WO2013028445A1 - Fatty acid synthase inhibitors - Google Patents

Fatty acid synthase inhibitors Download PDF

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Publication number
WO2013028445A1
WO2013028445A1 PCT/US2012/051062 US2012051062W WO2013028445A1 WO 2013028445 A1 WO2013028445 A1 WO 2013028445A1 US 2012051062 W US2012051062 W US 2012051062W WO 2013028445 A1 WO2013028445 A1 WO 2013028445A1
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Prior art keywords
alkyl
cyclopropylcarbonyl
methyl
pyrrolidinyl
phenyl
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PCT/US2012/051062
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French (fr)
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Steven Thomas DOCK
Allison K. MCSHERRY
Michael Lee Moore
Lance Howard Ridgers
Cynthia Ann Parrish
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Glaxosmithkline Llc
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Publication of WO2013028445A1 publication Critical patent/WO2013028445A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel carboxamides and reverse carboxamides 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 2 carbon donor, and NADPH as reducing equivalents
  • acetyl-CoA Lipids, Structure and function of animal fatty acid synthase, 39: 1045-1053 (2004), Asturias FJ et al., Structure and molecular organization of mammalian fatty acid synthase, Nature Struct. Mol. Biol. 12:225-232 (2005), Maier T, et al., Architecture of Mammalian Fatty Acid Synthase at 4.5 A Resolution, Science 31 1 :1258-1262 (2006)).
  • 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. A Study of Lipid Synthesis in
  • Neoplastic Tissue Slices in Vitro, Can Res, 13:27-29, (1953) FAS has now been shown to be overexpressed in numerous cancer types including prostate, ovary, colon, endometrium lung, bladder, stomach and kidney (Kuhajda FP, Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition; 16:202-208 (2000)). This differential expression and function of FAS in tumors and normal cells provide an approach for cancer therapy with the potential of a substantial therapeutic window.
  • This invention relates to compounds of the Formula (I), as shown below:
  • R 1 is phenyl, 5- or 6-membered heteroaryl, napthyl, 9- or 10-membered heterocyclyl; wherein said phenyl, 5- or 6-membered heteroaryl, napthyl, or 9- or 10-membered heterocyclyl is optionally substituted with from 1 to 3 substituents independently selected from halogen, C C 4 alkyl, -CF 3 , C 3 -C 7 cycloalkyl, -C(0)C C 4 alkyl, -C(0)C 3 -C 7 cycloalkyl, - CO(phenyl), -CONR 5 R 6 , phenyl, -S0 2 C C 4 alkyl, -S0 2 NR 5 R 6 , cyano, oxo, hydroxyl, Ci-C 4 alkoxy, C 3 -C 7 cycloalkoxy, hydroxyCi-C 4 alkyl-, Ci-C 4 alkoxyCrC 4 alkyl-, -
  • R 5 is selected from the group consisting of hydrogen, Ci-C 4 alkyl, phenyl, and CrC 3 alkylphenyl;
  • R 6 is hydrogen or d-C 4 alkyl
  • R 5 and R 6 taken together with the nitrogen to which they are attached represent a 3- to 7-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, which is optionally substituted 1 or 2 times independently by oxo or d-C 4 alkyl;
  • R 9 is a 5-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents selected from halogen, C C 4 alkyl, C C 4 alkoxy, and -NR 5 R 6 ;
  • each R 2 is independently selected from the group consisting of halogen, C-
  • A is selected from
  • R 3 is selected from the group consisting of CrC 4 alkyl, heteroaryl,
  • R 4 is selected from the group consisting of CrC 6 alkyl, -CF 3 , C 3 -C 7 cycloalkyl,
  • C 1 -C 4 alkoxy C 1 -C 4 alkoxy, and -NR 7 R 8 ; wherein C 3 -C 7 cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from the group of halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and -CONR 7 R 8 ;
  • R 7 and R 8 are each independently selected from hydrogen and C 1 -C 4 alkyl, or R 7 and R 8 taken together with the nitrogen to which they are attached represent a
  • n 0, 1 or 2;
  • n 1 or 2;
  • X is CH 2 ;
  • This invention also relates to pharmaceutical compositions, comprising compounds of Formula (I) and pharmaceutically acceptable carriers.
  • This invention also relates to methods of treating cancer comprising administering an effective amount of a compound of Formula (I) to a human in need thereof.
  • This invention also relates to methods of treating cancer comprising co-administering a compound of Formula (I) and a second compound to a human in need thereof.
  • This invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof.
  • This invention also relates to compounds of Formula (l)(A):
  • R 1 , R 2 , R 3 , R 4 and n and X are defined according to Formula (I).
  • This invention also relates to compounds of Formula (l)(B):
  • R 1 , R 2 , R 3 , R 4 and n and X are defined according to Formula (I).
  • this invention relates to compounds of Formula (I), (l)(A), or (l)(B),
  • R 1 is phenyl, 5- or 6-membered heteroaryl, napthyl, 9- or 10-membered heterocyclyl; wherein said phenyl, 5- or 6-membered heteroaryl, napthyl, or 9- or 10-membered heterocyclyl is optionally substituted with from 1 to 3 substituents independently selected from halogen, C C 4 alkyl, -CF 3 , C 3 -C 7 cycloalkyl, -C(0)C C 4 alkyl, -C(0)C 3 -C 7 cycloalkyl, - CO(phenyl), -CONR 5 R 6 , phenyl, -S0 2 C C 4 alkyl, -S0 2 NR 5 R 6 , cyano, oxo, hydroxyl, Ci-C 4 alkoxy, C 3 -C 7 cycloalkoxy, hydroxyC
  • R 5 is selected from the group consisting of hydrogen, Ci-C alkyl, phenyl, and CrC 3 alkylphenyl;
  • R 6 is hydrogen or Ci-C 4 alkyl
  • R 9 is a 5-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents selected from halogen, C 1 -C 4 alkyl, and -NR 5 R 6 ;
  • each R 2 is independently selected from the group consisting of halogen, d-C 6 alkyl, hydroxyl, CF 3 , and CrC 4 alkoxy;
  • R 3 is selected from the group consisting of CrC 4 alkyl, heteroaryl,
  • R 4 is selected from the group consisting of CrC 6 alkyl, -CF 3 , C 3 -C 7 cycloalkyl,
  • C 3 -C 7 cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from the group of halogen, CrC 4 alkyl, CrC 4 alkoxy, and -CONR 7 R 8 ;
  • R 7 and R 8 are each independently selected from hydrogen and CrC 4 alkyl, or R 7 and R 8 taken together with the nitrogen to which they are attached represent a 3- to 7-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen, and sulfur;
  • n 0, 1 or 2;
  • n 1 or 2;
  • X is CH 2 ;
  • this invention also relates to compounds of Formula (I),
  • this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein when present R 2 is fluoro, hydroxyl, methyl, or methoxy.
  • this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein R 3 is CrC 4 alkyl, pyridinyl, pyrimidynyl, and CrC 4 alkylphenyl.
  • this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein R 4 is cyclopropyl.
  • this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein R 1 is selected from the group of: furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, wherein said furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyr
  • this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein R 1 is selected from the group of benzofuranyl, isobenzofuryl, 2,3- dihydrobenzofuryl, 1 ,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, 1-H-indazolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl,
  • benzimidazolyl dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, benzoxadiazolyl, benzthiadiazolyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1 ,5- naphthyridinyl, 1 ,6-n
  • this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein R 2 is fluoro, hydroxyl, methyl, or methoxy.
  • this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), R 3 is selected from CrC 4 alkyl, pyridinyl, pyrimidynyl, and CrC 4 alkylphenyl.
  • this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), R 4 is cyclopropyl.
  • this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein R 1 is selected from the group of: phenyl, indolyl, benzofuranyl, indazolyl, benzoimidazolinyl, napthalyl, quinolyl, and wherein said phenyl is optionally substituted 1 to 3 times independently with a group selected from: methyloxy, cyano, NR 5 R 6 and halogen,
  • each R 2 is selected from the group consisting of halogen, C-
  • R 3 is selected from the group consisting of C-
  • R 4 is selected from the group consisting of CrC 6 alkyl and cyclopropyl
  • n 0, 1 or 2;
  • n 1 or 2;
  • X is CH 2;
  • nvention also relates to the following compounds
  • the invention provides compounds of Formula (I), Formula (l)(A) and Formula (l)(B) wherein when n is 2 there is an excess of one enantiomer over the other.
  • the invention provides compounds of Formula (l)(A) wherein when n is 2 said compound is an enantiomerically pure R isomer.
  • the invention provides compound according Formula (l)(B) wherein when n is 2 said compound is an enantiomerically pure S isomer.
  • compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a
  • the invention provides the use of an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer. In one embodiment, the invention provides the use of Formula (I) of a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cacner.
  • methods for treating cancer comprising administering to a human in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • 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,
  • medulloblastoma colon, head and neck, kidney, lung, liver, melanoma, renal, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, bladder, stomach, and giant cell tumor of bone and thyroid.
  • methods are provided of treating cancer in a mammal in need thereof comprising: administering to such mammal a therapeutically effective amount of a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and b) at least one anti-neoplastic agent.
  • 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 compounds of the present invention may comprise acid addition salts.
  • the salts are formed from pharmaceutically acceptable inorganic and organic acids.
  • suitable acid salts include maleic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumic, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, aleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methansulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, teroic, tannic, and the like.
  • salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, a
  • salts which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention.
  • These salts such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • the compound of Formula (I) or a salt thereof may exist in stereoisomeric forms
  • the scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. Also included within the scope of the invention are individual isomers of the compound represented by Formula (I), as well as any wholly or partially equilibrated mixtures thereof. The present invention also includes the individual isomers of the compound or salt represented by the Formula (I) as well as mixtures with isomers thereof in which one or more chiral centers are inverted. It is to be understood that the present invention includes all combinations and subsets of the particular groups defined hereinabove.
  • 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
  • alkyl refers to a straight or branched chain alkyl, 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. Suitable substituents are selected from the group consisting of: halogen, amino, substituted amino, cyano, hydroxyl, alkoxy, alkylthio, alkylsulfonyl, amidosulfonyl, carboxylic acid, carboxylic ester, carboxamide, aminocarbonyl, and heterocyclyl.
  • alkyl as used herein include 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, which optionally includes an alkylene linker through which the cycloalkyl may be attached.
  • 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 CrC 4 alkyl or C 3 -C 7 cycloalkyl as defined above.
  • substituted amino is meant -NR'R" wherein each R' and R" is independently selected from a group including hydrogen, Ci- 6 alkyl, acyl, C 3 - C 7 cycloalkyl, wherein at least one of R' and R" is not hydrogen.
  • substituted amino includes, but are not limited to alkylamino, dialkylaminio, acylamino, and cycloalkylamino.
  • 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.
  • Illustrative examples of heterocycloalkyls useful in the present invention include, but are not limited to, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl,
  • heterocyclyl refers to an unsubstituted or substituted mono- or polycyclic 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, benzthien
  • 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.
  • Other exemplary heteroaryl groups include, but are not limited to benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1 ,3-benzodioxolyl
  • heterocyclic As used herein "heterocyclic,” “heterocycle,” “heterocycl” groups or grammatical variations thereof include “heteroaryl” and “heterocycloalkyi” 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 C1 -3alkyl.
  • Optionally substituted indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cydoalkyi, cycloalkenyl, heterocycloalkyi, or heteroaryl, may be substituted with one to three substituents as defined herein.
  • “Optionally substituted” in reference to a group includes the unsubstituted group (e.g. "optionally substituted C-
  • substituted includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, or cyclization).
  • a single atom may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom.
  • the invention further provides a pharmaceutical composition (also referred to as pharmaceutical formulation) comprising a compound of Formula (I) or pharmaceutically acceptable salt, thereof and one or more excipients (also referred to as carriers and/or diluents in the pharmaceutical arts).
  • a pharmaceutical composition also referred to as pharmaceutical formulation
  • excipients also referred to as carriers and/or diluents in the pharmaceutical arts.
  • the excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
  • 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.
  • Diasteriomer refers to a compound having at least two chiral centers.
  • Diasteriomer 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.
  • physiologically functional 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, suffering from disease conditions 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.
  • 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.
  • therapeutically 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.
  • 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.
  • 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.
  • further active ingredient or ingredients includes any compound or therapeutic agent known to or that demonstrates advantageous properties when
  • the compounds are 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.
  • Typical 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 include 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; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.
  • anti-neoplastic agents are described below.
  • Examples of a further active ingredient or ingredients for use in combination or co- administered 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.
  • Examples of 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-1 ,2a,4,7p,10p, 13a-hexa-hydroxytax-1 1-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.
  • TAXOL® injectable solution
  • 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., 1 1 1 :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 Guide,. 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-ferf-butyl ester, 13-ester with 5 ⁇ - 20-epoxy-1 ,2a,4,7p, 10p, 13a-hexahydroxytax-1 1-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. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
  • Vinblastine vincaleukoblastine sulfate
  • VELBAN® an injectable solution.
  • testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.
  • 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 (1 :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 [1 , 1-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.
  • 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; and triazenes such as dacarbazine.
  • Cyclophosphamide 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1 ,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, 1 ,3-[bis(2-chloroethyl)-1 -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-1 -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, 1 1 -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.
  • Doxorubicin (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-8- glycoloyl, 7, 8, 9, 10-tetrahydro-6, 8, 1 1 -trihydroxy-1 -methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®.
  • Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblasts 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-p-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-p-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.
  • Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
  • 5-fluorouracil 5-fluoro-2,4- (1 H,3H) pyrimidinedione
  • fluorouracil is commercially available as fluorouracil.
  • Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death.
  • 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.
  • fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
  • Cytarabine 4-amino-1-p-D-arabinofuranosyl-2 (I H)-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 1 ,7-dihydro-6H-purine-6-thione monohydrate, 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
  • Thioguanine 2-amino-1 ,7-dihydro-6H-purine-6-thione
  • 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.
  • 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 G1/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) methyl]methylamino] 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)-10,1 1-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 HCI are myelosuppression, including neutropenia, and Gl effects, including diarrhea.
  • Topotecan HCI (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 monohydrochloride, 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 HCI is myelosuppression, primarily neutropenia.
  • Pazopanib which commercially available as VOTRIENT® is a tyrosine kinase inhibitor (TKI).
  • TKI tyrosine kinase inhibitor
  • Pazopanib is presented as the hydrochloride salt, with the chemical name 5- [[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide monohydrochloride.
  • Pazoponib is approved for treatment of patients with advanced renal cell carcinoma.
  • Bevacisumab which is commercially available as AVASTIN® is a humanized monoclonal antibody that blocks VEGF-A.
  • AVASTIN® is approved form the treatment of various cancers including colorectal, lung, breast, kidney, and glioblastomas.
  • 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).
  • Pertuzumab (also called 2C4, trade name Omnitarg) is a monoclonal antibody. The first of its class in a line of agents called "HER dimerization inhibitors". By binding to HER2, it inhibits the dimerization of HER2 with other HER receptors, which is hypothesized to result in slowed tumor growth. Pertuzumab is described in WO01/00245 published January 4, 2001 .
  • mTOR inhibitors include but are not limited to rapamycin (FK506) and rapalogs, RAD001 or everolimus (Afinitor), CCI-779 or temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687 and Pp121 .
  • Everolimus is sold as Afinitor® by Novartis and is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers. It has the following chemical structure (formula II) and chemical name: dihydroxy-12-[(2R)-1-[(1 S,3R,4/?)-4-(2-hydroxyethoxy)-3-m
  • 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).
  • 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]-/V-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.
  • Lapatinib, ⁇ /-(3- chloro-4- ⁇ [(3-fluorophenyl)methyl]oxy ⁇ phenyl)-6-[5-( ⁇ [2-(methylsulfonyl)ethyl]amino ⁇ methyl)- 2-furanyl]-4-quinazolinamine (represented by formula III, as illustrated), is a potent, oral, small-molecule, dual inhibitor of erbB-1 and erbB-2 (EGFR and HER2) tyrosine kinases that is approved in combination with capecitabine for the treatment of HER2-positive metastatic breast cancer.
  • the free base, HCI salts, and ditosylate salts of the compound of formula (III) 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 HCI 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, HCI salts, and diHCI salts of gefitinib may be prepared according to the procedures of International Patent Application No.
  • camptothecin derivative of formula A following, currently under development, including the racemic mixture (R,S) form as well as the R and S enantiomers:
  • 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
  • progestins 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
  • GnRH gonadotropin-releasing hormone
  • LH leutinizing hormone
  • FSH follicle stimulating hormone
  • 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, myoinositol 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.
  • PDGFr platelet derived growth factor receptor
  • VEGFr vascular endothelial growth factor receptor
  • PDGFr platelet derived growth factor receptor
  • erbB2 erbB2
  • VEGFr vascular endothelial growth factor receptor
  • TIE-2 immunoglobulin-like and epidermal growth factor homology domains
  • I insulin growth factor -I
  • Cfms macrophage colony stimulating factor
  • BTK BTK
  • ckit cmet
  • FGF fibroblast growth factor
  • TrkA, TrkB, and TrkC Trk receptors
  • ephrin (eph) receptors eph receptors
  • RET protooncogene RET protooncogene.
  • inhibitors of growth receptors are under development and 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.
  • Non-receptor tyrosine kinases useful in the present invention which are targets or potential targets of anti-cancer drugs, 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. and Corey, S.J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J.B., Brugge, J.S., (1997 Annual review of
  • 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. 1 101 -1 107; 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. 6,268,391 ; and Martinez- lacaci, L, et al, Int. J. Cancer (2000), 88(1 ), 44-52.
  • Inhibitors of Phosphotidyl inositol-3 Kinase family members including blockers of 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;
  • 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.
  • Another group of signal transduction pathway inhibitors are inhibitors of Ras
  • Oncogene Such 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, 51 17-5124.
  • 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.
  • non-receptor 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 Reilly 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
  • Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle.
  • a family of protein kinases called cyclin dependent kinases CDKs
  • CDKs cyclin dependent kinases
  • the coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle.
  • 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.
  • 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 according to Formula I are prepared using conventional organic syntheses. A suitable synthetic route is depicted below in the following general reaction schemes.
  • 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.
  • 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. All of the starting materials are commercially available or are readily made from commercially available starting materials by those of skill in the art unless otherwise noted in the experimental section.
  • Boc f-butyloxycarbonyl; Boc 2 0, di-t-butyl dicarbonate; DCE, 1 ,2-dichloroethane; DCM, dichloromethane; DIEA, diisopropylethylamine; DMAP, ⁇ , ⁇ -dimethylaminopyridine; DME, 1 ,2-dimethoxyethane; DMF, ⁇ , ⁇ -dimethyl formamide; EtOAc, ethyl acetate; EtOH, ethanol; HATU, 2-(7-aza-1 H-benzotriazole-1-yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate; HOAc, acetic acid; HOAT, 1-hydroxy-7-azabenzotriazole; LiHMDS, lithium
  • the racemic, Boc-protected aminomethylpyrrolidine A1 can be conveniently prepared from N 1 -benzyl-3-aminomethylpyrrolidine according to Scheme 1 .
  • the Boc-protected or acylated chiral aminomethylpyrrolidines A2 and A3 can be prepared from N-Boc-3-(R or S)- hydroxypyrrolidine according to Scheme 2.
  • acyl 3-(R or S)-aminomethylpyrrolidine 4-bromobenzamides A4 can be prepared by coupling the Boc-protected aminomethylpyrrolidines A2 with 4-bromobenzoic acid, removal of the Boc group, and then acylation with an acid chloride according to Scheme 3.
  • biaryl carboxylic acids may be coupled with Boc-protected aminomethylpyrrolidine A1 or A2 to afford intermediate A6.
  • Alkylation of the amide, deprotection, and acylation of the pyrrolidine amine affords the final product A8.
  • Reagents (a) 1 ,1-dimethylethyl-3(RS or S)-aminomethylpyrrolidine carboxylate, HATU, TEA, DMF; (b) LiHDMS or NaH, THF, then R 3 I; (c) HCI; (d) R 4 COCI, TEA, THF.
  • the Boc-protected aminomethylpyrrolidine 4- bromophenylcarboxamide intermediate A4 can be alkylated and then deprotected to afford intermediate A9. This can be acylated to afford A10, which is subjected to Suzuki coupling with an aryl boronic acid or ester to yield the final product A8.
  • Reagents (a) NaH, THF, then R 3 I; (b) HCI or TFA; (c) R 4 COCI, DIEA, DMAP, DCM; (d) R-
  • Reagents (a) aldehyde or ketone, Na(OAc) 3 BH, DCE; (b) biaryl carboxylic acid, SOCI 2 , TEA, DCM; (c) HCI or TFA; (d) R 4 COCI, TEA, THF. It is also possible to acylate intermediate A11 with optionally substituted 4-bromobenzoyl chlorides to afford the the bromophenyl carboxamide A13, as shown in Scheme 7.
  • Reagents (a) 4-bromobenzoyl chloride, DIEA, DCM; (b) HCI or TFA; (c) R 4 COCI, TEA, THF, (d) R 1 B(OR) 2 , Suzuki conditions.
  • R 3 is a heterocycle such as 2-pyridine or 2-(1 ,4-pyrazine)
  • the aryl moiety can be introduced on A1 or A2 via palladium-catalyzed coupling with the corresponding 3- chloropyridine or 2-chloro-1 ,4-pyrazine according to Scheme 8.
  • the subsequent steps of acylation with an optionally substituted 4-bromobenzoyl chloride, deprotection, acylation of the pyrrolidine nitrogen and Suzuki coupling proceed as in Scheme 7.
  • Scheme 8
  • Reagents (a) 3-chloropyridine or 2-chloro-1 ,4-pyrazine, NaOiBu, Pd(OAc) 2 , (R)-di-t-butyl- ⁇ 1(S)-2-
  • Reagents (a) ethyl chloroformate, NMM, THF, 0° to RT; (b) TFA, DCM; (c) R 4 COCI, TEA, DCM; (d) NaH, DMF, R 3 I; (e) R.,B(OR Suzuki conditions.
  • N-benzyl-3(RS)-aminomethylpyrrolidine 160 g was dissolved in 1.6 L DCM and cooled to 0 °C. Trifluoroacetic anhydride (320 ml.) was slowly added and the reaction mixture was allowed to warm to room temperature and stirred for 12 hr. The reaction mixture was washed with water (2 x 750 mL), brine (2 x 500 mL), dried over sodium sulfate and evaporated under reduced pressure to afford 190 g of the titled compound, which was used without further purification.
  • the product was determined to be a 95:5 ratio of enantiomers (i.e., 90% ee).
  • chiral HPLC Daicel Chiralpak AD- H column (4.6 x 150 mm) with a mobile phase of heptane:ethanol:isopropylamine
  • a sealable reaction flask was charged with 7-quinolinyl trifluoromethanesulfonate (5.17 g, bis(pinacolato)diboron (4.74 g), Pd(dppf)CI 2 (0.682 g), 1 , 1 '-bis(diphenylphosphino)ferrocene (0.517 g), potassium acetate (5.49 g) and 1 ,4-dioxane (100 mL).
  • the flask was purged with nitrogen, sealed and heated to 100 °C. After 2 hours, the reaction was allowed to cool to room temperature and diluted with EtOAc.
  • Methyl 4-biphenylcarboxylate (1.0 g, 4.71 mmol) was diluted with THF (6 ml_), water (8 ml.) and NaOH (47.13 mmol), then stirred for 12 h. The pH was adjusted to 1 with NaHS0 4 and the reaction diluted with brine. The product was extracted with ethyl acetate. The combined organic extracts were dried over MgS0 4 , filtered, concentrated and dried under hi-vacuum to afford the titled compound as white solids (971 mg, 104%). LCMS m/z 197 (M-H).
  • Methyl 4-bromo-2-(methyloxy)benzoate 845 mg, 3.45 mmol was dissolved in DMF and the solution sparged with N 2 for 5 minutes.
  • Pd(PPh 3 ) 4 (398 mg, 0.345 mmol) was added and the suspension sparged with N 2 for an additional 10 minutes.
  • Phenylboronic acid (589 mg, 4.83 mmol) and Na 2 C0 3 (731 mg, 6.9 mmol), dissolved in water, were added to the reaction and the suspension allowed to stir for 3d at 80 C. After cooling to room temperature the reaction was diluted with water, brine (50 mL) and the product extracted with ethyl acetate.
  • the reaction mixture was diluted with 50 mL each EtOAc and 2 N aqueous Na 2 C0 3 .
  • the organic layer was separated, washed with 50 mL each water and brine, dried over sodium sulfate and conceentrated to a solid.
  • the solid was triturated with 20 mL EtOAc and the filtrate concentrated to an orange-yellow oil which was purified by flash chromatography on silica gel using a gradient of EtOAc in hexanes to afford 280 mg of the titled compound as a colorless oil.
  • the resulting oil was diluted with anhydrous DCM (30.0 mL), cooled to 0 °C then treated successively with neat triethylamine (4.58 ml) and neat cyclopropylcarbonyl chloride (0.903 ml). After 30 minutes the resulting slurry was diluted with saturated aqueous sodium bicarbonate then extracted further with dichloromethane. The combined extracts were dried over sodium sulfate, treated with silica powder ( ⁇ 8g) then evaporated to dryness in vacuo. The crude product was purified by silica gel flash chromatography eluting with a gradient of 50-100% EtOAc/hexanes.
  • the resulting dark slurry was diluted with methanol, treated with silica powder ( ⁇ 1 g) then evaporated under reduced pressure to dryness. This was purified by silica gel flash chromatography eluting with EtOAc and then 3% MeOH/EtOAC, followed by preparative reverse phase HPLC. The desired HPLC fractions were combined and evaporated to a foam that was purified a second time by reverse phase HPLC. The combined desired HPLC fractions were treated with saturated aqueous sodium bicarbonate (10 ml) then extracted into DCM. The extracts were dried over sodium sulfate and evaporated to a colorless residue.
  • the resulting dark slurry was diluted with water and extracted into ethyl acetate then the extracts were dried with sodium sulfate, treated with silica powder ( ⁇ 2g) and evaporated under reduced pressure to dryness.
  • the desired HPLC fractions were combined and evaporated under reduced pressure to a brown-orange residue that was purified a second time by reverse phase HPLC.
  • the desired fractions were combined, treated with saturated aqueous sodium bicarbonate ( ⁇ 10ml) then concentrated under reduced pressure.
  • Inhibition of FAS activity can be measured based on the detection of residual NADPH substrate after the FAS assay is quenched.
  • This assay is run as a 10 ⁇ _ endpoint assay in 384-well format, where the reaction contains 20 ⁇ malonyl-CoA, 2 ⁇ acetyl-CoA, 30 ⁇ NADPH and 40 nM FAS in 50 mM sodium phosphate, pH 7.0.
  • the assay is run by sequentially dispensing 5 ⁇ of a malonyl-CoA solution, then enzyme solution Containing the acetyl-CoA, and NADPH) into a black, low volume assay plate (Greiner 784076) pre- dispensed with 100 nL compound solutions in DMSO.
  • the reaction is incubated at ambient temperature for 60 minutes, then quenched with 5 ⁇ _ of a developing solution composed of 90 ⁇ resazurin, 0.3 lU/ml diaphorase in 50 mM sodium phosphate, pH 7.0.
  • the developed reaction is read on a Molecular Devices Analyst or Acquest (or equivalent) plate reader using a 530 nm excitation wavelength filter, a 580 nm emission filter, and 561 nm dichroic filter.
  • the test compounds are prepared in neat DMSO at a concentration of 10 mM.
  • compounds are diluted using a three fold serial dilution and tested at 1 1 concentrations (e.g. 25 ⁇ -0.42 nM). Curves are analysed using ActivityBase and XLfit, and results are expressed as plC50 values.
  • Inhibition of FAS can also be quantified based on the detection of the CoA products with a thio-reactive coumarin dye.
  • This assay is run as a 10 ⁇ _ endpoint assay in 384-well format, where the reaction contains 20 ⁇ malonyl-CoA, 20 ⁇ acetyl-CoA, 40 ⁇ NADPH and 2 nM FAS in 50 mM sodium phosphate, pH 7.0, and 0.04% Tween-20.
  • the assay is run by adding 5 ⁇ _ enzyme solution to a black, low volume assay plate (Greiner 784076) pre- dispensed with 100 nl compound solutions in DMSO.
  • Exemplified compounds of the present invention were tested according to the above assays and were found to be inhibitors of FAS.
  • the IC 50 values ranged from about 1 to about 2,000 nM; the IC 50 values of the certain compounds ranged from about 1 to about 100 nM.
  • the compounds described below were tested generally according to the assays described herein. The IC 50 for each compound was either reported in at least one experiment or the average of multiple experiments.
  • Example 16 25 nM
  • Example 20 50 nM
  • Cultured primary human pre-adipocytes (Zen-Bio, Cat# ASC062801 ) are plated at confluence (3x104 cells/well) in 96-well plates Costar, Cat# 3598) coated with 0.2% gelatin (Sigma, Cat# G-6650) in DMEM/F12 medium (InvitroGen Cat# 1 1330-032) supplemented with 10% heat inactivated fetal bovine serum (InvitroGen, Cat# 16000-044.
  • the cell differentiation is induced by replacing the seeding medium with the differentiation medium composed of DMEM/F12 medium supplemented with 10% heat inactivated fetal bovine serum, 200 ⁇ 3-isobutyl-1-methylxanthine (Sigma, Cat# I-5879), 20 nM dexamethasone (Sigma, Cat# D-8893), 20 nM GW1929 (Sigma, Cat# G5668) and 20 nM insulin (InvitroGen, Cat# 03-01 10SA).
  • differentiation medium is replaced by the re-feed medium made of DMEM/F12 supplemented with 10% heat inactivated serum and 20 nM insulin. The appropriate concentration of tested compounds and controls are added into this medium at that time.
  • the relative amount of cellular triglyceride is estimated by using a Trinder kit (Sigma, Cat# TR0100). Re-feed medium is aspirated and cells are washed with PBS (InvitroGen, Cat# 14190-144 and the assay is performed according the kit manufacturer protocol. Briefly, reconstituted solutions A and B are mixed with 0,01 % digitonin (Sigma, Cat# D-5628) prior to performing the assay and added onto the cells; plates are incubated at 37 °C for one hour. The absorbance is read at 540 nm.
  • the data is first normalized using the following equation: 100 * ((UNK - Control 1 ) / Control 2 - Control 1 )) where Control 1 is the Robust Mean of the 0% response control and Control 2 is the Robust Mean of the 100% response control.

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Abstract

This invention relates to carboxamides and reverse carboxamides according to Formula (I) and the use of carboxamides and reverse carboxamides for the modulation, notably the inhibition of the activity or function of fatty acid synthase (FAS). Suitably, the present invention relates to the use of carboxamides and reverse carboxamides in the treatment of cancer.

Description

FATTY ACID SYNTHASE INHIBITORS
FIELD OF INVENTION
This invention relates to novel carboxamides and reverse carboxamides 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.
BACKGROUND
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 2 carbon donor, and NADPH as reducing equivalents (Wakil SJ, Lipids, Structure and function of animal fatty acid synthase, 39: 1045-1053 (2004), Asturias FJ et al., Structure and molecular organization of mammalian fatty acid synthase, Nature Struct. Mol. Biol. 12:225-232 (2005), Maier T, et al., Architecture of Mammalian Fatty Acid Synthase at 4.5 A Resolution, Science 31 1 :1258-1262 (2006)).
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. A Study of Lipid Synthesis in
Neoplastic Tissue Slices in Vitro, Can Res, 13:27-29, (1953)). FAS has now been shown to be overexpressed in numerous cancer types including prostate, ovary, colon, endometrium lung, bladder, stomach and kidney (Kuhajda FP, Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition; 16:202-208 (2000)). This differential expression and function of FAS in tumors and normal cells provide an approach for cancer therapy with the potential of a substantial therapeutic window.
Pharmacological and small interference RNA mediated inhibition of FAS has demonstrated a preferential inhibition of cancer cell proliferation. Additionally these inhibitors induce apoptosis in cancers cells in vitro and retard growth in human tumors in murine xenograft models in vivo (Menendez JS and Lupu R, Nature Reviews Cancer, 7: 763-777 (2007). Based upon these findings, FAS is considered a major potential target of antineoplastic intervention. Thus, there is a need for inhibitors of FAS.
SUMMARY OF THE INVENTION
This invention relates to compounds of the Formula (I), as shown below:
Figure imgf000003_0001
wherein
R1 is phenyl, 5- or 6-membered heteroaryl, napthyl, 9- or 10-membered heterocyclyl; wherein said phenyl, 5- or 6-membered heteroaryl, napthyl, or 9- or 10-membered heterocyclyl is optionally substituted with from 1 to 3 substituents independently selected from halogen, C C4alkyl, -CF3, C3-C7cycloalkyl, -C(0)C C4alkyl, -C(0)C3-C7cycloalkyl, - CO(phenyl),
Figure imgf000003_0002
-CONR5R6, phenyl, -S02C C4alkyl, -S02NR5R6, cyano, oxo, hydroxyl, Ci-C4alkoxy, C3-C7cycloalkoxy, hydroxyCi-C4alkyl-, Ci-C4alkoxyCrC4alkyl-, -OCF3, -NR5R6, R5R6NC C4alkyl-, -NHC(0)C C4alkyl, - NHCONR5R6, -NHS02Ci-C4alkyl, -NHS02NR5R6, and R9;
R5 is selected from the group consisting of hydrogen, Ci-C4alkyl, phenyl, and CrC3alkylphenyl;
R6 is hydrogen or d-C4alkyl;
or R5 and R6 taken together with the nitrogen to which they are attached represent a 3- to 7-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, which is optionally substituted 1 or 2 times independently by oxo or d-C4alkyl; R9 is a 5-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents selected from halogen, C C4alkyl, C C4alkoxy, and -NR5R6;
each R2 is independently selected from the group consisting of halogen, C-|-C6alkyl, hydroxyl, CF3 ,and Ci-C4alkoxy; A is selected from
Figure imgf000004_0001
(a) (b)
R3 is selected from the group consisting of CrC4alkyl, heteroaryl,
Ci-C4alkyl6-membered heteroaryl, and CrC4alkylphenyl;
R4 is selected from the group consisting of CrC6alkyl, -CF3, C3-C7cycloalkyl,
C1-C4alkoxy, and -NR7R8; wherein C3-C7cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from the group of halogen, C1-C4alkyl, C1-C4alkoxy, and -CONR7R8;
R7 and R8 are each independently selected from hydrogen and C1-C4alkyl, or R7 and R8 taken together with the nitrogen to which they are attached represent a
3- to 7-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen, and sulfur;
m is 0, 1 or 2;
n is 1 or 2;
X is CH2;
or a pharmaceutically acceptable salt thereof.
This invention also relates to pharmaceutical compositions, comprising compounds of Formula (I) and pharmaceutically acceptable carriers.
This invention also relates to methods of treating cancer comprising administering an effective amount of a compound of Formula (I) to a human in need thereof.
This invention also relates to methods of treating cancer comprising co-administering a compound of Formula (I) and a second compound to a human in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof.
This invention also relates to compounds of Formula (l)(A):
(l)(A)
or a pharmaceutically acceptable salts thereof wherein wherein R1, R2, R3, R4 and n and X are defined according to Formula (I).
This invention also relates to compounds of Formula (l)(B):
Figure imgf000005_0002
(l)(B)
or a pharmaceutically acceptable salts thereof wherein wherein R1, R2, R3, R4 and n and X are defined according to Formula (I).
In one embodiment, this invention relates to compounds of Formula (I), (l)(A), or (l)(B), R1 is phenyl, 5- or 6-membered heteroaryl, napthyl, 9- or 10-membered heterocyclyl; wherein said phenyl, 5- or 6-membered heteroaryl, napthyl, or 9- or 10-membered heterocyclyl is optionally substituted with from 1 to 3 substituents independently selected from halogen, C C4alkyl, -CF3, C3-C7cycloalkyl, -C(0)C C4alkyl, -C(0)C3-C7cycloalkyl, - CO(phenyl),
Figure imgf000005_0003
-CONR5R6, phenyl, -S02C C4alkyl, -S02NR5R6, cyano, oxo, hydroxyl, Ci-C4alkoxy, C3-C7cycloalkoxy, hydroxyCi-C4alkyl-, Ci-C4alkoxyCi-C4alkyl- -OCF3, -NR5R6, R5R6NC C4alkyl-, -NHC(0)C C4alkyl, - NHCONR5R6, -NHS02Ci-C4alkyl, -NHS02NR5R6, and R9;
R5 is selected from the group consisting of hydrogen, Ci-C alkyl, phenyl, and CrC3alkylphenyl;
R6 is hydrogen or Ci-C4alkyl;
or R5 and R6 taken together with the nitrogen to which they are attached represent a
3- to 7-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, which is optionally substituted 1 or 2 times independently by oxo or Ci-C4alkyl; R9 is a 5-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents selected from halogen, C1-C4alkyl,
Figure imgf000006_0001
and -NR5R6;
each R2 is independently selected from the group consisting of halogen, d-C6alkyl, hydroxyl, CF3 , and CrC4alkoxy;
R3 is selected from the group consisting of CrC4alkyl, heteroaryl,
Ci-C4alkyl6-membered heteroaryl, and CrC4alkylphenyl;
R4 is selected from the group consisting of CrC6alkyl, -CF3, C3-C7cycloalkyl,
CrC4alkoxy, and -NR7R8; wherein C3-C7cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from the group of halogen, CrC4alkyl, CrC4alkoxy, and -CONR7R8;
R7 and R8 are each independently selected from hydrogen and CrC4alkyl, or R7 and R8 taken together with the nitrogen to which they are attached represent a 3- to 7-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen, and sulfur;
m is 0, 1 or 2;
n is 1 or 2;
X is CH2;
or a pharmaceutically acceptable salt thereof.
In another embodiment, this invention also relates to compounds of Formula (I),
(l)(A), or (l)(B), wherein R1 is phenyl optionally substituted with from 1 to 3 substituents independently selected from halogen, CrC4alkyl, -CF3, C3-C7cycloalkyl, -C(0)Ci-C4alkyl, - C(0)C3-C7cycloalkyl, -CO(phenyl), -C C4(=0)OH, -C(=0)OC C4alkyl, -CONR5R6, phenyl, - S02Ci-C4alkyl, -S02NR5R6, cyano, oxo, hydroxyl, CrC4alkoxy, C3-C7cycloalkoxy,
hydroxyCi-C4alkyl-, Ci-C4alkoxyCi-C4alkyl-, -OCF3, -NR5R6, R5R6NC C4alkyl-,
-NHC(0)Ci-C4alkyl, -NHCONR5R6, -NHS02C C4alkyl, -NHS02NR5R6, and R9.
In another embodiment, this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein when present R2 is fluoro, hydroxyl, methyl, or methoxy. In another embodiment, this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein R3 is CrC4alkyl, pyridinyl, pyrimidynyl, and CrC4alkylphenyl. In another embodiment, this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein R4 is cyclopropyl. In another embodiment, this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein R1 is selected from the group of: furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, wherein said furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl all of which are optionally substituted with from 1 to 3 substituents independently selected from halogen, C C4alkyl, -CF3, C3-C7cycloalkyl, -C(0)Ci-C4alkyl, -C(0)C3- C7cycloalkyl, -C(0)phenyl,
Figure imgf000007_0001
-C(0)NR5R6, phenyl, - S02Ci-C4alkyl, -S02NR5R6, cyano, oxo, hydroxyl, Ci-C4alkoxy, C3-C7cycloalkoxy, hydroxyCi-C4alkyl-, C C4alkoxyCi-C4alkyl-, -OCF3, -NR5R6, R5R6NC C4alkyl-,
-NHC(0)Ci-C4alkyl, -NHCONR5R6, -NHS02C C4alkyl, and -NHS02NR5R6.
In another embodiment, this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein R1 is napthyl optionally substituted with from 1 to 3 substituents independently selected from halogen, Ci-C4alkyl, -CF3, C3-C7cycloalkyl, -C(0)Ci-C4alkyl, - C(0)C3-C7cycloalkyl, -CO(phenyl), -C C4(=0)OH, -C(=0)OC C4alkyl, -CONR5R6, phenyl, - S02C1-C4alkyl, -S02NR5R6, cyano, oxo, hydroxyl, CrC4alkoxy, C3-C7cycloalkoxy,
Figure imgf000007_0002
-OCF3, -NR5R6, R5R6NC C4alkyl-,
-NHC(0)C C4alkyl, -NHCONR5R6, -NHS02C C4alkyl, -NHS02NR5R6, and R9
In another embodiment, this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein R1 is selected from the group of benzofuranyl, isobenzofuryl, 2,3- dihydrobenzofuryl, 1 ,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, 1-H-indazolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl,
dihydrobenzoisothiazolyl, indazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, benzoxadiazolyl, benzthiadiazolyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1 ,8-naphthyridinyl, or pteridinyl, wherein said benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1 ,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, 1 -H-indazolyl,
benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, benzoxadiazolyl, benzthiadiazolyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1 ,5- naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1 ,8-naphthyridinyl, and pteridinyl all of which are optionally substituted with from 1 to 3 substituents independently selected from: halogen, C C4alkyl, -CF3, C3-C7cycloalkyl, -C(0)C C4alkyl, -C(0)C3-C7cycloalkyl, - C(0)phenyl,
Figure imgf000008_0001
-C(0)NR5R6, phenyl, -S02Ci-C4alkyl, -S02NR5R6, cyano, oxo, hydroxyl, Ci-C4alkoxy, C3-C7cycloalkoxy, hydroxyCi-C4alkyl-, Ci-C4alkoxyCrC4alkyl-, -OCF3, -NR5R6, R5R6NC C4alkyl-, -NHC(0)C C4alkyl, - NHC(0)NR5R6, -NHS02CrC4alkyl, -NHS02NR5R6, and R9.
In another embodiment, this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein R2 is fluoro, hydroxyl, methyl, or methoxy. In another embodiment, this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), R3 is selected from CrC4alkyl, pyridinyl, pyrimidynyl, and CrC4alkylphenyl. In another embodiment, this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), R4 is cyclopropyl.
In another embodiment, this invention also relates to compounds of Formula (I), (l)(A), or (l)(B), wherein R1 is selected from the group of: phenyl, indolyl, benzofuranyl, indazolyl, benzoimidazolinyl, napthalyl, quinolyl, and wherein said phenyl is optionally substituted 1 to 3 times independently with a group selected from: methyloxy, cyano, NR5R6 and halogen,
each R2 is selected from the group consisting of halogen, C-|-C6alkyl, hydroxyl, and CrC4alkoxy;
R3 is selected from the group consisting of C-|-C4alkyl, pyridinyl, pyrimidynyl, phenyl and (VC alkylphenyl; and
R4 is selected from the group consisting of CrC6alkyl and cyclopropyl;
m is 0, 1 or 2;
n is 1 or 2;
X is CH2;
or pharmaceutically acceptable salt thereof.
nvention also relates to the following compounds
Figure imgf000008_0002
Example No. Structure Name
2. OMe 0 0 A/-{[1-Cyclopropylcarbonyl)-3(RS)- pyrrolidinyl]methyl}-3-methyloxy-A/-methyl-
4-biphenylcarboxamide
3. OH o o A/-{[1-Cyclopropylcarbonyl)-3(RS)- pyrrolidinyl]methyl}-3-hydroxy-A/-methyl-4- biphenylcarboxamide
4. A/-{[(3S)-1-Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-4-(1 /-/-indol-6-yl)-/V- methylbenzamide
5. O 0 A/-{[(3S)-1-Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-A/-methyl-4'-
(methyloxy)-4-biphenylcarboxamide
6. 3'-Chloro-A/-{[(3S)-1-Cyclopropylcarbonyl)- 3-pyrrolidinyl]methyl}-4'-fluoro-A/-methyl-4- biphenylcarboxamide
7. 0 0 A/-{[(3S)-1-Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-4-(1 /-/-indol-5-yl)-/V- methylbenzamide
H
8. 0 0 A/-{[(3S)-1-Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-4-(1 /-/-indazol-5-yl)-/V- methylbenzamide
H
Figure imgf000010_0001
Figure imgf000011_0001
Example No. Structure Name
23. 0 0 A/-{[(3S)-1-Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-A/,3-dimethyl-4'-
(methyloxy)-4-biphenylcarboxamide
24. 4-( 1 -Benzof u ra n-5-yl )-A/-{[(3R)- 1 -
Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-A/-ethylbenzamide
25. 4-(1 H-Benzimidazol-5-yl)-A/-{[(3R)-1-
Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-A/-ethylbenzamide
H
26. A/-{[(3R)-1 -Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-A/-ethyl-4-(1 /-/-indol-4- yl)benzamide
27. 0 0 A/-{[(3R)-1 -Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-A/-ethyl-4-(1 /-/-indol-7- yl)benzamide
28. N-{[(3R)-1 -Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-N-ethyl-4'-(methyloxy)-
4-biphenylcarboxamide
29. 3'-Chloro-A/-{[(3R)-1-Cyclopropylcarbonyl)-
3-pyrrolidinyl]methyl}-A/-ethyl-4'-fluoro-4- biphenylcarboxamide
Figure imgf000013_0001
Figure imgf000014_0001
Example No. Structure Name
44. A/-{[(3R)-1 -Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-4-(1 /-/-indazol-5-yl)-/V-
(phenylmethyl)benzamide
H
45. A/-{[(3R)-1 -Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-4-(1 /-/-indazol-6-yl)-/V-
(phenylmethyl)benzamide
46. A/-{[(3R)-1 -Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-4-(1 /-/-indol-5-yl)-/V-
(phenylmethyl)benzamide
H
47. 4-( 1 -Benzof u ra n-5-yl )-A/-{[(3R)- 1 - Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-/V- (phenylmethyl)benzamide
48. 4-(1 H-Benzimidazol-5-yl)-A/-{[(3R)-1- Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-/V- (phenylmethyl)benzamide
H
49. A/-{[(3R)-1 -Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-4'-(methyloxy)-/V-
(phenylmethyl)-4-biphenylcarboxamide
50. A/-{[(3R)-1 -Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-4-(1 /-/-indol-6-yl)-/V-
(phenylmethyl)benzamide
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
In one embodiment, the invention provides compounds of Formula (I), Formula (l)(A) and Formula (l)(B) wherein when n is 2 there is an excess of one enantiomer over the other. In one embodiment the invention provides compounds of Formula (l)(A) wherein when n is 2 said compound is an enantiomerically pure R isomer. In another embodiment, the invention provides compound according Formula (l)(B) wherein when n is 2 said compound is an enantiomerically pure S isomer.
In one embodiment, pharmaceutical compositions are provided comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier. In one embodiment, the invention provides the use of an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer. In one embodiment, the invention provides the use of Formula (I) of a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cacner.
In another embodiment, methods are provided for treating cancer comprising administering to a human in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, 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,
medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, renal, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, bladder, stomach, and giant cell tumor of bone and thyroid.
In another embodiment, methods are provided of treating cancer in a mammal in need thereof comprising: administering to such mammal a therapeutically effective amount of a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and b) at least one anti-neoplastic agent.
This invention also relates to compounds exemplified in the Experimental section. Typically, but not absolutely, 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 compounds of the present invention may comprise acid addition salts. In general, the salts are formed from pharmaceutically acceptable inorganic and organic acids. More specific examples of suitable acid salts include maleic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumic, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, aleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methansulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, teroic, tannic, and the like.
Other representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.
Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention. These salts, such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
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 (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The invention also covers the individual isomers of the compound or salt represented by Formula (I) as mixtures with isomers thereof in which one or more chiral centers are inverted. Likewise, it is understood that a compound or salt of Formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention. It is to be understood that the present invention includes all combinations and subsets of the particular groups defined hereinabove. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. Also included within the scope of the invention are individual isomers of the compound represented by Formula (I), as well as any wholly or partially equilibrated mixtures thereof. The present invention also includes the individual isomers of the compound or salt represented by the Formula (I) as well as mixtures with isomers thereof in which one or more chiral centers are inverted. It is to be understood that the present invention includes all combinations and subsets of the particular groups defined hereinabove.
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). DEFINITIONS
Terms are used within their accepted meanings. The following definitions are meant to clarify, but not limit, the terms defined.
As used herein, the term "alkyl" (or "alkylene") refers to a straight or branched chain alkyl, 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. Suitable substituents are selected from the group consisting of: halogen, amino, substituted amino, cyano, hydroxyl, alkoxy, alkylthio, alkylsulfonyl, amidosulfonyl, carboxylic acid, carboxylic ester, carboxamide, aminocarbonyl, and heterocyclyl. Examples of "alkyl" as used herein include methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, t-butyl, isopentyl, n-pentyl, and the like, as well as substituted versions thereof.
As used herein, the term "cycloalkyl" refers to an unsubstituted or substituted mono- or polycyclic non-aromatic saturated ring, which optionally includes an alkylene linker through which the cycloalkyl may be attached. 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.
As used herein, the term "alkoxy" refers to the group -ORa, where Ra is CrC4alkyl or C3-C7cycloalkyl as defined above.
As used herein, the term "substituted amino" is meant -NR'R" wherein each R' and R" is independently selected from a group including hydrogen, Ci-6alkyl, acyl, C3- C7cycloalkyl, wherein at least one of R' and R" is not hydrogen. Examples of substituted amino includes, but are not limited to alkylamino, dialkylaminio, acylamino, and cycloalkylamino.
"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. Illustrative examples of 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-1 H-1 ,4-diazepinyl, azabicylo[3.2.1 ]octyl,
azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl and
1 ,5,9-triazacyclododecyl. As used herein, the term "heterocyclyl" refers to an unsubstituted or substituted mono- or polycyclic 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. Examples of "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. The term "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. Examples of 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, benzthiadiazolyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1 ,8-naphthyridinyl, and pteridinyl.
The term "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.
Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like. Unless otherwise indicated, the term "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.
As used herein, the term "heteroaryl", unless otherwise defined, is meant 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. Other exemplary 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, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1 ,8-naphthyridinyl, and pteridinyl. Suitable substituents for heteroaryl are described in the definition of "optionally substituted."
As used herein "heterocyclic," "heterocycle," "heterocycl" groups or grammatical variations thereof include "heteroaryl" and "heterocycloalkyi" groups.
As used herein, the term "cyano" refers to the group -CN.
As used herein, 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.
As used herein, unless otherwise defined, the phrase "optionally substituted" or variations thereof denote an optional substitution, including multiple degrees of substitution, with one or more substitutent group. The phrase should not be interpreted as duplicative of the substitutions herein described and depicted. 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 C1 -3alkyl. "Optionally substituted" indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cydoalkyi, cycloalkenyl, heterocycloalkyi, or heteroaryl, may be substituted with one to three substituents as defined herein. "Optionally substituted" in reference to a group includes the unsubstituted group (e.g. "optionally substituted C-| - C4alkyl" includes unsubstituted C-| -C4alkyl). It should be understood that the term "substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, or cyclization). A single atom may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents include -OR, -C(0)R, -C(0)OR, -CH(R)OR, -SR, -S(0)R, - S(0)2R, -N(R)(R), -N(R)C(0)OR, -N(R)C(0)R, -OC(0)N(R)(R), -N(H)C(=NR)N(R)(R) - C(0)N(R)(R), C(R)=NR, aryl, cyano, cycloalkyl, cycloalkenyl, halo, heterocycloalkyl, heteroaryl, nitro, and oxo; wherein each R is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, and heteroaryl.
The invention further provides a pharmaceutical composition (also referred to as pharmaceutical formulation) comprising a compound of Formula (I) or pharmaceutically acceptable salt, thereof and one or more excipients (also referred to as carriers and/or diluents in the pharmaceutical arts). The excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
"Enantiomerically enriched" refers to products whose enantiomeric excess is greater than zero. For example, 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. "Diasteriomer" refers to a compound having at least two chiral centers.
"Diasteriomer 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" (or "half-lives") 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.
"Oxo" refers to the substituent group =0.
As used herein, the term "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.
Compounds within the invention may occur in two or more tautometric forms; all such tautomeric forms are included within the scope of the invention.
In accordance with another aspect of the invention there is provided 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.
PHARMACEUTICAL COMPOSITIONS
Pharmaceutical compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose. Such 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. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.
Pharmaceutical 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. Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s).
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.
For instance, for oral administration in the form of a tablet or capsule, 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.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. 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,
carboxymethylcellulose, polyethylene glycol, waxes, and the like. 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. 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. As an alternative to granulating, 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.
Where appropriate, 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.
In the present invention, tablets and capsules are preferred for delivery of the pharmaceutical composition.
As used herein, the term "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, suffering from disease conditions 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.
As used herein, 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.
The term "therapeutically 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
administration, and will ultimately be at the discretion of the attending physician or veterinarian. Typically, 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.
COMBINATIONS
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. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
Typically, 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.
Examples of such agents can be found in Cancer Principles and Practice f Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical 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; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors. Non-limiting examples of anti-neoplastic agents are described below.
Examples of a further active ingredient or ingredients for use in combination or co- administered 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. Examples of 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 G2/M phases of the cell cycle. It is believed that the diterpenoids stabilize the β-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-1 ,2a,4,7p,10p, 13a-hexa-hydroxytax-1 1-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. One
mechanism for its activity relates to paclitaxel's capacity to bind tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA, 77:1561 -1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981 ). For a review of synthesis and anticancer activity of some paclitaxel derivatives see: D. G. I.
Kingston et al., Studies in Organic Chemistry vol. 26, entitled "New trends in Natural
Products Chemistry 1986", Attaur-Rahman, P.W. Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.
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., 1 1 1 :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 Guide,. 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-ferf-butyl ester, 13-ester with 5β- 20-epoxy-1 ,2a,4,7p, 10p, 13a-hexahydroxytax-1 1-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. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.
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 (1 :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, is commercially available as PLATINOL® as 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 [1 , 1-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. Examples of 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; and triazenes such as dacarbazine.
Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1 ,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
MYLERAN® TABLETS. 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, 1 ,3-[bis(2-chloroethyl)-1 -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-1 -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. Examples of 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, 1 1 -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.
Doxorubicin, (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-8- glycoloyl, 7, 8, 9, 10-tetrahydro-6, 8, 1 1 -trihydroxy-1 -methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblasts 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 G2 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-p-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-p-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.
Myelosuppression is the most common dose limiting side effect of teniposide. 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. Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
5-fluorouracil, 5-fluoro-2,4- (1 H,3H) pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death. 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.
Myelosuppression and mucositis are dose limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
Cytarabine, 4-amino-1-p-D-arabinofuranosyl-2 (I H)-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, 1 ,7-dihydro-6H-purine-6-thione monohydrate, 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-1 ,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 (β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the G1/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) methyl]methylamino] 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)-10,1 1-ethylenedioxy-20-camptothecin described below.
Irinotecan HCI, (4S)-4, 1 1-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]- 1 H-pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3, 14(4H, 12H)-dione hydrochloride, is commercially available as the injectable solution CAMPTOSAR®.
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 HCI are myelosuppression, including neutropenia, and Gl effects, including diarrhea.
Topotecan HCI, (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 monohydrochloride, 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 HCI is myelosuppression, primarily neutropenia.
Pazopanib which commercially available as VOTRIENT® is a tyrosine kinase inhibitor (TKI). Pazopanib is presented as the hydrochloride salt, with the chemical name 5- [[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide monohydrochloride. Pazoponib is approved for treatment of patients with advanced renal cell carcinoma. Bevacisumab which is commercially available as AVASTIN® is a humanized monoclonal antibody that blocks VEGF-A. AVASTIN® is approved form the treatment of various cancers including colorectal, lung, breast, kidney, and glioblastomas.
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).
Pertuzumab (also called 2C4, trade name Omnitarg) is a monoclonal antibody. The first of its class in a line of agents called "HER dimerization inhibitors". By binding to HER2, it inhibits the dimerization of HER2 with other HER receptors, which is hypothesized to result in slowed tumor growth. Pertuzumab is described in WO01/00245 published January 4, 2001 .
mTOR inhibitors include but are not limited to rapamycin (FK506) and rapalogs, RAD001 or everolimus (Afinitor), CCI-779 or temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687 and Pp121 .
Everolimus is sold as Afinitor® by Novartis and is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers. It has the following chemical structure (formula II) and chemical name:
Figure imgf000038_0001
dihydroxy-12-[(2R)-1-[(1 S,3R,4/?)-4-(2-hydroxyethoxy)-3-m
2-yl]-19,30-dimethoxy-15, 17,21 ,23,29,35-hexamethyl-1 1 ,36-dioxa-4- azatricyclo[30.3.1 .04'9]hexatriaconta-16,24,26,28-tetraene-2,3, 10, 14,20-pentone. 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). The chemical name is 4-[1- (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]-/V-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).
Examples of erbB inhibitors include lapatinib, erlotinib, and gefitinib. Lapatinib, Λ/-(3- chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)- 2-furanyl]-4-quinazolinamine (represented by formula III, as illustrated), is a potent, oral, small-molecule, dual inhibitor of erbB-1 and erbB-2 (EGFR and HER2) tyrosine kinases that is approved in combination with capecitabine for the treatment of HER2-positive metastatic breast cancer.
Figure imgf000039_0001
III
The free base, HCI salts, and ditosylate salts of the compound of formula (III) may be prepared according to the procedures disclosed in WO 99/35146, published July 15, 1999; and WO 02/02552 published January 10, 2002.
Erlotinib, A/-(3-ethynylphenyl)-6,7-bis{[2-(methyloxy)ethyl]oxy}-4-quinazolinamine
Commercially available under the tradename Tarceva) is represented by formula IV, as illustrated:
Figure imgf000039_0002
The free base and HCI salt of erlotinib may be prepared, for example, according to
U.S. 5,747,498, Example 20.
Gefitinib, 4-quinazolinamine,N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4- morpholin)propoxy] is represented by formula V, as illustrated:
Figure imgf000039_0003
V
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, HCI salts, and diHCI salts of gefitinib may be prepared according to the procedures of International Patent Application No.
PCT/GB96/00961 , filed April 23, 1996, and published as WO 96/33980 on October 31 , 1996.
Also of interest, is the camptothecin derivative of formula A following, currently under development, including the racemic mixture (R,S) form as well as the R and S enantiomers:
Figure imgf000040_0001
known by the chemical name "7-(4-methylpiperazino-methylene)-10, 1 1 -ethylenedioxy- 20(R,S)-camptothecin (racemic mixture) or "7-(4-methylpiperazino-methylene)-10, 1 1 - ethylenedioxy-20(R)-camptothecin (R enantiomer) or "7-(4-methylpiperazino-methylene)- 10, 1 1 -ethylenedioxy-20(S)-camptothecin (S enantiomer). Such compound as well as related compounds are described, including methods of making, in U.S. Patent Nos. 6,063,923; 5,342,947; 5,559,235; 5,491 ,237 and pending U.S. patent Application No. 08/977,217 filed November 24, 1997.
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. Examples of 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; progestins 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. Patent Nos. 5,681 ,835, 5,877,219, and 6,207,716, useful in the treatment of hormone dependent breast carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and analogues thereof which stimulate the release of leutinizing hormone (LH) and/or follicle stimulating hormone (FSH) for the treatment prostatic carcinoma, for instance, LHRH agonists and antagagonists such as goserelin acetate and luprolide.
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, myoinositol signaling, and Ras oncogenes.
Several protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such 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. Several inhibitors of growth receptors are under development and 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. Tyrosine kinases, which are not growth factor receptor kinases are termed nonreceptor tyrosine kinases. Non-receptor tyrosine kinases useful in the present invention, which are targets or potential targets of anti-cancer drugs, 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. and Corey, S.J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J.B., Brugge, J.S., (1997 Annual review of
Immunology. 15: 371-404.
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, and TGF beta receptor kinases. Such 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. 1 101 -1 107; 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. 6,268,391 ; and Martinez- lacaci, L, et al, Int. J. Cancer (2000), 88(1 ), 44-52.
Inhibitors of Phosphotidyl inositol-3 Kinase family members including blockers of 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.
Also useful in the present invention are Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues. Such 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. Another group of signal transduction pathway inhibitors are inhibitors of Ras
Oncogene. Such 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.
As mentioned above, 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. For example Imclone C225 EGFR specific antibody (see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4, 269-286); Herceptin® erbB2 antibody (see Tyrosine Kinase Signalling in Breast cancenerbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 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, 51 17-5124.
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. Thus, the combination of an erbB2/EGFR inhibitor with an inhibitor of angiogenesis makes sense. Accordingly, non-receptor tyrosine kinase inhibitors may be used in combination with the EGFR/erbB2 inhibitors of the present invention. For example, anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alphav beta3) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed erb family inhibitors. (See Bruns CJ et al (2000), Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469).
Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of formula (I). There are a number of 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 Reilly 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 (e.g., bcl-2 antisense oligonucleotides) 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. Studies have shown that the epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (i.e., mcl-1 ). Therefore, strategies designed to downregulate the expression of bcl-2 in tumors have demonstrated clinical benefit and are now in Phase ll/lll trials, namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptotic strategies using the antisense oligonucleotide strategy for bcl-2 are discussed in Water JS et al. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et al. (1994,
Antisense Res. Dev. 4: 71-79.
Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle. A family of protein kinases called cyclin dependent kinases CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Several inhibitors of cell cycle signalling are under development. For instance, examples of 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.
In one embodiment, 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. Compound Preparation
The compounds according to Formula I are prepared using conventional organic syntheses. A suitable synthetic route is depicted below in the following general reaction schemes.
The skilled artisan will appreciate that if 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. In some instances, 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. All of the starting materials are commercially available or are readily made from commercially available starting materials by those of skill in the art unless otherwise noted in the experimental section.
Carboxamides Reverse carboxamides
Figure imgf000045_0001
(I) (II)
Abbreviations
Boc, f-butyloxycarbonyl; Boc20, di-t-butyl dicarbonate; DCE, 1 ,2-dichloroethane; DCM, dichloromethane; DIEA, diisopropylethylamine; DMAP, Ν,Ν-dimethylaminopyridine; DME, 1 ,2-dimethoxyethane; DMF, Ν,Ν-dimethyl formamide; EtOAc, ethyl acetate; EtOH, ethanol; HATU, 2-(7-aza-1 H-benzotriazole-1-yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate; HOAc, acetic acid; HOAT, 1-hydroxy-7-azabenzotriazole; LiHMDS, lithium
hexamethyldisilazide; MeOH, methanol; MsCI, methanesulfonyl chloride; NaOfBu, sodium t- butoxide; NMM, N-methyl morpholine; NMP, N-methylpyrrolidine; Pd(dppf)CI2, 1 ,1 '- bis(diphenylphosphino)ferrocene-palladium(ll) dichloride; Pd(PPh3)4,
tetrakis(triphenylphosphine)palladium(0); TEA, triethylamine; TFA, trifluoroacetic acid; THF, tetrahydrofuran. Intermediates
The racemic, Boc-protected aminomethylpyrrolidine A1 can be conveniently prepared from N 1 -benzyl-3-aminomethylpyrrolidine according to Scheme 1 . The Boc-protected or acylated chiral aminomethylpyrrolidines A2 and A3 can be prepared from N-Boc-3-(R or S)- hydroxypyrrolidine according to Scheme 2.
Scheme 1
Figure imgf000046_0001
A1
Conditions: (a) trifluoroacetic anhydride, DCM, 0°; (b) H2, Pd/C, Pd(OH)2, MeOH, HOAc; (c) TEA, Boc20, 0°;
(d) MeOH/NaOH/H20
Scheme 2
Figure imgf000046_0002
A3
Conditions: (a) MsCI, DIEA, DCM; (b) NaCN, DMF, 100°; (c) Raney Ni, H2, EtOH; (d) HCI/dioxane; ROCI, DIEA, CHCI3
The acyl 3-(R or S)-aminomethylpyrrolidine 4-bromobenzamides A4 can be prepared by coupling the Boc-protected aminomethylpyrrolidines A2 with 4-bromobenzoic acid, removal of the Boc group, and then acylation with an acid chloride according to Scheme 3.
Scheme 3
Figure imgf000046_0003
A4 A5
Conditions: (a) COCI2, DCM/DMF; (b) 1 , 1 -dimethylethyl (3S)-3-(aminomet yl)-1-pyrrolidinecarboxylate, DCM, DIEA; (c) HCI/dioxane;
(d) RCOCI, DCM, DIEA, 0°.
Compounds
There are a number of approaches to assembly of the final compounds I. It should be appreciated that either racemic or chiral starting materials can be used in the following examples, and for the purposes of convenience, stereochemistry has beem omitted from the following schemes.
As shown in Scheme 4, commercially available biaryl carboxylic acids may be coupled with Boc-protected aminomethylpyrrolidine A1 or A2 to afford intermediate A6. Alkylation of the amide, deprotection, and acylation of the pyrrolidine amine affords the final product A8.
Scheme 4
Figure imgf000047_0001
Reagents: (a) 1 ,1-dimethylethyl-3(RS or S)-aminomethylpyrrolidine carboxylate, HATU, TEA, DMF; (b) LiHDMS or NaH, THF, then R3I; (c) HCI; (d) R4COCI, TEA, THF.
Alternatively, as shown in Scheme 5, the Boc-protected aminomethylpyrrolidine 4- bromophenylcarboxamide intermediate A4 can be alkylated and then deprotected to afford intermediate A9. This can be acylated to afford A10, which is subjected to Suzuki coupling with an aryl boronic acid or ester to yield the final product A8.
Scheme 5
Figure imgf000047_0002
Reagents: (a) NaH, THF, then R3I; (b) HCI or TFA; (c) R4COCI, DIEA, DMAP, DCM; (d) R-|B(OR)2, Suzuki conditions.
It is also possible to alkylate the protected aminomethylpyrrolidine intermediates A1 or A2 via reductive amination, as shown in Scheme 6. Intermediate A11 can then be acylated with commercially available biaryl carboxylic acids to afford A12. Deprotection and acylation of the pyrrolidine amine affords the final product A8.
Scheme 6
Figure imgf000048_0001
A8
Reagents: (a) aldehyde or ketone, Na(OAc)3BH, DCE; (b) biaryl carboxylic acid, SOCI2, TEA, DCM; (c) HCI or TFA; (d) R4COCI, TEA, THF. It is also possible to acylate intermediate A11 with optionally substituted 4-bromobenzoyl chlorides to afford the the bromophenyl carboxamide A13, as shown in Scheme 7.
Deprotection and acylation of A13 affords intermediate A14, which is subjected to Suzuki coupling with an aryl boronic acid or ester to afford the final product A8.
Scheme 7
Figure imgf000048_0002
Reagents: (a) 4-bromobenzoyl chloride, DIEA, DCM; (b) HCI or TFA; (c) R4COCI, TEA, THF, (d) R1B(OR)2, Suzuki conditions. When R3 is a heterocycle such as 2-pyridine or 2-(1 ,4-pyrazine), the aryl moiety can be introduced on A1 or A2 via palladium-catalyzed coupling with the corresponding 3- chloropyridine or 2-chloro-1 ,4-pyrazine according to Scheme 8. The subsequent steps of acylation with an optionally substituted 4-bromobenzoyl chloride, deprotection, acylation of the pyrrolidine nitrogen and Suzuki coupling proceed as in Scheme 7. Scheme 8
Figure imgf000049_0001
A17 A18
X = C,N
Reagents: (a) 3-chloropyridine or 2-chloro-1 ,4-pyrazine, NaOiBu, Pd(OAc)2, (R)-di-t-butyl-{1(S)-2-
[(dicyclohexylphosphanyl)ferrocenyl]ethyl}phosphine, DME, 100°; (b) 4-bromobenzoyl chloride, DIEA, DCM; (c) HCI or TFA; (d) R COCI, TEA, THF, (e) R-|B(OR)2, Suzuki conditions.
A preparation of the reverse carboxamides II is shown in Scheme 9. Optionally substituted 4- bromoanilines may be acylated with a protected pyrrolidine acetic acid to afford intermediate A19. Deprotection followed by acylation of the pyrrolidine amine affords intermediate A20, which is subjected to Suzuki coupling with an aryl boronic acid or ester to afford the final product A8.
Scheme 9
Figure imgf000050_0001
A8
Reagents: (a) ethyl chloroformate, NMM, THF, 0° to RT; (b) TFA, DCM; (c) R4COCI, TEA, DCM; (d) NaH, DMF, R3I; (e) R.,B(OR Suzuki conditions.
EXAMPLES The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
Intermediate 1
1 ,1 -Dimethylethyl (3 ?S)-3-(aminomethyl)-1 -pyrrolidinecarboxylate
Figure imgf000050_0002
(a) 2,2,2-Trifluoro-N-{[(3 ?S)-1 -(phenylmethyl)-3-pyrrolidinyl]methyl}acetamide
N-benzyl-3(RS)-aminomethylpyrrolidine (160 g) was dissolved in 1.6 L DCM and cooled to 0 °C. Trifluoroacetic anhydride (320 ml.) was slowly added and the reaction mixture was allowed to warm to room temperature and stirred for 12 hr. The reaction mixture was washed with water (2 x 750 mL), brine (2 x 500 mL), dried over sodium sulfate and evaporated under reduced pressure to afford 190 g of the titled compound, which was used without further purification.
(b) 2,2,2-Trifluoro-N-[(3 ?S)-3-pyrrolidinylmethyl]acetamide
2,2,2-Trifluoro-N-[(3RS)-1 -(phenylmethyl)-3-pyrrolidinylmethyl]acetamide (190 g) was dissolved in 2.0 L MeOH. The flask was purged with nitrogen and 10% Pd/C (9.5 g), Pd(OH)2 (9.5 g) and glacial acetic acid (200 mL) were added. The reaction mixture was stirred under a hydrogen atmosphere for 2 days at RT. The reaction mixture was filtered through Celite and evaporated under reduced pressure to afford 200 g of the titled compound containing some residual acetic acid, which was used without further purification.
(c) 1 ,1 -Dimethylethyl (3 ?S)-3-{[(trifluoroacetyl)amino]methyl}-1 -pyrrolidinecarboxylate
2,2,2-Trifluoro-N-[(3RS)-3-pyrrolidinylmethyl]acetamide (200 g) was dissolved in 2 L MeOH and cooled to 0 °C. To this was slowly added TEA (284 mL) and the reaction mixture was allowed to stir at 0 °C for 30 min. Di-t-butyl dicarbonate (220 mL) was then slowly added and the reaction mixture was allowed to warm to RT and stirred for 1 day. The reaction mixture was concentrated and the residue dissolved in 1 .5 L EtOAc. The EtOAc solution was washed with water (2 x 750 mL), brine (1 x 750 mL), dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using 10% EtOAc/90% petroleum ether to afford 150 g of the titled compound.
(d) 1 ,1 -Dimethylethyl (3 ?S)-3-(aminomethyl)-1 -pyrrolidinecarboxylate
1 , 1 -Dimethylethyl (3RS)-3-{[(trifluoroacetyl)amino]methyl}-1 -pyrrolidinecarboxylate (150 g) was dissolved in 1 L MeOH. A 15% aqueous solution of NaOH (150 mL) was then added and the reaction mixture allowed to stir at RT for 3 hr. The reaction mixture was
concentrated and the residue dissolved in 300 mL water. The aqueous solution was acidified by the addition of citric acid and extracted with diethyl ether (2 x 250 mL). The aqueous layer was then made basic by the addition of NaOH and extracted with diethyl ether (2 x 500 mL). These combined ether extracts were dried over sodium sulfate and evaporated under reduced pressure to afford 86 g of the titled compound. Intermediate 2
1 ,1 -Dimethylethyl (3S)-3-(aminomethyl)-1 -pyrrolidinecarboxylate
Figure imgf000052_0001
(a) 1 ,1 -Dimethylethyl (3S)-3-[(methylsulfonyl)oxy]-1 -pyrrolidinecarboxylate
A solution of 1 , 1 -dimethylethyl (3S)-3-hydroxy-1 -pyrrolidinecarboxylate (166 mmol) and N,N- diisopropylethylamine (265 mmol) in dichloromethane (200 ml.) at 0 °C under nitrogen atmosphere was treated with methanesulfonyl chloride (199 mmol) in dichloromethane and allowed to warm to ambient over 1 h. Analysis by LCMS indicated the reaction was complete. The mixture was washed with 1 M hydrochloric acid and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash
chromatography (0-5% methanol/dichloromethane) gave the title product in quantitative yield (166 mmol). 1 H NMR (400 MHz, CDCI3) δ ppm 1 .49 (s, 9 H) 2.08 - 2.21 (m, 1 H) 2.29 (br. s., 1 H) 3.07 (s, 3 H) 3.36 - 3.64 (m, 3 H) 3.65 - 3.75 (m, 1 H) 5.28 (tt, J=4.23, 2.08 Hz, 1 H).
(b) 1 ,1 -Dimethylethyl (3 ?)-3-cyano-1 -pyrrolidinecarboxylate
A mixture of 1 , 1 -dimethylethyl (3S)-3-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate (21 1 mmol) and sodium cyanide (633 mmol) in A/JV-dimethylformamide (300 ml.) was vigorously stirred with a mechanical stirrer while heating at 100 °C under a nitrogen atmosphere for 18 h. The mixture was allowed to cool to ambient temperature, filtered, and washed thoroughly with diethyl ether. The filtrate was diluted with dilute brine and extracted with diethyl ether (4 x 700 ml_). The combined organic extracts were washed with dilute brine, filtered through a pad of sodium sulfate, and concentrated in vacuo. Purification of the residue by flash chromatography (0-50% ethyl acetate/hexanes) gave the title product (141 mmol, 67 % yield). 1H NMR (400 MHz, CDCI3) δ ppm 1 .48 (s, 9 H) 2.14 - 2.37 (m, 2 H) 3.00 - 3.20 (m, 1 H) 3.45 (dt, J=1 1 .05, 6.98 Hz, 1 H) 3.53 - 3.66 (m, 2 H) 3.65 - 3.76 (m, 1 H).
C) 1 ,1 -Dimethylethyl (3S)-3-(aminomethyl)-1 -pyrrolidinecarboxylate
A solution of 1 , 1 -dimethylethyl (3R)-3-cyano-1 -pyrrolidinecarboxylate (73.9 mmol) in ethanol (100 ml.) was added to Raney Nickel (73.9 mmol; 2 scoops of Raney Nickel in water) in a Parr bottle under a stream of nitrogen. The mixture was well flushed with nitrogen then placed on a Parr shaker under hydrogen atmosphere at 60 psi for overnight. The mixture (under N2 stream) was filtered through Celite, washed with a little ethanol, and then the filter cake was immediately doused with water. The ethanol solution was concentrated in vacuo to afford the title product as a clear oil (71.9 mmol, 97 % yield). The product was determined to be a 95:5 ratio of enantiomers (i.e., 90% ee). The use of chiral HPLC (Daicel Chiralpak AD- H column (4.6 x 150 mm) with a mobile phase of heptane:ethanol:isopropylamine
(85:10:0.1 ), a flow rate of 1 .0 mL/min, and UV detection at 215 nm gave a retention time of 4.4 min for the 1 , 1-dimethylethyl (3R)-3-(aminomethyl)-1-pyrrolidinecarboxylate and 4.8 min for the 1 , 1-dimethylethyl (3S)-3-(aminomethyl)-1 -pyrrolidinecarboxylate). 1H NMR (400 MHz, CDCI3) 5 ppm 1.47 (s, 9 H) 1.54 - 1.73 (m, 1 H) 1.91 - 2.13 (m, 1 H) 2.28 - 2.52 (m, 1 H) 2.78 - 2.93 (m, 1 H) 2.95 - 3.16 (m, 1 H) 3.24 - 3.67 (m, 5 H).
Intermediate 3
{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}amine
Figure imgf000053_0001
(a) (3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinecarbonitrile
A solution of 1 , 1-dimethylethyl (3R)-3-cyano-1-pyrrolidinecarboxylate (138 mmol) in ethanol (200 ml.) was treated with 4N HCI in dioxane (480 mmol) and stirred for 2 h. The mixture was concentrated in vacuo to an oil and then azeotroped with ethanol and chloroform. The residue was dissolved in chloroform (300 ml.) and treated with A/JV-diisopropylethylamine (413 mmol) and cooled over an ice bath. The mixture was treated with cyclopropylcarbonyl chloride (165 mmol) in chloroform (100 ml.) and then the ice bath was removed and the mixture stirred for 2 h. The mixture was washed with 1 N hydrochloric acid and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (0-5% MeOH/DCM) gave the titled product (134 mmol, 97 % yield). 1H
NMR (400 MHz, CDCI3) δ ppm 0.73 - 0.91 (m, 2 H) 0.96 - 1.10 (m, 2 H) 1 .47 - 1.81 (m, 1 H) 2.08 - 2.52 (m, 2 H) 3.03 - 3.33 (m, 1 H) 3.48 - 4.13 (m, 4 H).
(b) {[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}amine
A solution of (3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinecarbonitrile (28.3 mmol) in ethanol (300 ml.) and ammonia solution (15 ml_, 28.3 mmol) was flushed with nitrogen and Raney nickel catalyst (1 scoop) was added. The mixture was placed on a Parr shaker and flushed several times with nitrogen and then shaken under a hydrogen atmosphere at 60 psi for 3 h. The mixture was flushed with nitrogen and filtered through Celite under a nitrogen atmosphere (keeping the catalyst wet), and then the filter cake was washed with a little ethanol then immediately doused with water. The filtrate was evaporated to provide the crude product as a clear oil (25.6 mmol, 90 % yield). Analysis by chiral HPLC indicated 75% of the title product, 2.4% of the other enantiomer, and -12% of the bis{[(3S)-1- Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}amine by-product. A sample of {[(3S)-1 - Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}amine (1 .06 g) was purified by chiral HPLC Chiralpak AD 20 μ column (101 x 250 mm) with a mobile phase of
heptane:EtOH:isopropylamine (75:25:0.1 ), a flow rate of 500 mL/min, and UV detection at 220 nm, which gave a retention time of 8.5 min for the {[(3R)-1-Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}amine and 1 1 min for the {[(3S)-1-Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}amine) to afford 720 mg (68% recovery) of chirally (> 99% ee) and chemically pure title compound. 1H NMR (400 MHz, CDCI3) δ ppm 0.69 - 0.83 (m, 2 H) 0.91 - 1.09 (m, 2 H) 1 .28 (br. s., 2 H) 1.52 - 1.82 (m, 2 H) 1.97 - 2.20 (m, 1 H) 2.20 - 2.45 (m, 1 H) 2.67 - 2.98 (m, 2 H) 3.06 - 3.38 (m, 1 H) 3.38 - 3.92 (m, 3 H).
Intermediate 4
1 ,1 -Dimethylethyl (3S)-3-({[(4-bromophenyl)carbonyl]amino}methyl)-1 - pyrrolidinecarboxylate
Figure imgf000054_0001
To a suspension of 4-bromobenzoic acid (3.01 g, 14.97 mmol) in DCM (100 ml) was added oxalyl chloride (6.55 ml, 74.9 mmol) and 1 drop of DMF and the reaction mixture stirred at 25 °C for 2 h at which time C02 evolution had ceased and complete solution had been obtained. The reaction mixture was concentrated to dryness and pumped dry under high vacuum to remove residual oxalyl chloride. The crystalline residue was redissolved in DCM (100 ml), cooled in an ice bath, and treated successively with 1 , 1-dimethylethyl (3S)-3- (aminomethyl)-l-pyrrolidinecarboxylate (3.00 g, 14.97 mmol) and DIEA (7.85 ml, 44.9 mmol). The reaction mixture was stirred for 1 h at ice-bath temperature and then allowed to warm to ambient temperature and stirred overnight. The reaction mixture was concentrated to dryness, dissolved in ether and a fine white solid filtered off. The filtrate was concentrated to dryness and purified on silica gel eluted with 20 to 70% EtOAc/hexanes to give 1 , 1- dimethylethyl (3S)-3-({[(4-bromophenyl)carbonyl]amino}methyl)-1-pyrrolidinecarboxylate
(4.63 g, 12.08 mmol, 81 % yield) as a white foam. 1 H NMR (400 MHz, DMSO-c/6) d ppm 8.64 (d, J=2.84 Hz, 1 H), 7.73 - 7.81 (m, 2 H), 7.63 - 7.69 (m, 2 H), 3.06 - 3.44 (m, 5 H), 2.87 - 3.04 (m, 1 H), 2.30 - 2.46 (m, 1 H), 1.78 - 1.95 (m, 1 H), 1.47 - 1.69 (m, 1 H), 1.36 (s, 9 H). LCMS m/z 384.94 (M+H). Intermediate 5
4-Bromo-N-{[(3S)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}benzamide
Figure imgf000055_0001
(a) 4-Bromo-N-[(3 ?)-3-pyrrolidinylmethyl]benzamide
1 , 1 -Dimethylethyl (3S)-3-({[(4-bromophenyl)carbonyl]amino}methyl)-1 -pyrrolidinecarboxylate (2.47 g, 6.44 mmol) was treated with 4 M HCI/Dioxane (15 ml, 60.0 mmol) at 25 °C.
Complete solution was obtained followed immediately by precipitation of a heavy white solid. The solid was collected by filtration and washed with ether to give the HCI salt of 4-bromo-N- [(3R)-3-pyrrolidinylmethyl]benzamide (2.00 g, 6.26 mmol, 97 % yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d ppm 8.95 (br. s., 2 H), 8.78 (t, J=5.68 Hz, 1 H), 7.78 - 7.83 (d, J=8.61 Hz, 2 H), 7.69 (d, J=8.61 Hz, 2 H), 3.01 - 3.57 (m, 5 H), 2.80 - 2.96 (m, 1 H), 2.50 - 2.60 (m, 1 H), 1.91 - 2.08 (m, 1 H), 1 .65 (m, 1 H). LCMS m/z 284.78 (M+H).
(b) 4-Bromo-N-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}benzamide
4-Bromo-N-[(3R)-3-pyrrolidinylmethyl]benzamide (2 g, 6.26 mmol) was dissolved in DCM (100 ml) with DIEA (3.28 ml, 18.77 mmol) and cooled to 0 °C. Cyclopropanecarbonyl chloride (0.687 g, 6.57 mmol) dissolved in DCM (10 ml) was added slowly to the reaction mixture and stirred at 0 °C for 1 h. The reaction mixture was allowed to warm to ambient temperature and washed twice with water. The organic phase was isolated, dried over MgS04, filtered and concentrated to dryness. The residue was purified by flash
chromatography on an 80 g silica gel column eluted with EtOAc to give 4-bromo-N-{[(3S)-1- Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}benzamide (2.04 g, 5.81 mmol, 93 % yield) as a white foam. LCMS m/z 352.19 (M+H).
Intermediate 6
1 ,1 -Dimethylethyl 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole-1 - carboxylate
Figure imgf000055_0002
(a) 1 ,1 -Dimethylethyl 6-bromo-1 H-indazole-1 -carboxylate
A suspension of 6-bromo-1 /-/-indazole (82.74 mmol), 4-(dimethylamino)pyridine (16.55 mmol), and triethylamine (19.56 ml.) in acetonitrile at 0 °C was treated with bis(1 , 1 - dimethylethyl) dicarbonate (82.74 mmol) in acetonitrile over 15 min such that the internal temperature remained at 5 °C. The reaction mixture was warmed to room temperature and stirred for 18 h. The reaction was concentrated in vacuo and the residue purified by flash chromatography (7% ethyl acetate/petroleum ether) to afford the title product as a solid (23.2 g, 94%).
(b) 1 ,1 -Dimethylethyl 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole-1 - carboxylate
To a solution of 1 , 1 -dimethylethyl 6-bromo-1 H-indazole-1 -carboxylate (10.1 mmol) in dioxane (60 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (1 1 .1 mmol), potassium acetate (30.3 mmol), triethylamine (1 .5 mL), palladium(ll) acetate (1 .01 mmol), and 1 ,1 '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (1.01 mmol). The reaction mixture was stirred at 1 10 °C overnight and then concentrated in vacuo. The residue was purified by flash chromatography (5-10% ethyl acetate/petroleum ether) to yield the title product as a solid (1 .61 g, 46%).
Intermediate 7
1 ,1 -Dimethylethyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole-1 - carboxylate
Figure imgf000056_0001
(a) 1 ,1 -Dimethylethyl 5-bromo-1 H-indazole-1 -carboxylate
Following the procedure described for Intermediate 6(a) with 5-bromo-1 H-indazole provided the title compound.
(b) 1 ,1 -Dimethylethyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole-1 - carboxylate
Following the procedure described for Intermediate 6(b) with 1 , 1-dimethylethyl 5-bromo-1 H- indazole-1 -carboxylate and purification by flash chromatography using 5% ethyl
acetate/petroleum ether gave the title product as a yellow solid (74%). Intermediate 8
Figure imgf000057_0001
1 ,1 -Dimethylethyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole-1 - carboxylate
(a) 1 ,1 -Dimethylethyl 5-bromo-1 H-indole-1 -carboxylate
5-Bromoindole (20 g) and DMAP (1 g) were dissolved in DCM (200 ml.) and cooled to 0 °C. To this was added di-t-butyl dicarbonate (29 g) in portions. The reaction was allowed to warm to room temperature and was stirred at RT for 16 hrs. The reaction mixture was diluted with water and the organic layer was separated. The aqueous layer was extracted once with DCM and the combined organic layers were dried and evaporated to dryness. The crude product was purified by flash chromatography on silica to afford 27 g of the titled compound.
(b) 1 ,1 -Dimethylethyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole-1 - carboxylate
To a solution of 1 , 1 -dimethylethyl 5-bromo-1 H-indole-1 -carboxylate (3 g) in 1 ,4-dioxane (50 mL) were added 4 ,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (2.841 g), potassium acetate (7.994 g) and TEA (2 mL). Pd(OAc)2 (228 mg) and Pd(dppf)CI2 (745 mg) were added under nitrogen and the reaction mixture was stirred under reflux (1 10 °C) overnight. The reaction mixture was washed with water three times and with saturated brine and dried over sodium sulfate. Solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (petroleum ether / EtOAc 100:1 ) to afford 1.61 g of the titled compound.
Intermediate 9
Figure imgf000057_0002
1 ,1 -Dimethylethyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazole-1 - carboxylate
To a solution of 1 , 1 -dimethylethyl 5-bromo-1 /-/-benzimidazole-1 -carboxylate (3.02 g) in 1 ,4- dioxane (50 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (2.837 g), potassium acetate (7.978 g) and TEA (2 mL). Pd(OAc)2 (227 mg) and Pd(dppf)CI2 (743 mg) were added under nitrogen and the reaction mixture was stirred under reflux (1 10 °C) overnight. The reaction mixture was washed with water three times and with saturated brine and dried over sodium sulfate. Solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (petroleum ether / EtOAc 8:1 ) to afford 1.47 g of the titled compound.
Intermediate 10
Figure imgf000058_0001
7-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline
(a) 7-Quinolinyl trifluoromethanesulfonate
To a cold (0 °C) suspension of 7-quinolinol (5.18 g) in DCM (100 mL) was added pyridine (3.75 mL) followed by dropwise addition of triflic anhydride (6.63 mL) over 5 minutes. After 5 minutes at 0 °C, the reaction was allowed to warm to room temperature. After 1 .5 hours the reaction was quenched with water and the organic layer was washed with brine followed by saturated aqueous NaHC03. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in 35% EtOAc in hexanes and DCM (needed for solubility) and purified by silica gel flash chromatography eluting with 40% EtOAc/ hexanes. The appropriate fractions were concentrated under reduced pressure. The resulting orange tacky solid was dissolved in boiling 10% EtOAc in hexanes. The mixture was allowed to cool to room temperature, scratched to initiate crystallization and allowed to stand on dry ice for -30 min. The solid was collected by filtration to afford 5.18 g of the titled compound. LCMS m/z 277.8 (M+H).
(b) 7-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline
A sealable reaction flask was charged with 7-quinolinyl trifluoromethanesulfonate (5.17 g, bis(pinacolato)diboron (4.74 g), Pd(dppf)CI2 (0.682 g), 1 , 1 '-bis(diphenylphosphino)ferrocene (0.517 g), potassium acetate (5.49 g) and 1 ,4-dioxane (100 mL). The flask was purged with nitrogen, sealed and heated to 100 °C. After 2 hours, the reaction was allowed to cool to room temperature and diluted with EtOAc. The mixture was filtered through a pad of Celite^ rinsing with EtOAc, and the filtrate was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 40-50%
EtOAc/hexanes. The appropriate fractions were concentrated under reduced pressure and dried to constant weight over 36 hours to provide 4.34 g of the titled compound as an off- white solid. LCMS m/z 174.0 (M+H).
Example 1
A -{[(3 ?S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A -methyl-4- biphenylcarboxamide
(a) 4-Biphenylcarboxylic acid
Methyl 4-biphenylcarboxylate (1.0 g, 4.71 mmol) was diluted with THF (6 ml_), water (8 ml.) and NaOH (47.13 mmol), then stirred for 12 h. The pH was adjusted to 1 with NaHS04 and the reaction diluted with brine. The product was extracted with ethyl acetate. The combined organic extracts were dried over MgS04, filtered, concentrated and dried under hi-vacuum to afford the titled compound as white solids (971 mg, 104%). LCMS m/z 197 (M-H).
(b) 1 ,1 -Dimethylethyl 3-{[(4-biphenylylcarbonyl)amino]methyl}-1 - pyrrolidinecarboxylate
4-Biphenylcarboxylic acid (971 mg, 4.9 mmol), 1 , 1-dimethylethyl-3(RS)-(aminomethyl)-1 - pyrrolidinecarboxylate (1.18 g, 5.88 mmol), HATU (2.23g, 5.88 mmol) and triethylamine (819 uL, 5.88 mmol) were combined in DMF and stirred for 12 h. The reaction was diluted 20X with water, the pH adjusted to 2 and the product extracted with ethyl acetate. The combined organic extracts were dried over MgS04, filtered and concentrated to gold solids. The solids were washed with dichloromethane and the filtrate collected. The filtrate was concentrated and subjected to flash chromatography (40 g Si02, 0-100% EtOAc/hexane), to afford the titled compound as a white solid (1 .16g, 62% yield). LCMS m/z 379 (M-H), 1H NMR (DMSO- d6) : 8.64 (br. s., OH), 7.95 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 1 H), 7.68-7.75 (m, 1 H), 7.46-7.53 (m, 1 H), 7.36-7.45 (m, OH), 3.15 - 3.49 (m, 5H), 2.93-3.08 (m, 1 H), 2.38-2.48 (m, 1 H), 1 .83-1.98 (m, 1 H), 1.54-1 .72 (m, 1 H), 1 .39 (s, 9H).
(c) A -Methyl-A -(3( ?S)-pyrrolidinylmethyl)-4-biphenylcarboxamide
1 , 1 -Dimethylethyl 3(RS)-{[(4-biphenylylcarbonyl)amino]methyl}-1 -pyrrolidinecarboxylate (55 mg, 0.141 mmol) was dissolved in anhydrous THF (1 mL). To this was added 1.0 M lithium bis(trimethylsilyl)amide (173 uL, 0.17 3mmol). After 5 minutes iodomethane (1 1 uL, 0.173 mmol) was added and the reaction stirred for 18 h. The Boc group was removed without workup by directly adding 500 uL of concentrated HCI to the reaction solution. After 5 minutes the reaction was diluted with brine and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 9 and the product extracted with dichloromethane. The combined organic extracts were dried over MgS04, filtered and concentrated to afford the titled compound as an orange oil (41 mg, 97% yield). LCMS m/z 295 (M+H).
(d) A -{[(3 ?S)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-A -methyl-4- biphenylcarboxamide
A/-Methyl-/\/-(3(/?S)-pyrrolidinylmethyl)-4-biphenylcarboxamide (41 mg, 0.139 mmol), triethylamine (29 uL, 0.208 mmol) and cyclopropanecarbonyl chloride (19 uL, 0.208 mmol) were combined in anhydrous THF (1 mL) and stirred for 3d. The reaction was concentrated and purified by reverse phase preparative HPLC (1 -99% 0.1 %TFA-CH3CN/0.1 %TFA-H2O over 4 minutes). The appropriate fractions were concentrated on a Genevac to afford the titled compound as a light yellow oil (23 mg, 44%). LCMS m/z 363 (M+H); 1H NMR (DMSO- d6) : 7.68-7.77 (m, 4H), 7.35-7.55 (m, 5H), 2.98 (s, 3H), 2.54-3.89 (m., 7H), 1 .21 -2.21 (m, 3H), 0.72 (br. s., 4H).
Example 2
A -{[1 -Cyclopropylcarbonyl)-3( ?S)^yrrolidinyl]methyl}-3-methyloxy-A -methyl-4- biphenylcarboxamide
(a) 3-(Methyloxy)-4-biphenylcarboxylic acid
Methyl 4-bromo-2-(methyloxy)benzoate ( 845 mg, 3.45 mmol) was dissolved in DMF and the solution sparged with N2 for 5 minutes. Next, Pd(PPh3)4 (398 mg, 0.345 mmol) was added and the suspension sparged with N2 for an additional 10 minutes. Phenylboronic acid (589 mg, 4.83 mmol) and Na2C03 (731 mg, 6.9 mmol), dissolved in water, were added to the reaction and the suspension allowed to stir for 3d at 80 C. After cooling to room temperature the reaction was diluted with water, brine (50 mL) and the product extracted with ethyl acetate. The organic extracts were filtered through a plug of celite and concentrated under vacuum to a yellow oil. The oil was dissolved in equal parts THF/water and sodium hydroxide (1.8 mL, 50%) was added to hydrolyze the methyl ester. After stirring for 18 h the reaction was diluted with brine and the pH adjusted to 2. The product was extracted with ethyl acetate, the combined organic extracts were dried over MgS04, filtered, concentrated under vacuum and dried under hi-vacuum to afford the titled compound as a brown oil. LCMS m/z 227 (M-H). (b) 1 ,1 -Dimethylethyl 3( ?S)-[({[3-(methyloxy)-4-biphenylyl]carbonyl}amino)methyl]-1 - pyrrolidinecarboxylate
3-(Methyloxy)-4-biphenylcarboxylic acid (400 mg, 1 .75 mmol), 1 , 1 -dimethylethyl 3{RS)- (aminomethyl)-l -pyrrolidinecarboxylate (386 mg, 1 .93 mmol), HATU (733 mg, 1 .93 mmol) and triethylamine (365 uL, 2.63 mmol) were combined in DMF and stirred for 18h. The reaction was diluted 20X with water and the product extracted with ethyl acetate. The combined organic extracts were dried over MgS04, filtered and concentrated to a yellow oil. The product was isolated by reverse phase preparative HPLC (25-99% 0.1 %TFA- CH3CN/0.1 %TFA-H2O over 4 minutes). The appropriate fractions were diluted 20X with brine and the product was extracted with ethyl acetate. The combined organic extracts were dried over MgS04, filtered, concentrated under vacuum and dried under hi-vacuum to provide the titled compound as an oil (259mg, 36% yield). 1 H NMR Chloroform-d) d: 8.22 (d, J = 8.1 Hz, 1 H), 8.12 (br. s., 1 H), 7.57-7.65 (m, 2H), 7.43-7.51 (m, 2H), 7.37-7.43 (m, 1 H), 7.31 (dd, J = 8.1 , 1 .5 Hz, 1 H), 7.16 (d, J = 1 .4 Hz, 1 H), 4.05 (s, 3H), 3.25-3.74 (m, 5H), 3.12 (br. s., 1 H), 2.44-2.67 (m, 1 H), 1 .99-2.16 (m, 1 H), 1 .69 (dd, J = 12.3, 8.3 Hz, 1 H), 1 .46 (s, 9H).
(c) A -Methyl-3-(methyloxy)-A -(3( ?S)-pyrrolidinylmethyl)-4-biphenylcarboxamide
To a solution of 1 , 1 -dimethylethyl 3(RS)-[({[3-(methyloxy)-4- biphenylyl]carbonyl}amino)methyl]-1 -pyrrolidinecarboxylate (259 mg, 0.632 mmol) in anhydrous THF (2 mL), 1 .0 M lithium bis(trimethylsilyl)amide (758 uL, 0.758 mmol) was added. After 10 minutes iodomethane (47 uL, 0.758 mmol) was added and the reaction stirred for 18 h. The reaction was diluted with methanol and 1 .2 mL of concentrated HCI was added to remove the Boc group. After 10 minutes the reaction was diluted with water and washed with ethyl acetate. The pH was then adjusted to 7 and the product extracted with ethyl acetate. The combined organic extracts were dried over MgS04, filtered, concentrated under vacuum and dried under hi-vacuum to provide the titled compound as an oil (131 mg, 64% yield). LCMS m/z 325 (M+H).
(d) A -{[1 -Cyclopropylcarbonyl)-3( ?S)^yrrolidinyl]methyl}-A -methyl-3-(methyloxy)-4- biphenylcarboxamide
A solution of /\/-methyl-3-(methyloxy)-/\/-(3(RS)-pyrrolidinylmethyl)-4-biphenylcarboxamide (131 mg, 0.404 mmol) and triethylamine (1 12 uL, 0.808 mmol) in anhydrous THF (6 mL) was prepared. To this was added cyclopropanecarbonyl chloride (55 uL, 0.606 mmol), followed by an additional equivalent of triethylamine (61 uL, 0.404 mmol). After 15 minutes the reaction was diluted with water and the product extracted with ethyl acetate. The organic extracts were dried over MgS04, filtered and concentrated under hi-vacuum. The product was purified by reverse phase preparative HPLC (25-99% 0.1 %TFA-CH3CN/0.1 %TFA-H2O over 4 minutes). The appropriate fractions were diluted 20X with brine and the product extracted with ethyl acetate. The combined organic extracts were dried over MgS04, filtered, concentrated under vacuum and dried under hi-vacuum to provide the titled compound as an oil. LCMS m/z 393 (M+H); 1H NMR Chloroform-d) d: 7.53-7.62 (m, 2H), 7.34-7.50 (m, 3H), 7.27-7.32 (m, 1 H), 7.20 (br. s., 1 H), 7.10 (s, 1 H), 3.86-4.04 (m, 3H), 3.64- 3.87 (m, 2H), 3.23-3.62 (m, 2H), 3.12-3.22 (m, 1 H), 2.87-3.02 (m, 3H), 2.73 (br. s., 1 H), 1.92-2.30 (m, 2H), 1.65 (d, J = 7.7 Hz, 2H), 1 .06 (d, J = 3.5 Hz, 2H), 0.83 (br. s., 2H).
Example 3
A -{[1 -Cyclopropylcarbonyl)-3( ?S)-pyrrolidinyl]methyl}-3-hydroxy-A -methyl-4- biphenylcarboxamide
A solution of /\/-{[1 -Cyclopropylcarbonyl)-3(RS)-pyrrolidinyl]methyl}-/\/-methyl-3-(methyloxy)- 4-biphenylcarboxamide (140 mg, 0.357 mmol) in anhydrous dichloromethane was prepared and cooled to -78 °C. To this was added 1 .0 M BBr3 (714 uL, 0.714 mmol) dropwise. After stirring for 5 minutes the reaction was removed from the cooling bath and allowed to warm to room temperature. After 2 h the reaction was quenched with methanol and concentrated under vacuum. The product was purified by reverse phase preparative HPLC (10-99% 0.1 %TFA-CH3CN/0.1 %TFA-H2O over 4 minutes). The appropriate fractions were
concentrated on a Genevac and dried under hi-vacuum to provide the titled compound as a white foam (57 mg, 41 % yield). LCMS m/z 377 (M-1 ) 379 (M+H); 1H NMR Chloroform-d) d: 7.55-7.63 (m, 3H), 7.41 -7.48 (m, 3H), 7.32-7.40 (m, 2H), 7.09 (dd, J = 8.1 , 1 .8 Hz, 1 H), 3.64- 3.85 (m, 3H), 3.55 (br. s., 2H), 3.27-3.38 (m, 1 H), 3.24 (s, 3H), 2.70 (br. s., 1 H), 2.09 (br. s., 1 H), 1 .75 (br. s., 1 H), 1 .49 - 1 .64 (m, 1 H), 0.99 (dd, J = 7.6, 4.5 Hz, 2H), 0.75 (dd, J = 7.9, 3.2 Hz, 2H).
Example 4
W-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-6-yl)-W- methylbenzamide
(a) 1 ,1 -Dimethylethyl (3S)-3-{[[(4-bromophenyl)carbonyl](methyl)amino]methyl}-1 - pyrrolidinecarboxylate
1 , 1 -Dimethylethyl (3S)-3-({[(4-bromophenyl)carbonyl]amino}methyl)-1 -pyrrolidinecarboxylate (7 g) was dissolved in THF (150 ml_). To this was added NaH (60% dispersion, 1.1 g) and the reaction mixture was stirred under nitrogen for 30 min. Methyl iodide (3.9 g) was then added slowly and the reaction mixture allowed to stir at RT overnight. The reaction mixture was cooled in an ice bath and quenched by the careful addition of water. The THF was removed under reduced pressure and the residue was extracted three times with EtOAc. The combined EtOAc extracts were washed with saturated brine, dried over sodium sulfate and evaporated to dryness to afford the titled compound (7 g), which was used without further purification.
(b) 4-Bromo-N-methyl-N-[(3 ?)-3-pyrrolidinylmethyl]benzamide hydrochloride salt To a solution of 1 , 1 -dimethylethyl (3S)-3-{[[(4-bromophenyl)carbonyl](methyl)amino]methyl}- 1-pyrrolidinecarboxylate (7 g) in MeOH was added HCI/MeOH (90 ml.) and the reaction mixture was stirred at RT for 1 hr. Solvent was removed under reduced pressure to afford 5 g of the titled product, which was used without further characterization.
(c) 4-Bromo-A -{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A - methylbenzamide
To a suspension of 4-bromo-N-methyl-N-[(3R)-3-pyrrolidinylmethyl]benzamide hydrochloride salt (5 g) in DCM (150 mL) was added DIEA (3.13 g) and DMAP (0.18 g). Once the starting material had gone into solution, cyclopropylcarbonyl chloride (2.4 g) was slowly added and the reaction mixture was stirred at RT for 1 hr. Water was added and the organic layer was separated. The aqueous layer was extracted twice with DCM and the combined DCM extracts were washed with saturated brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel column chromatography using petroleum ether/EtOAc 1 :2 as eluant to afford 3.6 g of the titled compound.
(d) A -{[(3S)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4-(1H-indol-6-yl)-A - methylbenzamide
To a solution of 4-bromo-N-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-N- methylbenzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 6-indolylboronic acid pinacol ester (90.2 mg) and K2C03 (171 .1 mg in 2 mL water) and the reaction mixture was stirred at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 67 mg of the titled compound. LCMS m/z 402.2 (M+H).
Example 5
A -{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A -methyl-4'-(methyloxy)-4- biphenylcarboxamide
To a solution of 4-bromo-N-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-N- methylbenzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 4-methoxyphenylboronic acid (56.4 mg) and K2C03 (171.4 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 53 mg of the titled compound. LCMS m/z 393.1 (M+H).
Example 6
3'-Chloro-A -{[(3S)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4'-fluoro-A -methyl-4- biphenylcarboxamide
To a solution of 4-bromo-N-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-N- methylbenzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 3-chloro-4-fluorophenylboronic acid (64.6 mg) and K2C03 (171 .1 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 108 mg of the titled compound. LCMS m/z 415.2 (M+H).
Example 7
A -{[(3S)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4-(1 H-indol-5-yl)-W- methylbenzamide
To a solution of 4-bromo-N-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-N- methylbenzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 5-indolylboronic acid pinacol ester (127.3 mg) and K2C03 (171.1 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 93 mg of the titled compound. LCMS m/z 402.2 (M+H). Example 8
A -{[(3S)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4-(1 H-indazol-5-yl)-A - methylbenzamide
To a solution of 4-bromo-N-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-N- methylbenzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 1 ,1 -dimethylethyl 5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole-1-carboxylate (127.7 mg) and K2C03 (171 .1 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 74 mg of the titled compound. LCMS m/z 403.2 (M+H).
Example 9
W-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indazol-6-yl)-W- methylbenzamide
To a solution of 4-bromo-N-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-N- methylbenzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 1 ,1 -dimethylethyl 6-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole-1-carboxylate (127.7 mg) and K2C03 (171 .1 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf) Cl2
(100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 73 mg of the titled compound. LCMS m/z 403.1 (M+H).
Example 10
4-(1 -Benzofuran-5-yl)-A -{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A - methylbenzamide
To a solution of 4-bromo-N-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-N- methylbenzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1-benzofuran (90.5 mg) and K2C03 (171 .1 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 82 mg of the titled compound. LCMS m/z 403.2 (M+H).
Example 11
4-(1H^enzimidazol-5-yl)-A -{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A - methylbenzamide
To a solution of 4-bromo-N-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-N- methylbenzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 1 H-benzimidazole-5-boronic acid pinacol ester (127.7 mg) and K2C03 (171 .1 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 63 mg of the titled compound. LCMS m/z 403.2 (M+H).
Example 12
A -{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-4-yl)-W- methylbenzamide
To a solution of 4-bromo-N-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-N- methylbenzamide (150 mg) in 1 ,4-dioxane (4 mL) was added indole-4-boronic acid pinacol ester (90.2 mg) and K2C03 (171 .1 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 33 mg of the titled compound. LCMS m/z 402.1 (M+H).
Example 13
W-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-7-yl)-W- methylbenzamide
To a solution of 4-bromo-N-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-N- methylbenzamide (150 mg) in 1 ,4-dioxane (4 mL) was added indole-7-boronic acid pinacol ester (90.2 mg) and K2C03 (171 .1 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 83 mg of the titled compound. LCMS m/z 402.2 (M+H).
Example 14
w-{[(3S)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-2-fluoro-4-(1 H-indol-5-yl)-A ^ methyl benzamide
(a) 1 ,1 -Dimethylethyl (3S)-3-({[(4-bromo-2-fluorophenyl)carbonyl]amino}methyl)-1 - pyrrolidinecarboxylate
To a mixture of 4-bromo-2-fluorobenzoic acid (200mg), HOAT (24.86 mg) and 1 , 1- dimethylethyl (3S)-3-(aminomethyl)-1 -pyrrolidinecarboxylate (183 mg) in DCM (5 mL) was added EDC (210 mg). The reaction was stirred at RT for 16 hours. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc. The combined EtOAc extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 400 mg of the titled compound, which was used without further purification. LCMS m/z 400.9 (M+H).
(b) 1 ,1 -Dimethylethyl (3S)-3-{[[(4-bromo-2- fluorophenyl)carbonyl](methyl)amino]methyl}-1 -pyrrolidinecarboxylate
A solution of 1 , 1-dimethylethyl (3S)-3-({[(4-bromo-2-fluorophenyl)carbonyl]amino}methyl)-1- pyrrolidinecarboxylate (400 mg) in anhydrous THF (6 mL) at 0 °C was treated portionwise with sodium hydride (60% dispersion in oil, 59.8 mg), allowed to warm to RT and stirred for 30 min. The reaction mixture treated with iodomethane (0.187 mL) in one portion and stirred for 18 hours. The reaction mixture was quenched with 5% aqueous citric acid and extracted with EtOAc. The extracts were combined, washed with aqueous citric acid, saturatedd sodium bicarbonate and saturated brine, dried over sodium sulfate and concentrated in vacuo to yield crude 380 mg of the titled compound, which was used without further purification. LCMS m/z 415.1 (M+H).
(c) 4-Bromo-2-fluoro-N-methyl-N-[(3 ?)-3-pyrrolidinylmethyl]benzamide hydrochloride
To a mixture of 1 , 1-dimethylethyl (3S)-3-{[[(4-bromo-2- fluorophenyl)carbonyl](methyl)amino]methyl}-1 -pyrrolidinecarboxylate (452 mg,) in 1 ,4- dioxane (6mL) was added 4N HCI in dioxane (2mL). The resulting slurry was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure and dried to constant weight under high vacuum to yield 340 mg of the titled compound, which was used without further purification. LCMS m/z 314.9 (M+H).
(d) 4-Bromo-N-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-fluoro-N- methylbenzamide
To a solution of 4-bromo-2-fluoro-N-methyl-N-[(3R)-3-pyrrolidinylmethyl]benzamide hydrochloride (1 .5 g) in DCM (10 mL) was added DIEA (2.494 mL) at RT. The reaction mixture was stirred for 5 minutes at RT and then cyclopropylcarbonyl chloride (0.523 mL) was added in one portion. The reaction was stirred at RT for 16 hr, then washed with water, 1 N aqueous NaHC03, and saturated brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield 300 mg of the titled compound, which was used without further purification. LCMS m/z 383.1 (M+H).
(e) W-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-fluoro-4-(1 H-indol-5-yl)-W- methylbenzamide
To a solution of 4-bromo-/V-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-fluoro-/\/- methylbenzamide (100 mg) in 1 ,4-dioxane (6 mL) was added 5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-indole (67.4 mg), Pd(dppf)CI2-CH2CI2 adduct (10.65 mg) and 2 M aqueous potassium carbonate (0.261 mL). This mixture was stirred at 100 °C under nitrogen overnight. The reaction mixture was allowed to cool to RT and was diluted with water and acidified to pH of 4 with 1 N HCI, then extracted with DCM (3 x 50mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 53.6 mg of the titled compound. LCMS m/z 420.2 (M+H).
Example 15
4-(1 -Benzofuran-5-yl)-A -{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-fluoro- W-methylbenzamide
To a solution of 4-bromo-/V-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-fluoro-/\/- methylbenzamide (100 mg) in 1 ,4-dioxane (6 mL) was added 5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 -benzofuran (67.6 mg), Pd(dppf)CI2-CH2CI2 adduct (10.65 mg) and 2 M aqueous potassium carbonate (0.261 mL). This mixture was stirred at 100 °C under nitrogen overnight. The reaction mixture was allowed to cool to RT and was then diluted with water and acidified to pH of 4 with 1 N HCI and extracted with DCM (3 x 50mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative reverse phase HPLC to yield 18 mg of the titled compound. LCMS m/z 421.1 (M+H). Example 16
w-{[(3S)-1 -Cyclopropylcarbonyl)-3^yrroN
methyl benzamide
To a solution of 4-bromo-/V-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-fluoro-/\/- methylbenzamide (250 mg) in 1 ,4-dioxane (6 mL) was added 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-indole (159 mg), Pd(dppf)CI2-CH2CI2 adduct (26.6 mg) and 2 M aqueous potassium carbonate (0.652 mL). This mixture was stirred at 100 °C under nitrogen overnight. The reaction mixture was allowed to cool to RT and then was diluted with water and acidified to pH of 4 with 1 N HCI and extracted with DCM (3 x 50mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative reverse phase HPLC to afford 39.5 mg of the titled compound. LCMS m/z 420.2 (M+H).
Example 17
4'-Cyano-A -{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-3-fluoro-A -methyl-4- biphenylcarboxamide
4-Cyanophenylboronic acid (42.2 mg) and Pd(dppf)CI2-CH2Cl2 adduct (10.65 mg) were added to a 5 mL microwave vial. To this was added 4-bromo-/V-{[(3S)-1- Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-fluoro-/\/-methylbenzamide (100 mg) in 1 ,4- dioxane (2.5 mL) followed by 2 M aqueous potassium carbonate (0.287 mL). The vial was purged with nitrogen, sealed and heated in a microwave reactor at 130 °C for 20 min. The reaction mixture was filtered, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N aqueous NaHC03 and saturated brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 10.2 mg of the titled compound. LCMS m/z 406.3 (M+H).
Example 18
A -{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-3-fluoro-A -methyl-4'- (methyloxy)-4-biphenylcarboxamide
4-Methoxyphenylboronic acid (47.4 mg) and Pd(dppf)CI2-CH2CI2 adduct (10.65 mg) were added to a 5 mL microwave vial. To this was added 4-bromo-N-{[(3S)-1-
Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-fluoro-N-methylbenzamide (100 mg) in 1 ,4- dioxane (2.5 mL) followed by 2 M aqueous potassium carbonate (0.287 mL). The vial was purged with nitrogen, sealed and heated in a microwave reactor at 130 °C for 20 min. The reaction mixture filtered, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N aqueous NaHC03 and saturated brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 45 mg of the titled compound. LCMS m/z 41 1.4 (M+H).
Example 19
4-(1 -Benzofuran-5-yl)-A -{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A ,2- dimethylbenzamide
(a) 1 ,1 -Dimethylethyl (3S)-3-({[(4-bromo-2-methylphenyl)carbonyl]amino}methyl)-1 - pyrrolidinecarboxylate
To a mixture of 4-bromo-2-methylbenzoic acid (2g), HOAT (0.253 g) and 1 , 1 -dimethylethyl (3S)-3-(aminomethyl)-1 -pyrrolidinecarboxylate (1 .86g) in DCM (5 ml.) was added EDC (2.139 g). The reaction was stirred at RT for 16 hr. The reaction mixture was diluted with water (150 ml.) and extracted with EtOAc. The combined EtOAc extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3.39 g of the titled compound, which was used without further purification. LCMS m/z 396.8 (M+H).
(b) 1 ,1 -Dimethylethyl (3S)-3-{[[(4-bromo-2- methylphenyl)carbonyl](methyl)amino]methyl}-1 -pyrrolidinecarboxylate
A solution of 1 , 1 -dimethylethyl (3S)-3-({[(4-bromo-2-methylphenyl)carbonyl]amino}methyl)-1- pyrrolidinecarboxylate ( (3.39 g) in anhydrous THF (6 ml.) at 0 °C was treated portionwise with sodium hydride (60% dispersion in oil, 0.512 g). The reaction mixture was allowed to warm to RT and stirred 30 min. The reaction mixture was then treated with iodomethane (1 .597 ml.) in one portion and stirred at RT for 18 hours. The reaction was quenched with 5% aqueous citric acid and extracted with EtOAc. The extracts were combined, washed with aqueous citric acid, saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate and concentrated in vacuo to afford 3.1 g of the titled compound, which was used without further purification. LCMS m/z 41 1 .3 (M+H).
(c) 4-Bromo-A ,2-dimethyl-A -[(3 ?)-3-pyrrolidinylmethyl]benzamide hydrochloride
To a mixture of 1 , 1 -dimethylethyl (3S)-3-{[[(4-bromo-2- methylphenyl)carbonyl](methyl)amino]methyl}-1 -pyrrolidinecarboxylate (3 g) in 1 ,4-dioxane (10 mL) was added 4 N HCI/dioxane (2.2 mL). The resulting slurry was stirred at room temperature fori 6 hr. The reaction mixture was concentrated under reduced pressure and dried to constant weight under high vacuum to yield 1.98 g of the titled compound, which was used without further purification. LCMS m/z 31 1 .1 (M+H). (d) 4-Bromo-A -{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A ,2- dimethylbenzamide
4- Bromo-/V,2-dimethyl-/V-[(3R)-3-pyrrolidinylmethyl]benzamide hydrochloride (2.8 g,) was dissolved in DCM (4 mL). DIEA (3.14 mL) was added and the solution was cooled to 0 °C. Cyclopropylcarbonyl chloride (0.824 mL) was dissolved in DCM (4 mL) and added dropwise to the cold reaction mixture. The ice bath was removed and the reaction allowed to warm to RT and stirred for 16 hr. The reaction mixture was washed with 1 N aqueous NaHC03, water, 1 N aqueous HCI and saturated brine, dried over sodium sulfate and evaporated to dryness to afford 3.0 g of the titled compound, which was used without further purification. LCMS m/z 379.2 (M+H).
(e) 4-(1 -Benzofuran-5-yl)-/V-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A ,2- dimethylbenzamide
5- (4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1-benzofuran (88 mg) and Pd(dppf)CI2- CH2CI2 adduct (13.46 mg) were added to a 5 mL microwave vial. To this was added 4- bromo-/V-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/,2-dimethylbenzamide (125 mg) in 1 ,4-dioxane (2.5 mL) followed by 2 M aqueous potassium carbonate (0.363 mL). The vial was purged with nitrogen, sealed and heated in the microwave reactor at 130 °C for 20 min.The reaction mixture filtered, diluted with water and extracted with EtOAc. The combined organic extracts were washed with 1 N aqueous NaHC03 and saturated brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 80 mg of the titled compound. LCMS m/z 417.2 (M+H).
Example 20
A -{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-5-yl)-A ,2- dimethylbenzamide
5-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole (88 mg) and Pd(dppf)CI2-CH2CI2 adduct (13.46 mg) were added to a 5 mL microwave vial. To this was added 4-bromo-/V- {[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/,2-dimethylbenzamide (125 mg) in 1 ,4- dioxane (2.5 mL) followed by 2 M aqueous potassium carbonate (0.363 mL). The vial was purged with nitrogen, sealed and heated in a microwave reactor at 130 °C for 20 min. The reaction mixture filtered, diluted with water and extracted with EtOAc. The combined organic extracts were washed with 1 N aqueous NaHC03 and saturated brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 39.6 mg of the titled compound. LCMS m/z 416.2 (M+H). Example 21
4'-Cyano-A -{[(3S)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-A ,3-dimethyl-4- biphenylcarboxamide
4-Cyanophenylboronic acid (63.9 mg) and Pd(dppf)CI2-CH2Cl2 adduct (16.15 mg) were added to a 5 ml. microwave vial. To this was added 4-bromo-/V-{[(3S)-1-
Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/,2-dimethylbenzamide (150 mg) in 1 ,4-dioxane (2.5 ml.) followed by 2 M aqueous potassium carbonate (0.435 ml_). The vial was purged with nitrogen, sealed and heated in the microwave reactor at 130 °C for 20 min. The reaction mixture was filtered, diluted with water and extracted with EtOAc. The combined organic extracts were washed with 1 N aqueous NaHC03 and saturated brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 1 19 mg of the titled compound. LCMS m/z 402.0 (M+H)
Example 22
A -{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4'-(dimethylamino)-A ,3- dimethyl-4-biphenylcarboxamide
4-Dimethylaminophenylboronic acid (71 .8 mg) and Pd(dppf)Cl2-CH2Cl2 adduct (16.15 mg) were added to a 5 ml. microwave vial. To this was added 4-bromo-/V-{[(3S)-1- Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/,2-dimethylbenzamide (150 mg) in 1 ,4-dioxane (2.5 ml.) followed by 2 M aqueous potassium carbonate (0.435 ml_). The vial was purged with nitrogen, sealed and heated in the microwave reactor at 130 °C for 20 min. The reaction mixture filtered, diluted with water and extracted with EtOAc. The combined organic extracts were washed with 1 N aqueous NaHC03 and saturated brine, dried over sodium sulfate and evaporated to dryness. The crude produce was purified by preparative reverse phase HPLC to afford 77 mg of the titled compound. LCMS m/z 420.3 (M+H).
Example 23
A -{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A ,3-dimethyl-4'-(methyloxy)-4- biphenylcarboxamide
4-Methoxyphenylboronic acid (60.1 mg) and Pd(dppf)CI2-CH2Cl2 adduct (16.15 mg) were added to a 5 mL microwave vial. To this was added 4-bromo-/V-{[(3S)-1- Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/,2-dimethylbenzamide (150 mg) in 1 ,4-dioxane (2.5 mL) followed by 2 M aqueous potassium carbonate (0.435 mL). The vial was purged with nitrogen, sealed and heated in the microwave reactor at 130 °C for 20 min. The reaction mixture was filtered, diluted with water and extracted with EtOAc. The combined organic extracts were washed with 1 N aqueous NaHC03 and saturated brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 96 mg of the titled compound. LCMS m/z 407.2 (M+H)
Example 24
4-(1 -Benzofuran-5-yl)-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A - ethylbenzamide
(a) 1 ,1 -dimethylethyl (3S)-3-{[[(4-bromophenyl)carbonyl](ethyl)amino]methyl}-1 - pyrrolidinecarboxylate
To a solution of 1 , 1 -dimethylethyl (3S)-3-({[(4-bromophenyl)carbonyl]amino}methyl)-1- pyrrolidinecarboxylate (5 g) in THF (50 ml.) was added NaH (60% oil dispersion, 0.63 g) at RT with stirring. The reaction mixture was stirred for 15 min at RT and then ethyl iodide (3.1 g) was added and the reaction was stirred at RT overnight. The reaction was quenched by the addition of saturated aqueous NaHC03. The THF was removed under reduced pressure and the resulting aqueous phase was extracted three times with EtOAc. The combined EtOAc extracts were dried over sodium sulfate and evaporated to dryness to afford 5.2 g of the titled compound.
(b) 4-Bromo-A -ethyl-A -[(3 ?)-3-pyrrolidinylmethyl]benzamide hydrochloride
1 , 1 -Dimethylethyl (3S)-3-{[[(4-bromophenyl)carbonyl](ethyl)amino]methyl}-1 - pyrrolidinecarboxylate (5.2 g) was dissolved in MeOH (15 ml_). To this was added
HCI/MeOH (30 ml.) and the reaction mixture allowed to stir at RT for 3 hr. Solvent was removed under reduced pressure to afford 4.4 g of the titled product.
(c) 4-Bromo-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-A -ethylbenzamide
To a solution of 4-bromo-/V-ethyl-/\/-[(3/?)-3-pyrrolidinylmethyl]benzamide hydrochloride (4.4 g) in DCM (100 ml.) was added DIEA (4.86 g) at RT. This was stirred at RT for 5 min, and then cyclopropylcarbonyl chloride (1.6 g) was added. The reaction mixture was allowed to stir overnight at RT. The reaction mixture was washed with water, saturated aqueous
NaHC03 and saturated brine, dried over sodium sulfate, and evaporated to dryness to afford 5.0 g of the titled compound.
(d) 4-(1 -Benzofuran-5-yl)-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A - ethylbenzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- ethylbenzamide (200 mg) in 1 ,4-dioxane (4 mL) was added 5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1-benzofuran (129.1 mg) and K2C03 (219 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 75 mg of the titled compound. LCMS m/z 417.1 (M+H).
Example 25
4-(1H-Benzimidazol-5-yl)-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A - ethylbenzamide
To a solution of 4-bromo-/V-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- ethylbenzamide (200 mg) in 1 ,4-dioxane (4 mL) was added 1 H-benzimidazole-5-boronic acid pinacol ester (182 mg) and K2C03 (219 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight.
Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 56 mg of the titled compound. LCMS m/z 417.1 (M+H).
Example 26
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-A -ethyl-4-(1 H-indol-4- yl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- ethylbenzamide (200 mg) in 1 ,4-dioxane (4 mL) was added indole-4-boronic acid pinacol ester (128.6 mg) and K2C03 (219 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 105 mg of the titled compound. LCMS m/z 416.1 (M+H).
Example 27
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-A -ethyl-4-(1 H-indol-7- yl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- ethylbenzamide (200 mg) in 1 ,4-dioxane (4 mL) was added indole-7-boronic acid pinacol ester (128.6 mg) and K2C03 (219 mg in 2 ml. water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 105 mg of the titled compound. LCMS m/z 416.1 (M+H).
Example 28
N-{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-N -ethyl -4'-(methyloxy)-4- biphenylcarboxamide
To a solution of 4-bromo-/V-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- ethylbenzamide (200 mg) in 1 ,4-dioxane (4 ml.) was added 4-methoxyphenylboronic acid (80.4 mg) and K2C03 (219 mg in 2 ml. water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 90 mg of the titled compound. LCMS m/z 407.2 (M+H).
Example 29
3'-Chloro-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A -ethyl-4'-fluoro-4- biphenylcarboxamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- ethylbenzamide (200 mg) in 1 ,4-dioxane (4 mL) was added 3-chloro-4-fluorophenylboronic acid (92.1 mg) and K2C03 (219 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 78 mg of the titled compound. LCMS m/z 429.2 (M+H). Example 30
w-{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-A -ethyl-4-(1 H-indaz
yl)benzamide
To a solution of 4-bromo-/\/-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- ethylbenzamide (200 mg) in 1 ,4-dioxane (4 mL) was added 1 , 1-dimethylethyl 6-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-indazole-1-carboxylate (182 mg) and K2C03 (219 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 15 mg of the titled compound. LCMS m/z 417.3 (M+H).
Example 31
Λ/-{[(3/?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-W-ethyl-4-(1 H-indol-6- yl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- ethylbenzamide (200 mg) in 1 ,4-dioxane (4 mL) was added indole-6-boronic acid pinacol ester (128.6 mg) and K2C03 (272.3 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 13 mg of the titled compound. LCMS m/z 416.3 (M+H).
Example 32
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-A -ethyl-4-(1 H-indol-5- yl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- ethylbenzamide (200 mg) in 1 ,4-dioxane (4 mL) was added 1 , 1 -Dimethylethyl 5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole-1-carboxylate (181.6 mg) and K2C03 (272.3 mg in 2 mL water) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (100 mg) was then added and the reaction vessel was flushed with nitrogen three times. The reaction mixture was heated at 80 °C overnight. Solvent was then removed under reduced pressure and the residue partitioned between EtOAc and water. The EtOAc layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative reverse phase HPLC to afford 27 mg of the titled compound. LCMS m/z 416.1 (M+H).
Example 33
A -{[(3 ?S)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-A -(1 -methylethyl)-4- biphenylcarboxamide
1 , 1 -Dimethylethyl 3(RS)-(aminomethyl)-1 -pyrrolidinecarboxylate (454 mg, 2.27 mmol) and acetone (173 uL, 2.37 mmol) were combined in dichloroethane and stirred for 18 h. To this was added sodium triactoxyborohydride (529 mg, 2.50 mmol), stirring for an additional 18 h. The reaction was diluted with methanol and the solids filtered off. The filtrate was
concentrated, dried under hi-vacuum and used without further purification or
characterization.
Thionyl chloride (440 uL, 6.05 mmol) was added to a suspension of 4-biphenylcarboxylic acid (120 mg, 0.605 mmol) in anhydrous THF. The suspension was heated to reflux temporarily until homogeneous, then allowed to cool to room temperature. The solution was concentrated under vacuum to white solids, which were dried under hi-vacuum. The crude 1 - dimethylethyl 3(RS)-{[(1 -methylethyl)amino]methyl}-1 -pyrrolidinecarboxylate (73 mg, 0.302 mmol) and triethyl amine were combined in anhydrous THF and added to the acid chloride. After 60 minutes the reaction was diluted with 500 uL of concentrated HCI. Stirring for 5 min was followed by reverse phase purification (25-99% 0.1 %TFA-CH3CN/0.1 %TFA-H2O over 4 minutes). Appropriate fractions were concentrated on a Genevac to give 20mg of Λ/-(1 - methylethyl)-/V-(3-pyrrolidinylmethyl)-4-biphenylcarboxamide.
An excess of cyclopropanecarbonyl chloride was added to a solution of triethylamine (84 uL, 0.605 mmol) and /\/-(1 -methylethyl)-/\/-(3(RS)-pyrrolidinylmethyl)-4-biphenylcarboxamide in anhydrous THF (1 ml_), stirring for 18 h. The crude reaction was purified directly by reverse phase preparative HPLC (1 -99% 0.1 %TFA-CH3CN/0.1 %TFA-H2O over 4 minutes), appropriate fractions concentrated on a Genevac and the clear foam dried under hi-vacuum (17mg, 14% yield for 3 steps). LCMS m/z 391 (M+H); 1 H NMR Chloroform-d) : 7.55-7.67 (m, 4H), 7.42-7.50 (m, 4H), 7.33-7.41 (m, 1 H), 4.15 (br. s., 1 H), 3.04-3.95 (m, 6H), 2.80 (br. s., 1 H), 1.97-2.34 (m, 1 H), 1 .52-1.96 (m, 1 H), 1.21 (br. s., 6H), 0.92-1 .08 (m, 2H), 0.77 (dd, J = 7.5, 2.1 Hz, 2H). Example 34
W-{[(3/?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]m^
methylethyl)benzamide
(a) 1 ,1 -Dimethylethyl (3S)-3-{[(1 -methylethyl)amino]methyl}-1 -pyrrolidinecarboxylate
To a solution of 1 , 1 -dimethylethyl (3S)-3-(aminomethyl)-1 -pyrrolidinecarboxylate (2.0 g) and acetone (638 mg) in DCM (50 ml.) was added NaBH(OAc)3 (6.4 g) followed by a few drops of acetic acid. The reaction mixture was stirred at RT for 4 hr. The reaction mixture was partitioned between water and DCM. The organic layer was separated, dried over sodium sulfate and evaporated to dryness to afford 570 mg of the titled compound.
(b) 1 ,1 -Dimethylethyl (3S)-3-{[[(4-bromophenyl)carbonyl](1 -methylethyl)amino]methyl}-
1 -pyrrolidinecarboxylate
To a solution of 1 , 1 -dimethylethyl (3S)-3-{[(1 -methylethyl)amino]methyl}-1- pyrrolidinecarboxylate (2.0 g) in DCM was added DIEA (3.2 g). 4-Bromobenzoyl chloride (2.2 g) in DCM was then added dropwise and the reaction mixture was stirred overnight at RT. The crude product was purified by preparative TLC to afford 1.1 g of the titled compound.
(c) 4-Bromo-W-(1 -methylethyl)-A -[(3 ?)-3-pyrrolidinylmethyl]benzamide hydrochloride
1 , 1 -Dimethylethyl (3S)-3-{[[(4-bromophenyl)carbonyl](1 -methylethyl)amino]methyl}-1 - pyrrolidinecarboxylate (1.1 g) was dissolved in MeOH and treated with HCI/MeOH at RT for
2 hrs. The solvent was removed under reduced pressure to afford the titled product, which was used without further purification.
(d) 4-Bromo-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-W-(1 - methylethyl)benzamide
4-Bromo-/V-(1 -methylethyl)-/\/-[(3/?)-3-pyrrolidinylmethyl]benzamide hydrochloride (824 mg) was suspended in DCM (10 ml_). To this was added DIEA (436 mg) and the resulting solution was stirred at RT for 30 min. Cyclopropylcarbonyl chloride (270 mg) was then added dropwise and the reaction allowed to stir at RT overnight. Solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to afford 800 mg of the titled compound.
(e) A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1H-indazol-6-yl)-A -(1 - methylethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-(1 - methylethyl)benzamide (100 mg) in 1 ,4-dioxane (2 mL) was added 1 , 1 -dimethylethyl 6- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole-1-carboxylate (96 mg), K2C03 (70 mg) and water (1 ml.) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (50 mg) was then added under nitrogen. The reaction vessel was flushed with nitrogen three times and then stirred at 80 °C overnight. The solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative HPLC to afford 52.1 mg of the titled compound. LCMS m/z 431.2 (M+H).
Example 35
Λ/-{[(3/?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indazol-5-yl)-W-(1 - methylethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-(1 - methylethyl)benzamide (100 mg) in 1 ,4-dioxane (2 mL) was added 1 , 1-dimethylethyl 5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole-1-carboxylate (96 mg), K2C03 (70 mg) and water (1 mL) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (50 mg) was then added under nitrogen. The reaction vessel was flushed with nitrogen three times and then stirred at 80 °C overnight. The solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative HPLC followed by preparative TLC to afford the titled compound. LCMS m/z 431.2 (M+H).
Example 36
Λ/-{[(3/?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-5-yl)-A -(1 - methylethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-(1 - methylethyl)benzamide (100 mg) in 1 ,4-dioxane (2 mL) was added 1 , 1-dimethylethyl 5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-indole-1-carboxylate (96 mg), K2C03 (70 mg) and water (1 mL) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (50 mg) was then added under nitrogen. The reaction vessel was flushed with nitrogen three times and then stirred at 80 °C overnight. The solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative TLC to afford the titled compound. LCMS m/z 430.3 (M+H). Example 37
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4-(1H-indol-6-yl)-A ^
methylethyl)benzamide
To a solution of 4-bromo-/\/-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-(1 - methylethyl)benzamide (100 mg) in 1 ,4-dioxane (2 mL) was added indole-6-boronic acid pinacol ester (68 mg), K2C03 (70 mg) and water (1 mL) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (50 mg) was then added under nitrogen. The reaction vessel was flushed with nitrogen three times and then stirred at 80 °C overnight. The solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative TLC to afford the titled compound. LCMS m/z 430.3 (M+H).
Example 38
4-(1 -Benzofuran-5-yl)-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A -(1 - methylethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-(1 - methylethyl)benzamide (100 mg) in 1 ,4-dioxane (2 mL) was added 5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 -benzofuran (68 mg), K2C03 (70 mg) and water (1 mL) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (50 mg) was then added under nitrogen. The reaction vessel was flushed with nitrogen three times and then stirred at 80 °C overnight. The solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative TLC to afford the titled compound. LCMS m/z 431 .2 (M+H).
Example 39
4-(1 H-Benzimidazol-5-yl)-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A -(1 - methylethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-(1 - methylethyl)benzamide (150 mg) in 1 ,4-dioxane (2 mL) was added 1 , 1-dimethylethyl 5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazole-1-carboxylate (156 mg), K2C03 (104 mg) and water (1 mL) and the reaction mixture was stirred briefly at RT.
Pd(dppf)CI2 (27 mg) was then added under nitrogen. The reaction vessel was flushed with nitrogen three times and then stirred at 80 °C overnight. The solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative HPLC to afford 29 mg of the titled compound. LCMS m/z 431.4 (M+H).
Example 40
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4-(1H-indol-7-yl)-A -(1 - methylethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-(1 - methylethyl)benzamide (150 mg) in 1 ,4-dioxane (2 mL) was added indole-7-boronic acid pinacol ester (1 10 mg), K2C03 (104 mg) and water (1 mL) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (27 mg) was then added under nitrogen. The reaction vessel was flushed with nitrogen three times and then stirred at 80 °C overnight. The solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative HPLC to afford 59 mg of the titled compound. LCMS m/z 430.3 (M+H).
Example 41
3'-Chloro-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4'-fluoro-A -(1 - methylethyl)-4-biphenylcarboxamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-(1 - methylethyl)benzamide (120 mg) in 1 ,4-dioxane (2 mL) was added 3-chloro-4- fluorophenylboronic acid (63.8 mg), K2C03 (85.5 mg) and water (1 mL) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (34.6 mg) was then added under nitrogen. The reaction vessel was flushed with nitrogen three times and then stirred at 80 °C overnight.
The solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative HPLC to afford 56 mg of the titled compound. LCMS m/z 443.2 (M+H).
Example 42
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A -(1 -methylethyl)-4'- (methyloxy)-4-biphenylcarboxamide
To a solution of 4-bromo-/V-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-(1 - methylethyl)benzamide (120 mg) in 1 ,4-dioxane (2 mL) was added 4-methoxyphenylboronic acid (56 mg), K2C03 (85.5 mg) and water (1 mL) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (34.6 mg) was then added under nitrogen. The reaction vessel was flushed with nitrogen three times and then stirred at 80 °C overnight. The solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative TLC to afford 21 mg of the titled compound. LCMS m/z 421.2 (M+H).
Example 43
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4-(1H-indol-4-yl)-A -(
methylethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-(1 - methylethyl)benzamide (150 mg) in 1 ,4-dioxane (2 mL) was added indole-4-boronic acid pinacol ester (1 10 mg), K2C03 (104 mg) and water (1 mL) and the reaction mixture was stirred briefly at RT. Pd(dppf)CI2 (27 mg) was then added under nitrogen. The reaction vessel was flushed with nitrogen three times and then stirred at 80 °C overnight. The solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was separated, washed with saturated brine and evaporated to dryness. The crude product was purified by preparative HPLC to afford 42 mg of the titled compound. LCMS m/z 430.3 (M+H).
Example 44
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indazol-5-yl)-A - (phenylmethyl)benzamide
(a) 1 ,1 -Dimethylethyl (3S)-3-{[(phenylmethyl)amino]methyl}-1 -pyrrolidinecarboxylate
To a solution of benzaldehyde (2.385 g) in THF (50 mL) were added 1 ,1 -dimethylethyl (3S)- 3-(aminomethyl)-1 -pyrrolidinecarboxylate (4.5g) and magnesium sulfate (9 g). The reaction mixture was cooled to 0 °C and acetic acid (3.3 g) was added dropwise. The reaction mixture was allowed to warm to RT and stirred for 4-5 hr, then cooled back to 0 °C.
NaBH(OAc)3 (9.54 g) was added portionwise and the reaction mixture was allowed to warm to RT and stirred overnight. Solvent was removed under reduced pressure and the reaction mixture was quenched by pouring it into a mixture of ice water and and saturated aqueous NaHC03. The quenched mixture was extracted with DCM (2 x 100 mL) and the combined DCM extracts were washed with saturated brine, dried over sodium sulfate and evaporated to dryness to afford 6.1 g of the titled compound, which was used without further purification. (b) 1 ,1 -Dimethylethyl (3S)-3-{[[(4-bromophenyl)carbonyl](phenylmethyl)amino]methyl}- 1 -pyrrolidinecarboxylate
1 , 1 -Dimethylethyl (3S)-3-{[(phenylmethyl)amino]methyl}-1 -pyrrolidinecarboxylate (6.1 g) and DIEA (8.127 g) were dissolved in DCM (60 ml_). To this was added dropwise a solution of 4- bromobenzoyl chloride (6.876 g) in DCM (10 ml.) and the reaction mixture was stirred at RT overnight. Saturated aqueous NaHC03 was then slowly added with stirring and the reaction mixture was extracted with EtOAc (2 x 100 ml_). The combined EtOAc extracts were dried over sodium sulfate, evaporated to dryness, and purified by silica gel column
chromatography using petroleum ether / EtOAc 5:1 to afford 2.9 g of the titled compound. (c) 4-Bromo-A -(phenylmethyl)-A -[(3 ?)-3-pyrrolidinylmethyl]benzamide hydrochloride
1 , 1 -Dimethylethyl (3S)-3-{[[(4-bromophenyl)carbonyl](phenylmethyl)amino]methyl}-1 - pyrrolidinecarboxylate (7.67 g) was dissolved in HCI/MeOH (100 ml.) and stirred at RT for 3- 4 hr. Solvent was removed under reduced pressure to afford 7.5 g of the titled compound, which was used without further purification.
(d) 4-Bromo-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/V- (phenylmethyl)benzamide
4-Bromo-/V-(phenylmethyl)-/\/-[(3/?)-3-pyrrolidinylmethyl]benzamide hydrochloride (7.5 g) was dissolved in DCM (80 ml_). To this was added DIEA (7.1 1 g) and the reaction mixture was stirred at RT for 30 min. Cyclopropylcarbonyl chloride (2.1 1 g) was then added under nitrogen and the reaction allowed to stir overnight at RT. Saturated aqueous NaHC03 was added dropwise to the reaction mixture and it was extracted with EtOAc. The EtOAc extract was washed with water and saturated brine, dried over sodium sulfate, evaporated to dryness and purified by silica gel column chromatography using petroleum ether/EtOAc 1 :1 to afford 4 g of the titled compound.
(e) Λ/-{[(3/?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indazol-5-yl)-W- (phenylmethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- (phenylmethyl)benzamide (200 mg) in 1 ,4-dioxane (4 mL) was added 1 , 1-Dimethylethyl 5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole-1-carboxylate (156.3 mg) and K2C03 (125 mg in 2 mL water) and the reaction mixture stirred briefly at RT. Pd(dppf)CI2 (100 mg) was added under nitrogen and the reaction vessel was flushed with nitrogen 3 times. The reaction mixture was stirred at 80 °C overnight. Solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The EtOAc layer was separated, washed with saturated brine, evaporated to dryness and purified by preparative HPLC to afford 52 mg of the titled compound. LCMS m/z 479.1 (M+H).
Example 45
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4-(1H-indazol-6-yl)-W- (phenylmethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- (phenylmethyl)benzamide (200 mg) in 1 ,4-dioxane (4 mL) was added 1 , 1-dimethylethyl 6- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole-1-carboxylate (156.3 mg) and K2C03 (125 mg in 2 mL water) and the reaction mixture stirred briefly at RT. Pd(dppf)CI2 (100 mg) was added under nitrogen and the reaction vessel was flushed with nitrogen 3 times. The reaction mixture was stirred at 80 °C overnight. Solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The EtOAc layer was separated, washed with saturated brine, evaporated to dryness and purified by preparative HPLC to afford 43 mg of the titled compound. LCMS m/z 479.2 (M+H).
Example 46
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-5-yl)-W- (phenylmethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- (phenylmethyl)benzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 1 , 1-dimethylethyl 5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole-1-carboxylate (128.7 mg) and K3PCy3H20 (272.3 mg in 2 mL water) and the reaction mixture stirred briefly at RT.
Pd(dppf)CI2 (100 mg) was added under nitrogen and the reaction vessel was flushed with nitrogen 3 times. The reaction mixture was stirred at 80 °C overnight. Solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The EtOAc layer was separated, washed with saturated brine, evaporated to dryness and purified by preparative HPLC to afford 40 mg of the titled compound. LCMS m/z 478.2 (M+H).
Example 47
4-(1 -Benzofuran-5-yl)-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A - (phenylmethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-
(phenylmethyl)benzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 -benzofuran (91 .53 mg) and K2C03 (141 .1 mg in 2 mL water) and the reaction mixture stirred briefly at RT. Pd(dppf)CI2 (100 mg) was added under nitrogen and the reaction vessel was flushed with nitrogen 3 times. The reaction mixture was stirred at 80 °C overnight. Solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The EtOAc layer was separated, washed with saturated brine, evaporated to dryness and purified by preparative HPLC to afford 60 mg of the titled compound. LCMS m/z 479.3 (M+H).
Example 48
4-(1H-Benzimidazol-5-yl)-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-A - (phenylmethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- (phenylmethyl)benzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 1 , 1-dimethylethyl 5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazole-1-carboxylate (129.1 mg) and K2C03 (141.1 mg in 2 mL water) and the reaction mixture stirred briefly at RT.
Pd(dppf)CI2 (100 mg) was added under nitrogen and the reaction vessel was flushed with nitrogen 3 times. The reaction mixture was stirred at 80 °C overnight. Solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The EtOAc layer was separated, washed with saturated brine, evaporated to dryness and purified by preparative HPLC to afford 8 mg of the titled compound. LCMS m/z 479.4 (M+H).
Example 49
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4'-(methyloxy)-A - (phenylmethyl)-4-biphenylcarboxamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- (phenylmethyl)benzamide (200 mg) in 1 ,4-dioxane (4 mL) was added 4- methoxyphenylboronic acid (82.9 mg) and K2C03 (188.1 mg in 2 mL water) and the reaction mixture stirred briefly at RT. Pd(dppf)CI2 (100 mg) was added under nitrogen and the reaction vessel was flushed with nitrogen 3 times. The reaction mixture was stirred at 80 °C overnight. Solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The EtOAc layer was separated, washed with saturated brine, evaporated to dryness and purified by preparative HPLC to afford 66 mg of the titled compound. LCMS m/z 469.2 (M+H).
Example 50
Λ/-{[(3/?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-6-yl)-W- (phenylmethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- (phenylmethyl)benzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 6-indoleboronic acid pinacol ester (91 .17 mg) and Κ3Ρ06·3 H20 (272.18 mg in 2 mL water) and the reaction mixture stirred briefly at RT. Pd(dppf)CI2 (100 mg) was added under nitrogen and the reaction vessel was flushed with nitrogen 3 times. The reaction mixture was stirred at 80 °C overnight. Solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The EtOAc layer was separated, washed with saturated brine, evaporated to dryness and purified by preparative HPLC to afford 58 mg of the titled compound. LCMS m/z 478.1 (M+H).
Example 51
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4-(1 H-indol-4-yl)-W- (phenylmethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-
(phenylmethyl)benzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 4-indoleboronic acid pinacol ester (91 .15 mg) and K2C03 (141.1 mg in 2 mL water) and the reaction mixture stirred briefly at RT. Pd(dppf)CI2 (100 mg) was added under nitrogen and the reaction vessel was flushed with nitrogen 3 times. The reaction mixture was stirred at 80 °C overnight.
Solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The EtOAc layer was separated, washed with saturated brine, evaporated to dryness and purified by preparative HPLC to afford 65 mg of the titled compound. LCMS m/z 478.2 (M+H).
Example 52
Λ -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-7-yl)-W- (phenylmethyl)benzamide
To a solution of 4-bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- (phenylmethyl)benzamide (150 mg) in 1 ,4-dioxane (4 mL) was added 7-indoleboronic acid pinacol ester (91 .15 mg) and K2C03 (141.1 mg in 2 mL water) and the reaction mixture stirred briefly at RT. Pd(dppf)CI2 (100 mg) was added under nitrogen and the reaction vessel was flushed with nitrogen 3 times. The reaction mixture was stirred at 80 °C overnight.
Solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The EtOAc layer was separated, washed with saturated brine, evaporated to dryness and purified by preparative HPLC to afford 120 mg of the titled compound. LCMS m/z 478.2 (M+H). Example 53
3'-Chloro-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4'-fluoro-A - (phenylmethyl)-4-biphenylcarboxamide
To a solution of 4-bromo-/\/-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/- (phenylmethyl)benzamide (200 mg) in 1 ,4-dioxane (4 mL) was added 3-chloro-4- fluorophenylboronic acid (94.9 mg) and K2C03 (188.12 mg in 2 mL water) and the reaction mixture stirred briefly at RT. Pd(dppf)CI2 (100 mg) was added under nitrogen and the reaction vessel was flushed with nitrogen 3 times. The reaction mixture was stirred at 80 °C overnight. Solvent was removed under reduced pressure and the residue partitioned between water and EtOAc. The EtOAc layer was separated, washed with saturated brine, evaporated to dryness and purified by preparative HPLC to afford 162 mg of the titled compound. LCMS m/z 491.1 (M+H).
Example 54
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4-(1 H-indol-5-yl)-A -3- pyridinylbenzamide
(a) 1 ,1 -Dimethylethyl (3S)-3-[(3-pyridinylamino)methyl]-1 -pyrrolidinecarboxylate
A 20 mL tube-shaped pressure bottle was charged with 3-chloropyridine (0.200 g) and sodium tert-butoxide (0.254 g) in 1 ,2-dimethoxyethane (DME) (5 mL) followed by palladium (II) acetate (9 mg) and (R)-(-)-di-tert-butyl-{1 -(S)-2- (dicyclohexylphosphanyl)ferrocenyl]ethyl}phosphine (9 mg) to give a brown suspension. 1 , 1 - Dimethylethyl (3S)-3-(aminomethyl)-1 -pyrrolidinecarboxylate (0.441 g) was then added and the closed vessel heated with stirring at 100 °C for 4 hr. The crude reaction mixture was poured directly onto a 20 g silica gel pad and eluted with 6 x 75 mL 100% EtOAc. The appropriate fractions were pooled and evaporated to dryness to afford 250 mg of the titled compound, which was used without further purification.
(b) 1 ,1 -Dimethylethyl (3S)-3-{[[(4-bromophenyl)carbonyl](3-pyridinyl)amino]methyl}-1 - pyrrolidinecarboxylate
1 , 1 -Dimethylethyl (3S)-3-[(3-pyridinylamino)methyl]-1 -pyrrolidinecarboxylate (0.25 g), triethylamine (0.188 ml), and DMAP (0.01 1 g) were dissolved in DCM (15 ml). 4- BromobenzoyI chloride (0.247 g) in DCM (5 mL) was added in one portion. The reaction was stirred at RT under nitrogen for 3 days. An additional 0.3 mL triethylamine and 0.25 g p- bromobenzoylbormide were added and the reaction stirrd at RT for 3 hr. The reaction mixture was diluted with 50 mL each EtOAc and 2 N aqueous Na2C03. The organic layer was separated, washed with 50 mL each water and brine, dried over sodium sulfate and conceentrated to a solid. The solid was triturated with 20 mL EtOAc and the filtrate concentrated to an orange-yellow oil which was purified by flash chromatography on silica gel using a gradient of EtOAc in hexanes to afford 280 mg of the titled compound as a colorless oil.
(c) 4-Bromo-A -3-pyridinyl-A -[(3 ?)-3-pyrrolidinylmethyl]benzamide dihydrochloride
1 , 1 -Dimethylethyl (3S)-3-{[[(4-bromophenyl)carbonyl](3-pyridinyl)amino]methyl}-1 - pyrrolidinecarboxylate (0.23 g) was dissolved in 1 ,4-dioxane (20 mL) and cooled to 10 °C in an ice bath. 4N HCI/dioxane (0.5 mL) was then added and the reaction was allowed to warm to RT and stirred for 2 hr. Diethyl ether (50 mL) was added and the reaction mixture sonicated briefly. The resulting solid was collected by filtration, washed with ether, air-dried and then dried in vacuum overnight. LCMS indicated that the reaction had not gone to completion, so the solid was dissolved in MeOH and transferred to a flask, evaporated to dryness, suspended in 1 ,4-dioxane (5 mL) and treated with 4 N HCI/dioxane (0.5 mL) for 4 hr at RT. The reaction mixture was allowed to settle and the solution decanted. The precipitate was dissolved in MeOH and evaporated to dryness to afford 0.17 g of the titled compound, which was used without further purification.
(d) 4-Bromo-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A -3- pyridinylbenzamide
4-Bromo-/V-3-pyridinyl-/\/-[(3/?)-3-pyrrolidinylmethyl]benzamide dihydrochloride (160 mg) and DMAP (4.5 mg) were dissolved in NMP (20 mL). To this was added DIEA (258 uL) followed by cyclopropylcarbonyl chloride (50 uL) and the reaction was allowed to stir at RT for 16 hr. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (2 x 50 mL) and saturated brine (50 mL), dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on silica gel using 5% MeOH/DCM to afford 176 mg of the titled compound.
(e) A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4-(1H-indol-5-yl)-A -3- pyridinylbenzamide
4-Bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-3-pyridinylbenzamide (86 mg), indole-5-boronic acid (65 mg), and tetrakis(triphenylphosphine)palladium(0) (23 mg) were suspended in 1 ,2-dimethoxyethane (2mL). To this was added 2 N aqueous Na2C03 (2 mL) and the reaction vessel was sealed at heated at 100 °C with stirring for 2 hr. After cooling, the organic layer was separated and the aqueous layer extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel column chromatography using a gradient of 0-10% MeOH/DCM to afford 60 mg of the titled compound. LCMS m/z 465.3 (M+H).
Example 55
A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4-(1H-indol-6-yl)-A -3- pyridinylbenzamide
4-Bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-3-pyridinylbenzamide (86 mg), indole-6-boronic acid (65 mg), and tetrakis(triphenylphosphine)palladium(0) (23 mg) were suspended in 1 ,2-dimethoxyethane (2ml_). To this was added 2 N aqueous Na2C03 (2 ml.) and the reaction vessel was sealed at heated at 100 °C with stirring for 2 hr. After cooling, the organic layer was separated and the aqueous layer extracted with EtOAc (2 x 5 ml_). The combined organic layers were dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel column chromatography using a gradient of 0-10% MeOH/DCM to afford 65 mg of the titled compound. LCMS m/z 465.3 (M+H).
Example 56
w-{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-5-yl)-A -2- pyrazinylbenzamide
(a) 1 ,1 -Dimethylethyl (3S)-3-[(2-pyrazinylamino)methyl]-1 -pyrrolidinecarboxylate
A 20 mL tube-shaped pressure bottle was charged with 3-chloropyridine (0.200 g) and dimethylethyl (3S)-3-(aminomethyl)-1 -pyrrolidinecarboxylate (0.437g) in 1 ,2- dimethoxyethane (DME) (5 mL), followed by sodium tert-butoxide (0.252 g), palladium (II) acetate (12 mg, 0.040 mmol) and (R)-(-)-di-tert-butyl-{1 -(S)-2- [(dicyclohexylphosphanyl)ferrocenyl]ethyl}phosphine (29 mg) to give a yellow
suspension.The reaction vessel was sealed and heated with stirring at 100 °C for 4 hr. The crude reaction mixture was poured directly onto a 20 g silica gel pad and eluted with 10 x 100 mL EtOAc/hexanes 1 :1. The appropriate fractions were pooled and evaporated to dryness to afford 240 mg of the titled compound, which was used without further
purification.
(b) 1 ,1 -Dimethylethyl (3S)-3-{[[(4-bromophenyl)carbonyl](2-pyrazinyl)amino]methyl}-1 - pyrrolidinecarboxylate
1 , 1 -dimethylethyl (3S)-3-[(2-pyrazinylamino)methyl]-1 -pyrrolidinecarboxylate (0.20 g), triethylamine (0.300 ml), and DMAP (8.78 mg) were dissolved in DCM (15 ml). 4- Bromobenzoyl chloride (0.394 g) in DCM (5 mL) was added was added in one portion and the reaction mixture allowed to stir overnight at RT. LCMS indicated that the reaction had not proceeded to completion so an additional 0.6 mL triethylamine and 0.42 g p-bromobenzoyl chloride was added. After stiring at RT for 3 days, the reaction is diluted with 50 mL each EtOAc and 2 N aqueous Na2C03. The organic layer was separated and washed with 50 mL brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel flash chromatography using a MeOH/DCM gradient to afford 199 mg of partially purified material as a pale yellow oil. This was further purified by silica gel flash
chromatography using a gradient of 0-5% MeOH/DCM to afford 151 mg of the titled compound.
(c) 4-Bromo-A -2-pyrazinyl-A -[(3 ?)-3-pyrrolidinylmethyl]benzamide hydrochloride
1 , 1 -Dimethylethyl (3S)-3-{[[(4-bromophenyl)carbonyl](2-pyrazinyl)amino]methyl}-1 - pyrrolidinecarboxylate (151 mg) was dissolved in 1 ,4-dioxane (5 mL). To this was added 4 N HCI/dioxane (0.327 mL) and the reaction allowed to stir at RT for 2 hr. LCMS indicated that the reaction had not gone to completion, so an additional aliquot of 4 N HCI/dioxane (0.327 mL) was added and the reaction mixture allowed to stir overnight at RT. The supernatant was carefully decanted and the oily residue washed once with dioxane, dissolved in MeOH, evaporated to dryness and dried under vacuum to afford 98 mg of the titled compound, which was used without further purification.
(d) 4-Bromo-A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A -2- pyrazinylbenzamide
4-Bromo-/V-2-pyrazinyl-/\/-[(3/?)-3-pyrrolidinylmethyl]benzamide hydrochloride (90 mg) and DMAP (2.77 mg) were dissolved in NMP (10 mL). To this was added DIEA (0.158 mL) followed by cyclopropylcarbonyl chloride (0.0.31 mL) and the reaction was stirred at RT for 3 hr. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (2 x 50 mL) and saturated brine (50 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel flash chromatography using a gradient of 10-90% EtOAc/hexanes to afford 54 mg of the titled compound.
(e) A -{[(3 ?)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]methyl}-4-(1H-indol-5-yl)-A -2- pyrazinylbenzamide
4-Bromo-/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-2-pyrazinylbenzamide (50 mg) and indole-5-boronic acid (37 mg) were dissolved in 1 ,2-dimethoxyethane (2 mL). To this was added 2 N aqueous Na2C03 (2 mL) followed by
tetrakis(triphenylphosphine)palladium(0) (13 mg). The reaction vessel was sealed and stirred at 100 °C for 2 hr. After cooling, the organic layer was separated and the aqueous layer washed with EtOAc (2 x 5 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel flash chromatography using a gradient of 0-10% MeOH/DCM to afford 39 mg of the titled compound. LCMS m/z 466.3 (M+H).
Example 57
A -[4-(1 -Benzofuran-5-yl)phenyl]-2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-W- methylacetamide
(a) 1 ,1 -Dimethylethyl (3S)-3-{2-[(4-bromophenyl)amino]-2-oxoethyl}-1 - pyrrolidinecarboxylate
A solution of ((3S)-1-{[(1 , 1 -dimethylethyl)oxy]carbonyl}-3-pyrrolidinyl)acetic acid (5.0 g,) and N-methylmorpholine (2.278 mL) in anhydrous THF (100 mL) was cooled to 0 °C then slowly treated with neat ethyl chloroformate (2.094 mL). The resulting cloudy suspension stirred for 10 minutes then solid 4-bromoaniline (3.75 g) was added. The ice bath was removed and the reaction was allowed to stir with warming to room temperature. Additional THF (100 mL) was added and stirring continued at room temperature for 18 hours. The resulting slurry was evaporated under reduced pressure then the residue was taken into DCM, washed with saturated aqueous sodium bicarbonate and brine then dried over sodium sulfate and evaporated to afford the crude product as a yellow oil. This was purified by silica gel flash chromatography using 1 :1 ethyl acetate and hexanes. The desired fractions were combined and evaporated under reduced pressure to a white solid which was recrystallized from ethyl acetate/hexanes to afford 4.83 g of the titled compound. LCMS m/z 383.1 (M+H).
(b) N-(4-Bromophenyl)-2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]acetamide
To a solution of 1 , 1 -dimethylethyl (3S)-3-{2-[(4-bromophenyl)amino]-2-oxoethyl}-1 - pyrrolidinecarboxylate (4.7 g,) in anhydrous dichloromethane DCM)(20 mL) was slowly added neat trifluoroacetic acid (5.0 ml). The reaction stirred at room temperature for 20 hours and then evaporated under reduced pressure then evaporated again from DCM to remove excess TFA. The resulting oil was taken into anhydrous DCM (40 mL), cooled to 0 °C then treated with neat triethylamine (5.13 ml,) followed by neat cyclopropanecarbonyl chloride (1.347 ml). After 30 minutes, the resulting slurry was evaporated under reduced pressure to a wet residue that was slurried in hot water and filtered. The light yellow solids were rinsed well with water then suction and vacuum dried. The solids were then triturated from a mixture of methanol (5ml), ethyl acetate (25ml) and hexanes (75ml), collected by filteration, rinsed with hexanes and suction dried to afford 4.0 g of the titled compound as a white solid. LCMS m/z 351.2, (M+H). (c) A -(4-bromophenyl)-2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-A - methylacetamide
To a stirred solution of N-(4-bromophenyl)-2-[(3S)-1 -Cyclopropylcarbonyl)-3- pyrrolidinyl]acetamide (1 .5 gl) in anhydrous DMF (15 ml.) was added 60% sodium hydride in mineral oil (205 mg) in one portion. The resulting murky solution stirred at room temperature for 15 minutes then was treated with neat iodomethane (320 μΙ). After 30 minutes, the reaction was quenched with water then extracted with ethyl acetate. The organics were dried over sodium sulfate and evaporated to a crude oil. This was purified by silica gel flash chromatography using 10% hexanes in ethyl acetate. The desired fractions were combined and evaporated to a colorless oil then evaporated again from DCM (3x) to afford 1 .34 g of the titled compound as a colorless oil. LCMS m/z 365.1 , (M+H).
(d) Λ -[4-(1 -Benzofuran-5-yl)phenyl]-2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-W- methylacetamide
A 25 ml microwave vial was charged with a suspension of N-(4-bromophenyl)-2-[(3S)-1- Cyclopropylcarbonyl)-3-pyrrolidinyl]-N-methylacetamide (128 mg), 5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 -benzofuran (128 mg), Pd(dppf)CI2-CH2CI2 adduct (14.31 mg) and 2.0 M aqueous potassium carbonate (0.701 ml) in 1 ,4-dioxane (2.804 ml) and then capped. The reaction was heated in an aluminum block at 95 °C for 18 hours. The resulting dark solution was diluted with methanol, treated with silica powder (~1 g) then evaporated to dryness. This was purified by silica gel flash chromatography using EtOAc followed by preparative reverse phase HPLC. The combined HPLC fractions were treated with saturated aqueous sodium bicarbonate (10 ml) then extracted in to DCM. The extracts were dried over sodium sulfate and evaporated to a colorless residue. This was taken into acetonitrile (~1 ml) and diluted with water (~4 ml), frozen and lyophilized to afford 73 mg of the titled compound as a white solid. LCMS m/z 403.1 (M+H).
Example 58
A -(4'-Cyano-4-biphenylyl)-2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-A - methylacetamide
A 25 ml microwave vial was charged with a suspension of N-(4-bromophenyl)-2-[(3S)-1- Cyclopropylcarbonyl)-3-pyrrolidinyl]-N-methylacetamide (132 mg), (4-cyanophenyl)boronic acid (80 mg), Pd(dppf)CI2-CH2Cl2 adduct (14.76 mg) and 2.0 M aqueous sodium carbonate (0.723 ml) in 1 ,4-dioxane (2.892 ml) and then capped. The reaction was heated in an aluminum block at 95 °C for 18 hours. The resulting dark solution was diluted with methanol, treated with silica powder (~1 g) then evaporated to dryness. This was purified by silica gel flash chromatography eluting with EtOAc followed by preparative reverse phase HPLC. The appropriate HPLC fractions were treated with saturated aqueous sodium bicarbonate (10 ml) then extracted with DCM. The extracts were dried over sodium sulfate and evaporated to a colorless residue. This was dissolved into acetonitrile (~1 ml) and diluted with water (~4ml), frozen and lyophilized to afford 89 mg of the titled compound as a white solid. LCMS m/z 388.2 (M+H).
Example 59
2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-A -methyl-A -[4-(2- naphthalenyl)phenyl]acetamide
A 25 ml microwave vial was charged with a suspension of N-(4-bromophenyl)-2-[(3S)-1- Cyclopropylcarbonyl)-3-pyrrolidinyl]-N-methylacetamide (133 mg), 2-naphthalenylboronic acid (94 mg), Pd(dppf)CI2-CH2Cl2 adduct (14.87 mg) and 2.M aqueous potassium carbonate (728 μΙ) in 1 ,4-dioxane (2.912 ml) and then capped. The reaction was heated in an aluminum block at 100 °C for 3 hours. The resulting dark solution was diluted with methanol, treated with silica powder (~1 g) then evaporated to dryness. This was purified by silica gel flash chromatography eluting with EtOAc, followed by preparative reverse phase HPLC. The desired HPLC fractions were treated with saturated aqueous sodium bicarbonate (10 ml) then extracted with DCM. The extracts were dried over sodium sulfate and evaporated to a colorless residue. This was dissolved in acetonitrile (~1 ml) and diluted with water (~3ml), frozen and lyophilized to afford 105 mg of the titled compound as a white solid. LCMS m/z 413.3 (M+H)
Example 60
2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-A -methyl-A -[4-(6- quinolinyl)phenyl]acetamide
A 25 ml microwave vial was charged with a suspension of N-(4-bromophenyl)-2-[(3S)-1- Cyclopropylcarbonyl)-3-pyrrolidinyl]-N-methylacetamide (141 mg), 6-quinolinylboronic acid (100 mg), Pd(dppf)CI2-CH2Cl2 adduct (15.76 mg) and 2.0 M aqueous potassium carbonate (772 μΙ) in 1 ,4-dioxane (3.088 ml) then capped. The reaction was heated in an aluminum block at 95 °C for 18 hours. The resulting dark solution was diluted with methanol, treated with silica powder (~1 g) then evaporated to dryness. This was purified by silica gel flash chromatography eluting with EtOAc and then 3% MeOH/EtOAc, followed by preparative reverse phase HPLC. The desired HPLC fractions were treated with saturated aqueous sodium bicarbonate (10 ml) then extracted into DCM. The extracts were dried over sodium sulfate and evaporated to a colorless residue. This was dissolved in acetonitrile (~1 ml) and diluted with water (~3ml), frozen and lyophilized to afford 48 mg of the titled compound as a white solid. LCMS m/z 414.2 (M+H). Example 61
2-[(3S)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]-A -[4-(1 H-indol-5-yl)phenyl]-W- methylacetamide
5-lndoleboronic acid pinacol ester (213 mg) and Pd(dppf)CI2-CH2Cl2 adduct (32.5 mg) were added to a 20 ml. microwave vial. To this was added N-(4-bromophenyl)-2-[(3S)-1 -
Cyclopropylcarbonyl)-3-pyrrolidinyl]-N-methylacetamide (291 mg) in 1 ,4-dioxane (10 ml.) followed by 2 M aqueous potassium carbonate (0.876 ml_). The flask was flushed with nitrogen, sealed and stirred at 130 °C in a microwave reactor for 20 min. The reaction mixture was partitioned between EtOAc (25 ml.) and water (25 ml_). The aqueous layer was separated and extracted with EtOAc (2 x 25 ml_). The combined EtOAc extracts were washed with 1 N NaHC03 (3 x 25 ml.) and saturated brine (25 ml_), dried over sodium sulfate and evaporated to dryness to afford 494 mg of crude product. This was was purified by flash chromatography on silica gel using a gradient of 0-5% MeOH/DCM. The appropriate fractions were combined, evaporated to dryness and then dried under high vacuum to afford a pale yellow glass. This material was dissolved in 5 ml. CH3CN and diluted with 15 ml_ water. The resulting emulsion was frozen and lyophilized to afford 130 mg of the titled compound as an off-white powder. LCMS m/z 402.0 (M+H).
Example 62
2-[(3S)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]-A -[2-fluoro-4-(1 H-indol-5-yl)phenyl]-W- methylacetamide
(a) 1 ,1 -Dimethylethyl (3S)-3-{2-[(4-bromo-2-fluorophenyl)amino]-2-oxoethyl}-1 - pyrrolidinecarboxylate
To a stirred solution of ((3S)-1 -{[(1 , 1-dimethylethyl)oxy]carbonyl}-3-pyrrolidinyl)acetic acid (2.49 g) and N-methylmorpholine (1.194 ml.) in anhydrous THF (60 ml.) at 0 °C was slowly added neat ethyl chloroformate (1 .043 ml_). The resulting cloudy solution was stirred at 0 °C for 10 minutes then solid 4-bromo-2-fluoroaniline (2.064 g) was added in one portion. The ice bath was removed and stirring continued at room temperature for 5 days. The cloudy suspension was treated with silica powder (10g) then evaporated under reduced pressure to dryness. This was purified by silica gel flash chromatography eluting with 50% hexanes in ethyl acetate. The desired fractions were combined and evaporated under reduced pressure then evaporated again from DCM (3x) to afford 3.37 g of the titled compound as a colorless glass. LCMS m/z 401.0 (M+H). (b) N-(4-Bromo-2-fluorophenyl)-2-[(3S)-1 -Cyclopropylcarbonyl)-3- pyrrolidinyljacetamide
To a stirred solution of 1 , 1 -dimethylethyl (3S)-3-{2-[(4-bromo-2-fluorophenyl)amino]-2- oxoethyl}-1 -pyrrolidinecarboxylate (3.30 g) in anhydrous DCM (30.0 mL) cooled to 0 °C was slowly added neat trifluoroacetic acid (3.0 ml). The ice bath was removed and stirring continued for 2 days. The solution was evaporated under reduced pressure then re- evaporated from DCM (5x) to remove excess TFA. The resulting oil was diluted with anhydrous DCM (30.0 mL), cooled to 0 °C then treated successively with neat triethylamine (4.58 ml) and neat cyclopropylcarbonyl chloride (0.903 ml). After 30 minutes the resulting slurry was diluted with saturated aqueous sodium bicarbonate then extracted further with dichloromethane. The combined extracts were dried over sodium sulfate, treated with silica powder (~8g) then evaporated to dryness in vacuo. The crude product was purified by silica gel flash chromatography eluting with a gradient of 50-100% EtOAc/hexanes. The desired fractions were combined and evaporated to a white residue that was triturated from 4:1 hexanes/ethyl acetate to afford 2.40 g of the titled compound as a white solid. LCMS m/z 368.9 (M+H).
(c) N-(4-Bromo-2-fluorophenyl)-2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-N- methylacetamide
To a stirred solution of N-(4-bromo-2-fluorophenyl)-2-[(3S)-1-Cyclopropylcarbonyl)-3- pyrrolidinyl]acetamide (1 .0 g) in anhydrous DMF (25 mL) was added 60% sodium hydride in mineral oil (130 mg) in one portion. After 15 minutes, neat iodomethane (203 μΙ) was added and stirring continued at ambient temperature for 1 hour. The solvents were removed under reduced pressure then the resulting oil was taken into ethyl acetate and washed with saturated aqueous sodium bicarbonate. The extracts were dried over sodium sulfate, treated with silica powder and evaporated under reduced pressure to dryness. This was purified by silica gel flash chromatography eluting with 10% hexanes/EtOAc to afford 1 .0 g of the titled compound as a colorless oil. LCMS(ES) m/z 383.2(M+H).
(d) 2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-N-[2-fluoro-4-(1 H-indol-5-yl)phenyl]- N-methylacetamide
A 25 ml microwave vial was charged with a suspension of N-(4-bromo-2-fluorophenyl)-2- [(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]-N-methylacetamide (120 mg), 5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole (1 14 mg), Pd(dppf)CI2-CH2CI2 adduct (12.78 mg) and 2.0 M aqueous potassium carbonate (626 μΙ) in 1 ,4-dioxane (2.504 ml) and then capped. The reaction was heated in an aluminum block at 100 °C for 3 hours. The resulting dark slurry was diluted with methanol then treated with silica powder and evaporated under reduced pressure to dryness. This was purified by silica gel flash chromatography eluting with 20% hexanes/EtOAc, followed by preparative HPLC. The combined desired HPLC fractions were treated with saturated aqueous sodium bicarbonate (5 ml) then concentrated under reduced pressure to a slurry. The solids were collected, rinsed with water then vacuum dried to afford 63 mg of the titled compound as a white solid. LCMS m/z 420.2 (M+H).
Example 63
A -[4-(1 -Benzofuran-5-yl)-2-fluorophenyl]-2-[(3S)-1 -Cyclopropylcarbonyl)-3- pyrrolidinyl]-A -methylacetamide
A 25 ml microwave vial was charged with a suspension of N-(4-bromo-2-fluorophenyl)-2- [(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]-N-methylacetamide (120 mg), 5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 -benzofuran (1 15 mg), Pd(dppf)CI2-CH2CI2 adduct (12.78 mg) and 2.0 M aqueous potassium carbonate (626 μΙ) in 1 ,4-dioxane (2.504 ml) and then capped. The reaction was heated in an aluminum block at 100 °C for 4 hours. The resulting dark slurry was diluted with brine and extracted into ethyl acetate then the extracts were dried over sodium sulfate and evaporated under reduced pressure and the resulting crude solid purified by reverse phase HPLC. The combined desired HPLC fractions were treated with saturated aqueous sodium bicarbonate (10 ml) then extracted with DCM, which was then dried over sodium sulfate and evaporated in vacuo to afford 86 mg of the titled compound as a light yellow solid. LCMS m/z 421 .1 (M+H).
Example 64
2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-A -[2-fluoro-4-(2-naphthalenyl)phenyl]-A - methylacetamide
A 25 ml microwave vial was charged with a suspension of N-(4-bromo-2-fluorophenyl)-2- [(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]-N-methylacetamide (120 mg), 2- naphthalenylboronic acid (81 mgl), 2.0 M aqueous potassium carbonate (0.626 ml) and Pd(dppf)CI2-CH2CI2 adduct (12.78 mg) in 1 ,4-dioxane (2.504 ml) and then capped. The reaction was heated in an aluminum block at 100 °C for 4 hours. The resulting dark solution was diluted with methanol, treated with silica powder (~1 g) then evaporated to dryness. This was purified by silica gel column chromatograpy eluting with EtOAc, followed by preparative reverse phase HPLC. The combined desired HPLC fractions were evaporated to a residue that was purified a second time by reverse phase HPLC. The combined desired fractions were treated with saturated aqueous sodium bicarbonate (10 ml) then extracted into DCM. The extracts were dried over sodium sulfate and evaporated to a colorless residue. This was dissolved into acetonitrile (~1 ml) and diluted with water (~5ml) then frozen and lyophilized to afford 103 mg of the titled compound. LCMS m/z 431.2 (M+H).
Example 65
A -(4'-Cyano-3-fluoro-4-biphenylyl)-2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-A - methylacetamide
A 25 ml microwave vial was charged with a suspension of N-(4-bromo-2-fluorophenyl)-2- [(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]-N-methylacetamide (120 mg), (4- cyanophenyl)boronic acid (69.0 mg), Pd(dppf)CI2-CH2CI2 adduct (12.78 mg) and 2.0 M aqueous potassium carbonate (0.626 ml) in 1 ,4-dioxane (2.504 ml) and then capped. The reaction was heated in an aluminum block at 100 °C for 4 hours. The resulting dark solution was diluted with methanol, treated with silica powder (~1 g) then evaporated to dryness. This was purified by silica gel flash chromatography eluting with EtOAc, followed by preparative reverse phase HPLC. The combined desired HPLC fractions were treated with saturated aqueous sodium bicarbonate (10 ml) then extracted with dichloromethane. The extracts were dried over sodium sulfate and evaporated to a colorless residue, which was dissolved into acetonitrile (~1 ml) and diluted with water (~5ml) then frozen and lyophilized to afford 83 mg of the titled compound as a white solid.
Example 66
2-[(3S)-1 -Cyclopropylcarbonyl)-3^yrrolidinyl]-A -[2-fluoro-4-(6-quinolinyl)phenyl]-A - methylacetamide
A 25 ml microwave vial was charged with a suspension of N-(4-bromo-2-fluorophenyl)-2- [(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]-N-methylacetamide (151 mg), 6- quinolinylboronic acid (102 mg), Pd(dppf)CI2-CH2CI2 adduct (16.09 mg) and 2.0 M aqueous potassium carbonate (0.788 ml_l) in 1 ,4-dioxane (3.15 ml.) and then capped. The reaction was heated in an aluminum block at 95 °C for 18 hours. The resulting dark slurry was diluted with methanol, treated with silica powder (~1 g) then evaporated under reduced pressure to dryness. This was purified by silica gel flash chromatography eluting with EtOAc and then 3% MeOH/EtOAC, followed by preparative reverse phase HPLC. The desired HPLC fractions were combined and evaporated to a foam that was purified a second time by reverse phase HPLC. The combined desired HPLC fractions were treated with saturated aqueous sodium bicarbonate (10 ml) then extracted into DCM. The extracts were dried over sodium sulfate and evaporated to a colorless residue. This was dissolved into acetonitrile (-1 ml) and diluted with water (~3ml) then frozen and lyophilized to afford 1 10 mg of the titled compound as a white solid. LCMS m/z 432.2 (M+H). Example 67
2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-A -[2-fluoro-4-(7-quinolinyl)phenyl]-A - methylacetamide
A 25 ml microwave vial was charged with a suspension of N-(4-bromo-2-fluorophenyl)-2- [(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]-N-methylacetamide (199 mg), 7-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline (199 mg), Pd(dppf)CI2-CH2CI2 adduct (21 .20 mg) and 2.0 M aqueous potassium carbonate (1.038 ml) in 1 ,4-dioxane (6.24 ml) and then capped. The reaction was heated in an aluminum block at 95 °C for 3 hours. The resulting dark slurry was diluted with water and extracted into ethyl acetate then the extracts were dried with sodium sulfate, treated with silica powder (~2g) and evaporated under reduced pressure to dryness. This was purified by silica gel flash chromatography eluting with a gradient of 0-7% MeOH/EtOAc, followed by preparative reverse phase HPLC. The desired HPLC fractions were combined and evaporated under reduced pressure to a brown-orange residue that was purified a second time by reverse phase HPLC. The desired fractions were combined, treated with saturated aqueous sodium bicarbonate (~10ml) then concentrated under reduced pressure. The resulting cloudy solution was extracted with DCM and the extracts were dried over sodium sulfate and evaporated under reduced pressure. The resulting colorless oil was dissolved in acetonitrile (1 ml) then water (2ml) was added and the solution was frozen and lyophilized to afford 138 mg of the titled compound as a white solid. LCMS m/z 432.3 (M+H).
Example 68
2-[1 -Cyclopropylcarbonyl)-3-azetidinyl]-N-[2-fluoro-4-(1 H-indol-5-yl)phenyl]-N- methylacetamide
(a) 1 ,1 -Dimethylethyl 3-{2-[(4-bromo-2-fluorophenyl)amino]-2-oxoethyl}-1 - azetidinecarboxylate
To a stirred solution of (1 -{[(1 ,1 -dimethylethyl)oxy]carbonyl}-3-azetidinyl)acetic acid (1 .0 g) and N-methylmorpholine (51 1 μΙ) in anhydrous THF (46 mL) cooled to 0 °C was added neat ethyl chloroformate (446 μΙ). After 10 minutes, the resulting cloudy solution was treaetd with solid 4-bromo-2-fluoroaniline (883 mg) in one portion. The ice bath was removed and stirring continued at room temperature for 3 days. The cloudy solution was treated with silica powder (~5g) then evaporated under reduced pressure to dryness. This was purified by silica gel flash chromatography eluting with a gradient of 30-50% EtOAc/hexanes. The desired fractions were combined and evaporated under reduced pressure then evaporated again from DCM (2x) to afford 1 .08 g of the titled compound as a white solid. LCMS m/z 387.0 (M+H). (b) N-(4-Bromo-2-fluorophenyl)-2-[1 -Cyclopropylcarbonyl)-3-azetidinyl]acetamide
A flask cooled to 0 °C and charged with solid 1 , 1 -dimethylethyl 3-{2-[(4-bromo-2- fluorophenyl)amino]-2-oxoethyl}-1-azetidinecarboxylate (1 .0 g) was treated with a solution of trifluoroacetic acid (2.0 ml.) in anhydrous DCM (20 ml_). The ice bath was removed and stirring continued for 2 hours whereupon the solvents were removed under reduced pressure. The resulting oil was taken into anhydrous DCM (20 ml_), cooled to 0 °C then treated successively with neat triethylamine (1.440 ml.) and cyclopropylcarbonyl chloride (0.284 ml_). After 3 hours, the reaction was quenched with saturated aqueous sodium bicarbonate then extracted with DCM. The extracts were dried over sodium sulfate, treated with silica powder then evaporated under reduced pressure to dryness. This was purified by silica gel flash chromatography eluting with a gradient of 50-100% EtOAc/hexanes to afford 426 mg of the titled compound. LCMS m/z 355.2, (M+H).
(c) N-(4-Bromo-2-fluorophenyl)-2-[1 -Cyclopropylcarbonyl)-3-azetidinyl]-N- methylacetamide
To a stirred solution of N-(4-bromo-2-fluorophenyl)-2-[1-Cyclopropylcarbonyl)-3- azetidinyl]acetamide (420 mg) in anhydrous DMF (12.0 ml.) was added 60% sodium hydride in mineral oil (56.8 mg) in one portion. After 10 minutes, neat iodomethane (89 μΙ_) was added and stirring continued for 1 hour. The solvents were removed under reduced pressure and the resulting residue was taken into saturated aqueous sodium bicarbonate and extracted into ethyl ether. The extracts were dried over magnesium sulfate, treated with silica powder and then evaporated to dryness. This was purified by silica gel flash chromatography eluting with EtOAc to afford 255 mg of the titled compound as a colorless glass. LCMS m/z 368.9 (M+H).
(d) 2-[1 -Cyclopropylcarbonyl)-3-azetidinyl]-N-[2-fluoro-4-(1 H-indol-5-yl)phenyl]-N- methylacetamide
A flask was charged with a suspension of N-(4-bromo-2-fluorophenyl)-2-[1 - Cyclopropylcarbonyl)-3-azetidinyl]-N-methylacetamide (126 mg), 5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-indole (124 mg), Pd(dppf)CI2-CH2CI2 adduct (13.93 mg) and 2.0 M aqueous potassium carbonate (0.683 ml) in 1 ,4-dioxane (2.73 ml) then heated at 100 °C for 1 hour. The resulting dark slurry was cooled and diluted with brine then extracted with ethyl acetate. The extracts were dried over sodium sulfate then treated with silica powder (~1 g) and evaporated under reduced pressure to dryness. This was purified by silica gel flash chromatography eluting with EtOAc, followed by preparative reverse phase HPLC. The combined desired fractions were treated with saturated aqueous sodium bicarbonate (10 ml) then extracted into DCM. The extracts were dried over sodium sulfate and evaporated to a colorless residue. This was dissolved into acetonitrile (~1 ml) and diluted with water (~3ml) then frozen and lyophilized to afford 103 mg of the titled compound. LCMS m/z 406.4 (M+H).
Example 69
2-[1 -Cyclopropylcarbonyl)-3-azetidinyl]-A -[2-fluoro-4-(7-quinolinyl)phenyl]-W- methylacetamide
A 25 ml microwave vial was charged with a suspension of N-(4-bromo-2-fluorophenyl)-2-[1 - Cyclopropylcarbonyl)-3-azetidinyl]-N-methylacetamide (126 mg), 7-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)quinoline (131 mg), Pd(dppf)CI2-CH2CI2 adduct (13.93 mg) and 2.0 M aqueous potassium carbonate (0.683 ml) in 1 ,4-dioxane (2.73 ml) and then capped. The reaction was heated in an aluminum block at 100 °C for 1 hour. The resulting dark slurry was cooled to room temperature then diluted brine and extracted with ethyl acetate. The extracts were dried over sodium sulfate then treated with silica powder (~1 g) and evaporated under reduced pressure to dryness. This was placed purified by silica gel flash chromatography eluting with EtOAc and then 3% MeOH/EtOAc, followed by preparative reverse phase HPLC. The combined desired fractions were treated with saturated aqueous sodium bicarbonate (10 ml) then extracted into DCM. The extracts were dried over sodium sulfate and evaporated to a colorless residue. This was dissolved into acetonitrile (~1 ml) and diluted with water (~3ml) then frozen and lyophilized to afford 100 mg of the titled compound as a white solid. LCMS m/z 418.2 (M+H).
Biological Assays
FAS assay
FAS activity was measured through one of the two following assays.
Assay #1 :
Inhibition of FAS activity can be measured based on the detection of residual NADPH substrate after the FAS assay is quenched. This assay is run as a 10 μΙ_ endpoint assay in 384-well format, where the reaction contains 20 μΜ malonyl-CoA, 2 μΜ acetyl-CoA, 30 μΜ NADPH and 40 nM FAS in 50 mM sodium phosphate, pH 7.0. The assay is run by sequentially dispensing 5 μΙ of a malonyl-CoA solution, then enzyme solution Containing the acetyl-CoA, and NADPH) into a black, low volume assay plate (Greiner 784076) pre- dispensed with 100 nL compound solutions in DMSO. The reaction is incubated at ambient temperature for 60 minutes, then quenched with 5 μΙ_ of a developing solution composed of 90 μΜ resazurin, 0.3 lU/ml diaphorase in 50 mM sodium phosphate, pH 7.0. The developed reaction is read on a Molecular Devices Analyst or Acquest (or equivalent) plate reader using a 530 nm excitation wavelength filter, a 580 nm emission filter, and 561 nm dichroic filter. The test compounds are prepared in neat DMSO at a concentration of 10 mM. For inhibition curves, compounds are diluted using a three fold serial dilution and tested at 1 1 concentrations (e.g. 25 μΜ-0.42 nM). Curves are analysed using ActivityBase and XLfit, and results are expressed as plC50 values.
Assay #2:
Inhibition of FAS can also be quantified based on the detection of the CoA products with a thio-reactive coumarin dye. This assay is run as a 10 μΙ_ endpoint assay in 384-well format, where the reaction contains 20 μΜ malonyl-CoA, 20 μΜ acetyl-CoA, 40 μΜ NADPH and 2 nM FAS in 50 mM sodium phosphate, pH 7.0, and 0.04% Tween-20. The assay is run by adding 5 μΙ_ enzyme solution to a black, low volume assay plate (Greiner 784076) pre- dispensed with 100 nl compound solutions in DMSO. After 30 minutes, 5 μΙ_ substrate is added, and the reaction incubated at ambient temperature for an additional 60 minutes. The reaction is then quenched with 10 μΙ_ of 6M guanidine-HCI containing 50 μΜ CPM (7- diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin CPM; thio-reactive dye), and incubated for 30 minutes. The plate is read on an Envision (PerkinElmer) or equivalent plate reader using a 380 nm excitation wavelength filter, and a 486 nm emission filter. Data fitting and compound preparations are done as described above.
Biological data
Exemplified compounds of the present invention (Examples 1 - 69) were tested according to the above assays and were found to be inhibitors of FAS. The IC50 values ranged from about 1 to about 2,000 nM; the IC50 values of the certain compounds ranged from about 1 to about 100 nM. The compounds described below were tested generally according to the assays described herein. The IC50 for each compound was either reported in at least one experiment or the average of multiple experiments.
Example 4 79 nM
Example 7 50 nM
Example 8 100 nM
Example 9 100 nM
Example 14: 20 nM
Example 15: 100
Example 16: 25 nM Example 20: 50 nM
Example 59: 79 nM
Example 61: 32 nM
Example 66: 25 nM
Example 63: 100 nM
Example 64: 50 nM
Example 67: 31 nM
Example 68: 25 nM
Example 69: 32 nM
Lipogenesis assay
Cultured primary human pre-adipocytes (Zen-Bio, Cat# ASC062801 ) are plated at confluence (3x104 cells/well) in 96-well plates Costar, Cat# 3598) coated with 0.2% gelatin (Sigma, Cat# G-6650) in DMEM/F12 medium (InvitroGen Cat# 1 1330-032) supplemented with 10% heat inactivated fetal bovine serum (InvitroGen, Cat# 16000-044. The following day (day 1 ) the cell differentiation is induced by replacing the seeding medium with the differentiation medium composed of DMEM/F12 medium supplemented with 10% heat inactivated fetal bovine serum, 200 μΜ 3-isobutyl-1-methylxanthine (Sigma, Cat# I-5879), 20 nM dexamethasone (Sigma, Cat# D-8893), 20 nM GW1929 (Sigma, Cat# G5668) and 20 nM insulin (InvitroGen, Cat# 03-01 10SA). On day 7, differentiation medium is replaced by the re-feed medium made of DMEM/F12 supplemented with 10% heat inactivated serum and 20 nM insulin. The appropriate concentration of tested compounds and controls are added into this medium at that time. On day 12, the relative amount of cellular triglyceride is estimated by using a Trinder kit (Sigma, Cat# TR0100). Re-feed medium is aspirated and cells are washed with PBS (InvitroGen, Cat# 14190-144 and the assay is performed according the kit manufacturer protocol. Briefly, reconstituted solutions A and B are mixed with 0,01 % digitonin (Sigma, Cat# D-5628) prior to performing the assay and added onto the cells; plates are incubated at 37 °C for one hour. The absorbance is read at 540 nm. The data is first normalized using the following equation: 100* ((UNK - Control 1 ) / Control 2 - Control 1 )) where Control 1 is the Robust Mean of the 0% response control and Control 2 is the Robust Mean of the 100% response control. When multiple dilutions of compounds are tested, pXC50 are calculated from curves using the 4-parameter curve fitting with the following equation: y=(a-d)/(1 +(s/c)Ab)+d and with IRLS (Iterative Re-weighted Least Squares) algorithms to weight outliers (Mosteller, F. & Tukey J.W. (1977 Data Analysis and Regression, pp 353-365, Addison-Wesley).

Claims

CLAIMS:
1. A compound according to Formula (I),
Figure imgf000103_0001
wherein
R1 is phenyl, 5- or 6-membered heteroaryl, napthyl, 9- or 10-membered heterocyclyl; wherein said phenyl, 5- or 6-membered heteroaryl, napthyl, or 9- or 10-membered heterocyclyl is optionally substituted with from 1 to 3 substituents independently selected from halogen, C C alkyl, -CF3, C3-C7cycloalkyl, -C(0)C C4alkyl, -C(0)C3-C7cycloalkyl, - CO(phenyl), -C C4(=0)OH, -C(=0)OC C4alkyl, -CONR5R6, phenyl, -S02C C4alkyl, -S02NR5R6, cyano, oxo, hydroxyl, C C alkoxy, C3-C7cycloalkoxy, hydroxyCrC alkyl-,
Figure imgf000103_0002
-OCF3, -NR5R6, R5R6NCrC4alkyl-, -NHC(0)C C4alkyl, - NHCONR5R6, -NHS02C C4alkyl, -NHS02NR5R6, and R9;
R5 is selected from the group consisting of hydrogen, CrC4alkyl, phenyl, and C C3alkylphenyl;
R6 is hydrogen or CrC4alkyl;
or R5 and R6 taken together with the nitrogen to which they are attached represent a 3- to 7-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, which is optionally substituted 1 or 2 times independently by oxo or C C4alkyl;
R9 is a 5-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents selected from halogen, C C alkyl, C C4alkoxy, and -NR5R6;
each R2 is independently selected from the group consisting of halogen, C C6alkyl, hydroxyl, CF3 and C C alkoxy;
A is selected from
Figure imgf000104_0001
(a)
R3 is selected from the group consisting of C C alkyl, heteroaryl,
CrC alkyl6-membered heteroaryl, and C C4alkylphenyi;
R4 is selected from the group consisting of C C6alkyl, -CF3, C3-C7cycloalkyl, C C4alkoxy, and -NR7R8; wherein C3-C7cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from the group of halogen, C C4alkyl, C C4alkoxy, and -CONR7R8;
R7 and R8 are each independently selected from hydrogen and CrC4alkyl, or R7 and R8 taken together with the nitrogen to which they are attached represent a 3- to 7-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen, and sulfur;
m is 0, 1 or 2;
n is 1 or 2;
X is CH2;
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 according to Formula (l)(A),
Figure imgf000104_0002
(l)(A)
wherein
R is phenyl, 5- or 6-membered heteroaryl, napthyl, 9- or 10-membered heterocyclyl; wherein said phenyl, 5- or 6-membered heteroaryl, napthyl, or 9- or 10-membered heterocyclyl is optionally substituted with from 1 to 3 substituents independently selected from halogen, CrC4alkyl, -CF3, C3-C7cycloalkyl, -C(0)C C4alkyl, -C(0)C3-C7cycloalkyl, - CO(phenyl), -C C4(=0)OH, -C(=0)OC C4alkyl, -CONR5R6, phenyl, -S02C C4alkyl, -S02NR5R6, cyano, oxo, hydroxyl, C C alkoxy, C3-C7cycloalkoxy, hydroxyCrC4alkyl-, C1-C4alkoxyC1-C4alkyl-, -OCF3, -NR5R6, R5R6NC C4alkyl-, -NHC(0)C C4alkyl, - NHCONR5R6, -NHS02C C4alkyl, -NHS02NR5R6, and R9;
R5 is selected from the group consisting of hydrogen, C C4alkyl, phenyl, and CrC3alkylphenyl;
R6 is hydrogen or C C4alkyl;
or R5 and R6 taken together with the nitrogen to which they are attached represent a 3- to 7-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, which is optionally substituted 1 or 2 times independently by oxo or CrC4alkyl; R9 is a 5-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents selected from halogen, CrC4alkyl, C C4alkoxy, and -NR5R6;
each R2 is independently selected from the group consisting of halogen, CrC6alkyl, hydroxyl, CF3 and C C alkoxy;
R3 is selected from the group consisting of CrC alkyl, heteroaryl,
C C alkyl6-membered heteroaryl, and CrC4alkylphenyl;
R4 is selected from the group consisting of C C6alkyl, -CF3, C3-C7cycloalkyl,
C C4alkoxy, and -NR7R8; wherein C3-C7cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from the group of halogen, C C alkyl, C C4alkoxy, and -CONR7R8;
R7 and R8 are each independently selected from hydrogen and C C4alkyl, or R7 and R8 taken together with the nitrogen to which they are attached represent a 3- to 7-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen, and sulfur;
m is 0, 1 or 2;
n is 1 or 2;
X is CH2;
or a pharmaceutically acceptable salt thereof.
3. A compound of claim 1 according to Formula (l)(B),
Figure imgf000106_0001
(0(B)
wherein
R1 is phenyl, 5- or 6-membered heteroaryl, napthyl, 9- or 10-membered heterocyclyl; wherein said phenyl, 5- or 6-membered heteroaryl, napthyl, or 9- or 10-membered heterocyclyl is optionally substituted with from 1 to 3 substituents independently selected from halogen, C C4alkyl, -CF3, C3-C7cycloalkyl, -C(0)C C4alkyl, -C(0)C3-C7cycloalkyl, - CO(phenyl), -C C4(=0)OH, -C(=0)OC C4alkyl, -CONR5R6, phenyl, -S02CrC4alkyl, -S02NR5R6, cyano, oxo, hydroxyl, C C4alkoxy, C3-C7cycloalkoxy, hydroxyCrC4alkyl-, CrCalkoxyd-Qalkyl-, -OCF3, -NR5R6, R5R6NC C4alkyl-, -NHC(0)C C4alkyl, - NHCONR5R6, -NHS02C C4alkyl, -NHS02NR5R6, and R9;
R5 is selected from the group consisting of hydrogen, CrC alkyl, phenyl, and C C3alkylphenyl;
R6 is hydrogen or Ci-C4alkyl;
or R5 and R6 taken together with the nitrogen to which they are attached represent a 3- to 7-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur, which is optionally substituted 1 or 2 times independently by oxo or C C4alkyl;
R9 is a 5-membered heteroaryl ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, which is optionally substituted with 1 or 2 substituents selected from halogen, C C4alkyl, C C4alkoxy, and -NR5R6;
each R2 is independently selected from the group consisting of halogen, CrC6alkyl, hydroxyl, CF3 and C C alkoxy;
R3 is selected from the group consisting of C C4alkyl, heteroaryl,
C C4alkyl6-membered heteroaryl, and C C4alkylphenyl;
R4 is selected from the group consisting of C C6alkyl, -CF3, C3-C7cycloalkyl,
C C4alkoxy, and -NR7R8; wherein C3-C7cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from the group of halogen, C C4alkyl, CrC4alkoxy, and -CONR7R8;
R7 and ¥ia are each independently selected from hydrogen and C C4alkyl, or R7 and R8 taken together with the nitrogen to which they are attached represent a 3- to 7-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen, and sulfur;
m is 0, 1 or 2;
n is 1 or 2;
X is CH2;
or a pharmaceutically acceptable salt thereof.
4. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein R1 is phenyl optionally substituted with from 1 to 3 substituents independently selected from halogen, C C4alkyl, -CF3, C3-C7cycloalkyl, -C(0)C C4alkyl, -C(0)C3- C7cycloalkyl, -CO(phenyl), -C C4(=0)OH, -C(=0)OCrC4alkyl, -CONR5R6, phenyl, - S02C1-C4alkyl, -S02NR5R6, cyano, oxo, hydroxyl, C C alkoxy, C3-C7cycloalkoxy, hydroxyC C4alkyl-, C1-C4alkoxyC1-C4alkyl-I -OCF3, -NR5R6, R5R6NC C4alkyl-,
-NHC(0)C C4alkyl, -NHCONR5R6, -NHS02CrC4alkyl, -NHS02NR5R6, and R9.
5. A compound or pharmaceutically acceptable salt according to anyone of claims 1 to 3, wherein R1 is selected from furanyl, thienyl, pyrroiyi, imidazoiyi, pyrazolyl, triazoiyi, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, wherein said furanyl, thienyl, pyrroiyi, imidazoiyi, pyrazolyl, triazoiyi, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl all of which are optionally substituted with from 1 to 3 substituents independently selected from halogen, CVC4alkyl, -CF3, C3-C7cycloalkyl, -C(0)C.,-C4alkyl, -C(0)C3-C7cycloalkyl, -C(0)phenyl, -C C4(=0)OH, -C(=0)OC C4alkyl, -C02C C4alkyl, -C(0)NR5R6, phenyl, -S02C C4alkyl, -S02NR5R6, cyano, oxo, hydroxyl, CrC4alkoxy, C3-C7cycloalkoxy, hydroxyC C4alkyl-,
d-C^lkoxyd^alkyl-, -OCF3, -NR5R6, R5R6NC C4alkyl-, -NHC(0)C C4alkyl, - NHCONR5R6, -NHS02C C4alkyl, and -NHS02NR5R6.
6. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein R is napthyl optionally substituted with from 1 to 3 substituents independently selected from halogen, C C alkyl, -CF3, C3-C7cycloalkyl, -C(0)C C4alkyl, -C(0)C3- C7cycloalkyl, -CO(phenyl), -C1-C4(=0)OH, -C(=0)OC C4alkyl, -CONR5R6, phenyl, - S02C C alkyl, -S02NR5R6, cyano, oxo, hydroxyl, C C4alkoxy, C3-C7cycloalkoxy, hydroxyC C4alkyl-, C1-C4alkoxyC1-C4alkyl-, -OCF3, -NR5R6, R5R6NC C4alkyl-,
-NHC(0)CrC4alkyl, -NHCONR5R6, -NHS02C C4aikyl, -NHS02NR5R6, and R9.
7. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein R is benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1 ,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyi, indolizinyl, indolyl, isoindoiyi, indolinyl, isoindoiinyl, 1-H- indazolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl,
pyrazolopyrimidinyi, benzoxadiazoiyi, benzthiadiazolyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyi, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7- naphthyridinyl, 1 ,8-naphthyridinyl, or pteridinyl, wherein said benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1 ,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyi, indolizinyl, indolyl, isoindoiyi, indolinyl, isoindoiinyl, 1 -H-indazolyl, benzimidazolyl,
dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyi, benzoxadiazoiyi, benzthiadiazolyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyi, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1 ,8-naphthyridinyl, and pteridinyl all of which are optionally substituted with from 1 to 3 substituents independently selected from halogen, C C4alkyl, -CF3, C3-C7cycloalkyl, -C(0)C C4alkyl, -C(0)C3-C7cycloalkyl, -C(0)phenyl, -C C4(=0)OH, -C(=0)OC C4alkyl, -C(0)NR5R6, phenyl, -S02CrC4alkyl, -S02NR5R6, cyano, oxo, hydroxyl, Ci-C4alkoxy, C3-C7cycloalkoxy, hydroxyC C alkyl-, CrC4alkoxyCi-C4alkyl-, -OCF3, -NR5R6, R5R6NC C4alkyl-, -NHC(0)C C4alkyl, -NHC(0)NR5R6, -NHS02C C4alkyl, - NHS02NR5R6, and R9.
8. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein R2 is fluoro, hydroxyl, methyl, or methoxy.
9. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein R3 is selected from C C4alkyl, pyridinyl, pyrimidynyl, and -Ci-C alkylphenyl.
10. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 9, wherein R4 is cyclopropyl.
1 1. The compound or pharmaceutically acceptable salt according claim 1 , wherein:
R is selected from the group of: phenyl, indolyl, benzofuranyl, indazolyl,
benzoimidazolinyl, napthalyl, quinolyl, and wherein said phenyl is optionally substituted with from 1 to 3 substituents independently selected from: methyloxy, cyano, NR5R6 and halogen,
107
RECTIFIED (RULE 91) - ISA/US each R2 is selected from the group consisting of halogen, C C6alkyl, hydroxyl, and C C4alkoxy;
R3 is selected from the group consisting of CrC4alkyl, pyridinyl, pyrimidynyl, phenyl and -C -C4alkyiphenyl; and
R4 is selected from the group consisting of C C6alkyl and cyclopropyl;
m is 0, 1 or 2;
n is 1 or 2;
X is CH2
or pharmaceutically acceptable salt thereof.
12. The compound or pharmaceutically acceptable salt according to claim 1 selected from:
A/-{[(3RS)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A/-methyl-4- biphenylcarboxamide;
/V-{[1 -Cyclopropylcarbonyl)-3(RS)-pyrrolidinyl]methyl}-3-methyloxy-/\/-methyl- 4-biphenylcarboxamide;
A/-{[1 -Cyclopropylcarb0nyl)-3(RS)-pyrrolidinyl]methyl}-3-hydr0xy-A/-methyl-4- biphenylcarboxamide;
A/-{[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-6-yl)- - methylbenzamide;
A/-{[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/V-methyl-4'- (methyloxy)-4-biphenylcarboxamide;
3'-Chloro-A/-{[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4'-fiuoro-A/- methyl-4-biphenyicarboxamide;
A/-{[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 /-/-indol-5-yl)-/V- methylbenzamide;
A/-{[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 V-indazol-5-yl)-/V- methylbenzamide;
/V-{[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 /-/-indazol-6-yl)-/V- methylbenzamide;
4-(1-Benzofuran-5-yl)-/V-{[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}- /V-methylbenzamide;
4-(1 H-benzimidazol-5-yl)-/V-{[(3S)-1 -Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-A/-methylbenzamide;
/V-{[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-4-yl)- \/- methylbenzamide;
A/-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 /-/-indol-7-yl)-/V- methylbenzamide;
A/-{[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-fluoro-4-(1 /-/-indol-5- yl)-/V-methylbenzamide;
108
RECTIFIED (RULE 91) - ISA/US 4-(1-Benzofuran-5-yl)- -{[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}- 2-fluoro-/V-methylbenzamide;
/V-{[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-fluoro-4-(1 /-/-indol-6- yl)-/\/-methylbenzamide;
4'-Cyano-/V-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-3-fluoro-/\/- methyl-4-biphenylcarboxamide;
/V-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-3-fluoro-/V-methyl-4'- (methyloxy)-4-biphenylcarboxamide;
4-(1-Benzofuran-5-yl)-A/-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]nnethyl}- A/,2-dimethylbenzamide;
A/-{[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 /-/-indol-5-yl)-/\/,2- dimethylbenzamide;
4'-Cyano-A/-{[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/,3-dimethyl- 4-biphenylcarboxamide;
/V-{[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4'-(dimethylamino)-/V,3- dimethyl-4-biphenylcarboxamide;
A/-{[(3S)-1-Cyclopropylcarbonyi)-3-pyrrolidinyl]nπethyl}-/ ,3-dimethyl-4,- (methyloxy)-4-biphenylcarboxamide;
4-(1 -Benzofuran-5-yl)-/V-{[(3f?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-V-ethylbenzamide;
4-{1 H-Benzimidazol-5-yl)-/V-{[(3ft)-1 -Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-/V-ethylbenzamide;
W-{[(3f?)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/V-ethyl-4-(1 H-indol-4- yl)benzamide;
A/-{[(3/?)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A/-ethyl-4-(1 H-indol-7- yl)benzamide;
N-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-N-ethyl-4'-(nnethyloxy)- 4-biphenylcarboxamide;
3'-Chloro-A/-{[(3«)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/V-ethyi-4'- fluoro-4-biphenylcarboxamide;
A/-{[(3/^)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A/-ethyl-4-(1 H-indazol- 6-yl)benzamide;
/\/-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/V-ethyl-4-(1 /-/-indol-6- yl)benzamide;
A/-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A/-ethyl-4-(1 /-/-indol-5- yl)benzamide;
A/-{[(3RS)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-/\/-(1 -iTiethylethyl)-4- biphenylcarboxamide;
A/-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indazol-6-yl)-/V- (l-methylethyl)benzamide;
A/-{[(3f?)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 /-/-indazol-5-yl)-/\/- (l-methylethyl)benzamide;
A/-{[(3f?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-5-yl)-A/-(1 - methylethyl)benzamide; /V-{[(3f?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 /-/-indol-6-yl)-A/-(1 - methylethyl)benzamide;
4-(1-Benzofuran-5-yl)-/V-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}- A/-(1-methylethyl)benzamide;
4-(1 H-Benzimidazol-5-yl)-/V-{[(3^)-1-Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-/V-(1 -methylethyl)benzamide;
A/-{[(3/ )-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-7-yl)- -(1- methylethyl)benzamide;
3'-Chloro-/V-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4'-fluoro-W- (1-methylethyl)-4-biphenylcarboxamide;
A/-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-A/-(1-methylethyl)-4'- (methyloxy)-4-biphenylcarboxamide;
A/-{[(3ft)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 /-/-indol-4-yl)-A/-(1 - methylethyl)benzamide;
A/-{[(3/^)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]nriethyl}-4-(1 /-/-indazol-5-yi)-A/- (phenylmethyl)benzamide;
A/-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indazol-6-yl)-/V- (phenylmethyl)benzamide;
/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 /-/-indol-5-yl)-/V- (phenylmethyl)benzamide;
4-(1 -Benzofuran-5-yl)-A/-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]rriethyl}- A/-(phenylmethyl)benzamide;
4-(1 W-Benzimidazol-5-yl)-/V-{[(3R)-1-Cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-A/-(phenylmethyl)benzannide;
A/-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4'-(methyloxy)-/V- (phenylmethyl)-4-biphenylcarboxamide;
/V-{[(3^)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 /-/-indol-6-yl)-/V- (phenylmethyl)benzamide;
/V-{[(3R)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 /-/-indol-4-yl)-/V- (phenylmethyl)benzamide;
A/-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-7-yl)-/V- (phenylmethyl)benzamide;
3'-Chloro-A/-{[(3 :?)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4'-fluoro-/\/- (phenylmethyl)-4-biphenylcarboxamide;
\/-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 /-/-indol-5-yl)-A -3- pyridinylbenzamide;
/V-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 /-/-indol-6-yl)-A/-3- pyridinylbenzamide;
A/-{[(3R)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-5-yl)- -2- pyrazinylbenzamide;
N-[4-(1 -Benzofuran-5-yl)phenyl]-2-[(3S)-1-Cyclopropylcarbonyl)-3- pyrrolidinyl]-N-methylacetamide;
A/-(4'-Cyano-4-biphenylyl)-2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-/V- methylacetamide; 2-[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]-A/-methyl-/V-[4-(2- naphthalenyl)phenyl]acetamide;
2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-/V-methyl-A/-[4-(6- quinolinyl)phenyl]acetamide;
2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-/V-[4-(1 /-/-indol-5-yl)phenyl]-A/- methylacetamide;
2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-/V-[2-fluoro-4-(1 /-/-indol-5- yl)phenyl]-/ -methyiacetamide ;
-[4-(1-Benzofuran-5-yl)-2-fluorophenyl]-2-[(3S)-1-Cyclopropylcarbonyl)-3- pyrrolidinyl]-/v-methylacetamide;
2-[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]-/V-[2-fluoro-4-(2- naphthalenyl)phenyl]-/V-methylacetamide;
/V-(4'-Cyano-3-fluoro-4-biphenylyl)-2-[(3S)-1-Cyclopropylcarbonyl)-3- pyrrolidinyl]-A/-methylacetamide;
2-[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]-/V-[2-fluoro-4-(6- quinolinyl)phenyl]-A/-methylacetamide;
2-[(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]-/V-[2-fluoro-4-(7- quinolinyl)phenyl]-/V-methylacetamide;
2-[1 -Cyclopropylcarbonyl)-3-azetidinyl]-N-[2-fluoro-4-(1 H-indol-5-yl)phenyl]-N- methylacetamide; and
2-[1 -Cyclopropylcarbonyl)-3-azetidinyl]-/V-[2-fluoro-4-(7-quinolinyl)phenyl]-/V- methylacetamide.
13. A compound according to any one of claims 1 to 11 wherein when n is 2 the compound has an enantiomeric excess of one enantiomer over the other.
14. A compound according to Formula (l)(A) of claim 2 wherein when n is 2 the compound is an enantiomerically pure R isomer.
15. A compound according to Formula (l)(B) of claim 3 wherein when n is 2 the compound is an enantiomerically pure S isomer.
16. A pharmaceutical composition comprising the compound or salt according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier.
17. A method of treating cancer comprising administering to a human in need thereof an effective amount of a compound according to any one of claims 1 to 16.
18. The method of claim 17 wherein the cancer is selected from the group consisting of: brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, renal, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, bladder, stomach, and giant cell tumor of bone and thyroid. ill
19. A method of treating cancer in a mammal in need thereof, which comprises: administering to such mammal a therapeutically effective amount of a) a compound of Formula (I), as described in claim 1 or a pharmaceutically acceptable salt thereof; and
b) at least one anti-neoplastic agent.
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