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WO2005118584A2 - Saframycin analogs as therapeutic agents in the treatment of cancer - Google Patents

Saframycin analogs as therapeutic agents in the treatment of cancer Download PDF

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Publication number
WO2005118584A2
WO2005118584A2 PCT/US2005/018504 US2005018504W WO2005118584A2 WO 2005118584 A2 WO2005118584 A2 WO 2005118584A2 US 2005018504 W US2005018504 W US 2005018504W WO 2005118584 A2 WO2005118584 A2 WO 2005118584A2
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WIPO (PCT)
Prior art keywords
alkyl
optionally substituted
heteroaryl
heteroaralkyl
hydrogen
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PCT/US2005/018504
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French (fr)
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WO2005118584A3 (en
Inventor
Hyunjin M. Kim
Martin Sendzik
Jeffrey R. Spencer
Penglie Zhang
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Axys Pharmaceuticals, Inc.
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Publication of WO2005118584A2 publication Critical patent/WO2005118584A2/en
Publication of WO2005118584A3 publication Critical patent/WO2005118584A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is directed to saframcyin analogs that are useful in the treatment of cancer.
  • Pharmaceutical compositions and processes for preparing these compounds are also disclosed.
  • Saframycins are a family of natural products that have antiproliferative activity (see Remers, W. Al The Chemistry of Antitumor Antibiotics; Wiley-Interscience, New York, 1988, Vol. 2, Chapter 3).
  • Several saframycin analogues have been isolated and characterized in recent years (see DE 2839668; U.S. Pat. Nos. 4,248,863; 4,372,947, 5,023,184 and EP 329606). Of these, saframycin A and C exhibit extreme cytotoxicity toward several experimental tumors including leukemias L1210 and P388 and Ehrlich carcinoma. Recently, U. S. Application Pub.
  • this invention is directed to a compound of Formula (I):
  • A is a ring represented by formula (a) or (b):
  • B is a ring represented by formula (c) or (d):
  • Y is methylene optionally substituted with one or two halo;
  • R 1 and R 8 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkyisulfinyl, alkylsulfonyl, acyl, cyano, nitro, acylamino, -COOR 13 (where R 13 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -CONR 14 R 15 (where R 14 and R 15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or
  • R 1 and R 8 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, cyano, nitro, acylamino, -COOR 13 (where R 13 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -CONR 14 R 15 (where R 14 and R 15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl
  • this invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
  • this invention is directed to a method for treating cancer in an animal comprising administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the cancer is soft tissue sarcoma, prostate cancer, breast cancer, lung melanoma, stomach cancer, neuroblastoma, colon cancer, pancreatic cancer, ovarian cancer, T-cell lymphoma, or leukemia such as myelogenous leukemia (MM) and acute myelogenous leukemia (AML).
  • leukemia such as myelogenous leukemia (MM) and acute myelogenous leukemia (AML).
  • this invention is directed to a method for treating cancer in an animal which method comprises administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in combination with radiation therapy and optionally in combination with one or more compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HTV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, or a DNA methyl transferase inhibitor.
  • this invention is direct to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.
  • Alicyclic means cycloalkyl and heterocycloalkyl rings as defined herein.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkenyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing one or two double bond(s), e.g., ethenyl, propenyl, 2-propenyl, butenyl (including all isomeric forms), and the like.
  • Alkenyloxy means a radical -OR where alkenyl is as defined above, e.g., allyloxy, and the like.
  • Alkenylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing one or two double bonds, e.g., ethenylene, propenylene, 2-propenylene, butenylene (including all isomeric forms), and the like.
  • Alkynyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing one or two tripe bond(s), e.g., ethynyl, propynyl, 2-propynyl, butynyl (including all isomeric forms), and the like.
  • Alkylthio means a -SR radical where R is alkyl as defined above, e.g., methylthio, ethylthio, propylthio (including all isomeric forms), butylthio (including all isomeric forms), and the like.
  • Alkylsulfmyl means a -S(O)R radical where R is alkyl as defined above, e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl (including all isomeric forms), and the like.
  • Alkylsulfonyl means a -SO 2 R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • Amino means a -NH 2 .
  • Alkylamino means a -NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, n-, ⁇ o-propylamino, n ⁇ , iso-, tert-butylamino, and the like.
  • Alkylaminoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, alkylamino group as defined above e.g., methylaminoethyl, 2-ethylamino-2-methylethyl, and the like.
  • Alkylaminoalkyloxy means a -O-R radial where R is alkylaminoalkyl as defined above, e.g., methylaminoethyloxy, 2-ethylamino-2-methylethyloxy, and the like.
  • Aminosulfonyl means a -SO 2 NRR' where R and R' are independently hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl as defined herein.
  • Alkoxy means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
  • Alkoxycarbonyl means a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
  • Alkoxycarbonylalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, alkoxycarbonyl group as defined above, e.g., methoxycarbonylmethyl, methoxycarbonylethyl, and the like.
  • Alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, preferably one or two alkoxy groups, as defined above, e.g., 2- methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.
  • Alkoxyalkyloxy means a -OR radical where R is alkoxyalkyl as defined above, e.g., methoxyethoxy, 2-ethoxyethoxy, and the like.
  • Alkoxyalkyloxyalkyl means a -(alkylene)-R radical where R is alkoxyalkyloxy as defined above, e.g., methoxyethoxymethyl, 2-ethoxyethoxymethyl, and the like.
  • Aminoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, -NRR' where R is hydrogen, alkyl, or -COR a where R is alkyl, and R' is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or haloalkyl, e.g., aminomethyl, methylaminoethyl, 2-ethylamino-2- methylethyl, 1,3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetylaminopropyl, and the like.
  • Aminoalkoxy or "aminoalkyloxy” means a -OR radical where R is aminoalkyl as defined above, e.g., 2-aminoethoxy, 2-dimethylaminopropoxy, and the like.
  • Aminocarbonyl means a -CONRR radical where each R is independently hydrogen or alkyl as defined above, e.g., -CONH 2 , methylaminocarbonyl, 2-dimethylaminocarbonyl, and the like.
  • Acyl means a -COR radical where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, as defined herein, e.g., acetyl, benzoyl, and the like.
  • Acyloxy means a -OCOR radical where R is alkyl, haloalkyl, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl_as defined herein, e.g., acetyloxy, benzoyloxy, and the like.
  • Acylamino means a -NHCOR radical where R is alkyl haloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, as defined herein, e.g., acetylamino, propionylamino, and the like.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms e.g., phenyl, naphthyl or anthracenyl.
  • Aryloxy means a -OR radical where R is aryl as defined above e.g., phenoxy, naphthyloxy, and the like.
  • Alkyl means a -(alkylene)-R radical where R is aryl as defined above, e.g., benzyl.
  • Alkyloxy means a -O-R radical where R is aralkyl as defined above, e.g., benzyloxy, and the like.
  • Alkylaminocarbonyloxy means a -OC(O)NH-(alkylene)-R radical where R is aryl as defined above, e.g., 2-phenethylaminocarbonyloxy, and the like.
  • Alkenyl means a -(alkenylene)-R radical where R is aryl as defined above.
  • Cycloalkyl means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl. The cycloalkyl is optionally substituted with optionally substituted phenyl. Cycloalkylalkyl” means a -(alkylene)-R radical where R is cycloalkyl as defined above; e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl, and the like.
  • Carboxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, -COOH, e.g., carboxymethyl, carboxyethyl, and the like.
  • Dialkylamino means a -NRR' radical where R and R' are independently alkyl as defined above, e.g., dimethylamino, diethylamino, methylpropylamino, methylethylamino, n-, iso-, or tert-butylamino, and the like.
  • Dialkylaminoalkyl means a -(alkylene)-R radical where R is dialkylamino as defined above e.g., dimethylaminomethyl, diethylaminoethyl, and the like.
  • Dialkylaminoalkyloxy means a -OR radical where R is dialkylaminoalkyl as defined above e.g., dimethylaminomethyloxy, diethylaminoethyloxy, and the like.
  • Disubstituted amino means a -NR c R d radical where R c and R d are independently selected from alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl as defined herein, e.g., dimethylamino, diethylamino, methylphenylamino, , and the like.
  • Disubstituted aminoalkyl means a -(alkylene)-R radical where R is disubstituted amino as defined above except R c and R d are not alkyl e.g., dimethylaminomethyl, ethylbenzylaminoethyl, and the like.
  • Disubstituted aminoalkyloxy means a -OR radical where R is disubstituted aminoalkyl as defined above e.g., dimethylaminomethyloxy, ethylbenzyla inoethyloxy, and the like.
  • Halo means fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.
  • Haloalkyl means alkyl substituted with one or more halogen atoms, preferably one to five halogen atoms, preferably fluorine or chlorine, including those substituted with different halogens, e.g., -CH 2 C1, -CF 3 , -CHF 2 , -CF 2 CF 3 , -CF(CH 3 ) 3 , and the like.
  • Haloalkoxy means a -OR radical where R is haloalkyl as defined above e.g., -OCF 3 , - OCHF 2 , and the like.
  • Haloalkoxyalkyl means a -(alkylene)-OR radical where R is haloalkyl as defined above e.g., trifluoromethyloxymethyl, 2,2,2-trifluoroethyloxymethyl, 2-trifluoromethoxyethyl, and the like.
  • Hydrocarbon radical means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2- methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1- (hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1- (hydroxymethyl)-2-hydroxyethyl.
  • "Hydroxyalkoxy" or "hydroxyalkyloxy” means a -OR radical where R is hydroxyalkyl as defined above.
  • Hydroxyalkoxyalkyl or "hydroxyalkyloxyalkyTmeans a -(alkylene)-OR radical where R is hydroxyalkyl as defined above e.g., hydroxymethyloxymethyl, hydroxyethyloxymethyl, and the like.
  • Hydroxylcarbonyloxy means a -OCOR radical where R is hydroxyalkyl as defined above e.g., hydroxymethylcarbonyloxy, and the like.
  • Heterocycloalkyl means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O) n , where n is an integer from 0 to 2, the remaining ring atoms being C. One or two ring carbon atoms can optionally be replaced by a -CO- group. More specifically the term heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, tetrahydroquinolinyl, thiomorpholino, and the like.
  • heterocycloalkyl is optionally fused to aryl.
  • Heterocycloalkyloxy means a -O-R radical where R is heterocycloalkyl ring as defined above e.g., tetrahydropyranyloxy, and the like.
  • Heterocycloalkylalkyl means a -(alkylene)-R radical where R is heterocycloalkyl ring as defined above e.g., piperazinylmethyl, morpholinylethyl, and the like.
  • Heterocycloalkylalkyloxy means a -O-R radical where R is heterocycloalkylalkyl as defined above e.g., tetrahydropyranylmethyloxy, and the like.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms where one or more, preferably one, two, or three, ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon.
  • heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, benzothiophenyl, benzthiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzopyranyl, and thiazolyl, and the like.
  • Heteroaryloxy means a -O-R radical where R is heteroaryl ring as defined above e.g., furanyloxy, pyridinyloxy, and the like.
  • Heteroarylamino means a NHR radical where R is heteroaryl as defined above.
  • Heteroaralkyl means a -(alkylene)-R radical where R is heteroaryl as defined above.
  • Heteroaralkyloxy means a -O-R radical where R is heteroaralkyl ring as defined above e.g., furanylmethyloxy, pyridinylethyloxy, and the like.
  • Heteroaralkenyl means a -(alkenylene)-R radical where R is heteroaryl as defined above.
  • Methylenedioxy means -O-CH 2 -O-.
  • Monosubstituted amino means a -NHR' radical where R' is alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl as defined herein, e.g., methylamino, ethylamino, phenylamino, , and the like.
  • “Monosubstituted aminoalkyl” means a -(alkylene)-R radical where R is monosubstituted amino as defined above except R' is not alkyl e.g., methylaminomethyl, benzylaminoethyl, and the like.
  • “Monosubstituted aminoalkyloxy” means a -OR radical where R is monosubstituted aminoalkyl as defined above e.g., methylaminomethyloxy, benzylaminoethyloxy, and the like.
  • Optionally substituted phenyl means a phenyl ring optionally substituted with one, two, or three substituents independently selected from alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, heteroaryl (that is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino), heterocycloalkyl (that is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino), amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, methylenedioxy, aminocarbonyl, acylamino, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxy or optionally substituted with five fluorine atoms unless stated
  • substituted phenyl When the phenyl ring is substituted with at least one substituent listed above it is referred to herein as substituted phenyl.
  • Optionally substituted phenylalkyl means a -(alkylene)-R radical where R is optionally substituted phenyl as defined above e.g., benzyl, phenylethyl, and the like.
  • Optionally substituted phenylalkyloxy means a -OR radical where R is optionally substituted phenylalkyl as defined above e.g., benzyloxy, phenylethyloxy, and the like.
  • Optionally substituted phenoxyalkyl means a -(alkylene)-OR radical where R is optionally substituted phenyl as defined above e.g., phenoxymethyl, phenoxyethyl, and the like.
  • Optionally substituted phenoxy means an -OR radical where R is optionally substituted phenyl as defined above e.g., phenoxy, and the like.
  • Optionally substituted heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms where one or more, preferably one, two, or three, ring atoms are heteroatoms selected from N, O, or S, the remaining ring atoms being carbon that is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, optionally substituted phenyl, optionally substituted phenoxy, carboxy, heteroaryl that is optionally substituted with alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino, heterocycloalkyl optionally substituted with one or two substituents independently selected from alkyl, halo,
  • optionally substituted heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyranyl, thiazolyl, and the like.
  • substituted heteroaryl When the heteroaryl ring is substituted with at least one substituent listed above it is referred to herein as substituted heteroaryl.
  • Optionally substituted heteroaralkyloxy means a -OR radical where R is optionally substituted heteroaralkyl ring as defined below.
  • Optionally substituted heteroaryloxyalkyl means a -(alkylene)-OR radical where R is optionally substituted heteroaryl ring as defined above.
  • Optionally substituted heteroaralkyl means a -(alkylene)-R radical where R is optionally substituted heteroaryl ring as defined above.
  • Optionally substituted heterocycloalkyl means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O) n , where n is an integer from 0 to 2, the remaining ring atoms being C.
  • One or two ring carbon atoms can optionally be replaced by a -CO- group.
  • heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino and the like.
  • the heterocycloalkyl is optionally fused to aryl and is optionally substituted with one, two, or three substituents independently selected from alkyl, cycloalkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, optionally substituted phenylalkyl, optionally substituted heteroaralkyl, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxy unless stated otherwise.
  • substituents independently selected from alkyl, cycloalkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, optionally substituted phenylalkyl, optionally substituted heteroaralkyl, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl
  • Optionally substituted heterocycloalkyloxy means a -OR radical where R is optionally substituted heterocycloalkyl ring as defined above.
  • Optionally substituted heterocycloalkylalkyloxy means a -OR radical where R is optionally substituted heterocycloalkylalkyl ring as defined above.
  • “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • heterocycloalkyl group optionally mono- or di-substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocycloalkyl group is mono- or disubstituted with an alkyl group and situations where the heterocycloalkyl group is not substituted with the alkyl group.
  • the present invention also includes the prodrugs of compounds of Formula (I).
  • prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula (I) when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo.
  • Prodrugs can be prepared by techniques known to one skilled in the art.
  • Prodrugs of compounds of Formula (I) include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified.
  • Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., NN-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like.
  • Prodrugs of compounds of Formula (I) are also within the scope of this invention.
  • the present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula (I).
  • compounds of Formula (I) when compounds of Formula (I) contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art.
  • compounds of Formula (I) when compounds of Formula (I) contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups.
  • a comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1991, the disclosure of which is incorporated herein by reference in its entirety.
  • the protected derivatives of compounds of Formula (I) can be prepared by methods well known in the art.
  • a "pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid
  • pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutically acceptable carrier/excipient as used in the specification and claims includes both one and more than one such excipient.
  • the compounds of the present invention may have asymmetric centers.
  • cyclic groups such as aryl, heteroaryl, heterocycloalkyl
  • they include all the positional isomers albeit only a few examples are set forth.
  • all polymorphic forms and hydrates of a compound of Formula (I) are within the scope of this invention.
  • Substituted heterocycloalkylalkyl means an -(alkylene)-R radical where R is substituted heterocycloalkyl ring as defined above.
  • Substituted heterocycloalkyloxyalkyl means an -(alkylene)-OR radical where R is substituted heterocycloalkyl as defined above e.g., piperidinyloxymethyl, pyrrolidinyloxyethyl, and the like.
  • Treating or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • treating cancer refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.
  • a “therapeutically effective amount” means the amount of a compound of Formula (I) that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • R 12 is -NHCOR 30 where R 30 is benzofuran-2-yl which is substituted with one or two R a .
  • a preferred group of compounds is that wherein benzofuran-2-yl is substituted with one R a selected from alkylaminoalkyl or dialkylaminoalkyl, preferably methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, or diethylaminoethyl, more preferably dimethylaminomethyl or diethylaminomethyl and is located at the 4- or 5-position of the benzofi ⁇ ran-2-yl ring, (ii) Within this embodiment (A), a preferred group of compounds is that wherein benzofuran-2-yl is substituted with one R a selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxalkyl, preferably methyl, ethyl, methoxy, fluoro, trifluoro
  • yet another preferred group of compounds is that wherein benzofuran-2-yl is substituted with one R a selected from optionally substituted heterocycloalkylalkyloxy or optionally substituted heterocycloalkyloxy.
  • tetrahydropyranyloxy piperidinyloxy, l-methylpiperidin-4-yloxy, l-ethylpiperidin-4-yloxy, morpholino-4-ylethoxy, piperazin-1-ylethoxy, pyrrolidin-1-ylethoxy, tetrahydrothiopyran-4- yloxy, 4-methylpiperazin-l-ylethoxy, or 4-(2-hydroxyethyl)piperazin-l-ylethoxy.
  • these groups are located at the 5-position of the benzofuran-2-yl ring. Even more preferably, R is tetrahydropyran-4-yloxy.
  • yet another preferred group of compounds is that wherein benzofuran-2-yl is substituted with one R a selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl, preferably methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy or hydroxy and another R a selected from optionally substituted heterocycloalkylalkyloxy or optionally substituted heterocycloalkyloxy, preferably, tetrahydropyranyloxy, piperidinyloxy, l-methylpiperidin-4- yloxy, l-ethylpiperidin-4-yloxy, morpholino-4-ylethoxy, piperazin-1-ylethoxy, pyrrolidin-1- ylethoxy, tetrahydrothiopyran-4-yl
  • yet another preferred group of compounds is that wherein benzofuran-2-yl is substituted with one R a selected from hydroxyalkyloxy, optionally substituted heteroaralkyloxy, monosubstituted aminoalkyloxy, disubstituted aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, substituted heterocycloalkyloxyalkyl, or substituted heterocycloalkylalkyl.
  • R a selected from hydroxyalkyloxy, optionally substituted heteroaralkyloxy, monosubstituted aminoalkyloxy, disubstituted aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted hetero
  • R a is alkylaminoalkyloxy, dialkylaminoalkyloxy, more preferably methylaminoethyloxy, or dimethylaminoethyloxy, hydroxyethyloxy and is located at the 5-position of the benzofuran-2- yl ring.
  • yet another preferred group of compounds is that wherein benzofuran-2-yl is substituted with one R a selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another R a selected from hydroxyalkyloxy, optionally substituted heteroaralkyloxy, monosubstituted aminoalkyloxy, disubstituted aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, substituted heterocycloalkyloxyalkyl, or substituted heterocycloalkylalkyl.
  • R a selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino
  • yet another preferred group of compounds is that wherein benzofuran-2-yl is substituted with one R a selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another R a selected from -alkylene-S(O)n-R 44 (where n is 0 to 2 and R 44 is alkyl, hydroxyalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl provided that when n is 2, R 44 is not alkyl), -NHSO 2 R 45 , -alkylene-NHSO 2 -R 45 (where R 45 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted hetero
  • R is -NHCOR where R is indolyl, coumarinyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, or pyrazinyl which is substituted with one or two R .
  • a preferred group of compounds is that wherein indolyl, coumarinyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, or pyrazinyl is substituted with with one R a selected from alkylaminoalkyl or dialkylaminoalkyl, preferably methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, or diethylaminoethyl, more preferably dimethylaminomethyl or diethylaminomethyl.
  • a preferred group of compounds is that wherein indolyl, coumarinyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, or pyrazinyl is substituted with with one R a selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl, preferably methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy or hydroxy and another R a selected from alkylaminoalkyl or dialkylaminoalkyl, preferably methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, or diethylaminoethyl.
  • yet another preferred group of compounds is that wherein indolyl, coumarinyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, or pyrazinyl is substituted with one R a selected from heteroaralkyloxy, monosubstituted aminoalkyloxy, disubstituted aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, substituted heterocycloalkyloxyalkyl, substituted heterocycloalkylalkyl, substituted heterocycloalkylalkyl, substituted heterocycloalkylalkyloxy, or substituted heterocycloalkyloxy.
  • yet another preferred group of compounds is that wherein indolyl, coumarinyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, or pyrazinyl is substituted with one R a selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another R a selected from - alkylene-S(O)n-R 44 (where n is 0 to 2 and R 44 is alkyl, hydroxyalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl provided that when n is 2, R 44 is not alkyl), -NHSO R 45 , - alkylene-NHSO 2 -R 45 (where R
  • R 12 is -NHCOR 30 where R 30 is aralkenyl substituted with one, two, or three R .
  • R 12 is -NHCOR 30 where R 30 is heteroaralkenyl substituted with one, two, or three R a .
  • a preferred group of compounds is that wherein the aromatic ring is substituted with alkylaminoalkyl or dialkylaminoalkyl, preferably methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, or diethylaminoethyl, more preferably dimethylaminomethyl or diethylaminomethyl.
  • a preferred group of compounds is that wherein the aromatic ring is substituted with one R a selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another R a selected from alkylaminoalkyl or dialkylaminoalkyl, preferably methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, or diethylaminoethyl.
  • another preferred group of compounds is that wherein the aromatic ring is substituted with one R a selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another R a selected from optionally
  • tetrahydropyranyloxy piperidinyloxy, l-methylpiperidin-4- yloxy, l-ethylpiperidin-4-yloxy, morpholino-4-ylethoxy, piperazin-1-ylethoxy, pyrrolidin-1- ylethoxy, tetrahydrothiopyran-4-yloxy, 4-methylpiperazin-l-ylethoxy, or 4-(2-hydroxyethyl)- piperazin- 1 -ylethoxy .
  • yet another preferred group of compounds is that wherein the aromatic ring is substituted with one R a selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another R a selected from hydroxyalkyloxy, optionally substituted heteroaralkyloxy, monosubstituted aminoalkyloxy, disubstituted aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, substituted heterocycloalkyloxyalkyl, or substituted heterocycloalkylalkyl .
  • R a selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino,
  • yet another preferred group of compounds is that wherein the aromatic ring is substituted with one R a selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroalkyl and another R a selected from -alkylene- S(O)n-R 44 (where n is 0 to 2 and R 44 is alkyl, hydroxyalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl provided that when n is 2, R 44 is not alkyl), -NHSO 2 R 45 , -alkylene-NHSO 2 -R 45 (where R 45 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl
  • R 11 is cyano.
  • R 11 is hydroxy.
  • R 8 is halo, alkyl, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, cyano, nitro, acylamino, -COOR 13 (where R 13 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -CONR 14 R 15 (where R 14 and R 15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or -NR 16 R 17 (where R 16 is hydrogen, alkyl, aryl, aralkyl, alkenyloxy
  • even more preferred group of compounds are those where Y is methylene and R 12 is as described in preferred group (A) above.
  • ring A and B are a group of formula (a) and (c) respectively, where R 12 is 5-tetrahydropyran-4-yloxybenzofuran-2-ylcarbonylamino.
  • R 12 is 5-tetrahydropyran-4-yloxybenzofuran-2-ylcarbonylamino.
  • R 1 , R 3 , R 6 , R 8 alkoxy
  • R 2 and R 7 alkyl
  • R 4 and R 5 OH
  • R 9 is hydrogen
  • R 10 hydrogen, -CH 3 or-CH 2 CH 3
  • R 11 is hydrogen or cyano
  • Y methylene.
  • Reference to the preferred embodiments set forth above is meant to include all combinations of particular and preferred groups unless stated otherwise.
  • GENERAL SYNTHESIS Compounds of this invention can be made by the methods depicted in the reaction scheme shown below.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St.
  • the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C and most preferably at about room (or ambient) temperature, e.g., about 20 °C.
  • the reactions described herein take place under inert gas, such as nitrogen or argon.
  • the reaction is carried out in the presence of a suitable acid such as hydrochloric acid, trifluoroacetic acid, and the like and lithium bromide in a suitable organic solvent such as dichloromethane, ethylene glycol dimethyl ether, and the like.
  • a suitable dehydrating reagent such as magnesium sulfate, sodium sulfate, and the like. Installation of group R 10 where R 10 is other than hydrogen can be carried on a compound of formula 3 under alkylation or reductive amination reaction conditions to provide a compound of formula 4.
  • reaction is carried out by reacting 3 with a suitable aldehyde in the presence of a suitable reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, and the like.
  • a suitable reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, and the like.
  • Removal of the amino protecting group in a compound of formula 4 provides a compound of formula 5.
  • the reaction conditions employed for removal of the protecting groups depend on the nature of the protecting groups. Suitable conditions for the protecting group removal can be found in T. W. Greene and P. G. M. Wuts Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1999.
  • Reaction of 5 with a 2-aminoacetaldehyde of formula 6 where PGi is a suitable amino protecting group provides a compound of formula 7.
  • the reaction is carried out in the presence of a suitable dehydrating reagent such as magnesium sulfate, sodium sulfate, and the like, in a suitable organic solvent such as dichloromethane, ethylene glycol dimethyl ether, dichloroethane, and the like.
  • a suitable acid such as hydrochloric acid, trifluoroacetic acid, and the like and lithium bromide.
  • Treatment of 7 with a suitable acid such as zinc(II) chloride and the like in a suitable organic solvent such as 2,2,2-trifluoroethanol, THF, and the like provides a compound of formula 8.
  • the cyclization reaction can be carried out in the presence of an external cyanide source such as trimethylsilyl cyanide, sodium cyanide, potassium cyanide and the like.
  • an external cyanide source such as trimethylsilyl cyanide, sodium cyanide, potassium cyanide and the like.
  • Removal of the amino protecting groups in a compound of formula 8 provides a compound of fo ⁇ nula 9.
  • the reaction conditions employed for removal of the protecting group depend on the nature of the protecting group. For example, if the protecting group is 9- fluorenylmethyl carbamate, it is removed under basic reaction conditions. Suitable bases are l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), morpholine, piperazine, and the like. Suitable conditions for other protecting group removal can be found in T. W. Greene and P. G. M. Wuts Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1999.
  • Compound 9 is then converted to a
  • a compound of Formula (I) where R 12 is -NHCOR 30 where R 30 is as defined in the Summary of the Invention can be readily prepared by reacting 9 with an acid halide of formula R 30 COX where X is halo or an acid of formula R 30 COOH. If acid halide is utilized, the reaction is carried out in the presence of a suitable base such as triethylamine, N,N- diethylaniline, NN-diisopropylethylamine and the like, in a suitable reaction solvent such as THF, DMF and the like.
  • a suitable base such as triethylamine, N,N- diethylaniline, NN-diisopropylethylamine and the like
  • the acid halide such as acid chloride can be obtained from commercial sources or can be prepared by reacting the corresponding acid with a halogenating agent such as oxalyl chloride, thionyl chloride, phosphorous oxychloride, and the like.
  • a halogenating agent such as oxalyl chloride, thionyl chloride, phosphorous oxychloride, and the like.
  • the reaction is carried out in the presence of suitable coupling agent such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC ⁇ C1), 1,3-dicyclohexyl- carbodiimide (DCC), or benzotriazol-l-yloxyltris(dimethylamino)phosphonium hexafluorophosphate (BOP), optionally in the presence of 1-hydroxybenzotriazole hydrate (HOBt»H 2 O) in a suitable organic solvents such as DMF and the like, and in the presence of a suitable base such as NN-diethylaniline and the like.
  • suitable coupling agent such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC ⁇ C1), 1,3-dicyclohexyl- carbodiimide (DCC), or benzotriazol-l-yloxyltris
  • a compound of Formula (I) where R 12 is - ⁇ R 34 SO 2 R 35 can be prepared by reacting 9 with a sulfonylating agent of formula R 35 S0 2 L where L is a leaving group such as halo under reaction conditions described for acid halides in (i) above.
  • a compound of Formula (I) where R 12 is -NR 36 R 37 and -NR 38 CHX 1 R 39 can be prepared by reacting 9 with a suitable alkylating agent by methods known in the art.
  • a compound of Formula (I) where R 12 is -OR 40 can be prepared first by converting the amine at the C-l position of the compound 9 to hydroxyl through diazo functionality followed by alkylation of the resulting hydroxyl group with suitable alkylating reagents under conditions well known in the art.
  • a compound of Formula (I) where R 12 is -OR 40 can be prepared reacting compound 5 with a hydroxy-protected hydroxyacetaldehyde of formula CH 2 (CHO)OPG such as tert-butyldimethylsilyloxy acetaldehyde instead of compound 6, followed by removal of the hydroxy protecting group to provide a compound of formula 9 where the C-l carbon carries a hydroxymethyl instead of aminomethyl group.
  • the hydroxy group can then be functionalized as described above.
  • a compound of Formula (I) where R 12 is -COOR 33 and -CONR 31 R 32 can be prepared by reacting 5 with 2-formylacetic acid methyl ester instead of compound 6, followed by removal of the carboxy protecting group to provide a compound of formula 9 where the C-l carbon carries a carboxymethyl instead of aminomethyl group. The carboxy group can then be converted to a compound of Formula (I) where R 12 is -COOR 33 and -CONR 31 R 32 by methods well known in the art.
  • a compound of Formula (I) where R 12 is -S(O) m sR 41 can be prepared by converting the hydroxy group in a compound of 9 carrying hydroxymethyl group at C-l to a leaving group such as toluenesulfonate and then reacting it with a sulfur nucleophile of formula R 41 SH, followed by oxidation of the sulfur with a suitable oxidizing agent such as m-chloroperbenzoic acid, and the like.
  • a compound of Formula (I) where R 11 is hydroxy or methoxy can be prepared from a corresponding compound of Formula (I) where R 11 is -CN by reacting it with a suitable Lewis acid such as AgNO 3 , AgBF 4 , and the like in the presence of a nucleophile such as water and methanol respectively.
  • a suitable Lewis acid such as AgNO 3 , AgBF 4 , and the like in the presence of a nucleophile such as water and methanol respectively.
  • a compound of formula 8 where Y is methylene, A and B are rings of formula (a) and (c) respectively, R 11 is cyano, hydroxy, or alkoxy, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 12 groups are as described in the Summary of the Invention can be prepared can be prepared by the procedure illustrated and described in Scheme B below.
  • the reaction is carried out in the presence of a suitable acid such as hydrochloric acid, trifluoroacetic acid, and the like, and lithium bromide in a suitable organic solvent such as dichloromethane, ethylene glycol dimethyl ether, and the like.
  • reaction is often carried out in the presence of a suitable dehydrating reagent such as magnesium sulfate, sodium sulfate, and the like.
  • a suitable dehydrating reagent such as magnesium sulfate, sodium sulfate, and the like.
  • Compound 11 is then converted to a compound of formula 12 where R 10 is other than hydrogen as described in Scheme A above.
  • Reduction of the ester group in compound 12 with a suitable reducing agent such as lithium borohydride, diisobutylaluminum hydride, lithium aluminum hydride, and the like, followed by removal of the hydroxy protecting group provides a compound of formula 13.
  • the reaction conditions employed for removal of the protecting group depend on the nature of the protecting groups. Suitable conditions for the protecting group removal can be found in T. W. Greene and P. G. M.
  • a compound of formula 14 is then converted to a compound of formula 14 by reacting it with a 2- aminoacetaldehyde of fonnula 6 as described in Scheme A above.
  • Synthesis of a compound of formula 8 is accomplished by oxidation of the alcohol of 14 to an aldehyde in the presence of a suitable nucleophile such as cyanide from sodium cyanide, potassium cyanide and the like.
  • a suitable nucleophile such as cyanide from sodium cyanide, potassium cyanide and the like.
  • An example of a suitable oxidation condition is the use of the mixture of oxalyl chloride, DMSO, and triethylamine.
  • Other suitable oxidizing agents include but are not limited to Dess-Martin periodinane, tetrapropylammonium perruthenate.
  • a compound of formula 1 can be prepared from a suitably substituted tyrosine type amino acid that are either commercially available or prepared from the commercially available starting materials following the methods known in the art.
  • a compound of formula 1, preferably a specific enantiomerically pure compound of fo ⁇ nula 1, can also be prepared by the procedure illustrated and described in Scheme C below.
  • Compound 16 can be converted to a compound of formula 17 by treating 16 with an organometallic reagent such as alkyllithium e.g., tert-butyllithium, «-butyllithium, and the like or magnesium metal to form a Grignard reagent, followed by quenching of the resulting organometallic species with a suitable formyl source such as N,N-dimethylformamide (DMF).
  • a suitable formyl source such as N,N-dimethylformamide (DMF).
  • Reduction of the aldehyde group in 17 is with a suitable reducing agent such as sodium borohydride, and the like, provides the corresponding alcohol compound of formula 18.
  • Compound 18 is then converted to the corresponding bromide compound of formula 19 using a suitable bromination reagent such as bromine in the presence of a suitable oxo-phile such as triphenylphosphine.
  • Compound 19 is then converted to a compound of formula 21, preferably enantiomerically pure compound, by stereoselective alkylation reaction between compound 19 and a compound of formula 20 where R* is a suitable amino protecting group or a suitable chiral auxiliary capable of exerting a chiral influence on the course of the alkylation.
  • R* is a suitable amino protecting group or a suitable chiral auxiliary capable of exerting a chiral influence on the course of the alkylation.
  • An example of such chiral auxiliary can be (-)-pseudoephedrine (Myers et al. J. Am. Chem. Soc. 1997, 119, 656).
  • the reaction is carried out in the presence of a suitable base such as lithium diisopropylamine, lithium bis(trimethylsilyl)amide, and the like in a suitable organic solvent such as THF.
  • a suitable organic solvent such as THF.
  • Lewis acids such as lithium chloride.
  • a suitable protecting group such 9- fluorenylmethyl carbonyl (Fmoc) or tert-butoxycarbonyl (Boc) and the like, provides a compound of formula 23 which is then converted to a compound of formula 1 under suitable oxidation reaction conditions.
  • a suitable oxidation condition is the use of the mixture of oxalyl chloride, DMSO, and triethylamine.
  • suitable oxidizing agents include but not limited to Dess-Martin periodinane, tetrapropylammonium perruthenate.
  • a compound of formula 22 can be prepared following the procedure illustrated and described in Scheme D below.
  • a suitable catalyst preferably a chiral catalyst such as Et-DuPHOS-Rh(I), BINAP-Ru(OAc) 2 , (+)-l,2-bis((2S, 5S)-2,5-diethylphospholano)- benzene(cyclooctadiene) rhodium(I) trifluoromethanesulfonate, and the like, provides a compound of formula 26.
  • a suitable catalyst preferably a chiral catalyst such as Et-DuPHOS-Rh(I), BINAP-Ru(OAc) 2 , (+)-l,2-bis((2S, 5S)-2,5-diethylphospholano)- benzene(cyclooctadiene) rhodium(I) trifluoromethanesulfonate, and the like.
  • Conversion of a compound of formula 27 to a compound of formula 22 is achieved by reduction of the ester to an alcohol using a suitable reducing agent such as L-Selectride, lithium aluminum hydride, lithium borohydride, diisobutylaluminum hydride in a suitable organic solvent such as THF, ethyl ether, and the like.
  • a suitable reducing agent such as L-Selectride, lithium aluminum hydride, lithium borohydride, diisobutylaluminum hydride in a suitable organic solvent such as THF, ethyl ether, and the like.
  • a compound of formula 2 can be prepared following the procedures illustrated and described in Scheme E below.
  • Compound 28 can be prepared by the same procedure described for formula 1 above.
  • Treatment of 29 with an amine nucleophile such as piperidine, pyrrolidine, dimethylamine, morpholine, and the like, preferably morpholine, in a suitable organic solvent such as 2,2,2-trifluoroethanol, CH 2 C1 2 , and the like provides a compound of formula 30. Removal of the amino protecting group in 30 then provides a compound of formula 2.
  • the reaction conditions employed for removal of the protecting groups depend on the nature of the protecting groups.
  • the protecting group is 9-fluorenylmethyl carbamate (Fmoc)
  • Fmoc 9-fluorenylmethyl carbamate
  • Suitable bases are 1,8-diaza- bicyclo[5.4.0]undec-7-ene (DBU), morpholine, piperazine, and the like.
  • DBU 1,8-diaza- bicyclo[5.4.0]undec-7-ene
  • morpholine 1,8-diaza- bicyclo[5.4.0]undec-7-ene
  • piperazine 1,8-diaza- bicyclo[5.4.0]undec-7-ene
  • Suitable conditions for the protecting group removal can be found in T. W. Greene and P. G. M. Wuts Protective . Groups in Organic Synthesis, John Wiley & Sons, Inc. 1999.
  • the compounds of this invention are useful in the treatment of proliferative diseases such as cancer such as soft tissue sarcoma, prostate cancer, breast cancer, lung melanoma, stomach cancer, neuroblastoma, colon cancer, pancreatic cancer, ovarian cancer, T-cell lymphoma, or leukemia such as myelogenous leukemia (MM) and acute myelogenous leukemia (AML). Testing
  • the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the actual amount of the compound of this invention, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
  • Therapeutically effective amounts of compounds of Formula (I) may range from approximately 0.1-50 mg per kilogram body weight of the recipient per day; preferably about 0.5-20 mg/kg/day.
  • compositions for administration to a 70 kg person, the dosage range would most preferably be about 35 mg to 1.4 g per day.
  • compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • the preferred manner of administration is oral or parenteral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction.
  • Oral compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • the compound of Formula (I) can be administered in combination with known anti-cancer agents.
  • known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors.
  • the compound of Formula (I) are particularly useful when adminsitered in combination with radiation therapy.
  • Preferred angiogenesis inhibitors are selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP (matrix metalloprotease) inhibitor, an integrin blocker, interferon- ⁇ , interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-0-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, and an antibody to VEGFR and EFGR.
  • Estrogen receptor modulators refers to compounds that interfere or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2-[4-[2-(l- piperidinyl)ethoxy]phenyl]-2H- 1 -benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4 '- dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and S ⁇ 646.
  • Preferred estrogen receptor modulators are tamoxifen and raloxifene.
  • “Androgen receptor modulators” refers to compounds that interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • “Retinoid receptor modulators” refers to compounds that interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • retinoid receptor modulators examples include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, ⁇ - difluoromethylornithine, ILX23-7553, trans-N-(4'-hydroxyphenyl) retinamide, andN-4- carboxyphenyl retinamide.
  • Cytotoxic agents refer to compounds which cause cell death primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mitosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.
  • cytotoxic agents include, but are not limited to, tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2- methyl-pyridine) platinum, benzylguanine, glufosfamide, GPXIOO, (trans, trans, trans)-bis-mu- (hexane-l,6-
  • microtubulin inhibitors include paclitaxel, docetaxel (also known as Taxotere ® , epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives); vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS 184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L- proline-
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ' ,4 '-O-exo-benzylidene-chartreusin, 9-methoxy-NN-dimethyl- 5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine, l-amino-9-ethyl-5-fluoro-2,3-dihydro- 9-hydroxy-4-methyl-lH,12H-benzo[de]pyrano[3',4':b,7]-indolizino[l,2b]quinoline- 10, 13(9 ⁇ , 15H)dione, lurtotecan, 7-[2-(N-isopropylamino)-ethyl]-(20S)camptothecin, B ⁇ P1350, BNPI1100, BN80915, BN80942,
  • Antiproliferative agents includes antisense R ⁇ A and D ⁇ A oligonucleotides such as G3139, OD ⁇ 698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'- methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)- sulfonyl]-N'-(3,4-dich
  • Antiproliferative agents also includes monoclonal antibodies to growth factors, other than those listed under “angiogenesis inhibitors”, such as trastuzumab, and tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134).
  • ⁇ MG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3-methylglutaryl- CoA reductase.
  • Compounds which have inhibitory activity for ⁇ MG-CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Pat. No. 4,231,938 at col.
  • ⁇ MG- CoA reductase inhibitor and “inhibitor of ⁇ MG-CoA reductase” have the same meaning when used herein. It has been reported that (Int. J. Cancer, 20, 97(6):746-50, (2002)) combination therapy with lovastatin, a ⁇ MG-CoA reductase inhibitor, and butyrate, an inducer of apoptosis in the Lewis lung carcinoma model in mice showed potentiating antitumor effects
  • ⁇ MG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR ® ; see U.S. Pat. Nos.
  • simvastatin ZOCOR ® ; see U.S. Pat. Nos. 4,444,784, 4,820,850, and 4,916,239)
  • pravastatin PRAVAC ⁇ OL ® ; see U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447, and 5,180,589)
  • fluvastatin LESCOL ® ; see U.S. Pat. Nos.
  • ⁇ MG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have ⁇ MG-CoA reductase inhibitory activity, and colchicin the use of such salts, esters, open-acid and lactone fonns is included within the scope of this invention.
  • salt and ester forms may preferably be formed from the open-acid, and all such forms are included within the meaning of the term "HMG-CoA reductase inhibitor" as used herein.
  • the HMG- CoA reductase inhibitor is selected from lovastatin and simvastatin, and most preferably simvastatin.
  • Prenyl-protein transferase inhibitor refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protem transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • FPTase farnesyl-protein transferase
  • GGPTase-I geranylgeranyl-protem transferase type I
  • GGPTase-II geranylgeranyl-protein transferase type-II
  • prenyl-protein transferase inhibiting compounds examples include ( ⁇ )-6-[amino(4-chlorophenyl)(l- methyl-lH-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-l-methyl-2(lH)-quinolinone, (-)-6- [amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-chloro phenyl)-l-methyl- 2(lH)-quinolinone, (+)-6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3- chloro phenyl)- 1 -methyl-2( 1 ⁇ )-quinolinone, 5 (S)-n-butyl- 1 -(2,3 -dimethylphenyl)-4- [ 1 -(4- cyanobenzy
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. ⁇ os. 5,420,245, 5,523,430, 5,532,359, 5,510,510, 5,589,485, 5,602,098, European Patent Publ. 0618221, European Patent Publ. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.
  • HIV protease inhibitors include amprenavir, abacavir, CGP-73547, CGP- 61755, DMP-450, indinavir, nelfmavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, andBMS-232, 632.
  • reverse transcriptase inhibitors examples include delaviridine, efavirenz, GS-840, HB Y097, lamivudine, nevirapine, AZT, 3TC, ddC, and ddl. It has been reported ((Nat. Med. 8(3):225-32, (2002)) that HIV protease inhibitors, such as indinavir or saquinavir, have potent anti-angiogenic activities and promote regression of Kaposi sarcoma "Angiogenesis inhibitors" refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFRl) and Flk-1/KDR (VEGFR20), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-oc, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxygenase-2 inhibitors like celecoxib, valdecoxib, and rofecoxib (PNAS, Vol.
  • NSAIDs nonsteroidal anti-inflammatories
  • NSAID's which are potent COX-2 inhibiting agents.
  • Such compounds include, but are not limited to those disclosed in, U.S. Pat. Nos.
  • angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-l- oxaspiro [2,5] oct-6 -yl(chloroacetyl)carbamate, 5 -amino- 1 - [[3 , 5 -dichloro-4-(4-chlorobenzoyl)- phenyl]-methyl]-lH-l,2,3-triazo le-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2- pyrrolocarbonyl-imino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-bis-
  • integralin Mockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ 3 integrin, to compounds which selectively antagonize, inhibit or counter-act binding of a physiological ligand to the v ⁇ 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the ⁇ v ⁇ 3 integrin and the ⁇ v ⁇ s integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the v ⁇ ; ⁇ v ⁇ s, oti ⁇ i, ⁇ 2 ⁇ l5 ⁇ s ⁇ i, ⁇ 6 ⁇ and ⁇ 6 ⁇ 4 integrins.
  • the term also refers to antagonists of any combination of ⁇ v ⁇ 3 , ⁇ v ⁇ 5 , ⁇ v ⁇ 6 , v ⁇ 8 , cci ⁇ i, ⁇ 2 ⁇ , 5 ⁇ , ⁇ 6 ⁇ and ⁇ 6 ⁇ 4 integrins.
  • tyrosine kinase inhibitors include N-(trifluoromethyl- phenyI)-5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)-indoIin-
  • the instant compound is also useful in combination with platelet fibrinogen receptor (GP Ilb/IIIa) antagonists, such as tirofiban, to inhibit metastasis of cancerous cells.
  • GP Ilb/IIIa platelet fibrinogen receptor
  • Tumor cells can activate platelets largely via thrombin generation. This activation is associated with the release of VEGF.
  • the release of VEGF enhances metastasis by increasing extravasation at points of adhesion to vascular endothelium (Amirkhosravi, Platelets 10, 285-292, (1999)). Therefore, the present compound can serve to inhibit metastasis in combination with GP Ilb/IIIa antagonists.
  • fibrinogen receptor antagonists examples include abciximab, eptifibatide, sibrafiban, lamifiban, lotrafiban, cromofiban, and CT50352.
  • the compound of this invention can be used with antineoplastic agents such as doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro- methotrexate, mitomycin C, porfiromycin, ⁇ erceptin ® , Rituxan ® , Avastin ® , Tarceva ® , 5- fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo- phyllotoxin derivatives such as colchicines, etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leuro
  • Such combination products employ the compound of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range.
  • Compound of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
  • administration e.g., "administering" a compound in reference to the compound of the invention means introducing the compound into the system of the animal in need of treatment.
  • other active agents e.g., a cytotoxic agent, etc.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Radiation therapy including x-rays or gamma rays that are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with the compounds of this invention alone to treat cancer.
  • reaction mixture was cooled to -78 °C and was treated with a solution of 21 (637 mg, 1.23 mmol) in THF (4.0 mL) dropwise. Resulting yellow clear solution was stirred at 0 °C under N 2 for 2 hr.
  • the reaction mixture was quenched by addition of CF 3 CH 2 OH (481 ⁇ L, 6.53 mmol) at 0 °C dropwise followed by addition of Et 2 O (5 mL) and a solution of NaHSO 4 (2.7 g, 22.6 mmol) in H 2 O (10 mL) in sequence. The reaction mixture was then stirred at 0 °C.
  • Step 2 To a solution of 5-methoxybenzofuran-2-carboxylic acid methyl ester (5.15 g, 25.0 mmol) in CH 2 C1 2 (15 mL) at - 40 °C was added boron tribromide (27.0 mL, 27.0 mmol, 1.0 M in CH 2 CI2) over the course of 1 hr using a syringe pump. The reaction mixture was stirred overnight while allowed slowly to warm to room temperature. After quenching the reaction mixture with MeOH (15 mL) at 0 °C, the reaction mixture was diluted with brine (100 mL) and extracted with EtOAc. The organic layers were combined, dried over MgSO 4 , filtered, and concentrated.
  • Step 3 To a solution of 5-hydroxybenzofuran-2-carboxylic acid methyl ester (1.10 g, 5.72 mmol), triphenylphosphine (1.66 g, 6.33 mmol), and tetrahydro-4H-pyran-4-ol (660 mg, 6.46 mmol) in T ⁇ F (15 mL) was added diisopropyl azodicarboxylate (1.35 mL, 6.86 mmol) over the course of 1 hr using a syringe pump. After 6 days of stirring at room temperature, most of the volatiles were removed by a rotary evaporator.
  • Step 1 To a solution of 9 (10.4 mg, 20.0 ⁇ mol,) in THF (1 mL), obtained from Reference A above, at 0 °C was added N, N-diethylaniline (3.5 ⁇ L, 1.1 equiv). After 5 min.
  • the reaction mixture was treated with 5-(tetrahydro-4H-pyran-4-yloxy)-benzofuran-2-carboxylic acid (6.8 mg, 1.3 equiv), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC» ⁇ C1) (5.0 mg, 1.4 equiv), and 1-hydroxybenzotriazole hydrate (HOBt «H 2 O) (3.7 mg, 1.2 equiv) in sequence.
  • EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole hydrate
  • Step l A suspension of 4-(bromomethyl)benzoic acid (4.3g, 20 mmol) in triethyl phosphite (3.77 mL, 22 mmol) was heated to reflux for 20 hr. The reaction was allowed to slowly cool to room temperature. The precipitate was collected by filtration, washed intensively with hexane (100 mL), and dried in vacuo to give 4-(diethylphosphono-methyl)benzoic acid (5.34 g, 98%) as a tan solid.
  • Step 2 Following the procedure described in Example 1 above using 9 (10.9 mg, 20.8 ⁇ mol), THF (1.5 mL), N, N-diethylaniline (3.7 ⁇ L, 1.1 equiv), 4-(diethylphosphono-methyl)benzoic acid (7.4 mg, 1.3 equiv), 1 -(3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HC1) (5.2 mg, 1.3 equiv), 1-hydroxybenzotriazole hydrate (HOBt «H 2 O) (3.4 mg, 1.2 equiv) and purification by prep-TLC (5%> methanol - dichloromethane) gave the title compound 35 (7.0 mg, 45%) as a white solid.
  • EM (calc): 778.3; MS (ESI) m/e: 777.4 (M-H) ' , 779.7 (M+H) + .
  • Example 8 Synthesis of a compound of Formula (I) where R 1 , R 3 , R 6 , and R 8 are OMe, R 2 , R 7 , and R 10 are Me, R 4 and R 5 are OH, R 9 is H, R 11 is CN, Y is CH 2 , and R 12 is 4-(5-dimethylaminonaphth-l- ylsulfonylaminomethyl)phenylcarbonylamino (compound 38)
  • Step l To a solution of methyl 4-(aminomethyl)benzoate hydrochloride (26.8 mg, 129 ⁇ mol) in CH 2 C1 2 (5 mL) was added TEA (39.7 ⁇ L, 284 ⁇ mol) and dansyl chloride (39.0 mg, 142 ⁇ ol). After 2 hr of stirring at room temperature under argon, the reaction mixture was diluted with EtOAc (50 mL) and washed with sat. NaHCO 3f ⁇ e j (2x 20 mL), brine (lx 20 mL), and dried over MgSO 4 . The crude product, dansylated benzoic acid methyl ester, was used for the next step without further purification.
  • Step 3 Synthesis of 38 was achieved by the union of the amine 9 and dansylated benzoic acid obtained from Step 2 above following a similar procedure as described in Example 1 above.
  • Example 9
  • Synthesis of 39 was achieved by the union of the amine 9 and 4-(tetrahydro-4H-pyran- 4-yloxy)-benzofuran-2-carboxylic acid following a similar procedure as described in Example 1 above.
  • Synthesis of 4-(tetrahydro-4H-pyran-4-yloxy)-benzofuran-2-carboxylic acid was prepared following similar procedure for the synthesis of 5-(tetrahydro-4H-pyran-4-yloxy)- benzofuran-2-carboxylic acid using 4-hydroxy-benzofuran-2-carboxylic acid methyl ester (Yamaguchi, S. et al. Bull. Chem. Soc. Jpn.
  • Synthesis of 40 was achieved by the union of the amine 9 and 6-(tetrahydro-4H-pyran- 4-yloxy)-benzofuran-2-carboxylic acid following a similar procedure as described in Example 1 above.
  • Synthesis of 6-(tetrahydro-4H-pyran-4-yloxy)-benzofuran-2-carboxylic acid was prepared following similar procedure for the synthesis of 5-(tetrahydro-4H-pyran-4-yloxy)- benzofuran-2-carboxylic acid using 6-hydroxy-benzofuran-2-carboxylic acid methyl ester and tetrahydro-4H-pyran-4-ol as starting materials.
  • EM calc): 768.9; MS (ESI) m/e: 769.9 (M+ ⁇ ) + , 767.9 (M-H) " .
  • Step l To a solution of 2,5-dihydroxy-benzaldehyde (2.76 g, 20.0 mmol) in THF (50 mL) were added diethyl malonate (3.4 mL, 22 mmol) and piperidine (4.9 mL, 50 mmol). After stirring overnight at room temperature, the reaction mixture was acidified to pH ⁇ l-2 with IN HClf aq) , and extracted with EtOAc.
  • Step 3 A solution of 6-methoxyethoxy-2-oxo-2H-chromene-3-carboxylic acid ethyl ester (60mg, 21 ⁇ mol) in MeO ⁇ (2 mL) was treated with IN LiO ⁇ (1 mL). After 1 hr of stirring at room temperature, the reaction mixture was acidified with IN ⁇ Cl ⁇ and extracted with EtOAc to give crude 6-methoxyethoxy-2-oxo-2H-chromene-3 -carboxylic acid, which was used without further purification.
  • Step 4 Synthesis of 41 was achieved by the union of the amine 9 and 6-methoxyethoxy-2-oxo- 2H-chromene-3 -carboxylic acid obtained from step 3 following a similar procedure as described in Example 1 above.
  • Step l To a solution of 2,4-dihydroxy-benzaldehyde (5.52 g, 40.0 mmol) in THF (50 mL) were added diethyl malonate (6.7 mL, 44 mmol) and piperidine (11.9 mL, 120 mmol). After 2 hr of stirring at room temperature, the reaction mixture was acidified to pH ⁇ l-2 with IN HClf ⁇ j, and extracted with large amount of EtOAc. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Step 2 To a solution of PPh 3 (288 mg, 1.10 mmol) in T ⁇ F (1 mL) was added DIAD (0.22 mL, 1.10 mmol) dropwise. The mixture turned into solid within 5 minutes. To the solid was added a solution of 2-methoxyethanol (0.08 mL, 1.0 mmol) and 7-hydroxy-2-oxo-2H-chromene-3- carboxylic acid ethyl ester (117 mg, 500 ⁇ mol) in T ⁇ F (2 mL).
  • Step 4 Synthesis of 42 was achieved by the union of the amine 9 and 7-methoxyethoxy-2-oxo- 2H-chromene-3 -carboxylic acid obtained from step 3 above following a similar procedure as described in Example 1 above.
  • Step l To a solution of PPh 3 (1.14 g, 4.32 mmol) in THF (2 mL) was added DIAD (894 ⁇ L, 4.32 mmol). After 5 min of stirring at room temperature, the reaction mixture was treated with a solution of methyl 4-hydroxycinnamate (513 mg, 2.88 mmol), and tetrahydro-4H-pyran-4-ol (280 ⁇ L, 2.88 mmol) in T ⁇ F (3 mL). The reaction mixture was agitated by means of ultrasonification for 5 min and stirred at room temperature for 25 hr. Then, the reaction mixture was concentrated in vacuo.
  • Step l A solution of ethyl 5-hydroxy-lH-indole-2-carboxylate (5.0 g, 24.4 mmol) in 1,4- dioxane (50 mL) was treated with TEA (6.7 mL, 36.6 mmol) followed by di-tert-butyl dicarbonate (8.0 g, 36.6 mmol) and heated to 70 °C (caution: gas development). After 2 hr - the reaction was completed - most of the solvent was removed in vacuo. The residue was dissolved in EtOAc (250 mL) and washed with 0.5N ⁇ Cl ⁇ , ⁇ 2 O, and brine. The organic phase was dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 2 To a solution of PPh 3 (6.5 g, 24.6 mmol) in anhydrous THF (20 mL) was added DIAD (4.8 mL, 24.6 mmol). The solution was stirred until a white precipitate was formed (2 to 10 min).
  • Step 3 A solution of ethyl N-Boc-5-(2-methoxyethoxy)-indole-2-carboxylate (3.2 g, 8.8 mmol) in ethanol (20 mL) was treated with 4M HCI in 1,4-dioxane (20 mL).
  • Step 4 Ethyl 5-(2-methoxyethoxy)-lH-indole-2-carboxylate (2.0 g, 7.4 mmol) in T ⁇ F (20 mL) was treated with a solution of LiO ⁇ « ⁇ 2 O (0.62 g, 14.8 mmol) and H 2 O (10 mL).
  • Step 5 To a solution of 9 (10.4 mg, 20 ⁇ mol, 1 equiv) in T ⁇ F (lmL), obtained from Reference A above, was added N, N-diethylaniline (3.5 ⁇ L, 1.1 equiv) at 0 °C.
  • Step 1 To a solution of 3-methyl-benzofuran-2-carboxylic acid (0.98 g, 5.6 mmol) and catalytic amount of DMF (5 drops) in THF (25 mL) was added oxalyl chloride (0.53 mL, 6.1 mmol). After stirring the solution for 1 hr at room temperature, MeOH (20 mL) and TEA (7.0 mL) were added. The reaction mixture was stirred overnight at room temperature, then concentrated, redissolved in EtOAc (100 mL) and washed with sat. NaHCO 3f ⁇ e ) (100 mL).
  • Step 2 A solution of methyl 3-methyl-benzofuran-2-carboxylate (1.0 g, 5.3 mmol), N- bromosucciniimide (0.95 g, 5.3 mmol) and 2,2'-azobisisobutyronitrile (87 mg, 0.53 mmol) was heated to reflux in CC1 (40 mL) for 3 hours, then cooled to room temperature and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with H 2 O (100 mL).
  • Step 3 To a solution of methyl 3-bromomethyl-benzofuran-2-carboxylate (269 mg, 1.0 mmol) in DMF was added dimethylamine (2M solution in THF, 1.5 mL, 3.0 mmol). The reaction mixture was stirred for 1-2 hours, diluted with EtOAc (50 mL), washed twice with sat. ⁇ aHCO 3f a ⁇ j ) (50 mL) and finally with brine (50 mL).
  • Step 5 To a solution of 9 (8 mg, 15 ⁇ mol, 1 equiv) in THF (lmL), obtained from Reference A above, at 0 °C was added N, N-diethylaniline (3 ⁇ L, 1.1 equiv). The reaction mixture was stirred at 0 °C.
  • Example 20 Synthesis of a compound of Formula (I) where R 1 , R 3 , R 6 , and R 8 are OMe, R 2 , R 7 , and R 10 are Me, R 4 and R 5 are OH, R 9 is H, R 11 is CN, Y is CH 2 , and R 12 is 6-(5-dimethylaminonaphth-l- ylsulfonylamino)naphth-2-ylcarbonylamino (compound 50)
  • Step 1 To a suspension of 6-amino-2-naphthoic acid (374 mg, 2.0 mmol) in CH 2 C1 2 (8 mL) were added TBDMS-Cl (301 mg, 2.0 mmol) and TEA (1.11 mL, 8.0 mmol) in sequence. After stirring for 1 hr, dansyl-chloride (701 mg, 2.6 mmol) was added to the reaction mixture and stirring was continued for an additional 1 hr. The reaction mixture was diluted with CH 2 C1 2 (50 mL) and IN HCl ⁇ . The separated organic phase was washed with IN HCl ⁇ (3x 50 mL) and sat. NaHCOs ⁇ (3x 50 mL) and concentrated in vacuo.
  • Step 2 Proceeding as described in Example 1 above, but substituting 5-(tetrahydro-4H-pyran- 4-yloxy)-benzofuran-2-carboxylic acid with 6-(5-dimethylamino-naphthalene-l-sulfonyl- amino)naphthalene-2-carboxylic acid provided compound 50 after purification by preparative TLC (3:7 EtOAc/ hexane) as a white solid.
  • Example 22 Synthesis of a compound of Formula (I) where A and B are rings (a) and (c) respectively where R 3 and R 6 are OMe, R 2 , R 7 , and R 10 are Me, R 9 is H, R 11 is CN, Y is CH 2 , and R 12 is 5- (tetrahydropyran-4-yloxy)benzofuran-2-ylcarbonylamino (compound 52)
  • Example 24 Synthesis of a compound of Formula (I) where A is a ring of formula (b) and B is a ring of formula (c), R R°, and R* are OMe, R z , R', and R 1 ⁇ 0 ⁇ are Me, R D is OH, R 9 is H, R ⁇ is CN, Y is CH 2 , and R 12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2- ylcarbonylamino (compound 61)
  • Step 2 To a solution of 60 (8 mg, 0.01 mmol) in CH 2 C1 2 (0.5 mL) was added TFA (0.05 mL) at ambient temperature. After stirring for 2 hr, the reaction mixture was diluted with EtOAc, washed with sat. NaHCO 3( - a2 j, brine, and dried over Na 2 SO 4 . Concentration in vacuo and purification by preparative TLC (97:3 CH 2 Cl 2 /MeOH) gave 61 (5 mg, 67%). EM (calc): 752.3; MS (ESI) m/e: 753.4 (M+H) + , 751.5 (M-H) " .
  • Example 25 Synthesis of a compound of Formula (I) where A is a ring of fo ⁇ nula (a) and B is a ring of formula (d), R 1 , R 3 , and R 6 are OMe, R 2 , R 7 , and R 10 are Me, R 4 is OH, R 9 is H, R 11 is CN, Y is CH 2 , and R 12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2- ylcarbonylamino (compound 64)
  • Example 27 Synthesis of a compound of Formula (I) where A is a ring of formula (a) and B is a ring of formula (d), R 1 , R 3 , R 4 and R 6 are OMe, R 2 , R 7 , and R 10 are Me, R 9 is H, R ⁇ is CN, Y is CH 2 , and R 12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 67)
  • R and R are 3,4-dihydroxyphenylethylaminocarbonyloxy, R is H, R 10 : is Me, R , 11 is CN, Y is CH 2 , and R 12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 74)
  • R 4 and R 5 is phenylethylaminocarbonyloxy, R 9 is H, R 10 is Me, R 11 is CN, Y is CH 2 , and R 12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 77)
  • R 4 is OH
  • R 5 is 3,4-dihydroxyphenylethylaminocarbonyloxy
  • R 9 is H
  • R 10 is Me
  • R 11 is CN
  • Y is CH 2
  • R 12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 84)
  • Example 36 Synthesis of a compound of Formula (I) where R 1 , R 3 , R 4 , R 6 , and R 8 are OMe, R 2 and R 7 are Me, R 5 is 3,4-dihydroxyphenylethylaminocarbonyloxy, R 9 is H, R 10 is Me, R 11 is CN, Y is CH2, and R 12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 86)
  • HCT-116 human colorectal carcinoma cells (American Type Culture Collection) were cultured as monolayer in McCoy's 5A Medium (Gibco, #16600-082) supplemented with 10%> fetal bovine serum at 37°C in a 5% CO 2 humidified incubator. For harvesting, cells were washed with phosphate buffered saline and were detached using Trypsin-EDTA (Gibco, #25300-054). Cells are plated in 0.1 ml of medium per well in 96-well microtiter plates (Corning, #3595).
  • the samples were removed from the incubator and 50 ul of a solution containing 9.6 ul of alamarBlue (Biosource, #DAL1100) and 40.4 ul of McCoy's 5A medium was added to each well.
  • the alamarBlue media solution was also added to a triplicate set of wells containing no cells to correct for background fluorescence.
  • the samples were incubated at 37 °C in a 5% CO 2 humidified incubator. After incubation for 4 hours, the samples were read for fluorescence using a fluorescent plate reader (Molecular Devices, type 374). Fluorescence was monitored at 544 excitation wavelength and 590 emission wavelength.
  • the GI5 0 (amount of compound that inhibits the cell growth by 50%) value of the compound of this invention was calculated as the percentage of survival of control calculated from the fluorescence corrected for background fluorescence. The surviving fraction of cells was determined by dividing the mean fluorescence values of the test compounds by the mean fluorescence of the control.
  • the GIso for compounds 1, 3-6 in Table 1 was ⁇ 50 nM and for compounds 2 and 3 was > 100 nM.
  • compositions containing a compound of Fo ⁇ nula (I) Tablet Formulation
  • the following ingredients are mixed intimately and pressed into single scored tablets.
  • Quantity per Ingredient tablet mg compound of this invention 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5
  • Capsule Formulation The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
  • Quantity per Ingredient capsule mg compound of this invention 200 lactose, spray-dried 148 magnesium stearate 2 Suspension Formulation
  • the following ingredients are mixed to form a suspension for oral administration.
  • Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mg distilled water q.s. to 100 ml Injectable Formulation The following ingredients are mixed to form an injectable formulation. Ingredient Amount compound of this invention 1.2 g lactate buffer solution, 0.1 M 10.0 ml HCI (1 N) or NaOH (1 N) q.s. to suitable pH saline (optional) q.s.
  • Suppository Formulation A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with WitepsolTM H-15 (triglycerides of saturated vegetable fatty acid; Riches- Nelson, Inc., New York), and has the following composition: compound of the invention 500 mg WitepsolTM H-15 balance

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Abstract

The present invention is directed to saframcyin analogs that are useful in the treatment of cancer. Pharmaceutical compositions and processes for preparing these compounds are also disclosed.

Description

NOVEL SAFRAMYCIN ANALOGS AS THERAPEUTIC AGENTS
BACKGROUND OF THE INVENTION
Field of the Invention The present invention is directed to saframcyin analogs that are useful in the treatment of cancer. Pharmaceutical compositions and processes for preparing these compounds are also disclosed.
State of the Art Saframycins are a family of natural products that have antiproliferative activity (see Remers, W. Al The Chemistry of Antitumor Antibiotics; Wiley-Interscience, New York, 1988, Vol. 2, Chapter 3). Several saframycin analogues have been isolated and characterized in recent years (see DE 2839668; U.S. Pat. Nos. 4,248,863; 4,372,947, 5,023,184 and EP 329606). Of these, saframycin A and C exhibit extreme cytotoxicity toward several experimental tumors including leukemias L1210 and P388 and Ehrlich carcinoma. Recently, U. S. Application Pub. No 2003/0008873 disclosed synthetic saframcyin analogues that exhibit antiproliferative activity in melanoma and lung cancers A375 and A549. This has sparked a great deal of interest in the scientific community to discover new saframcyin analogues having antitumor activity. The present invention fulfills this and related needs.
SUMMARY OF THE INVENTION In one aspect, this invention is directed to a compound of Formula (I):
Figure imgf000002_0001
(I) wherein: A is a ring represented by formula (a) or (b):
Figure imgf000002_0002
(a) (b) B is a ring represented by formula (c) or (d):
Figure imgf000003_0001
Y is methylene optionally substituted with one or two halo; R1 and R8 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkyisulfinyl, alkylsulfonyl, acyl, cyano, nitro, acylamino, -COOR13 (where R13 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -CONR14R15 (where R14 and R15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or -NR16R17 (where R16 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and R17 is alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R3 and R6 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, cyano, nitro, acylamino, -COOR18 (where R18is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -CONR19R20 (where R19 and R20 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or -NR R (where R is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and R22 is alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R4 and R5 are independently hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, aralkylaminocarbonyloxy, -COOR23 (where R23 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, or -CONR24R25 (where R24 and R25 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R2 and R7 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, or alkylsulfonyl; R9 is hydrogen, alkyl, cyano, halo, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, aryl, aralkyl, heteroaryl, heteroaralkyl, or =( ); R10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, acyloxy, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the aromatic or alicyclic ring in R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10, either alone or as part of another group, is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or hydroxy; Rπ is hydrogen, cyano, -SCN, hydroxy, alkoxy, halo, or =(O); and R12 is: (a) -NHC(=NR26)R27 (where R26 is hydrogen, alkyl, haloalkyl, hydroxy, or alkoxy, and R27 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl where the aromatic or alicyclic ring in aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkyl is substituted or unsubstituted); (b) -NHC(=NR28)NHR28 (where each R28 is independently hydrogen, alkyl, hydroxy, alkoxy, alkoxycarbonyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl where the aromatic or alicyclic ring in aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkyl is substituted or unsubstituted); (c) -NR29COR30 (where R29 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl and R30 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); (d) -CONR31R32 (where R31 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, aralkenyl (wherein the alkenyl chain is optionally substituted with acylamino), heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl and R32 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl); (e) -COOR33 (where R33 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl); (f) -NR34SO2R35 (where R34 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, and R35 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl); (g) -NR36R37 (where R36 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, and R37 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl) ; (h) -NR38CHX'R39 (where R38 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, X1 is haloalkyl, and R39 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl); (i) -OR40 (where R40 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); (j) -S(O)m5R41 (where m5 is 0 to 2 and R41 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); or (k) -S(O)2NR42R43 (where R42 is hydrogen or alkyl and R43 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl) ; wherein the aromatic or alicyclic ring, either alone or as part of another group, in R12 is substituted, except for R27 and R28 where it is optionally substituted, with one, two, or three Ra independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, monosubstituted aminoalkyl, disubstituted aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl, optionally substituted heteroaralkyloxy, monosubstituted aminoalkyloxy, disubstituted aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, substituted heterocycloalkyloxyalkyl, substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkyloxy, -alkylene-S(O)n-R44 (where n is 0 to 2 and R44 is alkyl, hydroxyalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl provided that when n is 2, R44 is not alkyl), -NHSO2R45, -alkylene-NHSO2-R45 (where R45 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -NHCO-R46 or -alkylene-NHCO-R46 (where R46 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl provided that when Ra is -NHCO-R46 , then (i) R46 is not alkyl and (ii) when R46 is optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl, the aromatic and alicyclic ring are substituted), -CONR46R47 or -alkylene-CONR46R47 (where R46 is as defined above and R47 is hydrogen or alkyl provided that when Ra is -CONR46R47, then (i) R46 is not alkyl and (ii) when R46 is optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl, the aromatic and alicyclic ring are substituted), - alkylene-NR48-alkyleneCONR46R49 (where R46 is as defined above and R48 and R49 are independently hydrogen or alkyl), -O-(alkylene)-P(O)(OR50)2 or -(alkylene)-P(O)(OR50)2 (where each R50 is independently selected from hydrogen, alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl), -COOR51 (where R51 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), -COR52 (where R52 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), or -O-(alkylene)-P(O)(OR53)(NHR54) (where R53 is selected from hydrogen, alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl and R54 is alkyl, carboxyalkyl, or alkoxycarbonylalkyl); or a pharmaceutically acceptable salt thereof: provided that: (a) all one, two, or three Ra are not independently selected from alkyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, or alkoxyalkyloxyalkyl; and (b) when R30, R32, R33, R35, R37, R39, R40, R41, and R43 are -(CH2)X-R where x is 0 to 3 and R is quinolinyl, tetrahydroquinolinyl, pyridinyl, indolyl, furanyl, thiophenyl, pyrrolyl, pyrazinyl or quinoxalinyl then each R is not, in addition to groups listed in (a) above, substituted heterocycloalkylalkyl; and (iii) when R30, R32, R33, R35, R37, R39, R40, R41, and R43 are -(CH )X-R where x is 0 to 3 and R is quinolinyl, tetrahydroquinolinyl, pyridinyl, indolyl, furanyl, thiophenyl, pyrrolyl, pyrazinyl or quinoxalinyl then if any Ra is heterocycloalkylalkyloxy, or heterocycloalkyloxy then these groups must be substituted; or a pharmaceutically acceptable salt thereof. Preferably, the compound of Formula (I) is a compound represented by Formula (la):
Figure imgf000006_0001
(la) wherein: Y is methylene optionally substituted with one or two halo; R1 and R8 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, cyano, nitro, acylamino, -COOR13 (where R13 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -CONR14R15 (where R14 and R15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or-NR16R17 (where R16 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and R17 is alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R3 and R6 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, cyano, nitro, acylamino, -COOR18 (where R18 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -CONR19R20 (where R19 and R20 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or -NR21R22 (where R21 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and R22 is alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R4 and R5 are independently hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, -COOR23 (where R23 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, or -CONR24R25 (where R24 and R25 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R2 and R7 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, or alkylsulfonyl; R9 is hydrogen, alkyl, cyano, halo, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, aryl, aralkyl, heteroaryl, heteroaralkyl, or =(O); R10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, acyloxy, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl ; wherein the aromatic or alicyclic ring in R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10, either alone or as part of another group, is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or hydroxy; R11 is hydrogen, cyano, -SCN, hydroxy, alkoxy, halo, =(O), aryl, or heteroaryl; and R12 is: (a) -NHC(=NR26)R27 (where R26 is hydrogen, alkyl, haloalkyl, hydroxy, or alkoxy, and R27 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl where the aromatic or alicyclic ring in aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkyl is substituted or unsubstituted); (b) -NHC(=NR28)NHR28 (where each R28 is independently hydrogen, alkyl, hydroxy, alkoxy, alkoxycarbonyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl where the aromatic or alicyclic ring in aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkyl is substituted or unsubstituted); (c) -NR29COR30 (where R29 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl and R30 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); (d) -CONR31R32 (where R31 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl and R32 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl); (e) -COOR33 (where R33 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl); (f) -NR34SO2R35 (where R34 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, and R35 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl) ; (g) -NR R (where R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, and R37 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl) ; (h) -NR38CHX1R39 (where R38 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, X1 is haloalkyl, and R39 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl); (i) -OR40 (where R40 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); (j) -S(O)msR41 (where m5 is 0 to 2 and R41 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); or (k) -S(O)2NR42R43 (where R42 is hydrogen or alkyl and R43 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl) ; wherein the aromatic or alicyclic ring, either alone or as part of another group, in R12 is substituted, except for R27 and R28 where it is optionally substituted, with one, two, or three Ra independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, monosubstituted aminoalkyl, disubstituted aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl, optionally substituted heteroaralkyloxy, monosubstituted aminoalkyloxy, disubstituted aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, substituted heterocycloalkyloxyalkyl, substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkyloxy, -alkylene-S(O)n-R44 (where n is 0 to 2 and R44 is alkyl, hydroxyalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl provided that when n is 2, R44 is not alkyl), -NHSO2R45, -alkylene-NHSO2-R45 (where R45 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -NHCO-R46 or -alkylene-NHCO-R46 (where R46 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl provided that when R is -NHCO-R46 , then (i) R46 is not alkyl and (ii) when R46 is optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl, the aromatic and alicyclic ring are substituted), -CONR46R47 or -alkylene-CONR46R47 (where R46 is as defined above and R47 is hydrogen or alkyl provided that when Ra is -CONR46R47, then (i) R46 is not alkyl and (ii) when R46 is optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl, the aromatic and alicyclic ring are substituted), - alkylene-NR48-alkyleneCONR46R49 (where R46 is as defined above and R48 and R49 are independently hydrogen or alkyl), -O-(alkylene)-P(O)(OR50)2 (where each R50 is independently selected from hydrogen, alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl), -COOR51 (where R51 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), -COR52 (where R52 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), or -O-(alkylene)- P(O)(OR53)(NHR54) (where R53 is selected from hydrogen, alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl and R54 is alkyl, carboxyalkyl, or alkoxycarbonylalkyl); or a pharmaceutically acceptable salt thereof: provided that: (a) all one, two, or three R are not independently selected from alkyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, or al ox alkyloxyalkyl; and (b) when R30, R32, R33, R35, R37, R39, R40, R41, and R43 are -(CH2)X-R where x is 0 to 3 and R is quinolinyl, tetrahydroquinolinyl, pyridinyl, indolyl, furanyl, thiophenyl, pyrrolyl, pyrazinyl or quinoxalinyl then each Ra is not, in addition to groups listed in (a) above, substituted heterocycloalkylalkyl; and (iii) when R30, R32, R33, R35, R37, R39, R40, R41, and R43 are -(CH2)X-R where x is 0 to 3 and R is quinolinyl, tetrahydroquinolinyl, pyridinyl, indolyl, furanyl, thiophenyl, pyrrolyl, pyrazinyl or quinoxalinyl then if any Ra is heterocycloalkylalkyloxy, or heterocycloalkyloxy then these groups must be substituted; or a pharmaceutically acceptable salt thereof. In a second aspect, this invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient. In a third aspect, this invention is directed to a method for treating cancer in an animal comprising administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Preferably, the cancer is soft tissue sarcoma, prostate cancer, breast cancer, lung melanoma, stomach cancer, neuroblastoma, colon cancer, pancreatic cancer, ovarian cancer, T-cell lymphoma, or leukemia such as myelogenous leukemia (MM) and acute myelogenous leukemia (AML). In a fourth aspect, this invention is directed to a method for treating cancer in an animal which method comprises administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in combination with radiation therapy and optionally in combination with one or more compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HTV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, or a DNA methyl transferase inhibitor. In a fifth aspect, this invention is direct to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.
Detailed Description of the Invention
Definitions: Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning: "Alicyclic" means cycloalkyl and heterocycloalkyl rings as defined herein. "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like. "Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like. "Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing one or two double bond(s), e.g., ethenyl, propenyl, 2-propenyl, butenyl (including all isomeric forms), and the like. "Alkenyloxy" means a radical -OR where alkenyl is as defined above, e.g., allyloxy, and the like. "Alkenylene" means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing one or two double bonds, e.g., ethenylene, propenylene, 2-propenylene, butenylene (including all isomeric forms), and the like. "Alkynyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing one or two tripe bond(s), e.g., ethynyl, propynyl, 2-propynyl, butynyl (including all isomeric forms), and the like. "Alkylthio" means a -SR radical where R is alkyl as defined above, e.g., methylthio, ethylthio, propylthio (including all isomeric forms), butylthio (including all isomeric forms), and the like. " Alkylsulfmyl" means a -S(O)R radical where R is alkyl as defined above, e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl (including all isomeric forms), and the like. "Alkylsulfonyl" means a -SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like. "Amino" means a -NH2. "Alkylamino" means a -NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, n-, ωo-propylamino, n~, iso-, tert-butylamino, and the like. "Alkylaminoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, alkylamino group as defined above e.g., methylaminoethyl, 2-ethylamino-2-methylethyl, and the like. "Alkylaminoalkyloxy" means a -O-R radial where R is alkylaminoalkyl as defined above, e.g., methylaminoethyloxy, 2-ethylamino-2-methylethyloxy, and the like. "Aminosulfonyl" means a -SO2NRR' where R and R' are independently hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl as defined herein.. "Alkoxy" means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like. "Alkoxycarbonyl" means a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like. "Alkoxycarbonylalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, alkoxycarbonyl group as defined above, e.g., methoxycarbonylmethyl, methoxycarbonylethyl, and the like. "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, preferably one or two alkoxy groups, as defined above, e.g., 2- methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like. "Alkoxyalkyloxy" means a -OR radical where R is alkoxyalkyl as defined above, e.g., methoxyethoxy, 2-ethoxyethoxy, and the like. "Alkoxyalkyloxyalkyl" means a -(alkylene)-R radical where R is alkoxyalkyloxy as defined above, e.g., methoxyethoxymethyl, 2-ethoxyethoxymethyl, and the like. "Aminoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, -NRR' where R is hydrogen, alkyl, or -CORa where R is alkyl, and R' is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or haloalkyl, e.g., aminomethyl, methylaminoethyl, 2-ethylamino-2- methylethyl, 1,3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetylaminopropyl, and the like. " Aminoalkoxy" or "aminoalkyloxy" means a -OR radical where R is aminoalkyl as defined above, e.g., 2-aminoethoxy, 2-dimethylaminopropoxy, and the like. "Aminocarbonyl" means a -CONRR radical where each R is independently hydrogen or alkyl as defined above, e.g., -CONH2, methylaminocarbonyl, 2-dimethylaminocarbonyl, and the like. "Acyl" means a -COR radical where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, as defined herein, e.g., acetyl, benzoyl, and the like. "Acyloxy" means a -OCOR radical where R is alkyl, haloalkyl, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl_as defined herein, e.g., acetyloxy, benzoyloxy, and the like. "Acylamino" means a -NHCOR radical where R is alkyl haloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, as defined herein, e.g., acetylamino, propionylamino, and the like. "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms e.g., phenyl, naphthyl or anthracenyl. "Aryloxy" means a -OR radical where R is aryl as defined above e.g., phenoxy, naphthyloxy, and the like. "Aralkyl" means a -(alkylene)-R radical where R is aryl as defined above, e.g., benzyl. "Aralkyloxy" means a -O-R radical where R is aralkyl as defined above, e.g., benzyloxy, and the like. "Aralkylaminocarbonyloxy" means a -OC(O)NH-(alkylene)-R radical where R is aryl as defined above, e.g., 2-phenethylaminocarbonyloxy, and the like. "Aralkenyl" means a -(alkenylene)-R radical where R is aryl as defined above. "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl. The cycloalkyl is optionally substituted with optionally substituted phenyl. Cycloalkylalkyl" means a -(alkylene)-R radical where R is cycloalkyl as defined above; e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl, and the like. "Carboxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, -COOH, e.g., carboxymethyl, carboxyethyl, and the like. "Dialkylamino" means a -NRR' radical where R and R' are independently alkyl as defined above, e.g., dimethylamino, diethylamino, methylpropylamino, methylethylamino, n-, iso-, or tert-butylamino, and the like. "Dialkylaminoalkyl" means a -(alkylene)-R radical where R is dialkylamino as defined above e.g., dimethylaminomethyl, diethylaminoethyl, and the like. "Dialkylaminoalkyloxy" means a -OR radical where R is dialkylaminoalkyl as defined above e.g., dimethylaminomethyloxy, diethylaminoethyloxy, and the like. "Disubstituted amino" means a -NRcRd radical where Rc and Rd are independently selected from alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl as defined herein, e.g., dimethylamino, diethylamino, methylphenylamino, , and the like. "Disubstituted aminoalkyl" means a -(alkylene)-R radical where R is disubstituted amino as defined above except Rc and Rd are not alkyl e.g., dimethylaminomethyl, ethylbenzylaminoethyl, and the like. "Disubstituted aminoalkyloxy" means a -OR radical where R is disubstituted aminoalkyl as defined above e.g., dimethylaminomethyloxy, ethylbenzyla inoethyloxy, and the like. "Halo" means fluoro, chloro, bromo, and iodo, preferably fluoro or chloro. "Haloalkyl" means alkyl substituted with one or more halogen atoms, preferably one to five halogen atoms, preferably fluorine or chlorine, including those substituted with different halogens, e.g., -CH2C1, -CF3, -CHF2, -CF2CF3, -CF(CH3)3, and the like. "Haloalkoxy" means a -OR radical where R is haloalkyl as defined above e.g., -OCF3, - OCHF2, and the like. "Haloalkoxyalkyl" means a -(alkylene)-OR radical where R is haloalkyl as defined above e.g., trifluoromethyloxymethyl, 2,2,2-trifluoroethyloxymethyl, 2-trifluoromethoxyethyl, and the like. "Hydroxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2- methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1- (hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1- (hydroxymethyl)-2-hydroxyethyl. "Hydroxyalkoxy" or "hydroxyalkyloxy" means a -OR radical where R is hydroxyalkyl as defined above. "Hydroxyalkoxyalkyl" or "hydroxyalkyloxyalkyTmeans a -(alkylene)-OR radical where R is hydroxyalkyl as defined above e.g., hydroxymethyloxymethyl, hydroxyethyloxymethyl, and the like. "Hydroxyalkylcarbonyloxy" means a -OCOR radical where R is hydroxyalkyl as defined above e.g., hydroxymethylcarbonyloxy, and the like. "Heterocycloalkyl" means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C. One or two ring carbon atoms can optionally be replaced by a -CO- group. More specifically the term heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, tetrahydroquinolinyl, thiomorpholino, and the like. The heterocycloalkyl is optionally fused to aryl. "Heterocycloalkyloxy" means a -O-R radical where R is heterocycloalkyl ring as defined above e.g., tetrahydropyranyloxy, and the like. Heterocycloalkylalkyl" means a -(alkylene)-R radical where R is heterocycloalkyl ring as defined above e.g., piperazinylmethyl, morpholinylethyl, and the like. Heterocycloalkylalkyloxy" means a -O-R radical where R is heterocycloalkylalkyl as defined above e.g., tetrahydropyranylmethyloxy, and the like. "Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms where one or more, preferably one, two, or three, ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon. More specifically the term heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, benzothiophenyl, benzthiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzopyranyl, and thiazolyl, and the like. Heteroaryloxy" means a -O-R radical where R is heteroaryl ring as defined above e.g., furanyloxy, pyridinyloxy, and the like. "Heteroarylamino" means a NHR radical where R is heteroaryl as defined above. "Heteroaralkyl" means a -(alkylene)-R radical where R is heteroaryl as defined above. Heteroaralkyloxy" means a -O-R radical where R is heteroaralkyl ring as defined above e.g., furanylmethyloxy, pyridinylethyloxy, and the like. "Heteroaralkenyl" means a -(alkenylene)-R radical where R is heteroaryl as defined above. "Methylenedioxy" means -O-CH2-O-. "Monosubstituted amino" means a -NHR' radical where R' is alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl as defined herein, e.g., methylamino, ethylamino, phenylamino, , and the like. "Monosubstituted aminoalkyl" means a -(alkylene)-R radical where R is monosubstituted amino as defined above except R' is not alkyl e.g., methylaminomethyl, benzylaminoethyl, and the like. "Monosubstituted aminoalkyloxy" means a -OR radical where R is monosubstituted aminoalkyl as defined above e.g., methylaminomethyloxy, benzylaminoethyloxy, and the like. "Optionally substituted phenyl" means a phenyl ring optionally substituted with one, two, or three substituents independently selected from alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, heteroaryl (that is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino), heterocycloalkyl (that is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino), amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, methylenedioxy, aminocarbonyl, acylamino, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxy or optionally substituted with five fluorine atoms unless stated otherwise. When the phenyl ring is substituted with at least one substituent listed above it is referred to herein as substituted phenyl. "Optionally substituted phenylalkyl" means a -(alkylene)-R radical where R is optionally substituted phenyl as defined above e.g., benzyl, phenylethyl, and the like. "Optionally substituted phenylalkyloxy" means a -OR radical where R is optionally substituted phenylalkyl as defined above e.g., benzyloxy, phenylethyloxy, and the like. "Optionally substituted phenoxyalkyl" means a -(alkylene)-OR radical where R is optionally substituted phenyl as defined above e.g., phenoxymethyl, phenoxyethyl, and the like. "Optionally substituted phenoxy" means an -OR radical where R is optionally substituted phenyl as defined above e.g., phenoxy, and the like. Optionally substituted heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms where one or more, preferably one, two, or three, ring atoms are heteroatoms selected from N, O, or S, the remaining ring atoms being carbon that is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, optionally substituted phenyl, optionally substituted phenoxy, carboxy, heteroaryl that is optionally substituted with alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino, heterocycloalkyl optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, amino, alkylamino or dialkylamino, heterocycloalkylalkyl optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, amino, alkylamino or dialkylamino, or heteroarylamino optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, amino, alkylamino or dialkylamino unless stated otherwise. More specifically the term optionally substituted heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyranyl, thiazolyl, and the like. When the heteroaryl ring is substituted with at least one substituent listed above it is referred to herein as substituted heteroaryl. "Optionally substituted heteroaralkyloxy" means a -OR radical where R is optionally substituted heteroaralkyl ring as defined below. "Optionally substituted heteroaryloxyalkyl" means a -(alkylene)-OR radical where R is optionally substituted heteroaryl ring as defined above. Optionally substituted heteroaralkyl" means a -(alkylene)-R radical where R is optionally substituted heteroaryl ring as defined above. "Optionally substituted heterocycloalkyl" means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C. One or two ring carbon atoms can optionally be replaced by a -CO- group. More specifically the term heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino and the like. The heterocycloalkyl is optionally fused to aryl and is optionally substituted with one, two, or three substituents independently selected from alkyl, cycloalkyl, halo, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, optionally substituted phenylalkyl, optionally substituted heteroaralkyl, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxy unless stated otherwise. When the heterocycloalkyl is substituted with at least one substituent listed above it is referred to herein as "substituted heterocycloalkyl". "Optionally substituted heterocycloalkyloxy" means a -OR radical where R is optionally substituted heterocycloalkyl ring as defined above. "Optionally substituted heterocycloalkylalkyloxy" means a -OR radical where R is optionally substituted heterocycloalkylalkyl ring as defined above. "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heterocycloalkyl group optionally mono- or di-substituted with an alkyl group" means that the alkyl may but need not be present, and the description includes situations where the heterocycloalkyl group is mono- or disubstituted with an alkyl group and situations where the heterocycloalkyl group is not substituted with the alkyl group. The present invention also includes the prodrugs of compounds of Formula (I). The term prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula (I) when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo. Prodrugs of compounds of Formula (I) include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., NN-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like. Prodrugs of compounds of Formula (I) are also within the scope of this invention. The present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula (I). For example, when compounds of Formula (I) contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. When compounds of Formula (I) contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups. A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1991, the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of Formula (I) can be prepared by methods well known in the art. A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference. A "pharmaceutically acceptable carrier or excipient" means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable carrier/excipient" as used in the specification and claims includes both one and more than one such excipient. The compounds of the present invention may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, racemic forms are within the scope of this invention, unless the specific stereochemistry or isomeric form is specifically indicated. Certain compounds of Formula (I) can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, individual and mixtures thereof are within the scope of this invention. Additionally, as used herein the terms alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as aryl, heteroaryl, heterocycloalkyl are substituted, they include all the positional isomers albeit only a few examples are set forth. Furthermore, all polymorphic forms and hydrates of a compound of Formula (I) are within the scope of this invention. Substituted heterocycloalkylalkyl" means an -(alkylene)-R radical where R is substituted heterocycloalkyl ring as defined above. "Substituted heterocycloalkyloxyalkyl" means an -(alkylene)-OR radical where R is substituted heterocycloalkyl as defined above e.g., piperidinyloxymethyl, pyrrolidinyloxyethyl, and the like. "Treating" or "treatment" of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. The term "treating cancer" or "treatment of cancer" refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer. A "therapeutically effective amount" means the amount of a compound of Formula (I) that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. Attorney Docket No. CL001530PCT
Representative compounds of Formula (I) where R ,1 - τR>10 groups are as depicted in structure below and R ,10 , r R>ll and R ,12 are as defined in Table 1 below are:
Figure imgf000021_0001
Figure imgf000021_0002
Attorney Docket No. CL001530PCT
Figure imgf000022_0002
Representative compounds of Formula (I) where R10 is methyl and A, B, Ru and R12 are as defined in Table 2 below are:
Figure imgf000022_0001
Attorney Docket No. CL001530PCT
Figure imgf000023_0001
Representative compounds of Formula (I) where R!-R3, R6-Rπ groups are as depicted in structure below and R4, R5, and R12 are as define in Table 3 below are:
Attorney Docket No. CL001530PCT
Figure imgf000024_0001
Figure imgf000024_0002
Preferred Embodiments While the broadest definition of this invention is set forth in the Summary of the < Invention, certain compounds of Formula (I) and (la) are preferred. For example: (A). In one embodiment, R12 is -NHCOR30 where R30 is benzofuran-2-yl which is substituted with one or two Ra.
(i) Within this embodiment (A), a preferred group of compounds is that wherein benzofuran-2-yl is substituted with one Ra selected from alkylaminoalkyl or dialkylaminoalkyl, preferably methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, or diethylaminoethyl, more preferably dimethylaminomethyl or diethylaminomethyl and is located at the 4- or 5-position of the benzofiιran-2-yl ring, (ii) Within this embodiment (A), a preferred group of compounds is that wherein benzofuran-2-yl is substituted with one Ra selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxalkyl, preferably methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy or hydroxy and another Ra selected from alkylaminoalkyl or dialkylaminoalkyl, preferably methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, or diethylaminoethyl, more preferably dimethylaminomethyl or diethylaminomethyl.
(iii) Within this embodiment (A), yet another preferred group of compounds is that wherein benzofuran-2-yl is substituted with one Ra selected from optionally substituted heterocycloalkylalkyloxy or optionally substituted heterocycloalkyloxy. Preferably, tetrahydropyranyloxy, piperidinyloxy, l-methylpiperidin-4-yloxy, l-ethylpiperidin-4-yloxy, morpholino-4-ylethoxy, piperazin-1-ylethoxy, pyrrolidin-1-ylethoxy, tetrahydrothiopyran-4- yloxy, 4-methylpiperazin-l-ylethoxy, or 4-(2-hydroxyethyl)piperazin-l-ylethoxy. Preferably, these groups are located at the 5-position of the benzofuran-2-yl ring. Even more preferably, R is tetrahydropyran-4-yloxy.
(iv) Within this embodiment (A), yet another preferred group of compounds is that wherein benzofuran-2-yl is substituted with one Ra selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl, preferably methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy or hydroxy and another Ra selected from optionally substituted heterocycloalkylalkyloxy or optionally substituted heterocycloalkyloxy, preferably, tetrahydropyranyloxy, piperidinyloxy, l-methylpiperidin-4- yloxy, l-ethylpiperidin-4-yloxy, morpholino-4-ylethoxy, piperazin-1-ylethoxy, pyrrolidin-1- ylethoxy, tetrahydrothiopyran-4-yloxy, 4-methylpiperazin-l-ylethoxy, or 4-(2-hydroxyethyl)- piperazin- 1 -ylethoxy. (v) Within this embodiment, yet another preferred group of compounds is that wherein benzofuran-2-yl is substituted with one Ra selected from hydroxyalkyloxy, optionally substituted heteroaralkyloxy, monosubstituted aminoalkyloxy, disubstituted aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, substituted heterocycloalkyloxyalkyl, or substituted heterocycloalkylalkyl. Preferably, Ra is alkylaminoalkyloxy, dialkylaminoalkyloxy, more preferably methylaminoethyloxy, or dimethylaminoethyloxy, hydroxyethyloxy and is located at the 5-position of the benzofuran-2- yl ring.
(vi) Within this embodiment, yet another preferred group of compounds is that wherein benzofuran-2-yl is substituted with one Ra selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another Ra selected from hydroxyalkyloxy, optionally substituted heteroaralkyloxy, monosubstituted aminoalkyloxy, disubstituted aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, substituted heterocycloalkyloxyalkyl, or substituted heterocycloalkylalkyl.
(vii) Within this embodiment, yet another preferred group of compounds is that wherein benzofuran-2-yl is substituted with one Ra selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another Ra selected from -alkylene-S(O)n-R44 (where n is 0 to 2 and R44 is alkyl, hydroxyalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl provided that when n is 2, R44 is not alkyl), -NHSO2R45, -alkylene-NHSO2-R45 (where R45 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -NHCO-R46 or -alkylene-NHCO-R46 (where R46 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl provided that when Ra is -NHCO-R46 , then (i) R46 is not alkyl and (ii) when R46 is optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl, the aromatic and alicyclic ring are substituted), -CONR46R47 or -alkylene- CONR46R47 (where R46 is as defined above and R47 is hydrogen or alkyl provided that when Ra is -CONR46R47, then (i) R46 is not alkyl and (ii) when R46 is optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl, the aromatic and alicyclic ring are substituted), -alkylene-NR48-alkyleneCONR46R4θ (where R46 is as defined above and R48 and R49 are independently hydrogen or alkyl), -O-(alkylene)-P(O)(OR50)2 (where each R50 is independently selected from hydrogen, alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl), -COOR51 (where RS1 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), -COR52 (where R52 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), or -O-(alkylene)- P(O)(OR53)(NHR54) (where R53 is selected from hydrogen, alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl and R54 is alkyl, carboxyalkyl, or alkoxycarbonylalkyl). (B). In another embodiment, R is -NHCOR where R is indolyl, coumarinyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, or pyrazinyl which is substituted with one or two R . (i) Within this embodiment (B), a preferred group of compounds is that wherein indolyl, coumarinyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, or pyrazinyl is substituted with with one Ra selected from alkylaminoalkyl or dialkylaminoalkyl, preferably methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, or diethylaminoethyl, more preferably dimethylaminomethyl or diethylaminomethyl. (ii) Within this embodiment (B), a preferred group of compounds is that wherein indolyl, coumarinyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, or pyrazinyl is substituted with with one Ra selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl, preferably methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy or hydroxy and another Ra selected from alkylaminoalkyl or dialkylaminoalkyl, preferably methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, or diethylaminoethyl.
(iii) Within this embodiment (B), yet another preferred group of compounds is that wherein indolyl, coumarinyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, or pyrazinyl is substituted with one Ra selected from heteroaralkyloxy, monosubstituted aminoalkyloxy, disubstituted aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, substituted heterocycloalkyloxyalkyl, substituted heterocycloalkylalkyl, substituted heterocycloalkylalkyloxy, or substituted heterocycloalkyloxy. Preferably, 1- methylpiperidin-4-yloxy, l-ethylpiperidin-4-yloxy, 4-methylpiperazin-l-ylethoxy, or 4-(2- hydroxyethyl)piperazin- 1 -ylethoxy .
(iv) Within this embodiment, yet another preferred group of compounds is that wherein indolyl, coumarinyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, or pyrazinyl is substituted with one Ra selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another Ra selected from - alkylene-S(O)n-R44 (where n is 0 to 2 and R44 is alkyl, hydroxyalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl provided that when n is 2, R44 is not alkyl), -NHSO R45, - alkylene-NHSO2-R45 (where R45 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -NHCO-R46 or -alkylene-NHCO-R46 (where R46 is alkyl, haloalkyl, hydroxy, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -CONR46R47 or -alkylene-CONR46R47 (where R46 is as defined above and R47 is hydrogen or alkyl), -alkylene-NR 8-alkyleneCONR46R49 (where R46 is as defined above and R4S and R49 are independently hydrogen or alkyl), -O-(alkylene)-P(O)(OR50)2 (where each R50 is independently selected from hydrogen, alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl), -COOR51 (where R51 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), -COR52 (where R52 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), or -O-(alkylene)- P(O)(OR53)(NHR54) (where R53 is selected from hydrogen, alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl and R54 is alkyl, carboxyalkyl, or alkoxycarbonylalkyl). (C). In yet another embodiment, R12 is -NHCOR30 where R30 is aryl substituted with one, two, or three R .
(D). In yet another embodiment, R12 is -NHCOR30 where R30 is aralkenyl substituted with one, two, or three R . (E). In yet another embodiment, R12 is -NHCOR30 where R30 is heteroaralkenyl substituted with one, two, or three Ra. (F). In yet another embodiment, R12 is -NHCOR30 where R30 is -NHC(=NR26)R27 or -NHC(=NR28)NHR28.
(i) Within the above groups (C-F), a preferred group of compounds is that wherein the aromatic ring is substituted with alkylaminoalkyl or dialkylaminoalkyl, preferably methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, or diethylaminoethyl, more preferably dimethylaminomethyl or diethylaminomethyl. (ii) Within the above groups (C-F), a preferred group of compounds is that wherein the aromatic ring is substituted with one Ra selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another Ra selected from alkylaminoalkyl or dialkylaminoalkyl, preferably methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, or diethylaminoethyl.' (iii) Within the above groups (C-F), another preferred group of compounds is that wherein the aromatic ring is substituted with one Ra selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another Ra selected from optionally substituted heterocycloalkylalkyloxy or optionally substituted heterocycloalkyloxy. Preferably, tetrahydropyranyloxy, piperidinyloxy, l-methylpiperidin-4- yloxy, l-ethylpiperidin-4-yloxy, morpholino-4-ylethoxy, piperazin-1-ylethoxy, pyrrolidin-1- ylethoxy, tetrahydrothiopyran-4-yloxy, 4-methylpiperazin-l-ylethoxy, or 4-(2-hydroxyethyl)- piperazin- 1 -ylethoxy .
(iv) Within the above groups (C-F), yet another preferred group of compounds is that wherein the aromatic ring is substituted with one Ra selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another Ra selected from hydroxyalkyloxy, optionally substituted heteroaralkyloxy, monosubstituted aminoalkyloxy, disubstituted aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, substituted heterocycloalkyloxyalkyl, or substituted heterocycloalkylalkyl .
(v) Within the above groups (C-F), yet another preferred group of compounds is that wherein the aromatic ring is substituted with one Ra selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroalkyl and another Ra selected from -alkylene- S(O)n-R44 (where n is 0 to 2 and R44 is alkyl, hydroxyalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl provided that when n is 2, R44 is not alkyl), -NHSO2R45, -alkylene-NHSO2-R45 (where R45 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -NHCO-R46 or -alkylene-NHCO-R46 (where R46 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl provided that when Ra is -NHCO-R46 , then (i) R46 is not alkyl and (ii) when R46 is optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl, the aromatic and alicyclic ring are substituted), -CONR46R47 or -alkylene- CONR46R47 (where R46 is as defined above and R47 is hydrogen or alkyl provided that when Ra is -COR46R47, then (i) R46 is not alkyl and (ii) when R46 is optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl, the aromatic and alicyclic ring are substituted), -alkylene-NR48-alkyleneCONR46R49 (where R46 is as defined above and R48 and R49 are independently hydrogen or alkyl), -O-(alkylene)-P(O)(OR50)2 (where each R50 is independently selected from hydrogen, alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl), -COOR51 (where R51 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), -COR52 (where R52 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), or -O-(alkylene)- P(O)(OR53)(NHR54) (where R53 is selected from hydrogen, alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl and R54 is alkyl, carboxyalkyl, or alkoxycarbonylalkyl).
(a) Within the above groups (A-F) above, and the preferred and more preferred groups contained therein, an even more preferred group of compounds is that wherein Y is methylene.
(b) Within the above groups (A-F) above, and the preferred and more preferred groups contained therein, an even more preferred group of compounds is that wherein Y is methylene, R1, R3, R6, R8 = alkoxy, R2 and R7 = alkyl, R4 and R5 = OH, R9 is hydrogen, and R10 = alkyl, more preferably R1, R3, R6, R8 = -OCH3, R2 and R7 = -CH3, R4 and R5 = OH, and R10 = -CH3. Within the above groups (A-F) above, and the preferred, more preferred and even more preferred groups contained therein R11 is cyano. Within the above groups (A-F) above, and the preferred, more preferred and even more preferred groups contained therein R11 is hydroxy.
(G). In yet another embodiment, R8 is halo, alkyl, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, cyano, nitro, acylamino, -COOR13 (where R13 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -CONR14R15 (where R14 and R15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or -NR16R17 (where R16 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and R17 is alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl). Within this group, more preferred group of compounds are those where R12 is as described in group (A-F) above. Within this more preferred groups, an even more preferred group of compounds is that wherein Y is methylene.
(i) Within the above preferred group (G) and the more preferred group contained therein R1, R3, R6, R8 = alkoxy, R2 and R7 = alkyl, R4 and R5 = OH, R9 is hydrogen, and R10 = alkyl, more preferably R1, R3, R6, R8 = -OCH3, R2 and R7 = -CH3, R4 and R5 = OH, and R10 = -CH3 and R11 is cyano.
(ii) Within the above preferred group (G) and the more preferred group contained therein R1, R3, R6, R8 = alkoxy, R2 and R7 = alkyl, R4 and R5 = OH, R9 is hydrogen, and R10 = alkyl, more preferably R1, R3, R6, R8 = -OCH3, R2 and R7 = -CH3, R4 and R5 = OH, and R10 = -CH3 and R11 is OH. Within the above preferred group (G) and the more preferred groups contained therein, even more preferred group of compounds are those where Y is methylene and R12 is as described in preferred group (A) above.
(H). In yet another embodiment, ring A and B are a group of formula (a) and (c) respectively, where R1, R3, R6, R8 = alkoxy, R2 and R7 = alkyl, R4 and R5 = OH, R9 is hydrogen, and R10 = hydrogen or alkyl, more preferably R1, R3, R6, R8 = -OCH3, R2 and R7 = - CH3, R4 and R5 = OH, and R10 = hydrogen, -CH3 or-CH2CH3; R11 is hydrogen or cyano; Y is methylene; and R12 is -NHCO-[4-CH2(P(O)(OCH2CH3)2)phenyl], -NHC[=NC(O)OC(CH3)3]- [NC(O)OC(CH3)3], -NHC(=NH)phenyl, 5-(tetrahydropyran-4-yloxy)benzofuran-2-ylCONH-, 5-(2-morpholin-4-ylethoxy)benzofuran-2-ylCONH-, 2-CH3-phenyl-CH=C(NHCOCH3)- CONH-, phenyl-C(OCH2CH3)=N-, 5-(tetrahydropyran-4-ylmethyloxy)indol-2-ylCONH-, 5-(2- methoxyethyloxy)indol-2-ylCONH-, 3-OH-4-CH3OCOphenylNHCOCH=CHCONH-, 4-[5- N(CH3)2naphth-l-ylSO2NHCH2]-phenylCONH-, 6-[5-N(CH3)2naphth-l-ylSO2NHCH2]- naphth-2-ylCONH-, 5 -(3 -dimethylaminomethyl)benzofuran-2-ylCONH~, 5 -(tetrahydropyran- 4-ylmethyloxy)benzofuran-2-ylCONH-, 5 -(2-methoxyethyloxy)benzofuran-2-ylCONH-, 4- (tetrahydropyran-4-yloxy)-benzofuran-2-ylCONH-, 6-(tetrahydropyran-4-yloxy)benzofuran-2- ylCONH-, 6-(2-methoxy-ethyloxy)coumarin-3-ylCONH-, 7-(2-methoxyethyloxy)coumarin-3- ylCONH-, or 4-(tetrahydropyran-4-yloxy)phenylCH=CHCONH-. (I). In yet another embodiment, ring A and B are a group of formula (a) and (c) respectively, where R12 is 5-tetrahydropyran-4-yloxybenzofuran-2-ylcarbonylamino. Within this group, a more preferred group of compounds is that wherein R1, R3, R6, R8 = alkoxy, R2 and R7 = alkyl, R4 and R5 = OH, R9 is hydrogen, and R10 = hydrogen or alkyl, more preferably R1, R3, R6, R8 = -OCH3, R2 and R7 = -CH3, R4 and R5 = OH, and R10 = hydrogen, -CH3 or-CH2CH3; R11 is hydrogen or cyano; and Y is methylene. (J). In yet another embodiment, ring A and B are a group of formula (a) and (c) respectively, wherein R1, R3, R6, R8 = alkoxy, R2 and R7 = alkyl, R4 and R5 = OH, R9 is hydrogen, and R10 = hydrogen or alkyl, more preferably R1, R3, R6, R8 = -OCH3, R2 and R7 = -CH3, R4 and R5 = OH, and R10 = hydrogen, -CH3 or-CH2CH3. Reference to the preferred embodiments set forth above is meant to include all combinations of particular and preferred groups unless stated otherwise.
GENERAL SYNTHESIS Compounds of this invention can be made by the methods depicted in the reaction scheme shown below. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data. Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C and most preferably at about room (or ambient) temperature, e.g., about 20 °C. Unless specified to the contrary, the reactions described herein take place under inert gas, such as nitrogen or argon.
Compounds of Formula (I) where Y is methylene, A and B are rings of formula (a) and (c) respectively, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R12 groups are as described in the Summary of the Invention and R11 is cyano, hydroxy, or alkoxy can be prepared by the procedure illustrated and described in Scheme A below.
Figure imgf000033_0001
Scheme A
Reaction of an aldehyde of formula 1 where R1, R2, R3, R4 are as defined in the Summary of the Invention or a suitable protected derivative thereof and PG is a suitable amino protecting group such as 9-fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and the like, with an amine of formula 2 where R5, R6, R7, R8, R9 are as defined in the Summary of the Invention or a suitable protected derivative thereof provides a compound of formula 3. The reaction is carried out in the presence of a suitable acid such as hydrochloric acid, trifluoroacetic acid, and the like and lithium bromide in a suitable organic solvent such as dichloromethane, ethylene glycol dimethyl ether, and the like. In addition, the reaction is often carried out in the presence of a suitable dehydrating reagent such as magnesium sulfate, sodium sulfate, and the like. Installation of group R10 where R10 is other than hydrogen can be carried on a compound of formula 3 under alkylation or reductive amination reaction conditions to provide a compound of formula 4. In case of reductive amination, the reaction is carried out by reacting 3 with a suitable aldehyde in the presence of a suitable reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. Removal of the amino protecting group in a compound of formula 4 provides a compound of formula 5. The reaction conditions employed for removal of the protecting groups depend on the nature of the protecting groups. Suitable conditions for the protecting group removal can be found in T. W. Greene and P. G. M. Wuts Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1999. Reaction of 5 with a 2-aminoacetaldehyde of formula 6 where PGi is a suitable amino protecting group provides a compound of formula 7. The reaction is carried out in the presence of a suitable dehydrating reagent such as magnesium sulfate, sodium sulfate, and the like, in a suitable organic solvent such as dichloromethane, ethylene glycol dimethyl ether, dichloroethane, and the like. Optionally, the reaction is carried out in the presence of a suitable acid such as hydrochloric acid, trifluoroacetic acid, and the like and lithium bromide. Treatment of 7 with a suitable acid such as zinc(II) chloride and the like in a suitable organic solvent such as 2,2,2-trifluoroethanol, THF, and the like provides a compound of formula 8. Optionally, the cyclization reaction can be carried out in the presence of an external cyanide source such as trimethylsilyl cyanide, sodium cyanide, potassium cyanide and the like. Removal of the amino protecting groups in a compound of formula 8 provides a compound of foπnula 9. The reaction conditions employed for removal of the protecting group depend on the nature of the protecting group. For example, if the protecting group is 9- fluorenylmethyl carbamate, it is removed under basic reaction conditions. Suitable bases are l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), morpholine, piperazine, and the like. Suitable conditions for other protecting group removal can be found in T. W. Greene and P. G. M. Wuts Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1999. Compound 9 is then converted to a compound of Formula (I) by methods well known in the art. For example:
(i) A compound of Formula (I) where R12 is -NHCOR30 where R30 is as defined in the Summary of the Invention can be readily prepared by reacting 9 with an acid halide of formula R30COX where X is halo or an acid of formula R30COOH. If acid halide is utilized, the reaction is carried out in the presence of a suitable base such as triethylamine, N,N- diethylaniline, NN-diisopropylethylamine and the like, in a suitable reaction solvent such as THF, DMF and the like. The acid halide such as acid chloride can be obtained from commercial sources or can be prepared by reacting the corresponding acid with a halogenating agent such as oxalyl chloride, thionyl chloride, phosphorous oxychloride, and the like. If acid is utilized, the reaction is carried out in the presence of suitable coupling agent such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCΗC1), 1,3-dicyclohexyl- carbodiimide (DCC), or benzotriazol-l-yloxyltris(dimethylamino)phosphonium hexafluorophosphate (BOP), optionally in the presence of 1-hydroxybenzotriazole hydrate (HOBt»H2O) in a suitable organic solvents such as DMF and the like, and in the presence of a suitable base such as NN-diethylaniline and the like. The acids are either commercially available or they can be prepared from commercially available starting materials by methods known in the art.
(ii) A compound of Formula (I) where R12 is -ΝR34SO2R35 can be prepared by reacting 9 with a sulfonylating agent of formula R35S02L where L is a leaving group such as halo under reaction conditions described for acid halides in (i) above.
(iii) A compound of Formula (I) where R12 is -NHC(=NR26)R27 can be prepared by reacting 9 with an amidine forming agent such as a thioimidic acid methyl ester of formula R27C(=NR26)SCH3, which is either commercially available or can be prepared by methods known in the art. The reaction is carried out in the presence of an acid such as acetic acid, trifluoroacetic acid, hydrochloric acid, and the like.
(iv) A compound of Formula (I) where R12 is -NHC(=NH)NHR28 can be prepared by reacting 9 with a guanidine forming agent such as pyrazole-carboxamidine, which are either commercially available or can be prepared by methods known in the art. (v) A compound of Formula (I) where R12 is -NR36R37 and -NR38CHX1R39 can be prepared by reacting 9 with a suitable alkylating agent by methods known in the art. (vi) A compound of Formula (I) where R12 is -OR40 can be prepared first by converting the amine at the C-l position of the compound 9 to hydroxyl through diazo functionality followed by alkylation of the resulting hydroxyl group with suitable alkylating reagents under conditions well known in the art. Alternatively, a compound of Formula (I) where R12 is -OR40 can be prepared reacting compound 5 with a hydroxy-protected hydroxyacetaldehyde of formula CH2(CHO)OPG such as tert-butyldimethylsilyloxy acetaldehyde instead of compound 6, followed by removal of the hydroxy protecting group to provide a compound of formula 9 where the C-l carbon carries a hydroxymethyl instead of aminomethyl group. The hydroxy group can then be functionalized as described above.
(vii) A compound of Formula (I) where R12 is -COOR33 and -CONR31R32 can be prepared by reacting 5 with 2-formylacetic acid methyl ester instead of compound 6, followed by removal of the carboxy protecting group to provide a compound of formula 9 where the C-l carbon carries a carboxymethyl instead of aminomethyl group. The carboxy group can then be converted to a compound of Formula (I) where R12 is -COOR33 and -CONR31R32 by methods well known in the art.
(viii) A compound of Formula (I) where R12 is -S(O)msR41 can be prepared by converting the hydroxy group in a compound of 9 carrying hydroxymethyl group at C-l to a leaving group such as toluenesulfonate and then reacting it with a sulfur nucleophile of formula R41SH, followed by oxidation of the sulfur with a suitable oxidizing agent such as m-chloroperbenzoic acid, and the like. A compound of Formula (I) where R11 is hydroxy or methoxy can be prepared from a corresponding compound of Formula (I) where R11 is -CN by reacting it with a suitable Lewis acid such as AgNO3, AgBF4, and the like in the presence of a nucleophile such as water and methanol respectively.
Alternatively, a compound of formula 8 where Y is methylene, A and B are rings of formula (a) and (c) respectively, R11 is cyano, hydroxy, or alkoxy, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R12 groups are as described in the Summary of the Invention can be prepared can be prepared by the procedure illustrated and described in Scheme B below.
Figure imgf000037_0001
Scheme B
Reaction of an aldehyde of formula 1 where R1, R2, R3, R4 are as defined in the Summary of the Invention or a suitable protected derivative thereof and PG is a suitable amino protecting group with an amine ester of formula 10 where Rs, R6, R7, R8, R9 are as defined in the Summary of the Invention or a suitable protected derivative thereof and PG2 is a suitable carboxy protecting group in the form of an ester provides a compound of formula 11. The reaction is carried out in the presence of a suitable acid such as hydrochloric acid, trifluoroacetic acid, and the like, and lithium bromide in a suitable organic solvent such as dichloromethane, ethylene glycol dimethyl ether, and the like. In addition, the reaction is often carried out in the presence of a suitable dehydrating reagent such as magnesium sulfate, sodium sulfate, and the like. Compound 11 is then converted to a compound of formula 12 where R10 is other than hydrogen as described in Scheme A above. Reduction of the ester group in compound 12 with a suitable reducing agent such as lithium borohydride, diisobutylaluminum hydride, lithium aluminum hydride, and the like, followed by removal of the hydroxy protecting group provides a compound of formula 13. The reaction conditions employed for removal of the protecting group depend on the nature of the protecting groups. Suitable conditions for the protecting group removal can be found in T. W. Greene and P. G. M. Wuts Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1999. Compound 13 is then converted to a compound of formula 14 by reacting it with a 2- aminoacetaldehyde of fonnula 6 as described in Scheme A above. Synthesis of a compound of formula 8 is accomplished by oxidation of the alcohol of 14 to an aldehyde in the presence of a suitable nucleophile such as cyanide from sodium cyanide, potassium cyanide and the like. An example of a suitable oxidation condition is the use of the mixture of oxalyl chloride, DMSO, and triethylamine. Other suitable oxidizing agents include but are not limited to Dess-Martin periodinane, tetrapropylammonium perruthenate.
A compound of formula 1 can be prepared from a suitably substituted tyrosine type amino acid that are either commercially available or prepared from the commercially available starting materials following the methods known in the art. For example, a compound of formula 1, preferably a specific enantiomerically pure compound of foπnula 1, can also be prepared by the procedure illustrated and described in Scheme C below.
Figure imgf000038_0001
Bromination reaction on a compound of formula 15 where R1, R2, R3, and R4 are defined as in the Summary of the Invention or a suitable protected derivative thereof provides a compound of formula 16. Compound 15 can be readily brominated in the desired position by treating it with bromine in the presence of pyridine in a suitable organic solvent such as DMF, and the like. Compounds of formula 15 are either commercially available or can be prepared from commercially available starting material by methods known in the art. Compound 16 can be converted to a compound of formula 17 by treating 16 with an organometallic reagent such as alkyllithium e.g., tert-butyllithium, «-butyllithium, and the like or magnesium metal to form a Grignard reagent, followed by quenching of the resulting organometallic species with a suitable formyl source such as N,N-dimethylformamide (DMF). Reduction of the aldehyde group in 17 is with a suitable reducing agent such as sodium borohydride, and the like, provides the corresponding alcohol compound of formula 18. Compound 18 is then converted to the corresponding bromide compound of formula 19 using a suitable bromination reagent such as bromine in the presence of a suitable oxo-phile such as triphenylphosphine. Compound 19 is then converted to a compound of formula 21, preferably enantiomerically pure compound, by stereoselective alkylation reaction between compound 19 and a compound of formula 20 where R* is a suitable amino protecting group or a suitable chiral auxiliary capable of exerting a chiral influence on the course of the alkylation. An example of such chiral auxiliary can be (-)-pseudoephedrine (Myers et al. J. Am. Chem. Soc. 1997, 119, 656). The reaction is carried out in the presence of a suitable base such as lithium diisopropylamine, lithium bis(trimethylsilyl)amide, and the like in a suitable organic solvent such as THF. Optionally the reaction can be carried out in the presence of Lewis acids such as lithium chloride. Removal of amino protecting group R* from 21 with concomitant reduction of amide functionality to alcohol functionality provides a compound of formula 22. Suitable amide deprotection method are found in T. W. Greene and P. G. M. Wuts Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1999. An example of such removal provides a compound of formula 22 by concomitant reduction of amide functionality to alcohol functionality by reducing agents such as lithium amidotrihydroborate and the like. Protection of the amino group in 22 with a suitable protecting group such 9- fluorenylmethyl carbonyl (Fmoc) or tert-butoxycarbonyl (Boc) and the like, provides a compound of formula 23 which is then converted to a compound of formula 1 under suitable oxidation reaction conditions. An example of a suitable oxidation condition is the use of the mixture of oxalyl chloride, DMSO, and triethylamine. Other suitable oxidizing agents include but not limited to Dess-Martin periodinane, tetrapropylammonium perruthenate. Alternatively, a compound of formula 22 can be prepared following the procedure illustrated and described in Scheme D below.
Figure imgf000040_0001
Scheme D
Wittig olefination reaction on a compound of formula 17 with a compound of phosphonate compound of formula 24 where PG and PG2 are a suitable amino and carboxy protecting groups in the presence of a suitable base such as sodium hydride, «-butyllithium, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like, provides a compound of formula 25. Hydrogenation of 25 in the presence of a suitable catalyst, preferably a chiral catalyst such as Et-DuPHOS-Rh(I), BINAP-Ru(OAc)2, (+)-l,2-bis((2S, 5S)-2,5-diethylphospholano)- benzene(cyclooctadiene) rhodium(I) trifluoromethanesulfonate, and the like, provides a compound of formula 26. Selective removal of the amino protecting group on a compound of formula 26 provides a compound of formula 27. The reaction conditions employed for removal of the protecting groups depend on the nature of the protecting groups. Suitable conditions for the protecting group removal can be found in T. W. Greene and P. G. M. Wuts Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1999. Conversion of a compound of formula 27 to a compound of formula 22 is achieved by reduction of the ester to an alcohol using a suitable reducing agent such as L-Selectride, lithium aluminum hydride, lithium borohydride, diisobutylaluminum hydride in a suitable organic solvent such as THF, ethyl ether, and the like.
A compound of formula 2 can be prepared following the procedures illustrated and described in Scheme E below.
Figure imgf000041_0001
Scheme E
Treatment of a compound of formula 28 with hydrogen cyanide, acetone cyanohydrin, and the like, provides a compound of formula 29. Compound 28 can be prepared by the same procedure described for formula 1 above. Treatment of 29 with an amine nucleophile such as piperidine, pyrrolidine, dimethylamine, morpholine, and the like, preferably morpholine, in a suitable organic solvent such as 2,2,2-trifluoroethanol, CH2C12, and the like, provides a compound of formula 30. Removal of the amino protecting group in 30 then provides a compound of formula 2. The reaction conditions employed for removal of the protecting groups depend on the nature of the protecting groups. For example, if the protecting group is 9-fluorenylmethyl carbamate (Fmoc), it is removed under basic reaction conditions. Suitable bases are 1,8-diaza- bicyclo[5.4.0]undec-7-ene (DBU), morpholine, piperazine, and the like. Suitable conditions for the protecting group removal can be found in T. W. Greene and P. G. M. Wuts Protective . Groups in Organic Synthesis, John Wiley & Sons, Inc. 1999.
Utility The compounds of this invention are useful in the treatment of proliferative diseases such as cancer such as soft tissue sarcoma, prostate cancer, breast cancer, lung melanoma, stomach cancer, neuroblastoma, colon cancer, pancreatic cancer, ovarian cancer, T-cell lymphoma, or leukemia such as myelogenous leukemia (MM) and acute myelogenous leukemia (AML). Testing
The ability of the compounds of this invention to inhibit cell growth can be tested using the in vitro assay described in biological assay Example 1 below. Administration and Pharmaceutical Compositions In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors. Therapeutically effective amounts of compounds of Formula (I) may range from approximately 0.1-50 mg per kilogram body weight of the recipient per day; preferably about 0.5-20 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 35 mg to 1.4 g per day. In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral or parenteral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Oral compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability. As stated previously, the compound of Formula (I) can be administered in combination with known anti-cancer agents. Such known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors. The compound of Formula (I) are particularly useful when adminsitered in combination with radiation therapy. Preferred angiogenesis inhibitors are selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP (matrix metalloprotease) inhibitor, an integrin blocker, interferon-α, interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-0-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, and an antibody to VEGFR and EFGR. "Estrogen receptor modulators" refers to compounds that interfere or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2-[4-[2-(l- piperidinyl)ethoxy]phenyl]-2H- 1 -benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4 '- dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SΗ646. Preferred estrogen receptor modulators are tamoxifen and raloxifene. "Androgen receptor modulators" refers to compounds that interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate. "Retinoid receptor modulators" refers to compounds that interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α- difluoromethylornithine, ILX23-7553, trans-N-(4'-hydroxyphenyl) retinamide, andN-4- carboxyphenyl retinamide. "Cytotoxic agents" refer to compounds which cause cell death primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mitosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors. Examples of cytotoxic agents include, but are not limited to, tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2- methyl-pyridine) platinum, benzylguanine, glufosfamide, GPXIOO, (trans, trans, trans)-bis-mu- (hexane-l,6-diamine)-mu-[diamine-platinum(II)]bis[diamine-(chloro)platinum(II)]- tetrachloride, diarizidinylspermine, arsenic trioxide, l-(ll-dodecyl-amino-10- hydroxyundecyl)-3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3'-deamino-3'- mo holino-13-deoxo-10-hydroxy-carminomycin, annamycin, galarubicin, elinafide, MEN10755, and 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (see WO 00/50032). Examples of microtubulin inhibitors include paclitaxel, docetaxel (also known as Taxotere®, epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives); vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS 184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L- proline-t-butylamide, TDX258, and BMS188797. Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ' ,4 '-O-exo-benzylidene-chartreusin, 9-methoxy-NN-dimethyl- 5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine, l-amino-9-ethyl-5-fluoro-2,3-dihydro- 9-hydroxy-4-methyl-lH,12H-benzo[de]pyrano[3',4':b,7]-indolizino[l,2b]quinoline- 10, 13(9Η, 15H)dione, lurtotecan, 7-[2-(N-isopropylamino)-ethyl]-(20S)camptothecin, BΝP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'- dimethylamino-2'-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6- dimethyl-6H-pyrido[4,3-b]carbazole- 1 -carboxamide, asulacrine, 6,9-bis[(2-aminoethyl)- amino]benzo[g]isoguinoline-5, 10-dione, 5-(3-aminopropylamino)-7, 10-dihydroxy-2-(2- hydroxyethylaminomethyl)-6H-ρyr azolo[4,5,l-de]acridin-6-one, N-[l-[2(diethylamino)- ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide, N-(2-(dimethyl- amino)ethyl)acridine-4-carboxamide, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H- indeno[2, l-c]quinolin-7-one, and dimesna. "Antiproliferative agents" includes antisense RΝA and DΝA oligonucleotides such as G3139, ODΝ698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'- methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)- sulfonyl]-N'-(3,4-dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]- glycylamino]-L-glycero-B-L-mannoheptopyranosyl]-adenine, aplidin, ecteinascidin-743, troxacitabine, 4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][l,4]thiazin-6-yl- (S)~ ethyl]-2,5-thienoyl-L-glutamic acid, aminopterin, 5-flurouracil, leucovorin, alanosine, 11- acetyl-8 -(carbamoyloxymethyl)-4-formyl-6-methoxy- 14-oxa- 1,11 -diazatetra cyclo(7.4.1.0.0)- tetradeca-2,4,6-trien-9-yl acetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-l-B-D-arabinofuranosyl cytosine, and 3- aminopyridine-2-carboxaldehyde thiosemicarbazone. "Antiproliferative agents" also includes monoclonal antibodies to growth factors, other than those listed under "angiogenesis inhibitors", such as trastuzumab, and tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134). "ΗMG-CoA reductase inhibitors" refers to inhibitors of 3-hydroxy-3-methylglutaryl- CoA reductase. Compounds which have inhibitory activity for ΗMG-CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33. The terms "ΗMG- CoA reductase inhibitor" and "inhibitor of ΗMG-CoA reductase" have the same meaning when used herein. It has been reported that (Int. J. Cancer, 20, 97(6):746-50, (2002)) combination therapy with lovastatin, a ΗMG-CoA reductase inhibitor, and butyrate, an inducer of apoptosis in the Lewis lung carcinoma model in mice showed potentiating antitumor effects Examples of ΗMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926, and 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850, and 4,916,239), pravastatin (PRAVACΗOL®; see U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447, and 5,180,589), fluvastatin (LESCOL®; see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946, and 5,356,896), atorvastatin (LIPITOR®; see U.S. Pat. Nos. 5,273,995, 4,681,893, 5,489,691, and 5,342,952) and cerivastatin (also known as rivastatin and BAYCΗOL®; see U.S. Pat. No. 5,177,080). The structural formulas of these and additional ΗMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89, Feb. 5, 1996) and U.S. Pat. Nos. 4,782,084 and 4,885,314. The term ΗMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have ΗMG-CoA reductase inhibitory activity, and colchicin the use of such salts, esters, open-acid and lactone fonns is included within the scope of this invention. In ΗMG-CoA reductase inhibitors where an open-acid form can exist, salt and ester forms may preferably be formed from the open-acid, and all such forms are included within the meaning of the term "HMG-CoA reductase inhibitor" as used herein. Preferably, the HMG- CoA reductase inhibitor is selected from lovastatin and simvastatin, and most preferably simvastatin. "Prenyl-protein transferase inhibitor" refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protem transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase). Examples of prenyl-protein transferase inhibiting compounds include (±)-6-[amino(4-chlorophenyl)(l- methyl-lH-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-l-methyl-2(lH)-quinolinone, (-)-6- [amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-chloro phenyl)-l-methyl- 2(lH)-quinolinone, (+)-6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3- chloro phenyl)- 1 -methyl-2( 1 Η)-quinolinone, 5 (S)-n-butyl- 1 -(2,3 -dimethylphenyl)-4- [ 1 -(4- cyanobenzyl)-5-imidazolylmethy l]-2-piperazinone, (S)-l-(3-chlorophenyl)-4-[l-(4-cyano- benzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)-methyl)-2-piperazinone, 5(S)-«-butyl- 1 -(2- methylphenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2 -piperazinone, l-(3-chlorophenyl) -A- [ 1 -(4-cyanobenzyl)-2-methyl-5 -imidazolylmethyl] -2-piperazinone, 1 -(2,2-diphenylethyl)-3 - [N-(l-(4-cyanobenzyl)-lH-imidazol-5-yIethyl)-carbamoyl]piperidine, 4-{5-[4-hydroxymethyl- 4-(4-chloropyridin-2-ylmethyl)-piperidine- 1 -ylmethyl]-2-methylimidazol- 1 -ylmethyl} - benzonitrile, 4- { 5 - [4-hydroxy-methyl-4-(3 -chlorobenzyl)-piperidine- 1 -ylmethyl] -2- methylimidazol- 1 -ylmethyl} -benzonitrile, 4- { 3 - [4-(2-oxo-2H-pyridin- 1 -yl)benzyl]-3H- imidazol-4-ylmethyl} -benzonitrile, 4-{3-[4-(5 -chloro-2-oxo-2H- [1,2 ' ]bipyridin-5 '-ylmethyl] - 3H-imidazol-4-ylmethyl}benzonitrile, 4-{3-[4-(2-oxo-2H-[l,2']bipyridin-5'-ylmethyl]-3H- imidazol-4-ylmethyl} benzonitrile, 4-[3-(2-oxo- 1 -phenyl- 1 ,2-dihydropyridin-4-ylmethyl)-3H- imidazol-4-ylmethyl}benzonitrile, 18,19-dihydro- 19-oxo-5Η, 17H-6, 10: 12, 16-dimetheno- 1H- imidazo[4,3 -c] [1,11 ,4]dioxa-azacyclononadecine-9-carbonitrile, (±)- 19,20-dihydro- 19-oxo- 5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][l,6,9,12]- oxatriaza-cyclooctadecine-9-carbonitrile, 19,20-dihydro- 19-oxo-5H, 17H- 18,21 -ethano-6, 10: 12, 16-dimetheno-22H-imidazo[3,4-h] [ 1 ,8, 11 , 14]oxatriazacyclo-eicosine-9-carbonitrile, and (±)- 19,20-dihydro-3-methyl- 19-oxo-5H- 18,21 -ethano- 12, 14-etheno-6, 10-met heno-22H- benzo[d]imidazo[4,3-k][l,6,9,12]oxa-triazacyclooctadecine-9-carbonitrile. Other examples of prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. Νos. 5,420,245, 5,523,430, 5,532,359, 5,510,510, 5,589,485, 5,602,098, European Patent Publ. 0618221, European Patent Publ. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ. 0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO 98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of a prenyl- protein transferase inhibitor on angiogenesis see J. of Cancer, Vol. 35, No. 9, pp.1394-1401 (1999). Examples of HIV protease inhibitors include amprenavir, abacavir, CGP-73547, CGP- 61755, DMP-450, indinavir, nelfmavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, andBMS-232, 632. Examples of reverse transcriptase inhibitors include delaviridine, efavirenz, GS-840, HB Y097, lamivudine, nevirapine, AZT, 3TC, ddC, and ddl. It has been reported ((Nat. Med. 8(3):225-32, (2002)) that HIV protease inhibitors, such as indinavir or saquinavir, have potent anti-angiogenic activities and promote regression of Kaposi sarcoma "Angiogenesis inhibitors" refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFRl) and Flk-1/KDR (VEGFR20), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-oc, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxygenase-2 inhibitors like celecoxib, valdecoxib, and rofecoxib (PNAS, Vol. 89, p. 7384 (1992); JNCI. Vol. 69, p. 475 (1982); Arch. Opthalmol. Vol. 108, p. 573 (1990); Anat. Rec. Vol. 238, p. 68 (1994); FEBS Letters, Vol. 372, p. 83 (1995); Clin., Orthop. Vol. 313, p. 76 (1995); J. Mol. Endocrinol, Vol. 16, p.107 (1996); Jpn. J. Pharmacol., Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)), carboxyamidotriazole, combretastatin A-4, squalamine, 6-( -chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, Nature Biotechnology, Vol. 17, pp.963-968 (October 1999); Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186). As described above, the combinations with NSAID's are directed to the use of NSAID's which are potent COX-2 inhibiting agents. Such compounds include, but are not limited to those disclosed in, U.S. Pat. Nos. 5,474,995, 5,861,419, 6,001,843, 6,020,343, 5,409,944, 5,436,265, 5,536,752, 5,550,142, 5,604,260, 5,698,584, 5,710,140, 5,344,991, 5,134,142, 5,380,738, 5,393,790, 5,466,823, 5,633,272, 6,313,138, and 5,932,598, and WO 94/15932, all of which are hereby incorporated by reference. Other examples of specific inhibitors of COX-2 include those disclosed in U.S. Patent the disclosure of which is incorporated herein by reference in its entirety. General and specific synthetic procedures for the preparation of the COX-2 inhibitor compounds described above are found in U.S. Pat. No. 5,474,995, 5,861,419, and 6,001,843, all of which are herein incorporated by reference. Compounds which are specific inhibitors of COX-2 and are therefore useful in the present invention, and methods of synthesis thereof, can be found in the following patents, pending applications and publications, which are herein incorporated by reference: U.S. Pat. Nos. 5,474,995, 5,861,419, 6,001,843, 6,020,343, 5,409,944, 5,436,265, 5,536,752, 5,550,142, 5,604,260, 5,698,584, and 5,710,140. Other examples of angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-l- oxaspiro [2,5] oct-6 -yl(chloroacetyl)carbamate, 5 -amino- 1 - [[3 , 5 -dichloro-4-(4-chlorobenzoyl)- phenyl]-methyl]-lH-l,2,3-triazo le-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2- pyrrolocarbonyl-imino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(l,3-naphthalene disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416). As used above, "integrin Mockers" refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the αvβ3 integrin, to compounds which selectively antagonize, inhibit or counter-act binding of a physiological ligand to the vβ5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the αvβ3 integrin and the αvβs integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the vβδ; αvβs, otiβi, α2βl5 αsβi, α6βι and α6β4 integrins. The term also refers to antagonists of any combination of αvβ3, αvβ5, αvβ6, vβ8, cciβi, α2βι, 5βι, α6βι and α6β4 integrins. Some specific examples of tyrosine kinase inhibitors include N-(trifluoromethyl- phenyI)-5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)-indoIin-
2-one, 17-(allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4-fluoro-phenylamino)-7- methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxy- ethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11, 12-hexahydro-10-(hydroxymethyl)-10- hydroxy-9-methyl-9,12-epoxy -lH-diindolo[l,2,3-fg:3',2',l'-kl]pyrrolo[3,4-i][l,6]- benzodiazocin-1-one, SΗ268, genistein, ST1571, CEP2563, 4-(3-chlorophenylamino)-5,6- dimethyl-7H-ρyrrolo [2,3-d]pyrimidinemethane sulfonate, 4-(3-bromo-4-hydroxyphenyι)- amino-6,7-dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, SU11248, STI571A, N-4-chloroρhenyl-4-(4-pyridylmethyl)-l-phthalazinamine, and EMD121974. The instant compound is also useful in combination with platelet fibrinogen receptor (GP Ilb/IIIa) antagonists, such as tirofiban, to inhibit metastasis of cancerous cells. Tumor cells can activate platelets largely via thrombin generation. This activation is associated with the release of VEGF. The release of VEGF enhances metastasis by increasing extravasation at points of adhesion to vascular endothelium (Amirkhosravi, Platelets 10, 285-292, (1999)). Therefore, the present compound can serve to inhibit metastasis in combination with GP Ilb/IIIa antagonists. Examples of other fibrinogen receptor antagonists include abciximab, eptifibatide, sibrafiban, lamifiban, lotrafiban, cromofiban, and CT50352. The compound of this invention can be used with antineoplastic agents such as doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro- methotrexate, mitomycin C, porfiromycin, Ηerceptin®, Rituxan®, Avastin®, Tarceva®, 5- fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo- phyllotoxin derivatives such as colchicines, etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, estramustine, cisplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT- 11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and inter leukins. If formulated as a fixed dose, such combination products employ the compound of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. Compound of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate. The term administration (e.g., "administering" a compound) in reference to the compound of the invention means introducing the compound into the system of the animal in need of treatment. When the compound of the invention is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), "administration" is understood to include concurrent and sequential introduction of the compound and other agents. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Radiation therapy, including x-rays or gamma rays that are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with the compounds of this invention alone to treat cancer.
EXAMPLES The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. Synthetic Examples
Reference A Synthesis of intermediate 9
Step 1
Figure imgf000050_0001
(a) To a solution of 2,4-dimethoxy-3-methylbenzaldehyde (10. l g, 56.3 mmol) and 3- chloroperoxybenzoic acid (57-86%, 19.7 g, 65.0 mmol) in CH2C12 (200 mL) at 0 °C was added j9-toluenesulfonic acid monohydrate (1.01 g, 5.31 mmol). After 15 min, the ice bath was removed and the reaction mixture was stirred for 2 hr as it warmed to room temperature. The reaction mixture was diluted with Et2O (300 mL) and sat. NaHCO3^ (200 mL). The organic phase was washed with sat. NaHCO3(aa), sat. Na2S2O3^, sat. NaHCO3^, and brine and dried over Na2SO4 and concentrated to give formic acid 2,4-dimethoxy-3-methylphenyl ester.
(b) To a solution of crude formic acid 2,4-dimethoxy-3-methylphenyl ester in methanol (90 mL) was added a solution of KOH (3.54 g, 5.31 mmol) in H2O (10 mL). After 40 min, the reaction mixture was acidified by the addition of 0.25 M HCl^ (240 mL). The reaction mixture was concentrated and the resulting layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with brine and dried over Na SO4 to give 2,4-dimethoxy-3-methylphenol. The crude product obtained was used without further purification. Additonal amounts of 2,4-dimethoxy-3-methylphenol via this procedure.
(c) To a solution of 2,4-dimethoxy-3-methylphenol (44.0 g, 262 mmol) and imidazole (19.5 g, 287 mmol) in DMF (250 mL) at 0 °C was added TBDMSCl (42.6 g, 286 mmol) in two portions. After 2 hr, the reaction mixture was diluted with ethyl acetate (1.2 L) and water (800 mL). The organic layer was washed with water, brine, and dried over Na2SO4. Upon concentration, TBS ether 15 (72.8 g, 99%) was obtained as a light colored oil.
Step 2
Figure imgf000051_0001
To a solution of 15 (72.8 g, 258 mmol) and pyridine (25.0 mL, 309 mmol) in DMF (200 mL) at 0 °C was added a solution of bromine (15.0 mL, 291 mmol) in DMF (15 mL) dropwise over the period of 50 min. After 90 min of stirring, additional aliquots of pyridine (5.0 mL, 62 mmol) and bromine (1.5 mL, 29 mmol) were added directly to the reaction mixture. After 30 min of additional stirring, the reaction mixture was diluted with ethyl acetate (500 mL), hexane (500 mL) and brine (500 mL). The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, 0.5 NHCl(aq), brine, and dried over Na2SO4. Purification by column chromatography (5% ethyl acetate-hexane) afforded 16 (84.3 g, 91%). Step 3
Figure imgf000052_0001
To a solution 16 (57.8 g, 160 mmol) in THF (600 mL) at -78 °C was added t-BuLi (235 mL, 400 mmol, 1.7 M in pentane) dropwise over a period of 55 min. After 15 min, DMF (56.4 g, 772 mmol) was added slowly and the reaction was stirred at -78 °C. After 30 min, the reaction mixture was diluted with ethyl acetate (350 mL) and brine (350 mL). The organic layer was washed with H2O, brine, and dried over Na2SO4 and concentrated to give 17 (49.7 g, 99%) obtained was used for the next reaction without further purification. Step 4
Figure imgf000052_0002
17 18
To a solution of the aldehyde 17 (1.78 g, 5.74 mmol) in absolute ethanol (20 mL) at 0 °C was added NaBH (132 mg, 3.44 mmol). The reaction mixture was stirred at 0 °C under N2 for 30 min. The reaction mixture was quenched by careful addition of sat. NH4C1^ (50 mL). The reaction mixture was diluted with CH C12 (50 mL) and H2O (50 mL), and stirred vigorously for 10 min. The layers were separated and the aqueous layer was extracted with CH2C12. All the organic layers were combined and dried over Na2SO4. Purification by column chromatography (20% ethyl acetate-hexanes) provided 18 (1.38 g, 78%) as slightly yellow oil. Step 5
Figure imgf000052_0003
To a cloudy mixture of triphenylphosphine (1.27 g, 4.81 mmol) and imidazole (361 mg, 5.25 mmol) in CH2C12 (15 mL) at 0 °C was added bromine (248 μL, 4.81 mmol). After 10 min, a solution of 18 (1.37 g, 4.37 mmol) in CH2C12 (15 mL) was added via syringe. The reaction mixture was quenched by addition of sat. Na2S2O3fø; after 10 min. of stirring at 0 °C.
The aqueous layer was extracted with CH2C12. The organic layers were combined and washed with sat. Na2S2O3fø), brine, and dried over Na2SO4. Purification of the crude product by column chromatography (50% CH2Cl2-hexanes) provided 19 (1.34 g, 82%) as colorless oil.
Step 6
Figure imgf000053_0001
To a suspension of anhydrous LiCl (635 mg, 15.0 mmol) in THF (9 mL) was added (-)- pseudoephedrine glycinamide monohydrate (20) (943 mg, 3.92 mmol) (Myers et al. J. Org. Chem. 1999, 64, 3322). The reaction mixture was cooled to 0 °C and treated with LHMDS (12.1 mL, 12.1 mmol, 1.0 M in THF) dropwise. The resulting yellow reaction mixture was stirred at 0 °C under N2. After 30 min. of stirring, a solution of 19 (1.34 g, 3.57 mmol) in THF (9 mL) was added to the reaction mixture dropwise and stirred at 0 °C for 30 min. The reaction mixture was quenched by addition of H2O (30 mL) and the layers were separated. The aqueous layer was extracted with CH2C12. The combined organic layers were dried over K2CO3 for 2 hr, filtered over a pad of cotton, and concentrated. The residue was dissolved in toluene (50 mL) and concentrated again. Recrystallization of the crude product in hexanes provided 21 (750 mg, 41%) as white solid. Step 7
Figure imgf000053_0002
22
To a solution of diisopropylamine (903 μL, 6.41 mmol) in THF (4.0 mL) at -78 °C was added a solution of «-BuLi (2.4 mL, 6.16 mmol, 2.5 M in THF). The reaction mixture was stirred at -78 °C under N2 for 10 min. and at 0 °C for 10 min. To the reaction mixture was added borane*ammonia (224 mg, 6.53 mmol) in one portion and the reaction mixture was stirred at 0 °C for 10 min and at room temperature for 10 min. The reaction mixture was cooled to -78 °C and was treated with a solution of 21 (637 mg, 1.23 mmol) in THF (4.0 mL) dropwise. Resulting yellow clear solution was stirred at 0 °C under N2 for 2 hr. The reaction mixture was quenched by addition of CF3CH2OH (481 μL, 6.53 mmol) at 0 °C dropwise followed by addition of Et2O (5 mL) and a solution of NaHSO4 (2.7 g, 22.6 mmol) in H2O (10 mL) in sequence. The reaction mixture was then stirred at 0 °C. After 2 hr of stirring, the reaction mixture was treated with triethylamine (915 μL, 6.53 mmol), H2O (5 mL), and sat. NaHCO3fø) (15 mL). The layers were separated and the aqueous layer was saturated with NaCI. Then the aqueous layer was extracted with CH2CI2. All the organic layers were combined and dried over K2CO . Purification of the crude product by column chromatography (starting gradient of 2% MeOH-CH2Cl2 + 1% TEA to 5% MeOH-CH2Cl2 + 1% TEA) provided 22 (389 mg, 89%). Additional amounts of 22 were prepared via this method. Step 8
Figure imgf000054_0001
To a solution of 22 (12.2 g, 34.4 mmol) in CH2C12 (25 mL) and THF (225 mL) were added triethylamine (5.3 mL, 37.9 mmol) and Fmoc-OSu (13.5 g, 37.9 mmol). After 30 min of stirring at room temperature, the reaction mixture was diluted with ethyl acetate (300 mL) and washed with half sat. NHfCl^, half sat. aHCO^), and brine, and dried over Na2SO4.
Purification by column chromatography (starting gradient of 200:1 CH2Cl2/MeOH to 50:1
CH2Cl2/MeOH) provided 23 (16.3 g, 82%) as white foam.
Step 9
Figure imgf000054_0002
To a solution of oxalyl chloride (896 μL, 1.77 mmol, 2.0 M in CH2C12) in CH2C12 (1 mL) was added methylsulfoxide (170 μL, 2.38 mmol) dropwise at -78 °C. After stirring at - 78 °C under N2 for 15 min, the reaction mixture was treated with a solution of 23 (345 mg, 596 μmol) in CH2C12 (5 mL) dropwise. The reaction mixture was kept stirred at -78 °C under N2 for 30 min, followed by addition of triethylamine (835 μL, 5.96 mmol) at -78 °C. The reaction mixture was warmed to -40 °C and kept stirred at that temperature for 20 min. Resulting white suspension was diluted with Et2O (100 mL) and H2O (50 mL). The layers were separated and the organic layer was washed with half sat. NTLCl^, H2O, and brine, and dried over Na2SO4. The crude product 1 was used without further purification. Step 10
Figure imgf000055_0001
(a) To a suspension of KCN (45.7 mg, 656 μmol) in MeOH (1 mL) was added AcOH (42.5 μL, 716 μmol). When the solid was completely dissolved, the reaction mixture was transferred into a flask containing a solution of 1 (343 mg, 596 μmol) in CH2C1 (3 mL) via syringe. After 1 hr, the reaction mixture was diluted with Et2O (50 mL), washed with a mixture of brine and sat. NaHCO3fαe), 4:1 brine/sat. NaHCO^), and dried over Na2SO4. The crude cyanohydrin obtained was used without further purification.
(b) To a solution of cyanohydrin from (a) above in 2,2,2-trifluoroethanol (3 mL) was added morpholine (257 μL, 2.98 mmol). After being stirred at room temperature under N2 for 4 hr, the reaction mixture was concentrated by rotary evaporator. The resulting oil was dissolved in toluene (5 mL) and again concentrated. The crude oil obtained was purified by column chromatography (25% ethyl acetate - hexanes) to yield 30 (319 mg, 80% over 2 steps) as a diastereomeric mixture. Additional amounts of 30 were prepared by this procedure.
Step 11
Figure imgf000055_0002
(a) To a solution of 30 (12.9 g, 19.2 mmol) in THF (70 mL) were added AcOH (2.6 mL, 46 mmol) and tetrabutylammonium fluoride (TBAF) (21 mL, 21 mmol, 1.0 M in THF) at 0 °C in sequence. After being stirred at room temperature for 1 hr, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with H2O and brine, and dried over Na2SO4. The crude desilylated material obtained was used in the next step without further purification.
(b) To a solution of the crude desilylated material in CH2CI2 (50 mL) was added 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) (4.5 mL, 25 mmol). After 30 min of stirring at room temperature, the reaction mixture was directly loaded on the column and purified by column chromatography (starting gradient from 100:1 ethylacetate/MeOH to 10:1 ethyl acetate/MeOH). The product obtained was further purified by second column chromatography (10:1 ethyl acetate/MeOH) to yield the diasteromerically pure 2 (2.32 g, 36%).
Step 12
Figure imgf000056_0001
(a) To a mixture of the aldehyde 1 (4.62 g, 8.02 mmol) and Na2SO4 (23.7g, 167 mmol) was added a solution of 2 (2.24 g, 6.69 mmol) in CH2CI2 (60 mL) via syringe. After being stirred at room temperature under N2 for 3 hr, the reaction mixture was filtered over a pad of cotton and concentrated. The crude product was azeotropically dried with toluene and further dried in vacuo. The crude imine intermediate was dissolved in ethylene glycol dimethyl ether (DME) (100 mL) via syringe to anhydrous lithium bromide (15.2g, 174 mmol) in a round bottom flask under N2. The resulting mixture was sonicated for 5 min. and then stirred at 35 °C under N2. After being stirred for 19 hr, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL). Then, the reaction mixture was washed with a mixture of brine and sat. NaHCO3fø) (3 x 150 mL, 4:1 brine/sat. NaHCO3fα2j), and dried over Na2SO4. Purification of the crude material by column chromatography (starting gradient from 30% ethyl acetate-hexanes to 40% ethyl acetate-hexanes) afforded 3 (3.71 g, 62%). Step 13
Figure imgf000057_0001
To a solution of 3 (3.71 g, 4.15 mmol) in acetonitrile (30 mL) were added formaldehyde (623 μL, 8.30 mmol, 35 wt% solution in H2O) and sodium triacetoxy- borohydride (1.40 g, 6.23 mmol) in sequence. After being stirred for 30 min. at room temperature, the reaction mixture was diluted with EtOAc (200 mL) and washed with a mixture of brine and sat. NaHCO3f-βaj (1:1 brine/sat. NaHCO3fαaj), and dried over Na2SO4. Purification of the crude material by column chromatography (40% ethyl acetate-hexanes) provided 4 (3.50 g, 93%). Step 14
Figure imgf000057_0002
(a) To a solution of 4 (2.64 g, 2.91 mmol) in THF (20 mL) were added AcOH (400 μL, 6.99 mmol) and tetrabutylammonium fluoride (TBAF) (3.2 mL, 3.2 mmol, 1.0 M solution in THF) in sequence. After 90 min, the reaction mixture was diluted with sat. NaHCO3f-αa) (50 mL) and H2O (150 mL), and extracted with Et2O. The organic layers were combined, dried over Na2S04 and concentrated to give desilylated product.
(b) Crude desilylated product from (a) above was dissolved in CH2C12 (10 mL). The reaction mixture was treated with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (578 μL, 3.79 mmol) and stirred at room temperature under N2 for 50 min The reaction mixture was then load directly on the column and purified by column chromatography (25:1 CH2Cl2/MeOH) to yield 5 (1.43 g, 86%). Step 15
Figure imgf000058_0001
6
To a suspension ofN-(9-fluorenylmethoxycarbonyl)ethanol (5.0 g, 18 mmol) in CH2C12 (50 mL) was added diisopropylethylamine (12.4 mL, 70.6 mmol) and the reaction mixture was cooled to - 40 °C.' A solution of sulfur trioxide pyridine complex (11.2 g, 70.6 mmol) in dimethylsulfoxide (49.5 mL) was added to the reaction mixture dropwise over a period of 15 min. After 1 hr of stirring at - 40 °C, the reaction mixture was treated with a mixture of iced H2O (150 mL) and brine (100 mL). The solvent was removed and the resulting off-white precipitates were filtered and dried in vacuo. Purification by column chromatography (50% ethyl acetate - hexanes) provided the N-Fmoc glycinal 6 (4.7g, 94%).
Step 16
Figure imgf000058_0002
A deoxygenated (3 freeze-pump-thaw cycles) solution of N-Fmoc glycinal 6 (952 mg, 3.38 mmol) in 1,2-dichloroethane (60 mL) was transferred via cannula to a solid mixture 5 (1.43 g, 2.51 mmol) and Νa2SO4 (9.0 g, 50 mmol). The resulting suspension was stirred at 55 °C under N2 for 21 hr. The reaction mixture was filtered over a pad of cotton and concentrated. Purification of the crude material by column chromatography (starting gradient from 2% MeOH - CH2C12 to 5% MeOH - CH2C12) provided 7 (1.28 g, 61%). Step 17
Figure imgf000059_0001
To a solution of 7 (1.28 g, 1.54 mmol) in 2,2,2-trifluoroethanol (26 mL) were added ZnCl2 (9.2 mL, 4.6 mmol, 0.5 M in THF) and trimethylsilyl cyanide (419 μL, 3.08 mmol) in sequence. The reaction mixture was stirred at room temperature under N2 for 7 hr. The reaction mixture was quenched by addition of EDTA solution (50 mL, 0.20 M (ethylenedinitrilo)tetraacetic acid, disodium salt - 0.40 M sodium hydroxide. pH 10) and then extracted with ethyl acetate. The organic layers were combined, washed with a mixture of sat. NaHCO3fα2) and brine (1:1 mixture of sat. NaHCO3^/brine), and dried over Na2SO4. Purification by column chromatography (50% ethyl acetate - hexanes) provided 8 (1.07 g, 94%). Step 18
Figure imgf000059_0002
To a solution of 8 (1.07 g, 1.44 mmol) in CH2C12 (7 mL) was added 1,8-diaza- bicyclo[5.4.0]undec-7-ene (DBU) (286 μL, 1.87 mmol). After 1 hr, the reaction mixture was directly loaded on a column and purified by column chromatography (10: 1 CH2Cl2/MeOH) to give the amine 9 (593 mg, 79%). EM (calc): 524.3; MS (ESI) m/e: 523.6 (M-H)\ 525.7 (M+H)+.
Reference B Alternate synthesis of intermediate 8
Figure imgf000060_0001
Step l
Figure imgf000060_0002
A solution of N-(benzyloxycarbonyl)- -phosphonoglycine trimethyl ester 24 (69.4 g, 209 mmol) in CH2C12 (118 mL), was treated with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (34.5 mL, 230 mmol). After 20 min, the light yellow solution was cooled to - 30 °C, and was treated with a solution of 17 (65.0 g, 209 mmol) in CH2C12 (262 mL) dropwise. The reaction mixture was then stirred at - 30 °C for 30 min. and at room temperature for an additional 30 min. The reaction mixture was diluted with diethyl ether (700 mL), and washed with 0.5 Ν HCl^, and brine, anddried over Νa2SO . The thick oil obtained upon drying in vacuo for overnight was purified by column chromatography (15% ethyl acetate in hexanes) provided a mixture of olefin 25 (69.8 g, 65%). Step 2
Figure imgf000060_0003
A solution of 25 (59.6 g, 116 mmol) in ethanol (600 mL) was treated with catalyst (+)- l,2-bis((2S, 5S)-2,5-diethylphospholano)benzene(cyclooctadiene) rhodium(I) trifluoromethanesulfonate (167 mg, 0.231 mmol) in a Parr flask. The yellow solution was placed on the Parr hydrogenator under hydrogen (50 PSI) for 20 hr. After removing the volatiles, the resulting orange oil was filtered though a pad of silica with ethyl acetate to give 26 (56.5 g, 94%) which was used without further purification. Step 3
Figure imgf000061_0001
A solution of olefin 25 (24.9 g, 48.3 mmol) in ethanol (250 mL) was treated with catalyst (+)-l,2-bis((2S, 5S)-2,5-diethylphospholano)benzene(cyclooctadiene) rhodium(I) trifluoromethanesulfonate (350 mg, 0.480 mmol) in a Parr flask. The yellow solution was placed on the Parr hydrogenator under hydrogen (60 PSI) for 3 days. Then, the reaction mixture was treated with 10% palladium on carbon (1.0 g, 0.94 mmol) and again placed on the Parr hydrogenator under hydrogen (50 PSI). After 16 hr, the reaction mixture was treated with additional portion of 10% Pd/C (2.0 g, 1.9 mmol) and kept placed on the Parr hydrogenator under hydrogen (50 PSI). After 3 hr, the reaction mixture was filtered through a pad of Celite and concentrated to give 27 (17.8 g, 96%) which was used in the next step without further purification. Step 4
Figure imgf000061_0002
To a solution amine 27 (17.8 g, 46.3 mmol) in tetrahydrofuran (430 mL) was added L- selectride (139 mL, 140 mmol, 1.0 M in THF) dropwise at - 78 °C. After the addition, the reaction mixture was warmed to 0 °C and stirred at that temperature for 1 hr. The reaction mixture was quenched with methanol (20 mL), brine (300 mL), and sat. NaHCO3^? (300 mL) and then extracted with ethyl acetate and dried over Na2SO4. Purification by column chromatography (10% MeOH/CH2Cl2 + 1% triethylamine) afforded 22 (23.8 g, quant.). Step 5
Figure imgf000062_0001
To a solution 26 (29.0 g, 56.1 mmol, from Step 2 above) in diethyl ether (250 mL) at 0 °C was added lithium borohydride (2.1 g, 94 mmol). After 5 min. the ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was cooled to 0 °C, and carefully treated with sat. ILCl^ (50 mL), followed by water (50mL). The layers were separated, and the organic layer was washed with brine, dried over Na2SO4 and concentrated to give 23 (26. lg, 95%) which was used without further purification. Step 6
Figure imgf000062_0002
To a solution of oxalyl chloride (5.2 mL, 10 mmol, 2.0 M in CH2C12) in CH C12 (15 mL) was added methylsulfoxide (0.90 mL, 13 mmol) dropwise at -78 °C. After stirring at -78 °C under N2 for 15 min, the reaction mixture was treated with a solution of 23 (1.3 g, 2.6 mmol) in CH2CI2 (25 mL) dropwise. The reaction mixture was kept stirred at - 78 °C under N2 for 1 hr, followed by addition of triethylamine (3.6 mL, 25.9 mmol) at - 78 °C. The reaction mixture was warmed to - 40 °C and stirred for 20 min. The resulting white suspension was diluted with CH2C12 (250 mL) and washed with half saturated
Figure imgf000062_0003
H2O, and brine, and dried over Na2SO to give 1 (1.3 g, 99%) which was used without further purification. Step 7
Figure imgf000062_0004
26 27 (a) To a solution of 26 (2.5 g, 4.8 mmol) in tetrahydrofuran (THF) (15 mL) was added tetrabutylammonium fluoride (7.2 mL, 7.2 mmol, 1.0 M in THF). After 2.5 hr, most of the volatiles were removed by a rotary evaporator, and the residues were dissolved in ethyl acetate (200 mL). The resulting solution was washed with water, brine, and dried over a2SO4 to give desilylated product (1.9 g, 97%) which was used without further purification.
(b) A solution of desilylated product obtained in (a) above (1.9 g, 4.7 mmol) in methanol (20 mL) was treated with 10% palladium on carbon (200 mg, 0.2 mmol), and the reaction mixture was stirred under hydrogen (1 atm). After 1.5 hr of vigorous stirring, the reaction mixture was filtered through a pad of celite, followed by filtration through a syringe filter. Most of the solvent was removed and the thick oily residue was dried azeotropically once with toluene to give a powder. The powder was washed once with hexane and filtered to give 27 (1.2 g, 92%).
Step 8
Figure imgf000063_0001
To a mixture of 1 (1.30 g, 2.56 mmol) and Na2SO4 (9.5g, 6.68 mmol) was added a solution of 10 (690 mg, 2.56 mmol) in CH2C12 (10 mL) via syringe. After stirring the reaction mixture at room temperature under N2 for 1 hr, the reaction mixture was filtered over a pad of cotton and concentrated. The crude product was azeotropically dried with toluene and further dried in vacuo. The crude imine intermediate was dissolved in ethylene glycol dimethyl ether (DME) (30 mL) via syringe to anhydrous lithium bromide (5.56g, 64.0 mmol) in a round bottom flask under N2. The resulting mixture was sonicated for 5 min. and then stirred at 35 °C under N2. After 17 hr, the reaction mixture was cooled to room temperature and diluted with EtOAc (150 mL). The reaction mixture was washed with a mixture of brine and sat. NaHCO3fα^, 4:1 brine/sat. NaHCO3^), and dried over Na2SO4. Purification of the crude material by column chromatography (starting gradient from 40% ethyl acetate - hexanes to 40% ethyl acetate - hexanes) afforded 11 (1.02 g, 53%). Step 9
Figure imgf000064_0001
To a solution of 11 (1.0 g, 1.3 mmol) in acetonitrile (30 mL) were added formaldehyde
(76 μL, 2.7 mmol, 35 wt% solution in H2O) and sodium triacetoxyborohydride (455 mg, 2.1 mmol) in sequence. After being stirred for 15 min. at room temperature, the reaction mixture was diluted with EtOAc (200 mL) and washed with water, brine, and dried over Na2SO4.
Upon concentration, 12 (945 mg, 92%) was obtained as a foamy solid.
Step 10
Figure imgf000064_0002
(a) To a solution of 12 (945 mg, 1.25 mmol) in ethyl ether (10 mL) was added lithium borohydride (591 mg, 27.1 mmol) at 0 °C and then the reaction mixture was allowed to warm to room temperature. After 22 hr, the reaction mixture was cooled to 0 °C and carefully treated with sat. TLClføj (5 mL). Once most of the gas evolution had subsided (20 min), H2O (5 mL) was added. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. Purification by column chromatography (40% ethyl acetate - hexanes) provided the alcohol (690 mg, 76%) as a foamy solid.
(b) To a solution of the alcohol from (a) above (690 mg, 0.95 mmol) in THF (10 mL) were added tetrabutylammonium fluoride (TBAF) (1.1 mL, 1.1 mmol, 1.0 M solution in THF) in sequence. After 40 min, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water, brine, and dried over Na2SO4. Purification by column chromatography (5% MeOH - CH2C12) provided the desilylated product (539 mg, 93%) as a foamy solid. (c) A solution of desilylated product from (b) above (539 mg, 0.88 mmol) in methanol (30 mL) was treated with 10% palladium on carbon (100 mg, 0.1 mmol). After being stirred under
H2 (1 atm) for 1 hr, the reaction mixture was filtered through a pad of Celite. Upon concentration, 13 (410 mg, 97%) was obtained as an orange foamy solid.
Step 11
Figure imgf000065_0001
A deoxygenated (3 freeze-pump-thaw cycles) solution of N-Fmoc glycinal 6 (26 mg, 91 μmol) in CH2C12 (2 mL) was transferred via cannula to a solid mixture of 13 (36 mg, 76 μmol) and Νa2SO4 (161 mg, 1.1 mmol). After stirring the suspension at 23 °C under N2 for 16 hr, the reaction mixture was filtered over a pad of cotton and concentrated. Purification of the crude material by column chromatography (5% MeOH - CH2C12) provided 14 (26 mg, 47%). Step 12
Figure imgf000065_0002
To a solution of oxalyl chloride (120 μL, 240 μmol, 2.0 M in CH2C12) in CH2C12 (5 mL) was added methylsulfoxide (34 μL, 480 μmol) dropwise at -78 °C. After stirring at -78 °C under N2 for 15 min, the reaction mixture was treated with a solution of 14 (8 mg, 10 μmol) in CH2CI2 (0.5 mL) dropwise. The reaction mixture was kept stirred at - 78 °C under N2 for 30 min, followed by addition of triethylamine (12 μL, 80 μmol) at - 78 °C. The reaction mixture was warmed to 0 °C and kept stirred at that temperature for 30 min. A solution of potassium cyanide (1 mg, 15 μmol) in methanol (0.2 mL) was added and the reaction mixture was concentrated and purified by preparative TLC (5% MeOH/CH2Cl2) to yield 8 (3 mg, 37%). EM (calc): 746.3; MS (ESI) m/e: 747.6 (M+H)+.
Reference C Synthesis of 5-(tetrahydro-4H-pyran-4-yloxy)-benzofuran-2-carboxylic acid Step l To a solution of 5-methoxybenzofuran-2-carboxylic acid (5.04g, 26.2 mmol) in MeOΗ (50 mL) was added thionyl chloride (2.3 mL, 32 mmol) dropwise at 0 °C. After 72 hr of stirring at room temperature, the reaction mixture was poured into Η2O (150 mL) and filtered to provide white solids. The white solids were dissolved in toluene (100 mL) and washed with 1 M NaHCO3(αft), brine, and dried over MgSO4. Upon drying in vacuo, 5-methoxybenzofuran- 2-carboxylic acid methyl ester (5.15 g, 95%) was obtained as a white solid. Step 2 To a solution of 5-methoxybenzofuran-2-carboxylic acid methyl ester (5.15 g, 25.0 mmol) in CH2C12 (15 mL) at - 40 °C was added boron tribromide (27.0 mL, 27.0 mmol, 1.0 M in CH2CI2) over the course of 1 hr using a syringe pump. The reaction mixture was stirred overnight while allowed slowly to warm to room temperature. After quenching the reaction mixture with MeOH (15 mL) at 0 °C, the reaction mixture was diluted with brine (100 mL) and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product obtained was dissolved in MeOH (30 mL) and treated with thionyl chloride (1.9 mL, 26 mmol) at 0 °C. After 72 hr of stirring at room temperature, the reaction mixture was treated with H2O (100 mL) and filtered to yield 5-hydroxybenzofuran-2- carboxylic acid methyl ester (4.53 g, 94%) as a yellow solid. Step 3 To a solution of 5-hydroxybenzofuran-2-carboxylic acid methyl ester (1.10 g, 5.72 mmol), triphenylphosphine (1.66 g, 6.33 mmol), and tetrahydro-4H-pyran-4-ol (660 mg, 6.46 mmol) in TΗF (15 mL) was added diisopropyl azodicarboxylate (1.35 mL, 6.86 mmol) over the course of 1 hr using a syringe pump. After 6 days of stirring at room temperature, most of the volatiles were removed by a rotary evaporator. Purification of the crude material by column chromatography (10%> ethyl acetate - CΗ2C12) provided 5-(tetrahydro-4H-pyran-4- yloxy)-benzofiiran-2-carboxylic acid methyl ester (1.12 g, 71%) as awhite solid. Step 4 To a solution of 5-(tetrahydro-4H-pyran-4-yloxy)-benzofuran-2-carboxylic acid methyl ester (1.12 g, 4.05 mmol) in ethylene glycol dimethyl ether (DME) (13 mL) at 0 °C was added 2.0 M LiOU(aq) (2.5 mL, 5.0 mmol) dropwise. After 2 hr of stirring at room temperature, the reaction mixture was cooled to 0 °C and treated with 0.5 M
Figure imgf000067_0001
(20 mL). The reaction mixture was then extracted with EtOAc and the combined organic layers were washed with brine and dried over MgSO4. Upon concentration, 5-(tetrahydro-4H-pyran-4-yloxy)- benzofuran-2-carboxylic acid (1.05 g, 99%) was obtained as a white solid.
Example 1
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OΗ, R9 is Η, R11 is CN, Y is CΗ2, and R12 is 5-tetrahydropyran-4- yloxybenzofuran-2-ylcarbonylamino (compound 31)
Figure imgf000067_0002
Step 1 To a solution of 9 (10.4 mg, 20.0 μmol,) in THF (1 mL), obtained from Reference A above, at 0 °C was added N, N-diethylaniline (3.5 μL, 1.1 equiv). After 5 min. of stirring, the reaction mixture was treated with 5-(tetrahydro-4H-pyran-4-yloxy)-benzofuran-2-carboxylic acid (6.8 mg, 1.3 equiv), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC»ΗC1) (5.0 mg, 1.4 equiv), and 1-hydroxybenzotriazole hydrate (HOBt«H2O) (3.7 mg, 1.2 equiv) in sequence. The reaction mixture was stirred while allowed to warm to room temperature. After 17 hr of stirring, the reaction mixture was diluted with EtOAc (10 mL) and washed with 0.1 Ν HCI. The organic layer was dried over Νa2SO4. The crude product was purified by preparatory TLC (60% ethyl acetate - hexanes) to give the title compound (8.9 mg, 60%) as a white solid. EM (calc): 768.3; MS (ESI) m/e: 767.8 (M-H)-, 769.4 (M+H)+.
Example 2
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is OH, Y is CH2, and R12 is 5-tetrahydropyran-4- yloxybenzofuran-2-ylcarbonylamino (compound 32)
Figure imgf000068_0001
To a solution of 31 (10.1 mg, 13.1 μmol) in water/acetonitrile (3/2, 3 mL) at room temperature was added a solution of silver nitrate (133 mg, 786 μmol) in water/acetonitrile (3/2, 0.5 mL). After 30 min of stirring, sat. NaHCO^ /brine (1/1, 2 mL) was added and the reaction mixture was vigorously stirred for additional 5 min. Additional sat. NaHCO3(^ /brine (1/1, 20 mL) was added, and the aqueous layer was extracted with dichloromethane (5 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by Prep-TLC (40%> ethyl acetate - hexanes) to give the title compound 32 (5.8 mg, 58%) as a white solid. EM (calc): 759.3; MS (ESI) m/e: 758.7 (M-H)-, 760.0 (M+H)+.
Example 3
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 5-(2-morpholin-4- ylethoxy)benzofuran-2-ylcarbonylamino (compound 33)
Figure imgf000068_0002
Proceeding as described in Example 1 above, but substituting 5-(tetrahydro-4H-pyran- 4-yloxy)-benzofuran-2-carboxylic acid with 5-(2-morpholin-4-yl-ethoxy)-benzofuran-2- carboxylic acid provided compound 33. 5-(2-Moφholin-4-yl-ethoxy)-benzofuran-2- carboxylic acid was prepared following similar procedure for the synthesis of 5-(tetrahydro- 4H-pyran-4-yloxy)-benzofuran-2-carboxylic acid using 5-hydroxy-benzofuran-2-carboxylic acid methyl ester and 4-(2-hydroxyethyl)morpholine as starting materials. EM (calc): 797.4; MS (ESI) m/e: 797.0 M", 798.9 (M+Η)+.
Example 4
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, Rn is CN, Y is CH2, and R12 is N, N'-bis(tert- butoxycarbonyl)guainidino (compound 34)
Figure imgf000069_0001
34
To a solution of the amine 9 (12.7 mg, 24.2 μmol) in THF (400 μL) was added N N'- bis(tert-butoxycarbonyl)-lH-pyrazoIe-l-carboxamidine (11.5 mg, 36.3 μmol). After 24 hr of stirring at room temperature, the reaction mixture was concentrated and purified by column chromatography (50% ethyl acetate -hexanes) to provide the title compound 34 (11.4 mg, 61%). EM (calc): 766.4; MS (ESI) m/e: 765.7 (M-Η)', 768.0 (M+Η)+.
Example 5
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CΝ, Y is CH2, and R12 is 4-( diethyl- phosphonomethyl)phenylcarbonylamino (compound 35)
Figure imgf000070_0001
Step l A suspension of 4-(bromomethyl)benzoic acid (4.3g, 20 mmol) in triethyl phosphite (3.77 mL, 22 mmol) was heated to reflux for 20 hr. The reaction was allowed to slowly cool to room temperature. The precipitate was collected by filtration, washed intensively with hexane (100 mL), and dried in vacuo to give 4-(diethylphosphono-methyl)benzoic acid (5.34 g, 98%) as a tan solid. Step 2 Following the procedure described in Example 1 above using 9 (10.9 mg, 20.8 μmol), THF (1.5 mL), N, N-diethylaniline (3.7 μL, 1.1 equiv), 4-(diethylphosphono-methyl)benzoic acid (7.4 mg, 1.3 equiv), 1 -(3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HC1) (5.2 mg, 1.3 equiv), 1-hydroxybenzotriazole hydrate (HOBt«H2O) (3.4 mg, 1.2 equiv) and purification by prep-TLC (5%> methanol - dichloromethane) gave the title compound 35 (7.0 mg, 45%) as a white solid. EM (calc): 778.3; MS (ESI) m/e: 777.4 (M-H)', 779.7 (M+H)+.
Example 6
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CΝ, Y is CH2, and R12 is 2-acetylamino-3-o-tolyl- acryloylamino (compound 36)
Figure imgf000071_0001
36
Synthesis of 36 was achieved by the union of the amine 9 and commercially available 2-acetylamino-3-ø-tolyl-acrylic acid following a similar procedure as described in Example 1 above. EM (calc): 725.8; MS (ESI) m/e: 726.7 (M+H)+, 724.4 (M-H)-.
Example 7
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 3-(3-hydroxy-4- methoxycarbonylphenylaminocarbonyl)acryloylamino (compound 37)
Figure imgf000071_0002
Synthesis of 37 was achieved by the union of the amine 9 and commercially available 4-(3-carboxy-acryloylamino)-2-hydroxy-benzoic acid methyl ester following a similar procedure as described in Example 1 above. EM (calc): 771.8; MS (ESI) m/e: 772.7 (M+H)+, 770.9 (M-H)".
Example 8 Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 4-(5-dimethylaminonaphth-l- ylsulfonylaminomethyl)phenylcarbonylamino (compound 38)
Figure imgf000072_0001
Step l To a solution of methyl 4-(aminomethyl)benzoate hydrochloride (26.8 mg, 129 μmol) in CH2C12 (5 mL) was added TEA (39.7 μL, 284 μmol) and dansyl chloride (39.0 mg, 142 μ ol). After 2 hr of stirring at room temperature under argon, the reaction mixture was diluted with EtOAc (50 mL) and washed with sat. NaHCO3fαej (2x 20 mL), brine (lx 20 mL), and dried over MgSO4. The crude product, dansylated benzoic acid methyl ester, was used for the next step without further purification. Step 2 To a solution of the dansylated benzoic acid methyl ester (14.1 mg, 35.4 μmol) in MeOH (2 mL) was added 4N NaOH^ (200 μL, 800 μmol). After 24 hr of stirring at 45 °C, the reaction mixture was acidified to pH 4 by addition of IN HCl^. Then, the reaction mixture was diluted with H2O (20 mL) and extracted with CH2C12 (4 x 10 mL). The organic layers were combined, dried over a2SO4, and filtered. The crude product obtained from the concentrated filtrate, dansylated benzoic acid, was used for the next step without further purification. Step 3 Synthesis of 38 was achieved by the union of the amine 9 and dansylated benzoic acid obtained from Step 2 above following a similar procedure as described in Example 1 above. EM (calc): 891.0; MS (ESI) m/e: 891.5 (M+H)+, 889.8 (M-H)". Example 9
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 4-tetrahydropyran-4-yloxybenzofuran-2-ylcarbonylamino (compound 39)
Figure imgf000073_0001
39
Synthesis of 39 was achieved by the union of the amine 9 and 4-(tetrahydro-4H-pyran- 4-yloxy)-benzofuran-2-carboxylic acid following a similar procedure as described in Example 1 above. Synthesis of 4-(tetrahydro-4H-pyran-4-yloxy)-benzofuran-2-carboxylic acid was prepared following similar procedure for the synthesis of 5-(tetrahydro-4H-pyran-4-yloxy)- benzofuran-2-carboxylic acid using 4-hydroxy-benzofuran-2-carboxylic acid methyl ester (Yamaguchi, S. et al. Bull. Chem. Soc. Jpn. 1989, 62, 4066-4068.) and tetrahydro-4H-pyran-4- ol as starting materials. EM (calc): 768.9; MS (ESI) m/e: 770.0 (M+Η)+, 768.0 (M-H)'.
Example 10
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 6~(tetrahydropyran-4- yloxyl)benzofuran-2-ylcarbonylamino (compound 40)
Figure imgf000074_0001
Synthesis of 40 was achieved by the union of the amine 9 and 6-(tetrahydro-4H-pyran- 4-yloxy)-benzofuran-2-carboxylic acid following a similar procedure as described in Example 1 above. Synthesis of 6-(tetrahydro-4H-pyran-4-yloxy)-benzofuran-2-carboxylic acid was prepared following similar procedure for the synthesis of 5-(tetrahydro-4H-pyran-4-yloxy)- benzofuran-2-carboxylic acid using 6-hydroxy-benzofuran-2-carboxylic acid methyl ester and tetrahydro-4H-pyran-4-ol as starting materials. EM (calc): 768.9; MS (ESI) m/e: 769.9 (M+Η)+, 767.9 (M-H)".
Example 11
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 6-(2- methoxyethyloxy)coumarin-3-ylcarbonylamino (compound 41)
Figure imgf000074_0002
Step l To a solution of 2,5-dihydroxy-benzaldehyde (2.76 g, 20.0 mmol) in THF (50 mL) were added diethyl malonate (3.4 mL, 22 mmol) and piperidine (4.9 mL, 50 mmol). After stirring overnight at room temperature, the reaction mixture was acidified to pH ~l-2 with IN HClfaq), and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo and titrated with a mixture of ethyl acetate and hexane (1 :3) to give 6- hydroxy-2-oxo-2H-chromene-3 -carboxylic acid ethyl ester as a yellow solid (0.51 g, 11%). Step 2 To a solution of PPh3 (144 mg, 550 μmol) in TΗF (1 mL) was added diisopropyl azodicarboxylate (DIAD, 0.11 mL, 550 μmol) dropwise. The reaction mixture turned into solid within 5 minutes. To the solid was added a solution of 2-methoxyethanol (0.04 mL, 500 μmol) and 6-hydroxy-2-oxo-2H-chromene-3 -carboxylic acid ethyl ester (117 mg, 500 μmol) in TΗF (2 mL). The reaction mixture was stirred at room temperature for 2 hr and concentrated in vacuo. Purification of the crude material by column chromatography (1 :2 ethyl acetate/hexane) provided 6-methoxyethoxy-2-oxo-2H-chromene-3-carboxylic acid ethyl ester (60 mg, 41%). Step 3 A solution of 6-methoxyethoxy-2-oxo-2H-chromene-3-carboxylic acid ethyl ester (60mg, 21 μmol) in MeOΗ (2 mL) was treated with IN LiOΗ^ (1 mL). After 1 hr of stirring at room temperature, the reaction mixture was acidified with IN ΗCl^ and extracted with EtOAc to give crude 6-methoxyethoxy-2-oxo-2H-chromene-3 -carboxylic acid, which was used without further purification. Step 4 Synthesis of 41 was achieved by the union of the amine 9 and 6-methoxyethoxy-2-oxo- 2H-chromene-3 -carboxylic acid obtained from step 3 following a similar procedure as described in Example 1 above. EM (calc): 770.8; MS (ESI) m/e: 771.7 (M+Η)+, 770.0 (M-H)"
Example 12
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 7-(2- methoxyethyloxy)coumarin-3-ylcarbonylamino (compound 42)
Figure imgf000076_0001
42
Step l To a solution of 2,4-dihydroxy-benzaldehyde (5.52 g, 40.0 mmol) in THF (50 mL) were added diethyl malonate (6.7 mL, 44 mmol) and piperidine (11.9 mL, 120 mmol). After 2 hr of stirring at room temperature, the reaction mixture was acidified to pH ~l-2 with IN HClføj, and extracted with large amount of EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude material by column chromatography provided 7-hydroxy-2-oxo-2H-chromene-3 -carboxylic acid ethyl ester as an off-white solid (5.9 g, 63%). Step 2 To a solution of PPh3 (288 mg, 1.10 mmol) in TΗF (1 mL) was added DIAD (0.22 mL, 1.10 mmol) dropwise. The mixture turned into solid within 5 minutes. To the solid was added a solution of 2-methoxyethanol (0.08 mL, 1.0 mmol) and 7-hydroxy-2-oxo-2H-chromene-3- carboxylic acid ethyl ester (117 mg, 500 μmol) in TΗF (2 mL). The mixture was stirred at room temperature for 2 hours and evaporated. Purification of the crude material by column chromatography (1:2 ethyl acetate/hexane) provided 7-methoxyethoxy-2-oxo-2H-chromene-3- carboxylic acid ethyl ester. Step 3 A solution of 7-methoxyethoxy-2-oxo-2H-chromene-3 -carboxylic acid ethyl ester obtained from above in MeOΗ (2 mL) was treated with IN LiOΗ^ (1.1 mL). After 1 hr of stirring at room temperature, the reaction mixture was acidified with IN ΗCl^ and extracted with EtOAc to give 7-methoxyethoxy-2-oxo-2H-chromene-3-carboxylic acid (75 mg, 57% over two steps). Step 4 Synthesis of 42 was achieved by the union of the amine 9 and 7-methoxyethoxy-2-oxo- 2H-chromene-3 -carboxylic acid obtained from step 3 above following a similar procedure as described in Example 1 above. EM (calc): 770.8; MS (ESI) m/e: 771.7 (M+H)+, 770.0 (M-H)"
Example 13
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 3-(4-tetrahydropyran-4- yloxyphenyl)acryloylamino (compound 43)
Figure imgf000077_0001
43
Step l To a solution of PPh3 (1.14 g, 4.32 mmol) in THF (2 mL) was added DIAD (894 μL, 4.32 mmol). After 5 min of stirring at room temperature, the reaction mixture was treated with a solution of methyl 4-hydroxycinnamate (513 mg, 2.88 mmol), and tetrahydro-4H-pyran-4-ol (280 μL, 2.88 mmol) in TΗF (3 mL). The reaction mixture was agitated by means of ultrasonification for 5 min and stirred at room temperature for 25 hr. Then, the reaction mixture was concentrated in vacuo. Purification of the crude material by column chromatography (2:8 EtOAc/hexane) provided methyl 4-(tetrahydro-4H-pyran-4- yloxy)cinnamate (755 mg, 100%) as a white solid. Step 2 To a solution of methyl 4-(tetrahydro-4H-pyran-4-yloxy)cinnamate (755 mg, 2.88 mmol) in MeOΗ (14 mL) was added 4N NaOΗ^j (7 mL, 32 mmol). After 5 hr of stirring at room temperature, the reaction mixture was diluted with Η2O (200 mL) and washed with EtOAc (3x 50 mL). Then, the aqueous layer was acidified to pH 1 by addition of IN HCl^, and extracted with EtOAc (4x 100 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to yield 4-(tetrahydro-4H-pyran-4-yloxy)cinnamic acid (519 mg, 73 %). Step 3 Synthesis of 43 was achieved by the union of the amine 9 and 4-(tetrahydro-4H-pyran- 4-yloxy)cinnamic acid obtained from Step 2 above following a similar procedure as described in Example 1 above. EM (calc): 754.9; MS (ESI) m/e: 755.7 (M+Η)+, 753.4 (M-H)".
Example 14
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is benzamidine (compound 44)
Figure imgf000078_0001
44
To a solution of 9 (10.4 mg, 0.02 mmol) in THF (3 mL) was added acetic acid (1.7 μL, 0.03 mmol) and thiobenzimidic acid methyl ester (6 mg, 0.04 mmol). After stirring for 7 d, the reaction mixture was concentrated in vacuo. Purification by reverse phase preparative HPLC (acetonitrile-H2O with 0.1% con HCI as the eluent) gave 44-hydrochloride (3 mg, 23%) as a white solid after lyophilization. EM (calc): 627.3; MS (ESI) m/e: 628.5 (M+H)+.
Example 15
Synthesis of a compound of Formula (I) where R , R , R , and R are OMe, R , R , and R are Me, R4 and R5 are OH, R9 is H, Rn is CN, Y is CH2, and R12 is 5-(2-methoxyethoxy)indol-2-ylcarbonylamino (compound 45)
Figure imgf000079_0001
Step l A solution of ethyl 5-hydroxy-lH-indole-2-carboxylate (5.0 g, 24.4 mmol) in 1,4- dioxane (50 mL) was treated with TEA (6.7 mL, 36.6 mmol) followed by di-tert-butyl dicarbonate (8.0 g, 36.6 mmol) and heated to 70 °C (caution: gas development). After 2 hr - the reaction was completed - most of the solvent was removed in vacuo. The residue was dissolved in EtOAc (250 mL) and washed with 0.5N ΗCl^, Η2O, and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was suspended in hexane and the generated precipitate was filtered off to provide ethyl N-Boc-5-hydroxy-indole- 2-carboxylate (8.2 g, 28.3 mmol) as an off-white solid. Step 2 To a solution of PPh3 (6.5 g, 24.6 mmol) in anhydrous THF (20 mL) was added DIAD (4.8 mL, 24.6 mmol). The solution was stirred until a white precipitate was formed (2 to 10 min). After additional 60 min, a solution of ethyl N-Boc-5-hydroxy-indole-2 -carboxylate (5.0 g, 16.4 mmol) and 1-methoxyethanol (1.3 mL, 16.4 mmol) in THF (20 mL) was added and stirring was continued for 16 hr. The reaction mixture was concentrated in vacuo and the residue was suspended in Et2O (150 mL). The precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was suspended in hexane and the generated precipitate was filtered off. The filtrate was concentrated in vacuo and purified by flash chromatography over silica gel (4:1 EtOAc/hexane) to provide ethyl N-Boc-5-(2-methoxyethoxy)-indole-2- carboxylate (3.2 g, 8.8 mmol) as a white solid. Step 3 A solution of ethyl N-Boc-5-(2-methoxyethoxy)-indole-2-carboxylate (3.2 g, 8.8 mmol) in ethanol (20 mL) was treated with 4M HCI in 1,4-dioxane (20 mL). After stirring for 1 hr, the solvent was removed in vacuo and the residue was suspended in Et2O (50 mL). The generated precipitate was filtered, washed with Et2O, and dried in vacuo to provide ethyl 5-(2- methoxyethoxy)-lH-indole-2-carboxylate (2.0 g, 7.4 mmol) as an off-white solid. Step 4 Ethyl 5-(2-methoxyethoxy)-lH-indole-2-carboxylate (2.0 g, 7.4 mmol) in TΗF (20 mL) was treated with a solution of LiOΗ«Η2O (0.62 g, 14.8 mmol) and H2O (10 mL). EtOH was added until a homogenous solution formed and stirring was continued for 16 hr. The reaction mixture was diluted with H2O (50 mL) and the organic solvents were removed in vacuo. The pH was adjusted to 4 with IN
Figure imgf000080_0001
and the aqueous solution was extracted with CH2CI2. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to provide 5-(2-methoxyethoxy)-lH-indole-2-carboxylic acid (1.7 g, 7.2 mmol) as a white solid. The crude acid was directly used in the next step without further purification. Step 5 To a solution of 9 (10.4 mg, 20 μmol, 1 equiv) in TΗF (lmL), obtained from Reference A above, was added N, N-diethylaniline (3.5 μL, 1.1 equiv) at 0 °C. After 5 minutes of stirring at 0 °C, the reaction mixture was treated with 5-(2-methoxy-ethoxy)-lH-indole-2-carboxylic acid (5.8 mg, 1.3 equiv), 1 -(3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC«ΗC1) (5 mg, 1.3 equiv), and 1-hydroxybenzotriazole hydrate (HOBt«H2O) (3.7 mg, L2 equiv) in sequence. The reaction mixture was stirred while allowed to warm to room temperature. After 17 hr of stirring, the reaction mixture was diluted with EtOAc (10 mL) and washed with 0.1Ν HCl^ (2 mL). The organic layer was dried over Νa2SO4. The crude product was purified by preparative TLC (6:4 EtOAc/hexane) to give 45 (9.4 mg, 64%) as a white solid. EM (calc): 741.2; MS (ESI) m/e: 742.8 (M+H)+, 740.8 (M-H)".
Example 16
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4- ylmethyloxy)indol-2-ylcarbonylamino (compound 46)
Figure imgf000081_0001
46
Proceeding as described in Example 1 above, but substituting 5-(tetrahydro-4H-pyran- 4-yloxy)-benzofuran-2-carboxylic acid with 5-(tetrahydro-4H-pyran-4-yl-methoxy)-lH-indole- 2-carboxylic acid provided compound 46 as a white solid. 5-(2-Tetrahydro-4H-pyran-4-yl- methoxy)-lH-indole-2-carboxylic acid was prepared following similar procedure for the synthesis of 5-(2-methoxyethoxy)-lH-indole-2-carboxylic acid as described in Example 15 above using ethyl 5-hydroxy-lH-indole-2-carboxylate and tetrahydropyran-4-methanol as starting materials. EM (calc): 781.3; MS (ESI) m/e: 782.5(M+Η)+, 780.6 (M-H)".
Example 17
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 3- dimethylaminomethylbenzofuran-2-ylcarbonylamino (compound 47)
Figure imgf000081_0002
Step 1 To a solution of 3-methyl-benzofuran-2-carboxylic acid (0.98 g, 5.6 mmol) and catalytic amount of DMF (5 drops) in THF (25 mL) was added oxalyl chloride (0.53 mL, 6.1 mmol). After stirring the solution for 1 hr at room temperature, MeOH (20 mL) and TEA (7.0 mL) were added. The reaction mixture was stirred overnight at room temperature, then concentrated, redissolved in EtOAc (100 mL) and washed with sat. NaHCO3fαe) (100 mL). The organic layer was dried over Na2SO and concentrated to provide crude methyl 3-methyl- benzofuran-2-carboxylate (1.0 g, 5.3 mmol) as a tan solid, which was used without further purification. Step 2 A solution of methyl 3-methyl-benzofuran-2-carboxylate (1.0 g, 5.3 mmol), N- bromosucciniimide (0.95 g, 5.3 mmol) and 2,2'-azobisisobutyronitrile (87 mg, 0.53 mmol) was heated to reflux in CC1 (40 mL) for 3 hours, then cooled to room temperature and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with H2O (100 mL). The organic layer was dried over MgSO4 and concentrated to provide crude methyl 3- bromomethyl-benzofuran-2-carboxylate (1.55 g) as yellowish solid, which was used in the next step without further purification. Step 3 To a solution of methyl 3-bromomethyl-benzofuran-2-carboxylate (269 mg, 1.0 mmol) in DMF was added dimethylamine (2M solution in THF, 1.5 mL, 3.0 mmol). The reaction mixture was stirred for 1-2 hours, diluted with EtOAc (50 mL), washed twice with sat. ΝaHCO3faιj) (50 mL) and finally with brine (50 mL). The organic extract was dried over Na2SO4 and then concentrated in vacuo. Purification by flash chromatography on silica gel (5:95 MeOH/CH2Cl2) gave methyl 3-dimethylaminomethyl-benzofuran-2-carboxylate (131 mg, 0.56 mmol). Step 4 To a solution of methyl 3-dimethylaminomethyl-benzofuran-2-carboxylate (131 mg, 0.56 mmol) in MeOH was added IN NaOHfαgj till the pH of the solution was 13. The reaction mixture was stirred for 60-90 min. Upon completion, the reaction mixture was acidified to pH 3 with HCl j and concentrated to dryness to give 3-dimethylaminomethyl-benzofuran-2- carboxylic acid as the HCI salt, which was used in the next step without further purification. Step 5 To a solution of 9 (8 mg, 15 μmol, 1 equiv) in THF (lmL), obtained from Reference A above, at 0 °C was added N, N-diethylaniline (3 μL, 1.1 equiv). The reaction mixture was stirred at 0 °C. After 5 min of stirring, the reaction mixture was treated with 3- dimethylaminomethyl-benzofuran-2-carboxylic acid hydrochloride (6 mg, 1.3 equiv), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC*HC1) (4 mg, 1.3 equiv), and
1-hydroxybenzotriazole hydrate (HOBt»H2θ) (3 mg, 1.2 equiv) in sequence. The reaction mixture was stirred while allowed to warm to room temperature. After 17 hr of stirring, the reaction mixture was diluted with EtOAc (10 mL) and washed with 0.1N HCl^ (2 mL). The organic layer was dried over Na2SO4 and the crude product was purified by reverse phase preparative HPLC (acetonitrile-H2O with 0.1% cone HCI as the eluent) to give 47 (4.8 mg, 51%) as a white solid after lyophilization. EM (calc): 725.3; MS (ESI) m/e: 726.3 (M+H)+, 724.7 (M-H)".
Example 18
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yl- methyloxy)benzofuran-2-ylcarbonylamino (compound 48)
Figure imgf000083_0001
Proceeding as described in Example 1 above, but substituting 5-(tetrahydro-4H-pyran- 4-yloxy)-benzofuran-2-carboxylic acid with 5-(tetrahydro-4H-pyran-4-yl-methoxy)- benzofuran-2-carboxylic acid provided compound 48 as a white solid. 5-(2-Tetrahydro-4H- pyran-4-yl-methoxy)-benzofuran-2-carboxylic acid was prepared following similar procedure for the synthesis of 5-(tetrahydro-4H-pyran-4-yloxy)-benzofuran-2-carboxylic acid using 5- hydroxy-benzofuran-2-carboxylic acid methyl ester and tetrahydropyran-4-methanol as starting materials. EM (calc): 782.4; MS (ESI) m/e: 783.6 (M+Η)+, 781.4 (M-H)".
Example 19
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 5-(2- methoxyethyloxy)benzofuran-2-ylcarbonylamino (compound 49)
Figure imgf000084_0001
Proceeding as described in Example 1 above, but substituting 5-(tetrahydro-4H-pyran- 4-yloxy)-benzofuran-2-carboxylic acid with 5-(2-methoxyethoxy)-benzofuran-2-carboxylic acid provided compound 49 as a white solid. 5-(2-Methoxyethoxy)-benzofuran-2-carboxylic acid was prepared following similar procedure for the synthesis of 5-(tetrahydro-4H-pyran-4- yloxy)-benzofuran-2-carboxylic acid using 5-hydroxy-benzofuran-2-carboxylic acid methyl ester and 1-methoxymethanol as starting materials. EM (calc): 742.3; MS (ESI) m/e: 743.6 (M+Η)+, 741.7 (M-H)'.
Example 20 Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is CN, Y is CH2, and R12 is 6-(5-dimethylaminonaphth-l- ylsulfonylamino)naphth-2-ylcarbonylamino (compound 50)
Figure imgf000084_0002
Step 1 To a suspension of 6-amino-2-naphthoic acid (374 mg, 2.0 mmol) in CH2C12 (8 mL) were added TBDMS-Cl (301 mg, 2.0 mmol) and TEA (1.11 mL, 8.0 mmol) in sequence. After stirring for 1 hr, dansyl-chloride (701 mg, 2.6 mmol) was added to the reaction mixture and stirring was continued for an additional 1 hr. The reaction mixture was diluted with CH2C12 (50 mL) and IN HCl^. The separated organic phase was washed with IN HCl^ (3x 50 mL) and sat. NaHCOs^ (3x 50 mL) and concentrated in vacuo. The residue was taken up in THF (3 mL) and treated with 2N NaOH^ (10 mL) and MeOH (3 mL). After vigorously stirring for 30 min, IN HCl^ was added to adjust the pH of the solution to pH ~7. The reaction mixture was concentrated in vacuo and the residue was redissolved in CH2C12 (10 mL) and H2O (10 mL). The aqueous layer was extracted with CH2C12 (3x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Precipitation was observed after 3 d and CH2CI2 (1 mL) was added to the residue. The precipitation was filtered off and washed with Et2O to afford crude 6-(5-dimethylamino-naphthalene-l-sulfonylamino)-naphthalene-2- carboxylic acid (150 mg, purity 92%), which was used in the next step without further purification. Step 2 Proceeding as described in Example 1 above, but substituting 5-(tetrahydro-4H-pyran- 4-yloxy)-benzofuran-2-carboxylic acid with 6-(5-dimethylamino-naphthalene-l-sulfonyl- amino)naphthalene-2-carboxylic acid provided compound 50 after purification by preparative TLC (3:7 EtOAc/ hexane) as a white solid. EM (calc): 926.4; MS (ESI) m/e: 927.9 (M+Η)+, 925.5 (M-H)".
Example 21
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 and R5 are OH, R9 is H, R11 is H, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)- benzofuran-2-ylcarbonylamino (compound 51)
Figure imgf000086_0001
31 51
To a solution of 31 (32 mg, 0.042 mmol) in THF (6.4 mL) was added borane- tetrahydrofuran complex (IM solution in THF, 0.21 mL, 0.208 mmol). After 2 hr, 1,4- diazabicyclo[2.2.2]octane (140 mg, 1.25 mmol) and H2O (1 mL) were added. After stirring for 4.5 hr, the reaction mixture was diluted with brine (20 mL) and extracted with EtOAc (3x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by preparative TLC (95:5 EtOAc MeOH) gave 51 (13.9 mg, 45%). EM (calc): 743.3; MS (ESI) m/e: 744.8 (M+H)+, 742.9 (M-H)".
Example 22 Synthesis of a compound of Formula (I) where A and B are rings (a) and (c) respectively where R3 and R6 are OMe, R2, R7, and R10 are Me, R9 is H, R11 is CN, Y is CH2, and R12 is 5- (tetrahydropyran-4-yloxy)benzofuran-2-ylcarbonylamino (compound 52)
Figure imgf000086_0002
31 52 To a solution of 31 (32 mg, 0.042 mmol) in acetone (3 mL) and H2O (0.3 mL) was added DDQ (28.3 mg, 0.125 mmol) at 0 °C. After 90 min the reaction mixture was diluted with EtOAc (20 mL) and sat. NaHCO3fασ/brine (1:1, 20 mL). The aqueous layer was extracted with EtOAc (2x 20 mL). The combined organic phases were dried over Na2SO4, and concentrated in vacuo. Purification by preparative TLC (9:1 EtOAc/hexane) gave 52 (13.5 mg, 44%). EM (calc): 736.3; MS (ESI) m/e: 736.7 (M+H)+, 735.0 (M-H)".
Example 23
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2, R7, and R10 are Me, R4 is OH, Rs is methoxymethyloxy, R9 is H, R11 is CN, Y is CH2, and R12 is 5- (tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 59)
Step 1
Figure imgf000087_0001
To a solution of 4 (360 mg, 0.40 mmol) in THF (9.0 mL) at 0 °C was added a solution of chloromethylmethylether (MOM-C1, 41 μL, 0.48 mmol) in THF (0.5 mL), NaH (60% dispersion, 20 mg, 0.48 mmol), and catalytic amount of sodium iodide. The reaction mixture was stirred for 1 hr at 0 °C. The reaction was dilute by a mixture sat. NaHCO3fø and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give crude 53 (360 mg), which was used in the next step without further purification. Step 2
Figure imgf000088_0001
To a solution of crude 53 in THF (1 mL) was added AcOH (0.05 mL, 0.80 mmol) and TBAF (IM in THF, 0.60 mL, 0.60 mmol) at ambient temperature. The reaction mixture was stirred for 1 hr and was then diluted with sat. NaHCO3fαa and Et2θ. The aqueous layer was separated and extracted with Et2O. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to give 54 (0.34 g), which was used in the next reaction without further purification. Step 3
Figure imgf000088_0002
To a solution of 54 in CH2C12 (1.5 mL) was added DBU (0.1 mL) at ambient temperature. After stirring for 30 min, the reaction mixture was loaded directly on the column and purified by flash column chromatography (93:7 CH2Cl2/MeOH) to yield 55 (0.21 g, 87% over 3 steps) as a yellowish foamy solid. EM (calc): 614.3; MS (ESI) m/e 613.5 (M-H)". Step 4
Figure imgf000089_0001
Proceeding as described in Reference A, Step 16, reaction of 55 (200 mg, 0.326 mmol) with 6 (110 mg, 0.39 mmol) yielded 56 (212 mg, 74%). EM (calc): 878.5; MS (ESI) m/e: 879.0 (M+H)+, 877.0 (M-H)'. Step 5
Figure imgf000089_0002
Proceeding as described in Reference A, Step 17, reaction of 56 (212 mg, 0.242 mmol) with ZnCl2 and TMSCN provided 57 (173 mg, 90%) as an off-white solid. EM (calc): 790.4; MS (ESI) m/e: 791.6 (M+H)+, 789.5 (M-H)". Step 6
Figure imgf000089_0003
57 58 Proceeding as described in Reference A, Step 18, deprotection of 57 (170 mg, 0.215 mmol) with DBU provided 58 (0.104 g, 85%) as an off-white solid. EM (calc): 568.3; MS (ESI) m/e: 569.6 (M+H)+, 567.4 (M-H)". Step 7
Figure imgf000090_0001
Proceeding as described in Example 1, Step 5, coupling of 58 (98 mg, 0.172 mmol) with benzofuranoic acid yielded product 59 (97 mg, 70%). EM (calc): 812.4; MS (ESI) m/e: 813.2 (M+H)+, 811.6 (M-H)".
Example 24 Synthesis of a compound of Formula (I) where A is a ring of formula (b) and B is a ring of formula (c), R R°, and R* are OMe, Rz, R', and R 1ι0υ are Me, RD is OH, R9 is H, Rπ is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2- ylcarbonylamino (compound 61)
Step 1
Figure imgf000090_0002
To a solution of 59 (12 mg, 0.015 mmol) in acetone (1.2 mL) and H2O (0.12 mL) at 0 °C was added DDQ (13 mg, 0.060 mmol). After 45 min the reaction mixture was diluted with sat. NaHCO3fαa) and EtOAc. The aqueous layer was separated and further extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified over silica gel by flash column chromatography (30:70 hexane/EtOAc) to give 60 (8 mg). Step 2
Figure imgf000091_0001
To a solution of 60 (8 mg, 0.01 mmol) in CH2C12 (0.5 mL) was added TFA (0.05 mL) at ambient temperature. After stirring for 2 hr, the reaction mixture was diluted with EtOAc, washed with sat. NaHCO3(-a2j, brine, and dried over Na2SO4. Concentration in vacuo and purification by preparative TLC (97:3 CH2Cl2/MeOH) gave 61 (5 mg, 67%). EM (calc): 752.3; MS (ESI) m/e: 753.4 (M+H)+, 751.5 (M-H)".
Example 25 Synthesis of a compound of Formula (I) where A is a ring of foπnula (a) and B is a ring of formula (d), R1, R3, and R6 are OMe, R2, R7, and R10 are Me, R4 is OH, R9 is H, R11 is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2- ylcarbonylamino (compound 64)
Step l
Figure imgf000091_0002
To a solution of 31 (16 mg, 0.021mmol) in CH2C12 (2 mL) at 0 °C was added diisopropylethylamine (43 μL, 0.25 mmol) and MOM-Cl (2 μL, 0.208 mmol). After stirring for 1.5 hr at 0 °C, the reaction was quenched with cold sat. aHCO3^. The aqueous layer was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by preparative TLC (25:75 hexane/EtOAc) gave 62 (contains 3-4% of the bis-MOM ether product, 15 mg, 89%). EM (calc): 812.4; MS (ESI) m/e: 813.6 (M+H)+, 811.7 (M-H)". Step 2
Figure imgf000092_0001
To a solution of 62 (15 mg, 0.018 mmol) in acetone (1.5 mL) and H2O (0.15 mL) at 0 °C was added DDQ (13 mg, 0.060 mmol). After 45 min, the reaction mixture was diluted with sat. NaHCO^ and EtOAc. The separated aqueous layer extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by preparative TLC (97:3 CH2Cl2/MeOH,) gave 63 (9 mg, 61%). EM (calc): 796.3; MS (ESI) m/e: 797.2 (M+H)+, 795.8 (M-H)". Step 3
Figure imgf000092_0002
To a solution of 63 (9 mg, 0.011 mmol) in CH2CI2 (0.5 mL) at ambient temperature was added TFA (0.05 mL) at ambient temperature. After stirring for 2 hr, the reaction mixture was diluted with EtOAc. The organic layer was washed with sat. NaHCO3f-α? , brine, dried over Na2SO4, and concentrated in vacuo. Purification by preparative TLC (20:80 hexane/EtOAc) yielded 64 (8 mg, 99%). EM (calc): 752.3; MS (ESI) m/e: 753.4 (M+H)+, 751.3 (M-H)".
Example 26 Synthesis of a compound of Formula (I) where R1, R3, R4, R6, and R8 are OMe, R2, R7, and R10 are Me, R5 is OH, R9 is H, R11 is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)- benzofuran-2-ylcarbonylamino (compound 66)
Step l
Figure imgf000093_0001
To a solution of 59 (42 mg, 0.052 mmol) in MeOH (1 mL) was added TMSCHN2 (2M solution in hexane, 0.25 mL, 0.5 mmol) and catalytic amount of 2-fluorophenol. After 2 hr of stirring, the solvent was removed in vacuo and purification by preparative TLC to give 65 (40 mg, 95%). EM (calc): 826.4; MS (ESI) m/e: 827.4 (M+H)+, 825.5 (M-H)". Step 2
Figure imgf000093_0002
To a solution of 65 (40 mg, 0.048 mmol) in CH2C12 (2.0 mL) was added TFA (0.2 mL) at ambient temperature. After stirring for 2 hr, the reaction mixture was diluted with EtOAc, washed with sat. NaHCO3^, brine, and dried over Na2SO4. Concentration in vacuo and purification by preparative TLC (25:74 hexane/EtOAc) gave 66 (32 mg, 86%). EM (calc): 782.4; MS (ESI) m/e: 783.6 (M+H)+, 781.4 (M-H)".
Example 27 Synthesis of a compound of Formula (I) where A is a ring of formula (a) and B is a ring of formula (d), R1, R3, R4 and R6 are OMe, R2, R7, and R10 are Me, R9 is H, Rπ is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 67)
Figure imgf000094_0001
To a solution of 66 (10 mg, 0.012 mmol) in acetone (0.9 mL) and H2O (0.09 mL) at 0 °C was added DDQ (8.3 mg, 0.036 mmol). After 45 min the reaction mixture was diluted with sat. NaHCO3(fl4) and EtOAc. The aqueous layer was separated and further extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by preparative TLC (97:3 CH2Cl2 MeOH) gave 67 (6 mg, 63%). EM (calc): 766.3; MS (ESI) m/e: 767.7 (M+H)+, 765.9 (M-H)".
Example 28
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2 and R7 are Me, R4 and R5 are OH, R9 is H, R10 is ethyl, R11 is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 69)
Step l
Figure imgf000094_0002
To a solution of 3 (125 mg, 0.14 mmol) in CH3CN (1.0 mL) was added successively acetaldehyde (100 μL, 1.78 mmol), CH3CO2H (26 μL, 0.462 mmol), andNaCNBH3 (26 mg, 0.42 mmol) at ambient temperature. The resulting yellow suspension was stirred at ambient temperature for 30 min, and was diluted with EtOAc and sat. NaHCO3fø . The aqueous layer was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified over silica gel by flash column chromatography (2:1 hexane/EtOAc) to give product (97 mg, 75%). EM (calc): 920.5; MS (ESI) m/e: 921.7 (M+H)+, 919.9 (M-H)". Step 2
Figure imgf000095_0001
Proceeding as described in Reference A, Step 14 - Step 18, and Example 1, Step 5, 69 was synthesized. EM (calc): 782.4; MS (ESI) m/e: 783.7 (M+H)+, 781.6 (M-H)'.
Example 29 Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2 and R7 are Me, R4 and R5 are OH, R9 and R10 are H, R11 is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino
(compound 72)
Step l
Figure imgf000096_0001
To a solution of 31 (14 mg, 0.018 mmol) in CH3CN (0.6 mL) was added diisopropylethylamine (0.25 mL, 1.86 mmol) and MOM-Cl (0.083 mL, 1.09 mmol) at ambient temperature. After stirring for 4 hr, the reaction mixture was diluted with EtOAc and sat. NaHCO3(αe). The aqueous layer was separated and extracted with EtOAc. The organic phase was combined, washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification over silica gel by flash column chromatography (9:1 CH-CyEtOAc) provided 70 (14 mg, 90%). EM (calc): 856.4; MS (ESI) m/e: 857.4 (M+H)+, 855.5 (M-H)+. Step 2
Figure imgf000096_0002
To a solution of 70 (14 mg, 0.016 mmol) in CHC13 (0.85 mL) at -25 °C was added mCPBA (0.065 g, 0.038 mmol). The mixture was stirred for 30 min at -25 °C, Et3N (211 μL, 1.51 mmol) was added and the reaction mixture was warmed to 0 °C. After 10 min at 0 °C, trifluoroacetic anhydride (62 μL, 0.44 mmol) was added. After stirring for additional 30 min, the reaction was poured into pH 7.5 phosphate buffer and extracted with CH2C12. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was treated with acetic acid H2θ (4: 1, 10 mL) at ambient temperature for 5 hr. The mixture was poured into pH 7.5 buffer and extracted with CH2CI2. The organic phase was combined, washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by preparative TLC (1:4 CH2Cl2/EtOAc) gave 71 (3 mg, 22%). EM (calc): 842.4; MS (ESI) m/e: 843.6 (M+H)+, 841.6 (M-H)".
Step 3
Figure imgf000097_0001
To a solution of 71 (3 mg, 0.004 mmol) in CH2C12 (0.3 mL) at ambient temperature was added TFA (0.3 mL). After stirring for 2 hr, the reaction mixture was diluted with EtOAc and washed with pH 7.5 phosphate buffer, brine, and dried over Na2SO4. Concentration in vacuo and purification by preparative TLC (1:9 CH2Cl2/EtOAc) provided 72 (2 mg, 60%). EM (calc): 754.3; MS (ESI) m/e: 755.7 (M+H)+, 753.7 (M-H)'.
Example 30 Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2 and R7 are Me,
R and R are 3,4-dihydroxyphenylethylaminocarbonyloxy, R is H, R 10 : is Me, R , 11 is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 74)
Step l
Figure imgf000097_0002
31 73 To a solution of 31 (30 mg, 0.040 mmol) in DMF (2 mL) at ambient temperature was added bis-(4-nitrophenyl)-carbonate (71 mg, 0.234 mmol) and diisopropylethylamine (40 μL, 0.234 mmol). After stirring for 1.5 hr, the reaction mixture was diluted with EtOAc, and the organic phase was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. Purification by preparative TLC (3:7 hexane/EtOAc) gave 73 (37 mg, 86 %). EM (calc): 1098.4; MS (ESI) m/e: 1099.9 (M+H)+. Step 2
Figure imgf000098_0001
To a solution of 73 (4 mg, 0.004 mmol) in DMF (0.3 mL) was added dopamine (HCI salt, 5.5 mg, 0.03 mmol) and Et3N (5 μL, 0.03 mmol) at ambient temperature. After stirring for 1.5 hr, the reaction mixture was diluted with EtOAc and H2O. The aqueous layer was separated and was further extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Purification by preparative TLC (95:5 CH2Cl2/MeOH) gave 74 (3 mg, 52%). EM (calc): 1126.4; MS (ESI) m/e: 1127.7 (M+H)+, 1125.4 (M-H)'.
Example 31 Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2 and R7 are Me, R4 and R5 are 4-hydroxy-3-methoxyphenylethylaminocarbonyloxy, R9 is H, R10 is Me, R11 is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 75)
Figure imgf000099_0001
Proceeding as described in Example 30 above, 75 (9 mg, 78%) was synthesized. EM (calc): 1154.5; MS (ESI) m/e: 1155.9 (M+H)+.,
Example 32
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2 and R7 are Me, R4 and R5 are 4-hydroxyphenylethylaminocarbonyloxy, R9 is H, R10 is Me, R11 is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 76)
Figure imgf000099_0002
Proceeding as described in Example 30 above, 76 (8 mg, 73%) was synthesized. EM (calc): 1094.5; MS (ESI) m/e 1095.6 (M+H)+.
Example 33 Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2 and R7 are Me,
R4 and R5 is phenylethylaminocarbonyloxy, R9 is H, R10 is Me, R11 is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 77)
Figure imgf000100_0001
Proceeding as described in Example 30 above, 77 (4 mg, 35%>) was synthesized. EM (calc): 1062.5; MS (ESI) m/e: 1064.0 (M+H)+.
Example 34
Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2 and R7 are Me, R4 is 3,4-dihydroxyphenylethylaminocarbonyloxy, R5 is hydroxy, R9 is H, R10 is Me, R11 is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 80) Step l
Figure imgf000100_0002
59 78 To a solution of 59 (16 mg, 0.02 mmol) in DMF (1.0 mL) was added bis-(4- nitrophenyl)-carbonate (24 mg, 0.079 mmol) and diisopropylethylamine (14 μL, 0.080 mmol) at ambient temperature. After stirring for 1.5 hr, the reaction mixture was diluted with EtOAc. The organic phase was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. Purification by preparative TLC (30:70 hexane/EtOAc) gave 78 (20 mg) Step 2
Figure imgf000101_0001
To a solution of 78 (20 mg, 0.02 mmol) in DMF (1.0 mL) at ambient temperature was added dopamine (HCI salt, 11 mg, 0.06 mmol) and Et3N (8 μL, 0.06 mmol) at ambient temperature. After stirring for 1 hr, the reaction mixture was diluted with EtOAc and H2O. The aqueous layer was separated and was further extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Purification by preparative TLC (95:5 CH2Cl2/MeOH) provided 79 (16 mg, 80%). EM (calc): 991.4; MS (ESI) m/e: 992.7 (M+H)+, 990.4 (M-H)'. Step 3
Figure imgf000101_0002
To a solution of 79 (15 mg, 0.015 mmol) in CH2C12 (1.0 mL) was added TFA (0.15 mL) at ambient temperature. After stirring for 2 hr, the reaction mixture was diluted with EtOAc, washed with sat. NaHCO3^, brine, and dried over a2SO4. The solvent was removed in vacuo and the crude residue was purified by preparative TLC (95:5 CH2Cl2/MeOH) to yield 80 (5 mg, 67%). EM (calc): 947.4; MS (ESI) m/e: 948.8 (M+H)+, 946.8 (M-H)'.
Example 35 Synthesis of a compound of Formula (I) where R1, R3, R6, and R8 are OMe, R2 and R7 are Me,
R4 is OH, R5 is 3,4-dihydroxyphenylethylaminocarbonyloxy, R9 is H, R10 is Me, R11 is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 84)
Step l
Figure imgf000102_0001
31 81 To a solution of 31 (12 mg, 0.016 mmol) in CH2C12 (1.5 mL) at 0 °C was added diisopropylethylamine (0.033 mL, 0.19 mmol) and MOM-Cl (12 mg, 0.156 mmol). After stirring for 1.5 hr at 0 °C, the reaction was quenched with the addition of cold sat. NaHCO3^. The aqueous layer was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude 81, which was used in the next step without further purification. Step 2
Figure imgf000102_0002
To a solution of crude 81 in DMF (1.0 mL) at ambient temperature was added bis-(4- nitrophenyl)-carbonate (22 mg, 0.045 mmol) and diisopropylethylamine (11 μL, 0.060 mmol) at ambient temperature. After stirring for 1.5 hr, the reaction mixture was diluted with EtOAc. The organic phase was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. Purification by preparative TLC (30:70 hexane EtOAc) gave 82 (11 mg). Step 3
Figure imgf000103_0001
82 83 To a solution of 82 (11 mg, 0.011 mmol) in DMF (0.8 mL) was added dopamine (HCI salt, 6.4 g, 0.034 mmol) and Et3N (8 μL, 0.06 mmol) at ambient temperature. After stirring for 3 hr, the reaction mixture was diluted with EtOAc and H2O. The aqueous layer was separated and was further extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Purification by preparative TLC (95:5 QB^CLJMeOH) provided 83 (9 mg, 82%). EM (calc): 991.4; MS (ESI) m/e: 992.5 (M+H)+, 990.6 (M-H)". Step 4
Figure imgf000103_0002
83 84 To a solution of 83 (9 mg, 0.009 mmol) in CH2C12 (0.6 mL) was added TFA (0.06 mL) at ambient temperature. After stirring for 2 hr, the reaction mixture was diluted with EtOAc, washed with sat. NaHCOs^, brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative TLC (95:5 CH2Cl2/MeOH) to yield 84 (7 mg, 78%). EM (calc): 947.4; MS (ESI) m/e: 948.5 (M+H)+, 946.6 (M-H)".
Example 36 Synthesis of a compound of Formula (I) where R1, R3, R4, R6, and R8 are OMe, R2 and R7 are Me, R5 is 3,4-dihydroxyphenylethylaminocarbonyloxy, R9 is H, R10 is Me, R11 is CN, Y is CH2, and R12 is 5-(tetrahydropyran-4-yloxy)-benzofuran-2-ylcarbonylamino (compound 86)
Step 1
Figure imgf000104_0001
66 85 To a solution of 66 (7 mg, 0.009 mmol) in DMF (0.6 mL) at ambient temperature was added bis-(4-nitrophenyl)-carbonate (8 mg, 0.027 mmol) and diisopropylethylamine (6.3 μL, 0.036 mmol) at ambient temperature. After stirring for 1.5 hr, the reaction mixture was diluted with EtOAc. The organic phase was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC (3:7 hexane/EtOAc) to give 85 (5 mg). Step 2
Figure imgf000105_0001
To a solution of 85 (5 mg, 0.004 mmol) in DMF (0.5 mL) was added dopamine (HCI salt, 5 mg, 0.027 mmol) and Et3N (8 μL, 0.06 mmol) at ambient temperature. After stirring for 30 min, the reaction mixture was diluted with EtOAc and H2O. The aqueous layer was separated and was further extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (95:5 CH2Cl2/MeOH) to give 86 (4 mg, 46%). EM (calc): 961.4; MS (ESI) m/e: 962.2 (M+H)+, 960.5 (M-H)".
Biological Examples
Example 1 Cell Growth Inhibition Assay in vitro assay
HCT-116 human colorectal carcinoma cells (American Type Culture Collection) were cultured as monolayer in McCoy's 5A Medium (Gibco, #16600-082) supplemented with 10%> fetal bovine serum at 37°C in a 5% CO2 humidified incubator. For harvesting, cells were washed with phosphate buffered saline and were detached using Trypsin-EDTA (Gibco, #25300-054). Cells are plated in 0.1 ml of medium per well in 96-well microtiter plates (Corning, #3595). Twenty-four hours later, 10 ul of a 2% DMSO in McCoy's 5A media solution containing 1 nM to 3 uM of test compound was added in triplicate to the wells for final test compound concentrations in the well of 0.1 to 300 nM. An aliquot of 10 ul of a 2% DMSO in McCoy's 5 A media solution without test compound was added in triplicate to the wells and served as the control for maximal cell proliferation. The samples were incubated at 37 °C for 48 hours in a 5% CO2 humidified incubator. After incubation, the samples were removed from the incubator and 50 ul of a solution containing 9.6 ul of alamarBlue (Biosource, #DAL1100) and 40.4 ul of McCoy's 5A medium was added to each well. The alamarBlue media solution was also added to a triplicate set of wells containing no cells to correct for background fluorescence. The samples were incubated at 37 °C in a 5% CO2 humidified incubator. After incubation for 4 hours, the samples were read for fluorescence using a fluorescent plate reader (Molecular Devices, type 374). Fluorescence was monitored at 544 excitation wavelength and 590 emission wavelength. The GI50 (amount of compound that inhibits the cell growth by 50%) value of the compound of this invention was calculated as the percentage of survival of control calculated from the fluorescence corrected for background fluorescence. The surviving fraction of cells was determined by dividing the mean fluorescence values of the test compounds by the mean fluorescence of the control. The GIso for compounds 1, 3-6 in Table 1 was < 50 nM and for compounds 2 and 3 was > 100 nM.
Pharmaceutical Composition Examples The following are representative pharmaceutical formulations containing a compound of Foπnula (I) Tablet Formulation The following ingredients are mixed intimately and pressed into single scored tablets. Quantity per Ingredient tablet, mg compound of this invention 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 Capsule Formulation The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Quantity per Ingredient capsule, mg compound of this invention 200 lactose, spray-dried 148 magnesium stearate 2 Suspension Formulation The following ingredients are mixed to form a suspension for oral administration. Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mg distilled water q.s. to 100 ml Injectable Formulation The following ingredients are mixed to form an injectable formulation. Ingredient Amount compound of this invention 1.2 g lactate buffer solution, 0.1 M 10.0 ml HCI (1 N) or NaOH (1 N) q.s. to suitable pH saline (optional) q.s. to suitable osmolarity water (distilled, sterile) q.s. to 20 ml Compound (1.2 g) is combined with 0.1 M lactate buffer (10 ml) and gently mixed. Sonication can be applied for several minutes if necessary to achieve a solution. Appropriate amount of acid or base is added q.s. to suitable pH (preferable pH 4). A sufficient amount of water is then added q.s. to 20 ml.
Suppository Formulation A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol™ H-15 (triglycerides of saturated vegetable fatty acid; Riches- Nelson, Inc., New York), and has the following composition: compound of the invention 500 mg Witepsol™ H-15 balance
The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.

Claims

What is Claimed:
1. A compound of Formula (I) :
Figure imgf000109_0001
(I) wherein: A is a ring represented by formula (a) or (b):
Figure imgf000109_0002
(a) (b) B is a ring represented by formula (c) or (d):
Figure imgf000109_0003
Y is methylene optionally substituted with one or two halo; R1 and R8 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, cyano, nitro, acylamino, -COOR13 (where R13 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -CONR14R15 (where R14 and R15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or-NR16R17 (where R16 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and R17 is alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R3 and R6 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, cyano, nitro, acylamino, -COOR18 (where R18is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -CONRI9R20 (where R19 and R20 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or -NR21R22 (where R21 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and R22 is alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R4 and R5 are independently hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, aralkylaminocarbonyloxy, -COOR23 (where R23 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, or -CONR24R25 (where R24 and R25 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R2 and R7 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, or alkylsulfonyl; R9 is hydrogen, alkyl, cyano, halo, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, aryl, aralkyl, heteroaryl, heteroaralkyl, or =(O); R10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, acyloxy, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the aromatic or alicyclic ring in R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10, either alone or as part of another group, is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or hydroxy; R11 is hydrogen, cyano, -SCN, hydroxy, alkoxy, halo, or =(O); and R12 is: (a) -NHC(=NR26)R27 (where R26 is hydrogen, alkyl, haloalkyl, hydroxy, or alkoxy, and R27 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl where the aromatic or alicyclic ring in aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkyl is substituted or unsubstituted); (b) -NHC(=NR28)NHR28 (where each R28 is independently hydrogen, alkyl, hydroxy, alkoxy, alkoxycarbonyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl where the aromatic or alicyclic ring in aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkyl is substituted or unsubstituted); (c) -NR29COR30 (where R29 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl and R30 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); (d) -CONR31R32 (where R31 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, aralkenyl (wherein the alkenyl chain is optionally substituted with acylamino), heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl and R32 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl); (e) -COOR33 (where R33 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl); (f) -NR34SO2R35 (where R34 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, and R35 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl) ; (g) -NR36R37 (where R36 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, and R37 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl) ; (h) -NR38CHX1R39 (where R38 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, X1 is haloalkyl, and R39 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl); (i) -OR40 (where R40 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); (j) -S(O)m5R41 (where m5 is 0 to 2 and R41 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); or (k) -S(O)2NR42R43 (where R42 is hydrogen or alkyl and R43 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl) ; wherein the aromatic or alicyclic ring, either alone or as part of another group, in R12 is substituted, except for R27 and R28 where it is optionally substituted, with one, two, or three Ra independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, monosubstituted aminoalkyl, disubstituted aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl, optionally substituted heteroaralkyloxy, monosubstituted aminoalkyloxy, disubstituted aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, substituted heterocycloalkyloxyalkyl, substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkyloxy, -alkylene-S(O)n-R44 (where n is 0 to 2 and R44 is alkyl, hydroxyalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl provided that when n is 2, R44 is not alkyl), -NHSO2R45, -alkylene-NHSO2-R45 (where R45 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -NHCO-R46 or -alkylene-NHCO-R46 (where R46 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substimted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl provided that when R is -NHCO-R46 , then (i) R46 is not alkyl and (ii) when R46 is optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl, the aromatic and alicyclic ring are substituted), -CONR46R47 or -alkylene-CONR46R47 (where R46 is as defined above and R47 is hydrogen or alkyl provided that when Ra is -CONR46R47, then (i) R46 is not alkyl and (ii) when R46 is optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl, the aromatic and alicyclic ring are substituted), - alkylene-NR48-alkyleneCONR46R49 (where R46 is as defined above and R48 and R49 are independently hydrogen or alkyl), -O-(alkylene)-P(O)(OR50)2 or -(alkylene)-P(O)(OR50)2 (where each R50 is independently selected from hydrogen, alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl), -COOR51 (where R51 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), -COR52 (where R52 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), or -O-(alkylene)-P(O)(OR53)(NHR54) (where R53 is selected from hydrogen, alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl and R54 is alkyl, carboxyalkyl, or alkoxycarbonylalkyl); or a pharmaceutically acceptable salt thereof:
2. The compound of Claim 1 having the structure represented by Formula (la):
Figure imgf000113_0001
(la) wherein: Y is methylene optionally substituted with one or two halo; R1 and R8 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, cyano, nitro, acylamino, -COOR13 (where R13 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), - CONR14R15 (where R14 and R15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or -NR16R17 (where R16 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and R17 is alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R3 and R6 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, cyano, nitro, acylamino, -COOR18 (where R18 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), - CONR19R20 (where R19 and R20 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or -NR21R22 (where R21 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and R22 is alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R4 and R5 are independently hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyl, -COOR23 (where R23 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, or -CONR24R25 (where R24 and R25 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R2 and R7 are independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, hydroxyalkylcarbonyloxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfmyl, or alkylsulfonyl; R9 is hydrogen, alkyl, cyano, halo, hydroxy, alkoxy, alkenyloxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, aryl, aralkyl, heteroaryl, heteroaralkyl, or =(O); R10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, acyloxy, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl ; wherein the aromatic or alicyclic ring in R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10, either alone or as part of another group, is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or hydroxy; R11 is hydrogen, cyano, -SCN, hydroxy, alkoxy, halo, =(O), aryl, or heteroaryl; and R12 is: (a) -NHC(=NR26)R27 (where R26 is hydrogen, alkyl, haloalkyl, hydroxy, or alkoxy, and R27 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl where the aromatic or alicyclic ring in aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkyl is substituted or unsubstituted); (b) -NHC(=NR28)NHR28 (where each R28 is independently hydrogen, alkyl, hydroxy, alkoxy, alkoxycarbonyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl where the aromatic or alicyclic ring in aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkyl is substituted or unsubstituted); (c) -NR29COR30 (where R29 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, and R30 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); (d) -CONR31R32 (where R31 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl and R32 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl); (e) -COOR33 (where R33 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl); (f) -NR34SO2R35 (where R34 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, and R35 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl); (g) -NR36R37 (where R36 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, and R37 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl) ; (h) -NR38CHX1R39 (where R38 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, X1 is haloalkyl, and R39 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl); (i) -OR40 (where R40 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); (j) -S(O)m5R41 (where m5 is 0 to 2 and R41 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); or (k) -S(O)2NR42R43 (where R42 is hydrogen or alkyl and R43 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl) ; wherein the aromatic or alicyclic ring, either alone or as part of another group, in R12 is substituted, except for R27 and R28 where it is optionally substituted, with one, two, or three Ra independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, monosubstituted aminoalkyl, disubstituted aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl, optionally substimted heteroaralkyloxy, monosubstituted aminoalkyloxy, disubstituted aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, haloalkoxyalkyl, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, substituted heterocycloalkyloxyalkyl, substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkyloxy, -alkylene-S(O)n-R44 (where n is 0 to 2 and R44 is alkyl, hydroxyalkyl, haloalkyl, optionally substituted phenyl, optionally substimted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl provided that when n is 2, R44 is not alkyl), -NHSO2R45, -aIkylene-NHSO2-R45 (where R45 is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -NHCO-R46 or -alkylene-NHCO-R46 (where R46 is alkyl, haloalkyl, optionally substimted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl provided that when Ra is -NHCO-R46 , then (i) R46 is not alkyl and (ii) when R46 is optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl, the aromatic and alicyclic ring are substituted), -CONR46R47 or -alkylene-CONR46R47 (where R46 is as defined above and R47 is hydrogen or alkyl provided that when Ra is -CONR46R47, then (i) R46 is not alkyl and (ii) when R46 is optionally substimted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substimted heterocycloalkyl, the aromatic and alicyclic ring are substimted), - alkylene-NR48-alkyleneCONR46R49 (where R46 is as defined above and R48 and R49 are independently hydrogen or alkyl), -O-(alkylene)-P(O)(OR50)2 (where each R50 is independently selected from hydrogen, alkyl, optionally substimted phenyl, or optionally substituted phenylalkyl), -COOR51 (where R51 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), -COR52 (where R52 is substituted phenyl, substituted phenylalkyl, substituted heteroaryl, or substituted heteroaralkyl), or -O-(alkylene)- P(O)(OR53)(NHR54) (where R53 is selected from hydrogen, alkyl, optionally substituted phenyl, or optionally substituted phenylalkyl and R54 is alkyl, carboxyalkyl, or alkoxycarbonylalkyl.
3. The compound of Claim 1 or 2 wherein R12 is -NHCOR30 where R30 is benzofuran-2-yl substituted with one Ra selected from alkylaminoalkyl or dialkylaminoalkyl.
4. The compound of Claim 1 or 2 wherein R12 is -NHCOR30 where R30 is benzofuran-2-yl substituted with one Ra selected alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another Ra selected from alkylaminoalkyl or dialkylaminoalkyl.
5. The compound of Claim 1 or 2 wherein R12 is -NHCOR30 where R30 is benzofuran-2-yl substituted with one Ra selected from optionally substituted heterocycloalkylalkyloxy or optionally substimted heterocycloalkyloxy.
6. The compound of Claim 1 or 2 wherein R12 is -NHCOR30 where R30 is benzofuran-2-yl substituted with one Ra selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl, preferably methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy or hydroxy and another Ra selected from optionally substituted heterocycloalkylalkyloxy or optionally substimted heterocycloalkyloxy.
7. The compound of Claim 1 or 2 wherein R12 is -NHCOR30 where R30 is aryl, aralkenyl or heteroaralkenyl substimted with one, two, or three Ra.
8. The compound of Claim 6 or 7 wherein one Ra is selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another R is selected from alkylaminoalkyl or dialkylaminoalkyl
9. The compound of Claim 6 or 7 wherein one Ra selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, or hydroxyalkyl and another Ra selected from optionally substituted heterocycloalkylalkyloxy or optionally substituted heterocycloalkyloxy.
10. The compound of any of the Claims 3-9 where Y is methylene.
11. The compound of any of the Claims 1-10 wherein R1, R3, R6, R8 = alkoxy, R2 and R7 = alkyl, R4 and R5 = OH, R9 is hydrogen, and R10 = alkyl.
12. The compound of any of the Claims 1-10 wherein R1, R3, R6, R8 = -OCH3, R2 and R7 = -CH3, R4 and R5 = OH, R9 is hydrogen, and R10 = -CH3.
13. The compound of any of the Claims 1-12 wherein R1 ! is cyano .
14. The compound of any of the Claims 1, 2, 10, 11, and 12 where R12 is -NHCOR30 where R30 is benzofuran-2-yl substimted at the 5-position with tetrahydropyran-4-yloxy.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of the Claims 1-14 or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
16. A method for treating cancer in an animal comprising administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of any of the Claims 1-14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
17. A method for treating cancer in an animal comprising administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of any of the Claims 1-14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in combination with radiation therapy and optionally in combination with one or more compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, or a DNA methyl transferase inhibitor.
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