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  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

• the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has a rich pharmacology arising from a heterogeneous population of at least seven receptor classes.
• the serotonin 5-HT 2 class is further subdivided into at least three subtypes, designated 5-HT 2A , 5-HT 2B , and 5-HT 2C .
• the 5-HT 2C receptor has been isolated and characterized (Julius, et al., U.S. Pat. No. 4,985,352), and transgenic mice lacking the 5-HT 2C receptor have been reported to exhibit seizures and an eating disorder resulting in increased consumption of food (Julius et al., U.S. Pat. No. 5,698,766).
• the 5-HT 2C receptor has also been linked to various other neurological disorders including obesity (Vickers et al., Psychopharmacology, 167: 274-280 (2003)), hyperphagia (Tecott et al., Nature, 374: 542-546 (1995)), obsessive compulsive disorder (Martin et al., Pharmacol. Biochem. Behav., 71: 615 (2002); Chou-Green et al., Physiology & Behavior, 78: 641-649 (2003)), depression (Leysen, Kelder, Trends in Drug Research II, 29: 49-61 (1998)), anxiety (Curr. Opin. Invest. Drugs 2(4), p.
• EP 0 285 287 describes certain substituted 2,3,4,5-tetrahydro-1H-benzo[d]azepine compounds for use as agents to treat gastrointestinal motility disorders, inter alia.
• WO 93/03015 and WO 93/04686 describe certain substituted 2,3,4,5-tetrahydro-1H-benzo[d]azepine compounds as alpha-adrenergic receptor antagonists for use as agents to treat hypertension and cardiovascular diseases in which changes in vascular resistance are desirable, inter alia.
• WO 02/074746 A1 describes certain substituted 2,3,4,5-tetrahydro-1H-benzo[d]azepine compounds as 5-HT 2C agonists for the treatment of hypogonadism, obesity, hyperphagia, anxiety, depression, sleep disorder, inter alia.
• WO 03/006466 A1 describes certain substituted tricyclic hexahydroazepinoindole and indoline compounds as 5-HT ligands and consequently their usefulness for treating diseases wherein modulation of 5-HT activity is desired.
• WO 05/019180 describes 6-(2,2,2-trifluoroethylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a potent and selective 5-HT 2C agonist for the treatment of obesity, anxiety, depression, and obsessive-compulsive disorder.
• High affinity 5-HT 2C receptor agonists would provide useful therapeutics for the treatment of the above mentioned 5-HT 2C receptor-associated disorders including obesity, hyperphagia, obsessive/compulsive disorder, depression, anxiety, substance abuse, sleep disorder, hot flashes, and hypogonadism.
• High affinity 5-HT 2C receptor agonists that are also selective for the 5-HT 2C receptor would provide such therapeutic benefit without the undesirable adverse events associated with current therapies.
• Achieving selectivity for the 5-HT 2C receptor, particularly as against the 5-HT 2A and 5-HT 2B receptors, has proven difficult in designing 5-HT 2C agonists.
• 5-HT 2A receptor agonists have been associated with problematic hallucinogenic adverse events.
• 5-HT 2B receptor agonists have been associated with cardiovascular related adverse events, such as valvulopathy. (V. Setola et al., Mol. Pharmacology, 63: 1223-1229 (2003), and ref. cited therein).
• the present invention provides selective 5-HT 2C agonist compounds of Formula I:
• compositions which comprise a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier, diluent, or excipient.
• a method for increasing activation of the 5-HT 2C receptor in mammals comprising administering to a mammal in need of such activation an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.
• the present invention also provides a method for treating obesity in mammals comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.
• the present invention also provides a method for treating obsessive/compulsive disorder in mammals comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.
• the present invention provides a method for treating depression in mammals comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.
• the present invention provides a method for treating anxiety in mammals comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.
• the mammal is a human.
• a compound of Formula I for use in selectively increasing activation of the 5-HT 2C receptor and/or for use in treating a variety of disorders associated with decreased activation of 5-HT 2C receptors.
• Preferred embodiments of this aspect of the invention include a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of obesity, hyperphagia, obsessive/compulsive disorder, depression, anxiety, substance abuse, sleep disorder, hot flashes, and/or hypogonadism.
• Particularly preferred embodiments of this aspect of the invention include the treatment of obesity, obsessive/compulsive disorder, depression, and/or anxiety.
• Particularly preferred embodiments of this aspect of the invention include the use of one or more compounds of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of medicaments for the treatment of obesity, obsessive/compulsive disorder, depression, and/or anxiety.
• the present invention provides a pharmaceutical formulation adapted for the treatment of obesity, or for the treatment of obsessive/compulsive disorder, or for the treatment of depression, or for the treatment of anxiety, each of which comprise a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier, diluent or excipient.
• alkyl refers to a branched or unbranched saturated hydrocarbon group.
• n-alkyl refers to an unbranched alkyl group.
• (C 1 -C 2 )alkyl refers to methyl and ethyl.
• (C 1 -C 3 )n-alkyl refers to methyl, ethyl, and propyl.
• (C 1 -C 3 )alkyl refers to methyl, ethyl, propyl, and isopropyl.
• (C 1 -C 5 )alkyl refers to all branched and unbranched alkyl groups having from one to five carbon atoms.
• (C 1 -C 6 )alkyl refers to all branched and unbranched alkyl groups having from one to six carbon atoms.
• (C 3 -C 6 )alkyl refers to all branched and unbranched alkyl groups having from three to six carbon atoms.
• (C 2 -C 6 )alkyl refers to all branched and unbranched alkyl groups having from two to six carbon atoms.
• (C x —C y )alkyl may also be used in conjunction with other substituents to indicate a branched or unbranched saturated hydrocarbon linker for the substituent, where x and y indicate the range of carbon atoms permitted in the linker moiety.
• —(C 0 -C 1 )alkyl refers to a single bond or a methylene linker moiety
• —(C 0 -C 2 )alkyl refers to a single bond, methylene, methyl-methylene, or ethylene linker moiety
• -(C 0 -C 3 )alkyl further includes trimethylene, alpha- or beta-methyl ethylene, or ethyl methylene
• —(C 0 -C 5 )alkyl refers to a bond or a saturated, branched or unbranched hydrocarbon linker having from 1 to 5 carbon atoms.
• —(C 1 -C 2 )alkyl, —(C 1 -C 3 )alkyl, —(C 1 -C 5 )alkyl, and —(C 1 -C 6 )alkyl refer to branched or unbranched allylene linkers having from 1 to 2, 3, 5, or 6 carbon atoms, respectively.
• alkenyl refers to a branched or unbranched hydrocarbon group having one or more carbon-carbon double bonds.
• (C 2 -C 6 )alkenyl refers to a branched or unbranched hydrocarbon group having from 2 to 6 carbon atoms and 1 or more carbon-carbon double bonds. Allyl means a propyl-2-en-1-yl moiety (CH 2 ⁇ CH—CH 2 —).
• (C 3 -C 7 )cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• Cycloalkylalkyl refers to a cycloalkyl moiety linked through a branched or unbranched alkylene linker, as for example, but without limitation, —CH 2 —, —CH 2 CH 2 —, —CH(CH 3 )—, —CH 2 CH 2 CH 2 —, —CH 2 CH(CH 3 )—, —CH(CH 3 )CH 2 —, —CH(CH 2 CH 3 )—, and the like.
• (C 3 -C 7 )cycloalkyl(C 0 -C 1, 2 or 3 )alkyl refers to a cycloalkyl moiety linked through a single bond (i.e. C 0 -alkyl) or an alkylene linker having 1, 2, or 3 carbon atoms, respectively.
• Each alkyl, cycloalkyl, and cycloalkylalkyl group may be optionally substituted as provided for herein.
• alkoxy refers to an alkyl group, phenyl group, sulfonyl group, or carbonyl group, respectively, that is bonded through an oxygen atom.
• alkylthio trifluoromethylthio
• cycloalkylthio (“cyclohexylthio”)
• phenylthio and “furanylthio” refer to an alkyl group, trifluoromethyl group, cycloalkyl (cyclohexyl) group, phenyl group, or furanyl group, respectively, that is bonded through a sulfur atom.
• alkylcarbonyl refers to an alkyl, alkoxy, phenyl, or phenyloxy group bonded through a carbonyl moiety.
• alkylsulfonyl (t-butylsulfonyl), “(C 3 -C 7 )cycloalkylsulfonyl”, “phenylsulfonyl”, “Ph 1 -(C 0 -C 3 )alkylsulfonyl”, and “Ar 2 —(C 0 -C 3 )alkylsulfonyl”, refer to an alkyl (t-butyl), (C 3 -C 7 )cycloalkyl, phenyl, Ph 1 -(C 0 -C 3 )alkyl, or Ar 2 —(C 0 -C 3 )alkyl group bonded through a sulfonyl moiety (—SO 2 —).
• N-linked means that the referenced moiety is linked through its nitrogen atom
• N-linked Het 1 means the Het 1 moiety is linked through a nitrogen atom in the ring of the Het 1 moiety.
• halo refers to fluoro, chloro, bromo, or iodo.
• Preferred halo groups are fluoro, chloro, and bromo. More preferred halo groups are fluoro and chloro.
• gem- refers to two identical substituents bonded to a common carbon atom, as for example, but without limitation, gem-methyl, 5 meaning two methyl groups bound to a common carbon atom, as for instance in a 3,3-dimethyltetrahydrobenzofuranyl group.
• gem-ethano means an ethylene substituent wherein both carbons are bound to the same carbon atom of the substituted group to form a cyclopropyl moiety, as for example, but without limitation, the ethano substituent on the 2-phenyl-(1,1-ethano)ethylamino group below:
• amino protecting group refers to a substituent commonly employed to block or protect the amino functionality while reacting other functional groups on the compound.
• amino protecting groups include the formyl group, the trityl group, the acetyl group, the trichloroacetyl group, the trifluoroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, carbamoyl-type blocking groups such as benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (“FMOC”), t-butoxycarbonyl (t-BOC), and like amino protecting groups.
• FMOC 9-fluorenylmethoxycarbonyl
• t-BOC t-butoxycarbonyl
• the species of amino protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of subsequent reactions on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule.
• the selection and use (addition and subsequent removal) of amino protecting groups is well known within the ordinary skill of the art. Further examples of groups referred to by the above terms are described by T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 3 rd edition, John Wiley and Sons, New York, N.Y., 1999, chapter 7, hereafter referred to as “Greene”.
• pharmaceutical or “pharmaceutically acceptable” when used herein as an adjective, means substantially non-toxic and substantially non-deleterious to the recipient.
• pharmaceutical composition it is further meant that the carrier, solvent, excipients and/or salt must be compatible with the active ingredient of the composition (e.g. a compound of Formula I). It is understood by those of ordinary skill in this art that the terms “pharmaceutical formulation” and “pharmaceutical composition” are generally interchangeable, and they are so used for the purposes of this application.
• an effective amount means an amount of a compound of Formula I which is capable of activating 5-HT 2C receptors and/or eliciting a given pharmacological effect.
• suitable solvent refers to any solvent, or mixture of solvents, inert to the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within which to effect the desired reaction.
• compounds of the present invention may exist as stereoisomers. As such, all enantiomers, diastereomers, and mixtures thereof, are included within the scope of the present invention. Where specific stereochemistries are identified in this application, the Cahn-Prelog-Ingold designations of (R)— and (S)— and the cis and trans designation of relative stereochemistry are used to refer to specific isomers and relative stereochemistry.
• Known optical rotations are designated by (+) and ( ⁇ ) for dextrorotatary and levorotatary, respectively. Where a chiral compound is resolved into its isomers, but absolute configurations or optical rotations are not determined, the isomers are arbitrarily designated as isomer 1, isomer 2, etc. While all enantiomers, diastereomers, and mixtures thereof, are contemplated within the present invention, preferred embodiments are single enantiomers and single diastereomers.
• Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric acid, and the like.
• Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used.
• Such pharmaceutically acceptable salts thus include chloride, bromide, iodide, nitrate, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, isobutyrate, phenylbutyrate, ⁇ -hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, nicotinate, isonicotinate, oxalate, phthalate, terephthalate, propiolate, propionate, phenylpropionate, sal
• salts in various molar ratios with the acid to provide, for example, the hemi-acid, mono-acid, di-acid salt, etc.
• the acid is added in a specific stoichiometric ratio, unless otherwise analyzed to confirm, the salt is presumed, but not known, to form in that molar ratio.
• Terms such as “(acid) x ” are understood to mean that the molar ratio of the salt formed is not known and can not be presumed, as for example, but without limitation, (HCl) x and (methanesulfonic acid) x .
• SCX chromatography means chromatography on a SCX column or cartridge.
• a methylene linker from the 6-position nitrogen atom to the phenyl or pyridyl moiety is preferred over longer or larger linkers, as in compounds wherein R 10 is Ph 2 -methyl- or R 10 is Ar 1- methyl-.
• 6-benzylamino compounds i.e. compounds wherein R 10 is Ph 2
• substitution at the para-position of the phenyl moiety is particularly preferred.
• One favored group of compounds of the present invention is that represented by formula (Ia), and pharmaceutically acceptable salts thereof:
• R 7a is halogen, and especially chloro
• R 20 is halo, hydroxy, or cyano
• Preferred compounds according to formula (Ia) are those wherein R 20 is fluoro or chloro.
• R 7a is halogen, and especially chloro
• R 13 is as defined in relation to formula (I).
• R 20 is halo, hydroxy, or cyano
• Preferred compounds according to formula (Ib) are those wherein R 20 is fluoro or chloro.
• R 7a is halogen, and especially chloro
• R 13 is as defined in relation to formula (I).
• R 20 is halo, hydroxy, or cyano
• Preferred compounds according to formula (Ic) are those wherein R 20 is fluoro or chloro.
• the compounds of the invention can be prepared according to the following synthetic schemes by methods well known and appreciated in the art. Suitable reaction conditions for the steps of these schemes are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art. Likewise, it will be appreciated by those skilled in the art that synthetic intermediates may by isolated and/or purified by various well known techniques as needed or desired, and that frequently, it will be possible to use various intermediates directly in subsequent synthetic steps with little or no purification. Furthermore, the skilled artisan will appreciate that in some circumstances, the order in which moieties are introduced is not critical.
• the compounds of Formula I may be prepared by a variety of procedures, some of which are described below. All substituents, unless otherwise indicated, are as previously defined, and all reagents are well known and appreciated in the art.
• the products of each step can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like.
• catalysts and ligands include tris(dibenzylideneacetone)-dipalladium(0), palladium(II) acetate or a mixture of both, and typical ligands include ( ⁇ )-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP).
• BINAP diphenylphosphino-1,1′-binaphthalene
• R 11 if needed, may be performed to provide compounds (d).
• Pg is a suitable protecting group for a secondary amine such as, but not limited to, trifluoroacetyl, tert-butoxycarbonyl, or benzyl.
• Compounds of Formula (Ia) where R 3 is H may be obtained from compounds (d) by removing the protecting group Pg under conditions well known to the skilled artisan.
• Compounds of Formula (Ia) where R 3 is methyl or ethyl may be either obtained from intermediates (c) where Pg is methyl or ethyl, respectively; or, alternately, compounds of Formula (Ia) where R 3 is H, may be converted to the N-methyl or N-ethyl derivatives (Ia) where R 3 is methyl or ethyl via alkylation conditions well known in the art.
• An appropriate compound of Formula (Ia) is one in which variables R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 and R 11 are as previously defined for Formula I.
• Amines (b) are either commercially available or may be prepared by a variety of methods.
• amines of formula (f) and (h) can be prepared from nitrites (e) and (g) in the presence of hydrogen, at atmospheric pressure or 60 psi, using Degussa-type Pd/C as catalyst in a suitable solvent, such as methanol/hydrochloric acid, ethanol/hydrochloric acid, methanol/water/acetic acid, ethanol/water/acetic acid, THF/iso-propanol and the like.
• hydrogenation can be performed at atmospheric pressure or 60 psi using Raney Nickel® as catalyst in a suitable solvent, typically methanol or ethanol in the presence of ammonia.
• nitrites (e) and (g) can be reduced using lithium aluminum hydride or borane (THF or dimethylsulfide complex) in a suitable solvent, typically THF.
• Nitriles (e) and (g) can be also reduced using cobalt(II) chloride hexahydrate or nickel(II) chloride hexahydrate and sodium borohydride in a suitable solvent, typically methanol or ethanol.
• Nitriles (e) and (g) are either commercially available or may be prepared by methods well known to the skilled artisan.
• nitrites (e) and (g) can be also reduced in the presence of a suitable protecting group for an amine such as, but not limited to, di-tert-butyl-dicarbonate.
• Reduction of nitrites (e) and (g) can be performed by hydrogen, at atmospheric pressure or 60 psi, using Degussa-type Pd/C as catalyst in a suitable solvent, such as methanol, ethanol, THF/iso-propanol, ethyl acetate and the like in the presence of di-tert-butyl-dicarbonate.
• Suitable reducing agents could be cobalt(II) chloride hexahydrate or nickel(II) chloride hexahydrate and sodium borohydride in a suitable solvent, typically methanol or ethanol in the presence of di-tert-butyl-dicarbonate. Deprotection of the nitrogen gives the desired amines (f) and (h).
• Nitriles (e) and (g) are either commercially available or may be prepared by methods well known to the skilled artisan.
• Amines (fa) and (ha) can also be prepared as illustrated in Scheme IV. Bromination of compounds (k) and (n) using NBS and AIBN in a suitable solvent, typically carbon tetrachloride, chloroform or dichloromethane provides bromides (l) and ( ⁇ ), respectively. Reaction of compounds (l) and ( ⁇ ) with di-tert-butyl-iminodicarboxylate in the presence of a base such as sodium hydride, potassium carbonate, cesium carbonate or potassium tert-butoxide, in a suitable solvent, typically DMF or THF, afford compounds (m) and (p). Deprotection gives the desired amines (f) and (h). Compounds (k) and (n) are either commercially available or may be prepared by methods well known to the skilled artisan.
• Amines (fb) and (hb) may be prepared from the corresponding alcohols (q) and (s), respectively, via reaction sequences well known to the skilled in the art, as illustrated in Scheme V.
• the alcohols are converted to intermediates (r) and (s) with a suitable leaving group, such as but not limited to chloride, bromide, or mesylate, which may be displaced by a nucleophile such as azide (N 3 ⁇ ), using a reagent such as sodium azide, di-tert-butyl-iminodicarboxylate in the presence of a suitable base or ammonia.
• a suitable leaving group such as but not limited to chloride, bromide, or mesylate
• a reagent such as sodium azide, di-tert-butyl-iminodicarboxylate in the presence of a suitable base or ammonia.
• Amines (fc) and (hc) may also be prepared as illustrated in Scheme VI via reductive amination procedures.
• Amines (fd), (fe), (hd), (he) may also be prepared as illustrated in Scheme VII.
• the corresponding nitriles (va) or esters (wa) may be dialkylated in the alpha-positions according to methods well known in the art. For example, reaction of compounds (va) with ethylene dibromide or ethylene dichloride in the presence of an appropriate base and in a suitable solvent, such as but not limited to K[NSi(CH 3 ) 2 ] in THF, can afford the gem-ethano compounds (vb). Reduction of the nitrile under conditions some of which have been described above may yield amines (fe) and (he).
• esters (wb) can be hydrolyzed to the corresponding carboxylic acids, which then can be converted to the amines (fd) and (hd), via a Curtius-type rearrangement in the presence of sodium azide and sulfuric acid.
• Gem-ethano esters (wb) may also be obtained from the corresponding unsaturated esters (wc), for example by reaction with CHBr 3 in the presence of base, such as for example NaOH under phase transfer catalysis conditions, followed by debromination for example with Mg in methanol, or by reaction with diazomethane under suitable conditions.
• base such as for example NaOH under phase transfer catalysis conditions
• debromination for example with Mg in methanol
• diazomethane under suitable conditions.
• Amines (ff) and (hf) can be prepared, as illustrated in Scheme VIII, by transformation of appropriately substituted intermediates (xa), (xc), (xd), (xe) into the appropriately substituted heteroaromatic compounds (xb) according to procedures known in the art. Transformations of the nitrile by following the procedures previously described give the desired amines (ff) and (hf). Compounds (xa), (xc), (xd), and (xe) are either commercially available or may be prepared by methods well known to the skilled artisan.
• Amines (fg) and (hg) can be also prepared, as illustrated in Scheme IX, by the couling of boronic acids (ya) with an appropriately substituted heteroaromatic bromide, chloride, iodide or triflate in the presence of a suitable palladium catalyst/ligand system, and a base in a suitable solvent, typically toluene, DMF or 1,4-dioxane under an inert atmosphere. Transformations of the nitriles (yb) by following the procedures previously described gives the desired amines (fg) and (hg). Boronic acids (ya) are either commercially available or may be prepared by methods well known to the skilled artisan.
• intermediates (yb) can be obtained by reaction of compounds (yc) with an appropriately activated heteroaryl derivative, under appropriate transition metal catalysis, especially in the presence of a suitable palladium reagent, as described in the literature and well known to the skilled artisan [see for example, Li and Gribble, Palladium in Heterocyclic Chemistry, Pergamon, Amsterdam (2000)].
• compounds of Formula (Ia) can be prepared alternately from 6-amino-2,3,4,5-tetrahydro-1H-benzo[d]azepines (za) by reaction with an appropriate bromide (zb), and an appropriate base, such as sodium hydride, potassium carbonate or cesium carbonate, in a suitable solvent, typically DMF, toluene, acetonitrile and the like.
• a suitable solvent typically DMF, toluene, acetonitrile and the like.
• R 11 if needed, may be performed to provide compounds (d).
• Pg is a suitable protecting group for a secondary amine such as, but not limited to, trifluoroacetyl or tert-butoxycarbonyl.
• the appropriately substituted 6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepines (a) may be prepared as described in Scheme XI starting from 1-naphthol.
• 1-Naphthol can be converted to 5-hydroxy-1,4-dihydronaphthalene (aa) by Birch reduction using ammonia and lithium metal at low temperature. Methylation of the 6-hydroxy group affords the compound (ab).
• Ozonolysis of compound (ab) and subsequent reduction with sodium borohydride provide the diol (ac).
• 5-Methoxy-1,4-dihydronaphthalene Add powdered potassium carbonate (193.1 g, 1.397 mol) to a solution of 5-hydroxy-1,4-dihydronaphthalene [68.08 g, 90% potency based on 1 H-NMR, 0.4657 mol, from Societa Italiana Medicinala Scandicci, s.r.l., Reggello (Firenze), Italy] in ethanol (700 mL). Cool the solution to 0° C. with ice/water and add dimethyl sulfate (88.1 g, 66.1 mL, 0.699 mol) dropwise, maintaining the temperature between 5° C. and 10° C. Then heat the reaction mixture to 40° C.
• 2,3-Bis-(2-hydroxyethyl)-1-methoxybenzene Charge a four-neck 5 L flask equipped with an over-head mechanical stirrer, reflux condenser, thermocouple, and gas dispersion apparatus with 5-methoxy-1,4-dihydronaphthalene (264.54 g, 89.5% potency based on 1 H-NMR, 1.478 mol) in DCM (1.3 L) and 2B-3 ethanol (1 L). Add sudan III (10 mg) to give a faint red color. Cool the solution to ⁇ 65° C.
• 2,3-Bis-(2-methanesulfonyloxethyl)-1-methoxybenzene To a slurry of 2,3-bis-(2-hydroxyethyl)-1-methoxybenzene (50.6 g, 0.258 mol, 1 equiv.) and triethylamine (78.3 g, 0.774 mol, 3 equiv.) in DCM (500 mL) at 0° C., add dropwise a solution of methanesulfonyl chloride (65.0 g, 0.567 mol, 2.2 equiv.) in DCM (100 mL) over 45 min.
• methanesulfonyl chloride 65.0 g, 0.567 mol, 2.2 equiv.
• 6-Methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine Dissolve 2,3-bis-(2-methanesulfonyloxyethyl)-1-methoxybenzene (474.4 g, 1.346 mol) in acetonitrile (7 L) and split the mixture into two equal lots.
• acetonitrile 7 L
• two separate runs add concentrated aqueous NH 4 OH (3.5 L) and charge the solution to a pressure vessel (Parr apparatus). Heat the solution in a closed reactor to 100° C. over 20 min (internal pressure reaches about 100 psi), and maintain at 100° C. until the reaction is complete (about 1 h, HPLC monitored). Cool the reaction mixture to ambient temperature.
• 6-Methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine Hydrochloride Dissolve crude 6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (35.1 g, 0.198 mol) in 2B-3 ethanol (250 ⁇ L), heat the solution to reflux and add 2M HCl in ethanol (108.9 mL, 0.218 mol, 1.1 equiv.). Slowly add heptane (700 mL) over 10 min, then remove the heating mantle and cool the solution to ambient temperature, and finally continue the cooling with an ice/water mixture.
• 6-Methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine To a slurry of 6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (35.3 g, 0.165 mol, 1 equiv.) and triethylamine (69.1 mL, 0.496 mol, 3 equiv.) in DCM (300 mL) cooled at 0° C.
• 6-Hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine To a 1M solution of BBr 3 (1.1 L, 1.6 equiv.), cooled at 0° C. with an ice-water bath, add 6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (187 g, 0.684 mol) in DCM (200 mL) over 1 h., while maintaining the temperature between 0° C. and 10° C. Warm the reaction mixture to ambient temperature and stir until HPLC indicates completion of the reaction (about 2 h.).
• 6-(4-Acetyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine Dissolve 7-chloro-6-[4-(2-methyl-[1,3]dioxolan-2-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (150 mg, 0.32 mmol) in methanol (5 mL) and add 1N aqueous HCl (1 mL). Stir the solution at room temperature for 2 h.
• N-Di-(tert-butoxycarbonyl)-4-(3-methyl-butyryl)-benzylamine Add di-tert-butyl-iminodicarboxylate (5.2 g, 24 mmol) to a slurry of sodium hydride (60% dispersion in mineral oil, 0.7 g, 17.6 mmol) in anhydrous DMF (75 mL) and stir at room temperature under nitrogen for 5 min. Add a solution of 1-(4-bromomethyl-phenyl)-3-methyl-butan-1-one in DMF (20 mL) and stir under nitrogen for 2 h. Quench with slow addition of water (50 mL) and partition between EtOAc/water (1: 1, 500 mL). Separate and dry the organic phase over Na 2 SO 4 and concentrate in vacuo to obtain the desired intermediate (5.4 g, 85%) as a brown oily solid suitable for use without additional purification.
• the compounds of Preparations 5-10 may be prepared essentially as described in Preparation 4 by using 4-cyanophenacyl bromide and the appropriately substituted thiourea.
• iso-Butylthiourea was prepared by following the procedure described in Tetrahedron Letters, 1988, 29, 1755-1758. Overall yields and MS (ES+) data are shown in the Table below.
• N-(tert-Butoxycarbonyl)-4-(2-methylamino-oxazol-4-yl)-benzylamine Dissolve 4-(2-methylamino-oxazol-4-yl)-benzonitrile (1.6 g, 7.9 mmol) in methanol (200 mL). Add di-tert-butyl-dicarbonate (2.2 g, 10.3 mmol) and nickel(II) chloride hexahydrate (188 mg, 0.8 mmol). Cool the solution to 0° C. under a nitrogen atmosphere. Add sodium borohydride (1.5 g, 39.7 mmol) portionwise over 5 min at 0° C. under a nitrogen atmosphere.
• the compound of Preparation 13 may be prepared essentially as described in Preparation 12 using 4-bromomethyl-benzonitrile and the appropriate thiol. Overall yield and MS (ES+) data are shown in the Table below.
• 2-Chloro-5-cyclopentylthiomethyl-pyridine Slurry 2-chloro-5-chloromethyl-pyridine (8.1 g, 45 mmol) and potassium hydroxide (10.3 g, 225 mmol) in methanol at 0° C. under nitrogen atmosphere. Add cyclopentyl mercaptan (4.8 mL, 45 mmol), warm the mixture 5 to room temperature and stir for 16 h. Concentrate in vacuo and partition the residue between water (50 ⁇ L) and DCM (200 mL).
• 5-Cyclopentylthiomethyl-pyridine-2-carbonitrile Set up reaction in 3 separate flasks. To flask number 1 slurry 2-chloro-5-cyclopentylthiomethyl-pyridine (1 g, 4.4 mmol) and copper(I) cyanide (0.78 g, 8.7 mmol) in DMF (5 mL). To flask number 2 slurry 2-chloro-5-cyclopentylthiolmethyl-pyridine (1 g, 4.4 mmol) and copper(I) cyanide (0.78 g, 8.7 mmol) in DMF (5 mL).
• 2-Aminomethyl-5-cyclopentylthiomethyl-pyridine Add borane-dimethylsulfide complex (6.9 mL, 13.7 mmol, 2M solution in THF) to a solution of 5-cyclopentylthiomethyl-pyridine-2-carbonitrile (1 g, 4 mmol) in THF (12 mL) at room temperature under a nitrogen atmosphere. Stir the solution at room temperature for 16 h. Concentrate the solution in vacuo, dissolve the residue in chloroform (50 mL), add ethylenediamine (0.72 g, 12 mmol) and stir at 50° C. for 1 h. Wash the mixture with water (10 mL), dry the organic phase over Na 2 SO 4 and concentrate in vacuo.
• the compound of Preparation 15 may be prepared essentially as described in Preparation 14 using 2-chloro-5-chloromethyl-pyridine and cyclohexyl mercaptan. Overall yield and MS (ES+) data are shown in the Table below.
• 5-Bromomethyl-pyridine-2-carbonitrile Add AIBN (0.25 g, 1.5 mmol) to a slurry of 5-methyl-pyridine-2-carbonitrile (2.5 g, 21.1 mmol) and NBS (3.7 g, 21.1 mmol) in carbon tetrachloride (150 mL) at reflux under a nitrogen atmosphere. Add AIBN (3 ⁇ 0.25 g, 3 ⁇ 1.5 mmol) to the reaction in 0.25 g portions every hour for 3 h. Stir the resulting mixture for one additional hour at reflux. Cool the mixture to room temperature and wash with saturated aqueous NaHCO 3 (30 mL).
• 5-iso-Propylthiomethyl-pyridine-2-carbonitrile Add 2-propanethiol (0.53 mL, 5.6 mmol) to a slurry of 5-bromomethyl-pyridine-2-carbonitrile (1.1 g, 5.6 mmol) and cesium carbonate (1.8 g, 5.6 mmol) in DMF (10 mL) at room temperature under a nitrogen atmosphere. Stir the mixture for 16 h at room temperature. Dilute the mixture with hexane/EtOAc (1:1, 100 mL) and wash with 5% aqueous NaCl (3 ⁇ 30 mL).
• 2-Aminomethyl-5-iso-propylthiomethyl-pyridine Add borane-dimethylsulfide complex (6.5 mL, 12.9 mmol, 2M solution in THF) to a solution of 5-iso-propylthiomethyl-pyridine-2-carbonitrile (0.83 g, 4.3 mmol) in THF (12 mL) at room temperature under a nitrogen atmosphere. Stir the solution at room temperature for 16 h. Add 5N aqueous HCl (2 mL) and stir for 2 h. Concentrate in vacuo to obtain the hydrochloride salt. Elute the compound through a SCX column to obtain the free base.
• the compound of Preparation 17 may be prepared essentially as described in Preparation 16 using 5-bromomethyl-pyridine-2-carbonitrile and 2-methyl-propanethiol. Overall yield and MS (ES+) data are shown in the Table below.
• 6-[(2,2-Dimethylpropyl)thiomethyl]-pyridine-3-carbonitrile To a solution of 2,2-dimethylpropylthiol (0.782 g, 7.32 mmol) in DMF (10 mL) add potassium tert-butoxide (0.82 g, 7.32 mmol) and stir at room temperature for 10 min. Add 6-bromomethyl-pyridine-3-carbonitrile (1.2 g, 6.1 mmol) and stir the solution at room temperature for 18h. Cool the mixture, dilute with water (100 mL) and extract with EtOAc (50 mL). Dry the organic phase over MgSO 4 , filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate as a clear oil (0.5 g, 37%).
• 3,3-Dimethylcyclohexanethiol To a solution of S-(3,3-dimethylcyclohexyl)-O-ethyl dithiocarbonate (4 g, 17.2 mmol) in DCM (100 mL) add ethylenediamine (6 mL) and stir at room temperature for 18 h. Treat the solution with 2N aqueous HCl (3 ⁇ 100 mL). Dry the organic phase over MgSO 4 , filter and concentrate in vacuo, while keeping the water-bath temperature below 25° C., to obtain the desired intermediate as a colourless oil (2 g, 80%).
• 6-[(3,3-Dimethylcyclohexyl)thio]-pyridine-3-carbonitrile Add potassium tert-butoxide (777 mg, 6.94 mmol) to a solution of 3,3-dimethylcyclohexanethiol (1 g, 6.94 mmol) in DMF (10 mL) and stir at room temperature for 10 min. Add 6-chloro-nicotinonitrile (547 mg, 3.96 mmol) and warm the solution to 60° C. for 18 h. Cool the mixture, dilute with water (100 mL) and extract with EtOAc (50 mL). Dry the organic phase over MgSO 4 , filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate as a clear oil that solidifies on standing to a white solid (0.37 g, 38%).
• 6-Bromomethyl-pyridine-3-carbonitrile Dissolve 6-methyl-nicotinonitrile (2 g, 17 mmol) and NBS (3.01 g, 17 mmol) in anhydrous DCE (56 mL) under nitrogen. Add AIBN (277 mg, 1.7 mmol) and heat the mixture at 80° C. for 1.5-2 h. Add another batch of AIBN (277 mg, 1.7 mmol) and heat the mixture at 80° C. for a further 1-2 h. Then add a third batch of AIBN (277 mg, 1.7 mmol) and heat the mixture at 80° C. for a further 1-2 h. Cool the reaction to room temperature and concentrate in vacuo.
• 6-(tert-Butylthio)methyl-pyridine-3-carbonitrile Dissolve 6-bromomethyl-pyridine-3-carbonitrile (6.2 g, 31.4 mmol) in anhydrous DMF (60 mL) under nitrogen. Add tert-butylthiol (5.32 mL, 47.2 mmol) followed by cesium carbonate (15.3 g, 47.2 mmol) and stir the resulting suspension overnight. Dissolve the reaction mixture in DCM (200 mL) and add water (200 mL). Extract the aqueous phase with DCM (2 ⁇ 200 mL) and dry the combined organic extracts over MgSO 4 . Filter, add silica gel and concentrate the mixture in vacuo.
• 6-Cyclohexyloxy-pyridine-3-carbonitrile Add sodium bis(trimethylsilyl)amide (3.9 mL, 7.93 mmol, 2M solution in THF) to a solution of cyclohexanol (824 ⁇ L, 7.93 mmol) in THF (10 mL). Stir for 30 min at room temperature and then add a solution of 6-chloro-nicotinonitrile (1 g, 7.2 mmol) in anhydrous THF (5 mL). Stir at room temperature overnight and then quench the reaction by addition of saturated aqueous NaHCO 3 (100 mL) and extract the aqueous phase with DCM (3 ⁇ 100 mL). Wash the combined organic extracts with brine (100 mL), dry over MgSO 4 and concentrate in vacuo to obtain the desired intermediate as a yellow solid (1.04 g, 71%).
• 3-Aminomethyl-6-cyclohexyloxy-pyridine Dissolve 6-cyclohexyloxy-pyridine-3-carbonitrile (1 g, 5 mmol) in anhydrous THF (7 mL) under nitrogen and cool the mixture at 0° C. Add borane-THE complex (15 mL, 15 mmol, 1M solution in THF) and stir the reaction mixture at room temperature overnight. Pour slowly the reaction mixture into an ice-cold 5N aqueous HCl (50 mL) and stir the resulting solution for 4 h.
• the compound of Preparation 26 may be prepared essentially as described in Preparation 25 using 6-chloro-nicotinonitrile and 4,4-dimethyl-cyclohexanol. Overall yield and MS (ES+) data are shown in the Table below.
• 6-(3,3-Dimethyl-cyclohexyloxy)-pyridine-3-carbonitrile Dissolve 3,3-dimethylcyclohexanol (6 g, 47 mmoles) in anhydrous THF (70 mL) under nitrogen atmosphere and cool at ⁇ 78° C. Add sodium bis(trimethylsilyl)amide (23.4 mL, 47 mmol, 2M solution in THF) to this solution and stir at ⁇ 78° C. for 30 min before raising to room temperature. Cool down again to ⁇ 78° C. and add a solution of 2-chloro-5-cyanopyridine (7.1 g, 51.7 mmoles) in anhydrous THF (20 mL) and stir overnight while warming to room temperature.
• 6-(iso-Propoxy)methyl-pyridine-3-carbonitrile Add iso-propanol (2.2 g, 25 mmol) and tetrabutylammonium sulfate (28 mg, 0.08 mmol) to a solution of potassium hydroxide (7.1 g, 127 mmol) in water (7 mL) and stir at room temperature for 15 min. Add 6-bromomethyl-pyridine-3-carbonitrile (1 g, 5.08 mmol) and stir the mixture for 24 h at room temperature. Add water (15 mL) and extract with DCM (15 mL). Filter through an IST® phase separator frit to separate the organic phase and concentrate in vacuo.
• 3-Aminomethyl-6-(iso-propoxy)methyl-pyridine Add a solution of borane-THF complex (4.5 mL, 4.54 mmol, 1M solution in THF) to neat 6-(iso-propoxy)methyl-pyridine-3-carbonitrile (0.4 g, 2.27 mmol) and stir the mixture for 16 h at reflux. Cool to room temperature and stir for 48 h. Add 2N aqueous HCl (10 mL) until gas evolution stops and 10 then concentrate in vacuo. Dissolve the crude mixture in methanol and filter through a SCX-2 column eluting with methanol followed by 3N ammonia in methanol to obtain the title compound (190 mg, 46%).
• 6-Chloro-3-cyclohexyloxy-pyridine Under a nitrogen atmosphere add 6-chloro-pyridin-3-ol (2.5 g, 19.3 mmol), cyclohexanol (1.93 g, 19.3 mmol), tri-n-butylphosphine (5.07 g, 25.1 mmol), and ADDP (6.32 g, 25.1 mmol) to benzene (100 mL) and THF (10 mL) at 0° C. Stir the mixture at 0° C. for 1 h and at room temperature for 12 h. Dilute with EtOAc and water. Separate the layers and extract the aqueous layer with EtOAc.
• 6-Chloro-3-cycloheptyloxy-pyridine Add 6-chloro-pyridin-3-ol (2 g, 15.4 mmol), cycloheptanol (1.93 g, 17 mmol), tri-n-butylphosphine (4.67 mL, 19.3 mmol), and ADDP (4.87 g, 19.3 mmol) to THF (60 mL) at 0° C. under a nitrogen atmosphere. Stir the mixture at 0° C. for 1 h and at room temperature for 12 h. Dilute with EtOAc (50 mL), add water (50 mL) and separate the layers. Extract the aqueous layer with EtOAc (4 ⁇ 30 mL).
• 5-Cycloheptyloxy-pyridine-2-carbonitrile Add 6-chloro-3-cycloheptyloxy-pyridine (2.35 g, 10.4 mmol) and copper(I) cyanide (1.16 g, 13.1 mmol) to NMP (25 mL). Heat the mixture to 190° C. and stir overnight. Cool the mixture to room temperature, add water (50 mL) and diethyl ether (30 mL). Extract the aqueous phase with diethyl ether (3 ⁇ 25 mL). Wash the combined organic extracts with brine (20 mL), dry over Na 2 SO 4 , filter, and concentrate in vacuo.
• 2-Aminomethyl-5-cycloheptyloxy-pyridine Dissolve 2-(tert-butoxycarbonylamino-methyl)-5-cycloheptyloxy-pyridine (1.9 g, 5.95 mmol) in methanol (25 mL) and cool to 0° C. Bubble hydrogen chloride through the vigorously stirred solution for 30 min. Evaporate in vacuo and partition the residue between 3N aqueous NaOH (10 mL) and DCM (20 mL). Separate the two layers and extract the aqueous layer with DCM (2 ⁇ 20 mL).
• 3,3-Dimethylcyclohexyl 4-methylbenzenesulfonate Under a nitrogen atmosphere, add 3,3-dimethylcyclohexanol (1 g, 9.75 mmol), DMAP (238 mg, 1.95 mmol), triethylamine (2.70 mL, 19.5 mmol), and p-toluenesulfonyl chloride (2.045 g, 10.72 mmol) to DCM (25 mL) at 0° C. Stir the mixture for 1 h at 0° C. and warm to room temperature overnight. Add saturated aqueous NaHCO 3 (20 mL) and separate the layers. Extract the aqueous layer with DCM (3 ⁇ 20 mL).
• 6-Chloro-3-(3,3-dimethylcyclohexyloxy)-pyridine Under a nitrogen atmosphere, add 3,3-dimethylcyclohexyl 4-methylbenzenesulfonate (1.2 g, 4.25 mmol), 6-chloro-pyridin-3-ol (0.5 g, 3.86 mmol) and potassium hydroxide (238 mg, 4.25 mmol) to DMF (10 mL). Heat the mixture to 60° C. and stir overnight. Add water (20 mL) and diethyl ether (20 mL) and separate the layers. Extract the aqueous layer with diethyl ether (3 ⁇ 20 mL).
• N-(tert-Butoxycarbonyl)-4-bromo-benzylamine Slurry 4-bromo-benzylamine hydrochloride (25 g, 112.6 mmol)-in DCM (400 mL). Add triethylamine (31.4 mL, 225.2 mmol) and di-tert-butyl-dicarbonate (24.55 g, 112.6 mmol) and stir the solution at room temperature for 16 h under a nitrogen atmosphere. Wash the mixture with water, dry the organic-phase over Na 2 SO 4 and concentrate in vacuo to obtain a solid. Wash the solid with hexane, filter and dry to obtain the desired intermediate as a white solid (31.735 g, 99%) suitable for use without further purification. MS (ES+) m/z: 230 [M-(t-Bu)+H] + .
• N-(tert-Butoxycarbonyl)-4-cyclohexylethynyl-benzylamine Add cyclohexylacetylene (1.1 mL, 8.4 mmol) to a slurry of N-(tert-butoxycarbonyl)-4-bromo-benzylamine (2 g, 6.9 mmol), dichlorobis(triphenylphosphine)palladium (147 mg, 0.2 mmol), copper(I) iodide (67 mg, 0.4 mmol) and triethylamine (1.4 mL, 9.7 mmol) in DMF (7 mL). Stir the reaction in a sealed flask at 110° C. for 16 h.
• (E)-2-Aminomethyl-5-(2-cyclohexylvinyl)-pyridine Cool a stirred solution of (E)-5-(2-cyclohexylvinyl)-pyridine-2-carbonitrile (1.76 g, 8.3 mmol) in THF (55 mL) to 0° C. under nitrogen. Carefully add lithium aluminum-hydride (1.26 g, 33.2 mmol) and warm to room temperature overnight. Quench the reaction mixture with sequential addition of water (1.26 mL), 15% aqueous NaOH (1.26 mL) and water (3 ⁇ 1.26 mL), and stir for 3 h. Filter the mixture through Celite®, wash with EtOAc, and concentrate in vacuo.
• 3-(tert-Butoxycarbonylamino-methyl)-6-cyclohexylethynyl-pyridine Under a nitrogen atmosphere, add 3-(tert-butoxycarbonylamino-methyl)-6-chloropyridine (1 g, 4.12 mmol), cyclohexylacetylene (0.446 g, 4.12 mmol), dichlorobis(triphenylphosphine)-palladium (578 mg, 0.824 mmol), copper(I) iodide (157 mg, 0.824 mmol) and triethylamine (8.6 mL, 6.18 mmol) to THF (20 mL). Heat the mixture to reflux overnight.
• 5-Cyclohexylethynyl-pyridine-2-carbonitrile Under a nitrogen atmosphere, add 5-bromo-2-cyano-pyridine (1.5 g, 8.2 mmol), cyclohexylacetylene (0.887 g, 8.2 mmol), dichlorobis(triphenylphosphine)palladium (575 mg, 0.82 mmol), copper(I) iodide (234 mg, 1.23 mmol) and triethylamine (11.4 mL, 82 mmol) to THF (50 mL). Heat the mixture to reflux and stir for 4 h.
• 4-(2-Cyclohexyl-2-oxo-ethyl)-benzonitrile Add 4-iodobenzonitrile (1.0 g, 4.37 mmol) and 1-cyclohexyl-ethanone (717 mg, 5.68 mmol) to a suspension of tris(dibenzylideneacetone)dipalladium(0) (60 mg, 0.065 mmol), BINAP (98 mg, 0.157 mmol) and sodium tert-butoxide (546 mg, 5.68 mmol) in anhydrous THF (26 mL). Heat the mixture at 70° C. under nitrogen atmosphere.
• 4-(Piperidin-1-ylmethyl)-benzylamine Add 4-(piperidin-1-ylmethyl)-benzonitrile (890 mg, 4.45 mmol), 2M hydrogen chloride in ether (8.9 mL, 17.8 mmol) and 10% Pd/C (90 mg) to methanol (100 mL) in a pressure vessel. Flush the vessel three times with hydrogen and charge to 50 psi with hydrogen. Stir at room temperature for 2 h. Filter the catalyst through Celite® and concentrate the filtrate in vacuo.
• the compound of Preparation 45 may be prepared essentially as described in Preparation 44 by using 4-cyanobenzaldehyde and ( ⁇ )-1-methyl-2,2,2-trifluoro-ethylamine. MS (ES+) data is shown in the Table below.
• (R)-1-Methyl-2,2,2-trifluoro-ethylamine Hydrochloride Dilute the first half (1230 g) of the above reaction mixture with heptane (1500 mL) and DCM (1500 mL). Add 5N aqueous HCl (1250 mL) to the solution mixture and stir for 30 min until only acetophenone is present in the organic phase. Wash the bottom aqueous phase with 1:1 heptane/DCM (2 ⁇ 500 mL) and then cool the aqueous phase in an ice bath. Add ice-cold DCM (1500 mL) and then cold 5N aqueous NaOH (1250 mL) dropwise to the biphasic mixture and stir for 15 min.
• the compound of Preparation 48 may be prepared essentially as described in Preparation 47 by using 4-cyanobenzaldehyde and homopiperidine. Overall yield and MS (ES+) data are shown in the Table below.
• 6-Chloro-3-(cyclohexylamino-methyl)-pyridine Under a nitrogen atmosphere, add sodium cyanoborohydride (3.53 g, 56 mmol) to a solution of 3-aminomethyl-6-chloro-pyridine (2 g, 14 mmol), cyclohexanone (1.38 g, 14 mmol) and acetic acid (168 mg, 0.2 mmol) in methanol (20 mL) at 0° C. Warm the mixture to room temperature and stir overnight. Add water (100 mL) and saturated aqueous K 2 CO 3 . Extract three times with DCM and wash the combined organic extracts with water and brine. Dry over Na 2 SO 4 , filter, and concentrate in vacuo.
• 6-Chloro-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-pyridine Add trifluoroacetic anhydride (4 g, 19.1 mmol) to 6-chloro-3-(cyclohexylamino-methyl)-pyridine (2.86 g, 12.7 mmol) and triethylamine (2.66 mL, 19.1 mmol) in DCM (20 mL) at 0° C. Warm to room temperature and stir for 12 h. Concentrate in vacuo and dilute with water and EtOAc. Separate the layers and extract the aqueous layer with EtOAc. Wash the combined organic extracts with water and brine.
• 6-Cyano-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-pyridine Under a nitrogen atmosphere add 6-chloro-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-pyridine (3.7 g, 11.5 mmol), zinc cyanide (2.02 g, 17.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.48 g, 0.57 mmol) and DPPF (0.63 g, 1.15 mmol) to DMF (40 mL). Heat the mixture at 95° C. for 2 h.
• 6-Aminomethyl-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-pyridine add 6-cyano-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-pyridine (1.5 g, 4.8 mmol), 2M hydrogen chloride in ether (7.2 mL, 14.4 mmol) and 10% Pd/C (0.3 g) to methanol (30 mL) in a pressure vessel. Flush the vessel three times with hydrogen and charge to 50 psi with hydrogen. Stir at room temperature for 4 h.
• 3-(tert-Butoxycarbonylamino-methyl)-6-cyano-pyridine Under a nitrogen atmosphere, add 3-(tert-butoxycarbonylamino-methyl)-6-chloropyridine (13.1 g, 54 mmol), zinc cyanide (9.5 g, 81 mmol), tris(dibenzylideneacetone)dipalladium(0) (494 mg, 0.54 mmol), and dppf (550 mg, 0.81 mmol) to DMF (130 mL). Heat the mixture at 70° C. overnight.
• 3-(tert-Butoxycarbonylamino-methyl)-6-hydrox methyl-pyridine Add 3-(tert-butoxycarbonylamino-methyl)-6-cyano-pyridine (10.81 g, 46.4 mmol), KHSO 4 (18.9 g, 16.2 mmol), 5% Pd/C (Degussa type E101, 4 g) to a mixture of methanol (250 mL) and water (20 mL) in a pressure vessel. Flush the vessel three times with hydrogen and charge with hydrogen to 50 psi. Stir at room temperature, recharging to 50 psi hydrogen as necessary, until no change in pressure is observed.
• 3-(tert-Butoxycarbonylamino-methyl)-6-chloromethyl-pyridine Add 3-(tert-butoxycarbonylamino-methyl)-6-hydroxymethyl-pyridine (2.3 g, 9.65 mmol) and triethylamine (2.05 mL, 14.5 mmol) to DCM (30 mL). Cool the mixture to 0° C. and add methanesulfonyl chloride (0.83 mL, 10.6 mmol) to the mixture. Allow the mixture to warm to room temperature and stir overnight. Dilute the mixture with water (10 mL) and saturated aqueous NaHCO 3 (10 mL). Separate the layers, and extract the aqueous layer with DCM (3 ⁇ 20 mL).
• N-(tert-Butoxycarbonyl)-4-(2,2-dimethyl-propionylamino)-benzylamine Add a solution of 4-(2,2-dimethyl-propionylamino)-benzonitrile (5 g, 24.7 mmol) in THF/iso-propanol (1:2, 60 mL) to 10% Pd/C (Degussa type E101, 3 g, 1.41 mmol) via cannula under nitrogen.
• Add a solution of di-tert-butyl-dicarbonate (6.74 g, 30.9 mmol) in THF (19 mL) to the reaction mixture via cannula under nitrogen. Purge the reaction mixture with nitrogen and then submit to hydrogenation at 50 psi overnight.
• 4-(2,2-Dimethyl-propionylamino)-benzylamine Add 4M hydrogen chloride in dioxane (20 mL) to a solution of N-(tert-butoxycarbonyl)-4-(2,2-dimethyl-propionylamino)-benzylamine (2 g, 6.53 mmol) in anhydrous 1,4-dioxane (50 mL) at room temperature. Stir overnight and partition the reaction mixture between saturated aqueous NaHCO 3 (200 mL) and DCM (500 mL).
• Preparations 57-58 may be prepared essentially as described in Preparation 56 using 4-aminobenzonitrile and the appropriate acid chloride. Overall yields and MS (ES+) data are shown in the Table below. Step 1 of Preparation 58 was purified by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 67:33 gradient over 71 min and 67:33 to 0:1 gradient over 71 min; 50 mL/min).
• N-(tert-Butoxycarbonyl)-4-[(2,2,3,3-tetramethyl-cyclopropanecarbonyl)-amino]-benzylamine Add a solution of di-tert-butyl-dicarbonate (1.8 g, 82.6 mmol) in methanol (7 mL) and nickel(II) chloride hexahydrate (0.098 g, 0.41 mmol) to a cooled solution of 4-[(2,2,3,3-tetramethyl-cyclopropanecarbonyl)-amino]-benzonitrile (1 g, 41.3 mmol) in methanol (30 mL) at 0° C.
• 4-(N-Methyl-2,2-dimethyl-propionylamino)-benzylamine Add a solution of 4-(N-methyl-2,2-dimethyl-propionylamino)-benzonitrile (55 mg, 0.25 mmol) in THF/iso-propanol (1:1, 8 mL) to 10% Pd/C (Degussa type E101, 31 mg, 0.15 mmol) under nitrogen. Purge the reaction mixture with nitrogen and then submit to hydrogenation at 50 psi for 1 h. Filter the catalyst through Celite® and wash thoroughly with THF (100 mL) and iso-propanol (100 mL).
• 4-(tert-Butoxycarbonylamino)-benzylamine Add a solution of 4-(tert-butoxycarbonylamino)-benzonitrile (1 g, 4.58 mmol) in THF/iso-propanol (1:1, 142 mL) to 10% Pd/C (Degussa type E101, 0.56 g, 0.26 mmol) via syringe under N 2 . Purge the reaction mixture with nitrogen and submit the mixture to hydrogenation at 50 psi overnight. Filter the catalyst through Celite® and wash thoroughly with iso-propanol (100 mL) and THF (100 mL).
• 6-(4-tert-Butoxycarbonylamino-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine Use a method similar to the General Procedure 1-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.32 g, 0.76 mmol) with a solution of 4-(tert-butoxycarbonylamino)-benzylamine (0.338 g, 1.524 mmol) in anhydrous toluene/dioxane (4:1, 10 mL).
• 6-(4-Amino-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine Hydrochloride Add 4M hydrogen chloride in dioxane (20 mL, 20 mmol) to a solution of 6-(4-tert-butoxycarbonylamino-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine (0.219, 0.44 mmol) in 1,4-dioxane/DCM (1:1, 40 mL). Stir overnight at room temperature, add diethyl ether and concentrate in vacuo to obtain the title compound (0.219 g, 100%) that was dried in vacuo.
• N-(tert-Butoxycarbonyl)-4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamine Add cyclopropane carbonyl chloride (0.3 mL, 3.3 mmol) to a stirred solution of ethyldiisopropylamine (1.35 mL, 7.73 mmol) and 4-(tert-butoxycarbonyl-aminomethyl)-benzylamine (0.6 g, 2.54 mmol) in DCM (12 mL). Stir the mixture for 1 h at room temperature. Partition the mixture between DCM and water. Extract the aqueous phase twice with DCM. Dry the combined organic extracts over MgSO 4 , filter and concentrate in vacuo.
• [4-(tert-Butoxycarbonylaminomethyl)-phenyl]-acetic acid Add NaOH (0.992 g, 24.8 mmol) and di-tert-butyl-dicarbonate (5.4 g, 24.8 mmol) to a solution of (4-aminomethyl-phenyl)-acetic acid hydrochloride (5.0 g, 24.8 mmol) in dioxane/water (1:1, 40 mL) and stir for 24 h. Remove dioxane in vacuo and acidify the aqueous phase with 10% aqueous citric acid. Extract twice with EtOAc, dry the combined organic extracts over Na 2 SO 4 , filter and concentrate in vacuo to obtain a solid. Wash the solid with hexane, filter and dry to obtain the desired intermediate (3.3 g, 50%).
• N-(tert-Butoxycarbonyl)-4-(iso-propylcarbamoyl-methyl)-benzylamine Combine [4-(tert-butoxycarbonylaminomethyl)-phenyl]-acetic acid (400 mg, 1.5 mmol), isopropylamine (0.14 mL, 1.65 mmol), EDC (345 mg, 1.8 mmol), HOBt (243 mg, 1.8 mmol), triethylamine (0.63 mL, 4.5 mmol) and DMAP (18.3 mg, 0.15 mmol) in anhydrous DCM (15 mL). Stir at room temperature for 1 day under nitrogen.
• the compound of Preparation 67 may be prepared essentially as described in Preparation 66 by using [4-(tert-butoxycarbonylaminomethyl)-phenyl]-acetic acid and 2,2-dimethyl-propylamine. Overall yield and MS (ES) data are shown in the Table below.
• N-(tert-Butoxycarbonyl)-4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-benzylamine Combine 4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-benzonitrile (200 mg, 0.93 mmol), di-tert-butyl-dicarbonate (244 mg, 1.1 mmol) and 10% Pd/C (Degussa type E101, 100 mg) in methanol (18 mL). Submit the mixture to hydrogenation at atmospheric pressure for 40 h. Filter the catalyst through Celite® and concentrate the filtrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:1) to obtain the desired intermediate as a white solid (267 mg, 90%).
• the compound of Preparation 71 may be prepared essentially as described in Preparation 70 using methyl (4-cyanophenyl)acetate and cyclohexylmethyl amine. Overall yield and MS (ES+) data are shown in the Table below.
• 3-Aminomethyl-6-[(2-methyl-2-propane)sulfonylmethyl]-pyridine Add a solution of 1-hydroxy-6-[(2-methyl-2-propane)sulfonylmethyl]-pyridine-3-carbonitrile (150 mg, 0.59 mmol) in ethanol (12 mL) to an aqueous slurry of Raney Ni (50%, 1 g). Submit the suspension to hydrogenation at 60 psi for 10 h and then filtrate the mixture through Celite® to provide an inseparable mixture of the title compound and the corresponding N-oxide.
• 2,2-Dimethyl-propane-1-thiol Add sulfur (3.05 g, 95 mmol) and ether (60 mL) to 2,2-dimethylpropylmagnesium chloride (95 mL, 95 mmol, 1M solution in diethyl ether) under nitrogen at 0° C. Warm the mixture to room temperature and stir for 2 h. Cool to 0° C. and add 1N aqueous HCl (120 mL). Extract into diethyl ether ( ⁇ 100 mL) by continuous extraction. Distill diethyl ether through a 22 cm long Vigreux column by heating with an oil bath (50-120° C.) under nitrogen. Cool and remove the Vigreux column and install a short path distillation head. Distill the product (60-100° C.) with the oil bath at ⁇ 140° C. to obtain the desired intermediate (8.5 g, 86%).
• 3-(tert-Butoxycarbonylamino-methyl)-6-[(2,2-dimethylpropyl)thiomethyl]-pyridine Under a nitrogen atmosphere, add sodium methoxide (630 mg, 3.51 mmol, 30% w/w in methanol) to a stirring mixture of 2,2-dimethyl-propane-1-thiol (365 mg, 3.51 mmol) and methanol (10 mL) at room temperature and stir for 30 min. Add 3-(tert-butoxycarbonylamino-methyl)-6-chloromethyl-pyridine (450 mg, 1.76 mmol) in methanol (5 mL) and stir the mixture for 2 h. Dilute the mixture with water and ethyl acetate.
• 3-(tert-Butoxycarbonylamino-methyl)-6-[(2,2-dimethyl-propane)-sulfonylmethyl]-pyridine Add m-CPBA (977 mg, 4.36 mmol, 70-77% pure) to a solution of 3-(tert-butoxycarbonylamino-methyl)-6-[(2,2-dimethylpropyl)thiomethyl]-pyridine (700 mg, 2.16 mmol) in DCM (20 mL) at 0° C. Warm the mixture to room temperature and stir overnight. Dilute the mixture with 10% aqueous K 2 CO 3 (30 mL) and DCM. Separate the layers and extract the aqueous phase with DCM. Wash the combined organic extracts with water and brine.
• 3-Aminomethyl-6-[(2,2-dimethyl-propane)sulfonylmethyl]-pyridine Bubble hydrogen chloride into a mixture of 3-(tert-butoxycarbonylamino-methyl)-6-[(2,2-dimethyl-propane)sulfonylmethyl]-pyridine (480 mg, 1.35 mmol), methanol (10 mL) and EtOAc (10 mL) at room temperature until saturated. After stirring for 1 h, concentrate the mixture in vacuo.
• the compound of Preparation 78 may be prepared essentially as described in Preparation 77 by using 3-(tert-butoxycarbonylamino-methyl)-6-chloromethyl-pyridine and cyclohexanethiol. Overall yield and MS (ES) data are shown in the Table below.
• 4-Dimethylthiocarbamoyloxy-benzonitrile Add sodium hydride (1.21 g, 95%) to a solution of 4-cyanophenol (5.71 g, 47.98 mmol) in anhydrous THF (70 mL) and stir the mixture for 5 min. Add dimethylthiocarbamoyl chloride (5.93 g, 47.98 mmol) and heat the mixture at reflux for 3 h. Cool the mixture to room temperature and add water. Extract the aqueous phase with EtOAc, dry the organic phase over MgSO 4 , filter and concentrate in vacuo to obtain a solid. Wash the solid with diethyl ether, filter and dry in vacuo to obtain the desired intermediate as a solid (4.41 g, 75%).
• 4-Dimethylcarbamoylthio-benzonitrile Place 4-dimethylthiocarbamoyloxy-benzonitrile (8.3 g, 40.29 mmol) into a sealed tube equipped with a magnetic stirrer. Immerse the tube in a preheated oil bath at 210° C. and stir at this temperature for 2 h. Cool to room temperature, dissolve the content in DCM and transfer the solution to a round bottom flask. Concentrate in vacuo to obtain a solid. Wash the solid with hexane and then with cold diethyl ether. Filter and dry in vacuo to obtain the desired intermediate as a beige solid (7.5 g, 90%).
• 4-Dimethylcarbamoylthio-benzylamine Dissolve 4-dimethylcarbamoylthio-benzonitrile (3.07 g, 14.9 mmol) in anhydrous THF (30 mL). Add borane-dimethylsulfide complex (4.24 mL, 44.7 mmol, 1M solution in diethyl ether) and stir the mixture at room temperature for 3 h. Add methanol dropwise until hydrogen evolution ceases. Concentrate the mixture in vacuo and purify the crude mixture by SCX chromatography eluting with methanol and 2M ammonia in methanol to obtain the title compound as a slightly impure oil (2.9 g).
• 6-(3,3-Dimethyl-2-oxo-butoxy)-pyridine-3-carbonitrile Dissolve sodium hydride (380 mg, 9.5 mmol) in anhydrous DMF (7 mL). Cool at 0° C., add dropwise 1-hydroxy-3,3-dimethylbutan-2-one (1.1 g, 9.5 mmol) and stir at this temperature for 30 min. Add a solution of 6-bromo-nicotinonitrile in DMF (7 mL) and heat at 70° C. overnight. Cool the reaction mixture with ice/water and work-up sequentially with EtOAc and water. Dry the organic fraction over MgSO 4 , filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate (424 mg, 50%). MS (ES+) 7/z: 219 (M+H) + .
• 6-Methoxycarbonylmethoxy-pyridine-3-carbonitrile Dissolve sodium hydride (380 mg, 9.5 mmol) in anhydrous DMF (7 mL). Cool at 0° C., add dropwise methyl 2-hydroxyacetate (0.7 mL, 9.5 mmol) and stir at this temperature for 30 min. Add a solution of 6-bromo-nicotinonitrile in DMF (7 mL) and heat at 70° C. overnight. Cool the reaction mixture with ice/water and work-up sequentially with EtOAc and water. Dry the organic phase over MgSO 4 , filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate (461 mg, 63%). MS (ES+) m/z: 193 (M+H) + .
• 6-[(2,2-Dimethyl-propylcarbamoyl)-methoxy]-pyridine-3-carbonitrile Dissolve under nitrogen 2,2-dimethylpropylamine (1.7 mL, 14.1 mmol) in anhydrous THF (10 mL). Cool the solution at 0° C. and add DIBAL-H (13.6 mL, 13.6 mmol, 1M solution in toluene). 2.5 Allow the mixture to warm up to room temperature and stir for 1 h. Add this complex to a solution of 6-methoxycarbonylmethoxy-pyridine-3-carbonitrile (461 mg, 2.4 mmol) in THF (10 mL) and stir at room temperature overnight.
• the compound of Preparation 89 may be prepared essentially as described in Preparation 4 by using 4-cyanophenacyl bromide and benzylthiourea. Overall yield and MS (ES+) data are shown in the Table below.
• 2,2,2-Trifluoroethyl-thiourea Slurry 1-benzoyl-3-(2,2,2-trifluoroethyl)-thiourea (5.5 g, 21.2 mmol) and potassium carbonate (11.7 g, 84.7 mmol) in methanol (180 mL) and water (40 mL). Stir the mixture at room temperature for 16 h. Concentrate the solution in vacuo to a paste. Triturate with hot water (20 mL, 60° C.), filter off the solids, wash with water (20 mL, 25° C.) and hexane (excess). Collect the solids, slurry in EtOAc and concentrate in vacuo twice to remove residual water. Dry the material in a vacuum oven at 45° C. for 16 h to obtain the desired intermediate as an off-white solid (2.2 g, 66%). MS (ES+) m/z: 159.1 (M+H) + .
• (R)-4-[2-(1-Methyl-2,2,2-trifluoroethylamino)-thiazol-4-yl]-benzylamine Add a solution of 1 M lithium aluminum hydride in THF (12 mL, 12 mmol) dropwise to an ice-cooled solution of (R)-4-[2-(1-methyl-2,2,2-trifluoroethylamino)-thiazol-4-yl]-benzonitrile in anhydrous THF (10 mL). Heat to reflux for 1 h, cool to room temperature, quench by slow addition of water (12 mL), ether (50 mL), 1N NaOH (12 mL) and additional water (36 mL).
• the compound of Preparation 93 may be prepared essentially as described in Preparation 92 by using (S)-1-methyl-2,2,2-trifluoroethylamine hydrochloride. Overall yield and MS (ES+) data are shown in the Table below.
• Cyclopropylmethyl-thiourea Add 1-benzoyl-3-cyclopropylmethyl-thiourea (718 g, 3.06 mol) to methanol (6 L) and heat gently to dissolve. Add a solution of potassium carbonate (1.70 kg, 12.3 mol) in water (2 L) and stir overnight at room temperature. Filter any solids that form and concentrate the filtrate in vacuo until 10% of the volume. Dilute the residue with water (2 L) and EtOAc ( ⁇ 3.5 L) and extract the aqueous phase with EtOAc (4 ⁇ 2.5 L). Wash the combined organic extracts with aqueous 1N NaOH (2 ⁇ 1 L) and brine (2 L). Dry the organic layer over Na 2 SO 4 , filter, and concentrate in vacuo.
• 2-Bromo-5-(2-bromo-acetyl)-pyridine Add pyridinium tribromide (7.0 g, 22 mmol) to a solution of 5-acetyl-2-bromo-pyridine (4.0 g, 20 mmol) in THF (100 mL) at room temperature. Stir the mixture for 16 h at room temperature under a nitrogen atmosphere. Quench the mixture with saturated aqueous NaHCO 3 (50 mL, pH to 7.8). Extract the mixture with EtOAc (150 mL). Wash the organic layer with brine (50 mL) and concentrate in vacuo to obtain the desired intermediate as a dark brown oil (11.5 g) that was used without further purification. MS (ES+) m/z: 280 (M+H) + .
• 6-Bromo-3-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine Slurry crude 2-bromo-5-(2-bromo-acetyl)-pyridine (11.5 g, ca. 48%), cyclopropylmethyl-thiourea (2.2 g, 16.9 mmol) and sodium bicarbonate (1.7 g, 20 mmol) in ethanol (100 mL) at room temperature. Stir the mixture at reflux for 1 h under a nitrogen atmosphere. Turn off heat and stir the mixture for 16 h at room temperature. Filter the slurry, then wash the solids with ethanol (50 mL), water (2 ⁇ 50 mL) and hexane (excess). Dry the solid in a vacuum oven for 20 h at 50° C. to obtain the desired intermediate as a tan solid (3.2 g, 61% over 2 steps). MS (ES+) m/z: 312 (M+2) + .
• 2-Aminomethyl-5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine Add lithium aluminum hydride (75 mg, 2.0 mmol) portionwise over 1 minute to a solution of 5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine-2-carbonitrile (340 mg, 1.3 mmol) in THF (20 mL) at room temperature under a nitrogen atmosphere. Stir the mixture for 10 min at room temperature. Quench the mixture successively with water (0.1 mL) and 1N NaOH (0.1 mL). Add sodium sulfate to absorb residual water, filter through Celite®, wash with DCM (30 mL) and concentrate in vacuo.
• 6-(1-Ethoxy-vinyl)-nicotinonitrile Slurry 6-bromo-nicotinonitrile (8.0 g, 43.7 mmol), 1-ethoxyvinyl-tributylstannane (17.4 g, 48 mmol), and dichlorobis(triphenylphosphine)-palladium (1.5 g, 2.2 mmol) in acetonitrile (680 mL) at room temperature. Stir the mixture at reflux for 16 h under a nitrogen atmosphere. Cool the mixture to room 5 temperature, add aqueous saturated potassium fluoride (100 mL), stir 30 min then filter and wash with EtOAc (200 mL). Wash the organic phase with water (250 mL). Dry the organic layer over Na 2 SO 4 , filter and concentrate in vacuo to obtain the desired intermediate (14.5 g) that was used without further purification. MS (ES+) m/z: 175 (M+H) + .
• 6-Acetyl-nicotinonitrile Dissolve crude 6-(1-ethoxy-vinyl)-nicotinonitrile (14.5 g, ca. 80%) in THF (120 mL) and 2.5 N hydrochloric acid (40 mL). Stir the solution for 16 h at room temperature. Quench the reaction with saturated aqueous NaHCO 3 (pH to 7.5). Extract the mixture with EtOAc (200 mL). Dry the organic layer over Na 2 SO 4 , filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (120 g) eluting with hexane/EtOAc (9:1 to 3:1 gradient) to obtain the desired intermediate (4.2 g, 65%).
• 6-(2-Bromo-acetyl)-nicotinonitrile Add pyridinium tribromide (9.2 g, 28.7 mmol) to a solution of 6-acetyl-nicotinonitrile (4.2 g, 28.7 mmol) in THF (200 mL) at room temperature. Filter off the solids and wash with minimal THF. Recrystallize the solid from EtOAc/hexane to obtain the desired intermediate as a light orange solid (5.2 g, 80%) that was used without further purification. MS (ES ⁇ ) m/z: 223 (M ⁇ H) ⁇ .
• 6-[2-(Cyclopropylmethylamino)-thiazol-4-yl]-nicotinonitrile Slurry crude 6-(2-bromo-acetyl)-nicotinonitrile (5.2 g), cyclopropylmethyl-thiourea (2.7 g, 20.8 mmol) and sodium bicarbonate (1.95 g, 23.1 mmol) in ethanol (135 mL) at room temperature. Stir the mixture at reflux for 1 h under a nitrogen atmosphere. Cool the mixture to room temperature and concentrate in vacuo to a solid. Recrystallize from ethanol (20 mL) and water (100 mL) at 5° C. to obtain the desired intermediate as a tan solid (4.8 g, 81%). MS (ES+) m/z: 257 (M+H) + .
• 3-Aminomethyl-6-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine Add 6-[2-(cyclopropylmethylamino)-thiazol-4-yl]-nicotinonitrile (2.0 g, 7.8 mmol), Raney Nickel (2.0 mL), and 2M ammonia in methanol (200 mL) to a pressure vessel under a nitrogen atmosphere. Pressurize the vessel to 60 psi with hydrogen, and stir the mixture for 6 h at 40° C. Filter the mixture through Celite® and concentrate in vacuo to an oil. Dissolve the oil in EtOAc (300 mL) and saturated ammonium hydroxide (50 mL).
• 4-(3-Amino-pyrazol-1-yl)-benzonitrile Suspend 4-cyanophenyl hydrazine hydrochloride (5 g, 29.58 mmol) in tert-butanol (60 mL). Add methoxyacrylonitrile (2.458 g, 29.58 mmol) and potassium tert-butoxide (3.975 g, 35.49 mmol) and heat the mixture at 90° C. overnight. Concentrate in vacuo and partition the residue between EtOAc/water. Extract the organic phase with 10% hydrochloric acid. Neutralize the aqueous phase with saturated aqueous NaHCO 3 and extract twice with EtOAc. Dry the combined organic extracts over MgSO 4 , filter and concentrate in vacuo to obtain a solid that was washed with ether/hexane. Filter and dry the solid in vacuo to obtain the desired intermediate.
• 6-Chloro-4-(cyclopropylmethyl-amino)-pyrimidine In a microwave reaction vessel, slurry 4,6-dichloropyrimidine (540 mg, 3.6 mmol), cyclopropylmethylamine (280 ⁇ L, 3.24 mmol), and diisopropylethylamine (1.25 mL, 7.2 mmol) in iso-propanol (3 mL). Irradiate in microwave (300 watts) at 140° C. for 40 min. Cool to room temperature and concentrate in vacuo.
• 2-Chloro-4-(cyclopropylmethyl-amino)-pyrimidine In a microwave reaction vessel, slurry 2,4-dichloropyrimidine (0.5 g, 3.36 mmol), cyclopropylmethylamine (275 ⁇ L, 3.18 mmol), and diisopropylethylamine (1.17 mL, 6.72 mmol) in iso-propanol (2 mL). Irradiate in microwave (300 watts) at 130° C. for 15 min. Cool to room temperature and concentrate in vacuo.
• N-(tert-Butoxycarbonyl)-4-[5-(3,3-dimethylbutyryl)tiophen-2-yl]-benzylamine To a solution of 2-bromo-5-(3,3-dimethylbutyryl)-thiophene (187 mg, 0.7 mmol) in dioxane (7 mL) add a solution of aqueous 2M Na 2 CO 3 (0.9 mL), [4-(N-tert-butoxycarbonyl-aminomethyl)phenyl]boronic acid (216 mg, 0.8 mmol) and tetrakis(triphenylphosphine)-palladium(0) (41 mg, 0.03 mmol). Heat the mixture at 90° C. overnight.
• N-(tert-Butoxycarbonyl)-3-aminomethyl-6-[(2,2-dimethylpropane)thio]-pyridine Add sodium hydride (590 mg, 15.5 mmol, 60% in mineral oil) to DMF (50 mL) and cool to 0° C. Add 2,2-dimethyl-propane-1-thiol (966 mg, 9.27 mmol) and stir the mixture for 1 h at 0° C. Add 3-(tert-butoxycarbonylamino-methyl)-6-chloropyridine (1.5 g, 6.18 mmol) to the mixture and heat to 70° C. overnight. Cool the mixture to room temperature and carefully dilute with water (50 mL). Extract the mixture with EtOAc (5 ⁇ 25 mL).
• N-(tert-Butoxycarbonyl)-3-aminomethyl-6-[(212-dimethylpropane)sulfonyl]-pyridine Add 3-chloroperbenzoic acid (1.83 g, ⁇ 70%, 7.44 mmol) to DCM (25 mL) and cool to 0° C. Slowly add a solution of N-(tert-butoxycarbonyl)-3-aminomethyl-6-[(2,2-dimethylpropane)thio]-pyridine (924 mg, 2.98 mmol) in DCM (10 mL) maintaining the temperature below 10° C. Allow the mixture to warm to room temperature and stir for 3 h.
• Examples 2-3 may be prepared essentially as described in Example 1 by using 6-(4-acetyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriate O-alkylhydroxylamine hydrochloride. Overall yields and MS (ES+) data are shown in the Table below.
• Example 5 may be prepared essentially as described in Example 4 using 7-chloro-6-[4-(3-methyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine and O-methylhydroxylamine hydrochloride.
• Example 5 was obtained as a mixture of E- and Z-isomers.
• Examples 7-12 may be prepared essentially as described in Example 6 using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately substituted benzylamine.
• deprotection to obtain the free base was performed using a method similar to the General Procedure 2-2.
• Overall yields and MS (ES+) data are shown in the Table below.
• Example 15 may be prepared essentially as described in Example 14 using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 4-(cyclohexylthiomethyl)-benzylamine. Overall yield and MS (ES+) data are shown in the Table below.
• Examples 17-19 may be prepared essentially as described in Example 16 by using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately substituted 2-aminomethyl-pyridine. Overall yields and MS (ES+) data are shown in the Table below.
• Examples 21-23 may be prepared essentially as described in Example 20 by using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately substituted amine. Overall yields and MS (ES+) data are shown in the Table below.
• Examples 26-32 may be prepared essentially as described in Example 25 using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately substituted amine. Overall yields and MS (ES+) data are shown in the Table below. Optical rotation for Example 26 is also shown in the Table below.
• Examples 34-36 may be prepared essentially as described in Example 33 using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately substituted-3-aminomethyl-pyridine. Overall yields and MS (ES+) data are shown in the Table below.
• Example 38 may be prepared essentially as described in Example 37 using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-aminomethyl-5-cycloheptyloxy-pyridine. Deprotection to obtain the free base was performed using a method similar to the General Procedure 2-3. Overall yields and MS (ES+) data are shown in the Table below.
• Examples 41-44 may be prepared essentially as described in Example 40 by using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately substituted amine.
• (L)-Tartrate salt was prepared essentially as described in General Procedure 3-2. Overall yields and MS (ES+) data are shown in the Table below.
• Examples 47-48 may be prepared essentially as described in Example 46 by using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately substituted benzylamine. Enantiomeric excess of Example 47 was 92.7% [Analytical chiral conditions: Chiralpak® AD column; 250 ⁇ 4.6 mm, eluting with hexane/iso-propanol (95:5 with 0.1% diethylamine)]. Overall yields and MS (ES+) data are shown in the Table below.
• Examples 50-52 may be prepared essentially as described in Example 49 by using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately substituted benzylamine. Overall yields and MS (ES+) data are shown in the Table below.
• Examples 54-55 may be prepared essentially as described in Example 53 by using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately substituted benzylamine. Overall yields and MS (ES+) data are shown in the Table below.
• Examples 60-61 may be prepared essentially as described in Example 59 using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately substituted benzylamine. Overall yields and MS (ES+) data are shown in the Table below.

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