WO2014008223A2 - Inhibiteurs d'acide gras synthase - Google Patents

Inhibiteurs d'acide gras synthase Download PDF

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Publication number
WO2014008223A2
WO2014008223A2 PCT/US2013/049010 US2013049010W WO2014008223A2 WO 2014008223 A2 WO2014008223 A2 WO 2014008223A2 US 2013049010 W US2013049010 W US 2013049010W WO 2014008223 A2 WO2014008223 A2 WO 2014008223A2
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Prior art keywords
alkyl
diazaspiro
oxa
undecan
cyclopropyl
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PCT/US2013/049010
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English (en)
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WO2014008223A3 (fr
Inventor
Nicholas David ADAMS
Amita M. Chaudhari
Terence John Kiesow
Allison K. MCSHERRY
Michael Lee Moore
Cynthia Ann Parrish
Alexander Joseph Reif
Lance Howard Ridgers
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Glaxosmithkline Llc
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Publication of WO2014008223A2 publication Critical patent/WO2014008223A2/fr
Publication of WO2014008223A3 publication Critical patent/WO2014008223A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • This invention relates to novel spirocyclic piperidines which are inhibitors of fatty acid synthase (FAS), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of cancers.
  • FOS fatty acid synthase
  • Fatty acids have an essential role in a variety of cellular processes including building blocks for membranes, anchors for targeting membrane proteins, precursors in the synthesis of lipid second messengers and as a medium to store energy (Menendez JS and Lupu R, Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis, Nature Reviews Cancer, 7: 763-777 (2007)).
  • Fatty acids can either be obtained from the diet or can be synthesized de novo from carbohydrate precursors. The biosynthesis of the latter is catalyzed by the muliti- functional homodimeric FAS.
  • FAS synthesizes long chain fatty acids by using acetyl-CoA as a primer and Malonyl Co-A as a two carbon donor, and NADPH as reducing equivalents
  • acetyl-CoA as a primer
  • Malonyl Co-A as a two carbon donor
  • NADPH as reducing equivalents
  • De novo fatty acid synthesis is active during embryogenesis and in fetal lungs where fatty acids are used for the production of lung surfactant. In adults, most normal human tissues preferentially acquire fatty acids from the diet. Therefore, the level of de novo lipogensis and expression of liopogenic enzymes is low (Weiss L, et al, Fatty-acid biosynthesis in man, a pathway of minor importance. Purification, optimal assay conditions, and organ distribution of fatty-acid synthase. Biological Chemistry Hoppe-Seyler 367(9): 905- 912 (1986)). In contrast, many tumors have high rates of de novo fatty acid synthesis (Medes G, et al, Metabolism of Neoplastic Tissue. IV.
  • This invention relates to compounds of the Formula (I), as shown below: A compound according to Formula (I)
  • X is CH 2 , NR 6 or O, wherein R 6 is H, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, or -Ci-C 3 alkylC 3 -C 7 cycloalkyl;
  • Y is C or N
  • R 5 is selected from the group consisting of hydrogen, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, -Ci-C 3 alkylC 3 -C 7 cycloalkyl, phenyl, and Ci-C 3 alkylphenyl;
  • R 6 is H, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, or -Ci-C 3 alkylC 3 -C 7 cycloalkyl; or R 5 and R 6 taken together with the nitrogen to which they are attached represent a 4- to 7-membered saturated or unsaturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, wherein said ring is optionally substituted by 1 to 3 substituents independently selected from oxo, hydoxyl, Ci-C 3 alkyl, and hydroxyCi-C 4 alkyl-;
  • R 9 is a 5- or 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents independently selected from halogen, Ci-C 4 alkyl, -CF 3 , Ci-C 4 alkoxy, and -NR 5 R 6 ;
  • each R 2 is independently selected from the group consisting of Ci-C 6 alkyl, cyano, Ci- C 4 alkoxy, hydroxyl, and halogen;
  • This invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof.
  • This invention also relates to compounds exemplified in the Experimental section.
  • the salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention.
  • Salts of the disclosed compounds containing a basic amine or other basic functional group may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulf
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, ⁇ - hydroxybutyrates, glycolates, tartrates mandelate
  • Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base.
  • a suitable base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, ⁇ , ⁇ '- dibenzylethylenediamine, 2-hydroxyethylamine, 3 ⁇ 4zs-(2-hydroxyethyl)amine, tri-(2- hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, ⁇ , ⁇ - ⁇ dehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine,
  • the compound of Formula (I) or a salt thereof may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms).
  • the individual stereoisomers may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms).
  • the invention also includes various deuterated forms of the compounds of Formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula (I). Commercially available deuterated starting materials may be employed in the preparation of deuterated forms of the compounds of Formula (I), or they may be synthesized using conventional techniques employing deuterated reagents (e.g. lithium aluminum deuteride).
  • deuterated reagents e.g. lithium aluminum deuteride
  • a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) a compound of Formula (I) or salt thereof with at least one excipient.
  • One particular embodiment of the invention is a compound of Formula (II),
  • R 5 is selected from the group consisting of hydrogen, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, -Ci-C 3 alkylC 3 -C 7 cycloalkyl, phenyl, and Ci-C 3 alkylphenyl;
  • R 6 is H, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, or -Ci-C 3 alkylC 3 -C 7 cycloalkyl; or R 5 and R 6 taken together with the nitrogen to which they are attached represent a 4- to 7-membered saturated or unsaturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, wherein said ring is optionally substituted by 1 to 3 substituents independently selected from oxo, hydoxyl, Ci-C 3 alkyl, and hydroxyCi-C 4 alkyl-;
  • R 9 is a 5- or 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents independently selected from halogen, Ci-C 4 alkyl, -CF 3 , Ci-C 4 alkoxy, and -NR 5 R 6 ;
  • each R 2 is independently selected from the group consisting of Ci-C 6 alkyl, cyano, Ci- C 4 alkoxy, hydroxyl, and halogen;
  • R 8 is hydrogen or deuterium
  • R 8a is hydrogen or deuterium; or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of Formula (III),
  • R 6 is H, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, or -Ci-C 3 alkylC 3 -C 7 cycloalkyl; or R 5 and R 6 taken together with the nitrogen to which they are attached represent a 4- to 7-membered saturated or unsaturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, wherein said ring is optionally substituted by 1 to 3 substituents independently selected from oxo, hydoxyl, Ci-C 3 alkyl, and hydroxyCi-C 4 alkyl-;
  • R 9 is a 5- or 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents independently selected from halogen, Ci-C 4 alkyl, -CF 3 , Ci-C 4 alkoxy, and -NR 5 R 6 ;
  • each R 2 is independently selected from the group consisting of Ci-C 6 alkyl, cyano, Ci-
  • R 8 is hydrogen or deuterium
  • R 8a is hydrogen or deuterium; or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of Formula (IV),
  • X is CH 2 , NR 6 or O, wherein R 6 is H, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, or -Ci-C 3 alkylC 3 -C 7 cycloalkyl; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, or 3;
  • R 5 is selected from the group consisting of hydrogen, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, -Ci-C alkylC -C 7 cycloalkyl, phenyl, and Ci-C alkylphenyl;
  • R 6 is H, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, or -Ci-C 3 alkylC 3 -C 7 cycloalkyl; or R 5 and R 6 taken together with the nitrogen to which they are attached represent a 4- to 7-membered saturated or unsaturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, wherein said ring is optionally substituted by 1 to 3 substituents independently selected from oxo, hydoxyl, Ci-C 3 alkyl, and hydroxyCi-C 4 alkyl-;
  • R 9 is a 5- or 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents independently selected from halogen, Ci-C 4 alkyl, -CF 3 , Ci-C 4 alkoxy, and -NR 5 R 6 ;
  • each R 2 is independently selected from the group consisting of Ci-C 6 alkyl, cyano, Ci- C 4 alkoxy, hydroxyl, and halogen;
  • R 3 is selected from the group consisting of Ci-C 6 alkyl, C 3 -C 7 cycloalkyl, or C 4 -
  • R 8 is hydrogen or deuterium
  • R 8a is hydrogen or deuterium; or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of Formula (V),
  • Y is C or N
  • Z is C or N; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, or 3;
  • R 5 is selected from the group consisting of hydrogen, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, -Ci-C 3 alkylC 3 -C 7 cycloalkyl, phenyl, and Ci-C 3 alkylphenyl;
  • R 6 is H, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, or -Ci-C 3 alkylC 3 -C 7 cycloalkyl; or R 5 and R 6 taken together with the nitrogen to which they are attached represent a 4- to 7-membered saturated or unsaturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, wherein said ring is optionally substituted by 1 to 3 substituents independently selected from oxo, hydoxyl, Ci-C 3 alkyl, and hydroxyCi-C 4 alkyl-;
  • R 9 is a 5- or 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents independently selected from halogen, Ci-C 4 alkyl, -CF 3 , Ci-C 4 alkoxy, and -NR 5 R 6 ;
  • each R 2 is independently selected from the group consisting of Ci-C 6 alkyl, cyano, Ci- C 4 alkoxy, hydroxyl, and halogen;
  • R 8 is hydrogen or deuterium; R 8a is hydrogen or deuterium; or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of Formula (VI),
  • Y is C or N
  • Z is C or N; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, or 3;
  • R 5 is selected from the group consisting of hydrogen, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, -Ci-C 3 alkylC 3 -C 7 cycloalkyl, phenyl, and Ci-C 3 alkylphenyl;
  • R 6 is H, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, or -Ci-C 3 alkylC 3 -C 7 cycloalkyl; or R 5 and R 6 taken together with the nitrogen to which they are attached represent a 4- to 7-membered saturated or unsaturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, wherein said ring is optionally substituted by 1 to 3 substituents independently selected from oxo, hydoxyl, Ci-C 3 alkyl, and hydroxyCi-C 4 alkyl-;
  • R 9 is a 5- or 6-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents independently selected from halogen, Ci-C 4 alkyl, -CF 3 , Ci-C 4 alkoxy, and -NR 5 R 6 ;
  • each R 2 is independently selected from the group consisting of Ci-C 6 alkyl, cyano, Ci- C 4 alkoxy, hydroxyl, and halogen;
  • R 8 is hydrogen or deuterium
  • R 8a is hydrogen or deuterium; or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from the group consisting of is benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl,
  • R 5 is selected from the group consisting of hydrogen, Ci-C 4 alkyl, phenyl, and Ci-C 3 alkylphenyl; R 6 is hydrogen or Ci-C 4 alkyl, or a pharmaceutically accepted salt thereof.
  • Another particular embodiment of the invention is a compound of Formula (I), (II), (III), (IV), (V), or (VI), wherein R 3 is selected from the group consisting of Ci-C 6 alkyl and C 3 -C 7 cycloalkyl, wherein said Ci-C 6 alkyl or C 3 -C 7 cycloalkyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of Ci- C 4 alkyl, hydroxyl, hydroxyCi-C 4 alkyl and Ci-C 4 alkoxyCi-C 4 alkyl-, or a pharmaceutically acceptable salt thereof.
  • alkyl refers to a straight or branched chain hydrocarbon radical, preferably having from one to twelve carbon atoms, which may be unsubstituted or substituted, saturated or unsaturated with multiple degrees of substitution included within the present invention.
  • the alkyl group is unsubstituted or substituted with suitable substituents selected from the group consisting of halogen, amino, substituted amino, cyano, hydroxyl, alkoxy, alkylthio, alkylsulfonyl, aminosulfonyl, carboxylic acid, carboxylic ester, carboxamide, aminocarbonyl, and heterocyclyl.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, t-butyl, isopentyl, n-pentyl, and the like, as well as substituted versions thereof.
  • cycloalkyl refers to an unsubstituted or substituted mono- or polycyclic non-aromatic saturated ring.
  • exemplary “cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, as well as unsubstituted and substituted versions thereof.
  • alkoxy refers to the group -OR a , where R a is Ci-C 4 alkyl or C3-Cycycloalkyl as defined above.
  • Ci-C 4 alkoxy refers to a straight- or
  • branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.
  • exemplary "(Ci-C 4 )alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 5-butoxy, and t-butoxy.
  • Heterocycloalkyl represents a group or moiety comprising a non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocycloalkyls useful in the present invention include, but are not limited to, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1 ,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, hexahydro-lH-l,4-diazepinyl, azabicylo[3.2.1]octyl,
  • heterocyclyl refers to an unsubstituted or substituted mono- or poly cyclic ring system containing one or more heteroatoms.
  • Preferred heteroatoms include nitrogen, oxygen, and sulfur, including N-oxides, sulfur oxides, and dioxides.
  • a heterocyclic ring may be, but is not limited to, three to eight-membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution are included within the present definition.
  • heterocyclic groups include, but are not limited to tetrahydrofuranyl, pyranyl, 1 ,4-dioxanyl, 1,3-dioxanyl, piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, piperazinyl, pyrrolidinonyl, piperazinonyl, pyrazolidinyl, and their various tautomers, as well as unsubstituted and substituted versions thereof.
  • 9- or 10-membered heterocyclyl represents a fully unsaturated or partially unsaturated, bicyclic group, containing 9 or 10 ring atoms, including 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, which group may be unsubstituted or substituted by one or more of the substituents defined herein.
  • Selected 9- or 10-membered heterocycyl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1, 2, 3, or 4 additional nitrogen ring atoms and/or 1 additional oxygen or sulfur atom.
  • 9- or 10-membered heterocyclyl groups include, but are not limited to, benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, benzoxadiazolyl, benzthiadiazol
  • aryl refers to a carbocyclic aromatic moiety (such as phenyl or naphthyl) containing the specified number of carbon atoms, particularly from 6-10 carbon atoms.
  • aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like.
  • aryl also includes each possible positional isomer of an aromatic hydrocarbon radical, such as in 1 -naphthyl, 2-naphthyl, 5- tetrahydronaphthyl, 6-tetrahydronaphthyl, 1 -phenanthridinyl, 2-phenanthridinyl, 3- phenanthridinyl, 4-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl, 9-phenanthridinyl and 10-phenanthridinyl.
  • heteroaryl an aromatic ring system containing carbon(s) and at least one heteroatom.
  • Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 8 hetero atoms.
  • a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junctions, for example, bicyclic heteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and heteroatoms).
  • Exemplary 5- to 6- memebered heteroaryls include, but are not limited to, furanyl, thiophenyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-traizolyl, oxazolyl, isoxazolyl, 1, 2, 3- oxadiazolyl, 1, 2, 5-oxadiazolyl, thiadiazolyl, isothiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.
  • heteroaryl groups include, but are not limited to benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, benzoxadiazolyl, benzthiadiazolyl, benzotriazoly
  • heterocyclic As used herein "heterocyclic,” “heterocycle,” “heterocycl” groups or grammatical variations thereof include “heteroaryl” and “heterocycloalkyl” groups.
  • cyano refers to the group -CN.
  • the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur.
  • Exemplary optional substituent groups include acyl, alkyl, alkylsulfonyl, alkoxy, alkoxycarbonyl, cyano, halogen, haloalkyl, hydroxyl, oxo, amide, sulfamide, urea, amino, substituted amino, acylamino, phenylcarbonyl, dialkylaminosulfonamide, morpholino, sulfonamide, thiourea, nitro, pyrrolidinyl, pyrazolyl, pyrrolyl, phenyl, and tetrazolyl, wherein pyrrolidinyl, pyrazolyl and tetrazolyl can be further substituted with one to three Ci-C3alkyl.
  • Enantiomerically enriched refers to products whose enantiomeric excess is greater than zero.
  • enantiomerically enriched refers to products whose enantiomeric excess is greater than about 50% ee, greater than about 75% ee, and greater than about 90%> ee.
  • Enantiomeric excess or "ee” is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%). "Enantiomerically pure” refers to products whose enantiomeric excess is 100% ee.
  • Diastereomer refers to a compound having at least two chiral centers.
  • Diastereomer excess or "de” is the excess of one diasteriomer over the others expressed as a percentage.
  • “Diasteriomerically pure” refers to products whose diasteriomeric excess is 100% de.
  • Half-life refers to the time required for half of a quantity of a substance to be converted to another chemically distinct specie in vitro or in vivo.
  • Halo or halogen refers to fluoro, chloro, bromo, or iodo.
  • Heteroatom refers to a nitrogen, sulphur, or oxygen atom.
  • Member atoms refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring.
  • physiologically functional derivative refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof.
  • Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1 : Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxico logical effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain a therapeutically effective dose of the compound of Formula (I) or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal, sublingual, or transdermal
  • vaginal or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • parenteral including subcutaneous, intramuscular, intravenous, or intradermal
  • compositions When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a "quick-dissolve" medicine.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate,
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.
  • the compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided.
  • Dyestuffs can be added to these coatings to distinguish different dosages.
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient.
  • Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound or salt of the invention in a non- toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.
  • tablets and capsules are preferred for delivery of the pharmaceutical composition.
  • treatment includes prophylaxis and refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.
  • Prophylaxis or prevention or delay of disease onset is typically accomplished by administering a drug in the same or similar manner as one would to a patient with the developed disease or condition.
  • the present invention provides a method of treatment in a mammal, especially a human, with at least one disease or condition targeted by the present compounds.
  • Such treatment comprises the step of administering a therapeutically effective amount of a compound of Formula (I) or salt thereof to said mammal, particularly a human.
  • Treatment can also comprise the step of administering a therapeutically effective amount of a pharmaceutical composition containing a compound of Formula (I) or salt thereof to said mammal, particularly a human.
  • methods are provided for treating cancer comprising
  • the cancer is selected from the group consisting of gastric, brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, meduUoblastoma, colon, head and neck, kidney, lung, liver, melanoma, renal, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, bladder, stomach, and giant cell tumor of bone and thyroid.
  • the therapy is the treatment of cancer.
  • the present invention provides uses of compounds of Formula I or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of cancer.
  • Suitable the present invention provides uses of Formula I or pharmaceutically acceptable salts thereof in treating cancer selected from the group consisting of gastric, brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, meduUoblastoma, colon, head and neck, kidney, lung, liver, melanoma, renal, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, bladder, stomach, and giant cell tumor of bone and thyroid.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
  • terapéuticaally effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy,
  • therapeutically effective amounts of a compound of Formula (I), as well as salts thereof may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition. While it is possible that, for use in therapy, a therapeutically effective amount of a compound of Formula (I) or salt thereof may be administered as the raw chemical, it is typically presented as the active ingredient of a pharmaceutical composition or formulation.
  • the precise therapeutically effective amount of a compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition, and route of
  • a compound of Formula (I) or salt thereof will be given for the treatment in the range of about 0.1 to 100 mg/kg body weight of recipient (patient, mammal) per day and more usually in the range of 0.1 to 10 mg/kg body weight per day.
  • Acceptable daily dosages may be from about 1 to about 1000 mg/day, and preferably from about 1 to about 100 mg/day. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of Formula (I) per se. Similar dosages should be appropriate for treatment (including prophylaxis) of the other conditions referred herein for treatment. In general, determination of appropriate dosing can be readily arrived at by one skilled in medicine or the pharmacy art.
  • a compound of Formula (I) When a compound of Formula (I) is administered for the treatment of cancer, the term “co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a FAS inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment.
  • the term further active ingredient or ingredients, as used herein includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
  • any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention.
  • anti-neoplastic agent that has activity versus a susceptible tumor being treated
  • examples of such agents can be found in Cancer Principles and Practice f Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins
  • anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins;
  • antimetabolites such as purine and pyrimidine analogues and anti- folate compounds
  • topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors;
  • Examples of a further active ingredient or ingredients for use in combination or coadministered with the present FAS inhibiting compounds are chemotherapeutic agents.
  • Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
  • Diterpenoids which are derived from natural sources, are phase specific anti -cancer agents that operate at the G 2 /M phases of the cell cycle. It is believed that the diterpenoids stabilize the ⁇ -tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
  • Paclitaxel, 5P,20-epoxy-l,2a,4,7P,10p,13a-hexa-hydroxytax-l l-en-9-one 4,10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325. 1971), who characterized its structure by chemical and X-ray crystallographic methods.
  • Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann. Intern, Med., I l l :273,1989) and for the treatment of breast cancer (Holmes et al. , J. Nat. Cancer Inst. , 83: 1797, 1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al, Sem. Oncol, 20:56, 1990).
  • the compound also shows potential for the treatment of polycystic kidney disease (Woo et. al, Nature, 368:750. 1994, lung cancer and malaria.
  • Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, R.J. et. al, Cancer Chemotherapy Pocket Guidei 1998) related to the duration of dosing above a threshold concentration (50nM) (Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16-23, 1995).
  • Docetaxel (2R,3S)- N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 5 ⁇ - 20-epoxy-l,2a,4,7 ,10 ,13a-hexahydroxytax-l l-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®.
  • Docetaxel is indicated for the treatment of breast cancer.
  • Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia.
  • Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into
  • microtubules Mitosis is believed to be arrested in metaphase with cell death following.
  • vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
  • Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution.
  • VELBAN® an injectable solution.
  • Myelosuppression is the dose limiting side effect of vinblastine.
  • Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as
  • ONCOVIN® as an injectable solution.
  • Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.
  • Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
  • Vinorelbine 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (l :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid.
  • Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
  • Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA.
  • the platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor.
  • Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
  • Cisplatin cis-diamminedichloroplatinum
  • PLATINOL® an injectable solution.
  • Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.
  • the primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
  • Carboplatin platinum, diammine [l,l-cyclobutane-dicarboxylate(2-)-0,0'], is commercially available as PARAPLATIN® as an injectable solution.
  • Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.
  • Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death.
  • alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan;
  • nitrosoureas such as carmustine
  • triazenes such as dacarbazine
  • Cyclophosphamide 2-[bis(2-chloroethyl)amino]tetrahydro-2H-l,3,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
  • Melphalan 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.
  • Chlorambucil 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.
  • Busulfan 1 ,4-butanediol dimethanesulfonate, is commercially available as
  • Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.
  • Carmustine, l,3-[bis(2-chloroethyl)-l -nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®.
  • Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.
  • dacarbazine 5-(3,3-dimethyl-l-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®.
  • dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.
  • Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death.
  • antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
  • Dactinomycin also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
  • Daunorubicin (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo- hexopyranosyl)oxy]-7,8,9, 10-tetrahydro-6,8, 11 -trihydroxy- 1 -methoxy-5, 12
  • naphthacenedione hydrochloride is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®.
  • Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.
  • ADRIAMYCIN RDF® ADRIAMYCIN RDF®.
  • Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.
  • Bleomycin a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin. Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
  • Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of
  • epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-ethylidene- -D- glucopyranoside] is commercially available as an injectable solution or capsules as
  • VePESID® and is commonly known as VP- 16.
  • Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
  • Teniposide 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-thenylidene- -D- glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children.
  • Teniposide can induce both leucopenia and thrombocytopenia.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows.
  • antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine. 5 -fluorouracil, 5-fluoro-2,4- (1H,3H) pyrimidinedione, is commercially available as fluorouracil.
  • 5- fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas.
  • cytarabine 4-amino-l-P-D-arabinofuranosyl-2 (lH)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain.
  • Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
  • Other cytidine analogs include 5-azacytidine and 2',2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis.
  • Mercaptopurine l,7-dihydro-6H-purine-6-thione monohydrate
  • PURINETHOL® is commercially available as PURINETHOL®.
  • Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses.
  • a useful mercaptopurine analog is azathioprine.
  • Thioguanine 2-amino-l,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®.
  • Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
  • Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting.
  • Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
  • Gemcitabine 2'-deoxy-2', 2'-difluorocytidine monohydrochloride ( ⁇ -isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the Gl/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer.
  • Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.
  • Methotrexate N-[4[[(2,4-diamino-6-pteridinyl) methyljmethylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate.
  • Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder.
  • Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.
  • Camptothecins including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4- methylpiperazino-methylene)- 10,11 -ethylenedioxy-20-camptothecin described below.
  • Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the
  • topoisomerase I DNA : irintecan or SN-38 ternary complex with replication enzymes.
  • Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum.
  • the dose limiting side effects of irinotecan HC1 are myelosuppression, including neutropenia, and GI effects, including diarrhea.
  • Topotecan HC1 (S)- 10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy- 1 H- pyrano[3 ' ,4 ' ,6,7]indolizino[ 1 ,2-b]quinoline-3 , 14-(4H, 12H)-dione mono hydrochloride, is commercially available as the injectable solution HYCAMTIN®.
  • Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule.
  • Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer.
  • the dose limiting side effect of topotecan HC1 is myelosuppression, primarily neutropenia.
  • Rituximab is a chimeric monoclonal antibody which is sold as RITUXAN® and MABTHERA®.
  • Rituximab binds to CD20 on B cells and causes cell apoptosis.
  • Rituximab is administered intravenously and is approved for treatment of rheumatoid arthritis and B-cell non-Hodgkin's lymphoma.
  • Ofatumumab is a fully human monoclonal antibody which is sold as ARZERRA®.
  • Ofatumumab binds to CD20 on B cells and is used to treat chronic lymphocytic leukemia CLL; a type of cancer of the white blood cells) in adults who are refractory to treatment with fludarabine (Fludara) and alemtuzumab Campath).
  • Trastuzumab (HEREPTIN®) is a humanized monoclonal antibody that binds to the
  • HER2 receptor It original indication is HER2 positive breast cancer.
  • Cetuximab (ERBITUX®) is a chimeric mouse human antibody that inhibits epidermal growth factor receptor (EGFR).
  • mTOR inhibitors include but are not limited to rapamycin (FK506) and rapalogs, RAD001 or everolimus (Afmitor), CCI-779 or temsirolimus, AP23573, AZD8055, WYE- 354, WYE-600, WYE-687 and Ppl21.
  • Bexarotene is sold as Targretin® and is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs).
  • RXRs retinoid X receptors
  • RARs retinoic acid receptors
  • the chemical name is 4-[l- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid.
  • Bexarotene is used to treat cutaneous T-cell lymphoma CTCL, a type of skin cancer) in people whose disease could not be treated successfully with at least one other medication.
  • Sorafenib marketed as Nexavar® is in a class of medications called multikinase inhibitors. Its chemical name is 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl-pyridine-2-carboxamide. Sorafenib is used to treat advanced renal cell carcinoma (a type of cancer that begins in the kidneys). Sorafenib is also used to treat unresectable hepatocellular carcinoma (a type of liver cancer that cannot be treated with surgery).
  • erbB inhibitors examples include lapatinib, erlotinib, and gefitinib.
  • the free base, HC1 salts, and ditosylate salts of the compound of formula (II) may be prepared according to the procedures disclosed in WO 99/35146, published July 15, 1999; and WO 02/02552 published January 10, 2002.
  • the free base and HC1 salt of erlotinib may be prepared, for example, according to
  • Gefitinib which is commercially available under the trade name IRESSA® (Astra-Zenenca) is an erbB-1 inhibitor that is indicated as monotherapy for the treatment of patients with locally advanced or metastatic non- small-cell lung cancer after failure of both platinum-based and docetaxel chemotherapies.
  • the free base, HC1 salts, and diHCl salts of gefitinib may be prepared according to the procedures of International Patent Application No.
  • Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer.
  • hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children ;
  • aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors
  • progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma
  • estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5a-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy
  • anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, as well as selective estrogen receptor modulators (SERMS) such those described in U.S.
  • SERMS selective estrogen receptor modulators
  • Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation.
  • Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases,
  • SH2/SH3domain blockers serine/threonine kinases, phosphotidyl inositol-3 kinases, myo- inositol signaling, and Ras oncogenes.
  • protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth.
  • protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
  • Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods.
  • Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor -I (IGFI) receptor, macrophage colony stimulating factor Cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene.
  • EGFr epidermal growth factor receptor
  • PDGFr platelet derived growth factor receptor
  • erbB2 erbB4
  • VEGFr vascular endothelial growth factor receptor
  • TIE-2 vascular endothelial growth factor receptor
  • TIE-2 insulin growth factor
  • inhibitors of growth receptors include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.
  • Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.
  • Non-receptor tyrosine kinases which are not growth factor receptor kinases are termed nonreceptor tyrosine kinases.
  • Non-receptor tyrosine kinases useful in the present invention include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl.
  • Such non- receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S.
  • SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP.
  • SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.
  • Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).
  • IkB kinase family IKKa, IKKb
  • PKB family kinases AKT kinase family members
  • TGF beta receptor kinases TGF beta receptor kinases.
  • Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64; Philip, P.A., and Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Patent No.
  • PI3-kinase, ATM, DNA-PK, and Ku are also useful in the present invention.
  • Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541-1545.
  • Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues.
  • signal inhibitors are described in Powis, G., and Kozikowski A., (1994 New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
  • Ras Oncogene inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras, thereby acting as antiproliferation agents.
  • Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and Bennett, C.F. and Cowsert, L.M. BioChim. Biophys. Acta, (1999) 1489(1): 19-30.
  • antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors.
  • This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases.
  • Imclone C225 EGFR specific antibody see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat.
  • Herceptin ® erbB2 antibody see Tyrosine Kinase Signalling in Breast cancenerbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183
  • 2CB VEGFR2 specific antibody see Brekken, R.A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124.
  • Non-receptor kinase angiogenesis inhibitors may also find use in the present invention.
  • Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases).
  • Angiogenesis in general is linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression.
  • an erbB2/EGFR inhibitor with an inhibitor of angiogenesis makes sense.
  • nonreceptor tyrosine kinase inhibitors may be used in combination with the EGFR/erbB2 inhibitors of the present invention.
  • anti-VEGF antibodies which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alpha v beta 3 ) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed erb family inhibitors.
  • VEGFR the receptor tyrosine kinase
  • small molecule inhibitors of integrin alpha v beta 3
  • endostatin and angiostatin non-RTK
  • Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of formula (I).
  • immunologic strategies to generate an immune response against erbB2 or EGFR. These strategies are generally in the realm of tumor vaccinations.
  • the efficacy of immunologic approaches may be greatly enhanced through combined inhibition of erbB2/EGFR signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in ReiUy RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.
  • Agents used in proapoptotic regimens may also be used in the combination of the present invention.
  • Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance.
  • EGF epidermal growth factor
  • cyclin dependent kinases including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.
  • methods are provided for treating cancer in a mammal in need thereof, which comprises: administering to such mammal a therapeutically effective amount of: a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and b) at least one anti-neoplastic agent.
  • the cancer treatment method of the claimed invention includes the co-administration a compound of Formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.
  • anti-neoplastic agent such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor t
  • the compounds of Formula (I) may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist.
  • the reaction sequences provided in these Schemes are applicable for producing compounds of the invention.
  • a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • suitable protecting groups and the methods for protecting and de- protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts,
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • a protected piperidone can be converted to a spirocyclic piperidine via the sequence outlined in Scheme I.
  • An epoxide can be prepared from a protected piperidone and then be opened with various amines to give an amino alcohol intermediate.
  • Cyclization to the spirocyclic lactam can be accomplished in two steps with a reagent such as chloroacetyl chloride. After removal of the protecting group with an acid such as hydrogen chloride, the resulting spirocyclic piperidine intermediate can be alkylated with functionalized benzyl bromides and then elaborated to final products by Suzuki cross-coupling with various boronates or boronic acids.
  • the spirocyclic piperidine intermediate can be elaborated to a spirocyclic aryl bromide intermediate through condensation with a functionalized aldehyde (Scheme II). Suzuki cross-coupling with various boronates or boronic acids then affords the final products.
  • an alkyl bromide or aldehyde intermediate suitable for coupling with the spirocyclic piperidine can be prepared by bromination or oxidation of a functionalized alcohol (Scheme III).
  • a functionalized carboxylic acid can be converted to an ester under acidic conditions, which can then be reduced to a functionalized alcohol.
  • a functionalized alcohol can be activated as a mesylate, for example, which can be coupled with the spirocyclic piperidine via alkylation to provide the spirocyclic aryl bromide intermediate.
  • the spirocyclic aryl bromide can also be converted to the intermediate boronate and then coupled with various aryl or heteroaryl halides to prepare the target compounds (Scheme IV).
  • Analogs containing substitution on the piperidine can be made from commercially available piperidinones or by enolate chemistry via a metal enolate or by reaction of a silyl enol ether with a suitable electrophile (Scheme V).
  • the functionalized piperidinones can then be elaborated to the spirocyclic products using methodology described above.
  • the aqueous layer was drained and the organic layer diluted with t-butyl methyl ether (1.5 L) and washed with a mixture of brine and saturated aq ammonium chloride (250 mL).
  • the organic layer was dried (Na 2 S0 4 ) and evaporated to afford the crude title product as a gel.
  • the orange solution was diluted with ethyl acetate (30 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to give the title compound (3.2 g, 90%>) as a pale orange solid.
  • Each tube was diluted with 5N sodium hydroxide solution (2 mL) and ethyl acetate (2 mL). The contents of each tube were combined and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid (52 mg, 51%).
  • the residue was purified by reverse phase HPLC (10-90% acetonitrile /water + 0.1% ⁇ 4 ⁇ ). An additional purification by reverse phase HPLC (10-90% acetonitrile + 0.1% TF A/water + 0.1% TFA) was required and performed.
  • the desired tubes were concentrated in vacuo. To each tube was added IN sodium hydroxide solution ( ⁇ 1 mL) followed by ethyl acetate (1 mL) and then all the contents of each tube were combined in a separatory funnel. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 30 mL).
  • dichloromethane complex (19 mg, 0.023 mmol) in 1,4-dioxane (4 mL) was stirred at 100 °C. The reaction was not complete after 2 h so it was stirred for 65 h (over the weekend). The reaction was cooled to room temperature to provide the intermediate 4-cyclopropyl-9-(2,6- difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)-l-oxa-4,9- diazaspiro[5.5]undecan-3-one.
  • the mixture was diluted with dichloromethane (-1200 mL), saturated brine solution (500 mL), saturated aqueous ammonium chloride (500 mL), and then extracted. The organic layer was isolated, dried over sodium sulfate, and concentrated to a residue. The residue was taken up in dichloromethane ( ⁇ 50 mL) and purified by silica gel chromatography (5-75% of 10% methanol in
  • the solution was then treated with 5-bromo-2-(bromomethyl)-l,3- difluorobenzene- ⁇ i2 (1.75 g, 6.08 mmol) and the resulting reaction mixture was subjected to microwave irradiation on the very high absorption setting (Biotage Initiator 60) at 130 °C for 25 minutes.
  • the reaction mixture was diluted with water (10 mL), transferred to a separatory funnel, and extracted with dichloromethane (2 x 20 mL). The organic layers were pooled, dried over sodium sulfate, filtered, and concentrated to ⁇ 5 mL total volume.
  • the solids were taken up in 1,4-dioxane (7.68 mL) and the suspension was treated with a 2M aqueous solution of potassium carbonate (1.20 mL, 2.40 mmol).
  • the microwave vial was sealed and the reaction mixture subjected to microwave irradiation on the very high absorption setting (Biotage Initiator 60) at 120 °C for 20 minutes.
  • the reaction mixture was cooled to room temperature, filtered through a pad of Celite, and the pad was washed with dichloromethane (10 mL).
  • the solution was partitioned between water (15 mL) and an additional 15 mL of dichloromethane and the desired materials extracted into the organic layer.
  • the resulting reaction mixture was subjected to microwave irradiation on the very high absorption setting (Biotage Initiator 60) at 120 °C for 20 minutes.
  • the reaction mixture was diluted with dichloromethane (20 mL) and water (10 mL) and then extracted. The organic layer was dried over sodium sulfate, filtered, and concentrated to a residue. The material was split evenly into 6 portions and only one portion was purified by preparative reverse phase HPLC
  • the reaction mixture was filtered through a pad of Celite and the pad was washed with ethyl acetate (20 mL). The filtrate was diluted with water ( ⁇ 10 mL) and extracted. The organic layer was isolated and the aqueous layer was extracted with ethyl acetate (15 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to a residue. The residue was purified by preparative reverse phase HPLC (acetonitrile/water; 0.1% TFA). Fractions containing the desired material were pooled, neutralized with saturated aqueous sodium bicarbonate solution, and extracted into dichloromethane. The organic layer was dried over sodium sulfate and concentrated to afford the purified material.
  • the mixture was stirred at room temperature for 30 minutes and then treated with 4-bromo-2,3,6-trifluorobenzaldehyde (0.993 g, 4.15 mmol), acetic acid (0.928 mL, 16.21 mmol), and sodium triacetoxyborohydride (1.031 g, 4.86 mmol) in succession.
  • the round bottom flask was capped with a needle- vented septum and the mixture stirred at room temperature for 2 h.
  • the reaction mixture was carefully quenched by the addition of IN aqueous sodium hydroxide solution (3 mL) and the entire reaction mixture was transferred to a separatory funnel.
  • the mixture was diluted with water (30 mL) and dichloromethane (100 mL) and extracted.
  • dichloromethane complex (0.071 g, 0.087 mmol), and benzene- 1 ,4-diyldiboronic acid (1.435 g, 8.66 mmol).
  • the solids were taken up in 1,4-dioxane (6.92 mL) and the resulting suspension was treated with a 2M aqueous solution of potassium carbonate (1.731 mL, 3.46 mmol).
  • the reaction mixture was subjected to microwave irradiation at 130 °C for 25 minutes on the very high absorption setting.
  • the reaction mixture was diluted with dichloromethane (20 mL) and methanol (2 mL) and the suspension was filtered through a pad of Celite.
  • the filtrate was diluted with water (10 mL) and extracted.
  • the organic phase was isolated and the aqueous layer was extracted with dichloromethane (10 mL).
  • the organic layers were pooled, dried over sodium sulfate, and concentrated to a residue.
  • the residue was taken up in dichloromethane ( ⁇ 4 mL) and purified by silica gel chromatography (2-95% 10% methanol in dichloromethane/dichloromethane). Fractions containing the desired material were pooled and concentrated to afford a residue.
  • the residue was taken up in ethyl acetate ( ⁇ 10 mL) and treated with dichloromethane (-500 ⁇ ) to afford a fine suspension.
  • 4-cyclopropyl-l-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride 500 mg, 2.026 mmol was placed in a 100 mL round bottom flask. Added to the flask was dichloromethane (20 mL) and triethylamine (290 ⁇ , 2.081 mmol). The solution was stirred at room temperature for 10 minutes. To the solution was added, in succession, 3-methyl-4- bromobenzaldehyde (410 mg, 2.060 mmol), acetic acid (290 ⁇ , 5.07 mmol), and sodium triacetoxyborohydride (515 mg, 2.432 mmol).
  • LCMS analysis displayed starting aldehyde and secondary amine, as well as desired product (2: 1 starting material : desired product).
  • the reaction solution was heated to 70 °C for 4 h. No change in the ratio of starting material to desired product was observed in the LCMS.
  • the solution was cooled to room temperature and was diluted with dichloromethane (50 mL).
  • the contents of the flask were transferred to a separatory funnel and brine was added.
  • the organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo.
  • the vial was capped and the contents were purged with nitrogen.
  • the reaction mixture was stirred at 80 °C for 3 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo, taken up in ethyl acetate (50 mL), and washed with a 1 : 1 solution of watenbrine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0-20% ethyl acetate/hexanes) afforded the title compound (0.5 g, 92%).
  • the vial was capped, purged with nitrogen, and stirred at 100 °C for 1 h.
  • the solution was set aside to cool to room temperature and to allow the phases to separate.
  • the dioxane layer was removed and passed through a plug of Celite and sodium sulfate. The plug was washed with dioxane (2 mL).
  • the filtrate was concentrated in vacuo. This was purified by reverse phase HPLC (30-90% acetonitrile /water w/ 0.1% NH 4 OH) then by reverse phase HPLC (25-55% acetonitrile w/ 0.1% TF A/water w/ 0.1% TFA). The desired fractions were combined and concentrated in vacuo.
  • a microwave vial was charged, in succession, with (5 -bromo-3 -fluoropyridin-2- yl)methanol (100 mg, 0.485 mmol), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (124 mg, 0.485 mmol), 1 , -bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (35 mg, 0.043 mmol), 1,4-dioxane (3 mL), and 2M aq. potassium carbonate (1.5 mL).
  • the vial was capped, purged with nitrogen, and stirred at 100 °C.
  • the vial was capped, purged with nitrogen, and stirred at 100 °C for 1 h.
  • the reaction was cooled and 7-bromo-3- methylquinoline (50 mg, 0.225 mmol) and 2M aq. potassium carbonate (1 mL) were added.
  • the vial was capped, purged with nitrogen, and returned to stirring at 100 °C.
  • the solution was cooled to room temperature.
  • the dioxane layer was decanted and filtered through a plug of Celite and sodium sulfate, with a small amount of Si-Thiol resin. The plug was washed with dioxane (4 mL).
  • the organic filtrates were combined and concentrated in vacuo. Purification by reverse phase HPLC (10-70% acetonitrile /water w/ 0.1% NH 4 OH) afforded the title compound (18 mg, 19%).
  • the vial was capped, purged with nitrogen, and stirred at 100 °C. After 1 h, the reaction mixture was cooled to room temperature, and 7-bromo-3- methoxyquinoline (80 mg, 0.336 mmol) and 2M aq. potassium carbonate (1 mL) were added to the vial. The vial was capped, purged with nitrogen, and allowed to stir overnight at 100 °C. The reaction mixture was cooled to room temperature. The ethanol layer was decanted and passed through a plug of Celite and sodium sulfate (with a small amount of Si-Thiol resin). The plug was washed with ethanol (4 mL). The combined ethanol filtrate was concentrated in vacuo. Purification by flash chromatography (0-10%
  • Phenylmethyl tra/?5-4-cyclopropyl-7-fluoro-3-oxo- 1 -oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate (3.1 g, 8.55 mmol) was taken up in ethanol (50 mL) and placed in a Parr shaker vessel. The vessel was placed under nitrogen and 10%> Pd/C (100 mg) was added. The vessel was placed on a Parr shaker and the mixture was shaken under 30 psi hydrogen for 2 h. The vessel was removed from the shaker and the solution was filtered under a stream of nitrogen through a pad of Celite, which was washed further with ethanol (100 mL).
  • a microwave vial was charged in succession with trans-9-(4-bromo-2-fluorobenzyl)- 4-cyclopropyl-7-fluoro-l-oxa-4,9-diazaspiro[5.5]undecan-3-one (606 mg, 1.459 mmol), 7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (380 mg, 1.489 mmol), potassium carbonate (810 mg, 5.86 mmol), and 1 , l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (50 mg, 0.061 mmol).
  • a 10 mL microwave vial was charged, in succession, with trans -4-cyclopropyl-7- fluoro-l-oxa-4,9-diazaspiro[5.5]undecan-3-one (520 mg, 2.278 mmol), 5-bromo-2- (bromomethyl)-l ,3-difluorobenzene (651 mg, 2.278 mmol), acetonitrile (6 mL), and N,N- diisopropylethylamine (1.2 ml, 6.87 mmol).
  • the vial was capped, purged with nitrogen, and irradiated in a microwave at 120 °C for 30 minutes.
  • the reaction was performed in two 10 mL microwave vials. Into each vial was placed tra/75-9-(4-bromo-2,6-difluorobenzyl)-4-cyclopropyl-7-fluoro-l-oxa-4,9- diazaspiro[5.5]undecan-3-one (350 mg, 0.808 mmol), 7-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)quinoline (225 mg, 0.882 mmol), potassium carbonate (450 mg, 3.255 mmol), 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (35 mg, 0.043 mmol), and a premixed and degassed 3 : 1 ethanokwater solution (8 mL total).
  • the vial was sealed, purged with nitrogen, and stirred at 80 °C. After 30 minutes, the solution was cooled to room temperature and poured into a separatory funnel containing dichloromethane (40 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over sodium sulfate (with 5 mg of Si-thiol resin). After 10 minutes of drying, the mixture was filtered and concentrated in vacuo. Purification via flash chromatography (0- 10% methanol: ethyl acetate) afforded product as the trans racemate.
  • dichloromethane complex (20 mg, 0.024 mmol), and 1,4-dioxane (2 mL).
  • the vial was capped, purged with nitrogen, and stirred at 80 °C.
  • the reaction mixture was cooled and 7-bromo-3-methoxyquinoline (60 mg, 0.252 mmol) and 2M aqueous potassium carbonate solution (1.000 mL) were added to the mixture.
  • the vial was capped, purged with nitrogen, and returned to stirring at 80 °C. After 1 h, the reaction mixture was cooled to room temperature and two layers formed. The dioxane layer was decanted.
  • the resulting reaction mixture was allowed to stir at room temperature for 18 h.
  • the reaction was quenched by slow addition of saturated aqueous sodium bicarbonate solution (10 mL) and was stirred for ⁇ 30 minutes.
  • the mixture was then filtered through a pad of Celite wet with ethyl acetate, and the pad was washed with ethyl acetate (2 x 20 mL).
  • the organic and aqueous phases of the filtrate were then separated and the aqueous phase was extracted with ethyl acetate.
  • the combined organic phases were then washed with brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo.
  • the reaction vessel was purged with nitrogen gas and irradiated at 120 °C for 15 minutes in a Biotage Initiator microwave.
  • the resulting mixture was diluted with water (50 mL) and extracted with dichloromethane.
  • the aqueous phase was diluted with brine (20 mL) and extracted with tetrahydrofuran.
  • the combined organic phase was treated with SiliaBond® thiol (Si-thiol) (20 mg) for 30 minutes, dried over sodium sulfate, filtered and concentrated to dryness in vacuo.
  • the extracts were dried (sodium sulfate) and evaporated to a crude orange-brown oil. This was taken into anhydrous tetrahydrofuran (25 mL), treated with 60% sodium hydride in mineral oil (17.73 mmol) then heated at reflux. After 24 h, the reaction was cooled, quenched with water and extracted with ethyl acetate. The dried extracted (sodium sulfate) were treated with silica powder and evaporated to dryness. This was purified by silica gel chromatography (20-80% ethyl acetate in hexanes).
  • a microwave vial was charged with a suspension of 4-[l- (hydroxymethyl)cyclopropyl]-l-oxa-4,9-diazaspiro[5.5]undecan-3-one (0.300 mmol), 5- bromo-2-(bromomethyl)-l,3-difluorobenzene (0.300 mmol) and potassium carbonate (1.498 mmol) in anhydrous ⁇ , ⁇ -dimethylformamide (DMF) (3.0 ml) then sealed with a standard aluminum crimp cap. The vessel was heated on an aluminum block at 80 °C for 2 h to form the intermediate aryl bromide.
  • DMF ⁇ , ⁇ -dimethylformamide
  • the suspension was cooled, treated with 7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.449 mmol), PdCL ⁇ dppfJ-CFLCb adduct (0.015 mmol), and water (500 ⁇ ) then resealed and heated at 100 °C. After 1 h the reaction was cooled, filtered through a teflon syringe adaptor and purified directly by reverse phase HPLC (10-35% acetonitrile w/ 0.1% TF A/water w/ 0.1% TFA). The combined fractions were treated with saturated aqueous sodium bicarbonate then concentrated under reduced pressure to remove the volatiles.

Abstract

L'invention concerne de nouvelles pipéridines spirocycliques selon la formule (I), qui sont des inhibiteurs d'acides gras synthase (FAS), des compositions pharmaceutiques les contenant, leurs procédés de préparation et leur utilisation dans une thérapie de traitement de cancers.
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