WO2008112280A1 - Substituted heterocycle fused gamma-carbolines synthesis - Google Patents

Substituted heterocycle fused gamma-carbolines synthesis Download PDF

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Publication number
WO2008112280A1
WO2008112280A1 PCT/US2008/003340 US2008003340W WO2008112280A1 WO 2008112280 A1 WO2008112280 A1 WO 2008112280A1 US 2008003340 W US2008003340 W US 2008003340W WO 2008112280 A1 WO2008112280 A1 WO 2008112280A1
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alkyl
formula
aryl
compounds
heteroaryl
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PCT/US2008/003340
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French (fr)
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John Charles Tomesch
Peng Li
Wei Yao
Qiang Zhang
James David Beard
Andrew S. Thompson
Hua Cheng
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Intra-Cellular Therapies, Inc.
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Priority to KR1020187017827A priority Critical patent/KR101999300B1/en
Priority to IN5670DEN2009 priority patent/IN2009DN05670A/en
Priority to EP08742074.1A priority patent/EP2134710B1/en
Priority to DK08742074.1T priority patent/DK2134710T3/en
Priority to CN2008800157710A priority patent/CN101796051B/en
Priority to KR1020097019338A priority patent/KR101805914B1/en
Priority to MX2009009773A priority patent/MX2009009773A/en
Priority to EP20153727.1A priority patent/EP3663294A1/en
Priority to US12/531,016 priority patent/US8309722B2/en
Priority to KR1020197013610A priority patent/KR102107954B1/en
Priority to KR1020157033684A priority patent/KR101981840B1/en
Priority to JP2009553626A priority patent/JP5567349B2/en
Priority to ES08742074T priority patent/ES2776889T3/en
Application filed by Intra-Cellular Therapies, Inc. filed Critical Intra-Cellular Therapies, Inc.
Priority to KR1020197019369A priority patent/KR102065319B1/en
Priority to AU2008226814A priority patent/AU2008226814C1/en
Priority to KR1020217009724A priority patent/KR102372149B1/en
Priority to KR1020207012082A priority patent/KR102238390B1/en
Priority to CA2679754A priority patent/CA2679754C/en
Publication of WO2008112280A1 publication Critical patent/WO2008112280A1/en
Priority to US13/593,097 priority patent/US8779139B2/en
Priority to US14/323,545 priority patent/US9315504B2/en
Priority to US15/066,962 priority patent/US9751883B2/en
Priority to US15/660,762 priority patent/US10221176B2/en
Priority to US16/244,796 priority patent/US10597395B2/en
Priority to US16/439,361 priority patent/US10464938B2/en
Priority to US16/594,603 priority patent/US11407751B2/en
Priority to US16/711,790 priority patent/US11066407B2/en
Priority to US17/808,836 priority patent/US20220332716A1/en

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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present invention relates to a method for the preparation of substituted heterocycle fused gamma-carbolines, intermediates useful for producing them, and a method for producing such intermediates.
  • Substituted heterocycle fused gamma-carbolines are useful as agonists or antagonists of 5-HT2 receptors, particularly 5-HT2A and 5-HT2C receptors, in treating central nervous system disorders, including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility.
  • This indole core is then reduced to afford the cis or trans tetracyclic dihydroindole (i.e., cis or trans tetracyclic indoline) product, which requires exhaustive purification procedures such as chiral column chromatography to afford enantiomerically pure product.
  • This method as a whole is inefficient because excess reagents and reaction intermediates are required to produce racemic products, wherein such product is purified at the final step to give a 25-50% yield at best. There is thus a need for a more efficient process to make enantiomerically pure substituted heterocycle fused gamma-carbolines.
  • the present invention provides methods for the preparation of substituted heterocycle fused gamma-carbolines in free or pharmaceutically acceptable salt forms, intermediates used in the preparation, for example enantiomerically pure 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole type intermediates, and methods for producing said intermediates and said substituted heterocycle fused gamma-carbolines are disclosed in the present invention.
  • R 6b , R 7 , R 8 , R 9 , R 10 , X, k, m, and n are as described in U.S. Patent Nos. 6,552,017; 6,548,493; 6,713, 471; and 6,849,619, U.S. Reissued Patent No. 39,680 and 38,679, and U.S. Application Nos. 10/787,941 and 10/786,935, the contents of each of which are all incorporated herein by reference.
  • 5- HT2 receptor agonists and antagonists used in treating disorders of the central nervous system including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility.
  • the present invention provides substantially enantiomerically pure cis dihydroindole (or indoline) type compounds as disclosed below in formulas 1C, ID, IE, IE', IF" and IG', e.g., at least 70%, preferably 80%, more preferably at least 90%, most preferably greater than 95% cis compounds of the following formulas (e.g., 1C, ID, IE, IE', IF" and IG') relative to all of their other stereoisomers, in free or pharmaceutically acceptable salt form, which are useful, e.g., as intermediates for the production of compounds of Formula IJ: 1.1: Compounds of Formula 1 C :
  • R , R and R are independently H or optionally substituted Ci- C ⁇ alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
  • k is 1 or 2;
  • R 7 , R 8 andR 9 are independently H or optionally substituted Ci-C 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
  • R 7 , R 8 and R 9 are independently H or optionally substituted C
  • n 1, 2 or 3;
  • (v) B is a protective group
  • R , R and R are R , R and R are independently H or optionally substituted Ci-C 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.; and
  • X-Y- is a HO-CH 2 -, HS-CH 2 -, H(R')N-CH 2 - or H(R')N-C(O)-, wherein R' is H or Ci-4alkyl.
  • n 1, 2 or 3;
  • R , R and R are R , R and R are independently H or optionally substituted Ci-C 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.; and
  • R , R and R are R , R and R are independently H or optionally substituted Ci-C 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.; and
  • R 10 is Ci- 4 alkyl, alkenyl or alkynyl.
  • R 7 , R and R are independently H or optionally substituted CpC 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
  • alkyl, alkenyl, alkynyl, alkoxy and haloalkyl independently comprises 1-6 carbon atoms.
  • the present invention further provides substantially optically pure cis dihydroindole (or indoline) type compounds as disclosed below in formulas 2C, 2D, 2E, 2E ⁇ 2F" and 2G', e.g., at least 70%, preferably 80%, more preferably at least 90%, most preferably greater than 95% cis isomer relative to all of their trans isomers, in free or pharmaceutically acceptable salt form, which are useful, e.g., as intermediates for the production of compounds of Formula U: 1.7: Compounds of Formula 2C:
  • R 5 is H or Ci.C 4 alkyl
  • R 5 R and R are independently H or optionally substituted C]-C 6 alkyl, C 3 - C 10 cycloalkyl, C 3 -Ci 0 heterocycloalkyl, hydroxy, Ci-C 6 alkoxy, nitro, halo, haloCj-C 6 alkyl, aryl, arylCi-Qalkyl, heteroaryl or heteroarylCi-Coalkyl.
  • ( ⁇ ) m is ; 0, 1 or 2;
  • R 5 is H or Ci.Qalkyl
  • R 7 , R 8 and R 9 are independently H or optionally substituted Ci-C 6 alkyl, C 3 - Ciocycloalkyl, C 3 -C 10 heterocycloalkyl, hydroxy, Cj-C 6 alkoxy, nitro, halo, haloCi-C ⁇ alkyl, aryl, arylCi-C ⁇ alkyl, heteroaryl or heteroarylCi-C 6 alkyl.
  • Formula 2E 1 wherein: 0) k is 1 or 2; ( ⁇ ) m is 0, 1 or 2; (iii) B is a protective group (iv) R 5 is H or Ci.C 4 alkyl;
  • R 7 , R 8 andR 9 are independently H or optionally substituted Ci-C 6 alkyl, C 3 -
  • CiQcycloalkyl C 3 -Cioheterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloCp
  • (V) B is a protective group
  • R 5 is H or Ci.Qalkyl
  • R 7 , R 8 and R 9 are independently H or optionally substituted Ci-C 6 alkyl, C 3 -
  • Ciocycloalkyl C 3 -Cioheterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloCj-
  • X-Y- is a HO-CH 2 -, HS-CH 2 -, H(R')N-CH 2 - or H(R')N-C(O)-, wherein R' is H or Ci-C 4 alkyl.
  • n 1, 2 or 3;
  • R 5 is H or C,.C 4 alkyl
  • R 7 , R 8 and R 9 are independently H or optionally substituted Ci-C 6 alkyl, C 3 - Ciocycloalkyl, Cs-Cjoheterocycloalkyl, hydroxy, Ci-C 6 alkoxy, nitro, halo, haloCi-C ⁇ alkyl, aryl, arylCi-C 6 alkyl, heteroaryl or heteroarylCi-C 6 alkyl; and
  • -X-Y- is -(R')N-C(O)-, wherein R' is H or C i -C 4 alkyl.
  • n 1, 2 or 3;
  • R 5 is H or d-C 4 alkyl
  • R 7 , R 8 and R 9 are independently H or optionally substituted Ci-C ⁇ alkyl, C 3 - Ciocycloalkyl, C 3 -Cioheterocycloalkyl, hydroxy, Ci. 6 alkoxy, nitro, halo, haloCi-C ⁇ alkyl, aryl, arylCi-C ⁇ alkyl, heteroaryl or heteroarylCi-C ⁇ alkyl; and
  • R 10 is H or C 1-4 alkyl.
  • the invention further provides compounds of the following formulae: 2.22. Formula 2G, wherein R 10 is H or Ci-C 4 alkyl;
  • R 7 , R 8 and R 9 are independently H or optionally substituted Ci-C 6 alkyl, C 3 -Ciocycloalkyl, C 3 -Cioheterocycloalkyl, hydroxy, Ci -6 alkoxy, nitro, halo, haloCi-C 6 alkyl, aryl, arylCi-C ⁇ alkyl, heteroaryl or heteroaryld- C 6 alkyl;
  • alkyl comprises alkyl, alkenyl and/or alkynyl.
  • the invention provides a method (Method 1C) for preparing compounds of Formula 1C or any of 2.12-2.21 :
  • the invention provides a method (Method 2C) for preparing compounds of Formula 1C or any of 2.37-2.48:
  • IB may be accomplished through the use of a reducing agent including, but not limited to: silanes in the presence of an acid (e.g., acetic or trifluoroacetic acid); metal (e.g., zinc) and mineral acid (e.g. hydrochloric acid); sodium and liquid ammonia; sodium in ethanol; or through the use of borane-amine complexes (e.g. borane-triethylamine in tetrahydrofuran); or sodium cyanoborohydride in the presence of an acid such as acetic or trifluoroacetic acid.
  • a reducing agent including, but not limited to: silanes in the presence of an acid (e.g., acetic or trifluoroacetic acid); metal (e.g., zinc) and mineral acid (e.g. hydrochloric acid); sodium and liquid ammonia; sodium in ethanol; or through the use of borane-amine complexes (e.g. borane-triethylamine in
  • the conversion of Compound of Formula IA to Formula IB may also be accomplished through catalytic hydrogenation wherein Compounds of Formula IA is treated with hydrogen in the presence of a catalyst such as palladium oxide, palladium on carbon or platinum oxide (See Hudlicky, M., "Reductions in Organic Chemistry", Ellis Horwood, Ltd., Chichester, UK, 1984).
  • a catalyst such as palladium oxide, palladium on carbon or platinum oxide
  • the reduction of Compounds of Formula 2 A to Compounds of Formula 2B may be accomplished through the use of similar agents as described for the reduction of Compounds of Formula IA to IB, for example silanes (e.g., triethylsilane) in the presence of an acid (e.g., acetic or trifluoroacetic acid); metal (e.g., zinc) and mineral acid (e.g. hydrochloric acid); sodium and liquid ammonia; sodium in ethanol; or through the use of borane-amine complexes (e.g.
  • silanes e.g., triethylsilane
  • metal e.g., zinc
  • mineral acid e.g. hydrochloric acid
  • sodium and liquid ammonia sodium in ethanol
  • borane-amine complexes e.g.
  • the conversion of Compound of Formula IA to Formula IB may also be accomplished through catalytic hydrogenation wherein Compounds of Formula IA is treated with hydrogen in the presence of a catalyst such as palladium oxide, palladium on carbon or platinum oxide. In an especially preferred embodiment, reduction is accomplished through the use of triethylsilane in the presence of trifluoroacetic acid.
  • IB may be achieved by chiral acid resolution wherein chiral acids such as chiral sulphonic acids or mono or di carboxylic acids or derivatives thereof are used.
  • chiral acids such as chiral sulphonic acids or mono or di carboxylic acids or derivatives thereof are used.
  • examples of such acids include, but are not limited to, (+/-)/(R/S) tartaric acid, (+/-)/ (RJS) (mono- or di-acetyl)tartaric acid, (+/-)/(R/S) (mono- or di-benzoyl)tartaric acid, (+/-)/(R/S) (mono- or di-pivaloyl)tartaric acid, (+/-)/(R/S) mandelic acid, (+/-)/ (RJS) acetoxyphenyl acetic acid, (+/-)/(R/S) methoxyphenyl acetic acid, (+/-)/(R/S) hydroxyman
  • acids include, but are not limited to, (+/-)/(R/S) tartaric acid, (+/-)/ (RJS) (mono- or di-acetyl)tartaric acid, (+/-)/(R/S) (mono- or di-benzoyl)tartaric acid, (+/-)/(R/S) (mono- or di-pivaloyl)tartaric acid, (+/- )/(R/S) mandelic acid, (+/-)/ (RJS) acetoxyphenyl acetic acid, (+/-)/(R/S) methoxyphenyl acetic acid, (+/-)/(R/S) hydroxymandelic acid, (+/-)/(R/S) halomandelic acid (e.g.
  • resolution of compounds of Formula 1 B or 2B is accomplished by using mandelic acid.
  • said acid is (S)-(+)-mandelic acid.
  • Resolution may be optimized where undesired enantiomer is removed first. Therefore, in an especially preferred embodiment, resolution is accomplished by adding (R)-(-)-mandelic acid to remove the undesired enantiomer first, followed by the addition of (S)-(+)-mandelic acid to obtain the desired product.
  • Formula IB may be achieved by using chiral chromatography, for example using amylose tris(3,5-dimethylphenylcarbamate) column sold under the tradename "CHIRALP AK® AD®".
  • the racemic compounds of Formula IB may be eluted with a mobile phase such as ethanol at a flow rate of 100-450mL/min.
  • the racemic compounds of Formula IB may be eluted with mobile phase such as methanol or isopropyl alcohol.
  • the fractions for the desired compounds, preferably, Compounds of Formula 1C or 2C, may be collected and isolated.
  • chiral chromatography comprises the use of CHIRALP AK® AD®, 20 ⁇ m, 5cm ID x 50cm L column and 100% ethanol mobile phase at a flow rate of 150mL/min. In another embodiment, chiral chromatography comprises the use of CHIRALP AK® AD®, 20 ⁇ m, 1 lcm ID x 25cm L column and 100% ethanol mobile phase at a flow rate of400mL/min.
  • Formula 2B may be achieved by using chiral chromatorgraphy as described above in Method for separating Compounds of Formula IB.
  • the invention provides a method (Method ID) for preparing compounds of Formula ID or any of 2.8-2.21 :
  • Formula ID as hereinbefore described in free or salt form which method comprises the step of protecting the piperidino-amine of compounds of Formula 1C: Formula 1C with a protecting agent in the presence of a base.
  • the protecting agent of Method ID comprises the general formula:
  • Y is halogen, imidazoyl, benzotriazole, N-(oxy)succinimide, alkoxy, -O- alkylaryl or -O-aryl;
  • Z is optionally substituted alkyl, aryl, alkylaryl or -OR wherein R is alkyl, aryl, arylalkyl or heteroarylalkyl;
  • P is -C(O)-, -C(O)O- or S(O) 2 .
  • the invention also provides a method (Method
  • the protecting agent of Method 2D comprises the general formula: wherein:
  • Y is halogen, imidazoyl, benzotriazole, N-(oxy)succinimide, alkoxy, alkoxycarbonyl, -O-alkylaryl or -O-aryl;
  • Z is optionally substituted alkyl, aryl, alkylaryl, alkoxycarbonyl, or -OR wherein R is alkyl, aryl, arylalkyl or heteroarylalkyl;
  • P is -C(O)-, -C(O)O-, -O- or S(O) 2 .
  • Examples of the protecting agent of compounds of Formula 1C or 2C include, but are not limited to benzyloxycarbonyl chloride (Cbz-Cl), triphenylmethyl chloride, ethyl chloroformate, /-butoxycarbonyl anhydride (BOC 2 ), benzyl N- succinimidyl carbonate, or benzoyl halide (e.g. benzoyl chloride or bromide), (benzyloxycarbonyl)-benzo triazole, benzyl halide (e.g. benzyl chloride or bromide), 1- arene sulfonyl chloride or toluene sulfonyl chloride.
  • benzyloxycarbonyl chloride Cbz-Cl
  • triphenylmethyl chloride ethyl chloroformate
  • /-butoxycarbonyl anhydride BOC 2
  • benzyl N- succinimidyl carbonate or benzoyl hal
  • protecting agent of Compounds of Formula 1C or 2C is p-methoxybenzyl ether.
  • the protective agents disclosed herein are not intended to be exhaustive.
  • amine protecting agent see one of the many general texts on the subject, for example, "Protective Groups in Organic Synthesis” by Theodora Green (publisher: John Wiley & Sons), the disclosure of which is hereby incorporated by reference.
  • substituent B Upon addition of the protecting agent to compounds of Formula 1C, substituent B therefore contains a general formula: wherein:
  • Z is optionally substituted alkyl, aryl, alkylaryl or -OR wherein R is alkyl, aryl, arylalkyl or heteroarylalkyl;
  • P is -C(O)-, -C(O)O- or S(O) 2 .
  • the protection step of this embodiment generally requires the addition of a base such as butyl lithium or metal hydrides (e.g., potassium hydride) or carbonates of alkali or alkaline earth metals (e.g., potassium or sodium carbonate), or organic amines (e.g., triethylamine).
  • a base such as butyl lithium or metal hydrides (e.g., potassium hydride) or carbonates of alkali or alkaline earth metals (e.g., potassium or sodium carbonate), or organic amines (e.g., triethylamine).
  • the protecting agent of compounds of Formula ID or 2D is ethyl chloroformate or BOC anhydride.
  • said protecting agent is ethyl chloroformate and said base is triethylamine.
  • the invention also provides a method (Method IE) for preparing compounds of Formula IE or any of 2.6-2.21 :
  • X-Y is a -HOCH 2 - -HSCH 2 - -H(R')N-CH 2 - or -H(R')N-C(O)-, wherein
  • R' is H or C M alkyl; (iii) n is 1, 2 or 3; and (b) a base.
  • the invention also provides a method (Method
  • X-Y is a -HOCH 2 -, -HSCH 2 -, -H(R')N-CH 2 - or -H(R')N-C(O)-, wherein R' is H or Ci- 4 alkyl;
  • n is 1, 2 or 3; and (b) a base.
  • nucleophilic alkyl halide for Method IE or 2E include, but are not limited to, 2-chloroacetamide, 2-bromoacetamide, chloroacetic acid, chloroproprionic acid, 2-chloroethanethioic S-acid.
  • base useful for Method IE or 2E include, but not limited to organic bases such as amine bases (e.g., ammonium, triethylamine, N,N'-diisopropylethyl amine or 4-(dimethylamino)pyridine (DMAP); l,5-diazabicycl[4.3.0]-non-5-ene (DBN), l,5-diazabicyclo[5.4.0]undec-5-ene (DBU)); or inorganic bases such as hydrides (e.g. sodium, lithium or potassium hydride), alkoxides, (e.g.
  • organic bases such as amine bases (e.g., ammonium, triethylamine, N,N'-diisopropylethyl amine or 4-(dimethylamino)pyridine (DMAP); l,5-diazabicycl[4.3.0]-non-5-ene (DBN), l,5-di
  • N-alkylation reaction may be achieved in the presence of an iodide source such as potassium iodide or sodium iodide, preferably potassium iodide.
  • an iodide source such as potassium iodide or sodium iodide, preferably potassium iodide.
  • compounds of Formula IE or 2E wherein X-Y- is H(R')N-C(O)- or H(R')N-CH 2 - R' is H and n is 1 are prepared by using 2-chloroacetamide in the presence of N,N'-diisopropylethyl amine and potassium iodide.
  • chloroacetamide, potassium iodide, isopropylethylamine in dixoane solvent is used.
  • the invention also provides a method (Method IF) for preparing compounds of Formula IF:
  • n 1, 2 or 3;
  • (iv) B is a protecting agent
  • R 5 R and R are independently H or optionally substituted Ci-C 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and
  • X-Y is -OCH 2 -, -SCH 2 -, -(R')N-CH 2 - or -(R')N-C(O)-, wherein R' is H or
  • R 5 is H or C r C 4 alkyl
  • R 7 , R 8 and R 9 are independently H or optionally substituted Ci-C ⁇ alkyl, C 3 -
  • -X-Y- is -OCH 2 - -SCH 2 - -(R')N-CH 2 - or -(R')N-C(O)-, wherein R' is H or C ⁇ alkyl; or any of 2.25-2.48, which method comprises the step of treating compounds of Formula 2E:
  • a transition metal catalyst selected from a group consisting of Group 8- 1 1 of the periodic table; and (b) a base.
  • the transitional metal catalyst of Method IF or 2F may be an atom, ion, salt or complex of transition metals selected from Groups 8-1 1 of the periodic table (e.g., palladium, copper, nickel, platinum, ruthenium, or rhodium).
  • transition metal catalyst examples include, but not limited to copper catalysts such as CuI, CuCl, CuBr, CuBr 2 , Cu(II) acetate, Cu 2 Cl 2 , Cu 2 O, Cu, or palladium or nickel catalysts such as Pd 2 (dba) 2 , Pd/C, PdCl 2 , Pd(OAc) 2 , (CH 3 CN) 2 PdCl 2 , Pd[P(C 6 H 5 ) 3 ] 4 , bis(dibenzylideneacetone) palladium [Pd 2 (dba) 3 ], Ni(acetylacetonate) 2 , NiCl 2 [P(C 6 H 5 )J 2 and Ni(1, 5-cyclooctadiene ⁇ as described in U.S.
  • copper catalysts such as CuI, CuCl, CuBr, CuBr 2 , Cu(II) acetate, Cu 2 Cl 2 , Cu 2 O, Cu
  • the transition metal catalyst is copper catalyst.
  • said catalyst is CuI.
  • the base useful for Method IF or 2F may be a bronsted base or a Lewis base well known in the art, including by way of example only, amine bases (e.g. triethylamine, trimethylamine, N,N'-diisopropylethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or l,4-diazabicyclo[2.2.2]octane (DABCO)), hydrides (e.g. sodium, lithium or potassium hydride), alkoxides (e.g. sodium or potassium tert-butoxide), carbonates (e.g.
  • amine bases e.g. triethylamine, trimethylamine, N,N'-diisopropylethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or l,4-diazabicyclo[2.2.2]octane (DABCO)
  • the base is a carbonate of alkali or alkali earth metals (e.g., sodium, potassium, cesium, barium, etc.). In an especially, said base is potassium carbonate.
  • Method IF further comprises the step of treating Compound of Formula IE with a mono or bi-dentate ligand known to ligate with transition metal catalysts.
  • ligand include, but are not limited to:
  • phenolic or amine ligands such as optionally substituted aryl alcohol, 1,2-diamine, 1,2-aminoalcohol, imidazolium carbene, 4-(dimethylamino)pyridine, 2- (aminomethyl)pyridine, 4,7-diphenyl- 1 , 10-phenanthroline, 4,7-dimethyl- 1,10- phenanthroline, 5-methyl- 1,10-phenanthroline, 5 -chloro- 1,10-phenanthroline, and 5- nitro- 1 , 10-phenanthroline;
  • a and B independently represent fused rings selected from the group consisting of monocyclic or polycyclic cycloalkyls, cycloalkenyls, aryls, and heterocyclic rings, said rings having from 4 to 8 atoms in a ring structure;
  • X represents NR 2 , P(alkyl) 2 , P(cycloalkyl) 2 , AsR 2 , or OR;
  • Y represents H, alkyl, NR 2 , or AsR 2 ;
  • R, R 3 , R b , R c , and Ra for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarba
  • R e and R f for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea,
  • R 3 and R b or R 0 and R ⁇ i, or both, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
  • Rg 0 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
  • m is an integer in the range 0 to 8 inclusive.
  • Y represents H, NR 2 , OR, or SR
  • R represents, independently for each occurrence, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or ⁇ (CH 2 ) m -R 8O ;
  • R 3 , R b , R c , R ⁇ i, R « , Rf, Rg, and R h for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime,
  • R 8O represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
  • m is an integer in the range 0 to 8 inclusive.
  • X represents NR 2 , P(alkyl) 2 , P(cycloalkyl) 2 , AsR 2 , or OR;
  • Y represents H, alkyl, NR 2 , AsR 2 , or OR;
  • R, R 3 , R b , R c , and Rj for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thioc
  • R e and R f for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea,
  • R 3 and R b or R 0 and R ⁇ , or both, taken together optionally represent a ring consisting of a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
  • R ⁇ o represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
  • m is an integer in the range 0 to 8 inclusive.
  • R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and ⁇ (CH2) m —R ⁇ o;
  • R 3 and R b are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR 3 , and —(CH2) m -Rs 0 ;
  • R 80 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
  • m is an integer in the range 0 to 8 inclusive.
  • R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and — (CH 2 ) m -R 80 ; the A, B, A 1 , and B 1 rings of the binaphthyl core independently are unsubstituted or substituted with R 3 , R b , R c , and R d , respectively, any number of times up to the limitations imposed by stability and the rules of valence; • R 3 , R b , R c , and R ⁇ i, are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR 3 , and ⁇ (CH2) m —
  • R 80 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
  • m is an integer in the range 0 to 8 inclusive.
  • R is cycloalkyl or aryl, there is at least one instance of R a , R b ,
  • R is selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and -(CH 2 ) m -R 80 ;
  • the A and A' rings of the biphenyl core independently may be unsubstituted or substituted with R 3 and R b , respectively, any number of times up to the limitations imposed by stability and the rules of valence;
  • R 3 and R b are selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR 3 , and ⁇ (CH 2 ) m —Rso;
  • R ⁇ o represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; m is an integer in the range 0 to 8 inclusive; and • the ligand, when chiral, may be provided in the form of a mixture of enantiomers or as a single enantiomer; and
  • R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and ⁇ (CH2) m —Rso;
  • P(R) 2 represents P(alkyl)2, or P(cycloalkyl) 2 ;
  • R 3 , R b , R c , and R d are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR 3 , and ⁇ (CH 2 ) m -R 80 ;
  • Rgo represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
  • m is an integer in the range 0 to 8 inclusive.
  • the ligand when chiral, is a mixture of enantiomers or a single enantiomer.
  • phenolic or amine ligands include, but are not limited to 2- phenylphenol, 2,6-dimethylphenol, 2-isopropylphenol, 1-naphthol, 8-hydroxyquinoline, 8-aminoquinoline, DBU, 2-(dimethylamino)ethanol, N,N-diethylsalicylamide, 2- (dimethylamino)glycine, N,N,N',N'-tetramethyl- 1 ,2-diaminoethane, 4,7-diphenyl- 1,10- phenanthroline, 4,7-dimethyl-l,10-phenanthroline, 5-methyl-l,10-phenanthroline, 5- chloro-l,10-phenanthroline, 5-nitro-l,10-phenanthroline, 4-(dimethylamino)pyridine, 2- (aminomethyl)pyridine, (methylimino)diacetic acid, cis-l ⁇ -diaminocyclo
  • Method 2F further comprises the step of treating Compound of Formula 2E with a mono or bi-dentate ligand known to ligate with transition metal catalysts.
  • a mono or bi-dentate ligand known to ligate with transition metal catalysts examples include, but are not limited to ligands disclosed above in Method IF.
  • the ligand of Method IF or 2F is optionally substituted 1,2-diamine ligands.
  • said ligand is N,N'-dimethyl-l,2-diaminoethyane, trans-N,N'- dimethyl-l,2-diaminocyclohexane, N-butylethylenediamine.
  • said ligand is N,N' -dimethyl- 1 ,2-diaminoethane. Without being bound to any theory, it is believed that the ligands facilitate the reaction by stabilizing and solubilizing the metal catalyst.
  • the invention also provides a method (Method
  • Formula IE' as hereinbefore described, which method comprises the step of treating compounds of Formula ID with (a) benzophenone imine; (b) a transition metal catalyst selected from Groups 8-11 of the Periodic Table; (c) a base; and (d) ligands selected from a group consisting of:
  • phenolic or amine ligands such as optionally substituted aryl alcohol, 1,2-diamine, 1,2-aminoalcohol, imidazolium carbene, 4-(dimethylamino)pyridine, 2- (aminomethyl)pyridine, 4,7-diphenyl- 1 , 10-phenanthroline, 4,7-dimethyl- 1,10- phenanthroline, 5 -methyl- 1,10-phenanthroline, 5-chloro-l,10-phenanthroline, and 5- nitro- 1 , 10-phenanthroline;
  • a and B independently represent fused rings selected from the group consisting of monocyclic or polycyclic cycloalkyls, cycloalkenyls, aryls, and heterocyclic rings, said rings having from 4 to 8 atoms in a ring structure;
  • X represents NR 2 , P(alkyl) 2 , P(cycloalkyl) 2 , AsR 2 , or OR;
  • Y represents H, alkyl, NR 2 , or AsR 2 ;
  • R, R 8 , Rb, R 0 , and Ra for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate,
  • R 6 and Rf for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or ⁇
  • a and B independently are unsubstituted or substituted with Rg and R f , respectively, any number of times up to the limitations imposed by stability and the rules of valence;
  • R 3 and R b , or R 0 and R d , or both, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
  • R 80 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
  • m is an integer in the range 0 to 8 inclusive.
  • Y represents H, NR 2 , OR, or SR
  • R represents, independently for each occurrence, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or ⁇ (CH 2 ) m —Rso;
  • R 3 , R b , Rc, Rd, Re, Rf, Rg 5 and Rh for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thio
  • R a , Rb, Rc, Rd, Re, Rf 5 Rg 5 and Rh taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
  • R 8O represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
  • m is an integer in the range 0 to 8 inclusive.
  • X represents NR 2 , P(alkyl) 2 , P(cycloalkyl) 2 , AsR 2 , or OR;
  • Y represents H, alkyl, NR 2 , AsR 2 , or OR;
  • R, R 8 , R b , R c , and Rd for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thioc
  • R e and R f for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea,
  • the B and B 1 rings of the binaphthyl core independently are unsubstituted or substituted with R e and R f , respectively, any number of times up to the limitations imposed by stability and the rules of valence; • R 3 and R b , or R 0 and Ra, or both, taken together optionally represent a ring consisting of a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
  • R 8O represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
  • m is an integer in the range 0 to 8 inclusive.
  • R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and ⁇ (CH 2 ) m -Rso;
  • the A and A 1 rings of the biphenyl core independently are unsubstituted or substituted with Rj and R 2 , respectively, any number of times up to the limitations imposed by stability and the rules of valence;
  • R 3 and R b are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR 3 , and — (CH 2 ) m --R 80 ;
  • R 8O represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle; m is an integer in the range 0 to 8 inclusive; and the ligand, when chiral, is a mixture of enantiomers or a single enantiomer; (6) ligand represented by structure 5:
  • R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and ⁇ (CH2) m -R 80 ;
  • the A, B, A 1 , and B 1 rings of the binaphthyl core independently are unsubstituted or substituted with R a , R b , R 0 , and R d , respectively, any number of times up to the limitations imposed by stability and the rules of valence;
  • R 3 , R b , R c , and R d are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR 3 , and — (CH 2 ) m — R 80 ;
  • R 80 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
  • m is an integer in the range 0 to 8 inclusive.
  • R is cycloalkyl or aryl, there is at least one instance of R 3 , R b ,
  • R is selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and -(CH 2 ) m -R 80 ;
  • the A and A' rings of the biphenyl core independently may be unsubstituted or substituted with R 3 and R b , respectively, any number of times up to the limitations imposed by stability and the rules of valence;
  • R 3 and R b are selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR 3 , and --(CH 2 ) m -Rs 0 ;
  • R 80 represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
  • m is an integer in the range 0 to 8 inclusive.
  • the ligand when chiral, may be provided in the form of a mixture of enantiomers or as a single enantiomer;
  • R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and — (CH 2 ) m —R%o',
  • P(R) 2 represents P(alkyl) 2 , or P(cycloalkyl) 2 ;
  • R 3 , R b , R c , and R d are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR 3 , and — (CH 2 ) m — R 80 ;
  • Rso represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
  • m is an integer in the range 0 to 8 inclusive.
  • the invention also provides a method (Method E') for preparing compounds of Formula 2E' or any of 2.31-2.48:
  • Formula 2E 1 as hereinbefore described, which method comprises the step of treating compounds of Formula 2D with (a) benzophenone imine; (b) a transition metal catalyst selected from Groups 8-11 of the Periodic Table; (c) a base; and (d) a ligand selected from a group consisting of ligands as described above in Method IE.
  • Useful transition metal catalysts of Method IE' and 2E' include atoms, ions, salts or complexes of transition metals selected from Groups 8-11 of the periodic table (e.g., palladium, copper, nickel, platinum, ruthenium, or rhodium).
  • transition metal catalyst examples include, but not limited to copper catalysts (e.g., CuI, CuCl, CuBr, CuBr 2 , Cu(II) acetate, Cu 2 Cl 2 , Cu 2 O, Cu).
  • Other examples of useful transition metal catalysts include complexes of palladium or nickel including, but not limited to Pd 2 (dba) 2 , Pd/C, PdCl 2 , Pd(OAc) 2 , (CH 3 CN) 2 PdCl 2 , Pd[P(C 6 H 5 ) 3 ] 4 , bis(dibenzylideneacetone) palladium [Pd 2 (dba) 2 ], Ni(acetylacetonate) 2 , NiCl 2 [P(C 6 H 5 )J 2 and Ni(l,5-cyclooctadiene) 2 as described in U.S. patents 6,759,554B2; 6,395,916Bl; 6,307,087Bl, here
  • Examples of a useful base for Method IE' or 2E' include, for example, amine bases (e.g., triethyl amine, N,N'-diisopropylethyl amine or 4- (dimethylamino)pyridine (DMAP); l,5-diazabicycl[4.3.0]non-5-ene (DBN), 1,5- diazabicyclo[5.4.0]undec-5-ene (DBU)) and 1,4-Diazabicyclo[2.2.2]octane (DABCO); inorganic bases such as hydrides (e.g. sodium, lithium and potassium hydride), alkoxides, (e.g.
  • Method IE' comprises the step of treating Compound ID with (1) benzophenone imine; (2) Pd 2 (dba) 2 ; (3) sodium tert-butoxide; and (4) 2,2'- bis(diphenylphosphino)- 1 , 1 '-binaphthyl.
  • the invention also provides a method (Method IF") for preparing compounds of Formula IF" or any of 2.3-2.21 :
  • A is Cl, Br or I
  • R 12 is C M alkyl; (2) a base.
  • Method IE' sodium or potassium iodide is present when the compound of Formula IE' is treated with the alkyl haloacetate.
  • Method IE' comprises the step of treating Compound of Formula ID with (1) ethyl bromoacetate; (2) sodium carbonate; and (3) potassium iodide.
  • the invention provides a method (Method
  • A is Cl, Br or I
  • R . 1 1 2 Z is C M alkyl
  • the invention also provides a method (Method IG) for preparing compounds of Formula 1 G:
  • n 1, 2 or 3;
  • R , R and R are independently H or optionally substituted Ci-C 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
  • X-Y is a -NC(O)- or -NCH 2 - ; and (vii) R 10 is alkenyl or alkynyl; or any of 2.1-2.21, in free or salt form, which method comprises the step of N-alkylating compounds of Formula IF':
  • n 1, 2 or 3;
  • (iv) B is a protecting agent
  • R 7 , R 8 and R 9 are independently H or optionally substituted Cj-C 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and
  • X-Y is - ⁇ R')N-CH 2 ⁇ or -(R')N-C(O)-, wherein R' is H.
  • the invention also provides a method (Method 2G) for preparing compounds of Formula 2G' :
  • n 1, 2 or 3;
  • (iv) B is a protective group;
  • R 5 is H or Ci-C 4 alkyl;
  • R 7 , R 8 and R 9 are independently H or optionally substituted Ci-C 6 alkyl, C 3 - Ciocycloalkyl, C 3 -Cioheterocycloalkyl, hydroxy, Ci-C 6 alkoxy, nitro, halo, haloCi-C ⁇ alkyl, aryl, arylCi-C 6 alkyl, heteroaryl or heteroarylCi-Cealkyl;
  • X-Y is a -NC(O)- or -NCH 2 - ;
  • R 10 is C M alkyl; or any of 2.22-2.48, in free or salt form, which method comprises the step of N- alkylating compounds of Formula 2F':
  • n 1, 2 or 3;
  • R 5 is H or C i .C 4 alkyl
  • R 7 , R 8 and R 9 are independently H or optionally substituted Ci-C 6 alkyl, C 3 - Ciocycloalkyl, C 3 -Cioheterocycloalkyl, hydroxy, C)-C 6 alkoxy, nitro, halo, haloCi-C ⁇ alkyl, aryl, arylCj-C ⁇ alkyl, heteroaryl or heteroarylCi-C ⁇ alkyl; and
  • -X-Y- is -(R')N-CH 2 - or -(R')N-C(O)-, wherein R' is H.
  • N-alkylation of Method 1 G or 2G may be achieved by treating compounds of Formula 2F' with an optionally substituted alkyl halide (e.g., methyl iodide, iodoethane) in the presence of a base (e.g., potassium carbonate).
  • an optionally substituted alkyl halide e.g., methyl iodide, iodoethane
  • a base e.g., potassium carbonate
  • the invention provides a method (Method 3G') for preparing compounds of Formula 2G which method comprises the step of treating a compound of Formula 2E" (wherein X-Y is HN(R')CH2 or HN(R')-C(O)-) with (i) a transition metal catalyst; (ii) a base and (iii) optionally a mono or bidentate ligand as disclosed in Method 2F".
  • the invention also provides Method 3 G for preparing compounds of Formula 2G as hereinbefore described which method comprises the steps of: a) treating a Compound of Formula 2D in free or salt form as hereinbefore described with (i) a nucleophilic alkyl halide of the general formula:
  • n X-Y as hereinbefore described, (ii) a base and (iii) potassium iodide in a solvent such as dioxane; and b) adding (i) a transition metal catalyst selected from a group consisting of Group 8-11 of the periodic table; (ii) a base; and (iii) optionally a mono or bi-dentate ligand known to ligate with transition metal catalysts.
  • the nucleophilic alkyl halide is chloroacetamide or N-methyl chloroacetamide and the base is isopropylethylamine.
  • the transition metal catalyst of step (b) of Method 3G may be those described in Methods IF and 2F (e.g., copper catalysts such as CuI, CuCl, CuBr, CuBr 2 , Cu(II) acetate, Cu 2 Cl 2 , Cu 2 O, Cu, or palladium or nickel catalysts such as Pd 2 (dba) 2 , Pd/C, PdCl 2 , Pd(OAc) 2 , (CH 3 CN) 2 PdCl 2 , Pd[P(C 6 Hs) 3 J 4 , bis(dibenzylideneacetone) palladium [Pd 2 (dba) 3 ], Ni(acetylacetonate) 2 , NiCl 2 [P
  • the invention also provides a method (Method IH) for preparing compounds of Formula IH:
  • n 1, 2 or 3;
  • R 5 R and R are independently H or optionally substituted Ci-C 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
  • X is a N; and
  • R 10 is H or C M alkyl;
  • R 6a and R 6b are independently selected from a group consisting of H; which method comprises the step of reducing the ketone of compounds of Formula IG:
  • n is i, 2 or 3;
  • R 7 , R 8 and R 9 are independently H or optionally substituted Ci-C 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
  • R 10 is Ci-4alkyl, alkenyl or alkynyl; to a methylene.
  • a reducing agent selected from a group consisting of metal hydrides (e.g., diisobutyl aluminum hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) or sodium cyanoborohydride); boranes (e.g., BH 3 -THF); or organoboranes (e.g. bis(benzyloxy)borane).
  • DIBAL diisobutyl aluminum hydride
  • Red-Al sodium bis(2-methoxyethoxy)aluminum hydride
  • Red-Al sodium cyanoborohydride
  • boranes e.g., BH 3 -THF
  • organoboranes e.g. bis(benzyloxy)borane
  • such conversion may also be accomplished through catalytic hydrogenation by using hydrogen
  • the invention also provides a method (Method 2H) for preparing compounds of Formula 2H:
  • R 5 is H or Ci.C 4 alkyl
  • R 7 , R 8 andR 9 are independently H or optionally substituted Ci-C 6 alkyl, C 3 -
  • X is a N; and
  • R 10 is H or C 1-4 alkyl;
  • R 6a and R 6b are independently selected from a group consisting of H; which method comprises the step of reducing the ketone of compounds of Formula 2G':
  • Formula 2G 1 in free or salt form as hereinbefore described to a methylene Such reduction may be accomplished through the use of a reducing agent selected from a group as described above in Method IH.
  • the reduction of the ketone comprises the use of 9-Borabicyclo [3.3.1 ]nonane (9-BBN).
  • the invention also provides a method (Method II) for preparing compounds of Formula II:
  • n 1, 2 or 3;
  • R 7 , R 8 and R 9 are independently H or optionally substituted Ci-C 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
  • X is a N, S or O;
  • R 10 is H or Ci ⁇ alkyl when X is N or R 10 is non-existent when X is O or S; and (vii) R 6a and R 6b are H; which method comprises the step of deprotecting compounds of Formula IH:
  • k is 1 or 2;
  • m is 0, 1 or 2;
  • n is 1, 2 or 3;
  • (iv) B is a protecting agent
  • R 7 , R 8 and R 9 are independently H or optionally substituted C 1 -C 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
  • X is a N, O or S;
  • R 10 is H or Ci ⁇ alkyl when X is N or R 10 is non-existent when X is O or S; and (viii) R 6a and R 6b are H.
  • the invention provides a method (Method 21) for preparing compounds of Formula 21:
  • n 1, 2 or 3;
  • R 5 is H or Ci-Qalkyl
  • R , R and R are independently H or optionally substituted Ci-C ⁇ alkyl, C 3 - Ciocycloalkyl, C 3 -C 1 oheterocycloalkyl, hydroxy, Ci -6 alkoxy, nitro, halo, haloCi-C 6 alkyl, aryl, arylCi-C 6 alkyl, heteroaryl or heteroarylCi-C ⁇ alkyl;
  • X is a N, S or O;
  • R 10 is H or C ⁇ alkyl when X is N or R 10 is non-existent when X is O or S; and (viii) R 6a and R 6b are H; which method comprises the step of deprotecting compounds of Formula 2H:
  • the deprotection conditions for the protective groups of Method II or 21 necessarily vary with the choice of protecting group and may involve acid or base catalysis or catalytic hydrogenation.
  • the protecting agent is an acyl group such as an alkanoyl or alkoxycarbonyl group (e.g., ethoxycarbonyl) or an aroyl group
  • deprotection may be accomplished for example, by hydrolysis with a base such as an alkali metal hydroxide, for example lithium, potassium or sodium hydroxide.
  • an acyl protecting agent such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid.
  • An arylmethoxycarbonyl protecting agent such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over acatalyst such as palladium-on-carbon, or by treatment with a Lewis acid such as boron tris(trifluoroacetate).
  • a Lewis acid such as boron tris(trifluoroacetate
  • the invention also provides a method (Method U) for preparing compounds of Formula U:
  • R , R and R are independently H or optionally substituted Ci-C 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
  • R 10 is H or when X is N or R 10 is non-existent when X is O or S;
  • R 6a and R 6b are H; and
  • R 1 is H or optionally substituted Ci-C 6 alkyl, cycloalkyl, aryl, arylalkyl (e.g., benzyl), heteroaryl, heteroarylalkyl, aryloxoalkyl (e.g., 4-(4-fluorophenyl)-4- oxobutyl)), aryloxyalkyl (e.g., 3-(4-fluorophenoxy)propyl)), heroaryloxoalkyl, heroaryloxyalkyl, aryl sulfinylalkyl or heteroaryl sulfinylalkyl; which method comprises the step of N-alkylating compounds of Formula II:
  • R 13 is optionally substituted aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl;
  • G is d-C 8 alkyl halide (e.g., propyl chloride); and (b) a base.
  • the invention also provides a method (Method
  • R 5 is H or C,-C 4 alkyl
  • R , R and R are independently H or optionally substituted Ci-C 6 alkyl, C 3 - Ciocycloalkyl, C 3 -Ci 0 heterocycloalkyl, hydroxy, Ci ⁇ alkoxy, nitro, halo, haloCi-C ⁇ alkyl, aryl, arylCi-C 6 alkyl, heteroaryl or heteroarylCi-C 6 alkyl;
  • R 10 is H or Ci ⁇ alkyl when X is N or R 10 is non-existent when X is O or S;
  • R 6a and R 6b are H;
  • R 1 is H or optionally substituted Ci-C 6 alkyl, cycloalkyl, aryl, arylC)-C 6 alkyl (e.g., benzyl), heteroaryl, heteroarylCi-C 6 alkyl, aryloxoCi-C ⁇ alkyl (e.g., 4-(4- fluorophenyl)-4-oxobutyl)), aryloxyCi-C 6 alkyl (e.g., 3-(4- fluorophenoxy)propyl)), heroaryloxoCj-C ⁇ alkyl, heroaryloxyCi-C 6 alkyl, aryl sulfinylCi-C ⁇ alkyl or heteroaryl sulfinylCj-C ⁇ alkyl; which method comprises the step of N-alkylating compounds of Formula 21:
  • R 13 is optionally substituted aryl, arylCi-C ⁇ alkyl, Ci-C 6 alkyl, heteroaryl, heteroarylCi-C ⁇ alkyl;
  • G is Ci-Cgalkyl halide (e.g., propyl chloride); and (b) a base.
  • the base useful for Method IJ or 2 J may be a Bronsted or Lewis base.
  • amine bases e.g., ammonium, triethylamine, N,N'-diisopropylethyl amine or 4-(dimethylamino)pyridine (DMAP); l,5-diazabicycl[4.3.0]-non-5-ene (DBN), l,5-diazabicyclo[5.4.0]undec-5-ene (DBU)); or hydrides (e.g. sodium, lithium or potassium hydride), alkoxides, (e.g.
  • Method 11 further comprises the use of sodium or potassium iodide.
  • compounds of Formula II are alkylated with 4-chloro-4'-fluoro- butyrophenone in the presence of triethyl amine and potassium iodide.
  • the invention provides a method (Method IK) for preparing pharmaceutically acceptable salts of compounds of Formula U or 2 J:
  • Formula U or Formula 2J as hereinbefore described, which method comprises the step of reacting free base of Compounds of Formula IJ or 2 J with an appropriate acid in water or in an organic solvent, or in a mixture of the two to give pharmaceutically acceptable acid addition salts of Formula U or 2 J of the present invention; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Appropriate acid may be, for example, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • the invention further provides methods for compounds of Formulas IC-
  • the invention further provides methods for compounds of Formulas 2C-
  • 2J (e.g., Formulas, 2C, 2D, 2E, 2E', 2F, 2G ⁇ 2G, 2H, 21 and 2J) as follows:
  • Method 4.1 wherein said acid is selected from a group consisting of hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic acid.
  • Method for the preparation of any compounds of Formulas 2J-2F, 2F" or 2E' or any of Methods 4.1-4.24 comprising the step of treating compounds of Formula 2D with benzophenone imine; Pd 2 (dba) 2 ; sodium t-butoxide; and 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl .
  • Method for the preparation of any of compounds of Formulas 2J-2F, 2F", 2E, 2E ⁇ 2D, 2C or any of Methods 4.1-4.35 comprising the step of (a) reducing compounds of Formula 2 A with triethylsilane in the presence of an acid and (b) resolving compounds of Formula 2B with a chiral acid or by chiral chromatography.
  • reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. Therefore, at times, reaction may require to be run at elevated temperature or for a longer or shorter period of time. It is understood by one skilled in the art of organic synthesis that functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. If not commercially available, starting materials for these processes may be made by procedures, which are selected from the chemical art using techniques similar or analogous to the synthesis of known compounds. All references cited herein are hereby incorporated in their entirety by reference.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • alkyl or "alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "Ci-C 6 alkyl” denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, sec-butyl, t-butyl, 3-methylpentyl, 4-methylpentyl, etc.
  • alkenyl or "alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration having a specified number of carbon atoms and one or more carbon-carbon double bonds which may occur in any stable point along the chain.
  • alkenyl include, but are not limited to, ethenyl, 1- propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 2-methyl- 2-propenyl, 4-methyl-3-pentenyl, and the like.
  • Alkynyl or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
  • Alkoxy or "alkyloxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n- butoxy, 5-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
  • alkylthio is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
  • Halo refers to fluoro, chloro, bromo, and iodo. Therefore, "alkyl halide” herein refers to a halogen group attached to alkyl group as defined above such as methyl iodide or iodobutane.
  • Cycloalkyl is intended to include monocyclic or polycyclic ring system comprising at least one aliphatic ring. Therefore, “cycloalkyl” may denote simply a cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and the like.
  • cycloalkyl is a polycyclic system
  • such system may contain an aliphatic ring fused to aromatic, non-aromatic, heteroaromatic or hetero nonaromatic rings such as octahydro-lH-indene, 2,3-dihydro-lH-indene or 5,6,7,8-tetrahydroquinoline.
  • heterocycloalkyl refers to a monocyclic or polycyclic system comprising at least one aliphatic ring containing at least one heteroatom selected from a group consisting of O, N and S. Therefore, heterocycloalkyl may refer to piperidinyl, piperazinyl, 2-pyrrolidonyl, 1,2,3,4-tetrahydroquinolinyl, 2H,6H- 1,5,2- dithiazinyl, 2H-pyrrolyl or l,2,3,4-tetrahydro-l,8-naphthyridine.
  • aryl is intended to mean a stable 5- to 7- membered monocyclic or polycyclic or 7- to 14-membered polycyclic ring system which comprises at least one aromatic ring (i.e., planar ring that contains 4n+2 Pi electrons, wherein n is an integer). Therefore, the term “aryl” includes phenyl, naphthyl and their derivatives. The term “aryl” is also intended to include polycyclic ring systems which contain at least one aromatic ring fused to one or more aromatic or non- aromatic or heteroaromatic rings (e.g., 2,3-dihydro-lH-indene).
  • heterocycle As used herein, the term “heterocycle”, “heterocyclic ring” or
  • heteroaryl is intended to mean a stable 5- to 7-membered monocyclic or polycyclic or 7- to 14-membered polycyclic ring which comprises at least one aromatic ring containing at least one heteroatom independently selected from the group consisting of N, O and S. Therefore, a “heterocycle” or “heterocyclic ring” or “heteroaryl” may include a single hetero aromatic ring or a hetero aromatic ring fused to other heteroaromatic ring or to a non-heteroaromatic or non-aromatic ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • heterocycles or heteroaryl group include, but are not limited to lH-indazole, thiazolyl, furyl, pyridyl, quinolinyl, pyryl, indole or 5,6,7,8-tetrahydroquinoline.
  • polycyclic or “polycycle” is intended to mean fused ring system comprising one or more aromatic, non-aromatic (i.e., alicyclic), heteroaromatic or hetero non-aromatic (hetero-alicyclic) rings fused together.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Therefore, optionally substituted alkyl may refer to an alkyl group as defined above whereby one or more hydrogens are replaced with a selection from the indicated group including, but not limited to, halogen, hydroxy, amino, sulfhydryl, alkyl, alkenyl, alkynyl, haloalkyl (e.g.
  • resolution is a term of art and refers to the separation of a racemic mixture into its enantiomers by reacting an organic acid or base with the components of the racemic mixture to form diasteromeric salts and separating said salt by, for example, crystallization techniques.
  • chiral acid resolution refers to the separation of a racemic mixture into its enantiomers through the use of a chiral acid.
  • chromatography is well known in the art and refers to a separation technique of a mixture by interacting it with a stationary phase and eluting the components of the mixture with a mobile phase such as ethanol, methanol, acetonitrile, water or mixtures thereof.
  • a mobile phase such as ethanol, methanol, acetonitrile, water or mixtures thereof.
  • chiral chromatography refers to chromatography wherein the stationary phase is chiral.
  • chiral acid refers to any optically active acid capable of forming disastereomeric salts with compounds of Formula IB.
  • mono or di- carboxylic acid or “sulfonic acid” herein refers to any compound that contains one or two carboxylic functional groups and a sulfonic acid group respectively.
  • Examples of such acid include but are not limited to (+/-)/(R/S) tartaric acid, (+/-)/ (R/S) (mono- or di-acetyl)tartaric acid, (+/-)/(R/S) (mono- or di-benzoyl)tartaric acid, (+/-)/(R/S) (mono- or di-pivaloyl)tartaric acid, (+/-)/(R/S) mandelic acid, (+/-)/(R/S) acetoxyphenyl acetic acid, (+/-)/(R/S) methoxyphenyl acetic acid, (+/-)/(R/S) hydroxymandelic acid, (+/-)/(R/S) halomandelic acid (e.g. 4-fiuoromandelic acid), (+/- ) /(R/S) lactic acid, and (+/-)/(R/S) camphor sulfonic acid.
  • protecting agent refers to any compound that reacts with the atom for which protection is desired so as to block or mask its functionality. It is typically used to temporarily modify a potentially reactive functional group so as to protect it from undesired chemical transformation.
  • a desirable protecting agent is one which is compatible with or stable to the reaction condition and is easily cleaved off at a later point when protection is no longer desired.
  • protecting agents see “Protective Groups in Organic Synthesis” by Theodora Green (publisher: John Wiley & Sons), the disclosure of which is hereby incorporated by reference.
  • deprotection or “deprotect” or “deprotecting” refers to the act of removing or cleaving off a protecting group.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group and may involve acid (e.g., hydrochloric, sulphuric, phosphoric or trifluoroacetic acid or a Lewis acid such as boron tris(trifluoroacetate)) or base (alkali metal hydroxide, e.g., lithium, potassium or sodium hydroxide) catalysis or catalytic hydrogenation condition (e.g., hydrogen and palladium-on-carbon).
  • acid e.g., hydrochloric, sulphuric, phosphoric or trifluoroacetic acid or a Lewis acid such as boron tris(trifluoroacetate)
  • base alkali metal hydroxide, e.g., lithium, potassium or sodium hydroxide
  • catalysis or catalytic hydrogenation condition e.g.,
  • catalyst refers to any substance or agent capable of affecting, inducing, increasing, influencing or promoting the reactivity of a compound or reaction without itself being consumed.
  • transition metal catalyst refers to any metal having electrons in the d-orbitals, e.g. metals selected from one of Groups 3-12 of the periodic table or from the lanthanide series.
  • the catalysts useful for the methods of this invention include atoms, ions, salts or complexes of transition metals from Groups 8-11 of the Periodic Table.
  • Group 3-12 of the Periodic Table refers to the groups of the Periodic Table as numbered according to the IUPAC system.
  • transition metals from Group 8-11 which include include iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver and gold.
  • catalysts include, but are not limited to CuI, CuCl, CuBr, CuBr 2 , Cu(II) acetate, Cu 2 Cl 2 , Cu 2 O, Cu, Pd 2 (dba) 2 , Pd/C, PdCl 2 , Pd(OAc) 2 , (CH 3 CN) 2 PdCl 2 , Pd[P(CoHs) 3 J 4 , bis(dibenzylideneacetone) palladium [Pd 2 (dba) 3 ], Ni(acetylacetonate) 2 , NiCl 2 [P(CoHs)J 2 and Ni(l,5-cyclooctadiene) 2 .
  • Catalysts are typically, but not necessarily used in substoichi
  • base refers to organic or inorganic bases such as amine bases (e.g., ammonium, triethylamine, N,N'-diisopropylethyl amine or 4- (dimethylamino)pyridine (DMAP); l,5-diazabicycl[4.3.0]-non-5-ene (DBN), 1,5- diazabicyclo[5.4.0]undec-5-ene (DBU)); hydrides (e.g. sodium, lithium or potassium hydride); alkoxides, (e.g.
  • amine bases e.g., ammonium, triethylamine, N,N'-diisopropylethyl amine or 4- (dimethylamino)pyridine (DMAP); l,5-diazabicycl[4.3.0]-non-5-ene (DBN), 1,5- diazabicyclo[5.4.0]undec-5-ene (DBU)
  • hydrides e
  • an alkali or alkaline earth metal e.g. sodium, magnesium, calcium, potassium, cesium or barium carbonate, bicarbonate, hydroxide or phosphate.
  • Bronsted base refers to an uncharged or charged atom or molecule, e.g., an oxide, amine, alkoxide, or carbonate, that is a proton acceptor.
  • Bronsted base include, but not limited to K 3 PO 4 , K 2 CO 3 , Na 2 CO 3 , Tl 2 CO 3 , Cs 2 CO 3 , K(OtBu), Li(OtBu), Na(OtBu), K(OPh), and Na(OPh), or mixtures thereof.
  • Lewis base are recognized in the art, and refer to a chemical moiety capable of donating a pair of electrons under certain reaction conditions.
  • Examples of Lewis base include but are not limited to uncharged compounds such as alcohols, thiols, olefins, and amines (e.g., ammonia, triethylamine), and charged moieties such as alkoxides, thiolates, carbanions, and a variety of other organic anions.
  • the term "acid” herein refers to Lewis or Bronsted acid.
  • Lewis acid is a term of art and refers to a chemical moiety capable of accept a pair of electrons (e.g., borontrifluoride).
  • Bronsted acid refers to any chemical moiety capable of donating a proton (e.g., acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid as well as other organic acids known in the art).
  • ligand refers to any atom, molecule or ion capable of donating or sharing one or more electrons through a coordinate and/or covalent bond with another central atom, typically a metal.
  • Monodentate ligand refers to ligands that have one binding site to the central atom (e.g., pyridine or ammonia).
  • Identityate ligand refers to ligands that have two binding site (e.g., N,N'- dimethylethylenediamine, N,N,N',N'-tetramethylethylenediamine or 1,10- phenathroline).
  • Examples of useful ligands for group 8-1 1 transition metals include, but not limited to, 2-phenylphenol, 2,6-dimethylphenol, 2-isopropylphenol, 1-naphthol, 8-hydroxyquinoline, 8-aminoquinoline, DBU, 2-(dimethylamino)ethanol, N 5 N- diethylsalicylamide, 2-(dimethylamino)glycine, N,N,N',N'-tetramethyl-l ,2- diaminoethane, 4,7-diphenyl-l,10-phenanthroline, 4,7-dimethyl-l,10-phenanthroline, 5- methyl- 1 , 10-phenanthroline, 5-chloro- 1 , 10-phenanthroline, 5-nitro- 1,10- phenanthroline, 4-(dimethylamino)pyridine, 2-(aminomethyl)pyridine, (methylimino)diacetic acid, cis-l,2-diaminocyclo
  • the amount of ligand used may be stoichiometric or excess amount.
  • ligand may be used as a solvent for the reaction. Therefore, reagents such as N 5 N- dimethylformamide, dimethylsulfoxide, 1 -methyl-2-pyrrolidinone or other liquid amines may serve as a solvent as well as ligand for the reaction.
  • N,N'-dimethylethylenediamine is used interchangeably with
  • nucleophilic alkyl halide refers to any compound having an alkyl halide functional group on one part of the molecule and a nucleophilic group on the other part of the molecule.
  • nucleophilic or “nucleophile” is well recognized in the art and refers to a chemical moiety having a reactive pair of electrons. Therefore, examples of a nucleophilic alkyl halide include, but not limited to 2- chloroacetamide, chloroacetic acid, chloroproprionic acid as well as those with the general formula:
  • A is a halo group and X is a nucleophile such as an -N-, -O- or - S- group.
  • reduction refers to the conversion of a functional group in a molecule from one oxidation state to a lower oxidation state.
  • reducing agent or “reductive agent” refers to any compound or complex that is known in the field for its effects in converting a functional group in a molecule from one oxidation state to a lower oxidation state. The reduction may be achieved via a direct electron, hydride or hydrogen-atom transfer.
  • Typical reducing agents useful for Methods 1C include metal hydrides (e.g., lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride) and hydrogen in the presence of a catalyst (e.g., Raney nickel, palladium on chracoal, nickel boride, platinum metal or its oxide, rhodium, ruthenium and zinc oxide, pentacyanocobaltate(II) Co(CN) 5 3" ).
  • Catalytic hydrogenation is typically carried out at room temperature and above atmospheric pressure, but higher temperature and pressure may be required for more resistant double bonds.
  • reducing agents useful for converting double bonds to single bonds include silane and acid; sodium cyanoborohydride and acid; zinc and acid; sodium and liquid ammonia; sodium in ethanol; and borane-triethylamine.
  • Typical reducing agents useful for reducing a ketone to a methylene as in Methods IH include but are not limited to metal hydrides (e.g., diisobutyl aluminum hydride (DIBAL), sodium bis(2- methoxyethoxy)aluminum hydride (Red- Al) or sodium cyanoborohydride); boranes (e.g., BH 3 -THF); or organoboranes (e.g. bis(benzyloxy)borane).
  • DIBAL diisobutyl aluminum hydride
  • Red- Al sodium bis(2- methoxyethoxy)aluminum hydride
  • Red- Al sodium cyanoborohydride
  • boranes e.g.,
  • such conversion may also be accomplished through catalytic hydrogenation by using hydrogen in presence of a catalyst (e.g. nickel, palladium on charcoal, nickel boride, platinum metal, platinum oxide, palladium oxide, rhodium oxide, ruthenium oxide or zinc oxide); Wolff-Kishner reduction by heating the ketone with hydrazine hydrate in the presence of a base such as sodium or potassium hydroxide (See Todd, Org. React. 4, 378-422 (1948)); or Clemmensen reduction by heating the ketone with zinc amalgam and aqueous mineral acid such as hydrochloric acid (See Vedejs, Org. React. 22, 401- 422 (1975)).
  • a catalyst e.g. nickel, palladium on charcoal, nickel boride, platinum metal, platinum oxide, palladium oxide, rhodium oxide, ruthenium oxide or zinc oxide
  • Wolff-Kishner reduction by heating the ketone with hydrazine hydrate in the presence of a base such
  • reducing agents see “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” by Jerry March, p. 771-790, John Wiley & Sons, Inc. (Fourth Edition).
  • alkylation refers to the introduction of an alkyl radical onto an organic compound by substitution or addition. Therefore, the term “N-alkylation” refers to the introduction of an alkyl radical onto the nitrogen atom of the organic compound.
  • 6-bromo-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indole hydrochloric acid salt may be prepared by mixing (2-bromophenyl) hydrazine hydrochloride (50.0 g, 219mmol), 4-piperidone monohydrate hydrochloride (36.0 g, 230mmol), ethanol (500 ml) and hydrochloric acid (50 ml). The resulting mixture is heated to reflux for 6 hours and is cooled to room temperature, filtered, washed with ethanol and dried to a solid.
  • [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-6]indole may be prepared by mixing 6-bromo-2,3,4,5-tetrahydro-lH-pyrido [4,3-6] indole hydrochloric acid salt with trifluoracetic acid (630 ml, 8.48mmol) and triethylsilane (172 ml). The mixture is stirred at room temperature under nitrogen for 19 hours. Excess trifluoroacetic acid and triethylsilane are removed in vacuo.
  • Enantiomeric separation of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-6]indole may be carried out by dissolving racemate 6-bromo- 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3- ⁇ ]indole (8g, 31.6mmol) in methanol (16OmL) at 50°C (oil bath) and adding (R)-mandelic acid (4.8g, 31.6mmol) in portions. The resulting clear solution is stirred at 50°C for several minutes and ether (8OmL) is added dropwise.
  • [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-l//- pyrido[4,3-6]indole may be separated by dissolving racemate 6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3- ⁇ ]indole (9.61g, 38.0mmol) in methanol (19OmL) at 50°C and adding (S)-(+)-Mandelic acid (5.78g, 38.0mmol) in portions. The resulting clear solution is stirred at 50 0 C for several minutes and ether (95mL) is added dropwise. The resulting solution is cooled to room temperature. The white precipitate (S-Mandelate salt, 4.Ig) is filtered off. ⁇ PLC analysis shows >99%ee.
  • Enantiomeric separation of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-6]indole may also be carried out by dissolving Racemic 6- bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-&]indole (1710 gm "as is," 1570gm by theory, 6.21 mol) in methanol (24 1) by warming to 40-50 0 C (under nitrogen). To the mixture is added (R)-(-)-Mandelic acid (944 g, 6.2 mol) in one portion.
  • the free base is extracted with dichloromethane (2 x 17L and 1 x 6L).
  • the DCM layers are combined, dried (Na 2 SO 4 ) and concentrated to afford a solid free base ( ⁇ 1150 g).
  • the free base is dissolved in methanol (17 L) by warming to 40-50 0 C under N 2 and (S)-(+)-Mandelic acid (692 g, 4.55 mol) is added.
  • the heating mantle is turned off and to the solution is added MTBE (8.5 L) in one portion.
  • the resulting solution is allowed to cool to room temperature with stirring and aged for 30-40 hours.
  • the product is isolated by filtration as a white to off-white precipitate and air dried at ambient temperature overnight.
  • the feeds are injected separately at 25mL volume and eluted with 100% Ethanol at a flow rate of 150mL/min at 25°C.
  • 42Og of racemic 6-bromo-2,3,4,4a,5,9b-hexahydro-lH- pyrido [4,3 -b] indole is similarly dissolved, filtered and injected at 55mL volumn onto a CHIRALPAK® AD® column, 20 ⁇ m, 1 lcm ID x 25cm L with a flow rate of 400mL/min.
  • the products are detected at an ultraviolet wavelength of 330nm.
  • the products are collected and the solvents are evaporated on rotary evaporators at 40 0 C and under a vacuum of 50-70mbar.
  • the products are analyzed through chiral HPLC analysis by using an AD-H 4.6mm ID x 250mm column at 30°C column temperature, 100% ethanol mobile phase at a flow rate of 0.7mL/min and dected at 200nm, 230nm, 250nm, 280nm or 325nm.
  • the products are also analyzed by achiral HPLC analysis using an Eclipse, 5 ⁇ m XDB-C8, 4.6mm ID x 250 mm column at 30°C column temperature, 75:25 methanol/0.1% aqueous diethylamine at a flow rate of lmL/min and detected at 250nm, 200nm, 230nm, 280nm or 325nm.
  • the isolated product is >98% ee.
  • 2(9bH)-carboxylate may be prepared by first optaining [4aS, 9bR]-6-bromo- 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-Z>]indole (36.0 g, 0.142mol)) as a free base by using 50% aqueous sodium hydroxide solution and extracting the product into MTBE.
  • the conversion to (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-l ⁇ -pyrido[4,3- b]indole-2(9bH)-carboxylate may then be done by cooling a suspension of compounds of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-*]indole (36.0 g, 0.142mol)) in THF (300 ml) and triethylamine (24 ml) in an ice- water bath.
  • the flask is charged with the S-mandelate starting material (5 g, 12.35 mmol), Na 2 CO 3 (2.88 g, 27.17 mmol), and 25 mL of T ⁇ F.
  • To the yellow reaction mixture at 25 0 C (heating block temperature) is added a solution of ethyl chloroformate (1.64 g, 15.11 mmol) in 5 mL of T ⁇ F dropwise over ca 70 minutes.
  • the batch is stirred at 25 0 C for another 10 min, and is checked by ⁇ PLC. Less than 2% of the starting material is observed by ⁇ PLC, and the desired product is registered at ca. 98%.
  • To the batch is added 12.5 mL of EtOH, and the batch is concentrated under reduced pressure to remove ca.
  • (4aS,9bR)-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro- lH-pyrido[4,3-b]indole-2(9bH)-carboxylate may be prepared by heating to a reflux a suspension of (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro- 1 H-pyrido[4,3-b]indole- 2(9bH)-carboxylate (5.648g, 17.4mmol), 2-chloroacetamide (7.32g, 78.2mmol), potassium iodide (19.2g, 77.7mol) and diisopropylethylamine (19mL, 115mmol) in acetonitrile (8OmL) for 27 hours. The solvent is removed in a vacuo and water (20OmL) is added
  • Example 5 Production of (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-2-oxo-lH- pyrido[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8-carboxylate [0086] A suspension of [4aS,9bR]-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-
  • the resulting mixture is heated to a reflux for another 3 hours and then at 73 °C for about 66 hours.
  • the reaction mixture is concentrated and passed through a short alumina column using 100:3:3 dichloromethan:triethylamine:methanol.
  • the resulting solvent from the column is evaporated to a solid and redissolved in dichloromethane.
  • the dichloromethane solution is washed with brine, dried with sodium phosphate and concentrated to a solid (3.7g, 95%, 83% pure by HPLC).
  • Example 5-A Production of (6bR,10aS)-ethyI 2,3,6b,9,10,10a-hexahydro-2-oxo-lH- pyrido [3 ',4' :4,5]-py rrolo [1 ,2,3-de] quinoxaline-8-carboxy late [0087]
  • (6bR, 1 OaS)-ethyl 3,6b,9, 10, 1 Oa- hexahydro-3 -methyl-2-oxo- 1 H-pyrido [3 ' ,4 ' :4,5]-pyrrolo [ 1 ,2,3 -de]quinoxaline-8- carboxylate may also be made in a one pot method starting from Compound of Formula ID.
  • a 2 liter 4 neck round bottom flask is equipped with a mechanical stirrer, reflux condenser, N 2 inlet, teflon covered K-type temperature probe with a controller, and a heating mantle.
  • To the flask is charged (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro- lH-pyrido[4,3-b]indole-2(9bH)-carboxylate (250 g, 769 mmol), chloroacetamide (124 g, 1153 mmol, 1.5 equiv), potassium iodide (191.5 g, 1160 mmol, 1.5 equiv), diisopropyl ethylamine (266 mL, 1531 mmol, 2.0 equiv), and dioxane (625 mL).
  • the reaction is heated to reflux temperature of about 103 0 C until less than 3% of the starting substrate is observed by HPLC (about 48 hours). Additional charge of N- methyl chloroacetamide and diisopropyl ethylamine maybe necessary.
  • the reaction is then cooled to ca. 80 0 C, and at this temperature copper iodide (29.2 g, 153.8 mmol, 0.2 equiv), potassium carbonate (232.5 g, 1682 mmol, 2.2 equiv), dimethylethylene diamine (49.6 mL, 461 mmol, 0.6 equiv), and additional dioxane (375 mL) is added.
  • the reaction is then re-heated to reflux and is monitored by HPLC. Reflux occurs at ca. 103 0 C. The reaction is monitored by HPLC.
  • Example 6 Production of (6bR,10aS)-ethyl 3,6b,9,10,10a-hexahydro-3-methyI-2- oxo-lH-pyrido[3',4':4,5]-pyrroIo[l,2,3-de]quinoxaline-8-carboxylate [0088] (6bR, 1 OaS)-ethyl 2,3,6b,9, 10, 1 Oa-hexahydro-2-oxo- 1 H-pyrido-
  • [3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8-carboxylate (17.3 g, 57.4mmol), K 2 CO 3 (15.8g, 114mmol), and methyl iodide (66 ml, lO ⁇ Ommol) are placed in a 2L pressure bottle and 500 ml of acetone is added. The bottle is heated in an oil bath at 109°C for 5.5 hours and cooled to room temperature. Acetone and excess methyl iodide are removed in vacuo and 200 ml of water is added and then extracted with DCM. The DCM layers are combined and washed with brine and dried (Na 2 SO 4 ).
  • (6bR, 1 OaS)-ethyl 3,6b,9, 10, 1 Oa- hexahydro-3-methyl-2-oxo-lH-pyrido[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8- carboxylate may also be made in a one pot method starting from Compound of Formula ID.
  • a 2 liter 4 neck round bottom flask is equipped with a mechanical stirrer, reflux condenser, N 2 inlet, teflon covered K-type temperature probe with a controller, and a heating mantle.
  • the reaction is heated to reflux temperature of about 103 0 C until less than 3% of the starting substrate is observed by HPLC (about 48 hours). Additional charge of N- methyl chloroacetamide and diisopropyl ethylamine maybe necessary.
  • the reaction is then cooled to ca. 80 0 C, and at this temperature copper iodide (29.2 g, 153.8 mmol, 0.2 equiv), potassium carbonate (232.5 g, 1682 mmol, 2.2 equiv), dimethylethylene diamine (49.6 mL, 461 mmol, 0.6 equiv), and additional dioxane (375 mL) is added.
  • the reaction is then re-heated to reflux and is monitored by HPLC. Reflux occurs at ca. 103 0 C. The reaction is monitored by HPLC.
  • the reaction is cooled to ca. 40 0 C and poured onto a plug of flash-grade silica gel (625 g, 2.5 g/g). It is eluted (under vacuum) with 6.25 L of ethyl acetate. The eluent is concentrated to a solid residue (320 gm), and then is dissolved in hot ethanol (800 ml). This mixture is allowed to cool to ambient temperature and stirred overnight. The next day it is cooled to 0-5 0 C, aged for Ih and filtered. The cake is washed with cold ethanol (150 ml) and allowed to air dry to afford 170 grams (70%) of product as a white solid which is >99A% pure by HPLC.
  • Example 7 Production of (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH- pyrido-[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8-carboxylate [0091] (6bR, 1 OaS)-ethyl 2,3 ,6b,9, 10, 1 Oa-hexahydro-3-methyl- 1 H-pyrido-
  • [3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8-carboxylate may be prepared by adding BH 3 THF (IM in THF, 143mL, 143mmol) dropwise at room temperature over 15 minutes to a suspension of (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-3-methyl-2- oxo- 1 H-pyrido[3 ' ,4 ' :4,5]-pyrrolo [ 1 ,2,3 -de]quinoxaline-8-carboxylate ( 18.Og, ca.57mmol) in 50 ml of THF. The resulting mixture is heated to a reflux for 3 hours.
  • BH 3 THF IM in THF, 143mL, 143mmol
  • (6bR, 10aS)-3-methyl-2,3,6b,9, 10, 1 Oa-hexahydro- 1 H- pyrido-[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline may be prepared as follows: To a 5 L, 3 -necked round-bottomed flask equipped with an overhead stirrer, an N 2 inlet, and a K- type Teflon covered temperature probe is charged with (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-3-methyl-2-oxo-lH-pyrido[3',4':4,5]-pyrrolo[l,2,3- de]quinoxaline-8-carboxylate (218 g, 691.3 mmol) using THF (ca.
  • the reaction vessel is vacuum/N 2 purged three times, and then is added a 1 M solution of BH 3 -THF complex in THF (1962 mL, 1962 mmol, 2.8 equiv) slowly through an addition funnel.
  • the resultant clear solution is then heated at 60 0 C.
  • the resultant batch is then stirred at 60 0 C for ca. 17 h, and showed 89.0% of the desired product with ca. 3.0% of unreacted substrate by HPLC.
  • the batch is stirred at 60 0 C for another 3 h, and then is cooled in an ice bath to ca. 10 0 C.
  • Example 9 Production of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH- pyrido- [3 ',4' :4,5] -pyrrolo [1 ,2,3-de] quinoxalin-8-(7H)-yI)-l -(4-fluorophenyl)-l- butanone
  • the reaction may be carried out in 3- pentanone.
  • a 5 L, three-necked, round-bottomed flask equipped with a mechanical stirrer, a N 2 inlet, a reflux condenser, and a temperature probe is charged with 230 g of (6bR, 10aS)-3-methyl-2,3,6b,9, 10, 1 Oa-hexahydro- 1 H-pyrido-[3 ',4' :4,5]-pyrrolo[l ,2,3- dejquinoxaline (1 mol), 249.78 g of KI (1.5 mol, 1.5 equiv), 194.12 g OfPr 2 NEt (1.5 mol, 1.5 equiv), 301.76 g of 4-chloro-4'-fluorobutyrophenone (1.5 mol, 1.5 equiv), and 2300 mL of 3-pentanone.
  • the resultant mixture is then heated at 95 0 C (internal temperature) for 17 h, and then is checked by HPLC for reaction completion.
  • the batch is then cooled to ca. 10 0 C with an ice bath, and then is added 5% NaOH solution (2300 mL).
  • the separated aqueous layer is then extracted with EtOAc (2300 mL).
  • the combined organic layer is filtered through a pad of silica gel (1 15 g) that is pre-packed with EtOAc.
  • the silica gel is then flushed with EtOAc (2300 mL).
  • the combined filtrate is concentrated under reduced pressure to afford a dark brown liquid.
  • EtOAc (2300 mL)
  • 1.5 N HCl solution 2300 mL).
  • the batch is stirred at rt for ca. 20 min, and layers are cut.
  • the separated organic layer is extracted with 1.5 N HCl solution (1150 mL), and the layers are separated.
  • the combined aqueous layer is cooled in an ice bath to ca. 10 0 C, and is added EtOAc (2300 mL).
  • To the stirring mixture is then added 25% NaOH solution (1000 mL) through an addition funnel while maintaining the internal temperature under 25 0 C.
  • the resultant mixture is stirred in an ice bath for ca. 20 min, and the layers are separated.
  • the aqueous layer shows a pH between 11 to 12 by pH paper.
  • the aqueous layer is back extracted with EtOAc (1 150 mL), and the layers are cut.

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Abstract

The present invention provides methods for the preparation of substituted heterocycle fused gamma-carbolines, intermediates useful in producing them and methods for producing such intermediates and such heterocycl fused gamma-carbolines.

Description

SUBSTITUTED HETEROCYCLE FUSED GAMMA-CARBOLINES SYNTHESIS
RELATED APPLICATION
[0001] This application claims priority from U.S. Provisional Application No.
60/906,473, filed Marchl2, 2007, the contents of which are hereby incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a method for the preparation of substituted heterocycle fused gamma-carbolines, intermediates useful for producing them, and a method for producing such intermediates.
BACKGROUND OF THE INVENTION
[0003] Substituted heterocycle fused gamma-carbolines are useful as agonists or antagonists of 5-HT2 receptors, particularly 5-HT2A and 5-HT2C receptors, in treating central nervous system disorders, including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility.
[0004] Traditional methods for the preparation of enantiomerically pure substituted heterocycle fused gamma-carbolines involve Fischer indole cyclization of aryl hydrazine (e.g., dihydroquinoxalin-l-(2H)-amine, 2Η-benzo[δ][l,4]oxazin-4(J//)- amine or 2H-benzo[b][l,4]thiazin-4(3H)-amine) with suitably substituted cyclic ketones (e.g., piperidin-4-one) to afford tetracyclic indole compounds (e.g., 1,3,7,8,9,10- hexahydro-lΗ-pyrido-[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline). This indole core is then reduced to afford the cis or trans tetracyclic dihydroindole (i.e., cis or trans tetracyclic indoline) product, which requires exhaustive purification procedures such as chiral column chromatography to afford enantiomerically pure product. This method as a whole is inefficient because excess reagents and reaction intermediates are required to produce racemic products, wherein such product is purified at the final step to give a 25-50% yield at best. There is thus a need for a more efficient process to make enantiomerically pure substituted heterocycle fused gamma-carbolines.
SUMMARY OF THE INVENTION
[0005] The present invention provides methods for the preparation of substituted heterocycle fused gamma-carbolines in free or pharmaceutically acceptable salt forms, intermediates used in the preparation, for example enantiomerically pure 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole type intermediates, and methods for producing said intermediates and said substituted heterocycle fused gamma-carbolines are disclosed in the present invention.
[0006] Substituted heterocycle fused gamma-carbolines and their pharmaceutically acceptable salts produced by the present invention are represented by the core structure shown in Formula IJ:
Figure imgf000003_0001
Formula U
[0007] Exemplary representations of compounds of the invention and R 1 , r R>6a
R6b, R7, R8, R9, R10, X, k, m, and n are as described in U.S. Patent Nos. 6,552,017; 6,548,493; 6,713, 471; and 6,849,619, U.S. Reissued Patent No. 39,680 and 38,679, and U.S. Application Nos. 10/787,941 and 10/786,935, the contents of each of which are all incorporated herein by reference. These compounds have been found to be useful as 5- HT2 receptor agonists and antagonists used in treating disorders of the central nervous system including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility. [0008] Accordingly, the present invention provides substantially enantiomerically pure cis dihydroindole (or indoline) type compounds as disclosed below in formulas 1C, ID, IE, IE', IF" and IG', e.g., at least 70%, preferably 80%, more preferably at least 90%, most preferably greater than 95% cis compounds of the following formulas (e.g., 1C, ID, IE, IE', IF" and IG') relative to all of their other stereoisomers, in free or pharmaceutically acceptable salt form, which are useful, e.g., as intermediates for the production of compounds of Formula IJ: 1.1: Compounds of Formula 1 C :
Figure imgf000004_0001
wherein: (i) k is 1 or 2; (ϋ) m is 0, 1 or 2; (iii) A = Cl, Br, F or I; (iv) R , R and R are independently H or optionally substituted Ci- Cόalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
1.2: Compounds of Formula ID:
Figure imgf000005_0001
Formula ID wherein:
0) k is 1 or 2;
(ϋ) m is 0, 1 or 2;
(iii) A = Cl, Br, F or I;
(iv) B is a protective group;
(V) R7, R8andR9 are independently H or optionally substituted Ci-C6alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
1.3 : Compounds of Formula IE':
Figure imgf000005_0002
Formula IE1 wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) B is a protective group. (iv) R7, R8and R9 are independently H or optionally substituted C|-C6alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
1.4: Compounds of Formula 1 E :
Figure imgf000006_0001
Formula IE
wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) A = Cl, Br, F or I;
(v) B is a protective group;
(vi) R , R and R are R , R and R are independently H or optionally substituted Ci-C6alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.; and
(vii) X-Y- is a HO-CH2-, HS-CH2-, H(R')N-CH2- or H(R')N-C(O)-, wherein R' is H or Ci-4alkyl.
1.5: Compounds of Formula IF"
Figure imgf000007_0001
Formula IF"
wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protective group;
(v) R , R and R are R , R and R are independently H or optionally substituted Ci-C6alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.; and
(vi) -X-Y- is ~{R')N-C(0)-, wherein R' is H or d^alkyL
1.6: Compounds of Formula IG':
Figure imgf000007_0002
Formula IG1 wherein:
(i) k is l or 2;
(ii) m is 0, 1 or 2; (Hi) n is 1, 2 or 3;
(iv) B is a protective group;
(v) R , R and R are R , R and R are independently H or optionally substituted Ci-C6alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.; and
(vi) R10 is Ci-4alkyl, alkenyl or alkynyl.
[0009] The invention further provides compounds of the following formulae:
2.1. Formula 1 G', wherein R10 is Cj-Qalkyl, alkenyl or alkynyl.
2.2. Formula IG', wherein R10 is methyl.
2.3. Formula IF", wherein -X-Y- is -(R')N-C(O)- wherein R' is H or Ci-4alkyl.
2.4. Any of Formulae IF", IG' or 2.1-2.3, wherein n is 1, 2 or 3.
2.5. Any of Formulae IF", IG or 2.1-2.3, wherein n is 1.
2.6. Formula 1 E, wherein X-Y- is HO-CH2-, HS-CH2-, H(R')N-CH2- or H(R')N-C(O)- and R' is H or C1-4alkyl.
2.7. Formula IE, wherein X-Y- is H(R')N-CH2- and R' is H or CMalkyl.
2.8. Any of Formulae ID, IE, IE', IF", IG' or 2.1-2.7, wherein B is a protective group.
2.9. Any of Formulae ID, IE, IE', IF", IG' or 2.1-2.7, wherein B has a general formula of -P-Z, wherein P is -C(O)-, -C(O)O-, or -S(O)2- and Z is alkyl or arylalkyl.
2.10. Any of Formulae ID, IE, IE', IF", IG' or 2.1-2.7, wherein B is - C(O)Oalkyl.
2.11. Any of Formulae ID, IE, IE', IF'", IG' or 2.1-2.7, wherein B is - C(O)OEt Or -C(O)OiPr.
2.12. Any of Formulae 1C, ID or 2.8-2.11, wherein A is Cl, Br, F or I.
2.13. Any of Formulae 1C, ID or 2.8-2.11, wherein A is Cl.
2.14. Any of Formulae 1C, ID, IE, IE' IF", IG' or 2.1-2.13, wherein R7, R and R are independently H or optionally substituted CpC6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
2.15. Any of Formulae 1C, ID, IE, IE' IF', IG' or 2.1-2.13, wherein R7, R8, and R9 are H.
2.16. Any of Formulae 1C, ID, IE, IE' IF', IG' or 2.1-2.15, wherein k and m are independently 0, 1, 2 or 3.
2.17. Any of Formulae 1C, ID, IE, IE' IF', IG' or 2.1-2.15, wherein k and m are 1.
2.18. Any of the preceding formulae wherein alkyl, alkenyl, alkynyl, alkoxy and haloalkyl independently comprises 1-6 carbon atoms.
2.19. Any of the preceding formulae wherein the alkyl of arylalkyl and heteroarylalkyl is independently 1-6 carbon atoms.
2.20. Any of the preceding formulae wherein cycloalkyl and heterocycloalkyl is independently 3-10 carbon atoms
2.21. Any of the preceding formulae wherein said compounds are at least 70%, preferably 80%, more preferably at least 90%, most preferably greater than 95% cis compounds of the following formulas (e.g., 1C, ID, IE, IE', IF" and IG') relative to all of their other stereoisomers, in free or pharmaceutically acceptable salt form.
[0010] The present invention further provides substantially optically pure cis dihydroindole (or indoline) type compounds as disclosed below in formulas 2C, 2D, 2E, 2E\ 2F" and 2G', e.g., at least 70%, preferably 80%, more preferably at least 90%, most preferably greater than 95% cis isomer relative to all of their trans isomers, in free or pharmaceutically acceptable salt form, which are useful, e.g., as intermediates for the production of compounds of Formula U: 1.7: Compounds of Formula 2C:
Figure imgf000010_0001
Formula 2C wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) A = Cl, Br, F or I;
(iv) R5 is H or Ci.C4alkyl;
(v) R 5 R and R are independently H or optionally substituted C]-C6alkyl, C3- C10cycloalkyl, C3-Ci0heterocycloalkyl, hydroxy, Ci-C6alkoxy, nitro, halo, haloCj-C6alkyl, aryl, arylCi-Qalkyl, heteroaryl or heteroarylCi-Coalkyl.
1.8: Compounds of Formula 2D:
Figure imgf000010_0002
Formula 2D wherein:
(i) k is l or 2;
(ϋ) m is ; 0, 1 or 2;
(iii) A = Cl, Br, F or I;
(iv) B is a protective group;
(V) R5 is H or Ci.Qalkyl; (vi) R7, R8and R9 are independently H or optionally substituted Ci-C6alkyl, C3- Ciocycloalkyl, C3-C10heterocycloalkyl, hydroxy, Cj-C6alkoxy, nitro, halo, haloCi-Cόalkyl, aryl, arylCi-Cβalkyl, heteroaryl or heteroarylCi-C6alkyl.
1.9: Compounds of Formula 2E' :
Figure imgf000011_0001
Formula 2E1 wherein: 0) k is 1 or 2; (ϋ) m is 0, 1 or 2; (iii) B is a protective group (iv) R5 is H or Ci.C4alkyl;
(V) R7, R8andR9 are independently H or optionally substituted Ci-C6alkyl, C3-
CiQcycloalkyl, C3-Cioheterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloCp
Cόalkyl, aryl, arylCi-C6alkyl, heteroaryl or heteroarylCi-Cόalkyl.
1.10: Compounds of Formula 2E :
Figure imgf000012_0001
Formula 2E
wherein
(i) k is 1 or 2; (ϋ) m is 0, 1 or 2; (iii) n is 1, 2 or 3; (iv) A = Cl, Br, F or I;
(V) B is a protective group;
(vi) R5 is H or Ci.Qalkyl; (vii) R7, R8and R9 are independently H or optionally substituted Ci-C6alkyl, C3-
Ciocycloalkyl, C3-Cioheterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloCj-
Cβalkyl, aryl, arylCi-C6alkyl, heteroaryl or heteroarylCi-Qalkyl; and (viii) X-Y- is a HO-CH2-, HS-CH2-, H(R')N-CH2- or H(R')N-C(O)-, wherein R' is H or Ci-C4alkyl.
1.11: Compounds of Formula 2F "
Figure imgf000012_0002
Formula 2F" wherein:
(i) k is 1 or 2; (ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protective group;
(v) R5 is H or C,.C4alkyl;
(vi) R7, R8and R9 are independently H or optionally substituted Ci-C6alkyl, C3- Ciocycloalkyl, Cs-Cjoheterocycloalkyl, hydroxy, Ci-C6alkoxy, nitro, halo, haloCi-Cόalkyl, aryl, arylCi-C6alkyl, heteroaryl or heteroarylCi-C6alkyl; and
(vii) -X-Y- is -(R')N-C(O)-, wherein R' is H or C i -C4alkyl.
1.12: Compounds of Formula 2G :
Figure imgf000013_0001
wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protective group;
(v) R5 is H or d-C4alkyl;
(vi) R7, R8and R9 are independently H or optionally substituted Ci-Cβalkyl, C3- Ciocycloalkyl, C3-Cioheterocycloalkyl, hydroxy, Ci.6alkoxy, nitro, halo, haloCi-Cόalkyl, aryl, arylCi-Cόalkyl, heteroaryl or heteroarylCi-Cόalkyl; and
(vii) R10 is H or C1-4alkyl.
[0011] The invention further provides compounds of the following formulae: 2.22. Formula 2G, wherein R10 is H or Ci-C4alkyl;
2.23. Formula 2G or 2.22, wherein R10 is H;
2.24. Formula 2G or 2.22, wherein R10 is methyl;
2.25. Formula 2F", wherein -X-Y- is -(R')N-C(O)-, wherein R' is H or CMalkyl;
2.26. Formula 2F' ' or 2.25, wherein -X-Y- is -{R')N-C(O)-, wherein R' is H or methyl;
2.27. Formula 2E, wherein X-Y- is HO-CH2- HS-CH2-, H(R')N-CH2- or H(R')N-C(O)- and R' is H or CMalkyl;
2.28. Formula 2E or 2.27, wherein X-Y- is H(R')N-CH2- and R' is H or CMalkyl;
2.29. Formula 2E or any of 2.27-2.28, wherein X-Y- is H(R')N-CH2- and R' is H;
2.30. Formula 2E or any of 2.27-2.29, wherein X-Y- is H(R')N-CH2- and R' is methyl;
2.31. Any of Formulae 2D, 2E, 2E', 2F", 2G or 2.22-2.30, wherein B is a protective group;
2.32. Any of Formulae 2D, 2E, 2E', 2F", 2G or 2.22-2.31, wherein B has a general formula of -P-Z, wherein P is -C(O)-, -C(O)O-, or -S(O)2- and Z is alkyl or arylalkyl;
2.33. Any of Formulae 2D, 2E, 2E\ 2F", 2G or 2.22-2.32, wherein B is - C(O)Oalkyl;
2.34. Any of Formulae 2D, 2E, 2E', 2F'", 2G or 2.1-1.7, wherein B is - C(O)OEt Or -C(O)OiPr;
2.35. Any of Formulae 2E, 2F", 2G or 2.22-2.34, wherein n is 1, 2 or 3.
2.36. Any of Formulae 2E, 2F", 2G or 2.22-2.35, wherein n is 1;
2.37. Any of Formulae 2C, 2D or 2.31-2.36, wherein A is Cl, Br, F or I.
2.38. Any of Formulae 2C, 2D or 2.31-2.37, wherein A is Cl or Br;
2.39. Any of Formulae 2C, 2D, 2E, 2E\ 2F", 2G or 2.22-2.38, wherein R7, R8and R9 are independently H or optionally substituted Ci-C6alkyl, C3-Ciocycloalkyl, C3-Cioheterocycloalkyl, hydroxy, Ci-6alkoxy, nitro, halo, haloCi-C6alkyl, aryl, arylCi-Cβalkyl, heteroaryl or heteroaryld- C6alkyl;
2.40. Any of Formulae 2C, 2D, 2E, 2E', 2F', 2G or 2.22-2.39, wherein R7, R8, and R9 are H;
2.41. Any of Formulae 2C, 2D, 2E, 2E\ 2F', 2G or 2.22-2.40, wherein k and m are independently 0, 1, 2 or 3;
2.42. Any of Formulae 2C, 2D, 2E5 2E\ 2F', 2G or 2.22-2.41, wherein k and m are 1 ;
2.43. Any of the preceding formulae wherein k is 1 and m is 1 ;
2.44. Any of the preceding formulae wherein R5 is H or Ci-C4alkyl;
2.45. Any of the preceding formulae wherein R5 is H;
2.46. Any of the preceding formulae wherein alkyl comprises alkyl, alkenyl and/or alkynyl.
2.47. Any of the preceding formulae wherein the two hydrogen atoms at the two chiral carbon atoms are cis to each other, thereby having the general structures as follows:
Figure imgf000015_0001
Formula .2C-I Formula 2C-2
Figure imgf000015_0002
Formula 2D- 1 Formula 2D-2
Figure imgf000016_0001
Formula 2E'-2
Formula 2E'-1
Figure imgf000016_0002
Formula 2E- 1 Formula 2E-2
Figure imgf000016_0003
Formula 2F"-1 Formula 2F"-2
Figure imgf000017_0001
Formula 2G- 1 Formula 2G-2 and
2.48. Any of the preceding formulae wherein the cis isomer is selected from formulae 2C-1, 2D-1, 2E-1, 2EM, 2FM, and 2G-1; in free or salt form.
METHOD
[0012] In another aspect, the invention provides a method (Method 1C) for preparing compounds of Formula 1C or any of 2.12-2.21 :
Figure imgf000017_0002
in free or salt form, as hereinbefore described, which method comprises the steps of: a) reducing compounds of Formula IA
Figure imgf000018_0001
Formula IA
to compounds of Formula IB; and
Figure imgf000018_0002
Formula IB b) separating the enantiomers of compounds of Formula IB by chiral acid resolution or chiral chromatography.
[0013] In another embodiment, the invention provides a method (Method 2C) for preparing compounds of Formula 1C or any of 2.37-2.48:
Formula 2C in free or salt form, as hereinbefore described, which method comprises the steps of: a) reducing compounds of Formula 2 A
Figure imgf000019_0001
to compounds of Formula 2B; and
Figure imgf000019_0002
b) separating the enantiomers of compounds of Formula 2B by chiral acid resolution or chiral chromatography.
[0014] The reduction of Compounds of Formula IA to Compounds of Formula
IB may be accomplished through the use of a reducing agent including, but not limited to: silanes in the presence of an acid (e.g., acetic or trifluoroacetic acid); metal (e.g., zinc) and mineral acid (e.g. hydrochloric acid); sodium and liquid ammonia; sodium in ethanol; or through the use of borane-amine complexes (e.g. borane-triethylamine in tetrahydrofuran); or sodium cyanoborohydride in the presence of an acid such as acetic or trifluoroacetic acid. The conversion of Compound of Formula IA to Formula IB may also be accomplished through catalytic hydrogenation wherein Compounds of Formula IA is treated with hydrogen in the presence of a catalyst such as palladium oxide, palladium on carbon or platinum oxide (See Hudlicky, M., "Reductions in Organic Chemistry", Ellis Horwood, Ltd., Chichester, UK, 1984). The reduction of Compounds of Formula 2 A to Compounds of Formula 2B may be accomplished through the use of similar agents as described for the reduction of Compounds of Formula IA to IB, for example silanes (e.g., triethylsilane) in the presence of an acid (e.g., acetic or trifluoroacetic acid); metal (e.g., zinc) and mineral acid (e.g. hydrochloric acid); sodium and liquid ammonia; sodium in ethanol; or through the use of borane-amine complexes (e.g. borane-triethylamine in tetrahydrofuran); NaBH(OAc)3; or sodium cyanoborohydride in the presence of an acid such as acetic or trifluoroacetic acid. The conversion of Compound of Formula IA to Formula IB may also be accomplished through catalytic hydrogenation wherein Compounds of Formula IA is treated with hydrogen in the presence of a catalyst such as palladium oxide, palladium on carbon or platinum oxide. In an especially preferred embodiment, reduction is accomplished through the use of triethylsilane in the presence of trifluoroacetic acid.
[0015] In one embodiment, enantiomeric separation of compounds of Formula
IB may be achieved by chiral acid resolution wherein chiral acids such as chiral sulphonic acids or mono or di carboxylic acids or derivatives thereof are used. Examples of such acids include, but are not limited to, (+/-)/(R/S) tartaric acid, (+/-)/ (RJS) (mono- or di-acetyl)tartaric acid, (+/-)/(R/S) (mono- or di-benzoyl)tartaric acid, (+/-)/(R/S) (mono- or di-pivaloyl)tartaric acid, (+/-)/(R/S) mandelic acid, (+/-)/ (RJS) acetoxyphenyl acetic acid, (+/-)/(R/S) methoxyphenyl acetic acid, (+/-)/(R/S) hydroxymandelic acid, (+/-)/(R/S) halomandelic acid (e.g. 4-fluoromandelic acid), (+/- )/(R/S) lactic acid, and (+/-)/(R/S) camphor sulfonic acid. Similarly, the enantiomeric separation of compounds of Formula 2B may be achieved by chiral acid resolution wherein chiral acids such as chiral sulphonic acids or mono or di carboxylic acids or derivatives thereof are used. Examples of such acids include, but are not limited to, (+/-)/(R/S) tartaric acid, (+/-)/ (RJS) (mono- or di-acetyl)tartaric acid, (+/-)/(R/S) (mono- or di-benzoyl)tartaric acid, (+/-)/(R/S) (mono- or di-pivaloyl)tartaric acid, (+/- )/(R/S) mandelic acid, (+/-)/ (RJS) acetoxyphenyl acetic acid, (+/-)/(R/S) methoxyphenyl acetic acid, (+/-)/(R/S) hydroxymandelic acid, (+/-)/(R/S) halomandelic acid (e.g. 4-fiuoromandelic acid), (+/-)/(R/S) lactic acid, and (+/-)/(R/S) camphor sulfonic acid. Preferably, resolution of compounds of Formula 1 B or 2B is accomplished by using mandelic acid. In an especially preferred embodiment, said acid is (S)-(+)-mandelic acid. Resolution may be optimized where undesired enantiomer is removed first. Therefore, in an especially preferred embodiment, resolution is accomplished by adding (R)-(-)-mandelic acid to remove the undesired enantiomer first, followed by the addition of (S)-(+)-mandelic acid to obtain the desired product.
[0016] In another embodiment, enantiomeric separation of compounds of
Formula IB may be achieved by using chiral chromatography, for example using amylose tris(3,5-dimethylphenylcarbamate) column sold under the tradename "CHIRALP AK® AD®". The racemic compounds of Formula IB may be eluted with a mobile phase such as ethanol at a flow rate of 100-450mL/min. In yet another embodiment, the racemic compounds of Formula IB may be eluted with mobile phase such as methanol or isopropyl alcohol. The fractions for the desired compounds, preferably, Compounds of Formula 1C or 2C, may be collected and isolated. In one embodiment, chiral chromatography comprises the use of CHIRALP AK® AD®, 20μm, 5cm ID x 50cm L column and 100% ethanol mobile phase at a flow rate of 150mL/min. In another embodiment, chiral chromatography comprises the use of CHIRALP AK® AD®, 20μm, 1 lcm ID x 25cm L column and 100% ethanol mobile phase at a flow rate of400mL/min.
[0017] In another embodiment, the enantiomeric separation of compounds of
Formula 2B may be achieved by using chiral chromatorgraphy as described above in Method for separating Compounds of Formula IB.
[0018] In another aspect, the invention provides a method (Method ID) for preparing compounds of Formula ID or any of 2.8-2.21 :
Figure imgf000021_0001
Formula ID as hereinbefore described in free or salt form, which method comprises the step of protecting the piperidino-amine of compounds of Formula 1C:
Figure imgf000022_0001
Formula 1C with a protecting agent in the presence of a base.
[0019] In a further embodiment, the protecting agent of Method ID comprises the general formula:
γ/p\z
wherein:
(i) Y is halogen, imidazoyl, benzotriazole, N-(oxy)succinimide, alkoxy, -O- alkylaryl or -O-aryl; (i) Z is optionally substituted alkyl, aryl, alkylaryl or -OR wherein R is alkyl, aryl, arylalkyl or heteroarylalkyl; (ii) P is -C(O)-, -C(O)O- or S(O)2.
[0020] In another embodiment, the invention also provides a method (Method
2D) for preparing compounds of Formula 2D or any of 2.31-2.48:
Figure imgf000022_0002
Formula 2D as hereinbefore described in free or salt form, which method comprises the step of protecting the piperidino-amine of compounds of Formula 2C:
Figure imgf000023_0001
with a protecting agent.
[0021] In a further embodiment, the protecting agent of Method 2D comprises the general formula:
Figure imgf000023_0002
wherein:
(iii) Y is halogen, imidazoyl, benzotriazole, N-(oxy)succinimide, alkoxy, alkoxycarbonyl, -O-alkylaryl or -O-aryl;
(ii) Z is optionally substituted alkyl, aryl, alkylaryl, alkoxycarbonyl, or -OR wherein R is alkyl, aryl, arylalkyl or heteroarylalkyl;
(iv) P is -C(O)-, -C(O)O-, -O- or S(O)2.
[0022] Examples of the protecting agent of compounds of Formula 1C or 2C include, but are not limited to benzyloxycarbonyl chloride (Cbz-Cl), triphenylmethyl chloride, ethyl chloroformate, /-butoxycarbonyl anhydride (BOC2), benzyl N- succinimidyl carbonate, or benzoyl halide (e.g. benzoyl chloride or bromide), (benzyloxycarbonyl)-benzo triazole, benzyl halide (e.g. benzyl chloride or bromide), 1- arene sulfonyl chloride or toluene sulfonyl chloride. Another example of protecting agent of Compounds of Formula 1C or 2C is p-methoxybenzyl ether. The protective agents disclosed herein are not intended to be exhaustive. For further examples of amine protecting agent, see one of the many general texts on the subject, for example, "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons), the disclosure of which is hereby incorporated by reference. Upon addition of the protecting agent to compounds of Formula 1C, substituent B therefore contains a general formula:
Figure imgf000024_0001
wherein:
(i) Z is optionally substituted alkyl, aryl, alkylaryl or -OR wherein R is alkyl, aryl, arylalkyl or heteroarylalkyl; (ii) P is -C(O)-, -C(O)O- or S(O)2.
[0023] The protection step of this embodiment generally requires the addition of a base such as butyl lithium or metal hydrides (e.g., potassium hydride) or carbonates of alkali or alkaline earth metals (e.g., potassium or sodium carbonate), or organic amines (e.g., triethylamine). Preferably, the protecting agent of compounds of Formula ID or 2D is ethyl chloroformate or BOC anhydride. In an especially preferred embodiment, said protecting agent is ethyl chloroformate and said base is triethylamine. [0024] In another aspect, the invention also provides a method (Method IE) for preparing compounds of Formula IE or any of 2.6-2.21 :
Figure imgf000024_0002
Formula IE in free or salt form as herein before described, which method comprises the step of N- alkylating compounds of Formula ID:
Figure imgf000024_0003
Formula ID with (a) a nucleophilic alkyl halide of the general formula: <> > »
X — Y wherein:
(i) A = Cl, F, Br or I;
(ii) X-Y is a -HOCH2- -HSCH2- -H(R')N-CH2- or -H(R')N-C(O)-, wherein
R' is H or CMalkyl; (iii) n is 1, 2 or 3; and (b) a base.
[0025] In another embodiment, the invention also provides a method (Method
2E) for preparing compounds of Formula 2E or any of 2.27-2.48:
Figure imgf000025_0001
in free or salt form as herein before described, which method comprises the step of N- alkylating compounds of Formula 2D:
Figure imgf000025_0002
Formula 2D with (a) a nucleophilic alkyl halide of the general formula:
A
x — Y wherein: (i) A = Cl, F, Br or I;
(ii) X-Y is a -HOCH2-, -HSCH2-, -H(R')N-CH2- or -H(R')N-C(O)-, wherein R' is H or Ci-4alkyl;
(iii) n is 1, 2 or 3; and (b) a base.
[0010] Examples of nucleophilic alkyl halide for Method IE or 2E include, but are not limited to, 2-chloroacetamide, 2-bromoacetamide, chloroacetic acid, chloroproprionic acid, 2-chloroethanethioic S-acid. Examples of base useful for Method IE or 2E include, but not limited to organic bases such as amine bases (e.g., ammonium, triethylamine, N,N'-diisopropylethyl amine or 4-(dimethylamino)pyridine (DMAP); l,5-diazabicycl[4.3.0]-non-5-ene (DBN), l,5-diazabicyclo[5.4.0]undec-5-ene (DBU)); or inorganic bases such as hydrides (e.g. sodium, lithium or potassium hydride), alkoxides, (e.g. sodium, potassium or lithium t-butoxide and K(OAr), Na(OAr)), or carbonate, bicarbonate, phosphate or hydroxide of an alkali or alkaline earth metal (e.g. sodium, magnesium, calcium, potassium, cesium or barium carbonate, bicarbonate, hydroxide or phosphate). Optionally, such N-alkylation reaction may be achieved in the presence of an iodide source such as potassium iodide or sodium iodide, preferably potassium iodide. In a preferred embodiment, compounds of Formula IE or 2E, wherein X-Y- is H(R')N-C(O)- or H(R')N-CH2- R' is H and n is 1 are prepared by using 2-chloroacetamide in the presence of N,N'-diisopropylethyl amine and potassium iodide. In another prefered embodiment, chloroacetamide, potassium iodide, isopropylethylamine in dixoane solvent is used.
[0011] In another aspect, the invention also provides a method (Method IF) for preparing compounds of Formula IF:
Figure imgf000026_0001
Formula IF wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protecting agent;
(v) R 5 R and R are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and
(vi) X-Y is -OCH2-, -SCH2-, -(R')N-CH2- or -(R')N-C(O)-, wherein R' is H or
C1-4alkyl; or any of 2.3-2.21, which method comprises the step of treating compounds of Formula IE:
Figure imgf000027_0001
Formula IE as hereinbefore described, with:
(a) a transition metal catalyst selected from a group consisting of Group 8-11 of the periodic table; and
(b) a base. 012] In another embodiment, the invention provides a method (Method 2F) for preparing compounds of Formula 2F:
Figure imgf000028_0001
Formula 2F
wherein:
(i) k is 1 or 2; (ϋ) m is 0, 1 or 2; (iii) n is 1, 2 or 3; (iv) B is a protective group;
(V) R5 is H or CrC4alkyl;
(vi) R7, R8and R9 are independently H or optionally substituted Ci-Cόalkyl, C3-
Cjocycloalkyl, C3-Ci0heterocycloalkyl, hydroxy, d-Cόalkoxy, nitro, halo, haloCrQalkyl, aryl, arylCi-C6alkyl, heteroaryl or heteroarylCi-C6alkyl; and
(vii) -X-Y- is -OCH2- -SCH2- -(R')N-CH2- or -(R')N-C(O)-, wherein R' is H or C^alkyl; or any of 2.25-2.48, which method comprises the step of treating compounds of Formula 2E:
Figure imgf000028_0002
as hereinbefore described with:
(a) a transition metal catalyst selected from a group consisting of Group 8- 1 1 of the periodic table; and (b) a base.
[0013] The transitional metal catalyst of Method IF or 2F may be an atom, ion, salt or complex of transition metals selected from Groups 8-1 1 of the periodic table (e.g., palladium, copper, nickel, platinum, ruthenium, or rhodium). Examples of such transition metal catalyst include, but not limited to copper catalysts such as CuI, CuCl, CuBr, CuBr2, Cu(II) acetate, Cu2Cl2, Cu2O, Cu, or palladium or nickel catalysts such as Pd2(dba)2, Pd/C, PdCl2, Pd(OAc)2, (CH3CN)2PdCl2, Pd[P(C6H5)3]4, bis(dibenzylideneacetone) palladium [Pd2(dba)3], Ni(acetylacetonate)2, NiCl2[P(C6H5)J2 and Ni(1, 5-cyclooctadiene^ as described in U.S. patents 6,759,554B2; 6,395,916Bl; 6,307,087Bl, herein incorporated by reference in their entirety. In a preferred embodiment, the transition metal catalyst is copper catalyst. In an especially preferred embodiment, said catalyst is CuI.
[0014] The base useful for Method IF or 2F may be a bronsted base or a Lewis base well known in the art, including by way of example only, amine bases (e.g. triethylamine, trimethylamine, N,N'-diisopropylethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or l,4-diazabicyclo[2.2.2]octane (DABCO)), hydrides (e.g. sodium, lithium or potassium hydride), alkoxides (e.g. sodium or potassium tert-butoxide), carbonates (e.g. sodium carbonate or bicarbonate, potassium or cesium carbonate) or phosphates (e.g. potassium phosphate). In a preferred embodiment, the base is a carbonate of alkali or alkali earth metals (e.g., sodium, potassium, cesium, barium, etc.). In an especially, said base is potassium carbonate.
[0015] In yet another embodiment, Method IF further comprises the step of treating Compound of Formula IE with a mono or bi-dentate ligand known to ligate with transition metal catalysts. Examples of such ligand include, but are not limited to:
(1) phenolic or amine ligands such as optionally substituted aryl alcohol, 1,2-diamine, 1,2-aminoalcohol, imidazolium carbene, 4-(dimethylamino)pyridine, 2- (aminomethyl)pyridine, 4,7-diphenyl- 1 , 10-phenanthroline, 4,7-dimethyl- 1,10- phenanthroline, 5-methyl- 1,10-phenanthroline, 5 -chloro- 1,10-phenanthroline, and 5- nitro- 1 , 10-phenanthroline;
(2) N,N-dimethylformamide, dimethylsulfoxide and 1 -methyl -2 -pyrrolidinone;
(3) ligand represented by structure 1 :
Figure imgf000030_0001
wherein
• A and B independently represent fused rings selected from the group consisting of monocyclic or polycyclic cycloalkyls, cycloalkenyls, aryls, and heterocyclic rings, said rings having from 4 to 8 atoms in a ring structure;
• X represents NR2, P(alkyl)2, P(cycloalkyl)2, AsR2, or OR;
• Y represents H, alkyl, NR2, or AsR2;
• X and Y are not identical;
• R, R3, Rb, Rc, and Ra, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or -(CH2)H1 -R80;
• Re and Rf, for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or — (CH2)m -R8Q ; • A and B independently are unsubstituted or substituted with Re and Rf, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3 and Rb, or R0 and R<i, or both, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• Rg0 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(4) ligand represented by structure 2:
Figure imgf000031_0001
wherein
• X represents PR2 ;
• Y represents H, NR2, OR, or SR;
• R represents, independently for each occurrence, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or ~(CH2)m -R8O ;
• R3, Rb, Rc, R<i, R«, Rf, Rg, and Rh, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or ~(CH2)m --Rso;
• one or more pairs of substituent, with an ortho-relationship therebetween, selected from the group consisting of R3, Rb, Rc, Rd, Re, Rf, Rg, and Rh, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• R8O represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(5) ligand represented by structure 3:
Figure imgf000032_0001
wherein
• X represents NR2, P(alkyl)2, P(cycloalkyl)2, AsR2, or OR;
• Y represents H, alkyl, NR2, AsR2, or OR;
• X and Y are not identical;
• R, R3, Rb, Rc, and Rj, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or -(CH2)m --R«o;
• Re and Rf, for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or — (CH2)m —RSQ ;
• the B and B' rings of the binaphthyl core independently are unsubstituted or substituted with Re and Rf, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3 and Rb, or R0 and R^, or both, taken together optionally represent a ring consisting of a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• Rβo represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(6) ligand represented by structure 4:
Figure imgf000033_0001
wherein: • R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and ~(CH2)m —Rβo;
• the A and A1 rings of the biphenyl core independently are unsubstituted or substituted with Ri and R2, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3 and Rb are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and —(CH2)m -Rs0;
• R80 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer; (7) ligand represented by structure 5:
Figure imgf000034_0001
R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and — (CH2)m -R80 ; the A, B, A1, and B1 rings of the binaphthyl core independently are unsubstituted or substituted with R3, Rb, Rc, and Rd, respectively, any number of times up to the limitations imposed by stability and the rules of valence; • R3, Rb, Rc, and R<i, are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and ~(CH2)m —Rso;
• R80 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
• provided that when R is cycloalkyl or aryl, there is at least one instance of Ra, Rb,
(8) ligand represented by structure 6:
Figure imgf000035_0001
R is selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and -(CH2)m -R80 ; the A and A' rings of the biphenyl core independently may be unsubstituted or substituted with R3 and Rb, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
R3 and Rb are selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and ~(CH2)m —Rso;
Rβo represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; m is an integer in the range 0 to 8 inclusive; and • the ligand, when chiral, may be provided in the form of a mixture of enantiomers or as a single enantiomer; and
(9) ligand represented by structure 7:
Figure imgf000036_0001
wherein
• R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and ~(CH2)m —Rso;
• P(R)2 represents P(alkyl)2, or P(cycloalkyl)2 ;
• the A, B, A1, and B' rings of the binaphthyl core independently are unsubstituted or substituted with R3, Rb, R0, and Rd, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3, Rb, Rc, and Rd, are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and ~(CH2)m -R80;
• Rgo represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
[0016] Examples of phenolic or amine ligands include, but are not limited to 2- phenylphenol, 2,6-dimethylphenol, 2-isopropylphenol, 1-naphthol, 8-hydroxyquinoline, 8-aminoquinoline, DBU, 2-(dimethylamino)ethanol, N,N-diethylsalicylamide, 2- (dimethylamino)glycine, N,N,N',N'-tetramethyl- 1 ,2-diaminoethane, 4,7-diphenyl- 1,10- phenanthroline, 4,7-dimethyl-l,10-phenanthroline, 5-methyl-l,10-phenanthroline, 5- chloro-l,10-phenanthroline, 5-nitro-l,10-phenanthroline, 4-(dimethylamino)pyridine, 2- (aminomethyl)pyridine, (methylimino)diacetic acid, cis-l^-diaminocyclohexane, trans- 1,2-diaminocyclohexane, a mixture of cis- and trans- 1 ,2-diaminocyclohexane, cis-N,N'- dimethyl- 1 ,2-diaminocyclohexane, trans-N,N'-dimethyl- 1 ,2-diaminocyclohexane, a mixture of cis- and trans-N,N'-dimethyl-l,2-diaminocyclohexane, cis-N-tolyl-1,2- diaminocyclohexane, trans-N-tolyl-l,2-diaminocyclohexane, a mixture of cis- and trans-N-tolyl-l,2-diaminocyclohexane, ethanolamine, 1 ,2-diaminoethane, N5N1- dimethyl- 1 ,2-diaminoethane, N,N-dimethyl-2-hydroxybenzamide, N,N-diethyl-2- hydroxybenzamide, fluoro-N,N-diethyl-2-hydroxybenzamide, chloro-N,N'-diethyl-2- hydroxybenzamide, (2-hydroxyphenyl)(pyrrolidin-l-yl)methanone, biphenyl-2-ol, 2- pyridylphenol, 1,2-benezenediamine, ammonia, N,N-dimethylformamide, dimethylsulfoxide and 1 -methyl -2-pyrrolidinone as described in U.S. patents 6,759,554B2; 6,395,916Bl; 6,307,087Bl, Klapars, A. et al., J. Am. Chem. Soc. (2002) 124, 7421-7428; Kang, S., et al., Synlett, 3, 427-430 (2002); Sugahara, M. and Ukita, T., Chem. Pharm. Bull. (1997) 45, 719-721, herein incorporated by reference.
[0017] In still another embodiment, Method 2F further comprises the step of treating Compound of Formula 2E with a mono or bi-dentate ligand known to ligate with transition metal catalysts. Examples of such ligand include, but are not limited to ligands disclosed above in Method IF. In a preferred embodiment, the ligand of Method IF or 2F is optionally substituted 1,2-diamine ligands. In an especially preferred embodiment, said ligand is N,N'-dimethyl-l,2-diaminoethyane, trans-N,N'- dimethyl-l,2-diaminocyclohexane, N-butylethylenediamine. In a most preferred embodiment, said ligand is N,N' -dimethyl- 1 ,2-diaminoethane. Without being bound to any theory, it is believed that the ligands facilitate the reaction by stabilizing and solubilizing the metal catalyst.
[0018] In another embodiment, the invention also provides a method (Method
IE') for preparing compounds of Formula IE' or any of 2.8-2.21 :
Figure imgf000038_0001
Formula IE' as hereinbefore described, which method comprises the step of treating compounds of Formula ID with (a) benzophenone imine; (b) a transition metal catalyst selected from Groups 8-11 of the Periodic Table; (c) a base; and (d) ligands selected from a group consisting of:
(1) phenolic or amine ligands such as optionally substituted aryl alcohol, 1,2-diamine, 1,2-aminoalcohol, imidazolium carbene, 4-(dimethylamino)pyridine, 2- (aminomethyl)pyridine, 4,7-diphenyl- 1 , 10-phenanthroline, 4,7-dimethyl- 1,10- phenanthroline, 5 -methyl- 1,10-phenanthroline, 5-chloro-l,10-phenanthroline, and 5- nitro- 1 , 10-phenanthroline;
(2) ligand represented by structure 1 :
Figure imgf000038_0002
wherein • A and B independently represent fused rings selected from the group consisting of monocyclic or polycyclic cycloalkyls, cycloalkenyls, aryls, and heterocyclic rings, said rings having from 4 to 8 atoms in a ring structure;
• X represents NR2, P(alkyl)2, P(cycloalkyl)2, AsR2, or OR;
• Y represents H, alkyl, NR2, or AsR2;
• X and Y are not identical;
• R, R8, Rb, R0, and Ra, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or — (CH2)m -R80;
• R6 and Rf, for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or ~(CH2)m -Rs0;
• A and B independently are unsubstituted or substituted with Rg and Rf, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3 and Rb, or R0 and Rd, or both, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• R80 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer; (3) ligand represented by structure 2:
Figure imgf000040_0001
2 wherein
• X represents PR2;
• Y represents H, NR2, OR, or SR;
• R represents, independently for each occurrence, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or ~(CH2)m —Rso;
• R3, Rb, Rc, Rd, Re, Rf, Rg5 and Rh, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or ~(CH2)m ~Rso;
• one or more pairs of substituent, with an ortho-relationship therebetween, selected from the group consisting of Ra, Rb, Rc, Rd, Re, Rf5 Rg5 and Rh, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• R8O represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer; (4) ligand represented by structure 3:
Figure imgf000041_0001
wherein
• X represents NR2, P(alkyl)2, P(cycloalkyl)2, AsR2, or OR;
• Y represents H, alkyl, NR2, AsR2, or OR;
• X and Y are not identical;
• R, R8, Rb, Rc, and Rd, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or ~(CH2)m -Rs0;
• Re and Rf, for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or ~(CH2)m -R80;
• the B and B1 rings of the binaphthyl core independently are unsubstituted or substituted with Re and Rf, respectively, any number of times up to the limitations imposed by stability and the rules of valence; • R3 and Rb, or R0 and Ra, or both, taken together optionally represent a ring consisting of a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• R8O represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(5) ligand represented by structure 4:
Figure imgf000042_0001
wherein:
R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and ~(CH2)m -Rso; the A and A1 rings of the biphenyl core independently are unsubstituted or substituted with Rj and R2, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
R3 and Rb are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and — (CH2)m --R80;
R8O represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle; m is an integer in the range 0 to 8 inclusive; and the ligand, when chiral, is a mixture of enantiomers or a single enantiomer; (6) ligand represented by structure 5:
Figure imgf000043_0001
• R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and ~(CH2)m -R80 ;
• the A, B, A1, and B1 rings of the binaphthyl core independently are unsubstituted or substituted with Ra, Rb, R0, and Rd, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3, Rb, Rc, and Rd, are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and — (CH2)m — R80;
• R80 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
• provided that when R is cycloalkyl or aryl, there is at least one instance of R3, Rb,
(7) ligand represented by structure 6:
Figure imgf000044_0001
• R is selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and -(CH2)m -R80;
• the A and A' rings of the biphenyl core independently may be unsubstituted or substituted with R3 and Rb, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3 and Rb are selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and --(CH2)m -Rs0;
• R80 represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, may be provided in the form of a mixture of enantiomers or as a single enantiomer;
(8) ligand represented by structure 7:
Figure imgf000044_0002
wherein • R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and — (CH2)m —R%o',
• P(R)2 represents P(alkyl)2, or P(cycloalkyl)2 ;
• the A, B, A1, and B' rings of the binaphthyl core independently are unsubstituted or substituted with R3, Rb, Rc, and Rd, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3, Rb, Rc, and Rd, are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and — (CH2)m — R80;
• Rso represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer; and
(9) 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl. 019] In another embodiment, the invention also provides a method (Method E') for preparing compounds of Formula 2E' or any of 2.31-2.48:
Figure imgf000045_0001
Formula 2E1 as hereinbefore described, which method comprises the step of treating compounds of Formula 2D with (a) benzophenone imine; (b) a transition metal catalyst selected from Groups 8-11 of the Periodic Table; (c) a base; and (d) a ligand selected from a group consisting of ligands as described above in Method IE. [0020] Useful transition metal catalysts of Method IE' and 2E' include atoms, ions, salts or complexes of transition metals selected from Groups 8-11 of the periodic table (e.g., palladium, copper, nickel, platinum, ruthenium, or rhodium). Examples of such transition metal catalyst include, but not limited to copper catalysts (e.g., CuI, CuCl, CuBr, CuBr2, Cu(II) acetate, Cu2Cl2, Cu2O, Cu). Other examples of useful transition metal catalysts include complexes of palladium or nickel including, but not limited to Pd2(dba)2, Pd/C, PdCl2, Pd(OAc)2, (CH3CN)2PdCl2, Pd[P(C6H5)3]4, bis(dibenzylideneacetone) palladium [Pd2(dba)2], Ni(acetylacetonate)2, NiCl2[P(C6H5)J2 and Ni(l,5-cyclooctadiene)2 as described in U.S. patents 6,759,554B2; 6,395,916Bl; 6,307,087Bl, herein incorporated by reference.
[0021] Examples of a useful base for Method IE' or 2E' include, for example, amine bases (e.g., triethyl amine, N,N'-diisopropylethyl amine or 4- (dimethylamino)pyridine (DMAP); l,5-diazabicycl[4.3.0]non-5-ene (DBN), 1,5- diazabicyclo[5.4.0]undec-5-ene (DBU)) and 1,4-Diazabicyclo[2.2.2]octane (DABCO); inorganic bases such as hydrides (e.g. sodium, lithium and potassium hydride), alkoxides, (e.g. sodium, potassium or lithium t-butoxide, K(OAr) or Na(OAr)), or carbonate, bicarbonate, phosphate or hydroxide of alkali or alkaline earth metals (e.g. sodium, magnesium, calcium, potassium, cesium, barium carbonate, bicarbonate, hydroxide and phosphate) and potassium hexamethyldisilazane. In a particularly preferred embodiment, Method IE' comprises the step of treating Compound ID with (1) benzophenone imine; (2) Pd2(dba)2; (3) sodium tert-butoxide; and (4) 2,2'- bis(diphenylphosphino)- 1 , 1 '-binaphthyl.
[0022] In another aspect, the invention also provides a method (Method IF") for preparing compounds of Formula IF" or any of 2.3-2.21 :
Figure imgf000047_0001
Formula IF' as hereinbefore described, which method comprises the step of treating compounds of Formula IE':
Figure imgf000047_0002
Formula IE' in free or salt form as hereinbefore described with (1) alkyl haloacetate having a general formula of:
Figure imgf000047_0003
wherein:
(i) A is Cl, Br or I; and
(ii) R12 is CMalkyl; (2) a base.
[0023] In yet another embodiment of Method IE', sodium or potassium iodide is present when the compound of Formula IE' is treated with the alkyl haloacetate. In an especially preferred embodiment, Method IE' comprises the step of treating Compound of Formula ID with (1) ethyl bromoacetate; (2) sodium carbonate; and (3) potassium iodide.
[0024] In still another embodiment, the invention provides a method (Method
2F") for preparing compounds of Formula 2F" or any of 2.25-2.48:
Figure imgf000048_0001
Formula 2F" as hereinbefore described, which method comprises the step of treating compounds of Formula 2E':
Figure imgf000048_0002
Formula 2E1 in free or salt form as hereinbefore described with (1) alkyl haloacetate having a general formula of:
Figure imgf000048_0003
wherein:
(i) A is Cl, Br or I; and
(ii) R . 112Z is CMalkyl;
(2) a base. [0025] In still another embodiment of Method 2E', sodium or potassium iodide is present when the compound of Formula 2E' is treated with the alkyl haloacetate.
[0026] In another aspect, the invention also provides a method (Method IG) for preparing compounds of Formula 1 G:
Figure imgf000049_0001
Formula IG wherein:
(i) k is 1 or 2;
(ϋ) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protective group;
(V) R , R and R are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
I I
(vi) X-Y is a -NC(O)- or -NCH2- ; and (vii) R10 is
Figure imgf000049_0002
alkenyl or alkynyl; or any of 2.1-2.21, in free or salt form, which method comprises the step of N-alkylating compounds of Formula IF':
Figure imgf000050_0001
Formula IF
wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protecting agent;
(v) R7, R8and R9 are independently H or optionally substituted Cj-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and
(vi) X-Y is -<R')N-CH2~ or -(R')N-C(O)-, wherein R' is H.
[0027] In another aspect, the invention also provides a method (Method 2G) for preparing compounds of Formula 2G' :
Figure imgf000050_0002
Formula 2G1
wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protective group; (v) R5 is H or Ci-C4alkyl;
(vi) R7, R8and R9 are independently H or optionally substituted Ci-C6alkyl, C3- Ciocycloalkyl, C3-Cioheterocycloalkyl, hydroxy, Ci-C6alkoxy, nitro, halo, haloCi-Cόalkyl, aryl, arylCi-C6alkyl, heteroaryl or heteroarylCi-Cealkyl;
I I
(vii) X-Y is a -NC(O)- or -NCH2- ; ^
(viii) R10 is CMalkyl; or any of 2.22-2.48, in free or salt form, which method comprises the step of N- alkylating compounds of Formula 2F':
Figure imgf000051_0001
Formula 2F' wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protective group;
(viii) R5 is H or C i .C4alkyl;
(v) R7, R8and R9 are independently H or optionally substituted Ci-C6alkyl, C3- Ciocycloalkyl, C3-Cioheterocycloalkyl, hydroxy, C)-C6alkoxy, nitro, halo, haloCi-Cόalkyl, aryl, arylCj-Cόalkyl, heteroaryl or heteroarylCi-Cόalkyl; and
(vi) -X-Y- is -(R')N-CH2- or -(R')N-C(O)-, wherein R' is H.
[0028] N-alkylation of Method 1 G or 2G may be achieved by treating compounds of Formula 2F' with an optionally substituted alkyl halide (e.g., methyl iodide, iodoethane) in the presence of a base (e.g., potassium carbonate). [0029] In another aspect, the invention provides a method (Method 3G') for preparing compounds of Formula 2G which method comprises the step of treating a compound of Formula 2E" (wherein X-Y is HN(R')CH2 or HN(R')-C(O)-) with (i) a transition metal catalyst; (ii) a base and (iii) optionally a mono or bidentate ligand as disclosed in Method 2F".
[0030] In still another embodiment, the invention also provides Method 3 G for preparing compounds of Formula 2G as hereinbefore described which method comprises the steps of: a) treating a Compound of Formula 2D in free or salt form as hereinbefore described with (i) a nucleophilic alkyl halide of the general formula:
A
<> > n X-Y as hereinbefore described, (ii) a base and (iii) potassium iodide in a solvent such as dioxane; and b) adding (i) a transition metal catalyst selected from a group consisting of Group 8-11 of the periodic table; (ii) a base; and (iii) optionally a mono or bi-dentate ligand known to ligate with transition metal catalysts.
[0031] The nucleophilic alkyl halide, base and potassium of step (a) of Method
3G may be those described above in Methods IE and 2E. In a preferred embodiment, the nucleophilic alkyl halide is chloroacetamide or N-methyl chloroacetamide and the base is isopropylethylamine. Examples of the transition metal catalyst of step (b) of Method 3G may be those described in Methods IF and 2F (e.g., copper catalysts such as CuI, CuCl, CuBr, CuBr2, Cu(II) acetate, Cu2Cl2, Cu2O, Cu, or palladium or nickel catalysts such as Pd2(dba)2, Pd/C, PdCl2, Pd(OAc)2, (CH3CN)2PdCl2, Pd[P(C6Hs)3J4, bis(dibenzylideneacetone) palladium [Pd2(dba)3], Ni(acetylacetonate)2, NiCl2[P(C6Hs)J2 and Ni(l,5-cyclooctadiene)2). In a particular embodiment, the catalyst is CuI. Examples of mono or bi-dentate ligand known to ligate with transition metal catalysts of Method 3G include those described above in methods IF and 2F.
[0032] In another aspect, the invention also provides a method (Method IH) for preparing compounds of Formula IH:
Figure imgf000053_0001
Formula IH wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protective group;
(v) R 5 R and R are independently H or optionally substituted Ci-C6alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; (vi) X is a N; and (vii) R10 is H or CMalkyl; and
(viii) R6a and R6b are independently selected from a group consisting of H; which method comprises the step of reducing the ketone of compounds of Formula IG:
Figure imgf000053_0002
Formula IG
wherein:
(i) k is 1 or 2; (ii) m is 0, 1 or 2;
(iii) n is i, 2 or 3;
(iv) B is a protective group;
(v) R7, R8and R9 are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
I (vi) X-Y is a — NC(O)-; and
(vii) R10 is Ci-4alkyl, alkenyl or alkynyl; to a methylene. Such reduction may be accomplished through the use of a reducing agent selected from a group consisting of metal hydrides (e.g., diisobutyl aluminum hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) or sodium cyanoborohydride); boranes (e.g., BH3-THF); or organoboranes (e.g. bis(benzyloxy)borane). Alternatively, such conversion may also be accomplished through catalytic hydrogenation by using hydrogen in presence of a catalyst (e.g. palladium on carbon, palladium oxide, etc.); Wolff-Kishner reduction by heating the ketone with hydrazine hydrate in the presence of a base such as sodium or potassium hydroxide {See Todd, Org. React. 4, 378-422 (1948)); or Clemmensen reduction by heating the ketone with zinc amalgam and aqueous mineral acid such as hydrochloric acid {See Vedejs, Org. React. 22, 401-422 (1975)). Other reagents that may also accomplish such reduction include triisopropyl phosphate, copper in the presence of sulfuric acid and tin in the presence of hydrochloric acid.
[0033] In another aspect, the invention also provides a method (Method 2H) for preparing compounds of Formula 2H:
Figure imgf000054_0001
Formula 2H wherein: (i) k is 1 or 2; (ϋ) m is 0, 1 or 2; (iii) n is 1, 2 or 3; (iv) B is a protective group;
(V) R5 is H or Ci.C4alkyl;
(vi) R7, R8andR9 are independently H or optionally substituted Ci-C6alkyl, C3-
Ciocycloalkyl, C3-Ci0heterocycloalkyl, hydroxy, Cj-Cόalkoxy, nitro, halo, haloCi-C6alkyl, aryl, aryld-C6alkyl, heteroaryl or heteroarylCi-Cδalkyl; (vii) X is a N; and (viii) R10 is H or C1-4alkyl; and
(ix) R6a and R6b are independently selected from a group consisting of H; which method comprises the step of reducing the ketone of compounds of Formula 2G':
Figure imgf000055_0001
Formula 2G1 in free or salt form as hereinbefore described to a methylene. Such reduction may be accomplished through the use of a reducing agent selected from a group as described above in Method IH. In another embodiment, the reduction of the ketone comprises the use of 9-Borabicyclo [3.3.1 ]nonane (9-BBN).
[0034] In another aspect, the invention also provides a method (Method II) for preparing compounds of Formula II:
Figure imgf000056_0001
Formula II
wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) R7, R8and R9 are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; (v) X is a N, S or O;
(vi) R10 is H or Ci^alkyl when X is N or R10 is non-existent when X is O or S; and (vii) R6a and R6b are H; which method comprises the step of deprotecting compounds of Formula IH:
Figure imgf000056_0002
Formula IH wherein:
(i) k is 1 or 2; (ii) m is 0, 1 or 2; (iii) n is 1, 2 or 3;
(iv) B is a protecting agent;
(v) R7, R8and R9 are independently H or optionally substituted C1-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; (vi) X is a N, O or S; and
(vii) R10 is H or Ci^alkyl when X is N or R10 is non-existent when X is O or S; and (viii) R6a and R6b are H.
[0035] In another embodiment, the invention provides a method (Method 21) for preparing compounds of Formula 21:
Figure imgf000057_0001
wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) R5 is H or Ci-Qalkyl;
(v) R , R and R are independently H or optionally substituted Ci-Cόalkyl, C3- Ciocycloalkyl, C3-C1 oheterocycloalkyl, hydroxy, Ci-6alkoxy, nitro, halo, haloCi-C6alkyl, aryl, arylCi-C6alkyl, heteroaryl or heteroarylCi-Cόalkyl; (vi) X is a N, S or O;
(vii) R10 is H or C^alkyl when X is N or R10 is non-existent when X is O or S; and (viii) R6a and R6b are H; which method comprises the step of deprotecting compounds of Formula 2H:
Figure imgf000058_0001
Formula 2H as herein before described.
[0036] The deprotection conditions for the protective groups of Method II or 21 necessarily vary with the choice of protecting group and may involve acid or base catalysis or catalytic hydrogenation. Thus, for example, wherein the protecting agent is an acyl group such as an alkanoyl or alkoxycarbonyl group (e.g., ethoxycarbonyl) or an aroyl group, deprotection may be accomplished for example, by hydrolysis with a base such as an alkali metal hydroxide, for example lithium, potassium or sodium hydroxide. Alternatively, an acyl protecting agent such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid. An arylmethoxycarbonyl protecting agent such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over acatalyst such as palladium-on-carbon, or by treatment with a Lewis acid such as boron tris(trifluoroacetate). For further examples of reagents useful for said deprotection step, see "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons).
[0037] In another aspect, the invention also provides a method (Method U) for preparing compounds of Formula U:
Figure imgf000059_0001
Foπnula IJ wherein:
(i) k is 1 or 2; (ϋ) m is 0, 1 or 2; (iii) n is 1, 2 or 3; (iv) X is N, S or O;
(V) R , R and R are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
(vi) R10 is H or
Figure imgf000059_0002
when X is N or R10 is non-existent when X is O or S; (vϋ) R6a and R6b are H; and (viii) R1 is H or optionally substituted Ci-C6alkyl, cycloalkyl, aryl, arylalkyl (e.g., benzyl), heteroaryl, heteroarylalkyl, aryloxoalkyl (e.g., 4-(4-fluorophenyl)-4- oxobutyl)), aryloxyalkyl (e.g., 3-(4-fluorophenoxy)propyl)), heroaryloxoalkyl, heroaryloxyalkyl, aryl sulfinylalkyl or heteroaryl sulfinylalkyl; which method comprises the step of N-alkylating compounds of Formula II:
Figure imgf000060_0001
Formula II
as hereinbefore described, with (a) a compound of the general formula:
G-Z wherein:
(i) Z is -C(O)-, -0-, Or S(O)2-;
(ii) R13 is optionally substituted aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl; and
(iii) G is d-C8alkyl halide (e.g., propyl chloride); and (b) a base.
[0038] In another embodiment, the invention also provides a method (Method
2J) for preparing compounds of Formula 2 J:
Figure imgf000060_0002
Formula 2J wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2; (iii) n is 1, 2 or 3;
(iv) X is N, S or O;
(v) R5 is H or C,-C4alkyl;
(vi) R , R and R are independently H or optionally substituted Ci-C6alkyl, C3- Ciocycloalkyl, C3-Ci0heterocycloalkyl, hydroxy, Ci^alkoxy, nitro, halo, haloCi-Cόalkyl, aryl, arylCi-C6alkyl, heteroaryl or heteroarylCi-C6alkyl;
(vii) R10 is H or Ci^alkyl when X is N or R10 is non-existent when X is O or S;
(viii) R6a and R6b are H; and
(ix) R1 is H or optionally substituted Ci-C6alkyl, cycloalkyl, aryl, arylC)-C6alkyl (e.g., benzyl), heteroaryl, heteroarylCi-C6alkyl, aryloxoCi-Cόalkyl (e.g., 4-(4- fluorophenyl)-4-oxobutyl)), aryloxyCi-C6alkyl (e.g., 3-(4- fluorophenoxy)propyl)), heroaryloxoCj-Cόalkyl, heroaryloxyCi-C6alkyl, aryl sulfinylCi-Cβalkyl or heteroaryl sulfinylCj-Cόalkyl; which method comprises the step of N-alkylating compounds of Formula 21:
Figure imgf000061_0001
Formula 21 as hereinbefore described, with (a) a compound of the general formula:
3
G-Z κR1
wherein:
(i) Z is -C(O)-, -0-, Or S(O)2-;
(ii) R13 is optionally substituted aryl, arylCi-Cόalkyl, Ci-C6alkyl, heteroaryl, heteroarylCi-Cόalkyl; and
(iii) G is Ci-Cgalkyl halide (e.g., propyl chloride); and (b) a base. [0039] The base useful for Method IJ or 2 J may be a Bronsted or Lewis base.
Examples of such bases include, but are not limited to amine bases (e.g., ammonium, triethylamine, N,N'-diisopropylethyl amine or 4-(dimethylamino)pyridine (DMAP); l,5-diazabicycl[4.3.0]-non-5-ene (DBN), l,5-diazabicyclo[5.4.0]undec-5-ene (DBU)); or hydrides (e.g. sodium, lithium or potassium hydride), alkoxides, (e.g. sodium, potassium or lithium f-butoxide and K(OAr), Na(OAr)), or carbonate, bicarbonate, phosphate or hydroxide of alkali or alkaline earth metals (e.g. sodium, magnesium, calcium, potassium, cesium or barium carbonate, bicarbonate, hydroxide or phosphate). Optionally, Method 11 further comprises the use of sodium or potassium iodide. In a preferred embodiment, compounds of Formula II are alkylated with 4-chloro-4'-fluoro- butyrophenone in the presence of triethyl amine and potassium iodide.
[0040] In another aspect, the invention provides a method (Method IK) for preparing pharmaceutically acceptable salts of compounds of Formula U or 2 J:
Figure imgf000062_0001
Formula U or Formula 2J as hereinbefore described, which method comprises the step of reacting free base of Compounds of Formula IJ or 2 J with an appropriate acid in water or in an organic solvent, or in a mixture of the two to give pharmaceutically acceptable acid addition salts of Formula U or 2 J of the present invention; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Appropriate acid may be, for example, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
[0041] The invention further provides methods for compounds of Formulas IC-
U (e.g., Formulas, 1C, ID, IE, IE', IF", IG', IG, IH, II and U) as follows:
3.1 Method for the preparation of any compounds of Formula 1 J comprising the step of treating compounds of Formula II with l-(3-chloropropoxy)-4- fluorobenzene and a base.
3.2 Method for the preparation of any compounds of Formula 1 J comprising the step of treating compounds of Formula II with l-(3-chloropropoxy)-4- fluorobenzene and triethylamine.
3.3 Method for the preparation of any compounds of Formula 1 J comprising the step of treating compounds of Formula II with 4-chloro-4'-fluoro- butyrophenone and a base.
3.4 Method for the preparation of any compounds of Formula U comprising the step of treating compounds of Formula II with 4-chloro-4'-fluoro- butyrophenone and triethylamine.
3.5 Method for the preparation of any compounds of Formulas U, II or any of Method 3.1-3.4, comprising the step of deprotecting compounds of Formula IH.
3.6 Method for the preparation of any compounds of Formulas U or II or any of Methods 3.1-3.4, comprising the step of deprotecting compounds of Formula IH with sodium hydroxide.
3.7 Method for the preparation of any compounds of Formulas U, II or any of Methods 3.1-3.4 comprising the step of deprotecting compounds of Formula IH with trifluoroacetic acid.
3.8 Method for the preparation of any compounds of Formulas U-IH or any of Methods 3.1-3.7 comprising the step of treating compounds of Formula IG' with a reducing agent.
3.9 Method for the preparation of any compounds of Formulas 1 J- 1 H or any of Methods 3.1-3.7 comprising the step of treating compounds of Formula IG' with borane-THF. 3.10 Method for the preparation of any compounds of Formulas 1 J- 1 G or any of Methods 3.1-3.9 comprising the step of treating compounds of Formula IF with an alkyl halide and a base.
3.11 Method for the preparation of any compounds of Formulas 1 J- 1 G or any of Methods 3.1-3.9 comprising the step of treating compounds of Formula IF with a methyl iodide and potassium carbonate.
3.12 Method for the preparation of any compounds of Formulas U-IG, lF" or any of Methods 3.1-3.11, comprising the step of treating compounds of Formula IE' with (a) A-(CH2)-C(O)-OR, wherein R is H or alkyl; and (b) base.
3.13 Method for the preparation of any compounds of Formulas 1 J- 1 G, 1 F " or any of Methods 3.1-3.11, comprising the step of treating compounds of Formula IE' with ethyl bromoacetate and sodium carbonate.
3.14 Method for the preparation of any of compounds of Formulas 1 J- 1 G, 1 F " , or any of Methods 3.1-3.11, comprising the step of treating compounds of Formula IE' with ethyl bromoacetate, sodium carbonate and potassium iodide.
3.15 Method for the preparation of any compounds of Formulas 1 J- 1 F or any of Methods 3.1-3.11 comprising the step of treating compounds of Formula IE with a transition metal catalyst selected from Groups 8-11 of the periodic table and a base.
3.16 Method for the preparation of any compounds of Formulas 1 J- 1 F or any of Methods 3.1-3.11 comprising the step of treating compounds of Formula IE with a copper catalyst and a base.
3.17 Method for the preparation of any compounds of Formulas 1 J- 1 F or any of Methods 3.1-3.11 comprising the step of treating compounds of Formula IE with CuI and a base.
3.18 Method for the preparation of any compounds of Formulas 1 J- 1 F or any of Methods 3.1-3.11 comprising the step of treating compounds of Formula IE with CuI and a Bronsted base. 3.19 Method for the preparation of any compounds of Formulas 1 J- 1 F or any of Methods 3.1-3.11 comprising the step of treating compounds of Formula IE with CuI and potassium carbonate.
3.20 Method for the preparation of any compounds of Formulas 1 J- 1 F or any of Methods 3.1-3.11 comprising the step of treating compounds of Formula IE with a transition metal catalyst selected from Groups 8-1 1, base and a mono or bidentate ligand.
3.21 Method for the preparation of any compounds of Formulas 1 J- 1 F or any of Methods 3.1-3.11 comprising the step of treating compounds of Formula IE with CuI, potassium carbonate and N,N'-dimethylethylenediamine.
3.22 Method for the preparation of any compounds of Formulas 1 J-IF, IE or any of Methods 3.1-3.21 comprising the step of treating compounds of Formula ID with (a) a compound of the general formula X-Y-(CHa)n-A as hereinbefore described; and (b) a base.
3.23 Method for the preparation of any compounds of Formulas 1 J- 1 F, 1 E or any of Methods 3.1-3.21 comprising the step of treating compounds of Formula ID with 2-chloroacetamide and diisopropylethylamine.
3.24 Method for the preparation of any compounds of Formulas U-IF, IE or any of Methods 3.1-3.21 comprising the step of treating compounds of Formula ID with 2-chloroacetamide, diisopropylethylamine and sodium or potassium iodide.
3.25 Method for the preparation of any compounds of Formulas 1 J-IF, lF'Or IE' or any of Methods 3.1-3.21 comprising the step of treating compounds of Formula ID with benzophenone imine; palladium catalyst; base and 2,2'- bis(diphenylphosphino)- 1 , 1 '-binaphthyl.
3.26 Method for the preparation of any compounds of Formulas 1 J-IF, IF" or IE' or any of Methods 3.1-3.21 comprising the step of treating compounds of Formula ID with benzophenone imine; Pd2(dba)2; sodium t-butoxide; and 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl. 3.27 Method for the preparation of any compounds of Formulas 1 J-IF, IF", IE, IE', ID or any of Methods 3.1-3.26 comprising the step of protecting compounds of Formula 1C with a protecting agent.
3.28 Method for the preparation of any compounds of Formulas 1J-1F, IF", IE, IE', ID or any of Methods 3.1-3.26 comprising the step of protecting compounds of Formula 1C with a protecting agent having the general formula of Y-P-Z as hereinbefore described in the presence of a base.
3.29 Method for the preparation of any compounds of Formulas 1 J-IF, IF", IE, IE', ID or any of Methods 3.1-3.26 comprising the step of protecting compounds of Formula 1C with ethyl chloroformate and a base.
3.30 Method for the preparation of any compounds of Formulas 1 J-IF, IF", IE, IE', ID or any of Methods 3.1-3.26 comprising the step of protecting compounds of Formula 1C with ethyl chloroformate and triethylamine.
3.31 Method for the preparation of any of compounds of Formulas 1 J- 1 F, IF", IE, IE', ID or any of Methods 3.1-3.26 comprising the step of protecting compounds of Formula 1C with Boc anhydride and a base.
3.32 Method for the preparation of any of compounds of Formulas U-IF, IF", IE, IE', ID, 1C or any of Methods 3.1-3.31 comprising the step of (a) reducing compounds of Formula IA with a reducing agent and (b) resolving compounds of Formula IB with a chiral acid.
3.33 Method for the preparation of any of compounds of Formulas U-IF, IF", IE, IE', ID, 1C or any of Methods 3.1-3.31 comprising the step of (a) reducing compounds of Formula IA with sodium cyanoborohydride and (b) resolving compounds of Formula IB with a chiral acid.
3.34 Method for the preparation of any of compounds of Formulas U-IF, IF", IE, IE', ID, 1C or any of Methods 3.1-3.31 comprising the step of (a) reducing compounds of Formula IA with triethylsilane in the presence of an acid and (b) resolving compounds of Formula IB with a chiral acid.
3.35 Method for the preparation of any of compounds of Formulas U-IF, IF", IE, IE', ID, 1C or any of Methods 3.1-3.31 comprising the step of (a) reducing compounds of Formula IA with triethylsilane in the presence of trifluoroacetic acid; and (b) separating the enantiomers of compounds of Formula 1 B by chiral acid resolution or by chiral chromatography.
3.36 Method for the preparation of any of compounds of Formulas U-IF, IF", IE, IE', ID, 1C or any of Methods 3.1-3.31 comprising the step of (a) reducing compounds of Formula IA with triethylsilane in the presence of trifluoroacetic acid; and (b) separating the enantiomers of compounds of Formula IB by chiral acid resolution or by chiral chromatography.
3.37 Method for the preparation of any of compounds of Formulas 1 J-IF, IF", IE, IE', ID, 1C or any of Methods 3.1-3.31 comprising the step of (a) reducing compounds of Formula IA with triethylsilane in the presence of trifluoroacetic acid; and (b) separating the enantiomers of compounds of formula IB by chiral chromatography.
3.38 Method for the preparation of any of compounds of Formulas 1 J- 1 F, IF", IE, IE', ID, 1C or any of Methods 3.1-3.31 comprising the step of (a) reducing compounds of Formula IA with triethylsilane in the presence of trifluoroacetic acid; and (b) separating te enantiomers of compounds of formula IB by the use of amylase tris(3,5-dimethylphenylcarbamate) column.
3.39 Method for the preparation of any of compounds of Formulas 1J-1F, IF", IE, IE', ID, 1C or any of Methods 3.1-3.31 comprising the step of (a) reducing compounds of Formula IA with triethylsilane in the presence of trifluoroacetic acid; and (b) separating te enantiomers of compounds of formula IB by the use of amylase tris(3,5-dimethylphenylcarbamate) column and eluting the desired product with ethanol mobile phase.
3.40 Method for the preparation of any of compounds of Formulas 1 J- 1 F, IF", IE, IE', ID, 1C or any of Methods 3.1-3.31 comprising the step of (a) reducing compounds of Formula IA with triethylsilane in the presence of trifluoroacetic acid; and (b) resolving compounds of Formula 1 B with (S)-(+)- mandelic acid.
3.41 Method for the preparation of any of compounds of Formulas 1 J- 1 F, IF", IE, IE', ID, 1C or any of Methods 3.1-3.31 comprising the step of (a) reducing compounds of Formula IA with a reducing agent; and (b) resolving compounds of Formula IB with (S)-(+)-mandelic acid.
3.42 Method for the preparation of any of compounds of Formulae U-IF, IF", IE, IE', ID, 1C or any of Methods 3.1-3.31 comprising the step of (a) reducing compounds of Formula IA with triethylsilane in the presence of trifluoroacetic acid; and (b) resolving compounds of Formula IB with (S)-(+)- mandelic acid.
[0042] The invention further provides methods for compounds of Formulas 2C-
2J (e.g., Formulas, 2C, 2D, 2E, 2E', 2F, 2G\ 2G, 2H, 21 and 2J) as follows:
4.1 Method for the preparation of pharmaceutically acceptable acid addition salts of any compounds of Formula 2 J comprising the step of treating free base of Compounds of Formula 2 J with an acid to give pharmaceutically acceptable acid addition salts of Formula U or 2 J of the present invention.
4.2 Method 4.1 wherein said acid is selected from a group consisting of hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic acid.
4.3 Method for the preparation of any compounds of Formula 2J or 4.1 -4.2, comprising the step of treating compounds of Formula 21 with l-(3- chloropropoxy)-4-fluorobenzene and a base.
4.4 Method for the preparation of any compounds of Formula 2 J comprising the step of treating compounds of Formula 21 with l-(3-chloropropoxy)-4- fluorobenzene and triethylamine or diisopropylethylamine.
4.5 Method for the preparation of any compounds of Formula 2 J comprising the step of treating compounds of Formula 21 with 4-chloro-4'-fluoro- butyrophenone and a base.
4.6 Method for the preparation of any compounds of Formula 2 J comprising the step of treating compounds of Formula 21 with 4-chloro-4'-fiuoro- butyrophenone and triethylamine or diisopropylethylamine. 4.7 Method for the preparation of any compounds of Formulas 2 J, 21 or any of Method 4.1-4.6, comprising the step of deprotecting compounds of Formula 2H.
4.8 Method for the preparation of any compounds of Formulas 2 J or 21 or any of Methods 4.1-4.7, comprising the step of deprotecting compounds of Formula 2H with a base (e.g., sodium hydroxide or potassium hydroxide).
4.9 Method for the preparation of any compounds of Formulas 2 J, 21 or any of Methods 4.1-4.7 comprising the step of deprotecting compounds of Formula 2H with trifluoroacetic acid.
4.10 Method for the preparation of any compounds of Formulas 2 J-2H or any of Methods 4.1-4.9 comprising the step of treating compounds of Formula 2G' with a reducing agent.
4.11 Method for the preparation of any compounds of Formulas 2 J-2H or any of Methods 4.1-4.9 comprising the step of treating compounds of Formula 2G' with borane-THF.
4.12 Method for the preparation of any compounds of Formulas 2 J-2G or any of Methods 4.1-4.11 comprising the step of treating compounds of Formula 2F with an alkyl halide and a base.
4.13 Method for the preparation of any compounds of Formulas 2 J-2G or any of Methods 4.1-4.11 comprising the step of treating compounds of Formula 2F with a methyl iodide and potassium carbonate.
4.14 Method for the preparation of any compounds of Formulas 2 J-2G, 2F" or any of Methods 4.1-4.13, comprising the step of treating compounds of Formula IE' with (a) A-(CH2)-C(O)-OR, wherein R is H or alkyl; and (b) base.
4.15 Method for the preparation of any compounds of Formulas 2 J-2G, 2F" or any of Methods 4.1-4.14, comprising the step of treating compounds of Formula 2E' with ethyl bromoacetate and sodium carbonate.
4.16 Method for the preparation of any of compounds of Formulas 2J-2G,2F", or any of Methods 4.1-4.13, comprising the step of treating compounds of Formula 2E' with ethyl bromoacetate, sodium carbonate and potassium iodide. 4.17 Method for the preparation of any compounds of Formulas 2 J-2F or any of Methods 4.1-4.13 comprising the step of treating compounds of Formula 2E with a transition metal catalyst selected from Groups 8-11 of the periodic table and a base.
4.18 Method for the preparation of any compounds of Formulas 2 J-2F or any of Methods 4.1-4.13 comprising the step of treating compounds of Formula 2E with a copper catalyst and a base.
4.19 Method for the preparation of any compounds of Formulas 2 J-2F or any of Methods 4.1-4.13 comprising the step of treating compounds of Formula 2E with CuI and a base.
4.20 Method for the preparation of any compounds of Formulas 2 J-2F or any of Methods 4.1-4.13 comprising the step of treating compounds of Formula 2E with CuI and a Bronsted base.
4.21 Method for the preparation of any compounds of Formulas 2J-2F or any of Methods 4.1-4.13 comprising the step of treating compounds of Formula 2E with CuI and potassium carbonate.
4.22 Method for the preparation of any compounds of Formulas 2J-2F or any of Methods 4.1-4.21 further comprising a mono or bidentate ligand.
4.23 Method for the preparation of any compounds of Formulas 2 J-2F or any of Methods 4.1-4.13 comprising the step of treating compounds of Formula 2E with a transition metal catalyst selected from Groups 8-11, base and a mono or bidentate ligand.
4.24 Method for the preparation of any compounds of Formulas 2 J-2F or any of Methods 4.1-4.23 comprising the step of treating compounds of Formula 3E with CuI, potassium carbonate and N,N'-dimethylethylenediamine.
4.25 Method for the preparation of any compounds of Formulas 2J-2F, 2E or any of Methods 4.1-4.24 comprising the step of treating compounds of Formula 2D with (a) a compound of the general formula X-Y-(CHa)n-A as hereinbefore described; and (b) a base. 4.26 Method for the preparation of any compounds of Formulas 2 J-2F, 2E or any of Methods 4.1-4.24 comprising the step of treating compounds of Formula 2D with 2-chloroacetamide and diisopropylethylamine.
4.27 Method for the preparation of any compounds of Formulas 2 J-2F, 2E or any of Methods 4.1-4.24 comprising the step of treating compounds of Formula 2D with 2-chloroacetamide, diisopropylethylamine and sodium or potassium iodide.
4.28 Method for the preparation of any compounds of Formulas 2J-2F, 2F"or 2E' or any of Methods 4.1-4.24 comprising the step of treating compounds of Formula 2D with benzophenone imine; palladium catalyst; base and 2,2'- bis(diphenylphosphino)- 1 , 1 '-binaphthyl.
4.29 Method for the preparation of any compounds of Formulas 2J-2F, 2F" or 2E' or any of Methods 4.1-4.24 comprising the step of treating compounds of Formula 2D with benzophenone imine; Pd2(dba)2; sodium t-butoxide; and 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl .
4.30 Method for the preparation of any compounds of Formulas 2J-2F, 2F", 2E, 2E', 2D or any of Methods 4.1-4.29 comprising the step of protecting compounds of Formula 2C with a protecting agent.
4.31 Method for the preparation of any compounds of Formulas 2J-2F, 2F", 2E, 2E', 2D or any of Methods 4.1-4.30 comprising the step of protecting compounds of Formula 2C with a protecting agent having the general formula of Y-P-Z as hereinbefore described in the presence of a base.
4.32 Method for the preparation of any compounds of Formulas 2 J-2F, 2F", 2E, 2E', 2D or any of Methods 4.1-4.30 comprising the step of protecting compounds of Formula 2C with ethyl chloroformate and a base.
4.33 Method for the preparation of any compounds of Formulas 2J-2F, 2F", 2E, 2E', 2D or any of Methods 4.1-4.32 comprising the step of protecting compounds of Formula 2C with ethyl chloroformate and triethylamine.
4.34 Method for the preparation of any of compounds of Formulas 2J-2F, 2F", 2E, 2E', 2D or any of Methods 4.1-4.31 comprising the step of protecting compounds of Formula 1C with Boc anhydride and a base. 4.35 Method for the preparation of any of compounds of Formulas 2J-2F, 2F", 2E, 2E', 2D, 2C or any of Methods 4.1-4.35 comprising the step of (a) reducing compounds of Formula 2 A with a reducing agent and (b) resolving compounds of Formula 2B with a chiral acid or by chiral chromatography.
4.36 Method for the preparation of any of compounds of Formulas 2J-2F, 2F", 2E, 2E', 2D, 2C or any of Methods 4.1-4.35 comprising the step of (a) reducing compounds of Formula 2 A with sodium cyanoborohydride and (b) resolving compounds of Formula 2B with a chiral acid or by chiral chromatography.
4.37 Method for the preparation of any of compounds of Formulas 2J-2F, 2F", 2E, 2E\ 2D, 2C or any of Methods 4.1-4.35 comprising the step of (a) reducing compounds of Formula 2 A with triethylsilane in the presence of an acid and (b) resolving compounds of Formula 2B with a chiral acid or by chiral chromatography.
4.38 Method for the preparation of any of compounds of Formulas 2J-2F, 2F", 2E, 2E', 2D, 2C or any of Methods 4.1-4.33 or 4.37 comprising the step of (a) reducing compounds of Formula 2A with triethylsilane in the presence of trifluoroacetic acid; and (b) separating the enantiomers of compounds of Formula 2B by chiral acid resolution or by chiral chromatography.
4.39 Method for the preparation of any of compounds of Formulas 2J2F, 2F", 2E, 2E\ 2D, 2C or any of Methods 4.1-4.35 or 4.37-4.38 comprising the step of (a) reducing compounds of Formula 2 A with triethylsilane in the presence of trifluoroacetic acid; and (b) separating the enantiomers of compounds of Formula 2B by chiral acid resolution or by chiral chromatography.
4.40 Method for the preparation of any of compounds of Formulas 2J-2F, 2F", 2E, 2E', 2D, 2C or any of Methods 4.1-4.39 comprising the step of (a) reducing compounds of Formula 2 A with triethylsilane in the presence of trifluoroacetic acid; and (b) resolving compounds of Formula 2B with (S)-(+)- mandelic acid.
4.41 Method for the preparation of any of compounds of Formulas 2J-2F, 2F", 2E, 2E', 2D, 2C or any of Methods 4.1-4.39 comprising the step of (a) reducing compounds of Formula 2 A with a reducing agent; and (b) resolving compounds of Formula 2B with (S)-(+)-mandelic acid.
4.42 Method for the preparation of any of compounds of Formulas 2J-2F, 2F", 2E, 2E', 2D, 2C or any of Methods 4.1-4.39 comprising the step of (a) reducing compounds of Formula 2 A with triethylsilane in the presence of trifluoroacetic acid; and (b) resolving compounds of Formula 2B with (S)-(+)- mandelic acid.
4.43 Method for the preparation of any of compounds of Formulas 2J-2F, 2F", 2E, 2E', 2D, 2C or any of Methods 4.1-4.35 comprising the step of (a) reducing compounds of Formula 2 A with triethylsilane in the presence of trifluoroacetic acid; and (b) separating the enantiomers of compounds of formula 2B by chiral chromatography.
4.44 Method for the preparation of any of compounds of Formulas 2J-2F, 2F", 2E, 2E\ 2D, 2C or any of Methods 4.1-4.35 or 4.43 comprising the step of (a) reducing compounds of Formula 2 A with triethylsilane in the presence of trifluoroacetic acid; and (b) separating te enantiomers of compounds of formula 2B by the use of amylase tris(3,5-dimethylphenylcarbamate) column.
4.45 Method for the preparation of any of compounds of Formulas 2J-2F, 2F", 2E, 2E', 2D, 2C or any of Methods 4.1-4.35 or 4.43-4.44 comprising the step of (a) reducing compounds of Formula 2 A with triethylsilane in the presence of trifluoroacetic acid; and (b) separating te enantiomers of compounds of formula 2B by the use of amylase tris(3,5-dimethylphenylcarbamate) column and eluting the desired product with ethanol, methanol or isopropyl alcohol mobile phase.
DETAILED DESCRIPTION OF THE INVENTION
[0043] The compounds described herein and their pharmaceutically acceptable salts may be made using the methods as described and exemplified herein and by methods similar thereto and by methods known in the chemical art. In the description of the synthetic methods described herein, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. Therefore, at times, reaction may require to be run at elevated temperature or for a longer or shorter period of time. It is understood by one skilled in the art of organic synthesis that functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. If not commercially available, starting materials for these processes may be made by procedures, which are selected from the chemical art using techniques similar or analogous to the synthesis of known compounds. All references cited herein are hereby incorporated in their entirety by reference.
[0044] The numbering of the tetracyclic ring-system as described herein is shown below as an example, when k is 1, m is 1, and n is 1 :
Figure imgf000074_0001
[0045] The numbering of the hexahydro- 1 H-pyrido [4,3 -b] indole derivative as described herein is shown below as an example, wheren k is 1 , m is 1 , and n is 1 :
Figure imgf000074_0002
[0046] Unless the terms are specifically defined for an embodiment, the terms used herein are generally defined as follows. [0047] The phrase "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
[0048] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
[0049] The term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "Ci-C6 alkyl" denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, sec-butyl, t-butyl, 3-methylpentyl, 4-methylpentyl, etc.
[0050] "Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either a straight or branched configuration having a specified number of carbon atoms and one or more carbon-carbon double bonds which may occur in any stable point along the chain. Examples of alkenyl include, but are not limited to, ethenyl, 1- propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 2-methyl- 2-propenyl, 4-methyl-3-pentenyl, and the like.
[0051] "Alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
[0052] "Alkoxy" or "alkyloxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n- butoxy, 5-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Similarly, "alkylthio" is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
[0053] "Halo", "halogen" or "halide" as used herein refers to fluoro, chloro, bromo, and iodo. Therefore, "alkyl halide" herein refers to a halogen group attached to alkyl group as defined above such as methyl iodide or iodobutane.
[0054] "Cycloalkyl" is intended to include monocyclic or polycyclic ring system comprising at least one aliphatic ring. Therefore, "cycloalkyl" may denote simply a cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and the like. Wherein cycloalkyl is a polycyclic system, such system may contain an aliphatic ring fused to aromatic, non-aromatic, heteroaromatic or hetero nonaromatic rings such as octahydro-lH-indene, 2,3-dihydro-lH-indene or 5,6,7,8-tetrahydroquinoline.
[0055] The term "heterocycloalkyl" herein refers to a monocyclic or polycyclic system comprising at least one aliphatic ring containing at least one heteroatom selected from a group consisting of O, N and S. Therefore, heterocycloalkyl may refer to piperidinyl, piperazinyl, 2-pyrrolidonyl, 1,2,3,4-tetrahydroquinolinyl, 2H,6H- 1,5,2- dithiazinyl, 2H-pyrrolyl or l,2,3,4-tetrahydro-l,8-naphthyridine.
[0056] As used herein, the term "aryl" is intended to mean a stable 5- to 7- membered monocyclic or polycyclic or 7- to 14-membered polycyclic ring system which comprises at least one aromatic ring (i.e., planar ring that contains 4n+2 Pi electrons, wherein n is an integer). Therefore, the term "aryl" includes phenyl, naphthyl and their derivatives. The term "aryl" is also intended to include polycyclic ring systems which contain at least one aromatic ring fused to one or more aromatic or non- aromatic or heteroaromatic rings (e.g., 2,3-dihydro-lH-indene).
[0057] As used herein, the term "heterocycle", "heterocyclic ring" or
"heteroaryl" is intended to mean a stable 5- to 7-membered monocyclic or polycyclic or 7- to 14-membered polycyclic ring which comprises at least one aromatic ring containing at least one heteroatom independently selected from the group consisting of N, O and S. Therefore, a "heterocycle" or "heterocyclic ring" or "heteroaryl" may include a single hetero aromatic ring or a hetero aromatic ring fused to other heteroaromatic ring or to a non-heteroaromatic or non-aromatic ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of heterocycles or heteroaryl group include, but are not limited to lH-indazole, thiazolyl, furyl, pyridyl, quinolinyl, pyryl, indole or 5,6,7,8-tetrahydroquinoline.
[0058] The term "polycyclic" or "polycycle" is intended to mean fused ring system comprising one or more aromatic, non-aromatic (i.e., alicyclic), heteroaromatic or hetero non-aromatic (hetero-alicyclic) rings fused together.
[0059] The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Therefore, optionally substituted alkyl may refer to an alkyl group as defined above whereby one or more hydrogens are replaced with a selection from the indicated group including, but not limited to, halogen, hydroxy, amino, sulfhydryl, alkyl, alkenyl, alkynyl, haloalkyl (e.g. CH2Cl, CF3, CH3CH2Br, etc.), amine, amido, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, alkoxy, carboxy, carbonyl, silyl, alkylamino, alkylamido, nitro, cyano, halo, -S(O)-alkyl, -S(O)2-alkyl, R-cycloalkyl, R-heterocycloalkyl, R-C(O)-, R-C(O)- OR', R-O-R', -N(R)(R') wherein R and R' are independently H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heteroarylalkyl or heterocycloalkyl. [0060] The term "resolution" is a term of art and refers to the separation of a racemic mixture into its enantiomers by reacting an organic acid or base with the components of the racemic mixture to form diasteromeric salts and separating said salt by, for example, crystallization techniques. The term "chiral acid resolution" refers to the separation of a racemic mixture into its enantiomers through the use of a chiral acid.
[0061] The term "chromatography" is well known in the art and refers to a separation technique of a mixture by interacting it with a stationary phase and eluting the components of the mixture with a mobile phase such as ethanol, methanol, acetonitrile, water or mixtures thereof. The term "chiral chromatography" refers to chromatography wherein the stationary phase is chiral.
[0062] The term "chiral acid" refers to any optically active acid capable of forming disastereomeric salts with compounds of Formula IB. The terms "mono or di- carboxylic acid" or "sulfonic acid" herein refers to any compound that contains one or two carboxylic functional groups and a sulfonic acid group respectively. Examples of such acid include but are not limited to (+/-)/(R/S) tartaric acid, (+/-)/ (R/S) (mono- or di-acetyl)tartaric acid, (+/-)/(R/S) (mono- or di-benzoyl)tartaric acid, (+/-)/(R/S) (mono- or di-pivaloyl)tartaric acid, (+/-)/(R/S) mandelic acid, (+/-)/(R/S) acetoxyphenyl acetic acid, (+/-)/(R/S) methoxyphenyl acetic acid, (+/-)/(R/S) hydroxymandelic acid, (+/-)/(R/S) halomandelic acid (e.g. 4-fiuoromandelic acid), (+/- ) /(R/S) lactic acid, and (+/-)/(R/S) camphor sulfonic acid.
[0063] The term "protecting agent" refers to any compound that reacts with the atom for which protection is desired so as to block or mask its functionality. It is typically used to temporarily modify a potentially reactive functional group so as to protect it from undesired chemical transformation. A desirable protecting agent is one which is compatible with or stable to the reaction condition and is easily cleaved off at a later point when protection is no longer desired. For examples of protecting agents, see "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons), the disclosure of which is hereby incorporated by reference.
[0064] The term "deprotection" or "deprotect" or "deprotecting" refers to the act of removing or cleaving off a protecting group. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group and may involve acid (e.g., hydrochloric, sulphuric, phosphoric or trifluoroacetic acid or a Lewis acid such as boron tris(trifluoroacetate)) or base (alkali metal hydroxide, e.g., lithium, potassium or sodium hydroxide) catalysis or catalytic hydrogenation condition (e.g., hydrogen and palladium-on-carbon).
[0065] The term "catalyst" herein refers to any substance or agent capable of affecting, inducing, increasing, influencing or promoting the reactivity of a compound or reaction without itself being consumed. The phrase "transition metal catalyst" refers to any metal having electrons in the d-orbitals, e.g. metals selected from one of Groups 3-12 of the periodic table or from the lanthanide series. The catalysts useful for the methods of this invention include atoms, ions, salts or complexes of transition metals from Groups 8-11 of the Periodic Table. "Group 3-12 of the Periodic Table" refers to the groups of the Periodic Table as numbered according to the IUPAC system. Therefore, transition metals from Group 8-11 which include include iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver and gold. Examples of such catalysts include, but are not limited to CuI, CuCl, CuBr, CuBr2, Cu(II) acetate, Cu2Cl2, Cu2O, Cu, Pd2(dba)2, Pd/C, PdCl2, Pd(OAc)2, (CH3CN)2PdCl2, Pd[P(CoHs)3J4, bis(dibenzylideneacetone) palladium [Pd2(dba)3], Ni(acetylacetonate)2, NiCl2[P(CoHs)J2 and Ni(l,5-cyclooctadiene)2. Catalysts are typically, but not necessarily used in substoichiometric amount relative to the reactants. Preferably, 0.5- 20 mol%, most preferably, 10 mol% of the transition metal catalyst relative to the reactants is used.
[0066] The term "base" herein refers to organic or inorganic bases such as amine bases (e.g., ammonium, triethylamine, N,N'-diisopropylethyl amine or 4- (dimethylamino)pyridine (DMAP); l,5-diazabicycl[4.3.0]-non-5-ene (DBN), 1,5- diazabicyclo[5.4.0]undec-5-ene (DBU)); hydrides (e.g. sodium, lithium or potassium hydride); alkoxides, (e.g. sodium, potassium or lithium /-butoxide and K(OAr), Na(OAr)); or carbonate, bicarbonate, phosphate or hydroxide of an alkali or alkaline earth metal (e.g. sodium, magnesium, calcium, potassium, cesium or barium carbonate, bicarbonate, hydroxide or phosphate).
[0067] The term "Bronsted base" is art-recognized and refers to an uncharged or charged atom or molecule, e.g., an oxide, amine, alkoxide, or carbonate, that is a proton acceptor. Examples of Bronsted base include, but not limited to K3PO4, K2CO3, Na2CO3, Tl2CO3, Cs2CO3, K(OtBu), Li(OtBu), Na(OtBu), K(OPh), and Na(OPh), or mixtures thereof.
[0068] The term "Lewis base" are recognized in the art, and refer to a chemical moiety capable of donating a pair of electrons under certain reaction conditions. Examples of Lewis base include but are not limited to uncharged compounds such as alcohols, thiols, olefins, and amines (e.g., ammonia, triethylamine), and charged moieties such as alkoxides, thiolates, carbanions, and a variety of other organic anions.
[0069] The term "acid" herein refers to Lewis or Bronsted acid. Lewis acid is a term of art and refers to a chemical moiety capable of accept a pair of electrons (e.g., borontrifluoride). Bronsted acid refers to any chemical moiety capable of donating a proton (e.g., acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid as well as other organic acids known in the art).
[0070] The term "ligand" refers to any atom, molecule or ion capable of donating or sharing one or more electrons through a coordinate and/or covalent bond with another central atom, typically a metal. "Monodentate ligand" refers to ligands that have one binding site to the central atom (e.g., pyridine or ammonia). "Bidentate ligand" refers to ligands that have two binding site (e.g., N,N'- dimethylethylenediamine, N,N,N',N'-tetramethylethylenediamine or 1,10- phenathroline). Examples of useful ligands for group 8-1 1 transition metals include, but not limited to, 2-phenylphenol, 2,6-dimethylphenol, 2-isopropylphenol, 1-naphthol, 8-hydroxyquinoline, 8-aminoquinoline, DBU, 2-(dimethylamino)ethanol, N5N- diethylsalicylamide, 2-(dimethylamino)glycine, N,N,N',N'-tetramethyl-l ,2- diaminoethane, 4,7-diphenyl-l,10-phenanthroline, 4,7-dimethyl-l,10-phenanthroline, 5- methyl- 1 , 10-phenanthroline, 5-chloro- 1 , 10-phenanthroline, 5-nitro- 1,10- phenanthroline, 4-(dimethylamino)pyridine, 2-(aminomethyl)pyridine, (methylimino)diacetic acid, cis-l,2-diaminocyclohexane, trans- 1,2- diaminocyclohexane, a mixture of cis- and trans- 1 ,2-diaminocyclohexane, cis-N,N'- dimethyl- 1 ,2-diaminocyclohexane, trans-N,N'-dimethyl- 1 ,2-diaminocyclohexane, a mixture of cis- and trans-N,N'-dimethyl-l,2-diaminocyclohexane, cis-N-tolyl-1,2- diaminocyclohexane, trans-N-tolyl-l,2-diaminocyclohexane, a mixture of cis- and trans-N-tolyl-l^-diaminocyclohexane, ethanolamine, 1 ,2-diaminoethane, N5N1- dimethyl- 1 ,2-diaminoethane, N,N-dimethyl-2-hydroxybenzamide, N,N-diethyl-2- hydroxybenzamide, fluoro-N,N-diethyl-2-hydroxybenzamide, chloro-N,N ' -diethyl-2- hydroxybenzamide, (2-hydroxyphenyl)(pyrrolidin-l-yl)methanone, biphenyl-2-ol, 2- pyridylphenol, 1 ,2-benezenediamine, ammonia, N,N-dimethylformamide, dimethylsulfoxide, 1 -methyl-2-pyrrolidinone or mixtures thereof as well as the biphenyl and binaphthyl ligands hereinbefore described. In certain embodiments, the amount of ligand used may be stoichiometric or excess amount. In other embodiments, ligand may be used as a solvent for the reaction. Therefore, reagents such as N5N- dimethylformamide, dimethylsulfoxide, 1 -methyl-2-pyrrolidinone or other liquid amines may serve as a solvent as well as ligand for the reaction.
[0071] The term "N,N'-dimethylethylenediamine" is used interchangeably with
"N,N'-dimethyl- 1 ,2-diaminoethane".
[0072] The phrase "nucleophilic alkyl halide" refers to any compound having an alkyl halide functional group on one part of the molecule and a nucleophilic group on the other part of the molecule. The term "nucleophilic" or "nucleophile" is well recognized in the art and refers to a chemical moiety having a reactive pair of electrons. Therefore, examples of a nucleophilic alkyl halide include, but not limited to 2- chloroacetamide, chloroacetic acid, chloroproprionic acid as well as those with the general formula:
A
x — Y <>>„ wherein A is a halo group and X is a nucleophile such as an -N-, -O- or - S- group.
[0073] The term "reduction" or "reducing" refers to the conversion of a functional group in a molecule from one oxidation state to a lower oxidation state. The term "reducing agent" or "reductive agent" refers to any compound or complex that is known in the field for its effects in converting a functional group in a molecule from one oxidation state to a lower oxidation state. The reduction may be achieved via a direct electron, hydride or hydrogen-atom transfer. Typical reducing agents useful for Methods 1C include metal hydrides (e.g., lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride) and hydrogen in the presence of a catalyst (e.g., Raney nickel, palladium on chracoal, nickel boride, platinum metal or its oxide, rhodium, ruthenium and zinc oxide, pentacyanocobaltate(II) Co(CN)5 3"). Catalytic hydrogenation is typically carried out at room temperature and above atmospheric pressure, but higher temperature and pressure may be required for more resistant double bonds. Other reducing agents useful for converting double bonds to single bonds include silane and acid; sodium cyanoborohydride and acid; zinc and acid; sodium and liquid ammonia; sodium in ethanol; and borane-triethylamine. Typical reducing agents useful for reducing a ketone to a methylene as in Methods IH include but are not limited to metal hydrides (e.g., diisobutyl aluminum hydride (DIBAL), sodium bis(2- methoxyethoxy)aluminum hydride (Red- Al) or sodium cyanoborohydride); boranes (e.g., BH3-THF); or organoboranes (e.g. bis(benzyloxy)borane). Alternatively, such conversion may also be accomplished through catalytic hydrogenation by using hydrogen in presence of a catalyst (e.g. nickel, palladium on charcoal, nickel boride, platinum metal, platinum oxide, palladium oxide, rhodium oxide, ruthenium oxide or zinc oxide); Wolff-Kishner reduction by heating the ketone with hydrazine hydrate in the presence of a base such as sodium or potassium hydroxide (See Todd, Org. React. 4, 378-422 (1948)); or Clemmensen reduction by heating the ketone with zinc amalgam and aqueous mineral acid such as hydrochloric acid (See Vedejs, Org. React. 22, 401- 422 (1975)). Other reagents that may also accomplish such reduction include triisopropyl phosphate, copper in the presence of sulfuric acid and tin in the presence of hydrochloric acid. For further examples of reducing agents, see "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" by Jerry March, p. 771-790, John Wiley & Sons, Inc. (Fourth Edition).
[0074] The term "alkylation" refers to the introduction of an alkyl radical onto an organic compound by substitution or addition. Therefore, the term "N-alkylation" refers to the introduction of an alkyl radical onto the nitrogen atom of the organic compound.
EXAMPLES [0075] The compounds of the present invention can be produced through the following reaction scheme:
Example 1: Production of 6-bromo-2,3>4,5-tetrahydro-lH-pyrido[4,3-6]indole hydrochloric acid salt. [Int-1]
[0076] 6-bromo-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indole hydrochloric acid salt may be prepared by mixing (2-bromophenyl) hydrazine hydrochloride (50.0 g, 219mmol), 4-piperidone monohydrate hydrochloride (36.0 g, 230mmol), ethanol (500 ml) and hydrochloric acid (50 ml). The resulting mixture is heated to reflux for 6 hours and is cooled to room temperature, filtered, washed with ethanol and dried to a solid.
Figure imgf000083_0001
Example 2: Production of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-li7- pyrido [4,3-6] indole
[0077] [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-6]indole may be prepared by mixing 6-bromo-2,3,4,5-tetrahydro-lH-pyrido [4,3-6] indole hydrochloric acid salt with trifluoracetic acid (630 ml, 8.48mmol) and triethylsilane (172 ml). The mixture is stirred at room temperature under nitrogen for 19 hours. Excess trifluoroacetic acid and triethylsilane are removed in vacuo. Ηexanes (550 ml) are added to the remaining oil and stirred at room temperature for 1 hour; the hexanes are decanted. An additional 250 ml of hexanes are added, stirred for 1 hour and decanted. 2N sodium hydroxide is added to the remaining oil until the pΗ=10 and then is extracted with dichloromethane. The organic layers are combined and washed with brine and dried (Na2SO4).
[0078] Enantiomeric separation of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-6]indole may be carried out by dissolving racemate 6-bromo- 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-ό]indole (8g, 31.6mmol) in methanol (16OmL) at 50°C (oil bath) and adding (R)-mandelic acid (4.8g, 31.6mmol) in portions. The resulting clear solution is stirred at 50°C for several minutes and ether (8OmL) is added dropwise. The resulting solution is cooled to room temperature and the white precipitate (R-Mandelate sale, 3.7g) is filtered off. HPLC analysis shows >99%ee. The filtrate is concentrated, treated with IN sodium hydroxyide (10OmL) and is extracted twice with dichloromenthane (2x5 OmL). The dichloromethane layers are combined, washed with brine (2x200mL) and dried with sodium sulphate. The dichoromethane solution is concentrated to an oil (5.59g) and is redissolved in methanol (9OmL) at 5O0C. (S)-(+)-mandelic acid (3.53g, 23.2mmol) is added in portions. The resulting clear solution is stirred at 500C for several minutes and ether (45mL) is added dropwise. The resulting solution is cooled to room temperature and the white precipitate (S- Mandelate salt, 4.19g) is filtered off. HPLC analysis shows >99%ee. R-Mandelate: [α]D 25 = -98.1, S-Mandelate: [α]D 25 = +102, solvent: DMSO. Alternatively, the resolution may be carried out in a mixutre of methanol and t-butylmethylether (MTBE).
[0079] Alternatively, [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-l//- pyrido[4,3-6]indole may be separated by dissolving racemate 6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-ό]indole (9.61g, 38.0mmol) in methanol (19OmL) at 50°C and adding (S)-(+)-Mandelic acid (5.78g, 38.0mmol) in portions. The resulting clear solution is stirred at 500C for several minutes and ether (95mL) is added dropwise. The resulting solution is cooled to room temperature. The white precipitate (S-Mandelate salt, 4.Ig) is filtered off. ΗPLC analysis shows >99%ee.
[0080] Enantiomeric separation of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-6]indole may also be carried out by dissolving Racemic 6- bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-&]indole (1710 gm "as is," 1570gm by theory, 6.21 mol) in methanol (24 1) by warming to 40-500C (under nitrogen). To the mixture is added (R)-(-)-Mandelic acid (944 g, 6.2 mol) in one portion. The power to the heating mantle is turned-off and MTBE (13L) is charged to the mixture. The resulting solution is allowed to cool to room temperature with stirring and aged for 30- 40hours at 15-250C with stirring. The product is isolated by filtration as a white to off- white precipitate and allowed to air dry at ambient temperature overnight. This affords 580 gm (23%) of the Int-2 R-Mandelate salt. Chiral ΗPLC analysis shows the undesired slower moving enantiomer is present as a single peak (>99%ee). [0081] The filtrate is concentrated, diluted with water (25 L), stirred and treated with 50% NaOH (800ml) to a pH of ~14 as measured by pH paper. The free base is extracted with dichloromethane (2 x 17L and 1 x 6L). The DCM layers are combined, dried (Na2SO4) and concentrated to afford a solid free base (~1150 g). The free base is dissolved in methanol (17 L) by warming to 40-500C under N2 and (S)-(+)-Mandelic acid (692 g, 4.55 mol) is added. The heating mantle is turned off and to the solution is added MTBE (8.5 L) in one portion. The resulting solution is allowed to cool to room temperature with stirring and aged for 30-40 hours. The product is isolated by filtration as a white to off-white precipitate and air dried at ambient temperature overnight. This afforded 828 gm (33%) of S-Mandelate salt. Chiral HPLC analysis showed the faster moving enantiomer is present (>99%ee) with two other impurities present at ~1% each (which elute just before the undesired enantiomer). R-Mandelate: [CC]D 25= -98.1, S- Mandelate: [α]D 25= +102, solvent:DMSO (about 10 mg in 3 ml DMSO). Chiral HPLC conditions: ChiralPak AD-H, 250 x 4.6 mm, 30% IPA in hexanes containing 0.1% diethylamine, flow 0.8 ml/min, UV detection at 254 ran. Samples are prepared by sonicating the salt in IPA.
[0082] Alternative to chiral resolution, enantiomeric separation of [4aS, 9bR]-6- bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-6]indole may also be achieved by preparative chromatography using CHIRALPAK® AD® column, 20μm, 5cm id x 50cm L. 26.4g, 23.Og and 14.8g of racemic 6-bromo-2,3,4,4a,5,9b-hexahydro-lH- pyrido[4,3-b]indole are dissolved separately in 100% ethanol with stirring (optionally with low heating) and then filtered through a 0.4 μm filter. The feeds are injected separately at 25mL volume and eluted with 100% Ethanol at a flow rate of 150mL/min at 25°C. Alternatively, 42Og of racemic 6-bromo-2,3,4,4a,5,9b-hexahydro-lH- pyrido [4,3 -b] indole is similarly dissolved, filtered and injected at 55mL volumn onto a CHIRALPAK® AD® column, 20μm, 1 lcm ID x 25cm L with a flow rate of 400mL/min. The products are detected at an ultraviolet wavelength of 330nm. The products are collected and the solvents are evaporated on rotary evaporators at 400C and under a vacuum of 50-70mbar. The products are analyzed through chiral HPLC analysis by using an AD-H 4.6mm ID x 250mm column at 30°C column temperature, 100% ethanol mobile phase at a flow rate of 0.7mL/min and dected at 200nm, 230nm, 250nm, 280nm or 325nm. The products are also analyzed by achiral HPLC analysis using an Eclipse, 5μm XDB-C8, 4.6mm ID x 250 mm column at 30°C column temperature, 75:25 methanol/0.1% aqueous diethylamine at a flow rate of lmL/min and detected at 250nm, 200nm, 230nm, 280nm or 325nm. The isolated product is >98% ee.
Figure imgf000086_0001
Formula 1 A-HCI Formula IB Formula 1C
Example 3: Production of (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH- pyrido[4,3-b]indoIe-2(9bH)-carboxylate
[0083] (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro- 1 H-pyrido[4,3-b]indole-
2(9bH)-carboxylate may be prepared by first optaining [4aS, 9bR]-6-bromo- 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-Z>]indole (36.0 g, 0.142mol)) as a free base by using 50% aqueous sodium hydroxide solution and extracting the product into MTBE. The conversion to (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lΗ-pyrido[4,3- b]indole-2(9bH)-carboxylate may then be done by cooling a suspension of compounds of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-*]indole (36.0 g, 0.142mol)) in THF (300 ml) and triethylamine (24 ml) in an ice- water bath. Ethyl chloroformate is added dropwise (13.5 ml, 0.142mol) via a syringe pump over 1 hour. The ice-water bath is removed and the reaction mixture is stirred at room temperature for another hour. The reaction mixture is passed through a pad of celite and the solvent is evaporated to give (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH-pyrido[4,3- b]indole-2(9bH)-carboxylate). 1H NMR (CDCl3, 300 MHz): 1.20-1.35 (m,3H), 1.73- 1.85 (m, IH), 1.85-1.99 (m, IH), 3.22-3.52 (m, 3H), 3.52-3.66 (m, IH), 3.66-3.95 (Br, IH), 3.95-4.21 (m, 4H), 6.60 (t, J = 7.7 Hz, IH), 7.04 (d, J = 7.2 Hz, IH), 7.20 (d, J = 8.1 Hz, IH).
[0084] Alternative to the use of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro- lH-pyrido[4,3-Z>]indole (Compound of Formual 1C) free base, the reaction may also be done by starting with the (S)-mandelate salt of [4aS, 9bR]-6-bromo-2,3,4,4a,5,9b- hexahydro-lH-pyrido[4,3-6]indole. A 100 mL round-bottomed flask is equipped with a magnetic stirring bar, a pressure-equalizing addition funnel, and a N2 inlet on top of the addition funnel. The flask is charged with the S-mandelate starting material (5 g, 12.35 mmol), Na2CO3 (2.88 g, 27.17 mmol), and 25 mL of TΗF. To the yellow reaction mixture at 25 0C (heating block temperature) is added a solution of ethyl chloroformate (1.64 g, 15.11 mmol) in 5 mL of TΗF dropwise over ca 70 minutes. The batch is stirred at 25 0C for another 10 min, and is checked by ΗPLC. Less than 2% of the starting material is observed by ΗPLC, and the desired product is registered at ca. 98%. To the batch is added 12.5 mL of EtOH, and the batch is concentrated under reduced pressure to remove ca. 30 mL of solvent (mostly TΗF). To the batch is then added 37.5 mL ofΗ2O, and the resultant mixture shows pH >9 by pH paper. The yellow mixture is then stirred at rt for ca. 1 h, and is filtered. The solid is rinsed with 25 mL of H2O. After drying in a vacuum oven at 58 0C for ca. 16 h, 3.9442 g of a yellow solid is obtained (98% yield). 1H NMR of the solid conformed, and showed no (s)-mandelic acid. HPLC analysis of the product shows the desired product at >99% purity. LC-MS showed a peak with M/e = 326 (M+ 1).
Figure imgf000087_0001
Formula 1C Formula 1D
Example 4: Production of [4aS,9bR] -ethyl 5-(2-amino-2-oxoethyl)-6-bromo- 3,4,4a,5-tetrahydro-lH-pyrido[4,3-b]indole-2(9bH)-carboxylate
[0085] (4aS,9bR)-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro- lH-pyrido[4,3-b]indole-2(9bH)-carboxylate may be prepared by heating to a reflux a suspension of (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro- 1 H-pyrido[4,3-b]indole- 2(9bH)-carboxylate (5.648g, 17.4mmol), 2-chloroacetamide (7.32g, 78.2mmol), potassium iodide (19.2g, 77.7mol) and diisopropylethylamine (19mL, 115mmol) in acetonitrile (8OmL) for 27 hours. The solvent is removed in a vacuo and water (20OmL) is added to the residue and stirred for 1 hour. The resulting white solid is filtered off, washed with ethanol and dried.
Figure imgf000088_0001
Example 5: Production of (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-2-oxo-lH- pyrido[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8-carboxylate [0086] A suspension of [4aS,9bR]-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-
3,4,4a,5-tetrahydro-lH-pyrido[4,3-b]indole-2(9bH)-carboxylate (254mg, 1.34mmol), cuprous iodide (254mg, 1.34mol), potassium carbonate (3.96g, 28.7mmol) and N,N'- dimethylethylenediamine (0.3 ImL, 2.87mmol) in dioxiane (2OmL) is heated at reflux for 4.5 hours. Another portion of cuprous iodide (250mg, 1.32mmol) and N5N'- dimethylethylenediamine (0.33mL, 3.05mmol) is added. The resulting mixture is heated to a reflux for another 3 hours and then at 73 °C for about 66 hours. The reaction mixture is concentrated and passed through a short alumina column using 100:3:3 dichloromethan:triethylamine:methanol. The resulting solvent from the column is evaporated to a solid and redissolved in dichloromethane. The dichloromethane solution is washed with brine, dried with sodium phosphate and concentrated to a solid (3.7g, 95%, 83% pure by HPLC).
CuI, Dioxane
Figure imgf000088_0002
Figure imgf000088_0003
Example 5-A: Production of (6bR,10aS)-ethyI 2,3,6b,9,10,10a-hexahydro-2-oxo-lH- pyrido [3 ',4' :4,5]-py rrolo [1 ,2,3-de] quinoxaline-8-carboxy late [0087] Alternative to Example 5 above, (6bR, 1 OaS)-ethyl 3,6b,9, 10, 1 Oa- hexahydro-3 -methyl-2-oxo- 1 H-pyrido [3 ' ,4 ' :4,5]-pyrrolo [ 1 ,2,3 -de]quinoxaline-8- carboxylate may also be made in a one pot method starting from Compound of Formula ID. A 2 liter 4 neck round bottom flask is equipped with a mechanical stirrer, reflux condenser, N2 inlet, teflon covered K-type temperature probe with a controller, and a heating mantle. To the flask is charged (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro- lH-pyrido[4,3-b]indole-2(9bH)-carboxylate (250 g, 769 mmol), chloroacetamide (124 g, 1153 mmol, 1.5 equiv), potassium iodide (191.5 g, 1160 mmol, 1.5 equiv), diisopropyl ethylamine (266 mL, 1531 mmol, 2.0 equiv), and dioxane (625 mL). The reaction is heated to reflux temperature of about 103 0C until less than 3% of the starting substrate is observed by HPLC (about 48 hours). Additional charge of N- methyl chloroacetamide and diisopropyl ethylamine maybe necessary. The reaction is then cooled to ca. 80 0C, and at this temperature copper iodide (29.2 g, 153.8 mmol, 0.2 equiv), potassium carbonate (232.5 g, 1682 mmol, 2.2 equiv), dimethylethylene diamine (49.6 mL, 461 mmol, 0.6 equiv), and additional dioxane (375 mL) is added. The reaction is then re-heated to reflux and is monitored by HPLC. Reflux occurs at ca. 103 0C. The reaction is monitored by HPLC.
Figure imgf000089_0001
Example 6: Production of (6bR,10aS)-ethyl 3,6b,9,10,10a-hexahydro-3-methyI-2- oxo-lH-pyrido[3',4':4,5]-pyrroIo[l,2,3-de]quinoxaline-8-carboxylate [0088] (6bR, 1 OaS)-ethyl 2,3,6b,9, 10, 1 Oa-hexahydro-2-oxo- 1 H-pyrido-
[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8-carboxylate (17.3 g, 57.4mmol), K2CO3 (15.8g, 114mmol), and methyl iodide (66 ml, lOόOmmol) are placed in a 2L pressure bottle and 500 ml of acetone is added. The bottle is heated in an oil bath at 109°C for 5.5 hours and cooled to room temperature. Acetone and excess methyl iodide are removed in vacuo and 200 ml of water is added and then extracted with DCM. The DCM layers are combined and washed with brine and dried (Na2SO4). Evaporation of the solvent results in (6bR,10aS)-ethyl 2,3,6b,9, 10,10a-hexahydro-3-methyl-2-oxo- IH- pyrido[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8-carboxylate.
Figure imgf000090_0001
Example 6-A: Production of (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-3-methyl- 2-oxo-lH-pyrido[3%4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8-carboxylate
[0089] Alternative to Example 6 above, (6bR, 1 OaS)-ethyl 3,6b,9, 10, 1 Oa- hexahydro-3-methyl-2-oxo-lH-pyrido[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8- carboxylate may also be made in a one pot method starting from Compound of Formula ID. A 2 liter 4 neck round bottom flask is equipped with a mechanical stirrer, reflux condenser, N2 inlet, teflon covered K-type temperature probe with a controller, and a heating mantle. To the flask is charged (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro- lH-pyrido[4,3-b]indole-2(9bH)-carboxylate (250 g, 769 mmol), N-methyl chloroacetamide (124 g, 1153 mmol, 1.5 equiv), potassium iodide (191.5 g, 1160 mmol, 1.5 equiv), diisopropyl ethylamine (266 mL, 1531 mmol, 2.0 equiv), and dioxane (625 mL). The reaction is heated to reflux temperature of about 103 0C until less than 3% of the starting substrate is observed by HPLC (about 48 hours). Additional charge of N- methyl chloroacetamide and diisopropyl ethylamine maybe necessary. The reaction is then cooled to ca. 80 0C, and at this temperature copper iodide (29.2 g, 153.8 mmol, 0.2 equiv), potassium carbonate (232.5 g, 1682 mmol, 2.2 equiv), dimethylethylene diamine (49.6 mL, 461 mmol, 0.6 equiv), and additional dioxane (375 mL) is added. The reaction is then re-heated to reflux and is monitored by HPLC. Reflux occurs at ca. 103 0C. The reaction is monitored by HPLC.
[0090] When complete, the reaction is cooled to ca. 40 0C and poured onto a plug of flash-grade silica gel (625 g, 2.5 g/g). It is eluted (under vacuum) with 6.25 L of ethyl acetate. The eluent is concentrated to a solid residue (320 gm), and then is dissolved in hot ethanol (800 ml). This mixture is allowed to cool to ambient temperature and stirred overnight. The next day it is cooled to 0-50C, aged for Ih and filtered. The cake is washed with cold ethanol (150 ml) and allowed to air dry to afford 170 grams (70%) of product as a white solid which is >99A% pure by HPLC. HPLC 10:90 to 90:10 CH3CN:H2O over 15 min. Hold at 90:10 for 2 min, 0.025% TFA Buffer, 1.5 mL/min, UV at 220 run, Phenomenex Jupiter Cl 8 column 4.6 mm x 250 mm. The product is 75A% pure by LC/MS in the total ion chromatogram. 1H-NMR (300MHz, CDCl3) 1.28(t, J= 6.9Hz, 3H), 1.86-1.96(m, 2H), 2.72(br, IH), 3.09-3.48(m, 7H), 3.86- 4.21(m, 5H), 6.75(dd, J= 1.2, 7.8Hz, IH), 6.82(t, J= 7.8Hz, IH), 6.90(dd, J= 1.2, 7.2Hz, IH).
Figure imgf000091_0001
Example 7: Production of (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH- pyrido-[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8-carboxylate [0091] (6bR, 1 OaS)-ethyl 2,3 ,6b,9, 10, 1 Oa-hexahydro-3-methyl- 1 H-pyrido-
[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline-8-carboxylate may be prepared by adding BH3 THF (IM in THF, 143mL, 143mmol) dropwise at room temperature over 15 minutes to a suspension of (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-3-methyl-2- oxo- 1 H-pyrido[3 ' ,4 ' :4,5]-pyrrolo [ 1 ,2,3 -de]quinoxaline-8-carboxylate ( 18.Og, ca.57mmol) in 50 ml of THF. The resulting mixture is heated to a reflux for 3 hours. The reaction mixture is cooled in an ice- water bath and 150 ml of 6N HCl is added dropwise. After THF is removed in vacuo, 2N NaOH is added until pH=9 followed by extraction with 500 ml of DCM. The DCM layer is washed with brine and dried over Na2SO4. Evaporation of the solvent yields crude (6bR, 1 OaS)-ethyl 2,3,6b,9,10,10a- hexahydro-3-methyl-lH-pyrido-[3',4':4,5]-pyrrolo[l,2,3-de]-quinoxaline-8- carboxylate. [0092] Alternatively, (6bR, 10aS)-3-methyl-2,3,6b,9, 10, 1 Oa-hexahydro- 1 H- pyrido-[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline may be prepared as follows: To a 5 L, 3 -necked round-bottomed flask equipped with an overhead stirrer, an N2 inlet, and a K- type Teflon covered temperature probe is charged with (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-3-methyl-2-oxo-lH-pyrido[3',4':4,5]-pyrrolo[l,2,3- de]quinoxaline-8-carboxylate (218 g, 691.3 mmol) using THF (ca. 50 mL). The reaction vessel is vacuum/N2 purged three times, and then is added a 1 M solution of BH3-THF complex in THF (1962 mL, 1962 mmol, 2.8 equiv) slowly through an addition funnel. The resultant clear solution is then heated at 60 0C. The resultant batch is then stirred at 60 0C for ca. 17 h, and showed 89.0% of the desired product with ca. 3.0% of unreacted substrate by HPLC. The batch is stirred at 60 0C for another 3 h, and then is cooled in an ice bath to ca. 10 0C. To the batch is added MeOH (327 mL, 8073 mmol, 11.7 equiv) slowly through an addition funnel while keeping the internal temperature below 25 0C. The resultant batch is stirred in the ice bath for ca. 30 min, and is concentrated in vacuo to afford a yellow paste. The crude paste is then partitioned between EtOAc (2180 mL) and H2O (2180 mL). The separated organic layer is dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 227.6 g of a yellow liquid. HPLC analysis of the liquid showed 89% of the desired product with 2.6% of an impurity at RRt 0.62 and 2.5% of the starting material. 1H NMR (CDCl3, 300 MHz) δ 1.28 (t, J- 7.0Hz, 3H), 1.79-1.95 (m, 2H), 2.74-2.92 (m, 5H), 3.02-3.22 (m, 2H), 3.22-3.38 (m, 3H), 3.54-3.64 (m, IH), 3.78-4.24 (m, 4H), 6.41(d, J= 7.8Hz, IH), 6.54 (d, J= 7.2Hz, IH), 6.66 (t, J= 7.7Hz, IH); 13C- NMR (CDCl3, 75 MHz) δ 14.9, 24.7, 37.7, 39.9, 41.4, 44.4, 45.8, 50.7, 61.4, 65.0, 109.3, 113.3, 120.6, 128.8, 135.1, 138.2, 155.6.
Figure imgf000092_0001
Example 8: Production of (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH- pyrido-[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline
[0093] (6bR, 10aS)-3-methyl-2,3 ,6b,9, 10, 1 Oa-hexahydro- 1 H-pyrido-[3 ' ,4' :4,5]- pyrrolo[l,2,3-de]quinoxaline-8-carboxylate (ca. 18.5 g, 57mmol), KOH (12.7g, 226mmol) and n-butanol are placed in a 300 ml pressure bottle and heated in an oil bath at 1200C for 3 hours, n-butanol is removed in vacuo and 300 ml of water is added and then extracted with DCM. The DCM layers are combined and washed with brine and dried (Na2SO4). Evaporation of the solvent gives (6bR, 10aS)-ethyl -3 -methyl - 2,3,6b,7,8,9,10,10a-octahydro-lH-pyrido-[3',4':4,5]-pyrrolo[l,2,3-de]quinoxaline.
[0094] Alternatively, to a 5-L, 3-necked, round bottomed flask, and the remaining Int-7 is dissolved crude in cone. HCl (1090 mL) before it is added (6bR, 10aS)-3-methyl-2,3,6b,9, 10, 1 Oa-hexahydro- 1 H-pyrido-[3 ',4' :4,5]-pyrrolo[l ,2,3- de]quinoxaline-8-carboxylate to the 5 L reaction vessel. The resultant solution is heated at 95 0C for 15 h. The batch is then cooled in an ice bath to ca. 10 0C, and is added MTBE (1090 mL). To the batch is then added 25% NaOH solution (1308 mL) slowly through an addition funnel while maintaining the internal temperature below 30 0C. The aqueous layer shows pH > 14 after the addition of NaOH solution. To the batch is then added EtOAc (1090 mL), and the resultant dark mixture is stirred in ice bath for ca. 5 min. Layers are separated, and the aqueous layer is extracted with EtOAc (1090 mL). The combined organic layers are washed with brined (1090 mL), filtered, and concentrated under reduced pressure to afford 166.8 g of a dark brown liquid (theoretical yield 158.5 g). HPLC analysis of the liquid showed 88.1% of the desired product. 1H NMR of the product conforms and shows no single impurity over 5%. LC- MS analysis shows ca. 93% of a major peak with M/e = 230 (M+ 1). The product is stored under N2 in the cold room. 1H NMR (CDCl3, 300 MHz) δ 1.71-1.97 (m, 2 H), 2.58-2.70 (m, 1 H), 2.80-2.92 (m, 6 H), 2.98-3.12 (m, 2 H), 3.26-3.37 (m, 3 H), 3.55- 3.64 (m, 1 H), 6.41 (d, J = 7.8 Hz, 1 H), 6.51 (d, J= 7.2 Hz, 1 H), 6.65 (t, J= 7.8 Hz, 1 H).
Figure imgf000094_0001
Example 9: Production of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH- pyrido- [3 ',4' :4,5] -pyrrolo [1 ,2,3-de] quinoxalin-8-(7H)-yI)-l -(4-fluorophenyl)-l- butanone
[0095] A suspension of (6bR, 10aS)-3-methyl-2,3,6b,9, 10, 1 Oa-hexahydro- 1 H- pyrido-[3',4':4,5]-pyrτolo[l,2,3-de]quinoxaline (ca. 11.8g, ca.50mmol), 4-chloro-4'- flurobutyrophenone (15.Og, 74.8mmol), triethylamine (3OmL, 214mmol), and potassium iodide (12.6g, 76mmol) in dioxane (65 ml) and toluene (65 ml) is heated to reflux for 7 hours. After filtration and evaporation of the solvent, 200 ml of DCM is added. The DCM solution is washed with brine, dried (Na2SO4) and concentrated to approximately 55 ml. The concentrated solution is added dropwise to 600 ml of 0.5N HCl ether solution. The solid is filtered off and washed with ether and then dissolved in water. The resulting aqueous solution is basifϊed with 2N NaOH and extracted with DCM. The DCM layers are combined, washed with brine (2x200mL) and dried (Na2SO4). Evaporation of the solvent and chromatography of the residue over silica gel gives 4-((6bR, 10aS)-3-methyl-2,3,6b,9, 10, 1 Oa-hexahydro- 1 H-pyrido-[3 ',4' :4,5]- pyrrolo[ 1 ,2,3-de]quinoxalin-8-(7H)-yl)- 1 -(4-fluorophenyl)- 1 -butanone.
[0096] Alternative to the use of dioxane, the reaction may be carried out in 3- pentanone. To a 5 L, three-necked, round-bottomed flask equipped with a mechanical stirrer, a N2 inlet, a reflux condenser, and a temperature probe is charged with 230 g of (6bR, 10aS)-3-methyl-2,3,6b,9, 10, 1 Oa-hexahydro- 1 H-pyrido-[3 ',4' :4,5]-pyrrolo[l ,2,3- dejquinoxaline (1 mol), 249.78 g of KI (1.5 mol, 1.5 equiv), 194.12 g OfPr2NEt (1.5 mol, 1.5 equiv), 301.76 g of 4-chloro-4'-fluorobutyrophenone (1.5 mol, 1.5 equiv), and 2300 mL of 3-pentanone. The resultant mixture is then heated at 95 0C (internal temperature) for 17 h, and then is checked by HPLC for reaction completion. The batch is then cooled to ca. 10 0C with an ice bath, and then is added 5% NaOH solution (2300 mL). The separated aqueous layer is then extracted with EtOAc (2300 mL). The combined organic layer is filtered through a pad of silica gel (1 15 g) that is pre-packed with EtOAc. The silica gel is then flushed with EtOAc (2300 mL). The combined filtrate is concentrated under reduced pressure to afford a dark brown liquid. To the liquid is then added EtOAc (2300 mL), and is added 1.5 N HCl solution (2300 mL). The batch is stirred at rt for ca. 20 min, and layers are cut. The separated organic layer is extracted with 1.5 N HCl solution (1150 mL), and the layers are separated. The combined aqueous layer is cooled in an ice bath to ca. 10 0C, and is added EtOAc (2300 mL). To the stirring mixture is then added 25% NaOH solution (1000 mL) through an addition funnel while maintaining the internal temperature under 25 0C. The resultant mixture is stirred in an ice bath for ca. 20 min, and the layers are separated. The aqueous layer shows a pH between 11 to 12 by pH paper. The aqueous layer is back extracted with EtOAc (1 150 mL), and the layers are cut. The combined organic layer is washed with brine (1150 mL), dried over Na2SO4 (230 g), filtered, and concentrated in vacuo to afford 368.8 g of a dark brown liquid. The crude free base is stored under N2 in a dark cold room.
Figure imgf000095_0001

Claims

Claims
What is claimed is:
1. Compounds of Formula 1C
Figure imgf000096_0001
Formula 1C
wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) A = Cl, Br, F or I;
(iv) R7, R8and R9 are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
2. Compounds as described in any of claims 1, wherein A are Cl, Br, F or I.
3. Compounds as described in any of claims 1-2, wherein A are Cl or Br
4. Compounds as described in any of claims 1-3, wherein R7, R8 and R9 are H.
5. Compounds as described in any of claims 1 -4, wherein compounds of Formula 1 C is:
Figure imgf000097_0001
6. A method for preparing stereoselective compounds of Formula 1C as defined in any of claims 1-5, comprising the steps of: a) reducing compounds of Formula IA
Figure imgf000097_0002
Formula IA
as hereinbefore described to compounds of Formula IB:
Figure imgf000097_0003
Formula IB as hereinbefore described and b) separating the enantiomers of compounds of Formula 1 B by chiral acid resolution or chiral chromatography.
7. The method as described in claim 6, wherein said reduction step comprises the use of a reducing agent selected from a group consisting of: a) silane and acid; b) sodium cyanoborohydride and acid; c) zinc and acid; d) sodium and liquid ammonia; e) sodium in ethanol; f) borane-triethylamine; and g) hydrogen and metal catalyst selected from a group consisting of nickel, palladium on charcoal, nickel boride, platinum metal, platinum oxide, rhodium oxide, ruthenium oxide and zinc oxide.
8. The method as described in any of claims 6-7, wherein said reducing agent is triethylsilane and acid.
9. The method as described in claim 8, wherein said acid is trifluoroacetic acid.
10. The method as described in any of claims 6-9, wherein said chiral acid resolution comprises the use of tartaric acid, dibenzoyltartaric acid or mandelic acid.
11. The method as described in any of claims 6-10, wherein said chiral acid resolution comprises the use of mandelic acid.
12. The method as described in any of claims 6-11, wherein said chiral acid resolution comprises the use of S-mandelic acid.
13. The method as described in any of claims 6-12, wherein said reducing agent is triethyl silane, said acid is trifluoroacetic acid and said chiral acid resolution comprises the use of S-mandelic acid.
14. The method as described in any of claims 6-9, wherein said chiral chromatography comprises the use of amylose tris(3,5-dirnethylphenylcarbamate) column.
15. The method as described in claim 14, wherein said chiral chromatography comprises the use of amylose tris(3,5-dimethylphenylcarbamate) stationary phase and ethanol mobile phase.
16. Compounds of Formula ID:
Figure imgf000099_0001
Formula ID wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) A = Cl, Br, F or I;
(iv) B is a protecting agent;
(v) R7, R8and R9 are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
17. Compounds as described in claim 16, wherein B has the general formula:
X wherein:
(i) Z is optionally substituted alkyl, aryl, alkylaryl or -OR wherein R is alkyl, aryl, arylalkyl or heteroarylalkyl; (ii) P is -C(O)-, -C(O)O- or -S(O)2-.
18. Compounds as described in any of claims 16 and 17, wherein B is t-butoxycarbonyl.
19. Compounds as described in any of claims 16 and 17, wherein B is ethoxycarbonyl.
20. Compounds as described in any of claims 16-19 wherein k and m are 1.
21. Compounds as described in any of claims 16-20 wherein R 7 , τ R>8 a «n_dJ RTD 9 are H
22. Compounds as described in any of claims 16-21, wherein A is Cl, Br, F or I.
23. Compounds as described in any of claims 16-21, wherein A is Cl.
24. Compounds as described in any of claims 14-23, wherein Compound of Formula ID is:
Figure imgf000100_0001
Formula ID
25. A method for preparing compounds of Formula ID as defined in any of claims 16-24 comprising the step of protecting the pyrido-nitrogen atom of compounds of Formula 1C:
Figure imgf000100_0002
Formula 1C
with a protecting agent in the presence of a base.
26. A method as described in claim 25, wherein said protecting agent has the general formula
wherein:
(i) Y is halogen, imidazoyl, benzotriazole, N-(oxy)succinimide, alkoxy, -O- alkylaryl or -O-aryl; (iii) Z is optionally substituted alkyl, aryl, alkylaryl or -OR wherein R is alkyl, aryl, arylalkyl or heteroarylalkyl; and (ii) P is -C(O)-, -C(O)O- or S(O)2.
27. The method as described in any of claims 25 and 26, wherein said protecting agent is selected from a group consisting of benzyloxycarbonyl chloride, triphenylmethyl chloride, ethyl chloroformate, /-butoxycarbonyl anhydride, benzyl iV-succinimidyl carbonate, benzoyl chloride, benzyl bromide, (benzyloxycarbonyl)-benzo triazole, benzyl chloride, benzyl bromide, 1 -arene sulfonyl chloride or toluene sulfonyl chloride.
28. The method as described in any of claims 25, 26 and 27, wherein said protecting agent is ethyl chloroformate.
29. The method as described in claim 25-28, wherein said base is triethylamine.
30. Compounds of Formula IE:
Figure imgf000102_0001
Formula IE wherein:
(i) k is l or 2;
(ϋ) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) A = Cl, Br, F or I;
(V) B is a protecting agent;
(vi) R7, R8and R9 are independently H or optionally substituted Ci -C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and
(vii) X-Y is a -HO-CH2-, -HS-CH2-, -H(R')N-CH2- or -H(R')N-C(O)-, wherein R' is H or CMalkyl.
31. Compounds as described in claim 30, wherein X-Y is -H(R')N-C(0)- wherein R' is
Figure imgf000102_0002
32. Compounds as described in claim 30, wherein X-Y is a -HO-CH2-.
33. Compounds as described in any of claims 30-32, wherein k, m and n are 1.
34. Compounds as described in any of claims 30-33, wherein B is ethoxycarboxyl or t- butoxycarbonyl.
35. Compounds as described in any of claims 30-34, wherein R 7 , τ Rj 8 and R are H.
36. Compound as described in any of claims 30-35, wherein said Compound of Formula IE is
Figure imgf000103_0001
Formula IE
37. Compound as described in any of claims 30-35, wherein said Compound of Formula IE is
38. A method for preparing compounds of Formula IE as defined in any of claims 30-37 comprising the step of treating compounds of Formula ID
Figure imgf000104_0001
Formula ID as herein before described with (a) a nucleophilic alkyl halide having the formula
A
X — Y wherein:
(i) A = Cl, F, Br or I;
(ii) X-Y is a -HOCH2-, -HSCH2-, -H(R')N-CH2- or -H(R')N-C(O)-. wherein
R' is H or Ci-4alkyl; and (iii) n is 1, 2 or 3. and (b) a base.
39. The method as described in claim 38, wherein said nucleophilic alkyl halide is 2- chloroacetamide.
40. The method as described in any of claims 38 and 39, wherein said base is N,N'- diisopropylethyl amine.
41. The method as described in any of claims 37-39, further comprising potassium or sodium iodide.
42. Compounds of Formula IE':
Figure imgf000105_0001
Formula IE' wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) B is a protecting agent.
(iv) R7, R8and R9 are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
43. Compounds as described in claim 42, wherein k and m are 1.
44. Compounds as described in claim 42 or 43, wherein B is ethoxycarbonyl or t- butoxycarbonyl.
45. Compounds as described in claim 42, 43 or 44, wherein R7, R8 and R9 are H.
46. Compounds as described in any of claims 42-45, wherein Compound of Formula IE' is
Figure imgf000106_0001
Formula IE'
47. A method for preparing Compounds of Formula IE' as described in any of claims 42- 46 comprising the step of treating compounds of Formula ID with:
(a) benzophenone imine;
(b) a transition metal catalyst selected from Groups 8-11;
(c) a base; and
(d) ligands selected from a group consisting of:
(1) phenolic or amine ligands selected from a group consisting of optionally substituted aryl alcohol, 1,2-diamine, 1,2- aminoalcohol, imidazolium carbene, 4- (dimethylamino)pyridine, 2-(aminomethyl)pyridine, 4,7- diphenyl- 1 , 10-phenanthroline, 4,7-dimethyl- 1,10- phenanthroline, 5-methyl- 1,10-phenanthroline, 5-chloro-l,10- phenanthroline, and 5 -nitro- 1,10-phenanthroline;
(2) ligand represented by structure 1 :
Figure imgf000107_0001
wherein
• A and B independently represent fused rings selected from the group consisting of monocyclic or polycyclic cycloalkyls, cycloalkenyls, aryls, and heterocyclic rings, said rings having from 4 to 8 atoms in a ring structure;
• X represents NR2, P(alkyl)2, P(cycloalkyl)2, AsR2, or OR;
• Y represents H, alkyl, NR2, or AsR2;
• X and Y are not identical;
• R, R3, Rb, Rc, and Rd, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or ~(CH2)m -R80;
• Re and Rf, for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or -(CH2)m -Rs0;
• A and B independently are unsubstituted or substituted with Re and Rf5, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3 and Rb, or R0 and Rd, or both, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• Rgo represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(3) ligand represented by structure 2:
Figure imgf000108_0001
2 wherein
• X represents PR2 ;
• Y represents H5 NR2, OR, or SR; • R represents, independently for each occurrence, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or ~(CH2)m -Rs0;
• R3, Rb, Rc, Rd, Re, Rf5 Rg, and Rh, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or ~(CH2)m --R80;
• one or more pairs of substituent, with an ortho-relationship therebetween, selected from the group consisting of R3, Rb, R0, Rd, Re, Rf, Rg, and Rh, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• R80 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(4) ligand represented by structure 3 :
Figure imgf000110_0001
wherein
X represents NR2, P(alkyl)2, P(cycloalkyl)2, AsR2, or OR; Y represents H, alkyl, NR2, AsR2, or OR; X and Y are not identical;
R, R3, Rb, Rc, and Rd, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or ~(CH2)m ~Rso; Re and Rf, for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or ~(CH2)m --Rso;
• the B and B1 rings of the binaphthyl core independently are unsubstituted or substituted with R5 and R6, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3 and Rb, or R0 and Rd, or both, taken together optionally represent a ring consisting of a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• R80 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(5) ligand represented by structure 4:
Figure imgf000111_0001
wherein:
R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and -
Figure imgf000111_0002
the A and A1 rings of the biphenyl core independently are unsubstituted or substituted with Ri and R2, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3 and Rb are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and ~(CH2)m~R80;
• R8o represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(6) ligand represented by structure 5:
Figure imgf000112_0001
wherein
R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and -
-(CH2)m --R80; the A, B, A1, and B1 rings of the binaphthyl core independently are unsubstituted or substituted with Ri5 R2, R3, and R4, respectively, any number of times up to the limitations imposed by stability and the rules of valence; • R3, Rb, Rc, and Ra, are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and — (CH2)m --Rso;
• Rgo represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
• provided that when R is cycloalkyl or aryl, there is at least one instance of Ra, Rb, Rc, or Rd;
(7) ligand represented by structure 6:
Figure imgf000113_0001
wherein
R is selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and — (CH2)m --Rso; the A and A' rings of the biphenyl core independently may be unsubstituted or substituted with Ra and Rb, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
R3 and Rb are selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and ~(CH2)m -Rso;
• Re0 represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, may be provided in the form of a mixture of enantiomers or as a single enantiomer;
(8) ligand represented by structure 7:
Figure imgf000114_0001
wherein
• R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and - -(CH2)m -R80;
• P(R)2 represents P(alkyl)2, or P(cycloalkyl)2 ;
• the A, B, A1, and B1 rings of the binaphthyl core independently are unsubstituted or substituted with R3, Rb, Rc, and Rd, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3, Rb, Rc, and Rj, are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and ~(CH2)m -Rs0; • Rgo represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer; and
(9) 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl.
48. The method as described in claim 47, wherein said metal is selected from a group consisting of Pd/C, PdCl2, Pd(OAc)2, palladium(O) bis(dibenzylideneacetone) (Pd2(dba)2), Ni(acetylacetonate)2, NiCl2[P(C6H5)J2, or Ni(l,10-phenanthroline)2.
49. The method as described in claims 47 or 48, wherein said catalyst is Pd2(dba)2.
50. The method as described in any of claims 47-49, wherein said base is selected from a group consisting of triethyl amine, N,N'-diisopropylethyl amine, 4-(dimethylamino)- pyridine, l,5-diazabicycl[4.3.0]non-5-ene, l,5-diazabicyclo[5.4.0]undec-5-ene, 1,4- Diazabicyclo[2.2.2]octane, sodium hydride, lithium hydride, potassium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, lithium /-butoxide, sodium hydroxide, potassium hydroxide, cesium carbonate, calcium carbonate, potassium phosphate, sodium t-butoxide, and potassium hexamethyldisilazane.
51. The method as described in any of claims 47-50, wherein said base is sodium t- butoxide.
52. The method as described in any of claims 47-51, wherein said ligand is 2,2'- bis(diphenylphosphino)- 1 , 1 '-binaphthyl.
53. The method as described in claim 47, wherein said catalyst is Pd2(dba)2, said base is sodium t-butoxide and said ligand is 2,2'-bis(diphenylphosphino)- 1,1 '-binaphthyl.
54. Compounds of Formula IF":
wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protecting agent;
(v) R , R and R are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and
(vi) X-Y is -(R')N-C(O)-, wherein R' is H or CMalkyl.
55. Compounds as described in any of claims 54 wherein k, m and n are 1.
56. Compounds as described in any of claims 54-55, wherein B is ethoxycarbonyl or t- butoxycarbonyl.
57. Compounds as described in any of claims 54-56, wherein R , R and R are H.
58. Compound as described in any of claims 54-57, wherein Compound of Formula IF" is
Figure imgf000117_0001
59. A method for preparing compounds of Formula IF
Figure imgf000117_0002
Formula IF
wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protecting agent;
(v) R7, R8and R9 are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and
(vi) X-Y is -OCH2- -SCH2-, -(R')N-CH2- or -(R')N-C(O)-, wherein R' is H or
CMalkyl; which method comprises the step of treating compounds of Formula IE:
Figure imgf000118_0001
Formula IE as hereinbefore described with (a) a transition metal catalyst selected from Groups 8-11 ; and (b) a base.
60. The method as described in claim 59, wherein said transition metal catalyst is a copper catalyst.
61. The method as described in any of claims 59 and 60, wherein said copper catalyst is CuI.
62. The method as described in any of claims 59-61, wherein said base is bronsted base.
63. The method as described in any of claims 60-62 wherein said base is potassium carbonate.
64. The method as described in any of claims 59-63, wherein said step further comprising the use of a ligand selected from a group consisting of:
(1) phenolic or amine ligands selected from a group consisting of optionally substituted aryl alcohol, 1,2-diamine, 1,2- aminoalcohol, imidazolium carbene, 4- (dimethylamino)pyridine, 2-(aminomethyl)pyridine, 4,7- diphenyl- 1 , 10-phenanthroline, 4,7-dimethyl- 1,10- phenanthroline, 5 -methyl- 1,10-phenanthroline, 5-chloro-l,10- phenanthroline, and 5-nitro- 1,10-phenanthroline; (2) ligand represented by structure 1 :
Figure imgf000119_0001
wherein
• A and B independently represent fused rings selected from the group consisting of monocyclic or polycyclic cycloalkyls, cycloalkenyls, aryls, and heterocyclic rings, said rings having from 4 to 8 atoms in a ring structure;
• X represents NR2, P(alkyl)2, P(cycloalkyl)2, AsR2, or OR;
• Y represents H, alkyl, NR2, or AsR2;
• X and Y are not identical;
• R, R3, Rb, Rc, and Rd, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or — (CH2)m -R80;
• Re and Rf, for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or ~(CH2)m -R80;
• A and B independently are unsubstituted or substituted with Re and Rf,, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• Ra and Rb, or R0 and Rd, or both, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• R8O represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(3) ligand represented by structure 2:
Figure imgf000120_0001
2 wherein
X represents PR2 ; • Y represents H, NR2, OR, or SR;
• R represents, independently for each occurrence, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or ~(CH2)m -Rs0;
• R3, Rb, Rc, Rd, R6, Rf, Rg, and Rh, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or --(CFb)™ —Rso ;
• one or more pairs of substituent, with an ortho-relationship therebetween, selected from the group consisting of R3, Rb, Rc, Rd, Re, Rf, Rg, and Rh, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• R8o represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(4) ligand represented by structure 3:
Figure imgf000122_0001
• X represents NR2, P(alkyl)2, P(cycloalkyl)2, AsR2, or OR;
• Y represents H, alkyl, NR2, AsR2, or OR;
• X and Y are not identical;
• R, R3, Rb, Rc, and Rd, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or -(CH2)H, -R80;
• Re and Rf, for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or ~(CH2)m -R80;
• the B and B1 rings of the binaphthyl core independently are unsubstituted or substituted with R5 and R6, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3 and Rb, or R0 and Ra, or both, taken together optionally represent a ring consisting of a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• R8O represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(5) ligand represented by structure 4:
wherein:
R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and -
-(CH2V-R80; the A and A' rings of the biphenyl core independently are unsubstituted or substituted with Ri and R2, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3 and Rb are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and ~(CH2)m~R80;
• Rβo represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(6) ligand represented by structure 5:
Figure imgf000124_0001
wherein
R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and -
Figure imgf000124_0002
the A, B, A', and B1 rings of the binaphthyl core independently are unsubstituted or substituted with Ri, R2, R3, and R4, respectively, any number of times up to the limitations imposed by stability and the rules of valence; • R3, Rb, Rc, and Rd, are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and ~(CH2)m --R80;
• Rgo represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
• provided that when R is cycloalkyl or aryl, there is at least one instance of Ra, Rb, R0, or Rj;
(7) ligand represented by structure 6:
Figure imgf000125_0001
wherein
• R is selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and — (CH2)m -R80;
• the A and A' rings of the biphenyl core independently may be unsubstituted or substituted with R3 and Rb, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3 and Rb are selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and --(CH2)m -R80;
• Rg0 represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, may be provided in the form of a mixture of enantiomers or as a single enantiomer;
(8) ligand represented by structure 7:
Figure imgf000126_0001
wherein
R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and -
Figure imgf000126_0002
;
P(R)2 represents P(alkyl)2, or P(cycloalkyl)2 ; the A, B, A', and B1 rings of the binaphthyl core independently are unsubstituted or substituted with R8, Rb, Rc, and Rj, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
R3, Rb, Rc, and Rd, are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and ~(CH2)m -Rs0; • R80 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer; and
(9) N,N-dimethylformamide, dimethylsulfoxide and l-methyl-2- pyrrolidinone.
65. The method as described in claim 64, wherein at least one ligand is selected from the group consisting of cis-l^-diaminocyclohexane, trans- 1 ,2-diaminocyclohexane, a mixture of cis- and trans-l^-diaminocyclohexane, cis-N,N'-dimethyl-l,2- diaminocyclohexane, trans-N,N'-dirnethyl-l,2-diaminocyclohexane, a mixture of cis- and trans-N,N'-dimethyl-l,2-diaminocyclohexane, cis-N-tolyl-1,2- diaminocyclohexane, trans-N-tolyl-l^-diaminocyclohexane, a mixture of cis- and trans-N-tolyl-l^-diaminocyclohexane, ethanolamine, 1 ,2-diaminoethane, and N,N'- dimethyl- 1 ,2-diaminoethane.
66. The method as described in any of claims 64 and 65, wherein said ligand is N5N'- dimethyl- 1 ,2-diaminoethane.
67. The method as described in claim 64, wherein at least one ligand is selected from the group consisting of 2-phenylphenol, 2,6-dimethylphenol, 2-isopropylphenol, 1- naphthol, 8-hydroxyquinoline, 8-aminoquinoline, DBU, 2-(dimethylamino)ethanol, N,N-diethylsalicylamide, 2-(dimethylamino)glycine, N,N,N',N'-tetramethyl-l ,2- diaminoethane, 4,7-diphenyl- 1 , 10-phenanthroline, 4,7-dimethyl- 1 , 10-phenanthroline, 5-methyl-l , 10-phenanthroline, 5-chloro- 1 , 10-phenanthroline, 5-nitro- 1,10- phenanthroline, 4-(dimethylamino)pyridine, 2-(aminomethyl)pyridine, and (methylimino)diacetic acid.
68. The method as described in any of claims 64-67, further comprising sodium or potassium iodide.
69. Compounds of Formula IG':
Figure imgf000128_0001
wherein: wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protecting agent;
(v) R7, R8and R9 are independently H or optionally substituted Cj-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and
(vi) R10 is
Figure imgf000128_0002
alkenyl or alkynyl; in free or salt form.
70. Compounds as described in claim 69, wherein B is ethyloxycarboxyl or t- butoxycarbonyl.
71. Compounds as described in any of claims 69 and 70, wherein R10 is alkyl.
72. Compounds as described in any of claims 69, 70 and 71, wherein R 10 is methyl.
73. Compounds as described in any of claims 69-70, wherein R , R 8 and j r R>9 are H.
74. Compounds as described in any of claims 69- 73, wherein k, m and n are 1.
75. Compounds as described in any of claims 69-74, wherein Compound of Formula IG' is:
Figure imgf000129_0001
76. A method for preparing compounds of Formula IG:
Figure imgf000129_0002
Formula IG
wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protecting agent; (v) R7, R8and R9 are independently H or optionally substituted C1-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
I I
(vi) X-Y is a -NC(O)- or -NCH2- ; and
(vii) R10 is C1-4alkyl, alkenyl or alkynyl; in free or salt form, which method comprises the step of N-alkylating compounds of Formula IF'
Figure imgf000130_0001
Formula IF
wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protecting agent;
*7 o Q
(V) R , R and R are independently H or optionally substituted C1-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and (vi) X-Y is -(RON-CH2- or -(R')N-C(O)-, wherein R' is H; with an alkyl halide and a base.
77. The method as described in claim 76, wherein said alkyl halide is methyl iodide.
78. The method as described in claim 76 or 77, wherein said base is a bronsted base.
79. The method as described in any of claims 78, wherein said base is potassium carbonate.
80. A method for preparing compounds of Formula IH:
Figure imgf000131_0001
Formula IH wherein: (i) k is 1 or 2; (ϋ) m is 0, 1 or 2; (iii) n is 1, 2 or 3; (iv) B is a protecting agent;
(V) R7, R8andR9 are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
(vi) X is a N; and
(vii) R10 is H or CMalkyl; and
(viii) R6a and R are independently selected from a group consisting of H; in free or salt form, which method comprises the step of reducing compounds of Formula
IG'
Figure imgf000132_0001
Formula IG1
wherein:
(i) k is l or 2;
(ϋ) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protecting agent;
(V) R7, R8andR9 are independently H or o alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
I (vi) X-Y is a -NC(O)-; and
(vii) R10 is Ci-4alkyl, alkenyl or alkynyl; with a reducing agent.
81. The method as described in claim 80, wherein said reducing agent is selected from a group consisting of metal hydrides; boranes, organoboranes; H2 and a catalyst; zinc amalgam and acid; hydrazine and base; copper and acid; and tin and acid.
82. The method as described in claim 80 or 81, wherein said reducing agent is borane- THF.
83. A method for preparing compounds of Formula II:
Figure imgf000133_0001
Formula II
wherein
(i) k is 1 or 2;
(ϋ) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) R7, R8and R9 are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
(V) X is a N, S or O;
(vi) R10 is H or Ci^alkyl when X is N or R10 is non-existent when X is O or S; and (vϋ) R6a and R6b are H; which method comprises the step of deprotecting compounds of Formula IH:
Figure imgf000133_0002
Formula IH
wherein:
(i) k is 1 or 2; (ii) m is 0, 1 or 2; (iii) n is 1, 2 or 3;
(iv) B is a protecting agent;
(v) R7, R8and R9 are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; (vi) X is a N, O or S; and
(vii) R10 is H or Ci^alkyl when X is N or R10 is non-existent when X is O or S; and (viii) R6a and R6b are H.
84. The method as described in claim 83, wherein said deprotection step comprises the use of an acid, a base or hydrogen and a catalyst.
85. The method as described in any of claims 83 and 84, wherein said deprotection step comprises the use of sodium hydroxide.
86. A method for preparing compounds of Formula U:
Formula U wherein:
(i) k is l or 2;
(ϋ) m is 0, 1 O] r 2;
(iii) n is 1, 2 or 3; (iv) R7, R8and R9 are independently H or optionally substituted C i -C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.;
(v) X is N, S or O; and
(vi) R10 is H or
Figure imgf000135_0001
when X is N or R10 is non-existent when X is -O- or -S-.
(vii) R6a and R6b are H; and
(viii) R1 is H or optionally substituted C!-C6alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxoalkyl, aryloxyalkyl, heroaryloxoalkyl, heroaryloxyalkyl, aryl sulfinylalkyl or heteroaryl sulfinylalkyl; which method comprises the step of N-alkylating compounds of Formula II
Figure imgf000135_0002
Formula II
as hereinbefore described with (a) a compound of the general formula:
R 13
/
G-Z
wherein:
(iv) Z is -C(O)-, -0-, Or -S(O)2-;
(v) R13 is optionally substituted aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl; and
(vi) G is C i -Cgalkyl halide; and (b) a base.
87. The method as described in claim 86, wherein the general formula R 13
/
G — Z
is selected from a group consisting of:
Figure imgf000136_0001
I. The method as described in any of claims 86 and 87, wherein said method further comprises prior to said N-alkylation step, the step of deprotecting compounds of Formula IH:
Figure imgf000136_0002
Formula IH
as hereinbefore described.
89. The method as described in claims 88, wherein said deprotection step comprises the use of (1) hydrogen and palladium, (2) an acid or (3) a base.
90. The method as described in any of claims 88 and 89, wherein said deprotection step comprises the use of sodium hydroxide.
91. The method as described in any of claims 88, 89 and 90, wherein said method further comprises prior to said deprotection reaction, the step of reducing the keto group of compounds of Formula IG':
Figure imgf000137_0001
to methylene of compounds of Formula IH:
Figure imgf000137_0002
Formula IH
with a reducing agent.
92. The method as described in claims 91, wherein said reducing agent is selected from a group consisting of metal hydrides; boranes; organoboranes; H2 and a catalyst; zinc amalgam and acid; hydrazine and base; copper and acid; and tin and acid.
93. The method as described in any of claims 91 and 92, wherein said reducing agent is borane-THF.
94. The method as described in any of claims 91, 92 and 93, which method further comprises prior to said reduction step, the step of N-alkylating compounds of Formula IF:
Figure imgf000138_0001
Formula IF
with an alkyl halide and a base.
95. The method as described in claim 94, wherein said alkyl halide is methyl iodide.
96. The method as described in claim 92-95, wherein said base is a Bronsted base.
97. The method as described in any of claims 92-96, wherein said base comprises potassium carbonate.
98. The method as described in any of claims 92-96, wherein said base comprises potassium iodide.
99. The method as described in any of claims 92-98, wherein said method further comprises prior to said N-alkylation step, the step of treating compounds of Formula IE:
Figure imgf000139_0001
Formula IE with a transition metal catalyst selected from Group 8-11 of the Periodic Table and a base.
100. The method as described in any of claim 99, wherein said transition metal catalyst is a copper catalyst.
101. The method as described in any of claims 99 and 100, wherein said transition metal catalyst is CuI.
102. The method as described in any of claims 99- 101, wherein said base is a Bronsted base.
103. The method as described in any of claims 99-101, wherein said base is potassium carbonate.
104. The method as described in any of claims 99- 103, further comprising the use of a ligand.
105. A method as described in any of claims 104, wherein said ligand is selected from a group consisting of
(1) phenolic or amine ligands selected from a group consisting of optionally substituted aryl alcohol, 1 ,2-diamine, 1 ,2- aminoalcohol, imidazolium carbene, 4- (dimethylamino)pyridine, 2-(aminomethyl)pyridine, 4,7- diphenyl- 1 , 10-phenanthroline, 4,7-dimethyl- 1,10- phenanthroline, 5-methyl- 1,10-phenanthroline, 5-chloro-l,10- phenanthroline, and 5 -nitro- 1,10-phenanthroline; (2) ligand represented by structure 1 :
Figure imgf000140_0001
wherein
• A and B independently represent fused rings selected from the group consisting of monocyclic or polycyclic cycloalkyls, cycloalkenyls, aryls, and heterocyclic rings, said rings having from 4 to 8 atoms in a ring structure;
• X represents NR2, P(alkyl)2, P(cycloalkyl)2, AsR2, or OR;
• Y represents H, alkyl, NR2, or AsR2;
• X and Y are not identical;
• R, R3, Rb, Rc, and Rj, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or — (CH2)m — R80; • R« and Rf, for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or — (CH2),,! -Rs0;
• A and B independently are unsubstituted or substituted with Re and Rf5, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3 and Rb, or R0 and R<j, or both, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• Rgo represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(3) ligand represented by structure 2
Figure imgf000141_0001
2 wherein
• X represents PR2;
• Y represents H, NR2, OR, or SR;
• R represents, independently for each occurrence, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or -(CH2)m -Rs0;
• R3, Rb, Rc> Rd, Re, Rf5 Rg5 and Rh, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or — (CH2)m --R80;
• one or more pairs of substituent, with an ortho-relationship therebetween, selected from the group consisting of R3, Rb, Rc5 Rd, Re, Rf, Rg, and Rh, taken together optionally represent a ring having a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• R8o represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(4) ligand represented by structure 3:
Figure imgf000143_0001
wherein
• X represents NR2, P(alkyl)2, P(cycloalkyl)2, AsR2, or OR;
• Y represents H, alkyl, NR2, AsR2, or OR;
• X and Y are not identical;
• R, R3, Rb, Rc, and Rd, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or — (CH2)m -R80;
• Re and Rf, for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or "(CH2)m -Rs0;
• the B and B1 rings of the binaphthyl core independently are unsubstituted or substituted with R5 and R6, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• Ra and Rb, or Rς and Rd, or both, taken together optionally represent a ring consisting of a total of 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is substituted or unsubstituted;
• Rso represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(5) ligand represented by structure 4:
Figure imgf000144_0001
wherein:
R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and -
-(CH2)m--Rgo; the A and A1 rings of the biphenyl core independently are unsubstituted or substituted with Rj and R2, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• Ra and Rb are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and ~(CH2)m~R80;
• R80 represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
(6) ligand represented by structure 5:
Figure imgf000145_0001
wherein
R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and -
Figure imgf000145_0002
the A, B, A', and B' rings of the binaphthyl core independently are unsubstituted or substituted with Ri, R2, R3, and R4, respectively, any number of times up to the limitations imposed by stability and the rules of valence; • Ra, Rb, R0, and R<j, are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and — (CH2)m -Rs0;
• R8O represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
• provided that when R is cycloalkyl or aryl, there is at least one instance OfR3, Rb, Rc, or Rj;
(7) ligand represented by structure 6:
Figure imgf000146_0001
wherein
R is selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and — (CH2)m — Rso; the A and A1 rings of the biphenyl core independently may be unsubstituted or substituted with R3 and Rb, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
R3 and Rb are selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and -(CH2)m -R80;
• Rgo represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, may be provided in the form of a mixture of enantiomers or as a single enantiomer;
(8) ligand represented by structure 7:
Figure imgf000147_0001
7 wherein
• R is selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and - -(CH2)m -R80;
• P(R)2 represents P(alkyl)2, or P(cycloalkyl)2;
• the A, B, A1, and B' rings of the binaphthyl core independently are unsubstituted or substituted with R3, Rb, Rc, and Rd, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
• R3, Rb, R0, and Rd, are selected, independently for each occurrence, from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, -SiR3, and ~(CH2)m -Rso; • R8o represents an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m is an integer in the range 0 to 8 inclusive; and
• the ligand, when chiral, is a mixture of enantiomers or a single enantiomer; and
(9) N,N-dimethylformamide, dimethylsulfoxide and l-methyl-2- pyrrolidinone.
106. The method as described in claim 105, wherein said ligand is optionally substituted 1,2-diamine ligand.
107. The method as described in claim 105 or 106, wherein said ligand is selected from a group consisting of cis-l,2-diaminocyclohexane, trans- 1 ,2-diaminocyclohexane, a mixture of cis- and trans- 1 ,2-diaminocyclohexane, cis-N,N'-dimethyl-l,2-diamino- cyclohexane, trans-N,N'-dimethyl-l,2-diaminocyclohexane, a mixture of cis- and trans-N,N'-dimethyl- 1 ,2-diaminocyclohexane, cis-N-tolyl- 1 ,2-diaminocyclo-hexane, trans-N-tolyl-l,2-diaminocyclohexane, a mixture of cis- and trans-N-to IyI- 1 ,2- diaminocyclohexane, ethanolamine, 1 ,2-diaminoethane, and N,N'-dimethyl-l,2- diaminoethane.
108. A method as described in any of claims 105-107, wherein said ligand is N,N'- dimethyl- 1 ,2-diaminoethane.
109. A method as described in any of claims 92- 108, wherein said method further comprising prior to said reaction, the step of treating compounds of Formula ID:
Figure imgf000149_0001
Formula ID with (a) a nucleophilic alkyl halide of the Formula
A
<> > n
X — Y
and (b) i i base.
110. The method as described in claim in claim 109, wherein said nucleophilic alkyl halide is 2-chloroacetamide.
111. The method as described in any of claims 109 and 110, wherein said base is diisopropylethylamine.
112. The method as described in any of claims 109- 1 11, wherein said method further comprises prior to said reaction, the step of protecting compounds of Formula 1C
Figure imgf000149_0002
Formula 1C with a protecting agent in the presence of a base.
113. The method as described in claim 112, wherein said protecting agent is ethyl chloroformate.
114. The method as described in claim 110 or 111, wherein said base is triethylamine.
115. The method as described in any of claims 112-114, wherein said method further comprises prior to said protection reaction, the steps of:
a) reducing compounds of Formula IA
Figure imgf000150_0001
Formula IA o compounds of Formula IB:
Formula IB
and b) resolving said compounds of Formula IB with a chiral acid.
116. The method as described in claim 115, wherein said reduction step comprises the use of a reducing agent selected from a group consisting of a) silane and acid; b) sodium cyanoborohydride and acid; c) zinc and acid; d) sodium and liquid ammonia; e) sodium in ethanol; f) borane-triethylamine; and g) hydrogen and metal catalyst selected from a group consisting of nickel, palladium on charcoal, nickel boride, platinum metal, platinum oxide, rhodium oxide, ruthenium oxide and zinc oxide.
117. The method as described in any of claims 115 and 116, wherein said reduction step comprises the use of triethylsilanes and acid.
118. The method as described in claim 117, wherein said acid is trifluoroacetic acid.
119. The method as described in any of claims 115-118, wherein said chiral acid is selected from a group consisting of optionally substituted tartaric acid and mandelic acid.
120. The method as described in any of claims 115-119, wherein said chiral acid is mandelic acid.
121. The method as described in any of claims 115-120, wherein said chiral acid is (S)- mandelic acid.
122. The method for preparing compounds of Formula U:
Figure imgf000152_0001
Formula IJ wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) R7, R8and R9 are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; (v) X is aN, S or O; and
(vi) R10 is H or C^alkyl when X is N or R10 is non-existent when X is -O- or -S- (vii) R6a and R6b are H; and (viii) R1 is H or optionally substituted Ci-C6alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxoalkyl, aryloxyalkyl, heroaryloxoalkyl, heroaryloxyalkyl, aryl sulfinylalkyl or heteroaryl sulfinylalkyl; comprising the method as described in any of claims 6-15. . A method for preparing compounds of Formula U:
Figure imgf000153_0001
Formula IJ wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is i, 2 or 3;
(iv) R , R and R are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; (v) X is a N, S or O; and
(vi) R10 is H or
Figure imgf000153_0002
when X is N or R10 is non-existent when X is -O- or -S- (vii) R6a and R6b are H; and (viii) R1 is H or optionally substituted Ci-C6alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxoalkyl, aryloxyalkyl, heroaryloxoalkyl, heroaryloxyalkyl, aryl sulfinylalkyl or heteroaryl sulfinylalkyl; comprising the method as described in any of claims 25-29.
124. A method for preparing compounds of Formula U:
Figure imgf000154_0001
Formula U wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) R7, R8and R9 are independently H or optionally substituted C1-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; (v) X is a N, S or O; and
(vi) R10 is H or C^alkyl when X is N or R10 is non-existent when X is -O- or -S- (vii) R6a and R6b are H; and (viii) R1 is H or optionally substituted Ci-C6alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxoalkyl, aryloxyalkyl, heroaryloxoalkyl, heroaryloxyalkyl, aryl sulfϊnylalkyl or heteroaryl sulfinylalkyl; comprising the method as described in any of claims 38-41. . A method for preparing compounds of Formula U:
Figure imgf000155_0001
Formula IJ wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) R7, R8and R9 are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; (v) X is a N, S or O; and
(vi) R10 is H or
Figure imgf000155_0002
when X is N or R10 is non-existent when X is -O- or -S- (vii) R6a and R6b are H; and (viii) R1 is H or optionally substituted d-C6alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxoalkyl, aryloxyalkyl, heroaryloxoalkyl, heroaryloxyalkyl, aryl sulfinylalkyl or heteroaryl sulfinylalkyl; comprising the method as described in any of claims 47-53. . A method for preparing compounds of Formula 1 J:
Figure imgf000156_0001
Formula U wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) R7, R8and R9 are independently H or optionally substituted Cj-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; (v) X is a N, S or O; and
(vi) R10 is H or Ci-4alkyl when X is N or R1 is non-existent when X is -O- or -S- (vii) R6a and R6b are H; and (viii) R1 is H or optionally substituted Ci-C6alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxoalkyl, aryloxyalkyl, heroaryloxoalkyl, heroaryloxyalkyl, aryl sulfinylalkyl or heteroaryl sulfinylalkyl; comprising the method as described in any of claims 59-68.
127. A method for preparing compounds of Formula 1 J:
Figure imgf000157_0001
Formula U wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) R7, R8and R9 are independently H or optionally substituted C1-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; (v) X is a N, S or O; and
(vi) R10 is H or
Figure imgf000157_0002
when X is N or R10 is non-existent when X is -O- or -S- (vii) R6a and R6b are H; and (viii) R1 is H or optionally substituted C!-C6alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxoalkyl, aryloxyalkyl, heroaryloxoalkyl, heroaryloxyalkyl, aryl sulfinylalkyl or heteroaryl sulfinylalkyl; comprising the method as described in any of claims 76-79.
128. A method for preparing compounds of Formula U:
Figure imgf000158_0001
Formula IJ wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) R7, R8and R9 are independently H or optionally substituted Cj-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; (v) X is a N, S or O; and
(vi) R10 is H or
Figure imgf000158_0002
when X is N or R1 is non-existent when X is -O- or — S- (vii) R6a and R6b are H; and (viii) R1 is H or optionally substituted C]-C6alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxoalkyl, aryloxyalkyl, heroaryloxoalkyl, heroaryloxyalkyl, aryl sulfinylalkyl or heteroaryl sulfinylalkyl; comprising the method as described in any of claims 80-82.
129. A method for preparing compounds of Formula IJ:
Figure imgf000159_0001
Formula U wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) R7, R8and R9 are independently H or optionally substituted C1-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
(V) X is a N, S or O; and
(vi) R10 is H or
Figure imgf000159_0002
when X is N or R10 is non-existent when X is -O- or -S- (vii) R6a and R6b are H; and
(viii) R1 is H or optionally substituted Ci-C6alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxoalkyl, aryloxyalkyl, heroaryloxoalkyl, heroaryloxyalkyl, aryl sulfinylalkyl or heteroaryl sulfinylalkyl;
(ix) heteroaryl, heteroarylalkyl, aryloxoalkyl, aryloxyalkyl, heroaryloxoalkyl, heroaryloxyalkyl, aryl sulfinylalkyl or heteroaryl sulfinylalkyl; comprising the method as described in any of claims 83-85.
130. A method for preparing compounds of Formula IJ:
Figure imgf000160_0001
Formula U wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) R7, R8and R9 are independently H or optionally substituted Ci-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; (v) X is a N, S or O; and
(vi) R10 is H or Ci^alkyl when X is N or R10 is non-existent when X is -O- or -S- (vii) R6a and R6b are H; and (viii) R1 is H or optionally substituted Ci-Cδalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxoalkyl, aryloxyalkyl, heroaryloxoalkyl, heroaryloxyalkyl, aryl sulfinylalkyl or heteroaryl sulfinylalkyl; comprising the method as described in any of claims 86-87.
131. A compounds of Formula 2C :
Figure imgf000160_0002
wherein:
(i) k is 1 or 2; (ii) m is 0, 1 or 2; (iii) A = Cl, Br, F or I; (iv) R5 is H or QAalkyl;
*7 fi Q
(v) R 5 R and R are independently H or optionally substituted Q-Cόalkyl, C3- Ciocycloalkyl, C3-Ci0heterocycloalkyl, hydroxy, Q-Cόalkoxy, nitro, halo, halod-Cβalkyl, aryl, arylCi-Cδalkyl, heteroaryl or heteroaryld-Qalkyl.
132. A method for preparing compounds of Formula 2C :
Figure imgf000161_0001
Formula 2C in free or salt form, as hereinbefore described, which method comprises the steps of: reducing compounds of Formula 2 A
Figure imgf000161_0002
to compounds of Formula 2B; and
Figure imgf000162_0001
separating the enantiomers of compounds of Formula 2B by chiral acid resolution or chiral chromatography.
133. The method of claim 132, wherein the reduction step comprises the use of triethylsilane and acid.
134. The method of claim 132 or 133, wherein separating the enantiomers comprises the use of a chiral acid.
135. The method of claim 134, wherein said chiral acid is S-mandelic acid.
136. A compound of Formula 2D:
Figure imgf000162_0002
Formula 2D wherein: k is 1 or 2; m is 0, 1 or 2;
A = Cl, Br, F or I;
B is a protective group;
R5 is H or Ci.C4alkyl; R >7', t R>88a.ndR9 are independently H or optionally substituted Q-Qalkyl, C3-
Ciocycloalkyl, C3-Ci0heterocycloalkyl, hydroxy, Ci-C6alkoxy, nitro, halo, haloCi-Cόalkyl, aryl, arylC)-C6alkyl, heteroaryl or heteroarylCi-Cόalkyl.
137. A method for preparing compounds of Formula 2D:
Figure imgf000163_0001
Formula 2D as hereinbefore described in free or salt form, which method comprises the step of protecting the piperidino-amine of compounds of Formula 2C:
Figure imgf000163_0002
Formula 2C with a protecting agent in the presence of a base.
138. Method of claim 137, wherein the protecting agent is ethyl chloroformate.
139. A compound of Formula 2E' :
Figure imgf000164_0001
Formula 2E' wherein:
0) k is 1 or 2; («) m is 0, 1 or 2; (iii) B is a protective group (iv) R5 is H or Ci.C4alkyl;
(V) R , R and R are independently H or optionally substituted Ci-Cδalkyl, C3-
Cjocycloalkyl, CrCjoheterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloCp
C6alkyl, aryl, arylCj-Cόalkyl, heteroaryl or heteroarylC!-C6alkyl.
140. A method of preparing compounds of Formula IE':
Figure imgf000164_0002
Formula 2E' as hereinbefore described, which method comprises the step of treating compounds of Formula 2D with (a) benzophenone imine; (b) a transition metal catalyst selected from Groups 8-11 of the Periodic Table; (c) a base; and (d) a ligand selected from a group consisting of ligands as described claim 30.
141. A compound of Formula 2E
Figure imgf000165_0001
Formula 2E
wherein (0 k is 1 or 2; (ϋ) m is 0, 1 or 2; (iii) n is 1, 2 or 3; (iv) A = Cl, Br, F or I;
(V) B is a protective group;
(vi) R5 is H or Ci.Qalkyl; (vii) R7, R8and R9 are independently H or optionally substituted Ci-Cόalkyl, C3- docycloalkyl, C3-Cioheterocycloalkyl, hydroxy, alkoxy, nitro, halo, haloCi-
C6alkyl, aryl, arylCi-Cόalkyl, heteroaryl or heteroarylCi-C6alkyl; and (viii) X-Y- is a HO-CH2-, HS-CH2-, H(R')N-CH2- or H(R')N-C(O)-, wherein R' is H or Ci-C4alkyl.
142. A method for preparing a compound of Formula 2E:
Figure imgf000166_0001
Formula 2E in free or salt form as herein before described, which method comprises the step of N- alkylating compounds of Formula 2D:
Figure imgf000166_0002
Formula 2D with (a) a nucleophilic alkyl halide of the general formula:
A
x — Y wherein:
(i) A = Cl, F, Br or I;
(ii) X-Y is a -HOCH2-, -HSCH2-, -H(R')N-CH2- or -H(R')N-C(O)-, wherein R' is H or CMalkyl;
(iii) n is 1, 2 or 3; and (b) a base.
143. The method according to claim 142, wherein said nucleophilic alkyl halide is 2- chloroacetamide.
144. The method according to claim 142 or 143, wherein said nucleophilic alkyl halide is 2-chloroacetamide and said base is isopropylethylamine.
145. The method according to claim 142, 143 or 144, further comprises potassium iodide.
146. A compound of Formula 2F " :
Figure imgf000167_0001
Formula 2F" wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protective group;
(v) R5 is H or Ci.C4alkyl;
(vi) R7, R8and R9 are independently H or optionally substituted Q-Coalkyl, C3- Ciocycloalkyl, C3-Cioheterocycloalkyl, hydroxy, Cj-C6alkoxy, nitro, halo, haloCi-Cόalkyl, aryl, arylCi-Qalkyl, heteroaryl or heteroarylCi-Cόalkyl; and
(vii) -X-Y- is -(R')N-C(O)-, wherein R' is H or Ci-C4alkyl.
147. A method for preparing a compound of Formula 2F:
Figure imgf000168_0001
Formula 2F
wherein:
0) k is 1 or 2; (ϋ) m is 0, 1 or 2; (iii) n is 1, 2 or 3; (iv) B is a protective group;
(V) R5 is H or d-C4alkyl;
"7 8 O
(vi) R , R and R are independently H or optionally substituted Ci-C6alkyl, C3- Ciocycloalkyl, C3-Cioheterocycloalkyl, hydroxy, Ci-Cόalkoxy, nitro, halo, haloCi-Cόalkyl, aryl, arylCi-Cόalkyl, heteroaryl or heteroarylCi-Cόalkyl; and
(vϋ) -X-Y- is -OCH2-, -SCH2-, -<R')N-CH2- or -(R')N-C(O}-, wherein R' is H or Ci-4alkyl; which method comprises the step of treating compounds of Formula 2E:
Figure imgf000168_0002
as hereinbefore described with:
(a) a transition metal catalyst selected from a group consisting of Group 8-11 of the periodic table; and
(b) a base.
148. The method according to claim 147, wherein the transition metal catalyst is copper catalysts.
149. The method according to claim 147 or 148, wherein the transition metal catalyst is CuI.
150. The method according to claim 147, 148 or 149, wherein the transition metal catalyst is CuI and the base is potassium carbonate.
151. The method according to any of claims 147- 150, which method further comprises the step of adding a mono or bi-dentate ligand known to ligate with transition metal catalysts.
152. The method according to claim 151, wherein said ligand is an amine ligand.
153. The method of claim 151 or 152, wherein said amine ligand is N,N'-dimethyl- 1 ,2-diaminoethane.
154. Compounds of Formula 2G:
Figure imgf000169_0001
wherein:
(i) k is 1 or 2; (ii) m is 0, 1 or 2;
(iii) n is i, 2 or 3;
(iv) B is a protective group;
(v) R5 is H or d-C4alkyl;
(vi) R7, R8and R9 are independently H or optionally substituted Cj-Cόalkyl, C3- Cjocycloalkyl, C3-Cioheterocycloalkyl, hydroxy, Ci-6alkoxy, nitro, halo, haloCi-Cβalkyl, aryl, arylCi-C6alkyl, heteroaryl or heteroarylCrC6alkyl; and
(vii) R10 is H or C1-4alkyl.
155. A method for preparing compounds of Formula 2G :
Figure imgf000170_0001
Formula 2G
wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protective group;
(v) R5 is H or d-C4alkyl;
(vi) R7, R8and R9 are independently H or optionally substituted Ci-Cόalkyl, C3- Ciocycloalkyl, C3-Cκ)heterocycloalkyl, hydroxy, Ci-Cόalkoxy, nitro, halo, haloCi-Cόalkyl, aryl, arylCi-Qalkyl, heteroaryl or heteroarylCi-C6alkyl;
I I
(vii) X-Y is a -NC(O)- or -NCH2- ; and
(viii) R10 is CMalkyl; in free or salt form, which method comprises the step of N-alkylating compounds of Formula 2F':
Figure imgf000171_0001
Formula 2F1 wherein:
(i) k is 1 or 2;
(ii) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protective group;
(ix) R5 is H or Ci.C4alkyl;
(v) R , R and R are independently H or optionally substituted Ci-Cόalkyl, C3- Ciocycloalkyl, C3-Cioheterocycloalkyl, hydroxy, Ci-C6alkoxy, nitro, halo, haloCj-Cβalkyl, aryl, arylCi-Cόalkyl, heteroaryl or heteroarylCi-C6alkyl; and
(vi) -X-Y- is -(R')N-CH2- or -(R')N-C(O)-, wherein R' is H.
156. The method according to claim 155, wherein
157. A method for preparing compounds of Formula 2G as hereinbefore described which method comprises the steps of: c) treating a Compound of Formula 2D in free or salt form as hereinbefore described with (i) a nucleophilic alkyl halide of the general formula:
■I>) ) n
as hereinbefore described, (ii) a base and (iii) potassium iodide in a solvent such as dioxane; and d) adding (i) a transition metal catalyst selected from a group consisting of Group 8-11 of the periodic table; (ii) a base; and (iii) optionally a mono or bi-dentate ligand known to ligate with transition metal catalysts.
158. The method according to claim 157, wherein nucleophilic alkyl halide of step (a) is N-methyl chloroacetamide, the base of step (a) is diisopropylethylamine.
159. The method according to claim 157 or 158, wherein the transition metal catalyst of step (b) is CuI; the base of step (b) is potassium carbonate.
160. The method according to claim 157, 158 or 159, wherein the mono or bi-dentate ligand known to ligate with transition metal catalysts is N5N'- dimethylethylenediamine .
161. A method for preparing compounds of Formula 2H:
Figure imgf000172_0001
Formula 2H wherein:
(i) k is 1 or 2;
(ϋ) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) B is a protective group;
(V) R5 is H or Ci.C4alkyl; "7 8 O
(vi) R , R and R are independently H or optionally substituted Ci-C6alkyl, C3- Ciocycloalkyl, C3-Cioheterocycloalkyl, hydroxy, d-Cόalkoxy, nitro, halo, haloCi-Cόalkyl, aryl, arylCi-Cβalkyl, heteroaryl or heteroarylCi-C6alkyl;
(vii) X is a N; and
(viii) R10 is H or CMalkyl; and
(ix) R6a and R6b are independently selected from a group consisting of H; which method comprises the step of reducing the ketone of compounds of Formula 2G':
Figure imgf000173_0001
Formula 2G1 in free or salt form as hereinbefore described to a methylene.
162. The method according to claim 161, wherein the reduction step may be accomplished through the use of borane-THF.
163. A method for preparing compounds of Formula 21 :
Figure imgf000173_0002
Formula 21 wherein:
(i) k is 1 or 2; (ii) m is 0, 1 or 2;
(iii) n is i, 2 or 3;
(iv) R5 is H or Ci-C4alkyl;
(v) R7, R8and R9 are independently H or optionally substituted Ci-C6alkyl, C3- Ciocycloalkyl, Ca-Cjoheterocycloalkyl, hydroxy, Ci^alkoxy, nitro, halo, haloCi-Cδalkyl, aryl, arylCi-C6alkyl, heteroaryl or heteroarylCi-Cόalkyl;
(vi) X is a N, S or O;
(vii) R10 is H or
Figure imgf000174_0001
when X is N or R10 is non-existent when X is O or S; and
(viii) R6a and R6b are H; which method comprises the step of deprotecting compounds of Formula 2H:
Figure imgf000174_0002
as herein before described.
164. The method according to claim 163, wherein the deprotection step comprises the use of a base or acid.
165. The method according to claim 163 or 164, wherein the deprotection step comprises the use of sodium hydroxide or potassium hydroxide.
166. The method according to claim 163 or 164, wherein the deprotection step comprises the use of hydrochloric acid.
167. A method for preparing compounds of Formula 2 J:
Figure imgf000175_0001
Formula 2J wherein:
(i) k is 1 or 2;
(H) m is 0, 1 or 2;
(iii) n is 1, 2 or 3;
(iv) X is N, S or O;
(V) R5 is H or Ci-C4alkyl;
(vi) R7, R8andR9 are independently H or optionally substituted Ci-Cβalkyl, C3-
Qocycloalkyl, C3-Cioheterocycloalkyl, hydroxy, Ci-6alkoxy, nitro, halo, haloCi-Cόalkyl, aryl, aryld-C6alkyl, heteroaryl or heteroarylCi-Cόalkyl;
(vii) R » 10 is H or C^alkyl when X is N or R io i •s non-existent when X is O or S;
(viii) R6a and R6b are H; and
(ix) R1 is H or optionally substituted Ci-C6alkyl, cycloalkyl, aryl, arylCi-C6alkyl (e.g., benzyl), heteroaryl, heteroarylCi-C6alkyl, aryloxoCt-C6alkyl (e.g., 4-(4- fluorophenyl)-4-oxobutyl)), aryloxyCrCόalkyl (e.g., 3-(4- fluorophenoxy)propyl)), heroaryloxoCrCόalkyl, heroaryloxyCi-C6alkyl, aryl sulfinylCi-Cόalkyl or heteroaryl sulfinylCj-Cδalkyl; which method comprises the step of N-alkylating compounds of Formula 21:
Figure imgf000176_0001
Formula 21 as hereinbefore described, with (a) a compound of the general formula:
G — Z wherein:
(i) Z is -C(O)-, -O-, or S(O)2-;
(ii) R13 is optionally substituted aryl, arylCi-Cόalkyl, Ci-C6alkyl, heteroaryl, heteroarylCi-Cδalkyl; and
(iii) G is Ci-C8alkyl halide (e.g., propyl chloride); and (b) a base.
168. The method according to claim 167, wherein the compound of the general formula
R13
G — Z is selected from a group consisting of:
Figure imgf000176_0002
169. The method according to claim 167 or 168, wherein the compound of the general formula
R13
/
G-Z
IS
Figure imgf000177_0001
170. A method for preparing pharmaceutically acceptable salts of compounds of Formula U or 2 J:
Figure imgf000177_0002
or Formula 2J as hereinbefore described, which method comprises the step of reacting the free base of Compounds of Formula U or 2 J with an acid.
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US14/323,545 US9315504B2 (en) 2007-03-12 2014-07-03 Preparation of 4-((6BR,10AS)-3-methyl-2,3,6B,9,10, 10A-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo [1,2,3-de]quinoxalin-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone or a pharmaceutically acceptable salt thereof
US15/066,962 US9751883B2 (en) 2007-03-12 2016-03-10 Preparation of certain [((6BR,10AS)-2,3,6B,7,8,9,10, 10A-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo [1,2,3-de]quinoxalines and pharmaceutically acceptable salts thereof
US15/660,762 US10221176B2 (en) 2007-03-12 2017-07-26 Preparation of certain substituted [((6bR,10aS)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalines and pharmaceutically acceptable salts thereof
US16/244,796 US10597395B2 (en) 2007-03-12 2019-01-10 Preparation of certain substituted 1-(4-fluorophenyl)-4-(2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-YL)butan-1-ones and pharmaceutically acceptable salts thereof
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