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EP2013197A1 - Phenethanolamine derivatives as beta2 adrenoreceptor agonists - Google Patents

Phenethanolamine derivatives as beta2 adrenoreceptor agonists

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Publication number
EP2013197A1
EP2013197A1 EP07716036A EP07716036A EP2013197A1 EP 2013197 A1 EP2013197 A1 EP 2013197A1 EP 07716036 A EP07716036 A EP 07716036A EP 07716036 A EP07716036 A EP 07716036A EP 2013197 A1 EP2013197 A1 EP 2013197A1
Authority
EP
European Patent Office
Prior art keywords
hydroxy
ethyl
amino
piperidin
oxo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07716036A
Other languages
German (de)
English (en)
French (fr)
Inventor
Lilian Alcaraz
Andrew Bailey
Rhona Cox
Premji Meghani
Garry Pairaudeau
Michael Stocks
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP2013197A1 publication Critical patent/EP2013197A1/en
Withdrawn legal-status Critical Current

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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to phenethanolamine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • Adrenoceptors are a group of G-protein coupled receptors divided into two major subfamilies, ⁇ and ⁇ . These sub-families are further divided into sub-types of which the ⁇ subfamily has at least 3 members: ⁇ l, ⁇ 2 and ⁇ 3. ⁇ 2 adrenoceptors (henceforth referred to as ⁇ 2 receptors) are mainly expressed on smooth muscle cells.
  • ⁇ 2 agonists act as functional antagonists to all bronchoconstrictor substances such as the naturally-occurring histamine and acetylcholine as well as the experimental substances methacholine and carbachol.
  • ⁇ 2 agonists are widely used to treat airway diseases including asthma and chronic obstructive pulmonary disease (COPD), and this has been extensively reviewed in the literature and incorporated into national guidelines for the treatment of these diseases (British Guideline on the Management of Asthma, NICE guideline No. 12 on the Management of COPD).
  • ⁇ 2 agonists are classed either as short-acting or long-acting. Short-acting ⁇ 2 agonists
  • SABAs such as salbutamol
  • LABAs Long-acting ⁇ 2 agonists
  • LABAs Long-acting ⁇ 2 agonists
  • They are particularly effective when administered in combination with inhaled corticosteroids. This benefit is not seen when inhaled corticosteroids are combined with SABAs (Kips and Pauwels, Am. J. Respir. Crit. Care Med., 2001, 164, 923-932).
  • LABAs are recommended as add-on therapy to patients already receiving inhaled corticosteroids for asthma to reduce nocturnal awakening and reduce the incidence of exacerbations of the disease.
  • Corticosteroids and LABAs are conveniently co-administered in a single inhaler to improve patient compliance.
  • Salmeterol a commonly used LABA
  • Salmeterol also has a long onset of action which precludes its use as both a rescue and a maintenance therapy.
  • All current LABAs are administered twice daily and there is a medical need for once daily treatments to improve treatment and patient compliance. Such once daily compounds, co-administered with corticosteroids, will become the mainstay of asthma treatment (Barnes, Nature Reviews, 2004, 3, 831-844).
  • Benzothiazolone derivatives having ⁇ 2 adrenoreceptor agonist properties are known from WO 2004/016601.
  • M is C(O), NR 0 , S or CR'R S ;
  • R 2 , R 3 , R 4 and R 5 are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(O) 2 R 9 , NR 10 S(O) 2 R 11 , C(O)NR 12 R 13 , NR 14 C(O)R 15 , C 1-6 allcyl, Ci -6 alkoxy, C(O)(C 1-6 allcyl) or C(O) 2 (C 1-6 allcyl);
  • R 3 can also be CH 2 OH or NHS(O) 2 NR 17 R 18 ;
  • X is a bond, CR 27 R 28 or CR 29 R 30 CR 31 R 32 ;
  • Y is CR 33 R 34 CR 35 R 36 , CR 37 R 38 CR 39 R 40 CR 41 R 42 or CR 43 R 44 CR 45 R 46 CR 47 R 48 CR 49 R 50 ; or Y is CR 51 R 52 provided that E is C(O)O-;
  • Z is a bond, CR 51 R 52 , CR 53 R 54 CR 55 R 56 , CR 57 R 58 CR 59 R 60 CR 61 R 62 or
  • A is a cycloalkyl-amino group selected from
  • cycloalkyl ring is unsubstituted or substituted by 1 or 2 substituents independently selected from halogen, Ci -4 alkyl (optionally substituted by OR 116 ,
  • OR A is a heterocyclyl ring selected from
  • heterocyclyl ring is unsubstituted or substituted by 1 or 2 substituents (for example a substituent is on the same ring carbon atom as that joining A to either X or Y) independently selected from halogen, C 1-4 allcyl (optionally substituted by OR 121 , NR 122 R 123 OrNR 124 C(O)R 125 ), OR 19 , NR 20 R 21 , C(O)NR 22 R 23 , NR 24 C(O)R 25 , CN, S(O) 2 R 126 Or S(O) 2 NR 114 R 115 ; when A is a heterocyclyl ring A is linked to Y through a ring nitrogen atom; when A is a heterocyclyl ring A can be linked to X through a ring carbon atom; or, when A is heterocyclyl having 2 ring-nitrogen atoms and X is CR 29 R 30 CR 31 R 32 , A can be linked to X through the second substituent
  • n and m are, independently, 1 or 2;
  • R 113 , R 114 , R 115 , R 116 , R 117 , R 118 , R 119 , R 120 , R 121 , R 122 , R 123 , R 124 and R 125 are, independently, hydrogen or C 1-6 alkyl;
  • R 52 can also be phenyl
  • R 72 can also be phenyl(C 1-4 alkyl) (for example benzyl);
  • R 9 , R ⁇ , R 16 , R 85 , R 87 , R", R 100 , R 109 , R 110 and R 126 are, independently, C 1-6 alkyl; provided that when R 1 is aryloxy, NR 76 aryl or S(O) 2 aryl; and E is O, S, S(O) 2 , NR 71 , C(O)NR 72 , S(O) 2 NR 74 or NR 75 S(O) 2 , then Z is CR 53 R 54 CR 55 R 56 , CR 57 R 58 CR 59 R 60 CR 61 R 62 or CR 63 R 64 CR 65 R 66 CR 67 R 68 CR 69 R 70 ; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula (I) wherein: Ar is:
  • M is C(O), NR 6 , S or CR 7 R 8 ;
  • R 2 , R 3 , R 4 and R 5 are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(O) 2 R 9 , NR 10 S(O) 2 R 11 , C(O)NR 12 R 13 , NR 14 C(O)R 15 , C 1-6 alkyl, C 1-6 alkoxy, C(O)(C 1-6 alkyl) or C(O) 2 (Ci -6 alkyl);
  • R 3 can also be CH 2 OH Or NHS(O) 2 NR 17 R 18 ;
  • X is a bond, CR 27 R 28 or CR 29 R 30 CR 31 R 32 ;
  • Y is CR 33 R 34 CR 35 R 36 , CR 37 R 38 CR 39 R 40 CR 41 R 42 or CR 43 R 44 CR 45 R 46 CR 47 R 48 CR 49 R 50 ; or Y is CR 51 R 52 provided that E is C(O)O-; Z is a bond, CR 51 R 52 , CR 53 R 54 CR 55 R 56 , CR 57 R 58 CR 59 R 60 CR 61 R 62 or
  • A is a cycloalkyl-amino group selected from wherein said cycloalkyl ring is unsubstituted or substituted by 1 or 2 substituents independently selected from halogen, C 1-4 alkyl (optionally substituted by OR 116 ,
  • OR A is a heterocyclyl ring selected from
  • heterocyclyl ring is unsubstituted or substituted by 1 or 2 substituents (for example a substituent is on the same ring carbon atom as that joining A to either X or Y) independently selected from halogen, Ci -4 alkyl (optionally substituted by OR 121 ,
  • E is O, S, S(O) 2 , NR 71 , C(O)NR 72 , NR 73 C(O), C(O)O, S(O) 2 NR 74 OrNR 75 S(O) 2 ;
  • R 1 is aryl, aryloxy, NR 76 aryl, S(O) 2 aryl, heteroaryl or C 3-10 cycloalkyl (optionally substituted by C 1-6 alkyl, halogen or phenyl); wherein the aryl and heteroaryl rings are optionally substituted by halogen, cyano, trifluoromethyl, phenyl, OCF 3 , O(CF 2 ) n O, O(CH 2 ) m O, OR 78 , SR 79 , NR 80 R 81 , C(O)NR 82 R 83 , NR 84 S(O) 2 R 85 , C(O)R 86 , S(O) 2 R 87 , S(O)
  • n and m are, independently, 1 or 2;
  • M is C(O), NR 6 or CR 7 R 8 ;
  • R 2 , R 3 , R 4 and R 5 are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(O) 2 R 9 , NR 10 S(O) 2 R 11 , C(O)NR 12 R 13 , NR 14 C(O)R 15 , Cj -6 alkyl, C 1-6 aUcoxy, C(O)(C 1-6 alkyl) or C(O) 2 (C 1-6 alkyl);
  • R 3 can also be CH 2 OH or NHS(O) 2 NR 17 R 18 ;
  • X is a bond, CR 27 R 28 or CR 29 R 30 CR 31 R 32 ;
  • Y is CR 33 R 34 CR 35 R 36 , CR 37 R 38 CR 39 R 40 CR 41 R 42 or CR 43 R 44 CR 45 R 46 CR 47 R 48 CR 49 R 50 ;
  • Z is a bond, CR 51 R 52 , CR 53 R 54 CR 55 R 56 , CR 57 R 58 CR 59 R 60 CR 61 R 62 or
  • A is a cycloalkyl ring selected from
  • cycloalkyl ring is unsubstituted or substituted by 1 or 2 substituents independently selected from halogen, Ci -4 alkyl (optionally substituted by OR 116 ,
  • NR 1 1 1 1 7 '-Rn l 1 l 1 S 0 o. rNR , 1 l 1 i 9 y / C- (O)R , 1 1 2 / O ⁇ N ), 0R » 1 i 9 y , NR >2'0 ⁇ ⁇ R>2 / 1 x , NR >2'4 4 C/- (O)R >2 / 5 3 , CN, S(O) 2 R .
  • NR 26 provided that X is CR 29 R 30 CR 31 R 32 ; when X is a bond A is not connected to X through the ring-carbon atom carrying NR 26 ;
  • OR A is a heterocyclyl ring selected from wherein the heterocyclyl ring is unsubstituted or substituted by 1 or 2 substituents independently selected from halogen, C 1-4 alkyl (optionally substituted by OR 121 , NR 122 R 123 OrNR 124 C(O)R 125 ), OR 19 , NR 20 R 21 , C(O)NR 22 R 23 , NR 24 C(O)R 25 , CN, S(O) 2 R 126 or S(O) 2 NR 114 R 115 ; when A is a heterocyclyl ring it is linked to Y through a ring nitrogen atom; when A is a heterocyclyl ring it is linked to X either through a ring carbon atom or through a second ring nitrogen atom provided that X is CR 29 R 30 CR 31 R 32 ;
  • E is O, S, S(O) 2 , NR 71 , C(O)NR 72 , NR 73 C(O), S(O) 2 NR 74 OrNR 75 S(O) 2 ;
  • R 1 is aryl, aryloxy, NR 76 aryl, S(O) 2 aryl, heteroaryl or C 3-7 cycloalkyl; wherein the aryl and heteroaryl rings are optionally substituted by halogen, cyano, trifluoromethyl, phenyl, O(CF 2 ) n O, 0(CH 2 ) m 0, OR 78 , SR 79 , NR 80 R 81 , C(O)NR 82 R 83 , NR 84 S(O) 2 R 85 , C(O)R 86 , S(O) 2 R 87 , S(O) 2 NR 88 R 89 , NR 90 C(O)R 91 , C(O)OR 92 , C
  • R 113 , R 114 , R 115 , R 116 , R 117 , R 118 , R 119 , R 120 , R 121 , R 122 , R 123 , R 124 and R 125 are, independently, hydrogen or C 1-6 alkyl;
  • R 9 , R 11 , R 16 , R 85 , R 87 , R", R 100 , R 109 , R 110 and R 126 are, independently, C 1-6 alkyl; provided that when R 1 is aryloxy, NR 76 aryl or S(O) 2 aryl; and E is O, S, S(O) 2 , NR 71 ,
  • Z is CR 53 R 54 CR 55 R 56 , CR 57 R 58 CR 59 R 60 CR 61 R 62 or CR 63 R 64 CR 65 R 66 CR 67 R 68 CR 69 R 70 ; or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention are selective ⁇ 2 receptor agonists and possess properties that make them more suitable for once-a-day administration.
  • Compounds have been optimised to have a predicted appropriate duration in an in vitro guinea pig trachea model, or mammalian model such as a histamine-challenged guinea pig.
  • the compounds also have advantageous pharmokinetic half lives in a rat system.
  • certain compounds of the invention are at least 10-fold more potent at the ⁇ 2 receptor compared to the ⁇ l, ⁇ l, or dopamine (D2) receptors.
  • Certain compounds are also notable for having a fast onset of action that is the time interval between administration of a compound of the invention to a patient and the compound providing symptomatic relief. Onset can be predicted in vitro using isolated trachea from guinea pig or human.
  • a suitable pharmaceutically acceptable salt is, for example, an acid addition salt, such as a hydrochloride, hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or p- toluenesulplionate.
  • an acid addition salt such as a hydrochloride, hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or p- toluenesulplionate.
  • acid addition salts are: bisulphate, benzenesulphonate, ethanesulphonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, 2-furoate, 3-furoate, napadisylate (naphthalene-l,5-disulfonate or naphthalene- 1 -(sulfonic acid)-5-sulfonate), edisylate (ethane- 1,2-disulfonate or ethane- 1- (sulfonic acid)-2-sulfonate), isethionate (2-hydroxyethylsulfonate), 2-mesitylenesulphonate and 2-naphthalenesulphonate.
  • the present invention covers all permissible ratios of compound of formla (I) to pharmaceutically acceptable salt, for example mono-hydrobromide, dihydrobromide or a hemi-salt (such as a hemi-fumarate).
  • an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched.
  • Examples of C 1 - 6 alkyl groups/moieties include methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl.
  • Aryl is, for example, phenyl or naphthyl.
  • C 3-1O Cycloalkyl is optionally bridged by 1, 2, 3 or 4 carbon atoms. Examples include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl. In one aspect of the invention C 3-1O cycloalkyl is, for example, cyclohexyl or adamantyl.
  • Heteroaryl is an aromatic monocyclic or bicyclic ring, containing 5 to 10 ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen.
  • heteroaryl include pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxadiazolyl, oxadiazolyl, isothiadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyridinonyl, pyrimidindionyl, benzfuranyl, benzthienyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazo
  • R 3 is CH 2 OH or NHC(O)H.
  • Ar is:
  • Ar is:
  • Ar is:
  • Ar is:
  • the present invention provides a compound of formula (I) wherein X is a bond or CR 27 R 28 or CR 29 R 30 CR 31 R 32 (for example X is a bond or CR 27 R 28 ).
  • R 27 , R 28 , R 29 , R 30 , R 31 and R 32 are, independently, hydrogen or C 1-4 alkyl (for example methyl).
  • R 27 , R 28 , R 29 , R 30 , R 31 and R 32 are all hydrogen.
  • the present invention provides a compound of formula (I) wherein X is a bond, CH 2 or C(CH 3 ) 2 or (CH 2 ) 2 (for example X is a bond, CH 2 or C(CH 3 ) 2 ).
  • the present invention provides a compound of formula (I) wherein X is a bond or CH 2 .
  • Y is CR 33 R 34 CR 35 R 36 , CR 37 R 38 CR 39 R 40 CR 41 R 42 or CR 43 R 44 CR 45 R 46 CR 47 R 48 CR 49 R 50 , or Y is CR 51 R 52 provided E is C(O)O.
  • the present invention provides a compound of formula (I) wherein Y is CR 33 R 34 CR 35 R 36 or CR 37 R 38 CR 39 R 40 CR 41 R 42 , or Y is CR 51 R 52 provided E is C(O)O.
  • Y is CR 33 R 34 CR 35 R 36 or CR 37 R 38 CR 39 R 40 CR 41 R 42 .
  • R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 and R 50 are, independently, hydrogen or C 1-4 alkyl (for example methyl).
  • R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 and R 50 are all hydrogen.
  • Y is (CHa) 2 , (CH 2 ) 3 or CH 2 C(CH 3 ) 2 CH 2 .
  • the present invention provides a compound of formula (I) wherein Y is (CHz) 2 .
  • the present invention provides a compound of formula (I) wherein Z is a bond, CR 51 R 52 , CR 53 R 54 CR 55 R 56 or CR 57 R 58 CR 59 R 60 CR 61 R 62 .
  • the present invention provides a compound of formula (I) wherein Z is CR 51 R 52 , CR 53 R 54 CR 55 R 56 or CR 57 R 58 CR 59 R 60 CR 61 R 62 .
  • the present invention provides a compound of formula (I) where ' in Z is a bond, CR 51 R 52 or CR 53 R 54 CR 55 R 56 .
  • R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 and R 62 are, independently, hydrogen or C 1-4 alkyl (for example methyl).
  • R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 and R 62 are all hydrogen
  • the present invention provides a compound of formula (I) wherein Z is a bond, CH 2 , (CH 2 ) 2 , (CH 2 ) 3 or CH 2 C(CH 3 ) 2 CH 2 .
  • the present invention provides a compound of formula (I) wherein Z is CH 2 , (CH 2 ) 2 , (CH 2 ) 3 or CH 2 C(CH 3 ) 2 CH 2 .
  • the present invention provides a compound of formula (I) wherein Z is a bond, CH 2 or (CH 2 ) 2 (for example Z is CH 2 or (CH 2 ) 2 ).
  • the present invention provides a compound of formula (I) wherein A is an azetidine, pyrrolidine, piperidine, morpholine, piperazine, azepane, 1,4-diazepane, 3,8- diazabicyclo[3.2.1]octane, 3-azabicyclo[3.1.0]hexane, 8-azabicyclo[3.2.1]octane, 9- azabicyclo[3.3.1]nonane, cyclobutane, cyclopentane, cyclohexane or cycloheptane ring.
  • A is an azetidine, pyrrolidine, piperidine, morpholine, piperazine, azepane, 1,4-diazepane, 3,8- diazabicyclo[3.2.1]octane, 3-azabicyclo[3.1.0]hexane, 8-azabicyclo[3.2.1]octane, 9- azabicyclo[
  • A is:
  • R 26 is hydrogen or C 1-4 alkyl (for example methyl). In one aspect R is hydrogen.
  • A is: wherein ** is linked to X and *** I linked to Y; A is optionally substituted as recited herein; and R 26 is as defined herein.
  • A is:
  • ** is linked to X and *** I linked to Y;
  • A is optionally substituted as recited herein.
  • A is unsubstituted or substituted at the ring-carbon linked to X by hydroxy, C 1-4 alkyl (such as methyl) or hydroxy(C 1-4 alkyl) (such as HOCH 2 ).
  • A is unsubstituted.
  • R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 114 , R 115 , R 121 , R 122 , R 123 , R 124 and R 125 , are, for example, hydrogen or Ci -4 alkyl; and R 126 is, for example, Ci -4 alkyl.
  • a further aspect of the invention provides compound of formula (I) wherein A is substituted (for example on the same ring carbon atom as that joining A to X or Y) by 1 substituent independently selected from halogen, C 1-4 alkyl (optionally substituted by OR 121 ) or OR 19 (for example OR 19 is hydroxy or C 1-4 alkoxy).
  • R 19 and R 121 are, independently, hydrogen or Ci -4 alkyl.
  • the present invention provides a compound of formula (I) wherein E is O 5 S(O) 2 , NR 71 , C(O)NR 72 OrNR 73 C(O).
  • the present invention provides a compound of formula (I) wherein E is O, S(O) 2 , C(O)NR 72 OrNR 73 C(O).
  • the present invention provides a compound of formula (I) wherein E is O or C(O)NR 72 ; wherein R 72 is hydrogen or C 1-4 alkyl (such as methyl or ethyl) (for example R 72 is hydrogen).
  • the present invention provides a compound of formula (I) wherein E no no is C(O)NR , wherein R is hydrogen or C 1-4 alkyl (such as methyl or ethyl).
  • R 72 is hydrogen.
  • the present invention provides a compound of formula (I) wherein E is O.
  • the present invention provides a compound of formula (I) wherein E is O and Z is CH 2 CH 2 .
  • the present invention provides a compound of formula (I) wherein E is C(O)NR 72 (for example R 72 is hydrogen); and Z is CH 2 .
  • the present invention provides a compound of formula (I) wherein R 1 is aryl, aryloxy or heteroaryl wherein these aryl and heteroaryl rings are optionally substituted by halogen, cyano, trifluorometliyl, phenyl, OR 78 , C(O)NR 82 R 83 , S(O) 2 R 87 , S(O) 2 NR 88 R 89 , NR 90 C(O)R 91 , Ci -3 alkyl or Ci -3 alkoxy; wherein 2 substituents on the aryl or heteroaryl ring which is R 1 can join together to form a 4- to 8-membered which is carbocyclic or heterocyclic (for example containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S), the fused ring being optionally substituted halogen, C 1-4 alkyl, CF 3 or C 1-4 alkoxy.
  • the variables R 78 , R 82 , R 83 are optional
  • the present invention provides a compound of formula (I) wherein R 1 is unsubstituted phenyl or phenyl substituted by (for example by 1, 2 or 3) the same or different: halogen (such as fluoro or chloro), C 1-4 alkyl (such as methyl), C 1-4 alkoxy (such a methoxy), cyano, OH, CF 3 , OCF 3 or phenyl.
  • R 1 is unsubstituted phenyl or phenyl substituted by (for example by 1, 2 or 3) the same or different: halogen (such as fluoro or chloro), C 1-4 alkyl (such as methyl), C 1-4 alkoxy (such a methoxy), cyano, OH, CF 3 , OCF 3 or phenyl.
  • the present invention provides a compound of formula (I) wherein R 1 is unsubstituted phenyl or phenyl substituted by (for example by 1 or 2) the same or different: halogen (such as fluoro or chloro) or C 1-4 alkyl (such as methyl).
  • the presenty invention provides a compound of formula (I) wherein R 1 is C 3-10 cycloalkyl (for example cyclopropyl, cyclohexyl or adamantyl) optionally substituted by phenyl.
  • R 1 is C 3-10 cycloalkyl (for example cyclopropyl, cyclohexyl or adamantyl) optionally substituted by phenyl.
  • the present invention provides a compound of formula (I) wherein Z is a bond, E is C(O) and R 1 is a group selected from:
  • the rpesent invention provides a compound of formula (I) wherein Z is a bond, E is C(O) and R 1 is:
  • X is a bond, CR 27 R 28 or CR 29 R 30 CR 31 R 32 ;
  • Y is CR 33 R 34 CR 35 R 36 , CR 37 R 38 CR 39 R 40 CR 41 R 42 or CR 43 R 44 CR 45 R 46 CR 47 R 48 CR 49 R 50 ; or Y is CR 51 R 52 provided that E is C(O)O-;
  • Z is a bond, CR 51 R 52 or CR 53 R 54 CR 55 R 56 ;
  • A is a heterocyclyl ring selected from
  • heterocyclyl ring is unsubstituted or substituted by 1 substituent (for example the substituent is on the same ring carbon atom as that joining A to Y) independently selected from C 1-4 alkyl (optionally substituted by OR 121 ) or OR 19 ;
  • E is O or C(O)NR 72 ;
  • R 1 is aryl or C 3-10 cycloalkyl (optionally substituted by C 1-6 alkyl, halogen or phenyl); wherein aryl is optionally substituted by halogen, cyano, trifluoromethyl, phenyl, OCF 3 , OR 78 , C 1-6 alkyl (optionally substituted by fluoro, trifluoromethyl, OR 93 OrNR 94 R 95 ) or C 1- 6 alkoxy (optionally substituted by fluoro, trifluoromethyl, OR 103 or NR 104 R 105 ); ⁇ for example R 1 is phenyl (optionally substituted by halogen, Ci -4 alkyl or phenyl) or C 3-1O cycloalkyl (optionally substituted by phenyl) ⁇ ; when Z is a bond E can also be C(O) provided R 1 is:
  • R 19 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 72 , R 78 , R 93 , R 94 , R 95 , R 103 , R 104 , R 105 and R 121 are, independently, hydrogen or C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
  • the invention further provides:
  • the present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above. Suitable processes are described below.
  • Process 1 Reacting a compound of formula (II), wherein Ar is as defined in formula (I), with or without a suitable protecting group (PG 2 ) on the phenolic group (as shown below) and wherein PG 1 is a suitable protecting group which may be the same or different to PG 2 , the variables being as defined in formula (I), with a compound of formula (III).
  • suitable protecting groups for PG 1 include tert-butyldimethylsilyl, tert-butyl- diphenylsilyl, methyldiphenylsilyl, tetrahydropyranyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl, benzyloxymethyl.
  • tert-butyldimethyl- silyl is used.
  • suitable protecting groups for PG 2 include benzyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl, benzyloxymethyl. In one aspect of the invention PG 2 is benzyl.
  • Suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride or hydrogen in the presence of a suitable catalyst such as palladium on carbon or palladium oxide, in the absence or presence of a suitable organic acid such as a C 1-6 aliphatic carboxylic acid.
  • a suitable catalyst such as palladium on carbon or palladium oxide
  • a suitable organic acid such as a C 1-6 aliphatic carboxylic acid.
  • sodium triacetoxyborohydride in the presence of acetic acid is used.
  • Suitable solvents include N-methyl-2-pyrrolidinone, acetonitrile, butyronitrile and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme.
  • the reaction can be performed at temperatures between O 0 C and 100 0 C.
  • N-methyl-2-pyrrolidinone or tetrahydrofuran at ambient (10-30 0 C) temperature is used.
  • Suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride in the presence of a suitable organic acid such as a C 1-6 aliphatic carboxylic acid.
  • a suitable organic acid such as a C 1-6 aliphatic carboxylic acid.
  • sodium triacetoxyborohydride in the presence of acetic acid 0 is used.
  • suitable solvents include JV-methyl-2-pyrrolidinone, acetonitrile, butyronitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme.
  • the reaction can be performed at temperatures between O 0 C and 100 0 C.
  • iV-methyl-2-pyrrolidinone at ambient (10-30 0 C) temperature is used.
  • suitable solvents include dimethylsulphoxide,N,N-dimethylformamide, N- methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-dioxane, glym, diglyme, alcohols such methanol, ethanol, isopropanol, tert-butanol or iso-butanol.
  • the process can be performed between 25 0 C and 15O 0 C. For example the process is conducted in methanol or ethanol at 50-90 0 C.
  • Process 2 Reacting a compound of general formula (V) wherein Ar is as defined in formula (I) with a suitable protecting group (PG ) on the phenolic group (as shown above), with a compound of formula (VI), wherein PG 1 is a suitable protecting group which may be the same or different to PG 2 and wherein the variables are as defind in formula (I), and L is a halogen,
  • Suitable catalysts include Li, Na, K iodides or tri-n-butylammonium iodide.
  • potassium iodide is optionally used.
  • L is a halogen such as chlorine or bromine.
  • bromine is used.
  • suitable protecting groups for PG 1 include tert-butyldimethylsilyl, tert-butyl- diphenylsilyl, methyldiphenylsilyl, tetrahydropyranyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl or benzyloxymethyl.
  • tert-butyldimethyl silyl is used.
  • suitable protecting groups for PG 2 include benzyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl, benzyloxymethyl.
  • benzyl is used.
  • Suitable bases include trialkylamines, such as triethylamine o ⁇ N,N- diisopropylethylamine, 2,6-lutidine, or pyridine (optionally in the presence of a catalyst such as 4-dimethylaminopyridine), or an alkali metal carbonate or bicarbonate (wherein alkali metal is, for example, Li, Na, K or Cs). For example sodium bicarbonate is used.
  • suitable solvents include dimethylsulphoxide, iV,iV-dimethylformamide, N- methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-dioxane, glyme or diglyme.
  • the process can be performed between 25 0 C and 15O 0 C. For example the process is conducted in dimethylsulphoxide at 65-145 0 C.
  • Suitable protecting groups for PG 2 include benzyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl, benzyloxymethyl.
  • benzyl is used.
  • suitable bases include trialkylamines, such as triethylamine or N 1 N- diisopropylethylamine or pyridine (optionally in the presence of a catalyst such as 4- dimethylaminopyridine) or an alkali metal carbonate or bicarbonate (wherein alkali metal is, for example, Li, Na, K or Cs).
  • suitable solvents include dimethylsulphoxide, N,N-dimethylforrnamide, ⁇ - methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-dioxane, glyme or diglyme.
  • the process can be performed between 25 0 C and 15O 0 C.
  • the process is conducted in dimethylsulphoxide at 90-145 0 C.
  • PG 1 is a suitable protecting group or hydrogen which may be the same or different to PG 2 and wherein the variables are as defined in formula (I).
  • the reaction is carried out in the presence of a suitable activating coupling agent, a suitable base and a suitable solvent.
  • activating coupling agents include carbonyldiimidazole or O-(7- azabenzotriazol-l-y ⁇ TVi ⁇ N' ⁇ '-tetramethyluroniurnhexafluorophosphate (HATU), or a mixture of iV-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 1- hydroxybenzotriazole.
  • HATU 0(7-azabenzotriazol-l-yi) N,N,N',N'- tetramethyluroniumhexafluorophosphate
  • Suitable bases include trialkylamines, such as triethylamine or N 1 N- diisopropyletliylamine or pyridine (optionally in the presence of a catalyst such as 4- dimethylaminopyridine).
  • triethylamine is used.
  • suitable solvents include N,iV-dimethylformamide, N-methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme or diglyme or chlorinated solvents such as dichloromethane or chloroform.
  • the process can be performed between O 0 C and 6O 0 C.
  • the process is conducted in N, N-dimethylformamide at ambient (10 to 30 0 C) temperature.
  • Suitable protecting groups for PG 1 include tert-butyldimethylsilyl, tert-butyl- diphenylsilyl, methyldiphenylsilyl, tetrahydropyranyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl or benzyloxymethyl.
  • tert-butyldimethyl silyl is used.
  • Suitable protecting groups for PG 2 include benzyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl, benzyloxymethyl.
  • benzyl is used.
  • Compounds of formula (II) can be prepared by reaction of compounds of formula (V) with a suitable nitrogen nucleophile in the presence (or absence) of a suitable base and solvent followed by reduction.
  • PG 1 and PG 2 are suitable protecting groups as described above.
  • nucleophiles examples include metal azides of Li, Na or K.
  • Suitable bases include trialkylamines, such as triethylamine or N,N- diisopropylethylamine or pyridine (optionally in the presence of a catalyst such as 4- dimethylaminopyridine) or an alkali metal carbonate or bicarbonate (alkali metal is, for example, Li, Na, K or Cs).
  • suitable solvents include dimethylsulphoxide, N,N-dimethylamides, ⁇ - methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme.
  • the reaction can be performed between 25 0 C and 100 0 C.
  • the process is conducted using sodium azide as nucleophile, in ⁇ , ⁇ -dimethylformamide as solvent and at 40-60 0 C.
  • Suitable reducing agents include hydrogen gas in the presence of a suitable catalyst and solvent or triphenylphosphine in the presence of water.
  • hydrogen gas in the presence of 10% palladium on charcoal is used in a mixture of tetrahydrofuran and ethanol at ambient (10-30 0 C) temperature.
  • compounds of formula (III) can be prepared by reacting compounds of formula (IX) through a ring or exocyclic nitrogen atom with compounds of formula (X) followed by deprotection of the carbonyl protecting group (PG 3 ) , wherein the variables are as defined in formula (I)
  • Suitable protecting group (PG 3 ) include alkyl / cyclic acetals or ketals.
  • ketal derived from ethylene glycol is used.
  • Suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride in the presence of a suitable organic acid such as a Ci -6 aliphatic carboxylic acid.
  • a suitable organic acid such as a Ci -6 aliphatic carboxylic acid.
  • sodium triacetoxyborohydride in the presence of acetic acid is used.
  • suitable solvents include JV-methyl-2-pyrrolidinone, acetonitrile, butyronitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme.
  • the reaction can be performed between O 0 C and 100 0 C.
  • tetrahydrofuran at ambient (10-30 0 C) temperature is used.
  • compounds of formula (III) can be prepared by reaction of compounds of formula (IX) with compounds of formula (XII) followed by subsequent reduction and deprotection
  • L is a leaving group (such as hydroxyl or halogen, for example chlorine) and the variables are as defined in formula (I).
  • an activating reagent for example, carbonyldiimidazole or O-(7-azabenzotriazol- 1 -yl) N 1 N 1 N', N'-tetramethyluroniumhexafluorophosphate (HATU), in organic solvent, for example, N,N-dimethylformamide or dichloromethane, at a temperature, for example in the range O 0 C to 6O 0 C.
  • the reaction is conveiently carried out in the presence of a base, for example triethylamine or N 5 N- diisopropylethylamine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range O 0 C to 25 0 C.
  • a base for example triethylamine or N 5 N- diisopropylethylamine
  • organic solvent for example, dichloromethane or tetrahydrofuran
  • subsequent reducing agents include borane-THF complex, lithium aluminium hydride or diisobutylaluminium hydride in a suitable solvent such as tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme at a temperature, for example, in the range O 0 C to 6O 0 C.
  • Suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride in the presence of a suitable organic acid such as a Cj -6 aliphatic carboxylic acid.
  • a suitable organic acid such as a Cj -6 aliphatic carboxylic acid.
  • sodium triacetoxyborohydride in the presence of acetic acid 5 is used.
  • Suitable solvents include iV-methyl-2-pyrrolidinone, acetonitrile, butyronitrile, and ethers such as tetrahydroruran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme.
  • the reaction can be performed between O 0 C and 100 0 C. For example 0 tetrahydrofuran at ambient (10-30 0 C) temperature is used.
  • compounds of formula (VIII) can be prepared by reaction of compounds of formula (XI) with compounds of formula (XII) followed by subsequent reduction and deprotection wherein L is a leaving group (such as hydroxyl or halogen, for example 5 chlorine) and the variables are as defined in formula (I).
  • L is a leaving group (such as hydroxyl or halogen, for example 5 chlorine) and the variables are as defined in formula (I).
  • the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole or O-(7-azabenzotriazol-l-yl) N 1 N 1 N ',N'- tetramethyluroniumhexafluorophosphate (HATU), in organic solvent, for example, N 1 N- dimethylformamide or dichloromethane, at a temperature, for example in the range O 0 C to o 6O 0 C.
  • an activating reagent for example, carbonyldiimidazole or O-(7-azabenzotriazol-l-yl) N 1 N 1 N ',N'- tetramethyluroniumhexafluorophosphate (HATU)
  • organic solvent for example, N 1 N- dimethylformamide or dichloromethane
  • the reaction is conveniently carried out in the presence of a base, for example triethylamine or N,N-diisopropylethylamine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range O 0 C to 25 0 C.
  • a base for example triethylamine or N,N-diisopropylethylamine
  • organic solvent for example, dichloromethane or tetrahydrofuran
  • subsequent reducing agents include borane-THF complex, lithium aluminium hydride or diisobutylaluminium hydride in a suitable solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme at a temperature, for example, in the range O 0 C to 6O 0 C.
  • Compounds of formula (VI) can be prepared from compounds of formula (III) by reaction with suitable sources of ammonia, for example, ammonium chloride in the presence of a suitable reducing agent, organic acid and solvent.
  • suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride in the presence of a suitable organic acid such as a C 1-6 aliphatic carboxylic acid.
  • sodium cyanoborohydride in the presence of acetic acid is used.
  • suitable solvents include N-methyl-2-pyrrolidinone, acetonitrile, butyronitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme.
  • the temperature of the reaction can be performed between O 0 C and 100 0 C.
  • tetrahydrofuran at ambient (O 0 C to 3O 0 C) temperature is used.
  • Suitable amine protecting groups include fert-butyloxycarbonyl, benzyloxycarbonyl, trifluromethylcarbonyl or phthalimido.
  • tert- butyloxycarbonyl is used.
  • suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride in the presence of a suitable organic acid such as a Cj -6 aliphatic carboxylic acid.
  • sodium triacetoxyborohydride in the presence of acetic acid is used.
  • suitable solvents include N-methyl-2-pyrrolidinone, acetonitrile, butyronitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme.
  • the temperature of the reaction can be performed between O 0 C and 100 0 C.
  • tetrahydrofuran at ambient (O 0 C to 3O 0 C) temperature is used.
  • compounds of formula (VI) can be prepared by reaction of compounds of formula (XIII) with compounds of formula (XII) followed by subsequent reduction and deprotection wherein L is a leaving group (such as hydroxyl or halogen, eg chlorine) and the variables are as defined in formula (I).
  • L is a leaving group (such as hydroxyl or halogen, eg chlorine) and the variables are as defined in formula (I).
  • the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole or O-(7-azabenzotriazol-l-yl) N,N,N',N'- tetramethyluroniumhexafluorophosphate (HATU), in organic solvent, for example, N 5 N- dimethylformamide or dichloromethane, at a temperature, for example in the range O 0 C to 6O 0 C.
  • an activating reagent for example, carbonyldiimidazole or O-(7-azabenzotriazol-l-yl) N,N,N',N'- tetramethyluroniumhexafluorophosphate (HATU)
  • organic solvent for example, N 5 N- dimethylformamide or dichloromethane
  • the reaction is conveiently carried out in the presence of a base, for example triethylamine or iV,iV-diisopropylethylamine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range O 0 C to 25 0 C.
  • a base for example triethylamine or iV,iV-diisopropylethylamine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range O 0 C to 25 0 C.
  • organic solvent for example, dichloromethane or tetrahydrofuran
  • subsequent reducing agents include borane-THF complex, lithium aluminium hydride or diisobutylaluminium hydride in a suitable solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane,
  • compounds of formula (III), (VIII), and (VI) may be prepared by reacting the correseponding compounds compounds (IX), (XI) and (XIII) with compounds of formula (XIV):
  • L is a leaving group (such as mesylate, tosylate, triflate or halogen, eg chlorine) and the variables are as defined in formula (I).
  • L is tosylate is used.
  • the reaction is conveniently carried out in the presence of a base, for example trialkylamines, such as triethylamine or N,iV-diisopropylethylamine or pyridine (optionally in the presence of a catalyst such as 4-dimethylaminopyridine) or an alkali metal carbonate or bicarbonate (alkali metal is, for example, Li, Na, K or Cs) and a suitable solvent.
  • a base for example trialkylamines, such as triethylamine or N,iV-diisopropylethylamine or pyridine (optionally in the presence of a catalyst such as 4-dimethylaminopyridine) or an alkali metal carbonate or bicarbonate (alkali metal is, for example, Li,
  • suitable solvents include 7V-methyl-2-pyrrolidinone, acetonitrile, butyronitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme.
  • the temperature of the reaction can be performed between O 0 C and 100 0 C.
  • triethylamine in iV-methyl-2-pyrrolidinone at 85 0 C is used.
  • nucleophiles include metal azides of Li, Na or K.
  • suitable bases include trialkylamines, such as triethylamine or N, N-diisopropylethylamine or pyridine (optionally in the presence of a catalyst such as 4-dimethylaminopyridine) or an alkali metal carbonate or bicarbonate (wherein alkali metal is, for example Li, Na, K or Cs).
  • suitable solvents include dimethylsulphoxide, ⁇ iV-dimethylformamide, N- methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme.
  • the temperature of the reaction can be performed between 25 0 C and 100 0 C.
  • the nucleophile is sodium azide in N,N-dimethylformamide as solvent at 5O 0 C (for example 4O 0 C to 6O 0 C) is used.
  • Suitable reducing agents include hydrogen gas in the presence of a suitable catalyst and solvent or triphenylphosphine in the presence of water.
  • hydrogen gas in the presence of 10% palladium on charcoal in a mixture of tetrahydrofuran and ethanol at ambient temperature (1O 0 C to 3O 0 C) is used
  • Compounds of formula (V), wherein Ar is as defined in formula (I) with a suitable protecting group (PG 2 ) on the phenolic group can be prepared by reaction of compounds of formula (XV) by reacting with a reagent capable of acting as a suitable protecting group (PG 1 ) such as tert-butyldimethylsilyl chloride or fert-butyldimethylsilyl triflate in the presence of a suitable base and solvent.
  • a suitable protecting group PG 1
  • tert-butyldimethylsilyl triflate is used.
  • Suitable bases include trialkylamines, such as triethylamine, N,N- diisopropylethylamine, 2,6-lutidine or pyridine (optionally in the presence of a catalyst such as imidazole or 4-dirnethylarninopyridine).
  • 2,6-lutidine is used.
  • suitable solvents include N, N-dimethylformamide, iV-methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme.
  • the reaction can be performed at temperatures between 25 0 C and 100 0 C.
  • N,iV-dimethylformamide at ambient temperature (1O 0 C to 3O 0 C) is used.
  • Compounds of formula (XV), wherein Ar is as defined in formula (I) with a suitable protecting group (PG 2 ) on the phenolic group can be prepared by reaction of compounds of formula (XVI), wherein L is a halogen, with a suitable reducing agent such as borane- THF complex in a solvent to produce achiral compounds or with a suitable chiral reducing agent in a suitable solvent to produce single enantiomeric compounds.
  • a suitable reducing agent such as borane- THF complex in a solvent to produce achiral compounds or with a suitable chiral reducing agent in a suitable solvent to produce single enantiomeric compounds.
  • Suitable chiral reducing agents include either (lR,2S)-(+)-cis-l-amino-2- indanol or (R)-(+)-2-methyl-CBS-oxazaborolidine in the presence of a reducing agent such as borane-tetrahydrofuran complex.
  • Suitable solvents include ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme.
  • the reaction can be performed at temperatures between -3O 0 C to +3O 0 C.
  • (R)-(+)-2-methyl- CBS-oxazaborolidine as catalyst with reducing agent borane-THF complex in tetrahydrofuran at - 10 0 C is used.
  • Compounds of formula (VII) can be prepared from compounds of formula (XV) in the presence of a suitable base and solvent, wherein L is a halogen and PG 2 is a suitable protecting group as described above.
  • suitable bases include an alkali metal carbonate or bicarbonate, such as a carbonate of Li, Na, K or Cs.
  • suitable solvents include dimethylsulphoxide, N, JV-dimethylamides, N-methyl-2-pyrrolidinone, butyronitrile, 2-butanone, water, acetonitrile, and ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme.
  • the reaction can be performed at temperatures between 25 0 C and 125 0 C.
  • potassium carbonate in butanone and water as solvent at reflux is used.
  • Compounds of formula (XXV) can be prepared by reacting a compound of formula (III) with a sulphur ylide for example timethylsulphonium- or trimethylsulphoxonium- methylide (prepared from timethylsulphonium- or trimethylsulphoxonium iodide and a base such as sodium hydride or potassium- or sodium-tert-butoxide) in a solvent such as dimethylsulfoxide and/or ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4- dioxane, glyme and diglyme.
  • the reaction can be performed at temperatures in the range from -10 to 100 0 C.
  • trimethylsulphoxnium iodide with sodium hydride in mixtures of dimethylsulphoxide and tetrahydrofuran are used at ambient temperature.
  • Suitable protecting groups for PG 1 include tert-butyldimethylsilyl, tert-butyl- diphenylsilyl, methyldiphenylsilyl, tetrahydropyranyl, trimethylsilylethoxymethyl, phenyloxymethyl, methyloxymethyl or benzyloxymethyl.
  • tert-butyldimethyl silyl is used.
  • Suitable protecting groups for PG 5 include, methyl, ethyl, propyl, wopropyl, butyl, wobutyl, tert-butyl or benzyl.
  • tert-butyl is used.
  • Suitable acids and bases include trifluoroacetic acid, hydrochloric acid, alkali metal hydroxides.
  • suitable solvents include dichloromethane, methanol, trifluoroacetic acid, tetrahydrofuran, water.
  • the reaction can be performed at temperatures between O 0 C and 60 0 C.
  • PG 5 is tert-butyl
  • trifluoroacetic acid in trifluoroacetic acid as solvent at ambient (1O 0 C to 30 0 C) temperature is used.
  • Compounds of formula (XX) can be prepared from the reaction of compounds of formula (XXI) with compounds of formula (II) or (IV) in the presence of a suitable reducing agent, acid and solvent.
  • Suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride or hydrogen in the presence of a suitable catalyst such as palladium on carbon or palladium oxide, in the absence or presence of a suitable organic acid such as a C 1-6 aliphatic carboxylic acid.
  • a suitable catalyst such as palladium on carbon or palladium oxide
  • a suitable organic acid such as a C 1-6 aliphatic carboxylic acid.
  • suitable organic acid such as a C 1-6 aliphatic carboxylic acid.
  • suitable organic acid such as a C 1-6 aliphatic carboxylic acid.
  • suitable organic acid such as a C 1-6 aliphatic carboxylic acid.
  • suitable organic acid such as a C 1-6 aliphatic carboxylic acid.
  • suitable solvents include N-methyl-2-pyrrolidinone, acetonitrile, butyronitrile and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-
  • compounds of formula (XX) can be prepared from the reaction of compounds of formula (XXII) with compounds of formula (V) in the presence of a suitable base and solvent (optionally in the presence of a catalyst such as a alkali metal iodide or tri-alkonium iodide may be used).
  • a catalyst such as a alkali metal iodide or tri-alkonium iodide may be used.
  • Suitable catalysts include Li, Na, K iodides or tri-n-butylammonium iodide.
  • potassium iodide is used.
  • Suitable bases include trialkylamines, such as triethylamine o ⁇ N,N- diisopropylethylamine, 2,6-lutidine, or pyridine (optionally in the presence of a catalyst such as 4-dimethylaminopyridine), or an alkali metal carbonate or bicarbonate (wherein alkali metal is, for example, Li, Na, K or Cs). For example sodium bicarbonate is used.
  • suitable solvents include dimethylsulphoxide, i ⁇ iV-dimethylformamide, N- methyl-2-pyrrolidinone, butyronitrile, acetonitrile, and ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-dioxane, glyme or diglyme.
  • the process can be performed between 25 0 C and 15O 0 C. For example the process is conducted in dimethylsulphoxide at 65-145 0 C.
  • Compounds of formula (XXI) can be prepared from the reaction of compounds of formula (XXIII) with compounds of formula (XXIV) in the presence of a suitable base and solvent wherein L is a suitable leaving group (such as a halogen, eg Cl, Br, I). For example where L is chlorine and bromine is used.
  • L is a suitable leaving group (such as a halogen, eg Cl, Br, I).
  • halogen eg Cl, Br, I
  • Suitable bases include trialkylamines, such as triethylamine or N,N ⁇ diisopropylethylamine or pyridine or l,5-diazabicyclo[5.4.0]undec-5-ene (optionally in the presence of a catalyst such as 4-dimethylaminopyridine) or an alkali metal carbonate or bicarbonate (wherein alkali metal is, for example, Li, Na, K or Cs).
  • a catalyst such as 4-dimethylaminopyridine
  • alkali metal carbonate or bicarbonate wherein alkali metal is, for example, Li, Na, K or Cs.
  • triethylamine is used.
  • suitable solvents include dimethylsulphoxide, ⁇ N-dimethylformamide, N- methyl-2-pyrrolidinone, butyronitrile, acetonitrile, chloroform, dichloromethane and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme or diglyme.
  • the process can be performed between 25 0 C and 15O 0 C. For example the process is conducted in chloroform at reflux.
  • Compounds of formula (XXII) can be prepared from the reaction of compounds of formula (XIII) with compounds of formula (XXIV) in the presence of a suitable base and solvent, followed by removal of the amine protecting group.
  • Suitable bases include trialkylamines, such as triethylamine or N,N- diisopropylethylamine or pyridine or l,5-diazabicyclo[5.4.0]undec-5-ene (optionally in the presence of a catalyst such as 4-dimethylaminopyridine) or an alkali metal carbonate or bicarbonate (wherein alkali metal is, for example, Li, Na, K or Cs).
  • triethylamine is used.
  • suitable solvents include dimethylsulphoxide, ⁇ iV-dimethylformamide, N- methyl-2-pyrrolidinone, butyronitrile, acetonitrile, chloroform, dichloromethane and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme or diglyme.
  • the process can be performed between 25 0 C and 15O 0 C. For example the process is conducted in chloroform at reflux.
  • compounds of formula (XXII) can be prepared from compounds of formula (XXI) by reaction with a suitable source of ammonia, in the presence of a suitable reducing agent, acid and solvent.
  • Suitable sources of ammonia include ammonia gas, ammonium chloride and ammonium acetate.
  • Suitable reducing agents include sodium cyanoborohydride or sodium triacetoxyborohydride or hydrogen in the presence of a suitable catalyst such as palladium on carbon or palladium oxide, in the absence or presence of a suitable organic acid such as a C 1-6 aliphatic carboxylic acid.
  • a suitable catalyst such as palladium on carbon or palladium oxide
  • a suitable organic acid such as a C 1-6 aliphatic carboxylic acid.
  • sodium triacetoxyborohydride in the presence of acetic acid is used.
  • suitable solvents include iV-methyl-2-pyrrolidinone, acetonitrile, butyronitrile and ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, glyme and diglyme.
  • the reaction can be performed at temperatures between 0 0 C and 100 0 C.
  • iV-methyl-2-pyrrolidinone or tetrahydrofuran at ambient (10-30 0 C) temperature is used.
  • the present invention further relates to novel chiral intermediate compounds, for example compounds of formula (IV)
  • the present invention also further relates to an intermediate compound of formula (XX):
  • Ar is as defind in formula (I);
  • PG 1 is suitable protecting group
  • X is a bond
  • A is piperidinyl linked to X through the 4-position and N-lmked to Y;
  • Y is (CH 2 ) 2 ;
  • PG 5 is either hydrogen or a suitable protecting group.
  • PG 1 is, for example, tert-butyldimethylsilyl, tert-butyl-diphenylsilyl or methyldiphenylsilyl.
  • PG 1 is, for example, tert- butyldimethyl silyl.
  • PG 5 is, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl or benzyl. In an embodiment of the invention PG 5 is, for example, tert-butyl.
  • Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures.
  • 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 0 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 5 chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vas
  • 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; osteoarthritis; 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 erythematos
  • arthritides 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);
  • 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-melanom
  • 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; 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;
  • 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; vulvo- vaginitis; 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; 11.
  • 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,
  • 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 provides a compound of formula (I) or a pharmaceutically- acceptable salt thereof as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • therapy also includes “prophylaxis” unless there are specific indications to the contrary.
  • therapeutic and “therapeutically” should be construed accordingly.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
  • Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
  • the invention still further provides 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) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
  • the compounds of this invention may be used in the treatment of adult respiratory distress syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma and rhinitis.
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • the daily dosage of the compound of the invention if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ( ⁇ g/kg) to 100 micrograms per kilogram body weight ( ⁇ g/kg).
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • 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, and such as from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler ® ; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
  • HFA heptafluoroalkane
  • Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
  • the compound is desirably finely divided.
  • the finely divided compound has, for example, a mass median diameter of less than 10 ⁇ m, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C 8 -C 2O fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • a dispersant such as a C 8 -C 2O fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • the compounds of the invention may also be administered by means of a dry powder inhaler.
  • the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
  • a carrier substance for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol.
  • Suitable carriers are sugars, for example, lactose, glucose, raff ⁇ nose, melezitose, lactitol, maltitol, trehalose, sucrose, manriitol; and starch.
  • the finely divided compound may be coated by another substance.
  • the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
  • This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • a multidose inhaler for example, that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • the active ingredient with or without a carrier substance, is delivered to the patient.
  • the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
  • the invention therefore further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, 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.
  • NSAIDs non-steroidal anti-inflammatory agents
  • COX-I / COX-2 inhibitors whether applied topically or systemically
  • 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
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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
  • the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-I), 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 5 invention, or a pharmaceutically acceptable salt thereof, 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 iV-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a I 0 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
  • the present invention further relates to the combination of a compound of the invention, or 15 a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4.
  • 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, 20 iralukast (CGP 45715A), and BAY x 7195.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective 5 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, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such o 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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 hydrochlor
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • Ml, M2, and M3 antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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.
  • a compound of the invention or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • 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, or a pharmaceutically acceptable salt thereof, and another systemic or topically-applied antiinflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • another systemic or topically-applied antiinflammatory 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcripta
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian 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 anti-Parkinsonian drug (such as deprenyl, L-dop
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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 agents, paracetamol, or a non-steroidal anti-inflammatory agent.
  • analgesic for example an opioid or derivative thereof
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof 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, or a pharmaceutically acceptable salt thereof, 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 BtIc, 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
  • -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 NK.subl.
  • NKP-608C SB-233412 (talnetant) or D-4418
  • elastase inhibitor such as UT-77 or ZD-0892
  • TACE TNF-alpha converting enzyme inhibitor
  • iNOS induced nitric oxide synthase
  • chemoattractant receptor-homologous molecule expressed on TH2 cells such as a CRTH2 antagonist
  • inhibitor of P38 agent modulating the function of Toll-like receptors (TLR),
  • agent modulating the activity of purinergic receptors such as P2X7
  • inhibitor of transcription factor activation such as NFkB, API, or STATS
  • a glucocorticoid receptor agonist a glucocorticoid receptor agonist.
  • the present invention provides a combination (for example for the treatment of COPD, asthma or allergic rhinitis) of a compound of formula (I) and one or more agents is selected from the list comprising: o a non-steroidal glucocorticoid receptor (GR-receptor) agonist; o a steriod (such as budesonide or fluticasone) o a PDE4 inhibitor including an inhibitor of the isoform PDE4D; o a muscarinic receptor antagonist (for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; o a modulator of chemokine receptor function (such as a CCRl receptor antagonist); or, o an inhibitor of p38 kinase function.
  • an antiproliferative/antineoplastic drug or a combination thereof, as used in medical s oncology such as an alkylating agent (for example cisplatin, 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 o adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such
  • 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 5 example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab
  • a farnesyl transferase inhibitor for example an EGFR family tyrosine kinase inhibitor such as iV-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholmopropoxy)quinazolin-4-amme (gefitinib, AZDl 839), iV-(3-ethynylphenyl)-6,7- o bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-iV-(3- chloro-4-fluorophenyl)-7-(3-mo ⁇ holinopropoxy)quinazolin-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family
  • an EGFR family tyrosine kinase inhibitor such as iV-(3-chloro-4-fluorophenyl)-7-methoxy-6-
  • 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-d
  • Reverse phase High Pressure Liquid Chromatography (HPLC) purification was performed using either a Waters Micromass LCZ with a Waters 600 pump controller, Waters 2487 detector and Gilson FC024 fraction collector or a Waters Delta Prep 4000 or a Gilson Auto Purification System, using a ACE ® , Symmetry ® , NovaPak ® or Xterra ® reverse phase silica column.
  • step (ii) The crude product from step (ii) was dissolved in methanol (5 mL).
  • methanol 5 mL
  • the product of example 5 step (ii) [5-((li?)-2-amino-l- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-8- 0 hydroxyquinolm-2(lH)-one (WO 2004/106333)] (0.25 g), was then added along with AcOH (0.043 mL). After stirring at room temperature for 2h, sodium cyanoborohydride (57 mg) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction was quenched with concentrated aqueous NH 3 solution and concentrated in vacuo.
  • the crude material was redissolved in DCM, filtered and purified by column 5 chromatography eluting with 1% NH 3 / 9% methanol in DCM.
  • the product fractions were concentrated in vacuo.
  • the product was redissolved in THF (5 mL) and treated with triethylamine trihydrofluoride (1.24 mL) and stirred for 18h at room temperature.
  • the reaction was concentrated in vacuo and the residue applied to Argonaut Technologies MP- TsOH(65) resin column (1 g). The resin was washed with methanol and the product eluted o with 3M methanolic NH 3 .
  • step (i) (8-(benzyloxy)-5-(bromoacetyl)quinolin-2(lH)-one) (5.0 g) was placed in an oven-dried flask and dried for 2 d under vacuum at 4O 0 C, then to it was added dry THF (100 mL).
  • (R)-(+)-2-Methyl-CBS-oxazaborolidine (2.20 mL, l.OM in toluene) was added and the mixture cooled to -1O 0 C.
  • Borane-THF complex (16.2 mL, 1.0M) was added over 3.5h using a syringe pump. The reaction mixture was stirred at -10 to O 0 C for Ih.
  • step (vii) 8-Hydroxy-5- ⁇ (lR)-l-hydroxy-2-[(*r ⁇ ns-4- ⁇ [2-(2- phenylethoxy)ethyl]amino ⁇ cyclohexyl)amino]ethyl ⁇ quinolin-2(li?)-one
  • a solution of the product from step (vii) (7 mg) in dry THF (1 mL) was treated with triethylamine trihydrofluoride (0.025 mL) and stirred at room temperature overnight.
  • step (i) (4-[(li?)-2-azido-l-hydroxyethyl]-8-(benzyloxy)quinolin-2(lH)- one) (0.71 g) was dissolved in ethanol (10 mL) and THF (2 mL) and to it was added a suspension of 10% palladium on charcoal (71 mg) in ethanol (5 mL). The reaction mixture was hydrogenated at 5 bar pressure for 14 h then filtered through glass microfibre paper and concentrated in vacuo to give the sub-title compound as a dull yellow solid. Yield: 0.64g MS APCI+ 311 [M+H] + Used without further purification in the next step (iii)
  • step (ii) (4-[(li?)-2-amino-l-hydroxyethyl]-8-(benzyloxy)quinolin- 2(lH)-one) (0.64 g) was dissolved in ethanol (20 niL), methanol (2 mL) and concentrated hydrochloric acid (1.5 mL) and to it was added a suspension of 10% palladium on charcoal (0.21 g) in ethanol (5 mL). The reaction mixture was hydrogenated at 5 bar pressure for 4 h.
  • the reaction mixture was then treated with 0.880 NH 3 (10 mL) and the volatiles removed in vacuo.
  • the residue was diluted with isopropanol (5 mL) and loaded onto a Argonaut Technologies MP-TsOH(65) resin column (4.6 g), which had previously been washed with isopropanol.
  • the column was eluted with —50 ml isopropanol, followed by 1 : 3 0.880 NH 3 :isopropanol.
  • the product-containing fraction was concentrated in vacuo to leave a dark yellow oil. This was purified using a Biotage 4OS column, eluting with 1% 7M NH 3 in methanol in DCM, increasing the amount of methanol to 10%.
  • step (iii) (5-[(li?)-l- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-( ⁇ l-[2-(2- phenylethoxy)ethyl]piperidin-4-yl ⁇ amino)ethyl]-8-hydroxyquinolin-2(lH)-one) (0.114 g) was suspended in THF (5 mL) and to it was added triethylamine trihydrofluoride (0.2 mL). The reaction mixture was stirred at room temperature for 3 d, then diluted with methanol and the volatiles evaporated.
  • step (iv) (iV-benzyl-3-(4- ⁇ [(2i?)-2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-(8- is hydroxy-2-oxo-l,2-dihydroquinolm-5-yl)ethyl]amino ⁇ piperidm-l-yl)propanamide) (0.20 g) in THF (5 mL) was treated with triethylamine trihydrofluoride (0.28 mL) and stirred at room temperature for 18 h. The volatiles were evaporated in vacuo and the resulting residue loaded onto a Varian Bond Elut SCX resin column (10 g). The column was eluted with 50 mL 1:1 isopropanol: acetonitrile, followed by 1:2:2 0.880
  • the sub-titled compound was prepared according to the procedure outlined in example 6 step (i) using piperidin-4-ylmethanol (2 g) in CHCl 3 (40 mL), tert-butyl 3- bromopropanoate (3.9 mL), triethylamine (2.8 mL) at reflux for 18 h to give the sub-title compound as an orange oil. Yield: 3 g
  • Oxalyl chloride (0.67 mL) was added dropwise to a cooled (-78 0 C) solution of DMSO (0.57 mL) in DCM (30 mL) and stirred for 30 min.
  • a solution of the product from step (i) (tert-butyl 4-[4-(hydroxymethyi)piperidm-l-yl]butanoate) (1.5g) in DCM was then added dropwise over 10 min and stirred for a further 1 h at -78 0 C.
  • triethylamine (1.9 mL) the reaction mixture was allowed to warm to room temperature and stirred for a further 18 h then diluted with DCM and H 2 O and the layers separated.
  • the sub-titled compound was prepared according to the procedure outlined in example 6 step (ii) using the intermediate compound detailed above (tert-butyl 4-(4-formylpiperidin- l-yl)butanoate) (0.48 g), the product from example 3 step (ii) (4-[(li?)-2-amino-l- hydroxyethyl]-8-(benzyloxy)quinolin-2(lH)-one) (0.34g) followed by AcOH (0.06 mL) in NMP (15 mL) at room temperature for 2 h. Sodium triacetoxyborohydride (0.42 g) was subsquently added and stirred for a further 2 h to afford the sub-title compound as a yellow oil.
  • step (iii) The sub-titled compound was prepared according to the procedure outlined in example 6 step (iii) using the product from step (ii) (tert-hutyl 3-[4-( ⁇ [(2i?)-2- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo-l,2-dihydroquinolin-5- o yl)ethyl]amino ⁇ methyl)piperidin-l-yl]propanoate) (0.53 g) in TFA (20 mL) at room temperature for 1 h to afford the sub-title compound as a dark yellow oil. Yield: 0.24 g MS APCI+ 504 [M+H] +
  • the sub-titled compound was prepared according to the procedure outlined in example 6 step (iv) using a solution of the product from step (iii) (3-[4-( ⁇ [(2i?)-2- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo-l,2-dihydroquinolin-5- yl)ethyl]amino ⁇ methyl)piperidin-l-yl]propanoic acid) (0.17 g), benzylamine (0.37 mL), o triethylamine (0.14 mL) and HATU (0.34 g) in DMF (6 mL) and acetonitrile (3 mL) at room temperature for 30 min to afford the sub-title compound as a dark yellow oil. Yield: 0.2 g MS APCI+ 593 [M+H] +
  • step (v) The sub-titled compound was prepared according to the procedure outlined in example 6 step (v) using a solution of the product from step (iv) (iV-benzyl-3-[4-( ⁇ [(2i?)-2- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo-l,2-dihydroquinolin-5- 0 yl)ethyl]amino ⁇ methyl)piperidin-l-yl]propanamide) (0.2 g), with triethylamine trihydrofluoride (0.30 mL) in THF (5 mL) at room temperature for 3 h to afford the title compound as a off white solid. Yield: 70 mg MS APCI+ 479 [M+H] +
  • the sub-titled compound was prepared according to the procedure outlined in Example 6 step (iv) using a solution of the product from example 6 step (iii) (3-(4- ⁇ [(2i?)-2- ⁇ [ter ⁇ - butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo-l,2-dihydroquinolin-5- yl)ethyl]amino ⁇ piperidin-l-yl)propanoic acid) (0.22 g) 5 1,2,3,4-tetrahydro-isoquinoline (0.12 g), triethylamine (0.17 mL) and HATU (0.31 g) in DMF (5 mL) at room temperature for 10 min to afford the sub-title compound as a dark yellow oil. Yield: 0.27 g MS APCI+ 605 [MH-H] +
  • the sub-titled compound was prepared according to the procedure outlined in Example 6 step (v) using a solution of the product from step (i) (5-[(IR)-I- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ -2-( ⁇ 1 -[3-(3 5 4-dihydroisoquinolin-2(l#)-yl)-3- oxopropyl]piperidin-4-yl ⁇ amino)ethyl]-8-hydroxyquinolin-2(lH)-one) (0.27 g), with triethylamine trihydrofluoride (0.36 mL) in THF (5 mL) at room temperature for 18 h to afford the title compound as an off-white solid.
  • Example 6 step (iv) The sub-titled compound was prepared according to the procedure outlined in Example 6 step (iv) using a solution of the product from Example 6 step (iii) (3-(4- ⁇ [(2R)-2- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo-l,2-dihydroquinolin-5- yl)ethyl]amino ⁇ piperidin-l-yl)propanoic acid) (0.22 g), l-(2-chlorophenyl)methanamine (0.13 g), triethylamine (0.17 mL) and HATU (0.31 g) in DMF (5 mL) at room temperature for 18 h to afford the sub-title compound as a dark yellow oil. Yield: 0.28 g.
  • the sub-titled compound was prepared according to the procedure outlined in Example 6 step (v) using a solution of the product from step (i) (3-(4- ⁇ [(2i?)-2- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo-l,2-dihydroquinolin-5- yl)ethyl]amino ⁇ piperidin-l-yl)-iV-(2-chlorobenzyl)propanamide) (0.28 g), with triethylamine trihydrofluoride (0.36 mL) in THF (5 mL) at room temperature for 18 h to afford the title compound as an off-white solid. Yield: 0.18 g
  • Example 6 5 step (iv) The sub-titled compound was prepared according to the procedure outlined in Example 6 5 step (iv) using a solution of the product from Example 6 step (iii) (3-(4- ⁇ [(2i?)-2- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo-l,2-dihydroquinolin-5- yl)ethyl] amino ⁇ piperidin-l-yl)propanoic acid) (0.22 g), l-(2-methoxyphenyl)methanamine (0.12 g), triethylamine (0.17 mL) and HATU (0.31 g) in DMF (5 mL) at room temperature for 18 h to afford the sub-title compound as a dark yellow oil. Yield: 0.27 g. o MS APCI+ 609 [M+H] +
  • the sub-titled compound was prepared according to the procedure outlined in Example 6 s step (v) using a solution of the product from step (i) (3-(4- ⁇ [(2i?)-2- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo-l,2-dihydroquinolin-5- yl)ethyl]amino ⁇ piperidin-l-yl)-iV-(2-methoxybenzyl)propanamide) (0.27 g), with triethylamine trihydrofluoride (0.36 mL) in THF (5 mL) at room temperature for 18 h to afford the title compound as an off-white solid.
  • Example 12 s iV-(4-Cyanobenzyl)-3-(4- ⁇ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-l,2-dihydroquinolin-5- yl)ethyl]amino ⁇ piperidin-l-yl)propanamide i) 3-(4- ⁇ [(2R)-2- ⁇ [ter ⁇ -Butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo-l,2- dihydroquinolin-5-yl)ethyl]amino ⁇ piperidin-l-yl)-iV-(4-cyanobenzyl)propanamide
  • Example 6 step (iv) The sub-titled compound was prepared according to the procedure outlined in Example 6 step (iv) using a solution of the product from Example 6 step (iii) (3-(4- ⁇ [(2R)-2- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo- 1 ,2-dihydroquinolin-5- yl)ethyl]amino ⁇ piperidin-l-yl)propanoic acid) (0.22 g), 4-(aminomethyl)benzonitrile (0.12 g), triethylamine (0.17 mL) and HATU (0.31 g) in DMF (5 mL) at room temperature for 18 h to afford the sub-title compound as a dark yellow oil. Yield: 0.27 g. MS APCI+ 604 [M+H] +
  • Example 6 step (iv) The sub-titled compound was prepared according to the procedure outlined in Example 6 step (iv) using a solution of the product from Example 6 step (iii) (3-(4- ⁇ [(2i?)-2- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo-l,2-dihydroquinolin-5- yl)ethyl]amino ⁇ piperidin-l-yl)propanoic acid) (0.22 g), 2-(aminomethyl)phenol (0.12 g), triethylamine (0.17 mL) and HATU (0.31 g) in DMF (5 mL) at room temperature for 18 h to afford the sub-title compound as a dark yellow oil. Yield: 0.27 g. MS APCI+ 595 [M+H] +
  • step (iii) The crude product from step (iii) was dissolved in methanol (7 mL).
  • the product of Example 5 step (ii) (5-((li?)-2-amino-l- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-8- hydroxyquinolin-2(lH)-one) (0.2 g), was then added along with AcOH (0.037 mL). After stirring at room temperature for 2 h, sodium cyanoborohydride (41 mg) was added and the reaction mixture was stirred for 18 h at room temperature. The solvent was evaoprated in vacuo and the residue partitioned between EtOAc and water.
  • the sub-titled compound was prepared according to the procedure outlined in Example 5 step (iii) using a solution of the product from Example 3 step (v) (l-[3-(2- phenylethoxy)propyl]piperidin-4-one) (0.5 g), trimethylsulfoxonium iodide (0.63 g), 60% sodium hydride (0.15 g) and DMSO (4 mL) to afford the sub-title compound as a colourless oil. Yield: 0.5 g
  • Example 5 step (iv) The sub-titled compound was prepared according to the procedure outlined in Example 5 step (iv) using a solution of the product from step (i) (6-[3-(2-phenylethoxy)propyl]-l-oxa- 6-azaspiro[2.5]octane) (0.26 g) and the product from Example 5 step (ii) (5-((li?)-2-amino- l- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-8-hydroxyquinolin-2(lH)-one) (0.32 g) in methanol (10 mL) and TV, N-diisopropylethyamine (0.092 mL) which was heated at reflux for 24 h.
  • step (v) The title compound was prepared according to the procedure outlined in Example 5 step (v) using a solution of the product from step (ii) (5- ⁇ (li?)-l- ⁇ [fert- butyl(dimethyl)silyl]oxy ⁇ -2-[( ⁇ 4-hydroxy-l-[3-(2-phenylethoxy)propyl]piperidin-4- yl ⁇ methyl)amino]ethyl ⁇ -8-hydroxyquinolin-2(lH)-one) (0.17 g) in THF (5mL), treated with triethylamine trihydrofluoride (0.23 mL).
  • step (iii) (8-(benzyloxy)-5- ⁇ (li?)-l- ⁇ [fert-butyl(dimethyl)silyl]oxy ⁇ -2- [( ⁇ 4-methyl- 1 - [2-(2-phenylethoxy)ethyl]piperidin-4-yl ⁇ methyl)amino] ethyl ⁇ quinolin- 2(li ⁇ )-one) (0.311 g) was dissolved in THF (5 mL) and treated with triethylamine trihydrofluoride (0.25 mL). The reaction mixture was stirred at room temperature overnight then the volatiles evaporated to afford the sub-title compound as a yellow oil, which was used without further purification. Yield: 0.259 g MS APCI+ 570 [M+H] +
  • step (iii) (4-(4- ⁇ [(2i?)-2-hydroxy-2-(8-hydroxy-2-oxo-l,2- dihydroquinolin-5-yl)ethyl]amino ⁇ piperidin-l-yl)butanoic acid) (0.267 g) was dissolved in DMF (3 mL) then benzylamine (0.65 mL), triethylamine (0.25 mL) and HATU (0.46 g) were added. After 2 h more HATU (0.51 g) was added.
  • step (vii) The title compound was prepared according to the procedure outlined in Example 2 step (vii) using the product of step (iv) (8-(benzyloxy)-5- ⁇ (li?)-l- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ -2-[( ⁇ 4-methoxy-l-[2-(2-phenylethoxy)ethyl]piperidin-4- yl ⁇ methyl)amino]ethyl ⁇ qumolm-2(lH)-one) (60 mg) in THF (2 mL) treated with triethylamine trihydrofluoride (0.14 mL) and stirred at room temperature for 5 h. The volatiles were evaporated and the residue azeoptroped with toluene (x2).
  • reaction mixture was stirred at -78 0 C for 1 hour and then treated dropwise with triethylamine (77 mg), after which the cooling bath was removed and the mixture was allowed to warm to room temperature.
  • the reaction mixture was added to aqueous phosphate buffer (pH 7.2) (1OmL) and extracted with dichloromethane. The organic layer was dried with anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure to give the sub-titled compound. Yield: 99 mg MS APCI+ 262 (M+H) +
  • step (iii) (7-((lR)-2-azido-l-hydroxyethyl)-4-benzyloxy-3H- benzothiazol-2-one) (195 mg) in a mixture of ethanol (8 mL) and tetrahydrofuran (4 mL) was treated with 10% palladium on carbon catalyst (20 mg) and the resultant mixture was stirred vigorously under 3 atmospheres pressure of hydrogen gas for 20 hours. The catalyst was filtered off and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica column, eluting with 1% concentrated aqueous ammonia and 12% methanol in dichloromethane.
  • step (iv) 4-(BenzyIoxy)-7- ⁇ (lR)-l-hydroxy-2-[( ⁇ l-[2-(2-phenylethoxy)ethyl]piperidin-4- yl ⁇ methyl)amino]ethyl ⁇ -l,3-benzothiazol-2(3H)-one io
  • a solution of the product of step (iv) (7-[(lR)-2-amino-l-hydroxyethyl]-4-(benzyloxy) ⁇ l,3-benzothiazol-2(3H)-one hydrochloride) (133 mg) and the product of step (ii) (l-(2- phenethyloxy-ethyl)-piperidine-4-carbaldehyde) (99 mg) in methanol (20 mL) was treated with acetic acid (20 mg) and stirred at room temperature for 2 hours.
  • the sub-titled compound was prepared from the product of step (ii) ( ⁇ l-[3-(2- phenylethoxy)propyl]azetidin-3-yl ⁇ methanol (350 mg) using the method of example 19 step (ii) to give the sub-titled compound. Yield: 280 mg MS APCI+ 248 (M+H) +
  • step (iv) (7-[(lR)-2-amino-l-hydroxyemyl]-4-hydroxy-l,3- benzothiazol-2(3H)-one hydrochloride) (193 mg) and the product of step (iii) (l-(3- phenethyloxy-propyl)-azetidine-3-carbaldehyde) (140 mg) in methanol (5 mL) was treated with acetic acid (140 mg) and stirred for 40 minutes at room temperature. Sodium cyanoborohydride (29 mg) was added and stirring was continued for 18 hours.
  • step (ii) (2-[l-(2-phenethyloxy-ethyl)-piperidin-4-yl]- ethanol) (250 mg) and triethylamine (273 mg) in dichloromethane (3 mL), cooled to -10 0 C, was added in one portion a solution of sulphur trioxide-pyridine complex (431 mg) in dimethyl sulphoxide (3 mL). The cooling bath was removed and the mixture was stirred vigorously for 10 minutes.
  • the titled compound was prepared from the product of example 20 step (iv) (7-[(lR)-2- amino-l-hydroxyetliyl]-4-hydroxy-l,3-benzothiazol-2(3H)-one hydrochloride) (80 mg) and the product of step (iii) ([l-(2-phenethyloxy-ethyl)-piperidin-4-yl]-acetaldehyde) (88 mg) using the method of example 20 step (v). Purification was by flash chromatography on silica gel eluting with 1% concentrated aqueous ammonia and 16% methanol in dichloromethane to give the titled compound. Yield: 16 mg MS APCI+ 486 (M+H + , 100%)
  • Toluenesulfonylchloride (1.40g) was added at ambient temperature to a solution of the product of step (ii) (2-Phenethyloxy-ethanol) (1.13g) and 4-dimethylaminopyridine (20mg) in pyridine (5ml) to give a purple solution. After 18 h, the reaction mixture was 5 concentrated by rotary evaporation.
  • step (iv) 4-Hydroxy-7- ⁇ l-hydroxy-2-[l-(2-phenethyloxy-ethyl)-piperidin-4-ylamino]-ethyl ⁇ - 3H-b enzothiazol-2-one s
  • the product of step (iv) (l-(2-Phenethyloxy-ethyl)-piperidin-4-one) (150mg) in methanol (10ml) was added to the product of example 20 step (iv) (7-(2- Amino- 1 -hydroxy-ethyl)-4- hydroxy-3H-benzothiazol-2-one hydrochloride) (lOOmg) and stirred at ambient temperature for 30 minutes.
  • reaction mixture was quenched by careful addition of ethyl acetate (3 mL) followed by water (5 mL). Most of the tetrahydrofuran was removed under reduced pressure and the residue was partitioned between aqueous brine and ethyl acetate, the aqueous layer was re-extracted with ethyl acetate and the combined organic layers were washed with excess dilute aqueous hydrochloric acid. The acidic layer was treated with excess solid sodium bicarbonate and the mixture extracted twice with dichloromethane.
  • the sub-titled compound was prepared from the product of step (ii) ((!/?)- [1 -(2- phenethyloxy-ethyl)-piperidin-3-yl] -methanol) (420 mg) using the method of example 21 step (iii) togive the sub-titled compound. Yield: 250 mg MS APCI+ 262 (MH-H) +
  • step (iv) (7- [(7i?)-2-amino-l -hydroxy ethyl] -4- hydroxy-l,3-benzothiazol-2(3H)-one hydrochloride) (70 mg) and the product of step (iii) ((3R)- l-(2-phenethyloxy-ethyl)-piperidine-3-carbaldehyde) (90 mg) in methanol (5 mL) was treated with acetic acid (32 mg). Sodium cyanoborohydride (10 mg) was added and stirring was continued for 18 hours.
  • the sub-titled compound was prepared from ethyl (>S)-nipecotate-D-tartrate (2.56 g) using the method of example 23 step (i) to give the sub-titled compound. Yield: 1.37 g s MS APCI+ 320 (M+H) +
  • the sub-titled compound was prepared from the product of step (i) ((3i?)-l-(2- phenethyloxy-acetyl)-piperidine-3-carboxylic acid ethyl ester) (1.37 g) using the method of io Example 23 step (ii) to give the sub-titled compound. Yield: 0.6g MS APCI+ 264 (M+H) +
  • the sub-titled compound was prepared from the product of step (ii) ((3i?)-[l-(2- I 5 phenethyloxy-ethyl)-piperidin-3-yl]-methanol) (250 mg) using the method of Example 21 step (iii) to give the sub-titled compound. Yield: 162mg MS APCI+ 262 (M+H) +
  • step (iii) ((3i?)-l-(2-phenethyloxy- ethyl)-piperidine-3-carbaldehyde) (70 mg) and the product of Example 20 step (iv) (7- [(li?)-2-amino-l-hydroxyethyl]-4-hydroxy-l,3-benzothiazol-2(3H)-one hydrochloride) (60 mg) using the method of example 23 step (iv) to give the titled compound.
  • the sub-titled compound was prepared by the method of Example 26 step (iii) using the product of step (ii) (4-aminomethyl-l-(3-benzyloxy-propyl)-piperidin-4-ol) (310mg) and the product of example 2 step (iii) (8-(Ben2ryloxy)-5-((li?)-2-bromo-l- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ ethyl)quinolin-2(lH)-one) (122mg) as a semi-solid. Yield: 110 mg
  • the sub-titled compound was prepared by the method of Example 26 step (iv) using the product of step (iii) (8-benzyloxy-5-[2- ⁇ [l-(3-benzyloxy-propyl)-4-hydroxy-piperidin-4- ylmethyl]-amino ⁇ -l-(tert-butyl-dimethyl-silanyloxy)-ethyl]-lH-quinolin-2-one) (lOOmg) as a solid. Yield: 19mg
  • the titled compound was prepared by the method of example 26 step (v), from the product of step (iv) (5-[2- ⁇ [1 -(3-benzyloxy-propyl)-4-hydroxy-piperidm-4-ylmethyl]-amino ⁇ - 1 - (tert-butyl-dimethyl-silanyloxy)-ethyl]-8-hydroxy-lH-quinolin-2-one) (19mg) as a solid. Yield: 9mg MS APCI+ 482 (M+H) +
  • Trimethylsilylcyanide (0.35Ig) was added dropwise to the product of step (i) (l-(2- benzyloxy-ethyl)-piperidin-4-one) (550 mg) plus zinc iodide (30mg) cooled in ice. After Ih at O 0 C the mixture was heated at 60 0 C for a further 3 h then cooled to ambient temperature. All volatiles were evaporated in vacuo at 6O 0 C and the residue dissolved in ether (10ml) plus dry THF (5ml) and cooled in ice. Lithium aluminium hydride (IM solution in ether, 4ml) was added and the mixture stirred for 2 h with in ice bath cooling.
  • IM solution in ether 4ml
  • step (iii) (benzyloxy-5-[2- ⁇ [l-(2-benzyloxy-ethyl)-4-hydroxy-piperidin-4- ylmethyl] -amino ⁇ - 1 -(tert-butyl-dimethyl-silanyloxy)-ethyl]- 1 H-quinolin-2-one) ( 170mg) in ethanol (3ml) plus 2M HCl (0.25ml) was hydrogenated at 5 bar pressure with 10% Pd/C 0 catalyst (10mg). After 3hr more catalyst (5mg) was added and the hydrogenation was " continued for a further 6 h. Catalyst was filtered off and the solvent was evaporated.
  • step (iv) The product from step (iv) (5-[2- ⁇ [l-(2-benzyloxy-ethyl)-4-hydroxy-piperidin-4- ylmethyl]-amino ⁇ -l-(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-hydroxy-lH-quinolin-2-one) (50mg) in dry THF (ImI) was treated with triethylamine trihydrofluoride (154mg) and stirred at ambient temperature overnight under nitrogen. The volatiles were evaporated in vacuo at 75 0 C. The residue was dissolved in MeOH and applied to a SCX cartridge, washed with further MeOH and finally eluted with 7N methanolic ammonia. Evaporation gave a gum which was dried in vacuo to give the titled compound as a semi-solid. Yield: 30mg
  • the sub-titled compound was prepared from the product of step (iv) (l- ⁇ 2-[2-(3- chlorophenyl)ethoxy]ethyl ⁇ piperidin-4-one) (0.27g), using 60% sodium hydride (82 mg), trimethylsulphoxonium iodide (0.23g) in DMSO (4 mL) by the method of example 5 step (iii) as a yellow oil. Yield:0.28 g
  • step (vi) (5-((li?)-l- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2- ⁇ [(l- ⁇ 2-[2-(3- chlorophenyl)ethoxy]ethyl ⁇ -4-hydroxypiperidin-4-yl)methyl] amino ⁇ ethyl)-8- hydroxyquinolin-2(lH)-one) (0.39 g) was dissolved in THF (5 ml) and to it was added triethylamine trihydrofiuoride (0.6 mL). The reaction mixture was stirred at ambient temperature for 3d then the volatiles evaporated to afford a yellow oil.
  • the sub-titled compound was prepared from 4-piperidinone monohydrate hydrochloride (01.5 g) dissolved in DMF (10 mL) followed by addition of anhydrous potassium carbonate (2.8 g) and benzyl bromoacetate (2.3 g). The mixture was stired at room temperature overnight then poured into water and extracted with with ethyl acetate (x 3) and the combined extracts washed with water, collected, dried ( Na 2 SO 4 ) to give a colourless oil which solidified on standing. Yield: 2.6 g. MS APCI+ 248 (M-18)+H+
  • the sub-titled compound was prepared from the product of Example 5 step (ii) (5-((li?)-2- amino-l- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-8-hydroxyquinolin-2(lH)-one) (100 mg) and the product from step (i) (benzyl (4-oxopiperidin-l-yl)acetate) (158 mg) dissolved in NMP (6 ml) followed by addition of acetic acid (1 drop) and activated 4 A molecular sieves (6 pellets). The mixture was stirred for 14 h before addition of sodium triacetoxyborohydride (253 mg) and further stirring for 24 h.
  • the titled compound was prepared from the product of step (ii) (benzyl (4- ⁇ [(2R)-2- ⁇ [tert- I 0 butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo- 1 ,2-dihydroqumolin-5- yl)ethyl]amino ⁇ piperidin-l-yl)acetate) (150 mg) dissolved in THF (4 ml) followed by addition of triethylaminetrihydrofluoride (0.3 ml) and the solution stirred at ambient temperature for 3 hours.
  • the subtitled compound was prepared from the product of step (i) (l-(4- phenoxybutyl)piperidin-4-one) (1.8 g), trimethylsilylcyanide (1.1 g) and zinc chloride (60 mg) in DMF (2 mL) followed by lithium aluminium hydride (12 mL, IM in THF) using the method of Example 26 step (ii) as a yellow solid. Yield: 2.5 g MS APCI+ 279 [M+H] +
  • step (iii) 8-(Benzyloxy)-5-[(lR)-l- ⁇ [te ⁇ -butyl(dimethyl)sUyl]oxy ⁇ -2-( ⁇ [4-hydroxy-l-(4- phenoxybutyl)piperidin-4-yl] methyl ⁇ amino)ethyl] quinolin-2(l/f)-one
  • step (ii) (4-(aminomethyl)-l-(4-phenoxybutyl)piperidin-4-ol) (0.2 g) and the product of Example 2 step (iii) (8-(benzyloxy)-5-((li?)-2-bromo-l- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ ethyl)quinolm-2(lH)-one) (0.23 g), potassium carbonate (0.19 g), sodium iodide (0.1 g) were heated in DMSO (2 mL) at 90 0 C for 6 h.
  • step (iii) (8-(benzyloxy)-5-[(li?)-l- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-( ⁇ [4- hydroxy-l-(4-phenoxybutyl)piperidin-4-yl]methyl ⁇ amino)ethyl]quinolin-2(lH)-one) (70 mg) in THF (2ml) was treated with triethylamine trihydroflouride (0.15 mL). After stirring for 18 h at ambient temperature the volatiles were evaporated in vacuo and the residue azeotroped with toluene (x2) to leave yellow gum.
  • Example 6 step (iii) (3-[4-( ⁇ [(2i?)-2- i 5 ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo-l,2-dihydroquinolm-5- yl)ethyl]amino ⁇ piperidin-l-yl]propanoic acid) (0.18 g), using HATU (0.29 g), triethylamine (0.19 mL) and adamantan-1 -amine (0.13 g) in dry DMF (4.1 mL) according to the procedure described in Example 27 step. Purification was by reverse phase HPLC using an Xterra® C8 5micron 19x50mm column eluting with a gradient of 95% 0.880 NH 3
  • step (iii) methyl 4-(azidomethyl)piperidine-4-carboxylate) (1.06 g) was added to a solution of the product from step (iv) 2-(2-phenylethoxy)ethyl trifluoromethanesulfonate (1.48 g) in DCM (55 mL). Hiinig's base (1.7 mL) was added and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO 3 , water, saturated aqueous NaCl, dried (Na 2 SO 4 ) and the volatiles evaporated.
  • step (vii) (8-(benzyloxy)-5- ⁇ (li?)-l- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2- [( ⁇ 4-(hydroxymethyl)-l-[2-(2-phenylethoxy)ethyl]piperidin-4-yl ⁇ methyl)amino]ethyl ⁇ - quinolin-2(lH)-one) (0.17 g) was dissolved in T ⁇ F (3 mL) and to it was added triethylamine trihydrofluoride (0.15 mL). The reaction mixture was stirred at room temperature for 2.5 h after which time further triethylamine trihydrofluoride (0.15 mL) was added. The mixture was stirred overnight then the volatiles evaporated to afford the subtitle compound as a yellow oil. Yield: 0.14 g MS APCI+ 586 [M+ ⁇ ] +
  • step (ii) (2,6-dichloro ⁇ iV-[2-(4-oxopiperidm-l- yl)ethyl]benzamide) (O.lg) and the product of Example 5 step (ii) (5-((li?)-2-amino-l- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-8-hydroxyquinolin-2(l/i)-one) (0.053g) in NMP (3 s mL) was treated with sodium triacetoxyborohydride (0.068g) and acetic acid (0.01 mL) at ambient temperature.
  • step (ii) 8-Hydroxy-5-[(R)-l-hydroxy-2-( ⁇ l-[2-((S)-2-phenylpropoxy)ethyl]piperidin-4- ylmethyl ⁇ amino)ethyl]-lH-quinolin-2-one i o
  • step (ii) 5 -(( 1 R)-2-amino- 1 - ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ ethyl)-8-hydroxy quinolin-2(lH)-one) (0.05 g) and the product of step (iii) (l-[2-(S)-2-phenylpropoxy)ethyl]piperidine-4-carbaldehyde) (0.04g) in methanol (1.6 mL) was treated with acetic acid (0.018 mL). Sodium cyanoborohydride (9.8 mg) was added and stirring continued for 18 h. The solvent was removed under reduced pressure
  • step (i) [2-(2-chloro-phenyl)-ethoxy]-acetic acid) (6.9g) was dissolved in DCM (100 mL) and treated with thionyl chloride (5 mL) with dry DMF (1 drop) at reflux. After 1 h at reflux all volatiles were evaporated and the residue was azeotroped with toluene. A solution of this acid chloride dissolved in DCM (50 mL) was then added to a solution of 4-hydroxy-piperidine (3.25g) dissolved in DCM (50 mL) and triethylamine
  • step (ii) (2-[2-(2-Chloro-phenyl)-ethoxy]-l-(4-hydroxy-piperidin-l-yl)- ethanone) (6.6g) in THF (100 mL) under nitrogen was treated with lithium aluminium hydride (50 mL, IM in THF,) and then set at reflux for 4 h, then left at room temperature for 24 h. Excess EtOAc was cautiously added and the reaction was stirred 2 h. IM NaOH solution (25 mL) was added and the whole was stirred until the solid mass broke up.
  • step (iii) (l- ⁇ 2-[2-(2-chloro-phenyl)-ethoxy]-ethyl ⁇ -piperidin-4-ol ) (710mg) was dissolved in dry DCM (6 mL) and N-methyl morpholine-N-oxide (360mg, 3.12mmol) and terapropylammonium perruthenate (7.5mol%, 66 mg) were added. The reaction was stirred at room temperature. After 1 h the reaction mixture was diluted with ether and filtered through a bed of alumina deactivated with 6% water. The bed was eluted with ether. Evaporation of fractions gave an oil which was purified by silica gel column chromatography eluting with EtOAc then EtOAc-0.5% triethylamine to afford the subtitle compound as an oil. Yield: 330mg
  • step (v) 5-((li?)-2- ⁇ [(l- ⁇ 2-[2-(2-chlorophenyl)ethoxy]ethyl ⁇ -4-hydroxypiperidin-4- yl)methyl]amino ⁇ -l-hydroxyethyI)-8-hydroxyquinolin-2(l J fiT)-one
  • step (v) (5- ⁇ l-(tert-butyl-dimethyl-silanyloxy)-2-[(l- ⁇ 2-[2-(2-chloro- phenyl)-ethoxy]-ethyl ⁇ -4-hydroxy-piperidin-4-ylmethyl)-amino]-ethyl ⁇ -8-hydroxy-lH- quinolin-2-one) (35 mg) was dissolved in dry THF (1 mL) and treated with triethylamine trihydrofluoride (0.2 mL) at room temperature for 16 h.

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UY30195A1 (es) 2007-10-31

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