HETEROCYCLIC COMPOUNDS USEFUL AS ANABOLIC AGENTS FOR
LIVESTOCK ANIMALS
The present invention relates to a series of 6 amino-7 hydroxy-4 5 6 7 tetrahydroimidazo[4 5 1-jk]-[1]benzazepin-2(1H)-ones More particularly it relates to a series of 6 (aryl-1-methylalkyl)amino-7-hydroxy-4 5 6 7-tetrahydroimidazo[4 5 1 jk][1]benzazepin-2(1H) ones The compounds act as agonists at the beta-2 adrenoceptor and are useful as anabolic agents for livestock animals
BACKGROUND
The pnmary focus in livestock production remains efficiency via optimising the conversion of feed into lean meat Feed constitutes a high proportion of the total economic investment in the final stages of livestock production and hence there is a continued demand for agents which enhance feed conversion ratio (FCR) The most effective way of improving FCR is via metabolic manipulation to enhance the animals potential to deposit muscle protein which also provides obvious benefits in yield grade and carcass composition
One approach to achieving higher quality meat and improving the meat yield is to administer agents that are agonists at the beta 2 adrenoceptor Examples of agents registered for such use in livestock animals are Zilmax™ (zilpaterol) and Optaflexx™ (ractopamine) Zilpaterol is (±) trans 6-(isopropylamino)-7-hydroxy-4 5 6 7-tetrahydro-imidazo[4 5 1 ,/fc](1]benzazepin 2(1H)-one Zilpaterol and similar analogues were first disclosed in FR2534257 and subsequently their use as animal feed additives was discussed in FR2608046 and EP272976 Ractopamine is (±)-4-(3-{[2-hydroxy 2-(4-hydroxyphenyl)ethyl]amino}butyl)phenol and was first disclosed by van Dijk and Moed (Reel Trav Chim Pays Bas, 1973 92 1281-1279) Its use as a feed additive was desenbed in GB2133986 Both zilpaterol and ractopamine are administered during the latter stages of a production animal s life and cause an activation of a biological cascade mechanism starting with interaction at the beta-2 adrenoceptor which promotes and enhances lean muscle growth A series of aryloxypropanolammes for improving livestock production have been recently disclosed in US-6841563
There is a continuing need for alternative beta 2 adrenoceptor agonists for use as agents to improve meat production in livestock animals and particularly for agonists with improved properties For reasons of economy the agent should preferably provide the desired improvement in meat production at a low dose It must also not produce any undesired effects in the target animal Finally the meat produced by the animal must be safe for human consumption which implies that the residual levels of the agent in the meat must be minimised The ideal agent will therefore have a high affinity for and be a fully efficacious agonist at the beta-2 adrenoceptor of the target animal species It will have a high degree of selectivity for this receptor and it will be rapidly cleared from the animal in order to minimise the presence of residues in the meat without requiring an extended withdrawal period A zero day withdrawal period provides the maximum economic benefit to the farmer Thus it is an aim of this invention to provide compounds which have a high affinity selectivity agonist efficacy and/or potency at
the beta-2 adrenoceptor of relevant livestock animals and/or that are rapidly metabolically cleared from
the animal
SUMMARY OF THE INVENTION
In a first aspect the present invention provides a compound of formula (I)
(Formula Removed)
or a pharmaceutically acceptable salt thereof wherein
A is -CH2- and
B is -CH2- -C(CH3)2 -O- -CH2-CH2- -CH2-0- or -0-CH2- or
-A B- is-CH=CH-
one of R1 and R2 is CH3 and the other is H
R' R4 R5 R8 and R7 are each independently selected from H R8 and R8 or
R4 and R5 together are -0-CH2-CH2- -CH2-CH2-0- or -O CH2 O- and R3 R8 and R7 are each
independently selected from H R8 and R9
R8 is halo CN C, C4 alkyl C1-C4 haloalkyl -CH2OH 0-(C1-C4 alkyl) 0-CH2-(C3-C5)cycloalkyl -C02H C02(CrC< alkyl) -CONH2 -CONH(C1-C4 alkyl) CONH(C1-C4 haloalkyl) -CONH(C3-C6 cycloalkyl) or NH2 and
R9 is -OH -NHSO2(C1-C3 alkyl) NHCO(C1- C4 alkyl) -NHCO(C1-C4 haloalkyl) NHSO2(C1-C3 haloalkyl) or-NHSO2(phenyl)
In a further aspect the present invention provides a feed additive for a livestock animal comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof
In a yet further aspect, the present invention provides a method of improving meat yield or meat quality in
a livestock animal comprising administering to said livestock animal an effective amount of a compound
of formula (I) or a pharmaceutically acceptable salt thereof
In a yet further aspect the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a medicament
In a yet further aspect the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof
DETAILED DESCRPTION OF THE INVENTION
For the purposes of the present document the following definitions apply
Alkyl means a saturated monovalent hydrocarbon radical CnH2n*i which may be linear or branched C1-C4 alkyl includes methyl ethyl n-propyl isopropyl (1-methylethyl) n butyl sec-butyl (1-methylpropyl) isobutyl (2-methylpropyl) and tert-butyl (1 1-dimethylethyl)
Cycloalkyl" means a saturated monovalent monocyclic or bridged or fused polycyclic hydrocarbon radical C3-C5 cycloalkyl includes cyclopropyl cyclobutyl and cyclopentyl
Halo" includes fluoro chloro bromo and lodo
Haloalkyl means an alkyl group as defined above wherein one or more hydrogen atoms is replaced by a halogen atom selected from fluorine chlorine bromine and iodine When the group contains more than one halogen atom then these atoms may be the same or different Haloalkyl includes perhaloalkyl i e an alkyl group wherein all the hydrogen atoms are replaced by halogen atoms C1-C4 haloalkyl groups include fluoromethyl difluoromethyl trifluoromethyl chlorodifluoromethyl 2-bromoethyl 2 2 2-trifluoroethyl 3-iodopropyl and 2 2 2 tnchloro-1 1-dimethylethyl
The compounds of formula (I) have three asymmetric carbon atoms (chiral centres) labelled 1 6 and 7 in the structural formula Certain embodiments of the substituents R3 to R7 may include additional chiral centres Unless otherwise indicated formula (I) depicts the relative stereochemistry at the three centres C-1 C-6 and C-7 It is not intended that the representation of formula (I) should be taken as implying the absolute stereochemistry at these centres Accordingly the present invention includes individual enantiomers of the compounds of formula (I) and mixtures thereof including racemates Where there is an additional chiral centre in a substituent then the invention includes diastereomenc mixtures as well as individual stereoisomers
The compounds of formula (I) wherein -A B- is -CH=CH- may exist as geometric isomers Unless otherwise indicated no particular geometry is implied by this notation Accordingly the present
invention encompasses such compounds in the as (Z-) or trans (E-) configuration as well as mixtures of
these geometric isomers
Certain compounds of formula (I) may exist in more than one tautomeric form The present invention encompasses all such tautomers as well as mixtures thereof
The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2H and 3H carbon, such as 11C 13C and 14C chlorine such as MCI fluorine such as 18F iodine such as 123l and 125l nitrogen such as 13N and 15N oxygen such as 150 170 and ,80, phosphorus such as 32P and sulphur such as 39S
Certain isotopically-labelled compounds of formula (i) for example those incorporating a radioactive isotope are useful in drug and/or substrate tissue distribution studies The radioactive isotopes tntium ie 3H andcarbon-14 le 14C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection
Substitution with heavier isotopes such as deuterium i e 2H may afford certain therapeutic advantages resulting from greater metabolic stability for example increased in vivo half life or reduced dosage requirements and hence may be preferred in some circumstances
Substitution with positron emitting isotopes such as 11C 18F 150 and 13N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy
Isotopically-labeied compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeied reagent in place of the non-labeled reagent previously employed
The compounds of formula (I) are able to form addition salts with acids Certain compounds of formula (I) which have an acidic functional group are able to form salts with suitable bases Such salts are included within the scope of the present invention to the extent that they are acceptable for veterinary or pharmaceutical use
Suitable acid addition salts are formed from acids which form non toxic salts Examples include the acetate adipate aspartate benzoate besylate bicarbonate/carbonate bisulphate/sulphate borate
camsylate citrate cyclamate edisylate esylate formate fumarate gluceptate gluconate glucuronate
hexafluorophosphate hibenzate hydrochlonde/chlonde hydrobromide/bromide hydroiodide/iodide
isethionate lactate malate maleate malonate mesylate methylsulphate naphthylate, 2 napsylate
nicotmate nitrate orotate oxalate palmitate pamoate phosphate/hydrogen phosphate/dihydrogen
phosphate pyroglutamate saccharate, stearate succinate tannate tartrate tosylate trrfluoroacetate
and xinafoate salts
Suitable base salts are formed from bases which form non toxic salts Examples include the aluminium argmine benzathine calcium choline diethylamine diolamine glycine lysine magnesium meglumine olamine potassium sodium tromethamme and zinc salts
Hemisalts of acids and bases may also be formed for example hemisulphate and hemicalcium salts
For a review on suitable salts see Handbook of Pharmaceutical Salts Properties Selection and Use by Stahl and Wermuth (Wiley-VCH 2002)
Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods
(i) by reacting the compound of formula (I) with the desired acid or base
(n) by removing an acid- or base-labile protecting group from a suitable precursor of the compound
of formula (I) or by ring-opening a suitable cyclic precursor for example a lactone or lactam
using the desired acid or base or (HI) by converting one salt of the compound of formula (I) to another by reaction with an appropriate
acid or base or by means of a suitable ion exchange column
All three reactions are typically carried out in solution The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent
The compounds of formula (I) and their salts may exist in a continuum of solid states ranging from fully amorphous to fully crystalline The term amorphous refers to a state in which the material lacks long range order at the molecular level and depending upon temperature may exhibit the physical properties of a solid or a liquid Typically such materials do not give distinctive X-ray diffraction patterns and while exhibiting the properties of a solid are more formally described as a liquid Upon heating a change from solid to liquid properties occurs which is charactensed by a change of state typically second order (glass transition ) The term crystalline refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X ray diffraction pattern with defined peaks Such materials when heated sufficiently will also exhibit the properties of a liquid but the change from solid to liquid is charactensed by a phase change typically first order (melting point)
The compounds of formula (I) and their salts may also exist in unsolvated and solvated forms The term
solvate is used herein to descnbe a molecular complex comprising the compound of the invention and
one or more pharmaceutically acceptable solvent molecules for example ethanol The term hydrate is
employed when said solvent is water
A currently accepted classification system for organic hydrates is one that defines isolated site channel or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K R Morris (Ed H G Bnttain Marcel Dekker 1995) Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules In channel hydrates the water molecules he in lattice channels where they are next to other water molecules In metal-ion coordinated hydrates the water molecules are bonded to the metal ion
When the solvent or water is tightly bound the complex will have a well-defined stoichiometry independent of humidity When however the solvent or water is weakly bound as in channel solvates and hygroscopic compounds the water/solvent content will be dependent on humidity and drying conditions In such cases non-stoichiometry will be the norm
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted e g D20 da-acetone d6-DMSO
Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometnc amounts Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions but could also be a complex of a neutral molecule with a salt Co-crystals may be prepared by melt crystallisation by recrystalhsation from solvents or by physically grinding the components together - see Chem Commun T7 1889-1896 byO Almarsson and M J Zaworotko (2004) For a general review of multi-component complexes see J PharmSci 64(8) 1269-1288 by Haleblian (August 1975)
The compounds of formula (I) and their salts may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution) Mesomorphism arising as the result of a change in temperature is described as thermotropic and that resulting from the addition of a second component such as water or another solvent is described as lyotropic' Compounds that have the potential to form lyotropic mesophases are described as amphiphilic and consist of molecules which possess an ionic (such as COO Na* -COO K* or SO3 Na*) or non ionic (such as N N*(CH3)3) polar head group For more information see Crystals and the Polanzing Microscope by N H Hartshorne and A Stuart 4th Edition (Edward Arnold 1970)
Hereinafter all references to compounds of formula (I) include references to salts solvates multi-component complexes and liquid crystals thereof and to solvates multi component complexes and liquid crystals of salts thereof
The present invention also includes so called prodrugs of the compounds of formula (I) Thus certain denvatives of compounds of formula (I) which may have little or no pharmacological activity themselves can when administered into or onto the body be converted into compounds of formula (I) having the desired activity for example by hydrolytic cleavage Such derivatives are referred to as prodrugs Further information on the use of prodrugs may be found in Pro-druqs as Novel Delivery Systems Vol 14 ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drua Desian Pergamon Press 1987 (Ed E B Roche Amencan Pharmaceutical Association)
Prodrugs in accordance with the invention can for example be produced by replacing appropriate functionalities present in the compounds of formula I with certain moieties known to those skilled in the art as pro-moieties as described for example in Desiqn of Prodrugs by H Bundgaard (Elsevier 1985)
Examples of prodrugs in accordance with the invention include
(i) derivatives of the C-7 hydroxyl function such as esters and acyloxymethyl ethers wherein the
hydrogen of the hydroxyl group is replaced by an acyl group such as (C1-C6 alkyl)CO- or (optionally substituted aryl)CO- or by an acyloxymethyl group such as (C1 C6 alkyl)C02CH2-and
(n) derivatives of the C-6 secondary amine function such as amides and carbamates wherein the hydrogen of the amine group is replaced by an acyl group such as (C1-C6 alkyl)CO- or by an alkyloxycarbonyl group such as (C1-C6 alkyl)OCO-
Certain of the options for R3 to R7 may also be amenable to the formation of prodrugs
In a further aspect the present invention provides processes for the preparation of a compound of formula (I) or a pharmaceutically vetennarily or agriculturally acceptable salt thereof or a pharmaceutically vetennarily or agriculturally acceptable solvate (including hydrate) of either entity as illustrated below
It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention This may be achieved by conventional
methods for example as described in Protective Groups in Organic Synthesis by T W Greene and
PGM Wuts John Wiley & Sons Inc (1999) and references therein
The following processes are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention
When one or more of R3, R4 R5 R6 and R7 contain reactive functional groups then additional protection may be provided according to standard procedures during the synthesis of compounds of formula (I) In the processes described below for all synthetic precursors used in the synthesis of compounds of formula (I) the definitions of R3 R4 R5 R8 and R7 wherein R3 R4, R5 R6 and R7 are as defined for formula (I) are intended to optionally include suitably protected variants P3 P4 P5 P6 and P7 Such suitable protecting groups for these functionalities are described in the references listed below and the use of these protecting groups where needed is specifically intended to fall within the scope of the processes described in the present invention for producing compounds of formula (I) and its precursors When suitable protecting groups are used then these will need to be removed to yield compounds of formula (I) Deprotection can be effected according to standard procedures including those described in the references listed below
1 Preparation of compounds of Formula (I) 1 1 Reductive Animation
Compounds of formula (I) may be synthesised by the reductive animation of the methyl ketones of formula (II) wherein R3 R4 R5 R6 R7 A and Bare as defined for formula (I) using the ammo-alcohol of formula (III) as illustrated in Scheme A
Scheme A
(Scheme Removed)
wherein the wedge and dashed bonds indicate the relative stereochemistry of the 6 amino and 7-hydroxy substituents The skilled person will appreciate that the individual enantiomers or the racemate of formula (III) may be used for the reductive animation reaction
A variety of reaction conditions may be used In general reaction of the ammo-alcohol (III) with the ketones of formula (II) yields an imine (IV) which may be reduced in situ to give compounds of formula (I) Imine formation is achieved by standard methods for example by reaction of the ammo-alcohol (III) with the ketones (II) in an alcoholic solvent preferably methanol in the presence of a base such as tnethylamine or potassium hydroxide Reaction conditions may vary from room temperature to 50°C for periods ranging from 10 minutes to 60 hours optionally under nitrogen and optionally heating in a microwave Compounds of formula (I) may then be prepared by in situ imine reduction typically using
sodium borohydnde or sodium cyanoborohydnde at temperatures ranging from 0 C to 60°C for 1-60
hours typically overnight
The imine reduction proceeds with a range of diastereoselectivities though no predictive trend has yet
been observed
Compounds of formula (I) wherein A-B is CH=CH may be prepared using similar conditions to those described above by reductive animation of the ammo-alcohol (III) with the a,{3-unsaturated enones of formula (VII) wherein R3 R4 R5 R6 and R7 are as defined for formula (I) as illustrated in Scheme B
Scheme B
(Scheme Removed)
Using excess borohydnde reducing agent will also reduce the double bond so using enones of formula (VII) may yield compounds of formula (I) wherein A B is CH2 CH2 or A B is CH=CH i e compounds of formula (IX) or compounds of formula (VIII)
Compounds of formula (I) wherein A B is CH2-CH2 may also be prepared from compounds of fonmula (I) wherein A B is CH=CH using standard reducing agents such as hydrogen in the presence of a metal catalyst such as Wilkinson s catalyst palladium on carbon or platinum oxide in a protic solvent for example methanol or those described in "Handbook of Reagents for Organic Synthesis - Oxidising and Reducing Agents" edited by S D Burke and R L Danheiser
2 Preparation of tricyclic intermediates 2 1 Ammoalcohol (III)
The ammo-alcohol of formula (III) may be prepared as shown in Scheme C
Scheme C
(Scheme Removed)
a) Ethyl acetoacetate xylenes 15(rC b) 4 Bromobutync acid methyl ester K2C03 acetone reflux
c)15%NaOH THF reflux d) Cone HCI THF e) SOCI2 DCM f) AICI3 DCM reflux g) t BuONO HCI AcOH 40°C h) Pd/C H2, MeOH cone HCI 1 5 atm i) NaBH4 MeOH 0°C
The preparation of the compounds of formula (XI) (XII) (XIII) (XIV) (XV) and (XVI) is disclosed in Tetrahedron Letters 1995, 36 9 1387 The preparation of the compounds of formula (XVII) and (III) is disclosed in US Patent US-4585770
The enantiomers of the ammo-alcohol (III) may be separated by chiral HPLC N-protection facilitates the separation Those skilled in the art will appreciate that a variety of N-protected compounds may be used for example the t-butyloxycarbamate prepared by reacting the ammo-alcohol (III) with t-BOC-anhydnde in a suitable solvent such as methanol, in the presence of a base such as triethylamine Following chiral HPLC separation the t-BOC protecting group may be removed by acid hydrolysis for example stirring in 4N HCI/dioxane at room temperature for several hours typically 1 hour
The desired enantiomer of the ammo-alcohol (III) may also be prepared by the enantioselective reduction of the keto-oxime (XVII) Those skilled in the art will appreciate that the degree of enantioselectivity will depend on the catalyst ligand solvent and reaction temperature Particularly useful conditions use hydrogen in the presence of a metal catalyst such as rhodium chloro(norbornadiene) dimer complexed with a ligand such as 1 [(S) ferrocenyl-2-(R)-ethyl-1-dimethylamino)phenyl]-(S)-phosphmo-1 dicyclohexylphosphino-ferrocene (Solvias AG) in a protic solvent typically aqueous methanol at elevated temperatures normally 80°C for 10-40 hours typically 16 hours
3 Preparation of ketones (II)
Many of the methyl ketones of formula (II) used in the reductive animation procedure are commercially available Those skilled in the art will appreciate that others may be prepared by experimental procedures as described in the literature
3 1 Compounds wherein A-B is CH=CW
Enones of formula (VII) may be prepared according to the method illustrated in Scheme D from benzaldehydes of formula (XVII) wherein R3 R4 R5 R8 and R7 are as defined for formula (I) by a base catalysed condensation with acetone typically using sodium hydroxide as base at 0°C
Scheme D
(Scheme Removed)
Substituted benzaldehydes of formula (XIX), can be obtained by lithiation of the aryl bromides (XX) using for example n-butyl lithium in tetrahydrofuran followed by reaction of the aryl lithium reagent with N N-dimethylformamide Alternatively enones of formula (VII) may be prepared by reaction of aldehydes of formula (XIX) with 1 tnphenylphosphoranylidene-2-propanone at reflux in a suitable solvent, such as tetrahydrofuran for 5-20 hours normally 12 hours
3 2 Compounds wherein A-B is CHrCH2
Ketones of formula (II) wherein A B is CH2 CH2 may be prepared from enones of formula (VII) wherein A B is CH=CH using standard reducing agents such as hydrogen in the presence of a metal catalyst such as palladium on alumina in a suitable solvent for example ethyl acetate or those described in Handbook of Reagents for Organic Synthesis - Oxidising and Reducing Agents" edited by S 0 Burke and R L Oanheiser as illustrated in Scheme E
Scheme (Scheme Removed)
(VII) Ketones of formula (II) wherein A-B is CH2-CH2 may also be prepared by Heck coupling of the lodo compounds (XXI) with but 3-en-2-ol using Pd(OAc)2 as catalyst in a suitable solvent such as N N-dimethylformamide in the presence of a base such as triethylamine with optionally added inorganic salts, such as lithium chloride as illustrated in Scheme F The a p-enone (VII) may be obtained as a by product of this Heck coupling reaction
(Scheme Removed)
(VII) Compounds wherein R3 and R7 are both H and Rs is OH i e ketones of formula (XXII) wherein R4 and R6 are as defined for formula (I) may be obtained by reaction of the phenols of formula (XXIII) with methyl vinyl ketone in a suitable solvent such as toluene in the presence of an acid catalyst typically sulphuric acid as illustrated in Scheme G Preferably reagent addition occurs at 0°C followed by stirring of the reaction mixture for 2-24 hours typically overnight
Scheme G
(Scheme Removed)
Compounds of formula (XXVIII), wherein W = -SO2 or -CO and R10 is as defined for fonmula (I) may be prepared as shown in Scheme H
Scheme H
(Scheme Removed)
The enones of formula (XXIV) may be protected as the ethylene ketals of formula (XXV) by reaction with ethylene glycol in a suitable solvent such as toluene in the presence of an acid catalyst such as p-toluene sulfonic acid by heating at reflux in a Dean-Stark apparatus for several hours typically 5 hours The amines of formula (XXVI) may be prepared from the compounds of formula (XXV) using standard reducing agents such as hydrogen in the presence of a metal catalyst such as 10% palladium on carbon in a suitable solvent for example methanol using a flow through H Cube hydrogenator or those described in Handbook of Reagents for Organic Synthesis - Oxidising and Reducing Agents edited by S D Burke and R L Danheiser The amines of formula (XXVI) may be acylated and sulphonylated using
standard literature conditions well known to those skilled in the art The ketals of formula (XXVII) may be
deprotected by acid catalysed hydrolysis for example stirring in concentrated HCL/methanol at room
temperature for several hours typically 2 hours
3 3 Compounds wherein A B is CHrC(CH3)2
Ketones of formula (II) wherein A-B = -CH2C(CH3)2- may be prepared by the reductive arylation of 4-methylpent-3-en-2-one (XXIX) with benzenediazonium salts of formula (XXX) in a suitable aprotic solvent such as N.N-dimethylformamide in the presence of a Lewis acid catalyst such as titanium tetrachlonde as illustrated in Scheme I
Scheme I
(Scheme Removed)
Compounds wherein R3 is OH i e the methyl ketones (XXXI) may be prepared by the sequence of reactions shown in Scheme J
Scheme J
(Scheme Removed)
The chromanones of formula (XXXIII) may be prepared by stirring a solution of compounds (XXXII) in a suitable solvent typically dichloroethane in the presence of a Lewis acid such as aluminium chloride under nitrogen for 5-24 hours typically overnight The morpholinamides (XXXIV) are obtained by heating (XXXIII) in morpholine at elevated temperature typically 85CC for several hours for example 2 hours Reaction of the morpholinamides (XXXIV) with methyl lithium in a suitable solvent such as tetrahydrofuran at reduced temperature typically -60°C under nitrogen yields the ketones of formula (XXXI)
3 4 Compounds wherein A-B is CHrO
Alkylation of a monohaloacetone with phenols of formula (XXXV) or the corresponding phenolate anion in a suitable aprotic solvent such as acetonitnle optionally in the presence of a base for example triethylamine gives ketones of formula (II) in which A-B = -CH20- as illustrated in Scheme K
Scheme K
(Scheme Removed)
3 5 Compounds wherein A-B Is CHrCHrO
Ketones of formula (II) wherein A B = -CH2CH20- may be prepared by the reaction of phenols of formula (XXXV) with methyl vinyl ketone using procedures similar to those described in J Amer Chem Soc 1971 93 4 985 as illustrated in Scheme L
Scheme L
(Scheme Removed)
3 6 Compounds wherein A-B Is CHrO-CH2
Ketones of formula (II) wherein A B = CH2OCH2 may be prepared by the alkylation of hydroxyacetone with the appropriate benzyl bromide (XXXVI) by methods similar to those descnbed in US-5360819 Example 36 as illustrated in Scheme M
Scheme M
(Scheme Removed)
3 7 Compounds wherein A-B is CHrCHrCH2
Ketones of formula (II) wherein A B = CH2CH2CH2 may be prepared by an organometallic coupling of for example an organozmc reagent of formula (XXXVII) with 4-chloro-2 butanone optionally in the presence of a copper catalyst and lithium salts as illustrated in Scheme N Those skilled in the art will recognise that other organometallic reagents may be used
Scheme N
(Scheme Removed)
The orgaonozinc reagents of formula (XXXVII) may be prepared from the corresponding benzyl bromides using standard literature procedures
4 Miscellaneous transformations
It will be appreciated that certain of the substituents on the phenyl ring of the compounds of formula (II) will be amenable to further synthetic manipulation For example the methods illustrated in Schemes G and I result in products that contain a phenolic hydroxyl group Where the corresponding ethers are required then O-alkylation of these phenols can be effected by reaction with the appropriate organic halides using a base such as potassium carbonate in a suitable solvent such as acetone Reactions are stirred at elevated temperatures typically reflux for several hours typically overnight
Phenols of formula (XXXVIII) wherein A and B are as defined for formula (I) readily undergo standard substitution reactions
Scheme O
(Scheme Removed)
For example compounds of formula (XXXIX) may be prepared by the reaction of compounds of formula
(XXXVIII) with N-bromosuccinimide in a suitable solvent such as N,N-dimethylformamide at room
temperature for 10-25 hours, typically 18 hours as shown in Scheme O
Amides of formula (XLI) wherein A and B are as defined for formula (I) may be prepared from the acids of formula (XL) as shown in Scheme P
Scheme P
(Scheme Removed)
Those skilled in the art will recognise that many standard literature reaction conditions may be used to effect such amide formation some of these are reviewed in Amide bond formation and peptide coupling C A G N Montalbetti and V Falque Tetrahedron 2005 61 10827 10852 For example the acids of formula (XL) may be converted to the corresponding acid chlorides by reaction with oxalyl chlonde in a suitable solvent such as N /V-dimethylformamide These acid chlorides may be reacted with amines of formula R11NH2 in a suitable solvent such as dichloromethane
It will also be appreciated by persons skilled in the art that within certain of the processes described the order of the synthetic steps employed may be vaned and will depend inter alia on factors such as the nature of other functional groups present in a particular substrate the availability of key intermediates and the protecting group strategy (if any) to be adopted Clearly such factors will also influence the choice of reagent for use in the said synthetic steps
The skilled person will appreciate that the compounds of the invention could be made by methods other than those herein described by adaptation of the methods herein described and/or adaptation of methods known in the art for example the art described herein or using standard textbooks such as Comprehensive Organic Transformations A Guide to Functional Group Transformations RC Larock Wiley-VCH (1999 or later editions)
It is to be understood that the synthetic transformation methods mentioned herein are exemplary only and they may be carried out in various different sequences in order that the desired compounds can be efficiently assembled The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound
In a preferred embodiment -A- is -CH2- and -B- is -CH2- or C(CH3)2 or -A B- is -CH=CH- In a more
preferred embodiment -A- is -CH2- and -B- is -CH2-
When -A-B- is -CH=CH- then the double bond preferably has the trans (or E ) configuration
In another preferred embodiment of the compounds of formula (I) R8 is halo CN C1-C4 alkyl C1-C4 haloalkyl CH2OH O (d-C4 alkyl) or -0-CH2-(C3-C5)cycloalkyl and R9 IS -OH or -NHSO2(C1-C3 alkyl)
In another preferred embodiment of the compounds of formula (I) R1 is H and R2 is methyl such that the compound of formula (I) has the VR, 6R 7R relative configuration More preferably the compound of formula (I) has the VR 6R, 7R absolute configuration
In another preferred embodiment of the compounds of formula (I) R3 R4 R5 R8 and R7 are each independently selected from H Re and R9, provided that at least two of R3 R4 R5 R8 and R7 are H or R4 and Rs together are -0-CH2-CH2- -CH2-CH2 O or -O-CH2-0- and R3 R8 and R7 are H R8 is halo -CN, C1-C4 alkyl -CF3 CH2OH -0-(d C4 alkyl) or 0-CH2-(C3-C5)cycloalkyl and R9 is -OH or -NHSO2(C1-C3 alkyl)
In another preferred embodiment of the compounds of formula (I) one of R3 R4 R5 R6 and R7 is R8 or R9 another two of R3 R4 Rs R8 and R7 are H or R8 and the other two of R3 R4 Rs R8 and R7 are H R8 is halo, -CN C1-C4 alkyl -CF3 -CH2OH -O (C1-C4 alkyl) or -0-CH2-(C3-C5)cycloalkyl and R9 IS -OH or -NHSO2(d-C3 alkyl) More preferably R9 is -OH
Another preferred embodiment is a compound of formula (I*)
(Scheme Removed)
or a pharmaceutically acceptable salt thereof wherein two of R4 R5 R8 and R7 are H or R8 and the other two of R4 R5 R8 and R7 are H and R8 is halo CN d-d alkyl -CF3 -CH2OH 0-(C1-C4 alkyl) or 0-CH2-(C3-C5)cycloalkyl
Another preferred embodiment is a compound of formula (I*) or a pharmaceutically acceptable salt thereof that has the 1 R QR 7R absolute configuration
Another preferred embodiment is a compound of formula (lB)
(Scheme Removed)
or a pharmaceutically acceptable salt thereof wherein one of R3 R4 R5 R8 and R7 is R8 or R9 and the other four of R3 RA R5 R6 and R7 are H, R8 is halo -CN (C1-C4)alkyl -CF3 -0-(C1-C4 alkyl) or 0-CH2-(Cj-C5)cycloalkyl and RB is -OH
Another preferred embodiment is a compound of formula (lB) or a pharmaceutically acceptable salt thereof that has the 1 R 6R 7R absolute configuration
In embodiments of the compounds of formula (I), (lA) and (lB) wherein R8 is halo then preferably it is fluoro or chloro In embodiments of the compounds of formula (I), (lA) and (lB) wherein R8 is (C1-C4)alkyl then preferably it is methyl ethyl propyl or isopropyl and more preferably it is methyl In embodiments of the compounds of formula (I), (lA) and (I8) wherein R8 is (C1-C4) haloalkyl then preferably it is trifluoromethyl In embodiments of the compounds of formula (I), (lA) and (lB) wherein R8 is -0-(d-C-4)alkyl then preferably it is methoxy ethoxy propoxy or isopropoxy and more preferably it is methoxy In embodiments of the compounds of formula (I), (lA) and (lB) wherein R8 is -0-CH2 (C3 C5)cycloalkyl then preferably it is cyclopropylmethoxy
Preferred individual compounds of formula (I) are
(6tf* 7R*)-7-hydroxy-6-{[(1R*)-1-methyl-3-phenylpropyl]arnino}-4 5 6 7-tetrahydroimidazo[4 5 1-
jk]I1]benzazepm-2(1H) one
(6R* 7R*)-7-hydroxy-6-{[(1S*)-1-methyl-3-phenylpropyl]amino}-4 5 6 7 te»rahydroimidazo[4 5 1-
jk][ 1 ]benzazepin-2( 1 H)-one
(6R 7R)-7-hydroxy-6-{[(1RS)-1-methyl-3-phenylpropyl]amino}-4 5 6 7 tetrahydroimidazo[4 5 1-
jk][1]benzazepin-2(1H) one
(6R 7R)7 hydroxy-6-{[(1R)-1-methyl-3-phenylpropyl]amino}-4 5 6 7-tetrahydroimidazo[4 5 1-
jk][1]benzazepm-2(1H) one
(6R 7R) 7 hydroxy 6-{[(1S)-1-methyl-3-phenylpropyllamino}-4 5 6 7 tetrahydroimidazo[4 5 1
jkf](1]benzazepin-2(1H) one
(6R* 7R)-7-hydroxy-6-{[(1R>3-(2-hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7-
tetrahydroimidazo[4 5 1 jk][1]benzazepm 2(1H)-one
(6R* 7R*)-7-hydroxy-6-{[(1S*)-3-(2-hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7-
tetrahydroimidazo[4 5 1-jk][1]benzazepin 2(1H)-one
(6R,7R)-7-hydroxy-6-{[(1RS)-3-(2-hydroxyphenyl)-1 methylpropyl]ammo}-4 5 6 7-
tetrahydroimidazo[4 5,1 y/c][1]benzazepin-2(1H)-one
(6R 7R)-7-hydroxy-6-{[(1R)-3-(2 hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7-tetrahydroimidazo[4 5 1
jk] ]benzazepm-2( 1 H)-one
(6R7R)-7-hydroxy-6-{[(1S)-3-(2-hydroxyphenyl)-1-methylpropyl]amino}~4 5 6 7-tetrahydroimidazo[4 5 1-
y/c][1]benzazepin-2(1 H)-one
(6R* 7R*)-7-hydroxy-6-{[(1R*)-3-(3 hydroxyphenyl0-1-methylpropyl]amino}-4 5 6 7-
tetrahydroimidazo[4 5 1 yfr][1]benzazepin 2(1H)-one
(6R* 7R*)-7-hydroxy 6-{[(1S*)-3-(3-hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7-
tetrahydroimidazo[4,5,1 jk][1]benzazepm-2(1 H)-one
(6R7R)-7-hydroxy-6-{[(1RS)-3-(3-hydroxyphenyl)-1-methylpropyl]aminoH 5 6 7-
tetrahydroimidazo[4 5 1-y/c][1]benzazepin-2(1H)-one
(6R 7R)-7 hydroxy 6-{[(1R)-3-(3-hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7-tetrahydroimidazo[4 5 1-
y/c][1]benzazepin-2(1 H)-one
(6R7R)-7-hydroxy-6-{[(1S)-3 (3-hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7-tetrahydroimidazo[4 5 1-
jk][1]benzazepin-2(1 H)-one
(6R* 7R*) 7 hydroxy 6-{[(1R*)-3 (4-hydroxyphenyl)-1 methylpropyl]amino}-4 5 6 7
tetrahydroimidazo[4 5 1-y/c][1]benzazepin-2(1H)-one
(6R* 7R*)-7-hydroxy 6-{[(1S*)-3-(4-hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7-
tetrahydroimidazo[4 5 1 jk][1]benzazepin-2(1H)-one
(6R,7R)-7 hydroxy-6-{[(1RS)-3-(4-hydroxyphenyl) 1-methylpropylJammo}-4 5 6 7-
tetrahydroimidazo[4 5 1-jk][1]benzazepin-2(1H)-one
(6R7R)-7 hydroxy-6-{[(1R)-3-(4-hydroxyphenyl) 1-methylpropyl]ammo}-4 5 67 tetrahydroimidazo(4 5 1-
jk][1]benzazepin-2(1 H)-one
(6R 7R)-7-hydroxy-6-{[(1 S)-3 (4-hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7 tetrahydroimidazo[4 5 1
y/c][1]benzazepm 2(1H)-one
(6R* 7R*)-7-hydroxy-6-{[(1R*)-3-(4-methoxyphenyl)-1-methylpropyl]amino>-4 5 6 7-
tetrahydroimidazo[4 5 1 yk][1]benzazepin-2(1H)-one
(6R* 7R*) 7-hydroxy-6-{[(1S*) 3-(4-methoxyphenyl)-1-methylpropyl]amino}-4 5 6 7-
tetrahydroimidazo[4 5 1-y/c][1]benzazepin-2(1H)-one
(6R 7R)-7 hydroxy-6-{[(1RS)-3-(4-methoxyphenyl)-1-methylpropyl]amino}-4 5 6 7
tetrahydroimidazo[4 5 1 yk][1Jbenzazepin-2(1H)-one
(6R7R)-7-hydroxy-6-{[(1R)-3-(4-methoxyphenyl) 1 methylpropyl]amino}-4 5 6 7 tetrahydroimidazo[4 5 1
jk][1 ]benzazepm-2( 1 H)-one
(6R 7R)-7-hydroxy-6-{[(1S)-3-(4-methoxyphenyl) 1 methylpropyl]amino}-4 5 6 7-tetrahydroimidazo[4 5 1-
jk][1]benzazepin-2(1H)-one
(6R*,7R*)-6-{[(1R*)-3-(4-(cyclopropylmethyloxy)phenyl)-1-methylpropyl]amino}-7 hydroxy-4 5 6 7
tetrahydroimidazo[4 5 1-jk][1]benzazepin-2(1H)-one
(6R* 7R*)-6-{[(1S*)-3-(4-(cyclopropylmethyloxy)phenyl)-1-methylpropyl]amino}-7-hydroxy-4 5 6 7
tetrahydroimidazo[4 5 1-jk][1]benzazepin-2(1H)-one
(6R 7R)-6-{[(1RS)-3-(4-(cyclopropylmethyloxy)phenyl)-1-methylpropyl]amino}-7-hydroxy-4 5 6 7
tetrahydroimidazo[4 5 1-jk][1]benzazepin-2(1H)-one
(6R 7R)-6-{[(1R)-3-(4-(cyclopropylmethyloxy)phenyl)-1-methylpropyl]amino}-7-hydroxy-4 5 6 7-
tetrahydroimidazo[4 5 1-jk][1]benzazepin-2(1H)-one and
(6R 7R)6-{[(1S)-3-(4-(cycloprapylmethyloxy)phenyl)-1-methylpropyl]amino}-7-hydroxy-4 5 6 7-
tetrahydroimidazo[4 5 1-jk][1]benzazepin-2(1H)-one
Further preferred individual compounds of formula (I) are
(6R* 7R*)-7-hydroxy-6-{(1R*)-[3-(4-hydroxyphenyl) 1-methylpropyl]ammo}-4 5 6 7-tetrahydro-imidazo[4 5 1-jk][1]benzazepin-2(1H)-one
(6R*,7R*)-7 hydroxy-6-{{1S*H3-(4-hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7-tetrahydro-imidazo[4 5 1-jk][1]benzazepin-2(1H)-one
(6R7R)-7-hydroxy-6-{(1RS)-[3-(4-hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7 tetrahydro imidazo[4 5 1 jk][1]benzazepm 2(1H)-one
(6R7R)-7 hydroxy-6-{(1SH3-(4-hydroxyphenyl) 1-methylprapylJamino}-4 5 6 7-tetrahydroimidazo[4 5 1-jk][ 1 ]benzazepin-2( 1 H)-one
(6R 7R) 7 hydroxy-6-{(1R)-[3-(4-hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7-tetrahydroimidazo[4 5 1-jk][1]benzazepin-2(1 H)-one
(6R* 7R*)-7-hydroxy-6-{[(1R*)-3-(2-hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7 tetrahydro-imidazo[4 5 1-jk][1]benzazepin-2(1H)-one
(6R* 7R*)-7 hydroxy-6-{[(1S*)-3-(2-hydroxyphenyl)-1 methylpropyl]amino}-4 5 6 7-tetrahydro-imidazo[4 5 1-jk][1]benzazepin-2(1H)-one
{6R,7R)-7 hydroxy 6-{[(1RS)-3-(2-hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7-tetrahydro-imidazo[4 5 1-jk][1]benzazepin-2(1H)-one
{6R7R) 7-hydroxy-6-{[(fR)-3-(2-hydroxypheny|)-1-methylpropyl]amino}-4 5 6 7-tetrahydroimidazo[4 5 1-
Vfc)[1]benzazepin-2(1H)-one '
(6R7fl)-7-hydroxy-6-{[(1S)-3-(2 hydroxyphenyl)-1-methylpropyl]amino}-4 5 6 7 tetrahydroimidazo[4 5 1 ;k)[1]benzazepin-2(1 H)-one
(6R* 7R*)-6-{[(1R*)-3 (5-fluoro-2-hydroxyphenyl) 1 methylpropyl]ammo}-7 hydroxy 4 5 6 7-tetrahydro-imidazo[4 5 1-y/r][1]benzazepin-2(1H)-one
(6R* 7R*)-6-{[(1S*)-3 (5-fluoro-2 hydroxyphenyl) 1-methylpropyl]amino}-7-hydroxy 4 5 6 7 tetrahydro-midazo[4 5 1-;k][1]benzazepin-2(1H)-one
(6R7fl)-6-{[(1RS)-3-(5-fluoro 2-hydroxyphenyl)-1 methylpropyl]amino}-7 hydroxy-4 5 6 7 tetrahydro-imidazo[4 5 1-jk][1]benzazepin-2(1H) one
(6R 7R)-6-{[(1R)-3-(5 fluoro-2-hydroxyphenyl) 1-methylpropyl]ammo} 7 hydroxy-4 5 6 7 tetrahydro-imidazo[4 5 1 jk[1]benzazepin-2(1H)-one
(6R,7R)-6-{[(1S)-3-(5-fluoro-2-hydroxyphenyl) 1 methylpropyl]ammo}-7 hydroxy-4 5 6 7-tetrahydro
imidazo[4 5,1-y/c][1]benzazepm-2(1H) one
(6R*,7R*)-6-{[(1R*)-3-(4 5-difluoro-2-hydroxyphenyl)-1-methylpropyl]amino}-7-hydroxy-4 5 6 7
tetrahydroimidazo[4 5 1 ;/f][1]benzazepm 2(1H)-one
(6R*,7R*)-6-{[(1S*)-3-(4 5-difluoro-2-hydroxyphenyl)-1 methylpropyl]amino}-7-hydroxy-4 5 6 7-tetrahydro
imidazo[4 5 1-jkc][1]benzazepin-2(1H)-one
(6R 7R)-6-{[(1RS)-3-(4 5-difluoro-2-hydroxyphenyl)-1-methylpropyl]amino}-7-hydroxy-4 5,6 7-tetrahydro-
imidazo[4 5 1-jk][1]benzazepin-2(1H)-one
(6R*7R*)-6-{[(1R)-3-(4 5-difluoro-2-hydroxyphenyl) 1-methylpropyl]amino}-7 hydroxy-4 5 6 7 tetrahydro-
imidazo[4 5 1-jk][1]benzazepin-2(1H) one and
(6R 7R)-6-{[(1S)-3-(4 5-difluoro-2-hydroxyphenyl)-1 methylpropyl]amino}-7-hydroxy-4 5 6 7-tetrahydro-
imidazo[4 5 1-jk][1]benzazepm 2(1H)-one
The compounds of formula (I) are agonists at the beta-2 adrenoceptor In particular they have good efficacy at the bovine and/or porcine beta-2 adrenoceptor as demonstrated in the assays set out below in the Examples
The compounds of formula (I) may be used to improve meat production in livestock animals Examples of livestock animals include ruminants such as cows bulls heifers steers goats, sheep and minor species such as buffalo bison and antelopes Other examples include pigs boars gilts sows and avians such as chickens ducks geese and turkeys A preferred use is in the improvement of meat production in cattle swine and poultry
Beta-2 agonists have also been reported to improve muscle production and feed efficiency in farmed fish Accordingly, the compounds of formula (I) may find use in the production of fish such as for example tuna salmon and trout
The compounds of formula (I) may be administered to the animal by any suitable route A preferred route of administration for improving meat production in livestock animals is the oral route For such administration the compounds of formula (I) may be added to the animals food drinking water or any other material ingested by the animals such as a salt lick
The compounds of formula (I) may be added directly to the feed or drinking water or may be presented as a concentrate for addition to the feed or drinking water
The concentrate may be a solid or a liquid Solid concentrates include simple mixtures of the compounds with a solid diluent such as corn starch and compositions wherein the compounds are adsorbed onto the diluent Examples of other diluents include alfalfa meal rice hulls corncob grits bone meal soybean meal ground corn inorganic diluents such as limestone sodium chloride vitamin
and mineral mixes Liquid concentrates include solutions and suspensions in water or another suitable
vehicle such as an oil especially a vegetable oil
A suitable concentrate for addition to feed comprises
Active agent 0 1 to 2wt% for example 0 5wt%
Crushed limestone 0 5 to 9wt% for example 4 5wt%
Rice hulls 90 to 99wt% for example 94 5wt%
Mineral oil 0 1 to 3wt% for example 1wt%
The concentration of the compound of formula (I) in the feed or water should be adjusted such that each animal receives a maximally effective amount For cattle an intake of between 0 1 and 1000mg/animal/day particularly 0 1 to 10Omg/animal/day may be suitable Preferably the amount may be between 0 5 and 50mg/animal/day and more preferably between 1 and 25mg/ammal/day For cattle consuming 10kg of feed per day these administration rates can be achieved by adding the compounds of formula (I) to the feed at an inclusion rate of 0 01 to 100ppm 0 01 to 10ppm, 0 05 to 5ppm and 0 1 to 2 5ppm respectively
Compounds of the present invention may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof)
For example compounds of formula (I) may be used in combination with other feed additives used in livestock production for example polyether lonophores such as monensin salinomycin narasm lasalocid and laidlomycin antibiotics such as the tetracyclines bacitracin tylosin tiamulin lincomycin virginiamycm, quinolone antibacterials and carbadox melengesterol acetate agents for the prevention or treatment of sub-acute rumen acidosis such as sodium bicarbonate acarbose and other amylase or glucosidase inhibitors carcass quality / anabolic agents such as ractopamine salbutamol almeterol and other beta adrenergic hgands enzymes minerals vitamins and other supplements The man skilled in the art will recognise that the agents listed above are examples of a wide range of feed additives which may be used in combination with compounds of formula (I) Other examples are referred to in 2006 Feed Additive Companion" and "Handbook of Feed Additives 2006"
Compounds of formula (I) may also be used in combination with anabolic agents such as zearanol trenbolone acetate and oestradiol and growth hormones such as bovine somatotropin and porcine somatotropin Compounds of formula (I) may also be used in combination with agents used in animal welfare for example endectocides such as ivermectin doramectin moxidectin abamectin and other macrocyclic lactones anthelmintics such as levamisole albendazole and other benzimidazole carbamates morantel pyrantel ectoparasiticides such as pyrethroids arylpyrazoles neonicotmoids
The compounds of formula (I) may also be used in the treatment of diseases of animals in which beta-2
agonists have or may have a beneficial effect In particular the compounds of formula (I) may be used
in the treatment of respiratory diseases of animals including the treatment of heaves in horses
The compounds of formula (I) also have agonist activity at the human beta-2 adrenoceptor and so are potentially useful in human medicine
Beta-2 agonists are currently used to treat allergic and non-allergic airways diseases such as asthma and chronic obstructive airways disease (COPD) Treatment guidelines for these diseases include both short and long acting inhaled beta-2 agonists Short acting rapid onset beta-2 agonists are used for rescue bronchodilation whereas long-acting forms provide sustained relief and are used as maintenance therapy
Bronchodilation is mediated via agonism of the beta-2 adrenoceptor expressed on airway smooth muscle cells which results in relaxation and hence bronchodilation Thus as functional antagonists beta-2 agonists can prevent and reverse the effects of all bronchoconstnctor substances including leukotnene D4 (LTD4) acetylcholine bradykinin prostaglandins histamine and endothelms Because beta 2 receptors are so widely distributed in the airway beta-2 agonists may also affect other types of cells that play a role in asthma For example it has been reported that beta-2 agonists may stabilize mast cells The inhibition of the release of bronchoconstnctor substances may be how beta-2 agonists block the bronchoconstnction induced by allergens exercise and cold air Furthermore beta-2 agonists inhibit cholinergic neurotransmission in the human airway which can result in reduced cholinergic-reflex bronchoconstnction
Therefore a further aspect of the present invention relates to the compounds of formula (I) or pharmaceutically acceptable salts thereof for use m the treatment of diseases disorders and conditions in which the beta-2 receptor is involved More specifically the present invention also concerns the compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of diseases disorders and conditions selected from the group consisting of
• asthma of whatever type etiology or pathogenesis in particular asthma that is a member selected from the group consisting of atopic asthma non-atopic asthma allergic asthma atopic bronchial IgE-mediated asthma bronchial asthma essential asthma true asthma mtnnsic asthma caused by pathophysiologic disturbances extrinsic asthma caused by environmental factors essential asthma of unknown or mapparent cause bronchitic asthma emphysematous asthma exercise-induced asthma allergen induced asthma cold air induced asthma occupational asthma infective asthma caused by bacterial fungal protozoal or viral infection non-allergic asthma incipient asthma wheezy infant syndrome and bronchiolytis
• chronic or acute bronchoconstnction chronic bronchitis small airways obstruction and emphysema
• obstructive or inflammatory airways diseases of whatever type etiology or pathogenesis in particular an obstructive or inflammatory airways disease that is a member
selected from the group consisting of chronic eosinophilic pneumonia chronic obstructive
pulmonary disease (COPD) COPD that includes chronic bronchitis pulmonary emphysema or
dyspnea associated or not associated with COPD COPD that is charactenzed by irreversible
progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerbation of
airways hyper-reactivity consequent to other drug therapy and airways disease that is associated
with pulmonary hypertension
• bronchitis of whatever type etiology or pathogenesis in particular bronchitis that is a member selected from the group consisting of acute bronchitis acute laryngotracheal bronchitis, arachidic bronchitis catarrhal bronchitis croupus bronchitis dry bronchitis infectious asthmatic bronchitis productive bronchitis staphylococcus or streptococcal bronchitis and vesicular bronchitis
• acute lung injury
• bronchiectasis of whatever type etiology or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis sacculated bronchiectasis fusiform bronchiectasis capillary bronchiectasis cystic bronchiectasis dry bronchiectasis and follicular bronchiectasis
In addition to the airways it has also been established that beta 2 adrenoceptors are also expressed in other organs and tissues and thus the compounds of formula (I) may have application in the treatment of other diseases such as but not limited to those of the nervous system premature labor congestive heart failure depression inflammatory and allergic skin diseases psoriasis proliferative skin diseases glaucoma and in conditions where there is an advantage in lowering gastric acidity particularly in gastric and peptic ulceration
When used in human therapy the compounds of formula (I) and their pharmaceutically acceptable salts will generally be administered as a formulation in association with one or more pharmaceutically acceptable excipients The term excipient is used herein to describe any ingredient other than the compound of the invention The choice of excipient will to a large extent depend on the particular mode of administration
The compounds of the invention may be administered orally Oral administration may involve swallowing so that the compound enters the gastrointestinal tract or buccal or sublingual admirystration may be employed by which the compound enters the blood stream directly from the mouth
Formulations suitable for oral administration include solid formulations such as tablets capsules containing particulates liquids or powders lozenges (including liquid-filled) and chews multi- and nano-particulates gels solid solutions liposomes films ovules sprays and liquid formulations
Liquid formulations include suspensions solutions syrups and elixirs Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier for example water ethanol
polyethylene glycol propylene glycol methylcellulose or a suitable oil and one or more emulsifying
agents and/or suspending agents Liquid formulations may also be prepared by the reconstitution of a
solid for example from a sachet
The compounds of the invention may also be used in fast-dissolving fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents 11 (6), 981-986 by Liang and Chen (2001)
For tablet dosage forms depending on dose the drug may make up from 1 weight % to 80 weight % of the dosage form more typically from 5 weight % to 60 weight % of the dosage form In addition to the drug tablets generally contain a disintegrant Examples of disintegrants include sodium starch glycolate sodium carboxymethyl cellulose calcium carboxymethyl cellulose croscarmellose sodium crospovidone polyvinylpyrrolidone, methyl cellulose microcrystalline cellulose lower alkyl-substituted hydroxypropyl cellulose starch pregelatmised starch and sodium alginate Generally the disintegrant will comprise from 1 weight % to 25 weight % preferably from 5 weight % to 20 weight % of the dosage form
Binders are generally used to impart cohesive qualities to a tablet formulation Suitable binders include microcrystalline cellulose gelatin sugars polyethylene glycol natural and synthetic gums polyvinylpyrrolidone pregelatmised starch hydroxypropyl cellulose and hydroxypropyl methylcellulose Tablets may also contain diluents such as lactose (monohydrate spray-dried monohydrate anhydrous and the like) mannitol xylitol dextrose sucrose sorbitol microcrystalline cellulose starch and dibasic calcium phosphate dihydrate
Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80 and glidants such as silicon dioxide and talc When present surface active agents may comprise from 0 2 weight % to 5 weight % of the tablet and glidants may comprise from 0 2 weight % to 1 weight % of the tablet
Tablets also generally contain lubricants such as magnesium stearate calcium stearate zinc stearate sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulphate Lubricants generally comprise from 0 25 weight % to 10 weight % preferably from 0 5 weight % to 3 weight % of the tablet
Other possible ingredients include and oxidants colourants flavouring agents preservatives and taste-masking agents
Exemplary tablets contain up to about 80% drug from about 10 weight % to about 90 weight % binder from about 0 weight % to about 85 weight % diluent from about 2 weight % to about 10 weight % disintegrant and from about 0 25 weight % to about 10 weight % lubricant
Tablet blends may be compressed directly or by roller to form tablets Tablet blends or portions of blends may alternatively be wet dry or melt-granulated melt congealed or extruded before tabletting The final formulation may comprise one or more layers and may be coated or uncoated it may even be encapsulated
The formulation of tablets is discussed in Pharmaceutical Dosage Forms Tablets Vol 1 by H Lieberman and L Lachman (Marcel Dekker New York 1980)
Consumable oral films for human use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I) a film-forming polymer a binder a solvent a humectant a plasticiser a stabiliser or emulsifier, a viscosity-modifying agent and a solvent Some components of the formulation may perform more than one function
The compound of formula (I) may be water-soluble or insoluble A water soluble compound typically comprises from 1 weight % to 80 weight % more typically from 20 weight % to 50 weight % of the solutes Less soluble compounds may comprise a greater proportion of the composition typically up to 88 weight % of the solutes Alternatively the compound of formula (I) may be in the form of multiparticulate beads
The film forming polymer may be selected from natural polysaccharides proteins or synthetic hydrocolloids and is typically present in the range 0 01 to 99 weight %, more typically in the range 30 to 80 weight %
Other possible ingredients include antioxidants colorants flavourings and flavour enhancers preservatives salivary stimulating agents, cooling agents co-solvents (including oils) emollients bulking agents anti foaming agents surfactants and taste-masking agents
Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper This may be done in a drying oven or tunnel typically a combined coater dryer or by freeze drying or vacuuming
Solid formulations for oral administration may be formulated to be immediate and/or modified release Modified release formulations include delayed- sustained- pulsed- controlled- targeted and programmed release
Suitable modified release formulations for the purposes of the invention are described in US Patent No 6 106 864 Details of other suitable release technologies such as high energy dispersions and osmotic
and coated particles are to be found in Pharmaceutical Technology On-line 25(2) 1-14 byVermaetal
(2001) The use of chewing gum to achieve controlled release is described in WO 00/35298
The compounds of the invention may also be administered directly into the blood stream into muscle or into an internal organ Suitable means for parenteral administration include intravenous intraarterial intrapentoneal intrathecal intraventncular intraurethral intrasternal intracranial intramuscular and subcutaneous Suitable devices for parenteral administration include needle (including microneedle) injectors needle-free injectors and infusion techniques
Parenteral formulations are typically aqueous solutions which may contain excipients such as salts carbohydrates and buffering agents (preferably to a pH of from 3 to 9) but, for some applications they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile pyrogen-free water
The preparation of parenteral formulations under sterile conditions for example, by lyophilisation may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art
The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques such as the incorporation of solubility enhancing agents
Formulations for parenteral administration may be formulated to be immediate and/or modified release Modified release formulations include delayed- sustained- pulsed- controlled- targeted and programmed release Thus compounds of the invention may be formulated as a solid semisolid or thixotropic liquid for administration as an implanted depot providing modified release of the active compound Examples of such formulations include drug-coated stents and PGLApoly(dl-lactic-coglycolic)acid (PGLA) microspheres
The compounds of the invention may also be administered topically to the skin or mucosa that is dermally or transdermal^ Typical formulations for this purpose include gels hydrogels lotions solutions creams ointments dusting powders dressings foams films skin patches wafers implants sponges fibres bandages and microemulsions Liposomes may also be used Typical carriers include alcohol water mineral oil liquid petrolatum white petrolatum glycerin polyethylene glycol and propylene glycol Penetration enhancers may be incorporated see for example J Pharm Sci 88(10) 955-958 by Finnin and Morgan (October 1999)
Other means of topical administration include delivery by electroporation iontophoresis phonophoresis sonophoresis and microneedle or needle free (e g Powderject™ Bioject™ etc) injection
Formulations for topical administration may be formulated to be immediate and/or modified release
Modified release formulations include delayed- sustained- pulsed controlled- targeted and
programmed release
The compounds of the invention can also be administered mtranasally or by inhalation typically in the form of a dry powder (either alone as a mixture for example in a dry blend with lactose or as a mixed component particle for example mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container pump spray atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist) or nebuliser with or without the use of a suitable propellant such as 1 1 1 2-tetrafluoroethane or 1 1 1 2 3 3 3-heptafluoropropane For intranasal use the powder may comprise a bioadhesive agent for example chitosan or cyclodextnn
The pressurised container pump spray atomizer or nebuliser contains a solution or suspension of the compound(s) of the invention comprising for example ethanol aqueous ethanol or a suitable alternative agent for dispersing solubilising or extending release of the active a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate oleic acid or an oligolactic acid
Prior to use in a dry powder or suspension formulation the drug product is micromsed to a size suitable for delivery by inhalation (typically less than 5 microns) This may be achieved by any appropriate comminuting method such as spiral jet milling fluid bed jet milling supercritical fluid processing to form nanoparticles high pressure homogenisation or spray drying
Capsules (made for example from gelatin or hydroxypropylmethylcellulose) blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as I-leucine mannitol or magnesium stearate The lactose may be anhydrous or in the form of the monohydrate, preferably the latter Other suitable excipients include dextran glucose maltose sorbitol xylitol fructose sucrose and trehalose
A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1ug to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 pi to 100ul A typical formulation may comprise a compound of formula (I) propylene glycol sterile water ethanol and sodium chloride Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol
Suitable flavours such as menthol and levomenthol or sweeteners such as saccharin or saccharin sodium may be added to those formulations of the invention intended for inhaled/intranasal administration
Formulations for mhaled/intranasal administration may be formulated to be immediate and/or modified
release using for example PGLA Modified release formulations include delayed- sustained- pulsed
controlled targeted and programmed release
In the case of dry powder inhalers and aerosols the dosage unit is determined by means of a valve which delivers a metered amount Units in accordance with the invention are typically arranged to administer a metered dose or puff" containing from 0 001mg to 10mg of the compound of formula (I) The overall daily dose will typically be in the range 0 001 mg to 40mg which may be administered in a single dose or more usually as divided doses throughout the day
The compounds of formula (I) are particularly suitable for an administration by inhalation
The compounds of the invention may be administered rectally or vaginally for example in the form of a suppository pessary or enema Cocoa butter is a traditional suppository base but various alternatives may be used as appropriate
Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release Modified release formulations include delayed- sustained- pulsed- controlled- targeted and programmed release
The compounds of the invention may also be administered directly to the eye or ear typically in the form of drops of a micronised suspension or solution in isotonic pH-adjusted sterile saline Other formulations suitable for ocular and aural administration include ointments biodegradable (e g absorbable gel sponges collagen) and non-biodegradable (e g silicone) implants wafers lenses and particulate or vesicular systems such as niosomes or liposomes A polymer such as crossed-linked polyacrylic acid polyvinylalcohol hyaluronic acid a cellulosic polymer for example hydroxypropylmethylcellulose hydroxyethylcellulose or methyl cellulose or a heteropolysacchande polymer for example gelan gum may be incorporated together with a preservative such as benzalkonium chloride Such formulations may also be delivered by iontophoresis
Formulations for ocular/aural administration may be formulated to be immediate and/or modified release Modified release formulations include delayed- sustained- pulsed- controlled- targeted or programmed release
The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrm and suitable derivatives thereof or polyethylene glycol-containing polymers in order to improve their solubility dissolution rate taste-masking bioavailability and/or stability for use in any of the aforementioned modes of administration
Drug-cyclodextrm complexes for example are found to be generally useful for most dosage forms and
administration routes Both inclusion and non inclusion complexes may be used As an alternative to
direct complexation with the drug the cyclodextrin may be used as an auxiliary additive i e as a carrier,
diluent or solubihser Most commonly used for these purposes are alpha- beta and gamma-
cyclodextnns examples of which may be found in International Patent Applications Nos WO 91/11172
WO 94/02518 and WO 98/55148
For administration to human patients the total daily dose of the compounds of the invention is typically in the range 0 001 mg to 5000mg depending of course on the mode of administration For example an intravenous daily dose may only require from 0 001 mg to 40mg The total daily dose may be administered in single or divided doses and may at the physician s discretion fall outside of the typical range given herein
These dosages are based on an average human subject having a weight of about 65kg to 70kg The physician will readily be able to determine doses for subjects whose weight falls outside this range such as infants and the elderly
When used for the treatment of human airway disease the compounds of formula (I) and their pharmaceutically acceptable salts may advantageously be used in combination with a second pharmacologically active agent Examples of such agents include H3 antagonists muscarinic M3 receptor antagonists PDE4 inhibitors glucocorticosteroids adenosine A2a receptor agonists modulators of cytokine signalling pathyways such as p38 MAP kinase or syk kinase and leukotnene antagonists (LTRAs) including antagonists of LTB4 LTC4 LTD4 and LTE»
Particularly preferred agents for such combination therapy are
glucocorticosteroids in particular inhaled glucocorticosteroids with reduced systemic side effects including prednisone prednisolone flunisolide, triamcinolone acetonide beclomethasone dipropionate budesonide fluticasone propionate ciclesonide and mometasone furoate, and
muscarinic M3 receptor antagonists or anticholinergic agents including in particular ipratropium salts namely bromide tiotropium salts namely bromide oxitropium salts namely bromide perenzepme and telenzepine
EXAMPLES
The following non-limiting Examples illustrate the preparation of compounds of the formula (I)
In the following experimental details nuclear magnetic resonance spectral data were obtained using Vanan Inova 300 Vanan Inova 400 Varian Mercury 400 Vanan Unityplus 400 Bruker AC 300MHz Bruker AM 250MHz or Varian T60 MHz spectrometers the observed chemical shifts being consistent with the proposed structures N m r chemical shifts are quoted in p p m downfield from
tetramethylsilane In the data presented below for some compounds only key n m r signals are listed
In the following Examples where an Example is indicated as being a mixture of diastereoisomers then
the n m r integrals shown refer to the relative ratio of integrals for the quoted chemical shift Mass
spectral data were obtained on a Finnigan Masslab Navigator a Fisons Instrument Trio 1000 or a
Hewlett Packard GCMS System Model 5971 spectrometer The calculated and observed ions quoted
refer to the isotopic composition of lowest mass HPLC means high performance liquid
chromatography Where indicated the following analytical HPLC methods have been used
HPLC Method A
Gilson system 150 x 4 6 mm Gemini C18 5µm column
Acetonitnle 0 1% aqueous ammonia [5 95 to 95 5] 1 ml/mm HPLC Method B
Gilson system 150 x 4 6 mm LUNA C18(2) 5nm column
Acetonitnle ammonium formate (20 mM) [5 95 to 98 2] 1 ml/mm HPLC Method C
Gilson system 250 x 4 6 mm Chiralcel OD-H 5um column
Ethanol hexane (20 80] 1 ml/mm HPLC Method D
Gilson system 250 x 4 6 mm ID Chiralpak AD-H 5µm column
Methanol ethanol hexane [5 15 80] with 0 1% v/v tnethylamine 1 ml/mm HPLC Method E
Gilson system 250 x 4 6 mm ID Chiralpak OD H 5µm column
Ethanol hexane [20 80] with 0 1% v/v tnethylamine 1 ml/mm HPLC Method F
Gilson system 250 x 4 6 mm ID Chiralpak OD-H 5µm column
Ethanol hexane [20 80] 1 ml/mm
Bioloqical Test
Compounds of the present invention have been found to display activity in a cAMP assay selective for
the bovine and porcine beta-2 adrenoceptors
CHO cells transfected with the bovine or porcine beta-2 adrenceptors were maintained in culture in DMEM/HAMS F12 + 10% FBS + 2mM glutamine + 500ug/ml geneticin (for the porcine receptor the medium was supplement with 1 5mM HEPES) at 37°C with a 5% C02 atmosphere
Cells were plated into 96 well viewplates in medium and incubated overnight at 37°C with a 5% C02 atmosphere The cells were pre-mcubated with 0 5mM IBMX in PBS for 30 minutes prior to incubation with increasing concentrations of experimental compound (5 x 1012to 10 5M) for 30 minutes at 37°C with a 5% CO2 atmosphere At the end of the incubation time the compound was removed and the cells assayed for cAMP using the DiscoveRx Hit Hunter cAMP II™ assay kit
Duplicate samples were run for each experimental compound and the data generated was analysed using EC50 analysis software in Graphpad Prism
Room temperature means 20 to 25°C N/A indicates no data available
In the following Examples structures are depicted as follows
(Scheme Removed)
Unless specified otherwise, the wedge and dashed bonds indicate relative stereochemistry only In particular the 7-hydroxyl and the 6-N-substituent are oriented in a trans configuration but the structures encompass both the 6R 7R and 6S 7S stereoisomers Formula (A) represents a compound which is a mixture of epimers at the carbon atom bearing the methyl substituent Formula (B) represents a compound which is a single unidentified epimer at the carbon atom bearing the methyl substituent Formulae (C) and (D) represent single epimers of known relative configuration Thus formula (A) represents a compound that is a mixture of (C) and (D) while (B) represents a compound that is either (C)or(D)
Example 1
6-([3-[4-(CyclopropylmethoxY)Dhenvll i.methylpropyl)amino)-7-hydroxy-4 5 6 7-tetrahydro
imidazof4 5 1-jk]f1lbenzazepin-2(1H)-one
(Scheme Removed)
A mixture of the compound of Preparation 1 (100 mg 0 4 mmol) triethylamine (80 nl 0 6 mmol) and the compound of Preparation 12 (204 mg 0 9 mmol) in methanol (2 ml) was stirred at room temperature for 18 h Sodium borohydride (44 mg 12 mmol) was added carefully and the reaction mixture was stirred at room temperature for another 18 h The mixture was diluted with methanol (8 ml) and Amberlyst® 15
ion-exchange resin (3 g prepared according to J Org Chem 1998 63 3471 3473) was added The
mixture was shaken overnight and the solution was filtered off The resin was washed with methanol (3 x
20 ml) and treated with ammonia in methanol (2N 5 ml) to release the captured ammo-alcohols After
shaking for 2 h the solution was filtered off and the resin was washed with ammonia in methanol (2N 2 x
5 ml) The combined methanol/ammoma washings were concentrated in vacuo to give the crude
product The residue was dissolved in acetonitnle water (11 1 ml) and purified by automated
preparative liquid chromatography (Gilson system 150 mm x 21 4 mm Gemini 5nm column) 20 ml/mm
using an acetonitnle 0 1% aqueous ammonia (1 9) acetonitnle 0 1% aqueous ammonia (9 1) gradient
[100 0 to 20 80 from 2 to 20 mm 20 80 to 0 100 from 20 to 25 mm] The appropriate fractions were
combined and concentrated to give the compound of Example 1a (60 mg) as a mixture of 4
diastereoisomers
Alternative route
To a suspension of the compound of Preparation 1 (15 5 g 60 5 mmol) in methanol (80 ml) was added potassium hydroxide (1 0 g 18 2 mmol) After stirring for 30 mm a solution of the compound of Preparation 12 (14 5 g 66 5 mmol) in methanol (80 ml) was added and the reaction mixture was cooled to 0°C Sodium cyanoborohydnde (5 7 g 90 7 mmol) was added and the reaction mixture was stirred at 0°C for 30 mm and then at room temperature for 48 h The reaction mixture was quenched with water (30 ml) and concentrated in vacuo A portion of the residue was purified by automated flash chromatography (Biotage™ 40M cartridge wet with dichloromethane) with gradient elution dichloromethane methanol [1 0 to 8 2] The appropriate fractions were combined and concentrated to give the compound of Example 1b (540 mg) as a pair of enantiomers
To a solution of the compound of Example 1b (540 mg 1 3 mmol) in methanol (5 ml) was added dropwise hydrogen chloride in diethyl ether (1M 1 3 ml) After stirring for 1 h diethyl ether (3 ml) was added dropwise and the precipitate was collected by filtration and washed with diethyl ether The solid was re-dissolved in warm methanol (8 ml) and precipitated with diethyl ether After washing with diethyl ether the solid was dried in a vacuum oven to give the compound of Example 1c (255 mg)

(Table Removed)
Example 1a
1H-NMR (CD3OD) 0 30 - 0 35 (2H) 0 49 - 0 60 (2H) 110-115 (3H) 1 20 1 22 (1H) 4 60 - 4 68 (1H) 6 75-6 85 (2H) 7 00-7 10 (4H) 7 14-720(1H)
Example 1c
1H-NMR (CD3OD) 0 30 0 35 (2H) 0 58 - 0 62 (2H), 1 17 -1 22 (1H) 1 35 1 43 (3H) 2 03 - 2 11 (2H)
4 80-4 84 (1H) 6 80 6 85 (2H) 7 04- 7 06 (1H) 7 10 7 18 (3H) 7 29-7 32 (1H)
Example 2
7-Hydroxy 6-({3-(4-hydroxyphenyl)-1-methylpropyl]amino)-4 5 6 7 tetrahydroimidazof4 5 1
jk[benzazepln-2(1H)-one
(Formula Removed)
To a suspension of the compound of Preparation 1 (18 3 g 715 mmol) in methanol (300 ml) was added tnethylamine (24 9 ml 179 mmol) and the compound of Preparation 106 (12 9 g 78 6 mmol) in methanol The reaction mixture was stirred at room temperature for 60 h cooled to 0CC and sodium borohydnde (4 1 g 107 2 mmol) was added portionwise After stirring at room temperature for 18 h the reaction mixture was quenched with water and silica (100 g) was added The mixture was concentrated in vacuo and the product/silica mix was loaded onto a silica column (pre-wet with dichloromethane) the column was eluted with dichloromethane methanol [1 0 to 4 6] The appropriate fractions were combined and concentrated to give the compound of Example 2a (25 2 g) as a mixture of 4 diastereoisomers
The compound of Example 2a (3 0 g 8 2 mmol) was purified using a Biotage™ system with gradient elution dichloromethane methanol [1 0 to 7 3] The appropriate fractions were combined and concentrated to give a solid This solid was further purified using a Biotage system with gradient elution dichloromethane methanol [85 15 to 65 35] The appropriate fractions were combined and concentrated to give the compound of Example 2b (300 mg) as a pair of enantiomers HPLC Method B -retention time 11 74 mm Other appropriate fractions were combined and concentrated to give the compound of Example 2c (323 mg) as a pair of enantiomers HPLC Method B retention time 12 00 mm
The compound of Example 2c (148 mg, 0 4 mmol) was dissolved in ethanol hexane (1 4) and the enantiomers were separated by automated preparative liquid chromatography (Gilson system 250 x 21 4 mm Chiralcel OD-H 10 µm column 10 ml/mm) using ethanol hexane [1 4] as the mobile phase The appropriate fractions were combined and concentrated to give the compound of Example 2d (68 mg) as a single enantiomer HPLC Method C retention time 14 96 mm
(Table Removed)
Example 2a
1 H-NMR (de-DMSO) 1 00-1 18(3H) 460-465(1H) 660-666 (2H) 684-689(1H) 690-700 (3H) 7 00-7 11 (1H)
Example 2b
1H-NMR (CDjOD) 1 21 - 1 28 (3H) 4 72 - 4 77 (1H) 6 62 6 68 (2H), 6 96 - 7 04 (3H) 7 08 - 7 10 (1H) 711-713 (1H)
Example 2c
1H-NMR (d6-DMSO) 0 90 1 00 (3H) 450-455(1H) 6 79-6 85 (2H), 6 80-6 87 (1H) 690-696 (3H) 7 00-705(1H)
Example 2d
'H NMR (CD3OD) 110-113 (3H) 1 74 -1 82 (2H) 4 63 4 66 (1H) 6 62 - 6 66 (2H) 6 97 - 7 09 (4H) 7 20 7 22(1H)
Example 3
6-([3-(2 3-Dihydro-1-benzofuran-5-yl) 1-methylpropyl]amino)-7-hydroxy-4 5 6 7-tetrahydro-
imidazof4 5 1 vfrinibenzazeDin 2(1rV)-one
(Formula Removed)
A mixture of the compound of Preparation 1 (117 mg 0 5 mmol) tnethylamine (100 ul 0 7 mmol) and the compound of Preparation 170 (190 mg 1 0 mmol) in methanol (2 ml) was heated at 80°C in a microwave oven (300W) for 40 mm The reaction mixture was stirred overnight at room temperature before addition of sodium borohydnde (120 mg 3 2 mmol) After stirring at room temperature for 18 h
the mixture was diluted with methanol (8 ml) and Amberlyst® 15 ion-exchange resin (4 g prepared
according to (J Org Chem 1998 63 3471-3473) was added The mixture was shaken overnight and
the solution was filtered off The resin was washed with methanol (3 x 20 ml) and treated with ammonia
in methanol (2N 15 ml) After shaking for 2 h the solution was filtered off and the resin was washed with
ammonia in methanol (2N 2x15 ml) The combined methanol/ammoma washings were concentrated in
vacuo and the residue was re-dissolved in methanol (5 ml) This solution was filtered and concentrated
in vacuo The residue was dissolved in acetonitnle water (1114 ml) and purified by automated
preparative liquid chromatography (Gilson system 150 mm x 19 mm XTERRA C18 5µm column) 20
ml/mm using an acetonitnle 0 1% aqueous ammonia (1 9) acetonitnle 0 1% aqueous ammonia (9 1)
gradient [1 0 to 0 1 from 0-20 mm 0 1 from 20 - 25 mm] The appropriate fractions were combined
and concentrated to give the compound of Example 3a (74 mg) as a mixture of 4 diastereoisomers
Alternative synthesis
To a suspension of the compound of Preparation 1 (0 95 g 3 7 mmol) in methanol (25 ml) was added the compound of Preparation 170 (776 mg 4 1 mmol) in methanol (25 ml) followed by tnethylamine (0 16 ml 1 1 mmol) The reaction mixture was stirred at room temperature for 1 h and sodium cyanoborohydnde (0 58 g 9 27 mmol) was added portionwise After stirring at room temperature for 60 h the reaction mixture was quenched with water (1 ml) and concentrated in vacuo The residue was purified by automated flash chromatography (Biotage™ 40M cartridge wet with dichloromethane) with gradient elution dichloromethane 2 5% ammonia in methanol [100 0 to 84 16] The appropriate fractions were combined and concentrated to give the compound of Example 3b (578 mg) as a pair of enantiomers HPLC Method A retention time 13 97 mm Other appropriate fractions were combined and concentrated to give the compound of Example 3c (563 mg) as a pair of enantiomers HPLC Method A retention time 14 25 mm
(Table Removed)
Example 3a
1H-NMR (CD3OD) 1 08-1 18 (3H) 3 16 3 21 (2H) 4 42 4 48 (2H) 4 61 4 64 (1H) 6 55 6 60(1H) 680 684(1H)699 7 05 (3H) 7 18 - 7 20 (1H)
Example 3b
1H-NMR (CD3OD) 1 14 119(3H)3 75 3 84 (1H) 3 93-4 00 (1H) 4 44 4 51 (2H) 4 63 4 66(1H)
6 54-6 58 (1H) 6 80-6 85 (1H) 6 98 -7 08 (3H) 7 15 -7 19 (1H)
Example 3c
1H-NMR (CD3OD) 1 10-1 15 (3H) 3 81 4 00 (2H) 4 41 4 50 (2H) 4 63 - 4 69 (1H), 6 56 6 60(1H) 6 83 - 6 90 (1H) 7 00 - 7 10 (3H) 7 19 - 7 21 (1H)
Example 4
7-Hydroxy-6-fr3-(2-hydroxyPhenvl)-1 3 dimethylbutyllaminol-4 5 6 7-tetrahydroimidarof4 5 1-
7MI11benzazepin-2(1H)-one
(Formula Removed)
To a solution of the compound of Preparation 1 (144 mg 0 6 mmol) and the compound of Preparation 13 (130 mg 0 7 mmol) in methanol (10 ml) was added tnethylamine (24 µl 0 2 mmol) The mixture was stirred at room temperature for 1 h before addition of sodium cyanoborohydnde (53 mg 0 9 mmol) After stirnng at room temperature for 60 h, the reaction mixture was heated at 60°C for 48 h and then quenched with water and concentrated in vacuo The residue was purified by automated flash chromatography (Biotage™ 25+M cartridge) with gradient elution dichloromethane 2 5% ammonia in methanol [96 4 to 80 20] The appropriate fractions were combined and concentrated and the residue was dissolved in acetonitnle water (9 1 1 ml) and purified by automated preparative liquid chromatography (Gilson system 150 mm x 21 4 mm Gemini C18 5µm column) 20 ml/mm using an acetonitnle 0 1% aqueous ammonia (5 95) acetonitnle 0 1% aqueous ammonia (95 5) gradient [1 0 to 0 1 from 0-20 mm 0 1 from 20 - 25 mm] The appropriate fractions were combined and concentrated to give the compound of Example 4 (3 mg) as a pair of enantiomers

(Table Removed)
Example 4
'H NMR (CD3OD) 0 90 0 97(3H)122 1 28 (6H) 4 47 4 50 (1H) 6 19 6 21 (1H) 6 50 6 53(1H) 6 67-671 (1H) 699 7 02 (4H)
Example 5
6-([3-(3-Chloro-2-hydroxyphenyl)-1-methylpropyllamino}-7 hydroxy-4 5 6 7 tetrahydro-
imidazor4 5 1-jk]benzazeDin-2(1H)-one
(Formula Removed)
To a solution of the compound of Preparation 1 (591 mg 2 3 mmol) in methanol (10 ml) was added the compound of Preparation 16 (500 mg 2 5 mmol) in methanol (10 ml) followed by triethylamine (97 ul 0 7 mmol) The mixture was stirred at room temperature for 1 h before addition of sodium cyanoborohydnde (363 mg 5 8 mmol) After stirring at room temperature for 5 days the reaction mixture was quenched with water (2 ml) before first the addition of citric acid (1 g) and then sodium hydrogen carbonate (3 g) The mixture was concentrated in vacuo and the residue was mixed with silica dissolved in methanol (50 ml) and re-concentrated The residue was purified by automated flash chromatography (Biotage™ 40M cartridge conditioned with dichloromethane 2 5% ammonia in methanol with gradient elution dichloromethane 2 5% ammonia in methanol [96 4 to 91 9] The appropriate fractions were combined and concentrated to give the compound of Example 5a (166 mg) as a pair of enantiomers HPLC Method A retention time 13 43 min Other appropriate fractions were combined and concentrated to give the compound of Example 5b (50 mg) as a pair of enantiomers HPLC Method A - retention time 14 36 mm
A portion of the compound of Example 5b (150 mg 0 4 mmol) was dissolved in ethanol methanol (1 1 4 ml) and heated at 120°C in a microwave oven (CEM 300W) for 2 mm to aid solubility The enantiomers were separated by automated preparative liquid chromatography (Gilson system 500 x 50 mm ID Chiralpak AD-H 20 urn column 50 ml/mm) using methanol ethanol hexane [5 15 80] with 0 1% v/v triethylamine as the mobile phase The appropriate fractions were combined and concentrated to give the compound of Example 5c (100 mg) as a single enantiomer HPLC Method D - retention time 17 97 mm
(Table Removed)
Example 5a
'H NMR (CD3OD) 114-118 (3H) 1 71 1 86 (2H) 4 66 - 4 69 (1H) 6 64 - 6 69 (1H) 6 93 - 7 05 (3H) 7 07-7 10 (1H) 7 14-7 18 (1H)
Example 5b
1H-NMR (CD3OD) 1 07 110 (3H) 1 75 -1 85 (2H) 4 74 - 4 77 (1H) 6 65 6 70 (1H) 6 96 - 7 10 (4H) 7 23 -7 27 (1H)
Example 5c
(6R 7R)-6-{[3-(3-Chloro-2-hydroxyphenylH1R)-1-methylpropvllamino)-7 hydroxy-4 5 6 7-
tetrahydroimidazo[4 5 1 jk]benzazepin-2(1H)-one
(Formula Removed)
1H-NMR (CD3OD) 1 10 115(3H)4 77 4 81 (1H) 6 68 - 6 73 (1H) 6 98 7 03 (2H) 7 06 7 13(2H) 7 26 -7 30 (1H)
Example 6
7-Hydroxy-6-([3-(2-hydroxyphenyl)-1-methylpropylamino}-4 5 6 7-tetrahydroimidazo[4 5 1
jk][1lbenzazepm-2(1H)-one
(Formula Removed)
To a solution of (he compound of Preparation 100 (7 0 g 43 2 mmol) in methanol (200 ml) was added the compound of Preparation 1 (10 0 g 39 2 mmol) followed by potassium hydroxide (0 7 g 43 2 mmol) After stirring for 20 mm sodium cyanoborohydnde (6 2 g 98 1 mmol) was added and the reaction mixture was heated at 60 C for 60 h The mixture was quenched with water (10 ml) and concentrated in vacuo The residue was azeotroped with methanol pre absorbed onto silica (60 g) and purified by
column chromatography (silica 280 g) with gradient elution 2% ammonia in methanol dichloromethane
[0 1 to 4 96] The appropriate fractions were combined and concentrated to give the compound of
Example 6a (2 0 g) as a pair of enantiomers HPLC Method A - retention time 13 38 mm
To a solution of the compound of Example 6a (5 0 g 13 7 mmol) in methanol (30 ml) was added dropwise hydrogen chloride in diethyl ether (1M 13 7 ml) After stirring for 2 h diethyl ether (200 ml) was added and the precipitate was collected by filtration washing through with methanol diethyl ether (15 85, 100 ml) The solid was dissolved in isopropyl alcohol (22 ml) and water (1 3 ml) at 98"C then cooled to 0°C and stirred for 45 mm The resulting solid was collected by filtration washed with cold isopropyl alcohol and diethyl ether and dried in a vacuum oven to give the hydrochloride salt the compound of Example 6b (1 21 g)
The compound of Example 6a (1 1 g 31 mmol) was dissolved in ethanol methanol (3 1 20 ml) and heated to aid solubility The enantiomers were separated by automated preparative liquid chromatography (Gilson system 500 x 50 mm ID Chiralcel OD 20 urn column 50 ml/mm) using methanol ethanol hexane [5 5 90] with 0 1% v/v triethylamine as the mobile phase The appropriate fractions were combined and concentrated to give the compound of Example 6c (432 mg) as a single enantiomer HPLC Method E - retention time 8 46 mm Other appropriate fractions were combined and concentrated to give the compound of Example 6d (502 mg) as a single enantiomer HPLC Method E -retention time 9 88 mm
To a solution of the compound of Example 6c (378 mg 1 0 mmol) in methanol (6 ml) at 0°C was added dropwise hydrogen chloride in diethyl ether (1M, 1 2 ml) After stirring for 1 5 h, diethyl ether (34 ml) was added and the precipitate was collected by filtration The resulting solid was washed with diethyl ether (2 x 40 ml) and dried in a vacuum oven at 50°C to give the hydrochloride salt the compound of Example 6e (394 mg)
To a solution of the compound of Example 6d (419 mg 1 1 mmol) in methanol (6 ml) at 0 C was added dropwise hydrogen chloride in diethyl ether (1M 1 3 ml) After stirring for 1 5 h diethyl ether (34 ml) was added and the precipitate was collected by filtration The resulting solid was washed with diethyl ether (2 x 40 ml) and dried in a vacuum oven at 50°C to give the hydrochloride salt the compound of Example 6f (418 mg)
(Formula Removed)
Example 6f- absolute stereochemistry
Alternative synthesis
To a solution of the compound of Preparation 1 (5 0 g 19 6 mmol) in methanol (100 ml) under nitrogen was added the compound of Preparation 41 (5 5 g 33 5 mmol) followed by tnethylamme (0 8 ml 5 9 mmol) After stirring for 20 mm sodium cyanoborohydnde (1 8 g 29 3 mmol) was added and the reaction mixture was heated at 50°C for 40 h The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane 2% ammonia in methanol (4 1 50 ml) and filtered through a silica plug The filtrate was concentrated in vacuo and the residue was purified by automated flash chromatography (Biotage™ 65i cartridge, conditioned with dichloromethane 2% ammonia in methanol with gradient elution dichloromethane 2% ammonia in methanol [94 6 to 87 13] The appropriate fractions were combined and concentrated to give the compound of Example 6a (2 14 g) as a pair of enantiomers
(Table Removed)
Example 6a
1H-NMR (CDjOD) 1 08-1 12 (3H) 4 63 4 66(1H) 6 65-6 70 (2H) 6 92-7 00 (3H) 7 02 7 06(1H) 7 19-7 22 (1H)
Example 6b
1H NMR (CD3OD) 1 38 1 42 (3H) 4 87-4 91 (1H) 6 72 6 77 (2H) 6 99 7 04 (2H) 7 07 7 12 <2H) 7 26-7 30 (1H)
Example 6d
1H-NMR (CD3OD) 1 38 - 1 44 (3H) 2 01-218 (2H) 4 87 - 4 91 (1H) 6 72 6 77 (2H) 6 98 - 7 04 (2H) 706-7 11 (2H) 725-729(1H)
Example 6f
1H-NMR (CD3OD) 1 38 -1 41 (3H) 2 01 2 17 (2H) 4 88 - 4 92 (1H) 6 74 6 78 (2H) 6 99 7 04 (2H) 7 06-7 10 (2H) 7 25 -7 29 (1H)
Example 7
6-fl3-(5-Fluoro-2-hydroxyphenylM-methYlpropvl1amino)-7-hydroxY-4 5 6 7 tetrahydro-
imidazo[4 5 1-/klMlbenzazepm-2(1H)-one
(Formula Removed)
To a solution of the compound of Preparation 1 (1 7 g 6 6 mmol) in methanol (34 ml) was added the compound of Preparation 42 (1 2 g 6 6 mmol) followed by tnethylamine (0 3 ml 2 0 mmol) After stirring at 50"C for 30 mm sodium cyanoborohydnde (662 mg 10 5 mmol) was added and the reaction mixture was heated at 50°C for 18 h The mixture was concentrated in vacuo and the residue was dissolved in methanol dichloromethane (1 4) and purified by automated flash chromatography (Biotage™ 65i cartridge conditioned with dichloromethane 2% ammonia in methanol with gradient elution dichloromethane 2% ammonia in methanol [96 4 to 85 15] The appropriate fractions were combined and concentrated to give the compound of Example 7a (900 mg) as a pair of enantiomers Retention time 13 23 mm Other appropriate fractions were combined and concentrated to give the compound of Example 7b (1 07 g) as a pair of enantiomers HPLC Method A retention time 13 89 mm
(Table Removed)
Example 7a
1H-NMR (CD3OD) 1 21 - 1 26 (3H) 2 52 2 64 (2H) 4 67 4 70 (1H) 6 60 - 6 71 (2H) 6 79 6 82 (1H) 6 98 7 06(2H) 7 18-7 21 (1H)
Example 7b
1H-NMR (CD3OD) 1 09-1 13 (3H) 1 70 - 1 85 (2H) 4 62-4 66 (1H) 6 60 - 6 66 (2H) 6 77-6 80 (1H) 6 95 7 05(2H) 7 18-721 (1H)
Example 8
7-Hydroxy-6-([3-(2 hydroxy 3-methoxyphenyl)-1-methylpropyllamino}-4 5 6 7 tetrahydro-
imidazof4 5 1-jk]benzazepm-2(1H)-one
(Formula Removed)
To a solution of the compound of Preparation 1 (0 6 g 2 4 mmol) in methanol (10 ml) was added the compound of Preparation 20 (500 mg 2 6 mmol) in methanol (5 ml) followed by tnethylamine (99 nl 0 7 mmol) After stirring for 1h sodium cyanoborohydnde (372 mg 5 2 mmol) was added and the reaction mixture was stirred at room temperature for 18 h The reaction mixture was quenched with water (1 ml) stirred for 60 mm and concentrated in vacuo The residue was dissolved in acetonitnle water (9 1 4 ml) and purified by automated preparative liquid chromatography (Gilson system 250 x 50 mm Gemini C18(2) column) 120 ml/mm using an acetonitnle 0 1% aqueous ammonia (5 95) acetonitnle 0 1% aqueous ammonia (95 5) gradient [100 0 to 75 25 from 0 to 32 mm 75 25 to 0 100 from 32 to 33 mm 0 100 from 33 to 36 mm] The appropriate fractions were combined and concentrated to give the compound of Example 8a (118 mg) as a pair of enantiomers HPLC Method A retention time 12 99 mm Other appropriate fractions were combined and concentrated to give the compound of Example 8b (150 mg) as a pair of enantiomers HPLC Method A retention time 13 46 mm

(Table Removed)
Example 8a
1H NMR(CD,OD) 1 12 1 16 (3H) 3 79 3 80 (3H) 4 58 4 61 (1H) 6 58 6 66 (2H) 6 70 6 73(1H) 6 95-7 05 (2H) 7 16 7 19(1H)
Example 8b
'H NMR (CD3OD) 1 09 - 1 12 (3H) 3 79 - 3 80 (3H) 4 63 - 4 66 (1H) 6 62 - 6 68 (2H) 6 70 6 73 (1H) 6 98 -7 06 (2H) 7 19 7 21 (1H)
Example 9
7-Hydroxy-6-f(1-methyl-3 phenylpropyDaminoM 5 6 7-tetrahydroimidazor4 5 1 /WfUbenzazepin-
2HH)-one
(Formula Removed)
A mixture of the compound of Preparation 1 (117 mg 0 5 mmol) tnethylamine (100 |il 0 7 mmol) and the compound of Preparation 112 (135 mg 1 0 mmol) in methanol (2 ml) was heated at 80°C in a microwave oven (300W) for 40 mm The reaction mixture was stirred overnight at room temperature before addition of sodium borohydnde (120 mg 3 2 mmol) After stirring at room temperature for 18 h the mixture was diluted with methanol (8 ml) and Amberlyst® 15 ion-exchange resin (4 g prepared according to (J Org Chem 1998 63 3471 3473) was added The mixture was shaken overnight and the solution was filtered off The resin was washed with methanol (3 x 20 ml) and treated with ammonia in methanol (2N 15 ml) After shaking for 2 h, the solution was filtered off and the resin was washed with ammonia in methanol (2N 2 x 15 ml) The combined methanol/ammonia washings were concentrated in vacuo and the residue was re-dissolved in methanol (5 ml) This solution was filtered and concentrated in vacuo The residue was dissolved in acetonitnle water (1112 ml) and purified by automated preparative liquid chromatography (Gilson system 150 mm x 19 mm XTERRA C18 5(im column) 20 ml/mm using an acetonitnle 0 1% aqueous ammonia (1 9) acetonitnle 0 1% aqueous ammonia (9 1) gradient [1 0 to 0 1 from 0-20 mm 0 1 from 20 - 25 mm] The appropriate fractions were combined and concentrated to give the compound of Example 9a (97 mg) as a mixture of 4 diastereoisomers
To a solution of the compound of Example 9a (350 mg 1 0 mmol) in methanol (7 ml) was added dropwise hydrogen chloride in diethyl ether (1M 10 ml) After stirring for 45 mm diethyl ether (30 ml) was added dropwise and the solution was allowed to stand overnight To the mixture was added methanol diethyl ether (1 4 20 ml) and the precipitate was collected by filtration The resulting solid was washed with methanol diethyl ether (14 3 x 15 ml) and diethyl ether (3x15 ml) and dried in a vacuum oven at 50°C to give the hydrochloride salt the compound of Example 9b (183 mg)
The compound of Example 9a (3 0 g 8 6 mmol) was dissolved in dichloromethane methanol (9 1 12 ml) and purified by automated flash chromatography (Biotage™ 65i cartridge) with gradient elution
dichloromethane 2% ammonia in methanol [94 6 to 90 10] The appropriate fractions were combined
and concentrated to give the compound of Example 9c (0 8 g) as a pair of enantiomers
To a solution of the compound of Example 9c (2 5 g 7 1 mmol) in methanol (38 ml) at 0°C was added dropwise hydrogen chloride in diethyl ether (1M 7 1 ml) After stirring for 45 mm diethyl ether (205 ml) was added slowly and the precipitate was collected by filtration The resulting solid was washed with diethyl ether (3 x 200 ml) and dried in a vacuum oven to give the hydrochloride salt the compound of Example 9d (2 6 g)
The compound of Example 9c (1 0 g 2 9 mmol) was dissolved in ethanol (30 ml) and heated to aid solubility The enantiomers were separated by automated preparative liquid chromatography (Gilson system 500 x 50 mm ID Chiralcel OD H 20 urn column) using ethanol hexane [15 85] as the mobile phase The appropriate fractions were combined and concentrated to give the compound of Example 9e (527 mg) as a single enantiomer HPLC Method F retention time 12 43 mm
(Table Removed)
Example 9b
1H-NMR (d"„-DMSO) 1 00 1 05 (3H) 4 50 4 57 (1H) 6 80 6 95 (2H) 7 01 - 7 04 (1H) 7 10 7 15 (3H) 7 20 7 25(2H)
Example 9d
1H-NMR (CDjOD) 141 -1 43 (3H) 2 69 2 85 (2H) 4 95 4 98(11-1) 7 02-7 04 (1H) 7 10 -7 15 (1H) 7 19-721 (1H) 7 23-7 30 (5H)
Example 9e
1H NMR (CD3OD) 1 10 113(3H)4 59 4 61 (1H) 6 98 - 7 05 (2H) 7 08 - 7 21 (6H)
Example 10
6-f[3-(3 5-Difluoro-2-hydroxyDhenvU-1 methylpropvllamino}-7-hydroxV"4 5 6 7 tetrahydro-imidazor4 5 1-ifrinibenzazepin-2(1H)-one
(Formula Removed)
To a solution of the compound of Preparation 1 (2 0 g 7 9 mmol) in methanol (40 ml) was added the compound of Preparation 48 (1 6 g 7 9 mmol) followed by triethylamine (330 jil 2 4 mmol) After stirnng for 25 mm sodium cyanoborohydnde (744 mg 11 8 mmol) was added and the reaction mixture was stirred at 50°C for 80 h The mixture was concentrated in vacuo to give the compound of Example 10a (4 8 g) as a mixture of 4 diastereoisomers
A solution of the compound of Example 10a (4 8 g 118 mmol) in dichloromethane 2 5% ammonia in methanol (2 1, 45 ml) was purified by automated flash chromatography (Biotage™ 65i cartridge conditioned with dichloromethane 2 5% ammonia in methanol [98 2]) with gradient elution dichloromethane 2 5% ammonia in methanol [97 3 to 88 12] The appropriate fractions were combined and concentrated to give the compound of Example 10b (1 1 g) as a pair of enantiomers HPLC Method A - retention time 12 69 mm

(Table Removed)
Example 10b
1H-NMR (CD3OD) 1 11 -1 14 (3H) 1 74 1 80 (2H) 4 70-474(1H) 663 671 (2H) 699-701 (1H) 7 04-7 08 (1H) 7 22 7 24(1H)
Example 11
64f3-(4 5-Difluoro-2-hydroxyphenyl)-1-methylproDvllaminoV7-hydroxy-4 5 6 7-tetrahydro-imidazor4 5 1-ikinibenzazeDin-2(1H)-one
(Formula Removed)
To a solution of the compound of Preparation 1 (2 7 g 10 6 mmol) in methanol (25 ml) was added the compound of Preparation 18 (2 9 g, 11 7 mmol) in methanol (25 ml) To the suspension was added triethylamine (0 5 ml 3 2 mmol) and the mixture was stirred at 45°C for 1 h before addition of sodium cyanoborohydnde (1 7 g 26 6 mmol) The reaction mixture was heated at 45°C for 5 days and then quenched by addition of water (4 ml) citric acid (2 0 g 10 4 mmol) and then sodium hydrogen carbonate (6 0 g) The mixture was concentrated in vacuo and to the residue was added methanol (100 ml) and silica The slurry was concentrated in vacuo and the product/silica mix was eluted with dichloromethane 2 5% ammonia in methanol [4 1] The appropriate fractions were combined and concentrated and the residue was purified by automated flash chromatography (Biotage™ 40M cartridge conditioned with dichloromethane 2 5% ammonia in methanol [96 4]) with gradient elution dichloromethane 2 5% ammonia in methanol [96 4 to 91 9] The appropriate fractions were combined and concentrated and the residue was dissolved in acetomtnle and dimethyl sulphoxide (1 1 4 ml) and further purified by automated preparative liquid chromatography (Gilson system 250 mm x 50 mm Gemini C18(2) column 20 ml/mm) using an acetomtnle 0 1% aqueous ammonia (5 95) acetomtnle 0 1% aqueous ammonia (95 5) gradient (9 1 to 7 3 (over 10 mm) then 7 3 to 5 95 (over 16 mm)] The appropriate fractions were combined and concentrated to give the compound of Example 11a (44 mg) as a pair of enantiomers HPLC Method A - retention time 13 6 mm
(Table Removed)
1H-NMR (CDjOD) 1 32 135(3H)198 2 05 (2H) 4 18 4 22 (1H) 6 59 - 6 64 (1H) 6 99 7 06 (2H) 7 09 7 12 (1H) 7 29 7 32(1H)
The following Examples were prepared by similar methods to those described above for Examples 1 11
(Table Removed)
Example 12
6-{[3-(1 3-Benzodioxol-5-yl) 1-methylpropyllammo} 7-hydroxy-4 5 6 7 tetrahydroimidazor4 5 1 /kiri]benzazepin-2(1H)-one
1H-NMR (CD3OD) 1 08 1 20 (3H) 4 61 - 4 68 (1H) 5 82 5 90 (2H) 6 50 6 70 (3H) 6 98 - 7 10 (2H) 7 17 7 22(11-1)
Example 13a
7 hydroxy-6-JM Methyl 3-(2 methylphenynpropvllaminoM 5 6 7 tetrahydroimidazoM 5 1-
/Wnibenzazepin-2(1 H)-one
1H-NMR (CD3OD) 1 17 -1 22 (3H) 2 21 - 2 24 (3H) 3 80 4 00 (2 H) 4 65 4 70 (1H) 7 00 7 12 (6H) 7 18-721 (1H)
Example 13b
7 hydroxy-6-fli-Methyl-3-(2 methylphenyltpropyllaminoM 5 6 7-tetrahydroimidazof4 5 1-
//clMlbenzazepin-2(1 H)-one
1H-NMR (d6-DMSO) 1 00 - 1 09 (3H) 2 22 2 23 (3H) 4 50 4 52 (1H) 6 81 6 83 (1H) 6 90 6 94 (1H) 7 01-711 (5H)
Example 14a
6-f(1 3-Dimethyl-3-phenylbutvDaminol-7-hydroxy-4 5 6 7 tetrahydroimidazo[4 5 1 /tf rHbenzazepm-
2(1W-one
1H-NMR (CD3OD) 0 99 1 05 (3H) 1 13 -1 19 (6H) 4 69 4 73 (1H) 6 96 7 03 (5H) 7 04 7 08(1H) 7 08 7 12(2H)
Example 14b
6-H1 3-Dimethyl-3 phenylbutyl)aminol-7-hydroxy-4,5 6 7 tetrahydroimidazor4 5 1-/tfnibenzazepin-
2(1Hl-one
1H-NMR (CD3OD) 0 89 - 0 95 (3H) 1 20 - 1 23 (3H) 1 35 1 40 (3H) 4 45 - 4 50 (1H) 6 80 - 6 85 (1H) 6 95-7 10 (5H) 7 20 - 7 26 (2H)
Example 15
7-Hydroxy-6-ff3-/4 hydroxy-3 5-dimethylphenvJM-methylproDvlJaminoM 5 6 7-tetrahydro-
imidazo(4 5 1-//f]f11benzazepin-2(1H)-one
1H-NMR (CD3OD) 1 09 1 15 (3H) 1 70 1 81 (2H) 2 15 -2 17 (6H) 4 60-4 62 (1H) 6 70 -6 73 (2H) 6 99 7 07(2H) 7 18 7 20(1H)
Example 16
7-Hydroxy-6-(r3-(4 isoDroDOXvohenvl) 1-methylDroDvllammoM 5 6 7 tetrahydroimidazof4 5 1 /frlf1]benzazepin-2f1W)-one
1H-NMR (CD3OD) 1 10-1 18 (3H) 1 25-1 29 (6H) 4 62-468(1H) 675-681 (2H) 699-710 (4H) 7 19-7 22 (1H)
Example 17
7-Hydroxy-6-fr3-{2 hydroxy-3-methylphenYl)-1-methylRropvriamino}-4 5 6 7-tetrahydro-
imidazoM 51-/Jtlf1lbenzazepin-2(1/fl-one
1H-NMR (CD3OD) 1 39-143(3H) 2 16-2 19 (3H) 4 86 4 90 (1H) 6 67 6 72 (1H) 6 90 6 96 (2H) 7 00-7 04 (1H) 7 06-7 12 (1H) 7 25-7 29 (1H)
Example 18
7-Hydroxv-6-({1-methyl-3-[4-(tnfluoromethyl)phertvllpropvl}amirtoM 5 6 7-tetrahydro
imidazof4 51-Wrlf1]benzazepin-2(1H)-one
1H-NMR (CDjOD) 1 15-1 17 (3H) 1 78 1 86 (2H) 4 62 4 64 (1H) 6 98 7 06 (2H) 7 18 7 21(1H) 7 38 - 7 41 (2H) 7 55 7 59 (2H)
Example 19a
64r3-f5-ChIoro-2-hydroxyphenyl)-1-methylproDvllamino}-7 hydroxy-4 5 6 7-tetrahydro
imidazof4 5 1-/JtH11benzazepin-2(1H)-one
1H-NMR (CDjOD) 1 39 1 43 (3H) 2 61 - 2 80 (2H) 4 88 4 92 (1H) 6 70 6 73 (1H) 6 97 7 04 (2H) 7 09 7 12(2H) 7 27 7 31 (1H)
Example 19b
6-tf3-(5-Chioro-2-hydroxyphenyl)-1-methyipropyllamino) 7-hydroxy-4 5 6 7-tetrahydro
imidazoH 5 1-//rinibenzazepin-2(1H)-one
1H-NMR (CDjOD) 1 15 1 19 (3H) 1 70-1 87 (2H) 4 63 4 67 (1H) 6 63 6 66 (1H) 6 91 7 05 (4H) 715-718(1H)
Example 20
7-Hydroxy-64f3-(2-methoxvphenyl)-1-methylpropvlIaminoM 5 6 7-tetrahydroimidazof4 5 1-
/kH1lbenzazepin-2(1H)-one
1H-NMR (CD3OD) 1 13-1 17 (3H) 3 73 - 3 75 (3H) 4 65 4 68 (1H) 6 78 6 87 (2H) 6 98 7 15(4H) 7 17-721 (1H)
Example 21
7-Hydroxy-6-(r3-(2-hydroxy 5-methoxvphenvO-l methylpropvllaminoM 5 6 7 tetrahydro
imidazor4 5 1-/Mf1lbenzazepin-2(1M-one
1H-NMR (CD3OD) 1 16-1 19 (3H) 3 66 3 69 (3H) 4 69 4 74 (1H) 6 58 6 61 (1H) 6 63 6 66 (2H)
6 99 -7 09 (2H) 7 22 7 24(1H)
Example 22
4 Hydroxy 3-(3-{r7-hydroxy-2-oxo-1 2 4 5 6 7-hexahydroimidazo[4 5 1-/fc]rilbenzazepm-6-
yllaminolbutvDbenzortitnle
'HNMR(CD30D) 1 15-1 19 (3H), 1 74 1 82 (2H) 4 71 4 75 (1H) 6 79 6 82 (1H) 6 99 7 09 (2H)
7 25-7 28 (1H) 7 35-7 39 (1H) 7 42 7 44(1H)
Example 23
6-{[3-(4-Fluorophenyl)-1-methylpropvllamino)-7 hydroxy-4 5 6 7-tetrahydroimidazor4,5 1-
;Wf1lbenzazepin-2(1H)-one
1H-NMR (CD3OD) 1 08-1 13 (3H) 1 71 1 81 (2H) 4 60 4 64 (1H) 6 88 6 99 (3H) 7 00 7 06(1H) 7 12-7 19 (3H)
Example 24
6-fr3-(4-Fluoro-2-hydroxyphenyll)-1 methylpropvllaminoW hydroxy-4 5 6 7 tetrahydro
imidazof4 5 1-;frl[ilbenzazepin-2f1rY)-one
1H-NMR (CD3OD) 1 09 -1 12 (3H) 1 70 1 80 (2H) 4 65 4 70 (1H) 6 40 6 48 (2H) 6 99 7 11 (3H) 7 22-7 25 (1H)
Example 25
64r3-(3 5-Dichloro 2-hydroxyphenyll)-1-methylpropvllamino}-7-hydroxy-4 5 6 7-tetrahydro-
imidazof4 5 1-/A1WbenzazeDin-2(1H)-one
1H-NMR (CD3OD) 1 09 -1 12 (3H) 1 80 1 88 (2H) 4 80 - 4 83 (1H) 7 00 7 03 (2H) 7 04 7 12 (2H) 7 27 7 29(1H)
Example 26
6-fl3-{4-Chloro-2-rtvdroxvDhenvn 1-methylpropvllamino} 7 hydroxy-4 5 6 7 tetrahydro
imidazof4 5 1-/Wnibenzazepin-2(1H)-one
1H-NMR (CD3OD) 1 12-1 17 (3H) 1 70 1 80 (2H) 4 63 - 4 66 (1H) 6 61 6 63 (1H) 6 77 6 79(1H) 6 99 7 10(3H) 7 20 7 22 (1H)
Example 27
6-tt3-<3-Chloro-5-fluoro-2-hydroxyphenyll)-1-methylpropvllamino)-7-hydroxy-4 5 6 7-tetrahydro-imidazoM 5 1-jk]benzazeDin-2(1H)-one
1HNMR(CD3OD) 109-1 12 (3H) 4 75-4 78 (1H) 680 6 82 (1H) 691 6 94 (1H) 700 703(1H) 7 07 7 10(1H) 7 25-7 30 (1H)
Example 28a
6-tf3-(3-Fluoro-2-hydroxyprienvl) 1-methyloropvllamlnol-7 hydroxy-4 5 6 7-tetrahydro-
imidazoF4 5 1-jk]benzazepin 2(1H)-one
1H NMR (CD3OD) 1 12 1 15 (3H) 1 74-1 81 (2H) 4 70 4 72 (1H) 6 63 - 6 66 (1H) 6 80 6 87 (2H) 6 99-7 10 (2H) 723 725(1H)
Example 28b
6-(r3-(3-Fluoro-2-hydroxyphenyll)-1-methylpropvllamino>-7-hydroxy-4 5 6 7-tetrahydro
imidazoM 5 1-/MHlbenzazepln-2(1H)-one
1H-NMR (CD3OD) 1 16 -1 20 (3H) 1 70 - 1 80 (2H) 4 65 - 4 68 (1H) 6 62 - 6 66 (1H) 6 80 - 6 89 (2H)
6 99 7 08(2H) 7 18-721 (1H)
Example 29
6-([3-(2 4-Dichlorophenyl)-1-methylpropynamino}-7-hydroxy-4 5 6 7-tetrahydroimidazof4 51-
jk[lbenzazepin-2(1H)-one
1H-NMR (CDjOD) 112-115 (3H) 1 70 1 80 (2H) 4 61 4 63 (1H) 6 96 - 7 04 (2H) 7 16 - 7 20 (2H)
7 22 7 24(1H) 7 36-7 38 (1H)
Example 30
7-Hydroxy-6-((1-methyl-3-[3-{tnfluoromethyl)phenyllpropvl}aminoM 5 6 7-tetrahydro-
imidazoM 5 1-jknibenzazepin-2(1H)-one
1H-NMR (CD3OD) 1 14-1 17 (3H) 1 78 1 87 (2H) 4 62 4 64 (1H) 6 99 7 09 (2H) 7 20 7 22(1H) 7 41 7 50(3H) 7 51 -7 52(1H)
Example 31
7-Hydroxy-6-((3-I2-hydroxy 5-(trifluoromethyllphenyll 1-methylpropvl)amino)-4 5 6 7-tetrahydro
imidazor4 5 1 jk][1]lbenzazepin-2(1H)-one
1H-NMR (CD3OD) 1 38 141(3H)2 00 2 10 (2H) 4 19 4 23 (1H) 6 88 6 91 (1H) 7 01 7 04(1H) 7 10-7 14 (1H) 7 30-7 35 (2H) 7 40 7 44(1H)
Example 32
6-([3-(2-Chloro-6-fluorophenyl)-1-methylpropyllamino) 7-hydroxy-4 5 6 7-tetrahydroimidazo[4 5 1-jk][1]benzazepin-2(1H)-one
1 H-NMR (d6-DMSO) 1 00-1 06 (3H) 4 50 4 55(1H) 6 81 6 85(1H) 6 90-696(1H) 701-705 (1H) 7 12 7 19 (1H) 7 20 - 7 26 (2H)
Example 33
N [2-(3-{[7-Hydroxy-2-oxo-1 2 4 5 6 7 hexahydroimidazo[4 5 1-/Mf1lbenzazepm-6
yllaminolbutvNphenyllmethanesulfonamide
1H-NMR (CD3OD) 1 10-1 13 (3H) 2 90 2 92 (3H) 4 90 4 92 (1H) 6 99 7 01 (1H) 7 06 - 7 08 (1H) 7 16-721 (2H) 725 7 34 (2H) 7 39 741 (1H)
Example 34
7-Hydroxy-6-(r3-(4-methoxvphenyl) 1-methylpropvllaminoM 5 6 7 tetrahydroimidazo[4 5 1
jk1lbenzazepin-2(1 H)-one
1H-NMR (CD,OD) 1 07 -1 15 (3H) 3 69 - 3 72 (3H) 4 59 - 4 64 (1H) 6 71 6 77 (2H) 6 96 7 05 (4H) 712-717 (1H)
Example 35
7-Hydroxy-6-ir3-(2 isopropoxyphenyl) 1-methylpropvllammo)-4 5 6 7 tetrahydrolmidazor4 5 1-
jk][1]benzazepin-2(1 H)-one
1H-NMR (CDjOD) 1 10 -1 14 (3H) 1 25 1 30 (6H) 4 50 4 52 (1H) 4 62 4 64 (1H) 6 75 6 79 (1H)
6 83-6 86 (1H) 7 00-711 (4H) 7 18-7 20 (1H)
Example 36
6-((3-(3-Fluoro-4-hydroxyphenyl)-1 methylpropyl]amino)-7-hydroxy-4 5 6 7 tetrahydro-
imidazo[4 5 1-jk][1]lbenzazepin-2(1H)-one
1 H-NMR (CD3OD) 1 15 118(3H)175 1 82 (2H) 4 63 4 65 (1H) 6 77 6 80 (2H) 6 85 6 87(1H)
7 00 7 02 (1H) 7 05 7 07 (1H) 7 20 7 22(1H)
Example 37
6-(r3-(2 3-Dlfluoro-4-hydroxyphenyl)-1-methylpropvllamino>-7 hydroxy-4 5 6 7 tetrahydro-
imidazor4 5 1-jknibenzazepin-2(1H)-one
1H-NMR (CD3OD) 1 20 122(3H)180 1 86 (2H) 4 73 4 75 (1H) 6 60 - 6 64 (1H) 6 79 6 82(1H) 7 00 7 02 <1H) 7 05 - 7 07 (1H) 7 21 7 23 (1H)
Example 36
64f3-(2-Fluoro-4-hydroxyphenyl)-1-methylpropyllamino>-7 hydroxy-4 5 6 7-tetrahydro imidazof4 5 1-jk][1]benzazepin-2(1H)-one
1H-NMR (CD3OD) 1 14 -1 16 (3H) 1 75 -1 81 (2H) 4 63 4 65 (1H) 6 78 - 6 80 (2H) 6 86 6 88 (1H)
7 00-7 02 (1H) 7 03-705(1H) 7 20-7 22 (1H) (
Example 39
7 Hydroxv-6-fr3-(3-hydroxyphenyl)-1-methylpropylaminol-4 5 6 7 tetrahydroimidazof4 5 1-
-jk][1]benzazepin-2f1 H)-one
1H-NMR (CD3OD) 110-113 (3H) 1 75 -1 82 (2H) 4 62 4 64 (1H) 6 57 6 59 (1H) 6 71 - 6 74 (2H) 6 98-7 05 (3H) 7 19 7 22 (1H)
Example 40
6-{f3-(2-Fluorophenyl)-1-methylproD-2-en-1-yllamino)-7-hydroxy-4 5 6 7-tetrahydroimidazo(4 5 1-
jk][1]benzazepin-2(1 H)-one
(Formula Removed)
To a solution of the compound of Preparation 1 (535 mg 2 1 mmol) in methanol (10 ml) was added the compound of Preparation 33 (378 mg 2 3 mmol) in methanol (5 ml) followed by tnethylamine (88 y\ 0 6 mmol) The reaction mixture was stirred at room temperature for 1 h before addition of sodium cyanoborohydride (329 mg 5 2 mmol) After stirring for 72 h sodium borohydnde (40 mg 1 1 mmol) was added and the mixture was quenched by addition of water The mixture was stirred for a further 1 h and then concentrated in vacuo The residue was extracted with ethyl acetate (3 x 15 ml) and the combined extracts were dried (MgSO4) and concentrated in vacuo The residue was dissolved in dichloromethane and purified by automated flash chromatography (Biotage™ 25M cartridge conditioned with dichloromethane 2 5% ammonia in methanol with gradient elution dichloromethane 2 5% ammonia in methanol [96 4 to 93 7] The appropriate fractions were combined and concentrated and the residue was dissolved in acetonitnle water (914 ml) and purified by automated preparative liquid chromatography (Gilson system 150 mm x 21 4 mm Gemini C18 5µm column) 20 ml/mm using an acetonitnle 0 1% aqueous ammonia (5 95) acetonitnle 0 1% aqueous ammonia (95 5) gradient [30 70 from 0 to 32 mm 30 70 to 5 95 from 32 to 33 mm 5 95 from 33 to 36 mm] The appropriate fractions were combined and concentrated to give the compound of Example 40a (9 mg) as a pair of enantiomers HPLC Method A - 14 14min Other appropriate fractions were combined and concentrated to give the compound of Example 40b (14 mg) as a pair of enantiomers HPLC Method A - retention time 14 41mm
(Table Removed)
Example 40a
1H-NMR (CD3OD) 121-1 24 (3H), 4 62-4 66 (1H) 6 10-6 16 (1H) 6 62 6 69(1H) 6 95-7 10 (4H) 7 15-721 (2H) 7 45-7 50 (1H)
Example 40b
1H-NMR (CD3OD) 1 19 123(3H) 4 73-4 77 (1H) 6 20-6 28 (1H) 6 70-6 76 (1H) 6 96-7 10 (4H) 7 18-7 22 (2H) 7 45 7 50 (1H)
Similarly prepared were
(Table Removed)
Example 41
7-Hydroxy-6-fr3-{3-hydroxyphenyl 1-methylprop-2 en-1 yI]amino)-4 5 6 7 tetrahydroimidazo[4 5 1-
jk][1]benzazepin-2(1H)-one
1H-NMR (CD3OD) 1 20-1 30 (3H) 4 65-4 76 (1H) 5 95-6 10 (1H) 6 40-6 50 (1H) 660-670 (1H) 6 80-6 90 (2H) 7 00-7 15 (3H) 7 20-726(1H)
Example 42
N-2-[3-([7-Hydroxy-2-oxo 1 2 4 5 6 7-hexahydroimidazo[4 5 1 jk][1]benzazepin-6-yl]amino}but 1
en-1-yllphenyl)methanesulfonamide
1H-NMR (CD3OD) 1 24 1 28 (3H) 2 90 - 2 92 (3H) 4 66 4 68 (1H) 6 03 - 6 09 (1H) 6 97 - 7 05 (3H) 7 20 7 26 (3H) 7 30 -7 32 (1H) 7 61 7 63(1H)
Example 43
7-Hydroxy-6-([3-(3-hydroxyphenyl)-1-methylpropyl]amino)-4 5 6 7-tetrahydroimidazo[4 5 1-
jk][1]benzazepin-2(1H)-one
(Formula Removed)
A mixture of the compound of Example 41 (15 mg 40 2 nmol) and palladium (10% on carbon 4 mg) in methanol (2 ml) was hydrogenated (60 psi) for 1 h The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give the compound of Example 43 (15 mg) as a mixture of 4 diastereoisomers (Table Removed)
Example 43
1H-NMR (CD3OD) 1 10 120(31-1)4 60 4 70 (1H) 6 58 6 70 (3H) 6 95 7 10 (3H) 7 15 7 22(1H)
Example 44
7-Hydroxy 6-(3 [3-(hydroxymethyl)phenyl]-methylpropyl)amino)-4 5 6 7-tetrahydro-
lmidazof4 5 1-jk][1]benzazepin-2(1H)-one
A mixture of the compound of Preparation 1 (100 mg 0 4 mmol) triethylamine (0 1ml 0 6 mmol) and the
compound of Preparation 34 (138 mg 0 8 mmol) in methanol (3 ml) was stirred at room temperature for 18 h Sodium borohydnde (44 mg 1 2 mmol) was then added and the reaction mixture was stirred at room temperature for 1 h The mixture was diluted with methanol (8 ml) and Amberlyst® 15 ion-exchange resin (3 5 g prepared according to J Org Chem 1998 63 3471-3473) was added The mixture was shaken overnight and the solution was filtered off The resin was washed with methanol (100 ml) and treated with ammonia in methanol (2N 5 ml) After shaking for 2 h the solution was filtered off and the resin was washed with ammonia in methanol (2N 2 x 5 ml) The combined methanol/ammonia washings were concentrated in vacuo and the residue was dissolved in acetonitnle water (1115 ml) and purified by automated preparative liquid chromatography (Gilson system 150 mm x 21 4 mm Gemini 5nm column 20 ml/mm) using a 0 1% aqueous ammonia acetonitnle (9 1) 0 1% aqueous ammonia acetonitnle gradient (1 9) [1 0 to 0 1 from 0-20 min 0 1 from 20 - 25 min] The appropriate fractions were combined and concentrated to give the unsaturated intermediate of the title compound (14 mg)
A mixture of the unsaturated intermediate of the title compound (14 mg 0 04 mmol) and platinum (IV) oxide (1 mg) in water (0 5 ml) and isopropyl alcohol (0 5 ml) was shaken under hydrogen (60 psi) for 30 mm The reaction mixture was filtered through Arbocel® washing through with isopropyl alcohol (0 5 ml) and the filtrate was concentrated in vacuo to give the compound of Example 44 (10 mg)

(Table Removed)
Example 44
'HNMRfCDaOD) 1 10 1 20 (3H) 4 50 - 4 60 (2H) 4 63 4 66 (1H) 6 90 - 7 10 (3H) 7 11 7 25 (3H)
Example 45
6-{[3-(4-Aminophenyl)-1 methylpropyl]amino)-7-hydroxy-4 5 6 7 tetrahydroimidazof4 5 1-
jk][1]benzazepin 2(1H)-one
(Formula Removed)
A solution of the compound of Preparation 67 (500 mg 1 3 mmol) in methanol (5 ml) was flowed through an H Cube hydrogenator (8 ml/mm 1 atm 55"C) using a palladium catalyst (10% on carbon) The solution was concentrated in vacuo and the residue was dissolved in acetonitnle (2 ml) and purified by
automated preparative liquid chromatography (Gilson system 150 mm x 21 mm Gemini C18 5^m
column 25 ml/mm) using a 1% aqueous ammonia acetonitnle gradient [5 95 to 40 60 (from 0 to 6 mm)
to 98 2 (from 10 to 10 5 mm)] The appropriate fractions were combined and concentrated to give the the
compound of Example 45 (4 mg) as a single enantiomer

(Table Removed)
Example 45
^H-NMR (de-DMSO) 0 97 -1 00 (3H) 2 61 2 65 (1H) 2 98 - 3 01 (1H) 4 77 - 4 79 (1H) 6 42 6 45 (2H) 6 79 6 82(2H) 6B2-6 84(1H) 6 90 -6 92 (1H) 7 03-7 05 (1H) HPLC Method A - retention time 11 80 mm
Similarly prepared was
Example 46
6-tf3-(3-Aminophenyl)-1 methylpropyl1ammo)-7 hydroxy-4 5 6 7-tetrahydroimidazof4 5 1
//rid lbenzazeDin-2(1 H)-one
(Table Removed)
HPLC Method A - retention time 11 98 mm
Example 47
6-([3-(3 5-Dibromo-2-hydroxyphenyl)-1 methylpropyl]amino) 7-hydroxy-4 5 6 7 tetrahydro-
imidazor4 5 1-jklbenzazepin-2(1H)-one
(Formula Removed)
To a solution of the compound of Preparation 69 (2 1 g 5 7 mmol) in A/,N-dimethylformamide (10 ml) and dichloromethane (40 ml) was added dropwise the compound of Preparation 148 (3 6 g 17 2 mmol) in N N-dimethylformamide (20 ml) The reaction mixture was stirred for 1 5 h before addition of dichloromethane (100 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml) After stirnng for 10 mm the solution was adjusted to pH 7 by addition of solid citric acid and aqueous sodium thiosulphate solution (50 ml) was added The solution was concentrated in vacuo and to the residue was added methanol (150 ml) and silica (50 g) The slurry was concentrated in vacuo and the silica/product mix was passed through a silica plug elutmg with dichloromethane 2 5% ammonia in methanol [4 1] The filtrate was concentrated in vacuo and the residue was triturated with dichloromethane (50 ml) To the residue was added methanol (50 ml) and silica (10 g) and the slurry was concentrated in vacuo The product/silica mix was purified by automated flash chromatography (Biotage™ 65i silica cartridge) with gradient elution dichloromethane 2 5% ammonia in methanol [96 4 to 90 10] The appropriate fractions were combined and concentrated to give the compound of Example 48 (300 mg) as a pair of enantiomers HPLC Method A retention time 12 8 mm
1H-NMR (d6-DMSO) 0 99 -1 02 (3H) 4 64 4 68 (1H) 6 85-6 87 (1H) 6 92 6 94 (1H) 7 15 7 17 (1H) 720 7 22(1H) 7 42-7 43(1H)

(Table Removed)
Example 48
Hydrochloride salt of 7 hydroxy 6 ([3 (2-hydroxyphenyl)-methylpropyl]amino)-4 5 6 7-tetrahydroimidazo[4 5 1-jk][1]benzazepin 2(1H)-one
(Formula Removed)
To a mixture of the compound of Preparation 9 (7 2 g 28 2 mmol) and triethylamine (1 2 ml 8 5 mmol) in methanol (40 ml) was added the compound of Preparation 41 (5 6 g 33 8 mmol) followed by sodium cyanoborohydride (2 7 g, 42 3 mmol) The reaction mixture was heated at 50°C for 18 h before addition of water (3 ml) citric acid (3 0 g) and sodium hydrogen carbonate (3 0 g) After stirring for 30 mm the solution was concentrated in vacuo and to the residue was added methanol (250 ml) and silica The slurry was concentrated in vacuo and the silica/product mix was passed through a silica plug eluting with dichloromethane 2 5% ammonia in methanol [4 1] The filtrate was concentrated in vacuo and purified by automated flash chromatography (Biotage™ 65M silica cartndge) with gradient elution dichloromethane 2 5% ammonia in methanol [95 5 to 93 7] The appropriate fractions were combined and concentrated and the residue was dissolved in acetonitnle (4 ml) and purified by automated preparative liquid chromatography (Gilson system 250 mm x 50 mm Gemini C18 10pm column 120 ml/mm) using an acetonitnle 0 1% aqueous ammonia (5 95) acetonitnle 0 1% aqueous ammonia (95 5) gradient [90 10 to 50 50 (from 3 to 10 mm) to 40 60 (from 18 to 20 mm) to 5 95 (from 20 to 21 mm)] The appropriate fractions were combined and concentrated to give the free base of the compound of Example 48 (1 1 g) as a single enantiomer To a solution of the free base the compound of Example 48 (419 mg 1 1 mmol) in methanol (6 ml) at 0°C was added dropwise hydrogen chloride in diethyl ether (1M 1 30 ml) After stirring for 1 5 h diethyl ether (34 ml) was added and the precipitate was collected by filtration The resulting solid was washed with diethyl ether (2 x 40 ml) and dried in a vacuum oven at 50°C to give the hydrochloride salt the compound of Example 48 (418 mg) HPLC method A - retention time 13 1 mm

(Table Removed)
Example 48
1H-NMR (CDjOD) 1 38 1 41 (3H) 2 01 2 17 (2H) 4 88 4 92 (1H) 6 74 6 78 (2H) 6 99 7 04 (2H) 7 06-7 10 (2H) 7 25-7 29 (1H)
Example 49
6-([3-(3 5-Dibromo-2-hydroxyphenyl)-1-methylpropyl]arnino)-7-hydroxy-4 5 6 7-tetrahydro-
imidazo[4 5 1-jk]benzazepin-2(1H)-one
(Formula Removed)
To a mixture of the compound of Preparation 9 (2 5 g 9 8 mmol) and triethylamine (0 4 ml 2 9 mmol) in methanol (15 ml) was added the compound of Preparation 70 (3 7 g, 11 0 mmol) followed by sodium cyanoborohydnde (0 9 g 14 7 mmol) The reaction mixture was heated at 50°C for 18 h cooled and quenched with citric acid The mixture was adjusted to pH 7 by addition of sodium hydrogen carbonate and concentrated in vacuo The residue was pre-absorbed onto silica and passed through a silica plug eluting with dichloromethane 2 5% ammonia in methanol [4 1] The filtrate was concentrated in vacuo and purified by automated flash chromatography (Biotage™ 65i silica cartridge) with gradient elution dichloromethane 2 5% ammonia in methanol [97 3 to 94 6] The appropriate fractions were combined and concentrated to give the compound of Example 49 (765 mg) as a single enantiomer HPLC Method A retention time 12 70 mm

(Table Removed)
Example 49
1H-NMR (d6-DMSO) 0 97 1 00 (3H) 4 68 - 4 70 (1H) 6 85 - 6 87 (1H) 6 94 6 97 (1H) 7 17 7 19 (1H) 7 20 7 22 (1H) 7 40-741 (1H)
Example 50
6-([3-{2 Chloro-3-hydroxyphenyll) 1 methylpropvllamino) 7 hydroxy-4 5 6 7-tetrahydro
imidazo[4 5 1 jk][1]benzazepin-2(1 Hi-one
(Formula Removed)
To a mixture of the compound of Preparation 9 (300 mg 1 2 mmol) and the compound of Preparation 49
(280 mg 1 4 mmol) in methanol (5 ml) under nitrogen was added triethylamine (0 05 ml 0 4 mmol)
After stirring for 20 mm sodium cyanoborohydnde (111 mg 18 mmol) was added and the reaction
mixture was heated at 60°C under nitrogen for 18 h After cooling citric acid (500 mg) was added and
the mixture was heated at 60°C for 3 h To the mixture was added water (0 2 ml) followed by excess
sodium hydrogen carbonate and the mixture was stirred at room temperature for 18 h The mixture was
concentrated in vacuo and the residue was purified by automated flash chromatography (Biotage™
40+M silica cartridge) with gradient elution dichloromethane 2 5% ammonia in methanol [96 4 to
89 11] The appropriate fractions were combined and concentrated and further purified by automated
preparative liquid chromatography (Gilson system 150 mm x 21 4 mm Gemini C18 5nm column 20
ml/mm) using an acetonitnle 0 1% aqueous ammonia (5 95) acetonitnle 0 1% aqueous ammonia
(95 5) gradient (90 10 to 78 22 (from 2 to 8 mm) to 50 50 (from 15 to 20 mm) to 5 95 (from 21 to 22 mm)]
The appropriate fractions were combined and concentrated to give the compound of Example 50 (61 mg)
as a single enantiomer HPLC method A retention time 11 51 mm

(Table Removed)
Example 50
1H-NMR (CD3OD) 1 26 -1 28 (3H) 1 78 -1 85 (2H) 4 65 - 4 67 (1H) 6 73 - 6 76 (2H) 6 98 7 03 (2H) 7 04 -7 07 (1H) 7 19-721 (1H)
Example 51
2 2 2-Trifluoro-AM2-f3-{r7-hydroxy 2-oxo-1 2 4 5 6 7 hexahydroimidazof4 5 1 //tinibenzazepm-6-
yl1amino)butyllphenyl}acetamide
(Formula Removed)
To a mixture of the compound of Preparation 9 (247 mg 1 0 mmol) and the compound of Preparation 71 (250 mg 1 0 mmol) in methanol (8 ml) under nitrogen was added triethylamine (0 04 ml 0 4 mmol) After stirring for 20 mm sodium cyanoborohydnde (91 mg 1 5 mmol) was added and the reaction mixture was heated at 60°C under nitrogen for 18 h After cooling citric acid (500 mg) was added and the mixture was heated at 60°C for 3 h To the mixture was added water (0 2 ml) followed by excess sodium hydrogen carbonate and the mixture was stirred at room temperature for 18 h The mixture was
concentrated in vacuo and the residue was pre-absorbed onto silica (10 g) and passed through a silica
plug (10 g) eluting with dichloromethane 2 5% ammonia in methanol [4 1] The filtrate was
concentrated in vacuo and the residue was dissolved in acetonitnle water (9 14 ml) and purified by
automated preparative liquid chromatography (Gilson system 150 mm x 21 4 mm Gemini C18 5\im
column 20 ml/mm) using an acetonitnle 0 1% aqueous ammonia (5 95) acetonitnle 0 1% aqueous
ammonia (95 5) gradient [90 10 to 80 20 (from 2 to 15 mm) to 50 50 (from 24 to 26 mm) to 5 95 (from 26
to 28 mm)] The appropriate fractions were combined and concentrated to give the compound of
Example 51 (61 mg) as a single enantiomer HPLC method A retention time 12 72 mm

(Table Removed)
Example 51
1H-NMR (CD3OD) 1 15 1 17 (3H) 2 57 - 2 60 (2H) 4 64 4 66 (1H) 6 59 6 61 (1H) 6 67 6 69(1H) 691 697(2H)699 701(1H)705 7 07 (1H) 7 20-7 22 (1H)
Example 52
4-[3-3-([7-Hydroxy-2-oxo-1 2 4 5 6 7-hexahydroimidazo[4 5 1 jk][1]benzazepin 6-yl)amino)butyl] N-
(2 2 2-trifluoroethyl)benzamide
(Formula Removed)
To a mixture of the compound of Preparation 9 (293 mg 1 1 mmol) and tnethylamine (0 05 ml 0 4 mmol) in methanol (15 ml) was added the compound of Preparation 89 (172 mg 0 6 mmol) followed by sodium cyanoborohydnde (108 mg 1 6 mmol) and the reaction mixture was heated at 50°C for 18 h After cooling the mixture was quenched by addition of water (3 ml) and citric acid was added followed by excess sodium hydrogen carbonate The mixture was stirred at room temperature for 30 mm and then passed through a silica plug eluting with dichloromethane 2 5% ammonia in methanol [3 1] The filtrate was concentrated in vacuo and the residue was dissolved in acetonitnle water (9 1 6 ml) and purified by automated preparative liquid chromatography (Gilson system 250 mm x 50 mm Gemini C18 10um column 120 ml/mm) using an acetonitnle 0 1% aqueousammonia (5 95) acetonitnle 0 1% aqueous ammonia (95 5) gradient [90 10 to 65 35 (from 2 to 5 mm) to 50 50 (from 11 to 12 mm) to 5 95 (from 14 to 15 mm)] The appropriate fractions were combined and concentrated to give the compound of Example 52 (120 mg) as a single enantiomer HPLC method A retention time 13 47 mm
(Table Removed)
Example 52
1H-NMR(CD3OD) 1 16-1 19 (3H), 2 75 2 79 (2H) 4 04 4 10 (2H) 4 63 - 4 65 (1H) 6 98 7 00(1H) 7 01 - 7 03 (1H) 7 19 7 21 (1H) 7 30 7 33 (2H) 7 75 - 7 77 (2H)
Example 53
3-rr3-ir7-Hydroxy-2-oxo-1 2 4 5 6 7-hexahydroimidazor4 5 1-/Wrilbenzazepm-6-
vllamino}butyllbenzoic acid
(Formula Removed)
To a mixture of the compound of Preparation 9 (277 mg 1 1 mmol) and tnethylamine (0 05 ml 0 3 mmol) in methanol (15 ml) was added the compound of Preparation 51 (250 mg 1 3 mmol) followed by sodium cyanoborohydnde (102 mg 1 6 mmol) and the reaction mixture was heated at 50°C for 18 h After cooling the mixture was quenched by addition of water (3 ml) and citric acid was added followed by excess sodium hydrogen carbonate The mixture was stirred at room temperature for 30 min and then passed through a silica plug eluting with dichloromethane 2 5% ammonia in methanol [3 1] The filtrate was concentrated in vacuo and the residue was dissolved in acetonitnle water (9 16 ml) and purified by automated preparative liquid chromatography (Gilson system 150 mm x 21 mm Gemini C18 5um column 25 ml/min) using a 0 1% aqueous ammonia acetonitnle gradient [5 95 to 20 80 (from 0 to 6 mm) to 98 2 (from 8 to 8 5 mm)) The appropriate fractions were combined and concentrated to give the compound of Example 53 (72 mg) as a single enantiomer HPLC method A - retention time 8 11 mm

(Table Removed)
Example 53
1H NMR (CDjOD) 1 38 1 40 (3H) 4 90 4 92 (2H) 7 00 7 02 (1H) 7 08 7 11 (1H) 7 27 7 33 (3H) 7 78 7 80(1H) 7 84-7 86 (1H)
Example 54
6-((3-(4 5-Dlfluoro 2-hydroxyphenyl)- methylpropynamino}-7-hydroxy-4 5 6 7-tetrahydro-
imidazo[4 5 1-jk][]benzazepin-2(1H)-one
(Formula Removed)
To a mixture of the compound of Preparation 9 (445 mg 1 7 mmol) and the compound of Preparation 52 (418 mg 2 1 mmol) in methanol (5 ml) under nitrogen was added triethylamine (0 07 ml 0 5 mmol) After stirring for 20 mm sodium cyanoborohydnde (164 mg 2 6 mmol) was added and the reaction mixture was heated at 60°C under nitrogen for 18 h After cooling citric acid (500 mg) was added and the mixture was heated at 60°C for 3 h To the mixture was added water (0 2 ml) followed by excess sodium hydrogen carbonate and the mixture was stirred at room temperature for 18 h The mixture was concentrated in vacuo and the residue was pre-absorbed onto silica (10 g) and passed through a silica plug (10 g) eluting with dichloromethane 2 5% ammonia in methanol [4 1] The filtrate was concentrated in vacuo and the residue was purified by automated flash chromatography (Biotage™ 40+M silica cartridge) with gradient elutton dichloromethane 2 5% ammonia in methanol [96 4 to 89 11] The appropriate fractions were combined and concentrated to give the compound of Example 54 (69 mg) as a single enantiomer HPLC method A - retention time 14 49 mm

(Table Removed)
Example 54
1H-NMR (CD3OD) 115 117 (3H) 1 70 - 1 76 (2H) 4 65 4 67 (1H) 6 58 - 6 60 (1H) 6 93 - 6 99 (2H) 7 02-7 04 (1H) 7 22 7 24(1H)
The following were prepared by methods similar to those used for Examples 48-54
(Table Removed)
Example 55
6-tf3-(2 6-Dlchloro-3-hydroxyphenyll)-1-methylpropyllamino}-7-hydroxy-4 5 6 7-tetrahydro-
imidazo[4 5 1-jkf1lbenzazepin-2(1H)-one
1H NMR(CDjOD) 1 18-1 20 (3H) 4 67 4 69 (1H) 6 74 6 76 (1H) 6 99 7 01 (1H) 7 03 7 05(1H)
7 08 7 10(1H) 7 20-7 22 (1H)
HPLC method A - retention time 11 28 mm
Example 56
N-(2 (3-([7-Hydroxy-2-oxo 12 4 5 6 7-hexahydroimidazof4 5 1 jk][1]benzazepin 6-
vl]amino}butyllprienyl)ethanesulfonamide
Experimental MH* 459 2, expected 459 2
*H NMR(CDJOD) 1 10-1 12 (3H) 1 28 1 31 (3H) 3 05-311 (2H) 415-4 19 (1H) 6 98-7 00 (1H)
706-708(1H) 712-718(2H),724-726(1H) 730 732(1H)738 7 40 (1H)
HPLC method A - retention time 12 77 mm
Example 57
2 2 2-Tnfluoro-N-[3-[3-{[7-hydroxy 2-oxo-1 2 4 5 6 7 hexahydroimidazo[4 5 1-jk[1]benzazepin-6
vl1amino)butyllphenyl)acetamide
HPLC method A - retention time 12 19 mm
Example 58
6-{[3-(3 Fluoro-4-hydroxyphenyl)-1-methylpropyl]amino)-7 hydroxy-4 5 6 7-tetrahydro-
imidazo[4 5 1-jk]benzazepin-2(1H)-one
1H-NMR (CD3OD) 1 40 142(3H)2 05 2 11 (2H) 4 95 4 97 (1H), 6 83 - 6 87 (2H) 6 97 - 7 00 (1H) 703-705(1H) 710 713(1H)730 732(1H)
Example 59
2 2 2-Trifluoro-N-(4-H3-{[7-hydroxy-2-oxo-1 2 4 5 6 7-hexahydroimidazor4 5 1-jk][1]benzazepin-6-
yl]amino)butyllphenyl}acetamide
'H NMR (CD3OD) 1 09 112 (3H) 1 70 -1 80 (2H) 4 61 - 4 63 (1H) 6 61 - 6 64 (2H), 6 88 6 91 (2H)
6 99 7 01 (1H) 7 03-7 05 (1H) 7 18 7 20(1H)
HPLC method A - retention time 11 90 mm
Example 60
7-Hydroxy 6-((3-[4-hydroxy-3-(tnfluoromethyl)phenyl-1-methylpropyl)amino)-4 5 6 7 tetrahydro
imidazoM 51-jk]lbenzazepin-2(1H)-one
1H NMR (CD3OD) 1 14 1 16 (3H) 1 76 -1 84 (2H), 4 64 4 66 (1H) 6 80-6 82 (1H) 6 99 7 01 (1H)
7 02 7 04(1H) 7 20-7 23 (2H) 7 29-731 (1H)
HPLC method A - retention time 12 50 mm
Example 61
rV43-[3-fr7-Hydroxy-2-oxo-1 2 4 5 6 7 hexahydroimidazo[4 5 1-/Mnibenzazepin-6
yllaminolbutyllDhenvDpropanamide
1H-NMR (CD3OD) 1 10-1 12(3H) 1 17 1 20 (3H) 2 36 2 40 (2H), 4 62 464(1H)689 6 91 (1H)
6 99 7 01 (1H) 7 02 -7 05 (1H) 7 17 -7 20 (2H) 7 30 7 32 (1H) 7 40-7 42 (1H)
HPLC method A - retention time 12 67 mm
Example 62
3-[3-([7-Hydroxy-2-oxo-1 2 4 5 6 7-hexahydroimidazor4 5 1jk][1]benzazepin-6-yl]amino)butyl]-N-
methylbenzamide
1H-NMR (CD3OD) 1 16 1 18 (3H) 2 90-291 (3H) 463 4 65 (1H) 698 7 01 (1H) 703 706(1H)
7 18 720(1H)732 7 37 (2H) 7 38-7 40 (1H) 7 65 767(1H)
HPLC method A - retention time 11 40 mm
Example 63
W-(2-(3-((7-Hydroxy-2-oxo-1 2 4 5 6 7 hexahydroimidazo(4 5 1 jk][1]benzazepin 6
vllamino)butyl1phenyl)acetamide
1H-NMR (CD3OD) 1 11 1 14 (3H) 2 07 - 2 09 (3H) 4 62 4 64 (1H) 6 99 7 01 (1H) 7 04 7 07(1H)
7 15-7 22 (3H) 7 22 7 27 (2H )
HPLC method A - retention time 11 46 mm
Example 64
N-CvcloDroDVM-[3-([7-hydroxy-2-oxo-1 2 4 5 6 7-hexahydroimidazor4 5 1 jk][1]benzazepin 6-yllaminolbutyllbenzamide
1H-NMR (d9-DMSO) 0 54 0 59 (2H) 0 62 - 0 66 (2H), 0 98 -1 02 (3H) 3 00 3 03 (1H) 4 47 4 50 (1H) 6 81 -6 83(1H) 6 89-6 92 (1H), 7 01 -7 04(1H) 7 20 7 23 (2H) 7 67 7 70 (2H) HPLC method A - retention time 12 01 mm
Example 65
AK3-f3-(f7-Hydroxy-2-oxo-1 2 4 5 6 7-hexahydroimidazor4 5 1 /MPllbenzazepin-6-
vUamino)butyllphenyl)methanesulfonamide
1H-NMR (CD3OD) 114-116 (3H) 2 90 - 2 92 (3H) 4 62 - 4 64 (1H) 6 97 7 01 (2H) 7 02 7 07 (2H)
7 09-711 (1H) 7 19 -7 22 (2H)
HPLC method A - retention time 10 00 mm
Example 66
3-[3-(7-Hydroxy-2-oxo-1 2 4 5 6 7 hexahydroimidazo[4 5 1-M[1lbenzazepin-6
vilaminolbutYllbenzamide
1H-NMR (CD3OD) 1 37 139(3H)4 86 4 88 (1H) 7 00 7 02 (1H) 7 07 7 10 (1H) 7 26 - 7 31 (3H)
7 78 -7 80 (1H) 7 85 7 86(1H)
HPLC method A - retention time 8 02 mm
Example 67
N-f4-[3-fnr-Hydroxy-2-oxo-1 2 4 5 6 7-hexahydroimidazor4 5 1 yMnibenzazepin-6-
vllamino)butyl]phenyl)benzenesulfonamide
'H NMR(CDJOD) 1 06-1 09 (3H) 4 60-4 62 (1H) 6 96 - 7 00 (2H) 7 00 - 7 06 (4H) 7 18-7 20(1H) 7 41-7 45 (2H) 7 49 7 51 (1H) 7 70 7 72 (2H) HPLC method A retention time 11 41 mm
Example 68
4-[3-([7 Hydroxy-2-oxo-1 2 4 5 6 7-hexahydroimidazo[4 5 1 y/clf1]benzazepin-6-
vllaminolbutyllbenzoic acid
1H-NMR (CDjOD) 1 25 1 27 (3H) 1 90 2 00 (2H) 4 78 4 80 (1H) 7 00 - 7 02 (1H) 7 06 7 09(1H)
7 20 - 7 24 (3H) 7 84 7 86 (2H)
HPLC method A retention time 8 02 mm
Example 69
1 1 1-Trifluoro-N-(4-[3 4[7-hydroxy-2-oxo-1 2 4 5 6 7 hexahydroimidazor4 5 1 jk][1]benzazepin-6-
vllamino)butyllphenyl)methanesulfonamide
1H-NMR (CD3OD) 1 36 1 38 (3H), 1 96 - 2 05 (2H) 4 80 - 4 82 (1H) 7 02 7 09 (5H) 7 09 7 12 (1H)
7 25-7 27 (1H)
HPLC method A - retention time 9 92 mm
Example 70
Methyl 4-[3-([7-hydroxy-2-oxo-1 2 4 5 6 7-hexahydroimidazo[4 5 l-jk][1]benzazepin-6-
vllamino)butyllbenzoate
(Formula Removed)
To a mixture of the compound of Preparation 9 (207 mg 0 8 mmol) and triethylamine (0 03 ml 0 2 mmol) in methanol (5 ml) was added the compound of Preparation 97 (186 mg 1 0 mmol) followed by sodium cyanoborohydnde (76 mg 1 2 mmol) and the reaction mixture was heated at 50°C for 18 h Additional sodium cyanoborohydnde (76 mg 1 2 mmol) was added and the reaction mixture was stirred at 50°c for another 18 days After cooling the mixture was quenched by addition of water (3 ml) and citric acid was added followed by excess sodium hydrogen carbonate The mixture was stirred at room temperature for 30 mm and then concentrated in vacuo To the residue was added methanol (250 ml) and silica and the mixture was concentrated in vacuo The product/silica mix was passed through a silica plug eluting with dichloromethane 2 5% ammonia in methanol [4 1] The filtrate was concentrated in vacuo and the residue was dissolved in acetomtnle water (9 14 ml) and purified by automated preparative liquid chromatography (Gilson system 150 mm x 21 4 mm Gemini C18 5µm column 20 ml/mm) using acetomtnle 0 1% aqueous ammonia (5 95) acetomtnle 0 1% aqueous ammonia (95 5) gradient [90 10 to 78 22 (from 2 to 5 mm) to 70 30 (from 16 to 18 mm) to 5 95 (from 30 to 31 mm)] The appropriate fractions were combined and concentrated to give the compound of Example 70 (6 mg) as a single enantiomer HPLC method A retention time 14 01 mm
(Table Removed)
Example 70
1H-NMR (dg-DMSO) 1 00 - 1 03 (3H) 3 79 3 82 (3H) 4 48 - 4 50 (1H) 6 83 - 6 85 (1H) 6 88 6 91 (1H) 7 02 7 05(1H) 7 30 7 33 (2H) 7 91 7 94 (2H)
Preparation 1
Hydrochloride salt of 6-amino-7-hydrpxy-4 5 6 7-tetrahydroimfdazor4 5 1-jk][1]benzazepm-2(1 H)
one
To a solution of the compound of Preparation 2 (53 5 g 211 mmol) in methanol (2600 ml) at 0°C was added sodium borohydnde (8 8 g 232 mmol), over 30 mm The reaction mixture was stirred at room temperature for 18 h before addition of hydrochloric acid (2N 120 ml) The mixture was concentrated in vacuo and the residue was re crystallised from isopropanol water (3 1, 700 ml) The solid was washed with diethyl ether and dried in a vacuum oven overnight to give the title compound (33 8 g) 1H-NMR (da DMSO) 2 00-2 10 (1H), 2 30-2 40 (1H) 3 60-3 70 (1H) 4 10-420(1H) 485-495 (1H) 6 45-6 50 (1H) 6 90-6 95 (1H) 6 95-7 00 (1H) 7 15-7 20 (1H)
Preparation 2
Hydrochloride salt of 6-amino-5 6-dihydroimidazo[4 5 1-jk][1]benzazepine-2 7(1H4H-dione
A mixture of the compound of Preparation 3 (35 3 g 153 mmol) and palladium (10% on carbon 11g) and concentrated hydrochloric acid (25 5 ml) in methanol (300 ml) was stirred at room temperature under hydrogen (22 psi) for 3 h The reaction mixture was filtered through ArboceKB washing through with methanol and water and ensuring the catalyst did not dry out The filtrate was concentrated in vacuo and the residue was triturated with acetone to give the title compound (30 0 g)
1H-NMR (dfl-DMSO) 2 20-230 (1H) 240-250 (1H) 370-380 (1H) 430-440(1H) 460-470 (1H) 710 715(1H) 7 25-7 30 (1H) 7 60-7 65 (1H)
Preparation 3
4 5-Dihydroimidazor4 5 1-jk][1]lbenzazepine-2 6 7(1H)-tnone 6-oxime
To a solution of the compound of Preparation 4 (10 3 g 51 mmol) in acetic acid (150 ml) was added tert butyl nitrite (16 ml 135 mmol) followed by hydrochloric acid (4N in dioxane 33 4 ml) The reaction mixture was stirred at room temperature for 3 h and then filtered The solid material was dried in a vacuum oven to give the title compound (10 0 g) Experimental MH* 232 1 expected 232 1
Preparation 4
5 6-Dihydroimidazor4 5 1-jk][1]benzazepme-2 7{1H4H)-dione
To a solution of the compound of Preparation 5 (45 0 g 0 2 mol) in dichloromethane (150 ml) was added thionyl chloride (30 ml 0 4 mol) and the reaction mixture was stirred at room temperature for 2 h The mixture was concentrated in vacuo and to the residue was added dichloromethane (1000 ml) and aluminium chloride (84 0 g 0 6 mol) added portionwise After stirring at room temperature overnight the reaction mixture was heated under reflux for 2 h and then concentrated in vacuo To the residue was
added ice water (2000 ml) and concentrated hydrochloric acid (50 ml) followed by additional ice water
(2000 ml) The resulting precipitate was collected by filtration washed with water (4 x 250 ml) and
dissolved in sodium hydroxide solution (1N 600 ml) The solution was washed with dichloromethane (2
x 150 ml) and cyclohexane (150 ml) and adjusted to pH 10 by addition of dry ice The solid material was
collected by filtration washed with water (3 x 50 ml) and dried overnight at 40°C to give the title
compound (30 0 g)
1H-NMR (d6-DMSO) 2 03-211 (2H) 2 90-3 00 (2H) 3 85 - 3 95 (2H) 7 02-7 10 (1H) 717-724
(1H) 7 50-7 58 (1H)
Preparation 5
4-(2-Oxo-2 3-dihydro-1H-benzimidazol-1-yl)butanoic acid
To a solution of the compound of Preparation 6 (152 0 g 0 6 mol) in tetrahydrofuran (600 ml) was added
concentrated hydrochloric acid (75 ml) The reaction mixture was stirred for 2 h and then poured into
water (700 ml) The mixture was filtered, washing through with water (750 ml) and the solid material was
dned overnight at 40°C to give the title compound (155 5 g)
1H-NMR (d„ DMSO) 1 80 - 1 89 (2H) 2 20 - 2 25 (2H) 3 74 - 3 82 (2H) 6 96 - 7 01 (3H) 7 05 - 7 10
(1H)
Preparation 6
4-(3-lsopropenvU2-oxo-2 3-dihydro-1H-benzimidazol-1-yl)butanolc acid
To a solution of the compound of Preparation 7 (223 8 g 0 7 mol) in tetrahydrofuran (500 ml) was added aqueous sodium hydroxide solution (15% w/w 500 ml) The reaction mixture was heated under reflux for 4 h, cooled to room temperature and stirred overnight The tetrahydrofuran was removed by vacuum distillation (38°C) and the aqueous layer was extracted with dichloromethane (2 x 400 ml) and cyclohexane (2 x 300 ml) To the aqueous layer was added glacial acetic acid (250 ml) and the solution was cooled to 2°C After stirring for 30 mm the product was collected by filtration washing through with water (3 x 250 ml) at 2°C The solid was dried overnight at 40°C to give the title compound (307 5 g) Experimental MH* 261 2 expected 261 1
Preparation 7
Ethyl 4-(3-isopropenyl-2-oxo 2 3-dihydro 1H benzimidazol-1-yl]butanoate
A mixture of the compound of Preparation 8 (114 0 g 0 7 mol) potassium carbonate (136 mg 1 mol) and the compound of Preparation 166 (167 4 g 0 9 mol) in acetone (500 ml) was heated under reflux for 18 h The reaction mixture was then cooled to room temperature and filtered washing through with acetone (250 ml) The filtrate was concentrated in vacuo and the residue was dried overnight at 40 C to give the title compound (223 8 g)
1H-NMR (d6 DMSO) 1 10-1 20 (3H) 2 10-2 15 (3H) 3 95-4 07 (2H) 510-5 12 (1H) 535-539 (1H) 7 00-7 10 (3H) 7 20-7 26 (1H)
Preparation 8
1-lsopropenvl-1 3-dihydro-2H-benzimidazol 2-one
To a solution of the compound of Preparation 140 (98 0 g 0 9 mol) in xylene (420 ml) at 120°C was added 1 8-diazobicylo{5 4 0]undec-7-ene (1 5 ml) followed by the compound of Preparation 141 (130 0 g, 1 0 mol), added over 30 mm The reaction mixture was heated at 150°C using a Dean-Stark apparatus, for 60 h and then cooled to room temperature The solid product was isolated by filtration washing with cold xylene (250 ml) and dried in a vacuum oven to give the title compound (208 4 g) 1H-NMR (d6-DMSO) 2 08-2 11 (3H) 5 05-511 (1H) 5 34-5 37 (1H) 698-701 (3H) 701-706 (1H) 10 90-11 00 (1H)
Preparation 9
Hydrochloride salt of (6R 7R)-6-amino-7-hydroxy-4 5 6 7-tetrahydroimidazor4 5 1 jk][1]benzazepin-
2(1H)-one
To the compound of Preparation 10 (160 mg 0 5 mmol) was added hydrogen chloride (4N in dioxane 1 25 ml) and the mixture was stirred at room temperature for 1 h The mixture was concentrated in vacuo and to the residue was added dioxane (10 ml) The solution was re-concentrated in vacuo to give the title compound as the hydrochloride salt (135 mg)
1H-NMR (CD3OD) 2 07-2 13(1 H) 241 -244 (1H) 350 3 54 (1H) 378 3 82 (1H) 420 426(1H) 7 01-7 04 (1H) 7 10-7 14 (1H) 7 35-7 37 (1H)
Alternative synthesis
A mixture of the compound of Preparation 3 (11 0 g 48 mmol) rhodium chloro(norbornadiene) dimer (55 mg 0 1 mmol) and 1-[(S)-ferrocenyl 2-(R) ethyl-1-dimethylamino)phenyl] (S) phosphino-1 dicyclohexylphosphmo-ferrocene (Solvias AG) (187 mg 0 3 mmol) in methanol (165 ml) and water (11 ml) was purged with nitrogen (x 3) and heated at 80°C under a hydrogen atmosphere (20 bar) for 16 h The mixture was filtered, washing through with methanol and the filtrate concentrated in vacuo To the residue was added hydrogen chloride (4M in dioxane 14ml) The solution was concentrated in vacuo and the residue was purified by azeotropic distillation with isopropanol (2 x 50 ml) The residue was re-crystallised from isopropanol water (6 1 150 ml) and again from isopropanol water (6 1 80 ml) to give the title compound (6 5 g) as the hydrochloride salt
'H NMR (drDMSO) 1 96 2 05 (1H) 2 30 2 38 (1H) 3 60 3 68 (1H) 4 08 4 15 (1H) 4 82-4 88 (1H) 6 45 650(1H) 690-693(1H) 697-701 (1H) 715 718(1H)
Preparation 10
tert-Butyl H6R 7R)-7-hydroxy-2-oxo-1 2 4 5 6 7 hexahydroimidazo[4 5 1-jk][1]lbenzazepin-6 yl]
carbamate
The compound of Preparation 11 (500 mg 1 6 mmol) was dissolved in isopropanol containing 0 1% diethylamine (100 ml) with heating and sonication The solution was purified by supercritical fluid chromatography (Berger Multigram III 250 x 30 mm Chiralcel OJ H 5 µm column 35°C 180ml/min)using supercritical carbon dioxide/isopropanol containing 0 1% diethylamine [85 15] as the mobile phase
The appropriate fractions were combined and concentrated to give the title compound as the desired
enantiomer which was used directly
Preparation 11
tert-Butyl [7-hydroxy-2-oxo 12 4 5 6 7 hexahydroimidazo[4 5 1-jk][1]benzazepin-6-yllcarbamate
To a solution of the compound of Preparation 1 (1 0 g 3 9 mmol) in methanol (20 ml) was added triethylamme (1 1 ml 7 8 mmol) followed by the compound of Preparation 142 (1 71 g 7 8 mmol) The reaction mixture was stirred for 1 h concentrated in vacuo and to the residue was added dichloromethane (50 ml) The solution was washed with water (50 ml) and the precipitate was collected by filtration and dried in a vacuum oven to give the title compound (500 mg) which was used directly
Preparation 12 4-[4-(Cyclopropylmethoxy)phenyllbutan-2-one
To a solution of the compound of Preparation 106 (5 0 g 31 mmol) in acetone (75 ml) was added caesium carbonate (20 0 g 61 0 mmol) followed by the compound of Preparation 107 (5 9 ml 61 mmol) and sodium iodide (0 46 g 31 0 mmol) The reaction mixture was heated under reflux for 24 h concentrated in vacuo and the residue was partitioned between ethyl acetate (75 ml) and water (100 ml) The two layers were separated and the aqueous layer was extracted with ethyl acetate (75 ml) The combined organic phases were washed with brine (100 ml) dried (MgSO4) and concentrated in vacuo to give the title compound (5 7 g) which was used directly for reductive animation with the compound of Preparation 1
Preparation 13
442 HydroxvphenvIM methylpentan 2-one
To a solution of the compound of Preparation 14 (222 mg 0 8 mmol) in tetrahydrofuran (2 ml) at 60 C and under nitrogen was added methylhthium (1 6M in diethyl ether 1 8 ml 2 8 mmol) dropwise over 5 mm The reaction mixture was stirred at -60°C for 30 mm quenched with ethanol (0 2 ml) and allowed to warm to room temperature overnight The mixture was partitioned between water and diethyl ether and the organic phase was separated washed with brine dried (MgSO<) and concentrated in vacuo to give the title compound (130 mg) Experimental (M-H*) 191 3 expected 191 1
Preparation 14
2-(1 1-Dimethyl-3 morpholin-4-yl-3-oxopropyl)phenol
A solution of the compound of Preparation 15 (950 mg 5 4 mmol) in morpholine (30 ml) was heated at 85"C for 18 h To the reaction mixture was added water (5 ml) and the precipitate was collected by filtration washed with water and dried in a vacuum oven to give the title compound (1 22 g) Experimental MH* 264 0 expected 264 2
Preparation 15
4 4-Dimethylchroman 2 one
To a solution of the compound of Preparation 105 (2 0 g 115 mmol) in 1 2-dichloroethane (20 ml) was added aluminium chloride (2 3 g 17 2 mmol) over 5 mm and the reaction mixture was stirred at room temperature under nitrogen for 60 h To the reaction mixture was added dichloromethane and the solution was concentrated in vacuo The residue was partitioned between water and dichloromethane and the two layers were separated The organic layer was further washed with water dried (MgSO4) and concentrated in vacuo The residue was purified by automated flash chromatography (Biotage™ 40M cartridge) with gradient elution cyclohexane dichloromethane [3 1 to 1 3] The appropriate fractions were combined and concentrated to give the title compound (1 4 g) Experimental MH* 177 2 expected 177 1
Preparation 16
4-(3-Chloro-2 hydroxyphenyll)but-3-en-2-one
To a solution of the compound of Preparation 108 (17 5 g 112 0 mmol) in acetone (49 ml) at 0°C was added aqueous sodium hydroxide solution (5M 33 ml) over 10 mm The reaction mixture was stirred at 0°C for 60 mm and then at room temperature for 18 h To the mixture was added water (500 ml) and the solution was extracted with dichloromethane (100 mi) The aqueous phase was acidified with excess aqueous citric acid solution and the resulting precipitate was collected by filtration The solid was washed with water (100 ml) aqueous sodium hydrogen carbonate solution (100 ml) aqueous sodium metabisulfite solution (100 ml) and additional water (3 x 100 ml) and air dried to give the title compound (20 g) 1H-NMR (CDCI3) 2 39 - 2 41 (3H) 6 78 - 6 93 (2H) 7 34 - 7 38 (1H) 7 41 - 7 46 (1H) 7 77 - 7 83 (1H)
Preparation 17
4-(5-Fluoro-2 hydroxyphenyl)but-3-en-2-one
To a solution of the compound of Preparation 110 (900 mg 6 4 mmol) in acetone (20 ml) at 0°C was added aqueous sodium hydroxide solution (5M 1 9 ml) After stirring at 0°C for 1 h water (50 ml) was added and the mixture was extracted with dichloromethane (50 ml) The aqueous phase was acidifed with hydrochloric acid (4M) and the solution was extracted with dichloromethane (100 ml) The combined organic phases were washed with water (20 ml) saturated aqueous sodium metabisulphite solution (30 ml) and additional water (3 x 20 ml) dried (MgSO4) and concentrated in vacuo to give the title compound (900 mg) 1H-NMR (CD3OD) 2 31 - 2 34 (3H) 6 76 6 83 (2H) 6 92 6 99 <1H) 7 24 7 28 (1H) 7 82 7 88(1H)
Preparation 18
4-(4 5-Drfluoro-2-hydroxyphenyl)but-3-en-2 one
To a solution of the compound of Preparation 60 (3 5 g 22 0 mmol) in acetone (50 ml) at 0°C was added aqueous sodium hydroxide solution (5M 6 6 ml 33 2 mmol) The reaction mixture was stirred at 0°C for 1 h and then at room temperature for 18 h The mixture was diluted with water (200 ml) and
acidifed with hydrochloric acid (4M) The mixture was extracted with diethyl ether (3 x 300 ml) and the combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (2 9 g) 1H-NMR (CDCI3) 2 39 2 43 (3H) 6 81 6 89 (1H) 7 25 7 31 (2H) 7 67-7 77 (1H)
(Table Removed)
Similarly prepared were
Preparation 19 4-f4-HydroxY-3-(tnfluoromethyl)phenyllbut-3-en 2-one
1H-NMR (CDCI3) 2 29 - 2 31 (3H) 6 60 6 64 (1H) 6 99 - 7 01 (1H) 7 43 7 46 (1H) 7 59 7 61 (1H) 7 70-7 72 (1H)
Preparation 22 4-hydroxy-3-[3-oxobut-1-en-1-vllbenzonitnle
1H-NMR (d6DMSO) 2 31 - 2 33 (3H) 6 97 - 7 10 (2H) 7 60 - 7 70 (2H) 8 09 - 8 11 (1H)
Preparation 23
4 (2-Hydroxy-3-methylphenyl)but 3-en 2-one
1H-NMR (d6-DMSO) 2 14 2 20 (3H) 2 25 2 32 (3H) 6 69 6 80 (2H) 7 11 7 17 (1H) 7 41 7 47 (1H) 7 88-7 94 (1H)
Preparation 24 4-(2-Methoxvphenyl)but-3-en-2-one
1H-NMR (d6-DMSO) 2 28 - 2 30 (3H) 3 83 - 3 86 (3H) 6 78 6 84 (1H) 6 95 - 7 00 (1H) 7 05 7 09 (1H) 7 37-7 43 (1H) 7 64 -7 69 (1H) 7 74 7 80(1H)
Preparation 25 4-(2-Hydroxy-5-methoxylphenyl)but-3-en 2-one
1H-NMR (d6-DMSO) 2 27 - 2 29 (3H) 3 68 3 71 (3H) 6 80 6 86 (3H) 7 11 - 7 15 (1H) 7 72 7 78 (1H)
Preparation 26 4-(4-Fluorophenyl)but-3-en-2-one
1H-NMR (CD3OD) 2 33 - 2 34 (3H) 7 10-715 (3H) 7 61 - 7 68 (3H)
Preparation 27 4-(4-Fluoro-2-hydroxyphenyl)but-3-en-2-one
1H-NMR (CD3OD) 2 37 2 39 (3H) 6 56 6 64 (2H) 6 79 6 82 (1H) 7 55 - 7 60 (1H) 7 82 - 7 85 (1H)
Preparation 32 4-r2-Hydroxy-5-(trifluoromethyl)phenyllbut-3-en-2-one
1H-NMR (CDCI3) 244 247(3H)702 7 06 (1H) 7 13 - 7 19 (1H) 7 47 - 7 52 (1H) 7 70 773(1H) 7 78 7 84(1H)
Preparation 35 4-(4-Nitrophenyl)but 3-en-2-one
To a solution of the compound of Preparation 145 (2 0 g 13 2 mmol) in tetrahydrofuran (100 ml) was added the compound of Preparation 150 (8 4 g 26 5 mmol) The reaction mixture was heated under reflux for 3 h and then cooled and concentrated in vacuo The residue was triturated with diethyl ether and then loaded onto a silica plug and eluted with diethyl ether The appropriate fractions were combined and concentrated and the residue was further purified using a silica plug eluting with diethyl ether The appropriate fractions were combined and concentrated to give the title compound (2 4 g) 1H-NMR (CDCI3) 2 39 2 41 (3H) 6 78-6 80 (1H) 7 48 7 50 (1H) 7 65 7 67 (2H) 8 20 8 22
Similarly prepared were

(Table Removed)
Preparation 37 4-(3-Nitrophenyl)but-3-en 2-one
1H-NMR (CDCI3) 2 39 - 2 41 (3H) 6 78 6 82 (1H) 7 56 7 59 (1H) 7 66 7 68 (1H) 7 80 7 82(1H) 818-821 (1H) 838-840(1H)
Preparation 38
4-{2 Nitrophenyl)but-3-en 2-one
1H-NMR (CDCL3) 2 40 - 2 41 (3H) 6 56 - 6 60 (1H) 7 42 7 46 (1H) 7 57 7 60 (1H) 7 62 - 7 65 (1H)
7 97 8 00(1H) 8 02-8 04 (1H)
Preparation 39 4-F3-Oxobut-1-en-1-yl]benzoic acid
1H-NMR (d6-DMSO) 2 17-2 19 (3H) 6 85 6 88 (1H) 7 61 7 64 (1H) 7 79 7 81 (2H) 7 91 - 7 93 (2H)
Preparation 40 3-[3-Oxobut-1-en-1-yl] benzoic acid
1H-NMR (CD,OD) 2 39 - 2 41 (3H) 6 80 - 6 83 (1H) 7 51 7 54 (2H) 7 66 7 69 (1H) 7 85 - 7 87 (1H)
8 06 8 08(1H) 8 23-8 25 (1H)
Preparation 41 4-(2-Hydroxyphenyl)butan-2-one
A suspension of palladium (5% on alumina 5 0 g 47 0 mmol) in ethyl acetate (500 ml) was stirred under hydrogen (60 psi) for 40 mm To this suspension was added the compound of Preparation 100 (50 0 g 308 mmol) and the reaction mixture was hydrogenated at 15 psi for 2 h The mixture was filtered through Celite® and the filtrate was concentrated in vacuo The residue was purified by column chromatography (silica 1 kg) eluting with dichloromethane The appropriate fractions were combined and concentrated and the residue was triturated with diethyl ether/pentane to give the title compound PF 01896702-00 (10 3 g) 1H NMR(CDCI3) 2 18 2 19 (3H) 2 80 2 95 (4H) 6 75 6 85 (2H) 7 00 - 7 11 (2H)
Preparation 42
4-(5-Fluoro-2 hydroxyphenyl)butan 2-one
A mixture of the compound of Preparation 17 (2 1 g 114 mmol) and palladium (2 wt % on strontium carbonate 800 mg) in ethyl acetate (40 ml) was stirred under hydrogen (1 atm) at room temperature for 18 h The mixture was filtered through Arbocel® and the filtrate was concentrated in vacuo The residue was dissolved in ethyl acetate cyclohexane [20 80 20 ml] and purified by automated flash chromatography (Biotage™ 40M cartridge) with gradient elution ethyl acetate cyclohexane [20 80 to 30 70] The appropriate fractions were combined and concentrated to give the title compound (1 2 g) 1H-NMR (CD3OD) 1 46-1 51 (3H) 1 70-1 80 (1H) 1 90-2 00(1H) 2 58-2 62 (1H) 2 85-2 95 (1H) 6 72 - 6 80 (3H)
Preparation 43 4-{2-Methylphenyl)butan-2-one
A mixture of the compound of Preparation 36 (840 mg 5 2 mmol) and chlorotns(tnphenylphosphine) rhodium(l) (242 mg 0 3 mmol) in ethyl acetate (25 ml) was stirred under hydrogen (5 atm) at 40°C for 60 h The mixture was concentrated in vacuo and to the residue was added ethyl acetate cyclohexane [1 3 30 ml] The solution was loaded on to a silica plug and eluted with ethyl acetate cyclohexane [1 3 300 ml] The filtrate was concentrated in vacuo to give the title compound (556 mg)
The following were prepared by methods similar to Preparations 41 - 43
(Table Removed)
Preparation 44 4-f4-(Tnfluoromethyl)Dhenvllbutan 2-one
1H-NMR (CD3OD) 2 08 2 12 (3H) 2 79 2 84 (2H) 2 87 2 92 (2H) 7 34 7 38 (1H) 7 49 7 54(1H)

Preparation 45
4-(2 4-Dichlorophenyl)butan-2-one
1H-NMR (CD,OD) 2 10-2 12 (3H) 2 74 - 2 79 (2H) 2 88 -2 93 (2H) 7 18 7 21(11-1) 7 23 7 27(1H) 7 36 7 38(1H)
Preparation 46 4-[3-(Trif1uoromethyl)phenyl]butan-2-one
1H-NMR (CDCI3) 2 14-216 (3H) 2 76 - 2 82 (2H) 2 92 - 2 98 (2H) 7 35 - 7 41 (2H) 7 42 - 7 48 (2H)
Preparation 47 4-(2-Chloro-6-fluorophenyl)butan-2-one
1H-NMR (CD3OD) 2 15-217 (3H) 2 70 - 2 76 (2H) 2 98 - 3 04 (2H) 7 01 7 07 (1H) 719 7 23 (2H)
Preparation 49 4-(2-Chloro-3-hydroxyphenyl)butan 2 one
1H-NMR (CDCI3) 2 11 2 13(3H) 2 70 - 2 73 (2H) 2 95 - 2 99 (2H) 6 78-6 80 (1H) 6 87 6 89(1H) 7 05 7 07(1H)
Preparation 50 4-(3-Oxobutyl)benzoic acid
1H-NMR (CD3OD) 2 16 2 18 (3H) 2 80 2 83 (2H) 2 89 2 92 (2H) 7 30 - 7 32 (2H) 7 90 - 7 93 (2H)
Preparation 51 3-(3-oxobutyl)benzoic acid
1H-NMR (CDCI3) 2 16 2 18 (3H) 2 79-2 82 (2H) 2 95 2 98 (2H) 7 38 7 40 (1H) 7 41 7 44(1H) 7 94 - 7 96 (2H)
Preparation 52
4-(4 5-Difluoro 2 hydroxyphenvUbutan-2-one
1H-NMR (CDCl3) 2 20 - 2 22 (3H) 2 74 - 2 77 (2H) 2 87 2 89 (2H) 6 70 6 73 (1H) 6 79 6 82 (1H)
Preparation 53
4-(2 6-Dichloro-3-hydroxyphenvi)butan-2-one
Experimental MH* 233 2 expected 233 0
Preparation 54
4-M-Hydroxy 3 (trifluoromethyl)phenyllbutan-2-one
1H-NMR (CDCI3) 2 17-2 19 (3H) 2 76 2 79 (2H) 2 81 2 83 (2H) 6 80 6 82 (1H) 7 18 7 21 (1H) 7 29-731 (1H)
Preparation 55
4-(4-Hydroxy-3 5-dimethylphenyl)butan 2-one
To a mixture of the compound of Preparation 117 (442 mg 3 6 mmol) and concentrated sulfuric acid (cone 0 9 ml) in toluene (4 ml) at 0°C was added dropwise the compound of Preparation 118 (116 mg 1 7 mmol) in toluene (2 ml) The reaction mixture was stirred at room temperature for 18 h and then partitioned between water and diethyl ether The organic phase was separated washed with water and brine dried (MgSO4) and concentrated in vacuo The residue was purified by column chromatography (Isolute cartridge 5 g) with gradient elution cyclohexane dichloromethane [3 1 to 0 1) The appropriate fractions were combined and concentrated to give the title compound (128 mg) 1H NMR (CDCI3) 2 09 2 10 (3H) 2 18 2 20 (6H) 2 61 - 2 72 (4H) 4 61 4 62 (1H) 6 78 6 79 (2H)
Preparation 56 4-(3-Fluoro-4-hydroxyphenyll)butan 2-one
To a solution of the compound of Preparation 156 (5 8 g 519 mmol) in toluene (25 ml) at 0°C was added concentrated sulphuric acid (1 1 ml 21 6 mmol) To the mixture was added dropwise the compound of Preparation 118 (3 0 g 43 2 mmo!) in toluene (5 ml) over 1 5 h and the reaction mixture was stirred for a further 2 h To the mixture was added water (25 ml) and the two layers were separated The organic phase was washed with water (2x10 ml) dried (MgSO4) and concentrated in vacuo The residue was dissolved in ethyl acetate cyclohexane [10 90 5 ml] and purified by automated flash chromatography (Biotage™ 40M cartridge) with gradient elution ethyl acetate cyclohexane [5 95 to 20 80] The appropriate fractions were combined and concentrated to give the title compound (747 mg) 1HNMR(CD3OD) 2 10-2 12 (3H) 2 75 2 78 (4H) 6 77 6 80 (2H) 6 84-6 86 (1H)
Similarly prepared were
(Table Removed)
Preparation 57
4-{2 3-Difluoro-4 hydroxyDhenyl)butan 2 one
'HNMR(CDCI,) 2 15 2 18 (3H) 2 70 2 73 (2H) 2 82 2 85 (2H) 6 65 - 6 69 (1H) 6 80 6 84(1H)
Preparation 58
4-2-Fluoro-4-hydroxyphenyl)butan-2-one
1H-NMR (CDCI3) 2 16 2 18 (3H) 2 71-2 75 (2H) 2 80 2 84 (2H) 6 50 - 6 54 (2H) 6 98 7 01 (1H)
Preparation 59
3 Formvl-4-hydroxybenzomtrile
To a solution of the compound of Preparation 123 (2 5 g 13 0 mmol) in anhydrous tetrahydrofuran (100 ml) at -7B°C and under nitrogen was added slowly n-butylhthium (1 6M 16 2 mil) via syringe The reaction mixture was stirred at -78°C for 30 mm before addition of N N-dimethylformamide (2 1 ml) The reaction mixture was allowed to warm to room temperature overnight and then diluted with water (100 ml) The mixture was concentrated in vacuo and the residue was acidified by addition of hydrochloric acid (2M) The precipitate was collected by filtration and dried in vacuo to give the title compound (1 13
9)
1H NMR (CDCI3) 7 02 - 7 17 (1H) 7 69 7 98 (2H) 9 86 - 9 97 (1H)
Preparation 60
4 5-Difluoro 2-hydroxybenzaldehyde
To a solution of the compound of Preparation 132 (5 0 g 20 0 mmol) in anhydrous tetrahydrofuran (100 ml) at 78°C and under nitrogen was added n-butyllithium (1 6M in hexanes 30 7 ml 49 0 mmol) via syringe The mixture was stirred at 78°Cfor30min before addition of A/rV-dimethylformamide (3 9 ml 50 mmol) The reaction mixture was then stirred at room temperature for 18 h To the mixture was added water (200 ml) and the solution was concentrated in vacuo The residue was acidified with excess hydrochloric acid (2M) and extracted with diethyl ether (2 x 300 ml) The combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (3 0 g) 1H-NMR (CDCI3) 677-683(11-1) 7 34 740(1H)977 979(1H)
Similarly prepared was
Preparation 61
2-Hydroxy-5 tnfluoromethylbenzaldehyde
From the compound of Preparation 133
'H NMR(CDCI3) 6 87-6 93 (1H) 7 09-7 13 (1H) 7 48 -7 53 (1H) 9 94-9 97 (1H)
Preparation 62 W-[2-(3-Oxobutyl)Dhenyllmethanesulfonamide
To a mixture of the compound of Preparation 64 (200 mg 0 7 mmol) palladium (II) acetate (10 mol% 15 mg 0 07 mmol) and lithium chloride (28 5 mg 0 7 mmol) under nitrogen was added triethylamine (0 34 ml 2 4 mmol) The reaction vessel was purged with nitrogen and de-gassed before addition of the compound of Preparation 139 (0 2 ml 2 4 mmol) The reaction mixture was then heated in a microwave oven (300W) at 120'C for 20 mm The mixture was concentrated in vacuo and to the residue was added
water (10 ml) The solution was extracted with ethyl acetate (3 x 25 ml) The combined extracts were
washed with hydrochloric acid (0 1M) and aqueous sodium hydrogen carbonate solution dried (MgSO4)
and concentrated in vacuo The residue was purified by column chromatography (Biotage™ 40S
cartridge conditioned with cyciohexane ethyl acetate [88 12]) with gradient elution cyciohexane ethyl
acetate [88 12 to 0 100] The appropriate fractions were combined and concentrated to give the title
compound (160 mg)
1H NMR (CDCl3) 2 12 2 15 (3H) 2 84 2 93 (4H) 3 02 - 3 06 (3H) 7 12-7 18 (1H) 7 19 - 7 25 (1H)
7 45-7 49 (1H) 8 24 8 33(1H)
Similarly prepared was
Preparation 63 4-(3hydroxyphenyl)butan-2-one
From the compound of Preparation 165
1H-NMR (CDCl3) 2 17-219 (3H) 2 75 - 2 79 (2H), 2 81 2 85 (2H) 6 65 6 68 (2H) 6 76 6 78 (1H)
7 13 7 16(1H)
Preparation 64 N-(2-lodophenyl)methanesulfonamide
To a solution of the compound of Preparation 135 (1 0 g 5 8 mmol) in pyridine (8 ml) was added dropwise the compound of Preparation 174 (0 7 ml 8 7 mmol) and the reaction mixture was stirred at room temperature for 18 h The mixture was concentrated in vacuo and to the residue was added water The solution was extracted with dichloromethane and the organic extract was acidified with hydrochloric acid (2M) neutralised with sodium hydrogen carbonate dried (MgSO4) and concentrated in vacuo To the residue was added dichloromethane (4 ml) and the supernatant liquid was removed and layered with cyciohexane from which a solid crystallised overnight The crystalline solid was filtered and dried to give the title compound (1 2 g) 1H-NMR (CDCI3) 2 98-3 02 (3H) 6 91-6 96 (1H) 7 35-7 42 (1H) 7 63 7 67(1H) 7 80-7 85 (1H)
Preparation 65
N-f2 f3-Oxobut-1-en-1-vlJphenyl}methanesulfonamide
To a solution of the compound of Preparation 64 (1 2 g 3 9 mmol) in N /V-dimethylformamide (24 ml) was added palladium (II) acetate (10 mol% 874 mg 3 9 mmol) the compound of Preparation 118 (0 5 ml 5 8 mmol) tetrabutylammonium chloride (1 08 g 3 9 mmol) and sodium hydrogen carbonate (818 mg 9 7 mmol) The reaction vessel was purged with nitrogen and the mixture heated at 60°C for 2 h and then stirred at room temperature for 18 h To the mixture was added water (50 ml) and the solution was extracted with ethyl acetate (4 x 100 ml) The combined extracts were concentrated in vacuo to give the crude product The residue was purified by column chromatography (silica 20 g conditioned with dichloromethane) with gradient elution cyciohexane ethyl acetate [80 20 to 0 100] The appropriate fractions were combined and concentrated to give the title compound (514 mg)
Experimental (M-H*) 237 9 expected 238 1
Preparation 66
4-(2 lsopropoxvphenyl)butan-2-one
To a solution of the compound of Preparation 41 (31 7 g 193 mmol) in acetone (750 ml) was added caesium carbonate (126 0 g 386 0 mmol) and the compound of Preparation 167 (38 5 ml 386 mmol) The reaction mixture was heated at 55"C for 18 h cooled to room temperature and partitioned between water (700 ml) and ethyl acetate (600 ml) The two layers were separated and the aqueous layer was extracted with ethyl acetate (600 ml) The combined organic phases were washed with brine (500 ml) and concentrated in vacuo to give the title compound (41 0 g)
'H NMR (CDCI3) 1 23 1 30 (6H) 2 09 - 2 10 (3H), 2 61 2 68 (2H) 2 90 - 2 98 (2H) 4 50 4 60(1H) 6 78 6 82(2H) 7 09-7 15 (2H)
Preparation 67
7-Hydroxy-6-([1-methyl-3-(4-nitrophenyl)propyllaminoM 5 6 7 tetrahydroimidazo[4 5 1-
jk][1]benzazepin-2(1H)-one
To a mixture of the compound of Preparation 9 (300 mg 1 2 mmol) and the compound of Preparation 35 (269 mg 1 4 mmol) in methanol (5 ml), under nitrogen was added triethylamine (0 05 ml 0 4 mmol) After stirring for 20 mm sodium cyanoborohydnde (111 mg 18 mmol) was added and the reaction mixture was heated at 60°C under nitrogen for 5 days After cooling, citric acid (500 mg) was added and the mixture was heated at 60°C for 3 h To the mixture was added water (0 2 ml) followed by excess sodium hydrogen carbonate and the mixture was stirred at room temperature for 18 h The mixture was concentrated in vacuo and the residue was pre-absorbed onto silica (10 g) and passed through a silica plug (10 g) eluting with dichloromethane 2 5% ammonia in methanol [4 1J The filtrate was concentrated in vacuo and the residue was washed with toluene and dried to give the title compound (600 mg) which was used directly
Similarly prepared was
Preparation 68
7-Hydroxy-6-([1-methyl 3-(3 nitroDhenvl)propyllamino)-4 5 6 7 tetrahydroimidazof4 5 1-
jk]1 lbenzaze oln-2(1 HI-one
From the compound of Preparation 37 The title compound was used directly in the next stage of reaction
Preparation 69
7-Hydroxy-6-{T3-(2-hydroxyohenyl)-1-methylpropvllarnino)-4 5 6 7-tetrahydroimidazof4 5 1-
jk]l(1lbenzazeDin-2(1H)-one
To a solution of the compound of Preparation 100 (7 1 g 43 3 mmol) in methanol (200 ml) was added the compound of Preparation 1 (10 1 g 39 4 mmol) followed by triethylamine (1 7 ml 118 mmol) After
stirring for 20 mm sodium cyanoborohydnde (6 2 g 98 5 mmol) was added and the reaction mixture was
stirred at room temperature for 60 h The mixture was quenched with water (10 ml) and concentrated in
vacuo The residue was azeotroped with methanol and the solution was concentrated in vacuo to give
the title compound (22 5 g) as a mixture of 4 diastereoisomers
Experimental MH* 368 1 expected 368 2
Preparation 70
4-(3 5-Dibromo-2-hydroxyphenyl)butan-2-one
To a solution of the compound of Preparation 41 (2 0 g 12 2 mmol) in dichloromethane (70 ml) was added dropwise the compound of Preparation 148 (4 3 g 24 4 mmol) in N N-dimethylformamide (8 ml) The reaction mixture was stirred at room temperature for 18 h before addition of dichloromethane (100 ml) The solution was washed with water (3 x 100 ml) and concentrated under a stream of nitrogen The residue was dissolved in ethyl acetate cyclohexane [5 95] and purified by automated flash chromatography (Biotage™, 65i silica cartridge) with gradient elution ethyl acetate cyclohexane [2 98 to 20 80] The appropriate fractions were combined and concentrated to give the title compound (3 7 g) 1H-NMR (CDCI3) 2 18 - 2 20 (3H) 2 77 2 80 (2H) 2 88 - 2 91 (2H) 7 15 7 17 (1H) 7 20 - 7 22 (1H)
Preparation 71
2 2 2-TrifIuoro-N-r2-(3-oxobutyl)phenyllacetamide
To a solution of the compound of Preparation 78 (400 mg 1 3 mmol) in methanol (10 ml) was added concentrated hydrochloric acid (0 1 ml) and the reaction mixture was stirred at room temperature for 2 h The mixture was concentrated in vacuo and to the residue was added dichloromethane (15 ml) The solution was washed with water (2x5 ml) dried (MgSO«) and concentrated in vacuo to give the title compound (250 mg) 1H-NMR (CDCI3) 2 16 2 19 (3H) 2 78 - 2 82 (2H) 2 97 - 3 00 (2H) 7 17 - 7 20 (2H) 7 60 - 7 65 (2H)
Similarly prepared were
(Table Removed)
Preparation 72
N-F2-(3-Oxobutyl)phenyllethanesulfonamlde
1H NMR(CDCI3) 1 40-1 44 (3H) 2 12-2 14 (3H) 2 86 2 89 (4H) 3 17 3 21 (2H) 7 11 7 16 (2H) 7 18-721 (1H) 741 743(1H)
Preparation 73
2 2 2-Trifluoro-N-[3-(3-oxobutyl)Dhenvllacetamide
1H-NMR (CDCI3) 2 13 - 2 15 (3H) 2 76 2 80 (2H) 2 87 2 91 (2H) 7 04 - 7 06 (1H) 7 27 - 7 30 (1H) 7 39 - 7 43 (2H)
Preparation 74
2,2 2 Tnfluoro N-[4-(3 oxobutyl)phenyl]acetamide
1H-NMR (CDCI3) 2 15-218 (3H) 2 76 2 80 (2H) 2 84 - 2 88 (2H) 7 20 7 23 (2H) 7 43 - 7 46 (2H)
Preparation 75 N-[3-(3-Oxobutyl)phenyllpropanamide
1H-NMR (CDCI,) 1 20 - 1 25 (3H) 2 10 2 13 (3H) 2 37 - 2 40 (2H) 2 76 2 79 (2H) 2 81 2 84 (2H)
6 90-6 93 (1H) 7 15 7 19 (2H) 7 26 7 28(1H)
Preparation 76 N-[2-(3-Oxobutyl)Dhentyl]acetamide
1H-NMR (CDCI3) 2 13 2 15(3H) 2 28-2 30 (3H) 2 80 - 2 83 (2H) 2 89 - 2 92 (2H) 7 03 7 07(1H) 719 7 22 (1H) 7 43 7 46 (1H), 7 62 - 7 64 (1H)
Preparation 77 N-[3-(3-Oxobutyl)phenyllmethanesulfonamide
1H-NMR (CDCI3) 2 16 2 18(31-1) 2 76 2 79 (2H) 2 84 2 87 (2H) 2 99 3 01 (3H) 7 00 7 05 (3H)
7 22-7 25 (1H)
Preparation 78
2 2 2-Tnfluoro-N-(2-[2-(2-methyl-1 3-dioxolan-2-yl]ethyl]phenyl}acetamide
To a solution of the compound of Preparation 83 (350 mg 1 7 mmol) in dichloromethane (10 ml) was added pyridine (534 mg 6 8 mmol) and the mixture was cooled in an acetonitnle/dry ice bath To the mixture was added dropwise the compound of Preparation 173 (0 3 ml 19 mmol) in dichloromethane (5 ml) and the reaction mixture was stirred for 10 mm The reaction mixture was allowed to warm to room temperature and stirred for 2 h before addition of excess sodium hydrogen carbonate After stirring for 18 h water (5 ml) and dichloromethane (10 ml) were added and the two layers were separated The organic phase was concentrated in vacuo to give the title compound (400 mg)
'H NMR (CDCI3) 1 20 - 1 23 (3H) 1 94 1 98 (2H) 2 68 2 72 (2H) 3 94 4 00 (4H) 7 20 7 25 (2H) 7 40 - 7 45 (2H)
Similarly prepared, using the appropriate acid chloride or acid anhydride, were
(Table Removed)
Preparation 79
2 2 2-TnfIuoro-AM3-r2-{2-methyl 1 3-dioxolan-2-yl)ethyllphenyl}acetamide
1H-NMR (CDCI3) 1 37 1 39 (3H) 1 95 1 99 (2H) 2 69 - 2 73 (2H) 3 96 - 4 00 (4H) 7 26 7 29 (1H),
6 38 6 42(21-1) 8 60 8 62(11-1)
Preparation 80
2 2,2-Trifluoro-N-(4-r2-(2-methYl-1.3-dioxolan-2-vnethvnphenyl}acetamid=H-NMR(CDCl3)
1 37 - 1 39 (3H) 1 90 -1 94 (2H), 2 68 - 2 73 (2H) 3 96 - 4 00 (4H) 7 19 - 7 22 (2H) 7 44 -
7 47 (2H)
Preparation 81
AM3-F2-(2 Methyl-1 3-dioxolan-2 yl)ethyllphenyl}propanamide
'H NMR (CDCI3) 1 08 112(3H)138 1 40 (3H) 1 95 1 99 (2H) 2 36 2 40 (2H) 2 65 - 2 70 (2H)
3 90-3 96 (4H) 6 91-6 94 (1H) 7 10-7 15 (1H) 7 22 7 28 (2H)
Preparation 82
N42 12-12 Methyl-1 3-dioxolan 2 yl)ethyllphenyl}acetamide
1H NMR (CDCI3) 1 36 -1 38 (3H) 1 94 -1 98 (2H) 2 09 2 11 (3H) 2 60 2 64 (2H) 3 90 - 3 94 (2H)
4 00 4 03 (2H) 7 01-7 04 (1H) 7 10 7 13 (1H) 7 42 - 7 45 (1H) 7 61 7 64(1H)
Preparation 83
2-f2-(2-Methyl 1 3-dioxolan 2 yDethyllaniline
A solution of the compound of Preparation 86 (550 mg 2 3 mmol) in methanol (75 ml) was flowed through an H-Cube hydrogenator (1 ml/mm 1 atm room temperature) using a palladium catalyst (10% on carbon) The solution was concentrated in vacuo to give the title compound (500 mg) 1H NMR (CDCIj) 1 38 1 40 (3H) 1 92 1 97 (2H) 2 58 2 62 (2H) 4 00 4 04 (4H) 6 67 6 73 (2H) 7 01 - 7 04 (2H)
Similarly prepared were
(Table Removed)
Preparation 84
3-|2-(2-Methyl-1 3-dioxolan-2-yl)ethyllaniline
1H-NMR (CDCIJ) 1 37 - 1 39 (3H) 1 90 1 94 (2H) 2 60 2 64 (2H) 3 96 - 4 00 (4H) 6 49 6 52 (2H)
6 60-6 62 (1H) 7 03 7 05(11-1)
Preparation 85
4-r2-(2-Methyl-1 3-dioxolan-2-yl)ethyllaniline
1H-NMR (CDCI3) 1 37 - 1 39 (3H) 1 88 1 92 (2H) 2 59 - 2 63 (2H) 3 97 4 00 (4H) 6 60 6 63 (2H)
6 98 7 00(2H)
Preparation 86
2 Methyl-2-f2 (2-nitrophenyl)vinyll-1 3 dioxolane
A mixture of the compound of Preparation 38 (2 5 g 13 1 mmol) ethylene glycol (1 6 g 26 2 mmol) and p-toluenesulphonic acid monohydrate (25 mg 0 1 mmol) in toluene (50 ml) was heated under reflux in a Dean Stark apparatus for 5 h After cooling the mixture was washed with saturated aqueous sodium carbonate solution (2 x 20 ml) and water dried (K2C03) and concentrated in vacuo to give the title compound (2 2 g) 1H-NMR (CDCIj) 2 58 2 61 (3H) 4 00 4 05 (4H) 6 05 - 6 09 (1H) 7 14 7 18 (1H) 7 55 7 57(1H)
7 64 7 68(2H) 7 95 7 97(1H)
Similarly prepared were

(Table Removed)
Preparation 87
2 Methyl-2-r2-(3-nitrophenyl)vinvll-1 3-dioxolane
1H NMR (CDCIj) 1 58 - 1 60 (3H) 3 92 - 3 97 (2H) 4 00 4 04 (2H), 6 26 - 6 30 (1H) 6 76 - 6 80 (1H)
7 48-751 (1H) 7 65-7 68 (1H) 808 811 (1H) 8 22-8 24 (1H)
Preparation 88
2 Methyl 2-f2-(4-mtrophenyl)vinvll-1 3-dioxolane
1H-NMR (CDCI3) 2 59-261 (3H) 395 3 99 (2H) 4 00 -4 05 (2H) 6 30-6 34 (1H) 676 680(1H)
7 52-7 55 (2H) 8 17 8 20 (2H)
Preparation 89
4-(3-OxobutvD-rV-(2 2 2-trifluoroethvDbenzamide
To a solution of the compound of Preparation 152 (0 6 ml 7 0 mmol) in dichloromethane (15 ml) was added the compound of Preparation 91 (367 mg 1 7 mmol) The reaction mixture was stirred for 15 mm and then extracted with water (2x2 ml) The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (670 mg) 1H-NMR (CDCIJ) 4 05 - 4 11 (1H) 7 25 - 7 30 (2H) 7 69 7 75 (2H)
Similarly prepared was
Preparation 90
N-Methyl 3-(3-oxobutyl)benzamide from the compound of Preparation 92 and Preparation 175 1H-NMR (CDCIj) 2 10 2 12 (3H) 2 75 - 2 79 (2H) 2 85 2 89 (2H) 2 96 - 2 98 (3H) 7 26 - 7 29 (2H) 7 54 7 57(1H) 7 60 7 62(1H)
Preparation 91 4-{3-Oxobutyl)benzoyl chloride
To a solution of the compound of Preparation 50 (1 2 g 6 2 mmol) in dichloromethane (15 ml) was added N N-dimethylformamide (30 ul) The mixture was cooled to 0°C and the compound of Preparation 147 (0 9 ml) was added The reaction mixture was allowed to warm to room temperature and stirred for 18 h The mixture was concentrated in vacuo to give the title compound (1 3 g) which was used directly
Similarly prepared was
Preparation 92
3-(3-Oxobutyl)benzoyl chloride from the compound of Preparation 51 and the compound of
Preparation 147
Preparation 93
N-(2-[2-(2-Methyl-1 3-dioxolan-2-yl]ethyl]phenyl}ethanesulfonamide
To a solution of the compound of Preparation 83 (350 mg 1 7 mmol) in dichloromethane (5 ml) was added pyridine (0 4 ml 5 1 mmol) and the mixture was cooled in an ice bath To the mixture was added dropwise the compound of Preparation 155 (0 2 ml 19 mmol) in dichloromethane (5 ml) After stirring for 10 mm the reaction mixture was allowed to warm to room temperature and stirred for a further 2 h Excess sodium hydrogen carbonate was added and the mixture was stirred for 18 h before addition of water (5 ml) and dichloromethane (10 ml) The two layers were separated and the organic phase was concentrated in vacuo to give the title compound (400 mg) which was used directly
Similarly prepared was
Preparation 94
N-(2-(2-Methyl-1 3-dioxolan 2-yl)ethyllphenyl)methanesulfonamide from the compound of
Preparation 84 and the compound of Preparation 174
Preparation 95
N-Cyclopropyl-4 (3-oxobutyl)benzamide
To a solution of the compound of Preparation 50 (200 mg 1 0 mmol) in acetonitnle (10 ml) was added thionyl chloride (151 ul 2 1 mmol) and the mixture was stirred at room temperature for 18 h To the mixture was added the compound of Preparation 160 (511 ul, 7 3 mmol) and the reaction mixture was stirred at room temperature for 30 mm The mixture was extracted with ethyl acetate and the combined extracts were washed with aqueous sodium hydrogen carbonate solution and water dried (MgSO«) and concentrated in vacuo to give the title compound (65 mg)
1H-NMR (CDCI3) 0 59 - 0 64 (2H) 0 82 0 87 (2H) 2 15-217 (3H) 2 70 - 2 74 (2H) 2 88 2 95 (3H) 7 20 - 7 23 (2H) 7 61 7 63 (2H)
Preparation 96 3-(3-Oxobutyl)benzamide
A solution of the compound of Preparation 92 (307 mg 1 5 mmol) in ammonia (0 5M in dioxane 17 5 ml) was stirred for 15 mm The mixture was extracted with water (2x2 ml) and the organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (130 mg)
1H-NMR (CDCI3) 2 14 2 16 (3H) 2 78-2 82 (2H) 2 95 2 99 (2H) 7 38 7 40 (1H) 7 41 7 43(1H) 7 90 7 92(2H)
Similarly prepared was
Preparation 97
4-{3-Oxobutyl)benzamide from the compound of Preparation 91
1H-NMR (CDCI3) 2 16 2 18 (3H) 2 78 2 81 (2H) 2 97 - 3 00 (2H) 7 30 - 7 32 (2H) 8 00 - 8 02 (2H)
Preparation 98 4-(2-Chloro-3-hydroxy-phenyl)-but-3-en-2-one
A mixture of the compound of Preparation 149 (157 mg 1 0 mmol) and the compound of Preparation 150 (637 mg 2 0 mmol) in tetrahydrofuran (20 ml) was heated under reflux for 12 h The mixture was concentrated in vacuo and the residue was purified by column chromatography (silica) elutmg with ethyl acetate hexane The appropriate fractions were combined and concentrated to give the title compound (100 mg) 1H-NMR (CDCI3) 2 40 2 42 (3H) 6 61 6 64 (1H) 7 08 - 7 10 (1H) 7 40 - 7 45 (2H) 7 80 7 82 (1H)
Similarly prepared was
Preparation 99
4-(2 6-Dichloro 3-hydroxy-phenyl)-but-3-en 2-one from Preparation 169
Experimental MH+ 233 2 expected 233 0
Preparation 100 4-(2-hydroxyphenyll)but-3-en-2-one
To a solution of the compound of Preparation 109 (150 0 g 12 mol) in acetone (700 ml) at 0°C and under nitrogen was added carefully aqueous sodium hydroxide solution (1N 1350 ml) ensuring the temperature of the mixture remained below 10°C The reaction mixture was allowed to warm to room temperature and stirred for 18 h To the mixture was added hydrochloric acid (3N 600 ml) and the resulting solid was collected by filtration under nitrogen The solid was washed with water (3 x 300 ml and 1 x 500 ml) followed by cyclohexane (250 ml) and dried in vacuo The residue was slurried in cyclohexane (750 ml) for 2 days filtered washed with cyclohexane (2 x 150 ml) and concentrated in vacuo to give the title compound (155 0 g)
1H NMR (CD3OD) 2 37-2 39 (3H) 6 81-6 83 (1H) 6 83 - 6 86 (2H) 7 20 7 23(1H) 7 51 7 53(1H) 7 93 7 96(11-1)
Preparation 101
N-14-13 Oxobutyl)phenyllbenzenesulfonamide
To a mixture of the compound of Preparation 103 (163 mg 1 0 mmol) and tnethylamme (35 µl 2 5 mmol) in tetrahydrofuran and dichloromethane (8 5 ml) was added the compound of Preparation 161 (194 mg 1 1 mmol) The reaction mixture was heated under reflux for 12 h and then concentrated in vacuo The residue was extracted with ethyl acetate and the combined extracts were dried (MgSO4) and concentrated in vacuo The residue was purified by column chromatography (silica) elutmg with ethyl
acetate hexane The appropriate fractions were combined and concentrated to give the title compound
(250 mg)
Experimental MH4 304 2, expected 304 1
Preparation 102
1 1 1-Trifluoro-N-[4-(3-oxobutylphenyl]methanesulfonamide
To a mixture of the compound of Preparation 103 (163 mg 1 0 mmol) and triethylamine (35 µl 2 5 mmol) in dichloromethane (8 5 ml) was added the compound of Preparation 162 (185 mg 1 1 mmol) The reaction mixture was stirred at room temperature for 12 h and then concentrated in vacuo To the residue was added methanol and aqueous sodium hydroxide solution and the mixture was stirred for a further 12 h The mixture was concentrated in vacuo and the residue was extracted with ethyl acetate The combined extracts were dried (MgSO*) and concentrated in vacuo The residue was purified by column chromatography (silica) eluting with ethyl acetate hexane The appropriate fractions were combined and concentrated to give the title compound (103 mg) 1H-NMR (d6-DMSO) 2 08 2 10 (3H) 2 72 2 75 (4H) 7 10 7 13 (2H) 6 40 6 42 (2H)
Preparation 103 4-(4-Amino-Dhenyl)-butan-2-one
A mixture of the compound of Preparation 100 (150 mg 0 8 mmol) and palladium (10% on carbon 15
mg) in ethanol (5 ml) was stirred under hydrogen (50 psi) at room temperature for 2 h The reaction
mixture was filtered through Celite® and the filtrate was concentrated in vacuo The residue was purified
by column chromatography (silica) eluting with ethyl acetate hexane The appropriate fractions were
combined and concentrated to give the title compound (114 mg)
1H NMR (d6-DMSO) 2 05 2 07 (3H) 2 56 - 2 60 (2H) 2 60 2 64 (2H) 6 42 6 44 (2H) 6 80 6 82
(2H)
Preparation 104
4 Isopropoxy-phenylbutanone
To a solution of the compound of Preparation 106 (1 00 g 6 1 mmol) in acetone (30 ml) was added potassium carbonate (1 70 g 12 2 mmol) the compound of Preparation 143 (1 15 ml 12 2 mmol) and potassium iodide (2 02 g 12 2 mmol) The reaction mixture was heated under reflux for 18 h and then quenched by addition of water The mixture was extracted with ethyl acetate (3 x 50 ml) and the combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (1 25 g) which was used directly
Preparation 105
Phenyl 3-methvlbut-2-enoate
To a solution of the compound of Preparation 176 (6 7 g 71 mmol) and the compound of Preparation 144 (8 5 g 71 mmol) in diethyl ether (150 ml) at 0°C was added dropwise triethylamine (10 0 ml 71 mmol) The reaction mixture was stirred for 30 mm and then filtered through Ceiite® washing through

with diethyl ether The filtrate was washed with water and brine dried (MgSO4) and concentrated in
vacuo to give the title compound (13 5 g)
Experimental MH* 177 3 expected 177 1
The following compounds may be obtained commercially
(Table Removed)
Source 1 Sigma-Aldnch PO Box 14508 St Louis MO, 63178 USA
Source 2 Fluorochem Ltd Wesley Street Old Glossop Derbyshire SK13 7RY UK
Source 3 Pfaltz& Bauer Inc 172 E Aurora Street Waterbury CT 06708 USA
Source 4 Apollo Scientific Ltd Whitefield Rd , Bredbury Stockport Cheshire SK6 2QR UK
Source 5 Lancaster Synthesis Ltd Newgate White Lund Morecambe Lancashire LA3 3BN UK
Source 6 ASDI Inc 601 Interchange Blvd Newark DE 19711 USA
Preparation 168 4-(5-Chloro-2-hydroxyphenyll)but 3-en-2-one
This compound was prepared according to the method described in WO-9946266 A1 Example 4
Preparation 169
2 6-Dichloro-3-hydroxybenzaldehyde
This compound was prepared according to the method described in Synthesis (2004) (12) 2062 2065
Preparation 170
4-(2 3-Oihydro-1-benzofuran 5-yl)butan-2-one
This compound was prepared according to the method described in WO-0279143 A1 Preparation 140
Preparation 171 4-(3hydroxyphenyl)but-3-en-2-one
This compound was prepared according to the method described in WO-0208188 A1 Example 1 Step 1
Preparation 172 3-(Hydroxymethyl)benzaldehyde
This compound was prepared according to the method described in Can J Chem 1973 51 3756-3764
The following compounds may be obtained commercially
(Table Removed)
Source! Sigma-Aldnch PO Box 14508 St Louis MO 63178 USA

CLAIMS
1. A compound of formula (I)
(Formula Removed)
or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically or veterinarily acceptable salt of said compound or prodrug, wherein:
A is -CH2-; and
B is -CH2-, -C(CH3)2-, -O-, -CH2-CH2-,-CH2-O-, or -O-CH2-; or
-A-B- is-CH=CH-;
one of R1 and R2 is CH3 and the other is H;
R3, R4, R5, R6 and R7 are each independently selected from H, Ra and R9; or
R4 and R5 together are -O-CH2-CH2-, -CH2-CH2-O- or -O-CH2-O-, and R3, R6 and R7 are each
independently selected from H, R8 and R°;
R8 is halo, -CN, C1-C4 alkyl, C1-C4 haloalkyl, -CH2OH, -O-(d-C4 alkyl), -O-CHr(C3-C5)cycloalkyl, -C02H, -C02(C1-C4 alkyl), -CONH2, -C0NH(C1-C4 alkyl), -C0NH(C1-C4 haloalkyl), -CONH(C3-C« cycloalkyl) or NH2; and
R9 is -OH, -NHSO2(C1-C3 alkyl), -NHCO(C1-C4 alkyl), -NHCO(C1-C4 haloalkyl), -NHSO2(C1-C3 haloalkyl) or -NHSO2(phenyl).
2. A compound according to claim 1, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutical^ or veterinarily acceptable salt of said compound or prodrug, wherein: -A- is -CH2- and -B- is -CH2-, or -C(CH3)2-; or -A-B- is -CH=CH-.
3. A compound according to claim 2, or a pharmaceutically acceptable prodrug thereof, or.a
pharmaceutically or veterinarily acceptable salt of said compound or prodrug, wherein -A- is -CH2-and -B- is -CH2-.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically or veterinarily acceptable salt of said compound or prodrug, wherein R1 is H and R2 is CH3.
5. A compound according to claim 4, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically or veterinarily acceptable salt of said compound or prodrug, wherein the absolute stereochemistry at C-1', C-6 and C-7 is R, R, R.
6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable prodrug
thereof, or a pharmaceutically or veterinarily acceptable salt of said compound or prodrug, wherein
R3, R4, R5, R9 and R7 are each independently selected from H, R8 and R8, provided that at least two
of R3, R4, R5, R8 and R7 are H; or
R4 and R5 together are -O-CH2-CH2-, -CH2-CH2-O- or -O-CH2-O-, and R3, R6 and R7 are H; R8 is halo, -CN, C1-C4 alkyl, -CF3, -CH2OH, -O-(C1-C4 alkyl), or -O-CH2-(C3-C5)cycloalkyl; and R8 is -OH or -NHSO2(C1-C3 alkyl).
7. A compound according to claim 6, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically or veterinarily acceptable salt of said compound or prodrug, wherein one of R3, R4, Rs, R8 and R7 is R8 or R8, another two of R3, R4, R5, R8 and R7 are H or R8, and the other two of R3, R4, R5, R6 and R7 are H.
8. A compound according to claim 7, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically or veterinarily acceptable salt of said compound or prodrug, wherein R3 is RB.
9. A compound according to claim 8, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically or veterinarily acceptable salt of said compound or prodrug, wherein R9 is -OH.
10. A compound according to claim 1 selected from: (6R,7R*)-7-hydroxy-6-{(1R)-[3-(4-hydroxyphenyl)-1-methylpropyl]amino}-4.5,6,7-tetrahydro-imidazo[4,5,1-jk][1]benzazepin-2(1 W)-one
(6R,7R*)-7-hydroxy-6-{(1S*)-[3-(4-hydroxyphenyl)-1-methylpropyl]amino}-4,5,6,7-tetrahydro-imidazo[4,5,1-jk](1 ]enzazepin-2(1 H)-one
(6R,7R)-7-hydroxy-6-{(1RS)-[3-(4-hydroxyphenyl)-1-methylpropyl]amino}-4,5,6,7-tetrahydro-imidazo[4,5,1-jk]benzazepin-2(1H)-one
(6R,7R)-7-hydroxy-6-{(1S)-[3-(4-hydroxyphenyl)-1-methylpropyl]amino}-4.5,6,7-tetrahydro-imidazo[4,5,1 -jk][1]benzazepin-2(1 H)-one
6R,7R)-7-hydroxy-6-{(1R)-[3-(4-hydroxyphenyl)-1-methylpropyl]amino}-4,5,6.7-tetrahydro-
imidazo[4,5,1-jk][1]benzazepin-2(1H)-one (6R.7R)-7-hydroxy-6-([(1R*)-3-(2-hydroxyphenyl)-1-methylpropyl]amino}-4.5.6,7-tetrahydro-
imidazo[4,5.1-jk][1]benzazepin-2(1H)-one (6R*.7R*)-7-hydroxy-6-{[(1S*)-3-(2-hydroxyphenyl)-1-methylpropy!]amino)-.5,6,7-tetrahydro-
imidazo(4,5,1-jk][1]benzazepin-2(1H)-one, (6R,7R)-7-hydroxy-6-{[(fRS)-3-(2-hydroxyphenyl)-1-methylpropyl]amino}-4,5,6,7-tetrahydro-
imidazo[4,5,1-yk][1]benzazepin-2(1H)-one, (6R,7R)-7-hydroxy-6-{[(1R)-3-(2-hydroxyphenyl)-1-methyipropyl]amino}-4.5.6,7-tetrahydro-
imidazo(4,5,1-yk][1]benzazepin-2(1H)-one, (6R,7R)-7-hydroxy-6-{[(1S)-3-(2-hydroxyphenyl)-1-methylpropylJamino}-4.5,6,7-tetrahydro-
imidazo[4.5,1-yk]{1]benzazepin-2(1H)-one,
(6R*,7R')-6-{[(1R*)-3-(5-fluoro-2-hydroxyphenyl)-1-methylpropyl]amino}-7-hydroxy-4l5.6,7-
tetrahydroimidazo[4,5,1-jk]I1]benzazepin-2(1H)-one,
(6R*,7R*)-6-{[(1S*):3-(5-fluoro-2-hyclroxyphenyl)-1-methylpropyl]amino}-7-hydroxy-4,5.6.7-
tetrahydromidazo[4,5,1-jk][1]benzazepin-2(1H)-one,
(6R,7R)-6-{[(1RS)-3-(5-nuoro-2-hydroxyphenyl)-1-methylpropyl]amino)-7-hydroxy-4,5,6l7-
tetrahydroimidazo[4,5,1-yk)[1]benzazepin-2(1H)-one,
(6R,7R}-6-{[(1R)-3-(5-fluoro-2-hydroxyphenyl)-1-methylpropyl]amino>-7-hydroxy-4,5.6,7-tetrahydro-
imidazo[4,5,1-jk][1]benzazepin-2(1H)-one,
(6R.7R)-6-{[(1S)-3-(5-nuoro-2-hydroxyphenyl)-1-methylpropyl]amino}-7-hydroxy-4,5,6,7-tetrahydro-
imidazo[4,5,1-jk][1]benzazepin-2(1H)-one,
(6R*,7R*)-6-{[(1R*)-3-(4,5-difluoro-2-hydroxyphenyl)-1-methylpropyl]amino)-7-hydroxy-4,5,6.7-
tetrahydroimidazo[4,5,1-jk][1]benzazepin-2(1H)-one,
(6R*,7R*)-6-{[(1S*)-3-(4,5-difIuoro-2-hydroxyphenyl)-1-methy1propyl]amino}-7-hydroxy-4,5,6,7-
tetrahydroimidazo{4,5,1-jk][1 ]benzazepin-2(1H)-one,
(6R,7R)-6-{[(rRS)-3-(4,5-difluoro-2-hydroxyphenyl)-1-methylpropyl]amino}-7-hydroxy-4,5,6,7-
tetrahydroimidazo[4,5,1-jk][1 Jbenzazepin-2( 1 H)-one,
(6R,7R)-6-{[(^R)-3-(4.5-drfluoro-2-hydroxyphenyl)-1-methylpropyl]amino}-7-hydroxy-4,5,6,7-
tetrahydroimidazo[4,5,1-jk][1]benzazepin-2(1H)-one, and
(6R,7R)-6-{l(7S)-3-(4,5-difluoro-2-hydroxyphenyl)-1-methylpropyl]amino}-7-hydroxy-4.5,6,7-
tetrahydroimidazo[4,5,1-jk][1]benzazepin-2(1H)-one,
or a pharmaceutically acceptable prodrug thereof, or a pharmaceutical^ or veterinarily acceptable
salt of said compound or prodrug.
11. A feed additive for a livestock animal comprising a compound according to any one of claims 1 to 1P, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically or veterinarily acceptable salt of said compound or prodrug.
12. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically or veterinarily acceptable salt of said compound or prodrug, for use as a medicament.
13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically or veterinarily acceptable salt of said compound or prodrug, and a pharmaceutically acceptable carrier.