ethanol [Example 5, Step a] (5.17 g) in ethanol (20 mL) was added dropwise to a suspension of (2-isopropylthiazol-4-yl)(l-oxa- 4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Preparation 4] (9.4 g) and potassium carbonate (6.75 g) in ethanol (75 mL) and the resulting mixture stirred overnight. The mixture was filtered, the filter cake was washed with ethanol (50 mL), and the filtrate and washings combined and evaporated. The residue was partitioned between water (100 mL) and ethyl acetate (250 mL). The phases were separated and the organic phase washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by flash silica chromatography using 95:5 ethyl acetate :triethylamine as solvent to give the titled compound as a clear oil. Yield 7.9 g. m/z 462 (M+H)+ (APCI). 1H NMR (500 MHz, D6-DMSO) δ 7.90 (s, IH), 7.18 (dd, J = 7.5, 1.8 Hz, IH), 7.12 - 7.08 (m, IH), 6.99 (dd, J = 10.0, 8.4 Hz, IH), 4.34 (t, J = 5.3 Hz, IH), 3.69 - 3.57 (m, 8H), 3.39 (s, 2H), 3.31 (septet, J = 6.9 Hz, IH), 2.74 (t, J = 7.0 Hz, 2H), 2.40 - 2.33 (m, 2H), 2.33 - 2.24 (m, 2H), 1.73 - 1.65 (m, 2H), 1.58 - 1.50 (m, 2H), 1.36 (d, J = 7.0 Hz, 6H). Example 6
(9-(2-Fluoro-5-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone
Figure imgf000056_0001
a) ter/-Butyl(4-fluorophenethoxy)dimethylsilane
Figure imgf000056_0002
te/t-Butyldimethylsilyl chloride (9.03 g) was added portionwise to a stirred solution of 2- (4-fluorophenyl)ethanol (7 g) and imidazole (4.08 g) in DMF (100 niL) at 200C. The reaction mixture was stirred for 3 hours at room temperature and then partitioned between ethyl acetate and brine. The organic layer was washed twice with brine, dried, filtered and the solvent concentrated under reduced pressure. The crude product was purified by flash silica chromatography eluting with 2% ethyl acetate in isohexane. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 11.60 g. 1H NMR (400 MHz, CDCl3) δ 7.18-7.13 (m, 2H), 6.98-6.93 (m, 2H), 3.77 (t, J = 6.9 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 0.86 (s, 9H), -0.03 (s, 6H). b) 5-(2-(ter/-Butyldimethylsilyloxy)ethyl)-2-fluorobenzaldehyde
Figure imgf000056_0003
To a solution of 2,2,6,6-tetramethylpiperidine (10.77 g) in THF (200 mL) at 00C was added over 25 minutes butyllithium (1.6M in hexanes, 48 mL). The mixture was cooled to -78°C and a solution of tert-butyl(4-fluorophenethoxy)dimethylsilane [Example 6, step a] (9.7 g) in THF (50 mL) was added dropwise over 25 minutes. The reaction mixture was stirred at -78°C for 90 minutes. DMF (9.3 mL) was then added dropwise over 10 minutes. The reaction mixture was stirred at 00C for 1 hour and then poured into ice-cold aqueous HCl (0.5M, 500 mL). The mixture was extracted with ethyl acetate and the organic layer washed twice with water, dried, filtered and the solvent concentrated under reduced pressure to give the subtitled compound. Yield 10.00 g.
1H NMR (400 MHz, CDCl3) δ 10.36 (s, IH), 7.72-7.69 (m, IH), 7.48-7.43 (m, IH), 7.11- 7.06 (m, IH), 3.80 (t, J= 6.5 Hz, 2H), 2.83 (t, J= 6.4 Hz, 2H), 0.85 (s, 9H), 0.04 (s, 6H). c) (5-(2-(ter/-Butyldimethylsilyloxy)ethyl)-2-fluorophenyl)methanol
Figure imgf000057_0001
Sodium borohydride (1.33 g) was added portionwise over 30 minutes to a solution at 00C of 5-(2-(fert-butyldimethylsilyloxy)ethyl)-2-fluorobenzaldehyde [Example 6, step b] (9.9 g) in ethanol (120 mL). The reaction mixture was then stirred at room temperature for 30 minutes before being reduced to half the initial volume by concentration under reduced pressure. The residue was partitioned between ethyl acetate and brine, the organic layer was washed with brine, dried, filtered and the solvent concentrated under reduced pressure. The crude product was purified by flash silica chromatography using 12% ethyl acetate in isohexane as solvent. Fractions containing the product were concentrated to dryness to afford the subtitled compound. Yield 7.30 g.
1H NMR (400 MHz, CDCl3) δ 7.26-7.23 (m, IH), 7.13-7.08 (m, IH), 6.98-6.93 (m, IH), 4.73 (d, J = 6.2 Hz, 2H), 3.78 (t, J = 6.9 Hz, 2H), 2.79 (t, J = 6.9 Hz, 2H), 1.71 (t, J = 6.5 Hz, IH), 0.87 (s, 9H), -0.02 (s, 6H). d) l-(9-(5-(2-(^r/-Butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-l-oxa-4,9- diazaspiro [5.5] undecan-4-yl)-2,2,2-trifluoroethanone
Figure imgf000057_0002
Methanesulphonyl chloride (1.3 mL) in DCM (20 mL) was added dropwise to a solution at 00C of (5-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorophenyl)methanol [Example 6, step c] (4.66 g) and triethylamine (2.5 mL) in DCM (100 mL). The mixture was stirred at 00C for 1 hour and then washed with water. The organic layer was dried, filtered and the solvent evaporated under reduced pressure. The resultant intermediate (5.9 g) was added portionwise over 30 minutes to a stirred solution at 200C of 2,2,2-trifluoro-l-(l-oxa-4,9- diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate [Preparation 8] (6 g) and triethylamine (9.1 mL) in acetonitrile (130 mL). The reaction mixture was stirred for 4 hours at 200C. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic layer was dried, filtered and the solvent evaporated under reduced pressure to give the subtitled compound. Yield 8.5 g. m/z 519 (M+H)+ (APCI). e) 2,2,2-Trifluoro-l-(9-(2-fluoro-5-(2-hydroxyethyl)benzyl)-l-oxa-4,9- diazaspiro [5.5] undecan-4-yl)ethanone
Figure imgf000058_0001
TBAF (IM in THF, 16.4 mL) was added to a solution of l-(9-(5-(2-(tert- butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-4-yl)- 2,2,2-trifluoroethanone [Example 6, step d] (8.5 g) in THF (100 mL) and the resultant solution allowed to stand at 200C for 18 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash silica chromatography, using 2% methanol in dichloromethane containing 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 4.2 g. m/z 405 (M+H)+ (APCI). f) 2-(3-(l-Oxa-4,9-diazaspiro [5.5] undecan-9-ylmethyl)-4-fluorophenyl)ethanol
Figure imgf000058_0002
A solution of sodium carbonate (1.4 g) in water (40 mL) was added to a solution of 2,2,2- trifluoro- 1 -(9-(2-fluoro-5-(2-hydroxyethyl)benzyl)- l-oxa-4,9-diazaspiro[5.5]undecan-4- yl)ethanone [Example 6, step e] (4.2 g) in acetonitrile (40 mL). The reaction mixture was stirred at 200C for 20 hours. The acetonitrile was removed under reduced pressure and the remaining aqueous solution was extracted with DCM (x 9). The combined DCM extracts were dried, filtered and the solvent removed under reduced pressure to yield the subtitled compound. Yield 2.7 g. m/z 309 (M+H)+ (APCI). g) (9-(2-Fluoro-5-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro [5.5] undecan-4-yl)(2- isopropylthiazol-4-yl)methanone
Figure imgf000059_0001
HATU (1.1 g) was added in one portion to a cooled solution of 2-(3-(l-oxa-4,9- diazaspiro[5.5]undecan-9-ylmethyl)-4-fluorophenyl)ethanol [Example 6, step fj (0.7 g) and 2-isopropylthiazole-4-carboxylic acid (0.39 g) and triethylamine (0.95 mL) in DMF (15 mL). The reaction mixture was stirred at 200C for 1 hour and then partitioned between ethyl acetate and brine. The organic layer was washed with brine (x 2), dried, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography, using 3% methanol in ethyl acetate containing 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the titled compound. Yield 0.61 g. m/z 462 (M+H)+ (APCI).
1H NMR (400 MHz, D6-DMSO) δ 7.90 (s, IH), 7.19 (d, J = 7.3 Hz, IH), 7.13 - 7.07 (m, IH), 6.97 (t, J = 9.3 Hz, IH), 4.28 - 4.24 (m, IH), 3.71 - 3.55 (m, 6H), 3.46 (s, 2H), 3.35 - 3.26 (m, IH), 3.00 (s, 2H), 2.70 (t, J = 6.7 Hz, 2H), 2.45 - 2.26 (m, 4H), 1.74 - 1.65 (m, 2H), 1.59 - 1.49 (m, 2H), 1.36 (d, J = 7.0 Hz, 6H).
Example 7
(9-(2,4-Difluoro-3-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5- methylthiophen-2-yl)methanone
Figure imgf000059_0002
Dibenzoyl peroxide (0.03 g) was added to a mixture of NBS (0.53 g) and 2-(2,6-difluoro- 3-methylphenyl)acetic acid (0.50 g) in DCM (10 mL). The reaction was heated at reflux for 4 h. DCM (10 mL) and water (20 mL) were added and the organic phase separated. The organic phase was washed with brine (20 mL), dried over sodium sulphate, filtered and evaporated. The residue was redissolved in THF (10 mL) and cooled in an ice bath. A solution of borane dimethyl sulfide complex (2M in THF, 4 mL) was added dropwise and the mixture stirred for 1 h. Methanol (2 mL) was cautiously added dropwise and once bubbling had ceased the solvent was evaporated. The residue was redissolved in acetonitrile (10 mL) and (5-methylthiophen-2-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4- yl)methanone trifluoroacetate [Preparation 6] (0.8 g) was added followed by triethylamine (1.12 mL). The resulting mixture was stirred overnight, evaporated and purified by silica gel chromatography eluting with 99:1 :0.1 to 97:3:0.3 DCM:methanol:'880' aqueous ammonia gradient to give the titled compound as a clear foam. Yield 0.37 g. m/z 451(M+H)+ (APCI).
1H NMR (400 MHz, D6-DMSO) 5 7.28 - 7.17 (m, 2H), 6.97 - 6.91 (m, IH), 6.81 - 6.78 (m, IH), 4.53 - 4.40 (m, IH), 3.69 - 3.43 (m, 10H), 2.79 (t, J = 7.0 Hz, 2H), 2.47 - 2.32 (m, 7H, obscured by solvent peak), 1.77 - 1.65 (m, 2H), 1.55 - 1.43 (m, 2H). Example 8 (9-(4-(2-Hydroxyethyl)phenethyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone
Figure imgf000060_0001
a) 4-(2-Hydroxyethyl)phenethyl methanesulfonate
Figure imgf000060_0002
Methanesulfonyl chloride (0.67 mL) in DCM (2 mL) was added dropwise to a stirred solution at 00C of 2,2'-(l,4-phenylene)diethanol (1.30 g) and triethylamine (1.36 mL) in DCM (30 mL). The reaction mixture was stirred for 1 hour at 00C and then washed with water. The aqueous layer was re-extracted with DCM and the combined organic phases were dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 3% methanol in dichloromethane as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.56 g. 1H NMR (400 MHz, D6-DMSO) δ 7.21 - 7.14 (m, 4H), 4.60 (t, J = 5.3 Hz, IH), 4.38 (t, J = 6.8 Hz, 2H), 3.60 - 3.55 (m, 2H), 3.10 (s, 3H), 2.95 (t, J = 6.8 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H). b) (9-(4-(2-Hydroxyethyl)phenethyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone
Figure imgf000061_0001
Potassium carbonate (0.634 g) was added to a solution of (2-isopropylthiazol-4-yl)(l-oxa- 4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Preparation 4] (0.971 g) and 4-(2-hydroxyethyl)phenethyl methanesulfonate [Example 8, step a] (0.56 g) in acetonitrile (20 mL) and water (0.3 mL). The reaction mixture was heated at 600C for 1 day. The solvent was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The aqueous layer was re-extracted with ethyl acetate and the combined organic phases were dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, using 2% methanol in dichloromethane with 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the titled compound. Yield 0.68 g. m/z 458 (M+H)+ (APCI).
1H NMR (500 MHz, D6-DMSO, 900C) δ 7.91 (s, IH), 7.08 (s, 4H), 4.20 (t, J = 4.7 Hz, IH), 3.70 - 3.58 (m, 8H), 3.35 - 3.27 (m, IH), 2.71 - 2.65 (m, 4H), 2.57 - 2.32 (m, 6H), 1.75 - 1.67 (m, 2H), 1.59 - 1.52 (m, 2H), 1.36 (d, J = 6.8 Hz, 6H). Example 9 a) (9-(3-(2-Hydroxyethyl)phenethyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone
Figure imgf000061_0002
A mixture of (2-isopropylthiazol-4-yl)(l -oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride [Preparation 5] (10 g) and 2-(3-(2-bromoethyl)phenyl)ethanol [Organometallics 2002, 21(20), 4217] (10 g) and potassium carbonate (16 g) in acetonitrile (600 mL) and water (10 mL) was heated at 600C for 36 hours. The solvent was decanted off and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and brine, the aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were dried, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash silica chromatography, using 5% methanol in ethyl acetate containing 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the titled compound. Yield H g. m/z 458 (M+H)+ (APCI).
1H NMR (500 MHz, D6-DMSO 900C) δ 7.91 (s, IH), 7.13 (t, J= 8.5 Hz, IH), 7.05 - 6.98 (m, 3H), 4.20 (t, J= 5.4 Hz, IH), 3.71 - 3.59 (m, 8H), 3.35 - 3.27 (m, IH), 2.73 - 2.64 (m, 4H), 2.55 - 2.33 (m, 6H), 1.74 - 1.66 (m, 2H), 1.58 - 1.51 (m, 2H), 1.36 (d, J= 6.9 Hz, 6H). Example 9a
(9-(3-(2-Hydroxyethyl)phenethyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone tosic acid salt
A solution of (9-(3-(2-hydroxyethyl)phenethyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone (1.12 g, 2.45 mmol) in ethanol (50 mL) was treated with TosicAcid monohydrate (0.466 g, 2.45 mmol) and the solvent was evaporated under reduced pressure. The residue was tritrurated with ether to yield 1.58 g of (9-(3-(2- hydroxyethyl)phenethyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4- yl)methanone tosic acid salt as a white crystalline solid.
IH NMR (400 MHz, DMSO, 900C) δ 9.06 (s, IH), 7.98 (s, IH), 7.50 (d, J = 7.9 Hz, 2H), 7.23 (t, J = 7.4 Hz, IH), 7.15 - 7.03 (m, 5H), 3.77 - 3.59 (m, 8H), 3.50 - 3.26 (m, 5H), 3.18 - 2.88 (m, 4H), 2.72 (t, J = 6.9 Hz, 2H), 2.28 (s, 3H), 2.20 - 2.02 (m, 2H), 1.77 - 1.62 (m, 2H), 1.36 (d, J = 6.8 Hz, 6H). plus 1 exchangeable not observed m/z 458.1 (M+H)+ Example 10
(9-(2-Fluoro-3-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone
Figure imgf000063_0001
a) tert-Butyl(2-fluorophenethoxy)dimethylsilane
Figure imgf000063_0002
A solution of 2-(2-fluorophenyl)ethanol (5.5 g) and imidazole (8.0 g) in DMF (50 niL) was cooled in ice-water, treated with te/t-butyldimethylchlorosilane (6.52 g), then removed from the cooling bath and stirred at room temperature for 3.5 hours. The solution was poured into water and extracted three times with diethyl ether. The combined organic extracts were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and concentrated under reduced pressure to afford the subtitled compound as a colourless oil. Yield 9.9 g.
1H NMR (400 MHz, CDCl3) δ 7.25 - 7.14 (m, 2H), 7.07 - 6.97 (m, 2H), 3.81 (t, J= 7.0 Hz, 2H), 2.87 (t, J= 6.9 Hz, 2H), 0.86 (s, 9H), -0.03 (s, 6H). b) 3-(2-(ter/-Butyldimethylsilyloxy)ethyl)-2-fluorobenzaldehyde
Figure imgf000063_0003
A solution of 2,2,6, 6-tetramethylpiperidine (11.0 g) in anhydrous THF (200 mL) was cooled to -78° and treated with butyllithium (37.5 mL), added steadily over 5 minutes via a syringe. The solution was stirred at -78° for 15 minutes and then treated with a solution of fert-butyl(2-fluorophenethoxy)dimethylsilane [Example 10, step a] (9.9 g) in THF (25 mL), added dropwise over 15 minutes. The solution that was stirred at -78° for 2 hours, then treated with a solution of DMF (9.0 mL) in THF (25 mL), added dropwise over 10 minutes. The solution was stirred at -78° for 1 hour, then the cooling bath was removed and the solution was allowed to warm to room temperature overnight. The reaction mixture was poured into aqueous HCl (0.5M) and extracted three times with ethyl acetate. The combined organic phases were washed three times with water, once with brine, then dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the subtitled compound. Yield 10.1 g.
1H NMR (400 MHz, CDCl3) δ 10.41 (s, IH), 7.79 - 7.74 (m, IH), 7.55 (td, J = 7.4, 1.6
Hz, IH), 7.22 (t, J= 7.6 Hz, IH), 3.88 (t, J= 6.5 Hz, 2H), 2.96 (t, J= 6.6 Hz, 2H), 0.88 (s,
9H), 0.00 (s, 6H). c) (9-(3-(2-(ter/-Butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-l-oxa-4,9- diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone
Figure imgf000064_0001
3-(2-(tert-Butyldimethylsilyloxy)ethyl)-2-fluorobenzaldehyde [Example 10, step b] (4.07 g) was added to (2-isopropylthiazol-4-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4- yl)methanone trifluoroacetate [Preparation 4] (6.10 g) in a mixture of JV-methyl-2- pyrrolidinone (50 mL) and acetic acid (0.83 mL) and stirred for 30 min. Sodium triacetoxyborohydride (4.58 g) was then added and the mixture stirred overnight. The reaction mixture was poured into water (100 mL), the pH was adjusted to 8 using saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with water (3 x 100 mL) and brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purifed by flash silica chromatography using 77.5:17.5:5 isohexane: ethyl acetate :triethylamine as solvent to give the subtitled compound as a clear oil. Yield 5.35 g.
1H NMR (400 MHz, D6-DMSO, 900C) δ 7.96 (s, IH), 7.29 - 7.18 (m, 2H), 7.09 (t, J = 7.4 Hz, IH), 3.85 (t, J = 6.5 Hz, 2H), 3.74 - 3.67 (m, 6H), 3.54 (s, 2H), 3.37 (septet, J = 6.9 Hz, IH), 2.88 - 2.82 (m, 2H), 2.50 - 2.34 (m, 4H), 1.79 - 1.71 (m, 2H), 1.63 - 1.54 (m, 2H), 1.42 (d, J = 6.9 Hz, 6H), 0.87 (s, 9H), 0.00 (s, 6H). d) (9-(2-Fluoro-3-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone
Figure imgf000064_0002
TBAF (IM in THF, 13.9 mL) was added to a solution of (9-(3-(2-(tert- butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone [Example 10, step c] (5.35 g) in THF (50 mL) and the resulting mixture was stirred for 1 h. The solvent was evaporated and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The crude material was purified by flash silica chromatography, elution gradient 4:1 isohexane: ethyl acetate to 100% ethyl acetate to give the titled compound as a clear oil. Yield 3.9O g. m/z 462 (M+H)+ (APCI).
1H NMR (300 MHz, D6-DMSO) δ 7.93 (s, IH), 7.23 - 7.14 (m, 2H), 7.03 (t, J = 7.5 Hz, IH), 4.48 - 4.40 (m, IH), 3.69 - 3.56 (m, 8H), 3.48 (s, 2H), 3.38 - 3.24 (m, IH), 2.75 (t, J = 6.9 Hz, 2H), 2.45 - 2.23 (m, 4H), 1.76 - 1.62 (m, 2H), 1.60 - 1.47 (m, 2H), 1.35 (d, J = 6.9 Hz, 6H). Example 11
(9-(2-Chloro-3-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- ethylthiazol-4-yl)methanone
Figure imgf000065_0001
a) 3-(Bromomethyl)-2-chlorobenzoic acid
Figure imgf000065_0002
Benzoyl peroxide (1.33 g) was added to a suspension of 2-chloro-3-methylbenzoic acid (25 g) and Λ/-bromosuccinimide (28.7 g) in chlorobenzene (250 mL) and the resulting mixture was heated to 85°C for 4 h. The mixture was diluted with ethyl acetate (100 mL) and washed with 10% aqueous brine (3 x 100 mL). The organic layer was dried over magnesium sulphate, filtered and evaporated. The beige solid was recrystallised from ethyl acetate (~75 mL)/isohexane (-250 niL) to give the subtitled compound as a white solid. Yield 25.3 g.
1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.7 Hz, IH), 7.66 (d, J = 7.4 Hz, IH), 7.36 (t, J
= 7.7 Hz, IH), 4.67 (s, 2H). One exchangeable proton not observed. b) 2-Chloro-3-(cyanomethyl)benzoic acid
Figure imgf000066_0001
A solution of 3-(bromomethyl)-2-chlorobenzoic acid [Example 11, step a] (13.2 g) in DMF (150 mL) was treated with a solution of potassium cyanide (7.23 g) in water (50 mL) and the resulting solution was stirred at room temperature overnight. The mixture was diluted with water (200 mL) and carefully acidified with concentrated hydrochloric acid (25 mL), venting any liberated HCN through bleach solution via a stream of nitrogen. After being stirred for 2 hours, the aqueous phase was extracted with ethyl acetate (3 x 250 mL). The combined organic phases were washed with water (3 x 250 mL) and brine (250 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a white solid. Yield 10.3 g.
1H NMR (300 MHz, D6-DMSO) δ 13.54 (s, IH), 7.75 - 7.67 (m, 2H), 7.48 (t, J = 7.7 Hz, IH), 4.16 (s, 2H). c) 3-(Carboxymethyl)-2-chlorobenzoic acid
Figure imgf000066_0002
Concentrated sulfuric acid (60 mL) was added dropwise to ice-cold water (75 mL) and the resulting solution was added to 2-chloro-3-(cyanomethyl)benzoic acid [Example 11, step b] (14 g). The resulting suspension was heated to reflux (165°C) for 30 min during which the starting material dissolved and a new precipitate was observed. The reaction was allowed to cool and was diluted with water (250 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic phases were washed with water (250 mL) and brine (250 mL), then dried over magnesium sulphate and evaporated to give the subtitled compound as a white solid. Yield 13.7 g. 1H NMR (400MHz, D6-DMSO) δ 7.62 (dd, J = 7.7, 1.8 Hz, IH), 7.54 (dd, J = 7.7, 1.8 Hz, IH), 7.37 (t, J = 7.7 Hz, IH), 3.78 (s, 2H). Two exchangeable protons not observed. d) 2-(2-Chloro-3-(hydroxymethyl)phenyl)ethanol
Figure imgf000067_0001
A solution of borane dimethyl sulfide complex (2M in THF, 220 mL) was added portionwise over 5 minutes to a suspension of 3-(carboxymethyl)-2-chlorobenzoic acid [Example 11, step c] (18.9 g) in dry THF (800 mL) at room temperature. The resulting effervescing suspension was stirred at room temperature for 30 minutes, then heated to reflux for 60 minutes, and allowed to cool to room temperature overnight. The mixture was quenched by the portionwise addition of methanol (100 mL) over 15 minutes and stirred until bubbling ceased. Concentrated aqueous HCl (25 mL) was added, the mixture was stirred for 30 min and concentrated under reduced pressure. The gummy residue was partitioned between ethyl acetate (500 mL) and aqueous HCl (2M, 200 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (2 x 300 mL). The combined organic phases were washed with brine (300 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a yellow oil. Yield 17.8 g.
1H NMR (400 MHz, D6-DMSO) δ 7.40 (dd, J = 7.0, 2.2 Hz, IH), 7.29 - 7.21 (m, 2H), 5.34 (t, J = 5.5 Hz, IH), 4.71 (t, J = 4.9 Hz, IH), 4.55 (d, J = 5.1 Hz, 2H), 3.63 - 3.56 (m, 2H), 2.87 (t, J = 7.2 Hz, 2H). e) 2-Chloro-3-(2-hydroxyethyl)benzaldehyde
Figure imgf000067_0002
Manganese (IV) dioxide (43.1 g) was added to a slight suspension of 2-(2-chloro-3- (hydroxymethyl)phenyl)ethanol [Example 11, step d] (18.5 g) in chloroform (500 mL), and the resulting suspension was heated at reflux for 2 h. The reaction mixture was cooled, filtered through Celite and the filter pad washed with DCM (3 x 300 mL). The combined washings and filtrate were evaporated and the residue purified by flash silica chromatography eluting with 3:1 to 1 :1 isohexane: ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a white solid. Yield 12.0 g.
1H NMR (400 MHz, CDCl3) δ 10.55 (s, IH), 10.54 (t, J = 5.6 Hz, IH), 7.83 (dd, J = 7.7,
1.8 Hz, IH), 7.55 (dd, J = 7.4, 1.8 Hz, IH), 7.35 (t, J = 7.6 Hz, IH), 3.94 (q, J = 6.4 Hz,
2H), 3.11 (t, J = 6.5 Hz, 2H). f) (9-(2-Chloro-3-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- ethylthiazol-4-yl)methanone
Figure imgf000068_0001
To a suspension of 2-chloro-3 -(2 -hydroxy ethyl)benzaldehyde [Example 9, step e] (1.5 g) and (2-ethylthiazol-4-yl)(l -oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Preparation 7] (4.25 g) in tetrahydrofuran (50 mL) was added triethylamine (2.5 mL) in one portion. The mixture was stirred for 0.5 h, sodium triacetoxyborohydride (2.58 g) was then added in one portion and the resultant solution was stirred for 2 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate solution (50 mL). The mixture was shaken vigorously for 10 min and the layers were separated. The aqueous phase was extracted with ethyl acetate (100 mL). The combined organic solutions were washed with brine, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash silica chromatography using 95:5 ethyl acetate :triethylamine as solvent. The fractions containing the product were combined and evaporated to give the titled compound as a clear oil. Yield 3.4O g. m/z 464/466 (M+H)+ (APCI).
1H NMR (400 MHz, D6-DMSO, 900C) δ 7.89 (s, IH), 7.33 - 7.28 (m, IH), 7.24 - 7.16 (m, 2H), 4.35 (t, J = 5.4 Hz, IH), 3.68 - 3.60 (m, 8H), 3.55 (s, 2H), 3.02 (q, J = 7.5 Hz, 2H), 2.89 (t, J = 6.9 Hz, 2H), 2.46 - 2.31 (m, 4H), 1.75 - 1.67 (m, 2H), 1.59 - 1.51 (m, 2H), 1.33 (t, J = 7.6 Hz, 3H). Example 12
(9-(2-(4-(Hydroxymethyl)phenoxy)ethyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- methylthiazol-4-yl)methanone
Figure imgf000069_0001
a) [4-(2,2-Diethoxy-ethoxy)-phenyl] -methanol
Figure imgf000069_0002
Caesium carbonate (39.4 g) was added to a solution of 4-hydroxymethyl-phenol (10 g) and 2-bromo-l,l-diethoxy ethane (12.73 rnL) in DMF (200 rnL) and the resulting mixture stirred at 900C for 16 h. The reaction was poured into water (500 mL) and extracted with ethyl acetate (3 x 250 mL). The combined organic solutions were washed with water (250 mL) and brine (250 mL), then dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with an isohexane to diethyl ether gradient to give the subtitled compound as a yellow oil. Yield 9.5 g. 1H NMR (400 MHz, CDCl3) δ 7.29-7.25 (m, 2H), 6.93-6.88 (m, 2H), 4.83 (t, J = 5.2Hz, IH), 4.61 (s, 2H), 4.00 (d, J = 5.2Hz, 2H), 3.81-3.72 (m, 2H), 3.68-3.58 (m, 2H), 1.25 (t, J = 7.0Hz, 6H). One exchangeable proton not observed. b) 2-(4-(Hydroxymethyl)phenoxy)acetaldehyde
Figure imgf000069_0003
Aqueous HCl (2M, 4 mL) was added to a solution of (4-(2,2- diethoxyethoxy)phenyl)methanol [Example 12, step a] (0.9 g) in acetone (20 mL) and the resulting mixture was stirred for 16 h at room temperature. The reaction was concentrated in vacuo and the resulting aqueous solution extracted with ethyl acetate (3 x 20 mL). The combined organic solutions were dried over magnesium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a clear gum, which was used directly in the next step. Yield 0.5O g. c) (9-(2-(4-(Hydroxymethyl)phenoxy)ethyl)-l-oxa-4,9-diazaspiro [5.5] undecan-4-yl)(2- methylthiazol-4-yl)methanone
Figure imgf000070_0001
(2-Methylthiazol-4-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride [Preparation 2] (0.38 g) was added to a solution of 2-(4-
(hydroxymethyl)phenoxy)acetaldehyde [Example 12, step b] (0.17 g) in NMP (10 rnL) and acetic acid (0.06 rnL). The resulting mixture was stirred for 30 min then cooled in an ice bath. Sodium triacetoxyborohydride (0.32 g) was then added and the reaction allowed to warm to room temperature and stirred for 16 h. The reaction was diluted with methanol (30 mL) and applied to a SCX cartridge pre -wetted with methanol. The cartridge was washed with methanol (250 mL) and eluted with ammonia solution (3M in methanol, 150 mL). The eluent was evaporated in vacuo and the residue purified by silica gel chromatography eluting with 95:5 ethyl acetate :triethylamine to give the titled compound as a gum. Yield 0.32 g. m/z 432 (M+H)+ (APCI).
1H NMR (300 MHz, D6-DMSO) δ 7.86 (s, IH), 7.23-7.16 (m, 2H), 6.85 (dt, J = 8.7, 1.1 Hz, 2H), 4.72-4.62 (m, IH), 4.44-4.38 (m, 2H), 4.10-3.99 (m, 2H), 3.66 (d, J = 6.7 Hz, 4H), 3.61-3.55 (m, 2H), 2.71-2.64 (m, 5H), 2.47-2.42 (m, 4H), 1.76-1.64 (m, 2H), 1.59- 1.45 (m, 2H). Example 13
(9-(2-(4-(2-Hydroxyethyl)phenoxy)ethyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- methylthiazol-4-yl)methanone
Figure imgf000071_0001
a) 2-(4-(2,2-Diethoxyethoxy)phenyl)ethanol
Figure imgf000071_0002
Caesium carbonate (28.3 g) was added to a solution of 4-(2-hydroxyethyl)phenol (10 g) and 2-bromo-l,l-diethoxy ethane (11.79 rnL) in DMF (150 rnL). The resulting suspension was heated at 900C for 16 h. The reaction was poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (3 x 200 mL). The combined organic solutions were washed with water (200 mL) and brine (200 mL), then dried over magnesium sulfate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with isohexane to 1 :1 ethyl acetate :isohexane gradient to give the subtitled compound as a yellow oil. Yield 1O g.
1H NMR (300 MHz, CDCl3) δ 7.14 (d, J = 6.9 Hz, 2H), 6.88 (d, J = 6.9 Hz, 2H), 4.83 (t, J = 5.0 Hz, IH), 4.00 (d, J = 5.0 Hz, 2H), 3.87-3.70 (m, 4H), 3.70-3.56 (m, 2H), 2.81 (t, J = 6.4 Hz, 2H), 1.25 (t, J = 6.9 Hz, 6H). One exchangeable proton not observed. b) 2-(4-(2-Hydroxyethyl)phenoxy)acetaldehyde
Figure imgf000071_0003
Concentrated hydrochloric acid (5 mL) was added to a solution of 2-(4-(2,2- diethoxyethoxy)phenyl)ethanol [Example 13, step a] (0.76 g) in 1,4-dioxane (10 mL) and the resulting mixture was stirred for 1 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 rnL). The combined organic solutions were washed with water (50 mL) and brine (50 mL), then dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound, which was used directly.
Yield 0.35 g. c) (9-(2-(4-(2-Hydroxyethyl)phenoxy)ethyl)-l-oxa-4,9-diazaspiro [5.5] undecan-4-yl)(2- methylthiazol-4-yl)methanone
Figure imgf000072_0001
(2-Methylthiazol-4-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride [Preparation 2] (0.63 g) was added to a solution of 2-(4-(2- hydroxyethyl)phenoxy)acetaldehyde [Example 13, step b] (0.541 g) in a mixture of NMP (10 mL) and acetic acid (0.11 mL). The resulting mixture was stirred at room temperature for 30 min then cooled in an ice bath. Sodium triacetoxyborohydride (0.64 g) was then added and the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction was diluted with methanol (30 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (100 mL) and eluted with ammonia solution (3M in methanol, 100 mL). The eluent was evaporated in vacuo and the residue purified by silica gel chromatography, eluting with 95:5 ethyl acetate :triethylamine to give the titled compound as a brown oil. Yield 0.74 g. m/z 446 (M+H)+ (APCI).
1H NMR (300 MHz, D6-DMSO) δ 7.86 (s, IH), 7.09 (d, J = 8.4 Hz, 2H), 6.84-6.77 (m, 2H), 4.24-4.15 (m, IH), 4.02 (t, J = 6.0 Hz, 2H), 3.68-3.54 (m, 8H), 3.00 (s, 2H), 2.71 - 2.61 (m, 5H), 2.51-2.42 (m, 4H), 1.75-1.65 (m, 2H), 1.59-1.45 (m, 2H). Example 14
(2-Ethylthiazol-4-yl)(9-(4-(2-hydroxyethyl)phenethyl)-l-oxa-4,9- diazaspiro [5.5] undecan-4-yl)methanone
Figure imgf000073_0001
A solution of 2-(4-(2-bromoethyl)phenyl)ethanol [Organometallics 2002, 21(20). 4217] (1.71 g) in NMP (5 mL) was added to a suspension of (2-ethylthiazol-4-yl)(l-oxa-4,9- diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Preparation 7] (3.0 g) and cesium carbonate (5.60 g) in NMP (10 mL) and the mixture stirred at 75°C under nitrogen for 4 hours. More 2-(4-(2-bromoethyl)phenyl)ethanol (0.65 g) was added and the mixture stirred at 75°C for 18 hours. The mixture was cooled, diluted with water and extracted into ethyl acetate (x 3). The combined extracts were washed with 10% brine, 30% brine and saturated brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by flash silica chromatography, successively eluted with 50% ethyl acetate in isohexane with 5% triethylamine, then 100% ethyl acetate with 5% triethylamine, then 10% methanol in ethyl acetate with 5% triethylamine. Fractions containing the product were evaporated to dryness to afford the titled compound as a yellow oil. Yield 1.90 g. m/z 444 (M+H)+ (APCI). Example 15
(9-(2-Fluoro-3-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- (pentan-3-yl)thiazol-4-yl)methanone
Figure imgf000073_0002
a) 2-(3-(l-Oxa-4,9-diazaspiro [5.5] undecan-9-ylmethyl)-2-fluorophenyl)ethanol
Figure imgf000073_0003
3-(2-(tert-Butyldimethylsilyloxy)ethyl)-2-fluorobenzaldehyde [Example 10, Step b] (5.0 g) was added to a solution of 2,2,2-trifluoro-l-(l-oxa-4,9-diazaspiro[5.5]undecan-4- yl)ethanone trifluoroacetate [Preparation 8] (9.3 g) and acetic acid (1.0 mL) in JV-methyl-2- pyrrolidinone (50 mL). The resulting mixture was stirred for 15 min, then cooled in an ice bath. Sodium triacetoxyborohydride (5.64 g) was then added and the mixture was stirred overnight. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution:brine (1 :5) and extracted four times with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to afford an oil. The oil was dissolved in THF (100 mL) and treated with TBAF (IM in THF, 18.0 mL). The resulting solution was stirred at room temperature for 50 minutes, then more TBAF (IM in THF, 18.0 mL) was added and the mixture was stirred for a further 100 minutes. The solution was then concentrated in vacuo to afford an oil. The oil was dissolved in methanol (100 mL), the solution was treated with '880' aqueous ammonia (20 mL), stirred at room temperature for 50 minutes, then concentrated in vacuo to give an oil. The oil was dissolved in methanol and concentrated onto flash silica in vacuo. The resulting powder was purified by flash chromatography on silica eluted with '880' aqueous ammonia:methanol:dichloromethane (1 :10:89) to afford the subtitled compound as a yellow oil. Yield 5.8 g, 60% pure. Used crude, m/z 309 (M+H)+ (APCI). b) (9-(2-Fluoro-3-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- (pentan-3-yl)thiazol-4-yl)methanone
Figure imgf000074_0001
HATU (0.35 g) was added to a colourless solution of 2-(3-(l-oxa-4,9- diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol [Example 15, step a] (0.364 g), 2-(pentan-3-yl)thiazole-4-carboxylic acid [Preparation 9] (0.141 g) and triethylamine (0.30 mL) in DMF (10 mL), pre-cooled in ice-water. The resulting yellow mixture was stirred in ice-water for 1 hour, then at room temperature for 1 hour. The solution was poured into a mixture of water and brine and extracted twice with ethyl acetate. The combined organic extracts were washed three times with water, once with brine, then dried (MgSO4), filtered and concentrated onto flash silica in vacuo. The resulting powder was purified by flash chromatography on silica eluted with triethylamine methanol :dichloromethane (1 :2:97) to afford the titled compound. Yield
0.324 g. m/z 490 (M+H)+ (APCI).
1H NMR (400 MHz, DMSO) δ 7.93 (s, IH), 7.22 - 7.14 (m, 2H), 7.03 (t, J = 7.6 Hz, IH),
4.39 - 4.32 (m, IH), 3.69 - 3.58 (m, 6H), 3.52 - 3.46 (m, 2H), 2.97 - 2.90 (m, IH), 2.75
(t, J = 7.3 Hz, 2H), 2.70 (s, 2H), 2.46 - 2.29 (m, 4H), 1.82 - 1.66 (m, 6H), 1.58 - 1.47 (m,
2H), 0.85 (t, J = 7.3 Hz, 6H).
Example 16
(9-(2-Chloro-3-(2-hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone
Figure imgf000075_0001
Prepared by the method of Example 11, step fusing (2-isopropylthiazol-4-yl)(l-oxa-4,9- diazaspiro[5.5]undecan-4-yl)methanone hydrochloride [Preparation 5] (1.37 g) in place of (2-ethylthiazol-4-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate, and 2-methyltetrahydrofuran (50 mL) in place of tetrahydrofuran. Yield 1.00 g. m/z 478/480 (M+H)+ (APCI).
1H NMR (400 MHz, D6-DMSO 900C) δ 7.91 (d, J = 1.3 Hz, IH), 7.30 (d, J = 7.2 Hz, IH), 7.24 - 7.16 (m, 2H), 4.36 (t, J = 5.1 Hz, IH), 3.73 - 3.59 (m, 8H), 3.55 (s, 2H), 3.32 (septet, J = 6.8 Hz, IH), 2.89 (t, J = 7.0 Hz, 2H), 2.46 - 2.40 (m, IH), 2.40 - 2.28 (m, IH), 2.17 (t, J = 8.1 Hz, IH), 1.91 (quintet, J = 7.5 Hz, IH), 1.77 - 1.65 (m, 2H), 1.62 - 1.50 (m, 2H), 1.36 (d, J = 6.5 Hz, 6H). Example 17
(9-(2-(5-(2-Hydroxyethyl)thiophen-3-yl)ethyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4- yl)(2-isopropylthiazol-4-yl)methanone
Figure imgf000075_0002
a) Mixture of 4-(2-(ter^butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde with 3- (2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde
Figure imgf000076_0001
Butyllithium (36.1 niL) was added dropwise to stirred solution of ter£-butyldimethyl(2- (thiophen-3-yl)ethoxy)silane [J. Med. Chem. 2000, 43(8). 1508] (10.0 g) in THF (200 niL) cooled to -78°C. After the addition the reaction mixture was stirred in an ice bath for Ih and then cooled to -78°C. DMF (31.9 mL) was added dropwise over 5 min, and after a further 10 min the cooling bath was removed. After Ih, the reaction mixture was partitioned between water and ethyl acetate and the ethyl acetate solution was washed twice with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. Purification by silica gel chromatography eluting with ethyl acetate:isohexane, 1 :20, gave a 5:1 mixture of 4-(2-(tert- butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde and 3 -(2-(tert- butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde by 1H NMR as an oil. Yield 8.1 g. 4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde: 1H NMR (400 MHz, CDCl3) δ 9.93 (d, J = 1.2 Hz, IH), 7.71 (d, J = 1.5 Hz, IH), 7.52 (s, IH), 3.92 - 3.84 (m, 2H), 2.91 (t, J = 6.5 Hz, 2H), 0.92 (s, 9H), 0.04 (s, 6H). 3-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde:
1H NMR (400 MHz, CDCl3) δ 10.08 (s, IH), 7.69 (d, J = 5.0 Hz, IH), 7.09 (d, J = 5.0 Hz, IH), 3.92 - 3.84 (m, 2H), 3.22 (t, J = 6.5 Hz, 2H), 0.89 (s, 9H), -0.01 (s, 6H). b) (4-(2-(ter/-Butyldimethylsilyloxy)ethyl)thiophen-2-yl)methanol
Figure imgf000076_0002
Sodium borohydride (1.40 g) was added portionwise to a stirred solution at 00C of 4-(2- (tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde [Example 17, Step a] (10 g) in ethanol (70 mL). The reaction mixture was stirred for 1 hour at 00C and then partitioned between ethyl acetate and aqueous brine and separated. The organic layer was dried, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 12% ethyl acetate in isohexane as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 6.00 g.
1H NMR (400 MHz, D6-DMSO) δ 7.04 (s, IH), 6.82 (s, IH), 5.35 (t, J = 5.6 Hz, IH),
4.55 (d, J = 5.6 Hz, 2H), 3.73 (t, J = 7.0 Hz, 2H), 2.69 (t, J = 6.9 Hz, 2H), 0.85 (s, 9H),
0.00 (s, 6H). c) 2-(4-(2-(tert-Butyldimethylsilyloxy)ethyl)thiophen-2-yl)acetonitrile
Figure imgf000077_0001
Triphenylphosphine (7.16 g) followed by carbon tetrabromide (8.62 g) were added in one portion to (4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)methanol [Example 17, Step b] (6.00 g) in DCM (50 mL) at 00C under nitrogen. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was cooled to O0C and treated with tetraethylammonium cyanide (4.92 g), added in one portion. The mixture was diluted further with dichloromethane (20 mL) and stirred at room temperature for 40 minutes. The reaction mixture was partitioned between dichloromethane and aqueous brine, the organic layer was separated, dried over sodium sulphate and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% ethyl acetate in isohexane. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 4.20 g.
1H NMR (400 MHz, CDCl3) δ 6.93 (s, IH), 6.92 (s, IH), 3.86 (s, 2H), 3.78 (t, J = 6.7 Hz, 2H), 2.78 (t, J = 6.7 Hz, 2H), 0.88 (s, 9H), 0.00 (s, 6H). d) 2-(4-(2-Hydroxyethyl)thiophen-2-yl)acetic acid
Figure imgf000077_0002
A solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)acetonitrile [Example 17, step c] (4.20 g) dissolved in ethanol (30 mL) was added to a stirred solution of potassium hydroxide (1.67 g) in water (30 mL). The resulting mixture was stirred at 1000C for 3 hours. The mixture was partitioned between aqueous brine and ethyl acetate, and the phases separated. The aqueous layer was cooled with ice and acidified by dropwise addition of concentrated hydrochloric acid. The aqueous layer was then extracted with ethyl acetate (x 2), the combined organic phases were washed with aqueous brine, dried over sodium sulphate and the solvent evaporated under reduced pressure to give a yellow solid which was triturated with ether (20 rnL) to give the subtitled compound. Yield 2.33 g.
1H NMR (400 MHz, D6-DMSO) δ 12.46 (s, IH), 7.00 (s, IH), 6.81 (s, IH), 4.61 (t, J =
4.9 Hz, IH), 3.73 (s, 2H), 3.60 - 3.54 (m, 2H), 2.66 (t, J = 7.0 Hz, 2H). e) 2-(4-(2-(ter/-Butyldimethylsilyloxy)ethyl)thiophen-2-yl)ethanol
Figure imgf000078_0001
te/t-Butyldimethylsilyl chloride (2.21 g) was added portionwise to a mixture of imidazole (1.00 g) and 2-(4-(2-hydroxyethyl)thiophen-2-yl)acetic acid [Example 17, step d] (1.3 g) in DMF (15 mL) at 200C over a period of 20 minutes. The resulting solution was stirred at 200C for 1 hour. The reaction mixture was diluted with THF (15 mL), cooled in ice-water, and treated with a solution of potassium carbonate (1.35 g) in water (15 mL). This mixture was stirred at O0C for 20 minutes. The mixture was partitioned between ethyl acetate and aqueous brine, and the phases separated. The organic layer was washed twice with aqueous brine, dried, filtered and the solvent removed under reduced pressure. The residue was dissolved in THF (40 mL), cooled in an ice bath and treated with borane tetrahydrofuran complex (IM in THF, 21 mL), added dropwise. The resultant solution was stirred at 2O0C for 2 hours. The reaction mixture was quenched by dropwise addition of methanol (10 mL) and the solvents were removed under reduced pressure. The crude product was purified by flash silica chromatography using 17% ethyl acetate in isohexane as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 1.25 g.
1H NMR (400 MHz, D6-DMSO) δ 6.94 (s, IH), 6.75 (s, IH), 4.75 (t, J = 5.3 Hz, IH), 3.74 (t, J = 6.9 Hz, 2H), 3.62 - 3.56 (m, 2H), 2.86 (t, J = 6.9 Hz, 2H), 2.69 (t, J = 6.8 Hz, 2H), 0.85 (s, 9H), 0.00 (s, 6H). f) 2-(4-(2-(^r/-Butyldimethylsilyloxy)ethyl)thiophen-2-yl)ethyl acetate
Figure imgf000078_0002
A solution of acetyl chloride (0.36 mL) in dry THF (3 mL) was added dropwise over 10 minutes to a stirred solution at 200C of 2-(4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen- 2-yl)ethanol [Example 17, Step e] (1.10 g) and triethylamine (1.18 niL) in dry THF (30 mL). The mixture was stirred at 200C for 20 minutes and then partitioned between ethyl acetate and brine. The organic layer was dried, filtered and the solvent evaporated under reduced pressure to give the subtitled compound. Yield 1.20 g.
1H NMR (400 MHz, CDCl3) δ 6.81 (s, IH), 6.72 (s, IH), 4.27 (t, J = 6.9 Hz, 2H), 3.78 (t,
J = 6.9 Hz, 2H), 3.09 (t, J = 6.8 Hz, 2H), 2.77 (t, J = 6.9 Hz, 2H), 2.06 (s, 3H), 0.88 (s,
9H), 0.00 (s, 6H). g) 2-(4-(2-Hydroxyethyl)thiophen-2-yl)ethyl acetate
Figure imgf000079_0001
TBAF (IM in THF, 3.65 mL) was added dropwise to a solution of 2-(4-(2-(tert- butyldimethylsilyloxy)ethyl)thiophen-2-yl)ethyl acetate [Example 17, Step f] (1.2 g) in dry THF (30 mL). This solution was allowed to stand at 200C for 1 hour, then the solvents were evaporated under reduced pressure and the residue was purified by flash silica chromatography, using 40% ethyl acetate in isohexane as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.63 g. 1H NMR (400 MHz, D6-DMSO) δ 6.97 (s, IH), 6.80 (s, IH), 4.60 (t, J = 5.3 Hz, IH), 4.17 (t, J = 6.7 Hz, 2H), 3.60 - 3.54 (m, 2H), 3.04 (t, J = 6.5 Hz, 2H), 2.65 (t, J = 7.0 Hz, 2H), 2.01 (s, 3H). h) 2-(4-(2-(Methylsulfonyloxy)ethyl)thiophen-2-yl)ethyl acetate
Figure imgf000079_0002
A solution of 2-(4-(2-hydroxyethyl)thiophen-2-yl)ethyl acetate [Example 17, Step g] (0.6 g) and triethylamine (0.47 mL) in DCM (30 mL) at 00C was treated dropwise over 20 minutes with a solution of methanesulphonyl chloride (0.24 mL) in DCM (3 mL). The mixture was stirred at 200C for 1 hour and then washed with water. The organic layer was dried, filtered and the solvent evaporated under reduced pressure to afford the titled compound. Yield 0.80 g.
1H NMR (500 MHz, CDCl3) δ 6.91 (s, IH), 6.74 (s, IH), 4.40 (t, J = 6.7 Hz, 2H), 4.27 (t, J = 6.7 Hz, 2H), 3.11 (t, J = 6.5 Hz, 2H), 3.02 (t, J = 6.8 Hz, 2H), 2.91 (s, 3H), 2.07 (s, 3H). i) 2-(4-(2-(4-(2-Isopropylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)ethyl)thiophen-2-yl)ethyl acetate
Figure imgf000080_0001
Prepared by the method of Example 8, step b using the hydrochloride salt of (2- isopropylthiazol-4-yl)(l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone [Preparation 5] (1 g) in place of its trifluoroacetate salt, and 2-(4-(2-(methylsulfonyloxy)ethyl)thiophen-2- yl)ethyl acetate [Example 17, Step h] (0.8 g) in place of 4-(2-hydroxyethyl)phenethyl methanesulfonate. Yield 1.0 g. m/z 506 (M+H)+ (APCI). j) (9-(2-(5-(2-Hydroxyethyl)thiophen-3-yl)ethyl)-l-oxa-4,9-diazaspiro [5.5] undecan-4- yl)(2-isopropylthiazol-4-yl)methanone
Figure imgf000080_0002
Aqueous sodium hydroxide (IM, 4.9 mL) was added to a solution of 2-(4-(2-(4-(2- isopropylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)thiophen-2- yl)ethyl acetate [Example 17, Step i] (1.0 g) in methanol (20 mL) and the resulting mixture was stirred for 1 hour at 200C. The mixture was partitioned between ethyl acetate and brine and separated. The organic phase was dried, filtered and the solvent evaporated under reduced pressure to afford the titled compound. Yield 0.92 g. m/z 464 (M+H)+ (APCI).
1H NMR (400 MHz, D6-DMSO, 900C) δ 7.91 (s, IH), 6.86 (s, IH), 6.70 (s, IH), 4.39 (t, J = 5.3 Hz, IH), 3.70 - 3.58 (m, 8H), 3.35 - 3.27 (m, IH), 2.86 (t, J = 6.8 Hz, 2H), 2.63 (t, J = 7.7 Hz, 2H), 2.52 - 2.30 (m, 6H), 1.73 - 1.65 (m, 2H), 1.58 - 1.50 (m, 2H), 1.36 (d, J = 6.9 Hz, 6H). Example 18
3-(3-(2-(4-(2-Isopropylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)ethyl)phenethoxy)propanoic acid
Figure imgf000081_0001
a) ter/-Butyl 3-(3-(2-(4-(2-isopropylthiazole-4-carbonyl)-l-oxa-4,9- diazaspiro [5.5] undecan-9-yl)ethyl)phenethoxy)propanoate
Figure imgf000081_0002
(9-(3-(2-Hydroxyethyl)phenethyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone [Example 9] (2.4 g) was dissolved in acetonitrile (2 niL) and tert-butyi acrylate (1.7 niL) added, followed by benzyltrimethylammonium hydroxide (40% in water, 0.72 rnL). The mixture was stirred at ambient temperature for 3 hours. The volatiles were removed under reduced pressure and the residue purified by flash silica chromatography eluting with 3% methanol in dichloromethane containing 1% '880' aqueous ammonia to afford the subtitled compound Yield 2.7 g. m/z 586 (M+H)+ (APCI). b) 3-(3-(2-(4-(2-Isopropylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)ethyl)phenethoxy)propanoic acid
Figure imgf000081_0003
tert-Butyi 3-(3-(2-(4-(2-isopropylthiazole-4-carbonyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan- 9-yl)ethyl)phenethoxy)propanoate [Example 18, step a] (0.70 g) was stirred in dichloromethane (8 mL) and trifluoroacetic acid (2 mL) was added. The solution was stirred for 18 hours, then the volatiles were removed under reduced pressure to afford the titled compound. Yield 1.0 g. m/z 530 (M+H)+ (APCI). Example 19
3-(4-(2-(4-(2-Isopropylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)ethyl)phenethoxy)propanoic acid
Figure imgf000082_0001
a) ter/-Butyl 3-(4-(2-(4-(2-isopropylthiazole-4-carbonyl)-l-oxa-4,9 diazaspiro [5.5] undecan-9-yl)ethyl)phenethoxy)propanoate
Figure imgf000082_0002
Benzyltrimethylammonium hydroxide (40% in methanol, 0.031 mL) was added to a solution of (9-(4-(2-hydroxyethyl)phenethyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2- isopropylthiazol-4-yl)methanone [Example 8] (0.62 g) in toluene (20 mL). The solvent was removed under reduced pressure and the residue azeotroped with toluene. The resultant liquid, which was just mobile with traces of toluene, was treated dropwise with tert-butyi acrylate (0.225 g). The reaction mixture was stirred at 200C for 18 hours. The mixture was purified by flash silica chromatography using 2% methanol in dichloromethane with 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.550 g. m/z 586 (M+H)+ (APCI). b) 3-(4-(2-(4-(2-Isopropylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)ethyl)phenethoxy)propanoic acid
Figure imgf000082_0003
Trifluoroacetic acid (10 mL) was added to a solution o 3-(κ4-(2-(4-(2- isopropylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)ethyl)phenethoxy)propanoate [Example 19, step a] (0.55 g) in DCM (20 mL) and the resultant solution allowed to stand at 200C for 1 hour. Toluene (30 mL) was added and the solvents were evaporated under reduced pressure. The residue was azeotroped with acetonitrile (x 2) to yield the titled compound. Yield 0.60 g. m/z 530 (M+H)+ (APCI). Example 20
3-(4-(2-(4-(2-Ethylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)ethyl)phenethoxy)propanoic acid
Figure imgf000083_0001
a) /er/-Butyl 3-(4-(2-(4-(2-ethylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan- 9-yl)ethyl)phenethoxy)propanoate
Figure imgf000083_0002
Benzyltrimethylammonium hydroxide (40% in water, 0.51 mL) was added to a solution of (2-ethylthiazol-4-yl)(9-(4-(2-hydroxyethyl)phenethyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan- 4-yl)methanone [Example 14] (1.9 g) and tert-butyl acrylate (1.32 mL) in acetonitrile (1.5 mL) and the mixture stirred at ambient temperature for 4 hours. The mixture was concentrated in vacuo and the crude product purified by flash silica chromatography, elution gradient 50 to 75% ethyl acetate in isohexane with 5% triethylamine. Fractions containing the product were evaporated to dryness to afford the subtitled compound as a colourless oil. Yield 2.19 g. m/z 572 (M+H)+ (APCI). b) 3-(4-(2-(4-(2-Ethylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)ethyl)phenethoxy)propanoic acid
Figure imgf000083_0003
Prepared by the method of Example 19, step b using tert-butyl 3-(4-(2-(4-(2-ethylthiazole-
4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoate
[Example 20, step a] (2.2 g) in place of tert-butyl 3-(4-(2-(4-(2-isopropylthiazole-4- carbonyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoate. Yield
3.36 g. m/z 516 (M+H)+ (APCI).
1H NMR (400 MHz, CDCl3) δ 7.90 (s, IH), 7.13 (dd, J = 29.9, 8.1 Hz, 4H), 3.97 - 3.92 (m,
IH), 3.82 - 3.77 (m, 3H), 3.74 - 3.67 (m, 4H), 3.64 - 3.56 (m, IH), 3.35 - 3.27 (m, IH),
3.10 - 3.00 (m, 6H), 2.85 (t, J = 6.5 Hz, 2H), 2.61 - 2.55 (m, 2H), 2.21 - 2.13 (m, 2H),
2.03 - 1.92 (m, 6H), 1.45 - 1.34 (m, 3H). One exchangeable proton not observed.
Example 21
3-(2-Fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-
9-yl)methyl)phenethoxy)propanoic acid
Figure imgf000084_0001
a) tert-Butyl 3-(2-fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-l-oxa-4,9- diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate
Figure imgf000084_0002
Prepared by the method of Example 18, step a using (9-(2-fluoro-3-(2- hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4- yl)methanone [Example 10] (3.85 g) in place of (9-(3 -(2 -hydroxy ethyl)phenethyl)- 1-oxa- 4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone. The crude product was purified by flash silica chromatography, elution gradient 1 :1 ethyl acetate :isohexane with 5% triethylamine to 95:5 ethyl acetate:triethylamine. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 3.95 g. m/z 590 (M+H)+ (APCI). b) 3-(2-Fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-l-oxa-4,9- diazaspiro [5.5] undecan-9-yl)methyl)phenethoxy)propanoic acid
Figure imgf000085_0001
TFA (10 mL) was cautiously added to a solution of tert-butyi 3-(2-fluoro-3-((4-(2- isopropylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)methyl)phenethoxy)propanoate [Example 21, step a] (3.95 g) in DCM (40 mL). The resulting mixture was stirred for 2 h. The solvent was evaporated and the residue azeotroped twice with acetonitrile. The residue was dissolved in freshly distilled 2- methyltetrahydrofuran (100 mL) and washed 3 times with a mixture of brine and saturated sodium bicarbonate solution (10:1, 100 mL). The organic phase was dried over sodium sulphate, filtered and evaporated. The residue was azeotroped 3 times with isohexane to give the titled compound as a white foam. Yield 2.92 g. m/z 534 (M+H)+ (APCI).
1H NMR (300 MHz, D6-DMSO) δ 8.00 (s, IH), 7.58 - 7.01 (m, 3H), 3.75 - 3.54 (m, 12H), 3.42 - 3.25 (m, 5H), 2.83 (t, J = 6.6 Hz, 2H), 2.42 (t, J = 6.3 Hz, 2H), 1.87 - 1.47 (m, 4H), 1.34 (d, J = 6.9 Hz, 6H). One exchangeable proton not observed. Example 22
3-(2-Chloro-3-((4-(2-isopropylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan- 9-yl)methyl)phenethoxy)propanoic acid
Figure imgf000085_0002
a) ter/-Butyl 3-(2-chloro-3-((4-(2-isopropylthiazole-4-carbonyl)-l-oxa-4,9- diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate
Figure imgf000085_0003
Prepared by the method of Example 19, step a using (9-(2-chloro-3-(2- hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4- yl)methanone [Example 16] (1.0 g) in place of (9-(4-(2 -hydroxy ethyl)phenethyl)-l-oxa-
4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone. Yield 0.93 g. m/z 606 M+ (APCI). b) 3-(2-chloro-3-((4-(2-isopropylthiazole-4-carbonyl)-l-oxa-4,9- diazaspiro [5.5] undecan-9-yl)methyl)phenethoxy)propanoic acid
Figure imgf000086_0001
Prepared by the method of Example 21, step b using tert-butyi 3-(2-chloro-3-((4-(2- isopropylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)methyl)phenethoxy)propanoate [Example 22, step a] (0.93 g) in place of tert-butyl 3-(2- fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-9- yl)methyl)phenethoxy)propanoate. Yield 0.76 g. m/z 550 M+ (APCI).
1H NMR (400 MHz, D6-DMSO) δ 7.94 (s, IH), 7.51 (ddd, J = 20.1, 7.6, 1.6 Hz, IH), 7.36 (t, J = 7.6 Hz, IH), 7.26 - 7.08 (m, IH), 4.47 (s, 2H), 3.76 - 3.60 (m, 10H), 3.37 - 3.13 (m, 5H), 3.00 (t, J = 6.8 Hz, 2H), 2.42 (t, J = 6.3 Hz, 2H), 2.11 - 1.96 (m, 2H), 1.88 - 1.67 (m, 2H), 1.35 (d, J = 7.3 Hz, 6H). One exchangeable proton not observed. Example 23
3-(2-Chloro-3-((4-(2-ethylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)methyl)phenethoxy)propanoic acid
Figure imgf000086_0002
a) ter/-Butyl 3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-l-oxa-4,9- diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate
Figure imgf000086_0003
Triton-B (40% in water, 0.94 rnL) was added to a solution of (9-(2-chloro-3-(2- hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-ethylthiazol-4- yl)methanone [Example 11] (3.2 g) and tert-butyi acrylate (1.5 mL) in acetonitrile (1 rnL) and the resulting mixture stirred overnight at RT. The solvent was evaporated and the residue was purified by flash silica chromatography, elution gradient 1 : 1 :0.05 ethyl acetate :isohexane:triethylamine to 95:5 ethyl acetate :triethylamine to give the subtitled compound as a clear oil. Yield 3.2 g. m/z 592 M+ (APCI). b) 3-(2-Chloro-3-((4-(2-ethylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)methyl)phenethoxy)propanoic acid
Figure imgf000087_0001
TFA (10 mL) was added to a solution of tert-butyl 3-(2-chloro-3-((4-(2-ethylthiazole-4- carbonyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate [Example 23, step a] (3.1 g) in DCM (30 mL) and the resulting mixture stirred for 2 h, then evaporated. The residue was partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate solution (50 mL). The phases were separated and the aqueous phase was washed with more ethyl acetate (2 x 100 mL). The aqueous phase was then acidified with acetic acid and extracted with ethyl acetate (3 x 100 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give the titled compound as a white foam. Yield 2.7 g. m/z 536 M+ (APCI).
1H NMR (400 MHz, D6-DMSO, 900C) δ 7.92 (s, IH), 7.60 - 7.53 (m, IH), 7.44 - 7.39 (m, IH), 7.32 (t, J = 7.6 Hz, IH), 3.76 - 3.56 (m, 12H), 3.12 - 2.92 (m, 8H), 2.42 (t, J = 6.4 Hz, 2H), 2.01 - 1.73 (m, 4H), 1.33 (t, J = 7.6 Hz, 3H). One exchangeable proton not observed. Example 24
(9-(4-Chlorobenzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4- yl)methanone hydrochloride salt
Figure imgf000088_0001
To a stirred solution of 4-chlorobenzaldehyde (0.17 g) and (2-methylthiazol-4-yl)(l-oxa- 4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride [Preparation 2] (0.28 g) in NMP (2 mL) was added sodium triacetoxyborohydride (0.32 g) and the reaction was stirred overnight. The reaction was diluted with methanol (2 mL) and the mixture was passed through a SCX column flushing with methanol. The product was eluted with ammonia solution (7N in methanol) and the resulting residue after concentration was purified by chromatography on silica gel eluting with 1-5% (0.7N ammonia in methanol) in dichloromethane. Fractions containing the product were concentrated and the residue was dissolved in diethyl ether (5 mL), treated with HCl (4N in 1,4-dioxane, 2 mL), and the resulting white solid removed by filtration to afford the titled compound. Yield 0.33 g. m/z 406 (M+H)+ (APCI).
1H NMR (300 MHz, CD3OD) δ 7.90 (s, IH), 7.64 (d, 2H), 7.49 (d, 2H), 4.28 (s, 2H), 3.69 (s, 4H), 3.63-3.57 (m, IH), 3.22-3.14 (m, 3H), 3.08-2.93 (m, 2H), 2.69 (s, 3H), 2.10-1.80 (4, 4H).
Examples 25-89
a) 9-(4-Chlorophenylmethyl)- l-oxa-4,9-diazaspiro[5.5]undecane
Figure imgf000088_0002
To a solution of l-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylic acid, 1,1-dimethylethyl ester (WuXi PharmaTech) (6.5 g) in THF (200 mL) was added A- chlorophenylbenzaldehyde (2.56 g) followed by sodium triacetoxyborohydride (4.87 g) and the mixture stirred for 24 hours. The mixture was evaporated to dryness and the residue taken up into DCM (300 mL), washed well with water and dried over magnesium sulfate. Filtration and evaporation gave a crude residue which was redissolved in a mixture of DCM (30 mL) and TFA (30 mL) and the mixture allowed to stand for 1 hour. The mixture was evaporated to dryness and the residue was dissolved in methanol and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol and the product eluted with ammonia solution (3M in methanol). The eluent was evaporated in vacuo to give the subtitled compound as a colourless foam. Yield 7.1 g. m/z 281(M+H)+ (APCI). b) General procedure for preparation of Examples 25-89:
To a solution of the carboxylic acid (0.1 mmol) in NMP (0.5 mL) was added Hunig's base (0.1 mL) followed by a solution of bromo-tris- pyrrolidinophosphoniumhexafluorophosphate (PYBROP, 0.1 mmol) dissolved in NMP (0.2 mL). This mixture was shaken for 1 minute, then added to 9-(4-chlorophenylmethyl)- l-oxa-4,9-diazaspiro[5.5]undecane [Examples 25-89, step a] (0.1 mmol) dissolved in NMP (0.2 mL) and the mixture shaken overnight. The crude mixture was then evaporated to dryness and purified (HPLC, Waters XTerra®, 0.1% aqueous ammonium acetate :acetonitrile, gradient elution 95:05 to 5-95 over 15 mins) to give the following compounds:
Figure imgf000089_0001
The title compounds of Examples 25 to 89 were purified using ammonium acetate. It will be understood that, for each individual Example the purification process used may have produced the title compound as an acetate salt, a partial acetate salt or the free base.
Figure imgf000089_0002
Figure imgf000090_0001
Ex. O Observed Retention
Name
No. Λ Ar1 (M+H)+ time (min)
(9-(4-chlorobenzyl)- 1 -oxa-4,9-
37 diazaspiro [5.5 ]undecan-4-y 1) (m- 398 1.39 tolyl)methanone
(9-(4-chlorobenzyl)- 1 -oxa-4,9-
38 diazaspiro [5.5]undecan-4-yl)(thiophen- 390 1.34
Figure imgf000091_0001
3-yl)methanone
(9-(4-chlorobenzyl)- 1 -oxa-4,9-
O ■N*N
39 diazaspiro[5.5]undecan-4-yl)(l,2,3- 392 1.20 thiadiazol-4-yl)methanone
1 -(9-(4-chlorobenzyl)- 1 -oxa-4,9-
40 diazaspiro [5.5]undecan-4-yl)-4-
Figure imgf000091_0002
442 1.57 phenoxybutan- 1 -one
(9-(4-chlorobenzyl)- 1 -oxa-4,9-
O N =\
41 diazaspiro[5.5]undecan-4-yl)(pyrazin- 386 1.14
^
2-yl)methanone
1 -(9-(4-chlorobenzyl)- 1 -oxa-4,9-
42 diazaspiro[5.5]undecan-4-yl)-2-(2,3- 438 1.52 dihydro- 1 H-inden-2-yl)ethanone
1 -(9-(4-chlorobenzyl)- 1 -oxa-4,9-
43 diazaspiro [5.5]undecan-4-yl)-3 -(3 - 428 1.36 hydroxyphenyl)propan- 1 -one
1 -(9-(4-chlorobenzyl)- 1 -oxa-4,9-
44 diazaspiro [5.5]undecan-4-yl)-3 -(3 - 442 1.49 methoxyphenyl)propan- 1 -one
(9-(4-chlorobenzyl)- 1 -oxa-4,9-
45 diazaspiro [5.5]undecan-4-yl)(3 - 404 1.42
Figure imgf000091_0003
methylthiophen-2-yl)methanone
(9-(4-chlorobenzyl)- 1 -oxa-4,9-
46 2>1A 1.24 diazaspiro[5.5]undecan-4-yl)(fiαran-2- VO O^
Figure imgf000092_0001
Ex. O Observed Retention
Name
No. Λ Ar1 (M+H)+ time (min)
1 -(9-(4-chlorobenzyl)- 1 -oxa-4,9-
56 diazaspiro[5.5]undecan-4-yl)-2-(2- 430 1.31 hydroxyphenoxy)ethanone
(9-(4-chlorobenzyl)- 1 -oxa-4,9-
57 diazaspiro [5.5]undecan-4-yl)(3 - 412 1.47 ethylphenyl)methanone
(9-(4-chlorobenzyl)- 1 -oxa-4,9-
58 diazaspiro [5.5]undecan-4-yl)( 1 - 424 1.45 phenylcyclopropyl)methanone
1 -(9-(4-chlorobenzyl)- 1 -oxa-4,9-
59 diazaspiro [5.5]undecan-4-yl)-3 -(2- 442 1.46 methoxyphenyl)propan- 1 -one
1 -(9-(4-chlorobenzyl)- 1 -oxa-4,9-
60 diazaspiro [5.5]undecan-4-yl)-3 -p- 426 1.56
Figure imgf000093_0001
tolylpropan- 1 -one
1 -(9-(4-chlorobenzyl)- 1 -oxa-4,9-
61 diazaspiro [5.5]undecan-4-yl)-4-p- 440 1.65
Figure imgf000093_0002
tolylbutan- 1 -one
(9-(4-chlorobenzyl)- 1 -oxa-4,9-
62 diazaspiro [5.5]undecan-4-yl)(5- 388 1.31 methylfuran-2-yl)methanone
(9-(4-chlorobenzyl)- 1 -oxa-4,9-
63 diazaspiro [5.5]undecan-4-yl)(5- 418 1.48 ethylthiophen-2-yl)methanone
(9-(4-chlorobenzyl)- 1 -oxa-4,9-
64 diazaspiro [5.5]undecan-4-yl)( 1 H- 424 1.31 indazol-3 -yl)methanone
Figure imgf000093_0003
Figure imgf000094_0001
Figure imgf000095_0001
Ex. O Observed Retention
Name
No. Λ Ar1 (M+H)+ time (min)
chlorophenyl)ethanone
1 -(9-(4-chlorobenzyl)- 1 -oxa-4,9-
85 diazaspiro [5.5]undecan-4-yl)-2- 398 1.36 phenylethanone
2-(benzo[d][l,3]dioxol-5-yl)-l-(9-(4-
86 chlorobenzyl)- l-oxa-4,9- 442 1.44 diazaspiro [5.5]undecan-4-yl)ethanone
1 -(9-(4-chlorobenzyl)- 1 -oxa-4,9-
87 diazaspiro[5.5]undecan-4-yl)-2-(4- 441 1.05
(dimethylamino)phenyl)ethanone
1 -(9-(4-chlorobenzyl)- 1 -oxa-4,9- diazaspiro[5.5]undecan-4-yl)-2-(4- 444 1.46
(methylthio)pheny 1) ethanone
1 -(9-(4-chlorobenzyl)- 1 -oxa-4,9-
89 diazaspiro[5.5]undecan-4-yl)-2-(3,4- 434 1.43 difluorophenyl)ethanone
Figure imgf000096_0001
Examples 90-170
General Procedure for preparation of Examples 90 to 170:
Figure imgf000096_0002
A solution of aldehyde (195 μmol) in dichloromethane (0.5 niL) was treated with a solution of the amine [prepared according to the procedure used in Preparation 2] (150 μmol) in DMSO (0.5 mL). [N. B. If any of the reactants were used as salts, triethylamine (20 μL, 150 μmol) was added]. The resulting reaction was stirred on a Vortex stirrer. The reaction was treated with a solution of sodium triacetoxyborohydride (255 μmol) in dichloromethane (0.5 mL) and acetic acid (25 μL) was added. The reaction mixture was stirred for 24 h at room temperature. The completeness of the reaction was monitored by LCMS. Dichloromethane was evaporated and residue was purified directly by reverse phase HPLC using a gradient of acetonitrile in 0.1% aqueous TFA solution using a SunFire™ prep Cl 8 OBD™ 5μm 19 x 50 mm column (Waters Corporation) at a flow rate of 20 mL/min to give the following compounds:
Figure imgf000097_0001
It will be understood that the compounds of Examples 90-170 are produced as trifluoroacetate salts.
Figure imgf000097_0002
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0002
Examples 171-202 a) 3-((4-(2-Methylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro [5.5] undecan-9- yl)methyl)benzaldehyde
Figure imgf000113_0001
A solution of (2-methylthiazol-4-yl)(l -oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Preparation 3] (0.408 g), 3-(bromomethyl)benzaldehyde (0.205 g) and triethylamine (0.36 mL) in acetonitrile (10 mL) was stirred at room temperature overnight. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed twice with water, once with brine, then dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 5% methanol in dichloromethane to afford the subtitled compound as a yellow gum. Yield 0.325 g. m/z 400 (M+H)+ (APCI).
1H NMR (400 MHz, D6-DMSO, 900C ) δ 10.01 (s, IH), 7.85 (d, J = 0.8 Hz, IH), 7.80 (s,
IH), 7.76 (d, J = 7.4 Hz, IH), 7.61 (d, J = 7.4 Hz, IH), 7.52 (t, J = 7.4 Hz, IH), 3.71 - 3.46
(m, 8H), 2.68 (s, 3H), 2.44 - 2.29 (m, 4H), 1.78 - 1.65 (m, 2H), 1.61 - 1.46 (m, 2H). b) General procedure for preparation of Examples 171 to 202:
A suitable amine (0.05 mmol) was treated with solutions of 3-((4-(2-methylthiazole-4- carbonyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzaldehyde [Examples 171- 202, step a] (19 mg) and acetic acid (6 mg) in methanol (0.4 mL) and shaken until dissolved. The solutions were then treated with solutions of sodium triacetoxyborohydride (32 mg) in ethanol (0.4 mL) and stirred overnight. They were then applied to a pre-washed bed of Tosic-65 resin and washed with methanol. The products were eluted with methanolic ammonia solution and allowed to evaporate. The residues were taken up in DMSO (0.4 mL) and purified by reverse phase HPLC using a gradient of acetonitrile in 0.1% aqueous TFA solution using a SunFire™ prep Cl 8 OBD™ 5μm 19 x 50mm column (Waters Corporation) at a flow rate of 20 mL/min to give the following compounds:
Figure imgf000114_0001
It will be understood that the compounds of Examples 171-202 are produced as trifluoroacetate salts.
Figure imgf000114_0002
Ex. Observed Retention
Name RV
No. (M+H)+ time (min)
(9-(3-((2- methoxyethylamino)methyl)ben
172 zyl)-l-oxa-4,9- 458 0.90
H diazaspiro [5.5 ]undecan-4-yl)(2- methylthiazol-4-yl)methanone
(R)-(9-(3-((2-hydroxy-l- phenylethylamino)methyl)benz
173 yl)-l-oxa-4,9- 520 1.02 diazaspiro [5.5 ]undecan-4-yl)(2-
Figure imgf000115_0001
methylthiazol-4-yl)methanone
(9-(3-((3- chlorobenzylamino)methyl)ben
174 zyl)-l-oxa-4,9- 524 1.11
Figure imgf000115_0002
diazaspiro [5.5 ]undecan-4-yl)(2- methylthiazol-4-yl)methanone
(2-methylthiazol-4-yl)(9-(3-((2- phenoxyethylamino)methyl)ben
175 zyl)-l-oxa-4,9- 520 1.09
Figure imgf000115_0003
diazaspiro [5.5 ]undecan-4- yl)methanone
(9-(3-((3-chloro-4- methylbenzylamino)methyl)ben
176 zyl)-l-oxa-4,9- 538 1.18 diazaspiro [5.5 ]undecan-4-yl)(2-
Figure imgf000115_0004
methylthiazol-4-yl)methanone
(9-(3-((2,6- dichlorobenzylamino)methyl)be
177 nzyl)-l-oxa-4,9- 558 1.08 diazaspiro [5.5 ]undecan-4-yl)(2-
Figure imgf000115_0005
methylthiazol-4-yl)methanone
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Ex. ved Retention
Name RV Obser
No. (M+H)+ time (min)
(9-(3-((2- fluorophenethylamino)methyl)b
199 enzyl)- 1 -oxa-4,9- 522 1.09 diazaspiro [5.5 ]undecan-4-yl)(2-
Figure imgf000120_0001
methylthiazol-4-yl)methanone
(9-(3-((3- chlorophenethylamino)methyl)b
200 enzyl)- 1 -oxa-4,9- 538 1.17 diazaspiro [5.5 ]undecan-4-yl)(2-
Figure imgf000120_0002
methylthiazol-4-yl)methanone
(9-(3-((4- chlorophenethylamino)methyl)b
201 enzyl)- 1 -oxa-4,9- 538 1.19 diazaspiro [5.5 ]undecan-4-yl)(2-
Figure imgf000120_0003
methylthiazol-4-yl)methanone
(9-(3-((3- fluorophenethylamino)methyl)b
202 enzyl)- 1 -oxa-4,9- 522 1.11 diazaspiro [5.5 ]undecan-4-yl)(2-
Figure imgf000120_0004
methylthiazol-4-yl)methanone
Examples 203-228
a) 4-(2-(4-(2-Methylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9- yl)ethoxy)benzaldehyde
Figure imgf000120_0005
Manganese dioxide (0.65 g) was added to a solution of (9-(2-(4-
(hydroxymethyl)phenoxy)ethyl)- 1 -oxa-4,9-diazaspiro [5.5 ]undecan-4-yl)(2-methylthiazol-
4-yl)methanone [Example 12] (0.32 g) in DCM (20 niL) and the resulting black suspension was heated under reflux for 1 h. After cooling, the reaction mixture was passed through a pad of Celite. The pad was washed with DCM (2 x 30 mL) and the combined filtrate and washings evaporated in vacuo to give the subtitled compound as a gum. Yield 0.25 g. m/z 430 (M+H)+ (APCI).
1H NMR (300 MHz, D6-DMSO) δ 9.86 (s, IH), 7.96 (s, IH), 7.88-7.83 (m, 2H), 7.13 (d, J
= 8.5 Hz, 2H), 4.26-4.11 (m, 2H), 3.77-3.46 (m, 6H), 2.78 - 2.65 (m, 5H), 2.48-2.34 (m,
4H), 1.76-1.36 (m, 4H). b) General procedure for preparation of Examples 203-228:
Figure imgf000121_0001
The amine (0.025 mmol) was treated with solutions of 4-(2-(4-(2-methylthiazole-4- carbonyl)-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethoxy)benzaldehyde [Example 201, step a] (4.5 mg) and acetic acid (3 mg) in methanol (0.4 mL) and shaken until dissolved. The resulting mixture was then treated with a solution of sodium triacetoxyborohydride (16 mg) in methanol (0.2 mL) and allowed to stand over the weekend. The solution was then treated with a solution of sodium triacetoxyborohydride (16 mg) in ethanol (0.2 mL) and allowed to stand overnight. The reaction mixture was applied to a pre-washed bed of Tosic-65 resin and washed with methanol. The product was eluted with methanolic ammonia solution and allowed to evaporate. The residue was taken up in DMSO (0.4 mL) and purified by reverse phase HPLC using a gradient of acetonitrile in 0.1% aqueous TFA solution using a SunFire™ prep Cl 8 OBD™ 5μm 19 x 50mm column (Waters Corporation) at a flow rate of 20 mL/min.
Figure imgf000122_0001
It will be understood that the compounds of Examples 203-228 are produced as trifluoroacetate salts.
Figure imgf000122_0002
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Example 229-254 a) 2-(4-(2-(4-(2-Methylthiazole-4-carbonyl)-l-oxa-4,9-diazaspiro [5.5] undecan-9- yl)ethoxy)phenyl)acetaldehyde
Figure imgf000126_0002
Trifluoroacetic acid (0.04 niL) was added to a solution of (9-(2-(4-(2- hydroxyethyl)phenoxy)ethyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4- yl)methanone [Example 13] (0.22 g) in DCM (3 niL) and the resulting mixture was stirred for 5 min. Dess-Martin periodinane (0.31 g) was then added and the resulting mixture stirred for 5 min. A mixture of saturated sodium thiosulphate solution (0.5 mL), sodium bicarbonate solution (0.5 mL) and ether (5 mL) was then added and the resulting mixture stirred for 5 min. The organic layer was separated and washed with sodium bicarbonate solution (1 mL) and water (1 mL), then dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a clear oil which was used immediately. Yield 0.19 g. b) General procedure for preparation of Examples 229-254:
Figure imgf000127_0001
The amine (0.025 mmol) was treated with solutions of 2-(4-(2-(4-(2-methylthiazole-4- carbonyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethoxy)phenyl)acetaldehyde [Example 227, step a] (4.5 mg) and acetic acid (3 mg) in methanol (0.4 mL) and shaken until dissolved. The resulting solution was then treated with a solution of sodium triacetoxyborohydride (16 mg) in methanol (0.2 mL) and allowed to stand over the weekend. The reaction mixture was then treated with a solution of sodium triacetoxyborohydride (16 mg) in ethanol (0.2 mL) and allowed to stand overnight. The reaction mixture was applied to a pre-washed bed of Tosic-65 resin and washed with methanol. The product was eluted with methanolic ammonia solution and allowed to evaporate. The residue was taken up in DMSO (0.4 mL) and purified by reverse phase HPLC using a gradient of acetonitrile in 0.1% aqueous TFA solution using a SunFire™ prep Cl 8 OBD™ 5μm 19 x 50mm column (Waters Corporation) at a flow rate of 20 mL/min.
Figure imgf000128_0001
It will be understood that the compounds of Examples 229-254 are produced as trifluoroacetate salts.
Figure imgf000128_0002
Figure imgf000129_0001
Ex. R1^
N Observed Retention
Name
No. FT (M+H)+ time (min)
(S)-N-ethyl-l-(4-(2-(4-(2- methylthiazole-4-carbonyl)- 1 -oxa-
239 4,9-diazaspiro[5.5]undecan-9- 569 1.00 yl)ethoxy)phenethyl)pyrrolidine-2-
Figure imgf000130_0001
carboxamide
(2-methylthiazol-4-yl)(9-(2-(4-(2- morpholinoethyl)phenoxy)ethyl)- 1 -
240 O N-* 514 0.92 oxa-4,9-diazaspiro[5.5]undecan-4- yl)methanone
(9-(2-(4-(2-(4-(3- hydroxyphenyl)piperazin- 1 -
241 yl)ethyl)phenoxy)ethyl)- 1 -oxa-4,9- 605 1.06
Figure imgf000130_0002
diazaspiro[5.5]undecan-4-yl)(2- methylthiazol-4-yl)methanone l-(4-(4-(2-(4-(2-methylthiazole-4- carbonyl)- 1 -oxa-4,9-
242 diazaspiro[5.5]undecan-9- 569 0.94
Figure imgf000130_0003
yl)ethoxy)phenethyl)- 1 ,4-diazepan-
1 -yl)ethanone
N-methyl-N-(l-(4-(2-(4-(2- methylthiazole-4-carbonyl)- 1 -oxa-
O
243 4,9-diazaspiro [5.5]undecan-9- -( N
569 1.01 yl)ethoxy)phenethyl)pyrrolidin-3- yl)acetamide
N-ethyl-N-(l-(4-(2-(4-(2- methylthiazole-4-carbonyl)- 1 -oxa-
O
244 4,9-diazaspiro[5.5]undecan-9- < 583 1.02 yl)ethoxy)phenethyl)pyrrolidin-3- <JN' yl)acetamide
Figure imgf000131_0001
Figure imgf000132_0002
Example 255-273 a). 2-Isopropyl-thiazole-4-carboxylic acid ethyl-(2-{l-[4-fluoro-3-(2-oxo-ethyl)- benzyl]-piperidin-4-yloxy}-ethyl)-amide
Figure imgf000132_0001
Trifluoroacetic acid (0.178 mL, 2.31 mmol) was added to a solution of (9-(4-fluoro-3-(2- hydroxyethyl)benzyl)-l-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4- yl)methanone (1.066 g, 2.31 mmol) in DCM (20 mL) at O0C and the resulting mixture stirred for 5min. Dess-MartinPeriodinane (1.470 g, 3.47 mmol) was then added and the mixture stirred at RT until consumption of the alcohol by LC-MS (45min). saturated sodium thiosulphate solution (5mL), saturated sodium bicabonate solution (5mL) and ethyl acetate (2OmL) was then added and the mixture stirred for 1OmIn. The aqueous was separated and extracted with ethyl acetate (2OmL). The combined organics were washed with brine. AcOH (-0.ImL) was then added and the mixture dried over sodium sulphate, filtered and evaporated. The crude aldehyde, still a bit wet so weight slightly high, was dissolved in methanol (2mL) and used immediately in the following experiments.
m/z 460 (M+H)+ (APCI) b) General reductive amination procedure for Examples 255-273
Figure imgf000133_0001
Amine (0.05mmol) was treated with solutions of 2-(2-fluoro-5-((4-((2-isopropylthiazol-4- yl)methyl)- 1 -oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenyl)acetaldehyde (23mg) and acetic acid (6mg) in methanol (0.4ml) and shaken until dissolved. The solutions were then treated with solutions of sodium triacetoxyborohydride (32mg) in ethanol (0.4ml) and stirred overnight. They were then applied to a pre-washed bed of tosic 65 resin and washed with methanol. The products were eluted with methanolic ammonia solution and allowed to evaporate. The residues were taken up in DMSO (0.4ml) and purified by reverse phase HPLC using a gradient of acetonitrile in 0.1% aqueous TFA solution using a SunFire™ prep Cl 8 OBD™ 5μm 19 x 50mm column (Waters Corporation) at a flow rate of 20 mL/min.
It will be understood that the compounds of Examples 255-273 are produced as trifluoroacetate salts.
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
The following experimental procedures were used to determine the muscarinic activity of the compounds from the invention: Assay 1: Muscarinic 3 receptor calcium mobilisation assay, Spot Test (a), lOuM
The activity (% inhibition of fluorescence) of compounds on the M3 receptor is determined by hrM3 mediated intracellular calcium mobilisation in Fluo-4 loaded CHO (Chinese hamster ovary) cells expressing the human muscarinic acetylcholine M3 receptor (M3-ACh) using a FLIPR (fluorescence imaging plate reader).
CHO M3-ACh cells (Euroscreen ES-212-C) in Hams F 12 nutrient mixture containing glutamine (Sigma H6658) supplemented with 10% Foetal Calf Serum (PAA), 1% Nonessential Amino Acid Solution (Sigma), 0.5mg/ml geneticin (Invitrogen), are distributed into the wells of a 384 well plate at a density of 2.0 x 105 cells/ml. The cells are incubated at 37°C at 95%/5 % (v/v) air/CO2 in 95% relative humidity for 18hrs. The Molecular Devices Calcium assay kit (R8033-BLA4) is used to determine the calcium mobilisation response. Briefly, the culture medium is removed and the cells loaded with fluorescent dye for 60 minutes at 37°C, according to the manufacturers instructions. Candidate compounds are then added to the cells at a final concentration of 10 μM in Dimethyl sulfoxide and incubated for 15 minutes at 37°C. The cell plates are then transferred to the FLIPR; an EClOO of Acetyl-β-methylcholine bromide (Sigma A2126) is added to the cells and fluorescence measured. The compound activity at 10 μM, defined as % inhibition of fluorescent response, is determined. Assay 2: Muscarinic 3 receptor binding assay, Spot Test (a), 1 and lOuM The activity (% inhibition specific binding) of compounds on the M3 receptor is determined by competition binding of [ H]N-methyl scopolamine (NMS) to CHO-Kl (Chinese Hamster Ovary) cell membranes expressing the human muscarinic acetylcholine M3 receptor (M3-ACh) in a scintillation proximity assay (SPA) format. SPA beads are precoated with membranes and then incubated at 2mg of beads per well with 1 or 10 μM compound of the invention, [3H]NMS at 0.1 nM, quarter Kd (experimentally determined dissociation constant) and assay buffer (20 mM HEPES pH 7.4 containing 5 mM MgCl2 and 0.1% (w/v) bovine serum albumin). The assay is conducted in a final volume of 200 μL, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO). Total binding of [ H]NMS is determined in the absence of competing compound and nonspecific binding of [ H]NMS is determined in the presence of 1 μM atropine. The plates are incubated for 16 hours at room temperature and then read on Wallac Microbeta using a normalised H protocol. The compound activity at 1 or 10 μM, defined as % inhibition specific [3H]-NMS binding, is determined. Assay 3 Muscarinic 3 receptor binding assay pICgn
The affinity (pIC50) of compounds binding to the M3 receptor is determined by competition binding of [ H]N-methyl scopolamine (NMS) to CHO-Kl (Chinese Hamster Ovary) cell membranes expressing the human muscarinic acetylcholine M3 receptor (M3- ACh) in a scintillation proximity assay (SPA) format.
SPA beads are precoated with membranes and then incubated at 2mg of beads per well with serial dilutions of compounds of the invention, [3H]NMS at O.lnM, quarter Kd (experimentally determined dissociation constant) and assay buffer (20 mM HEPES pH 7.4 containing 5 mM MgCl2 and 0.1% (w/v) bovine serum albumin). The assay is conducted in a final volume of 200 μL, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO). Total binding of [ H]NMS is determined in the absence of competing compound and nonspecific binding of [ H]NMS is determined in the presence of 1 μM atropine. The plates are incubated for 16 hours at room temperature and then read on Wallac Microbeta using a normalised H protocol. The pICso, defined as the negative logarithm of the molar concentration of compound required for 50% reduction in specific [3H]-NMS binding, is determined. Assay 4
Methacholine Induced Bronchoconstriction in vivo
Dunkin-Hartley guinea-pigs (300 - 60Og) are supplied by a designated breeding establishment. Animals are dosed with test compound or vehicle either by inhalation in conscious guinea-pigs or by intratracheal instillation (0.5ml/kg) under recoverable gaseous anaesthesia (5% halothane). Animals are allowed to recover from the anaesthesia prior to the measurement of bronchoconstriction. Up to 48 hours post-dosing guinea-pigs are terminally anaesthetized with sodium pentobarbitone (60 mg/kg), the trachea cannulated for artificial ventilation and the jugular vein is cannulated for intravenous administration of methacholine. The guinea-pigs are ventilated using a constant volume respiratory pump (Harvard Rodent Ventilator model 683) at a rate of 60 breath/min and a tidal volume of 5 ml/kg during surgical preparation. Lung function (lung resistance and compliance) is measured in anaesthetised and ventilated guinea-pigs using a pulmonary measurement Flexivent system (SCIREQ, Montreal, Canada) connected to the tracheal cannulae. The animals are ventilated (quasi-sinusoidal ventilation pattern) at 60 breaths/min at a tidal volume of 5 ml/kg. A positive end expiratory pressure of 2-3 CmH2O is applied. Respiratory resistance is measured using the Flexivent "snapshot" facility (1 second duration, 1 Hz frequency). Lung resistance and compliance is measured before and after intravenous administration of methacholine (3, 10 and 30 ug/kg). The peak increase in resistance following methacholine challenge is calculated and the effect of the test compound on methacholine -induced lung function changes is calculated. Percentage inhibition of bronchoconstriction is calculated at each dose of methacholine as follows:
[Change in resistance in vehicle treated group - Change in resistance in compound treated groupl x lOOJChange in resistance in vehicle treated group] Assay 5
Inhibition of pilocarpine induced salivation by i.n. administered compounds. Guinea pigs (450-55Og) supplied by Harlan UK or David Hall, Staffs UK and acclimatised to the in-house facilities for a minimum of three days before use. Guinea pigs are randomly assigned into treatment groups and weighed. Each animal is lightly anaesthetised (4% Halothane) and administered compound or vehicle intranasally (0.5ml/kg) at up to 24 hours before challenge with pilocarpine. At the test time point, guinea pigs are terminally anaesthetised with urethane (25% solution in H20, 1.5g/kg). Once sufficient anaesthesia had developed (absence of toe pinch reflex) each animal had an absorbent pad placed in the mouth for 5 minutes to dry residual saliva, this pad is removed and replaced with a new pre -weighed pad for 5 minutes to establish a reading of baseline saliva production. At the end of this 5 minute period the pad is removed and weighed. A new pre-weighed pad is inserted into the mouth before each animal received s. c. pilocarpine administered under the skin at the back of the neck (0.6mg/kg @ 2ml/kg). The pad is removed, weighed and replaced with a new pre-weighed pad every 5 minutes up to 15 minutes.
Saliva production is calculated by subtracting the pre-weighed weight of the pad from each 5 minute period post weighed pad and these numbers added together to produce an accumulation of saliva over 15 minutes. Each 5 minute period may be analysed in addition to the whole 15 minute recording period. Baseline production of saliva is assumed to be constant and multiplied by three to produce a reading for baseline saliva production over 15 minutes.
Inhibition of saliva produced by the compound may be calculated by using the following equation: (l-(Test-baseline)/(Veh-baseline))* 100. Biological Results:
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001

Claims

1. A compound of formula (I) :
Figure imgf000149_0001
(I) wherein R1 is selected from the following;
(i) an optionally substituted 4-8 membered ring, said ring being aromatic or fully or partially saturated and wherein up to four of the ring atoms may be replaced by heteroatoms independently selected from N, O and S;
(ii) an optionally substituted fused bicyclic ring system of up to 10 atoms, said rings being aromatic or fully or partially saturated, and wherein up to four of the ring atoms may be replaced by heteroatoms independently selected from N, O and S;
(iii) an optionally substituted Ci_6 alkyl group wherein one or two of the carbon atoms can be replaced by O, S or N and wherein said alkyl group may be substituted once or twice by a ring system independently selected from (i) and (ii) above, and wherein the Ci_6 alkyl chain may be substituted by up to five substituents selected from halogen, cyano, S(0)o-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8R9, OR10, C1-6 alkyl and C3.6 cycloalkyl (wherein two C1-3 alkyl chains may be joined to form a cycloalkyl ring of up to eight ring atoms), wherein any ring may be optionally substituted by up to three substituents independently selected from halogen, cyano, SH, S(O)0-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R11, NR10C(O)OR11, NR10C(O)NR8R9, OR10). and wherein for the ring systems in (i) and (ii) above "optionally substituted" means optionally substituted by up to four substituents independently selected from halogen, cyano, nitro, SH, S(O)0-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8R9, OR10, C1-6 alkyl or C3-6 cycloalkyl (wherein a carbon atom of alkyl or cycloalkyl may be optionally replaced by N, O or S) and alkyl or cycloalkyl may be optionally substituted by up to five substituents selected from C1-6 alkyl, halogen, cyano, SH, S(O)0-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8R9, OR10), phenyl or a 4-8 membered heterocyclic ring (containing up to 4 heteroatoms selected from N, O or S) and wherein the phenyl or 4-8 membered heterocyclic rings may be optionally substituted by up to 3 substituents independently selected from halogen, cyano, nitro, SH, S(O)0-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8R9, OR10, C1-6 alkyl or C3-6 cycloalkyl (wherein alkyl or cycloalkyl may be optionally substituted by up to 3 substituents selected from halogen or OR10 ); and wherein the saturated ring systems in (i) and (iii) may also be substituted by up to three Ci_6 alkyl groups that can be joined to form bridged ring structures, optionally substituted by halogen or OR10;
X represents O, S(O)0-2 or CR12R13; m = O, 1, 2 or 3; n = 1, 2, 3 or 4; provided that m + n is greater than or equal to 2;
W represents CR12R13-CR12R13 or CR12R13-CR12R13-CR12R13;
V and Z independently represent a bond, CR12R13 or CR12R13-CR12R13 , provided that when X represents either O or S(O)0-2 then m, V and Z are such that all the heteroatoms in the rings are separated by at least two carbon atoms;
Y represents C(O), C(O)NR10, SO2 or SO2NR10;
R2 is a lone pair, or Ci-6 alkyl, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or R3 is a group of formula (II)
Figure imgf000150_0001
wherein L1 and L2 independently represent hydrogen, Ci-6 alkyl or C3-6 cycloalkyl, wherein the Ci-6 alkyl and C3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci-6 alkoxy; or L1 and/or L2 may be linked to carbon atoms in the group L, or L1 and L2 may be linked to each other, to form aliphatic rings of up to 6 ring atoms, wherein each ring may comprise up to three heteroatoms independently selected from N, O and S; and wherein L represents a straight or branched hydrocarbyl chain of up to 15 carbon atoms; wherein up to three of the carbon atoms in the chain are optionally substituted once or twice by groups independently selected from halogen, cyano, S(O V2R10, NR14R15, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8R9, OR10, C1-6 alkyl and C3.6 cycloalkyl, and wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy; wherein up to three carbon atoms of the chain may be replaced by groups independently selected from O, NR10, S, S(O), S(O)2, C(O)O, OC(O), NR10C(O)NR10, NR10S(O)2NR10, OC(O)NR10, NR10C(O)O, provided that any such groups in the chain are separated by at least two chain carbon atoms; and wherein up to six carbon atoms of the chain may form part of an aryl, heteroaryl, fused bicyclic, alicyclic, or heteroaliphatic ring having up to four heteroatoms independently selected from N, O or S, said ring comprising up to 10 ring atoms, and wherein the ring is optionally substituted by up to three substituents independently selected from halogen, cyano, S(O)0-2R10, NR8R9, S(O)2NR8R9, C(O)NR8R9, C(O)OR10, NR10S(O)2R11, NR10C(O)R10, NR10C(O)OR11, NR10C(O)NR8R9, =0, OR10, C1-6 alkyl and C3_6 cycloalkyl, and wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy, with the proviso that L does not comprise an optionally substitued para- or meta-hydroxy phenyl- 1- hydroxy-ethylamino- group (or fused bicyclic derivative thereof) or an optionally substituted 4-hydroxy-2-pyridyl-l-hydroxy-ethylamino- group;
R8 and R9 are independently hydrogen, Ci_6 alkyl or C3-6 cycloalkyl, or R8 and R9 may be joined together to form a heterocyclic ring comprising up to 9 ring atoms (optionally containing a further heteroatom selected from O, N or S) wherein the ring may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl, Ci_6 alkyl or C3_6 cycloalkyl, and wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy;
R10 represents hydrogen, Ci_6 alkyl or C3-6 cycloalkyl, wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_6 alkoxy;
R11 represents Ci_6 alkyl or C3-6 cycloalkyl, wherein the Ci_6 alkyl and C3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl or Ci_6 alkoxy;
R12 and R13 each independently represent hydrogen, fluorine, Ci_6 alkyl or C3_6 cycloalkyl; or R12 and R13 when attached to the same carbon atom, together with the carbon atom to which they are both attached, may additionally form a 3 to 6 membered aliphatic ring;
R14 represents hydrogen, Ci_6 alkyl or C3-6 cycloalkyl, and;
R15 represents (i) hydrogen or;
(ii) an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring, or;
(iii) a Ci-6 straight- or branched chain alkyl optionally containing an oxygen or sulfur atom in the chain and optionally substituted by up to 3 substituents selected from halogen, hydroxyl, OR10, -COOR10, C(=O)NR8R9, NR10C(=O)R10 (wherein R8' R9, and R10 are as defined above and each independently may additionally represent an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring), or an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring, or; (iv) a C3-8 cycloalkyl group optionally substituted by up to 3 substituents selected from halogen, hydroxyl, OR10, -COOR10, C(=O)NR8R9, NR10C(=O)R10 (wherein R8' R9, and R10 are as defined above and each independently may additionally represent an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring), or an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring; or R14 and R15 are joined together with the nitrogen atom to which they are attached to form a heterocyclic ring (optionally fused to an aryl or heteroaryl ring), optionally containing a further heteroatom selected from O, N, or S, and optionally substituted by Ci_ galkyl, =0, -C(=O)NR8R9, -NR10C(=O)R10, -C(=O)R10(wherein R8' R9, and R10 are as defined above and each independently may additionally represent an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring), or an optionally substituted aryl, heteroaryl, fused bicyclic, alicyclic or heteroaliphatic ring; and pharmaceutically acceptable salts thereof.
2. A compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof and wherein R1 represents
(i) an optionally substituted phenyl or 5-6-membered heteroaryl ring;
(ii) an optionally fused bicyclic ring ; or
(iii) an optionally substituted Ci_6 alkyl group wherein one or two of the carbon atoms can be replaced by O, S or N and wherein said alkyl group may be substituted by the ring systems described in (i) and (ii), and wherein each ring in (i), (ii) and (iii) is optionally substituted by up to three substituents independently selected from halogen, cyano, OR10, Ci_6 alkyl, C3-8 cycloalkyl, or an optionally substituted phenyl ring.
3. A compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy.
4. The use of a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in therapy.
5. A method of treating, or reducing the risk of, an inflammatory disease or condition (including a reversible obstructive airways disease or condition) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
7. A process for the preparation of a pharmaceutical composition which comprises mixing a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable adjuvant, diluent or carrier.
8. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises reacting a compound of formula (IV)
Figure imgf000154_0001
wherein R1, m, n, V, W, X, Y and Z are as defined in formula (I) and L, L1 and L2 are as defined in formula (II), with an Ci_6alkyl halide.
PCT/GB2009/051657 2008-12-09 2009-12-07 Diazaspiro [5.5] undecane derivatives and related compounds as muscarinic-receptor antagonists and beta-adrenoreceptor agonists for the treatment of pulmonary disorders WO2010067102A1 (en)

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GB0913344A GB0913344D0 (en) 2009-07-31 2009-07-31 Compounds 762

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US11149022B2 (en) 2017-10-17 2021-10-19 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4

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CN104387288A (en) * 2014-11-25 2015-03-04 广东东阳光药业有限公司 Compound as neuraminidase inhibitor and application of compound in medicine
CN104447390A (en) * 2014-12-03 2015-03-25 广东东阳光药业有限公司 Substituted cyclobutane neuraminidase inhibitors as well as using method and application thereof
CN104496839A (en) * 2014-12-03 2015-04-08 广东东阳光药业有限公司 Substituted-cyclobutane neuraminidase inhibitor as well as using method and application of substituted-cyclobutane neuraminidase inhibitor
CN104496838A (en) * 2014-12-03 2015-04-08 广东东阳光药业有限公司 Substituted-cyclobutane neuraminidase inhibitor as well as using method and application of substituted-cyclobutane neuraminidase inhibitor
CN104447390B (en) * 2014-12-03 2016-03-02 广东东阳光药业有限公司 Substituted ring butanes neuraminidase inhibitor and using method thereof and purposes
CN104496838B (en) * 2014-12-03 2016-04-20 广东东阳光药业有限公司 Substituted ring butanes neuraminidase inhibitor and using method thereof and purposes
CN104496839B (en) * 2014-12-03 2016-04-20 广东东阳光药业有限公司 Substituted ring butanes neuraminidase inhibitor and using method thereof and purposes
US11149022B2 (en) 2017-10-17 2021-10-19 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
WO2019126559A1 (en) * 2017-12-20 2019-06-27 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor m4
US11325896B2 (en) 2017-12-20 2022-05-10 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4

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