WO2006066183A2 - Novel saframycin analogs as therapeutic agents - Google Patents

Novel saframycin analogs as therapeutic agents Download PDF

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Publication number
WO2006066183A2
WO2006066183A2 PCT/US2005/045880 US2005045880W WO2006066183A2 WO 2006066183 A2 WO2006066183 A2 WO 2006066183A2 US 2005045880 W US2005045880 W US 2005045880W WO 2006066183 A2 WO2006066183 A2 WO 2006066183A2
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Prior art keywords
alkyl
hydrogen
aryl
heteroaryl
haloalkyl
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PCT/US2005/045880
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French (fr)
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WO2006066183A3 (en
Inventor
Joseph H. Saugier
Martin Sendzik
Jeffrey R. Spencer
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Axys Pharmaceuticals, Inc.
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Publication of WO2006066183A2 publication Critical patent/WO2006066183A2/en
Publication of WO2006066183A3 publication Critical patent/WO2006066183A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • 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 rumors including leukemias L 1210 and P388 and Ehrlich carcinoma. Recently, U. S. Application Pub.
  • this invention is directed to a compound of Formula (Ia), (Ib), (Ic), or (Id):
  • n is 0 or 1 ;
  • Y is alkylene optionally substituted with one to five halo
  • R 1 is hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, - C(O)OR 13 (where R 13 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, nitro, mono or disubstituted amino, acylamino, or -C(O)NR 14 R 15 (where R 14 and R 15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
  • R 3 and R 6 are as defined above or are independently hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, -C(O)OR 16 (where R 16 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, nitro, mono or disubstituted amino, acylamino, Or-C(O)NR 17 R 18 (where R 17 and R 18 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
  • R 4 and R 5 are independently hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, -C(O)OR 19 (where R 19 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, or -C(O)NR 20 R 21 (where R 20 and R 21 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
  • R 8 is hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, - C(O)OR 22 (where R 22 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, nitro, mono or disubstituted amino, or acylamino;
  • R 10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the aromatic or alicyclic ring in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 , either alone or as part of another group within the scope of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 , is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and hydroxy provided that the ring formed by R 2 together with R 3 or R 7 together with R 6 is not substituted;
  • R 11 is cyano, -SCN, hydroxy, alkoxy, or halo
  • R 12 is:
  • R 26 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl and R 27 is alkyl, alkoxy, haloalkyl, cycloalkyl, cycloalkylalkyl, acyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl);
  • R 28 and R 29 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl) ;
  • R 30 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl);
  • R 31 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl and R 32 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl);
  • R 43 is hydrogen or alkyl and R 44 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl);
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (Ia), (Ib), (Ic), or (Id) 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 (Ia), (Ib), (Ic), or (Id) 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).
  • 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 (Ia), (Ib), (Ic), or (Id) 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, and a DNA methyl transferase inhibitor.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (Ia), (Ib), (Ic), or (Id) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in combination with radiation
  • this invention is direct to the use of a compound of Formula (Ia), (Ib), (Ic), or (Id) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.
  • the medicament is 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.
  • Alkynylene 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., ethynylene, propynylene, 2-propynylene, butynylene (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.
  • Alkylsulfinyl 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-, zso-propylamino, n-, iso-, tert-butylamino, and the like.
  • Aminosulfonyl means a -SO 2 NRR' radical 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 te7t-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.
  • 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 -C(O)R a where R a is alkyl, and R' is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and 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 -C(O)NRR radical where each R is independently hydrogen or alkyl as defined above, e.g., -C(O)NH 2 , methylaminocarbonyl, 2-dimethylaminocarbonyl, and the like.
  • Acyl means a -C(O)R radical where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, as defined herein, e.g., acetyl, benzoyl, and the like.
  • Acyloxy means a -OC(O)R 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 -NHC(O)R 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 polycyclic 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 -0-R radical where R is aralkyl as defined above, e.g., benzyloxy, and the like.
  • Aryloxyalkyl means a -(alkylene)-OR radical where R is aryl as defined above, e.g., phenoxymethyl, phenoxyethyl, and the like.
  • Alkenyl means a -(alkenylene)-R radical where R is aryl as defined above.
  • Aralkynyl means a -(alkynylene)-R radical where R is aryl as defined above.
  • Cycloalkyl means a mono or bicyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.
  • Cycloalkylalkyl means a -(alkylene)-R radical where R is cycloalkyl as defined above; e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl, and the like.
  • Cycloalkenyl means a cyclic monovalent hydrocarbon radical of three to ten carbon atoms containing one or two double bond(s), e.g., cyclopentenyl, cyclohexenyl, 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.
  • Disubstituted amino means a -NR c R d radical where R c and R d are independently selected from alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, defined herein, e.g., dimethylamino, diethylamino, methylphenylamino, 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 Cl, -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-trifluoroethyloxyinethyl, 2-trifluoromethoxyethyl, and the like.
  • Hydroalkyl 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, l-(hydroxymethyl)-2- hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and l-(hydroxymethyl)-2-hydroxyethyl.
  • Hydroalkoxy or "hydroxyalkyloxy” means a -OR radical where R is hydroxyalkyl as defined above.
  • Hydroxyalkoxyalkyl or "hydroxyalkyloxyalkyl”means a -(alkylene)-OR radical where R is hydroxyalkyl as defined above e.g., hydroxyethoxymethyl, hydroxymethoxyethyl, and the like.
  • Heterocycloalkyl means a saturated or unsaturated monovalent cyclic group of 3 to 10 ring atoms in which one or two ring atoms are heteroatom selected from N, O, and S(O) n , where n is an integer from 0 to 2, the remaining ring atoms being C where one or two ring carbon atoms can optionally be replaced by a -C(O)- group.
  • the heterocycloalkyl may be fused to a phenyl or heteroaryl ring.
  • heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, tetrahydroquinolinyl, thiomorpholino, or l,3-dioxo-l,3-dihydroisoindol-2-yl, and the like.
  • Heterocycloalkyloxy means a -OR 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 -OR radical where R is heterocycloalkylalkyl as defined above e.g., tetrahydropyranylmethyoxy, morpholin-4-ylethoxy, and the like.
  • Heterocycloalkyloxyalkyl means a -(alkylene)-R radical where R is heterocycloalkyloxy as defined above.
  • 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, and 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.
  • 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.
  • Heter ⁇ aryloxyalkyl means a -(alkylene)-R radical where R is heteroaryloxy as defined above.
  • Heteroaralkenyl means a -(alkenylene)-R radical where R is heteroaryl as defined above.
  • Heteroaralkynyl means a -(alkynylene)-R radical where R is heteroaryl as defined above.
  • “Monosubstituted amino” means a -NHR' radical where R is alkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, or heteroaralkyl defined herein, e.g., methylamino, ethylamino, phenylamino, and the like.
  • 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.
  • 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, niethanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid
  • 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. 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.
  • prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like.
  • esters e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g., N,N-dimethylaminocarbonyl
  • amides e.g., trifluoroacetylamino, acetylamino, 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. 1999, 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.
  • 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 through asymmetric synthesis or 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.
  • alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth.
  • cyclic groups such as aryl, heteroaryl, heterocycloalkyl are substituted, 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.
  • 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.
  • Treating” or “treatment” of a disease includes:
  • 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.
  • Y is alkylene
  • R 1 is hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy;
  • R 3 and R 6 are defined as above or are independently hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy;
  • R 4 and R 5 are independently hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy;
  • R 8 is hydrogen, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy;
  • R 9 is hydrogen
  • R 10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the aromatic or alicyclic ring in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 10 , either alone or as part of another group within the scope of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 10 , is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and hydroxy provided that the ring formed by R 2 together with R 3 or R 7 together with R 6 is not substituted;
  • R 11 is cyano, -SCN, hydroxy, alkoxy, or halo
  • R 12 is as defined in the Summary of the Invention.
  • Y is methylene
  • R 1 , R 3 , R 4 , R 5 , and R 6 are independently hydroxy or alkoxy
  • R 2 is alkyl and R 3 is as defined above; or R 2 together with R 3 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl;
  • R 7 is alkyl and R 6 is as defined above; or R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl; provided that at least one of R 2 together with R 3 and R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )- (CH 2 )-; preferably both R 2 together with R 3 and R 7 together with R 6 form -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl;
  • R 8 is hydrogen, hydroxy, or alkoxy
  • R 9 is hydrogen
  • R 10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the aromatic or alicyclic ring in R 10 , either alone or as part of another group within the scope of R 10 , is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and hydroxy; and
  • R 11 is cyano, -SCN, hydroxy, alkoxy, or halo.
  • Y is methylene
  • R 1 , R 3 , and R 6 are alkoxy
  • R 2 is alkyl and R 3 is as defined above; or R 2 together with R 3 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl;
  • R 7 is alkyl and R 6 is as defined above; or R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl; provided that at least one of R 2 together with R 3 and R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )-
  • R 4 and R 5 are hydroxy
  • R 8 is hydrogen or alkoxy
  • R 9 is hydrogen
  • R 10 is alkyl
  • R 1 , R 3 , R 6 , and R 8 are methoxy
  • R 4 and R 5 are hydroxy
  • R 2 is methyl and R 3 is as defined above; or R 2 together with R 3 forms -(CH 2 )C(CH 3 ) 2 O-;
  • R 7 is methyl and R 6 is as defined above; or R 7 together with R 6 forms -(CH 2 )C(CH 3 ) 2 O-; provided that at least one of R 2 together with R 3 and R 7 together with R 6 forms -(CH 2 )C(CH 3 ) 2 O-; more preferably both R 2 together with R 3 and R 7 together with R 6 form - (CH 2 )C(CHs) 2 O-;
  • R 9 is hydrogen
  • R 10 is methyl
  • R 11 is cyano, hydroxy, or halo.
  • Y is methylene
  • R 1 , R 3 , R 4 , R 5 , and R 6 are independently hydroxy or alkoxy
  • R 2 is alkyl and R 3 is as defined above; or R 2 together with R 3 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl;
  • R 7 is alkyl and R 6 is as defined above; or R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl; provided that at least one of R 2 together with R 3 and R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )- (CH 2 )-; preferably both R 2 together with R 3 and R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl;
  • R 8 is hydrogen, hydroxy, or alkoxy
  • R 9 is hydrogen
  • R 10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the aromatic or alicyclic ring in R 10 , either alone or as part of another group within the scope of R 10 , is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and hydroxy; and
  • R 11 is cyano, -SCN, hydroxy, alkoxy, or halo.
  • Y is methylene
  • R 1 , R 3 , and R 6 are alkoxy
  • R 2 is alkyl and R 3 is as defined above; or R 2 together with R 3 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl;
  • R 7 is alkyl and R 6 is as defined above; or R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl; provided that at least one of R 2 together with R 3 and R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )- (CH 2 )-;
  • R 4 and R 5 are hydroxy
  • R 8 is hydrogen or alkoxy
  • R 9 is hydrogen
  • R 10 is alkyl
  • R 1 , R 3 , R 6 , and R 8 are methoxy; R 4 and R 5 are hydroxy;
  • R 2 is methyl and R 3 is as defined above; or R 2 together with R 3 forms -(CH 2 )C(CH 3 ) 2 O-;
  • R 7 is methyl and R 6 is as defined above; or R 7 together with R 6 forms -(CH 2 )C(CH 3 ) 2 O-; provided that at least one of R 2 together with R 3 and R 7 together with R 6 forms - (CH 2 )C(CEb) 2 O-; more preferably both R 2 together with R 3 and R 7 together with R 6 forms - (CH 2 )C(CHs) 2 O-;
  • R 9 is hydrogen
  • R 10 is methyl
  • R 11 is cyano, hydroxy, or halo.
  • Y is methylene
  • R 3 and R 6 are independently hydroxy or alkoxy
  • R 2 is alkyl and R 3 is as defined above; or R 2 together with R 3 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl;
  • R 7 is alkyl and R 6 is as defined above; or R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl; provided that at least one of R 2 together with R 3 and R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )- (CH 2 )-; preferably both R 2 together with R 3 and R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl;
  • R 9 is hydrogen
  • R 10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the aromatic or alicyclic ring in R 10 , either alone or as part of another group within the scope of R 10 , is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and hydroxy; and
  • R 11 is cyano, -SCN, hydroxy, alkoxy, or halo.
  • Y is methylene
  • R 3 and R 6 are alkoxy
  • R 2 is alkyl and R 3 is as defined above; or R 2 together with R 3 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl;
  • R 7 is alkyl and R 6 is as defined above; or R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )- where R a and R b are independently hydrogen or alkyl; provided that at least one of R 2 together with R 3 and R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )- (CH 2 )-;
  • R 8 is hydrogen or alkoxy
  • R 9 is hydrogen
  • R 10 is alkyl
  • R 3 and R 6 are -OCH 3 ;
  • R 2 is methyl and R 3 is as defined above; or R 2 together with R 3 fo ⁇ ns -(CH 2 )C(CH 3 ) 2 O-;
  • R 7 is methyl and R 6 is as defined above; or R 7 together with R 6 forms -(CH 2 )C(CH 3 ) 2 O-; provided that at least one of R 2 together with R 3 and R 7 together with R 6 forms -(CH 2 )C(R a R b )O- or -OC(R a R b )-(CH 2 )-; preferably both R 2 together with R 3 and R 7 together with R 6 forms - (CH 2 )C(CHs) 2 O-; more preferably both R 2 together with R 3 and R 7 together with R 6 forms -(CH 2 )C(CHs) 2 O-;
  • R 9 is hydrogen
  • R 10 is methyl
  • R 11 is cyano, hydroxy, or halo.
  • R 27 is cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or heteroaralkenyl wherein the aromatic or alicyclic ring, either alone or as part of another group, in R 27 is optionally substituted with one, two, or three R c independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyl, heterocycloalkyl
  • R 27 is phenyl or heteroaryl, more preferably pyridinyl, pyrazinyl, benzofuranyl, indolyl, benzothiophenyl, quinolinyl, or isoquinolinyl optionally substituted with one, two, or three R c independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyloxy, heterocycloalkyloxyalkyl, heterocyclo
  • R 27 is phenyl or heteroaryl, more preferably pyridinyl, pyrazinyl, benzofuranyl, indolyl, benzothiophenyl, quinolinyl, or isoquinolinyl optionally substituted with one, two, or three R c independently selected from methyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methylamino, dimethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl, diethylaminomethyl, diethylaminoethyl, dimethylaminoethyl, dimethylaminoethoxy, diethylaminoethoxy, hydroxy, hydroxymethyl, hydroxyethoxy, methoxy, phenyl, pyridinyloxy, tetrahydropyranyloxy, piperidinyloxy, morpholinylethoxy, piperidinylethoxy, piperazinylethoxy
  • R 12 is heterocycloalkyl wherein the heterocycloalkyl is a 5 or 6 membered ring containing 3 or 4 carbon ring atoms and one or two heteroatom(s) selected from N, O, and S(O) 2 ; where one or two carbon(s) is optionally replaced by a -C(O)- group; and where the 5 or 6 membered ring is optionally fused to a phenyl or heteroaryl ring.
  • Heterocycloalkyl is optionally substituted (at either ring when fused) with one, two, or three R c independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyloxy, heterocycloalkyloxyalkyl, heterocycloalkyl-alkyl, and heterocycloalkylalkyloxy.
  • the heterocycloalkyl ring is l,3-dioxo-l,3- dihydroisoindol-2-yl linked to Y via the nitrogen ring atom and is optionally substituted on the phenyl part of the ring with one or two R c independently selected from methyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methylamino, dimethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl, diethylaminomethyl, diethylaminoethyl, dimethylaminoethyl, dimethylaminoethoxy, diethylaminoethoxy, hydroxy, hydroxymethyl, hydroxyethoxy, methoxy, phenyl, pyridinyloxy, tetrahydropyranyloxy, piperidinyloxy, morpholinylethoxy, piperidinylethoxy, piperazinylethoxy, pyrroli
  • R 41 is cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or heteroaralkenyl optionally substituted with one, two, or three R c independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyloxy, heterocycloalkyloxyalkyl, heterocycloalkylalkylalkyl, and
  • a particularly preferred group of compound is that wherein R 11 is cyano.
  • a particularly preferred group of compound is that wherein R 11 is hydroxy.
  • 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).
  • the reactions described herein take place at atmospheric pressure over a temperature range from about -78 0 C to about 150 0 C, more preferably from about 0 0 C to about 125 0 C and most preferably at about room (or ambient) temperature, e.g., about 20 0 C.
  • the reactions described herein take place under inert gas, such as nitrogen or argon.
  • reaction is carried in the presence of anhydrous lithium bromide in a suitable organic solvent such as dichloromethane, ethylene glycol dimethyl ether, and the like.
  • a suitable drying reagent such as magnesium sulfate, sodium sulfate, and the like.
  • Reaction of compound 20 with an aldehyde compound of formula 21 where n and Y are as defined in the Summary of the Invention and R z is R 12 as defined in the Summary of the invention or a precursor group to R 12 provides a compound of formula 22.
  • the reaction is carried out in the presence of a suitable drying 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 drying reagent such as magnesium sulfate, sodium sulfate, and the like
  • a suitable organic solvent such as dichloromethane, ethylene glycol dimethyl ether, dichloroethane, and the like.
  • the reaction is carried out in the presence of lithium bromide or a suitable acid such as hydrochloric acid, trifluoroacetic acid, and the like.
  • Reaction of a compound of formula 22 in the presence of a suitable Lewis acid such as anhydrous 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 (I) where R z is R 12 or a compound of formula 23 where R z is a precursor group to R 12 such as protected amino or hydroxy group.
  • a suitable Lewis acid such as anhydrous zinc(II) chloride and the like in a suitable organic solvent such as 2,2,2- trifluoroethanol, THF, and the like
  • a suitable organic solvent such as 2,2,2- trifluoroethanol, THF, and the like
  • an external cyanide source such as trimethylsilyl cyanide, sodium cyanide, potassium cyanide and the like.
  • R z group in 23 is then converted to R 12 as defined in the Summary of the Invention to provide a compound of Formula (Ia).
  • R z is a protected amino or hydroxy group
  • removal of the protecting group provides a compound of Formula (Ia) where R 12 is amino or hydroxy.
  • the reaction conditions employed for removal of the protecting group depend on the nature of the protecting group. For example, if R z is an amino group protected with Fmoc, it is deprotected under basic reaction conditions. Suitable bases are 1,8- 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 (Ia) can be converted to other compounds of Formula (Ia) by methods well known in the art. For example:
  • a compound of Formula (Ia) where R 12 is -NHC(O)R 27 where R 27 is as defined in the Summary of the Invention can be readily prepared by reacting a corresponding compound of Formula (Ia) where R 12 is amino with an acid halide of formula R 27 C(O)X where X is halo or an acid of formula R 27 C(O)OH. If acid halide is utilized, the reaction is carried out in the presence of a suitable base such as triethylamine, N,N-diethylaniline, diisopropylethylamine and the like in a suitable reaction solvents such as THF, DMF and the like.
  • a suitable base such as triethylamine, N,N-diethylaniline, diisopropylethylamine and the like in a suitable reaction solvents 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 corresponding acids with a halogenating agent such as oxalyl chloride, thionyl chloride, phosphorous oxy chloride, and the like.
  • a halogenating agent such as oxalyl chloride, thionyl chloride, phosphorous oxy chloride, and the like.
  • the reaction is carried out in the presence of suitable coupling agent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC'HCl), 1,3-dicyclohexylcarbodiimide (DCC), or benzotriazol-1- yloxyltris(dimethylamino)phosphonium hexafluorophosphate (BOP), optionally in the presence of 1-hydroxybenzotriazole hydrate (HOBt 1 H 2 O) in a suitable organic solvents such as DMF and the like, in the presence of a suitable base such as N.N-diethylaniline and the like.
  • suitable coupling agent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC'HCl), 1,3-dicyclohexylcarbodiimide (DCC), or benzotriazol-1- yloxyltris
  • a compound of Formula (Ia) where R 12 is -NHSO 2 R 32 can be prepared by reacting a compound of Formula (Ia) where R 12 is amino with a sulfonylating agent of formula R 32 SO 2 L where L is a leaving group such as halo under reaction conditions described for acid halides in (i) above.
  • a guanidine forming agent such as pyrazole-carboxamidine
  • a compound of Formula (Ia) where R 12 is -NR 33 R 34 and -NR 35 CHXR 36 can be prepared by reacting a compound of Formula (Ia) where R 12 is amino with a suitable alkylating agent by methods known in the art.
  • a compound of Formula (Ia) where R 12 is -OR 37 can be prepared first by converting the amino group in a compound of Formula (I) where R 12 is amino to hydroxy through diazo functionality and alkylation of the resulting hydroxy group with suitable alkylating reagents under conditions well known in the art.
  • a compound of Formula (Ia) where R 12 is -OR 37 can be prepared reacting compound 5 with a hydroxy-protected hydroxyacetaldehyde of formula CH 2 (CHO)OPG such as tert-butyldimethylsilyloxyacetaldehyde, followed by removal of the hydroxy protecting group to provide a compound of Formula (Ia) where R 12 is hydroxymethyl.
  • a hydroxy-protected hydroxyacetaldehyde of formula CH 2 (CHO)OPG such as tert-butyldimethylsilyloxyacetaldehyde
  • a compound of Formula (Ia) where R 12 is -C(O)OR 30 and -C(O)NR 28 R 29 can be prepared by reacting 5 with 2-formylacetic acid methyl ester, followed by removal of the carboxy protecting group to provide a compound of Formula (I) where R 12 is carboxymethyl.
  • the carboxy group can then be converted to other compounds of Formula (Ia) where R 12 is - C(O)OR 30 and -C(O)NR 28 R 29 by methods well known in the art.
  • a compound of Formula (Ia) where R 12 is -S(O) ml R 38 can be prepared by reacting a compound of Formula (Ia) where R 12 is hydroxy with ⁇ -toluenesulfonyl chloride to form a leaving group such as toluenesulfonate and then reacting it with a sulfur nucleophile of formula R 38 SH to give a compound of Formula (Ia) where ml is O. Oxidation of the sulfur with a suitable oxidizing agent such as w-chloroperbenzoic acid, and the like can provide corresponding a compound of Formula (Ia) where ml is 1 or 2.
  • a compound of Formula (Ia) where R 11 is hydroxy or methoxy can be prepared from a corresponding compound of Formula (Ia) 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 (Ia) can be converted to a corresponding compound of Formula (Ib), (Ic) or (Id) by treating it with a suitable oxidizing agent such as 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone, and the like.
  • a suitable oxidizing agent such as 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone, and the like.
  • a mono quinone compound of the Invention i.e., a compound of Formula (Ib) or (Ic) and compound (Ia) contains a phenolic group in the both the aromatic rings, then the phenolic group in aromatic ring that is not being oxidized has to be selectively protected with a suitable protecting group such as MOM prior to oxidation step, followed by removal of the hydroxy protecting group.
  • Compounds of formula 10 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 10, preferably a specific enantiomerically pure compound of formula 10 can also be prepared by the procedure illustrated and described in Scheme B below.
  • Bromination reaction on a compound of formula 1 where R 1 , R 2 , R 3 , and R 4 are defined as in the Summary of the Invention or a suitably protected derivative thereof provides a compound of formula 2.
  • Compound 1 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 1 are either commercially available or can be prepared from commercially available starting material by methods known in the art.
  • Compound 2 is converted to a compound of formula 3 by treating 2 with an organometallic reagent such as alkyllithium e.g., tert-butyllithium, r ⁇ -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).
  • organometallic reagent such as alkyllithium e.g., tert-butyllithium, r ⁇ -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).
  • organometallic reagent such as alkyllithium e.g., tert-butyllithium, r ⁇ -butyllithium, and the like or magnesium
  • a suitable catalyst preferably a chiral catalyst such as Et-DuPHOS-Rh(I), BINAP-RU(OAC) 2 , (+)-l,2-bis((25 ( , 5S)-2,5- diethylphospholano)benzene(cyclooctadiene) rhodium(I) trifluoromethanesulfonate, and the like, provides a compound of formula 6.
  • a suitable catalyst preferably a chiral catalyst such as Et-DuPHOS-Rh(I), BINAP-RU(OAC) 2 , (+)-l,2-bis((25 ( , 5S)-2,5- diethylphospholano)benzene(cyclooctadiene) rhodium(I) trifluoromethanesulfonate, and the like, provides a compound of formula 6.
  • Conversion of a compound of formula 6 to a compound of formula 7 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.
  • Compound 7 is then converted to a compound of formula 10 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 are not limited to Dess-Martin periodinane, tetrapropylammonium perrut
  • the amino acid protecting group in compound 7 is the same as in compound 10. If however, a different amino acid protecting group than the one present in compound 7 is desired in compound 10, deprotection followed by protection of the amino group in compound 7 provides a compound 9 where PG 1 is different than PG. Compound 9 is then converted to a compound of formula 10 as described above.
  • R 1 and R 3 are methoxy and R 2 is hydrogen or methyl can be prepared from commercially available 2,4-dimethoxybenzaldehyde and 2,4-dimethoxy-3- methylbenzaldehyde respectively.
  • Compound of formula 10 where R 1 is nitro, R 4 is hydroxy or alkyl, and R 2 and R 3 together with the carbon atoms to which they are attached independently form -(CH 2 )C(CH 3 ) 2 O- can be prepared by nitration of 2,3-dihydro-2,2-dimethyl-7- benzofuranol or its alkoxy derivative with nitric acid in nitromethane under the reaction conditions described in Kemp, D. S., et al. J. Org. Chem. 1986, 51, 1829-1838. Reduction of the nitro group provides the amino group that can then be converted to mono or disubstituted amino groups under conditions well known in the art.
  • a compound of formula 10 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 10, preferably a specific enantiomerically pure compound of formula 1 can also be prepared by the procedure illustrated and described in Scheme C below. 80
  • Compound 11 is then converted to the corresponding bromide compound of formula 12 using a suitable bromination reagent such as bromine in the presence of a suitable oxo-phile such as triphenylphosphine .
  • Compound 12 is then converted to a compound of formula 14, preferably enantiomerically pure compound, by stereoselective alkylation reaction between compound 12 and a compound of formula 13 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 a ⁇ . 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.
  • the reaction can be carried out in the presence of Lewis acids such as anhydrous lithium chloride.
  • Treatment of a compound of formula 10 with hydrogen cyanide, acetone cyanohydrin, and the like provides a compound of formula 15.
  • Treatment of 15 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 Cl 2 , and the like provides a compound of formula 16.
  • Removal of the amino protecting group in 16 provides a compound of formula 17.
  • 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- diazabicyclo[5.4.0]-undec-7-ene (DBU), morpholine, piperazine, and the like.
  • DBU 1,8- diazabicyclo[5.4.0]-undec-7-ene
  • morpholine 1,8- diazabicyclo[5.4.0]-undec-7-ene
  • piperazine 1,8- diazabicyclo[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).
  • 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).
  • 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 mye
  • 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.
  • 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.
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • 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.
  • compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the 005/045880
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of Formula (I) are described below.
  • the compounds of this invention 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, DNA methyl tranferase inhibitors, and other angiogenesis inhibitors.
  • the compound of the present invention compounds are particularly useful when administered 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, 45880
  • Preferred estrogen receptor modulators are tamoxifen and raloxifene.
  • 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, LYl 17081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl- 1 -oxopropoxy-4-methyl-2-[4-[2-(l - piperidinyl)ethoxy]phenyl]-2H-l-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'- dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and S ⁇ 646.
  • Androgen receptor modulators refers to compounds which 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 which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • retinoid receptor modulators 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 myosis, 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 tosylate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2- methyl-pyridine) platinum, benzylguanine, glufosfamide, GPXlOO, (trans, trans, trans)-bis-mu- (hexane-l,6-
  • microtubulin inhibitors include paclitaxel, vindesine sulfate, 3',4'- didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPRl 09881, BMS184476, 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-te/ ⁇ -butylaniide, TDX258, and BMS 188797.
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-O-exo-benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5- nitropyrazolo[3 ,4,5 -kl] acridine-2-(6H)propanamine, 1 -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 ⁇ ,15 ⁇ )dione, lurtotecan, 7-[2-(N-isopropylamino)-ethyl]-(20S)camptothecin, B ⁇ P1350, BNPIIlOO, BN8091
  • 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-dichlor
  • alanosine 1 l-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-l,l 1-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-arabino fliranosyl 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, for example).
  • angiogenesis inhibitors such as trastuzumab
  • tumor suppressor genes such as p53
  • HMG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3-methylglutaryl- CoA reductase.
  • Compounds which have inhibitory activity for HMG-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 "HMG- CoA reductase inhibitor” and “inhibitor of HMG-CoA reductase” have the same meaning when used herein. It has been reported that (Int. J.
  • HMG-CoA reductase inhibitors examples include but are not limited to lovastatin (MEVACOR ® ; see U.S. Pat. Nos.4,231,938; 4,294,926; 4,319,039), simvastatin (ZOCOR ® ; see U.S. Pat. Nos. 4,444,784; 4,820,850; 4,916,239), pravastatin (PRAVACHOL ® ; 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.
  • HMG-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 HMG- CoA reductase inhibitory activity, and colchicine the use of such salts, esters, open-acid and lactone forms 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 45880
  • HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin, and most preferably simvastatin.
  • the term "pharmaceutically acceptable salts" with respect to the HMG-CoA reductase inhibitor shall mean non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N, ⁇ '- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, l-p-chlorobenzyl-2-pyrrolidine-r-yl-methylbenzimidazole, diethylamine, piperazine, and tris(hydroxymethyl) aminomethane.
  • a suitable organic or inorganic base particularly those formed from cations such as
  • salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium hydroxy, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, hydroxy, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palm
  • Ester derivatives of the described HMG-CoA reductase inhibitor compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
  • 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-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • FPTase farnesyl-protein transferase
  • GGPTase-I geranylgeranyl-protein transferase type I
  • GGPTase-II geranylgeranyl-protein transferase type-II
  • prenyl-protein transferase inhibiting compounds examples include (+)-6-[amino(4-chloropheny I)(I -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)-l-methyl- 2(lH)-quinolinone, 5(S)- «-butyl-l-(2,3-dimethylphenyl)-4-[l-(4-cyanobenzyl)-5-
  • 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. 0 618 221, European Patent Publ. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.
  • ⁇ IV protease inhibitors examples include amprenavir, abacavir, CGP-73547, CGP- 61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232, 632.
  • reverse transcriptase inhibitors examples include delaviridine, efavirenz, 005/045880
  • 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 FIt-I (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-infiammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxygenase-2 inhibitors like celecoxib, valecoxib, and rofecoxib (PNAS, Vol.
  • NSAIDs nonsteroidal anti-inf
  • NSAID's which are potent COX-2 inhibiting agents.
  • an NSAID is potent if it possess an IC 50 for the inhibition of COX-2 of 1 ⁇ M or less as measured by the cell or microsomal assay known in the art.
  • NSAID's which are selective COX-2 inhibitors are defined as those which possess a specificity for inhibiting COX-2 over COX-I of at least 100 fold as measured by the ratio of IC5 0 for COX-2 over IC 5 0 for COX-I evaluated by the cell or microsomal assay disclosed hereinunder.
  • Such compounds include, but are not limited to those disclosed in U.S. Pat. No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan. 19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat. No.
  • 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, acetyldinaline, 5-amino-l-[[3,5-dichloro-4-(4- chlorobenzoyl)phenyl] -methyl] - IH- 1 ,2, 3 -triazole-4-carboxamide, CM 101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentose phosphate, 7,7-(carbonyl-bis[imino- N-methyl-4,2-pyrrolocarbonyl-imino[N-methyl-4,2-pyrrole]-carbonylimino]-
  • integrin blockers 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 ⁇ 6 ; ⁇ v ⁇ 8, oci ⁇ i, ⁇ 2 ⁇ i, ⁇ s ⁇ t, ⁇ 6 ⁇ l5 and ⁇ 6 ⁇ 4 integrins.
  • the term also refers to antagonists of any combination of ⁇ v ⁇ 3 , ⁇ v ⁇ s, ⁇ v ⁇ 6 , ⁇ v ⁇ s, Ci 1 ⁇ l5 ⁇ 2 ⁇ 1; ⁇ s ⁇ u ⁇ 6 ⁇ i and ⁇ 6 ⁇ 4 integrins.
  • tyrosine kinase inhibitors include N-(trifluoromethyl-phenyl)- 5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)-indolin-2-one, 17- (allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenyl-amino)-7-methoxy-6-[3- (4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-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,
  • the instant compounds are also useful, alone or 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 compounds can serve to inhibit metastasis, alone or in combination with GP Ilb/IIIa) antagonists.
  • fibrinogen receptor antagonists include abciximab, eptifibatide, sibrafiban, lamifiban, lotrafiban, cromofiban, and CT50352.
  • D ⁇ A methyltransferase inhibitor refers to compounds which inhibit the methylation of the D ⁇ A base cytosine at the C-5 position of that base by the D ⁇ A methyltransferase enzyme.
  • D ⁇ A methyltransferase inhibitor examples include compounds disclosed in US Patents 6,329,412 and 6,268,137.
  • Specific DNA methyltransferase inhibitors include 5-azacytosine and zebularine®.
  • Such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range.
  • Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
  • administration and variants thereof in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.)
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • 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.
  • the compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the compounds of the instant invention may also be coadministered with other well known cancer therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • Included in such combinations of therapeutic agents are combinations of the farnesyl-protein transferase inhibitors disclosed in US Patent 6,313,138 and an antineoplastic agent. It is also understood that such a combination of antineoplastic agent and inhibitor of farnesyl-protein transferase may be used in conjunction with other methods of treating cancer and/or tumors, including radiation therapy and surgery.
  • antineoplastic agent examples include, in general, microtubule-stabilizing agents (such as paclitaxel (also known as Taxol ® ), docetaxel (also known as Taxotere ® , epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives); microtubule- disruptor agents; alkylating agents, anti-metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.
  • microtubule-stabilizing agents such as paclitaxel (also known as Taxol ® ), docetaxel (also known as Taxotere ® , epothilone A, epothilone B, desoxyepothilone A,
  • Example classes of antineoplastic agents include, for example, the anthracycline family of drugs, the vinca drags, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins.
  • Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as colchicines, etoposide, etoposide phosphate or teniposide, vinblastine, vincristine, leurosidine, vindesine, leurosine, and the like.
  • antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabine, idatrexate, trimetrexate, dacarbazine, L- asparaginase, camptothecin, CPT-Il, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
  • the preferred class of antineoplastic agents is the taxanes and the preferred antineoplastic agent is paclitaxel.
  • 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 diluted with diethyl ether (700 mL), washed with 0.5 N aqueous HCl, brine, and dried over sodium sulfate.
  • the thick oil obtained upon drying in vacuo was purified by flash chromatography over silica gel with ethyl acetate/hexanes (15/85) to provide olefin 5-a (69.8 g,
  • R 4 is -O-tert-butyldimethylsilyl
  • PG is Fmoc
  • R 4 is -OH (following Scheme D)
  • reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo to provide crude 5-(tetrahydro ⁇ 4H-pyran-4- yloxy)-benzofuran-2-carboxylic acid (1.05 g, 99%) as a white solid.
  • the crude imine intermediate was dissolved in anhydrous ethylene glycol dimethyl ether (20 mL) and added to a suspension of anhydrous lithium bromide (1.65 g, 19.1 mmol) in anhydrous ethylene glycol dimethyl ether (5 mL). The resulting mixture was stirred at 35 0 C for 15 h, cooled to room temperature, and diluted with ethyl acetate (200 mL). The organic layer was washed with brine/saturated aqueous NaHCO 3 (4/1, 3 x 100 mL), dried over sodium sulfate, and concentrated in vacuo.
  • Y is -CH 2 -, and R 12 is -OH
  • HCT-116 human colorectal carcinoma cells (American Type Culture Collection) were cultured as monolayer in McCoy's 5 A Medium (Gibco, #16600-082) supplemented with 10% fetal bovine serum at 37 0 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 microliter 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 0 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 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.
  • 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.O 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
  • the following ingredients are mixed to form an injectable formulation.
  • 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.
  • a suppository of total weight 2.5 g is prepared by mixing the compound of the invention with WitepsolTMH-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition: compound of the invention 500 mg WitepsolTMH-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 rumors including leukemias L 1210 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 (Ia), (Ib), (Ic), or (Id):
Figure imgf000003_0001
(Id) wherein: n is 0 or 1 ;
Y is alkylene optionally substituted with one to five halo;
R1 is hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, - C(O)OR13 (where R13 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, nitro, mono or disubstituted amino, acylamino, or -C(O)NR14R15 (where R14 and R15 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
R2 is hydrogen, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, or alkylsulfonyl; or R2 together with R3 forms -(CH2)qC(RaRb)X- or -XC(RaRb)-(CH2)q- where q is 1-2, X is -NR- (where R is hydrogen or alkyl), -0-, or -S-, and Ra and Rb are independently hydrogen or alkyl or Ra and Rb together with the carbon atom to which they are attached form (=0);
R7 is hydrogen, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, or alkylsulfonyl; or R7 together with R6 forms -(CH2)qC(RaRb)X- or -XC(RaRb)-(CH2)q- where q is 1-2, X is -NR- (where R is hydrogen or alkyl), -O-, or -S-, and Ra and Rb are independently hydrogen or alkyl or Ra and Rb together with the carbon atom to which they are attached form (=0); provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)qC(RaRb)X- or -XC(RaRb)-(CH2)q-;
R3 and R6 are as defined above or are independently hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, -C(O)OR16 (where R16 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, nitro, mono or disubstituted amino, acylamino, Or-C(O)NR17R18 (where R17 and R18 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
R4 and R5 are independently hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, -C(O)OR19(where R19 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, or -C(O)NR20R21 (where R20 and R21 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
R8 is hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, - C(O)OR22 (where R22 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, nitro, mono or disubstituted amino, or acylamino;
R9 is hydrogen, alkyl, cyano, halo, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, or (=0);
R10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, 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 within the scope of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10, is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and hydroxy provided that the ring formed by R2 together with R3 or R7 together with R6 is not substituted;
R11 is cyano, -SCN, hydroxy, alkoxy, or halo; and
R12 is:
(i) alkyl;
(ii) alkenyl; (iii) alkynyl;
(iv) aryl;
(v) aralkenyl;
(vi) aralkynyl;
(vii) heteroaryl;
(viii) heteroaralkenyl;
(ix) heteroaralkynyl;
(x) heterocycloalkyl;
(xi) -NHC(=NR23)R24 (where R23 is hydrogen, alkyl, or haloalkyl and R24 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl);
(xii) -NHC(=NH)NHR25 (where R25 is hydrogen, alkyl, hydroxy, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl);
(xiii) -NR26C(O)R27 (where R26 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl and R27 is alkyl, alkoxy, haloalkyl, cycloalkyl, cycloalkylalkyl, acyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl);
(xiv) -C(O)NR28R29 (where R28 and R29 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl) ;
(xv) -C(O)OR30 (where R30 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl);
(xvi) -NR31SO2R32 (where R31 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl and R32 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl);
(xvii) -NR33R34 (where R33 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl and R34 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl provided that n=l);
(xviii) -NR35CHXR36 (where R35 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, X is haloalkyl, and R36 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl provided that n=l); (xix) -OR37 (where R37 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); (xx) -S(O)mlR38 (where ml is 0 to 2 and R38 is hydrogen when ml is 0, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl); or (xxi) -S(O)2NR39R40 (where R39 is hydrogen or alkyl and R40 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl);
(xxii) -OC(O)R41 (where R41 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl); (xxiii) -C(O)R42 (where R42 is alkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl) ; (xxiv) cycloalkyl; (xxv) cycloalkylalkyl; (xxvi) cycloalkenyl;
(xxvii) -OC(O)NR43R44 (where R43 is hydrogen or alkyl and R44 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl);
(xxviii) -SiR45R46R47 where R45, R46, and R47 are independently alkyl; or (xxix) -P(=O)(X1R48)Y1R49 (where X1 and Y1 is a single bond or -O- and R48 and R49 are independently hydrogen, alkyl, aryl, or aralkyl); wherein the aromatic or alicyclic ring, either alone or as part of another group, in R12 is optionally substituted with one, two, or three Rc independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyloxy, heterocycloalkyloxyalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, -(alkylene)nl-S(O)n2- R50 (where nl is O or 1, n2 is 0-2, and R50 is alkyl, haloalkyl, amino, alkylamino, dialkylamino, aryl, or heteroaryl), -(alkylene)n3-NHSO2-R51 (where n3 is 0 or 1 and R51 is alkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkyl), -(alkylene)n4-NHC(O)-R52 (where n4 is 0 or 1 and R52 is alkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkyl), and -(alkylene)n5-C(O)NR53R54 (where n5 is 0 or 1 and R53 is alkyl, haloalkyl, hydroxy, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl and R54 is hydrogen or alkyl) and: fUrther wherein the aromatic or alicyclic ring, either alone or part of another group in Rc is optionally substituted with one, two, or three Rd independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonyl, and cyano; 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 (Ia), (Ib), (Ic), or (Id) 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 (Ia), (Ib), (Ic), or (Id) 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 (Ia), (Ib), (Ic), or (Id) 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, and a DNA methyl transferase inhibitor.
In a fifth aspect, this invention is direct to the use of a compound of Formula (Ia), (Ib), (Ic), or (Id) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament. Preferably the medicament is for the treatment of cancer. Detailed Description of the Invention
Definitions:
Unless otherwise specified, the terms used herein 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.
"Alkynylene" 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., ethynylene, propynylene, 2-propynylene, butynylene (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. "Alkylsulfinyl" 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-, zso-propylamino, n-, iso-, tert-butylamino, and the like.
"Aminosulfonyl" means a -SO2NRR' radical 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 te7t-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.
"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 -C(O)Ra where Ra is alkyl, and R' is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and 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 -C(O)NRR radical where each R is independently hydrogen or alkyl as defined above, e.g., -C(O)NH2, methylaminocarbonyl, 2-dimethylaminocarbonyl, and the like.
"Acyl" means a -C(O)R radical where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, as defined herein, e.g., acetyl, benzoyl, and the like. " Acyloxy" means a -OC(O)R 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 -NHC(O)R 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 polycyclic 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 -0-R radical where R is aralkyl as defined above, e.g., benzyloxy, and the like.
"Aryloxyalkyl" means a -(alkylene)-OR radical where R is aryl as defined above, e.g., phenoxymethyl, phenoxyethyl, and the like.
"Aralkenyl" means a -(alkenylene)-R radical where R is aryl as defined above.
" Aralkynyl" means a -(alkynylene)-R radical where R is aryl as defined above.
"Cycloalkyl" means a mono or bicyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.
"Cycloalkylalkyl" means a -(alkylene)-R radical where R is cycloalkyl as defined above; e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl, and the like.
"Cycloalkenyl means a cyclic monovalent hydrocarbon radical of three to ten carbon atoms containing one or two double bond(s), e.g., cyclopentenyl, cyclohexenyl, 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.
"Disubstituted amino" means a -NRcRd radical where Rc and Rd are independently selected from alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, defined herein, e.g., dimethylamino, diethylamino, methylphenylamino, 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., -CH2Cl, -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-trifluoroethyloxyinethyl, 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, l-(hydroxymethyl)-2- hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and l-(hydroxymethyl)-2-hydroxyethyl.
"Hydroxyalkoxy" or "hydroxyalkyloxy" means a -OR radical where R is hydroxyalkyl as defined above.
"Hydroxyalkoxyalkyl" or "hydroxyalkyloxyalkyl"means a -(alkylene)-OR radical where R is hydroxyalkyl as defined above e.g., hydroxyethoxymethyl, hydroxymethoxyethyl, and the like.
"Heterocycloalkyl" means a saturated or unsaturated monovalent cyclic group of 3 to 10 ring atoms in which one or two ring atoms are heteroatom selected from N, O, and S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C where one or two ring carbon atoms can optionally be replaced by a -C(O)- group. The heterocycloalkyl may be fused to a phenyl or heteroaryl ring. More specifically the term heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, tetrahydroquinolinyl, thiomorpholino, or l,3-dioxo-l,3-dihydroisoindol-2-yl, and the like.
Heterocycloalkyloxy" means a -OR 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 -OR radical where R is heterocycloalkylalkyl as defined above e.g., tetrahydropyranylmethyoxy, morpholin-4-ylethoxy, and the like.
" Heterocycloalkyloxyalkyl" means a -(alkylene)-R radical where R is heterocycloalkyloxy as defined above.
"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, and 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.
"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.
"Heterόaryloxyalkyl" means a -(alkylene)-R radical where R is heteroaryloxy as defined above.
"Heteroaralkenyl" means a -(alkenylene)-R radical where R is heteroaryl as defined above.
"Heteroaralkynyl" means a -(alkynylene)-R radical where R is heteroaryl as defined above.
"Methylenedioxy" means -0-CH2-O-.
"Monosubstituted amino" means a -NHR' radical where R is alkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, or heteroaralkyl defined herein, e.g., methylamino, ethylamino, phenylamino, and the like.
"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.
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, niethanesulfonic 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, 3,3,3-trimethylpropionic 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.
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., N,N-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. 1999, 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. 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 through asymmetric synthesis or 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.
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.
"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.
Representative compounds of Formula (Ia) where R1 -R10 groups are as depicted in the structure below and R12 is as defined in Table 1 below are:
Figure imgf000015_0001
Figure imgf000015_0002
Preferred Embodiments
While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (Ia), (Ib), (Ic) and (Id) are preferred. For example: (A) A preferred group of compounds of Formulae (Ia), (Ib), (Ic) and (Id) is that wherein: n is 1;
Y is alkylene;
R1 is hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy;
R2 is alkyl; or R2 together with R3 forms -(CH2)qC(RaRb)X- or -XC(RaRb)-(CH2)q- where q is 1-2, X is -NR- (where R is hydrogen or alkyl), -0-, or -S-, and Ra and Rb are independently hydrogen or alkyl or Ra and Rb together with the carbon atom to which they are attached form (=0);
R7 is alkyl; or R7 together with R6 forms -(CH2)qC(RaRb)X- or -XC(RaRb)-(CH2)q- where q is 1-2, X is -NR- (where R is hydrogen or alkyl), -0-, or -S-, and Ra and Rb are independently hydrogen or alkyl or Ra and Rb together with the carbon atom to which they are attached form O=O); provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)qC(RaRb)X- or -XC(RaRb)-(CH2)q-; preferably both R2 together with R3 and R7 together with R6 form -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Raand Rb are independently hydrogen or alkyl;
R3 and R6 are defined as above or are independently hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy;
R4 and R5 are independently hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy;
R8 is hydrogen, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy;
R9 is hydrogen;
R10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the aromatic or alicyclic ring in R1, R2, R3, R4, R5, R6, R7, R8, and R10, either alone or as part of another group within the scope of R1, R2, R3, R4, R5, R6, R7, R8, and R10, is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and hydroxy provided that the ring formed by R2 together with R3 or R7 together with R6 is not substituted;
R11 is cyano, -SCN, hydroxy, alkoxy, or halo; and
R12 is as defined in the Summary of the Invention.
(1) Within the above preferred group (A), a more preferred group of compounds is a compound of Formula (Ia) wherein:
Y is methylene;
R1, R3, R4, R5, and R6 are independently hydroxy or alkoxy;
R2 is alkyl and R3 is as defined above; or R2 together with R3 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Ra and Rb are independently hydrogen or alkyl;
R7 is alkyl and R6 is as defined above; or R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Ra and Rb are independently hydrogen or alkyl; provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)- (CH2)-; preferably both R2 together with R3 and R7 together with R6 form -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Ra and Rb are independently hydrogen or alkyl;
R8 is hydrogen, hydroxy, or alkoxy;
R9 is hydrogen;
R10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the aromatic or alicyclic ring in R10, either alone or as part of another group within the scope of R10, is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and hydroxy; and
R11 is cyano, -SCN, hydroxy, alkoxy, or halo.
Even more preferably, a compound of Formula I(a) wherein:
Y is methylene;
R1, R3, and R6 are alkoxy;
R2 is alkyl and R3 is as defined above; or R2 together with R3 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Raand Rb are independently hydrogen or alkyl;
R7 is alkyl and R6 is as defined above; or R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Ra and Rb are independently hydrogen or alkyl; provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)-
R4 and R5 are hydroxy;
R8 is hydrogen or alkoxy;
R9 is hydrogen; and
R10 is alkyl.
Particularly preferably, a compound of Formula (Ia) wherein:
R1, R3, R6, and R8 are methoxy;
R4 and R5 are hydroxy;
R2 is methyl and R3 is as defined above; or R2 together with R3 forms -(CH2)C(CH3)2O-;
R7 is methyl and R6 is as defined above; or R7 together with R6 forms -(CH2)C(CH3)2O-; provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)C(CH3)2O-; more preferably both R2 together with R3 and R7 together with R6 form - (CH2)C(CHs)2O-;
R9 is hydrogen;
R10 is methyl; and
R11 is cyano, hydroxy, or halo. (2) Within the above preferred group (A), a more preferred group of compounds is a compound of Formula (Ib) or (Ic) wherein:
Y is methylene;
R1, R3, R4, R5, and R6 are independently hydroxy or alkoxy;
R2 is alkyl and R3 is as defined above; or R2 together with R3 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Ra and Rb are independently hydrogen or alkyl;
R7 is alkyl and R6 is as defined above; or R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Raand Rbare independently hydrogen or alkyl; provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)- (CH2)-; preferably both R2 together with R3 and R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Ra and Rb are independently hydrogen or alkyl;
R8 is hydrogen, hydroxy, or alkoxy;
R9 is hydrogen;
R10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the aromatic or alicyclic ring in R10, either alone or as part of another group within the scope of R10, is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and hydroxy; and
R11 is cyano, -SCN, hydroxy, alkoxy, or halo.
Even more preferably, a compound of Formula (Ib) or (Ic) wherein:
Y is methylene;
R1, R3, and R6 are alkoxy;
R2 is alkyl and R3 is as defined above; or R2 together with R3 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Raand Rb are independently hydrogen or alkyl;
R7 is alkyl and R6 is as defined above; or R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Ra and Rb are independently hydrogen or alkyl; provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)- (CH2)-;
R4 and R5 are hydroxy;
R8 is hydrogen or alkoxy;
R9 is hydrogen; and
R10 is alkyl.
Particularly preferably, a compound of Formula I(b) or I(c) wherein:
R1, R3, R6, and R8 are methoxy; R4 and R5 are hydroxy;
R2 is methyl and R3 is as defined above; or R2 together with R3 forms -(CH2)C(CH3)2O-;
R7 is methyl and R6 is as defined above; or R7 together with R6 forms -(CH2)C(CH3)2O-; provided that at least one of R2 together with R3 and R7 together with R6 forms - (CH2)C(CEb)2O-; more preferably both R2 together with R3 and R7 together with R6 forms - (CH2)C(CHs)2O-;
R9 is hydrogen;
R10 is methyl; and
R11 is cyano, hydroxy, or halo.
(3) Within the above preferred group (A), a more preferred group of compounds is a compound of Formula (Id) wherein:
Y is methylene;
R3 and R6 are independently hydroxy or alkoxy;
R2 is alkyl and R3 is as defined above; or R2 together with R3 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Ra and Rb are independently hydrogen or alkyl;
R7 is alkyl and R6 is as defined above; or R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Ra and Rb are independently hydrogen or alkyl; provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)- (CH2)-; preferably both R2 together with R3 and R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Ra and Rb are independently hydrogen or alkyl;
R9 is hydrogen;
R10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the aromatic or alicyclic ring in R10, either alone or as part of another group within the scope of R10, is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and hydroxy; and
R11 is cyano, -SCN, hydroxy, alkoxy, or halo.
Even more preferably, a compound of Formula (Id) wherein:
Y is methylene;
R3 and R6 are alkoxy;
R2 is alkyl and R3 is as defined above; or R2 together with R3 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Raand Rb are independently hydrogen or alkyl;
R7 is alkyl and R6 is as defined above; or R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Raand Rb are independently hydrogen or alkyl; provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)- (CH2)-;
R8 is hydrogen or alkoxy;
R9 is hydrogen; and
R10 is alkyl.
Particularly preferably, a compound of Formula I(d) wherein:
R3 and R6 are -OCH3;
R2 is methyl and R3 is as defined above; or R2 together with R3 foπns -(CH2)C(CH3)2O-;
R7 is methyl and R6 is as defined above; or R7 together with R6 forms -(CH2)C(CH3)2O-; provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)-; preferably both R2 together with R3 and R7 together with R6 forms - (CH2)C(CHs)2O-; more preferably both R2 together with R3 and R7 together with R6 forms -(CH2)C(CHs)2O-;
R9 is hydrogen;
R10 is methyl; and
R11 is cyano, hydroxy, or halo.
(i) Within the above group (A) and A(I -3) and the more preferred groups contained therein, a particularly preferred group of compounds is that wherein R12 is:
-NHC(O)R27 where R27 is cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or heteroaralkenyl wherein the aromatic or alicyclic ring, either alone or as part of another group, in R27 is optionally substituted with one, two, or three Rc independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyloxy, heterocycloalkyloxyalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, -(alkylene)nl-S(O)n2- R50 (where nl is O or 1, n2 is 0-2, and R50 is alkyl, haloalkyl, amino, alkylamino, dialkylamino, aryl, or heteroaryl), -(alkylene)n3-NHSO2-R51 (where n3 is O or 1 and R51 is alkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkyl), -(alkylene)n4-NHC(O)R52 (where n4 is O or 1 and R52 is alkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkyl), and -(alkylene)n5-C(O)NR53R54 (where n5 is O or 1 and R53 is alkyl, haloalkyl, hydroxy, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl and R54 is hydrogen or alkyl) and: further wherein the aromatic or alicyclic ring, either alone or part of another group, in Rc is optionally substituted with one, two, or three Rd independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonyl, and cyano.
Preferably, R27 is phenyl or heteroaryl, more preferably pyridinyl, pyrazinyl, benzofuranyl, indolyl, benzothiophenyl, quinolinyl, or isoquinolinyl optionally substituted with one, two, or three Rc independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyloxy, heterocycloalkyloxyalkyl, or heterocycloalkylalkyl, and heterocycloalkylalkyloxy and further wherein the aromatic or alicyclic ring, either alone or part of another group, in Rc is optionally substituted with one, two, or three Rd independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonyl, and cyano.
Preferably, R27 is phenyl or heteroaryl, more preferably pyridinyl, pyrazinyl, benzofuranyl, indolyl, benzothiophenyl, quinolinyl, or isoquinolinyl optionally substituted with one, two, or three Rc independently selected from methyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methylamino, dimethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl, diethylaminomethyl, diethylaminoethyl, dimethylaminoethyl, dimethylaminoethoxy, diethylaminoethoxy, hydroxy, hydroxymethyl, hydroxyethoxy, methoxy, phenyl, pyridinyloxy, tetrahydropyranyloxy, piperidinyloxy, morpholinylethoxy, piperidinylethoxy, piperazinylethoxy, pyrrolidinylethoxy, l-methylpiperidin-4-yloxy, 1- ethylpiperidin-4-yloxy, 4-methyl-piperazin-l-ylethoxy, and 4-(2-hydroxyethyl)piperazin-l- ylethoxy.
(ii) Within the above group (A) and A(l-3) and the more preferred groups contained therein, another particularly preferred group of compounds is that wherein R12 is heterocycloalkyl wherein the heterocycloalkyl is a 5 or 6 membered ring containing 3 or 4 carbon ring atoms and one or two heteroatom(s) selected from N, O, and S(O)2; where one or two carbon(s) is optionally replaced by a -C(O)- group; and where the 5 or 6 membered ring is optionally fused to a phenyl or heteroaryl ring. Heterocycloalkyl is optionally substituted (at either ring when fused) with one, two, or three Rc independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyloxy, heterocycloalkyloxyalkyl, heterocycloalkyl-alkyl, and heterocycloalkylalkyloxy. Preferably the heterocycloalkyl ring is l,3-dioxo-l,3- dihydroisoindol-2-yl linked to Y via the nitrogen ring atom and is optionally substituted on the phenyl part of the ring with one or two Rc independently selected from methyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methylamino, dimethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl, diethylaminomethyl, diethylaminoethyl, dimethylaminoethyl, dimethylaminoethoxy, diethylaminoethoxy, hydroxy, hydroxymethyl, hydroxyethoxy, methoxy, phenyl, pyridinyloxy, tetrahydropyranyloxy, piperidinyloxy, morpholinylethoxy, piperidinylethoxy, piperazinylethoxy, pyrrolidinylethoxy, 1- methylpiperidin-4-yloxy, l-ethylpiperidin-4-yloxy, 4-methylpiperazin-l-ylethoxy, and 4-(2- hydroxyethyl)piperazin- 1 -ylethoxy .
(iii) Within the above group (A) and A(l-3) and the more preferred groups contained therein, yet another particularly preferred group of compounds is that wherein R12 is:
-OC(O)R41 where R41 is cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or heteroaralkenyl optionally substituted with one, two, or three Rc independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyloxy, heterocycloalkyloxyalkyl, heterocycloalkylalkyl, and heterocycloalkylalkyloxy; and further wherein the aromatic or alicyclic ring, either alone or part of another group, in Rc is optionally substituted with one, two, or three Rd independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonyl, and cyano.
Preferably, R41 is phenyl, phenyl-CH=CH-, or heteroaryl, more preferably pyridinyl, pyrazinyl, benzofuranyl, indolyl, indolyl, benzothiophenyl, quinolinyl, or isoquinolinyl optionally substituted with one, two, or three Rc independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyloxy, heterocycloalkyloxyalkyl, heterocycloalkylalkyl, and heterocycloalkylalkyloxy; and fUrther wherein the aromatic or alicyclic ring, either alone or part of another group, in R0 is optionally substituted with one, two, or three Rd independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonyl, and cyano.
Preferably, R41 is phenyl, phenyl-CH=CH-, or heteroaryl, more preferably pyridinyl, pyrazinyl, benzofuranyl, indolyl, indolyl, benzothiophenyl, quinolinyl, or isoquinolinyl optionally substituted with one, two, or three Rc independently selected from methyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methylamino, dimethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl, diethylaminomethyl, diethylaminoethyl, dimethylaminoethyl, dimethylaminoethoxy, diethylaminoethoxy, hydroxy, hydroxymethyl, hydroxyethoxy, methoxy, phenyl, pyridinyloxy, tetrahydropyranyloxy, piperidinyloxy, morpholinylethoxy, piperidinylethoxy, piperazinylethoxy, pyrrolidinylethoxy, 1- methylpiperidin-4-yloxy, l-ethylpiperidin-4-yloxy, 4-methylpiperazin-l-ylethoxy, and 4-(2- hydroxyethyl)piperazin-l-ylethoxy.
(iv) Within the above group (A) and A(I -3) and the more preferred groups contained therein, yet another particularly preferred group of compounds is that wherein R12 is hydroxy.
Within the above groups (A), A(I), A(i-iv), A(l)(i-iv), A(2)(i-iv), and A(3)(i-iv), and the preferred groups contained therein a particularly preferred group of compound is that wherein R11 is cyano.
Within the above groups (A), A(I), A(i-iv), A(I)(Hv), A(2)(i-iv), and A(3)(i-iv), and the preferred groups contained therein a particularly preferred group of compound is that wherein R11 is hydroxy.
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 0C to about 1500C, more preferably from about 00C to about 1250C and most preferably at about room (or ambient) temperature, e.g., about 200C. Unless specified to the contrary, the reactions described herein take place under inert gas, such as nitrogen or argon.
Compounds of Formula (Ia) where R1, R2, R3, R4, R5, R6, R7, R8, R10, and R12 groups are as described in the Summary of the Invention, R9 is hydrogen, and R11 is cyano can be prepared by the procedure illustrated and described in Scheme A below.
Scheme A
Figure imgf000025_0001
Figure imgf000025_0002
23 where Rz is not R12 © or (I) where R! MS R12
Reaction of an aldehyde of formula 10 where R1, R2, R3, and R4 are as defined in the Summary of the Invention or a suitably protected derivative thereof and where 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 17 where R5, R6, R7, and R8 are as defined in the Summary of the Invention or a suitably protected derivative thereof provides a compound of formula 18. The reaction is carried in the presence of anhydrous 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 drying reagent such as magnesium sulfate, sodium sulfate, and the like.
Installation of group R10 as defined in the Summary of the Invention where R10 is other than hydrogen can be carried out on a compound of formula 18 under alkylation or reductive amination reaction conditions to provide a compound of formula 19. In case of reductive amination, the reaction is carried out with a suitable aldehyde and a suitable reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. IfR1, R2, R3, and/or R4 is a protected group, the protecting group can be optionally be removed in compound 19 to provide a compound of formula 20 where R1, R2, R3, and R4 are as defined in the Summary of the Inventon.
Reaction of compound 20 with an aldehyde compound of formula 21 where n and Y are as defined in the Summary of the Invention and Rz is R12 as defined in the Summary of the invention or a precursor group to R12 provides a compound of formula 22. The reaction is carried out in the presence of a suitable drying 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 lithium bromide or a suitable acid such as hydrochloric acid, trifluoroacetic acid, and the like.
Compounds of formula 21 such as 2-formylacetic acid methyl ester, Fmoc-glycinal, 3- (Fmoc-amino)-l-propanal, Fmoc-L-β-homoproline, hexanal, 4-pentenal, 2-octynal, benzaldehyde, α-methylcinnamaldehyde, isonicotinaldehyde, β-(4-pyridyl)acrolein, morpholine- 4-yl-acetaldehyde, cyclopropanecarboxaldehyde and cyclohexylacetaldehyde are commercially available. Others can be prepared from commercially available starting materials by methods well known in the art.
Reaction of a compound of formula 22 in the presence of a suitable Lewis acid such as anhydrous 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 (I) where Rz is R12 or a compound of formula 23 where Rz is a precursor group to R12 such as protected amino or hydroxy group. Optionally, the reaction is carried out in the presence of an external cyanide source such as trimethylsilyl cyanide, sodium cyanide, potassium cyanide and the like.
The Rz group in 23 is then converted to R12 as defined in the Summary of the Invention to provide a compound of Formula (Ia). For example wherein Rz is a protected amino or hydroxy group, removal of the protecting group provides a compound of Formula (Ia) where R12 is amino or hydroxy. The reaction conditions employed for removal of the protecting group depend on the nature of the protecting group. For example, if Rz is an amino group protected with Fmoc, it is deprotected under basic reaction conditions. Suitable bases are 1,8- 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 (Ia) can be converted to other compounds of Formula (Ia) by methods well known in the art. For example:
(i) A compound of Formula (Ia) where R12 is -NHC(O)R27 where R27 is as defined in the Summary of the Invention can be readily prepared by reacting a corresponding compound of Formula (Ia) where R12 is amino with an acid halide of formula R27C(O)X where X is halo or an acid of formula R27C(O)OH. If acid halide is utilized, the reaction is carried out in the presence of a suitable base such as triethylamine, N,N-diethylaniline, diisopropylethylamine and the like in a suitable reaction solvents 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 corresponding acids with a halogenating agent such as oxalyl chloride, thionyl chloride, phosphorous oxy chloride, 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 (EDC'HCl), 1,3-dicyclohexylcarbodiimide (DCC), or benzotriazol-1- yloxyltris(dimethylamino)phosphonium hexafluorophosphate (BOP), optionally in the presence of 1-hydroxybenzotriazole hydrate (HOBt1H2O) in a suitable organic solvents such as DMF and the like, in the presence of a suitable base such as N.N-diethylaniline and the like. The acids and acid halides 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 (Ia) where R12 is -NHSO2R32 can be prepared by reacting a compound of Formula (Ia) where R12 is amino with a sulfonylating agent of formula R32SO2L where L is a leaving group such as halo under reaction conditions described for acid halides in (i) above.
(iii) A compound of Formula (Ia) where R12 is -NHC(=NR23)R24 can be prepared by reacting a compound of Formula (Ia) where R12 is amino with an amidine forming agent such as a thioimidic acid methyl ester of formula R24C(=NR23)SCH3, which can be 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 (Ia) where R12 is -NHC(=NH)NHR25 can be prepared by reacting a compound of Formula (Ia) where R12 is amino with a guanidine forming agent such as pyrazole-carboxamidine, which are be commercially available or can be prepared by methods known in the art.
(v) A compound of Formula (Ia) where R12 is -NR33R34 and -NR35CHXR36 can be prepared by reacting a compound of Formula (Ia) where R12 is amino with a suitable alkylating agent by methods known in the art. (vi) A compound of Formula (Ia) where R12 is -OR37 can be prepared first by converting the amino group in a compound of Formula (I) where R12 is amino to hydroxy through diazo functionality and alkylation of the resulting hydroxy group with suitable alkylating reagents under conditions well known in the art. Alternatively, a compound of Formula (Ia) where R12 is -OR37 can be prepared reacting compound 5 with a hydroxy-protected hydroxyacetaldehyde of formula CH2(CHO)OPG such as tert-butyldimethylsilyloxyacetaldehyde, followed by removal of the hydroxy protecting group to provide a compound of Formula (Ia) where R12 is hydroxymethyl. The hydroxy group can then be functionalized as described above, (vii) A compound of Formula (Ia) where R12 is -C(O)OR30 and -C(O)NR28R29 can be prepared by reacting 5 with 2-formylacetic acid methyl ester, followed by removal of the carboxy protecting group to provide a compound of Formula (I) where R12 is carboxymethyl. The carboxy group can then be converted to other compounds of Formula (Ia) where R12 is - C(O)OR30 and -C(O)NR28R29 by methods well known in the art.
(viii) A compound of Formula (Ia) where R12 is -S(O)mlR38 can be prepared by reacting a compound of Formula (Ia) where R12 is hydroxy with^-toluenesulfonyl chloride to form a leaving group such as toluenesulfonate and then reacting it with a sulfur nucleophile of formula R38SH to give a compound of Formula (Ia) where ml is O. Oxidation of the sulfur with a suitable oxidizing agent such as w-chloroperbenzoic acid, and the like can provide corresponding a compound of Formula (Ia) where ml is 1 or 2.
A compound of Formula (Ia) where R11 is hydroxy or methoxy can be prepared from a corresponding compound of Formula (Ia) 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.
(ix) A compound of Formula (Ia) can be converted to a corresponding compound of Formula (Ib), (Ic) or (Id) by treating it with a suitable oxidizing agent such as 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone, and the like. If a mono quinone compound of the Invention is desired i.e., a compound of Formula (Ib) or (Ic) and compound (Ia) contains a phenolic group in the both the aromatic rings, then the phenolic group in aromatic ring that is not being oxidized has to be selectively protected with a suitable protecting group such as MOM prior to oxidation step, followed by removal of the hydroxy protecting group.
Compounds of formula 10 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 10, preferably a specific enantiomerically pure compound of formula 10, can also be prepared by the procedure illustrated and described in Scheme B below.
Scheme B
Figure imgf000029_0001
Bromination reaction on a compound of formula 1 where R1, R2, R3, and R4 are defined as in the Summary of the Invention or a suitably protected derivative thereof provides a compound of formula 2. Compound 1 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 1 are either commercially available or can be prepared from commercially available starting material by methods known in the art.
Compound 2 is converted to a compound of formula 3 by treating 2 with an organometallic reagent such as alkyllithium e.g., tert-butyllithium, rø-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).
Wittig olefination reaction on a compound of formula 3 with a compound of phosphonate compound of formula 4 where PG1 is alkyl, preferably methyl and PG is a suitable amino acid protecting group such as Fmoc, Cbz, and the like, is carried out in the presence of a suitable base such as sodium hydride, n-butyllithium, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like provides a compound of formula 5. 45880
Hydrogenation of 5 in the presence of a suitable catalyst, preferably a chiral catalyst such as Et-DuPHOS-Rh(I), BINAP-RU(OAC)2, (+)-l,2-bis((25(, 5S)-2,5- diethylphospholano)benzene(cyclooctadiene) rhodium(I) trifluoromethanesulfonate, and the like, provides a compound of formula 6. Conversion of a compound of formula 6 to a compound of formula 7 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. Compound 7 is then converted to a compound of formula 10 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 are not limited to Dess-Martin periodinane, tetrapropylammonium perruthenate. In this route, the amino acid protecting group in compound 7 is the same as in compound 10. If however, a different amino acid protecting group than the one present in compound 7 is desired in compound 10, deprotection followed by protection of the amino group in compound 7 provides a compound 9 where PG1 is different than PG. Compound 9 is then converted to a compound of formula 10 as described above.
Compounds of formula 10 where R1 and R3 are methoxy and R2 is hydrogen or methyl can be prepared from commercially available 2,4-dimethoxybenzaldehyde and 2,4-dimethoxy-3- methylbenzaldehyde respectively. Compound of formula 10 where R1 is nitro, R4 is hydroxy or alkyl, and R2 and R3 together with the carbon atoms to which they are attached independently form -(CH2)C(CH3)2O- can be prepared by nitration of 2,3-dihydro-2,2-dimethyl-7- benzofuranol or its alkoxy derivative with nitric acid in nitromethane under the reaction conditions described in Kemp, D. S., et al. J. Org. Chem. 1986, 51, 1829-1838. Reduction of the nitro group provides the amino group that can then be converted to mono or disubstituted amino groups under conditions well known in the art.
Alternatively, a compound of formula 10 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 10, preferably a specific enantiomerically pure compound of formula 1, can also be prepared by the procedure illustrated and described in Scheme C below. 80
Scheme C
Figure imgf000031_0001
Reduction of the aldehyde group in 3 with a suitable reducing agent such as sodium borohydride, and the like, provides the corresponding alcohol compound of formula 11. Compound 11 is then converted to the corresponding bromide compound of formula 12 using a suitable bromination reagent such as bromine in the presence of a suitable oxo-phile such as triphenylphosphine .
Compound 12 is then converted to a compound of formula 14, preferably enantiomerically pure compound, by stereoselective alkylation reaction between compound 12 and a compound of formula 13 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 aϊ. 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 anhydrous lithium chloride.
Removal of amino protecting group R* from 14 with conversion of the amide functionality to alcohol functionality provides a compound of formula 8 which is then converted to a compound of formula 10 as described in Scheme B above. A compound of formula 17 can be prepared following the procedures illustrated and described in Scheme D below.
Scheme D
Figure imgf000032_0001
Treatment of a compound of formula 10 with hydrogen cyanide, acetone cyanohydrin, and the like provides a compound of formula 15. Treatment of 15 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, CH2Cl2, and the like, provides a compound of formula 16. Removal of the amino protecting group in 16 provides a compound of formula 17. 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- diazabicyclo[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.
The compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the 005/045880
compound of Formula (I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of Formula (I) are described below.
As stated previously, the compounds of this invention 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, DNA methyl tranferase inhibitors, and other angiogenesis inhibitors. The compound of the present invention compounds are particularly useful when administered 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, 45880
6-(o-chloroacetylcarbonyl)-fumagillol, thalidomide, angiostatin, troponin- 1, and an antibody to VEGF.
Preferred estrogen receptor modulators are tamoxifen and raloxifene.
"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, LYl 17081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl- 1 -oxopropoxy-4-methyl-2-[4-[2-(l - piperidinyl)ethoxy]phenyl]-2H-l-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'- dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SΗ646.
"Androgen receptor modulators" refers to compounds which 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 which 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 myosis, 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 tosylate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2- methyl-pyridine) platinum, benzylguanine, glufosfamide, GPXlOO, (trans, trans, trans)-bis-mu- (hexane-l,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]-tetrachloride, diarizidinylspermine, arsenic trioxide, l-(ll-dodecylamino-10-hydroxyundecyl)-3,7- dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3'-deamino-3'-morpholino-13-deoxo-10- US2005/045880
hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755, and 4-demethoxy-3- deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin {see WO 00/50032).
Examples of microtubulin inhibitors include paclitaxel, vindesine sulfate, 3',4'- didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPRl 09881, BMS184476, 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-te/^-butylaniide, TDX258, and BMS 188797.
Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-O-exo-benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5- nitropyrazolo[3 ,4,5 -kl] acridine-2-(6H)propanamine, 1 -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,15Η)dione, lurtotecan, 7-[2-(N-isopropylamino)-ethyl]-(20S)camptothecin, BΝP1350, BNPIIlOO, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, T- dimethylamino-2'-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6- dimethyl-6H-pyrido[4,3-b]carbazole-l-carboxamide, asulacrine, (5a, 5aB, 8aa,9b)-9-[2-[N-[2- (dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]- 5,5a,6,8,8a,9-hexohydrofuro(3',4': 6,7)colchic(2,3-d)-l,3-dioxol-6-one, 2,3-(methylenedioxy)- 5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium, 6,9-bis[(2-aminoethyl)- amino]benzo[g]isoquinoline-5,10-dione, 5-(3-aminopropylamino)-7,10-dihydroxy-2-(2- hydroxyethylaminomethyl)-6H-pyrazolo[4,5,l-de]acridin-6-one, N-[I- [2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide, N-(2- (dimethylamino)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, Ν6-[4-deoxy-4-[Ν2-[2(E),4(E)- tetradecadienoyllglycylaminol-L-glycero-B-L-manno-heptopyranosylJ-adenine, aplidine, ecteinascidin, 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, 45880
alanosine, 1 l-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-l,l 1-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-arabino fliranosyl 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, for example).
"HMG-CoA reductase inhibitors" refers to inhibitors of 3-hydroxy-3-methylglutaryl- CoA reductase. Compounds which have inhibitory activity for HMG-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 "HMG- CoA reductase inhibitor" and "inhibitor of HMG-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 HMG-CoA reductase inhibitor, and butyrate, an inducer of apoptosis in the Lewis lung carcinoma model in mice showed potentiating antitumor effects
Examples of HMG-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; 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784; 4,820,850; 4,916,239), pravastatin (PRAVACHOL®; 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; 5,356,896), atorvastatin (LIPITOR®; see U.S. Pat. Nos. 5,273,995; 4,681,893; 5,489,691; 5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL®; see U.S. Pat. No. 5,177,080). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the methods of the present invention 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 HMG-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 HMG- CoA reductase inhibitory activity, and colchicine the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
In HMG-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 45880
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.
Herein, the term "pharmaceutically acceptable salts" with respect to the HMG-CoA reductase inhibitor shall mean non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,Ν'- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, l-p-chlorobenzyl-2-pyrrolidine-r-yl-methylbenzimidazole, diethylamine, piperazine, and tris(hydroxymethyl) aminomethane. Further examples of salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium hydroxy, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, hydroxy, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.
Ester derivatives of the described HMG-CoA reductase inhibitor compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
"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-protein 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-chloropheny I)(I -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)-l-methyl- 2(lH)-quinolinone, 5(S)-«-butyl-l-(2,3-dimethylphenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethy l]-2-piperazinone, (S)-l-(3-chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl]-5-[2-(ethanesulfonyl)-methyl)-2-piperazinone, 5(S)-n-butyl-l-(2- 45880
methylphenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2 -piperazinone, l-(3-chlorophenyl) -4-[l-(4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]-2-piperazinone, l~(2,2-diphenylethyl)-3- [N-( 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -ylethyl)carbamoyl]piperidine, 4- { 5 -[4-hydroxymethyl-4- (4-chloropyridin-2-ylmethyl)-piperidine-l-ylmethyl]-2-methylimidazol-l-ylmethyl}benzonitrile, 4- { 5-[4-hydroxymethyl-4-(3 -chlorobenzyl)-piperidine- 1 -ylmethyl] -2-methylimidazol- 1 - ylmethyl}benzonitrile, 4-{3-[4-(2-oxo-2H-pyridin-l-yl)benzyl]-3H-imidazol-4- ylmethyl}benzonitrile, 4-{3-[4-(5-chloro-2-oxo-2H-[l,2']bipyridin-5'-ylmethyl]-3H-imidazol-4- ylmethyljbenzonitrile, 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-l 9-oxo-5Η, 17H-6, 10: 12, 16-dimetheno- lH-imidazo[4,3- c] [ 1 , 11 ,4]dioxa-azacyclononadecine-9-carbonitrile, (+)-l 9,20-dihydro- 19-oxo-5H-l 8,21 -ethano- 12,14-etheno-6, 10-metheno-22H-benzo [d] imidazo[4,3 -k] [ 1 ,6,9, 12] -oxatriaza-cyclooctadecine- 9-carbonitrile, 19,20-dihydro- 19-oxo-5Η, 17H- 18,21 -ethano-6, 10: 12, 16-dimetheno-22H- imidazo[3,4-h][l,8,l l,14]oxatriazacyclo-eicosine-9-carbonitrile, and (+)-19,20-dihydro-3- methyl- 19-oxo-5H- 18,21 -ethano- 12, 14-etheno-6, 10-metheno-22H-benzo[d]imidazo[4,3 - k] [ 1 ,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. 0 618 221, 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 ΗIV protease inhibitors include amprenavir, abacavir, CGP-73547, CGP- 61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232, 632. Examples of reverse transcriptase inhibitors include delaviridine, efavirenz, 005/045880
GS-840, HB Y097, lamivudine, nevirapine, AZT, 3TC, ddC, and ddl. It has been reported (Nat. Med.;S(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 FIt-I (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-infiammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxygenase-2 inhibitors like celecoxib, valecoxib, and rofecoxib (PNAS, Vol. 89, p. 7384 (1992); JNC/, 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. MoI. 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. MoI. Med., Vol. 2, p. 715 (1998); J Biol Chem., Vol. 274, p. 9116 (1999)), carboxyamidotriazole, combretastatin A-4, squalamine, 6-0-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. For purposes of this specification an NSAID is potent if it possess an IC50 for the inhibition of COX-2 of 1 μM or less as measured by the cell or microsomal assay known in the art.
The invention also encompasses combinations with NSAID's which are selective COX-2 inhibitors. For purposes of this specification NSAID's which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting COX-2 over COX-I of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-I evaluated by the cell or microsomal assay disclosed hereinunder. Such compounds include, but are not limited to those disclosed in U.S. Pat. No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan. 19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat. No. 6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944, issued Apr. 25, 1995, U.S. Pat. No. 5,436,265, issued JuI. 25, 1995, U.S. Pat. No. 5,536,752, issued JuI. 16, 1996, U.S. Pat. No. 5,550,142, issued Aug. 27, 1996, U.S. Pat. No. 5,604,260, issued Feb. 18, 1997, U.S. Pat. No. 5,698,584, issued Dec. 16,
1997, U.S. Pat. No. 5,710,140, issued Jan. 20, 1998, WO 94/15932, published JuI. 21, 1994, U.S. Pat. No. 5,344,991, issued Jun. 6, 1994, U.S. Pat. No. 5,134,142, issued JuI. 28, 1992, U.S. Pat. No. 5,380,738, issued Jan. 10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995, U.S. Pat. No. 5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272, issued May 27, 1997, and U.S. Pat. No. 5,932,598, issued Aug. 3, 1999, all of which are hereby incorporated by reference. Other examples of specific inhibitors of COX-2 include those disclosed in U.S. Patent 6,313, 138 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, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan. 19, 1999, and U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, all of which are herein incorporated by reference.
Compounds which are described as 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: WO 94/15932, published JuI. 21, 1994, U.S. Pat. No. 5,344,991, issued Jun. 6, 1994, U.S. Pat. No. 5,134,142, issued JuI. 28, 1992, U.S. Pat. No. 5,380,738, issued Jan. 10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995, U.S. Pat. No. 5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272, issued May 27, 1997, and U.S. Pat. No. 5,932,598, issued Aug. 3, 1999.
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. No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan. 19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat. No. 6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944, issued Apr. 25, 1995, U.S. Pat. No. 5,436,265, issued JuI. 25, 1995, U.S. Pat. No. 5,536,752, issued JuI. 16, 1996, U.S. Pat. No. 5,550,142, issued Aug. 27, 1996, U.S. Pat. No. 5,604,260, issued Feb. 18, 1997, U.S. Pat. No. 5,698,584, issued Dec. 16, 1997, and U.S. Pat. No. 5,710,140, issued Jan. 20, 1998.
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, acetyldinaline, 5-amino-l-[[3,5-dichloro-4-(4- chlorobenzoyl)phenyl] -methyl] - IH- 1 ,2, 3 -triazole-4-carboxamide, CM 101, 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 blockers" 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 αvβ5 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 αvβ6;αvβ8, ociβi, α2βi, αsβt, α6βl5 and α6β4 integrins. The term also refers to antagonists of any combination of αvβ3, αvβs, αvβ6, αvβs, Ci1 βl5 α2β1; αsβu α6βi and α6β4 integrins.
Some specific examples of tyrosine kinase inhibitors include N-(trifluoromethyl-phenyl)- 5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)-indolin-2-one, 17- (allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenyl-amino)-7-methoxy-6-[3- (4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-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-l-one, SΗ268, genistein, ST1571, CEP2563, 4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo [2,3- djpyrimidinemethane sulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, SUl 1248, STI571A, N-4- chlorophenyl-4-(4-pyridylmethyl)- 1 -phthalazinamine, and EMD 121974.
The instant compounds are also useful, alone or 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 compounds can serve to inhibit metastasis, alone or in combination with GP Ilb/IIIa) antagonists. Examples of other fibrinogen receptor antagonists include abciximab, eptifibatide, sibrafiban, lamifiban, lotrafiban, cromofiban, and CT50352.
"DΝA methyltransferase inhibitor" refers to compounds which inhibit the methylation of the DΝA base cytosine at the C-5 position of that base by the DΝA methyltransferase enzyme. Examples of such DΝA methyltransferase inhibitor include compounds disclosed in US Patents 6,329,412 and 6,268,137. Specific DNA methyltransferase inhibitors include 5-azacytosine and zebularine®.
If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
The term administration and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof 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.
The compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the compounds of the instant invention may also be coadministered with other well known cancer therapeutic agents that are selected for their particular usefulness against the condition that is being treated. Included in such combinations of therapeutic agents are combinations of the farnesyl-protein transferase inhibitors disclosed in US Patent 6,313,138 and an antineoplastic agent. It is also understood that such a combination of antineoplastic agent and inhibitor of farnesyl-protein transferase may be used in conjunction with other methods of treating cancer and/or tumors, including radiation therapy and surgery.
Examples of an antineoplastic agent include, in general, microtubule-stabilizing agents (such as paclitaxel (also known as Taxol®), docetaxel (also known as Taxotere® , epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives); microtubule- disruptor agents; alkylating agents, anti-metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors. Example classes of antineoplastic agents include, for example, the anthracycline family of drugs, the vinca drags, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins. Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as colchicines, etoposide, etoposide phosphate or teniposide, vinblastine, vincristine, leurosidine, vindesine, leurosine, and the like. Other useful antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabine, idatrexate, trimetrexate, dacarbazine, L- asparaginase, camptothecin, CPT-Il, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins. The preferred class of antineoplastic agents is the taxanes and the preferred antineoplastic agent is paclitaxel.
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 10-a where R1 and R3 are methoxy, R2 is methyl, R4 is -O-tert- butyldimethylsilyl, and PG is Fmoc (following Scheme B)
Figure imgf000044_0001
10-a Step 1
Figure imgf000045_0001
1-a
(a) To a solution of 2,4-dimethoxy-3-methylbenzaldehyde (10.1 g, 56.3 mmol) and 3- chloroperoxybenzoic acid (57-86%, 19.7 g, 65.0 mmol) in dichloromethane (200 mL) at 0 0C was added p-toluenesulfonic acid monohydrate (1.01 g, 5.31 mmol). After stirring for 15 min, the bath was removed and the reaction mixture was stirred for additional 2 h as it warmed to room temperature. The reaction mixture was diluted with diethyl ether (300 mL) and saturated aqueous NaHCO3 (200 mL). The organic phase was washed with saturated aqueous NaHCO3, saturated aqueous Na2S2O3, saturated aqueous NaHCO3, brine, and dried over sodium sulfate. Concentration in vacuo provided crude formic acid 2,4-dimethoxy-3-methylphenyl ester, which was used without further purification.
(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 water (10 mL). After stirring for 40 min, the reaction mixture was acidified by the addition of 0.25 N aqueous HCl (240 mL). The reaction mixture was concentrated and the separated aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give crude 2,4-dimethoxy-3-methylphenol, which was used without further purification.
(c) To a solution of crude 2,4-dimethoxy-3-methylphenol (44.0 g, 262 mmol) and imidazole (19.5 g, 287 mmol) in DMF (250 mL) at 0 0C was added tørt-butyldimethylsilyl chloride (42.6 g, 286 mmol) in two portions. After stirring for 2 h, 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 sodium sulfate. Concentration in vacuo provided crude 3-ført-butyldimethylsilyloxy-2,6- dimethoxytoluene (1-a, 72.8 g, 99%) as a light colored oil, which was used without further purification. EM (calc): 282.2; MS (ESI) m/z: 283.1 (M+l)+
Step 2
Figure imgf000045_0002
1-a 2-a
To a solution of 3-tert-butyldimethylsilyloxy-2,6-dimethoxytoluene (1-a, 72.8 g, 258 mmol) and pyridine (25.0 mL, 309 mmol) in DMF (200 mL) at 0 0C was added a solution of bromine (15.0 mL, 291 mmol) in DMF (15 mL) over a period of 50 min. After stirring for 90 min, 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 separated aqueous layer was extracted with ethyl acetate (3 x 400 mL) and the combined organic layers were washed with brine, 0.5 N aqueous HCl, brine, and dried over sodium sulfate. Concentration in vacuo and purification by flash chromatography over silica gel with ethyl acetate/hexane (5/95) afforded 2-a (84.3 g, 91%).
Step 3
Figure imgf000046_0001
2-a 3-a
To a solution of 2-a (57.8 g, 160 mmol) in anhydrous THF (600 mL) at -78 0C was added t-BuLi (235 mL, 400 mmol, 1.7 M in pentane) over a period of 55 min. After stirring for additional 15 min, DMF (56.4 g, 772 mmol) was added slowly. After 30 min, the reaction mixture was diluted with ethyl acetate (350 mL) and brine (350 mL) and allowed to warm to 0 0C. The separated organic layer was washed with water, brine, dried over sodium sulfate, and concentrated in vacuo to give crude 3-a (49.7 g, 99%), which was used without further purification. Step 4
Figure imgf000046_0002
3-a 4-a 5-a
A solution of N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (4-a, 69.4 g, 209 mmol) in dichloromethane (118 mL) was treated with l,8-diaza-bicyclo[5.4.0]undec-7-ene (34.5 mL, 230 mmol). After 20 min the light yellow solution was cooled to -30 0C and treated with a solution of 3-a (65.0 g, 209 mmol) in dichloromethane (262 mL). The reaction mixture was stirred at -30 °C for 30 min and at room temperature for additional 30 min. The reaction mixture was diluted with diethyl ether (700 mL), washed with 0.5 N aqueous HCl, brine, and dried over sodium sulfate. The thick oil obtained upon drying in vacuo was purified by flash chromatography over silica gel with ethyl acetate/hexanes (15/85) to provide olefin 5-a (69.8 g,
Step 5
Figure imgf000047_0001
5-a 6-a
A solution of 5-a (59.6 g, 116 mmol) in anhydrous denatured ethanol (600 mL) was treated with catalyst (+)-l,2-bis((25r, 55)-2,5-diethylphospholano)benzene-(cyclooctadiene) rhodium(I) trifluoromethanesulfonate ((S^-DUPHOS-Rh, 167 mg, 0.231 mmol) in a Parr flask. The yellow solution was placed on the Parr hydrogenator under hydrogen (50 PSI) for 20 h. The reaction was monitored/evaluated by 1H NMR for completion. After completion the volatiles were removed, the resulting orange oil was filtered though a pad of silica with ethyl acetate to give 6-a (56.5 g, 94%), which was used without further purification.
Step 6
Figure imgf000047_0002
6-a 7-a
To a solution of 6-a (29.0 g, 56.1 mmol) in diethyl ether (250 mL) at 0 0C was added lithium borohydride (2.1 g, 94 mmol). After 5 min, the ice bath was removed and the reaction mixture was stirred for 1 h at room temperature, cooled to 0 0C, and carefully treated with saturated aqueous NH4Cl (50 mL) and water (5OmL). The separated organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give crude 7-a (26.1g, 95%), which was used without further purification. Step 7
Figure imgf000048_0001
7-a 8-a
To a solution of 7-a (26.1 g, 53.3 mmol) in ethanol (180 niL) was added 10% palladium on carbon (1.14 g, 1.05 mmol). The solution was placed on the Parr hydrogenator under hydrogen (50 psi) for 16 h. The reaction mixture was filtered through Celite® and the solvent was removed in vacuo to provide crude 8-a (19.O g, quantitative), which was used without further purification.
Step 8
Figure imgf000048_0002
8-a 9-a
To a solution of 8-a (12.2 g, 34.4 mmol) in dichloromethane (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 stirring for 30 min at room temperature, the reaction mixture was diluted with ethyl acetate (300 mL) and washed with half saturated aqueous NH4CI and brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography over silica gel with ethyl acetate/hexane (2/3) provided 9-a (16.3 g, 82%) as white foam.
Step 9
Figure imgf000048_0003
9-a 10-a
To a solution of oxalyl chloride (0.896 mL, 1.77 mmol, 2M in dichloromethane) in dichloromethane (10 mL) at -78 0C was added slowly methylsulfoxide (0.170 mL, 2.38 mmol). After stirring at -78 0C for 15 min, the reaction mixture was treated slowly with a solution of 9- a (345 mg, 0.60 mmol) in dichloromethane (5 mL) and stirring was continued for additional 30 min. After the addition of triethylamine (0.84 mL, 5.96 mmol) at -78 0C the reaction mixture was warmed up to -40 0C and stirred at that temperature for 20 min. The resulting white suspension was diluted with diethyl ether (100 mL) and washed with half saturated aqueous NH4Cl, water, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide crude aldehyde 10-a (345 mg, quantitative).
Reference B
Synthesis of intermediate 10-b, where R1 is methoxy, R2 together with R3 forms -CH2C(CH3)2-
O-, R4 is -O-tert-butyldimethylsilyl, and PG is Fmoc
(following Scheme B)
Step l
Figure imgf000049_0001
To a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (10.13 g, 61.7 mmol) in water/ethanol (7/3, 450 mL) was added potassium nitrosodisulfonate (Fremy '$ salt, 48.26 g, 179 mmol) in seven portions. After stirring for additional 10 min, the reaction was diluted with water (-900 mL) and extracted with dichloromethane. The combined organic extracts were washed with water (400 mL), brine (400 mL), and concentrated in vacuo. Purification by flash chromatography afforded 2,2-dimethyl-2,3-dihydrobenzofuran-4,7-dione (9.23 g, 84%) as colorless oil. Steps 2- 3
Figure imgf000049_0002
A solution of 2,2-dimethyl-2,3-dihydrobenzofuran-4,7-dione (18.34 g, 106.9 mmol) in anhydrous THF (300 mL) was treated with palladium on carbon (10%, 197 mg) and hydrogenated at atmospheric pressure (balloon). After 80 min the reduction to 2,2-dimethyl-2,3- dihydrobenzofuran-4,7-dione was determined to be complete by HPLC analysis to give 2,2- dimethyl-2,3-dihydrobenzofuran-4,7-diol. Tert-butyldimethylsilyl chloride (20.69 g, 137 mmol) in THF (100 mL) was added to the reaction mixture. After cooling to -78 0C imidazole (21.67 g, 318 mmol) was added in one portion and the reaction mixture was stirred and allowed to warm up to room temperature over night. The reaction was quenched with water (100 mL) and most of the THF was removed in vacuo. An additional portion of water (~500 mL) was added before extracting with dichloromethane (4 x 100 mL). The combined organic layers were washed with 1 N aqueous HCl (-500 mL) and brine (~500 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography over silica gel with ethyl acetate/hexane (1/9 to 1/4) afforded 7-(te7"t-butyldimethylsilanyloxy)-2,2-dimethyl- 2,3-dihydrobenzofuran-4-ol (23.17 g, 74%).
Step 4
Figure imgf000050_0001
1-b
To a solution of 7-(tert-butyldimethylsilanyloxy)-2,2-dimethyl-2,3-dihydro-benzofuran- 4-ol (57.98 g, 0.197 mol) in THF (600 mL) was added slowly sodium hydride (60% dispersion in mineral oil, 23.66 g, 0.592 mol). The reaction mixture was stirred for 15 min and methyl iodide (50 mL, 113.8 g, 0.801 mol) was added slowly over 24 min. After stirring overnight, the reaction was quenched with THF/water (4/1, 25 mL) and diluted with additional water (250 mL) and ethyl acetate/hexane (1/4, 800 mL). The separated aqueous layer was extracted with ethyl acetate/hexane (1/4, 2x 300 mL) and the combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was taken up in ethyl acetate/hexane (1/4, 200 mL) and filtered through Celite®. Concentration in vacuo provided crude fert-butyl-(4-methoxy-2,2-dimethyl-2,3 -dihydrobenzofuran-7-yloxy)dimethylsilane (1-b, 64.9 g, quantitative), which was used without further purification.
Step 5
Figure imgf000050_0002
1-b 2-b To a solution of tert-butyl-(4-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7- yloxy)dimethylsilane (1-b, 5.06 g, 16.4 mmol) and pyridine (1.75 niL, 23.1 mmol) in DMF (15 mL) at 0 0C was added a solution of bromine (2.87 mL, 18.0 mmol) in DMF (5 mL) dropwise over the period of 15 min. After stirring for 65 min, the reaction mixture was diluted with ethyl acetate, hexane, and brine. The separated aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with 1 N aqueous HCl (125 mL), brine, and dried over sodium sulfate. Purification by flash chromatography over silica gel with ethyl acetate/hexane (1/19) afforded 2-b (5.32 g, 84%).
Step 6
Figure imgf000051_0001
2-b 3-b
To a solution of 2-b (5.32 g, 13.7 mmol) in THF (22 mL) at -78 0C was added slowly tert-BuLi (22 mL, 37.4 mmol, 1.7M in pentane) over a period of 7 min. After stirring for additional 50 min at -78 0C, DMF (5.5 mL, 71 mmol) was added slowly. After 13 min, the reaction mixture was diluted with ethyl acetate (35 mL) and brine (35 mL). The separated organic layer was washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated in vacuo to give crude 3-b (4.60 g, quantitative), which was used without further purification. Step 7
Figure imgf000051_0002
A solution of N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (4-a, 5.60 g, 16.6 mmol) in dichloromethane (10 mL) was treated with l,8-diazabicyclo[5.4.0]-undec-7-ene (31.3 mL, 21.1 mmol). After 30 min, the light yellow solution was cooled to —40 0C and treated with a solution of 3-b (5.15 g, 15.7 mmol) in dichloromethane (18 mL). The reaction mixture was stirred at -40 0C to -45 0C for 30 min and warmed up to 10 0C over 6 h. The reaction mixture was diluted with diethyl ether (150 mL), washed with 0.5 Ν aqueous HCl (75 mL), brine, and dried over sodium sulfate. The thick oil obtained upon drying in vacuo was purified by flash chromatography over silica gel with ethyl acetate/hexanes (1/3) to provide pure 5-b (7.96 g, 88%). Step 8
Figure imgf000052_0001
5-b 6-b
A solution of olefin 5-b (4.94 g, 9.60 mmol) in anhydrous denatured ethanol (60 mL) was treated with catalyst (+)-l,2-bis((2.S', 55)-2,5-diethylphospholano)benzene-(cyclooctadiene) rhodium® trifluoromethanesulfonate ((5,,S)-DUPHOS-Rh, 104 mg, 0.144 mmol) in a Parr flask. The yellow solution was placed on the Parr hydrogenator under hydrogen (60 PSI) for 20 h. The reaction was monitored/evaluated by 1H NMR for completion. After completion the volatiles were removed, the resulting orange oil was filtered though a pad of silica with ethyl acetate to give 6-b (5.24 g, quantitative), which was used without further purification.
Step 9
Figure imgf000052_0002
6-b 7-b
To a solution of 6-b (2.94 g, 5.42 mmol) in diethyl ether (50 mL) at 0 0C was added lithium borohydride (266 mg, 12.2 mmol). After 5 min, the ice bath was removed and the reaction mixture was stirred for 2 h at room temperature, cooled to 0 0C, and carefully treated with saturated aqueous NH4Cl and water. The separated aqueous layer was extracted with diethyl ether and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give crude 7-b (2.47 g, 88%), which was used without further purification.
Step 10
Figure imgf000052_0003
To a solution of 7-c (6.01 g, 11.7 mmol) in ethanol (40 mL) was added 10% palladium on carbon (250 mg, 0.23 mmol). The solution was placed on the Parr hydrogenator under hydrogen (50 PSI) for 16 h. The reaction mixture was filtered through Celite® and the solvent was removed in vacuo to provide crude 8-b (4.47 g, quantitative), which was used without further purification.
Step 11
Figure imgf000053_0001
8-b 9-b
To a solution of 8-b (4.45 g, 11.7 mmol) in dichloromethane (6.0 mL) and THF (55.0 mL) were added triethylamine (1.95 mL, 13.9 mmol) and Fmoc-OSu (4.32 g, 12.8 mmol). After stirring for 30 min at room temperature, the reaction mixture was diluted with ethyl acetate (300 mL) and washed with half saturated aqueous NH4Cl and brine, dried over sodium sulfate, and concentrated in vacuo. Purification by column chromatography with ethyl acetate/hexane (2/3) provided 9-b (6.12 g, 87%) as white foam. EM (calc): 603.30; MS (ESI) m/z: 604.7 (M+l)+.
Step 12
Figure imgf000053_0002
9-b 10-b
To a solution of oxalyl chloride (20.3 mL, 40.6 mmol, 2 M in dichloromethane) in dichloromethane (10 mL) at -78 0C was added slowly methylsulfoxide (3.6 mL, 50.7 mmol). After stirring at -78 0C for 15 min, the reaction mixture was treated slowly with a solution of 9- b (6.12 g, 10.1 mmol) in dichloromethane (70 mL) and stirring was continued for additional 30 min. After the addition of triethylamine (14.1 mL, 101.4 mmol) at -78 0C, the reaction mixture was warmed up to -40 0C and stirred at that temperature for 20 min. The resulting white suspension was diluted with diethyl ether (300 mL) and washed with half saturated aqueous NH4Cl, water, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide crude aldehyde 10-b (6.62 g, quantitative), which was directly used without further purification. Reference C
Synthesis of intermediate 10-a, where R1 and R3 are methoxy, R2 is methyl, R4 is -O-tert- butyldimethylsilyl, and PG is Fmoc (following Scheme C)
Figure imgf000054_0001
10-a
Step l
Figure imgf000054_0002
3-a 11-a
To a solution of the aldehyde 3-a (1.78 g, 5.74 mmol) in absolute ethanol (20 niL) at O 0C was added sodium borohydride (132 mg, 3.44 mmol). The reaction mixture was stirred at O 0C under nitrogen for 30 min. The reaction mixture was quenched by careful addition of saturated aqueous NH4Cl (50 mL). The reaction mixture was diluted with dichloromethane (50 mL) and water (50 mL) and stirred vigorously for 10 min. The separated aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography over silica gel with ethyl acetate/hexanes (20/80) provided 11-a (1.38 g, 78%) as slightly yellow oil.
Step 2
Figure imgf000054_0003
11-a 12-a
To a suspension of triphenylphosphine (1.27 g, 4.81 mmol) and imidazole (361 mg, 5.25 mmol) in dichloromethane (15 mL) at 0 0C was added bromine (248 μL, 4.81 mmol). After 10 min, a solution of 11-a (1.37 g, 4.37 mmol) in dichloromethane (15 mL) was added slowly. After stirring for 10 min at 0 0C the reaction mixture was diluted with saturated aqueous Na2S2O3. The separated aqueous layer was extracted with dichloromethane and the combined organic layers were washed with saturated aqueous Na2S2O3, brine, and dried over sodium sulfate. Purification by flash chromatography over silica gel with dichloromethane/hexanes (50/50) provided 12-a (1.34 g, 82%) as colorless oil. EM (calc): 375.4; MS (ESI) m/z: 376.0 (M+l)+.
Step 3
Figure imgf000055_0001
13-a 14-a
To a suspension of anhydrous lithium chloride (635 mg, 15.0 mmol) in THF (9 mL) was added (~-)-pseudoephedrine glycinamide monohydrate 13-a (943 mg, 3.92 mmol) (Myers et al. J. Org. Chem. 1999, 64, 3322.). The reaction mixture was cooled to 0 0C and treated with LHMDS (12.1 mL, 12.1 mmol, 1.0 M in THF). The resulting yellow reaction mixture was stirred at 0 0C under nitrogen. After stirring for 30 min, a solution of 12-a (1.34 g, 3.57 mmol) in THF (9 mL) was added to the reaction mixture and stirring was continued for 30 min at 0 0C. The reaction mixture was quenched with water (30 mL). The separated aqueous layer was extracted with dichloromethane and the combined organic layers were dried over K2CO3 for 2 h, filtered over a pad of cotton, and concentrated in vacuo. The residue was dissolved in toluene (50 mL) and concentrated again. Recrystallization of the crude product in hexane provided 14-a (750 mg, 41%) as white solid. Step 4
Figure imgf000055_0002
14-a 8-a
To a solution of diisopropylamine (903 μL, 6.41 mmol) in THF (4.0 mL) at -78 0C was added a solution of «-BuLi (2.4 mL, 6.16 mmol, 2.5 M in THF). The reaction mixture was stirred for 10 min at -78 0C and for 10 min at 0 0C. To the reaction mixture was added borane-ammonia (224 mg, 6.53 mmol) in one portion and the reaction mixture was stirred at for 10 min 0 0C and for additional 10 min at room temperature. The reaction mixture was cooled to -78 0C and treated with a solution of 14-a (637 mg, 1.23 mmol) in THF (4.0 mL). The resulting yellow clear solution was stirred for 2 h at 0 0C. The reaction mixture was quenched by addition of 2,2,2-trifluoroethanol (481 μL, 6.53 mmol) at 0 0C dropwise followed by addition of diethyl ether (5 mL) and a solution OfNaHSO4 (2.7 g, 22.6 mmol) in water (10 mL) in sequence. After stirring for 2 h at 0 0C the reaction mixture was treated with triethylamine (915 μL, 6.53 mmol), H2O (5 mL), and saturated aqueous NaHCO3 (15 mL). The separated aqueous layer was saturated with NaCl and extracted with dichloromethane. The combined organic layers were dried over K2CO3 and concentrated in vacuo. Purification by flash chromatography over silica gel with methanol/dichloromethane/triethylamine (2/97/1 to 5/94/1) provided 8-a (389 mg, 89%), which was converted into 10-a as described in Reference A, Steps 8, 9.
Reference D
Synthesis of intermediate 17-a, R1 and R3 are methoxy, R2 is methyl, and R4 is hydroxy
(following Scheme D)
Step 1
Figure imgf000056_0001
10-a 15-a
To a suspension of potassium cyanide (45.7 mg, 656 μmol) in methanol (1 mL) was added acetic acid (42.5 μL, 716 μmol). When the solid was completely dissolved, the reaction mixture was transferred into a flask containing a solution of 10-a (343 mg, 0.60 mmol) in dichloromethane (3 mL) via syringe. After 1 h, the reaction mixture was diluted with diethyl ether (50 mL) and washed with brine/saturated aqueous NaHCO3 (4/1). The organic phase was dried over sodium sulfate and concentration in vacuo to provided crude 15-a, which was used without further purification. Step 2
Figure imgf000057_0001
15-a 16-a
To a solution of cyanohydrin 15-a (from Step 1 above) in 2,2,2-trifluoroethanol (3 mL) was added morpholine (257 μL, 2.98 mmol). After stirring for 4 h at room temperature, the reaction mixture was concentrated in vacuo. The resulting oil was dissolved in toluene (5 mL) and again concentrated. The crude oil obtained was purified by flash chromatography over silica gel with ethyl acetate/hexanes (1/3) to provide 16-a (319 mg, 80% over 2 steps) as a diastereomeric mixture. Step 3
Figure imgf000057_0002
To a solution of 16-a (12.9 g, 19.2 mmol) in THF (70 mL) were added acetic acid (2.6 mL, 46 mmol) and tetrabutylammonium fluoride (21 mL, 21 mmol, 1.0 M in THF) at 0 0C in sequence. After stirring for 1 h at room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide crude 16-b, which was used in the next step without further purification. Step 4
Figure imgf000058_0001
16-b Rβ-17-a S,S-17-a
To a solution of the crude 16-b (from Step 3 above) in dichloromethane (50 niL) was added l,8-diazabicyclo[5.4.0]undec-7-ene (4.5 niL, 25 mmol). After stirring for 30 min at room temperature, the reaction mixture was directly loaded on the column and purified by flash chromatography over silica gel with ethylacetate/methanol (100/1 to 10/1). A second purification by flash chromatography over silica gel with ethyl acetate/methanol (10/1) provided diasteromerically pure RJS-ll-a (2.32 g, 36%).
Reference E Synthesis of intermediate 17-b, R1 is -OCH3, R2 and R3 together form -CH2-C(CH3)2-O-, and
R4 is -OH (following Scheme D)
Step l
Figure imgf000058_0002
10-b 15-b
To a solution of aldehyde 10-b (6.62 g, 11.0 mmol) in dichloromethane (50 niL) were added acetone cyanohydrin (2.01 mL, 22.0 mmol) and triethylamine (0.15 mL, 1.10 mmol). After stirring for 16 h at room temperature, the solution was diluted with diethyl ether (300 mL) and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to provide the crude cyanohydrin 15-b (5.84 g, 84%), which was used without further purification. Step 2
Figure imgf000059_0001
To a solution of cyanohydrin 15-b (5.84 g, 9.24 mmol) in 2,2,2-trifluoroethanol (18 mL) was added morpholine (8.1 mL, 9.29 mmol). After stirring for 21 h at room temperature, the reaction mixture was concentrated in vacuo. The resulting oil was taken up in ethyl acetate (300 mL) and washed with saturated aqueous NH4Cl and brine . The organic phase was dried over sodium sulfate and concentrated in vacuo to provide the crude cyanomorpholine 16-c (6.87 g, quantitative) as a diastereomeric mixture, which was used without further purification. EM (calc): 697.4; MS (ESI) m/z: 698.4 (M+l)+. Step 3
Figure imgf000059_0002
To a solution of 16-c (6.87 g, 9.84 mmol) in THF (70 mL) was added acetic acid (1.42 mL, 23.6 mmol) and tetrabutylammonium fluoride (11.8 mL, 11.8 mmol, 1 M in THF) at 0 0C in sequence. After stirring for 1 h at room temperature, the reaction mixture was diluted with ethyl acetate (300 mL) and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide crude 16-d (5.29 g, 92%), which was used without further purification. Step 4
Figure imgf000060_0001
16-d R^S-17-b S,S-17-b
To a solution of 16 -d(5.26 g, 9.01 mmol) in dichloromethane (30 mL) was added 1,8- diazabicyclo[5.4.0]undec-7-ene (1.76 mL, 11.8 mmol). After stirring for 30 min at room temperature, the reaction mixture was directly loaded on the column and purified by flash chromatography over silica gel with triethylamine/methanol/ethylacetate (1/2/97 to 1/5/94) to provide the diasteromerically pure Rβ-17-b (1.14 g, 35%) and Sβ-17-b (947 mg, 29%). To a solution of Sβ-17-b (0.94 g, 2.60 mmol) in trifluoroethanol (17 mL) was added morpholine (0.23 mL, 2.60 mmol), the solution was then heated at 700C for 3 h. The reaction mixture was cooled to room temperature, trifluroethanol was removed in vacuo and the residue was purified by flash chromatography over silica gel with triethylamine/methanol/ethylacetate (1/2/97 to 1/5/94) to provide additional Rβ-17-b (0.423 g, 13%) and recovered Sβ-17-b (0.222 g, 7%). EM (calc): 361.2; Rβ-17-b: MS (ESI) m/z: 359.9 (M-H); 362.1 (M+l)+; S,S-17-b: MS (ESI) m/z: 360.2 (M-H)", 362.5 (M+l)+.
Reference F Synthesis of 5-(tetrahydro-4H-pyran-4-yloxy)-benzofuran-2-carboxylic acid
Figure imgf000060_0002
Step 1
To a solution of 5-methoxybenzofuran-2-carboxylic acid (5.04 g, 26.2 mmol) in methanol (50 mL) was added thionyl chloride (2.3 mL, 32 mmol) dropwise at 0 0C. After stirring for 72 h at room temperature, the reaction mixture was poured into water (150 mL) and filtered to provide white solids. The white solids were dissolved in toluene (100 mL) and washed with 1 M aqueous NaHCO3, brine, and dried over magnesium sulfate. Concentration in vacuo provided crude S-methoxybenzofuran^-carboxylic acid methyl ester (5.15 g, 95%) as a white solid, which was used without further purification. Step 2
To a solution of 5-methoxybenzofuran-2-carboxylic acid methyl ester (5.15 g, 25.0 mmol) in dichloromethane (15 mL) at -40 0C was added boron tribromide (27.0 mL, 27.0 mmol, 1.0 M in dichloromethane) over the course of 1 h using a syringe pump. The reaction mixture was stirred overnight while allowed slowly to warm to room temperature. After quenching the reaction mixture with methanol (15 mL) at 0 ° brine (100 mL) was added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude product obtained was dissolved in methanol (30 mL) and treated with thionyl chloride (1.9 mL, 26 mmol) at 0 0C. After stirring for 72 h at room temperature the reaction mixture was treated with water (100 mL) and filtered to yield crude 5- hydroxybenzofuran-2-carboxylic acid methyl ester (4.53 g, 94%) as a yellow solid, which was used without further purification. 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 h using a syringe pump. After 6 days of stirring at room temperature most of the volatiles were removed in vacuo. Purification of the crude material by flash chromatography over silica gel with ethyl acetate/dichloromethane (1/9) provided 5-(tetrahydro-4H-pyran-4- yloxy)-benzofuran-2~carboxylic acid methyl ester (1.12 g, 71%) as a white 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 (13 mL) at 0 0C was added 2 M aqueous LiOH (2.5 mL, 5.0 mmol). After stirring for 2 h at room temperature, the reaction mixture was cooled to 0 0C and treated with 0.5 N aqueous HCl (20 mL). The reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo to provide crude 5-(tetrahydro~4H-pyran-4- yloxy)-benzofuran-2-carboxylic acid (1.05 g, 99%) as a white solid.
Example 1
Synthesis of a compound of Formula (Ia)-a where R1 and R8 are methoxy, R2 together with R3 and R7 together with R6 each form -CΗ2C(CΗ3)2-O-, R10 is methyl, R4 and R5 are hydroxy, R9 is hydrogen, R11 is CN, Y is -CH2-, and R12 is -NH2
Figure imgf000062_0001
(Ia)-a
Step l
Figure imgf000062_0002
10-b Rβ-17-b 18-a
To a mixture of the aldehyde 10-b (458 mg, 0.76 mmol) and sodium sulfate (2.26 g, 15.9 mmol) was added a solution of Rβ-17-b (275 mg, 0.76 mmol) in dichloromethane (15 mL) via syringe. After stirring at room temperature for 1 h, the reaction mixture was filtered over a pad of cotton and concentrated. The crude product was azeotropically dried with dichloromethane and further dried in vacuo for 1 h. The crude imine intermediate was dissolved in anhydrous ethylene glycol dimethyl ether (20 mL) and added to a suspension of anhydrous lithium bromide (1.65 g, 19.1 mmol) in anhydrous ethylene glycol dimethyl ether (5 mL). The resulting mixture was stirred at 35 0C for 15 h, cooled to room temperature, and diluted with ethyl acetate (200 mL). The organic layer was washed with brine/saturated aqueous NaHCO3 (4/1, 3 x 100 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography over silica gel with ethyl acetate/hexane (1/4 to 2/3) afforded 18-a (282.3 mg, 41%). EM (calc): 944.48; MS (ESI) m/z: 946.0 (M+l)+. Step 2
Figure imgf000063_0001
18-a 19-a
To a solution of 18-a (282 nig, 0.298 mmol) in acetonitrile (6.0 niL) were added formaldehyde (45 μL, 0.60 mmol, 37 wt % solution in water) and sodium triacetoxyborohydride (95 mg, 0.45 mmol) in sequence. After stirring for 70 min at room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with brine/saturated aqueous NaHCO3 (1/1, 50 mL), and dried over sodium sulfate. Concentration in vacuo provided crude 19-a (286 mg, quantitative), which was used without further purification. EM (calc): 958.5; MS (ESI) m/z: 958.1 (M-H)-, 960.0 (M+l)+. Step 3
Figure imgf000063_0002
19-a 19-b
To a solution of 19-a (286 mg, 0.298 mmol) in THF (1.0 mL) were added acetic acid (41 μL, 0.716 mmol) and tetrabutylammonium fluoride (358 μL, 0.358 mmol, 1 M solution in THF) in sequence. After stirring for 2 h, the reaction mixture was diluted with water, saturated aqueous NaHCO3, and diethyl ether (100 mL). The separated aqueous layer was extracted with diethyl ether and the combined organic layers were dried over sodium sulfate and concentrated in vacuo to give crude 19-b (237 mg, 94%), which was used without further purification. Step 4
Figure imgf000064_0001
19-b 20-a
To a solution of crude 19-b (237 mg, 0.281 mmol) in dichloromethane (1.0 mL) was added l,8-diazabicyclo[5.4.0]undec-7-ene (126 μL, 0.841 mmol). After stirring for 30 min at room temperature, the reaction mixture was loaded directly on the column and purified by flash chromatography over silica gel with methanol/dichloromethane (5/95 to 7/93) to yield 20-a (143 g, 77%) as orange solid. EM (calc): 622.3; MS (ESI) m/z: 623.8 (M-H)-, 621.8 (M+l)+. Step 5
Figure imgf000064_0002
21-a
To a suspension of N-(9-fluorenylmethoxycarbonyl)ethanol (5.0 g, 18 mmol) in dichloromethane (50 mL) was added diisopropylethylamine (12.4 mL, 70.6 mmol). The reaction mixture was cooled to -40 0C and a solution of sulfur trioxide pyridine complex (11.2 g, 70.6 mmol) in dimethylsulfoxide (49.5 mL) was added over a period of 15 min. After stirring for 1 h at -40 0C, the reaction mixture was treated with a mixture of iced water and brine. The solvent was removed and the resulting off-white precipitates were filtered and dried in vacuo. Purification by flash chromatography over silica gel with ethyl acetate/hexanes (1/1) provided the N-Fmoc glycinal 21-a (4.7 g, 94%).
Step 6
Figure imgf000065_0001
20-a 22-a
A deoxygenated (4 freeze-pump-thaw cycles) solution of N-Fmoc glycinal 21-a (80.3 nig, 0.285 mmol) in anhydrous dichloromethane (5.0 mL) was transferred via cannula to a solid mixture of 20-a (143 mg, 0.230 mmol) and sodium sulfate (501 mg, 3.52 mmol). The resulting suspension was stirred for 17 h at room temperature. After cooling to room temperature the reaction mixture was filtered over a pad of cotton and concentrated in vacuo. Purification by flash chromatography over silica gel with methanol/dichloromethane (1/1) provided 22-a (69.9 mg, 35%). EM (calc): 885.4; MS (ESI) m/z: 886.6 (M+l)+. Step 7
Figure imgf000065_0002
22-a 23-a
To a solution of 22-a (69.9 mg, 0.807 mmol) in 2,2,2-trifluoroethanol (1.0 mL) were added ZnCl2 (0.5 mL, 0.250 mmol, 0.5M in THF) and trimethylsilyl cyanide (22.4 μL, 0.168 mmol) in sequence. After stirring for 18 h, the reaction mixture was quenched by addition of aqueous EDTA solution (5.0 mL, 0.2M (ethylenedinitrilo)tetraacetic acid, disodium salt - 0.4M sodium hydroxide, pH 10) and then extracted with ethyl acetate (3x 25 mL). The combined organic layers were washed with brine/saturated aqueous NaHCO3 (1/1, 75 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by chromatography over silica gel with ethyl acetate/hexanes (1/1) provided 23-a (63.5 g, 99%). EM (calc): 798.4; MS (ESI) m/z: 799.7 (M+l)+. Step 8
Figure imgf000066_0001
23-a (Ia)-a
To a solution of 23-a (63.5 mg, 0.080 mmol) in dichloromethane (0.35 niL) was added l,8-diazabicyclo[5.4.0]undec-7-ene (15.5 μL, 0.104 mmol). After stirring for 30 min at room temperature, the reaction mixture was loaded directly on the column and purified by chromatography over silica gel with ethyl acetate/hexane (1/1) to yield (Ia)-a (30.4 mg, 70%). EM (calc): 576.3; MS (ESI) m/z: 575.8 (M-Hy, 577.7 (M+l)+.
Example 2
Synthesis of a compound of Formula (Ia)-b where R1 and R8 are OMe, R2 and R3 and R7 and R6 form -CH2C(CH3)2-O-, R10 is Me, R4 and R5 are OH, R9 is H, R11 is CN,
Y is -CH2-, and R12 is -OH
Figure imgf000066_0002
(Ia)-b
Step 1
Figure imgf000067_0001
20-a 22-b
A deoxygenated (3 freeze-pump-thaw cycles) solution of (tert-butyldimethyl- silyloxy)acetaldehyde 21-b (53 μL, 0.276 mmol) in anhydrous dichloromethane (5 mL) was transferred via cannula to a solid mixture of 20-a (143 mg, 0.230 mmol) and sodium sulfate (490 mg, 3.45 mmol). The resulting suspension was stirred for 20 h at room temperature, filtered over a pad of cotton, and concentrated in vacuo. Purification by flash chromatography over silica gel with ethyl acetate/dichloromethane (1/1) provided 22-b (175 mg, 98%). EM (calc): 778.4; MS (ESI) m/z: 777.6 (M-H)", 779.8 (M+l)+. Step 2
Figure imgf000067_0002
22-b 23-b
To a solution of 22-b (175 mg, 0.225 mmol) in 2,2,2-trifluoroethanol (2.5 mL) were added ZnCl2 (1.35 mL, 0.674 mmol, 0.5M in THF) and trimethylsilyl cyanide (60 μL, 0.450 mmol) in sequence. After stirring for 7 h, the reaction mixture was treated with additional ZnCl2 (1.35 mL, 0.674 mmol, 0.5M in THF) and trimethylsilyl cyanide (60 μL, 0.450 mmol) and stirring was continued for 16 h. The reaction was quenched by addition of aqueous EDTA solution (40 mL, 0.2M (ethylenedinitrilo)tetraacetic acid, disodium salt- 0.4M sodium hydroxide, pH 10) and then extracted with ethyl acetate (3x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography over silica gel with ethyl acetate/hexanes (1/3) provided 23-b (114 mg, 73%). EM (calc): 691.4; MS (ESI) m/z\ 690.8 (M-H)", 692.9 (M+l)+. Step 3
Figure imgf000068_0001
23-b (Ia)-b
To a solution of 23-b (38 mg, 0.055 mmol) in THF (1.0 niL) were added acetic acid (7.6 μL, 0.132 mmol) and tetrabutylammonium fluoride (66 μL, 0.066 mmol, 1 M solution in THF) in sequence. After stirring for 45 min, the reaction mixture was diluted with ethyl acetate (25 mL) and brine/saturated aqueous NaHCO3 (1/1, 50 mL). The separated aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography over silica gel with ethyl acetate/hexane (1/1) provided (Ia)-b (21.9 mg, 69%). EM (calc): 577.3; MS (ESI) m/z: 576.8 (M-H)", 578.7 (M+l)+.
Example 3
Synthesis of a compound of Formula (Id) where R2 together with R3 and R7 together with R6 form -CH2C(CHa)2-O-, R10 is methyl, R9 is hydrogen, R11 is CN, Y is CH2, and R12 is hydroxy
Figure imgf000068_0002
(Ia)-b (Id)
To a solution of (Ia)-b (14 mg, 0.024 mmol), prepared as described in Example 2 above, in acetone/water (10/1, 3.3 mL) at 0 0C was added 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (22 mg, 0.097 mmol). After stirring for 50 min at 0 °C, the reaction mixture was diluted with ethyl acetate (30 mL) and brine/saturated aqueous NaHCO3 (3/1, 50 mL). The separated aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography over silica gel with ethyl acetate/hexane (1/1) provided the title compound (Id) (10.2 mg, 77%). EM (calc): 545.2; MS (ESI) m/z: 544.3 (M-H)", 546.5 (M+l)+.
Example 4
Synthesis of a compound of Formula (Ia)-C where R1 and R8 are methoxy, R2 together with R3 and R7 together with R6 each form -CH2C(CHs)2-O-, R10 is methyl, R4 and R5 are hydroxy, R9 is hydrogen, R11 is CN, Y is -CH2-, and R12 is -NHC(O)-quinolin-2-yl
Figure imgf000069_0001
(Ia)-C
To a solution of (Ia)-a (16.2 mg, 0.028 mmol), prepared in Example 1, in dichloromethane (1.0 mL) at 0 0C were added quinoline-2-carbonyl chloride (6.9 mg, 0.036 mmol) and N,N-diethylaniline (5 μL, 0.031 mmol) in sequence. After stirring for 10 min at 0 0C, the reaction mixture was allowed to warm up to room temperature and stirring was continued for additional 3 h. The reaction mixture was diluted with chloroform (10 mL) and washed with half saturated aqueous NaHCO3 (17 mL). The aqueous layers were extracted with chloroform and the combined organic layers were washed with brine/saturated aqueous NaHCO3 (1/1, 19 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by chromatography over silica gel with ethyl acetate/hexane (2/1) afforded the title compound (Ia)- c (15 mg, 73%). EM (calc): 731.3; MS (ESI) m/z: 732.6 (M+l)+.
Example 5
Synthesis of a compound of Formula (Ia)-d where R1 and R8 are methoxy, R2 together with R3 and R7 together with R6 each form -CH2C(CH3)2-O-, R10 is methyl, R4 and R5 are hydroxy, R9 is hydrogen, R11 is CN, Y is CH2, and R12 is -NHC(O)-l,3-dioxo-l,3-dihydroisoindol-2-yl
Figure imgf000070_0001
(Ia)-d
To a solution of (Ia)-a (8.0 mg, 0.014 mmol), prepared in Example 1 above, in anhydrous dichloromethane (0.6 mL) was added phthalic anhydride (2.3 mg, 0.015 mmol). After stirring for 3.5 h at room temperature, carbonyl diimidazole (2.4 mg, 0.015 mmol) was added and the reaction was stirred for additional 4.5 h. The reaction was quenched with saturated aqueous NH4CI (10 mL) and diluted with ethyl acetate (10 mL). The separated aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by chromatography with ethyl acetate/hexane (3/2) provided the title compound (Ta)-d (4.0 mg, 40% yield) as an off-white solid. EM (calc): 706.3; MS (ESI) m/z: 707 ' .1 (M+l)+.
Example 6
Synthesis of a compound of Formula (Ia)-e where R1 and R8 are methoxy, R2 together with R3 and R7 together with R6 each forms -CH2C(CBb)2-O-, R10 is methyl, R4 and R5 are hydroxy, R9 is hydrogen, R11 is CN, Y is CH2, and R12 is -NHC(O)-5-(tetrahydropyran-4-yloxy)benzofuran-
2-yl
Figure imgf000071_0001
(Ia)-e
Step 1
A solution of 5-(tetrahydro-4H-pyran-4-yloxy)-benzofuran-2-carboxylic acid (9.3 mg, 0.035 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.8 mg, 0.035 mmol), and 1-hydroxybenzotriazole hydrate (catalytic amount) in TΗF (0.75 mL) was stirred for 30 min at room temperature and then cooled to 0 0C. To the reaction mixture were added a solution of (Ia)-a (16.2 mg, 0.028 mmol), prepared as described in Example 1 above, in TΗF (0.75 mL) and N,N-diethylaniline (13.4 μL, 0.084 mmol) in sequence. The mixture was allowed to warm up to room temperature and stirring was continued for additional 3 h. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with brine/saturated aqueous NaHCO3 (1/1, 20 mL). The separated aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by chromatography over silica gel with ethyl acetate/hexane (3/1) followed by a second chromatography with ethyl acetate/dichloromethane (2/1) provided the title compound (Ia)-e (9.3 mg, 40%). EM (calc): 820.4; MS (ESI) m/z: 821.5 (M+l)+.
Biological Examples
Example 1
Cell Growth Inhibition Assay
HCT-116 human colorectal carcinoma cells (American Type Culture Collection) were cultured as monolayer in McCoy's 5 A Medium (Gibco, #16600-082) supplemented with 10% fetal bovine serum at 370C 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 microliter 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 5A 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 370C 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 370C 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.
Pharmaceutical Composition Examples
The following are representative pharmaceutical formulations containing a compound of Formula (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.O 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, 0.1M 10.0 ml
HCl (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 (Ia), (Ib), (Ic), or (Id):
Figure imgf000075_0001
(Id) wherein: n is 0 or 1 ;
Y is alkylene optionally substituted with one to five halo;
R1 is hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, - C(O)OR13 (where R13 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, nitro, mono or disubstituted amino, acylamino, or -C(O)NR14R15 (where R14 and R1S are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
R2 is hydrogen, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, or alkylsulfonyl; or R2 together with R3 forms -(CH2)qC(RaRb)X- or -XC(RaRb)-(CH2)q- where q is 1-2, X is -NR- (where R is hydrogen or alkyl), -0-, or -S-, and Ra and Rb are independently hydrogen or alkyl or Ra and Rb together with the carbon atom to which they are attached form (=0);
R7 is hydrogen, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, or alkylsulfonyl; or R7 together with R6 forms -(CH2)qC(RaRb)X- or -XC(RaRb)-(CH2)q- where q is 1-2, X is -NR- (where R is hydrogen or alkyl), -O-, or -S-, and Ra and Rb are independently hydrogen or alkyl or Ra and Rb together with the carbon atom to which they are attached form (=O); provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)qC(RaRb)X- or -XC(RaRb)-(CH2)q-;
R3 and R6 are as defined above or are independently hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfϊnyl, alkylsulfonyl, acyl, -C(O)OR16 (where R16 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, nitro, mono or disubstituted amino, acylamino, or -C(O)NR17R18 (where R17 and R18 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
R4 and R5 are independently hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, -C(O)OR19(where R19 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, or -C(O)NR20R21 (where R20 and R21 are independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl);
R8 is hydrogen, halo, alkyl, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, - C(O)OR22 (where R22 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), cyano, nitro, mono or disubstituted amino, or acylamino;
R9 is hydrogen, alkyl, cyano, halo, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, or (=0);
R10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, 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 within the scope of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10, is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and hydroxy provided that the ring formed by R2 together with R3 or R7 together with R6 is not substituted;
R11 is cyano, -SCN, hydroxy, alkoxy, or halo; and
R12 is: (i) alkyl;
(ii) alkenyl;
(iii) alkynyl;
(iv) aryl;
(v) aralkenyl;
(vi) aralkynyl;
(vii) heteroaryl;
(viii) heteroaralkenyl;
(ix) heteroaralkynyl;
(x) heterocycloalkyl;
(xi) -NHC(=NR23)R24 (where R23 is hydrogen, alkyl, or haloalkyl and R24 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl);
(xii) -NHC(=NH)NHR25 (where R25 is hydrogen, alkyl, hydroxy, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl);
(xiii) -NR26C(O)R27 (where R26 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl and R27 is alkyl, alkoxy, haloalkyl, cycloalkyl, cycloalkylalkyl, acyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl);
(xiv) -C(O)NR28R29 (where R28 and R29 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl) ;
(xv) -C(O)OR30 (where R30 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl);
(xvi) -NR31SO2R32 (where R31 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl and R32 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl);
(xvii) -NR33R34 (where R33 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl and R34 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl provided that n=l);
(xviii) -NR35CHXR36 (where R35 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, X is haloalkyl, and R36 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl provided that n=l); (xix) -OR37 (where R37 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); (xx) -S(O)mlR38 (where ml is 0 to 2 and R38 is hydrogen when ml is 0, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl); or (xxi) -S(O)2NR39R40 (where R39 is hydrogen or alkyl and R40 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl); (xxii) -OC(O)R41 (where R41 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl); (xxiii) -C(O)R42 (where R42 is alkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl); (xxiv) cycloalkyl; (xxv) cycloalkylalkyl; (xxvi) cycloalkenyl; (xxvii) -OC(O)NR43R44 (where R43 is hydrogen or alkyl and R44 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, or heterocycloalkylalkyl);
(xxviii) -SiR45R46R47 where R45, R46, and R47 are independently alkyl; or (xxix) -P(=O)(X1R48)Y1R49 (where X1 and Y1 is a single bond or -O- and R48 and R49 are independently hydrogen, alkyl, aryl, or aralkyl); wherein the aromatic or alicyclic ring, either alone or as part of another group, in R12 is optionally substituted with one, two, or three Rc independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyloxy, heterocycloalkyloxyalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, -(alkylene)nl-S(O)n2- R50 (where nl is 0 or 1, n2 is 0-2, and R50 is alkyl, haloalkyl, amino, alkylamino, dialkylamino, aryl, or heteroaryl), -(alkylene)n3-NHSO2-R51 (where n3 is 0 or 1 and R51 is alkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkyl), -(alkylene)n4-NHC(O)R52 (where n4 is 0 or 1 and R52 is alkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkyl), and -(alkylene)n5-C(O)NR53R54 (where n5 is 0 or 1 and R53 is alkyl, haloalkyl, hydroxy, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl and R54 is hydrogen or alkyl) and: further wherein the aromatic or alicyclic ring, either alone or part of another group in Rc is optionally substituted with one, two, or three Rd independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonyl, and cyano; or a pharmaceutically acceptable salt thereof.
2. The compound of Claim 1 wherein: n is 1;
Y is alkylene;
R1 is hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy;
R2 is alkyl; or R2 together with R3 forms -(CH2)qC(RaRb)X- or -XC(RaRb)-(CH2)q- where q is 1-2, X is -NR- (where R is hydrogen or alkyl), -O-, or -S-, and Ra and Rb are independently hydrogen or alkyl or Raand Rb together with the carbon atom to which they are attached =(O);
R7 is alkyl; or R7 together with R6 forms -(CH2)qC(RaRb)X- or -XC(RaRb)-(CH2)q- where q is 1-2, X is -NR- (where R is hydrogen or alkyl), -O-, or -S-, and Ra and Rb are independently hydrogen or alkyl or Raand Rb together with the carbon atom to which they are attached =(0); provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)qC(RaRb)X- or -XC(RaRb)-(CH2)q-;
R3 and R6 are defined as above or are independently hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy;
R4 and R5 are independently hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy; R is hydrogen, hydroxy, alkoxy, alkenyloxy, haloalkoxy, hydroxyalkoxy, alkoxyalkyloxy, acyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy;
R9 is hydrogen;
R10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the aromatic or alicyclic ring in R1, R2, R3, R4, R5, R6, R7, R8, and R10, either alone or as part of another group within the scope of R1, R2, R3, R4, R5, R6, R7, R8, and R10, is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and hydroxy; and
R11 is cyano, -SCN, hydroxy, alkoxy, or halo.
3. The compound of Claim 1 or 2 wherein the compound is a compound of Formula (Ia) wherein:
Y is methylene;
R1, R3, R4, R5, and R6 are independently hydroxy or alkoxy;
R2 is alkyl and R3 is as defined above; or R2 together with R3 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Ra and Rb are independently hydrogen or alkyl;
R7 is alkyl and R6 is as defined above; or R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)-(CH2)- where Raand Rbare independently hydrogen or alkyl; provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)C(RaRb)O- or -OC(RaRb)- (CH2)-;
R8 is hydrogen, hydroxy, or alkoxy;
R9 is hydrogen;
R10 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the aromatic or alicyclic ring in R10, either alone or as part of another group within the scope of R10, is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and hydroxy; and
R11 is cyano, -SCN, hydroxy, alkoxy, or halo.
4. The compound of any of the Claims 1-3 wherein:
Y is methylene;
R1, R3, and R6 are independently alkoxy;
R2 is alkyl and R3 is as defined above; or R2 together with R3 forms -(CH2)C(CH3)2O-; R7 is alkyl and R6 is as defined above; or R7 together with R6 forms -(CH2)C(CEb)2O- provided that at least one of R2 together with R3 and R7 together with R6 forms -(CH2)C(CHs)2O-;
R4 and R5 are hydroxy;
R8 is hydrogen or alkoxy;
R9 is hydrogen; and
R10 is alkyl.
5. The compound of any of the Claims 1-3 wherein: Y is methylene;
R1 is alkoxy;
R2 together with R3 and R7 together with R6 each form -(CH2)C(CH3)2O-;
R4 and R5 are hydroxy;
R8 is hydrogen or alkoxy;
R9 is hydrogen; and
R10 is alkyl.
6. The compound of any of the Claims 1-5 wherein R12 is -NHC(O)R27 where R27 is cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or heteroaralkenyl wherein the aromatic or alicyclic ring, either alone or as part of another group, in R27 is optionally substituted with one, two, or three Rc independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyloxy, heterocycloalkyloxyalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, -(alkylene)ni-S(O)n2-R50 (where nl is O or 1, n2 is 0-2, and R50 is alkyl, haloalkyl, amino, alkylamino, dialkylamino, aryl, or heteroaryl), - (alkylene)n3-NHSO2-R51 (where n3 is 0 or 1 and R51 is alkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkyl), -(alkylene)n4-NHC(O)R52 (where n4 is 0 or 1 and R52 is alkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkyl), and -(alkylene)n5-C(O)NR53R54 (where n5 is 0 or 1 and R53 is alkyl, haloalkyl, hydroxy, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl and R54 is hydrogen or alkyl) and: further wherein the aromatic or alicyclic ring, either alone or part of another group, in Rc is optionally substituted with one, two, or three Rd independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonyl, and cyano.
7. The compound of any of the Claims 1-5 wherein R12 is -NHC(O)R27 where R27 is phenyl or heteroaryl optionally substituted with one, two, or three Rc independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyloxy, heterocycloalkyloxyalkyl, heterocycloalkylalkyl, and heterocycloalkylalkyloxy and further wherein the aromatic or alicyclic ring, either alone or part of another group, in Rc is optionally substituted with one, two, or three Rd independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, carboxy, alkoxycarbonyl, aminosulfonyl, alkylsulfonyl, and cyano.
8. The compound of any of the Claims 1 -5 wherein R12 is -NHC(O)R27 wherein R27 is phenyl or heteroaryl optionally substituted with one, two, or three Rc independently selected from methyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, methylamino, dimethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl, diethylaminomethyl, diethylaminoethyl, dimethylaminoethyl, dimethylaminoethoxy, diethylaminoethoxy, hydroxy, hydroxymethyl, hydroxyethoxy, methoxy, phenyl, pyridinyloxy, tetrahydropyranyloxy, piperidinyloxy, morpholinylethoxy, piperidinylethoxy, piperazinylethoxy, pyrrolidinylethoxy, 1- methylpiperidin-4-yloxy, l-ethylpiperidin-4-yloxy, 4-methylpiperazin-l-ylethoxy, and 4-(2- hydroxyethyl)piperazin- 1 -ylethoxy .
9. The compound of any of the Claims 1-5 wherein R12 is heterocycloalkyl wherein the heterocycloalkyl is a 5 or 6 membered ring containing 3 or 4 carbon ring atoms and one or two heteroatom(s) selected from N, O, and S(O)2; where one or two carbon(s) is optionally replaced by a -C(O)- group; where the 5 or 6 membered ring is optionally fused to a phenyl or heteroaryl ring; and where the heterocycloalkyl is optionally substituted with one, two, or three Rc independently selected from alkyl, halo, haloalkyl, haloalkoxy, haloalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkoxyalkyl, methylenedioxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aryl, aralkyloxy, aryloxyalkyl, heteroaralkyloxy, heteroaryloxyalkyl, heterocycloalkyloxy, heterocycloalkyloxyalkyl, heterocycloalkyl-alkyl, and heterocycloalkylalkyloxy.
10. The compound of any of the Claims 1-9 wherein R11 is cyano.
11. The compound of any of the Claims 1-9 wherein R11 is hydroxy.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of the Claims 1-11 or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
13. 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 1-11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
14. 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 1-11 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, and a DNA methyl transferase inhibitor.
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